Effect of bioactive compounds from Cornus mas L. fruits on the level of advanced glycation end-products (AGEs) and receptors for ages in blood plasma and leukocytes of rats with streptozotocin-induced diabetes mellitus

Background. Мetabolic distortions mediated сhronic hyperglycemia lead to pathophysiological alterations in diabetes mellitus. Persistent elevation of blood glucose promotes non-enzymatic glycation of proteins and lipids, leading to the accumulation of advanced glycation end-products (AGEs). Accumulation of AGEs reflects impaired metabolic clearance and/or excretion and is therefore considered a marker of both long-term glycemic control and oxidative-carbonyl stress in tissues. The biological effects of AGEs are largely mediated through their interaction with the receptor for advanced glycation end products (RAGE), triggering pro-inflammatory signaling pathways. Accordingly, this study investigated the effects of bioactive compounds extracted from сornelian cherry fruits (Cornus mas L.) on AGEs and RAGEs levels in plasma and blood leukocytes of rats with experimental diabetes mellitus. Materials and Methods. Experiments were conducted in streptozotocin-induced diabetic rats divided into three experimental groups. Starting on day 10 after diabetes induction, animals received oral administration of fruit extracts from сornelian cherry cultivars ‘Podolski’, ‘Yantarnyi’ & ‘Flava’, as well as the iridoid glycoside loganic acid isolated from these fruits, at a dose of 20 mg/kg body weight for 14 consecutive days. Control and untreated diabetic rats received distilled water (1 mL per rat) by oral gavage. On day 24 of the experiment, blood samples were collected. Levels of fluorescent and non-fluorescent AGEs were determined in plasma and leukocytes. Full-length receptor for AGEs (flRAGE) expression in leukocyte membranes was assessed using an indirect immunoperoxidase assay, while plasma concentrations of the soluble form of RAGE (sRAGE) were measured by immunoblotting. Results. One of the mechanisms of the deleterious effect of high glucose level, in particular its ability to react non-enzymatically with proteins with the formation of AGEs, has been studied. An increase for AGEs in blood plasma of rats with diabetes was found, instead, interesting results were obtained, indicating a decrease in the fluorescent and non-fluorescent AGEs level in leukocytes. This is likely due to impaired leukocyte glucose uptake in condition of diabetic hypoinsulinemia. There was a significant increase in the number of RAGEs+ leukocytes and the level of sRAGEs in plasma of rats with diabetes. It was found that the content of the fluorescent and non-fluorescent AGEs significantly increased in leukocytes of rats with DM after administration of the fruit extracts of the cornelian cherry ‘Podolski’ and ‘Yantarnyi‘ & ‘Flava‘ cultivars, and the loganic acid. It is worth noting that the extract from the fruits of Cornus mas L. ‘Podolski’ cultivar showed the best effect among all studied extracts and led to reduce the level of AGEs in the blood plasma and receptors to them. Conclusions. The fruit extract of Cornus mas L. ‘Podolski’ cultivar demonstrates therapeutic potential in the correction of impaired glucose metabolism in diabetes mellitus. The beneficial effects of the extract’s bioactive compounds are associated with the inhibition of glycation, the formation of AGEs, and normalize the level of RAGEs in blood plasma and leukocytes.