skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

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

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. 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 =more » 0.01) 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:
Research Org.:
Los Alamos National Lab. (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
Resource Type:
Journal Article: 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. 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, 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. doi: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 = {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) 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.},
doi = {10.1111/jvh.12551},
journal = {Journal of Viral Hepatitis},
issn = {1352-0504},
number = 9,
volume = 23,
place = {United States},
year = {2016},
month = {6}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 1 work
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

Successful prevention of hepatitis C virus (HCV) liver graft reinfection by silibinin mono-therapy
journal, June 2010


Identification of transferrin receptor 1 as a hepatitis C virus entry factor
journal, June 2013

  • Martin, D. N.; Uprichard, S. L.
  • Proceedings of the National Academy of Sciences, Vol. 110, Issue 26
  • DOI: 10.1073/pnas.1301764110

Serum amyloid A has antiviral activity against hepatitis C virus by inhibiting virus entry in a cell culture system
journal, December 2006

  • Lavie, Muriel; Voisset, Cécile; Vu-Dac, Ngoc
  • Hepatology, Vol. 44, Issue 6
  • DOI: 10.1002/hep.21406

Intravenous silibinin monotherapy shows significant antiviral activity in HCV-infected patients in the peri-transplantation period
journal, March 2013


Silibinin Is a Potent Antiviral Agent in Patients With Chronic Hepatitis C Not Responding to Pegylated Interferon/Ribavirin Therapy
journal, November 2008


Progression of fibrosis in chronic hepatitis C
journal, January 2003

  • Ghany, Marc G.; Kleiner, David E.; Alter, Harvey
  • Gastroenterology, Vol. 124, Issue 1
  • DOI: 10.1053/gast.2003.50018

Silymarin Inhibits In Vitro T-Cell Proliferation and Cytokine Production in Hepatitis C Virus Infection
journal, February 2010


Silibinin modulates lipid homeostasis and inhibits nuclear factor kappa B activation in experimental nonalcoholic steatohepatitis
journal, June 2012

  • Salamone, Federico; Galvano, Fabio; Cappello, Francesco
  • Translational Research, Vol. 159, Issue 6
  • DOI: 10.1016/j.trsl.2011.12.003

Anti-Cancer Efficacy of Silybin Derivatives - A Structure-Activity Relationship
journal, March 2013


Human Serum Amyloid A Protein Inhibits Hepatitis C Virus Entry into Cells
journal, February 2007


Hepatoprotective and antiviral functions of silymarin components in hepatitis C virus infection
journal, February 2013

  • Polyak, Stephen J.; Ferenci, Peter; Pawlotsky, Jean-Michel
  • Hepatology, Vol. 57, Issue 3
  • DOI: 10.1002/hep.26179

Near Completely Humanized Liver in Mice Shows Human-Type Metabolic Responses to Drugs
journal, September 2004


Antiviral activity and safety profile of silibinin in HCV patients with advanced fibrosis after liver transplantation: a randomized clinical trial
journal, May 2014

  • Rendina, Maria; D'Amato, Massimo; Castellaneta, Antonino
  • Transplant International, Vol. 27, Issue 7
  • DOI: 10.1111/tri.12324

Practical evaluation of a mouse with chimeric human liver model for hepatitis C virus infection using an NS3-4A protease inhibitor
journal, February 2010


The iron regulatory hormone hepcidin inhibits expression of iron release as well as iron uptake proteins in J774 cells
journal, December 2012


Therapeutic Efficacy of Silibinin on Human Neuroblastoma Cells: Akt and NF-κB Expressions May Play an Important Role in Silibinin-Induced Response
journal, June 2012

  • Yousefi, Meysam; Ghaffari, Seyed H.; Soltani, Bahram M.
  • Neurochemical Research, Vol. 37, Issue 9
  • DOI: 10.1007/s11064-012-0827-9

Legalon® SIL: The Antidote of Choice in Patients with Acute Hepatotoxicity from Amatoxin Poisoning
journal, July 2012

  • Mengs, Ulrich; Torsten Pohl, Ralf -; Mitchell, Todd
  • Current Pharmaceutical Biotechnology, Vol. 13, Issue 10
  • DOI: 10.2174/138920112802273353

Rescue therapy with intravenous silibinin in liver transplant recipients with recurrent HCV hepatitis – two case reports
journal, January 2014


