Background: Diosgenin, a natural steroidal saponin isolated from Trigonella foenumgraecum, has been reported to exert anti-cancer effects. Inhibitors of enhancer of zeste homology 2 (EZH2) have been widely used in treatment of cancers. However, the effects of combined treatment with diosgenin and an EZH2 inhibitor on gastric cancer (GC) cells, and the mechanism for those effects are not fully understood. Methods: AGS and SGC-7901 gastric cancer cells were treated with diosgenin (0 to 8 μM), followed by treatment with either diosgenin or an EZH2 inhibitor, GSK126 alone. Afterwards, an EZH2 overexpression plasmid and Rho inhibitor, GSK429286A was involved in cells. Cell proliferation, cell cycle distribution, and cell apoptosis, migration, and invasion were examined by CCK-8 assays, flow cytometry, and transwell assays. Western blotting was performed to detect the relative levels of protein expression. Results: Treatment with diosgenin alone caused a dose-dependent decrease in the cell viability, and combined treatment with an EZH2 inhibitor plus GSK126 caused a further significant decrease. A further analysis revealed that treatment with either diosgenin or GSK126 alone induced significant increases in G0/G1 cell cycle arrest and apoptosis, and combined treatment with both agents induced further increases in those parameters. In addition, combined treatment with diosgenin and GSK126 synergistically induced even stronger effects on impaired cell proliferation, G0/G1 phase arrest, and cell apoptosis when compared to treatment with either diosgenin or GSK126 treatment alone. At the molecular level, we demonstrated that inhibition of Rho/ROCK signaling by combined treatment with diosgenin and GSK126 could downregulate the expression of epithelial-mesenchymal transition (EMT)-related molecules. We also found that EZH2 overexpression reversed the anti-tumor effect of diosgenin by inducing cell survival, blocking G1-phase arrest, and promoted EMT. While, these biological properties were further reversed by GSK429286A. Conclusion: Collectively, combined treatment with diosgenin and GSK126 produced even more significant effects on GC cell inhibition by targeting EZH2 via Rho/ROCK signalingmediated EMT, which might be a therapeutic strategy for improving the poor therapeutic outcomes obtained with GSK126 monotherapy.
Objective. To construct a novel nomogram model that predicts the risk of diabetic nephropathy (DN) incidence in Chinese patients with type 2 diabetes mellitus (T2DM). Methods. Questionnaire surveys, physical examinations, routine blood tests, and biochemical index evaluations were conducted on 1095 patients with T2DM from Guilin. A least absolute contraction selection operator (LASSO) regression and multivariable logistic regression analysis were used to screen out DN risk factors. A logistic regression analysis incorporating the screened risk factors was used to establish a predictive nomogram model. The performance of the nomogram model was evaluated using the C-index, an area under the receiver operating characteristic curve (AUC), calibration plots, and a decision curve analysis. Bootstrapping was applied for internal validation. Results. Independent predictors for DN incidence risk included gender, age, hypertension, medicine use, duration of diabetes, body mass index, blood urea nitrogen level, serum creatinine level, neutrophil to lymphocyte ratio, and red blood cell distribution width. The nomogram model exhibited moderate prediction ability with a C-index of 0.819 (95% confidence interval (CI): 0.783–0.853) and an AUC of 0.813 (95%CI: 0.778–0.848). The C-index from internal validation reached 0.796 (95%CI: 0.763–0.829). The decision curve analysis displayed that the DN risk nomogram was clinically applicable when the risk threshold was between 1 and 83%. Conclusion. Our novel and simple nomogram containing 10 factors may be useful in predicting DN incidence risk in T2DM patients.
ObjectiveUBR5, recently identified as a potential target for cancer therapeutics, is overexpressed in multiple malignant tumors. In addition, it is closely associated with the growth, prognosis, metastasis, and treatment response of multiple types of cancer. Although emerging evidence supports the relationship between UBR5 and cancer, there are limited cancer analyses available.MethodsIn this study, online databases (TIMER2, GEPIA2, UALCAN, c-BioPortal, STRING) were employed to comprehensively explore expression levels and prognostic values of the UBR5 gene in cancer, using bioinformatic methods.ResultsWe found that various characteristics of the UBR5 gene such as gene expression, survival value, genetic mutation, protein phosphorylation, immune infiltration, and pathway activities in the normal tissue were remarkably different from those in the primary tumor. Furthermore, "protein processing in spliceosome" and "ubiquitin mediated proteolysis" have provided evidence for their potential involvement in the development of cancer.ConclusionOur findings may provide insights for the selection of novel immunotherapeutic targets and prognostic biomarkers for cancer.
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