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Hepatitis C virus dynamics and cellular gene expression in uPA-SCID chimeric mice with humanized livers during intravenous silibinin monotherapy.
J Viral Hepat. 2016 09; 23(9):708-17.JV

Abstract

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.

Authors+Show Affiliations

The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA. Department of Mathematics and Computational Science, University of South Carolina-Beaufort, Bluffton, SC, USA.Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA. Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, UK.Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA.German Association of Phytotherapy, Speyer, Germany.Rottapharm Biotech SRL, Monza (MB), Italy.The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA.PhoenixBio Co. Ltd., Higashi-Hiroshima, Japan.The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA.Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27272497

Citation

DebRoy, S, et al. "Hepatitis C Virus Dynamics and Cellular Gene Expression in uPA-SCID Chimeric Mice With Humanized Livers During Intravenous Silibinin Monotherapy." Journal of Viral Hepatitis, vol. 23, no. 9, 2016, pp. 708-17.
DebRoy S, Hiraga N, Imamura M, et al. Hepatitis C virus dynamics and cellular gene expression in uPA-SCID chimeric mice with humanized livers during intravenous silibinin monotherapy. J Viral Hepat. 2016;23(9):708-17.
DebRoy, S., Hiraga, N., Imamura, M., Hayes, C. N., Akamatsu, S., Canini, L., Perelson, A. S., Pohl, R. T., Persiani, S., Uprichard, S. L., Tateno, C., Dahari, H., & Chayama, K. (2016). Hepatitis C virus dynamics and cellular gene expression in uPA-SCID chimeric mice with humanized livers during intravenous silibinin monotherapy. Journal of Viral Hepatitis, 23(9), 708-17. https://doi.org/10.1111/jvh.12551
DebRoy S, et al. Hepatitis C Virus Dynamics and Cellular Gene Expression in uPA-SCID Chimeric Mice With Humanized Livers During Intravenous Silibinin Monotherapy. J Viral Hepat. 2016;23(9):708-17. PubMed PMID: 27272497.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hepatitis C virus dynamics and cellular gene expression in uPA-SCID chimeric mice with humanized livers during intravenous silibinin monotherapy. AU - DebRoy,S, AU - Hiraga,N, AU - Imamura,M, AU - Hayes,C N, AU - Akamatsu,S, AU - Canini,L, AU - Perelson,A S, AU - Pohl,R T, AU - Persiani,S, AU - Uprichard,S L, AU - Tateno,C, AU - Dahari,H, AU - Chayama,K, Y1 - 2016/06/08/ PY - 2015/12/16/received PY - 2016/04/04/accepted PY - 2016/6/9/entrez PY - 2016/6/9/pubmed PY - 2017/11/4/medline KW - anti-inflammatory KW - chimeric mice with humanized livers KW - gene expression KW - uPA-SCID KW - viral kinetic modelling SP - 708 EP - 17 JF - Journal of viral hepatitis JO - J. Viral Hepat. VL - 23 IS - 9 N2 - 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. SN - 1365-2893 UR - https://www.unboundmedicine.com/medline/citation/27272497/Hepatitis_C_virus_dynamics_and_cellular_gene_expression_in_uPA_SCID_chimeric_mice_with_humanized_livers_during_intravenous_silibinin_monotherapy_ L2 - https://doi.org/10.1111/jvh.12551 DB - PRIME DP - Unbound Medicine ER -