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  1 / 175 MEDLINE  
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[PMID]:28594916
[Au] Autor:Sasaki T; Mita M; Ikari N; Kuboyama A; Hashimoto S; Kaneko T; Ishiguro M; Shimizu M; Inoue J; Sato R
[Ad] Endereço:Food Biochemistry Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan.
[Ti] Título:Identification of key amino acid residues in the hTGR5-nomilin interaction and construction of its binding model.
[So] Source:PLoS One;12(6):e0179226, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:TGR5, a member of the G protein-coupled receptor (GPCR) family, is activated by bile acids. Because TGR5 promotes energy expenditure and improves glucose homeostasis, it is recognized as a key target in treating metabolic diseases. We previously showed that nomilin, a citrus limonoid, activates TGR5 and confers anti-obesity and anti-hyperglycemic effects in mice. Information on the TGR5-nomilin interaction regarding molecular structure, however, has not been reported. In the present study, we found that human TGR5 (hTGR5) shows higher nomilin responsiveness than does mouse TGR5 (mTGR5). Using mouse-human chimeric TGR5, we also found that three amino acid residues (Q77ECL1, R80ECL1, and Y893.29) are important in the hTGR5-nomilin interaction. Based on these results, an hTGR5-nomilin binding model was constructed using in silico docking simulation, demonstrating that four hydrophilic hydrogen-bonding interactions occur between nomilin and hTGR5. The binding mode of hTGR5-nomilin is vastly different from those of other TGR5 agonists previously reported, suggesting that TGR5 forms various binding patterns depending on the type of agonist. Our study promotes a better understanding of the structure of TGR5, and it may be useful in developing and screening new TGR5 agonists.
[Mh] Termos MeSH primário: Aminoácidos/química
Benzoxepinas/química
Benzoxepinas/metabolismo
Limoninas/química
Limoninas/metabolismo
Modelos Moleculares
Receptores Acoplados a Proteínas-G/química
Receptores Acoplados a Proteínas-G/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Células HEK293
Seres Humanos
Camundongos
Simulação de Acoplamento Molecular
Mutação/genética
Especificidade por Substrato
Ácido Taurolitocólico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acids); 0 (Benzoxepins); 0 (GPBAR1 protein, human); 0 (Limonins); 0 (Receptors, G-Protein-Coupled); 516-90-5 (Taurolithocholic Acid); 751-03-1 (obacunone); DRM0753K4T (nomilin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170609
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0179226


  2 / 175 MEDLINE  
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[PMID]:26642860
[Au] Autor:Huang W; Cane MC; Mukherjee R; Szatmary P; Zhang X; Elliott V; Ouyang Y; Chvanov M; Latawiec D; Wen L; Booth DM; Haynes AC; Petersen OH; Tepikin AV; Criddle DN; Sutton R
[Ad] Endereço:NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of Liverpool, Liverpool, UK.
[Ti] Título:Caffeine protects against experimental acute pancreatitis by inhibition of inositol 1,4,5-trisphosphate receptor-mediated Ca2+ release.
[So] Source:Gut;66(2):301-313, 2017 Feb.
[Is] ISSN:1468-3288
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Caffeine reduces toxic Ca signals in pancreatic acinar cells via inhibition of inositol 1,4,5-trisphosphate receptor (IP R)-mediated signalling, but effects of other xanthines have not been evaluated, nor effects of xanthines on experimental acute pancreatitis (AP). We have determined effects of caffeine and its xanthine metabolites on pancreatic acinar IP R-mediated Ca signalling and experimental AP. DESIGN: Isolated pancreatic acinar cells were exposed to secretagogues, uncaged IP or toxins that induce AP and effects of xanthines, non-xanthine phosphodiesterase (PDE) inhibitors and cyclic adenosine monophosphate and cyclic guanosine monophosphate (cAMP/cGMP) determined. The intracellular cytosolic calcium concentration ([Ca ] ), mitochondrial depolarisation and necrosis were assessed by confocal microscopy. Effects of xanthines were evaluated in caerulein-induced AP (CER-AP), taurolithocholic acid 3-sulfate-induced AP (TLCS-AP) or palmitoleic acid plus ethanol-induced AP (fatty acid ethyl ester AP (FAEE-AP)). Serum xanthines were measured by liquid chromatography-mass spectrometry. RESULTS: Caffeine, dimethylxanthines and non-xanthine PDE inhibitors blocked IP -mediated Ca oscillations, while monomethylxanthines had little effect. Caffeine and dimethylxanthines inhibited uncaged IP -induced Ca rises, toxin-induced Ca release, mitochondrial depolarisation and necrotic cell death pathway activation; cAMP/cGMP did not inhibit toxin-induced Ca rises. Caffeine significantly ameliorated CER-AP with most effect at 25 mg/kg (seven injections hourly); paraxanthine or theophylline did not. Caffeine at 25 mg/kg significantly ameliorated TLCS-AP and FAEE-AP. Mean total serum levels of dimethylxanthines and trimethylxanthines peaked at >2 mM with 25 mg/kg caffeine but at <100 µM with 25 mg/kg paraxanthine or theophylline. CONCLUSIONS: Caffeine and its dimethylxanthine metabolites reduced pathological IP R-mediated pancreatic acinar Ca signals but only caffeine ameliorated experimental AP. Caffeine is a suitable starting point for medicinal chemistry.
