{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T17:55:05Z","timestamp":1793382905400,"version":"4.5.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T00:00:00Z","timestamp":1742947200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Periodontitis is a chronic inflammatory disease closely associated with mitochondrial dysfunction. Uncoupling protein 2 (UCP2), located in the inner membrane of mitochondria, reduces mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) synthesis by promoting proton leakage across the membrane. This leads to decreased energy metabolism efficiency, impairing cellular glucose uptake, and disrupting intracellular energy balance. Genipin (GP), a recognized UCP2 inhibitor, exhibits anti-inflammatory and antioxidant properties. This study aimed to investigate the specific role of GP in periodontal tissue redox signaling and the potential mechanism of UCP2 in the development of periodontitis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we constructed a model of H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>-induced oxidative stress in human periodontal ligament cells (hPDLCs). <jats:italic>In vivo<\/jats:italic>, a rat periodontitis model was established to evaluate the effects and mechanisms of GP in alleviating oxidative damage in periodontal tissues and cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Cell experiments showed that GP effectively alleviated H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>-induced mitochondrial dysfunction and oxidative damage in hPDLCs by inhibiting UCP2 expression and function, restoring cell viability, and reducing cell apoptosis. Additionally, GP intervention increased the expression of glucose transporter 4 (GLUT4), thereby promoting cellular glucose uptake. The results of animal experiments demonstrated that GP intervention reduced alveolar bone resorption and periodontal tissue destruction in rats with periodontitis, inhibited osteoclast differentiation, improved mitochondrial dysfunction in periodontal tissue, promoted GLUT4 expression, and reduced oxidative stress levels and cell apoptosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>GP regulates oxidative damage in periodontal tissues by maintaining mitochondrial homeostasis, promoting glucose transporter expression, and enhancing glucose uptake, with UCP2 playing a central role.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1446574","type":"journal-article","created":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T08:22:53Z","timestamp":1742977373000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Genipin attenuates oxidative damage in periodontal tissues by alleviating mitochondrial dysfunction and abnormal glucose uptake through inhibition of UCP2"],"prefix":"10.3389","volume":"16","author":[{"given":"Yu","family":"Deng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruobing","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqi","family":"Shang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengting","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xirui","family":"Xin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubo","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weixian","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinchan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1038\/82565","article-title":"Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production","volume":"26","author":"Arsenijevic","year":"2000","journal-title":"Nat. Genet."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1432","DOI":"10.1902\/jop.2014.130654","article-title":"Lipid peroxidation levels and total oxidant\/antioxidant status in serum and saliva from patients with chronic and aggressive periodontitis. Oxidative stress index: a new biomarker for periodontal disease?","volume":"85","author":"Baltac\u0131o\u011flu","year":"2014","journal-title":"J. Periodontol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"5672","DOI":"10.3390\/ijms23105672","article-title":"Uncoupling proteins as therapeutic targets for neurodegenerative diseases","volume":"23","author":"Barnstable","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1038\/s41580-019-0173-8","article-title":"Mitochondria as multifaceted regulators of cell death","volume":"21","author":"Bock","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1019405","DOI":"10.3389\/fendo.2022.1019405","article-title":"Ubiquitin-like processing of TUG proteins as a mechanism to regulate glucose uptake and energy metabolism in fat and muscle","volume":"13","author":"Bogan","year":"2022","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1221053","DOI":"10.3389\/fphar.2023.1221053","article-title":"18-\u03b1-glycyrrhetinic acid alleviates oxidative damage in periodontal tissue by modulating the interaction of Cx43 and JNK\/NF-\u03baB pathways","volume":"14","author":"Cao","year":"2023","journal-title":"Front. Pharmacol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"102694","DOI":"10.1016\/j.conb.2023.102694","article-title":"Metabolic defects shared by Alzheimer's disease and diabetes: a focus on mitochondria","volume":"79","author":"Carvalho","year":"2023","journal-title":"Curr. Opin. Neurobiol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.freeradbiomed.2019.03.027","article-title":"Mitochondria and oxidative stress in ovarian endometriosis","volume":"136","author":"Chen","year":"","journal-title":"Free Radic. Biol. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1111\/jcpe.13112","article-title":"Oxidative stress-related biomarkers in saliva and gingival crevicular fluid associated with chronic periodontitis: a systematic review and meta-analysis","volume":"46","author":"Chen","year":"","journal-title":"J. Clin. Periodontol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"e324","DOI":"10.1002\/ctm2.324","article-title":"IL-22-mediated renal metabolic reprogramming via PFKFB3 to treat kidney injury","volume":"11","author":"Chen","year":"2021","journal-title":"Clin. Transl. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1016\/j.bbrc.2018.12.143","article-title":"Mitochondrial abnormalities are involved in periodontal ligament fibroblast apoptosis induced by oxidative stress","volume":"509","author":"Chen","year":"","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B12","doi-asserted-by":"publisher","first-page":"5637","DOI":"10.3390\/ijms23105637","article-title":"Genipin, an inhibitor of UCP2 as a promising new anticancer agent: a review of the literature","volume":"23","author":"Cho","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.molmed.2011.08.003","article-title":"Mitochondrial uncoupling protein 2 (UCP2) in glucose and lipid metabolism","volume":"18","author":"Diano","year":"2012","journal-title":"Trends Mol. Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1111\/jre.13071","article-title":"The role of Sirt3-induced autophagy in renal structural damage caused by periodontitis in rats","volume":"58","author":"Ding","year":"2022","journal-title":"J. Periodontal Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1016\/j.adaj.2018.04.023","article-title":"Periodontitis in US adults: national health and nutrition examination survey 2009-2014","volume":"149","author":"Eke","year":"2018","journal-title":"J. Am. Dent. Assoc."},{"key":"B16","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1016\/j.molcel.2023.02.022","article-title":"HK2: gatekeeping microglial activity by tuning glucose metabolism and mitochondrial functions","volume":"83","author":"Fang","year":"2023","journal-title":"Mol. Cell"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1604","DOI":"10.1167\/iovs.19-26553","article-title":"Enhancing retinal endothelial glycolysis by inhibiting UCP2 promotes physiologic retinal vascular development in a model of retinopathy of prematurity","volume":"60","author":"Han","year":"2019","journal-title":"Invest Ophthalmol. Vis. Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"322","DOI":"10.3390\/antiox11020322","article-title":"The uncoupling proteins: a systematic review on the mechanism used in the prevention of oxidative stress","volume":"11","author":"Hirschenson","year":"2022","journal-title":"Antioxidants (Basel)"},{"key":"B19","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1146\/annurev-physiol-042222-025000","article-title":"Mitochondrial dysfunction in kidney tubulopathies","volume":"86","author":"Hoogstraten","year":"2024","journal-title":"Annu. Rev. Physiol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1111\/jre.13152","article-title":"The role of mitochondrial dysfunction in periodontitis: from mechanisms to therapeutic strategy","volume":"58","author":"Jiang","year":"2023","journal-title":"J. Periodontal Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1055\/s-2004-825752","article-title":"Glucose catabolic gene mRNA levels in skeletal muscle exhibit non-coordinate expression in hyperglycemic mice","volume":"36","author":"Kato","year":"2004","journal-title":"Horm. Metab. Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.jare.2023.08.015","article-title":"Triad3A-Mediated K48-Linked ubiquitination and degradation of TLR9 impairs mitochondrial bioenergetics and exacerbates diabetic cardiomyopathy","volume":"61","author":"Kong","year":"2024","journal-title":"J. Adv. Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"552","DOI":"10.3390\/cells9030552","article-title":"Alterations in glucose metabolism during the transition to heart failure: the contribution of UCP-2","volume":"9","author":"Kutsche","year":"2020","journal-title":"Cells"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1230","DOI":"10.1038\/s41598-022-05398-2","article-title":"Intracellular glucose starvation affects gingival homeostasis and autophagy","volume":"12","author":"Li","year":"","journal-title":"Sci. Rep."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1812","DOI":"10.1111\/odi.14148","article-title":"Resveratrol protects renal damages induced by periodontitis via preventing mitochondrial dysfunction in rats","volume":"29","author":"Li","year":"","journal-title":"Oral Dis."