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1.
Chemosphere ; 266: 129177, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33310519

RESUMO

Long-term exposure to arsenic, a widely distributed environmental toxicant, may result in damage to various organs, including the liver. Mice exposed chronically to arsenite developed hepatic damage, inflammation, and fibrosis, as well as increased levels of microRNA-21 (miR-21) and hypoxia-inducible factor (HIF)-1α. The levels of miR-21 and HIF-1α were also enhanced in primary hepatocytes and L-02 cells exposed to arsenite. The culture media from these cells induced the activation of hepatic stellate cells (HSCs), as demonstrated by up-regulation of the protein levels of α-smooth muscle actin (α-SMA) and collagen1A2 (COL1A2) and by increased activity in gel contractility assays. For L-02 cells, knockdown of miR-21 blocked the arsenite-induced up-regulation of HIF-1α and vascular endothelial growth factor (VEGF), which prevented the activation of LX-2 cells induced by medium from arsenite-exposed L-02 cells. However, these effects were reversed by down-regulation of von Hippel Lindau protein (pVHL). In arsenite-treated L-02 cells, miR-21 knockdown elevated the levels of ubiquitination and accelerated the degradation of HIF-1α via pVHL. In the livers of miR-21-/- mice exposed chronically to arsenite, there were less hepatic damage, lower fibrosis, lower levels of HIF-1α and VEGF, and higher levels of pVHL than for wild-type mice. In summary, we propose that miR-21, acting via the HIF-1α/VEGF signaling pathway, is involved in arsenite-induced hepatic fibrosis through mediating aberrant cross-talk of hepatocytes and HSCs. The findings provide evidence relating to the pathogenesis of hepatic fibrosis induced by exposure to arsenic.


Assuntos
Arsenitos , MicroRNAs , Animais , Arsenitos/toxicidade , Células Estreladas do Fígado , Hepatócitos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Camundongos , MicroRNAs/genética , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/genética
2.
Rev Soc Bras Med Trop ; 54: e01452020, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33338108

RESUMO

INTRODUCTION: We evaluated the association between genetic polymorphisms in exon 1 (A/O alleles) and promoter regions at positions -550 (H/L variant, rs11003125) and -221 (X/Y variant, rs7096206) MBL2 and periportal fibrosis regression. METHODS: This was a retrospective cohort study involving 114 Brazilians infected with Schistosoma mansoni, who were subjected to follow-up for three years after specific treatment for schistosomiasis to estimate the probability of periportal fibrosis regression. RESULTS: A risk association was observed between polymorphism at the exon 1 MBL2 and periportal fibrosis regression. CONCLUSIONS: This study suggests that the polymorphism of exon 1 MBL2 may potentially be used to predict periportal fibrosis regression in this population.


Assuntos
Lectina de Ligação a Manose , Esquistossomose , Animais , Brasil , Éxons/genética , Predisposição Genética para Doença , Genótipo , Humanos , Cirrose Hepática/genética , Lectina de Ligação a Manose/genética , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Esquistossomose/genética
3.
Zhongguo Zhong Yao Za Zhi ; 45(21): 5256-5264, 2020 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-33350243

RESUMO

Ophiocordyceps lanpingensis is mainly used as an ethnic medicine to treat the diseases of liver, kidney and other diseases, but the pharmacological mechanism is not clear yet. In this study, the components and contents of monosaccharides in the O.lanpingensis polysaccharides(OLP) were analyzed. The results showed that the OLP were composed of mannose, glucose, galactose and arabinose, with mass percentages of 19.1%, 21.8%, 21.1%, and 38.0%, respectively. Based on the hepatic fibrosis model induced by CCl_4 in mice, OLP could significantly relieve the inflammation and fibrosis levels of hepatic tissues, reverse the CCl_4-induced increasing levels of alanine aminotransferase(ALT) and aspartate aminotransferase(AST) in mice serum, and recover the functions of liver to a normal state. This study proved that OLP significantly decreased the mRNA expression levels of fibrotic genes, alpha-smooth muscle actin(α-SMA) and collagen type 1(Col-1), as well as the content of hydroxyproline(HYP) in the liver tissues; meanwhile, the contents of antioxidants superoxide dismutase(SOD) and glutathione(GSH) were enhanced and the production of lipid peroxide malondialdehyde(MDA) was reduced. Moreover, OLP inhibited the gene expression levels of tumor necrosis factor-α(TNF-α), interleukin-6(IL-6) and nuclear factor kappa B(NF-κB) in the livers of mice. Further study indicated that OLP could restrain the apoptosis of hepatic cells due to the decrease of the apoptosis index and down-regulations of protein expression levels of Bcl-2 associated X protein(Bax), cysteinyl aspartate specific proteinase-3(caspase-3) and cysteinyl aspartate specific proteinase-9(caspase-9), and the promotion of protein expression level of B-cell lymphoma-2(Bcl-2) in livers. To sum up, the mechanism of OLP for alleviating hepatic fibrosis was likely related to the synergy by remitting the oxidative stress of the body, alleviating inflammatory response, anti-apoptosis of hepatic cells, and so on.


