Redox regulation of antioxidants, autophagy, and the response to stress: implications for electrophile therapeutics.
Redox regulation of antioxidants, autophagy, and the response to stress: implications for electrophile therapeutics.
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DOI：
10.1016/j.freeradbiomed.2014.03.025
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发表时间：
2014-06
影响因子：
7.4
通讯作者：
Darley-Usmar, Victor M.
中科院分区：
文献类型：
--
作者：
Levonen, Anna-Liisa;Hill, Bradford G.;Kansanen, Emilia;Zhang, Jianhua;Darley-Usmar, Victor M.
细胞内的氧化还原网络整合了控制新陈代谢、能量、细胞存活和死亡的信号通路。调节这些途径的生理第二信使包括一氧化氮、过氧化氢和亲电体。亲电体通过酶和非酶的脂质过氧化在细胞中产生，也是饮食中相对丰富的成分。这些化合物与含有半胱氨酸的氧化还原敏感蛋白家族共价结合，这些家族构成了电泳响应蛋白质组，其亚蛋白质组存在于定位的细胞内域中。这些蛋白质包括那些控制对胞浆中氧化应激反应的蛋白质，特别是Keap1-Nrf2途径，自噬-溶酶体途径，以及其他隔室中的蛋白质，包括线粒体和内质网。亲电体发挥作用的信号通路具有独特的特性，可用于新的治疗干预措施；然而，由于缺乏对这种形式的氧化还原信号控制机制的基本了解，此类治疗策略的开发一直具有挑战性。在这篇综述中，我们讨论了目前对硫醇亲电信号的基本机制的了解，以及它对将这一重要的氧化还原生物学领域转化到临床上的潜在影响。对硫代电泳体相互作用和氧化还原信号的理解表明，氧化应激假说被一种新的氧化还原生物学范式所取代，这为指导翻译研究提供了一个令人兴奋和有影响力的框架。
Redox networks in the cell integrate signaling pathways that control metabolism, energetics, cell survival, and death. The physiological second messengers that modulate these pathways include nitric oxide, hydrogen peroxide, and electrophiles. Electrophiles are produced in the cell via both enzymatic and nonenzymatic lipid peroxidation and are also relatively abundant constituents of the diet. These compounds bind covalently to families of cysteine-containing, redox-sensing proteins that constitute the electrophile-responsive proteome, the subproteomes of which are found in localized intracellular domains. These include those proteins controlling responses to oxidative stress in the cytosol—notably the Keap1-Nrf2 pathway, the autophagy-lysosomal pathway, and proteins in other compartments including mitochondria and endoplasmic reticulum. The signaling pathways through which electro-philes function have unique characteristics that could be exploited for novel therapeutic interventions; however, development of such therapeutic strategies has been challenging due to a lack of basic understanding of the mechanisms controlling this form of redox signaling. In this review, we discuss current knowledge of the basic mechanisms of thiol-electrophile signaling and its potential impact on the translation of this important field of redox biology to the clinic. Emerging understanding of thiolelectrophile interactions and redox signaling suggests replacement of the oxidative stress hypothesis with a new redox biology paradigm, which provides an exciting and influential framework for guiding translational research.
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影响因子：
3.3
作者：
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通讯作者：
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DOI：
10.1152/ajpheart.00378.2004
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影响因子：
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作者：
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