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Neuroprotective Compounds through Induction of Heat Shock Proteins

通过热休克蛋白诱导产生神经保护化合物

基本信息

批准号：
22500282
负责人：
SATOH Takumi
金额：
$ 2.91万
依托单位：
Iwate University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2011
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22500282/
关键词：
親電子性物質 Nrf2 HSF-1 熱ショック蛋白質脳

项目摘要

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 (desi … More gnated 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. Furthermore, NRF2 was translocatd into nuclei by D1 but HSF-1 was already in nuclei in control cells, thus activating NRF2-and HSF-1.responsive transcriptional elements. 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. Less

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更有效的生物活性亲电试剂的概念，用于诱导2相酶，而不会产生毒副作用。我们合成了几种新的对苯二酚型亲电化合物（desi ...更多信息 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。此外，NRF 2被D1易位到细胞核中，而HSF-1已经在对照细胞的细胞核中，从而激活NRF 2和HSF-1应答转录元件。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。少

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dual neuroprotective pathways of a pro-electrophilic compound via HSF-1-activated heat-shock proteins and Nrf2-activated phase 2 antioxidant response enzymes.

DOI：
10.1111/j.1471-4159.2011.07449.x
发表时间：
2011-11
期刊：
Journal of neurochemistry
影响因子：
4.7
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
通讯作者：
Lipton SA

Carnosic acid prevents obesity and hepatic steatosis in ob/ob mice