Abstract
Sepsis is a dysregulated systemic response to infection, and no effective treatment options are available. Acacetin is a natural flavonoid found in various plants, including Sparganii rhizoma, Sargentodoxa cuneata and Patrinia scabiosifolia. Studies have revealed that acacetin potentially exerts anti-inflammatory and antioxidative effects on sepsis. In this study, we investigated the potential protective effect of acacetin on sepsis and revealed the underlying mechanisms using a network pharmacology approach coupled with experimental validation and molecular docking. First, we found that acacetin significantly suppressed pathological damage and pro-inflammatory cytokine expression in mice with LPS-induced fulminant hepatic failure and acute lung injury, and in vitro experiments further confirmed that acacetin attenuated LPS-induced M1 polarization. Then, network pharmacology screening revealed EGFR, PTGS2, SRC and ESR1 as the top four overlapping targets in a PPI network, and GO and KEGG analyses revealed the top 20 enriched biological processes and signalling pathways associated with the therapeutic effects of acacetin on sepsis. Further network pharmacological analysis indicated that gap junctions may be highly involved in the protective effects of acacetin on sepsis. Finally, molecular docking verified that acacetin bound to the active sites of the four targets predicted by network pharmacology, and in vitro experiments further confirmed that acacetin significantly inhibited the upregulation of p-src induced by LPS and attenuated LPS-induced M1 polarization through gap junctions. Taken together, our results indicate that acacetin may protect against sepsis via a mechanism involving multiple targets and pathways and that gap junctions may be highly involved in this process.
Highlights
Sepsis is a severe systemic inflammatory response to microbial infection, and lipopolysaccharide (LPS) is well known to induce this phenomenon (Chen et al, 2020)
We investigated the potential targets of acacetin in subjects with sepsis and predicted the underlying mechanisms by network pharmacology coupled with molecular docking and experimental validation
The levels of IL-1β, IL-6 and TNF-α in the liver and lung tissues of the model group were significantly higher than those in the control group tissues, while those in the acacetin group were decreased compared to those in the control group (Figures 1F–H,J–L p < 0.05). These results indicated that acacetin improves liver and lung injury by decreasing the levels of IL-1β, IL-6 and TNF-α
Summary
Sepsis is a severe systemic inflammatory response to microbial infection, and lipopolysaccharide (LPS) is well known to induce this phenomenon (Chen et al, 2020). LPS by intratracheal instillation are recognized as promising experimental models of fulminant hepatic failure (FHF) and acute lung injury (ALI) (Zhang et al, 2019; Liu et al, 2020a). Macrophage polarization is involved in the pathogenesis of sepsis, an uncontrolled inflammatory response caused by infection or acute insult (Fan et al, 2020). Acacetin has diverse biological functions, including anti-inflammatory, antioxidant, and antimicrobial activity, and exerts protective effects on cardiac tissue and neurons (Singh et al, 2020). Acacetin was shown to attenuate ALI in LPS-induced mice via augmenting haem oxygenase-1 (HO-1) activity (Sun et al, 2018) and to protect against GalN/LPS-induced liver injury by suppressing the TLR4 signalling pathway (Cho et al, 2014)
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