title: Polyhydroxylated fullerene attenuates oxidative stress-induced apoptosis via a fortifying Nrf2-regulated cellular antioxidant defence system.
abstract: Polyhydroxylated derivatives of fullerene C60, named fullerenols (C60[OH]n), have stimulated great interest because of their potent antioxidant properties in various chemical and biological systems, which enable them to be used as a new promising pharmaceutical for the future treatment of oxidative stress-related diseases, but the details remain unknown. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a principal transcription factor that regulates expression of several antioxidant genes via binding to the antioxidant response element and plays a crucial role in cellular defence against oxidative stress. In this study we investigated whether activation of the Nrf2/antioxidant response element pathway contributes to the cytoprotective effects of C60(OH)24. Our results showed that C60(OH)24 enhanced nuclear translocation of Nrf2 and upregulated expression of phase II antioxidant enzymes, including heme oxygenase-1 (HO-1), NAD(P)H: quinine oxidoreductase 1, and γ-glutamate cysteine ligase in A549 cells. Treatment with C60(OH)24 resulted in phosphorylation of p38 mitogen-activated protein kinases (p38 MAPK), extracellular signal-regulated kinases, and c-Jun-N-terminal kinases. By using inhibitors of cellular kinases, we showed that pretreatment of A549 cells with SB203580, a specific inhibitor of p38 MAPK, abolished nuclear translocation of Nrf2 and induction of HO-1 protein induced by C60(OH)24, indicating an involvement of p38 MAPK in Nrf2/HO-1 activation by C 60(OH)24. Furthermore, pretreatment with C60(OH)24 attenuated hydrogen peroxide-induced apoptotic cell death in A549 cells, and knockdown of Nrf2 by small interfering ribonucleic acid diminished C60(OH)24-mediated cytoprotection. Taken together, these findings demonstrate that C60(OH)24 may attenuate oxidative stress-induced apoptosis via augmentation of Nrf2-regulated cellular antioxidant capacity, thus providing insights into the mechanisms of the antioxidant properties of C60(OH)24.
authors.affiliation: Department of Biomaterials, Research Center of Biomedical Engineering, College of Materials, Xiamen University, Xiamen, People's Republic of China.
authors.forename: Shefang
authors.initials: S
authors.lastname: Ye
authors.affiliation: Department of Biomaterials, Research Center of Biomedical Engineering, College of Materials, Xiamen University, Xiamen, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Biomaterials, Research Center of Biomedical Engineering, College of Materials, Xiamen University, Xiamen, People's Republic of China ; First Affiliated Hospital of Xiamen University, Xiamen, People's Republic of China.
authors.forename: Yuanqin
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Marine Biogenetic Resources, Third Institute of Oceanography, State Oceanic Administration, Xiamen, People's Republic of China.
authors.forename: Mingliang
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Biomaterials, Research Center of Biomedical Engineering, College of Materials, Xiamen University, Xiamen, People's Republic of China.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Biomaterials, Research Center of Biomedical Engineering, College of Materials, Xiamen University, Xiamen, People's Republic of China.
authors.forename: Yange
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biomaterials, Research Center of Biomedical Engineering, College of Materials, Xiamen University, Xiamen, People's Republic of China.
authors.forename: Zhenqing
authors.initials: Z
authors.lastname: Hou
authors.affiliation: Department of Biomaterials, Research Center of Biomedical Engineering, College of Materials, Xiamen University, Xiamen, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Ren
mesh_terms: D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D037741:Fullerenes / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D008422:Materials Testing; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D037741:Fullerenes; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species
keywords: A549 cells; Nrf2; cytoprotection; fullerenol; oxidative stress