Integrated network pharmacology and experimental validation to elucidate the mechanism of celastrol in mitigating sepsis-induced acute lung injury in mice
Danli Zhu , Jinghan Zhang , Xiaochun Huang , Na Wei , Jinxiu Jiang , Jiayao Li , Li Liu , Yulin Liu , Jun Zhou , Jing Jia
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引用次数: 0
Abstract
Background
Sepsis is an acute, life-threatening condition that precipitates multiple organ failure, including acute lung injury (ALI), characterized by a complex pathophysiological process and elevated mortality rates. Celastrol, a pentacyclic triterpenoid quinone derived from traditional Chinese medicine, exhibits diverse pharmacological properties, including immunomodulatory, anti-inflammatory, anticancer, and antifibrotic effects, and has demonstrated favorable safety profiles in vivo. However, the precise mechanism by which CSL contributes to sepsis-induced ALI remains to be elucidated.
Purpose
The study aimed to explore the mechanisms by which celastrol mitigates sepsis-induced ALI using network pharmacology, followed by experimental validation of its regulatory effects on sepsis-induced ALI.
Methods
Utilizing a network pharmacology analysis, the potential targets and pathways of celastrol were identified. To explore celastrol's therapeutic effects on ALI, a rat model of sepsis was induced via cecal ligation and puncture, followed by assessment through hematoxylin-eosin staining, Real-time quantitative polymerase chain reaction (RT-qPCR), and Western blotting. Further investigation involved evaluating celastrol's influence on LPS-stimulated A549 and Raw264.7 cells, employing RT-qPCR, Western blotting, and immunofluorescence techniques.
Results
Network pharmacological analysis identified 10 core targets and 31 pathways relevant to sepsis-induced ALI, with STAT3, TLR4, HIF-1α, and NF-κB1 emerging as central targets. Animal experiments demonstrated that celastrol treatment significantly reduced lung tissue inflammation, as evidenced by immunohistochemistry, Western blot, and RT-qPCR results, in comparison to the cecal ligation and puncture group. Notably, the levels of IL-1β, TNF-α, HIF-1α, STAT3, and NF-κB1 proteins and mRNA in the celastrol treatment group were significantly reduced compared to those in the cecal ligation and puncture (CLP) group and the LPS-treated group. Additionally, Western blot and immunofluorescence analyses confirmed the activation of the NF-κB pathway in vitro.
Conclusion
This study indicates that celastrol significantly suppresses the expression of inflammatory factors in sepsis-induced ALI by inhibiting the NF-κB/HIF-1α pathway in both in vivo and in vitro models, highlighting its therapeutic potential for modulating inflammation. These findings provide valuable evidence for future clinical research and drug development.
期刊介绍:
Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.