{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T11:22:39Z","timestamp":1793618559393,"version":"4.5.0"},"reference-count":73,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T00:00:00Z","timestamp":1666137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"King Saud University","award":["RSP2022R502"],"award-info":[{"award-number":["RSP2022R502"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Cis-diamminedichloroplatinum (II) (CDDP) is a widely used antineoplastic agent with numerous associated side effects. We investigated the mechanisms of action of the indole derivative N\u2019-(4-dimethylaminobenzylidene)-2-1-(4-(methylsulfinyl) benzylidene)-5-fluoro-2-methyl-1H-inden-3-yl) acetohydrazide (MMINA) to protect against CDDP-induced testicular damage. Five groups of rats (n = 7) were treated with saline, DMSO, CDDP, CDDP + MMINA, or MMINA. Reproductive hormones, antioxidant enzyme activity, histopathology, daily sperm production, and oxidative stress markers were examined. Western blot analysis was performed to access the expression of steroidogenic acute regulatory protein (StAR) and inflammatory biomarker expression in testis, while expression of calcium-dependent cation channel of sperm (CatSper) in epididymis was examined. The structural and dynamic molecular docking behavior of MMINA was analyzed using bioinformatics tools. The construction of molecular interactions was performed through KEGG, DAVID, and STRING databases. MMINA treatment reversed CDDP-induced nitric oxide (NO) and malondialdehyde (MDA) augmentation, while boosting the activity of glutathione peroxidase (GPx) and superoxide dismutase (SOD) in the epididymis and testicular tissues. CDDP treatment significantly lowered sperm count, sperm motility, and epididymis sperm count. Furthermore, CDDP reduced epithelial height and tubular diameter and increased luminal diameter with impaired spermatogenesis. MMINA rescued testicular damage caused by CDDP. MMINA rescued CDDP-induced reproductive dysfunctions by upregulating the expression of the CatSper protein, which plays an essential role in sperm motility, MMINA increased testosterone secretion and StAR protein expression. MMINA downregulated the expression of NF-\u03baB, STAT-3, COX-2, and TNF-\u03b1. Hydrogen bonding and hydrophobic interactions were predicted between MMINA and 3\u03b2-HSD, CatSper, NF-\u03ba\u03b2, and TNF\u03b1. Molecular interactome outcomes depicted the formation of one hydrogen bond and one hydrophobic interaction between 3\u03b2-HSD that contributed to its strong binding with MMINA. CatSper also made one hydrophobic interaction and one hydrogen bond with MMINA but with a lower binding affinity of -7.7 relative to 3\u03b2-HSD, whereas MMINA made one hydrogen bond with NF-\u03ba\u03b2 residue Lys37 and TNF-\u03b1 reside His91 and two hydrogen bonds with Lys244 and Thr456 of STAT3. Our experimental and in silico results revealed that MMINA boosted the antioxidant defense mechanism, restored the levels of fertility hormones, and suppressed histomorphological alterations.<\/jats:p>","DOI":"10.3390\/antiox11102063","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T20:32:23Z","timestamp":1666211543000},"page":"2063","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Prevention of Testicular Damage by Indole Derivative MMINA via Upregulated StAR and CatSper Channels with Coincident Suppression of Oxidative Stress and Inflammation: In Silico and In Vivo Validation"],"prefix":"10.3390","volume":"11","author":[{"given":"Tayyaba","family":"Afsar","sequence":"first","affiliation":[{"name":"Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 12372, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suhail","family":"Razak","sequence":"additional","affiliation":[{"name":"Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 12372, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3597-2611","authenticated-orcid":false,"given":"Janeen H.","family":"Trembley","sequence":"additional","affiliation":[{"name":"Minneapolis VA Health Care System Research Service, Minneapolis, MN 55455, USA"},{"name":"Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA"},{"name":"Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9946-9057","authenticated-orcid":false,"given":"Khushbukhat","family":"Khan","sequence":"additional","affiliation":[{"name":"Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad 44000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5685-3059","authenticated-orcid":false,"given":"Maria","family":"Shabbir","sequence":"additional","affiliation":[{"name":"Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad 44000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Almajwal","sequence":"additional","affiliation":[{"name":"Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 12372, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3375-8796","authenticated-orcid":false,"given":"Nawaf W.","family":"Alruwaili","sequence":"additional","affiliation":[{"name":"Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 12372, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Umar","family":"Ijaz","sequence":"additional","affiliation":[{"name":"Department of Zoology, Wildlife, and Fisheries, University of Agriculture, Faisalabad 38040, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.ejphar.2014.07.025","article-title":"Cisplatin in cancer therapy: Molecular mechanisms of action","volume":"740","author":"Dasari","year":"2014","journal-title":"Eur. 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