bluuebunny/crossref_metadata_2025_split huggingface dataset:
The GPCR‐associated sorting protein 1 regulates ligand‐induced down‐regulation of GPR55
Authors: Kargl J , Balenga NA , Platzer W , Martini L , Whistler JL , Waldhoer M 
Published: June 2011

BACKGROUND AND PURPOSE Many GPCRs, including the CB1 cannabinoid receptor, are down‐regulated following prolonged agonist exposure by interacting with the GPCR‐associated sorting protein‐1 (GASP‐1). The CB1 receptor antagonist rimonabant has also recently been described to be an agonist at GPR55, a cannabinoid‐related receptor. Here we investigated the post‐endocytic properties of GPR55 after agonist exposure and tested whether GASP‐1 is involved in this process.EXPERIMENTAL APPROACH We evaluated the direct protein‐protein interaction of GPR55 with GASP‐1 using (i) GST‐binding assays and (ii) co‐immunoprecipitation assays in GPR55‐HEK293 cells with endogenous GASP‐1 expression. We further tested the internalization, recycling and degradation of GPR55 using confocal fluorescence microscopy and biotinylation assays in the presence and absence of GASP‐1 (lentiviral small hairpin RNA knockdown of GASP‐1) under prolonged agonist [rimonabant (RIM), lysophosphatidylinositol (LPI)] stimulation.KEY RESULTS We showed that the prolonged activation of GPR55 with rimonabant or LPI down‐regulates GPR55 via GASP‐1. GASP‐1 binds to GPR55 in vitro, and this interaction was required for targeting GPR55 for degradation. Disrupting the GPR55‐GASP‐1 interaction prevented post‐endocytic receptor degradation, and thereby allowed receptor recycling.CONCLUSION AND IMPLICATIONS These data implicate GASP‐1 as an important regulator of ligand‐mediated down‐regulation of GPR55. By identifying GASP‐1 as a key regulator of the trafficking and, by extension, functional expression of GPR55, we may be one step closer to gaining a better understanding of this receptor in response to cannabinoid drugs.LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue‐8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue‐7
Involvement of neuropeptide FF receptors in neuroadaptive responses to acute and chronic opiate treatments
Authors: Elhabazi K , Trigo JM , Mollereau C , Moulédous L , Zajac J‐M , Bihel F , Schmitt M , Bourguignon JJ , Meziane H , Petit‐demoulière B , Bockel F , Maldonado R , Simonin F 
Published: June 2011

BACKGROUND AND PURPOSE Opiates remain the most effective compounds for alleviating severe pain across a wide range of conditions. However, their use is associated with significant side effects. Neuropeptide FF (NPFF) receptors have been implicated in several opiate‐induced neuroadaptive changes including the development of tolerance. In this study, we investigated the consequences of NPFF receptor blockade on acute and chronic stimulation of opioid receptors in mice by using RF9, a potent and selective antagonist of NPFF receptors that can be administered systemically.EXPERIMENTAL APPROACH The effects of RF9 were investigated on opioid pharmacological responses including locomotor activity, antinociception, opioid‐induced hyperalgesia, rewarding properties and physical dependence.KEY RESULTS RF9 had no effect on morphine‐induced horizontal hyperlocomotion and slightly attenuated the decrease induced in vertical activity. Furthermore, RF9 dose‐dependently blocked the long‐lasting hyperalgesia produced by either acute fentanyl or chronic morphine administration. RF9 also potentiated opiate early analgesic effects and prevented the development of morphine tolerance. Finally, RF9 increased morphine‐induced conditioned place preference without producing any rewarding effect by itself and decreased naltrexone‐precipitated withdrawal syndrome following chronic morphine treatment.CONCLUSION AND IMPLICATIONS The NPFF system is involved in the development of two major undesirable effects: tolerance and dependence, which are clinically associated with prolonged exposure to opiates. Our findings suggest that NPFF receptors are interesting therapeutic targets to improve the analgesic efficacy of opiates by limiting the development of tolerance, and for the treatment of opioid dependence.
OX1 orexin/hypocretin receptor activation of phospholipase D
Authors: Jäntti MH , Putula J , Somerharju P , Frohman MA , Kukkonen JP 
Published: June 2011