},{"key":"B26","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1111\/jre.13158","article-title":"Roles of trained immunity in the pathogenesis of periodontitis","volume":"58","author":"Li","year":"2023","journal-title":"J. Periodontal Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1007\/s10787-019-00639-9","article-title":"Genipin attenuates dextran sulfate sodium-induced colitis via suppressing inflammatory and oxidative responses","volume":"28","author":"Li","year":"2020","journal-title":"Inflammopharmacology"},{"key":"B28","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/s41368-023-00269-6","article-title":"Sema3A secreted by sensory nerve induces bone formation under mechanical loads","volume":"16","author":"Mei","year":"2024","journal-title":"Int. J. Oral Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1111\/jcpe.12662","article-title":"Cross-sectional associations of impaired glucose metabolism measures with bleeding on probing and periodontitis","volume":"44","author":"P\u00e9rez","year":"2017","journal-title":"J. Clin. Periodontol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e13674","DOI":"10.1111\/acel.13674","article-title":"Mitochondrial uncoupling protein-2 reprograms metabolism to induce oxidative stress and myofibroblast senescence in age-associated lung fibrosis","volume":"21","author":"Rangarajan","year":"2022","journal-title":"Aging Cell"},{"key":"B31","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1111\/prd.12342","article-title":"Periodontitis is an inflammatory disease of oxidative stress: we should treat it that way","volume":"84","author":"Sczepanik","year":"2020","journal-title":"Periodontol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.freeradbiomed.2021.05.031","article-title":"Crosstalk between reactive oxygen species and Dynamin-related protein 1 in periodontitis","volume":"172","author":"Shi","year":"2021","journal-title":"Free Radic. Biol. Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1016\/j.biochi.2014.10.008","article-title":"Genipin inhibits MMP-1 and MMP-3 release from TNF-a-stimulated human periodontal ligament cells","volume":"107","author":"Shindo","year":"2014","journal-title":"Biochimie"},{"key":"B34","doi-asserted-by":"publisher","first-page":"155596","DOI":"10.1016\/j.phymed.2024.155596","article-title":"Genipin ameliorates diabetic retinopathy via the HIF-1\u03b1 and AGEs-RAGE pathways","volume":"129","author":"Sun","year":"2024","journal-title":"Phytomedicine"},{"key":"B35","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1111\/jcpe.12711","article-title":"Mitochondrial dysfunction is involved in the aggravation of periodontitis by diabetes","volume":"44","author":"Sun","year":"2017","journal-title":"J. Clin. Periodontol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1111\/jcpe.13811","article-title":"Activation of PGC-1\u03b1-dependent mitochondrial biogenesis supports therapeutic effects of silibinin against type I diabetic periodontitis","volume":"50","author":"Sun","year":"2023","journal-title":"J. Clin. Periodontol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.3389\/fphys.2018.01060","article-title":"Uncoupling protein 2 in cardiovascular health and disease","volume":"9","author":"Tian","year":"2018","journal-title":"Front. Physiol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1016\/j.cell.2016.02.010","article-title":"UCP2 regulates mitochondrial fission and ventromedial nucleus control of glucose responsiveness","volume":"164","author":"Toda","year":"2016","journal-title":"Cell"},{"key":"B39","doi-asserted-by":"publisher","first-page":"910","DOI":"10.3389\/fphys.2017.00910","article-title":"Oxidative stress and antioxidant system in periodontitis","volume":"8","author":"Wang","year":"2017","journal-title":"Front. Physiol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s12958-020-00679-9","article-title":"Genipin improves reproductive health problems caused by circadian disruption in male mice","volume":"18","author":"Xu","year":"2020","journal-title":"Reprod. Biol. Endocrinol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1012","DOI":"10.1111\/odi.13616","article-title":"The role of TLR4\/MyD88\/NF-\u03baB pathway in periodontitis-induced liver inflammation of rats","volume":"27","author":"Yue","year":"2021","journal-title":"Oral Dis."},{"key":"B42","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/j.cmet.2006.04.010","article-title":"Genipin inhibits UCP2-mediated proton leak and acutely reverses obesity- and high glucose-induced beta cell dysfunction in isolated pancreatic islets","volume":"3","author":"Zhang","year":"2006","journal-title":"Cell Metab."},{"key":"B43","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1186\/s13018-021-02210-1","article-title":"Genipin and insulin combined treatment improves implant osseointegration in type 2 diabetic rats","volume":"16","author":"Zhang","year":"2021","journal-title":"J. Orthop. Surg. Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1186\/s10020-022-00552-y","article-title":"AAV-ie-mediated UCP2 overexpression accelerates inner hair cell loss during aging in vivo","volume":"28","author":"Zhao","year":"2022","journal-title":"Mol. Med."},{"key":"B45","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1038\/s41392-024-01839-8","article-title":"Mitochondrial dysfunction: mechanisms and advances in therapy","volume":"9","author":"Zong","year":"2024","journal-title":"Signal Transduct. Target Ther."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1446574\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T08:22:57Z","timestamp":1742977377000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1446574\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,26]]},"references-count":45,"alternative-id":["10.3389\/fphar.2025.1446574"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1446574","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,26]]},"article-number":"1446574"}}