[Mh] Termos MeSH primário: Células Acinares/efeitos dos fármacos
Cafeína/farmacologia
Cálcio/metabolismo
Receptores de Inositol 1,4,5-Trifosfato/antagonistas & inibidores
Pâncreas/patologia
Pancreatite/prevenção & controle
Inibidores de Fosfodiesterase/farmacologia
[Mh] Termos MeSH secundário: Células Acinares/metabolismo
Animais
Cafeína/uso terapêutico
Morte Celular/efeitos dos fármacos
Células Cultivadas
Ceruletídeo
AMP Cíclico/metabolismo
GMP Cíclico/metabolismo
Citosol/metabolismo
Etanol
Ácidos Graxos Monoinsaturados
Inositol 1,4,5-Trifosfato/metabolismo
Masculino
Camundongos
Microscopia Confocal
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/fisiologia
Necrose/diagnóstico por imagem
Pancreatite/sangue
Pancreatite/induzido quimicamente
Inibidores de Fosfodiesterase/uso terapêutico
Transdução de Sinais/efeitos dos fármacos
Ácido Taurolitocólico/análogos & derivados
Xantinas/sangue
Xantinas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fatty Acids, Monounsaturated); 0 (Inositol 1,4,5-Trisphosphate Receptors); 0 (Phosphodiesterase Inhibitors); 0 (Xanthines); 15324-65-9 (taurolithocholic acid 3-sulfate); 209B6YPZ4I (palmitoleic acid); 3G6A5W338E (Caffeine); 3K9958V90M (Ethanol); 516-90-5 (Taurolithocholic Acid); 85166-31-0 (Inositol 1,4,5-Trisphosphate); 888Y08971B (Ceruletide); E0399OZS9N (Cyclic AMP); H2D2X058MU (Cyclic GMP); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:151209
[St] Status:MEDLINE
[do] DOI:10.1136/gutjnl-2015-309363


  3 / 175 MEDLINE  
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[PMID]:27686613
[Au] Autor:Dixit AK; Sarver AE; Yuan Z; George J; Barlass U; Cheema H; Sareen A; Banerjee S; Dudeja V; Dawra R; Subramanian S; Saluja AK
[Ad] Endereço:Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida; and.
[Ti] Título:Comprehensive analysis of microRNA signature of mouse pancreatic acini: overexpression of miR-21-3p in acute pancreatitis.
[So] Source:Am J Physiol Gastrointest Liver Physiol;311(5):G974-G980, 2016 Nov 01.
[Is] ISSN:1522-1547
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In the current study, we have characterized the global miRNA expression profile in mouse pancreatic acinar cells and during acute pancreatitis using next-generation RNA sequencing. We identified 324 known and six novel miRNAs that are expressed in mouse pancreatic acinar cells. In the basal state, miR-148a-3p, miR-375-3p, miR-217-5p, and miR-200a-3p were among the most abundantly expressed, whereas miR-24-5p and miR-421-3p were the least abundant. Treatment of acinar cells with caerulein (100 nM) and taurolithocholic acid 3-sulfate [TLC-S (250 µM)] induced numerous changes in miRNA expression profile. In particular, we found significant overexpression of miR-21-3p in acini treated with caerulein and TLC-S. We further looked at the expression of miR-21-3p in caerulein, l-arginine, and caerulein + LPS-induced acute pancreatitis mouse models and found 12-, 21-, and 50-fold increased expression in the pancreas, respectively. In summary, this is the first comprehensive analysis of global miRNA expression profile of mouse pancreatic acinar cells in normal and disease conditions. Our analysis shows that miR-21-3p expression level correlates with the severity of the disease.
