Cordycepin, a major bioactive component of Cordyceps militaris, ameliorates diabetes-induced testicular damage through the Sirt1/Foxo3a pathway

Diabetes-induced male dysfunction is considered as a worldwide challenge, and testicular damage mainly caused by oxidative stress is its most common manifestation. Cordycepin, a natural antioxidant, has been used in the treatment of diabetic complications. However, the protective action and underlying mechanism of cordycepin on hyperglycaemia-induced testicular damage are unclear. This study aimed to investigate the protective effects and molecular mechanisms of cordycepin against diabetes-induced testicular damage. The type 2 diabetes model was established in C57BL/6 male mice via high-fat diet for 4 weeks and injected intraperitoneally with 50 mg/kg/day streptozotocin for five consecutive days. Then mice were treated with cordycepin (10 and 20 mg/kg, respectively) for 8 weeks. At the end of experiment, biochemical indicators, microstructure of testicular tissue, sperm morphology, TUNEL staining and protein expressions were evaluated. In the present study, cordycepin alleviated the testicular damage, restored disruption of the blood-testis barrier, and improved spermatogenic function via the antiapoptotic and antioxidant capacity. Mechanistically, cordycepin significantly enhanced SIRT1 expression and triggered the activity of Foxo3a, further to induce the expression of its downstream antioxidant enzymes, including Mn-SOD and CAT. These findings indicated that cordycepin could improve hyperglycaemia-induced testicular damage by regulating downstream antioxidant enzymes activity through the SIRT1/Foxo3a signalling pathway.