Register      Login
Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology
RESEARCH ARTICLE

Resveratrol directly affects ovarian cell sirtuin, proliferation, apoptosis, hormone release and response to follicle-stimulating hormone (FSH) and insulin-like growth factor I (IGF-I)

Alexander Sirotkin A B E , Richard Alexa A , Attila Kádasi C , Erika Adamcová A , Saleh Alwasel D and Abdel Halim Harrath D
+ Author Affiliations
- Author Affiliations

A Constantine the Philosopher University, 949 74 Nitra, Slovakia.

B Department of Genetics and Reproduction, Research Institute of Animal Production, 951 41 Lužianky, Slovakia.

C Department of Animal Physiology, Slovak University of Agriculture in Nitra, 949 76 Nitra, Slovakia.

D King Saud University, Department of Zoology, College of Science, Riyadh 11451, Saudi Arabia.

E Corresponding author. Email: asirotkin@ukf.sk

Reproduction, Fertility and Development 31(8) 1378-1385 https://doi.org/10.1071/RD18425
Submitted: 26 October 2018  Accepted: 12 February 2019   Published: 12 April 2019

Abstract

The objective of our study was to examine the influence of the plant polyphenol resveratrol (R) on the rapamycin signalling pathway (mammalian target of rapamycin; mTOR) and basic ovarian cell functions in mammalian targets, as well as on their response to the physiological hormonal stimulators follicle-stimulating hormone (FSH) and insulin-like growth factor I (IGF-I). Resveratrol was found to stimulate sirtuin 1 accumulation and apoptosis, inhibit proliferation, suppress P and promote T and E release. Alone, FSH promoted proliferation and had no effect on apoptosis, but had an inhibitory effect on these processes when combined with R. IGF-I alone stimulated proliferation and inhibited apoptosis and promoted P production but not that of T; however, in the presence of R, the addition of IGF-I switched from having an anti-apoptotic to a pro-apoptotic effect and stimulated T release, but it did not modify the effect of IGF-I on proliferation and P output. These observations: (1) demonstrate that R directly affects the basic ovarian cell functions of proliferation, apoptosis and steroidogenesis, (2) provide further evidence of the involvement of FSH and IGF-I in the regulation of these processes, (3) demonstrate the ability of R to prevent and even invert the effects of FSH and IGF-I on ovarian cells and (4) indicate that the effects of R may be mediated by the mTOR–sirtuin intracellular signalling system.

Additional keywords: bax, caspase 3, granulosa cells, mTOR–sirtuin, ovarian follicle, PCNA, progesterone, testosterone.


References

Betz, C., and Hall, M. N. (2013). Where is mTOR and what is it doing there? J. Cell Biol. 203, 563–574.
Where is mTOR and what is it doing there?Crossref | GoogleScholarGoogle Scholar | 24385483PubMed |

Cabello, E., Garrido, P., Morán, J., González del Rey, C., Llaneza, P., Llaneza-Suárez, D., Alonso, A., and González, C. (2015). Effects of resveratrol on ovarian response to controlled ovarian hyperstimulation in ob/ob mice. Fertil. Steril. 103, 570–579.e1.
Effects of resveratrol on ovarian response to controlled ovarian hyperstimulation in ob/ob mice.Crossref | GoogleScholarGoogle Scholar | 25467042PubMed |

Ergenoglu, M., Yildirim, N., Yildirim, A. G., Yeniel, O., Erbas, O., Yavasoglu, A., Taskiran, D., and Karadadas, N. (2015). Effects of resveratrol on ovarian morphology, plasma anti-Mullerian hormone, IGF-1 levels, and oxidative stress parameters in a rat model of polycystic ovary syndrome. Reprod. Sci. 22, 942–947.
Effects of resveratrol on ovarian morphology, plasma anti-Mullerian hormone, IGF-1 levels, and oxidative stress parameters in a rat model of polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 25667201PubMed |

Goodman, M. T., and Tung, K. H. (2003). Alcohol consumption and the risk of borderline and invasive ovarian cancer. Obstet. Gynecol. 101, 1221–1228.
| 12798528PubMed |

Kolahdooz, F., Ibiebele, T. I., van der Pols, J. C., and Webb, P. M. (2009). Dietary patterns and ovarian cancer risk. Am. J. Clin. Nutr. 89, 297–304.
Dietary patterns and ovarian cancer risk.Crossref | GoogleScholarGoogle Scholar | 19056595PubMed |

