Exploring the shared molecular mechanism of microvascular and macrovascular complications in diabetes: Seeking the hub of circulatory system injury.

Background: Microvascular complications, such as diabetic retinopathy (DR) and diabetic nephropathy (DN), and macrovascular complications, referring to atherosclerosis (AS), are the main complications of diabetes. Blindness or fatal microvascular diseases are considered to be identified earlier than fatal macrovascular complications. Exploring the intrinsic relationship between microvascular and macrovascular complications and the hub of pathogenesis is of vital importance for prolonging the life span of patients with diabetes and improving the quality of life. Materials and methods: The expression profiles of GSE28829, GSE30529, GSE146615 and GSE134998 were downloaded from the Gene Expression Omnibus database, which contained 29 atherosclerotic plaque samples, including 16 AS samples and 13 normal controls; 22 renal glomeruli and tubules samples from diabetes nephropathy including 12 DN samples and 10 normal controls; 73 lymphoblastoid cell line samples, including 52 DR samples and 21 normal controls. The microarray datasets were consolidated and DEGs were acquired and further analyzed by bioinformatics techniques including GSEA analysis, GO-KEGG functional clustering by R (version 4.0.5), PPI analysis by Cytoscape (version 3.8.2) and String database, miRNA analysis by Diana database, and hub genes analysis by Metascape database. The drug sensitivity of characteristic DEGs was analyzed. Result: A total of 3709, 4185 and 8086 DEGs were recognized in AS, DN, DR, respectively, with 1820, 1666, 888 upregulated and 1889, 2519, 7198 downregulated. GO and KEGG pathway analyses of DEGs and GSEA analysis of common differential genes demonstrated that these significant sites focused primarily on inflammation-oxidative stress and immune regulation pathways. PPI networks show the connection and regulation on top-250 significant sites of AS, DN, DR. MiRNA analysis explored the non-coding RNA upstream regulation network and significant pathway in AS, DN, DR. The joint analysis of multiple diseases shows the common influenced pathways of AS, DN, DR and explored the interaction between top-1000 DEGs at the same time. Conclusion: In the microvascular and macrovascular complications of diabetes, immune-mediated inflammatory response, chronic inflammation caused by endothelial cell activation and oxidative stress are the three links linking atherosclerosis, diabetes retinopathy and diabetes nephropathy together. Our study has clarified the intrinsic relationship and common tissue damage mechanism of microcirculation and circulatory system complications in diabetes, and explored the mechanism center of these two vascular complications. It has far-reaching clinical and social value for reducing the incidence of fatal events and early controlling the progress of disabling and fatal circulatory complications in diabetes.

Exploration of shared TF-miRNA‒mRNA and mRNA-RBP-pseudogene networks in type 2 diabetes mellitus and breast cancer.

Type 2 diabetes mellitus (T2DM) has been confirmed to be closely associated with breast cancer (BC). However, the shared mechanisms between these diseases remain unclear. By comparing different datasets, we identified shared differentially expressed (DE) RNAs in T2DM and BC, including 427 mRNAs and 6 miRNAs from the GEO(Gene Expression Omnibus) database. We used databases to predict interactions to construct two critical networks. The transcription factor (TF)-miRNA‒mRNA network contained 236 TFs, while the RNA binding protein (RBP)-pseudogene-mRNA network showed that the pseudogene S-phase kinase associated protein 1 pseudogene 1 (SKP1P1) might play a key role in regulating gene expression. The shared mRNAs between T2DM and BC were enriched in cytochrome (CYP) pathways, and further analysis of CPEB1 and COLEC12 expression in cell lines, single cells and other cancers showed that they were strongly correlated with the survival and prognosis of patients with BC. This result suggested that patients with T2DM presenting the downregulation of CPEB1 and COLEC12 might have a higher risk of developing BC. Overall, our work revealed that high expression of CYPs in patients with T2DM might be a susceptibility factor for BC and identified novel gene candidates and immune features that are promising targets for immunotherapy in patients with BC.