Abstract：
Cerebral ischemia-induced systemic inflammation and inflammasome-dependent pyroptotic cell death in ileum, causing serious intestinal injury. Glucocorticoid receptor (GR) mediates the effects of glucocorticoids and participates in inflammation. Escin has corticosteroid-like, neuroprotective, and anti-intestinal dysfunction effects. This study aimed to investigate the effect of Escin on the intestinal barrier injury in rats subjected to middle cerebral artery occlusion (MCAO) and on Caco-2 cells exposed to lipopolysaccharides. The MCAO-caused brain injury was evaluated by assessing neurological function, cerebral infarct volume, and plasma corticosterone (Cort) levels. Intestinal injury was evaluated by observing the histopathological changes, assessing the intestinal barrier function, and determining blood FD4, endotoxin and IL-1β levels. The levels of the tight-junction proteins such as claudin-1, occludin, and ZO-1, and proteins involved in the GR/p38 MAPK/NF-κB pathway and NLRP3-inflammasome activation were evaluated using western blotting or immunofluorescence. Administration of Escin suppressed the cerebral ischemia-induced increases in Garcia-test scores and infarct volume, alleviated the injury to the intestinal barrier, and decreased the levels of Cort, endotoxin, and IL-1β. Additionally, Escin upregulated GR and downregulated phospho(p)-p65, p-p38MAPK, NLRP3, GSDMD-N, and cleaved-caspase-1 in the intestine. The effects of Escin could be suppressed by the GR antagonist RU486 or enhanced by the p38 MAPK antagonist SB203580. We revealed details how Escin improves cerebral ischemia-induced intestinal barrier injury by upregulating GR and thereby inhibiting the pyroptosis induced by NF-κB-mediated NLRP3 activation. This study will provide a experimental foundation for the features of glucocorticoid-like activity and the discovery of new clinical application for Escin.
摘要：
脑缺血引起的全身性炎症和回肠炎性体依赖性细胞凋亡，造成严重的肠道损伤。糖皮质激素受体（GR）介导糖皮质激素的作用并参与炎症反应。Escin有皮质类固醇样，神经保护,和抗肠道功能障碍的作用。本研究旨在探讨Escin对大脑中动脉阻塞(MCAO)大鼠肠屏障损伤及脂多糖对Caco-2细胞的影响。通过评估神经功能来评估MCAO引起的脑损伤，脑梗死体积,和血浆皮质酮（Cort）水平。通过观察组织病理学变化评估肠损伤，评估肠屏障功能，并测定血液FD4、内毒素和IL-1β水平。紧密连接蛋白的水平，如claudin-1，occludin，和ZO-1，以及参与GR/p38MAPK/NF-κB通路和NLRP3-炎性体激活的蛋白质使用蛋白质印迹或免疫荧光进行评估。服用Escin抑制了脑缺血引起的Garcia测试分数和梗死体积的增加，减轻了对肠道屏障的损伤，降低了科尔特的水平，内毒素,和IL-1β。此外,Escin上调GR并下调磷酸化（p）-p65，p-p38MAPK，NLRP3,GSDMD-N,和肠道中切割的半胱天冬酶-1。Escin的作用可以被GR拮抗剂RU486抑制或被p38MAPK拮抗剂SB203580增强。我们揭示了Escin如何通过上调GR从而抑制NF-κB介导的NLRP3激活诱导的焦亡来改善脑缺血诱导的肠屏障损伤。本研究为Escin的糖皮质激素样活性特征及临床应用提供实验基础。
