Alpha-lipoic acid effectively attenuates ionizing radiation-mediated testicular dysfunction in rats: Crosstalk of NF-ĸB, TGF-ß, and PPAR-ϒ pathways.

Radiotherapy is one of the principal approaches employed in the treatment of pelvic cancers. Nevertheless, testicular dysfunction and infertility are among the most common adverse effects in young adult cancer survivors. Clinically, alpha-lipoic acid (LA) has been applied to improve the quality of sperm with a satisfactory effect. Therefore, the present study investigated the underlying mechanisms of the radioprotective effects of LA against testicular damage. Male Sprague-Dawley rats were exposed to 10 Gy of whole-body ϒ-radiation and LA (50 mg/kg, P.O.) was administered one week before and three days post-irradiation. LA showed remarkable capacity in preserving testicular tissue against radiation damage by improving histological and ultrastructural changes of disorganized seminiferous tubules, besides enhancing its diameter, germinal epithelial thickness, and Johnsen's score. Radiation instigated a significant decrease in sperm quality and quantity associated with depletion of serum testosterone levels, while the LA administration maintained spermatogenesis. Strikingly, LA exhibited antioxidant properties by restoring reduced glutathione levels and antioxidant enzyme activities such as catalase and glutathione-s-transferase, besides diminishing malondialdehyde levels in the testis of irradiated group. Furthermore, LA alleviated testicular inflammation through downregulation of nuclear factor-ĸB (NF-ĸB) expression with a subsequent reduction in interleukin (IL)-6 and cyclooxygenase-2 expression, accompanied by the augmented expression of the anti-inflammatory cytokine IL-10. Additionally, testicular fibrosis markers including Masson's trichrome and transforming growth factor (TGF)-ß expression were noticeably declined in LA-treated irradiated rats, together with the upregulation of peroxisome proliferator-activated receptor-ϒ expression. Collectively, LA ameliorates radiation-mediated spermatogenesis-defects and testicular-damage via suppression of oxidative stress/NF-ĸB/TGF-ß signaling.

The tyrosine kinase inhibitor, sunitinib malate, induces cognitive impairment in vivo via dysregulating VEGFR signaling, apoptotic and autophagic machineries.

Chemobrain refers to a cluster of cognitive deficits which affects almost 4-75% of chemotherapy-treated cancer patients. Sunitinib, an FDA-approved multityrosine kinase inhibitor, is currently used in treating different types of tumors. Despite being regarded as targeted therapy which blunts sustained angiogenesis in cancer milieu through inhibiting vascular endothelial growth factor receptor 2 (VEGFR2) signaling, the latter has a cardinal role in cognition. Recent clinical reports warned that sunitinib adversely affected memory processing in cancer patients. Nevertheless, the underlying mechanisms have not been investigated yet. Hence, we explored the impact of a clinically relevant dose of sunitinib on memory processing in vivo and questioned the implication of VEGFR2 signaling, autophagy and apoptosis. Strikingly, sunitinib preferentially impaired spatial cognition as evidenced in Morris water maze, T-maze and passive avoidance task. Consistently, sunitinib degenerated cortical and hippocampal neurons as assessed by histopathological examination and toluidine blue staining. Ultrastructural examination also depicted chromatin condensation, mitochondrial damage and accumulated autophagosomes. Digging deeper, central VEGF/VEGFR2/mTOR signaling was robustly suppressed. Besides, sunitinib boosted cortical and hippocampal p53 and executioner caspase-3 and decreased nuclear factor kappa B and Bcl-2 levels promoting apoptotic cell death. It also profoundly impeded neuronal autophagic flux as shown by decreased beclin-1 and Atg5 and increased p62/SQTSM1 levels. To our knowledge, this is the first study to provide molecular insights into sunitinib-induced chemofog where impeded VEGFR2 signaling and autophagic and hyperactivated apoptotic machineries act in neurodegenerative concert. Importantly, our findings shed light on potential therapeutic strategies to be exploited in the management of sunitinib-induced chemobrain.

Resveratrol inhibits inflammatory signaling implicated in ionizing radiation-induced premature ovarian failure through antagonistic crosstalk between silencing information regulator 1 (SIRT1) and poly(ADP-ribose) polymerase 1 (PARP-1).

This study hypothesized that resveratrol, a silencing information regulator 1 (SIRT1) activator, would counteract the inflammatory signaling associated with radiotherapy-induced premature ovarian failure (POF). Immature female Sprague-Dawley rats were subjected to a single dose of γ-radiation to induce POF and treated with resveratrol (25mg/kg) once daily for two weeks before and three days post irradiation. Resveratrol preserves the entire ovarian follicle pool manifested by increasing serum anti-Müllerian hormone (AMH) levels. Radiation triggered inflammatory process in the ovary through enhanced NF-κB and poly(ADP-ribose) polymerase (PARP)-1 expression which convinced the expression of inflammatory markers including IL-6, IL-8, and visfatin mRNA levels, as well as inducible nitric oxide synthase and cyclooxygenase-2 protein expression with a concomitant reduction in IL-10 mRNA levels. Resveratrol significantly counteracted the effect of radiation and upregulated the gene expression of peroxisome proliferator-activated receptor γ (PPAR-γ) and SIRT1. Resveratrol-activated SIRT1 expression was associated with inhibition of PARP-1 and NF-κB expression-mediated inflammatory cytokines. Our findings suggest that resveratrol restored ovarian function through increasing AMH levels, and diminishing ovarian inflammation, predominantly via upregulation of PPAR-γ and SIRT1 expression leading to inhibition of NF-κB provoked inflammatory cytokines.

Sodium selenite treatment restores long-lasting ovarian damage induced by irradiation in rats: impact on oxidative stress and apoptosis.

The deleterious damage of reproductive function following radiotherapy is of increasing importance. In the present study, we investigated the impact of long-term sodium selenite (SS) treatment on radiotherapy-induced ovarian injury in a rat model. Two-week after radiation exposure vaginal cyclicity was arrested, and serum FSH level was elevated in irradiated female rats. SS significantly ameliorated ovarian and uterine oxidative stress induced by irradiation through decreasing the lipid peroxide level and increasing the glutathione level, and glutathione peroxidase activity. In the presence of SS, ovarian cytochrome c and caspase 3 expressions triggered by radiotherapy were decreased. SS significantly counteracted radiation-induced a widespread loss of ovarian follicles and caused further stimulation of follicular proliferation through enhancing PCNA expression. Despite such alteration in ovarian function, serum estradiol level did not change after irradiation, whereas SS significantly increased it. In conclusion, long-term SS treatment improved reproductive development, which was impaired by radiotherapy.