Dietary flavonoid (-)epicatechin stimulates phosphatidylinositol 3-kinase-dependent anti-oxidant response element activity and up-regulates glutathione in cortical astrocytes
Dietary flavonoid (-)epicatechin stimulates phosphatidylinositol 3-kinase-dependent anti-oxidant response element activity and up-regulates glutathione in cortical astrocytes
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DOI：
10.1111/j.1471-4159.2008.05542.x
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发表时间：
2008-09-01
影响因子：
4.7
通讯作者：
Williams, Robert J.
中科院分区：
文献类型：
--
作者：
Bahia, Parmvir K.;Rattray, Marcus;Williams, Robert J.
类黄酮是植物来源的多酚化合物，具有神经保护特性。最近的研究表明，除了充当氢供体之外，它们还激活保护性信号通路。抗氧化反应元件 (ARE) 促进保护性蛋白的表达，包括谷胱甘肽合成所需的蛋白（xCT 胱氨酸逆向转运蛋白、γ-谷氨酰半胱氨酸合成酶和谷胱甘肽合成酶）。使用荧光素酶报告基因 (ARE-luc) 检测表明，饮食中的 flavan-3-ol (-)表儿茶素可激活原代皮质星形胶质细胞中的这一通路，但不会激活神经元中的这一通路。我们还检查了 NF-E2 相关因子 2 (Nrf2) 的分布，Nrf2 是 ARE 介导的基因表达中的关键转录因子。我们使用免疫细胞化学发现，暴露于叔丁基氢醌（100 μM）和（-）表儿茶素（100 nM）后，Nrf2 在星形胶质细胞的细胞核中积累。 (-) 通过 Nrf2 的表儿茶素信号传导被渥曼青霉素抑制，这涉及磷脂酰肌醇 3 激酶依赖性途径。最后，(-)表儿茶素增加了星形胶质细胞中的谷胱甘肽水平，这与 ARE 介导的基因表达的上调一致。总之，这表明类黄酮可能通过增加抗氧化基因表达来发挥细胞保护作用。
Flavonoids are plant-derived polyphenolic compounds with neuroprotective properties. Recent work suggests that, in addition to acting as hydrogen donors, they activate protective signalling pathways. The anti-oxidant response element (ARE) promotes the expression of protective proteins including those required for glutathione synthesis (xCT cystine antiporter, gamma-glutamylcysteine synthetase and glutathione synthase). The use of a luciferase reporter (ARE-luc) assay showed that the dietary flavan-3-ol (-)epicatechin activates this pathway in primary cortical astrocytes but not neurones. We also examined the distribution of NF-E2-related factor-2 (Nrf2), a key transcription factor in ARE-mediated gene expression. We found, using immunocytochemistry, that Nrf2 accumulated in the nuclei of astrocytes following exposure to tert-butylhydroquinone (100 mu M) and (-)epicatechin (100 nM). (-)Epicatechin signalling via Nrf2 was inhibited by wortmannin implicating a phosphatidylinositol 3-kinase-dependent pathway. Finally, (-)epicatechin increased glutathione levels in astrocytes consistent with an up-regulation of ARE-mediated gene expression. Together, this suggests that flavonoids may be cytoprotective by increasing anti-oxidant gene expression.