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Title: Hepatitis C virus dynamics and cellular gene expression in uPA-SCID chimeric mice with humanized livers during intravenous silibinin monotherapy

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)more » 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.« less
Authors:
 [1] ;  [2] ;  [2] ;  [2] ;  [2] ;  [3] ;  [4] ;  [5] ;  [6] ;  [7] ;  [8] ;  [7] ;  [2]
  1. Loyola Univ. Medical Center, Maywood, IL (United States). Dept. of Medicine. Division of Hepatology. The Program for Experimental and Theoretical Modeling; Univ. of South Carolina Beaufort, Bluffton, SC (United States). Dept. of Mathematics and Computational Science
  2. Hiroshima Univ. (Japan). Inst. of Biomedical and Health Sciences. Dept. of Gastroenterology and Metabolism
  3. Loyola Univ. Medical Center, Maywood, IL (United States). Dept. of Medicine. Division of Hepatology. The Program for Experimental and Theoretical Modeling; Univ. of Edinburgh, Scotland (United Kingdom). Centre for Immunity, Infection and Evolution
  4. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics
  5. German Association of Phytotherapy, Speyer (Germany)
  6. Rottapharm Biotech SRL, Monza (Italy)
  7. Loyola Univ. Medical Center, Maywood, IL (United States). Dept. of Medicine. Division of Hepatology. The Program for Experimental and Theoretical Modeling
  8. PhoenixBio Co. Ltd., Higashihiroshima (Japan)
Publication Date:
OSTI Identifier:
1325641
Report Number(s):
LA-UR--15-28931
Journal ID: ISSN 1352-0504
Grant/Contract Number:
AC52-06NA25396; P20-GM103452; R01-AI028433; R01-AI011095; R01-AI078881; 1698:BB/L001330/1
Type:
Accepted Manuscript
Journal Name:
Journal of Viral Hepatitis
Additional Journal Information:
Journal Volume: 23; Journal Issue: 9; Journal ID: ISSN 1352-0504
Publisher:
Wiley
Research Org:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Hiroshima Univ. (Japan); Loyola Univ. Medical Center, Maywood, IL (United States)
Sponsoring Org:
USDOE; National Inst. of Health (NIH) (United States); PhoenixBio Co. Ltd. (Japan); Biotechnology and Biological Sciences Research Council (BBSRC) (United Kingdom)
Contributing Orgs:
PhoenixBio Co. Ltd., Higashihiroshima (Japan); German Association of Phytotherapy, Speyer (Germany); Rottapharm Biotech SRL, Monza (Italy)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES anti-inflammatory; chimeric mice with humanized livers; gene expression; uPA-SCID; viral kinetic modelling