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[PMID]:28681695
[Au] Autor:Yu H; Zhang X; Liu R; Li H; Xiao X; Zhou Y; Wei C; Yang M; Liao M; Zhao J; Xia Z; Liao Q
[Ad] Endereço:1 Xiangya Hospital, Central South University, Changsha, P.R. China.
[Ti] Título:Mcl-1 suppresses abasic site repair following bile acid-induced hepatic cellular DNA damage.
[So] Source:Tumour Biol;39(7):1010428317712102, 2017 Jul.
[Is] ISSN:1423-0380
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In cholestasis, increases in bile acid levels result in the generation of reactive oxygen species and the induction of DNA damage and mutation. It is believed that bile acid accumulation is associated with liver tumorigenesis. However, the mechanism that underpins this phenomenon remains to be elucidated. Mcl-1, which is overexpressed in hepatic cells, is a pro-survival member of the Bcl-2 family. In this study, we observed that Mcl-1 potently suppresses the repair of bile acid-induced abasic (apurinic/apyrimidinic) sites in DNA lesions. Upon exposure of hepatic cells to glycochenodeoxycholate, one of the major conjugated human bile acids, we observed an increase in AP site accumulation along with induction of poly(ADP-ribose) polymerase and XRCC1 ( X-Ray Repair Cross Complementing 1). In addition, accumulation of Mcl-1 was observed in the nuclei of QGY-7703 cells in response to glycochenodeoxycholate stimulation. Knockdown of endogenous Mcl-1 by RNA interference significantly accelerated the repair of DNA lesions in glycochenodeoxycholate-treated cells. However, unlike XRCC1, poly(ADP-ribose) polymerase was induced following Mcl-1 knockdown. Conversely, poly(ADP-ribose) polymerase suppression was observed following glycochenodeoxycholate treatment of cells overexpressing Mcl-1. Moreover, AP-site counting analyses revealed that DNA repair activity was enhanced in cells overexpressing poly(ADP-ribose) polymerase under glycochenodeoxycholate stress conditions. It is well known that poly(ADP-ribose) polymerase plays a crucial role in the base excision repair pathway. Thus, our findings suggest that Mcl-1 suppresses base excision repair by inhibiting poly(ADP-ribose) polymerase induction following glycochenodeoxycholate-induced DNA damage. These results potentially explain how bile acid accumulation results in genetic instability and carcinogenesis.
[Mh] Termos MeSH primário: Colestase/genética
Proteínas de Ligação a DNA/genética
Neoplasias Hepáticas/genética
Proteína de Sequência 1 de Leucemia de Células Mieloides/genética
Poli(ADP-Ribose) Polimerases/genética
[Mh] Termos MeSH secundário: Ácido Apurínico/genética
Ácidos e Sais Biliares/normas
Ácidos e Sais Biliares/toxicidade
Colestase/metabolismo
Colestase/patologia
Dano ao DNA/efeitos dos fármacos
Reparo do DNA/genética
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Técnicas de Silenciamento de Genes
Ácido Glicoquenodesoxicólico/toxicidade
Células Hep G2
Hepatócitos/efeitos dos fármacos
Hepatócitos/metabolismo
Hepatócitos/patologia
Seres Humanos
Neoplasias Hepáticas/metabolismo
Neoplasias Hepáticas/patologia
Espécies Reativas de Oxigênio/metabolismo
Proteína 1 Complementadora Cruzada de Reparo de Raio-X
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (DNA-Binding Proteins); 0 (MCL1 protein, human); 0 (Myeloid Cell Leukemia Sequence 1 Protein); 0 (Reactive Oxygen Species); 0 (X-ray Repair Cross Complementing Protein 1); 0 (XRCC1 protein, human); 11002-22-5 (Apurinic Acid); 640-79-9 (Glycochenodeoxycholic Acid); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170707
[St] Status:MEDLINE
[do] DOI:10.1177/1010428317712102


  2 / 213 MEDLINE  
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[PMID]:28336546
[Au] Autor:Minacapelli CD; Bajpai M; Geng X; Cheng CL; Chouthai AA; Souza R; Spechler SJ; Das KM
[Ad] Endereço:Division of Gastroenterology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey; and.
[Ti] Título:Barrett's metaplasia develops from cellular reprograming of esophageal squamous epithelium due to gastroesophageal reflux.
