Deshmukh Prashant, Unni Sruthi, Krishnappa Gopinatha, Padmanabhan Balasundaram
Department of Biophysics, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India.
Biophys Rev. 2017 Feb;9(1):41-56. doi: 10.1007/s12551-016-0244-4. Epub 2016 Dec 6.
The overproduction of reactive oxygen species (ROS) generates oxidative stress in cells. Oxidative stress results in various pathophysiological conditions, especially cancers and neurodegenerative diseases (NDD). The Keap1-Nrf2 [Kelch-like ECH-associated protein 1-nuclear factor (erythroid-derived 2)-like 2] regulatory pathway plays a central role in protecting cells against oxidative and xenobiotic stresses. The Nrf2 transcription factor activates the transcription of several cytoprotective genes that have been implicated in protection from cancer and NDD. The Keap1-Nrf2 system acts as a double-edged sword: Nrf2 activity protects cells and makes the cell resistant to oxidative and electrophilic stresses, whereas elevated Nrf2 activity helps in cancer cell survival and proliferation. Several groups in the recent past, from both academics and industry, have reported the potential role of Nrf2-mediated transcription to protect from cancer and NDD, resulting from mechanisms involving xenobiotic and oxidative stress. It suggests that the Keap1-Nrf2 system is a potential therapeutic target to combat cancer and NDD by designing and developing modulators (inhibitors/activators) for Nrf2 activation. Herein, we review and discuss the recent advancement in the regulation of the Keap1-Nrf2 system, its role under physiological and pathophysiological conditions including cancer and NDD, and modulators design strategies for Nrf2 activation.
活性氧（ROS）的过度产生会在细胞中引发氧化应激。氧化应激会导致各种病理生理状况，尤其是癌症和神经退行性疾病（NDD）。Keap1-Nrf2[kelch样ECH相关蛋白1-核因子（红细胞衍生2）样2]调控通路在保护细胞免受氧化应激和外源性应激方面发挥着核心作用。Nrf2转录因子激活了几个细胞保护基因的转录，这些基因与预防癌症和NDD有关。Keap1-Nrf2系统犹如一把双刃剑：Nrf2活性保护细胞并使细胞对氧化应激和亲电应激产生抗性，而Nrf2活性升高则有助于癌细胞的存活和增殖。近期，学术界和工业界的几个团队都报道了Nrf2介导的转录在预防癌症和NDD方面的潜在作用，其机制涉及外源性应激和氧化应激。这表明，通过设计和开发Nrf2激活调节剂（抑制剂/激活剂），Keap1-Nrf2系统是对抗癌症和NDD的潜在治疗靶点。在此，我们回顾并讨论Keap1-Nrf2系统调控的最新进展、其在生理和病理生理状况（包括癌症和NDD）下的作用以及Nrf2激活的调节剂设计策略。