[Mh] Termos MeSH primário: Células Acinares/metabolismo
MicroRNAs/metabolismo
Pancreatite/metabolismo
[Mh] Termos MeSH secundário: Células Acinares/efeitos dos fármacos
Animais
Ceruletídeo/farmacologia
Expressão Gênica/efeitos dos fármacos
Perfilação da Expressão Gênica
Sequenciamento de Nucleotídeos em Larga Escala
Camundongos
MicroRNAs/genética
Pancreatite/genética
Ácido Taurolitocólico/análogos & derivados
Ácido Taurolitocólico/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MicroRNAs); 15324-65-9 (taurolithocholic acid 3-sulfate); 516-90-5 (Taurolithocholic Acid); 888Y08971B (Ceruletide)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161001
[St] Status:MEDLINE
[do] DOI:10.1152/ajpgi.00191.2016


  4 / 175 MEDLINE  
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[PMID]:27406326
[Au] Autor:Ferdek PE; Jakubowska MA; Gerasimenko JV; Gerasimenko OV; Petersen OH
[Ad] Endereço:Medical Research Council Group, Cardiff School of Biosciences, Cardiff University, Cardiff, CF10 3AX, Wales, UK. ferdekpe@cardiff.ac.uk, petersenoh@cardiff.ac.uk.
[Ti] Título:Bile acids induce necrosis in pancreatic stellate cells dependent on calcium entry and sodium-driven bile uptake.
[So] Source:J Physiol;594(21):6147-6164, 2016 Nov 01.
[Is] ISSN:1469-7793
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:KEY POINTS: Acute biliary pancreatitis is a sudden and severe condition initiated by bile reflux into the pancreas. Bile acids are known to induce Ca signals and necrosis in isolated pancreatic acinar cells but the effects of bile acids on stellate cells are unexplored. Here we show that cholate and taurocholate elicit more dramatic Ca signals and necrosis in stellate cells compared to the adjacent acinar cells in pancreatic lobules; whereas taurolithocholic acid 3-sulfate primarily affects acinar cells. Ca signals and necrosis are strongly dependent on extracellular Ca as well as Na ; and Na -dependent transport plays an important role in the overall bile acid uptake in pancreatic stellate cells. Bile acid-mediated pancreatic damage can be further escalated by bradykinin-induced signals in stellate cells and thus killing of stellate cells by bile acids might have important implications in acute biliary pancreatitis. ABSTRACT: Acute biliary pancreatitis, caused by bile reflux into the pancreas, is a serious condition characterised by premature activation of digestive enzymes within acinar cells, followed by necrosis and inflammation. Bile acids are known to induce pathological Ca signals and necrosis in acinar cells. However, bile acid-elicited signalling events in stellate cells remain unexplored. This is the first study to demonstrate the pathophysiological effects of bile acids on stellate cells in two experimental models: ex vivo (mouse pancreatic lobules) and in vitro (human cells). Sodium cholate and taurocholate induced cytosolic Ca elevations in stellate cells, larger than those elicited simultaneously in the neighbouring acinar cells. In contrast, taurolithocholic acid 3-sulfate (TLC-S), known to induce Ca oscillations in acinar cells, had only minor effects on stellate cells in lobules. The dependence of the Ca signals on extracellular Na and the presence of sodium-taurocholate cotransporting polypeptide (NTCP) indicate a Na -dependent bile acid uptake mechanism in stellate cells. Bile acid treatment caused necrosis predominantly in stellate cells, which was abolished by removal of extracellular Ca and significantly reduced in the absence of Na , showing that bile-dependent cell death was a downstream event of Ca signals. Finally, combined application of TLC-S and the inflammatory mediator bradykinin caused more extensive necrosis in both stellate and acinar cells than TLC-S alone. Our findings shed new light on the mechanism by which bile acids promote pancreatic pathology. This involves not only signalling in acinar cells but also in stellate cells.
