S100B/RAGE/Ceramide signaling pathway is involved in sepsis-associated encephalopathy
S100B/RAGE/Ceramide signaling pathway is involved in sepsis-associated encephalopathy
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S100B/RAGE/神经酰胺信号通路参与脓毒症相关脑病
DOI：
10.1016/j.lfs.2021.119490
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发表时间：
2021
期刊：
影响因子：
6.1
通讯作者：
Yuhang Ai
中科院分区：
文献类型：
--
作者：
Lina Zhang;Yuan Jiang;Songyun Deng;Yunan Mo;Yan Huang;Wenchao Li;Chenglong Ge;Xinshu Ren;Haisong Zhang;Xiaolei Zhang;Qianyi Peng;Zhiyong Liu;Li Huang;Fan Zhou;Yuhang Ai
脓毒症相关性脑病（SAE）是脓毒症最常见的并发症之一，可导致长期的认知功能障碍和残疾。本研究旨在探讨S100钙结合蛋白B（S100 B）/神经酰胺/神经酰胺信号通路在脓毒症急性脑损伤和长期认知功能障碍中的作用。此外，本研究还利用Mdivi-1（Drp 1抑制剂）和Drp 1 siRNA研究了C2-ceramide对神经元线粒体的影响，并探讨了C2-ceramide诱导HT 22小鼠海马神经元细胞死亡的具体机制。尼氏染色和Morris水迷宫（MWM）测试显示，FPS-ZM 1抑制RIPs显著减轻盲肠结扎穿孔（CLP）诱导的脑损伤和认知功能障碍。此外，FPS-ZM 1减轻脓毒症诱导的C2-神经酰胺积累和异常的线粒体动力学。此外，神经酰胺的抑制作用在体内和体外也表现出相似的保护作用。此外，Mdivi-1和Drp 1 siRNA显著降低C2-ceramide诱导的神经元线粒体碎片化和细胞凋亡in vitro. Significance本研究证实S100 B通过β 2-ceramide/ceramide通路调节线粒体动力学，除了该通路在脓毒症急性脑损伤和长期认知障碍中的作用外.
AimsSepsis-associated encephalopathy (SAE) is one of the most common complications of sepsis, and it might lead to long-term cognitive dysfunction and disability. This study aimed to explore the role of S100 calcium binding protein B (S100B)/RAGE/ceramide signaling pathway in SAE.Main methodsFPS-ZM1 (an inhibitor of RAGE), myriocin and GW4869 (an inhibitor of ceramide) were used to explore the role of S100B/RAGE/ceramide in acute brain injury and long-term cognitive impairment in sepsis. In addition, Mdivi-1 (inhibitor of Drp1) and Drp1 siRNA were utilized to assess the effects of C2-ceramide on neuronal mitochondria, and to explore the specific underlying mechanism in C2 ceramide-induced death of HT22 mouse hippocampal neuronal cells.Key findingsWestern blot analysis showed that sepsis significantly up-regulated S100B and RAGE. Nissl staining and Morris water maze (MWM) test revealed that inhibition of RAGE with FPS-ZM1 markedly attenuated cecal ligation and puncture (CLP)-induced brain damage and cognitive dysfunction. Furthermore, FPS-ZM1 relieved sepsis-induced C2-ceramide accumulation and abnormal mitochondrial dynamics. Moreover, inhibition of ceramide also showed similar protective effects bothin vivoandin vitro. Furthermore, Mdivi-1 and Drp1 siRNA significantly reduced C2-ceramide-induced neuronal mitochondrial fragmentation and cell apoptosisin vitro.SignificanceThis study confirmed that S100B regulates mitochondrial dynamics through RAGE/ceramide pathway, in addition to the role of this pathway in acute brain injury and long-term cognitive impairment during sepsis.