Base de dados : MEDLINE
Pesquisa : A11.561 [Categoria DeCS]
Referências encontradas : 2360 [refinar]
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[PMID]:27775690
[Au] Autor:Kennedy LL; Meng F; Venter JK; Zhou T; Karstens WA; Hargrove LA; Wu N; Kyritsi K; Greene J; Invernizzi P; Bernuzzi F; Glaser SS; Francis HL; Alpini G
[Ad] Endereço:Research, Central Texas Veterans Health Care System, Temple, TX, USA.
[Ti] Título:Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice.
[So] Source:Lab Invest;96(12):1256-1267, 2016 12.
[Is] ISSN:1530-0307
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cholestasis is a condition that leads to chronic hepatobiliary inflammation, fibrosis, and eventually cirrhosis. Many microRNAs (miRs) are known to have a role in fibrosis progression; however, the role of miR-21 during cholestasis remains unknown. Therefore, the aim of this study was to elucidate the role of miR-21 during cholestasis-induced biliary hyperplasia and hepatic fibrosis. Wild-type (WT) and miR-21 mice underwent Sham or bile duct ligation (BDL) for 1 week, before evaluating liver histology, biliary proliferation, hepatic stellate cell (HSC) activation, fibrotic response, and small mothers against decapentaplegic 7 (Smad-7) expression. In vitro, immortalized murine biliary cell lines (IMCLs) and human hepatic stellate cell line (hHSC) were treated with either miR-21 inhibitor or control before analyzing proliferation, apoptosis, and fibrotic responses. In vivo, the levels of miR-21 were increased in total liver and cholangiocytes after BDL, and loss of miR-21 decreased the amount of BDL-induced biliary proliferation and intrahepatic biliary mass. In addition, loss of miR-21 decreased BDL-induced HSC activation, collagen deposition, and expression of the fibrotic markers transforming growth factor-ß1 and α-smooth muscle actin. In vitro, IMCL and hHSCs treated with miR-21 inhibitor displayed decreased proliferation and expression of fibrotic markers and enhanced apoptosis when compared with control treated cells. Furthermore, mice lacking miR-21 show increased Smad-7 expression, which may be driving the decrease in biliary hyperplasia and hepatic fibrosis. During cholestatic injury, miR-21 is increased and leads to increased biliary proliferation and hepatic fibrosis. Local modulation of miR-21 may be a therapeutic option for patients with cholestasis.
[Mh] Termos MeSH primário: Ductos Biliares Intra-Hepáticos/metabolismo
Colestase Intra-Hepática/metabolismo
Modelos Animais de Doenças
Células Estreladas do Fígado/metabolismo
MicroRNAs/metabolismo
Regulação para Cima
[Mh] Termos MeSH secundário: Animais
Apoptose
Ductos Biliares Intra-Hepáticos/patologia
Biomarcadores/metabolismo
Linhagem Celular
Proliferação Celular
Células Cultivadas
Colestase Intra-Hepática/patologia
Colestase Intra-Hepática/fisiopatologia
Progressão da Doença
Regulação da Expressão Gênica
Células Estreladas do Fígado/patologia
Seres Humanos
Hiperplasia
Cirrose Hepática/etiologia
Masculino
Camundongos
Camundongos Knockout
MicroRNAs/antagonistas & inibidores
MicroRNAs/biossíntese
Interferência de RNA
Proteína Smad7/genética
Proteína Smad7/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Biomarkers); 0 (MIRN21 microRNA, human); 0 (MIRN21 microRNA, mouse); 0 (MicroRNAs); 0 (Smad7 Protein)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE
[do] DOI:10.1038/labinvest.2016.112


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[PMID]:29406047
[Au] Autor:Mehta KJ; Coombes JD; Briones-Orta M; Manka PP; Williams R; Patel VB; Syn WK
[Ad] Endereço:Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver Research, London, UK; Faculty of Life Sciences & Medicine, King's College London, London, UK; Department of Biomedical Sciences, University of Westminster, London, UK.
[Ti] Título:Iron Enhances Hepatic Fibrogenesis and Activates Transforming Growth Factor-ß Signaling in Murine Hepatic Stellate Cells.
[So] Source:Am J Med Sci;355(2):183-190, 2018 02.
