Hepatitis C virus dynamics and cellular gene expression in uPA-SCID chimeric mice with humanized livers during intravenous silibinin monotherapy [electronic resource].
- Published
- Washington, D.C. : United States. Dept. of Energy, 2016.
Oak Ridge, Tenn. : Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy - Physical Description
- 708-717 : digital, PDF file
- Additional Creators
- Los Alamos National Laboratory, United States. Department of Energy, National Institutes of Health (U.S.), and United States. Department of Energy. Office of Scientific and Technical Information
Access Online
- Restrictions on Access
- Free-to-read Unrestricted online access
- Summary
- 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. In this paper, 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. Finally, 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.
- Report Numbers
- E 1.99:la-ur-15-28931
la-ur-15-28931 - Subject(s)
- Other Subject(s)
- Note
- Published through SciTech Connect.
06/08/2016.
"la-ur-15-28931"
Journal of Viral Hepatitis 23 9 ISSN 1352-0504 AM
Swati DebRoy; Nobuhiko Hiraga; Michio Imamura; C. Nelson Hayes; Sakura Akamatsu; Laetitia Canini; Alan S. Perelson; Ralf T. Pohl; Stefano Persiani; Susan L. Uprichard; Chise Tateno; Harel Dahari; Kazuaki Chayama.
PhoenixBio Co. Ltd. (Japan)
Biotechnology and Biological Sciences Research Council (BBSRC) (United Kingdom) - Funding Information
- AC52-06NA25396
P20-GM103452
R01-AI028433
R01-AI011095
R01-AI078881
1698:BB/L001330/1
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