The new method for premature ovarian insufficiency treatment based on the effect of omaveloxolone (RTA 408) on the mitochondrial function of granulosa cells

Cover Page


Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

Background: Premature ovarian insufficiency is a syndrome characterized by secondary hypergonadotropic ovarian insufficiency and a decrease in the ovarian function in women under 40 years of age, thereby leading to impaired reproductive function, metabolic changes, and a decrease in the quality of life. Increased production of reactive oxygen species inhibits the mitochondrial respiration chain and leads to mitochondrial dysfunction and oxidative stress, which are considered as the triggers of premature ovarian insufficiency. To date, there is no universal method of premature ovarian insufficiency prevention, and accepted treatment methods can only compensate for clinical symptoms, but not restore the lost ovarian reserve.

Aim: The aim of this study was to develop a new method of premature ovarian insufficiency treatment based on an experimental ovarian granulosa cell model using omaveloxolone (RTA 408).

Materials and methods: The cell model of premature ovarian insufficiency used in the study was realized according to the Patent RU 2 815 539 C1, 2023 (by M.I. Yarmolinskaya, K.A. Zakuraeva, A.Yu. Vinokurov, M.Yu. Pogonyalova). Ovarian granulosa cells isolated from three-month Wistar rats were subcultivated five times with subsequent seeding on coverslips. The cells on the coverslips were divided into three groups (three coverslip in each group). In Group 1 (comparison group — premature ovarian insufficiency model without treatment), cells were treated with cyclophosphamide (0.1 mg/ml) during 6 h. In Group 2 (main group — premature ovarian insufficiency model with experimental treatment) cells were pretreated with RTA 408 (2 µl/ml) during 1 h with subsequent addition of cyclophosphamide (0.1 mg/ml) and cultivation during 6 h. And in Group 3 (control group), cells were added no substances.

Results: Compared to Groups 2 and 3, the use of omaveloxolone (RTA 408) led to an increase in reduced glutathione level and a decrease in reactive oxygen species production rate, which indicates the antioxidant and anti-inflammatory effects of the drug and may be considered as a perspective strategy of premature ovarian insufficiency treatment. The claimed method expands the number of premature ovarian insufficiency treatment strategies and avoids the use of hormonal medications and surgical procedures, thus reducing the risk of side effects and complications associated with their use.

Full Text

Restricted Access

About the authors

Karina А. Zakuraeva

The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott

Email: zakuraevak@icloud.com
ORCID iD: 0000-0002-8128-306X
SPIN-code: 5215-7869

MD

Russian Federation, Saint Petersburg

Maria I. Yarmolinskaya

The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott

Email: m.yarmolinskaya@gmail.com
ORCID iD: 0000-0002-6551-4147
SPIN-code: 3686-3605

MD, Dr. Sci. (Medicine), Professor, Professor of the Russian Academy of Sciences

Russian Federation, St. Petersburg

Andrey Yu. Vinokurov

Oryol State University

Email: vinokurovayu@oreluniver.ru
ORCID iD: 0000-0001-8436-1353
SPIN-code: 5518-3107

Cand. Sci. (Engineering)

Russian Federation, Oryol

Marina Yu. Pogonyalova

Oryol State University

Author for correspondence.
Email: mpogonalova@gmail.com
ORCID iD: 0000-0001-6919-0728
SPIN-code: 1300-9791
Russian Federation, Oryol

