title: Activation of Nrf2 Reduces UVA-Mediated MMP-1 Upregulation via MAPK/AP-1 Signaling Cascades: The Photoprotective Effects of Sulforaphane and Hispidulin.
abstract: UVA irradiation plays a role in premature aging of the skin through triggering oxidative stress-associated stimulation of matrix metalloproteinase-1 (MMP-1) responsible for collagen degradation, a hallmark of photoaged skin. Compounds that can activate nuclear factor E2-related factor 2 (Nrf2), a transcription factor regulating antioxidant gene expression, should therefore serve as effective antiphotoaging agents. We investigated whether genetic silencing of Nrf2 could relieve UVA-mediated MMP-1 upregulation via activation of mitogen-activated protein kinase (MAPK)/activator protein 1 (AP-1) signaling using human keratinocyte cell line (HaCaT). Antiphotoaging effects of hispidulin (HPD) and sulforaphane (SFN) were assessed on their abilities to activate Nrf2 in controlling MMP-1 and collagen expressions in association with phosphorylation of MAPKs (extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38), c-Jun, and c-Fos, using the skin of BALB/c mice subjected to repetitive UVA irradiation. Our findings suggested that depletion of Nrf2 promoted both mRNA expression and activity of MMP-1 in the UVA-irradiated HaCaT cells. Treatment of Nrf2 knocked-down HaCaT cells with MAPK inhibitors significantly suppressed UVA-induced MMP-1 and AP-1 activities. Moreover, pretreatment of the mouse skin with HPD and SFN, which could activate Nrf2, provided protective effects against UVA-mediated MMP-1 induction and collagen depletion in correlation with the decreased levels of phosphorylated MAPKs, c-Jun, and c-Fos in the mouse skin. In conclusion, Nrf2 could influence UVA-mediated MMP-1 upregulation through the MAPK/AP-1 signaling cascades. HPD and SFN may therefore represent promising antiphotoaging candidates.
authors.affiliation: Department of Pharmacology (A.C., J.L., K.S., S.S., P.A. and U.P.) and Center of Applied Thai Traditional Medicine, Faculty of Medicine (P.A.), Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Anyamanee
authors.initials: A
authors.lastname: Chaiprasongsuk
authors.affiliation: Department of Pharmacology (A.C., J.L., K.S., S.S., P.A. and U.P.) and Center of Applied Thai Traditional Medicine, Faculty of Medicine (P.A.), Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Jinaphat
authors.initials: J
authors.lastname: Lohakul
authors.affiliation: Department of Pharmacology (A.C., J.L., K.S., S.S., P.A. and U.P.) and Center of Applied Thai Traditional Medicine, Faculty of Medicine (P.A.), Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Kitipong
authors.initials: K
authors.lastname: Soontrapa
authors.affiliation: Department of Pharmacology (A.C., J.L., K.S., S.S., P.A. and U.P.) and Center of Applied Thai Traditional Medicine, Faculty of Medicine (P.A.), Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Somponnat
authors.initials: S
authors.lastname: Sampattavanich
authors.affiliation: Department of Pharmacology (A.C., J.L., K.S., S.S., P.A. and U.P.) and Center of Applied Thai Traditional Medicine, Faculty of Medicine (P.A.), Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Pravit
authors.initials: P
authors.lastname: Akarasereenont
authors.affiliation: Department of Pharmacology (A.C., J.L., K.S., S.S., P.A. and U.P.) and Center of Applied Thai Traditional Medicine, Faculty of Medicine (P.A.), Siriraj Hospital, Mahidol University, Bangkok, Thailand uraiwan.pan@mahidol.ac.th.
authors.forename: Uraiwan
authors.initials: U
authors.lastname: Panich
mesh_terms: D019588:Aging, Premature / Q000209:etiology / Q000378:metabolism; D000818:Animals; D016587:Antimutagenic Agents / Q000494:pharmacology; D002460:Cell Line; D003094:Collagen / Q000378:metabolism*; D004789:Enzyme Activation / Q000528:radiation effects; D047309:Flavones / Q000494:pharmacology*; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D015603:Keratinocytes; D020935:MAP Kinase Signaling System / Q000528:radiation effects; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D012867:Skin / Q000378:metabolism; D015595:Skin Aging / Q000187:drug effects / Q000528:radiation effects; D013454:Sulfoxides; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*; D015854:Up-Regulation / Q000528:radiation effects
chemical_list: D016587:Antimutagenic Agents; D047309:Flavones; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; D013454:Sulfoxides; D018808:Transcription Factor AP-1; D003094:Collagen; D020781:Matrix Metalloproteinase 1; C016766:sulforaphane; C055957:hispidulin