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1.
Medicine (Baltimore) ; 98(44): e17867, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689880

RESUMO

Glycogen storage disease (GSD) type IX, characterized by liver enlargement and elevated aminotransferase levels, is the most frequent type of GSD. The global incidence of GSD type IXa is only about 1/100,000 individuals. Case reports of GSD type IX are rare in China. We present the first case report of GSD type IXa in Northeast China caused by mutation of PHKA2.An 11-year-old boy was referred to our hospital because of liver enlargement with consistently elevated transaminase levels over 6 months.Histopathological results following an ultrasound-guided liver biopsy confirmed a diagnosis of GSD. Further genetic testing showed that the patient had GSD type IXa caused by the c.133C>T mutation in PHAK2.We placed the patient on a high-protein and high-starch diet and provided hepatoprotective and supportive therapy.The patient's transaminase levels decreased significantly and were nearly normal at 10-month follow-up.This is the first reported case of GSD type IXa in Northeast China. We hope that the detailed and complete report of this case will provide a reference for the diagnosis of liver enlargement of unknown etiology in future clinical practice.


Assuntos
Carcinoma Hepatocelular/virologia , Hepatite B Crônica/genética , Interleucinas/genética , Cirrose Hepática/virologia , Neoplasias Hepáticas/virologia , Polimorfismo de Nucleotídeo Único , Adulto , Consumo de Bebidas Alcoólicas/efeitos adversos , Grupo com Ancestrais do Continente Asiático/genética , Carcinoma Hepatocelular/genética , Estudos de Casos e Controles , Progressão da Doença , Feminino , Hepatite B Crônica/complicações , Humanos , Cirrose Hepática/genética , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade , Mutação Puntual , Estudos Retrospectivos , Fumar/efeitos adversos
2.
Nat Rev Gastroenterol Hepatol ; 16(9): 544-558, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31253940

RESUMO

Telomerase is a key enzyme for cell survival that prevents telomere shortening and the subsequent cellular senescence that is observed after many rounds of cell division. In contrast, inactivation of telomerase is observed in most cells of the adult liver. Absence of telomerase activity and shortening of telomeres has been implicated in hepatocyte senescence and the development of cirrhosis, a chronic liver disease that can lead to hepatocellular carcinoma (HCC) development. During hepatocarcinogenesis, telomerase reactivation is required to enable the uncontrolled cell proliferation that leads to malignant transformation and HCC development. Part of the telomerase complex, telomerase reverse transcriptase, is encoded by TERT, and several mechanisms of telomerase reactivation have been described in HCC that include somatic TERT promoter mutations, TERT amplification, TERT translocation and viral insertion into the TERT gene. An understanding of the role of telomeres and telomerase in HCC development is important to develop future targeted therapies and improve survival of this disease. In this Review, the roles of telomeres and telomerase in liver carcinogenesis are discussed, in addition to their potential translation to clinical practice as biomarkers and therapeutic targets.


Assuntos
Carcinoma Hepatocelular/metabolismo , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/metabolismo , Telomerase/metabolismo , Telômero/metabolismo , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/genética , Divisão Celular/fisiologia , Sobrevivência Celular/fisiologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Humanos , Fígado/metabolismo , Cirrose Hepática/genética , Neoplasias Hepáticas/genética , Camundongos , Mutação , Telomerase/genética , Telômero/genética
3.
Gut ; 68(12): 2214-2227, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31171625

RESUMO

OBJECTIVE: Although glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor-ß superfamily, its function in liver fibrosis has rarely been studied. Here, we investigated the role of GDNF in hepatic stellate cell (HSC) activation and liver fibrosis in humans and mice. DESIGN: GDNF expression was examined in liver biopsies and sera from patients with liver fibrosis. The functional role of GDNF in liver fibrosis was examined in mice with adenoviral delivery of the GDNF gene, GDNF sgRNA CRISPR/Cas9 and the administration of GDNF-blocking antibodies. GDNF was examined on HSC activation using human and mouse primary HSCs. The binding of activin receptor-like kinase 5 (ALK5) to GDNF was determined using surface plasmon resonance (SPR), molecular docking, mutagenesis and co-immunoprecipitation. RESULTS: GDNF mRNA and protein levels are significantly upregulated in patients with stage F4 fibrosis. Serum GDNF content correlates positively with α-smooth muscle actin (α-SMA) and Col1A1 mRNA in human fibrotic livers. Mice with overexpressed GDNF display aggravated liver fibrosis, while mice with silenced GDNF expression or signalling inhibition by GDNF-blocking antibodies have reduced fibrosis and HSC activation. GDNF is confined mainly to HSCs and contributes to HSC activation through ALK5 at His39 and Asp76 and through downstream signalling via Smad2/3, but not through GDNF family receptor alpha-1 (GFRα1). GDNF, ALK5 and α-SMA colocalise in human and mouse HSCs, as demonstrated by confocal microscopy. CONCLUSIONS: GDNF promotes HSC activation and liver fibrosis through ALK5/Smad signalling. Inhibition of GDNF could be a novel therapeutic strategy to combat liver fibrosis.


