{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T21:02:59Z","timestamp":1789074179221,"version":"build-2803163510"},"reference-count":104,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T00:00:00Z","timestamp":1676419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Life Sciences \u201cKing Mihai I\u201d"},{"name":"Research Institute for Biosecurity and Bioengineering"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Cyclophosphamide (CP) is a cytotoxic, cell cycle, non-specific, and antiproliferative drug. This study aimed to address the toxic effects of CP on male fertility and the possible ameliorative role of hesperidin (HSP). Thirty-two adult albino rats were randomly divided into four groups, namely, the negative control, HSP, CP-treated, and CP+HSP-treated groups. The CP-treated rats showed a significant reduction in the levels of serum LH, FSH, testosterone, prolactin, testicular glutathione peroxidase (GPx), and total antioxidant capacity (TAC) with an elevation in levels of malondialdehyde (MDA), and p53, and iNOS immune expression, compared to the control group. A significant downregulation in hypothalamic KISS-1, KISS-1r, and GnRH, hypophyseal GnRHr, and testicular mRNA expression of steroidogenesis enzymes, PGC-1\u03b1, PPAR-1, IL10, and GLP-1, as well as a significant upregulation in testicular mRNA of P53 and IL1\u03b2 mRNA expression, were detected in the CP-treated group in comparison to that in the control group. The administration of HSP in CP-treated rats significantly improved the levels of serum LH, FSH, testosterone, prolactin, testicular GPx, and TAC, with a reduction in levels of MDA, and p53, and iNOS immune expression compared to the CP-treated group. A significant upregulation in hypophyseal GnRHr, and testicular mRNA expression of CYP19A1 enzymes, PPAR-1, IL10, and GLP-1, as well as a significant downregulation in testicular mRNA of P53 and IL1\u03b2 mRNA expression, were detected in the CP+HSP-treated group in comparison to that in the CP-treated group. In conclusion, HSP could be a potential auxiliary agent for protection from the development of male infertility.<\/jats:p>","DOI":"10.3390\/ph16020301","type":"journal-article","created":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T05:37:46Z","timestamp":1676439466000},"page":"301","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Hesperidin Mitigates Cyclophosphamide-Induced Testicular Dysfunction via Altering the Hypothalamic Pituitary Gonadal Axis and Testicular Steroidogenesis, Inflammation, and Apoptosis in Male Rats"],"prefix":"10.3390","volume":"16","author":[{"given":"Tarek","family":"Khamis","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdelmonem Awad","family":"Hegazy","sequence":"additional","affiliation":[{"name":"Anatomy and Embryology, Faculty of Dentistry, Zarqa University, Zarqa 13110, Jordan"},{"name":"Human Anatomy & Embryology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samaa Salah Abd","family":"El-Fatah","sequence":"additional","affiliation":[{"name":"Human Anatomy & Embryology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eman Ramadan","family":"Abdelfattah","sequence":"additional","affiliation":[{"name":"Human Anatomy & Embryology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwa Mohamed Mahmoud","family":"Abdelfattah","sequence":"additional","affiliation":[{"name":"Human Anatomy & Embryology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liana Mihaela","family":"Fericean","sequence":"additional","affiliation":[{"name":"Biology Department, Faculty of Agriculture, University of Life Sciences \u201cKing Michael I of Romania\u201d from Timisoara, Aradului St. 119, 300645 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1330-6311","authenticated-orcid":false,"given":"Ahmed Hamed","family":"Arisha","sequence":"additional","affiliation":[{"name":"Department of Animal Physiology and Biochemistry, Faculty of Veterinary Medicine, Badr University in Cairo, Badr City 11829, Egypt"},{"name":"Department of Physiology, Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,15]]},"reference":[{"key":"ref_1","first-page":"346","article-title":"MPV, NLR, and platelet count: New hematologic markers in diagnosis of malignant ovarian tumor","volume":"38","author":"Yilmaz","year":"2017","journal-title":"Eur. J. Gynaecol. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/S0140-6736(04)15640-7","article-title":"Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: Double-blind randomised controlled trial","volume":"363","author":"Klareskog","year":"2004","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.ejca.2015.12.007","article-title":"Cyclophosphamide pharmacokinetics and pharmacogenetics in children with B-cell non-Hodgkin\u2019s lymphoma","volume":"55","author":"Veal","year":"2016","journal-title":"Eur. J. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.ecoenv.2017.02.003","article-title":"Immune responses in the aquatic gastropod Lymnaea stagnalis under short-term exposure to pharmaceuticals of concern for immune systems: Diclofenac, cyclophosphamide and cyclosporine A","volume":"139","author":"Boisseaux","year":"2017","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Grzesiuk, M., Mielecki, D., Pil\u017cys, T., Garbicz, D., Marcinkowski, M., and Grzesiuk, E. (2018). How cyclophosphamide at environmentally relevant concentration influences Daphnia magna life history and its proteome. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0197416"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1007\/s00210-020-01987-y","article-title":"The effects of chrysin and naringin on cyclophosphamide-induced erythrocyte damage in rats: Biochemical evaluation of some enzyme activities in vivo and in vitro","volume":"394","author":"Temel","year":"2021","journal-title":"Naunyn Schmiedebergs Arch Pharm."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1093\/humupd\/dmz027","article-title":"Ovarian damage from chemotherapy and current approaches to its protection","volume":"25","author":"Spears","year":"2019","journal-title":"Hum. Reprod. Update"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e13095","DOI":"10.1111\/jfbc.13095","article-title":"Protective effect of curcumin on fertility in cyclophosphamide exposed rats: Involvement of multiple pathways","volume":"44","author":"Akomolafe","year":"2020","journal-title":"J. Food Biochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"174188","DOI":"10.1016\/j.ejphar.2021.174188","article-title":"Breast milk MSCs upregulated \u03b2-cells PDX1, Ngn3, and PCNA expression via remodeling ER stress\/inflammatory\/apoptotic signaling pathways in type 1 diabetic rats","volume":"905","author":"Khamis","year":"2021","journal-title":"Eur. J. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"165577","DOI":"10.1016\/j.bbadis.2019.165577","article-title":"Early intervention with breast milk mesenchymal stem cells attenuates the development of diabetic-induced testicular dysfunction via hypothalamic Kisspeptin\/Kiss1r-GnRH\/GnIH system in male rats","volume":"1866","author":"Khamis","year":"2020","journal-title":"Biochim. Et Biophys. Acta-Mol. Basis Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e14341","DOI":"10.1111\/and.14341","article-title":"Cyclophosphamide-induced testicular oxidative-inflammatory injury is accompanied by altered immunosuppressive indoleamine 2, 3-dioxygenase in Wister rats: Influence of dietary quercetin","volume":"54","author":"Ebokaiwe","year":"2022","journal-title":"Andrologia"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Van den Boogaard, W.M.C., Komninos, D.S.J., and Vermeij, W.P. (2022). Chemotherapy Side-Effects: Not All DNA Damage Is Equal. Cancers, 14.","DOI":"10.3390\/cancers14030627"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"116797","DOI":"10.1016\/j.lfs.2019.116797","article-title":"Chrysin: Pharmacological and therapeutic properties","volume":"235","author":"Naz","year":"2019","journal-title":"Life Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1007\/s00204-020-02689-3","article-title":"Antioxidants and antioxidant methods: An updated overview","volume":"94","author":"Gulcin","year":"2020","journal-title":"Arch. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Kopustinskiene, D.M., Jakstas, V., Savickas, A., and Bernatoniene, J. (2020). Flavonoids as Anticancer Agents. Nutrients, 12.","DOI":"10.3390\/nu12020457"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1177\/1535370219831615","article-title":"Hesperidin improves the follicular development in 3D culture of isolated preantral ovarian follicles of mice","volume":"244","author":"Shoorei","year":"2019","journal-title":"Exp. Biol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1200\/JCO.18.00965","article-title":"Gonadal Functioning and Perceptions of Infertility Risk Among Adult Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study","volume":"37","author":"Lehmann","year":"2019","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Fusco, R., Salinaro, A.T., Siracusa, R., D\u2019Amico, R., Impellizzeri, D., Scuto, M., Ontario, M.L., Crea, R., Cordaro, M., and