2024/04/12 更新

写真a

タベタ コウイチ
多部田 康一
TABETA Koichi
所属
教育研究院 医歯学系 歯学系列 教授
医歯学総合研究科 口腔生命科学専攻 摂食環境制御学 教授
職名
教授
外部リンク

学位

  • 博士(歯学) ( 2001年3月   新潟大学 )

研究キーワード

  • 歯周病

  • PCSK9

  • 動脈硬化

  • 自然免疫

  • 分泌型IgA

研究分野

  • ライフサイエンス / 保存治療系歯学  / 歯周病学

経歴(researchmap)

  • 新潟大学大学院 医歯学総合研究科 歯周診断・再建学分野   教授

    2018年10月 - 現在

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  • UT Southwestern Medical Center   Visiting Assistant Prof.

    2016年11月 - 2017年10月

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  • 新潟大学   Institute for Research Promotion   研究准教授

    2016年10月 - 2018年9月

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  • 新潟大学   医歯学総合研究科 口腔生命科学専攻 摂食環境制御学   助教

    2012年12月 - 2018年9月

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  • 新潟大学   研究推進機構 超域学術院   准教授

    2011年12月 - 2012年11月

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  • 新潟大学   超域研究機構   准教授

    2007年12月 - 2011年10月

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  • 新潟大学   歯学部 歯学科   助教

    2005年4月 - 2007年11月

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  • The Scripps Research Institute   Research fellow

    2002年1月 - 2005年3月

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  • 新潟大学   歯学部附属病院   医員

    2001年4月 - 2001年12月

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▶ 全件表示

経歴

  • 新潟大学   医歯学総合研究科 口腔生命科学専攻 摂食環境制御学   教授

    2018年10月 - 現在

  • 新潟大学   医歯学総合研究科 口腔生命科学専攻 摂食環境制御学   助教

    2012年12月 - 2018年9月

  • 新潟大学   研究推進機構 超域学術院   准教授

    2011年4月 - 2012年11月

  • 新潟大学   超域研究機構   准教授

    2007年4月 - 2011年3月

  • 新潟大学   歯学部附属病院   医員

    2001年4月 - 2001年12月

所属学協会

  • 特定非営利活動法人 日本歯科保存学会

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  • 特定非営利活動法人 日本免疫学会

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  • 国際歯科研究学会

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  • 特定非営利活動法人 日本歯周病学会

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委員歴

  • 日本学術振興会科学研究費専門委員  

    2016年 - 2017年   

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    団体区分:その他

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  • 日本歯周病学会   評議員  

    2011年 - 現在   

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    団体区分:学協会

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  • 日本学術振興会科学研究費専門委員  

    2011年 - 2013年   

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    団体区分:その他

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留学歴

  • テキサス大学サウスウェスタンメディカルセンター   客員教員

    2016年11月 - 2017年10月

  • スクリプス研究所   ポストドクトラルフェロー

    2002年1月 - 2005年3月

 

論文

  • Secretory leucocyte protease inhibitor regulates bone metabolism and inflammation in experimental mouse periodontitis 査読

    Yutaka Terao, Karin Sasagawa, Hisanori Domon, Satoru Hirayama, Tomoki Maekawa, Toshihito Isono, Koichi Tabeta

    2024年2月

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    出版者・発行元:Research Square Platform LLC  

    Abstract

    Secretory leukocyte protease inhibitor (SLPI), mainly secreted by epithelial cells, is abundant in saliva and other mucus secretions. In healthy periodontal tissues, SLPI maintains homeostasis by modulating immune responses and inhibiting tissue destruction through its neutrophil elastase activity. Recently, decreased SLPI levels have been found in severe periodontitis when compared to healthy individuals. In this study, we hypothesized that intragingival administration of SLPI would inhibit periodontal tissue destruction caused by periodontitis. SLPI administration significantly reduced neutrophil elastase activity in periodontal tissue and alleviated alveolar bone loss in mice. Real-time PCR analysis revealed that SLPI administration downregulated the transcription of proinflammatory cytokines and osteoclast-related factors in gingival tissue. In vitro, treatment of bone marrow macrophages with SLPI resulted in the downregulation of osteoclast differentiation. SLPI also inhibited osteoclast differentiation and promoted osteoblast mineralization in vitro. These findings suggest that SLPI prevents periodontal tissue destruction by affecting inflammation and bone metabolism.

    DOI: 10.21203/rs.3.rs-3806269/v1

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    その他リンク: https://www.researchsquare.com/article/rs-3806269/v1.html

  • A novel macrolide–Del-1 axis to regenerate bone in old age 査読

    Kridtapat Sirisereephap, Hikaru Tamura, Jong-Hyung Lim, Meircurius Dwi Condro Surboyo, Toshihito Isono, Takumi Hiyoshi, Andrea L. Rosenkranz, Yurie Sato-Yamada, Hisanori Domon, Akari Ikeda, Tomoyasu Hirose, Toshiaki Sunazuka, Nagako Yoshiba, Hiroyuki Okada, Yutaka Terao, Takeyasu Maeda, Koichi Tabeta, Triantafyllos Chavakis, George Hajishengallis, Tomoki Maekawa

    iScience   27 ( 2 )   108798 - 108798   2024年2月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.isci.2024.108798

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  • The Pneumococcal Protein SufC Binds to Host Plasminogen and Promotes Its Conversion into Plasmin 査読

    Yoshihito Yasui, Satoru Hirayama, Takumi Hiyoshi, Toshihito Isono, Hisanori Domon, Tomoki Maekawa, Koichi Tabeta, Yutaka Terao

    Microorganisms   11 ( 12 )   2969 - 2969   2023年12月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:MDPI AG  

    Streptococcus pneumoniae causes otitis media, sinusitis, and serious diseases such as pneumonia and bacteremia. However, the in vivo dynamics of S. pneumoniae infections and disease severity are not fully understood. In this study, we investigated pneumococcal proteins detected in the bronchoalveolar lavage fluid of an S. pneumoniae-infected mouse, which were assumed to be expressed during infection. Analysis of three proteins with unknown infection-related functions revealed that recombinant Fe-S cluster assembly ATP-binding protein (SufC) binds to the host plasminogen and promotes its conversion into plasmin. SufC was detected in the bacterial cell-surface protein fraction, but it had no extracellular secretory signal. This study suggests that S. pneumoniae releases SufC extracellularly through LytA-dependent autolysis, binding to the bacterial cell surface and host plasminogen and promoting its conversion into plasmin. The recruitment of plasmin by S. pneumoniae is considered useful for bacterial survival and spread, and SufC is suggested to facilitate this process.

    DOI: 10.3390/microorganisms11122969

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  • Characterization of the cellular heterogeneity and bone regenerative potential of cultured human periosteal cells. 査読 国際誌

    Takahiro Tsuzuno, Naoki Takahashi, Masaki Nagata, Yuta Ueda, Shunya Motosugi, Aoi Yamada, Mai Mizuguchi, Tran Thi Thuy Diep, Yukari Aoki-Nonaka, Koh Nakata, Koichi Tabeta

    Regenerative therapy   24   642 - 650   2023年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    INTRODUCTION: Cell-based bone regenerative therapy exhibits considerable potential in the treatment of bone defects caused by trauma, disease, and congenital anomalies. The periosteum, a fibrous membrane covering the outer surface of bone, plays a crucial role in bone formation and regeneration by sourcing osteoprogenitor cells. The remarkable osteogenic potential of periosteal cells (PCs) has led to the effective clinical implementation of PC-based regenerative therapies and tissue engineering. The abundance of progenitor cells in cultured PCs is well established; however, the heterogeneity of the cell population and its impact on bone regeneration remain uncertain. In this study, we aimed to characterize the heterogeneity of cultured PCs via single-cell RNA-sequencing (scRNA-seq) and to examine their osteogenic potential in vivo. METHODS: Human PCs cultivated using the tissue explant method were utilized in this study. scRNA-seq and real-time PCR were performed to examine the cellular heterogeneity and osteogenic capacity of the cultured PCs. Experimental bone formation by the cultured PCs was examined using the rat model of subcutaneous implantation. RESULTS: ScRNA-seq analysis showed that the cultured PCs were categorized into three cell types (osteoprogenitor cells, mesenchymal stem cells, and fibroblasts) with specific gene expression patterns. In addition, the cellular population and osteogenic capacity differed between the central and peripheral regions in the culture dish. The PCs in the central region showed higher osteogenic potential than those in the peripheral region. CONCLUSIONS: This study revealed the diversity of the composition of the PCs and their distinct osteogenic capabilities in different regions in the culture dish. The findings may provide promising prospects for the development of more efficacious regenerative therapeutic applications using cultured PCs in the future.

    DOI: 10.1016/j.reth.2023.11.006

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  • Erythromycin Restores Osteoblast Differentiation and Osteogenesis Suppressed by Porphyromonas gingivalis Lipopolysaccharide 査読 国際誌

    Hikaru Tamura, Tomoki Maekawa, Hisanori Domon, Kridtapat Sirisereephap, Toshihito Isono, Satoru Hirayama, Takumi Hiyoshi, Karin Sasagawa, Fumio Takizawa, Takeyasu Maeda, Yutaka Terao, Koichi Tabeta

    Pharmaceuticals   16 ( 2 )   303 - 303   2023年2月

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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: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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  • Ozone ultrafine bubble water exhibits bactericidal activity against pathogenic bacteria in the oral cavity and upper airway and disinfects contaminated healthcare equipment. 査読 国際誌

    Fumio Takizawa, Hisanori Domon, Takumi Hiyoshi, Hikaru Tamura, Kana Shimizu, Tomoki Maekawa, Koichi Tabeta, Akiomi Ushida, Yutaka Terao

    PloS one   18 ( 4 )   e0284115   2023年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Ozone is strong oxidizing agent that is applied in aqueous form for sanitation. However, ozonated water is unstable and has a short half-life. Ultrafine bubble technology is promising to overcome these issues. Ultrafine bubble is nanoscale bubble and can exist in water for a considerable duration of time. This study aims to investigate the application of ozone ultrafine bubble water (OUFBW) as a disinfectant. We produced an OUFBW generator which generates OUFBW containing 4-6 ppm of ozone. Thereafter, we examined the bactericidal activity of the OUFBW against various pathogenic bacteria in oral cavity and upper airway, including antibiotic-susceptible and antibiotic-resistant Streptococcus pneumoniae, Pseudomonas aeruginosa, Streptococcus mutans, Streptococcus sobrinus, Fusobacterium nucleatum, Prevotella intermedia, and Porphyromonas gingivalis. Exposure of planktonic culture of these bacterial species to OUFBW reduced viable bacteria by > 99% within 30s. Additionally, OUFBW exerted bactericidal activity against S. pneumoniae and P. aeruginosa adhered to toothbrush and gauze, respectively. We also observed disruption of bacterial cell wall of S. pneumoniae exposed to OUFBW by transmission electron microscope. Additionally, OUFB did not show any significant cytotoxicity toward the human gingival epithelial cell line Ca9-22. These results suggest that OUFBW exhibits bactericidal activity against broad spectrum of bacteria and has low toxicity towards human cells.

    DOI: 10.1371/journal.pone.0284115

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  • The Serum Immunoglobulin G Titers Against <i>Porphyromonas gingivalis</i> as a Predictor of Clinical Response to One-Year Treatment with Biological Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis Patients: A Retrospective Cohort Study 査読 国際誌

    Tetsuo Kobayashi, Satoshi Ito, Akira Murasawa, Hajime Ishikawa, Koichi Tabeta

    Modern Rheumatology   33 ( 5 )   918 - 927   2022年8月

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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:Oxford University Press (OUP)  

    ABSTRACT

    Objectives

    To evaluate the relevance of serum immunoglobulin G (IgG) titers against periodontopathic bacteria to predict the clinical response to one-year treatment with biological disease-modifying antirheumatic drugs (bDMARDs) in rheumatoid arthritis (RA) patients.

    Methods

    Data were collected from 50 RA patients who had received conventional synthetic DMARDs, corticosteroids, or non-steroidal anti-inflammatory drugs before (baseline) and after one-year treatment with bDMARDs in a retrospective cohort study. Changes in rheumatologic conditions were compared between the two groups for low and high baseline IgG titers against Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans according to their median measurements.

    Results

    Twenty-five patients with low anti-P. gingivalis IgG titers showed significantly greater decreases in changes in the clinical disease activity index (CDAI) and swollen joint count than 25 patients with high anti-P. gingivalis IgG titers (p=0.04 for both). Bivariate and multivariate analyses revealed a significantly positive association of baseline anti-P. gingivalis IgG titers with CDAI changes (p=0.02 and p=0.002). However, post-treatment rheumatologic conditions were comparable between 25 patients each in the low and high baseline anti-A. actinomycetemcomitans IgG titer groups.

    Conclusions

    Baseline serum anti-P. gingivalis IgG titers are predictive of the clinical response to one-year treatment with bDMARDs in RA patients.

    DOI: 10.1093/mr/roac093

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  • Quantitative Visualization of Two-Phase Acoustic Streaming Emitted from Ultrasonic Scaler 査読

    Takayuki Yamagata, Kota Kato, Naoki Takahashi, Syuhei Mineo, Koichi Tabeta

    Journal of Flow Control, Measurement &amp;amp; Visualization   10 ( 03 )   87 - 97   2022年7月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Scientific Research Publishing, Inc.  

    DOI: 10.4236/jfcmv.2022.103006

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  • Soybean peptide inhibits the biofilm of periodontopathic bacteria via bactericidal activity 査読 国際誌

    Hnin Yu Lwin, Yukari Aoki-Nonaka, Aoi Matsugishi, Naoki Takahashi, Takumi Hiyoshi, Koichi Tabeta

    Archives of Oral Biology   142   105497 - 105497   2022年7月

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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 BV  

    OBJECTIVE: This study aimed to clarify the antibacterial mechanism and antibiofilm effect of soybean-derived peptide BCBS-11 against periodontopathic bacteria. DESIGN: The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of BCBS-11 against Porphyromonas gingivalis (P. gingivalis), Fusobacterium nucleatum (F. nucleatum), and Streptococcus mitis (S. mitis) were determined for the antibacterial mechanism. The effect of BCBS-11 on membrane permeability and depolarization activity were investigated using propidium iodide (PI) staining and 3, 3'-dipropylthiadicarbocyanine iodide (DiSC3-(5)) analysis. Monospecies and multispecies biofilms were cultured on 96-well plates. The amount of biofilm was determined using crystal violet staining to determine the inhibition of biofilm formation and the eradication of established biofilm using BCBS-11. The cytotoxicity of BCBS-11 was evaluated using 3-(4, 5-Dimethylthiazol-2-yl)- 2, 5-diphenyltetrazolium bromide (MTT) assay. RESULTS: The MIC and MBC indicated the bactericidal activity of BCBS-11 against P. gingivalis and F. nucleatum. The PI staining revealed that BCBS-11 disrupted the bacterial membrane integrity. The DiSC3-(5) analysis indicated that BCBS-11 depolarized the bacterial cytoplasmic membrane. These results indicate the antimicrobial action of BCBS-11 through membrane disruption and the collapse of membrane electrochemical gradient. BCBS-11 significantly inhibited the monospecies biofilm formation of P. gingivalis and F. nucleatum and also inhibited dual-species biofilm. BCBS-11 was not cytotoxic toward human oral epithelial cells. CONCLUSIONS: BCBS-11 inhibits the monospecies and multispecies biofilm formation of P. gingivalis and F. nucleatum, and their bactericidal activity results from membrane disruption.

    DOI: 10.1016/j.archoralbio.2022.105497

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  • Neutrophil elastase aggravates periodontitis by disrupting gingival epithelial barrier via cleaving cell adhesion molecules. 査読 国際誌

    Takumi Hiyoshi, Hisanori Domon, Tomoki Maekawa, Hikaru Tamura, Toshihito Isono, Satoru Hirayama, Karin Sasagawa, Fumio Takizawa, Koichi Tabeta, Yutaka Terao

    Scientific reports   12 ( 1 )   8159 - 8159   2022年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Neutrophil elastase (NE) functions as a host defense factor; however, excessive NE activity can potentially destroy human tissues. Although NE activity is positively correlated to gingival crevicular fluid and clinical attachment loss in periodontitis, the underlying mechanisms by which NE aggravates periodontitis remain elusive. In this study, we investigated how NE induces periodontitis severity and whether NE inhibitors were efficacious in periodontitis treatment. In a ligature-induced murine model of periodontitis, neutrophil recruitment, NE activity, and periodontal bone loss were increased in the periodontal tissue. Local administration of an NE inhibitor significantly decreased NE activity in periodontal tissue and attenuated periodontal bone loss. Furthermore, the transcription of proinflammatory cytokines in the gingiva, which was significantly upregulated in the model of periodontitis, was significantly downregulated by NE inhibitor injection. An in vitro study demonstrated that NE cleaved cell adhesion molecules, such as desmoglein 1, occludin, and E-cadherin, and induced exfoliation of the epithelial keratinous layer in three-dimensional human oral epithelial tissue models. The permeability of fluorescein-5-isothiocyanate-dextran or periodontal pathogen was significantly increased by NE treatment in the human gingival epithelial monolayer. These findings suggest that NE induces the disruption of the gingival epithelial barrier and bacterial invasion in periodontal tissues, aggravating periodontitis.

    DOI: 10.1038/s41598-022-12358-3

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  • Osteoimmunology in Periodontitis: Local Proteins and Compounds to Alleviate Periodontitis. 査読 国際誌

    Kridtapat Sirisereephap, Tomoki Maekawa, Hikaru Tamura, Takumi Hiyoshi, Hisanori Domon, Toshihito Isono, Yutaka Terao, Takeyasu Maeda, Koichi Tabeta

    International journal of molecular sciences   23 ( 10 )   2022年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Periodontitis is one of the most common oral diseases resulting in gingival inflammation and tooth loss. Growing evidence indicates that it results from dysbiosis of the oral microbiome, which interferes with the host immune system, leading to bone destruction. Immune cells activate periodontal ligament cells to express the receptor activator of nuclear factor kappa-B (NF-κB) ligand (RANKL) and promote osteoclast activity. Osteocytes have active roles in periodontitis progression in the bone matrix. Local proteins are involved in bone regeneration through functional immunological plasticity. Here, we discuss the current knowledge of cellular and molecular mechanisms in periodontitis, the roles of local proteins, and promising synthetic compounds generating a periodontal regeneration effect. It is anticipated that this may lead to a better perception of periodontitis pathophysiology.

    DOI: 10.3390/ijms23105540

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  • Laminin Isoforms in Human Dental Pulp: Lymphatic Vessels Express Laminin-332, and Schwann Cell-Associated Laminin-211 Modulates CD163 Expression of M2-like Macrophages. 査読 国際誌

    Nagako Yoshiba, Naoki Edanami, Naoto Ohkura, Tomoki Maekawa, Naoki Takahashi, Takahiro Tsuzuno, Takeyasu Maeda, Koichi Tabeta, Kenji Izumi, Yuichiro Noiri, Kunihiko Yoshiba

    ImmunoHorizons   5 ( 12 )   1008 - 1020   2021年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Laminin, a basement membrane heterotrimeric glycoprotein composed of α/β/γ subunits, has important tissue-specific functions in the control of cellular behavior. Our recent study showed the colocalization of CD163+ M2-like macrophages with Schwann cells in human dental pulp, leading us to hypothesize that the laminin isoform of Schwann cells is associated with CD163 expression. The present study investigated the distribution of laminin isoforms in human dental pulp and the underlying mechanisms that affect macrophage phenotypes. Immunofluorescence analysis indicated that blood vessels were exclusively positive for laminin α4 and α5, whereas laminin α2 was associated with Schwann cells. Unexpectedly, laminin α3/laminin-332 (α3β3γ2) was detected on lymphatic vessels. In intact and carious teeth, CD163+ cells were associated with laminin α2, whereas CD206 single-positive cells were present inside, outside, and along blood vessels. In vitro incubation of THP-1 macrophages in plates coated with laminin-211/511 or its functionally analogous E8 fragments of α-chain (E8-α) indicated that cell shapes differed between macrophages grown on laminin-211/E8-α2 and macrophages grown on laminin-511/E8-α5. Laminin-211/E8-α2-coated plates upregulated CD163 expression, compared with laminin-511/E8-α5-coated plates. Integrin α3- and integrin α6-neutralizing Abs altered the shape of THP-1 macrophages and upregulated mRNA levels of CD206 and CD163 in macrophages grown on laminin-511; the neutralizing Abs did not affect macrophages grown on laminin-211. These findings suggest that laminin isoforms differentially regulate macrophage behavior via distinct integrin-laminin affinities. Of note, laminin-332 is expressed by pulpal lymphatic vessels, the existence of which has been debated; laminin-211 might have a role in maintaining CD163 expression on macrophages.

