{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:47:30Z","timestamp":1790693250553,"version":"4.1.0"},"reference-count":92,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T00:00:00Z","timestamp":1765238400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T00:00:00Z","timestamp":1765238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"National Research Centre Egypt"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Ovarian Res"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Premature ovarian failure (POF) and ovarian reserve loss are common problems associated with cancer therapies. Carvacrol (Carva) showed significant efficacies in ameliorating several toxicological impacts and complications associated with chemotherapeutic agents. Thus, this study was established to speculate on the efficacy of Carva against cyclophosphamide (Cyclo)-provoked POF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A twenty-four mature female rats were randomly and equally allocated into four groups; normal group, Carva (15\u00a0mg\/kg\/day\/orally\/3 weeks) group, Cyclo (75\u00a0mg\/kg\/i.p\/once weekly\/3 weeks) group, and Carva\u2009+\u2009Cyclo group. Assessments of serum sex hormones, as well as ovarian oxidative stress-related pathways, along with histopathological alterations in ovary and uterine tissues, have been investigated. In addition, monitoring the rats\u2019 estrous cycle was performed via vaginal cytology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our findings revealed that Carva ameliorated the disturbance of rats\u2019 estrous cycle, as well as loss of rats\u2019 body weight, and reproductive tract weight brought on by Cyclo. In addition, Carva administration modulated the disturbances in serum Anti-Mullerian hormone, estradiol, total estrogen, progesterone, follicle-stimulating hormone, and luteinizing hormone that resulted from Cyclo toxicity. The incidence of oxidative stress following Cyclo was significantly corrected by Carva, as indicated by a decline in ovarian malondialdehyde content and an increase in glutathione level. Carva effectively abrogated the increase in phosphorylated forms of protein kinase B (AKT), forkhead box protein O3a (FOXO3a), phosphoinositide 3-kinases (PI3K), and phosphatase and tensin homolog protein content in the ovarian tissue following Cyclo. Moreover, Carva ameliorated the structural changes of Cyclo in the ovarian and uterus tissues, and collagen condensation in the uterus. A marked preservation in the follicle count was recorded in the Cyclo\u2009+\u2009Carva group. The immunohistochemical findings revealed the hyper-expression of p-AKT along with activation of caspase 3 in the ovarian regions of Cyclo group, which is down-regulated by Carva.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Hence, it could be concluded that Carva could preserve rat ovarian function from the degenerative impacts of Cyclo treatment by lessening the oxidative and apoptotic insult via regulating the PI3K\/AKT\/FOXO3a pathways in the ovarian tissues, along with successful attenuation of uterine fibrosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13048-025-01880-3","type":"journal-article","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T07:15:57Z","timestamp":1765264557000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Carvacrol ameliorates cyclophosphamide-induced rat premature ovarian failure and uterine fibrosis via regulating PI3K\/AKT\/FOXO3a signaling pathway"],"prefix":"10.1186","volume":"18","author":[{"given":"Zeinab A.","family":"El-Gendy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seham Samir","family":"Soliman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed S.","family":"Aly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3714-2120","authenticated-orcid":false,"given":"Sara M.","family":"Baraka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,9]]},"reference":[{"key":"1880_CR1","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/s40738-021-00105-7","volume":"7","author":"B Sun","year":"2021","unstructured":"Sun B, Yeh J. Onco-fertility and personalized testing for potential for loss of ovarian reserve in patients undergoing chemotherapy: proposed next steps for development of genetic testing to predict changes in ovarian reserve. Fertility Res Pract. 2021;7:13.","journal-title":"Fertility Res Pract"},{"key":"1880_CR2","doi-asserted-by":"crossref","unstructured":"Fran\u00e7a MM, Mendonca BB. Genetics of ovarian insufficiency and defects of folliculogenesis. Best Pract Res Clin Endocrinol Metab. 2022;36:101594.","DOI":"10.1016\/j.beem.2021.101594"},{"key":"1880_CR3","doi-asserted-by":"publisher","first-page":"223","DOI":"10.11005\/jbm.2021.28.3.223","volume":"28","author":"JH Kim","year":"2021","unstructured":"Kim JH, Yang YR, Kwon K-S, Kim N. Anti-M\u00fcllerian hormone negatively regulates osteoclast differentiation by suppressing the receptor activator of nuclear Factor-\u03baB ligand pathway. J Bone Metabolism. 