{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:59:48Z","timestamp":1785437988470,"version":"3.56.0"},"reference-count":95,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Modafinil (MOD) is a nootropic nonamphetamine medication of growing therapeutic interest. Despite the drug's rapidly expanding usage, little is known about its toxic effects on male reproduction. The present study aimed to reveal the dose\u2010dependent MOD\u2010induced reproductive toxicity and the potential mitigating effects of selenium (Se) in testis. Adult male rats were administered MOD300 or 600\u2009mg\/kg\/day alone for 14 days or co\u2010treated with Se either 0.1 or 0.2\u2009mg\/kg\/day for 21 days. Functional, biochemical (Testosterone, Follicle\u2010stimulating hormone, Luteinizing hormone, Nitric oxide, Malondialdehyde, Superoxide Dismutase, and Total Antioxidant Capacity), molecular, histopathological, and Transmission electron microscopy examinations were studied. Results revealed that MOD doses significantly induced deterioration of erectile function and sperm quality accompanied by a significant alteration in reproductive hormonal levels (Total and Free testosterone, LH, and FSH). MOD doses also evoked a significant increase in MDA, and NO, with a significant decrease in SOD and TAC. Furthermore, upregulation of the PI3K\/Akt\/NF\u2010\u04a1B pathway and the increased expression of the inflammatory gene (iNOS) were demonstrated with both MOD doses. Molecular docking highlighted the virtual mechanism of binding of MOD towards the tested proteins. The observed toxicity was further confirmed by the histopathological and ultrastructural changes. The results demonstrated a significant improvement in the parameters when a Se dose of 0.2\u2009mg\/kg\/day was co\u2010administered. In conclusion, MOD interferes with male reproductive function in a dose\u2010dependent manner, and Se may be a potentially helpful new approach for abating such toxicity.<\/jats:p>","DOI":"10.1002\/jbt.70548","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T07:07:16Z","timestamp":1760598436000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Selenium Ameliorates Modafinil\u2010Induced Male Reproductive Toxicity via Modulation of PI3K\/Akt\/NF\u2010\u04a1B Pathway: Experimental Study and Molecular Docking Verification"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2810-3613","authenticated-orcid":false,"given":"Shaimaa A.","family":"Shehata","sequence":"first","affiliation":[{"name":"Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine Suez Canal University (SCU) Ismailia Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7425-9096","authenticated-orcid":false,"given":"Mahrous A.","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine Suez Canal University (SCU) Ismailia Egypt"},{"name":"Forensic Medicine and Clinical Toxicology, College of Medicine Jouf University Sakaka Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5540-0819","authenticated-orcid":false,"given":"Ezzat A.","family":"Ismail","sequence":"additional","affiliation":[{"name":"Department of Urology, Faculty of Medicine Suez Canal University (SCU) Ismailia Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6251-8516","authenticated-orcid":false,"given":"Eman","family":"Kolieb","sequence":"additional","affiliation":[{"name":"Physiology Department, Faculty of Medicine Suez Canal University (SCU) Ismailia Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dina A.","family":"Ali","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Department, Faculty of Medicine Suez Canal University (SCU) Ismailia Egypt"},{"name":"Center of Excellence in Molecular and Cellular Medicine (CEMCM), Faculty of Medicine Suez Canal University (SCU) Ismailia Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1852-4374","authenticated-orcid":false,"given":"Noha M.","family":"Abd El\u2010Fadeal","sequence":"additional","affiliation":[{"name":"Medical Biochemistry and Molecular Biology Department, Faculty of Medicine Suez Canal University (SCU) Ismailia Egypt"},{"name":"Biochemistry Department Ibn Sina National College for Medical Studies Jeddah Saudi Arabia"},{"name":"Oncology Diagnostic Unit, Faculty of Medicine Suez Canal University (SCU) Ismailia Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5493-4189","authenticated-orcid":false,"given":"Ghada","family":"AbdelKader","sequence":"additional","affiliation":[{"name":"Human Anatomy and Embryology Department, Faculty of Medicine Suez Canal University (SCU) Ismailia Egypt"},{"name":"Human anatomy and embryology, Faculty of Medicine BADR University in Cairo (BUC)  Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4454-6390","authenticated-orcid":false,"given":"Mohamed S.","family":"Nafie","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Sciences University of Sharjah Sharjah United Arab Emirates"},{"name":"Chemistry Department, Faculty of Science Suez Canal University (SCU) Ismailia Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3843-2899","authenticated-orcid":false,"given":"Enas