{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T14:43:06Z","timestamp":1776436986873,"version":"3.51.2"},"reference-count":62,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100006752","name":"Universidade do Porto","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100006752","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Clin Oral Invest"],"abstract":"<jats:sec>\n            <jats:title>Abstract<\/jats:title>\n            <jats:p>Periodontal diseases (PDs) are prevalent chronic inflammatory conditions linked to the progression of systemic disorders. Gingipains, cysteine proteases produced by <jats:italic>Porphyromonas gingivalis<\/jats:italic>, are key virulence factors involved in PD pathogenesis and host-tissue degradation. Inhibiting these enzymes has emerged as a promising therapeutic approach.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Objective<\/jats:title>\n            <jats:p>This systematic review evaluates the potential of gingipain inhibitors in the management of PDs and related systemic conditions.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>A systematic search was conducted across PubMed, Scopus, and Web of Science using the PICOS framework. Studies were evaluated based on their objectives, experimental models, inhibitor types, and outcomes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Seven preclinical studies met the inclusion criteria. No clinical studies were identified. In preclinical models, gingipain inhibitors demonstrated consistent therapeutic benefits, including reduced inflammation, bacterial load, and tissue destruction in PDs, as well as improved outcomes in cardiovascular and AD models. Dual inhibitors targeting both Rgp and Kgp enzymes were more effective than single-target agents.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>Gingipain inhibitors hold promise as therapeutic agents for PDs and associated systemic diseases. However, the absence of clinical studies highlights the need for further development and clinical evaluation to support their translational potential.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Clinical relevance<\/jats:title>\n            <jats:p>By targeting specific and key components of host\u2013bacterium interactions, gingipain inhibitors represent a promising adjunctive therapy for modulating periopathogen virulence factors, thereby mitigating the progression of PDs and associated systemic diseases.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s00784-025-06472-5","type":"journal-article","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T05:03:12Z","timestamp":1755752592000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Gingipain inhibitors as an innovative therapy for periodontal and associated-systemic diseases: a systematic review"],"prefix":"10.1007","volume":"29","author":[{"given":"Maria Elisa","family":"Pedrosa","sequence":"first","affiliation":[]},{"given":"Victor","family":"Martin","sequence":"additional","affiliation":[]},{"given":"Maria Helena","family":"Fernandes","sequence":"additional","affiliation":[]},{"given":"Pedro Sousa","family":"Gomes","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,8,21]]},"reference":[{"key":"6472_CR1","doi-asserted-by":"publisher","first-page":"766560","DOI":"10.3389\/fimmu.2021.766560","volume":"12","author":"J Zhang","year":"2021","unstructured":"Zhang J et al (2021) The effects of Porphyromonas gingivalis on atherosclerosis-related cells. Front Immunol 12:766560","journal-title":"Front Immunol"},{"issue":"7","key":"6472_CR2","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1016\/j.adaj.2018.04.023","volume":"149","author":"PI Eke","year":"2018","unstructured":"Eke PI et al (2018) Periodontitis in US adults: National health and nutrition examination survey 2009\u20132014. J Am Dent Association 149(7):576\u2013588 .e6","journal-title":"J Am Dent