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Gastrodin Regulates the Notch Signaling Pathway and Sirt3 in Activated Microglia in Cerebral Hypoxic-Ischemia Neonatal Rats and in Activated BV-2 Microglia
NeuroMolecular Medicine ( IF 3.5 ) Pub Date : 2020-10-23 , DOI: 10.1007/s12017-020-08627-x
Jing Guo 1 , Xiao-Li-Na Zhang 1, 2 , Zhang-Rui Bao 1 , Xue-Ke Yang 1 , Ling-Shuang Li 1 , Yu Zi 1 , Fan Li 3 , Chun-Yun Wu 1 , Juan-Juan Li 1 , Yun Yuan 1
Affiliation  

In response to hypoxic-ischemic brain damage (HIBD), microglia activation and its mediated inflammation contribute to neuronal damage. Inhibition of over-activated microglia is deemed to be a potential therapeutic strategy. Our previous studies showed that gastrodin efficiently depressed the neuroinflammation mediated by activated microglia in HIBD neonatal rats. The underlying mechanisms through which gastrodin acts on activated microglia have not been fully elucidated. This study is designed to determine whether gastrodin would regulate the Notch signaling pathway and Sirtuin3 (Sirt3), which are implicated in regulating microglia activation. The present results showed that gastrodin markedly suppressed the expression of members of Notch signaling pathway (Notch-1, NICD, RBP-JK and Hes-1) in activated microglia both in vivo and in vitro. Conversely, Sirt3 expression was enhanced. In BV-2 microglia treated with a γ-secretase inhibitor of Notch pathway- DAPT, the expression of RBP-JK, Hes-1, and NICD was suppressed in activated microglia. Treatment with DAPT and gastrodin further decreased NICD and Hes-1 expression. Sirt3 expression was also decreased after DAPT treatment. However, Sirt3 expression in activated BV-2 microglia given a combined DAPT and gastrodin treatment was not further increased. In addition, combination of DAPT and Gastrodin cumulatively decreased tumor necrosis factor-α (TNF-α) expression. The results suggest that gastrodin regulates microglia activation via the Notch signaling pathway and Sirt3. More importantly, interference of the Notch signaling pathway inhibited Sirt3 expression, indicating that Sirt3 is a downstream gene of the Notch signaling pathway. It is suggested that Notch and Sirt3 synergistically regulate microglia activation such as in TNF-α production.



中文翻译:

天麻素调节脑缺氧缺血新生大鼠和活化的 BV-2 小胶质细胞活化小胶质细胞中的 Notch 信号通路和 Sirt3

作为对缺氧缺血性脑损伤 (HIBD) 的反应,小胶质细胞的激活及其介导的炎症会导致神经元损伤。抑制过度激活的小胶质细胞被认为是一种潜在的治疗策略。我们之前的研究表明,天麻素可有效抑制 HIBD 新生大鼠活化小胶质细胞介导的神经炎症。天麻素作用于活化小胶质细胞的潜在机制尚未完全阐明。本研究旨在确定天麻素是否会调节 Notch 信号通路和 Sirtuin3 (Sirt3),它们与调节小胶质细胞活化有关。目前的结果表明,天麻素在体内和体外均显着抑制激活的小胶质细胞中 Notch 信号通路成员(Notch-1、NICD、RBP-JK 和 Hes-1)的表达。相反,Sirt3 表达增强。在用 Notch 途径的 γ-分泌酶抑制剂-DAPT 处理的 BV-2 小胶质细胞中,活化的小胶质细胞中 RBP-JK、Hes-1 和 NICD 的表达受到抑制。DAPT 和天麻素治疗进一步降低了 NICD 和 Hes-1 的表达。在 DAPT 处理后,Sirt3 的表达也降低了。然而,给予 DAPT 和天麻素联合治疗后,活化的 BV-2 小胶质细胞中的 Sirt3 表达没有进一步增加。此外,DAPT 和天麻素的组合累积降低了肿瘤坏死因子-α (TNF-α) 的表达。结果表明,天麻素通过 Notch 信号通路和 Sirt3 调节小胶质细胞的活化。更重要的是,Notch信号通路的干扰抑制了Sirt3的表达,说明Sirt3是Notch信号通路的下游基因。

更新日期:2020-10-30
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