2021;28:223.","journal-title":"J Bone Metabolism"},{"key":"1880_CR4","doi-asserted-by":"publisher","first-page":"112040","DOI":"10.1016\/j.biopha.2021.112040","volume":"142","author":"S Ghafouri-Fard","year":"2021","unstructured":"Ghafouri-Fard S, Shoorei H, Abak A, Seify M, Mohaqiq M, Keshmir F, et al. Effects of chemotherapeutic agents on male germ cells and possible ameliorating impact of antioxidants. Biomed Pharmacother. 2021;142:112040.","journal-title":"Biomed Pharmacother"},{"key":"1880_CR5","doi-asserted-by":"publisher","first-page":"763412","DOI":"10.3389\/fimmu.2021.763412","volume":"12","author":"A Furlan","year":"2021","unstructured":"Furlan A, Forner G, Cipriani L, Vian E, Rigoli R, Gherlinzoni F, et al. COVID-19 in B cell-depleted patients after rituximab: a diagnostic and therapeutic challenge. Front Immunol. 2021;12:763412.","journal-title":"Front Immunol"},{"key":"1880_CR6","doi-asserted-by":"publisher","first-page":"127184","DOI":"10.1016\/j.cej.2020.127184","volume":"407","author":"S Mukherjee","year":"2021","unstructured":"Mukherjee S, Mehta D, Dhangar K, Kumar M. Environmental fate, distribution and state-of-the-art removal of antineoplastic drugs: A comprehensive insight. Chem Eng J. 2021;407:127184.","journal-title":"Chem Eng J"},{"key":"1880_CR7","doi-asserted-by":"publisher","first-page":"15426","DOI":"10.3390\/ijms232315426","volume":"23","author":"L Man","year":"2022","unstructured":"Man L, Lustgarten Guahmich N, Vyas N, Tsai S, Arazi L, Lilienthal D, et al. Ovarian reserve disorders, can we prevent them? A review. Int J Mol Sci. 2022;23:15426.","journal-title":"Int J Mol Sci"},{"key":"1880_CR8","doi-asserted-by":"publisher","first-page":"2769","DOI":"10.3390\/pharmaceutics14122769","volume":"14","author":"A Al-Shahat","year":"2022","unstructured":"Al-Shahat A, Hulail MAE, Soliman NMM, Khamis T, Fericean LM, Arisha AH, et al. Melatonin mitigates cisplatin-induced ovarian dysfunction via altering steroidogenesis, inflammation, apoptosis, oxidative stress, and PTEN\/PI3K\/Akt\/mTOR\/AMPK signaling pathway in female rats. Pharmaceutics. 2022;14:2769.","journal-title":"Pharmaceutics"},{"key":"1880_CR9","doi-asserted-by":"publisher","first-page":"2505","DOI":"10.1007\/s43032-021-00768-z","volume":"29","author":"RS Barberino","year":"2022","unstructured":"Barberino RS, Lins TLBG, Monte APO, Gouveia BB, Campinho DSP, Palheta RC Jr, et al. Melatonin attenuates cyclophosphamide-induced primordial follicle loss by interaction with MT1 receptor and modulation of PTEN\/Akt\/FOXO3a proteins in the mouse ovary. Reproductive Sci. 2022;29:2505\u201314.","journal-title":"Reproductive Sci"},{"key":"1880_CR10","doi-asserted-by":"crossref","unstructured":"Titus S, Szymanska KJ, Musul B, Turan V, Taylan E, Garcia-Milian R, et al. In Vivo Mechanisms of Chemotherapy-Induced Acute Follicle Loss in the Human Ovary: An Individual-Oocyte Transcriptomic Analysis from Human Ovarian Xenografts. bioRxiv. 2020;2006\u201320.","DOI":"10.1101\/2020.06.23.167783"},{"key":"1880_CR11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13048-023-01161-x","volume":"16","author":"ASS Abdoon","year":"2023","unstructured":"Abdoon ASS, Al-Atrash AME, Soliman SS, El-Sanea AM, el Gamal AA, Fahmy HM. Lyophilized equine platelet-rich plasma (L-GFequina) antagonize the reproductive toxicity and oxidative stress induced by cyclophosphamide in female rats. J Ovarian Res. 2023;16:1\u201311.","journal-title":"J Ovarian Res"},{"key":"1880_CR12","doi-asserted-by":"publisher","first-page":"1716","DOI":"10.3390\/ph17121716","volume":"17","author":"E Karaman","year":"2024","unstructured":"Karaman E, Yavuz A. Boric acid protects the uterus and fallopian tubes from Cyclophosphamide-Induced toxicity in a rat model. Pharmaceuticals. 2024;17:1716.","journal-title":"Pharmaceuticals"},{"key":"1880_CR13","doi-asserted-by":"crossref","unstructured":"Bady AR, Saad Eldien HM, Hussein O, Al Sayed M, Hetta H, Abdelhaffez A. Bone marrow mesenchymal stem cells improve Cyclophosphamide-Induced ovarian and uterine injury in adult female rats via T-Cell modulation. Egypt J Histol. 2022.","DOI":"10.21608\/ejh.2022.156450.1754"},{"key":"1880_CR14","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1080\/10408398.2011.653458","volume":"55","author":"ZE Suntres","year":"2015","unstructured":"Suntres ZE, Coccimiglio J, Alipour M. The bioactivity and toxicological actions of carvacrol. Crit Rev Food Sci Nutr. 2015;55:304\u201318.","journal-title":"Crit Rev Food Sci Nutr"},{"key":"1880_CR15","doi-asserted-by":"publisher","first-page":"3544","DOI":"10.1002\/fsn3.2994","volume":"10","author":"M Imran","year":"2022","unstructured":"Imran M, Aslam M, Alsagaby SA, Saeed F, Ahmad I, Afzaal M, et al. Therapeutic application of carvacrol: A comprehensive review. Food Sci Nutr. 2022;10:3544\u201361.","journal-title":"Food Sci Nutr"},{"key":"1880_CR16","doi-asserted-by":"crossref","first-page":"72","DOI":"10.3923\/rjmp.2011.72.78","volume":"5","author":"M Uyanoglu","year":"2011","unstructured":"Uyanoglu M, Canbek M, Ceyhan E, Senturk H, Bayramoglu G, Gunduz O, et al. Preventing organ injury with carvacrol after renal ischemia\/reperfusion. J Med Plants Res. 2011;5:72\u201380.","journal-title":"J Med Plants Res"},{"key":"1880_CR17","doi-asserted-by":"crossref","unstructured":"Nouri A, Izak-Shirian F, Fanaei V, Dastan M, Abolfathi M, Moradi A et al. Carvacrol exerts nephroprotective effect in rat model of diclofenac-induced renal injury through regulation of oxidative stress and suppression of inflammatory response. Heliyon. 2021;7:1\u20137.","DOI":"10.1016\/j.heliyon.2021.e08358"},{"key":"1880_CR18","doi-asserted-by":"publisher","first-page":"125521","DOI":"10.1016\/j.foodchem.2019.125521","volume":"307","author":"B Tohidi","year":"2020","unstructured":"Tohidi B, Rahimmalek M, Arzani A, Sabzalian MR. Thymol, carvacrol, and antioxidant accumulation in thymus species in response to different light spectra emitted by light-emitting diodes. Food Chem. 2020;307:125521.","journal-title":"Food Chem"},{"key":"1880_CR19","doi-asserted-by":"publisher","first-page":"E19","DOI":"10.25011\/cim.v37i1.20865","volume":"37","author":"M Bozkurt","year":"2014","unstructured":"Bozkurt M, Em S, Oktayoglu P, Turkcu G, Yuksel H, Saryldz MA, et al. Carvacrol prevents methotrexate-induced renal oxidative injury and renal damage in rats. Clin Invest Med. 2014;37:E19\u201325.","journal-title":"Clin Invest Med"},{"key":"1880_CR20","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1007\/s43450-021-00127-8","volume":"31","author":"AAA Khalaf","year":"2021","unstructured":"Khalaf AAA, Elhady MA, Hassanen EI, Azouz AA, Ibrahim MA, Galal MK, et al. Antioxidant role of carvacrol against hepatotoxicity and nephrotoxicity induced by Propiconazole in rats. Revista Brasileira De Farmacognosia. 2021;31:67\u201374.","journal-title":"Revista Brasileira De Farmacognosia"},{"key":"1880_CR21","doi-asserted-by":"publisher","first-page":"108456","DOI":"10.1016\/j.reprotox.2023.108456","volume":"121","author":"A Uyar","year":"2023","unstructured":"Uyar A, Cellat M, Kanat \u00d6, Etyemez M, Kutlu T, Deveci MYZ, et al. Carvacrol showed a curative effect on reproductive toxicity caused by bisphenol AF via antioxidant, anti-inflammatory and anti-apoptotic properties. Reprod Toxicol. 2023;121:108456.","journal-title":"Reprod Toxicol"},{"key":"1880_CR22","doi-asserted-by":"publisher","first-page":"3137","DOI":"10.1002\/fsn3.4014","volume":"12","author":"MR Khazdair","year":"2024","unstructured":"Khazdair MR, Moshtagh M, Anaeigoudari A, Jafari S, Kazemi T. Protective effects of carvacrol on lipid profiles, oxidative stress, hypertension, and cardiac dysfunction\u2013A comprehensive review. Food Sci Nutr. 2024;12:3137\u201349.","journal-title":"Food Sci Nutr"},{"key":"1880_CR23","doi-asserted-by":"publisher","first-page":"8847212","DOI":"10.1155\/2021\/8847212","volume":"2021","author":"E Panahi kokhdan","year":"2021","unstructured":"Panahi kokhdan E, Sadeghi H, Kazemi S, Doustimotlagh AH. Nephroprotective effects of Zataria multiflora Boiss. Hydroalcoholic extract, carvacrol, and thymol on kidney toxicity induced by cisplatin in rats. Evidence-Based Complement Altern Med. 2021;2021:8847212.","journal-title":"Evidence-Based Complement Altern Med"},{"key":"1880_CR24","doi-asserted-by":"publisher","first-page":"109825","DOI":"10.1016\/j.biopha.2020.109825","volume":"125","author":"Y Liu","year":"2020","unstructured":"Liu Y, Wei J, Ma K-T, Li C-L, Mai Y-P, Qiu X-X, et al. Carvacrol protects against diabetes-induced hypercontractility in the aorta through activation of the PI3K\/Akt pathway. Biomed Pharmacother. 2020;125:109825.","journal-title":"Biomed Pharmacother"},{"key":"1880_CR25","doi-asserted-by":"publisher","first-page":"680","DOI":"10.1007\/s11655-020-3193-5","volume":"27","author":"A Mari","year":"2021","unstructured":"Mari A, Mani G, Nagabhishek SN, Balaraman G, Subramanian N, Mirza FB, et al. Carvacrol promotes cell cycle arrest and apoptosis through PI3K\/AKT signaling pathway in MCF-7 breast cancer cells. Chin J Integr Med. 2021;27:680\u20137.","journal-title":"Chin J Integr Med"},{"key":"1880_CR26","doi-asserted-by":"publisher","first-page":"3044","DOI":"10.3390\/ijms22063044","volume":"22","author":"NM Abogresha","year":"2021","unstructured":"Abogresha NM, Mohammed SS, Hosny MM, Abdallah HY, Gadallah AM, Greish SM. Diosmin mitigates cyclophosphamide induced premature ovarian insufficiency in rat model. Int J Mol Sci. 2021;22:3044.","journal-title":"Int J Mol Sci"},{"key":"1880_CR27","first-page":"597","volume":"45","author":"MD Safwat","year":"2022","unstructured":"Safwat MD, Elagwany AM, Abd El Mottelib LM, Zahran NM. Effect of Platelet-Rich plasma in Cyclophosphamide-Induced ovarian failure in albino rats: histological and anatomical study. Egypt J Histol. 2022;45:597\u2013618.","journal-title":"Egypt J Histol"},{"key":"1880_CR28","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1007\/s11010-011-1043-7","volume":"360","author":"S Jayakumar","year":"2012","unstructured":"Jayakumar S, Madankumar A, Asokkumar S, Raghunandhakumar S, Gokula dhas K, Kamaraj S, et al. Potential preventive effect of carvacrol against diethylnitrosamine-induced hepatocellular carcinoma in rats. Mol Cell Biochem. 2012;360:51\u201360.","journal-title":"Mol Cell Biochem"},{"key":"1880_CR29","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","volume":"72","author":"MM Bradford","year":"1976","unstructured":"Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248\u201354.","journal-title":"Anal Biochem"},{"key":"1880_CR30","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1002\/bdrb.20106","volume":"80","author":"JM Goldman","year":"2007","unstructured":"Goldman JM, Murr AS, Cooper RL. The rodent estrous cycle: characterization of vaginal cytology and its utility in toxicological studies. Birth Defects Res Part B: Dev Reproductive Toxicol. 2007;80:84\u201397.","journal-title":"Birth Defects Res Part B: Dev Reproductive Toxicol"},{"key":"1880_CR31","unstructured":"Sahar O, Abeer AAS. Modified vaginal smear cytology the determination of the rat estrous cycle phases, versus ordinary papanning electron microscopic examination of the endometrium. 2007."},{"key":"1880_CR32","doi-asserted-by":"publisher","first-page":"137","DOI":"10.5897\/AJPP10.276","volume":"5","author":"S Parhizkar","year":"2011","unstructured":"Parhizkar S, Latiff LA, Rahman SA, Dollah MA, Parichehr H. Assessing estrogenic activity of Nigella sativa in ovariectomized rats using vaginal cornification assay. Afr J Pharm Pharmacol. 2011;5:137\u201342.","journal-title":"Afr J Pharm Pharmacol"},{"key":"1880_CR33","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1016\/j.beproc.2018.03.020","volume":"157","author":"TH Barker","year":"2018","unstructured":"Barker TH, Kind KL, Groves PD, Howarth GS, Whittaker AL. Oestrous phase Cyclicity influences judgment biasing in rats. Behav Process. 2018;157:678\u201384.","journal-title":"Behav Process"},{"key":"1880_CR34","unstructured":"Suvarna KS, Layton C, Bancroft JD. Bancroft\u2019s theory and practice of histological techniques. Elsevier health sciences; 2018."},{"key":"1880_CR35","doi-asserted-by":"publisher","first-page":"836","DOI":"10.3390\/ijms17060836","volume":"17","author":"X-Y Chen","year":"2016","unstructured":"Chen X-Y, Xia H-X, Guan H-Y, Li B, Zhang W. Follicle loss and apoptosis in cyclophosphamide-treated mice: what\u2019s the matter? Int J Mol Sci. 2016;17:836.","journal-title":"Int J Mol Sci"},{"key":"1880_CR36","first-page":"14904","volume":"10","author":"Y Chen","year":"2017","unstructured":"Chen Y, Yu Q, Xu C-B. A convenient method for quantifying collagen fibers in atherosclerotic lesions by ImageJ software. Int J Clin Exp Med. 2017;10:14904\u201310.","journal-title":"Int J Clin Exp Med"},{"key":"1880_CR37","doi-asserted-by":"publisher","first-page":"1485","DOI":"10.1093\/bioinformatics\/btaa847","volume":"37","author":"G Landini","year":"2021","unstructured":"Landini G, Martinelli G, Piccinini F. Colour deconvolution: stain unmixing in histological imaging. Bioinformatics. 2021;37:1485\u20137.","journal-title":"Bioinformatics"},{"key":"1880_CR38","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1262\/jrd.09-094H","volume":"56","author":"W Ding","year":"2010","unstructured":"Ding W, Wang W, Zhou B, Zhang W, Huang P, Shi F, et al. Formation of primordial follicles and immunolocalization of PTEN, PKB and FOXO3A proteins in the ovaries of fetal and neonatal pigs. J Reprod Dev. 2010;56:162\u20138.","journal-title":"J Reprod Dev"},{"key":"1880_CR39","doi-asserted-by":"crossref","unstructured":"Mowaad NA, Baraka SM, Ibrahim S, Mansour DA, Korany RMS, El-Sayed AF, et al. Cerium oxide nanoparticles attenuate hepatic failure via blocking TGF-\u03b2\/Smads and upregulating Nrf2\/HO-1 signaling pathways in liver fibrosis rat model. Naunyn-Schmiedeberg\u2019s Arch Pharmacol. 2025;1\u201323.","DOI":"10.1007\/s00210-025-04435-x"},{"key":"1880_CR40","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1007\/s11011-024-01513-6","volume":"40","author":"DAH Deabes","year":"2025","unstructured":"Deabes DAH, El-Abd EAW, Baraka SM, El-Gendy ZA, Korany RMS, Elbatanony MM. Metabolomics analyses and comparative insight to neuroprotective potential of unripe fruits and leaves of citrus aurantium ethanolic extracts against cadmium-induced rat brain dysfunction: involvement of oxidative stress and akt-mediated CREB\/BDNF and GSK3\u03b2\/NF-\u03baB signaling pathways. Metab Brain Dis. 2025;40:89.","journal-title":"Metab Brain Dis"},{"key":"1880_CR41","doi-asserted-by":"publisher","first-page":"106465","DOI":"10.1016\/j.jddst.2024.106465","volume":"104","author":"EAW El-Abd","year":"2025","unstructured":"El-Abd EAW, Baraka SM, Kassem IAA, El-Gendy ZA, El-Sayed AF, Ibrahim S, et al. Anti-ulcerogenic activity of citrus medica var. Sarcodactylis fruit extract nano-emulsion in gastric ulcer rat model through modulating HMBG1\/TLR4\/NF-\u03baB and Nrf2\/HSP70\/PGE2 signaling pathways. J Drug Deliv Sci Technol. 2025;104:106465.","journal-title":"J Drug Deliv Sci Technol"},{"key":"1880_CR42","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.bpobgyn.2021.09.010","volume":"81","author":"L Cacciottola","year":"2022","unstructured":"Cacciottola L, Donnez J, Dolmans M-M. Ovarian tissue and oocyte cryopreservation prior to iatrogenic premature ovarian insufficiency. Best Pract Res Clin Obstet Gynecol. 