BACKGROUND AND PURPOSEOrexin receptors potently signal to lipid messenger systems, and our previous studies have suggested that PLD would be one of these. We thus wanted to verify this by direct measurements and clarify the molecular mechanism of the coupling.EXPERIMENTAL APPROACHOrexin receptor‐mediated PLD activation was investigated in CHO cells stably expressing human OX1 orexin receptors using [14C]‐oleic acid‐prelabelling and the transphosphatidylation assay.KEY RESULTSOrexin stimulation strongly increased PLD activity – even more so than the phorbol ester TPA (12‐O‐tetradecanoyl‐phorbol‐13‐acetate), a highly potent activator of PLD. Both orexin and TPA responses were mediated by PLD1. Orexin‐A and ‐B showed approximately 10‐fold difference in potency, and the concentration–response curves were biphasic. Using pharmacological inhibitors and activators, both orexin and TPA were shown to signal to PLD1 via the novel PKC isoform, PKCδ. In contrast, pharmacological or molecular biological inhibitors of Rho family proteins RhoA/B/C, cdc42 and Rac did not inhibit the orexin (or the TPA) response, nor did the molecular biological inhibitors of PKD. In addition, neither cAMP elevation, Gαi/o nor Gβγ seemed to play an important role in the orexin response.CONCLUSIONS AND IMPLICATIONSStimulation of OX1 receptors potently activates PLD (probably PLD1) in CHO cells and this is mediated by PKCδ but not other PKC isoforms, PKDs or Rho family G‐proteins. At present, the physiological significance of orexin‐induced PLD activation is unknown, but this is not the first time we have identified PKCδ in orexin signalling, and thus some specific signalling cascade may exist between orexin receptors and PKCδ.
Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non‐competitive allosteric inhibitor
Authors: Bertini R , Barcelos LS , Beccari AR , Cavalieri B , Moriconi A , Bizzarri C , Di Benedetto P , Di Giacinto C , Gloaguen I , Galliera E , Corsi MM , Russo RC , Andrade SP , Cesta MC , Nano G , Aramini A , Cutrin JC , Locati M , Allegretti M , Teixeira MM 
Published: June 2011

BACKGROUND AND PURPOSE DF 2156A is a new dual inhibitor of IL‐8 receptors CXCR1 and CXCR2 with an optimal pharmacokinetic profile. We characterized its binding mode, molecular mechanism of action and selectivity, and evaluated its therapeutic potential.EXPERIMENTAL APPROACH The binding mode, molecular mechanism of action and selectivity were investigated using chemotaxis of L1.2 transfectants and human leucocytes, in addition to radioligand and [35S]‐GTPγS binding approaches. The therapeutic potential of DF 2156A was evaluated in acute (liver ischaemia and reperfusion) and chronic (sponge‐induced angiogenesis) experimental models of inflammation.KEY RESULTS A network of polar interactions stabilized by a direct ionic bond between DF 2156A and Lys99 on CXCR1 and the non‐conserved residue Asp293 on CXCR2 are the key determinants of DF 2156A binding. DF 2156A acted as a non‐competitive allosteric inhibitor blocking the signal transduction leading to chemotaxis without altering the binding affinity of natural ligands. DF 2156A effectively and selectively inhibited CXCR1/CXCR2‐mediated chemotaxis of L1.2 transfectants and leucocytes. In a murine model of sponge‐induced angiogenesis, DF 2156A reduced leucocyte influx, TNF‐α production and neovessel formation. In vitro, DF 2156A prevented proliferation, migration and capillary‐like organization of HUVECs in response to human IL‐8. In a rat model of liver ischaemia and reperfusion (I/R) injury, DF 2156A decreased PMN and monocyte‐macrophage infiltration and associated hepatocellular injury.CONCLUSION AND IMPLICATIONS DF 2156A is a non‐competitive allosteric inhibitor of both IL‐8 receptors CXCR1 and CXCR2. It prevented experimental angiogenesis and hepatic I/R injury in vivo and, therefore, has therapeutic potential for acute and chronic inflammatory diseases.
Emodin induces chloride secretion in rat distal colon through activation of mast cells and enteric neurons
Authors: Xu J‐D , Liu S , Wang W , Li L‐S , Li X‐F , Li Y , Guo H , Ji T , Feng X‐Y , Hou X‐L , Zhang Y , Zhu J‐X 
Published: June 2011

