title: Hydroxytyrosol improves mitochondrial function and reduces oxidative stress in the brain of db/db mice: role of AMP-activated protein kinase activation.
abstract: Hydroxytyrosol (HT) is a major polyphenolic compound found in olive oil with reported anti-cancer and anti-inflammatory activities. However, the neuroprotective effect of HT on type 2 diabetes remains unknown. In the present study, db/db mice and SH-SY-5Y neuroblastoma cells were used to evaluate the neuroprotective effects of HT. After 8 weeks of HT administration at doses of 10 and 50 mg/kg, expression levels of the mitochondrial respiratory chain complexes I/II/IV and the activity of complex I were significantly elevated in the brain of db/db mice. Likewise, targets of the antioxidative transcription factor nuclear factor erythroid 2 related factor 2 including p62 (sequestosome-1), haeme oxygenase 1 (HO-1), and superoxide dismutases 1 and 2 increased, and protein oxidation significantly decreased. HT treatment was also found to activate AMP-activated protein kinase (AMPK), sirtuin 1 and PPARγ coactivator-1α, which constitute an energy-sensing protein network known to regulate mitochondrial function and oxidative stress responses. Meanwhile, neuronal survival indicated by neuron marker expression levels including activity-regulated cytoskeleton-associated protein, N-methyl-d-aspartate receptor and nerve growth factor was significantly improved by HT administration. Additionally, in a high glucose-induced neuronal cell damage model, HT effectively increased mitochondrial complex IV and HO-1 expression through activating AMPK pathway, followed by the prevention of high glucose-induced production of reactive oxygen species and declines of cell viability and VO2 capacity. Our observations suggest that HT improves mitochondrial function and reduces oxidative stress potentially through activation of the AMPK pathway in the brain of db/db mice.
authors.affiliation: The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University,Xi'an710049,People's Republic of China.
authors.forename: Adi
authors.initials: A
authors.lastname: Zheng
authors.affiliation: The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University,Xi'an710049,People's Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.affiliation: The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University,Xi'an710049,People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology, Xi'an Jiaotong University,28 West Xianning Road,Xi'an710049,People's Republic of China.
authors.forename: Ke
authors.initials: K
authors.lastname: Cao
authors.affiliation: The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University,Xi'an710049,People's Republic of China.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University,Xi'an710049,People's Republic of China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Pu
authors.affiliation: The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University,Xi'an710049,People's Republic of China.
authors.forename: Ziqi
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology, Xi'an Jiaotong University,28 West Xianning Road,Xi'an710049,People's Republic of China.
authors.forename: Yunhua
authors.initials: Y
authors.lastname: Peng
authors.affiliation: The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University,Xi'an710049,People's Republic of China.
authors.forename: Jiangang
authors.initials: J
authors.lastname: Long
authors.affiliation: The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University,Xi'an710049,People's Republic of China.
authors.forename: Jiankang
authors.initials: J
authors.lastname: Liu
authors.affiliation: Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology, Xi'an Jiaotong University,28 West Xianning Road,Xi'an710049,People's Republic of China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Feng
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy; D000069463:Olive Oil; D018384:Oxidative Stress / Q000187:drug effects*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D010938:Plant Oils / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D000099156:Superoxide Dismutase 2
chemical_list: D055372:AMP-Activated Protein Kinases; D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D051547:Heme Oxygenase-1; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; D000069463:Olive Oil; D047495:PPAR gamma; D010626:Phenylethyl Alcohol; D010938:Plant Oils; D017382:Reactive Oxygen Species; D000071456:Sequestosome-1 Protein; D056564:Sirtuin 1; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000099156:Superoxide Dismutase 2; C495636:Nfe2l2 protein, mouse; C101343:Sqstm1 protein, mouse; C005975:3,4-dihydroxyphenylethanol; C496542:Hmox1 protein, mouse; C000606291:Sod1 protein, mouse; C470545:Sirt1 protein, mouse
keywords:    db/db Mice; AMP-activated protein kinase pathway; Hydroxytyrosol; Mitochondrial function; Oxidative stress; Reactive oxygen species