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Objective: Both periodontal disease and obesity are risk factors for dementia, but their links to 1brain function remain unclear. In this study, we examined the effects of oral infection with a periodontal pathogen on cognitive function in a mouse model of obesity, focusing on the roles of microglia. Methods: To create a mouse model of diet-induced obesity and periodontitis, male C57BL/6 J mice were first fed a high-fat diet containing 60% lipid calories for 18 weeks, beginning at 12 weeks of age, to achieve diet-induced obesity. Then, Porphyromonas gingivalis administration in the oral cavity twice weekly for 6 weeks was performed to induce periodontitis in obese mice. Results: Obese mice orally exposed to P. gingivalis showed cognitive impairment in the novel object recognition test. Increased expression levels of inflammatory cytokines (e.g. interleukin-1β and tumor necrosis factor-α) were observed in the hippocampus of P. gingivalis-treated obese mice. Immunohistochemical analysis revealed that microglia cell body size was increased in the hippocampus and prefrontal cortex of P. gingivalis-treated obese mice, indicating microglial activation. Furthermore, depletion of microglia by PLX3397, a colony-stimulating factor 1 receptor inhibitor, ameliorated cognitive dysfunction. Conclusion: These results suggest that microglia mediate periodontal infection-induced cognitive dysfunction in obesity. [ABSTRACT FROM AUTHOR]

Drug‐induced gingival enlargement (DIGE) is a side effect of ciclosporin, calcium channel blockers, and phenytoin. DIGE is a serious disease that leads to masticatory and esthetic disorders, severe caries, and periodontitis but currently has no standard treatment. We recently reported that nuclear receptor 4A1 (NR4A1) is a potential therapeutic target for DIGE. This study aimed to evaluate the therapeutic effects of n‐butylidenephthalide (BP), which increases the expression of NR4A1, on DIGE. In this study, NR4A1 mRNA expression was analyzed in the patients with periodontal disease (PD) and DIGE. We evaluated the effect of BP on NR4A1 expression in gingival fibroblasts and in a DIGE mouse model. RNA sequencing (RNA‐seq) was conducted to identify the mechanisms by which BP increases NR4A1 expression. The results showed that NR4A1 mRNA expression in the patients with DIGE was significantly lower than the patients with PD. BP suppressed the upregulation of COL1A1 expression, which was upregulated by TGF‐β. BP also ameliorated gingival overgrowth in DIGE mice and reduced Col1a1 and Pai1 expression. BP also decreased Il1β mRNA expression in gingival tissue in DIGE. RNA‐seq results showed an increase in the expression of several genes related to mitogen‐activated protein kinase including DUSP genes in gingival fibroblasts stimulated by BP. Treatment with ERK and JNK inhibitors suppressed the BP‐induced increase in NR4A1 expression. In addition, BP promoted the phosphorylation of ERK in gingival fibroblasts. In conclusion, BP increases NR4A1 expression in gingival fibroblasts through ERK and JNK signaling, demonstrating its potential as a preventive and therapeutic agent against DIGE. [ABSTRACT FROM AUTHOR]

