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. 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.
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.
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DebRoy
Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
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Hiraga
Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
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Imamura
Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
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Hayes
Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
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Akamatsu
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.
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Canini
Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA.
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Perelson
German Association of Phytotherapy, Speyer, Germany.
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Pohl
Rottapharm Biotech SRL, Monza (MB), Italy.
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Persiani
The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA.
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Uprichard
PhoenixBio Co. Ltd., Higashi-Hiroshima, Japan.
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Tateno
The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA.
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Dahari
Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
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Chayama
D061605:Administration, Intravenous; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D016174:Hepacivirus / Q000302:isolation & purification; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D008099:Liver / Q000473:pathology* / Q000821:virology*; D016513:Mice, SCID; D046228:Microarray Analysis; D008962:Models, Theoretical; D012367:RNA, Viral / Q000032:analysis; D017422:Sequence Analysis, DNA; D012709:Serum Albumin / Q000032:analysis; D000077385:Silybin; D012838:Silymarin / Q000008:administration & dosage / Q000494:pharmacology*; D016896:Treatment Outcome; D019562:Viral Load
D000998:Antiviral Agents; D012367:RNA, Viral; D012709:Serum Albumin; D012838:Silymarin; D000077385:Silybin
anti-inflammatory; chimeric mice with humanized livers; gene expression; uPA-SCID; viral kinetic modelling