title: Nrf2 signaling contributes to the neuroprotective effects of urate against 6-OHDA toxicity.
abstract: BACKGROUND
  Mounting evidence shows that urate may become a biomarker of Parkinson's disease (PD) diagnosis and prognosis and a neuroprotectant candidate for PD therapy. However, the cellular and molecular mechanisms underlying its neuroprotective actions remain poorly understood.
  
  
  RESULTS
  In this study, we showed that urate pretreatment protected dopaminergic cell line (SH-SY5Y and MES23.5) against 6-hydroxydopamine (6-OHDA)- and hydrogen peroxide- induced cell damage. Urate was found to be accumulated into SH-SY5Y cells after 30 min treatment. Moreover, urate induced NF-E2-related factor 2 (Nrf2) accumulation by inhibiting its ubiquitinationa and degradation, and also promoted its nuclear translocation; however, it did not modulate Nrf2 mRNA level or Kelch-like ECH-associated protein 1 (Keap1) expression. In addition, urate markedly up-regulated the transcription and protein expression of γ-glutamate-cysteine ligase catalytic subunit (γ-GCLC) and heme oxygenase-1 (HO-1), both of which are controlled by Nrf2 activity. Furthermore, Nrf2 knockdown by siRNA abolished the intracellular glutathione augmentation and the protection exerted by urate pretreatment.
  
  
  CONCLUSIONS
  Our findings demonstrated that urate treatment may result in Nrf2-targeted anti-oxidant genes transcription and expression by reducing Nrf2 ubiquitination and degradation and promoting its nuclear translocation, and thus offer neuroprotection on dopaminergic cells against oxidative stresses.
authors: Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu, China; Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China.
authors: Ning
authors: N
authors: Zhang
authors: Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu, China.
authors: Hai-Yang
authors: HY
authors: Shu
authors: Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu, China; Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China.
authors: Tingting
authors: T
authors: Huang
authors: Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu, China.
authors: Qi-Lin
authors: QL
authors: Zhang
authors: Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu, China.
authors: Da
authors: D
authors: Li
authors: Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu, China.
authors: Guan-Qun
authors: GQ
authors: Zhang
authors: Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu, China.
authors: Xiao-Yan
authors: XY
authors: Peng
authors: Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu, China; Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China.
authors: Chun-Feng
authors: CF
authors: Liu
authors: Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu, China; Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China.
authors: Wei-Feng
authors: WF
authors: Luo
authors: Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu, China; Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China; Department of Pharmacology, Soochow University, Suzhou, Jiangsu, China.
authors: Li-Fang
authors: LF
authors: Hu
mesh_terms: D021581:Active Transport, Cell Nucleus; D002460:Cell Line; D045744:Cell Line, Tumor; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016627:Oxidopamine / Q000633:toxicity*; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D034622:RNA Interference; D015398:Signal Transduction; D014158:Transcription, Genetic; D054875:Ubiquitination / Q000187:drug effects; D014527:Uric Acid / Q000494:pharmacology*
chemical_list: D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D014527:Uric Acid; D016627:Oxidopamine; D006861:Hydrogen Peroxide