Objective: To investigate the production of leucine‐rich α‐2‐glycoprotein‐1 (LRG1) in periodontitis patients and its effectiveness as a new diagnostic marker for periodontitis. Subjects and Methods: In vitro experiments were conducted to analyze LRG1 mRNA expression in human gingival epithelial cells and fibroblasts via quantitative real‐time PCR. In vivo experiments were conducted to analyze LRG1 localization in periodontitis patients. The correlation between the serum LRG1 levels and alveolar bone resorption in the mouse periodontitis model was also investigated. Results: A positive correlation existed between the periodontal inflamed surface area and serum LRG1 levels (Spearman's rank correlation coefficient: 0.60). LRG1 mRNA expression in human gingival epithelial cells and fibroblasts was upregulated by Porphyromonas gingivalis stimulation or tumor necrosis factor‐α stimulation. Interleukin‐6 in human gingival epithelial cells and fibroblasts induced the production of LRG1 and transforming growth factor‐β. LRG1 levels in the periodontal tissue and serum in the periodontitis model were higher than those in control mice. LRG1 local administration resulted in alveolar bone resorption, whereas the administration of interleukin‐6R antibody inhibited bone resorption. Conclusions: LRG1 levels in serum and periodontal tissue are upregulated in periodontitis and are implicated in periodontal tissue destruction through interleukin‐6 production. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the factors influencing the clinical outcomes of regenerative therapy using recombinant human fibroblast growth factor‐2 (rhFGF‐2). Background: rhFGF‐2 promotes periodontal regeneration, and identifying the factors influencing this regeneration is important for optimizing the effectiveness of rhFGF‐2. Methods and Materials: This study used a hospital information‐integrated database to identify patients who underwent periodontal regenerative therapy with rhFGF‐2. Factors included age, smoking status, diabetes mellitus (DM), periodontal inflamed surface area (PISA) at the initial visit, whether the most posterior tooth was involved or not, and preoperative radiological bone defect angle. Periodontal regenerative therapy outcomes were defined as good if radiographic bone fill ≥35% or periodontal pocket closure at 9–15 months after surgery. Bone fill rate (%) and periodontal pocket depth (mm) were also used as outcome measures. Factors were evaluated by simple regression analysis, and then the association between factors and the outcomes was determined by multivariate analysis. Results: PISA and age at the first visit did not significantly influence the success or failure of bone fill rate byrhFGF‐2. However, DM, radiographic bone defect angle, and the most posterior tooth significantly influenced the regenerative effect (success/failure in bone fill) of rhFGF‐2. The most posterior tooth was significantly associated with bone fill rate by rhFGF‐2. Examination of the association between pocket closure and factors shows that the most posterior tooth significantly influenced. The most posterior tooth and preoperative PPD were significantly associated with pocket reduction depth. For the most posterior tooth, a significantly higher bone regeneration rate (p <.05) was observed with a combination of autologous bone graft and rhFGF‐2 than with rhFGF‐2 alone, and the effect was significant in multivariate analysis. Conclusions: The radiographic bone defect angle, the involvement of most posterior teeth, and the presence of DM influenced the effectiveness of rhFGF‐2 in periodontal regeneration. However, PISA values and age at the initial visit had no significant effect. [ABSTRACT FROM AUTHOR]

Objectives The variable region of most ACPA IgG molecules in the serum of RA patients carries N -glycan (N -glycanV). To analyse the pathogenicity of N -glycanV of ACPAs, we analysed the pathogenicity of a monoclonal ACPA, CCP-Ab1, with or without N -glycanV, which had been isolated from a patient with RA. Methods CCP-Ab1 with no N -glycosylation site in the variable region (CCP-Ab1 N-rev) was generated, and antigen binding, the effect on in vitro differentiation of osteoclasts from bone marrow mononuclear cells of autoimmune arthritis–prone SKG mice (the cell size of TRAP+ cells and bone resorption capacity) and the in vivo effect on the onset or exacerbation of autoimmune arthritis in SKG mice were evaluated in comparison with glycosylated CCP-Ab1. Results Amino acid residues in citrullinated peptide (cfc1), which are essential for binding to CCP-Ab1 N-rev and original CCP-Ab1, were almost identical. The size of TRAP+ cells was significantly larger and osteoclast bone resorption capacity was enhanced in the presence of CCP-Ab1, but not with CCP-Ab1 N-rev. This enhancing activity required the sialic acid of the N -glycan and Fc region of CCP-Ab1. CCP-Ab1, but not CCP-Ab1 N-rev, induced the exacerbation of experimental arthritis in the SKG mouse model. Conclusions These data showed that N -glycanV was required for promoting osteoclast differentiation and bone resorption activity in both in vitro and in vivo assays. The present study demonstrated the important role of N -glycanV in the exacerbation of experimental arthritis by ACPAs. [ABSTRACT FROM AUTHOR]