Assuntos
Tetracloreto de Carbono , Cirrose Hepática , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Tetracloreto de Carbono/metabolismo , Hypocreales , Fígado/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Malondialdeído/metabolismo , Camundongos , Estresse Oxidativo , Polissacarídeos/metabolismo
4.
PLoS One ; 15(8): e0237840, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822420

RESUMO

BACKGROUND AND OBJECTIVES: The hydroxylation to 25-hydroxy vitamin D (25(OH)D) occurs in the liver and the impact of liver disease on vitamin D is unclear. This study evaluated the relationship between vitamin D concentrations and hepatic histopathology, seasonality and patient characteristics in well-characterized patients having undergone a liver biopsy. METHOD: 25(OH)D was measured post-hoc in pre-treatment serum from 331 North European patients with chronic HCV genotype 2 or 3 infection (NORDynamIC study). Liver biopsies were scored for fibrosis and inflammation according to the Ishak protocol, and graded for steatosis. Non-invasive markers of hepatic fibrosis as well as baseline viral and host characteristics, including genetic polymorphisms rs2228570, rs7975232, and rs10877012 were also evaluated. RESULTS: Mean 25(OH)D concentration was 59 ±23 nmol/L, with 41% having values <50 nmol/L and 6% were <30 nmol/L. 25(OH)D correlated with fibrosis (r = -0.10, p ≤0.05) in univariate but not in multivariate analyses. No association was observed between 25(OH)D and hepatic inflammation, but with steatosis in HCV genotype 2 infected patients. None of the genetic polymorphisms impacted on 25(OH)D levels or fibrosis. 25(OH)D levels were significantly inversely correlated to BMI (r = -0.19, p = 0.001), and was also associated with season and non-Caucasian ethnicity. CONCLUSION: Fibrosis was not independently associated with 25(OH)D concentration and no association was seen with hepatic inflammation, but HCV genotype 2 infected patients with moderate-to-severe steatosis had lower 25(OH)D levels compared to those without steatosis. A high percentage had potential risk of 25(OH)D deficiency, and BMI, seasonality and ethnicity were independently associated with 25(OH)D as previously reported.


Assuntos
Fígado Gorduroso/sangue , Hepatite C Crônica/sangue , Cirrose Hepática/sangue , Fígado/patologia , Vitamina D/análogos & derivados , Adulto , Biópsia , Índice de Massa Corporal , Dinamarca , Grupos Étnicos , Europa (Continente)/epidemiologia , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Fígado Gorduroso/virologia , Feminino , Finlândia , Genótipo , Hepacivirus/genética , Hepacivirus/metabolismo , Hepatite C Crônica/genética , Hepatite C Crônica/patologia , Humanos , Fígado/citologia , Cirrose Hepática/genética , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Noruega , Polimorfismo Genético , Análise de Regressão , Estações do Ano , Suécia , Vitamina D/sangue
5.
Am J Pathol ; 190(11): 2251-2266, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32712019