[So] Source:Am J Physiol Gastrointest Liver Physiol;312(6):G615-G622, 2017 Jun 01.
[Is] ISSN:1522-1547
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Gastroesophageal reflux disease (GERD) clinically predisposes to columnar Barrett's metaplasia (BM) in the distal esophagus. We demonstrate evidence supporting the cellular origin of BM from reprograming or transcommitment of resident normal esophageal squamous (NES) epithelial cells in response to acid and bile (A + B) exposure using an in vitro cell culture model. The hTERT-immortalized NES cell line NES-B10T was exposed 5 min/day to an A + B mixture for 30 wk. Morphological changes, mRNA, and protein expression levels for the inflammatory marker cyclooxygenase-2; the lineage-determining transcription factors TAp63 (squamous), CDX2, and SOX9 (both columnar); and the columnar lineage markers Villin, Muc-2, CK8, and mAb Das-1 (incomplete phenotype of intestinal metaplasia) were assessed every 10 wk. Markers of columnar lineage and inflammation increased progressively, while squamous lineage-determining transcriptional factors were significantly decreased both at the mRNA and/or protein level in the NES-B10T cells at/after A + B treatment for 30 wk. Distinct modifications in morphological features were only observed at/after 30 wk of A + B exposure. These changes acquired by the NES-B10T 30-wk cells were retained even after cessation of A + B exposure for at least 3 wk. This study provides evidence that chronic exposure to the physiological components of gastric refluxate leads to repression of the discernable squamous transcriptional factors and activation of latent columnar transcriptional factors. This reflects the alteration in lineage commitment of the precursor-like biphenotypic, NES-B10T cells in response to A + B exposure as the possible origin of BM from the resident NES cells. This study provides evidence of the origins of Barrett's metaplasia from lineage transcommitment of resident esophageal cells after chronic exposure to gastroesophageal refluxate. The preterminal progenitor-like squamous cells alter their differentiation and develop biphenotypic characteristics, expressing markers of incomplete-type columnar metaplasia. Development of these biphenotypic precursors in vitro is a unique model to study pathogenesis of Barrett's metaplasia and esophageal adenocarcinoma.
[Mh] Termos MeSH primário: Esôfago de Barrett/etiologia
Reprogramação Celular
Células Epiteliais/patologia
Mucosa Esofágica/patologia
Refluxo Gastroesofágico/complicações
[Mh] Termos MeSH secundário: Esôfago de Barrett/metabolismo
Esôfago de Barrett/patologia
Linhagem Celular Transformada
Linhagem da Célula
Forma Celular
Reprogramação Celular/efeitos dos fármacos
Células Epiteliais/efeitos dos fármacos
Células Epiteliais/metabolismo
Mucosa Esofágica/efeitos dos fármacos
Mucosa Esofágica/metabolismo
Regulação da Expressão Gênica
Ácido Glicoquenodesoxicólico/toxicidade
Seres Humanos
Ácido Clorídrico/toxicidade
Metaplasia
Fenótipo
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Telomerase/genética
Telomerase/metabolismo
Fatores de Tempo
Fatores de Transcrição/genética
Fatores de Transcrição/metabolismo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Messenger); 0 (Transcription Factors); 640-79-9 (Glycochenodeoxycholic Acid); EC 2.7.7.49 (TERT protein, human); EC 2.7.7.49 (Telomerase); QTT17582CB (Hydrochloric Acid)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170811
[Lr] Data última revisão:
170811
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170325
[St] Status:MEDLINE
[do] DOI:10.1152/ajpgi.00268.2016


  3 / 213 MEDLINE  
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[PMID]:27490694
[Au] Autor:González-Rubio S; Linares CI; Aguilar-Melero P; Rodríguez-Perálvarez M; Montero-Álvarez JL; de la Mata M; Ferrín G
[Ad] Endereço:Maimonides Institute of Biomedical Research in Córdoba (IMIBIC), Reina Sofía University Hospital, University of Córdoba, Córdoba, Spain.
[Ti] Título:AP-1 Inhibition by SR 11302 Protects Human Hepatoma HepG2 Cells from Bile Acid-Induced Cytotoxicity by Restoring the NOS-3 Expression.