Association"},{"issue":"4","key":"6472_CR3","doi-asserted-by":"publisher","first-page":"3695","DOI":"10.1007\/s11357-023-00835-0","volume":"46","author":"M Bertolini","year":"2024","unstructured":"Bertolini M, Clark D (2024) Periodontal disease as a model to study chronic inflammation in aging. Geroscience 46(4):3695\u20133709","journal-title":"Geroscience"},{"issue":"9","key":"6472_CR4","doi-asserted-by":"publisher","first-page":"978","DOI":"10.2174\/1567205014666170316163340","volume":"14","author":"M Sochocka","year":"2017","unstructured":"Sochocka M et al (2017) Association between periodontal health status and cognitive abilities. The role of cytokine profile and systemic inflammation. Curr Alzheimer Res 14(9):978\u2013990","journal-title":"Curr Alzheimer Res"},{"key":"6472_CR5","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1016\/j.bbi.2017.06.002","volume":"65","author":"Z Wu","year":"2017","unstructured":"Wu Z et al (2017) Cathepsin B plays a critical role in inducing Alzheimer\u2019s disease-like phenotypes following chronic systemic exposure to lipopolysaccharide from Porphyromonas gingivalis in mice. Brain Behav Immun 65:350\u2013361","journal-title":"Brain Behav Immun"},{"issue":"1","key":"6472_CR6","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/s13195-017-0282-6","volume":"9","author":"CK Chen","year":"2017","unstructured":"Chen CK, Wu YT, Chang YC (2017) Association between chronic periodontitis and the risk of Alzheimer\u2019s disease: a retrospective, population-based, matched-cohort study. Alzheimers Res Ther 9(1):56","journal-title":"Alzheimers Res Ther"},{"issue":"3","key":"6472_CR7","doi-asserted-by":"publisher","first-page":"e0151081","DOI":"10.1371\/journal.pone.0151081","volume":"11","author":"M Ide","year":"2016","unstructured":"Ide M et al (2016) Periodontitis and cognitive decline in Alzheimer\u2019s disease. PLoS One 11(3):e0151081","journal-title":"PLoS One"},{"key":"6472_CR8","doi-asserted-by":"publisher","DOI":"10.1038\/s41514-017-0015-x","volume":"3","author":"N Ishida","year":"2017","unstructured":"Ishida N et al (2017) Periodontitis induced by bacterial infection exacerbates features of Alzheimer\u2019s disease in transgenic mice. NPJ Aging Mech Dis 3:15","journal-title":"NPJ Aging Mech Dis"},{"key":"6472_CR9","doi-asserted-by":"crossref","unstructured":"da Costa LFNP et al (2017) Chlorhexidine mouthwash as an adjunct to mechanical therapy in chronic periodontitis: A meta-analysis, in Journal of the American Dental Association. American Dental Association. pp. 308\u2013318","DOI":"10.1016\/j.adaj.2017.01.021"},{"issue":"6","key":"6472_CR10","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1111\/jre.13283","volume":"59","author":"J Wang","year":"2024","unstructured":"Wang J et al (2024) Microbial- and host immune cell-derived extracellular vesicles in the pathogenesis and therapy of periodontitis: a narrative review. J Periodontal Res 59(6):1115\u20131129","journal-title":"J Periodontal Res"},{"issue":"2","key":"6472_CR11","doi-asserted-by":"publisher","first-page":"141","DOI":"10.3390\/pharmaceutics17020141","volume":"17","author":"A Ferreira da Silva","year":"2025","unstructured":"Ferreira da Silva A et al (2025) Exploring the link between periodontitis and alzheimer\u2019s disease-could a nanoparticulate vaccine break it? Pharmaceutics 17(2):141","journal-title":"Pharmaceutics"},{"key":"6472_CR12","doi-asserted-by":"publisher","first-page":"262","DOI":"10.3389\/fcimb.2019.00262","volume":"9","author":"L Jia","year":"2019","unstructured":"Jia L et al (2019) Pathogenesis of important virulence factors of via toll-like receptors. Front Cell Infect Microbiol 9:262. https:\/\/doi.org\/10.3389\/fcimb.2019.00262","journal-title":"Front Cell Infect Microbiol"},{"issue":"1","key":"6472_CR13","doi-asserted-by":"publisher","first-page":"10462","DOI":"10.1038\/s41598-025-94954-7","volume":"15","author":"Y Zheng","year":"2025","unstructured":"Zheng Y et al (2025) Gingipain regulates