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

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          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.

          Graphical abstract

          Highlights

          • •

            Celastrol inhibits HCV replication.

          • •

            Celastrol induces HO-1 production.

          • •

            Celastrol induces interferon-α production and inhibits HCV NS3/4A protease.

          • •

            Celastrol synergistically inhibits HCV replication in combination with IFN-α, sofosbuvir or daclatasvir.

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          Most cited references38

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          Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors.

          P Talalay, T C Chou (1984)
          A generalized method for analyzing the effects of multiple drugs and for determining summation, synergism and antagonism has been proposed. The derived, generalized equations are based on kinetic principles. The method is relatively simple and is not limited by whether the dose-effect relationships are hyperbolic or sigmoidal, whether the effects of the drugs are mutually exclusive or nonexclusive, whether the ligand interactions are competitive, noncompetitive or uncompetitive, whether the drugs are agonists or antagonists, or the number of drugs involved. The equations for the two most widely used methods for analyzing synergism, antagonism and summation of effects of multiple drugs, the isobologram and fractional product concepts, have been derived and been shown to have limitations in their applications. These two methods cannot be used indiscriminately. The equations underlying these two methods can be derived from a more generalized equation previously developed by us (59). It can be shown that the isobologram is valid only for drugs whose effects are mutually exclusive, whereas the fractional product method is valid only for mutually nonexclusive drugs which have hyperbolic dose-effect curves. Furthermore, in the isobol method, it is laborious to find proper combinations of drugs that would produce an iso-effective curve, and the fractional product method tends to give indication of synergism, since it underestimates the summation of the effect of mutually nonexclusive drugs that have sigmoidal dose-effect curves. The method described herein is devoid of these deficiencies and limitations. The simplified experimental design proposed for multiple drug-effect analysis has the following advantages: It provides a simple diagnostic plot (i.e., the median-effect plot) for evaluating the applicability of the data, and provides parameters that can be directly used to obtain a general equation for the dose-effect relation; the analysis which involves logarithmic conversion and linear regression can be readily carried out with a simple programmable electronic calculator and does not require special graph paper or tables; and the simplicity of the equation allows flexibility of application and the use of a minimum number of data points. This method has been used to analyze experimental data obtained from enzymatic, cellular and animal systems.
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            Epidemiology of hepatitis C virus infection.

            Miriam J Alter (2007)
            Globally, hepatitis C virus (HCV) has infected an estimated 130 million people, most of whom are chronically infected. HCV-infected people serve as a reservoir for transmission to others and are at risk for developing chronic liver disease, cirrhosis, and primary hepatocellular carcinoma (HCC). It has been estimated that HCV accounts for 27% of cirrhosis and 25% of HCC worldwide. HCV infection has likely been endemic in many populations for centuries. However, the wave of increased HCV-related morbidity and mortality that we are now facing is the result of an unprecedented increase in the spread of HCV during the 20th century. Two 20th century events appear to be responsible for this increase; the widespread availability of injectable therapies and the illicit use of injectable drugs.
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              Signaling to heme oxygenase-1 and its anti-inflammatory therapeutic potential.

              Ananta Paine, Britta Eiz-Vesper, Rainer Blasczyk … (2010)
              Heme oxygenase (HO)-1 is the inducible isoform of the first and rate-limiting enzyme of heme degradation. Induction of HO-1 protects against the cytotoxicity of oxidative stress and apoptotic cell death. More recently, HO-1 has been recognized to have major immunomodulatory and anti-inflammatory properties, which have been demonstrated in HO-1 knockout mice and a human case of genetic HO-1 deficiency. Beneficial protective effects of HO-1 in inflammation are not only mediated via enzymatic degradation of proinflammatory free heme, but also via production of the anti-inflammatory compounds bilirubin and carbon monoxide. The immunomodulatory role of HO-1 is associated with its cell type-specific functions in myeloid cells (eg. macrophages and monocytes) and in endothelial cells, as both cell types are crucially involved in the regulation of inflammatory responses. This review covers the molecular mechanisms and signaling pathways that are involved in HO-1 gene expression. In particular, it is discussed how redox-dependent transcriptional activators such as NF-E2 related factor 2 (Nrf2), NF-κB and AP-1 along with the transcription repressor BTB and CNC homologue 1 (Bach1) control the inducible HO-1 gene expression. The role of central pro- and anti-inflammatory cellular signaling cascades including p38 MAPK and phosphatidylinositol-3 kinase (PI3K)/Akt in HO-1 regulation is highlighted. Finally, emerging strategies that apply targeted pharmacological induction of HO-1 for therapeutic interventions in inflammatory conditions are summarized. Copyright © 2010 Elsevier Inc. All rights reserved.
              Article 0 comments Cited 218 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Jin-Ching Lee
                Kung-Chia Young
                Journal
                Journal ID (nlm-ta): Antiviral Res
                Journal ID (iso-abbrev): Antiviral Res
                Title: Antiviral Research
                Publisher: Elsevier B.V.
                ISSN (Print): 0166-3542
                ISSN (Electronic): 1872-9096
                Publication date PMC-release: 19 September 2017
                Publication date (Print): October 2017
                Publication date (Electronic): 19 September 2017
                Volume: 146
                Pages: 191-200
                Affiliations
                [a ]Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
                [b ]Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan
                [c ]Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
                [d ]Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
                [e ]Doctoral Degree Program in Marine Biotechnology, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
                [f ]Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
                [g ]Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
                [h ]Research Center for Natural Products and Drug Development, Kaohsiung Medical University, Kaohsiung, Taiwan
                [i ]Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
                Author notes
                [∗ ]Corresponding author. Department of Biotechnology, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, San Ming District, 807, Kaohsiung City, Taiwan. jclee@ 123456kmu.edu.tw
                [∗∗ ]Corresponding author. No. 1, University Rd., Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan. t7908077@ 123456mail.ncku.edu.tw
                Article
                Publisher ID: S0166-3542(17)30417-5
                DOI: 10.1016/j.antiviral.2017.09.010
                PMC ID: 7113881
                PubMed ID: 28935193
                SO-VID: eb322ce3-1af9-4fbe-9152-cae25cb3fe03
                Copyright © © 2017 Elsevier B.V. All rights reserved.
                License:

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                Date received : 2 June 2017
                Date revision received : 13 August 2017
                Date accepted : 18 September 2017
                Categories
                Subject: Article

                ScienceOpen disciplines: Infectious disease & Microbiology
                Keywords: hcv,celastrol,heme oxygenase 1,jnk mitogen-activated protein kinase
                Data availability:
                ScienceOpen disciplines: Infectious disease & Microbiology
                Keywords: hcv, celastrol, heme oxygenase 1, jnk mitogen-activated protein kinase

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