RESUMO

Activation of the substance P (SP)/neurokinin 1 receptor (NK1R) axis triggers biliary damage/senescence and liver fibrosis in bile duct ligated and Mdr2-/- (alias Abcb4-/-) mice through enhanced transforming growth factor-ß1 (TGF-ß1) biliary secretion. Recent evidence indicates a role for miR-31 (MIR31) in TGF-ß1-induced liver fibrosis. We aimed to define the role of the SP/NK1R/TGF-ß1/miR-31 axis in regulating biliary proliferation and liver fibrosis during cholestasis. Thus, we generated a novel model with double knockout of Mdr2-/- and NK1R-/ (alias Tacr1-/-) to further address the role of the SP/NK1R axis during chronic cholestasis. In vivo studies were performed in the following 12-week-old male mice: (i) NK1R-/-; (ii) Mdr2-/-; and (iii) NK1R-/-/Mdr2-/- (Tacr1-/-/Abcb4-/-) and their corresponding wild-type controls. Liver tissues and cholangiocytes were collected, and liver damage, changes in biliary mass/senescence, and inflammation as well as liver fibrosis were evaluated by both immunohistochemistry in liver sections and real-time PCR. miR-31 expression was measured by real-time PCR in isolated cholangiocytes. Decreased ductular reaction, liver fibrosis, biliary senescence, and biliary inflammation were observed in NK1R-/-/Mdr2-/- mice compared with Mdr2-/- mice. Elevated expression of miR-31 was observed in Mdr2-/- mice, which was reduced in NK1R-/-/Mdr2-/- mice. Targeting the SP/NK1R and/or miR-31 may be a potential approach in treating human cholangiopathies, including primary sclerosing cholangitis.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiência , Ductos Biliares , Colangite Esclerosante , Cirrose Hepática , Receptores da Neurocinina-1/deficiência , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Ductos Biliares/lesões , Ductos Biliares/metabolismo , Ductos Biliares/patologia , Colangite Esclerosante/genética , Colangite Esclerosante/metabolismo , Colangite Esclerosante/patologia , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Camundongos Knockout , Receptores da Neurocinina-1/metabolismo
6.
Metabolism ; 111S: 154320, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32712221

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a multifaceted metabolic disorder, whose spectrum covers clinical, histological and pathophysiological developments ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and liver fibrosis, potentially evolving into cirrhosis, hepatocellular carcinoma and liver failure. Liver biopsy remains the gold standard for diagnosing NAFLD, while there are no specific treatments. An ever-increasing number of high-throughput Omics investigations on the molecular pathobiology of NAFLD at the cellular, tissue and system levels produce comprehensive biochemical patient snapshots. In the clinical setting, these applications are considerably enhancing our efforts towards obtaining a holistic insight on NAFLD pathophysiology. Omics are also generating non-invasive diagnostic modalities for the distinct stages of NAFLD, that remain though to be validated in multiple, large, heterogenous and independent cohorts, both cross-sectionally as well as prospectively. Finally, they aid in developing novel therapies. By tracing the flow of information from genomics to epigenomics, transcriptomics, proteomics, metabolomics, lipidomics and glycomics, the chief contributions of these techniques in understanding, diagnosing and treating NAFLD are summarized herein.


Assuntos
Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/patologia , Animais , Genômica/métodos , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Metabolômica/métodos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteômica/métodos
7.
Anim Sci J ; 91(1): e13434, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32696560

RESUMO

Liver fibrosis is a major health concern, which might progress to cirrhosis. To date, treatment trials rely mainly on the removal of the causative factor. The current study investigated the potential ameliorative role of sidr honey on thioacetamide (TAA)-induced liver fibrosis in rats. Forty-eight Wistar albino rats were equally allocated into four groups: control; sidr honey (5g/kg body weight (BW), orally); TAA (200 mg/kg BW, IP three times weekly/15 weeks); and sidr honey plus TAA at the same dose and administration rout. Rats co-treated with sidr honey plus TAA revealed significant reduction in hepatic malondialdehyde, hyaluronic acid (HA), alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transferase, direct bilirubin, and hepatic mRNA expression of transforming growth factor (TGF)-ß1 and collagen type I alpha 1 chain (COL1a1) compared to TAA-exposed rats. In addition, the hepatoprotective potential of sidr honey was indicated via improvement of histopathologic picture of hepatocytes and upregulation of total antioxidant capacity, reduced glutathione, catalase, glutathione peroxidase, superoxide dismutase, total protein, and albumin compared to TAA-treated rats. In conclusion, daily administration of sidr honey (5 g/kg BW) is a promising natural antioxidant and fibrosuppressive agent that could ameliorate liver fibrosis via downregulation of fibrosis genes including TGF-ß1 and COL1a1 and HA and via enhancement of antioxidant system.


