Gypenoside XLIX Activates the Sirt1/Nrf2 Signaling Pathway to Inhibit NLRP3 Inflammasome Activation to Alleviate Septic Acute Lung Injury.

Abstract

Currently, treatment options for acute lung injury (ALI) are limited. Gypenoside XLIX (Gyp-XLIX) is known for its anti-inflammatory properties, but there is a lack of extensive research on its effects against ALI. This study induced ALI in mice through cecal ligation and puncture surgery and investigated the biological activity and potential mechanisms of Gypenoside XLIX (40 mg/kg) by intraperitoneal injection. The in vitro ALI model was established using mouse lung epithelial (MLE-12) cells stimulated with lipopolysaccharide (LPS) and adenosine triphosphate (ATP). Various methods, including Hematoxylin and Eosin (H&E) staining, biochemical assay kits, Quantitative Polymerase Chain Reaction (qPCR) analysis, Western blotting, Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) assay, immunofluorescence, and flow cytometry, were employed for this research. The results indicated that pretreatment with Gypenoside XLIX significantly alleviated pathological damage in mouse lung tissues and reduced the expression levels of inflammatory factors. Additionally, Gypenoside XLIX inhibited ROS levels and NLRP3 inflammasome, possibly mediated by the Sirt1/Nrf2 signaling pathway. Moreover, Gypenoside XLIX significantly inhibited sepsis-induced lung cell apoptosis and excessive autophagy of mitochondria. Specifically, it suppressed mitochondrial pathway apoptosis and the Pink1/Parkin pathway of mitochondrial autophagy. These findings reveal the multifaceted effects of Gypenoside XLIX in anti-inflammatory, antioxidative, and inhibition of cell apoptosis and autophagy. This provides strong support for its therapeutic potential in sepsis-related lung injuries.