[Is] ISSN:1538-2990
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Although excess iron induces oxidative stress in the liver, it is unclear whether it directly activates the hepatic stellate cells (HSC). MATERIALS AND METHODS: We evaluated the effects of excess iron on fibrogenesis and transforming growth factor beta (TGF-ß) signaling in murine HSC. Cells were treated with holotransferrin (0.005-5g/L) for 24 hours, with or without the iron chelator deferoxamine (10µM). Gene expressions (α-SMA, Col1-α1, Serpine-1, TGF-ß, Hif1-α, Tfrc and Slc40a1) were analyzed by quantitative real time-polymerase chain reaction, whereas TfR1, ferroportin, ferritin, vimentin, collagen, TGF-ß RII and phospho-Smad2 proteins were evaluated by immunofluorescence, Western blot and enzyme-linked immunosorbent assay. RESULTS: HSC expressed the iron-uptake protein transferrin receptor 1 (TfR1) and the iron-export protein ferroportin. Holotransferrin upregulated TfR1 expression by 1.8-fold (P < 0.03) and ferritin accumulation (iron storage) by 2-fold (P < 0.01), and activated HSC with 2-fold elevations (P < 0.03) in α-SMA messenger RNA and collagen secretion, and a 1.6-fold increase (P < 0.01) in vimentin protein. Moreover, holotransferrin activated the TGF-ß pathway with TGF-ß messenger RNA elevated 1.6-fold (P = 0.05), and protein levels of TGF-ß RII and phospho-Smad2 increased by 1.8-fold (P < 0.01) and 1.6-fold (P < 0.01), respectively. In contrast, iron chelation decreased ferritin levels by 30% (P < 0.03), inhibited collagen secretion by 60% (P < 0.01), repressed fibrogenic genes α-SMA (0.2-fold; P < 0.05) and TGF-ß (0.4-fold; P < 0.01) and reduced levels of TGF-ß RII and phospho-Smad2 proteins. CONCLUSIONS: HSC express iron-transport proteins. Holotransferrin (iron) activates HSC fibrogenesis and the TGF-ß pathway, whereas iron depletion by chelation reverses this, suggesting that this could be a useful adjunct therapy for patients with fibrosis. Further studies in primary human HSC and animal models are necessary to confirm this.
[Mh] Termos MeSH primário: Regulação da Expressão Gênica
Células Estreladas do Fígado/metabolismo
Ferro/metabolismo
Cirrose Hepática/metabolismo
Transdução de Sinais
Fator de Crescimento Transformador beta/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Ferritinas/biossíntese
Células Estreladas do Fígado/patologia
Cirrose Hepática/patologia
Camundongos
Proteínas Serina-Treonina Quinases/biossíntese
RNA Mensageiro/biossíntese
Receptores da Transferrina/biossíntese
Receptores de Fatores de Crescimento Transformadores beta/biossíntese
Proteína Smad2/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (RNA, Messenger); 0 (Receptors, Transferrin); 0 (Receptors, Transforming Growth Factor beta); 0 (Smad2 Protein); 0 (Smad2 protein, mouse); 0 (Tfrc protein, mouse); 0 (Transforming Growth Factor beta); 9007-73-2 (Ferritins); E1UOL152H7 (Iron); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.30 (transforming growth factor-beta type II receptor)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180301
[Lr] Data última revisão:
180301
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180207
[St] Status:MEDLINE


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[PMID]:29278707
[Au] Autor:Nguyen G; Park SY; Le CT; Park WS; Choi DH; Cho EH
[Ad] Endereço:Department of Internal Medicine, School of Medicine, Kangwon National University, Republic of Korea.
[Ti] Título:Metformin ameliorates activation of hepatic stellate cells and hepatic fibrosis by succinate and GPR91 inhibition.