    DOI: 10.4049/immunohorizons.2100110

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  • Matcha Green Tea Exhibits Bactericidal Activity against Streptococcus pneumoniae and Inhibits Functional Pneumolysin. 査読 国際誌

    Karin Sasagawa, Hisanori Domon, Rina Sakagami, Satoru Hirayama, Tomoki Maekawa, Toshihito Isono, Takumi Hiyoshi, Hikaru Tamura, Fumio Takizawa, Yoichi Fukushima, Koichi Tabeta, Yutaka Terao

    Antibiotics (Basel, Switzerland)   10 ( 12 )   2021年12月

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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 causative pathogen of several human infectious diseases including community-acquired pneumonia. Pneumolysin (PLY), a pore-forming toxin, plays an important role in the pathogenesis of pneumococcal pneumonia. In recent years, the use of traditional natural substances for prevention has drawn attention because of the increasing antibacterial drug resistance of S. pneumoniae. According to some studies, green tea exhibits antibacterial and antitoxin activities. The polyphenols, namely the catechins epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin gallate (ECG), and epicatechin (EC) are largely responsible for these activities. Although matcha green tea provides more polyphenols than green tea infusions, its relationship with pneumococcal pneumonia remains unclear. In this study, we found that treatment with 20 mg/mL matcha supernatant exhibited significant antibacterial activity against S. pneumoniae regardless of antimicrobial resistance. In addition, the matcha supernatant suppressed PLY-mediated hemolysis and cytolysis by inhibiting PLY oligomerization. Moreover, the matcha supernatant and catechins inhibited PLY-mediated neutrophil death and the release of neutrophil elastase. These findings suggest that matcha green tea reduces the virulence of S. pneumoniae in vitro and may be a promising agent for the treatment of pneumococcal infections.

    DOI: 10.3390/antibiotics10121550

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  • Periodontitis Severity Affects the Clinical Response to Biological Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis: A 1-Year Follow-up Study. 国際誌

    Tetsuo Kobayashi, Satoshi Ito, Akira Murasawa, Hajime Ishikawa, Koichi Tabeta

    Modern rheumatology   33 ( 1 )   81 - 87   2021年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVES: To assess whether periodontitis severity affects the clinical response to biological disease-modifying antirheumatic drugs (bDMARDs) for 1 year in rheumatoid arthritis (RA) patients. METHODS: Data were collected from 50 RA patients who had received corticosteroids, conventional synthetic DMARDs, or non-steroidal anti-inflammatory drugs before (baseline) and after 1 year of bDMARD therapy in a retrospective study. Rheumatologic conditions were compared between the two periodontitis severity groups according to the periodontal inflamed surface area (PISA) or Centers for Disease Control Prevention (CDC)/ American Academy of Periodontology (AAP) case definitions. RESULTS: Twenty-eight patients with no or mild periodontitis showed significantly greater decreases in changes in Clinical Disease Activity Index (CDAI) and tender and swollen joint count in comparison to 22 patients with moderate and severe periodontitis (p = 0.02, p = 0.01, and p = 0.03). Both bivariate and multivariate analyses revealed a significantly positive association between the baseline CDC/AAP definitions and CDAI changes (p = 0.005 and p = 0.0038). However, rheumatologic conditions were comparable between 25 patients each in the low and high PISA groups. CONCLUSIONS: Baseline periodontitis severity according to the CDC/AAP definitions is associated with the clinical response to bDMARDs for 1 year in RA patients.

    DOI: 10.1093/mr/roab121

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  • Oral Pathobiont-Induced Changes in Gut Microbiota Aggravate the Pathology of Nonalcoholic Fatty Liver Disease in Mice

    Kyoko Yamazaki, Tamotsu Kato, Yuuri Tsuboi, Eiji Miyauchi, Wataru Suda, Keisuke Sato, Mayuka Nakajima, Mai Yokoji-Takeuchi, Miki Yamada-Hara, Takahiro Tsuzuno, Aoi Matsugishi, Naoki Takahashi, Koichi Tabeta, Nobuaki Miura, Shujiro Okuda, Jun Kikuchi, Hiroshi Ohno, Kazuhisa Yamazaki

    Frontiers in Immunology   12   2021年10月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Frontiers Media {SA}  

    <jats:sec><jats:title>Background &amp;amp; Aims</jats:title><jats:p>Periodontitis increases the risk of nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanisms are unclear. Here, we show that gut dysbiosis induced by oral administration of <jats:italic>Porphyromonas gingivalis</jats:italic>, a representative periodontopathic bacterium, is involved in the aggravation of NAFLD pathology.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>C57BL/6N mice were administered either vehicle, <jats:italic>P. gingivalis</jats:italic>, or <jats:italic>Prevotella intermedia</jats:italic>, another periodontopathic bacterium with weaker periodontal pathogenicity, followed by feeding on a choline-deficient, l-amino acid-defined, high-fat diet with 60 kcal% fat and 0.1% methionine (CDAHFD60). The gut microbial communities were analyzed by pyrosequencing the 16S ribosomal RNA genes. Metagenomic analysis was used to determine the relative abundance of the Kyoto Encyclopedia of Genes and Genomes pathways encoded in the gut microbiota. Serum metabolites were analyzed using nuclear magnetic resonance-based metabolomics coupled with multivariate statistical analyses. Hepatic gene expression profiles were analyzed <jats:italic>via</jats:italic> DNA microarray and quantitative polymerase chain reaction.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>CDAHFD60 feeding induced hepatic steatosis, and in combination with bacterial administration, it further aggravated NAFLD pathology, thereby increasing fibrosis. Gene expression analysis of liver samples revealed that genes involved in NAFLD pathology were perturbed, and the two bacteria induced distinct expression profiles. This might be due to quantitative and qualitative differences in the influx of bacterial products in the gut because the serum endotoxin levels, compositions of the gut microbiota, and serum metabolite profiles induced by the ingested <jats:italic>P. intermedia</jats:italic> and <jats:italic>P. gingivalis</jats:italic> were different.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Swallowed periodontopathic bacteria aggravate NAFLD pathology, likely due to dysregulation of gene expression by inducing gut dysbiosis and subsequent influx of gut bacteria and/or bacterial products.</jats:p></jats:sec>

    DOI: 10.1021/acsomega.1c06891

    DOI: 10.1093/pcp/pcac114

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  • The relationship between dental metal allergy, periodontitis, and palmoplantar pustulosis: An observational study.

    Yurina Takaoka, Yosuke Akiba, Masako Nagasawa, Akiko Ito, Yukiko Masui, Nami Akiba, Kaori Eguchi, Haruna Miyazawa, Koichi Tabeta, Katsumi Uoshima

    Journal of prosthodontic research   66 ( 3 )   438 - 444   2021年9月

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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 PROSTHODONTIC SOC  

    PURPOSE: This study aimed to investigate the relationship between dental metal allergy, periodontitis, and palmoplantar pustulosis among patients from a dental metal allergy clinic over a period of 8 years. METHODS: This study included 436 patients who visited our dental metal allergy clinic between April 1, 2009 and March 31, 2016. Diagnoses of skin diseases, periodontal records, dental metal series patch test results, and electron probe microanalysis (EPMA) data were obtained from medical records. Relative risk (RR) values were estimated from these data. RESULTS: Of the 359 patients who underwent the patch test, 241 showed a positive reaction. Of the 187 patients who underwent EPMA, 113 had allergenic metals in their dental prostheses. These patients were suspected to have a dental metal allergy. Furthermore, 150 of the 436 patients were diagnosed with palmoplantar pustulosis (PPP). The RR of metal allergy between patients with PPP and healthy subjects was 3.88. The RR of periodontal disease between patients with PPP and PPP-negative patients in the national average was 2.54. CONCLUSIONS: In this study, both dental metal allergy and periodontitis showed a high RR for PPP.

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  • Rice bran-derived protein fractions enhance sulforaphane-induced anti-oxidative activity in gingival epithelial cells. 国際誌

    Shuhei Mineo, Naoki Takahashi, Miki Yamada-Hara, Takahiro Tsuzuno, Yukari Aoki-Nonaka, Koichi Tabeta

    Archives of oral biology   129   105215 - 105215   2021年9月

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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 bioactive peptides have been reported to exhibit various beneficial effects, including anti-microbial, anti-inflammatory, and anti-oxidant properties. Oxidative stress has been implicated in the development of several inflammatory diseases such as periodontal disease. However, the anti-oxidative effect of food-derived bioactive peptides in gingival epithelial cells (GECs) is unknown. Therefore, we examined the bioactivity of the peptides in GECs. DESIGN: Food-derived peptide fractionations derived from rice bran, rice endosperm, corn, and soy were screened for anti-oxidative effects using anti-oxidant response element (ARE)-luciferase-transfected HEK 293 cells. The induction of anti-oxidation-related genes and proteins in GECs by the fractions were examined by quantitative PCR and Western blotting, respectively. Then, the fraction-mediated anti-oxidative effects were examined by measuring intracellular reactive oxygen species (ROS) levels using flow cytometry. Furthermore, the anti-oxidative response-related cellular signaling pathways were analyzed via Western blotting. RESULTS: Although treatment with the food-derived peptides alone did not activate anti-oxidative responses, co-treatment with sulforaphane (SFN; a potent anti-oxidant) and certain food-derived peptides enhanced anti-oxidative responses in ARE-luciferase-transfected HEK 293 cells. The fractions augmented heme oxygenase-1 mRNA and protein expression in GECs. The percentage of ROS-positive cells was significantly decreased by co-treatment with SFN and peptide fractions derived from rice bran. Furthermore, the involvement of both nuclear factor erythroid 2-related factor 2 (Nrf2) and extracellular signal-regulated kinase (ERK) in the enhancement of anti-oxidative responses was demonstrated by Western blotting. CONCLUSIONS: Peptides derived from rice bran enhances SFN-induced anti-oxidative responses in GECs through ERK-Nrf2-ARE signaling.

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  • Association among periodontitis severity, anti-agalactosyl immunoglobulin G titer, and the disease activity of rheumatoid arthritis 査読 国際誌

    Chihiro Kaneko, Tetsuo Kobayashi, Satoshi Ito, Noriko Sugita, Akira Murasawa, Hajime Ishikawa, Koichi Tabeta

    JOURNAL OF PERIODONTAL RESEARCH   56 ( 4 )   702 - 709   2021年8月

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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  

    Objective The aim of the present study was to evaluate the association between the periodontal and serological parameters and the disease activity of rheumatoid arthritis (RA) and between the anti-agalactosyl immunoglobulin G (IgG) titer and periodontitis severity. The objective was also to assess the effect of supragingival scaling on the serological parameters in patients with RA.Background The periodontal and serological parameters in relation to the autoimmune inflammatory response have been linked to RA disease activity. However, the association of the anti-agalactosyl IgG titer with RA disease activity and periodontitis severity has not been elucidated.Methods The periodontal, rheumatologic, and serological data were collected from 127 patients with RA in a retrospective cohort study. Of the 127 patients, 21 had been randomly assigned to receive oral hygiene instruction and supragingival scaling. The anti-agalactosyl IgG titer was determined by an electrochemiluminescence immunoassay.Results The patients with a moderate to high RA disease activity showed significantly higher levels of probing depth (PD), clinical attachment level, anti-cyclic citrullinated peptide IgG, and anti-agalactosyl IgG titer and greater mean percentages of severe periodontitis than those with a low RA disease activity (p < .05 for all). Both univariate and multivariate analyses revealed a significantly positive correlation between the PD and RA disease activity (p = .009 and p = .001), between the anti-agalactosyl IgG titer and RA disease activity (p = .002 and p < .001), and between the anti-agalactosyl IgG titer and PD (p < .001 for both). Supragingival scaling significantly decreased the anti-agalactosyl IgG titer (p = 0.03).Conclusion The PD and anti-agalactosyl IgG titer are positively interrelated, both of which are correlated positively with RA disease activity and influenced by supragingival scaling in patients with RA.

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  • Cells/colony motion of oral keratinocytes determined by non-invasive and quantitative measurement using optical flow predicts epithelial regenerative capacity. 査読 国際誌

    Emi Hoshikawa, Taisuke Sato, Kenta Haga, Ayako Suzuki, Ryota Kobayashi, Koichi Tabeta, Kenji Izumi

    Scientific reports   11 ( 1 )   10403 - 10403   2021年5月

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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 RESEARCH  

    Cells/colony motion determined by non-invasive, quantitative measurements using the optical flow (OF) algorithm can indicate the oral keratinocyte proliferative capacity in early-phase primary cultures. This study aimed to determine a threshold for the cells/colony motion index to detect substandard cell populations in a subsequent subculture before manufacturing a tissue-engineered oral mucosa graft and to investigate the correlation with the epithelial regenerative capacity. The distinctive proliferating pattern of first-passage [passage 1 (p1)] cells reveals the motion of p1 cells/colonies, which can be measured in a non-invasive, quantitative manner using OF with fewer full-screen imaging analyses and cell segmentations. Our results demonstrate that the motion index lower than 40 μm/h reflects cellular damages by experimental metabolic challenges although this value shall only apply in case of our culture system. Nonetheless, the motion index can be used as the threshold to determine the quality of cultured cells while it may be affected by any different culture conditions. Because the p1 cells/colony motion index is correlated with epithelial regenerative capacity, it is a reliable index for quality control of oral keratinocytes.

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  • Ingestion of Porphyromonas gingivalis exacerbates colitis via intestinal epithelial barrier disruption in mice 査読 国際誌

    Takahiro Tsuzuno, Naoki Takahashi, Miki Yamada-Hara, Mai Yokoji-Takeuchi, Benso Sulijaya, Yukari Aoki-Nonaka, Aoi Matsugishi, Kyoko Katakura, Koichi Tabeta, Kazuhisa Yamazaki

    JOURNAL OF PERIODONTAL RESEARCH   56 ( 2 )   275 - 288   2021年4月

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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  

    Objective This study aimed to evaluate the effects of ingested periodontal pathogens on experimental colitis in mice and to elucidate its underlying mechanisms.Background Inflammatory bowel disease (IBD) is defined as a chronic intestinal inflammation that results in damage to the gastrointestinal tract. Epidemiological studies have shown an association between IBD and periodontitis. Although a large number of ingested oral bacteria reach gastrointestinal tract constantly, the effect of ingested periodontal pathogens on intestinal inflammation is still unknown.Methods Experimental colitis was induced by inclusion of dextran sodium sulfate solution in drinking water of the mice. Major periodontal pathogens (Porphyromonas gingivalis, Prevotella intermedia, and Fusobacterium nucleatum) were administered orally every day during the experiment. The severity of colitis between the groups was compared. In vitro studies of the intestinal epithelial cell line were conducted to explore the molecular mechanisms by which periodontal pathogens affect the development of colitis.Results The oral administration of P. gingivalis significantly increased the severity of colitis when compared to other pathogens in the DSS-induced colitis model. The ingested P. gingivalis disrupted the colonic epithelial barrier by decreasing the expression of tight junction proteins in vivo. In vitro permeability assays using the intestinal epithelial cell line suggested the P. gingivalis-specific epithelial barrier disruption. The possible involvement of gingipains in the exacerbation of colitis was implied by using P. gingivalis lacking gingipains.Conclusion Porphyromonas gingivalis exacerbates gastrointestinal inflammation by directly interacting with the intestinal epithelial barrier in a susceptible host.

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  • Prospective Longitudinal Changes in the Periodontal Inflamed Surface Area Following Active Periodontal Treatment for Chronic Periodontitis 査読 国際誌

    Yoshiaki Nomura, Toshiya Morozumi, Atsushi Saito, Atsutoshi Yoshimura, Erika Kakuta, Fumihiko Suzuki, Fusanori Nishimura, Hideki Takai, Hiroaki Kobayashi, Kazuyuki Noguchi, Keiso Takahashi, Koichi Tabeta, Makoto Umeda, Masato Minabe, Mitsuo Fukuda, Naoyuki Sugano, Nobuhiro Hanada, Nobuo Yoshinari, Satoshi Sekino, Shogo Takashiba, Soh Sato, Toshiaki Nakamura, Tsutomu Sugaya, Yohei Nakayama, Yorimasa Ogata, Yukihiro Numabe, Taneaki Nakagawa

    JOURNAL OF CLINICAL MEDICINE   10 ( 6 )   2021年3月

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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:MDPI  

    Periodontal disease is a chronic inflammatory disease of the periodontal tissue. The periodontal inflamed surface area (PISA) is a proposed index for quantifying the inflammatory burden resulting from periodontitis lesions. This study aimed to investigate longitudinal changes in the periodontal status as evaluated by the PISA following the active periodontal treatment. To elucidate the prognostic factors of PISA, mixed-effect modeling was performed for clinical parameters, tooth-type, and levels of periodontal pathogens as independent variables. One-hundred-twenty-five patients with chronic periodontitis who completed the active periodontal treatment were followed-up for 24 months, with evaluations conducted at 6-month intervals. Five-times repeated measures of mean PISA values were 130+/-173, 161+/-276, 184+/-320, 175+/-417, and 209+/-469 mm(2). Changes in clinical parameters and salivary and subgingival periodontal pathogens were analyzed by mixed-effect modeling. Plaque index, clinical attachment level, and salivary levels of Porphyromonas gingivalis were associated with changes in PISA at the patient- and tooth-level. Subgingival levels of P. gingivalis and Prevotella intermedia were associated with changes in PISA at the sample site. For most patients, changes in PISA were within 10% of baseline during the 24-month follow-up. However, an increase in the number of bleeding sites in a tooth with a deep periodontal pocket increased the PISA value exponentially.

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  • Effects of Erythromycin on Osteoclasts and Bone Resorption via DEL-1 Induction in Mice 査読 国際誌

    Hikaru Tamura, Tomoki Maekawa, Hisanori Domon, Takumi Hiyoshi, Satoru Hirayama, Toshihito Isono, Karin Sasagawa, Daisuke Yonezawa, Naoki Takahashi, Masataka Oda, Takeyasu Maeda, Koichi Tabeta, Yutaka Terao

    ANTIBIOTICS-BASEL   10 ( 3 )   na   2021年3月

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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:MDPI  

    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.

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  • Estimation of the Periodontal Inflamed Surface Area by Simple Oral Examination 査読 国際誌

    Yoshiaki Nomura, Toshiya Morozumi, Yukihiro Numabe, Yorimasa Ogata, Yohei Nakayama, Tsutomu Sugaya, Toshiaki Nakamura, Soh Sato, Shogo Takashiba, Satoshi Sekino, Nobuo Yoshinari, Nobuhiro Hanada, Naoyuki Sugano, Mitsuo Fukuda, Masato Minabe, Makoto Umeda, Koichi Tabeta, Keiso Takahashi, Kazuyuki Noguchi, Hiroaki Kobayashi, Hideki Takai, Fusanori Nishimura, Fumihiko Suzuki, Erika Kakuta, Atsutoshi Yoshimura, Atsushi Saito, Taneaki Nakagawa

    JOURNAL OF CLINICAL MEDICINE   10 ( 4 )   2021年2月

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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:MDPI  

    The periodontal inflamed surface area (PISA) is a useful index for clinical and epidemiological assessments, since it can represent the inflammation status of patients in one contentious variable. However, calculation of the PISA is difficult, requiring six point probing depth measurements with or without bleeding on probing on 28 teeth, followed by data input in a calculation program. More simple methods are essential for screening periodontal disease or in epidemiological studies. In this study, we tried to establish a convenient partial examination method to estimate PISA. Cross-sectional data of 254 subjects who completed active periodontal therapy were analyzed. Teeth that represent the PISA value were selected by an item response theory approach. The maxillary second molar, first premolar, and lateral incisor and the mandibular second molar and lateral incisor were selected. The sum of the PISAs of these teeth was significantly correlated with the patient's PISA (R-2 = 0.938). More simply, the sum of the maximum values of probing pocket depth with bleeding for these teeth were also significantly correlated with the patient's PISA (R-2 = 0.6457). The simple model presented in this study may be useful to estimate PISA.