[So] Source:PLoS One;11(8):e0160525, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The harmful effects of bile acid accumulation occurring during cholestatic liver diseases have been associated with oxidative stress increase and endothelial nitric oxide synthase (NOS-3) expression decrease in liver cells. We have previously reported that glycochenodeoxycholic acid (GCDCA) down-regulates gene expression by increasing SP1 binding to the NOS-3 promoter in an oxidative stress dependent manner. In the present study, we aimed to investigate the role of transcription factor (TF) AP-1 on the NOS-3 deregulation during GCDCA-induced cholestasis. The cytotoxic response to GCDCA was characterized by 1) the increased expression and activation of TFs cJun and c-Fos; 2) a higher binding capability of these at position -666 of the NOS-3 promoter; 3) a decrease of the transcriptional activity of the promoter and the expression and activity of NOS-3; and 4) the expression increase of cyclin D1. Specific inhibition of AP-1 by the retinoid SR 11302 counteracted the cytotoxic effects induced by GCDCA while promoting NOS-3 expression recovery and cyclin D1 reduction. NOS activity inhibition by L-NAME inhibited the protective effect of SR 11302. Inducible NOS isoform was no detected in this experimental model of cholestasis. Our data provide direct evidence for the involvement of AP-1 in the NOS-3 expression regulation during cholestasis and define a critical role for NOS-3 in regulating the expression of cyclin D1 during the cell damage induced by bile acids. AP-1 appears as a potential therapeutic target in cholestatic liver diseases given its role as a transcriptional repressor of NOS-3.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Regulação para Baixo/efeitos dos fármacos
Ácido Glicoquenodesoxicólico/toxicidade
Óxido Nítrico Sintase Tipo III/metabolismo
Retinoides/farmacologia
Fator de Transcrição AP-1/metabolismo
[Mh] Termos MeSH secundário: Carcinoma Hepatocelular/metabolismo
Carcinoma Hepatocelular/patologia
Ciclina D1/antagonistas & inibidores
Ciclina D1/metabolismo
Genes Reporter
Células Hep G2
Seres Humanos
Neoplasias Hepáticas/metabolismo
Neoplasias Hepáticas/patologia
NG-Nitroarginina Metil Éster/farmacologia
Óxido Nítrico Sintase Tipo III/antagonistas & inibidores
Estresse Oxidativo/efeitos dos fármacos
Regiões Promotoras Genéticas
Proteínas Proto-Oncogênicas c-fos/metabolismo
Proteínas Proto-Oncogênicas c-jun/metabolismo
Retinoides/química
Retinoides/metabolismo
Fator de Transcrição AP-1/antagonistas & inibidores
Regulação para Cima/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Proto-Oncogene Proteins c-fos); 0 (Proto-Oncogene Proteins c-jun); 0 (Retinoids); 0 (SR 11302); 0 (Transcription Factor AP-1); 136601-57-5 (Cyclin D1); 640-79-9 (Glycochenodeoxycholic Acid); EC 1.14.13.39 (NOS3 protein, human); EC 1.14.13.39 (Nitric Oxide Synthase Type III); V55S2QJN2X (NG-Nitroarginine Methyl Ester)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170823
[Lr] Data última revisão:
170823
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160805
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0160525


  4 / 213 MEDLINE  
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[PMID]:27050423
[Au] Autor:Lang E; Pozdeev VI; Gatidis S; Qadri SM; Häussinger D; Kubitz R; Herebian D; Mayatepek E; Lang F; Lang KS; Lang PA
[Ti] Título:Bile Acid-Induced Suicidal Erythrocyte Death.
[So] Source:Cell Physiol Biochem;38(4):1500-9, 2016.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: In nucleated cells, bile acids may activate cation channels subsequently leading to entry of Ca2+. In erythrocytes, increase of cytosolic Ca2+ activity triggers eryptosis, the suicidal death of erythrocytes characterized by phosphatidylserine exposure at the cell surface and cell shrinkage. Eryptosis is triggered by bile duct ligation, an effect partially attributed to conjugated bilirubin. The present study explored, whether bile acids may stimulate eryptosis. METHODS: Phosphatidylserine exposing erythrocytes have been identified utilizing annexin V binding, cell volume estimated from forward scatter, cytosolic Ca2+ activity determined using Fluo-3 fluorescence, and ceramide abundance at the erythrocyte surface utilizing specific antibodies. RESULTS: The exposure of human erythrocytes to glycochenodesoxycholic (GCDC) and taurochenodesoxycholic (TCDC) acid was followed by a significant decrease of forward scatter and significant increase of Fluo-3 fluorescence, ceramide abundance as well as annexin V binding. The effect on annexin V binding was significantly blunted, but not abolished by removal of extracellular Ca2+. CONCLUSION: Bile acids stimulate suicidal cell death, an effect paralleled by and in part due to Ca2+ entry and ceramide. The bile acid induced eryptosis may in turn lead to accelerated clearance of circulating erythrocytes and, thus, may contribute to anemia in cholestatic patients.
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/toxicidade
Eriptose/efeitos dos fármacos
[Mh] Termos MeSH secundário: Compostos de Anilina/química
Compostos de Anilina/metabolismo
Cálcio/metabolismo
Células Cultivadas
Ceramidas/metabolismo
Colagogos e Coleréticos/farmacologia
Detergentes/farmacologia
Eritrócitos/citologia
Eritrócitos/efeitos dos fármacos
Eritrócitos/metabolismo
Citometria de Fluxo
Ácido Glicoquenodesoxicólico/toxicidade
Hemólise/efeitos dos fármacos
Seres Humanos
Fosfatidilserinas/metabolismo
Ácido Tauroquenodesoxicólico/toxicidade
Xantenos/química
Xantenos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aniline Compounds); 0 (Bile Acids and Salts); 0 (Ceramides); 0 (Cholagogues and Choleretics); 0 (Detergents); 0 (Phosphatidylserines); 0 (Xanthenes); 23D4W0B50Y (Fluo-3); 516-35-8 (Taurochenodeoxycholic Acid); 640-79-9 (Glycochenodeoxycholic Acid); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170206
[Lr] Data última revisão:
170206
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160407
[St] Status:MEDLINE
[do] DOI:10.1159/000443091


  5 / 213 MEDLINE  
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[PMID]:26999807
[Au] Autor:Webster CR; Anwer MS
[Ad] Endereço:Department of Clinical Science, Cummings School of Veterinary Medicine at Tufts University, Grafton, Massachusetts; and cynthia.leveille-webster@tufts.edu.
[Ti] Título:Hydrophobic bile acid apoptosis is regulated by sphingosine-1-phosphate receptor 2 in rat hepatocytes and human hepatocellular carcinoma cells.
[So] Source:Am J Physiol Gastrointest Liver Physiol;310(10):G865-73, 2016 May 15.
[Is] ISSN:1522-1547
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The hepatotoxic bile acid glycochenodeoxycholate (GCDC) modulates hepatocyte cell death through activation of JNK, Akt, and Erk. The nonhepatotoxic bile acid taurocholate activates Akt and Erk through the sphingosine-1-phosphate receptor 2 (S1PR2). The role of the S1PR2 in GCDC-mediated apoptosis and kinase activation is unknown. Studies were done in rat hepatocytes, HUH7 cells, and HUH7 cells stably transfected with rat Ntcp (HUH7-Ntcp). Cells were treated with GCDC and apoptosis was monitored morphologically by Hoechst staining and biochemically by immunoblotting for the active cleaved fragment of caspase 3. Kinase activation was determined by immunoblotting with phospho-specific antibodies. JTE-013, an inhibitor of S1PR2, significantly attenuated morphological evidence of GCDC-induced apoptosis and prevented caspase 3 cleavage in rat hepatocytes and HUH7-Ntcp cells. In hepatocytes, JTE-013 mildly suppressed, augmented, and had no effect on GCDC-induced JNK, Akt, and Erk phosphorylation, respectively. Similar results were seen in HUH7-Ntcp cells except for mild suppression of JNK and Erk phosphorylation. Knockdown of S1PR2 in HUH7-Ntcp augmented Akt, inhibited JNK, and had no effect on Erk phosphorylation. GCDC failed to induce apoptosis or kinase activation in HUH7 cells. In conclusion, SIPR2 inhibition attenuates GCDC-induced apoptosis and inhibits and augments GCDC-induced JNK and Akt phosphorylation, respectively. In addition, GCDC must enter hepatocytes to mediate cell death or activate kinases. These results suggest that SIPR2 activation is proapoptotic in GCDC-induced cell death but that this effect is not due to direct ligation of the S1PR2 by the bile acid.