isoform switches of PD-L1 in macrophages infected with Porphyromonas gingivalis. Sci Rep 15(1):10462","journal-title":"Sci Rep"},{"issue":"1","key":"6472_CR14","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1902\/jop.2003.74.1.111","volume":"74","author":"T Imamura","year":"2003","unstructured":"Imamura T (2003) The role of gingipains in the pathogenesis of periodontal disease. J Periodontol 74(1):111\u2013118","journal-title":"J Periodontol"},{"key":"6472_CR15","doi-asserted-by":"publisher","first-page":"197","DOI":"10.3389\/fcimb.2017.00197","volume":"7","author":"M Sochalska","year":"2017","unstructured":"Sochalska M, Potempa J (2017) Manipulation of neutrophils by Porphyromonas gingivalis in the development of periodontitis. Front Cell Infect Microbiol 7:197","journal-title":"Front Cell Infect Microbiol"},{"key":"6472_CR16","doi-asserted-by":"publisher","first-page":"1551","DOI":"10.3389\/fimmu.2020.01551","volume":"11","author":"JM Nunes","year":"2020","unstructured":"Nunes JM et al (2020) Gingipain R1 and lipopolysaccharide from Porphyromonas gingivalis have major effects on blood clot morphology and mechanics. Front Immunol 11:1551","journal-title":"Front Immunol"},{"key":"6472_CR17","doi-asserted-by":"publisher","first-page":"p5193572","DOI":"10.1155\/2017\/5193572","volume":"2017","author":"ES Rovai","year":"2017","unstructured":"Rovai ES, Holzhausen M (2017) The role of Proteinase-Activated receptors 1 and 2 in the regulation of periodontal tissue metabolism and disease. J Immunol Res 2017:p5193572","journal-title":"J Immunol Res"},{"issue":"1","key":"6472_CR18","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1902\/jop.2002.73.1.79","volume":"73","author":"D Grenier","year":"2002","unstructured":"Grenier D et al (2002) Inhibition of proteolytic, serpinolytic, and progelatinase-B activation activities of periodontopathogens by doxycycline and the non-antimicrobial chemically modified tetracycline derivatives. J Periodontol 73(1):79\u201385","journal-title":"J Periodontol"},{"issue":"3","key":"6472_CR19","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1038\/bjc.2017.409","volume":"118","author":"MT Nieminen","year":"2018","unstructured":"Nieminen MT et al (2018) Treponema denticola chymotrypsin-like proteinase may contribute to orodigestive carcinogenesis through immunomodulation. Br J Cancer 118(3):428\u2013434","journal-title":"Br J Cancer"},{"issue":"9","key":"6472_CR20","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1111\/j.1600-051X.1995.tb00831.x","volume":"22","author":"T Sorsa","year":"1995","unstructured":"Sorsa T et al (1995) Cellular source, activation and inhibition of dental plaque collagenase. J Clin Periodontol 22(9):709\u2013717","journal-title":"J Clin Periodontol"},{"issue":"3","key":"6472_CR21","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1111\/j.1399-302X.1988.tb00092.x","volume":"3","author":"VJ Uitto","year":"1988","unstructured":"Uitto VJ et al (1988) Degradation of basement membrane collagen by proteases from some anaerobic oral micro-organisms. Oral Microbiol Immunol 3(3):97\u2013102","journal-title":"Oral Microbiol Immunol"},{"issue":"11","key":"6472_CR22","doi-asserted-by":"publisher","first-page":"4491","DOI":"10.1128\/iai.60.11.4491-4495.1992","volume":"60","author":"T Sorsa","year":"1992","unstructured":"Sorsa T et al (1992) Identification of proteases from periodontopathogenic bacteria as activators of latent human neutrophil and fibroblast-type interstitial collagenases. Infect Immun 60(11):4491\u20134495","journal-title":"Infect Immun"},{"key":"6472_CR23","doi-asserted-by":"publisher","first-page":"987683","DOI":"10.3389\/fcimb.2022.987683","volume":"12","author":"YC Chow","year":"2022","unstructured":"Chow YC et al (2022) Implications of Porphyromonas gingivalis peptidyl arginine deiminase and gingipain R in human health and diseases. Front Cell Infect Microbiol 12:987683","journal-title":"Front Cell