title: Regeneration of glutathione by α-lipoic acid via Nrf2/ARE signaling pathway alleviates cadmium-induced HepG2 cell toxicity.
abstract: Alpha-lipoic acid (α-LA) is an important antioxidant that is capable of regenerating other antioxidants, such as glutathione (GSH). However, the underlying molecular mechanism by which α-LA regenerates GSH remains poorly understood. The current study aimed to investigate whether α-LA regenerates GSH by activation of Nrf2 to alleviate cadmium-induced cytotoxicity in HepG2 cells. In the present study, we found that cadmium induced cell death by depletion of GSH through inactivation of Nrf2. Addition of α-LA to cadmium-treated cells reactivated Nrf2 and regenerated GSH through elevating the Nrf2-downstream genes γ-glutamate-cysteine ligase (γ-GCL) and GR, both of which are key enzymes for GSH synthesis. However, blocking Nrf2 with brusatol in the cells co-treated with α-LA and cadmium reduced the mRNA and the protein levels of γ-GCL and GR, thus suppressed GSH regeneration by α-LA. Our results indicated that α-LA activated Nrf2 signaling pathway, which upregulated the transcription of the enzymes for GSH synthesis and therefore GSH contents to alleviate cadmium-induced cytotoxicity in HepG2 cells.
authors.affiliation: Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, PR China; Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, PR China.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, PR China; Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, PR China.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, PR China; Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, PR China.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Wu
authors.affiliation: Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, PR China; Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, PR China.
authors.forename: Jiachun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, PR China; Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Xie
authors.affiliation: Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, PR China; Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, PR China. Electronic address: great_wuzg@sina.com.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Wu
mesh_terms: D061745:Antioxidant Response Elements / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D000975:Antioxidants / Q000494:pharmacology*; D002104:Cadmium / Q000633:toxicity*; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D004785:Environmental Pollutants / Q000633:toxicity*; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D005978:Glutathione / Q000378:metabolism*; D005980:Glutathione Reductase / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction; D008063:Thioctic Acid / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D004785:Environmental Pollutants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D002104:Cadmium; D008063:Thioctic Acid; D005980:Glutathione Reductase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione
keywords: Cadmium; Glutathione; Nrf2; Regeneration; α-Lipoic acid