M. A.","family":"Mostafa","sequence":"additional","affiliation":[{"name":"Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine Suez Canal University (SCU) Ismailia Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,16]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1080\/08897077.2019.1700584"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/01480545.2020.1803906"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.2741\/4736"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13181-010-0017-6"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1177\/0269881113513850"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/20961790.2019.1704482"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0227818"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chemosphere.2019.06.016"},{"issue":"5","key":"e_1_2_8_10_1","article-title":"Dependence on Supratherapeutic Doses of Modafinil: A Case Report","volume":"14","author":"Kate N.","year":"2012","journal-title":"Primary Care Companion for CNS Disorders"},{"key":"e_1_2_8_11_1","first-page":"S83","article-title":"Psychosis Due to High Dose Self\u2010Administered Modafnil \u2010 A Case Report","volume":"54","author":"Vidyendaran R.","year":"2012","journal-title":"Indian Journal of Psychiatry"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.4103\/0976-500X.149149"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.30773\/pi.2016.10.25"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0142713"},{"key":"e_1_2_8_15_1","unstructured":"ehealthMe. Erectile Dysfunction and Drugs of Ingredients of Modafinil \u2010 a Phase IV Clinical Study of FDA data [Internet]. (November2022) https:\/\/www.ehealthme.com\/is\/modafinil\/erectile-dysfunction\/."},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1743-6109.2009.01509.x"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40263-013-0084-8"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s43032-021-00795-w"},{"issue":"5","key":"e_1_2_8_19_1","article-title":"The Impact of Oxidative Stress on Testicular Function and the Role of Antioxidants in Improving It: A Review","volume":"11","author":"Asadi N.","year":"2017","journal-title":"Journal of Clinical and Diagnostic Research"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/toxics11010002"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/917246"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms221810043"},{"key":"e_1_2_8_23_1","first-page":"7835","article-title":"Phosphoinositide 3\u2011kinase\/protein Kinase B Regulates Inflammation Severity via Signaling of Toll\u2011Like Receptor 4 in Severe Acute Pancreatitis","volume":"17","author":"Wang J.","year":"2018","journal-title":"Mol Med Report"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1070692"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12011-019-02016-7"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s42452-022-05208-4"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.anireprosci.2014.01.009"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2019.05.001"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/and.13669"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1385\/BTER:101:1:73"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1590\/S1516-8913201500098"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.12749\/RDB.2014.38.3.107"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11356-023-31093-4"},{"key":"e_1_2_8_34_1","volume-title":"Anesthesia and Analgesia in Laboratory Animals","author":"Fish R.","year":"2011"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.4103\/jnsm.jnsm_153_20"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12011-017-0997-z"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxrep.2020.01.012"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1111\/and.14050"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12011-025-04539-8"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtemb.2017.08.003"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules21121687"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.3791\/56798"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1464-410x.1998.00529.x"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.3168\/jds.S0022-0302(70)86184-7"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.14334\/jitv.v26i2.2729"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcla.24794"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2020.109841"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1111\/andr.13333"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-54523-w"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1111\/andr.12852"},{"key":"e_1_2_8_51_1","unstructured":"World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen\u2010 5th Edition.5th ed.2010[cited 2023 May 28] https:\/\/apps.who.int\/iris\/handle\/10665\/44261."