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1.
Life Sci ; 259: 118293, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32822714

RESUMO

AIMS: Liver fibrosis is an inflammatory and fibrogenic process that occurs following chronic liver damage. TGFß1 is the key inducer of fibrosis. MiR-21 and miR-122 are two miRNAs that their expression changes during fibrosis. In the present study, we investigate the effects of curcumin, quercetin, and atorvastatin on the expression levels of miR-21 and miR-122 and evaluated their correlation with TGFß1 expression in bile duct ligation (BDL)-induced fibrotic rats. MATERIALS AND METHODS: Thirty two adult male Wistar rats were divided into 8 groups (n = 8 for each): Sham, Sham + curcumin (100 mg/kg/day), Sham + quercetin (30 mg/kg/day), Sham + atorvastatin (15 mg/kg/day), BDL, BDL + curcumin, BDL + quercetin, BDL + atorvastatin and treated for four weeks via oral gavage. The expression of miR-21, miR-122, and TGFß1 was evaluated via RT-qPCR. KEY FINDINGS: The expression levels of TGFß1 and miR-21 were significantly increased in the BDL group compared to the Sham group (P < 0.05), but the expression of miR-122 was significantly decreased in the BDL group compared to the Sham group (P < 0.05). Curcumin, quercetin, and atorvastatin treatment lead to down-regulation of miR-21 and TGFß1 and up-regulation of miR-122 in the BDL groups. There was no significant difference between these drugs in altering gene expression and all had the same effects. Moreover, a direct significant correlation was observed between mir-21 and TGFß1 and an inverse significant correlation between mir-122 and TGFß1 expression. SIGNIFICANCE: In summary, targeting these molecular pathways may partially prevent the progression of liver fibrosis.


Assuntos
Atorvastatina/farmacologia , Curcumina/farmacologia , Cirrose Hepática/metabolismo , MicroRNAs/metabolismo , Quercetina/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/etiologia , Masculino , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real
2.
DNA Cell Biol ; 39(9): 1711-1722, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32833553

RESUMO

High mobility group box 1 (HMGB1) is essential for the pathogenesis of liver injury and liver fibrosis. We previously revealed that miR-146b promotes hepatic stellate cells (HSCs) activation and proliferation. Nevertheless, the potential mechanisms are still unknown. Herein, HMGB1 increased HSCs proliferation and COL1A1 and α-SMA protein levels. However, the knockdown of miR-146b inhibited HSCs proliferation and COL1A1 and α-SMA protein levels induced via HMGB1 treatment. miR-146b was upregulated by HMGB1 and miR-146b targeted hepatocyte nuclear factor 1A (HNF1A) 3'-untranslated region (3'UTR) to modulate its expression negatively. Further, we confirmed that HMGB1 might elicit miR-146b expression via p65 within HSCs. Knockdown or block of HMGB1 relieved the CCl4-induced liver fibrosis. In fibrotic liver tissues, miR-146b expression was positively correlated with p65 mRNA, but HNF1A mRNA was inversely correlated with p65, and miR-146b expression. In summary, our findings suggest that HMGB1/p65/miR-146b/HNF1A signaling exerts a crucial effect on liver fibrogenesis via the regulation of HSC function.


Assuntos
Proteína HMGB1/metabolismo , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Cirrose Hepática/metabolismo , Transdução de Sinais , Regiões 3' não Traduzidas , Animais , Linhagem Celular , Proteína HMGB1/genética , Células Estreladas do Fígado/metabolismo , Fator 1-alfa Nuclear de Hepatócito/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo
3.
Chem Biol Interact ; 329: 109213, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32739323

RESUMO

Phytoestrogens are plant-derived substances with a similar structure to 17-beta-estradiol, which have protective roles in estrogen-dependent diseases. Isoflavones, the most well-known subgroup of phytoestrogens, play protective roles against chemicals-induced liver injuries through several molecular mechanisms. Hepatoprotective effects of isoflavones are, partly, associated with their antioxidant, anti-inflammatory, immunomodulatory, and anti-fibrotic properties. Besides, isoflavones can reduce gut-derived endotoxins, accelerate alcohol metabolism, stimulate detoxification of hepatotoxic chemicals, suppress the bioactivation of these chemicals, inhibit hepatocytes apoptosis, and restore autophagy activity during chemicals-induced liver diseases. This review provides a summary of the molecular mechanisms underlying the hepatoprotective effects of isoflavones. It seems that further studies are needed to investigate the hepatoprotective potential of isoflavones in patients with different stages of chemicals-induced liver injuries.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Isoflavonas/metabolismo , Substâncias Protetoras/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Modelos Animais de Doenças , Inflamação/prevenção & controle , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Cirrose Hepática/metabolismo , Cirrose Hepática/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia
4.
Proc Natl Acad Sci U S A ; 117(25): 14231-14242, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32513687

