Andrographolide exerts anti-hepatitis C virus activity by up-regulating haeme oxygenase-1 via the p38 MAPK/Nrf2 pathway in human hepatoma cells

Authors

  • Jin-Ching Lee,

    Corresponding author
    1. Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
    2. Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
    • Correspondence

      Jin-Ching Lee, Department of Biotechnology, College of Life Science, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, San Ming District, 807 Kaohsiung City, Taiwan. E-mail: jclee@kmu.edu.tw

    Search for more papers by this author
  • Chin-Kai Tseng,

    1. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    2. Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    Search for more papers by this author
  • Kung-Chia Young,

    1. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    2. Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    3. Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    Search for more papers by this author
  • Hung-Yu Sun,

    1. Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    Search for more papers by this author
  • Shainn-Wei Wang,

    1. Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    Search for more papers by this author
  • Wei-Chun Chen,

    1. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
    Search for more papers by this author
  • Chun-Kuang Lin,

    1. Doctoral Degree Program in Marine Biotechnology, National Sun Yat-Sen University, Kaohsiung, Taiwan
    Search for more papers by this author
  • Yu-Hsuan Wu

    1. Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
    Search for more papers by this author

Abstract

Background and Purpose

This study aimed to evaluate the anti-hepatitis C virus (HCV) activity of andrographolide, a diterpenoid lactone extracted from Andrographis paniculata, and to identify the signalling pathway involved in its antiviral action.

Experimental Approach

Using HCV replicon and HCVcc infectious systems, we identified anti-HCV activity of andrographolide by measuring protein and RNA levels. A reporter activity assay was used to determine transcriptional regulation of anti-HCV agents. A specific inhibitor and short hairpin RNAs were used to investigate the mechanism responsible for the effect of andrographolide on HCV replication.

Key Results

In HCV replicon and HCVcc infectious systems, andrographolide time- and dose-dependently suppressed HCV replication. When combined with IFN-α, an inhibitor targeting HCV NS3/4A protease (telaprevir), or NS5B polymerase (PSI-7977), andrographolide exhibited a significant synergistic effect. Andrographolide up-regulated the expression of haeme oxygenase-1 (HO-1), leading to increased amounts of its metabolite biliverdin, which was found to suppress HCV replication by promoting the antiviral IFN responses and inhibiting NS3/4A protease activity. Significantly, these antiviral effects were attenuated by an HO-1-specific inhibitor or HO-1 gene knockdown, indicating that HO-1 contributed to the anti-HCV activity of andrographolide. Andrographolide activated p38 MAPK phosphorylation, which stimulated nuclear factor erythroid 2-related factor 2 (Nrf2)–mediated HO-1 expression, and this was found to be associated with its anti-HCV activity.

Conclusions and Implications

Our results demonstrate that andrographolide has the potential to control HCV replication and suggest that targeting the Nrf2–HO-1 signalling pathway might be a promising strategy for drug development.

Ancillary