References

  1. Adamyan LV, Dementieva VO, Asaturova AV. Complex treatment of premature ovarian insufficiency using surgical technologies. Criteria for the selection of patients: own experience based on the management of more than 100 patients. Russian Journal of Human Reproduction. 2022;28(4):106–114. EDN: SDPGOP doi: 10.17116/repro202228041106
  2. Li M, Zhu Y, Wei J, et al. The global prevalence of premature ovarian insufficiency: a systematic review and meta-analysis. Climacteric. 2022;26(2):95–102. doi: 10.1080/13697137.2022.2153033
  3. Llarena N, Hine C. Reproductive longevity and aging: geroscience approaches to maintain long-term ovarian fitness. J Gerontol A Biol Sci Med Sci. 2021;76(9):1551–1560. doi: 10.1093/gerona/glaa204
  4. Tilly JL. Commuting the death sentence: how oocytes strive to survive. Nat Rev Mol Cell Biol. 2001;2(11):838–848. doi: 10.1038/35099086
  5. Zhou J, Peng X, Mei S. Autophagy in ovarian follicular development and atresia. Int J Biol Sci. 2019;15(4):726–737. doi: 10.7150/ijbs.30369
  6. Dhanushi Fernando W, Vincent A, Magraith K. Premature ovarian insufficiency and infertility. Aust J Gen Pract. 2023;52(1–2):32–38. doi: 10.31128/ajgp-08-22-6531
  7. Zhang S., Zhu D., Mei X., et al. Advances in biomaterials and regenerative medicine for primary ovarian insufficiency therapy. Bioact Mater. 2021;6(7):1957–1972. doi: 10.1016/j.bioactmat.2020.12.008
  8. Zheng Q, Fu X, Jiang J, et al. Umbilical cord mesenchymal stem cell transplantation prevents chemotherapy-induced ovarian failure via the NGF/TrkA pathway in rats. BioMed Res Int. 2019;2019:e6539294. doi: 10.1155/2019/6539294
  9. Fink KD, Rossignol J, Crane AT, et al. Transplantation of umbilical cord-derived mesenchymal stem cells into the striata of R6/2 mice: behavioral and neuropathological analysis. Stem Cell Res Ther. 2013;4(5):130. doi: 10.1186/scrt341
  10. Wang Z, Wei Q, Wang H, et al. Mesenchymal stem cell therapy using human umbilical cord in a rat model of autoimmune-induced premature ovarian failure. Stem Cells Int. 2020;2020:1–13. doi: 10.1155/2020/3249495
  11. Shareghi-Oskoue O, Aghebati-Maleki L, Yousefi M. Transplantation of human umbilical cord mesenchymal stem cells to treat premature ovarian failure. Stem Cell Res Ther. 2021;12(1):454. doi: 10.1186/s13287-021-02529-w
  12. Patent RUS № 2660587 / 06.07.2018. Elistratov PA, Krasnov MS, Ilyina AP, et al. Protein-peptide complex that increases the viability of follicles in the ovaries of mammals. (In Russ.) [cited 2024 Nov 28] Available from: https://yandex.ru/patents/doc/RU2660587C1_20180706?ysclid=m2vmpfq4g015576818
  13. Patent RUS № 2629871 / 04.09.2017. Yudin SM, Lunin VG, Sovetkin SV, et al. Drug for stimulating folliculogenesis and a method for its use. (In Russ.) EDN: ZTZFQL [cited 2024 Nov 28] Available from: https://yandex.ru/patents/doc/RU2629871C1_20170904
  14. Patent RUS № 2785397 / 07.12.2022. Borovskaya TG, Vychuzhanina AV, et al. A means for correcting ovarian damage caused by cytostatic effects. (In Russ.) EDN: VXAMVA [cited 2024 Nov 28] Available from: https://patenton.ru/patent/RU2785397C1?ysclid=m2vmwkdbve893482532
  15. Yavorovskaya KA, Ivanets ТYu, Kolodko VG, Features of folliculogenesis, early embryogenesis and early pregnancy in women with initial hyperproduction of STH in the IVF program. Rus J Hum Reprod. 2010;(5):72–74. (In Russ.)
  16. Patent RUS № 2492866 / 20.09.2013. Kay LYu. Methods for maturation of ovarian follicles in vitro. (In Russ.) EDN: SDKGKF [cited 2024 Nov 28] Available from: https://patents.google.com/patent/RU2492866C2/ru
  17. Kawamura K, Cheng Y, Suzuki N, et al. Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment. Proc Natl Acad Sci USA. 2013;110(43):17474–17479. doi: 10.1073/pnas.1312830110
  18. Díaz-García C, Herraiz S, Pamplona L, et al. Follicular activation in women previously diagnosed with poor ovarian response: a randomized, controlled trial. Fertil Steril. 2022;117(4):747–755. doi: 10.1016/j.fertnstert.2021.12.034
  19. Patent RUS № 2759168 / 09.11.2021. Gasparov AS, Dmitrieva NV, Dubinskaya ED, et al Method for activating ovarian function in case of low ovarian reserve. (In Russ.) EDN: ONJZHU [cited 2024 Nov 28] Available from: https://new.fips.ru/registers-doc-view/fips_servlet?DB=RUPAT&DocNumber=2759168&TypeFile=htm