[So] Source:Biochem Biophys Res Commun;495(4):2649-2656, 2018 01 22.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Chronic liver disease is becoming a major cause of morbidity and mortality worldwide. During liver injury, hepatic stellate cells (HSCs) trans-differentiate into activated myofibroblasts, which produce extracellular matrix. Succinate and succinate receptor (G-protein coupled receptor91, GPR91) signaling pathway has now emerged as a regulator of metabolic signaling. A previous study showed that succinate and its specific receptor, GPR91, are involved in the activation of HSCs and the overexpression of α-smooth muscle actin (α-SMA). Metformin, a well-known anti-diabetic drug, inhibits hepatic gluconeogenesis in the liver. Many studies have shown that metformin not only prevented, but also reversed, steatosis and inflammation in a nonalcoholic steatohepatitis (NASH) animal model. However, the role of metformin in HSC activation and succinate-GPR91 signaling has not been clarified. METHODS: The immortalized human HSCs, LX-2 cells, were used for the in vitro study. For the in vivo study, male C57BL/J6 mice were randomly divided into 3 groups and were fed with a methionine-choline-deficient diet (MCD diet group) as a nonalcoholic steatohepatitis (NASH) mouse model with or without 0.1% metformin for 12 weeks, or were fed a control methionine-choline-sufficient diet (MCS diet group). RESULTS: In our study, metformin and 5-aminoimidazole-4-carboxamide 1-ß-d-ribofuranoside (AICAR), which is an analog of adenosine monophosphate, were shown to suppress α-SMA expression via enhanced phosphorylation of AMP-activated protein kinase (AMPK) and inhibition of succinate-GPR91 signaling in activated LX-2 cells induced by palmitate- or succinate. Metformin and AICAR also reduced succinate concentration in the cell lysates when LX-2 cells were treated with palmitate. Moreover, metformin and AICAR reduced interleukin-6 and, transforming growth factor-ß1 production in succinate-treated LX-2 cells. Both metformin and AICAR inhibited succinate-stimulated HSC proliferation and cell migration. Mice fed a MCD diet demonstrated increased steatohepatitis and liver fibrosis compared to that of mice fed control diet. Metformin ameliorated steatohepatitis, liver fibrosis, inflammatory cytokine production and decreased α -SMA and GPR91expression in the livers of the MCD diet-fed mice. CONCLUSION: This study shows that metformin can attenuate activation of HSCs by activating the AMPK pathway and inhibiting the succinate-GPR91 pathway. Metformin has therapeutic potential for treating steatohepatitis and liver fibrosis.
[Mh] Termos MeSH primário: Células Estreladas do Fígado/efeitos dos fármacos
Células Estreladas do Fígado/metabolismo
Cirrose Hepática/tratamento farmacológico
Cirrose Hepática/metabolismo
Metformina/administração & dosagem
Receptores Acoplados a Proteínas-G/metabolismo
Ácido Succínico/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Relação Dose-Resposta a Droga
Regulação para Baixo/efeitos dos fármacos
Células Estreladas do Fígado/patologia
Seres Humanos
Hipoglicemiantes/administração & dosagem
Cirrose Hepática/patologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (GPR91 protein, mouse); 0 (Hypoglycemic Agents); 0 (Receptors, G-Protein-Coupled); 9100L32L2N (Metformin); AB6MNQ6J6L (Succinic Acid)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171227
[St] Status:MEDLINE


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[PMID]:27776340
[Au] Autor:Liang L; Yang X; Yu Y; Li X; Wu Y; Shi R; Jiang J; Gao L; Ye F; Zhao Q; Li R; Wei L; Han Z
[Ad] Endereço:Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China.
[Ti] Título:Babao Dan attenuates hepatic fibrosis by inhibiting hepatic stellate cells activation and proliferation via TLR4 signaling pathway.
[So] Source:Oncotarget;7(50):82554-82566, 2016 Dec 13.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Babao Dan (BBD), a traditional Chinese medicine, has been widely used as a complementary and alternative medicine to treat chronic liver diseases. In this study, we aimed to observe the protective effect of BBD on rat hepatic fibrosis induced by diethylnitrosamine (DEN) and explore it possible mechanism. BBD was administrated while DEN was given. After eight weeks, values of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) indicated that BBD significantly protected liver from damaging by DEN and had no obvious side effect on normal rat livers. Meanwhile, BBD attenuated hepatic inflammation and fibrosis in DEN-induced rat livers through histopathological examination and hepatic hydroxyproline content. Furthermore, we found that BBD inhibited hepatic stellate cells activation and proliferation without altering the concentration of lipopolysaccharide (LPS) in portal vein. In vitro study, serum from BBD treated rats (BBD-serum) could also significantly suppress LPS-induced HSCs activation through TLR4/NF-κB pathway. In addition, BBD-serum also inhibited the proliferation of HSCs by regulating TLR4/ERK pathway. Our study demonstrated that BBD may provide a new therapy strategy of hepatic injury and hepatic fibrosis.
