title: Zeaxanthin induces Nrf2-mediated phase II enzymes in protection of cell death.
abstract: Zeaxanthin (Zea) is a major carotenoid pigment contained in human retina, and its daily supplementation associated with lower risk of age-related macular degeneration. Despite known property of Zea as an antioxidant, its underlying molecular mechanisms of action remain poorly understood. In this study, we aim to study the regulation mechanism of Zea on phase II detoxification enzymes. In normal human retinal pigment epithelium cells, Zea promoted the nuclear translocation of NF-E2-related factor 2 (Nrf2) and induced mRNA and protein expression of phase II enzymes, the induction was suppressed by specific knockdown of Nrf2. Zea also effectively protected against tert-butyl hydroperoxide-induced mitochondrial dysfunction and apoptosis. Glutathione (GSH) as the most important antioxidant was also induced by Zea through Nrf2 activation in a time- and dose-dependent manner, whereas the protective effects of Zea were decimated by inhibition of GSH synthesis. Finally, Zea activated the PI3K/Akt and MAPK/ERK pathway, whereas only PI3K/Akt activation correlated with phase II enzymes induction and Zea protection. In further in vivo analyses, Zea showed effects of inducing phase II enzymes and increased GSH content, which contributed to the reduced lipid and protein peroxidation in the retina as well as the liver, heart, and serum of the Sprague-Dawley rats. For the first time, Zea is presented as a phase II enzymes inducer instead of being an antioxidant. By activating Nrf2-mediated phase II enzymes, Zea could enhance anti-oxidative capacity and prevent cell death both in vivo and in vitro.
authors.affiliation: 1] Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China [2] Center for Translational Medicine, Frontier Institute of Science and Technology, FIST, Xi'an Jiaotong University, Xi'an, China.
authors.forename: X
authors.initials: X
authors.lastname: Zou
authors.affiliation: 1] Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China [2] Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology, FIST, Xi'an Jiaotong University, Xi'an, China.
authors.forename: J
authors.initials: J
authors.lastname: Gao
authors.affiliation: Jinan Central Hospital Affiliated to Shandong University, Jinan, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: 1] Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China [2] Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology, FIST, Xi'an Jiaotong University, Xi'an, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: 1] Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China [2] Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology, FIST, Xi'an Jiaotong University, Xi'an, China.
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.affiliation: 1] Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China [2] Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology, FIST, Xi'an Jiaotong University, Xi'an, China.
authors.forename: K
authors.initials: K
authors.lastname: Cao
authors.affiliation: 1] Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China [2] Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology, FIST, Xi'an Jiaotong University, Xi'an, China.
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.affiliation: 1] Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China [2] Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology, FIST, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: 1] Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China [2] Center for Translational Medicine, Frontier Institute of Science and Technology, FIST, Xi'an Jiaotong University, Xi'an, China.
authors.forename: W
authors.initials: W
authors.lastname: Lu
authors.affiliation: 1] Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China [2] Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology, FIST, Xi'an Jiaotong University, Xi'an, China.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: 1] Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China [2] Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology, FIST, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Feng
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000096:biosynthesis* / Q000235:genetics; D005982:Glutathione Transferase / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D050217:Metabolic Detoxication, Phase II; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D013997:Time Factors; D014162:Transfection; D024341:Xanthophylls / Q000494:pharmacology*; D065146:Zeaxanthins
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D016877:Oxidants; D012333:RNA, Messenger; D024341:Xanthophylls; D065146:Zeaxanthins; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005982:Glutathione Transferase; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D005978:Glutathione