{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T23:09:38Z","timestamp":1789772978632,"version":"4.0.1"},"reference-count":72,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,10,10]],"date-time":"2023-10-10T00:00:00Z","timestamp":1696896000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,10,10]],"date-time":"2023-10-10T00:00:00Z","timestamp":1696896000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000272","name":"NIHR","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"crossref"}]},{"name":"ODRT"},{"DOI":"10.13039\/501100000691","name":"The Academy of Medical Sciences","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000691","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Transl Med"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Despite the improvements in treatment over the last decades, periodontal disease (PD) affects millions of people around the world and the only treatment available is based on controlling microbial load. Diabetes is known to increase the risk of PD establishment and progression, and recently, glucose metabolism modulation by pharmaceutical or dietarian means has been emphasised as a significant modulator of non-communicable disease development.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The impact of pharmaceutically controlling glucose metabolism in non-diabetic animals and humans (REBEC, UTN code: U1111-1276-1942) was investigated by repurposing Metformin, as a mean to manage periodontal disease and its associated systemic risk factors.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We found that glucose metabolism control via use of Metformin aimed at PD management resulted in significant prevention of bone loss during induced periodontal disease and age-related bone loss in vivo. Metformin also influenced the bacterial species present in the oral environment and impacted the metabolic epithelial and stromal responses to bacterial dysbiosis at a single cell level. Systemically, Metformin controlled blood glucose levels and age-related weight gain when used long-term. Translationally, our pilot randomized control trial indicated that systemic Metformin was safe to use in non-diabetic patients and affected the periodontal tissues. During the medication window, patients showed stable levels of systemic blood glucose, lower circulating hsCRP and lower insulin levels after periodontal treatment when compared to placebo. Finally, patients treated with Metformin had improved periodontal parameters when compared to placebo treated patients.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>This is the first study to demonstrate that systemic interventions using Metformin in non-diabetic individuals aimed at PD prevention have oral-systemic effects constituting a possible novel form of preventive medicine for oral-systemic disease management.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12967-023-04456-1","type":"journal-article","created":{"date-parts":[[2023,10,9]],"date-time":"2023-10-09T23:02:55Z","timestamp":1696892575000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Repurposing Metformin for periodontal disease management as a form of oral-systemic preventive medicine"],"prefix":"10.1186","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5111-269X","authenticated-orcid":false,"given":"Vitor C. M.","family":"Neves","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana","family":"Satie Okajima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eyad","family":"Elbahtety","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Joseph","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Daly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athul","family":"Menon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayste","family":"Volkyte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Mainas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathy","family":"Fung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawan","family":"Dhami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre A.","family":"Pelegrine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Sharpe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Nibali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Ide","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,10,10]]},"reference":[{"issue":"9499","key":"4456_CR1","doi-asserted-by":"publisher","first-page":"1809","DOI":"10.1016\/S0140-6736(05)67728-8","volume":"366","author":"BL Pihlstrom","year":"2005","unstructured":"Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal diseases. Lancet. 