Polymyxin B Reduces Brain Injury in Ischemic Stroke Rat Through a Mechanism Involving Targeting ESCRT-III Machinery and RIPK1/RIPK3/MLKL Pathway
Polymyxin B Reduces Brain Injury in Ischemic Stroke Rat Through a Mechanism Involving Targeting ESCRT-III Machinery and RIPK1/RIPK3/MLKL Pathway
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多粘菌素 B 通过针对 ESCRT-III 机制和 RIPK1/RIPK3/MLKL 通路的机制减少缺血性中风大鼠的脑损伤
DOI：
10.1007/s12265-022-10224-1
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发表时间：
2022-03
影响因子：
3.4
通讯作者：
Jun Peng
中科院分区：
文献类型：
--
作者：
Jing Tian;Yi-Yue Zhang;Ya-Wei Peng;Bin Liu;Xiao-Jie Zhang;Zhong-Yang Hu;Chang-Ping Hu;Xiu-Ju Luo;Jun Peng
转运III所需的内体分选复合物（ESCRT-III）机制是抵消经历坏死性凋亡的细胞中混合谱系激酶结构域样假激酶（MLKL）诱导的质膜破裂的关键组分。基于生物信息学分析，预测多肽抗生素多粘菌素B同时与ESCRT-III亚基和坏死性凋亡相关蛋白相互作用。本研究旨在探讨多粘菌素B是否可以通过增强ESCRT-III机制和/或抑制RIPK 1/RIPK 3/MLKL通路来减少卒中大鼠脑中的坏死性凋亡。中风大鼠表现出明显的脑损伤，伴随着ESCRT-III亚基的下调和坏死相关蛋白的上调。缺血后给予多粘菌素B可减轻脑损伤，并伴有ESCRT-Ⅲ亚单位水平的恢复和坏死相关蛋白的抑制。多粘菌素B对缺氧处理的HT 22细胞也有类似的作用。我们得出结论，多粘菌素B可以通过增强ESCRT-III机制并同时抑制RIPK 1/RIPK 3/MLKL通路来减少中风大鼠脑中的坏死性凋亡。
Endosomal sorting complex required for transport III (ESCRT-III) machinery is a key component to counteract the mixed lineage kinase domain-like pseudokinase (MLKL)-induced plasma membrane broken in cells undergoing necroptosis. Based on the bioinformatics analysis, polymyxin B, a polypeptide antibiotic, is predicted to simultaneously interact with ESCRT-III subunits and necroptosis-relevant proteins. This study aims to explore whether polymyxin B could reduce necroptosis in the stroke rat brain via enhancing the ESCRT-III machinery and/or suppressing the RIPK1/RIPK3/MLKL pathway. The stroke rats showed evident brain injury, concomitant with the downregulation of ESCRT-III subunits and the upregulation of necroptosis-relevant proteins. Post-ischemic administration of polymyxin B could alleviate the brain injury, accompanied by restoration of the levels of ESCRT-III subunits and suppression of necroptosis-relevant proteins. And, polymyxin B exerted similar effects in hypoxia-treated HT22 cells. We conclude that polymyxin B can reduce necroptosis in the stroke rat brain via enhancing the ESCRT-III machinery and suppressing the RIPK1/RIPK3/MLKL pathway simultaneously.Graphical abstract
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