Assuntos
Regulação da Expressão Gênica , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Proteínas Smad/genética , Adulto , Animais , Biópsia , Linhagem Celular , Modelos Animais de Doenças , Feminino , Seguimentos , Fator Neurotrófico Derivado de Linhagem de Célula Glial/biossíntese , Células Estreladas do Fígado/patologia , Humanos , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos , RNA/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/biossíntese , Estudos Retrospectivos , Transdução de Sinais , Proteínas Smad/biossíntese , Regulação para Cima
4.
Medicine (Baltimore) ; 98(23): e15924, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31169710

RESUMO

To explore interleukin-17 (IL-17) and its epigenetic regulation during the progression of chronic hepatitis B virus (HBV) infection.A total of 162 patients with chronic HBV infection, including 75 with chronic hepatitis B (CHB), 54 with hepatitis B-associated liver cirrhosis and 33 with hepatitis B-associated hepatocellular carcinoma (HBV-HCC), were enrolled in this study. Thirty healthy adults of the same ethnicity were enrolled in the control group. Whole venous blood was obtained from the patients and normal controls (n = 30). Clinical and laboratory parameters were assessed, and we performed enzyme-linked immunosorbent assay and quantitative real-time PCR to measure the serum levels and relative mRNA expression of IL-17, respectively. IL-17 promoter methylation in peripheral blood mononuclear cells was assessed by methylation-specific PCR. We analyzed the serum and mRNA levels of IL-17 and IL-17 promoter methylation in the 4 groups as well as the effect of methylation on serum IL-17 levels. Correlations between the IL-17 promoter methylation status and clinical parameters were analyzed by Spearman correlation analysis.Compared to the normal control group, the patient groups exhibited significantly higher serum and relative mRNA levels of IL-17. The methylation distribution among the patients was significantly lower than that among the normal controls (P < .05), with the HBV-HCC group showing the lowest IL-17 gene methylation frequency. The average IL-17 promoter CG methylation level was negatively correlated with IL-17 mRNA expression (r = -0.39, P = .03), and negative correlations between IL-17 promoter methylation and prothrombin time activity (r = -0.585, P = .035), alanine aminotransferase (r = -0.522, P < .01), aspartate aminotransferase (r = -0.315, P < .05), and the model for end-stage liver disease score (r = -0.461, P < .05) were observed. IL-17 serum levels in the methylated-promoter groups were significantly lower than those in the unmethylated-promoter groups.IL-17 expression and promoter methylation were associated with chronic HBV infection progression, especially in the HBV-HCC group. The IL-17 promoter status may help clinicians initiate the correct treatment strategy at the CHB stage.


Assuntos
Progressão da Doença , Vírus da Hepatite B , Hepatite B Crônica/genética , Interleucina-17/sangue , Regiões Promotoras Genéticas/genética , Adulto , Idoso , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Metilação de DNA , Epigênese Genética , Feminino , Hepatite B Crônica/sangue , Hepatite B Crônica/virologia , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/genética , Cirrose Hepática/virologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade
5.
Biochimie ; 163: 128-136, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31082428

RESUMO

This study aimed at the participation of lncRNA H19, endothelial NADPH oxidases (NOX4) and miR-148b-3p in hypoxia stress in human hepatic sinusoidal endothelial cells (HHSEC), and clarifying the relationship among them. The expression of lnc H19, NOX4 and miR-148b-3p in cirrhotic patients and hypoxic HHSEC were measured by RT-PCR. The nitric oxide and hydrogen peroxide content in HHSEC were determined using ultraviolet chromatometry. The protein levels of NOX4, endothelial NOS (eNOS) and phosphorylated eNOS (p-eNOS) were measured via western blotting. The interaction between NOX4 promoter and lnc H19/miR-148b-3p was measured by dual-luciferase reporter gene detection system. The present results indicated that the expressions of NOX4 mRNA and lnc H19 were increased but miR-148b-3p was decreased in both cirrhotic patients and hypoxic HHSEC. Further, hypoxia induced the up-regulation of hydrogen peroxide and the down-regulation of eNOS/NO signaling in HHSEC. And these symptoms were ameliorated by lnc H19 shRNA and miR-148b-3p mimics. But the beneficial effects of lnc H19 shRNA and miR-148b-3p mimics were further abolished by miR-148b-3p inhibitor and NOX4 over-expression, respectively. In addition, NOX4 was a direct, negatively regulated target of miR-148b-3p, and miR-148b-3p was negatively regulated by lnc H19. Collectively, lnc H19 is a negatively regulator of microRNA-148b-3p, and participate in hypoxia stress in HHSEC via positively regulating NOX4 and negatively regulating eNOS/NO signaling.