2005;366(9499):1809\u201320. https:\/\/doi.org\/10.1016\/S0140-6736(05)67728-8.","journal-title":"Lancet"},{"issue":"12","key":"4456_CR2","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1038\/s41579-018-0089-x","volume":"16","author":"RJ Lamont","year":"2018","unstructured":"Lamont RJ, Koo H, Hajishengallis G. The oral microbiota: dynamic communities and host interactions. Nat Rev Microbiol. 2018;16(12):745\u201359.","journal-title":"Nat Rev Microbiol"},{"issue":"1","key":"4456_CR3","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1111\/prd.12296","volume":"83","author":"MA Curtis","year":"2020","unstructured":"Curtis MA, Diaz PI, Van Dyke TE. The role of the microbiota in periodontal disease. Periodontol 2000. 2020;83(1):14\u201325. https:\/\/doi.org\/10.1111\/prd.12296.","journal-title":"Periodontol 2000"},{"issue":"9","key":"4456_CR4","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1111\/j.1600-051X.2004.00563","volume":"31","author":"P Axelsson","year":"2004","unstructured":"Axelsson P, Nystr\u00f6m B, Lindhe J. The long-term effect of a plaque control program on tooth mortality, caries and periodontal disease in adults. Results after 30 years of maintenance. J Clin Periodontol. 2004;31(9):749\u201357. https:\/\/doi.org\/10.1111\/j.1600-051X.2004.00563.","journal-title":"J Clin Periodontol"},{"issue":"1","key":"4456_CR5","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1111\/j.1600-051x.1984.tb01309.x","volume":"11","author":"A Badersten","year":"1984","unstructured":"Badersten A, Nilveus R, Egelberg J. Effect of nonsurgical periodontal therapy. II. Severely advanced periodontitis. J Clin Periodontol. 1984;11(1):63\u201376. https:\/\/doi.org\/10.1111\/j.1600-051x.1984.tb01309.x.","journal-title":"J Clin Periodontol"},{"issue":"10194","key":"4456_CR6","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/S0140-6736(19)31146-8","volume":"394","author":"MA Peres","year":"2019","unstructured":"Peres MA, Macpherson LMD, Weyant RJ, Daly B, Venturelli R, Mathur MR, Listl S, Celeste RK, Guarnizo-Herre\u00f1o CC, Kearns C, Benzian H, Allison P, Watt RG. Oral diseases: a global public health challenge. Lancet. 2019;394(10194):249\u201360. https:\/\/doi.org\/10.1016\/S0140-6736(19)31146-8.","journal-title":"Lancet"},{"issue":"1","key":"4456_CR7","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1186\/1743-7075-9-88","volume":"9","author":"E Marchetti","year":"2012","unstructured":"Marchetti E, Monaco A, Procaccini L, Mummolo S, Gatto R, Tet\u00e8 S, Baldini A, Tecco S, Marzo G. Periodontal disease: the influence of metabolic syndrome. Nutr Metab (Lond). 2012;9(1):88. https:\/\/doi.org\/10.1186\/1743-7075-9-88.","journal-title":"Nutr Metab (Lond)"},{"issue":"1","key":"4456_CR8","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1111\/prd.12379","volume":"87","author":"FQ Pirih","year":"2021","unstructured":"Pirih FQ, Monajemzadeh S, Singh N, Sinacola RS, Shin JM, Chen T, Fenno JC, Kamarajan P, Rickard AH, Travan S, Paster BJ, Kapila Y. Association between metabolic syndrome and periodontitis: the role of lipids, inflammatory cytokines, altered host response, and the microbiome. Periodontol 2000. 2021;87(1):50\u201375. https:\/\/doi.org\/10.1111\/prd.12379.","journal-title":"Periodontol 2000"},{"issue":"3","key":"4456_CR9","doi-asserted-by":"publisher","first-page":"273","DOI":"10.14219\/jada.archive.1994.0034","volume":"125","author":"BA Burt","year":"1994","unstructured":"Burt BA. Periodontitis and aging: reviewing recent evidence. J Am Dent Assoc. 1994;125(3):273\u20139.","journal-title":"J Am Dent Assoc"},{"issue":"4","key":"4456_CR10","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1177\/0022034515625962","volume":"95","author":"Y Wu","year":"2016","unstructured":"Wu Y, et al. Effect of aging on periodontal inflammation, microbial colonization, and disease susceptibility. J Dent Res. 2016;95(4):460\u20136.","journal-title":"J Dent Res"},{"issue":"6","key":"4456_CR11","doi-asserted-by":"publisher","first-page":"2196","DOI":"10.1152\/jappl.1998.85.6.2196","volume":"85","author":"LS Piers","year":"1998","unstructured":"Piers LS, Soares MJ, McCormack LM, O\u2019Dea K. Is there evidence for an age-related reduction in metabolic rate? J Appl Physiol. 1998;85(6):2196\u2013204. https:\/\/doi.org\/10.1152\/jappl.1998.85.6.2196.","journal-title":"J Appl Physiol"},{"issue":"6556","key":"4456_CR12","doi-asserted-by":"publisher","first-page":"808","DOI":"10.1126\/science.abe5017","volume":"373","author":"H Pontzer","year":"2021","unstructured":"Pontzer H, Yamada Y, Sagayama H, et al. Daily energy expenditure through the human life course. Science. 