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  • A large-scale observational study to investigate the current status of diabetic complications and their prevention in Japan (JDCP study 6): baseline dental and oral findings 査読

    Koji Inagaki, Takeshi Kikuchi, Toshihide Noguchi, Akio Mitani, Keiko Naruse, Tatsuaki Matsubara, Masamitsu Kawanami, Jun Negishi, Yasushi Furuichi, Eiji Nemoto, Satoru Yamada, Hiromasa Yoshie, Koichi Tabeta, Sachiyo Tomita, Atsushi Saito, Sayaka Katagiri, Yuichi Izumi, Hiroshi Nitta, Takanori Iwata, Yukihiro Numabe, Matsuo Yamamoto, Nobuo Yoshinari, Tsuyoshi Fujita, Hidemi Kurihara, Fusanori Nishimura, Toshihiko Nagata, Hiromichi Yumoto, Toru Naito, Kazuyuki Noguchi, Koichi Ito, Shinya Murakami, Rimei Nishimura, Naoko Tajima

    DIABETOLOGY INTERNATIONAL   12 ( 1 )   52 - 61   2021年1月

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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 JAPAN KK  

    Japan Diabetes Complication and Prevention prospective (JDCP) study was conducted to examine the association between glycemic control and oral conditions in a large database of Japanese patients with diabetes. It included a total of 6099 patients with diabetes (range, 40-75 years) who had been treated as outpatients between 2007 and 2009. The mean number of present teeth at baseline was 19.8 and women with type 2 diabetes had fewer teeth than men with type 2 diabetes. Within the previous year, 17% of all patients had lost teeth. At baseline, 32% had experienced gingival swelling, 69% had brushed more than twice a day, 37% had used interdental cleaning aids, and 43% had undergone regular dental checkups. Multiple logistic regression analysis indicated that type 1 patients with HbA1c >= 7.0% were at higher risk of having fewer than 20 teeth (odds ratio [OR] 2.38; 95% confidence interval [CI] 1.25-4.78), and type 2 patients with HbA1c >= 8.0% also were at high risk of having fewer than 20 teeth (OR 1.16; 95% CI 1.00-1.34), after adjustment for nine possible confounding factors. In conclusion, patients with diabetes were found to be at high risk of tooth loss, and the poorer the glycemic control, the higher the risk of tooth loss in these patients.

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  • Rice peptide with amino acid substitution inhibits biofilm formation by Porphyromonas gingivalis and Fusobacterium nucleatum 査読 国際誌

    Aoi Matsugishi, Yukari Aoki-Nonaka, Mai Yokoji-Takeuchi, Miki Yamada-Hara, Yoshikazu Mikami, Manabu Hayatsu, Yutaka Terao, Hisanori Domon, Masayuki Taniguchi, Naoki Takahashi, Kazuhisa Yamazaki, Koichi Tabeta

    ARCHIVES OF ORAL BIOLOGY   121   104956 - 104956   2021年1月

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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: Rice peptide has antibacterial properties that have been tested in planktonic bacterial culture. However, bacteria form biofilm at disease sites and are resistant to antibacterial agents. The aim of this study was to clarify the mechanisms of action of rice peptide and its amino acid substitution against periodontopathic bacteria and their antibiofilm effects.Design: Porphyromonas gingivalis and Fusobacterium nucleatum were treated with Amyl-1-18 rice peptide or its arginine-substituted analog, G12R, under anaerobic conditions. The amount of biofilm was evaluated by crystal violet staining. The integrity of the bacteria cytoplasmic membrane was studied in a propidium iodide (PI) stain assay and transmission electron microscopy (TEM).Results: Both Amyl-1-18 and G12R inhibited biofilm formation of P. gingivalis and F. nucleatum; in particular, G12R inhibited F. nucleatum at lower concentrations. However, neither peptide eradicated established biofilms significantly. According to the minimum inhibitory concentration and minimum bactericidal concentration against P. gingivalis, Amyl-1-18 has bacteriostatic properties and G12R has bactericidal activity, and both peptides showed bactericidal activity against F. nucleatum. PI staining and TEM analysis indicated that membrane disruption by G12R was enhanced, which suggests that the replacement amino acid reinforced the electostatic interaction between the peptide and bacteria by increase of cationic charge and alpha-helix content.Conclusions: Rice peptide inhibited biofilm formation of P. gingivalis and F. nucleatum, and bactericidal activity via membrane destruction was enhanced by amino acid substitution.

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  • Oral Pathobiont-Induced Changes in Gut Microbiota Aggravate the Pathology of Nonalcoholic Fatty Liver Disease in Mice. 国際誌

    Kyoko Yamazaki, Tamotsu Kato, Yuuri Tsuboi, Eiji Miyauchi, Wataru Suda, Keisuke Sato, Mayuka Nakajima, Mai Yokoji-Takeuchi, Miki Yamada-Hara, Takahiro Tsuzuno, Aoi Matsugishi, Naoki Takahashi, Koichi Tabeta, Nobuaki Miura, Shujiro Okuda, Jun Kikuchi, Hiroshi Ohno, Kazuhisa Yamazaki

    Frontiers in immunology   12   766170 - 766170   2021年

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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  

    Background & Aims: Periodontitis increases the risk of nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanisms are unclear. Here, we show that gut dysbiosis induced by oral administration of Porphyromonas gingivalis, a representative periodontopathic bacterium, is involved in the aggravation of NAFLD pathology. Methods: C57BL/6N mice were administered either vehicle, P. gingivalis, or Prevotella intermedia, another periodontopathic bacterium with weaker periodontal pathogenicity, followed by feeding on a choline-deficient, l-amino acid-defined, high-fat diet with 60 kcal% fat and 0.1% methionine (CDAHFD60). The gut microbial communities were analyzed by pyrosequencing the 16S ribosomal RNA genes. Metagenomic analysis was used to determine the relative abundance of the Kyoto Encyclopedia of Genes and Genomes pathways encoded in the gut microbiota. Serum metabolites were analyzed using nuclear magnetic resonance-based metabolomics coupled with multivariate statistical analyses. Hepatic gene expression profiles were analyzed via DNA microarray and quantitative polymerase chain reaction. Results: CDAHFD60 feeding induced hepatic steatosis, and in combination with bacterial administration, it further aggravated NAFLD pathology, thereby increasing fibrosis. Gene expression analysis of liver samples revealed that genes involved in NAFLD pathology were perturbed, and the two bacteria induced distinct expression profiles. This might be due to quantitative and qualitative differences in the influx of bacterial products in the gut because the serum endotoxin levels, compositions of the gut microbiota, and serum metabolite profiles induced by the ingested P. intermedia and P. gingivalis were different. Conclusions: Swallowed periodontopathic bacteria aggravate NAFLD pathology, likely due to dysregulation of gene expression by inducing gut dysbiosis and subsequent influx of gut bacteria and/or bacterial products.

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  • The periodontal inflamed surface area is associated with the clinical response to biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a retrospective study 査読 国際誌

    Moe Yamashita, Tetsuo Kobayashi, Satoshi Ito, Chihiro Kaneko, Akira Murasawa, Hajime Ishikawa, Koichi Tabeta

    MODERN RHEUMATOLOGY   30 ( 6 )   990 - 996   2020年11月

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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:TAYLOR & FRANCIS LTD  

    Objectives: We evaluated whether the periodontal inflamed surface area (PISA), a measure of the inflammatory burden posed by periodontitis, is associated with the clinical response to biological disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA). Methods: We conducted a retrospective study that collected rheumatologic and periodontal data from 54 patients with RA who had received corticosteroid, conventional synthetic DMARDs, or non-steroidal anti-inflammatory drugs before (baseline) and after 6 months of bDMARD therapy. After the patients were divided into two groups based on high or low PISA according to the median measurements at baseline, the rheumatologic condition was compared between the groups. Results: The patients with a low PISA showed significantly lower values for the Clinical Disease Activity Index (CDAI) (p = .008), swollen joint count (p = .02), and patient's and evaluator's global assessment (p = .01 and p = .03) and significantly greater decreases in changes in the CDAI from baseline to 6 months than the patients with a high PISA (p = .01), although these values were comparable at baseline. Both univariate and multivariate analyses revealed a significantly positive correlation between the baseline PISA and changes in the CDAI (p = .04 and p < .001). Conclusion: The PISA is associated with the clinical response to bDMARDs in patients with RA.

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  • Association between serum IgG antibody titers against Porphyromonas gingivalis and liver enzyme levels: A cross-sectional study in Sado Island 査読 国際誌

    Kei Takamisawa, Noriko Sugita, Shigeki Komatsu, Minako Wakasugi, Akio Yokoseki, Akihiro Yoshihara, Tetsuo Kobayashi, Kazutoshi Nakamura, Osamu Onodera, Takeshi Momotsu, Naoto Endo, Kenji Sato, Ichiei Narita, Hiromasa Yoshie, Koichi Tabeta

    HELIYON   6 ( 11 )   e05531   2020年11月

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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 SCI LTD  

    Background: Previous studies have reported associations between nonalcoholic fatty liver disease, periodontitis, and obesity. Serum immunoglobulin G (IgG) antibody titer against Porphyromonas gingivalis, a major pathogen of periodontitis, is an established indicator of periodontal infection. However, the relationship between the antibody titer and liver enzyme levels has not been clarified yet. A study in the elderly was needed to evaluate the effect of long-term persistent bacterial infection on liver function. The objective of this study was to investigate the association between liver function and infection by P. gingivalis, and the effect of obesity on the association.Methods: A cross-sectional study was conducted in adult outpatients visiting Sado General Hospital, in Niigata Prefecture, Japan, from 2008 to 2010. The final participants included 192 men and 196 women (mean age 68.1 years). Multivariable logistic regression analyses were performed to assess the association between the serum IgG antibody titer and the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamine transferase (GGT) levels.Results: In women, serum IgG antibody titers against P. gingivalis was associated with elevated ALT, but not with AST or GGT, independent of covariates (p = 0.015). No significant association was found between the antibody titer and the elevated liver enzymes in men. The effect of obesity on the relationship between antibody titer and liver enzyme levels was not statistically significant.Conclusions: A cross-sectional analysis of adult outpatients suggested an association between P. gingivalis infection and ALT levels in women. The effect of obesity on this association was not statistically significant.

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  • Epithelial TRPV1 channels: Expression, function, and pathogenicity in the oral cavity 査読 国際誌

    Naoki Takahashi, Takahiro Tsuzuno, Shuhei Mineo, Miki Yamada-Hara, Yukari Aoki-Nonaka, Koichi Tabeta

    JOURNAL OF ORAL BIOSCIENCES   62 ( 3 )   235 - 241   2020年9月

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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  

    Background: The oral cavity serves as an entrance to the body and is therefore exposed to various exogenous stimuli, including mechanical forces, chemical agents, and bacterial components. The oral mucosa responds to these stimuli to maintain homeostasis and good oral health. The transient receptor potential vanilloid 1 (TRPV1) ion channel functions as an environment-sensing protein and is involved in a wide variety of cellular responses. Recent studies have revealed that epithelial TRPV1 ion channels in the oral cavity play pivotal roles in several pathophysiological conditions. In this review, we summarize the features of epithelial TRPV1 channels in the oral cavity and focus on their cellular function and pathogenicity with reference to related findings in other organs and tissues.Highlight: TRPV1 channels are widely expressed in epithelial cells in the oral cavity and play pivotal roles in fundamental cellular processes and disease progression.Conclusion: This review suggests that oral epithelial TRPV1 contributes to several cellular functions such as cell proliferation, barrier function, and inflammation. Further understanding of the characteristics of epithelial TRPV1 in the oral cavity may provide new insights into the prevention or treatment of diseases. (C) 2020 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.job.2020.05.005

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  • Erythromycin inhibits neutrophilic inflammation and mucosal disease by upregulating DEL-1 査読 国際誌

    Tomoki Maekawa, Hikaru Tamura, Hisanori Domon, Takumi Hiyoshi, Toshihito Isono, Daisuke Yonezawa, Naoki Hayashi, Naoki Takahashi, Koichi Tabeta, Takeyasu Maeda, Masataka Oda, Athanasios Ziogas, Vasileia Ismini Alexaki, Triantafyllos Chavakis, Yutaka Terao, George Hajishengallis

    JCI INSIGHT   5 ( 15 )   2020年8月

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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  

    Macrolide antibiotics exert antiinflammatory effects; however, little is known regarding their immunomodulatory mechanisms. In this study, using 2 distinct mouse models of mucosal inflammatory disease (LPS-induced acute lung injury and ligature-induced periodontitis), we demonstrated that the antiinflammatory action of erythromycin (ERM) is mediated through upregulation of the secreted homeostatic protein developmental endothelial locus-1 (DEL-1). Consistent with the anti-neutrophil recruitment action of endothelial cell-derived DEL-1, ERM inhibited neutrophil infiltration in the lungs and the periodontium in a DEL-1-dependent manner. Whereas ERM (but not other antibiotics, such as josamycin and penicillin) protected against lethal pulmonary inflammation and inflammatory periodontal bone loss, these protective effects of ERM were abolished in Dell-deficient mice. By interacting with the growth hormone secretagogue receptor and activating JAK2 in human lung microvascular endothelial cells, ERM induced DEL1 transcription that was mediated by MAPK p38 and was CCAAT/enhancer binding protein-beta dependent. Moreover, ERM reversed IL-17-induced inhibition of DEL-1 transcription, in a manner that was dependent not only on JAK2 but also on P13K/AKT signaling. Because DEL-1 levels are severely reduced in inflammatory conditions and with aging, the ability of ERM to upregulate DEL-1 may lead to a novel approach for the treatment of inflammatory and aging-related diseases.

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  • Nutritional Supplements and Periodontal Disease Prevention—Current Understanding 査読

    Yukari Aoki-Nonaka, Aoi Matsugishi, Hnin Yu Lwin, Naoki Takahashi, Koichi Tabeta

    Current Oral Health Reports   7 ( 2 )   154 - 164   2020年6月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    Purpose of Review: This review updates the current knowledge on nutrient supplements, which are reported as effective in maintaining the health of periodontal tissues or preventing diseases, as a complementary therapy to existing periodontal treatments. Recent Findings: The latest meta-analysis reported that green tea component might be used as a complementary method to existing periodontal treatments. New multifunctional food-derived components such as rice- and soybean-derived proteins and amino acids have also been reported recently. Summary: Several previous reports describe that nutritional supplements may help bacterial control and host immune regulation based on cellular or animal experiments, but evidence regarding most nutritional supplements is still insufficient to apply for prevention or treatment of periodontal disease. Complementary use of green tea extract, including catechin, potentially controlling the symptoms of periodontal disease combined with existing therapies could be beneficial, although randomized clinical trials and larger cohort studies are required properly.

    DOI: 10.1007/s40496-020-00261-7

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  • マウス歯牙結紮歯周炎モデルにおけるヒノキチオールの骨吸収抑制作用の解析

    日吉 巧, 土門 久哲, 前川 知樹, 田村 光, 米澤 大輔, 國友 栄治, 寺尾 豊, 多部田 康一

    日本歯周病学会会誌   62 ( 春季特別 )   133 - 133   2020年5月

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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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  • コメペプチドとそのアミノ酸置換体はPorphyromonas gingivalis、Fusobacterium nucleatumのバイオフィルム形成を阻害する

    松岸 葵, 野中 由香莉, 竹内 麻衣, 原 実生, 早津 学, 三上 剛和, 牛木 辰男, 土門 久哲, 山崎 和久, 多部田 康一

    日本歯周病学会会誌   62 ( 春季特別 )   133 - 133   2020年5月

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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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  • 広汎型重度慢性歯周炎患者に対して歯周組織再生療法を行った一症例

    野中 由香莉, 松岸 葵, 目黒 史也, 高橋 直紀, 多部田 康一

    日本歯周病学会会誌   62 ( 春季特別 )   155 - 155   2020年5月

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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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  • Protective effect of hinokitiol against periodontal bone loss in ligature-induced experimental periodontitis in mice. 査読 国際誌

    Takumi Hiyoshi, Hisanori Domon, Tomoki Maekawa, Daisuke Yonezawa, Eiji Kunitomo, Koichi Tabeta, Yutaka Terao

    Archives of oral biology   112   104679 - 104679   2020年4月

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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 overall objective of this study was to investigate the effects of hinokitiol on periodontal bone loss in a murine model of experimental periodontitis and evaluate the anti-inflammatory activity of hinokitiol in vitro. DESIGN: Periodontitis was induced by tying a silk ligature around the maxillary second molar of mice for 8 days. Hinokitiol was injected once a day for 7 days into the palatal gingiva of the ligated molar. Periodontal bone loss was then assessed morphometrically in the maxillary second molar, and the number of tartrate-resistant acid phosphatase positive multinucleated giant cells around the molar was quantified. The bacterial load of the silk ligature was calculated by counting the number of colony-forming units, while the transcription levels of proinflammatory cytokine-related genes in the palatal gingiva were evaluated by real-time qPCR. The activity of hinokitiol against LPS-induced transcription of proinflammatory genes in RAW 264.7 macrophages was also examined. RESULTS: Local treatment with hinokitiol significantly inhibited the alveolar bone loss and osteoclast differentiation induced by tooth ligation. In addition, hinokitiol treatment decreased the oral bacterial load of the silk ligature and downregulated the mRNA levels of inflammatory cytokine-related genes, both in vitro and in vivo. CONCLUSION: The results indicated that hinokitiol exhibits antibacterial and anti-inflammatory activity and exerts a protective effect against periodontitis.

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  • M2 Phenotype Macrophages Colocalize with Schwann Cells in Human Dental Pulp 査読 国際誌

    N. Yoshiba, N. Edanami, N. Ohkura, T. Maekawa, N. Takahashi, A. Tohma, K. Izumi, T. Maeda, A. Hosoya, H. Nakamura, K. Tabeta, Y. Noiri, K. Yoshiba

    Journal of Dental Research   99 ( 3 )   329 - 338   2020年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Macrophages are immune cells with high plasticity that perform many functions related to tissue injury and repair. They are generally categorized as 2 functional phenotypes: M1 (proinflammatory) and M2 (anti-inflammatory and prohealing). To investigate the role of macrophages in human dental pulp, we examined the localization and distributional alterations of macrophages in healthy dental pulp as well as during the reparative process of pulp capping with mineral trioxide aggregate (MTA) and in cariously inflamed pulp of adult human teeth. We also quantified the populations of M1/M2 macrophages in healthy dental pulp by flow cytometric analysis. CD68+CD86+ cells (M1 phenotype) and CD68+CD163+ cells (M2 phenotype) were 2.11% ± 0.50% and 44.99% ± 2.22%, respectively, of 2.96% ± 0.41% CD68+ cells (pan-macrophages) in whole healthy dental pulp. Interestingly, M2 phenotype macrophages were associated with Schwann cells in healthy pulp, during mineralized bridge formation, and in pulp with carious infections in vivo. Furthermore, the M2 macrophages associated with Schwann cells expressed brain-derived neurotrophic factor (BDNF) under all in vivo conditions. Moreover, we found that plasma cells expressed BDNF. Coculture of Schwann cells isolated from human dental pulp and human monocytic cell line THP-1 showed that Schwann cells induced M2 phenotypic polarization of THP-1 cell-derived macrophages. The THP-1 macrophages that maintained contact with Schwann cells were stimulated, leading to elongation of their cell shape and expression of M2 phenotype marker CD163 in cocultures. In summary, we revealed the spatiotemporal localization of macrophages and potent induction of the M2 phenotype by Schwann cells in human dental pulp. M2 macrophages protect neural elements, whereas M1 cells promote neuronal destruction. Therefore, suppressing the neurodestructive M1 phenotype and maintaining the neuroprotective M2 phenotype of macrophages by Schwann cells may be critical for development of effective treatment strategies to maintain the viability of highly innervated dental pulp.

    DOI: 10.1177/0022034519894957

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  • A bacterial metabolite induces Nrf2-mediated anti-oxidative responses in gingival epithelial cells by activating the MAPK signaling pathway 査読 国際誌

    Mai Yokoji-Takeuchi, Naoki Takahashi, Miki Yamada-Hara, Benso Sulijaya, Takahiro Tsuzuno, Yukari Aoki-Nonaka, Koichi Tabeta, Shigenobu Kishino, Jun Ogawa, Kazuhisa Yamazaki

    ARCHIVES OF ORAL BIOLOGY   110   104602 - 104602   2020年2月

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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: Oxidative stress, which is defined as an imbalance between pro-oxidant and antioxidant systems, has been implicated in the development and/or progression of several inflammatory diseases, including periodontal disease. The reactive oxygen species (ROS) are the primary inducers of oxidative stress. In the induction of cytoprotective enzymes, the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling in antioxidant systems takes a main role. Notably, 10-oxo-trans-11-octadecenoic acid (KetoC), known as a bioactive metabolite generated by intestinal microorganisms, has been reported to have beneficial effects on several biological responses. Therefore, we investigated the antioxidant effect of KetoC on gingival epithelial cells (GECs) in this present study.Methods: An SV40-T antigen-transformed human gingival epithelial cell line (Epi4) was used for experiments. The alteration of anti-oxidative stress related genes was analyzed by qPCR. The cellular ROS levels were evaluated by flow cytometry. To explore its molecular mechanisms, ARE promotor activity was analyzed by luciferase assay; the involvement of mitogen-activated protein kinase (MAPK) and G protein-coupled receptor 120 (GPR120) were evaluated by Western blotting and luciferase assay, respectively.Results: KetoC significantly increased the expression of antioxidant-related genes in GECs. The level of ROS was significantly inhibited by the pretreatment of KetoC. Extracellular signal-regulated kinase (ERK) phosphorylation by KetoC promoted both the nuclear translocation of Nrf2 and its binding to the ARE in GECs. Further, GPR120 regulated the activation of KetoC induced-Nrf2-ARE signaling.Conclusion: KetoC exerts a protective function against the oxidative stress in GECs through GPR120-dependent ERK-Nrf2-ARE signaling.