[Mh] Termos MeSH primário: Proliferação Celular/efeitos dos fármacos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle
Medicamentos de Ervas Chinesas/farmacologia
Células Estreladas do Fígado/efeitos dos fármacos
Cirrose Hepática Experimental/prevenção & controle
Fígado/efeitos dos fármacos
Substâncias Protetoras/farmacologia
Transdução de Sinais/efeitos dos fármacos
Receptor 4 Toll-Like/metabolismo
[Mh] Termos MeSH secundário: Animais
Doença Hepática Induzida por Substâncias e Drogas/metabolismo
Doença Hepática Induzida por Substâncias e Drogas/patologia
Ciclina D1/metabolismo
Citocinas/metabolismo
Citoproteção
Dietilnitrosamina
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Células Estreladas do Fígado/metabolismo
Células Estreladas do Fígado/patologia
Lipopolissacarídeos/farmacologia
Fígado/metabolismo
Fígado/patologia
Cirrose Hepática Experimental/induzido quimicamente
Cirrose Hepática Experimental/metabolismo
Cirrose Hepática Experimental/patologia
Masculino
NF-kappa B/metabolismo
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ccnd1 protein, rat); 0 (Cytokines); 0 (Drugs, Chinese Herbal); 0 (Lipopolysaccharides); 0 (NF-kappa B); 0 (Protective Agents); 0 (Tlr4 protein, rat); 0 (Toll-Like Receptor 4); 136601-57-5 (Cyclin D1); 3IQ78TTX1A (Diethylnitrosamine); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.12783


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[PMID]:29366478
[Au] Autor:Park SY; Le CT; Sung KY; Choi DH; Cho EH
[Ad] Endereço:Department of Internal Medicine, School of Medicine, Kangwon National University, Republic of Korea.
[Ti] Título:Succinate induces hepatic fibrogenesis by promoting activation, proliferation, and migration, and inhibiting apoptosis of hepatic stellate cells.
[So] Source:Biochem Biophys Res Commun;496(2):673-678, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Liver fibrosis is a progressive pathological process that accompanies wound healing; however, therapeutics for reversing hepatic fibrosis are unavailable. Activation of hepatic stellate cells (HSCs) play a critical role in liver fibrosis. Recent reports showed that succinate and its receptor, G-protein coupled receptor 91 (GPR91), act as signaling molecules during the activation of HSCs. However, the role of succinate in proliferation, apoptosis, and migration of HSCs has not been studied. In this study, we determined whether succinate regulates proliferation, apoptosis, and migration of HSCs and induces liver fibrosis in a mouse model. Succinate treatment not only induced activation of HSCs, but also increased the proliferation and migration of LX-2 HSCs and inhibited apoptosis. To investigate whether succinate causes hepatic fibrosis, 100 mg/kg succinate or control PBS was administered by intraperitoneal injection to mice once a day for four weeks. There were significant molecular changes such as increased α-SMA and collagen type 1 production and increased production of inflammatory cytokines such as IL-6 and TNF-α, but not TGF-ß, in the succinate-treated group compared to the control group. However, no morphological changes were observed in Masson's trichrome staining. In conclusion, the present study demonstrated that succinate induces activation, proliferation, and migration of HSCs and attenuates apoptosis in LX-2 HSCs. Therefore, inhibition of succinate accumulation may be an effective method for reversing liver fibrosis by controlling HSC survival and growth.
[Mh] Termos MeSH primário: Células Estreladas do Fígado/patologia
Cirrose Hepática/metabolismo
Fígado/patologia
Ácido Succínico/metabolismo
[Mh] Termos MeSH secundário: Actinas/análise
Actinas/metabolismo
Animais
Apoptose
Linhagem Celular
Movimento Celular
Proliferação Celular
Células Estreladas do Fígado/citologia
Células Estreladas do Fígado/metabolismo
Seres Humanos
Fígado/citologia
Fígado/metabolismo
Cirrose Hepática/patologia
Masculino
Camundongos Endogâmicos C57BL
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Actins); 0 (alpha-smooth muscle actin, mouse); AB6MNQ6J6L (Succinic Acid)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180216
[Lr] Data última revisão:
180216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180126
[St] Status:MEDLINE


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[PMID]:29307832
[Au] Autor:Zhu J; Zhang Z; Zhang Y; Li W; Zheng W; Yu J; Wang B; Chen L; Zhuo Q; Chen L; Zhang J; Liu J
[Ad] Endereço:Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, PR China.