Infect Microbiol"},{"key":"6472_CR24","doi-asserted-by":"publisher","first-page":"34","DOI":"10.3389\/fnagi.2019.00034","volume":"11","author":"J Miao","year":"2019","unstructured":"Miao J et al (2019) Pathological tau from Alzheimer\u2019s brain induces site-specific hyperphosphorylation and SDS- and reducing agent-resistant aggregation of tau in vivo. Front Aging Neurosci 11:34","journal-title":"Front Aging Neurosci"},{"issue":"1","key":"6472_CR25","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aau3333","volume":"5","author":"SS Dominy","year":"2019","unstructured":"Dominy SS et al (2019) Porphyromonas gingivalis in Alzheimer\u2019s disease brains: evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv 5(1):eaau3333","journal-title":"Sci Adv"},{"issue":"4","key":"6472_CR26","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.3233\/JAD-200393","volume":"75","author":"U Haditsch","year":"2020","unstructured":"Haditsch U et al (2020) Alzheimer\u2019s disease-like neurodegeneration in Porphyromonas gingivalis infected neurons with persistent expression of active gingipains. J Alzheimers Dis 75(4):1361\u20131376","journal-title":"J Alzheimers Dis"},{"issue":"5","key":"6472_CR27","doi-asserted-by":"publisher","first-page":"2612","DOI":"10.3390\/ijms25052612","volume":"25","author":"D Cichonska","year":"2024","unstructured":"Cichonska D, Mazus M, Kusiak A (2024) Recent aspects of periodontitis and alzheimer\u2019s disease-a narrative review. Int J Mol Sci 25(5):2612","journal-title":"Int J Mol Sci"},{"issue":"5","key":"6472_CR28","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1093\/jb\/mvj202","volume":"140","author":"M Hashimoto","year":"2006","unstructured":"Hashimoto M et al (2006) Selective proteolysis of apolipoprotein B-100 by Arg-gingipain mediates atherosclerosis progression accelerated by bacterial exposure. J Biochem 140(5):713\u2013723","journal-title":"J Biochem"},{"issue":"3","key":"6472_CR29","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1111\/jre.12527","volume":"53","author":"J L\u00f6nn","year":"2018","unstructured":"L\u00f6nn J et al (2018) Lipoprotein modifications by gingipains of Porphyromonas gingivalis. J Periodontal Res 53(3):403\u2013413","journal-title":"J Periodontal Res"},{"issue":"4","key":"6472_CR30","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1159\/000519737","volume":"14","author":"LT Song","year":"2022","unstructured":"Song LT et al (2022) Porphyromonas gingivalis gingipains-mediated degradation of plasminogen activator inhibitor-1 leads to delayed wound healing responses in human endothelial cells. J Innate Immun 14(4):306\u2013319","journal-title":"J Innate Immun"},{"issue":"8","key":"6472_CR31","doi-asserted-by":"publisher","first-page":"3027","DOI":"10.3390\/jcm12083027","volume":"12","author":"DM Castillo","year":"2023","unstructured":"Castillo DM et al (2023) The interaction effect of anti-RgpA and anti-PPAD antibody titers: an indicator for rheumatoid arthritis diagnosis. J Clin Med 12(8):3027\u20133027","journal-title":"J Clin Med"},{"issue":"6","key":"6472_CR32","doi-asserted-by":"publisher","first-page":"1599","DOI":"10.1124\/mol.104.004366","volume":"66","author":"T Kadowaki","year":"2004","unstructured":"Kadowaki T et al (2004) Suppression of pathogenicity of Porphyromonas gingivalis by newly developed gingipain inhibitors. Mol Pharmacol 66(6):1599\u20131606","journal-title":"Mol Pharmacol"},{"issue":"1","key":"6472_CR33","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1254\/jjp.85.84","volume":"85","author":"S Kitano","year":"2001","unstructured":"Kitano S et al (2001) Suppression of gingival inflammation induced by Porphyromonas gingivalis in rats by leupeptin. Jpn J Pharmacol 85(1):84\u201391","journal-title":"Jpn J Pharmacol"},{"issue":"8","key":"6472_CR34","doi-asserted-by":"publisher","first-page":"3564","DOI":"10.1096\/fj.14-252130","volume":"28","author":"S Kataoka","year":"2014","unstructured":"Kataoka