{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T15:35:17Z","timestamp":1790868917935,"version":"4.1.0"},"reference-count":56,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T00:00:00Z","timestamp":1718582400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004035","name":"Jordan University of Science and Technology","doi-asserted-by":"publisher","award":["20210433"],"award-info":[{"award-number":["20210433"]}],"id":[{"id":"10.13039\/501100004035","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Empagliflozin (EMPA) showed antiapoptotic, oxidative and anti-inflammatory potential effect. EMPA attenuates the inflammation and oxidative stress biomarkers in patients with heart failure while significantly decreases the malondialdehyde (a lipid peroxidation marker) levels in the plasma of diabetic patients. The present study examined the effects of moderate hyperglycemia on reproductive function. Sixty male Wister rats \u200e were divided and randomly allocated into four groups of 15 animals each\u200e\u200e. Diabetes was induced by a single intraperitoneal injection of a prepared solution containing STZ diluted in 0.1 M sodium citrate buffer (pH 4.5) at a dosage of 40 mg\/kg body weight in selected in groups II and III for seven days before starting the treatment with EMPA. The current study revealed that EMPA for eight weeks prevented testicular high glucose-induced oxidative stress markers such as penile nitric oxide (NO), glutathione peroxidase (GPX) and total anti-oxidant capacity (TAC) in STZ-induced hyperglycemia in a rat model. In addition, EMPA ameliorated the high levels of endogenous Interleukin-6 (IL-6) present in gonads in response to an acute inflammatory found in the hyperglycemic STZ-induced rats. The present study further suggested the protective effects of EMPA and how it has a beneficial role and can effectively attenuate hyperglycemia-induced testicular oxidative damage and inflammatory markers as well as androgen dependent testicular enzymes activity as a protective role against the consequences of hyperglycemia and male sub-infertility.<\/jats:p>","DOI":"10.1371\/journal.pone.0305636","type":"journal-article","created":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T17:34:20Z","timestamp":1718645660000},"page":"e0305636","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Effects of empagliflozin on gonadal functions of hyperglycemic male wistar rats"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1103-5180","authenticated-orcid":true,"given":"Roba","family":"Bdeir","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nour A.","family":"Al-Sawalha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"O\u2019la","family":"Al-Fawares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4672-3303","authenticated-orcid":true,"given":"Lama","family":"Hamadeneh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alia","family":"Khawaldeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,6,17]]},"reference":[{"issue":"1","key":"pone.0305636.ref001","doi-asserted-by":"crossref","first-page":"61","DOI":"10.7748\/ns.2021.e11709","article-title":"Diabetes mellitus: an overview of the types, symptoms, complications and management","volume":"37","author":"L. Cloete","year":"2021","journal-title":"Nursing Standard"},{"issue":"11","key":"pone.0305636.ref002","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.2522\/ptj.20080020","article-title":"Epidemiology of diabetes and diabetes-related complications","volume":"88","author":"A.D. Deshpande","year":"2008","journal-title":"Physical therapy"},{"issue":"4","key":"pone.0305636.ref003","doi-asserted-by":"crossref","first-page":"681","DOI":"10.3390\/diagnostics13040681","article-title":"The Bidirectional Relationship between Periodontal Disease and Diabetes Mellitus\u2014A Review","volume":"13","author":"I. P\u0103unic\u0103","year":"2023","journal-title":"Diagnostics"},{"issue":"1","key":"pone.0305636.ref004","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/1573399817666210309104740","article-title":"Sexual dysfunction in men and women with diabetes: a reflection of their complications?","volume":"18","author":"A. Sansone","year":"2022","journal-title":"Current