2021;373(6556):808\u201312. https:\/\/doi.org\/10.1126\/science.abe5017.","journal-title":"Science"},{"issue":"8","key":"4456_CR13","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1016\/S2213-8587(18)30026-3","volume":"6","author":"AW van den Beld","year":"2018","unstructured":"van den Beld AW, Kaufman JM, Zillikens MC, Lamberts SWJ, Egan JM, van der Lely AJ. The physiology of endocrine systems with ageing. Lancet Diabetes Endocrinol. 2018;6(8):647\u201358. https:\/\/doi.org\/10.1016\/S2213-8587(18)30026-3.","journal-title":"Lancet Diabetes Endocrinol"},{"issue":"1","key":"4456_CR14","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.cmet.2016.09.017","volume":"25","author":"TES Kauppila","year":"2017","unstructured":"Kauppila TES, Kauppila JHK, Larsson NG. Mammalian mitochondria and aging: an update. Cell Metab. 2017;25(1):57\u201371. https:\/\/doi.org\/10.1016\/j.cmet.2016.09.017.","journal-title":"Cell Metab"},{"issue":"9","key":"4456_CR15","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1016\/S2213-8587(18)30110-4","volume":"6","author":"A Clegg","year":"2018","unstructured":"Clegg A, Hassan-Smith Z. Frailty and the endocrine system. Lancet Diabetes Endocrinol. 2018;6(9):743\u201352. https:\/\/doi.org\/10.1016\/S2213-8587(18)30110-4.","journal-title":"Lancet Diabetes Endocrinol"},{"issue":"1","key":"4456_CR16","doi-asserted-by":"publisher","first-page":"89","DOI":"10.2337\/db09-0591","volume":"59","author":"H Karakelides","year":"2010","unstructured":"Karakelides H, Irving BA, Short KR, O\u2019Brien P, Nair KS. Age, obesity, and sex effects on insulin sensitivity and skeletal muscle mitochondrial function. Diabetes. 2010;59(1):89\u201397. https:\/\/doi.org\/10.2337\/db09-0591.","journal-title":"Diabetes"},{"issue":"9499","key":"4456_CR17","doi-asserted-by":"publisher","first-page":"1809","DOI":"10.1016\/S0140-6736(05)67728-8","volume":"366","author":"BL Pihlstrom","year":"2005","unstructured":"Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal diseases. Lancet. 2005;366(9499):1809\u201320. https:\/\/doi.org\/10.1016\/S0140-6736(05)67728-8.","journal-title":"Lancet"},{"issue":"10","key":"4456_CR18","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1177\/0022034512457373","volume":"91","author":"PI Eke","year":"2012","unstructured":"Eke PI, Dye BA, Wei L, Thornton-Evans GO, Genco RJ. CDC Periodontal disease surveillance workgroup: James beck (University of North Carolina, Chapel Hill, USA), Gordon Douglass (Past President, American Academy of Periodontology), Roy Page (University of Washin. Prevalence of periodontitis in adults in the United States: 2009 and 2010. J Dent Res. 2012;91(10):914\u201320. https:\/\/doi.org\/10.1177\/0022034512457373.","journal-title":"J Dent Res"},{"issue":"4","key":"4456_CR19","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1111\/acel.12338","volume":"14","author":"VD Longo","year":"2015","unstructured":"Longo VD, Antebi A, Bartke A, Barzilai N, Brown-Borg HM, Caruso C, Curiel TJ, de Cabo R, Franceschi C, Gems D, Ingram DK, Johnson TE, Kennedy BK, Kenyon C, Klein S, Kopchick JJ, Lepperdinger G, Madeo F, Mirisola MG, Mitchell JR, Passarino G, Rudolph KL, Sedivy JM, Shadel GS, Sinclair DA, Spindler SR, Suh Y, Vijg J, Vinciguerra M, Fontana L. Interventions to slow aging in humans: are we ready? Aging Cell. 2015;14(4):497\u2013510. https:\/\/doi.org\/10.1111\/acel.12338.","journal-title":"Aging Cell"},{"issue":"4 Suppl","key":"4456_CR20","doi-asserted-by":"publisher","first-page":"S106","DOI":"10.1902\/jop.2013.1340011","volume":"84","author":"IL Chapple","year":"2013","unstructured":"Chapple IL, Genco R. working group 2 of the joint EFP\/AAP workshop. Diabetes and periodontal diseases: consensus report of the Joint EFP\/AAP workshop on periodontitis and systemic diseases. J Periodontol. 2013;84(4 Suppl):S106-12. https:\/\/doi.org\/10.1902\/jop.2013.1340011.","journal-title":"J Periodontol"},{"issue":"12","key":"4456_CR21","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1016\/S2213-8587(18)30038-X","volume":"6","author":"F D'Aiuto","year":"2018","unstructured":"D\u2019Aiuto F, Gkranias N, Bhowruth D, Khan T, Orlandi M, Suvan J, Masi S, Tsakos G, Hurel S, Hingorani AD, Donos N, Deanfield JE, TASTE Group. Systemic effects of periodontitis treatment in patients with type 2 diabetes: a 12 month, single-centre, investigator-masked, randomised trial. Lancet Diabetes Endocrinol. 