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Legalon SIL ( SIL) is a chemically hydrophilized version of silibinin, an extract of milk thistle ( Silybum marianum) seeds that has exhibited hepatoprotective and antiviral effectiveness against hepatitis C virus ( HCV) in patients leading to viral clearance in combination with ribavirin. To elucidate the incompletely understood mode of action of SIL against HCV, mathematical modelling of HCV kinetics and human hepatocyte gene expression studies were performed in uPA- SCID-chimeric mice with humanized livers. Chronically HCV-infected mice ( n = 15) were treated for 14 days with daily intravenous SIL at 469, 265 or 61.5 mg/kg. Serum HCV and human albumin ( hAlb) were measured frequently, and liver HCV RNA was analysed at days 3 and 14. Microarray analysis of human hepatocyte gene expression was performed at days 0, 3 and 14 of treatment. While hAlb remained constant, a biphasic viral decline in serum was observed consisting of a rapid 1st phase followed by a second slower phase (or plateau with the two lower SIL dosings). SIL effectiveness in blocking viral production was similar among dosing groups (median ε = 77%). However, the rate of HCV-infected hepatocyte decline, δ, was dose-dependent. Intracellular HCV RNA levels correlated ( r = 0.66, P = 0.01) with serum HCV RNA. Pathway analysis revealed increased anti-inflammatory and antiproliferative gene expression in human hepatocytes in SIL-treated mice. The results suggest that SIL could lead to a continuous second-phase viral decline, that is potentially viral clearance, in the absence of adaptive immune response along with increased anti-inflammatory and antiproliferative gene expression in human hepatocytes. [ABSTRACT FROM AUTHOR]

Pathogen-specific mi RNA profiles might reveal potential new avenues for therapy. To identify mi RNAs directly associated with hepatitis B virus ( HBV) in hepatocytes, we performed a mi RNA array analysis using urokinase-type plasminogen activator (u PA)-severe combined immunodeficiency ( SCID) mice where the livers were highly repopulated with human hepatocytes and human immune cells are absent. Mice were inoculated with HBV-infected patient serum samples. Eight weeks after HBV infection, human hepatocytes were collected from liver tissues, and mi RNAs were analysed using the Toray 3 D array system. The effect of mi RNAs on HBV replication was analysed using HBV-transfected Hep G2 cells. Four mi RNAs, hsa-mi R-486-3p, hsa-mi R-1908, hsa-mi R-675 and hsa-mi R-1231 were upregulated in mouse and human livers with HBV infection. These mi RNAs were associated with immune response pathways such as inflammation mediated by chemokine and cytokine signalling. Of these mi RNAs, hsa-mi R-1231, which showed high homology with HBV core and HBx sequences, was most highly upregulated. In HBV-transfected Hep G2 cells, overexpression of hsa-mi R-1231 resulted in suppression of HBV replication with HBV core reduction. In conclusion, a novel interaction between hsa-mi R-1231 and HBV replication was identified. This interaction might be useful in developing new therapeutic strategies against HBV. [ABSTRACT FROM AUTHOR]

Complementary DNA microarray analysis of human livers cannot exclude the influence of the immunological response. In this study, complementary DNA microarray analysis was performed under immunodeficient conditions with human hepatocyte chimeric mice, and gene expression profiles were analyzed by hepatitis B virus (HBV) infection and/or interferon treatment. The expression levels of 183 of 525 genes upregulated by interferon treatment were significantly suppressed in response to HBV infection. Suppressed genes were statistically significantly associated with the interferon signaling pathway and pattern recognition receptors in the bacteria/virus recognition pathway (P = 1.0 x 10(-8) and P = 1.2 x 10(-8), respectively). HBV infection attenuated virus recognition and interferon response in hepatocytes, which facilitated HBV escape from innate immunity. [ABSTRACT FROM AUTHOR]

The cover image, by Kazuaki Chayama et al., is based on the Original Article Hepatitis C virus dynamics and cellular gene expression in uPA‐SCID chimeric mice with humanized livers during intravenous silibinin monotherapy, DOI: 10.1111/jvh.12551. [ABSTRACT FROM AUTHOR]