Modulation of Oxidative Stress, Inflammation, and Apoptosis and Restoration of Sirt1/Nrf2/HO-1 Signaling by Diosmin Protect Against Diabetes-Induced Testicular Damage in Rats

Diabetes mellitus (DM) is recognized as a major contributor to impaired testicular function and compromised male fertility. In the present study, the protective effects of the natural flavonoid diosmin (Dios) against diabetes-induced testicular injury were investigated using a rat model of streptozotocin (STZ)-induced diabetes. Diabetes was induced in rats via a single intraperitoneal injection of STZ at a dose of 50 mg/kg body weight. Dios was administered at doses of 25 and 50 mg/kg body weight for eight weeks. Diabetic rats displayed marked testicular dysfunction, evidenced by reduced serum testosterone levels, deteriorated sperm parameters, and pronounced histopathological alterations in testicular tissues. Biochemical analysis revealed elevated levels of oxidative stress markers, including malondialdehyde and protein carbonyls, along with decreased levels of reduced glutathione and diminished activities of catalase and superoxide dismutase in the testicular tissues. Furthermore, diabetes exacerbated testicular inflammation, as indicated by increased immunoexpression of NF-κB p65 and levels of pro-inflammatory cytokines. Likewise, diabetes induced testicular apoptosis, demonstrated by increased Bax and caspase-3 levels and decreased Bcl-2 levels. Treatment of diabetic rats with Dios significantly attenuated sperm parameters and testicular architecture and mitigated oxidative stress, inflammatory responses, and apoptotic cell death. Additionally, Dios enhanced antioxidant defense mechanisms and restored the Sirt1/Nrf2/HO-1 signaling pathway in the testicular tissues of diabetic rats. These results suggest that Dios may serve as an adjuvant therapeutic agent for diabetes-associated testicular dysfunction.