[Mh] Termos MeSH primário: Apoptose
Carcinoma Hepatocelular/metabolismo
Ácido Glicoquenodesoxicólico/metabolismo
Hepatócitos/metabolismo
Neoplasias Hepáticas/metabolismo
Receptores de Lisoesfingolipídeo/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Células Cultivadas
Ácido Glicoquenodesoxicólico/toxicidade
Seres Humanos
MAP Quinase Quinase 4/metabolismo
Sistema de Sinalização das MAP Quinases
Masculino
Proteínas Proto-Oncogênicas c-akt/metabolismo
Pirazóis/farmacologia
Piridinas/farmacologia
Ratos
Ratos Wistar
Receptores de Lisoesfingolipídeo/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (JTE 013); 0 (Pyrazoles); 0 (Pyridines); 0 (Receptors, Lysosphingolipid); 0 (S1PR2 protein, human); 0 (sphingosine-1-phosphate receptor-2, rat); 640-79-9 (Glycochenodeoxycholic Acid); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.12.2 (MAP Kinase Kinase 4)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170714
[Lr] Data última revisão:
170714
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160322
[St] Status:MEDLINE
[do] DOI:10.1152/ajpgi.00253.2015


  6 / 213 MEDLINE  
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[PMID]:26851371
[Au] Autor:Zhen CL; Yan J; Zhao Y; Li SL; Liu MY; Shen X; Li N; Zhang YH; Zhang YQ; Ma CY; Wang CG; Gao JL; Wei YY; Dong DL
[Ad] Endereço:Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical
[Ti] Título:Taurochenodeoxycholate relaxes rat mesenteric arteries through activating eNOS: Comparing with glycochenodeoxycholate and tauroursodeoxycholate.
[So] Source:Eur J Pharmacol;774:118-26, 2016 Mar 05.
[Is] ISSN:1879-0712
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The bile acids (BAs) and their conjugates have vascular activities and the serum levels of BAs and their conjugates are increased in liver diseases. In the present study, we examined the in vitro vasoactivities of BAs conjugates taurochenodeoxycholate (TCDC) (5-80 µM), glycochenodeoxycholate (GCDC) (20-150 µM) and tauroursodeoxycholate (TUDC) (20-150 µM) in rat mesenteric arteries and thoracic aorta. The isometric tension of rat mesenteric arteries and thoracic aorta was recorded by using multi-wire myograph systems. TCDC induced significant concentration-dependent relaxation in endothelium-intact but not endothelium-denuded rat mesenteric arteries pre-contracted with phenylephrine (PE). TCDC also showed vasorelaxant effects on high K(+) induced contraction in rat mesenteric arteries. L-NAME treatment inhibited TCDC-induced relaxation in mesenteric arteries pre-contracted with PE. Acute treatment with TCDC increased protein expression of P-eNOS (ser1177) in human umbilical vein endothelial cells. GCDC dose-dependently relaxed PE-induced vasoconstriction in both endotheium-intact and endothelium-denuded rat mesenteric arteries, but GCDC showed no effect on high K(+)-induced vasoconstriction. Both GCDC and TCDC showed no apparent relaxation on PE and high K(+)-induced vasoconstriction in rat thoracic aorta. TUDC showed no effect on PE and high K(+)-induced vasoconstriction in rat mesenteric arteries and thoracic aorta. The study demonstrates that TCDC relaxes rat mesenteric arteries through activating eNOS. TCDC might be the major BAs conjugate for vasorelaxation in vivo.
[Mh] Termos MeSH primário: Ácido Glicoquenodesoxicólico/farmacologia
Artérias Mesentéricas/efeitos dos fármacos
Artérias Mesentéricas/fisiologia
Óxido Nítrico Sintase Tipo III/metabolismo
Ácido Tauroquenodesoxicólico/farmacologia
Vasodilatação/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Aorta Torácica/efeitos dos fármacos
Aorta Torácica/fisiologia
Relação Dose-Resposta a Droga
Endotélio Vascular/efeitos dos fármacos
Ativação Enzimática/efeitos dos fármacos
Seres Humanos
Masculino
Artérias Mesentéricas/enzimologia
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
516-35-8 (Taurochenodeoxycholic Acid); 60EUX8MN5X (tauroursodeoxycholic acid); 640-79-9 (Glycochenodeoxycholic Acid); EC 1.14.13.39 (Nitric Oxide Synthase Type III)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160207
[St] Status:MEDLINE


  7 / 213 MEDLINE  
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[PMID]:26613247
[Au] Autor:Horváth G; Bencsura Á; Simon Á; Tochtrop GP; DeKoster GT; Covey DF; Cistola DP; Toke O
[Ad] Endereço:Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
[Ti] Título:Structural determinants of ligand binding in the ternary complex of human ileal bile acid binding protein with glycocholate and glycochenodeoxycholate obtained from solution NMR.
