6, 18 We also found that TGFβ played a major role in the HCV-induced

elevation of Nox4 in hepatocytes, although other factors might also be involved (Fig. 8; unpublished findings, Wang, Ito, and Choi, 2010). Some of these findings were corroborated by a recent study by Boudreau et al.21 Importantly, hepatocellular carcinoma, associated with chronic hepatitis C, is typically preceded by cirrhosis. Therefore, hepatocyte Nox protein(s) may provide a link between inflammation, fibrogenesis, and hepatocarcinogenesis during chronic hepatitis C. In particular, nuclear Nox4 is likely Everolimus datasheet to be highly significant in the HCV-induced DNA damage in the initiation of cancer as well as reversible and/or irreversible protein modifications in the modulation of cell signaling and host gene expression. The ability to regulate Nox proteins also makes them potential targets for therapy. Therefore, our study provides new insights into

a possible mechanism of HCV-induced pathogenesis and points to potential targets for therapy directed at the source of ROS. The authors thank Takaji Wakita for JFH1 constructs, Mark Zern for telomerase-reconstituted primary human hepatocytes, Balaraman Kalyanaraman for the 2-OH-E+ standard, and Henry Jay Forman for LY2835219 order the HPLC systems and discussion. They also thank Muhammad Sheikh, Michael David, Matthew Meyer, David Ojcius, Rui-Ming Liu, and the late T. S. Benedict Yen for discussion and Anna Nandipati, Simrita Kaur (McNair Scholars Program), Sam Chung, and Armand McGee (Basic and Advanced Science and Technology Academies of Research program) for technical

assistance. Additional Supporting Information may be found in the online version of this article. “
“Chronic infection with the human hepatitis B virus (HBV) is a global health problem and a main cause of progressive liver diseases. HBV exhibits a narrow host range, replicating primarily in hepatocytes. Both host and hepatocyte specificity presumably involve specific receptor interactions on the target cell; however, direct evidence for this hypothesis is missing. Following the observation that HBV entry is specifically blocked by L-protein-derived preS1-lipopeptides, we visualized specific HBV receptor/ligand complexes on hepatic this website cells and quantified the turnover kinetics. Using fluorescein isothiocyanate-labeled, myristoylated HBV preS1-peptides we demonstrate (1) the presence of a highly specific HBV receptor on the plasma membrane of HBV-susceptible primary human and tupaia hepatocytes and HepaRG cells but also on hepatocytes from the nonsusceptible species mouse, rat, rabbit and dog; (2) the requirement of a differentiated state of the hepatocyte for specific preS1-binding; (3) the lack of detectable amounts of the receptor on HepG2 and HuH7 cells; (4) a slow receptor turnover at the hepatocyte membrane; and (5) an association of the receptor with actin microfilaments.