[Ti] Título:MicroRNA-212 activates hepatic stellate cells and promotes liver fibrosis via targeting SMAD7.
[So] Source:Biochem Biophys Res Commun;496(1):176-183, 2018 01 29.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:There has been an increasing number of researches about microRNAs (miRNAs) in the progression of liver fibrosis from the point of their comprehensive functions in regulating the activation of hepatic stellate cells (HSCs). Among them, it has been reported that miR-212 is up-regulated in activated rat primary HSCs. However, its mechanism has not been determined yet. Here, we confirmed that the level of miR-212-3p was up-regulated in livers of carbon tetrachloride (CCl )-treated mice compared with the normal control, which is a classical model of chronically damaged fibrotic liver. In vitro, we demonstrated that TGF-ß, a master fibrogenic cytokine, could induce the level of miR-212. In turn, overexpression of miR-212 could induce the activation marker of HSC including α-smooth muscle actin (α-SMA) and collagens by activating TGF-ß signaling pathway. Furthermore, SMAD7, a dominant suppressor of TGF-ß pathway, was identified as a direct target of miR-212-3p. Our results indicate that miR-212-3p facilitates the activation of HSCs and TGF-ß pathway by targeting SMAD7, highlighting that it can be served as a novel biomarker or therapeutic target for liver fibrosis.
[Mh] Termos MeSH primário: Células Estreladas do Fígado/metabolismo
Células Estreladas do Fígado/patologia
Cirrose Hepática/metabolismo
Cirrose Hepática/patologia
Fígado/metabolismo
MicroRNAs/metabolismo
Proteína Smad7/metabolismo
[Mh] Termos MeSH secundário: Animais
Tetracloreto de Carbono
Células Cultivadas
Fígado/patologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Ligação Proteica
Fator de Crescimento Transformador beta/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (MIRN212 microRNA, mouse); 0 (MicroRNAs); 0 (Smad7 Protein); 0 (Smad7 protein, mouse); 0 (Transforming Growth Factor beta); CL2T97X0V0 (Carbon Tetrachloride)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180109
[St] Status:MEDLINE


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[PMID]:28458351
[Au] Autor:Yamaguchi M; Saito SY; Nishiyama R; Nakamura M; Todoroki K; Toyo'oka T; Ishikawa T
[Ad] Endereço:Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka.
[Ti] Título:Caffeine Suppresses the Activation of Hepatic Stellate Cells cAMP-Independently by Antagonizing Adenosine Receptors.
[So] Source:Biol Pharm Bull;40(5):658-664, 2017.
[Is] ISSN:1347-5215
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:During liver injury, hepatic stellate cells (HSCs) are activated by various cytokines and transdifferentiated into myofibroblast-like activated HSCs, which produce collagen, a major source of liver fibrosis. Therefore, the suppression of HSC activation is regarded as a therapeutic target for liver fibrosis. Several epidemiological reports have revealed that caffeine intake decreases the risk of liver disease. In this study, therefore, we investigated the effect of caffeine on the activation of primary HSCs isolated from mice. Caffeine suppressed the activation of HSC in a concentration-dependent manner. BAPTA-AM, an intracellular Ca chelator, had no effect on the caffeine-induced suppression of HSC activation. None of the isoform-selective inhibitors of phosphodiesterase1 to 5 affected changes in the morphology of HSC during activation, whereas CGS-15943, an adenosine receptor antagonist, inhibited them. Caffeine had no effect on intracellular cAMP level or on the phosphorylation of extracellular signal-regulated kinase (ERK)1/2. In contrast, caffeine significantly decreased the phosphorylation of Akt1. These results suggest that caffeine inhibits HSC activation by antagonizing adenosine receptors, leading to Akt1 signaling activation.
[Mh] Termos MeSH primário: Cafeína/farmacologia
AMP Cíclico/metabolismo
Células Estreladas do Fígado/efeitos dos fármacos
Inibidores de Fosfodiesterase/farmacologia
Receptores Purinérgicos P1/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Quelantes/farmacologia
Relação Dose-Resposta a Droga
Ácido Egtázico/análogos & derivados
Ácido Egtázico/farmacologia
Cirrose Hepática/tratamento farmacológico
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Masculino
Camundongos
Fosforilação
Quinazolinas/farmacologia
Triazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chelating Agents); 0 (Phosphodiesterase Inhibitors); 0 (Quinazolines); 0 (Receptors, Purinergic P1); 0 (Triazoles); 104615-18-1 (9-chloro-2-(2-furyl)-(1,2,4)triazolo(1,5-c)quinazolin-5-imine); 139890-68-9 (1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester); 3G6A5W338E (Caffeine); 526U7A2651 (Egtazic Acid); E0399OZS9N (Cyclic AMP)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.1248/bpb.b16-00947


  8 / 2360 MEDLINE  
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[PMID]:29197497
[Au] Autor:Cheng Y; Zhu X; Cheng F; Ji L; Zhou Y
[Ad] Endereço:Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Qi xiou road 19, Nantong 226001, Jiangsu, China.
