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担当区分：責任著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

The macrolide erythromycin (ERM) inhibits excessive neutrophil accumulation and bone resorption in inflammatory tissues. We previously reported that the expression of developmental endothelial locus-1 (DEL-1), an endogenous anti-inflammatory factor induced by ERM, is involved in ERM action. Furthermore, DEL-1 is involved in the induction of bone regeneration. Therefore, in this study, we investigated whether ERM exerts an osteoblastogenic effect by upregulating DEL-1 under inflammatory conditions. We performed in vitro cell-based mechanistic analyses and used a model of Porphyromonas gingivalis lipopolysaccharide (LPS)-induced periodontitis to evaluate how ERM restores osteoblast activity. In vitro, P. gingivalis LPS stimulation suppressed osteoblast differentiation and bone formation. However, ERM treatment combined with P. gingivalis LPS stimulation upregulated osteoblast differentiation-related factors and Del1, indicating that osteoblast differentiation was restored. Alveolar bone resorption and gene expression were evaluated in a periodontitis model, and the results confirmed that ERM treatment increased DEL-1 expression and suppressed bone loss by increasing the expression of osteoblast-associated factors. In conclusion, ERM restores bone metabolism homeostasis in inflammatory environments possibly via the induction of DEL-1.

DOI： 10.3390/ph16020303

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担当区分：責任著者   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/ijms23105540

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-022-12358-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.4049/immunohorizons.2100110

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/antibiotics10121550

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.it.2021.08.001

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担当区分：責任著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Macrolides are used to treat various infectious diseases, including periodontitis. Furthermore, macrolides are known to have immunomodulatory effects; however, the underlying mechanism of their action remains unclear. DEL-1 has emerged as an important factor in homeostatic immunity and osteoclastogenesis. Specifically, DEL-1 is downregulated in periodontitis tissues. Therefore, in the present study, we investigated whether the osteoclastogenesis inhibitory effects of erythromycin (ERM) are mediated through upregulation of DEL-1 expression. We used a ligature-induced periodontitis model in C57BL/6Ncrl wild-type or DEL-1-deficient mice and in vitro cell-based mechanistic studies to investigate how ERM inhibits alveolar bone resorption. As a result of measuring alveolar bone resorption and gene expression in the tooth ligation model, ERM treatment reduced bone loss by increasing DEL-1 expression and decreasing the expression of osteoclast-related factors in wild-type mice. In DEL-1-deficient mice, ERM failed to suppress bone loss and gene expression of osteoclast-related factors. In addition, ERM treatment downregulated osteoclast differentiation and calcium resorption in in vitro experiments with mouse bone marrow-derived macrophages. In conclusion, ERM promotes the induction of DEL-1 in periodontal tissue, which may regulate osteoclastogenesis and decrease inflammatory bone resorption. These findings suggest that ERM may exert immunomodulatory effects in a DEL-1-dependent manner.

DOI： 10.3390/antibiotics10030312

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0240329

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1172/jci.insight.136706

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Streptococcus mutans is the main pathogen of dental caries and adheres to the tooth surface via soluble and insoluble glucans produced by the bacterial glucosyltransferase enzyme. Thus, the S. mutans glucosyltransferase is an important virulence factor for this cariogenic bacterium. Sulfated vizantin effectively inhibits biofilm formation by S. mutans without affecting its growth. In this study, less S. mutans biofilm formation occurred on hydroxyapatite discs coated with sulfated vizantin than on noncoated discs. Sulfated vizantin showed no cytotoxicity against the human gingival cell line Ca9-22. Sulfated vizantin dose-dependently inhibited the extracellular release of cell-free glucosyltransferase from S. mutans and enhanced the accumulation of cell-associated glucosyltransferase, compared with that observed with untreated bacteria. Sulfated vizantin disrupted the localization balance between cell-associated glucosyltransferase and cell-free glucosyltransferase, resulting in inhibited biofilm maturation. These results indicate that sulfated vizantin can potentially serve as a novel agent for preventing dental caries.

DOI： 10.1111/1348-0421.12797

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1074/jbc.RA120.013024.

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掲載種別：論文集(書籍)内論文  

DOI： 10.1007/978-3-030-42990-4_2

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.4049/jimmunol.1900746

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.archoralbio.2020.104679

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1177/0022034519894957

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/1348-0421.12688

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aggregatibacter actinomycetemcomitans is considered to be associated with periodontitis. Leukotoxin (LtxA), which destroys leukocytes in humans, is one of this bacterium's major virulence factors. Amounts of neutrophil elastase (NE), which is normally localized in the cytoplasm of neutrophils, are reportedly increased in the saliva of patients with periodontitis. However, the mechanism by which NE is released from human neutrophils and the role of NE in periodontitis is unclear. In the present study, it was hypothesized that LtxA induces NE release from human neutrophils, which subsequently causes the breakdown of periodontal tissues. LtxA-treatment did not induce significant cytotoxicity against human gingival epithelial cells (HGECs) or human gingival fibroblasts (HGFs). However, it did induce significant cytotoxicity against human neutrophils, leading to NE release. Furthermore, NE and the supernatant from LtxA-treated human neutrophils induced detachment and death of HGECs and HGFs, these effects being inhibited by administration of an NE inhibitor, sivelestat. The present results suggest that LtxA mediates human neutrophil lysis and induces the subsequent release of NE, which eventually results in detachment and death of HGECs and HGFs. Thus, LtxA-induced release of NE could cause breakdown of periodontal tissue and thereby exacerbate periodontitis.

DOI： 10.1111/1348-0421.12672

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記述言語：英語  

Increase in antimicrobial resistance (AMR) among pathogenic bacteria is a serious threat to public health. Surveillance studies to monitor shifting trends in resistance are important and guide the selection of appropriate antimicrobial agents for a particular organism. Furthermore, these studies help in dissemination of accurate information regarding AMR to the public. In this study, we investigated the antimicrobial susceptibility patterns of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis clinical isolates from outpatient children with acute otitis media in Japan from 2014 to 2017. A total of 8693 strains (2415 of S. pneumoniae, 3657 of H. influenzae, and 2621 of M. catarrhalis) were clinically isolated, and their antimicrobial susceptibilities to benzylpenicillin (PCG), ampicillin (ABPC), amoxicillin-clavulanic (AMPC/CVA), azithromycin (AZM), ceftriaxone (CTRX), and levofloxacin (LVFX) were investigated. Based on the minimum inhibitory concentration (MIC) breakpoints, the average proportion of S. pneumoniae isolates non-susceptible to PCG and AZM was 38.2% and 82.0% respectively. The average proportion of H. influenzae isolates non-susceptible to ABPC, CVA/AMPC, and CTRX was 61.9%, 43.5%, and 49.4%, respectively. The high prevalence of these resistant organisms is attributed to frequent use of antibiotic agents in Japan. Moreover, the proportion of LVFX-non-susceptible H. influenzae isolates increased in this four-year study. Here, we report updates regarding the AMR trends amongst the major pathogens that cause acute otitis media in Japan. Continuing surveillance of antimicrobial susceptibility and application of control measures against further transmission are required to decrease the emergence of resistant strains.