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  • 機能性糖脂質ビザンチンのStreptococcus mutansに対する抗バイオフィルム効果 スクロース濃度の影響とバイオフィルム形成関連遺伝子の発現解析 査読

    竹中 彰治, 長谷川 泰輔, 小田 真隆, 高橋 直紀, 磯野 俊仁, 大倉 直人, 山本 博文, 多部田 康一, 野杁 由一郎

    日本歯科保存学雑誌   63 ( 1 )   61 - 72   2020年2月

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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  

    目的:機能性糖脂質ビザンチン(Viz-S)は,Streptococcus mutansバイオフィルムを易剥離性に変化させることで抗バイオフィルム作用を示す.本研究では,培養条件のうち,スクロース濃度を変化させたときのS.mutansの抗バイオフィルム効果,各種バイオフィルム形成関連遺伝子の転写量ならびにグルコシルトランスフェラーゼ(GTF)の発現について解析を行った.材料と方法:実験1・スクロース濃度を変化させたときのS.mutansの抗バイオフィルム効果;0.2,0.4,0.8%および1.6%のスクロース含有Brain Heart Infusion培地に,0,10,50μmol/lおよび75μmol/lのViz-Sを添加した.S.mutans UA159株を24時間嫌気培養することで,in vitroバイオフィルムモデルを作製した.リン酸緩衝生理食塩水(PBS)で2回洗浄したときの残存バイオフィルム量をクリスタルバイオレット法(CV法)により定量した.実験2・遺伝子発現動態の解析;0,10μmol/lおよび50μmol/lのViz-S存在下で24時間培養後のバイオフィルム形成菌を回収し,mRNAを抽出後,cDNAを合成した.バイオフィルム形成関連遺伝子の転写量をReal-time PCR法で解析した.実験3・ウエスタンブロッティング解析;in vitroバイオフィルムモデルを作製後,バイオフィルム形成菌と上清をそれぞれ回収した.タンパク質を抽出しSDS-PAGEを行った.疎水性膜に転写し,菌体結合型GTF(CA-GTF)抗体および遊離型GTF(CF-GTF)抗体を反応させた後,酵素標識二次抗体を反応させた.化学発光法により可視化し,タンパクの発現量を比較した.成績:10μmol/l Viz-S群のバイオフィルムは,PBSによる2回の洗浄により構造は変化しなかったが,50μmol/l Viz-S群は0.8%までのスクロース含有条件下においてバイオフィルム構造が93%減少した.1.6%のスクロース含有条件では32%のバイオフィルムが残存した.75μmol/l Viz-S群は,全スクロース濃度においてバイオフィルム形成が阻害された.10μmol/l Viz-S群は,すべての条件下において,遺伝子転写量の有意な変化はなかった.50μmol/l Viz-S群のgtfBおよびgtfC遺伝子の転写は,0.4%以上のスクロース含有条件で,コントロール群(Viz-S非含有)と比較して有意に増加したが,gtfDの転写は,すべてのスクロース含有群で0.46〜0.66倍に減少した.ウエスタンブロッティング解析で50μmol/l Viz-S群のGTFBおよびGTFCの産生量を比較したところ,コントロール群と比較して0.2%および0.4%スクロース含有条件下で有意に低下し,0.8%および1.6%スクロース含有条件下で有意に増加した.一方,GTFDは,コントロール群と比較して1/20以下に産生量が減少した.結論:50μmol/lのViz-Sは口腔粘膜への為害性が低く,殺菌ではない機序でS.mutansのバイオフィルムを剥離した.その機序の一つは,GTFDのタンパク発現を低下させることによるバイオフィルムの構造安定性の低下であった.75μmol/lのViz-Sはバイオフィルム形成を抑制した.(著者抄録)

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  • Mutual inhibition between Prkd2 and Bcl6 controls T follicular helper cell differentiation 査読 国際誌

    Takuma Misawa, Jeffrey A. SoRelle, Jin Huk Choi, Tao Yue, Kuan-Wen Wang, William McAlpine, Jianhui Wang, Aijie Liu, Koichi Tabeta, Emre E. Turer, Bret Evers, Evan Nair-Gill, Subhajit Poddar, Lijing Su, Feiya Ou, Liyang Yu, Jamie Russell, Sara Ludwig, Xiaoming Zhan, Sara Hildebrand, Xiaohong Li, Miao Tang, Anne R. Murray, Eva Marie Y. Moresco, Bruce Beutler

    SCIENCE IMMUNOLOGY   5 ( 43 )   2020年1月

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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 ADVANCEMENT SCIENCE  

    T follicular helper cells (T-FH) participate in germinal center (GC) development and are necessary for B cell production of high-affinity, isotype-switched antibodies. In a forward genetic screen, we identified a missense mutation in Prkd2, encoding the serine/threonine kinase protein kinase D2, which caused elevated titers of immunoglobulin E (IgE) in the serum. Subsequent analysis of serum antibodies in mice with a targeted null mutation of Prkd2 demonstrated polyclonal hypergammaglobulinemia of IgE, IgG1, and IgA isotypes, which was exacerbated by the T cell-dependent humoral response to immunization. GC formation and GC B cells were increased in Prkd2(-/-) spleens. These effects were the result of excessive cell-autonomous T-FH development caused by unrestricted Bcl6 nuclear translocation in Prkd2(-/-) CD4(+) T cells. Prkd2 directly binds to Bcl6, and Prkd2-dependent phosphorylation of Bcl6 is necessary to constrain Bcl6 to the cytoplasm, thereby limiting T-FH development. In response to immunization, Bcl6 repressed Prkd2 expression in CD4(+) T cells, thereby committing them to T(FH )development. Thus, Prkd2 and Bcl6 form a mutually inhibitory positive feedback loop that controls the stable transition from naive CD4(+) T cells to T-FH during the adaptive immune response.

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  • A large-scale observational study to investigate the current status of diabetic complications and their prevention in Japan: Oral and dental findings at baseline -JDCP study 6-

    Koji Inagaki, Takeshi Kikuchi, Toshihide Noguchi, Akio Mitani, Keiko Naruse, Tatsuaki Matsubara, Masamitsu Kawanami, Jun Negishi, Yasushi Furuichi, Eiji Nemoto, Satoru Yamada, Hiromasa Yoshie, Koichi Tabeta, Sachiyo Tomita, Atsushi Saito, Sayaka Katagiri, Yuichi Izumi, Hiroshi Nitta, Takanori Iwata, Yukihiro Numabe, Matsuo Yamamoto, Nobuo Yoshinari, Tsuyoshi Fujita, Hidemi Kurihara, Fusanori Nishimura, Toshihiko Nagata, Hiromichi Yumoto, Toru Naito, Kazuyuki Noguchi, Koichi Ito, Shinya Murakami, Rimei Nishimura, Naoko Tajima

    Journal of the Japan Diabetes Society   63 ( 4 )   195 - 205   2020年

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    掲載種別:研究論文(学術雑誌)  

    The Japan Diabetes Complications and its Prevention (JDCP) prospective study was conducted to analyze the association between glycemic control and oral conditions in a large database of Japanese patients with diabetes. It included a total of 6,099 patients with diabetes (range, 40-75 years) who were treated as outpatients between 2007 and 2009. The mean number of teeth at baseline was 19.8 and women had fewer teeth than men in type 2 diabetes. Within the previous year, 17 % had lost teeth. At baseline, 32 % had experienced gingival swelling, 69 % brushed more than twice a day, 37 % used interdental devices, and 43 % received dental regular checkups. A multiple logistic regression analysis indicated that type 1 diabetic patients with HbAlc 7.0 % had a higher risk having fewer than 20 teeth (odds ratio [OR]: 2.38; 95 % confidence interval [CI]: 1.25-4.78), and type 2 diabetic patients with HbAlc 8.0 % also had a high risk having fewer than 20 teeth (OR: 1.16; 95 % CI: 1.00-1.34), after adjusting for 9 possible confounders. In conclusion, diabetic patients had a high risk of tooth loss and the poorer the glycemic control, the higher the risk of tooth loss.

    DOI: 10.11213/tonyobyo.63.195

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  • Antimicrobial function of the polyunsaturated fatty acid KetoC in an experimental model of periodontitis 査読 国際誌

    Benso Sulijaya, Miki Yamada-Hara, Mai Yokoji-Takeuchi, Yumi Matsuda-Matsukawa, Kyoko Yamazaki, Aoi Matsugishi, Takahiro Tsuzuno, Keisuke Sato, Yukari Aoki-Nonaka, Naoki Takahashi, Shigenobu Kishino, Jun Ogawa, Koichi Tabeta, Kazuhisa Yamazaki

    JOURNAL OF PERIODONTOLOGY   90 ( 12 )   1470 - 1480   2019年12月

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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  

    Background The bioactive metabolite KetoC, generated by intestinal bacteria, exerts various beneficial effects. Nevertheless, its function in the pathogenesis of periodontitis remains unclear. Here, we investigated the effect of KetoC in a mouse model of periodontitis and explored the underlying mechanism. Methods Thirty-one 8-week-old male C57BL/6N mice were randomly divided into four groups (non-ligation, non-ligation + KetoC, ligation + Porphyromonas gingivalis, and ligation + P. gingivalis + KetoC) (n = 7/8 mice/group) and given a daily oral gavage of KetoC (15 mg/mL) or vehicle for 2 weeks. To induce periodontitis, a 5-0 silk ligature was placed on the maxillary left second molar on day 7, and P. gingivalis W83 (10(9) colony-forming unit [CFU]) was administered orally every 3 days. On day 14, all mice were euthanized. Alveolar bone destruction was determined from the level of the cemento-enamel junction to the alveolar bone crest. Moreover, bone loss level was confirmed from gingival tissue sections stained with hematoxylin and eosin. The presence of P. gingivalis was quantified using real-time polymerase chain reaction. In vitro, the bacteriostatic and bactericidal effects of KetoC were assessed by analyzing its suppressive activity on the proliferation of P. gingivalis and using a live/dead bacterial staining kit, respectively. A double-bond-deficient metabolite (KetoB) was then used to investigate the importance of double-bond structure in the antimicrobial activity of KetoC on P. gingivalis. Results In vivo, KetoC attenuated alveolar bone destruction and suppressed P. gingivalis in the periodontitis group. In vitro, KetoC (but not KetoB) downregulated the proliferation and viability of P. gingivalis in a dose-dependent manner. Conclusions KetoC reduced alveolar bone destruction in a periodontitis model via its antimicrobial function. Therefore, this bioactive metabolite may be valuable in clinical applications to support periodontal therapy.

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  • The AmyI-1-18 peptide derived from rice inhibits alveolar bone resorption via suppression of inflammatory cytokine production induced by lipopolysaccharide and interleukin-1β in mice. 査読 国際誌

    Aoki-Nonaka Y, Tabeta K, Yokoji M, Matsugishi A, Matsuda Y, Takahashi N, Sulijaya B, Domon H, Terao Y, Taniguchi M, Yamazaki K

    Journal of periodontology   90 ( 10 )   1160 - 1169   2019年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Gingival epithelial barrier: regulation by beneficial and harmful microbes 査読 国際誌

    Naoki Takahashi, Benso Sulijaya, Miki Yamada-Hara, Takahiro Tsuzuno, Koichi Tabeta, Kazuhisa Yamazaki

    Tissue Barriers   7 ( 3 )   e1651158 - 10   2019年7月

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    記述言語:英語   出版者・発行元:TAYLOR & FRANCIS INC  

    The gingival epithelium acts as a physical barrier to separate the biofilm from the gingival tissue, providing the first line of defense against bacterial invasion in periodontal disease. Disruption of the gingival epithelial barrier, and the subsequent penetration of exogenous pathogens into the host tissues, triggers an inflammatory response, establishing chronic infection. Currently, more than 700 different bacterial species have been identified in the oral cavity, some of which are known to be periodontopathic. These bacteria contribute to epithelial barrier dysfunction in the gingiva by producing several virulence factors. However, some bacteria in the oral cavity appear to be beneficial, helping gingival epithelial cells maintain their integrity and barrier function. This review aims to discuss current findings regarding microorganism interactions and epithelial barrier function in the oral cavity, with reference to investigations in the gut, where this interaction has been extensively studied.

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  • Bmp signaling in molar cusp formation 査読 国際誌

    Fumiya Meguro, Thantrira Porntaveetus, Maiko Kawasaki, Katsushige Kawasaki, Akane Yamada, Yoshito Kakihara, Makio Saeki, Koichi Tabeta, John A. Kessler, Takeyasu Maeda, Atsushi Ohazama

    GENE EXPRESSION PATTERNS   32   67 - 71   2019年6月

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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  

    Tooth cusp is a crucial structure, since the shape of the molar tooth is determined by number, shape, and size of the cusp. Bone morphogenetic protein (Bmp) signaling is known to play a critical role in tooth development, including in initiation. However, it remains unclear whether Bmp signaling is also involved in cusp formation. To address this question, we examined cusp in two different transgenic mouse lines: mice with overexpression of Bmp4 (K14-Bmp4), and those with Bmp inhibitor, Noggin, (K14-Noggin) under keratin14 (K14) promoter. K14-Noggin mice demonstrated extra cusps, whereas reduced number of cusps was observed in K14-Bmp4 mice. To further understand how Bmps are expressed during cusp formation, we performed whole-mount in situ hybridisation analysis of three major Bmps (Bmp2, Bmp4, and Bmp7) in murine maxillary and mandibular molars from E14.5 to P3. The linear expressions of Bmp2 and Bmp4 were observed in both maxillary and mandibular molars at E14.5. The expression patterns of Bmp2 and Bmp4 became significantly different between the maxillary and mandibular molars at E16.5. At P3, all Bmps were expressed in all the cusp regions of the maxillary molar; however, the patterns differed. All Bmps thus exhibited dynamic temporo-spatial expression during the cusp formation. It could therefore be inferred that Bmp signaling is involved in regulating cusp formation.

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  • 歯周炎マウスモデルにおける生物活性代謝産物の抗菌機能(Antimicrobial Function of Bioactive Metabolite in Periodontitis Mice Model)

    Sulijaya Benso, Yamada-Hara Miki, Yokoji-Takeuchi Mai, Matsuda-Matsukawa Yumi, Yamazaki Kyoko, Matsugishi Aoi, Tsuzuno Takahiro, Sato Keisuke, Aoki-Nonaka Yukari, Takahashi Naoki, Tabeta Koichi, Yamazaki Kazuhisa

    日本歯周病学会会誌   61 ( 春季特別 )   119 - 119   2019年5月

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    記述言語:英語   出版者・発行元:(NPO)日本歯周病学会  

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  • Aggregatibacter actinomycetemcomitans induces detachment and death of human gingival epithelial cells and fibroblasts via elastase release following leukotoxin-dependent neutrophil lysis. 査読 国際誌

    Takumi Hiyoshi, Hisanori Domon, Tomoki Maekawa, Kosuke Nagai, Hikaru Tamura, Naoki Takahashi, Daisuke Yonezawa, Tomohiro Miyoshi, Akihiro Yoshida, Koichi Tabeta, Yutaka Terao

    Microbiology and immunology   63 ( 3-4 )   100 - 110   2019年3月

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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  

    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.

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  • Indirect regulation of PCSK9 gene in inflammatory response by Porphyromonas gingivalis infection (vol 5, e01111, 2019) 査読 国際誌

    Mai Yokoji-Takeuchi, Koichi Tabeta, Naoki Takahashi, Kei Arimatsu, Haruna Miyazawa, Yumi Matsuda-Matsukawa, Keisuke Sato, Miki Yamada, Kazuhisa Yamazaki

    HELIYON   5 ( 2 )   e01210   2019年2月

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    [This corrects the article DOI: 10.1016/j.heliyon.2018.e01111.].

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  • Peptides from rice endosperm protein restrain periodontal bone loss in mouse model of periodontitis 査読 国際誌

    Hikaru Tamura, Tomoki Maekawa, Hisanori Damon, Takumi Hiyoshi, Daisuke Yonezawa, Kosuke Nagai, Akihito Ochiai, Masayuki Taniguchi, Koichi Tabeta, Takeyasu Maeda, Yutaka Terao

    ARCHIVES OF ORAL BIOLOGY   98   132 - 139   2019年2月

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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: 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 unligated (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.

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  • Indirect regulation of PCSK9 gene in inflammatory response by Porphyromonas gingivalis infection 査読 国際誌

    Mai Yokoji-Takeuchi, Koichi Tabeta, Naoki Takahashi, Kei Arimatsu, Haruna Miyazawa, Yumi Matsuda-Matsukawa, Keisuke Sato, Miki Yamada, Kazuhisa Yamazaki

    HELIYON   5 ( 1 )   e01111   2019年1月

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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 SCI LTD  

    Pro-protein convertase subtilisin/kexin type 9 (PCSK9), a secreted serine protease, regulates serum low-density lipoprotein (LDL) cholesterol levels by targeting the degradation of LDL receptor (LDLR) in the liver. Although previous reports describe elevated levels of PCSK9 in patients with periodontitis, the mechanisms that trigger this increase in serum PCSK9 levels and induce the related inflammatory response remain unclear. In an unc93b1-deficient mouse of Porphyromonas gingivalis infection, nucleic acid antigen recognition via Toll-like receptors was found to promote PCSK9 production, suggesting an indirect role for tumor necrosis factor-alpha as an inducer of PCSK9 in contrast to that reported in previous studies. Furthermore, PCSK9 production was independent of the TIR domain-containing adapter-inducing interferon-beta-dependent signaling pathway. These results indicate that changes in LDLR expression precede an increase in the serum PCSK9 level in the context of an infectious disease such as periodontitis.

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  • Noninvasive measurement of cell/colony motion using image analysis methods to evaluate the proliferative capacity of oral keratinocytes as a tool for quality control in regenerative medicine 査読

    Emi Hoshikawa, Taisuke Sato, Yoshitaka Kimori, Ayako Suzuki, Kenta Haga, Hiroko Kato, Koichi Tabeta, Daisuke Nanba, Kenji Izumi

    Journal of Tissue Engineering   10   2019年

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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  

    Image-based cell/colony analyses offer promising solutions to compensate for the lack of quality control (QC) tools for noninvasive monitoring of cultured cells, a regulatory challenge in regenerative medicine. Here, the feasibility of two image analysis algorithms, optical flow and normalised cross-correlation, to noninvasively measure cell/colony motion in human primary oral keratinocytes for screening the proliferative capacity of cells in the early phases of cell culture were examined. We applied our software to movies converted from 96 consecutive time-lapse phase-contrast images of an oral keratinocyte culture. After segmenting the growing colonies, two indices were calculated based on each algorithm. The correlation between each index of the colonies and their proliferative capacity was evaluated. The software was able to assess cell/colony motion noninvasively, and each index reflected the observed cell kinetics. A positive linear correlation was found between cell/colony motion and proliferative capacity, indicating that both algorithms are potential tools for QC.

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  • <i>β</i> <sub>2</sub>-Microglobulin and Neutrophil Gelatinase-Associated Lipocalin, Potential Novel Urine Biomarkers in Periodontitis: A Cross-Sectional Study in Japanese. 査読 国際誌

    Nakajima M, Hosojima M, Tabeta K, Miyauchi S, Yamada-Hara M, Takahashi N, Miyazawa H, Matsuda-Matsukawa Y, Sato K, Sugita N, Komatsu Y, Ishikawa T, Akiishi K, Yamazaki K, Kato K, Saito A, Yoshie H

    International journal of dentistry   2019   1394678 - 1394678   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Gingival epithelial barrier: regulation by beneficial and harmful microbes 査読 国際誌

    Naoki Takahashi, Benso Sulijaya, Miki Yamada-Hara, Takahiro Tsuzuno, Koichi Tabeta, Kazuhisa Yamazaki

    TISSUE BARRIERS   7 ( 3 )   e1651158   2019年

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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:TAYLOR & FRANCIS INC  

    The gingival epithelium acts as a physical barrier to separate the biofilm from the gingival tissue, providing the first line of defense against bacterial invasion in periodontal disease. Disruption of the gingival epithelial barrier, and the subsequent penetration of exogenous pathogens into the host tissues, triggers an inflammatory response, establishing chronic infection. Currently, more than 700 different bacterial species have been identified in the oral cavity, some of which are known to be periodontopathic. These bacteria contribute to epithelial barrier dysfunction in the gingiva by producing several virulence factors. However, some bacteria in the oral cavity appear to be beneficial, helping gingival epithelial cells maintain their integrity and barrier function. This review aims to discuss current findings regarding microorganism interactions and epithelial barrier function in the oral cavity, with reference to investigations in the gut, where this interaction has been extensively studied.

