Identification of plumericin as a potent new inhibitor of the NF-κB pathway with anti-inflammatory activity in vitro and in vivo

Autor:	Fakhrudin, N, Waltenberger, B, Cabaravdic, M, Atanasov, A G, Malainer, C, Schachner, D, Heiss, E H, Liu, R, Noha, S M, Grzywacz, A M, Mihaly-Bison, J, Awad, E M, Schuster, D, Breuss, J M, Rollinger, J M, Bochkov, V, Stuppner, H, Dirsch, V M
Jazyk:	angličtina
Rok vydání:	2014
Předmět:	Male natural products Anti-Inflammatory Agents Transfection IκB NF-κB Mice Human Umbilical Vein Endothelial Cells Animals Humans adhesion molecules Iridoids Phosphorylation peritonitis Inflammation Dose-Response Relationship Drug Plant Extracts NF-kappa B I-kappa B Kinase Apocynaceae Mice Inbred C57BL Disease Models Animal HEK293 Cells IKK-β Indenes plumericin Thioglycolates I-kappa B Proteins Inflammation Mediators Cell Adhesion Molecules Research Paper Signal Transduction
Zdroj:	British Journal of Pharmacology
ISSN:	1476-5381 0007-1188
Popis:	BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH 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. KEY 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. CONCLUSION AND IMPLICATIONS 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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=pmid________::bf98ef6c491e6102e75d7de6b19eb690 http://europepmc.org/articles/PMC3966748 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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