{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T03:34:12Z","timestamp":1789097652421,"version":"build-2803163510"},"reference-count":63,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,7,11]],"date-time":"2022-07-11T00:00:00Z","timestamp":1657497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Cadmium, a ubiquitous environmental toxicant, disrupts testicular function and fertility. The dipeptidyl peptidase-4 inhibitor linagliptin has shown pronounced anti-inflammatory and anti-apoptotic features; however, its effects against cadmium-evoked testicular impairment have not been examined. Herein, the present study investigated targeting inflammation, apoptosis, and autophagy by linagliptin for potential modulation of cadmium-induced testicular dysfunction in rats. After 60 days of cadmium chloride administration (5 mg\/kg\/day, by gavage), testes, epididymis, and blood were collected for analysis. The present findings revealed that linagliptin improved the histopathological lesions, including spermatogenesis impairment and germ cell loss. Moreover, it improved sperm count\/motility and serum testosterone. The favorable effects of linagliptin were mediated by curbing testicular inflammation seen by dampening of HMGB1\/TLR4 pathway and associated lowering of nuclear NF-\u03baBp65. In tandem, linagliptin suppressed the activation of NLRP3 inflammasome\/caspase 1 axis with consequent lowering of the pro-inflammatory IL-1\u03b2 and IL-18. Jointly, linagliptin attenuated testicular apoptotic responses seen by Bax downregulation, Bcl-2 upregulation, and suppressed caspase 3 activity. With respect to autophagy, linagliptin enhanced the testicular autophagy flux seen by lowered accumulation of p62 SQSTM1 alongside upregulation of Beclin 1. The observed autophagy stimulation was associated with elevated AMPK (Ser487) phosphorylation and lowered mTOR (Ser2448) phosphorylation, indicating AMPK\/mTOR pathway activation. In conclusion, inhibition of testicular HMGB1\/TLR4\/NLRP3 pro-inflammatory axis and apoptosis alongside stimulation of autophagy were implicated in the favorable actions of linagliptin against cadmium-triggered testicular impairment.<\/jats:p>","DOI":"10.3390\/ph15070852","type":"journal-article","created":{"date-parts":[[2022,7,12]],"date-time":"2022-07-12T03:50:36Z","timestamp":1657597836000},"page":"852","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Repositioning Linagliptin for the Mitigation of Cadmium-Induced Testicular Dysfunction in Rats: Targeting HMGB1\/TLR4\/NLRP3 Axis and Autophagy"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4195-6901","authenticated-orcid":false,"given":"Hany H.","family":"Arab","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alzahraa A.","family":"Elhemiely","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Egyptian Drug Authority (EDA), Giza 12654, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3726-0386","authenticated-orcid":false,"given":"Azza A. K.","family":"El-Sheikh","sequence":"additional","affiliation":[{"name":"Basic Health Sciences Department, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9051-8262","authenticated-orcid":false,"given":"Hana J. Al","family":"Khabbaz","sequence":"additional","affiliation":[{"name":"Biochemistry Division, College of Pharmacy, Riyadh Elm University, P.O. Box 84891, Riyadh 11681, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9034-6624","authenticated-orcid":false,"given":"El-Shaimaa A.","family":"Arafa","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Health Sciences, Ajman University, Ajman 346, United Arab Emirates"},{"name":"Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman 346, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2118-0499","authenticated-orcid":false,"given":"Ahmed M.","family":"Ashour","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al Qura University, P.O. Box 13578, Makkah 21955, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5101-8011","authenticated-orcid":false,"given":"Ahmed M.","family":"Kabel","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta 31527, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed H.","family":"Eid","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Egyptian Drug Authority (EDA), Giza 12654, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.jes.2018.07.015","article-title":"Effects of environmental contaminants on fertility and reproductive health","volume":"77","author":"Ma","year":"2019","journal-title":"J. Environ. 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