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  • Increased serum PCSK9, a potential biomarker to screen for periodontitis, and decreased total bilirubin associated with probing depth in a Japanese community survey 査読

    K. Tabeta, M. Hosojima, M. Nakajima, S. Miyauchi, H. Miyazawa, N. Takahashi, Y. Matsuda, N. Sugita, Y. Komatsu, K. Sato, T. Ishikawa, K. Akiishi, K. Yamazaki, K. Kato, A. Saito, H. Yoshie

    Journal of Periodontal Research   53 ( 3 )   446 - 456   2018年6月

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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 Munksgaard  

    Background and Objectives: Previous reports suggest that several serum biomarkers play roles in the pathogenesis, inflammatory response, and oxidative stress in periodontitis caused by bacterial infections, linking chronic periodontitis to atherosclerotic vascular disease (ASVD). The aim of this preliminary study was to investigate, in a Japanese cross-sectional community survey, potential serum biomarkers of periodontitis that are associated with ASVD and chronic periodontitis. Material and Methods: The study cohort included a total of 108 male subjects who underwent annual health examinations. Serum biomarkers (high-sensitivity C-reactive protein [hs-CRP], proprotein convertase subtilisin/kexin type 9 [PCSK9], interleukin-6, tumor necrosis factor-α, soluble CD14, myeloperoxidase, matrix metalloproteinase-3, adiponectin, total bilirubin [TBIL], and serum lipids) were analyzed to determine their association (if any) with periodontal parameters. Aortic stiffness was evaluated using the brachial-ankle aortic pulse wave velocity (PWV) index and the cardio-ankle vascular index (CAVI). Results: The concentrations of PCSK9 and hs-CRP were increased (P =.001 and.042, respectively), and the concentration of TBIL was decreased (P =.046), in subjects with periodontal disease (determined as a probing depth of ≥4 mm in at least one site) compared with periodontally healthy subjects. The ratio of low-density lipoprotein cholesterol (LDL-C) to high-density lipoprotein cholesterol and the concentrations of triglycerides, remnant-like particles-cholesterol, and oxidized LDL were elevated in subjects with periodontal disease compared with periodontally healthy subjects (P =.038,.007,.002, and.049, respectively). Multivariate regression analyses indicated that the number of sites with a pocket depth of ≥4 mm was associated with the concentration of PCSK9 and inversely associated with the concentration of TBIL independently (standardized β =.243, P =.040; standardized β = −.443, P =.0002; respectively). Analysis of receiver operating characteristic curves of PCSK9 indicated moderate accuracy for predicting the presence of disease sites (probing depth ≥ 4 mm) (area under the curve = 0.740). No significance in the values of PWV and CAVI was observed between subjects with periodontal disease and periodontally healthy subjects. Conclusion: In Japanese male subjects, the concentrations of serum PCSK9 and TBIL were correlated with periodontal parameters. Moreover, PCSK9 could be a candidate biomarker for diagnosing chronic periodontitis, and may also have potential to evaluate the risk for periodontitis to cause ASVD. Longitudinal studies of larger populations are necessary to confirm the exact association of periodontitis with increased serum PCSK9 and decreased TBIL.

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  • A bacterial metabolite ameliorates periodontal pathogen-induced gingival epithelial barrier disruption via GPR40 signaling 査読 国際誌

    Miki Yamada, Naoki Takahashi, Yumi Matsuda, Keisuke Sato, Mai Yokoji, Benso Sulijaya, Tomoki Maekawa, Tatsuo Ushiki, Yoshikazu Mikami, Manabu Hayatsu, Yusuke Mizutani, Shigenobu Kishino, Jun Ogawa, Makoto Arita, Koichi Tabeta, Takeyasu Maeda, Kazuhisa Yamazaki

    SCIENTIFIC REPORTS   8 ( 1 )   9008 - 9008   2018年6月

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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.

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  • Pneumococcal DNA-binding proteins released through autolysis induce the production of proinflammatory cytokines via toll-like receptor 4 査読 国際誌

    Kosuke Nagai, Hisanori Domon, Tomoki Maekawa, Masataka Oda, Takumi Hiyoshi, Hikaru Tamura, Daisuke Yonezawa, Yoshiaki Arai, Mai Yokoji, Koichi Tabeta, Rie Habuka, Akihiko Saitoh, Masaya Yamaguchi, Shigetada Kawabata, Yutaka Terao

    CELLULAR IMMUNOLOGY   325   14 - 22   2018年3月

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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:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    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-3phosphate 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 proin-flammatory cytokines in macrophages, and might cause host tissue damage and affect the development of pneumococcal diseases.

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  • Useful immunochromatographic assay of calprotectin in gingival crevicular fluid for diagnosis of diseased sites in patients with periodontal diseases 査読 国際誌

    Jun-ichi Kido, Shinya Murakami, Masahiro Kitamura, Manabu Yanagita, Koichi Tabeta, Kazuhisa Yamazaki, Hiromasa Yoshie, Hisashi Watanabe, Yuichi Izumi, Reiko Suda, Matsuo Yamamoto, Hideki Shiba, Tsuyoshi Fujita, Hidemi Kurihara, Mitsuharu Mizuno, Akihiro Mishima, Nobumasa Kawahara, Kazuhiro Hashimoto, Koji Naruishi, Toshihiko Nagata

    JOURNAL OF PERIODONTOLOGY   89 ( 1 )   67 - 75   2018年1月

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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 ACAD PERIODONTOLOGY  

    Background: Calprotectin, an inflammation-related protein, is present in gingival crevicular fluid (GCF), and the determination of calprotectin is useful for diagnosing periodontal diseases. The authors have recently developed a novel immunochromatographic (IC) chip system to determine calprotectin levels in GCF. In the present study, the usefulness of this diagnostic system is investigated in patients with periodontal diseases.Methods: Thirty-six patients with periodontal diseases participated in this clinical test at multiple centers. Periodontitis sites (n = 118) and non-periodontitis (healthy) sites (n = 120) were selected after periodontal examination. GCF collection and periodontal examination were performed at baseline, after supragingival and subgingival scaling and root planing. Calprotectin levels in GCF were determined using a novel IC chip system and evaluated as a visual score and an IC reader value. Correlations between GCF calprotectin levels, clinical indicators, and changes in calprotectin levels by periodontal treatments were investigated. Receiver operating characteristic (ROC) analysis of IC reader value for GCF calprotectin was performed to predict periodontal diseases.Results: The visual score of GCF calprotectinwas highly correlated with the IC reader value. IC reader values of GCF calprotectin in the periodontitis group were higher than those of the healthy group at three dental examination stages, and they significantly decreased with periodontal treatments. Visual scores and IC reader values of GCF calprotectin were correlated to levels of clinical indicators. ROC analysis for GCF calprotectin showed an optimal cutoff value to predict periodontal diseases.Conclusion: Determination ofGCF calprotectin using a novel IC chip system is useful for diagnosis of periodontal diseases.

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  • An ENU-induced splice site mutation of mouse Col1a1 causing recessive osteogenesis imperfecta and revealing a novel splicing rescue 査読 国際誌

    Koichi Tabeta, Xin Du, Kei Arimatsu, Mai Yokoji, Naoki Takahashi, Norio Amizuka, Tomoka Hasegawa, Karine Crozat, Tomoki Maekawa, Sayuri Miyauchi, Yumi Matsuda, Takako Ida, Masaru Kaku, Kasper Hoebe, Kinji Ohno, Hiromasa Yoshie, Kazuhisa Yamazaki, Eva Marie Y. Moresco, Bruce Beutler

    SCIENTIFIC REPORTS   7 ( 1 )   11717 - 11717   2017年9月

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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  

    GU-AG consensus sequences are used for intron recognition in the majority of cases of pre-mRNA splicing in eukaryotes. Mutations at splice junctions often cause exon skipping, short deletions, or insertions in the mature mRNA, underlying one common molecular mechanism of genetic diseases. Using N-ethyl-N-nitrosourea, a novel recessive mutation named seal was produced, associated with fragile bones and susceptibility to fractures (spine and limbs). A single nucleotide transversion (T. A) at the second position of intron 36 of the Col1a1 gene, encoding the type I collagen, alpha 1 chain, was responsible for the phenotype. Col1a1seal mRNA expression occurred at greatly reduced levels compared to the wild-type transcript, resulting in reduced and aberrant collagen fibers in tibiae of seal homozygous mice. Unexpectedly, splicing of Col1a1seal mRNA followed the normal pattern despite the presence of the donor splice site mutation, likely due to the action of a putative intronic splicing enhancer present in intron 25, which appeared to function redundantly with the splice donor site of intron 36. Seal mice represent a model of human osteogenesis imperfecta, and reveal a previously unknown mechanism for splicing "rescue."

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  • 新潟大学歯学部臨床実習における臨床能力評価

    藤井 規孝, 竹中 彰治, 多部田 康一, 佐藤 直子, 秋葉 奈美, 小田 陽平, 勝見 祐二, 小野 和宏, 前田 健康

    日本歯科医学教育学会雑誌   33 ( 1 )   4 - 11   2017年4月

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    記述言語:日本語   出版者・発行元:(一社)日本歯科医学教育学会  

    歯学教育を改善するために、各大学歯学部・歯科大学においてさまざまな取り組みが行われている。なかでも、診療参加型の臨床実習を充実させることは重視されており、それぞれの歯学部・歯科大学は信頼される歯科医師を輩出するという最も大きな社会的命題を果たすべく努力を続けている。新潟大学歯学部では、卒業生の質の保証を目的に、臨床実習においてACCEPT Projectを立ち上げ、「ACKPIS」と称する方法を用いて学生の臨床能力を評価してきた。ACKPISは診療を自験する学生に対し、どのような専門領域においても必要不可欠となる6つの基本項目を、それぞれの専門処置を評価課題として確認するものである。今回、ACKPISの効果を検証するために、平成28年度の受検生にアンケート調査を行った。ACKPISの基本項目は、ADEAやGDCが提唱する歯科医師に求められるコンピテンシーの中にも該当する記述がみられ、国内外で医師に対して行われている臨床能力評価法同様、診療現場でのフィードバックを含んでいることから、歯学生の臨床能力を評価するために適当であると考えられた。また、アンケート結果から、受検した学生もACKPISの必要性や重要性を認識し、受検方法や合否判定の妥当性を認めていることが明らかになった。以上のことから、ACKPISは臨床実習中の学生の臨床能力を評価するための有用な方法となり得ることが示唆された。(著者抄録)

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  • Neuronal TRPV1 activation regulates alveolar bone resorption by suppressing osteoclastogenesis via CGRP 査読 国際誌

    Naoki Takahashi, Yumi Matsuda, Keisuke Sato, Petrus R. de Jong, Samuel Bertin, Koichi Tabeta, Kazuhisa Yamazaki

    SCIENTIFIC REPORTS   6   29294 - 29294   2016年7月

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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  

    The transient receptor potential vanilloid 1 (TRPV1) channel is abundantly expressed in peripheral sensory neurons where it acts as an important polymodal cellular sensor for heat, acidic pH, capsaicin, and other noxious stimuli. The oral cavity is densely innervated by afferent sensory neurons and is a highly specialized organ that protects against infections as well as physical, chemical, and thermal stresses in its capacity as the first part of the digestive system. While the function of TRPV1 in sensory neurons has been intensively studied in other organs, its physiological role in periodontal tissues is unclear. In this study we found that Trpv1(-/-) mice developed severe bone loss in an experimental model of periodontitis. Chemical ablation of TRPV1-expressing sensory neurons recapitulated the phenotype of Trpv1(-/-) mice, suggesting a functional link between neuronal TRPV1 signaling and periodontal bone loss. TRPV1 activation in gingival nerves induced production of the neuropeptide, calcitonin gene-related peptide (CGRP), and CGRP treatment inhibited osteoclastogenesis in vitro. Oral administration of the TRPV1 agonist, capsaicin, suppressed ligature-induced bone loss in mice with fewer tartrate-resistant acid phosphatase (TRAP)-positive cells in alveolar bone. These results suggest that neuronal TRPV1 signaling in periodontal tissue is crucial for the regulation of osteoclastogenesis via the neuropeptide CGRP.

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    その他リンク: http://orcid.org/0000-0002-7019-1872

  • Microbiological and Clinical Effects of Sitafloxacin and Azithromycin in Periodontitis Patients Receiving Supportive Periodontal Therapy 査読 国際誌

    Takako Nakajima, Takafumi Okui, Harue Ito, Mayuka Nakajima, Tomoyuki Honda, Yasuko Shimada, Koichi Tabeta, Kohei Akazawa, Kazuhisa Yamazaki

    ANTIMICROBIAL AGENTS AND CHEMOTHERAPY   60 ( 3 )   1779 - 1787   2016年3月

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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 MICROBIOLOGY  

    Sitafloxacin (STFX) is a newly developed quinolone that has robust antimicrobial activity against periodontopathic bacteria. We previously reported that oral administration of STFX during supportive periodontal therapy was as effective as conventional mechanical debridement under local anesthesia microbiologically and clinically for 3 months. The aim of the present study was to examine the short-term and long-term microbiological and clinical effects of systemic STFX and azithromycin (AZM) on active periodontal pockets during supportive periodontal therapy. Fifty-one patients receiving supportive periodontal therapy were randomly allocated to the STFX group (200 mg/day of STFX for 5 days) or the AZM group (500 mg/day of AZM for 3 days). The microbiological and clinical parameters were examined until 12 months after the systemic administration of each drug. The concentration of each drug in periodontal pockets and the antimicrobial susceptibility of clinical isolates were also analyzed. The proportions of red complex bacteria, i.e., Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia, which are the representative periodontopathic bacteria, were significantly reduced at 1 month and remained lower at 12 months than those at baseline in both the STFX and AZM groups. Clinical parameters were significantly improved over the 12-month period in both groups. An increase in the MIC of AZM against clinical isolates was observed in the AZM group. These results indicate that monotherapy with systemic STFX and AZM might be an alternative treatment during supportive periodontal therapy in patients for whom invasive mechanical treatment is inappropriate.

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    その他リンク: http://orcid.org/0000-0002-7019-1872

  • Microbiological and Clinical Effects of Sitafloxacin and Azithromycin in Periodontitis Patients Receiving Supportive Periodontal Therapy. 査読 国際誌

    Takako Nakajima, Takafumi Okui, Harue Ito, Mayuka Nakajima, Tomoyuki Honda, Yasuko Shimada, Koichi Tabeta, Kohei Akazawa, Kazuhisa Yamazaki

    Antimicrobial agents and chemotherapy   60 ( 3 )   1779 - 87   2016年1月

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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 MICROBIOLOGY  

    Sitafloxacin (STFX) is a newly developed quinolone that has robust antimicrobial activity against periodontopathic bacteria. We previously reported that oral administration of STFX during supportive periodontal therapy was as effective as conventional mechanical debridement under local anesthesia microbiologically and clinically for 3 months. The aim of the present study was to examine the short-term and long-term microbiological and clinical effects of systemic STFX and azithromycin (AZM) on active periodontal pockets during supportive periodontal therapy. Fifty-one patients receiving supportive periodontal therapy were randomly allocated to the STFX group (200 mg/day of STFX for 5 days) or the AZM group (500 mg/day of AZM for 3 days). The microbiological and clinical parameters were examined until 12 months after the systemic administration of each drug. The concentration of each drug in periodontal pockets and the antimicrobial susceptibility of clinical isolates were also analyzed. The proportions of red complex bacteria, i.e., Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia, which are the representative periodontopathic bacteria, were significantly reduced at 1 month and remained lower at 12 months than those at baseline in both the STFX and AZM groups. Clinical parameters were significantly improved over the 12-month period in both groups. An increase in the MIC of AZM against clinical isolates was observed in the AZM group. These results indicate that monotherapy with systemic STFX and AZM might be an alternative treatment during supportive periodontal therapy in patients for whom invasive mechanical treatment is inappropriate. (This study has been registered with the University Hospital Medical Information Network-Clinical Trials Registry [UMIN-CTR] under registration number UMIN000007834.).

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  • Resveratrol suppresses the inflammatory responses of human gingival epithelial cells in a SIRT1 independent manner 査読

    T. Minagawa, T. Okui, N. Takahashi, T. Nakajima, K. Tabeta, S. Murakami, K. Yamazaki

    Journal of Periodontal Research   50 ( 5 )   586 - 593   2015年10月

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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: In periodontitis, chronic infection by periodontopathic bacteria induces uncontrolled inflammation, which leads to periodontal tissue destruction. Human gingival epithelial cells (HGECs) constitute a critical first line of defense against periodontopathic bacteria, both as a physical barrier and as regulators of inflammation. Resveratrol, a polyphenol found in grapes and red wine, reportedly has anti-inflammatory properties. Therefore, we investigated the effects of resveratrol on the Porphyromonas gingivalis-induced inflammatory responses of HGECs and their mechanism. Material and Methods: We stimulated the HGEC line, epi 4, with live or heat-killed P. gingivalis in the presence of resveratrol, and analyzed expressions of the interleukin-8, monocyte chemoattractant protein-1 and interleukin-1β genes. We determined the involvement of SIRT1 in the effect of resveratrol using sirtinol (a SIRT1 inhibitor) or SIRT1 knockdown. We also examined whether the effects were mediated by activation of AMP-activated kinase, suppression of reactive oxygen species, or inhibition of nuclear factor-κB (NF-κB). Results: Resveratrol treatment decreased the expression of inflammatory cytokines and slightly increased the expression of SIRT1. However, neither SIRT1 inhibition nor SIRT1 knockdown counteracted its anti-inflammatory effects. Although resveratrol did not affect AMP-activated kinase activation or reactive oxygen species production, it slightly suppressed NF-κB translocation when cells were stimulated with heat-killed P. gingivalis. Conclusion: Resveratrol suppressed the inflammatory responses of P. gingivalis-stimulated HGECs, probably by inhibiting NF-κB signaling but independent of SIRT1.

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    その他リンク: http://orcid.org/0000-0002-7019-1872

  • Epithelial TRPV1 signaling accelerates gingival epithelial cell proliferation 査読

    N. Takahashi, Y. Matsuda, H. Yamada, K. Tabeta, T. Nakajima, S. Murakami, K. Yamazaki

    Journal of Dental Research   93 ( 11 )   1141 - 1147   2014年11月

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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  

    Transient receptor potential cation channel subfamily V member 1 (TRPV1), a member of the calcium-permeable thermosensitive transient receptor potential superfamily, is a sensor of thermal and chemical stimuli. TRPV1 is activated by noxious heat (> 43°C), acidic conditions (pH < 6.6), capsaicin, and endovanilloids. This pain receptor was discovered on nociceptive fibers in the peripheral nervous system. TRPV1 was recently found to be expressed by non-neuronal cells, such as epithelial cells. The oral gingival epithelium is exposed to multiple noxious stimuli, including heat and acids derived from endogenous and exogenous substances; however, whether gingival epithelial cells (GECs) express TRPV1 is unknown. We show that both TRPV1 mRNA and protein are expressed by GECs. Capsaicin, a TRPV1 agonist, elevated intracellular Ca2+ levels in the gingival epithelial cell line, epi 4. Moreover, TRPV1 activation in epi 4 cells accelerated proliferation. These responses to capsaicin were inhibited by a specific TRPV1 antagonist, SB-366791. We also observed GEC proliferation in capsaicin-treated mice in vivo. No effects were observed on GEC apoptosis by epithelial TRPV1 signaling. To examine the molecular mechanisms underlying this proliferative effect, we performed complementary (c)DNA microarray analysis of capsaicin-stimulated epi 4 cells. Compared with control conditions, 227 genes were up-regulated and 232 genes were down-regulated following capsaicin stimulation. Several proliferation-related genes were validated by independent experiments. Among them, fibroblast growth factor-17 and neuregulin 2 were significantly up-regulated in capsaicin-treated epi 4 cells. Our results suggest that functional TRPV1 is expressed by GECs and contributes to the regulation of cell proliferation.

