University of California San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C102, San Diego, CA 92103-8467, USA.
J Pharmacol Exp Ther. 2012 Sep;342(3):608-18. doi: 10.1124/jpet.112.192120. Epub 2012 Jun 13.
In this review I report evidence that the mainstream field of oxidative damage biology has been running fast in the wrong direction for more than 50 years. Reactive oxygen species (ROS) and chronic oxidative changes in membrane lipids and proteins found in many chronic diseases are not the result of accidental damage. Instead, these changes are the result of a highly evolved, stereotyped, and protein-catalyzed "oxidative shielding" response that all eukaryotes adopt when placed in a chemically or microbially hostile environment. The machinery of oxidative shielding evolved from pathways of innate immunity designed to protect the cell from attack and limit the spread of infection. Both oxidative and reductive stress trigger oxidative shielding. In the cases in which it has been studied explicitly, functional and metabolic defects occur in the cell before the increase in ROS and oxidative changes. ROS are the response to disease, not the cause. Therefore, it is not the oxidative changes that should be targeted for therapy, but rather the metabolic conditions that create them. This fresh perspective is relevant to diseases that range from autism, type 1 diabetes, type 2 diabetes, cancer, heart disease, schizophrenia, Parkinson's disease, and Alzheimer disease. Research efforts need to be redirected. Oxidative shielding is protective and is a misguided target for therapy. Identification of the causal chemistry and environmental factors that trigger innate immunity and metabolic memory that initiate and sustain oxidative shielding is paramount for human health.
在这篇综述中，我报告了一个证据，即氧化损伤生物学的主流领域在过去 50 多年中一直朝着错误的方向快速发展。在许多慢性疾病中发现的活性氧（ROS）和膜脂质及蛋白质的慢性氧化变化，并不是偶然损伤的结果。相反，这些变化是高度进化的、刻板的、由蛋白质催化的“氧化屏蔽”反应的结果，所有真核生物在处于化学或微生物敌对环境时都会采用这种反应。氧化屏蔽的机制源自先天免疫途径，旨在保护细胞免受攻击并限制感染的传播。氧化和还原应激都会引发氧化屏蔽。在已经被明确研究的情况下，在 ROS 增加和氧化变化之前，细胞中就会出现功能和代谢缺陷。ROS 是疾病的反应，而不是疾病的原因。因此，应该针对引发它们的代谢条件进行治疗，而不是针对氧化变化。这种新视角与从自闭症、1 型糖尿病、2 型糖尿病、癌症、心脏病、精神分裂症、帕金森病和阿尔茨海默病等疾病相关。研究工作需要重新定向。氧化屏蔽具有保护作用，是治疗的一个误导性目标。确定引发先天免疫和代谢记忆的因果化学和环境因素，这些因素会引发并维持氧化屏蔽，对于人类健康至关重要。
