The therapeutic role of Aronia melanocarpa on cyclophosphamide-induced premature ovarian failure

Hümeyra Çelik; Sinem Kara; Bihter Gökçe Bozat; Firdevs Uluç; Ayhan Çetinkaya; Tülin Fırat

doi:10.29228/jrp.887

The therapeutic role of Aronia melanocarpa on cyclophosphamide-induced premature ovarian failure

Abstract

The purpose of the study was to evaluate the effects of Aronia melanocarpa (A. melanocarpa) extract on ovarian cell apoptosis, vascularization, and follicle reserve in the premature ovarian failure (POF) induced by cyclophosphamide (CYC). After creating a premature ovarian failure model with 100 mg/kg CYC, A. melanocarpa was given to Wistar albino female rats by gavage 15 times every other day (200 mg/kg).Vaginal smears were taken to evaluate the estrus cycles before, during and at the end of the experiment. Histological ovarian follicle count was performed by examining the ovaries with Hematoxylin&Eosin staining. Immunohistochemical evaluation of apoptosis markers of caspase-3 (cas-3), caspase-9 (cas-9) and vascular endothelial growth factor (VEGF) was performed. A. melanocarpa reregulated the estrus cycles in a similar way to the controls by reducing cas-3 and cas-9 in ovarian cells and increasing the number of ovarian cells. While CYC disrupted ovarian vascularization, A. melanocarpa contributed to ovarian reserve by increasing VEGF immunopositivity. In chemotherapy-induced POF, A. melanocarpa extract increases ovarian reserve by providing vascularization, decreasing apoptosis and providing cycle control in female rats.

Keywords

References

[1] Kramer A, Yaoliwasi A, Yuemaier M, Tuerhong M, Kadeer N, Yilike X. The effect of chronic stress on the levels of E2, FSH, LH and β-EP in serum of rats with premature ovarian failure. Zhonghua Zhongyiyao Xuekan. 2019; 37: 631-634. https://doi.org/10.13193/j.issn.1673-7717.2019.03.02.
[2] Sklar CA, Mertens AC, Mitby P, Whitton J, Stovall M, Kasper C, Mulder J, Green D, Stacy Nicholson H, Yasui Y, Robinson LL. Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study. J Nat Cancer Inst 2006; 98(13): 890–896. https://doi.org/10.1093/jnci/djj243.
[3] Tucker EJ, Grover SR, Bachelot A, Touraine P, Sinclair AH. Premature ovarian ınsufficiency: New perspectives on genetic cause and phenotypic spectrum. Endocr Rev. 2016; 37(6):609-635. https://doi.org/10.1210/er.2016-1047.
[4] 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. https://doi.org/10.1186/s13287-021 02529-w.
[5] Anderson RA, Mitchell RT, Kelsey TW, Spears N, Telfer EE, Wallace WH. Cancer treatment and gonadal function: Experimental and established strategies for fertility preservation in children and young adults. Lancet Diabetes Endocrinol. 2015; 3(7):556-567. https://doi.org/10.1016/S2213-8587(15)00039-X.
[6] Li F, Turan V, Lierman S, Cuvelier C, De Sutter P, Oktay K. Sphingosine-1-phosphate prevents chemotherapy induced primordial https://doi.org/10.1093/humrep/det391. follicle death. Hum Reprod. 2014; 29(1):107-113.
[7] Oktem O, Oktay K. A novel ovarian xenografting model to characterize the impact of chemotherapy agents on human primordial follicle reserve. Cancer Res. 2007; 67(21):10159-10162. https://doi.org/10.1158/0008-5472.CAN 07-2042.
[8] Melekoglu R, Ciftci O, Eraslan S, Cetin A, Basak N. Beneficial effects of curcumin and capsaicin on cyclophosphamide-induced premature ovarian failure in a rat model. J Ovarian Res. 2018; 11(1):33. https://doi.org/10.1186/s13048-018-0409-9.

