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Aim: To explore the predictive value of plasma YAP1 for esophageal varices (EV) and high-risk EV (HRV) in patients with liver cirrhosis. Materials & methods: A total of 208 patients with liver cirrhosis were enrolled and categorized into four groups. Correlation analysis, logistic regression analysis and receiver operating characteristic curve analysis were performed to evaluate the diagnostic performance of plasma YAP1 for EV and HRV. Results: Plasma YAP1 levels were significantly elevated with the occurrence and progression of EV in cirrhotic patients. The multivariate logistic regression analysis revealed that plasma YAP1 is an independent predictor for EV and HRV. For predicting EV and HRV, the YAP1 cut-off values of 5.43 and 6.98 ng/ml yielded the area under the receiver operating characteristic curves of 0.944 and 0.955, respectively. Conclusion: Plasma YAP1 is a potential novel noninvasive biomarker for predicting EV and HRV in patients with liver cirrhosis.
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Biomarcadores/sangre , Várices Esofágicas y Gástricas/sangre , Hemorragia Gastrointestinal/sangre , Cirrosis Hepática/sangre , Proteínas Señalizadoras YAP/sangre , Várices Esofágicas y Gástricas/diagnóstico , Femenino , Hemorragia Gastrointestinal/diagnóstico , Humanos , Cirrosis Hepática/diagnóstico , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Pronóstico , Factores de Riesgo , Sensibilidad y EspecificidadRESUMEN
Hepatic fibrosis is a crucial pathological process involved in the development of chronic hepatitis C (CHC) and may progress to liver cirrhosis and hepatocellular carcinoma. Activated peripheral blood monocytes and intrahepatic macrophages further promote hepatic fibrogenesis by releasing proinflammatory and profibrogenic cytokines. The present study aimed to investigate the role of peripheral CD14+ monocytes and intrahepatic CD163+ macrophages in hepatitis C virus (HCV)-associated liver fibrosis and clarify whether serum soluble CD163 (sCD163) may serve as a fibrosis marker in patients with CHC. A total of 87 patients with CHC and 20 healthy controls were recruited. Serum sCD163 levels were measured by ELISA. Frequencies of peripheral CD14+ monocytes and inflammatory cytokines expressed by CD14+ monocytes were analyzed by flow cytometry. The degree of fibrosis in human liver biopsies was graded using the Metavir scoring system and patients were stratified into two groups based on those results (F<2 vs. F≥2). Hepatic expression of CD163 was examined by immunohistochemical staining. The diagnostic values of sCD163, aspartate aminotransferase to platelet ratio index (APRI), fibrosis 4 score (FIB-4) and the aspartate aminotransferase to alanine aminotransferase ratio (AAR) in significant fibrosis (F≥2) were evaluated and compared using receiver operating characteristic (ROC) curves. The results indicated that the serum sCD163 levels and the frequency of CD14+ monocytes were significantly higher in the patients than that in the controls and positively correlated with liver fibrosis. The level of serum sCD163 was consistent with hepatic CD163 expression in the liver sections from patients. The frequencies of interleukin (IL)-8- and tumor necrosis factor-α-expressing monocytes were increased and that of IL-10-expressing monocytes was decreased in the patients. The area under the ROC curve (AUROC) for sCD163, APRI, FIB-4 and AAR was 0.876, 0.785, 0.825 and 0.488, respectively, and the AUROC for sCD163 was significantly higher than those for APRI and AAR. In conclusion, sCD163 may serve as a novel marker for assessing the degree of liver fibrosis in HCV-infected patients.