Cuzzocrea, S. (2021). Hidrox(\u00ae) Counteracts Cyclophosphamide-Induced Male Infertility through NRF2 Pathways in a Mouse Model. Antioxidants, 10.","DOI":"10.3390\/antiox10050778"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1080\/17425255.2017.1277205","article-title":"The mechanisms of cyclophosphamide-induced testicular toxicity and the protective agents","volume":"13","author":"Ghobadi","year":"2017","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1177\/1534735415610427","article-title":"Efficacy and Interaction of Antioxidant Supplements as Adjuvant Therapy in Cancer Treatment: A Systematic Review","volume":"15","author":"Yasueda","year":"2016","journal-title":"Integr. Cancer Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1007\/s11224-020-01594-w","article-title":"How the ascorbic acid and hesperidin do improve the biological activities of the cinnamon: Theoretical investigation","volume":"31","author":"Zouchoune","year":"2020","journal-title":"Struct. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1002\/tox.23068","article-title":"Protective effect of hesperidin against N,N\u2019-dimethylhydrazine induced oxidative stress, inflammation, and apoptotic response in the colon of Wistar rats","volume":"36","author":"Afzal","year":"2020","journal-title":"Environ. Toxicol."},{"key":"ref_23","first-page":"102","article-title":"Effect of cyclophosphamide on liver in albino rats: A comparative dose dependent histomorphological study","volume":"8","author":"Khorwal","year":"2017","journal-title":"Int. J. Biomed. Adv. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e22591","DOI":"10.1002\/jbt.22591","article-title":"Protective roles and mechanisms of rosmarinic acid in cyclophosphamide-induced premature ovarian failure","volume":"34","author":"Yao","year":"2020","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2156587218757649","DOI":"10.1177\/2156587218757649","article-title":"Protective Effect of Kolaviron on Cyclophosphamide-Induced Cardiac Toxicity in Rats","volume":"23","author":"Omole","year":"2018","journal-title":"J. Evid.-Based Integr. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"44","DOI":"10.21315\/mjms2019.26.1.4","article-title":"Ameliorative Effects of Aquilaria malaccensis Leaves Aqueous Extract on Reproductive Toxicity Induced by Cyclophosphamide in Male Rats","volume":"26","author":"Razak","year":"2019","journal-title":"Malays. J. Med. Sci.: MJMS"},{"key":"ref_27","first-page":"2397847318812794","article-title":"Aluminium phosphide-induced testicular toxicity through oxidative stress in Wistar rats: Ameliorative role of hesperidin","volume":"2","author":"Afolabi","year":"2018","journal-title":"Toxicol. Res. Appl."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"150","DOI":"10.21608\/blj.2016.48192","article-title":"Protective Effect Of Hesperidin And Tiger Nut Against DMBA Carcinogenicity In Female Rats","volume":"12","author":"Hamdy","year":"2016","journal-title":"Biochem. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e14196","DOI":"10.1111\/and.14196","article-title":"Protective effects of sinapic acid against cyclophosphamide-induced testicular toxicity via inhibiting oxidative stress, caspase-3 and NF-kB activity in BALB\/c mice","volume":"53","author":"Rezaei","year":"2021","journal-title":"Andrologia"},{"key":"ref_30","first-page":"78","article-title":"Protective Effect of Gallic Acid on Testicular Tissue, Sperm Parameters, and DNA Fragmentation against Toxicity Induced by Cyclophosphamide in Adult NMRI Mice","volume":"17","author":"Mehraban","year":"2020","journal-title":"Urol. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1111\/and.12135","article-title":"Protective effect of Zingiber officinale extract on rat testis after cyclophosphamide treatment","volume":"46","author":"Mohammadi","year":"2014","journal-title":"Andrologia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4272575","DOI":"10.1155\/2018\/4272575","article-title":"GnRH Antagonist Improves Pubertal Cyclophosphamide-Induced Long-Term Testicular Injury in Adult Rats","volume":"2018","author":"Xie","year":"2018","journal-title":"Int. J. Endocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"152406","DOI":"10.1016\/j.tox.2020.152406","article-title":"Aberrations of miR-126-3p, miR-181a and sirtuin1 network mediate Di-(2-ethylhexyl) phthalate-induced testicular damage in rats: The protective role of hesperidin","volume":"433\u2013434","author":"Helmy","year":"2020","journal-title":"Toxicology"},{"key":"ref_34","first-page":"553","article-title":"Study the Effect of Silymarin on Cyclophosphamide Induced Testicular Damage in Adult Albino Rats","volume":"41","author":"Shabaan","year":"2021","journal-title":"Bull. Egypt. Soc. Physiol. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e13978","DOI":"10.1111\/and.13978","article-title":"Iprodione and chlorpyrifos induce testicular damage, oxidative stress, apoptosis and suppression of steroidogenic- and spermatogenic-related genes in immature male albino rats","volume":"53","author":"Hassan","year":"2021","journal-title":"Andrologia"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3005","DOI":"10.21608\/ejhm.2022.244529","article-title":"Protective Effect of Hesperidin on Kidneys and Testes of Adult Male Rats Exposed to Bisphenol A","volume":"88","author":"Kasem","year":"2022","journal-title":"Egypt. J. Hosp. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"28749","DOI":"10.1007\/s11356-019-06066-1","article-title":"Morin ameliorates the testicular apoptosis, oxidative stress, and impact on blood\u2013testis barrier induced by photo-extracellularly synthesized silver nanoparticles","volume":"26","author":"Arisha","year":"2019","journal-title":"Environ. Sci. Pollut. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"29074","DOI":"10.1007\/s11356-019-06091-0","article-title":"Amelioration of titanium dioxide nanoparticle reprotoxicity by the antioxidants morin and rutin","volume":"26","author":"Hussein","year":"2019","journal-title":"Environ. Sci. Pollut. Res."},{"key":"ref_39","first-page":"138","article-title":"Protective Effect of Ghrelin on Oxidative Stress and Tissue Damages of Mice Testes Followed By Chemotherapy With Cyclophosphamide","volume":"5","author":"Salimnejad","year":"2018","journal-title":"Crescent J. Med. Biol. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"100109","DOI":"10.1016\/j.jnim.2020.100109","article-title":"Antioxidant potential of garlic oil supplementation prevents cyclophosphamide-induced oxidative testicular damage and endocrine depletion in rats","volume":"18","author":"Famurewa","year":"2019","journal-title":"J. Nutr. Intermed. Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"12599","DOI":"10.1038\/s41598-020-68608-9","article-title":"Chemoprotective effects of inositol hexaphosphate against cyclophosphamide-induced testicular damage in rats","volume":"10","author":"Alkhalaf","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1111\/andr.12681","article-title":"Hesperidin attenuated apoptotic-related genes in testicle of a male rat model of varicocoele","volume":"8","author":"Shokoohi","year":"2020","journal-title":"Andrology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"112435","DOI":"10.1016\/j.ecoenv.2021.112435","article-title":"Thymol alleviates imidacloprid-induced testicular toxicity by modulating oxidative stress and expression of steroidogenesis and apoptosis-related genes in adult male rats","volume":"221","author":"Saber","year":"2021","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"30426","DOI":"10.1007\/s11356-020-09366-z","article-title":"Argan oil ameliorates sodium fluoride-induced renal damage via inhibiting oxidative damage, inflammation, and intermediate filament protein expression in male rats","volume":"27","author":"Saber","year":"2020","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e13535","DOI":"10.1111\/and.13535","article-title":"Ameliorative effect of nerolidol on cyclophosphamide-induced gonadal toxicity in Swiss Albino mice: Biochemical-, histological- and immunohistochemical-based evidences","volume":"52","author":"Iqubal","year":"2020","journal-title":"Andrologia"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5","DOI":"10.4103\/ijpvm.IJPVM_184_18","article-title":"Cerium Oxide Nanoparticles Protect Cyclophosphamide-induced Testicular Toxicity in Mice","volume":"10","author":"Hamzeh","year":"2019","journal-title":"Int. J. Prev. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.tice.2018.08.006","article-title":"Ameliorative effect of zinc oxide nanoparticles on cyclophosphamide induced testicular injury in adult rat","volume":"54","author":"Anan","year":"2018","journal-title":"Tissue Cell"},{"key":"ref_48","first-page":"35","article-title":"Antioxidant effects of Spirulina platensis (Arthrospira platensis) on cyclophosphamide-induced testicular injury in rats","volume":"9","author":"Hasanzadeh","year":"2018","journal-title":"Vet. Res. Forum: Int. Q. J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"126574","DOI":"10.1016\/j.jtemb.2020.126574","article-title":"Cyclophosphamide induced oxidative stress, lipid per oxidation, apoptosis and histopathological changes in rats: Protective role of boron","volume":"62","author":"Cengiz","year":"2020","journal-title":"J. Trace Elem. Med. Biol. Organ Soc. Miner. Trace Elem. (GMS)"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"403","DOI":"10.29252\/ijrm.15.7.403","article-title":"Combined protective effect of zinc oxide nanoparticles and melatonin on cyclophosphamide-induced toxicity in testicular histology and sperm parameters in adult Wistar rats","volume":"15","author":"Torabi","year":"2017","journal-title":"Int. J. Reprod. Biomed."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Nakazawa, H., Chang, K., Shinozaki, S., Yasukawa, T., Ishimaru, K., Yasuhara, S., Yu, Y.M., Martyn, J.A., Tompkins, R.G., and Shimokado, K. (2017). iNOS as a Driver of Inflammation and Apoptosis in Mouse Skeletal Muscle after Burn Injury: Possible Involvement of Sirt1 S-Nitrosylation-Mediated Acetylation of p65 NF-\u03baB and p53. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0170391"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"152439","DOI":"10.1016\/j.tox.2020.152439","article-title":"LCZ696 (sacubitril\/valsartan) protects against cyclophosphamide-induced testicular toxicity in rats: Role of neprilysin inhibition and lncRNA TUG1 in ameliorating apoptosis","volume":"437","author":"Salama","year":"2020","journal-title":"Toxicology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/and.12435","article-title":"Fenugreek seed extract attenuates cisplatin-induced testicular damage in Wistar rats","volume":"48","author":"Hamza","year":"2016","journal-title":"Andrologia"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"113","DOI":"10.4103\/jhrs.jhrs_190_20","article-title":"Observable Protective Activities of Quercetin on Aluminum Chloride-Induced Testicular Toxicity in Adult Male Wistar Rat","volume":"14","author":"Olanrewaju","year":"2021","journal-title":"J. Hum. Reprod. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"119911","DOI":"10.1016\/j.lfs.2021.119911","article-title":"Regulation of Keap-1\/Nrf2\/AKT and iNOS\/NF-\u03baB\/TLR4 signals by apocynin abrogated methotrexate-induced testicular toxicity: Mechanistic insights and computational pharmacological analysis","volume":"284","author":"Sayed","year":"2021","journal-title":"Life Sci."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Azouz, R.A., Korany, R.M.S., and Noshy, P.A. (2022). Silica Nanoparticle-Induced Reproductive Toxicity in Male Albino Rats via Testicular Apoptosis and Oxidative Stress. Biol. Trace Elem. Res.","DOI":"10.1007\/s12011-022-03280-w"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e13786","DOI":"10.1111\/and.13786","article-title":"Ginger juice prevents cisplatin-induced oxidative stress, endocrine imbalance and NO\/iNOS\/NF-\u03baB signalling via modulating testicular redox-inflammatory mechanism in rats","volume":"52","author":"Famurewa","year":"2020","journal-title":"Andrologia"},{"key":"ref_58","first-page":"730","article-title":"Protective Effect of Hesperidin against Cyclophosphamide Hepatotoxicity in Rats","volume":"8","author":"Fouad","year":"2014","journal-title":"Int. J. Bioeng. Life Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.yexmp.2015.11.012","article-title":"Chemopreventive efficacy of hesperidin against chemically induced nephrotoxicity and renal carcinogenesis via amelioration of oxidative stress and modulation of multiple molecular pathways","volume":"99","author":"Siddiqi","year":"2015","journal-title":"Exp. Mol. Pathol."},{"key":"ref_60","first-page":"891","article-title":"Possible Protective Effect of Melatonin on Cisplatin-Induced Testicular Toxicity in Adult Albino Rats. A Histological and Immunohistochemical Study","volume":"43","author":"Filobbos","year":"2020","journal-title":"Egypt. J. Histol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"151750","DOI":"10.1016\/j.aanat.2021.151750","article-title":"Antioxidant and antiapoptotic paracrine effects of mesenchymal stem cells on spermatogenic arrest in oligospermia rat model","volume":"237","author":"Zickri","year":"2021","journal-title":"Ann. Anat. Anat. Anz. Off. Organ Anat. Ges."