title: Downregulation of Nrf2/HO-1 pathway and activation of JNK/c-Jun pathway are involved in homocysteic acid-induced cytotoxicity in HT-22 cells.
abstract: Previous studies have suggested that elevated blood homocysteic acid (HCA) levels increased the risk of Alzheimer's disease (AD), but the underlying mechanisms are unclear. Herein, we studied the neuronal toxicity of HCA and the underlying mechanisms in HT-22 cells. Results showed that HCA induced cell death in concentration- and time-dependent manners, but did not activate Caspase-3. Additionally, HCA increased ROS production, depleted GSH, inactivated the Nrf2/HO-1 pathway, decreased mitochondrial membrane potential and increased the ratio of Bax/Bcl-2, two apoptosis-related proteins. Furthermore, HCA significantly increased the levels of p-JNK and p-c-Jun and its toxicity dramatically attenuated by SP600125, a specific JNK pathway inhibitor. Taken together, our results provide evidence that HCA induced cytotoxicity in HT-22 cells through down-regulating of Nrf2/HO-1 pathway and activating JNK/c-Jun pathway, supporting that HCA might be a therapeutic target for AD.
authors.affiliation: Department of Traditional Chinese Medicine Chemistry, College of Chinese Materia Madica, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Department of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
authors.forename: Min
authors.initials: M
authors.lastname: Tan
authors.forename: Ying
authors.initials: Y
authors.lastname: Ouyang
authors.forename: Minghua
authors.initials: M
authors.lastname: Jin
authors.forename: Meihui
authors.initials: M
authors.lastname: Chen
authors.forename: Peiqing
authors.initials: P
authors.lastname: Liu
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Chao
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Chen
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Chen
authors.forename: Charles
authors.initials: C
authors.lastname: Ramassamy
authors.forename: Youheng
authors.initials: Y
authors.lastname: Gao
authors.forename: Rongbiao
authors.initials: R
authors.lastname: Pi
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000873:Anthracenes; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D006710:Homocysteine; C007956:homocysteic acid; C432165:pyrazolanthrone; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
keywords: Cytotoxicity; HO-1; Homocysteic acid; JNK; Nrf2; c-Jun