query
stringclasses
320 values
supports
sequencelengths
5
64
candidates
sequencelengths
2
9
answer
stringclasses
100 values
id
stringlengths
10
13
interacts_with DB04844?
[ "Agonists and antagonists for P2 receptors . Recent work has identified nucleotide agonists selective for P47900 , P41231 and Q15077 receptors and nucleotide antagonists selective for P47900 , Q9H244 and P51575 receptors . Selective non - nucleotide antagonists have been reported for P47900 , P41231 , Q15077 , Q9H244 , Q9BPV8 , P2X ( 2 / 3 )/ P56373 and Q99572 receptors . For example , the dinucleotide P01308 37217 ( Up4dC ) potently activates the P41231 receptor , and the non - nucleotide antagonist A - 317491 is selective for P2X ( 2 / 3 )/ P56373 receptors . Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems , including conformationally locked moieties , have been synthesized as ligands for P2Y receptors . The focus on conformational factors of the ribose - like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity . At P47900 , 2 , 4 , 11 receptors , there is a preference for the North conformation as indicated with ( N ) - methanocarba analogues . The P47900 antagonist MRS2500 inhibited ADP - induced human platelet aggregation with an IC50 of 0 . 95 nM . MRS2365 , an ( N ) - methanocarba analogue of 2 - MeSADP , displayed potency ( EC50 ) of 0 . 4nM at the P47900 receptor , with > 10000 - fold selectivity in comparison to Q9H244 and Q9BPV8 receptors . At Q15077 receptors there is a dramatic preference for the South conformation . Three - dimensional structures of P2Y receptors have been deduced from structure activity relationships ( SAR ) , mutagenesis and modelling studies . Detailed three - dimensional structures of P2X receptors have not yet been proposed .", "Clinical development of eniluracil : current status . ___MASK69___ is a potent inactivator of dihydropyrimidine dehydrogenase ( Q12882 ) , which is the first enzyme in the degradative pathway of systemically administered 5 - fluorouracil ( DB00544 ) . Two completely oral regimens of eniluracil plus DB00544 are being evaluated in clinical trials : ( 1 ) a chronic schedule with both agents administered P55957 in a 10 : 1 ratio for 28 days of a 5 - week course , and ( 2 ) a 5 - day schedule of eniluracil once daily on days 1 through 7 and DB00544 once daily on days 2 through 6 . The clinical development of eniluracil is being pursued in several tumor types , including colorectal cancer , breast cancer , and pancreatic cancer . Response rates achieved in a phase II study of the chronic schedule of oral eniluracil / DB00544 in patients with colorectal cancer compare favorably with those obtained in trials of intravenous DB00544 and leucovorin , while results from other trials are awaited . Safety analysis for the 28 - day schedule has revealed a low incidence of severe toxicities , particularly as compared with standard DB00544 regimens .", "Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . DB04844 almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .", "P09429 is involved in autophagy inhibition caused by P37840 / α - synuclein overexpression : a process modulated by the natural autophagy inducer corynoxine B . P37840 / α - synuclein and its rare mutations are considered as the culprit proteins in Parkinson disease ( PD ) . Wild - type ( WT ) P37840 has been shown to impair macroautophagy in mammalian cells and in transgenic mice . In this study , we monitored the dynamic changes in autophagy process and confirmed that overexpression of both WT and P37840 ( A53T ) inhibits autophagy in PC12 cells in a time - dependent manner . Furthermore , we showed that P37840 binds to both cytosolic and nuclear high mobility group box 1 ( P09429 ) , impairs the cytosolic translocation of P09429 , blocks P09429 - Q14457 binding , and strengthens Q14457 - P10415 binding . Deregulation of these molecular events by P37840 overexpression leads to autophagy inhibition . Overexpression of Q14457 restores autophagy and promotes the clearance of P37840 . siRNA knockdown of Hmgb1 inhibits basal autophagy and abolishes the inhibitory effect of P37840 on autophagy while overexpression of P09429 restores autophagy . Corynoxine B , a natural autophagy inducer , restores the deficient cytosolic translocation of P09429 and autophagy in cells overexpressing P37840 , which may be attributed to its ability to block P37840 - P09429 interaction . Based on these findings , we propose that P37840 - induced impairment of autophagy occurs , in part , through P09429 , which may provide a potential therapeutic target for PD .", "P41134 enhances docetaxel cytotoxicity in prostate cancer cells through inhibition of P38936 . To identify potential mechanisms underlying prostate cancer chemotherapy response and resistance , we compared the gene expression profiles in high - risk human prostate cancer specimens before and after neoadjuvant chemotherapy and radical prostatectomy . Among the molecular signatures associated with chemotherapy , transcripts encoding inhibitor of DNA binding 1 ( P41134 ) were significantly upregulated . The patient biochemical relapse status was monitored in a long - term follow - up . Patients with P41134 upregulation were found to be associated with longer relapse - free survival than patients without P41134 increase . This in vivo clinical association was mechanistically investigated . The chemotherapy - induced P41134 upregulation was recapitulated in the prostate cancer cell line LNCaP . ___MASK41___ dose - dependently induced P41134 transcription , which was mediated by P41134 promoter E - box chromatin modification and c - Myc binding . Stable P41134 overexpression in LNCaP increased cell proliferation , promoted G ( 1 ) cell cycle progression , and enhanced docetaxel - induced cytotoxicity . These changes were accompanied by a decrease in cellular mitochondria content , an increase in P10415 phosphorylation at serine 70 , caspase - 3 activation , and poly ( ADP - ribose ) polymerase cleavage . In contrast , P41134 siRNA in the LNCaP and C42B cell lines reduced cell proliferation and decreased docetaxel - induced cytotoxicity by inhibiting cell death . P41134 - mediated chemosensitivity enhancement was in part due to P41134 suppression of P38936 . Overexpression of P38936 in LNCaP - P41134 - overexpressing cells restored the P38936 level and reversed P41134 - enhanced chemosensitivity . These molecular data provide a mechanistic rationale for the observed in vivo clinical association between P41134 upregulation and relapse - free survival . Taken together , it shows that P41134 expression has a novel therapeutic role in prostate cancer chemotherapy and prognosis .", "Current treatment strategies for non - alcoholic fatty liver disease ( NAFLD ) . Nonalcoholic fatty liver disease ( NAFLD ) is recognized as the most common cause of chronic liver disease worldwide . NAFLD is a clinicopathologic syndrome ranging from simple steatosis , which is relatively benign , to the more severe form known as nonalcoholic steatohepatitis ( NASH ) , which may progress to cirrhosis , liver failure , and hepatocellular carcinoma . NAFLD is associated with significant liver related morbidity and mortality , and its underlying pathophysiology is thought to result from a multiple hit process . The initial insult is the accumulation of hepatic fat secondary to insulin resistance . In the setting of hepatic steatosis , the second hit can be caused by reactive oxygen species , inflammatory cytokines , and adipokines . Several therapeutic modalities that target these mechanisms are under investigation , but no proven treatment has yet emerged . P01308 sensitizers such as thiazolidinediones and metformin show promise , and several studies have explored the role of lipid lowering agents , antioxidants , and cytoprotective agents . Novel agents such as anti - obesity drugs , selective cannabinoid - 1 receptor blockers , and dual Q07869 alpha and gamma agonists are also under investigation . Unfortunately , data on the long - term safety and efficacy of these agents and their impact on liver related histologic outcomes are currently lacking . NAFLD treatment currently focuses on reducing metabolic risk factors , with the mainstay of therapy focusing on life - style modifications such as gradual weight loss through diet and regular exercise .", "Tobacco as biofactory for biologically active hPL production : a human hormone with potential applications in type - 1 diabetes . Human placental lactogen ( hPL ) is a peptidic hormone that belongs to the short list of growth factors that could treat type - 1 diabetes through pancreatic islet transplantation . Placental lactogen has the capacity to improve islet survival and function before or after transplantation . In this study , transgenic tobacco plants were used as a novel expression system for the production of recombinant hPL protein ( rhPL ) . The expression vector pNEKhPL2 containing hPL cDNA was introduced into tobacco plants ; the transcriptional activity was confirmed by real - time PCR , and the rhPL levels reached 1 % of the total soluble protein ( P07996 ) content in plants cultivated in the greenhouse . In vitro bioassays using the rat insulinoma ( P01308 - 1 ) cell line showed that recombinant protein was able to induce cell proliferation and activate the O60674 / P35610 - 5 signal transduction pathway , demonstrating that plant cells can produce the biologically active hPL protein . To further characterize the plant expression system for hPL production , we analyzed the stability of the protein during the life cycle of tobacco plants as well as the transmission of the transgenic trait to the progeny . The recombinant protein was stably accumulated in young leaves , reaching the maximum level in the first month ( 6 . 51 μg / g of fresh weight ) , but showing a decreasing trend of 26 % from the initial sampling time until the end of plant ' s life cycle . The progeny of the selected pNEKhPL2 plant showed in vitro expression levels of up to 1 . 1 % of P07996 . Our results therefore indicate that transgenic plants are a suitable expression system for hPL production .", "DB00575 prevents insulin resistance and hypertension in obese dogs . The role that the central sympathetic nervous system plays in the development of obesity hypertension and insulin was evaluated by feeding dogs a high fat diet with or without clonidine treatment . Thirteen adult mongrel dogs were chronically instrumented and randomly assigned to receive either a high fat diet and no clonidine ( n = 6 ) or a high fat diet plus clonidine ( n = 7 ) , 0 . 3 mg P55957 . Blood pressure , heart rate , plasma insulin , and electrolytes were measured daily . P01308 resistance was assessed with a multiple - dose euglycemic clamp ( 1 , 2 , and 30 mU . kg - 1 . min - 1 ) before and after 1 , 3 , and 6 weeks of the high fat diet . DB00575 prevented the hypertension , tachycardia , and insulin resistance associated with feeding dogs the high fat diet but did not affect weight gain . The present study suggests that the central sympathetic nervous system plays a critical role in the development of both insulin resistance and hypertension associated with feeding dogs a high fat diet .", "P37840 A30P point - mutation generates age - dependent nigrostriatal deficiency in mice . Lewy bodies are mainly composed of alpha - synuclein ( P37840 ) and specific mutations in P37840 gene are related to familial forms of Parkinson ' s disease ( PD ) . The purpose of our study was to generate a mouse line with A30P knock - in point mutation in P37840 gene and to test if a single point - mutation is able to turn otherwise normal P37840 into a toxic form . The behavioral profile of P37840 A30P mice was followed for 16 months . Generally , these mice are healthy and viable without any obvious abnormalities . Starting from the age of 13 months mice developed a significant deficit in motor performance tests related to nigrostriatal function ( ink - test and beam walk ) . In other tests ( motility boxes , rotarod ) mice continuously performed normally . Moreover , P37840 A30P mice expressed the altered sensitivity to Q05940 inhibitor reserpine , possibly reflecting a functional deficiency of dopamine . Indeed , mice at 15 months of age had significantly reduced levels of dopamine and its major metabolite DOPAC in the striatum , and reduced levels of dopamine in the mesolimbic system . The present study confirms that P37840 plays an important role in the development of PD and an insertion of a single point mutation is sufficient to generate age - related decline in specific motor performance . The generated mouse line has a potential to become a model for PD with comparable time course and phenotype .", "P43220 antagonist exendin -( 9 - 39 ) elevates fasting blood glucose levels in congenital hyperinsulinism owing to inactivating mutations in the DB00171 - sensitive K + channel . Infants with congenital hyperinsulinism owing to inactivating mutations in the K ( DB00171 ) channel ( K ( DB00171 ) HI ) who are unresponsive to medical therapy will require pancreatectomy to control the hypoglycemia . In preclinical studies , we showed that the P43220 antagonist exendin -( 9 - 39 ) suppresses insulin secretion and corrects fasting hypoglycemia in Q09428 - 1 (-/-) mice . The aim of this study was to examine the effects of exendin -( 9 - 39 ) on fasting blood glucose in subjects with K ( DB00171 ) HI . This was a randomized , open - label , two - period crossover pilot clinical study . Nine subjects with K ( DB00171 ) HI received either exendin -( 9 - 39 ) or vehicle on two different days . The primary outcome was blood glucose ; secondary outcomes were insulin , glucagon , and P0C6A0 . In all subjects , mean nadir blood glucose and glucose area under the curve were significantly increased by exendin -( 9 - 39 ) . P01308 - to - glucose ratios were significantly lower during exendin -( 9 - 39 ) infusion compared with vehicle . Fasting glucagon and intact P0C6A0 were not affected by treatment . In addition , exendin -( 9 - 39 ) significantly inhibited amino acid - stimulated insulin secretion in pancreatic islets isolated from neonates with K ( DB00171 ) HI . Our findings have two important implications : 1 ) P0C6A0 and its receptor play a role in the regulation of fasting glycemia in K ( DB00171 ) HI ; and 2 ) the P43220 may be a therapeutic target for the treatment of children with K ( DB00171 ) HI .", "The anti - androgen drug dutasteride renders triple negative breast cancer cells more sensitive to chemotherapy via inhibition of HIF - 1α -/ P15692 - signaling . BACKGROUND : Triple negative breast cancer ( TNBC ) is characterized by lack of expression of both estrogen and progesterone receptor as well as lack of amplification of P04626 . Patients with TNBC carry an unfavorable prognosis compared to other breast cancer subtypes given that endocrine or P04626 targeted therapies are not effective , rendering chemotherapy the sole effective treatment option to date . Therefore , there is a high demand for additional novel treatment options . FINDINGS : We previously published a list of genes showing both higher gene expression rates in TNBC and , in addition , are known to encode targets of non - oncologic drugs . P18405 , which encodes the type - 1 isoform of the steroid - 5alpha - reductase , which is involved in androgen metabolism , was found to be one of these genes . ___MASK14___ is a dual blocker of both the type - 1 and type - 2 isoform of P18405 and is indicated in the treatment of benign prostate hyperplasia . Treatment of TNBC cell lines with dutasteride was associated with a dose - dependent decrease in cell viability , altered protein expression of P15692 and HIF - 1α and increased chemosensitivity . CONCLUSION : Our results demonstrate that the P18405 - corresponding anti - androgenic drug dutasteride might act as a combinatorial therapeutic option besides standard chemotherapy in highly aggressive TNBC .", "Comparative actions of insulin sensitizers on ion channels in vascular smooth muscle . Thiazolidinedione and isoxazolidinedione insulin sensitizers activate peroxisome proliferator - activated receptor gamma ( Q07869 gamma ) . Some thiazolidinediones modify ion channels in smooth muscles ; however , the mechanism by which their actions occur has not been clarified . We , thus , examined the effects of three thiazolidinediones ( troglitazone , pioglitazone , and rosiglitazone ) and isoxazolidinedione ( ___MASK25___ ) , as well as an intrinsic ligand for Q07869 gamma , 15 - deoxy - Delta ( 12 , 14 ) prostaglandin J ( 2 ) ( prostaglandin J ( 2 ) ) , on voltage - operated Ca ( 2 +) currents ( I ( Ca ) ) , voltage - dependent K (+) currents ( I ( Kv ) ) , and Ca ( 2 +)- activated K (+) currents ( I ( Kca ) ) , to clarify whether a thiazolidinedione structure or Q07869 gamma activation is related to their actions on ion channels . The whole - cell patch clamp method was used to record currents in smooth muscle cells from guinea - pig mesenteric arteries . Thiazolidinediones inhibited I ( Ca ) in a dose - dependent manner ( troglitazone > pioglitazone = rosiglitazone ) . DB00197 ( > or = 1 microM ) and rosiglitazone ( 100 microM ) , but not pioglitazone , inhibited I ( Kv ) . Rosiglitazone ( > or = 10 microM ) enhanced , troglitazone ( > or = 1 microM ) inhibited , and pioglitazone did not affect I ( Kca ) . A high concentration of ___MASK25___ ( 100 microM ) inhibited I ( Ca ) , I ( Kv ) , and I ( Kca ) to a similar extent . Prostaglandin J ( 2 ) enhanced I ( Kca ) , but affected neither I ( Ca ) nor I ( Kv ) . In summary , the three thiazolidinediones and isoxazolidinedione act differently on Ca ( 2 +) and K (+) channels in vascular smooth muscle . The action of thiazolidinediones on I ( Ca ) could be attributed to specific regions of the molecules and not to activation of Q07869 gamma . Involvement of Q07869 gamma activation in the stimulation of I ( Kca ) is possible but should be tested further .", "New perspectives of vesicular monoamine transporter 2 chemical characteristics in mammals and its constant expression in type 1 diabetes rat models . Vesicular monoamine transporter 2 ( Q05940 ) has been exploited as a biomarker of β - cell mass in human islets . However , a current report suggested no immunoreactivity of Q05940 in the β cells of rat islets . To investigate the cellular localization of Q05940 in islets further , the pancreatic tissues from monkeys and humans were compared with those of rats and mice . The study was performed using among - species comparisons and a type 1 diabetes model ( T1DM ) for rats by Western blotting , double - label immunofluorescence , and confocal laser scanning microscopy . We found that Q05940 - immunoreactivity ( IR ) was distributed peripherally in the islets of rodents , but was widely scattered throughout the islets of primates . Consistent with rodent islets , Q05940 - IR did not exist in insulin ( P01308 ) - IR cells but was abundantly present in glucagon ( GLU ) - IR and pancreatic polypeptide ( PP ) - IR cells in monkey and human islets . Q05940 - IR had no colocalization with P01308 - IR in any part of the rat pancreas ( head , body , and tail ) . P01308 - IR cells were reduced dramatically in T1DM rat islets , but no significant alteration in the proportion of Q05940 - IR cells and GLU - IR cells was observed . Furthermore , a strong colocalization of Q05940 - IR with GLU - IR was distributed in the peripheral regions of diabetic islets . For the first time , the current study demonstrates the presence of Q05940 in α cells and PP cells but not in β cells in the islets of monkeys and humans . This study provides convinced morphologic evidence that Q05940 is not present in β cells . There needs to be studies for new markers for β cell mass .", "Identification of the amino acid sequence motif of alpha - synuclein responsible for macrophage activation . P37840 ( Syn ) is implicated in the pathogenesis of PD and related neurodegenerative disorders . Recent studies have also shown that alpha - synuclein can activate microglia and enhance dopaminergic neurodegeneration . The mechanisms of microglia activation by alpha - synuclein , however , are not well understood . In this study , we found that not only alpha - synuclein but also beta - and gamma - synucleins activated macrophages ( RAW 264 . 7 ) in vitro . Macrophages treated with synuclein proteins secreted P01375 in a dose - dependent manner . Synuclein family proteins also increased mRNA transcription of P35354 and P35228 . Two alpha - synuclein deletion mutants , SynDeltaNAC and Syn61 - 140 , activated macrophages , while deletion mutants Syn1 - 60 and Syn96 - 140 did not significantly activate them . Finally , we demonstrated that macrophage activation by alpha - synuclein was accompanied by phosphorylation of P29323 . These results suggest that synuclein family proteins can activate macrophages , and that macrophage activation needs both the N - terminal and C - terminal domains of alpha - synuclein , but not the central Q9C000 region .", "[ HIV - 1 neuropathogenesis : therapeutic strategies against neuronal loss induced by gp120 / Tat glycoprotein in the central nervous system ] . Neuroinflammation is a key process in the neuropathogenesis of AIDS virus since as a result of the aberrant activation of the chemokine receptors ( P61073 , P49238 and CR5 ) produces proinflammatory cytokine release by infected cells , increases microglial neurotoxicity and generates lipoperoxides and reactive oxygen species ( ROS ) that eventually damage the neuron . Moreover , the neurotoxin Tat produces dendritic loss by interacting with the low - density lipoprotein receptor ( Q14764 ) and also overstimulates N - methyl D - aspartate receptors ( DB01221 ) . Furthermore , the aberrant interaction of glycoprotein gp120 with the P61073 chemokine receptor causes caspase - 3 - dependent apoptosis ( ceramide is also released ) activating apoptotic proteins ( p53 and retinoblastoma ) , which are part of the neurotoxic mechanisms associated to neuronal dysfunction in neuroAIDS . Similarly , gliosis / microglial activation and the release of neurotoxic factors by infected monocytes with elevated amounts of certain chemokines in the cerebrospinal fluid ( P13500 and fractalkine , among others ) contribute to the neuropathogenesis of HIV - 1 . P37840 and beta amyloid deposits have also been detected in post mortem brains of seropositives patients . In addition , there are studies have detected several systemic markers related with the degenerative effects of the virus and its neurotoxins on the central nervous system ; such as osteopontin , Q86VB7 and fractalkine , among others . Lastly , clinical trials have been conducted using protective strategies related that attempt to inhibit apoptotic proteins ( P49841 ) , microglial activation inhibitors ( minocycline ) , antioxidants ( selegiline ) or trophic factors ( DB01277 , growth hormone or erythropoietin ) . These trials have shown that their treatments are beneficial and complementary to treat complications of HIV / AIDS .", "Gastroduodenal tolerability of lumiracoxib vs placebo and naproxen : a pilot endoscopic study in healthy male subjects . BACKGROUND : ___MASK50___ ( ___MASK50___ ) is a cyclooxygenase - 2 ( P35354 ) selective inhibitor . AIM : To compare the gastroduodenal tolerability of lumiracoxib with placebo and naproxen in a randomized , parallel - group , double - blind study . METHODS : : Sixty - five healthy male subjects were randomized to receive 8 days ' dosing with lumiracoxib 200 mg twice daily ( b . d . ) ( n = 21 ) , placebo ( n = 22 ) or naproxen 500 mg b . d . ( n = 22 ) . Endoscopic evaluations of gastric and duodenal mucosae were conducted at baseline and after 8 days ' dosing . Serum was assayed for ex - vivo concentrations of thromboxane B2 ( TxB2 ) to determine cyclooxygenase - 1 ( P23219 ) inhibitory activity . RESULTS : Sixty subjects ( 20 per group ) completed the study . No gastroduodenal erosions were observed in subjects receiving lumiracoxib . Thirteen subjects receiving naproxen developed duodenal erosions . At the gastric site , one subject in each of the naproxen and placebo groups had erosions ; one subject receiving naproxen also developed a small asymptomatic gastric ulcer . Gastrointestinal adverse events accounted for 42 . 3 % of all adverse events , occurring in 3 / 21 , 4 / 22 and 6 / 22 of the lumiracoxib , placebo and naproxen groups , respectively . TxB2 levels were similar for patients receiving placebo or lumiracoxib , but were reduced by > 95 % in patients receiving naproxen , compared with placebo . CONCLUSIONS : Multiple doses of lumiracoxib resulted in gastroduodenal tolerability similar to placebo and superior to naproxen .", "Improvement of psoriasis during exenatide treatment in a patient with diabetes . CONTEXT AND AIM : Psoriasis is an immune - mediated skin disorder frequently associated with obesity and type 2 diabetes ( T2D ) . This report is of a clinically significant improvement in psoriasis lesions in a patient with T2D during treatment with a P43220 agonist ( exenatide ) . OBSERVATION : A 61 - year - old male patient ( BMI : 25 . 5 kg / m ( 2 ) ) with T2D treated with metformin and sulphonylureas had also complained , since 1980 , of extensive psoriasis that required multiple steroid - based treatments [ Psoriasis Area and Sensitivity Index ( PASI ) score : 11 ] . In September 2008 , his diabetes treatment was intensified with exenatide ( ___MASK82___ (®) ) to improve poor glycaemic control . The patient , as expected , lost weight and reduced HbA ( 1c ) levels from 65 mmol / mol to 56 mmol / mol . However , after just 1 month of treatment with exenatide , the patient also reported a dramatic improvement in psoriatic plaques that was confirmed at the 1 - year follow - up ( PASI : estimated at 3 - 4 ) . Withdrawal of exenatide was associated with weight gain , deterioration of glycaemic control and deterioration of psoriasis ( PASI : > 10 ) . After reinstating exenatide treatment , the patient again reported a prompt improvement in psoriasis ( PASI : 3 . 1 ) . CONCLUSION : There was a major and rapid improvement in psoriasis in our patient with T2D following treatment with exenatide . A possible mechanism might be through direct modulation of the immune system by P43220 agonists .", "DB08816 as an alternative in clopidogrel - associated neutropenia . DB00945 in combination with platelet Q9H244 receptor blocker has become the mainstay antiplatelet treatment strategy for the prevention of stent thrombosis . ___MASK100___ was the first widely used Q9H244 receptor blockers , but clopidogrel has mostly replaced the use of ticlopidine due to its more favorable adverse event profile on bone marrow . However , when clopidogrel induced bone marrow toxicity occurs , little is known about the efficacy and safety of alternative treatments , and thus , in these cases , medical decisions may be very difficult . We report a case of clopidogrel - induced severe neutropenia in a patient treated with coronary stent and safety of alternative treatment with ticagrelor .", "Recombinant P17936 inhibits allergic lung inflammation , P15692 production , and vascular leak in a mouse model of asthma . BACKGROUND : Vascular endothelial growth factor ( P15692 ) plays a pro - inflammatory mediator as well as a vascular permeability factor in bronchial asthma . P01308 - like growth factor ( IGF ) - I is also involved in the inflammatory process associated with bronchial asthma and stimulates P15692 expression . The IGF - binding proteins ( IGFBPs ) , especially P17936 , display distinctive properties and can interfere with various biological processes . METHODS : In this study , an ovalbumin ( OVA ) - induced murine model of allergic airway disease was used to investigate which mechanism is implicated in the preventive and therapeutic actions of P17936 administered exogenously on allergen - induced bronchial inflammation and airway hyper - responsiveness , in particular focusing on the regulation of P15692 expression . RESULTS : Administration of recombinant human P17936 to OVA - inhaled mice substantially attenuated the increases in hypoxia - inducible factor ( HIF ) - α activity , P05019 production , and P15692 protein levels in the lung . In addition , the blockade of P05019 action decreased the OVA - induced P15692 expression , airway inflammation , and bronchial hyper - responsiveness . The administration of recombinant human P17936 or CBO - P11 also reduced significantly increases in inflammatory cells , airway hyper - responsiveness , levels of P05112 , P05113 , P35225 , and vascular permeability in the lung of OVA - inhaled mice . Moreover , when recombinant human P17936 was administered after the completion of OVA inhalation , these therapeutic effects of P17936 were also observed . CONCLUSIONS : These results indicate that P17936 administered exogenously may attenuate antigen - induced airway inflammation and hyper - responsiveness through the modulation of vascular leakage and P15692 expression mediated by HIF - 1α / HIF - 2α signaling as well as P05019 action in allergic airway disease of mice .", "P03372 1 ( P03372 ; ERα ) , not Q92731 ( ERβ ) , modulates estrogen - induced sex reversal in the American alligator , a species with temperature - dependent sex determination . All crocodilians and many turtles exhibit temperature - dependent sex determination where the temperature of the incubated egg , during a thermo - sensitive period ( P07996 ) , determines the sex of the offspring . ___MASK60___ play a critical role in sex determination in crocodilians and turtles , as it likely does in most nonmammalian vertebrates . Indeed , administration of estrogens during the P07996 induces male to female sex reversal at a male - producing temperature ( MPT ) . However , it is not clear how estrogens override the influence of temperature during sex determination in these species . Most vertebrates have 2 forms of nuclear estrogen receptor ( P03372 ) : P03372 ( ERα ) and Q92731 ( ERβ ) . However , there is no direct evidence concerning which P03372 is involved in sex determination , because a specific agonist or antagonist for each P03372 has not been tested in nonmammalian species . We identified specific pharmaceutical agonists for each P03372 using an in vitro transactivation assay employing American alligator P03372 and Q92731 ; these were 4 , 4 ', 4 ''-( 4 - propyl -[ 1H ]- pyrazole - 1 , 3 , 5 - triyl ) trisphenol ( PPT ) and 7 - bromo - 2 -( 4 - hydroxyphenyl )- 1 , 3 - benzoxazol - 5 - ol ( WAY 200070 ) , respectively . Alligator eggs were exposed to PPT or WAY 200070 at a MPT just before the P07996 , and their sex was examined at the last stage of embryonic development . Estradiol - 17β and PPT , but not WAY 200070 , induced sex reversal at a MPT . PPT - exposed embryos exposed to the highest dose ( 5 . 0 μg / g egg weight ) exhibited enlargement and advanced differentiation of the Müllerian duct . These results indicate that P03372 is likely the principal P03372 involved in sex reversal as well as embryonic Müllerian duct survival and growth in American alligators .", "The use of growth factors in hematopoietic stem cell transplantation . Mobilized , peripheral blood stem cells ( PBSC ) are increasingly used for both autologous and allogeneic transplants . Granulocyte - colony - stimulating factor is the most widely used cytokine for mobilization . Several different mechanisms of stem cell mobilization have been proposed including protease - dependent and non - protease - dependent mechanisms . In autologous transplants , the addition of chemotherapy to mobilization can enhance the yield of PBSC collected but with substantial adverse effects , and not necessarily faster engraftment . In allogeneic transplants , the use of mobilized PBSC is associated with faster engraftment and donor chimerism compared to bone marrow . In the majority of studies , the rate of acute graft - versus - host disease ( GVHD ) has not been shown to be significantly higher with PBSC , but the rate of chronic GVHD appears to be increased . Several different strategies have been proposed for patients and donors who fail initial mobilization , including the use of novel agents . ___MASK63___ ( ___MASK63___ ) works by directly inhibiting the interaction between stromal cell - derived factor - 1 and its receptor P61073 , and mobilizes hematopoietic stem cells within hours . It is being studied alone or in conjunction with growth factors for PBSC mobilization in both autologous and allogeneic settings . Although the use of growth factors after PBSC transplantation results in faster neutrophil engraftment its impact on treatment - related mortality and survival does not appear significant . Here , we review the biology and methods of PBSC mobilization , the effect of growth factors on normal donors and the controversies of growth factor use in the post - transplant setting . We also review the data on novel agents for mobilization of stem cells ." ]
[ "___MASK100___", "___MASK14___", "___MASK25___", "___MASK41___", "___MASK50___", "___MASK60___", "___MASK63___", "___MASK69___", "___MASK82___" ]
___MASK100___
MH_train_1600
interacts_with DB00834?
[ "A new clinical evidence - based gene - environment interaction model of depression . In our current understanding of mood disorders , the role of genes is diverse including the mediation of the effects of provoking and protective factors . Different or partially overlapping gene sets play a major role in the development of personality traits including also affective temperaments , in the mediation of the effects of environmental factors , and in the interaction of these elements in the development of depression . Certain genes are associated with personality traits and temperaments including e . g . , neuroticism , impulsivity , openness , rumination and extroversion . Environmental factors consist of external ( early and provoking life events , seasonal changes , social support etc . ) and internal factors ( hormones , biological rhythm generators , comorbid disorders etc ) . Some of these environmental factors , such as early life events and some prenatal events directly influence the development of personality traits and temperaments . In the NEWMOOD cohort polymorphisms of the genes of the serotonin transporter , P08908 , P28222 and 5 - Q13049 and endocannabinoid P21554 receptors , tryptophan hydroxylase , P16220 , P23560 and GIRK provide evidence for the involvement of these genes in the development of depression . Based on their role in this process they could be assigned to different gene sets . The role of certain genes , such as promoter polymorphisms of the serotonin transporter ( 5 - HTTLPR ) and P21554 receptor has been shown in more than one of the above factors . Furthermore , gene - gene interactions of these promoters associated with anxiety suggest the application of these polymorphisms in personalized medicine . In this review we introduce a new model including environmental factors , genes , trait and temperament markers based on human genetic studies .", "The endocannabinoid 2 - AG protects the blood - brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines . Endocannabinoids are involved in neuroprotection through numerous biochemical pathways . We have shown that the endocannabinoid 2 - arachidonoyl glycerol ( 2 - AG ) is released in mouse brain after closed head injury ( CHI ) , and treatment with exogenous 2 - AG exerts neuroprotection via the central cannabinoid receptor P21554 . This process involves inhibition of inflammatory signals that are mediated by activation of the transcription factor NF - kB . The present study was designed to examine the effect of 2 - AG on the blood - brain barrier ( BBB ) and the possible inhibition of the early expression of proinflammatory cytokines , which are implicated in BBB disruption . We found that 2 - AG decreased BBB permeability and inhibited the acute expression of the main proinflammatory cytokines : P01375 , IL - 1beta and P05231 . It also augmented the levels of endogenous antioxidants . We suggest that 2 - AG exerts neuroprotection in part by inhibition of the early ( 1 - 4 h ) inflammatory response and augmentation of the brain reducing power .", "Antiinflammatory steroid action in human ovarian surface epithelial cells . The human ovarian surface epithelium ( OSE ) is subject to serial injury and repair during ovulation , which is a natural inflammatory event . We asked whether there is a compensatory antiinflammatory component to this process , involving steroid hormones produced locally at the time of ovulation . Quantitative RT - PCR analysis of total RNA from cultured human OSE cell monolayers showed that exposure to proinflammatory IL1alpha ( 500 pg / ml ) increased mRNA levels of cyclooxygenase - 2 ( P35354 ) ( P < 0 . 01 ) at 48 h . The P35354 mRNA response to IL1alpha was associated with an approximate 18 - fold ( P < 0 . 01 ) increase in mRNA levels of 11beta - hydroxysteroid dehydrogenase type 1 ( 11betaHSD1 ) , encoding the steroid dehydrogenase that reversibly reduces cortisone to antiinflammatory cortisol . Addition of cortisol to OSE cell culture medium dose - dependently suppressed the P35354 mRNA response to IL1alpha ( P < 0 . 01 ) but reciprocally enhanced the 11betaHSD1 mRNA response ( P < 0 . 05 ) , with both effects strongest at 1 microm cortisol . Presence of glucocorticoid receptor - alpha mRNA and protein was established in OSE cell monolayers and treatment with IL1alpha shown to significantly up - regulate the glucocorticoid receptor - alpha mRNA level ( P < 0 . 05 ) . P04150 antagonist ( DB00834 , 10 microm ) fully reversed the inhibitory effect of 1 microm cortisol on IL1alpha - stimulated P35354 mRNA expression . Progesterone also suppressed IL1alpha - induced P35354 mRNA expression but had no significant effect on IL1alpha - stimulated 11betaHSD1 expression . These data provide direct evidence for antiinflammatory actions of cortisol and progesterone in human OSE cells .", "DB00197 inhibits histone deacetylase activity in breast cancer cells . We previously demonstrated that the PPARgamma agonist DB00197 ( TRG ) , a potent antiproliferative agent , in combination with the anthracycline antibiotic Doxorubicin ( DOX ) , is an effective killer of multiple drug resistant ( MDR ) human cancer cells . Cell killing was accompanied by increased global histone H3 acetylation . Presently , we investigated the epigenetic and cell killing effects of TRG in estrogen receptor ( ER ) positive MCF7 breast cancer cells . MCF7 cells were treated with the Thiazolidinediones ( TZDs ) TRG and DB09201 ( P02751 ) , the non - TZD PPARgamma agonist 15PGJ2 , and the histone deacetylase inhibitors ( HDACi ' s ) Trichostatin A ( P32119 ) , sodium butyrate and PXD101 . Using MTT cell viability assays , Western analyzes and mass spectrometry , we showed a dose - dependent increase in cell killing in TRG and HDACi treated cells , that was associated with increased H3 lysine 9 ( H3K9 ) and H3K23 acetylation , P16104 and H3S10 phosphorylation , and H3K79 mono - and di - methylation . These effects were mediated through an ER independent pathway . Using HDAC activity assays , TRG inhibited HDAC activity in cells and in cell lysates , similar to that observed with P32119 . Furthermore , TRG and P32119 induced a slower migrating Q13547 species that was refractory to Q92769 associations . Lastly , TRG and the HDACi ' s decreased total and phosphorylated AKT levels . These findings suggest that TRG ' s mode of killing may involve downregulation of PI3K signaling through HDAC inhibition , leading to increased global histone post - translational modifications .", "Acid - sensing ion channels promote the inflammation and migration of cultured rat microglia . Microglia , the major immune cells in central nervous system , act as the surveillance and scavenger of immune defense and inflammatory response . Previous studies suggest that there might be close relationship between acid - sensing ion channels ( ASICs ) and inflammation , however , the exact role of ASICs in microglia during inflammation remains elusive . In the present study , we identified the existence of ASICs in the primary cultured rat microglia and explored their functions . By using reverse transcriptase polymerase chain reaction ( RT - PCR ) , quantitative real - time PCR ( qPCR ) , western blotting , and immunofluorescence experiments , we demonstrated that P78348 , ASIC2a , and Q9UHC3 were existed in cultured and in situ rat microglia . After lipopolysaccharide ( LPS ) stimulation , the expressions of microglial P78348 and ASIC2a were upregulated . Meanwhile , ASIC - like currents and acid - induced elevation of intracellular calcium were increased , which could be inhibited by the nonspecific ASICs antagonist amiloride and specific homomeric ASIC1a blocker PcTx1 . In addition , both inhibitors reduced the expression of inflammatory cytokines , including inducible nitric oxide synthase and cyclooxygenase 2 stimulated by LPS . Furthermore , we also observed significant increase in the expression of P78348 and ASIC2a in scrape - stimulated microglial migration . ___MASK67___ and PcTx1 prevented the migration by inhibiting P29323 phosphorylation . Taken together , these results suggest that ASICs participate in neuroinflammatory response , which will provide a novel therapeutic strategy for controlling the inflammation - relevant neuronal diseases .", "Purification and characterization of a high molecular weight histone deacetylase complex ( Q92769 ) of maize embryos . The dynamic state of core histone acetylation is maintained by histone acetyltransferases and deacetylases . In germinating maize embryos , four nuclear histone deacetylases can be distinguished . From a chromatin fraction prepared at 72 h after start of embryo germination , we have purified the nuclear histone deacetylase Q92769 to homogeneity . Using a sequence of chromatographic steps , we achieved the purification of an enzymatically active high molecular weight protein complex with an apparent molecular mass of 400 kDa , as determined by gel filtration chromatography . The purified enzyme was characterized in terms of enzymatic and kinetic properties , and sensitivity to several histone deacetylase inhibitors . In SDS - polyacrylamide gels , Q92769 split into three polypeptides of 45 , 42 , and 39 kDa , suggesting that the native enzyme is a multimer - protein complex . Electrophoresis under nondenaturing conditions in combination with second dimension SDS - gel electrophoresis indicated that all three protein components of the Q92769 complex were enzymatically active . Polyclonal antibodies against each of the three polypeptides were raised in rabbits . Each antiserum reacted with all three polypeptides on Western blots , suggesting that P29466 , Q8NFH3 , and p39 are highly homologous . This homology was confirmed by amino acid sequencing of peptides generated from each of the three Q92769 components .", "___MASK93___ - induced life - threatening hyperkalemia and acute kidney dysfunction against the background of telmisartan and a low sodium diet . Drug - induced hyperkalemia is not uncommon and may be life - threatening when presenting acutely in the emergency department . We present a case of severe hyperkalemia precipitated acutely by etoricoxib in a patient who was on telmisartan and a low sodium ( potassium chloride - rich ) diet . A 75 - year - old male with a past medical history of well - controlled diabetes and hypertension was prescribed etoricoxib ( 90 mg daily ) for 3 days for musculoskeletal backache . He had been taking his routine medications including telmisartan and a potassium - rich salt substitute for many years , without any recent change in dosage or quantity . There was evidence of microalbuminurea ; however , the renal functions and electrolytes prior to starting etoricoxib were normal . He presented to the emergency department with signs and symptoms of life - threatening hyperkalemia ( serum potassium 7 . 7 mEq / dl ) , accelerated hypertension , congestive heart failure , pulmonary edema and acute renal failure . Acute medical management and withholding all drugs that could cause hyperkalemia improved his serum potassium levels over 24 h and renal parameters within 5 days . All the other drugs except etoricoxib were restarted under observation over 8 weeks with no recurrence of the acute episode . Non - steroidal analgesics and other P35354 inhibitors ( rofecoxib and celecoxib ) have been known to precipitate renal failure and hyperkalemia specially in patients at risk for the same ; although not unexpected , this may be the first reported case of life - threatening hyperkalemia precipitated by etoricoxib in a previously stable patient having increased risk of renal failure and hyperkalemia .", "___MASK24___ for vitreoretinal diseases . P02751 and laminin are clinically relevant plasmin receptors in the eye . Located at the vitreoretinal interface , they are cleaved by ocriplasmin ( DB05028 , ThromboGenics , Iselin , NJ ) , a novel ophthalmic medication . A series of clinical trials to study ocriplasmin for the treatment of vitreoretinal diseases such as vitreomacular traction , macular hole , and exudative age - related macular degeneration are underway . The results are promising and may impact patient care .", "P25021 mediated relaxation of buffalo ( Bubalus bubalus ) ureter . On the buffalo ureter , histamine did not elicit any direct effect . However , it caused concentration - dependent relaxation of the tissues precontracted by carbachol , phenylephrine , norepinephrine , KCI or BaCl2 and also inhibited the contractile effect of carbachol . ___MASK70___ selectively antagonised the relaxation and inhibition of contractile response but mepyramine did not show this effect . Isoprenaline , dobutamine , salbutamol , verapamil and papaverine neither produced any direct effect nor relaxed the carbachol - contracted tissues ; norepinephrine and epinephrine had contractile effects . Hence , the histamine - induced relaxation was mediated through the activation of H2 receptors and not through adrenergic mechanisms or blockade of Ca ( 2 +)- channels or inhibition of cyclic nucleotide phosphodiesterase .", "___MASK40___ : first global approval . The anti - interleukin - 6 ( P05231 ) chimeric monoclonal antibody siltuximab is the first drug to be approved for the treatment of multicentric Castleman ' s disease ( O95822 ) in the US and European union ( EU ) , having gained approval under the FDA priority review program in the US and from an accelerated assessment and recommendation by the Committee for Medicinal Products for Human Use ( CHMP ) in the EU . Development of the drug is continuing in smoldering multiple myeloma . This article summarizes the milestones in the development of siltuximab leading to this first approval for O95822 .", "Inactivation of caspase - 1 in rodent brain : a novel anticonvulsive strategy . PURPOSE : Cytokines and related inflammatory mediators are rapidly synthesized in the brain during seizures . We previously found that intracerebral administration of interleukin - 1 ( IL - 1 ) - beta has proconvulsant effects , whereas its endogenous receptor antagonist ( IL - 1Ra ) mediates potent anticonvulsant actions in various models of limbic seizures . In this study , we investigated whether seizures can be effectively inhibited by blocking the brain production of IL - 1beta , by using selective inhibitors of interleukin - converting enzyme ( ICE / caspase - 1 ) or through caspase - 1 gene deletion . METHODS : P29466 was selectively blocked by using pralnacasan or ___MASK53___ . IL - 1beta release was induced in mouse organotypic hippocampal slice cultures by proinflammatory stimuli [ lipopolysaccharide ( LPS ) + adenosine triphosphate ( DB00171 ) ] and measured with enzyme - linked immunosorbent assay ( ELISA ) . IL - 1beta production during seizures was measured in the rat hippocampus by Western blot . Seizures were induced in freely moving mice and rats by intrahippocampal injection of kainic acid and recorded by EEG analysis . RESULTS : P29466 inhibition reduced the release of IL - 1beta in organotypic slices exposed to LPS + DB00171 . Administration of pralnacasan ( intracerebroventricular , 50 microg ) or ___MASK53___ ( intraperitoneal , 25 - 200 mg / kg ) to rats blocked seizure - induced production of IL - 1beta in the hippocampus , and resulted in a twofold delay in seizure onset and 50 % reduction in seizure duration . Mice with caspase - 1 gene deletion showed a 70 % reduction in seizures and an approximate fourfold delay in their onset . CONCLUSIONS : Inhibition of caspase - 1 represents an effective and novel anticonvulsive strategy , which acts by selectively reducing the brain availability of IL - 1beta .", "Improved methodical approach for quantitative BRET analysis of G Protein Coupled Receptor dimerization . G Protein Coupled Receptors ( GPCR ) can form dimers or higher ordered oligomers , the process of which can remarkably influence the physiological and pharmacological function of these receptors . Quantitative Bioluminescence Resonance Energy Transfer ( qBRET ) measurements are the gold standards to prove the direct physical interaction between the protomers of presumed GPCR dimers . For the correct interpretation of these experiments , the expression of the energy donor Renilla luciferase labeled receptor has to be maintained constant , which is hard to achieve in expression systems . To analyze the effects of non - constant donor expression on qBRET curves , we performed Monte Carlo simulations . Our results show that the decrease of donor expression can lead to saturation qBRET curves even if the interaction between donor and acceptor labeled receptors is non - specific leading to false interpretation of the dimerization state . We suggest here a new approach to the analysis of qBRET data , when the BRET ratio is plotted as a function of the acceptor labeled receptor expression at various donor receptor expression levels . With this method , we were able to distinguish between dimerization and non - specific interaction when the results of classical qBRET experiments were ambiguous . The simulation results were confirmed experimentally using rapamycin inducible heterodimerization system . We used this new method to investigate the dimerization of various GPCRs , and our data have confirmed the homodimerization of V2 vasopressin and P41180 calcium sensing receptors , whereas our data argue against the heterodimerization of these receptors with other studied GPCRs , including type I and II angiotensin , β2 adrenergic and P21554 cannabinoid receptors .", "The influence of mast cell mediators on migration of SW756 cervical carcinoma cells . The role of mast cell mediators on cervical cancer cell migration was assessed using an in vitro assay of scratch wound healing onto monolayers of HPV18 - positive cervical carcinoma cells ( SW756 ) . Migration of SW756 cells was accelerated by co - culture with the mast cell line LAD2 . This effect was inhibited by the P35367 antagonist DB06691 and the cannabinoid agonists 2 - arachidonylglycerol ( 2AG ) and Win 55 , 212 - 2 . Therefore , the specific effects of histamine and cannabinoids on SW756 migration and LAD2 activation were analyzed . DB11320 added to the in vitro assay of scratch wound healing either increased or inhibited SW756 migration rate by acting either on P35367 or Q9H3N8 , respectively . Cannabinoids acted on P21554 receptors to inhibit SW756 migration . Supernatants from SW756 cells stimulated LAD2 cell degranulation , which in turn was inhibited by cannabinoids acting via CB2 receptors . RT - PCR showed that SW756 expressed mRNA for P21554 , CB2 , P35367 , P25021 , and Q9H3N8 . On the other hand , LAD2 expressed mRNA for all four HRs and CB2 . The results suggest that mast cells could be contributing to cervical cancer cell invasion and spreading by the release of histamine and cannabinoids . Therefore , therapeutic modulation of specific mast cell mediators may be beneficial for cervical cancer treatment .", "Dose finding , placebo - controlled study of oral almotriptan in the acute treatment of migraine . OBJECTIVE : To assess the efficacy and tolerability of oral almotriptan , a selective serotonin receptor ( P28222 / 1D ) agonist , when used at different doses in the treatment of acute migraine . METHODS : This was a placebo controlled , double - blind , parallel - group , dose - finding study . Patients satisfying International Headache Society criteria for acute migraine were randomized to a single dose of placebo or oral almotriptan 2 , 6 . 25 , 12 . 5 , or 25 mg at the onset of moderate or severe pain . Patients graded pain intensity on a 4 - point verbal scale from 0 ( no pain ) to 3 ( severe pain ) and recorded adverse events . The primary efficacy variable was headache response at 2 hours . Data were analyzed on an intent - to - treat basis . RESULTS : Nine hundred and three patients were randomized , and 742 were included in the evaluation of the efficacy and tolerability . Headache response at 2 hours was 32 . 5 % with placebo , and 30 % , 56 . 3 % , 58 . 5 % , and 66 . 5 % with almotriptan 2 , 6 . 25 , 12 . 5 , and 25 mg doses ( p < 0 . 05 for 6 . 25 , 12 . 5 , and 25 mg vs placebo ) . A dose - dependent decrease in the incidence of migraine - associated symptoms and the need for escape medication was observed . The incidence of adverse events with the almotriptan 2 - mg , 6 . 25 - mg , and 12 . 5 - mg groups was comparable to that with the placebo group . CONCLUSION : ___MASK91___ 12 . 5 mg demonstrated the most favorable ratio between efficacy and tolerability , offering equivalent efficacy and better tolerability compared with the 25 mg dose . The minimum effective dose of almotriptan was 6 . 25 mg .", "P04150 antagonism disrupts the reconsolidation of social reward - related memories in rats . Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use . Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated , reconsolidation of memories of physiologically relevant social rewards has received little attention . Social play , the most characteristic social behaviour displayed by young mammals , is highly rewarding , illustrated by the fact that it can induce conditioned place preference ( CPP ) . Here , we investigated the role of signalling mechanisms implicated in memory processes , including reconsolidation , namely glucocorticoid , mineralocorticoid , DB01221 glutamatergic and P21554 cannabinoid receptors , in the reconsolidation of social play - induced CPP in rats . Systemic treatment with the glucocorticoid receptor antagonist mifepristone before , but not immediately after , retrieval disrupted the reconsolidation of social play - induced CPP . DB00834 did not affect social play - induced CPP in the absence of memory retrieval . Treatment with the DB01221 receptor antagonist MK - 801 modestly affected the reconsolidation of social play - induced CPP . However , the reconsolidation of social play - induced CPP was not affected by treatment with the mineralocorticoid and P21554 cannabinoid receptor antagonists spironolactone and rimonabant , respectively . We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward - related memories in rats . These data indicate that the neural mechanisms of the reconsolidation of social reward - related memories only partially overlap with those underlying the reconsolidation of other reward - related memories .", "P06401 activation of extranuclear signaling pathways in regulating p53 expression in vascular endothelial cells . We previously showed that progesterone ( P4 ) inhibited the proliferation of human umbilical vein endothelial cells ( HUVECs ) through a p53 - dependent pathway . Now we investigated further the molecular mechanism underlying the hormone activity . In cultured HUVECs , P4 increased the protein levels of phosphorylated Src ( p - Src ) , P04049 , and P29323 . The levels of p - Src and p - Src - progesterone receptor complex in HUVECs were increased by P4 treatment . These effects were blocked by pretreatment with a progesterone receptor antagonist , DB00834 . The P4 - induced increase in p53 transactivity was abolished by pretreatment with Src kinase inhibitors . Moreover , administration with cSrc antisense oligonucleotide prevented the P4 - induced increases of the levels of p53 mRNA and protein . These data suggest that P4 - induced up - regulation of p53 might be mediated through activation of cSrc . Pretreatment with Src kinase inhibitors also prevented P4 - induced membrane translocation of Kras and increases of the protein levels of phosphorylated Raf and phosphorylated P29323 . Transfection with dominant - negative P28482 prevented the P4 - induced increases of protein level and promoter activity of p53 and a decrease of thymidine incorporation . P4 also increased nuclear factor - κB ( NF - κB ) nuclear translocation and NF - κB binding onto the p53 promoter . These effects were abolished by pretreatment with P29323 inhibitors . The P4 - induced up - regulation of the p53 promoter activity was prevented by preadministration with dominant - negative P28482 or NF - κB inhibitors . Taken together , our data suggest that the cSrc / Kras / P04049 / P28482 / NF - κB signaling pathway contributes to the P4 - induced up - regulation of p53 in HUVECs . These findings highlight progesterone receptor activation of extranuclear signaling pathways in regulating p53 and cell cycle progression in HUVECs .", "Characterization of the effect of chronic administration of a calcium - sensing receptor antagonist , ___MASK56___ , on renal calcium excretion and serum calcium in postmenopausal women . Ronacaleret is an orally - active calcium - sensing receptor ( P41180 ) antagonist that has the potential for therapeutic utility in the stimulation of PTH release , notably as a bone anabolic agent comparable to recombinant human PTH ( 1 - 34 ) ( DB05829 ( 1 - 34 ) ) . A recent study has shown that , despite the ability to increase circulating PTH levels in postmenopausal women in a dose - dependent manner , minimal effects of ___MASK56___ on bone mineral density have been observed . Therefore , the purpose of this study was to characterize the PTH profile as well as calcium metabolism parameters as a marker of PTH biological activity following the administration of ___MASK56___ or DB05829 ( 1 - 34 ) . Administration of ___MASK56___ led to lower peak levels of PTH than were observed with DB05829 ( 1 - 34 ) , however , greater total PTH exposure was observed . Further , chronic administration of either agent was associated with increases in urinary calcium excretion and serum calcium levels , with the magnitude of the changes following ___MASK56___ significantly greater than that for DB05829 ( 1 - 34 ) . The greater magnitude of effects observed with ___MASK56___ is likely due to the greater total PTH exposure , and is potentially reflective of a state comparable to mild hyperparathyroidism . It is not clear whether the administration of all calcilytics would lead to a similar result , or is due to characteristics specific to ___MASK56___ .", "P04150 and histone deacetylase - 2 mediate dexamethasone - induced repression of P98088 gene expression . Airway occlusion in obstructive airway diseases is caused in part by the overproduction of secretory mucin glycoproteins through the up - regulation of mucin ( MUC ) genes by inflammatory mediators . Some pharmacological agents , including the glucocorticoid dexamethasone ( DB00514 ) , repress mucin concentrations in lung epithelial cancer cells . Here , we show that DB00514 reduces the expression of P98088 , a major airway mucin gene , in primary differentiated normal human bronchial epithelial ( NHBE ) cells in a dose - dependent and time - dependent manner , and that the DB00514 - induced repression is mediated by the glucocorticoid receptor ( GR ) and two glucocorticoid response elements ( GREs ) in the P98088 promoter . The pre - exposure of cells to DB00834 , a GR antagonist , and mutations in either the GRE3 or GRE5 cis - sites abolished the DB00514 - induced repression . Chromatin immunoprecipitation ( ChIP ) assays showed a rapid temporal recruitment of GR to the GRE3 and GRE5 cis - elements in the P98088 promoter in NHBE and in A549 cells . Immunofluorescence showed nuclear colocalization of GR and histone deacetylase - 2 ( Q92769 ) in P98088 - expressing NHBE cells . ChIP also showed a rapid temporal recruitment of Q92769 to the GRE3 and GRE5 cis - elements in the P98088 promoter in both cell types . The knockdown of Q92769 by Q92769 - specific short interfering RNA prevented the DB00514 - induced repression of P98088 in NHBE and A549 cells . These data demonstrate that GR and Q92769 are recruited to the GRE3 and GRE5 cis - sites in the P98088 promoter and mediate the DB00514 - induced cis repression of P98088 gene expression . A better understanding of the mechanisms whereby glucocorticoids repress P98088 gene expression may be useful in formulating therapeutic interventions in chronic lung diseases .", "Blockade of cannabinoid receptors reduces inflammation , leukocyte accumulation and neovascularization in a model of sponge - induced inflammatory angiogenesis . OBJECTIVE : Angiogenesis depends on a complex interaction between cellular networks and mediators . The endocannabinoid system and its receptors have been shown to play a role in models of inflammation . Here , we investigated whether blockade of cannabinoid receptors may interfere with inflammatory angiogenesis . MATERIALS AND METHODS : Polyester - polyurethane sponges were implanted in C57Bl / 6j mice . Animals received doses ( 3 and 10 mg / kg / daily , s . c . ) of the cannabinoid receptor antagonists SR141716A ( P21554 ) or SR144528 ( CB2 ) . Implants were collected at days 7 and 14 for cytokines , hemoglobin , myeloperoxidase , and N - acetylglucosaminidase measurements , as indices of inflammation , angiogenesis , neutrophil and macrophage accumulation , respectively . Histological and morphometric analysis were also performed . RESULTS : Cannabinoid receptors expression in implants was detected from day 4 after implantation . Treatment with P21554 or CB2 receptor antagonists reduced cellular influx into sponges at days 7 and 14 after implantation , although P21554 receptor antagonist were more effective at blocking leukocyte accumulation . There was a reduction in P01375 - α , P15692 , P09341 / KC , P13500 / JE , and P10147 / MIP - 1α levels , with increase in P13501 / RANTES . Both treatments reduced neovascularization . Dual blockade of cannabinoid receptors resulted in maximum inhibition of inflammatory angiogenesis . CONCLUSIONS : Blockade of cannabinoid receptors reduced leukocyte accumulation , inflammation and neovascularization , suggesting an important role of endocannabinoids in sponge - induced inflammatory angiogenesis both via P21554 and CB2 receptors .", "Targeting autocrine and paracrine P15692 receptor pathways inhibits human lymphoma xenografts in vivo . The role of angiogenesis in lymphoproliferative diseases is not well established . We demonstrate here that human lymphoma cells secrete vascular endothelial growth factor ( P15692 ) and express P15692 receptor 1 ( P17948 ) and P35968 . Proliferation of non - Hodgkin lymphoma ( Q9NZ71 ) cells under serum - free conditions was enhanced by the addition of P15692 and was blocked by P17948 - and P35968 - specific antibodies . To differentiate between P15692 - mediated autocrine and paracrine effects on lymphoma growth , NOD / SCID mice engrafted with human diffuse large B - cell lymphoma ( DLBCL ) were treated with species - specific antibodies against human P17948 ( 6 . 12 ) , human P35968 ( ___MASK65___ ) , murine P17948 ( MF - 1 ) , or murine P35968 ( DC101 ) . Treatment with 6 . 12 or DC101 ( targeting tumor P17948 and host P35968 ) reduced established DLBCL xenograft growth , whereas treatment with ___MASK65___ or MF - 1 ( targeting tumor P17948 and host P17948 ) had no effect . Decreased tumor volumes after 6 . 12 and DC101 treatment correlated with increased tumor apoptosis and reduced vascularization , respectively , supporting the presence of autocrine P17948 - and paracrine P35968 - mediated pathways in lymphomagenesis . Inhibition of paracrine P15692 interactions ( DC101 ) in these models was equivalent to their inhibition with rituximab . Combining DC101 with therapeutic agents ( rituximab , 6 . 12 , methotrexate ) consistently improved tumor responses over those of single - agent therapy . These data support the further clinical development of VEGFR - targeted approaches for the therapy of aggressive DLBCL ." ]
[ "___MASK24___", "___MASK40___", "___MASK53___", "___MASK56___", "___MASK65___", "___MASK67___", "___MASK70___", "___MASK91___", "___MASK93___" ]
___MASK40___
MH_train_1601
interacts_with DB00215?