[So] Source:FEBS J;283(3):541-55, 2016 Feb.
[Is] ISSN:1742-4658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:UNLABELLED: Besides aiding digestion, bile salts are important signal molecules exhibiting a regulatory role in metabolic processes. Human ileal bile acid binding protein (I-BABP) is an intracellular carrier of bile salts in the epithelial cells of the distal small intestine and has a key role in the enterohepatic circulation of bile salts. Positive binding cooperativity combined with site selectivity of glycocholate and glycochenodeoxycholate, the two most abundant bile salts in the human body, make human I-BABP a unique member of the family of intracellular lipid binding proteins. Solution NMR structure of the ternary complex of human I-BABP with glycocholate and glycochenodeoxycholate reveals an extensive network of hydrogen bonds and hydrophobic interactions stabilizing the bound bile salts. Conformational changes accompanying bile salt binding affects four major regions in the protein including the C/D, E/F and G/H loops as well as the helical segment. Most of these protein regions coincide with a previously described network of millisecond time scale fluctuations in the apo protein, a motion absent in the bound state. Comparison of the heterotypic doubly ligated complex with the unligated form provides further evidence of a conformation selection mechanism of ligand entry. Structural and dynamic aspects of human I-BABP-bile salt interaction are discussed and compared with characteristics of ligand binding in other members of the intracellular lipid binding protein family. PROTEIN DATA BANK ACCESSION NUMBERS: The coordinates of the 10 lowest energy structures of the human I-BABP : GCDA : GCA complex as well as the distance restraints used to calculate the final ensemble have been deposited in the Brookhaven Protein Data Bank with accession number 2MM3.
[Mh] Termos MeSH primário: Proteínas de Transporte/química
Ácido Glicoquenodesoxicólico/química
Ácido Glicocólico/química
Glicoproteínas de Membrana/química
[Mh] Termos MeSH secundário: Sítios de Ligação
Seres Humanos
Ligações de Hidrogênio
Interações Hidrofóbicas e Hidrofílicas
Ligantes
Espectroscopia de Ressonância Magnética
Estrutura Molecular
Soluções
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Ligands); 0 (Membrane Glycoproteins); 0 (Solutions); 0 (bile acid binding proteins); 640-79-9 (Glycochenodeoxycholic Acid); G59NX3I3RT (Glycocholic Acid)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:160206
[Lr] Data última revisão:
160206
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151128
[St] Status:MEDLINE
[do] DOI:10.1111/febs.13610


  8 / 213 MEDLINE  
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[PMID]:26176423
[Au] Autor:Woolbright BL; McGill MR; Yan H; Jaeschke H
[Ad] Endereço:Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
[Ti] Título:Bile Acid-Induced Toxicity in HepaRG Cells Recapitulates the Response in Primary Human Hepatocytes.
[So] Source:Basic Clin Pharmacol Toxicol;118(2):160-7, 2016 Feb.
[Is] ISSN:1742-7843
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cholestatic liver injury is a pathological component of numerous disease states. Much of the current literature on cholestatic liver injury is derived from in vitro studies using rodent hepatocytes or cell lines transfected with bile acid (BA) uptake transporters. While these studies demonstrate BA-driven apoptosis, it is debatable whether these models reflect the human pathophysiology, as primary human hepatocytes undergo primarily necrosis. HepaRG cells are a bipotential, human hepatoma line that express apical and basolateral BA transporters. Thus, we sought to determine whether HepaRG cells could replicate the response of primary human hepatocytes to BA exposure in vitro. HepG2 cells, primary murine hepatocytes (PMH) or HepaRG cells, were exposed to taurocholic acid (TCA), or glycochenodeoxycholate (GCDC) and lactate dehydrogenase release were measured to determine cell death. Cell death occurred dose-responsively in HepaRG cells when exposed to GCDC; however, HepG2 cells died acutely only at very high concentrations of GCDC. In HepaRG cells, pre-treatment with the caspase inhibitor z-VD-FMK had no effect on cell death, indicating a lack of apoptotic cell death, and while c-jun N-terminal kinase (JNK) protein was activated by GCDC treatment in HepaRG cells, the inhibition of JNK did not protect. Although previous data indicate that TCA stimulates pro-inflammatory gene induction in PMH, there was no change in gene expression after TCA stimulation in HepaRG cells, which mimicked previous data found in primary human hepatocytes. These data provide evidence for HepaRG cells as a new model for the study of the effect of BA on human hepatocytes.