[Ti] Título:Delta-like homolog1/GATA binding protein 2 axis mediates leptin inhibition of PPARγ2 expression in hepatic stellate cells in vitro.
[So] Source:Life Sci;192:183-189, 2018 Jan 01.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: Peroxisome-proliferator activated receptor γ (PPARγ) plays a pivotal role in inhibition of hepatic stellate cell (HSC) activation, a key step for liver fibrogenesis. Adipocyte-derived hormone leptin has been shown to promote liver fibrosis in murine and human. PPARγ includes two subtypes, PPARγ1 and PPARγ2. Our previous study indicated that leptin down-regulated PPARγ1 expression in HSCs. The aim of this study was to investigate the effect of leptin on PPARγ2 expression and the underlying mechanisms in HSCs. MAIN METHODS: Real-time PCR and western blot analyses were used to examine gene expression. The promoter activities were detected by luciferase assay. KEY FINDINGS: Leptin reduced PPARγ2 expressions at promoter level, mRNA level, and protein level in HSCs, which required ß-catenin, p38 mitogen-activated protein kinase, and delta-like homolog1 (DLK1) signaling pathways. Leptin induced GATA binding protein 2 (GATA2) expression through DLK1 pathway and GATA2 reduced PPARγ2 expression. Ectopic expression of PPARγ2 reduced the protein levels of α-smooth muscle actin and α1(I)collagen in HSCs. SIGNIFICANCE: Since obese patients, often accompanied by hyperleptinemia, are more prone to liver fibrosis, the data from this study might have potential implications for clarifying the mechanisms for liver fibrogenesis in obese patients with hyperleptinemia.
[Mh] Termos MeSH primário: Fator de Transcrição GATA2/efeitos dos fármacos
Células Estreladas do Fígado/metabolismo
Peptídeos e Proteínas de Sinalização Intercelular/biossíntese
Leptina/farmacologia
PPAR gama/antagonistas & inibidores
PPAR gama/biossíntese
[Mh] Termos MeSH secundário: Actinas/biossíntese
Animais
Colágeno Tipo I/biossíntese
Fator de Transcrição GATA2/biossíntese
Fator de Transcrição GATA2/genética
Peptídeos e Proteínas de Sinalização Intercelular/genética
Camundongos
Camundongos Endogâmicos C57BL
Cultura Primária de Células
Regiões Promotoras Genéticas/genética
Transdução de Sinais/efeitos dos fármacos
Transdução de Sinais/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (Collagen Type I); 0 (Dlk1 protein, mouse); 0 (GATA2 Transcription Factor); 0 (Gata2 protein, mouse); 0 (Intercellular Signaling Peptides and Proteins); 0 (Leptin); 0 (PPAR gamma); 0 (alpha-smooth muscle actin, mouse)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171204
[St] Status:MEDLINE


  9 / 2360 MEDLINE  
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[PMID]:28746817
[Au] Autor:Wang L; Bai G; Chen F
[Ad] Endereço:a Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China.
[Ti] Título:Human bone marrow mesenchymal stem cells suppress the proliferation of hepatic stellate cells by inhibiting the ubiquitination of p27.
[So] Source:Biochem Cell Biol;95(6):628-633, 2017 Dec.