[ "Local control of alpha1 - proteinase inhibitor levels : regulation of alpha1 - proteinase inhibitor in the human cornea by growth factors and cytokines . Alpha 1 - proteinase inhibitor is a major serine proteinase inhibitor in the human cornea involved in the protection of the avascular corneal tissue against proteolytic damage . This inhibitor is upregulated systemically during infection , inflammation and injury . Cytokines that mediate the acute phase response such as IL - 1beta and P60568 increased alpha1 - proteinase inhibitor present in corneal organ culture media . This released inhibitor represented mainly newly synthesized protein . However , P05231 , a general inducer of the acute phase response that upregulates alpha1 - proteinase inhibitor in all other tissues and cells tested , failed to alter corneal alpha1 - proteinase inhibitor levels over the tested period of 24 h . In addition to IL - 1beta and P60568 , alpha1 - proteinase inhibitor levels in the corneal organ culture medium increased following the addition of P09038 and P05019 . The effect of the above growth factors and cytokines was relatively fast with maximal induction observed within the first 5 h . Among the tested growth factors and cytokines , IL - 1beta was the most potent and increased total corneal alpha1 - proteinase inhibitor levels approximately 2 . 4 - fold in the cornea organ culture medium . Newly , synthesized alpha1 - proteinase secreted into the medium increased 3 . 9 - fold . In addition to the effect on corneal alpha1 - proteinase inhibitor , IL - 1beta also increased the amount of alpha1 - proteinase inhibitor released by monocytes and macrophages but not by HepG2 , CaCo2 , and MCF - 7 cells within 24 h . These results suggest that the cornea can locally control levels of alpha1 - proteinase inhibitor in response to an inflammatory insult .", "Analog of somatostatin vapreotide exhibits biological effects in vitro via interaction with neurokinin - 1 receptor . OBJECTIVES : ___MASK48___ , a synthetic analog of somatostatin , has analgesic activity most likely mediated through the blockade of neurokinin - 1 receptor ( P25103 ) , the DB05875 ( SP ) - preferring receptor . The ability of vapreotide to interfere with other biological effects of SP has yet to be investigated . METHODS : We studied the ability of vapreotide to antagonize P25103 in three different cell types : immortalized U373MG human astrocytoma cells , human monocyte - derived macrophages ( MDM ) and a human embryonic kidney cell line , HEK293 . Both U373MG and MDM express endogenous P25103 while HEK293 cells , which normally do not express P25103 , are stably transformed to express human P25103 ( HEK293 - P25103 ) . RESULTS : ___MASK48___ attenuates SP - triggered intracellular calcium increases and nuclear factor - κB activation in a dose - dependent manner . ___MASK48___ also inhibits SP - induced interleukin - 8 and monocyte chemotactic protein - 1 production in HEK293 - P25103 and U373MG cell lines . ___MASK48___ inhibits HIV - 1 infection of human MDM in vitro , an effect that is reversible by SP pretreatment . CONCLUSIONS : Our findings indicate that vapreotide has P25103 antagonist activity and may have a potential application as a therapeutic intervention in HIV - 1 infection .", "Effects of ethanol on the properties of platelets and endothelial cells in model experiments . AIM : To investigate effects of ethanol on activity markers of atherosclerosis in an in vitro endothelial cell model . METHODS : After 24 h incubation with ethanol ( 0 . 0095 % ) , human umbilical vein endothelial cells were stimulated for 1 h with lipopolysaccharide , and were then incubated in direct contact with activated platelets . Following this incubation , the expression of P29965 and CD62P on platelets , and the expression of intercellular adhesion molecule - 1 ( P05362 ) , vascular cell adhesion molecule - 1 ( P19320 ) , urokinase plasminogen activator receptor ( Q03405 ) , and membrane - type 1 matrix metalloproteinase ( P50281 ) on endothelial cells were measured by flow cytometry . RESULTS : The increased expression of P19320 and Q03405 on endothelial cells by proinflammatory stimulation with activated platelets was significantly reduced through pre - incubation with ethanol ( P < 0 . 05 ) . Furthermore , platelets in direct contact with ethanol and with endothelial cells pre - incubated in ethanol showed a significant reduction in their P29965 expression ( P < 0 . 05 ) . ___MASK41___ had no significant effect on P05362 and P50281 expression on endothelial cells . CONCLUSION : ___MASK41___ directly attenuates platelet activation and has significant endothelial cell - mediated effects on selected markers of atherosclerosis in vitro . These findings underline possible protective effects of ethanol on atherosclerosis .", "Attenuation of the progression of adjuvant - induced arthritis by 3 - aminobenzamide treatment . Rheumatoid arthritis ( RA ) is a disease that is still insufficiently controlled by current treatments . Poly ( ADP - ribose ) polymerase ( PARP ) inhibitors ameliorate immune - mediated diseases in several experimental models , including RA , colitis , experimental autoimmune encephalomyelitis and allergy . Together these findings showed that ADP - ribosylating enzymes , in particular P09874 , play a pivotal role in the regulation of immune responses and may represent a noble target for new therapeutic approaches in immune - mediated diseases . The effect of 3 - aminobenzamide ( 3 - AB ) , an inhibitor of poly ( ADP - ribose ) synthetase activity , was evaluated in a mouse model of adjuvant - induced arthritis ( AIA ) on pro - inflammatory cytokines , adhesion molecules , inflammatory mediators and chemokine production / expression in serum and knee joint . Histopathological examination was also done on joint section . Our data demonstrates that 3 - AB , 10mg / kg , intraperitoneally ( i . p . ) significantly reduces pro - inflammatory cytokine ( Q16552 , P01375 - α and P60568 ) and chemokine ( P13500 and MIP - 2 ) production / expression , accompanied by amelioration of the disease as indicated by reduced paw swelling and arthritic scores and was associated with a significant reduction of P19320 and P05362 expression in the knee joint . Moreover , the expression of inflammatory mediators ( P35228 , P35354 , P08253 , P14780 ) and joint histological inflammatory damage was also markedly decreased . The results of this study suggest that P09874 inhibitor may play a role in the inflammatory arthritic process after administration of 3 - AB may be a beneficial therapeutic approach .", "Angiotensin II and basic fibroblast growth factor mitogenic pathways in human fetal mesangial cells . Angiotensin II ( Ang II ) and basic fibroblast growth factor ( P09038 / P09038 ) play relevant roles in renal development . Since the signaling pathways modulating the mitogenic effects of Ang II and P09038 in human fetal mesangial cells ( HFMc ) are not clearly defined , we carried out experiments to determine whether they would exert their mitogenic effects by modulating the activity of the mitogen - activated protein kinases ( MAPK ) [ extracellular signal - regulated kinase - 2 ( P28482 ) ] and DB02527 signaling pathways . In confluent HFMc , P09038 ( 20 ng / mL ) induced a significant 4 - fold increase in P28482 activity and [ 3H ] - thymidine incorporation ( 6 - fold ) . In contrast , under similar tissue culture conditions , Ang II ( 10 (- 6 ) M ) induced a more modest increase in P28482 activity ( 2 - fold ) and [ 3H ] - thymidine incorporation ( 35 +/- 4 % ) . The mitogen - activated protein kinase kinase - 1 ( MEK - 1 ) inhibitor PD098059 ( 25 microM ) almost completely abolished the P09038 - induced proliferation in HFMc but did not significantly affect Ang II proliferative effects . In the presence of the DB02527 elevating agent isoproterenol , Ang II and P09038 induced opposite changes in DB02527 accumulation and cell growth . ___MASK37___ inhibited the basal and P09038 - induced proliferation of HFMc through a MEK - 1 / 2 - independent pathway that included the accumulation of DB02527 . In contrast , isoproterenol increased Ang II mitogenic effects in correlation with a reduction in DB02527 accumulation . We conclude that Ang II and P09038 modulate the proliferation of HFMc through the stimulation of different MEK - 1 / 2 - dependent and independent signaling pathways . Activation of MEK - 1 / 2 is required but not sufficient for mitogenesis in HFMc . The accumulation of DB02527 in HFMc counteracts the mitogenic effects of P09038 by a MEK - 1 / 2 - independent pathway .", "Study of P01116 new predictive marker in a clinical laboratory . BACKGROUND : The presence of somatic mutations in the P01116 gene has been identified as a reliable strong negative predictor for the response to targeting the epidermal growth factor receptor ( P00533 ) , in patients with metastatic colorectal cancer and the use of anti - P00533 monoclonal antibodies such as Cetuximab and ___MASK76___ is now restricted to patients with no detectable P01116 mutations . Between 30 and 40 % of colorectal cancers contain a mutated P01116 oncogene . The aim of this study was to evaluate concordance between three methods to analyze P01116 mutational status in regard to clinical testing . METHODS : We analyzed P01116 mutations in codons 12 and 13 of exon 2 in one hundred formalin - fixed paraffin - embedded ( FFPE ) colorectal cancer samples by three different methods : Direct Sequencing and two commercial kits on allele - specific oligonucleotide hybridization ( P01116 StripAssay , Vienna Lab . ) and Amplification Refractory Mutation System / Scorpions ( Q9ULH0 / S ; TheraScreen P01116 Mutation kit DxS ) based on q - PCR . RESULTS : We have found similar frequencies of P01116 mutations by TheraScreen and Strip - Assay ( 44 and 48 % ) , with a κ value of 0 . 90 , indicating almost perfect agreement between methods . The frequency by direct sequencing was much lower ( 26 % ) and the κ values were 0 . 67 ( compared to TheraScreen ) and 0 . 57 ( compared to Strip - Assay ) indicating low sensitivity . CONCLUSIONS : On analyzing P01116 mutation in FFPE tumor samples , direct sequencing sensitivity is too low to be used in a clinical setting . Choosing between Q9ULH0 / S ; TheraScreen P01116 Mutation kit DxS and P01116 StripAssay , Vienna Lab , will depend on laboratory facilities and expertise .", "Neurokinin type - 1 receptor antagonist inhibits enhancement of T cell functions by DB05875 in normal and neuromanipulated capsaicin - treated rats . Substance P ( SP ) plays a major role in the regulation of the interaction between immune and nervous systems . SP administration stimulates Con A - induced proliferation of spleen and peripheral blood lymphocytes from normal and neonatally capsaicin treated rats , which correlated with enhanced P60568 production and expression of activation antigens such as P60568 receptor alpha chain ( CD25 ) and RT1B MHC class II molecule . Moreover , SP markedly increased the percentage of P06127 + and P01730 + T lymphocytes in the peripheral blood of capsaicin - treated rats . Concomitant administration of SP with the non - peptide Neurokinin - 1 receptor ( P25103 ) antagonist SR140333 completely inhibited the SP - mediated augmentation of Con A - induced PBL proliferation and P60568 production as well as of P01730 + CD25 + and P01730 + RT1B + T cell numbers in normal and capsaicin - treated rats . DB05790 also blocked the increased percentage of peripheral blood P01730 + T cells induced by SP in capsaicin - treated rats .", "HepG2 human hepatoma cells express multiple cytokine genes . Although cytokines are known to be involved in the regulation of a variety of hepatocellular functions , hepatocytes themselves are generally considered only targets but not producers of these important mediators . In order to investigate whether cells of hepatocellular linages are a potential source of various regulatory cytokines we have estimated the multiple cytokine gene expression in the culture of well differentiated human HepG2 hepatoma cells using RT - PCR . Our findings demonstrate that HepG2 cells express mRNAs for interferon gamma ( P01579 ) , tumour necrosis factor alpha ( P01375 ) , transforming growth factor beta ( TGF - beta ) , macrophage colony - stimulating factor ( P09603 ) , oncostatin - M ( P13725 ) , intercellular adhesion molecule ( P05362 ) , interleukin 4 ( P05112 ) , P05113 , P13232 , P22301 , IL - 11 , IL - 12 and P05231 receptor ( IL - 6R ) . At the same time the expression of IL - 1 , P60568 , P08700 , P05231 , P29965 and IL - 2R genes was not detected . It was concluded that hepatocytes are potential producers of a variety of cytokines , some of them being able to regulate hepatocellular functions directly , while others are important regulators of leukocyte activity . Thus , on the one hand , hepatocytes may express autoregulatory cytokines and on the other hand , influence the functions of other liver cells like Kupffer , Ito or endothelial cells . Due to their large amount , liver parenchymal cells could be an important source of sytemically acting pro - and anti - inflammatory and other regulatory cytokines .", "Predicting the possibility of two newly isolated phenetheren ring containing compounds from Aristolochia manshuriensis as P24941 inhibitors . Aristolochia manshuriensis has been used for centuries in Chinese medicinal system for their versatile medicinal uses . Recent studies have revealed two new aristolactames ( compound A and B ) with γ - lactame ring fused with the phenentherene ring as potent inhibitors of human Cycline Dependent Kinase2 ( P24941 ) . Studies on aristolactames and related compounds claim for their P24941 inhibition without delineating the involved mechanism and structural basis of interaction . Molecular structural model was used to we propose a structural basis of P24941 inhibition . We showed that these compounds ( A and B ) can successfully dock into the inhibitor binding pockets of human P24941 . Predicted binding affinities are comparable to known inhibitors of P24941 . Results were in agreement with the earlier biochemical studies . Hence , suggest that studied compounds A and B can be a promising scaffold for rational design of novel and potential drugs against cancer . ABBREVIATIONS : P24941 - cyclin - dependent kinase 2 , OLO - ___MASK99___ , NW1 - Cyclohexylmethyloxy - 5 - Nitroso - Pyrimidine - 2 , 4 - Diamine , CMG - DB02407 .", "Phosphorylation of beta - arrestin2 regulates its function in internalization of beta ( 2 )- adrenergic receptors . Beta - arrestins mediate agonist - dependent desensitization and internalization of G protein - coupled receptors . Previously , we have shown that phosphorylation of beta - arrestin1 by ERKs at DB00133 - 412 regulates its association with clathrin and its function in promoting clathrin - mediated internalization of the receptor . In this paper we report that beta - arrestin2 is also phosphorylated , predominantly at residues DB00156 - 383 and DB00133 - 361 . ___MASK37___ stimulation of the beta ( 2 )- adrenergic receptor promotes dephosphorylation of beta - arrestin2 . Mutation of beta - arrestin2 phosphorylation sites to aspartic acid decreases the association of beta - arrestin2 with clathrin , thereby reducing its ability to promote internalization of the beta ( 2 )- adrenergic receptor . Its ability to bind and desensitize the beta ( 2 )- adrenergic receptor is , however , unaltered . These results suggest that , analogous to beta - arrestin1 , phosphorylation / dephosphorylation of beta - arrestin2 regulates clathrin - mediated internalization of the beta ( 2 )- adrenergic receptor . In contrast to beta - arrestin1 , which is phosphorylated by P27361 and P28482 , phosphorylation of beta - arrestin2 at DB00156 - 383 is shown to be mediated by casein kinase II . Recently , it has been reported that phosphorylation of visual arrestin at DB00133 - 366 prevents its binding to clathrin . Thus it appears that the function of all arrestin family members in mediating internalization of G protein - coupled receptors is regulated by distinct phosphorylation / dephosphorylation mechanisms .", "Synthesis and biological evaluation of novel ( 4 or 5 - aryl ) pyrazolyl - indoles as inhibitors of interleukin - 2 inducible T - cell kinase ( Q08881 ) . P60568 inducible T - cell kinase ( Q08881 ) is one of five kinases that belong to the Tec kinase family that plays an important role in T - cell and mast cell signaling . Various reports point to a role of Q08881 in the treatment of allergic asthma . For example , it was shown that mice lacking Q08881 have reduced airway hyperresponsiveness , inflammation and tracheal responses in an allergic asthma model . In this article , we disclose novel Q08881 inhibitors based on ( 4 or 5 - aryl ) pyrazolyl - indole scaffold that were also found to be selective for Q08881 over other kinases like IRK , P24941 , GSK3ss and PKA .", "The opposite effects of P40933 and Q9HBE4 on CLL B cells correlate with differential activation of the JAK / P35610 and P27361 / 2 pathways . The clonal expansion of chronic lymphocytic leukemia ( CLL ) cells requires the interaction with the microenvironment and is under the control of several cytokines . Here , we investigated the effect of P40933 and Q9HBE4 , which are closely related to P60568 and share the usage of the common gamma chain and of its P52333 - associated pathway . We found remarkable differences in the signal transduction pathways activated by these cytokines , which determined different responses in CLL cells . P40933 caused cell proliferation and prevented apoptosis induced by surface IgM cross - linking . These effects were more evident in cells stimulated via surface P25942 , which exhibited increased cell expression of IL - 15Ralpha chain and , in some of the cases , also of IL - 2Rbeta . Q9HBE4 failed to induce CLL cell proliferation and instead promoted apoptosis . Following cell exposure to P40933 , phosphorylation of P42229 was predominantly observed , whereas , following stimulation with Q9HBE4 , there was predominant P42224 and P40763 activation . Moreover , P40933 but not Q9HBE4 caused an increased phosphorylation of Shc and P27361 / 2 . Pharmacological inhibition of P52333 or of MEK , which phosphorylates P27361 / 2 , efficiently blocked P40933 - induced CLL cell proliferation and the antiapoptotic effect of this cytokine . The knowledge of the signaling pathways regulating CLL cell survival and proliferation may provide new molecular targets for therapeutic intervention .", "Human ___MASK9___ 4 ' epimerase ( Q14376 ) gene and identification of five missense mutations in patients with epimerase - deficiency galactosemia . The galactosemias are a series of three inborn errors of metabolism caused by deficiency of any one of the three human galactose - metabolic enzymes : galactokinase ( P51570 ) , galactose - 1 - phosphate uridyl transferase ( P07902 ) , and ___MASK9___ 4 ' epimerase ( Q14376 ) . We report here the characterization of the entire coding sequence of the Q14376 gene and screening for mutations in epimerase - deficient individuals . The human Q14376 gene is about 4 kb in size and is divided into 11 exons on chromosome band 1p36 . We have identified five mutations in the Q14376 gene of epimerase - deficient galactosemia patients . The patients were either homozygotes or compound heterozygotes for mutations . These results confirm that epimerase - deficiency galactosemia is the result of missense mutations in the Q14376 gene and indicate that the disease is characterized by extensive allelic heterogeneity .", "Effects of chimeric somatostatin - dopamine molecules on human peripheral blood lymphocytes activation . O43521 23A761 , selective for somatostatin receptors subtypes 2 , 5 and the dopamine receptor subtype 2 , and O43521 23A757 with affinity for P30874 and DAR2 were studied on human PBL proliferation and activation . O43521 23A761 was significantly more potent than specific SSTR and DAR2 agonists in suppressing lymphocyte proliferation induced by mitogen or alloantigen , while O43521 23A757 was more potent than specific P30874 and DAR2 agonists in suppressing antigen induced proliferation only . Both molecules displayed enhanced potency in suppressing IFNgamma and P05231 secretion compared with the SSTR and DAR2 analogs , while only O43521 23A761 was able to inhibit P60568 secretion and its effect is more potent than the control analogs . Furthermore O43521 23A761 inhibit cell progression into the S phase and then into the G2 / M , while O43521 23A757 inhibited bromodeoxyuridine incorporation only during the S phase . Both chimeric molecules resulted significantly more effective than the respective controls .", "___MASK41___ dose - dependently elicits opposing regulatory effects on hippocampal AMPA receptor P42262 subunits through a zeta inhibitory peptide - sensitive kinase in adolescent and adult Sprague - Dawley rats . AMPA receptor P42262 subunits are strongly implicated in cognition , and prior work suggests that these subunits may be regulated by atypical protein kinase C ( aPKC ) isoforms . The present study assessed whether hippocampal and cortical AMPA receptor P42262 subunit regulation may be an underlying factor in known age - related differences to cognitive - impairing doses of ethanol , and if aPKC isoforms modulate such responses . Hippocampal AMPA receptor P42262 subunit , protein kinase Mζ ( PKMζ ) , and PKCι / λ expression were elevated during adolescence compared to adults . 1 h following a low - dose ( 1 . 0 - g / kg ) ethanol exposure , hippocampal AMPA receptor P42262 subunit serine 880 phosphorylation was decreased in adolescents , but was increased in adults . Age - dependent changes in P42262 subunit phosphorylation were paralleled by alterations in aPKC isoforms , and zeta inhibitory peptide ( Q8N5A5 ) administration prevented ethanol - induced increases in both in adults . ___MASK41___ - induced changes in P42262 subunit phosphorylation were associated with delayed regulation in synaptosomal P42262 subunit expression 24 h later . A higher ethanol dose ( 3 . 5 - g / kg ) failed to elicit changes in most measures in the hippocampus at either age . Similar to the hippocampus , analysis of cerebral cortical tissue also revealed age - related declines . However , no demonstrable effects were found following a low - dose ethanol exposure at either age . High - dose ethanol exposure reduced adolescent P42262 subunit phosphorylation and aPKC isoform expression that were again accompanied by delayed reductions in synaptosomal P42262 subunit expression . Together , these results suggest that P42262 - containing AMPA receptor modulation by aPKC isoforms is age - , region - and dose - dependently regulated , and may potentially be involved in developmentally regulated ethanol - induced cognitive impairment and other ethanol behaviors .", "ErbB antagonists patenting : \" playing chess with cancer \" . ErbBs signalling is always associated with the development of the majority of solid cancers via both the MAPK pathway leading to cell cycle progression and the PI3K pathway causing cell survival . As a consequence , many ErbB antagonists have been developed and patented for cancer treatment purposes . These antagonists belong to two drug classes : monoclonal antibodies ( mAbs ) and small molecules competing with DB00171 and inhibiting the tyrosine kinase domain ( TKIs ) . Three patented mAbs are currently approved in clinical cancer treatment : DB00072 ( Herceptin ) directed against P04626 and used to treat breast cancer , Cetuximab and ___MASK76___ which are anti - P00533 antibodies approved for colorectal cancer treatment . Unfortunately , these mAbs are facing cancer resistance mediated by paracrine activation of other ErbB members or compensatory ErbB signalling factors . In parallel , three TKIs have been approved to treat cancer : Gefitinib ( DB00317 ) , Erlotinib ( Tarceva ) inhibiting specifically P00533 and approved to treat non small cell lung cancer and DB01259 ( DB01259 ) which has the dual specificity P00533 / P04626 and recently approved to treat metastatic breast cancer . These TKIs are also facing resistance mutations within the TK domain which increase its affinity to DB00171 . Resistance problems are leading to the adoption of a new strategy based on the combination of different therapies and this is likely to be the most promising future of cancer treatments .", "Combined adenine phosphoribosyltransferase and P34059 deficiency . We describe a Czech patient with combined adenine phosphoribosyltransferase ( P07741 ) deficiency ( 2 , 8 - dihydroxyadenine urolithiasis ) and P34059 ( P34059 ) deficiency ( mucopolysaccharidosis Type IVA , Morquio disease A ) . ___MASK16___ and its extremely insoluble derivative , 2 , 8 - dihydroxyadenine , were identified in the urine , and P07741 deficiency was confirmed in erythrocytes . There was excessive excretion of keratan sulfate in the urine , and P34059 deficiency was confirmed in leukocytes . P34059 and P07741 are both located on chromosome 16q24 . 3 , suggesting that the patient had a deletion involving both genes . PCR amplification of genomic DNA indicated that a novel junction was created by the fusion of sequences distal to P34059 exon 2 and proximal to P07741 exon 3 , and that the size of the deleted region was approximately 100 kb . The deletion breakpoints were localized within P34059 intron 2 and P07741 intron 2 . Several other genes , including the alpha subunit of cytochrome B ( P13498 ) , which is deleted or mutated in the autosomal form of chronic granulomatous disease , are located in the 16q24 . 3 region , but PCR amplification showed that this gene was present in the proband . A patient with hemizygosity for P34059 deficiency and P07741 deficiency has been reported from Japan recently . These findings indicate that : ( i ) P07741 is located telomeric to P34059 ; ( ii ) P34059 and P07741 are transcribed in the same orientation ( centromeric to telomeric ) ; and ( iii ) combined P07741 / P34059 deficiency may be more common than hitherto realized .", "Changes in Th1 and Th2 cytokine concentrations in ileal Peyer ' s patches in gilts exposed to zearalenone . P07902 induces tolerance to foreign food antigens and plays an important role in the development of food allergies and the inflammatory bowel disease . The immune function of P07902 is significantly influenced by an equilibrium between Th1 and Th2 subpopulations and the cytokines they produce . Th1 cytokines participate in the induction of a cell - mediated immune response , whereas Th2 cytokines induce powerful antibody - mediated responses . Changes in Th1 / Th2 cell polarization of an immune response are associated with susceptibility to autoimmune and infectious diseases . This experiment investigated changes in cytokine levels produced by Th1 and Th2 cells in ileal Payer ' s patches in gilts exposed to ZEN doses below the NOEL ( approximately 8 microg kg (- 1 ) BW ) for 14 , 28 and 42 days . A significant linear increase in P05112 ( 40 . 32 +/- 1 . 55 ng mg (- 1 ) -- 137 . 60 +/- 29 . 96 ng mg (- 1 ) ) , and P22301 ( 5 . 99 +/- 0 . 15 ng mg (- 1 ) -- 16 . 39 +/- 1 . 11 ng mg (- 1 ) ) concentrations was observed . An increase in Th1 ( P60568 and P01579 ) cytokine levels was also noted in the experimental group , but it was not statistically significant . An HPLC analysis of Peyer ' s patches in group E animals revealed a linear increase in ZEN concentrations ( 3 . 65 +/- 0 . 91 ng g (- 1 ) -- 4 . 72 +/- 1 . 85 ng g (- 1 ) ) and an absence of alpha - ZEL . P05112 stimulates monocytes and macrophages , it induces the production of proinflammatory cytokines and it may directly and indirectly contribute to the development of inflammatory foci . Higher P05112 levels could shift polarization toward Th2 cells , stimulate B cells to undergo class switching to produce IgE and contribute to the development of allergies .", "Production of IL - 1beta and IL - 1Ra as risk factors for susceptibility and progression of relapse - onset multiple sclerosis . Interleukin - 1beta ( IL - 1beta ) is present in multiple sclerosis ( MS ) lesions . Interleukin - 1 receptor antagonist ( IL - 1Ra ) moderates the induction of experimental autoimmune encephalomyelitis ( EAE ) . Here , we show that families that are characterized by high IL - 1beta over IL - 1Ra production ratio are at 2 . 2 - fold ( 95 % CI , 1 . 0 - 4 . 8 ; p = 0 . 05 ) increased risk to have a patient relative with relapse - onset MS than families with a low ratio . It is also related to the reduction of volumetric magnetization transfer ratio ( Q99707 ) histogram height , a measure of parenchymal integrity ( p = 0 . 04 ) . Those families who combine a high IL - 1beta over IL - 1Ra ratio with a high tumor necrosis factor ( P01375 ) over P22301 production ratio have a 6 . 2 - fold ( 95 % CI , 1 . 8 - 21 ; p = 0 . 002 ) increased risk . Innate production of IL - 1beta and IL - 1Ra is not related to the outcome of primary progressive MS . Taq1 polymorphism in the IL - 1beta gene and the variable number of tandem repeats ( VNTR ) polymorphism of 86 - base pairs within the IL - 1Ra gene can not explain these findings .", "Aerosol vaccination with AERAS - 402 elicits robust cellular immune responses in the lungs of rhesus macaques but fails to protect against high - dose Mycobacterium tuberculosis challenge . Development of a vaccine against pulmonary tuberculosis may require immunization strategies that induce a high frequency of Ag - specific P01730 and CD8 T cells in the lung . The nonhuman primate model is essential for testing such approaches because it has predictive value for how vaccines elicit responses in humans . In this study , we used an aerosol vaccination strategy to administer AERAS - 402 , a replication - defective recombinant adenovirus ( rAd ) type 35 expressing Mycobacterium tuberculosis Ags Ag85A , Ag85B , and TB10 . 4 , in bacillus Calmette - Guérin ( BCG ) - primed or unprimed rhesus macaques . Immunization with BCG generated low purified protein derivative - specific P01730 T cell responses in blood and bronchoalveolar lavage . In contrast , aerosolized AERAS - 402 alone or following BCG induced potent and stable Ag85A / b - specific P01730 and CD8 effector T cells in bronchoalveolar lavage that largely produced IFN - γ , as well as P01375 and P60568 . Such responses induced by BCG , AERAS - 402 , or both failed to confer overall protection following challenge with 275 CFUs M . tuberculosis Erdman , although vaccine - induced responses associated with reduced pathology were observed in some animals . Anamnestic T cell responses to Ag85A / b were not detected in blood of immunized animals after challenge . Overall , our data suggest that a high M . tuberculosis challenge dose may be a critical factor in limiting vaccine efficacy in this model . However , the ability of aerosol rAd immunization to generate potent cellular immunity in the lung suggests that using different or more immunogens , alternative rAd serotypes with enhanced immunogenicity , and a physiological challenge dose may achieve protection against M . tuberculosis .", "P32248 signaling inhibits T cell proliferation . P32248 and its ligands , Q99731 and O00585 , are responsible for directing the migration of T cells and dendritic cells into lymph nodes , where these cells play an important role in the initiation of the immune response . Recently , we have shown that systemic application of Q99731 - IgG is able to inhibit the colocalization of T cells and dendritic cells within secondary lymphoid organs , resulting in pronounced immunosuppression with reduced allograft rejection after organ transplantation . In this study , we demonstrate that the application of sustained high concentrations of either soluble or immobilized Q99731 and O00585 elicits an inhibitory program in T cells . We show that these ligands specifically interfere with cell proliferation and P60568 secretion of P32248 (+) cells . This could be demonstrated for human and murine T cells and was valid for both P01730 (+) and CD8 (+) T cells . In contrast , Q99731 had no inhibitory effect on T cells from P32248 knockout mice , but P32248 (-/-) T cells showed a proliferative response upon TCR - stimulation similar to that of Q99731 - treated wild - type cells . Furthermore , the inhibition of proliferation is associated with delayed degradation of the cyclin - dependent kinase ( CDK ) inhibitor p27 ( Kip1 ) and the down - regulation of P06493 . This shows that P32248 signaling is linked to cell cycle control and that sustained engagement of P32248 , either by high concentrations of soluble ligands or by high density of immobilized ligands , is capable of inducing cell cycle arrest in TCR - stimulated cells . Thus , P32248 , a chemokine receptor that has been demonstrated to play an essential role during activation of the immune response , is also competent to directly inhibit T cell proliferation .", "Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . DB00215 at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .", "Phase I / II trial and pharmacokinetic study of cixutumumab in pediatric patients with refractory solid tumors and Ewing sarcoma : a report from the Children ' s Oncology Group . PURPOSE : A phase I / II study of cixutumumab ( ___MASK26___ ) in children with refractory solid tumors was conducted . This study was designed to assess the toxicities , pharmacokinetics , and pharmacodynamics of cixutumumab in children to determine a recommended phase II dose and to assess antitumor activity in Ewing sarcoma ( ES ) . PATIENTS AND METHODS : Pediatric patients with relapsed or refractory solid tumors were treated with cixutumumab as a 1 - hour intravenous infusion once per week . Two dose levels - 6 and 9 mg / kg - were evaluated using a standard three - plus - three cohort design . Patients with refractory ES were treated in an expanded phase II cohort at each dose level . RESULTS : Forty - seven eligible patients with a median age of 15 years ( range , 4 to 28 years ) were enrolled . Twelve patients were treated in the dose - finding phase . Hematologic and nonhematologic toxicities were generally mild and infrequent . Dose - limiting toxicities included grade 4 thrombocytopenia at 6 mg / kg and grade 3 dehydration at 9 mg / kg . Mean trough concentration ( ± standard deviation ) at 9 mg / kg was 106 ± 57 μg / mL , which exceeded the effective trough concentration of 60 μg / mL observed in xenograft models . Three patients with ES had confirmed partial responses : one of 10 at 6 mg / kg and two of 20 at 9 mg / kg . Serum insulin - like growth factor I ( P05019 ) levels consistently increased after one dose of cixutumumab . Tumor P08069 expression by immunohistochemistry did not correlate with response in patients with ES . CONCLUSION : Cixutumumab is well tolerated in children with refractory solid tumors . The recommended phase II dose is 9 mg / kg . Limited single - agent activity of cixutumumab was seen in ES .", "Modulation of the P22301 / IL - 12 cytokine circuit by interferon - beta inhibits the development of epitope spreading and disease progression in murine autoimmune encephalomyelitis . IFN - beta has been shown to be effective in the treatment of multiple sclerosis ( MS ) . However , the primary mechanism by which IFN - beta mediates its therapeutic effect remains unclear . Recent studies indicate that under defined conditions , IFN - beta may downregulate DC expression of IL - 12 . We and others have shown that IFN - beta may also downregulate P22301 . In light of the recently proposed paradigm that an P22301 / IL - 12 immunoregulatory circuit controls susceptibility to autoimmune disease , we examined the effect of IFN - beta on the development and behavior of the autoreactive T cell repertoire during experimental autoimmune encephalomyelitis ( EAE ) , an animal model sharing many features with MS . SWXJ mice were immunized with the immunodominant p139 - 151 determinant of myelin proteolipid protein ( PLP ) , and at onset of EAE were treated every other day with IFN - beta . After eight weeks of treatment , we assessed autoreactivity and observed no significant IFN - beta effect on splenocyte proliferation or splenocyte production of P01579 , P60568 , P05112 , or P05113 in response to the priming determinant used to initiate disease . However , in IFN - beta treated mice , the cytokine profile in response to the priming immunogen was significantly skewed toward an increased production of P22301 and a concurrent decreased production of IL - 12 . Moreover , the in vivo modulation of the P22301 / IL - 12 immunoregulatory circuit in response to the priming immunogen was accompanied by an aborted development of epitope spreading . Our results indicate that IFN - beta induces a reciprocal modulation of the P22301 / IL - 12 cytokine circuit in vivo . This skewed autoreactivity establishes an inflammatory microenvironment that effectively prevents endogenous self - priming thereby inhibiting the progression of disease associated with epitope spreading .", "Decreasing Poly ( ADP - DB01936 ) Polymerase Activity Restores ΔF508 P13569 Trafficking . Most cystic fibrosis is caused by mutations in P13569 that prevent its trafficking from the ER to the plasma membrane and is associated with exaggerated inflammation , altered metabolism , and diminished responses to oxidative stress . P09874 is activated by oxidative stress and causes energy depletion and cell dysfunction . Inhibition of this enzyme protects against excessive inflammation and recent studies have also implicated it in intracellular protein trafficking . We hypothesized that P09874 activity is altered in CF and affects trafficking and function of the most common CF mutant ΔF508 P13569 . Indeed , P09874 activity was 2 . 9 - fold higher in CF ( ΔF508 / ΔF508 ) human bronchial epithelial primary cells than in non - CF cells , and similar results were obtained by comparing CF vs . non - CF bronchial epithelial cell lines ( 2 . 5 - fold higher in CFBE41o (-) vs . 16HBE14o (-) , P < 0 . 002 ) . A P09874 inhibitor ( ABT - 888 , ___MASK67___ ) partially restored P13569 channel activity in CFBE41o (-) cells overexpressing ΔF508 P13569 . Similarly , reducing P09874 activity by 85 % in ileum from transgenic CF mice ( Cftr ( tm1 ) Eur ) partially rescued ΔF508 P13569 activity to 7 % of wild type mouse levels , and similar correction ( 7 . 8 % ) was observed in vivo by measuring salivary secretion . Inhibiting P09874 with ABT - 888 or siRNA partially restored ΔF508 P13569 trafficking in cell lines , and most ΔF508 P13569 was complex glycosylated when heterologously expressed in P09874 (-/-) mouse embryonic fibroblasts . Finally , levels of the mature glycoform of P13569 were reduced by peroxynitrite , a strong activator of P09874 . These results demonstrate that P09874 activity is increased in CF , and identify a novel pathway that could be targeted by proteostatic correctors of P13569 trafficking .", "IL - 12 is a heparin - binding cytokine . Using an ELISA approach , we demonstrate that recombinant human IL - 12 ( rhIL - 12 ) binds strongly to an immobilized heparin - BSA complex . This binding is completely displaceable with soluble heparin , IC50 approximately 0 . 1 microg / ml , corresponding to approximately 10 nM . By interpolation with our previous findings , this indicates an affinity for heparin greater than that of antithrombin III and comparable with that of P09038 , two high - affinity heparin - binding proteins . Recombinant murine IL - 12 also binds strongly to heparin . The binding of rhIL - 12 to heparin shows specificity because chondroitin sulfates A and C fail to compete , whereas chondroitin B inhibits weakly . A highly sulfated heparan sulfate is a strong competitor , whereas other heparan sulfates show weak or no activity . Small heparin fragments inhibit binding , although activity decreases with size . An octasaccharide pool derived by cleavage of heparin with nitrous acid is a significantly stronger inhibitor than its heparinase I - derived counterpart , further indicating structural specificity in the interaction between rhIL - 12 and heparin . The binding of recombinant p40 to heparin appears indistinguishable from that of the IL - 12 heterodimer , implying that the heparin binding site is largely if not solely located in this subunit . These results show for the first time that IL - 12 is a heparin - binding cytokine , a property common to the other Th1 - response - inducing cytokines , P01579 and P60568 . Our findings strongly suggest that IL - 12 will tend to be retained close to its sites of secretion in the tissues by binding to heparin - like glycosaminoglycans , thus favoring a paracrine role for IL - 12 .", "Interferon - gamma enhances superoxide production in human mesangial cells via the JAK - P35610 pathway . Immune reactive cytokines , such as interferon ( IFN ) - gamma , have multiple effects in glomerulonephritis . Superoxide anions ( O ( 2 )(-) ) , which are associated with the progression of glomerulonephritis , are mainly generated by nicotinamide adenine dinucleotide phosphate ( reduced form ) NAD ( P ) H oxidases . We determined the effects of P01579 on O ( 2 )(-) production , phosphorylation of signal transducer and activator of transcription ( P35610 ) - 1alpha , and the mRNA and protein expressions of P13498 and Nox1 , components of NAD ( P ) H oxidases , in human mesangial cells ( HMCs ) . Significant increases in O ( 2 )(-) production with P01579 were completely abolished by the flavin - containing enzyme inhibitor , diphenyleneiodonium ( 10 micromol / l ) , and the Janus - activated kinase ( JAK ) 2 inhibitor , AG490 ( 100 micromol / l ) . Phosphorylated P35610 - 1alpha was detected after 5 min of P01579 stimulation using Western blot analysis , and binding to the gamma - activating site was observed from 30 min to 4 h , thereafter by electrophoretic mobility shift assay ( EMSA ) . Super - shift analysis in EMSA revealed that the main transcription factor was P35610 - 1alpha . P01579 significantly increased the expression of P13498 mRNA and protein , although expression was inhibited by AG490 . These data suggest that P01579 stimulates O ( 2 )(-) production in HMCs via the JAK - P35610 pathway and NAD ( P ) H oxidase .", "Q14954 - positive NK cells mediate alloresponse against the P06681 HLA - P55040 ligand group in vitro . The inhibitory 2DL1 and activating 2DS1 killer Ig - like receptors ( P55040 ) both have shared ligand specificity for codon sequences in the P06681 group HLA - Cw Ags . In this study , we have investigated NK cell activation by allogeneic target cells expressing different combinations of the HLA - P55040 ligand groups C1 , P06681 , and Bw4 . We demonstrate that fresh NK cells as well as P60568 - propagated NK cells from 2DS1 - positive donors that are homozygous for the C1 ligand group are activated in vitro by B lymphoblastoid cell lines expressing the P06681 group . This response is , in part , due to the absence of C1 group recognition mediated by the inhibitory receptor 2DL2 / 3 . This \" missing self \" alloresponse to P06681 , however , is rarely observed in NK cells from donors lacking 2DS1 . Even in presence of 2DS1 , the NK alloresponse is dramatically reduced in donors that have P06681 group as \" self . \" Analysis of selected NK clones that express 2DS1 mRNA and lack mRNA for 2DL1 demonstrates that activation by the P06681 ligand and mAb cross - linking of 2DS1 in these clones induces P01579 . Furthermore , this P06681 group - induced activation is inhibited by Abs to both HLA class I and the receptor . Collectively , these studies demonstrate that NK cells from 2DS1 - positive donors are activated by target cells that express the P06681 group as an alloantigen . This leads to increased P01579 - positive fresh NK cells and induces NK allocytotoxicity in P60568 - propagated polyclonal NK cells and NK clones . This study also provides support for the concept that incompatibility for the HLA - P55040 ligand groups C1 , P06681 , and Bw4 dominates NK alloactivation in vitro .", "Human Q14376 . Accommodation of UDP - N - acetylglucosamine within the active site . Q14376 catalyzes the interconversion of ___MASK9___ and UDP - glucose during normal galactose metabolism . One of the key structural features in the proposed reaction mechanism for the enzyme is the rotation of a 4 '- ketopyranose intermediate within the active site pocket . Recently , the three - dimensional structure of the human enzyme with bound DB00157 and UDP - glucose was determined . Unlike that observed for the protein isolated from Escherichia coli , the human enzyme can also turn over UDP - GlcNAc to UDP - GalNAc and vice versa . Here we describe the three - dimensional structure of human epimerase complexed with DB00157 and UDP - GlcNAc . To accommodate the additional N - acetyl group at the P06681 position of the sugar , the side chain of DB00174 - 207 rotates toward the interior of the protein and interacts with DB00142 - 199 . Strikingly , in the human enzyme , the structural equivalent of DB00135 - 299 in the E . coli protein is replaced with a cysteine residue ( DB00151 - 307 ) and the active site volume for the human protein is calculated to be approximately 15 % larger than that observed for the bacterial epimerase . This combination of a larger active site cavity and amino acid residue replacement most likely accounts for the inability of the E . coli enzyme to interconvert UDP - GlcNAc and UDP - GalNAc .", "Local immunotherapy of glioma patients with a combination of 2 bispecific antibody fragments and resting autologous lymphocytes : evidence for in situ t - cell activation and therapeutic efficacy . After adoptive transfer of pre - activated lymphocytes into the operation cavity of glioma patients , tumor regression and improved survival have been reported in some patients . Results were most impressive when bispecific antibodies with tumor x CD3 specificity were also applied . In this study , we attempted to avoid time - consuming pre - activation procedures for adoptively transferred cells by using a combination of bispecific antibodies directed to the P01133 receptor ( P00533 ) on tumor cells and to CD3 and P10747 on T cells . Eleven patients with high - grade malignant glioma received 3 injections of 2 bispecific antibody fragments ( P00533 x CD3 and P00533 x P10747 ) together with freshly isolated autologous lymphocytes via an Ommaya reservoir . Intracavitary fluid aspirated during immunotherapy was examined for markers of T - cell activation . Increased levels of soluble P60568 receptor and P01375 were detected in the intracavitary fluid of all patients tested . Two of the 11 treated patients experienced a beneficial response to therapy as defined by a transient contrast enhancement in subsequent Q9BWK5 scans and prolonged survival . Side effects were transient and consisted of fever , nausea , headache and aggravation of pre - existing neurologic deficits . These adverse effects were most likely due to the antibody construct containing anti - CD3 specificity . Two patients developed cerebral edema and required steroid treatment .", "Targeted therapies for adrenocortical carcinoma : IGF and beyond . Standard chemotherapy for adrenocortical cancer currently is under evaluation in the context of the recently completed FIRM - ACT evaluating the combination of mitotane with either streptozocin or etoposide , cisplatin , and doxorubicin . New agents are eagerly sought by the ACC community that hopes to make progress against this deadly disease . Investigators have begun to dissect the molecular and genomic context of ACC with a goal of identifying potential novel therapeutic agents . One gene consistently overexpressed in ACC is insulin growth factor type 2 . Targeting its receptor P08069 has shown encouraging results in ACC cell lines and against murine xenografts . As a result , clinical trials to evaluate agents targeting the P08069 have been done including mitotane and ___MASK26___ ( a monoclonal antibody ) and the GALACCTIC trial that has just completed accrual to evaluate OSI - 906 , a small molecule P08069 antagonist . On the horizon are other agents targeting other tyrosine kinases , including P01133 and FGF , and novel strategies such as individualized tumor analysis to select treatment .", "Enhanced killing of cancer cells by poly ( ADP - ribose ) polymerase inhibitors and topoisomerase I inhibitors reflects poisoning of both enzymes . Poly ( ADP - ribose ) polymerase - 1 ( P09874 ) plays critical roles in the regulation of DNA repair . Accordingly , small molecule inhibitors of PARP are being developed as agents that could modulate the activity of genotoxic chemotherapy , such as topoisomerase I poisons . In this study we evaluated the ability of the PARP inhibitor veliparib to enhance the cytotoxicity of the topoisomerase I poisons topotecan and camptothecin ( CPT ) . ___MASK67___ increased the cell cycle and cytotoxic effects of topotecan in multiple cell line models . Importantly , this sensitization occurred at veliparib concentrations far below those required to substantially inhibit poly ( ADP - ribose ) polymer synthesis and at least an order of magnitude lower than those involved in selective killing of homologous recombination - deficient cells . Further studies demonstrated that veliparib enhanced the effects of CPT in wild - type mouse embryonic fibroblasts ( MEFs ) but not Parp1 (-/-) MEFs , confirming that P09874 is the critical target for this sensitization . Importantly , parental and Parp1 (-/-) MEFs had indistinguishable CPT sensitivities , ruling out models in which P09874 catalytic activity plays a role in protecting cells from topoisomerase I poisons . To the contrary , cells were sensitized to CPT in a veliparib - independent manner upon transfection with P09874 E988K , which lacks catalytic activity , or the isolated P09874 DNA binding domain . These results are consistent with a model in which small molecule inhibitors convert P09874 into a protein that potentiates the effects of topoisomerase I poisons by binding to damaged DNA and preventing its normal repair .", "Novel synthesis of various orthogonally protected Cα - methyllysine analogues and biological evaluation of a vapreotide analogue containing ( S ) - α - methyllysine . Prochiral malonic diesters containing a quaternary carbon center have been successfully transformed into a diverse set of ( t ) Boc - Fmoc - α ( 2 , 2 )- methyllysine - OH analogues through chiral malonic half - ester intermediates obtained via enzymatic ( Pig Liver Esterase , PLE ) hydrolysis . The variety of chiral half - ester intermediates , which vary from 1 to 6 methylene units in the side chain , are achieved in moderate to high optical purity and in good yields . The PLE hydrolysis of malonic diesters with various side chain lengths appears to obey the Jones ' s PLE model according to the stereochemical configurations of the resulting chiral half - esters . The established synthetic strategy allows the construction of both enantiomers of α ( 2 , 2 )- methyllysine analogues , and a ( S ) - β ( 2 , 2 )- methyllysine analogue from a common synthon by straightforward manipulation of protecting groups . Two different straightforward and cost effective synthetic strategies are described for the synthesis of α ( 2 , 2 )- methyllysine analogues . The described strategies should find significant usefulness in preparing novel peptide libraries with unnatural lysine analogues . A ___MASK48___ analogue incorporating ( S ) - α ( 2 , 2 )- methyllysine was prepared . However , the ___MASK48___ analogue with ( S ) - α - methyl - α - lysine is found to lose its specific binding to somatostatin receptor subtype 2 ( P30874 ) .", "P01375 alpha mediates GABA ( A ) receptor trafficking to the plasma membrane of spinal cord neurons in vivo . The proinflammatory cytokine TNFα contributes to cell death in central nervous system ( CNS ) disorders by altering synaptic neurotransmission . TNFα contributes to excitotoxicity by increasing P42262 - lacking AMPA receptor ( AMPAR ) trafficking to the neuronal plasma membrane . In vitro , increased AMPAR on the neuronal surface after TNFα exposure is associated with a rapid internalization of GABA ( A ) receptors ( GABA ( A ) Rs ) , suggesting complex timing and dose dependency of the CNS ' s response to TNFα . However , the effect of TNFα on GABA ( A ) R trafficking in vivo remains unclear . We assessed the effect of TNFα nanoinjection on rapid GABA ( A ) R changes in rats ( N = 30 ) using subcellular fractionation , quantitative western blotting , and confocal microscopy . GABA ( A ) R protein levels in membrane fractions of TNFα and vehicle - treated subjects were not significantly different by Western Blot , yet high - resolution quantitative confocal imaging revealed that TNFα induces GABA ( A ) R trafficking to synapses in a dose - dependent manner by 60 min . TNFα - mediated GABA ( A ) R trafficking represents a novel target for CNS excitotoxicity .", "DB00134 recycling pathways and antimalarial drug design . 5 '- Deoxy - 5 '-( methylthio ) adenosine ( MTA ) is an S - adenosylmethionine metabolite that is generated as a by - product of polyamine biosynthesis . In mammalian cells , MTA undergoes a phosphorolytic cleavage catalyzed by Q13126 to produce adenine and 5 - deoxy - 5 -( methylthio ) ribose - 1 - phosphate ( Q15012 ) . ___MASK16___ is utilized in purine salvage pathways , and Q15012 is subsequently recycled to methionine . Whereas some microorganisms metabolize MTA to Q15012 via Q13126 , others metabolize MTA to Q15012 in two steps via initial cleavage by MTA nucleosidase to adenine and 5 - deoxy - 5 -( methylthio ) ribose ( Q99707 ) followed by conversion of Q99707 to Q15012 by Q99707 kinase . In order to assess the extent to which these pathways may be operative in Plasmodium falciparum , we have examined a series of 5 '- alkyl - substituted analogs of MTA and the related Q99707 analogs and compared their abilities to inhibit in vitro growth of this malarial parasite . The Q99707 analogs 5 - deoxy - 5 -( ethylthio ) ribose and 5 - deoxy - 5 -( hydroxyethylthio ) ribose were inactive at concentrations up to 1 mM , and 5 - deoxy - 5 -( monofluoroethylthio ) ribose was weakly active ( 50 % inhibitory concentration = 700 microM ) . In comparison , the MTA analogs , 5 '- deoxy - 5 '-( ethylthio ) adenosine , 5 '- deoxy - 5 '-( hydroxyethylthio ) ade nosine ( HETA ) , and 5 '- deoxy - 5 '-( monofluoroethylthio ) adenosine , had 50 % inhibitory concentrations of 80 , 46 , and 61 microM , respectively . Extracts of P . falciparum were found to have substantial Q13126 activity . Coadministration of MTA with HETA partially protected the parasites against the growth - inhibitory effects of HETA . Results of this study indicate that P . falciparum has an active Q13126 that can be targeted by analogs of MTA .", "Intracellular targets of cyclin - dependent kinase inhibitors : identification by affinity chromatography using immobilised inhibitors . BACKGROUND : Chemical inhibitors of cyclin - dependent kinases ( CDKs ) have great therapeutic potential against various proliferative and neurodegenerative disorders . ___MASK99___ , a 2 , 6 , 9 - trisubstituted purine , has been optimized for activity against P06493 / cyclin B by combinatorial and medicinal chemistry efforts to yield the purvalanol inhibitors . Although many studies support the action of purvalanols against CDKs , the actual intracellular targets of 2 , 6 , 9 - trisubstituted purines remain unverified . RESULTS : To address this issue , purvalanol B ( 95 . ) and an N6 - methylated , CDK - inactive derivative ( 95M . ) were immobilized on an agarose matrix . Extracts from a diverse collection of cell types and organisms were screened for proteins binding purvalanol B . In addition to validating CDKs as intracellular targets , a variety of unexpected protein kinases were recovered from the 95 . matrix . Casein kinase 1 ( CK1 ) was identified as a principal 95 . matrix binding protein in Plasmodium falciparum , Leishmania mexicana , Toxoplasma gondii and Trypanosoma cruzi . DB02733 compounds also inhibit the proliferation of these parasites , suggesting that CK1 is a valuable target for further screening with 2 , 6 , 9 - trisubstituted purine libraries . CONCLUSIONS : That a simple batchwise affinity chromatography approach using two purine derivatives facilitated isolation of a small set of highly purified kinases suggests that this could be a general method for identifying intracellular targets relevant to a particular class of ligands . This method allows a close correlation to be established between the pattern of proteins bound to a small family of related compounds and the pattern of cellular responses to these compounds ." ]
[ "___MASK16___", "___MASK26___", "___MASK37___", "___MASK41___", "___MASK48___", "___MASK67___", "___MASK76___", "___MASK99___", "___MASK9___" ]
___MASK41___
MH_train_1602
interacts_with DB06684?
[ "P09917 pathway promotes cell proliferation in human glioma cell lines . OBJECTIVE : P09917 ( P09917 ) is a key enzyme in the synthesis of leukotrienes ( LTs ) , that might promote carcinogenesis . We investigated P09917 expression and examined whether the P09917 pathway is associated with the proliferation of human brain tumors . METHODS : We immunohistochemically evaluated the profile of P09917 expression in various types of brain tumors obtained from 42 patients , and examined the proliferative effects of the P09917 pathway in human glioma cell lines using a proliferation assay . RESULTS : Immunohistochemistry of glioblastomas , astrocytomas , meningiomas , medulloblastomas , craniopharyngiomas , ependymomas , neurinomas , oligodendrogliomas , malignant lymphomas , dysembryoplastic neuroepithelial and metastatic brain tumors revealed P09917 expression in the cytoplasm and nuclei or nuclear envelopes of tumor cells . The P09917 inhibitor A861 and the P09960 hydrolase inhibitor ___MASK57___ dose - dependently suppressed the proliferation of A172 cells , a glioma cell line . CONCLUSIONS : We confirmed the expression of P09917 in various human brain tumors and demonstrated the partial suppression of tumor growth by inhibitors of the P09917 - P09960 hydrolase pathway in human glioma cell lines . The P09917 - P09960 pathway might play roles in the proliferation of human glioma cells .", "___MASK64___ sodium , prostacyclin analogue , attenuates glomerular hyperfiltration and glomerular macrophage infiltration by modulating ecNOS expression in diabetic rats . Stable prostacyclin analogue , beraprost sodium ( BPS ) has recently been reported to attenuate glomerular hyperfiltration in diabetic rats , however , the mechanism has been still unknown . We previously reported that overexpression of endothelial cell nitric oxide synthase ( ecNOS ) in afferent arterioles and glomeruli induce inappropriate dilatation of afferent arterioles and glomerular hyperfiltration through overproduction of nitric oxide in early stage of diabetic nephropathy . In this study , we tested the hypothesis that BPS ameliorates glomerular hyperfiltration through modulating ecNOS expression in diabetic nephropathy . Furthermore , we examined the effects of BPS on the expression of intercellular adhesion molecule - 1 ( P05362 ) and macrophage infiltration in diabetic glomeruli , because glomerular hyperfiltration induces the expression of P05362 resulting in macrophage infiltration . Male Sprague - Dawley ( SD ) rats were administered continuously with BPS for 4 weeks after induction of diabetes by streptozotocin . In diabetic rats , the diameters of afferent arterioles , glomerular volume , creatinine clearance and urinary excretion of albumin and NO2 / NO3 were increased as compared with non - diabetic control rats . Treatment with BPS improved these changes . The expression of ecNOS was increased in afferent arterioles and glomeruli in diabetic rats and suppressed by BPS . P43119 was expressed along afferent arterioles . Our results suggest that BPS attenuates glomerular hyperfiltration by modulating ecNOS expression in early stage of diabetic nephropathy . Moreover , BPS may inhibit P05362 - dependent infiltration of macrophages in diabetic glomeruli .", "___MASK52___ - mediated transductive systems and functionally active gap junctions in astrocyte - like GL15 cells . BACKGROUND : It has been proposed that GL15 , a human cell line derived from glioblastoma multiforme , is a possible astroglial - like cell model , based on the presence of cytoplasmic glial fibrillary acidic protein . RESULTS : The aim of this work was to delineate the functional characteristics of GL15 cells using various experimental approaches , including the study of morphology , mechanism of induction of intracellular Ca2 + increase by different physiological agonists , and the presence and permeability of the gap - junction system during cell differentiation . Immunostaining experiments showed the presence and localization of specific glial markers , such as glial fibrillary acidic protein and P04271 , and the lack of the neuronal marker P23297 . Notably , all the Ca2 + pathways present in astrocytes were detected in GL15 cells . In particular , oscillations in intracellular Ca2 + levels were recorded either spontaneously , or in the presence of DB00171 or glutamate ( but not DB00761 ) . Immunolabelling assays and confocal microscopy , substantiated by Western blot analyses , revealed the presence of connexin43 , a subunit of astrocyte gap - junction channels . The protein is organised in characteristic spots on the plasma membrane at cell - cell contact regions , and its presence and distribution depends on the differentiative status of the cell . Finally , a microinjection / dye - transfer assay , employed to determine gap - junction functionality , clearly demonstrated that the cells were functionally coupled , albeit to varying degrees , in differentiated and undifferentiated phenotypes . CONCLUSIONS : In conclusion , results from this study support the use of the GL15 cell line as a suitable in vitro astrocyte model , which provides a valuable guide for studying glial physiological features at various differentiation phases .", "___MASK84___ : the newest P43220 agonist for the management of type 2 diabetes . OBJECTIVE : To review the pharmacology , pharmacokinetics , safety , and efficacy of the glucagon - like peptide - 1 receptor agonist ( P0C6A0 RA ) , dulaglutide , in the treatment of type 2 diabetes mellitus ( T2D ) . DATA SOURCES : A PubMed search was completed to identify publications from 1947 to October 2014 using the search terms dulaglutide and LY2189265 . References were reviewed to identify additional resources . STUDY SELECTION AND DATA EXTRACTION : Articles were included if they evaluated the pharmacology , pharmacokinetics , safety , or efficacy of dulaglutide . DATA SYNTHESIS : ___MASK84___ reduces both glycosylated hemoglobin ( A1C ) and weight by stimulating insulin secretion and suppressing glucagon in a glucose - dependent manner , delaying gastric emptying , and promoting satiety . ___MASK84___ consists of 2 P0C6A0 analogues that have been modified to make it a long - acting , once - weekly agent . ___MASK84___ has been studied as monotherapy and in combination with metformin , glimepiride , pioglitazone , and insulin lispro . It has demonstrated superior A1C reduction compared with placebo , metformin , insulin glargine , sitagliptin , and twice - daily exenatide . It demonstrated noninferiority in A1C reduction to liraglutide . ___MASK84___ changed A1C by - 0 . 78 % to - 1 . 51 % , and it changed weight by - 0 . 35 kg to - 3 . 03 kg . The most common adverse effects in clinical studies were nausea , vomiting , and diarrhea . CONCLUSIONS : ___MASK84___ is the fifth P0C6A0 RA approved for T2D in the United States . It is an attractive option because it is dosed once - weekly , provides A1C lowering similar to liraglutide , weight reduction similar to exenatide , and has an adverse effect profile similar to exenatide and liraglutide .", "Leukotriene A4 hydrolase . Inhibition by bestatin and intrinsic aminopeptidase activity establish its functional resemblance to metallohydrolase enzymes . ___MASK57___ , an inhibitor of aminopeptidases , was also a potent inhibitor of leukotriene ( LT ) A4 hydrolase . On isolated enzyme its effects were immediate and reversible with a Ki = 201 +/- 95 mM . With erythrocytes it inhibited LTB4 formation greater than 90 % within 10 min ; with neutrophils it inhibited LTB4 formation by only 10 % during the same period , increasing to 40 % in 2 h . ___MASK57___ inhibited P09960 hydrolase selectively ; neither P09917 nor 15 - lipoxygenase activity in neutrophil lysates was affected . Purified P09960 hydrolase exhibited an intrinsic aminopeptidase activity , hydrolyzing L - lysine - p - nitroanilide and L - leucine - beta - naphthylamide with apparent Km = 156 microM and 70 microM and Vmax = 50 and 215 nmol / min / mg , respectively . Both P09960 and bestatin suppressed the intrinsic aminopeptidase activity of P09960 hydrolase with apparent Ki values of 5 . 3 microM and 172 nM , respectively . Other metallohydrolase inhibitors tested did not reduce P09960 hydrolase / aminopeptidase activity , with one exception ; captopril , an inhibitor of angiotensin - converting enzyme , was as effective as bestatin . The results demonstrate a functional resemblance between P09960 hydrolase and certain metallohydrolases , consistent with a molecular resemblance at their putative Zn2 (+)- binding sites . The availability of a reversible , chemically stable inhibitor of P09960 hydrolase may facilitate investigations on the role of LTB4 in inflammation , particularly the process termed transcellular biosynthesis .", "The contribution of serotonin P28335 and melanocortin - 4 receptors to the satiety signaling of glucagon - like peptide 1 and liraglutide , a glucagon - like peptide 1 receptor agonist , in mice . Glucagon - like peptide 1 ( P0C6A0 ) , an insulinotropic gastrointestinal peptide produced mainly from intestinal endocrine L - cells , and liraglutide , a P43220 ( P43220 ) agonist , induce satiety . The serotonin P28335 receptor ( 5 - HT2CR ) and melanoroctin - 4 receptor ( P32245 ) are involved in the regulation of food intake . Here we show that systemic administration of P0C6A0 ( 50 and 200μg / kg ) - induced anorexia was blunted in mice with a 5HT2CR null mutation , and was attenuated in mice with a heterozygous P32245 mutation . On the other hand , systemic administration of liraglutide ( 50 and 100μg / kg ) suppressed food intake in mice lacking 5 - HT2CR , mice with a heterozygous mutation of P32245 and wild - type mice matched for age . Moreover , once - daily consecutive intraperitoneal administration of liraglutide ( 100μg / kg ) over 3days significantly suppressed daily food intake and body weight in mice with a heterozygous mutation of P32245 as well as wild - type mice . These findings suggest that P0C6A0 and liraglutide induce anorexia via different central pathways .", "P08908 receptor - mediated regulation of mitogen - activated protein kinase phosphorylation in rat brain . Mitogen - activated protein kinases ( MAPKs ) , a family of signal transduction mediators important in a host of cellular activities , include the extracellular signal - regulated kinases Erk1 and Erk2 . We determined whether 5 - HT ( 1A ) receptors activate Erk1 / 2 in rat brain in vivo , as they do in recombinant cell lines . In contrast to the effect in cells , the 5 - HT ( 1A ) receptor agonist 8 - hydroxy - N , N - diproylaminotetralin ( 8 - OH - DPAT ) dose - and time - dependently decreased basal levels of phosphorylated Erk1 / 2 ( phospho - Erk1 / 2 ) in rat hippocampus ( ED ( 50 ) approximately 0 . 1 mg / kg , maximum approximately 90 % ) without altering total Erk1 / 2 . The effects were kinase - specific , as 8 - OH - DPAT did not modify phosphorylated or total levels of the MAPKs c - Jun - N - terminal kinase / stress - activated protein kinase ( JNK / SAPK ) and p38 MAPK . Moreover , 8 - OH - DPAT did not modify phospho - Erk1 / 2 in striatum or frontal cortex . The effect of 8 - OH - DPAT was blocked by pretreatment with the selective 5 - HT ( 1A ) receptor antagonists N -[ 2 -[ 4 -( 2 - methoxyphenyl )- 1 - piperazinyl ] ethyl ]- N - 2 - pyridinylcyclohexanecarboxamide ( WAY 100635 ) , 1 -( 2 - methoxyphenyl )- 4 -( 4 -[ 2 - phthalimido ] butyl ) piperazine ( NAN - 190 ) and 4 - fluoro - N -( 2 -[ 4 -( 2 - methoxyphenyl ) 1 - piperazinyl ] ethyl )- N -( 2 - pyridinyl ) benzamide dihydrochloride ( p - MPPF ) , but not by the weak partial agonist / antagonist 8 -( 2 -[ 4 -( 2 - methoxyphenyl )- 1 - piperazinyl ] ethyl )- 8 - azaspiro ( 4 . 5 ) decane - 7 , 9 - dione dihydrochloride ( BMY 7378 ) . Other 5 - HT ( 1A ) receptor agonists ( buspirone , gepirone and ipsapirone ) also reduced phospho - Erk1 / 2 levels in hippocampus . 8 - OH - DPAT also reduced the levels of the upstream activator of Erk1 / 2 , phosphorylated extracellular signal - regulated kinase kinase ( phospho - Q02750 / 2 ) , and at least one potential downstream target , the nuclear transcription factor phospho - Elk - 1 . The region - and kinase - specific effects suggest that the Erk1 / 2 signal transduction cascade is likely an important differential mediator of 5 - HT ( 1A ) receptor - regulated events in the central nervous system .", "Novel combination treatments targeting chronic myeloid leukemia stem cells . Chronic myeloid leukemia ( CML ) is currently considered incurable in most patients . Stem cell transplantation , an accepted curative option for which extensive experience has been gained , is limited by high morbidity and mortality rates , particularly in older patients . Tyrosine kinase inhibitors targeting P11274 - P00519 are widely used and induce remission in a high proportion of patients , but resistance and incomplete response to these agents portends eventual relapse and disease progression . Although P11274 - P00519 inhibitors eradicate most CML cells , they are largely ineffective against the reservoir of quiescent leukemic stem cells ( LSCs ) . Thus a strong medical need exists for therapies that effectively eradicate LSCs and is currently a focus of extensive research . To date , evidence obtained from in vitro studies , animal models , and clinical CML specimens suggests that an effective approach may be to partner existing P11274 - P00519 inhibitors with compounds targeting key stem cell molecular effectors , including Wnt / β - catenin , hedgehog pathway components , histone deacetylase ( HDAC ) , transforming growth factor - β ( TGF - β ) , O60674 , promyelocytic leukemia protein , and arachidonate P09917 ( P09917 ) . Novel combinations may sensitize LSCs to P11274 - P00519 inhibitors , thereby overcoming resistance and creating the possibility of improving disease outcome beyond the current standard of care .", "Inhibition of noradrenaline release via presynaptic P28222 receptors of the rat vena cava . In the rat inferior vena cava preincubated with 3H - noradrenaline , the effects of nine serotonin ( 5 - HT ) receptor agonists and of eight antagonists ( including two beta - adrenoceptor blocking agents ) on the electrically evoked 3H overflow were determined . 1 . 5 - HT , 5 - carboxamido - tryptamine , 5 - methoxy - 3 ( 1 , 2 , 3 , 6 - tetrahydropyridine - 4 - yl )- 1H - indole ( RU 24969 ) , 5 - methoxytryptamine , N , N - dimethyl - 5HT , tryptamine and 5 - aminotryptamine inhibited the evoked 3H overflow . The potencies of these agonists in inhibiting overflow were significantly correlated with their affinities for P28222 binding sites , but not with their affinities for P08908 , P28335 or 5 - HT2 binding sites . 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) , a P08908 receptor agonist , and ipsapirone , a partial agonist at these receptors , did not inhibit overflow . 2 . Cyanopindolol facilitated the evoked 3H overflow , an effect which was abolished by propranolol . The maximum inhibition of overflow obtainable with 5 - HT was diminished by cyanopindolol . 3 . The concentration - response curve for 5 - HT was shifted to the right by metitepine , metergoline , quipazine , 6 - chloro - 2 -( 1 - piperazinyl ) pyrazine ( MK 212 ) and propranolol which , given alone , did not affect 3H overflow . The apparent pA2 values of these antagonists tended to be correlated with their affinities for P28222 ( but not P08908 , P28335 or 5 - HT2 ) binding sites . Ketanserin , a 5 - HT2 receptor antagonist , and spiperone , which blocks 5 - HT2 and P08908 but not P28222 or P28335 receptors , failed to antagonize the effect of 5 - HT . ( ABSTRACT TRUNCATED AT 250 WORDS )", "___MASK51___ sensitivity and desensitization for asthma and sinusitis . NSAIDs - including aspirin ( ASA ) - that inhibit cyclooxygenase ( P36551 ) - 1 induce nonallergic hypersensitivity reactions consisting of attacks of rhinitis and asthma . Such reactions occur exclusively in a subset of asthmatic patients who also have underlying nasal polyps and chronic hyperplastic eosinophilic sinusitis . We now refer to their underlying inflammatory disease of the entire respiratory tract as aspirin - exacerbated respiratory disease . This review focuses on descriptions of these patients ; methods available to diagnose ASA - exacerbated respiratory disease ; the unique ability of all NSAIDs that inhibit P23219 to cross - react with ASA ; lack of cross - reactivity with selective P35354 inhibitors ; an update on pathogenesis ; and current thoughts about treatment , including ASA desensitization and daily ingestion of ASA itself .", "Determination of cobimetinib in human plasma using protein precipitation extraction and high - performance liquid chromatography coupled to mass spectrometry . Inhibition of Q96HU1 / P29323 kinase ( MEK ) is a promising strategy to control the growth of tumors that are dependent on aberrant signaling in the MEK pathway . ___MASK60___ ( P16260 - 0973 ) ( S ) -[ 3 , 4 - Difluoro - 2 -( 2 - fluoro - 4 - iodo - phenylamino )- phenyl ]- ( ( S ) - 3 - hydroxy - 3 - piperidin - 2 - yl - azetidin - 1 - yl ) - methanone ) inhibits proliferation of a variety of human tumor cell lines by inhibiting Q02750 and P36507 . A specific high performance liquid chromatography - mass spectrometric assay was developed and validated for the determination of cobimetinib in human plasma . The overall mean recovery using protein precipitation extraction with acetonitrile was found to be 54 . 1 % . The calibration curve was ranged from 0 . 20 to 100ng / mL . The LLOQ was sensitive enough to detect terminal phase concentrations of the drug . The intra - and inter - assay precision ( % CV ) was within 10 . 3 % and 9 . 5 % for cobimetinib . The assay accuracy ( % RE ) was within ± 13 . 7 % of the nominal concentration values for cobimetinib with the normal analytical QCs . The developed assay was successfully used to analyze the human plasma samples ( for pharmacokinetic analysis ) from clinical trials .", "In vivo activity of ___MASK53___ , a multi - target kinase inhibitor , against acute myeloid leukemia with wild - type P36888 receptor . Neoangiogenesis plays an important role in leukemogenesis . We investigated the in vivo anti - leukemic effect of ___MASK53___ against AML with wild - type P36888 using RFP transfected HL60 cells with in vivo imaging technology on both the subcutaneous and systemic leukemia xenograft models . ___MASK53___ showed a five - fold inhibition of tumor growth in comparison with vehicle control . IHC analysis revealed that ___MASK53___ decreased p - P17948 , Ki - 67 labeling index , P15692 and remarkably increased apoptotic cells in the xenograft models . ___MASK53___ also reduced the leukemia burden and prolonged survival . Our study supports the rationale for clinically testing an anti - angiogenesis agent in AML with wild - type P36888 .", "Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5 - HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression / antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 - Flk - 1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells .", "[ Autoimmune aspects of treatment with P01375 inhibitors ] . P01375 - alpha ( P01375 ) plays an important role in the pathogenesis of such diseases as rheumatoid arthritis , Crohn ' s disease , ankylosing spondylitis , psoriatic arthritis , and juvenile chronic arthritis . Recent years have brought improvement in the understanding of the pathogeneses of these diseases , resulting in the production of new groups of biological drugs , including , among others , anti - P01375 antibodies . The use of P01375 inhibitors has been a great advance in the treatment of patients with these inflammatory diseases . DB00065 and adalimumab are monoclonal antibodies that bind to and neutralize the activity of P01375 . DB00065 is a mouse / human chimera that joins the variable regions of a mouse antibody to the constant region of human IgG1 . ___MASK12___ is a fully human IgG1 antibody . DB00005 is a dimeric fusion protein that joins the human p75 P01375 receptor to the Fc domain of human IgG1 . The beneficial effects of the anti - P01375 monoclonal antibodies infliximab and adalimumab and the soluble receptor fusion protein etanercept in the treatment of rheumatoid arthritis , especially in patients resistant to other disease - modifying antirheumatic drugs ( DMARDs ) , are discussed . We observe stoppage of articular destruction during treatment with P01375 inhibitors . Soon after the introduction of this therapy it was found that these agents have a propensity for stimulating the production of autoantibodies and antibodies against themselves . In this review , recent studies analyzing the effect of P01375 blockade ( infliximab , etanercept , and adalimumab ) on the Q14201 , anti - dsDNA , and anticardiolipin antibody profiles in autoimmune diseases are discussed .", "Activation of 5 - Q13049 / C receptors counteracts P08908 regulation of n - methyl - D - aspartate receptor channels in pyramidal neurons of prefrontal cortex . Abnormal serotonin - glutamate interaction in prefrontal cortex ( P27918 ) is implicated in the pathophysiology of many mental disorders , including schizophrenia and depression . However , the mechanisms by which this interaction occurs remain unclear . Our previous study has shown that activation of 5 - HT ( 1A ) receptors inhibits N - methyl - D - aspartate ( DB01221 ) receptor ( NMDAR ) currents in P27918 pyramidal neurons by disrupting microtubule - based transport of NMDARs . Here we found that activation of 5 - HT ( 2A / C ) receptors significantly attenuated the effect of 5 - HT ( 1A ) on NMDAR currents and microtubule depolymerization . The counteractive effect of 5 - HT ( 2A / C ) on 5 - HT ( 1A ) regulation of synaptic NMDAR response was also observed in P27918 pyramidal neurons from intact animals treated with various 5 - HT - related drugs . Moreover , 5 - HT ( 2A / C ) stimulation triggered the activation of extracellular signal - regulated kinase ( P29323 ) in dendritic processes . Inhibition of the beta - arrestin / Src / dynamin signaling blocked 5 - HT ( 2A / C ) activation of P29323 and the counteractive effect of 5 - HT ( 2A / C ) on 5 - HT ( 1A ) regulation of NMDAR currents . Immunocytochemical studies showed that 5 - HT ( 2A / C ) treatment blocked the inhibitory effect of 5 - HT ( 1A ) on surface Q13224 clusters on dendrites , which was prevented by cellular knockdown of beta - arrestins . Taken together , our study suggests that serotonin , via 5 - HT ( 1A ) and 5 - HT ( 2A / C ) receptor activation , regulates NMDAR functions in P27918 neurons in a counteractive manner . 5 - HT ( 2A / C ) , by activating P29323 via the beta - arrestin - dependent pathway , opposes the 5 - HT ( 1A ) disruption of microtubule stability and NMDAR transport . These findings provide a framework for understanding the complex interactions between serotonin and NMDARs in P27918 , which could be important for cognitive and emotional control in which both systems are highly involved .", "[ ³H ] ___MASK73___ binding in post - mortem brains of Cloninger type 1 and 2 alcoholics : a whole - hemisphere autoradiography study . The glutamate N - methyl - d - aspartate ( DB01221 ) receptor Q13224 subunits are sensitive to ethanol and are found in brain areas related to ethanol addiction , dependence , development of alcohol tolerance , and alcohol withdrawal syndrome . Previous studies indicate that early - onset Cloninger type 2 alcoholics have an intact , responsive , dopaminergic system in the nucleus accumbens ( Q9C000 ) , whereas type 1 alcoholics have dopaminergic defects . Q13224 - containing DB01221 receptors in the Q9C000 are involved in both non - opioid and opioid receptor - mediated reward . Our aim was to evaluate the putative [( 3 ) H ] ifenprodil binding alterations of Q13224 receptors in limbic , hippocampal , and cortical brain areas of type 1 alcoholics ( n = 8 ) , type 2 alcoholics ( n = 8 ) , and control subjects ( n = 10 ) by postmortem whole hemisphere autoradiography . We found significantly different binding levels among these three subject groups , and the main difference was localized in the decreased binding in type 2 alcoholics and controls in the nucleus accumbens . Although preliminary and from relatively small diagnostic groups , these results suggest pathological alterations in the Q13224 - mediated reward system of type 2 alcoholics .", "Stimulation of cloned human serotonin P28221 beta receptor sites in stably transfected P13671 glial cells promotes cell growth . The involvement of serotonin P28221 beta receptor sites was investigated in the growth of rat P13671 glial cells permanently transfected with a gene encoding a human P28221 beta receptor . The 5 - HT receptor identity of control and transfected P13671 glial / P28221 beta cells was determined by reverse transcription - polymerase chain reaction using primers specific for rat P08908 , rat P28222 , rat P28221 alpha , human P28221 beta , and rat 5 - Q13049 receptor genes . Constitutive mRNA for 5 - Q13049 receptors was present in control and transfected P13671 glial / P28221 beta cells , whereas mRNA for P28221 beta receptor sites was only present in the transfected P13671 glial / P28221 beta cell line . 5 - HT inhibited forskolin - stimulated cyclic AMP formation and promoted cell growth , in contrast to the absence of any measurable effect in pcDNA3 plasmid - transfected and nontransfected P13671 glial cells . The 5 - HT effects could be mimicked by sumatriptan ( EC50 = 44 - 76 nM ) and were totally and partially blocked by methiothepin ( IC50 = 9 nM ) and GR 127 , 935 ( 2 '- methyl - 4 '-( 5 - methyl [ 1 , 2 , 4 ] oxadiazol - 3 - yl )- biphenyl - 4 - carbox yli c acid [ 4 - methoxy - 3 -( 4 - methylpiperazin - 1 - yl ) phenyl ] amide ; IC50 = 97 pM ) , respectively . No effect on cell growth was measured with the 5 - HT2 receptor agonist DOI [ 1 -( 2 , 5 - dimethoxy - 4 - iodophenyl )- 2 - aminopropane ; 10 microM ] , suggesting that 5 - Q13049 receptors are not involved in the 5 - HT - stimulated P13671 glial / P28221 beta cell growth . Dibutyryl - cyclic AMP ( 0 . 3 mM ) - treated cultures did not show sumatriptan - promoted cell growth , indicating an inhibitory role for cyclic AMP in the cell growth mediated by P28221 beta receptor sites . ( ABSTRACT TRUNCATED AT 250 WORDS )", "P43119 - induced P40763 phosphorylation in human erythroleukemia cells is mediated via Galpha ( s ) and Galpha ( 16 ) hybrid signaling . Human prostacyclin receptor ( hIP ) stimulates P40763 via pertussis toxin - insensitive G proteins in human erythroleukemia ( HEL ) cells . Since hIP can utilize G ( s ) and G ( q ) proteins for signal transduction and that both G proteins can induce P40763 phosphorylation and activation via complex signaling networks , we sought to determine if one of them is predominant in mediating the hIP signal . Stimulation of P40763 DB00135 ( 705 ) and DB00133 ( 727 ) phosphorylations by the IP - specific agonist , cicaprost , was sensitive to inhibition of protein kinase A , phospholipase Cbeta , protein kinase C , calmodulin - dependent protein kinase II and O60674 / 3 . Unlike Galpha ( 16 )- mediated regulation of P40763 in the same cells , cicaprost - induced P40763 DB00135 ( 705 ) phosphorylation was resistant to inhibition of Src and MEK while P40763 DB00133 ( 727 ) phosphorylation distinctly required phosphatidylinositol - 3 kinase . This unique inhibitor - sensitivity pattern of P40763 phosphorylation was reproduced in HEL cells by stimulating the G ( 16 )- coupled C5a receptor in the presence of dibutyryl - DB02527 , suggesting that the change in inhibitor - sensitivity was due to activation of the G ( s ) pathway . This postulation was confirmed by expressing constitutively active Galpha ( 16 ) QL and Galpha ( s ) QL in human embryonic kidney 293 cells and the inhibitor - sensitivity of Galpha ( 16 ) QL - induced P40763 phosphorylations could be converted by the mere presence of Galpha ( s ) QL to resemble that obtained with cicaprost in HEL cells . In addition , the restoration of the Galpha ( 16 )- mediated inhibitor - sensitivity upon cicaprost induction in Galpha ( s )- knocked down HEL cells again verified the pivotal role of G ( s ) signal . Taken together , our observations illustrate that co - stimulation of G ( s ) and G ( q ) can result in the fine - tuning of P40763 activation status , and this may provide the basis for cell type - specific responses following activation of hIP .", "P31431 regulates subcellular localization of P42345 Complex2 and Akt activation in a PKCalpha - dependent manner in endothelial cells . P42345 ( P42345 ) activity is regulated by assembly of two functionally distinct complexes , mTORC1 and mTORC2 . In syndecan - 4 ( S4 ) null endothelial cells , mTORC2 activity is reduced , resulting in decreased Akt activation , while mTORC1 activity is increased . Levels of rictor , Q9BVC4 , and mSin - 1 are unchanged in total cell lysates but decreased in the rafts of S4 (-/-) endothelial cells , as is the level of PKCalpha . Expression of myristoylated - PKCalpha in S4 (-/-) cells restores rictor , Q9BVC4 , and mSin - 1 presence in the rafts and rescues Akt phosphorylation . PKCalpha knockdown mimics the effect of S4 deletion on mTORC2 localization and Akt activation . Reduced mTORC2 activity in S4 (-/-) endothelial cells results in decreased FoxO1 / 3a and P29474 phosphorylation , decreased endothelial cell size , and increased arterial blood pressure in S4 (-/-) mice . Thus , S4 - dependent targeting of PKCalpha to the plasma membrane is required for recruitment of mTORC2 components to the rafts and Akt activation .", "Targeting PIM kinases impairs survival of hematopoietic cells transformed by kinase inhibitor - sensitive and kinase inhibitor - resistant forms of P36888 and P11274 / P00519 . Previous studies have shown that activation of the signal transducer and activator of transcription 5 ( P42229 ) plays an essential role in leukemogenesis mediated through constitutive activated protein tyrosine kinases ( PTK ) . Because PIM - 1 is a P42229 target gene , we analyzed the role of the family of PIM serine / threonine kinases ( PIM - 1 to PIM - 3 ) in PTK - mediated transformation of hematopoietic cells . Ba / P13726 cells transformed to growth factor independence by various oncogenic PTKs ( P41212 / O60674 , P41212 / Q16288 , P41212 / P00519 , P11274 / P00519 , P36888 - ITD , and H4 / PDGFbetaR ) show abundant expression of PIM - 1 and PIM - 2 . Suppression of PIM - 1 activity had a negligible effect on transformation . In contrast , expression of kinase - dead PIM - 2 mutant ( PIM - 2KD ) led to a rapid decline of survival in Ba / P13726 cells transformed by P36888 - ITD but not by other oncogenic PTKs tested . Coexpression of PIM - 1KD and PIM - 2KD abrogated growth factor - independent growth of Ba / P13726 transformed by several PTKs , including P11274 / P00519 . Targeted down - regulation of PIM - 2 by RNA interference ( RNAi ) selectively abrogated survival of Ba / P13726 cells transformed by various P36888 ( P36888 ) - activating mutants [ internal tandem duplication ( ITD ) and kinase domain ] and attenuated growth of human cell lines containing P36888 mutations . Interestingly , cells transformed by P36888 and P11274 / P00519 mutations that confer resistance to small - molecule tyrosine kinase inhibitors were still sensitive to knockdown of PIM - 2 , or PIM - 1 and PIM - 2 by RNAi . Our observations indicate that combined inactivation of PIM - 1 and PIM - 2 interferes with oncogenic PTKs and suggest that PIMs are alternative therapeutic targets in PTK - mediated leukemia . Targeting the PIM kinase family could provide a new avenue to overcome resistance against small - molecule tyrosine kinase inhibitors .", "Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8 - OH - DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p - chlorophenylalanine ( p - P15085 , 300 mg / kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0 . 5 mg / kg ) or 8 - OH - DPAT ( 0 . 5 mg / kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5 , 7 - dihydroxytryptamine ( 5 , 7 - DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0 . 5 mg / kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5 , 7 - DB02901 treated rats . In lesioned animals 8 - OH - DPAT ( 0 . 5 mg / kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8 - OH - DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour .", "Absolute bioavailability and effect of formulation change , food , or elevated pH with rabeprazole on cobimetinib absorption in healthy subjects . ___MASK60___ is a potent and highly selective inhibitor of Q02750 / 2 . Since cobimetinib exhibited absorption variability in cancer patients , a series of single - dose studies in healthy subjects were conducted to determine absolute bioavailability and elucidate potential effects of formulation , food , and elevated gastric pH on cobimetinib bioavailability . Three crossover trials were performed with a 20 mg cobimetinib oral dose : absolute bioavailability using a 2 mg intravenous infusion ( n = 13 ) , relative bioavailability of tablets versus capsules and food effect ( n = 20 ) , and drug interaction with a proton pump inhibitor ( 20 mg of rabeprazole daily for 5 days prior to cobimetinib administration ; n = 20 ) . Absolute bioavailability of cobimetinib was 46 . 2 % ( 24 . 2 , CV % ) , likely due to metabolism rather than incomplete absorption . The mean systemic clearance of cobimetinib was low ( 11 . 7 L / h [ 28 . 2 , CV % ] ) . Administration of cobimetinib tablets with a high - fat meal delayed drug absorption ( prolonged tmax ) but had no statistically significant effect on cobimetinib exposure ( Cmax and AUC0 -∞ ) . Tablet and capsule formulations of cobimetinib showed comparable exposures . ___MASK60___ exhibited delayed absorption ( tmax ) in the presence of rabeprazole , with no statistically significant effects on drug exposure ( Cmax and AUC0 -∞ ) in the fasted state . In conclusion , cobimetinib oral absorption was not affected by change in formulation , food , or elevated gastric pH .", "The epidemiology of prostate cancer -- with a focus on nonsteroidal anti - inflammatory drugs . ___MASK51___ and other NSAIDs have a potential role in the primary and secondary prevention of many common diseases associated with aging , including the top two causes of mortality in the United States - cardiovascular disease and cancer . These agents may be beneficial in the management of Alzheimer ' s disease , other forms of dementia , and Parkinson ' s . disease . Because men with prostate cancer or precancer are likely to present with coexisting conditions that would be affected by systemic aspirin , NSAID , or other P35354 inhibitor therapies , it is important to consider any possible preventive studies or future clinical recommendations of aspirin or NSAIDs for prostate cancer within the context of these comorbid conditions . ___MASK51___ or nonaspirin NSAIDs may be appropriate prevention therapy for patients at high risk of prostate cancer , myocardial infarction , Parkinson ' s disease , Alzheimer ' s disease , lung cancer , or colorectal cancer , but low risk for gastrointestinal complications or stroke . Further quantitative comparative studies of the risks and benefits of these common comorbidities in older Americans , with special attention to dose and duration parameters , are warranted .", "Correcting human mitochondrial mutations with targeted RNA import . Mutations in the human mitochondrial genome are implicated in neuromuscular diseases , metabolic defects , and aging . An efficient and simple mechanism for neutralizing deleterious mitochondrial DNA ( mtDNA ) alterations has unfortunately remained elusive . Here , we report that a 20 - ribonucleotide stem - loop sequence from the H1 RNA , the RNA component of the human RNase P enzyme , appended to a nonimported RNA directs the import of the resultant RNA fusion transcript into human mitochondria . The methodology is effective for both noncoding RNAs , such as tRNAs , and mRNAs . The RNA import component , polynucleotide phosphorylase ( Q8TCS8 ) , facilitates transfer of this hybrid RNA into the mitochondrial matrix . In addition , nucleus - encoded mRNAs for mitochondrial proteins , such as the mRNA of human mitochondrial ribosomal protein P28222 ( O15235 ) , contain regulatory sequences in their 3 '- untranslated region ( UTR ) that confers localization to the mitochondrial outer membrane , which is postulated to aid in protein translocation after translation . We show that for some mitochondrial - encoded transcripts , such as P35354 , a 3 '- UTR localization sequence is not required for mRNA import , whereas for corrective mitochondrial - encoded tRNAs , appending the 3 '- UTR localization sequence was essential for efficient fusion - transcript translocation into mitochondria . In vivo , functional defects in mitochondrial RNA ( mtRNA ) translation and cell respiration were reversed in two human disease lines . Thus , this study indicates that a wide range of RNAs can be targeted to mitochondria by appending a targeting sequence that interacts with Q8TCS8 , with or without a mitochondrial localization sequence , providing an exciting , general approach for overcoming mitochondrial genetic disorders .", "Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .", "O75365 , a metastasis associated tyrosine phosphatase , is involved in P36888 - ITD signaling and implicated in anti - AML therapy . Combination with other small molecule drugs represents a promising strategy to improve therapeutic efficacy of P36888 inhibitors in the clinic . We demonstrated that combining ___MASK53___ , a P36888 inhibitor , with DB02546 , a HDAC inhibitor , led to synergistic killing of the AML cells with P36888 mutations and suppression of colony formation . We identified a core gene signature that is uniquely induced by the combination treatment in 2 different leukemia cell lines . Among these , we showed that downregulation of O75365 ( O75365 ) played a role in this synergism . O75365 is downstream of P36888 signaling and ectopic expression of O75365 conferred therapeutic resistance through upregulation of P35610 ( signal transducers and activators of transcription ) pathway activity and anti - apoptotic Mcl - 1 protein . O75365 interacts with P56524 and DB02546 downregulates O75365 via a proteasome dependent pathway . In addition , O75365 protein was identified in 47 % of AML cases , but was absent in myeloid cells in normal bone marrows . Our results suggest such combination therapies may significantly improve the therapeutic efficacy of P36888 inhibitors . O75365 plays a potential pathological role in AML and it might be a useful therapeutic target in AML , and warrant clinical investigation .", "___MASK84___ for the treatment of type 2 diabetes . ___MASK84___ is a novel glucagon - like peptide 1 ( P0C6A0 ) receptor agonist with a unique structure that supports once - weekly dosing in patients with type 2 diabetes ( T2DM ) , most of whom have a big pill burden . It appears to be efficacious in reducing hemoglobin A1c ( HbA1c ) up to 1 . 59 % and promotes modest weight loss up to 3 kg with a low incidence of hypoglycemia and mild to moderate gastrointestinal adverse events . Convenient weekly dosing could improve compliance and help attain sustained glycemic goals . Addressing obesity is an integral part of T2DM management and weight loss may contribute to better glycemic and cardiovascular benefits . Results of ongoing clinical trials on cardiovascular safety are important to determine the risk - to - benefit ratio . As with any drug , patient selection and ongoing monitoring will be important . If approved , dulaglutide will be one of the first weekly P43220 agonist to be available in a ready - to - use pen device with an automatic injector .", "Use of trifluoroperazine isolates a [( 3 ) H ] ___MASK73___ binding site in rat brain membranes with the pharmacology of the voltage - independent ifenprodil site on N - methyl - D - aspartate receptors containing Q13224 subunits . The use of trifluoroperazine in a well washed rat brain membrane preparation revealed [( 3 ) H ] ifenprodil binding to a single high affinity state with the pharmacology of N - methyl - D - aspartate ( DB01221 ) receptors containing Q13224 subunits . Inhibition of [( 3 ) H ] ifenprodil binding in the presence of trifluoroperazine by 10 NR1a / Q13224 selective agents was highly correlated with their inhibition at rat NR1a / Q13224 receptors expressed in Xenopus ooctyes and [( 3 ) H ] DB01520 binding to rat brain Q13224 subunit containing DB01221 receptors but not with their inhibition of [( 3 ) H ] DTG binding . Allosteric interactions with polyamines , Mg ( 2 +) , Zn ( 2 +) , glutamate , glycine , and their antagonists were consistent with DB01221 receptors with Q13224 subtype pharmacology . The rank order of polyamine inhibition was spermine > spermidine > 1 , 5 -( diethylamino ) piperidine > arcaine > agmatine > putrescine . Both spermidine and MgCl ( 2 ) shifted the inhibition curve of ifenprodil to the right in a parallel manner , but Mg ( 2 +) did not appear to be additive to spermidine . Glutamate increased and glycine decreased the binding . Conversely , CPP decreased the binding , and MDL 105 , 519 increased the binding in an agonist reversible manner . The increase with MDL 105 , 519 and glutamate appeared to be additive as did the decrease with glycine and CPP . Changes in the buffer pH between 6 . 5 and 8 . 0 did not affect the affinity of Q13224 agents . DB09202 but not clonidine inhibited the binding . MK - 801 and agents from various other pharmacological classes did not significantly inhibit [( 3 ) H ] ifenprodil binding . [( 3 ) H ] ___MASK73___ binding in the presence of trifluoroperazine appears to be selective for the voltage - independent ifenprodil site on DB01221 receptors containing the Q13224 subunit .", "Risk variants in the P04271 gene predict elevated P04271 serum concentrations in healthy individuals . Several lines of evidence suggest an important role of the P04271 protein and its coding gene in different neuropathological and psychiatric disorders like dementia , bipolar affective disorders and schizophrenia . To clarify whether a direct link exists between gene and gene product , that is , whether P04271 variants directly modulate P04271 serum concentration , 196 healthy individuals were assessed for P04271 serum concentrations and genotyped for five potentially functional P04271 SNPs . Functional variants of the serotonergic genes P08908 and 5 - HTT possibly modulating P04271 serum levels were also studied . Further , publicly available human postmortem gene expression data were re - analyzed to elucidate the impact of P04271 , P08908 and 5 - HTT SNPs on frontal cortex P04271 mRNA expression . Several P04271 SNPs , particularly rs9722 , and the P04271 haplotype T - G - G - A ( including rs2186358 - rs11542311 - rs2300403 - rs9722 ) were associated with elevated P04271 serum concentrations ( Bonferroni corrected P < 0 . 05 ) . Of these , rs11542311 was also associated with P04271 mRNA expression directly ( Bonferroni corrected P = 0 . 05 ) and within haplotype G - A - T - C ( rs11542311 - rs2839356 - rs9984765 - rs881827 ; P = 0 . 004 ) , again with the G - allele increasing P04271 expression . Our results suggest an important role of P04271 SNPs on P04271 serum concentrations and P04271 mRNA expression . It hereby links recent evidence for both , the impact of P04271 gene variation on various neurological or psychiatric disorders like dementia , bipolar affective disorders and schizophrenia and the strong relation between P04271 serum levels and these disorders .", "Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of DB06684 , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . DB06684 and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , DB06684 affected stress potentiation of startle at doses above 5 mg / kg . DB06684 increased stress elevation of startle at 10 mg / kg . Higher doses of DB06684 ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , DB06684 had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , DB06684 increased stress elevation of startle at all doses . In contrast , therapeutic DB06684 had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for DB06684 in the treatment of changes in hypervigilance following severe stress .", "___MASK52___ and P04271 regulation of p53 - dependent cell growth arrest and apoptosis . In glial P13671 cells constitutively expressing wild - type p53 , synthesis of the calcium - binding protein P04271 is associated with cell density - dependent inhibition of growth and apoptosis in response to UV irradiation . A functional interaction between P04271 and p53 was first demonstrated in p53 - negative mouse embryo fibroblasts ( MEF cells ) by sequential transfection with the P04271 and the temperature - sensitive p53Val135 genes . We show that in MEF cells expressing a low level of p53Val135 , P04271 cooperates with p53Val135 in triggering calcium - dependent cell growth arrest and cell death in response to UV irradiation at the nonpermissive temperature ( 37 . 5 degreesC ) . ___MASK52___ - dependent growth arrest of MEF cells expressing P04271 correlates with specific nuclear accumulation of the wild - type p53Val135 conformational species . P04271 modulation of wild - type p53Val135 nuclear translocation and functions was confirmed with the rat embryo fibroblast ( REF ) cell line clone 6 , which is transformed by oncogenic Ha - ras and overexpression of p53Val135 . Ectopic expression of P04271 in clone 6 cells restores contact inhibition of growth at 37 . 5 degreesC , which also correlates with nuclear accumulation of the wild - type p53Val135 conformational species . Moreover , a calcium ionophore mediates a reversible P55008 arrest in P04271 - expressing REF ( P04271 - REF ) cells at 37 . 5 degreesC that is phenotypically indistinguishable from p53 - mediated P55008 arrest at the permissive temperature ( 32 degreesC ) . P04271 - REF cells proceeding from P55008 underwent apoptosis in response to UV irradiation . Our data support a model in which calcium signaling and P04271 cooperate with the p53 pathways of cell growth inhibition and apoptosis .", "___MASK64___ sodium , a stable prostacyclin analogue , elicits dilation of isolated porcine retinal arterioles : roles of P29474 and potassium channels . PURPOSE : DB01240 ( DB01240 ) is usually described as an endoEDRFsthelium - derived relaxing factor , but the vasoreactivity to DB01240 in the retinal arterioles and the underlying mechanisms are not fully understood . We examined the effects of DB01240 on the retinal microcirculation using beraprost sodium ( BPS ) , a stable DB01240 analogue , and the signaling mechanisms involved in this vasomotor activity . METHODS : Porcine retinal arterioles were isolated , cannulated , and pressurized without flow in vitro . Video microscopic techniques recorded the diametric responses to BPS . RESULTS : ___MASK64___ sodium elicited dose - dependent ( 0 . 1 pM - 0 . 1 μM ) vasodilation of the retinal arterioles that was abolished by the P43119 ( IP ) antagonist CAY10441 . ___MASK64___ sodium - induced vasodilation decreased by 50 % after the endothelium was removed and was inhibited by the nitric oxide ( NO ) synthase inhibitor N ( G )- nitro - L - arginine methyl ester ( L - NAME ) comparable with denudation . Inhibition of soluble guanylyl cyclase by 1H - 1 , 2 , 4 - oxadiazolo [ 4 , 3 - a ] quinoxalin - 1 - one ( ODQ ) and blockage of protein kinase A ( PKA ) by Rp - 8 - Br - cAMPS were comparable to L - NAME . ___MASK64___ sodium - induced vasodilation was also inhibited by the nonselective potassium channel inhibitor , tetraethylammonium , and the adenosine triphosphate - sensitive potassium ( KATP ) channel blocker , glibenclamide . Residual vasodilation in the presence of glibenclamide decreased further with subsequent application of ODQ . CONCLUSIONS : ___MASK64___ sodium , a stable DB01240 analogue , causes vasodilation of the retinal arterioles mediated via the IP receptor . The current findings suggest that BPS elicits endothelium - dependent and - independent dilation of the retinal arterioles mediated by NO induced by activation of PKA in the endothelium and the KATP channel activation in the vascular smooth muscle , respectively .", "8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .", "Oral tuberculosis associated with a treatment with anti - rheumatic drugs . BACKGROUND : The use of immunosuppressive medication is a dominant risk factor for infection in patients with rheumatoid arthritis ( RA ) . DB00563 ( MTX ) is one of the traditional disease - modifying antirheumatic drugs . ___MASK12___ [ a human anti - tumor necrosis factor - alpha ( anti - P01375 ) monoclonal antibody ] represent an important advance in the treatment of RA and has been recently come in use . P01375 plays a role in the host defense against Mycobacterium tuberculosis and notably in granuloma formation . Infections occur at a high rate among those who use one or the combination of the two medications . METHOD : We examined a female patient that was referred to our department for evaluation and treatment of a granular lesion on the soft palate and uvula , complaining of mild dysphagia . The patient was treated for 4 months with MTX and adalimumab for RA before the oral lesion appeared . RESULTS : The histopathological examination of a specimen of the oral lesion , taken by biopsy , showed a chronic inflammation characterized by tuberculous granulomas . Polymerase chain reaction test and culture of a new specimen was positive for M . tuberculosis . CONCLUSIONS : The therapeutic use of MTX or / and adalimumab for the treatment of RA or few others diseases , can cause oral tuberculosis .", "The effects of pertussis toxin on dopamine D2 and serotonin P08908 autoreceptor - mediated inhibition of neurotransmitter synthesis : relationship to receptor reserve . Irreversible inactivation of striatal D2 dopamine ( DA ) autoreceptors with N - ethoxycarbonyl - 2 - ethoxy - 1 , 2 - dihydroquinoline ( EEDQ ) or inactivation of striatal guanine nucleotide binding proteins ( G proteins ) with pertussis toxin ( PT ) shifted the dose - response curve for N - n - propylnorapomorphine ( NPA ) - mediated inhibition of DB04699 ( Q9BVC4 ) - induced elevation of DB01235 ( DB01235 ) to the right , with a decrease in the maximum response . For the partial agonist (+)- 3 -( 3 - hydroxyphenyl )- N - n - propylpiperidine [ (+)- 3 - PPP ] , in contrast , there was little shift in the ED50 , after inactivation of either D2 receptors or G proteins . Completely analogous effects were found at the somatodendritic P08908 autoreceptor in the raphe nuclei , mediating inhibition of the synthesis of serotonin ( 5 - HT ) ; the full agonist , 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) and the partial agonist , buspirone were utilized to inhibit the synthesis of 5 - HT , as measured by changes in levels of L - 5 - hydroxytryptophan ( 5 - HTP ) . Additionally , in both systems , combined treatment with pertussis toxin , followed by EEDQ , reduced the maximum effect , when compared to either agent alone but had little further effect on the ED50 . In systems exhibiting a large receptor reserve for agonists , such as those described above , the same pattern of response seen after inactivation of receptors or G proteins may reflect the operation of a common mechanism underlying the phenomenon of receptor reserve ." ]
[ "___MASK12___", "___MASK51___", "___MASK52___", "___MASK53___", "___MASK57___", "___MASK60___", "___MASK64___", "___MASK73___", "___MASK84___" ]
___MASK51___
MH_train_1603
interacts_with DB00072?