[9] Sonigo C, Beau I, Binart N, Grynberg M. The impact of chemotherapy on the ovaries: Molecular aspects and the prevention of ovarian damage. Int J Mol Sci. 2019; 20(21):5342. https://doi.org/10.3390/ijms20215342.
[10] Chrubasik C, Li G, Chrubasik S. The clinical effectiveness of chokeberry: A systematic review. Phytother Res. 2010; 24(8):1107-1114. https://doi.org/10.1002/ptr.3226.
[11] Tian Y, Liimatainen J, Alanne AL, Lindstedt A, Liu P, Sinkkonen J, Kallio H, Yang B. Phenolic compounds extracted by acidic aqueous ethanol from berries and leaves of different berry plants. Food Chem. 2017; 220:266-281. https://doi.org/10.1016/j.foodchem.2016.09.145.
[12] Vagiri M, Jensen M. Influence of juice processing factors on quality of black chokeberry pomace as a future resource for colour extraction. Food Chem. 2017; 217:409-417. https://doi.org/10.1016/j.foodchem.2016.08.121.
[13] Jurendić T, Ščetar M. Aronia melanocarpa products and by-products for health and nutrition: A review. Antioxidants (Basel). 2021; 10(7):1052. https://doi.org/10.3390/antiox10071052.
[14] Sharif T, Alhosin M, Auger C, Minker C, Kim JH, Etienne-Selloum N, Bories P, Gronemeyer H, Lobstein A, Bronner C, Fuhrmann G, Schini-Kerth VB. Aronia melanocarpa juice induces a redox-sensitive p73-related caspase 3 dependent apoptosis in human leukemia cells. PLoS One. 2012; 7(3):e32526. https://doi.org/10.1371/journal.pone.0032526.
[15] Buda V, Andor M, Diana A, Ardelean F, Pavel IZ, Dehelean C, Socia C, Folescu R, Andrei F, Dancui C. Cardioprotective effects of cultivated black chokeberries (Aronia spp.): Traditional uses, phytochemistry and therapeutic effects. In : Sharma K, Mishra K, Senapati KK, Danciu C. (Eds). Bioactive Compounds in Nutraceutical and Functional Food for Good Human Health. IntechOpen Limited, London, 2020; pp. 1-23. https://doi.org/10.5772/intechopen.92238.
[16] Lee HY, Weon JB, Ryu G, Yang WS, Kim NY, Kim MK, Ma CJ. Neuroprotective effect of Aronia melanocarpa extract against glutamate-induced oxidative stress in HT22 cells. BMC Complement Altern Med. 2017; 17(1):207. https://doi.org/10.1186/s12906-017-1716-1.
[17] Efenberger-Szmechtyk M, Nowak A, Nowak A. Cytotoxic and DNA-damaging effects of Aronia melanocarpa, Cornus mas, and Chaenomeles superba leaf extracts on the human colon adenocarcinoma cell line Caco-2. Antioxidants (Basel). 2020; 9(11):1030. https://doi.org/10.3390/antiox9111030.
[18] Zapolska-Downar D, Nowicka G, Sygitowicz G, Jarosz M. Anthocyanin-rich Aronox extract from Aronia melanocarpa E protects against 7-beta-hydroxycholesterol-induced apoptosis of endothelial cells. Ann Nutr Metab. 2008; 53(3 4):283-294. https://doi.org/10.1159/000191290.
[19] Ahles S, Stevens YR, Joris PJ, Vauzour D, Adam J, de Groot E, Plat J. The effect of long-term Aronia melanocarpa extract supplementation on cognitive performance, mood, and vascular function: A randomized controlled trial in healthy, middle-aged individuals. Nutrients. 2020; 12(8):2475. https://doi.org/10.3390/nu12082475.
[20] Vural B, Duruksu G, Vural F, Gorguc M, Karaoz E. Effects of VEGF + mesenchymal stem cells and platelet-rich plasma on ınbred rat ovarian functions in cyclophosphamide-ınduced premature ovarian ınsufficiency model. Stem Cell Rev Rep. 2019; 15(4):558-573. https://doi.org/10.1007/s12015-019-09892-5
[21] Mohamed SA, Shalaby SM, Abdelaziz M, Brakta S, Hill WD, Ismail N, Al-Hendy A. Human mesenchymal stem cells partially reverse ınfertility in chemotherapy-ınduced ovarian failure. Reprod Sci. 2018; 25(1):51-63. https://doi.org/10.1177/1933719117699705.
[22] Myers M, Britt KL, Wreford NG, Ebling FJ, Kerr JB. Methods for quantifying follicular numbers within the mouse ovary. Reproduction. 2004; 127(5):569-580. https://doi.org/10.1530/rep.1.00095.