    DOI: 10.1177/0022034514552826

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    その他リンク: http://orcid.org/0000-0002-7019-1872

  • Age-related alterations in gene expression of gingival fibroblasts stimulated with Porphyromonas gingivalis 査読

    H. Domon, K. Tabeta, T. Nakajima, K. Yamazaki

    Journal of Periodontal Research   49 ( 4 )   536 - 543   2014年8月

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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: Elderly people exhibit increased susceptibility to a number of autoimmune and infectious diseases, such as periodontitis. Although aging is reportedly associated with a decline in immune function, age-related alterations in periodontal tissue have remained elusive. In the present study, we comprehensively analyzed the effect of aging on the expression of selected genes using mouse gingival fibroblasts. Material and Methods: Gingival fibroblasts derived from young (8 wk of age) and old (≥ 24 mo of age) C57BL/6 mice were stimulated with Porphyromonas gingivalis lipopolysaccharide or live P. gingivalis strain W83. Expression of cytokines/chemokines, innate immune receptors, growth factors, matrix metalloproteinases, tissue inhibitors of metalloproteinases and osteoclastogenesis-related molecules were evaluated using real-time polymerase chain reaction and ELISA for interleukin-6 and transforming growth factor-β1. Results: Gingival fibroblasts derived from old mice exhibited decreased gene expression of Il-6, Cxcl1, Tlr2, Tlr4, Irak3 (IRAK-M), Kgf, Timp1, Timp3 and Rankl under resting conditions, whereas the expression levels of Tgfβ1, Mmp3, Mmp13 and Opg were increased. Age-related differences were also detected at the protein level. Although P. gingivalis W83 upregulated Vegf, Fgf-2 and Bmp2 expression in both young and old gingival fibroblasts, the stimulatory effect on these genes was significantly lower in old gingival fibroblasts. Conclusion: Our findings demonstrated that aging altered the expression of a number of genes in gingival fibroblasts. Thus, alterations in the balance of these molecules could play a critical role in periodontitis progression in the elderly. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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    その他リンク: http://orcid.org/0000-0002-7019-1872

  • Natural killer T cells mediate alveolar bone resorption and a systemic inflammatory response in response to oral infection of mice with Porphyromonas gingivalis 査読

    Y. Aoki-Nonaka, T. Nakajima, S. Miyauchi, H. Miyazawa, H. Yamada, H. Domon, K. Tabeta, K. Yamazaki

    Journal of Periodontal Research   49 ( 1 )   69 - 76   2014年2月

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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: T and B cells are known to be involved in the disease process of periodontitis. However, the role of natural killer T cells in the pathogenesis of periodontitis has not been clarified. Materials and Methods: To examine the role of these cells, C57BL/6J (wild-type), CD1d-/- and α-galactosylceramide (αGC)-stimulated wild-type mice were orally infected with Porphyromonas gingivalis strain W83. Results: Apart from CD1d-/- mice, the level of alveolar bone resorption was elevated by the infection and was further accelerated in αGC-stimulated mice. The infection induced elevated levels of serum amyloid A and P. gingivalis-specific IgG in the sera, although the degree of elevation was much smaller in the CD1d-/- mice. Infection-induced RANKL elevation was only observed in αGC-stimulated mice. Although the cytokines produced by splenocytes were mainly T-helper 1 type in wild-type mice, those in αGC-stimulated mice were predominantly T-helper 2 type. In the liver, the infection demonstrated no effect on the gene expression for interferon-γ, interleukin-4 and RANKL except αGC-stimulated mice in which the infection upregulated the gene expressions. Conclusion: This study is the first to show that natural killer T cells upregulated systemic and local inflammatory responses induced by oral infection with P. gingivalis, thereby contributing to the progression of alveolar bone resorption. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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  • No antigen-presentation defect in Unc93b1(3d/3d) (3d) mice Response 査読 国際誌

    Koichi Tabeta, Kasper Hoebe, Edith M. Janssen, Yu Xia, Bruce Beutler

    NATURE IMMUNOLOGY   14 ( 11 )   1102 - 1103   2013年11月

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    記述言語:英語   出版者・発行元:NATURE PUBLISHING GROUP  

    DOI: 10.1038/ni.2734

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  • A deep intronic mutation in the ankyrin-1 gene causes diminished protein expression resulting in hemolytic anemia in mice. 査読 国際誌

    Hua Huang, PengXiang Zhao, Kei Arimatsu, Koichi Tabeta, Kazuhisa Yamazaki, Lara Krieg, Emily Fu, Tian Zhang, Xin Du

    G3 (Bethesda, Md.)   3 ( 10 )   1687 - 95   2013年10月

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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:GENETICS SOC AM  

    Linkage between transmembrane proteins and the spectrin-based cytoskeleton is necessary for membrane elasticity of red blood cells. Mutations of the proteins that mediate this linkage result in various types of hemolytic anemia. Here we report a novel N-ethyl-N-nitrosourea-induced mutation of ankyrin-1, named hema6, which causes hereditary spherocytosis in mice through a mild reduction of protein expression. The causal mutation was traced to a single nucleotide transition located deep into intron 13 of gene Ank1. In vitro minigene splicing assay revealed two abnormally spliced transcripts containing cryptic exons from fragments of Ank1 intron 13. The inclusion of cryptic exons introduced a premature termination codon, which leads to nonsense-mediated decay of the mutant transcripts in vivo. Hence, in homozygous mice, only wild-type ankyrin-1 is expressed, albeit at 70% of the level in wild-type mice. Heterozygotes display a similar hereditary spherocytosis phenotype stemming from intermediate protein expression level, indicating the haploinsufficiency of the mutation. Weakened linkage between integral transmembrane protein, band 3, and underlying cytoskeleton was observed in mutant mice as the result of reduced high-affinity binding sites provided by ankyrin-1. Hema6 is the only known mouse mutant of Ank1 allelic series that expresses full-length canonical ankyrin-1 at a reduced level, a fact that makes it particularly useful to study the functional impact of ankyrin-1 quantitative deficiency.

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  • Profiling biomarkers in gingival crevicular fluid using multiplex bead immunoassay 査読 国際誌

    Yasuko Shimada, Koichi Tabeta, Noriko Sugita, Hiromasa Yoshie

    ARCHIVES OF ORAL BIOLOGY   58 ( 6 )   724 - 730   2013年6月

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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: Biomarkers in gingival crevicular fluid (GCF) have been investigated; however, measurements were limited by the small sample volume available. The aim of this study was to determine the levels of 40 different cytokines and chemokines in GCF samples.Design: Eleven patients with generalised chronic periodontitis participating in a supportive periodontal therapy programme with remaining probing pocket depths (PDs) of >5 mm were enrolled. One healthy and two diseased sites were sampled in each subject. Forty biomarkers in GCF were examined using a multiplex bead immunoassay. Porphyromonas gingivalis from the diseased sites was quantified by real-time polymerase chain reaction.Results: Twenty-six biomarkers were detected in the GCF samples using the multiplex bead immunoassay. The levels of nine biomarkers were significantly different between the diseased and healthy sites after adjustment with Bonferroni's correction. The level of 26 biomarkers in diseased sites was compared between bleeding on probing (BOP)-positive and BOP-negative sites. Interleukin (IL)-1 beta and interferon-inducible protein (IP)-10 levels were significantly higher in BOP-positive diseased sites than BOP-negative diseased sites after adjustment for multiple comparisons (IL-1 beta, p = 0.0007, IP-10; p = 0.0009). In addition, the levels of IL-1 beta in GCF were found to be strongly correlated with the P. gingivalis ratio (r = 0.646, p = 0.0012).Conclusion: IL-1 beta levels in GCF correlate with the PDs, BOP and the presence of P. gingivalis in subgingival plaque. Multiplex bead assays can be useful in GCF studies. These findings can help in identifying new diagnostic methods in the diagnosis of periodontal disease. (C) 2012 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.archoralbio.2012.11.012

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  • ENU-induced phenovariance in mice: inferences from 587 mutations. 査読 国際誌

    Carrie N Arnold, Michael J Barnes, Michael Berger, Amanda L Blasius, Katharina Brandl, Ben Croker, Karine Crozat, Xin Du, Celine Eidenschenk, Philippe Georgel, Kasper Hoebe, Hua Huang, Zhengfan Jiang, Philippe Krebs, Diantha La Vine, Xiaohong Li, Stephen Lyon, Eva Marie Y Moresco, Anne R Murray, Daniel L Popkin, Sophie Rutschmann, Owen M Siggs, Nora G Smart, Lei Sun, Koichi Tabeta, Victoria Webster, Wataru Tomisato, Sungyong Won, Yu Xia, Nengming Xiao, Bruce Beutler

    BMC research notes   5   577 - 577   2012年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: We present a compendium of N-ethyl-N-nitrosourea (ENU)-induced mouse mutations, identified in our laboratory over a period of 10 years either on the basis of phenotype or whole genome and/or whole exome sequencing, and archived in the Mutagenetix database. Our purpose is threefold: 1) to formally describe many point mutations, including those that were not previously disclosed in peer-reviewed publications; 2) to assess the characteristics of these mutations; and 3) to estimate the likelihood that a missense mutation induced by ENU will create a detectable phenotype. FINDINGS: In the context of an ENU mutagenesis program for C57BL/6J mice, a total of 185 phenotypes were tracked to mutations in 129 genes. In addition, 402 incidental mutations were identified and predicted to affect 390 genes. As previously reported, ENU shows strand asymmetry in its induction of mutations, particularly favoring T to A rather than A to T in the sense strand of coding regions and splice junctions. Some amino acid substitutions are far more likely to be damaging than others, and some are far more likely to be observed. Indeed, from among a total of 494 non-synonymous coding mutations, ENU was observed to create only 114 of the 182 possible amino acid substitutions that single base changes can achieve. Based on differences in overt null allele frequencies observed in phenotypic vs. non-phenotypic mutation sets, we infer that ENU-induced missense mutations create detectable phenotype only about 1 in 4.7 times. While the remaining mutations may not be functionally neutral, they are, on average, beneath the limits of detection of the phenotypic assays we applied. CONCLUSIONS: Collectively, these mutations add to our understanding of the chemical specificity of ENU, the types of amino acid substitutions it creates, and its efficiency in causing phenovariance. Our data support the validity of computational algorithms for the prediction of damage caused by amino acid substitutions, and may lead to refined predictions as to whether specific amino acid changes are responsible for observed phenotypes. These data form the basis for closer in silico estimations of the number of genes mutated to a state of phenovariance by ENU within a population of G3 mice.

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  • Effect of Porphyromonas gingivalis infection on post-transcriptional regulation of the low-density lipoprotein receptor in mice. 査読 国際誌

    Haruna Miyazawa, Koichi Tabeta, Sayuri Miyauchi, Yukari Aoki-Nonaka, Hisanori Domon, Tomoyuki Honda, Takako Nakajima, Kazuhisa Yamazaki

    Lipids in health and disease   11   121 - 121   2012年9月

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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:BMC  

    BACKGROUND: Periodontal disease is suggested to increase the risk of atherothrombotic disease by inducing dyslipidemia. Recently, we demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9), which is known to play a critical role in the regulation of circulating low-density lipoprotein (LDL) cholesterol levels, is elevated in periodontitis patients. However, the underlying mechanisms of elevation of PCSK9 in periodontitis patients are largely unknown. Here, we explored whether Porphyromonas gingivalis, a representative periodontopathic bacterium, -induced inflammatory response regulates serum PCSK9 and cholesterol levels using animal models. METHODS: We infected C57BL/6 mice intraperitoneally with Porphyromonas gingivalis, a representative strain of periodontopathic bacteria, and evaluated serum PCSK9 levels and the serum lipid profile. PCSK9 and LDL receptor (LDLR) gene and protein expression, as well as liver X receptors (Lxrs), inducible degrader of the LDLR (Idol), and sterol regulatory element binding transcription factor (Srebf)2 gene expression, were examined in the liver. RESULTS: P. gingivalis infection induced a significant elevation of serum PCSK9 levels and a concomitant elevation of total and LDL cholesterol compared with sham-infected mice. The LDL cholesterol levels were significantly correlated with PCSK9 levels. Expression of the Pcsk9, Ldlr, and Srebf2 genes was upregulated in the livers of the P. gingivalis-infected mice compared with the sham-infected mice. Although Pcsk9 gene expression is known to be positively regulated by sterol regulatory element binding protein (SREBP)2 (human homologue of Srebf2), whereas Srebf2 is negatively regulated by cholesterol, the elevated expression of Srebf2 found in the infected mice is thought to be mediated by P. gingivalis infection. CONCLUSIONS: P. gingivalis infection upregulates PCSK9 production via upregulation of Srebf2, independent of cholesterol levels. Further studies are required to elucidate how infection regulates Srebf2 expression and subsequently influences lipid metabolism.

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  • Effect of Porphyromonas gingivalis infection on post-transcriptional regulation of the low-density lipoprotein receptor in mice 査読 国際誌

    Haruna Miyazawa, Koichi Tabeta, Sayuri Miyauchi, Yukari Aoki-Nonaka, Hisanori Domon, Tomoyuki Honda, Takako Nakajima, Kazuhisa Yamazaki

    LIPIDS IN HEALTH AND DISEASE   11   121 - 121   2012年9月

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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:BMC  

    Background: Periodontal disease is suggested to increase the risk of atherothrombotic disease by inducing dyslipidemia. Recently, we demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9), which is known to play a critical role in the regulation of circulating low-density lipoprotein (LDL) cholesterol levels, is elevated in periodontitis patients. However, the underlying mechanisms of elevation of PCSK9 in periodontitis patients are largely unknown. Here, we explored whether Porphyromonas gingivalis, a representative periodontopathic bacterium, -induced inflammatory response regulates serum PCSK9 and cholesterol levels using animal models.Methods: We infected C57BL/6 mice intraperitoneally with Porphyromonas gingivalis, a representative strain of periodontopathic bacteria, and evaluated serum PCSK9 levels and the serum lipid profile. PCSK9 and LDL receptor (LDLR) gene and protein expression, as well as liver X receptors (Lxrs), inducible degrader of the LDLR (Idol), and sterol regulatory element binding transcription factor (Srebf)2 gene expression, were examined in the liver.Results: P. gingivalis infection induced a significant elevation of serum PCSK9 levels and a concomitant elevation of total and LDL cholesterol compared with sham-infected mice. The LDL cholesterol levels were significantly correlated with PCSK9 levels. Expression of the Pcsk9, Ldlr, and Srebf2 genes was upregulated in the livers of the P. gingivalis-infected mice compared with the sham-infected mice. Although Pcsk9 gene expression is known to be positively regulated by sterol regulatory element binding protein (SREBP)2 (human homologue of Srebf2), whereas Srebf2 is negatively regulated by cholesterol, the elevated expression of Srebf2 found in the infected mice is thought to be mediated by P. gingivalis infection.Conclusions: P. gingivalis infection upregulates PCSK9 production via upregulation of Srebf2, independent of cholesterol levels. Further studies are required to elucidate how infection regulates Srebf2 expression and subsequently influences lipid metabolism.

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  • 歯周病安定期治療における全身抗菌療法の効果

    中島 貴子, 奥井 隆文, 伊藤 晴江, 宮内 小百合, 多部田 康一, 山崎 和久

    日本歯科医師会雑誌   65 ( 5 )   624 - 624   2012年8月

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  • Oral infection with Porphyromonas gingivalis and systemic cytokine profile in C57BL/6.KOR-ApoE <sup>shl</sup> mice 査読

    S. Miyauchi, T. Maekawa, Y. Aoki, H. Miyazawa, K. Tabeta, T. Nakajima, K. Yamazaki

    Journal of Periodontal Research   47 ( 3 )   402 - 408   2012年6月

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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 apolipoproteinE-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 3day intervals and were then killed. Splenocytes were isolated and analysed for proliferative activity and immunoglobulinG (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-α 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. © 2011 John Wiley & Sons A/S.

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  • Relationship between serum antibody titres to Porphyromonas gingivalis and hs-CRP levels as inflammatory markers of periodontitis 査読 国際誌

    Hirotaka Miyashita, Tomoyuki Honda, Tomoki Maekawa, Naoki Takahashi, Yukari Aoki, Takako Nakajima, Koichi Tabeta, Kazuhisa Yamazaki

    ARCHIVES OF ORAL BIOLOGY   57 ( 6 )   820 - 829   2012年6月

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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.

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  • Increased serum PCSK9 concentrations are associated with periodontal infection but do not correlate with LDL cholesterol concentration 査読 国際誌

    Haruna Miyazawa, Tomoyuki Honda, Sayuri Miyauchi, Hisanori Domon, Takafumi Okui, Takako Nakajima, Koichi Tabeta, Kazuhisa Yamazaki

    CLINICA CHIMICA ACTA   413 ( 1-2 )   154 - 159   2012年1月

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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: Periodontal disease increases the risk of atherothrombotic disease, and high concentrations of low density lipoprotein (LDL) cholesterol are considered to be involved: however, the underlying mechanisms are largely unknown. Recent studies demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in circulating LDL cholesterol concentrations. The aim of the present study is to analyze serum PCSK9 concentrations and their relation to lipoprotein concentrations in periodontitis patients.Methods: Sera were obtained from 40 periodontitis patients and 30 control subjects. PCSK9 concentrations, high-sensitivity C-reactive protein (hs-CRP), IL-6, TNF-alpha and Porphyromonas gingivalis antibodies were measured by ELISA, and lipid profiles were determined by a commercial laboratory.Results: Periodontitis patients demonstrated significantly higher serum antibody titer to P. gingivalis and hs-CRP concentrations than control subjects, suggesting infection with P. gingivalis and a systemic inflammatory response. PCSK9 concentrations in periodontitis patients were significantly higher than those in control subjects. However, the concentrations of total and LDL cholesterols were not significantly different between periodontitis patients and control subjects. Moreover, no correlations were observed between PCSK9 concentrations and lipid profiles.Conclusion: Periodontal infection upregulates PCSK9 production. However, further studies are required to elucidate how periodontal infection affects PCSK9 concentrations and subsequent lipid metabolism. (C) 2011 Elsevier B.V. All rights reserved.

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  • Increased expression of C-reactive protein gene in inflamed gingival tissues could be derived from endothelial cells stimulated with interleukin-6 査読 国際誌

    Tomoki Maekawa, Koichi Tabeta, Keiko Kajita-Okui, Takako Nakajima, Kazuhisa Yamazaki

    ARCHIVES OF ORAL BIOLOGY   56 ( 11 )   1312 - 1318   2011年11月

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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.

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  • Effect of interleukin-17 on the expression of chemokines in gingival epithelial cells 査読 国際誌

    Naoki Takahashi, Takafumi Okui, Koichi Tabeta, Kazuhisa Yamazaki

    EUROPEAN JOURNAL OF ORAL SCIENCES   119 ( 5 )   339 - 344   2011年10月

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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  

    The role of interleukin (IL)-17 in cellular communication in inflammation has been well described, and a positive correlation between the severity of periodontitis and the level of IL-17 was reported. Although epithelial cells are a major target of IL-17, little is known about the effect of IL-17 on the production of chemokines by human gingival epithelial cells (HGECs). We evaluated the effects of IL-17 on the expression of CXCL8 and CCL2 by HGECs using quantitative real-time PCR and ELISA. In addition, the role of the nuclear factor (NF)-kappa B signalling pathway in the IL-17-mediated expression of chemokines was assessed using a specific inhibitor. Stimulation with IL-17 up-regulated the expression of CXCL8 mRNA but not of CCL2 mRNA in HGECs, whereas tumour necrosis factor-alpha (TNF-alpha) elevated the expression of mRNA for both chemokines. Stimulation with IL-17 up-regulated the secretion of CXCL8 protein, but not the secretion of CCL2 protein. The effect of IL-17 on CXCL8 production was suppressed using an anti-IL-17R Ig, suggesting a role for a specific receptor-ligand interaction. Inhibition of the NF-kappa B signalling pathway demonstrated that NF-kappa B activation is required for the CXCL8 expression in HGECs. In conclusion, IL-17 is involved in the regulation of the innate immune response in HGECs by inducing CXCL8 production.

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  • Chronic Oral Infection with Porphyromonas gingivalis Accelerates Atheroma Formation by Shifting the Lipid Profile 査読 国際誌

    Tomoki Maekawa, Naoki Takahashi, Koichi Tabeta, Yukari Aoki, Hirotaka Miyashita, Sayuri Miyauchi, Haruna Miyazawa, Takako Nakajima, Kazuhisa Yamazaki

    PLOS ONE   6 ( 5 )   e20240   2011年5月

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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.

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  • Elevated Antibody Titers to Porphyromonas gingivalis as a Possible Predictor of Ischemic Vascular Disease: Results from the Tokamachi-Nakasato Cohort Study 査読

    Koichi Tabeta, Naohito Tanabe, Daisuke Yonezawa, Hirotaka Miyashita, Tomoki Maekawa, Naoki Takahashi, Takafumi Okui, Takako Nakajima, Kazuhisa Yamazaki

    JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS   18 ( 9 )   808 - 817   2011年

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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.