Assuntos
Células Endoteliais/metabolismo , Hipóxia/metabolismo , Cirrose Hepática/metabolismo , Fígado/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Idoso , Capilares/metabolismo , Capilares/fisiopatologia , Células Endoteliais/fisiologia , Regulação da Expressão Gênica , Humanos , Hipóxia/genética , Fígado/irrigação sanguínea , Fígado/fisiopatologia , Cirrose Hepática/genética , MicroRNAs/genética , Pessoa de Meia-Idade , NADPH Oxidase 4/genética , NADPH Oxidase 4/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Fisiológico
6.
Ter Arkh ; 91(2): 32-39, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-31094169

RESUMO

MATERIALS AND METHODS: 253 patients with chronic hepatitis C (CHC) and liver cirrhosis were included in the study. Assessment of gene polymorphisms of genes involved in inflammatory reactions and antiviral immunity (IL-1ß-511C/T, IL-10 -1082G/A, IL28B C/T, IL28B T/G, TNF-α -238G/A, TGF-ß -915G/C, IL-6 -174G/C), activators of local hepatic fibrosis (AGT G-6A, AGT 235 M/T, ATR1 1166 A/C), hemochromatosis (HFE C282Y, HFE H63D), platelet receptors (ITGA2 807 C/T, ITGB3 1565 T/C), coagulation proteins and endothelial dysfunction (FII 20210 G/A, FV 1691G/A, FVII 10976 G/A, FXIII 103 G/T, eNOS 894 G/T, CYBA 242 C/T, FBG -455 G/A, PAI-675 5G/4G, MTHFR 677 C/T) was carried. Using Bayesian networks we studied the predictor value of clinical and laboratory factors for the following conditions - end points (EP): development of cirrhosis (EP1), fibrosis rate (EP2), presence of portal hypertension (EP3) and cryoglobulins (EP4). RESULTS AND DISCUSSION: In addition to traditional factors we have shown the contribution of the following mutations. Predicting EP1- liver cirrhosis - HFE H63D, C282Y, CYBA 242 C/T, AGT G-6G, ITGB31565 T/C gene mutations were significant. We also found a link between the rate of progression of liver fibrosis and gene polymorphisms of AGT G-6G, AGT M235T, FV 1691G/A, ITGB31565 T/C. Among the genetic factors associated with portal hypertension there are gene polymorphisms of PAI-I-675 5G/4G, FII 20210 G/A, CYBA 242 C/T, HFE H63D and Il-6 174GC. Cryoglobulins and cryoglobuliemic vasculitis (EP4) are associated with gene mutations MTHFR C677T, ATR A1166C and HFE H63D. CONCLUSION: The results obtained allow to detect the major pathophysiological and genetic factors which determine the status of the patient and the outcome of the disease, to clarify their contribution, and to reveal the significance of point mutations of genes that control the main routes of HCV course and progression.


Assuntos
Hepatite C Crônica/fisiopatologia , Cirrose Hepática/fisiopatologia , Polimorfismo Genético , Teorema de Bayes , Hemocromatose , Hepatite C Crônica/genética , Humanos , Interferons , Interleucinas , Cirrose Hepática/genética , Mutação
7.
Indian J Med Res ; 149(1): 9-17, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-31115369

RESUMO

Hepatocellular carcinoma (HCC) is the sixth most common cancer in world and third largest cause of cancer-related deaths. The last few decades have witnessed the emergence of non-viral causes of HCC, the most important being non-alcoholic fatty liver disease (NAFLD). NAFLD ranges from simple steatosis in the absence of excessive alcohol intake to non-alcoholic steatohepatitis (NASH) with or without cirrhosis. About 3-15 per cent of the obese patients with NASH progress to cirrhosis and about 4-27 per cent of NASH with cirrhosis patients transform to HCC. It is also known that HCC can develop de novo in patients with NASH without the presence of cirrhosis. Yearly cumulative incidence of NASH-related HCC is low (2.6%) compared to four per cent of viral-HCC. NAFLD has been associated with risk factors such as metabolic syndrome, insulin resistance, altered gut flora and persistent inflammation. Due to alarming rise in metabolic diseases, both in the developing as well as the developed world, it is expected that the incidence of NAFLD/NASH-HCC would rise manifold in future. No definite guidelines have been drawn for surveillance and management of NAFLD/NASH-associated HCC. It is thus important to discuss the entity of HCC in NAFLD at length with special focus on its epidemiology, risk factors, pathophysiology, diagnosis, clinical presentation and prevention.