Assuntos
Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Regulação para Baixo/genética , Expressão Gênica , Mel , Ácido Hialurônico/metabolismo , Cirrose Hepática/genética , Cirrose Hepática/terapia , Estresse Oxidativo/genética , Fitoterapia , Tioacetamida/efeitos adversos , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Ziziphus , Animais , Modelos Animais de Doenças , Cirrose Hepática/induzido quimicamente , Masculino , Ratos Wistar
8.
Nat Rev Gastroenterol Hepatol ; 17(8): 457-472, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32483353

RESUMO

Liver disease is a major global health-care problem, affecting an estimated 844 million people worldwide. Despite this substantial burden, therapeutic options for liver disease remain limited, in part owing to a paucity of detailed analyses defining the cellular and molecular mechanisms that drive these conditions in humans. Single-cell transcriptomic technologies are transforming our understanding of cellular diversity and function in health and disease. In this Review, we discuss how these technologies have been applied in hepatology, advancing our understanding of cellular heterogeneity and providing novel insights into fundamental liver biology such as the metabolic zonation of hepatocytes, endothelial cells and hepatic stellate cells, and the cellular mechanisms underpinning liver regeneration. Application of these methodologies is also uncovering critical pathophysiological changes driving disease states such as hepatic fibrosis, where distinct populations of macrophages, endothelial cells and mesenchymal cells reside within a spatially distinct fibrotic niche and interact to promote scar formation. In addition, single-cell approaches are starting to dissect key cellular and molecular functions in liver cancer. In the near future, new techniques such as spatial transcriptomics and multiomic approaches will further deepen our understanding of disease pathogenesis, enabling the identification of novel therapeutic targets for patients across the spectrum of liver diseases.


Assuntos
Perfilação da Expressão Gênica , Hepatopatias/genética , Fígado/metabolismo , Análise de Célula Única , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Fibroblastos/metabolismo , Fibroblastos/fisiologia , Gastroenterologia , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/fisiologia , Hepatócitos/metabolismo , Hepatócitos/fisiologia , Humanos , Inflamação/imunologia , Macrófagos do Fígado/imunologia , Fígado/citologia , Fígado/imunologia , Fígado/fisiologia , Cirrose Hepática/genética , Cirrose Hepática/imunologia , Cirrose Hepática/metabolismo , Hepatopatias/imunologia , Hepatopatias/metabolismo , Macrófagos/imunologia , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/fisiologia , Regeneração , Análise de Sequência de RNA
9.
Arch Biochem Biophys ; 689: 108445, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32524998

RESUMO

Liver fibrogenesis is defined as a dynamic and highly integrated process occurring during chronic injury to liver parenchyma that can result in excess deposition of extracellular matrix (ECM) components (i.e., liver fibrosis). Liver fibrogenesis, together with chronic inflammatory response, is then primarily involved in the progression of chronic liver diseases (CLD) irrespective of the specific etiology. In the present review we will first offer a synthetic and updated overview of major basic concepts in relation to the role of myofibroblasts (MFs), macrophages and other hepatic cell populations involved in CLD to then offer an overview of established and emerging issues and mechanisms that have been proposed to favor and/or promote CLD progression. A special focus will be dedicated to selected issues that include emerging features in the field of cholangiopathies, the emerging role of genetic and epigenetic factors as well as of hypoxia, hypoxia-inducible factors (HIFs) and related mediators.


Assuntos
Cirrose Hepática/patologia , Fígado/patologia , Animais , Doença Crônica , Progressão da Doença , Epigênese Genética , Humanos , Inflamação/genética , Inflamação/patologia , Fígado/metabolismo , Cirrose Hepática/genética , Macrófagos/metabolismo , Macrófagos/patologia , Miofibroblastos/metabolismo , Miofibroblastos/patologia
10.
Life Sci ; 255: 117818, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32445757

