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We focused primarily on the activity of sirtuins in the context of women’s gynecological health, including investigations on female animal models and cell lines. In contrast to high glucose, 2-deoxy-d-glucose (2-DG) extends the lifespan of Hs68 cells by increasing NAD+ levels and SIRT1 activity, and 2-DG has potential as a caloric restriction mimetic,therefore, 2-DG may activate SIRT1 expression in HAECs. A study in The Journal of Clinical Investigation found that sirtuin activation, which is directly influenced by NAD+, can enhance the function of Leydig cells, thereby boosting testosterone levels. Additionally, sirtuins may help combat age-related decline in testosterone by improving the function of Leydig cells, the cells in the testes responsible for producing testosterone. NAD+ activates sirtuins, a family of proteins that play a crucial role in regulating metabolism, aging, and cellular health.
Engin-Ustun et al. examined SIRT1 levels in women with RIF, healthy women who had conceived by IVF, and women with a 1-cycle failure of IVF, used as controls. These data show that SIRT1 and SIRT6 are significantly involved in human reproduction, and they may play a role in oocyte maturation and clinical pregnancy in vitro fertilization (IVF), but definitive conclusions cannot be drawn and studies should be continued. Follicular fluid resveratrol levels were also significantly lower in pregnant compared with non-pregnant women, but serum resveratrol levels were similar in both groups.
However, due to the relatively small number of subjects in the examined group, indicated as a limitation of their study, the authors showed that their results did not reflect the exact contribution of polymorphism in the development of disease. On the basis of the PCR-CCTP method and single-nucleotide polymorphism (SNP) analysis, they revealed no significant correlation with endometrial cancer. SIRT7 knockdown also resulted in an increase of pro-apoptotic NF-κB target proteins Caspase-3, Bad, and Bax.
Collective evidence suggests sirtuins are involved in both promoting and suppressing tumorigenesis depending on cellular and molecular contexts. A different compound, inauhzin, inhibits the activity of SIRT1 and efficiently reactivates p53 to promote a p53-dependent apoptosis of human cancer cells without causing visible genotoxic stress . Administration of this compound strongly increased the acetylation of p53 protein at K382 following the induction of DNA damage in human mammary epithelial cells and some tumor cell lines . Finally, NAD+-dependent sirtuin activity has also been shown to increase when cells or animals are treated with NAD+ precursors such as niacin, nicotinamide, nicotinamide riboside or nicotinamide mononucleotide .
In addition to the deacetylation of nucleosomal histones and metabolic enzymes, the sirtuins may also exhibit other activities. The N- and C-terminal extensions are the targets for posttranslational modifications that can affect the functions of sirtuins . It is believed that activation of sirtuins may be advantageous not only in metabolic diseases such as type 2 diabetes and obesity, but also in neurodegenerative diseases . These cellular enzymes are metabolic sensors sensitive to NAD+ levels that maintain physiological homeostasis in the animal and plant cells.
Recently, researchers have been interested in the role and usefulness of resveratrol in the normalization of disorders related to aging of the ovaries or impairment of their function. Mimics of miR-152 and miR-24 induced autophagy by increasing the level of SIRT1, which deacetylated LC3. Tong et al. examined the levels of serum miR-152, miR-205, miR-222, miR-24, miR-150, and SIRT1 in patients with uterine sarcoma and healthy subjects by quantitative real-time polymerase chain reaction (qRT-PCR). It was documented that the Bcl-2 inhibitor ABT737 can significantly improve the effect of cisplatin and induce mitochondrial pathway apoptosis. The authors observed significantly lower SIRT4 concentration in endometrioid adenocarcinoma than in non-neoplastic tissue counterpart.
Authors concluded that perturbations caused by SIRT3 via post-translational protein modification in human granulosa and cumulus cells may be a causative factor in the decline of oocyte viability in women with reduced ovarian reserve and advanced maternal age. The action of this deacetylase on glutamate GDH has been confirmed in granulosa cells obtained from young healthy women by subjecting them to resveratrol and nicotinamide action (as known sirtuins activator and inhibitor, respectively). They also found that only SIRT3 mRNA expression is altered by RSV, but SIRT1, 3 and 5 overexpression did not result in a change in the steroid profile of H295R cells, which suggests that resveratrol may not significantly engage sirtuins to modulate steroid production. The authors reported that cisplatin, accompanied with ABT737, promoted apoptosis and decreased the mitochondrial membrane potential of ovarian cancer cells.