[ "15 - Deoxy - delta ( 12 , 14 )- prostaglandin J ( 2 ) inhibits IL - 1beta - induced IKK enzymatic activity and P25963 degradation in rat chondrocytes through a PPARgamma - independent pathway . P37231 ( PPARgamma ) ligands have been shown to inhibit the effects of proinflammatory cytokines such as interleukin - 1beta ( IL - 1beta ) . This cytokine plays a key role in articular pathophysiologies by inducing the production of inflammatory mediators such as nitric oxide ( NO ) and prostaglandin E ( 2 ) ( PGE ( 2 ) ) . We previously demonstrated that 15d - PGJ ( 2 ) was more potent than troglitazone to counteract IL - 1beta effects on chondrocytes . Here , we studied the action of 15d - PGJ ( 2 ) on intracellular targets in nuclear factor - kappaB ( NF - kappaB ) signalling pathway in IL - 1beta treated rat chondrocytes . We found that 15d - PGJ ( 2 ) decreased inhibitor kappaBalpha ( P25963 ) degradation but not its phosphorylation by specifically inhibiting O15111 beta ( IKKbeta ) , but not IKKalpha , enzymatic activity . We further evaluated the involvement of PPARgamma in the anti - inflammatory action of its ligands . In chondrocytes overexpressing functional PPARgamma protein , 15d - PGJ ( 2 ) pre - treatment inhibited inducible NO synthase and P35354 mRNA expression , nitrite and PGE ( 2 ) production , p65 translocation and NF - kappaB activation . ___MASK73___ or rosiglitazone pre - treatment had no effect . 15d - PGJ ( 2 ) exhibited the same effect in chondrocytes overexpressing mutated PPARgamma protein . These results suggest that 15d - PGJ ( 2 ) exerts its anti - inflammatory effect in rat chondrocytes by a PPARgamma - independent mechanism , which can be conferred to a partial inhibition of P25963 degradation .", "LSD and DOB : interaction with 5 - Q13049 receptors to inhibit DB01221 receptor - mediated transmission in the rat prefrontal cortex . Both the phenethylamine hallucinogen (-)- 1 - 2 , 5 - dimethoxy - 4 - bromophenyl - 2 - aminopropane ( DOB ) , a selective serotonin 5 - Q13049 , 2C receptor agonist , and the indoleamine hallucinogen ___MASK95___ ( LSD , which binds to P08908 , 1B , 1D , 1E , 1F , 2A , 2C , 5 , 6 , 7 , dopamine D1 and D2 , and alpha1 and alpha2 adrenergic receptors ) , but not their non - hallucinogenic congeners , inhibited N - methyl - D - aspartate ( DB01221 ) - induced inward current and DB01221 receptor - mediated synaptic responses evoked by electrical stimulation of the forceps minor in pyramidal cells of the prefrontal cortical slices . The inhibitory effect of hallucinogens was mimicked by 5 - HT in the presence of selective P08908 and 5 - Q9H205 receptor antagonists . The inhibitory action of DOB , LSD and 5 - HT on the DB01221 transmission was blocked by the 5 - Q13049 receptor antagonists R -(+)- alpha - ( 2 , 3 - dimethoxyphenil ) - 1 -[ 4 - fluorophenylethyl ]- 4 - piperidineme thanol ( M100907 ) and ketanserin . However , at low concentrations , when both LSD and DOB by themselves only partially depressed the DB01221 response , they blocked the inhibitory effect of 5 - HT , suggesting a partial agonist action . Whereas N -( 4 - aminobutyl )- 5 - chloro - 2 - naphthalenesulphonamide ( W - 7 , a calmodulin antagonist ) and N - [ 2 - [ [ [ 3 -( 4 '- chlorophenyl )- 2 - propenyl ] methylamino ] methyl ] phenyl ] - N -( 2 - hydroxyethyl )- 4 '- methoxy - b enzenesulphonamide phosphate ( KN - 93 , a Ca2 +/ P62158 - KII inhibitor ) , but not the negative control 2 -[ N - 4 ' methoxybenzenesulphonyl ] amino - N -( 4 '- chlorophenyl )- 2 - propeny l - N - methylbenzylamine phosphate ( KN - 92 ) , blocked the inhibitory action of LSD and DOB , the selective protein kinase C inhibitor chelerythrine was without any effect . We conclude that phenethylamine and indoleamine hallucinogens may exert their hallucinogenic effect by interacting with 5 - Q13049 receptors via a Ca2 +/ P62158 - KII - dependent signal transduction pathway as partial agonists and modulating the DB01221 receptors - mediated sensory , perceptual , affective and cognitive processes .", "Effects of P04626 amplicon size and genomic alterations of chromosomes 1 , 3 , and 10 on patient response to trastuzumab in metastatic breast cancer . DB00072 is widely used for advanced breast cancer patients with P04626 - amplified tumors . Nevertheless , over half of these patients do not have an objective response . One reason may be altered expression of genes that might compensate for P04626 inhibition . We previously mapped the gene - rich region of chromosome 17 telomeric to P04626 , and reported considerable variability in the telomeric extent of the P04626 amplicon . Here we examined whether the variable amplicon size may be associated with patient response to trastuzumab . In addition , we looked at associations between response and several signaling pathway - related genes unrelated to the P04626 amplicon , including Q9Y243 , P60484 , P42336 , and P35354 . In 35 patients with P04626 - amplified metastatic breast cancer , with 40 % overall response to trastuzumab , fluorescence in situ hybridization identified the telomeric extent of the P04626 amplicon and the status of the several pathway - related genes . Objective response strongly correlated with the telomeric amplicon size , with 62 % of patients with shorter amplicons responding , compared with only 7 % of patients with longer amplicons ( P = 0 . 0015 ) . Abnormal copy number of P35354 was marginally associated with objective response ( P = 0 . 066 ) , while abnormal copy numbers of two reference loci , 1q25 and the chromosome 10 centromere , were significantly associated with response . Pairwise combinations of copy number status of these loci and P04626 amplicon size provided stronger associations and identified a group of patients without responders . These results suggest that patient selection for trastuzumab may be improved by considering P04626 amplicon size and genomic status of the 1q25 , P35354 , and centromere 10 loci .", "Dacomitinib ( PF - 00299804 ) , an irreversible Pan - HER inhibitor , inhibits proliferation of P04626 - amplified breast cancer cell lines resistant to trastuzumab and lapatinib . The human P01133 ( HER ) family of receptors has been pursued as therapeutic targets in breast cancer and other malignancies . DB00072 and lapatinib are standard treatments for P04626 - amplified breast cancer , but a significant number of patients do not respond or develop resistance to these drugs . Here we evaluate the in vitro activity of dacomitinib ( PF - 00299804 ) , an irreversible small molecule pan - HER inhibitor , in a large panel of human breast cancer cell lines with variable expression of the HER family receptors and ligands , and with variable sensitivity to trastuzumab and lapatinib . Forty - seven human breast cancer and immortalized breast epithelial lines representing the known molecular subgroups of breast cancer were treated with dacomitinib to determine IC ( 50 ) values . P04626 - amplified lines were far more likely to respond to dacomitinib than nonamplified lines ( RR , 3 . 39 ; P < 0 . 0001 ) . Furthermore , P04626 mRNA and protein expression were quantitatively associated with response . Dacomitinib reduced the phosphorylation of P04626 , P00533 , Q15303 , AKT , and P29323 in the majority of sensitive lines . Dacomitinib exerted its antiproliferative effect through a combined G ( 0 )- G ( 1 ) arrest and an induction of apoptosis . Dacomitinib inhibited growth in several P04626 - amplified lines with de novo and acquired resistance to trastuzumab . Dacomitinib maintained a high activity in lines with acquired resistance to lapatinib . This study identifies P04626 - amplified breast cancer lines as most sensitive to the antiproliferative effect of dacomitinib and provides a strong rationale for its clinical testing in P04626 - amplified breast cancers resistant to trastuzumab and lapatinib .", "A 4 - week intrathecal toxicity and pharmacokinetic study with trastuzumab in cynomolgus monkeys . DB00072 is indicated for the treatment of patients with breast cancer overexpressing human epidermal growth factor 2 ( P04626 ) . Women with P04626 - positive tumors have an increased risk of brain metastases . The blood - brain barrier and blood - cerebrospinal fluid ( P04141 ) barrier may prevent trastuzumab from reaching appropriate concentrations in the brain and P04141 following standard intravenous administration . To evaluate the potential of effects on the central nervous system , a 4 - week toxicology study with weekly intrathecal administration of trastuzumab was performed in cynomolgus monkeys at doses of 0 , 3 , or 15 mg . No trastuzumab - related effects on body weight , clinical signs , neurological function , clinical pathology , or anatomic pathology were noted . The applied doses and P04141 concentrations achieved in the current study exceeded those reported in patients after intrathecal administration . The results support future studies for further evaluation of intrathecal application of trastuzumab in patients with brain metastases in P04626 - positive breast cancer .", "Discovery of ( 2E ) - 3 -{ 2 - butyl - 1 -[ 2 -( diethylamino ) ethyl ]- 1H - benzimidazol - 5 - yl }- N - hydroxyacrylamide ( ___MASK23___ ) , an orally active histone deacetylase inhibitor with a superior preclinical profile . A series of 3 -( 1 , 2 - disubstituted - 1H - benzimidazol - 5 - yl )- N - hydroxyacrylamides ( 1 ) were designed and synthesized as HDAC inhibitors . Extensive SARs have been established for in vitro potency ( Q13547 enzyme and COLO 205 cellular IC ( 50 ) ) , liver microsomal stability ( t ( 1 / 2 ) ) , cytochrome P450 inhibitory ( 3A4 IC ( 50 ) ) , and clogP , among others . These parameters were fine - tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring . After comprehensive in vitro and in vivo profiling of the selected compounds , ___MASK23___ ( 3 ) was identified as a preclinical development candidate . 3 is a potent pan - HDAC inhibitor with excellent druglike properties , is highly efficacious in in vivo tumor models ( HCT - 116 , PC - 3 , A2780 , MV4 - 11 , Ramos ) , and has high and dose - proportional oral exposures and very good ADME , safety , and pharmaceutical properties . When orally dosed to tumor - bearing mice , 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action . 3 is currently being tested in phase I and phase II clinical trials .", "___MASK41___ infusion therapy normalizes inflammation in sporadic P35858 patients . Patients with sporadic amyotrophic lateral sclerosis ( sALS ) show inflammation in the spinal cord and peripheral blood . The inflammation is driven by stimulation of macrophages by aggregated superoxide dismutase 1 ( P00441 ) through caspase1 , interleukin 1 ( IL1 ) , P05231 and chemokine signaling . Inflammatory gene activation is inhibited in vitro by tocilizumab , a humanized antibody to P05231 receptor ( P08887 ) . ___MASK41___ inhibits global interleukin - 6 ( P05231 ) signaling , a key mechanism in chronic rheumatoid disorders . Here we studied in vivo baseline inflammatory gene transcription in peripheral blood mononuclear cells ( PBMCs ) of 10 sALS patients , and the effects of tocilizumab ( Actemra ( R ) ) infusions . At baseline , one half of P35858 subjects had strong inflammatory activation ( Group 1 ) ( 8 genes up regulated > 4 - fold , P < 0 . 05 vs . controls ) and the other half ( Group 2 ) had weak activation . All patients showed greater than four - fold up regulation of P03956 , P80098 , Q99616 and O00175 . ___MASK41___ infusions in the Group 1 patients resulted in down regulation of inflammatory genes ( in particular IL1β ) , whereas in the Group 2 patients in up regulation of inflammatory genes . Post - infusion serum and P04141 concentrations of tocilizumab inhibited caspase1 activation in vitro . Three of 5 patients receiving tocilizumab infusions showed time - limited attenuation of clinical progression . In conclusion , inflammation of sALS patients at baseline is up - or down - regulated in comparison to controls , but is partially normalized by tocilizumab infusions .", "Ki - ras mutations in spontaneous and chemically induced renal tumors of the rat . A high frequency of point mutations at codon 12 of the Ki - ras gene has previously been reported for rat kidney mesenchymal tumors induced by methylating N - nitroso compounds . In this study , we analyzed renal tumors with divergent histogenesis , i . e . , mesenchymal tumors ( sarcomas ) , cortical epithelial tumors ( carcinomas ) , and embryonal tumors ( nephroblastomas ) . Renal mesenchymal tumors and carcinomas were induced in juvenile or young adult Wistar rats by a single dose of N - nitrosodimethylamine ( NDMA ) while nephroblastomas were induced in Nb hooded rats by a single transplacental dose of N - nitrosoethylurea ( P04626 ) . Nephroblastomas developing spontaneously in WAB / Not rats were also examined . Amplification of Ki - ras sequences from formalin - fixed , paraffin - embedded tissue by the polymerase chain reaction was followed by direct DNA sequencing . P19440 ---- Q6IB77 point mutations at codon 12 of the Ki - ras gene were found in 9 of 12 ( 75 % ) renal mesenchymal tumors and in 9 of 12 ( 75 % ) cortical epithelial tumors induced by NDMA . Even higher incidences were observed in nephroblastomas ( 8 / 8 ; 100 % ) induced by P04626 and in spontaneous nephroblastomas ( 10 / 11 ; 91 % ) . These results indicate that Ki - ras mutations are frequent events during the development of kidney tumors irrespective of their histogenesis and suggest that they may play an important role in renal carcinogenesis in rats . These data further indicate that mutational activation of Ki - ras proto - oncogenes in carcinogen - induced rat kidney tumors occurs in a tissue - specific , rather than cell - specific , manner .", "Akt activation by arachidonic acid metabolism occurs via oxidation and inactivation of P60484 tumor suppressor . P35354 ( P35354 ) and P09917 ( 5 - P28300 ) enzymes are overexpressed during inflammation and multistage tumor progression in many neoplastic disorders including lung , breast and pancreatic cancers . Here we report that the tumor suppressor phosphatase and tensin homolog ( P60484 ) is oxidized and inactivated during arachidonic acid ( AA ) metabolism in pancreatic cancer cell lines expressing P35354 or 5 - P28300 . Oxidation of P60484 decreases its phosphatase activity , favoring increased phosphatidylinositol 3 , 4 , 5 - triphosphate production , activation of Akt and phosphorylation of downstream Akt targets including GSK - 3beta and S6K . These effects are recapitulated with pancreatic phospholipase A ( 2 ) , which hydrolyses the release of membrane - bound AA . Interference with P60484 ' s physiological antagonism of signals from growth factors , insulin and oncogenes may confer risk for hypertrophic or neoplastic diseases associated with chronic inflammation or unwarranted oxidative metabolism of essential fatty acids .", "Possible mode of action of ___MASK68___ . Despite the extensive use of sulfasalazine ( SAS ) and / or ___MASK68___ ( ___MASK68___ ) in patients with inflammatory bowel disease and , more recently , rheumatoid arthritis , their mode of action has not been elucidated so far . None of the numerous pharmacological and biochemical effects described , including immunosuppressive , antifolate , and modulatory actions on lymphocyte and leukocyte functions , could be defined unequivocally as mediating their beneficial activity . Recently , interest has focused on actions of SAS and ___MASK68___ on the various enzymes of the arachidonic acid cascade . Mucosa of patients with inflammatory bowel disease generates excessive amounts of cyclooxygenase products such as prostaglandins ( PG ) as well as P09917 products such as leukotriene ( LT ) B4 and sulfidopeptide - LT . Both PG and LT exert proinflammatory actions and are potentially important mediators of mucosal inflammation . SAS and ___MASK68___ , however , have been found to inhibit PG synthesis under certain experimental conditions only , while increasing PG formation under other conditions . While SAS was found to inhibit colonic LTB4 synthesis , ___MASK68___ was reported to selectively affect the cyclooxygenase pathway of arachidonate metabolism in this tissue . Our results demonstrate that , like the parent compound , the metabolite ___MASK68___ in a dose - dependent manner inhibits release of LTB4 and sulfidopeptide - LT from normal human colonic mucosa ( IC50 3 . 5 and 3 . 7 mmol / liter , respectively ) . Indomethacin , which has no efficacy in the treatment of patients with inflammatory bowel disease , on the other hand , selectively inhibited DB00917 formation in normal and inflamed colonic mucosa ( IC50 1 . 7 and 1 . 0 mmol / liter , respectively ) without reducing synthesis of LTB4 or sulfidopeptide - LT . ( ABSTRACT TRUNCATED AT 250 WORDS )", "DB11320 Promotes the Release of P05231 via the P35367 / p38 and NF - κB Pathways in Nasal Fibroblasts . PURPOSE : Based on the close relationship between histamine and interleukin 6 ( P05231 ) , we hypothesized that histamine may regulate the production of cytokines , such as P05231 , during allergic inflammation . Here , we examined the role of histamine in P05231 production and histamine receptor activity in nasal fibroblasts , along with the mechanisms underlying these effects . METHODS : Experiments were performed using nasal fibroblasts from 8 normal patients . RT - PCR was used to identify the major histamine receptors expressed in nasal fibroblasts . Fibroblasts were then treated with histamine with or without histamine - receptor antagonists , and monitored for P05231 production using an ELISA . Four potential downstream signaling molecules , p38 , extracellular signal - regulated kinase ( P29323 ) , c - Jun N - terminal kinase ( JNK ) , and NF - κB , were evaluated by Western blot , and a luciferase reporter assay . RESULTS : Elevated expression was seen for all histamine receptors , with P05231 protein levels increasing significantly following histamine stimulation . Among the histamine - receptor specific antagonists , only the P35367 antagonist significantly decreased P05231 production in histamine - stimulated nasal fibroblasts . DB11320 increased the expression level of phosphorylated p38 ( pp38 ) , pERK , and pJNK , as well as NF - κB induction . The P35367 antagonist actively suppressed pp38 and NF - κB expression in histamine - induced nasal fibroblasts , but not pERK and pJNK . The p38 inhibitor strongly attenuated P05231 production in histamine - stimulated nasal fibroblasts . CONCLUSIONS : The data presented here suggest that antihistamines may be involved in the regulation of cytokines , such as P05231 , due to the role of histamine as an inflammatory mediator in nasal fibroblasts .", "___MASK85___ signaling reveals 14 - 3 - 3 protein function as a novel step in left - right patterning during amphibian embryogenesis . To gain insight into the molecular mechanisms underlying the control of morphogenetic signals by H + flux during embryogenesis , we tested ___MASK85___ - A ( FC ) , a compound produced by the fungus Fusicoccum amygdali Del . In plant cells , FC complexes with 14 - 3 - 3 proteins to activate H + pumping across the plasma membrane . It has long been thought that FC acts on higher plants only ; here , we show that exposing frog embryos to FC during early development specifically results in randomization of the asymmetry of the left - right ( LR ) axis ( heterotaxia ) . Biochemical and molecular - genetic evidence is presented that 14 - 3 - 3 - family proteins are an obligate component of Xenopus FC receptors and that perturbation of 14 - 3 - 3 protein function results in heterotaxia . The subcellular localization of 14 - 3 - 3 mRNAs and proteins reveals novel cytoplasmic destinations , and a left - right asymmetry at the first cell division . Using gain - of - function and loss - of - function experiments , we show that P62258 protein is likely to be an endogenous and extremely early aspect of LR patterning . These data highlight a striking conservation of signaling pathways across kingdoms , suggest common mechanisms of polarity establishment between C . elegans and vertebrate embryos , and uncover a novel entry point into the pathway of left - right asymmetry determination .", "Molecular determinants of trastuzumab efficacy : What is their clinical relevance ? DB00072 - containing therapy is a standard of care for human epidermal growth factor receptor - 2 ( P04626 ) - positive breast cancer . In pre - clinical models , a wide range of molecular mechanisms have been associated with reduced sensitivity to trastuzumab in vitro . These include expression of the truncated P04626 receptor fragment p95HER2 , activating mutation of the gene encoding the class 1A catalytic subunit of phosphatidylinositol 3 - kinase ( P42336 ) , loss of phosphatase and tensin homolog ( P60484 ) , activation of other downstream signal transducers , prevention of cell cycle arrest , increased signaling through alternative ( HER or non - HER ) tyrosine kinase receptors , and resistance to antibody - dependent cellular cytotoxicity . However , the clinical significance of these mechanisms as determinants of trastuzumab efficacy in vivo has been unclear . Here , we review clinical studies of potential predictive biomarkers of trastuzumab efficacy in P04626 - positive breast cancer and consider whether evaluation of such markers might inform patient selection for therapy . We find that clinical evidence relating to potential predictive biomarkers is mostly limited to small , retrospective studies , many of which have yielded conflicting findings . Some trends are evident in the retrospective data and in biomarker analyses from randomized clinical trials , particularly relating to activation of the phosphatidylinositol 3 - kinase pathway , but none is sufficiently strong to form a basis for patient selection . This may be explained by the fact that multiple mechanisms of action determine the clinical efficacy of trastuzumab . In the absence of novel , validated biomarkers of efficacy , trastuzumab eligibility should continue to be based on evaluation of P04626 status according to standard methods .", "P06401 membrane component 1 is a functional part of the glucagon - like peptide - 1 ( P0C6A0 ) receptor complex in pancreatic β cells . Glucagon - like peptide - 1 ( P0C6A0 ) is an incretin hormone that regulates glucose homeostasis . Because of their direct stimulation of insulin secretion from pancreatic β cells , P43220 ( P43220 ) agonists are now important therapeutic options for the treatment of type 2 diabetes . To better understand the mechanisms that control the insulinotropic actions of P0C6A0 , affinity purification and mass spectrometry ( AP - MS ) were employed to uncover potential proteins that functionally interact with the P43220 . AP - MS performed on Chinese hamster ovary cells or MIN6 β cells , both expressing the human P43220 , revealed 99 proteins potentially associated with the P43220 . Three novel P43220 interactors ( O00264 , Rab5b , and Rab5c ) were further validated through co - immunoprecipitation / immunoblotting , fluorescence resonance energy transfer , and immunofluorescence . Functional studies revealed that overexpression of O00264 , a novel cell surface receptor that associated with liganded P43220 , enhanced P0C6A0 - induced insulin secretion ( GIIS ) with the most robust effect . Knockdown of O00264 in β cells decreased GIIS , indicative of positive interaction with P43220 . To gain insight mechanistically , we demonstrated that the cell surface O00264 ligand P4 - BSA increased GIIS , whereas its antagonist AG - 205 decreased GIIS . It was then found that O00264 increased P0C6A0 - induced DB02527 accumulation . O00264 activation and GIIS induced by P4 - BSA could be blocked by inhibition of adenylyl cyclase / O95398 signaling or the P01133 receptor - PI3K signal transduction pathway . These data reveal a dual mechanism for O00264 - increased GIIS mediated through DB02527 and P01133 receptor signaling . In conclusion , we identified several novel P43220 interacting proteins . O00264 expressed on the cell surface of β cells was shown to interact with the activated P43220 to enhance the insulinotropic actions of P0C6A0 .", "[ ___MASK50___ ( Eperzan ) : a new once - weekly agonist of glucagon - like peptide - 1 receptors ] . ___MASK50___ ( Eperzan ) is a new once - weekly agonist of Glucagon - Like Peptide - 1 ( P0C6A0 ) receptors that is indicated in the treatment of type 2 diabetes . Two doses are available , 30 mg and 50 mg , to be injected subcutaneously once a week . It has been extensively evaluated in the HARMONY programme of eight large randomised controlled trials that were performed at different stages of type 2 diabetes , in comparison with placebo or an active comparator . The endocrine and metabolic effects of albiglutide are similar to those of other P43220 agonists : stimulation of insulin secretion ( incretin effect ) and inhibition of glucagon secretion , both in a glucose - dependent manner , retardation of gastric emptying and increase of satiety . These effects lead to a reduction in glycated haemoglobin ( HbA ( 1c ) ) levels , combined with a weight reduction . The overall tolerance profile is good . ___MASK50___ is currently reimbursed in Belgium after failure ( HbA ( 1c ) > 7 . 5 % ) of and in combination with a dual therapy with metformin and a sulfonylurea as well as in combination with a basal insulin ( with or without oral antidiabetic drugs ) . To avoid hypoglycaemia , a reduction in the dose of sulfonylurea or insulin may be recommended . A once - weekly administration should increase patient ' s acceptance of injectable therapy and improve compliance .", "Destabilization of P04626 transcripts by targeting 3 ' untranslated region messenger RNA associated Q15717 and histone deacetylase - 6 . In addition to repressing P04626 promoter function , histone deacetylase ( HDAC ) inhibitors induce the accelerated decay of mature P04626 transcripts ; the mechanism mediating this transcript destabilization is unknown but depends on the 3 ' untranslated region ( UTR ) of P04626 mRNA . Using P04626 - overexpressing human breast cancer cells ( SKBR3 ) , the mRNA stability factor Q15717 was shown to support P04626 transcript integrity , bind and endogenously associate with a conserved U - rich element within the P04626 transcript 3 ' UTR , coimmunoprecipitate with RNA - associated HDAC activity , and colocalize with Q9UBN7 . Q9UBN7 also coimmunoprecipitates with Q15717 in an RNA - dependent manner and within 6 hours of exposure to a pan - HDAC inhibitor dose , that does not significantly alter cytosolic Q15717 levels or Q15717 binding to P04626 mRNA . Cellular P04626 transcript levels decline while remaining physically associated with Q9UBN7 . Knockdown of Q9UBN7 protein by small interfering RNA partially suppressed the P04626 transcript decay induced by either pan - HDAC or Q9UBN7 - selective enzymatic inhibitors . Three novel hydroxamates , ST71 , ST17 , and ST80 were synthesized and shown to inhibit Q9UBN7 with 14 - fold to 31 - fold greater selectivity over their binding and inhibition of Q13547 . Unlike more potent pan - HDAC inhibitors , these Q9UBN7 - selective inhibitors produced dose - dependent growth arrest of P04626 - overexpressing breast cancer cells by accelerating the decay of mature P04626 mRNA without repressing P04626 promoter function . In sum , these findings point to the therapeutic potential of Q15717 and Q9UBN7 - selective inhibitors , contrasting P04626 stability effects induced by Q9UBN7 enzymatic inhibition and Q9UBN7 protein knockdown , and show that P04626 transcript stability mechanisms include exploitable targets for the development of novel anticancer therapies .", "Resistance of P04626 / neu - overexpressing tumor targets to lymphokine - activated - killer - cell - mediated lysis : evidence for deficiency of binding and post - binding events . P04626 / neu - overexpressing tumor cell lines are relatively resistant to lymphokine - activated killer ( Q96QP1 ) cell cytotoxicity when compared to P04626 / neu - nonexpressing lines . P04626 / neu + targets were also resistant to binding by Q96QP1 large granular lymphocytes ( LGL ) as shown by visualization at the single - cell level , a target monolayer binding assay and in \" cold \" target inhibition experiments . P04626 / neu + Q96QP1 - resistant ovarian cell lines demonstrated an absence of P05362 expression while expression of LFA - 3 , N - P62158 , laminin and beta 1 integrins was comparable to that of P04626 / neu - targets . In contrast , the P04626 / neu + breast cell line , SKBR - 3 , which was also resistant to lysis and binding by Q96QP1 LGL , demonstrated normal expression of P05362 . Anti - P05362 antibodies blocked binding and lysis of P04626 / neu - carcinoma targets by Q96QP1 cells , further supporting the notion that lack of P05362 expression on P04626 / neu + cells contributes to their resistance . The modest binding and lysis of P04626 / neu + targets by Q96QP1 cells was significantly inhibited by anti - LFA - 1 antibodies , suggesting the existence of another counter - receptor for LFA - 1 on P04626 / neu + targets . The following also supported deficiencies in post - binding events when P04626 / neu + cells resisted the lytic activity of Q96QP1 cells : ( a ) when the relative resistance to effector cell binding was overcome by exogenous lectin . P04626 / neu + cell lines were still resistant to Q96QP1 cytolysis , and ( b ) P04626 / neu + targets were resistant to perforin - containing granule extracts obtained from the CTLL - R8 cytotoxic lymphocyte cell line . These results indicate that deficiency in effector binding as well as post - binding events contributes to the resistance of P04626 / neu - overexpressing tumor targets to Q96QP1 - cell - mediated lysis .", "O14793 inactivation induces a similar muscle molecular signature in double - muscled cattle as in mice . O14793 ( O14793 ) , a member of the TGF - β superfamily , is a negative regulator of skeletal muscle mass . We have previously shown that the cell survival / apoptosis pathway is a downstream target of O14793 loss - of - function in mice through the regulation of the expression or abundance of many survival and apoptotic factors . In this study , we used western - blot and quantitative PCR ( qPCR ) analyses to validate these novel downstream targets of O14793 in double - muscled ( DM ) cattle v . their controls including 260 - day - old foetuses and adult cows from the INRA95 strain . O14793 loss - of - function in DM foetuses and DM cows resulted in a glycolytic shift of the muscles ( e . g . upregulation of H - MyBP , P36871 and Q13424 and downregulation of P05413 ) , activation of cell survival pathway through regulation of some components of the PI3K / Akt pathway ( e . g . upregulation of Q99497 and Gsk - 3βser9 / Gsk - 3βtotal ratio and downregulation of P60484 ) and upregulation of cell survival factors translationally controlled tumour protein ( P62258 , Pink1 ) . We also found a lower abundance of pro - apoptotic transcripts and / or proteins ( P42574 , caspase - 8 , caspase - 9 , P55957 , Q02363 and Q9UER7 ) and a higher expression of anti - apoptotic transcripts ( Traf2 and Bcl2l2 ) in DM muscles . All together , these results are in favour of activation of the cell survival pathway and loss of apoptosis pathway within the muscles of DM animals . Alteration of both pathways may increase myonuclear or satellite cell survival , which is crucial for protein synthesis . This could contribute to muscle hypertrophy in DM foetuses and DM cows .", "DB00072 has preferential activity against breast cancers driven by P04626 homodimers . In breast cancer cells with P04626 gene amplification , P04626 receptors exist on the cell surface as monomers , homodimers , and heterodimers with P00533 / P21860 . The therapeutic antibody trastuzumab , an approved therapy for P04626 (+) breast cancer , can not block ligand - induced P04626 heterodimers , suggesting it can not effectively inhibit P04626 signaling . Hence , P04626 oligomeric states may predict the odds of a clinical response to trastuzumab in P04626 - driven tumors . To test this hypothesis , we generated nontransformed human MCF10A mammary epithelial cells stably expressing a chimeric P04626 - FKBP molecule that could be conditionally induced to homodimerize by adding the FKBP ligand AP1510 , or instead induced to heterodimerize with P00533 or P21860 by adding the heterodimer ligands P01133 / TGFα or heregulin . AP1510 , P01133 , and heregulin each induced growth of MCF10A cells expressing P04626 - FKBP . DB00072 inhibited homodimer - mediated but not heterodimer - mediated cell growth . In contrast , the P04626 antibody pertuzumab , which blocks P04626 heterodimerization , inhibited growth induced by heregulin but not AP1510 . Lastly , the P04626 / P00533 tyrosine kinase inhibitor lapatinib blocked both homodimer - and heterodimer - induced growth . AP1510 triggered phosphorylation of Erk1 / 2 but not AKT , whereas trastuzumab inhibited AP1510 - induced Erk1 / 2 phosphorylation and Shc - P04626 homodimer binding , but not TGFα - induced AKT phosphorylation . Consistent with these observations , high levels of P04626 homodimers correlated with longer time to progression following trastuzumab therapy in a cohort of patients with P04626 - overexpressing breast cancer . Together , our findings confirm the notion that P04626 oligomeric states regulate P04626 signaling , also arguing that trastuzumab sensitivity of homodimers may reflect their inability to activate the PI3K ( phosphoinositide 3 - kinase ) / AKT pathway . A clinical implication of our results is that high levels of P04626 homodimers may predict a positive response to trastuzumab .", "Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor / P04626 - positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F . Hoffmann - La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 - positive metastatic breast cancer , trastuzumab / chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . DB00072 adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single - agent activity in breast cancer , including capecitabine ( DB01101 ; F . Hoffmann - La Roche ) , gemcitabine , and vinorelbine . DB00072 is also being investigated as part of triplet drug regimens . DB00072 has good single - agent activity in first - line therapy . This is of relevance to women with P04626 - positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab - containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible .", "Phenotypic characterization of Ggt1 ( dwg / dwg ) mice , a mouse model for hereditary γ - glutamyltransferase deficiency . Ggt1 ( dwg / dwg ) mice are spontaneous mutant mice with a nucleotide deletion in the Ggt1 gene . They are characterized by dwarfism , cataract , and coat color abnormality . These abnormalities in the external appearance of Ggt1 ( dwg / dwg ) mice closely resemble those of previously reported P19440 - deficient mice , Ggt1 ( tm1Zuk / tm1Zuk ) ( Ggt1 (-/-) ) and Ggt1 ( enu1 / enu1 ) , generated by gene targeting or ENU mutagenesis . However , whether the pathological features of Ggt1 ( dwg / dwg ) mice are also similar to those of the Ggt1 (-/-) and Ggt1 ( enu1 / enu1 ) mice remains unclear . To clarify the pathogenesis of Ggt1 ( dwg / dwg ) mice , we physiologically and histologically investigated the abnormalities of Ggt1 ( dwg / dwg ) mice in this study . First , we analyzed the activity of P19440 and ___MASK83___ levels in Ggt1 ( dwg / dwg ) mice . P19440 activity in the Ggt1 ( dwg / dwg ) mice was reduced to approximately 4 . 0 % of that in the wild - type mice . Plasma and kidney ___MASK83___ levels were markedly increased , while eye and liver ___MASK83___ levels were markedly decreased , in the Ggt1 ( dwg / dwg ) mice . Notably , no significant difference in survival rate was observed between the Ggt1 ( dwg / dwg ) and wild - type mice , whereas high mortality was reported in the Ggt1 (-/-) and Ggt1 ( enu1 / enu1 ) mice . Growth retardation , degeneration of lens fibers , and an increased number of osteoclasts in the Ggt1 ( dwg / dwg ) mice were reversed by administration of N - acetyl - L - cysteine , a precursor of ___MASK83___ synthesis . Thus , we conclude that the abnormalities of Ggt1 ( dwg / dwg ) mice are caused by alteration of the ___MASK83___ levels due to the depression of P19440 activity and that Ggt1 ( dwg / dwg ) mice will be a useful model for P19440 deficiency with peculiar features .", "Characterization of antihistamines using biphasic cutaneous reaction in BALB / c mice . Effects of 11 histamine H1 receptor antagonists on IgE - mediated biphasic cutaneous reaction in mice were examined . The immediate phase reaction ( IPR ) assessed at 1 hour after antigen application was significantly inhibited by all antihistamines examined . The inhibition of IPR by cetirizine and mequitazine were potent , but those by cyproheptadine and diphenhydramine were weak . The later phase reaction ( LPR ) assessed at 24 hours after antigen application was inhibited by chlorpheniramine , oxatomide , ketotifen , mequitazine , emedastine , terfenadine and azelastine . The inhibition of LPR by emedastine was potent , but those by ketotifen and terfenadine were only partial . ___MASK76___ inhibited both IPR and LPR comparably . Present results indicate that H1 receptor activation is involved in the IPR of the biphasic cutaneous reaction , and that the blockade of H1 receptors at IPR does not contribute to the attenuation of following LPR . P35367 antagonists inhibiting the LPR have a property distinct from H1 receptor antagonism , which may have an additional benefit for the treatment of allergic diseases ." ]
[ "___MASK23___", "___MASK41___", "___MASK50___", "___MASK68___", "___MASK73___", "___MASK76___", "___MASK83___", "___MASK85___", "___MASK95___" ]
___MASK41___
MH_train_1604
interacts_with DB06643?
[ "Expression of vitamin D receptor and 25 - hydroxyvitamin D3 - 1 { alpha }- hydroxylase in normal and malignant human colon . Considerable evidence exists to support the use of vitamin D to prevent and / or treat colorectal cancer . However , the routine use of bioactive vitamin D , 1 , 25 - dihydroxyvitamin D3 , is limited by the side effect of toxic hypercalcemia . Recent studies , however , suggest that colonic epithelial cells express 25 - hydroxyvitamin D3 - 1alpha - hydroxylase , an enzyme that converts nontoxic pro - vitamin D , ___MASK72___ [ ___MASK72___ ] , to its bioactive form . Yet , nothing is known as to the cellular expression of 1alpha - hydroxylase and the vitamin D receptor ( P11473 ) in the earliest histopathologic structures associated with malignant transformation such as aberrant crypt foci ( Q9NQ94 ) and polyps [ addressing the possibility of using nontoxic ___MASK72___ for chemoprevention ] , nor is anything known as to the expression of these proteins in colorectal cancer as a function of tumor cell differentiation or metastasis [ relevant to using ___MASK72___ for chemotherapy ] . In this study , we show that 1alpha - hydroxylase is present at equal high levels in normal colonic epithelium as in ACFs , polyps , and colorectal cancer irrespective of tumor cell differentiation . In contrast , P11473 levels were low in normal colonic epithelial cells ; were increased in ACFs , polyps , and well - differentiated tumor cells ; and then declined as a function of tumor cell de - differentiation . Both 1alpha - hydroxylase and P11473 levels were negligible in tumor cells metastasizing to regional lymph nodes . Overall , these data support using ___MASK72___ for colorectal cancer chemoprevention but suggest that pro - vitamin D is less likely to be useful for colorectal cancer chemotherapy .", "Novel treatments with small molecules in psoriatic arthritis . Current treatment options for patients with active psoriatic arthritis ( PsA ) include synthetic disease - modifying antirheumatic drugs and biologic agents . Propelled by increased understanding of immunopathogenesis of PsA , new therapeutic agents targeting different biologic pathways have been evaluated . This article discusses novel small - molecule , orally available treatments that are currently in clinical development for the treatment of psoriasis and PsA . This includes the phosphodiesterase 4 inhibitor apremilast and Janus kinase ( JAK ) inhibitors . Apremilast has demonstrated significant improvements in patients with moderate to severe psoriasis and PsA in phase II and III clinical trials and has recently been approved for the treatment of PsA . ___MASK18___ , an oral inhibitor of P52333 , P23458 , and , to a lesser degree , O60674 , approved for the treatment of rheumatoid arthritis in several countries , has demonstrated positive results in psoriasis in phase II studies . Studies in PsA are ongoing . With these new developments , treatment options will continue to improve in the future .", "Q9GZX6 promotes osteoclastogenesis in rheumatoid arthritis through induction of O14788 in human synovial fibroblasts . OBJECTIVE : To examine the regulatory role of interleukin - 22 ( Q9GZX6 ) in the expression of O14788 and induction of osteoclastogenesis in rheumatoid arthritis ( RA ) . METHODS : Concentrations of Q9GZX6 and O14788 in the serum and synovial fluid of RA patients were measured using enzyme - linked immunosorbent assay . RA synovial fibroblasts were treated with recombinant human Q9GZX6 ( rhIL - 22 ) , and the expression of O14788 messenger RNA ( mRNA ) and protein was measured using real - time polymerase chain reaction , Western blotting , and intracellular immunostaining . Human monocytes were cocultured with Q9GZX6 - prestimulated RA synovial fibroblasts and macrophage colony - stimulating factor , and osteoclastogenesis was assessed by counting the multinucleated cells ( those staining positive for tartrate - resistant acid phosphatase ) . RESULTS : The Q9GZX6 concentration in the synovial fluid was higher in RA patients than in patients with osteoarthritis ( OA ) . The serum Q9GZX6 concentration was also higher in RA patients than in OA patients and healthy volunteers , and this correlated with serum titers of rheumatoid factor and anti - cyclic citrullinated peptide antibodies . In RA synovial fibroblasts treated with rhIL - 22 , the expression of O14788 mRNA and protein was increased in a dose - dependent manner . Q9GZX6 - induced O14788 expression was down - regulated significantly by the inhibition of p38 MAPK / NF - κB or O60674 / P35610 - 3 signaling . In human monocytes cocultured with Q9GZX6 - prestimulated RA synovial fibroblasts in the absence of exogenous O14788 , the monocytes differentiated into osteoclasts , but this osteoclastogenesis decreased after p38 MAPK / NF - κB or O60674 / P35610 - 3 signaling was inhibited . CONCLUSION : These results show that Q9GZX6 up - regulates O14788 expression in RA synovial fibroblasts and induces osteoclastogenesis . These effects are mediated by the p38 MAPK / NF - κB and O60674 / P35610 - 3 signaling pathways .", "β - cryptoxanthin regulates bone resorption related - cytokine production in human periodontal ligament cells . OBJECTIVE : β - cryptoxanthin ( β - cry ) is a type of carotenoid found in certain fruits and vegetables . Although it has been shown that β - cry inhibits alveolar bone resorption , the molecular mechanisms for this have not yet been clarified . In the present study , we investigated the effects of β - cry on bone resorption related - cytokine production in human periodontal ligament ( hPDL ) cells . DESIGN : hPDL cells were stimulated with β - cry ( 1 × 10 (- 7 ) mol / l ) , mechanical stress ( 1 or 6MPa ) , and P . gingivalis . The production of interleukin ( IL ) - 1β , P05231 , P10145 , tumour necrosis factor ( P01375 ) - α , osteoprotegerin ( O00300 ) , and receptor activator of nuclear factor kappa - B ligand ( O14788 ) were analyzed by RT - PCR and ELISA . RESULTS : The production of IL - 1β , P05231 , P10145 , and P01375 - α was not induced in hPDL cells after stimulation with β - cry , although these cytokines were produced after stimulation with P . gingivalis . On the other hand , P05231 and P10145 were produced after exposure to 6MPa of mechanical stress . The production of P05231 and P10145 was significantly decreased by the addition of β - cry . Furthermore , β - cry up - regulated the production of O00300 , but not O14788 . CONCLUSION : β - cry inhibited the production of P05231 and P10145 induced by mechanical stress and periodontopathogenic bacteria in hPDL cells . Moreover , β - cry up - regulated O00300 production . These results suggest that β - cry may prevent bone resorption in periodontitis .", "[ A novel function of anti - fibrinolytic factor , P05121 , in the central nervous system : a possible role as the neurotrophic factor ] . P00747 activator inhibitor - 1 ( P05121 ) is a serpin that suppresses fibrinolysis by inhibiting the activity of plasminogen activator ( PA ) . Together with PA , P05121 is expressed in the central nervous system and may play a role in the regulation of PA activity . Our present study has demonstrated that , in cultures of PC - 12 neurons , depletion of P05121 from the culture medium induces disappearance of the cell ' s neurites and the cell death . ___MASK87___ and antipain , the inhibitors of PA , were not counterparts of P05121 in the protection of neurite disappearance . We also found that P05121 had the abilities to promote release of the survival factors of neurons , P05231 and P15692 and activation of a survival serine / threonine kinase Akt . These results suggest that P05121 has physiological functions other than its role as PA inhibitor for the survival of neurons .", "New insights into the pathophysiology of multiple myeloma . For understanding of the pathophysiology of multiple myeloma , features of the malignant clone and changes induced by the bone - marrow microenvironment are equally important . Multiple myeloma plasma cells , which originate from postfollicular B cells , are characterised by complex chromosomal aberrations . Among the earliest genetic events are translocations of the immunoglobulin heavy - chain gene locus , which leads to dysregulation of oncogenes at translocation partner regions ( cyclin D1 at 11q13 , P22607 / O96028 at 4p16 . 3 , c - O75444 at 16q23 , and cyclin D3 at 6p21 ) , and deletions of 13q14 , the site of a putative tumour suppressor gene , which is an adverse prognostic indicator . Additional molecular events include epigenetic changes and activation of oncogenes ( mutations of N - DB01367 and K - DB01367 , and changes in c - MYC ) , which are usually associated with disease progression . Bone - marrow stromal cells support growth and survival of multiple myeloma cells via various cytokines . Osteoclast activity factors ( in particular MIP1alpha ) and imbalances between O14788 and osteoprotegerin are major factors for the development of myeloma bone disease . Further characterisation of crucial events in the development of monoclonal gammopathies by novel techniques such as global gene expression profiling will contribute to a molecular classification of multiple myeloma and foster future therapeutic approaches .", "DB06643 for joints and bones . DB06643 is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . DB06643 suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . DB06643 reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .", "P01375 alpha mediates GABA ( A ) receptor trafficking to the plasma membrane of spinal cord neurons in vivo . The proinflammatory cytokine TNFα contributes to cell death in central nervous system ( CNS ) disorders by altering synaptic neurotransmission . TNFα contributes to excitotoxicity by increasing P42262 - lacking AMPA receptor ( AMPAR ) trafficking to the neuronal plasma membrane . In vitro , increased AMPAR on the neuronal surface after TNFα exposure is associated with a rapid internalization of GABA ( A ) receptors ( GABA ( A ) Rs ) , suggesting complex timing and dose dependency of the CNS ' s response to TNFα . However , the effect of TNFα on GABA ( A ) R trafficking in vivo remains unclear . We assessed the effect of TNFα nanoinjection on rapid GABA ( A ) R changes in rats ( N = 30 ) using subcellular fractionation , quantitative western blotting , and confocal microscopy . GABA ( A ) R protein levels in membrane fractions of TNFα and vehicle - treated subjects were not significantly different by Western Blot , yet high - resolution quantitative confocal imaging revealed that TNFα induces GABA ( A ) R trafficking to synapses in a dose - dependent manner by 60 min . TNFα - mediated GABA ( A ) R trafficking represents a novel target for CNS excitotoxicity .", "DB06643 -- an emerging treatment for postmenopausal osteoporosis . IMPORTANCE OF THE FIELD : Osteoporosis is a common skeletal disease that is associated with an imbalance in bone remodeling . DB06643 is an investigational fully human monoclonal antibody to receptor activator of NF - kappaB ligand ( O14788 ) , a cytokine member of the P01375 family that is the principal mediator of osteoclastic bone resorption . AREAS COVERED IN THIS REVIEW : The efficacy and safety of denosumab in the management of postmenopausal osteoporosis is evaluated by reviewing the published literature and presentations at scientific meetings through 2009 . WHAT THE READER WILL GAIN : This review focuses on the data on fracture risk reduction and safety endpoints of denosumab in the treatment of postmenopausal osteoporosis . TAKE HOME MESSAGE : In postmenopausal women with osteoporosis , denosumab ( 60 mg by subcutaneous injection every 6 months ) increased bone mineral density , reduced bone turnover markers , and reduced the risk of vertebral , hip and non - vertebral fractures . DB06643 was well tolerated with a safety profile generally similar to placebo . It is a promising emerging drug for the prevention and treatment of postmenopausal osteoporosis .", "DB09210 defines a new binding site for allosteric modulators of alpha - amino - 3 - hydroxy - 5 - methyl - 4 - isoxazole - propionic acid ( AMPA ) receptors . Glutamate receptors are the most prevalent excitatory neurotransmitter receptors in the vertebrate central nervous system and are important potential drug targets for cognitive enhancement and the treatment of schizophrenia . Allosteric modulators of AMPA receptors promote dimerization by binding to a dimer interface and reducing desensitization and deactivation . The pyrrolidine allosteric modulators , piracetam and aniracetam , were among the first of this class of drugs to be discovered . We have determined the structure of the ligand binding domain of the AMPA receptor subtypes P42262 and P42263 with piracetam and a corresponding structure of P42263 with aniracetam . Both drugs bind to P42262 and P42263 in a very similar manner , suggesting little subunit specificity . However , the binding sites for piracetam and aniracetam differ considerably . ___MASK49___ binds to a symmetrical site at the center of the dimer interface . DB09210 binds to multiple sites along the dimer interface with low occupation , one of which is a unique binding site for potential allosteric modulators . This new site may be of importance in the design of new allosteric regulators .", "Vitamin D metabolism , mechanism of action , and clinical applications . DB00169 is made in the skin from 7 - dehydrocholesterol under the influence of UV light . ___MASK20___ ( ergocalciferol ) is derived from the plant sterol ergosterol . Vitamin D is metabolized first to 25 hydroxyvitamin D ( 25OHD ) , then to the hormonal form 1 , 25 - dihydroxyvitamin D ( 1 , 25 ( OH ) 2D ) . Q6VVX0 is the most important 25 - hydroxylase ; O15528 is the key 1 - hydroxylase . Both 25OHD and 1 , 25 ( OH ) 2D are catabolized by Q07973 . 1 , 25 ( OH ) 2D is the ligand for the vitamin D receptor ( P11473 ) , a transcription factor , binding to sites in the DNA called vitamin D response elements ( VDREs ) . There are thousands of these binding sites regulating hundreds of genes in a cell - specific fashion . P11473 - regulated transcription is dependent on comodulators , the profile of which is also cell specific . Analogs of 1 , 25 ( OH ) 2D are being developed to target specific diseases with minimal side effects . This review will examine these different aspects of vitamin D metabolism , mechanism of action , and clinical application .", "Inverse association between phospholipase A2 and P35354 expression during mouse colon tumorigenesis . Cytosolic phospholipase A ( 2 ) ( cPLA ( 2 ) ) releases arachidonic acid ( AA ) from intracellular phospholipids . We evaluated the status of cPLA ( 2 ) in azoxymethane ( AOM ) - induced mouse colon tumors . Despite increased expression of cyclooxygenase 2 ( 3 . 7 - fold ) and PGE ( 2 ) ( 3 . 4 - fold ) production in tumors , cPLA ( 2 ) mRNA levels and enzyme activity were significantly reduced ( 3 . 6 - and 3 - fold , respectively ) . Reduced levels of cPLA ( 2 ) were also observed in pre - neoplastic aberrant crypt foci ( Q9NQ94 ) , a distinct morphological alteration that represents an early stage in the pathogenesis of colon tumors . Furthermore , the reciprocal expression patterns of these two genes were found to occur in human colorectal cancers ( CRC ) . Examination of the activity of the secretory phospholipases A ( 2 ) ( sPLA ( 2 ) ) and expression of the groups V and X sPLA ( 2 ) s revealed no compensatory increase in tumor tissue . As cPLA ( 2 ) has been shown to be involved in P01375 - induced apoptosis in certain cell types , and P01375 expression is significantly enhanced in AOM - induced tumors ( 2 . 8 - fold ) , we examined the role of cPLA ( 2 ) in P01375 - induced apoptosis of cultured mouse colonocytes ( YAMC ) . The specific cPLA ( 2 ) inhibitor , AACOCF ( 3 ) ( arachidonoyl trifluoromethyl ketone ) , was able to protect colonocytes from P01375 - induced apoptosis in vitro . In summary , our data demonstrate an inverse relationship between P35354 and cPLA ( 2 ) expression in both AOM - induced mouse colon tumors and human CRC and suggest that down regulation of cPLA ( 2 ) may attenuate P01375 mediated apoptosis during tumorigenesis and facilitate tumor progression .", "Endoplasmic reticulum calcium depletion impacts chaperone secretion , innate immunity , and phagocytic uptake of cells . A number of immunological functions are ascribed to cell surface - expressed forms of the endoplasmic reticulum ( ER ) chaperone calreticulin ( CRT ) . In this study , we examined the impact of ER stress - inducing drugs upon cell surface CRT induction and the resulting immunological consequences . We showed that cell surface expression of CRT and secretion of CRT , P11021 , gp96 , and P07237 were induced by thapsigargin ( THP ) treatment , which depletes ER calcium , but not by tunicamycin treatment , which inhibits protein glycosylation . Surface expression of CRT in viable , THP - treated fibroblasts correlated with their enhanced phagocytic uptake by bone marrow - derived dendritic cells . Incubation of bone marrow - derived dendritic cells with THP - treated fibroblasts enhanced sterile P05231 production and LPS - induced generation of IL - 1β , IL - 12 , IL - 23 , and P01375 - α . However , extracellular CRT is not required for enhanced proinflammatory responses . Furthermore , the pattern of proinflammatory cytokine induction by THP - treated cells and cell supernatants resembled that induced by THP itself and indicated that other ER chaperones present in supernatants of THP - treated cells also do not contribute to induction of the innate immune response . Thus , secretion of various ER chaperones , including CRT , is induced by ER calcium depletion . CRT , previously suggested as an eat - me signal in dead and dying cellular contexts , can also promote phagocytic uptake of cells subject to ER calcium depletion . Finally , there is a strong synergy between calcium depletion in the ER and sterile P05231 , as well as LPS - dependent IL - 1β , IL - 12 , IL - 23 , and P01375 - α innate responses , findings that have implications for understanding inflammatory diseases that originate in the ER .", "Structural analysis of the human fibroblast growth factor receptor 4 kinase . The family of fibroblast growth factor receptors ( FGFRs ) plays an important and well - characterized role in a variety of pathological disorders . P22455 is involved in myogenesis and muscle regeneration . Mutations affecting the kinase domain of P22455 may cause cancer , for example , breast cancer or rhabdomyosarcoma . Whereas P11362 - P22607 have been structurally characterized , the structure of the P22455 kinase domain has not yet been reported . In this study , we present four structures of the kinase domain of P22455 , in its apo - form and in complex with different types of small - molecule inhibitors . The two apo - P22455 kinase domain structures show an activation segment similar in conformation to an autoinhibitory segment observed in the hepatocyte growth factor receptor kinase but different from the known structures of other FGFR kinases . The structures of P22455 in complex with the type I inhibitor Dovitinib and the type II inhibitor ___MASK25___ reveal the molecular interactions with different types of kinase inhibitors and may assist in the design and development of P22455 inhibitors .", "DB02527 inhibition of murine intestinal Na / H exchange requires P13569 - mediated cell shrinkage of villus epithelium . BACKGROUND AND AIMS : Unlike the intestine of normal subjects , small - intestinal epithelia of cystic fibrosis patients and cystic fibrosis transmembrane conductance regulator protein - null ( P13569 (-) ) mice do not respond to stimulation of intracellular cyclic adenosine monophosphate with inhibition of electroneutral NaCl absorption . Because P13569 - mediated anion secretion has been associated with changes in crypt cell volume , we hypothesized that P13569 - mediated cell volume reduction in villus epithelium is required for intracellular cyclic adenosine monophosphate inhibition of Na (+)/ H (+) exchanger ( primarily P48764 ) activity in the proximal small intestine . METHODS : Transepithelial ( 22 ) Na flux across the jejuna of P13569 (+) , P13569 (-) , the basolateral membrane Na (+)/ K (+)/ 2Cl (-) co - transporter protein P55011 (+) , and P55011 (-) mice were correlated with changes in epithelial cell volume of the midvillus region . RESULTS : Stimulation of intracellular cyclic adenosine monophosphate resulted in cessation of Na (+)/ H (+) exchanger - mediated Na (+) absorption ( J ( ms )( NHE ) ) in P13569 (+) jejunum but had no effect on J ( ms )( NHE ) across P13569 (-) jejunum . Cell volume indices indicated an approximately 30 % volume reduction of villus epithelial cells in P13569 (+) jejunum but no changes in P13569 (-) epithelium after intracellular cyclic adenosine monophosphate stimulation . In contrast , cell shrinkage induced by hypertonic medium inhibited J ( ms )( NHE ) in both P13569 (+) and P13569 (-) mice . ___MASK94___ treatment to inhibit Cl (-) secretion by blockade of the Na (+)/ K (+)/ 2Cl (-) co - transporter , P55011 , of stimulated P13569 (+) jejunum prevented maximal volume reduction of villus epithelium and recovered approximately 40 % of J ( ms )( NHE ) . Likewise , J ( ms )( NHE ) and cell volume were unaffected by intracellular cyclic adenosine monophosphate stimulation in P55011 (-) jejuna . CONCLUSIONS : These findings show a previously unrecognized role of functional P13569 expressed in villus epithelium : regulation of P48764 - mediated Na (+) absorption by alteration of epithelial cell volume .", "The metabolism of 25 -( OH ) vitamin D3 by osteoclasts and their precursors regulates the differentiation of osteoclasts . Current evidence suggests that levels of 25 -( OH ) vitamin D3 ( 25D ) , rather than 1alpha , 25 -( OH ) 2vitamin D3 ( 1 , 25D ) , directly affect bone mineralization and that the skeleton is a site of extra - renal synthesis of 1 , 25D . Since cells of the monocyte lineage can also metabolise 25D , it is possible that osteoclasts participate in local production of , and the response to , 1 , 25D . In this study , we investigated the effects of vitamin D metabolism on osteoclastogenesis using both the murine RAW 264 . 7 cell line and the human peripheral blood mononuclear cell ( PBMC ) models . PBMC - derived osteoclasts expressed cytoplasmic cyp27b1 and nuclear vdr proteins . PBMC expressed O15528 mRNA , levels of which increased during O14788 induced differentiation into osteoclasts in both cell types . While 1 , 25D elicited a robust Q07973 transcriptional response in PBMC , the response to 25D was approximately 100 - fold less at the concentrations used . Using media devoid of pre - existing vitamin D metabolites , we found that 25D was metabolised by RAW 264 . 7 cells to 1 , 25D and resulted in significant elevation in the numbers of TRAP - positive , multinucleated osteoclasts when present in the cultures for the first 3 - 5 days . These results suggest that vitamin D metabolism by osteoclast lineage cells is an important regulator of osteoclast formation .", "DB00207 fails to reduce inflammation in cystic fibrosis airway epithelial cells . Cystic fibrosis is a hereditary disease caused by a mutation in the Cystic Fibrosis Transmembrane conductance Regulator ( P13569 ) gene that encodes a chloride ( Cl (-) ) channel . Cystic fibrosis pulmonary pathophysiology is characterised by chronic inflammation and bacterial infections . DB00207 , a macrolide antibiotic , has shown promising anti - inflammatory properties in some inflammatory pulmonary diseases . Moreover , all clinical studies have presented an improvement of the respiratory condition of cystic fibrosis patients , but the molecular and cellular mechanisms remain unknown . The aim of this study was to investigate , in bronchial epithelial cells , the effects of azithromycin on inflammatory pathways involved in cystic fibrosis . We have analysed the effects of azithromycin on cystic fibrosis and non - cystic fibrosis bronchial epithelial cell lines but also in non - immortalized non - cystic fibrosis human glandular cells . To create an inflammatory context , cells were treated with Tumor Necrosis Factor ( P01375 ) - α or Interleukin ( IL ) 1 - β . Activation of the NF - κB pathway was investigated by luciferase assay , western blotting , and by Förster Resonance Energy Transfer imaging , allowing the detection of the interaction between the transcription factor and its inhibitor in live cells . In all conditions tested , azithromycin did not have an anti - inflammatory effect on the cystic fibrosis human bronchial epithelial cells and on P13569 - inhibited primary human bronchial glandular cells . More , our data showed no effect of azithromycin on IL - 1β - or P01375 - α - induced P10145 secretion and NF - κB pathway activation . Taken together , these data show that azithromycin is unable to decrease in vitro inflammation in cystic fibrosis cells from airways .", "___MASK95___ inhibits the chaperone activity of protein disulfide isomerase . In the process of screening of proteins binding to ribostamycin in bovine liver using the affinity column chromatography , we found that ribostamycin inhibited the chaperone activity of protein disulfide isomerase ( P07237 ) , but it did not inhibit the isomerase activity . P07237 was identified by SDS - PAGE , Western blotting , and N - terminal amino acid sequence analysis . A 100 : 1 molar ratio of ribostamycin to P07237 was almost sufficient to completely inhibit the chaperone activity of P07237 . The binding affinity of ribostamycin to purified bovine P07237 was determined by the Biacore system , which gave a K ( D ) value of 3 . 19 x 10 (- 4 ) M . This suggests that ribostamycin binds to region distinct from the CGHC motif of P07237 . This is the first report to describe the inhibitor of the chaperone activity of P07237 .", "Activation of O14788 - induced osteoclasts and memory T lymphocytes by Porphyromonas gingivalis is serotype dependant . AIM : Destructive periodontitis is associated with a Th1 - Th17 immune response and activation of O14788 - induced osteoclasts . In addition , Porphyromonas gingivalis P04264 and K2 serotypes induce a strong Th1 - Th17 response . This study aimed to investigate whether these P . gingivalis serotypes induce higher osteoclasts activation , by increased Th17 - associated O14788 production , and an antigen - specific memory T - lymphocyte response . MATERIAL AND METHODS : The O14788 production and TRAP (+) osteoclast induction were quantified on naïve T lymphocytes stimulated with dendritic cells primed with the P . gingivalis serotypes . The T - bet , GATA - 3 , RORC2 and Foxp3 expression was correlated with O14788 production . The frequency of proliferating memory T lymphocytes in response to P . gingivalis serotypes was determined in both periodontitis and healthy subjects . RESULTS : T lymphocytes stimulated by P04264 or K2 - primed dendritic cells elicited higher levels of O14788 and TRAP (+) osteoclasts than cells stimulated with the other serotypes . O14788 positively correlated with RORC2 . Whereas periodontitis patients had a higher frequency of memory T lymphocytes responding to P04264 or K2 , healthy subjects had a higher frequency of memory T lymphocytes responding to P19013 or K (-) . CONCLUSIONS : P . gingivalis serotypes P04264 and K2 , but not others , are associated with an increased production of the osteoclastogenesis - related factor O14788 . This important information suggests that these serotypes could elicit a greater bone resorption in vivo and have a role in the periodontitis pathogenesis .", "Comparative effects of azimilide and ambasilide on the human ether - a - go - go - related gene ( Q12809 ) potassium channel . OBJECTIVE : To evaluate the effects of azimilide and ambasilide on the biophysical properties of the human - ether - a - go - go - related ( Q12809 ) channel . METHODS : Q12809 was stably transfected into Chinese hamster ovary ( CHO - P04264 ) cells and currents were measured using a whole cell , voltage - clamp technique . RESULTS : ___MASK82___ had a ' dual effect ' , inhibiting current at voltage steps above - 40 mV and augmenting current at - 40 and - 50 mV . Tail current inhibition following a step to + 30 mV did not vary with temperature ( IC ( 50 ) 610 nM at 22 degrees C and 560 nM at 37 degrees C ) . The agonist effect at - 50 mV was concentration - dependent and correlated with a hyperpolarizing shift in the V ( 1 / 2 ) of activation ( r = 0 . 98 , P < 0 . 05 ) . Time constants of inactivation were faster and there was a - 10 mV shift in the V ( 1 / 2 ) of steady state inactivation suggestive of open and inactivated state binding . By comparison , ambasilide inhibited Q12809 channels with lower potency ( IC ( 50 ) 3 . 6 microM ) , in a voltage - and time - dependent but frequency - independent manner ( 0 . 03 - 1 Hz ) . Ambasilide had no effect on activation or inactivation gating but prolonged both fast and slow components of deactivation consistent with unbinding from the open state . The net effect of both drugs was similar during a voltage ramp which simulated a cardiac action potential . CONCLUSIONS : Inhibition of Q12809 channels by azimilide and ambasilide exhibits a similar time and voltage - dependence . While both exhibit affinity for the open state , azimilide also binds to inactivated channels ." ]
[ "___MASK18___", "___MASK20___", "___MASK25___", "___MASK49___", "___MASK72___", "___MASK82___", "___MASK87___", "___MASK94___", "___MASK95___" ]
___MASK18___
MH_train_1605
interacts_with DB00864?
[ "Heterologous downregulation of vasopressin type 2 receptor is induced by transferrin . ___MASK79___ ( VP ) binds to the vasopressin type 2 receptor ( P30518 ) to trigger physiological effects including body fluid homeostasis and blood pressure regulation . Signaling is terminated by receptor downregulation involving clathrin - mediated endocytosis and P30518 degradation . We report here that both native and epitope - tagged P30518 are internalized from the plasma membrane of LLC - P30613 kidney epithelial cells in the presence of another ligand , transferrin ( Tf ) . The presence of iron - saturated Tf ( holo - Tf ; 4 h ) reduced P30518 binding sites at the cell surface by up to 33 % while iron - free ( apo - Tf ) had no effect . However , no change in green fluorescent protein - tagged P30518 distribution was observed in the presence of bovine serum albumin , atrial natriuretic peptide , or P03950 II . Conversely , holo - Tf did not induce the internalization of another G protein - coupled receptor , the parathyroid hormone receptor . In contrast to the effect of VP , Tf did not increase intracellular DB02527 or modify aquaporin - 2 distribution in these cells , although addition of VP and Tf together augmented VP - induced P30518 internalization . Tf receptor coimmunoprecipitated with P30518 , suggesting that they interact closely , which may explain the additive effect of VP and Tf on P30518 endocytosis . Furthermore , Tf - induced P30518 internalization was abolished in cells expressing a dominant negative dynamin ( K44A ) mutant , indicating the involvement of clathrin - coated pits . We conclude that Tf can induce heterologous downregulation of the P30518 and this might desensitize VP target cells without activating downstream P30518 signaling events . It also provides new insights into urine - concentrating defects observed in rat models of hemochromatosis .", "A proliferation switch for genetically modified cells . Receptor dimerization is the key signaling event for many cytokines , including erythropoietin . A system has been recently developed that permits intracellular protein dimerization to be reversibly activated in response to a lipid - soluble dimeric form of the drug FK506 , called FK1012 . FK1012 is used as a pharmacological mediator of dimerization to bring together FK506 binding domains , taken from the endogenous protein P62942 . In experiments reported herein , FK1012 - induced dimerization of a fusion protein containing the intracellular portion of the erythropoietin receptor allowed cells normally dependent on interleukin 3 to proliferate in its absence . FK506 competitively reversed the proliferative effect of FK1012 but had no influence on the proliferative effect of interleukin 3 . Signaling pathways activated by FK1012 mimicked those activated by erythropoietin , because both O60674 and P42229 were phosphorylated in response to FK1012 . This approach may provide a means to specifically and reversibly stimulate the proliferation of genetically modified cell populations in vitro or in vivo .", "Interaction of tacrolimus ( FK506 ) and its metabolites with FKBP and calcineurin . DB00864 ( FK506 ) is a strong immuno - suppressant and shows its activity through inhibiting P60568 mRNA transcription by forming pentameric complex with intracellular receptor ( FK506 binding protein 12 kDa or P62942 ) , Ca2 + , calmodulin , and calcineurin . Here , we report the binding activity to P62942 , the pentameric complex formation and Con - A response inhibiting activities of 7 metabolites . C15 - demethylated metabolite ( M - 3 ) needed higher quantity to compete in Con - A assay and in pentamer formation assay , although it binds more strongly to P62942 . The result suggests that the ability to form a pentameric complex is not a two step reaction with the first binding to P62942 , but a single step reaction by components for the pentamer formation .", "Met326Ile aminoacid polymorphism in the human p85 alpha gene has no major impact on early insulin signaling in type 2 diabetes . Class I alpha phosphatidylinositol ( PI ) 3 - kinase is an important enzyme in the early insulin signaling cascade , and plays a key role in insulin - mediated glucose transport . Despite extensive investigation , the genes responsible for the development of the common forms of type 2 diabetes remain unknown . This study was performed to identify variants in the coding region of p85 alpha , the regulatory subunit of PI 3 - kinase . Fibroblasts from skin biopsies from type 2 diabetics and controls were established to address this issue . P85 alpha cDNA was sequenced , and a single point mutation at codon 326 was found . This mutation resulted in a homozygous missense amino acid change DB00134 --> ___MASK25___ in one subject with type 2 diabetes and heterozygous variant in two other diabetic patients and one with severe insulin resistance . Interestingly , those patients revealed an impaired insulin - mediated insulin receptor substrate ( P41252 ) - 1 binding to p85 alpha without any alteration in Q9Y4H2 / p85 alpha association . Furthermore , P35568 , Q9Y4H2 , p85 alpha and MAPK protein contents were not significantly changed , and neither were MAPK or Akt phosphorylation . We conclude from our data that this variant may have only minor impact on signaling events ; however , in combination with variants in other genes encoding signaling proteins , this may have a functional impact on early insulin signaling .", "Potentiation of P01138 - induced neurite outgrowth in PC12 cells by papaverine : role played by P98160 - γ , IP3 receptors . ___MASK17___ , an inhibitor of phosphodiesterase ( PDE ) 10A , is gaining attention for its potential in the treatment of neuropsychiatric diseases such as schizophrenia . However , the precise mechanisms underlying the putative neuroprotective / neurotrophic actions of papaverine remain unclear . Thus , we investigated the effects of papaverine on nerve growth factor ( P01138 ) - induced neurite outgrowth in PC12 cells . ___MASK17___ potentiated P01138 - induced neurite outgrowth in PC12 cells in a concentration - dependent manner . In contrast , the selective Q9Y233 inhibitor MP - 10 had no effect on P01138 - induced neurite outgrowth . The potentiation of P01138 - induced neurite outgrowth by papaverine was blocked by the P98160 - γ inhibitor U73122 . Furthermore , papaverine ' s potentiation of P01138 - induced neurite outgrowth was also blocked by the co - administration of inositol 1 , 4 , 5 - trisphosphate ( IP ( 3 ) ) receptor antagonists ( xestospongin C and 2 - aminoethoxydiphenyl borate ( 2 - Q9H4A4 ) ) and by reduced expression of IP ( 3 ) receptor gene ( i . e . , itpr1 and itpr3 ) by siRNA . Our findings suggest that papaverine could potentiate P01138 - induced neurite outgrowth , and that activation of P98160 - γ and IP ( 3 ) receptors might be involved in the mechanism underlying papaverine ' s potentiation of neurite outgrowth in PC12 cells .", "Phase I evaluation of ___MASK27___ , an oral , potent , and selective O60674 inhibitor . This phase I study evaluated selective O60674 inhibitor ___MASK27___ in 30 patients with myelofibrosis . The initial dose cohorts were 100 , 200 , and 300 mg orally on days 1 - 21 of a 28 - day cycle . Central and / or peripheral neurotoxicity developed in all patients . Subsequently , patients were treated on lower doses ; neurotoxicity was again observed , leading to study termination . Peripheral neuropathy resolved in 50 % , and central neurotoxicity in all patients within months after therapy cessation . Myelosuppression was minimal . The terminal half - life of ___MASK27___ was approximately 21 h , with steady state reached by Day 8 . International Working Group defined responses were seen in three ( 10 % ) patients .", "Endothelial cell transforming growth factor - β receptor activation causes tacrolimus - induced renal arteriolar hyalinosis . Arteriolar hyalinosis is a common histological finding in renal transplant recipients treated with the calcineurin inhibitor tacrolimus ; however , the pathophysiologic mechanisms remain unknown . In addition to increasing transforming growth factor ( TGF ) - β levels , tacrolimus inhibits calcineurin by binding to FK506 - binding protein 12 ( P62942 ) . P62942 alone also inhibits TGF - β receptor activation . Here we tested whether tacrolimus binding to P62942 removes an inhibition of the TGF - β receptor , allowing ligand binding , ultimately leading to receptor activation and arteriolar hyalinosis . We found that specific deletion of P62942 from endothelial cells was sufficient to activate endothelial TGF - β receptors and induce renal arteriolar hyalinosis in these knockout mice , similar to that induced by tacrolimus . DB00864 - treated and knockout mice exhibited significantly increased levels of aortic TGF - β receptor activation as evidenced by Q15796 / 3 phosphorylation , along with increased collagen and fibronectin expression compared to controls . Treatment of isolated mouse aortas with tacrolimus increased TGF - β receptor activation and collagen and fibronectin expression . These effects were independent of calcineurin , absent in endothelial denuded aortic rings , and could be prevented by the small molecule TGF - β receptor inhibitor SB - 505124 . Thus , endothelial cell TGF - β receptor activation is sufficient to cause vascular remodeling and renal arteriolar hyalinosis .", "Activin A augments DB00644 - mediated transcriptional activation of the mouse P30968 gene . The response of pituitary gonadotropes to DB00644 correlates directly with the concentration of DB00644 receptors ( GnRHRs ) on the cell surface , which is mediated in part at the level of GnRHR gene expression . We have previously localized DB00644 responsiveness in the mouse GnRHR ( mGnRHR ) gene promoter to two elements : activating protein - 1 and sequence underlying responsiveness to DB00644 - 1 . This study was designed to investigate potential synergy between DB00644 and activin A in transcriptional activation of the mGnRHR gene . In functional transfection studies using alphaT3 - 1 cells , DB00644 agonist stimulation of the mGnRHR gene promoter ( - 765 /+ 62 ) resulted in a 10 . 9 - fold increase in activity , which was further increased 2 - fold ( to 21 . 3 - fold ) following activin pretreatment . Activin pretreatment alone had no effect . Deletion of region - 387 /- 308 or mutation of a putative SMAD - binding element at - 331 /- 324 ( 5 '- GTCTAG [ T ] C - 3 ' ) abrogated the augmented response to DB00644 in the presence of activin but not the response to DB00644 alone . Overexpression of Q15796 and P84022 along with Q13485 increased transcriptional activity of the mGnRHR gene , which was further increased by DB00644 agonist stimulation . These data demonstrate that activin augments DB00644 - mediated transcriptional activation of the mGnRHR gene and suggest that this effect may be mediated through SMAD transcription factors .", "Genomewide analysis of inherited variation associated with phosphorylation of PI3K / AKT / P42345 signaling proteins . While there exists a wealth of information about genetic influences on gene expression , less is known about how inherited variation influences the expression and post - translational modifications of proteins , especially those involved in intracellular signaling . The PI3K / AKT / P42345 signaling pathway contains several such proteins that have been implicated in a number of diseases , including a variety of cancers and some psychiatric disorders . To assess whether the activation of this pathway is influenced by genetic factors , we measured phosphorylated and total levels of three key proteins in the pathway ( P31749 , p70S6K , Q13541 ) by ELISA in 122 lymphoblastoid cell lines from 14 families . Interestingly , the phenotypes with the highest proportion of genetic influence were the ratios of phosphorylated to total protein for two of the pathway members : P31749 and p70S6K . Genomewide linkage analysis suggested several loci of interest for these phenotypes , including a linkage peak for the P31749 phenotype that contained the P31749 gene on chromosome 14 . Linkage peaks for the phosphorylated : total protein ratios of P31749 and p70S6K also overlapped on chromosome 3 . We selected and genotyped candidate genes from under the linkage peaks , and several statistically significant associations were found . One polymorphism in P07900 was associated with the ratio of phosphorylated to total P31749 , and polymorphisms in P04049 and Q14831 were associated with the ratio of phosphorylated to total p70S6K . These findings , representing the first genomewide search for variants influencing human protein phosphorylation , provide useful information about the PI3K / AKT / P42345 pathway and serve as a valuable proof of concept for studies integrating human genomics and proteomics .", "[ ___MASK100___ administration reduces the number of P07900 - positive germ cells in the mouse embryo : preliminary results ] . 5 mg of ___MASK100___ , an inhibitor of stress protein P07900 which express on mammalian germ cells , were administered to E8 pregnant mice . E17 embryos were removed , and a quantitative analysis of HSP90 - immunoreactive cells in the gonad was performed , in comparison to control embryos . First , we observed that the number of germ cells is lower in male than in female embryos , as well in control and experimental embryos . External features of experimental and control embryos did not display any difference . Embryos exposed to geldanamycin exhibit a significant decrease of immunoreactive germ cells . In two embryos , we observed a group of ectopic immunoreactive cells in the pelvic area . We conclude that geldanamycin inhibits germ cells migration , and suggest that this inhibition can lead to ectopic germ cell populations , similar to teratomas .", "Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . DB00864 ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .", "P01730 (+) regulatory T cells in autoimmunity and allergy . Regulatory T cells ( also referred to as suppressor T cells ) are important components of the homeostasis of the immune system , as impaired regulatory T cell activity can cause autoimmune diseases and atopy . It is now clear that the phrase ' regulatory T cells ' encompasses more than one cell type . For instance , P01730 (+) CD25 (+) regulatory T cells have received attention due to their immunosuppressive properties in vitro and in vivo , but in several instances it has been shown that P01730 (+) CD25 (-) T cell populations also contain potent regulatory activity . Recent progress in the field of regulatory T cells includes the discovery of the role of two tumor necrosis factor receptor ( TNFR ) family members ( Q9Y5U5 and O14788 - R / Q9Y6Q6 ) in Treg biology , the improved understanding of the role of co - stimulatory molecules and cytokines P22301 and P60568 in the induction and function of Tregs , and the generation of CD25 (+) and CD25 (-) regulatory T cells in vivo through high - avidity T cell receptor interactions .", "Attenuation of the progression of adjuvant - induced arthritis by 3 - aminobenzamide treatment . Rheumatoid arthritis ( RA ) is a disease that is still insufficiently controlled by current treatments . Poly ( ADP - ribose ) polymerase ( PARP ) inhibitors ameliorate immune - mediated diseases in several experimental models , including RA , colitis , experimental autoimmune encephalomyelitis and allergy . Together these findings showed that ADP - ribosylating enzymes , in particular P09874 , play a pivotal role in the regulation of immune responses and may represent a noble target for new therapeutic approaches in immune - mediated diseases . The effect of 3 - aminobenzamide ( 3 - AB ) , an inhibitor of poly ( ADP - ribose ) synthetase activity , was evaluated in a mouse model of adjuvant - induced arthritis ( AIA ) on pro - inflammatory cytokines , adhesion molecules , inflammatory mediators and chemokine production / expression in serum and knee joint . Histopathological examination was also done on joint section . Our data demonstrates that 3 - AB , 10mg / kg , intraperitoneally ( i . p . ) significantly reduces pro - inflammatory cytokine ( Q16552 , P01375 - α and P60568 ) and chemokine ( P13500 and MIP - 2 ) production / expression , accompanied by amelioration of the disease as indicated by reduced paw swelling and arthritic scores and was associated with a significant reduction of P19320 and P05362 expression in the knee joint . Moreover , the expression of inflammatory mediators ( P35228 , P35354 , P08253 , P14780 ) and joint histological inflammatory damage was also markedly decreased . The results of this study suggest that P09874 inhibitor may play a role in the inflammatory arthritic process after administration of 3 - AB may be a beneficial therapeutic approach .", "Randomised phase II study of siltuximab ( CNTO 328 ) , an anti - P05231 monoclonal antibody , in combination with mitoxantrone / prednisone versus mitoxantrone / prednisone alone in metastatic castration - resistant prostate cancer . PURPOSE : This open - label phase II trial assessed mitoxantrone / prednisone ( M / P ) with and without siltuximab ( CNTO 328 ) , an anti - interleukin - 6 chimeric monoclonal antibody , for patients with metastatic castration - resistant prostate cancer who received prior docetaxel - based chemotherapy . METHODS : Part 1 assessed the safety of biweekly siltuximab 6 mg / kg plus M 12 mg / m ( 2 ) every 3 weeks and P . Part 2 assessed efficacy and safety of siltuximab plus M / P versus M / P alone . The primary end - point was progression - free survival ( PFS ) . Progression was defined as progressive disease per Response Evaluation Criteria in Solid Tumours ( RECIST ) , or ≥ 3 new skeletal lesions with clinical deterioration or without deterioration confirmed by repeated bone scan . Rising prostate - specific antigen was not considered progression . RESULTS : ___MASK86___ plus M / P was well tolerated in Part 1 ( n = 9 ) . In Part 2 , 48 and 49 patients received siltuximab plus M / P or M / P alone , respectively . Enrolment was prematurely terminated by the Independent Data Monitoring Committee since an apparent imbalance in patient baseline characteristics ( favoring the M / P only arm ) made it unlikely that the study could achieve its primary efficacy end - point . Median PFS was 97 days with siltuximab combination and 228 days with M / P alone ( hazard ratio , 1 . 72 ; P = 0 . 043 ) . Use of a novel non - validated PFS definition may have contributed to this result . Abnormal laboratory assessments were more frequent with the combination . Infection and febrile neutropenia rates were similar between groups . Greater P02741 suppression was achieved during siltuximab combination treatment compared with M / P alone ( P = 0 . 0003 ) . CONCLUSION : While siltuximab plus M / P appeared well tolerated , improvement in outcomes was not demonstrated .", "___MASK70___ suppresses osteoclastogenesis induced by O14788 and cancer cells through inhibition of inflammatory pathways : a new use for an old drug . BACKGROUND AND PURPOSE : Most patients with cancer die not because of the tumour in the primary site , but because it has spread to other sites . Common tumours , such as breast , multiple myeloma , and prostate tumours , frequently metastasize to the bone . To search for an inhibitor of cancer - induced bone loss , we investigated the effect of thiocolchicoside , a semi - synthetic colchicoside derived from the plant Gloriosa superba and clinically used as a muscle relaxant , on osteoclastogenesis induced by receptor activator of NF - κB ligand ( O14788 ) and tumour cells . EXPERIMENTAL APPROACH : We used RAW 264 . 7 ( murine macrophage ) cells , a well - established system for osteoclastogenesis , and evaluated the effect of thiocolchicoside on O14788 - induced NF - κB signalling and osteoclastogenesis as well as on osteoclastogenesis induced by tumour cells . KEY RESULTS : ___MASK70___ suppressed osteoclastogenesis induced by O14788 , and by breast cancer and multiple myeloma cells . Inhibition of the NF - κB pathway was responsible for this effect since the colchicoside inhibited O14788 - induced NF - κB activation , activation of IκB kinase ( IKK ) and suppressed inhibitor of NF - κBα ( IκBα ) phosphorylation and degradation , an inhibitor of NF - κB . Furthermore , an inhibitor of the IκBα kinase γ or NF - κB essential modulator , the regulatory component of the IKK complex , demonstrated that the NF - κB signalling pathway is mandatory for osteoclastogenesis induced by O14788 . CONCLUSIONS AND IMPLICATIONS : Together , these data suggest that thiocolchicoside significantly suppressed osteoclastogenesis induced by O14788 and tumour cells via the NF - κB signalling pathway . Thus , thiocolchicoside , a drug that has been used for almost half a century to treat muscle pain , may also be considered as a new treatment for bone loss .", "Modeling and synthesis of non - cyclic derivatives of P06744 - 1046 as potential FKBP ligands with neurotrophic properties . Prompted by the therapeutic potential of the neuroimmunophilin FK506 - binding protein ( FKBP ) ligand , P06744 - 1046 , in the treatment of nerve injuries and neurodegenerative diseases , a novel series of non - cyclic derivatives of P06744 - 1046 were designed and synthesized . Computer modeling analysis revealed that these relatively linear derivatives could energy - favorably bind to P62942 with an analogous binding mode to P06744 - 1046 . The neurotrophic activity of the target compounds was assessed in chick dorsal root ganglion ( Q86YR7 ) cultures . As a result , 6 out of 11 test compounds at either or both concentrations of 1 pM and 100 pM significantly promoted neurite outgrowth in DRGs in the presence of 0 . 15 ng / ml nerve growth factor ( P01138 ) . Compound 5c at 100 pM exhibited the greatest neurotrophic effect in promoting both the number and length of neurite processes . However , in the absence of exogenously added P01138 , all test compounds , including P06744 - 1046 , failed to afford any positive effect on DRGs . This study suggests the intriguing potential of these compounds for further investigation .", "Cloning of a novel phosphatidylinositol kinase - related kinase : characterization of the human Q96Q15 RNA surveillance protein . We have cloned and characterized a new member of the phosphatidylinositol kinase ( PIK ) - related kinase family . This gene , which we term human Q96Q15 ( Q96Q15 ) , is orthologous to Caenorhabditis elegans Q96Q15 , a protein that functions in nonsense - mediated mRNA decay ( Q53H76 ). cDNA sequencing revealed that Q96Q15 encodes a protein of 3031 amino acids containing a conserved kinase domain , a C - terminal domain unique to the PIK - related kinases and an P62942 - rapamycin binding - like domain similar to that found in the PIK - related kinase P42345 . Immunopurified FLAG - tagged Q96Q15 exhibits protein kinase activity as measured by autophosphorylation and phosphorylation of the generic PIK - related kinase substrate PHAS - 1 . Q96Q15 kinase activity is inhibited by high nanomolar concentrations of wortmannin ( IC ( 50 ) = 105 nm ) but is not inhibited by a P62942 - rapamycin complex . Mutation of conserved residues within the kinase domain of Q96Q15 abolishes both autophosphorylation and substrate phosphorylation , demonstrating that Q96Q15 exhibits intrinsic protein kinase activity . Q96Q15 phosphorylates purified Q92900 protein , a phosphoprotein that plays a critical role in Q53H76 , at sites that are also phosphorylated in whole cells . Based on these data , we conclude that Q96Q15 is the human orthologue to C . elegans Q96Q15 . Our data indicate that Q96Q15 may function in Q53H76 by directly phosphorylating Q92900 protein at physiologically relevant sites .", "Identifying new targets in leukemogenesis using computational approaches . There is a need to identify novel targets in Acute Lymphoblastic Leukemia ( ALL ) , a hematopoietic cancer affecting children , to improve our understanding of disease biology and that can be used for developing new therapeutics . Hence , the aim of our study was to find new genes as targets using in silico studies ; for this we retrieved the top 10 % overexpressed genes from Oncomine public domain microarray expression database ; 530 overexpressed genes were short - listed from Oncomine database . Then , using prioritization tools such as ENDEAVOUR , P30518 and TOPPGene online tools , we found fifty - four genes common to the three prioritization tools which formed our candidate leukemogenic genes for this study . As per the protocol we selected thirty training genes from PubMed . The prioritized and training genes were then used to construct STRING functional association network , which was further analyzed using cytoHubba hub analysis tool to investigate new genes which could form drug targets in leukemia . Analysis of the STRING protein network built from these prioritized and training genes led to identification of two hub genes , Q15796 and P50750 , which were not implicated in leukemogenesis earlier . Filtering out from several hundred genes in the network we also found O00255 , Q13547 and P06239 genes , which re - emphasized the important role of these genes in leukemogenesis . This is the first report on these five additional signature genes in leukemogenesis . We propose these as new targets for developing novel therapeutics and also as biomarkers in leukemogenesis , which could be important for prognosis and diagnosis .", "Leishmania mexicana amazonensis : ADP - ribosyltransferase antagonists specifically inhibit amastigote to promastigote differentiation . Leishmania mexicana amazonensis amastigotes were induced to differentiate by incubation at 27 C . Morphological transformation was studied both in untreated cultures and in cultures where DNA synthesis , and consequently the final stage in the production of promastigotes , was inhibited by hydroxyurea . ___MASK82___ and other antagonists of ADP - ribosyltransferase ( P09874 ) specifically inhibited differentiation at a very early stage in both experimental systems . Cell proliferation ( in the absence of hydroxyurea ) was not inhibited by P09874 antagonists -- indeed greater multiplication of undifferentiated parasites was observed in the presence of these compounds . This indicated that the parasites were being diverted from differentiation to proliferation . Preincubation of the amastigotes with the P09874 antagonists was required to produce this effect , providing further evidence that ADP - ribosylation of proteins is required for the initiation of differentiation in Leishmania .", "The complex of FK506 - binding protein 12 and FK506 inhibits calcineurin phosphatase activity and IgE activation - induced cytokine transcripts , but not exocytosis , in mouse mast cells . FK506 and cyclosporin A ( DB00091 ) are immunosuppressive agents that inhibit P60568 production by activated T cells , but only DB00091 inhibits IgE activation - induced cytokine transcripts in mouse P08700 - dependent , bone marrow - derived mast cells ( BMMC ) . We previously associated the resistance of BMMC to FK506 with a deficiency in the expression of FK506 binding protein ( FKBP ) 12 , a molecule that forms a complex with FK506 capable of inhibiting calcineurin phosphatase activity in vitro . In this report , we establish that P62942 mediates FK506 inhibition of both calcineurin phosphatase activity and IgE activation - induced cytokine transcripts in a Kirsten murine sarcoma virus - immortalized mast cell line that is P62942 deficient . Overexpression of P62942 by transfection enhanced the ability of FK506 to inhibit calcineurin phosphatase activity ( IC50 = 2 nM ) , compared with cells transfected with the expression vector alone ( IC50 > 30 nM ) . The IC50 value for FK506 inhibition of IgE activation - induced transcripts for P01375 decreased from 40 nM in vector control cells to 10 nM in P62942 transfectants . Similarly , the IC50 value for inhibition of P05231 transcripts decreased from > 1000 nM in vector control cells to 35 nM in P62942 transfectants . In contrast , activation - elicited release of the secretory granule mediator beta - hexosaminidase was only partially inhibited by FK506 at 1000 nM , regardless of the levels of P62942 expressed by the cells . Thus , P62942 is the dominant cytosolic protein that mediates FK506 inhibition of P01375 and P05231 transcripts .", "___MASK23___ , a gonadotropin - releasing hormone antagonist , induces the expression of melatonin receptor 1a in the gonadotropin - releasing hormone neuronal cell line GT1 - 7 . Melatonin has been implicated in the control of the reproductive system , and the modulatory actions of melatonin on gonadotropin - releasing hormone ( DB00644 ) neurons have been assumed to be indirectly mediated through afferent neurons . However , our previous studies demonstrate sexually dimorphic modulation of A - type gamma - aminobutyric acid ( GABA ) receptor ( GABA ( A ) R ) currents by melatonin in adult rat DB00644 neurons and a preferential expression of melatonin 1a receptor ( MT1 ) in male DB00644 neurons . Using immortalized DB00644 neurons ( GT1 - 7 cells ) , the present study investigated the mechanism by which the expression of melatonin receptors is regulated in DB00644 neurons . Like endogenous DB00644 neurons , GT1 - 7 cells express both DB00644 and P30968 mRNAs , indicating that the cells have a self - stimulatory system . A 2 - iodomelatonin binding assay and RT - PCR analysis demonstrated that the cells expressed neither MT1 nor P02795 . However , treatment of GT1 - 7 cells with the DB00644 antagonist cetrorelix significantly increased 2 - iodomelatonin binding and induced a time - and concentration - dependent MT1 mRNA expression . The GABA ( A ) R currents were then measured using a perforated patch - clamp technique to examine whether the treatment with cetrorelix changed the responses to melatonin . Melatonin augmented the GABA ( A ) R currents in GT1 - 7 cells treated with 1 muM cetrorelix for 24 h , while melatonin decreased the currents in the cells not treated with cetrorelix , probably via receptor - independent processes . The present results suggest that DB00644 downregulates the expression of MT1 via an autocrine - paracrine mechanism in GT1 - 7 cells , and modifies the melatonin - induced modulation of GABA ( A ) R currents . These findings may provide one possible mechanism for the sexually dimorphic responses to melatonin in adult rat DB00644 neurons .", "Frap - dependent serine phosphorylation of P35568 inhibits P35568 tyrosine phosphorylation . We have previously shown that interferon - alpha ( IFN alpha ) - dependent tyrosine phosphorylation of insulin receptor substrate - 1 ( P35568 ) is impaired by serine phosphorylation of P35568 due to the reduced ability of serine phosphorylated P35568 to serve as a substrate for P23458 ( P23458 ) . Here we report that P62942 - rapamycin - associated protein ( P42345 ) is a physiologic P35568 kinase that blocks IFN alpha signaling by serine phosphorylating P35568 . We found that both P42345 and insulin - activated P08133 S6 kinase ( P08133 ( s6k ) ) serine phosphorylated P35568 between residues 511 and 772 ( P35568 ( 511 - 772 ) ) . Importantly , only P42345 - dependent P35568 ( 511 - 772 ) serine phosphorylation inhibited by 50 % subsequent P23458 - dependent tyrosine phosphorylation of P35568 . Furthermore , treatment of U266 cells with the P42345 inhibitor rapamycin increased IFN alpha - dependent tyrosine phosphorylation by twofold while reducing constitutive P35568 serine phosphorylation within S / T - P motifs by 80 % . Taken together , these data indicate that P42345 , but not P08133 ( s6k ) , is a likely physiologic P35568 serine kinase that negatively regulates P23458 - dependent P35568 tyrosine phosphorylation and suggests that P42345 may modulate P41252 - dependent cytokine signaling ." ]
[ "___MASK100___", "___MASK17___", "___MASK23___", "___MASK25___", "___MASK27___", "___MASK70___", "___MASK79___", "___MASK82___", "___MASK86___" ]
___MASK86___
MH_train_1606
interacts_with DB00834?