2018;6(12):954\u201365. https:\/\/doi.org\/10.1016\/S2213-8587(18)30038-X.","journal-title":"Lancet Diabetes Endocrinol"},{"issue":"9","key":"4456_CR22","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1038\/nri.2016.70","volume":"16","author":"LA O'Neill","year":"2016","unstructured":"O\u2019Neill LA, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016;16(9):553\u201365. https:\/\/doi.org\/10.1038\/nri.2016.70.","journal-title":"Nat Rev Immunol"},{"issue":"6","key":"4456_CR23","doi-asserted-by":"publisher","first-page":"1052","DOI":"10.1016\/j.cmet.2020.04.022","volume":"31","author":"CH Ly","year":"2020","unstructured":"Ly CH, Lynch GS, Ryall JG. A metabolic roadmap for somatic stem cell fate. Cell Metab. 2020;31(6):1052\u201367. https:\/\/doi.org\/10.1016\/j.cmet.2020.04.022.","journal-title":"Cell Metab"},{"issue":"7764","key":"4456_CR24","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1038\/s41586-019-1365-2","volume":"571","author":"J Campisi","year":"2019","unstructured":"Campisi J, Kapahi P, Lithgow GJ, Melov S, Newman JC, Verdin E. From discoveries in ageing research to therapeutics for healthy ageing. Nature. 2019;571(7764):183\u201392. https:\/\/doi.org\/10.1038\/s41586-019-1365-2.","journal-title":"Nature"},{"issue":"11","key":"4456_CR25","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1038\/nrm.2016.93","volume":"17","author":"MS Bonkowski","year":"2016","unstructured":"Bonkowski MS, Sinclair DA. Slowing ageing by design: the rise of NAD+\u00a0and sirtuin-activating compounds. Nat Rev Mol Cell Biol. 2016;17(11):679\u201390. https:\/\/doi.org\/10.1038\/nrm.2016.93.","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"6","key":"4456_CR26","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1016\/j.cmet.2014.09.018","volume":"20","author":"M Foretz","year":"2014","unstructured":"Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: from mechanisms of action to therapies. Cell Metab. 2014;20(6):953\u201366. https:\/\/doi.org\/10.1016\/j.cmet.2014.09.018.","journal-title":"Cell Metab"},{"key":"4456_CR27","doi-asserted-by":"publisher","first-page":"2192","DOI":"10.1038\/ncomms3192.PMID:23900241;PMCID:PMC3736576","volume":"4","author":"A Martin-Montalvo","year":"2013","unstructured":"Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192. https:\/\/doi.org\/10.1038\/ncomms3192.PMID:23900241;PMCID:PMC3736576.","journal-title":"Nat Commun"},{"issue":"6","key":"4456_CR28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s12276-019-0264-9","volume":"51","author":"A Sanchis","year":"2019","unstructured":"Sanchis A, Garc\u00eda-Gimeno MA, Ca\u00f1ada-Mart\u00ednez AJ, Sequedo MD, Mill\u00e1n JM, Sanz P, V\u00e1zquez-Manrique RP. Metformin treatment reduces motor and neuropsychiatric phenotypes in the zQ175 mouse model of Huntington disease. Exp Mol Med. 2019;51(6):1\u201316. https:\/\/doi.org\/10.1038\/s12276-019-0264-9.","journal-title":"Exp Mol Med"},{"issue":"8","key":"4456_CR29","doi-asserted-by":"publisher","first-page":"e0183506","DOI":"10.1371\/journal.pone.0183506","volume":"12","author":"AA Ara\u00fajo","year":"2017","unstructured":"Ara\u00fajo AA, Pereira ASBF, Medeiros CACX, Brito GAC, Leit\u00e3o RFC, Ara\u00fajo LS, Guedes PMM, Hiyari S, Pirih FQ, Ara\u00fajo J\u00fanior RF. Effects of metformin on inflammation, oxidative stress, and bone loss in a rat model of periodontitis. PLoS ONE. 2017;12(8):e0183506. https:\/\/doi.org\/10.1371\/journal.pone.0183506.","journal-title":"PLoS ONE"},{"issue":"6","key":"4456_CR30","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1111\/jre.12573","volume":"53","author":"Z Akram","year":"2018","unstructured":"Akram Z, Vohra F, Javed F. Locally delivered metformin as adjunct to scaling and root planing in the treatment of periodontal defects: a systematic review and meta-analysis. J Periodontal Res. 2018;53(6):941\u20139. https:\/\/doi.org\/10.1111\/jre.12573.","journal-title":"J Periodontal Res"},{"issue":"10","key":"4456_CR31","doi-asserted-by":"publisher","first-page":"5864","DOI":"10.1128\/IAI.68.10.5864-5868.2000","volume":"68","author":"PJ Baker","year":"2000","unstructured":"Baker PJ, Dixon M, Roopenian DC. Genetic control of susceptibility to Porphyromonas gingivalis-induced alveolar bone loss in mice. Infect Immun. 2000;68(10):5864\u20138.","journal-title":"Infect Immun"},{"issue":"1","key":"4456_CR32","first-page":"44","volume":"57","author":"LA Morley","year":"2018","unstructured":"Morley LA, Gomez TH, Goldman JL, Flores R, Robinson MA. Accuracy of 5 point-of-care glucometers in C57BL\/6J Mice. J Am Assoc Lab Anim Sci. 2018;57(1):44\u201350.","journal-title":"J Am Assoc Lab Anim Sci"},{"issue":"1","key":"4456_CR33","first-page":"e01222","volume":"6","author":"S Joseph","year":"2021","unstructured":"Joseph S, Aduse-Opoku J, Hashim A, Hanski E, Streich R, Knowles SCL, Pedersen AB, Wade WG, Curtis MA. A 16S rRNA gene and draft genome database for the murine oral bacterial community. Systems. 