DOI： 10.1016/j.jiac.2018.08.018

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掲載種別：研究論文（学術雑誌）  

DOI： 10.3389/fimmu.2019.00406

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Food-derived peptides have been reported to exhibit antibacterial activity against periodontal pathogenic bacteria. However, no effect has been shown on inflammation and bone resorption in periodontal pathology. The overall objective of the current study was to investigate how rice peptides influence biological defense mechanisms against periodontitis-induced inflammatory bone loss, and identify their novel functions as a potential anti-inflammatory drug. DESIGN: The expression of inflammatory and osteoclast-related molecules was examined in mouse macrophage-derived RAW 264.7 cell cultures using qPCR. Subsequently, the effect of these peptides on inflammatory bone loss in mouse periodontitis was examined using a mouse model of tooth ligation. Briefly, periodontal bone loss was induced for 7 days in mice by ligating the maxillary second molar and leaving the contralateral tooth un-ligated (baseline control). The mice were microinjected daily with the peptide in the gingiva until the day before euthanization. One week after the ligation, TRAP-positive multinucleated cells (MNCs) were enumerated from five random coronal sections of the ligated sites in each mouse. RESULTS: Rice peptides REP9 and REP11 significantly inhibited transcription activity of inflammatory and osteoclast-related molecules. Local treatment with the rice peptides, in mice subjected to ligature-induced periodontitis, inhibited inflammatory bone loss, explaining the decreased numbers of osteoclasts in bone tissue sections. CONCLUSION: Therefore, these data suggested that the rice peptides possess a protective effect against periodontitis.

DOI： 10.1016/j.archoralbio.2018.11.021

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Vaccination is an effective strategy to prevent pneumococcal diseases. Currently, licensed vaccines include the pneumococcal polysaccharide vaccine (PPSV) and the pneumococcal conjugate vaccine (PCV), which target some of the most common of the 94 serotypes of S. pneumoniae based on their capsular composition. However, it has been reported that PPSV is not effective in children aged less than 2 years old and PCV induces serotype replacement, which means that the pneumococcal population has changed following widespread introduction of these vaccines, and the non-vaccine serotypes have increased in being the cause of invasive pneumococcal disease. Therefore, it is important that there is development of novel pneumococcal vaccines to either replace or complement current polysaccharide-based vaccines. Our previous study suggested that S. pneumoniae releases elongation factor Tu (EF-Tu) through autolysis followed by the induction of proinflammatory cytokines in macrophages via toll-like receptor 4, that may contribute to the development of pneumococcal diseases. In this study, we investigated the expression of EF-Tu in various S. pneumoniae strains and whether EF-Tu could be an antigen candidate for serotype-independent vaccine against pneumococcal infection. Western blotting and flow cytometry analysis revealed that EF-Tu is a common factor expressed on the surface of all pneumococcal strains tested, as well as intracellularly. In addition, we demonstrate that immunization with recombinant (r) EF-Tu induced the production of inflammatory cytokines and the IgG1 and IgG2a antibodies in mice, and increased the CD4+ T-cells proportion in splenocytes. We also reveal that anti-EF-Tu serum increased the phagocytic activity of mouse peritoneal macrophages against S. pneumoniae infection, independent of their serotypes. Finally, our results indicate that mice immunized with rEF-Tu were significantly and non-specifically protected against lethal challenges with S. pneumoniae serotypes (2 and 15A). Therefore, pneumococcal EF-Tu could be an antigen candidate for the serotype-independent vaccine against pneumococcal infection.

DOI： 10.1016/j.vaccine.2018.11.015

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature Publishing Group  

Several studies have demonstrated the remarkable properties of microbiota and their metabolites in the pathogenesis of several inflammatory diseases. 10-Hydroxy-cis-12-octadecenoic acid (HYA), a bioactive metabolite generated by probiotic microorganisms during the process of fatty acid metabolism, has been studied for its protective effects against epithelial barrier impairment in the intestines. Herein, we examined the effect of HYA on gingival epithelial barrier function and its possible application for the prevention and treatment of periodontal disease. We found that GPR40, a fatty acid receptor, was expressed on gingival epithelial cells
activation of GPR40 by HYA significantly inhibited barrier impairment induced by Porphyromonas gingivalis, a representative periodontopathic bacterium. The degradation of E-cadherin and beta-catenin, basic components of the epithelial barrier, was prevented in a GPR40-dependent manner in vitro. Oral inoculation of HYA in a mouse experimental periodontitis model suppressed the bacteria-induced degradation of E-cadherin and subsequent inflammatory cytokine production in the gingival tissue. Collectively, these results suggest that HYA exerts a protective function, through GPR40 signaling, against periodontopathic bacteria-induced gingival epithelial barrier impairment and contributes to the suppression of inflammatory responses in periodontal diseases.

DOI： 10.1038/s41598-018-27408-y

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記述言語：英語  

Streptococcus pneumoniae is a leading cause of community-acquired pneumonia. Over the past 2 decades, macrolide resistance among S. pneumoniae organisms has been increasing steadily and has escalated at an alarming rate worldwide. However, the use of macrolides in the treatment of community-acquired pneumonia has been reported to be effective regardless of the antibiotic susceptibility of the causative pneumococci. Although previous studies suggested that sub-MICs of macrolides inhibit the production of the pneumococcal pore-forming toxin pneumolysin by macrolide-resistant S. pneumoniae (MRSP), the underlying mechanisms of the inhibitory effect have not been fully elucidated. Here, we show that the release of pneumococcal autolysin, which promotes cell lysis and the release of pneumolysin, was inhibited by treatment with azithromycin and erythromycin, whereas replenishing with recombinant autolysin restored the release of pneumolysin from MRSP. Additionally, macrolides significantly downregulated ply transcription followed by a slight decrease of the intracellular pneumolysin level. These findings suggest the mechanisms involved in the inhibition of pneumolysin in MRSP, which may provide an additional explanation for the benefits of macrolides on the outcome of treatment for pneumococcal diseases.

