Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, 119991 Moscow, Russia.
Biochemistry (Mosc). 2013 Feb;78(2):111-26. doi: 10.1134/S0006297913020016.
The transcription factor Nrf2 governs the expression of a considerable group of genes involved in cell protection against oxidants, electrophiles, and genotoxic compounds. The activity of Nrf2 is sensitive to xenobiotics and endogenous electrophiles. Nrf2 is negatively regulated by specific suppressor protein Keap1, which is also a receptor of electrophiles and adapter for Cul3 ubiquitin ligase. Electrophiles react with critical thiol groups of Keap1 leading to the loss of its ability to inhibit Nrf2. The Keap1-Nrf2 signaling pathway also down-regulates NF-κB transcriptional activity and attenuates cytokine-mediated induction of proinflammatory genes. Pharmacological activation of the Keap1-Nrf2 pathway can be used for treatment and prevention of many diseases. Widely known natural Keap1-Nrf2 activators include curcumin, quercetin, resveratrol, and sulforaphane. The most effective Keap1-Nrf2 activators are synthetic oleanane triterpenoids.
转录因子 Nrf2 调控着大量参与细胞抵御氧化剂、亲电试剂和遗传毒性化合物的基因的表达。Nrf2 的活性对外源亲电试剂和内源性亲电试剂敏感。Nrf2 受到特定抑制蛋白 Keap1 的负调控，Keap1 也是亲电试剂的受体和 Cul3 泛素连接酶的衔接蛋白。亲电试剂与 Keap1 的关键巯基反应，导致其抑制 Nrf2 的能力丧失。Keap1-Nrf2 信号通路还下调 NF-κB 的转录活性，并减弱细胞因子介导的促炎基因的诱导。Keap1-Nrf2 通路的药理学激活可用于治疗和预防许多疾病。众所周知的天然 Keap1-Nrf2 激活剂包括姜黄素、槲皮素、白藜芦醇和萝卜硫素。最有效的 Keap1-Nrf2 激活剂是合成的齐墩果酸三萜。
