title: 7,8-Dihydroxyflavone protects human keratinocytes against oxidative stress-induced cell damage via the ERK and PI3K/Akt-mediated Nrf2/HO-1 signaling pathways.
abstract: This study investigated the effect of 7,8-dihydroxyflavone (DHF) on the expression and activity of heme oxygenase-1 (HO-1), an enzyme with potent antioxidant properties, as well as the molecular mechanisms involved. DHF markedly upregulated HO-1 mRNA and protein expression in human keratinocytes (HaCaT cells), resulting in increased HO-1 activity. DHF also increased the protein level of transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates HO-1 expression by binding to the antioxidant response element (ARE) within the HO-1 gene promoter, in a time-dependent manner. Moreover, DHF decreased the expression of Kelch-like ECH-associated protein 1, a repressor of Nrf2 activity, and induced the translocation of Nrf2 from the cytosol into the nucleus, thereby allowing its association with the ARE site. DHF activated extracellular-regulated kinase (ERK) and protein kinase B (PKB, Akt) in keratinocytes, while the ERK and Akt inhibitors attenuated DHF-enhanced Nrf2 and HO-1 expression. DHF also protected the keratinocytes against hydrogen peroxide- and ultraviolet B-induced oxidative damage, while HO-1, ERK and Akt inhibitors markedly suppressed DHF-mediated cytoprotection. Taken together, the results suggested that DHF activates ERK- and Akt-Nrf2 signaling cascades in HaCaT cells, leading to the upregulation of HO-1 and cytoprotection against oxidative stress.
authors: Food and Nutrition, Duksung Women's University, Seoul 132-714, Republic of Korea.
authors: Min Ju
authors: MJ
authors: Ryu
authors: School of Medicine and Institute for Nuclear Science and Technology, Jeju National University, Jeju 690-756, Republic of Korea.
authors: Kyoung Ah
authors: KA
authors: Kang
authors: School of Medicine and Institute for Nuclear Science and Technology, Jeju National University, Jeju 690-756, Republic of Korea.
authors: Mei Jing
authors: MJ
authors: Piao
authors: School of Medicine and Institute for Nuclear Science and Technology, Jeju National University, Jeju 690-756, Republic of Korea.
authors: Ki Cheon
authors: KC
authors: Kim
authors: School of Medicine and Institute for Nuclear Science and Technology, Jeju National University, Jeju 690-756, Republic of Korea.
authors: Jian
authors: J
authors: Zheng
authors: School of Medicine and Institute for Nuclear Science and Technology, Jeju National University, Jeju 690-756, Republic of Korea.
authors: Cheng Wen
authors: CW
authors: Yao
authors: School of Medicine and Institute for Nuclear Science and Technology, Jeju National University, Jeju 690-756, Republic of Korea.
authors: Ji Won
authors: JW
authors: Cha
authors: Food and Nutrition, Duksung Women's University, Seoul 132-714, Republic of Korea.
authors: Ha Sook
authors: HS
authors: Chung
authors: Biospectrum Life Science Institute, Seongnam, Gyunggi Do 442‑13, Republic of Korea.
authors: Sang Cheol
authors: SC
authors: Kim
authors: Biospectrum Life Science Institute, Seongnam, Gyunggi Do 442‑13, Republic of Korea.
authors: Eunsun
authors: E
authors: Jung
authors: Biospectrum Life Science Institute, Seongnam, Gyunggi Do 442‑13, Republic of Korea.
authors: Deokhoon
authors: D
authors: Park
authors: Aging Research Center, Korea Institute of Oriental Medicine, Daejeon 305-811, Republic of Korea.
authors: Sungwook
authors: S
authors: Chae
authors: School of Medicine and Institute for Nuclear Science and Technology, Jeju National University, Jeju 690-756, Republic of Korea.
authors: Jin Won
authors: JW
authors: Hyun
mesh_terms: D061745:Antioxidant Response Elements / Q000235:genetics; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D047309:Flavones / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C485383:6,7-dihydroxyflavone; D047309:Flavones; D051267:NF-E2-Related Factor 2; D020011:Protective Agents; D012333:RNA, Messenger; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases