{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T12:54:21Z","timestamp":1789390461763,"version":"build-2803163510"},"reference-count":113,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:00:00Z","timestamp":1760313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Testicular cytofunctional defects are among the most hazardous effects of cancer chemotherapies. Propolis mitigates the fertility problems associated with gonadotoxic agents through its redox stabilizing, anti-apoptotic, and cytoprotective properties due to presence of bioactive agents identified in our study by gas chromatography\u2013mass spectrometry analysis including, flavonoids, terpenes, aliphatic and aromatic compounds, and amino acids. Herein, we investigated the potential reversal effects of aqueous propolis on busulfan-induced reproductive abnormalities in adult rats.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Thirty rats were randomly assigned to five experimental groups, with six animals per group, for duration of 6\u00a0weeks. The control group received only the vehicle daily through oral gavage. The DMSO group was given a single intraperitoneal injection of DMSO. The busulfan group received a single intraperitoneal injection of busulfan at a dose of 20\u00a0mg\/kg body weight, followed by daily oral gavage. The propolis group was administered propolis daily via oral gavage at a dose of 100\u00a0mg\/kg body weight. In the busulfan + propolis group, rats received a single intraperitoneal injection of busulfan at 20\u00a0mg\/kg body weight, combined with daily oral gavage of propolis at a dose of 100\u00a0mg\/kg body weight.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results and discussion<\/jats:title><jats:p>Busulfan exposure led to a decrease in serum levels of follicle-stimulating hormone, testosterone, and estradiol 17\u03b2, along with an increase in luteinizing hormone. It negatively affected sperm outcomes, causing a decline in sperm count and the percentages of live, normal, and motile sperm, while increasing the percentages of dead and abnormal sperm. Furthermore, busulfan disrupted the testicular defense system, as indicated by elevated testicular malondialdehyde levels and reductions in testicular nitric oxide and reduced glutathione levels, catalase and superoxide dismutase activities, as well as serum total antioxidant capacity. Marked histopathological changes were observed, in concomitant with strong immunoreactivity for proliferating cell nuclear antigen and caspase-3 in germ cells. Propolis supplementation effectively mitigated all these abnormalities in busulfan-intoxicated rats. Propolis is suggested as a potential complementary adjuvant for managing busulfan-induced reproductive dysfunction, owing to its reproductive hormone-modulating, redox-stabilizing, sperm-protective, and anti-apoptotic properties.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1656541","type":"journal-article","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T05:27:01Z","timestamp":1760333221000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Propolis mitigates busulfan-induced testicular dysfunction in rats: insights into redox stabilization, PCNA modulation, and caspase-3 inhibition"],"prefix":"10.3389","volume":"16","author":[{"given":"Elham A.","family":"AbdAllah","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basant A.","family":"Eid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan A.","family":"Hussein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nasser S.","family":"Abou khalil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sohair M. M.","family":"Ragab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmaa Y.","family":"Wahman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailah M.","family":"Almohaimeed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rehab H.","family":"Moneeb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanem S.","family":"Abdel-Tawab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuhair M.","family":"Mohammedsaleh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jameel","family":"Barnawi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanan S. A.","family":"Waly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.1080\/01480545.2020.1803905","article-title":"The protective effect of rutin against busulfan-induced testicular damage in adult rats","volume":"45","author":"Abarikwu","year":"2022","journal-title":"Drug Chem. Toxicol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1080\/01913123.2023.2234470","article-title":"The impact of busulfan on the testicular structure in prepubertal rats: a histological, ultrastructural and immunohistochemical study","volume":"47","author":"Abd El-Hay","year":"2023","journal-title":"Ultrastruct. Pathol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"e13394","DOI":"10.1111\/and.13394","article-title":"The role of propolis against paclitaxel\u2010induced oligospermia, sperm abnormality, oxidative stress and DNA damage in testes of male rats","volume":"52","author":"Abd\u2010Elrazek","year":"2020","journal-title":"Andrologia"},{"key":"B4","doi-asserted-by":"publisher","first-page":"114436","DOI":"10.1016\/j.fct.2024.114436","article-title":"Ameliorative effects of rutin and rutin-loaded chitosan nanoparticles on testicular oxidative stress and histological damage induced by cyclophosphamide in male rats","volume":"184","author":"AbdElrazek","year":"2024","journal-title":"Food Chem. Toxicol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"281","DOI":"10.4103\/aja.aja_81_20","article-title":"Glutathione (GSH) improves sperm quality and testicular morphology in streptozotocin-induced diabetic mice","volume":"23","author":"Abdullah","year":"2021","journal-title":"Asian J. Androl."},{"key":"B6","doi-asserted-by":"publisher","first-page":"984","DOI":"10.1111\/cbdd.13823","article-title":"Therapeutic potential and pharmacological activities of \u03b2\u2010eudesmol","volume":"97","author":"Acharya","year":"2021","journal-title":"Chem. Biol. Drug Des."},{"key":"B7","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1007\/s43032-021-00651-x","article-title":"Astaxanthin relieves busulfan-induced oxidative apoptosis in cultured human spermatogonial stem cells by activating the Nrf-2\/HO-1 pathway","volume":"29","author":"Afzali","year":"2022","journal-title":"Reprod. Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"20503121231216585","DOI":"10.1177\/20503121231216585","article-title":"Pinostrobin attenuates azoxymethane-induced colorectal cytotoxicity in rats through augmentation of apoptotic Bax\/Bcl-2 proteins and antioxidants","volume":"11","author":"Ali Abed Wahab","year":"2023","journal-title":"SAGE Open Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"421","DOI":"10.14202\/vetworld.2024.421-426","article-title":"Ameliorative impacts of propolis against testicular toxicity promoted by doxorubicin","volume":"17","author":"Alsyaad","year":"2024","journal-title":"Vet. World"},{"key":"B10","doi-asserted-by":"publisher","first-page":"53052","DOI":"10.1007\/s11356-024-34673-0","article-title":"Efficacy of propolis and royal jelly in attenuating cadmium-induced spermatogenesis and steroidogenesis dysregulation, causing infertility in rats","volume":"31","author":"Amr","year":"2024","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"B11","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1007\/s12015-016-9685-1","article-title":"Underlying mechanisms that restore spermatogenesis on transplanting healthy niche cells in busulphan treated mouse testis","volume":"12","author":"Anand","year":"2016","journal-title":"Stem Cell Rev. Rep."},{"key":"B12","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1007\/s00441-001-0472-0","article-title":"Bax and other pro-apoptotic Bcl-2 family killer-proteins and their victim the mitochondrion","volume":"306","author":"Antonsson","year":"2001","journal-title":"Cell Tissue Res."},{"key":"B13","doi-asserted-by":"publisher","first-page":"493","DOI":"10.18502\/ijrm.v19i6.9371","article-title":"Role of sperm apoptosis and oxidative stress in male infertility: a narrative review","volume":"19","author":"Asadi","year":"2021","journal-title":"Int. J. Reprod. Biomed."},{"key":"B14","doi-asserted-by":"publisher","first-page":"IE01","DOI":"10.7860\/JCDR\/2017\/23927.9886","article-title":"The impact of oxidative stress on testicular function and the role of antioxidants in improving it: a review","volume":"11","author":"Asadi","year":"2017","journal-title":"J. Clin. Diagn. Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1416238","DOI":"10.3389\/fphar.2024.1416238","article-title":"Propolis attenuates diabetes-induced testicular injury by protecting against DNA damage and suppressing cellular stress","volume":"15","author":"Ashour","year":"2024","journal-title":"Front. Pharmacol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"764","DOI":"10.3390\/life15050764","article-title":"Propolis stands out as a multifaceted natural product: meta-analysis on its sources, bioactivities, applications, and future perspectives","volume":"15","author":"Ayad","year":"2025","journal-title":"Life"},{"key":"B17","doi-asserted-by":"publisher","first-page":"09603271241269019","DOI":"10.1177\/09603271241269019","article-title":"The effects of Wharton\u2019s jelly MSCs secretomes for restoring busulfan-induced reproductive toxicity in male mice","volume":"43","author":"Bahmyari","year":"2024","journal-title":"Hum. Exp. Toxicol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e03557","DOI":"10.1016\/j.heliyon.2020.e03557","article-title":"Inhibitory effect of chrysin on estrogen biosynthesis by suppression of enzyme aromatase (CYP19): a systematic review","volume":"6","author":"Balam","year":"2020","journal-title":"Heliyon"},{"key":"B19","doi-asserted-by":"publisher","first-page":"105","DOI":"10.21451\/1984-3143-AR736","article-title":"The effects of propolis on sperm quality, reproductive organs and testicular antioxidant status of male rats treated with cyclosporine-A","volume":"13","author":"Baykalir","year":"2018","journal-title":"Anim. Reprod."