RESUMO

Transforming growth factor ß-activated kinase1 (TAK1) encoded by the gene MAP3K7 regulates multiple important downstream effectors involved in immune response, cell death, and carcinogenesis. Hepatocyte-specific deletion of TAK1 in Tak1 ΔHEP mice promotes liver fibrosis and hepatocellular carcinoma (HCC) formation. Here, we report that genetic inactivation of RIPK1 kinase using a kinase dead knockin D138N mutation in Tak1 ΔHEP mice inhibits the expression of liver tumor biomarkers, liver fibrosis, and HCC formation. Inhibition of RIPK1, however, has no or minimum effect on hepatocyte loss and compensatory proliferation, which are the recognized factors important for liver fibrosis and HCC development. Using single-cell RNA sequencing, we discovered that inhibition of RIPK1 strongly suppresses inflammation induced by hepatocyte-specific loss of TAK1. Activation of RIPK1 promotes the transcription of key proinflammatory cytokines, such as CCL2, and CCR2+ macrophage infiltration. Our study demonstrates the role and mechanism of RIPK1 kinase in promoting inflammation, both cell-autonomously and cell-nonautonomously, in the development of liver fibrosis and HCC, independent of cell death, and compensatory proliferation. We suggest the possibility of inhibiting RIPK1 kinase as a therapeutic strategy for reducing liver fibrosis and HCC development by inhibiting inflammation.


Assuntos
Carcinoma Hepatocelular/metabolismo , Hepatócitos/metabolismo , Inflamação/metabolismo , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Biomarcadores Tumorais , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma Hepatocelular/genética , Morte Celular , Quimiocina CCL2/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Hepatócitos/patologia , Inflamação/patologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/genética , MAP Quinase Quinase Quinases/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Receptores CCR2/metabolismo
5.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(1): 1-5, 2020 Jan 28.
Artigo em Chinês | MEDLINE | ID: mdl-32476365

RESUMO

OBJECTIVE: To observe the role of calcium sensitive receptor (CaSR) in the pathogenesis of diabetic liver injury. METHODS: Forty Wistar rats were randomly divided into normal control group (control, n=10) and diabetes group (T1D, STZ 60 mg/kg intraperitoneal injection, n=30), and the samples were collected at the 2nd, 4th and 8th week. Rats hepatic stellate cells (HSC) were randomly divided into normal control group (Control, 10% FBS-DMEM culture, n=5), high glucose group (HG, 10% FBS-DMEM+40 mmol/L glucose, treated for 48 h, n=5) and CaSR inhibitor group (HG+Calhex 231, 10% FBS-DMEM+40 mmol/L glucose+2.5 µmol/L Calhex231 for 48h, n=5). The body weight, blood glucose, serum glutamic oxaloacetic transaminase (AST) and alanine aminotransferase (ALT) activities were measured dynamically. The changes of liver morphology and ultrastructure were observed by HE staining and Masson staining by transmission electron microscopy. The changes of CaSR and liver fibrosis related indexes were detected by Western blot. RESULTS: Compared with the control group, diabetic rats lost weight, while blood glucose, AST and ALT increased significantly, and the expression of CaSR, collagen 1(CO 1), collagen 3 (CO 3), matrix metalloproteinase(MMP)-1, -2 and -9 increased significantly. The results of the cell model were basically the same as those in vivo. Compared with the control group, the expression of α-smooth muscle actin (α-SMA) was increased, indicating that HSC differentiated into myofibroblasts in HG group. The expression of the main components of ECM (CO 1 and CO 3), and the key enzyme of ECM degradation (MMP9) were also increased, while CaSR inhibitor, Calhex231, could reduce the above changes. CONCLUSION: The up-regulation of CaSR expression is involved in the occurrence of diabetic liver injury and fibrosis.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Cirrose Hepática/metabolismo , Receptores de Detecção de Cálcio/metabolismo , Animais , Células Cultivadas , Diabetes Mellitus Experimental/complicações , Matriz Extracelular/metabolismo , Células Estreladas do Fígado , Fígado/patologia , Cirrose Hepática/etiologia , Metaloproteinases da Matriz/metabolismo , Distribuição Aleatória , Ratos , Ratos Wistar
7.
Life Sci ; 256: 117909, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32512009

