{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:34:49Z","timestamp":1790793289912,"version":"4.1.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T00:00:00Z","timestamp":1669248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004242","name":"Princess Nourah Bint Abdulrahman University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004242","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Hypothyroidism has been linked to many testicular structural and dysfunctional changes in males. Thymoquinone (TQ) has shown a potent testicular protective effect through its antioxidant, anti-inflammatory, antiapoptotic, fertility-enhancing, and endocrine modulatory activities.<\/jats:p><jats:p><jats:bold>Objectives:<\/jats:bold> This study aimed to investigate the efficacy of TQ in preserving the testicular structure of a model of experimentally induced hypothyroidism in rats and identify the mechanism behind this effect.<\/jats:p><jats:p><jats:bold>Materials and methods:<\/jats:bold> Propylthiouracil (PTU) was used to induce hypothyroidism in adult male Wistar rats, who were then treated with TQ (50\u00a0mg\/kg\/body weight) for 4\u00a0weeks and compared to the untreated rats. Thyroid hormonal profile, oxidants\/antioxidants profile, and serum testosterone levels were assessed. Gene expression and immune expression of SIRT1 and pro-inflammatory cytokines TNF-\u03b1 and NF-\u03baB were also assessed in the testicular tissue.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> TQ administration successfully improved PTU-induced disturbance in the thyroid hormonal profile (T3, T4, and TSH), serum testosterone level, and pancreatic antioxidants compared to the untreated hypothyroid group. TQ significantly downregulated (<jats:italic>p<\/jats:italic> = 0.001, <jats:italic>p<\/jats:italic> \u02c2 0.001) TNF-\u03b1 and NF-\u03baB transcription, while it significantly upregulated (<jats:italic>p<\/jats:italic> = 0.01) SIRT1 transcription in the testes of hypothyroid rats. TQ markedly relieved the histopathological testicular changes induced by PTU and significantly increased (<jats:italic>p<\/jats:italic> = 0.002, <jats:italic>p<\/jats:italic> = 0.01) the sectional area of seminiferous tubules and germinal epithelial height, respectively. TUNEL-positive apoptotic germinal cells were significantly decreased (<jats:italic>p<\/jats:italic> \u02c2 0.001), while PCNA-positive proliferating germinal cells and androgen receptor expression were significantly increased (<jats:italic>p<\/jats:italic> \u02c2 0.001) in the testes of TQ-treated hypothyroid rats.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Thymoquinone could limit the hypothyroidism-induced structural changes in the testis, mostly through the upregulation of SIRT1 expression, which seems to mediate its promising antioxidant, anti-inflammatory and antiapoptotic effects that were evident in this study. Therefore, TQ is recommended as an adjuvant safe supplement in managing hypothyroidism, especially in males.<\/jats:p>","DOI":"10.3389\/fphar.2022.1040857","type":"journal-article","created":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T21:57:02Z","timestamp":1669327022000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["Thymoquinone protects the testes of hypothyroid rats by suppressing pro-inflammatory cytokines and oxidative stress and promoting SIRT1 testicular expression"],"prefix":"10.3389","volume":"13","author":[{"given":"Sami A.","family":"Algaidi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khadija A.","family":"Faddladdeen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghadeer I.","family":"Alrefaei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Safa H.","family":"Qahl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emad A.","family":"Albadawi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailah M.","family":"ALmohaimeed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nasra N.","family":"Ayuob","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e14368","DOI":"10.1111\/and.14368","article-title":"Oral thymoquinone modulates cyclophosphamide\u2010induced testicular toxicity in adolescent Wistar rats","volume":"54","author":"Adana","year":"2022","journal-title":"Andrologia"},{"key":"B2","doi-asserted-by":"publisher","first-page":"100404","DOI":"10.1016\/j.hermed.2020.100404","article-title":"An updated knowledge of Black seed (Nigella sativa Linn.): Review of phytochemical constituents and pharmacological properties","volume":"25","author":"Ahmad","year":"2021","journal-title":"J. Herb. Med."},{"key":"B3","doi-asserted-by":"publisher","first-page":"248","DOI":"10.16965\/ijims.2016.109","article-title":"Effect of Nigella sativa seed and thymoquinone on reproductive parameters in sterptozotocine induced diabetic and normal male albino rats","volume":"3","author":"Aithal","year":"2016","journal-title":"Int. J. Intg Med. Sci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/s12902-019-0350-y","article-title":"The expression of sirtuins, superoxide dismutase, and lipid peroxidation status in peripheral blood from patients with diabetes and hypothyroidism","volume":"19","author":"Al-Khaldi","year":"2019","journal-title":"BMC Endocr. Disord."