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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.

SUBMITTER: Ouyang Y

PROVIDER: S-EPMC8415621 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimThis study aimed to predict the key targets and endocrine mechanisms of Guizhi Fuling Wan (GZFLW) in treating adenomyosis (AM) through network pharmacology, molecular docking, and animal experiment verification.MethodsThe related ingredients and targets of GZFLW in treating AM were screened out using TCMSP, BATMAN-TCM, SwissTargetPrediction, and PubChem Database. Then, the protein-protein interaction (PPI) analysis and the network of compound-hub targets were constructed. At the same time, the key targets were uploaded to the Metascape Database for KEGG pathway enrichment analysis. After that, the molecular docking technology of the main active components and hub targets was performed. Furthermore, animal experiments were used to verify the results of network pharmacology analysis.ResultsA total of 55 active ingredients of GZFLW and 44 overlapping targets of GZFLW in treating AM were obtained. After screening, 25 hub targets were collected, including ESR1, EGF, and EGFR. Then, the KEGG pathway enrichment analysis results indicated that the endocrine therapeutic mechanism of GZFLW against AM is mainly associated with the estrogen signaling pathway, endocrine resistance, and an EGFR tyrosine kinase signaling pathway. Then, molecular docking showed that the significant compounds of GZFLW had a strong binding ability with ERα and EGFR. More importantly, the animal experiments confirmed that the GZFLW could downregulate the abnormal infiltration of the endometrial epithelium into the myometrium and had no interference with the normal sexual cycle. This effect may be directly related to intervening the local estrogen signaling pathway of the endometrial myometrial interface (EMI). It may also be associated with the myometrium cells' estrogen resistance via GPER/EGFR signaling pathway.ConclusionThe endocrine mechanism of GZFLW in treating AM was explored based on network pharmacology, molecular docking, and animal experiments, which provided a theoretical basis for the clinical application of GZFLW.

Project description:ObjectivesTo determine the potential molecular mechanisms underlying the therapeutic effect of curcumin on hepatocellular carcinoma (HCC) by network pharmacology and experimental in vitro validation.MethodsThe predictive targets of curcumin or HCC were collected from several databases. the identified overlapping targets were crossed with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) platform. Two of the candidate pathways were selected to conduct an experimental verification. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium (MTT) assay was used to determine the effect of curcumin on the viability of HepG2 and LO2 cells. The apoptosis and autophagy of HepG2 cells were respectively detected by flow cytometry and transmission electron microscopy. Besides, western blot and real-time polymerase chain reaction (PCR) were employed to verify the p53 apoptotic pathway and adenosine 5'-monophosphate (AMP)‍-activated protein kinase (AMPK) autophagy pathway. HepG2 cells were pretreated with pifithrin-‍α (PFT-‍α) and GSK690693 for further investigation.ResultsThe 167 pathways analyzed by KEGG included apoptosis, autophagy, p53, and AMPK pathways. The GO enrichment analysis demonstrated that curcumin was involved in cellular response to drug, regulation of apoptotic pathway, and so on. The in vitro experiments also confirmed that curcumin can inhibit the growth of HepG2 cells by promoting the apoptosis of p53 pathway and autophagy through the AMPK pathway. Furthermore, the protein and messenger RNA (mRNA) of the two pathways were downregulated in the inhibitor-pretreated group compared with the experimental group. The damage-regulated autophagy modulator (DRAM) in the PFT-‍α-pretreated group was downregulated, and p62 in the GSK690693-pretreated group was upregulated.ConclusionsCurcumin can treat HCC through the p53 apoptotic pathway and the AMPK/Unc-51-like kinase 1 (ULK1) autophagy pathway, in which the mutual transformation of autophagy and apoptosis may occur through DRAM and p62.

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

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