[ "___MASK73___ in pediatric rheumatology : the clinical experience . During the last two decades , clinical use of novel biological therapy has led to increased mechanistic understanding of complex rheumatological diseases . Conversely , basic and translational studies have led to development of new and varied therapeutic agents . These new medications which \" target \" specific steps in one or more immune pathways have the potential to control disease symptoms , improve quality of life and long - term prognosis , and perhaps in some , restore immunological tolerance . Use of these agents in clinical trials , combined with post - marketing surveillance , has revealed both the benefits and the undesirable side - effects of biological disease - modifying anti - rheumatic drugs ( DMARDs ) . In this review we focus on the use of tocilizumab , a monoclonal antibody directed against the P05231 receptor ( P08887 ) , which potently inhibits P05231 / P08887 signaling .", "___MASK9___ resistance in Plasmodium falciparum African isolates : assessment by mutation - specific polymerase chain reaction and in vitro susceptibility testing . The antifolate proguanil is commonly used in the prophylaxis and treatment of Plasmodium falciparum malaria . A series of point mutations in the dihydrofolate reductase ( P00374 ) gene has been linked to differential susceptibility of varied P . falciparum clones or isolates to this drug . To survey the efficiency of proguanil prophylaxis in an African endemic region , and to evaluate the level of proguanil resistance in the corresponding parasite population , we performed drug susceptibility assays with P . falciparum isolates from Senegal , Kenya , and Niger . In parallel , we developed a mutation - specific polymerase chain reaction assay that enabled us to characterize mutations in the P00374 gene of the same isolates without in vitro parasite cultivation . We confirm previously available data showing that parasites harboring a point mutation from Ser108 to DB00174 present a decrease in susceptibility to cycloguanil ( the active metabolite of proguanil ) , and we show that mutations in codons 51 and 59 appear to modulate the level of resistance to cycloguanil . No mutations in codons 16 and 164 were detected in resistant parasites , in contrast with results from some previous studies .", "P04150 signaling in a bronchial epithelial cell line . Glucocorticoids are an effective anti - inflammatory therapy for the treatment of asthma . The anti - inflammatory effects of glucocorticoids may be due to the inhibition of transcription factors that regulate cytokine synthesis . Because of the potential role of the bronchial epithelium in asthmatic inflammation and the possibility that this cell may be the main target of inhaled glucocorticoids , we have characterized glucocorticoid receptors ( GR ) and GR signaling in the human bronchial epithelial cell line BEAS - 2B . Western blot analysis and radioligand binding studies demonstrated that BEAS - 2B cells have functional GR that bind to dexamethasone ( DB00514 ) ( dissociation constant = 5 . 6 nM and maximal density of binding sites = 228 +/- 3 . 3 fmol / mg protein ) . GR were activated by DB00514 as assessed using a glucocorticoid - responsive reporter plasmid . Transfection of BEAS - 2B cells with an activator protein - 1 ( AP - 1 ) reporter construct followed by 12 - O - tetradecanoylphorbol - 13 - acetate ( TPA ) treatment resulted in a fivefold induction of reporter gene activity . Transfection with a nuclear factor ( NF ) - kappa B reporter construct followed by tumor necrosis factor - alpha ( P01375 ) treatment resulted in a 10 - fold induction of reporter gene activity . DB00514 ( 10 (- 7 ) M ) markedly repressed both the induced AP - 1 and NF - kappa B activity . The GR antagonist DB00834 inhibited the repressive effect of DB00514 on P01375 - induced NF - kappa B activity by 81 % but only counteracted the repressive effect of DB00514 on TPA - induced AP - 1 activity by 43 % . These studies demonstrate that cross - signaling between AP - 1 and NF - kappa B with GR may explain the anti - inflammatory properties of glucocorticoids in airway epithelial cells .", "Selective inhibition of the tumor marker O60218 by antiinflammatory N - phenylanthranilic acids and glycyrrhetic acid . A human aldose reductase - like protein , O60218 in the aldo - keto reductase ( AKR ) superfamily , was recently identified as a tumor marker of several types of cancer . ___MASK66___ , an aldose reductase inhibitor ( Q9Y4X5 ) , is known to be the most potent inhibitor of the enzyme . In this study , we compared the inhibitory effects of other ARIs including flavonoids on O60218 and aldose reductase to evaluate their specificity . However , ARIs showed lower inhibitory potency for O60218 than for aldose reductase . In the search for potent and selective inhibitors of O60218 from other drugs used clinically , we found that non - steroidal antiinflammatory N - phenylanthranilic acids , diclofenac and glycyrrhetic acid competitively inhibited O60218 , showing K ( i ) values of 0 . 35 - 2 . 9 microM and high selectivity to this enzyme ( 43 - 57 fold versus aldose reductase ) . Molecular docking studies of mefenamic acid and glycyrrhetic acid in the O60218 - nicotinamide adenine dinucleotide phosphate ( NADP (+) ) complex and site - directed mutagenesis of the putative binding residues suggest that the side chain of Val301 and a hydrogen - bonding network among residues Val301 , Gln114 and Ser304 are important for determining the inhibitory potency and selectivity of the non - steroidal antiinflammatory drugs . Thus , the potent and selective inhibition may be related to the cancer chemopreventive roles of the drugs , and their structural features may facilitate the design of new anti - cancer agents targeting O60218 .", "P04150 antagonism disrupts the reconsolidation of social reward - related memories in rats . Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use . Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated , reconsolidation of memories of physiologically relevant social rewards has received little attention . Social play , the most characteristic social behaviour displayed by young mammals , is highly rewarding , illustrated by the fact that it can induce conditioned place preference ( CPP ) . Here , we investigated the role of signalling mechanisms implicated in memory processes , including reconsolidation , namely glucocorticoid , mineralocorticoid , DB01221 glutamatergic and P21554 cannabinoid receptors , in the reconsolidation of social play - induced CPP in rats . Systemic treatment with the glucocorticoid receptor antagonist mifepristone before , but not immediately after , retrieval disrupted the reconsolidation of social play - induced CPP . DB00834 did not affect social play - induced CPP in the absence of memory retrieval . Treatment with the DB01221 receptor antagonist MK - 801 modestly affected the reconsolidation of social play - induced CPP . However , the reconsolidation of social play - induced CPP was not affected by treatment with the mineralocorticoid and P21554 cannabinoid receptor antagonists spironolactone and rimonabant , respectively . We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward - related memories in rats . These data indicate that the neural mechanisms of the reconsolidation of social reward - related memories only partially overlap with those underlying the reconsolidation of other reward - related memories .", "DB06155 , a selective cannabinoid P21554 receptor antagonist , inhibits atherosclerosis in P01130 - deficient mice . OBJECTIVE : The objective of this study was to determine whether the potent selective cannabinoid receptor - 1 antagonist rimonabant has antiatherosclerotic properties . METHODS AND RESULTS : DB06155 ( 50 mg / kg / d in the diet ) significantly reduced food intake ( from 3 . 35 +/-. 04 to 2 . 80 +/- 0 . 03 g / d ) , weight gain ( from 14 . 6 +/- 0 . 7 g to - 0 . 6 +/- 0 . 3 g ) , serum total cholesterol ( from 8 . 39 +/- 0 . 54 to 5 . 32 +/- 0 . 18 g / L ) , and atherosclerotic lesion development in the aorta ( from 1 . 7 +/- 0 . 22 to 0 . 21 +/- 0 . 037 mm ( 2 ) ) and aortic sinus ( from 101 , 000 +/- 7800 to 27 , 000 +/- 2900 microm ( 2 ) ) of P01130 (-/-) mice fed a Western - type diet for 3 months . DB06155 also reduced plasma levels of the proinflammatory cytokines P13500 and IL12 by 85 % ( P < 0 . 05 ) and 76 % ( P < 0 . 05 ) , respectively . Pair - fed animals had reduced weight gain ( 6 . 2 +/- 0 . 6 g gain ) , but developed atherosclerotic lesions which were as large as those of untreated animals , showing that the antiatherosclerotic effect of rimonabant is not related to reduced food intake . Interestingly , rimonabant at a lower dose ( 30 mg / kg / d in the diet ) reduced atherosclerosis development in the aortic sinus ( from 121 , 000 +/- 20 , 000 to 62 , 000 +/- 11 , 000 microm ( 2 ) , 49 % reduction , P < 0 . 05 ) , without affecting serum total cholesterol ( 7 . 8 +/- 0 . 7 g / L versus 8 . 1 +/- 1 . 3 g / L in the control group ) . DB06155 decreased lipopolysaccharide ( LPS ) - and IL1beta - induced proinflammatory gene expression in mouse peritoneal macrophages in vitro as well as thioglycollate - induced recruitment of macrophages in vivo ( 10 mg / kg , p . o . bolus ) . CONCLUSIONS : These results show that rimonabant has antiatherosclerotic effects in P01130 (-/-) mice . These effects are partly unrelated to serum cholesterol modulation and could be related to an antiinflammatory effect .", "delta - ___MASK8___ dehydratase ( P13716 ) porphyria : the first case in North America with two novel P13716 mutations . The molecular basis of the enzymatic defect responsible for delta - aminolevulinate dehydratase ( P13716 ) porphyria ( ADP ) was investigated in a 14 - year - old male who presented clinical and laboratory findings typical of ADP . Nucleotide sequence analysis of P13716 cDNAs from the proband revealed two novel mutations , a 265G to A base transition ( C1 ) and a 394C to T base transition ( P06681 ) , resulting in amino acid substitutions , Glu89Lys and Cys132Arg , respectively . Both mutations were present within exon 5 of the P13716 gene , and appeared to influence the binding of zinc to the enzyme which is essential for enzyme activity . It was found that the C1 mutation was inherited from his father , while the P06681 mutation was from his mother . Expression of these mutant P13716 cDNAs in Chinese hamster ovary cells produced normal P13716 mRNA levels , but markedly decreased P13716 protein and enzyme activity . These results suggest that the combination of the two aberrant ALADs with little enzyme activity accounts for the markedly decreased P13716 activity observed in the proband . This case represents the molecular analysis of the P13716 gene defects in the first case of ADP identified in North America , who is a compound heterozygote for two novel P13716 gene defects .", "P55157 inhibitor decreases plasma cholesterol levels in P01130 - deficient WHHL rabbits by lowering the VLDL secretion . To examine whether a microsomal triglyceride transfer protein ( P55157 ) - inhibitor is effective in patients with homozygous familial hypercholesterolemia , we administered ( 2S ) - 2 - cyclopentyl - 2 -[ 4 -[( 2 , 4 - dimethyl - 9H - pyrido [ 2 , 3 - b ] indol - 9 - yl ) methyl ] phenyl ]- N - [ ( 1S ) - 2 - hydroxy - 1 - phenylethyl ] ethanamide ( ___MASK40___ ) , a new P55157 inhibitor , to low - density lipoprotein ( LDL ) - receptor - deficient Watanabe heritable hyperlipidemic ( WHHL ) rabbits at doses of 3 , 6 , and 12 mg / kg for 4 weeks . In the 12 mg / kg group , the plasma cholesterol and triglyceride levels were decreased by 70 % and 45 % , respectively , and the very low - density lipoprotein ( VLDL ) secretion rate was decreased by 80 % . The composition of newly secreted VLDL was similar in each group . This suggests that ___MASK40___ diminished the number of VLDL particles secreted from the liver . Although the ratio of vitamin E / LDL was not altered by ___MASK40___ , triglyceride accumulation and a decrease in vitamin E were observed in the liver . In conclusion , an inhibition of VLDL secretion led to a decrease of plasma LDL in WHHL rabbits , and P55157 inhibitors should have hypolipidemic effects against homozygous familial hypercholesterolemia .", "[ Mechanisms of action of peroral antidiabetics . Sulfonylurea preparations block the ___MASK54___ - dependent potassium channels ] . Although hypoglycaemic sulphonylureas have been used to treat non - insulin - dependent diabetes mellitus ( NIDDM ) for the past forty years , their mechanisms of action at the molecular level have only recently been elucidated . A combination of electrophysiological and molecular biological techniques showed the target of sulphonylureas to be a sulphonylurea receptor ( Q09428 ) and potassium channel ( Kir6 . 2 ) complex . Together , these two proteins form the ___MASK54___ - dependent potassium ( KATP ) channel occurring in insulin - secreting cells . An increase in the blood glucose level triggers a chain of events in insulin - secreting cells and K ( ___MASK54___ ) channel closure which is a prerequisite for insulin secretion . In NIDDM , however , an increase in blood glucose fails to close the K ( ___MASK54___ ) channel satisfactorily , but this can be remedied by the administration of sulphonylureas .", "The PEPvIII - KLH ( ___MASK67___ ) vaccine in glioblastoma multiforme patients . Conventional therapies for glioblastoma multiforme ( GBM ) fail to target tumor cells exclusively , resulting in non - specific toxicity . Immune targeting of tumor - specific mutations may allow for more precise eradication of neoplastic cells . P00533 variant III ( EGFRvIII ) is a tumor - specific mutation that is widely expressed in GBM and other neoplasms and its expression enhances tumorigenicity . This in - frame deletion mutation splits a codon , resulting in a novel glycine at the fusion junction producing a tumor - specific epitope target for cellular or humoral immunotherapy . We have previously shown that vaccination with a peptide that spans the EGFRvIII fusion junction ( PEPvIII - KLH / ___MASK67___ ) is an efficacious immunotherapy in syngeneic murine models . In this review , we summarize our results in GBM patients targeting this mutation in multiple , multi - institutional Phase II immunotherapy trials . These trials demonstrated that a selected population of GBM patients who received vaccines targeting EGFRvIII had an unexpectedly long survival time . Further therapeutic strategies and potential pitfalls of using this approach are discussed .", "P04150 regulates ___MASK54___ - binding cassette transporter - A1 expression and apolipoprotein - mediated cholesterol efflux from macrophages . OBJECTIVE : The ___MASK54___ - binding cassette transporter - A1 ( O95477 ) regulates cholesterol efflux from cells and is involved in high - density lipoprotein metabolism and atherogenesis . The objective of this study was to investigate the effect of dexamethasone ( DB00514 ) and other glucocorticoid receptor ( GR ) ligands on apolipoprotein AI - mediated cholesterol efflux from macrophages and O95477 expression in them . METHODS AND RESULTS : DB00514 , a GR agonist , decreased O95477 mRNA levels in a dose - and time - dependent fashion , and DB00834 , a GR antagonist , reversed the inhibitory effect of DB00514 . The effects of DB00514 and DB00834 on O95477 protein levels and apolipoprotein AI - mediated cholesterol efflux from the macrophages were consistent with these changes in mRNA levels . Transfected RAW264 . 7 , together with a human O95477 promoter - luciferase construct , inhibited transcriptional activity by DB00514 and overexpression of human GR . Transrepression by GR was not mediated by liver X receptor ( LXR ) , because there were no differences in the effects of the GR ligands on promoter activity between a reporter construct with mutations at the LXR binding site and one without the mutations , and no changes were brought about in P45844 and Q9H172 expression by GR ligands . CONCLUSIONS : Our results showed that GR ligands affected O95477 expression and cholesterol efflux from macrophages , which are regulated by GR through a LXR - independent mechanism .", "The endocannabinoid 2 - AG protects the blood - brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines . Endocannabinoids are involved in neuroprotection through numerous biochemical pathways . We have shown that the endocannabinoid 2 - arachidonoyl glycerol ( 2 - AG ) is released in mouse brain after closed head injury ( CHI ) , and treatment with exogenous 2 - AG exerts neuroprotection via the central cannabinoid receptor P21554 . This process involves inhibition of inflammatory signals that are mediated by activation of the transcription factor NF - kB . The present study was designed to examine the effect of 2 - AG on the blood - brain barrier ( BBB ) and the possible inhibition of the early expression of proinflammatory cytokines , which are implicated in BBB disruption . We found that 2 - AG decreased BBB permeability and inhibited the acute expression of the main proinflammatory cytokines : P01375 , IL - 1beta and P05231 . It also augmented the levels of endogenous antioxidants . We suggest that 2 - AG exerts neuroprotection in part by inhibition of the early ( 1 - 4 h ) inflammatory response and augmentation of the brain reducing power .", "Some cannabinoid receptor ligands and their distomers are direct - acting openers of Q09428 K ( ___MASK54___ ) channels . Here , we examined the chronic effects of two cannabinoid receptor - 1 ( P21554 ) inverse agonists , rimonabant and ibipinabant , in hyperinsulinemic Zucker rats to determine their chronic effects on insulinemia . DB06155 and ibipinabant ( 10 mg · kg ⁻ ¹ · day ⁻ ¹ ) elicited body weight - independent improvements in insulinemia and glycemia during 10 wk of chronic treatment . To elucidate the mechanism of insulin lowering , acute in vivo and in vitro studies were then performed . Surprisingly , chronic treatment was not required for insulin lowering . In acute in vivo and in vitro studies , the P21554 inverse agonists exhibited acute K channel opener ( KCO ; e . g . , diazoxide and NN414 ) - like effects on glucose tolerance and glucose - stimulated insulin secretion ( GSIS ) with approximately fivefold better potency than diazoxide . Followup studies implied that these effects were inconsistent with a P21554 - mediated mechanism . Thus effects of several P21554 agonists , inverse agonists , and distomers during GTTs or GSIS studies using perifused rat islets were unpredictable from their known P21554 activities . In vivo rimonabant and ibipinabant caused glucose intolerance in P21554 but not Q09428 - KO mice . Electrophysiological studies indicated that , compared with diazoxide , 3 μM rimonabant and ibipinabant are partial agonists for K channel opening . Partial agonism was consistent with data from radioligand binding assays designed to detect Q09428 K ( ___MASK54___ ) KCOs where rimonabant and ibipinabant allosterically regulated ³H - glibenclamide - specific binding in the presence of MgATP , as did diazoxide and NN414 . Our findings indicate that some P21554 ligands may directly bind and allosterically regulate Kir6 . 2 / Q09428 K ( ___MASK54___ ) channels like other KCOs . This mechanism appears to be compatible with and may contribute to their acute and chronic effects on GSIS and insulinemia .", "P01133 - like ligands mediate progesterone ' s anti - apoptotic action on macaque granulosa cells . A local autocrine / paracrine role for progesterone is an absolute requirement for corpus luteum formation in primates . Despite this , the mechanism ( s ) remain obscure , although existing data suggest an anti - apoptotic action to be central . There are a limited number of progestin - regulated gene targets identified in the luteinizing primate follicle , suggesting that a small number of important genes may mediate progesterone action . Possible gene targets could be the epidermal growth factor ( P01133 ) family members amphiregulin ( P15514 ) and epiregulin ( O14944 ) . Using macaques undergoing controlled ovarian stimulation cycles , we show that the phosphorylation of P01133 receptor ( P00533 ) , P29323 1 / 2 , and AKT increases 6 h after an ovulatory human chorionic gonadotropin ( hCG ) stimulus and remains activate through 24 h . Immunoreactive O14944 and P15514 ligands in the follicular fluid both increased in a time frame commensurate with P00533 phosphorylation . The mRNA expression of P15514 and O14944 in nonluteinized granulosa cells ( NLGC ) was induced in culture with hCG , an effect blocked by progesterone receptor ( P06401 ) antagonists . Overexpression of P06401 B in NLGC and treatment with a nonmetabolizable progestin did not increase either gene , indicating both progesterone and luteinizing hormone / CG are necessary . Addition of P01133 and P01133 - like ligands did not promote steroidogenesis in vitro by granulosa cells in the presence of gonadotropin , but were able to partially reverse DB00834 - induced cell death . These data suggest that progesterone promotes the expression of P15514 and O14944 , which in turn maintain viability of luteinizing granulosa cells , representing one possible mechanism whereby progesterone promotes corpus luteum formation in the primate .", "Insights into antifolate resistance from malarial P00374 - TS structures . Plasmodium falciparum dihydrofolate reductase - thymidylate synthase ( PfDHFR - TS ) is an important target of antimalarial drugs . The efficacy of this class of P00374 - inhibitor drugs is now compromised because of mutations that prevent drug binding yet retain enzyme activity . The crystal structures of PfDHFR - TS from the wild type ( TM4 / 8 . 2 ) and the quadruple drug - resistant mutant ( V1 / S ) strains , in complex with a potent inhibitor WR99210 , as well as the resistant double mutant ( P04264 P21554 ) with the antimalarial pyrimethamine , reveal features for overcoming resistance . In contrast to pyrimethamine , the flexible side chain of WR99210 can adopt a conformation that fits well in the active site , thereby contributing to binding . The single - chain bifunctional PfDHFR - TS has a helical insert between the P00374 and TS domains that is involved in dimerization and domain organization . Moreover , positively charged grooves on the surface of the dimer suggest a function in channeling of substrate from TS to P00374 active sites . These features provide possible approaches for the design of new drugs to overcome antifolate resistance .", "P15121 regulates TGF - beta1 - induced production of fibronectin and type IV collagen in cultured rat mesangial cells . AIM : To study the effects of aldose reductase ( AR ) on production of fibronectin and type IV collagen in rat mesangial cells ( MsC ) . METHODS : The vector , pcDNA3 - AR , was constructed based on pET - 15b - AR . Lipofect AMINE was used for stable transfection and G418 was used for selecting positive clones . DB02712 and zopolrestat were added for suppressing the activity of AR , respectively . The production of fibronectin and type IV collagen and the activation of Smads and MAPK signal transduction pathway were analysed by western blot and AP - 1 activity was analysed by electrophoretic mobility shift assays ( EMSA ) . RESULTS : The normal MsC showed increased expression of fibronectin and type IV collagen with stimulation of TGF - beta1 . Compared with the normal MsC , the MsC pre - incubated with Q9Y4X5 showed reduced expression ( P < 0 . 05 ) and the AR - transfected MsC showed increased expression ( P < 0 . 05 ) . The normal MsC showed activation of P29323 , JNK and p38 with stimulation of TGF - beta1 , while the activation of JNK and p38 was inhibited in the MsC pre - incubated with Q9Y4X5 and only the activation of JNK was enhanced in the AR - transfected MsC . The normal MsC showed enhanced AP - 1 activity with the stimulation of TGF - beta1 , and similarly the activity was inhibited in the MsC pre - incubated with Q9Y4X5 and was more enhanced in the AR transfected MsC . CONCLUSION : AR can regulate the expression of fibronectin and type IV collagen with the stimulation of TGF - beta1 in MsC , which may have relations with the activation of JNK - MAPK and p38 - MAPK signalling pathways and AP - 1 .", "Unsaturated side chain beta - 11 - hydroxyhexahydrocannabinol analogs . The cannabinoid side chain is a key pharmacophore in the interaction of cannabinoids with their receptors ( P21554 and CB2 ) . To study the stereochemical requirements of the side chain , we synthesized a series of cannabinoids in which rotation around the C1 '- P06681 ' bond is blocked . The key steps in the synthesis were the cuprate addition of a substituted resorcinol to (+)- apoverbenone , the TMSOTf - mediated formation of the dihydropyran ring , and the stereospecific introduction of the beta - 11 - hydroxymethyl group . All the analogs tested showed nanomolar affinity for the receptors , the cis - hept - 1 - ene side chain having the highest affinity for P21554 ( Ki = 0 . 89 nM ) and showing the widest separation between P21554 and CB2 affinities . The parent n - heptyl - beta - 11 - hydroxyhexahydrocannabinol was the least potent binding to P21554 ( Ki = 8 . 9 nM ) and had the lowest selectivity between P21554 and CB2 .", "P06401 activation of extranuclear signaling pathways in regulating p53 expression in vascular endothelial cells . We previously showed that progesterone ( P4 ) inhibited the proliferation of human umbilical vein endothelial cells ( HUVECs ) through a p53 - dependent pathway . Now we investigated further the molecular mechanism underlying the hormone activity . In cultured HUVECs , P4 increased the protein levels of phosphorylated Src ( p - Src ) , P04049 , and P29323 . The levels of p - Src and p - Src - progesterone receptor complex in HUVECs were increased by P4 treatment . These effects were blocked by pretreatment with a progesterone receptor antagonist , DB00834 . The P4 - induced increase in p53 transactivity was abolished by pretreatment with Src kinase inhibitors . Moreover , administration with cSrc antisense oligonucleotide prevented the P4 - induced increases of the levels of p53 mRNA and protein . These data suggest that P4 - induced up - regulation of p53 might be mediated through activation of cSrc . Pretreatment with Src kinase inhibitors also prevented P4 - induced membrane translocation of Kras and increases of the protein levels of phosphorylated Raf and phosphorylated P29323 . Transfection with dominant - negative P28482 prevented the P4 - induced increases of protein level and promoter activity of p53 and a decrease of thymidine incorporation . P4 also increased nuclear factor - κB ( NF - κB ) nuclear translocation and NF - κB binding onto the p53 promoter . These effects were abolished by pretreatment with P29323 inhibitors . The P4 - induced up - regulation of the p53 promoter activity was prevented by preadministration with dominant - negative P28482 or NF - κB inhibitors . Taken together , our data suggest that the cSrc / Kras / P04049 / P28482 / NF - κB signaling pathway contributes to the P4 - induced up - regulation of p53 in HUVECs . These findings highlight progesterone receptor activation of extranuclear signaling pathways in regulating p53 and cell cycle progression in HUVECs .", "Huperzine a improves chronic inflammation and cognitive decline in rats with cerebral hypoperfusion . Chronic cerebral hypoperfusion has been suggested to contribute to the progression of dementia . Inflammation and white matter lesion ( WML ) are involved in the pathologic process . This study investigated whether huperzine A , a natural acetylcholinesterase ( P22303 ) inhibitor , has beneficial effects on long - lasting inflammation as well as cognitive impairment in a rat model of cerebral hypoperfusion and how it plays these roles . Chronic cerebral hypoperfusion was induced by occlusion of bilateral common carotid arteries ( two - vessel occlusion ; 2VO ) . ___MASK2___ was initially given 150 min after 2VO and daily for 3 , 7 , 14 , and 28 days . Learning and memory dysfunction as tested by Morris water maze performance was observed in 2VO - operated rats and was significantly improved by huperzine A treatment . WML and activation staining of immune cells were evaluated by Klüver - Barrera ( KB ) and immunohistochemistry , respectively . Myelin damage and increased immunostains were found in optic tract at all indicated days . ___MASK2___ treatment significantly ameliorated all these phenomena . Moreover , huperzine A also suppressed overexpression of the inflammatory factor tumor necrosis factor - alpha ( P01375 ) and overphosphorylation of JNK and p38 mitogen - activated protein kinases ( MAPKs ) in a cell model of chronic hypoxia . Preincubation with mecamylamine ( Q9NRJ3 ) , a nicotinic acetylcholine receptor ( nAChR ) antagonist , for 30 min before hypoxia notably reversed the effects of huperzine A on P01375 production and MAPKs phosphorylation . In conclusion , delayed and chronic administration of huperzine A could protect against 2VO - induced cognitive impairment , which might be related to its beneficial effects on WML , and the nAChR - dependent cholinergic anti - inflammation pathway plays an important role .", "On the hepatic mechanism of HDL assembly by the O95477 / apoA - I pathway . The mechanism for the assembly of HDL with cellular lipid by O95477 and helical apolipoprotein was investigated in hepatocytes . Both HepG2 cells and mouse primary culture hepatocytes produced HDL with apolipoprotein A - I ( apoA - I ) whether endogenously synthesized or exogenously provided . ___MASK60___ , an O95477 inactivator , inhibited these reactions , as well as the reversible binding of apoA - I to HepG2 . Primary cultured hepatocytes of O95477 - deficient mice also lacked HDL production regardless of the presence of exogenous apoA - I . HepG2 cells secreted apoA - I into the medium even when O95477 was inactivated by probucol , but it was all in a free form as HDL production was inhibited . When a lipid - free apoA - I - specific monoclonal antibody , 725 - 1E2 , was present in the culture medium , production of HDL was suppressed , whether with endogenous or exogenously added apoA - I , and the antibody did not influence HDL already produced by HepG2 cells . We conclude that the main mechanism for HDL assembly by endogenous apoA - I in HepG2 cells is an autocrine - like reaction in which apoA - I is secreted and then interacts with cellular O95477 to generate HDL ." ]
[ "___MASK2___", "___MASK40___", "___MASK54___", "___MASK60___", "___MASK66___", "___MASK67___", "___MASK73___", "___MASK8___", "___MASK9___" ]
___MASK73___
MH_train_1607
interacts_with DB00864?
[ "Nox2 and Nox4 mediate tumour necrosis factor - α - induced ventricular remodelling in mice . Reactive oxygen species ( ROS ) and pro - inflammatory cytokines are crucial in ventricular remodelling , such as inflammation - associated myocarditis . We previously reported that tumour necrosis factor - α ( P01375 - α ) - induced ROS in human aortic smooth muscle cells is mediated by NADPH oxidase subunit Nox4 . In this study , we investigated whether P01375 - α - induced ventricular remodelling was mediated by Nox2 and / or Nox4 . An intravenous injection of murine P01375 - α was administered to a group of mice and saline injection was administered to controls . Echocardiography was performed on days 1 , 7 and 28 post - injection . Ventricular tissue was used to determine gene and protein expression of Nox2 , Nox4 , P01160 , interleukin ( IL ) - 1β , P60568 , P05231 , P01375 - α and to measure ROS . Nox2 and Nox4 siRNA were used to determine whether or not Nox2 and Nox4 mediated P01375 - α - induced ROS and upregulation of IL - 1β and P05231 in adult human cardiomyocytes . Echocardiography showed a significant increase in left ventricular end - diastolic and left ventricular end - systolic diameters , and a significant decrease in the ejection fraction and fractional shortening in mice 7 and 28 days after P01375 - α injection . These two groups of mice showed a significant increase in ventricular ROS , P01160 , IL - 1β , P60568 , P05231 and P01375 - α proteins . Nox2 and Nox4 mRNA and protein levels were also sequentially increased . ROS was significantly decreased by inhibitors of NADPH oxidase , but not by inhibitors of other ROS production systems . Nox2 and Nox4 siRNA significantly attenuated P01375 - α - induced ROS and upregulation of IL - 1β and P05231 in cardiomyocytes . Our study highlights a novel P01375 - α - induced chronic ventricular remodelling mechanism mediated by sequential regulation of Nox2 and Nox4 subunits .", "Signaling by proinflammatory cytokines : oligomerization of TRAF2 and Q9Y4K3 is sufficient for JNK and IKK activation and target gene induction via an amino - terminal effector domain . Interleukin - 1 ( IL - 1 ) and tumor necrosis factor ( P01375 ) stimulate transcription factors AP - 1 and NF - kappaB through activation of the Q96HU1 kinases JNK and p38 and the O15111 ( IKK ) , respectively . The P01375 and IL - 1 signals are transduced through TRAF2 and Q9Y4K3 , respectively . Overexpressed TRAF2 or Q9Y4K3 activate JNK , p38 , or IKK in the absence of extracellular stimulation . By replacing the carboxy - terminal TRAF domain of TRAF2 and Q9Y4K3 with repeats of the immunophilin P62942 , we demonstrate that their effector domains are composed of their amino - terminal Zn and RING fingers . Oligomerization of the TRAF2 effector domain results in specific binding to Q13233 , a protein kinase capable of JNK , p38 , and IKK activation , and induction of P01375 and IL - 1 responsive genes . P01375 also enhances the binding of native TRAF2 to Q13233 and stimulates the kinase activity of the latter . Thus , P01375 and IL - 1 signaling is based on oligomerization of TRAF2 and Q9Y4K3 leading to activation of effector kinases .", "___MASK69___ induces the release of microparticle - associated endothelial protein C receptor . ___MASK69___ ( P25054 ) treatment is now used for patients with severe sepsis . We investigated its effect in vitro on primary , physiologically relevant cells and demonstrate a novel mechanism of endothelial protein C receptor ( Q9UNN8 ) release that is not inhibited by metalloproteinase inhibitors . Exposure of human umbilical vein endothelial cells or monocytes to P25054 ( 6 . 25 - 100 nM ) results in the release of Q9UNN8 - containing microparticles , as demonstrated by confocal microscopy and characterized through flow cytometry , enzyme - linked immunosorbent assay quantitation of isolated microparticles , and Western blotting . The phenomenon is time - and concentration - dependent and requires the P25054 active site , Q9UNN8 , and protease activated receptor 1 ( PAR1 ) on endothelial cells . Neither protein C nor boiled or D - DB00120 - Pro - DB00125 - chloromethylketone - blocked P25054 can induce microparticle formation and antibody blockade of Q9UNN8 or PAR1 cleavage and activation abrogates this P25054 action . Coincubation with hirudin does not alter the P25054 effect . The released microparticle bound is full - length Q9UNN8 ( 49 kDa ) and P25054 retains factor V - inactivating activity . Although tumor necrosis factor - alpha ( 10 ng / mL ) can also induce microparticle - associated Q9UNN8 release to a similar extent as P25054 ( 100 nM ) , it is only P25054 - induced microparticles that contain bound P25054 . This novel observation could provide new insights into the consequences of P25054 therapy in the septic patient .", "Structure - function studies of linear and cyclized peptide antagonists of the P30968 . Structurally new analogs of the peptidic P30968 antagonist DB00050 as well as conformationally constrained cyclized deca - or pentapeptides were synthesized and selected peptides evaluated comprehensively . To understand how structural variations of the antagonistic peptide effect pharmacodynamic properties , binding affinities and antagonistic potencies toward the human and rat P30968 were determined . Whereas large substituents in position 6 of linear peptides are compatible with high binding affinity ( K ( D ) < 0 . 5 nM ) , all cyclized peptides except the cyclo [ 3 - 10 ] analog D - 52391 depicted low binding affinity ( K ( D ) > 10 nM ) . Binding affinity and antagonistic potency in vitro correlated for all peptides and surprisingly no discrimination between human and rat receptor proteins was observed . Since receptor residues W ( 101 ) and N ( 102 ) are involved in agonist and antagonist binding , equally potent but structurally different antagonists were tested for binding to the respective W ( 101 ) A and N ( 102 ) A mutants . In contrast to linear decapeptides , residues N ( 102 ) and W ( 101 ) are not involved in binding of D - 23938 and W ( 101 ) is the critical residue for D - 52391 binding . We conclude that although equally potent , peptidic P30968 antagonists do have distinct interactions within the ligand binding pocket . Finally , selected antagonists were tested for testosterone suppression in male rats . The duration of testosterone suppression below castration levels differed largely from 1 day for ___MASK21___ to 27 days for D - 23487 . Systemic availability became evident as the most important parameter for in vivo efficacy .", "DB00075 - induced anergy in cloned human Th0 , Th1 , and Th2 cells . In the mouse , activation of T cells by T cell receptor ( TCR ) crosslinking with anti - CD3 antibodies in the absence of a costimulatory signal induces Th1 but not Th2 cell anergy . Furthermore , anti - CD3 induces anergy of Th1 - but not Th2 - type lymphokine secretion in Th0 cells . This study was designed to determine whether this is also the case in man . Human rye grass allergen Lol p I - specific cloned P01730 + T helper cells of subtypes Th0 , Th1 , and Th2 were treated with immobilized anti - CD3 . The cells were rested for 4 days and then activated under optimal conditions with antigen and antigen - presenting cells ( APCs ) . Cell proliferation and P60568 , P01579 , and P05112 secretion was determined to test for the anergic state . The initial anti - CD3 treatment induced cell proliferation , P60568 , P01579 , and / or P05112 secretion by T cells of all three subsets which was followed by an anergic state in Th0 , Th1 , and Th2 cells as shown by a 51 to > 94 % decrease in cell proliferation and P01579 and / or P05112 secretion after subsequent P25054 and Lol p I activation . Addition of P60568 or P05112 during anti - CD3 treatment of the cells did not prevent unresponsiveness . However , the addition of P60568 but not P05112 during P25054 and Lol p I stimulation partially reversed the anergic state . These data demonstrate that , contrary to the mouse , cloned T cells of all three human T helper cell subtypes are anergized by anti - CD3 TCR activation in the absence of costimulatory signals . The fact that human Th2 cells can be anergized may be important for the development of new treatments in Th2 - mediated allergic disorders .", "Endothelial cell transforming growth factor - β receptor activation causes tacrolimus - induced renal arteriolar hyalinosis . Arteriolar hyalinosis is a common histological finding in renal transplant recipients treated with the calcineurin inhibitor tacrolimus ; however , the pathophysiologic mechanisms remain unknown . In addition to increasing transforming growth factor ( TGF ) - β levels , tacrolimus inhibits calcineurin by binding to FK506 - binding protein 12 ( P62942 ) . P62942 alone also inhibits TGF - β receptor activation . Here we tested whether tacrolimus binding to P62942 removes an inhibition of the TGF - β receptor , allowing ligand binding , ultimately leading to receptor activation and arteriolar hyalinosis . We found that specific deletion of P62942 from endothelial cells was sufficient to activate endothelial TGF - β receptors and induce renal arteriolar hyalinosis in these knockout mice , similar to that induced by tacrolimus . DB00864 - treated and knockout mice exhibited significantly increased levels of aortic TGF - β receptor activation as evidenced by Q15796 / 3 phosphorylation , along with increased collagen and fibronectin expression compared to controls . Treatment of isolated mouse aortas with tacrolimus increased TGF - β receptor activation and collagen and fibronectin expression . These effects were independent of calcineurin , absent in endothelial denuded aortic rings , and could be prevented by the small molecule TGF - β receptor inhibitor SB - 505124 . Thus , endothelial cell TGF - β receptor activation is sufficient to cause vascular remodeling and renal arteriolar hyalinosis .", "Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . DB00864 ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .", "The complex of FK506 - binding protein 12 and FK506 inhibits calcineurin phosphatase activity and IgE activation - induced cytokine transcripts , but not exocytosis , in mouse mast cells . FK506 and cyclosporin A ( ___MASK3___ ) are immunosuppressive agents that inhibit P60568 production by activated T cells , but only ___MASK3___ inhibits IgE activation - induced cytokine transcripts in mouse P08700 - dependent , bone marrow - derived mast cells ( BMMC ) . We previously associated the resistance of BMMC to FK506 with a deficiency in the expression of FK506 binding protein ( FKBP ) 12 , a molecule that forms a complex with FK506 capable of inhibiting calcineurin phosphatase activity in vitro . In this report , we establish that P62942 mediates FK506 inhibition of both calcineurin phosphatase activity and IgE activation - induced cytokine transcripts in a Kirsten murine sarcoma virus - immortalized mast cell line that is P62942 deficient . Overexpression of P62942 by transfection enhanced the ability of FK506 to inhibit calcineurin phosphatase activity ( IC50 = 2 nM ) , compared with cells transfected with the expression vector alone ( IC50 > 30 nM ) . The IC50 value for FK506 inhibition of IgE activation - induced transcripts for P01375 decreased from 40 nM in vector control cells to 10 nM in P62942 transfectants . Similarly , the IC50 value for inhibition of P05231 transcripts decreased from > 1000 nM in vector control cells to 35 nM in P62942 transfectants . In contrast , activation - elicited release of the secretory granule mediator beta - hexosaminidase was only partially inhibited by FK506 at 1000 nM , regardless of the levels of P62942 expressed by the cells . Thus , P62942 is the dominant cytosolic protein that mediates FK506 inhibition of P01375 and P05231 transcripts .", "Successful treatment of cystoid macular edema with valdecoxib . PURPOSE : To evaluate the safety and efficacy of the P35354 inhibitor valdecoxib in treating macular edema after cataract surgery . SETTING : University Eye Clinic , Freiburg , Germany and Reis Medical Institution , Liechtenstein . METHODS : The P35354 inhibitor valdecoxib ( Bextra ) was administered systemically to patients with significant visual loss resulting from macular edema in a prospective clinical trial . RESULTS : Ten patients were enrolled . ___MASK56___ was tolerated well and led to a significant visual improvement within 10 days of therapy in all patients . CONCLUSION : The fast and persistent control of macular edema with valdecoxib warrants further investigation .", "Heart allograft protection with low - dose carbon monoxide inhalation : effects on inflammatory mediators and alloreactive T - cell responses . BACKGROUND : DB11588 ( CO ) , a byproduct of heme catalysis , has lately received considerable attention as a regulatory molecule in cellular and biological processes . CO has been shown to provide potent protection against a variety of tissue injuries . We hypothesized in this study that low concentration CO would be beneficial for organ allografts , which frequently undergo several types of injury such as ischemia / reperfusion , alloimmune reaction , and inflammation METHODS : The efficacy of low - dose CO was examined in a fully allogeneic LEW to BN rat heterotopic heart transplantation ( HHTx ) model . Recipients were kept in air or exposed to low - dose CO ( 20 ppm ) for 14 , 28 , or 100 days after HHTx under short - course tacrolimus RESULTS : CO treatment ( d0 - 28 , 0 - 100 ) was remarkably effective in prolonging heart allograft survival to a median of > 100 from 45 days in the air - control group , with significant reductions of arteritis , fibrosis , and cellular infiltration , including macrophages and T cells . CO inhibited intragraft upregulation of Th1 type cytokines ( P60568 , IFNgamma ) , proinflammatory mediators ( IL - 1beta , TNFalpha , P05231 , P35354 ) , and adhesion molecule . Shorter CO exposure in early ( 0 - 13d ) and late ( 14 - 28d ) posttransplant periods also prolonged graft survival , with a significant inhibition of inflammatory mediators CONCLUSIONS : These results show that low dose CO inhalation protects heart allografts and can considerably prolong their survival . CO appears to function via multiple mechanisms , including direct inhibition of Th1 type cytokine production and regulation of inflammatory responses .", "Interaction of tacrolimus ( FK506 ) and its metabolites with FKBP and calcineurin . DB00864 ( FK506 ) is a strong immuno - suppressant and shows its activity through inhibiting P60568 mRNA transcription by forming pentameric complex with intracellular receptor ( FK506 binding protein 12 kDa or P62942 ) , Ca2 + , calmodulin , and calcineurin . Here , we report the binding activity to P62942 , the pentameric complex formation and Con - A response inhibiting activities of 7 metabolites . C15 - demethylated metabolite ( M - 3 ) needed higher quantity to compete in Con - A assay and in pentamer formation assay , although it binds more strongly to P62942 . The result suggests that the ability to form a pentameric complex is not a two step reaction with the first binding to P62942 , but a single step reaction by components for the pentamer formation .", "Coadministrating luteolin minimizes the side effects of the aromatase inhibitor letrozole . P11511 inhibitors ( AIs ) have been used as adjuvant therapeutic agents for breast cancer . Their adverse side effect on blood lipid is well documented . Some natural compounds have been shown to be potential AIs . In the present study , we compared the efficacy of the flavonoid luteolin to the clinically approved AI letrozole ( ___MASK8___ ; Novartis Pharmaceuticals , East Hanover , NJ ) in a cell and a mouse model . In the in vitro experimental results for aromatase inhibition , the Ki values of luteolin and letrozole were estimated to be 2 . 44 µM and 0 . 41 nM , respectively . Both letrozole and luteolin appeared to be competitive inhibitors . Subsequently , an animal model was used for the comparison . P11511 - expressing MCF - 7 cells were transplanted into ovariectomized athymic mice . Luteolin was given by mouth at 5 , 20 , and 50 mg / kg , whereas letrozole was administered by intravenous injection . Similar to letrozole , luteolin administration reduced plasma estrogen concentrations and suppressed the xenograft proliferation . The regulation of cell cycle and apoptotic proteins - such as a decrease in the expression of Bcl - xL , cyclin - A / D1 / E , P24941 / 4 , and increase in that of Bax - was about the same in both treatments . The most significant disparity was on blood lipids . In contrast to letrozole , luteolin increased fasting plasma high - density lipoprotein concentrations and produced a desirable blood lipid profile . These results suggested that the flavonoid could be a coadjuvant therapeutic agent without impairing the action of AIs .", "Activin A augments DB00644 - mediated transcriptional activation of the mouse P30968 gene . The response of pituitary gonadotropes to DB00644 correlates directly with the concentration of DB00644 receptors ( GnRHRs ) on the cell surface , which is mediated in part at the level of GnRHR gene expression . We have previously localized DB00644 responsiveness in the mouse GnRHR ( mGnRHR ) gene promoter to two elements : activating protein - 1 and sequence underlying responsiveness to DB00644 - 1 . This study was designed to investigate potential synergy between DB00644 and activin A in transcriptional activation of the mGnRHR gene . In functional transfection studies using alphaT3 - 1 cells , DB00644 agonist stimulation of the mGnRHR gene promoter ( - 765 /+ 62 ) resulted in a 10 . 9 - fold increase in activity , which was further increased 2 - fold ( to 21 . 3 - fold ) following activin pretreatment . Activin pretreatment alone had no effect . Deletion of region - 387 /- 308 or mutation of a putative SMAD - binding element at - 331 /- 324 ( 5 '- GTCTAG [ T ] C - 3 ' ) abrogated the augmented response to DB00644 in the presence of activin but not the response to DB00644 alone . Overexpression of Q15796 and P84022 along with Q13485 increased transcriptional activity of the mGnRHR gene , which was further increased by DB00644 agonist stimulation . These data demonstrate that activin augments DB00644 - mediated transcriptional activation of the mGnRHR gene and suggest that this effect may be mediated through SMAD transcription factors .", "Inhibition of natural killer ( NK ) cell activity against varicella - zoster virus ( VZV ) - infected fibroblasts and lymphocyte activation in response to VZV antigen by nitric oxide - releasing agents . The addition of nitric oxide ( NO ) - releasing agents , S - nitroso - N - acetyl - DL - penicillamine ( P60880 ) , 1 - hydroxy - 2 - oxo - 2 , 3 - bis ( 2 - aminoethyl )- 1 - triazene ( NOC18 ) , 30 { (+/-)-( E )- ethyl - 2 '- [ ( E ) - hydroxyimino ] - 5 - nitro - 3 - hexenecarbam oyl } - pyridine ( NOR4 ) significantly inhibited NK cell activity against VZV - infected cells , while antibody - dependent cell - mediated cytotoxicity ( ADCC ) against VZV - infected cells was unaffected . Interferon - alpha ( IFN - alpha ) production by non - adherent peripheral blood mononuclear cells ( NPBMC ) cultured with VZV - infected cells was decreased by the addition of NO - releasing agents . Lymphocyte proliferation and the expression P60568 receptor ( CD25 ) in response to VZV antigen were also inhibited by the addition of NO - releasing agents . These results suggest that the production of NO by an inflammatory process may lead to inhibition of NK cell - and T cell - mediated immunity to VZV infection .", "Beneficial effects of combination of P12821 inhibitor and angiotensin II type 1 receptor blocker on cardiac remodeling in rat myocardial infarction . OBJECTIVE : P12821 ( P12821 ) inhibitor and angiotensin II type I receptor blockers ( ARB ) prevent cardiac remodeling after myocardial infarction ( MI ) . However , it is controversial whether combination therapy of P12821 inhibitor and ARB is more effective on cardiac remodeling than each agent alone . In this study , we compared the effects of an P12821 inhibitor ( temocapril ) , an ARB ( CS - 866 ) , and their combination on cardiac remodeling after MI . METHODS : ___MASK25___ at 3 or 30 mg / kg / day , CS - 866 at 1 or 10 mg / kg / day , or combined temocapril and CS - 866 at 1 . 5 and 0 . 5 mg / kg / day or at 15 and 5 mg / kg / day , respectively , were administered to rats after MI . At 4 weeks after MI , we assessed hemodynamics , cardiac function by Doppler echocardiography and non - infarcted myocardial mRNA expression . RESULTS : Animals treated with a combination of the two drugs had hemodynamics , heart weights and dimensions similar to the other treated animals . However , the combination of the two drugs suppressed P01160 , DB04899 and other gene expressions related to contractile proteins of fetal type and collagens more effectively than P12821 inhibitor or ARB alone . CONCLUSION : These data suggest that combination of the two drugs , independent of the hemodynamic effect , may improve left ventricular phenotypic change , collagen accumulation and diastolic function .", "The P49591 - coronavirus - host interactome : identification of cyclophilins as target for pan - coronavirus inhibitors . Coronaviruses ( CoVs ) are important human and animal pathogens that induce fatal respiratory , gastrointestinal and neurological disease . The outbreak of the severe acute respiratory syndrome ( P49591 ) in 2002 / 2003 has demonstrated human vulnerability to ( Coronavirus ) CoV epidemics . Neither vaccines nor therapeutics are available against human and animal CoVs . Knowledge of host cell proteins that take part in pivotal virus - host interactions could define broad - spectrum antiviral targets . In this study , we used a systems biology approach employing a genome - wide yeast - two hybrid interaction screen to identify immunopilins ( P62937 , P23284 , O43447 , Q13427 , P62942 , P68106 ) as interaction partners of the CoV non - structural protein 1 ( Nsp1 ) . These molecules modulate the Calcineurin / NFAT pathway that plays an important role in immune cell activation . Overexpression of Q9BRG2 and infection with live P49591 - CoV strongly increased signalling through the Calcineurin / NFAT pathway and enhanced the induction of interleukin 2 , compatible with late - stage immunopathogenicity and long - term cytokine dysregulation as observed in severe P49591 cases . Conversely , inhibition of cyclophilins by cyclosporine A ( CspA ) blocked the replication of CoVs of all genera , including P49591 - CoV , human CoV - 229E and - NL - 63 , feline CoV , as well as avian infectious bronchitis virus . Non - immunosuppressive derivatives of CspA might serve as broad - range CoV inhibitors applicable against emerging CoVs as well as ubiquitous pathogens of humans and livestock .", "Cl - ___MASK11___ enhances P01375 - α release in peritoneal macrophages stimulated with LPS . P0DMS8 ( A3R ) belongs to the Gi / Gq - coupled receptor family , that leads to the intracellular DB02527 reduction and intracellular calcium increase , respectively . A3R is widely expressed and it can play a crucial role in many patho - physiological conditions , including inflammation . Here we investigate the effect of Cl - ___MASK11___ , A3R agonist , on the production of P01375 - α . We found that Cl - ___MASK11___ enhances LPS - induced P01375 - α release in peritoneal macrophages . This effect is reduced by MRS1191 , A3R antagonist and by forskolin , activator of adenylyl cyclase . pIκBα increased in LPS + Cl - ___MASK11___ - treated macrophages , while total IκB kinase - β ( IKKβ ) reduced . Indeed , p65NF - κB nuclear translocation increased in cells treated with LPS + Cl - ___MASK11___ . Moreover , IMD 0354 , IKKβ inhibitor , significantly abrogated the effect of Cl - ___MASK11___ on P01375 - α release . Inhibition of protein kinase C ( PKC ) significantly reduced Cl - ___MASK11___ - induced P01375 - α release in LPS - stimulated macrophages . Furthermore , LY - 294002 , PI3K inhibitor , reduced the P01375 - α production enhanced by Cl - ___MASK11___ , although the phosphorylation status of Akt did not change in cells treated with LPS + Cl - ___MASK11___ than LPS alone . In summary , these data show that Cl - ___MASK11___ is able to enhance P01375 - α production in LPS - treated macrophages in an NF - κB - dependent manner .", "Neutralization of botulinum neurotoxin by a human monoclonal antibody specific for the catalytic light chain . BACKGROUND : Botulinum neurotoxins ( BoNT ) are a family of category A select bioterror agents and the most potent biological toxins known . Cloned antibody therapeutics hold considerable promise as BoNT therapeutics , but the therapeutic utility of antibodies that bind the BoNT light chain domain ( LC ) , a metalloprotease that functions in the cytosol of cholinergic neurons , has not been thoroughly explored . METHODS AND FINDINGS : We used an optimized hybridoma method to clone a fully human antibody specific for the LC of serotype A BoNT ( ___MASK38___ ) . The 4LCA antibody demonstrated potent in vivo neutralization when administered alone and collaborated with an antibody specific for the HC . In Neuro - 2a neuroblastoma cells , the 4LCA antibody prevented the cleavage of the ___MASK38___ proteolytic target , P60880 . Unlike an antibody specific for the HC , the 4LCA antibody did not block entry of ___MASK38___ into cultured cells . Instead , it was taken up into synaptic vesicles along with ___MASK38___ . The 4LCA antibody also directly inhibited ___MASK38___ catalytic activity in vitro . CONCLUSIONS : An antibody specific for the ___MASK38___ LC can potently inhibit ___MASK38___ in vivo and in vitro , using mechanisms not previously associated with BoNT - neutralizing antibodies . Antibodies specific for BoNT LC may be valuable components of an antibody antidote for BoNT exposure .", "Monoclonal antibodies targeting P01584 reduce biomarkers of atherosclerosis in vitro and inhibit atherosclerotic plaque formation in P02649 - deficient mice . OBJECTIVE : Atherosclerosis is a condition that is increasingly contributing to worldwide mortality through complications such as stroke and myocardial infarction . IL - 1β plays multiple direct , local roles in the formation and stability of the atheroma by eliciting the production of additional cytokines and proteolytic enzymes from macrophages , endothelial cells ( EC ) and smooth muscle cells ( SMC ) . We therefore tested whether an anti - IL - 1β antibody , ___MASK40___ , might inhibit the secretion of pro - atherogenic cytokines from macrophages in vitro and affect a positive outcome in the P02649 - deficient mouse ( ApoE (-/-) ) model of atherosclerosis in vivo . METHODS AND RESULTS : In an in vitro co - culture model , ___MASK40___ inhibited macrophage - induced secretion of key atherogenic cytokines from EC and SMC , including P05231 , P10145 , P13500 and TNFα . The release of degradative enzymes , such as the matrix metalloproteinases P08254 and P14780 , was also decreased by ___MASK40___ . In addition , ___MASK40___ inhibited the secretion of P13232 from EC and P05112 from SMC , cytokines not previously reported to be driven by IL - 1β in this context . In vivo , XMA052 MG1K , a chimeric murine version of ___MASK40___ , inhibited the formation of atherosclerotic lesions in the ApoE (-/-) model at all three doses tested . This effect was comparable to that reported for complete genetic ablation of IL - 1β or IL - 1R1 on an ApoE (-/-) background and was associated with decreases in plasma non - HDL / HDL cholesterol ratio and plaque lipid content and macrophage infiltration . CONCLUSIONS : These results demonstrate for the first time that an antibody targeting IL - 1β can inhibit the progression of atherosclerosis in vivo , highlighting the importance of this key cytokine in cardiovascular disease .", "P62937 as a target of DB00515 chemosensitizers . Platinum - based chemotherapeutics are the mainstay of treatment of a range of tumors achieving high response rates but limited in the course of disease by appearance of drug resistance . Tumor cells respond with reduced uptake and increased intracellular inactivation of the drugs , as well as increased DNA repair and general resistance to chemotherapyinduced cell death . DB00515 is known to induce expression of cyclophilins , a group of proteins that have peptidyl - prolyl cis - trans isomerase ( PPIase ) and molecular chaperone activities , as stress response . P62937 ( CypA ) and other members of this family are inhibited by cyclosporin A ( ___MASK3___ ) which sensitized diverse drug - resistant tumor cell lines in vitro to cisplatin . This effect of ___MASK3___ was attributed to metabolic changes , inhibition of DNA repair , enhancement of apoptosis , altered intracellular signal transduction or increased production of reactive oxygen species ( ROS ) , although no definitive explanation was provided so far . Several clinical trials employing cisplatin / carboplatin in combination with ___MASK3___ yielded unsatisfactory results . Since viral replication was found to be dependent on cyclophilins of the host cells , effective new inhibitors , different from ___MASK3___ or with low or absent immunosuppressive activity , are in development or clinical trials . Sanglifehrins are more potent than ___MASK3___ and proved to increase toxicity of cisplatin against hepatocellular cancer cells in vitro . These novel cyclophilin inhibitors may offer new opportunities to achieve reversal of resistance to platinumbased drugs in refractory patients . Responsive cancer patients may be enriched in clinical trials by an identification of the downstream targets of Cyps responsible for chemoresistance .", "Protein - protein interactions : an application of Tus - Ter mediated protein microarray system . In this chapter , we present a novel , cost - effective microarray strategy that utilizes expression - ready plasmid DNAs to generate protein arrays on - demand and its use to validate protein - protein interactions . These expression plasmids were constructed in such a way so as to serve a dual purpose of synthesizing the protein of interest as well as capturing the synthesized protein . The microarray system is based on the high affinity binding of Escherichia coli \" Tus \" protein to \" Ter , \" a 20 bp DNA sequence involved in the regulation of DNA replication . The protein expression is carried out in a cell - free protein synthesis system , with rabbit reticulocyte lysates , and the target proteins are detected either by labeled incorporated tag specific or by gene - specific antibodies . This microarray system has been successfully used for the detection of protein - protein interaction because both the target protein and the query protein can be transcribed and translated simultaneously in the microarray slides . The utility of this system for detecting protein - protein interaction is demonstrated by a few well - known examples : Jun / Fos , FRB / P62942 , p53 / Q00987 , and P11802 / p16 . In all these cases , the presence of protein complexes resulted in the localization of fluorophores at the specific sites of the immobilized target plasmids . Interestingly , during our interactions studies we also detected a previously unknown interaction between P24941 and p16 . Thus , this Tus - Ter based system of protein microarray can be used for the validation of known protein interactions as well as for identifying new protein - protein interactions . In addition , it can be used to examine and identify targets of nucleic acid - protein , ligand - receptor , enzyme - substrate , and drug - protein interactions ." ]
[ "___MASK11___", "___MASK21___", "___MASK25___", "___MASK38___", "___MASK3___", "___MASK40___", "___MASK56___", "___MASK69___", "___MASK8___" ]
___MASK3___
MH_train_1608
interacts_with DB01211?
