title: Involvement of heme oxygenase-1 induction via Nrf2/ARE activation in protection against H2O2-induced PC12 cell death by a metabolite of sesamin contained in sesame seeds.
abstract: Induction of phase II antioxidant enzymes by activation of Nrf2/ARE (antioxidant response element) signaling has been considered as a promising strategy to combat with oxidative stress-related diseases. In the present study, we tested for potential effects of sesamin, a major lignan contained in sesame seeds, its stereoisomer episesamin, and their metabolites on Nrf2/ARE activation in rat pheochromocytoma PC12 cells. Luciferase reporter assays showed that primary metabolites of sesamin and episesamin, SC-1 and EC-1 were the most potent ARE activators among all tested compounds. SC-1 {(1R,2S,5R,6S)-6-(3,4-dihydroxyphenyl)-2-(3,4-methylenedioxyphenyl)-3,7-dioxabicyclo-[3,3,0]octane} enhanced nuclear translocation of Nrf2 and up-regulated expression of phase II antioxidant enzymes including heme oxygenase-1 (HO-1). Treatment with SC-1 resulted in increased phosphorylation of p38 MAP kinase and transient increase in intracellular ROS levels. N-acetylcysteine (NAC) treatment abolished p38 phosphorylation as well as HO-1 induction caused by SC-1, indicating that ROS are upstream signals of p38 in Nrf2/ARE activation by SC-1. Furthermore, preconditioning with SC-1 attenuated H(2)O(2)-induced cell death in a dose-dependent manner. Finally, treatment with a HO-1 inhibitor, Zn-protoporphyrin (ZnPP), and overexpression of a dominant-negative mutant of Nrf2 diminished SC-1-mediated neuroprotection. Our results demonstrate that SC-1 is capable of protecting against oxidative stress-induced neuronal cell death in part through induction of HO-1 via Nrf2/ARE activation, suggesting its potential to reduce oxidative stress and ameliorate oxidative stress-related neurodegenerative diseases.
authors.affiliation: Department of Longevity and Aging Research, Gifu International Institute of Biotechnology, 1-1 Naka-fudogaoka, Kakamigahara, Gifu 504-0838, Japan.
authors.forename: Nanako
authors.initials: N
authors.lastname: Hamada
authors.forename: Arisa
authors.initials: A
authors.lastname: Tanaka
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Fujita
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Itoh
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Ono
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kitagawa
authors.forename: Namino
authors.initials: N
authors.lastname: Tomimori
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Kiso
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Akao
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nozawa
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ito
mesh_terms: D000818:Animals; D017209:Apoptosis; D004149:Dioxoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000737:chemistry / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D017705:Lignans / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D036226:Seedlings / Q000737:chemistry; D031685:Sesamum / Q000737:chemistry*
chemical_list: D004149:Dioxoles; D017705:Lignans; D051267:NF-E2-Related Factor 2; D006861:Hydrogen Peroxide; D051547:Heme Oxygenase-1; C054125:sesamin