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HCV (hepatitis C virus) infection affects an estimated 180 million people in the world's population. Adverse effects occur frequently with current standard treatment of interferon and ribavirin, while resistance of new direct anti-viral agents, NS3 protease inhibitors, is a major concern because of their single anti-HCV mechanism against the viral factor. New anti-viral agents are needed to resolve the problems. Amiodarone, an anti-arrhythmic drug, has recently been shown to inhibit HCV infection in vitro. The detailed mechanism has yet to be clarified. The aim of the present study was to elucidate the molecular mechanism of the inhibitory effect of amiodarone on HCV life cycle. The effect of amiodarone on HCV life cycle was investigated in Huh-7.5.1 cells with HCVcc (cell culture-derived HCV), HCVpp (HCV pseudoviral particles), sub-genomic replicons, IRES (internal ribosomal entry site)-mediated translation assay, and intracellular and extracellular infectivity assays. The administration of amiodarone appeared to inhibit HCV entry independent of genotypes, which was attributed to the down-regulation of CD81 receptor expression. The inhibitory effect of amiodarone also manifested in the HCV assembly step, via the suppression of MTP (microsomal triacylglycerol transfer protein) activity. Amiodarone revealed no effects on HCV replication and translation. With the host factor-targeting characteristics, amiodarone may be an attractive agent for the treatment of HCV infection. [ABSTRACT FROM AUTHOR]

Besides cardioprotective effects, the AT1R (angiotensin-II type 1 receptor) antagonist losartan protects the liver from IRI [IR (ischaemia/reperfusion) injury], but the mechanism has not been fully determined. The HIF (hypoxia inducible factor)-1α and Wnt/β-catenin signalling pathways have been reported to be involved in the mechanism of liver IRI. Therefore the aim of the present study was to determine whether the Wnt/HIF axis is part of the mechanism of the positive effect of AngII inhibition by losartan in liver IRI in rats. Various measurements were made in MCD/HF-NASH (methionine- and choline-deficient-diet/high-fat-diet-induced non-alcoholic steatohepatitis) rats with liver IRI. Acute losartan pre-administration markedly reversed the IR-suppressed levels of the hepatic-protective factors IL (interleukin)-6, IFN (interferon)-γ , Wnt3a, β-catenin and HIF-1α, and decreased hepatic blood flow and IR-elevated serum ALT (alanine aminotransferase), hepatic TNF (tumour necrosis factor)-α, IL-1α, hepatic congestion, vacuolization and necrosis, hepatic Suzuki IRI scores, necrotic index and levels of TBARS (thiobarbituric acid-reacting substances) in MCD/HF-NASH rats. Furthermore, acute Wnt3a pre-treatment significantly inhibited IR-elevated serum ALT, hepatic Suzuki IRI scores and TBARS, and restored the IR-depleted β-catenin/HIF-1α activity in MCD/HF-NASH rats. Simultaneous acute sFRP2 (secreted frizzled-related protein 2; a Wnt3a inhibitor) pre-treatment eliminated the losartan-related beneficial effects in MCD/HF-NASH rats with liver IRI, which was accompanied by a decrease in hepatic HIF-1α/β-catenin activity. Losartan-induced up-regulation of HIF-1α and Wnt/β-catenin signalling was associated with the recovery of IR-inhibited hepatic Bcl-2, Mn-SOD (manganese superoxide), Cu/Zn-SOD (copper/zinc superoxide) and GSH levels, and the suppression of IR-increased hepatic catalase and caspase 3/caspase 8 levels in MCD/HF-NASH rats. In conclusion, up-regulation of the HIF-1α and Wnt/β-catenin signalling pathways are part of the mechanism of the positive effects of losartan-related AngII inhibition in MCD/HF-NASH rats with liver IRI. Our study highlights the potential of the dual-organ protective agent losartan in NASH patients with steatotic livers and cardiovascular risk. [ABSTRACT FROM AUTHOR]

In cirrhosis, the development of ascites and the response to diuretics are determined by the RAAS (renin–angiotensin–aldosterone system) and renal sodium handling system. We hypothesized that SNPs (single nucleotide polymorphisms) affecting candidate genes in the RAAS and renal sodium handling pathway may influence initial diuretic responsiveness and affect clinical outcome in non-azotaemic cirrhotic patients with moderate ascites. We prospectively recruited 176 patients and 245 controls and determined their genetic polymorphisms for 24 SNPs of ten genes involved in the RAAS and renal sodium handling pathway. In cirrhotic patients with moderate ascites, multivariate analysis showed that diuretic unresponsiveness was predicted by a high basal plasma aldosterone level, by a high aldosterone/renin ratio and by specific risk genotypes of ACE (gene encoding angiotensin-converting enzyme), CYP11B2 (gene encoding aldosterone synthase) and ADDA (gene encoding α-adducin). This association between genetic polymorphisms and diuretic unresponsiveness was confirmed by an independent validation cohort. Notably, additive effects in relation to diuretic unresponsiveness were observed in cases where there was the simultaneous presence of the three risk genotypes. Among patients carrying any of the risk genotypes, more episodes of paracentesis and ascites-related readmission after 3 months of treatment, as well as a reduced 1-year survival rate, were observed. In addition to traditional predictors, our present study provides additional genetic and neurohormonal predictors that will help to identify diuretic non-responders among cirrhotic patients with moderate ascites. Among those carrying unfavourable risk genotypes, additional therapies, including paracentesis and albumin infusion, should be started as early as possible. [ABSTRACT FROM AUTHOR]

Chronic infections with hepatitis B and C viruses (HBV and HCV) are etiologically linked to hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Both viruses may induce activation of nuclear factor-kappa B (NF-κB) in hepatocytes that plays a crucial role in the regulation of cell growth and apoptosis. Functional proteomics analysis of proteins associated with NF-κB signaling complexes in both viruses-related HCC tumor and non-tumor tissues may disclose possible common mechanisms in hepatocarcinogenesis. By functional proteomics, we analyzed proteins associated with NF-κB-signaling complexes in four-paired human HCC tumor and non-tumor tissues from HBV- and HCV-infected patients, respectively, and in one-paired tissue with dual viral infection. The quantity of NF-κB-associated proteins was semi-quantitatively measured by protein spot intensity on the gels of two-dimensional polyacrylamide gel electrophoresis. The results showed that overexpression of NF-κB-associated Wnt-1 protein in tumor part was detected in the␣majority of HBV- and HCV-infected HCC samples. These data suggest that enhanced expression of NF-κB-associated Wnt-1 protein might be a mechanism of hepatocarcinogenesis common to HBV- and HCV-infected patients. NF-κB signaling pathway and Wnt-1 protein could be potential targets for designing highly effective therapeutic agents in treating HCC and for chemoprevention of hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]