Assuntos
Carcinoma Hepatocelular/epidemiologia , Cirrose Hepática/epidemiologia , Neoplasias Hepáticas/epidemiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/prevenção & controle , Humanos , Resistência à Insulina/genética , Cirrose Hepática/complicações , Cirrose Hepática/genética , Cirrose Hepática/prevenção & controle , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/prevenção & controle , Síndrome Metabólica/complicações , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , Síndrome Metabólica/patologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Fatores de Risco
8.
Mol Med Rep ; 20(1): 368-374, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115505

RESUMO

The activation of hepatic stellate cells (HSCs) is considered associated with liver fibrosis. However, the exact role of syndecan­1 (SDC1), a protein that regulates the interaction between cells and the microenvironment, in the activation of HSCs resulting in liver fibrosis remains elusive. The objective of the present study was to explore the effects and mechanism of action of SDC1 in the activation of HSCs. HSCs were isolated from mouse liver and cultured to detect the expression of SDC1, transforming growth factor (TGF)­ß1, Smad3 and α­smooth muscle actin (α­SMA; a marker of HSC activation) by western blotting and reverse transcription­quantitative PCR. The expression of SDC1 was found to be downregulated, while the expression of TGF­ß1, Smad3 and α­SMA was upregulated in HSCs during cell culture. In addition, following stimulation of HSCs with recombinant SDC1, the expression of TGF­ß1, Smad3 and α­SMA in HSCs was downregulated, whereas small interfering RNA targeting Smad3 antagonized the effects of recombinant SDC1 on α­SMA. Taken together, these data suggest that SDC1 plays a key role in the development of liver fibrosis.


Assuntos
Actinas/genética , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/genética , Sindecana-1/genética , Animais , Microambiente Celular/genética , Regulação da Expressão Gênica , Células Estreladas do Fígado/patologia , Humanos , Cirrose Hepática/patologia , Camundongos , Transdução de Sinais , Proteína Smad3/genética , Fator de Crescimento Transformador beta1/genética
9.
Int J Mol Sci ; 20(10)2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31117267

RESUMO

Liver fibrosis is an essential component of chronic liver disease (CLD) and hepatocarcinogenesis. The fibrotic stroma is a consequence of sustained liver damage combined with exacerbated extracellular matrix (ECM) accumulation. In this context, activation of hepatic stellate cells (HSCs) plays a key role in both initiation and perpetuation of fibrogenesis. These cells suffer profound remodeling of gene expression in this process. This review is focused on the epigenetic alterations participating in the transdifferentiation of HSCs from the quiescent to activated state. Recent advances in the field of DNA methylation and post-translational modifications (PTM) of histones (acetylation and methylation) patterns are discussed here, together with altered expression and activity of epigenetic remodelers. We also consider recent advances in translational approaches, including the use of epigenetic marks as biomarkers and the promising antifibrotic properties of epigenetic drugs that are currently being used in patients.


Assuntos
Carcinogênese/genética , Epigênese Genética , Células Estreladas do Fígado , Cirrose Hepática/genética , Animais , Metilação de DNA , Humanos , Fígado
10.
Yonsei Med J ; 60(6): 561-569, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31124340

RESUMO

PURPOSE: Liver fibrosis is a major cause of morbidity and mortality and the outcome of various chronic liver diseases. Activation of hepatic stellate cells (HSCs) is the key event in liver fibrosis. Studies have confirmed that miR-140-3p plays a potential regulatory effect on HSC activation. However, whether miR-140-3p mediates the liver fibrosis remains unknown. MATERIALS AND METHODS: Expression of miR-140-3p was detected by real-time quantitative PCR (qPCR). Cell proliferation was measured by MTT, while cell apoptosis rate was determined via flow cytometry. Western blot assay was used to detect the expression of cleaved PARP. The fibrogenic effect was evaluated by expression of α-smooth muscle actin and desmin. Functional experiments were performed in transforming growth factor ß1 (TGF-ß1)-induced HSC-T6 cells with transfection of anti-miR-140-3p and/or siPTEN. Target binding between miR-140-3p and PTEN was predicted by the TargetScan database and identified using luciferase reporter assay and RNA immunoprecipitation. RESULTS: TGF-ß1 induced the activation of HSC-T6 cells, and miR-140-3p expression varied according to HSC-T6 cell activation status. Knockdown of miR-140-3p reduced cell proliferation and the expressions of α-SMA and desmin, as well as increased apoptosis, in TGF-ß1-induced HSC-T6 cells, which could be blocked by PTEN silencing. Additionally, inactivation of the AKT/mTOR signaling pathway stimulated by miR-140-3p knockdown was abolished when silencing PTEN expression. PTEN was negatively regulated by miR-140-3p via direct binding in HSC-T6 cells. CONCLUSION: miR-140-3p is an important mediator in HSC-T6 cell activation, and miR-140-3p knockdown suppresses cell proliferation and fibrogenesis in TGF-ß1-induced HSC-T6 cells, indicating that miR-140-3p may be a potential novel molecular target for liver fibrosis.


Assuntos
Técnicas de Silenciamento de Genes , Células Estreladas do Fígado/patologia , Cirrose Hepática/genética , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Apoptose/efeitos dos fármacos , Sequência de Bases , Linhagem Celular , Proliferação de Células/genética , Regulação da Expressão Gênica , Inativação Gênica , Células Estreladas do Fígado/metabolismo , Humanos , Cirrose Hepática/patologia , MicroRNAs/genética , Transdução de Sinais/efeitos dos fármacos
11.
World J Surg Oncol ; 17(1): 77, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31043166

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is the major pathological type of primary liver cancer, one of the leading causes of cancer death worldwide. In addition, the long-term survival rates of HCC still remain low. Therefore, we attempted to identify the potential key genes in the occurrence of HCC by comparing the expression profiles of very early HCC tissue samples with that of chronic cirrhotic tissue samples by integrating the bioinformatics analysis in this study. METHODS: Gene expression profiles of 19 very early HCC and 19 cirrhotic tissue samples were selected from GSE63898. Differentially expressed genes (DEGs) were also identified by using online tool GEO2R. Furthermore, the GO and KEGG enrichment analysis of the DGEs were conducted on DAVID datasets. Then a protein-protein interaction (PPI) network was constructed and the modules were analyzed based on STRING database and Cytoscape software. The hub genes were screened by applying the cytoHubba plugin and then analyzed with the Kaplan Meier plotter. RESULTS: A total of 118 DEGs were identified between very early HCC and cirrhotic tissue samples. These DGEs were strongly associated with several biological processes, such as negative regulation of growth and p53 signaling pathway. A PPI network was constructed and top eight hub genes, including CDKN3, CDK1, CCNB1, TOP2A, CCNA2, CCNB2, PRC1, and RRM2, were determined. High expressions of CDK1, CCNB1, TOP2A, CCNA2, PRC1, RRM2, CDKN3, and CCNB2 were associated with poorer overall survivals (OS) in HCC patients. CONCLUSION: We had compared the expression profiles between the very early HCC and cirrhotic tissue samples by using bioinformatics analysis tools, which might help us better to understand the molecular mechanism of the initiation of HCC and even to find novel targets for HCC therapy.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Biologia Computacional/métodos , Redes Reguladoras de Genes , Cirrose Hepática/genética , Neoplasias Hepáticas/genética , Idoso , Carcinoma Hepatocelular/patologia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Mapas de Interação de Proteínas , Transdução de Sinais
12.
Adv Clin Exp Med ; 28(9): 1237-1241, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30929321

RESUMO

BACKGROUND: Oxidative stress is extremely important in the pathogenesis of chronic hepatitis C virus (HCV). In response to oxidative stress, adaptive antioxidant defenses are upregulated in the liver. The balance between antioxidant response and oxidative stress plays a key role in hepatic injury in HCV infection. OBJECTIVES: The objective of this study was to assess the hepatic expression of the antioxidant genes GFER (growth factor erv1-like) and NQO1 (NAD(P)H:quinone oxidoreductase-1) and the regulatory gene NFE2L2 (nuclear factor erythroid 2-related factor-2) in liver biopsy specimens obtained from chronic HCV patients with regard to selected clinical parameters and histology, and to determine whether GFER and NQO1 expression is dependent on NFE2L2. MATERIAL AND METHODS: The study group consisted of 42 patients with chronic HCV. Reverse transcription polymerase chain reaction (RT-PCR) was used to analyze the expression of antioxidant and regulatory genes in liver biopsy samples. RESULTS: Positive correlation was observed between the hepatic expression of NFE2L2 and NQO1 in the chronic HCV patients (p < 0.0001). The hepatic expression of NFE2L2 was significantly lower in patients with advanced liver fibrosis (p = 0.05). However, there was no significant difference in the hepatic expression of GFER and NQO1 in relation to the progression of liver steatosis, inflammation and fibrosis. CONCLUSIONS: The hepatic expression of NFE2L2 is associated with NQO1 and low stage of hepatic fibrosis in patients infected with HCV.