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e13987","DOI":"10.1111\/jfbc.13987","article-title":"Lepidium draba L. leaves extract ameliorated cyclophosphamide-induced testicular toxicity by modulation of ROS-dependent Keap1\/Nrf2\/HO1, Bax\/Bcl2\/p53\/caspase-3, and inflammatory signaling pathways","volume":"45","author":"Wang","year":"2021","journal-title":"J. Food Biochem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3565360","DOI":"10.1155\/2021\/3565360","article-title":"Melatonin Alleviated Potassium Dichromate-Induced Oxidative Stress and Reprotoxicity in Male Rats","volume":"2021","author":"Bashandy","year":"2021","journal-title":"BioMed. Res. Int."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"113810","DOI":"10.1016\/j.jep.2021.113810","article-title":"BaZiBuShen alleviates altered testicular morphology and spermatogenesis and modulates Sirt6\/P53 and Sirt6\/NF-\u03baB pathways in aging mice induced by D-galactose and NaNO(2)","volume":"271","author":"Li","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"111481","DOI":"10.1016\/j.biopha.2021.111481","article-title":"Melatonin protects rats testes against bleomycin, etoposide, and cisplatin-induced toxicity via mitigating nitro-oxidative stress and apoptosis","volume":"138","author":"Moradi","year":"2021","journal-title":"Biomed. Pharmacother. = Biomed. Pharmacother."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"90391","DOI":"10.1007\/s11356-022-20944-1","article-title":"Hesperidin partly ameliorates the decabromodiphenyl ether-induced reproductive toxicity in pubertal mice","volume":"29","author":"Li","year":"2022","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1111\/and.12332","article-title":"Hesperidin protects testicular and spermatological damages induced by cisplatin in rats","volume":"47","author":"Kaya","year":"2015","journal-title":"Andrologia"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"928","DOI":"10.5114\/aoms.2015.47697","article-title":"Protective effects of hesperidin in experimental testicular ischemia\/reperfusion injury in rats","volume":"12","author":"Celik","year":"2016","journal-title":"Arch. Med. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"201","DOI":"10.21608\/EJH.2017.4077","article-title":"The Potential Protective Role of Hesperidin Against Capecitabine-Induced Corneal Toxicity in Adult Male Albino Rat. Light and Electron Microscopic Study","volume":"40","author":"Elwan","year":"2017","journal-title":"Egypt. J. Histol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s12011-018-1443-6","article-title":"Protective Effect of Hesperidin on Sodium Arsenite-Induced Nephrotoxicity and Hepatotoxicity in Rats","volume":"189","author":"Turk","year":"2019","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"75","DOI":"10.31557\/APJCP.2021.22.1.75","article-title":"Efficacy of Quercetin-Sensitized Cisplatin against N-Nitroso-NMethylurea Induced Testicular Carcinogenesis in Wistar Rats","volume":"22","author":"Refaat","year":"2021","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e14368","DOI":"10.1111\/and.14368","article-title":"Oral thymoquinone modulates cyclophosphamide-induced testicular toxicity in adolescent Wistar rats","volume":"54","author":"Adana","year":"2022","journal-title":"Andrologia"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"234","DOI":"10.29261\/pakvetj\/2019.127","article-title":"Casticin Alleviates Testicular and Spermatological Damage Induced by Cisplatin in Rats","volume":"40","author":"Ijaz","year":"2020","journal-title":"Pak. Vet. J."},{"key":"ref_74","first-page":"249","article-title":"Exploring the main effects of phoenix dactylifera on destructive changes caused by cyclophosphamide in male reproductive system in mice","volume":"13","author":"Delgarm","year":"2022","journal-title":"Vet. Res. Forum Int. Q. J."},{"key":"ref_75","first-page":"79","article-title":"Ethyl Pyruvate Ameliorates The Damage Induced by Cyclophosphamide on Adult Mice Testes","volume":"10","author":"Bakhtiary","year":"2016","journal-title":"Int. J. Fertil. Steril."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.lfs.2018.08.074","article-title":"Hesperetin, a citrus flavonoid, attenuates testicular damage in diabetic rats via inhibition of oxidative stress, inflammation, and apoptosis","volume":"210","author":"Samie","year":"2018","journal-title":"Life Sci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"564","DOI":"10.5958\/0974-360X.2018.00105.1","article-title":"Ameliorative effect of Quercetin and Hesperidin on Antioxidant and Histological Changes in the Testis of Etoposide-Induced Adult Male Rats","volume":"11","author":"Alanbaki","year":"2018","journal-title":"Res. J. Pharm. Technol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"89","DOI":"10.3109\/19396368.2014.998350","article-title":"Alleviative effect of quercetin on rat testis against arsenic: A histological and biochemical study","volume":"61","author":"Jahan","year":"2015","journal-title":"Syst. Biol. Reprod. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e11614","DOI":"10.1590\/1414-431x2021e11614","article-title":"The protective effect of melatonin supplementation against taxol-induced testicular cytotoxicity in adult rats","volume":"55","author":"Aboelwafa","year":"2022","journal-title":"Braz. J. Med. Biol. Res. Rev. Bras. Pesqui. Med. Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.theriogenology.2019.04.035","article-title":"Potential inhibitory effect of swimming exercise on the Kisspeptin\u2013GnRH signaling pathway in male rats","volume":"133","author":"Arisha","year":"2019","journal-title":"Theriogenology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e12981","DOI":"10.1111\/and.12981","article-title":"Quercetin and rutin ameliorates sulphasalazine-induced spermiotoxicity, alterations in reproductive hormones and steroidogenic enzyme imbalance in rats","volume":"50","author":"Osawe","year":"2018","journal-title":"Andrologia"},{"key":"ref_82","first-page":"72","article-title":"Curcumin and Quercetin Ameliorated Cypermethrin and Deltamethrin-Induced Reproductive System Impairment in Male Wistar Rats by Upregulating The Activity of Pituitary-Gonadal Hormones and Steroidogenic Enzymes","volume":"12","author":"Sharma","year":"2018","journal-title":"Int. J. Fertil. Steril."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"112922","DOI":"10.1016\/j.jep.2020.112922","article-title":"Ethanolic extract of Moringa oleifera leaves alleviate cyclophosphamide-induced testicular toxicity by improving endocrine function and modulating cell specific gene expression in mouse testis","volume":"259","author":"Nayak","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"152528","DOI":"10.1016\/j.tox.2020.152528","article-title":"Tert-butylhydroquinone preserve testicular steroidogenesis and spermatogenesis in cisplatin-intoxicated rats by targeting oxidative stress, inflammation and apoptosis","volume":"441","author":"Nna","year":"2020","journal-title":"Toxicology"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"100268","DOI":"10.1016\/j.phyplu.2022.100268","article-title":"Ameliorating and protective potential of 1-isothiocyanato-4-methyl sulfonyl butane on cisplatin induced oligozoospermia and testicular dysfunction via redox-inflammatory pathway: Histomorphometric and immunohistochemical evaluation using proliferating cell nuclear antigen","volume":"2","author":"Adelakun","year":"2022","journal-title":"Phytomedicine Plus"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"153208","DOI":"10.1016\/j.tox.2022.153208","article-title":"Alterations in reproductive parameters and steroid biosynthesis induced by nickel oxide nanoparticles in male rats: The ameliorative effect of hesperidin","volume":"473","author":"Noshy","year":"2022","journal-title":"Toxicology"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1080\/01480545.2020.1856130","article-title":"Investigation into the protective effects of Hypericum Triquetrifolium Turra seed against cyclophosphamide-induced testicular injury in Sprague Dawley rats","volume":"45","author":"Can","year":"2022","journal-title":"Drug Chem. Toxicol."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Ye, H., Ng, H.W., Sakkiah, S., Ge, W., Perkins, R., Tong, W., and Hong, H. (2016). Pathway Analysis Revealed Potential Diverse Health Impacts of Flavonoids that Bind Estrogen Receptors. Int. J. Environ. Res. Public Health, 13.","DOI":"10.3390\/ijerph13040373"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.febslet.2009.11.026","article-title":"Structural activity relationship of flavonoids with estrogen-related receptor gamma","volume":"584","author":"Huang","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1111\/andr.13015","article-title":"Is there a role for glucagon-like peptide-1 receptor agonists in the treatment of male infertility?","volume":"9","author":"Cannarella","year":"2021","journal-title":"Andrology"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"16813","DOI":"10.1038\/s41598-020-73630-y","article-title":"Reduced