Investigations on potential drug targets for mitigating diabetic complications

Abstract

Diabetes mellitus is one of the most common chronic diseases worldwide. Microvascular complications of diabetes include nephropathy, retinopathy, and neuropathy whereas macrovascular complications involve atherosclerosis-related diseases, such as peripheral vascular disease, coronary artery disease, stroke, and possibly cognitive dysfunction. It is unlikely that one universal mechanism may be involved in the development of diabetic complications instead, interactions between multiple pathways are known to exist, making targeting such systems increasingly challenging. The goal of this research work was to address this issue, by moving beyond the simple glucose-centric view and address the organ-specific pathogenic mechanisms using a diverse range of therapeutic approaches. Ferulic acid (FA) alone and its combination with insulin improved peripheral nerve function in diabetic rats highlighting its role as an efficacious agent for treating diabetic neuropathy. Moreover, treatment with tetramethylpyrazine (TMP) alleviated learning and memory deficits in type 2 diabetic rats by activating the Akt/CREB/BDNF pathway. Furthermore, our findings also demonstrated promising wound healing activity of astaxanthin (ATX) as it effectively up-regulated HIF-1and#945;/VEGF signaling pathway and reduced oxidative stress markers, inflammatory mediators, and MMP-9 levels. Lastly, intervention with dimethylfumarate (DMF) alone and in combination with telmisartan reduced diabetic kidney injury by activating the Nrf2 signaling pathway and inhibiting AGE newlineformation and TGF-and#946;/SMAD signaling pathway. The overall findings indicate that the interventions FA, TMP, ATX, and DMF offered significant protection against diabetic complications and may serve as effective therapeutic adjuvants to first-line hypoglycemic agents in the management of diabetic complications. newline newline