[Mh] Termos MeSH primário: Clorometilcetonas de Aminoácidos/farmacologia
Apoptose/efeitos dos fármacos
Colestase/metabolismo
Ácido Glicoquenodesoxicólico
Hepatócitos
Ácido Taurocólico
[Mh] Termos MeSH secundário: Animais
Ácidos e Sais Biliares/metabolismo
Ácidos e Sais Biliares/toxicidade
Ácido Glicoquenodesoxicólico/metabolismo
Ácido Glicoquenodesoxicólico/toxicidade
Células Hep G2
Hepatócitos/efeitos dos fármacos
Hepatócitos/metabolismo
Seres Humanos
Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo
Camundongos
Substâncias Protetoras/farmacologia
Ácido Taurocólico/metabolismo
Ácido Taurocólico/toxicidade
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Amino Acid Chloromethyl Ketones); 0 (Bile Acids and Salts); 0 (Protective Agents); 0 (benzyloxycarbonyl-valyl-aspartic acid fluoromethyl ketone); 5E090O0G3Z (Taurocholic Acid); 640-79-9 (Glycochenodeoxycholic Acid); EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:170725
[Lr] Data última revisão:
170725
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150716
[St] Status:MEDLINE
[do] DOI:10.1111/bcpt.12449


  9 / 213 MEDLINE  
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[PMID]:26208104
[Au] Autor:James L; Yan K; Pence L; Simpson P; Bhattacharyya S; Gill P; Letzig L; Kearns G; Beger R
[Ad] Endereço:Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, United States of America; Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, United States of America.
[Ti] Título:Comparison of Bile Acids and Acetaminophen Protein Adducts in Children and Adolescents with Acetaminophen Toxicity.
[So] Source:PLoS One;10(7):e0131010, 2015.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Metabolomics approaches have enabled the study of new mechanisms of liver injury in experimental models of drug toxicity. Disruption of bile acid homeostasis is a known mechanism of drug induced liver injury. The relationship of individual bile acids to indicators of oxidative drug metabolism (acetaminophen protein adducts) and liver injury was examined in children with acetaminophen overdose, hospitalized children with low dose exposure to acetaminophen, and children with no recent exposure to acetaminophen. Nine bile acids were quantified through targeted metabolomic analysis in the serum samples of the three groups. Bile acids were compared to serum levels of acetaminophen protein adducts and alanine aminotransferase. Glycodeoxycholic acid, taurodeoxycholic acid, and glycochenodeoxycholic acid were significantly increased in children with acetaminophen overdose compared to healthy controls. Among patients with acetaminophen overdose, bile acids were higher in subjects with acetaminophen protein adduct values > 1.0 nmol/mL and modest correlations were noted for three bile acids and acetaminophen protein adducts as follows: taurodeoxycholic acid (R=0.604; p<0.001), glycodeoxycholic acid (R=0.581; p<0.001), and glycochenodeoxycholic acid (R=0.571; p<0.001). Variability in bile acids was greater among hospitalized children receiving low doses of acetaminophen than in healthy children with no recent acetaminophen exposure. Compared to bile acids, acetaminophen protein adducts more accurately discriminated among children with acetaminophen overdose, children with low dose exposure to acetaminophen, and healthy control subjects. In children with acetaminophen overdose, elevations of conjugated bile acids were associated with specific indicators of acetaminophen metabolism and non-specific indicators of liver injury.