DOI： 10.1128/AAC.00161-18

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1021/acs.jproteome.8b00263

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Blackwell Publishing Asia  

Vizantin is an insoluble adjuvant that activates macrophages and lymphocytes. Recently, 2,2′,3,3′,4,4′-hexasulfated-vizantin (sulfated vizantin), which enables solubilization of vizantin, was developed by the present team. Sulfated vizantin was found to enhance bactericidal activity against multi-drug resistant Pseudomonas aeruginosa in RAW264.7 cells. In addition, spread of P. aeruginosa was inhibited in RAW264.7 cells treated with sulfated vizantin. When only sulfated vizantin and P. aeruginosa were incubated, sulfated vizantin did not affect growth of P. aeruginosa. Formation of DNA-based extracellular traps (ETs), a novel defense mechanism in several types of innate immune cells, helps to eliminate pathogens. In the present study, ET-forming macrophages constituted the majority of immune cells. Sulfated vizantin induced ET formation in RAW264.7 cells, whereas a Ca-chelating reagent, EDTA, and T-type calcium channel blocker, tetrandrine, inhibited ET formation and attenuated inhibition of spread of P. aeruginosa in sulfated vizantin-treated cells. Thus, sulfated vizantin induces ET formation in phagocytic cells in a Ca-dependent manner, thus preventing spread of P. aeruginosa. Hence, sulfated vizantin may be useful in the management of infectious diseases.

DOI： 10.1111/1348-0421.12589

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Streptococcus pneumoniae is a leading cause of bacterial pneumonia. Our previous study suggested that S. pneumoniae autolysis-dependently releases intracellular pneumolysin, which subsequently leads to lung injury. In this study, we hypothesized that pneumococcal autolysis induces the leakage of additional intracellular molecules that could increase the pathogenicity of S. pneumoniae. Liquid chromatography tandem-mass spectrometry analysis identified that chaperone protein DnaK, elongation factor Tu (EF-Tu), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were released with pneumococcal DNA by autolysis. We demonstrated that recombinant (r) DnaK, rEF-Tu, and rGAPDH induced significantly higher levels of interleukin-6 and tumor necrosis factor production in peritoneal macrophages and THP-1-derived macrophage-like cells via toll-like receptor 4. Furthermore, the DNA-binding activity of these proteins was confirmed by surface plasmon resonance assay. We demonstrated that pneumococcal DnaK, EF-Tu, and GAPDH induced the production of proinflammatory cytokines in macrophages, and might cause host tissue damage and affect the development of pneumococcal diseases.

DOI： 10.1016/j.cellimm.2018.01.006

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記述言語：英語  

Excessive activation of neutrophils results in the release of neutrophil elastase (NE), which leads to lung injury in severe pneumonia. Previously, we demonstrated a novel immune subversion mechanism involving microbial exploitation of this NE ability, which eventually promotes disruption of the pulmonary epithelial barrier. In the present study, we investigated the effect of NE on host innate immune response. THP-1-derived macrophages were stimulated with heat-killed Streptococcus pneumoniae or lipopolysaccharide in the presence or absence of NE followed by analysis of toll-like receptor (TLR) and cytokine expression. Additionally, the biological significance of NE was confirmed in an in vivo mouse intratracheal infection model. NE downregulated the gene transcription of multiple cytokines in THP-1-derived macrophages through the cleavage of TLRs and myeloid differentiation factor 2. Additionally, NE cleaved inflammatory cytokines and chemokines. In a mouse model of intratracheal pneumococcal challenge, administration of an NE inhibitor significantly increased proinflammatory cytokine levels in bronchoalveolar lavage fluid, enhanced bacterial clearance, and improved survival rates. Our work indicates that NE subverts the innate immune response and that inhibition of this enzyme may constitute a novel therapeutic option for the treatment of pneumococcal pneumonia.

DOI： 10.3389/fimmu.2018.00732

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC CLINICAL INVESTIGATION INC  

Hematopoietic stem cells (HSCs) remain mostly quiescent under steady-state conditions but switch to a proliferative state following hematopoietic stress, e.g., bone marrow (BM) injury, transplantation, or systemic infection and inflammation. The homeostatic balance between quiescence, self-renewal, and differentiation of HSCs is strongly dependent on their interactions with cells that constitute a specialized microanatomical environment in the BM known as the HSC niche. Here, we identified the secreted extracellular matrix protein Del-1 as a component and regulator of the HSC niche. Specifically, we found that Del-1 was expressed by several cellular components of the HSC niche, including arteriolar endothelial cells, CXCL12-abundant reticular (CAR) cells, and cells of the osteoblastic lineage. Del-1 promoted critical functions of the HSC niche, as it regulated long-term HSC (LT-HSC) proliferation and differentiation toward the myeloid lineage. Del-1 deficiency in mice resulted in reduced LT-HSC proliferation and infringed preferentially upon myelopoiesis under both steady-state and stressful conditions, such as hematopoietic cell transplantation and G-CSF-or inflammation-induced stress myelopoiesis. Del-1-induced HSC proliferation and myeloid lineage commitment were mediated by beta 3 integrin on hematopoietic progenitors. This hitherto unknown Del-1 function in the HSC niche represents a juxtacrine homeostatic adaptation of the hematopoietic system in stress myelopoiesis.

DOI： 10.1172/JCI92571

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：FRONTIERS MEDIA SA  

The Streptococcus pyogenes phospholipase A(2) (SIaA) gene is highly conserved in the M3 serotype of group AS. pyogenes, which often involves hypervirulent clones. However, the role of SIaA in S. pyogenes pathogenesis is unclear. Herein, we report that SIaA induces the expression of intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1) via the arachidonic acid signaling cascade. Notably, recombinant SIaA induced ICAM1 and VCAM1 expression in human umbilical vein endothelial cells (HUVECs), resulting in enhanced adhesion of human monocytic leukemia (THP-1) cells. However, Cl 34A, a variant enzyme with no enzymatic activity, did not induce such events. In addition, culture supernatants from S. pyogenes SSI-1 enhanced the adhesion of THP-1 cells to HUVECs, but culture supernatants from the AslaA isogenic mutant strain had limited effects. Aspirin, a cyclooxygenase 2 inhibitor, prevented the adhesion of THP-1 cells to HUVECs and did not induce ICAM1 and VCAM1 expression in HUVECs treated with SIaA. However, zileuton, a 5-lipoxygenase inhibitor, did not exhibit such effects. Furthermore, pre-administration of aspirin in mice intravenously injected with SIaA attenuated the transcriptional abundance of ICAM1 and VCAM1 in the aorta. These results suggested that SIaA from S. pyogenes stimulates the expression of adhesion molecules in vascular endothelial cells. Thus, SIaA contributes to the inflammation of vascular endothelial cells upon S. pyogenes infection.

