烟酰胺 N-氧化物通过上调噬丝分裂抑制小胶质细胞嗜热性并缓解大鼠创伤性脑损伤后的神经损伤

IF 4.5 2区 医学 Q2 CELL BIOLOGY
Xiaoyan Li, Lan Luo, Pengyu Duan, Yonghong Bi, Yao Meng, Xiaoqian Zhang, Weiyu Feng, Zhehao Jin, Kun Zuo, Xiangcheng Zhao, Bing Zhang
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引用次数: 0

摘要

创伤性脑损伤(TBI)是一种以神经炎症和氧化应激为特征的严重损伤。NAMO(烟酰胺 n-氧化物)具有抗炎和抑制神经系统疾病中小胶质细胞过度激活的作用。然而,NAMO 在创伤性脑损伤后小胶质细胞脓毒症中的作用和机制尚不清楚。本研究旨在通过体内和体外模型研究 NAMO 对创伤性脑损伤的影响及其潜在机制。本研究通过提取脑组织线粒体进行了 Western 印迹检测,结果显示 NAMO 促进了有丝分裂相关蛋白(p62、LC3B 和 TOMM20)的表达,降低了 ROS 水平,抑制了嗜热相关蛋白(NLRP3、GSDMD、GSDMD-N 和 Caspase-1)和炎症细胞因子(IL-1β 和 IL-18)。我们随后对 GSDMD 和 IBA 1 进行了免疫荧光共定位,结果表明 NAMO 抑制了小胶质细胞的脓毒症。此外,NAMO 还能促进创伤性脑损伤后的神经功能恢复。体外实验表明,在脂多糖(LPS)+三磷酸腺苷(ATP)刺激 HMC3 细胞后,NAMO 可上调小胶质细胞的有丝分裂,改善线粒体功能障碍,降低 ROS 水平。我们还发现,NAMO 可抑制热蛋白沉积相关蛋白。为了进一步说明 NAMO 是否通过有丝分裂来影响热噬,我们在体内和体外模型中应用了有丝分裂抑制剂 Mdivi-1。结果表明,Mdivi-1 逆转了 NAMO 对小胶质细胞热噬的抑制作用。综上所述,我们的研究结果表明,NAMO 可通过上调有丝分裂抑制小胶质细胞的嗜热,从而改善神经系统的恢复,这表明 NAMO 可能是治疗创伤性脑损伤的一种潜在药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Nicotinamide N-oxide Inhibits Microglial Pyroptosis by Upregulating Mitophagy and Alleviates Neural Damage in Rats after TBI.

Traumatic brain injury (TBI) is a severe injury characterized by neuroinflammation and oxidative stress. NAMO (Nicotinamide n-oxide) has anti-inflammatory and inhibits microglial overactivation in neurological disorders. However, the role and mechanism of NAMO in microglial pyroptosis after TBI are unknown. The aim of this study was to investigate the effects of NAMO on TBI and its potential mechanisms through in vivo and in vitro models. In this study, western blot assays were performed by extracting brain tissue mitochondria, and the results showed that NAMO promoted the expression of mitophagy-associated proteins (p62, LC3B, and TOMM20), reduced ROS levels, and inhibited pyroptosis-associated proteins (NLRP3, GSDMD, GSDMD-N, and Caspase-1) and inflammatory cytokines (IL-1β and IL-18). We followed up with immunofluorescence co-localization of GSDMD and IBA 1, which showed that NAMO inhibited microglial pyroptosis. In addition, NAMO promoted neurological recovery after TBI. In vitro experiments showed that NAMO upregulated mitophagy, improved mitochondrial dysfunction, and reduced ROS levels in microglia following lipopolysaccharide (LPS) + adenosine triphosphate (ATP) stimulation in HMC3 cells. We also found that NAMO inhibited pyroptosis-related proteins. To further illustrate whether NAMO affects pyroptosis through mitophagy, we applied the mitophagy inhibitor Mdivi-1 in both in vivo and in vitro models. The results showed that Mdivi-1 reversed NAMO's inhibitory effect on microglial pyroptosis. Taken together, our findings demonstrate that NAMO improves neurological recovery by inhibiting microglial pyroptosis through upregulation of mitophagy, suggesting that NAMO could be a potential therapeutic agent for TBI.

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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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