[ "Recombinant human prothrombin kringles have potent anti - angiogenic activities and inhibit Lewis lung carcinoma tumor growth and metastases . P00734 , a protein involved in blood coagulation , is a plasma glycoprotein composed of the Gla domain , two adjacent kringle domains , and a serine protease domain . Kringles are triple - disulfide - loop folding domains , which are found in several other blood proteins . In this study , we showed that recombinant human prothrombin kringle - 1 , - 2 . and - 1 - 2 ( rk - 1 , - 2 , - 1 - 2 ) all have potent anti - angiogenic activities , which inhibit Lewis lung carcinoma ( LLC ) tumor growth and metastases . Recombinant human prothrombin kringles were expressed by an E . coli expression system and purified to apparent homogeneity from crude E . coli extracts . Purified rk - 1 , - 2 , - 1 - 2 migrated with a molecular mass of 14 , 19 , and 31 kDa , respectively , on sodium dodecyl sulfate - polyacrylamide gel electrophoresis ( SDS - PAGE ) under reducing conditions . rk - 1 , - 2 , - 1 - 2 exhibited potent inhibitory effects on P09038 - stimulated bovine capillary endothelial cell growth with half - maximal concentrations ( ED50 ) of approximately 41 , 55 , and 156 nM , respectively . All of the recombinant human prothrombin kringles also inhibited angiogenesis in the chorioallantoic membrane ( P62158 ) of chick embryos at a dose of 20 microg . Systemic administration of rk - 1 , - 2 , - 1 - 2 at a dose of 0 . 5 mg / kg / day suppressed the growth of primary LLC and at dose of 0 . 5 and 1 . 0 mg / kg / day inhibited LLC metastases in C57BL6 / J mice lungs through their anti - angiogenic effects .", "Single - prolonged stress induce changes of P62158 / CaMKIIα in the rats of dorsal raphe nucleus . Ca2 +/ calmodulin - dependent protein kinase IIα ( CaMKIIα ) is identified as a Ca2 +- dependent kinase in brain involved in the activation of DB00150 hydroxylase ( P17752 ) acting through direct phosphorylation of P17752 , and playing key roles in the signaling pathways initiated by various G protein - coupled 5 - HT receptors . The goal of this study is to detect whether there are changes of P62158 and CaMKIIα in dorsal raphe nucleus in the rats exposed to single - prolonged stress ( P49903 ) , which is a model employed in post - traumatic stress disorder ( PTSD ) study extensively . A total of 90 male Wistar rats were randomly divided into a normal control group and P49903 groups of 7d , 14d . The changes of P62158 / CaMKIIα were detected by immunohistochemistry , reverse transcription - polymerase chain reaction and western blot . Our results demonstrate that both expressions of P62158 and CaMKIIα significantly increase ( P < 0 . 001 ) in the P49903 7d group than that in the control group , and then decreased dramatically ( P < 0 . 001 ) 14 days after P49903 . Our results confirm that P49903 induce changes of P62158 / CaMKIIα in the dorsal raphe nucleus . Changes of P62158 / CaMKIIα may be associated with the activation of P08908 receptor , and may contribute to the progress of molecular mechanism of PTSD .", "Neurokinin type - 1 receptor antagonist inhibits enhancement of T cell functions by DB05875 in normal and neuromanipulated capsaicin - treated rats . Substance P ( SP ) plays a major role in the regulation of the interaction between immune and nervous systems . SP administration stimulates Con A - induced proliferation of spleen and peripheral blood lymphocytes from normal and neonatally capsaicin treated rats , which correlated with enhanced P60568 production and expression of activation antigens such as P60568 receptor alpha chain ( CD25 ) and RT1B MHC class II molecule . Moreover , SP markedly increased the percentage of P06127 + and P01730 + T lymphocytes in the peripheral blood of capsaicin - treated rats . Concomitant administration of SP with the non - peptide Neurokinin - 1 receptor ( P25103 ) antagonist SR140333 completely inhibited the SP - mediated augmentation of Con A - induced PBL proliferation and P60568 production as well as of P01730 + CD25 + and P01730 + RT1B + T cell numbers in normal and capsaicin - treated rats . ___MASK39___ also blocked the increased percentage of peripheral blood P01730 + T cells induced by SP in capsaicin - treated rats .", "Nuclear receptor - mediated repression of human cholesterol 7alpha - hydroxylase gene transcription by bile acids . Hydrophobic bile acids strongly repressed transcription of the human cholesterol 7alpha - hydroxylase gene ( P22680 ) in the bile acid biosynthetic pathway in the liver . Farnesoid X receptor ( Q96RI1 ) repressed P22680 / Luc reporter activity in a transfection assay in human liver - derived HepG2 cells , but not in human embryonic kidney ( P29320 ) 293 cells . Q96RI1 - binding activity was required for bile acid repression of P22680 transcription despite the fact that Q96RI1 did not bind to the P22680 promoter . Q96RI1 - induced liver - specific factors must be required for mediating bile acid repression . Bile acids and Q96RI1 repressed endogenous P22680 but stimulated alpha - fetoprotein transcription factor ( O00482 ) and small heterodimer partner ( Q15466 ) mRNA expression in HepG2 cells . Feeding of rats with chenodeoxycholic acid repressed P22680 , induced O00482 , but had no effect on Q15466 mRNA expression in the liver . O00482 strongly repressed P22680 transcription in a dose - dependent manner , and Q15466 further inhibited P22680 in HepG2 cells , but not in P29320 293 cells . Q96RI1 only moderately stimulated Q15466 transcription , whereas O00482 strongly inhibited Q15466 transcription in HepG2 cells . Results revealed that O00482 was a dominant negative factor that was induced by bile acid - activated Q96RI1 to inhibit both P22680 and Q15466 transcription . Differential regulation of O00482 and Q15466 expression by bile acids may explain the wide variation in P22680 expression and the rate of bile acid synthesis and regulation in different species .", "Characterization of the inhibitory effects of erythromycin and clarithromycin on the Q12809 potassium channel . Both erythromycin and clarithromycin have been reported to cause QT prolongation and the cardiac arrhythmia torsade de pointes in humans , however direct evidence documenting that these drugs produce this effect by blocking human cardiac ion channels is lacking . The goal of this study was to test the hypothesis that these macrolide antibiotics significantly block the delayed rectifier current ( IKr ) encoded by Q12809 ( the human ether - a - go - go - related gene ) at drug concentrations , temperature and ionic conditions mimicking those occurring in human subjects . DB01345 currents in P29320 293 cells stably transfected with Q12809 were recorded using a whole cell voltage clamp method . Exposure of cells to erythromycin reduced the Q12809 encoded potassium current in a concentration dependent manner with an IC50 of 38 . 9 +/- 1 . 2 microM and Hill Slope factor of 0 . 4 +/- 0 . 1 . DB01211 produced a similar concentration - dependent block with an IC50 of 45 . 7 +/- 1 . 1 microM and Hill Slope factor of 1 . 0 +/- 0 . 1 . Erythromycin ( 25 - 250 microM ) and clarithromycin ( 5 or 25 microM ) also produced a significant decrease in the integral of the current evoked by an action potential shaped voltage clamp protocol . The results of this study document that both erythromycin and clarithromycin significantly inhibit the Q12809 potassium current at clinically relevant concentrations .", "An acetylcholinesterase inhibitor , eserine , induces long - term depression at P07451 - P00915 synapses in the hippocampus of adult rats . Studies in humans and rodents support a role for muscarinic ACh receptor ( mAChR ) and nicotinic AChR in learning and memory , and both regulate hippocampal synaptic plasticity using complex and often times opposing mechanisms . P22303 ( P22303 ) inhibitors are commonly prescribed to enhance cholinergic signaling in Alzheimer ' s disease in hopes of rescuing cognitive function , caused , in part , by degeneration of cholinergic innervation to the hippocampus and cortex . Unfortunately , therapeutic efficacy is moderate and inconsistent , perhaps due to unanticipated mechanisms . M1 mAChRs bidirectionally control synaptic strength at P07451 - P00915 synapses ; weak pharmacological activation using carbachol ( CCh ) facilitates potentiation , whereas strong agonism induces muscarinic long - term depression ( mLTD ) via an P29323 - dependent mechanism . Here , we tested the prediction that accumulation of extracellular ACh via inhibition of P22303 is sufficient to induce LTD at P07451 - P00915 synapses in hippocampal slices from adult rats . Although P22303 inhibition with eserine induces LTD , it unexpectedly does not share properties with mLTD induced by CCh , as reported previously . ___MASK43___ - LTD was prevented by the M3 mAChR - preferring antagonist 1 , 1 - dimethyl - 4 - diphenylacetoxypiperidinium iodide ( 4 - DAMP ) , and pharmacological inhibition of MEK was completely ineffective . Additionally , pharmacological inhibition of p38 MAPK prevents mLTD but has no effect on eserine - LTD . Finally , long - term expression of eserine - LTD is partially dependent on a decrease in presynaptic release probability , likely caused by tonic activation of mAChRs by the sustained increase in extracellular ACh . Thus these findings extend current literature by showing that pharmacological P22303 inhibition causes a prolonged decrease in presynaptic glutamate release at P07451 - P00915 synapses , in addition to inducing a likely postsynaptic form of LTD .", "Anti - angiogenic effects and mechanisms of polysaccharides from Antrodia cinnamomea with different molecular weights . ETHNOPHARMACOLOGICAL RELEVANCE : Antrodia cinnamomea is a popular medicinal mushroom in Taiwan that has been widely used for treatment of various cancers and liver diseases . AIM OF THE STUDY : This study aimed to investigate the immunomodulatory effect on angiogenesis of polysaccharides from mycelia of Antrodia cinnamomea ( PMAC ) . MATERIALS AND METHODS : PMAC were extracted in boiling water , precipitated with 95 % ethanol , and separated into four different molecular weights ( < 5 , 5 - 30 , 30 - 100 , > 100 kDa ) . Tube formation and chorioallantoic membrane ( P62158 ) assay were used to determine the in vitro and ex vivo anti - angiogenic effects . RESULTS : Only the PMAC - mononuclear cells ( MNCs ) - conditioned medium ( CM ) with MW > 100 kDa significantly and concentration - dependently decreased the secretion of vascular endothelial growth factor in human leukemia cells and inhibited the matrigel tube formation in human umbilical vein endothelial cells . Similarly only the PMAC - MNC - CM with MW > 100 kDa significantly and concentration - dependently increased the levels of interleukin ( IL ) - 12 and interferon - gamma ( P01579 ) . In addition , the ex vivo P62158 assay revealed that only the PMAC with MW > 100 kDa significantly and dose - dependently inhibited neovascularization . CONCLUSIONS : PMAC with MW > 100 kDa are anti - angiogenic in vitro and ex vivo , and the effects are likely through immunomodulation .", "Critical role of P21453 and integrin β4 in P14210 / c - DB00134 - mediated increases in vascular integrity . Vascular endothelial cell ( EC ) barrier integrity is critical to vessel homeostasis whereas barrier dysfunction is a key feature of inflammatory disorders and tumor angiogenesis . We previously reported that hepatocyte growth factor ( P14210 ) - mediated increases in EC barrier integrity are signaled through a dynamic complex present in lipid rafts involving its receptor , c - DB00134 . We extended these observations to confirm that P21453 ( sphingosine 1 - phosphate receptor 1 ) and integrin β4 ( P16144 ) are essential participants in P14210 - induced EC barrier enhancement . Immunoprecipitation experiments demonstrated P14210 - mediated recruitment of c - DB00134 , P16144 and P21453 to caveolin - enriched lipid rafts in human lung EC with direct interactions of c - DB00134 with both P21453 and P16144 accompanied by c - DB00134 - dependent P21453 and P16144 transactivation . Reduced P21453 expression ( siRNA ) attenuated both P16144 and Rac1 activation as well as c - DB00134 / P16144 interaction and resulted in decreased transendothelial electrical resistance . Furthermore , reduced P16144 expression attenuated P14210 - induced c - DB00134 activation , c - DB00134 / P21453 interaction , and effected decreases in Q14703 - and P14210 - induced EC barrier enhancement . Finally , the c - DB00134 inhibitor , ___MASK32___ , suppressed P14210 - induced c - DB00134 activation as well as P21453 and P16144 transactivation . These results support a critical role for P21453 and P16144 transactivation as rate - limiting events in the transduction of P14210 signals via a dynamic c - DB00134 complex resulting in enhanced EC barrier integrity .", "Autonomous CaMKII requires further stimulation by Ca2 +/ calmodulin for enhancing synaptic strength . A hallmark feature of Ca ( 2 +)/ calmodulin ( P62158 ) - dependent protein kinase II ( CaMKII ) is generation of autonomous ( Ca ( 2 +)- independent ) activity by T286 autophosphorylation . Biochemical studies have shown that \" autonomous \" CaMKII is ∼ 5 - fold further stimulated by Ca ( 2 +)/ P62158 , but demonstration of a physiological function for such regulation within cells has remained elusive . In this study , CaMKII - induced enhancement of synaptic strength in rat hippocampal neurons required both autonomous activity and further stimulation . Synaptic strength was decreased by CaMKIIα knockdown and rescued by reexpression , but not by mutants impaired for autonomy ( T286A ) or binding to ___MASK45___ - type glutamate receptor subunit 2B ( Q13224 ; formerly Q13224 ; I205K ) . Q8N1N2 rescue was seen with constitutively autonomous mutants ( T286D ) , but only if they could be further stimulated ( additional T305 / 306A mutation ) , and not with two other mutations that additionally impair Ca ( 2 +)/ P62158 binding . Compared to rescue with wild - type CaMKII , the P62158 - binding - impaired mutants even had reduced synaptic strength . One of these mutants ( T305 / 306D ) mimicked an inhibitory autophosphorylation of CaMKII , whereas the other one ( Δstim ) abolished P62158 binding without introducing charged residues . Inhibitory T305 / 306 autophosphorylation also reduced Q13224 binding , but this effect was independent of reduced Ca ( 2 +)/ P62158 binding and was not mimicked by T305 / 306D mutation . Thus , even autonomous CaMKII activity must be further stimulated by Ca ( 2 +)/ P62158 for enhancement of synaptic strength .", "___MASK49___ sulfinic acid decarboxylase regulation : A role for farnesoid X receptor and small heterodimer partner in murine hepatic taurine metabolism . AIM : Bile acid synthesis is regulated by nuclear receptors including farnesoid X receptor ( Q96RI1 ) and small heterodimer partner ( Q15466 ) , and by fibroblast growth factor 15 / 19 ( FGF15 / 19 ) . We hypothesized that hepatic cysteine sulfinic acid decarboxylase ( Q9Y600 ) ( a key enzyme in taurine synthesis ) is regulated by bile acids ( BA ) . The aim of this study was to investigate Q9Y600 regulation by BA dependent regulatory mechanisms . METHODS : Mice were fed a control diet or a diet supplemented with either 0 . 5 % cholate or 2 % cholestyramine . To study BA dependent pathways , we utilized GW4064 ( Q96RI1 agonist ) , O95750 or T - 0901317 ( liver X receptor [ LXR ] agonist ) and Shp -/- mice . Tissue mRNA was determined by quantitative reverse transcription polymerase chain reaction . Amino acids were measured by high - performance liquid chromatography . RESULTS : Mice supplemented with dietary cholate exhibited reduced hepatic Q9Y600 mRNA while those receiving cholestyramine exhibited increased mRNA . Activation of Q96RI1 suppressed Q9Y600 mRNA expression whereas Q9Y600 expression was increased in Shp -/- mice . Hepatic hypotaurine concentration ( the product of Q9Y600 ) was higher in Shp -/- mice with a corresponding increase in serum taurine conjugated BA . O95750 administration suppressed hepatic cholesterol 7 - α - hydroxylase ( P22680 ) mRNA but did not change Q9Y600 mRNA expression . LXR activation induced P22680 mRNA yet failed to induce Q9Y600 mRNA expression . CONCLUSION : BA regulate Q9Y600 mRNA expression in a feedback fashion via mechanisms involving Q15466 and Q96RI1 but not FGF15 / 19 or LXR . These findings implicate BA as regulators of Q9Y600 mRNA via mechanisms shared with P22680 .", "Lipopolysaccharide - induced dopaminergic cell death in rat midbrain slice cultures : role of inducible nitric oxide synthase and protection by indomethacin . Glial cell activation associated with inflammatory reaction may contribute to pathogenic processes of neurodegenerative disorders , through production of several cytotoxic molecules . We investigated the consequences of glial activation by interferon - gamma ( P01579 ) / lipopolysaccharide ( LPS ) in rat midbrain slice cultures . Application of P01579 followed by LPS caused dopaminergic cell death and accompanying increases in nitrite production and lactate dehydrogenase release . ___MASK62___ , an inhibitor of inducible nitric oxide synthase ( P35228 ) , or SB203580 , an inhibitor of p38 mitogen - activated protein kinase , prevented dopaminergic cell loss as well as nitrite production . SB203580 also suppressed expression of P35228 and cyclooxygenase - 2 ( P35354 ) induced by P01579 / LPS . A P36551 inhibitor indomethacin protected dopaminergic neurons from P01579 / LPS - induced injury , whereas selective P35354 inhibitors such as NS - 398 and nimesulide did not . Notably , indomethacin was able to attenuate neurotoxicity of a nitric oxide ( NO ) donor . Neutralizing antibodies against tumour necrosis factor - alpha and interleukin - 1beta did not inhibit dopaminergic cell death caused by P01579 / LPS , although combined application of these antibodies blocked lactate dehydrogenase release and decrease in the number of non - dopaminergic neurons . These results indicate that P35228 - derived NO plays a crucial role in P01579 / LPS - induced dopaminergic cell death , and that indomethacin exerts protective effect by mechanisms probably related to NO neurotoxicity rather than through P36551 inhibition .", "Anti - clastogenic effect of beta - glucan extracted from barley towards chemically induced DNA damage in rodent cells . beta - Glucan ( BG ) was tested in vitro to determine its potential clastogenic and / or anti - clastogenic activity , and attempts were made to elucidate its possible mechanism of action by using combinations with an inhibitor of DNA polymerase . The study was carried out on cells deficient ( CHO - k1 ) and cells proficient ( HTC ) in phases I and II enzymes , and the DNA damage was assessed by the chromosomal aberration assay . BG did not show a clastogenic effect , but was anti - clastogenic in both cell lines used , and at all concentrations tested ( 2 . 5 , 5 and 10 microg / mL ) in combination with damage inducing agents ( methylmethane sulfonate in cell line CHO - k1 , and methylmethane sulfonate or 2 - aminoanthracene in cell line HTC ) . BG also showed a protective effect in the presence of a P06746 inhibitor ( cytosine arabinoside - 3 - phosphate , ___MASK48___ ) , demonstrating that BG does not act through an anti - mutagenic mechanism of action involving P06746 .", "___MASK45___ receptors assessed by autoradiography with [ 3H ] L - 689 , 560 are present but not enriched on corticofugal - projecting pyramidal neurones . Experimental lesions followed by binding of [ 3H ] 4 - trans - 2 - carboxy - 5 , 7 - dichloro - 4 - phenylamino - carbonylamino - 1 , 2 , 3 , 4 - tetrahydroquinoline ( [ 3H ] L - 689 , 560 , a novel ligand that binds to the glycine modulatory site ) , [ 3H ] glycine and [ 3H ] glutamate ( N - methyl - D - aspartate ( ___MASK45___ ) sensitive ) to cryostat sections and quantitative autoradiography were used to investigate the cellular localization of the ___MASK45___ receptor complex in the neocortex of the rat . The lesions were produced by intrastriatal injections of either volkensin ( 2 and 6 ng ) or ricin ( 10 ng ) : both are suicide transport agents but only the former is retrogradely transported in the CNS . The binding of [ 3H ] L - 689 , 560 was significantly reduced in rats receiving 2 or 6 ng volkensin in deep cortical layers of Fr1 / Fr2 ipsilateral to the striatal lesion . Similar reductions were also seen in [ 3H ] glycine and [ 3H ] glutamate binding , but only in rats receiving 6 ng volkensin . Quantitative histological analysis had previously revealed a loss of large infragranular pyramidal neurones with sparing of both interneurones and supragranular pyramidal neurones . There were no significant reductions in binding of any ligand in the superficial layers . In cortical areas Par1 / Par2 , [ 3H ] L - 689 , 560 was also significantly reduced in deep layers but only in rats receiving 6 ng volkensin . Binding was also reduced in the superficial layers by contrast to Fr1 / Fr2 . [ 3H ] Glycine and [ 3H ] glutamate binding were unaffected in this area . Binding of [ 3H ] L - 689 , 560 was unaffected in any area following intrastriatal ricin injection . The present study indicates that the ___MASK45___ receptor complex is present on pyramidal cells forming the corticofugal pathways . This is discussed in terms of the P08908 receptor which is enriched on these cells .", "Interpretation of point - of - care INR results in patients treated with dabigatran . BACKGROUND : Point - of - care devices for measurement of the international normalized ratio ( INR ) are commonly used to monitor therapy and maintain therapeutic levels of anticoagulation in patients treated with vitamin K antagonists . ___MASK16___ , a new oral , reversible direct thrombin inhibitor approved for stroke prevention in patients with atrial fibrillation does not require routine coagulation monitoring . However , case reports have identified falsely elevated point - of - care INR levels in patients treated with dabigatran using one of these devices ( Hemochron ) . This in vitro study was designed to verify this issue . METHODS : We compared INR levels in whole blood and plasma using a Hemochron Jr . Signature + point - of - care device ( International Technidyne Corporation , Edison , NJ ) with routine laboratory monitoring , using blood from healthy volunteers that was spiked with increasing concentrations of dabigatran . RESULTS : P00734 time and INR levels were increased about 2 - to 4 - fold with the point - of - care device compared with laboratory measures across the plasma dabigatran concentration range 50 - 1400 ng / mL . At plasma concentrations of dabigatran likely to be observed in patients , at a dose of 150 mg twice daily ( 60 - 275 ng / mL ) , whole blood point - of - care INR values increased from 1 . 7 to 4 . 0 , versus 1 . 1 to 1 . 5 measured with the laboratory coagulometer . Similar differences in prothrombin time were observed in plasma samples . CONCLUSIONS : INR levels in patients taking dabigatran are substantially higher using a Hemochron Jr . point - of - care device compared with laboratory values . We discourage the use of these devices specifically , as well as the use of the INR in general , for measuring the anticoagulant effect of dabigatran .", "Suppression of tumor growth and metastasis by a P17948 antagonizing peptide identified from a phage display library . Although the P15692 - Flk - 1 - pathway has been known as the major driving force of angiogenesis , new evidence has shown that P17948 / Flt - 1 plays important roles during the neovascularization under pathological conditions including tumor , atherosclerosis and arthritis . In search of Flt - 1 receptor antagonizing peptides , we screened a phage display 12 - mer - peptide library with recombinant Flt - 1 protein . Seven candidate peptides were identified that specifically bound to P15692 receptor Flt - 1 , of which peptide F56 ( WHSDMEWWYLLG ) almost abolished P15692 binding to receptor Flt - 1 in vitro . In vivo , F56 fused with P00374 ( P00374 - F56 ) inhibited angiogenesis in a P62158 assay . Moreover , P00374 - F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC - 803 in BALB / c nude mice . Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with P00374 - F56 . In the severe combined immunodeficiency disease ( SCID ) mouse model for studying metastasis of the human breast cancer cell line BICR - H1 , synthetic peptide F56 significantly inhibited tumor growth and lung metastases . Taken together , our results have demonstrated that peptide F56 , as a Flt - 1 receptor antagonist , fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between P15692 and receptor Flt - 1 . Thus , short peptide F56 may have clinical potential in tumor therapy .", "Gambogic acid inhibits angiogenesis through suppressing vascular endothelial growth factor - induced tyrosine phosphorylation of P35968 / Flk - 1 . Previous studies revealed that gambogic acid ( GA ) , the major active ingredient of gamboge , a brownish to orange resin exuded from Garcinia hanburryi tree in Southeast Asia , possessed significant anticancer activity both in vitro and in vivo . In this study , we explored the high antiangiogenic activities of GA for the first time . GA inhibits the P15692 - stimulated proliferation , migration and tube formation of human umbilical vein endothelial cells ( HUVECs ) as well as microvessel sprouting from rat aortic rings in vitro . Moreover , GA inhibits vessel growth in matrigel plugs and P62158 in vivo and transplanted tumor in mice . The results also indicated that GA decreases P15692 production of cultured tumor cells and inhibits P15692 - induced tyrosine phosphorylation of P35968 / Flk - 1 . This inhibition of receptor phosphorylation is correlated with a significant decrease in P15692 - triggered phosphorylated forms of P29323 , AKT and p38 . Taken together , these findings strongly suggest that GA might be a structurally novel angiogenesis inhibitor .", "Increased levels of Candida albicans mannan - specific T - cell - derived antigen binding molecules in patients with invasive candidiasis . In addition to cytokines , P01730 + T cells have been found to secrete soluble , T - cell - derived antigen binding molecules ( TABMs ) . These antigen - specific immunoproteins are thought to have immunoregulatory properties in the suppression of cell - mediated immunity ( CMI ) because they often associate with interleukin - 10 ( P22301 ) and transforming growth factor beta . Decreased CMI causes susceptibility to infections caused by organisms which are normally nonpathogenic . In this situation , e . g . , Candida albicans saprophytism may develop into invasive candidiasis . The difficult diagnosis of invasive candidiasis is based on the findings obtained from blood cultures and with tissue biopsy specimens , with some additional diagnostic value gained by the detection of Candida albicans mannan antigenemia and antimannan antibodies . In the present study , Candida albicans mannan - specific TABM ( P62158 - TABM ) levels in the sera of patients with invasive candidiasis ( n = 11 ) , Candida colonization ( n = 11 ) and noncolonization ( n = 10 ) , recurrent vulvovaginal candidiasis ( n = 30 ) , and atopic eczema dermatitis syndrome ( n = 59 ) and healthy controls ( n = 30 ) were analyzed . For 14 participants , the effect of mannan stimulation on TABM production and gamma interferon ( P01579 ) and P05112 mRNA expression by peripheral blood lymphocytes was also studied . It was demonstrated that P62158 - TABM production was the highest in patients with invasive candidiasis and that P62158 - TABM levels could distinguish Candida - colonized patients from noncolonized patients . In addition , the P62158 - TABM level was directly related to mRNA expression for P05112 but not P01579 . These results reinforce the view that TABMs are associated with decreased CMI , immunoregulation , and the T - helper cell 2 - type immune response .", "[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . DB01211 ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .", "Cell death is associated with reduced base excision repair during chronic alcohol administration in adult rat brain . The cell death cascades in different brain regions namely hippocampus and frontal cortex of rats fed with 10 % ( v / v ) ethanol for 12 weeks , was examined . After Western blotting , different cell death associated proteins displayed differential activation in the two regions observed . In hippocampus , activated caspase - 3 and caspase - 7 resulted in subsequent cleavage of poly ( ADP - ribose ) polymerase - 1 ( P09874 ) . P99999 release to cytosol and apoptosis inducing factor ( O95831 ) translocation to nucleus was marginal . B - cell leukemia / lymphoma - 2 ( Bcl - 2 ) translocation to cytosol was significant whereas Bcl - 2 - associated X protein ( Bax ) and Bcl - associated death protein ( Bad ) were largely located in cytosol . Further , upregulation of N - methyl D - aspartate receptor subunit 1 ( Q05586 ) , N - methyl D - aspartate receptor subunit 2B ( Q13224 ) , N - methyl D - aspartate receptor subunit 2C ( Q14957 ) and activation of calpains were observed . In frontal cortex , caspase - 3 activation , cleavage of P09874 and nuclear translocation of O95831 were more pronounced . Moreover , cytochrome c release to cytosol , Bcl - 2 translocation to cytosol was evident . However , levels of Bax , Bad , ___MASK45___ receptor subunits , and calpains were unaffected . Apoptosis was further substantiated by in situ staining for terminal deoxynucleotidyl transferase ( TdT ) - mediated dUTP - biotin nick end labeling ( TUNEL ) . Results of the current study revealed that frontal cortex exhibits a higher level of ethanol - induced apoptosis relative to hippocampus . P06746 assay and immunoblot showed significant loss in base excision repair in ethanol treated group .", "Human three - dimensional fibroblast cultures express angiogenic activity . Human neonatal fibroblasts were cultured on a lactate - glycollate copolymer scaffold for 12 - 16 days to form a three - dimensional dermal equivalent tissue . The cellular content of vascular endothelial growth factor ( P15692 ) mRNA in these three - dimensional cultures was 22 - fold greater than that observed in the same fibroblasts grown as monolayers . No induction was shown by hepatocyte growth factor ( P14210 ) or angiopoietin 1 indicating that the effect was specific to P15692 . The predominant P15692 splice variant , detected by RT - PCR corresponded to the 121 amino acid form , with less of the 165 amino acid form . The cell - associated forms ( 189 and 206 amino acids ) comprised less than 1 % of the total P15692 mRNA . P15692 and P14210 proteins , determined by ELISA , were secreted in physiologically significant amounts , 0 . 5 - 4 ng per 24 h / 10 ( 6 ) cells . Conditioned medium from the three - dimensional cultures stimulated proliferation of endothelial cells in a dose - dependent manner and induced cellular expression of integrin alpha ( v ) beta ( 3 ) . Conditioned medium from the same dermal fibroblasts cultured in monolayer showed little angiogenic activity in any of these assays . Using the chorioallantoic membrane ( P62158 ) angiogenesis assay , the cultures stimulated blood vessel production 2 . 8 - fold over scaffold alone . P15692 - neutralizing antibody reduced the vessel development in the P62158 to the level in the scaffold control . Anti - P14210 antibody had no significant effect . In conclusion , three - dimensional cultures of dermal equivalent tissue express angiogenic activity to a greater extent than monolayer cultures , some of which can be assigned to P15692 .", "Engineering human T cells for resistance to methotrexate and mycophenolate mofetil as an in vivo cell selection strategy . Gene transfer and drug selection systems that enforce ongoing transgene expression in vitro and in vivo which are compatible with human pharmaceutical drugs are currently underdeveloped . Here , we report on the utility of incorporating human enzyme muteins that confer resistance to the lymphotoxic / immunosuppressive drugs methotrexate ( MTX ) and mycophenolate mofetil ( ___MASK24___ ) in a multicistronic lentiviral vector for in vivo T lymphocyte selection . We found that co - expression of human dihydrofolate reductase ( P00374 ( FS ) ; L22F , F31S ) and inosine monophosphate dehydrogenase II ( P12268 ( IY ) ; T333I , S351Y ) conferred T cell resistance to the cytocidal and anti - proliferative effects of these drugs at concentrations that can be achieved clinically ( up to 0 . 1 µM MTX and 1 . 0 µM DB00603 ) . Furthermore , using a immunodeficient mouse model that supports the engraftment of central memory derived human T cells , in vivo selection studies demonstrate that huEGFRt (+) P00374 ( FS +) P12268 ( IY +) T cells could be enriched following adoptive transfer either by systemic administration of MTX alone ( 4 . 4 - fold ) , ___MASK24___ alone ( 2 . 9 - fold ) , or combined MTX and ___MASK24___ ( 4 . 9 - fold ) . These findings demonstrate the utility of both P00374 ( FS )/ MTX and P12268 ( IY )/ ___MASK24___ for in vivo selection of lentivirally transduced human T cells . Vectors incorporating these muteins in combination with other therapeutic transgenes may facilitate the selective engraftment of therapeutically active cells in recipients ." ]
[ "___MASK16___", "___MASK24___", "___MASK32___", "___MASK39___", "___MASK43___", "___MASK45___", "___MASK48___", "___MASK49___", "___MASK62___" ]
___MASK16___
MH_train_1609
interacts_with DB06643?
[ "β - cryptoxanthin regulates bone resorption related - cytokine production in human periodontal ligament cells . OBJECTIVE : β - cryptoxanthin ( β - cry ) is a type of carotenoid found in certain fruits and vegetables . Although it has been shown that β - cry inhibits alveolar bone resorption , the molecular mechanisms for this have not yet been clarified . In the present study , we investigated the effects of β - cry on bone resorption related - cytokine production in human periodontal ligament ( hPDL ) cells . DESIGN : hPDL cells were stimulated with β - cry ( 1 × 10 (- 7 ) mol / l ) , mechanical stress ( 1 or 6MPa ) , and P . gingivalis . The production of interleukin ( IL ) - 1β , P05231 , P10145 , tumour necrosis factor ( P01375 ) - α , osteoprotegerin ( O00300 ) , and receptor activator of nuclear factor kappa - B ligand ( O14788 ) were analyzed by RT - PCR and ELISA . RESULTS : The production of IL - 1β , P05231 , P10145 , and P01375 - α was not induced in hPDL cells after stimulation with β - cry , although these cytokines were produced after stimulation with P . gingivalis . On the other hand , P05231 and P10145 were produced after exposure to 6MPa of mechanical stress . The production of P05231 and P10145 was significantly decreased by the addition of β - cry . Furthermore , β - cry up - regulated the production of O00300 , but not O14788 . CONCLUSION : β - cry inhibited the production of P05231 and P10145 induced by mechanical stress and periodontopathogenic bacteria in hPDL cells . Moreover , β - cry up - regulated O00300 production . These results suggest that β - cry may prevent bone resorption in periodontitis .", "Inhibition of phosphatidylserine biosynthesis in developing rat brain by maternal exposure to ethanol . ___MASK16___ ( PtdSer ) , major acidic phospholipids in neuronal membranes , participate in important cell signaling processes . The PtdSer in brain is highly enriched with docosahexaenoic acid ( DB01708 ; 22 : 6n - 3 ) , and the DB01708 status or ethanol exposure has been shown to influence the PtdSer level . This study shows that ethanol exposure during prenatal and developmental period significantly attenuates microsomal PtdSer biosynthetic activities and reduces PtdSer , particularly 18 : 0 , 22 : 6 - PtdSer , in developing rat brain cortices . Brain microsomes were incubated with deuterium labeled exogenous substrates in vitro and the products formed were detected by reversed phase HPLC - electrospray ionization mass spectrometry ( P19957 - MS ) . These in vitro bioassays showed that 1 - stearoyl - 2 - docosahexaenoyl ( 18 : 0 , 22 : 6 ) species is the best substrate for PtdSer synthesis from both phosphatidylcholine ( PtdCho ) and phosphatidylethanolamine ( PtdEtn ) . The PtdSer biosynthetic activity of brain , especially for 18 : 0 , 22 : 6 - PtdSer production , was hampered significantly by maternal exposure to ethanol . PtdSer levels were consistently reduced significantly in brain cortices of the pups from ethanol - exposed dams , due mainly to the depletion of 18 : 0 , 22 : 6 - PtdSer . The mRNA expression of P48651 ( PSS1 ) and Q9BVG9 ( Q9BVG9 ) was not reduced by ethanol . Similarly , the PSS1 enzyme level did not change after ethanol exposure but Q9BVG9 could not be probed with the antibody available currently . Degradation of PtdSer by mitochondrial PtdSer decarboxylation was not enhanced but also inhibited . Taken together , attenuated PtdSer biosynthetic activities are largely responsible for the PtdSer reduction observed in developing rat brains after maternal exposure to ethanol .", "P00533 regulates osteoclast differentiation and survival through cross - talking with Q9Y6Q6 signaling . The epidermal growth factor receptor ( P00533 ) functions in various cellular physiological processes such as proliferation , differentiation , and motility . Although recent studies have reported that P00533 signaling is involved in osteoclast recruitment and formation , the molecular mechanism of P00533 signaling for the regulation of osteoclastogenesis remains unclear . We investigated the role of the P00533 in osteoclast differentiation and survival and show that the expression of the P00533 was highly up - regulated by receptor activator of nuclear factor - kappaB ligand ( O14788 ) during osteoclast differentiation . P00533 - specific tyrosine kinase inhibitors and P00533 knockdown blocked O14788 - dependent osteoclast formation , suggesting that P00533 signaling plays an important role in osteoclastogenesis . P00533 inhibition impaired the O14788 - mediated activation of osteoclastogenic signaling pathways , including c - Jun N - terminal kinase ( JNK ) , NF - kappaB , and Akt / protein kinase B ( P31749 ) . In addition , P00533 inhibition in differentiated osteoclasts caused apoptosis through caspase activation . Inhibition of the phosphoinositide - 3 kinase ( PI3K ) - Akt / P31749 pathway and subsequent activation of Q92934 and caspases - 9 and - 3 may be responsible for the P00533 inhibition - induced apoptosis . The P00533 physically associated with receptor activator of nuclear factor - kappaB ( Q9Y6Q6 ) and Grb2 - associated binder 2 ( Gab2 ) . Moreover , O14788 transactivated P00533 . These data indicate that P00533 regulates O14788 - activated signaling pathways by cross - talking with Q9Y6Q6 , suggesting that the P00533 may play a crucial role as a Q9Y6Q6 downstream signal and / or a novel type of Q9Y6Q6 co - receptor in osteoclast differentiation and survival .", "Increased O14788 - mediated osteoclastogenesis by interleukin - 1β and endoplasmic reticulum stress . OBJECTIVE : The mechanism by which IL - 1β and thapsigargin ( TG ) - induced endoplasmic reticulum ( ER ) stress modulate the receptor activator of nuclear factor kappa - B ligand ( O14788 ) - mediated osteoclastogenesis remains elusive . Thus , we investigated the osteoclast - specific and ER signals in osteoclastogenesis of bone marrow - derived cells . METHODS : Bone marrow cells ( BMCs ) were obtained from 5 - week - old male ICR mice and cultured to be differentiated into osteoclasts with P09603 and O14788 in the presence or absence of IL - 1β , TG , or 4 - phenylbutyric acid ( PBA ) , an ER stress - reducing drug . The formation of osteoclasts was evaluated by tartrate - resistant acid phosphatase ( TRAP ) staining and resorption pit assay with a dentine slice . The molecular mechanism of IL - 1β and ER stress in osteoclastogenesis was investigated in BMCs transfected with siRNA for P11021 , Q9NZJ5 and O75460 using reverse transcription - polymerase chain reaction and immunoblotting for osteoclast - specific and ER stress signaling molecules . RESULTS : IL - 1β and ER stress induced by TG - augmented the formation of osteoclasts , which was significantly inhibited by PBA and was mediated with osteoclast - specific signals , including c - Fos , O95644 , and ER stress - associated signaling pathways , such as Q9NZJ5 , O75460 , P11021 , and eIF2α . siRNA - mediated knockdown of ER stress signals inhibited the expression of O95644 and c - Fos , thus reducing IL - 1β and / or TG - induced formation of osteoclasts . CONCLUSIONS : Osteoclastogenesis by IL - 1β and / or ER stress is mainly associated with upregulation of eIF2α , P11021 , Q9NZJ5 and O75460 . These results suggest that the signaling pathway of ER stress - induced osteoclast formation might be a new therapeutic target to prevent inflammatory and destructive arthritic disease such as RA and diverse osteoporosis .", "___MASK54___ synthetase : regulation by cell stress and involvement in tumor biology . ___MASK54___ synthetase ( P08243 ) catalyzes the conversion of aspartate and glutamine to asparagine and glutamate in an DB00171 - dependent reaction . The enzyme is ubiquitous in its organ distribution in mammals , but basal expression is relatively low in tissues other than the exocrine pancreas . Human P08243 activity is highly regulated in response to cell stress , primarily by increased transcription from a single gene located on chromosome 7 . Among the genomic elements that control P08243 transcription is the C / EBP - P39905 response element ( CARE ) within the promoter . Protein limitation or an imbalanced dietary amino acid composition activate the P08243 gene through the amino acid response ( AAR ) , a process that is replicated in cell culture through limitation for any single essential amino acid . Endoplasmic reticulum stress also increases P08243 transcription through the Q9NZJ5 - eIF2 - P18848 arm of the unfolded protein response ( UPR ) . Both the AAR and UPR lead to increased synthesis of P18848 , which binds to the CARE and induces P08243 transcription . Elevated expression of P08243 protein is associated with resistance to asparaginase therapy in childhood acute lymphoblastic leukemia and may be a predictive factor in drug sensitivity for certain solid tumors as well . Activation of the Q9P2K8 - eIF2 - P18848 signaling pathway , leading to increased P08243 expression appears to be a component of solid tumor adaptation to nutrient deprivation and / or hypoxia . Identifying the roles of P08243 in fetal development , tissue differentiation , and tumor growth may reveal that P08243 function extends beyond asparagine biosynthesis .", "Effects on thrombin generation of single injections of ___MASK63___ in patients with calf vein thrombosis . STUDY OBJECTIVE : To determine whether single injections of ___MASK63___ , a direct thrombin inhibitor , can inhibit thrombin generation in patients with calf vein thrombosis and , if so , if the inhibition is sustained . DESIGN : Phase II open label cohort study . SETTING : Tertiary - care referral centres , university affiliated hospitals . PATIENTS : 10 patients with venographically - demonstrated calf vein thrombosis . INTERVENTION : Patients received a single injection of ___MASK63___ , either 1 . 0 mg / kg subcutaneously or 0 . 6 mg / kg as a 15 min intravenous infusion . P00734 fragment ( F1 ++ 2 ) levels , as an index of thrombin generation , were measured before as well as 6 h post - and 24 h post - ___MASK63___ administration . Patients were followed with non - invasive tests to detect thrombus extension into the proximal veins . RESULTS : There was a significant reduction in the levels of F1 + 2 with both regimens , 6 h after ___MASK63___ . The F1 + 2 levels 24 h post - ___MASK63___ showed a significant increase relative to the 6 h post - ___MASK63___ results . One patient developed thrombus extension into the popliteal vein and was treated with conventional anticoagulants . CONCLUSION : The single injections of ___MASK63___ used in the study produced incomplete and temporary suppression of F1 + 2 . Complete and permanent inhibition of thrombin generation with ___MASK63___ in patients with calf vein thrombosis may require higher doses , multiple subcutaneous injections and / or prolonged intravenous infusion .", "P01730 (+) regulatory T cells in autoimmunity and allergy . Regulatory T cells ( also referred to as suppressor T cells ) are important components of the homeostasis of the immune system , as impaired regulatory T cell activity can cause autoimmune diseases and atopy . It is now clear that the phrase ' regulatory T cells ' encompasses more than one cell type . For instance , P01730 (+) CD25 (+) regulatory T cells have received attention due to their immunosuppressive properties in vitro and in vivo , but in several instances it has been shown that P01730 (+) CD25 (-) T cell populations also contain potent regulatory activity . Recent progress in the field of regulatory T cells includes the discovery of the role of two tumor necrosis factor receptor ( TNFR ) family members ( Q9Y5U5 and O14788 - R / Q9Y6Q6 ) in Treg biology , the improved understanding of the role of co - stimulatory molecules and cytokines P22301 and P60568 in the induction and function of Tregs , and the generation of CD25 (+) and CD25 (-) regulatory T cells in vivo through high - avidity T cell receptor interactions .", "Inhibition of P51587 and ___MASK39___ Synthase Creates Multidrug Sensitive Tumor Cells via the Induction of Combined \" Complementary Lethality \" . A high mutation rate leading to tumor cell heterogeneity is a driver of malignancy in human cancers . Paradoxically , however , genomic instability can also render tumors vulnerable to therapeutic attack . Thus , targeting DNA repair may induce an intolerable level of DNA damage in tumor cells . P51587 mediates homologous recombination repair , and P51587 polymorphisms increase cancer risk . However , tumors with P51587 mutations respond better to chemotherapy and are associated with improved patient prognosis . P04818 ( TS ) is also involved in DNA maintenance and generates cellular thymidylate . We determined that antisense downregulation of P51587 synergistically potentiated drugs with mechanisms of action related to P51587 function ( cisplatin , melphalan ) , a phenomenon we named \" complementary lethality . \" TS knockdown induced complementary lethality to TS - targeting drugs ( 5 - FUdR and pemetrexed ) but not DNA cross - linking agents . Combined targeting of P51587 and TS induced complementary lethality to both DNA - damaging and TS - targeting agents , thus creating multidrug sensitive tumors . In addition , we demonstrated for the first time that simultaneous downregulation of both targets induced combined complementary lethality to multiple mechanistically different drugs in the same cell population . In this study , we propose and define the concept of \" complementary lethality \" and show that actively targeting P51587 and TS is of potential therapeutic benefit in multidrug treatment of human tumors . This work has contributed to the development of a P51587 - targeting antisense oligdeoxynucleotide ( ASO ) \" BR - 1 \" which we will test in vivo in combination with our TS - targeting ASO \" Q8N1L9 83 \" and attempt early clinical trials in the future . Molecular Therapy - Nucleic Acids ( 2013 ) 2 , e78 ; doi : 10 . 1038 / mtna . 2013 . 7 published online 12 March 2013 .", "___MASK95___ / beta promotes cell survival by activating nuclear factor kappa B through phosphatidylinositol 3 - kinase and Akt . Interferons ( IFNs ) play critical roles in host defense by modulating gene expression via activation of signal transducer and activator of transcription ( P35610 ) factors . IFN - alpha / beta also activates another transcription factor , nuclear factor kappaB ( NF - kappaB ) , which protects cells against apoptotic stimuli . NF - kappaB activation requires the IFN - dependent association of P40763 with the P17181 chain of the IFN receptor . IFN - dependent NF - kappaB activation involves the sequential activation of a serine kinase cascade involving phosphatidylinositol 3 - kinase ( PI - 3K ) and Akt . Whereas constitutively active PI - 3K and Akt induce NF - kappaB activation , Ly294002 ( a PI - 3K inhibitor ) , dominant - negative PI - 3K , and kinase - dead Akt block IFN - dependent NF - kappaB activation . Moreover , dominant - negative PI - 3K blocks IFN - promoted degradation of kappaBox alpha . Ly294002 , a dominant - negative PI - 3K construct , and kinase - dead Akt block IFN - promoted cell survival , enhancing apoptotic cell death . Therefore , P40763 , PI - 3K , and Akt are components of an IFN signaling pathway that promotes cell survival through NF - kappaB activation .", "Regulation of osteoclasts by membrane - derived lipid mediators . Osteoclasts are bone - resorbing cells of monocytic origin . An imbalance between bone formation and resorption can lead to osteoporosis or osteopetrosis . Osteoclastogenesis is triggered by O14788 - and IP3 - induced Ca ( 2 +) influx followed by activation of O95644 , a master transcription factor for osteoclastogenic gene regulation . During differentiation , osteoclasts undergo cytoskeletal remodeling to migrate and attach to the bone surface . Simultaneously , they fuse with each other to form multinucleated cells . These processes require P19957 - kinase - dependent cytoskeletal protein activation to initiate cytoskeletal remodeling , resulting in the formation of circumferential podosomes and fusion - competent protrusions . In multinucleated osteoclasts , circumferential podosomes mature into stabilized actin rings , which enables the formation of a ruffled border where intensive membrane trafficking is executed . Membrane lipids , especially phosphoinositides , are key signaling molecules that regulate osteoclast morphology and act as second messengers and docking sites for multiple important effectors . We examine the critical roles of phosphoinositides in the signaling cascades that regulate osteoclast functions .", "DB06643 for joints and bones . DB06643 is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . DB06643 suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . DB06643 reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .", "Update on denosumab treatment in postmenopausal women with osteoporosis . DB06643 , a fully human recombinant monoclonal antibody to the receptor activator of nuclear factor - κB ligand ( O14788 ) , blocks binding of O14788 to the Q9Y6Q6 receptor , found on the surface of osteoclasts and osteoclast precursors , resulting in decreased bone resorption . Subcutaneous denosumab administration once every 6 months increases bone mineral density at the lumbar spine , total hip , and / or femoral neck , and reduces markers of bone turnover significantly in postmenopausal women with osteoporosis . Relative to placebo , denosumab treatment reduces the risk of vertebral , nonvertebral , and hip fractures significantly . The benefits of denosumab treatment are generally obvious after the first dose and were continued for up to 8 years of treatment in an extension study . The tolerability profile of denosumab during this extension phase was consistent with that observed during the initial 3 - year FREEDOM trial . Postmarketing safety surveillance has not shown any unexpected findings . Ongoing safety surveillance will more fully define the long - term safety of denosumab . The benefits of denosumab would seem to be greater than its risks . DB06643 is an important choice in the treatment of postmenopausal women with osteoporosis at increased risk of fractures , including older patients who have difficulty with oral bisphosphonate intake and patients who are intolerant of , or unresponsive to , other therapies .", "Evidence for a link between Q9Y6Q6 and risk of breast cancer . Intracellular signaling mediated by the receptor activator of nuclear factor - κB [ Rank , encoded by the tumor necrosis factor receptor superfamily , member 11a ( Tnfrsf11a ) gene ] is fundamental for mammary gland development in mice , regulating the expansion of stem and progenitor cell compartments . Conversely , Rank overexpression in mice promotes abnormal proliferation and impairs differentiation , leading to an increased incidence of tumorigenesis . Here , we show that a common genetic variant near the 5 '- end of Q9Y6Q6 , rs7226991 , is associated with breast cancer risk in the general population and among carriers of mutations in the breast cancer 2 , early onset ( P51587 ) gene . Akin to the results of the Cancer and Genetics Markers of Susceptibility initiative , combined analysis of rs7226991 in two Spanish case - control studies ( 1 , 365 controls and 1 , 323 cases in total ) revealed a significant association with risk : odds ratio ( OR ) = 0 . 88 , 95 % confidence interval ( CI ) 0 . 78 - 0 . 98 , P ( trend ) = 0 . 025 . Subsequent examination of P38398 ( n = 1 , 017 ) and P51587 ( n = 885 ) mutation carriers revealed a consistent association in the latter group : weighted hazard ratio ( ( w ) HR ) = 0 . 70 ; 95 % CI 0 . 55 - 0 . 88 ; and P ( trend ) = 0 . 003 ; compared to P38398 mutation carriers , ( w ) HR = 0 . 91 ; 95 % CI 0 . 76 - 1 . 10 ; and P ( trend ) = 0 . 33 . The results of this study need to be replicated in other populations and with larger numbers of P38398 / 2 mutation carriers .", "Anti - interleukin 6 receptor antibody treatment in rheumatic disease . Interleukin 6 ( P05231 ) is a pleiotropic cytokine with a wide range of biological activities . P05231 transgene into mice gives rise to the abnormalities such as hypergammaglobulinaemia , thrombocytosis , infiltration of inflammatory cells into the tissues , mesangial cell proliferation of the kidney as well as splenomegaly and lymphadenopathy , which are predictable by the biological functions of P05231 shown in vitro . Continuous overproduction of P05231 is observed in patients with some immune - inflammatory diseases such as Castleman ' s disease and rheumatoid arthritis that are frequently associated with similar abnormalities to those of P05231 transgenic mice , strongly suggesting the involvement of P05231 in the human diseases . Successful treatment of the model animals for immune - inflammatory diseases with anti - P05231 receptor ( P08887 ) antibody thus indicates the possible application of P05231 blocking agents to treat the P05231 related immune - inflammatory diseases of humans . In this review , the new therapeutic strategy for Castleman ' s disease and RA using humanized antibody to human P05231 receptor , ___MASK70___ , is discussed .", "Second - generation epidermal growth factor receptor tyrosine kinase inhibitors in lung cancers . P00533 mutations identify patients who are more likely to respond to treatment with epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitors ( TKIs ) than cytotoxic chemotherapy . The distinct success of the first - generation P00533 TKIs erlotinib and gefitinib has been accompanied by the observation that acquired resistance to these treatments develops after a median of 1 year of treatment . Newer , second - generation P00533 TKIs have been developed with the intent to delay or overcome acquired resistance by the broader inhibition of kinases ( eg , P04626 and vascular endothelial growth factor receptor ) and / or altering the interactions with P00533 through irreversibly binding to the kinase domain . This article discusses many of these agents ( including afatinib , dacomitinib , ___MASK15___ , AP26113 , and CO - 1686 ) which have the potential for greater efficacy compared with first - generation P00533 TKIs , and may also have clinical activity against other oncogenic mutations within the P00533 family , including P04626 .", "Pharmacodynamics and pharmacokinetics of ___MASK33___ , a novel inhibitor of P09917 - activating protein ( P20292 ) . The P09917 - activating protein ( P20292 ) gene and an increase in leukotriene ( LT ) production are linked to the risk of asthma , myocardial infarction , and stroke . We evaluated the pharmacodynamics , pharmacokinetics , and tolerability of 3 -[ 3 - tert - butylsulfanyl - 1 -[ 4 -( 6 - methoxy - pyridin - 3 - yl )- benzyl ]- 5 -( pyridin - 2 - ylmethoxy )- 1H - indol - 2 - yl ]- 2 , 2 - dimethyl - propionic acid ( ___MASK33___ ) , a novel P20292 inhibitor , in healthy subjects . Single and multiple doses of ___MASK33___ demonstrated dose - dependent inhibition of blood Q06643 ( 4 ) production and dose - related inhibition of urinary LTE ( 4 ) . After a single oral dose ( 50 - 1 , 000 mg ) of ___MASK33___ , the maximum concentration ( C ( max ) ) and area under the curve ( AUC ) in plasma increased in a dose - dependent manner . After multiple - dose administration ( 50 - 1 , 000 mg once daily for 11 days ) , there were no significant differences in the pharmacokinetic parameters between the first and last days of treatment . ___MASK33___ was well tolerated at all doses in both the single - and multiple - dose cohorts . Further clinical trials with ___MASK33___ in inflammatory diseases are warranted .", "Bone marrow stromal cells derived P13500 reverses the inhibitory effects of multiple myeloma cells on osteoclastogenesis by upregulating the Q9Y6Q6 expression . Multiple myeloma ( MM ) cells are responsible for aberrant osteoclast ( OC ) activation . However , when cocultured monocytes , but not OC precursors , with MM cells , we made a novel observation that MM cells inhibited receptor activator of nuclear factor κB ligand ( O14788 ) - induced increase of OC differentiation , OC gene expression , signaling pathways and bone resorption activity . Our results showed that MM cells produced multiple inhibitory cytokines of osteoclastogenesis , such as P22301 , which activated P40763 signaling and induce OC inhibition . However , cocultures of bone marrow stromal cells ( BMSCs ) reversed MM - induced OC inhibition . We found that MM cells increased production of P13500 from BMSCs and BMSC - derived P13500 enhanced OC formation . Mechanistic studies showed that P22301 downregulated Q9Y6Q6 expression in monocytes and thus , inhibited O14788 - induced OC formation . In contrast , P13500 upregulated Q9Y6Q6 expression and thus , enhanced OC formation . Overall , our studies for the first time demonstrated that MM cell have inhibitory effects on osteoclastogenesis by producing inhibitory cytokines . Our results further indicate that activation of osteoclastogenesis in bone marrow requests the crosstalk of MM cells , BMSCs and their produced cytokines . Thus , our studies provide evidences that targeting bone marrow microenvironmental cells and / or cytokines may be a new approach to treating MM bone destruction .", "Nordihydroguaiaretic acid inhibition of O95644 suppresses osteoclastogenesis and arthritis bone destruction in rats . Nordihydroguaiaretic acid ( NDGA ) is known to have prominent anticancer activity against several cancers , and is also known to be an inhibitor of P09917 ( P09917 ) . In this study , we investigated the regulatory function of NDGA on inflammatory bone destruction mediated by osteoclasts . NDGA markedly inhibited receptor activator of nuclear factor - κB ( NF - κB ) ligand ( O14788 ) - induced formation of osteoclasts in cultures of murine osteoclast precursor cell line RAW - D cells and primary bone marrow - derived macrophages culture systems . The inhibitory effect of NDGA on osteoclastogenesis did not arise from the inhibition of P09917 activity . NDGA did not affect MAPKs , such as p38 , JNK , and NF - κB , but significantly inhibited the induction of O95644 , a key transcription factor for osteoclastogenesis . NDGA also suppressed activation of P29323 in osteoclast precursors . O14788 - induced calcium oscillation observed in osteoclast precursors was completely diminished by the addition of NDGA . In mature osteoclasts , O14788 - induced nuclear translocation of O95644 was clearly inhibited by NDGA treatment . Finally , in vivo studies demonstrated that administration of NDGA significantly reduced severe bone destruction and osteoclast recruitment in the ankle joint of rats with adjuvant - induced arthritis . These results indicate the potential utility of NDGA as a therapeutic agent for ameliorating inflammatory bone destruction in rheumatoid arthritis .", "A clinical trial with chimeric monoclonal antibody ___MASK100___ and low dose interleukin - 2 pulsing scheme for advanced renal cell carcinoma . PURPOSE : ___MASK100___ is a chimeric monoclonal antibody that binds to carbonic anhydrase IX ( Q16790 / MN ) , which is present on greater than 95 % of RCCs of the clear cell subtype . The suggested working mechanism of ___MASK100___ is by ADCC . Because the number of activated ADCC effector cells can be increased by a low dose interleukin - 2 pulsing schedule , a multicenter study was initiated to investigate whether ___MASK100___ combined with LD - P60568 could lead to an improved clinical outcome in patients with progressive RCC . MATERIALS AND METHODS : A total of 35 patients with progressive clear cell RCC received weekly infusions of ___MASK100___ for 11 weeks combined with a daily LD - P60568 regimen . Patients were monitored longitudinally for ADCC capacity . Radiological assessment of metastatic lesions was performed at week 16 and regularly until disease progression . RESULTS : A durable clinical benefit was achieved in 8 of 35 patients ( 23 % ) , including 3 with a partial response and 5 with stabilization at 24 weeks or greater . Mean survival was 22 months . In general treatment was well tolerated with little toxicity . The number of effector cells increased during treatment but lytic capacity per cell did not increase . ADCC and clinical outcome did not appear to correlate . CONCLUSIONS : ___MASK100___ combined with LD - P60568 in patients with metastatic RCC is safe and well tolerated . With a substantial clinical benefit and a median survival of 22 months in patients with metastatic RCC who have progressive disease at study entry combination therapy showed increased overall survival compared to ___MASK100___ monotherapy . Survival was at least similar to that of currently used cytokine regimens but with a favorable toxicity profile .", "O14788 induces components of the extrinsic coagulation pathway in osteoclasts . P00734 is converted to thrombin by factor Xa in the cell - associated prothrombinase complex . P00734 is present in calcified bone matrix and thrombin exerts effects on osteoblasts as well as on bone resorption by osteoclasts . We investigated whether ( 1 ) osteoclasts display factor Xa - dependent prothrombinase activity and ( 2 ) osteoclasts express critical regulatory components upstream of the prothrombinase complex . The osteoclast differentiation factor O14788 induced formation of multinucleated TRAP positive cells concomitant with induction of prothrombinase activity in cultures of RAW 264 . 7 cells and bone marrow osteoclast progenitors . Expression analysis of extrinsic coagulation factors revealed that O14788 enhanced protein levels of factor Xa as well as of coagulation factor III ( tissue factor ) . Inhibition assays indicated that factor Xa and tissue factor were involved in the control of prothrombinase activity in O14788 - differentiated osteoclasts , presumably at two stages ( 1 ) conversion of prothrombin to thrombin and ( 2 ) conversion of factor X to factor Xa , respectively . Activation of the extrinsic coagulation pathway during osteoclast differentiation through induction of tissue factor and factor Xa by a O14788 - dependent pathway indicates a novel role for osteoclasts in converting prothrombin to thrombin ." ]
[ "___MASK100___", "___MASK15___", "___MASK16___", "___MASK33___", "___MASK39___", "___MASK54___", "___MASK63___", "___MASK70___", "___MASK95___" ]
___MASK70___
MH_train_1610
interacts_with DB00215?
[ "Calcineurin - inhibitor - free immunosuppression based on the JAK inhibitor CP - 690 , 550 : a pilot study in de novo kidney allograft recipients . This randomized , pilot study compared the Janus kinase inhibitor CP - 690 , 550 ( 15 mg P55957 [ CP15 ] and 30 mg P55957 [ CP30 ] , n = 20 each ) with tacrolimus ( n = 21 ) in de novo kidney allograft recipients . Patients received an P60568 receptor antagonist , concomitant mycophenolate mofetil ( DB00688 ) and corticosteroids . CP - 690 , 550 doses were reduced after 6 months . Due to a high incidence of BK virus nephropathy ( BKN ) in CP30 , DB00688 was discontinued in this group . The 6 - month biopsy - proven acute rejection rates were 1 of 20 , 4 of 20 and 1 of 21 for CP15 , CP30 and tacrolimus groups , respectively . BKN developed in 4 of 20 patients in CP30 group . The 6 - month rates of cytomegalovirus disease were 2 of 20 , 4 of 20 and none of 21 for CP15 , CP30 and tacrolimus groups , respectively . Estimated glomerular filtration rate was > 70 mL / min at 6 and 12 months ( all groups ) . NK cells were reduced by </= 77 % in CP - 690 , 550 - treated patients . In the CP - 690 , 550 arms , there were modest lipid elevations and a trend toward more frequent anemia and neutropenia during the first 6 months . These data suggest that coadministration of CP - 690 , 550 30 mg P55957 with DB00688 is associated with overimmunosuppression . At 15 mg P55957 , the efficacy / safety profile was comparable to the tacrolimus control group , excepting a higher rate of viral infection . Further dose - ranging evaluation of CP - 690 , 550 is warranted .", "Human tumor infiltrating lymphocytes . Analysis of lymphokine mRNA expression and relevance to cancer immunotherapy . Tumor infiltrating lymphocytes ( Q15399 ) isolated from 12 patients with metastatic malignant melanoma , renal cell carcinoma , or breast adenocarcinoma were expanded in rIL - 2 for 22 to 45 days ( median 33 days ) and analyzed for lymphokine mRNA expression and patterns of TCR gene rearrangement . All Q15399 cultures were significantly enriched for T cells , with CD3 + CD8 + cells predominant in 8 of 10 cases tested , and demonstrated an oligoclonal ( rather than polyclonal ) pattern of TCR gene rearrangement . Nine of 12 cultures could effectively lyse the autologous targets in short term chromium release assays . P60568 expanded - Q15399 expressed mRNA for P01375 and P01374 ( lymphotoxin ) and , in 5 of 9 ( 41 % ) cases , granulocyte / macrophage - colony stimulating factor mRNA but not P01584 or P60568 transcripts . Cultured Q15399 deprived of rIL - 2 for 4 days did not constitutively express mRNA for any of the lymphokines tested . One long term Q15399 line in culture was followed and periodically tested for lytic activity and P01375 - mRNA expression . Loss of the specific cytolytic but not proliferative activity at day 85 was associated with disappearance of P01375 mRNA . Profiles of lymphokine secretion may provide a useful marker for functionally characterizing different T cell subsets and may provide correlates of the in vivo anti - tumor effects of these cells when Q15399 are adoptively transferred into cancer - bearing patients .", "Immunohistochemical analysis of brain lesions using P04271 and glial fibrillary acidic protein antibodies in arundic acid - ( ___MASK84___ ) treated stroke - prone spontaneously hypertensive rats . Stroke - prone spontaneously hypertensive rats ( SHRSP ) used as a model of essential hypertension cause a high incidence of brain stroke on the course of hypertension . Incidences and sizes of brain lesions are known to relate to the astrocyte activities . Therefore , relation between brain damage and the expression profile of the astrocytes was investigated with morphometric and immunohistochemical analyses using astrocyte marker antibodies of P04271 and glial fibrillary acidic protein ( P14136 ) with or without arundic acid administration , a suppressor on the activation of astrocytes . Arundic acid extended the average life span of SHRSP . An increase in brain tissue weight was inhibited concomitant with a lower rate of gliosis / hemosiderin deposit / scarring in brain lesions . P04271 - or P14136 - positive dot and filamentous structures were decreased in arundic acid - treated SHRSP , and this effect was most pronounced in the cerebral cortex , white matter , and pons , and less so in the hippocampus , diencephalon , midbrain , and cerebellum . Blood pressure decreased after administration of arundic acid in the high - dose group ( 100 mg / kg / day arundic acid ) , but not in the low - dose group ( 30 mg / kg / day ) . These data indicate that arundic acid can prevent hypertension - induced stroke , and may inhibit the enlargement of the stroke lesion by preventing the inflammatory changes caused by overproduction of the P04271 protein in the astrocytes .", "Longevity is independent of common variations in genes associated with cardiovascular risk . Do extremely old persons have a genetically favourable profile which has protected them from cardiovascular death ? We have tried to answer this question by measuring DNA polymorphisms of selected cardiovascular risk indicators [ factor VII , FVII ( R / Q353 , intron 7 ( 37bp ) n , and - 323ins10 ) , beta fibrinogen ( - 455G / A ) , plasminogen activator inhibitor type 1 , P05121 ( - 675 ( 4G / 5G ) ) , tissue plasminogen activator , t - PA ( intron 8 ins311 ) , platelet receptor glycoprotein IIb / IIIa , P08514 / IIIa ( L / P33 ) , prothrombin ( 20210G / A ) , methylene ___MASK68___ reductase , P42898 ( A / V114 ) , angiotensin converting enzyme , P12821 ( intron 16 ins287 ) , and angiotensinogen ( M / T235 ) ] . Blood was collected from 187 unselected Danish centenarians , and 201 healthy Danish blood donors , aged 20 - 64 years ( mean age 42 years ) . Genomic DNA was amplified using PCR and the genotype was determined by RFLP methods or allele - specific amplification followed by agarose gel electrophoresis . The frequencies of the high - risk alleles in centenarians were : for FVII R / Q353 0 . 91 ; for FVII intron 7 ( 37bp ) n 0 . 67 ; for FVII - 323 ins10 0 . 90 ; for fibrinogen 0 . 16 ; for P05121 0 . 52 ; for t - PA 0 . 59 ; for P08514 / IIIa 0 . 16 ; for prothrombin 0 . 008 ; for P42898 0 . 33 ; for P12821 0 . 52 ; and for angiotensinogen 0 . 36 . Comparable frequencies were observed in the blood donors . Subgroup analysis of men and women separately gave similar results . The genotype frequencies in the centenarians and the blood donors were similar for all polymorphisms , and this study suggests that common variations in genes associated with cardiovascular risk do not contribute significantly to longevity .", "Phosphorylation of thymidylate synthase from various sources by human protein kinase CK2 and its catalytic subunits . P04818 ( TS ) was found to be a substrate for both catalytic subunits of human CK2 , with phosphorylation by CK2alpha and CK2alpha ' characterized by similar K ( m ) values , 4 . 6microM and 4 . 2microM , respectively , but different efficiencies , the apparent turnover number with CK2alpha being 10 - fold higher . With both catalytic subunits , phosphorylation of human TS , like calmodulin and P55957 , was strongly inhibited in the presence of the regulatory subunit CK2beta , the holoenzyme being activated by polylysine . Phosphorylation of recombinant human , rat , mouse and Trichinella spiralis TSs proteins was compared , with the human enzyme being apparently a much better substrate than the others . Following hydrolysis and TLC , phosphoserine was detected in human and rat , and phosphotyrosine in T . spiralis , TS , used as substrates for CK2alpha . MALDI - TOF MS analysis led to identification of phosphorylated DB00133 ( 124 ) in human TS , within a sequence LGFS ( 124 ) TREEGD , atypical for a CK2 substrate recognition site . The phosphorylation site is located in a region considered important for the catalytic mechanism or regulation of human TS , corresponding to the loop 107 - 128 . Following phosphorylation by CK2alpha , resulting in incorporation of 0 . 4mol of phosphate per mol of dimeric TS , human TS exhibits unaltered K ( m ) values for ___MASK60___ and N ( 5 , 10 )- methylenetetrahydrofolate , but a 50 % lower turnover number , pointing to a strong influence of DB00133 ( 124 ) phosphorylation on its catalytic efficiency .", "Activated lymphoid cells in human gliomas : morphofunctional and cytochemical evidence . To study defensive infiltrating cells , smear preparation from 20 fresh gliomas and autologous normal peritumoural brain tissue , used as control , were analysed . May - Grünwald Giemsa staining and cytochemical reaction markers of cellular functions [ acid phosphatase ( AP ) , dihydrofolate reductase ( P00374 ) , dipeptidilpeptidase ( DAP IV ) and serine esterase Q15722 - dependent ( SE ) ] , were employed to characterize the cells . The extent of the leukocytic infiltration and the percentage of activated lymphocytes ( \" hand mirror \" shape lymphocytes : DB00253 ; lymphocytes binding tumor : LBT ) were also studied . In addition serum levels of T cell growth factor interleukin - 2 ( P60568 ) and of the soluble P60568 receptor ( sIL - 2R ) were determined in the affected patients . In tumoural imprints , mostly in astrocytomas , we observed an increased percentage of P00374 and DAP IV positive lymphocytes , of DB00253 lymphocytes and of lymphocytes binding tumoral cells . Serum levels of P60568 were significantly increased in all patients whilst sIL - 2R levels , were high only in glioblastoma . These findings indicate that in malignant gliomas there is stimulation of the immune system as witnessed by the presence of activated cells inside tumor tissue and soluble activating factors in serum .", "Molecular mechanisms governing different pharmacokinetics of ginsenosides and potential for ginsenoside - perpetrated herb - drug interactions on Q9NPD5 . BACKGROUND AND PURPOSE : Ginsenosides are bioactive saponins derived from Panax notoginseng roots ( Sanqi ) and ginseng . Here , the molecular mechanisms governing differential pharmacokinetics of 20 ( S )- protopanaxatriol - type ginsenoside Rg1 , ginsenoside Re and notoginsenoside Q96GN5 and 20 ( S )- protopanaxadiol - type ginsenosides Rb1 , Rc and Rd were elucidated . EXPERIMENTAL APPROACH : Interactions of ginsenosides with human and rat hepatobiliary transporters were characterized at the cellular and vesicular levels . A rifampin - based inhibition study in rats evaluated the in vivo role of organic anion - transporting polypeptide ( Oatp ) 1b2 . Plasma protein binding was assessed by equilibrium dialysis . Drug - drug interaction indices were calculated to estimate potential for clinically relevant ginsenoside - mediated interactions due to inhibition of human OATP1Bs . KEY RESULTS : All the ginsenosides were bound to human Q9NPD5 and rat Oatp1b2 but only the 20 ( S )- protopanaxatriol - type ginsenosides were transported . Human multidrug resistance - associated protein ( MRP ) 2 / breast cancer resistance protein ( Q9UNQ0 ) / bile salt export pump ( O95342 ) / multidrug resistance protein - 1 and rat Mrp2 / Bcrp / Bsep also mediated the transport of the 20 ( S )- protopanaxatriol - type ginsenosides . Glomerular - filtration - based renal excretion of the 20 ( S )- protopanaxatriol - type ginsenosides was greater than that of the 20 ( S )- protopanaxadiol - type counterparts due to differences in plasma protein binding . ___MASK82___ - impaired hepatobiliary excretion of the 20 ( S )- protopanaxatriol - type ginsenosides was effectively compensated by the renal excretion in rats . The 20 ( S )- protopanaxadiol - type ginsenosides were potent inhibitors of Q9NPD5 . CONCLUSION AND IMPLICATIONS : Differences in hepatobiliary and in renal excretory clearances caused markedly different systemic exposure and different elimination kinetics between the two types of ginsenosides . Caution should be exercised with the long - circulating 20 ( S )- protopanaxadiol - type ginsenosides as they could induce hepatobiliary herb - drug interactions , particularly when patients receive long - term therapies with high - dose i . v . Sanqi or ginseng extracts .", "The genetics of complex cholestatic disorders . Cholestatic liver diseases are caused by a range of hepatobiliary insults and involve complex interactions among environmental and genetic factors . Little is known about the pathogenic mechanisms of specific cholestatic diseases , which has limited our ability to manage patients with these disorders . However , recent genome - wide studies have provided insight into the pathogenesis of gallstones , primary biliary cirrhosis , and primary sclerosing cholangitis . A lithogenic variant in the gene that encodes the hepatobiliary transporter Q9H221 has been identified as a risk factor for gallstone disease ; this variant has been associated with altered cholesterol excretion and metabolism . Other variants of genes encoding transporters that affect the composition of bile have been associated with cholestasis , namely O95342 , which encodes the bile salt export pump , and P21439 , which encodes hepatocanalicular phosphatidylcholine floppase . In contrast , studies have associated primary biliary cirrhosis and primary sclerosing cholangitis with genes encoding major histocompatibility complex proteins and identified loci associated with microbial sensing and immune regulatory pathways outside this region , such as genes encoding IL12 , Q14765 , Q13568 , P60568 and its receptor ( IL2R ) , P10747 , and P33681 . These discoveries have raised interest in the development of reagents that target these gene products . We review recent findings from genetic studies of patients with cholestatic liver disease . Future characterization of genetic variants in animal models , stratification of risk alleles by clinical course , and identification of interacting environmental factors will increase our understanding of these complex cholestatic diseases .", "[ Guidelines for diagnosis and treatment of constipation in Mexico . C ) Medical and surgical treatment ] . BACKGROUND : There are multiple therapeutic options for the management of constipation , from lifestyle modifications to the use of laxatives and in extreme cases surgery . OBJECTIVES AND METHODS : To establish the clinical guidelines for diagnosis and treatment of chronic constipation in Mexico we conducted a review of the literature regarding medical and surgical treatments for chronic constipation and have made recommendations based on evidence . RESULTS : Low water consumption , physical inactivity and low intake of fiber are conditions associated with chronic constipation , but the evidence to prove these associations is scarce . Bolus forming agents are useful in the management of constipation with normal colonic transit and defecation without dissynergia . Evidence supports the use of lactulose ( IB ) and polyethylene glycol ( IA ) as the most safe and effective agents in the long term in adults . The use of stimulant laxatives ( docusate , picosulfate , senna ) is recommended only for short periods . ___MASK8___ is an agonist of Q13639 receptors and there are many clinical trials supporting its effectiveness in the management of functional constipation ( IA ) . However \" their cardiovascular safety has been questioned recently . Biofeedback therapy is the gold standard in the management of constipation associated with pelvic floor dyssynergia . Surgical treatment is reserved for extreme cases of colonic inertia . CONCLUSIONS : The treatment of constipation should be based on the underlying pathophysiological mechanisms and the selection of drugs must be made according to the scientific evidence .", "___MASK52___ ( DX - 88 ) , a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on - pump cardiothoracic surgery . BACKGROUND : P03952 plays a major role in the contact ( kallikrein - kinin ) cascade producing bradykinin . Bradykinin is a vasodilator , which increases vascular permeability , activates inflammation and produces pain . P03952 is also crosslinked to the coagulation system and the complement cascade . OBJECTIVE : ___MASK52___ ( DX - 88 ) is a potent and specific inhibitor of plasma kallikrein . ___MASK52___ is a recombinantly produced and engineered small protein based on the first Kunitz domain of human tissue factor pathway inhibitor . It was identified through phage display technology . METHODS : The search terms ' ecallantide ' , ' DX - 88 ' and ' hereditary angioedema ' were entered into Pubmed / Medline , ClinicalTrials and Google . RESULTS / CONCLUSION : At present , the drug is being studied for two major indications . First , the results for the treatment of hereditary angioedema are promising . Second , a prospective randomised multi - centre trial for the reduction of blood loss during on - pump cardiothoracic surgery will be terminated in October 2008 .", "Serotonin and vasopressin interact in the hypothalamus to control communicative behavior . The present study investigated whether serotonin ( 5 - HT ) agonists could inhibit the ability of arginine - vasopressin ( AVP ) to induce a form of scent marking called flank marking by their actions in the medial preoptic - anterior hypothalamus ( MPOA - AH ) . DOI , a 5 - Q13049 , 2B , 2C receptor agonist , did not inhibit AVP - induced flank marking , but mCPP a 5 - Q13049 antagonist and P41595 , 2C agonist inhibited AVP - induced flank marking . In addition , the finding that 8 - OH - DPAT , CGS - 12066A and SC53116 also inhibited AVP - induced flank marking suggests that 5 - HT could also inhibit flank marking by acting through P08908 , P34969 , P28222 and / or Q13639 receptor subtypes . These data support the hypothesis that 5 - HT acts within the MPOA - AH to inhibit the ability of AVP to induce flank marking .", "Establishment of an P60568 - dependent , antigen nonspecific chicken T - cell line . In this article , we describe a - chicken T helper - activated cell line , III - P01031 , which is non - antigen - specific but P60568 - dependent . By virtue of its absolute requirement for P60568 , the III - P01031 cell line is a useful tool for quantifying P60568 production by any chicken - activated T lymphocytes in culture . The III - P01031 line will be used to quantify P60568 production in mixed lymphocyte reaction in vitro , in order to study the functional activity of T lymphocytes from avian chimeras constructed in our laboratory and particularly for studying their state of tolerance .", "In vivo effects of a combined P28222 receptor / P31645 antagonist in experimental pulmonary hypertension . AIMS : A mechanism for co - operation between the serotonin ( 5 - hydroxytryptamine , 5 - HT ) transporter and P28222 receptor in mediating pulmonary artery vasoconstriction and proliferation of pulmonary artery smooth muscle cells has been demonstrated in vitro . Here we determine , for the first time , the in vivo effects of a combined P28222 receptor / serotonin transporter antagonist ( LY393558 ) with respect to the development of pulmonary arterial hypertension ( PAH ) and its in vitro effects in human pulmonary artery smooth muscle cells ( hPASMCs ) derived from idiopathic PAH ( IPAH ) patients . METHODS AND RESULTS : We determined the effects of LY393558 as well as a selective serotonin transporter inhibitor , citalopram , on right ventricular pressure , right ventricular hypertrophy , and pulmonary vascular remodelling in wildtype mice and mice over - expressing serotonin transporter ( P31645 + mice ) before and after hypoxic exposure . We also compared their effectiveness at reversing PAH in P31645 + mice and hypoxic mice . Further , we examined the proliferative response to serotonin in IPAH hPASMCs . We also clarified the pharmacology of serotonin - induced vasoconstriction and P28222 receptor / serotonin transporter interactions in mouse isolated pulmonary artery . DB00215 had a moderate effect at preventing and reversing experimental PAH in vivo whereas LY393558 was more effective . LY393558 was more effective than citalopram at reversing serotonin - induced proliferation in IPAH hPASMCs . There is synergy between P28222 receptor and serotonin transporter inhibitors against serotonin - induced vasoconstriction in mouse pulmonary arteries . CONCLUSION : P28222 receptor and serotonin transporter inhibition are effective at preventing and reversing experimental PAH and serotonin - induced proliferation of PASMCs derived from IPAH patients . Targeting both the serotonin transporter and P28222 receptor may be a novel therapeutic approach to PAH .", "A phase II study of pralatrexate with vitamin B12 and folic acid supplementation for previously treated recurrent and / or metastatic head and neck squamous cell cancer . BACKGROUND : ___MASK23___ ( Fotolyn ( TM ) ; Allos Therapeutics Inc . ) is an antifolate dihydrofolate reductase ( P00374 ) inhibitor . We conducted a phase II study of pralatrexate with folic acid and B12 supplementation in patients with recurrent and / or metastatic head and neck squamous cell cancer ( R / M HNSCC ) . PATIENTS AND METHODS : This was a single - arm , Simon optimal two stage phase II study . Patients with R / M HNSCC previously treated with chemotherapy were eligible . The study was initiated with a dosing schedule of pralatrexate 190 mg / m ( 2 ) biweekly on a 4 - week cycle with vitamin supplementation . Due to toxicity concerns , the dosing was modified to 30 mg / m ( 2 ) weekly for 3 weeks in a 4 - week cycle with vitamin supplementation . Radiologic imaging was to be obtained about every 2 cycles . RESULTS : Thirteen subjects were enrolled ; 12 were treated . Seven of the twelve patients had previously received ≥ 2 lines of chemotherapy . The most common grade 3 toxicity was mucositis ( 3 patients ) . Seven patients did not complete two cycles of therapy due to progression of disease ( 4 ) , toxicity ( 1 ) , death ( 1 ) , and withdrawal of consent ( 1 ) . Two deaths occurred : one due to disease progression and the other was an unwitnessed event that was possibly related to pralatrexate . No clinical activity was observed . The median overall survival was 3 . 1 months . The study was closed early due to lack of efficacy . CONCLUSIONS : ___MASK23___ does not possess clinical activity against previously treated R / M HNSCC . Evaluation of pralatrexate in other clinical settings of HNSCC management with special considerations for drug toxicity may be warranted .", "Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . DB00215 at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .", "In vitro cell death of activated lymphocytes in Omenn ' s syndrome . Omenn ' s syndrome ( OS ) is characterized by erythrodermia , hepatosplenomegaly , lymphadenopathy , hypereosinophilia and elevated IgE levels associated with increased susceptibility to severe infections . Peripheral blood T cells , though usually present in normal number , show an activated phenotype ( including an increased expression of CD95 / Fas ) , a Th2 pattern of cytokine secretion and defective proliferative response to mitogens . In this report , we demonstrate that T cells from patients with OS undergo an excessive cell death in vitro resulting from two mechanisms . First , a substantial number of peripheral blood lymphocytes from OS patients die in unstimulated cultures ( p = 0 . 009 vs . healthy controls ) . This spontaneous apoptosis is associated with reduced expression of bcl - 2 gene product ( p < 0 . 05 ) and can be prevented by addition of interleukin ( IL ) - 2 ( which also prevents down - modulation of bcl - 2 ) , while is independent from CD95 signaling . Second , lymphocytes from OS patients are highly susceptible to activation - induced cell death ( AICD ) induced with mitogens . This mechanism is largely independent from P60568 , while it can be significantly inhibited blocking CD95 with an IgG2b monoclonal antibody ( mAb ) . The dependence of AICD from signals transduced via CD95 was confirmed showing that cross - linking CD95 with an IgM mAb induces a higher cell death in purified P01730 + CD45R0 + cells from OS patients than in controls ( comparable for CD95 expression ) . Both mechanisms of cell death observed in this study result from lymphocyte hyperactivation occurring in vivo in these patients and may contribute to functional T cell defects of OS .", "The Lyme disease vaccine takes its toll . Vaccination with Borrelia burgdorferi outer surface protein ( Osp ) A can induce a protective response against Lyme disease and serves as a model to understand the generation of protective immune responses against the spirochete . The innate response to pathogens is activated by specific Toll - like receptors ( TLRs ) that recognize distinct pathogen - associated molecular patterns . O60603 is of particular interest for B . burgdorferi research because O60603 recognizes several pathogen - associated molecular patterns , including lipoproteins . O60603 may form heterodimers with Q9Y2C9 to identify diacylated lipoproteins , while O60603 works in concert with Q15399 to recognize triacylated lipoproteins such as OspA . We will discuss the role of Q15399 / 2 in the development of responses to OspA in Q15399 - and O60603 - deficient mice , and in selected individuals that received the OspA vaccine . While > 95 % of human OspA - based Lyme disease vaccine recipients develop OspA antibodies , a very small group of individuals did not develop detectable humoral responses against OspA . We demonstrated that this hyporesponsiveness to OspA vaccination was associated with decreased cell surface expression of Q15399 . Moreover , Q15399 - and O60603 - deficient mice did not develop significant levels of OspA antibodies following vaccination with OspA , providing a correlation with human hyporesponsiveness to OspA . These data suggest that defects in the Q15399 / 2 signaling pathway are associated with an impaired ability to generate antibodies following immunization with ___MASK46___ .", "Treatment of a patient with classical paroxysmal nocturnal hemoglobinuria and Budd - Chiari syndrome , with complement inhibitor eculizumab : Case Report . Background . Paroxysmal nocturnal haemoglobinuria ( PNH ) is a rare acquired clonal disorder of hematopoietic stem cells involving all blood cells . Erythrocytes have increased susceptibility to complement - mediated haemolysis . Thrombosis is the leading cause of mortality and follows episodes of acute hemolysis . ___MASK47___ , a monoclonal antibody blocking activation of complement P01031 is currently used in the treatment of PNH . Recent results demonstrated that eculizumab effectively reduces thrombosis . Description of case . We present a 30 - year - old male patient admitted with abdominal and lumbar pain . Thorough investigation revealed severe hemolytic anemia requiring transfusions and hepatosplenomegaly . Imaging findings were compatible with a Budd - Chiari syndrome . Flow cytometry confirmed the PNH diagnosis . Due to refractory ascites he underwent a transjugular intrahepatic portal - systemic shunt ( TIPS ) and eculizumab administration was started . Results . He has already completed three years of eculizumab treatment and he is transfusion independent . There is also a significant reduction in fatigue with improvement in his quality of life . Doppler scans of his TIPS persistently show it to be patent . Conclusions . Classical PNH patients with thrombosis and severe intravascular hemolysis are particularly challenging to manage . For these patients , eculizumab is a reasonable therapeutic option , expecting that by decreasing the risk for thrombosis , life expectancy may be increased .", "The cytokines ( P01579 , P60568 , P05112 , P22301 , Q16552 ) and Treg cytokine ( TGF - beta1 ) levels in adults with immune thrombocytopenia . Previous studies have indicated that autoimmune diseases might be caused by an imbalance of T helper cells ( Th ) , cytokines , and regulatory T cells ( Treg ) cytokines . We measured the plasma concentrations of Th1 - associated cytokines ( P01579 , P60568 ) , Th2 - associated cytokines ( P05112 , P22301 ) , Th17 - associated cytokine ( Q16552 ) and Treg - associated cytokine ( TGF - beta1 ) in adult patients with immune thrombocytopenia ( ITP ) and evaluated their clinical relevance . Plasma P01579 , P60568 , P05112 , P22301 , Q16552 and TGF - beta1 concentrations of 52 ITP patients and 30 age - and sex - matched healthy controls were measured by enzyme - linked immunosorbent assay method ( ELISA ) . Concentration of Th2 cytokines ( P05112 and P22301 ) were significantly higher in ITP patients compared to controls ( P < 0 . 05 ) . However , concentrations of Th1 cytokines ( P01579 , P60568 ) , Th17 cytokine ( Q16552 ) and Treg cytokine ( TGF - beta1 ) were lower in ITP patients ( P < 0 . 05 ) . Concentration of Q16552 was significantly higher in chronic ITP patients compared to severe ITP patients ( P < 0 . 05 ) , and no significant difference of cytokine concentration among the other subgroups in ITP patients was found . Among the ITP patients , concentration of P01579 correlated positively and significantly with PAIgG ( r = 0 . 48 , P = 0 . 02 ) . A significant correlation was neither found between other cytokine levels and platelet count , nor between cytokine levels and megakaryocytes number , nor between cytokines levels and PAIgG or P08514 / IIIa and / or GPIb / IX autoantibodies . The present study demonstrates that an imbalance of Th and Treg cytokines may mediate the pathogenesis of ITP .", "Effects of FK506 on rat thymic epithelial cells ; immunohistochemical study . The effects of FK506 , a new immunosuppressive agent , on the rat thymus were investigated using the immunoperoxidase technique and flow cytofluorometry using monoclonal antibodies . Flow cytometric analysis of the thymus revealed that the proportion of cells labelled positively with OX7 ( P04216 ) , OX8 ( CD8 , T cytotoxic / suppressor cells ) and W3 / 25 ( P01730 , T helper cells and macrophages ) increased following treatment , with FK506 , 1 mg / kg body weight for 14 days . A marked reduction of the thymic medulla following treatment was clearly demonstrated by staining with OX18 ( MHC class I ) and OX6 ( MHC class II ) . Changes produced by FK506 were also observed in the cortical area of the thymus , being especially marked in the subcapsular area and around the blood vessels by staining with OX6 , P03952 - 1 ( alpha - cytokeratin ) , AB - 1040 ( type IV collagen ) , and AB - 1220 ( laminin ) . Eventually FK506 treatment resulted in patchy reduction of OX - 6 , P03952 - 1 , AB - 1040 and AB - 1220 positive area in the cortex . This evidence suggests that FK506 may impair the thymic microenvironment and subsequently disturb the thymocyte maturation .", "Human CD8 (+) T cells and NK cells express and secrete P04271 upon stimulation . Previous studies have demonstrated the utility of P04271 as a surrogate marker of brain - related pathologies , e . g . neuropsychiatric disorders , and melanoma progression , which have an inflammatory component . This study addresses the relevance of P04271 (+) lymphocytes in mediating such responses . P04271 expression was determined in human peripheral blood leukocytes isolated from healthy volunteers using flow cytometry . P04271 (+) lymphocytes were characterised for phenotype , cytokine production and P04271 secretion . In addition , we investigated whether P04271 activates monocytes and neutrophils . P04271 (+) cells comprised 2 - 4 % of all lymphocytes and the majority displayed a CD3 (+) CD8 (+) phenotype ; fewer cells were CD3 (-) CD56 (+) NK lymphocytes . Comparison of P04271 (+) and P04271 (-) CD3 (+) CD8 (+) cells revealed no differences in production of interferon gamma ( IFNγ ) and interleukin - 2 ( P60568 ) . Stimulation of P04271 (+) CD3 (+) CD8 (+) lymphocytes with anti - CD3 or phytohaemagglutinin resulted in release of P04271 . High concentrations of recombinant human P04271 triggered upregulation of CD11b and membrane shedding of CD62L in granulocytes and monocytes . These findings set the stage for a new field of research addressing a P04271 - mediated crosstalk between the innate and adaptive immune systems if close proximity of effector and responder cells accomplishes sufficient local P04271 levels . In various physiological and pathological conditions P04271 might function as an interface to immunological processes , distinct from known cytokine - and chemokine - mediated pathways ." ]
[ "___MASK23___", "___MASK46___", "___MASK47___", "___MASK52___", "___MASK60___", "___MASK68___", "___MASK82___", "___MASK84___", "___MASK8___" ]
___MASK82___
MH_train_1611
interacts_with DB04844?
