PMID- 37289398 OWN - NLM STAT- MEDLINE DCOM- 20231023 LR - 20240124 IS - 1573-2576 (Electronic) IS - 0360-3997 (Linking) VI - 46 IP - 5 DP - 2023 Oct TI - Glipizide Alleviates Periodontitis Pathogenicity via Inhibition of Angiogenesis, Osteoclastogenesis and M1/M2 Macrophage Ratio in Periodontal Tissue. PG - 1917-1931 LID - 10.1007/s10753-023-01850-1 [doi] AB - New consensus indicates type 2 diabetes mellitus (T2DM) and periodontitis as comorbidity and may share common pathways of disease progression. Sulfonylureas have been reported to improve the periodontal status in periodontitis patients. Glipizide, a sulfonylurea widely used in the treatment of T2DM, has also been reported to inhibit inflammation and angiogenesis. The effect of glipizide on the pathogenicity of periodontitis, however, has not been studied. We developed ligature-induced periodontitis in mice and treated them with different concentrations of glipizide and then analyzed the level of periodontal tissue inflammation, alveolar bone resorption, and osteoclast differentiation. Inflammatory cell infiltration and angiogenesis were analyzed using immunohistochemistry, RT-qPCR, and ELISA. Transwell assay and Western bolt analyzed macrophage migration and polarization. 16S rRNA sequencing analyzed the effect of glipizide on the oral microbial flora. mRNA sequencing of bone marrow-derived macrophages (BMMs) stimulated by P. gingivalis lipopolysaccharide (Pg-LPS) after treatment with glipizide was analyzed. Glipizide decreases alveolar bone resorption, periodontal tissue degradation, and the number of osteoclasts in periodontal tissue affected by periodontitis (PAPT). Glipizide-treated periodontitis mice showed reduced micro-vessel density and leukocyte/macrophage infiltration in PAPT. Glipizide significantly inhibited osteoclast differentiation in vitro experiments. Glipizide treatment did not affect the oral microbiome of periodontitis mice. mRNA sequencing and KEGG analysis showed that glipizide activated PI3K/AKT signaling in LPS-stimulated BMMs. Glipizide inhibited the LPS-induced migration of BMMs but promoted M2/M1 macrophage ratio in LPS-induced BMMs via activation of PI3K/AKT signaling. In conclusion, glipizide inhibits angiogenesis, macrophage inflammatory phenotype, and osteoclastogenesis to alleviate periodontitis pathogenicity suggesting its' possible application in the treatment of periodontitis and diabetes comorbidity. CI - (c) 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - Guo, Xueqi AU - Guo X AD - Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, 510182, Guangdong, China. FAU - Huang, Zhijun AU - Huang Z AD - Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, 510182, Guangdong, China. FAU - Ge, Qing AU - Ge Q AD - Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, 510182, Guangdong, China. FAU - Yang, Luxi AU - Yang L AD - Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, 510182, Guangdong, China. FAU - Liang, Dongliang AU - Liang D AD - Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, 510182, Guangdong, China. FAU - Huang, Yinyin AU - Huang Y AD - Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, 510182, Guangdong, China. FAU - Jiang, Yiqin AU - Jiang Y AD - Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, 510182, Guangdong, China. FAU - Pathak, Janak Lal AU - Pathak JL AD - Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, 510182, Guangdong, China. FAU - Wang, Lijing AU - Wang L AD - School of Life Sciences and Biopharmaceutics, Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China. FAU - Ge, Linhu AU - Ge L AD - Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, 510182, Guangdong, China. gelinhu@yeah.net. LA - eng PT - Journal Article DEP - 20230608 PL - United States TA - Inflammation JT - Inflammation JID - 7600105 RN - X7WDT95N5C (Glipizide) RN - 0 (Lipopolysaccharides) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - 0 (RNA, Ribosomal, 16S) RN - 0 (RNA, Messenger) SB - IM MH - Humans MH - Mice MH - Animals MH - Osteogenesis MH - Glipizide/metabolism/pharmacology MH - *Diabetes Mellitus, Type 2/metabolism MH - Lipopolysaccharides/pharmacology MH - Proto-Oncogene Proteins c-akt/metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - RNA, Ribosomal, 16S/metabolism MH - Virulence MH - *Periodontitis/drug therapy/metabolism MH - Osteoclasts/metabolism MH - Inflammation/metabolism MH - Macrophages/metabolism MH - *Alveolar Bone Loss/drug therapy/prevention & control/metabolism MH - RNA, Messenger/metabolism OTO - NOTNLM OT - PI3K/AKT signaling. OT - angiogenesis OT - glipizide OT - macrophage OT - osteoclastogenesis OT - periodontitis EDAT- 2023/06/08 13:07 MHDA- 2023/10/23 00:44 CRDT- 2023/06/08 11:14 PHST- 2023/04/02 00:00 [received] PHST- 2023/05/29 00:00 [accepted] PHST- 2023/05/11 00:00 [revised] PHST- 2023/10/23 00:44 [medline] PHST- 2023/06/08 13:07 [pubmed] PHST- 2023/06/08 11:14 [entrez] AID - 10.1007/s10753-023-01850-1 [pii] AID - 10.1007/s10753-023-01850-1 [doi] PST - ppublish SO - Inflammation. 2023 Oct;46(5):1917-1931. doi: 10.1007/s10753-023-01850-1. Epub 2023 Jun 8.