RESUMO

Activation of hepatic stellate cells (HSCs) is a central event in the pathogenesis of liver fibrosis and is characterized by the disappearance of lipid droplets. Although the exogenous supplementation of lipid droplet content can effectively reverse the activation of HSCs, the underlying molecular mechanisms are largely unknown. In our current study, we sought to investigate the role of lncRNA-H19 in the process of lipid droplets disappearance and to further examine the underlying molecular mechanisms. We found that the lncRNA-H19 level was increased in CCl4-induced fibrotic liver, which activated HSCs. Further research showed that hypoxia inducible factor-1α (HIF-1α) significantly increased lncRNA-H19 expression by binding to the lncRNA-H19 promoter at two hypoxia response element (HRE) sites located at 492-499 and 515-522 bp. Importantly, lncRNA-H19 knockdown markedly inhibited HSC activation and alleviated liver fibrosis, indicating that lncRNA-H19 may be a potential target for anti-fibrosis therapeutic approaches. Moreover, lncRNA-H19 knockdown could reverse the lipid droplet phenotype of activated HSCs, inhibiting the phosphorylated AMPKα-mediated lipid oxidation signaling pathway. The AMPK agonist AICAR promoted AMPKα phosphorylation and abrogated lipid droplets restoration in HSCs transfected with the lncRNA-H19 knockdown plasmid. Experimental molecular analysis showed that lncRNA-H19 triggered AMPKα to interact with LKB1 and resulted in AMPKα phosphorylation, which accelerating lipid droplets degradation and lipid oxidation. Taken together, our results highlighted the role of lncRNA-H19 in the metabolism of lipid droplets in HSCs, and revealed a new molecular target for alleviating liver fibrosis.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Células Estreladas do Fígado/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Cirrose Hepática/patologia , RNA Longo não Codificante/genética , Animais , Linhagem Celular , Técnicas de Silenciamento de Genes , Humanos , Gotículas Lipídicas/metabolismo , Cirrose Hepática/genética , Masculino , Camundongos , Camundongos Endogâmicos ICR , Elementos de Resposta/genética
11.
Exp Mol Pathol ; 115: 104447, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32380055

RESUMO

BACKGROUND: The purpose of this research is to reveal the improvement effect and potential mechanism of Huagan tongluo Fang (HGTLF) on liver fibrosis. METHODS: A mouse model of liver fibrosis induced by CCl4 was established to analyze the effect of HGTLF on liver fibrosis. The expression changes of miRNA after HGTLF stimulation were detected by qRT-PCR. After interference with miR-184 in Th17 cells, the concentration of IL-17A in cell culture supernatants was detected by ELISA and the proportion of Th17 cells was analyzed by flow cytometry. The relationship between miR-184 and FOXO1 was verified by online software and dual-luciferase reporter system. After HGTLF treatment of Th17 cells overexpressing miR-184, the protein level of FOXO1 was detected by Western blot. RESULTS: HGTLF could significantly improve liver fibrosis in mice. By qRT-PCR, miR-184 was most significantly expressed after HGTLF drug stimulation, and miR-184 was considered to be the major RNA involved in Th17 cell differentiation. Interference with miR-184 in Th17 cells inhibited the differentiation of Th17 cells. By online software and dual-luciferase reporter system assay, the direct interaction of miR-184 with FOXO1 was confirmed. After HGTLF treatment of Th17 cells overexpressing miR-184, FOXO1 protein levels were significantly up-regulated and inhibited the differentiation of Th17 cells, which was reversed by miR-184 inhibitors. The Vivo experiments also confirmed the improvement effect of HGTLF on liver fibrosis in mice. CONCLUSION: Our results indicated that HGTLF could improve liver fibrosis via down-regulating miR-184 and up-regulating of FOXO1 to inhibit Th17 cell differentiation.


Assuntos
Diferenciação Celular , Regulação para Baixo/genética , Medicamentos de Ervas Chinesas/uso terapêutico , Proteína Forkhead Box O1/metabolismo , Cirrose Hepática/tratamento farmacológico , MicroRNAs/genética , Células Th17/citologia , Regulação para Cima/genética , Animais , Sequência de Bases , Tetracloreto de Carbono , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Proteína Forkhead Box O1/genética , Cirrose Hepática/genética , Cirrose Hepática/imunologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo
12.
Int J Infect Dis ; 96: 541-547, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32422377