BACKGROUND AND PURPOSE Emodin (1,3,8‐trihydroxy‐6‐methylanthraquinone) is an active component of many herb‐based laxatives. However, its mechanism of action is unclear. The aim of the present study was to investigate the role of mast cells and enteric neurons in emodin‐induced ion secretion in the rat colon.EXPERIMENTAL APPROACH Short‐circuit current (ISC) recording was used to measure epithelial ion transport. A scanning ion‐selective electrode technique was used to directly measure Cl‐ flux (JCl−) across the epithelium. RIA was used to measure emodin‐induced histamine release.KEY RESULTS Basolateral addition of emodin induced a concentration‐dependent increase in ISC in colonic mucosa/submucosa preparations, EC50 75 µM. The effect of emodin was blocked by apically applied glibenclamide, a Cl‐ channel blocker, and by basolateral application of bumetanide, an inhibitor of the Na+‐K+‐2Cl‐ cotransporter. Emodin‐evoked JCl− in mucosa/submucosa preparations was measured by scanning ion‐selective electrode technique, which correlated to the increase in ISC and was significantly suppressed by glibenclamide and bumetanide. Pretreatment with tetrodotoxin and the muscarinic receptor antagonist atropine had no effect on emodin‐induced ΔISC in mucosa‐only preparations, but significantly reduced emodin‐induced ΔISC and JCl− in mucosa/submucosa preparations. The COX inhibitor indomethacin, the mast cell stabilizer ketotifen and H1 receptor antagonist pyrilamine significantly reduced emodin‐induced ΔISC in mucosa and mucosa/submucosa preparations. The H2 receptor antagonist cimetidine inhibited emodin‐induced ΔISC and JCl− only in the mucosa/submucosa preparations. Furthermore, emodin increased histamine release from the colonic mucosa/submucosa tissues.CONCLUSIONS AND IMPLICATIONS The results suggest that emodin‐induced colonic Cl‐ secretion involves mast cell degranulation and activation of cholinergic and non‐cholinergic submucosal neurons.
Hepatic aflatoxin B1‐DNA adducts and TP53 mutations in patients with hepatocellular carcinoma despite low exposure to aflatoxin B1 in southern Japan
Authors: Shirabe Ken , Toshima Takeo , Taketomi Akinobu , Taguchi Kennichi , Yoshizumi Tomoharu , Uchiyama Hideaki , Harimoto Norifumi , Kajiyama Kiyoshi , Egashira Akinori , Maehara Yoshihiko 
Published: June 2011

Abstract
Background & aims: Hepatitis B or C virus infection is considered to be the main cause of hepatocellular carcinoma (HCC) in Japan. Aflatoxin B1 (AFB1) is a carcinogen associated with HCC in regions with high exposure. Mutations in codon 249, exon 7 are a hallmark of AFB1 exposure. Therefore, to clarify the role of AFB1 in hepatocarcinogenesis, we examined AFB1‐DNA in liver tissue and sequenced TP53 in Japanese patients with HCC.
Methods: Hepatocyte AFB1‐DNA adducts were determined immunohistochemically and direct sequencing of TP53 was done to determine mutations in 188 of 279 patients who underwent hepatic resection for HCC. We assessed hepatitis C virus antibodies (HCV Ab) and HBSAg expression; patients without either were defined as having non‐B non‐C hepatocellular carcinoma (NBNC HCC).
Results: AFB1‐DNA adducts were detected in hepatocyte nuclei in 18/279 patients (6%), including13/83 patients (16%) with NBNC HCC and 5/51 patients (10%) expressing hepatitis B surface antigen. None of the patients with HCV Ab (n=136) were positive for AFB1‐DNA. The incidence of the G–T transversion and mutations in exon 7 of TP53 in patients with AFB1‐DNA adducts were significantly higher in patients with than in patients without AFB1‐DNA adducts. All three patients with the codon 249 AGG–AGT mutation had AFB1‐DNA adducts.
Conclusion: Although exposure to AFB1 is thought to be low in Japan, it is still associated with hepatocarcinogenesis, particularly in NBNC HCC and hepatitis B individuals.
A systems biology approach for understanding the collagen regulatory network in alcoholic liver disease
Authors: Nieto Natalia 
Published: June 2011

SummaryAmong the pathogenesis and risk factors of alcoholic liver disease (ALD) are the source of dietary fat, obesity, insulin resistance, adipokines and acetaldehyde. Translocation of Gram‐negative bacteria from the gut, the subsequent effects mediated by endotoxin, and the increased production of matricellular proteins, cytokines, chemokines and growth factors, actively participate in the progression of liver injury. In addition, generation of reactive oxygen and nitrogen species and the activation of non‐parenchymal cells also contribute to the pathophysiology of ALD. A key event leading to liver damage is the transition of quiescent hepatic stellate cells into activated myofibroblasts, with the consequent deposition of fibrillar collagen I resulting in significant scarring. Thus, it is becoming clearer that matricellular proteins are critical players in the pathophysiology of liver disease; however, additional mechanistic insight is needed to understand the signalling pathways involved in the up‐regulation of collagen I protein. At present, systems biology approaches are helping to answer the many unresolved questions in this field and are allowing to more comprehensively identify protein networks regulating pathological collagen I deposition in hopes of determining how to prevent the onset of liver fibrosis and/or to slow disease progression. Thus, this review article provides a snapshot on current efforts for identifying pathological protein regulatory networks in the liver using systems biology tools. These approaches hold great promise for future research in liver disease.
Long‐term effect of maternal HBeAg on delayed HBeAg seroconversion in offspring with chronic hepatitis B infection
Authors: Tseng Yu‐Ru , Wu Jia‐Feng , Ni Yen‐Hsuan , Chen Huey‐Ling , Chen Chih‐Cheng , Wen Wan‐Hsin , Hsu Hong‐Yuan , Chang Mei‐Hwei 
Published: June 2011