Assuntos
Hepatite C Crônica , Cirrose Hepática , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fígado Gorduroso , Hepacivirus , Hepatite C Crônica/genética , Hepatite C Crônica/metabolismo , Humanos , Cirrose Hepática/genética , Cirrose Hepática/metabolismo
13.
Clin Lab ; 65(4)2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30969085

RESUMO

BACKGROUND: Sensitive and specific diagnostic indicators are essential for liver cirrhosis. This study aims to analyze two plasma microRNAs (miR-625 and miR-920) as possible biomarkers for liver cirrhosis. METHODS: miR-625 and miR-920 expressions were analyzed in the plasma of 40 patients with liver cirrhosis and 41 healthy controls. Plasma levels of miR-625 and miR-920 were assessed by qRT-PCR. Analysis of the results was performed by the Mann-Whitney U-test. Spearman's test was used to show correlations between the miR-625 and clinical parameters. Receiver operating characteristic (ROC) analysis was performed to assess sensitivity and specificity. RESULTS: miR-625 is downregulated in patients with liver cirrhosis. Expression of miR-625 correlated with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. ROC curve analysis revealed that miR-625 had a sensitivity of 82.4% and specificity of 88.9% (area under the curve (AUC): 0.902) which indicated a high diagnostic power for cirrhosis. CONCLUSIONS: This study demonstrates for the first time that, miR-625 may be considered as a potential noninvasive biomarker for diagnosis of liver cirrhosis in patients, irrespective of etiology.


Assuntos
Biomarcadores/sangue , Cirrose Hepática/sangue , MicroRNAs/sangue , Adulto , Alanina Transaminase/genética , Aspartato Aminotransferases/genética , Biomarcadores Tumorais , Feminino , Perfilação da Expressão Gênica , Humanos , Irã (Geográfico) , Cirrose Hepática/genética , Masculino , Pessoa de Meia-Idade , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Sensibilidade e Especificidade
14.
BMC Cancer ; 19(1): 395, 2019 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-31029128

RESUMO

BACKGROUND: The liver microenvironment plays a key role in the progression and metastasis of hepatocellular carcinoma (HCC). Gene expression profiling of non-cancerous hepatic tissues obtained from patients with metastatic HCC exhibit a unique immune response signature, including upregulation of CCN3. However, the role of CCN3 secreted from non-cancerous hepatic tissues in the progression of HCC remains unclear. METHODS: Using tissue microarrays, we examined CCN3 in non-cancerous hepatic tissues of patients with HCC and correlated expression with clinical and pathological features. In addition, CCN3 localization and mechanisms of HCC progression were investigated in tissues and cell lines. Finally, correlations between CCN3 and cirrhosis were explored in patients. RESULTS: CCN3 was primarily localized to hepatic cells of non-cancerous hepatic tissues and was associated with vascular invasion and poor prognosis in patients with HCC. CCN3 expression in non-cancerous hepatic tissues also correlated with the degree of liver fibrosis. Compared with conditioned media from wild-type LO2 cells, conditioned media from hepatic cell line LO2 activated by LX2 (aLO2-CM) induced CCN3 expression and HCC cell proliferation and metastasis. Further, aLO2-CM activated MAPK signaling and epithelial-mesenchymal transition in HCC cells. Finally, CCN3 was inversely related to cirrhosis in the prognosis of HCC and negatively regulated hepatic stellate cells (HSCs) in vitro with downregulation of α-SMA, TGF-ß, and collagens. CONCLUSIONS: CCN3 was secreted from hepatic cells activated by HSCs and increased MAPK signaling, EMT, proliferation and metastasis of HCC cells. CCN3 was also inversely related to cirrhosis, regulating HSCs through a negative feedback loop.


Assuntos
Carcinoma Hepatocelular/genética , Hepatócitos/metabolismo , Neoplasias Hepáticas/genética , Proteína Sobre-Expressa em Nefroblastoma/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Hepatócitos/patologia , Humanos , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Proteína Sobre-Expressa em Nefroblastoma/metabolismo , Comunicação Parácrina/genética , Transdução de Sinais/genética , Microambiente Tumoral/genética
15.
Nat Commun ; 10(1): 1909, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015417

RESUMO

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. ß-catenin is widely thought to be a major oncogene in HCC based on the frequency of mutations associated with aberrant Wnt signaling in HCC patients. Challenging this model, our data reveal that ß-catenin nuclear accumulation is restricted to the late stage of the disease. Until then, ß-catenin is primarily located at the plasma membrane in complex with multiple cadherin family members where it drives tumor cell survival by enhancing the signaling of growth factor receptors such as EGFR. Therefore, our study reveals the evolving nature of ß-catenin in HCC to establish it as a compound tumor promoter during the progression of the disease.