DOI： 10.3389/fcimb.2017.00300

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE PUBLICATIONS INC  

The Wingless/integrase-1 (Wnt) family of protein ligands and their functional antagonists, secreted frizzled-related proteins (sFRPs), regulate various biological processes ranging from embryonic development to immunity and inflammation. Wnt5a and sFRP5 comprise a typical ligand/antagonist pair, and the former molecule was recently detected at the messenger RNA (mRNA) level in human periodontitis. The main objective of this study was to investigate the interrelationship of expression of Wnt5a and sFRP5 in human periodontitis (as compared to health) and to determine their roles in inflammation and bone loss in an animal model. We detected both Wnt5a and sFRP5 mRNA in human gingiva, with Wnt5a dominating in diseased and sFRP5 in healthy tissue. Wnt5a and sFRP5 protein colocalized in the gingival epithelium, suggesting epithelial cell expression, which was confirmed in cultured human gingival epithelial cells (HGECs). The HGEC expression of Wnt5a and sFRP5 was differentially regulated by a proinflammatory stimulus (lipopolysaccharide [LPS] from Porphyromonas gingivalis) in a manner consistent with the clinical observations (i.e., LPS upregulated Wnt5a and downregulated sFRP5). In HGECs, exogenously added Wnt5a enhanced whereas sFRP5 inhibited LPS-induced inflammation, as monitored by interleukin 8 production. Consistent with this, local treatment with sFRP5 in mice subjected to ligature-induced periodontitis inhibited inflammation and bone loss, correlating with decreased numbers of osteoclasts in bone tissue sections. As in humans, mouse periodontitis was associated with high expression of Wnt5a and low expression of sFRP5, although this profile was reversed after treatment with sFRP5. In conclusion, we demonstrated a novel reciprocal relationship between sFRP5 and Wnt5a expression in periodontal health and disease, paving the way to clinical investigation of the possibility of using the Wnt5a/sFRP5 ratio as a periodontitis biomarker. Moreover, we showed that sFRP5 blocks experimental periodontal inflammation and bone loss, suggesting a promising platform for the development of a new host modulation therapy in periodontitis.

DOI： 10.1177/0022034516687248

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

AimWe have previously shown that the secreted glycoprotein milk fat globule epidermal growth factor 8 (MFG-E8) has anti-inflammatory and anti-osteoclastogenic properties. Our objective was to investigate the potential of MFG-E8 as a diagnostic or therapeutic agent in periodontitis.
Materials and MethodsPeriodontitis was induced in non-human primates (NHPs) by placing ligatures around posterior teeth on both halves of the mandible for a split-mouth design: one side was treated with MFG-E8-Fc and the other with Fc control. Disease was assessed by clinical periodontal examinations, radiographic analysis of bone loss, and analysis of cytokine mRNA expression in gingival biopsy samples. Gingival crevicular fluid (GCF) was collected from human healthy volunteers or subjects with gingivitis, chronic moderate periodontitis, or chronic severe periodontitis. Additionally, GCF was collected from a subset of severe periodontitis patients following scaling and root planing (SRP) and after pocket reduction surgery. GCF was analysed to quantify MFG-E8 and periodontitis-relevant cytokines using multiplex assays.
ResultsIn NHPs, sites treated with MFG-E8-Fc exhibited significantly less ligature-induced periodontal inflammation and bone loss than Fc control-treated sites. In humans, the GCF levels of MFG-E8 were significantly higher in health than in periodontitis, whereas the reverse was true for the proinflammatory cytokines tested. Consistently, MFG-E8 was elevated in GCF after both non-surgical (SRP) and surgical periodontal treatment of periodontitis patients.
ConclusionMFG-E8 is, in principle, a novel therapeutic agent and biomarker of periodontitis.

DOI： 10.1111/jcpe.12707

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-017-10343-9

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記述言語：英語  

Streptococcus pneumoniae is a leading cause of bacterial pneumonia and is the principal cause of morbidity and mortality worldwide. Previous studies suggested that excessive activation of neutrophils results in the release of neutrophil elastase, which contributes to lung injury in severe pneumonia. Although both pneumococcal virulence factors and neutrophil elastase contribute to the development and progression of pneumonia, there are no studies analysing relationships between these factors. Here, we showed that pneumolysin, a pneumococcal pore-forming toxin, induced cell lysis in primary isolated human neutrophils, leading to the release of neutrophil elastase. Pneumolysin exerted minimal cytotoxicity against alveolar epithelial cells and macrophages, whereas neutrophil elastase induced detachment of alveolar epithelial cells and impaired phagocytic activity in macrophages. Additionally, activation of neutrophil elastase did not exert bactericidal activity against S. pneumoniae in vitro. P2X7 receptor, which belongs to a family of purinergic receptors, was involved in pneumolysin-induced cell lysis. These findings suggested that infiltrated neutrophils are the primary target cells of pneumolysin, and that S. pneumoniae exploits neutrophil-elastase leakage to induce the disruption of pulmonary immune defences, thereby causing lung injury.

DOI： 10.1038/srep38013

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

AimHuman periodontitis is associated with overactivation of complement, which is triggered by different mechanisms converging on C3, the central hub of the system. We assessed whether the C3 inhibitor Cp40 inhibits naturally occurring periodontitis in non-human primates (NHPs).
Materials and MethodsNon-human primates with chronic periodontitis were intra-gingivally injected with Cp40 either once (5 animals) or three times (10 animals) weekly for 6weeks followed by a 6-week follow-up period. Clinical periodontal examinations and collection of gingival crevicular fluid and biopsies of gingiva and bone were performed at baseline and during the study. A one-way repeated-measures anova was used for data analysis.
ResultsWhether administered once or three times weekly, Cp40 caused a significant reduction in clinical indices that measure periodontal inflammation (gingival index and bleeding on probing), tissue destruction (probing pocket depth and clinical attachment level) or tooth mobility. These clinical changes were associated with significantly reduced levels of pro-inflammatory mediators and decreased numbers of osteoclasts in bone biopsies. The protective effects of Cp40 persisted, albeit at reduced efficacy, for at least 6weeks following drug discontinuation.
ConclusionCp40 inhibits pre-existing chronic periodontal inflammation and osteoclastogenesis in NHPs, suggesting a novel adjunctive anti-inflammatory therapy for treating human periodontitis.

