title: Cytoprotective effects of esculetin against oxidative stress are associated with the upregulation of Nrf2-mediated NQO1 expression via the activation of the ERK pathway.
abstract: Esculetin, a coumarin derivative isolated from a variety of medicinal herbs, has been reported to possess multiple therapeutic and pharmacological actions. Although several studies have demonstrated the antioxidant activity of esculetin, its mechanisms of action have not been clearly established. The aim of this study was to evaluate the effects of esculetin against hydrogen peroxide (H2O2)‑induced oxidative stress in C2C12 myoblasts and to investigate the mechanisms involved in this process. Our data indicated that esculetin preconditioning significantly attenuated H2O2‑induced growth inhibition and DNA damage and the apoptosis of C2C12 cells by suppressing intracellular reactive oxygen species (ROS) accumulation. Treatment with esculetin effectively increased the phosphorylation of nuclear factor erythroid 2‑related factor 2 (Nrf2) and the expression of NAD(P)H:quinone oxidoreductase 1 (NQO1). Esculetin treatment also activated extracellular signal‑regulated kinase (ERK), and pre‑treatment with PD98059, an ERK‑specific inhibitor, blocked esculetin-mediated phosphorylation of Nrf2 and the induction of NQO1 expression. In addition, the protective effects of esculetin against H2O2‑induced ROS accumulation, apoptosis and growth inhibition were abrogated in the C2C12 cells pre‑treated with PD98059. Thus, the present study demonstrates that esculetin protects C2C12 cells against oxidative stress-induced injury, possibly through the activation of the Nrf2/NQO1 pathway.
authors.affiliation: Natural Products Research Team, National Marine Biodiversity Institute of Korea, Seocheon 325‑902, Republic of Korea.
authors.forename: Min Ho
authors.initials: MH
authors.lastname: Han
authors.affiliation: Department of Molecular Biology, College of Natural Sciences and Human Ecology, Dongeui University, Busan 614‑714, Republic of Korea.
authors.forename: Cheol
authors.initials: C
authors.lastname: Park
authors.affiliation: Natural Products Research Team, National Marine Biodiversity Institute of Korea, Seocheon 325‑902, Republic of Korea.
authors.forename: Dae-Sung
authors.initials: DS
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, Dongeui University College of Korean Medicine, Busan 614‑052, Republic of Korea.
authors.forename: Su-Hyun
authors.initials: SH
authors.lastname: Hong
authors.affiliation: Department of Microbiology, College of Medicine, Inje University, Busan 608‑756, Republic of Korea.
authors.forename: Il-Whan
authors.initials: IW
authors.lastname: Choi
authors.affiliation: Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Jeju 690‑756, Republic of Korea.
authors.forename: Gi-Young
authors.initials: GY
authors.lastname: Kim
authors.affiliation: Department of Safety and System Management, Korea Lift College, Geochang 670‑802, Republic of Korea.
authors.forename: Sung Hyun
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Natural Medicine Research Institute, Department of Pharmacy, College of Pharmacy, Mokpo National University, Jeonnam 534‑729, Republic of Korea.
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Shim
authors.affiliation: Department of Dental Pharmacology, School of Dentistry, BK21 Plus, Chonbuk National University, Jeonju 561‑756, Republic of Korea.
authors.forename: Jung-Il
authors.initials: JI
authors.lastname: Chae
authors.affiliation: Department of Anatomy and Cell Biology, Dong‑A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602‑714, Republic of Korea.
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Yoo
authors.affiliation: Department of Biochemistry, Dongeui University College of Korean Medicine, Busan 614‑052, Republic of Korea.
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004249:DNA Damage / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014468:Umbelliferones / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D014468:Umbelliferones; D006861:Hydrogen Peroxide; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; C007628:esculetin