RESUMO

Hepatic fibrosis (HF) is a wound-healing response that occurs during chronic liver injury and features by an excessive accumulation of extracellular matrix (ECM) components. Activation of hepatic stellate cell (HSC), the leading effector in HF, is responsible for overproduction of ECM. It has been documented that transforming growth factor-ß1 (TGF-ß1) stimulates superfluous accumulation of ECM and triggers HSCs activation mainly via canonical Smad-dependent pathway. Also, the pro-fibrogenic TGF-ß1 is correlated with generation of reactive oxygen species (ROS) and inhibition of antioxidant mechanisms. Moreover, involvement of oxidative stress (OS) can be clearly elucidated as a fundamental event in liver fibrogenesis. Nuclear factor erythroid 2-related factor 2-antioxidant response elements (Nrf2-AREs) pathway, a group of OS-mediated transcription factors with diverse downstream targets, is associated with the induction of diverse detoxifying enzymes and the most pivotal endogenous antioxidative system. More specifically, Nrf2-AREs pathway has recently assigned as a new therapeutic target for cure of HF. The overall goal of this review will focus on recent findings about activation of Nrf2-AREs-mediated antioxidant and suppression of profibrotic TGF-ß1/Smad3 pathway in the liver, providing an overview of recent advances in transcriptional repressors that dislocated during HF formation, and highlighting possible novel therapeutic targets for liver fibrosis.


Assuntos
Elementos de Resposta Antioxidante/efeitos dos fármacos , Antioxidantes/farmacologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/prevenção & controle , Fator 2 Relacionado a NF-E2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Antioxidantes/metabolismo , Descoberta de Drogas , Matriz Extracelular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Células Estreladas do Fígado/patologia , Humanos , Fígado/metabolismo , Cirrose Hepática/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
8.
Life Sci ; 256: 117926, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32535081

RESUMO

AIMS: Hepatic stellate cells (HSCs) play an essential role in the development of liver fibrosis by producing extracellular matrix proteins, growth factors, and pro-inflammatory and pro-fibrogenic cytokines once activated. We previously demonstrated that astaxanthin (ASTX), a xanthophyll carotenoid, attenuates HSC activation. The objective of this study was to investigate whether there is a difference in glycolysis between quiescent and activated HSCs and the effect of ASTX on glycolysis during HSC activation. MATERIALS AND METHODS: Mouse primary HSCs were activated for 7 days in the presence or absence of 25 µM of ASTX. Quiescent HSCs (qHSCs), 1 day after isolation, and activated HSCs (aHSCs) treated with/without ASTX were plated in a Seahorse XF24 cell culture microplate for Glycolysis Stress tests. KEY FINDINGS: aHSCs had significantly lower glycolysis, but higher glycolytic capacity, maximum capacity of glycolysis, and non-glycolytic acidification than qHSCs. Importantly, ASTX markedly increased glycolysis during HSC activation with a concomitant increase in lactate formation and secretion. Compared with qHSCs, aHSCs had significantly lower expression of glucose transporter 1, the major glucose transporter in HSCs, and its transcription factor hypoxia-inducible factor 1α, which was markedly increased by ASTX in aHSCs. SIGNIFICANCE: Our data suggest that ASTX may prevent the activation of HSCs by altering glycolysis and the expression of genes involved in the pathways.


Assuntos
Glicólise/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/metabolismo , Animais , Regulação da Expressão Gênica , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Glicólise/genética , Humanos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Xantofilas/metabolismo
9.
Am J Physiol Gastrointest Liver Physiol ; 319(2): G151-G156, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32597708

RESUMO

Laursen TL, Sandahl TD, Kazankov K, Eriksen PL, Kristensen LH, Holmboe CH, Laursen AL, Vilstrup H, Grønbæk H. Early normalization of reduced urea synthesis capacity after direct-acting antiviral therapy in hepatitis C cirrhosis. Am J Physiol Gastrointest Liver Physiol 319: G151-G156, 2020. First published June 29, 2020; doi:10.1152/ajpgi.00128.2020.-Effects of direct-acting antiviral (DAA) treatment of chronic hepatitis C (CHC) cirrhosis on metabolic liver function are unknown but important for prognosis. Ureagenesis is an essential metabolic liver function involved in whole body nitrogen homeostasis. We aimed to investigate the ureagenesis capacity before and immediately after DAA therapy and relate the findings to hepatic inflammation and structural changes. In an observational before-and-after intervention study, the ureagenesis capacity was quantified by functional hepatic nitrogen clearance (FHNC) in 9 CHC patients with cirrhosis and 10 healthy volunteers. Hepatic inflammation was evaluated by alanine aminotransferase (ALT) and the macrophage activation markers sCD163 and sMR. Structural changes were estimated as liver stiffness and by portal hypertension as the hepatic venous pressure gradient (HVPG). Before treatment, the FHNC in the patients was half of the controls [16.4 L/h (8.2-24.5) vs. 33.4 (29.2-37.6), P = 0.0004]; after successful DAA treatment, it normalized [28.4 (15.9-40.9), P = 0.008 vs. baseline]. DAA treatment normalized ALT (P < 0.0001) and decreased the elevated sCD163 from 5.6 mg/L (3.5-7.7) to 3.4 (2-0-4.8) (P < 0.001) and sMR from 0.35 mg/L (0.21-0.49) to 0.31 (0.17-0.45) (P < 0.01). Liver stiffness fell by 30% (P < 0.05) but remained over the cirrhosis threshold. HVPG was not affected (P = 0.59). DAA treatment restored the severely reduced ureagenesis capacity, along with amelioration of hepatic inflammation but without normalization of other cirrhosis characteristics. Our findings indicate that the anti-inflammatory effect of virus eradication independent of hepatic structural effects rapidly improves metabolic dysfunction. We suggest this effect to be an important early onset part of the expected clinical DAA treatment benefit.NEW & NOTEWORTHY Antiviral treatment of chronic hepatitis C restores the liver's reduced capacity to produce urea along with an improvement in liver inflammation without immediate effects on structural liver changes. The effect is suggested to be an important early onset part of the expected clinical treatment benefit.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/metabolismo , Ureia/metabolismo , Adulto , Estudos de Coortes , Feminino , Hepatite C Crônica/patologia , Humanos , Masculino , Pessoa de Meia-Idade
10.
Expert Opin Pharmacother ; 21(13): 1637-1650, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32543284

RESUMO

INTRODUCTION: Chronic liver disease is due to various causes of persistent liver damage and will eventually lead to the development of liver fibrosis. If no treatment is initiated, this condition may progress to cirrhosis and hepatocellular carcinoma. Current treatments comprise the elimination of the cause of injury, such as by lifestyle changes, alcohol abstinence, and antiviral agents. However, such etiology-driven therapy is often insufficient in patients with late-stage fibrosis/cirrhosis, therefore maintaining the need for efficient antifibrotic pharmacotherapeutic interventions. AREAS COVERED: The authors discuss the recent advances in the development of antifibrotic drugs, which target various pathways of the fibrogenesis process, including cell death, inflammation, gut-liver axis, and myofibroblast activation. Due to the significant burden of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), various agents which specifically target metabolic pathways and their related receptors/ligands have been developed. For some of them, e.g., obeticholic acid, advanced stage clinical trials indicate antifibrotic efficacy in NAFLD and NASH. EXPERT OPINION: Significant advances have been made in the development of novel antifibrotic pharmacotherapeutics. The authors expect that the development of combinatorial therapies, which combine compounds that target various pathways of fibrosis progression, will have a major impact as future etiology-independent therapies.


Assuntos
Cirrose Hepática/tratamento farmacológico , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Ensaios Clínicos como Assunto , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Humanos , Inflamação , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Terapia de Alvo Molecular , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia
11.
Toxicol Appl Pharmacol ; 401: 115101, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32512072

