title: The cytoprotective effect of isorhamnetin against oxidative stress is mediated by the upregulation of the Nrf2-dependent HO-1 expression in C2C12 myoblasts through scavenging reactive oxygen species and ERK inactivation.
abstract: This study was designed to confirm the protective effects of isorhamnetin against oxidative stress-induced cellular damage. Our results indicated that isorhamnetin inhibited the hydrogen peroxide (H2O2)-induced growth inhibition and exhibited scavenging activity against the intracellular reactive oxygen species (ROS) in mouse-derived C2C12 myoblasts. Isorhamnetin also significantly attenuated H2O2-induced DNA damage and apoptosis, and increased the levels of the nuclear factor erythroid 2-related factor 2 (Nrf2) and its phosphorylation associated with the induction of heme oxygenase-1 (HO-1). However, the protective effects of isorhamnetin on H2O2-induced ROS and growth inhibition were significantly abolished by an HO-1 competitive inhibitor. Moreover, the potential of isorhamnetin to mediate HO-1 induction and protect against H2O2-mediated growth inhibition was abrogated by transient transfection with Nrf2-specific small interfering RNA. Additionally, isorhamnetin induced the activation of mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK. However, the specific inhibitor of ERK, but not JNK and p38 MAPK, was able to abolish the HO-1 upregulation and the Nrf2 phosphorylation. Collectively, these results demonstrate that isorhamnetin augments the cellular antioxidant defense capacity by activating the Nrf2/HO-1 pathway involving the activation of the ERK pathway, thus protecting the C2C12 cells from H2O2-induced cytotoxicity.
authors.affiliation: Department of Biochemistry, Dongeui University College of Korean Medicine, 52-57, Yangjeong-ro, Busanjin, Busan 614-052, Republic of Korea. choiyh@deu.ac.kr.
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D032446:Myoblasts / Q000187:drug effects / Q000502:physiology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011794:Quercetin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D016166:Free Radical Scavengers; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; C047368:3-methylquercetin; D011794:Quercetin; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse