bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alteration of cochlear pericytes in response to noise trauma and the involvement of HIF‐1α and VEGF
Authors: Shi Xiaorui 
Published: June 2021

This study explored the effect of acoustic trauma on cochlear pericytes. Transmission electron microscopy revealed that pericytes on the capillaries of the stria vascularis were closely associated with the endothelium in control guinea pigs and mice. Foot processes of the pericytes were tightly positioned adjacent to endothelial cells. Exposure to wide‐band noise at the level of 120 dB for 3 hours per day for two consecutive days produced a significant hearing threshold shift and structurally damaged blood vessels in the stria vascularis. The serum protein, IgG, leaked from capillaries of the stria vascularis. Pericytes lost their tight association with endothelial cells. A pericyte structural protein, desmin, substantially increased after noise exposure in guinea pigs and mice, with a corresponding increase in pericyte coverage of vessels. The increased expression of desmin was associated with the induction of hypoxia‐induced factor (HIF‐1α) and the upregulation of vascular endothelial growth factor (VEGF). Inhibition of HIF‐1αactivity decreased VEGF expression in the vessels of the stria vascularis. Blocking VEGF activity significantly attenuated the expression of desmin in the pericytes. Taken together, these data demonstrate that cochlear pericytes were markedly affected by acoustic trauma and displayed an abnormal morphology. HIF‐1α activation and VEGF upregulation are important factors for the alteration of pericyte structural protein desmin.Supported by NIDCD DC 008888 and NIDCD DC 005983
Role of the proximal tubule AT1A receptor in sodium transport regulation
Authors: Riquier Anne DM , McDonough Alicia A , Kou Dow‐Ning , Coffman Thomas M , Gurley Susan B 
Published: June 2021

Chronic AngII infusion raises blood pressure (BP) in mice which depends on renal AngII receptors (AT1R). AngII is anti‐natriuretic while high BP is natriuretic.Aim 1To determine how AngII infusion affects Na+ transporter abundance and phosphorylation (by immunoblot of homogenates). AngII infusion (1 μg/kg/min x 14d) increases systolic BP ~30 mmHg. Versus sham infused (=1.0), AngII decreased total NHE3 to 0.7±0.1, NHE3‐P (at Ser552) to 0.8±0.1 without altering NHE3 ‐P/total ratio. NaPi2 and myosin VI were unchanged. Distal convoluted tubule (DCT) total NCC increased to 2.2±0.3, NCC‐P (at Thr60) to 5.4 ± 1.6 and NCC‐P/total ratio to 2.2±0.5 fold.Aim 2To determine the role of proximal tubule (PT) AT1R in regulation of Na+ transporters in mice lacking PT AT1R (KO). BP decreased 10mmHg in KO vs. WT and baseline expression of NHE3, NaPi2, and NCC were unchanged in KO vs. WT. AngII infusion increased BP 20mmHg less than in WT. AngII infusion in KO decreased: total NHE3 to 0.55±0.1, NHE3‐P to 0.66±0.1 (no change in ‐P/total NHE3 ratio), myosin VI to 0.56±0.1, NaPi2 to 0.64±0.1. NCC total and NCC‐P were unchanged in the AngII infused KO.Conclusions1) increased NCC contributes to AngII induced high BP while decreased PT NHE3 compensates for high BP in WT, 2) AngII dependent increase in NCC depends on PT AT1R, and 3) the removal of PT AT1R facilitates pressure natriuresis by further decreasing PT transporters during AngII infusion.
Angiotensin II and Oxidative Stress Increases JNK and IRS‐1ser307 Activity and Inhibits Insulin Signal Transduction in Rats with Insulin Resistance Induced by Low Salt Intake
Authors: Coelho Michella Soares , Negri Heloisa B. , Oliveira Ivone B. , Ferreira Daniele N. , Shimizu Maria HM. , Casarini Dulce E. , Prada Patricia O. , Dolnikoff Miriam S. , Saad Mario JA. , Heimann Joel C. 
Published: June 2021