},{"key":"B20","doi-asserted-by":"publisher","first-page":"6078","DOI":"10.1080\/87559129.2022.2089164","article-title":"Recent advances in the chemical composition and biological activities of propolis","volume":"39","author":"Belmehdi","year":"2023","journal-title":"Food Rev. Int."},{"key":"B21","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1016\/j.bpobgyn.2011.11.008","article-title":"Chemotherapy and fertility","volume":"26","author":"Blumenfeld","year":"2012","journal-title":"Best. Pract. Res. Clin. Obstet. Gynaecol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"248768","DOI":"10.1155\/2014\/248768","article-title":"Effects of the czech propolis on sperm mitochondrial function","volume":"2014","author":"Cedikova","year":"2014","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"114107","DOI":"10.1016\/j.biopha.2022.114107","article-title":"Glutathione improves testicular spermatogenesis through inhibiting oxidative stress, mitochondrial damage, and apoptosis induced by copper deposition in mice with Wilson disease","volume":"158","author":"Chen","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"B24","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1007\/s10616-018-0189-5","article-title":"Progress on the study of the mechanism of busulfan cytotoxicity","volume":"70","author":"Chen","year":"2018","journal-title":"Cytotechnology"},{"key":"B25","first-page":"153","article-title":"Androgens and spermatogenesis. 64th international meeting of clinical endocrinology","volume-title":"Hormones & Fertility","author":"Christin-Maitre","year":"2022"},{"key":"B26","doi-asserted-by":"publisher","first-page":"291","DOI":"10.3390\/cells12020291","article-title":"Fresh medium or L-cystine as an effective Nrf2 inducer for cytoprotection in cell culture","volume":"12","author":"Dai","year":"2023","journal-title":"Cells"},{"key":"B27","doi-asserted-by":"publisher","first-page":"117433","DOI":"10.1016\/j.taap.2025.117433","article-title":"Pinocembrin protects against cisplatin-induced liver injury via modulation of oxidative stress, TAK-1 inflammation, and apoptosis","volume":"502","author":"Darwish","year":"2025","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"100364","DOI":"10.1016\/j.androl.2023.100364","article-title":"Propolis ameliorates ischemia\/reperfusion-induced testicular damage by reducing oxidative stress","volume":"21","author":"Demir","year":"2023","journal-title":"Rev. Int. Androl."},{"key":"B29","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1007\/s11255-023-03817-5","article-title":"Alpha-pinene neutralizes cisplatin-induced reproductive toxicity in male rats through activation of Nrf2 pathway","volume":"56","author":"Demir","year":"2024","journal-title":"Int. Urol. Nephrol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1016\/j.jpha.2018.05.003","article-title":"Primula vulgaris extract induces cell cycle arrest and apoptosis in human cervix cancer cells","volume":"8","author":"Demir","year":"2018","journal-title":"J. Pharm. Anal."},{"key":"B31","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1007\/s00520-020-05527-5","article-title":"Higher reproductive concerns associated with fertility consultation: a cross-sectional study of young adult male cancer survivors","volume":"29","author":"Drizin","year":"2021","journal-title":"Support. Care Cancer"},{"key":"B32","volume-title":"Protective potentialities of propolis towards spermatogonial oxidative damage","author":"Duarte","year":"2024"},{"key":"B33","doi-asserted-by":"publisher","first-page":"e1900094","DOI":"10.1002\/cbdv.201900094","article-title":"Insight on propolis from mediterranean countries: chemical composition, biological activities and application fields","volume":"16","author":"El\u2010Guendouz","year":"2019","journal-title":"Chem. Biodivers."},{"key":"B34","doi-asserted-by":"publisher","first-page":"115159","DOI":"10.1016\/j.biopha.2023.115159","article-title":"Genkwanin: an emerging natural compound with multifaceted pharmacological effects","volume":"165","author":"El Menyiy","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"B35","first-page":"13","article-title":"Clinico-hormonal correlation of oligospermic patients in the below sea level environment (Jordan Valley)","volume":"26","author":"El-Migdadi","year":"2005","journal-title":"Neuro. Endocrinol. Lett."},{"key":"B36","doi-asserted-by":"publisher","first-page":"155260","DOI":"10.1016\/j.cyto.2020.155260","article-title":"Stromal cell-derived factor-1\u03b1 predominantly mediates the ameliorative effect of linagliptin against cisplatin-induced testicular injury in adult male rats","volume":"136","author":"Elrashidy","year":"2020","journal-title":"Cytokine"},{"key":"B37","doi-asserted-by":"publisher","first-page":"30607","DOI":"10.1038\/s41598-024-81949-z","article-title":"Propolis extract nanoparticles alleviate diabetes-induced reproductive dysfunction in male rats: antidiabetic, antioxidant, and steroidogenesis modulatory role","volume":"14","author":"Emil","year":"2024","journal-title":"Sci. Rep."},{"key":"B38","doi-asserted-by":"publisher","first-page":"5209480","DOI":"10.1155\/2023\/5209480","article-title":"Exogenous ascorbate administration elevates testicular oxidative damage and histological injuries in rats after busulfan treatment","volume":"2023","author":"Ezim","year":"2023","journal-title":"Andrologia"},{"key":"B39","first-page":"197","article-title":"Histological study on the protective effect of endogenous stem cell mobilization in busulfan-induced testicular injury in albino rats","volume":"6","author":"Fotouh","year":"2018","journal-title":"J. Microsc. Ultrastruct."},{"key":"B40","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.etp.2007.05.004","article-title":"Busulfan-induced apoptosis in rat placenta","volume":"59","author":"Furukawa","year":"2007","journal-title":"Exp. Toxicol. Pathol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"115241","DOI":"10.1016\/j.jpba.2023.115241","article-title":"Comprehensive estrogenic\/anti-estrogenic, anticancer, mutagenic\/anti-mutagenic, and genotoxic\/anti-genotoxic activity studies on chemically characterized black poplar and Eurasian aspen propolis types","volume":"226","author":"Guzelmeric","year":"2023","journal-title":"J. Pharm. Biomed. Anal."},{"key":"B42","doi-asserted-by":"crossref","DOI":"10.1088\/1755-1315\/276\/1\/012056","article-title":"Does propolis extract alleviate male reproductive performance through gonadotropic hormone levels and sperm quality?","volume-title":"IOP conference series: earth and environmental science","author":"Handayani","year":"2019"},{"key":"B43","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1186\/s13020-022-00651-2","article-title":"Propolis: an update on its chemistry and pharmacological applications","volume":"17","author":"Hossain","year":"2022","journal-title":"Chin. Med."},{"key":"B44","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1113\/jphysiol.2009.186262","article-title":"Glycine transporter GLYT1 is essential for glycine\u2010mediated protection of human intestinal epithelial cells against oxidative damage","volume":"588","author":"Howard","year":"2010","journal-title":"J. Physiol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1070692","DOI":"10.3389\/fendo.2023.1070692","article-title":"Unraveling the harmful effect of oxidative stress on male fertility: a mechanistic insight","volume":"14","author":"Hussain","year":"2023","journal-title":"Front. Endocrinol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"899434","DOI":"10.3389\/fvets.2022.899434","article-title":"The impact of rumen-protected l-arginine oral supplementation on libido, semen quality, reproductive organ biometry, and serum biochemical parameters of rams","volume":"9","author":"Hussein","year":"2022","journal-title":"Front. Vet. Sci."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1984","DOI":"10.7150\/ijms.44834","article-title":"Oral administration of Korean propolis extract ameliorates DSS-induced colitis in BALB\/c mice","volume":"17","author":"Hwang","year":"2020","journal-title":"Int. J. Med. Sci."},{"key":"B48","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1007\/s13770-020-00309-w","article-title":"The therapeutic potential of amniotic fluid-derived stem cells on busulfan-induced azoospermia in adult rats","volume":"18","author":"Ibrahim","year":"2021","journal-title":"Tissue Eng. Regen. Med."},{"key":"B49","doi-asserted-by":"publisher","first-page":"e25337","DOI":"10.1016\/j.heliyon.2024.e25337","article-title":"Curative effects of tectochrysin on paraquat-instigated testicular toxicity in rats: a biochemical and histopathological based study","volume":"10","author":"Ijaz","year":"2024","journal-title":"Heliyon"},{"key":"B50","doi-asserted-by":"publisher","first-page":"e13593","DOI":"10.1111\/jfbc.13593","article-title":"Chrysin protects against testicular toxicity caused by lead acetate in rats with its antioxidant, anti\u2010inflammatory, and antiapoptotic properties","volume":"45","author":"Ileriturk","year":"2021","journal-title":"J. Food Biochem."},{"key":"B51","doi-asserted-by":"publisher","first-page":"4383","DOI":"10.1007\/s00044-014-1007-z","article-title":"Synthesis, anti-inflammatory and antioxidant activity of ring-A-monosubstituted chalcone derivatives","volume":"23","author":"Iqbal","year":"2014","journal-title":"Med. Chem. Res."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1171","DOI":"10.3390\/biom14091171","article-title":"L-Cysteine upregulates testosterone biosynthesis and blood\u2013testis barrier genes in cultured human Leydig cells and thp-1 monocytes and increases testosterone secretion in human Leydig cells","volume":"14","author":"Justin Margret","year":"2024","journal-title":"Biomolecules"},{"key":"B53","doi-asserted-by":"publisher","first-page":"423","DOI":"10.2478\/jvetres-2019-0054","article-title":"Protective role of propolis on low and high dose furan-induced hepatotoxicity and oxidative stress in rats","volume":"63","author":"Kaya","year":"2019","journal-title":"J. Vet. Res."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1840","DOI":"10.1182\/blood.v99.5.1840","article-title":"A cure for murine sickle cell disease through stable mixed chimerism and tolerance induction after nonmyeloablative conditioning and major histocompatibility complex\u2013mismatched bone marrow transplantation","volume":"99","author":"Kean","year":"2002","journal-title":"Blood"},{"key":"B55","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1095\/biolreprod59.4.890","article-title":"Rat epididymal sperm quantity, quality, and transit time after guanethidine-induced sympathectomy","volume":"59","author":"Kempinas","year":"1998","journal-title":"Biol. Reprod."},{"key":"B56","doi-asserted-by":"publisher","first-page":"301","DOI":"10.3390\/ph16020301","article-title":"Hesperidin mitigates cyclophosphamide-induced testicular dysfunction via altering the hypothalamic pituitary gonadal axis and testicular steroidogenesis, inflammation, and apoptosis in male rats","volume":"16","author":"Khamis","year":"2023","journal-title":"Pharmaceuticals"},{"key":"B57","first-page":"e77335","article-title":"An investigation into the effect of exogenous melatonin on spermatogenesis of pinealectomised busulfan induced oligospermic adult rats","volume":"16","author":"Khosoroshahi","year":"2013","journal-title":"J. Kermanshah. Univ. Med. Sci."},{"key":"B58","doi-asserted-by":"publisher","first-page":"882","DOI":"10.5534\/wjmh.220100","article-title":"Effect of n-acetyl-l-cysteine on testicular tissue in busulfan-induced dysfunction in the male reproductive system","volume":"41","author":"Kim","year":"2023","journal-title":"World J. Mens. Health"},{"key":"B59","doi-asserted-by":"publisher","first-page":"78","DOI":"10.3390\/molecules19010078","article-title":"Structure and antioxidant activity of polyphenols derived from propolis","volume":"19","author":"Kurek-G\u00f3recka","year":"2013","journal-title":"Molecules"},{"key":"B60","doi-asserted-by":"publisher","first-page":"82","DOI":"10.3390\/antiox8040082","article-title":"Protective effect of glutathione against oxidative stress-induced cytotoxicity in RAW 264.7 macrophages through activating the nuclear factor erythroid 2-related factor-2\/heme oxygenase-1 pathway","volume":"8","author":"Kwon","year":"2019","journal-title":"Antioxidants"},{"key":"B61","doi-asserted-by":"publisher","first-page":"9719906","DOI":"10.1155\/2021\/9719906","article-title":"Protective effect of honey and propolis against gentamicin\u2010induced oxidative stress and hepatorenal damages","volume":"2021","author":"Laaroussi","year":"2021","journal-title":"Oxid. Med. Cell. Longev."},{"key":"B62","doi-asserted-by":"publisher","first-page":"1794","DOI":"10.1007\/s12035-015-9125-2","article-title":"The natural flavonoid pinocembrin: molecular targets and potential therapeutic applications","volume":"53","author":"Lan","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"B63","doi-asserted-by":"publisher","first-page":"1","DOI":"10.32371\/jfp\/246156","article-title":"Semen cryopreservation in men with cancer: identifying patterns and challenges","volume":"3","author":"Ledesma","year":"2023","journal-title":"J. Fertil. Preserv."},{"key":"B64","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s12958-018-0341-2","article-title":"The in vitro modulation of steroidogenesis by inflammatory cytokines and insulin in TM3 Leydig cells","volume":"16","author":"Leisegang","year":"2018","journal-title":"Reprod. Biol. Endocrinol."},{"key":"B65","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1089\/ars.2016.6792","article-title":"Melatonin ameliorates busulfan-induced spermatogonial stem cell oxidative apoptosis in mouse testes","volume":"28","author":"Li","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"B66","doi-asserted-by":"publisher","first-page":"115231","DOI":"10.1016\/j.biopha.2023.115231","article-title":"Puerarin improves busulfan-induced disruption of spermatogenesis by inhibiting MAPK pathways","volume":"165","author":"Li","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"B67","doi-asserted-by":"publisher","first-page":"526","DOI":"10.4103\/0253-7613.84961","article-title":"An evaluation of antioxidant, anti-inflammatory, and antinociceptive activities of essential oil from Curcuma longa. L","volume":"43","author":"Liju","year":"2011","journal-title":"L. Indian J. Pharmacol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"1389","DOI":"10.1016\/s1097-2765(00)00136-2","article-title":"The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues","volume":"6","author":"Lindsten","year":"2000","journal-title":"Mol. Cell."