{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T23:08:16Z","timestamp":1789081696970,"version":"build-2803163510"},"reference-count":43,"publisher":"Georg Thieme Verlag KG","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Planta Med"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Periodontitis is a chronic inflammatory disease driven by dysbiosis of the\n                    subgingival microbiota, leading to immune dysregulation and progressive alveolar\n                    bone loss. In recent years, immunotherapeutic approaches, particularly those\n                    involving natural products, have gained attention as potential adjuvants to\n                    conventional therapy. This study evaluated the effects of four alkaloids,\n                    boldine, laurolitsine, laurotetanine, and N-methyl-laurotetanine, on\n                    alveolar bone loss and local immune regulation in experimental\n                    periodontitis.<\/jats:p>\n                  <jats:p>Male and female C57BL\/6 mice with ligature-induced periodontitis received daily\n                    oral administration of each alkaloid (20\u2009mg\/kg) for 10 days. Alveolar bone loss\n                    was quantified by micro-computed tomography (micro-CT). Periodontal immune\n                    responses were assessed by RT-qPCR analysis of pro-inflammatory cytokines,\n                    T-cell-related transcription factors, and bone metabolism mediators (RANKL and\n                    OPG). In addition, regulatory T (Treg) cells in cervical lymph nodes were\n                    analyzed by flow cytometry.<\/jats:p>\n                  <jats:p>Boldine and laurolitsine significantly reduced alveolar bone loss compared with\n                    untreated periodontitis, in parallel with decreased RANKL expression. All four\n                    alkaloids significantly reduced IL-6 expression, with laurolitsine additionally\n                    suppressing IL-17A expression in periodontal tissues, whereas\n                    N-methyl-laurotetanine reduced IL-10 expression. No significant changes\n                    were observed in CD4+, CD4+FoxP3+, and\n                        CD4+FoxP3+CD25+ T-cell frequencies between\n                    treated and untreated groups.<\/jats:p>\n                  <jats:p>Oral administration of boldine and laurolitsine attenuates\n                    periodontitis-associated alveolar bone loss, likely through differential\n                    modulation of cytokine networks and osteoclastogenic signaling. These findings\n                    support their potential as host-modulating agents in the management of\n                    periodontitis.<\/jats:p>","DOI":"10.1055\/a-2834-4446","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T23:56:51Z","timestamp":1773705411000},"page":"1030-1040","source":"Crossref","is-referenced-by-count":1,"title":["Boldine and Laurolitsine Protect against Periodontitis-Associated\n                    Bone Loss via RANKL Downregulation"],"prefix":"10.1055","volume":"92","author":[{"given":"Sebasti\u00e1n","family":"Castro-Saavedra","sequence":"additional","affiliation":[{"name":"Laboratorio de Qu\u00edmica Biodin\u00e1mica, Facultad de Ciencias, Departamento\n                    de Qu\u00edmica, Universidad de Chile, Santiago, Chile"},{"name":"Laboratorio de Biolog\u00eda Periodontal, Facultad de Odontolog\u00eda,\n                    Universidad de Chile, Santiago, Chile"},{"name":"SAPHYCHEM, Santiago, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gonzalo","family":"Fuentes-Barros","sequence":"additional","affiliation":[{"name":"SAPHYCHEM, Santiago, Chile"},{"name":"Programa de Doctorado en Pol\u00edticas P\u00fablicas, Universidad Mayor,\n                    Santiago, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Rojas","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Periodontal, Facultad de Odontolog\u00eda,\n                    Universidad de Chile, Santiago, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Pellegrini","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Periodontal, Facultad de Odontolog\u00eda,\n                    Universidad de Chile, Santiago, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Garc\u00eda","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Periodontal, Facultad de Odontolog\u00eda,\n                    Universidad de Chile, Santiago, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcela","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Periodontal, Facultad de Odontolog\u00eda,\n                    Universidad de Chile, Santiago, Chile"},{"name":"Departamento de Patolog\u00eda y Medicina Oral, Facultad de Odontolog\u00eda,\n                    Universidad de Chile, Santiago, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolando","family":"Vernal","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Periodontal, Facultad de Odontolog\u00eda,\n                    Universidad de Chile, Santiago, Chile"},{"name":"Departamento de Odontolog\u00eda Conservadora, Facultad de Odontolog\u00eda,\n                    Universidad de Chile, Santiago, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce K.","family":"Cassels","sequence":"additional","affiliation":[{"name":"Laboratorio de Qu\u00edmica Biodin\u00e1mica, Facultad de Ciencias, Departamento\n                    de Qu\u00edmica, Universidad de Chile, Santiago, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1316","DOI":"10.1186\/s12889-025-22566-x","article-title":"Global burden of periodontal diseases among the working-age population from\n                    1990\u20132021: Results from the Global Burden of Disease Study 2021","volume":"25","author":"H Fu","year":"2025","journal-title":"BMC Public