{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:37:24Z","timestamp":1787027844714,"version":"build-2736575974"},"reference-count":31,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,16]],"date-time":"2025-08-16T00:00:00Z","timestamp":1755302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Augusta University","award":["R01DE033982"],"award-info":[{"award-number":["R01DE033982"]}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research (NIDCR) of the National Institutes of Health (NIH)","doi-asserted-by":"publisher","award":["R01DE033982"],"award-info":[{"award-number":["R01DE033982"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Adenosine signaling plays protective roles in gingival mitochondrial health and inflammation control, with the ectoenzyme CD73 implicated in periodontitis. Here, we investigated the effects of selective adenosine A2a receptor (A2aR) stimulation using the agonist CGS21680 in a mouse model of ligature-induced periodontitis (LIP) and in gingival fibroblast mitochondrial function. Mature C57Bl\/6 mice underwent LIP and received daily intraperitoneal injections of CGS21680 (0.1 mg\/Kg) or saline. After 8 days, gingival tissues and maxillae were analyzed for alveolar bone loss and Il-1\u03b2 levels. In parallel, murine gingival fibroblasts (mGFs) were treated with Tnf-\u03b1 (5 ng\/mL) \u00b1 CGS21680 (10 \u00b5M) to assess mitochondrial function, morphology, and quality control. A2aR activation significantly reduced alveolar bone loss and Il-1\u03b2 expression in vivo. In vitro, CGS21680 suppressed Tnf-\u03b1-induced Cxcl10 and Cxcl12 expressions and enhanced Vegf production. Mitochondrial analysis revealed increased mitochondrial complex levels, membrane potential, and mass, alongside reduced reactive oxygen species (ROS), proton leak, and mitochondrial stress. Ultrastructural studies showed elongated, healthier mitochondria and increased pro-fusion markers, indicating enhanced mitochondrial quality control. Overall, A2aR stimulation attenuates periodontal inflammation and confers mitoprotective effects on gingival fibroblasts, supporting its potential as a therapeutic strategy to both mitigate periodontitis progression and preserve tissue bioenergetics supporting cellular resilience.<\/jats:p>","DOI":"10.3390\/cells14161266","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T07:53:12Z","timestamp":1755503592000},"page":"1266","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Adenosine A2a Receptor Stimulation Mitigates Periodontitis and Is Mitoprotective in Gingival Fibroblasts Promoting Cellular Resilience"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4749-571X","authenticated-orcid":false,"given":"A. C.","family":"Morandini","sequence":"first","affiliation":[{"name":"Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Dawson","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N.","family":"Paladines","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N.","family":"Adams","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0228-4257","authenticated-orcid":false,"given":"E. S.","family":"Ramos-Junior","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1111\/j.1600-0757.1997.tb00190.x","article-title":"The microbial challenge in periodontitis","volume":"14","author":"Darveau","year":"1997","journal-title":"Periodontol. 2000"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Duran-Pinedo, A., Solbiati, J.O., Teles, F., Yanping, Z., and Frias-Lopez, J. (2025). Longitudinal host-microbiome dynamics of metatranscription identify hallmarks of progression in periodontitis. Microbiome, 13.","DOI":"10.1186\/s40168-025-02108-8"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1111\/prd.12169","article-title":"Host modulation: Controlling the inflammation to control the infection","volume":"75","author":"Bartold","year":"2017","journal-title":"Periodontol. 2000"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/prd.12296","article-title":"The role of the microbiota in periodontal disease","volume":"83","author":"Curtis","year":"2020","journal-title":"Periodontol. 2000"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3989","DOI":"10.1210\/jc.2007-2522","article-title":"Association of the metabolic syndrome with severe periodontitis in a large U.S. population-based survey","volume":"93","author":"Sabbah","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Marruganti, C., Suvan, J.E., and D\u2019Aiuto, F. (2023). Periodontitis and metabolic diseases (diabetes and obesity): Tackling multimorbidity. Periodontol. 2000.","DOI":"10.1111\/prd.12536"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1111\/prd.12616","article-title":"Periodontal disease: A systemic condition","volume":"96","author":"Villoria","year":"2024","journal-title":"Periodontol. 2000"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Paladines, N., Dawson, S., Ryan, W., Serrano-Lopez, R., Messer, R., Huo, Y., Cutler, C.W., Ramos-Junior, E.S., and Morandini, A.C. (2023). Metabolic reprogramming through mitochondrial biogenesis drives adenosine anti-inflammatory effects: New mechanism controlling gingival fibroblast hyper-inflammatory state. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1148216"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/JPER.19-0137","article-title":"CD73-dependent adenosine dampens interleukin-1beta-induced CXCL8 production in gingival fibroblasts: Association with heme oxygenase-1 and adenosine monophosphate-activated protein kinase","volume":"91","author":"Pedram","year":"2020","journal-title":"J. Periodontol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ramos-Junior, E.S., Dawson, S., Ryan, W., Clinebell, B., Serrano-Lopez, R., Russell, M., Brumbaugh, R., Zhong, R., Goncalves Fernandes, J., and Shaddox, L.M. (2023). The protective role of CD73 in periodontitis: Preventing hyper-inflammatory fibroblasts and driving osteoclast energy metabolism. Front. Oral Health, 4.","DOI":"10.3389\/froh.2023.1308657"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.molmed.2013.03.005","article-title":"CD39 and CD73 in immunity and inflammation","volume":"19","author":"Antonioli","year":"2013","journal-title":"Trends Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Hasko, G., and Cronstein, B. (2013). Regulation of inflammation by adenosine. Front. Immunol., 4.","DOI":"10.3389\/fimmu.2013.00085"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.tem.2013.02.001","article-title":"Adenosine and bone metabolism","volume":"24","author":"Mediero","year":"2013","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/S0006-2952(02)01548-4","article-title":"Use of the A(2A) adenosine receptor as a physiological immunosuppressor and to engineer inflammation in vivo","volume":"65","author":"Sitkovsky","year":"2003","journal-title":"Biochem. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1038\/414916a","article-title":"Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage","volume":"414","author":"Ohta","year":"2001","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1165\/rcmb.2008-0168OC","article-title":"The adenosine a2a receptor inhibits matrix-induced inflammation in a novel fashion","volume":"40","author":"Scheibner","year":"2009","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5027","DOI":"10.1096\/fj.201902459R","article-title":"Adenosine A2A receptor (A2AR) stimulation enhances mitochondrial metabolism and mitigates reactive oxygen species-mediated mitochondrial injury","volume":"34","author":"Castro","year":"2020","journal-title":"FASEB J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"247","DOI":"10.14573\/altex.1509271","article-title":"Cellular resilience","volume":"32","author":"Smirnova","year":"2015","journal-title":"Altex"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"113729","DOI":"10.1016\/j.jim.2024.113729","article-title":"Mitochondrial function in oral health and disease","volume":"532","author":"Morandini","year":"2024","journal-title":"J. Immunol. Methods"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e23891","DOI":"10.1096\/fj.202400672RR","article-title":"The effects of the atrial natriuretic peptide deficiency on renal cortical mitochondrial bioenergetics in the Dahl SS rat","volume":"38","author":"Cherezova","year":"2024","journal-title":"FASEB J."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lew, S.Y., Mohd Hisam, N.S., Phang, M.W.L., Syed Abdul Rahman, S.N., Poh, R.Y.Y., Lim, S.H., Kamaruzzaman, M.A., Chau, S.C., Tsui, K.C., and Lim, L.W. (2023). Adenosine Improves Mitochondrial Function and Biogenesis in Friedreich\u2019s Ataxia Fibroblasts Following L-Buthionine Sulfoximine-Induced Oxidative Stress. Biology, 12.","DOI":"10.3390\/biology12040559"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/j.molcel.2023.02.012","article-title":"Determinants and outcomes of mitochondrial dynamics","volume":"83","author":"Scorrano","year":"2023","journal-title":"Mol. Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.ajpath.2011.10.017","article-title":"Adenosine A(2A) receptor ligation inhibits osteoclast formation","volume":"180","author":"Mediero","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3487","DOI":"10.1096\/fj.201700217R","article-title":"Adenosine A(2A) receptor (A2AR) stimulation modulates expression of semaphorins 4D and 3A, regulators of bone homeostasis","volume":"32","author":"Mediero","year":"2018","journal-title":"FASEB J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1111\/jcpe.12010","article-title":"Adenosine receptor stimulation by polynucleotides (PDRN) reduces inflammation in experimental periodontitis","volume":"40","author":"Bitto","year":"2013","journal-title":"J. Clin. Periodontol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1007\/s12010-019-03171-2","article-title":"Polydeoxyribonucleotide Activates Mitochondrial Biogenesis but Reduces MMP-1 Activity and Melanin Biosynthesis in Cultured Skin Cells","volume":"191","author":"Kim","year":"2020","journal-title":"Appl. Biochem. Biotechnol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"115172","DOI":"10.1016\/j.celrep.2024.115172","article-title":"Metabolic reprogramming of macrophages by PKM2 promotes IL-10 production via adenosine","volume":"44","author":"Viacava","year":"2025","journal-title":"Cell Rep."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Zanfardino, P., Amati, A., Perrone, M., and Petruzzella, V. (2025). The Balance of MFN2 and OPA1 in Mitochondrial Dynamics, Cellular Homeostasis, and Disease. Biomolecules, 15.","DOI":"10.20944\/preprints202502.1547.v1"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3525","DOI":"10.1091\/mbc.e09-03-0252","article-title":"Mitofusins and OPA1 mediate sequential steps in mitochondrial membrane fusion","volume":"20","author":"Song","year":"2009","journal-title":"Mol. Biol. Cell"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Ihenacho, U.K., Meacham, K.A., Harwig, M.C., Widlansky, M.E., and Hill, R.B. (2021). Mitochondrial Fission Protein 1: Emerging Roles in Organellar Form and Function in Health and Disease. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.660095"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Brillo, V., Chieregato, L., Leanza, L., Muccioli, S., and Costa, R. (2021). Mitochondrial Dynamics, ROS, and Cell Signaling: A Blended Overview. Life, 11.","DOI":"10.3390\/life11040332"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/16\/1266\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:28:51Z","timestamp":1760034531000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/16\/1266"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,16]]},"references-count":31,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["cells14161266"],"URL":"https:\/\/doi.org\/10.3390\/cells14161266","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,16]]}}}