{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:49:35Z","timestamp":1785905375739,"version":"3.56.0"},"reference-count":118,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"King Faisal University","award":["KFU261157"],"award-info":[{"award-number":["KFU261157"]}]},{"award":["KFU261157"],"award-info":[{"award-number":["KFU261157"]}],"id":[{"id":"https:\/\/ror.org\/00dn43547","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Diabetes mellitus (DM) induces significant endocrine disruption and oxidative stress (OS) within the testes, resulting in impaired spermatogenesis, increased sperm abnormalities, and compromised reproductive function. This study aimed to evaluate the combined protective effects of Semaglutide (SEM) combined with Carica papaya (papaya) juice against type 2 diabetes-induced testicular damage in rats. Forty adult male albino rats were divided into four experimental groups: a control group, a Streptozotocin (STZ)-induced diabetic group, a diabetic group treated with SEM (0.3 mg\/kg), and a diabetic group treated with SEM (0.3 mg\/kg) in combination with 10% papaya juice, administered for eight weeks. Statistically significant superiority over SEM alone was observed for selected endpoints; the findings primarily support the potential of papaya as a dose-sparing adjunct rather than demonstrating uniformly enhanced efficacy. They significantly improved systemic metabolic parameters, as evidenced by reduced fasting blood glucose (FBG) and glycated hemoglobin (HbA1c) levels and restoration of the lipid profile. Importantly, it also attenuated diabetes-induced testicular injury, as demonstrated by improved reproductive hormone levels, enhanced sperm parameters, restoration of antioxidant defenses, modulation of inflammatory and apoptotic signaling, and marked histopathological recovery of seminiferous tubular architecture. Antioxidant markers revealed a notable reduction in malondialdehyde (MDA) and cytochrome P450 2E1 (CYP2E1), along with significant increases in reduced glutathione, catalase (CAT), and superoxide dismutase (SOD). Furthermore, a marked modulation of key pro-inflammatory and pro-apoptotic mediators was observed, including forkhead box protein O1 (FOXO1), microRNA-155 (miR-155), tumor necrosis factor-alpha (TNF-\u03b1), nuclear factor kappa B cell subunit 1 (NF-\u03baB1), interleukin-6 (IL-6), caspase-3 (CASP3), and BCL2-Associated X Apoptosis Regulator (Bax), while a significant upregulation of sirtuin-1 (SIRT1), microRNA-34c (miR-34c), and B-cell lymphoma-2 (Bcl-2) was also detected. Histopathological assessments confirmed the restoration of normal testicular architecture in the treated groups. These findings indicate that the combination strategy may have the potential to achieve dose savings while maintaining efficacy comparable to the standard-dose SEM, through the enhancement of the antioxidant defenses, modulation of inflammation, and apoptosis, specifically via the modulation of the miR-34c\/miR-155 and SIRT1\/FOXO1 signaling.<\/jats:p>","DOI":"10.3390\/ijms27156956","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T12:57:56Z","timestamp":1785761876000},"page":"6956","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Can Carica papaya Serve as an Adjunct to Semaglutide in Mitigating Diabetes-Induced Testicular Injury Through Modulation of Oxidative Stress, Inflammation, Apoptosis, and the miR-34c\/miR-155\u2013SIRT1\/FOXO1 Axis? An Experimental and Chem-Bio-Informatics Study"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-0997-0695","authenticated-orcid":false,"given":"Mohamed M.","family":"Zeweil","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4235-669X","authenticated-orcid":false,"given":"Asmaa F.","family":"Khafaga","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3425-0898","authenticated-orcid":false,"given":"Marium M.","family":"Shamaa","sequence":"additional","affiliation":[{"name":"Biochemistry Department, Clinical and Biological Sciences Division, College of Pharmacy, Arab Academy for Science Technology and Maritime Transport, Alexandria 1029, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2148-6444","authenticated-orcid":false,"given":"Wafaa Abdelaziz","family":"Emam","sequence":"additional","affiliation":[{"name":"Medical Biochemistry Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo 11884, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8876-0925","authenticated-orcid":false,"given":"Amena Rezk","family":"Mohammed","sequence":"additional","affiliation":[{"name":"Medical Biochemistry Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo 11884, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwa Hassan","family":"Sedira","sequence":"additional","affiliation":[{"name":"Medical Biochemistry Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo 11884, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7599-225X","authenticated-orcid":false,"given":"Safa H.","family":"Qahl","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, College of Science, University of Jeddah, P.O. Box 80327, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9401-4996","authenticated-orcid":false,"given":"Fatma EL-Zahraa Abd","family":"El-Hakam","sequence":"additional","affiliation":[{"name":"Pharmacology Department, Faculty of Medicine for Girls, Al-Azhar University, Nasr City, Cairo 11884, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2888-2618","authenticated-orcid":false,"given":"Shih-Min","family":"Hsia","sequence":"additional","affiliation":[{"name":"School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 110301, Taiwan"},{"name":"School of Food Safety, Taipei Medical University, Taipei 110301, Taiwan"},{"name":"Nutrition Research Center, Taipei Medical University Hospital, Taipei 110301, Taiwan"},{"name":"Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei 110301, Taiwan"},{"name":"TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei 110301, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2105-107X","authenticated-orcid":false,"given":"Nadia M.","family":"Hamdy","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1089\/jir.2013.0059","article-title":"The serine protease granzyme B as an inflammatory marker, in relation to the insulin receptor cleavage in human obesity and type 2 diabetes mellitus","volume":"34","author":"Hamdy","year":"2014","journal-title":"J. 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