The Natural Carotenoid Crocetin and the Synthetic Tellurium Compound AS101 Protect the Ovary against Cyclophosphamide by Modulating SIRT1 and Mitochondrial Markers

Figure 8

Possible mechanisms through which crocetin and AS101 reverse the early adaptive response of the ovary to CPM. Based on our results and current literature, CPM causes the activation of the PI3K/AKT/FOXO3A signalling pathway that ends with the activation of primordial follicles (“burnout” hypothesis). Increased oxidative stress, which probably arisen from reduced GSH due to ovarian PM detoxification, is evidenced by reduced SOD2 levels and upregulation of the OS sensors SIRT1 and SIRT3. Upregulation of SIRT1 may contribute to CPM-induced follicle activation; upregulation of SIRT3 along with reduction of PGC1-α and SOD2 marks the CPM-induced mitochondrial damage. By contrast, the finding that crocetin and AS101 exert fertoprotective effects, prevent SIRT1 and SIRT3 rise, and maintain pFOXO3a, PGC1-α, and SOD2 levels provides evidence for a link between the burnout hypothesis, oxidative stress, and mitochondrial damage.