Abstract
Background and aims: This cohort study investigated the long‐term effect of maternal hepatitis B virus (HBV) sero‐status on the spontaneous HBeAg seroconversion in offspring with chronic HBV infection.
Methods: A total of 185 HBeAg‐positive chronic HBV‐infected children, with maternal HBV seromarkers checked, were enrolled. The median age at enrolment and follow‐up duration was 5.7 years (range, neonate to 16.5 years) and 20.2 years (range, 4.2–31.0 years) respectively. These children were grouped according to the initial maternal HBsAg and HBeAg status: (i) children of non‐carrier mothers (n=48); (ii) children of HBeAg‐negative chronic HBV‐infected mothers (n=57); (iii) children of HBeAg‐positive chronic HBV‐infected mothers (n=80). HBV seromarkers and liver function profiles of these children were performed at 6‐month intervals.
Results: One hundred and twenty‐one (65.4%) subjects had achieved spontaneous HBeAg seroconversion at the end of this follow‐up study. Spontaneous HBeAg seroconversion was achieved in 83.3% of children with non‐carrier mothers, 73.7% of children with HBeAg‐negative chronic HBV‐infected mothers and 48.8% of children with HBeAg‐positive mothers during similar duration (P<0.001). Positive maternal HBeAg and genotype C were associated with delayed spontaneous HBeAg seroconversion in multivariate analysis (P=0.01 and P=0.002 respectively). In children of HBeAg‐positive chronic HBV‐infected mothers, persistent presence of maternal HBeAg showed a trend of association with delayed HBeAg seroconversion in their offspring (P=0.06). Children of late maternal HBeAg seroconversion (>40 years old) had delayed HBeAg seroconversion compared with those of early HBeAg seroconversion mothers (P=0.06).
Conclusions: Persistence of maternal HBeAg is an important risk factor for delayed spontaneous HBeAg seroconversion in children with chronic HBV infection.
Tooth Tissue Engineering: Optimal Dental Stem Cell Harvest Based on Tooth Development
Authors: Duailibi Monica Talarico , Duailibi Silvio Eduardo , Duailibi Neto Eduardo Felippe , Negreiros Renata Matalon , Jorge Waldyr Antonio , Ferreira Lydia Masako , Vacanti Joseph Phillip , Yelick Pamela Crotty 
Published: June 2011

AbstractOur long‐term objective is to devise reliable methods to generate biological replacement teeth exhibiting the physical properties and functions of naturally formed human teeth. Previously, we demonstrated the successful use of tissue engineering approaches to generate small, bioengineered tooth crowns from harvested pig and rat postnatal dental stem cells (DSCs). To facilitate characterizations of human DSCs, we have developed a novel radiographic staging system to accurately correlate human third molar tooth developmental stage with anticipated harvested DSC yield. Our results demonstrated that DSC yields were higher in less developed teeth (Stages 1 and 2), and lower in more developed teeth (Stages 3, 4, and 5). The greatest cell yields and colony‐forming units (CFUs) capability was obtained from Stages 1 and 2 tooth dental pulp. We conclude that radiographic developmental staging can be used to accurately assess the utility of harvested human teeth for future dental tissue engineering applications.
Outcomes of Displaced and Nondisplaced Pelvic and Sacral Fractures in Elderly Adults
Authors: Mears Simon C. , Berry Daniel J. 
Published: June 2011

