The chemotherapeutic combination of bleomycin, etoposide, and cisplatin (BEP) is well-documented to exert gonadotoxic effects, ultimately leading to impaired fertility. This experimental rat study investigated the potential protective role of repeated medical ozone therapy in mitigating the deleterious effects of BEP treatment in male rats. Thirty-two adult male Sprague Dawley rats were randomly assigned to four groups: (i) a healthy control group, (ii) a group receiving injections of the BEP regimen over nine weeks, (iii) a group receiving the same BEP regimen plus medical ozone (1 mg/kg IP) twice weekly, and (iv) a group receiving only ozone therapy. BEP treatment significantly reduced sperm concentration and increased morphological abnormalities, both of which were partially restored by ozone co-administration. Ozone therapy also elevated testosterone and thyroid-stimulating hormone (TSH) levels when co-administered with BEP compared to BEP treatment alone. Oxidative stress analysis demonstrated that total oxidative status (TOS) and total antioxidant status (TAS) levels were significantly improved in the BEP + ozone group. Histopathological analysis revealed that ozone treatment ameliorated BEP-induced testicular damage, as evidenced by improved Johnsen scores and increased thickness of the seminiferous tubule epithelium. In conclusion, repeated medical ozone therapy appears to mitigate BEP-induced reproductive toxicity by preserving sperm quality, endocrine function, and redox homeostasis.

Background and Objectives: Diabetes mellitus (DM) is frequently associated with impaired wound healing due to persistent oxidative stress, chronic inflammation, and dysregulated proteasome activity, leading to delayed tissue repair and increased risk of chronic ulcers. The present study aimed to investigate the role of the immunoproteasome system in diabetic wound healing, with a particular focus on its involvement in oxidative stress and inflammatory pathways, and to evaluate whether pharmacological inhibition with ONX-0914 improves tissue repair. Materials and Methods: Experimental diabetes was induced in rats using streptozotocin (STZ), and the animals were allocated to three groups: healthy control, STZ-induced diabetic, and STZ + ONX-0914 treatment. Wound healing was evaluated by macroscopic analysis of wound closure and histopathological examination at days 3, 7, and 14. Oxidative stress and antioxidant status were assessed by measuring malondialdehyde (MDA) levels and antioxidant enzyme activities (SOD, CAT, and GSH-Px) in serum and wound tissues. Proteasome activity was analyzed fluorometrically, while systemic and local inflammatory responses were determined by ELISA and Western blot analysis of IL-1β, TNF-α, and IL-6. Results: STZ-induced diabetes significantly delayed wound closure, increased lipid peroxidation, reduced antioxidant enzyme activities, and elevated systemic and tissue inflammatory cytokine levels. Treatment with ONX-0914 markedly accelerated wound closure and improved histological healing parameters, including re-epithelialization, granulation tissue formation, and angiogenesis. Moreover, ONX-0914 significantly reduced MDA levels while restoring SOD, CAT, and GSH-Px activities in both serum and wound tissues. The treatment also inhibited proteasome activity and significantly suppressed the expression of IL-1β, TNF-α, and IL-6. Conclusions: ONX-0914 significantly improves diabetic wound healing by restoring antioxidant defenses, reducing oxidative damage, and attenuating inflammatory signaling pathways. These findings suggest that immunoproteasome inhibition represents a promising therapeutic strategy for enhancing tissue repair in diabetic conditions.