Hesperidin-mediated selenium nanoparticles protect against diabetic cisplatin-induced testicular injury via modulation of Nrf2/Keap1, TLR4/NF-κB/MAPK, and PERK/CHOP Signaling.
Abstract
Background
Type 2 diabetes mellitus (T2DM) and cisplatin-induced toxicity are major contributors to male reproductive dysfunction. The present study investigated the protective impacts of hesperidin (HSP), sodium selenite, and hesperidin-mediated selenium nanoparticles (HSP-SeNPs) against testicular damage induced by the combined impact of T2DM and cisplatin.
Methods
Selenium nanoparticles were biosynthesized using hesperidin and characterized by DLS, zeta potential, TEM, FTIR, and UV-Vis analyses. Adult male Wistar rats were allocated into six groups: control, T2DM, T2DM-CIS, and treatment groups T2DM-CIS&HSP, T2DM-CIS&Na2SeO3, or T2DM-CIS&HSP-SeNPs. Metabolic parameters, oxidative stress markers, antioxidant defense, inflammatory cytokines, ER stress markers, apoptotic indices, steroidogenic gene expression, reproductive hormones, and sperm parameters were evaluated.
Results
T2DM and cisplatin significantly induced oxidative stress (MDA, NO, Keap-1), inflammation (TNF-α, IL-1β, IL-6, NF-κB), ER stress (PERK, CHOP), and dysregulated apoptosis (Bax, Casp-3; BCL2), alongside suppression of Nrf2/HO-1 signaling and reduced expression of StAR, CYP17A1, and HSD3B. These alterations were associated with decreased testosterone, FSH, and LH levels, and impaired sperm quality. Treatment with HSP and sodium selenite significantly improved these parameters; however, HSP-SeNPs exhibited the most pronounced effects, restoring redox balance, reducing inflammatory and apoptotic pathways, and markedly improving steroidogenesis and sperm function.
Conclusion
Hesperidin-mediated selenium nanoparticles provide superior protection against T2DM and cisplatin-induced testicular dysfunction through multi-target mechanisms. These results provide evidence of the impact of HSP-SeNPs as a candidate drug for preserving male fertility under complex pathological conditions.