title: Celastrol inhibits dengue virus replication via up-regulating type I interferon and downstream interferon-stimulated responses.
abstract: Tripterygium wilfordii (lei gong teng; Thunder of God Vine), a member of the Celastraceae family, is a medicinal plant used to treat a range of illnesses. Celastrol is a quinone methide triterpene and the most abundant bioactive constituent isolated from the root extracts of T. wilfordii. Previous studies have shown that celastrol exhibits antiviral activity against HIV and SARS-CoV. To date, no investigations of the anti-DENV activity of celastrol have been reported. This work aimed to investigate the anti-DENV effect and possible mechanism of celastrol in vitro and in vivo.
  
  
  
  A four-serotype DENV infection system was performed to determine the anti-DENV effect of celastrol by detecting DENV RNA replication and protein synthesis. The precise anti-DENV replication mechanism of celastrol was clarified using specific RNA silencing and specific inhibitor. In addition, the therapeutic efficacy of celastrol was evaluated by monitoring survival rates and clinical scores in a DENV-infected Institute of Cancer Research (ICR) suckling mouse model.
  
  
  
  Celastrol inhibited DENV-1, -2, -3, and -4 RNA replication with EC50values of 0.19 ± 0.09, 0.12 ± 0.11, 0.16 ± 0.14, and 0.17 ± 0.08 μM, respectively. This antiviral effect of celastrol was associated with celastrol-induced interferon-α (IFN-α) expression and was attenuated by a specific inhibitor of the JAK-STAT signaling pathway downstream of IFN-α or specific shRNA. Furthermore, celastrol protected ICR suckling mice against life-threatening DENV infection.
  
  
  
  Celastrol represents a potential anti-DENV agent that induces IFN-α expression and stimulates a downstream antiviral response, making the therapy a promising drug or dietary supplement for the treatment of DENV-infected patients.
authors.affiliation: Department of Chinese Medicine, Chi Mei Medical Center, Tainan 71004, Taiwan; Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan.
authors.forename: Jung-Sheng
authors.initials: JS
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: Chin-Kai
authors.initials: CK
authors.lastname: Tseng
authors.affiliation: Doctoral Degree Program in Marine Biotechnology, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
authors.forename: Chun-Kuang
authors.initials: CK
authors.lastname: Lin
authors.affiliation: Department of Chinese Medicine, Chi Mei Medical Center, Tainan 71004, Taiwan.
authors.forename: Yao-Chin
authors.initials: YC
authors.lastname: Hsu
authors.affiliation: 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.
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Wu
authors.affiliation: Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan; Department of Chinese Medicine, China Medical University Hospital, Taichung 40447, Taiwan; Research Center for Chinese Medicine and Acupuncture, China Medical University, Taichung 40402, Taiwan. Electronic address: clhsieh@mail.cmuh.org.tw.
authors.forename: Ching-Liang
authors.initials: CL
authors.lastname: Hsieh
authors.affiliation: 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.
authors.forename: Jin-Ching
authors.initials: JC
authors.lastname: Lee
mesh_terms: D000818:Animals; D000833:Animals, Suckling; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D004261:DNA Replication / Q000187:drug effects; D003715:Dengue / Q000188:drug therapy / Q000821:virology; D003716:Dengue Virus / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D007370:Interferon Type I / Q000235:genetics*; D016898:Interferon-alpha / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D053978:Pentacyclic Triterpenes; D034622:RNA Interference; D016019:Survival Analysis; D015533:Transcriptional Activation / Q000187:drug effects; D014315:Triterpenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D015854:Up-Regulation; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D007370:Interferon Type I; D016898:Interferon-alpha; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; C050414:celastrol
keywords: Antiviral interferon response; Celastrol; Dengue virus