2021;6(1):e01222-20.","journal-title":"Systems"},{"issue":"7","key":"4456_CR34","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/nmeth.3869","volume":"13","author":"BJ Callahan","year":"2016","unstructured":"Callahan BJ, McMurdie PJ, Rosen MJ, Han AW, Johnson AJ, Holmes SP. DADA2: High-resolution sample inference from Illumina amplicon data. Nat Methods. 2016;13(7):581\u20133. https:\/\/doi.org\/10.1038\/nmeth.3869.","journal-title":"Nat Methods"},{"issue":"12","key":"4456_CR35","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550. https:\/\/doi.org\/10.1186\/s13059-014-0550-8.","journal-title":"Genome Biol"},{"issue":"4","key":"4456_CR36","doi-asserted-by":"publisher","first-page":"e61217","DOI":"10.1371\/journal.pone.0061217","volume":"8","author":"PJ McMurdie","year":"2013","unstructured":"McMurdie PJ, Holmes S. phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data. PLoS ONE. 2013;8(4):e61217. https:\/\/doi.org\/10.1371\/journal.pone.0061217.","journal-title":"PLoS ONE"},{"key":"4456_CR37","doi-asserted-by":"publisher","first-page":"e50388","DOI":"10.3791\/50388","volume":"77","author":"G Mizraji","year":"2013","unstructured":"Mizraji G, Segev H, Wilensky A, Hovav AH. Isolation, processing and analysis of murine gingival cells. J Vis Exp. 2013;77:e50388. https:\/\/doi.org\/10.3791\/50388.","journal-title":"J Vis Exp"},{"key":"4456_CR38","doi-asserted-by":"publisher","DOI":"10.1111\/jcpe.13290","author":"M Sanz","year":"2020","unstructured":"Sanz M, Herrera D, Kebschull M, Chapple I, Jepsen S, Beglundh T, Sculean A, Tonetti MS. EFP workshop participants and methodological consultants treatment of stage I-III periodontitis\u2014the EFP S3 level clinical practice guideline. J Clin Periodontol. 2020. https:\/\/doi.org\/10.1111\/jcpe.13290.","journal-title":"J Clin Periodontol"},{"issue":"10","key":"4456_CR39","doi-asserted-by":"publisher","first-page":"4151","DOI":"10.1128\/IAI.00600-10","volume":"78","author":"S Zaric","year":"2010","unstructured":"Zaric S, Shelburne C, Darveau R, Quinn DJ, Weldon S, Taggart CC, Coulter WA. Impaired immune tolerance to Porphyromonas gingivalis lipopolysaccharide promotes neutrophil migration and decreased apoptosis. Infect Immun. 2010;78(10):4151\u20136. https:\/\/doi.org\/10.1128\/IAI.00600-10.","journal-title":"Infect Immun"},{"key":"4456_CR40","doi-asserted-by":"publisher","DOI":"10.3389\/fdmed.2022.815810","author":"D Fraser","year":"2022","unstructured":"Fraser D, Caton J, Benoit DSW. Periodontal wound healing and regeneration: insights for engineering new therapeutic approaches. Front Dent Med. 2022. https:\/\/doi.org\/10.3389\/fdmed.2022.815810.","journal-title":"Front Dent Med"},{"key":"4456_CR41","doi-asserted-by":"publisher","first-page":"e62810","DOI":"10.7554\/eLife.62810","volume":"10","author":"AJ Caetano","year":"2021","unstructured":"Caetano AJ, Yianni V, Volponi A, Booth V, D\u2019Agostino EM, Sharpe P. Defining human mesenchymal and epithelial heterogeneity in response to oral inflammatory disease. Elife. 2021;10:e62810. https:\/\/doi.org\/10.7554\/eLife.62810.","journal-title":"Elife"},{"issue":"5","key":"4456_CR42","doi-asserted-by":"publisher","first-page":"3041","DOI":"10.3892\/ijmm.2018.3478","volume":"41","author":"Y Jia","year":"2018","unstructured":"Jia Y, Qin Q, Fang CP, Shen W, Sun TT, Huang YL, Li WJ, Deng AM. UVB induces apoptosis via downregulation of CALML3-dependent JNK1\/2 and ERK1\/2 pathways in cataract. Int J Mol Med. 2018;41(5):3041\u201350. https:\/\/doi.org\/10.3892\/ijmm.2018.3478.","journal-title":"Int J Mol Med"},{"issue":"9","key":"4456_CR43","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.3389\/fphar.2018.01048","volume":"17","author":"H Li","year":"2018","unstructured":"Li H, Zuo J, Tang W. Phosphodiesterase-4 inhibitors for the treatment of inflammatory diseases. Front Pharmacol. 2018;17(9):1048. https:\/\/doi.org\/10.3389\/fphar.2018.01048.","journal-title":"Front Pharmacol"},{"issue":"5","key":"4456_CR44","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.1111\/j.0022-202X.2004.22511.x","volume":"122","author":"S Tsuchida","year":"2004","unstructured":"Tsuchida S, Bonkobara M, McMillan JR, Akiyama M, Yudate T, Aragane Y, Tezuka T, Shimizu H, Cruz PD Jr, Ariizumi K. Characterization of Kdap, a protein secreted by keratinocytes. J Invest Dermatol. 