RESUMO

OBJECTIVES: Genes of host immunity play an important role in disease pathogenesis and are determinants of clinical courses of infections, including hepatitis B virus (HBV). Killer-cell immunoglobulin-like receptor (KIR), expressed on the surface of natural killer cells (NK), regulate NK cell cytotoxicity by interacting with human leukocyte antigen (HLA) class I molecules and are candidates for influencing the course of HBV. This study evaluated whether variations in KIR gene content and HLA-C ligands are associated with HBV and with the development of liver cirrhosis and hepatocellular carcinoma. METHODS: A Vietnamese study cohort (HBV n = 511; controls n = 140) was genotyped using multiplex sequence-specific polymerase chain reaction (PCR-SSP) followed by melting curve analysis. RESULTS: The presence of the functional allelic group of KIR2DS4 was associated with an increased risk of chronic HBV (OR = 1.86, pcorr = 0.02), while KIR2DL2+HLA-C1 (OR = 0.62, pcorr = 0.04) and KIR2DL3+HLA-C1 (OR = 0.48, pcorr = 0.04) were associated with a decreased risk. The pair KIR2DL3+HLA-C1 was associated with liver cirrhosis (OR = 0.40, pcorr = 0.01). The presence of five or more activating KIR variants was associated with hepatocellular carcinoma (OR = 0.53, pcorr = 0.04). CONCLUSIONS: KIR gene content variation and combinations KIR-HLA influence the outcome of HBV infection.


Assuntos
Vírus da Hepatite B/fisiologia , Hepatite B Crônica/genética , Receptores KIR2DL2/genética , Receptores KIR2DL3/genética , Receptores KIR/genética , Adulto , Idoso , Alelos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/virologia , Estudos de Coortes , Feminino , Variação Genética , Genótipo , Antígenos HLA-C/genética , Antígenos HLA-C/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Humanos , Cirrose Hepática/genética , Cirrose Hepática/imunologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Receptores KIR/imunologia , Receptores KIR2DL2/imunologia , Receptores KIR2DL3/imunologia , Vietnã , Adulto Jovem
14.
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
15.
Mol Immunol ; 123: 32-39, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32413787

RESUMO

At present, most studies on the relationship between hepatitis B virus (HBV) and IL-33/ST2 axis focus on clinical detection, but the underlying molecular mechanisms of HBx and IL-33/ST2 axis regulation and Th cell function regulation have not been explored. In this study, serum samples of patients with chronic hepatitis B (CHB) and HBV-related liver cancer (HBV-HCC), and healthy controls, as well as the supernatant solutions of HL7702-WT, HL7702-NC, and HL7702-HBx cells were collected to detect the content of soluble ST2 (sST2). The contents of Th1 cytokines (TNF-α and TNF-γ) and Th2 cytokines (IL-6 and IL-10) in the supernatant of different co-culture groups were detected. The effects of GATA2 on ST2 promoter transcription were investigated by upregulation or interference with GATA2 expression, dual-luciferase reporting, and ChIP experiments. The combined detection of sST2 and FIB-4 was beneficial to the non-invasive diagnosis of liver fibrosis. HBx promotes sST2 expression in liver cells, upregulates Th2 cell function, and inhibits Th1 cell function through IL-33/ST2 axis. HBx interacts with GATA2 to influence the activity of ST2 promoter. Serum sST2 detection is an invaluable indicator for the assessment of the progress of HBV infectious diseases, and the IL-33/ST2 axis plays an important role in changing the cellular immune function caused by HBV infection.


Assuntos
Fator de Transcrição GATA2/fisiologia , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Transativadores/farmacologia , Adulto , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Estudos de Casos e Controles , Células Cultivadas , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/complicações , Hepatite B Crônica/genética , Hepatite B Crônica/patologia , Humanos , Interleucina-33/fisiologia , Fígado/patologia , Cirrose Hepática/genética , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
16.
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
17.
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
18.
Aliment Pharmacol Ther ; 51(11): 1160-1168, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32323349

