氧化和化学应激的防御性转导通路——Nrf2/ARE

Nrf2/ARE是近年新发现的机体抵抗内外界氧化和化学等刺激的防御性转导通路．生理条件下,NF-E2相关因子2(Nrf2,NF-E2-related factor 2)在细胞质中与Keap1结合处于非活性、易降解的状态.在内外界自由基和化学物质刺激时,Keap1的构象改变或者Nrf2直接被磷酸化,导致Nrf2与Keap1解离而活化．活化的Nrf2进入细胞核,与抗氧化反应元件(ARE)结合,启动ARE下游的Ⅱ相解毒酶、抗氧化蛋白、蛋白酶体/分子伴侣等基因转录和表达以抵抗内外界的有害刺激．MAPK、PI3K/AKT、PKC等信号通路分子广泛参与了Nrf2的活化和核转位过程,但是具体何种通路被激动、何种通路发挥主导作用,取决于刺激物种类、刺激方式和细胞类型．本文就Nrf2分子结构、Nrf2活化机制、Nrf2/ARE调控的下游基因、与Nrf2相关的信号通路分子以及其在肿瘤、炎症、衰老等应用领域的最新进展进行综述．     

Recent Advances of Natural Polyphenols Activators for Keap1‐Nrf2 Signaling Pathway

The Keap1‐Nrf2/ARE signaling pathway is an important defense system against exogenous and endogenous oxidative stress injury. The dysregulation of the signaling pathway is associated with many diseases, such as cancer, diabetes, and respiratory diseases. Over the years, a wide range of natural products has provided sufficient resources for the discovery of potential therapeutic drugs. Among them, polyphenols possess Nrf2 activation, not only inhibit the production of ROS, inhibit Keap1‐Nrf2 protein–protein interaction, but also degrade Keap1 and regulate the Nrf2 related pathway. In fact, with the continuous improvement of natural polyphenols separation and purification technology and further studies on the Keap1‐Nrf2 molecular mechanism, more and more natural polyphenols monomer components of Nrf2 activators have been gradually discovered. In this view, we summarize the research status of natural polyphenols that have been found with apparent Nrf2 activation and their action modes. On the whole, this review may guide the design of novel Keap1‐Nrf2 activator.     

Plant phenols and autophagy

Many plant phenols (stilbenes, curcumins, catechins, flavonoids, etc.) are effective antioxidants and protect cells during oxidative stress. Extensive clinical studies on the potential of phenolic compounds for treatment of cardiovascular, neurodegenerative, oncological, and inflammatory diseases are now being conducted. In addition to direct antioxidant effect, plant phenols may provide a protective effect via activation of the Keap1/Nrf2/ARE redox-sensitive signaling system and regulation of autophagy. In this review, mechanisms of effects of the most common plant phenols on autophagy are presented.     

Involvement of Nrf2 and Keap1 in the activation of antioxidant responsive element (ARE) by chemopreventive agent peptides from soft-shelled turtle

The antioxidant response element (ARE) is a cis-acting enhancer sequence located in the region containing genes related to antioxidant and detoxification. Under oxidative stress, the induction of nuclear factor-E2-related factor 2 (Nrf2)/ARE is considered as a fundamental process involved in defending reactive oxygen species (ROS) and providing protection against toxic xenobiotics. In this study, we obtained seven antioxidant peptides from soft-shelled turtle and concluded that Glu-Asp-Tyr-Gly-Ala (EDYGA) is the most potent ARE-luciferase inducer. To gain fundamental insights into the role of EDYGA in oxidative stress, we evaluated the effects of EDYGA on the Nrf2/Keap1 system in HepG₂ cells. The results revealed that EDYGA modulated the Nrf2/ARE pathway by enhancing Nrf2 level through the stabilization of Nrf2, which was accomplished by a decrease in the level of Keap1. These actions eventually led to an increase in nuclear Nrf2 accumulation and ARE-binding activity. Moreover, silencing Nrf2 markedly reduced ARE-driven activity induced by EDYGA. Docking results proved that glutamate residues of peptide EDYGA directly bind to Arg 415 of Kelch domain receptor pocke. The results were helpful in understanding the antioxidant activity of peptides from soft-shelled turtle which have potential to be used in foods and drugs as functional ingredients.     

Keap1/Nrf2/ARE通路相关基因在热诱导的氧化应激小鼠肝脏中的表达

为了研究热应激对小鼠肝脏抗氧化功能及Keap1 (kelch-like ECH-associated protein- 1)/Nrf2（NF-E2-related factor 2）/ARE (antioxidant response element)通路相关基因表达的影响,选用30只8周龄雄性小鼠随机分成6组,每 d连续42 ℃热处理2 h,分别在热处理0 d(对照组)、1 d、2 d、4 d、8 d和12 d时观察肝脏组织形态学和免疫组织化学分析,另取一部分肝脏组织保存于-80 ℃用于后续荧光定量PCR实验,检测肝脏抗氧化指标及Keap1/Nrf2/ARE通路相关基因的表达．结果显示：小鼠的体表温度和直肠温度在热处理后都极显著高于热处理前．组织形态学观察发现,热处理导致小鼠肝脏组织充血和肝细胞水肿．小鼠肝脏氧化应激指标 MDA (malondialdehyde)含量在热处理第2 d较对照组显著升高,GSH (glutathione)含量、GSH-PX (glutathione peroxidase)活力和总SOD (superoxide dismutase)活力在第4 d和12 d都有升高．免疫组织化学发现,与对照组和第12 d组相比,Nrf2蛋白在第1 d,2 d,4 d,8 d表达明显,其中Nrf2蛋白在第4 d表达最为显著. 荧光定量RT PCR结果表明,与对照组比较Keap1基因的表达量从热处理第1 d开始显著降低,Nrf2基因的表达量在第4 d和12 d显著升高,HO-1 (Heme oxygenase-1)基因的表达量在第1 d显著升高,NQO1 (Quinone oxidoreductase)和GCLC (Glutamate cysteine ligase catalytic)基因的表达量在第1 d和4 d显著升高．上述结果表明,热应激引起了小鼠肝脏氧化损伤, Keap1/Nrf2/ARE通路可能参与了肝脏自身缓解热应激的过程.     

Nrf2及天然产物导向的Nrf2激活剂研究进展

氧化应激能够破坏细胞内氧化还原平衡,造成系统和组织损伤,最终引起一系列疾病的产生.转录因子E2相关因子2(Nrf2),受Kelch样环氧氯丙烷相关蛋白1(Keap1)蛋白的调控,是细胞氧化应激反应中的关键因子,在氧化应激条件下,Nrf2从Keap1中分离,然后进入细胞核与抗氧化反应元件(ARE)结合,增加了Ⅱ相解毒酶的...