[23] Bhavina K, Radhika J, Pandian SS. VEGF and eNOS expression in umbilical cord from pregnancy complicated by hypertensive disorder with different severity. Biomed Res Int. 2014; 2014:982159. https://doi.org/10.1155/2014/982159.
[24] Nie Z, Zhang L, Chen W, Zhang Y, Hua R, Wang W, Zhang T, Wu H. The protective effects of pretreatment with resveratrol in cyclophosphamide-induced rat ovarian granulosa cell injury: In vitro study. Reprod Toxicol. 2020; 95:66-74. https://doi.org/10.1016/j.reprotox.2020.05.005.
[25] Jurikova T, Mlcek J, Skrovankova S, Sumczynski D, Sochor J, Hlavacova I, Snopek L, Orsavova J. Fruits of black chokeberry Aronia melanocarpa in the prevention of chronic diseases. Molecules. 2017; 22(6):944. https://doi.org/10.3390/molecules22060944.
[26] Tolić MT, Jurčević IL, Krbavčić IP, Marković K, Vahčić N. Phenolic content, antioxidant capacity and quality of chokeberry (Aronia melanocarpa) products. Food Technol Biotechnol. 2015; 53(2):171-179. https://doi.org/10.17113/ftb.53.02.15.3833.
[27] Banach M, Wiloch M, Zawada K, Cyplik W, Kujawski W. Evaluation of antioxidant and anti-ınflammatory activity of anthocyanin-rich water-soluble Aronia dry extracts. Molecules. 2020; 25(18):4055. https://doi.org/10.3390/molecules25184055.
[28] Gill NK, Rios D, Osorio-Camacena E, Mojica BE, Kaur B, Soderstrom MA, Gonzalez M, Plaat B, Poblete C, Kaur N, Singh H, Forester SC. Anticancer effects of extracts from three different chokeberry species. Nutr Cancer. 2021; 73(7):1168-1174. https://doi.org/10.1080/01635581.2020.1789679.
[29] Ben-Aharon I, Shalgi R. What lies behind chemotherapy-induced ovarian toxicity? Reproduction. 2012; 144(2):153 163. https://doi.org/10.1530/REP-12-0121.
[30] Tilly JL. Commuting the death sentence: how oocytes strive to survive. Nat Rev Mol Cell Biol. 2001; 2(11):838-848. https://doi.org/10.1038/35099086.
[31] Kalich-Philosoph L, Roness H, Carmely A, Fishel-Bartal M, Ligumsky H, Paglin S, Wolf I, Kanety H, Sredni B, Meirow D. Cyclophosphamide triggers follicle activation and "burnout"; AS101 prevents follicle loss and preserves fertility. Sci Transl Med. 2013; 5(185):185ra62. https://doi.org/10.1126/scitranslmed.3005402.
[32] Luan Y, Edmonds ME, Woodruff TK, Kim SY. Inhibitors of apoptosis protect the ovarian reserve from cyclophosphamide. J Endocrinol. 2019; 240(2):243-256. https://doi.org/10.1530/JOE-18-0370.
[33] Yoo M, Tanaka T, Konishi H, Tanabe A, Taniguchi K, Komura K, Hayashi M, Ohmichi M. The protective effect of testosterone on the ovarian reserve during cyclophosphamide treatment. Onco Targets Ther. 2020; 13:2987-2995. https://doi.org/10.2147/OTT.S242703.
[34] Ekiz Yılmaz T, Taşdemir M, Kaya M, Arıcan N, Ahıshalı B. The effects of magnesium sulfate on cyclophosphamide induced ovarian damage: Folliculogenesis. Acta Histochem. 2020; 122(2):151470. https://doi.org/10.1016/j.acthis.2019.151470.
[35] Federico SM, Caldwell KJ, McCarville MB, Daryani VM, Stewart CF, Mao S, Wu J, Davidoff AM, Santana VM, Furman WL, Pappo AS, Navid F. Phase I expansion cohort to evaluate the combination of bevacizumab, sorafenib and low-dose cyclophosphamide in children and young adults with refractory or recurrent solid tumours. Eur J Cancer. 2020; 132:35-42. https://doi.org/10.1016/j.ejca.2020.03.010.
[36] Bahceci SA, Kuruş M, Şimşek F, Keselik E, Kara S. Histopathological ınvestigation of the effects of Aronia melanocarpa on the ovarian tissue of polycystic over syndrome in rats. 2nd Internetional Medical Congress Of Izmir Democracy University, Fulltext&Abstract Book, 2020, pp.244. http://imcidu.idu.edu.tr/index.php/kongre kitaplari/.
