International Journal of COPD (Aug 2024)
Network Pharmacology Followed by Experimental Validation to Explore the Mechanism of Stigmasterol in Sangbaipi Decoction Regulating PI3K/Akt Signaling to Alleviate Acute Exacerbation of Chronic Obstructive Pulmonary Disease
Abstract
Haidong He,1 Shuihua Sun,2 Weihua Xu,1 Mingwan Zhang3 1Department of Pulmonary and Critical Care Medicine, Tongde Hospital of Zhejiang Province, Hangzhou City, Zhejiang Province, People’s Republic of China; 2Department of Medical Oncology, Tongde Hospital of Zhejiang Province, Hangzhou City, Zhejiang Province, People’s Republic of China; 3Department of Pharmacy, Tongde Hospital of Zhejiang Province, Hangzhou City, Zhejiang Province, People’s Republic of ChinaCorrespondence: Haidong He, Department of Pulmonary and Critical Care Medicine, Tongde Hospital of Zhejiang Province, 234 Gucui Road, Cuiyuan Street, Xihu District, Hangzhou City, Zhejiang Province, 310012, People’s Republic of China, Tel +86-571-89972427, Email [email protected]: Sangbaipi decoction (SBPD), a traditional Chinese medicine (TCM) prescription, has been widely used to treat acute exacerbation of chronic obstructive pulmonary disease (AECOPD), while the underlying pharmacological mechanism remains unclear due to the complexity of composition.Methods: A TCM-active ingredient-drug target network of SBPD was constructed utilizing the TCM-Systems-Pharmacology database. AECOPD-relevant proteins were gathered from Gene Cards and the Online-Mendelian-Inheritance-in-Man database. Protein–protein interaction, GO and KEGG enrichment analyses of the targets from the intersection of SBPD and AECOPD targets were performed to identify the core signaling pathway, followed by molecular docking verification of its interaction with active ingredients. The network pharmacology results were checked using in-vivo experiments. To induce AECOPD, rats were exposure to combined tobacco smoke and lipopolysaccharide (LPS). Then rats underwent gavage with stigmasterol (SM) after successful modeling. The involvement of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling was investigated using its inhibitor, LY294002. Lung function and histopathology were examined. The levels of inflammatory cytokines in the lung and serum were assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot and/or Enzyme-linked immunosorbent assay (ELISA).Results: SM was recognized as an active ingredient of SBPD and stably bound to Akt1. SM improved lung function and histological abnormalities, concomitant with suppressed PI3K/Akt signaling, downregulated lung and serum Interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) levels and serum transforming growth factor-β (TGF-β) levels and upregulated lung and serum Interleukin 10 (IL-10) levels in AECOPD rats. In AECOPD rats, LY294002 restored lung function, and it also improved lung histological abnormalities and inflammation, which was found to be potentiated by SM.Conclusion: SM targets PI3K/Akt signaling to reduce lung injury and inflammation in AECOPD rats.Keywords: sangbaipi decoction, stigmasterol, acute exacerbation of chronic obstructive pulmonary disease, PI3K/Akt signaling, lung inflammation