},{"key":"B69","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/s12610-021-00140-w","article-title":"Male cancer patient sperm cryopreservation for fertility preservation: 10-year monocentric experience","volume":"31","author":"Liu","year":"2021","journal-title":"Basic Clin. Androl."},{"key":"B71","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1177\/0960327110368416","article-title":"Protective effects of melatonin and Glycyrrhiza glabra extract on ochratoxin A\u2014induced damages on testes in mature rats","volume":"30","author":"Malekinejad","year":"2011","journal-title":"Hum. Exp. Toxicol."},{"key":"B72","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.phytochem.2017.09.016","article-title":"Chrysin: sources, beneficial pharmacological activities, and molecular mechanism of action","volume":"145","author":"Mani","year":"2018","journal-title":"Phytochemistry"},{"key":"B73","first-page":"321","article-title":"Extraction and initial characterization of propolis from stingless bees (Trigona biroi Friese)","volume-title":"Asian Apicultural Association conference and 10. BEENET symposium and technofora","author":"Matienzo","year":"2004"},{"key":"B74","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/aja.2009.14","article-title":"Clinical significance of the low normal sperm morphology value as proposed in the fifth edition of the WHO laboratory manual for the examination and processing of human semen","volume":"12","author":"Menkveld","year":"2010","journal-title":"Asian J. Androl."},{"key":"B75","doi-asserted-by":"publisher","first-page":"4154","DOI":"10.1210\/jc.82.12.4154","article-title":"Evidence for production and functional activity of nitric oxide in seminiferous tubules and blood vessels of the human testis","volume":"82","author":"Middendorff","year":"1997","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B76","doi-asserted-by":"publisher","first-page":"409","DOI":"10.3322\/caac.21731","article-title":"Cancer treatment and survivorship statistics, 2022","volume":"72","author":"Miller","year":"2022","journal-title":"Cancer. J. Clin."},{"key":"B77","first-page":"1","article-title":"The cell as a unit of health and disease","volume-title":"Robbins and cotran pathologic basis of disease","author":"Mitchell","year":"2015"},{"key":"B78","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.3390\/antiox11051029","article-title":"Anti-inflammatory, anti-apoptotic, and antioxidant roles of honey, royal jelly, and propolis in suppressing nephrotoxicity induced by doxorubicin in male albino rats","volume":"11","author":"Mohamed","year":"2022","journal-title":"Antioxidants"},{"key":"B79","doi-asserted-by":"publisher","first-page":"4387","DOI":"10.3390\/app13074387","article-title":"Overview of the effects of moringa oleifera leaf extract on oxidative stress and male infertility: a review","volume":"13","author":"Mohlala","year":"2023","journal-title":"Appl. Sci."},{"key":"B80","doi-asserted-by":"publisher","first-page":"21127","DOI":"10.1038\/s41598-020-78014-w","article-title":"Chemical composition of Polish propolis and its antiproliferative effect in combination with Bacopa monnieri on glioblastoma cell lines","volume":"10","author":"Moskwa","year":"2020","journal-title":"Sci. Rep."},{"key":"B81","first-page":"97","article-title":"Effect of ribavirin on epididymal sperm count in rat","volume":"46","author":"Narayana","year":"2002","journal-title":"Indian J. Physiol. Pharmacol."},{"key":"B82","doi-asserted-by":"publisher","first-page":"533","DOI":"10.29252\/JCT.6.4.533","article-title":"Study of side effects of busulfan on testis tissue and epididymal sperm of adult mice following treatment with clinical dose","volume":"6","author":"Nasimi","year":"2016","journal-title":"Cell Tissue J."},{"key":"B83","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1111\/andr.12739","article-title":"Malaysian propolis and metformin mitigate subfertility in streptozotocin\u2010induced diabetic male rats by targeting steroidogenesis, testicular lactate transport, spermatogenesis and mating behaviour","volume":"8","author":"Nna","year":"2020","journal-title":"Andrology"},{"key":"B84","doi-asserted-by":"publisher","first-page":"2990","DOI":"10.1002\/tox.23654","article-title":"Glycine protects the male reproductive system against lead toxicity via alleviating oxidative stress, preventing sperm mitochondrial impairment, improving kinematics of sperm, and blunting the downregulation of enzymes involved in the steroidogenesis","volume":"37","author":"Ommati","year":"2022","journal-title":"Environ. Toxicol."