RESUMO

Non-alcoholic steatohepatitis (NASH) is becoming of increasing significance due to its growing global prevalence and risk of progression to end-stage liver disease. This study was carried out to investigate the potential anti-inflammatory, insulin sensitizing, and antifibrotic effects of diosmin in an experimental model of NASH induced in rats using high-fat diet (HFD) and 30 mg/kg streptozotocin (STZ). Diosmin was administered orally at dose of 100 mg/kg for 8 weeks. Stained tissue sections were examined for histopathological signs of NASH, collagen deposition, and alpha smooth muscle actin (α-SMA) expression. In addition, insulin resistance, dyslipidemia, inflammation, and fibrosis markers were assessed. HFD/STZ successfully induced different NASH features such as insulin resistance seen by elevated fasting blood glucose levels and homeostasis model assessment for insulin resistance. Moreover, induced rats demonstrated dyslipidemia, a significant elevation in tumor necrosis factor alpha (TNF-α) and interleukin-6 levels, and an imbalance in the oxidative status of the liver. Those events altogether precipitated initiation of liver fibrosis as confirmed by elevated transforming growth factor beta (TGF-ß) levels. Treatment with diosmin demonstrated multiple beneficial effects as it significantly ameliorated histopathological NASH findings, lowered TNF-α, interleukin-6, and malondialdehyde levels, improved lipid and glucose metabolism, and lowered hepatic TGF-ß, α-SMA, and collagen content compared to untreated rats. The present study represents a drug repositioning scenario as diosmin is widely used for management of blood vessel disorders and is known to be well tolerated. This encourages the extension of our study to the clinical setting to explore diosmin effects in NASH patients.


Assuntos
Diosmina/uso terapêutico , Resistência à Insulina/fisiologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Dieta Hiperlipídica/efeitos adversos , Diosmina/farmacologia , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/metabolismo , Cirrose Hepática/etiologia , Masculino , Hepatopatia Gordurosa não Alcoólica/etiologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
12.
Chem Biol Interact ; 327: 109176, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32534989

RESUMO

Alcoholic liver disease (ALD) is a progressively aggravated liver disease with high incidence in alcoholics. Ethanol-induced fat accumulation and the subsequent lipopolysaccharide (LPS)-driven inflammation bring liver from reversible steatosis, to irreversible hepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma. Peroxisome proliferator-activated receptor α (PPARα) is a member of the nuclear receptor superfamily of ligand-activated transcription factors and plays pivotal roles in the regulation of fatty acid homeostasis as well as the inflammation control in the liver. It has been well documented that PPARα activity and/or expression are downregulated in liver of mice exposed to ethanol, which is thought to be one of the prime contributors to ethanol-induced steatosis, hepatitis and fibrosis. This article summarizes the current evidences from in vitro and animal models for the critical roles of PPARα in the onset and progression of ALD. Importantly, it should be noted that the expression of PPARα in human liver is reported to be similar to that in mice, and PPARα expression is downregulated in the liver of patients with nonalcoholic fatty liver disease (NAFLD), a disease sharing many similarities with ALD. Therefore, clinical trials investigating the expression of PPARα in the liver of ALD patients and the efficacy of strong PPARα agonists for the prevention and treatment of ALD are warranted.


Assuntos
Fígado Gorduroso Alcoólico/etiologia , PPAR alfa/metabolismo , Adiponectina/metabolismo , Animais , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Regulação para Baixo , Etanol , Fígado Gorduroso Alcoólico/metabolismo , Humanos , Inflamação/induzido quimicamente , Inflamação/etiologia , Inflamação/metabolismo , Fígado/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/metabolismo , PPAR alfa/agonistas , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
13.
Life Sci ; 254: 117795, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32417373

RESUMO

AIMS: The primary focus of this study was to explore the effects of cyclic AMP response element-binding protein H (CREBH) on the development of nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: CREBH knockout (KO) and wildtype (WT) mice were averagely divided into a methionine and choline-deficient (MCD) or high fat (HF) diet group and respective chow diet (CD) groups. Mice were sacrificed after 4-week treatment for MCD model and 24-week treatment for HF model. KEY FINDINGS: Characteristics of nonalcoholic steatohepatitis-related liver fibrosis in KO-MCD/HF group were verified by hepatic histological analyses. Compared with WT-MCD/HF group, levels of plasma ALT and hepatic hydroxyproline increased in KO-MCD/HF group. Significantly higher levels of MCP-1, αSMA, Desmin, COL-1, TIMP-1, TGF-ß1, TGF-ß2 were found while MMP-9 and FGF21 mRNA levels decreased in KO-MCD/HF group. There was also a distinct difference of mRNA levels of TNFα, CTGF and CCND1 in KO-HF group compared with controls. Protein levels of MCP-1, BAX, αSMA, COL-1, TGF-ß1 and SMAD2/3 significantly increased in KO-MCD/HF group and CCND1 was also upregulated in KO-HF group compared to their counterparts. SIGNIFICANCE: CREBH knockout may primarily regulate the TGF-ß1 signaling pathway via TGF-ß2 and FGF21 resulting in more severe inflammation and fibrosis in NAFLD.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Cirrose Hepática/genética , Hepatopatia Gordurosa não Alcoólica/genética , Fator de Crescimento Transformador beta/metabolismo , Alanina Transaminase/sangue , Animais , Deficiência de Colina , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/deficiência , Dieta Hiperlipídica , Fatores de Crescimento de Fibroblastos/biossíntese , Hidroxiprolina/metabolismo , Lipídeos/sangue , Cirrose Hepática/sangue , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Metionina/deficiência , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de Sinais/genética
14.
PLoS Genet ; 16(5): e1008796, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32428001