2004;122(5):1225\u201334. https:\/\/doi.org\/10.1111\/j.0022-202X.2004.22511.x.","journal-title":"J Invest Dermatol"},{"key":"4456_CR45","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/j.redox.2018.08.016","volume":"19","author":"J Yang","year":"2018","unstructured":"Yang J, Chen Z, Liu N, Chen Y. Ribosomal protein L10 in mitochondria serves as a regulator for ROS level in pancreatic cancer cells. Redox Biol. 2018;19:158\u201365. https:\/\/doi.org\/10.1016\/j.redox.2018.08.016.","journal-title":"Redox Biol"},{"issue":"1","key":"4456_CR46","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1186\/s12891-021-04278-6","volume":"22","author":"M Ishida","year":"2021","unstructured":"Ishida M, Kawao N, Mizukami Y, Takafuji Y, Kaji H. Influence of Angptl1 on osteoclast formation and osteoblastic phenotype in mouse cells. BMC Musculoskelet Disord. 2021;22(1):398. https:\/\/doi.org\/10.1186\/s12891-021-04278-6.","journal-title":"BMC Musculoskelet Disord"},{"issue":"11","key":"4456_CR47","doi-asserted-by":"publisher","first-page":"e80723","DOI":"10.1371\/journal.pone.0080723","volume":"8","author":"AR Everitt","year":"2013","unstructured":"Everitt AR, Clare S, McDonald JU, Kane L, Harcourt K, Ahras M, Lall A, Hale C, Rodgers A, Young DB, Haque A, Billker O, Tregoning JS, Dougan G, Kellam P. Defining the range of pathogens susceptible to Ifitm3 restriction using a knockout mouse model. PLoS ONE. 2013;8(11):e80723. https:\/\/doi.org\/10.1371\/journal.pone.0080723.","journal-title":"PLoS ONE"},{"issue":"9","key":"4456_CR48","doi-asserted-by":"publisher","first-page":"1570","DOI":"10.1016\/j.bbadis.2016.05.018","volume":"1862","author":"T Koehne","year":"2016","unstructured":"Koehne T, Markmann S, Schweizer M, Muschol N, Friedrich RE, Hagel C, Glatzel M, Kahl-Nieke B, Amling M, Schinke T, Braulke T. Mannose 6-phosphate-dependent targeting of lysosomal enzymes is required for normal craniofacial and dental development. Biochim Biophys Acta. 2016;1862(9):1570\u201380. https:\/\/doi.org\/10.1016\/j.bbadis.2016.05.018.","journal-title":"Biochim Biophys Acta"},{"key":"4456_CR49","doi-asserted-by":"publisher","first-page":"110241","DOI":"10.1016\/j.cellsig.2022.110241","volume":"91","author":"M Li","year":"2022","unstructured":"Li M, Huang S, Zhang Y, Song Z, Fu H, Lin Z, Huang X. Regulation of the unfolded protein response transducer IRE1\u03b1 by SERPINH1 aggravates periodontitis with diabetes mellitus via prolonged ER stress. Cell Signal. 2022;91:110241. https:\/\/doi.org\/10.1016\/j.cellsig.2022.110241.","journal-title":"Cell Signal"},{"key":"4456_CR50","doi-asserted-by":"publisher","first-page":"863231","DOI":"10.3389\/froh.2022.863231","volume":"3","author":"OA Gonzalez","year":"2022","unstructured":"Gonzalez OA, Kirakodu S, Nguyen LM, Orraca L, Novak MJ, Gonzalez-Martinez J, Ebersole JL. Comparative analysis of gene expression patterns for oral epithelial cell functions in periodontitis. Front Oral Health. 2022;3:863231. https:\/\/doi.org\/10.3389\/froh.2022.863231.","journal-title":"Front Oral Health"},{"key":"4456_CR51","doi-asserted-by":"publisher","first-page":"559267","DOI":"10.3389\/fmolb.2020.559267","volume":"7","author":"Y Luo","year":"2020","unstructured":"Luo Y, Guo J, Xu P, Gui R. Long non-coding RNA GAS5 maintains insulin secretion by regulating multiple miRNAs in INS-1 832\/13 cells. Front Mol Biosci. 2020;7:559267. https:\/\/doi.org\/10.3389\/fmolb.2020.559267.","journal-title":"Front Mol Biosci"},{"issue":"4","key":"4456_CR52","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1091\/mbc.e08-10-0999","volume":"20","author":"S Bibert","year":"2009","unstructured":"Bibert S, Aebischer D, Desgranges F, Roy S, Schaer D, Kharoubi-Hess S, Horisberger JD, Geering K. A link between FXYD3 (Mat-8)-mediated Na, K-ATPase regulation and differentiation of Caco-2 intestinal epithelial cells. Mol Biol Cell. 2009;20(4):1132\u201340. https:\/\/doi.org\/10.1091\/mbc.e08-10-0999.","journal-title":"Mol Biol Cell"},{"issue":"5","key":"4456_CR53","doi-asserted-by":"publisher","first-page":"2865","DOI":"10.3892\/or.2017.5528","volume":"37","author":"WQ Li","year":"2017","unstructured":"Li WQ, Zhong NZ, He J, Li YM, Hou LJ, Liu HM, Xia CY, Wang LZ, Lu YC. High ATP2A2 expression correlates with better prognosis of diffuse astrocytic tumor patients. Oncol Rep. 2017;37(5):2865\u201374. https:\/\/doi.org\/10.3892\/or.2017.5528.","journal-title":"Oncol Rep"},{"key":"4456_CR54","doi-asserted-by":"publisher","first-page":"690627","DOI":"10.3389\/fcvm.2021.690627","volume":"8","author":"Y Yan","year":"2021","unstructured":"Yan Y, Li T, Li Z, He M, Wang D, Xu Y, Yang X, Bai Y, Lao Y, Zhang Z, Wu W. Metformin suppresses the progress of diabetes-accelerated atherosclerosis by inhibition of vascular smooth muscle cell migration through AMPK-Pdlim5 pathway. Front Cardiovasc Med. 2021;8:690627. https:\/\/doi.org\/10.3389\/fcvm.2021.690627.","journal-title":"Front Cardiovasc Med"},{"issue":"4","key":"4456_CR55","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1007\/s10522-014-9501-8","volume":"15","author":"I Bentov","year":"2014","unstructured":"Bentov I, Damodarasamy M, Plymate S, Reed MJ. Decreased proliferative capacity of aged dermal fibroblasts in a three dimensional matrix is associated with reduced IGF1R expression and activation. Biogerontology. 