2. Academic Validation
  3. Celastrol inhibits hepatitis C virus replication by upregulating heme oxygenase-1 via the JNK MAPK/Nrf2 pathway in human hepatoma cells

Celastrol inhibits hepatitis C virus replication by upregulating heme oxygenase-1 via the JNK MAPK/Nrf2 pathway in human hepatoma cells

  • Antiviral Res. 2017 Oct;146:191-200. doi: 10.1016/j.antiviral.2017.09.010.
Chin-Kai Tseng 1,  Sung-Po Hsu 2,  Chun-Kuang Lin 3,  Yu-Hsuan Wu 1,  Jin-Ching Lee 4,  Kung-Chia Young 5
Affiliations

Affiliations

  • 1 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 2 Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 3 Doctoral Degree Program in Marine Biotechnology, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
  • 4 Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; Research Center for Natural Products and Drug Development, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: jclee@kmu.edu.tw.
  • 5 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address: t7908077@mail.ncku.edu.tw.
PMID: 28935193 DOI: 10.1016/j.antiviral.2017.09.010
Abstract

Background and purpose: Celastrol, a quinone methide triterpene isolated from the root extracts of Tripterygium wilfordii, can greatly induce the gene expression activity of heme oxygenase-1 (HO-1) to achieve disease prevention and control. HO-1 induction was recently shown to result in anti-HCV activity by inducing type I interferon and inhibiting hepatitis C virus (HCV) NS3/4A protease activity. The aim of the present study is to evaluate the anti-HCV activity of celastrol and characterize its mechanism of inhibition.

Methods: The anti-HCV activity of celastrol was evaluated using the HCV subgenomic replicon and HCVcc Infection systems. The anti-HCV mechanism of celastrol targeting HO-1 expression was clarified using specific inhibitors against several signaling pathways. The transcriptional regulation of celastrol on target gene expression was determined using promoter-based reporter activity assay. The synergistic effect of celastrol and a numbers of clinically used anti-HCV drugs was determined via a drug combination assay.

Results: Celastrol inhibited HCV replication in both the HCV subgenomic and HCVcc Infection systems with EC50 values of 0.37 ± 0.022 and 0.43 ± 0.019 μM, respectively. Celastrol-induced heme oxygenase 1 (HO-1) expression promoted Antiviral interferon responses and inhibition of NS3/4A protease activity, thereby blocking HCV replication. These Antiviral effects were abrogated by treatment with the HO-1-specific inhibitor SnMP or silencing of HO-1 expression by transfection of shRNA, which indicates that HO-1 induction contributes to the anti-HCV activity of celastrol. JNK mitogen-activated protein kinase and nuclear factor erythroid 2-related factor 2 (Nrf2) were confirmed to be involved in the inductive effect of celastrol on HO-1 expression. Celastrol exhibited synergistic effects in combination with interferon-alpha, the NS5A inhibitor daclatasvir, and the NS5B inhibitor sofosbuvir.

Conclusion: Celastrol can serve as a potential supplement for blocking HCV replication. Targeting the JNK/Nrf2/HO-1 axis presents a promising strategy against HCV Infection.

Keywords

Celastrol; HCV; Heme oxygenase 1; JNK mitogen-activated protein kinase.

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