S et al (2014) A novel, potent dual inhibitor of Arg-gingipains and Lys-gingipain as a promising agent for periodontal disease therapy. FASEB J 28(8):3564\u20133578","journal-title":"FASEB J"},{"key":"6472_CR35","doi-asserted-by":"publisher","first-page":"816047","DOI":"10.3389\/fmicb.2022.816047","volume":"13","author":"N Yoshino","year":"2022","unstructured":"Yoshino N, Ikeda T, Nakao R (2022) Dual inhibitory activity of petroselinic acid enriched in fennel against. Front Microbiol 13:816047. https:\/\/doi.org\/10.3389\/fmicb.2022.816047","journal-title":"Front Microbiol"},{"issue":"5","key":"6472_CR36","doi-asserted-by":"publisher","first-page":"1744","DOI":"10.1021\/jm0600141","volume":"49","author":"A Bialas","year":"2006","unstructured":"Bialas A et al (2006) Exploring the Sn binding pockets in gingipains by newly developed inhibitors: Structure-based design, chemistry, and activity. J Med Chem 49(5):1744\u20131753","journal-title":"J Med Chem"},{"issue":"1","key":"6472_CR37","doi-asserted-by":"publisher","DOI":"10.1186\/s13643-021-01626-4","volume":"10","author":"MJ Page","year":"2021","unstructured":"Page MJ et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev 10(1):89","journal-title":"Syst Rev"},{"key":"6472_CR38","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.ejphar.2018.01.028","volume":"824","author":"R Takii","year":"2018","unstructured":"Takii R et al (2018) Inhibition of gingipains prevents Porphyromonas gingivalis-induced preterm birth and fetal death in pregnant mice. Eur J Pharmacol 824:48\u201356","journal-title":"Eur J Pharmacol"},{"issue":"2","key":"6472_CR39","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1002\/JPER.19-0688","volume":"92","author":"S Yu","year":"2021","unstructured":"Yu S et al (2021) The sialidase inhibitor, DANA, reduces Porphyromonas gingivalis pathogenicity and exerts anti-inflammatory effects: an in vitro and in vivo experiment. J Periodontol 92(2):286\u2013297","journal-title":"J Periodontol"},{"key":"6472_CR40","doi-asserted-by":"publisher","first-page":"36023","DOI":"10.1038\/srep36023","volume":"6","author":"M Widziolek","year":"2016","unstructured":"Widziolek M et al (2016) Zebrafish as a new model to study effects of periodontal pathogens on cardiovascular diseases. Sci Rep 6:36023","journal-title":"Sci Rep"},{"issue":"11","key":"6472_CR41","doi-asserted-by":"publisher","first-page":"1616","DOI":"10.1902\/jop.2011.100785","volume":"82","author":"H Inaba","year":"2011","unstructured":"Inaba H et al (2011) Proliferation of smooth muscle cells stimulated by Porphyromonas gingivalis is inhibited by Apple polyphenol. J Periodontol 82(11):1616\u20131622","journal-title":"J Periodontol"},{"issue":"10","key":"6472_CR42","first-page":"18327","volume":"8","author":"C Cao","year":"2015","unstructured":"Cao C et al (2015) Gingipains from Porphyromonas gingivalis promote the transformation and proliferation of vascular smooth muscle cell phenotypes. Int J Clin Exp Med 8(10):18327\u201318334","journal-title":"Int J Clin Exp Med"},{"key":"6472_CR43","doi-asserted-by":"publisher","first-page":"816047","DOI":"10.3389\/fmicb.2022.816047","volume":"13","author":"N Yoshino","year":"2022","unstructured":"Yoshino N, Ikeda T, Nakao R (2022) Dual inhibitory activity of petroselinic acid enriched in fennel against Porphyromonas gingivalis. Front Microbiol 13:816047","journal-title":"Front Microbiol"},{"issue":"9","key":"6472_CR44","doi-asserted-by":"publisher","first-page":"1103","DOI":"10.1902\/jop.2016.160047","volume":"87","author":"H Inaba","year":"2016","unstructured":"Inaba H et al (2016) Apple- and hop-polyphenols inhibit Porphyromonas gingivalis-mediated precursor of matrix metalloproteinase-9 activation and invasion of oral squamous cell carcinoma cells. J Periodontol 87(9):1103\u20131111","journal-title":"J Periodontol"},{"key":"6472_CR45","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-020-02205-z","author":"HY