title: Naringenin targets ERK2 and suppresses UVB-induced photoaging.
abstract: A number of natural phytochemicals have anti-photoaging properties that appear to be mediated through the inhibition of matrix metalloproteinase-1 (MMP-1) expression, but their direct target molecule(s) and mechanism(s) remain unclear. We investigated the effect of naringenin, a major flavonoid found in citrus, on UVB-induced MMP-1 expression and identified its direct target. The HaCaT human skin keratinocyte cell line and 3-dimensional (3-D) human skin equivalent cultures were treated or not treated with naringenin for 1 hr before exposure to UVB. The mechanism and target(s) of naringenin were analysed by kinase assay and multiplex molecular assays. Dorsal skins of hairless mice were exposed to UVB 3 times per week, with a dose of irradiation that was increased weekly by 1 minimal erythema dose (MED; 45 mJ/cm(2)) to 4 MED over 15 weeks. Wrinkle formation, water loss and water content were then assessed. Naringenin suppressed UVB-induced MMP-1 expression and AP-1 activity, and strongly suppressed UVB-induced phosphorylation of Fos-related antigen (FRA)-1 at Ser265. Importantly, UVB irradiation-induced FRA1 protein stability was reduced by treatment with naringenin, as well as with a mitogen-activated protein kinase (MEK) inhibitor. Naringenin significantly suppressed UVB-induced extracellular signal-regulated kinase 2 (ERK2) activity and subsequently attenuated UVB-induced phosphorylation of p90(RSK) by competitively binding with ATP. Constitutively active MEK (CA-MEK) increased FRA1 phosphorylation and expression and also induced MMP-1 expression, whereas dominant-negative ERK2 (DN-ERK2) had opposite effects. U0126, a MEK inhibitor, also decreased FRA1 phosphorylation and expression as well as MMP-1 expression. The photoaging data obtained from mice clearly demonstrated that naringenin significantly inhibited UVB-induced wrinkle formation, trans-epidermal water loss and MMP-13 expression. Naringenin exerts potent anti-photoaging effects by suppressing ERK2 activity and decreasing FRA1 stability, followed by down-regulation of AP-1 transactivation and MMP-1 expression.
authors: The Hormel Institute, University of Minnesota, Minnesota, MN, USA.|Division of Functional Food Research, Korea Food Research Institute, Seongnam, Korea.
authors: Sung Keun
authors: SK
authors: Jung
authors: Division of Functional Food Research, Korea Food Research Institute, Seongnam, Korea.
authors: Su Jeong
authors: SJ
authors: Ha
authors: Division of Functional Food Research, Korea Food Research Institute, Seongnam, Korea.
authors: Chang Hwa
authors: CH
authors: Jung
authors: Division of Functional Food Research, Korea Food Research Institute, Seongnam, Korea.
authors: Yun Tai
authors: YT
authors: Kim
authors: College of Pharmacy, Gachon University, Incheon, Korea.
authors: Hoo-Keun
authors: HK
authors: Lee
authors: The Hormel Institute, University of Minnesota, Minnesota, MN, USA.
authors: Myoung Ok
authors: MO
authors: Kim
authors: The Hormel Institute, University of Minnesota, Minnesota, MN, USA.|China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China.
authors: Mee-Hyun
authors: MH
authors: Lee
authors: The Hormel Institute, University of Minnesota, Minnesota, MN, USA.
authors: Madhusoodanan
authors: M
authors: Mottamal
authors: The Hormel Institute, University of Minnesota, Minnesota, MN, USA.
authors: Ann M
authors: AM
authors: Bode
authors: WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul, Korea.|Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Korea.|Research Institute of Bio Food Industry, Institute of Green Bio Science and Technology, Seoul National University, Pyeongchang, Korea.
authors: Ki Won
authors: KW
authors: Lee
authors: The Hormel Institute, University of Minnesota, Minnesota, MN, USA.
authors: Zigang
authors: Z
authors: Dong
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D018929:Cell Culture Techniques; D002460:Cell Line; D005260:Female; D044950:Flavanones / Q000494:pharmacology*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008812:Mice, Hairless; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015595:Skin Aging / Q000187:drug effects* / Q000235:genetics / Q000473:pathology; D013473:Sunscreening Agents / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*; D014867:Water / Q000378:metabolism; D000099169:Fos-Related Antigen 1
chemical_list: D002070:Butadienes; D044950:Flavanones; D008156:Luciferases; D020781:Matrix Metalloproteinase 1; D019950:Mitogen-Activated Protein Kinase 1; D009570:Nitriles; D016760:Proto-Oncogene Proteins c-fos; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D013473:Sunscreening Agents; D018808:Transcription Factor AP-1; D014867:Water; D000099169:Fos-Related Antigen 1; C113580:U 0126; C535150:MAPK1 protein, human; C005273:naringenin
keywords: Fos-related antigen 1; extracellular signal-regulated kinase 2; matrix metalloproteinase-1; naringenin; photoaging