2014;15(4):329\u201337. https:\/\/doi.org\/10.1007\/s10522-014-9501-8.","journal-title":"Biogerontology"},{"issue":"17","key":"4456_CR56","doi-asserted-by":"publisher","first-page":"1753","DOI":"10.1093\/hmg\/10.17.1753","volume":"10","author":"WH Lin","year":"2001","unstructured":"Lin WH, Chiu KC, Chang HM, Lee KC, Tai TY, Chuang LM. Molecular scanning of the human sorbin and SH3-doamain-containing-1 (SORBS1) gene: positive association of the T228A polymorphism with obesity and type 2 diabetes. Hum Mol Genet. 2001;10(17):1753\u201360. https:\/\/doi.org\/10.1093\/hmg\/10.17.1753.","journal-title":"Hum Mol Genet"},{"issue":"7","key":"4456_CR57","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1038\/s41577-020-00488-6","volume":"21","author":"G Hajishengallis","year":"2021","unstructured":"Hajishengallis G, Chavakis T. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nat Rev Immunol. 2021;21(7):426\u201340. https:\/\/doi.org\/10.1038\/s41577-020-00488-6.","journal-title":"Nat Rev Immunol"},{"issue":"1","key":"4456_CR58","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1111\/prd.12002","volume":"64","author":"A Cekici","year":"2014","unstructured":"Cekici A, Kantarci A, Hasturk H, Van Dyke TE. Inflammatory and immune pathways in the pathogenesis of periodontal disease. Periodontol 2000. 2014;64(1):57\u201380. https:\/\/doi.org\/10.1111\/prd.12002.","journal-title":"Periodontol 2000"},{"key":"4456_CR59","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1111\/j.1600-0757.2009.00325.x","volume":"53","author":"J Slots","year":"2010","unstructured":"Slots J. Human viruses in periodontitis. Periodontol 2000. 2010;53:89\u2013110. https:\/\/doi.org\/10.1111\/j.1600-0757.2009.00325.x.","journal-title":"Periodontol 2000"},{"issue":"4","key":"4456_CR60","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1111\/jre.12543","volume":"53","author":"T Morozumi","year":"2018","unstructured":"Morozumi T, Yashima A, Gomi K, Ujiie Y, Izumi Y, Akizuki T, Mizutani K, Takamatsu H, Minabe M, Miyauchi S, Yoshino T, Tanaka M, Tanaka Y, Hokari T, Yoshie H. Increased systemic levels of inflammatory mediators following one-stage full-mouth scaling and root planing. J Periodontal Res. 2018;53(4):536\u201344. https:\/\/doi.org\/10.1111\/jre.12543.","journal-title":"J Periodontal Res"},{"issue":"11","key":"4456_CR61","doi-asserted-by":"publisher","first-page":"511","DOI":"10.3389\/fimmu.2020.00511","volume":"31","author":"TE Van Dyke","year":"2020","unstructured":"Van Dyke TE, Bartold PM, Reynolds EC. The nexus between periodontal inflammation and dysbiosis. Front Immunol. 2020;31(11):511. https:\/\/doi.org\/10.3389\/fimmu.2020.00511.","journal-title":"Front Immunol"},{"issue":"2","key":"4456_CR62","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1111\/j.1600-051x.1977.tb01888.x","volume":"4","author":"JG Silver","year":"1977","unstructured":"Silver JG, Martin AW, McBride BC. Experimental transient bacteraemias in human subjects with varying degrees of plaque accumulation and gingival inflammation. J Clin Periodontol. 1977;4(2):92\u20139. https:\/\/doi.org\/10.1111\/j.1600-051x.1977.tb01888.x.","journal-title":"J Clin Periodontol"},{"issue":"7","key":"4456_CR63","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1161\/CIRCRESAHA.120.316653","volume":"127","author":"MC Flynn","year":"2020","unstructured":"Flynn MC, Kraakman MJ, Tikellis C, Lee MKS, Hanssen NMJ, Kammoun HL, Pickering RJ, Dragoljevic D, Al-Sharea A, Barrett TJ, Hortle F, Byrne FL, Olzomer E, McCarthy DA, Schalkwijk CG, Forbes JM, Hoehn K, Makowski L, Lancaster GI, El-Osta A, Fisher EA, Goldberg IJ, Cooper ME, Nagareddy PR, Thomas MC, Murphy AJ. Transient intermittent hyperglycemia accelerates atherosclerosis by promoting myelopoiesis. Circ Res. 2020;127(7):877\u201392. https:\/\/doi.org\/10.1161\/CIRCRESAHA.120.316653.","journal-title":"Circ Res"},{"issue":"Suppl 22","key":"4456_CR64","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1111\/jcpe.13264","volume":"47","author":"W Teughels","year":"2020","unstructured":"Teughels W, Feres M, Oud V, Mart\u00edn C, Matesanz P, Herrera D. Adjunctive effect of systemic antimicrobials in periodontitis therapy: a systematic review and meta-analysis. J Clin Periodontol. 