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  • Interleukin-1 receptor-associated kinase-M in gingival epithelial cells attenuates the inflammatory response elicited by Porphyromonas gingivalis 査読

    N. Takahashi, T. Honda, H. Domon, T. Nakajima, K. Tabeta, Kazuhisa Yamazaki

    Journal of Periodontal Research   45 ( 4 )   512 - 519   2010年8月

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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  

    Takahashi N, Honda T, Domon H, Nakajima T, Tabeta K, Yamazaki K. Interleukin-1 receptor-associated kinase-M in gingival epithelial cells attenuates the inflammatory response elicited by Porphyromonas gingivalis. J Periodont Res 2010; 45: 512-519. © 2010 John Wiley & Sons A/S Background and Objective: Recent studies have revealed that negative regulatory molecules, including interleukin-1 receptor-associated kinase-M (IRAK-M), control the overactivation of Toll-like receptor (TLR) signaling. The role of IRAK-M in human gingival epithelial cells (HGECs), which express TLRs, remains unclear. The present study examined the role of IRAK-M on interleukin-8 and macrophage chemoattractant protein-1 (MCP-1) expression in HGECs stimulated with Porphyromonas gingivalis and TLR ligands. Material and Methods: Primary HGECs and an SV40 T-antigen-immortalized HGEC line (epi 4) were stimulated with live or heat-killed P. gingivalis, P. gingivalis lipopolysaccharide or the synthetic lipopeptide PAM3CSK4, and subsequent expression of IRAK-M, interleukin-8 and MCP-1 was evaluated at the mRNA and protein levels. The effects of IRAK-M on interleukin-8 and MCP-1 expressions were evaluated by IRAK-M-specific RNA interference (RNAi)-based loss-of-function assay. Results: All tested stimulants up-regulated the expression of IRAK-M in HGECs. The P. gingivalis lipopolysaccharide or PAM3CSK4 increased MCP-1 expression, whereas live P. gingivalis down-regulated the MCP-1 expression in HGECs. However, IRAK-M RNAi increased the expression of MCP-1 irrespective of up- or down-regulation mediated by the respective stimulants. Interleukin-8 gene expression, up-regulated by all tested stimulants, was further enhanced by IRAK-M RNAi. In contrast, IRAK-M RNAi had no effect on the interleukin-8 protein levels, irrespective of the stimulant, indicating that post-translational modification, not IRAK-M, controls interleukin-8 protein expression. Conclusion: Interleukin-1 receptor-associated kinase-M appeared to have distinct regulatory roles on the interleukin-8 and MCP-1 produced by HGECs, further suggesting an important role for interleukin-8 in the immune reponse to periodontopathic bacteria. © 2010 John Wiley & Sons A/S.

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  • Analysis of immunostimulatory activity of Porphyromonas gingivalis fimbriae conferred by Toll-like receptor 2. 査読 国際誌

    Yukari Aoki, Koichi Tabeta, Yukitaka Murakami, Fuminobu Yoshimura, Kazuhisa Yamazaki

    Biochemical and biophysical research communications   398 ( 1 )   86 - 91   2010年7月

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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:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Bacterial fimbriae are an important pathogenic factor. It has been demonstrated that fimbrial protein encoded by fimA gene (FimA fimbriae) of Porphyromonas gingivalis not only contributes to the abilities of bacterial adhesion and invasion to host cells, but also strongly stimulates host innate immune responses. However, FimA fimbriae separated from P. gingivalis ATCC 33277 using a gentle procedure showed very weak proinflammatory activity compared with previous reports. Therefore, in the present study, biological characteristics of FimA fimbriae were further analyzed in terms of proinflammatory activity in macrophages. Macrophages differentiated from THP-1 cells were stimulated with native, heat-denatured, or either proteinase- or lipoprotein lipase-treated FimA fimbriae of P. gingivalis ATCC 33277. Stimulating activities of these FimA fimbriae were evaluated by TNF-alpha-inducing activity in the macrophages. To clarify the mode of action of FimA fimbriae, anti-Toll-like receptor (TLR) 2 blocking antibody was added prior to stimulation. Weak stimulatory activity of native FimA fimbriae was enhanced by heat treatment and low-dose proteinase K treatment. Higher dose of proteinase K treatment abrogated this up-regulation. The activity of treated FimA fimbriae was suppressed by anti-TLR2 antibody, and more substantially by lipoprotein lipase treatment. These results suggest that lipoproteins or lipopeptides associated with FimA fimbriae could at least in part account for signaling via TLR2 and subsequent TNF-alpha production in macrophages.

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  • Periodontitis-associated up-regulation of systemic inflammatory mediator level may increase the risk of coronary heart disease 査読

    T. Nakajima, T. Honda, H. Domon, T. Okui, K. Kajita, H. Ito, N. Takahashi, T. Maekawa, K. Tabeta, K. Yamazaki

    Journal of Periodontal Research   45 ( 1 )   116 - 122   2010年2月

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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-α (TNF-α). Material and Methods: The concentrations of serum hs-CRP, IL-6 and TNF-α 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-α 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-α. 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. © 2009 John Wiley & Sons A/S.

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  • Porphyromonas gingivalis Antigens and Interleukin-6 Stimulate the Production of Monocyte Chemoattractant Protein-1 via the Upregulation of Early Growth Response-1 Transcription in Human Coronary Artery Endothelial Cells 査読 国際誌

    Tomoki Maekawa, Naoki Takahashi, Tomoyuki Honda, Daisuke Yonezawa, Hirotaka Miyashita, Takafumi Okui, Koichi Tabeta, Kazuhisa Yamazaki

    JOURNAL OF VASCULAR RESEARCH   47 ( 4 )   346 - 354   2010年

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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

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  • Analysis of immune responses to purified recombinant antigens of periodontal pathogens. 査読 国際誌

    Koichi Tabeta, Kazuhisa Yamazaki

    Methods in molecular biology (Clifton, N.J.)   666   345 - 57   2010年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The accumulating knowledge about host-pathogen interactions in infectious diseases shows how the immune system interfaces with pathogens, and thus, helps us in understanding the pathogenesis of diseases and improving their treatment. Purified antigens are indispensable while investigating the immune response in both innate and acquired immunities. It is ideal to use native antigens purified from the host organisms in native conditions that sustain their biological activity completely. However, purification of native antigens, especially on a large scale, is technically difficult and generally time consuming. Purifying protein as a peptide-tagged fusion protein is an effective approach. Purification of a recombinant protein engineered to incorporate a polyhistidine tag at either the carboxyl or amino terminus is an established method, and it can be easily modified to obtain optimal results under different conditions. Heat-shock proteins were highly conserved during evolution and are highly homologous between prokaryotic and eukaryotic cells. Their molecular mimicry might have roles in the pathogenesis of chronic inflammatory diseases. We successfully generated histidine-tagged recombinant heat-shock proteins from the periodontopathogens, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. The recombinant proteins allowed us to evaluate the immune response to these antigens in periodontitis patients.

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  • Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing. 査読 国際誌

    Ryutaro Fukui, Shin-ichiroh Saitoh, Fumi Matsumoto, Hiroko Kozuka-Hata, Masaaki Oyama, Koichi Tabeta, Bruce Beutler, Kensuke Miyake

    The Journal of experimental medicine   206 ( 6 )   1339 - 50   2009年6月

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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:ROCKEFELLER UNIV PRESS  

    Toll-like receptors (TLRs) 3, 7, and 9 recognize microbial nucleic acids in endolysosomes and initiate innate and adaptive immune responses. TLR7/9 in dendritic cells (DCs) also respond to self-derived RNA/DNA, respectively, and drive autoantibody production. Remarkably, TLR7 and 9 appear to have mutually opposing, pathogenic or protective, impacts on lupus nephritis in MRL/lpr mice. Little is known, however, about the contrasting relationship between TLR7 and 9. We show that TLR7 and 9 are inversely linked by Unc93B1, a multiple membrane-spanning endoplasmic reticulum (ER) protein. Complementation cloning with a TLR7-unresponsive but TLR9-responsive cell line revealed that amino acid D34 in Unc93B1 repressed TLR7-mediated responses. D34A mutation rendered Unc93B1-deficient DCs hyperresponsive to TLR7 ligand but hyporesponsive to TLR9 ligand, with TLR3 responses unaltered. Unc93B1 associates with and delivers TLR7/9 from the ER to endolysosomes for ligand recognition. The D34A mutation up-regulates Unc93B1 association with endogenous TLR7 in DCs, whereas Unc93B1 association with TLR9 was down-regulated by the D34A mutation. Consistently, the D34A mutation up-regulated ligand-induced trafficking of TLR7 but down-regulated that of TLR9. Collectively, TLR response to nucleic acids in DCs is biased toward DNA-sensing by Unc93B1.

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  • Assessment of Chromosome 19 for Genetic Association in Severe Chronic Periodontitis 査読 国際誌

    Koichi Tabeta, Yasuko Shimada, Hideaki Tai, Yuichi Ishihara, Toshihide Noguchi, Yoshihiko Soga, Shogo Takashiba, Genki Suzuki, Terukazu Kobayashi, Akira Oka, Tetsuo Kobayashi, Kazuhisa Yamazaki, Hidetoshi Inoko, Hirornasa Yoshie

    JOURNAL OF PERIODONTOLOGY   80 ( 4 )   663 - 671   2009年4月

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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 ACAD PERIODONTOLOGY  

    Background: A genome-association study is a powerful toot for analyzing small gene effects in complex diseases such as chronic periodontitis (CP), although the cost of analysis is prohibitive. We designed a study using the DNA pooling method, which could be a breakthrough in lowering such costs. This study was conducted to assess the genetic association in severe CP in a Japanese population.Methods: We adopted a DNA pooling method by genotyping 454 densely spaced microsatellite (MS) markers in chromosome 19 as a pilot study, with the possibility of future use in a whole-genome study. This can reduce the high cost and technical burden, which is generally unavoidable in a genomic association study. Pooled DNA samples from 300 case subjects, 300 control subjects, and 200 systemically healthy subjects were screened by genotyping MS markers. The case-control association in the candidate region was analyzed by individual typing of MS and single nucleotide polymorphisms (SNPs).Results: The single MS marker allele 17 of 1902G31 was isolated in association with severe CP (P = 0.0012 for 2 x 2; P<0.046 for 2 x m, where m refers to the number of polymorphic alleles observed in a population). No other SNP or MS polymorphism hypothesized to affect biologic functions in the critical region was found in the linkage disequilibrium block analysis.Conclusions: We efficiently isolated the susceptible locus for severe CP in chromosome 19 and identified a useful marker to evaluate the risk for disease. This approach can be applied to a whole-genome study in severe CP. J Periodontol 2009;80:663-671.

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  • Up-regulation of the endoplasmic reticulum stress-response in periodontal disease. 査読 国際誌

    Hisanori Domon, Naoki Takahashi, Tomoyuki Honda, Takako Nakajima, Koichi Tabeta, Yoshimitsu Abiko, Kazuhisa Yamazaki

    Clinica chimica acta; international journal of clinical chemistry   401 ( 1-2 )   134 - 40   2009年3月

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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: Endoplasmic reticulum (ER) stress is the cell response by activation of the unfolded protein response (UPR) pathway in a variety of conditions such as infection and aging. The UPR may be associated with the pathogenesis of periodontal disease because of the induction of apoptosis and activation of nuclear factor-kappaB (NF-kappaB), a transcription factor for pro-inflammatory cytokines. However, the relationship between ER stress and periodontal disease is yet to be determined. METHODS: The expression of UPR-related molecules was analyzed by real-time polymerase chain reaction and immunohistochemistry, respectively and compared between gingivitis and periodontitis. The gene expressions were also analyzed for macrophages stimulated with lipopolysaccharides (LPS) from Escherichia coli (E. coli), and Porphyromonas gingivalis (P. gingivalis) or IFN-gamma. RESULTS: The expression levels of UPR-related genes and HSP60 were significantly higher in periodontitis compared with gingivitis lesions. However, LPS from P. gingivalis but not E. coli or IFN-gamma failed to up-regulate the gene expression in macrophage. CONCLUSIONS: An inflammatory response may have profound effect on the UPR response, particularly in periodontitis patients. Considering the histological nature of periodontitis and the link between UPR and inflammatory responses via NF-kappaB, ER stress in B cells could be another pathological mechanism underlying periodontal disease.

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  • Attenuated Activation of Macrophage TLR9 by DNA from Virulent Mycobacteria 査読 国際誌

    Alexandra K. Kiemer, Ryan H. Senaratne, Jessica Hoppstaedter, Britta Diesel, Lee W. Riley, Koichi Tabeta, Stefan Bauer, Bruce Beutler, Bruce L. Zuraw

    JOURNAL OF INNATE IMMUNITY   1 ( 1 )   29 - 45   2009年

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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  

    Alveolar macrophages are the first line of host defence against mycobacteria, but an insufficient host response allows survival of bacteria within macrophages. We aimed to investigate the role of Toll-like receptor 9 (TLR9) activation in macrophage defence against mycobacteria. Human in vitro differentiated macrophages as well as human and mouse alveolar macrophages showed TLR9 mRNA and protein expression. The cells were markedly activated by DNA isolated from attenuated mycobacterial strains (H37Ra and Mycobacterium bovis BCG) as assessed by measuring cytokine expression by real-time PCR, whereas synthetic phosphorothioate-modified oligonucleotides had a much lower potency to activate human macrophages. Intracellular replication of H37Ra was higher in macrophages isolated from TLR9-deficient mice than in macrophages from wild-type mice, whereas H37Rv showed equal survival in cells from wild-type or mutant mice. Increased bacterial survival in mouse macro-phages was accompanied by altered cytokine production as determined by Luminex bead assays. In vivo infection experiments also showed differential cytokine production in TLR9-deficient mice compared to wild-type animals. Both human monocyte-derived macrophages as well as human alveolar macrophages showed reduced activation upon treatment with DNA isolated from bacteria from virulent (M. bovis and H37Rv) compared to attenuated mycobacteria. We suggest attenuated TLR9 activation contributes to the insufficient host response against virulent mycobacteria. Copyright (C) 2008 S. Karger AG, Basel

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  • Elevated expression of IL-17 and IL-12 genes in chronic inflammatory periodontal disease. 査読 国際誌

    Tomoyuki Honda, Yukari Aoki, Naoki Takahashi, Tomoki Maekawa, Takako Nakajima, Harue Ito, Koichi Tabeta, Takafumi Okui, Keiko Kajita, Hisanori Domon, Kazuhisa Yamazaki

    Clinica chimica acta; international journal of clinical chemistry   395 ( 1-2 )   137 - 41   2008年9月

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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.

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  • 歯周疾患が脂質代謝に及ぼす影響

    中島 貴子, 本田 朋之, 奥井 隆文, 梶田 桂子, 土門 久哲, 高橋 直紀, 前川 知樹, 天沼 亮子, 伊藤 晴江, 多部田 康一, 山崎 和久

    日本歯科医師会雑誌   61 ( 5 )   551 - 551   2008年8月

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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  

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  • Quantitative messenger RNA expression of Toll-like receptors and interferon-α1 in gingivitis and periodontitis 査読

    K. Kajita, T. Honda, R. Amanuma, H. Domon, T. Okui, H. Ito, H. Yoshie, K. Tabeta, T. Nakajima, K. Yamazaki

    Oral Microbiology and Immunology   22 ( 6 )   398 - 402   2007年12月

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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  

    Introduction: In addition to bacteria, viruses have been reportedly implicated in periodontitis. However, the available data are confined to Toll-like receptor 2 (TLR2) and TLR4, which recognize bacterial products in periodontitis. In the present study, we investigated the expression levels of TLR5, -7, and -9 messenger RNAs (mRNAs) in addition to those of TLR2 and -4, and compared gingivitis and periodontitis. Interferon-α1 (IFN-α1), which is important for the antiviral response, was also compared. Methods: Gene expression was analyzed using quantitative real-time polymerase chain reaction for 59 periodontitis and 27 gingivitis tissue samples together with viral serology in some patients. The presence of plasmacytoid dendritic cells (pDCs), a robust producer of IFN-α, was immunohistochemically analyzed in an additional seven periodontitis and two gingivitis specimens. Results: The expression levels of TLR2, -4, -7, and -9 were significantly higher in periodontitis lesions than gingivitis lesions. The expression level of TLR5 was comparable to levels of TLR2 and -4; however, no significant difference was found between gingivitis and periodontitis. Although the expression of IFN-α1 mRNA was higher in periodontitis lesions compared with gingivitis lesions, the level was quite low. Only a few pDCs were found in some periodontitis specimens. No difference was found for antibody-positivity between gingivitis and periodontitis. Conclusion: This is the first study to show that a variety of TLRs are up-regulated in periodontitis lesions compared with gingivitis lesions, suggesting that diverse microbial and possibly viral antigens are involved in the pathogenic mechanisms for periodontal diseases. However, the ligands recognized by the various TLRs in periodontal lesions remain to be determined. © 2007 The Authors.

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  • Point mutations in the melanocortin-4 receptor cause variable obesity in mice 査読 国際誌

    Thomas P. Meehan, Koichi Tabeta, Xin Du, Lanette S. Woodward, Karen Firozi, Bruce Beutler, Monica J. Justice

    MAMMALIAN GENOME   17 ( 12 )   1162 - 1171   2006年12月

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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  

    Mutations in the melanocortin-4 receptor (MC4R) are associated with early-onset obesity in humans. Furthermore, a null Mc4r allele in mice leads to severe obesity due to hyperphagia and decreased energy expenditure. As part of independent N-ethyl-N-nitrosourea (ENU) mutagenesis screens, two obesity mutants, Fatboy and Southbeach, were isolated. Mapping revealed linkage to the melanocortin-4 receptor (Mc4r) and sequencing found single amino acid changes in Mc4r for each line. Expression of the mutant receptors in HEK 293 cells revealed defects in receptor signaling. The mutated Fatboy receptor (I194T) shows an increase in the effective concentration necessary for 50% of maximal signaling (EC50) when stimulated with alpha-MSH. Based on competitive binding, I194T is expressed on the cell surface at lower levels than the nonmutated receptor. In contrast, Southbeach (L300P) displays minimal receptor signaling when stimulated with the natural ligand alpha-MSH or the synthetic agonist NDP-alpha-MSH. Cell surface binding is absent, which usually indicates a lack of cell surface expression. However, antibody binding to Flag-tagged receptors by flow cytometry analysis and immunofluorescence demonstrates that L300P is translocated to the plasma membrane at a level comparable to the wild-type receptor. These results indicate a correlation with remaining receptor activity and the severity of the obesity in the mice homozygous for the mutations. Southbeach has less receptor activity and becomes more obese. These mutants will serve as good models for the variability in phenotype in humans carrying mutations in the MC4R gene.

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  • TLR signaling pathways: Opportunities for activation and blockade in pursuit of therapy 査読

    K. Hoebe, Z. Jiang, P. Georgel, K. Tabeta, E. Janssen, X. Du, Bruce Beutler

    Current Pharmaceutical Design   12 ( 32 )   4123 - 4134   2006年11月

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    記述言語:英語   出版者・発行元:BENTHAM SCIENCE PUBL LTD  

    The identification of the TLRs as key sensors of microbial infection has presented a series of new targets for drug development. The TLRs are linked to the most powerful inflammatory pathways in mammals. The question arises from the start: do we wish to stimulate TLR signaling in order to eradicate specific infections and/or neoplastic diseases? Or do we wish to block TLR signaling to treat inflammatory diseases? If we accept that it would be useful to modulate TLR signaling, the next step is to identify the correct molecular target(s) for the task. Perhaps it might even be possible to exercise selectivity, modulating some aspects of TLR signaling and not others. Classical and reverse genetic analyses offer insight into the possibilities that exist, and point to specific checkpoints within signaling pathways at which modulation might normally be imposed. © 2006 Bentham Science Publishers Ltd.

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  • Herpes simplex virus encephalitis in human UNC-93B deficiency. 査読 国際誌

    Armanda Casrouge, Shen-Ying Zhang, Céline Eidenschenk, Emmanuelle Jouanguy, Anne Puel, Kun Yang, Alexandre Alcais, Capucine Picard, Nora Mahfoufi, Nathalie Nicolas, Lazaro Lorenzo, Sabine Plancoulaine, Brigitte Sénéchal, Frédéric Geissmann, Koichi Tabeta, Kasper Hoebe, Xin Du, Richard L Miller, Bénédicte Héron, Cyril Mignot, Thierry Billette de Villemeur, Pierre Lebon, Olivier Dulac, Flore Rozenberg, Bruce Beutler, Marc Tardieu, Laurent Abel, Jean-Laurent Casanova

    Science (New York, N.Y.)   314 ( 5797 )   308 - 12   2006年10月

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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 ADVANCEMENT SCIENCE  

    Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is the most common form of sporadic viral encephalitis in western countries. Its pathogenesis remains unclear, as it affects otherwise healthy patients and only a small minority of HSV-1-infected individuals. Here, we elucidate a genetic etiology for HSE in two children with autosomal recessive deficiency in the intracellular protein UNC-93B, resulting in impaired cellular interferon-alpha/beta and -lambda antiviral responses. HSE can result from a single-gene immunodeficiency that does not compromise immunity to most pathogens, unlike most known primary immunodeficiencies. Other severe infectious diseases may also reflect monogenic disorders of immunity.

