title: Fisetin inhibits TNF-α-induced inflammatory action and hydrogen peroxide-induced oxidative damage in human keratinocyte HaCaT cells through PI3K/AKT/Nrf-2-mediated heme oxygenase-1 expression.
abstract: Oxidative skin damage and skin inflammation play key roles in the pathogenesis of skin-related diseases. Fisetin is a naturally occurring flavonoid abundantly found in several vegetables and fruits. Fisetin has been shown to exert various positive biological effects, such as anti-cancer, anti-proliferative, neuroprotective and anti-oxidative effects. In this study, we investigate the skin protective effects and anti-inflammatory properties of fisetin in hydrogen peroxide- and TNF-α-challenged human keratinocyte HaCaT cells. When HaCaT cells were treated with non-cytotoxic concentrations of fisetin (1-20μM), heme oxygenase (HO)-1 mRNA and protein expression increased in a dose-dependent manner. Furthermore, fisetin dose-dependently increased cell viability and reduced ROS production in hydrogen peroxide-treated HaCaT cells. Fisetin also inhibited the production of NO, PGE2 IL-1β, IL-6, expression of iNOS and COX-2, and activation of NF-κB in HaCaT cells treated with TNF-α. Fisetin induced Nrf2 translocation to the nuclei. HO-1 siRNA transient transfection reversed the effects of fisetin on cytoprotection, ROS reduction, NO, PGE2, IL-1β, IL-6, and TNF-α production, and NF-κB DNA-binding activity. Moreover, fisetin increased Akt phosphorylation and a PI3K pathway inhibitor (LY294002) abolished fisetin-induced cytoprotection and NO inhibition. Taken together, these results provide evidence for a beneficial role of fisetin in skin therapy.
authors.affiliation: Department of Cosmetology, Dongshin University, Naju, Jeonnam 520-714, Republic of Korea.
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Seo
authors.affiliation: College of Pharmacy, Keimyung University, Dae-gu 704-701, Republic of Korea. Electronic address: gsjeong@kmu.ac.kr.
authors.forename: Gil-Saeng
authors.initials: GS
authors.lastname: Jeong
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors* / Q000633:toxicity; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control*; D015603:Keratinocytes / Q000187:drug effects*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D016877:Oxidants / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000633:toxicity
chemical_list: D000975:Antioxidants; D005419:Flavonoids; D044948:Flavonols; D051547:Heme Oxygenase-1; D006861:Hydrogen Peroxide; D051267:NF-E2-Related Factor 2; D051058:Oncogene Protein v-akt; D016877:Oxidants; D019869:Phosphatidylinositol 3-Kinases; D014409:Tumor Necrosis Factor-alpha; C495635:NFE2L2 protein, human; C017875:fisetin
keywords: Anti-skin inflammation; Fisetin; Heme oxygenase-1; Human keratinocyte HaCaT; Skin protective effects