Assuntos
Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Proteína Wnt3A/genética , beta Catenina/genética , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Caderinas/genética , Caderinas/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Progressão da Doença , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Knockout , Estadiamento de Neoplasias , Fatores Sexuais , Transdução de Sinais , Carga Tumoral , Proteína Wnt3A/metabolismo , beta Catenina/metabolismo
16.
Genet Test Mol Biomarkers ; 23(5): 325-331, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30942619

RESUMO

Aims: This study was designed to determine if vitamin D receptor (VDR), carrier globulin/binding protein (GC), and cytochrome P-450 family 2, subfamily R, polypeptide 1 (CYP2R1) gene polymorphisms are risk factors in the development of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-infected patients from Northeast India. Materials and Methods: A total of 351 HCV-infected patients were enrolled of which 167 were diagnosed with chronic hepatitis C (CHC), 124 with liver cirrhosis (LC), and 60 with HCC together with 102 age- and sex-matched healthy controls. VDR (BsmI, ApaI, and TaqI), GC (rs4588, rs7051), and CYP2R1 (rs10741657) gene polymorphisms were genotyped for all subjects. Statistical data were analyzed using SPSS ver. 22.0. Results: The frequency of the ApaI CC genotype, ApaI C allele, and bAt haplotype of the VDR gene was significantly higher in HCC and LC patients than controls. After adjusting for other covariates (age, gender, platelet count, AST, ALT, serum albumin, and viral load) logistic regression analysis showed that the ApaI CC genotype and bAt haplotype were independent predictors of HCC development. No significant associations was found for the GC and CYP2R1 polymorphisms examined with the occurrence of HCC. Conclusions: The presence of the VDR ApaI CC genotype and bAt haplotype appear to be important indicators in the development of HCC among HCV-infected patients. Larger studies are needed to further clarify and establish this potential causal relationship.


Assuntos
Carcinoma Hepatocelular/genética , Receptores de Calcitriol/genética , Adulto , Idoso , Alelos , Carcinoma Hepatocelular/metabolismo , Colestanotriol 26-Mono-Oxigenase/genética , Colestanotriol 26-Mono-Oxigenase/metabolismo , Família 2 do Citocromo P450/genética , Família 2 do Citocromo P450/metabolismo , Feminino , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Genótipo , Haplótipos , Hepacivirus/patogenicidade , Hepatite C/complicações , Hepatite C/genética , Hepatite C Crônica/genética , Humanos , Índia , Cirrose Hepática/genética , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Receptores de Calcitriol/metabolismo , Proteína de Ligação a Vitamina D/genética , Proteína de Ligação a Vitamina D/metabolismo
17.
Artigo em Inglês | MEDLINE | ID: mdl-30881922

RESUMO

The sodium taurocholate co-transporting polypeptide (NTCP) acts as a cellular receptor for the hepatitis B virus (HBV) infection on host hepatocytes. We aim to investigate how the NTCP p.Ser267Phe variant affects HBV-related disease progression and analyze viral genomic variability under a host genetic background carrying the p.Ser267Phe variant. A total of 3187 chronic hepatitis B (CHB) patients were enrolled and genotyped for the p.Ser267Phe variant. The variant's association with disease progression was evaluated by logistic regression analysis. We also enrolled 83 treatment-naive CHB patients to analyze the variability of the HBV preS1 region. The frequency of the NTCP p.Ser267Phe variant was significantly lower in patients diagnosed with acute-on-chronic liver failure [OR (95% CI) = 0.33 (0.18-0.58), P = 1.34 × 10-4], cirrhosis [OR (95% CI) = 0.47 (0.31-0.72), P = 4.04 × 10-4], and hepatocellular carcinoma [OR (95% CI) = 0.54 (0.34-0.86), P = 9.83 × 10-3] as compared with CHB controls under the additive model after adjustment. Furthermore, the percentage of amino acid mutations in HBV preS1 region was significantly higher in the NTCP p.Ser267Phe heterozygote group than in the NTCP wild type homozygote group (P < 0.05). We herein demonstrate that the NTCP p.Ser267Phe variant is a protective factor reducing CHB patient risk for liver failure, cirrhosis, and hepatocellular carcinoma. A host genetic background carrying NTCP p.Ser267Phe exerts selective pressure on the virus, leading to more variability.


Assuntos
Variação Genética , Antígenos de Superfície da Hepatite B/genética , Vírus da Hepatite B/genética , Hepatite B Crônica/genética , Hepatite B Crônica/virologia , Proteínas Mutantes/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Simportadores/genética , Adulto , Idoso , Substituição de Aminoácidos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Progressão da Doença , Feminino , Genótipo , Hepatite B Crônica/complicações , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/genética , Cirrose Hepática/virologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade
18.
Gene ; 702: 153-157, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-30922710