DOI： 10.1111/jcpe.12507

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記述言語：日本語   出版者・発行元：(一社)日本摂食嚥下リハビリテーション学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/ncomms9272

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC ADVANCEMENT SCIENCE  

DEL-1 (developmental endothelial locus-1) is an endothelial cell-secreted protein that regulates LFA-1 (lymphocyte function-associated antigen-1) integrin-dependent leukocyte recruitment and inflammation in various tissues. We identified a novel regulatory mechanism of DEL-1 in osteoclast biology. Specifically, we showed that DEL-1 is expressed by human and mouse osteoclasts and regulates their differentiation and resorptive function. Mechanistically, DEL-1 inhibited the expression of NFATc1, a master regulator of osteoclastogenesis, in a Mac-1 integrin-dependent manner. In vivo mechanistic analysis has dissociated the anti-inflammatory from the anti-bone-resorptive action of DEL-1 and identified structural components thereof mediating these distinct functions. Locally administered human DEL-1 blocked inflammatory periodontal bone loss in nonhuman primates-a relevant model of human periodontitis. The ability of DEL-1 to regulate both upstream (inflammatory cell recruitment) and downstream (osteoclastogenesis) events that lead to inflammatory bone loss paves the way to a new class of endogenous therapeutics for treating periodontitis and perhaps other inflammatory disorders.

DOI： 10.1126/scitranslmed.aac5380

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC IMMUNOLOGISTS  

B-lineage cells (B lymphocytes and plasma cells) predominate in the inflammatory infiltrate of human chronic periodontitis. However, their role in disease pathogenesis and the factors responsible for their persistence in chronic lesions are poorly understood. In this regard, two cytokines of the TNF ligand superfamily, a proliferation-inducing ligand (APRIL) and B-lymphocyte stimulator (BLyS), are important for the survival, proliferation, and maturation of B cells. Thus, we hypothesized that APRIL and/or BLyS are upregulated in periodontitis and contribute to induction of periodontal bone loss. This hypothesis was addressed in both human and mouse experimental systems. We show that, relative to healthy controls, the expression of APRIL and BLyS mRNA and protein was upregulated in natural and experimental periodontitis in humans and mice, respectively. The elevated expression of these cytokines correlated with increased numbers of B cells/plasma cells in both species. Moreover, APRIL and BLyS partially colocalized with kappa L chain-expressing B-lineage cells at the epithelial-connective tissue interface. Ligature-induced periodontitis resulted in significantly less bone loss in B cell-deficient mice compared with wild-type controls. Ab-mediated neutralization of APRIL or BLyS diminished the number of B cells in the gingival tissue and inhibited bone loss in wild-type, but not in B cell-deficient, mice. In conclusion, B cells and specific cytokines involved in their growth and differentiation contribute to periodontal bone loss. Moreover, APRIL and BLyS have been identified as potential therapeutic targets in periodontitis.

DOI： 10.4049/jimmunol.1500496

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER-VERLAG BERLIN  

The complement system is a network of interacting fluid-phase and cell surface-associated molecules that trigger, amplify, and regulate immune and inflammatory signaling pathways. Dysregulation of this finely balanced network can destabilize host-microbe homeostasis and cause inflammatory tissue damage. Evidence from clinical and animal model-based studies suggests that complement is implicated in the pathogenesis of periodontitis, a polymicrobial community-induced chronic inflammatory disease that destroys the tooth-supporting tissues. This review discusses molecular mechanisms of complement involvement in the dysbiotic transformation of the periodontal microbiome and the resulting destructive inflammation, culminating in loss of periodontal bone support. These mechanistic studies have additionally identified potential therapeutic targets. In this regard, interventional studies in preclinical models have provided proof-of-concept for using complement inhibitors for the treatment of human periodontitis.

DOI： 10.1007/978-3-319-18603-0_4

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Background and ObjectiveAn increasing body of evidence suggests that the use of probiotic bacteria is a promising intervention approach for the treatment of inflammatory diseases with a polymicrobial etiology. The objective of this study was to determine whether Lactobacillus brevis CD2 could inhibit periodontal inflammation and bone loss in experimental periodontitis.
Material and MethodsPeriodontitis was induced by placing a silk ligature around the second maxillary molar of mice treated with L.brevis CD2 (8x10(5)CFU in 1mm(2) lyopatch) or placebo, which were placed between the gingiva and the buccal mucosa near the ligated teeth. The mice were killed after 5d and bone loss was measured morphometrically, gingival expression of proinflammatory cytokines was determined by quantitative real-time polymerase chain reaction, and CFU counts of periodontitis-associated bacteria were determined after aerobic and anaerobic culture. To determine the role of arginine deiminase released by L.brevis CD2, soluble extracts with or without formamidine (arginine deiminase inhibitor) were tested in in vitro cellular activation assays.
ResultsMice topically treated with L.brevis CD2 displayed significantly decreased bone loss and lower expression of tumor necrosis factor, and interleukin-1, -6 and -17A as compared to placebo-treated mice. Moreover, L.brevis CD2-treated mice displayed lower counts of anaerobic bacteria but higher counts of aerobic bacteria than placebo-treated mice. In in vitro assays, the anti-inflammatory effects of soluble L.brevis CD2 extracts were heavily dependent on the presence of functional arginine deiminase, an enzyme that can inhibit nitric oxide synthesis.
ConclusionThese data provide proof-of-concept that the probiotic L.brevis CD2 can inhibit periodontitis through modulatory effects on the host response and the periodontal microbiota.

DOI： 10.1111/jre.12164

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CELL PRESS  

Certain low-abundance bacterial species, such as the periodontitis-associated oral bacterium Porphyromonas gingivalis, can subvert host immunity to remodel a normally symbiotic microbiota into a dysbiotic, disease-provoking state. However, such pathogens also exploit inflammation to thrive in dysbiotic conditions. How these bacteria evade immunity while maintaining inflammation is unclear. As previously reported, P. gingivalis remodels the oral microbiota into a dysbiotic state by exploiting complement. Now we show that in neutrophils P. gingivalis disarms a host-protective TLR2-MyD88 pathway via proteasomal degradation of MyD88, whereas it activates an alternate TLR2-Mal-PI3K pathway. This alternate TLR2-Mal-PI3K pathway blocks phagocytosis, provides "bystander'' protection to otherwise susceptible bacteria, and promotes dysbiotic inflammation in vivo. This mechanism to disengage bacterial clearance from inflammation required an intimate crosstalk between TLR2 and the complement receptor C5aR and can contribute to the persistence of microbial communities that drive dysbiotic diseases.