Peng","year":"2020","unstructured":"Peng HY et al (2020) Targeting a cysteine protease from a pathobiont alleviates experimental arthritis. Arthritis Res Ther. https:\/\/doi.org\/10.1186\/s13075-020-02205-z","journal-title":"Arthritis Res Ther"},{"issue":"6","key":"6472_CR46","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1515\/BC.2003.102","volume":"384","author":"T Kadowaki","year":"2003","unstructured":"Kadowaki T et al (2003) Isolation and characterization of a novel and potent inhibitor of Arg-gingipain from streptomyces sp. strain FA-70. Biol Chem 384(6):911\u2013920","journal-title":"Biol Chem"},{"issue":"1","key":"6472_CR47","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.562","volume":"8","author":"S Arastu-Kapur","year":"2020","unstructured":"Arastu-Kapur S et al (2020) Treatment of Porphyromonas gulae infection and downstream pathology in the aged dog by lysine-gingipain inhibitor COR388. Pharmacol Res Perspect 8(1):e00562","journal-title":"Pharmacol Res Perspect"},{"issue":"1","key":"6472_CR48","doi-asserted-by":"publisher","first-page":"11759","DOI":"10.1038\/s41598-017-12173-1","volume":"7","author":"Y Liu","year":"2017","unstructured":"Liu Y et al (2017) Infection of microglia with Porphyromonas gingivalis promotes cell migration and an inflammatory response through the gingipain-mediated activation of protease-activated receptor-2 in mice. Sci Rep 7(1):11759","journal-title":"Sci Rep"},{"key":"6472_CR49","doi-asserted-by":"crossref","unstructured":"DeStefano F et al (1993) Dental disease and risk of coronary heart disease and mortality. BMJ 306(6879):688\u2013691","DOI":"10.1136\/bmj.306.6879.688"},{"issue":"4","key":"6472_CR50","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1007\/s40496-022-00319-8","volume":"9","author":"MI Ryder","year":"2022","unstructured":"Ryder MI (2022) The link between periodontitis and alzheimer\u2019s disease: reality or yet another association, in current oral health reports. Curr Oral Health Rep 9(4):157\u2013166","journal-title":"Curr Oral Health Rep"},{"issue":"1","key":"6472_CR51","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1034\/j.1600-0757.2001.22250103.x","volume":"25","author":"RI Garcia","year":"2001","unstructured":"Garcia RI, Henshaw MM, Krall EA (2001) Relationship between periodontal disease and systemic health. Periodontol 2000 25(1):21\u201336","journal-title":"Periodontol 2000"},{"key":"6472_CR52","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00045","author":"M Hussain","year":"2015","unstructured":"Hussain M, Stover CM, Dupont A (2015) P. gingivalis in periodontal disease and atherosclerosis - scenes of action for antimicrobial peptides and complement. Front Immunol. https:\/\/doi.org\/10.3389\/fimmu.2015.00045","journal-title":"Front Immunol"},{"issue":"7","key":"6472_CR53","doi-asserted-by":"publisher","first-page":"3073","DOI":"10.1007\/s00784-018-2727-0","volume":"23","author":"B Pretzl","year":"2019","unstructured":"Pretzl B et al (2019) Administration of systemic antibiotics during non-surgical periodontal therapy\u2014a consensus report. Clin Oral Invest 23(7):3073\u20133085","journal-title":"Clin Oral Invest"},{"issue":"3","key":"6472_CR54","doi-asserted-by":"publisher","first-page":"950","DOI":"10.1021\/acs.jcim.2c01198","volume":"63","author":"S Movilla","year":"2023","unstructured":"Movilla S et al (2023) Computational study of the inhibition of RgpB gingipain, a promising target for the treatment of alzheimer\u2019s disease. J Chem Inf Model 63(3):950\u2013958","journal-title":"J Chem Inf Model"},{"issue":"1","key":"6472_CR55","doi-asserted-by":"publisher","first-page":"4935","DOI":"10.1038\/s41598-019-41354-3","volume":"9","author":"T Guevara","year":"2019","unstructured":"Guevara T et al (2019) Structural determinants of inhibition of gingipain K by KYT-36, a potent, selective, and bioavailable peptidase inhibitor. Sci Rep 