  20. Patent RUS № 2754060 / 06.07.2018. Gasparov AS, Dubinskaya ED, Kolesnikova SN, et al. Method for surgical activation of ovarian function in case of low ovarian reserve. [cited 2024 Nov 28] Available from: https://patents.google.com/patent/RU2754060C1/ru (In Russ.)
  21. Patent RUS № 2748246 / 05.21.2021. Adamyan LV, Smolnikova VYu, Asaturova AV, et al. One-stage surgical method for activating ovarian function for the treatment of premature ovarian failure and restoring ovarian function. [cited 2024 Nov 28] Available from: https://patents.s3 .yandex.net/RU2748246C1_20210521.pdf (In Russ.)
  22. Patent RUS № 2418604 / 27.11.2007. Goujon A, Lume E. Method for regulating ovarian follicular reserve, method for treating deviations in dormant follicle growth in women, means for stimulating follicle development, and means for determining the effect of compounds on accelerating or slowing down follicle growth during toxicological testing (variants). (In Russ.) [cited 2024 Nov 28] Available from: https://patentimages.storage.googleapis.com/24/10/e4/589c1ae50217a7/RU2418604C2.pdf
  23. Patent RUS №2815539 / 18.03.2024. Yarmolinskaya MI, Zakuraeva KA, Vinokurov AYu, et al. ethod for creating a cellular model of premature ovarian failure in Wistar rats. (in Russ.) [cited 2024 Nov 28] Available from: https://patenton.ru/patent/RU2815539C1?ysclid=m3ccb9513d579822671
  24. Chen Y, Zhao Y, Miao C, et al. Quercetin alleviates cyclophosphamide-induced premature ovarian insufficiency in mice by reducing mitochondrial oxidative stress and pyroptosis in granulosa cells. J Ovarian Res. 2022;15(1):138. doi: 10.1186/s13048-022-01080-3
  25. Xiao Q, Zhao Y, Ma L, et al. Orientin reverses acetaminophen-induced acute liver failure by inhibiting oxidative stress and mitochondrial dysfunction. J Pharm Sci. 2022;149(1):11–19. doi: 10.1016/j.jphs.2022.01.012
  26. Seli E, Wang T, Horvath TL. Mitochondrial unfolded protein response: a stress response with implications for fertility and reproductive aging. Fertil Steril. 2019;111(2):197–204. doi: 10.1016/j.fertnstert.2018.11.048
  27. Tarin JJ. Cell cycle: aetiology of age-associated aneuploidy: a mechanism based on the “free radical theory of ageing”. Hum Reprod. 1995;10(6):1563–1565. doi: 10.1093/humrep/10.6.1563
  28. Shi L, Zhang J, Lai Z, et al. Long-term moderate oxidative stress decreased ovarian reproductive function by reducing follicle quality and progesterone production. PLoS One. 2016;11(9):e0162194. doi: 10.1371/journal.pone.0162194
  29. Zhang J, Wang X, Vikash V, et al. ROS and ROS-mediated cellular signaling. Oxid Med Cell Longev. 2016;2016:1–18. doi: 10.1155/2016/4350965
  30. Sahoo BM, Banik BK, Borah P, et al. Reactive Oxygen Species (ROS): key components in cancer therapies. Anticancer Agents Med Chem. 2022;22(2):215–222. doi: 10.2174/1871520621666210608095512
  31. Franasiak JM, Forman EJ, Hong KH, et al. The nature of aneuploidy with increasing age of the female partner: a review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening. Fertil Steril. 2014;101(3):656–663.e1. doi: 10.1016/j.fertnstert.2013.11.004
  32. Iqubal A, Iqubal MK, Sharma S, et al. Molecular mechanism involved in cyclophosphamide-induced cardiotoxicity: old drug with a new vision. Life Sci. 2019;218:112–131. doi: 10.1016/j.lfs.2018.12.018
  33. Pimenta GF, Awata WMC, Orlandin GG, et al. Melatonin prevents overproduction of reactive oxygen species and vascular dysfunction induced by cyclophosphamide. Life Sci. 2024;338:122361. doi: 10.1016/j.lfs.2023.122361
  34. Sheng Y, Chen YJ, Qian ZM, et al. Cyclophosphamide induces a significant increase in iron content in the liver and spleen of mice. Hum Exp Toxicol. 2020;39(7):973–983. doi: 10.1177/0960327120909880
  35. Hsueh AJW, Kawamura K, Cheng Y, et al. Intraovarian control of early folliculogenesis. Endocr Rev. 2015;36(1):1–24. doi: 10.1210/er.2014-1020
  36. Wang R, Wang W, Wang L, et al. FTO protects human granulosa cells from chemotherapy-induced cytotoxicity. Reprod Biol Endocrinol. 2022;20(1):39. doi: 10.1186/s12958-022-00911-8
  37. Marí M, Morales A, Colell A, et al. Mitochondrial glutathione, a key survival antioxidant. Antioxid Redox Signal. 2009;11(11):2685–2700. doi: 10.1089/ars.2009.2695
  38. Morris G, Anderson G, Dean O, et al. The glutathione system: a new drug target in neuroimmune disorders. Molec Neurobiol. 2014;50(3):1059–1084. doi: 10.1007/s12035-014-8705-x