Diabetes Reviews"},{"key":"pone.0305636.ref005","doi-asserted-by":"crossref","first-page":"107843","DOI":"10.1016\/j.diabres.2019.107843","article-title":"Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas","volume":"157","author":"P. Saeedi","year":"2019","journal-title":"Diabetes research and clinical practice"},{"key":"pone.0305636.ref006","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1007\/s40265-018-0937-z","article-title":"EMPAgliflozin: a review in type 2 diabetes","volume":"78","author":"J.E. Frampton","year":"2018","journal-title":"Drugs"},{"key":"pone.0305636.ref007","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.2147\/DMSO.S194688","article-title":"EMPAgliflozin in type 1 diabetes","author":"C. Mathieu","year":"2019","journal-title":"Diabetes, Metabolic Syndrome Obesity: Targets Therapy"},{"issue":"11","key":"pone.0305636.ref008","first-page":"1088","article-title":"New oral hypoglycemic agents and cardiovascular risk. Crossing the metabolic border","volume":"69","author":"B. Dalama","year":"2016","journal-title":"Revista Espa\u00f1ola de Cardiolog\u00eda"},{"key":"pone.0305636.ref009","article-title":"EMPAgliflozin-Metformin Combination Has Antioxidative and Anti-Inflammatory Properties that Correlate with Vascular Protection in Adults with Type 1 Diabetes.","author":"M. Jani\u0107","year":"2022","journal-title":"Journal of Diabetes Research"},{"issue":"1","key":"pone.0305636.ref010","doi-asserted-by":"crossref","first-page":"15","DOI":"10.21608\/besps.2019.14918.1029","article-title":"Effect of the combination between EMPAgliflozin and calcipotriol on cadmium-induced testicular toxicity in rats","volume":"40","author":"H.M. Borg","year":"2020","journal-title":"Bulletin of Egyptian Society for Physiological Sciences"},{"key":"pone.0305636.ref011","doi-asserted-by":"crossref","first-page":"1059942","DOI":"10.3389\/fendo.2022.1059942","article-title":"Effects of EMPAgliflozin on the expression of kisspeptin gene and reproductive system function in streptozotocin-induced diabetic male rats","volume":"13","author":"P. Dana","year":"2022","journal-title":"Frontiers in Endocrinology"},{"key":"pone.0305636.ref012","article-title":"Protective effects of EMPAgliflozin on testicular injury induced by torsion\/detorsion in adult male rats","author":"M.R. Khezri","year":"2023","journal-title":"Journal of Pediatric Urology"},{"issue":"5","key":"pone.0305636.ref013","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.21873\/invivo.12531","article-title":"Diabetes mellitus causes male reproductive dysfunction: a review of the evidence and mechanisms","volume":"35","author":"Z. He","year":"2021","journal-title":"In vivo"},{"issue":"6","key":"pone.0305636.ref014","doi-asserted-by":"crossref","first-page":"948","DOI":"10.4103\/1008-682X.150844","article-title":"The effects of diabetes on male fertility and epigenetic regulation during spermatogenesis","volume":"17","author":"G.-L. Ding","year":"2015","journal-title":"Asian journal of andrology"},{"issue":"1","key":"pone.0305636.ref015","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.aju.2017.12.004","article-title":"Lifestyle causes of male infertility","volume":"16","author":"D. Durairajanayagam","year":"2018","journal-title":"Arab journal of urology"},{"issue":"3","key":"pone.0305636.ref016","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1111\/andr.13140","article-title":"The impact of diabetes mellitus type 1 on male fertility: Systematic review and meta\u2010analysis","volume":"10","author":"P. Facondo","year":"2022","journal-title":"Andrology"},{"key":"pone.0305636.ref017","first-page":"25","article-title":"Impact of 5\u2019-amp-activated protein kinase on male gonad and spermatozoa functions","volume":"5","author":"T.M.D. Nguyen","year":"2017","journal-title":"Frontiers in Cell Developmental Biology"},{"key":"pone.0305636.ref018","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s12020-010-9375-8","article-title":"GnRH secretion is inhibited by adiponectin through activation of AMP-activated protein kinase and extracellular signal-regulated kinase","volume":"39","author":"X.