Persulfide-Dependent Regulation of Electrophilic Redox Signaling in Neural Cells
Persulfide-Dependent Regulation of Electrophilic Redox Signaling in Neural Cells
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DOI：
10.1089/ars.2020.8130
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发表时间：
2020-07-21
影响因子：
6.6
通讯作者：
Kasamatsu, Shingo
中科院分区：
文献类型：
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作者：
Kasamatsu, Shingo
意义：氧化还原稳态是由复杂的系统，调节生产，消除和亲电物质（亲电体）在神经系统中的代谢精确调制。自从第一次报道了细胞中内源性产生反应性过硫化物物质，如半胱氨酸过硫化物（CysSSH）以来，这些反应性物质一直是氧化还原生物学领域中非常感兴趣的话题;过硫化物/多硫化物具有独特的化学性质，并参与多种细胞功能。研究进展：亲电信号主要受内源性亲电体和外源性亲电体的调节，内源性亲电体由活性氧、一氧化氮及其衍生物在应激反应中产生，外源性亲电体包括食物中的化合物和环境污染物，如甲基汞。8-硝基鸟苷3 '，5'-环一磷酸（8-nitroguanosine 3 '，5'-cyclicmonophosphate，8-nitro-cGMP）是一种内源性的亲电物质，具有独特的氧化还原性质，其生物合成途径、信号转导机制和细胞内代谢已被阐明。关键问题：内源性产生的过硫化物（如CysSSH）与8-硝基-cGMP代谢密切相关。神经元暴露于外源性神经毒物甲基汞，通过破坏过硫化物依赖的8-硝基-cGMP代谢导致严重的神经变性。未来方向：越来越多的证据表明，过硫化物参与各种细胞功能的生理和病理条件下。与过硫化物相关的氧化还原生物学的这些新方面可能是细胞研究、神经退行性疾病的医学和临床研究以及其他领域的前沿。因此，8-硝基cGMP介导的信号传导及其在细胞中的过硫化物依赖性代谢可能是药物开发的潜在目标，这可能导致发现许多疾病的新治疗剂，包括神经退行性疾病。
Significance:Redox homeostasis is precisely modulated by intricate systems that regulate production, elimination, and metabolism of electrophilic substances (electrophiles) in the nervous system. Since the first report of the endogenous production of reactive persulfide species in cells, such as cysteine persulfides (CysSSH), these reactive species have been a topic of extreme interest in the field of redox biology; persulfides/polysulfides possess unique chemical properties and are involved in multiple cellular functions. Recent Advances:Electrophilic signaling is mainly regulated by endogenous electrophiles that are generated from reactive oxygen species, nitric oxide, and their derivatives during stress responses, as well as by exogenous electrophiles, including compounds in foods and environmental pollutants, such as methylmercury (MeHg). Among diverse electrophiles that are endogenously generated, 8-nitroguanosine 3 ',5 '-cyclic monophosphate (8-nitro-cGMP) possesses unique redox properties, of which the biosynthetic pathway, signaling mechanism, and metabolism in cells have been elucidated. Critical Issues:Persulfides, such as CysSSH, that are endogenously produced are critically involved in 8-nitro-cGMP metabolism. Exposure of neurons to the exogenous neurotoxicant, MeHg, causes severe neurodegenerationviadisruption of persulfide-dependent 8-nitro-cGMP metabolism. Future Directions:Accumulating evidence indicates that persulfides are involved in various cellular functions under physiological and pathological conditions. These new aspects of redox biology related to persulfides may be frontiers of cell research, medical and clinical investigations of neurodegenerative diseases, as well as other fields. 8-Nitro-cGMP-mediated signaling and its persulfide-dependent metabolism in cells could, therefore, be potential targets for drug development, which may lead to the discovery of new therapeutic agents for many diseases, including neurodegenerative diseases.