Hepatitis C virus dynamics and cellular gene expression in uPA-SCID chimeric mice with humanized livers during intravenous silibinin monotherapy
Abstract
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,more »
- Authors:
-
- 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)
- Publication Date:
- Research Org.:
- Los Alamos National Laboratory (LANL), Los Alamos, NM (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 Org.:
- PhoenixBio Co. Ltd., Higashihiroshima (Japan); German Association of Phytotherapy, Speyer (Germany); Rottapharm Biotech SRL, Monza (Italy)
- OSTI Identifier:
- 1325641
- Alternate Identifier(s):
- OSTI ID: 1401679
- 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; DE‐AC52‐06NA25396
- Resource 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
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Biological Science
Citation Formats
DebRoy, Swati, Hiraga, Nobuhiko, Imamura, Michio, Hayes, C. Nelson, Akamatsu, Sakura, Canini, Laetitia, Perelson, Alan S., Pohl, Ralf T., Persiani, Stefano, Uprichard, Susan L., Tateno, Chise, Dahari, Harel, and Chayama, Kazuaki. Hepatitis C virus dynamics and cellular gene expression in uPA-SCID chimeric mice with humanized livers during intravenous silibinin monotherapy. United States: N. p., 2016.
Web. doi:10.1111/jvh.12551.
DebRoy, Swati, Hiraga, Nobuhiko, Imamura, Michio, Hayes, C. Nelson, Akamatsu, Sakura, Canini, Laetitia, Perelson, Alan S., Pohl, Ralf T., Persiani, Stefano, Uprichard, Susan L., Tateno, Chise, Dahari, Harel, & Chayama, Kazuaki. Hepatitis C virus dynamics and cellular gene expression in uPA-SCID chimeric mice with humanized livers during intravenous silibinin monotherapy. United States. https://doi.org/10.1111/jvh.12551
DebRoy, Swati, Hiraga, Nobuhiko, Imamura, Michio, Hayes, C. Nelson, Akamatsu, Sakura, Canini, Laetitia, Perelson, Alan S., Pohl, Ralf T., Persiani, Stefano, Uprichard, Susan L., Tateno, Chise, Dahari, Harel, and Chayama, Kazuaki. Wed .
"Hepatitis C virus dynamics and cellular gene expression in uPA-SCID chimeric mice with humanized livers during intravenous silibinin monotherapy". United States. https://doi.org/10.1111/jvh.12551. https://www.osti.gov/servlets/purl/1325641.
@article{osti_1325641,
title = {Hepatitis C virus dynamics and cellular gene expression in uPA-SCID chimeric mice with humanized livers during intravenous silibinin monotherapy},
author = {DebRoy, Swati and Hiraga, Nobuhiko and Imamura, Michio and Hayes, C. Nelson and Akamatsu, Sakura and Canini, Laetitia and Perelson, Alan S. and Pohl, Ralf T. and Persiani, Stefano and Uprichard, Susan L. and Tateno, Chise and Dahari, Harel and Chayama, Kazuaki},
abstractNote = {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.},
doi = {10.1111/jvh.12551},
journal = {Journal of Viral Hepatitis},
number = 9,
volume = 23,
place = {United States},
year = {2016},
month = {6}
}
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