title: Up-regulation of Nrf2-mediated heme oxygenase-1 expression by eckol, a phlorotannin compound, through activation of Erk and PI3K/Akt.
abstract: The aim of the present study was to examine the cytoprotective effect of eckol, a phlorotannin found in Ecklonia cava and to elucidate underlying mechanisms. Heme oxygenase-1 (HO-1) is an important antioxidant enzyme that plays a role in cytoprotection against oxidative stress. Eckol-induced HO-1 expression both at the level of mRNA and protein in Chinese hamster lung fibroblast (V79-4) cells, resulting in increased HO-1 activity. The transcription factor NF-E2-related factor 2 (Nrf2) is a critical regulator of HO-1, achieved by binding to the antioxidant response element (ARE). Eckol treatment resulted in the enhanced level of phosphorylated form, nuclear translocation, ARE-binding, and transcriptional activity of Nrf2. Extracellular regulated kinase (Erk) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB, Akt) contributed to ARE-driven HO-1 expression. Eckol activated both Erk and Akt, and treatments with U0126 (an Erk kinase inhibitor), LY294002 (a PI3K inhibitor), specific Erk1 siRNA, and Akt siRNA suppressed the eckol-induced activation of Nrf2, resulting in a decrease in HO-1 expression. ZnPP (a HO-1 inhibitor), HO-1 siRNA, and Nrf2 siRNA markedly abolished the cytoprotective effect of eckol against hydrogen peroxide-induced cell damage. Likewise, U0126 and LY294002 inhibited the eckol-induced cytoprotective effect against oxidative cell damage. These studies demonstrate that eckol attenuates oxidative stress by activating Nrf2-mediated HO-1 induction via Erk and PI3K/Akt signaling.
authors.affiliation: School of Applied Marine Science, Jeju National University, Jeju-si, South Korea.
authors.forename: Ki Cheon
authors.initials: KC
authors.lastname: Kim
authors.forename: Kyoung Ah
authors.initials: KA
authors.lastname: Kang
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Mei Jing
authors.initials: MJ
authors.lastname: Piao
authors.forename: Gi Young
authors.initials: GY
authors.lastname: Kim
authors.forename: Mi Young
authors.initials: MY
authors.lastname: Kang
authors.forename: Su Jae
authors.initials: SJ
authors.lastname: Lee
authors.forename: Nam Ho
authors.initials: NH
authors.lastname: Lee
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
authors.forename: Jin Won
authors.initials: JW
authors.lastname: Hyun
mesh_terms: D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics; D004147:Dioxins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000166:cytology; D020935:MAP Kinase Signaling System / Q000187:drug effects; 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; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D004147:Dioxins; D051267:NF-E2-Related Factor 2; C060311:eckol; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases