Institute of Normal and Pathological Physiology, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovak Republic.
Physiol Res. 2020 Dec 31;69(Suppl 4):S541-S553. doi: 10.33549/physiolres.934612.
Reactive oxygen species are an important element of redox regulation in cells and tissues. During physiological processes, molecules undergo chemical changes caused by reduction and oxidation reactions. Free radicals are involved in interactions with other molecules, leading to oxidative stress. Oxidative stress works two ways depending on the levels of oxidizing agents and products. Excessive action of oxidizing agents damages biomolecules, while a moderate physiological level of oxidative stress (oxidative eustress) is necessary to control life processes through redox signaling required for normal cellular operation. High levels of reactive oxygen species (ROS) mediate pathological changes. Oxidative stress helps to regulate cellular phenotypes in physiological and pathological conditions. Nrf2 (nuclear factor erythroid 2-related factor 2, NFE2L2) transcription factor functions as a target nuclear receptor against oxidative stress and is a key factor in redox regulation in hypertension and cardiovascular disease. Nrf2 mediates transcriptional regulation of a variety of target genes. The Keap1-Nrf2-ARE system regulates many detoxification and antioxidant enzymes in cells after the exposure to reactive oxygen species and electrophiles. Activation of Nrf2/ARE signaling is differentially regulated during acute and chronic stress. Keap1 normally maintains Nrf2 in the cytosol and stimulates its degradation through ubiquitination. During acute oxidative stress, oxidized molecules modify the interaction of Nrf2 and Keap1, when Nrf2 is released from the cytoplasm into the nucleus where it binds to the antioxidant response element (ARE). This triggers the expression of antioxidant and detoxification genes. The consequence of long-term chronic oxidative stress is activation of glycogen synthase kinase 3beta (GSK-3beta) inhibiting Nrf2 activity and function. PPARgamma (peroxisome proliferator-activated receptor gamma) is a nuclear receptor playing an important role in the management of cardiovascular diseases, hypertension and metabolic syndrome. PPARgamma targeting of genes with peroxisome proliferator response element (PPRE) has led to the identification of several genes involved in lipid metabolism or oxidative stress. PPARgamma stimulation is triggered by endogenous and exogenous ligands - agonists and it is involved in the activation of several cellular signaling pathways involved in oxidative stress response, such as the PI3K/Akt/NOS pathway. Nrf2 and PPARgamma are linked together with their several activators and Nrf2/ARE and PPARgamma/PPRE pathways can control several types of diseases.
活性氧是细胞和组织氧化还原调节的重要组成部分。在生理过程中，分子会经历由还原和氧化反应引起的化学变化。自由基参与与其他分子的相互作用，导致氧化应激。氧化应激有两种作用方式，具体取决于氧化剂和产物的水平。氧化剂的过度作用会破坏生物分子，而适度的生理水平的氧化应激（氧化适应）对于通过正常细胞功能所需的氧化还原信号控制生命过程是必要的。高水平的活性氧（ROS）介导病理性变化。氧化应激有助于调节生理和病理条件下的细胞表型。Nrf2（核因子红细胞 2 相关因子 2，NFE2L2）转录因子作为针对氧化应激的靶核受体发挥作用，是高血压和心血管疾病中氧化还原调节的关键因素。Nrf2 介导多种靶基因的转录调节。Keap1-Nrf2-ARE 系统在细胞暴露于活性氧和亲电子物质后调节细胞内的许多解毒和抗氧化酶。在急性和慢性应激期间，Nrf2/ARE 信号的激活受到差异调节。Keap1 通常将 Nrf2 维持在细胞质中，并通过泛素化刺激其降解。在急性氧化应激期间，氧化分子修饰 Nrf2 和 Keap1 的相互作用，此时 Nrf2 从细胞质释放到细胞核内，与抗氧化反应元件（ARE）结合。这触发了抗氧化和解毒基因的表达。长期慢性氧化应激的后果是激活糖原合酶激酶 3beta（GSK-3beta）抑制 Nrf2 活性和功能。PPARγ（过氧化物酶体增殖物激活受体γ）是一种核受体，在心血管疾病、高血压和代谢综合征的管理中发挥重要作用。过氧化物酶体增殖物反应元件（PPRE）的基因靶向已导致几种参与脂质代谢或氧化应激的基因的鉴定。PPARγ 配体的刺激由内源性和外源性配体（激动剂）触发，它参与涉及氧化应激反应的几种细胞信号通路的激活，如 PI3K/Akt/NOS 通路。Nrf2 和 PPARγ 通过它们的几种激活剂相互连接，并且 Nrf2/ARE 和 PPARγ/PPRE 途径可以控制几种类型的疾病。