},{"key":"B85","doi-asserted-by":"publisher","first-page":"e40073","DOI":"10.5812\/jjnpp.40073","article-title":"Phenolic characterisation and antioxidant activity of Primula vulgaris and its antigenotoxic effect on fibroblast cells","volume":"12","author":"Ozkan","year":"2017","journal-title":"Jundishapur J. Nat. Pharm. Prod."},{"key":"B86","doi-asserted-by":"publisher","first-page":"188","DOI":"10.3390\/ph3010188","article-title":"Effects of adaptogens on the central nervous system and the molecular mechanisms associated with their stress\u2014protective activity","volume":"3","author":"Panossian","year":"2010","journal-title":"Pharmaceuticals"},{"key":"B87","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1002\/med.21743","article-title":"Evolution of the adaptogenic concept from traditional use to medical systems: pharmacology of stress\u2010and aging\u2010related diseases","volume":"41","author":"Panossian","year":"2021","journal-title":"Med. Res. Rev."},{"key":"B88","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1186\/s13287-020-01803-7","article-title":"Human amnion mesenchymal stem cells restore spermatogenesis in mice with busulfan-induced testis toxicity by inhibiting apoptosis and oxidative stress","volume":"11","author":"Qian","year":"2020","journal-title":"Stem Cell Res. Ther."},{"key":"B89","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1016\/s0006-2952(99)00149-5","article-title":"Mitochondrial permeability transition and release of cytochrome c induced by retinoic acids","volume":"58","author":"Rigobello","year":"1999","journal-title":"Biochem. Pharmacol."},{"key":"B90","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1186\/s12906-022-03650-w","article-title":"Ellagic acid effects on testis, sex hormones, oxidative stress, and apoptosis in the relative sterility rat model following busulfan administration","volume":"22","author":"Rostami","year":"2022","journal-title":"BMC Complement. Med. Ther."},{"key":"B91","doi-asserted-by":"publisher","first-page":"e13540","DOI":"10.1111\/and.13540","article-title":"Bee glue (propolis) improves reproductive organs, sperm quality and histological changes and antioxidant parameters of testis tissues in rats exposed to excess copper","volume":"52","author":"Seven","year":"2020","journal-title":"Andrologia"},{"key":"B92","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1016\/j.joim.2021.08.002","article-title":"The in-vivo assessment of Turkish propolis and its nano form on testicular damage induced by cisplatin","volume":"19","author":"Seven","year":"2021","journal-title":"J. Integr. Med."},{"key":"B93","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1002\/ptr.5605","article-title":"Biological properties and therapeutic applications of propolis","volume":"30","author":"Sforcin","year":"2016","journal-title":"Phytother. Res."},{"key":"B94","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/j.jep.2010.10.032","article-title":"Propolis: is there a potential for the development of new drugs?","volume":"133","author":"Sforcin","year":"2011","journal-title":"J. Ethnopharmacol."},{"key":"B95","doi-asserted-by":"publisher","first-page":"8067","DOI":"10.3390\/ijms21218067","article-title":"The emerging and diverse roles of bis (monoacylglycero) phosphate lipids in cellular physiology and disease","volume":"21","author":"Showalter","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B96","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2018\/1875870","article-title":"Oxidative stress, apoptosis, and mitochondrial function in diabetic nephropathy","volume":"2018","author":"Sifuentes-Franco","year":"2018","journal-title":"Int. J. Endocrinol."},{"key":"B97","doi-asserted-by":"publisher","first-page":"147502","DOI":"10.1016\/j.gene.2023.147502","article-title":"Beneficial effects of Chrysin on cadmium\u2010induced nephrotoxicity in rats: modulating the levels of Nrf2\/HO\u20101, RAGE\/NLRP3, and Caspase-3\/Bax\/Bcl-2 signaling pathways","volume":"875","author":"\u015eim\u015fek","year":"2023","journal-title":"Gene"},{"key":"B98","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.semcdb.2014.02.012","article-title":"The regulation of spermatogenesis by androgens","volume":"30","author":"Smith","year":"2014","journal-title":"Semin. Cell Dev. Biol."},{"key":"B99","doi-asserted-by":"publisher","first-page":"e14165","DOI":"10.1111\/jfbc.14165","article-title":"Chrysin abrogates gibberellic acid\u2010induced testicular oxidative stress and dysfunction via the regulation of antioxidants and steroidogenesis\u2010and apoptosis\u2010associated genes","volume":"46","author":"Soliman","year":"2022","journal-title":"J. Food Biochem."},{"key":"B100","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.biopha.2016.02.002","article-title":"Protective effects of propolis on methotrexate-induced testis injury in rat","volume":"79","author":"S\u00f6nmez","year":"2016","journal-title":"Biomed. Pharmacother."