title: Identification of plumericin as a potent new inhibitor of the NF-κB pathway with anti-inflammatory activity in vitro and in vivo.
abstract: OBJECTIVE
  The transcription factor NF-κB orchestrates many pro-inflammatory signals and its inhibition is considered a promising strategy to combat inflammation. Here we report the characterization of the natural product plumericin as a highly potent inhibitor of the NF-κB pathway with a novel chemical scaffold, which was isolated via a bioactivity-guided approach, from extracts of Himatanthus sucuuba, an Amazonian plant traditionally used to treat inflammation-related disorders.
  
  
  METHODS
  A NF-κB luciferase reporter gene assay was used to identify NF-κB pathway inhibitors from H. sucuuba extracts. Monitoring of TNF-α-induced expression of the adhesion molecules VCAM-1, ICAM-1 and E-selectin by flow cytometry was used to confirm NF-κB inhibition in endothelial cells, and thioglycollate-induced peritonitis in mice to confirm effects in vivo. Western blotting and transfection experiments were used to investigate the mechanism of action of plumericin.
  
  
  RESULTS
  Plumericin inhibited NF-κB-mediated transactivation of a luciferase reporter gene (IC50 1 μM), abolished TNF-α-induced expression of the adhesion molecules VCAM-1, ICAM-1 and E-selectin in endothelial cells and suppressed thioglycollate-induced peritonitis in mice. Plumericin exerted its NF-κB pathway inhibitory effect by blocking IκB phosphorylation and degradation. Plumericin also inhibited NF-κB activation induced by transfection with the constitutively active catalytic subunit of the IκB kinase (IKK-β), suggesting IKK involvement in the inhibitory action of this natural product.
  
  
  CONCLUSIONS
  Plumericin is a potent inhibitor of NF-κB pathways with a new chemical scaffold. It could be further explored as a novel anti-inflammatory lead compound.
authors: Department of Pharmacognosy, University of Vienna, Vienna, Austria; Department of Pharmaceutical Biology, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia.
authors: N
authors: N
authors: Fakhrudin
authors: B
authors: B
authors: Waltenberger
authors: M
authors: M
authors: Cabaravdic
authors: A G
authors: AG
authors: Atanasov
authors: C
authors: C
authors: Malainer
authors: D
authors: D
authors: Schachner
authors: E H
authors: EH
authors: Heiss
authors: R
authors: R
authors: Liu
authors: S M
authors: SM
authors: Noha
authors: A M
authors: AM
authors: Grzywacz
authors: J
authors: J
authors: Mihaly-Bison
authors: E M
authors: EM
authors: Awad
authors: D
authors: D
authors: Schuster
authors: J M
authors: JM
authors: Breuss
authors: J M
authors: JM
authors: Rollinger
authors: V
authors: V
authors: Bochkov
authors: H
authors: H
authors: Stuppner
authors: V M
authors: VM
authors: Dirsch
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D029062:Apocynaceae; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007192:Indenes / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D039823:Iridoids / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D010936:Plant Extracts / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013864:Thioglycolates; D014162:Transfection
chemical_list: D000893:Anti-Inflammatory Agents; D015815:Cell Adhesion Molecules; D020672:I-kappa B Proteins; D007192:Indenes; D018836:Inflammation Mediators; D039823:Iridoids; D016328:NF-kappa B; D010936:Plant Extracts; D013864:Thioglycolates; D051550:I-kappa B Kinase; C068511:plumericin
keywords: IKK-β; IκB; NF-κB; adhesion molecules; inflammation; natural products; peritonitis; plumericin