Document Detail


ME3738 enhances the effect of interferon and inhibits hepatitis C virus replication both in vitro and in vivo.
MedLine Citation:
PMID:  21145867     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND & AIMS: ME3738 (22β-methoxyolean-12-ene-3β, 24-diol), a derivative of soyasapogenol B, attenuates liver disease in several animal models of acute and chronic liver injury. ME3738 is thought to inhibit replication of hepatitis C virus (HCV) by enhancing interferon (IFN)-β production, as determined using the HCV full-length binary expression system. We examined the effect of ME3738 combined with IFN-α on HCV replication using the genotype 1b subgenomic replicon system and an in vivo mouse HCV model.
METHODS: HCV replicon cells (ORN/3-5B/KE cells and Con1 cells) were incubated with ME3738 and/or IFN-α, and then intracellular IFN-stimulated genes (ISGs) and HCV RNA replication were analyzed by reverse-transcription-real time polymerase chain reaction and luciferase reporter assay. HCV-infected human hepatocyte chimeric mice were also treated with ME3738 and/or IFN-α for 4 weeks. Mouse serum HCV RNA titer, HCV core antigen, and ISGs expression in the liver were measured.
RESULTS: ME3738 induced gene expression of oligoadenylate synthetase 1 and inhibited HCV replication in both HCV replicon cells. The drug enhanced the effect of IFN to significantly increase ISG expression levels, inhibit HCV replication in replicon cells, and reduce mouse serum HCV RNA and core antigen levels in mouse livers. The combination treatment was not hepatotoxic as evident histologically and did not reduce human serum albumin in mice.
CONCLUSIONS: ME3738 inhibited HCV replication, enhancing the effect of IFN-α to increase ISG expression both in vitro and in vivo, suggesting that the combination of ME3738 and IFN might be useful therapeutically for patients with chronic hepatitis C.
Authors:
Hiromi Abe; Michio Imamura; Nobuhiko Hiraga; Masataka Tsuge; Fukiko Mitsui; Tomokazu Kawaoka; Shoichi Takahashi; Hidenori Ochi; Toshiro Maekawa; C Nelson Hayes; Chise Tateno; Katsutoshi Yoshizato; Shoichi Murakami; Nobuyuki Yamashita; Takashi Matsuhira; Kenji Asai; Kazuaki Chayama
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-11-29
Journal Detail:
Title:  Journal of hepatology     Volume:  55     ISSN:  1600-0641     ISO Abbreviation:  J. Hepatol.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-06-17     Completed Date:  2011-11-08     Revised Date:  2012-08-24    
Medline Journal Info:
Nlm Unique ID:  8503886     Medline TA:  J Hepatol     Country:  England    
Other Details:
Languages:  eng     Pagination:  11-8     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Affiliation:
Department of Medicine and Molecular Science, Hiroshima University, Hiroshima-shi 734-8551, Japan.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antiviral Agents / administration & dosage*
Base Sequence
Cell Line
Disease Models, Animal
Drug Synergism
Hepacivirus / drug effects*,  genetics,  physiology
Hepatitis C, Chronic / drug therapy*,  virology
Hepatocytes / drug effects,  transplantation,  virology
Humans
Interferon Type I / administration & dosage*
Mice
Mice, SCID
Oleanolic Acid / administration & dosage,  analogs & derivatives*
RNA, Viral / genetics
Recombinant Proteins
Replicon / drug effects
Transplantation Chimera
Virus Replication / drug effects*
Chemical
Reg. No./Substance:
0/Antiviral Agents; 0/Interferon Type I; 0/ME3738; 0/RNA, Viral; 0/Recombinant Proteins; 508-02-1/Oleanolic Acid

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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