[Mh] Termos MeSH primário: Bile/metabolismo
Sinalização do Cálcio
Células Estreladas do Pâncreas/metabolismo
Pancreatite Necrosante Aguda/metabolismo
Sódio/metabolismo
[Mh] Termos MeSH secundário: Células Acinares/efeitos dos fármacos
Células Acinares/metabolismo
Células Acinares/patologia
Animais
Bradicinina/farmacologia
Células Cultivadas
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Células Estreladas do Pâncreas/efeitos dos fármacos
Células Estreladas do Pâncreas/patologia
Pancreatite Necrosante Aguda/etiologia
Ácido Taurolitocólico/análogos & derivados
Ácido Taurolitocólico/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
15324-65-9 (taurolithocholic acid 3-sulfate); 516-90-5 (Taurolithocholic Acid); 9NEZ333N27 (Sodium); S8TIM42R2W (Bradykinin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160714
[St] Status:MEDLINE
[do] DOI:10.1113/JP272774


  5 / 175 MEDLINE  
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[PMID]:27273788
[Au] Autor:Xie G; Wang X; Huang F; Zhao A; Chen W; Yan J; Zhang Y; Lei S; Ge K; Zheng X; Liu J; Su M; Liu P; Jia W
[Ad] Endereço:Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
[Ti] Título:Dysregulated hepatic bile acids collaboratively promote liver carcinogenesis.
[So] Source:Int J Cancer;139(8):1764-75, 2016 Oct 15.
[Is] ISSN:1097-0215
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Dysregulated bile acids (BAs) are closely associated with liver diseases and attributed to altered gut microbiota. Here, we show that the intrahepatic retention of hydrophobic BAs including deoxycholate (DCA), taurocholate (TCA), taurochenodeoxycholate (TCDCA), and taurolithocholate (TLCA) were substantially increased in a streptozotocin and high fat diet (HFD) induced nonalcoholic steatohepatitis-hepatocellular carcinoma (NASH-HCC) mouse model. Additionally chronic HFD-fed mice spontaneously developed liver tumors with significantly increased hepatic BA levels. Enhancing intestinal excretion of hydrophobic BAs in the NASH-HCC model mice by a 2% cholestyramine feeding significantly prevented HCC development. The gut microbiota alterations were closely correlated with altered BA levels in liver and feces. HFD-induced inflammation inhibited key BA transporters, resulting in sustained increases in intrahepatic BA concentrations. Our study also showed a significantly increased cell proliferation in BA treated normal human hepatic cell lines and a down-regulated expression of tumor suppressor gene CEBPα in TCDCA treated HepG2 cell line, suggesting that several hydrophobic BAs may collaboratively promote liver carcinogenesis.
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/metabolismo
Neoplasias Hepáticas/etiologia
Neoplasias Hepáticas/metabolismo
[Mh] Termos MeSH secundário: Animais
Carcinogênese/metabolismo
Carcinogênese/patologia
Linhagem Celular
Ácido Desoxicólico/metabolismo
Dieta Hiperlipídica
Feminino
Microbioma Gastrointestinal
Células Hep G2
Seres Humanos
Neoplasias Hepáticas/microbiologia
Neoplasias Hepáticas/patologia
Neoplasias Hepáticas Experimentais/etiologia
Neoplasias Hepáticas Experimentais/metabolismo
Neoplasias Hepáticas Experimentais/microbiologia
Neoplasias Hepáticas Experimentais/patologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Hepatopatia Gordurosa não Alcoólica/etiologia
Hepatopatia Gordurosa não Alcoólica/metabolismo
Hepatopatia Gordurosa não Alcoólica/microbiologia
Hepatopatia Gordurosa não Alcoólica/patologia
Gravidez
Estreptozocina
Ácido Tauroquenodesoxicólico/metabolismo
Ácido Taurocólico/metabolismo
Ácido Taurolitocólico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bile Acids and Salts); 005990WHZZ (Deoxycholic Acid); 516-35-8 (Taurochenodeoxycholic Acid); 516-90-5 (Taurolithocholic Acid); 5E090O0G3Z (Taurocholic Acid); 5W494URQ81 (Streptozocin)
[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:160609
[St] Status:MEDLINE
[do] DOI:10.1002/ijc.30219


  6 / 175 MEDLINE  
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[PMID]:27072966
[Au] Autor:Hu MX; Zhang HW; Fu Q; Qin T; Liu CJ; Wang YZ; Tang Q; Chen YX
[Ad] Endereço:Department of Hepatobiliary Pancreatic Surgery, Shandong Qilu Hospital, Shandong University, Jinan, 250000, China.
