Effective amelioration of ischemia/reperfusion (I/R)‐induced intestinal injury and revealing its mechanisms remain the challenges in both preclinic and clinic. Potential mechanisms of naringin in ameliorating I/R‐induced intestinal injury remain unknown. Based on pre‐experiments, I/R‐injured rat intestine in vivo and hypoxia–reoxygenation (H/R)‐injured IEC‐6 cells in vitro were used to verify that naringin‐alleviated I/R‐induced intestinal injury was mediated via deactivating cGAS‐STING signaling pathway. Naringin improved intestinal damage using hematoxylin and eosin staining and decreased alanine aminotransferase and aspartate aminotransferase contents in plasma. Naringin decreased inflammation characterized by reducing IL‐6, IL‐1β, TNF‐α, and IFN‐β contents in both plasma and IEC‐6 cells. Naringin mitigated oxidative stress via recovering superoxide dismutase, glutathione, and malondialdehyde levels in the I/R‐injured intestine. Naringin reduced the expression of apoptotic proteins, including Bax, caspase‐3, and Bcl‐2, and reduced terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin nick‐end labeling‐positive cells both in vivo and in vitro, and decreased Hoechst 33342 signals in vitro. cGAS, STING, p‐TBK1, p‐IRF3, and NF‐κB expressions were up‐regulated both in vivo and in vitro respectively and the up‐regulated indexes were reversed by naringin. Transfection of cGAS‐siRNA and cGAS‐cDNA significantly down‐regulated and up‐regulated cGAS‐STING signaling‐related protein expressions, respectively, and partially weakened naringin‐induced amelioration on these indexes, suggesting that deactivation of cGAS‐STING signaling is the crucial target for naringin‐induced amelioration on I/R‐injured intestine.
Multiple studies have confirmed the significance of microRNA (miR)-122a in disease regulation. However, its impact on ischaemia/reperfusion (I/R) injury is unknown. Therefore, in order to uncover new pharmacological targets for treating this condition, the regulation of intestinal I/R injury by miR-122a became the focus of this study. Two models, including hypoxia/reoxygenation (H/R)-injured IEC-6 cells in vitro and ischemia/reperfusion (I/R)-injured C57BL/6 mice intestinal tissues in vivo, were used in this study. Applying dual-luciferase reporter assays and transfection tests, the regulatory impacts of miR-122a were examined by promoting pyroptosis on intestinal I/R injury via targeting epidermal growth factor receptor (EGFR)- NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) signaling pathway. Both H/R-injured IEC-6 cells and I/R-injured mice intestinal tissues had elevated miR-122a expression, which targeted EGFR directly. Increased miR-122a expression significantly inhibited EGFR activity, decreased EGFR mRNA and protein expression, increased NLRP3 mRNA and protein expression, and up-regulated caspase 1, N-GSDMD, ASC, IL-1β, and IL-18 protein expression to promote pyroptosis. Furthermore, in IEC-6 cells, a miR-122a inhibitor and an EGFR-overexpression plasmid significantly reduced pyroptosis, alleviating intestinal I/R injury via activating the EGFR-NLRP3 signaling pathway. miR-122a is very essential for regulating intestinal I/R injury. It promotes pyroptosis by blocking the EGFR-NLRP3 signaling pathway, which should be evaluated as a therapeutic target for this disease.
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