},{"key":"B101","doi-asserted-by":"publisher","first-page":"456","DOI":"10.3389\/fnins.2014.00456","article-title":"Activation of the hypothalamic-pituitary-adrenal stress axis induces cellular oxidative stress","volume":"8","author":"Spiers","year":"2015","journal-title":"Front. Neurosci."},{"key":"B102","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/978-1-4419-6857-9_13","article-title":"Acridine Orange Test for assessment of human sperm DNA integrity","volume-title":"Sperm chromatin: biological and clinical applications in Male infertility and assisted reproduction","author":"Varghese","year":"2011"},{"key":"B103","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1111\/iep.12195","article-title":"Seminiferous epithelium damage after short period of busulphan treatment in adult rats and vitamin B12 efficacy in the recovery of spermatogonial germ cells","volume":"97","author":"Vasiliausha","year":"2016","journal-title":"Int. J. Exp. Pathol."},{"key":"B104","doi-asserted-by":"publisher","first-page":"176405","DOI":"10.1016\/j.ejphar.2024.176405","article-title":"5-methylcytidine effectively improves spermatogenesis recovery in busulfan-induced oligoasthenospermia mice","volume":"967","author":"Wang","year":"2024","journal-title":"Eur. J. Pharmacol."},{"key":"B105","doi-asserted-by":"publisher","first-page":"e112598","DOI":"10.1371\/journal.pone.0112598","article-title":"Profiling of Cxcl12 receptors, Cxcr4 and Cxcr7 in murine testis development and a spermatogenic depletion model indicates a role for Cxcr7 in controlling Cxcl12 activity","volume":"9","author":"Westernstr\u00f6er","year":"2014","journal-title":"PLoS One"},{"key":"B106","doi-asserted-by":"publisher","first-page":"2426","DOI":"10.3390\/molecules25102426","article-title":"Polish propolis\u2014chemical composition and biological effects in tongue cancer cells and macrophages","volume":"25","author":"Wezgowiec","year":"2020","journal-title":"Molecules"},{"key":"B107","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1095\/biolreprod.114.123570","article-title":"Ghrelin partially protects against cisplatin-induced male murine gonadal toxicity in a GHSR-1a-dependent manner","volume":"92","author":"Whirledge","year":"2015","journal-title":"Biol. Reprod."},{"key":"B108","doi-asserted-by":"publisher","first-page":"117075","DOI":"10.1016\/j.biopha.2024.117075","article-title":"Apigenin improves testosterone synthesis by regulating endoplasmic reticulum stress","volume":"177","author":"Wu","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"B109","doi-asserted-by":"publisher","first-page":"104756","DOI":"10.1016\/j.fitote.2020.104756","article-title":"Interplay between male reproductive system dysfunction and the therapeutic effect of flavonoids","volume":"147","author":"Ye","year":"2020","journal-title":"Fitoterapia"},{"key":"B110","doi-asserted-by":"publisher","first-page":"116063","DOI":"10.1016\/j.ecoenv.2024.116063","article-title":"Exosomes derived from umbilical cord mesenchymal stem cells ameliorate male infertility caused by busulfan in vivo and in vitro","volume":"272","author":"Yue","year":"2024","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"B111","doi-asserted-by":"publisher","first-page":"107158","DOI":"10.1016\/j.anireprosci.2022.107158","article-title":"Regulation of spermatogenic cell apoptosis by the pro-apoptotic proteins in the testicular tissues of mammalian and avian species","volume":"247","author":"Zakariah","year":"2022","journal-title":"Anim. Reprod. Sci."},{"key":"B112","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.freeradbiomed.2024.12.047","article-title":"Protective effects of flavonoids on fluoride-induced testicular DNA damage in mice","volume":"228","author":"Zhang","year":"2025","journal-title":"Free Radic. Biol. Med."},{"key":"B113","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1038\/nrm1443","article-title":"Apoptosis and genomic instability","volume":"5","author":"Zhivotovsky","year":"2004","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B114","doi-asserted-by":"publisher","first-page":"116262","DOI":"10.1016\/j.biopha.2024.116262","article-title":"3-O-Methyl-D-glucose blunts cold ischemia damage in kidney via inhibiting ferroptosis","volume":"173","author":"Zou","year":"2024","journal-title":"Biomed. Pharmacother."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1656541\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T05:27:04Z","timestamp":1760333224000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1656541\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,13]]},"references-count":113,"alternative-id":["10.3389\/fphar.2025.1656541"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1656541","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,13]]},"article-number":"1656541"}}