title: Dysfunction of methionine sulfoxide reductases to repair damaged proteins by nickel nanoparticles.
abstract: BACKGROUND
  Protein oxidation is considered to be one of the main causes of cell death, and methionine is one of the primary targets of reactive oxygen species (ROS). However, the mechanisms by which nickel nanoparticles (NiNPs) cause oxidative damage to proteins remain unclear.
  
  
  OBJECTIVE
  The objective of this study is to investigate the effects of NiNPs on the methionine sulfoxide reductases (MSR) protein repairing system.
  
  
  METHODS
  Two physically similar nickel-based nanoparticles, NiNPs and carbon-coated NiNP (C-NiNPs; control particles), were exposed to human epithelial A549 cells. Cell viability, benzo(a)pyrene diolepoxide (BPDE) protein adducts, methionine oxidation, MSRA and B3, microtubule-associated protein 1A/1B-light chain 3 (LC3) and extracellular signal-regulated kinase (ERK) phosphorylation were investigated.
  
  
  RESULTS
  Exposure to NiNPs led to a dose-dependent reduction in cell viability and increased BPDE protein adduct production and methionine oxidation. The methionine repairing enzymatic MSRA and MSRB3 production were suppressed in response to NiNP exposure, suggesting the oxidation of methionine to MetO by NiNP was not reversed back to methionine. Additionally, LC3, an autophagy marker, was down-regulated by NiNPs. Both NiNP and C-NiNP caused ERK phosphorylation. LC3 was positively correlated with MSRA (r = 0.929, p < 0.05) and MSRB3 (r = 0.893, p < 0.05).
  
  
  CONCLUSIONS
  MSR was made aberrant by NiNP, which could lead to the dysfunction of autophagy and ERK phosphorylation. The toxicological consequences may be dependent on the chemical characteristics of the nanoparticles.
authors.affiliation: Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: 13199@s.tmu.edu.tw.
authors.forename: Po-Hao
authors.initials: PH
authors.lastname: Feng
authors.affiliation: Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan. Electronic address: ylhuang@tmu.edu.tw.
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Huang
authors.affiliation: Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan. Electronic address: kjc@tmu.edu.tw.
authors.forename: Kai-Jen
authors.initials: KJ
authors.lastname: Chuang
authors.affiliation: Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: a112378633@gmail.com.
authors.forename: Kuan-Yuan
authors.initials: KY
authors.lastname: Chen
authors.affiliation: Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: kangyunlee68@gmail.com.
authors.forename: Kang-Yun
authors.initials: KY
authors.lastname: Lee
authors.affiliation: Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan; School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: shu-chuan@tmu.edu.tw.
authors.forename: Shu-Chuan
authors.initials: SC
authors.lastname: Ho
authors.affiliation: School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan. Electronic address: mybien@tmu.edu.tw.
authors.forename: Mauo-Ying
authors.initials: MY
authors.lastname: Bien
authors.affiliation: School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: ylyang@tmu.edu.tw.
authors.forename: You-Lan
authors.initials: YL
authors.lastname: Yang
authors.affiliation: Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan; School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: r92841005@ntu.edu.tw.
authors.forename: Hsiao-Chi
authors.initials: HC
authors.lastname: Chuang
mesh_terms: D001580:Benzopyrenes / Q000378:metabolism; D002460:Cell Line / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D053768:Metal Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D008715:Methionine / Q000378:metabolism; D051150:Methionine Sulfoxide Reductases / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009532:Nickel / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects
chemical_list: D001580:Benzopyrenes; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C072116:BPDE-II; D009532:Nickel; D008715:Methionine; D051150:Methionine Sulfoxide Reductases; C027219:methionine sulfoxide reductase; C524352:MSRB3 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Autophagy; Benzo(a)pyrene diolepoxide protein adduct; Extracellular signal-regulated kinase; Methionine oxidation; Methionine sulfoxide reductases; Nickel nanoparticle