Hepatitis C virus dynamics and cellular gene expression in uPA-SCID chimeric mice with humanized livers during intravenous silibinin monotherapy
- 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
- Hiroshima Univ. (Japan). Inst. of Biomedical and Health Sciences. Dept. of Gastroenterology and Metabolism
- 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
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics
- German Association of Phytotherapy, Speyer (Germany)
- Rottapharm Biotech SRL, Monza (Italy)
- Loyola Univ. Medical Center, Maywood, IL (United States). Dept. of Medicine. Division of Hepatology. The Program for Experimental and Theoretical Modeling
- PhoenixBio Co. Ltd., Higashihiroshima (Japan)
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. 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 ( hA lb) 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 hA lb 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.
- Research Organization:
- Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
- Sponsoring Organization:
- USDOE; National Inst. of Health (NIH) (United States); PhoenixBio Co. Ltd. (Japan); Biotechnology and Biological Sciences Research Council (BBSRC) (United Kingdom)
- Contributing Organization:
- PhoenixBio Co. Ltd., Higashihiroshima (Japan); German Association of Phytotherapy, Speyer (Germany); Rottapharm Biotech SRL, Monza (Italy)
- Grant/Contract Number:
- AC52-06NA25396; P20-GM103452; R01-AI028433; R01-AI011095; R01-AI078881; 1698:BB/L001330/1; DE‐AC52‐06NA25396
- OSTI ID:
- 1325641
- Alternate ID(s):
- OSTI ID: 1401679
- Report Number(s):
- LA-UR-15-28931
- Journal Information:
- Journal of Viral Hepatitis, Vol. 23, Issue 9; ISSN 1352-0504
- Publisher:
- WileyCopyright Statement
- Country of Publication:
- United States
- Language:
- English
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