A Systematic Study of the Mechanism of Acacetin Against Sepsis Based on Network Pharmacology and Experimental Validation

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.

Effect of Dietary Supplements with ω-3 Fatty Acids, Ascorbic Acid, and Polyphenolic Antioxidant Flavonoid on Gene Expression, Organ Failure, and Mortality in Endotoxemia-Induced Septic Rats

“…The dietary flavonoid fisetin extracted from berries protects against polymicrobial sepsis-induced inflammatory response and multiple organ dysfunction [ 38 ]. The flavonoid acacetin exerts protection against sepsis [ 88 ]. Oral consumption of the flavonoid kaempferol showed decreased acute lung injury in polymicrobial sepsis [ 89 ].…”

Forsythoside B alleviates osteoarthritis through the HMGB1/TLR4/NF‐κB and Keap1/Nrf2/HO‐1 pathways

“…TLR4 signaling also promotes chondrocyte apoptosis and inhibits extracellular matrix synthesis. [49][50][51] Moreover, elevated TLR4 signaling pathway can activate the NLRP3 inflammasome, resulting in the production of mature IL-1β and IL-18. In turn, the NLRP3 inflammasome can activate the TLR4 signaling pathway via the production of pro-inflammatory IL-1 family cytokines, which ultimately leads to sustained inflammation in OA.…”

Mechanism of acacetin regulating hepatic stellate cell apoptosis based on network pharmacology and experimental verification

“…Network pharmacology is an effective method to screen drug disease targets and predict possible underlying mechanisms through bioinformatics analysis [ 15 ]. For example, based on network pharmacology and experimental validation analysis, acacetin can fight sepsis through multiple targets and pathways [ 16 ]. Acacetin was shown to be a key component in Weishu decoction and could alleviate gastrointestinal motility disorders by inhibiting the activation of the PI3K-AKT signaling pathway by network pharmacology analysis [ 17 ].…”