-B. Cheng","year":"2011","journal-title":"Endocrine"},{"issue":"1\u20132","key":"pone.0305636.ref019","first-page":"1","article-title":"Role of AMPK in mammals reproduction: Specific controls and whole-body energy sensing","volume":"342","author":"T.M.D. Nguyen","year":"2019","journal-title":"Comptes Rendus Biologies"},{"key":"pone.0305636.ref020","doi-asserted-by":"crossref","first-page":"593005","DOI":"10.3389\/fcell.2020.593005","article-title":"Roles of AMP-activated protein kinase (AMPK) in mammalian reproduction.","volume":"8","author":"W. Yang","year":"2020","journal-title":"Frontiers in Cell Developmental Biology"},{"issue":"11","key":"pone.0305636.ref021","doi-asserted-by":"crossref","first-page":"3932","DOI":"10.1002\/jcb.26046","article-title":"Steroidogenic acute regulatory protein (StAR) overexpression reduces inflammation and insulin resistance in obese mice.","volume":"118","author":"Y. Qiu","year":"2017","journal-title":"Journal of Cellular Biochemistry"},{"issue":"2","key":"pone.0305636.ref022","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1210\/en.2016-1340","article-title":"The steroidogenic acute regulatory protein (StAR) is regulated by the H19\/let-7 axis","volume":"158","author":"Y. Men","year":"2017","journal-title":"Endocrinology"},{"issue":"3","key":"pone.0305636.ref023","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1093\/humupd\/dmn004","article-title":"Oxidative stress and male infertility\u2014a clinical perspective","volume":"14","author":"K. Tremellen","year":"2008","journal-title":"Human reproduction update"},{"issue":"3","key":"pone.0305636.ref024","first-page":"307","article-title":"Stress hormone and oxidative stress biomarkers link obesity and diabetes with reduced fertility potential","volume":"21","author":"S. Abbasihormozi","year":"2019","journal-title":"Cell Journal"},{"key":"pone.0305636.ref025","first-page":"274","article-title":", Streptozotocin as a tool for induction of rat models of diabetes: A practical guide","volume":"22","author":"A. Ghasemi","year":"2023","journal-title":"EXCLI journal"},{"issue":"4","key":"pone.0305636.ref026","doi-asserted-by":"crossref","first-page":"e78","DOI":"10.1002\/cpz1.78","article-title":"Streptozotocin-Induced Diabetic Models in Mice and Rats.","volume":"1","author":"B.L. Furman","year":"2021","journal-title":"Curr Protoc"},{"issue":"4","key":"pone.0305636.ref027","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.3390\/ijms22041509","article-title":"The role of oxidative stress in pancreatic \u03b2 cell dysfunction in diabetes","volume":"22","author":"N. Eguchi","year":"2021","journal-title":"International journal of molecular sciences"},{"key":"pone.0305636.ref028","author":"ZE Yesilyurt","year":"2021","journal-title":"The Effects of Low-dose EMPAgliflozin on Cardiac Function in a Rat Model of Streptozotocin-induced Diabetes"},{"issue":"4","key":"pone.0305636.ref029","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/0892-0362(92)90004-T","article-title":"Euthanasia by decapitation: evidence that this technique produces prompt, painless unconsciousness in laboratory rodents","volume":"14","author":"RR Holson","year":"1992","journal-title":"Neurotoxicology and teratology"},{"issue":"1","key":"pone.0305636.ref030","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/0003-2697(89)90192-9","article-title":"An assay for superoxide dismutase activity in mammalian tissue homogenates","volume":"179","author":"DR Spitz","year":"1989","journal-title":"Analytical biochemistry"},{"key":"pone.0305636.ref031","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/978-1-60761-849-2_4","article-title":"Histopathology procedures: from tissue sampling to histopathological evaluation","author":"M Slaoui","year":"2011","journal-title":"Drug Safety Evaluation: Methods and Protocols"},{"key":"pone.0305636.ref032","first-page":"237","volume-title":"Oxidative stress in men with obesity, metabolic syndrome and type 2 diabetes mellitus: Mechanisms and management of reproductive dysfunction, in Oxidative Stress and Toxicity in Reproductive Biology and Medicine: A Comprehensive Update on Male Infertility-Volume