The protective effect of ginsenoside Rg1 against sepsis-induced lung injury through PI3K-Akt pathway: insights from molecular dynamics simulation and experimental validation

• Published in: Scientific reports 2024-07, Vol.14 (1), p.16071-19, Article 16071
• Main Authors: Zhong, Kaiqiang, Huang, Yingui, Chen, Rui, Pan, Qiusha, Li, Jun, Xi, Xiaotu
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/154; 631/154/436; Acute Lung Injury - drug therapy; Acute Lung Injury - etiology; Acute Lung Injury - metabolism; Acute Lung Injury - pathology; AKT protein; AKT1 protein; ALI; Alveoli; Animals; Apoptosis; Apoptosis - drug effects; BAX protein; Bcl-2 protein; Caspase-3; Cell Line; Disease Models, Animal; Epithelial cells; ESR1 protein; Flow cytometry; Ginsenoside Rg1; Ginsenosides; Ginsenosides - chemistry; Ginsenosides - pharmacology; Ginsenosides - therapeutic use; Herbal medicine; Humanities and Social Sciences; Inflammation; Insulin-like growth factor I; Lipopolysaccharides; Lungs; Male; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; multidisciplinary; Pharmacology; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Science; Science (multidisciplinary); Sepsis; Sepsis - complications; Sepsis - drug therapy; Sepsis - metabolism; Signal Transduction - drug effects; Stat3 protein; Survival; Traditional Chinese medicine; Tumor necrosis factor-α
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-66908-y

Sepsis-induced acute lung injury (SALI) poses a significant threat with high incidence and mortality rates. Ginsenoside Rg1 (GRg1), derived from Ginseng in traditional Chinese medicine, has been found to reduce inflammation and protect lung epithelial cells against tissue damage. However, the specific roles and mechanisms by which GRg1 mitigates SALI have yet to be fully elucidated. In this context, we employed a relevant SALI mouse model, alongside network pharmacology, molecular docking, and molecular dynamics simulation to pinpoint GRg1's action targets, complemented by in vitro assays to explore the underlying mechanisms. Our research shows that GRg1 alleviates CLP-induced SALI, decreasing lung tissue damage and levels of serum proinflammatory factor IL-6, TNF-α, and IL-1β, also enhancing the survival rate of CLP mice. A total of 116 common targets between GRg1 and ALI, with specific core targets including AKT1, VEGFA, SRC, IGF1, ESR1, STAT3, and ALB. Further in vitro experiments assessed GRg1's intervention effects on MLE-12 cells exposed to LPS, with qRT-PCR analysis and molecular dynamics simulations confirming AKT1 as the key target with the favorable binding activity for GRg1. Western blot results indicated that GRg1 increased the Bcl-2/Bax protein expression ratio to reduce apoptosis and decreased the high expression of cleaved caspase-3 in LPS-induced MLE-12 cells. More results showed significant increases in the phosphorylation of PI3K and AKT1. Flow cytometric analysis using PI and Annexin-V assays further verified that GRg1 decreased the apoptosis rate in LPS-stimulated MLE-12 cells (from 14.85 to 6.54%, p