RESUMO

Sex differences in the incidence and progression of many liver diseases, including liver fibrosis and hepatocellular carcinoma, are associated with sex-biased hepatic expression of hundreds of genes. This sexual dimorphism is largely determined by the sex-specific pattern of pituitary growth hormone secretion, which controls a transcriptional regulatory network operative in the context of sex-biased and growth hormone-regulated chromatin states. Histone H3K27-trimethylation yields a major sex-biased repressive chromatin mark deposited at many strongly female-biased genes in male mouse liver, but not at male-biased genes in female liver, and is catalyzed by polycomb repressive complex-2 through its homologous catalytic subunits, Ezh1 and Ezh2. Here, we used Ezh1-knockout mice with a hepatocyte-specific knockout of Ezh2 to investigate the sex bias of liver H3K27-trimethylation and its functional role in regulating sex-differences in the liver. Combined hepatic Ezh1/Ezh2 deficiency led to a significant loss of sex-biased gene expression, particularly in male liver, where many female-biased genes were increased in expression while male-biased genes showed decreased expression. The associated loss of H3K27me3 marks, and increases in the active enhancer marks H3K27ac and H3K4me1, were also more pronounced in male liver. Further, Ezh1/Ezh2 deficiency in male liver, and to a lesser extent in female liver, led to up regulation of many genes linked to liver fibrosis and liver cancer, which may contribute to the observed liver pathologies and the increased sensitivity of these mice to hepatotoxin exposure. Thus, Ezh1/Ezh2-catalyzed H3K27-trimethyation regulates sex-dependent genetic programs in liver metabolism and liver fibrosis through its sex-dependent effects on the epigenome, and may thereby determine the sex-bias in liver disease susceptibility.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/genética , Cirrose Hepática/genética , Fígado/metabolismo , Complexo Repressor Polycomb 2/genética , Animais , Modelos Animais de Doenças , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Histonas/metabolismo , Cirrose Hepática/metabolismo , Masculino , Metilação , Camundongos , Complexo Repressor Polycomb 2/metabolismo , Análise de Sequência de RNA , Caracteres Sexuais
15.
PLoS One ; 15(5): e0233702, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32442221

RESUMO

Liver fibrosis is a manifestation of chronic liver injury. It leads to hepatic dysfunction and is a critical element in the pathogenesis of cirrhosis and hepatocellular carcinoma. The activation of hepatic stellate cells (HSC) plays a central role in liver fibrogenesis of different etiologies. To elucidate the molecular mechanism of this phenomenon, it is important to analyze the changes in gene expression that accompany the HSC activation process. In this study, we isolated quiescent and activated HSCs from control mice and mice with CCl4-induced liver fibrosis, respectively, and performed RNA sequencing to compare the differences in gene expression patterns between the two types of HSCs. We also reanalyzed public gene expression data for fibrotic liver tissues isolated from patients with HBV infection, HCV infection, and nonalcoholic fatty liver disease to investigate the gene expression changes during liver fibrosis of these three etiologies. We detected 146 upregulated and 18 downregulated genes in activated HSCs, which were implicated in liver fibrosis as well. Among the overlapping genes, seven transcription factor-encoding genes, ARID5B, GATA6, MITF, PBX1, PLAGL1, SOX4, and SOX9, were upregulated, while one, RXRA, was downregulated. These genes were suggested to play a critical role in HSC activation, and subsequently, in the promotion of liver fibrosis. We undertook the RNA sequencing of quiescent and activated HSCs and analyzed the expression profiles of genes associated with HSC activation in liver fibrotic tissues from different liver diseases, and also aimed to elucidate the changes in gene expression patterns associated with HSC activation and liver fibrosis.


