RESUMO
Nuclear factor erythroid-2-related factor 2 (Nrf2) is a stress-activated transcription factor regulating antioxidant genes, and a deficiency thereof, slowing lymphangiogenesis, has been reported in diabetic foot ulcer (DFU). The mode of Nrf2 regulation in DFU has been less explored. Emerging studies on miRNA-mediated target regulation show miRNA to be the leading player in the pathogenesis of the disease. In the present study, we demonstrated the role of miR-27b in regulating Nrf2-mediated angiogenesis in DFU. A lower expression of mRNA targets, such as Nrf2, HO-1, SDF-1α, and VEGF, was observed in tissue biopsied from chronic DFU subjects, which was in line with miR-27b, signifying a positive correlation with Nrf2. Similarly, we found significantly reduced expression of miR-27b and target mRNAs Nrf2, HO-1, SDF-1α, and VEGF in endothelial cells under a hyperglycemic microenvironment (HGM). To confirm the association of miR-27b on regulating Nrf2-mediated angiogenesis, we inhibited its expression through RNA interference-mediated knockdown and observed disturbances in angiogenic signaling with reduced endothelial cell migration. In addition, to explore the role of miR-27b and angiogenesis in the activation of Nrf2, we pretreated the endothelial cells with two well-known pharmacological compounds-pterostilbene and resveratrol. We observed that activation of Nrf2 through these compounds ameliorates impaired angiogenesis on HGM-induced endothelial cells. This study suggests a positive role of miR-27b in regulating Nrf2, which seems to be decreased in DFU and improves on treatment with pterostilbene and resveratrol.
RESUMO
The majority of the non-protein-coding RNAs are being identified with diversified functions that participate in cellular homeostasis. The circular RNAs (circRNAs) are emerging as noncoding transcripts with a key role in the initiation and development of many physiological and pathological conditions. The advancements in high-throughput RNA sequencing and bioinformatics tools help us to identify several circRNA regulatory pathways, one of which is microRNA (miRNA)-mediated regulation. Besides the direct influence over mRNA transcription, the circRNA can also control the target's expression via sponging miRNAs or the RNA-binding proteins. Studies have demonstrated the dysregulation of the circRNA-miRNA-mRNA interaction network in the pathogenesis of many diseases, including diabetes. This intricate mechanism is associated with the pathogenesis of diabetes and its complications. This review will focus on the circRNA-miRNA-mRNA interaction network that influences the gene expression in the progression of diabetes and its associated complications.