[Ti] Título:Functional role of MicroRNA-19b in acinar cell necrosis in acute necrotizing pancreatitis.
[So] Source:J Huazhong Univ Sci Technolog Med Sci;36(2):221-5, 2016 Apr.
[Is] ISSN:1672-0733
[Cp] País de publicação:China
[La] Idioma:eng
[Ab] Resumo:The expression of microRNA-19b (miR-19b) in acute necrotizing pancreatitis (ANP) and its functional role in acinar cell necrosis of SD rats were investigated. Twelve SD rats were divided into two groups randomly, including control group and ANP group. The rat ANP models were established by intraperitoneal injection of L-arginine (2400 mg/kg body weight), and equal volume of 0.9% NaCl was injected in the control group. MiRNA chip assay was performed to examine the expression of miRNAs in the pancreas in two different groups. Besides, to further explore the role of miR-19b in ANP in vitro, taurolithocholic acid 3-sulfate disodium salt (TLC-S) (200 µmol/L) was administrated to treat the rat pancreatic acinar cell line, AR42J, for establishing the ANP cells model. The quantitative real-time PCR (qRT-PCR) was adopted to measure the miR-19b expression. Moreover, the mimic miRNA, miRNA antisense oligonucleotide (AMO) and control vector were used to transfect AR42J cells, the expression of miR-19b was confirmed by qRT-PCR and the necrotizing rate of AR42J cells was detected with AO/EB method. The expression of miR-19b was significantly higher in ANP group than in control group as displayed by the miRNA chip assay. Furthermore, after inducing necrosis of AR42J cells in vitro, the expression of miR-19b was significantly increased by 2.51±0.14 times in comparison with the control group. As revealed by qRT-PCR assay, the expression of miR-19b was 5.94±0.95 times higher in the mimic miRNA group than in the control vector group, companied with an obviously increased acinar cell necrotizing rate (50.3%±1.5% vs. 39.6%±2.3%, P<0.05). Moreover, the expression of miR-19b in the miRNA AMO group was 0.38±0.15 times lower than in the control vector group, and the cell necrosis rate was much lower accordingly (23.1%±3.3% vs. 39.6%±2.3%, P<0.05). Besides, there was no significant difference between the control vector cells and the cells without treatment (P>0.05). The expression of miR-19b was significantly induced in ANP. In addition, up-regulation of miR-19b could promote the necrosis of pancreatic acinar cells and miR-19b deficiency could decrease the rate of pancreatic acinar cell necrosis.
[Mh] Termos MeSH primário: Células Acinares/metabolismo
MicroRNAs/genética
Pancreatite Necrosante Aguda/metabolismo
[Mh] Termos MeSH secundário: Células Acinares/patologia
Animais
Arginina/toxicidade
Linhagem Celular
MicroRNAs/metabolismo
Necrose
Pancreatite Necrosante Aguda/etiologia
Ratos
Ratos Sprague-Dawley
Ácido Taurolitocólico/análogos & derivados
Ácido Taurolitocólico/toxicidade
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MIRN19 microRNA, rat); 0 (MicroRNAs); 15324-65-9 (taurolithocholic acid 3-sulfate); 516-90-5 (Taurolithocholic Acid); 94ZLA3W45F (Arginine)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:171104
[Lr] Data última revisão:
171104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160414
[St] Status:MEDLINE
[do] DOI:10.1007/s11596-016-1570-2


  7 / 175 MEDLINE  
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[PMID]:27012769
[Au] Autor:Schonhoff CM; Park SW; Webster CR; Anwer MS
[Ad] Endereço:Department of Biomedical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts; and.
[Ti] Título:p38 MAPK α and ß isoforms differentially regulate plasma membrane localization of MRP2.