DOI： 10.1016/j.chom.2014.05.012

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC IMMUNOLOGISTS  

Chronic periodontitis is induced by a dysbiotic microbiota and leads to inflammatory destruction of tooth-supporting connective tissue and bone. The third component of complement, C3, is a point of convergence of distinct complement activation mechanisms, but its involvement in periodontitis was not previously addressed. We investigated this question using two animal species models, namely, C3-deficient or wild-type mice and nonhuman primates (NHPs) locally treated with a potent C3 inhibitor (the compstatin analog Cp40) or an inactive peptide control. In mice, C3 was required for maximal periodontal inflammation and bone loss, and for the sustenance of the dysbiotic microbiota. The effect of C3 on the microbiota was therefore different from that reported for the C5a receptor, which is required for the initial induction of dysbiosis. C3-dependent bone loss was demonstrated in distinct models, including Porphyromonas gingivalis-induced periodontitis, ligature-induced periodontitis, and aging-associated periodontitis. Importantly, local treatment of NHPs with Cp40 inhibited ligature-induced periodontal inflammation and bone loss, which correlated with lower gingival crevicular fluid levels of proinflammatory mediators (e.g., IL-17 and RANKL) and decreased osteoclastogenesis in bone biopsy specimens, as compared with control treatment. To our knowledge, this is the first time, for any disease, that complement inhibition in NHPs was shown to inhibit inflammatory processes that lead to osteoclastogenesis and bone loss. These data strongly support the feasibility of C3-targeted intervention for the treatment of human periodontitis.

DOI： 10.4049/jimmunol.1400569

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記述言語：英語   出版者・発行元：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

Complement plays a key role in immunity and inflammation through direct effects on immune cells or via crosstalk and regulation of other host signaling pathways. Deregulation of these finely balanced complement activities can link infection to inflammatory tissue damage. Periodontitis is a polymicrobial community-induced chronic inflammatory disease that can destroy the tooth-supporting tissues. In this review, we summarize and discuss evidence that complement is involved in the dysbiotic transformation of the periodontal microbiota and in the inflammatory process that leads to the destruction of periodontal bone. Recent insights into the mechanisms of complement involvement in periodontitis have additionally provided likely targets for therapeutic intervention against this oral disease. (C) 2013 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.smim.2013.04.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

Objective: The present study was designed to investigate whether titres of antibody to two strains of Porphyromonas gingivalis, FDC381 and SU63, are associated with serum high-sensitivity C-reactive protein (hs-CRP) levels in Japanese periodontitis patients.
Design: Forty-nine patients with moderate to advanced periodontitis and 40 periodontally healthy control subjects were included in this study. hs-CRP levels and antibody titres to P. gingivalis were measured at baseline and reassessment 3-4 months after periodontal treatment in periodontitis patients as well as at the time of examination in the periodontally healthy subjects. Further, the effect of periodontal therapy, including surgical treatment and use of antibacterials on both markers, was analysed in patients.
Results: hs-CRP levels and antibody titres to P. gingivalis were higher in periodontitis patients than in control subjects, and they significantly decreased following periodontal treatment (p < 0.005). Also, a significant decrease in hs-CRP levels as a result of periodontal treatment was found in patients with hs-CRP levels >1 mgl(-1) at baseline (p < 0.005). Probing depth, clinical attachment level, and alveolar bone loss in patients were significantly associated with a higher antibody titre to both strains of P. gingivalis (p < 0.05), but were not related to hs-CRP levels. No relationship was observed between hs-CRP levels and tertiles as defined by titres of antibody to P. gingivalis strains FDC381 and SU63.
Conclusions: Our data indicate that hs-CRP levels were independent of antibody titres to P. gingivalis in Japanese periodontitis patients. (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.archoralbio.2011.11.008

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Background and Objective: Periodontal infection affects atherosclerotic diseases, such as coronary heart diseases. Mouse models have revealed that oral infection with Porphyromonas gingivalis induces changes in inflammatory-and lipid metabolism-related gene expression, regardless of the development of atherosclerotic lesions. However, the serum protein expression profile in the oral infection model has not been investigated. The present study aimed to analyse the effect of oral infection with P. gingivalis on the expression levels of multiple cytokines in the serum in apolipoprotein E-deficient mice by using a cytokine antibody array. Material and Methods: C57BL/ 6. KOR-Apoe shl mice were orally infected with P. gingivalis five times at 3 day intervals and were then killed. Splenocytes were isolated and analysed for proliferative activity and immunoglobulin G (IgG) production in response to in vitro restimulation with P. gingivalis. The expression levels of various cytokines in the sera were analysed using a mouse antibody array glass chip. Results: Splenocytes from P. gingivalis-infected mice demonstrated significantly greater proliferation and IgG production in response to P. gingivalis compared with those from sham-infected mice. Antibody array analysis revealed the selective upregulation of matrix metalloproteinase 3, intercellular adhesion molecule 1, insulin-like growth factor binding protein 2 and chemokine (C-X-C motif) ligand 7 and the downregulation of interleukin-17, tumor necrosis factor-a and L-selectin. Conclusion: These data demonstrate that oral infection with P. gingivalis induces alterations in systemic cytokine production. These cytokines could play roles in the development not only of periodontitis but also of atherosclerosis.

DOI： 10.1111/j.1600-0765.2011.01441.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

Background: Epidemiological studies have suggested periodontitis as a risk factor for ischemic heart disease. High sensitive C-reactive protein (hs-CRP), a predictor of cardiovascular risk, is elevated in periodontitis patients. Therefore, local infection-induced elevation of systemic CRP could account for the relationship between the 2 diseases. However, the underlying mechanism of CRP production in the periodontal tissues has not been fully elucidated. Therefore, the aim of the present study was to clarify the mechanism of CRP production in periodontal tissues.
Methods: Gene expression of CRP in gingival biopsies was analysed by quantitative PCR. Human gingival epithelial cells (HGECs), human gingival fibroblasts (HGFBs), and human coronary artery endothelial cells (HCAECs) were characterized for CRP-producing ability by incubating with interleukin (IL)-1 beta, IL-6, soluble IL-6 receptor (sIL-6R), and Porphyromonas gingivalis strain W83.
Results: Gene expression of CRP is significantly elevated in periodontitis lesions compared with gingivitis lesions. HCAECs, but not HGECs and HGFBs, produced CRP in response to IL-6 and IL-1 beta in the presence of sIL-6R. In contrast to IL-6, the effect of IL-1 beta on CRP production was indirect via induction of IL-6. IL-1 beta was produced by HGECs and HGFBs with stimulation of P. gingivalis antigens.
Conclusion: These results suggest that CRP induced locally by periodontal infection may play another role in the pathogenesis of periodontal disease, and to a much lesser extent, has the potential to modulate systemic CRP level by extra-hepatic CRP production. (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.archoralbio.2011.04.010

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記述言語：日本語   出版者・発行元：(NPO)日本歯科保存学会  

