Dzydzan O. Antidiabetic and antioxidant effects of cornelian cherry (Cornus mas L.) fruit extracts under experimental diabetes mellitus

Diabetes mellitus (DM) is still one of the most pressing medical and social problems in society, as it belongs to the 10 most common diseases in the world and affects many systems and organs. Considering this, the search for drugs that are characterized not only by hypoglycemic properties, but also able to reduce the negative effects of oxidative stress is important in the treatment of DM. Therefore, obtaining extracts of Cornus mas L. fruits and studying their biological properties will allow us to assess the prospects of using the extracts as possible drugs for the diabetes treatment. The qualitative and quantitative composition of red and yellow fruits extracts of Cornus mas L. was analyzed, 29 compounds from two main groups were found: 8 iridoids and 21 phenolic compounds, in particular anthocyanins, phenolic acids and flavonols. At the same time, it was found that anthocyanins and kaempferol derivatives were identified exclusively in the red fruit extract of cornelian cherry. It was found that the content of loganic acid in both extracts is the highest among all identified compounds and in particular the iridoids. Therefore, loganic acid was extracted from the yellow fruits of cornelian cherry and was studied as a separate extract. The hypoglycemic effect of red and yellow fruit extracts of cornelian cherry was found under administration at a dose of 20 mg/kg body weight for 14 days to rats with streptozotocin-induced diabetes, evidenced by a decrease in glucose concentration and integral area under glycemic curves. Loganic acid did not improve blood glucose level. The inhibitory effect of all cornelian cherry extracts on the ????-glucosidase Saccharomyces cerevisiae was revealed. At the same time, yellow and red fruit extracts possess mixed type and loganic acid has non-competitive type of ????-glucosidase inhibition. These results may explain the difference in the extracts efficacy on enzyme activity in vitro and their hypoglycemic potential in vivo. Extracts of cornelian cherry fruit were found to increase body weight in rats with DM. It was also revealed that extracts of red and yellow fruits contributed to an increase in the population of erythrocytes with increased resistance to acid hemolytic. At the same time, administration of loganic acid did not cause positive changes and led to an increase in cells with reduced resistance. An in vitro study of the antioxidant properties of Cornus mas L. red and yellow fruit extracts in a model of phosphatidylcholine liposome demonstrated the ability of both extracts to protect the lipid membrane from free radicals induced by chemical and physical factors. The in vivo antioxidant properties of Cornus mas L. fruit extracts were also studied and their effect on pro/antioxidant status of peripheral blood leukocytes of rats in diabetes was established for the first time. It was found that the studied extracts caused a decrease in the level of ROS, were reducing the intensity of oxidative modification of proteins and lipid peroxidation in plasma and leukocytes and led to increase the activity of some antioxidant enzyme in blood leukocytes of animals with diabetes. Relation between MPO and development of oxidative stress in diabetes, which was manifested by an increase in the level of another biomarker of oxidative damage of proteins – advanced oxidation protein products (AOPPs) in blood plasma, has been confirmed. Extracts of red and yellow fruits of Cornus mas L. were found to increase the activity of MPO and the level of AOPPs in leukocytes, and loganic acid affected only the content of AOPPs. It was shown that administration of extracts of red and yellow fruits also contributed to the reduction of both indicators in blood plasma, while loganic acid led only to the decrease in the activity of MPO. It was found that the extract of red and yellow fruits of cornelian cherry caused a decrease in plasma glycation end products (AGEs) in animals with DM. Only red fruit extract caused a decrease in their receptors (RAGE) on the membrane of leukocytes and soluble form in plasma due to hypoglycemic and antioxidant properties of this extract. It was analyzed as the reasons for decrease in the activity of antioxidant enzymes and leukocytes’ functional disorders development in the condition of diabetes. A reduced uptake of fluorescently labeled glucose analogue by leukocytes under experimental diabetes mellitus was found compared to control values. At the same time, a decrease in the level of ATP in blood leukocytes of rats with diabetes was established. Administration of cornelian cherry red and yellow fruit extracts and loganic acid contributed to the increase in glucose uptake by leukocytes and the concomitant increase in intracellular ATP levels.