Kolesarova, A., Capcarova, M., Maruniakova, N., Lukac, N., Ciereszko, R. E., and Sirotkin, A. V. (2012). Resveratrol inhibits reproductive toxicity induced by deoxynivalenol. J. Environ. Sci. Health A. Tox. Hazard. Subst. Environ. Eng 47, 1329–1334.
Resveratrol inhibits reproductive toxicity induced by deoxynivalenol.Crossref | GoogleScholarGoogle Scholar | 22540658PubMed |

Kordowitzki, P., Klein, S., Hadeler, K. G., Aldag, P., Nowak-Imialek, M., Lucas-Hahn, A., and Niemann, H. (2017). 3 SIRT1 – a possible marker for reproductive aging of in vivo-derived bovine oocytes? Reprod. Fertil. Dev. 29, 109.
3 SIRT1 – a possible marker for reproductive aging of in vivo-derived bovine oocytes?Crossref | GoogleScholarGoogle Scholar |

Kwon, H. S., and Ott, M. (2008). The ups and downs of SIRT1. Trends Biochem. Sci. 33, 517–525.
The ups and downs of SIRT1.Crossref | GoogleScholarGoogle Scholar | 18805010PubMed |

Kyselova, V., Peknicova, J., Buckiova, D., and Boubelik, M. (2003). Effects of p-nonylphenol and resveratrol on body and organ weight and in vivo fertility of outbred CD-1 mice. Reprod. Biol. Endocrinol. 1, 30.
Effects of p-nonylphenol and resveratrol on body and organ weight and in vivo fertility of outbred CD-1 mice.Crossref | GoogleScholarGoogle Scholar | 12749770PubMed |

Liu, M., Yin, Y., Ye, X., Zeng, M., Zhao, Q., Keefe, D. L., and Liu, L. (2013). Resveratrol protects against age-associated infertility in mice. Hum. Reprod. 28, 707–717.
Resveratrol protects against age-associated infertility in mice.Crossref | GoogleScholarGoogle Scholar | 23293221PubMed |

Macedo, T. J. S., Barros, V. R. P., Monte, A. P. O., Gouveia, B. B., Bezerra, M. É. S., Cavalcante, A. Y. P., Barberino, R. S., Menezes, V. G., and Matos, M. H. T. (2017). Resveratrol has dose-dependent effects on DNA fragmentation and mitochondrial activity of ovine secondary follicles cultured in vitro. Zygote 25, 434–442.

Morita, Y., Wada-Hiraike, O., Yano, T., Shirane, A., Hirano, M., Hiraike, H., Koyama, S., Oishi, H., Yoshino, O., Miyamoto, Y., Sone, K., Oda, K., Nakagawa, S., Tsutsui, K., and Taketani, Y. (2012). Resveratrol promotes expression of SIRT1 and StAR in rat ovarian granulosa cells: an implicative role of SIRT1 in the ovary. Reprod. Biol. Endocrinol. 10, 14.
Resveratrol promotes expression of SIRT1 and StAR in rat ovarian granulosa cells: an implicative role of SIRT1 in the ovary.Crossref | GoogleScholarGoogle Scholar | 22357324PubMed |

Nakayama, Y., and Yamaguchi, N. (2013). Role of cyclin B1 levels in DNA damage and DNA damage-induced senescence. Int. Rev. Cell Mol. Biol. 305, 303–337.
Role of cyclin B1 levels in DNA damage and DNA damage-induced senescence.Crossref | GoogleScholarGoogle Scholar | 23890385PubMed |

Nguyen, C., Savouret, J. F., Widerak, M., Corvol, M. T., and Rannou, F. (2017). Resveratrol, potential therapeutic interest in joint disorders: a critical narrative review. Nutrients 9, E45.
Resveratrol, potential therapeutic interest in joint disorders: a critical narrative review.Crossref | GoogleScholarGoogle Scholar | 28067817PubMed |

Ortega, I., and Duleba, A. J. (2015). Ovarian actions of resveratrol. Ann. N. Y. Acad. Sci. 1348, 86–96.
Ovarian actions of resveratrol.Crossref | GoogleScholarGoogle Scholar | 26315293PubMed |

Pavlová, S., Klucska, K., Vašíček, D., Ryban, L., Harrath, A. H., Alwasel, S. H., and Sirotkin, A. V. (2013). The involvement of SIRT1 and transcription factor NF-κB (p50/p65) in regulation of porcine ovarian cell function. Anim. Reprod. Sci. 140, 180–188.
The involvement of SIRT1 and transcription factor NF-κB (p50/p65) in regulation of porcine ovarian cell function.Crossref | GoogleScholarGoogle Scholar | 23886618PubMed |

