Combinatorial Chemistry & High Throughput Screening - Volume 28, Issue 9, 2025

This study aimed to identify the bioactive compounds and explore the multi-target mechanisms of Salvia miltiorrhiza Bunge (SMB) against coronary heart disease (CHD) using an integrated serum pharmacochemistry and network pharmacology approach.

The chemical constituents of SMB were characterized by UPLC-MS. The absorbed ingredients and metabolites after oral SMB administration were identified in rat serum. Therapeutic targets of SMB against CHD were predicted by intersecting the targets of absorbed compounds from databases and CHD-associated genes. Protein-protein interaction network, pathway analysis, molecular docking, and molecular dynamic simulation were performed.

A total of 61 SMB-derived compounds were identified in rat serum. Network analysis revealed 111 candidate targets highly related to CHD pathways. Further topological analysis identified 10 hub targets and 20 key active compounds, constructing an informative compound-target-pathway network. PTGS2 and TNF were predicted as primary targets of SMB against CHD based on molecular dynamic simulation.

This integrated approach identified bioactive compounds and multi-target mechanisms of SMB against CHD. The results provide scientific evidence supporting SMB's clinical efficacy and reveal potential anti-CHD targets.

To explore the mechanism of KLF15 on the biological activity and autophagy of gastric cancer cells based on the PI3K/Akt/mTOR signaling pathway.

The gastric cancer AGS cells were divided into the Con group, pcDNA-NC group, pcDNA-KLF15 group, LY294002 group and IGF-1 group. RT-PCR was used to detect the expression of KLF15 in human gastric mucosal cells and gastric cancer cells; MTT method to detect cell proliferation; Transwell method to detect cell invasion; flow cytometry to detect cell apoptosis; Western blotting to detect PI3K, Akt, mTOR in cells, LC3, Beclin1, p62 protein expression. P<0.05 was used to indicate statistical significance.

Compared with the human gastric mucosal cell line GES-1 cells, the expression of KLF15 in human gastric cancer cell lines MKN-28, MFC, SCG-7901 and AGS cells was significantly decreased, And the expression of KLF15 in AGS cells, was the lowest (P=0.006). Compared with the Con group, The expression of KLF15 in the cells of the PCDNA-KLF15 group was significantly increased (P=0.018); There was no significant difference in the expression of KLF15 between the Con group and the PCDNA-NC group (P=0.225). Compared with the Con group, the proliferation and invasion abilities of the cells in the pcDNA-KLF15 group were significantly reduced, And the apoptosis ability was significantly increased (P=0.019). The ratio of LC3II/LC31 and the expression of Beclin1 Protein in the control group were significantly higher than those in the Con group (P=0.017).

Overexpression of KLF15 can inhibit the proliferation and invasion of Gastric cancer cells and promote cell apoptosis and autophagy, and its mechanism may be related to the regulation of the PI3K/Akt/mTOR signaling pathway.

Various cancer types have been studied and understood using long noncoding RNA (lncRNA). Despite this, only a few studies have examined anoikis-related lncRNAs in kidney renal clear cell carcinoma (KIRC). As a result, this study evaluated a powerful prognostic model for KIRC patients based on anoikis-lncRNAs and identified potential biological targets.

Anoikis-related lncRNAs associated with patient prognosis were identified using Pearson correlation, variance, and univariate Cox regression analyses. A predictive model that incorporated 4 anoikis-related lncRNAs has been constructed using the least absolute shrinkage and selection operator (LASSO) regression algorithm. The prognostic performance of the proposed model has also been assessed utilizing Kaplan-Meier (KM) survival and receiver operating characteristic (ROC) curve analyses. An ESTIMATE analysis was carried out on the low- as well as high-risk subtypes to evaluate immune cell infiltration status. Furthermore, CIBERSORT, TIMER, and QUANTISEQ along with other algorithms were applied for determining the infiltration status of numerous immune cells across both groups. In addition, immune checkpoint gene expression in both groups was also determined. Finally, drug sensitivity assays and in vitro experiments were performed to validate the results.

A total of sixty-three lncRNAs associated with anoikis and KIRC prognosis were identified via univariate cox analysis, and four lncRNAs (Z99289.2, AC084876.1, LINC00460, and AC090337.2.) were selected as hub lncRNAs. A prognostic signature has been developed based on the expression levels and coefficiency of these four lncRNAs while establishing its efficacy in part and whole TCGA KIRC cohort. Furthermore, by using this risk signature, high- as well as low-risk KIRC patients could be distinguished more precisely it can predict patient outcomes as well. The survival predictions by the nomogram exhibited an absolute degree of concordance with actual situations. In vitro experiments verified that LINC00460 downregulation contributed to the growth inhibition of KIRC cell lines and promoted apoptosis of cancer cells.

