二氯乙酸通过PDK4/NLRP3抑制小胶质细胞的嗜热,从而预防败血症相关脑病的发生

IF 4.5 2区 医学 Q2 CELL BIOLOGY Inflammation Pub Date : 2024-08-23 DOI:10.1007/s10753-024-02105-3
Xuliang Huang, Yuhao Zheng, Nan Wang, Mingming Zhao, Jinhui Liu, Wen Lin, Ye Zhu, Xiaofan Xie, Ya Lv, Junlu Wang, Yunchang Mo
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引用次数: 0

摘要

二氯乙酸(DCA)是一种丙酮酸脱氢酶激酶抑制剂,常用于治疗乳酸中毒和恶性肿瘤。越来越多的研究表明,DCA 具有神经保护作用。在此,我们探讨了DCA在败血症相关脑病(SAE)中的作用和机制。单细胞分析用于确定 PDK4 在 SAE 中的重要作用并识别细胞类型。利用GO和GSEA分析确定了DCA与热昏迷之间的相关性。通过LPS + ATP刺激,建立了小胶质细胞脓毒症模型,观察DCA干预下细胞内脓毒症相关蛋白的表达水平,并进一步检测细胞内ROS和JC-1的变化。此外,还简单构建了小胶质细胞和神经元的共培养环境,以评估DCA对活化的小胶质细胞介导的神经元凋亡的影响。最后,通过新颖物体识别测试和莫里斯水迷宫来探讨DCA干预后对不同组小鼠认知功能的影响。基于以上实验,本研究得出结论:DCA能改善外周和中枢M1巨噬细胞的比例,通过ROS和线粒体膜电位(MMP)抑制NLRP3介导的热凋亡。DCA 可减少 SAE 导致的神经元死亡,改善 LPS 小鼠的认知功能。对于 SAE,DCA 可能是治疗小胶质细胞介导的神经炎症的潜在候选药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Dichloroacetate Prevents Sepsis Associated Encephalopathy by Inhibiting Microglia Pyroptosis through PDK4/NLRP3.

Dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, is often used to treat lactic acidosis and malignant tumors. Increasing studies have shown that DCA has neuroprotective effects. Here, we explored the role and mechanism of DCA in Sepsis associated encephalopathy (SAE). Single-cell analysis was used to determine the important role of PDK4 in SAE and identify the cell type. GO and GSEA analysis were used to determine the correlation between DCA and pyroptosis. Through LPS + ATP stimulation, a microglia pyroptosis model was established to observe the expression level of intracellular pyroptosis-related proteins under DCA intervention, and further detect the changes in intracellular ROS and JC-1. Additionally, a co-culture environment of microglia and neuron was simply constructed to evaluate the effect of DCA on activated microglia-mediated neuronal apoptosis. Finally, Novel object recognition test and the Morris water maze were used to explore the effect of DCA on cognitive function in mice from different groups after intervention. Based on the above experiments, this study concludes that DCA can improve the ratio of peripheral and central M1 macrophages, inhibit NLRP3-mediated pyroptosis through ROS and mitochondrial membrane potential (MMP). DCA can reduce neuron death caused by SAE and improve cognitive function in LPS mice. In SAE, DCA may be a potential candidate drug for the treatment of microglia-mediated neuroinflammation.

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来源期刊
Inflammation
Inflammation 医学-免疫学
CiteScore
9.70
自引率
0.00%
发文量
168
审稿时长
3.0 months
期刊介绍: Inflammation publishes the latest international advances in experimental and clinical research on the physiology, biochemistry, cell biology, and pharmacology of inflammation. Contributions include full-length scientific reports, short definitive articles, and papers from meetings and symposia proceedings. The journal''s coverage includes acute and chronic inflammation; mediators of inflammation; mechanisms of tissue injury and cytotoxicity; pharmacology of inflammation; and clinical studies of inflammation and its modification.
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