K of the signature of positive selection on the GBV-C E2 sequence was notsurprising because GBV-C might have successfully invaded the immune-compromised host without any functional modification by the alternation of amino acid at its membrane Autophagy protein in order to adapt the new environment.AcknowledgmentsWe thank Drs. Zisis Kozlakidis, John Cason and three anonymous reviewers for critics which greatly improved the manuscript.Author ContributionsConceived and designed the experiments: XG. Performed the experiments: HW XG. Analyzed the data: AP. Contributed reagents/materials/analysis tools: PT XG. Wrote the paper: XG AP HW JX PT. Patients’ enrollment and follow up: JX.
Hepatitis C virus (HCV) infects approximately 170 million people worldwide [1,2]. It causes chronic liver diseases inhibitor including chronic hepatitis, cirrhosis and hepatocellular carcinoma. HCVassociated chronic liver disease is the leading indication for liver 1326631 transplantation [3]. Currently, there is no vaccine for HCV prevention; the standard therapy for HCV is pegylated interferonalpha (IFN-a) plus 
ribavirin. However, the treatment results in sustained virologic response in approximately 50 patients with genotype 1 HCV infection, and is associated with significant side effect. Thus, understanding the pathogenesis of HCV and improvement of antiviral drugs for better efficacy for anti-HCV therapeutics are necessary. Human hepcidin, also known as liver-expressed antimicrobial peptide-1, or LEAP-1, was first discovered and characterized as a highly disulfide-bonded peptide with antimicrobial activity [4]. Several studies have demonstrated that hepcidin has antimicrobial activity against bacteria and fungi [5,6,7]. Its major role appears to be in regulating iron homoeostasis. It is involved in the negative regulation of iron transport from intestinal enterocytes, reticuloendothelial macrophages, and hepatocytes to the plasma by binding it receptor ferroportin on the plasma membranes of these cells [8]. Iron is an essential element for all living organisms because it is required by a wide range of metabolic processes including DNAsynthesis, oxygen transport, and energy production. However, excessive iron is harmful to the organism by evoking inflammatory cytokines, reactive oxygen species, liver fibrosis, and hepatic carcinogenesis [9,10]. Chronic HCV infection can also result in iron accumulation in the liver, which possibly contributes to liver injury [11,12]. However, little is known about the mechanism of iron accumulation in liver with HCV. A study has shown that HCV patients have low hepcidin levels in the liver [13], which raises the possibility that HCV inhibits hepcidin expression. The control of hepcidin expression is complex. Oxidative stress can 
suppress hepcidin expression through inactivation of transcriptional factors including CCAAT/enhancer-binding protein a (C/EBPa) and signal transducer and activator of transcription 3 (STAT3) in alcohol-fed mice and in hypoxia treated cells [14,15]. A recent study indicated that HCV-induced oxidative stress suppresses hepcidin expression in human hepatoma cell lines via histone deacetylase (HDAC) activation [16]. There are two signaling transduction pathways which are the major inducers of hepcidin expression: the hemojuvelin/bone morphogenetic protein/small mother against decapentaplegic homolog (HJV/BMP/ SMAD) [17] and the STAT3 pathways [18,19]. The STAT3 pathway is specifically involved in the inflammatory response linked with.K of the signature of positive selection on the GBV-C E2 sequence was notsurprising because GBV-C might have successfully invaded the immune-compromised host without any functional modification by the alternation of amino acid at its membrane protein in order to adapt the new environment.AcknowledgmentsWe thank Drs. Zisis Kozlakidis, John Cason and three anonymous reviewers for critics which greatly improved the manuscript.Author ContributionsConceived and designed the experiments: XG. Performed the experiments: HW XG. Analyzed the data: AP. Contributed reagents/materials/analysis tools: PT XG. Wrote the paper: XG AP HW JX PT. Patients’ enrollment and follow up: JX.
Hepatitis C virus (HCV) infects approximately 170 million people worldwide [1,2]. It causes chronic liver diseases including chronic hepatitis, cirrhosis and hepatocellular carcinoma. HCVassociated chronic liver disease is the leading indication for liver 1326631 transplantation [3]. Currently, there is no vaccine for HCV prevention; the standard therapy for HCV is pegylated interferonalpha (IFN-a) plus ribavirin. However, the treatment results in sustained virologic response in approximately 50 patients with genotype 1 HCV infection, and is associated with significant side effect. Thus, understanding the pathogenesis of HCV and improvement of antiviral drugs for better efficacy for anti-HCV therapeutics are necessary. Human hepcidin, also known as liver-expressed antimicrobial peptide-1, or LEAP-1, was first discovered and characterized as a highly disulfide-bonded peptide with antimicrobial activity [4]. Several studies have demonstrated that hepcidin has antimicrobial activity against bacteria and fungi [5,6,7]. Its major role appears to be in regulating iron homoeostasis. It is involved in the negative regulation of iron transport from intestinal enterocytes, reticuloendothelial macrophages, and hepatocytes to the plasma by binding it receptor ferroportin on the plasma membranes of these cells [8]. Iron is an essential element for all living organisms because it is required by a wide range of metabolic processes including DNAsynthesis, oxygen transport, and energy production. However, excessive iron is harmful to the organism by evoking inflammatory cytokines, reactive oxygen species, liver fibrosis, and hepatic carcinogenesis [9,10]. Chronic HCV infection can also result in iron accumulation in the liver, which possibly contributes to liver injury [11,12]. However, little is known about the mechanism of iron accumulation in liver with HCV. A study has shown that HCV patients have low hepcidin levels in the liver [13], which raises the possibility that HCV inhibits hepcidin expression. The control of hepcidin expression is complex. Oxidative stress can suppress hepcidin expression through inactivation of transcriptional factors including CCAAT/enhancer-binding protein a (C/EBPa) and signal transducer and activator of transcription 3 (STAT3) in alcohol-fed mice and in hypoxia treated cells [14,15]. A recent study indicated that HCV-induced oxidative stress suppresses hepcidin expression in human hepatoma cell lines via histone deacetylase (HDAC) activation [16]. There are two signaling transduction pathways which are the major inducers of hepcidin expression: the hemojuvelin/bone morphogenetic protein/small mother against decapentaplegic homolog (HJV/BMP/ SMAD) [17] and the STAT3 pathways [18,19]. The STAT3 pathway is specifically involved in the inflammatory response linked with.
