Exposure to Electrophiles Impairs Reactive Persulfide-Dependent Redox Signaling in Neuronal Cells
Exposure to Electrophiles Impairs Reactive Persulfide-Dependent Redox Signaling in Neuronal Cells
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DOI：
10.1021/acs.chemrestox.7b00120
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发表时间：
2017-09-01
影响因子：
4.1
通讯作者：
Akaike, Takaaki
中科院分区：
文献类型：
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作者：
Ihara, Hideshi;Kasamatsu, Shingo;Akaike, Takaaki
亲电体如甲基汞（MeHg）通过与内源性硫醇共价修饰来影响细胞功能。活性过硫化物因其强的亲核性而介导抗氧化反应和氧化还原信号传导。在这项研究中，我们使用甲基汞作为环境亲电试剂，发现细胞暴露于外源亲电试剂会升高内源性亲电分子8-硝基鸟苷3 '，5'-环一磷酸（8-nitro-cGMP）的细胞内浓度，并伴有反应性过硫化物和8-SH-cGMP（8-nitro-cGMP的代谢产物）的消耗。暴露于甲基汞还诱导S-鸟苷酸化和激活的H-Ras随后损伤小脑颗粒神经元。亲电诱导的氧化还原信号的激活和随之而来的细胞损伤减弱预处理与反应性过硫化物物种供体。总之，外源性亲电体，如甲基汞具有较强的亲电性损害的氧化还原信号调节机制，特别是细胞内的活性过硫化物物种，因此导致细胞的发病机制。我们的研究结果表明，活性过硫化物物种可能是潜在的治疗目标，为减轻细胞损伤的亲电试剂。
Electrophiles such as methylmercury (MeHg) affect, cellular functions by covalent modification with endogenous thiols. Reactive persulfide species were recently reported to mediate antioxidant responses and redox signaling because of their strong nucleophilicity. In this study, we used MeHg as an environmental electrophile and found that exposure of cells to the exogenous electrophile elevated intracellular concentrations of the endogenous electrophilic molecule 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), accompanied by depletion of reactive persulfide species and 8-SH-cGMP which is a metabolite of 8-nitro-cGMP. Exposure to MeHg also induced S-guanylation and activation of H-Ras followed by injury to cerebellar granule neurons. The electrophile-induced activation of redox signaling and the consequent cell damage were attenuated by pretreatment with a reactive persulfide species donor. In conclusion, exogenous electrophiles such as MeHg with strong electrophilicity impair the redox signaling regulatory mechanism, particularly of intracellular reactive persulfide species and therefore lead to cellular pathogenesis. Our results suggest that reactive persulfide species may be potential therapeutic targets for attenuating cell injury by electrophiles.