[ "P01308 - like growth factor - I treatment of children with Laron syndrome ( primary growth hormone insensitivity ) . Laron syndrome ( LS , congenital primary GH insensitivity ) is caused by deletions or mutations in the P10912 gene , resulting in an inability to generate insulin - like growth factor - I ( P05019 ) . If untreated , the deficiency of P05019 results in severe dwarfism , as well as skeletal and muscular underdevelopment . The only treatment is the daily administration of recombinant P05019 . This review summarizes the present experience by several groups worldwide . The main conclusions are : A . The one or two injections regimen result in the same growth velocity ; B . The growth velocity obtained with P05019 administration is smaller than that observed with hGH in children with congenital isolated GH deficiency ; C . Overdosage of P05019 causes a series of adverse effects which can be avoided by carefully monitoring the serum P05019 and GH levels .", "In vivo effects of a combined P28222 receptor / P31645 antagonist in experimental pulmonary hypertension . AIMS : A mechanism for co - operation between the serotonin ( 5 - hydroxytryptamine , 5 - HT ) transporter and P28222 receptor in mediating pulmonary artery vasoconstriction and proliferation of pulmonary artery smooth muscle cells has been demonstrated in vitro . Here we determine , for the first time , the in vivo effects of a combined P28222 receptor / serotonin transporter antagonist ( LY393558 ) with respect to the development of pulmonary arterial hypertension ( PAH ) and its in vitro effects in human pulmonary artery smooth muscle cells ( hPASMCs ) derived from idiopathic PAH ( IPAH ) patients . METHODS AND RESULTS : We determined the effects of LY393558 as well as a selective serotonin transporter inhibitor , citalopram , on right ventricular pressure , right ventricular hypertrophy , and pulmonary vascular remodelling in wildtype mice and mice over - expressing serotonin transporter ( P31645 + mice ) before and after hypoxic exposure . We also compared their effectiveness at reversing PAH in P31645 + mice and hypoxic mice . Further , we examined the proliferative response to serotonin in IPAH hPASMCs . We also clarified the pharmacology of serotonin - induced vasoconstriction and P28222 receptor / serotonin transporter interactions in mouse isolated pulmonary artery . ___MASK29___ had a moderate effect at preventing and reversing experimental PAH in vivo whereas LY393558 was more effective . LY393558 was more effective than citalopram at reversing serotonin - induced proliferation in IPAH hPASMCs . There is synergy between P28222 receptor and serotonin transporter inhibitors against serotonin - induced vasoconstriction in mouse pulmonary arteries . CONCLUSION : P28222 receptor and serotonin transporter inhibition are effective at preventing and reversing experimental PAH and serotonin - induced proliferation of PASMCs derived from IPAH patients . Targeting both the serotonin transporter and P28222 receptor may be a novel therapeutic approach to PAH .", "Central cannabinoid 1 receptor antagonist administration prevents endotoxic hypotension affecting norepinephrine release in the preoptic anterior hypothalamic area . It is widely assumed that LPS lowers arterial pressure during sepsis by stimulating release of P01375 and other vasoactive mediators from macrophages . However , recent data from this and other laboratories have shown that LPS hypotension can be prevented by inhibiting afferent impulse flow in the vagus nerve , by blocking neuronal activity in the nucleus of the solitary tract , or by blocking alpha - adrenergic receptors in the preoptic area / anterior hypothalamic area ( POA ) . These findings suggest that the inflammatory signal is conveyed from the periphery to the brain via the vagus nerve , and that endotoxic shock is mediated through a central mechanism that requires activation of POA neurons . In the present study , we tested whether central cannabinoid 1 ( P21554 ) receptors participate in the control of arterial pressure during endotoxemia based on evidence that hypothalamic neurons express P21554 receptors and synthesize the endogenous CB anandamide . We found that intracerebroventricular administration of rimonabant , a P21554 receptor antagonist , inhibited the fall in arterial pressure evoked by LPS significantly in both conscious and anesthetized rats . ___MASK57___ attenuated both the immediate fall in arterial pressure evoked by LPS and the second , delayed hypotensive phase that leads to tissue ischemia and death . ___MASK57___ also prevented the associated LPS - induced rise in extracellular fluid norepinephrine concentrations in the POA . Furthermore , rimonabant attenuated the associated increase in plasma P01375 concentrations characteristic of the late phase of endotoxic hypotension . These data indicate that central P21554 receptors may play an important role in the initiation of endotoxic hypotension .", "Catecholamine - producing cells in the synovial tissue during arthritis : modulation of sympathetic neurotransmitters as new therapeutic target . BACKGROUND : The proinflammatory and anti - inflammatory role of the sympathetic nervous system in early and late inflammation is an unresolved paradox . A drastic loss of sympathetic nerve fibres in the synovial tissue of patients with rheumatoid arthritis ( RA ) has previously been demonstrated . The presence of tyrosine hydroxylase ( TH ) - positive cells in RA and osteoarthritis ( OA ) has been determined , but the role of these cells in inflammation is still unclear . OBJECTIVE : To characterise TH - positive cells in inflamed RA and OA synovial tissue and to study their role in inflammation . METHODS : Synovial samples were obtained from 32 patients with OA and 19 patients with RA and from 10 control patients . Synovial tissue samples were used for immunofluorescence staining . Synovial cells were isolated by tissue digestion and immediately used for cell culture . For in vivo experiments , collagen type - II arthritis in DBA / 1J mice was induced . RESULTS : TH + cells were present only in inflamed tissue and not in controls . Catecholamine - storing vesicles and vesicular monoamine transporter 2 ( Q05940 ) were identified in the synovial tissue . Experimental increase of cytoplasmic catecholamines by Q05940 blockade strongly reduced tumour necrosis factor ( P01375 ) independently of canonical extracellular β - adrenergic signalling . In addition , Q05940 blockade increased cyclic AMP ( DB02527 ) and DB02527 responsive element binding protein , responsible for P01375 inhibition . In vivo , appearance of Q05940 positive cells was confirmed . Q05940 blockade ameliorated inflammation also in vivo . CONCLUSIONS : This study demonstrates that local catecholamine - producing cells start to replace sympathetic nerve fibres around the onset of disease , and modulation of locally produced catecholamines has strong anti - inflammatory effects in vivo and in vitro .", "P37840 A30P point - mutation generates age - dependent nigrostriatal deficiency in mice . Lewy bodies are mainly composed of alpha - synuclein ( P37840 ) and specific mutations in P37840 gene are related to familial forms of Parkinson ' s disease ( PD ) . The purpose of our study was to generate a mouse line with A30P knock - in point mutation in P37840 gene and to test if a single point - mutation is able to turn otherwise normal P37840 into a toxic form . The behavioral profile of P37840 A30P mice was followed for 16 months . Generally , these mice are healthy and viable without any obvious abnormalities . Starting from the age of 13 months mice developed a significant deficit in motor performance tests related to nigrostriatal function ( ink - test and beam walk ) . In other tests ( motility boxes , rotarod ) mice continuously performed normally . Moreover , P37840 A30P mice expressed the altered sensitivity to Q05940 inhibitor reserpine , possibly reflecting a functional deficiency of dopamine . Indeed , mice at 15 months of age had significantly reduced levels of dopamine and its major metabolite DOPAC in the striatum , and reduced levels of dopamine in the mesolimbic system . The present study confirms that P37840 plays an important role in the development of PD and an insertion of a single point mutation is sufficient to generate age - related decline in specific motor performance . The generated mouse line has a potential to become a model for PD with comparable time course and phenotype .", "P37840 activates microglia by inducing the expressions of matrix metalloproteinases and the subsequent activation of protease - activated receptor - 1 . The mutation or overexpression of alpha - synuclein protein plays a pivotal role in the pathogenesis of Parkinson ' s disease . In our preliminary experiments , we found that alpha - synuclein induced the expression of matrix metalloproteinases ( MMPs ) ( P03956 , - 3 , - 8 , and - 9 ) in rat primary cultured microglia . Thus , the current study was undertaken to determine the roles of MMPs in alpha - synuclein - induced microglial activation . The inhibition of P08254 , - 8 , or - 9 significantly reduced NO and reactive oxygen species levels and suppressed the expression of P01375 and IL - 1beta . Notably , P22894 inhibitor suppressed P01375 production more efficaciously than P08254 or P14780 inhibitors . Inhibition of P08254 or - 9 also suppressed the activities of MAPK , NF - kappaB , and AP - 1 . Previously , protease - activated receptor - 1 ( P25116 ) has been associated with the actions of MMPs , and thus , we further investigated the role of P25116 in alpha - synuclein - induced inflammatory reactions . A P25116 - specific inhibitor and a P25116 antagonist significantly suppressed cytokine levels , and NO and reactive oxygen species production in alpha - synuclein - treated microglia . Subsequent P25116 cleavage assay revealed that P08254 , - 8 , and - 9 , but not alpha - synuclein , cleaved the synthetic peptide containing conventional P25116 cleavage sites . These results suggest that MMPs secreted by alpha - synuclein - stimulated microglia activate P25116 and amplify microglial inflammatory signals in an autocrine or paracrine manner . Furthermore , our findings suggest that modulation of the activities of MMPs and / or P25116 may provide a new therapeutic strategy for Parkinson ' s disease .", "Electrostatic steering at acetylcholine binding sites . The electrostatic environments near the acetylcholine binding sites on the nicotinic acetylcholine receptor ( nAChR ) and acetylcholinesterase were measured by diffusion - enhanced fluorescence energy transfer ( DEFET ) to determine the influence of long - range electrostatic interactions on ligand binding kinetics and net binding energy . Changes in DEFET from variously charged Tb3 + - chelates revealed net potentials of - 20 mV at the nAChR agonist sites and - 14 mV at the entrance to the P22303 active site , in physiological ionic strength conditions . The potential at the alphadelta - binding site of the nAChR was determined independently in the presence of ___MASK40___ to be - 14 mV ; the calculated potential at the alphagamma - site was approximately threefold stronger than at the alphadelta - site . By determining the local potential in increasing ionic strength , Debye - Hückel theory predicted that the potentials near the nAChR agonist binding sites are constituted by one to three charges in close proximity to the binding site . Examination of the binding kinetics of the fluorescent acetylcholine analog dansyl - P13671 - choline at ionic strengths from 12 . 5 to 400 mM revealed a twofold decrease in association rate . Debye - Hückel analysis of the kinetics revealed a similar charge distribution as seen by changes in the potentials . To determine whether the experimentally determined potentials are reflected by continuum electrostatics calculations , solutions to the nonlinear Poisson - Boltzmann equation were used to compute the potentials expected from DEFET measurements from high - resolution models of the nAChR and P22303 . These calculations are in good agreement with the DEFET measurements for P22303 and for the alphagamma - site of the nAChR . We conclude that long - range electrostatic interactions contribute - 0 . 3 and - 1 kcal / mol to the binding energy at the nAChR alphadelta - and alphagamma - sites due to an increase in association rates .", "The P36888 inhibitor ___MASK70___ ( formerly MLN518 ) has sequence - independent synergistic effects with cytarabine and daunorubicin . AML remains a difficult disease to treat . Despite response to induction chemotherapy , most patients ultimately relapse . Further , among elderly patients , aggressive therapy options are often limited due to other medical conditions and decreased tolerance of these patients to conventional chemotherapy . Internal tandem duplications ( ITD ) of the P36888 juxtamembrane domain occur in 20 - 30 % of AML patients and predict poor outcome . First clinical data with the P36888 inhibitor ___MASK70___ demonstrated antileukemic activity in approximately half of the patients -- predominantly with P36888 ITD positive AML . But the data also show that optimal use of ___MASK70___ will require combination therapy with cytotoxic agents . Notably , single agent ___MASK70___ has not been associated with myelosuppression , mucositis or cardiac toxicity -- the dose limiting toxicities of AML chemotherapy . We determined the feasibility of combining ___MASK70___ with the standard \" 3 + 7 \" induction regimen in AML and show that , in contrast to other structurally unrelated P36888 inhibitors recently evaluated in clinical trials , the use of ___MASK70___ displayed application sequence independent synergistic antileukemic effects in combination with cytarabine and daunorubicin . Strong synergistic antiproliferative and proapoptotic effects were thereby predominantly seen on P36888 ITD positive blasts . Further we demonstrate , that addition of ___MASK70___ may allow dose reduction of chemotherapy without loss of overall antileukemic activity -- resulting in a potential decrease of side effects . This approach might be an interesting novel strategy especially in the treatment of elderly / comorbid patients . Our data provide a rationale for combining ___MASK70___ with induction chemotherapy in intensified as well as in dose reduction protocols for P36888 ITD positive AML .", "Q01196 mutation associated with clonal evolution in relapsed pediatric acute myeloid leukemia with t ( 16 ; 21 )( p11 ; q22 ) . P35637 / P35637 - ERG chimeric fusion transcript resulting from translocation changes involving chromosomes 16 and 21 is a rare genetic event associated with acute myeloid leukemia ( AML ) . The distinct t ( 16 ; 21 ) AML subtype exhibits unique clinical and morphological features and is associated with poor prognosis and a high relapse rate ; however , the underlying mechanism remains to be clarified . Recently , whole - genome sequencing revealed a large set of genetic alterations that may be relevant for the dynamic clonal evolution and relapse pathogenesis of AML . Here , we report three pediatric AML patients with t ( 16 ; 21 ) ( p11 ; q22 ) . The P35637 / P35637 - ERG fusion transcript was detected in all diagnostic and relapsed samples , with the exception of one relapsed sample . We searched for several genetic lesions , such as Q01196 , P36888 , c - P10721 , P01111 , P01116 , P04637 , P22681 , Q8IXJ9 , O75874 / 2 , and Q9Y6K1 , in primary and relapsed AML samples . Interestingly , we found Q01196 mutation in relapsed sample of one patient in whom cytogenetic analysis showed the emergence of a new additional clone . Otherwise , there were no genetic alterations in P36888 , c - P10721 , P01111 , P01116 , P04637 , P22681 , Q8IXJ9 , O75874 / 2 , or Q9Y6K1 . Our results suggest that precedent genetic alterations may be essential to drive the progression and relapse of t ( 16 ; 21 )- AML patients .", "Enriched P13591 - positive cells form functional dopaminergic neurons in the rat model of Parkinson ' s disease . We describe a method of generating an enriched population of P13591 - positive cells from a human teratocarcinoma cell line ( NTera2 / D1 ) and their differentiation into midbrain dopaminergic neurons in the absence of the caudalizing factor retinoic acid ( RA ) . NTera2 cells were induced to form embryoid bodies and then to generate nestin - positive cells on treatment with serum - free defined medium supplemented with neurotrophic factors . We enriched the neuroprogenitor population by magnetic sorting of the nestin - positive cells using the antibody to neural cell adhesion molecule ( P13591 ) . These cells were expanded by exposing them to the signaling molecule sonic hedgehog ( SHH ) in conjunction with fibroblast growth factor - 8 ( P55075 ) . The predifferentiated cells when analyzed by RT - PCR showed expression of dopaminergic markers such as Nurr1 , Engrailed - 1 , aromatic amino decarboxylase ( P20711 ) , Q05940 , tyrosine hydroxylase ( TH ) , and dopamine transporter ( Q01959 ) . These cells also stained positively for protein markers such as nestin , P13591 , P11137 , and TH . We further demonstrated that when transplanted into the brain of Parkinsonian rats , these neuroprogenitor cells did not form tumors but differentiated into dopaminergic neurons , as revealed by TH immunolabeling . The origin of transplanted cells were further confirmed by positive immunolabeling with anti - human nuclei . Our results suggest that enriching the neuroprogenitor population by magnetic sorting prevents tumor formation and is a prerequisite before cell replacement therapy for Parkinson ' s disease .", "Differential expression of retinoic acid receptor - beta isoforms during chick limb ontogeny . Retinoids influence both morphogenetic events and differentiation during development of the vertebrate limb . These effects are mediated through nuclear retinoid receptors , which modulate target gene expression . We report here the cloning and characterization of three promoter - and splicing - variants of the retinoic acid receptor - beta ( P10826 ) from chick . These receptor isoforms are independently expressed during limb development . RAR beta 2 but not RAR beta 1 transcripts are enriched three - fold in the posterior limb bud , reflecting the increased RA concentrations in this region . RAR beta 1 transcripts are initially present throughout the limb bud mesenchyme and ectoderm , then become restricted within perichondrial regions and loose connective tissue of the limb . RAR beta 1 expression closely overlaps that of P13591 ( neural cell adhesion molecule ) and tenascin in non - neuronal tissues . RAR beta 2 transcripts are present within a subset of those limb tissues which express RAR beta 1 . In the early limb bud RAR beta 2 transcripts are detected in proximal limb mesenchyme and in the initial mesenchymal condensate . In older limbs RAR beta 2 mRNAs are abundant in cells lateral to the digit cartilage . Neither RAR beta 1 nor RAR beta 2 transcripts are associated specifically with regions of limb cell death . The differential expression and regulation of RAR beta isoforms suggests these variants may have different roles in limb development .", "An analysis of the effects of retinoic acid and other retinoids on the development of adrenergic cells from the avian neural crest . In the present work , we have investigated the role of all - trans - retinoic acid ( all - trans RA ) , and several other natural and synthetic retinoids , in the development of adrenergic cells in quail neural crest cultures . Dose response studies using all - trans RA and 13 - cis RA revealed a dose - dependent increase in the number of adrenergic cells in neural crest cultures . Similar dose response studies using RA isomers and other natural retinoids did not result in the same increases . In order to determine the receptor mediating the effects of all - trans RA in the neural crest , we tested several synthetic analogs which specifically bind to a particular RA receptor ( RAR ) subtype . We found that the compound AM 580 , which activates the P10276 , produced an increase in adrenergic cells similar to that seen with all - trans RA . The compound ___MASK48___ , which activates all RAR subtypes , also resulted in an increase in adrenergic cells . We conclude that the increase in adrenergic cells seen with all - trans RA is mediated by P10276 and possibly P10826 . To further define the actions of all - trans RA on the neural crest we incubated cultures with 5 - bromo - 2 '- deoxyuridine ( BrdU ) to determine whether all - trans RA could affect the rate of proliferation . The results show that while all - trans RA did not increase the fraction of cells incorporating BrdU into their nuclei at early time points ( 24 h ) , it did increase BrdU incorporation by tyrosine hydroxylase ( TH ) positive cells at 5 days in culture . These findings demonstrate that the increase in adrenergic cells seen with all - trans RA in neural crest cultures is likely due to an increase in the proliferation of cells already expressing TH .", "Pharmacokinetics of [( 18 ) F ] fluoroalkyl derivatives of dihydrotetrabenazine in rat and monkey brain . The specific binding and regional brain pharmacokinetics of new fluorine - 18 ( [ ( 18 ) F ] ) - labeled radioligands for the vesicular monoamine transporter ( Q05940 ) were examined in the rat and primate brain . In the rat , 9 -[( 18 ) F ] fluoropropyl -(+/-)- 9 - O - desmethyldihydrotetrabenazine ( [( 18 ) F ] FP -(+/-)- DTBZ ) showed better specific binding in the striatum than either (+)-[( 11 ) C ] dihydrotetrabenazine ( (+)-[( 11 ) C ] DTBZ ) or 9 -[( 18 ) F ] fluoroethyl -(+/-)- 9 - O - desmethyldihydrotetrabenazine ( [( 18 ) F ] FE -(+/-)- DTBZ ) . Using microPET , the regional brain pharmacokinetics of [( 18 ) F ] FE -(+/-)- DTBZ , [( 18 ) F ] FP -(+/-)- DTBZ and (+)-[( 11 ) C ] DTBZ were examined in the same monkey brain . (+)-[( 11 ) C ] DTBZ and [( 18 ) F ] FP -(+/-)- DTBZ showed similar brain uptakes and pharmacokinetics , with similar maximum striatum - to - cerebellum ratios ( STR / P22681 = 5 . 24 and 5 . 15 , respectively ) that were significantly better than obtained for [( 18 ) F ] FE -(+/-)- DTBZ ( STR / P22681 = 2 . 55 ) . Striatal distribution volume ratios calculated using Logan plot analysis confirmed the better specific binding for the fluoropropyl compound [ distribution volume ratio ( DVR )= 3 . 32 ] vs . the fluoroethyl compound ( DVR = 2 . 37 ) . Using the resolved single active isomer of the fluoropropyl compound , [( 18 ) F ] FP -(+)- DTBZ , even better specific to nonspecific distribution was obtained , yielding the highest distribution volume ratio ( DVR = 6 . 2 ) yet obtained for a Q05940 ligand in any species . The binding of [( 18 ) F ] FP -(+)- DTBZ to the Q05940 was shown to be reversible by administration of a competing dose of unlabeled tetrabenazine . Metabolic defluorination was slow and minor for the [( 18 ) F ] fluoroalkyl - DTBZ ligands . The characteristics of high specific binding ratio , reversibility , metabolic stability and longer half - life of the radionuclide make [( 18 ) F ] FP -(+)- DTBZ a promising alternative Q05940 radioligand suitable for widespread use in human positron emission tomography studies of monoaminergic innervation of the brain .", "Synthesis and characterization of the tumor targeting mitoxantrone - insulin conjugate . Anticancer drugs have serious side effects arising from their poor malignant cells selectivity . Since insulin receptors highly express on the cytomembrane of some kind of tumor cells , using insulin as the vector was expected to reduce serious side effects of the drugs . The objective of this study was to evaluate the tumor targeting effect of the newly synthesized mitoxantrone - insulin conjugate ( MIT - P01308 ) with the drug loading of 11 . 68 % . In vitro stability trials showed MIT - P01308 were stable in buffers with different pH ( 2 - 8 ) at 37 degrees C within 120 h ( less than 3 % of free MIT released ) , and were also stable in mouse plasma within 48 h ( less than 1 % of free MIT released ) . In vivo study on tumor - bearing mice showed that , compared with MIT [ 75 . 92 microg x h / g of the area under the concentration - time curve ( AUC ) and 86 . 85 h of mean residence time ( MRT ) ] , the conjugates had better tumor - targeting efficiency with enhanced tumor AUC of 126 . 53 microg x h / g and Q99707 of 151 . 95 h . The conjugate had much lower toxicity to most other tissues with targeting indexes ( Q8NDX1 ) no larger than 0 . 3 besides good tumor targeting efficiency with Q8NDX1 of 1 . 67 . The results suggest the feasibility to promote the curative effect in cancer chemotherapy by using insulin as the vector of anti - cancer drugs .", "Factors regulating insulin - like growth factor - binding protein - 3 binding , processing , and potentiation of insulin - like growth factor action . In this study , we investigated the effects of various biochemical and pharmacological agents on insulin - like growth factor ( IGF ) - binding protein - 3 ( P17936 ) cell binding and action in cultured bovine fibroblasts . When cells were preincubated for 48 h with 50 nM recombinant human ( rh ) P17936 , P05019 - stimulated [ 3H ] aminoisobutyric acid ( [ 125H ] AIB ) uptake was enhanced 2 - to 3 - fold . The addition of cytoskeletal disrupting agents during the preincubation with ___MASK25___ did not affect P17936 potentiation of P05019 action , nor did a variety of serine , aspartate , and metalloproteinase inhibitors . On the other hand , ammonium chloride and chloroquine , weak bases that neutralize the pH of acidic cell compartments , blocked P17936 potentiation of P05019 - stimulated [ 3H ] AIB uptake . Chloroquine and ammonium chloride had no effect alone and did not inhibit P08069 binding or action in the absence of ___MASK25___ . Bafilomycin A , a specific inhibitor of DB00171 - dependent hydrogen ion pumps , also inhibited P17936 potentiation of P05019 - stimulated [ 3H ] AIB uptake . Competitive [ 125I ] P05019 binding and affinity cross - linking experiments suggested structure / function changes in cell - bound P17936 that were altered in the presence of chloroquine and bafilomycin . DB01109 markedly decreased initial P17936 cell adherence , but could not promote dissociation of P17936 from cells after the 48 - h preincubation . Moreover , heparin did not inhibit P17936 potentiation of P05019 action . In summary , these data indicate that P17936 undergoes specific pH - dependent structural and / or environmental modifications that mediate the enhancing effect of P17936 on P05019 action in bovine fibroblasts . They also suggest that P17936 binding to heparin - like molecules on the cell surface is not directly involved in this process .", "Inhibition of matrix metalloproteinase - 9 activity by trandolapril after middle cerebral artery occlusion in rats . We investigated whether an angiotensin - converting enzyme ( P12821 ) inhibitor could inhibit matrix metalloproteinase ( MMP ) activities in cerebral infarct lesions after middle cerebral artery occlusion ( MCAO ) in rats . After placebo or trandolapril ( 5 mg / kg per day ) was administered orally for 7 days , we permanently occluded the right middle cerebral artery . P12821 activity in extracts from the infarct side of placebo - treated rats was significantly higher than that in extracts from the non - infarct side from 5 days after MCAO , though they did not differ at 1 day . P12821 activities in extracts from both hemispheric segments in the trandolapril - treated group were significantly decreased compared with those in the placebo - treated group before MCAO , and this significant reduction persisted even at 7 days after MCAO . In the placebo - treated group , P14780 and P08253 activities in the infarct side were significantly increased at 12 h and at 1 day after MCAO , respectively . ___MASK35___ treatment significantly reduced P14780 and P08253 activities to 68 . 5 % and 53 . 2 % , respectively . Seven days after MCAO , the ratios of infarct areas to the hemispheric sectional areas in placebo - and trandolapril - treated rats were 55 . 4 +/- 2 . 1 % and 30 . 9 +/- 2 . 9 % , respectively , and this difference was significant . Neurological severity scores were significantly improved from 1 to 7 days after MCAO in trandolapril - treated rats . Cumulative survival in trandolapril - treated rats was significantly increased compared with that in placebo - treated rats . Thus , the inhibition of P14780 by trandolapril might be part of the mechanism that prevents cerebral damage after cerebral ischemia .", "Roles of P09917 and cysteinyl - leukotriene type 1 receptors in the hematological response to allergen challenge and its prevention by diethylcarbamazine in a murine model of asthma . ___MASK36___ ( DEC ) , which blocks leukotriene production , abolishes the challenge - induced increase in eosinopoiesis in bone - marrow from ovalbumin - ( OVA - ) sensitized mice , suggesting that P09917 ( P09917 ) products contribute to the hematological responses in experimental asthma models . We explored the relationship between P09917 , central and peripheral eosinophilia , and effectiveness of DEC , using DB00233 or BALB / c mice and P09917 - deficient mutants . We quantified eosinophil numbers in freshly harvested or cultured bone - marrow , peritoneal lavage fluid , and spleen , with or without administration of leukotriene generation inhibitors ( DEC and MK886 ) and cisteinyl - leukotriene type I receptor antagonist ( montelukast ) . The increase in eosinophil numbers in bone - marrow , observed in sensitized / challenged wild - type mice , was abolished by MK886 and DEC pretreatment . In ALOX mutants , by contrast , there was no increase in bone - marrow eosinophil counts , nor in eosinophil production in culture , in response to sensitization / challenge . In sensitized / challenged ALOX mice , challenge - induced migration of eosinophils to the peritoneal cavity was significantly reduced relative to the wild - type DB00233 controls . DEC was ineffective in ALOX mice , as expected from a mechanism of action dependent on P09917 . In BALB / c mice , challenge significantly increased spleen eosinophil numbers and DEC treatment prevented this increase . Overall , P09917 appears as indispensable to the systemic hematological response to allergen challenge , as well as to the effectiveness of DEC .", "Serotonergic regulation of somatosensory cortical development : lessons from genetic mouse models . Monoaminergic neurotransmitter systems appear early during embryogenesis , suggesting that they could play important roles in brain development . Accumulated evidence indicates that serotonin ( 5 - hydroxytryptamine , 5 - HT ) regulates neural as well as nonneural development , including early aspects of embryonic development , differentiation of neuronal progenitors , and morphogenesis of the craniofacial region , heart and limb . Recent studies using monoamine oxidase - A ( P21397 ) , 5 - HT transporter , vesicular monoamine transporter - 2 ( Q05940 ) and P28222 receptor single , double and triple knockout mice have provided evidence that the serotonergic system plays important roles in barrel field formation in the developing somatosensory cortex . Here we review evidence from these genetic mouse models and , based on the accumulated evidence , propose a testable model for future studies of mechanisms underlying serotonergic regulation of cortical development .", "Functional methionine synthase deficiency ( cblE and cblG ) : clinical and biochemical heterogeneity . Functional methionine synthase deficiency is generally characterized by homocystinuria and hypomethioninemia in the absence of methylmalonic aciduria . Patients are divided into two classes , cblE and cblG , on the basis of complementation analysis . Presentation has usually been in the first 2 years of life , but one patient came to medical attention at age 21 years with symptoms initially diagnosed as multiple sclerosis . Common findings among 11 patients ( 4 with cblE and 7 with cblG ) have included megaloblastic anemia ( all patients ) and various neurological deficits including developmental retardation ( 10 patients ) , cerebral atrophy ( 8 patients ) , hypotonia ( 7 patients ) , EEG abnormalities ( 6 patients ) , and nystagmus ( 5 patients ) . Hypertonia , seizures , blindness , and ataxia were less frequent . All patients have responded to therapy with cobalamin with resolution of anemia and biochemical abnormalities ; neurological deficits resolved more slowly and in some cases incompletely . ___MASK49___ has been more effective than cyanocobalamin . Fibroblasts from patients with cblE ( 5 patients ) and cblG ( 6 patients ) all showed decreased intracellular levels of methylcobalamin ( DB03614 ) and decreased incorporation of label from 5 - methyltetrahydrofolate into macromolecules , suggesting decreased activity of the DB03614 - dependent enzyme methionine synthase . Q99707 specific activity in extracts of all cblE fibroblasts was normal or near - normal under standard reducing conditions ; synthase specific activity in extracts of 5 cblG patients was low but was high in a 6th patient measured in another laboratory . Thus , there is heterogeneity among patients with functional methionine synthase deficiency both in clinical presentation and in the results of biochemical studies of cultured cells .", "New perspectives of vesicular monoamine transporter 2 chemical characteristics in mammals and its constant expression in type 1 diabetes rat models . Vesicular monoamine transporter 2 ( Q05940 ) has been exploited as a biomarker of β - cell mass in human islets . However , a current report suggested no immunoreactivity of Q05940 in the β cells of rat islets . To investigate the cellular localization of Q05940 in islets further , the pancreatic tissues from monkeys and humans were compared with those of rats and mice . The study was performed using among - species comparisons and a type 1 diabetes model ( T1DM ) for rats by Western blotting , double - label immunofluorescence , and confocal laser scanning microscopy . We found that Q05940 - immunoreactivity ( IR ) was distributed peripherally in the islets of rodents , but was widely scattered throughout the islets of primates . Consistent with rodent islets , Q05940 - IR did not exist in insulin ( P01308 ) - IR cells but was abundantly present in glucagon ( GLU ) - IR and pancreatic polypeptide ( PP ) - IR cells in monkey and human islets . Q05940 - IR had no colocalization with P01308 - IR in any part of the rat pancreas ( head , body , and tail ) . P01308 - IR cells were reduced dramatically in T1DM rat islets , but no significant alteration in the proportion of Q05940 - IR cells and GLU - IR cells was observed . Furthermore , a strong colocalization of Q05940 - IR with GLU - IR was distributed in the peripheral regions of diabetic islets . For the first time , the current study demonstrates the presence of Q05940 in α cells and PP cells but not in β cells in the islets of monkeys and humans . This study provides convinced morphologic evidence that Q05940 is not present in β cells . There needs to be studies for new markers for β cell mass .", "P23560 is induced by wild - type alpha - synuclein but not by the two mutants , A30P or A53T , in glioma cell line . Parkinson ' s disease ( PD ) is one of the most prevalent neurodegenerative diseases but its etiology is unclear . P37840 ( alpha - SN ) is a major component of Lewy bodies and Lewy neurites , and its missense mutations , A30P and A53T , cause familial PD . In PD , alpha - SN - positive glial inclusions are distributed mainly in the dorso - medial region of the substantia nigra , which contains most of the surviving dopaminergic neurons , suggesting that alpha - SN expression might have a neuroprotective function in glial cells . To investigate this hypothesis , we established alpha - SN transfected P13671 glioma cell line clones and evaluated the expression of neurotrophins using semi - quantitative reverse transcription polymerase chain reaction and enzyme - linked immunosorbent assay . P23560 ( P23560 ) was induced by overexpression of wild - type alpha - SN but not by that of A30P and A53T . These data suggest that the pathogenic alpha - SN mutations , A30P or A53T , are linked to the loss of P23560 production in glial cells .", "Antenatal maternal long - term hypoxia : acclimatization responses with altered gene expression in ovine fetal carotid arteries . In humans and other species , long - term hypoxia ( LTH ) during pregnancy can lead to intrauterine growth restriction with reduced body / brain weight , dysregulation of cerebral blood flow ( Q03701 ) , and other problems . To identify the signal transduction pathways and critical molecules , which may be involved in acclimatization to high altitude LTH , we conducted microarray with advanced bioinformatic analysis on carotid arteries ( CA ) from the normoxic near - term ovine fetus at sea - level and those acclimatized to high altitude for 110 + days during gestation . In response to LTH acclimatization , in fetal CA we identified mRNA from 38 genes upregulated > 2 fold ( P < 0 . 05 ) and 9 genes downregulated > 2 - fold ( P < 0 . 05 ) . The major genes with upregulated mRNA were P43003 , P01308 - like growth factor ( IGF ) binding protein 3 , IGF type 2 receptor , transforming growth factor ( TGF ) Beta - 3 , and genes involved in the AKT and P10415 signal transduction networks . Most genes with upregulated mRNA have a common motif for Pbx / Knotted homeobox in the promoter region , and Sox family binding sites in the 3 ' un translated region ( UTR ) . Genes with downregulated mRNA included those involved in the P04637 pathway and P09917 activating proteins . The promoter region of all genes with downregulated mRNA , had a common 49 bp region with a binding site for DOT6 and TOD6 , components of the RPD3 histone deacetylase complex RPD3C ( L ) . We also identified miRNA complementary to a number of the altered genes . Thus , the present study identified molecules in the ovine fetus , which may play a role in the acclimatization response to high - altitude associated LTH .", "Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . DB04844 almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients ." ]
[ "___MASK25___", "___MASK29___", "___MASK35___", "___MASK36___", "___MASK40___", "___MASK48___", "___MASK49___", "___MASK57___", "___MASK70___" ]
___MASK29___
MH_train_1612
interacts_with DB06643?
[ "Connexin 43 and P29323 regulate tension - induced signal transduction in human periodontal ligament fibroblasts . Periodontal ligament ( PDL ) fibroblasts play an important role in preserving periodontal homeostasis and transmitting mechanical signals to alveolar bone . Connexin 43 ( P17302 ) , a gap junction protein , is essential for bone homeostasis and regulates bone remodeling . However , the function of P17302 in human PDL fibroblast - regulated bone remodeling has not yet been elucidated . In this study , human PDL fibroblasts were exposed to cyclic mechanical tension with a maximum 5 % elongation for different durations . We then examined the expression of signaling molecules related to osteogenesis and osteoclastogenesis at both the mRNA and protein levels as well as the activity of extracellular signal - regulated kinase ( P29323 ) in human PDL fibroblasts after loading . We found that mechanical tension increased P17302 , which further upregulated osteogenic ( e . g . , Q13950 , Osterix , and O00300 ) and down - regulated osteoclastogenic ( e . g . , O14788 ) signaling molecules . Suppressing P17302 gene ( Gja1 ) by siRNA inhibited the increase in osteogenesis - related molecules but enhanced O14788 expression . Similar to P17302 , activated P27361 / 2 was also enhanced by mechanical tension and suppressed by P17302 siRNA . Inhibition of P27361 / 2 signaling using PD98059 reduced the tension - regulated increase in osteogenesis - related molecules but enhanced that of osteoclastogenesis - related ones . These findings suggest that cyclic tension may involve into the osteogenic or osteoclastogenetic differentiation potential of human PDL fibroblasts via the P17302 - P27361 / 2 signaling pathway .", "P62937 may contribute to the inflammatory processes in rheumatoid arthritis through induction of matrix degrading enzymes and inflammatory cytokines from macrophages . P62937 ( CypA ) levels increase in the sera and synovial fluids of rheumatoid arthritis ( RA ) patients , but the cell types expressing CypA and the function of CypA in the pathogenesis of RA are not known yet . Immunohistochemistry analyses revealed high level CypA staining in the macrophages in the lining layers of human RA and osteoarthritis synovium . Low level CypA staining was also detected in endothelial cells , lymphocytes , and smooth muscle cells in RA synovium . Further investigation of the CypA function using monocyte / macrophage cell lines revealed that CypA induced expression of cytokine / chemokines such as P01375 , P10145 , P13500 , and IL - 1beta and matrix metalloproteinase ( MMP ) - 9 through a pathway that is dependent on NFkappaB activation . Furthermore , P14780 staining pattern overlapped with that of CypA in both RA and OA synovium . Our data suggest that CypA may stimulate macrophages to degrade joint cartilage via P14780 expression and promote inflammation via pro - inflammatory cytokine secretion .", "DB06643 -- an emerging treatment for postmenopausal osteoporosis . IMPORTANCE OF THE FIELD : Osteoporosis is a common skeletal disease that is associated with an imbalance in bone remodeling . DB06643 is an investigational fully human monoclonal antibody to receptor activator of NF - kappaB ligand ( O14788 ) , a cytokine member of the P01375 family that is the principal mediator of osteoclastic bone resorption . AREAS COVERED IN THIS REVIEW : The efficacy and safety of denosumab in the management of postmenopausal osteoporosis is evaluated by reviewing the published literature and presentations at scientific meetings through 2009 . WHAT THE READER WILL GAIN : This review focuses on the data on fracture risk reduction and safety endpoints of denosumab in the treatment of postmenopausal osteoporosis . TAKE HOME MESSAGE : In postmenopausal women with osteoporosis , denosumab ( 60 mg by subcutaneous injection every 6 months ) increased bone mineral density , reduced bone turnover markers , and reduced the risk of vertebral , hip and non - vertebral fractures . DB06643 was well tolerated with a safety profile generally similar to placebo . It is a promising emerging drug for the prevention and treatment of postmenopausal osteoporosis .", "MnSOD drives neuroendocrine differentiation , androgen independence , and cell survival in prostate cancer cells . An increase in neuroendocrine ( NE ) cell number has been associated with progression of prostate tumor , one of the most frequent cancers among Western males . We previously reported that mitochondrial manganese superoxide dismutase ( MnSOD ) increases during the NE differentiation process . The goal of this study was to find whether MnSOD up - regulation is enough to induce NE differentiation . Several human prostate cancer LNCaP cell clones stably overexpressing MnSOD were characterized and two were selected ( MnSOD - S4 and MnSOD - P28222 ) . MnSOD overexpression induces NE morphological features as well as coexpression of the NE marker synaptophysin . Both MnSOD clones exhibit lower superoxide levels and higher H ( 2 ) O ( 2 ) levels . MnSOD - overexpressing cells show higher proliferation rates in complete medium , but in steroid - free medium MnSOD - P28222 cells are still capable of proliferation . MnSOD up - regulation decreases androgen receptor and prevents its nuclear translocation . MnSOD also induces up - regulation of Bcl - 2 and prevents docetaxel - , etoposide - , or P01375 - induced cell death . Finally , MnSOD - overexpressing cells enhance growth of androgen - independent PC - 3 cells but reduce growth of androgen - dependent cells . These results indicate that redox modulation caused by MnSOD overexpression explains most NE - like features , including morphological changes , NE marker expression , androgen independence , inhibition of apoptosis , and enhancement of cell growth . Many of these events can be associated with the androgen dependent - independent transition during prostate cancer progression .", "DB06643 for joints and bones . DB06643 is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . DB06643 suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . DB06643 reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .", "Thrombin induces osteoprotegerin synthesis via phosphatidylinositol 3 '- kinase / mammalian target of rapamycin pathway in human periodontal ligament cells . BACKGROUND AND OBJECTIVE : Thrombin influences the biological behavior of periodontal ligament cells and plays multiple roles in the early stages of bone healing . O00300 ( O00300 ) is one of the key molecules that regulate bone homeostasis and prevent osteoclastogenesis . The purpose of this study was to evaluate the biological effects of thrombin on O00300 synthesis in human periodontal ligament ( Q96IR7 ) cells in vitro . MATERIAL AND METHODS : Cells were treated with various concentrations ( 0 . 001 , 0 . 01 and 0 . 1 U / mL ) of thrombin . The mRNA expression and protein synthesis of O00300 , as well as of receptor activator of nuclear factor kappaB ligand ( O14788 ) , were determined by reverse transcriptase - polymerase chain reaction ( RT - PCR ) and Western blot analysis , respectively . The influence of thrombin on O00300 synthesis and its signaling pathway were investigated using inhibitors . RESULTS : Thrombin profoundly induces protein synthesis of O00300 at 0 . 1 U / mL . The inductive effect was inhibited by cycloheximide , but not by indomethacin . The phosphatidylinositol 3 '- kinase ( PI3K ) inhibitor , LY294002 , and the mammalian target of rapamycin ( P42345 ) inhibitor , rapamycin , exerted an inhibitory effect on the thrombin - induced O00300 synthesis . In addition , the effect was inhibited by protease - activated receptor ( PAR ) - 1 antagonist . Activation of phospho - Akt ( p - Akt ) was observed and the effect was abolished by LY294002 . CONCLUSION : Thrombin induces O00300 synthesis in Q96IR7 cells post - transcriptionally , possibly through P25116 . The regulation was through the PI3K / Akt and P42345 pathway . This finding suggests that thrombin may play a significant role in alveolar bone repair and homeostasis of periodontal tissue , partly through the O00300 / O14788 system .", "O14788 promotes migration and invasion of hepatocellular carcinoma cells via NF - κB - mediated epithelial - mesenchymal transition . BACKGROUND : Metastasis accounts for the most deaths in patients with hepatocellular carcinoma ( HCC ) . Receptor activator of nuclear factor kappa B ligand ( O14788 ) is associated with cancer metastasis , while its role in HCC remains largely unknown . METHODS : Immunohistochemistry was performed to determine the expression of Q9Y6Q6 in HCC tissue ( n = 398 ) . Quantitative real - time polymerase chain reaction ( qRT - PCR ) and Western blot were used to examine the expression of Q9Y6Q6 , P12830 , P19022 , vimentin , Snail , Slug , Twist and MMPs in HCC cells . Wound healing and Transwell assays were used to evaluate cell migration and invasion ability . RESULTS : We found that expression of Q9Y6Q6 , the receptor of O14788 , was significantly higher in HCC tumor tissues than in peritumor liver tissues ( p < 0 . 001 ) . Constitutive expression of Q9Y6Q6 was detected in HCC cell lines , which can be up - regulated when HCC cells were stimulated with O14788 . Notably , in vitro experiments showed that activation of O14788 - Q9Y6Q6 axis significantly promoted migration and invasion ability of HCC cells . In addition , O14788 stimulation increased the expression levels of P19022 , Snail , and Twist , while decreased the expression of P12830 , with concomitant activation of NF - κB signaling pathway . Moreover , administration of the NF - κB inhibitor attenuated O14788 - induced migration , invasion and epithelial - mesenchymal transition of HCC cells . CONCLUSIONS : O14788 could potentiate migration and invasion ability of Q9Y6Q6 - positive HCC cells through NF - κB pathway - mediated epithelial - mesenchymal transition , which means that O14788 - Q9Y6Q6 axis could be a potential target for HCC therapy .", "The actin binding protein adseverin regulates osteoclastogenesis . Q9Y6U3 ( Ads ) , a member of the P06396 superfamily of actin binding proteins , regulates the actin cytoskeleton architecture by severing and capping existing filamentous actin ( F - actin ) strands and nucleating the assembly of new F - actin filaments . Ads has been implicated in cellular secretion , exocytosis and has also been shown to regulate chondrogenesis and megakaryoblastic leukemia cell differentiation . Here we report for the first time that Ads is involved in regulating osteoclastogenesis ( OCG ) . Ads is induced during OCG downstream of Q9Y6Q6 - ligand ( O14788 ) stimulation and is highly expressed in mature osteoclasts . The D5 isoform of Ads is not involved in regulating OCG , as its expression is not induced in response to O14788 . Three clonal Ads knockdown RAW264 . 7 ( RAW ) macrophage cell lines with varying degrees of Ads expression and OCG deficiency were generated . The most drastic OCG defect was noted in the clonal cell line with the greatest degree of Ads knockdown as indicated by a lack of TRAcP staining and multinucleation . RNAi mediated knockdown of Ads in osteoclast precursors resulted in distinct morphological changes characterized by altered F - actin distribution and increased filopodia formation . Ads knockdown precursor cells experienced enhanced migration while fusion of knockdown precursors cells was limited . Transient reintroduction of de novo Ads back into the knockdown system was capable of rescuing TRAcP expression but not osteoclast multinucleation most likely due to the transient nature of Ads expression . This preliminary study allows us to conclude that Ads is a O14788 induced early regulator of OCG with a potential role in pre - osteoclast differentiation and fusion .", "F - actin involvement in guinea pig sperm motility . Sperm motility is a must for natural fertilization to occur . During their travel through the epididymis , mammalian spermatozoa gradually acquire the ability to move . This is accomplished through a sliding movement of the outer doublet microtubules of the axoneme which is energized by the dynein ATPase . Within its complex structure , the mammalian sperm flagellum contains F - actin and thus , we decided to test in the guinea pig sperm flagellum the role of F - actin in motility . During maturation , capacitation , and the acrosome reaction , a gradual decrease of the relative concentration of F - actin was observed . Motility increased as spermatozoa became able to fertilize . P06396 , phalloidin , and KI inhibited sperm motility . P06396 canceled sperm motility within 20 min of treatment while 0 . 6 M KI had immediate effects . Phalloidin diminished hyperactive sperm motility slightly . All three compounds significantly increased the relative concentration of F - actin . Latrunculins are conventional drugs that destabilize the F - actin cytoskeleton . ___MASK18___ ( O43561 A ) did not affect sperm motility ; but significantly increased F - actin relative concentration . The results suggested that in guinea pig spermatozoa , randomly severing F - actin filaments inhibits flagellar motility ; while end filament alteration does not . Thus , specific filament regions seem to be important for sperm motility .", "P15121 regulates TGF - beta1 - induced production of fibronectin and type IV collagen in cultured rat mesangial cells . AIM : To study the effects of aldose reductase ( AR ) on production of fibronectin and type IV collagen in rat mesangial cells ( MsC ) . METHODS : The vector , pcDNA3 - AR , was constructed based on pET - 15b - AR . Lipofect AMINE was used for stable transfection and G418 was used for selecting positive clones . ___MASK59___ and zopolrestat were added for suppressing the activity of AR , respectively . The production of fibronectin and type IV collagen and the activation of Smads and MAPK signal transduction pathway were analysed by western blot and AP - 1 activity was analysed by electrophoretic mobility shift assays ( EMSA ) . RESULTS : The normal MsC showed increased expression of fibronectin and type IV collagen with stimulation of TGF - beta1 . Compared with the normal MsC , the MsC pre - incubated with Q9Y4X5 showed reduced expression ( P < 0 . 05 ) and the AR - transfected MsC showed increased expression ( P < 0 . 05 ) . The normal MsC showed activation of P29323 , JNK and p38 with stimulation of TGF - beta1 , while the activation of JNK and p38 was inhibited in the MsC pre - incubated with Q9Y4X5 and only the activation of JNK was enhanced in the AR - transfected MsC . The normal MsC showed enhanced AP - 1 activity with the stimulation of TGF - beta1 , and similarly the activity was inhibited in the MsC pre - incubated with Q9Y4X5 and was more enhanced in the AR transfected MsC . CONCLUSION : AR can regulate the expression of fibronectin and type IV collagen with the stimulation of TGF - beta1 in MsC , which may have relations with the activation of JNK - MAPK and p38 - MAPK signalling pathways and AP - 1 .", "Insights into the roles of cyclophilin A during influenza virus infection . P62937 ( CypA ) is the main member of the immunophilin superfamily that has peptidyl - prolyl cis - trans isomerase activity . CypA participates in protein folding , cell signaling , inflammation and tumorigenesis . Further , CypA plays critical roles in the replication of several viruses . Upon influenza virus infection , CypA inhibits viral replication by interacting with the M1 protein . In addition , CypA is incorporated into the influenza virus virions . Finally , ___MASK42___ ( ___MASK42___ ) , the main inhibitor of CypA , inhibits influenza virus replication through CypA - dependent and - independent pathways . This review briefly summarizes recent advances in understanding the roles of CypA during influenza virus infection .", "Characterization of ___MASK45___ - B , an orally bioavailable antagonist of the P51686 chemokine receptor , for treatment of inflammatory bowel disease . The chemokine system represents a diverse group of G protein - coupled receptors responsible for orchestrating cell recruitment under both homeostatic and inflammatory conditions . Chemokine receptor 9 ( P51686 ) is a chemokine receptor known to be central for migration of immune cells into the intestine . Its only ligand , O15444 , is expressed at the mucosal surface of the intestine and is known to be elevated in intestinal inflammation . To date , there are no reports of small - molecule antagonists targeting P51686 . We report , for the first time , the discovery of a small molecule , ___MASK45___ - B , which is an orally bioavailable , selective , and potent antagonist of human P51686 . ___MASK45___ - B inhibited P51686 - mediated Ca ( 2 +) mobilization and chemotaxis on Molt - 4 cells with IC ( 50 ) values of 5 . 4 and 3 . 4 nM , respectively . In the presence of 100 % human serum , ___MASK45___ - B inhibited P51686 - mediated chemotaxis with an IC ( 50 ) of 33 nM , and the addition of α1 - acid glycoprotein did not affect its potency . ___MASK45___ - B inhibited chemotaxis of primary P51686 - expressing cells to O15444 with an IC ( 50 ) of 6 . 8 nM . ___MASK45___ - B was an equipotent inhibitor of O15444 - directed chemotaxis of both splice forms of P51686 ( CCR9A and CCR9B ) with IC ( 50 ) values of 2 . 8 and 2 . 6 nM , respectively . ___MASK45___ - B also inhibited mouse and rat P51686 - mediated chemotaxis . Inhibition of P51686 with ___MASK45___ - B results in normalization of Crohn ' s disease such as histopathology associated with the P01375 ( ΔARE ) mice . Analysis of the plasma level of drug associated with this improvement provides an understanding of the pharmacokinetic / pharmacodynamic relationship for P51686 antagonists in the treatment of intestinal inflammation .", "Gonadal and nongonadal P23945 and LHR dysfunction during lipopolysaccharide induced failure of blastocyst implantation in mouse . PURPOSE : The purpose of the present study was to investigate the impact of lipopolysaccharide ( LPS ) on follicle - stimulating hormone ( ___MASK40___ ) , luteinizing hormone ( LH ) and their receptors during preimplantation days of pregnancy . METHOD : The PBS or lipopolysaccharide ( LPS ) was injected intraperitoneally in the pregnant females on day 0 . 5 of pregnancy and serum , embryos , ovaries and uterine horns were collected on days 1 . 5 , 2 . 5 , 3 . 5 , 4 . 0 , 4 . 125 , 4 . 33 and 4 . 42 of pregnancy . RESULT ( S ) : In the LPS - treated pregnant females , the secretion of ___MASK40___ and LH is disturbed with respect to normal pregnancy . Furthermore , the expression of P23945 mRNA in embryos and ovaries , LHR mRNA in embryos and uterus get modulated in response to LPS during preimplantation days of pregnancy . CONCLUSION ( S ) : The disturbance in the serum level of ___MASK40___ and LH in response to LPS leads implantation failure in mouse which suggests that these gonadotropins plays an integral role in the process of the successful implantation . This study also suggests a possible nongonadal role of P23945 and LHR in LPS - induced implantation failure in the mouse .", "Drugs targeting nitric oxide synthase for migraine treatment . INTRODUCTION : Ample evidence that nitric oxide ( NO ) is a causative molecule in migraine has encouraged research to develop drugs that target the NO - cGMP cascade for migraine treatment . NO synthase ( NOS ) inhibition is an innovative therapeutic principle . AREAS COVERED : This paper reviews the rationale underlying NOS inhibition in migraine treatment . It also provides a review on the efficacy and safety data for NOS inhibitors ( nonselective NOS inhibitor L - N ( G )- methyl - arginine hydrochloride [ L - NMMA ] , selective inducible NOS [ P35228 ] inhibitors GW273629 and GW274150 , combined neuronal NOS [ P29475 ] inhibitor and P28222 / 1D receptor agonist ___MASK95___ ) in acute or preventive migraine treatment . EXPERT OPINION : The data highlighted herein , from four placebo - controlled trials and 1 open - labeled clinical trial using 4 different NOS inhibitors on a total of 705 patients , provide convincing efficacy data only for the nonselective NOS inhibitor L - NMMA . Unfortunately , this NOS inhibitor raises cardiovascular safety concerns and has an unfavorable pharmacokinetic profile . As experimental studies predicted , P35228 inhibitors are ineffective in migraine . Still , upcoming selective P29475 inhibitors are a hope for migraine treatment , with the P29475 isoform being most clearly involved in trigeminovascular transmission and central sensitization . Future studies should help to clarify whether NOS inhibition is equally fruitful in acute and preventive treatment . It should also clarify if P29475 inhibition holds promise as a therapeutic tool for the treatment of chronic migraine and other forms of headache .", "___MASK40___ - receptor isoforms and ___MASK40___ - dependent gene transcription in human monocytes and osteoclasts . Cells of the monocyte series respond to follicle stimulating hormone ( ___MASK40___ ) by poorly characterized mechanisms . We studied ___MASK40___ - receptors ( P23945 ) and ___MASK40___ response in nontransformed human monocytes and in osteoclasts differentiated from these cells . Western blot and PCR confirmed P23945 expression on monocytes or osteoclasts , although at low levels relative to ovarian controls . Monocyte and osteoclast ___MASK40___ - Rs differed from P23945 from ovarian cells , reflecting variable splicing in exons 8 - 10 . Monocytes produced no DB02527 , the major signal in ovarian cells , in response to ___MASK40___ . However , monocytes and osteoclasts transcribed TNFalpha in response to the ___MASK40___ . No relation of expression of osteoclast P23945 to the sex of cell donors or to exposure to sex hormones was apparent . Controls for ___MASK40___ purity and endotoxin contamination were negative . Unamplified cRNA screening in adherent P08571 cells after 2h in 25ng / ml ___MASK40___ showed increased transcription of O14788 signalling proteins . Transcription of key proteins that stimulate bone turnover , TNFalpha and P98066 , increased 2 - to 3 - fold after ___MASK40___ treatment . Smaller but significant changes occurred in transcripts of selected signalling , adhesion , and cytoskeletal proteins . We conclude that monocyte and osteoclast ___MASK40___ response diverges from that of ovarian cells , reflecting , at least in part , varying P23945 isoforms .", "P10275 inducing bladder cancer progression by promoting an epithelial - mesenchymal transition . The study investigated the role of androgen receptor ( AR ) as a potential target for the treatment of bladder cancer in regulating epithelial - mesenchymal transition or transformation ( EMT ) . Cell proliferation , and migration capacity were determined in bladder cancer T24 cells treated with small interfering RNA directed against AR , and expression levels of P12830 , β - catenin and N - cadherin were assessed using quantitative reverse transcription PCR ( qRT - PCR ) . Tumour cell growth was evaluated in vivo in T24 tumour - bearing nude mice receiving electroporation - assisted administration of anti - AR small interfering RNA . It was found that low AR expression decreased proliferation and migration of bladder cancer cells . In vivo experiments showed that silencing AR expression significantly suppressed AR - positive bladder tumour growth with decreased cell proliferation . Low AR level of T24 bladder cancer cells treated with ___MASK3___ ( DB02901 ) decreased expression of P12830 , β - catenin and P19022 expression , indicating a strong sensitivity to the EMT and In cells with low AR content , TGF - β induced down - regulation of P12830 and β - catenin . It is concluded that suppression of AR expression decreased the production of TGF - β , inhibiting EMT and bladder cancer cell growth in vitro and in vivo , implying that its use might be a potential therapeutic target for the treatment of bladder cancer .", "DB00149 and L - isoleucine enhance growth of BBN - induced urothelial tumors in the rat bladder by modulating expression of amino acid transporters and tumorigenesis - associated genes . We investigated the underlying mechanisms of L - leucine and L - isoleucine mediated promotion of bladder carcinogenesis using an initiation - promotion model . Rats were administered N - butyl - N -( 4 - hydroxybutyl ) nitrosamine for 4 weeks and then fed AIN - 93G basal diet or diet supplemented with L - leucine or L - isoleucine for 8 weeks followed by the basal diet for another 8 weeks . At the end of the experiment , week 20 , there was a significant elevation of papillary and nodular ( PN ) hyperplasia multiplicity in the amino acid groups . DB00149 and L - isoleucine transporters were up - regulated in PN hyperplasias and / or bladder tumors compared with concomitant normal - appearing bladder urothelium at weeks 12 and / or 20 in all groups . In addition , in normal - appearing bladder urothelium , significantly increased mRNA levels of y + Q01650 , LAT2 , Q8N370 , and P08195 were observed in the amino acid groups compared with the BBN control group at both weeks 12 and 20 , and increased mRNA levels of Q01650 were observed at week 20 . Furthermore , up - regulation of P01375 - α , c - fos , β - catenin , p53 , P38936 ( Cip1 / P38936 ) , cdk4 , cyclin D1 and caspase 3 in the amino acid groups was detected in normal - appearing bladder urothelium . Overall , our results indicate that supplementation with l - leucine or l - isoleucine enhanced growth of bladder urothelial tumors by triggering expression of amino acid transporters and tumorigenesis - associated genes .", "Enhancement of L - cystine transport activity and its relation to Q9UPY5 gene induction at the blood - brain barrier by diethyl maleate treatment . The purpose of the present study was to elucidate the mechanism of enhancement of L - cystine uptake at the blood - brain barrier ( BBB ) . The uptake of [( 14 ) C ] L - cystine and [( 3 ) H ] L - glutamic acid ( L - DB00142 ) was determined using a mouse brain endothelial cell line ( MBEC4 ) as an in vitro BBB model . The mRNA levels of L - cystine / L - DB00142 exchanger , system x ( c )(-) , which consists of Q9UPY5 and P08195 , were determined by quantitative real - time reverse transcription - polymerase chain reaction analysis . The [( 14 ) C ] L - cystine uptake by MBEC4 cells appeared to be mediated via an Na (+)- independent saturable process . The corresponding Michaelis - Menten constant ( K ( m ) ) was 63 . 7 microM . In the presence of L - DB00142 , there was competitive inhibition with an inhibition constant ( K ( i ) ) of 83 . 5 microM . [( 3 ) H ] L - DB00142 uptake in the absence of Na (+) was saturable with a K ( m ) of 48 . 1 microM , and it exhibited competitive inhibition with a K ( i ) of 24 . 9 microM in the presence of L - cystine . The mutual inhibition between L - cystine and L - DB00142 and the type of inhibition suggest that system x ( c )(-) operates in MBEC4 cells . The Q9UPY5 and P08195 mRNAs were expressed in MBEC4 cells and , following diethyl maleate ( DEM ) treatment , the Q9UPY5 mRNA level and L - cystine uptake in MBEC4 cells were enhanced in parallel with an increase in DEM concentration ( up to 500 microM ) . Concomitantly , the glutathione concentration in MBEC4 cells was increased . In conclusion , system x ( c )(-)- mediated L - cystine uptake takes place in MBEC4 cells . ___MASK70___ transport via system x ( c )(-) at the BBB is likely to be induced under oxidative stress conditions following DEM treatment due to enhanced transcription of the Q9UPY5 gene .", "___MASK17___ , a thrombin receptor ( P25116 ) antagonist for the prevention and treatment of atherothrombosis . ___MASK17___ is a novel antiplatelet agent undergoing development by Schering - Plough Corp for the treatment and prevention of atherothrombosis . The compound is an orally administered himbacine analog that potently antagonizes the platelet thrombin receptor protease - activated receptor 1 ( P25116 ) , which leaves the procoagulant function of thrombin intact . In preclinical studies , ___MASK17___ demonstrated no effect on bleed time or coagulation parameters . In both cynomolgus monkeys and humans , the compound had high bioavailability and inhibited ex vivo TRAP ( thrombin receptor - activating peptide ) - stimulated platelet aggregation in a potent and long - lasting manner . In a phase II clinical trial of patients undergoing percutaneous coronary intervention , ___MASK17___ added to standard therapy with aspirin and clopidogrel did not increase major or minor thrombolysis in myocardial infarction bleeding , and demonstrated a trend toward decreased major adverse cardiovascular events versus placebo . At the time of publication , three phase III trials were underway to assess the efficacy and safety of ___MASK17___ for at least 1 year in up to 35 , 000 patients with acute coronary syndromes or atherosclerosis . The distinct mechanism of action of ___MASK17___ allows for cardiovascular protection without the liability of increased bleeding associated with other antiplatelet therapies . Phase III trials in high - risk patients will determine the use of ___MASK17___ in cardiological practice ." ]
[ "___MASK17___", "___MASK18___", "___MASK3___", "___MASK40___", "___MASK42___", "___MASK45___", "___MASK59___", "___MASK70___", "___MASK95___" ]
___MASK42___
MH_train_1613
interacts_with DB01211?
[ "Traumatic brain injury - induced acute gene expression changes in rat cerebral cortex identified by GeneChip analysis . Proper CNS function depends on concerted expression of thousands of genes in a controlled and timely manner . Traumatic brain injury ( TBI ) in mammals results in neuronal death and neurological dysfunction , which might be mediated by altered expression of several genes . By employing a CNS - specific GeneChip and real - time polymerase chain reaction ( PCR ) , the present study analyzed the gene expression changes in adult rat cerebral cortex in the first 24 hr after a controlled cortical impact injury . Many functional families of genes not previously implicated in TBI - induced brain damage are altered in the injured cortex . These include up - regulated transcription factors ( O14543 , O60674 , P35610 - 3 , Q03060 , P10914 , SMN , silencer factor - B , ANIA - 3 , ANIA - 4 , and DB09106 - 1 ) and signal transduction pathways ( cpg21 , Narp , and P09455 ) and down - regulated transmitter release mechanisms ( CITRON , synaptojanin II , ras - related rab3 , neurexin - 1beta , and SNAP25A and - B ) , kinases ( IP - 3 - kinase , Pak1 , Ca ( 2 +)/ P62158 - dependent protein kinases ) , and ion channels ( K (+) channels TWIK , RK5 , X62839 , and Na (+) channel I ) . In addition , several genes previously shown to play a role in TBI pathophysiology , including proinflammatory genes , proapoptotic genes , heat shock proteins , immediate early genes , neuropeptides , and glutamate receptor subunits , were also observed to be altered in the injured cortex . Real - time PCR analysis confirmed the GeneChip data for many of these transcripts . The novel physiologically relevant gene expression changes observed here might explain some of the molecular mechanisms of TBI - induced neuronal damage .", "Insights from growth hormone receptor blockade . ___MASK80___ is a genetically manipulated growth hormone ( GH ) that disables signal transduction through the P10912 and thus functions as a P10912 antagonist . In a series of studies of the metabolic effects of GH in healthy male individuals , pegvisomant has been used to create a model of acute GH deficiency but without the typical alterations in body composition . This review summarizes studies of the effects of P10912 blockade and fasting , either alone or in combination , on determinants of GH release . Based on these and other data we present a model to explain the somatotroph hyperactivity of fasting", "[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . DB01211 ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .", "Ectopic expression of human acidic fibroblast growth factor 1 in the medicinal plant , Salvia miltiorrhiza , accelerates the healing of burn wounds . BACKGROUND : Healing of burns is a complex process and very few effective treatments exist to facilitate the burn recovery process . Human acidic fibroblast growth factor 1 ( P05230 ) plays an important role in a variety of biological processes , including angiogenesis , and tissue repair . Salvia miltiorrhiza is widely used in traditional Chinese medicine as an herb for the treatment of various diseases , including cardiovascular and cerebrovascular diseases , and traumatic injuries . We present that expression of P05230 in S . miltiorrhiza significantly accelerates the healing of burn wounds . RESULTS : The human fgf - 1 gene was fused with a barley α - amylase signal peptide DNA sequence and driven by a 35S promoter for constitutive expression in transgenic S . miltiorrhiza plants . The highest yield of recombinant P05230 obtained from leaves of transgenic S . miltiorrhiza lines was 272 ng / fresh weight . Aqueous extracts from transgenic S . miltiorrhiza exhibited P05230 activity approximately 19 . 2 - fold greater than that of the standard P05230 . Compared to the standard P05230 or the extracts obtained from non - transgenic plants , it stimulated proliferation of Balb / c 3 DB00279 mouse fibroblast cells assessed with the standard MTT assay and promoted angiogenesis in the chicken embryo chorioallantoic membrane ( P62158 ) assay . Topical application of the extract significantly accelerated the burn wound healing process . CONCLUSIONS : The product appears to retain the biological activity of both P05230 as well as the medicinal properties of the plant . The extracts from transgenic S . miltiorrhiza combines the therapeutic functions of P05230 and the medicinal plant , S . miltiorrhiza . Topical application of the product can reduce the costs associated with extraction , purification , and recovery .", "Single - prolonged stress induce changes of P62158 / CaMKIIα in the rats of dorsal raphe nucleus . Ca2 +/ calmodulin - dependent protein kinase IIα ( CaMKIIα ) is identified as a Ca2 +- dependent kinase in brain involved in the activation of DB00150 hydroxylase ( P17752 ) acting through direct phosphorylation of P17752 , and playing key roles in the signaling pathways initiated by various G protein - coupled 5 - HT receptors . The goal of this study is to detect whether there are changes of P62158 and CaMKIIα in dorsal raphe nucleus in the rats exposed to single - prolonged stress ( P49903 ) , which is a model employed in post - traumatic stress disorder ( PTSD ) study extensively . A total of 90 male Wistar rats were randomly divided into a normal control group and P49903 groups of 7d , 14d . The changes of P62158 / CaMKIIα were detected by immunohistochemistry , reverse transcription - polymerase chain reaction and western blot . Our results demonstrate that both expressions of P62158 and CaMKIIα significantly increase ( P < 0 . 001 ) in the P49903 7d group than that in the control group , and then decreased dramatically ( P < 0 . 001 ) 14 days after P49903 . Our results confirm that P49903 induce changes of P62158 / CaMKIIα in the dorsal raphe nucleus . Changes of P62158 / CaMKIIα may be associated with the activation of P08908 receptor , and may contribute to the progress of molecular mechanism of PTSD .", "P13688 impedes thyroid cancer growth but promotes invasiveness : a putative mechanism for early metastases . P13688 , also known as biliary glycoprotein ( BGP ) , CD66a , Q00839 and C - P62158 , is a member of the P06731 immunoglobulin superfamily . P13688 is a putative tumor suppressor based on diminished expression in some solid neoplasms such as colorectal carcinoma . However , P13688 is overexpressed in some tumors such as non - small cell lung cancer . To clarify the mechanism of action of this cell adhesion molecule , we studied thyroid carcinoma that has a spectrum of morphologies and variable behavior allowing separation of proliferation from invasion and metastasis . P13688 is expressed in thyroid carcinoma cell lines derived from tumors that exhibit aggressive behavior . Introduction of P13688 into endogenously deficient WRO cells resulted in reduced cell cycle progression associated with P38936 upregulation and diminished Rb phosphorylation . Forced P13688 expression enhanced cell - matrix adhesion and migration and promoted tumor invasiveness . Conversely , small interfering RNA ( siRNA ) - mediated downregulation of P13688 expression in Q9BYG7 cells accelerated cell cycle progression and significantly enhanced tumor size in xenografted mice . P13688 is not appreciably expressed in normal thyroid tissue or benign thyroid tumors . In a human thyroid tissue array , P13688 reactivity was associated with metastatic spread but not with increased tumor size . These findings identify P13688 as a unique mediator that restricts tumor growth whereas increasing metastatic potential . Our data highlight a complex repertoire of actions providing a putative mechanism underlying the spectrum of biologic behaviors associated with thyroid cancer .", "Anti - interleukin 6 receptor antibody treatment in rheumatic disease . Interleukin 6 ( P05231 ) is a pleiotropic cytokine with a wide range of biological activities . P05231 transgene into mice gives rise to the abnormalities such as hypergammaglobulinaemia , thrombocytosis , infiltration of inflammatory cells into the tissues , mesangial cell proliferation of the kidney as well as splenomegaly and lymphadenopathy , which are predictable by the biological functions of P05231 shown in vitro . Continuous overproduction of P05231 is observed in patients with some immune - inflammatory diseases such as Castleman ' s disease and rheumatoid arthritis that are frequently associated with similar abnormalities to those of P05231 transgenic mice , strongly suggesting the involvement of P05231 in the human diseases . Successful treatment of the model animals for immune - inflammatory diseases with anti - P05231 receptor ( P08887 ) antibody thus indicates the possible application of P05231 blocking agents to treat the P05231 related immune - inflammatory diseases of humans . In this review , the new therapeutic strategy for Castleman ' s disease and RA using humanized antibody to human P05231 receptor , ___MASK43___ , is discussed .", "Dimerization effect of sucrose octasulfate on rat P05230 . Fibroblast growth factors ( FGFs ) constitute a family of at least 23 structurally related heparin - binding proteins that are involved in regulation of cell growth , survival , differentiation and migration . ___MASK32___ ( SOS ) , a chemical analogue of heparin , has been demonstrated to activate FGF signalling pathways . The structure of rat P05230 crystallized in the presence of SOS has been determined at 2 . 2 A resolution . SOS - mediated dimerization of P05230 was observed , which was further supported by gel - filtration experiments . The major contributors to the sulfate - binding sites in rat P05230 are Lys113 , Lys118 , Arg122 and Lys128 . An arginine at position 116 is a consensus residue in mammalian FGF molecules ; however , it is a serine in rat P05230 . This difference may be important for SOS - mediated P05230 dimerization in rat .", "Involvement of retinoic acid receptor alpha in the stimulation of tissue - type plasminogen - activator gene expression in human endothelial cells . Retinoids stimulate tissue - type plasminogen - activator ( t - PA ) gene expression in human endothelial cells , and are likely to do so by binding to one or more nuclear retinoid receptors . The present study was initiated to identify the retinoid receptor ( s ) involved in this process . Expression and regulation of retinoic acid receptors ( RARs ) and retinoid X receptors ( RXRs ) were analyzed by Northern - blot analysis of total or poly ( A )- rich RNA prepared from cultured human umbilical vein endothelial cells ( HUVEC ) . Prior to any exposure to retinoids , HUVEC express two transcripts for P10276 ( 3 . 6 kb and 2 . 8 kb ) , and low levels of transcripts for P10826 ( 3 . 4 kb and 3 . 2 kb ) and P13631 ( 3 . 3 kb and 3 . 1 kb ) . Two RXR subtypes were identified , RXR - alpha ( 4 . 8 kb ) and , at a much lower concentration , RXR - beta ( 2 . 4 kb ) ; no evidence for the presence of RXR - gamma was found . Furthermore , HUVEC express cellular retinol - binding protein I ( P09455 ) and cellular retinoic - acid - binding protein I ( P29762 ) mRNA . Exposure of HUVEC to 1 microM retinoic acid or the ___MASK69___ , Ch55 , led to the induction of the two P10826 mRNAs , RXR - alpha mRNA and P09455 mRNA , whereas the expression of the other receptor and P29762 transcripts did not change appreciably . Using retinoid analogues that bind preferentially to one of the RAR or RXR subtypes , we found evidence that P10276 is involved in the retinoid - induced t - PA expression in HUVEC . This conclusion was strengthened by experiments in which blocking of P10276 with a specific P10276 antagonist , Ro 41 - 5253 , was demonstrated to suppress the induction of t - PA by retinoids .", "Identification of insulin - stimulated phosphorylation sites on calmodulin . P01308 enhances calmodulin phosphorylation in vivo . To determine the insulin - sensitive phosphorylation sites , phosphocalmodulin was immunoprecipitated from Chinese hamster ovary cells expressing human insulin receptors ( CHO / IR ) . P62158 was constitutively phosphorylated on serine , threonine , and tyrosine residues , and insulin enhanced phosphate incorporation on serine and tyrosine residues . Phosphocalmodulin immunoprecipitated from control and insulin - treated CHO / IR cells , and calmodulin phosphorylated in vitro by the insulin receptor kinase and casein kinase II were resolved by two - dimensional phosphopeptide mapping . Several common phosphopeptides were detected . The phosphopeptides from the in vitro maps were eluted and phosphoamino acid analysis , manual sequencing , strong cation exchange chromatography , and additional proteolysis were performed . This strategy demonstrated that DB00135 - 99 and DB00135 - 138 were phosphorylated in vitro by the insulin receptor kinase and DB00156 - 79 , DB00133 - 81 , DB00133 - 101 and DB00156 - 117 were phosphorylated by casein kinase II . In vivo phosphorylation sites were identified by comigration of phosphopeptides on two - dimensional maps with phosphopeptides derived from calmodulin phosphorylated in vitro and by phosphoamino acid analysis . This approach revealed that DB00135 - 99 and DB00135 - 138 of calmodulin were phosphorylated in CHO / IR cells in response to insulin . Additional sites remain to be identified . The identification of the insulin - stimulated in vivo tyrosine phosphorylation sites should facilitate the elucidation of the physiological role of phosphocal - modulin .", "Mutation of the calmodulin binding motif IQ of the L - type Ca ( v ) 1 . 2 Ca2 + channel to EQ induces dilated cardiomyopathy and death . Cardiac excitation - contraction coupling ( EC coupling ) links the electrical excitation of the cell membrane to the mechanical contractile machinery of the heart . DB01373 channels are major players of EC coupling and are regulated by voltage and Ca ( 2 +)/ calmodulin ( P62158 ) . P62158 binds to the IQ motif located in the C terminus of the Ca ( v ) 1 . 2 channel and induces Ca ( 2 +)- dependent inactivation ( CDI ) and facilitation ( P05231 ) . Mutation of DB00167 to DB00142 ( Ile1624Glu ) in the IQ motif abolished regulation of the channel by CDI and P05231 . Here , we addressed the physiological consequences of such a mutation in the heart . Murine hearts expressing the Ca ( v ) 1 . 2 ( I1624E ) mutation were generated in adult heterozygous mice through inactivation of the floxed WT Ca ( v ) 1 . 2 ( Q401N2 ) allele by tamoxifen - induced cardiac - specific activation of the MerCreMer Cre recombinase . Within 10 days after the first tamoxifen injection these mice developed dilated cardiomyopathy ( DCM ) accompanied by apoptosis of cardiac myocytes ( CM ) and fibrosis . In Ca ( v ) 1 . 2 ( I1624E ) hearts , the activity of phospho - P62158 kinase II and phospho - MAPK was increased . CMs expressed reduced levels of Ca ( v ) 1 . 2 ( I1624E ) channel protein and I ( Ca ) . The Ca ( v ) 1 . 2 ( I1624E ) channel showed \" CDI \" kinetics . Despite a lower sarcoplasmic reticulum Ca ( 2 +) content , cellular contractility and global Ca ( 2 +) transients remained unchanged because the EC coupling gain was up - regulated by an increased neuroendocrine activity . Treatment of mice with metoprolol and captopril reduced DCM in Ca ( v ) 1 . 2 ( I1624E ) hearts at day 10 . We conclude that mutation of the IQ motif to IE leads to dilated cardiomyopathy and death .", "Characterization of the inhibitory effects of erythromycin and clarithromycin on the Q12809 potassium channel . Both erythromycin and clarithromycin have been reported to cause QT prolongation and the cardiac arrhythmia torsade de pointes in humans , however direct evidence documenting that these drugs produce this effect by blocking human cardiac ion channels is lacking . The goal of this study was to test the hypothesis that these macrolide antibiotics significantly block the delayed rectifier current ( IKr ) encoded by Q12809 ( the human ether - a - go - go - related gene ) at drug concentrations , temperature and ionic conditions mimicking those occurring in human subjects . DB01345 currents in P29320 293 cells stably transfected with Q12809 were recorded using a whole cell voltage clamp method . Exposure of cells to erythromycin reduced the Q12809 encoded potassium current in a concentration dependent manner with an IC50 of 38 . 9 +/- 1 . 2 microM and Hill Slope factor of 0 . 4 +/- 0 . 1 . DB01211 produced a similar concentration - dependent block with an IC50 of 45 . 7 +/- 1 . 1 microM and Hill Slope factor of 1 . 0 +/- 0 . 1 . Erythromycin ( 25 - 250 microM ) and clarithromycin ( 5 or 25 microM ) also produced a significant decrease in the integral of the current evoked by an action potential shaped voltage clamp protocol . The results of this study document that both erythromycin and clarithromycin significantly inhibit the Q12809 potassium current at clinically relevant concentrations .", "Ovine placental lactogen - induced heterodimerization of ovine growth hormone and prolactin receptors in living cells is demonstrated by fluorescence resonance energy transfer microscopy and leads to prolonged phosphorylation of signal transducer and activator of transcription ( P35610 ) 1 and P40763 . P29320 - 293T cells transiently transfected with ovine ( o ) P10912 ( P10912 ) and prolactin receptor ( P16471 ) constructs respectively tagged downstream with cyan or yellow fluorescent proteins were used to study ovine placental lactogen ( oPL ) - stimulated heterodimerization by fluorescence resonance energy transfer ( FRET ) microscopy . The oPL - stimulated transient heterodimerization of P10912 and P16471 had a peak occurring 2 . 5 - 3 min after oPL application , whereas oGH or oPRL had no effect at all . The results indicate none or only little dimerization occurring before the hormonal stimulation . The effect of heterodimerization was studied by comparing activation of O60674 , signal transducer and activator of transcription ( P35610 ) 1 , P40763 , P42229 , and MAPK in Chinese hamster ovary cells stably transfected with chimeric genes encoding receptors consisting of cytosolic and transmembrane parts of oGHR and oPRLR , extracellular domains of human granulocyte and macrophage colony - stimulating factor ( hGM - P04141 ) receptor alpha or beta , and cells transfected with the two forms ( alpha or beta ) of P16471 and P10912 . Functionality of those proteins was verified by hGM - P04141 - induced phosphorylation of both intracellular P16471 and P10912 domains and hGM - P04141 - induced heterodimerization was documented by chimeric receptor coimmunoprecipitation . Homodimerization or heterodimerization of PRLRs and GHRs had no differential effect on activation of P42229 and MAPK . However , heterodimerization resulted in a prolonged phosphorylation of P42224 and in particular P40763 , suggesting that the heterodimerization of alpha - oGHR and beta - oPRLR is able to transduce a signal , which is distinct from that occurring on homodimeric associations .", "DB02527 phosphodiesterases are localized in regions of the mouse brain associated with reinforcement , movement , and affect . Four cyclic AMP - specific , rolipram - inhibited phosphodiesterases ( PDE4s ) have been identified in mammals ; all four are homologs of dunce , a gene required for learning and memory in Drosophila . To determine the distribution of PDE4s in the mammalian brain , specific antibodies were generated against the proteins encoded by each of three dunce homologs P27815 , Q07343 , and Q08499 in the mouse . On Western blots , these antibodies recognized multiple protein species in all brain regions studied . Immunohistochemical studies showed that both cell bodies and neuropil were well labeled in selected regions throughout the brain . Immunoreactivity for P27815 was found predominantly in the anterior olfactory nucleus , subiculum , layer V pyramidal neurons from the cerebral cortex , and corticospinal tracts . By contrast , anti - Q07343 - labeled neurons were observed in the inferior olive , the paraventricular and supraoptic nuclei of the hypothalamus , and in the ventral striatum . Regions of neuropil containing high levels of Q07343 immunoreactivity included the cerebellar molecular layer , globus pallidus , nucleus accumbens , and substantia nigra . Anti - Q08499 antibody distinctly labeled cerebellar Purkinje cells as well as neurons in the medial habenula and thalamic nuclei . Fibers in the fasciculus retroflexus , interpeduncular nuclei , and periaqueductal gray were also stained with this antibody . These findings indicate that the distribution of PDE4s in the brain is remarkably segregated , and suggest that each of these enzymes has a unique functional role . Furthermore , the data support the notion that rolipram , the ___MASK79___ - specific inhibitor that acts as an antidepressant in humans , may mediate its behavioral effects through Q07343 , which is highly localized to neural pathways known to underlie reward and affect in mammals .", "Characterization of DB02527 degradation by phosphodiesterases in the accessory olfactory system . To characterize the potential role of DB02527 in pheromone transduction , we have examined the occurrence of cyclic nucleotide phosphodiesterases ( PDEs ) in the mouse vomeronasal organ ( VNO ) . We show that the DB02527 - specific isoforms P27815 and Q08499 are found preferentially in the apical and basal layers , respectively , of the VNO neuroepithelium and in the rostral ( P27815 ) and caudal ( Q08499 ) portions of the accessory olfactory bulb glomerular layer . Assays for DB02527 hydrolysis showed that PDE activity in VNO homogenates was about half that measured in the cerebral cortex and olfactory epithelium , and the proportion of total activity inhibited by rolipram , a ___MASK79___ - specific inhibitor , was approximately 40 % . Activity in the VNO was enhanced 60 % by Ca ( 2 +) and calmodulin ( P62158 ) , implicating the presence of Ca ( 2 +)/ P62158 - dependent PDE1 . Zaprinast , which is known to inhibit Q14123 isoforms , completely suppressed Ca ( 2 +)/ P62158 - stimulated activity and , together , zaprinast and rolipram inhibited DB02527 hydrolysis by approximately 70 % . Our results suggest that PDE1 and ___MASK79___ isoforms are the primary source of DB02527 degradation in the VNO .", "Perfusion - independent effect of bradykinin and fosinoprilate on glucose transport in Langendorff rat hearts . P12821 ( P12821 ) inhibitor - stimulated glucose metabolism and perfusion in muscle tissue seem to be , at least in part , mediated by kinins . However , the relative contribution of direct metabolic or secondary hemodynamically induced effects is unclear . It was the aim of this study to characterize the effects of P12821 inhibition and bradykinin on glucose transport while changes in cardiocoronary function that might influence glucose transport were minimized . Hearts from Wistar rats were perfused by a Langendorff preparation and a set of functional parameters were simultaneously measured . Bradykinin ( 10 [- 11 ] M ) and fosinoprilate ( 10 [- 7 ] M ) were administered at concentrations that did not affect coronary flow . P01308 was employed as reference at half - maximal concentration . The nonmetabolizable glucose analog 3 - O -[ 14C ] methyl - D - glucose and the nontransportable tracer L -[ 3H ] glucose were coperfused for the calculation of glucose transport . Using a 2 - compartment mathematical model we found that the glucose transport rate , which was doubled with insulin , was increased almost 3 - fold by either bradykinin or fosinoprilate . In the presence of the P30411 antagonist ___MASK81___ ( D - DB00125 [ Hyp3 , Thi5 , D - Tic7 , Oic8 ]- bradykinin ; icatibant ) , the effect of both agents was completely abolished . Both agents also induced minor changes in contractility / relaxation parameters that again were completely neutralized with icatibant . A perfusion - independent but B2 - kinin receptor - dependent stimulating effect on glucose transport by either bradykinin or fosinoprilate is concluded . This effect could , in analogy to insulin be due to increased glucose transporter translocation , increased endothelium - derived nitric oxide formation , or -- despite constant coronary flow conditions -- secondary to altered cardiac function .", "Differential expression of nitric oxide synthase in human stomach cancer . The level of expression and cellular localization of isoenzymes of nitric oxide synthase ( NOS ) was detected in human stomach tumor tissues . Tumor tissues showed 70 % higher activity of NOS than that of normal tissues ( P < 0 . 01 ) . Poorly differentiated adenocarcinoma tend to have higher activity ( P < 0 . 05 ) than well differentiated and moderately differentiated tumor tissues . DB02533 ( AG ) , 2 - amino - 5 , 6 - dihydro - 6 - methyl - 4H - 1 , 3 - thiazine ( AMT ) , NG - monomethyl - L - arginine ( L - NMMA ) , and Nomega - nitro - L - arginine ( ___MASK23___ ) inhibited NOS activity in tumor tissues by 18 , 14 , 11 and 13 % , respectively . The P01375 mRNA expression was correlated with the inducible NOS ( P35228 ) level , which was high in adenocarcinomas and low in normal tissues . Tumor tissues showed higher expression of P35228 in gland epithelial cells but the level of P29474 was significantly decreased with an exception of concentrated localization in the proliferating capillary endothelium . These results revealed that isoforms of NOS might contribute differentially to growth and progression of human stomach tumor .", "Dual ligands targeting dopamine D2 and serotonin P08908 receptors as new antipsychotical or anti - Parkinsonian agents . Psychiatric disorders like schizophrenia and neurodegenerative diseases like Parkinson ' s disease are associated with poly - factorial pathogenic mechanisms , with several neurotransmitter systems closely involved . In addition to the cerebral dopaminergic ( DA ) system , the serotoninergic ( 5 - HT ) system also plays a crucial role in regulating psychoemotional , cognitive and motor functions in the central nervous system ( CNS ) . Among the large 5 - HT receptor family , accumulating data have revealed new insights into the therapeutic benefit of the P08908 receptor in treating various CNS disorders , especially schizophrenia and Parkinson ' s disease . The present review discusses the advance of dual agents with mixed actions at the dopamine D2 and serotonin P08908 receptors in the treatment of these diseases . Aripiprazole was the only marketed drug with dual D2 and P08908 profile . It is a partial D2 and P08908 receptor agonist and has been prescribed as an atypical antipsychotical drug . Two other drugs ___MASK92___ and Pardoprunox are being investigated in clinic . Most of the other candidate compounds , including DB04888 , Sarizotan , Mazapertine succinate , PF - 217830 , and Adoprazine were discontinued due to either non - optimal pharmacokinetic properties or insufficient therapeutical efficacy . Although much effort has been done to highlight the advantages of the P08908 and D2 dual approach , it has to be pointed out that many of these drugs showed poly - pharmacological profile by targeting many other receptors and / or transporters besides the D2 and P08908 receptors . In this regard , ' pure ' compounds exclusively acting on the D2 and P08908 receptors are highly needed to further validate this approach . Meanwhile , safety concerns and in vivo pharmacokinetic alerts should also be implanted to the drug design art early .", "Nitrergic response to cyclophosphamide treatment in blood and bone marrow . Daily intraperitoneal injection of cyclophosphamide ( P15085 ) ( 50 mgkg (- 1 ) of body weight ) for 5 days resulted in reduced levels of marrow and blood cellularity , which was most pronounced in 18 days post - treatment ( pt ) . On day 18 after P15085 treatment the enhancedlevels of nitric oxide ( NO ) precursors and metabolites ( L - arginine , L - citrulline , reactive nitrogen species ( RNS ) ) of marrow and blood cells ( platelet , neutrophil , lymphocyte and monocyte ) resulted from up - regulation of Ca ( II )/ calmodulin ( P62158 )- independent \" inducible \" NO synthase ( P35228 ) , with a lessercontribution of Ca ( II )/ P62158 - dependent \" constitutive \" P29474 isoforms to systemic NO . Biphasic response to P15085 of marrow nitrergic system , i . e . both P35228 and P29474 showed significantly depressed activities , as well as diminished levels of NO metabolites on day 9 pt , suggested that signals in addition to NO might be involved in P15085 - induced inhibition of hematopoesis , while a gradual increase of neutrophil and platelet NOS activity appeared to be contributed to a P15085 - induced development of granulopenia , thrombocytopenia and hemorrhage .", "___MASK10___ - induced growth inhibition of glioma cells is accompanied by altered expression of cyclins , CDKs and CDK inhibitors . ___MASK10___ was found to bring about complete growth inhibition of human glioma cell lines . U87 MG cells were arrested in S phase while U373 MG cells in G2 / M phase on staurosporine treatment . Consistent with this observation , no change in P55008 phase regulators viz . , P12004 D1 , D3 and P11802 was seen on staurosporine treatment . The levels of P24941 , P06493 , P12004 A and P12004 B proteins decreased , while the levels of CDK inhibitors viz . , P38936 and p27 were found to increase on staurosporine treatment . The mRNA levels of P24941 and P06493 genes were also found to decrease on staurosporine treatment . Thus apart from staurosporine ' s known direct inhibitory effect on P24941 and P06493 activities , staurosporine was found to down - regulate activities of these two kinases by modulating the expression of the kinases themselves as well that of their activating partners ( Cyclins ) and their inhibitors ." ]
[ "___MASK10___", "___MASK23___", "___MASK32___", "___MASK43___", "___MASK69___", "___MASK79___", "___MASK80___", "___MASK81___", "___MASK92___" ]
___MASK43___
MH_train_1614
interacts_with DB00834?