  39. Lushchak VI. Glutathione homeostasis and functions: potential targets for medical interventions. J Amino Acids. 2012;2012:1–26. doi: 10.1155/2012/736837
  40. Lu GD, Shen HM, Chung MCM, et al. Critical role of oxidative stress and sustained JNK activation in aloe-emodin-mediated apoptotic cell death in human hepatoma cells. Carcinogenesis. 2007;28(9):1937–1945. doi: 10.1093/carcin/bgm143
  41. Franco R, Cidlowski JA. Apoptosis and glutathione: beyond an antioxidant. Cell Death Differ. 2009;16(10):1303–1314. doi: 10.1038/cdd.2009.107
  42. Franco R, Panayiotidis MI, Cidlowski JA. Glutathione depletion is necessary for apoptosis in lymphoid cells independent of reactive oxygen species formation. J Biol Chem. 2007;282(42):30452–30465. doi: 10.1074/jbc.M703091200
  43. Jones DP. Extracellular redox state: refining the definition of oxidative stress in aging. Rejuvenation Res. 2006;9(2):169–181. doi: 10.1089/rej.2006.9.169
  44. Jones DP, Go YM, Anderson CL, et al. Cysteine/cystine couple is a newly recognized node in the circuitry for biologic redox signaling and control. FASEB J. 2004;18(11):1246–1248. doi: 10.1096/fj.03-0971fje
  45. Bertrand RL. Iron accumulation, glutathione depletion, and lipid peroxidation must occur simultaneously during ferroptosis and are mutually amplifying events. Med Hypotheses. 2017;101:69–74. doi: 10.1016/j.mehy.2017.02.017
  46. Latunde-Dada GO. Ferroptosis: role of lipid peroxidation, iron and ferritinophagy. Biochim Biophys Acta Gen Subj. 2017;1861(8):1893–1900. doi: 10.1016/j.bbagen.2017.05.019
  47. Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation. Trends Cell Biol. 2016;26(3):165–176. doi: 10.1016/j.tcb.2015.10.014
  48. Araújo É de S, Garcia RS, Dambrós B, et al. Impacto da suplementação de vitamina C sobre níveis de peroxidação lipídica e glutationa reduzida em tecido hepático de camundongos com imunossupressão induzida por ciclofosfamida. Revista de Nutrição. 2016;29(4):579–587. doi: 10.1590/1678-98652016000400012
  49. Friedman HS, Colvin OM, Aisaka K, et al. Glutathione protects cardiac and skeletal muscle from cyclophosphamide-induced toxicity. Cancer Res. 1990;50(8):2455–2462.
  50. Zhang H, Davies KJA, Forman HJ. Oxidative stress response and Nrf2 signaling in aging. Free Radic Biol Med. 2015;88:314–336. doi: 10.1016/j.freeradbiomed.2015.05.036
  51. Di Emidio G, Falone S, Vitti M, et al. SIRT1 signalling protects mouse oocytes against oxidative stress and is deregulated during aging. Hum Reprod. 2014;29(9):2006–2017. doi: 10.1093/humrep/deu160
  52. Pan H, Guan D, Liu X, et al. SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2. Cell Res. 2016;26(2):190–205. doi: 10.1038/cr.2016.4
  53. Li GH, Li YR, Jiao P, et al. Therapeutic potential of salviae miltiorrhizae radix et rhizoma against human diseases based on activation of Nrf2-mediated antioxidant defense system: bioactive constituents and mechanism of action. Oxid Med Cell Longev. 2018;2018:7309073. doi: 10.1155/2018/7309073
  54. Akino N, Wada-Hiraike O, Isono W, et al. Activation of Nrf2/Keap1 pathway by oral Dimethylfumarate administration alleviates oxidative stress and age-associated infertility might be delayed in the mouse ovary. Reprod Biol Endocrinol. 2019;17(1):23. doi: 10.1186/s12958-019-0466-y
  55. Slocum SL, Kensler TW. Nrf2: control of sensitivity to carcinogens. Arch Toxicol. 2011;85(4):273–284. doi: 10.1007/s00204-011-0675-4
  56. Chen H, Song L, Xu X, et al. The effect of icariin on autoimmune premature ovarian insufficiency via modulation of Nrf2/HO-1/Sirt1 pathway in mice. Reprod Biol. 2022;22(2):100638–100638. doi: 10.1016/j.repbio.2022.100638
  57. Reisman SA, Lee CYI, Meyer CJ, et al. Topical application of the synthetic triterpenoid RTA 408 protects mice from radiation-induced dermatitis. Radiat Res. 2014;181(5):512. doi: 10.1667/rr13578.1

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Reactive oxygen species levels in granulosa cells

Download (74KB)
Indexing metadata
3. Fig. 2. Reduced glutathione levels in granulosa cells

Download (111KB)
Indexing metadata
4. Fig. 3. Staining intensity reflecting reduced glutathione levels in granulosa cells

Download (317KB)
Indexing metadata

Copyright (c) 2024 Eсо-Vector


СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 66759 от 08.08.2016 г. 
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия Эл № 77 - 6389 от 15.07.2002 г.