title: DSePA Antagonizes High Glucose-Induced Neurotoxicity: Evidences for DNA Damage-Mediated p53 Phosphorylation and MAPKs and AKT Pathways.
abstract: Hyperglycemia as the major hallmark of diabetic neuropathy severely limited its therapeutic efficiency. Evidences have revealed that selenium (Se) as an essential trace element could effectively reduce the risk of neurological diseases. In the present study, 3,3'-diselenodipropionic acid (DSePA), a derivative of selenocystine, was employed to investigate its protective effect against high glucose-induced neurotoxicity in PC12 cells and evaluate the underlying mechanism. The results suggested that high glucose showed significant cytotoxicity through launching mitochondria-mediated apoptosis in PC12 cells, accompanied by poly (ADP-ribose) polymerase (PARP) cleavage, caspase activation, and mitochondrial dysfunction. Moreover, high glucose also triggered DNA damage and dysregulation of MAPKs and AKT pathways through reactive oxygen species (ROS) overproduction. p53 RNA interference partially suppressed high glucose-induced cytotoxicity and apoptosis, indicating the role of p53 in high glucose-induced signal. However, DSePA pretreatment effectively attenuated high glucose-induced cytotoxicity, inhibited the mitochondrial dysfunction through regulation of Bcl-2 family, and ultimately reversed high glucose-induced apoptotic cell death in PC12 cells. Attenuation of caspase activation, PARP cleavage, DNA damage, and ROS accumulation all confirmed its protective effects. Moreover, DSePA markedly alleviated the dysregulation of AKT and MAPKs pathways induced by high glucose. Our findings revealed that the strategy of using DSePA to antagonize high glucose-induced neurotoxicity may be a highly effective strategy in combating high glucose-mediated neurological diseases.
authors.affiliation: Key Lab of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China.|Taishan Vocational College of Nursing, Taian, Shandong, 271000, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.affiliation: School of Basic Medicine, Taishan Medical University, Taian, Shandong, 271000, China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Fu
authors.affiliation: Key Lab of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China.
authors.forename: Xiao-Ting
authors.initials: XT
authors.lastname: Fu
authors.affiliation: Key Lab of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China.
authors.forename: Ya-Jun
authors.initials: YJ
authors.lastname: Hou
authors.affiliation: Key Lab of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Fang
authors.affiliation: Key Lab of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Key Lab of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China.
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Yang
authors.affiliation: Key Lab of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China.
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Li
authors.affiliation: Key Lab of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China.
authors.forename: Lei-Lei
authors.initials: LL
authors.lastname: Mao
authors.affiliation: Taishan Vocational College of Nursing, Taian, Shandong, 271000, China.
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Sun
authors.affiliation: Affiliated Hospital of Taishan Medical University, Taian, Shandong, 271000, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Key Lab of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China.
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Yang
authors.affiliation: Key Lab of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China. tsmc_nks@tsmc.edu.cn.
authors.forename: Cun-Dong
authors.initials: CD
authors.lastname: Fan
authors.affiliation: Key Lab of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China. zongyongzhanghust@163.com.
authors.forename: Zong-Yong
authors.initials: ZY
authors.lastname: Zhang
authors.affiliation: Key Lab of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China. blsun@tsmc.edu.cn.|Affiliated Hospital of Taishan Medical University, Taian, Shandong, 271000, China. blsun@tsmc.edu.cn.
authors.forename: Bao-Liang
authors.initials: BL
authors.lastname: Sun
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004249:DNA Damage; D005947:Glucose / Q000633:toxicity*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009498:Neurotoxins / Q000633:toxicity*; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D018036:Selenium Compounds / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C524945:3,3'-diselenodipropionic acid; D009498:Neurotoxins; D011422:Propionates; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D018036:Selenium Compounds; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
keywords: Apoptosis; DNA damage; Hyperglycemia; Selenium; p53 phosphorylation