spermatozoa functionality during stress is the consequence of adrenergic-mediated disturbance of mitochondrial dynamics markers","volume":"10","author":"Starovlah","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"170711","DOI":"10.1016\/j.peptides.2021.170711","article-title":"Semaglutide early intervention attenuated testicular dysfunction by targeting the GLP-1-PPAR-\u03b1-Kisspeptin-Steroidogenesis signaling pathway in a testicular ischemia-reperfusion rat model","volume":"149","author":"Abdullah","year":"2022","journal-title":"Peptides"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"8487248","DOI":"10.1155\/2018\/8487248","article-title":"Evaluation of the Protective Effect of Olive Leaf Extract on Cisplatin-Induced Testicular Damage in Rats","volume":"2018","author":"Almeer","year":"2018","journal-title":"Oxid Med. Cell Longev."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1002\/tox.23406","article-title":"Investigation of the effects of hesperidin administration on abamectin-induced testicular toxicity in rats through oxidative stress, endoplasmic reticulum stress, inflammation, apoptosis, autophagy, and JAK2\/STAT3 pathways","volume":"37","author":"Gur","year":"2022","journal-title":"Environ. Toxicol."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Negm, W.A., El-Kadem, A.H., Hussein, I.A., and Alqahtani, M.J. (2022). The Mechanistic Perspective of Bilobetin Protective Effects against Cisplatin-Induced Testicular Toxicity: Role of Nrf-2\/Keap-1 Signaling, Inflammation, and Apoptosis. Biomedicines, 10.","DOI":"10.3390\/biomedicines10051134"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.etp.2010.10.012","article-title":"Efficacy of hesperidin on plasma, heart and liver tissue lipids in rats subjected to isoproterenol-induced cardiotoxicity","volume":"64","author":"Selvaraj","year":"2012","journal-title":"Exp. Toxicol. Pathol. Off. J. Ges. Fur Toxikol. Pathol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2769","DOI":"10.3390\/pharmaceutics14122769","article-title":"Melatonin Mitigates Cisplatin-Induced Ovarian Dysfunction via Altering Steroidogenesis, Inflammation, Apoptosis, Oxidative Stress, and PTEN\/PI3K\/Akt\/mTOR\/AMPK Signaling Pathway in Female Rats","volume":"14","author":"Hulail","year":"2022","journal-title":"Pharmaceutics."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1095\/biolreprod63.4.977","article-title":"Regulation of Leydig cell steroidogenic function during aging","volume":"63","author":"Zirkin","year":"2000","journal-title":"Biol. Reprod."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1426846","DOI":"10.1155\/2020\/1426846","article-title":"Effect of Light-Dark Cycle Misalignment on the Hypothalamic-Pituitary-Gonadal Axis, Testicular Oxidative Stress, and Expression of Clock Genes in Adult Male Rats","volume":"2020","author":"Moustafa","year":"2020","journal-title":"Int. J. Endocrinol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2\u2212\u0394\u0394CT Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_101","unstructured":"Suvarna, S.K., Layton, C., and Bancroft, J.D. (2019). Bancroft\u2019s Theory and Practice of Histological Techniques, Elsevier. [8th ed.]."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2405","DOI":"10.1210\/endo.142.6.8317","article-title":"Murine germ cells do not require functional androgen receptors to complete spermatogenesis following spermatogonial stem cell transplantation","volume":"142","author":"Johnston","year":"2001","journal-title":"Endocrinology"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1038\/embor.2012.50","article-title":"Sperm counts and fertility in men: A rocky road ahead. Science & Society Series on Sex and Science","volume":"13","author":"Sharpe","year":"2012","journal-title":"EMBO Rep."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1002\/ar.22641","article-title":"Quantitative analysis of histological staining and fluorescence using ImageJ","volume":"296","author":"Jensen","year":"2013","journal-title":"Anat. Rec."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/2\/301\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:36:34Z","timestamp":1760121394000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/2\/301"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,15]]},"references-count":104,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ph16020301"],"URL":"https:\/\/doi.org\/10.3390\/ph16020301","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,15]]}}}