RESUMEN
The underlying mechanism of fibroblast growth factor receptor 1 (FGFR1) mediated carcinogenesis is still not fully understood. For instance, FGFR1 upregulation leads to endocrine therapy resistance in breast cancer patients. The current study aimed to identify FGFR1-linked genes to devise improved therapeutic strategies. RNA-seq and microarray expression data of 1,425 breast cancer patients from two independent cohorts were downloaded for the analysis. Gene Set Enrichment Analysis (GSEA) was performed to identify differentially expressed pathways associated with FGFR1 expression. Validation was done using 150 fresh tumor biopsy samples of breast cancer patients. The clinical relevance of mRNA and protein expression of FGFR1 and its associated genes were also evaluated in mouse embryonic fibroblasts (MEFs) and breast cancer cell line (MDA-MB-231). Furthermore, MDA-MB-231 cell line was treated with AZD4547 and GANT61 to identify the probable role of FGFR1 and its associated genes on cells motility and invasion. According to GSEA results, SHH pathway genes were significantly upregulated in FGFR1 patients in both discovery cohorts of breast cancer. Statistical analyses using both discovery cohorts and 150 fresh biopsy samples revealed strong association of FGFR1 and GLI1, a member of SHH pathway. The increase in the expression of these molecules was associated with poor prognosis, lymph node involvement, late stage, and metastasis. Combined exposures to AZD4547 (FGFR1 inhibitor) and GANT61 (GLI1 inhibitor) significantly reduced cell proliferation, cell motility, and invasion, suggesting molecular crosstalk in breast cancer progression and metastasis. A strong positive feedback mechanism between FGFR1-GLI1 axis was observed, which significantly increased cell proliferation and metastasis. Targeting FGFR1-GLI1 simultaneously will significantly improve the prognosis of breast cancer in patients.
RESUMEN
Antioxidants are one of the effective treatment lines in managing type 2 diabetes (typ2diab) and its complications. Nanoformulations could help in ameliorating the oral bioavailability and biocompatibility properties. Ellagic acid (Ella) is a natural antioxidant compound commonly present in fruits. This study examined the effect Ella nanoparticles (Ella NPs) alone and combined with metformin, the standard antidiabetic drug, on controlling blood glucose in typ2diab. Forty-eight adult Sprague-Dawley rats were used in this study. Except for the control group that was fed a regular pellet diet, all animals were fed a high-fat diet (HFD) for 9 weeks. For the last 4 weeks, rats were injected with streptozotocin (35 mg/kg). Then the rats were randomized into 8 groups: control, HFD, diabetic, Ella, Ella + metformin, Ella NPs, and Ella NPs + metformin. Data showed that Ella NPs improved blood glucose levels and the body weights of diabetic rats throughout all the weeks of the experiment whereas effects of the regular Ella were limited to the last two weeks of the treatment. Additionally, data demonstrated that the antidiabetic action of Ella NPs and its effective duration were similar to metformin. Ella NPs led to a lowering effect on lipid profile markers (total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL)), superior to the regular Ella, which reduced only TG and VLDL. Results of the pathological examination showed improved number and activity of beta islets in all treatment groups. The most enhanced islets were in the Ella NPs and metformin group. The different treatments decreased caspase 3 and increased insulin gene expression, and the effect was superior in the Ella NPs and metformin group. The results of this study confirmed that Ella could manage typ2diab by lowering glucose and lipid levels and improving body weight with the superiority of Ella NPs. The mechanisms behind these effects are inhibition of beta-cell apoptosis and stimulation of insulin production.
