Dual neuroprotective pathways of a pro-electrophilic compound via HSF-1-activated heat-shock proteins and Nrf2-activated phase 2 antioxidant response enzymes.
Dual neuroprotective pathways of a pro-electrophilic compound via HSF-1-activated heat-shock proteins and Nrf2-activated phase 2 antioxidant response enzymes.
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DOI：
10.1111/j.1471-4159.2011.07449.x
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发表时间：
2011-11
影响因子：
4.7
通讯作者：
Lipton SA
中科院分区：
文献类型：
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作者：
Satoh T;Rezaie T;Seki M;Sunico CR;Tabuchi T;Kitagawa T;Yanagitai M;Senzaki M;Kosegawa C;Taira H;McKercher SR;Hoffman JK;Roth GP;Lipton SA
已知Keap 1/Nrf 2通路的激活和随后的2相抗氧化酶的诱导提供神经保护。在这里，我们提出了一系列新的亲电化合物，通过这一途径保护神经元。天然产物，如鼠尾草酸（CA），在草药迷迭香和鼠尾草中以高含量存在，作为邻二氢醌，并引起了特别的关注，因为它们通过氧化应激转化为它们的活性形式（邻醌类），刺激Keap 1/Nrf 2转录途径。一旦激活，该途径导致产生一系列抗氧化剂2相酶。因此，此类二氢醌充当氧化还原活化的“亲电试剂前体”。在这里，我们探索了相关的对二氢醌代表甚至更有效的生物活性亲电试剂，用于诱导2相酶而不产生毒副作用的概念。我们合成了几种新的对苯二酚型亲电化合物（命名为D1和D2），以分析其保护机制。DNA微阵列、PCR和Western印迹分析显示，化合物D1诱导热休克蛋白（HSP）的表达，包括HSP 70、HSP 27和DnaJ，以及2相酶如血红素加氧酶-1（HO-1）、NADP（H）奎宁氧化还原酶1和Na+非依赖性胱氨酸/谷氨酸盐交换剂。用D1处理导致Nrf 2和HSF-1转录元件的活化，从而分别诱导2相酶和HSP。以这种方式，D1保护神经元细胞免受氧化和内质网（ER）相关的应激。此外，D1抑制GRP 78（一种ER伴侣蛋白）的诱导，并抑制过氧化物酶氧还蛋白2（PRX 2）的过氧化，PRX 2是一种在还原状态下可以保护免受氧化应激的分子。这些结果表明，D1是一种新的亲电子化合物，激活Nrf 2和HSF-1途径，因此可能提供保护，免受氧化和ER应激。
Activation of the Keap1/Nrf2 pathway and consequent induction of phase 2 antioxidant enzymes is known to afford neuroprotection. Here, we present a series of novel electrophilic compounds that protect neurons via this pathway. Natural products, such as carnosic acid (CA), are present in high amounts in the herbs rosemary and sage as ortho-dihydroquinones, and have attracted particular attention because they are converted by oxidative stress to their active form (ortho-quinone species) that stimulate the Keap1/Nrf2 transcriptional pathway. Once activated, this pathway leads to the production of a series of antioxidant phase 2 enzymes. Thus, such dihydroquinones function as redox-activated “pro-electrophiles.” Here, we explored the concept that related para-dihydroquinones represent even more effective bioactive pro-electrophiles for the induction of phase 2 enzymes without producing toxic side effects. We synthesized several novel para-hydroquinone-type pro-electrophilic compounds (designated D1 and D2) in order to analyze their protective mechanism. DNA microarray, PCR, and Western blot analyses showed that compound D1 induced expression of heat-shock proteins (HSPs), including HSP70, HSP27 and DnaJ, in addition to phase 2 enzymes such as hemeoxygenase-1 (HO-1), NADP(H) quinine-oxidoreductase1, and the Na+-independent cystine/glutamate exchanger. Treatment with D1 resulted in activation of Nrf2 and HSF-1 transcriptional elements, thus inducing phase 2 enzymes and HSPs, respectively. In this manner, D1 protected neuronal cells from both oxidative and endoplasmic reticulum (ER)-related stress. Additionally, D1 suppressed induction of GRP78, an ER chaperone protein, and inhibited hyperoxidation of peroxiredoxin 2 (PRX2), a molecule that in it reduced state can protect from oxidative stress. These results suggest that D1 is a novel pro-electrophilic compound that activates both the Nrf2 and HSF-1 pathways, and may thus offer protection from oxidative and ER stress.