title: Celastrol prevents cadmium-induced neuronal cell death by blocking reactive oxygen species-mediated mammalian target of rapamycin pathway.
abstract: Increasing evidence has suggested cadmium (Cd), as an inducer of ROS, is a potential pathogenic factor in human neurodegenerative diseases. Thus, it is important to find effective interventions for Cd-induced oxidative stress in the CNS. Here, we have studied the effects of celastrol, a plant-derived triterpene, on ROS production and cell death in neuronal cells, induced by Cd.
  
  
  
  PC12, SH-SY5Y cells and primary murine neurons were used to study celastrol neuroprotection against Cd-poisoning. Cd-induced changes in cell viability, apoptosis, ROS and AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway in the cells were analysed by Trypan blue exclusion, DAPI and TUNEL staining, ROS imaging, immunofluorescence staining and Western blotting. Pharmacological and genetic approaches were employed to investigate the mechanisms underlying Cd neurotoxicity.
  
  
  
  Celastrol attenuated Cd-induced apoptosis by suppressing Cd activation of mTOR, which was attributed to preventing Cd inactivation of AMPK. Inhibition of AMPK with compound C or expression of dominant negative AMPKα prevented celastrol from hindering Cd-induced dephosphorylation of AMPKα, activation of mTOR and apoptosis. Inhibition of mTOR with rapamycin or knockdown of mTOR potentiated prevention by celastrol, of Cd-induced phosphorylation of p70 S6 kinase 1/eukaryotic initiation factor 4E binding protein 1 and apoptosis. Celastrol attenuated Cd-induced cell death by suppressing induction of mitochondrial ROS.
  
  
  
  Celastrol prevented the inactivation of AMPK by mitochondrial ROS, thus attenuating Cd-induced mTOR activation and neuronal apoptosis. Celastrol may be a promising agent for prevention of Cd-induced oxidative stress and neurodegenerative diseases.
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, China.
authors.forename: Ruijie
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, China.
authors.forename: Nana
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, China.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Dong
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, China.
authors.forename: Xiaoxue
authors.initials: X
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.|Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: ABSL-III Laboratory for Animal Experiment Center, State Key Laboratory of Virology, Wuhan University School of Medicine, Wuhan, China.
authors.forename: Sijun
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.|Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
authors.forename: Shile
authors.initials: S
authors.lastname: Huang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, China.
authors.forename: Long
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002104:Cadmium / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D053978:Pentacyclic Triterpenes; D017382:Reactive Oxygen Species; D014315:Triterpenes; D002104:Cadmium; D058570:TOR Serine-Threonine Kinases; C050414:celastrol