[37] Rudic J, Jakovljevic V, Jovic N, Nikolic M, Sretenovic J, Mitrovic S, Bolevich S, Bolevich S, Mitrovic M, Raicevic S, Andric K, Dimkic Milenkovic A, Rakic D, Joksimovic Jovic J. Antioxidative effects of standardized Aronia melanocarpa extract on reproductive and metabolic disturbances in a rat model of polycystic ovary syndrome. Antioxidants. 2022; 11(6):1099. https://doi.org/10.3390/antiox11061099.
[38] Valcheva-Kuzmanova S, Borisova P, Galunska B, Krasnaliev I, Belcheva A. Hepatoprotective effect of the natural fruit juice from Aronia melanocarpa on carbon tetrachloride-induced acute liver damage in rats. Exp Toxicol Pathol. 2004; 56(3):195-201. https://doi.org/10.1016/j.etp.2004.04.012.
[39] Meng L, Xin G, Li B, Li D, Sun X, Yan T, Li L, Shi L, Cao S, Meng X. Anthocyanins extracted from Aronia melanocarpa protect SH-SY5Y Cells against amyloid-beta (1-42)-ınduced apoptosis by regulating Ca2+homeostasis and ınhibiting mitochondrial dysfunction. J Agric Food Chem. 2018; 66(49):12967-12977. https://doi.org/10.1021/acs.jafc.8b05404.
[40] Li L, Li J, Xu H, Zhu F, Li Z, Lu H, Zhang J, Yang Z, Liu Y. The protective effect of anthocyanins extracted from Aronia Melanocarpa berry in renal ıschemia-reperfusion ınjury in mice. Mediators Inflamm. 2021; 2021:7372893. https://doi.org/10.1155/2021/7372893.
[41] Öktem Ö, Urman B. Reprodüktif Yaşam Siklusu: Folikülogenez ve Menstruasyon. J Turkish Soc Obstet Gynecol. 2012; 9(1): 1-24. https://doi.org/10.5505/tjod.2012.37039.
[42] He L, Long X, Yu N, Li Y, Liu X, Cheng X. Premature ovarian ınsufficiency (POI) ınduced by dynamic ıntensity modulated radiation therapy via P13K-AKT-FOXO3a in rat models. Biomed Res Int. 2021; 2021:7273846. https://doi.org/10.1155/2021/7273846.
[43] Charnock-Jones DS, Sharkey AM, Rajput-Williams J, Burch D, Schofield JP, Fountain SA, Boocock CA, Smith SK. Identification and localization of alternately spliced mRNAs for vascular endothelial growth factor in human uterus and estrogen regulation in endometrial carcinoma cell lines. Biol Reprod. 1993; 48(5):1120-1128. https://doi.org/10.1095/biolreprod48.5.1120.
[44] Yan Z, Hunter V, Weed J, Hutchison S, Lyles R, Terranova P. Tumor necrosis factor-alpha alters steroidogenesis and stimulates proliferation of human ovarian granulosal cells in vitro. Fertil Steril. 1993; 59(2):332-338. https://doi.org/10.1016/s0015-0282(16)55676-3.
[45] Qin B, Anderson RA. An extract of chokeberry attenuates weight gain and modulates insulin, adipogenic and inflammatory signalling pathways in epididymal adipose tissue of rats fed a fructose-rich diet. Br J Nutr. 2012;108(4):581-587. https://doi.org/10.1017/S000711451100599X.
[46] Eldin DN, Fahim HI, Ahmed HY, Abdelgawad MA, Abourehab MAS, Ahmed OM. Preventive effects of mandarin fruit peel hydroethanolic extract, hesperidin, and quercetin on acetaminophen-ınduced hepatonephrotoxicity in Wistar rats. Oxid Med Cell Longev. 2022; 2022:7065845. https://doi.org/10.1155/2022/7065845.
[47] Kamat BR, Brown LF, Manseau EJ, Senger DR, Dvorak HF. Expression of vascular permeability factor/vascular endothelial growth factor by human granulosa and theca lutein cells. Role in corpus luteum development. Am J Pathol. 1995; 146(1):157-165.
[48] Alkış İ, Ekin S, Yildirim S, Bakir A, Eser G, Firat M. Evaluation of the protective effect of chlorogenic acid and Rhabdosciadium anatolyi against cyclophosphamide-induced ovarian toxicity in the rat with histopathological and immunohistochemical findings. Kafkas Univ Vet Fak Derg. 2020; 26(6):757-763.
[49] Ezoe K, Murata N, Yabuuchi A, Okuno T, Kobayashi T, Kato O, Kato K. Long-term adverse effects of cyclophosphamide on follicular growth and angiogenesis in mouse ovaries. Reprod Biol. 2014; 14(3):238-242. https://doi.org/10.1016/j.repbio.2014.04.007.

