Qingqi Liangying formula inhibits brain endothelial cell pyroptosis via NLRP3/caspase-1/GSDMD in sepsis-associated encephalopathy

Résumé fourni par la source

BACKGROUND: Sepsis is a life-threatening systemic inflammatory condition frequently complicated by sepsis-associated encephalopathy (SAE). The Qingqi Liangying (QL) formula has not yet been systematically investigated in SAE. PURPOSE: This study investigates whether the QL formula protects against SAE by inhibiting brain endothelial cell pyroptosis, focusing on the NOD-like receptor family pyrin domain-containing 3 (NLRP3)/caspase-1/gasdermin D (GSDMD) pathway. METHODS: The chemical composition of the QL formula was characterized by UHPLC/Q-TOF-MS, and network pharmacology was applied to predict candidate targets and pathways. In vivo, an SAE mouse model was induced by continuous LPS infusion, and the QL formula treatment was assessed by measuring mean arterial pressure (MAP), histopathology (H&E and Nissl staining), and Evans blue leakage. Inflammatory cytokines, adhesion molecules, junction proteins, and pyroptosis-related proteins were measured by Western blot, immunofluorescence staining, immunohistochemistry staining, and enzyme-linked immunosorbent assay. In vitro, LPS/nigericin-stimulated hCMEC/D3 cells were treated with the QL formula or MCC950. Pyroptosis-related proteins, pro-inflammatory cytokines, and caspase-1 activity were analyzed. RESULTS: A total of 62 major compounds were detected in the QL formula. Network pharmacology analysis revealed involvement of the vascular barrier integrity and NLRP3 pathway. In LPS-induced SAE mice, the QL formula treatment significantly improved MAP, attenuated brain, liver, heart, and kidney damage, and reduced interleukin (IL)-6, IL-1β, and TNF-α levels in plasma. In brain tissue, the QL formula also reduced TNF-α levels, downregulated levels of VCAM-1, ICAM-1, Caveolin-1, MMP-9, Collagen IV, and upregulated VE-cadherin and occludin expression. Notably, the QL formula suppressed NLRP3, cleaved caspase-1 p20, GSDMD, IL-1β, and IL-18 expression in both cellular and animal models, with effects comparable to MCC950. CONCLUSIONS: The QL formula attenuates brain endothelial cell pyroptosis by inhibiting the NLRP3/caspase-1/GSDMD pathway. Our findings suggest that brain endothelial cell pyroptosis may be a critical pathological process in SAE and provide preclinical evidence that the QL formula has the potential to serve as a therapeutic option.

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