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

• 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

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 Keap1/Nrf2 途径的激活和随后的 2 相抗氧化酶的诱导可提供神经保护作用，在此，我们提出了一系列通过该途径保护神经元的新型亲电子化合物，例如鼠尾草酸 (CA)。以邻二氢醌形式大量存在于迷迭香和鼠尾草草本植物中，并引起特别关注，因为它们会通过氧化应激转化为活性形式（邻醌类）刺激 Keap1/Nrf2 转录途径，该途径会导致一系列抗氧化剂 2 相酶的产生，因此，此类二氢醌起到氧化还原激活的“亲电子试剂”的作用。我们探索了这样的概念：相关的对二氢醌代表了更有效的生物活性亲电子试剂，可诱导第 2 相酶，且不会产生毒副作用。对氢醌型亲电子化合物（设计为 D1 和 D2），以分析其保护机制，DNA 微阵列、PCR 和蛋白质印迹分析表明，化合物 D1 诱导热休克蛋白 (HSP) 的表达，包括 HSP70、HSP27 和 DnaJ，以及血红素加氧酶-1 (HO-1)、NADP(H) 等 2 相酶此外，NRF2 通过 D1 转位到细胞核中，但 HSF-1 已经在对照细胞的细胞核中，从而激活 NRF2 和 HSF-1 响应转录元件。以这种方式，D1 可以保护神经元细胞免受氧化和内质网 (ER) 相关应激，此外，D1 还能抑制诱导。 GRP78（一种 ER 伴侣蛋白）和抑制过氧化还原蛋白 2 (PRX2) 的过度氧化，该分子在还原状态下可以防止氧化应激。这些结果表明，D1 是一种新型亲电子化合物，可激活 NRF2 和 HSF-。 1 途径，因此可以提供针对氧化和内质网应激的保护。

项目成果

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

鼠尾草酸可预防 ob/ob 小鼠的肥胖和肝脂肪变性

• 发表时间: 2011
• 影响因子: 4.2
• 作者: Wang T; Takikawa Y; Satoh T; Y oshioka Y; Kosaka K; Tatemichi Y; Suzuki K
• 通讯作者: Suzuki K

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

鼠尾草酸可预防 ob/ob 小鼠的肥胖和肝脂肪变性

• 发表时间: 2011
• 作者: Wang T; Takikawa Y; Satoh T; Yoshioka Y; Kosaka K; Tatemichi Y; Suzuki K.
• 通讯作者: Suzuki K.

Carnosic acid, a pro-electrophilic compound, inhibits LPS-induced activation of microglia

鼠尾草酸是一种亲电子化合物，可抑制 LPS 诱导的小胶质细胞活化

• 发表时间: 2011
• 作者: Yanagitai M; Itoh S; Kitagawa T; Takenouchi T; Kitani H; Satoh T
• 通讯作者: Satoh T

Phenylenediamine Derivatives Induce GDF-15/MIC-1 and Inhibit Adipocyte Differentiation of Mouse 3T3-L1 Cells

苯二胺衍生物诱导 GDF-15/MIC-1 并抑制小鼠 3T3-L1 细胞的脂肪细胞分化

• 发表时间: 2012
• 作者: Yanagitai Y; Kitagawa T; Okawa K; Koyama H; Satoh T
• 通讯作者: Satoh T

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

亲电子化合物通过 HSF-1 激活的热休克蛋白和 Nrf2 激活的 2 相抗氧化反应酶的双重神经保护途径

• 发表时间: 2011
• 影响因子: 4.7
• 作者: Satoh T; Raraie 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.