title: Andrographolide exerts anti-hepatitis C virus activity by up-regulating haeme oxygenase-1 via the p38 MAPK/Nrf2 pathway in human hepatoma cells.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
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.
authors.forename: Jin-Ching
authors.initials: JC
authors.lastname: Lee
authors.forename: Chin-Kai
authors.initials: CK
authors.lastname: Tseng
authors.forename: Kung-Chia
authors.initials: KC
authors.lastname: Young
authors.forename: Hung-Yu
authors.initials: HY
authors.lastname: Sun
authors.forename: Shainn-Wei
authors.initials: SW
authors.lastname: Wang
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: Chen
authors.forename: Chun-Kuang
authors.initials: CK
authors.lastname: Lin
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Wu
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001664:Biliverdine / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000821:virology; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004789:Enzyme Activation; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D006790:Host-Parasite Interactions; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000821:virology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010766:Phosphorylation; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects*; D000069474:Sofosbuvir; D013997:Time Factors; D014162:Transfection; D014542:Uridine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D001664:Biliverdine; D004224:Diterpenes; D051547:Heme Oxygenase-1; D051267:NF-E2-Related Factor 2; D009842:Oligopeptides; D000069474:Sofosbuvir; D014542:Uridine Monophosphate; D017361:Viral Nonstructural Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C495635:NFE2L2 protein, human; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C080107:NS4B protein, flavivirus; C030419:andrographolide; C486464:telaprevir; C496541:HMOX1 protein, human
keywords: HCV; andrographolide; heme oxygenase-1; nuclear factor erythroid 2-related factor 2; p38 MAPK