title: Carbon disulfide activates p62-Nrf2-keap1 pathway in rat nerve tissues.
abstract: Oxidative stress is associated with the pathogenesis of carbon disulfide (CS2) induced polyneuropathy. The nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in protecting cells against oxidative stress. However, whether there exists a Nrf2-mediated antioxidative machinery in CS2-induced neuropathy has not been elucidated. In the present study, male wistar rats were randomly divided into three experimental groups and one control group. The rats in experimental groups were treated with CS2by gavage at dosages of 200, 400 and 600mg/kg/day respectively, six times per week for 6 weeks. Nrf2-keap1 antioxidative pathway and p62-related kinase signaling in rat nerve tissues was examined by western blotting and real-time PCR. The results demonstrated that CS2treatment resulted in Nrf2 translocation from the cytosol to the nucleus in rat spinal cords. In the meantime, the expression of antioxidative enzymes such as NAD(P)H quinone oxidoreductase-1, heme oxygenase-1, and glutamate-cysteine ligase was significantly increased. Furthermore, CS2treatment increased the level of p62 and its phosphorylation status, while decreased the level of keap1. In addition, CS2also lead to the activation of CAMKK2 and ULK1 kinase signaling in rat spinal cords and sciatic nerves. Taken together, our results indicated that CS2intoxication was associated with the activation of Nrf2-ARE antioxidative machinery, which might play a protective role against CS2-induced neuronal damage.
authors.affiliation: Institute of Toxicology, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, PR China; Center for Disease Control and Prevention of Hongta District, 34 Mingzhu Road, Yuxi, Yunnan, 653100, PR China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Wang
authors.affiliation: Institute of Toxicology, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, PR China.
authors.forename: Yisi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute of Toxicology, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, PR China.
authors.forename: Ruirui
authors.initials: R
authors.lastname: Kou
authors.affiliation: Institute of Toxicology, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Toxicology, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zeng
authors.affiliation: Institute of Toxicology, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, PR China.
authors.forename: Keqin
authors.initials: K
authors.lastname: Xie
authors.affiliation: Institute of Toxicology, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, PR China. Electronic address: fysong3707@sdu.edu.cn.
authors.forename: Fuyong
authors.initials: F
authors.lastname: Song
mesh_terms: D000818:Animals; D002246:Carbon Disulfide / Q000494:pharmacology*; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009417:Nerve Tissue / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D011115:Polyneuropathies / Q000139:chemically induced / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D000071456:Sequestosome-1 Protein / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
chemical_list: C486610:KEAP1 protein, rat; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D000071456:Sequestosome-1 Protein; C491079:Sqstm1 protein, rat; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; D005721:Glutamate-Cysteine Ligase; D002246:Carbon Disulfide
keywords: Carbon disulfide; Nuclear factor erythroid 2-related factor 2 (Nrf2); Toxic neuropathy