title: Cadmium Activates Reactive Oxygen Species-dependent AKT/mTOR and Mitochondrial Apoptotic Pathways in Neuronal Cells.
abstract: OBJECTIVE
  To examine the role of Cd-induced reactive oxygen species (ROS) generation in the apoptosis of neuronal cells.
  
  
  METHODS
  Neuronal cells (primary rat cerebral cortical neurons and PC12 cells) were incubated with or without Cd post-pretreatment with rapamycin (Rap) or N-acetyl-L-cysteine (NAC). Cell viability was determined by MTT assay, apoptosis was examined using flow cytometry and fluorescence microscopy, and the activation of phosphoinositide 3'-kinase/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and mitochondrial apoptotic pathways were measured by western blotting or immunofluorescence assays.
  
  
  RESULTS
  Cd-induced activation of Akt/mTOR signaling, including Akt, mTOR, p70 S6 kinase (p70 S6K), and eukaryotic initiation factor 4E binding protein 1 (4E-BP1). Rap, an mTOR inhibitor and NAC, a ROS scavenger, blocked Cd-induced activation of Akt/mTOR signaling and apoptosis of neuronal cells. Furthermore, NAC blocked the decrease of B-cell lymphoma 2/Bcl-2 associated X protein (Bcl-2/Bax) ratio, release of cytochrome c, cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP), and nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G (Endo G).
  
  
  CONCLUSIONS
  Cd-induced ROS generation activates Akt/mTOR and mitochondrial pathways, leading to apoptosis of neuronal cells. Our findings suggest that mTOR inhibitors or antioxidants have potential for preventing Cd-induced neurodegenerative diseases.
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China.
authors.forename: Fei Fei
authors.initials: FF
authors.lastname: Hu
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China.
authors.forename: Chen Yang
authors.initials: CY
authors.lastname: Jiang
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China.
authors.forename: Ya Jing
authors.initials: YJ
authors.lastname: Zhang
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China.
authors.forename: Jin Long
authors.initials: JL
authors.lastname: Yang
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China.
authors.forename: Shi Wen
authors.initials: SW
authors.lastname: Zhao
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China.
authors.forename: Jian Hong
authors.initials: JH
authors.lastname: Gu
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China.
authors.forename: Xue Zhong
authors.initials: XZ
authors.lastname: Liu
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China.
authors.forename: Jian Chun
authors.initials: JC
authors.lastname: Bian
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China.
authors.forename: Zong Ping
authors.initials: ZP
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002104:Cadmium / Q000633:toxicity*; D020169:Caspases / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D016716:PC12 Cells; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D002104:Cadmium; C546845:mTOR protein, rat; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020169:Caspases
keywords: AKT/mTOR pathway; Apoptosis; Cadmium; Mitochondrial apoptotic pathway; PC12 cells; Primary rat cerebral cortical neurons