Low salt diet (LS) increases angiotensin II (AII) and oxidative stress (TBARS), which may enhance JNK and IRS1ser307 phosphorylation (PP) decreasing insulin signaling (INS‐S).ObjectiveTo evaluate if losartan (LOS) improves INS resistance by decreasing JNK and IRS1ser307 PP.MethodsTwelve‐week‐old rats were fed a LS (0.15% NaCl) or normal salt diet (NS: 1.3%) since weaning. Groups: LS+LOS (30mg/kg/day), LS+vehicle, NS+LOS and NS+vehicle. Blood pressure (BP), blood glucose (G), plasma INS and TBARS, HOMA, and tissue AII were evaluated. The INS‐S and inflammatory signaling (IS) were determined by Western blot and immunoprecipitation. AT1 receptor gene expression was determined by RT‐PCR.Results (mean±SEM, P<0.05, n=8)BP and AT1 did not differ among groups. INS, HOMA and TBARS were higher in LS (INS: 712±60) than in NS (257±40 pmol/l). G and TBARS were lower and INS was higher in LS+LOS (TBARS: 4±0.5) than in LS (6±1 nmol/ml). Liver AII was higher in LS than in NS. INS receptor and Akt PP were higher and JNK (120±3) and IRS1ser307 PP (100±6 AU) were lower in the liver of LS+LOS compared to LS. IkBα PP was lower in LS (20±2) than in NS (100±4 AU) suggesting an activation of IS in LS. Similar results were observed in the muscle.ConclusionsINS resistance induced by LS is associated with alterations in regulation of INS‐S, activated IS, and higher tissue AII and TBARS. In LS, LOS improves INS‐S by decreasing JNK and IRS1ser307 PP with no change in BP.FAPESP
Dual effect of Alternariol on Acetylcholinestrase and Monoamine oxidase Extracted from Different Parts of Rat Brain
Authors: Osman Mohamed Yousry Hassan , Osman Hassan Mohamed Yousry 
Published: June 2021

Alternariol is a metabolite product of different strains of alternaria tenuis. It's structure has a similarity to cannabinol derivatives .It has a chemical formula 3,4,5 trihydroxy 6‐ methyl dibenzox ‐pyrone.The effect of the alternariol on both acetylcholinestrase (AChE) and monoamineoxidase ( MAO) isozymes which were extracted from whole brain male albino rats and it's different five parts namely : frontal cortex, basal ganglia, cerebellum, pons , medulla oblongata was studied. Kinetic studies were done to determine the type of inhibition of AChE and MAO isozyme, and the enzyme ‐inhibitor dissociation constant (Ki) by alternariol.The results indicated that alternariol inhibited both AChE and MAO isozymes of the cortex and cerebellam more than the extracts of the other parts of the brain .These parts are responsible for perception , motor, sensony, psychic activities, coordination of movements and balance.The inhibition of these isozymes increased with increasing the amount of alternariol added to the assay mixture, i.e., the inhibition was dose dependent and of the competitive type. The values of Ki for alternariol ‐ AChE isozymesvaried from 12.0 to 15.0 mmol/L and for alternariol ‐ MAO isozymes varied from 28 to 30 mmol/L.The difference in the degree of inhibition of the extracts of these parts of the brain could be attributed to the slight difference in the structure ( arrangement of the amino acids) of these isozymes ( isozyme phenomenon) and to the distinct gene loci. The inhibition of AChE and MAO by alternariol may save ACh and biogenic amines which are ofgreat importance for the patients suffering from Alzheimer and dementia.
Aerobic capacity of African American males: Association with serum levels of IGF‐1, IGF‐1 binding protein and prostate cancer cell growth
Authors: Sridhar Rajagopalan , Bond Vernon , Cousins Valerie Marie , Jackson Anwar , Millis Richard , Zhang Renshu 
Published: June 2021