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Background: Recent studies have suggested that periodontal disease increases the risk of atherothrombotic disease. Atherosclerosis has been characterized as a chronic inflammatory response to cholesterol deposition in the arteries. Although several studies have suggested that certain periodontopathic bacteria accelerate atherogenesis in apolipoprotein E-deficient mice, the mechanistic link between cholesterol accumulation and periodontal infection-induced inflammation is largely unknown.
Methodology/Principal Findings: We orally infected C57BL/6 and C57BL/6. KOR-Apoe(shl) (B6.Apoeshl) mice with Porphyromonas gingivalis, which is a representative periodontopathic bacterium, and evaluated atherogenesis, gene expression in the aorta and liver and systemic inflammatory and lipid profiles in the blood. Furthermore, the effect of lipopolysaccharide (LPS) from P. gingivalis on cholesterol transport and the related gene expression was examined in peritoneal macrophages. Alveolar bone resorption and elevation of systemic inflammatory responses were induced in both strains. Despite early changes in the expression of key genes involved in cholesterol turnover, such as liver X receptor and ATP-binding cassette A1, serum lipid profiles did not change with short-term infection. Long-term infection was associated with a reduction in serum high-density lipoprotein (HDL) cholesterol but not with the development of atherosclerotic lesions in wild-type mice. In B6.Apoeshl mice, long-term infection resulted in the elevation of very low-density lipoprotein (VLDL), LDL and total cholesterols in addition to the reduction of HDL cholesterol. This shift in the lipid profile was concomitant with a significant increase in atherosclerotic lesions. Stimulation with P. gingivalis LPS induced the change of cholesterol transport via targeting the expression of LDL receptor-related genes and resulted in the disturbance of regulatory mechanisms of the cholesterol level in macrophages.
Conclusions/Significance: Periodontal infection itself does not cause atherosclerosis, but it accelerates it by inducing systemic inflammation and deteriorating lipid metabolism, particularly when underlying hyperlidemia or susceptibility to hyperlipidemia exists, and it may contribute to the development of coronary heart disease.

DOI： 10.1371/journal.pone.0020240

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN ATHEROSCLEROSIS SOC  

Aim: Limited epidemiological studies have investigated the relationship between ischemic vascular disease and periodontitis in non-Western populations. We investigated this relationship in a Japanese cohort by measuring serum titers of antibodies to periodontopathic bacteria.
Methods: As part of the Tokamachi-Nakasato cohort study, we followed up 7021 participants regarding cardiovascular events over 5 years, and observed 99 ischemic vascular events: 66 cerebral infarctions and 33 cases of ischemic heart disease (IHD). For a nested case-control study, we selected 495 sex-and age-matched control subjects. Conditional logistic regression analysis was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) of ischemic vascular events associated with antibody titers to Porphyromonas gingivalis FDC381 and SU63. Multivariable models were adjusted for traditional cardiovascular risk factors using propensity scores.
Results: The highest tertile category of antibody titers to P. gingivalis FDC381 in men was significantly associated with an increased risk of cerebral infarction in only the crude model. The 2nd and 3rd tertile categories of antibody titers to P. gingivalis SU63 were significantly associated with an increased risk of cerebral infarction in men (multivariable ORs (95% CIs) were 7.12 (1.51-33.5) and 9.03 (1.97-41.5), respectively). The association was not appreciably modified when we further adjusted for serum high-sensitivity C-reactive protein levels. Antibody titers to P. gingivalis were not dose-dependently associated with the risk of IHD.
Conclusion: High serum antibody titers to P. gingivalis SU63 could be a predictor of cerebral infarction in Japanese men independent of traditional risk factors and inflammation.

DOI： 10.5551/jat.6957

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記述言語：日本語   出版者・発行元：(NPO)日本歯科保存学会  

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：日本語   出版者・発行元：(一社)日本摂食嚥下リハビリテーション学会  

【目的】舌ブラシには、歯ブラシのような植毛タイプや、アーチワイヤー状のタイプ、細かいループ状のナイロン毛が植毛されたナイロンブラシタイプなどいろいろな形状がある。ナイロンブラシは舌苔が厚い場合に有効である一方、使用後に水洗をしても汚れが落ちにくかったり、細菌が繁殖しやすくなったりする恐れがある。そこで、ナイロン毛のループ部分をカットしたブラシを作製し、細菌の除去効果を従来のブラシと比較した。さらに、流水下での洗浄によるブラシに付着した細菌の残留について比較した。【方法】ナイロン毛がループ状になっているループブラシ(W-1ブラシ、SHIKIEN)と、ループ部の一部をカットしたループカットブラシを使用した。各ブラシでBHI寒天培地上に播種したS.aureusを擦過し、除去した細菌数を比較した。また、洗浄方法を検討するため、洗浄なし、手でブラシを擦らず流水下に10秒おいたブラシ、流水下でブラシを0、5、10、30秒擦ったブラシに付着していた細菌数を比較した。【結果】ループブラシおよびループカットブラシで除去した細菌数の中央値はそれぞれ2.0×10^11cfu/mL、2.1×10^11cfu/mLで、統計学的有意差は認められず、細菌の除去能力は同等であった。また、ループブラシ、ループカットブラシのいずれも、洗浄前と比較して、5、10、30秒の手洗いで有意に付着細菌数が減少していた。特にループカットブラシでは、5秒時に99.9%細菌数が減少し、10秒時にはさらに減少していた。10秒時と30秒時では統計学的有意差は認められなかった。したがって、ループカットブラシは、ループブラシと同様な細菌除去効果をもちながらも、洗浄後に付着している細菌数が少なく、感染源となる可能性が低いこと、また、5秒間の流水下での洗浄で99.9%の細菌が除去できる可能性があることが示された。(著者抄録)

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2020&ichushi_jid=J03152&link_issn=&doc_id=20200925110007&doc_link_id=10.32136%2Fjsdr.24.2_170&url=https%3A%2F%2Fdoi.org%2F10.32136%2Fjsdr.24.2_170&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：日本語   出版者・発行元：(NPO)日本歯科保存学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

Background and Objective: Although an elevation in the concentration of high-sensitivity C-reactive protein (hs-CRP) as a result of periodontal infection may account for an increased risk of developing coronary heart disease (CHD), the effect of periodontal infection on the level of hs-CRP in an otherwise healthy Japanese population has not yet been reported. The aim of the present study was to confirm, on a larger scale, our previous pilot study findings that both chronic periodontitis and subsequent periodontal treatment alter the serum levels of C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha).
Material and Methods: The concentrations of serum hs-CRP, IL-6 and TNF-alpha were measured in 78 periodontitis patients at baseline and at re-assessment, and in 40 periodontally healthy subjects at the time of examination.
Results: The concentrations of hs-CRP and IL-6 in the sera of periodontitis patients were significantly higher than those in control subjects. By contrast, the concentration of TNF-alpha was significantly lower in periodontitis patients than in control subjects. Whereas periodontal treatment decreased the levels of serum hs-CRP and IL-6, no such effect was observed for TNF-alpha. When the patients were subdivided into four groups according to their initial concentration of hs-CRP, only the CRP and IL-6 concentrations of the highest quartile group showed a significant reduction following periodontal treatment. No significant difference in the initial clinical parameters was observed in any quartile.
Conclusion: Although periodontal infection does affect the concentration of hs-CRP and IL-6 in serum, a subgroup of patients exist who are highly susceptible to an increased risk of CHD associated with periodontitis, suggesting that there may be subjects who have an elevated risk of CHD independent of susceptibility to periodontal tissue destruction per se.

