2. Academic Validation
  3. Escin alleviates cerebral ischemia-induced intestinal pyroptosis via the GR-dependent p38 MAPK/NF-κB signaling and NLRP3 inflammasome activation

Escin alleviates cerebral ischemia-induced intestinal pyroptosis via the GR-dependent p38 MAPK/NF-κB signaling and NLRP3 inflammasome activation

  • Int Immunopharmacol. 2024 Sep 10:138:112592. doi: 10.1016/j.intimp.2024.112592.
Min Li 1,  Fenghua Fu 2,  Tian Wang 3
Affiliations

Affiliations

  • 1 Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, PR China; School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, PR China. Electronic address: 202353014@bucm.edu.cn.
  • 2 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, PR China.
  • 3 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, PR China. Electronic address: bluewangtian@ytu.edu.cn.
PMID: 38955024 DOI: 10.1016/j.intimp.2024.112592
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.

Keywords

Escin; GR; HPA axis; Intestinal barrier; Ischemic stroke; Pyroptosis.

Figures
Products