[So] Source:Am J Physiol Gastrointest Liver Physiol;310(11):G999-G1005, 2016 Jun 01.
[Is] ISSN:1522-1547
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In hepatocytes, cAMP both activates p38 mitogen-activated protein kinase (MAPK) and increases the amount of multidrug resistance-associated protein-2 (MRP2) in the plasma membrane (PM-MRP2). Paradoxically, taurolithocholate (TLC) activates p38 MAPK but decreases PM-MRP2 in hepatocytes. These opposing effects of cAMP and TLC could be mediated via different p38 MAPK isoforms (α and ß) that are activated differentially by upstream kinases (MKK3, MKK4, and MKK6). Thus we tested the hypothesis that p38α MAPK and p38ß MAPK mediate increases and decreases in PM-MRP2 by cAMP and TLC, respectively. Studies were conducted in hepatocytes isolated from C57BL/6 wild-type (WT) and MKK3-knockout (MKK3(-/-)) mice and in a hepatoma cell line (HuH7) that overexpresses sodium-taurocholate cotransporting polypeptide (NTCP) (HuH-NTCP). Cyclic AMP activated MKK3, p38 MAPK, and p38α MAPK and increased PM-MRP2 in WT hepatocytes, but failed to activate p38α MAPK or increase PM-MRP2 in MKK3(-/-) hepatocytes. In contrast to cAMP, TLC activated total p38 MAPK but decreased PM-MRP2, and did not activate MKK3 or p38α MAPK in WT hepatocytes. In MKK3(-/-) hepatocytes, TLC still decreased PM-MRP2 and activated p38 MAPK, indicating that these effects are not MKK3-dependent. Additionally, TLC activated MKK6 in MKK3(-/-) hepatocytes, and small interfering RNA knockdown of p38ß MAPK abrogated TLC-mediated decreases in PM-MRP2 in HuH-NTCP cells. Taken together, these results suggest that p38α MAPK facilitates plasma membrane insertion of MRP2 by cAMP, whereas p38ß MAPK mediates retrieval of PM-MRP2 by TLC.
[Mh] Termos MeSH primário: Membrana Celular/metabolismo
Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo
Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Linhagem Celular Tumoral
Células Cultivadas
Colagogos e Coleréticos/farmacologia
AMP Cíclico/metabolismo
Hepatócitos/efeitos dos fármacos
Hepatócitos/metabolismo
Seres Humanos
Isoenzimas/genética
Isoenzimas/metabolismo
MAP Quinase Quinase 3/genética
MAP Quinase Quinase 3/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Transporte Proteico
Ácido Taurolitocólico/farmacologia
Proteínas Quinases p38 Ativadas por Mitógeno/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cholagogues and Choleretics); 0 (Isoenzymes); 0 (Multidrug Resistance-Associated Proteins); 4AF605U6JN (multidrug resistance-associated protein 2); 516-90-5 (Taurolithocholic Acid); E0399OZS9N (Cyclic AMP); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases); EC 2.7.12.2 (MAP Kinase Kinase 3); EC 2.7.12.2 (Map2k3 protein, mouse)
[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:160326
[St] Status:MEDLINE
[do] DOI:10.1152/ajpgi.00005.2016


  8 / 175 MEDLINE  
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[PMID]:26347551
[Au] Autor:Hansson KA; Døving KB; Skjeldal FM
[Ad] Endereço:Department of Biosciences, University of Oslo, Oslo N-0316, Norway k.a.hansson@medisin.uio.no.
[Ti] Título:Mixed input to olfactory glomeruli from two subsets of ciliated sensory neurons does not impede relay neuron specificity in the crucian carp.
[So] Source:J Exp Biol;218(Pt 20):3257-63, 2015 Oct.