2022;81:119\u201333.","journal-title":"Best Pract Res Clin Obstet Gynecol"},{"key":"1880_CR43","doi-asserted-by":"publisher","first-page":"100730","DOI":"10.1016\/j.blre.2020.100730","volume":"45","author":"A Cattoni","year":"2021","unstructured":"Cattoni A, Parissone F, Porcari I, Molinari S, Masera N, Franchi M, et al. Hormonal replacement therapy in adolescents and young women with chemo-or radio-induced premature ovarian insufficiency: practical recommendations. Blood Rev. 2021;45:100730.","journal-title":"Blood Rev"},{"key":"1880_CR44","doi-asserted-by":"crossref","unstructured":"Wang Y, Zou Z, Jaisi A, Olatunji OJ. Unravelling the protective effects of emodin against cyclophosphamide induced gonadotoxicity in male Wistar rats. Drug Des Devel Ther. 2021;4403\u201311.","DOI":"10.2147\/DDDT.S333383"},{"key":"1880_CR45","doi-asserted-by":"publisher","first-page":"25310","DOI":"10.18632\/oncotarget.15813","volume":"8","author":"H Yang","year":"2017","unstructured":"Yang H, Xie Y, Yang D, Ren D. Oxidative stress-induced apoptosis in granulosa cells involves JNK, p53 and Puma. Oncotarget. 2017;8:25310.","journal-title":"Oncotarget"},{"key":"1880_CR46","doi-asserted-by":"publisher","first-page":"14379","DOI":"10.3390\/ijms232214379","volume":"23","author":"S Gonfloni","year":"2022","unstructured":"Gonfloni S, Jodice C, Gustavino B, Valentini E. DNA damage stress response and follicle activation: signaling routes of mammalian ovarian reserve. Int J Mol Sci. 2022;23:14379.","journal-title":"Int J Mol Sci"},{"key":"1880_CR47","doi-asserted-by":"publisher","first-page":"111424","DOI":"10.1016\/j.colsurfb.2020.111424","volume":"197","author":"E Mauriello","year":"2021","unstructured":"Mauriello E, Ferrari G, Dons\u00ec F. Effect of formulation on properties, stability, carvacrol release and antimicrobial activity of carvacrol emulsions. Colloids Surf B. 2021;197:111424.","journal-title":"Colloids Surf B"},{"key":"1880_CR48","doi-asserted-by":"crossref","unstructured":"Arivalagan S, Thomas NS, Kuppusamy T, Namashivayam N. Radioprotective effect of carvacrol against X-radiation\u2009\u2013\u2009induced cellular damage in cultured human peripheral blood lymphocytes. J Environ Pathol Toxicol Oncol. 2015;34.","DOI":"10.1615\/JEnvironPatholToxicolOncol.2015013548"},{"key":"1880_CR49","doi-asserted-by":"publisher","first-page":"102187","DOI":"10.1016\/j.coph.2022.102187","volume":"63","author":"J Liu","year":"2022","unstructured":"Liu J, Zhang Q, Tao T, Wang L-Y, Sun J-Y, Wu C-J, et al. Health benefits of spices in individuals with chemotherapeutic drug-induced cardiotoxicity. Curr Opin Pharmacol. 2022;63:102187.","journal-title":"Curr Opin Pharmacol"},{"key":"1880_CR50","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1016\/j.tjog.2022.11.011","volume":"62","author":"K Dinc","year":"2023","unstructured":"Dinc K, Ozyurt R, Coban TA, Yazici GN, Suleyman Z, Yavuzer B, et al. The effect of carvacrol on the Proinflammatory cytokines, histology, and fertility outcome of cisplatin-related ovarian change in a rat model. Taiwan J Obstet Gynecol. 2023;62:256\u201363.","journal-title":"Taiwan J Obstet Gynecol"},{"key":"1880_CR51","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.1177\/0960327119865588","volume":"38","author":"MA Elkady","year":"2019","unstructured":"Elkady MA, Shalaby S, Fathi F, El-Mandouh S. Effects of Quercetin and Rosuvastatin each alone or in combination on cyclophosphamide-induced premature ovarian failure in female albino mice. Hum Exp Toxicol. 2019;38:1283\u201395.","journal-title":"Hum Exp Toxicol"},{"key":"1880_CR52","doi-asserted-by":"publisher","first-page":"376","DOI":"10.2174\/1566524020666200905113907","volume":"21","author":"H Chen","year":"2021","unstructured":"Chen H, Liu C, Zhu S, Li S, Zhang Q, Song L, et al. The therapeutic effect of stem cells on chemotherapy-induced premature ovarian failure. Curr Mol Med. 2021;21:376.","journal-title":"Curr Mol Med"},{"key":"1880_CR53","doi-asserted-by":"publisher","first-page":"e202200053","DOI":"10.1002\/cbdv.202200053","volume":"19","author":"J Hu","year":"2022","unstructured":"Hu J, Tong C, Zhou J, Gao C, Olatunji OJ. Protective effects of Shorea Roxburghii phenolic extract on nephrotoxicity induced by cyclophosphamide: impact on oxidative Stress, biochemical and histopathological alterations. Chem Biodivers. 2022;19:e202200053.","journal-title":"Chem Biodivers"},{"key":"1880_CR54","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.ejpb.2019.12.008","volume":"147","author":"M Mir","year":"2020","unstructured":"Mir M, Permana AD, Ahmed N, Khan GM, ur Rehman A, Donnelly RF. Enhancement in site-specific delivery of carvacrol for potential treatment of infected wounds using infection responsive nanoparticles loaded into dissolving microneedles: A proof of concept study. Eur J Pharm Biopharm. 2020;147:57\u201368.","journal-title":"Eur J Pharm Biopharm"},{"key":"1880_CR55","doi-asserted-by":"publisher","first-page":"6899","DOI":"10.3390\/molecules26226899","volume":"26","author":"GIP Cical\u0103u","year":"2021","unstructured":"Cical\u0103u GIP, Babes PA, Calniceanu H, Popa A, Ciavoi G, Iova GM, et al. Anti-inflammatory and antioxidant properties of carvacrol and magnolol, in periodontal disease and diabetes mellitus. Molecules. 