{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T23:07:15Z","timestamp":1791846435016,"version":"4.3.4"},"reference-count":53,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,1,12]],"date-time":"2025-01-12T00:00:00Z","timestamp":1736640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Periodontal Research"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Aim<\/jats:title><jats:p>Periodontitis is a chronic inflammatory disease initiated by dysbiosis of the local microbial community. As a non\u2010specific phosphodiesterase inhibitor, dipyridamole features anti\u2010oxidant and anti\u2010inflammatory properties. This study aimed to investigate the effects of dipyridamole in an experimental rat model of periodontitis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Thirty rats were divided randomly into three groups (<jats:italic>n<\/jats:italic>\u2009=\u200910): non\u2010ligature group (NL), ligature\u2010induced periodontitis group (L), and ligature\u2010induced periodontitis with dipyridamole administered group (L\u2009+\u2009D). All rats were euthanized on Day 14. Alveolar bone resorption was analyzed by microcomputed tomography. The mRNA levels of <jats:italic>Il1b<\/jats:italic>, <jats:italic>Il6<\/jats:italic>, tumor necrosis factor alpha (<jats:italic>Tnfa<\/jats:italic>), and inducible nitric oxide synthase (<jats:italic>iNos<\/jats:italic>) in gingival tissue were assessed by real\u2010time quantitative polymerase chain reaction (qRT\u2010PCR). Inflammation level, osteoclasts, and macrophages infiltration were analyzed histologically. RAW264.7 macrophages were stimulated with <jats:styled-content style=\"fixed-case\"><jats:italic>Porphyromonas gingivalis<\/jats:italic><\/jats:styled-content> lipopolysaccharide (<jats:italic>P.g.<\/jats:italic> LPS) to induce M1 polarization. Different concentration of dipyridamole (0\/2\/10\u2009\u03bcM) was added simultaneously. To explore the role of PKA\/PKG pathways, RAW 264.7 macrophages were pretreated with 10\u2009\u03bcM H\u201089 (PKA inhibitor) or 1\u2009\u03bcM KT\u20105823 (PKG inhibitor), respectively. Expression of pro\u2010inflammatory cytokines and M1 markers were detected by qRT\u2010PCR, ELISA, and flow cytometry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Dipyridamole administration reduced alveolar bone loss, protein levels of inflammatory cytokines, and osteoclastogenesis in rats with experimental periodontitis. It also showed a tendency to decrease mRNA levels of <jats:italic>Il1b<\/jats:italic>, <jats:italic>Il6<\/jats:italic>, <jats:italic>and Tnfa<\/jats:italic> but without significant differences\u00a0in gingival tissues. Moreover, the infiltration of macrophage and M1 macrophage polarization in gingival tissue of periodontitis rats were inhibited by dipyridamole administration. In addition, dipyridamole could downregulate the gene expression of <jats:italic>Il1b<\/jats:italic> and <jats:italic>Tnfa<\/jats:italic>, as well as the protein level of TNF\u2010\u03b1, CD86, and iNOS in RAW264.7 treated with <jats:italic>P.g.<\/jats:italic> LPS. When PKA\/PKG pathways were blocked, the suppression of TNF\u2010\u03b1, CD86, and iNOS was reversed significantly.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Dipyridamole alleviated experimental periodontitis in rat models by regulating M1 polarization via activation of PKA\/PKG pathways and emerges as a hopeful remedy for periodontitis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jre.13378","type":"journal-article","created":{"date-parts":[[2025,1,12]],"date-time":"2025-01-12T08:14:09Z","timestamp":1736669649000},"page":"710-722","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Dipyridamole Attenuates Experimental Periodontitis by Regulating <scp>M1<\/scp> Macrophage Polarization via <scp>PKA<\/scp>\/<scp>PKG<\/scp> Pathways"],"prefix":"10.1111","volume":"60","author":[{"given":"Jiaying","family":"Song","sequence":"first","affiliation":[{"name":"Hospital of Stomatology Sun Yat\u2010Sen 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