Infection of human hepatocyte chimeric mouse with genetically engineered hepatitis B virus
journal, November 2005

  • Tsuge, Masataka; Hiraga, Nobuhiko; Takaishi, Hideki
  • Hepatology, Vol. 42, Issue 5
  • DOI: 10.1002/hep.20892

Inhibition of T-Cell Inflammatory Cytokines, Hepatocyte NF-κB Signaling, and HCV Infection by Standardized Silymarin
journal, May 2007


Multiple effects of silymarin on the hepatitis C virus lifecycle
journal, February 2010

  • Wagoner, Jessica; Negash, Amina; Kane, Olivia J.
  • Hepatology, Vol. 51, Issue 6
  • DOI: 10.1002/hep.23587

Hepcidin directly inhibits transferrin receptor 1 expression in astrocytes via a cyclic AMP-protein kinase a pathway
journal, March 2011

  • Du, Fang; Qian, Christopher; Ming Qian, Zhong
  • Glia, Vol. 59, Issue 6
  • DOI: 10.1002/glia.21166

Hepatitis C Viral Dynamics in Vivo and the Antiviral Efficacy of Interferon- Therapy
journal, October 1998


The Impact of Infection on Population Health: Results of the Ontario Burden of Infectious Diseases Study
journal, September 2012


Intravenous silibinin as ‘rescue treatment’ for on-treatment non-responders to pegylated interferon/ribavirin combination therapy
journal, January 2011

  • Rutter, Karoline; Scherzer, Thomas-Matthias; Beinhardt, Sandra
  • Antiviral Therapy, Vol. 16, Issue 8
  • DOI: 10.3851/IMP1942

Silibinin and Related Compounds Are Direct Inhibitors of Hepatitis C Virus RNA-Dependent RNA Polymerase
journal, March 2010


Sofosbuvir and Ribavirin for Hepatitis C in Patients With HIV Coinfection
journal, July 2014


Osteopontin is up-regulated in chronic hepatitis C and is associated with cellular permissiveness for hepatitis C virus replication
journal, February 2014

  • Choi, Steve S.; Claridge, Lee C.; Jhaveri, Ravi
  • Clinical Science, Vol. 126, Issue 12
  • DOI: 10.1042/CS20130473

Silymarin Suppresses Cellular Inflammation By Inducing Reparative Stress Signaling
journal, July 2015


Inhibition of HIV by Legalon-SIL is independent of its effect on cellular metabolism
journal, January 2014


Elimination of hepatitis C virus by short term NS3-4A and NS5B inhibitor combination therapy in human hepatocyte chimeric mice
journal, May 2011


Severity of liver disease affects HCV kinetics in patients treated with intravenous silibinin monotherapy
journal, January 2014

  • Canini, Laetitia; DebRoy, Swati; Mariño, Zoe
  • Antiviral Therapy, Vol. 20, Issue 2
  • DOI: 10.3851/IMP2806

Sustained virological response with intravenous silibinin: individualized IFN-free therapy via real-time modelling of HCV kinetics
journal, October 2014

  • Dahari, Harel; Shteingart, Shimon; Gafanovich, Inna
  • Liver International, Vol. 35, Issue 2
  • DOI: 10.1111/liv.12692

Suppression of Dual Specificity Phosphatase I Expression Inhibits Hepatitis C Virus Replication
journal, March 2015


Understanding silibinin’s modes of action against HCV using viral kinetic modeling
journal, May 2012


Analysis of hepatitis C virus resistance to silibinin in vitro and in vivo points to a novel mechanism involving nonstructural protein 4B
journal, February 2013

  • Esser-Nobis, Katharina; Romero-Brey, Inés; Ganten, Tom M.
  • Hepatology, Vol. 57, Issue 3
  • DOI: 10.1002/hep.26260

Modeling Subgenomic Hepatitis C Virus RNA Kinetics during Treatment with Alpha Interferon
journal, April 2009

  • Dahari, H.; Sainz, B.; Perelson, A. S.
  • Journal of Virology, Vol. 83, Issue 13
  • DOI: 10.1128/JVI.02612-08

Structural proteins of Hepatitis C virus induce interleukin 8 production and apoptosis in human endothelial cells
journal, December 2005


    Works referencing / citing this record:

    Lignans and Their Derivatives from Plants as Antivirals
    journal, January 2020