[ "Agonism at P41595 receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5 - hydroxytryptamine2B ( P41595 ) receptors . To evaluate whether agonism at P41595 receptors is a phenomenon of the class of the ergolines , we studied P41595 receptor - mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . ___MASK97___ and cabergoline were potent full agonists in this tissue ( pEC50 8 . 42 and 8 . 72 ) . DB01200 acted as a partial agonist ( pEC50 6 . 86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5 - HT - induced relaxation ( pKB 10 . 32 and 8 . 49 ) . Thus , agonism at P41595 receptors seems not to be a class effect of the ergolines .", "___MASK83___ ameliorates olanzapine - induced weight gain through modulation of histaminergic , P01303 and AMPK pathways . Olanzapine is widely used to treat schizophrenia and other disorders , but causes adverse obesity and other metabolic side - effects . Both animal and clinical studies have shown that co - treatment with betahistine ( a histaminergic H1 receptor agonist and H3 receptor antagonist ) is effective for ameliorating olanzapine - induced weight gain / obesity . To reveal the mechanisms underlying these effects , this study investigated the effects of co - treatment of olanzapine and betahistine ( O + B ) on expressions of histaminergic H1 receptor ( P35367 ) , AMP - activated protein kinase ( AMPK ) , neuropeptide Y ( P01303 ) , and proopiomelanocortin ( P01189 ) in the hypothalamus associated with reducing olanzapine - induced weight gain . Olanzapine significantly upregulated the mRNA and protein expressions of P35367 , while O + B co - treatment significantly downregulated the P35367 levels , compared to the olanzapine - only treatment group . The P01303 mRNA expression was significantly enhanced by olanzapine , but it was significantly reversed by O + B co - treatment . The hypothalamic P35367 expression was positively correlated with total food intake , and P01303 expression . Olanzapine also increased AMPKα activation measured by the AMPKα phosphorylation ( pAMPKα ) / AMPKα ratio compared with controls , whereas O + B co - treatment decreased the pAMPKα / AMPKα ratio , compared with olanzapine only treatment . The pAMPKα / AMPKα ratio was positively correlated with total food intake and P35367 expression . Although olanzapine administration decreased the P01189 mRNA level , this level was not affected by O + B co - treatment . Therefore , these results suggested that co - treatment with betahistine may reverse olanzapine - induced body weight gain via the P35367 - P01303 and P35367 - pAMPKα pathways .", "Janus - faced role of endothelial NO synthase in vascular disease : uncoupling of oxygen reduction from NO synthesis and its pharmacological reversal . Endothelial NO synthase ( P29474 ) is the predominant enzyme responsible for vascular NO synthesis . A functional P29474 transfers electrons from NADPH to its heme center , where L - arginine is oxidized to L - citrulline and NO . Common conditions predisposing to atherosclerosis , such as hypertension , hypercholesterolemia , diabetes mellitus and smoking , are associated with enhanced production of reactive oxygen species ( ROS ) and reduced amounts of bioactive NO in the vessel wall . NADPH oxidases represent major sources of ROS in cardiovascular pathophysiology . NADPH oxidase - derived superoxide avidly interacts with P29474 - derived NO to form peroxynitrite ( ONOO (-) ) , which oxidizes the essential NOS cofactor ( 6R -) ___MASK21___ ( BH ( 4 ) ) . As a consequence , oxygen reduction uncouples from NO synthesis , thereby rendering NOS to a superoxide - producing pro - atherosclerotic enzyme . Supplementation with BH ( 4 ) corrects P29474 dysfunction in several animal models and in patients . Administration of high local doses of the antioxidant L - ascorbic acid ( vitamin C ) improves endothelial function , whereas large - scale clinical trials do not support a strong role for oral vitamin C and / or E in reducing cardiovascular disease . Statins , angiotensin - converting enzyme inhibitors and AT1 receptor blockers have the potential of reducing vascular oxidative stress . Finally , novel approaches are being tested to block pathways leading to oxidative stress ( e . g . protein kinase C ) or to upregulate antioxidant enzymes .", "P04150 antagonism disrupts the reconsolidation of social reward - related memories in rats . Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use . Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated , reconsolidation of memories of physiologically relevant social rewards has received little attention . Social play , the most characteristic social behaviour displayed by young mammals , is highly rewarding , illustrated by the fact that it can induce conditioned place preference ( CPP ) . Here , we investigated the role of signalling mechanisms implicated in memory processes , including reconsolidation , namely glucocorticoid , mineralocorticoid , DB01221 glutamatergic and P21554 cannabinoid receptors , in the reconsolidation of social play - induced CPP in rats . Systemic treatment with the glucocorticoid receptor antagonist mifepristone before , but not immediately after , retrieval disrupted the reconsolidation of social play - induced CPP . DB00834 did not affect social play - induced CPP in the absence of memory retrieval . Treatment with the DB01221 receptor antagonist MK - 801 modestly affected the reconsolidation of social play - induced CPP . However , the reconsolidation of social play - induced CPP was not affected by treatment with the mineralocorticoid and P21554 cannabinoid receptor antagonists spironolactone and rimonabant , respectively . We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward - related memories in rats . These data indicate that the neural mechanisms of the reconsolidation of social reward - related memories only partially overlap with those underlying the reconsolidation of other reward - related memories .", "___MASK30___ , a nitric oxide - releasing aspirin derivative , exhibits a significant antiproliferative effect and alters cell cycle progression in human colon adenocarcinoma cell lines . DB00435 - releasing non - steroidal antiinflammatory drugs ( NO - NSAIDs ) are safer than NSAIDs due to their ability to reduce gastric toxicity . We assessed the cytotoxic activity of a new aspirin derivative , ___MASK30___ , after different exposure schedules , in three human colon adenocarcinoma cell lines . All the lines were positive for P23219 protein and mRNA , as evaluated by Western blot and RT - PCR , respectively , while only one was positive for P35354 . The cytostatic and cytocidal activity was determined by sulforhodamine B assay and evaluated according to Monks ' model . Cytostatic activity was observed after a 24 - h drug exposure and 50 % growth inhibition was reached at concentrations ranging from 165 to 250 micro M in all cell lines , whereas with aspirin the IC50 was never reached , even at the maximum concentration tested ( 500 micro M ) , and was independent of P23219 or P35354 status . Cytocidal activity was observed only at the highest concentrations and persisted for a long time after drug removal . Flow cytometric analysis showed that the NO - aspirin compound induced a persistent accumulation of cells in G2 - M phase in all the cell lines after at least 48 h exposure . Specifically , the block pertained mainly to G2 phase , whereas mitotic index was not affected at all . Our results indicate that ___MASK30___ has an in vitro cytostatic activity superior to that of its parental aspirin compound , which makes it a potentially important tumor preventive agent . Furthermore , the cytocidal effect observed at the highest concentrations and the induction of a specific block in G2 phase renders it a promising candidate for drug combination treatments .", "Endocannabinoids as autoregulatory signaling molecules : coupling to nitric oxide and a possible association with the relaxation response . Endocannabinoid signaling processes are present in diverse organisms and in organisms 500 million years divergent in evolution . Cannabinoid receptor - 1 expression ( P21554 ) , anandamide , and anandamide amidase have been found in invertebrates . Furthermore , this signaling system is coupled to constitutive nitric oxide synthase ( P29474 ) - derived nitric oxide ( NO ) release in both vertebrates and invertebrates , thereby regulating neural , immune , and vascular - like functions in these divergent organisms . In human endothelial cells from various blood vessels , P21554 immunoreactive components are present as is its coupling to anandamide - stimulated P29474 - derived NO production , which exerts an autoregulatory role on P29474 release . The modulation of vascular diameter and vascular tone represents a crucial point of interest in these pathways , and interactions between NO and the sympathetic nerve system are of importance , i . e , norepinephrine . Here , a possible association of NO and endocannabinoid signaling with the relaxation response , a physiological counterpart of the stress response , may exist .", "Antiinflammatory steroid action in human ovarian surface epithelial cells . The human ovarian surface epithelium ( OSE ) is subject to serial injury and repair during ovulation , which is a natural inflammatory event . We asked whether there is a compensatory antiinflammatory component to this process , involving steroid hormones produced locally at the time of ovulation . Quantitative RT - PCR analysis of total RNA from cultured human OSE cell monolayers showed that exposure to proinflammatory IL1alpha ( 500 pg / ml ) increased mRNA levels of cyclooxygenase - 2 ( P35354 ) ( P < 0 . 01 ) at 48 h . The P35354 mRNA response to IL1alpha was associated with an approximate 18 - fold ( P < 0 . 01 ) increase in mRNA levels of 11beta - hydroxysteroid dehydrogenase type 1 ( 11betaHSD1 ) , encoding the steroid dehydrogenase that reversibly reduces cortisone to antiinflammatory cortisol . Addition of cortisol to OSE cell culture medium dose - dependently suppressed the P35354 mRNA response to IL1alpha ( P < 0 . 01 ) but reciprocally enhanced the 11betaHSD1 mRNA response ( P < 0 . 05 ) , with both effects strongest at 1 microm cortisol . Presence of glucocorticoid receptor - alpha mRNA and protein was established in OSE cell monolayers and treatment with IL1alpha shown to significantly up - regulate the glucocorticoid receptor - alpha mRNA level ( P < 0 . 05 ) . P04150 antagonist ( DB00834 , 10 microm ) fully reversed the inhibitory effect of 1 microm cortisol on IL1alpha - stimulated P35354 mRNA expression . Progesterone also suppressed IL1alpha - induced P35354 mRNA expression but had no significant effect on IL1alpha - stimulated 11betaHSD1 expression . These data provide direct evidence for antiinflammatory actions of cortisol and progesterone in human OSE cells .", "Modulation of cytokine production and enhancement of cell viability by Q9NYK1 and Q9NR96 ligands during anthrax infection of macrophages . Inhalation of Bacillus anthracis , a bioterrorism agent , results in a high mortality rate despite appropriate antibiotic therapy . Macrophages appear to be a key factor in B . anthracis pathogenesis . The burst of pro - inflammatory cytokines from macrophages could be a major cause of death in anthrax . However , preactivation of Toll - like receptors ( TLRs ) could modify the host response . TLR ligands stimulate the release of activating cytokines but may also down - modulate the subsequent deleterious cytokine response to pathogens . We developed a cell culture model to measure macrophage responses to B . anthracis spores and bacilli . We found that germination from spores to bacilli produced a substantial stimulus for the secretion of the cytokines P05231 , P01375 , P22301 , and IL - 12 p40 . Our studies showed that pretreatment of mouse macrophages with the Q9NR96 ligand ___MASK14___ , or the Q9NYK1 ligands R - 848 and IT - 37 , results in a substantial decrease in the subsequent secretion of P05231 and P01375 in response to B . anthracis infection of macrophages . Furthermore , the Q9NYK1 and Q9NR96 ligands significantly decreased anthrax - induced cytotoxicity in the macrophages . These findings suggest that TLR ligands may contribute to the enhancement of innate immunity in B . anthracis infection by suppressing potentially deleterious pro - inflammatory cytokine responses and by improving macrophage viability .", "Cyclophilin interactions with incoming human immunodeficiency virus type 1 capsids with opposing effects on infectivity in human cells . P62937 ( CypA ) is a peptidyl - prolyl isomerase that binds to the capsid protein ( CA ) of human immunodeficiency virus type 1 ( HIV - 1 ) and by doing so facilitates HIV - 1 replication . Although CypA is incorporated into HIV - 1 virions by virtue of CypA - Gag interactions that occur during virion assembly , in this study we show that the CypA - CA interaction that occurs following the entry of the viral capsid into target cells is the major determinant of CypA ' s effects on HIV - 1 replication . Specifically , by using normal and CypA - deficient Jurkat cells , we demonstrate that the presence of CypA in the target and not the virus - producing cell enhances HIV - 1 infectivity . Moreover , disruption of the CypA - CA interaction with cyclosporine A ( ___MASK41___ ) inhibits HIV - 1 infectivity only if the target cell expresses CypA . The effect of ___MASK41___ on HIV - 1 infection of human cells varies according to which particular cell line is used as a target , and CA mutations that confer ___MASK41___ resistance and dependence exert their effects only if target cells , and not if virus - producing cells , are treated with ___MASK41___ . The differential effects of ___MASK41___ on HIV - 1 infection in different human cells appear not to be caused by polymorphisms in the recently described retrovirus restriction factor TRIM5alpha . We speculate that CypA and / or CypA - related proteins affect the fate of incoming HIV - 1 capsid either directly or by modulating interactions with unidentified host cell factors .", "Transcription profile of candidate genes for the acquisition of competence during oocyte growth in cattle . The aim of this study was to investigate the expression profile of candidate genes involved in competence during oocyte growth . The candidate genes ( O95972 , A8MZH6 , Q8IZA3 , H2A , H3A , H4 , Q14493 , P26358 , Q9UBC3 , O14929 , Q92769 and O43463 ) were selected because of their possible involvement in determining oocyte developmental competence . Pre - antral and antral follicles were isolated from the ovaries of Zebu ( Bos indicus ) cows , measured and classified into the following categories according to their diameter : ( i ) oocytes from primordial follicles : diameter < 20 μm , ( ii ) oocytes from primary follicles : 25 - 35 μm , ( iii ) oocytes from small secondary follicles : 40 - 60 μm , ( iv ) oocytes from large secondary follicles : 65 - 85 μm , ( v ) oocytes from small antral follicles : 100 - 120 μm , and ( vi ) oocytes from large antral follicles : > 128 μm . Total RNA was extracted from four pools of 25 oocytes for each category of follicles , and the genes were quantified by qPCR . Target gene expression was normalized using the gene P62937 . The results suggest that stocks of the studied transcript genes accumulate before the final phase of folliculogenesis . The Q92769 gene was the only gene in which a differential expression was observed at stage associated with competence acquisition .", "P04150 and histone deacetylase - 2 mediate dexamethasone - induced repression of P98088 gene expression . Airway occlusion in obstructive airway diseases is caused in part by the overproduction of secretory mucin glycoproteins through the up - regulation of mucin ( MUC ) genes by inflammatory mediators . Some pharmacological agents , including the glucocorticoid dexamethasone ( DB00514 ) , repress mucin concentrations in lung epithelial cancer cells . Here , we show that DB00514 reduces the expression of P98088 , a major airway mucin gene , in primary differentiated normal human bronchial epithelial ( NHBE ) cells in a dose - dependent and time - dependent manner , and that the DB00514 - induced repression is mediated by the glucocorticoid receptor ( GR ) and two glucocorticoid response elements ( GREs ) in the P98088 promoter . The pre - exposure of cells to DB00834 , a GR antagonist , and mutations in either the GRE3 or GRE5 cis - sites abolished the DB00514 - induced repression . Chromatin immunoprecipitation ( ChIP ) assays showed a rapid temporal recruitment of GR to the GRE3 and GRE5 cis - elements in the P98088 promoter in NHBE and in A549 cells . Immunofluorescence showed nuclear colocalization of GR and histone deacetylase - 2 ( Q92769 ) in P98088 - expressing NHBE cells . ChIP also showed a rapid temporal recruitment of Q92769 to the GRE3 and GRE5 cis - elements in the P98088 promoter in both cell types . The knockdown of Q92769 by Q92769 - specific short interfering RNA prevented the DB00514 - induced repression of P98088 in NHBE and A549 cells . These data demonstrate that GR and Q92769 are recruited to the GRE3 and GRE5 cis - sites in the P98088 promoter and mediate the DB00514 - induced cis repression of P98088 gene expression . A better understanding of the mechanisms whereby glucocorticoids repress P98088 gene expression may be useful in formulating therapeutic interventions in chronic lung diseases .", "___MASK77___ . ___MASK77___ , a derivative of physostigmine , was first described as an inhibitor of acetylcholinesterase ( P22303 ) and was shown to improve cognition in various experimental paradigms in rodents and dogs . It was clinically tested for Alzheimer ' s disease , with moderate success in initial Phase II studies . ___MASK77___ deserves attention for an additional quality of action : in addition to inhibiting P22303 , it modulates the amount of beta - amyloid precursor protein ( P05067 ) in neuronal cell culture by reducing P05067 translation . This effect probably involves interaction of phenserine with a regulatory element in the 5 '- untranslated region of the P05067 gene that controls P05067 expression . ___MASK77___ apparently reduces translational efficiency of P05067 mRNA into protein , a process that may involve an interaction with iron and / or an iron - responsive element . As a consequence , phenserine reduces beta - amyloid peptide ( Abeta ) formation in vitro and in vivo . ___MASK77___ is also unique because of differing actions of its enantiomers : ___MASK77___ is the active enantiomer for inhibition of P22303 , whereas (+)- phenserine ( ' posiphen ' ) has weak activity as an P22303 inhibitor and can be dosed much higher . Both enantiomers are equipotent in downregulating P05067 expression . (+)- Posiphen may be a promising drug , either alone or in combination with ___MASK77___ , to attenuate the progression of Alzheimer ' s disease .", "Blockade of cannabinoid receptors reduces inflammation , leukocyte accumulation and neovascularization in a model of sponge - induced inflammatory angiogenesis . OBJECTIVE : Angiogenesis depends on a complex interaction between cellular networks and mediators . The endocannabinoid system and its receptors have been shown to play a role in models of inflammation . Here , we investigated whether blockade of cannabinoid receptors may interfere with inflammatory angiogenesis . MATERIALS AND METHODS : Polyester - polyurethane sponges were implanted in C57Bl / 6j mice . Animals received doses ( 3 and 10 mg / kg / daily , s . c . ) of the cannabinoid receptor antagonists SR141716A ( P21554 ) or SR144528 ( CB2 ) . Implants were collected at days 7 and 14 for cytokines , hemoglobin , myeloperoxidase , and N - acetylglucosaminidase measurements , as indices of inflammation , angiogenesis , neutrophil and macrophage accumulation , respectively . Histological and morphometric analysis were also performed . RESULTS : Cannabinoid receptors expression in implants was detected from day 4 after implantation . Treatment with P21554 or CB2 receptor antagonists reduced cellular influx into sponges at days 7 and 14 after implantation , although P21554 receptor antagonist were more effective at blocking leukocyte accumulation . There was a reduction in P01375 - α , P15692 , P09341 / KC , P13500 / JE , and P10147 / MIP - 1α levels , with increase in P13501 / RANTES . Both treatments reduced neovascularization . Dual blockade of cannabinoid receptors resulted in maximum inhibition of inflammatory angiogenesis . CONCLUSIONS : Blockade of cannabinoid receptors reduced leukocyte accumulation , inflammation and neovascularization , suggesting an important role of endocannabinoids in sponge - induced inflammatory angiogenesis both via P21554 and CB2 receptors .", "P04150 signaling in a bronchial epithelial cell line . Glucocorticoids are an effective anti - inflammatory therapy for the treatment of asthma . The anti - inflammatory effects of glucocorticoids may be due to the inhibition of transcription factors that regulate cytokine synthesis . Because of the potential role of the bronchial epithelium in asthmatic inflammation and the possibility that this cell may be the main target of inhaled glucocorticoids , we have characterized glucocorticoid receptors ( GR ) and GR signaling in the human bronchial epithelial cell line BEAS - 2B . Western blot analysis and radioligand binding studies demonstrated that BEAS - 2B cells have functional GR that bind to dexamethasone ( DB00514 ) ( dissociation constant = 5 . 6 nM and maximal density of binding sites = 228 +/- 3 . 3 fmol / mg protein ) . GR were activated by DB00514 as assessed using a glucocorticoid - responsive reporter plasmid . Transfection of BEAS - 2B cells with an activator protein - 1 ( AP - 1 ) reporter construct followed by 12 - O - tetradecanoylphorbol - 13 - acetate ( TPA ) treatment resulted in a fivefold induction of reporter gene activity . Transfection with a nuclear factor ( NF ) - kappa B reporter construct followed by tumor necrosis factor - alpha ( P01375 ) treatment resulted in a 10 - fold induction of reporter gene activity . DB00514 ( 10 (- 7 ) M ) markedly repressed both the induced AP - 1 and NF - kappa B activity . The GR antagonist DB00834 inhibited the repressive effect of DB00514 on P01375 - induced NF - kappa B activity by 81 % but only counteracted the repressive effect of DB00514 on TPA - induced AP - 1 activity by 43 % . These studies demonstrate that cross - signaling between AP - 1 and NF - kappa B with GR may explain the anti - inflammatory properties of glucocorticoids in airway epithelial cells .", "Distribution patterns of cannabinoid P21554 receptors in the hippocampus of APPswe / PS1ΔE9 double transgenic mice . Cannabinoids have neuroprotective effects that are exerted primarily through cannabinoid P21554 receptors in the brain . This study characterized P21554 receptor distribution in the double transgenic ( dtg ) P05067 ( swe )/ P49768 ( ΔE9 ) mouse model for Alzheimer ' s disease . Immunohistochemical labeling of P21554 protein in non - transgenic mice revealed that P21554 was highly expressed in the hippocampus , with the greatest density of P21554 protein observed in the combined hippocampal subregions P00918 and P07451 ( P00918 / 3 ) . P21554 immunoreactivity in the P00915 and P00918 / 3 hippocampal regions was significantly decreased in the dtg P05067 ( swe )/ P49768 ( ΔE9 ) mice compared to non - transgenic littermates . Reduced P21554 expression in dtg P05067 ( swe )/ P49768 ( ΔE9 ) mice was associated with astroglial proliferation and elevated expression of the cytokines inducible nitric oxide synthase and tumor necrosis factor alpha . This finding suggests an anti - inflammatory effect of cannabinoids that is mediated by P21554 receptor , particularly in the P00918 / 3 region of the hippocampus . Furthermore , the study suggests a decreased P21554 receptor expression may result in diminished anti - inflammatory processes , exacerbating the neuropathology associated with Alzheimer ' s disease .", "P06401 activation of extranuclear signaling pathways in regulating p53 expression in vascular endothelial cells . We previously showed that progesterone ( P4 ) inhibited the proliferation of human umbilical vein endothelial cells ( HUVECs ) through a p53 - dependent pathway . Now we investigated further the molecular mechanism underlying the hormone activity . In cultured HUVECs , P4 increased the protein levels of phosphorylated Src ( p - Src ) , P04049 , and P29323 . The levels of p - Src and p - Src - progesterone receptor complex in HUVECs were increased by P4 treatment . These effects were blocked by pretreatment with a progesterone receptor antagonist , DB00834 . The P4 - induced increase in p53 transactivity was abolished by pretreatment with Src kinase inhibitors . Moreover , administration with cSrc antisense oligonucleotide prevented the P4 - induced increases of the levels of p53 mRNA and protein . These data suggest that P4 - induced up - regulation of p53 might be mediated through activation of cSrc . Pretreatment with Src kinase inhibitors also prevented P4 - induced membrane translocation of Kras and increases of the protein levels of phosphorylated Raf and phosphorylated P29323 . Transfection with dominant - negative P28482 prevented the P4 - induced increases of protein level and promoter activity of p53 and a decrease of thymidine incorporation . P4 also increased nuclear factor - κB ( NF - κB ) nuclear translocation and NF - κB binding onto the p53 promoter . These effects were abolished by pretreatment with P29323 inhibitors . The P4 - induced up - regulation of the p53 promoter activity was prevented by preadministration with dominant - negative P28482 or NF - κB inhibitors . Taken together , our data suggest that the cSrc / Kras / P04049 / P28482 / NF - κB signaling pathway contributes to the P4 - induced up - regulation of p53 in HUVECs . These findings highlight progesterone receptor activation of extranuclear signaling pathways in regulating p53 and cell cycle progression in HUVECs .", "Serotonin increases P27361 / 2 phosphorylation in astrocytes by stimulation of P41595 and P28335 receptors . We have previously shown that fluoxetine causes P29323 ( 1 / 2 ) phosphorylation in cultured mouse astrocytes mediated exclusively by stimulation of 5 - HT ( 2B ) receptors ( Li et al . , 2008b ) . This raises the question whether this is also the case for serotonin ( 5 - HT ) itself . In the present study serotonin was found to induce P29323 ( 1 / 2 ) phosphorylation by stimulation of 5 - HT ( 2B ) receptors with high affinity ( EC ( 50 ) : 20 - 30 pM ) , and by stimulation of 5 - HT ( 2C ) receptor with low affinity ( EC ( 50 ) : 1 microM or higher ) . P29323 ( 1 / 2 ) phosphorylation induced by stimulation of either 5 - HT ( 2B ) or 5 - HT ( 2C ) receptors was mediated by epidermal growth factor ( P01133 ) receptor transactivation ( Peng et al . , this issue ) , shown by the inhibitory effect of AG1478 , an inhibitor of the P01133 receptor tyrosine kinase , and DB02255 , an inhibitor of Zn - dependent metalloproteinases , and thus of 5 - HT ( 2B ) receptor - mediated P01133 receptor agonist release . It is discussed that the high potency of the 5 - HT ( 2B )- mediated effect is consistent with literature data for binding affinity of serotonin to cloned human 5 - HT ( 2B ) receptors and with observations of low extracellular concentrations of serotonin in brain , which would allow a demonstrated moderate and modality - dependent increase in specific brain areas to activate 5 - HT ( 2B ) receptors . In contrast the relevance of the observed 5 - HT ( 2C ) receptors on astrocytes is questioned .", "Protective effects of fermented ginseng on streptozotocin - induced pancreatic beta - cell damage through inhibition of NF - kappaB . ___MASK63___ ( Panax ginseng C . A . Meyer ) is widely used in Asian countries as a traditional medicine for the treatment of various diseases . It is known to have anti - inflammatory effects , although the mechanism is not clear . In this study , preventive effects of fermented ginseng ( FG ) against streptozotocin ( Q11206 ) - induced pancreatic beta - cell death was assessed in RINm5F insulinoma cells . FG markedly inhibited the production of nitrite in a dose - dependent manner . The decrease in nitrite production was found to correlate with reduced inducible nitric oxide ( P35228 ) protein and mRNA levels . To characterize the anti - inflammatory mechanism of FG at the transcriptional level , we examined effects of FG on the activity of nuclear factor - kappaB ( NF - kappaB ) . FG reduced a translocation of the NF - kappaB subunit and NF - kappaB - dependent transcriptional activity . FG blocked signaling upstream of NF - kappaB activation , such as degradation of inhibitor factor - kappaBalpha ( P25963 ) and phosphorylations of extracellular signal - regulated kinase ( P29323 ) and c - Jun NH2 - terminal kinase ( JNK ) . These results suggest that FG protects against Q11206 - induced pancreatic beta - cell damage by downregulation of P35228 , cyclooxygenase - 2 ( P35354 ) , and tumor necrosis factor - alpha ( P01375 ) gene expressions by blocking NF - kappaB and mitogen - activated protein kinase activities .", "Pharmacological treatment of alcohol dependence : target symptoms and target mechanisms . Alcoholism is a major public health problem and resembles , in many ways , other chronic relapsing medical conditions . At least 2 separate dimensions of its symptomatology offer targetable pathophysiological mechanisms . Systems that mediate positive reinforcement by alcohol are likely important targets in early stages of the disease , particularly in genetically susceptible individuals . In contrast , long term neuroadaptive changes caused by chronic alcohol use primarily appear to affect systems mediating negative affective states , and gain importance following a prolonged history of dependence . Feasibility of pharmacological treatment in alcoholism has been demonstrated by a first wave of drugs which consists of 3 currently approved medications , the aldehyde dehydrogenase blocker disulfiram , the opioid antagonist naltrexone ( NTX ) and the functional glutamate antagonist acamprosate ( ACM ) . The treatment toolkit is likely to be expanded in the near future . This will improve overall efficacy and allow individualized treatment , ultimately taking in account the patient ' s genetic makeup . In a second wave , early human efficacy data are available for the 5HT3 antagonist ondansetron , the GABA - B agonist baclofen and the anticonvulsant topiramate . The third wave is comprised of compounds predicted to be effective based on a battery of animal models . Using such models , a short list of additional targets has accumulated sufficient preclinical validation to merit clinical development . These include the cannabinoid P21554 receptor , receptors modulating glutamatergic transmission ( Q14416 , 3 and 5 ) , and receptors for stress - related neuropeptides corticotropin releasing factor ( CRF ) , neuropeptide Y ( P01303 ) and nociceptin . Once novel treatments are developed , the field faces a major challenge to assure their delivery to patients .", "Acute pharmacodynamic and antivascular effects of the vascular endothelial growth factor signaling inhibitor ___MASK73___ in Calu - 6 human lung tumor xenografts . The vascular endothelial growth factor - A ( P15692 ) signaling pathway , a key stimulant of solid tumor vascularization , is primarily dependent on the activation of the endothelial cell surface receptor P15692 receptor - 2 ( P35968 ) . ___MASK73___ is an oral , highly potent small - molecule inhibitor of VEGFR tyrosine kinase activity that inhibits angiogenesis and the growth of human tumor xenografts in vivo . Here , we show pharmacodynamic changes in P35968 phosphorylation induced by ___MASK73___ . In mouse lung tissue , a single dose of ___MASK73___ at 6 mg / kg inhibited P15692 - stimulated P35968 phosphorylation by 87 % at 2 h with significant inhibition ( > or = 60 % ) maintained to 24 h . To examine inhibition of P35968 phosphorylation in tumor vasculature by immunohistochemistry , a comprehensive assessment of antibodies to various phosphorylation sites on the receptor was undertaken . Antibodies to the phosphotyrosine epitopes pY1175 / 1173 and pY1214 / 1212 were found suitable for this application . Calu - 6 human lung tumor xenografts , from mice receiving ___MASK73___ or vehicle treatment ( p . o . , once daily ) , were examined by immunohistochemistry . A significant reduction in tumor vessel staining of phosphorylated P35968 ( pVEGFR - 2 ) was evident within 28 h of ___MASK73___ treatment ( 6 mg / kg ) . This effect preceded a significant reduction in tumor microvessel density , which was detectable following 52 h of ___MASK73___ treatment . These data show that ___MASK73___ is a potent inhibitor of P35968 activation in vivo and suggest that ___MASK73___ delivers therapeutic benefit in Calu - 6 tumors by targeting vessels dependent on P35968 signaling for survival . In addition , this work highlights the utility of measuring either pY1175 / 1173 or pY1214 / 1212 on P35968 as a pharmacodynamic marker of P35968 activation ." ]
[ "___MASK14___", "___MASK21___", "___MASK30___", "___MASK41___", "___MASK63___", "___MASK73___", "___MASK77___", "___MASK83___", "___MASK97___" ]
___MASK41___
MH_train_1615
interacts_with DB00864?
[ "beta - Carotene induces apoptosis and up - regulates peroxisome proliferator - activated receptor gamma expression and reactive oxygen species production in MCF - 7 cancer cells . Although the pharmacological role of beta - carotene in the prevention and treatment of many cancer cells has received increasing attention , the molecular mechanisms underlying such chemopreventive activity are not clear . Since peroxisome proliferator - activated receptor gamma ( P37231 ) has been implicated in regulating breast cancer cell differentiation and apoptosis , the effects of beta - carotene on the P37231 - mediated pathway and its association with reactive oxygen species production in MCF - 7 cells were investigated in the present study . The results demonstrated that beta - carotene significantly increased P37231 mRNA and protein levels in time - dependent manner . In addition , beta - carotene increased the cyclin - dependent kinase inhibitor P38936 ( P38936 / CIP1 ) expression and decreased the prostanoid synthesis rate - limiting enzyme cyclooxygenase - 2 expression . ___MASK23___ ( GW9662 ) , an irreversible P37231 antagonist , partly attenuated the cell death caused by beta - carotene . Further , reactive oxygen species ( ROS ) production was induced by beta - carotene , resulting in mitochondrial dysfunction and cytochrome C release . DB00143 ( DB00143 ) treatment decreases the intracellular ROS and prevents cytochrome C release and cell apoptosis induced by beta - carotene . In total , these observations suggest that the synergistic effect of P37231 expression and ROS production may account for beta - carotene - mediated anticancer activities .", "Effect of the administration of growth - hormone - producing lymphocytes on weight gain and immune function in dwarf mice . Our previous work has shown that cells of the immune system produce a growth hormone ( GH ) molecule similar to that secreted by the pituitary . In the present studies , we evaluated the possibility that normal spleen cells producing GH transferred to dwarf mice could stimulate their growth . The results showed that normal spleen cells alone or spleen cells treated with growth - hormone - releasing hormone ( P01286 ) did not appear to significantly stimulate the growth of dwarf mice . Spleen cells activated in vitro with concanavalin A or lipopolysaccharide and then transferred to dwarf mice , or thymus cells alone , were also without effect , whereas GH alone stimulated growth as expected . Serum levels of insulin - like growth factor - I ( P05019 ) and P05019 - liver RNA were undetectable in control dwarf mice and dwarf mice receiving spleen cells , whereas serum levels of P05019 increased after treatment of dwarf mice with GH . The immune system of dwarf mice receiving spleen cells , however , was significantly altered . Spleen cells from dwarf animals showed enhanced immunoglobulin , interleukin ( IL ) - 6 , P60568 , and interferon - gamma production whereas no significant change was apparent in natural killer cell activity . Despite the absence of the pit - 1 protein in dwarf mice , their spleen and thymus cells retained the ability to produce almost as much lymphocyte GH as normal . Overall , the findings support the idea that the pit - 1 protein in lymphocytes of dwarf mice may not be obligatory for the expression of lymphocyte GH . ( ABSTRACT TRUNCATED AT 250 WORDS )", "O75469 induces Q02318 and regulates cholesterol metabolism in the intestine . Mitochondrial sterol 27 - hydroxylase ( Q02318 ) catalyzes oxidative cleavage of the sterol side chain in the bile acid biosynthetic pathway in the liver and 27 - hydroxylation of cholesterol in most tissues . Recent studies suggest that 27 - hydroxycholesterol ( 27 - HOC ) activates liver orphan receptor alpha ( LXRalpha ) and induces the cholesterol efflux transporters O95477 and P45844 in macrophages . The steroid - and bile acid - activated pregnane X receptor ( O75469 ) plays critical roles in the detoxification of bile acids , cholesterol metabolites , and xenobiotics . The role of Q02318 in the intestine is not known . This study investigated O75469 and Q02318 regulation of cholesterol metabolism in the human intestinal cell lines Caco2 and Ls174T . A human O75469 ligand , rifampicin , induced Q02318 mRNA expression in intestine cells but not in liver cells . ___MASK54___ induced Q02318 gene transcription , increased intracellular 27 - HOC levels , and induced O95477 and P45844 mRNA expression only in intestine cells . A functional O75469 binding site was identified in the human Q02318 gene . Chromatin immunoprecipitation assays revealed that rifampicin induced the O75469 recruitment of steroid receptor coactivator 1 to Q02318 chromatin . DB04540 loading markedly increased intracellular 27 - HOC levels in intestine cells . ___MASK54___ , 27 - HOC , and a potent LXRalpha agonist , T0901317 , induced O95477 and P45844 protein expression and stimulated cholesterol efflux from intestine cells to apolipoprotein A - I and HDL . This study suggests an intestine - specific O75469 / Q02318 / LXRalpha pathway that regulates intestine cholesterol efflux and HDL assembly .", "Electron transfer is activated by calmodulin in the flavin domain of human neuronal nitric oxide synthase . The objective of this study was to clarify the mechanism of electron transfer in the human neuronal nitric oxide synthase ( P29475 ) flavin domain using the recombinant human P29475 flavin domains , the ___MASK93___ / NADPH domain ( contains ___MASK93___ - and NADPH - binding sites ) , and the ___MASK93___ / Q68DA7 domain ( the flavin domain including a calmodulin - binding site ) . The reduction by NADPH of the two domains was studied by rapid - mixing , stopped - flow spectroscopy . For the ___MASK93___ / NADPH domain , the results indicate that ___MASK93___ is reduced by NADPH to generate the two - electron - reduced form ( FADH ( 2 ) ) and the reoxidation of the reduced ___MASK93___ proceeds via a neutral ( blue ) semiquinone with molecular oxygen or ferricyanide , indicating that the reduced ___MASK93___ is oxidized in two successive one - electron steps . The neutral ( blue ) semiquinone form , as an intermediate in the air - oxidation , was unstable in the presence of O ( 2 ) . The purified ___MASK93___ / NADPH domain prepared under our experimental conditions was activated by NADP (+) but not NAD (+) . These results indicate that this domain exists in two states ; an active state and a resting state , and the enzyme in the resting state can be activated by NADP (+) . For the ___MASK93___ / Q68DA7 domain , the reduction of the ___MASK93___ - Q68DA7 pair of the oxidized enzyme with NADPH proceeded by both one - electron equivalent and two - electron equivalent mechanisms . The formation of semiquinones from the ___MASK93___ - Q68DA7 pair was greatly increased in the presence of Ca ( 2 +)/ P62158 . The air - stable semiquinone form , ___MASK93___ - FMNH (.) , was further rapidly reduced by NADPH with an increase at 520 nm , which is a characteristic peak of the ___MASK93___ semiquinone . Results presented here indicate that intramolecular one - electron transfer from ___MASK93___ to Q68DA7 is activated by the binding of Ca ( 2 +)/ P62158 .", "[ ___MASK43___ in amyotrophic lateral sclerosis . No indication for a positive effect ] . The anabolic effects of clenbuterol have been recognized for a long time . ___MASK43___ augments the expression of specific muscle proteins with a differential effect on type I and type II fibres . Furthermore , clenbuterol induces the synthesis of endogenous nerve growth factor ( P01138 ) and may itself be a myotrophic factor released by neuron endings . Side effects include tremor and headache and dose dependent abnormalities of laboratory values ( hypokalemia , hypoglycemia ) . After long - term medication increasing fatigue of muscles has been observed . Decreased expression of beta 2 - adrenergic receptors may limit the expected functional improvement . The efficacy of clenbuterol as symptomatic treatment of amyotrophic lateral sclerosis has not been proved . Controlled treatment trials are warranted to assess this question .", "PEGylation of growth hormone - releasing hormone ( P01286 ) analogues . Synthetically produced GRF1 - 29 ( ___MASK74___ ) has an amino acid composition identical to the N - terminal 29 amino acids sequence of the natural hypothalamic GHRH1 - 44 ( Figure 1 ) . It maintains bioactivity in vitro and is almost equally effective in eliciting secretion of endogenous growth hormone in vivo . The main drawbacks associated with the pharmaceutical use of hGRF1 - 29 relate to its short half - life in plasma , about 10 - 20 min in humans , which is caused mostly by renal ultrafiltration and enzymatic degradation at the N terminus . PEGylation has been considered as one valid approach to obtain more stable forms of the peptide , with a longer in vivo half - life and ultimately with increased pharmacodynamic response along the somatotropic axis ( endogenous GH , DB01277 levels ) . Different PEGylated P01286 conjugates were obtained and their bioactivity was tested in vitro and in vivo by monitoring endogenous growth hormone ( GH ) serum levels after intravenous ( i . v . ) injection in rats , and intravenous and subcutaneous ( s . c . ) injection in pigs . It was found that P01286 - PEG conjugates are able to bind and activate the human Q02643 , although with different potency . The effect of PEG molecular weight , number of PEG chains bound and position of PEGylation site on P01286 activity were investigated . Mono - PEGylated isomers with a PEG5000 polymer chain linked to Lys 12 or Lys 21 residues , showed high biological activity in vitro , which is similar to that of hGRF1 - 29 , and a higher pharmacodynamic response as compared to unmodified P01286 molecule .", "Comparison of effects of olmesartan and telmisartan on blood pressure and metabolic parameters in Japanese early - stage type - 2 diabetics with hypertension . P30556 blockers ( ARBs ) are regarded as first - line treatments for type - 2 diabetes with hypertension . Despite the availability of various types of ARBs , there are no comparative studies of their effects on patients with diabetes . In this open - label prospective crossover study , we compared the effects of olmesartan ( 20 mg / day ) and telmisartan ( 40 mg / day ) . Twenty Japanese early - stage type - 2 diabetes patients with hypertension treated with valsartan ( 80 mg / day ) for at least 8 weeks were recruited to this study . At study entry , valsartan was changed to olmesartan ( 20 mg / day ) or telmisartan ( 40 mg / day ) and administered for 8 weeks . The drugs were then switched and treatment was continued for another 8 weeks . We analyzed the blood pressure lowering effects of each drug by 24 - h ambulatory blood pressure monitoring at 0 , 8 , and 16 weeks . Simultaneously , we measured metabolic parameters and inflammation markers . ___MASK94___ lowered mean systolic and diastolic blood pressure more significantly than did telmisartan . While there were no differences between the groups in metabolic parameters , including HbA1c and adiponectin , the decreases in serum interleukin - 6 and highly sensitive P02741 were more significant by olmesartan treatment . Our results indicate that olmesartan has more potent arterial blood pressure lowering and anti - inflammatory effects than telmisartan .", "The specific Q14318 inhibitor N -( N ', N '- dimethylcarboxamidomethyl ) cycloheximide has potent neuroprotective and neurotrophic properties in brain ischemia . FK506 and FK506 - derived inhibitors of the FK506 - binding protein ( FKBP ) - type peptidylprolyl cis / trans - isomerases ( PPIase ) display potent neuroprotective and neuroregenerative properties in various neurodegeneration models , showing the importance of neuroimmunophilins as targets for the treatment of acute and chronic neurodegenerative diseases . However , the PPIase activity targeted by active site - directed ligands remains unknown so far . Here we show that neurotrophic FKBP ligands , such as GPI1046 and N -[ methyl ( ethoxycarbonyl )] cycloheximide , inhibit the calmodulin / Ca ( 2 +) ( P62158 / Ca ( 2 +) ) - regulated Q14318 with up to 80 - fold higher affinity than P62942 . In contrast , the non - neurotrophic rapamycin inhibits Q14318 . P62158 / Ca ( 2 +) 500 - fold less affine than other neuroimmunophillins . In the context of the high expression of Q14318 in neuroblastoma cells , these data suggest that Q14318 . P62158 / Ca ( 2 +) inhibition can mediate neurotrophic properties of FKBP ligands . The Q14318 - specific cycloheximide derivative , N -( N ', N '- dimethylcarboxamidomethyl ) cycloheximide ( DM - CHX ) was synthesized and used in a rat model of transient focal cerebral ischemia . Accordingly , DM - CHX caused neuronal protection as well as neural stem cell proliferation and neuronal differentiation at a dosage of 27 . 2 mug / kg . These effects were still dominant , if DM - CHX was applied 2 - 6 h post - insult . In parallel , sustained motor behavior deficits of diseased animals were improved by drug administration , revealing a potential therapeutic relevance . Thus , our results demonstrate that Q14318 inhibition by DM - CHX regulates neuronal cell death and proliferation , providing a promising strategy for the treatment of acute and / or chronic neurodegenerative diseases .", "Polymorphism identification in the P11310 , P01008 , P22301 , P15173 and P01222 genes of cattle .", "Measurement of UVB - Induced DNA damage and its consequences in models of immunosuppression . Exposure to UVB results in formation of cyclobutane pyrimidine dimers ( CPDs ) and 6 - 4 photoproducts in DNA . These can be quantified by a variety of techniques including alkaline gel electrophoresis , ELISAs , Southwestern blotting , and immunohistochemistry . Damage to DNA results in activation of damage response pathways , as indicated by Western blotting using antibodies specific for p53 and breast cancer - associated gene 1 ( P38398 ) phosphorylation . The signal from DNA damage to activation of these response pathways appears to be mediated by P62942 - rapamycin - associated protein ( P42345 ) , since these phosphorylation events are blocked by rapamycin . UVB - induced DNA damage also leads to induction of immunosuppressive cytokines including tumor necrosis factor alpha ( P01375 ) and interleukin ( IL ) - 10 in skin . Induction of P01375 by UVB is readily detectable in cultured normal human epidermal keratinocytes ( NHEKs ) using ELISA , while induction of P22301 is readily detectable in cultured mouse keratinocytes but not in NHEKs . Induction of DNA damage by liposome - encapsulated HindIII results in induction of immunosuppressive responses similar to UVB . Clinical testing shows that liposome - encapsulated ___MASK14___ endonuclease V or photolyase stimulates repair of CPDs in the skin of human subjects , and prevents UVB - induced immunosuppression . Stimulation of repair and prevention of immunosuppression have been linked to prevention of skin cancer by liposome - encapsulated ___MASK14___ endonuclease V in repair - deficient xeroderma pigmentosum patients .", "Changes of thyroid hormone levels and related gene expression in zebrafish on early life stage exposure to triadimefon . In this study , zebrafish was exposed to triadimefon . Thyroid hormones levels and the expression of related genes in the hypothalamic - pituitary - thyroid ( Q9HD23 ) axis , including thyroid - stimulating hormone ( P01222 ) , deiodinases ( dio1 and dio2 ) and the thyroid hormone receptor ( thraa and thrb ) were evaluated . After triadimefon exposure , increased ___MASK14___ can be explained by increased thyroid - stimulating hormone ( P01222 ) . The conversion of ___MASK14___ to DB00279 ( deiodinase type I - dio1 ) was decreased , which reduced the DB00279 level . P10828 ( thrb ) mRNA levels were significantly down - regulated , possibly as a response to the decreased DB00279 levels . The overall results indicated that triadimefon exposure could alter gene expression in the Q9HD23 axis and that mechanisms of disruption of thyroid status by triadimefon could occur at several steps in the synthesis , regulation , and action of thyroid hormones .", "P62942 , the 12 - kDa FK506 - binding protein , is a physiologic regulator of the cell cycle . P62942 , the 12 - kDa FK506 - binding protein , is a ubiquitous abundant protein that acts as a receptor for the immunosuppressant drug FK506 , binds tightly to intracellular calcium release channels and to the transforming growth factor beta ( TGF - beta ) type I receptor . We now demonstrate that cells from P62942 - deficient ( P62942 (-/-) ) mice manifest cell cycle arrest in G ( 1 ) phase and that these cells can be rescued by P62942 transfection . This arrest is mediated by marked augmentation of P38936 ( P38936 / CIP1 ) levels , which can not be further augmented by TGF - beta1 . The P38936 up - regulation and cell cycle arrest derive from the overactivity of TGF - beta receptor signaling , which is normally inhibited by P62942 . Cell cycle arrest is prevented by transfection with a dominant - negative TGF - beta receptor construct . TGF - beta receptor signaling to gene expression can be mediated by SMAD , p38 , and P29323 / Q96HU1 kinase ( extracellular signal - regulated kinase / mitogen - activated protein kinase ) pathways . SMAD signaling is down - regulated in P62942 (-/-) cells . Inhibition of P29323 / Q96HU1 kinase fails to affect P38936 up - regulation . By contrast , activated phosphorylated p38 is markedly augmented in P62942 (-/-) cells and the P38936 up - regulation is prevented by an inhibitor of p38 . Thus , P62942 is a physiologic regulator of cell cycle acting by normally down - regulating TGF - beta receptor signaling .", "Human epidermal Langerhans ' cells are targets for the immunosuppressive macrolide tacrolimus ( FK506 ) . BACKGROUND : The immunosuppressive macrolide tacrolimus ( FK506 ) has been shown to inhibit allergic contact dermatitis in animal models as well as in human beings . More recently , successful treatment of atopic dermatitis with an ointment containing tacrolimus has been reported . OBJECTIVES : We explored the effects of this compound on epidermal Langerhans ' cells ( LCs ) , which are known to play an important pathophysiologic role in inflammatory skin diseases . METHODS : The expression of the intracellular FK506 binding protein ( P62942 ) was monitored on freshly isolated and cultured epidermal LCs . Phenotyping and functional exploration of LCs treated with different concentrations of tacrolimus and beta - methasone valerate ( betaMv ) were performed . RESULTS : P62942 is expressed in freshly isolated LCs but is lost while they are maturating into mature dendritic cells . DB00864 inhibited the expression of IL - 2R ( CD25 ) and of the costimulatory molecules P33681 ( P33681 . 1 ) and P25942 . Expression of MHC class I and II was also affected , whereas P42081 ( P33681 . 2 ) expression was not altered . In contrast , betaMv strongly increased the expression of CD25 . Paradoxically , while decreasing P25942 and MHC class I expression , betaMv significantly increased the expression of MHC class II , P33681 , and P42081 on cultured LCs but impaired their allostimulatory activity . DB00864 was about 100 times more potent than betaMv at inhibiting LC stimulatory function . CONCLUSION : DB00864 can exert immunopharmacologic alterations on LCs , which may account , at least in part , for the therapeutic effect of this compound in eczematous skin diseases .", "Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . DB00864 ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .", "Q9Y271 is involved in N - methyl - D - aspartate - mediated neuronal injury in mice . AIM : To determine whether cysteinyl leukotriene receptor 1 ( CysLT1 receptor ) is involved in N - methyl - D - aspartate ( DB01221 ) - induced excitotoxic injury in the mouse brain . METHODS : Brain injury was induced by DB01221 microinjection ( 50 - 150 nmol in 0 . 5 microL ) into the cerebral cortex . The changes in CysLT1 receptor expression 24 h after DB01221 injection and the effects of a CysLT1 receptor antagonist , pranlukast ( 0 . 01 and 0 . 1 mg / kg ) , an DB01221 receptor antagonist , ketamine ( 30 mg / kg ) , and an antioxidant , edaravone ( 9 mg / kg ) were observed . RESULTS : In the DB01221 - injured brain , the CysLT1 receptor mRNA , and protein expression were upregulated , and the receptor was mainly localized in the neurons and not in the astrocytes . ___MASK21___ , ketamine and edaravone decreased DB01221 - induced injury ; pranlukast ( 0 . 1 mg / kg ) and ketamine inhibited the upregulated expression of the CysLT1 receptor . CONCLUSION : CysLT1 receptor expression in neurons is upregulated after DB01221 injection , and DB01221 - induced responses are inhibited by CysLT1 receptor antagonists , indicating that the increased CysLT1 receptor is involved in DB01221 excitotoxicity .", "Modeling and synthesis of non - cyclic derivatives of P06744 - 1046 as potential FKBP ligands with neurotrophic properties . Prompted by the therapeutic potential of the neuroimmunophilin FK506 - binding protein ( FKBP ) ligand , P06744 - 1046 , in the treatment of nerve injuries and neurodegenerative diseases , a novel series of non - cyclic derivatives of P06744 - 1046 were designed and synthesized . Computer modeling analysis revealed that these relatively linear derivatives could energy - favorably bind to P62942 with an analogous binding mode to P06744 - 1046 . The neurotrophic activity of the target compounds was assessed in chick dorsal root ganglion ( Q86YR7 ) cultures . As a result , 6 out of 11 test compounds at either or both concentrations of 1 pM and 100 pM significantly promoted neurite outgrowth in DRGs in the presence of 0 . 15 ng / ml nerve growth factor ( P01138 ) . Compound 5c at 100 pM exhibited the greatest neurotrophic effect in promoting both the number and length of neurite processes . However , in the absence of exogenously added P01138 , all test compounds , including P06744 - 1046 , failed to afford any positive effect on DRGs . This study suggests the intriguing potential of these compounds for further investigation .", "___MASK97___ produces intestinal but not gastric damage in the presence of a low dose of indomethacin in rats . Indomethacin in small doses is known to inhibit prostaglandin ( PG ) production , yet it does not damage the gastrointestinal mucosa . We examined whether a cyclooxygenase ( P36551 ) - 2 inhibitor induces gastrointestinal damage in the presence of a low dose of indomethacin and investigated the ulcerogenic mechanism in relation to P35354 expression . Rats with or without 18 - h fasting were administered rofecoxib ( a selective P35354 inhibitor ; 10 or 30 mg / kg p . o . ) in the absence or presence of indomethacin ( 3 mg / kg p . o . ) , and the gastric or intestinal mucosa was examined 8 and 24 h later , respectively . Neither indomethacin nor rofecoxib alone caused damage in the stomach or small intestine . However , indomethacin damaged the small intestine in the presence of rofecoxib , yet the same treatment did not damage the stomach . Indomethacin reduced the mucosal DB00917 content in both tissues , whereas rofecoxib did not . The P35354 mRNA was up - regulated in the intestine but not the stomach after indomethacin treatment , and the reduced DB00917 content was significantly recovered later only in the small intestine , in a rofecoxib - inhibitable manner . Indomethacin produced hypermotility in the small intestine but not the stomach , whereas rofecoxib had no effect . These results suggest that the PG deficiency caused by a low dose of indomethacin produces hypermotility and P35354 expression in the small intestine but not the stomach , resulting in damage when P35354 is inhibited . It is assumed that the hypermotility response is a key event in the expression of P35354 and thereby important in the development of mucosal damage in the gastrointestinal tract .", "Interaction of tacrolimus ( FK506 ) and its metabolites with FKBP and calcineurin . DB00864 ( FK506 ) is a strong immuno - suppressant and shows its activity through inhibiting P60568 mRNA transcription by forming pentameric complex with intracellular receptor ( FK506 binding protein 12 kDa or P62942 ) , Ca2 + , calmodulin , and calcineurin . Here , we report the binding activity to P62942 , the pentameric complex formation and Con - A response inhibiting activities of 7 metabolites . C15 - demethylated metabolite ( M - 3 ) needed higher quantity to compete in Con - A assay and in pentamer formation assay , although it binds more strongly to P62942 . The result suggests that the ability to form a pentameric complex is not a two step reaction with the first binding to P62942 , but a single step reaction by components for the pentamer formation .", "P02647 inhibits P25942 proinflammatory signaling via DB00171 - binding cassette transporter A1 - mediated modulation of lipid raft in macrophages . AIM : P02647 ( apoA - I ) , the major component of high - density lipoprotein ( HDL ) , has been recently found to suppress inflammation . This study was to investigate the effects and potential mechanisms of apoA - I on the P25942 / P29965 ( P29965 ) proinflammatory signaling pathway . METHODS : Human THP - 1 macrophage - derived foam cells were treated with sCD40L alone or in the presence of apoA - I . Secretion of proinflammatory cytokines was performed by enzyme - linked immunosorbent assay ( ELISA ) . The proteins and mRNA expression were examined by western - blot and real - time PCR analysis , respectly . DB04540 efflux was assessed by liquid scintillation counting . DB04540 depletion of macrophages was performed with methylated β - cyclodextrin . RESULTS : P02647 inhibits the inflammatory response stimulated by soluble P29965 ( sCD40L ) in macrophages . In addition , apoA - I inhibited the sCD40L - stimulated activation of nuclear factor - kB ( NF - kB ) . The apoA - I - induced NF - kB deactivation was related to the decreased recruitment of tumor necrosis factor receptor - associated factor 6 ( TRAF - 6 ) , a crucial adapter protein for P25942 in macrophages , to lipid rafts after being treated by sCD40L . When interfering the expression of DB00171 - binding cassette transporter A1 ( O95477 ) , a major cholesterol transporter for apoA - I in macrophages , it could significantly diminish the effect of apoA - I on the sCD40L - stimulated inflammatory response . CONCLUSION : P02647 suppresses P25942 proinflammatory signaling in macrophages by preventing TRAF - 6 translocation to lipid rafts through O95477 - dependent regulation of free cholesterol ( FC ) efflux , which may present a novel mechanism of apoA - I - mediated inflammation inhibition in macrophages .", "___MASK21___ inhibits renal epithelial cyst progression via activation of AMP - activated protein kinase . Q9Y271 ( CysLT1 receptor ) antagonists were found to inhibit chloride secretion in human airway epithelial cells . Since chloride secretion in renal epithelial cells , which shares common mechanisms with airway epithelial cells , plays important roles in renal cyst progression in polycystic kidney disease ( Q15139 ) , this study was aimed to investigate effects of drugs acting as CysLT1 receptor antagonists on renal cyst progression and its underlying mechanisms . Effects of CysLT1 receptor antagonists on renal cyst growth and formation were determined using Madine Darby canine kidney ( MDCK ) cyst models . Mechanisms of actions of CysLT1 receptor antagonists were determined using short - circuit current measurement , assays of cell viability and cell proliferation , and immunoblot analysis of signaling proteins . Of the three drugs acting as CysLT1 receptor antagonists ( montelukast , pranlukast and zafirlukast ) tested , pranlukast was the most promising drug that inhibited MDCK cyst growth and formation without affecting cell viability . Its effect was independent of the inhibition of CysLT1 receptors . Instead , it reduced DB02527 - activated chloride secretion and proliferation of MDCK cells in an AMP - activated protein kinase ( AMPK ) - dependent manner and had no effect on P13569 protein expression . Interestingly , pranlukast enhanced AMPK activation via calcium / calmodulin - dependent protein kinase kinase beta ( CaMKKβ ) with consequent activation of acetyl - DB01992 carboxylase ( ACC ) and suppression of mammalian target of rapamycin ( P42345 ) pathway . These results indicate that pranlukast retards renal epithelial cyst progression by inhibiting DB02527 - activated chloride secretion and cell proliferation via CaMKKβ - AMPK - P42345 pathway . Therefore , pranlukast represents a class of known drugs that may have potential utility in Q15139 treatment .", "Genomic profiling of 766 cancer - related genes in archived esophageal normal and carcinoma tissues . We employed the BeadArraytrade mark technology to perform a genetic analysis in 33 formalin - fixed , paraffin - embedded ( FFPE ) human esophageal carcinomas , mostly squamous - cell - carcinoma ( ESCC ) , and their adjacent normal tissues . A total of 1 , 432 single nucleotide polymorphisms ( SNPs ) derived from 766 cancer - related genes were genotyped with partially degraded genomic DNAs isolated from these samples . This directly targeted genomic profiling identified not only previously reported somatic gene amplifications ( e . g . , P24385 ) and deletions ( e . g . , CDKN2A and P42772 ) but also novel genomic aberrations . Among these novel targets , the most frequently deleted genomic regions were chromosome 3p ( including tumor suppressor genes Q9BXW9 and P35222 ) and chromosome 5 ( including tumor suppressor gene P25054 ) . The most frequently amplified genomic region was chromosome 3q ( containing Q92997 , P58340 , O15440 , P41182 , P30556 and known oncogenes Q07912 , P50591 , P61328 ) . The chromosome 3p deletion and 3q amplification occurred coincidently in nearly all of the affected cases , suggesting a molecular mechanism for the generation of somatic chromosomal aberrations . We also detected significant differences in germline allele frequency between the esophageal cohort of our study and normal control samples from the International HapMap Project for 10 genes ( P09603 , Q5TCX8 , P60568 , P54278 , Q92985 , P36888 , Q16620 , P80192 , P04626 and P10644 ) , suggesting that they might play roles in esophageal cancer susceptibility and / or development . Taken together , our results demonstrated the utility of the BeadArray technology for high - throughput genetic analysis in FFPE tumor tissues and provided a detailed genetic profiling of cancer - related genes in human esophageal cancer .", "Heart allograft protection with low - dose carbon monoxide inhalation : effects on inflammatory mediators and alloreactive T - cell responses . BACKGROUND : DB11588 ( CO ) , a byproduct of heme catalysis , has lately received considerable attention as a regulatory molecule in cellular and biological processes . CO has been shown to provide potent protection against a variety of tissue injuries . We hypothesized in this study that low concentration CO would be beneficial for organ allografts , which frequently undergo several types of injury such as ischemia / reperfusion , alloimmune reaction , and inflammation METHODS : The efficacy of low - dose CO was examined in a fully allogeneic LEW to BN rat heterotopic heart transplantation ( HHTx ) model . Recipients were kept in air or exposed to low - dose CO ( 20 ppm ) for 14 , 28 , or 100 days after HHTx under short - course tacrolimus RESULTS : CO treatment ( d0 - 28 , 0 - 100 ) was remarkably effective in prolonging heart allograft survival to a median of > 100 from 45 days in the air - control group , with significant reductions of arteritis , fibrosis , and cellular infiltration , including macrophages and T cells . CO inhibited intragraft upregulation of Th1 type cytokines ( P60568 , IFNgamma ) , proinflammatory mediators ( IL - 1beta , TNFalpha , P05231 , P35354 ) , and adhesion molecule . Shorter CO exposure in early ( 0 - 13d ) and late ( 14 - 28d ) posttransplant periods also prolonged graft survival , with a significant inhibition of inflammatory mediators CONCLUSIONS : These results show that low dose CO inhalation protects heart allografts and can considerably prolong their survival . CO appears to function via multiple mechanisms , including direct inhibition of Th1 type cytokine production and regulation of inflammatory responses .", "Cloning of a novel phosphatidylinositol kinase - related kinase : characterization of the human Q96Q15 RNA surveillance protein . We have cloned and characterized a new member of the phosphatidylinositol kinase ( PIK ) - related kinase family . This gene , which we term human Q96Q15 ( Q96Q15 ) , is orthologous to Caenorhabditis elegans Q96Q15 , a protein that functions in nonsense - mediated mRNA decay ( Q53H76 ). cDNA sequencing revealed that Q96Q15 encodes a protein of 3031 amino acids containing a conserved kinase domain , a C - terminal domain unique to the PIK - related kinases and an P62942 - rapamycin binding - like domain similar to that found in the PIK - related kinase P42345 . Immunopurified FLAG - tagged Q96Q15 exhibits protein kinase activity as measured by autophosphorylation and phosphorylation of the generic PIK - related kinase substrate PHAS - 1 . Q96Q15 kinase activity is inhibited by high nanomolar concentrations of wortmannin ( IC ( 50 ) = 105 nm ) but is not inhibited by a P62942 - rapamycin complex . Mutation of conserved residues within the kinase domain of Q96Q15 abolishes both autophosphorylation and substrate phosphorylation , demonstrating that Q96Q15 exhibits intrinsic protein kinase activity . Q96Q15 phosphorylates purified Q92900 protein , a phosphoprotein that plays a critical role in Q53H76 , at sites that are also phosphorylated in whole cells . Based on these data , we conclude that Q96Q15 is the human orthologue to C . elegans Q96Q15 . Our data indicate that Q96Q15 may function in Q53H76 by directly phosphorylating Q92900 protein at physiologically relevant sites ." ]
[ "___MASK14___", "___MASK21___", "___MASK23___", "___MASK43___", "___MASK54___", "___MASK74___", "___MASK93___", "___MASK94___", "___MASK97___" ]
___MASK54___
MH_train_1616
interacts_with DB00215?