Health"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"e116","DOI":"10.1590\/1807-3107bor-2024.vol38.0116","article-title":"Prevalence of periodontal diseases: Latin America and the Caribbean Consensus\n                    2024","volume":"38","author":"P Carvajal","year":"2024","journal-title":"Braz Oral Res"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"e023","DOI":"10.1590\/1807-3107bor-2020.vol34.0023","article-title":"Periodontal disease and its impact on general health in Latin America. Section\n                    II: Introduction part II","volume":"34","author":"P Carvajal","year":"2020","journal-title":"Braz Oral Res"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"e70118","DOI":"10.1002\/jev2.70118","article-title":"Induced Treg-derived extracellular vesicles suppress CD4+ T-Cell-mediated\n                    inflammation and ameliorate bone loss during periodontitis partly through\n                    CD73\/Adenosine-dependent immunomodulatory mechanisms","volume":"14","author":"C Rojas","year":"2025","journal-title":"J Extracell Vesicles"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1007\/s00774-020-01165-3","article-title":"RANKL and osteoimmunology in periodontitis","volume":"39","author":"M Tsukasaki","year":"2021","journal-title":"J Bone Miner Metab"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1111\/prd.12371","article-title":"Polymicrobial communities in periodontal disease: Their quasi-organismal nature\n                    and dialogue with the host","volume":"86","author":"G Hajishengallis","year":"2021","journal-title":"Periodontol 2000"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"5499","DOI":"10.1007\/s00784-023-05168-y","article-title":"Revealing leukocyte populations in human peri-implantitis and periodontitis\n                    using flow cytometry","volume":"27","author":"O Ginesin","year":"2023","journal-title":"Clin Oral Investig"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1664","DOI":"10.3389\/fimmu.2019.01664","article-title":"Osteoimmunology of oral and maxillofacial diseases: Translational applications\n                    based on biological mechanisms","volume":"10","author":"C Alvarez","year":"2019","journal-title":"Front Immunol"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1385436","DOI":"10.3389\/fimmu.2024.1385436","article-title":"An update on periodontal inflammation and bone 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Huang","year":"2021","journal-title":"Front Immunol"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1016\/j.archoralbio.2010.06.003","article-title":"IL-17A stimulates the expression of inflammatory cytokines via celecoxib-blocked\n                    prostaglandin in MC3\u2009T3-E1 cells","volume":"55","author":"F Zhang","year":"2010","journal-title":"Arch Oral Biol"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1435054","DOI":"10.3389\/fimmu.2024.1435054","article-title":"Cytokines in gingivitis and periodontitis: From pathogenesis to therapeutic\n                    targets","volume":"15","author":"N Neurath","year":"2024","journal-title":"Front Immunol"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1469414","DOI":"10.3389\/fmicb.2024.1469414","article-title":"Periodontitis: Etiology, conventional treatments, and emerging bacteriophage and\n                    predatory bacteria therapies","volume":"15","author":"A \u0141asica","year":"2024","journal-title":"Front Microbiol"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"546","DOI":"10.3390\/biom15040546","article-title":"Regenerative strategies in dentistry: Harnessing stem cells, biomaterials and\n                    bioactive materials for tissue repair","volume":"15","author":"V R Umapathy","year":"2025","journal-title":"Biomolecules"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"31","DOI":"10.2174\/2215083804666181113112928","article-title":"Boldo, its secondary metabolites and their derivatives","volume":"5","author":"B K Cassels","year":"2019","journal-title":"Curr Tradit Med"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/B978-0-12-822923-1.00006-6","volume-title":"A Centum of Valuable Plant Bioactives","author":"B K Cassels","year":"2021","edition":"1st 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mice","volume":"68","author":"S Li","year":"2024","journal-title":"Mol Nutr Food Res"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1002\/JPER.20-0055","article-title":"Boldine inhibits the alveolar bone resorption during ligature-induced\n                    periodontitis by modulating the Th17\/Treg imbalance","volume":"92","author":"E A Cafferata","year":"2021","journal-title":"J Periodontol"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1258\/ebm.2012.011416","article-title":"Norisoboldine, an alkaloid compound isolated from Radix Linderae, inhibits\n                    synovial angiogenesis in adjuvant-induced arthritis rats by moderating Notch1\n                    pathway-related endothelial tip cell phenotype","volume":"237","author":"Q Lu","year":"2012","journal-title":"Exp Biol Med"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1016\/j.phymed.2010.01.013","article-title":"Therapeutic effect of norisoboldine, an alkaloid isolated from Radix Linderae,\n                    on collagen-induced arthritis in mice","volume":"17","author":"Y Luo","year":"2010","journal-title":"Phytomedicine"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/1043-6618(94)80093-6","article-title":"Boldo and boldine: An emerging case of natural drug development","volume":"29","author":"H Speisky","year":"1994","journal-title":"Pharmacol Res"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/j.fitote.2018.02.020","article-title":"Variation of the alkaloid content of Peumus boldus (boldo)","volume":"127","author":"G