2021;26:6899.","journal-title":"Molecules"},{"key":"1880_CR56","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13048-018-0409-9","volume":"11","author":"R Melekoglu","year":"2018","unstructured":"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\u20138.","journal-title":"J Ovarian Res"},{"key":"1880_CR57","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s43141-021-00278-0","volume":"19","author":"AI Hassan","year":"2021","unstructured":"Hassan AI, Ghoneim MAM, Mahmoud MG, Asker MS. Assessment role of total phenols and flavonoids extracted from pleurotus columbinus mushroom on the premature ovarian failure induced by chemotherapy in rats. J Genetic Eng Biotechnol. 2021;19:1\u201311.","journal-title":"J Genetic Eng Biotechnol"},{"key":"1880_CR58","first-page":"10","volume":"1","author":"\u0130 G\u00f6k\u00e7ek","year":"2024","unstructured":"G\u00f6k\u00e7ek \u0130, Uyan\u0131k G, Tutar T, G\u00f6zer A. Effects of carvacrol on hormonal, inflammatory, antioxidant changes, and ovarian reserve in polycystic ovary syndrome in Wistar rats. Naunyn-Schmiedeberg\u2019s Archives Pharmacol. 2024;1:10.","journal-title":"Naunyn-Schmiedeberg\u2019s Archives Pharmacol"},{"key":"1880_CR59","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1093\/biolre\/ioaa073","volume":"103","author":"LE Simon","year":"2020","unstructured":"Simon LE, Kumar TR, Duncan FE. In vitro ovarian follicle growth: a comprehensive analysis of key protocol variables. Biol Reprod. 2020;103:455\u201370.","journal-title":"Biol Reprod"},{"key":"1880_CR60","doi-asserted-by":"publisher","first-page":"4565","DOI":"10.3390\/ijms21124565","volume":"21","author":"E Gershon","year":"2020","unstructured":"Gershon E, Dekel N. Newly identified regulators of ovarian folliculogenesis and ovulation. Int J Mol Sci. 2020;21:4565.","journal-title":"Int J Mol Sci"},{"key":"1880_CR61","doi-asserted-by":"publisher","first-page":"999440","DOI":"10.3389\/fmed.2022.999440","volume":"9","author":"X Bai","year":"2022","unstructured":"Bai X, Wang S. Signaling pathway intervention in premature ovarian failure. Front Med. 2022;9:999440.","journal-title":"Front Med"},{"key":"1880_CR62","doi-asserted-by":"publisher","first-page":"8016","DOI":"10.1039\/D1GC01500A","volume":"23","author":"MD Garrison","year":"2021","unstructured":"Garrison MD, Storch PJ, Eck WS, Adams VH, Fedick PW, Harvey BG. BPA-free high-performance sustainable polycarbonates derived from non-estrogenic bio-based phenols. Green Chem. 2021;23:8016\u201329.","journal-title":"Green Chem"},{"key":"1880_CR63","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1007\/s00210-020-01975-2","volume":"394","author":"WY Abdelzaher","year":"2021","unstructured":"Abdelzaher WY, Abdel-Hafez SMN, Rofaeil RR, Ali AHSA, Hegazy A, Bahaa HA. The protective effect of fenofibrate, triptorelin, and their combination against premature ovarian failure in rats. Naunyn-Schmiedeberg\u2019s Archives Pharmacol. 2021;394:137\u201349.","journal-title":"Naunyn-Schmiedeberg\u2019s Archives Pharmacol"},{"key":"1880_CR64","doi-asserted-by":"publisher","first-page":"895095","DOI":"10.3389\/fendo.2022.895095","volume":"13","author":"J Feng","year":"2022","unstructured":"Feng J, Ma W-W, Li H-X, Pei X-Y, Deng S-L, Jia H, et al. Melatonin prevents cyclophosphamide-induced primordial follicle loss by inhibiting ovarian granulosa cell apoptosis and maintaining AMH expression. Front Endocrinol. 2022;13:895095.","journal-title":"Front Endocrinol"},{"key":"1880_CR65","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1080\/10715762.2024.2320383","volume":"58","author":"L Chen","year":"2024","unstructured":"Chen L, Mo Q, Wu Y, Chen W, Deng K, Xiao Y. Ameliorative effect of Salidroside on the cyclophosphamide-induced premature ovarian failure in a rat model. Free Radic Res. 2024;58:107\u201316.","journal-title":"Free Radic Res"},{"key":"1880_CR66","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1080\/14712598.2022.2086042","volume":"22","author":"SA Farhat","year":"2022","unstructured":"Farhat SA, Jabbari F, Jabbari P, Rezaei N. Targeting signaling pathways involved in primordial follicle growth or dormancy: potential application in prevention of follicular loss and infertility. Expert Opin Biol Ther. 2022;22:871\u201381.","journal-title":"Expert Opin Biol Ther"},{"key":"1880_CR67","doi-asserted-by":"publisher","first-page":"bqac048","DOI":"10.1210\/endocr\/bqac048","volume":"163","author":"X Lu","year":"2022","unstructured":"Lu X, Ding F, Chen Y, Ke S, Yuan S, Qiu H, et al. Deficiency of C1QL1 reduced murine ovarian follicle reserve through intraovarian and endocrine control. Endocrinology. 2022;163:bqac048.","journal-title":"Endocrinology"},{"key":"1880_CR68","doi-asserted-by":"publisher","first-page":"200","DOI":"10.3390\/cells9010200","volume":"9","author":"M Maidarti","year":"2020","unstructured":"Maidarti M, Anderson RA, Telfer EE. Crosstalk between PTEN\/PI3K\/Akt signalling and DNA damage in the oocyte: implications for primordial follicle activation, oocyte quality and ageing. Cells. 