Screening of Advanced Glycation End products inhibitors and their role in ameliorating the underlying consequences in Diabetes

Abstract

Diabetes Mellitus is characterized by abnormal hyperglycaemia either due to insufficient or inefficient insulin or in some cases, both. The persistent hyperglycaemia in the blood leads to the production of ROS which results in the oxidative stress and if unmanaged, leads to the secondary complication of diabetes. One of the major outcomes in diabetic patients is the development of diabetic nephropathy (DN) and end stage renal disease. Several factors play an important role as an inducer of DN; one of them is the formation of advanced glycation end products (AGEs). AGEs elicit their harmful effects via interacting with its receptor for advanced glycation end products (RAGE), by induction of pro-inflammatory cytokines, oxidative stress, endoplasmic reticulum (ER) stress and fibrosis in the kidney tissues leading to the loss of renal function. Therefore, it is of prime importance, that strategies to inhibit either the formation of AGEs or the stimulation of AGE-RAGE axis should be investigated to prevent the complication of diabetes. Therefore, in the present study, we have aimed at screening and isolating the inhibitor of AGEs which can prevent the DN under hyperglycaemic conditions. newlineWe have screened various formulations and found that Enicostemma littorale could significantly inhibit the formations of AGEs when compared with other formulations. Its active component swertiamarin (SM) was successfully isolated and characterized in the lab using HPLC, FTIR and LC-MS. Further SM could inhibit the formation of AGEs more significantly than Metformin in both in vitro and in vivo conditions. SM inhibited the structural changes in the protein molecule due to glycation, by retaining the inherent structure of the protein and preventing its loss of function. SM could prevent the inflammation (TNF-and#945;, IL-1and#946;, IL-6, etc) the oxidative stress (Nrf-2, HO-1, MDA, etc.) and fibrosis (TGF-and#946;, E-cadherin, Fibronectin-1) in the kidney tissue along with the inhibition of newlineviii newlineepithelial mesenchymal transition, which further prevented th