One","author":"K. Leisegang","year":"2022"},{"issue":"1","key":"pone.0305636.ref033","doi-asserted-by":"crossref","first-page":"13074","DOI":"10.1038\/s41598-019-49600-4","article-title":"Hyperglycemia induces spermatogenic disruption via major pathways of diabetes pathogenesis","volume":"9","author":"C.C. Maresch","year":"2019","journal-title":"Scientific Reports"},{"issue":"2","key":"pone.0305636.ref034","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1111\/j.1439-0272.1978.tb01327.x","article-title":"Fertility of the streptozotocin\u2010diabetic male rat","volume":"10","author":"G.P. Frenkel","year":"1978","journal-title":"Andrologia"},{"issue":"1","key":"pone.0305636.ref035","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/S0022-5347(17)43042-4","article-title":"The effect of streptozotocin-induced diabetes on the neuroendocrine-male reproductive tract axis of the adult rat","volume":"138","author":"L. Seethalakshmi","year":"1987","journal-title":"The Journal of urology"},{"issue":"7","key":"pone.0305636.ref036","first-page":"1869","article-title":"Insulin rescues impaired spermatogenesis via the hypothalamic-pituitary-gonadal axis in Akita diabetic mice and restores male fertility","volume":"61","author":"E.L. Schoeller","year":"2012","journal-title":"Diabetes research and clinical practice"},{"issue":"1","key":"pone.0305636.ref037","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1111\/andr.12567","article-title":"Down\u2010regulation of steroidogenesis\u2010related genes and its accompanying fertility decline in streptozotocin\u2010induced diabetic male rats: ameliorative effect of metformin.","volume":"7","author":"V. Nna","year":"2019","journal-title":"Andrology"},{"issue":"7","key":"pone.0305636.ref038","doi-asserted-by":"crossref","first-page":"2882","DOI":"10.1210\/en.2002-0090","article-title":"Reactive oxygen disrupts mitochondria in MA-10 tumor Leydig cells and inhibits steroidogenic acute regulatory (StAR) protein and steroidogenesis","volume":"144","author":"T. Diemer","year":"2003","journal-title":"Endocrinology"},{"issue":"1\u20132","key":"pone.0305636.ref039","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.mce.2004.03.012","article-title":"Effect of ascorbic acid supplementation on testicular steroidogenesis and germ cell death in cadmium-treated male rats","volume":"221","author":"R.S. Gupta","year":"2004","journal-title":"Molecular cellular endocrinology"},{"issue":"6","key":"pone.0305636.ref040","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.3390\/nu12061561","article-title":"Glycemic index (GI) or glycemic load (GL) and dietary interventions for optimizing postprandial hyperglycemia in patients with T2 diabetes: A review.","volume":"12","author":"D. Vlachos","year":"2020","journal-title":"Nutrients"},{"issue":"1","key":"pone.0305636.ref041","doi-asserted-by":"crossref","DOI":"10.51847\/42rWHfIT62","article-title":"The Use of Medicinal Herbs to Treat Male Infertility in Jordan: Evidence-Based Review.","volume":"12","author":"D. Al-Tawalbeh","year":"2023","journal-title":"International Journal of pharmaceutical research allied sciences"},{"issue":"5","key":"pone.0305636.ref042","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.3390\/jcm9051400","article-title":"Diet and nutritional factors in male (in) fertility\u2014underestimated factors.","volume":"9","author":"K. Skoracka","year":"2020","journal-title":"Journal of clinical medicine"},{"issue":"3","key":"pone.0305636.ref043","doi-asserted-by":"crossref","first-page":"241","DOI":"10.3390\/biology10030241","article-title":"Dietary antioxidants in the treatment of male infertility: counteracting oxidative stress","volume":"10","author":"E. Torres-Arce","year":"2021","journal-title":"Biology"},{"key":"pone.0305636.ref044","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13098-021-00728-2","article-title":"Association of diabetes and obesity with sperm parameters and testosterone levels: a meta-analysis.","volume":"13","author":"O. Zhong","year":"2021","journal-title":"Diabetology Metabolic Syndrome"},{"issue":"10","key":"pone.0305636.ref045","doi-asserted-by":"crossref","first-page":"16775","DOI":"10.1002\/jcb.28936","article-title":"Evaluation