The occurrence and development of rheumatoid arthritis (RA) is regulated by numerous cytokines. Interleukin 27 (IL-27) is a soluble cytokine that exerts biological effects by regulating the Janus tyrosine kinase (JAK)/signal transducer and activator of the transcription (STAT) signaling pathway via the IL-27 receptor. IL-27 is known for its pleiotropic roles in modulating inflammatory responses. Previous studies found that IL-27 levels are elevated in RA blood, synovial fluid, and rheumatoid nodules. Cellular and animal experiments indicated that IL-27 exerts multiple regulatory functions in RA patients via different mechanisms. IL-27 inhibits ectopic-like structure (ELS) formation and CD4+ T helper type 2 (Th2) cell, CD4+ T helper type 17 (Th17) cell, and osteoclast differentiation in RA, contributing to alleviating RA. However, IL-27 promotes Th1 cell differentiation, which may exacerbate RA synovitis. Moreover, IL-27 also acts on RA synovial fibroblasts (RA-FLSs) and regulatory T cells (Tregs), but some of its functions are unclear. There is currently insufficient evidence to determine whether IL-27 promotes or relieves RA. Targeting IL-27 signaling in RA treatment should be deliberate based on current knowledge.
A network pharmacology integrated molecular docking strategy was used to predict the underlying molecular mechanism of Ermiao san in the treatment of hyperuricemia and gout. Traditional Chinese medicine systems pharmacology (TCMSP) database and analysis platform were used to screen out the active compounds and their targets of Ermiao san. The disease target genes related to hyperuricemia (HUA) and gout were obtained by searching CTD, DisGeNET, DrugBank, GeneCards, OMIM, TTD, and PharmGKB databases with “Hyperuricemia” and “Gout” as keywords, respectively. The potential targets of Ermiao san in the treatment of HUA and gout were screened through a Venn diagram. The protein–protein interaction network was constructed using Cytoscape software. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were then conducted. Finally, some compounds and core targets were selected for molecular docking verification by Autodock Vina and Pymol software. Forty-six active compounds, such as quercetin, wogonin and beta-sitosterol, etc were identified. Ermiao san plays a therapeutic role in HUA and gout regulating various biological processes, cellular compounds, and molecular functions. The core targets of Ermiao san for treating HUA and gout are AT1 (namely Protein Kinase Bα), interleukin-1 beta, prostaglandin-endoperoxide synthase 2, JUN, etc. And the key pathways are nuclear factor-κB, interleukin-17 and tumor necrosis factor. The results of molecular docking analyses suggested that active compounds of Ermiao san could bind well to the core protein receptors. Ermiao san has a synergistic mechanism of multiple compounds, multiple targets, and multiple pathways in the treatment of HUA and gout, which provides a good theoretical basis for the clinical application.
Objective. A network pharmacology integrated molecular docking strategy was used to predict the underlying molecular mechanism of Simiao pills (SMP) in the treatment of hyperuricemic nephropathy (HN). Methods. The active compounds and targets of SMP were screened by TCMSP database. Then, the disease databases such as CTD, DisGeNET, DrugBank, GeneCards, OMIM, TTD and PharmGKB were searched to determine the targets related to HN. STRING and Cytoscape software were applied to analysis and construct PPI network. R software was used to screen common targets, find the core targets of SMP in the treatment of HN, and perform Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis on the core targets, to clarify the core targets and mechanism of action of SMP in the treatment of HN. Finally, active compounds and core targets were selected for molecular docking verification by AutoDock Vina and Pymol software. Results. In this study, 65 related active compounds of SMP, 203 drug-related targets and 91 common targets of SMP and HN were screened. The network suggests that baicalein, kaempferol, quercetin, wogonin, beta-sitosterol and rutaecarpine may be the effective compounds of SMP in the treatment of HN. GO and KEGG pathway enrichment analyses identified the mechanism. Molecular docking revealed that the active compounds in SMP showed strong affinity towards the core protein receptors.Conclusions. SMP has a synergistic mechanism of multi-molecules, multi-targets and multi-pathways in the treatment of HN, which provides a theoretical basis for further exploring the molecular mechanism of SMP in the treatment of HN.
Gao et al.: Mechanism of Sodium Valproate Combined with Decitabine in Inhibiting Hepatocellular Carcinoma Cells Sodium valproate combined with decitabine can inhibit cancer by inhibiting the invasion and metastasis of liver cancer cells of which the mechanism is not yet clear. In this study, valproic acid and decitabine were used during the culture of liver cancer cell that is human hepatocarcinoma cell line SMMC-7721 and the p38 mitogen-activated protein kinase activator anisomycin was added. Western blot was used to detect the expression of E-cadherin and vimentin proteins. Transwell experiment was used to detect the migration and invasion ability of liver cancer cells. Quantitative reverse transcription polymerase chain reaction and western blot were used to detect p38 mitogen-activated protein kinase/heat shock protein 27 signaling pathway expression changes and p53 expression levels. The results show that the combination of valproic acid and decitabine can significantly reduce the invasion and metastasis ability of SMMC-7721 cells and the expression of vimentin protein, occurrence of epithelial-mesenchymal transition and p38 mitogen-activated protein kinase/phospho-p38 mitogen-activated protein kinase/heat shock protein 27/phospho heat shock protein 27. At the same time, it increases the expression of E-cadherin protein and the expression level of p53 (p<0.05) and the p38 mitogen-activated protein kinase activator anisomycin can inhibit the mentioned effects.These data show that the inhibition of epithelial-mesenchymal transition and invasion and metastasis of liver cancer cells may be achieved by increasing the expression of p53 which is through inhibiting the expression of p38 mitogen-activated protein kinase/heat shock protein 27 and its phosphorylation level when valproic acid and decitabine is combined.
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