This study suggests that anoikis-related lncRNAs could serve as valuable prognostic markers for KIRC. Additionally, they may provide insight into future KIRC treatment options by reflecting on the situation of the kidney immune microenvironment.

Malignant melanoma is the leading cause of skin cancer-related death, with high malignancy and rapid progression. Total glucosides of paeony (TGP) are extracted from the roots of Paeonia Lactiflora Pall and are widely used in the treatment of chronic hepatitis, rheumatoid arthritis, and adjuvant therapy of tumor chemotherapy.

In the present research, M14 and A375 cells were treated with TGP. CCK8, transwell and western blotting were performed to analyze the effect of TGP on cell function.

TGP treatment impeded the proliferation and migration and activated the apoptosis pathway in melanoma cells. Importantly, TGP induced the degradation of α5-nAChR. Overexpression of α5-nAChR inhibited the anti-cancer effect of TGP. In addition, TGP treatment released cytochrome c from mitochondria into the cytoplasm, inducing mitochondrial dysfunction in melanoma cells. TGP also inhibited the phosphorylation of P38-MAPK, and P38-MAPK inhibitor reduced the promoting effect of α5-nAChR in cell proliferation and migration.

TGP inhibited cell viability and migration and induced mitochondrial dysfunction and apoptosis by promoting the degradation of α5-nAChR in melanoma cells. This research provided a potential therapeutic anti-cancer drug for treatment strategies of melanoma.

Myocardial infarction (MI) is the foremost cause of mortality in cardiovascular diseases. MI ultimately exacerbates cardiotoxicity due to the release of toxicity biomarkers and inflammatory infiltration.

Vernodalin (VN) is a renowned cytotoxic sesquiterpene lactone that possesses antioxidant, anticancer, and anti-inflammatory properties. The cardioprotective mechanism of VN remains concealed. Hence, we explored the cardioprotective efficacy of VN on isoproterenol (ISO)-mediated MI and analyzed its underlying mechanism.

To investigate the cardioprotective potential of VN (10 mg/kg bw), Wistar albino rats were subcutaneously injected with ISO (85 mg/kg bw) to induce MI. The assessment included measurements of heart weight/body weight index, hemodynamics, toxicity enzymes, histology, inflammatory mediators, and signaling pathway. While decreasing hemodynamic parameters and VEGF-B, AMPK, and eNOS signaling pathways, ISO increased heart weight/body weight index, cardiotoxicity enzymes, biomarkers, inflammation, and histological alterations.

Treatment with VN could significantly (p<0.05) mitigate the heart weight/body weight index, cardiotoxicity enzymes, biomarkers, inflammatory cytokines, and histopathological changes while enhancing hemodynamic parameters and VEGF-B, AMPK, and eNOS signaling pathways. Collectively, our findings revealed that the VN ameliorated defensive action against MI and averted myocardial injury by reducing the NF-κB-mediated inflammatory pathways in rats.

These findings established that VN expressively preserves the myocardium and employs anti-inflammatory actions by regulating NF-κB, VEGF-B, AMPK, and eNOS signaling pathways.

Wuling capsule is a traditional Chinese medicine composed of four herbals. It has been widely used to treat chronic active hepatitis and has shown significant efficacy in hyperlipidemia. However, the treatment of NAFLD disease has not been studied in depth.

Firstly, the potential bioactive compounds in Wuling capsules were identified by TCMSP (https://old.tcmsp-e.com/tcmsp.php). Secondly, the pathway and GO function were analyzed by using the DAVID database (https://david.ncifcrf.gov/). Then, the molecular docking techniques were used to confirm the accuracy of binding between key targets and components. Furthermore, the experimental pharmacology validation was conducted using RT-qPCR and WB of the NAFLD model.

A total of 138 active compounds and 40 common potential targets associated with NAFLD were identified through network pharmacology. The pathway and functional enrichment analysis showed that the Wuling capsule was associated with the PI3K-AKT and HIF-1α signaling pathways. In vivo experiments showed that the Wuling capsule could reduce IL-6, TNF-α, and HIF-1α proteins and up-regulate STAT3 and VEGFA levels (P < 0.05), thus alleviating liver inflammation.

With the support of network pharmacology and animal experiments, the study preliminarily investigated the effect of the Wuling capsule on liver inflammation by regulating the HIF-1α signaling pathway, thereby protecting liver function and treating NAFLD.