Details

Primary Language

English

Subjects

Pharmacology and Pharmaceutical Sciences (Other)

Journal Section

Research Article

Authors

Hümeyra Çelik ^* This is me
0000-0002-3394-2438
Türkiye

Sinem Kara This is me
0000-0002-6179-1200
Türkiye

Bihter Gökçe Bozat This is me
Türkiye

Firdevs Uluç This is me
0000-0002-7983-4483
Türkiye

Ayhan Çetinkaya This is me
Türkiye

Tülin Fırat This is me
0000-0002-8317-7092
Türkiye

Publication Date

June 28, 2025

Submission Date

March 1, 2023

Acceptance Date

February 11, 2024

Published in Issue

Year 2024 Volume: 28 Number: 6

DOI

https://doi.org/10.29228/jrp.887

IZ

https://izlik.org/JA46WN73XS

Cite

RIS / Bibtex

APA

Çelik, H., Kara, S., Bozat, B. G., Uluç, F., Çetinkaya, A., & Fırat, T. (2025). The therapeutic role of Aronia melanocarpa on cyclophosphamide-induced premature ovarian failure. Journal of Research in Pharmacy, 28(6), 2126-2136. https://doi.org/10.29228/jrp.887

AMA

1.Çelik H, Kara S, Bozat BG, Uluç F, Çetinkaya A, Fırat T. The therapeutic role of Aronia melanocarpa on cyclophosphamide-induced premature ovarian failure. J. Res. Pharm. 2025;28(6):2126-2136. doi:10.29228/jrp.887

Chicago

Çelik, Hümeyra, Sinem Kara, Bihter Gökçe Bozat, Firdevs Uluç, Ayhan Çetinkaya, and Tülin Fırat. 2025. “The Therapeutic Role of Aronia Melanocarpa on Cyclophosphamide-Induced Premature Ovarian Failure”. Journal of Research in Pharmacy 28 (6): 2126-36. https://doi.org/10.29228/jrp.887.

EndNote

Çelik H, Kara S, Bozat BG, Uluç F, Çetinkaya A, Fırat T (July 1, 2025) The therapeutic role of Aronia melanocarpa on cyclophosphamide-induced premature ovarian failure. Journal of Research in Pharmacy 28 6 2126–2136.

IEEE

[1]H. Çelik, S. Kara, B. G. Bozat, F. Uluç, A. Çetinkaya, and T. Fırat, “The therapeutic role of Aronia melanocarpa on cyclophosphamide-induced premature ovarian failure”, J. Res. Pharm., vol. 28, no. 6, pp. 2126–2136, July 2025, doi: 10.29228/jrp.887.

ISNAD

Çelik, Hümeyra - Kara, Sinem - Bozat, Bihter Gökçe - Uluç, Firdevs - Çetinkaya, Ayhan - Fırat, Tülin. “The Therapeutic Role of Aronia Melanocarpa on Cyclophosphamide-Induced Premature Ovarian Failure”. Journal of Research in Pharmacy 28/6 (July 1, 2025): 2126-2136. https://doi.org/10.29228/jrp.887.

JAMA

1.Çelik H, Kara S, Bozat BG, Uluç F, Çetinkaya A, Fırat T. The therapeutic role of Aronia melanocarpa on cyclophosphamide-induced premature ovarian failure. J. Res. Pharm. 2025;28:2126–2136.

MLA

Çelik, Hümeyra, et al. “The Therapeutic Role of Aronia Melanocarpa on Cyclophosphamide-Induced Premature Ovarian Failure”. Journal of Research in Pharmacy, vol. 28, no. 6, July 2025, pp. 2126-3, doi:10.29228/jrp.887.

Vancouver

1.Hümeyra Çelik, Sinem Kara, Bihter Gökçe Bozat, Firdevs Uluç, Ayhan Çetinkaya, Tülin Fırat. The therapeutic role of Aronia melanocarpa on cyclophosphamide-induced premature ovarian failure. J. Res. Pharm. 2025 Jul. 1;28(6):2126-3. doi:10.29228/jrp.887