9(1):4935. https:\/\/doi.org\/10.1038\/s41598-019-41354-3","journal-title":"Sci Rep"},{"issue":"25","key":"6472_CR56","doi-asserted-by":"publisher","first-page":"17955","DOI":"10.1074\/jbc.274.25.17955","volume":"274","author":"Y Shi","year":"1999","unstructured":"Shi Y et al (1999) Genetic analyses of proteolysis, hemoglobin binding, and hemagglutination of Porphyromonas gingivalis. Construction of mutants with a combination of rgpa, rgpb, kgp, and HagA. J Biol Chem 274(25):17955\u201317960","journal-title":"J Biol Chem"},{"issue":"11","key":"6472_CR57","doi-asserted-by":"publisher","first-page":"1041","DOI":"10.1515\/BC.2004.135","volume":"385","author":"N Abe","year":"2004","unstructured":"Abe N et al (2004) Roles of Arg- and Lys-gingipains in coaggregation of Porphyromonas gingivalis: identification of its responsible molecules in translation products of rgpa, kgp, and HagA genes. Biol Chem 385(11):1041\u20131047","journal-title":"Biol Chem"},{"issue":"3\u20134","key":"6472_CR58","first-page":"223","volume":"378","author":"J Potempa","year":"1997","unstructured":"Potempa J, Pike R, Travis J (1997) Titration and mapping of the active site of cysteine proteinases from Porphyromonas gingivalis (gingipains) using peptidyl chloromethanes. Biol Chem 378(3\u20134):223\u2013230","journal-title":"Biol Chem"},{"issue":"40","key":"6472_CR59","doi-asserted-by":"publisher","first-page":"23619","DOI":"10.1074\/jbc.270.40.23619","volume":"270","author":"K Nakayama","year":"1995","unstructured":"Nakayama K et al (1995) Construction and characterization of arginine-specific cysteine proteinase (Arg-gingipain)-deficient mutants of Porphyromonas gingivalis. Evidence for significant contribution of Arg-gingipain to virulence. J Biol Chem 270(40):23619\u201323626","journal-title":"J Biol Chem"},{"issue":"7\u20138","key":"6472_CR60","first-page":"1223","volume":"383","author":"A Baba","year":"2002","unstructured":"Baba A et al (2002) Roles for Arg- and Lys-gingipains in the disruption of cytokine responses and loss of viability of human endothelial cells by Porphyromonas gingivalis infection. Biol Chem 383(7\u20138):1223\u20131230","journal-title":"Biol Chem"},{"issue":"1","key":"6472_CR61","doi-asserted-by":"publisher","first-page":"24800","DOI":"10.3402\/jom.v6.24800","volume":"6","author":"I Olsen","year":"2014","unstructured":"Olsen I, Potempa J (2014) Strategies for the inhibition of gingipains for the potential treatment of periodontitis and associated systemic diseases. J Oral Microbiol 6(1):24800. https:\/\/doi.org\/10.3402\/jom.v6.24800","journal-title":"J Oral Microbiol"},{"issue":"7","key":"6472_CR62","doi-asserted-by":"publisher","first-page":"e3000410","DOI":"10.1371\/journal.pbio.3000410","volume":"18","author":"N Percie du Sert","year":"2020","unstructured":"Percie du Sert N et al (2020) The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. PLoS Biol 18(7):e3000410\u2013e3000410","journal-title":"PLoS Biol"}],"container-title":["Clinical Oral Investigations"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00784-025-06472-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00784-025-06472-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00784-025-06472-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T23:02:32Z","timestamp":1758063752000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00784-025-06472-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,21]]},"references-count":62,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["6472"],"URL":"https:\/\/doi.org\/10.1007\/s00784-025-06472-5","relation":{},"ISSN":["1436-3771"],"issn-type":[{"value":"1436-3771","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,21]]},"assertion":[{"value":"27 May 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 July 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 August 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not Applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"418"}}