RESUMO

BACKGROUND: Fibrosis progression in autoimmune hepatitis can be attenuated by immunosuppressive treatment; however, some patients progress despite therapy. Single nucleotide polymorphisms (SNPs) such as PNPLA3-rs738409, TM6SF2-rs58542926 and MBOAT7-rs641738 are associated with non-alcoholic fatty liver disease and fibrosis progression, whereas a splice variant in HSD17B13-rs72613567:TA has been shown to be protective. AIM: To analyse the impact of different SNPs on the long-term outcome of patients with autoimmune hepatitis. METHODS: We included 239 patients into this study who had been treated between 1983 and 2018 for autoimmune hepatitis. Genomic DNA was isolated from whole blood and SNPs were determined by PCR analysis. Liver biopsies were available for 215/239 patients (90%). Clinical and laboratory patient data were assessed by chart review. RESULTS: Mean age at baseline was 42.1 years with 74.1% being female. The median follow-up was 9.4 years (IQR 3.5-15.0), 11.7% of the patients (n = 28) died or required liver transplantation. In the Kaplan-Meier analysis of the combined endpoint time to liver transplantation or death, we observed that patients with the PNPLA3-rs738409 GG variant met more frequently the primary endpoint (P = 0.005). In Cox regression analysis PNPLA3-rs738409 GG as well as liver cirrhosis were identified as strong predictors for time to liver transplantation or death (HR 4.5 [CI 1.48-13.72], P = 0.008 and HR 9.24 [CI 2.11-40.44], P = 0.003, respectively). Neither steatosis, diabetes mellitus nor obesity were associated with outcome. CONCLUSIONS: PNPLA3-rs738409 variant GG is a predictor for time to liver transplantation or death and may help to identify autoimmune hepatitis patients at risk for disease progression.


Assuntos
Hepatite Autoimune/diagnóstico , Hepatite Autoimune/genética , Lipase/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Progressão da Doença , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Hepatite Autoimune/patologia , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/genética , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Prognóstico , Estudos Retrospectivos , Adulto Jovem
19.
Lab Invest ; 100(8): 1042-1056, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32291390

RESUMO

Sparc/osteonectin, cwcv, and kazal-like domain proteoglycan 1 (SPOCK1) is a matricellular protein which regulates cell proliferation, invasion, and survival but the function of SPOCK1 in liver fibrosis is obscure. In this study, we found that SPOCK1 expression increased significantly in fibrotic liver tissues and activated primary rat hepatic stellate cells (R-HSCs). SPOCK1 co-localized with α-smooth muscle actin (α-SMA) in the cytoplasm. Mechanistically, we found platelet-derived growth factor-BB (PDGF-BB) induced SPOCK1 expression by activating the PI3K/Akt/forkhead box M1 (FoxM1) signaling pathway. Intracellular SPOCK1 downregulation decreased the HSC activation, proliferation, and migration induced by PDGF-BB. Furthermore, intracellular SPOCK1 overexpression or recombinant SPOCK1 treatment promoted HSC activation, proliferation, and migration by activating the PI3K/Akt signaling pathway. Co-immunoprecipitation, double immunofluorescence staining indicated that SPOCK1 interacted with integrin α5ß1, and neutralization of integrin α5ß1 significantly reduced the role of recombinant SPOCK1 in HSCs. In vivo HSC-specific SPOCK1 knockdown following lentivirus administration dramatically ameliorated thioacetamide (TAA)-induced collagen deposition in rat livers. Collectively, our study indicates that SPOCK1 is crucial for hepatic fibrosis and it might be a promising therapeutic target.


Assuntos
Becaplermina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/genética , Proteínas/metabolismo , Proteoglicanas/genética , Animais , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Células Estreladas do Fígado/metabolismo , Humanos , Integrina alfa5beta1/metabolismo , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/metabolismo , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Proteoglicanas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
20.
PLoS Genet ; 16(4): e1008629, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32282858

RESUMO

Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10-11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10-43), alkaline phosphatase (-0.025 SD, 1.2*10-37), total cholesterol (-0.030 SD, p = 1.9*10-36) and LDL cholesterol (-0.027 SD, p = 5.1*10-30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.


Assuntos
Fígado Gorduroso/genética , Fígado Gorduroso/prevenção & controle , Predisposição Genética para Doença , Cirrose Hepática/genética , Cirrose Hepática/prevenção & controle , Proteínas Mitocondriais/genética , Mutação de Sentido Incorreto/genética , Oxirredutases/genética , Alelos , LDL-Colesterol/sangue , Doença da Artéria Coronariana/genética , Conjuntos de Dados como Assunto , Fígado Gorduroso/sangue , Fígado Gorduroso/enzimologia , Feminino , Homozigoto , Humanos , Fígado/enzimologia , Cirrose Hepática/sangue , Cirrose Hepática/enzimologia , Cirrose Hepática Alcoólica/sangue , Cirrose Hepática Alcoólica/enzimologia , Cirrose Hepática Alcoólica/genética , Cirrose Hepática Alcoólica/prevenção & controle , Mutação com Perda de Função/genética , Masculino , Pessoa de Meia-Idade
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