},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.4103\/jhrs.jhrs_190_20"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1186\/1477-7827-9-100"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.steroids.2019.108485"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-84235-4"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23063017"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdiacomp.2010.03.003"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.3389\/fchem.2020.592688"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sxmr.2021.01.003"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2011.02.008"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.7717\/peerj.2000"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.3390\/app13074387"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox8080268"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1177\/0960327111424301"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1177\/0960327118816134"},{"issue":"3","key":"e_1_2_8_66_1","first-page":"88","article-title":"Therapeutic Potentials of Superoxide Dismutase","volume":"12","author":"Younus H.","year":"2018","journal-title":"International Journal of Health Sciences"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.5534\/wjmh.2014.32.1.1"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.1111\/andr.12630"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox9020170"},{"issue":"2","key":"e_1_2_8_70_1","first-page":"18","article-title":"The Role of Nitric Oxide on Male and Female Reproduction","volume":"29","author":"Dutta S.","year":"2022","journal-title":"MJMS"},{"key":"e_1_2_8_71_1","doi-asserted-by":"publisher","DOI":"10.1007\/s43188-023-00200-5"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.envpol.2017.07.081"},{"issue":"07","key":"e_1_2_8_73_1","first-page":"621","article-title":"The PI3K\/AKT Signaling Pathway:How Does It Regulate Development of Sertoli Cells and Spermatogenic Cells?","volume":"37","author":"Chen K. Q.","year":"2022","journal-title":"Histology and Histopathology"},{"issue":"7","key":"e_1_2_8_74_1","doi-asserted-by":"crossref","first-page":"412","DOI":"10.31083\/ph.2019.9373","article-title":"Vitamin D Attenuates Lipopolysaccharide\u2010Induced Inflammatory Response in Endothelial Cells Through Inhibition of PI3K\/Akt\/NF\u2010\u03baB Signaling Pathway","volume":"74","author":"Zhou W.","year":"2019","journal-title":"Die Pharmazie"},{"key":"e_1_2_8_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2020.08.014"},{"key":"e_1_2_8_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2006.04.076"},{"key":"e_1_2_8_77_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2007.05.012"},{"key":"e_1_2_8_78_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-011-0691-9"},{"key":"e_1_2_8_79_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10787-017-0387-3"},{"key":"e_1_2_8_80_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules170910446"},{"key":"e_1_2_8_81_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2017.05.003"},{"key":"e_1_2_8_82_1","doi-asserted-by":"publisher","DOI":"10.1080\/21565562.2014.996025"},{"key":"e_1_2_8_83_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2019.01.033"},{"key":"e_1_2_8_84_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2014.02.010"},{"key":"e_1_2_8_85_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.48767"},{"key":"e_1_2_8_86_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2018.00763"},{"key":"e_1_2_8_87_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox12081559"},{"key":"e_1_2_8_88_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2003.04.006"},{"key":"e_1_2_8_89_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2012.05.011"},{"key":"e_1_2_8_90_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1939-4640.2001.tb02208.x"},{"key":"e_1_2_8_91_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12958-018-0406-2"},{"key":"e_1_2_8_92_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox10060837"},{"key":"e_1_2_8_93_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2020.115274"},{"key":"e_1_2_8_94_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2007.05.018"},{"key":"e_1_2_8_95_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.envpol.2019.113079"},{"key":"e_1_2_8_96_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202303167"}],"container-title":["Journal of Biochemical and Molecular Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbt.70548","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jbt.70548","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbt.70548","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:27:27Z","timestamp":1785436047000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jbt.70548"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,16]]},"references-count":95,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2025,11]]}},"alternative-id":["10.1002\/jbt.70548"],"URL":"https:\/\/doi.org\/10.1002\/jbt.70548","archive":["Portico"],"relation":{},"ISSN":["1095-6670","1099-0461"],"issn-type":[{"value":"1095-6670","type":"print"},{"value":"1099-0461","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,16]]},"assertion":[{"value":"2024-08-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-26","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70548"}}