Ursini Fulvio, Maiorino Matilde, Forman Henry Jay
Department of Molecular Medicine, University of Padova, Viale G. Colombo 3, I-35121 Padova, Italy.
Andrus Gerontology Center of the Davis School of Gerontology, University of Southern, California, 3715 McClintock Ave, Los Angeles, CA 90089-0191, USA.
Redox Biol. 2016 Aug;8:205-15. doi: 10.1016/j.redox.2016.01.010. Epub 2016 Jan 19.
The notion that electrophiles serve as messengers in cell signaling is now widely accepted. Nonetheless, major issues restrain acceptance of redox homeostasis and redox signaling as components of maintenance of a normal physiological steady state. The first is that redox signaling requires sudden switching on of oxidant production and bypassing of antioxidant mechanisms rather than a continuous process that, like other signaling mechanisms, can be smoothly turned up or down. The second is the misperception that reactions in redox signaling involve "reactive oxygen species" rather than reaction of specific electrophiles with specific protein thiolates. The third is that hormesis provides protection against oxidants by increasing cellular defense or repair mechanisms rather than by specifically addressing the offset of redox homeostasis. Instead, we propose that both oxidant and antioxidant signaling are main features of redox homeostasis. As the redox shift is rapidly reversed by feedback reactions, homeostasis is maintained by continuous signaling for production and elimination of electrophiles and nucleophiles. Redox homeostasis, which is the maintenance of nucleophilic tone, accounts for a healthy physiological steady state. Electrophiles and nucleophiles are not intrinsically harmful or protective, and redox homeostasis is an essential feature of both the response to challenges and subsequent feedback. While the balance between oxidants and nucleophiles is preserved in redox homeostasis, oxidative stress provokes the establishment of a new radically altered redox steady state. The popular belief that scavenging free radicals by antioxidants has a beneficial effect is wishful thinking. We propose, instead, that continuous feedback preserves nucleophilic tone and that this is supported by redox active nutritional phytochemicals. These nonessential compounds, by activating Nrf2, mimic the effect of endogenously produced electrophiles (parahormesis). In summary, while hormesis, although globally protective, results in setting up of a new phenotype, parahormesis contributes to health by favoring maintenance of homeostasis.
亲电试剂在细胞信号传导中充当信使这一观点如今已被广泛接受。尽管如此，一些主要问题限制了氧化还原稳态和氧化还原信号传导作为维持正常生理稳态组成部分的被接受程度。第一个问题是，氧化还原信号传导需要突然开启氧化剂生成并绕过抗氧化机制，而不是像其他信号传导机制那样可以平稳上调或下调的连续过程。第二个问题是误解，即氧化还原信号传导中的反应涉及“活性氧物种”，而不是特定亲电试剂与特定蛋白质硫醇盐的反应。第三个问题是，应激效应通过增强细胞防御或修复机制来提供对氧化剂的保护，而不是通过专门解决氧化还原稳态的偏移。相反，我们提出氧化剂和抗氧化剂信号传导都是氧化还原稳态的主要特征。由于氧化还原转变通过反馈反应迅速逆转，通过亲电试剂和亲核试剂生成与消除的连续信号传导来维持稳态。氧化还原稳态，即亲核基调的维持，构成了健康的生理稳态。亲电试剂和亲核试剂本身并非有害或具有保护作用，氧化还原稳态是应对挑战及后续反馈的基本特征。虽然在氧化还原稳态中氧化剂和亲核试剂之间的平衡得以维持，但氧化应激会引发一种全新的、根本改变的氧化还原稳态的建立。认为抗氧化剂清除自由基具有有益作用的普遍观点只是一厢情愿。相反，我们提出连续反馈维持亲核基调，这得到了具有氧化还原活性的营养植物化学物质的支持。这些非必需化合物通过激活Nrf2，模拟内源性产生的亲电试剂的作用（类应激效应）。总之，虽然应激效应虽然具有全局保护作用，但会导致新表型的形成，而类应激效应通过促进稳态维持对健康有益。
