title: Fisetin, a bioactive flavonol, attenuates allergic airway inflammation through negative regulation of NF-κB.
abstract: Persistent activation of nuclear factor-κB (NF-κB) has been associated with the development of asthma. Fisetin (3,7,3',4'-tetrahydroxyflavone), a naturally occurring bioactive flavonol, has been shown to inhibit NF-κB activity. We hypothesized that fisetin may attenuate allergic asthma via negative regulation of the NF-κB activity. Female BALB/c mice sensitized and challenged with ovalbumin developed airway inflammation. Bronchoalveolar lavage fluid was assessed for total and differential cell counts, and cytokine and chemokine levels. Lung tissues were examined for cell infiltration and mucus hypersecretion, and the expression of inflammatory biomarkers. Airway hyperresponsiveness was monitored by direct airway resistance analysis. Fisetin dose-dependently inhibited ovalbumin-induced increases in total cell count, eosinophil count, and IL-4, IL-5 and IL-13 levels recovered in bronchoalveolar lavage fluid. It attenuated ovalbumin-induced lung tissue eosinophilia and airway mucus production, mRNA expression of adhesion molecules, chitinase, IL-17, IL-33, Muc5ac and inducible nitric oxide synthase in lung tissues, and airway hyperresponsiveness to methacholine. Fisetin blocked NF-κB subunit p65 nuclear translocation and DNA-binding activity in the nuclear extracts from lung tissues of ovalbumin-challenged mice. In normal human bronchial epithelial cells, fisetin repressed TNF-α-induced NF-κB-dependent reporter gene expression. Our findings implicate a potential therapeutic value of fisetin in the treatment of asthma through negative regulation of NF-κB pathway.
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore.
authors.forename: Fera Y
authors.initials: FY
authors.lastname: Goh
authors.forename: Nadine
authors.initials: N
authors.lastname: Upton
authors.forename: Shouping
authors.initials: S
authors.lastname: Guan
authors.forename: Chang
authors.initials: C
authors.lastname: Cheng
authors.forename: Muthu K
authors.initials: MK
authors.lastname: Shanmugam
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Leung
authors.forename: W S Fred
authors.initials: WS
authors.lastname: Wong
mesh_terms: D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002452:Cell Count / Q000379:methods / Q000706:statistics & numerical data; D018925:Chemokines / Q000378:metabolism; D002688:Chitinases / Q000096:biosynthesis; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005419:Flavonoids / Q000494:pharmacology / Q000627:therapeutic use*; D044948:Flavonols / Q000494:pharmacology / Q000627:therapeutic use*; D017930:Genes, Reporter / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D055271:Mucin 5AC / Q000096:biosynthesis; D009093:Mucus / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D010047:Ovalbumin; D021381:Protein Transport / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: D015815:Cell Adhesion Molecules; D018925:Chemokines; D016207:Cytokines; D004268:DNA-Binding Proteins; D005419:Flavonoids; D044948:Flavonols; D018836:Inflammation Mediators; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D016210:Methacholine Chloride; D010047:Ovalbumin; D052247:Nitric Oxide Synthase Type II; D002688:Chitinases; C017875:fisetin