},{"key":"B5","first-page":"158","article-title":"Pharmacology of free radicals and the impact of reactive oxygen species on the testis","volume":"14","author":"Aprioku","year":"2013","journal-title":"J. Reprod. Infertil."},{"key":"B6","doi-asserted-by":"publisher","first-page":"3495","DOI":"10.1242\/dev.110627","article-title":"SirT1 is required in the male germ cell for differentiation and fecundity in mice","volume":"141","author":"Bell","year":"2014","journal-title":"Development"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e33258","DOI":"10.1371\/journal.pone.0033258","article-title":"Hypoxia inducible factor 1-alpha (HIF-1 alpha) is induced during reperfusion after renal ischemia and is critical for proximal tubule cell survival","volume":"7","author":"Conde","year":"2012","journal-title":"PloS one"},{"key":"B8","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1530\/JOE-12-0420","article-title":"Thyroid hormone regulation of Sirtuin 1 expression and implications to integrated responses in fasted mice","volume":"216","author":"Cordeiro","year":"2013","journal-title":"J. Endocrinol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1111\/j.1439-0272.2011.01245.x","article-title":"Expression of inducible nitric oxide synthase (iNOS) in the azoospermic human testis","volume":"44","author":"Co\u015ftur","year":"2012","journal-title":"Andrologia"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e1571","DOI":"10.1371\/journal.pone.0001571","article-title":"Sirt1 deficiency attenuates spermatogenesis and germ cell function","volume":"3","author":"Coussens","year":"2008","journal-title":"PloS one"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1943","DOI":"10.1111\/asj.12883","article-title":"Effects of hyper\u2010and hypothyroidism on the development and proliferation of testicular cells in prepubertal rats","volume":"88","author":"Fadlalla","year":"2017","journal-title":"Animal Sci. J."},{"key":"B12","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1080\/19396368.2019.1626933","article-title":"Thymoquinone ameliorates obesity-induced metabolic dysfunction, improves reproductive efficiency exhibiting a dose-organ relationship","volume":"65","author":"Harphoush","year":"2019","journal-title":"Syst. Biol. Reprod. Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.lfs.2019.05.067","article-title":"Thymoquinone attenuates testicular and spermotoxicity following subchronic lead exposure in male rats: Possible mechanisms are involved","volume":"230","author":"Hassan","year":"2019","journal-title":"Life Sci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"41","DOI":"10.21608\/ZUMJ.2018.192417","article-title":"Effect of experimentally induced hypothyroidism on structure of adult albino rats\u2019 testes and possible protective role of L-carnitine","volume":"24","author":"Hegazy","year":"2018","journal-title":"Zagazig Univ. Med. J."},{"key":"B15","doi-asserted-by":"publisher","first-page":"R33","DOI":"10.1530\/JOE-19-0550","article-title":"Thyroid hormone action in the developing testis: Intergenerational epigenetics","volume":"244","author":"Hernandez","year":"2020","journal-title":"J. Endocrinol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"42995","DOI":"10.1038\/srep42995","article-title":"Thymoquinone: An IRAK1 inhibitor with in vivo and in vitro anti-inflammatory activities","volume":"7","author":"Hossen","year":"2017","journal-title":"Sci. Rep."},{"key":"B17","doi-asserted-by":"publisher","first-page":"352","DOI":"10.5603\/FM.a2020.0071","article-title":"Hypothyroidism: Morphological and metabolic changes in the testis of adult albino rat and the amelioration by alpha-lipoic acid","volume":"80","author":"Ibrahim","year":"2021","journal-title":"Folia Morphol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4236\/cm.2014.51003","article-title":"Can Nigella sativa oil (NSO) reverse hypothyroid status induced by PTU in rat? Biochemical and histological studies","volume":"10","author":"Khalawi","year":"2013","journal-title":"Life Sci. J."},{"key":"B19","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1002\/jcph.1507","article-title":"The impact of testosterone on metformin action on hypothalamic\u2010pituitary\u2010thyroid axis activity in men: A pilot study","volume":"60","author":"Krysiak","year":"2020","journal-title":"J. Clin. Pharmacol."},{"key":"B20","first-page":"77","article-title":"Correction of androgen deficiency in men with hypothyroidism","author":"Krytskyy","year":"2019","journal-title":"Georgian Med. News"},{"key":"B21","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1007\/s12020-017-1303-8","article-title":"Impact of thyroid disease on testicular function","volume":"58","author":"La Vignera","year":"2017","journal-title":"Endocrine"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2058738418775241","DOI":"10.1177\/2058738418775241","article-title":"Thyroid dysfunction and semen quality","volume":"32","author":"La Vignera","year":"2018","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"6757154","DOI":"10.1155\/2016\/6757154","article-title":"Thyroid hormones, oxidative stress, and inflammation","volume":"2016","author":"Mancini","year":"2016","journal-title":"Mediat. Inflamm."