2020;9:200.","journal-title":"Cells"},{"key":"1880_CR69","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.4161\/cc.5.14.3005","volume":"5","author":"F Vazquez","year":"2006","unstructured":"Vazquez F, Devreotes P. Regulation of PTEN function as a PIP3 gatekeeper through membrane interaction. Cell Cycle. 2006;5:1523\u20137.","journal-title":"Cell Cycle"},{"key":"1880_CR70","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1038\/nrm3330","volume":"13","author":"MS Song","year":"2012","unstructured":"Song MS, Salmena L, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol. 2012;13:283\u201396.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"1880_CR71","doi-asserted-by":"publisher","first-page":"116703","DOI":"10.1016\/j.jep.2023.116703","volume":"315","author":"C Su","year":"2023","unstructured":"Su C, Zhang R, Zhang X, Lv M, Liu X, Ao K, et al. Dingkun pill modulate ovarian function in chemotherapy-induced premature ovarian insufficiency mice by regulating PTEN\/PI3K\/AKT\/FOXO3a signaling pathway. J Ethnopharmacol. 2023;315:116703.","journal-title":"J Ethnopharmacol"},{"key":"1880_CR72","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1002\/jcb.30433","volume":"124","author":"K Verma","year":"2023","unstructured":"Verma K, Jaiswal R, Paliwal S, Dwivedi J, Sharma S. An insight into PI3k\/Akt pathway and associated protein\u2013protein interactions in metabolic syndrome: A recent update. J Cell Biochem. 2023;124:923\u201342.","journal-title":"J Cell Biochem"},{"key":"1880_CR73","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1111\/bcpt.13696","volume":"130","author":"S Zheng","year":"2022","unstructured":"Zheng S, Ma M, Chen Y, Li M. Effects of Quercetin on ovarian function and regulation of the ovarian PI3K\/Akt\/FoxO3a signalling pathway and oxidative stress in a rat model of cyclophosphamide-induced premature ovarian failure. Basic Clin Pharmacol Toxicol. 2022;130:240\u201353.","journal-title":"Basic Clin Pharmacol Toxicol"},{"key":"1880_CR74","doi-asserted-by":"publisher","first-page":"1719","DOI":"10.1021\/acs.chemrestox.0c00005","volume":"33","author":"A Alhoshani","year":"2020","unstructured":"Alhoshani A, Alanazi FE, Alotaibi MR, Attwa MW, Kadi AA, Aldhfyan A, et al. EGFR inhibitor gefitinib induces cardiotoxicity through the modulation of cardiac PTEN\/Akt\/FoxO3a pathway and reactive metabolites formation: in vivo and in vitro rat studies. Chem Res Toxicol. 2020;33:1719\u201328.","journal-title":"Chem Res Toxicol"},{"key":"1880_CR75","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.fct.2016.11.004","volume":"98","author":"I Poto\u010dnjak","year":"2016","unstructured":"Poto\u010dnjak I, Domitrovi\u0107 R. Carvacrol attenuates acute kidney injury induced by cisplatin through suppression of ERK and PI3K\/Akt activation. Food Chem Toxicol. 2016;98:251\u201361.","journal-title":"Food Chem Toxicol"},{"key":"1880_CR76","doi-asserted-by":"publisher","first-page":"e01042","DOI":"10.1128\/mbio.01042-22","volume":"13","author":"H Zhang","year":"2022","unstructured":"Zhang H, Domma AJ, Goodrum FD, Moorman NJ, Kamil JP. The Akt forkhead box O transcription factor axis regulates human cytomegalovirus replication. MBio. 2022;13:e01042\u201322.","journal-title":"MBio"},{"key":"1880_CR77","doi-asserted-by":"publisher","first-page":"1921","DOI":"10.1038\/s41418-018-0165-9","volume":"25","author":"J-H Kim","year":"2018","unstructured":"Kim J-H, Choi TG, Park S, Yun HR, Nguyen NNY, Jo YH, et al. Mitochondrial ROS-derived PTEN oxidation activates PI3K pathway for mTOR-induced myogenic autophagy. Cell Death Differ. 2018;25:1921\u201337.","journal-title":"Cell Death Differ"},{"key":"1880_CR78","doi-asserted-by":"publisher","first-page":"100415","DOI":"10.1016\/j.jbo.2022.100415","volume":"33","author":"H Pang","year":"2022","unstructured":"Pang H, Wu T, Peng Z, Tan Q, Peng X, Zhan Z, et al. Baicalin induces apoptosis and autophagy in human osteosarcoma cells by increasing ROS to inhibit PI3K\/Akt\/mTOR, ERK1\/2 and \u03b2-catenin signaling pathways. J Bone Oncol. 2022;33:100415.","journal-title":"J Bone Oncol"},{"key":"1880_CR79","doi-asserted-by":"publisher","first-page":"5497","DOI":"10.1038\/onc.2008.245","volume":"27","author":"TL Yuan","year":"2008","unstructured":"Yuan TL, Cantley L. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27:5497\u2013510.","journal-title":"Oncogene"},{"key":"1880_CR80","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1095\/biolreprod.111.095224","volume":"86","author":"PJ Devine","year":"2012","unstructured":"Devine PJ, Perreault SD, Luderer U. Roles of reactive oxygen species and antioxidants in ovarian toxicity. Biol Reprod. 2012;86:21\u20137.","journal-title":"Biol Reprod"},{"key":"1880_CR81","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1093\/humupd\/dmi001","volume":"11","author":"MR Hussein","year":"2005","unstructured":"Hussein MR. Apoptosis in the ovary: molecular mechanisms. Hum Reprod Update. 