of testis hormonal and histopathological alterations in type I and type II diabetic rats","volume":"120","author":"S. Barsiah","year":"2019","journal-title":"Journal of cellular biochemistry"},{"issue":"4","key":"pone.0305636.ref046","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1177\/00236772211001895","article-title":"Comparison of streptozotocin-induced diabetes at different moments of the life of female rats for translational studies","volume":"55","author":"Y.K. Sinzato","year":"2021","journal-title":"Laboratory Animals"},{"key":"pone.0305636.ref047","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.biopha.2017.10.095","article-title":"Taurine enhances spermatogenic function and antioxidant defense mechanisms in testes and epididymis of L-NAME-induced hypertensive rats.","volume":"97","author":"I.A. Adedara","year":"2018","journal-title":"Biomedicine Pharmacotherapy"},{"issue":"40","key":"pone.0305636.ref048","doi-asserted-by":"crossref","first-page":"56491","DOI":"10.1007\/s11356-021-14339-x","article-title":"Iprodione and\/or chlorpyrifos exposure induced testicular toxicity in adult rats by suppression of steroidogenic genes and SIRT1\/TERT\/PGC-1\u03b1 pathway","volume":"28","author":"Y.M. Abd-Elhakim","year":"2021","journal-title":"Environmental Science Pollution Research"},{"issue":"4","key":"pone.0305636.ref049","first-page":"281","article-title":"Toxic effects of atrazine on reproductive system of male rats.","volume":"27","author":"S. Yang","year":"2014","journal-title":"Biomedical environmental sciences"},{"key":"pone.0305636.ref050","doi-asserted-by":"crossref","first-page":"5935","DOI":"10.1007\/s11033-021-06593-6","article-title":"Pro-inflammatory cytokines and microRNAs in male infertility","volume":"48","author":"H. Attia","year":"2021","journal-title":"Molecular Biology Reports"},{"key":"pone.0305636.ref051","doi-asserted-by":"crossref","first-page":"103984","DOI":"10.1016\/j.jri.2023.103984","article-title":"A review on immunological aspects in male reproduction: an immune cells and cytokines","author":"U.R. Wanjari","year":"2023","journal-title":"Journal of Reproductive Immunology"},{"issue":"18","key":"pone.0305636.ref052","doi-asserted-by":"crossref","first-page":"10043","DOI":"10.3390\/ijms221810043","article-title":"Oxidative stress, testicular inflammatory pathways, and male reproduction","volume":"22","author":"S. Dutta","year":"2021","journal-title":"International journal of molecular sciences"},{"issue":"5","key":"pone.0305636.ref053","doi-asserted-by":"crossref","first-page":"1557988320970053","DOI":"10.1177\/1557988320970053","article-title":"Reactive oxygen species secreted by leukocytes in semen induce self-expression of interleukin-6 and affect sperm quality","volume":"14","author":"X. Li","year":"2020","journal-title":"American Journal of Men\u2019s Health"},{"key":"pone.0305636.ref054","first-page":"499","volume":"195","author":"A.A. Fouad","year":"2020","journal-title":"Diacerein downregulates NLRP3\/Caspase-1\/IL-1\u03b2 and IL-6\/STAT3 pathways of inflammation and apoptosis in a rat model of cadmium testicular toxicity"},{"issue":"3","key":"pone.0305636.ref055","first-page":"296","volume":"13","author":"S. Russell","year":"2001","journal-title":"The in vitro role of tumour necrosis factor\u2010alpha and interleukin\u20106 in the hypothalamic\u2010pituitary gonadal axis"},{"issue":"5","key":"pone.0305636.ref056","first-page":"1499","volume":"9","author":"R. Cannarella","year":"2021","journal-title":"Is there a role for glucagon\u2010like peptide\u20101 receptor agonists in the treatment of male infertility?"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0305636","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T01:12:03Z","timestamp":1732237923000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0305636"}},"subtitle":[],"editor":[{"given":"Yasmina","family":"Abd\u2010Elhakim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,6,17]]},"references-count":56,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,6,17]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0305636","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,17]]}}}