Prostate cancer incidence is disproportionately high in blacks. High levels of insulin‐like growth factor‐1 (IGF‐1) and low levels of insulin‐like growth factor binding protein‐3 (IGFBP‐3) are associated with increased risk for prostate cancer. This study examined levels of IGF‐1 and IGFBP‐3 in African American males with low (N=8) and high (N=9) levels of aerobic fitness. The growth rate of LNCaP human prostate cancer cells were examined in culture medium fortified with serum from different individuals. RPMI‐1640 medium was supplemented with 10% serum from each individual for comparing the relative abilities of sera to support the growth of androgen sensitive LNCaP cancer cells. Cell growth was estimated using the MTT assay for cell proliferation. The serum concentrations of testosterone, IGF‐1, and IGFBP‐3 were measured using ELISA kits. Serum levels of IGF‐1 were significantly higher in the low fitness group compared to the high fitness group (p<0.05). Serum levels of IGFBP‐3 in the high fitness group were significantly higher compared to those in the low fitness group (p<0.01). Growth rates of LNCaP cells were significantly higher in medium supplemented with sera from men in the low fitness group compared to those from high fitness group (p<0.05). There was no significant intergroup difference in serum testosterone levels. These results suggest that the rate of prostate cancer cell growth may be higher in sedentary men than in physically active men.(Supported in part by USMRMC grant DAMD17‐03‐1‐0123 and grant 2G12 RR003048 from RCMI program of NCRR, NIH and grant R25 HL003679 from HLBI, NIH)
Enhancing Production of Recombinant BMP‐2 in Mammalian Cell Culture
Authors: Zhou Aileen , Clokie Cameron ML , Peel Sean AF 
Published: June 2021

BackgroundBone morphogenetic proteins (BMPs) have been used successfully for bone repair; however recombinant BMPs are produced at relatively low yields in mammalian cells. Literature suggests the BMP pro‐domain may be involved in folding, stability, and secretion of the mature protein.ObjectiveInvestigate inhibition of pro‐domain cleavage on recombinant BMP‐2 production.MethodsCHO cells transfected with the hBMP‐2 gene were cultured in the presence of various concentrations of the pro‐protein convertase inhibitor IND‐1 in 24 and 72hr multi‐well, and two‐month bioreactor cultures. Mature and proBMP‐2 secretion was measured by enzyme‐linked immunosorbent assay and characterized by Western blot. BMP activity was determined by C2C12 bioassay. Cytotoxicity was determined by lactate dehydrogenase assay and cell viability counts.ResultsIND‐1 significantly enhanced secretion of both pro‐ and mature recombinant human BMP‐2 (rhBMP‐2) in short and long term cultures, without negative effects on cell growth or viability. The rhBMP‐2 was biologically active. ProBMP‐2 could be converted by enzymatic treatment into mature BMP‐2.ConclusionsAddition of IND‐1 in cell culture medium increased rhBMP‐2 production in CHO‐BMP2 cells and is a simple, but effective way to enhance the production of active rhBMP‐2 in such production systems.GrantOral Surgery Foundation.
Adult rats, but not adolescents, become tolerant to Δ9‐tetrahydrocannabinol in a hippocampal learning task
Authors: Moore Nicole L T , Wilson Wilkie A , Swartzwelder H Scott , Kuhn Cynthia M 
Published: June 2021

Previous work in rats has shown that adolescent spatial learning in the Morris water maze task is more impaired by Δ9‐tetrahydrocannabinol (THC) than in adults, especially during the first three days of training. We hypothesized that development of tolerance in adults but not adolescents might mediate this difference. To investigate this hypothesis, we evaluated water maze performance and CB1 receptor function after brief repeated treatment with THC. Adolescents (PN28‐35) or adults (PN70‐75) were treated with THC (10 mg/kg) or vehicle for 5 days. Then they began water maze training, receiving vehicle or additional THC (10 mg/kg) during each day of training. To assess receptor function, adolescent and adult rats were treated with THC (10 mg/kg) or vehicle for 3 or 7 days, CB1 receptor function assessed by the ability of the agonist WIN55,212‐2 to stimulate GTPγS activation. Adults pre‐treated with THC were significantly less impaired by THC during training, whereas adolescents showed no effect of THC pre‐treatment. Hippocampal membrane GTPγS assays showed that adult CB1 receptors became more desensitized than adolescents. We conclude that greater THC‐induced adolescent learning impairment is due to lesser tolerance development to THC in adolescents.Supported by R01‐DA019346.
CFA and IFA can independently provoke myocarditis in rats
Authors: Morozova Marya P , Gavrilova Svetlana A , Knyazhentseva Alina K , Zemcova Ludmila V , Pogodina Larisa S , Chentsov Yury S 
Published: June 2021