RESUMO

Irregular methylation, including DNA hypomethylation and/or promoter gene CpG hypermethylation, is involved in the pathogenesis of several solid tumors, including liver cancer. miRNAs are small, endogenous, noncoding RNAs that serve as posttranscriptional regulators of gene expression. Previous research has focused on identifying the factors that regulate the expression of miRNAs in hepatic carcinogenesis. The factors that regulate miRNA expression are not clear; in particular, the role of DNA methylation, an epigenetic regulatory factor that controls miRNA transcription, has not been clarified. The goal of this study is to explore our understanding of the mechanism by which HCC may develop and progress through identification of the role of epigenetically regulated miRNAs influences in the liver carcinogenesis. The current study included 60 patients who were well diagnosed as HCC patients. 60 patients who suffer from liver cirrhosis were also enrolled in the current study and 30 healthy control subjects who serve as control group. All patients will be subjected to: full clinical assessment, abdominal ultrasound, Blood sample will be withdrawn from every patients for both biochemical and serum detection of microRNAs (191-203 -335) by real time PCR. We found that all studied microRNAs were down regulated among HCC patients when compared to cirrhotic patients and controls (p value: 0.005, 0.005 and 0.001 for microRNAs 191, 203 and 335 respectively). Moreover, these microRNAs can discriminate cases of HCC from risky cirrhotic patients. We can conclude that downregulated microRNAs among HCC cases proposed a pattern to explain the role of DNA methylation on miRNA and gene expression in HCC.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroRNAs/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/diagnóstico , Metilação de DNA , Feminino , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico , Cirrose Hepática/genética , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/diagnóstico , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade
19.
Int J Mol Sci ; 20(6)2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30875804

RESUMO

Previous large-scale genetic studies identified single nucleotide polymorphisms (SNPs) of the TM6SF2 and MBOAT7 genes as risk factors for alcoholic liver cirrhosis and non-alcoholic fatty liver disease. In this study, we tried to evaluate the association between TM6SF2 variant rs58542926 and MBOAT7 variant rs641738 and the risk of hepatic fibrosis or liver cirrhosis of different etiology. In parallel, we also aimed to evaluate whether these two SNPs modify the effects of the PNPLA3 rs738409 risk variant for the development of hepatic fibrosis and liver cirrhosis. The study was conducted at the Department of Gastroenterology, Lithuanian University of Health Sciences Hospital, and included 334 patients with liver cirrhosis, 128 patients with liver fibrosis, and 550 controls. SNPs were genotyped by quantitative PCR, using TaqMan allelic discrimination assays. Overall, TM6SF2 rs58542926 as well as MBOAT7 rs641738 were not linked to hepatic fibrosis, alcohol or hepatitis C virus induced liver cirrhosis in an Eastern European population. These genetic variations also did not mediate the effect of PNPLA3 rs738409 SNP for liver developing liver fibrosis or liver cirrhosis.


Assuntos
Aciltransferases/genética , Cirrose Hepática/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Fígado Gorduroso Alcoólico/genética , Feminino , Predisposição Genética para Doença , Hepatite C/complicações , Hepatite C/genética , Humanos , Lipase/genética , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade
20.
Int J Mol Sci ; 20(6)2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30875826

RESUMO

BACKGROUND: Interleukin-1 (IL-1)ß and IL-1 receptor antagonist (IL-1Ra) have been proposed as important mediators during chronic liver diseases. We aimed to determine whether the modulation of IL-1ß signaling with IL-1Ra impacts on liver fibrosis. METHODS: We assessed the effects of IL-1ß on human hepatic stellate cells (HSC) and in mouse models of liver fibrosis induced by bile duct ligation (BDL) or carbon tetrachloride treatment (CCl-4). RESULTS: Human HSCs treated with IL-1ß had increased IL-1ß, IL-1Ra, and MMP-9 expressions in vitro. HSCs treated with IL-1ß had reduced α-smooth muscle actin expression. These effects were all prevented by IL-1Ra treatment. In the BDL model, liver fibrosis and Kuppfer cell numbers were increased in IL-1Ra KO mice compared to wild type mice and wild type mice treated with IL-1Ra. In contrast, after CCl-4 treatment, fibrosis, HSC and Kupffer cell numbers were decreased in IL-1Ra KO mice compared to the other groups. IL-1Ra treatment provided a modest protective effect in the BDL model and was pro-fibrotic in the CCl-4 model. CONCLUSIONS: We demonstrated bivalent effects of IL-1Ra during liver fibrosis in mice. IL-1Ra was detrimental in the CCl-4 model, whereas it was protective in the BDL model. Altogether these data suggest that blocking IL-1-mediated inflammation may be beneficial only in selective liver fibrotic disease.


Assuntos
Actinas/genética , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1beta/genética , Cirrose Hepática/genética , Metaloproteinase 9 da Matriz/genética , Animais , Tetracloreto de Carbono/efeitos adversos , Contagem de Células , Células Cultivadas , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Humanos , Macrófagos do Fígado/citologia , Macrófagos do Fígado/efeitos dos fármacos , Macrófagos do Fígado/imunologia , Cirrose Hepática/etiologia , Cirrose Hepática/imunologia , Masculino , Camundongos , Regulação para Cima
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