2020;47(Suppl 22):257\u201381. https:\/\/doi.org\/10.1111\/jcpe.13264.","journal-title":"J Clin Periodontol"},{"issue":"6","key":"4456_CR65","doi-asserted-by":"publisher","first-page":"8691","DOI":"10.3892\/mmr.2017.7707","volume":"16","author":"X Han","year":"2017","unstructured":"Han X, Tao Y, Deng Y, Yu J, Sun Y, Jiang G. Metformin accelerates wound healing in type 2 diabetic db\/db mice. Mol Med Rep. 2017;16(6):8691\u20138. https:\/\/doi.org\/10.3892\/mmr.2017.7707.","journal-title":"Mol Med Rep"},{"key":"4456_CR66","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.arr.2017.08.003","volume":"40","author":"JM Campbell","year":"2017","unstructured":"Campbell JM, Bellman SM, Stephenson MD, Lisy K. Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. Ageing Res Rev. 2017;40:31\u201344. https:\/\/doi.org\/10.1016\/j.arr.2017.08.003.","journal-title":"Ageing Res Rev"},{"key":"4456_CR67","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1038\/s43587-021-00080-0","volume":"1","author":"AJ Scott","year":"2021","unstructured":"Scott AJ, Ellison M, Sinclair DA. The economic value of targeting aging. Nat Aging. 2021;1:616\u201323. https:\/\/doi.org\/10.1038\/s43587-021-00080-0.","journal-title":"Nat Aging"},{"key":"4456_CR68","unstructured":"Time to take gum disease seriously: the societal and economic impact of periodontitis. https:\/\/impact.economist.com\/perspectives\/healthcare\/time-take-gum-disease-seriously-societal-and-economic-impact-periodontitis"},{"issue":"9","key":"4456_CR69","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1038\/s41569-018-0064-2","volume":"15","author":"L Ferrucci","year":"2018","unstructured":"Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol. 2018;15(9):505\u201322. https:\/\/doi.org\/10.1038\/s41569-018-0064-2.","journal-title":"Nat Rev Cardiol"},{"issue":"3","key":"4456_CR70","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/S2213-8587(14)70134-2","volume":"3","author":"AJ Cox","year":"2015","unstructured":"Cox AJ, West NP, Cripps AW. Obesity, inflammation, and the gut microbiota. Lancet Diabetes Endocrinol. 2015;3(3):207\u201315. https:\/\/doi.org\/10.1016\/S2213-8587(14)70134-2.","journal-title":"Lancet Diabetes Endocrinol"},{"issue":"1","key":"4456_CR71","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1111\/prd.12135","volume":"72","author":"JL Ebersole","year":"2016","unstructured":"Ebersole JL, Graves CL, Gonzalez OA, Dawson D 3rd, Morford LA, Huja PE, Hartsfield JK Jr, Huja SS, Pandruvada S, Wallet SM. Aging, inflammation, immunity and periodontal disease. Periodontol 2000. 2016;72(1):54\u201375. https:\/\/doi.org\/10.1111\/prd.12135.","journal-title":"Periodontol 2000"},{"issue":"1","key":"4456_CR72","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1186\/s13756-022-01192-x","volume":"11","author":"A Bajalan","year":"2022","unstructured":"Bajalan A, Bui T, Salvadori G, Marques D, Schumacher A, R\u00f6sing CK, Dahle UR, Petersen FC, Ricomini-Filho AP, Nicolau BF, Junges R. Awareness regarding antimicrobial resistance and confidence to prescribe antibiotics in dentistry: a cross-continental student survey. Antimicrob Resist Infect Control. 2022;11(1):158. https:\/\/doi.org\/10.1186\/s13756-022-01192-x.","journal-title":"Antimicrob Resist Infect Control"}],"container-title":["Journal of Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-023-04456-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12967-023-04456-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-023-04456-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,17]],"date-time":"2023-11-17T22:20:46Z","timestamp":1700259646000},"score":1,"resource":{"primary":{"URL":"https:\/\/translational-medicine.biomedcentral.com\/articles\/10.1186\/s12967-023-04456-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,10]]},"references-count":72,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["4456"],"URL":"https:\/\/doi.org\/10.1186\/s12967-023-04456-1","relation":{},"ISSN":["1479-5876"],"issn-type":[{"value":"1479-5876","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,10]]},"assertion":[{"value":"30 May 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 August 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 October 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study protocol was approved by the ethical committee of the University S\u00e3o Leopoldo\u2014MANDIC (Brazil) (Approval code: 4.719.922) through the \u201cPlataforma Brasil\u201d (40340320.1.0000.537 4) and registered in the public platform REBEC (UTN code: U1111-1276-1942). All participants were provided with the subject information sheet and gave written informed consent to the study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"655"}}