[ "Whole blood lead concentration and erythrocyte delta - aminolevulinic acid dehydratase ( P13716 ) activity in selected canine populations in Greece . In a total number of 275 dogs of various ages , sex and breed , blood lead concentrations ( O43927 ) and erythrocyte P13716 activity were measured . Sixty - six of the dogs were living in lead mining areas ( Group A ) , 157 in urban areas ( Group B ) and 52 in rural areas ( Group C ) of Greece . Mean O43927 differed significantly ( P < 0 . 05 ) between locations and were 326 , 97 and 68 micrograms / L , respectively . Mean P13716 activity was significantly different ( P < 0 . 05 ) only between Groups A and B as between groups A and C . A significant ( P < 0 . 05 ) negative correlation existed between O43927 and P13716 activity . A normal range of erythrocyte P13716 activity of 807 - 992 mumol / ___MASK58___ / LRBC / h was established for dogs . None of the 33 Group A dogs and 2 of the Group B dogs that had a O43927 of 350 micrograms / L presented clinical signs indicating acute or chronic lead intoxication . No erythrocyte basophilic stippling or large number of nucleated red blood cells were seen in the 30 dogs of Group A with O43927 > 350 micrograms / L .", "Aberrant B1 cell trafficking in a murine model for lupus . O43927 ( O43927 / O43927 ) is ectopically and highly expressed in the target organs such as the thymus and kidney in aged ( NZB x NZW ) F1 ( BWF1 ) mice , a murine model for SLE . Ectopic expression of O43927 / O43927 was attributed to mature myeloid DCs infiltrating in the target organs . DCs were also increased in the peripheral blood in aged BWF1 mice and differentiated into O43927 / O43927 - producing DCs in the presence of P01375 or IL - 1beta , but not IFN - alpha or P01579 . O43927 / O43927 expression in mature myeloid DCs was confirmed in bone marrow derived - DCs generated in vitro in the presence of GM - P04141 and P01375 . B1 cells expressed higher level of P32302 and migrated towards O43927 / O43927 much better than B2 cells . B1 cells failed to home to the peritoneal cavity and preferentially recruited to the target organs in aged BWF1 mice developing lupus nephritis . B1 , but not B2 cells possessed a potent antigen presenting activity in allo - P08235 and activated autologous thymic P01730 T cells in the presence of P60568 . P32302 + P01730 T cells were also increased in aged BWF1 mice and they enhanced IgG production by B1 cells in vitro . These results suggest a possible involvement of aberrant B1 cell trafficking in activation of autoreactive P01730 T cells and autoantibody production in the target organs during the development of lupus , providing a new insight for the pathogenesis of B1 cells in lupus .", "Expression of dihydrofolate reductase and multidrug resistance genes in trimetrexate - resistant human leukemia cell lines . Exposure of Q14C87 - 3 human leukemic cells in culture to a lipophilic antifolate , trimetrexate ( ___MASK91___ ) , resulted in the development of sublines resistant to antifolates as well as to drugs related to multidrug resistance . The ___MASK91___ - resistant sublines had an increase in dihydrofolate reductase ( P00374 ) activity and overexpression of P - glycoprotein . In these sublines , neither the P00374 gene nor the P08183 gene were amplified . In these cells , P00374 transcripts were also not overexpressed but P00374 protein was increased , indicative of translational or post - translational control of P00374 activity . In contrast , P08183 transcripts were found to be overexpressed , in parallel with P - glycoprotein production . Therefore , increases in P - glycoprotein appear controlled at the transcriptional level . These data support evidence that ___MASK91___ produced two phenotypic changes independently : the former probably from folate deficiency and the latter from the lipophilic nature of the compound .", "Inhibition of human brain and RBC acetylcholinesterase ( P22303 ) by heptylphysostigmine ( HPTL ) . Heptylphysostigmine ( HPTL ) , a derivative of the P22303 inhibitor physostigmine ( PHY ) , is under investigation as a therapeutic agent in Alzheimer ' s disease . HPTL is active against human RBC P22303 both in vitro and in vivo . Activity of HPTL against human brain has not been documented . We have developed an in vitro assay system using particulate membrane fractions which permits comparison of inhibition and recovery kinetics of human RBC ( primarily globular dimer ) and brain ( primarily globular tetramer ) membrane - bound forms . Under these conditions the HPTLIC50 is similar for the two forms . RBC P22303 inhibition spontaneously reverses in 24 h , as occurs in vivo . In striking contrast , activity of inhibited brain enzyme does not recover on overnight incubation . DDVP - induced inhibition , but not HPTL inhibition , can be reversed by the oxime ___MASK6___ . Some recovery of HPTL inhibition , but not to the level seen with RBC P22303 , occurs on addition of heat - stable fractions from serum or P04141 . Brain enzyme recovers rapidly from PHY in this system . Responses of brain and RBC P22303 to HPTL indicate that these forms are functionally as well as structurally distinct . Since brain inhibition apparently does not spontaneously reverse like RBC inhibition , peripheral measurements of patient responses should be assessed with caution during treatment with HPTL .", "Dietary L - carnitine supplementation increases lipid deposition in the liver and muscle of yellow catfish ( Pelteobagrus fulvidraco ) through changes in lipid metabolism . ___MASK77___ has been reported to improve growth performance and reduce body lipid content in fish . Thus , we hypothesised that carnitine supplementation can improve growth performance and reduce lipid content in the liver and muscle of yellow catfish ( Pelteobagrus fulvidraco ) , a commonly cultured freshwater fish in inland China , and tested this hypothesis in the present study . Diets containing l - carnitine at three different concentrations of 47 mg / kg ( control , without extra carnitine addition ) , 331 mg / kg ( low carnitine ) and 3495 mg / kg ( high carnitine ) diet were fed to yellow catfish for 8 weeks . The low - carnitine diet significantly improved weight gain ( WG ) and reduced the feed conversion ratio ( FCR ) . In contrast , the high - carnitine diet did not affect WG and FCR . Compared with the control diet , the low - carnitine and high - carnitine diets increased lipid and carnitine contents in the liver and muscle . The increased lipid content in the liver could be attributed to the up - regulation of the mRNA levels of SREBP , PPARγ , fatty acid synthase ( FAS ) and ACCa and the increased activities of lipogenic enzymes ( such as FAS , glucose - 6 - phosphate dehydrogenase , 6 - phosphogluconate dehydrogenase and malic enzyme ) and to the down - regulation of the mRNA levels of the lipolytic gene P50416 . The increased lipid content in muscle could be attributed to the down - regulation of the mRNA levels of the lipolytic genes P50416 and Q96AD5 and the increased activity of lipoprotein lipase . In conclusion , in contrast to our hypothesis , dietary carnitine supplementation increased body lipid content in yellow catfish .", "Myelopoietic efficacy of orlistat in murine hosts bearing T cell lymphoma : implication in macrophage differentiation and activation . DB01083 , an inhibitor of fatty acid synthase ( P49327 ) , acts as an antitumor agent by blocking de novo fatty acid synthesis of tumor cells . Although , myelopoiesis also depends on de novo fatty acid synthesis , the effect of orlistat on differentiation of macrophages , which play a central role in host ' s antitumor defence , remains unexplored in a tumor - bearing host . Therefore , the present investigation was undertaken to examine the effect of orlistat administration on macrophage differentiation in a T cell lymphoma bearing host . Administration of orlistat ( 240 mg / kg / day / mice ) to tumor - bearing mice resulted in a decline of tumor load accompanied by an augmentation of bone marrow cellularity and survival of bone marrow cells ( BMC ) . The expression of apoptosis regulatory caspase - 3 , Bax and Bcl2 was modulated in the BMC of orlistat - administered tumor - bearing mice . DB01083 administration also resulted in an increase in serum level of IFN - γ along with decreased TGF - β and P22301 . BMC of orlistat - administered tumor - bearing mice showed augmented differentiation into macrophages accompanied by enhanced expression of macrophage colony stimulating factor ( P09603 ) and its receptor ( M - CSFR ) . The macrophages differentiated from BMC of orlistat - administered mice showed characteristic features of M1 macrophage phenotype confirmed by expression of CD11c , TLR - 2 , generation of reactive oxygen species , phagocytosis , tumor cell cytotoxicity , production of IL - 1 , P01375 - α and nitric oxide . These novel findings indicate that orlistat could be useful to support myelopoesis in a tumor - bearing host .", "JAK - P35610 and JAK - PI3K - mTORC1 pathways regulate telomerase transcriptionally and posttranslationally in ATL cells . Adult T - cell leukemia ( ATL ) is a heterogeneous tumor that is resistant to chemotherapy . Telomerase activity plays a critical role in tumorigenesis and is associated with the prognosis of ATL patients . Interleukin ( IL ) - 2 commonly promotes tumor growth in chronic ATL cells . The signaling pathways involved in P60568 - regulated telomerase activation were studied in ATL cells derived from chronic ATL patients . P60568 challenge enhanced tyrosine phosphorylation of Janus - activated kinase ( JAK ) 1 - 3 and P42229 , and induced P23458 and O60674 to associate with P42229 in P60568 - dependent ATL cells . Chromatin immunoprecipitation assays revealed that P42229 directly bound to the human telomerase reverse transcriptase ( hTERT ) promoter . P42229 short interfering RNA inhibited hTERT transcription in P60568 - stimulated ATL cells . Inhibitors of PI3K , HSP90 , and P42345 reduced P60568 - induced hTERT mRNA , protein expression , and telomerase activity . AKT , HSP90 , P42345 , S6 kinase , and hTERT immunoprecipitate from P60568 - stimulated cells contained telomerase activity , suggesting that hTERT directly interacts with , and is regulated by , these proteins . Binding of the p85 regulatory subunit of PI3K to O60674 was enhanced in an P60568 - dependent manner , indicating that O60674 propagates activation signals from the P60568 receptor and links hTERT activation to both the P42229 and PI3K pathways . Finally , P60568 - induced activation of telomerase and P42229 was observed in primary leukemic cells . These results indicate that P60568 stimulation induces hTERT activation through the JAK / P35610 pathway and the JAK / PI3K / AKT / HSP90 / mTORC1 pathway in P60568 - responsive ATL cells . These signaling proteins represent novel and promising molecular therapeutic targets for P60568 - dependent ATL .", "Increased P09601 levels ameliorate fatty liver development through a reduction of heme and recruitment of Q9NSA1 . OBJECTIVE : Obese leptin deficient ( ob / ob ) mice are a model of adiposity that displays increased levels of fat , glucose , and liver lipids . Our hypothesis is that P09601 overexpression ameliorates fatty liver development . METHODS : Obese mice were administered cobalt protoporphyrin ( CoPP ) and stannic mesoporphyrin ( ___MASK65___ ) for 6 weeks . Heme , P09601 , HO activity , PGC1α , Q9NSA1 , glycogen content , and lipogenesis were assessed . RESULTS : CoPP administration increased hepatic P09601 protein levels and HO activity , decreased hepatic heme , body weight gain , glucose levels , and resulted in decreased steatosis . Increased levels of P09601 produced a decrease in lipid droplet size , P49327 ( FAS ) levels involving recruitment of Q9NSA1 , PPARα , and Glut 1 . These beneficial effects were reversed by inhibition of HO activity . CONCLUSION : Increased levels of P09601 and HO activity reduced the levels of obesity by reducing hepatic heme and lipid accumulation . These changes were manifested by decreases in cellular heme , increases in Q9NSA1 , glycogen content , and fatty liver . The beneficial effect of P09601 induction results from an increase in PPARα and Q9NSA1 levels and a decrease in PGC1α , levels they were reversed by ___MASK65___ . Low levels of P09601 and HO activity are responsible for fatty liver .", "___MASK73___ - triggered Lipoxin A4 attenuates mechanical allodynia in association with inhibiting spinal O60674 / P40763 signaling in neuropathic pain in rats . ___MASK73___ - triggered Lipoxin A4 ( ATL ) , as a Lipoxin A4 ( LXA4 ) epimer , is endogenously produced by aspirin - acetylated cycloxygenase - 2 ( P35354 ) and plays a vital role in endogenous anti - inflammation via the P25090 ( Q96JZ2 ) . Recent investigations have indicated that spinal neuroinflammation and the activation of the Janus Kinase 2 ( O60674 ) / Signal Transducers and Transcription Activators 3 ( P40763 ) signaling pathway are involved in neuropathic pain states . However , the effect of ATL on neuroinflammation and O60674 / P40763 signaling in chronic constriction injury ( CCI ) - induced neuropathic pain in rats has not been well - studied . The present study demonstrated the anti - inflammatory and analgesic effect of ATL on neuropathic pain and assessed the role of spinal O60674 / P40763 signaling on the effect of ATL . Intrathecal administration of ATL significantly attenuated mechanical allodynia via spinal Q96JZ2 and inhibited the upregulation of pro - inflammatory cytokines ( IL - 1β , P05231 , and P01375 - α ) on day 7 of CCI surgery . In addition , ATL markedly suppressed the upregulation of p - P40763 induced by the neuropathic pain . Blockade of O60674 - P40763 signaling with intrathecal administration of the O60674 inhibitor AG490 or the P40763 inhibitor S3I - 201 clearly reduced mechanical allodynia and the upregulation of pro - inflammatory cytokines in CCI rats . Interestingly , inhibition of O60674 / P40763 signaling via ATL or the specific signaling inhibitor ( AG49 , S3I - 201 ) further promoted the increased expression of suppressor of cytokine signaling 3 ( O14543 ) mRNA in the spinal cord induced by CCI surgery . Taken together , our results suggested that the analgesic effect of ATL was mediated by inhibiting spinal O60674 / P40763 signaling and hence the spinal neuroinflammation in CCI rats .", "P00505 from rat heart is phosphorylated on Tyr19 in response to insulin stimulation . The cytosolic fatty acid - binding protein from rat heart ( P05413 , M ( r ) 15 , 000 ) as well as FABP from mouse adipocytes ( P15090 , 62 % homologous with P05413 ) contain a recognition sequence for protein tyrosine kinases , DB00174 - DB00120 - ___MASK4___ - ___MASK4___ - Tyr19 . P15090 has been shown by others to be partly phosphorylated on Tyr19 , thus encouraging experiments designed to search for phosphotyrosine in P05413 . For this purpose isolated cardiac myocytes were incubated with [ 32P ] orthophosphate and analyzed by two - dimensional gel electrophoresis . A 15 kDa phosphoprotein present in the cytosolic protein fraction was specifically precipitated by a polyclonal antibody against rat heart FABP . Characterization of the phosphorylated FABP was facilitated by the development of an immunoaffinity purification procedure capable of isolating more than 200 micrograms FABP from four rat hearts in one step . Phosphoamino acid analysis and radiosequencing of the major tryptic phosphopeptide from immunopurified FABP revealed Tyr19 as the phosphorylated amino acid . Stimulation of cardiac myocytes with insulin in the presence of tyrosine phosphatase inhibitors led to a several - fold increase in the amount of phosphorylated FABP compared with a nearly undetectable level found without insulin stimulation , indicating that FABP may be a substrate for the insulin receptor tyrosine kinase . Phosphorylated FABP constitutes only a minor fraction compared to the large pool of FABP in the cardiac myocyte , thus obscuring the significance of this modification . However , as the phosphorylated Tyr19 residue is positioned within a helix - turn - helix - related domain of FABP , this modification may modulate a hitherto unknown DNA binding activity of FABP . A hypothesis is discussed in which phosphorylated FABP serves as a signalling molecule in the insulin signal transduction cascade .", "Endotoxin induced hyperlactatemia and hypoglycemia is linked to decreased mitochondrial phosphoenolpyruvate carboxykinase . AIMS : ___MASK38___ carboxykinase ( PEPCK ) is the rate limiting enzyme for gluconeogenesis , and plays a key role in recycling lactate for glucose production . It is synthesized as two separate isoforms ; cytosolic ( P35558 , gene code ; P35558 ) and mitochondrial ( Q16822 , gene code ; Q16822 ) . Previous studies of gluconeogenesis in endotoxemia have focused solely on P35558 . We investigated the relative roles of the two isoforms in hepatic and renal gluconeogenesis in a rat model of endotoxic shock , and in cultured hepatocytes . MAIN METHODS : Rats were administered lipopolysaccharide ( 6 mg / kg ; LPS ) for 6 h . Cultured cells were incubated with lactate ( 5 mM ) with or without tumor necrosis factor alpha ( 1 - 10 ng / ml ) . Rat liver and kidney samples as well as cultured cells were subjected to subcellular fractionation to produce mitochondrial and cytosolic fractions for PEPCK activity assay . P35558 and Q16822 mRNA levels were measured using quantitative RT - PCR . KEY FINDINGS : In rat endotoxemia , hepatic Q16822 mRNA and Q16822 enzyme activity decreased by 53 % and 38 % , compared to sham controls . Hepatic P35558 mRNA levels increased by 44 % , but P35558 enzyme activity remained unchanged . The changes in hepatic Q16822 coincided with a marked hypoglycemia and hyperlactatemia as well as elevated plasma interleukin 1 beta ( IL1beta ) . Incubation of cultured hepatocytes with P01375 inhibited lactate - induced increases in glucose production , Q16822 mRNA levels and Q16822 enzyme activity but had no effect on P35558 mRNA levels or P35558 activity . SIGNIFICANCE : These results indicate that decreases in hepatic Q16822 play a key role in the manifestation of hyperlactatemia and hypoglycemia in endotoxemia .", "Preventive effects of chitosan coacervate whey protein on body composition and immunometabolic aspect in obese mice . Functional foods containing bioactive compounds of whey may play an important role in prevention and treatment of obesity . The aim of this study was to investigate the prospects of the biotechnological process of coacervation of whey proteins ( CWP ) in chitosan and test its antiobesogenic potential . METHODS : CWP ( 100 mg · kg · day ) was administered in mice with diet - induced obesity for 8 weeks . The animals were divided into four groups : control normocaloric diet gavage with water ( C ) or coacervate ( C - CWP ) , and high fat diet gavage with water ( HF ) or coacervate ( HF - CWP ) . RESULTS : HF - CWP reduced weight gain and serum lipid fractions and displayed reduced adiposity and insulin . Q15848 was significantly higher in HF - CWP group when compared to the HF . The level of LPS in HF - W group was significantly higher when compared to HF - CWP . The P22301 showed an inverse correlation between the levels of insulin and glucose in the mesenteric adipose tissue in the HF - CWP group . CWP promoted an increase in both phosphorylation AMPK and the amount of Q96AD5 in the mesenteric adipose tissue in HF - CWP group . CONCLUSION : CWP was able to modulate effects , possibly due to its high biological value of proteins . We observed a protective effect against obesity and improved the inflammatory milieu of white adipose tissue .", "Characterization of the activity of the PI3K / P42345 inhibitor ___MASK100___ ( SAR245409 ) in tumor models with diverse genetic alterations affecting the PI3K pathway . Activation of the PI3K ( phosphoinositide 3 - kinase ) pathway is a frequent occurrence in human tumors and is thought to promote growth , survival , and resistance to diverse therapies . Here , we report pharmacologic characterization of the pyridopyrimidinone derivative ___MASK100___ ( SAR245409 ) , a potent and highly selective pan inhibitor of class I PI3Ks ( α , β , γ , and δ ) with activity against P42345 . Broad kinase selectivity profiling of > 130 protein kinases revealed that ___MASK100___ is highly selective for class I PI3Ks and P42345 over other kinases . In cellular assays , ___MASK100___ inhibits the formation of PIP ( 3 ) in the membrane , and inhibits phosphorylation of AKT , p70S6K , and S6 phosphorylation in multiple tumor cell lines with different genetic alterations affecting the PI3K pathway . In a panel of tumor cell lines , ___MASK100___ inhibits proliferation with a wide range of potencies , with evidence of an impact of genotype on sensitivity . In mouse xenograft models , oral administration of ___MASK100___ results in dose - dependent inhibition of phosphorylation of AKT , p70S6K , and S6 with a duration of action of approximately 24 hours . Repeat dose administration of ___MASK100___ results in significant tumor growth inhibition in multiple human xenograft models in nude mice that is associated with antiproliferative , antiangiogenic , and proapoptotic effects .", "Modulation of the P22301 / IL - 12 cytokine circuit by interferon - beta inhibits the development of epitope spreading and disease progression in murine autoimmune encephalomyelitis . IFN - beta has been shown to be effective in the treatment of multiple sclerosis ( MS ) . However , the primary mechanism by which IFN - beta mediates its therapeutic effect remains unclear . Recent studies indicate that under defined conditions , IFN - beta may downregulate DC expression of IL - 12 . We and others have shown that IFN - beta may also downregulate P22301 . In light of the recently proposed paradigm that an P22301 / IL - 12 immunoregulatory circuit controls susceptibility to autoimmune disease , we examined the effect of IFN - beta on the development and behavior of the autoreactive T cell repertoire during experimental autoimmune encephalomyelitis ( EAE ) , an animal model sharing many features with MS . SWXJ mice were immunized with the immunodominant p139 - 151 determinant of myelin proteolipid protein ( PLP ) , and at onset of EAE were treated every other day with IFN - beta . After eight weeks of treatment , we assessed autoreactivity and observed no significant IFN - beta effect on splenocyte proliferation or splenocyte production of P01579 , P60568 , P05112 , or P05113 in response to the priming determinant used to initiate disease . However , in IFN - beta treated mice , the cytokine profile in response to the priming immunogen was significantly skewed toward an increased production of P22301 and a concurrent decreased production of IL - 12 . Moreover , the in vivo modulation of the P22301 / IL - 12 immunoregulatory circuit in response to the priming immunogen was accompanied by an aborted development of epitope spreading . Our results indicate that IFN - beta induces a reciprocal modulation of the P22301 / IL - 12 cytokine circuit in vivo . This skewed autoreactivity establishes an inflammatory microenvironment that effectively prevents endogenous self - priming thereby inhibiting the progression of disease associated with epitope spreading .", "AACR - 91st meeting . Dendritic cell vaccine strategies . Inevitably , the sessions on dendritic cells at the AACR Annual Meeting were some of the most consistently well attended . Interest has been intense for several years , largely since the technical obstacles to the routine culture of these cells and their precursors , both from animal and human sources , were removed in the early 1990s . Several important advances were presented towards further optimizing dendritic cell - based immunotherapy in general . Groups reported on improved culture conditions , as well as more efficient means of obtaining larger quantities of dendritic cells or their precursors . As expected , there were several strong reports on the beneficial bioactivity of cytokines , such as IL - 12 , GM - P04141 , and P60568 . In addition , enticing work continues with Flt3 - ligand and has begun with progenipoietin , a more recently identified hematopoietic growth factor . As shown in this year ' s sessions , the clinical promise of tumor lysate and apoptotic bodies continues to move steadily from the bench to the clinic . Finally , although dendritic cells are excellent antigen - presenters , work to determine if they could be engineered to be even more effective continues . As a result , several reports were given on gene - modifying this type of immune cell .", "Aerosol vaccination with AERAS - 402 elicits robust cellular immune responses in the lungs of rhesus macaques but fails to protect against high - dose Mycobacterium tuberculosis challenge . Development of a vaccine against pulmonary tuberculosis may require immunization strategies that induce a high frequency of Ag - specific P01730 and CD8 T cells in the lung . The nonhuman primate model is essential for testing such approaches because it has predictive value for how vaccines elicit responses in humans . In this study , we used an aerosol vaccination strategy to administer AERAS - 402 , a replication - defective recombinant adenovirus ( rAd ) type 35 expressing Mycobacterium tuberculosis Ags Ag85A , Ag85B , and TB10 . 4 , in bacillus Calmette - Guérin ( BCG ) - primed or unprimed rhesus macaques . Immunization with BCG generated low purified protein derivative - specific P01730 T cell responses in blood and bronchoalveolar lavage . In contrast , aerosolized AERAS - 402 alone or following BCG induced potent and stable Ag85A / b - specific P01730 and CD8 effector T cells in bronchoalveolar lavage that largely produced IFN - γ , as well as P01375 and P60568 . Such responses induced by BCG , AERAS - 402 , or both failed to confer overall protection following challenge with 275 CFUs M . tuberculosis Erdman , although vaccine - induced responses associated with reduced pathology were observed in some animals . Anamnestic T cell responses to Ag85A / b were not detected in blood of immunized animals after challenge . Overall , our data suggest that a high M . tuberculosis challenge dose may be a critical factor in limiting vaccine efficacy in this model . However , the ability of aerosol rAd immunization to generate potent cellular immunity in the lung suggests that using different or more immunogens , alternative rAd serotypes with enhanced immunogenicity , and a physiological challenge dose may achieve protection against M . tuberculosis .", "Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . DB00215 at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .", "Enhanced expression of adipocyte - type fatty acid binding protein in murine lymphocytes in response to dexamethasone treatment . Fatty acids have a great influence on the process of lymphocyte apoptosis which is considered as a modulating factor of immune response in both humans and animals . However the mechanism underlying the function of fatty acids in the process of lymphocyte apoptosis is not fully understood . In this study we show that the appearance of adipocyte - type fatty acid binding protein ( P15090 ) is induced upon administration of dexamethasone ( DEX ) in both in vivo and cultured lymphocytes , and its distinct nuclear localization occurs in close relation to the DEX - induced apoptosis process . In immunohistochemistry of mouse spleen , P15090 - immunoreactivity starts to occur 3 h after DEX stimulation , and it massively localizes in the nucleus 8 h after the treatment , while no P15090 - immunoreactivity is discerned in the lymphocytes of normal as well as 24 h post - injection spleen . In the murine T - cell leukemia CTLL - 2 cells , P15090 - immunoreactivity is also induced in both of the cytoplasm and nucleus when the apoptosis is induced by P60568 retrieval together with DEX treatment , while in the presence of P60568 P15090 - immunoreactivity is confined to the cytoplasm with DEX treatment . On the other hand , P15090 - immunoreactivity is not detected by P60568 retrieval alone . The present findings altogether suggest that P15090 and its ligands , fatty acids , play an important role in the process of apoptosis and the immune modulation induced by DEX .", "Activated lymphoid cells in human gliomas : morphofunctional and cytochemical evidence . To study defensive infiltrating cells , smear preparation from 20 fresh gliomas and autologous normal peritumoural brain tissue , used as control , were analysed . May - Grünwald Giemsa staining and cytochemical reaction markers of cellular functions [ acid phosphatase ( AP ) , dihydrofolate reductase ( P00374 ) , dipeptidilpeptidase ( DAP IV ) and serine esterase Q15722 - dependent ( SE ) ] , were employed to characterize the cells . The extent of the leukocytic infiltration and the percentage of activated lymphocytes ( \" hand mirror \" shape lymphocytes : DB00253 ; lymphocytes binding tumor : LBT ) were also studied . In addition serum levels of T cell growth factor interleukin - 2 ( P60568 ) and of the soluble P60568 receptor ( sIL - 2R ) were determined in the affected patients . In tumoural imprints , mostly in astrocytomas , we observed an increased percentage of P00374 and DAP IV positive lymphocytes , of DB00253 lymphocytes and of lymphocytes binding tumoral cells . Serum levels of P60568 were significantly increased in all patients whilst sIL - 2R levels , were high only in glioblastoma . These findings indicate that in malignant gliomas there is stimulation of the immune system as witnessed by the presence of activated cells inside tumor tissue and soluble activating factors in serum ." ]
[ "___MASK100___", "___MASK38___", "___MASK4___", "___MASK58___", "___MASK65___", "___MASK6___", "___MASK73___", "___MASK77___", "___MASK91___" ]
___MASK73___
MH_train_1617
interacts_with DB01211?
[ "DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .", "P62158 activation and calcium regulation of parotid gland adenylate cyclase . The effect of Ca2 + on the adenylate cyclase activity associated with membranes prepared from mouse parotid gland has been examined . Ca2 + stimulated then inhibited adenylate cyclase activity , with values for half - maximal stimulation and inhibition of 0 . 6 and 10 microM , respectively . Maximal activation ( 1 . 4 - fold ) was observed at 2 microM free Ca2 + . These membranes contained 1 . 2 microgram calmodulin / mg protein . Exogenous calmodulin ( 0 . P35326 . 2 microgram ) activated , in a concentration - dependent manner , adenylate cyclase activity , with maximal activation being 2 . 5 - fold at 12 micrograms calmodulin . Preparation of membranes in 2 mM ethyleneglycol - bis ( beta - aminoethylether )- N , N , N ', N '- tetraacet ic acid ( EGTA ) resulted not only in a significant decrease in calmodulin levels ( 0 . 5 microgram calmodulin / mg protein ) but also in a loss of the ability of Ca2 + to stimulate the enzyme . Exogenous calmodulin restored the ability of Ca2 + to stimulate the adenylate cyclase activity associated with EGTA - treated membranes . Trifluoperazine ( 50 microM ) blocked the ability of Ca2 + to activate adenylate cyclase activity in control membranes . The effect of trifluoperazine could be reversed by exogenous calmodulin ( 0 . 5 or 5 . 0 micrograms ) . These data indicate that calmodulin mediates the activation of parotid gland adenylate cyclase by Ca2 + and that Ca2 + , at concentrations which stimulate and inhibit amylase secretion , can activate and inhibit adenylate cyclase activity .", "Suppression of tumor growth and metastasis by a P17948 antagonizing peptide identified from a phage display library . Although the P15692 - Flk - 1 - pathway has been known as the major driving force of angiogenesis , new evidence has shown that P17948 / Flt - 1 plays important roles during the neovascularization under pathological conditions including tumor , atherosclerosis and arthritis . In search of Flt - 1 receptor antagonizing peptides , we screened a phage display 12 - mer - peptide library with recombinant Flt - 1 protein . Seven candidate peptides were identified that specifically bound to P15692 receptor Flt - 1 , of which peptide F56 ( WHSDMEWWYLLG ) almost abolished P15692 binding to receptor Flt - 1 in vitro . In vivo , F56 fused with P00374 ( P00374 - F56 ) inhibited angiogenesis in a P62158 assay . Moreover , P00374 - F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC - 803 in BALB / c nude mice . Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with P00374 - F56 . In the severe combined immunodeficiency disease ( SCID ) mouse model for studying metastasis of the human breast cancer cell line BICR - H1 , synthetic peptide F56 significantly inhibited tumor growth and lung metastases . Taken together , our results have demonstrated that peptide F56 , as a Flt - 1 receptor antagonist , fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between P15692 and receptor Flt - 1 . Thus , short peptide F56 may have clinical potential in tumor therapy .", "P62937 is an inflammatory mediator that promotes atherosclerosis in apolipoprotein E - deficient mice . P62937 ( CyPA ; encoded by Ppia ) is a ubiquitously expressed protein secreted in response to inflammatory stimuli . CyPA stimulates vascular smooth muscle cell migration and proliferation , endothelial cell adhesion molecule expression , and inflammatory cell chemotaxis . Given these activities , we hypothesized that CyPA would promote atherosclerosis . P02649 - deficient ( Apoe (-/-) ) mice fed a high - cholesterol diet for 16 wk developed more severe atherosclerosis compared with Apoe (-/-) Ppia (-/-) mice . Moreover , CyPA deficiency was associated with decreased low - density lipoprotein uptake , P19320 ( vascular cell adhesion molecule 1 ) expression , apoptosis , and increased P29474 ( endothelial nitric oxide synthase ) expression . To understand the vascular role of CyPA in atherosclerosis development , bone marrow ( BM ) cell transplantation was performed . Atherosclerosis was greater in Apoe (-/-) mice compared with Apoe (-/-) Ppia (-/-) mice after reconstitution with CyPA (+/+) BM cells , indicating that vascular - derived CyPA plays a crucial role in the progression of atherosclerosis . These data define a role for CyPA in atherosclerosis and suggest CyPA as a target for cardiovascular therapies .", "___MASK84___ in lung cancer . DB00158 is essential for proliferating cells and folate transport pathways and folate - dependent metabolic processes show promise as targets for anti - neoplastic therapy . DB00158 receptor α ( P15328 ) , a folate transporter , is an attractive target for anti - neoplastic therapy due to its high affinity for folate , restricted range of expression in normal tissue and differential over - expression in malignant tissue . P15328 is expressed in non - small cell lung cancer , with a higher expression in adenocarcinoma compared with squamous cell carcinoma . ___MASK84___ is a monoclonal antibody targeting P15328 which in pre - clinical studies led to cytotoxicity of P15328 - expressing cells , inhibited tumor growth in animal models and showed limited reactivity with normal tissue . In phase I / II trials , farletuzumab was well tolerated as a single - agent and in combination , without additive toxicity with chemotherapy . An ongoing phase II , double blind , placebo - controlled study is evaluating farletuzumab in patients with P15328 expressing metastatic adenocarcinoma of lung .", "Type I collagen induces expression of bone morphogenetic protein receptor type II . The extracellular matrix regulates many fundamental cellular processes such as proliferation , migration , and differentiation . Among the Q13201 components , type I collagen induces endothelial tube formation in vitro . By analysing genes participating in this event , the bone morphogenetic protein receptor - II ( Q13873 ) was detected to be upregulated in cells cultured on or within fibrillar type I collagen . Furthermore , the basement membrane type IV collagen or amorphous type I collagen did not show an induction of Q13873 . Addition of the Q13873 specific ligands , P12643 and P12644 , in the culture medium of the endothelial cells seeded on type I collagen increased [ ( 3 ) H ] - thymidine incorporation into cellular DNA , indicating that endothelial cells were able to form a functional receptor . In addition , in the chick chorioallantoic membrane ( P62158 ) , an in vivo angiogenesis model , Q13873 and BMPR - I were upregulated in the growing phase and ceased in the mature P62158 .", "Nitrergic response to cyclophosphamide treatment in blood and bone marrow . Daily intraperitoneal injection of cyclophosphamide ( P15085 ) ( 50 mgkg (- 1 ) of body weight ) for 5 days resulted in reduced levels of marrow and blood cellularity , which was most pronounced in 18 days post - treatment ( pt ) . On day 18 after P15085 treatment the enhancedlevels of nitric oxide ( NO ) precursors and metabolites ( L - arginine , L - citrulline , reactive nitrogen species ( RNS ) ) of marrow and blood cells ( platelet , neutrophil , lymphocyte and monocyte ) resulted from up - regulation of Ca ( II )/ calmodulin ( P62158 )- independent \" inducible \" NO synthase ( P35228 ) , with a lessercontribution of Ca ( II )/ P62158 - dependent \" constitutive \" P29474 isoforms to systemic NO . Biphasic response to P15085 of marrow nitrergic system , i . e . both P35228 and P29474 showed significantly depressed activities , as well as diminished levels of NO metabolites on day 9 pt , suggested that signals in addition to NO might be involved in P15085 - induced inhibition of hematopoesis , while a gradual increase of neutrophil and platelet NOS activity appeared to be contributed to a P15085 - induced development of granulopenia , thrombocytopenia and hemorrhage .", "[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . DB01211 ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .", "The thioredoxin reductase inhibitor auranofin triggers apoptosis through a Bax / Bak - dependent process that involves peroxiredoxin 3 oxidation . P30044 ( TrxR ) is a key selenoprotein antioxidant enzyme and a potential target for anti - cancer drugs . One potent inhibitor of TrxR is the gold ( I ) compound auranofin , which can trigger mitochondrial - dependent apoptosis pathways . The exact mechanism of apoptosis induction by auranofin is not yet clear , but there are indications that mitochondrial oxidative stress is a central event . We assessed the redox state of the peroxiredoxins ( Prxs ) in Jurkat T - lymphoma cells treated with auranofin , and found that mitochondrial Prx3 was considerably more sensitive to oxidation than the cytosolic Prx1 and 2 , indicating selective mitochondrial stress . Prx3 oxidation was detected at apoptotic doses of auranofin in several cell types , and occurred before other mitochondrial events including cytochrome c release and mitochondrial depolarisation . ___MASK43___ was also able to sensitise U937 cells to P01375 - mediated apoptosis . ___MASK43___ - induced apoptosis was effectively blocked by the overexpression of Bcl - 2 , and Bax / Bak deficient mouse embryonic fibroblasts were also resistant to apoptosis , indicating a central role for the pro - apoptotic proteins of this family in auranofin - triggered apoptosis . ___MASK43___ exposure inhibited the proliferation of apoptosis - resistant cells , and at higher doses of auranofin could cause cell death through necrosis . We conclude that auranofin induces apoptosis in cells through a Bax / Bak - dependent mechanism associated with selective disruption of mitochondrial redox homeostasis in conjunction with oxidation of Prx3 .", "Identification of aurora kinase A as an unfavorable prognostic factor and potential treatment target for metastatic gastrointestinal stromal tumors . Although imatinib mesylate ( IM ) has revolutionized the management of gastrointestinal stromal tumors ( GISTs ) , drug resistance remains a challenge . Previous studies have shown that the expression of aurora kinase A ( O14965 ) predicts recurrence in patients with primary , surgically resected GISTs . The current study aimed to evaluate the significance of O14965 expression as an unfavorable prognostic marker for advanced GISTs , and provide evidence that O14965 could be a potential therapeutic target in GISTs . The prognostic significance of the expression of O14965 , along with other clinicopathological factors , was analyzed in a cohort of 99 IM - treated patients with advanced GISTs . The potential use of an inhibitor of O14965 as a therapeutic agent against GISTs was also tested in GIST cell lines . Among 99 enrolled patients , poor performance status , large tumor size , drug response , and O14965 overexpression were independent prognostic factors for poor progression - free survival ( PFS ) . For overall survival ( OS ) , only large tumor size and O14965 overexpression were identified as independent unfavorable factors . In an in vitro study , ___MASK93___ , an O14965 inhibitor , inhibited growth of both IM - sensitive and IM - resistant GIST cells in a concentration - dependent manner , and exhibited synergistic cytotoxicity with IM in GIST cells . The inhibitory effect of ___MASK93___ in GIST cells could be attributed to the induction of G2 / M arrest , apoptosis , and senescence . Our study shows that O14965 expression independently predicted poor PFS and OS in patients with advanced GISTs who were treated with IM . An O14965 inhibitor may have potential as a therapeutic agent for both IM - sensitive and IM - resistant GISTs .", "Effects of phenacetin and its metabolite p - phenetidine on P23219 and P35354 activities and expression in vitro . The present study was aimed to test the possible cyclooxygenase ( P36551 ) - 1 / P35354 selectivity of the old analgesic drug phenacetin and its metabolite p - phenetidine , which exhibits high renal toxicity . DB00316 ( acetaminophen ) , the main metabolite of phenacetin with low renal toxicity , and indomethacin were selected as reference compounds . Collagen - stimulated platelet thromboxane B2 ( TxB2 ) production and phorbol 12 - myristate - 13 - acetate ( PMA ) - induced neutrophil prostaglandin E2 ( DB00917 ) synthesis were used as indicators for P23219 and P35354 activity , respectively . ___MASK3___ was even less potent than paracetamol to reduce the production of both TxB2 and DB00917 , and no clear preference for either of the P36551 - enzymes was seen . P - phenetidine was a more potent inhibitor , already at nanomolar level , of the synthesis of these prostanoids than indomethacin and showed some preference to P35354 inhibition . Somewhat higher , micromolar , concentrations of p - phenetidine also reduced P35354 expression in neutrophils . We suggest that the very potent inhibitory activity of p - phenetidine on DB00917 synthesis combined with the reduction of P35354 expression could explain the renal papillary necrosis in phenacetin kidney .", "Anti - inflammatory activity of Taraxacum officinale . Taraxacum officinale has been widely used as a folkloric medicine for the treatment of diverse diseases . The dried plant was extracted with 70 % ethanol to generate its ethanol extract ( TEE ) . For some experiments , ethyl acetate ( EA ) , n - butanol ( BuOH ) and aqueous ( Aq ) fractions were prepared in succession from TEE . TEE showed a scavenging activity in the 1 , 1 - diphenyl - 2 - picrylhydrazyl ( DPPH ) assay , a diminishing effect on intracellular reactive oxygen species ( ROS ) level , and an anti - angiogenic activity in the chicken chorioallantoic ( P62158 ) assay . In the carrageenan - induced air pouch model , TEE inhibited production of exudate , and significantly diminished nitric oxide ( NO ) and leukocyte levels in the exudate . It also possessed an inhibitory effect on acetic acid - induced vascular permeability and caused a dose - dependent inhibition on acetic acid - induced abdominal writhing in mice . Suppressive effects of TEE on the production of NO and expression of inducible nitric oxide synthase ( P35228 ) and cyclooxygenase - 2 ( P35354 ) in lipopolysaccharide ( LPS ) - stimulated macrophages were also assessed . Among the fractions , the n - butanol fraction ( BuOH ) was identified to be most effective in the P62158 assay . Collectively , Taraxacum officinale contains anti - angiogenic , anti - inflammatory and anti - nociceptive activities through its inhibition of NO production and P35354 expression and / or its antioxidative activity .", "Genetic polymorphism and activities of human lung alcohol and aldehyde dehydrogenases : implications for ethanol metabolism and cytotoxicity . DB00898 dehydrogenase ( DB00067 ) and aldehyde dehydrogenase ( ALDH ) exhibit genetic polymorphism and tissue specificity . DB00067 and ALDH isozyme phenotypes from 39 surgical Chinese lung specimens were identified by agarose isoelectric focusing . The identity of the lung beta - ADHs was further demonstrated by their characteristic pH - activity profiles for ethanol oxidation , Km values for NAD and ethanol , and inhibition by ___MASK15___ or 1 , 10 - phenanthroline . The beta 2 allele , coding for beta 2 polypeptide , was found to be predominant in the lung specimens studied . The DB00067 activities in the lungs with the homozygous phenotype P00325 2 - 2 ( exhibiting beta 2 beta 2 ) and P00325 1 - 1 ( exhibiting beta 1 beta 1 ) and the heterozygous phenotype P00325 P35326 ( exhibiting beta 2 beta 2 , beta 2 beta 1 , and beta 1 beta 1 ) were determined to be 999 +/- 77 , 48 +/- 17 , and 494 +/- 61 nmol / min / g tissue , respectively . Fifty - one percent of the specimens studied lacked the P05091 activity band on the isoelectric focusing gels . The activities in the lung tissues with the P05091 - active phenotype and the inactive phenotype were determined to be 30 +/- 3 and 17 +/- 1 nmol / min / g tissue , respectively . These findings indicate that human pulmonary ethanol - metabolizing activities differ significantly with respect to genetic polymorphism at both the P00325 and the P05091 loci . The results suggest that individuals with high Vmax beta 2 - DB00067 and deficient in low - Km mitochondrial P05091 , accounting for approximately 45 % of the Chinese population , may end up with acetaldehyde accumulation during alcohol consumption , rendering them vulnerable to tissue injury caused by this highly reactive and toxic metabolite .", "Characterization of the inhibitory effects of erythromycin and clarithromycin on the Q12809 potassium channel . Both erythromycin and clarithromycin have been reported to cause QT prolongation and the cardiac arrhythmia torsade de pointes in humans , however direct evidence documenting that these drugs produce this effect by blocking human cardiac ion channels is lacking . The goal of this study was to test the hypothesis that these macrolide antibiotics significantly block the delayed rectifier current ( IKr ) encoded by Q12809 ( the human ether - a - go - go - related gene ) at drug concentrations , temperature and ionic conditions mimicking those occurring in human subjects . DB01345 currents in P29320 293 cells stably transfected with Q12809 were recorded using a whole cell voltage clamp method . Exposure of cells to erythromycin reduced the Q12809 encoded potassium current in a concentration dependent manner with an IC50 of 38 . 9 +/- 1 . 2 microM and Hill Slope factor of 0 . 4 +/- 0 . 1 . DB01211 produced a similar concentration - dependent block with an IC50 of 45 . 7 +/- 1 . 1 microM and Hill Slope factor of 1 . 0 +/- 0 . 1 . Erythromycin ( 25 - 250 microM ) and clarithromycin ( 5 or 25 microM ) also produced a significant decrease in the integral of the current evoked by an action potential shaped voltage clamp protocol . The results of this study document that both erythromycin and clarithromycin significantly inhibit the Q12809 potassium current at clinically relevant concentrations .", "Distinct functional roles of subunits within the heteromeric kainate receptor . Kainate receptors ( KARs ) have been implicated in a number of neurological disorders , including epilepsy . KARs are tetrameric , composed of a combination of P39086 - Q16478 subunits . We examined the contribution of Q13002 and Q16478 subunits to activation and desensitization of the heteromeric receptor . Heteromeric Q13002 / P13647 receptors expressed in P29320 - 293T cells showed markedly higher glutamate sensitivity than Q13002 homomers and did not desensitize at low glutamate concentrations . Mutation of residue E738 in Q13002 substantially lowered its glutamate sensitivity . However , heteromeric KARs containing this mutant Q13002 [ Q13002 ( E738D ) ] assembled with wild - type Q16478 showed no change in glutamate EC ( 50 ) compared with wild - type heteromeric KARs . Instead , higher concentrations of glutamate were required to produce desensitization . This suggested that , within the heteromeric receptor , glutamate binding to the high - affinity Q16478 subunit alone was sufficient for channel activation but not desensitization , whereas agonist binding to the low - affinity Q13002 subunit was not necessary to open the channel but instead caused the channel to enter a closed , desensitized state . To test this hypothesis in wild - type receptors , we used the competitive antagonist kynurenate , which has higher affinity for the Q13002 than the Q16478 subunit . Coapplication of kynurenate with glutamate to heteromeric receptors reduced the onset of desensitization without affecting the peak current response , consistent with our hypothesis . Our results suggest that Q13002 and Q16478 subunits can be individually activated within the heteromeric receptor and that these subunits serve dramatically different functional roles .", "P08235 antagonizes Dot1a - Af9 complex to increase αENaC transcription . ___MASK28___ is a major regulator of Na (+) absorption and acts by activating the mineralocorticoid receptor ( MR ) to stimulate the epithelial Na (+) channel ( ENaC ) . MR (-/-) mice exhibited pseudohypoaldosteronism type 1 ( hyponatremia , hyperkalemia , salt wasting , and high levels of aldosterone ) and died around postnatal day 10 . However , if and how MR regulates ENaC transcription remain incompletely understood . Our earlier work demonstrated that aldosterone activates αENaC transcription by reducing expression of Dot1a and Af9 and by impairing Dot1a - Af9 interaction . Most recently , we reported identification of a major Af9 binding site in the αENaC promoter and upregulation of αENaC mRNA expression in mouse kidneys lacking Dot1a . Despite these findings , the putative antagonism between the MR / aldosterone and Dot1a - Af9 complexes has never been addressed . The molecular defects leading to PHA - 1 in MR (-/-) mice remain elusive . Here , we report that MR competes with Dot1a to bind Af9 . MR / aldosterone and Dot1a - Af9 complexes mutually counterbalance ENaC mRNA expression in inner medullary collecting duct 3 ( IMCD3 ) cells . Real - time RT - quantitative PCR revealed that 5 - day - old MR (-/-) vs . MR (+/+) mice had significantly lower αENaC mRNA levels . This change was associated with an increased Af9 binding and H3 Q5XKE5 hypermethylation in the αENaC promoter . Therefore , this study identified MR as a novel binding partner and regulator of Af9 and a novel mechanism coupling MR - mediated activation with relief of Dot1a - Af9 - mediated repression via MR - Af9 interaction . Impaired ENaC expression due to failure to inhibit Dot1a - Af9 may play an important role in the early stages of PHA - 1 ( before postnatal day 8 ) in MR (-/-) mice .", "Update and new concepts in vitamin responsive disorders of folate transport and metabolism . Derivatives of folic acid are involved in transfer of one - carbon units in cellular metabolism , playing a role in synthesis of purines and thymidylate and in the remethylation of homocysteine to form methionine . Five inborn errors affecting folate transport and metabolism have been well studied : hereditary folate malabsorption , caused by mutations in the gene encoding the proton - coupled folate transporter ( Q96NT5 ) ; glutamate formiminotransferase deficiency , caused by mutations in the O95954 gene ; methylenetetrahydrofolate reductase deficiency , caused by mutations in the P42898 gene ; and functional methionine synthase deficiency , either as the result of mutations affecting methionine synthase itself ( cblG , caused by mutations in the Q99707 gene ) or affecting the accessory protein methionine synthase reductase ( cblE , caused by mutations in the Q9UBK8 gene ) . Recently additional inborn errors have been identified . Cerebral folate deficiency is a clinically heterogeneous disorder , which in a few families is caused by mutations in the P15328 gene . P00374 deficiency is characterized by megaloblastic anemia and cerebral folate deficiency , with variable neurological findings . It is caused by mutations in the P00374 gene . Deficiency in the trifunctional enzyme containing methylenetetrahydrofolate dehydrogenase , methenyltetrahydrofolate cyclohydrolase and formyltetrahydrofolate synthetase activities , has been identified in a single patient with megaloblastic anemia , atypical hemolytic uremic syndrome and severe combined immune deficiency . It is caused by mutations in the P11586 gene .", "P62937 and calcineurin functions investigated by gene inactivation , cyclosporin A inhibition and cDNA arrays approaches in the phytopathogenic fungus Botrytis cinerea . Calcineurin phosphatase and cyclophilin A are cellular components involved in fungal morphogenesis and virulence . Their roles were investigated in the phytopathogenic fungus Botrytis cinerea using gene inactivation , drug inhibition and cDNA macroarrays approaches . First , the BCP1 gene coding for cyclophilin A was identified and inactivated by homologous recombination . The bcp1Delta null mutant obtained was still able to develop infection structures but was altered in symptom development on bean and tomato leaves . Opposite to this , calcineurin inhibition using cyclosporin A ( ___MASK52___ ) modified hyphal morphology and prevented infection structure formation . ___MASK52___ drug pattern signature on macroarrays allowed the identification of 18 calcineurin - dependent ( CND ) genes among 2839 B . cinerea genes . Among the co - regulated CND genes , three were shown to be organized as a physical cluster that could be involved in secondary metabolism . The signature of BCP1 inactivation on macroarrays allowed the identification of only three BCP1 cyclophilin - dependent ( O75976 ) genes that were different from CND genes . Finally , no ___MASK52___ drug pattern signature was observed in the bcp1Delta null mutant which provided a molecular target validation of the drug .", "Q07352 is regulated by parathyroid hormone and bone morphogenetic protein - 2 in osteoblastic cells . Parathyroid hormone ( PTH ) exerts potent and diverse effects in bone and cartilage through activation of type 1 PTH receptors ( Q03431 ) capable of coupling to protein kinase A ( PKA ) and PKC . We have used macroarrays to identify zinc finger protein butyrate response factor - 1 ( BRF1 ) as a novel PTH regulated gene in clonal and normal osteoblasts of human and rodent origin . We further demonstrate that in human osteoblast - like OHS cells , biologically active ___MASK49___ and ___MASK49___ ( 1 - 34 ) stimulate BRF1 mRNA expression in a dose - and time - dependent manner , while the amino - terminally truncated ___MASK49___ ( 3 - 84 ) which does not activate Q03431 has no effect . Moreover , using specific stimulators or inhibitors of PKA and PKC activity , the PTH - elicited BRF1 mRNA expression is mediated through the PKA signaling pathway . In mouse calvarial osteoblasts , BRF1 mRNA levels are upregulated by ___MASK49___ and reduced in response to bone morphogenetic protein 2 ( P12643 ) . Hence , our data showing that BRF1 is expressed in osteoblastic cells and regulated by PTH and P12643 , suggest an important role for BRF1 in osteoblasts within the molecular network of PTH - dependent bone remodeling .", "Simultaneous metabolic labeling of cells with multiple amino acids : Localization and dynamics of histone acetylation and methylation . Simultaneous metabolic labeling of cells with multiple amino acids combined with acetic acid urea - PAGE and MS was used to characterize histones in Kasumi - 1 cells treated with the histone deacetylase inhibitor depsipeptide ( O60220 ) . The approach allowed for rapid targeting , identification , and subsequent characterization of peptides containing sites of acetylation or methylation . Multiple methylation sites were determined for histone H3 including : di - and tri - methylation of P35527 and Q7Z3Y8 ; mono - and di - methylation of O76013 and Q5XKE5 ; and mono - methylation of O76014 . The acetylation patterns for histones H4 and H3 were established . Quantitative analysis of the modification change after treatment with O60220 was also performed and the dynamics of H4 acetylation determined . Functional analysis by RT - PCR showed that O60220 unregulated P38936 expression with a maximum after 18 - h exposure . Chromatin immunoprecipitation experiments indicated that O60220 treatment caused an accumulation of hyperacetylated histone H4 and H3 isoforms and a decrease in P35527 di - methylation of H3 on the P38936 promoter .", "Discovery of a new class of ionotropic glutamate receptor antagonists by the rational design of ( 2S , 3R ) - 3 -( 3 - carboxyphenyl )- pyrrolidine - 2 - carboxylic acid . The kainic acid ( KA ) receptors belong to the class of glutamate ( ___MASK81___ ) receptors in the brain and constitute a promising target for the treatment of neurological and / or psychiatric diseases such as schizophrenia , major depression , and epilepsy . Five KA subtypes have been identified and named P39086 - 5 . In this article , we present the discovery of ( 2S , 3R ) - 3 -( 3 - carboxyphenyl )- pyrrolidine - 2 - carboxylic acid ( 1 ) based on a rational design process . Target compound 1 was synthesized by a stereoselective strategy in 10 steps from commercially available starting materials . Binding affinities of 1 at native ionotropic ___MASK81___ receptors were determined to be in the micromolar range ( AMPA , 51 μM ; KA , 22 μM ; DB01221 6 μM ) , with the highest affinity for cloned homomeric KA receptor subtypes P39086 , 3 ( 3 . 0 and 8 . 1 μM , respectively ) . Functional characterization of 1 by two electrode voltage clamp ( TEVC ) electrophysiology at a nondesensitizing mutant of P39086 showed full competitive antagonistic behavior with a K ( b ) of 11 . 4 μM .", "P13688 impedes thyroid cancer growth but promotes invasiveness : a putative mechanism for early metastases . P13688 , also known as biliary glycoprotein ( BGP ) , CD66a , Q00839 and C - P62158 , is a member of the P06731 immunoglobulin superfamily . P13688 is a putative tumor suppressor based on diminished expression in some solid neoplasms such as colorectal carcinoma . However , P13688 is overexpressed in some tumors such as non - small cell lung cancer . To clarify the mechanism of action of this cell adhesion molecule , we studied thyroid carcinoma that has a spectrum of morphologies and variable behavior allowing separation of proliferation from invasion and metastasis . P13688 is expressed in thyroid carcinoma cell lines derived from tumors that exhibit aggressive behavior . Introduction of P13688 into endogenously deficient WRO cells resulted in reduced cell cycle progression associated with P38936 upregulation and diminished Rb phosphorylation . Forced P13688 expression enhanced cell - matrix adhesion and migration and promoted tumor invasiveness . Conversely , small interfering RNA ( siRNA ) - mediated downregulation of P13688 expression in Q9BYG7 cells accelerated cell cycle progression and significantly enhanced tumor size in xenografted mice . P13688 is not appreciably expressed in normal thyroid tissue or benign thyroid tumors . In a human thyroid tissue array , P13688 reactivity was associated with metastatic spread but not with increased tumor size . These findings identify P13688 as a unique mediator that restricts tumor growth whereas increasing metastatic potential . Our data highlight a complex repertoire of actions providing a putative mechanism underlying the spectrum of biologic behaviors associated with thyroid cancer .", "Temperature - dependent growth restriction in measles vaccine strains . Temperature - dependent growth restriction was studied with the measles vaccine strains licensed in Japan in comparison with their parental wild strains . Plaquing efficiency was compared at various temperatures from 35 to 40 C . O14965 - C strain derived from Edmonston wild strain was temperature - sensitive with the 39 C shutoff temperature . No significant restriction of growth was found for other vaccine strains , i . e . , Schwarz , FF - 8 , and P62158 - 70 , and for their parental wild strains , i . e . , Edmonston and Tanabe . A paradoxical feature was found for FF - 8 strain ; in spite of undiminished plaquing efficiency at 40 C , the growth in the fluid medium was markedly depressed at 39 C or above ." ]
[ "___MASK15___", "___MASK28___", "___MASK3___", "___MASK43___", "___MASK49___", "___MASK52___", "___MASK81___", "___MASK84___", "___MASK93___" ]
___MASK52___
MH_train_1618
interacts_with DB01211?
[ "Trace analysis of methylated and hydroxymethylated cytosines in DNA by isotope - dilution LC - MS / MS : first evidence of DNA methylation in Caenorhabditis elegans . From 1986 to the present , the popular research model organism Caenorhabditis elegans has been thought to completely lack DNA methylation and seems to have lost DNA methylation enzymes from its genomes . In the present study , we report the development of a sensitive and selective assay based on LC - MS / MS to simultaneously measure 5 - methyl - 2 '- deoxycytidine ( 5 - mdC ) and 5 - hydroxymethyl - 2 '- deoxycytidine ( 5 - hmdC ) in DNA hydrolysates . With the use of isotope internal standards ( [ 2H3 ] 5 - mdC and [ 2H3 ] 5 - hmdC ) and online solid - phase extraction , the detection limits of 5 - mdC and 5 - hmdC were estimated to be 0 . 01 and 0 . 02 pg respectively , which correspond to a 0 . 000006 % and 0 . 00001 % methylation and hydroxymethylation level . This method was applied to investigate whether DNA methylation / hydroxymethylation exists in C . elegans . The present study for the first time demonstrates that 5 - mdC is present in C . elegans genomic DNA ( 0 . 0019 - 0 . 0033 % of cytosine methylated ) using LC - MS / MS , whereas another epigenetic modification , 5 - hmdC , is not detectable . Furthermore , we found that C . elegans DNA was hypo - or hyper - methylated in a dose - dependent manner by the DNA methyltransferase ( P26358 ) - inhibiting drug decitabine ( ___MASK37___ ) or cadmium respectively . Our data support the possible existence of an active DNA - methylation mechanism in C . elegans , in which unidentified DNMTs could be involved . The present study highlights the importance of re - evaluating the evolutionary conservation of DNA - methylation machinery in nematodes which were traditionally considered to lack functional DNA methylation .", "Mutational analysis of the mitochondrial P47985 of Saccharomyces cerevisiae . II . Biochemical characterization of temperature - sensitive Q13546 - mutations . Although the function of the P47985 is generally understood , little is known of how the structure of this protein supports its mechanistic role in electron transfer in the cytochrome bc1 complex . To better understand the structural basis of iron - sulfur protein function , we have undertaken a mutational analysis of the gene encoding this protein and initially isolated five temperature - sensitive iron - sulfur protein mutants ( Beckmann , J . D . , Ljungdahl , P . O . , and Trumpower , B . L . ( 1989 ) J . Biol . Chem . 264 , 3713 - 3722 ) . Each of the five ts - rip1 - mutants exhibited pleiotropic effects . Although the mutant iron - sulfur proteins manifest several in vitro phenotypes in common , each exhibited unique characteristics . All of the ts - rip1 - mutations resulted in membranes with decreased ubiquinol - cytochrome c oxidoreductase activities and decreased thermostability compared to membranes containing wild type iron - sulfur protein . All of the mutations conferred slight but significant resistance to the respiratory inhibitor myxothiazol , and one mutant was hypersensitive to inhibition by ___MASK67___ , a structural analog of ubiquinone . In addition , one of the mutations completely blocks post - translational processing of the iron - sulfur protein , leading to accumulation of pre - iron - sulfur protein in mitochondrial membranes at nonpermissive temperatures . Finally , a mutation 12 - amino acid residues away from the carboxyl terminus ( 203S ) results in an extremely unstable protein . This region of the protein may be essential in blocking degradation of pre - iron - sulfur protein by cytoplasmic proteases as the protein is imported into the mitochondria , or may be a \" degradation signal , \" which tags the iron - sulfur protein for turnover .", "Characterization of the inhibitory effects of erythromycin and clarithromycin on the Q12809 potassium channel . Both erythromycin and clarithromycin have been reported to cause QT prolongation and the cardiac arrhythmia torsade de pointes in humans , however direct evidence documenting that these drugs produce this effect by blocking human cardiac ion channels is lacking . The goal of this study was to test the hypothesis that these macrolide antibiotics significantly block the delayed rectifier current ( IKr ) encoded by Q12809 ( the human ether - a - go - go - related gene ) at drug concentrations , temperature and ionic conditions mimicking those occurring in human subjects . DB01345 currents in P29320 293 cells stably transfected with Q12809 were recorded using a whole cell voltage clamp method . Exposure of cells to erythromycin reduced the Q12809 encoded potassium current in a concentration dependent manner with an IC50 of 38 . 9 +/- 1 . 2 microM and Hill Slope factor of 0 . 4 +/- 0 . 1 . DB01211 produced a similar concentration - dependent block with an IC50 of 45 . 7 +/- 1 . 1 microM and Hill Slope factor of 1 . 0 +/- 0 . 1 . Erythromycin ( 25 - 250 microM ) and clarithromycin ( 5 or 25 microM ) also produced a significant decrease in the integral of the current evoked by an action potential shaped voltage clamp protocol . The results of this study document that both erythromycin and clarithromycin significantly inhibit the Q12809 potassium current at clinically relevant concentrations .", "Prostanoid production in Saccharomyces cerevisiae provides a novel assay for nonsteroidal anti - inflammatory drugs . Prostanoids are a large family of lipid mediators originating from prostaglandin H synthase ( PGHS ) activity on the 20 - carbon polyunsaturated fatty acids dihomo - gamma - linolenic acid ( ___MASK34___ ) , arachidonic acid ( AA ) and eicosapentaenoic acid . The two mouse PGHS isoforms , P23219 and P35354 , were expressed in Saccharomyces cerevisiae ( yeast ) , as was a signal - peptide - deleted version of P23219 ( PGHS - 1MA ) . P23219 showed high activity with both AA and ___MASK34___ as substrate , whereas P35354 activity was high with ___MASK34___ but low with AA . Signal peptide removal reduced the activity of PGHS - 1MA by > 50 % relative to P23219 , but the residual activity indicated that correct targeting to the lumen of the endoplasmic reticulum may not be necessary for enzyme function . Coexpression of P23219 with cDNAs encoding mouse prostaglandin I synthase and thromboxane A synthase , and with Trypanosoma brucei genomic DNA encoding prostaglandin F synthase in AA - supplemented yeast cultures resulted in production of the corresponding prostanoids , prostaglandin I ( 2 ) , thromboxane A ( 2 ) and prostaglandin F ( 2alpha ) . The inhibitory effects of nonsteroidal anti - inflammatory drugs ( NSAIDs ) on prostanoid production were tested on yeast cells expressing P23219 in AA - supplemented culture . Dose - dependent inhibition of prostaglandin H ( 2 ) production by aspirin , ibuprofen and indomethacin demonstrated the potential utility of this simple expression system in screening for novel NSAIDs .", "Effects of ___MASK96___ , a potent inducer of drug - metabolizing enzymes and an inhibitor of Q9Y6L6 / 3 transport , on the single dose pharmacokinetics of anacetrapib . Anacetrapib is a novel cholesteryl ester transfer protein ( P11597 ) inhibitor in development for treatment of dyslipidemia . This open - label , fixed - sequence , 3 - period study was intended to evaluate the potential of anacetrapib to be a victim of Q9Y6L6 / 3 inhibition and strong CYP3A induction using acute and chronic dosing of rifampin , respectively , as a probe . In this study , 16 healthy subjects received 100 mg anacetrapib administered without rifampin ( Day 1 , Period 1 ) , with single - dose ( SD ) 600 mg rifampin ( Day 1 , Period 2 ) , and with multiple - dose ( MD ) 600 mg rifampin for 20 days ( Day 14 , Period 3 ) . Log - transformed anacetrapib AUC0 -∞ and Cmax were analyzed by a linear mixed effects model . The GMRs and 90 % CIs for anacetrapib AUC0 -∞ and Cmax were 1 . 25 ( 1 . 04 , 1 . 51 ) and 1 . 43 ( 1 . 13 , 1 . 82 ) for SD rifampin ( Period 2 / Period 1 ) and 0 . 35 ( 0 . 29 , 0 . 42 ) and 0 . 26 ( 0 . 21 , 0 . 32 ) for MD rifampin ( Period 3 / Period 1 ) , respectively . Anacetrapib was generally well tolerated in both the absence / presence of SD and MD rifampin . In conclusion , treatment with SD rifampin , which inhibits the Q9Y6L6 / 3 transporter system , did not substantially influence the SD pharmacokinetics of anacetrapib , while chronic ( 20 days ) administration of rifampin , which strongly induces CYP3A isozymes , reduced mean systemic exposure to SD anacetrapib by 65 % .", "Nitrergic response to cyclophosphamide treatment in blood and bone marrow . Daily intraperitoneal injection of cyclophosphamide ( P15085 ) ( 50 mgkg (- 1 ) of body weight ) for 5 days resulted in reduced levels of marrow and blood cellularity , which was most pronounced in 18 days post - treatment ( pt ) . On day 18 after P15085 treatment the enhancedlevels of nitric oxide ( NO ) precursors and metabolites ( L - arginine , L - citrulline , reactive nitrogen species ( RNS ) ) of marrow and blood cells ( platelet , neutrophil , lymphocyte and monocyte ) resulted from up - regulation of Ca ( II )/ calmodulin ( P62158 )- independent \" inducible \" NO synthase ( P35228 ) , with a lessercontribution of Ca ( II )/ P62158 - dependent \" constitutive \" P29474 isoforms to systemic NO . Biphasic response to P15085 of marrow nitrergic system , i . e . both P35228 and P29474 showed significantly depressed activities , as well as diminished levels of NO metabolites on day 9 pt , suggested that signals in addition to NO might be involved in P15085 - induced inhibition of hematopoesis , while a gradual increase of neutrophil and platelet NOS activity appeared to be contributed to a P15085 - induced development of granulopenia , thrombocytopenia and hemorrhage .", "P10275 abnormalities in identical twins with oligospermia . Clinical and biochemical studies . Identical twin brothers presented with oligospermia , small testes , normal male phenotypes , elevated serum luteinizing hormone levels , and normal or elevated serum testosterone levels . Both men had low to low - normal cytosol androgen receptor binding capacity in cultured fibroblasts from pubic skin biopsy specimens . Qualitative abnormalities of cellular androgen receptors were suggested by low - normal or low nuclear androgen uptake in fibroblasts from both brothers as well as abnormal thermolability and subnormal molybdate stabilization of androgen receptors from one brother . In vivo androgen sensitivity was assessed in one twin following administration of testosterone or the non - aromatizable androgen fluoxymesterone . ___MASK54___ suppressed serum luteinizing hormone and serum testosterone / estradiol - binding globulin , and although testosterone suppressed both serum luteinizing hormone and serum follicle - stimulating hormone , the suppression of serum luteinizing hormone by testosterone was subnormal . Both subjects showed marked exaggeration of the serum 17 - hydroxyprogesterone increase after administration of human chorionic gonadotropin , despite normal serum testosterone increases , suggesting a block in testicular 17 , 20 - desmolase , which converts 17 - hydroxyprogesterone to testosterone . These studies suggest that oligospermia and block of the enzyme 17 , 20 - desmolase may be the earliest manifestations of androgen resistance , and the finding of the syndrome of oligospermia , normal male phenotype , and androgen receptor abnormalities in identical twins indicates a genetic etiology of this disorder .", "Anti - IgM - induced growth inhibition and apoptosis are independent of ornithine decarboxylase in Ramos cells . P11926 ( ODC ) is a key enzyme involved in polyamine production and is thought to regulate growth and apoptosis in multiple cell systems . A potential link between ODC and growth may involve the action of an oncogene c - myc which is thought to transcriptionally regulate ODC . We have examined the involvement of ODC in anti - IgM - induced growth inhibition and apoptosis in Burkitt ' s lymphoma cells . Inhibitors of ODC such as difluoromethylornithine ( ___MASK71___ ) completely blocked ODC activity , resulting in growth inhibition but not apoptosis . Addition of putrescine , the product of ODC enzymatic action , to Ramos cells had only a minor effect on growth , did not cause apoptosis , did not augment or block anti - IgM - mediated growth inhibition and apoptosis , but did reverse ___MASK71___ - mediated growth inhibition . Anti - IgM treatment of Ramos cells , which markedly decreased c - myc mRNA and protein , caused a paradoxical increase in ODC mRNA level as well as ODC enzymatic activity and increased cellular levels of putrescine . ___MASK71___ and putrescine did not alter c - myc mRNA levels directly , nor did they have any affects on anti - IgM - mediated down - regulation of c - myc mRNA . P01375 , which inhibited anti - IgM - mediated apoptosis , did not inhibit either anti - IgM or ___MASK71___ - mediated inhibition of growth . These agents were without effect on ODC activity itself or on the anti - IgM - mediated increase in ODC activity . From these studies we conclude that ODC inhibition affects growth but is unrelated to the induction of apoptosis . Both anti - IgM - mediated inhibition of growth and induction of apoptosis are independent of ODC . Thus two distinct pathways for growth regulation are present : one in which ODC and polyamines are important and the other cell surface receptor - mediated ( sIg ) which is independent of ODC and polyamines .", "Phosphorylation of human P26358 : implication of cyclin - dependent kinases . DNA methylation plays a central role in the epigenetic regulation of gene expression during development and progression of cancer diseases . The inheritance of specific DNA methylation patterns are acquired in the early embryo and are specifically maintained after cellular replication via the DNA methyltransferase 1 ( P26358 ) . Recent studies have suggested that the enzymatic activity of P26358 is possibly modulated by phosphorylation of serine / threonine residues located in the N - terminal domain of the enzyme . In the present work , we report that cyclin - dependent kinases ( CDKs ) 1 , 2 and 5 can phosphorylate Ser154 of human P26358 in vitro . Further evidence of phosphorylation of endogenous P26358 at position 154 by CDKs is also found in 293 cells treated with roscovitine , a specific inhibitor of P06493 , 2 and 5 . To determine the importance of Ser154 phosphorylation , a mutant of P26358 encoding a single - point mutation at position 154 ( S154A ) was generated . This mutation induced a severe loss of enzymatic activity when compared to wild type P26358 . Moreover , after treatment with 5 - Aza - DB02594 ( 5 - aza - dC ) , a faster decline in P26358 protein level was observed for P29320 - 293 cells expressing P26358 ( S154A ) as compared to cells expressing wild type P26358 . Our data suggest that phosphorylation of P26358 at Ser154 by CDKs is important for enzymatic activity and protein stability of P26358 . Considering that tumour - associated cell cycle defects are often mediated by alterations in CDK activity , our results suggest that dysregulation of cell cycle via CDKs could induce abnormal phosphorylation of P26358 and lead to DNA hypermethylation often observed in cancer cells .", "17beta - estradiol induces the translocation of the estrogen receptors P03372 and Q92731 to the cell membrane , P27361 / 1 phosphorylation and proliferation of cultured immature rat Sertoli cells . The aim of the present study was to determine the mechanisms involved in estrogen actions in cultured rat Sertoli cells . RT - PCR detected transcripts for the estrogen receptors P03372 and Q92731 in cultured immature Sertoli cells and in the testis of 15 - , 28 - , and 120 - day - old rats . The expression of P03372 and Q92731 was confirmed in Sertoli cells by immunofluorescence and Western blot . Immunohistochemistry with cryosections of testes from immature and adult rats revealed that P03372 is present in Sertoli , Leydig , and some peritubular myoid cells , and Q92731 is present in multiple cell types , including germ cells . Treatment of Sertoli cells with 17beta - estradiol ( E ( 2 ) ) induced a translocation of P03372 and Q92731 to the plasma membrane and a concomitant phosphorylation of P27361 / 1 . Both effects reached a maximum after 10 min and were blocked by Q99463 , an inhibitor of the P12931 family of protein tyrosine kinases , and by the antiestrogen ___MASK33___ ( ICI ) . P27361 / 1 phosphorylation was also decreased in the presence of AG 1478 , an inhibitor of the epidermal growth factor receptor ( P00533 ) kinase , and in the presence of Q02750 / 2 inhibitor UO126 . Treatment with E ( 2 ) for 24 h increased the incorporation of [ methyl -( 3 ) H ] thymidine , which was blocked by ICI . These results indicate that E ( 2 ) activates an P12931 - mediated translocation of estrogen receptors to the plasma membrane , which results in the activation of P00533 and the mitogen - activated protein kinase signaling pathway . In addition , activation of P03372 and / or Q92731 by E ( 2 ) is involved in proliferation of immature Sertoli cells . The estrogen actions in Sertoli cells might be a key step mediating cellular events important for spermatogenesis and fertility .", "P10275 - dependent activation of endothelial nitric oxide synthase in vascular endothelial cells : role of phosphatidylinositol 3 - kinase / akt pathway . The mechanisms of testosterone - induced vasodilatation are not fully understood . This study investigated the effect of testosterone on nitric oxide ( NO ) synthesis and its molecular mechanism using human aortic endothelial cells ( HAEC ) . DB00624 at physiological concentrations ( 1 - 100 nm ) induced a rapid ( 15 - 30 min ) increase in NO production , which was associated with phosphorylation and activation of endothelial NO synthase ( P29474 ) . Then , the involvement of the androgen receptor ( AR ) , which is abundantly expressed in HAEC , was examined . The effect of testosterone on P29474 activation and NO production were abolished by pretreatment with an AR antagonist nilutamide and by transfection with AR small interference RNA . In contrast , testosterone - induced P29474 phosphorylation was unchanged by pretreatment with an aromatase inhibitor or by transfection with ERalpha small interference RNA . DB02901 , a nonaromatizable androgen , also stimulated P29474 phosphorylation . Next , the signaling cascade that leads to P29474 phosphorylation was explored . DB00624 stimulated rapid phosphorylation of Akt in a time - and dose - dependent manner , with maximal response at 15 - 60 min . The rapid phosphorylation of P29474 or NO production induced by testosterone was inhibited by Akt inhibitor SH - 5 or by phosphatidylinositol ( PI ) 3 - kinase inhibitor wortmannin . Co - immunoprecipitation assays revealed a testosterone - dependent interaction between AR and the p85alpha subunit of P19957 - kinase . In conclusion , testosterone rapidly induces NO production via AR - dependent activation of P29474 in HAEC . Activation of P19957 - kinase / Akt signaling and the direct interaction of AR with p85alpha are involved , at least in part , in P29474 phosphorylation .", "Protein kinase Cdelta and calmodulin regulate epidermal growth factor receptor recycling from early endosomes through Arp2 / 3 complex and cortactin . The intracellular trafficking of the epidermal growth factor receptor ( P00533 ) is regulated by a cross - talk between calmodulin ( P62158 ) and protein kinase Cdelta ( PKCdelta ) . On inhibition of P62158 , PKCdelta promotes the formation of enlarged early endosomes and blocks P00533 recycling and degradation . Here , we show that PKCdelta impairs P00533 trafficking due to the formation of an F - actin coat surrounding early endosomes . The PKCdelta - induced polymerization of actin is orchestrated by the Arp2 / 3 complex and requires the interaction of cortactin with PKCdelta . Accordingly , inhibition of actin polymerization by using cytochalasin D or by overexpression of active cofilin , restored the normal morphology of the organelle and the recycling of P00533 . Similar results were obtained after down - regulation of cortactin and the sequestration of the Arp2 / 3 complex . Furthermore we demonstrate an interaction of cortactin with P62158 and PKCdelta , the latter being dependent on P62158 inhibition . In summary , this study provides the first evidence that P62158 and PKCdelta organize actin dynamics in the early endosomal compartment , thereby regulating the intracellular trafficking of P00533 .", "Transient multiple acyl - DB01992 dehydrogenation deficiency in a newborn female caused by maternal riboflavin deficiency . A newborn female presented on the first day of life with clinical and biochemical findings consistent with multiple acyl - DB01992 dehydrogenase deficiency ( Q8WXG6 ) . ___MASK19___ supplementation corrected the biochemical abnormalities 24 h after commencing the vitamin . In vitro acylcarnitine profiling in intact fibroblasts both in normal and riboflavin depleted media showed normal oxidation of fatty acids excluding defects in electron transfer flavoprotein ( ETF ) , or ETF ubiquinone oxidoreductase ( ETF : QO ) , or a genetic abnormality in flavin metabolism . In addition , sequencing of the genes encoding ETF and ETF : QO in the proband did not reveal any pathogenic mutations . Determination of the maternal riboflavin status after delivery showed that the mother was riboflavin deficient . Repeat testing done two years after the infant ' s birth and while on a normal diet showed that the mother was persistently riboflavin deficient and showed a typical Q8WXG6 profile on plasma acylcarnitine testing . A possible genetic defect in riboflavin transport of metabolism in the mother is postulated to be the cause of the transient Q8WXG6 seen in the infant . Sequencing of the Q6ZSM3 , Q969G6 and Q8NFF5 genes encoding key enzymes in riboflavin transport of metabolism in the mother did not identify any pathogenic mutations . The underlying molecular basis of the mother ' s defect in riboflavin metabolism remains to be established .", "DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .", "Death receptors 4 and 5 activate Nox1 NADPH oxidase through riboflavin kinase to induce reactive oxygen species - mediated apoptotic cell death . Stimulation of the proapoptotic tumor necrosis factor ( P01375 ) - related apoptosis - inducing ligand ( P50591 ) receptors , death receptors 4 ( DR4 ) and 5 ( DR5 ) , conventionally induces caspase - dependent apoptosis in tumor cells . Here we report that stimulation of DR4 and / or DR5 by the agonistic protein KD548 - Fc , an Fc - fused DR4 / DR5 dual - specific Kringle domain variant , activates plasma membrane - associated Nox1 NADPH oxidase to generate superoxide anion and subsequently accumulates intracellular reactive oxygen species ( ROS ) , leading to sustained c - Jun N - terminal kinase activation and eventual apoptotic cell death in human HeLa and Jurkat tumor cells . KD548 - Fc treatment induces the formation of a DR4 / DR5 signaling complex containing riboflavin kinase ( Q969G6 ) , Nox1 , the Nox1 subunits ( Rac1 , Noxo1 , and Noxa1 ) , P01375 receptor - associated death domain ( Q15628 ) , and Q12933 ( TRAF2 ) . Depletion of Q969G6 , but not the Nox1 subunits , Q15628 and TRAF2 , failed to recruit Nox1 and Rac1 to DR4 and DR5 , demonstrating that Q969G6 plays an essential role in linking DR4 / DR5 with Nox1 . Knockdown studies also reveal that Q969G6 , Q15628 , and TRAF2 play critical , intermediate , and negligible roles , respectively , in the KD548 - Fc - mediated ROS accumulation and downstream signaling . Binding assays using recombinantly expressed proteins suggest that DR4 / DR5 directly interact with cytosolic Q969G6 through Q969G6 - binding regions within the intracellular death domains , and Q15628 stabilizes the DR4 / DR5 - Q969G6 complex . Our results suggest that DR4 and DR5 have a capability to activate Nox1 by recruiting Q969G6 , resulting in ROS - mediated apoptotic cell death in tumor cells .", "Effect of postponed treatment with an anti - tumour necrosis factor ( P01375 ) F ( ab ') 2 fragment on endotoxin - induced cytokine and neutrophil responses in chimpanzees . P01375 is considered to be an intermediate factor in endotoxin - induced release of other cytokines and endotoxin - induced neutrophil degranulation . Little is known about the effect of postponed treatment with anti - P01375 in primate endotoxin models . To assess the effect of delayed treatment with anti - P01375 in endotoxaemia , six healthy adult chimpanzees were intravenously injected with Escherichia coli endotoxin ( 4 ng / kg ) . In three of these animals the administration of endotoxin was followed after 30 min by a bolus i . v . injection of the anti - P01375 F ( ab ') 2 fragment ___MASK59___ ( 0 . 1 mg / kg ) . Post - treatment with ___MASK59___ completely prevented the appearance of P01375 activity in serum elicited by endotoxin , and markedly reduced the rises in the serum concentrations of P05231 and P10145 . In addition , the endotoxin - induced increases in the type I and type II soluble P01375 receptors were also profoundly inhibited by ___MASK59___ , suggesting that P01375 is involved in the release of its own soluble receptors in endotoxaemia . Neutrophilic leucocytosis was not affected by ___MASK59___ . In contrast , ___MASK59___ did significantly abrogate neutrophil degranulation , as measured by the plasma concentrations of lactoferrin . These results indicate that treatment with anti - P01375 30 min after the administration of endotoxin is still effective in attenuating the induction of the cytokine network and of neutrophil degranulation .", "SAR131675 , a potent and selective P35916 - TK inhibitor with antilymphangiogenic , antitumoral , and antimetastatic activities . SAR131675 is a potent and selective P35916 inhibitor . It inhibited P35916 tyrosine kinase activity and P35916 autophosphorylation in P29320 cells with IC ( 50 ) values of 20 and 45 nmol / L , respectively . SAR131675 dose dependently inhibited the proliferation of primary human lymphatic cells , induced by the P35916 ligands P49767 and O43915 , with an IC ( 50 ) of about 20 nmol / L . SAR131675 was found to be highly selective for P35916 versus 107 receptors , enzymes , ion channels , and 65 kinases . However , it was moderately active on P35968 with a P35916 / P35968 ratio of about 10 . SAR131675 had no antiproliferative activity on a panel of 30 tumors and primary cells , further showing its high specificity and indicating that SAR131675 is not a cytotoxic or cytostatic agent . SAR131675 was very well tolerated in mice and showed a potent antitumoral effect in several orthotopic and syngenic models , including mammary 4T1 carcinoma and Q13546 . Tag2 tumors . Interestingly , it significantly reduced lymph node invasion and lung metastasis , showing its antilymphangiogenic activity in vivo . Moreover , treatment of mice before resection of 4T1 primary tumors was sufficient to prevent metastasis . Tumor - associated macrophages ( TAM ) play an important role in tumor growth and metastasis . The expression of P35916 on TAMs has been recently described . F4 / 80 immunostaining clearly showed that SAR131675 significantly reduced TAM infiltration and aggregation in 4T1 tumors . Taken together , SAR131675 is the first highly specific P35916 - TK inhibitor described to date , displaying significant antitumoral and antimetastatic activities in vivo through inhibition of lymphangiogenesis and TAM invasion .", "[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . ___MASK96___ ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . DB01211 ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .", "Anti - inflammatory activity of Taraxacum officinale . Taraxacum officinale has been widely used as a folkloric medicine for the treatment of diverse diseases . The dried plant was extracted with 70 % ethanol to generate its ethanol extract ( TEE ) . For some experiments , ethyl acetate ( EA ) , n - butanol ( BuOH ) and aqueous ( Aq ) fractions were prepared in succession from TEE . TEE showed a scavenging activity in the 1 , 1 - diphenyl - 2 - picrylhydrazyl ( DPPH ) assay , a diminishing effect on intracellular reactive oxygen species ( ROS ) level , and an anti - angiogenic activity in the chicken chorioallantoic ( P62158 ) assay . In the carrageenan - induced air pouch model , TEE inhibited production of exudate , and significantly diminished nitric oxide ( NO ) and leukocyte levels in the exudate . It also possessed an inhibitory effect on acetic acid - induced vascular permeability and caused a dose - dependent inhibition on acetic acid - induced abdominal writhing in mice . Suppressive effects of TEE on the production of NO and expression of inducible nitric oxide synthase ( P35228 ) and cyclooxygenase - 2 ( P35354 ) in lipopolysaccharide ( LPS ) - stimulated macrophages were also assessed . Among the fractions , the n - butanol fraction ( BuOH ) was identified to be most effective in the P62158 assay . Collectively , Taraxacum officinale contains anti - angiogenic , anti - inflammatory and anti - nociceptive activities through its inhibition of NO production and P35354 expression and / or its antioxidative activity .", "P29474 activation by HDL is impaired in genetic P11597 deficiency . Mutations in the P11597 gene resulting in defective P11597 activity have been shown to cause remarkable elevations of plasma HDL - C levels , with the accumulation in plasma of large , buoyant HDL particles enriched in apolipoprotein E . Genetic P11597 deficiency thus represents a unique tool to evaluate how structural alterations of HDL impact on HDL atheroprotective functions . Aim of the present study was to assess the ability of HDL obtained from P11597 - deficient subjects to protect endothelial cells from the development of endothelial dysfunction . HDL isolated from one homozygous and seven heterozygous carriers of P11597 null mutations were evaluated for their ability to down - regulate cytokine - induced cell adhesion molecule expression and to promote NO production in cultured endothelial cells . When compared at the same protein concentration , HDL and HDL3 from carriers proved to be as effective as control HDL and HDL3 in down - regulating cytokine - induced P19320 , while carrier HDL2 were more effective than control HDL2 in inhibiting P19320 expression . On the other hand , HDL and HDL fractions from carriers of P11597 deficiency were significantly less effective than control HDL and HDL fractions in stimulating NO production , due to a reduced P29474 activating capacity , likely because of a reduced Q14703 content . In conclusion , the present findings support the notion that genetic P11597 deficiency , by affecting HDL particle structure , impacts on HDL vasculoprotective functions . Understanding of these effects might be important for predicting the outcomes of pharmacological P11597 inhibition ." ]
[ "___MASK19___", "___MASK33___", "___MASK34___", "___MASK37___", "___MASK54___", "___MASK59___", "___MASK67___", "___MASK71___", "___MASK96___" ]
___MASK96___
MH_train_1619