[Is] ISSN:1208-6002
[Cp] País de publicação:Canada
[La] Idioma:eng
[Ab] Resumo:Bone marrow mesenchymal stem cells (BMSCs) have considerable therapeutic potential for the treatment of end-stage liver disease. Previous studies have demonstrated that BMSCs secrete growth factors and cytokines that inactivate hepatic stellate cells (HSCs), which inhibited the progression of hepatic fibrosis. The aim of this study was to determine the mechanism by which BMSCs suppress the function of HSCs in fibrosis. Our results showed that co-culture of BMSCs and HSCs induced cell cycle arrest at the G10/G1 phase and cell apoptosis of HSCs, which finally inhibited the cell proliferation of HSCs. Consistent with the cell cycle arrest, co-culture of BMSCs and HSCs increased the abundance of the cell cycle protein p27. Mechanistically, we further uncovered that following the co-culture with BMSCs, the expression level of the E3 ligase S-phase kinase-associated protein 2 (SKP2) that is responsible for the ubiquitination of p27 was decreased, which attenuated the ubiquitination of p27 and increased the stability of p27 in HSCs. Collectively, our results indicated the potential involvement of the SKP2-p27 axis for the inhibitory effect of BSMCs on the cell proliferation of HSCs.
[Mh] Termos MeSH primário: Inibidor de Quinase Dependente de Ciclina p27/antagonistas & inibidores
Células Estreladas do Fígado/metabolismo
Células Mesenquimais Estromais/metabolismo
Ubiquitinação
[Mh] Termos MeSH secundário: Apoptose
Proliferação Celular
Técnicas de Cocultura
Inibidor de Quinase Dependente de Ciclina p27/metabolismo
Voluntários Saudáveis
Seres Humanos
Células Mesenquimais Estromais/citologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171227
[Lr] Data última revisão:
171227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.1139/bcb-2017-0127


  10 / 2360 MEDLINE  
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[PMID]:28745378
[Au] Autor:Jiang X; Shen T; Tang X; Yang W; Guo H; Ling W
[Ad] Endereço:Department of Food Science and Engineering, Institute of Science and Technology, Jinan University, Guangzhou 510632, People's Republic of China and Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou 510080, People's Republic of China.
[Ti] Título:Cyanidin-3-O-ß-glucoside combined with its metabolite protocatechuic acid attenuated the activation of mice hepatic stellate cells.
[So] Source:Food Funct;8(8):2945-2957, 2017 Aug 01.
[Is] ISSN:2042-650X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Previous studies indicated that cyanidin-3-O-ß-glucoside (C3G) as a classical anthocyanin exerted an anti-fibrotic effect in the liver, but its bioavailability was quite low. This study was undertaken to explore the restraining effect of C3G and its metabolite protocatechuic acid (PCA) on the activation of hepatic stellate cells (HSCs). Our data demonstrated that the treatment of a carbon tetrachloride-treated mice model with C3G inhibited liver fibrosis and HSC activation. In vitro, both C3G and PCA preserved the lipid droplets and retinol in primary HSCs, and additionally inhibited the mRNA expression of α-smooth muscle actin and collagen I, but elevated the level of matrix metalloproteinase-2 and liver X receptors. Only PCA suppressed the levels of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) secreted from HSCs significantly. In addition, C3G and PCA inhibited the proliferation and migration of HSCs. In conclusion, PCA mainly explained the in vivo inhibiting effect of C3G on HSC activation and liver fibrosis.
[Mh] Termos MeSH primário: Antocianinas/administração & dosagem
Glucosídeos/administração & dosagem
Células Estreladas do Fígado/efeitos dos fármacos
Hidroxibenzoatos/administração & dosagem
Cirrose Hepática/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Antocianinas/metabolismo
Tetracloreto de Carbono/efeitos adversos
Movimento Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Células Cultivadas
Sinergismo Farmacológico
Glucosídeos/metabolismo
Células Estreladas do Fígado/metabolismo
Seres Humanos
Hidroxibenzoatos/metabolismo
Interleucina-6/genética
Interleucina-6/metabolismo
Cirrose Hepática/genética
Cirrose Hepática/metabolismo
Cirrose Hepática/fisiopatologia
Masculino
Metaloproteinase 2 da Matriz/genética
Metaloproteinase 2 da Matriz/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Fator de Necrose Tumoral alfa/genética
Fator de Necrose Tumoral alfa/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anthocyanins); 0 (Glucosides); 0 (Hydroxybenzoates); 0 (Interleukin-6); 0 (Tumor Necrosis Factor-alpha); 36R5QJ8L4B (protocatechuic acid); 7084-24-4 (cyanidin 3-O-glucoside); CL2T97X0V0 (Carbon Tetrachloride); EC 3.4.24.24 (Matrix Metalloproteinase 2)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171215
[Lr] Data última revisão:
171215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.1039/c7fo00265c



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