Assuntos
Hepacivirus/metabolismo , Células Estreladas do Fígado/metabolismo , Vírus da Hepatite B/metabolismo , Hepatite B/metabolismo , Hepatite C/metabolismo , Cirrose Hepática/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Linhagem Celular , Regulação da Expressão Gênica , Células Estreladas do Fígado/patologia , Células Estreladas do Fígado/virologia , Hepatite B/patologia , Hepatite C/patologia , Humanos , Cirrose Hepática/patologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/patologia , Fatores de Transcrição/biossíntese
16.
J Pharmacol Sci ; 143(3): 165-175, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32387002

RESUMO

yeyachun and danshen exist as Chinese patent medicine, Xuemai Tong, and are clearly effective at alleviating liver fibrosis (LF). Previous studies have indicated that triterpenoids from yeyachun (EFT), and phenolic acids from danshen (SMP) are effective in the treatment of LF. The regulation of intestinal flora is an effective method for treating LF. The aim of this study was to investigate the effect of a mixture of EFT and SMP on carbon tetrachloride (CCl4) induced LF. Our results showed the mixture significantly decreased liver damage and fibrosis index, and maintained liver tissue composition, compared to the model group. Moreover, the imbalance of symptoms of intestinal flora was improved. The mixture also caused changes to metabolites of gut flora. Furthermore, the expression of CD68 in liver tissues from the treated groups was significantly decreased when compared to the model group. However, no significant difference was observed from microstructure of gut tissues and LPS concentrations in the serum between mixture treated mice and model mice. This study suggests that the mixture of EFT and SMP had a significant effect on CCl4 induced LF, and the mechanism of this action, at least in part, involved the regulation of intestinal flora and their metabolites.


Assuntos
Tetracloreto de Carbono/efeitos adversos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Hidroxibenzoatos/farmacologia , Hidroxibenzoatos/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/microbiologia , Fitoterapia , Salvia miltiorrhiza/química , Triterpenos/farmacologia , Triterpenos/uso terapêutico , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/isolamento & purificação , Fígado/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Masculino , Camundongos Endogâmicos ICR , Triterpenos/isolamento & purificação
17.
Artigo em Inglês | MEDLINE | ID: mdl-32374676

RESUMO

The liver is the central metabolic hub for carbohydrate, lipid, and protein metabolism. It is composed of four major types of cells, including hepatocytes, endothelial cells (ECs), Kupffer cells, and stellate cells. Hepatic ECs are highly heterogeneous in both mice and humans, representing the second largest population of cells in liver. The majority of them line hepatic sinusoids known as liver sinusoidal ECs (LSECs). The structure and biology of LSECs and their roles in physiology and liver disease were reviewed recently. Here, we do not give a comprehensive review of LSEC structure, function, or pathophysiology. Instead, we focus on the recent progress in LSEC research and other hepatic ECs in physiology and nonalcoholic fatty liver disease and other hepatic fibrosis-related conditions. We discuss several current areas of interest, including capillarization, scavenger function, autophagy, cellular senescence, paracrine effects, and mechanotransduction. In addition, we summarize the strengths and weaknesses of evidence for the potential role of endothelial-to-mesenchymal transition in liver fibrosis.


Assuntos
Capilares/metabolismo , Células Endoteliais/metabolismo , Cirrose Hepática/metabolismo , Fígado/irrigação sanguínea , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Autofagia , Capilares/patologia , Diferenciação Celular , Proliferação de Células , Senescência Celular , Células Endoteliais/patologia , Transição Epitelial-Mesenquimal , Humanos , Mediadores da Inflamação/metabolismo , Cirrose Hepática/patologia , Mecanotransdução Celular , Hepatopatia Gordurosa não Alcoólica/patologia , Comunicação Parácrina , Espécies Reativas de Oxigênio/metabolismo
19.
Parasitol Res ; 119(7): 2177-2187, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32377911