The aim of this research was producing model of autoimmune myocarditis induced by immunization with cardiac myosin and identification of acute stage of inflammation.We shown that single subcutaneous injection of cardiac myosin (400 μg/kg) combined with incomplete Freund's adjuvant (CFA) or CFA alone led to inflammatory response in rat myocardium with maximal reaction on 14–21 days after immunization. It was earlier confirmed by test of antibody levels in blood serum, light and electron microscopy of heart sections, expression of inflammatory cytokines and iNOS by RT‐PCR methods and analysis of nitrite and nitrate levels in blood serum and myocardial homogenates on 2, 3, 4, 7, 14, 21 and 28 days after immunization. We substituted CFA by incomplete Freund's adjuvant (IFA) without Mycobacterium tuberculosis wall components and repeated experiment and all testes on 4, 14 and 21 days. Our data shown that immunization of rats with myosin mixed with IFA caused the inflammatory response in myocardium on 4 day with maximum was detected on 21 day. In IFA injected rats the inflammation was also detected, but had a slow onset and developed to 21 day's.We examined two models of autoimmune myocarditis and shown that CFA and IFA can independently provoke inflammation in myocardium.
FGF‐2 Regulates Valve Interstitial Cell Repair Through TGF‐b/Smad Signaling
Authors: Han Li , Gotlieb Avrum I 
Published: June 2021

BackgroundTransforming growth factor‐β (TGF‐β) and fibroblast growth factor‐2 (FGF‐2) both promote valve interstitial cell (VIC) repair. The relationship between TGF‐β and FGF‐2 in wound repair is not understood.MethodsVIC confluent monolayers were wounded and treated with FGF‐2, FGF‐2 neutralizing antibody, TGF‐β neutralizing antibody and/or betaglycan antibody. Phosphorylated‐Smad2/3 (pSmad2/3) was localized at the wound edge (WE). Down‐regulation of pSmad2/3 protein expression was achieved via siRNA transfection.ResultsFGF‐2 treatment increased the number of VICs with nuclear pSmad2/3 staining at the WE compared to nontreated WE. Treatment with TGF‐β neutralizing antibody alone or with FGF‐2 present resulted in a similar decrease in nuclear pSmad2/3. Treatment with FGF‐2 neutralizing antibody alone or with FGF‐2 present showed a similar decrease in nuclear pSmad2/3; however the effect of FGF‐2 neutralizing antibody was less than that of TGF‐β neutralizing antibody. Incubation with betaglycan antibody inhibited FGF‐2‐mediated pSmad2/3 signaling. Down‐regulation of pSmad2/3 reduced the extent to which FGF‐2 promoted wound closure.ConclusionFGF‐2 promotes in vitro VIC wound repair, at least in part, through the TGF‐β/Smad2/3 signaling pathway. Supported by the Heart and Stroke Foundation of Ontario (grant NA6204) and the Canadian Institutes for Health Research (grant 84228).
Fatty acid amide hydrolase is a key regulator of the endocannabinoid‐induced myocardial tissue injury
Authors: Horvath Bela , Mukhopadhyay Partha , Rajesh Mohanraj , Matsumoto Shingo , Saito Keita , Bátkai Sándor , Gao Yue R , Cravatt Benjamin F , Haskó György , Pacher Pál 
Published: June 2021

