title: KB-34, a newly synthesized chalcone derivative, inhibits lipopolysaccharide-stimulated nitric oxide production in RAW 264.7 macrophages via heme oxygenase-1 induction and blockade of activator protein-1.
abstract: Chalcones, a subclass of the flavonoid family, are widely known for their anti-inflammatory and anti-oxidative properties. In the present study, we synthesized the chalcone derivative, KB-34 (3-Phenyl-1-(2,4,6-tris (methoxymethoxy)phenyl)prop-2-yn-1-one), and examined its effect on nitric oxide (NO) production. KB-34 potently inhibited nitrite production in RAW 264.7 macrophages stimulated by lipopolysaccharide (LPS). KB-34 treatment also markedly inhibited inducible nitric oxide synthase (iNOS) expression, as assessed by Western blot and quantitative RT-PCR analyses. Treatment of cells with KB-34 significantly inhibited LPS-induced transcriptional activation by activator protein-1 (AP-1) as determined by luciferase reporter gene assay, whereas nuclear factor-kappaB (NF-kappaB) activity was not affected by KB-34, indicating that down-regulation of iNOS gene expression by KB-34 is mainly attributed by blockade of AP-1 activation. We also demonstrated that KB-34 treatment led to an increase in heme oxygenase-1 (HO-1) mRNA and protein expression, mediated by stimulating the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2). Treatment with SnPP, a selective inhibitor of HO-1, reversed the KB-34-mediated inhibition of nitrite production, suggesting that HO-1 plays an important role in the suppression of NO production by KB-34. In contrast, SnPP treatment did not counteract the KB-34-mediated suppression of AP-1 activity, suggesting that inhibition of AP-1 activation by KB-34 is independent of HO-1 induction. Taken together, these results indicate that KB-34 suppresses NO production in LPS-stimulated RAW 264.7 macrophages via simultaneous induction of HO-1 expression and blockade of AP-1 activation. This study reveals that KB-34 would be a promising agent for the treatment of inflammation-associated disease.
authors.affiliation: College of Pharmacy, Medicinal Resources Research Institute and Institute of Pharmaceutical Research and Development, Wonkwang University, Jeon-Buk, South Korea.
authors.forename: Pil-Hoon
authors.initials: PH
authors.lastname: Park
authors.forename: Hak Sung
authors.initials: HS
authors.lastname: Kim
authors.forename: Xing Yu
authors.initials: XY
authors.lastname: Jin
authors.forename: Feng
authors.initials: F
authors.lastname: Jin
authors.forename: Jin
authors.initials: J
authors.lastname: Hur
authors.forename: Geonil
authors.initials: G
authors.lastname: Ko
authors.forename: Dong Hwan
authors.initials: DH
authors.lastname: Sohn
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002460:Cell Line; D002599:Chalcone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: C543194:3-phenyl-1-(2,4,6-tris(methoxymethoxy)phenyl)prop-2-yn-1-one; D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D009573:Nitrites; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D009569:Nitric Oxide; D002599:Chalcone; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1