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Triad3A-Dependent TLR4 Ubiquitination and Degradation Contributes to the Anti-Inflammatory Effects of Pterostilbene on Vascular Dementia
Journal of Agricultural and Food Chemistry ( IF 6.1 ) Pub Date : 2022-05-09 , DOI: 10.1021/acs.jafc.2c01219
Jikai Xu 1, 2 , Jingyu Liu 1, 2 , Yan Mi 1, 2 , Ting Zhao 1 , Danyang Mu 1 , Qingqi Meng 1 , Feng Wang 1 , Ning Li 3 , Yue Hou 1, 2
Affiliation  

Pterostilbene, a methylated stilbene derived from many plant foods, has significant anti-inflammatory activity. Meanwhile, vascular dementia (VaD) is the second most common subtype of dementia, in which inflammation is one of the major pathogenic contributors. However, the protective effect of pterostilbene on VaD is not well understood. In this work, we investigated the effect of pterostilbene on VaD and explored its underlying mechanisms using in vivo and in vitro models. Y-maze and Morris water maze tests showed pterostilbene-attenuated cognitive impairment in mice with bilateral common carotid artery occlusion (BCCAO). The hippocampal neuronal death and microglial activation in BCCAO mice were also reduced by pterostilbene treatment. Further, pterostilbene inhibited the expression of TLR4 and downstream inflammatory cytokines in these mice, with similar results observed in an oxygen–glucose deprivation and reperfusion (OGD/R) BV-2 cell model. In addition, its anti-inflammatory effect on OGD/R BV-2 cells was partially blocked by TLR4 overexpression. Moreover, Triad3A–TLR4 interactions were increased by pterostilbene following enhanced ubiquitination and degradation of TLR4, and the inhibitory effect of pterostilbene on inflammation was blocked by Triad3A knockdown in OGD/R-stimulated BV-2 cells. Together, these results reveal that pterostilbene could reduce vascular cognitive impairment and that Triad3A-mediated TLR4 degradation might be the key target.

中文翻译:

Triad3A 依赖性 TLR4 泛素化和降解有助于紫檀芪对血管性痴呆的抗炎作用

紫檀芪是一种从许多植物性食物中提取的甲基化芪,具有显着的抗炎活性。同时,血管性痴呆(VaD)是第二常见的痴呆亚型,其中炎症是主要的致病因素之一。然而,紫檀芪对 VaD 的保护作用尚不清楚。在这项工作中,我们研究了紫檀芪对 VaD 的影响,并使用体内和体外模型探索了其潜在机制。Y 迷宫和莫里斯水迷宫测试显示,在患有双侧颈总动脉闭塞 (BCCAO) 的小鼠中,紫檀芪减弱了认知障碍。BCCAO 小鼠的海马神经元死亡和小胶质细胞活化也因紫檀芪治疗而减少。此外,紫檀芪抑制了这些小鼠中 TLR4 和下游炎性细胞因子的表达,在氧 - 葡萄糖剥夺和再灌注(OGD / R)BV-2细胞模型中观察到类似的结果。此外,其对 OGD/R BV-2 细胞的抗炎作用被 TLR4 过表达部分阻断。此外,在 TLR4 泛素化和降解增强后,紫檀芪增加了 Triad3A-TLR4 相互作用,并且在 OGD/R 刺激的 BV-2 细胞中敲低 Triad3A 阻断了紫檀芪对炎症的抑制作用。总之,这些结果表明紫檀芪可以减少血管性认知障碍,而 Triad3A 介导的 TLR4 降解可能是关键目标。在 TLR4 泛素化和降解增强后,紫檀芪增加了 Triad3A-TLR4 相互作用,并且在 OGD/R 刺激的 BV-2 细胞中,紫檀芪对炎症的抑制作用被 Triad3A 敲低阻断。总之,这些结果表明紫檀芪可以减少血管性认知障碍,而 Triad3A 介导的 TLR4 降解可能是关键目标。在 TLR4 泛素化和降解增强后,紫檀芪增加了 Triad3A-TLR4 相互作用,并且在 OGD/R 刺激的 BV-2 细胞中,紫檀芪对炎症的抑制作用被 Triad3A 敲低阻断。总之,这些结果表明紫檀芪可以减少血管性认知障碍,而 Triad3A 介导的 TLR4 降解可能是关键目标。
更新日期:2022-05-09
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