Increased levels of endocannabinoids in various cardiovascular disorders (e.g. shock, cardiomyopathies, atherosclerosis) through the activation of CB1 cannabinoid receptors may promote cardiovascular dysfunction and tissue injury. We have investigated the role of the main endocannabinoid anandamide metabolizing enzyme (the fatty acid amide hydrolase; FAAH) in the myocardial injury induced by an important chemotherapeutic drug doxorubicin (DOX; known for its cardiotoxicity mediated by increased reactive oxygen and nitrogen species generation) using well‐established acute and chronic cardiomyopathy models in mice. The DOX‐induced myocardial oxidative/nitrative stress correlated with multiple cell death markers, which were enhanced in FAAH knockout mice exhibiting significantly increased DOX‐induced mortality and cardiac dysfunction compared to their wild type littermates. The effects of DOX in FAAH knockout mice were attenuated by CB1 receptor antagonists. Furthermore, anandamide induced enhanced cell death in human cardiomyocytes pretreated by FAAH antagonist, and enhanced ROS generation in inflammatory cells of FAAH knockouts. These results suggest that in pathological conditions associated with acute oxidative/nitrative stress FAAH plays a key role in controlling the tissue injury, which is, at least in part, mediated by the activation of CB1 receptors by endocannabinoids.This study was supported by the Intramural Research Program of NIH/NIAAA (P.P.) and OTKA MB08‐A 80238 (B.H.)
Histomorphometric comparison of temporal and masseter muscles on an experimental malocclusion model
Authors: Gomes Marcolino , Farinha Rodrigo , Cabrita A.M. Silvério 
Published: June 2021

Occlusal disarrangements are very often in the basis of the temporomandibular disfunction's sintomatology, and can course with muscular involvement. The aim of this study is to contribute to the understanding of pre‐morphologic changes in the masseter and temporal muscles in an experimental model of malocclusion, by morphometric analysis of muscular fibers areas, in transversal cuts.20 male Wistar rats, 12 weeks old were distributed in 2 groups: the control (I), with the animals kept in the standard conditions and the test (II), in which we created a change of the normal occlusal contacts by adding fotopolimerized resin on the right upper teeth. After 2 weeks, all animals were sacrificed and the complete necropsy performed. Fractions of masseter and temporal muscles were collected for histopathological and morphometric analysis (using ImageJ).The average area of muscle fibers on transversal section was bigger on masseter muscle of the left side, on group II. On the right side, we observed the opposite, with smaller average areas on group II.The temporal muscle presented with an average area of muscle fibers much bigger on group II. These results suggest that both muscles are influenced by occlusal interferences, although the response is quite different between them. It was observed a difference of response on working and non‐working masseter muscles, too.
Nuclear localized GRP75 binds to retinoic acid receptors (RAR/RXR) and promotes retinoic acid‐induced neuronal differentiation of neuroblastoma
Authors: Shih Yu‐Yin , Pan Chien‐Yuan , Hsu Wen‐Ming , Liao Yung‐Feng 
Published: June 2021

Neuroblastoma (NB) is the most common and deadly extracranial solid tumor in children. Retinoic acid (RA) has been used in clinic to treat NB by inducing neuronal differentiation of tumor cells. We previously found that glucose‐regulated protein 75 (GRP75) is correlated with the RA‐elicited neuronal differentiation of NB cells. In the present study, we further demonstrated that GRP75 can be translocated into nucleus and interact with retinoic acid receptor (RAR)α and retinoid X receptor (RXR)α to augment RA‐elicited neuronal differentiation. Down‐regulation of GRP75 diminishes the recruitment of RARα/RXRα to the retinoic acid response element (RARE) in the regulatory region of RA target gene promoters, resulting in a significant decrease in RA‐triggered gene expression. GRP75 also plays an essential role in stabilizing RARα/RXRα complexes in the presence of RA by reducing the proteasome‐mediated degradation of RARα and RXRα. Most intriguingly, the interaction between GRP75 and RARα/RXRα receptors was tightly associated with favorable outcome in NB patients and in a xenograft NB mouse model. Together, our present findings delineate a mechanism underlying the GRP75‐dependent regulation of RARα/RXRα‐mediated gene expression in the RA‐induced neuronal differentiation of NB, providing the basis for the development of novel therapeutics for NB.Grant Funding Source: Academia Sinica
Report of a cubilin deficient patient
Authors: Storm Tina , Emma Francesco , Verroust Pierre J. , Hertz Jens Michael , Nielsen Rikke , Christensen Erik Ilsø 
Published: June 2021