OBJECTIVES: To identify fracture types in a series of older adults with pelvic fractures and to determine whether the type of pelvic fracture affected short‐term outcomes and morbidity.DESIGN: Retrospective chart review.SETTING: Teaching hospital.PARTICIPANTS: One hundred eighty‐one individuals aged 65 and older with low‐energy pelvic fractures.MEASUREMENTS:Fracture type, in‐hospital complications, mortality, maximal return to function, and return to living situation.RESULTS: Of the 181 participants, 119 had unilateral displaced pubic rami fractures, 38 had nondisplaced pubic rami fractures, 14 had sacral insufficiency fractures, and 10 had bilateral displaced pubic rami fractures. There were no significant differences found in participant age; comorbidities; diagnosis of dementia; in‐hospital complications; or 30‐day, 90‐day, or 1‐year mortality rates between fracture types. Fracture type did not affect the ability of the participants to return home or their use of ambulatory aid.CONCLUSION: For older adults, morbidity and mortality rates for nondisplaced pubic rami fractures and sacral insufficiency fractures are similar to those for displaced pelvic fractures.
Comparing Antidepressant Treatment Patterns in Older and Younger Adults: A Claims Database Analysis
Authors: Sanglier Thibaut , Saragoussi Delphine , Milea Dominique , Auray Jean‐Paul , Valuck Robert J. , Tournier Marie 
Published: June 2011

OBJECTIVES: To compare depressed older (≥65) and younger (25–64) adults with regard to antidepressant treatment patterns and to assess factors associated with 180‐day nonpersistence.DESIGN: Retrospective matched cohort study.SETTING: U.S. managed care population.PARTICIPANTS: Older and matched younger adults diagnosed with depression and treated with antidepressants.MEASUREMENTS: Sociodemographic characteristics, comorbidities, polypharmacy, and characteristics of antidepressant treatment at 180 days were compared between older and younger adults. Analyses were conducted before and after the implementation of Medicare Part D on January 1, 2006, to consider the effect of this policy.RESULTS: Few participants received psychotherapy, especially older ones; rates were constant before and after 2006. Before 2006, older adults more frequently received antidepressants at lower (odds ratio (OR)=5.38, 95% confidence interval (CI)=3.57–8.13) or intermediate dose (OR=2.42, 95% CI=1.93–3.02) and had poorer adherence to treatment (P<.001) than younger adults. After 2006, older adults received similar proportions of intermediate or high antidepressant doses as younger adults, but a lower dosage was still more likely to be prescribed (OR=1.87, 95% CI=1.09–3.20) and had higher treatment adherence (P<.001). Medication profile did not significantly affect the risk of nonpersistence, but increased with lower antidepressant dose (P<.001). Whereas nonpersistence was higher in older adults before 2006 (hazard ratio (HR)=1.25, 95% CI=1.22–1.46), the trend reversed after 2006 (HR=0.76, 95% CI=0.66–0.88).CONCLUSION: More than half of participants with depression discontinued antidepressant treatment, and psychotherapy was rarely used. Implementation of Medicare Part D was associated with substantial changes in treatment of older adults with depression. The presence of comorbidities or polypharmacy was not associated with nonpersistence in depressed older adults.
Sustained Economic Benefits of Resistance Training in Community‐Dwelling Senior Women
Authors: Davis Jennifer C. , Marra Carlo A. , Robertson M. Clare , Najafzadeh Mehdi , Liu‐Ambrose Teresa 
Published: June 2011

OBJECTIVES:To determine whether the health and cost benefits of resistance training were sustained 12 months after formal cessation of the intervention.DESIGN:Cost–utility analysis conducted alongside a randomized controlled trial.SETTING:Community‐dwelling women aged 65 to 75 living in Vancouver, British Columbia.PARTICIPANTS:One hundred twenty‐three of the 155 community‐dwelling women aged 65 to 75 years who originally were randomly allocated to once‐weekly resistance training (n=54), twice‐weekly resistance training (n=52), or twice‐weekly balance and tone exercises (control group; n=49) participated in the 12‐month follow‐up study. Of these, 98 took part in the economic evaluation (twice‐weekly balance and tone exercises, n=28; once‐weekly resistance training, n=35; twice‐weekly resistance training, n=35).MEASUREMENTS:The primary outcome measure was incremental cost per quality‐adjusted life year (QALY) gained. Healthcare resource utilization was assessed over 21 months (2009 prices); health status was assessed using the EuroQol‐5D to calculate QALYs using a 21‐month time horizon.RESULTS:Once‐ and twice‐weekly resistance training were less costly than balance and tone classes, with incremental mean healthcare costs of Canadian dollars (CAD$)1,857 and CAD$1,077, respectively. The incremental QALYs for once‐ and twice‐weekly resistance training were −0.051 and −0.081, respectively, compared with balance and tone exercises.CONCLUSION:The cost benefits of participating in a 12‐month resistance training intervention were sustained for the once‐ and twice‐weekly resistance training group, whereas the health benefits were not.