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METHODS: Mice were fed with a methionine-choline-deficient (MCD) diet for 8 weeks to induce steatohepatitis-related liver fibrosis and were treated with HO-1 inducer Hemin and inhibitor ZnPP. Mouse sera were collected for the biochemical analysis, and livers were obtained for further histological observation and gene expression analysis. HSC-T6 cells were cultured for the in vitro study and were administrated with Hemin and si-HO-1 to induce or inhibit the expression of HO-1. qPCR and Western blot were used to assess the mRNA and protein levels of genes. RESULTS: MCD-fed mice developed marked macrovesicular steatosis, focal necrosis, and inflammatory infiltration and pericellular fibrosis in liver sections. Administration of Hemin could significantly ameliorate the severity of steatosis, inflammation, and fibrosis and also could decrease the serum ALT and AST. We demonstrated that HO-1 induction was able to downregulate the key regulator of the canonical Wnt pathway Wnt1 and the noncanonical Wnt pathway Wnt5a. The downstream factors of the Wnt pathway ß-catenin and NFAT5 were inhibited by Hemin, but GSK-3ß was upregulated compared to the MCD group, which were consistent with the in vitro study. Hemin markedly inhibited the TGF-ß1/Smad signaling pathway in both in vivo and in vitro studies. CONCLUSION: Our study demonstrated that HO-1 inhibited the activation of canonical and noncanonical Wnt signaling pathways in NASH-related liver fibrosis. Thus, these results may suggest a new therapeutic strategy for NASH-related liver fibrosis.
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Hemo-Oxigenasa 1 , Cirrosis Hepática/metabolismo , Proteínas de la Membrana , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Vía de Señalización Wnt , Animales , Línea Celular , Técnicas de Silenciamiento del Gen , Hemo Oxigenasa (Desciclizante)/genética , Hemo Oxigenasa (Desciclizante)/metabolismo , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratas , Vía de Señalización Wnt/genética , Vía de Señalización Wnt/fisiologíaRESUMEN
OBJECTIVE(S): Long noncoding RNAs (lncRNAs)-activated by transforming growth factor beta (lncRNA-ATB) is known to be involved in the invasion of hepatocellular carcinoma by regulating target genes of miR-200a. However, the role and molecular mechanisms of lncRNA-ATB/miR-200a in HCV-related liver fibrosis remains unclear. In this study, we examined the expression of lncRNA-ATB/miR-200a, and their target gene ß-Catenin in liver tissues of HCV patients and hepatic stellate cells (HSCs) to elucidate the possible role of lncRNA-ATB/miR-200a axis in HSC activation and development of liver fibrosis. MATERIALS AND METHODS: Liver tissues were obtained by biopsy or surgery from eighteen HCV patients with severe liver fibrosis and six healthy subjects (control). Conditioned media (CM) from cultured HepG2-CORE cells (HepG2 cells stably expressing HCV core protein) were used to treat LX-2 cells. The binding sites between lncRNA-ATB/miR-200a and ß-catenin were predicted and then verified by a dual luciferase reporter assay. The effect of lncRNA-ATB/miR-200a/ß-catenin on HSC activation was assessed by examining the expression of alpha-smooth muscle actin (α-SMA) and collagen type 1 alpha 1 (Col1A1) in HSCs. Further, the regulatory role of lncRNA-ATB on HSC activation and miR-200a/ß-catenin expression was assessed by using siRNA-mediated knockdown of lncRNA-ATB. RESULTS: LncRNA-ATB was up-regulated in fibrotic liver tissues and activated LX-2 cells treated with CM from HepG2-CORE cells. Dual luciferase reporter assays confirmed that lncRNA-ATB contained common binding sites for miR-200a and ß-catenin. Decreased expression of miR-200a and increased expression of ß-catenin were observed in liver tissues of patients with HCV-related hepatic fibrosis and activated HSCs. Knockdown of lncRNA-ATB could down-regulate ß-catenin expression by up-regulating the endogenous miR-200a and suppress the activation of LX-2 cells. CONCLUSION: LncRNA-ATB/miR-200a/ß-catenin regulatory axis likely contributed to the development of liver fibrosis in HCV patients. Knockdown of lncRNA-ATB might be a novel therapeutic target for HCV-related liver fibrosis.