title: Sulforaphane Suppresses Hepatitis C Virus Replication by Up-Regulating Heme Oxygenase-1 Expression through PI3K/Nrf2 Pathway.
abstract: Hepatitis C virus (HCV) infection-induced oxidative stress is a major risk factor for the development of HCV-associated liver disease. Sulforaphane (SFN) is an antioxidant phytocompound that acts against cellular oxidative stress and tumorigenesis. However, there is little known about its anti-viral activity. In this study, we demonstrated that SFN significantly suppressed HCV protein and RNA levels in HCV replicon cells and infectious system, with an IC50 value of 5.7 ± 0.2 μM. Moreover, combination of SFN with anti-viral drugs displayed synergistic effects in the suppression of HCV replication. In addition, we found nuclear factor erythroid 2-related factor 2 (Nrf2)/HO-1 induction in response to SFN and determined the signaling pathways involved in this process, including inhibition of NS3 protease activity and induction of IFN response. In contrast, the anti-viral activities were attenuated by knockdown of HO-1 with specific inhibitor (SnPP) and shRNA, suggesting that anti-HCV activity of SFN is dependent on HO-1 expression. Otherwise, SFN stimulated the phosphorylation of phosphoinositide 3-kinase (PI3K) leading Nrf2-mediated HO-1 expression against HCV replication. Overall, our results indicated that HO-1 is essential in SFN-mediated anti-HCV activity and provide new insights in the molecular mechanism of SFN in HCV replication.
authors.affiliation: Department of Chinese Medicine, Chi Mei Medical Center, Tainan, 71004, Taiwan.|Graduate Institute of Integrated Medicine, China Medical University, Taichung, 40402, Taiwan.
authors.forename: Jung-Sheng
authors.initials: JS
authors.lastname: Yu
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: Chen
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: Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|School of Medicine, Graduate Institute of Medicine, Sepsis Research Center, Center for Dengue Fever Control and Research, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, HsinChu, Taiwan.|Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yen-Hsu
authors.initials: YH
authors.lastname: Chen
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.
authors.forename: Jin-Ching
authors.initials: JC
authors.lastname: Lee
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D001663:Bilirubin / Q000096:biosynthesis; D001664:Biliverdine / Q000096:biosynthesis; D045744:Cell Line, Tumor; D004357:Drug Synergism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007372:Interferons / Q000494:pharmacology; D017879:Isothiocyanates / Q000494:pharmacology*; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D012367:RNA, Viral / Q000378:metabolism; D012093:Replicon / Q000187:drug effects; D013454:Sulfoxides; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D001663:Bilirubin; D001664:Biliverdine; D051547:Heme Oxygenase-1; D007372:Interferons; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; D019869:Phosphatidylinositol 3-Kinases; D012367:RNA, Viral; D013454:Sulfoxides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C016766:sulforaphane