Fuentes-Barros","year":"2018","journal-title":"Fitoterapia"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"100502","DOI":"10.1016\/j.jarmap.2023.100502","article-title":"Phytochemical variation of wild and farmed populations of boldo (Peumus\n                        boldus Molina)","volume":"35","author":"G Fuentes-Barros","year":"2023","journal-title":"J Appl Res Med Aromat Plants"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"1427147","DOI":"10.3389\/fphar.2024.1427147","article-title":"Pharmacology of boldine: Summary of the field and update on recent advances","volume":"15","author":"J Saez","year":"2024","journal-title":"Front Pharmacol"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1039\/D0NJ04028B","article-title":"Structure\u2013antioxidant activity relationships in boldine and glaucine: A DFT\n                    study","volume":"45","author":"A V\u00e1squez-Espinal","year":"2021","journal-title":"New J Chem"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cbi.2005.09.002","article-title":"Boldine and its antioxidant or health-promoting properties","volume":"159","author":"P O\u02bcBrien","year":"2006","journal-title":"Chem Biol Interact"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1111\/j.1365-2249.2007.03441.x","article-title":"The expanding family of interleukin-1 cytokines and their role in destructive\n                    inflammatory disorders","volume":"149","author":"H E Barksby","year":"2007","journal-title":"Clin Exp Immunol"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"3201","DOI":"10.2147\/JIR.S507269","article-title":"Osteoclast activation and inflammatory bone diseases: Focusing on receptors in\n                    osteoclasts","volume":"18","author":"W Zhao","year":"2025","journal-title":"J Inflamm Res"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.job.2022.04.005","article-title":"Immunopathogenesis and distinct role of Th17 in periodontitis: A review","volume":"64","author":"V Kini","year":"2022","journal-title":"J Oral Biosci"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"781378","DOI":"10.3389\/fimmu.2021.781378","article-title":"Immunomodulation in the treatment of periodontitis: Progress and\n                    perspectives","volume":"12","author":"B Yang","year":"2021","journal-title":"Front Immunol"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1111\/jre.12654","article-title":"IL-22\u2013expressing CD4+AhR+ T lymphocytes are associated with RANKL-mediated\n                    alveolar bone resorption during experimental periodontitis","volume":"54","author":"G Monasterio","year":"2019","journal-title":"J Periodontal Res"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1002\/JPER.17-0563","article-title":"Alveolar bone resorption and Th1\/Th17-associated immune response triggered\n                    during Aggregatibacter actinomycetemcomitans-induced experimental\n                    periodontitis are serotype-dependent","volume":"89","author":"G Monasterio","year":"2018","journal-title":"J Periodontol"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"664756","DOI":"10.3389\/fimmu.2021.664756","article-title":"RvE1 impacts the gingival inflammatory infiltrate by inhibiting the T Cell\n                    response in experimental periodontitis","volume":"12","author":"C Alvarez","year":"2021","journal-title":"Front Immunol"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1007\/s00223-026-01482-1","article-title":"Understanding bone metabolism biomarker variability across the menstrual cycle:\n                    A systematic review","volume":"117","author":"I Guisado-Cuadrado","year":"2026","journal-title":"Calcif Tissue Int"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1124945","DOI":"10.3389\/fmicb.2023.1124945","article-title":"The associations of gut microbiota, endocrine system and bone metabolism","volume":"14","author":"Y Tu","year":"2023","journal-title":"Front Microbiol"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1002\/JPER.18-0755","article-title":"The down-regulation of Notch 1 signaling contributes to the severity of bone\n                    loss in aggressive periodontitis","volume":"91","author":"I Mijailovic","year":"2020","journal-title":"J Periodontol"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1111\/jre.12801","article-title":"Impact of Notch signalling molecules and bone resorption regulators on clinical\n                    parameters in periodontitis","volume":"56","author":"A Djinic Krasavcevic","year":"2021","journal-title":"J Periodontal Res"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1111\/jcpe.13282","article-title":"Interleukin-35 inhibits alveolar bone resorption by modulating the Th17\/Treg\n                    imbalance during periodontitis","volume":"47","author":"E A Cafferata","year":"2020","journal-title":"J Clin Periodontol"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"100330","DOI":"10.1016\/j.xpro.2021.100330","article-title":"Method for voluntary oral administration of drugs in mice","volume":"2","author":"L Zhang","year":"2021","journal-title":"STAR Protoc"}],"container-title":["Planta Medica"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-2834-4446.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T22:30:34Z","timestamp":1789079434000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-2834-4446"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,16]]},"references-count":43,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,9,10]]},"published-print":{"date-parts":[[2026,9]]}},"URL":"https:\/\/doi.org\/10.1055\/a-2834-4446","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["0032-0943","1439-0221"],"issn-type":[{"value":"0032-0943","type":"print"},{"value":"1439-0221","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,3,16]]},"published":{"date-parts":[[2026,3,16]]}}}