Rauf, A., Imran, M., Butt, M. S., Nadeem, M., Peters, D. G., and Mubarak, M. S. (2018). Resveratrol as an anti-cancer agent: a review. Crit. Rev. Food Sci. Nutr. 58, 1428–1447.
Resveratrol as an anti-cancer agent: a review.Crossref | GoogleScholarGoogle Scholar | 28001084PubMed |

Shiomi, Y., and Nishitani, H. (2017). Control of genome integrity by RFC complexes; conductors of PCNA loading onto and unloading from chromatin during DNA replication. Genes (Basel) 8, 52.
Control of genome integrity by RFC complexes; conductors of PCNA loading onto and unloading from chromatin during DNA replication.Crossref | GoogleScholarGoogle Scholar |

Sirotkin, A. V. (2014). ‘Regulators of Ovarian Functions’. (Nova Publishers, Inc: New York.)

Sirotkin, A. V. (2016). The role and application of sirtuins and mTOR signaling in the control of ovarian functions. Cells 5, 42.
The role and application of sirtuins and mTOR signaling in the control of ovarian functions.Crossref | GoogleScholarGoogle Scholar |

Sirotkin, A. V., Makarevich, A. V., Kotwica, J., Marnet, P. G., Kwon, H. B., and Hetenyi, L. (1998). Isolated porcine ovarian follicles as a model for the study of hormone and growth factor action on ovarian secretory activity. J. Endocrinol. 159, 313–321.
Isolated porcine ovarian follicles as a model for the study of hormone and growth factor action on ovarian secretory activity.Crossref | GoogleScholarGoogle Scholar | 9795373PubMed |

Sirotkin, A. V., Dekanová, P., Harrath, A. H., Alwasel, S. H., and Vašíček, D. (2014). Interrelationships between sirtuin 1 and transcription factors p53 and NF-κB (p50/p65) in the control of ovarian cell apoptosis and proliferation. Cell Tissue Res. 358, 627–632.
Interrelationships between sirtuin 1 and transcription factors p53 and NF-κB (p50/p65) in the control of ovarian cell apoptosis and proliferation.Crossref | GoogleScholarGoogle Scholar | 25027053PubMed |

Sirotkin, A. V., Alexa, R., Dekanová, P., Kádasi, A., Štochmaľová, A., Grossmann, R., Alwasel, S. H., and Harrath, A. H. (2015). The mTOR system can affect basic porcine ovarian cell functions and mediate the effect of ovarian hormonal regulators. Int. J. Pharmacol. 11, 570–578.
The mTOR system can affect basic porcine ovarian cell functions and mediate the effect of ovarian hormonal regulators.Crossref | GoogleScholarGoogle Scholar |

Sirotkin, A. V., Florkovičová Koničková, I., Schaeffer, H. J., Laurincik, J., and Harrath, A. H. (2017). Interrelationships between ovarian follicles grown in culture and possible mediators. Reprod. Biol. 17, 97–104.
Interrelationships between ovarian follicles grown in culture and possible mediators.Crossref | GoogleScholarGoogle Scholar | 28163019PubMed |

van Duursen, M. B. M. (2017). Modulation of estrogen synthesis and metabolism by phytoestrogens in vitro and the implications for women’s health. Toxicol. Res. (Camb.) 6, 772–794.
Modulation of estrogen synthesis and metabolism by phytoestrogens in vitro and the implications for women’s health.Crossref | GoogleScholarGoogle Scholar |

Varoni, E. M., Lo Faro, A. F., Sharifi-Rad, J., and Iriti, M. (2016). Anticancer molecular mechanisms of resveratrol. Front. Nutr. 3, 8.
Anticancer molecular mechanisms of resveratrol.Crossref | GoogleScholarGoogle Scholar | 27148534PubMed |

Zhang, X. M., Li, L., Xu, J. J., Wang, N., Liu, W. J., Lin, X. H., Fu, Y. C., and Luo, L. L. (2013). Rapamycin preserves the follicle pool reserve and prolongs the ovarian lifespan of female rats via modulating mTOR activation and sirtuin expression. Gene 523, 82–87.
Rapamycin preserves the follicle pool reserve and prolongs the ovarian lifespan of female rats via modulating mTOR activation and sirtuin expression.Crossref | GoogleScholarGoogle Scholar | 23566837PubMed |