},{"key":"B24","doi-asserted-by":"publisher","first-page":"87","DOI":"10.2108\/zsj.19.87","article-title":"PCNA protein expression during spermatogenesis of the Japanese eel (Anguilla japonica)","volume":"19","author":"Miura","year":"2002","journal-title":"Zool. Sci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1891","DOI":"10.23812\/19-334-L","article-title":"Inflammatory markers as prognosticators of cardiovascular dysfunction in hypothyroid patients","volume":"33","author":"Naseem","year":"2019","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"B27","doi-asserted-by":"publisher","first-page":"3","DOI":"10.2174\/1872211311666171129121128","article-title":"Thymoquinone a potential therapeutic molecule from the plant Nigella sativa: Role of colloidal carriers in its effective delivery","volume":"12","author":"Negi","year":"2018","journal-title":"Recent Pat. Drug Deliv. Formul."},{"key":"B28","doi-asserted-by":"publisher","first-page":"e2763","DOI":"10.3791\/2763","article-title":"DNA extraction from paraffin embedded material for genetic and epigenetic analyses","author":"Pikor","year":"2011","journal-title":"J. Vis. Exp."},{"key":"B29","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1097\/01.ehx.0000418020.81995.dc","article-title":"Acrylamide-mediated subacute testicular and genotoxicity, is it reversible?","volume":"35","author":"Rajeh","year":"2012","journal-title":"Egypt. J. Histology"},{"key":"B30","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.ygcen.2007.11.007","article-title":"Hypothyroidism impairs antioxidant defence system and testicular physiology during development and maturation","volume":"156","author":"Sahoo","year":"2008","journal-title":"Gen. Comp. Endocrinol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.cbi.2011.02.029","article-title":"Thymoquinone ameliorates chemical induced oxidative stress and \u03b2-cell damage in experimental hyperglycemic rats","volume":"190","author":"Sankaranarayanan","year":"2011","journal-title":"Chem. Biol. Interact."},{"key":"B32","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.vph.2015.03.005","article-title":"The role of oxidative stress, antioxidants and vascular inflammation in cardiovascular disease (a review)","volume":"71","author":"Siti","year":"2015","journal-title":"Vasc. Pharmacol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"e70097","DOI":"10.1371\/journal.pone.0070097","article-title":"SIRT1 is a direct coactivator of thyroid hormone receptor \u03b21 with gene-specific actions","volume":"8","author":"Suh","year":"2013","journal-title":"PLoS One"},{"key":"B34","doi-asserted-by":"publisher","first-page":"179","DOI":"10.3831\/KPI.2017.20.021","article-title":"Review on clinical trials of black seed (Nigella sativa ) and its active constituent, thymoquinone","volume":"20","author":"Tavakkoli","year":"2017","journal-title":"J. Pharmacopuncture"},{"key":"B35","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1007\/s13105-017-0576-y","article-title":"Multi-regulatory network of ROS: The interconnection of ROS, PGC-1 alpha, and AMPK-SIRT1 during exercise","volume":"73","author":"Thirupathi","year":"2017","journal-title":"J. Physiol. Biochem."},{"key":"B36","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-319-72102-6_6","article-title":"Epidemiology of thyroid disorders","volume-title":"The thyroid and its diseases: A comprehensive guide for the clinician","author":"Vanderpump","year":"2019"},{"key":"B37","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/s0921-4488(97)00130-2","article-title":"Effect of propylthiouracil-induced hypothyroidism on thyroid hormone profiles and tissue deiodinase activity in cashmere goats","volume":"29","author":"Villar","year":"1998","journal-title":"Small ruminant Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/b978-0-12-824462-3.00001-9","article-title":"Therapeutic effects of Nigella sativa on hormonal dysfunctions","volume":"2022","author":"Wani","year":"2022","journal-title":"Black Seeds (Nigella sativa)"},{"key":"B40","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1038\/sj.ijir.3901346","article-title":"Activity of single components of Ferula hermonis on male rat sexual behavior","volume":"17","author":"Zanoli","year":"2005","journal-title":"Int. J. Impot. Res."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.1040857\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T21:57:07Z","timestamp":1669327027000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.1040857\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,24]]},"references-count":38,"alternative-id":["10.3389\/fphar.2022.1040857"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.1040857","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,24]]},"article-number":"1040857"}}