[Is] ISSN:1477-9145
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The consensus view of olfactory processing is that the axons of receptor-specific primary olfactory sensory neurons (OSNs) converge to a small subset of glomeruli, thus preserving the odour identity before the olfactory information is processed in higher brain centres. In the present study, we show that two different subsets of ciliated OSNs with different odorant specificities converge to the same glomeruli. In order to stain different ciliated OSNs in the crucian carp Carassius carassius we used two different chemical odorants, a bile salt and a purported alarm substance, together with fluorescent dextrans. The dye is transported within the axons and stains glomeruli in the olfactory bulb. Interestingly, the axons from the ciliated OSNs co-converge to the same glomeruli. Despite intermingled innervation of glomeruli, axons and terminal fields from the two different subsets of ciliated OSNs remained mono-coloured. By 4-6 days after staining, the dye was transported trans-synaptically to separately stained axons of relay neurons. These findings demonstrate that specificity of the primary neurons is retained in the olfactory pathways despite mixed innervation of the olfactory glomeruli. The results are discussed in relation to the emerging concepts about non-mammalian glomeruli.
[Mh] Termos MeSH primário: Carpas/fisiologia
Bulbo Olfatório/metabolismo
Condutos Olfatórios/fisiologia
Neurônios Receptores Olfatórios/efeitos dos fármacos
Olfato
[Mh] Termos MeSH secundário: Animais
Corantes
Dextranos
Hipoxantinas/farmacologia
Bulbo Olfatório/efeitos dos fármacos
Condutos Olfatórios/efeitos dos fármacos
Neurônios Receptores Olfatórios/metabolismo
Sinapses/metabolismo
Ácido Taurolitocólico/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Coloring Agents); 0 (Dextrans); 0 (Hypoxanthines); 516-90-5 (Taurolithocholic Acid)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170113
[Lr] Data última revisão:
170113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150909
[St] Status:MEDLINE
[do] DOI:10.1242/jeb.125476


  9 / 175 MEDLINE  
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[PMID]:26305546
[Au] Autor:Huang YH; Tiao MM; Huang LT; Chuang JH; Kuo KC; Yang YL; Wang FS
[Ad] Endereço:Departments of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
[Ti] Título:Activation of Mir-29a in Activated Hepatic Stellate Cells Modulates Its Profibrogenic Phenotype through Inhibition of Histone Deacetylases 4.
[So] Source:PLoS One;10(8):e0136453, 2015.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Recent studies have shown that microRNA-29 (miR-29) is significantly decreased in liver fibrosis and that its downregulation influences the activation of hepatic stellate cells (HSCs). In addition, inhibition of the activity of histone deacetylases 4 (HDAC4) has been shown to strongly reduce HSC activation in the context of liver fibrosis. OBJECTIVES: In this study, we examined whether miR-29a was involved in the regulation of HDAC4 and modulation of the profibrogenic phenotype in HSCs. METHODS: We employed miR-29a transgenic mice (miR-29aTg mice) and wild-type littermates to clarify the role of miR-29a in cholestatic liver fibrosis, using the bile duct-ligation (BDL) mouse model. Primary HSCs from both mice were treated with a miR-29a mimic and antisense inhibitor in order to analyze changes in profibrogenic gene expression and HSC activation using real-time quantitative RT-PCR, immunofluorescence staining, western blotting, and cell proliferation and migration assays. RESULTS: After BDL, overexpression of miR-29a decreased collagen-1α1, HDAC4 and activated HSC markers of glial fibrillary acidic protein expression in miR-29aTg mice compared to wild-type littermates. Overexpression of miR-29a and HDAC4 RNA-interference decreased the expression of fibrotic genes, HDAC4 signaling, and HSC migration and proliferation. In contrast, knockdown of miR-29a with an antisense inhibitor increased HDAC4 function, restored HSC migration, and accelerated HSC proliferation. CONCLUSIONS: Our results indicate that miR-29a ameliorates cholestatic liver fibrosis after BDL, at least partially, by modulating the profibrogenic phenotype of HSCs through inhibition of HDAC4 function.
