title: Yangonin blocks tumor necrosis factor-α-induced nuclear factor-κB-dependent transcription by inhibiting the transactivation potential of the RelA/p65 subunit.
abstract: The nuclear factor-κB (NF-κB) transcription factors control many physiological processes including inflammation, immunity, and apoptosis. In our search for NF-κB inhibitors from natural resources, we identified yangonin from Piper methysticum as an inhibitor of NF-κB activation. In the present study, we demonstrate that yangonin potently inhibits NF-κB activation through suppression of the transcriptional activity of the RelA/p65 subunit of NF-κB. This compound significantly inhibited the induced expression of the NF-κB-reporter gene. However, this compound did not interfere with tumor necrosis factor-α (TNF-α)-induced inhibitor of κBα (IκBα) degradation, p65 nuclear translocation, and DNA-binding activity of NF-κB. Further analysis revealed that yangonin inhibited not only the induced NF-κB activation by overexpression of RelA/p65, but also transactivation activity of RelA/p65. Moreover, yangonin did not inhibit TNF-α-induced activation of p38, but it significantly impaired activation of extracellular signal-regulated kinase 1/2 and stress-activated protein kinase/c-Jun NH(2)-terminal kinase. We also demonstrated that pretreatment of cells with this compound prevented TNF-α-induced expression of NF-κB target genes, such as interleukin 6, interleukin 8, monocyte chemotactic protein 1, cyclooxygenase-2 and inducible nitric oxide. Taken together, yangonin could be a valuable candidate for the intervention of NF-κB-dependent pathological conditions such as inflammation.
authors.affiliation: Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Yanbian University, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Ma
authors.forename: He
authors.initials: H
authors.lastname: Liang
authors.forename: Hong Ri
authors.initials: HR
authors.lastname: Jin
authors.forename: Nguyen Tien
authors.initials: NT
authors.lastname: Dat
authors.forename: Shan Yu
authors.initials: SY
authors.lastname: Zhang
authors.forename: Ying Zi
authors.initials: YZ
authors.lastname: Jiang
authors.forename: Ji Xing
authors.initials: JX
authors.lastname: Nan
authors.forename: Donghao
authors.initials: D
authors.lastname: Li
authors.forename: Xue
authors.initials: X
authors.lastname: Wu
authors.forename: Jung Joon
authors.initials: JJ
authors.lastname: Lee
authors.forename: Xuejun
authors.initials: X
authors.lastname: Jin
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology*; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D011753:Pyrones / Q000737:chemistry / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects* / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
chemical_list: D016328:NF-kappa B; D021122:Protein Subunits; D011753:Pyrones; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C110481:yangonin