[Mh] Termos MeSH primário: Acetaminofen/envenenamento
Ácidos e Sais Biliares/sangue
Doença Hepática Induzida por Substâncias e Drogas/sangue
Overdose de Drogas/sangue
[Mh] Termos MeSH secundário: Acetaminofen/metabolismo
Adolescente
Alanina Transaminase/metabolismo
Biomarcadores/sangue
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico
Criança
Pré-Escolar
Diagnóstico Diferencial
Overdose de Drogas/diagnóstico
Feminino
Ácido Glicoquenodesoxicólico/sangue
Ácido Glicodesoxicólico/sangue
Homeostase
Seres Humanos
Masculino
Metabolômica/métodos
Ligação Proteica
Sensibilidade e Especificidade
Ácido Taurodesoxicólico/sangue
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (Biomarkers); 360-65-6 (Glycodeoxycholic Acid); 362O9ITL9D (Acetaminophen); 516-50-7 (Taurodeoxycholic Acid); 640-79-9 (Glycochenodeoxycholic Acid); EC 2.6.1.2 (Alanine Transaminase)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150725
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0131010


  10 / 213 MEDLINE  
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[PMID]:26118716
[Au] Autor:Chen Y; Qing W; Sun M; Lv L; Guo D; Jiang Y
[Ad] Endereço:a Department of Hepatobiliary Surgery , Fuzhou General Hospital , Fuzhou , China.
[Ti] Título:Melatonin protects hepatocytes against bile acid-induced mitochondrial oxidative stress via the AMPK-SIRT3-SOD2 pathway.
[So] Source:Free Radic Res;49(10):1275-84, 2015 Oct.
[Is] ISSN:1029-2470
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mitochondrial oxidative damage is hypothesized to contribute to the pathogenesis of chronic cholestatic liver diseases. Melatonin, an indolamine synthesized in the pineal gland, shows a wide range of physiological functions, and is under clinical investigation for expanded applications. Melatonin has demonstrated efficient protective effects against various types of oxidative damage in the liver system. This study investigates the protective effects of melatonin pretreatment on glycochenodeoxycholic acid (GCDCA)-induced hepatotoxicity and elucidates the potential mechanism of melatonin-mediated protection. Melatonin markedly decreased mitochondrial ROS (mROS) production in L02 cells treated with 100 µM GCDCA, and inhibited GCDCA-stimulated cytotoxicity. Notably, melatonin exerted its hepatoprotective effects by upregulating sirtuin 3 (SIRT3) activity and its expression level, thus regulating superoxide dismutase 2 (SOD2) acetylation and inhibiting the production of mROS induced by GCDCA. Moreover, siRNA targeting SIRT3 blocked the melatonin-mediated elevation in mitochondrial function by inhibiting SIRT3/SOD2 signaling. Importantly, melatonin-activated SIRT3 activity was completely abolished by AMP-activated, alpha 1 catalytic subunit (AMPK) siRNA transfection. Similar results were obtained in rat with bile duct ligation or BDL. In summary, our findings indicate that melatonin is a novel hepatoprotective small molecule that functions by elevating SIRT3, stimulating SOD2 activity, and suppressing mitochondrial oxidative stress at least through AMPK, and that SIRT3 may be of therapeutic value in liver cell protection for GCDCA-induced hepatotoxicity.
[Mh] Termos MeSH primário: Proteínas Quinases Ativadas por AMP/fisiologia
Ácido Glicoquenodesoxicólico/toxicidade
Hepatócitos/efeitos dos fármacos
Melatonina/farmacologia
Mitocôndrias Hepáticas/efeitos dos fármacos
Estresse Oxidativo/efeitos dos fármacos
Transdução de Sinais/efeitos dos fármacos
Sirtuína 3/fisiologia
Superóxido Dismutase/fisiologia
[Mh] Termos MeSH secundário: Acetilação
Trifosfato de Adenosina/metabolismo
Animais
Hepatócitos/metabolismo
Seres Humanos
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Mitocôndrias Hepáticas/metabolismo
Processamento de Proteína Pós-Traducional
Interferência de RNA
RNA Mensageiro/biossíntese
RNA Mensageiro/genética
RNA Interferente Pequeno/genética
Distribuição Aleatória
Ratos
Sirtuína 3/biossíntese
Sirtuína 3/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (RNA, Messenger); 0 (RNA, Small Interfering); 640-79-9 (Glycochenodeoxycholic Acid); 8L70Q75FXE (Adenosine Triphosphate); EC 1.15.1.1 (Superoxide Dismutase); EC 1.15.1.1 (superoxide dismutase 2); EC 2.7.11.31 (AMP-Activated Protein Kinases); EC 3.5.1.- (SIRT3 protein, human); EC 3.5.1.- (Sirtuin 3); JL5DK93RCL (Melatonin)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150630
[St] Status:MEDLINE
[do] DOI:10.3109/10715762.2015.1067806



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