title: Fumigaclavine C inhibits tumor necrosis factor α production via suppression of toll-like receptor 4 and nuclear factor κB activation in macrophages.
abstract: OBJECTIVE
  Atherosclerosis is the main cause of cardiovascular disease and is widely treated with statins. However, there are a few cases of intolerable adverse reactions by statins; thus, there is still a need for new drugs to prevent atherosclerosis. The inflammation associated with the activation of Toll-like receptor 4 (TLR4) and nuclear factor κB (NFκB) has been shown to be an important factor in the development of atherosclerosis. In the current study, we investigated the anti-inflammatory action of the fungal alkaloid fumigaclavine C (FC), its effects on the TLR4 and NFκB signaling pathway, and its potential relevance as an anti-atherosclerotic agent.
  
  
  METHODS
  The inhibitory effects of FC on tumor necrosis factor α (TNFα) production were determined by enzyme-linked immunosorbent assays (ELISA). The mRNA and protein expression of TLR4 and p65NFκB were detected by quantitative real-time polymerase chain reaction and western blot analysis, respectively. The effect of FC on NFκB was determined using the Dual-Luciferase reporter assay.
  
  
  RESULTS
  FC reduced TNFα production in LPS-stimulated human whole blood and RAW 264.7 macrophages via reduced IκBα phosphorylation associated with the decreased expression of p65NFκB. FC also suppressed LPS-induced TLR4 overexpression at the mRNA and protein level.
  
  
  CONCLUSIONS
  FC attenuated TNFα via the TLR4-NFκB signaling transduction pathway, suggesting that this alkaloid might serve as a promising molecule for anti-inflammatory treatment of atherosclerosis.
authors.affiliation: School of Medicine, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
authors.forename: Rong Hui
authors.initials: RH
authors.lastname: Du
authors.forename: Er Guang
authors.initials: EG
authors.lastname: Li
authors.forename: Yin
authors.initials: Y
authors.lastname: Cao
authors.forename: Yong Chun
authors.initials: YC
authors.lastname: Song
authors.forename: Ren Xiang
authors.initials: RX
authors.lastname: Tan
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology; D004876:Ergot Alkaloids / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D026121:Indole Alkaloids / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004876:Ergot Alkaloids; D026121:Indole Alkaloids; D016328:NF-kappa B; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C492995:fumigaclavine C; D003474:Curcumin