RESUMO

Liver fibrosis is a dynamic process that occurs in response to chronic liver disease resulting from factors such as chronic infections, autoimmune reactions, allergic responses, toxins, radiation, and infectious agents. Among the infectious agents, multicellular parasites cause chronic inflammation and fibrosis. Twenty-five patients with different stages of cystic echinococcosis (CE) were enrolled in the study. The expression of ACTA2, COL3A1, IFN-γ, MMP2, MMP9, TGF-ß1, and TNF-α genes was determined by qRT-PCR in healthy and fibrotic liver tissue of the CE patients. TGF-ß1 expression was evaluated by immunohistochemistry, and histology was conducted to assess the development of liver fibrosis. Expression of MMP9, ACTA2, COL3A1, and MMP2 was found significantly higher in the fibrotic tissue compared to healthy tissue. We observed a significant correlation between TGF-ß1 and TNF-α gene expressions and liver fibrosis. The mRNA level of IFN-γ was lower in the fibrotic than in the healthy hepatic tissue. Immunohistochemistry analysis revealed TGF-ß1 upregulation in the fibrotic tissue. Histology showed inflammation and fibrosis to be significantly higher in the fibrotic tissue. The findings of this study suggest that Echinococcus granulosussensu lato can promotes fibrosis through the overexpression of TGF-ß1, MMP9, ACTA2, COL3A1, and MMP2. The downregulation of IFN-γ mRNA in fibrotic samples is probably due to the increased production of TGF-ß1 and the suppression of potential anti-fibrotic role of IFN-γ during advanced liver injury caused by E. granulosussensu lato.


Assuntos
Equinococose/patologia , Cirrose Hepática/patologia , Adolescente , Adulto , Animais , Criança , Equinococose/genética , Equinococose/metabolismo , Equinococose/parasitologia , Echinococcus granulosus/fisiologia , Feminino , Perfilação da Expressão Gênica , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/parasitologia , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Adulto Jovem
20.
Life Sci ; 253: 117606, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32320707

RESUMO

BACKGROUND/AIMS: In cirrhosis, the levels of proinflammatory cytokines are high in the liver and blood. Endotoxin decreases level of consciousness in cirrhotic rats. Phosphatidylserine exists in the cell membrane structure and is essential for the survival of neurons. Phosphatidylserine receptor is found in phagocytic cells and also activates the signaling of membrane proteins in apoptotic process. Therefore this study was aimed to explore the hypothesis that hepatic encephalopathy is prevented by phosphatidylserine treatment and if so, whether this is associated with altered level of proinflammatory cytokines in the brain. METHODS: Cirrhosis was induced by surgical ligation of the bile duct in male Wister rats. The groups were treated with phosphatidylserine and saline for 4 weeks. Brain IL6, TNFα and the expression of phosphatidylserine receptor were assessed. Intraperitoneal injections of either saline or lipopolysaccharide (0.1 mg/kg) were administered to each group. Finally, animal behavior, blood ammonia and the expression of toll like receptor 4 were examined in the brain. RESULTS: Cirrhosis in rats was associated with altered expression of toll-like receptor4 in brain cortex and phosphatidylserine treatment increases toll-like receptor4 receptor expression. Phosphatidylserine had anti-inflammatory effect in healthy rats but no effect in cirrhotic rats. Chronic phosphatidylserine treatment decreased blood ammonia in BDL cirrhotic rats treated with lipopolysaccharide. CONCLUSION: The brain of cirrhotic rat is more susceptible to acute endotoxemia and chronic phosphatidylserine treatment decreases blood ammonia and encephalopathy in cirrhotic rats by encountering endotoxin. Phosphatidylserine may boost immune system against endotoxin.


Assuntos
Anti-Inflamatórios/farmacologia , Endotoxemia/tratamento farmacológico , Encefalopatia Hepática/tratamento farmacológico , Encefalopatia Hepática/prevenção & controle , Cirrose Hepática/metabolismo , Fosfatidilserinas/farmacologia , Animais , Anti-Inflamatórios/metabolismo , Apoptose/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Ductos Biliares/metabolismo , Encéfalo , Citocinas/metabolismo , Endotoxinas/metabolismo , Encefalopatia Hepática/complicações , Lipopolissacarídeos/metabolismo , Fígado , Cirrose Hepática Experimental , Masculino , Fagócitos/efeitos dos fármacos , Fosfatidilserinas/metabolismo , Ratos , Ratos Wistar , Receptores de Superfície Celular/metabolismo , Receptor 4 Toll-Like/metabolismo , Resultado do Tratamento
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