DOI： 10.1111/j.1600-0765.2009.01209.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Background: Individuals with periodontitis have elevated serum levels of IL-6 and C-reactive protein and have been reported to have a significantly increased risk of developing cardiovascular disease. The transcription factor early growth response factor 1 (Egr-1) has been shown to play an important role in the development and progression of atherosclerosis. However, it is not known whether periodontal infection affects the expression of Egr-1 and subsequent endothelial cells expression of monocyte chemoattractant protein (MCP)-1, a key molecule of leukocyte chemoattraction into vessels. Methods: Human coronary artery endothelial cells (HCAECs) were stimulated with either sonicated extracts from Porphyromonas gingivalis strains 381 or SU63, or a combination of IL-6 and soluble IL-6 receptor (IL-6/sIL-6R). The expression of Egr-1, and subsequently MCP-1, was then analyzed. The role of Egr-1 on MCP-1 expression was analyzed by siRNA transfection. Results: Both P. gingivalis anti-gens and IL-6/sIL-6R stimulations upregulated the expression of Egr-1, with a more robust effect by IL-6/sIL-6R. Increased expression of Egr-1 coincided with MCP-1 production, and Egr-1 downregulation by siRNA suppressed this effect. Conclusion: These results clearly suggest that periodontal infection has the potential to affect HCAECs and hence contribute to the development of subsequent atherosclerosis. Copyright (C) 2009 S. Karger AG, Basel

DOI： 10.1159/000265568

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Background: A number of different theories have been postulated to explain the progression of gingivitis to periodontitis in the context of the Th1/Th2 paradigm. However, no consistent results have been obtained. Th17, a new T-cell subset producing IL-17, which is implicated in many aspect of inflammatory tissue destruction, overcomes many of the discrepant findings in the studies related to the Th1/Th2 hypothesis. We compared the gene expression profile of Th17-related molecules in gingivitis and periodontitis lesions showing distinct clinical entities.
Methods: Gingival tissue samples were obtained from 23 gingivitis and 24 periodontitis tissues. The gene expression was measured by using quantitative real-time PCR for IL-17A, IL-17F, CCR4, CCR6, IL-12 p35 and IL-23 p19. The difference of gene expressions between gingivitis and periodontitis was analyzed by Mann-Whitney U-test. Correlations between each gene expression were also analyzed.
Results: The expression level of IL-17A was higher than that of IL-17F and a significant difference in expression between gingivitis and periodontitis was observed only for IL-17A. CCR4 and CCR6 tended to be higher in periodontitis compared with gingivitis, although the differences were not statistically significant. Whereas the gene expression of IL-12 p35 was significantly higher in periodontitis compared with gingivitis, that of IL-23 p19 was not different between the two diseases.
Conclusion: This study demonstrates the elevated expression of IL-17 and IL-12 in periodontitis, i.e.. the tissue destruction form of periodontal diseases, as compared with gingivitis, and provides new insight into the T-cell mediated immunopathogenesis of periodontal disease. (C) 2008 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.cca.2008.06.003

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：日本語   出版者・発行元：(公社)日本歯科医師会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(NPO)日本歯科保存学会  

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：日本語   出版者・発行元：(一社)歯科基礎医学会  

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記述言語：日本語   出版者・発行元：(一社)歯科基礎医学会  

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記述言語：日本語   出版者・発行元：(一社)歯科基礎医学会  

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：日本語   出版者・発行元：新潟歯学会  

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：英語   出版者・発行元：日本細菌学会  

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記述言語：日本語   出版者・発行元：新潟歯学会  

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記述言語：日本語   出版者・発行元：新潟歯学会  

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記述言語：日本語   出版者・発行元：(一社)歯科基礎医学会  

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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記述言語：日本語   出版者・発行元：新潟歯学会  

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記述言語：日本語  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：日本語  

J-GLOBAL

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記述言語：日本語  

J-GLOBAL

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記述言語：日本語  

J-GLOBAL

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記述言語：英語   出版者・発行元：新潟歯学会  

歯周病は細菌のバイオフィルムによって引き起こされる感染症であり、宿主との免疫反応によって歯周組織の破壊と歯槽骨の吸収を引き起こす。Wnt5aは、歯周病を含む炎症反応と強い関連が報告されている。Soluble frizzled related protein-5(sFRP5)はWnt5aの受容体の相同体であり、Wnt5a経路を阻害する。歯周炎組織と健常歯肉組織においてWnt5aとsFRP5の関連性については不明な点が多い。そこで本研究では、ヒト歯肉サンプルでのWnt5aとsFRP5のmRNA発現、ヒト歯肉上皮細胞(HGECs)におけるinterleukin-8(IL-8)mRNAとケモカインのレベルを定量的PCRおよびELISAにて各々解析した。健常組織と比べて歯周病罹患組織においてWnt5a遺伝子発現は高く、sFRP5発現は抑制されていることが明らかになった。同様に、HGECsにおいてもPorphyromonas gingivalisリポ多糖によりWnt5a発現の上昇とsFRP5発現の抑制が認められた。加えて、sFRP5のHGECsにおけるIL-8の産生抑制効果が認められた。以上の事から、HGECsではWnt5aとsFRP5は双方発現し負の相関関係にあることが初めて示された。また、Wnt5aは歯周病治療の対象となること、sFPR5が歯周病治療化合物として使用可能であることが示唆された。(著者抄録)

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J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)歯科基礎医学会  

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記述言語：日本語   出版者・発行元：新潟歯学会  

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記述言語：日本語   出版者・発行元：新潟歯学会  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2010&ichushi_jid=J00999&link_issn=&doc_id=20100727540010&doc_link_id=%2Fdj2ngtdt%2F2010%2F004001%2F010%2F0079-0081%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdj2ngtdt%2F2010%2F004001%2F010%2F0079-0081%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

J-GLOBAL

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J-GLOBAL

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER IRELAND LTD  

Web of Science

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記述言語：日本語   出版者・発行元：新潟歯学会  

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記述言語：日本語   出版者・発行元：新潟歯学会  

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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J-GLOBAL

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J-GLOBAL

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会議種別：シンポジウム・ワークショップ パネル（指名）  

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会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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