2005;11:162\u201378.","journal-title":"Hum Reprod Update"},{"key":"1880_CR82","unstructured":"Davis BJ, Heindel JJ. Ovarian toxicants: multiple mechanisms of action. Reprod Dev Toxicol. 1998;373:395."},{"key":"1880_CR83","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1093\/toxsci\/kfj086","volume":"90","author":"P Desmeules","year":"2006","unstructured":"Desmeules P, Devine PJ. Characterizing the ovotoxicity of cyclophosphamide metabolites on cultured mouse ovaries. Toxicol Sci. 2006;90:500\u20139.","journal-title":"Toxicol Sci"},{"key":"1880_CR84","unstructured":"Liang C, Daokuan Z, Guoqing T, Li L. Apoptotic mechanism of premature ovarian failure and rescue effect of traditional Chinese medicine: a review. J Tradit Chin Med. 2021;41:491."},{"key":"1880_CR85","doi-asserted-by":"publisher","first-page":"4079425","DOI":"10.1155\/2017\/4079425","volume":"2017","author":"P Wang","year":"2017","unstructured":"Wang P, Luo Q, Qiao H, Ding H, Cao Y, Yu J, et al. The neuroprotective effects of carvacrol on ethanol-induced hippocampal neurons impairment via the antioxidative and antiapoptotic pathways. Oxidative Med Cell Longev. 2017;2017:4079425.","journal-title":"Oxidative Med Cell Longev"},{"key":"1880_CR86","doi-asserted-by":"publisher","first-page":"98","DOI":"10.3390\/pathogens9020098","volume":"9","author":"DM Khodeer","year":"2020","unstructured":"Khodeer DM, Mehanna ET, Abushouk AI, Abdel-Daim MM. Protective effects of evening primrose oil against cyclophosphamide-induced biochemical, histopathological, and genotoxic alterations in mice. Pathogens. 2020;9:98.","journal-title":"Pathogens"},{"key":"1880_CR87","first-page":"102","volume":"8","author":"G Khorwal","year":"2017","unstructured":"Khorwal G, Chauhan R, Nagar M, Khorwal G. Effect of cyclophosphamide on liver in albino rats: A comparative dose dependent histomorphological study. Int J Biomedical Adv Res. 2017;8:102\u20137.","journal-title":"Int J Biomedical Adv Res"},{"key":"1880_CR88","doi-asserted-by":"publisher","first-page":"e425","DOI":"10.1002\/mco2.425","volume":"4","author":"X Hu","year":"2023","unstructured":"Hu X, Wu H, Yong X, Wang Y, Yang S, Fan D, et al. Cyclical endometrial repair and regeneration: molecular mechanisms, diseases, and therapeutic interventions. MedComm. 2023;4:e425.","journal-title":"MedComm"},{"key":"1880_CR89","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.3390\/cells8101123","volume":"8","author":"Z-R Tang","year":"2019","unstructured":"Tang Z-R, Zhang R, Lian Z-X, Deng S-L, Yu K. Estrogen-receptor expression and function in female reproductive disease. Cells. 2019;8:1123.","journal-title":"Cells"},{"key":"1880_CR90","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1016\/j.ogc.2011.05.004","volume":"38","author":"N Santoro","year":"2011","unstructured":"Santoro N, Randolph JF. Reproductive hormones and the menopause transition. Obstet Gynecol Clin. 2011;38:455\u201366.","journal-title":"Obstet Gynecol Clin"},{"key":"1880_CR91","unstructured":"G\u00f6k\u00e7ek \u0130, G\u00fcven\u00e7 M. Impact of carvacrol on ovarian and uterine changes induced by hyperthyroidism in rats. Firat Universitesi Saglik Bilimleri Veteriner Dergisi. 2024;38:240\u2013245."},{"key":"1880_CR92","doi-asserted-by":"publisher","first-page":"4607","DOI":"10.1007\/s00210-024-03588-5","volume":"398","author":"\u0130 G\u00f6k\u00e7ek","year":"2025","unstructured":"G\u00f6k\u00e7ek \u0130, Uyan\u0131k G, Tutar T, G\u00f6zer A. Effects of carvacrol on hormonal, inflammatory, antioxidant changes, and ovarian reserve in polycystic ovary syndrome in Wistar rats. Naunyn-Schmiedeberg\u2019s Archives Pharmacol. 2025;398:4607\u201316.","journal-title":"Naunyn-Schmiedeberg\u2019s Archives Pharmacol"}],"container-title":["Journal of Ovarian Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13048-025-01880-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13048-025-01880-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13048-025-01880-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T19:02:03Z","timestamp":1765306923000},"score":1,"resource":{"primary":{"URL":"https:\/\/ovarianresearch.biomedcentral.com\/articles\/10.1186\/s13048-025-01880-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,9]]},"references-count":92,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["1880"],"URL":"https:\/\/doi.org\/10.1186\/s13048-025-01880-3","relation":{},"ISSN":["1757-2215"],"issn-type":[{"value":"1757-2215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,9]]},"assertion":[{"value":"12 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 December 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The animal experimental studies were approved by the Medical Research Ethics Committee (MERC), National Research Centre, Giza, Egypt (Ethical Approval NO.3444052023). The committee approved the animal studies, verifying their alignment with the instructions outlined in the ARRIVE guidelines and the Guide for Care and Use of Laboratory Animals (8\n                      th\n                      ed. 2011).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"291"}}