[Mh] Termos MeSH primário: Células Estreladas do Fígado/metabolismo
Células Estreladas do Fígado/patologia
Histona Desacetilases/metabolismo
Cirrose Hepática/enzimologia
Cirrose Hepática/genética
MicroRNAs/metabolismo
[Mh] Termos MeSH secundário: Acetilação/efeitos dos fármacos
Animais
Movimento Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Células Cultivadas
Colestase/complicações
Colestase/enzimologia
Colestase/genética
Modelos Animais de Doenças
Regulação para Baixo/efeitos dos fármacos
Proteína Glial Fibrilar Ácida/metabolismo
Células Estreladas do Fígado/efeitos dos fármacos
Histona Desacetilases/genética
Histonas/metabolismo
Cirrose Hepática/complicações
Masculino
Camundongos Transgênicos
MicroRNAs/genética
Fenótipo
Ácido Taurolitocólico/farmacologia
Cicatrização/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Glial Fibrillary Acidic Protein); 0 (Histones); 0 (MIRN29 microRNA, mouse); 0 (MicroRNAs); 516-90-5 (Taurolithocholic Acid); EC 3.5.1.98 (Hdac5 protein, mouse); EC 3.5.1.98 (Histone Deacetylases)
[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:150826
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0136453


  10 / 175 MEDLINE  
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[PMID]:26280129
[Au] Autor:Brighton CA; Rievaj J; Kuhre RE; Glass LL; Schoonjans K; Holst JJ; Gribble FM; Reimann F
[Ad] Endereço:University of Cambridge (C.A.B., J.R., L.L.G., F.M.G., F.R.), Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; Novo Nordisk Foundati
[Ti] Título:Bile Acids Trigger GLP-1 Release Predominantly by Accessing Basolaterally Located G Protein-Coupled Bile Acid Receptors.
[So] Source:Endocrinology;156(11):3961-70, 2015 Nov.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Bile acids are well-recognized stimuli of glucagon-like peptide-1 (GLP-1) secretion. This action has been attributed to activation of the G protein-coupled bile acid receptor GPBAR1 (TGR5), although other potential bile acid sensors include the nuclear farnesoid receptor and the apical sodium-coupled bile acid transporter ASBT. The aim of this study was to identify pathways important for GLP-1 release and to determine whether bile acids target their receptors on GLP-1-secreting L-cells from the apical or basolateral compartment. Using transgenic mice expressing fluorescent sensors specifically in L-cells, we observed that taurodeoxycholate (TDCA) and taurolithocholate (TLCA) increased intracellular cAMP and Ca(2+). In primary intestinal cultures, TDCA was a more potent GLP-1 secretagogue than taurocholate (TCA) and TLCA, correlating with a stronger Ca(2+) response to TDCA. Using small-volume Ussing chambers optimized for measuring GLP-1 secretion, we found that both a GPBAR1 agonist and TDCA stimulated GLP-1 release better when applied from the basolateral than from the luminal direction and that luminal TDCA was ineffective when intestinal tissue was pretreated with an ASBT inhibitor. ASBT inhibition had no significant effect in nonpolarized primary cultures. Studies in the perfused rat gut confirmed that vascularly administered TDCA was more effective than luminal TDCA. Intestinal primary cultures and Ussing chamber-mounted tissues from GPBAR1-knockout mice did not secrete GLP-1 in response to either TLCA or TDCA. We conclude that the action of bile acids on GLP-1 secretion is predominantly mediated by GPBAR1 located on the basolateral L-cell membrane, suggesting that stimulation of gut hormone secretion may include postabsorptive mechanisms.
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/farmacologia
Células Enteroendócrinas/efeitos dos fármacos
Peptídeo 1 Semelhante ao Glucagon/secreção
Receptores Acoplados a Proteínas-G/metabolismo
[Mh] Termos MeSH secundário: Animais
Cálcio/metabolismo
Células Cultivadas
AMP Cíclico/metabolismo
Células Enteroendócrinas/metabolismo
Peptídeo 1 Semelhante ao Glucagon/metabolismo
Intestino Delgado/efeitos dos fármacos
Intestino Delgado/metabolismo
Espaço Intracelular/efeitos dos fármacos
Espaço Intracelular/metabolismo
Masculino
Camundongos Knockout
Camundongos Transgênicos
Microscopia de Fluorescência
Ratos Wistar
Receptores Acoplados a Proteínas-G/genética
Ácido Taurodesoxicólico/farmacologia
Ácido Taurolitocólico/farmacologia
Técnicas de Cultura de Tecidos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (Gpbar1 protein, mouse); 0 (Receptors, G-Protein-Coupled); 516-50-7 (Taurodeoxycholic Acid); 516-90-5 (Taurolithocholic Acid); 89750-14-1 (Glucagon-Like Peptide 1); E0399OZS9N (Cyclic AMP); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:150818
[St] Status:MEDLINE
[do] DOI:10.1210/en.2015-1321



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