BackgroundCubilin is an important receptor involved in intestinal absorption of vitamin B12 and reabsorption of proteins from the glomerular ultrafiltrate. Murine studies furthermore suggest that both cubilin and the receptor partner amnionless are essential for normal embryonic development. Cubilin function is affected in Imerslund‐Gräsbeck syndrome (IGS) patients. IGS is a rare, autosomal recessive disorder characterized by a selective, intestinal, intrinsic factor‐vitamin B12 malabsorption and is often accompanied by an additional proteinuria.AimTo investigate the role of cubilin in renal protein handling in a patient with cubilin deficiency.ResultsA novel homozygous null mutation of the CUBN gene was identified in a conserved donor splice site in a male IGS patient. No cubilin was detected in a renal biopsy and an abnormal, cytoplasmic distribution of the receptor partner amnionless was also observed. Immunoblotting of patient urine, accordingly, showed selective tubular proteinuria with increased excretion of cubilin ligands.ConclusionsThis clearly demonstrates a central role of cubilin in handling of filtered proteins in the human kidney and demonstrates the interdependent relationship of cubilin and amnionless in man. This patient furthermore, presented with no additional developmental abnormalities suggesting that cubilin is not essential for human embryonic development.
Lymphocytic Variant of Hypereosinophilic Syndrome: diagnostic features of a rare entity
Authors: SHAHAB ASIF SAIYED , ZULFIQAR MUHAMMAD IMRAN 
Published: June 2021

Hypereosinophilic syndrome (HES) includes a spectrum of diseases with eosinophilia and tissue damage. Two idiopathic causes of HES are the myeloproliferative variant (M‐HES)and the lymphocytic variant (L‐HES). L‐HES is a rare entity. It is characterized by clonal population of phenotypically abnormal T‐ lymphocytes. Clinical manifestations vary but cutaneous involvement is common. In this case we report a patient diagnosed with L‐HES with no clinical symptoms on presentation.A 56 year old male was initially being evaluated for leukocytosis with a differential showing 33% eosinophilia. Physical exam was unremarkable. The patient had an extensive workup to rule out secondary causes. Bone marrow biopsy revealed cellular marrow with eosinophilia (10% of cellularity). No evidence of myeloproliferative disorders. JAK2 mutation was negative as well as FISH for bcl‐abr gene and PDGFRA gene. Flow cytometry revealed an unusual population of CD4+, CD2+, CD3‐, and CD8‐ T‐lymphocytes.HES is an extremely heterogeneous disorder. Diagnostic criteria includes persistent eosinophilia of 1.5 × 109 eosinophils/L of blood, lack of evidence for secondary causes and presumptive signs of organ involvement. The L‐HES is an uncommon variant. Patients usually present with dermatologic manifestations. GI symptoms and obstructive lung disease are also common. Endomyocardial fibrosis and myelofibrosis are rarely seen. Cytokine IL‐5 also plays a role in pathogenesis. The most prevalent T cell clone associated with LHES seems to be the CD3‐CD4+ clone. L‐HES has a much better prognosis than M‐HES but patients with the CD3‐CD4+ clone can progress to T cell lymphoma. Despite the relatively low mortality in patients with LHES, morbidity is significant. L‐HES is steroid responsive while M‐HES is not. It is crucial to differentiate between the variants because of the vastly different treatment regimens and thus disease course.