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  • Efficient T cell activation via a Toll-interleukin 1 Receptor-independent pathway 査読 国際誌

    Edith Janssen, Koichi Tabeta, Michael J. Barnes, Sophie Rutschmann, Sara McBride, Keith S. Bahjat, Stephen P. Schoenberger, Argyrios N. Theofilopoulos, Bruce Beutler, Kasper Hoebe

    IMMUNITY   24 ( 6 )   787 - 799   2006年6月

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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:CELL PRESS  

    Here, we describe a previously unrecognized pathway for activation of antigen-specific adaptive immune responses that was independent of Toll-Interleukin 1 Receptor signaling and directed toward detection of antigens expressed by apoptotic cells. This pathway is represented within Flt-3 Ligand-derived dendritic cells (DCs) that represent immature lymphoid DCs, but not within GM-CSF-treated bone marrow-derived dendritic cells. Exposure of these DCs to apoptotic cells resulted in production of type I interferon and favored the development of cytotoxic T cell responses. The N-Ethyl-N-Nitrosourea-induced germline mutation 3d (Unc3b1(3d/3d)) abolished both MHC class I and 11 responses elicited by this pathway, whereas a null allele of Cd36 selectively abolished class 11 responses. We propose that this mode of adaptive immune activation evolved to permit the sensitive detection of intracellular microbial infections, particularly viral infections, which frequently induce apoptotic cell death, but may also be important in transplantation, autoimmunity, and vaccine development.

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  • The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. 査読 国際誌

    Koichi Tabeta, Kasper Hoebe, Edith M Janssen, Xin Du, Philippe Georgel, Karine Crozat, Suzanne Mudd, Navjiwan Mann, Sosathya Sovath, Jason Goode, Louis Shamel, Anat A Herskovits, Daniel A Portnoy, Michael Cooke, Lisa M Tarantino, Tim Wiltshire, Benjamin E Steinberg, Sergio Grinstein, Bruce Beutler

    Nature immunology   7 ( 2 )   156 - 64   2006年2月

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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  

    Here we have identified 'triple D' (3d), a recessive N-ethyl-N-nitrosourea-induced mutation and phenotype in which no signaling occurs via the intracellular Toll-like receptors 3, 7 and 9 (sensors for double-stranded RNA, single-stranded RNA and unmethylated DNA, respectively). The 3d mutation also prevented cross-presentation and diminished major histocompatibility complex class II presentation of exogenous antigen; it also caused hypersusceptibility to infection by mouse cytomegalovirus and other microbes. By positional identification, we found 3d to be a missense allele of Unc93b1, which encodes the 12-membrane-spanning protein UNC-93B, a highly conserved molecule found in the endoplasmic reticulum with multiple paralogs in mammals. Innate responses to nucleic acids and exogenous antigen presentation, which both initiate in endosomes, thus seem to depend on an endoplasmic reticulum-resident protein, which suggests communication between these organellar systems.

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  • Genetic analysis of innate immunity 査読

    Kasper Hoebe, Zhengfan Jiang, Koichi Tabeta, Xin Du, Philippe Georgel, Karine Crozat, Bruce Beutler

    ADVANCES IN IMMUNOLOGY, VOL 91   91   175 - 226   2006年

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    記述言語:英語   掲載種別:論文集(書籍)内論文   出版者・発行元:ELSEVIER ACADEMIC PRESS INC  

    The inflammatory response to microbes-and host perception of microbes in general-is largely initiated by a single class of receptors, named for their similarity to the prototypic Toll receptor of Drosophila. The mammalian Toll-like receptors (TLRs) are ultimately responsible for most phenomena associated with infection. This includes both "good" effects of infection (e.g., the induction of lasting specific immunity to an infectious agent) and "bad" effects of infection (systemic inflammation and shock). Although they are essential for host defense, no other endogenous proteins can match their lethal potential. The TLR complexes transduce the toxicity of lipopolysaccharide (LPS), cysteinyl lipopeptides, and many other molecules of microbial origin. The identification of the TLRs as the key conduit to host awareness of microbial infection was a victory for reductionism, proving that the complexity of infectious inflammation as a phenomenon belies the simplicity of its origins. It was achieved by a classical genetic approach, proceeding from phenotype to gene. Further analysis of the signaling pathways activated by the TLRs has depended on both classical and reverse genetic methods. Additional work will ultimately disclose the extent to which sterile inflammatory diseases are mediated by aberrations in these pathways.

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  • Genetic analysis of innate immunity. 査読 国際誌

    Kasper Hoebe, Zhengfan Jiang, Koichi Tabeta, Xin Du, Philippe Georgel, Karine Crozat, Bruce Beutler

    Advances in immunology   91   175 - 226   2006年

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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 ACADEMIC PRESS INC  

    The inflammatory response to microbes--and host perception of microbes in general--is largely initiated by a single class of receptors, named for their similarity to the prototypic Toll receptor of Drosophila. The mammalian Toll-like receptors (TLRs) are ultimately responsible for most phenomena associated with infection. This includes both "good" effects of infection (e.g., the induction of lasting specific immunity to an infectious agent) and "bad" effects of infection (systemic inflammation and shock). Although they are essential for host defense, no other endogenous proteins can match their lethal potential. The TLR complexes transduce the toxicity of lipopolysaccharide (LPS), cysteinyl lipopeptides, and many other molecules of microbial origin. The identification of the TLRs as the key conduit to host awareness of microbial infection was a victory for reductionism, proving that the complexity of infectious inflammation as a phenomenon belies the simplicity of its origins. It was achieved by a classical genetic approach, proceeding from phenotype to gene. Further analysis of the signaling pathways activated by the TLRs has depended on both classical and reverse genetic methods. Additional work will ultimately disclose the extent to which sterile inflammatory diseases are mediated by aberrations in these pathways.

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  • An essential role for Rxr alpha in the development of Th2 responses. 査読 国際誌

    Xin Du, Koichi Tabeta, Navjiwan Mann, Karine Crozat, Suzanne Mudd, Bruce Beutler

    European journal of immunology   35 ( 12 )   3414 - 23   2005年12月

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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-V C H VERLAG GMBH  

    A viable hypomorphic allele of mouse retinoid X receptor alpha (Rxralpha) was created by random germline mutagenesis. The mutation (I273N) alters the ligand binding and heterodimerization domain, and causes a 90% decline in ligand-inducible transactivation. Homozygotes develop progressive alopecia and dermal cysts, and progressive exaggeration of Th1 and loss of Th2 responses to antigen. Th1 skewing is directly caused by aberrant function of both antigen-presenting cells and naïve CD4 T cells; the predominant Th1 response to antigen is attributable to decreased suppression of regulatory T cells in mutant mouse. Dietary depletion of vitamin A in Th2-prone wild-type mice mimics the immune phenotype caused by the mutation. Hence, RXRalpha plays an important post-developmental role in the regulation of adaptive immune responses, and provides a plausible link between nutritional environment and the type of adaptive response that results from immunization.

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  • Genetic analysis of innate immunity: identification and function of the TIR adapter proteins. 査読 国際誌

    Bruce Beutler, Kasper Hoebe, Philippe Georgel, Koichi Tabeta, Xin Du

    Advances in experimental medicine and biology   560   29 - 39   2005年

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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  

    The innate immune system senses pathogens largely through signals initiated by a collection of phylogenetically related proteins known as "Toll-like receptors" (TLRs), of which ten representatives are encoded in the human genome. The sensing role of the TLRs first came to light when one member of this family, TLR4, was shown to serve the detection of endotoxin (lipopolysaccharide; LPS) in mice. This discovery was based upon positional cloning of a spontaneous mutation affecting a locus known as Lps. The recognition specificities of other TLRs have since been established by reverse genetic methods. The understanding of the biochemical circuitry that maintains the innate capacity for immune recognition and response has loomed as the next hurdle in the field. A total of five adapter proteins with cytoplasmic domain homology to the TLRs are known to exist in mammals. These proteins are not entirely promiscuous in their interaction with TLRs, but rather, show preferential association with individual family members, giving a particular character to the signals that distinct micro-organisms initiate. The adaptive immune response is dependent upon upregulation of costimulatory molecules (UCM) such as CD80 and CD86. Very recently, it has been shown that this upregulation is dependent upon an adapter encoded by a locus known as Lps2, known as Trif or Ticam-1, and upon type I interferon receptor signaling. LPS and dsRNA both signal via Trif, but dsRNA has an accessory pathway for UCM, that is independent of both Trif/Ticam-1 and the known dsRNA receptor, TLR3. Other key innate immunity genes have also been disclosed by germline mutagenesis, and are discussed in the present review.

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  • Genetic analysis of innate immunity: TIR adapter proteins in innate and adaptive immune responses. 査読 国際誌

    Bruce Beutler, Kasper Hoebe, Philippe Georgel, Koichi Tabeta, Xin Du

    Microbes and infection   6 ( 15 )   1374 - 81   2004年12月

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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  

    The innate immune system senses pathogens largely through signals initiated by a collection of phylogenetically related proteins known as "Toll-like receptors" (TLRs), of which 10 representatives are encoded in the human genome. Our understanding of the sensing role played by the TLRs began with the positional cloning of a spontaneous mutation (Lps(d)) in the gene encoding the mammalian lipopolysaccharide (LPS) receptor. Other key innate immunity proteins have been disclosed by germline mutagenesis, and are discussed in the present review.

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  • T-cell clonality to Porphyromonas gingivalis and human heat shock protein 60s in patients with atherosclerosis and periodontitis 査読

    Kazuhisa Yamazaki, Y. Ohsawa, H. Itoh, K. Ueki, K. Tabeta, T. Oda, T. Nakajima, H. Yoshie, S. Saito, F. Oguma, M. Kodama, Y. Aizawa, G. J. Seymour

    Oral Microbiology and Immunology   19 ( 3 )   160 - 167   2004年6月

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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 MUNKSGAARD  

    Individuals with periodontitis have been reported to have a significantly increased risk of developing coronary heart disease. Several studies have demonstrated that the immune response to heat shock protein 60 (HSP60) may be involved in the pathogenesis of both atherosclerosis and chronic periodontitis. To investigate this possible link between these diseases, cellular and humoral immune responses to HSP60 in atherosclerosis patients were compared with those in periodontitis patients and healthy subjects using human and Porphyromonas gingivalis HSP60 (GroEL) as antigens. Antibody levels to both human and P. gingivalis HSP60s were the highest in atherosclerosis patients, followed by periodontitis patients and healthy subjects. Clonal analysis of the T cells clearly demonstrated the presence of not only human HSP60- but also P. gingivalis GroEL-reactive T-cell populations in the peripheral circulation of atherosclerosis patients. Furthermore, these HSP60-reactive T cells seemed to be present in atherosclerotic lesions in some patients. These results suggest that T-cell clones with the same specificity may be involved in the pathogenesis of the different diseases.

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  • Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. 査読 国際誌

    Koichi Tabeta, Philippe Georgel, Edith Janssen, Xin Du, Kasper Hoebe, Karine Crozat, Suzanne Mudd, Louis Shamel, Sosathya Sovath, Jason Goode, Lena Alexopoulou, Richard A Flavell, Bruce Beutler

    Proceedings of the National Academy of Sciences of the United States of America   101 ( 10 )   3516 - 21   2004年3月

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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:NATL ACAD SCIENCES  

    Several subsets of dendritic cells have been shown to produce type I IFN in response to viral infections, thereby assisting the natural killer cell-dependent response that eliminates the pathogen. Type I IFN production can be induced both by unmethylated CpG-oligodeoxynucleotide and by double-stranded RNA. Here, we describe a codominant CpG-ODN unresponsive phenotype that results from an N-ethyl-N-nitrosourea-induced missense mutation in the Tlr9 gene (Tlr9(CpG1)). Mice homozygous for the Tlr9(CpG1) allele are highly susceptible to mouse cytomegalovirus infection and show impaired infection-induced secretion of IFN-alpha/beta and natural killer cell activation. We also demonstrate that both the Toll-like receptor (TLR) 9 --> MyD88 and TLR3 --> Trif signaling pathways are activated in vivo on viral inoculation, and that each pathway contributes to innate defense against systemic viral infection. Whereas both pathways lead to type I IFN production, neither pathway offers full protection against mouse cytomegalovirus infection in the absence of the other. The Tlr9(CpG1) mutation alters a leucine-rich repeat motif and lies within a receptor domain that is conserved within the evolutionary cluster encompassing TLRs 7, 8, and 9. In other TLRs, including three mouse-specific TLRs described in this paper, the affected region is not represented. The phenotypic effect of the Tlr9(CpG1) allele thus points to a critical role for TLR9 in viral sensing and identifies a vulnerable amino acid within the ectodomain of three TLR proteins, essential for a ligand response.

    DOI: 10.1073/pnas.0400525101

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  • Velvet, a dominant Egfr mutation that causes wavy hair and defective eyelid development in mice. 査読 国際誌

    Xin Du, Koichi Tabeta, Kasper Hoebe, Haiquan Liu, Navjiwan Mann, Suzanne Mudd, Karine Crozat, Sosathya Sovath, Xiaohua Gong, Bruce Beutler

    Genetics   166 ( 1 )   331 - 40   2004年1月

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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:GENETICS SOC AM  

    In the course of a large-scale program of ENU mutagenesis, we isolated a dominant mutation, called Velvet. The mutation was found to be uniformly lethal to homozygotes, which do not survive E13.5. Mice heterozygous for the Velvet mutation are born with eyelids open and demonstrate a wavy coat and curly vibrissae. The mutation was mapped to the proximal end of chromosome 11 by genome-wide linkage analysis. On 249 meioses, the locus was confined to a 2.7-Mb region, which included the epidermal growth factor receptor gene (Egfr). An A --> G transition in the Egfr coding region of Velvet mice was identified, causing the amino acid substitution D833G. This substitution alters an essential triad of amino acids (DFG --> GFG) that is normally required for coordination of the ATP substrate. As such, kinase activity is at least mostly abolished, but quaternary structure of the receptor is presumably maintained, accounting for the dominant effect. Velvet is the first known dominant representative of the Egfr allelic series that is fully viable, a fact that makes it particularly useful for developmental studies.

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  • The nonsense allele oblivious reveals a sensor of di-acylglycerides acting in conjunction with TLR2 and TLR6. 査読

    Hoebe K, Tabeta K, Georgel P, Du X, Mudd S, Sovath S, Shamel L, Hartung T, Zähringer U, Beutler B

    Arthritis Research & Therapy   2004年

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  • Single-nucleotide polymorphism in the CD14 promoter and periodontal disease expression in a Japanese population 査読

    K. Yamazaki, K. Ueki-Maruyama, T. Oda, K. Tabeta, Y. Shimada, H. Tai, T. Nakajima, H. Yoshie, D. Herawati, G. J. Seymour

    Journal of Dental Research   82 ( 8 )   612 - 616   2003年8月

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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:INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R  

    It has been reported that there is a relationship between a single-nucleotide polymorphism (SNP) in the promoter region of the CD14 gene at position -159 (C→T) and infectious diseases. The aim of the present study was to test the hypthesis that expression of this SNP correlates with periodontal disease in a Japanese population. The CD14 genotype was determined in 163 subjects with periodontitis and in 104 age- and gender-matched control subjects without periodontitis. The genotype distribution and allele frequency within the periodontitis patients were not significantly different from those of control subjects. There was, however, a significant difference in the genotype distribution between young patients (< 35 yrs) and older patients (≥ 35 yrs). These findings suggest that CD14 -159C/T polymorphism is not related to the development of periodontitis in a Japanese population, but that, within the periodontitis subjects, expression of the SNP may be related to early disease activity.

    DOI: 10.1177/154405910308200808

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  • Identification of Lps2 as a key transducer of MyD88-independent TIR signalling 査読

    K. Hoebe, X. Du, P. Georgel, E. Janssen, K. Tabeta, S. O. Kim, J. Goode, P. Lin, N. Mann, S. Mudd, K. Crozat, S. Sovath, J. Han, B. Beutler

    Nature   424 ( 6950 )   743 - 748   2003年

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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  

    In humans, ten Toll-like receptor (TLR) paralogues sense molecular components of microbes, initiating the production of cytokine mediators that create the inflammatory response. Using N-ethyl-N-nitrosourea, we induced a germline mutation called Lps2, which abolishes cytokine responses to double-stranded RNA and severely impairs responses to the endotoxin lipopolysaccharide (LPS), indicating that TLR3 and TLR4 might share a specific, proximal transducer. Here we identify the Lps2 mutation: a distal frameshift error in a Toll/interleukin-1 receptor/resistance (TIR) adaptor protein known as Trif or Ticam-1. TrifLps2 homozygotes are markedly resistant to the toxic effects of LPS, and are hypersusceptible to mouse cytomegalovirus, failing to produce type I interferons when infected. Compound homozygosity for mutations at Trif and MyD88 (a cytoplasmic TIR-domain-containing adaptor protein) loci ablates all responses to LPS, indicating that only two signalling pathways emanate from the LPS receptor. However, a Trif-independent cell population is detectable when TrifLps2 mutant macrophages are stimulated with LPS. This reveals that an alternative MyD88-dependent 'adaptor X' pathway is present in some, but not all, macrophages, and implies afferent immune specialization.

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  • Lps2 and signal transduction in sepsis: at the intersection of host responses to bacteria and viruses. 査読 国際誌

    Bruce Beutler, Kasper Hoebe, Xin Du, Edith Janssen, Philippe Georgel, Koichi Tabeta

    Scandinavian journal of infectious diseases   35 ( 9 )   563 - 7   2003年

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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:TAYLOR & FRANCIS AS  

    A phenotype-driven approach led to the first understanding of precisely what the Toll-like receptors (TLR) did, when it was determined that the mammalian endotoxin (lipopolysaccharide; LPS) receptor is encoded by TLR4. The TLRs are the primary sensors of the innate immune system, and without them, small inocula of microorganisms pose a major threat to the host, growing unchecked for a long period before they are recognized. Mutations that affect innate immune sensing may account for a substantial fraction of sepsis, and a highly significant excess of mutations in TLR4 has been identified in patients with systemic meningococcal disease. As such, it is important to understand the pathways that are responsible for innate immune sensing, including the signaling intermediates utilized by the TLRs. Random germline mutagenesis identified a locus, Lps2, which is required for normal responses to double-stranded RNA and LPS. Hence, a single transducer was found to serve both the TLR3 and TLR4 response pathways. The Lps2 mutation was found to ablate entirely the MyD88-independent pathway for LPS sensing, indicating that two and only two branches of the LPS sensing pathway exist in macrophages, and homozygotes for the mutation were resistant to LPS, but markedly susceptible to infection with mouse cytomegalovirus. Remarkably, Lps2 mutant mice entirely failed to produce type I interferons in response to a viral infection. It would appear that Lps2 is the most proximal component of a signal integration system required for innate immune responses to both viral and bacterial diseases. Positional cloning revealed that the TIR adapter protein Trif/Ticam-1 is structurally altered by the Lps2 mutation. This adapter is responsible for shared effects of responses to viral and bacterial pathogens.

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  • 動脈硬化症におけるPorphyromonas gingivalis GroELに対する免疫応答の解析

    多部田 康一, 山崎 和久, 大澤 豊, 伊藤 晴江, 植木 薫, 斉藤 了, 小熊 文昭, 小玉 誠, 相澤 義房, 吉江 弘正

    BACTERIAL ADHERENCE & BIOFILM   15   31 - 38   2002年6月

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    記述言語:日本語   出版者・発行元:日本バイオフィルム学会  

    動脈硬化症患者7名より動脈硬化組織,末梢血を採取し,歯周疾患と動脈硬化症の両疾患に関与すると報告されている60kDa heat shock protein(hsp60)とPorphyromonas gingivalis(Pg)のヒトhspホモローグであるGroELに対する動脈硬化患者における免疫応答について検索した.検討した7名中1名を除いて,PgまたはA.actinomycetemcomitans GroELとhsp60において反応する抗体産生が認められた.さらに分析結果より,歯周炎と動脈硬化症の疫学的因果関係を裏付ける可能性も考えられた

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  • Accumulation of human heat shock protein 60-reactive T cells in the gingival tissues of periodontitis patients. 査読 国際誌

    Kazuhisa Yamazaki, Yutaka Ohsawa, Koichi Tabeta, Harue Ito, Kaoru Ueki, Taro Oda, Hiromasa Yoshie, Gregory J Seymour

    Infection and immunity   70 ( 5 )   2492 - 501   2002年5月

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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 MICROBIOLOGY  

    Heat shock protein 60s (hsp60) are remarkably immunogenic, and both T-cell and antibody responses to hsp60 have been reported in various inflammatory conditions. To clarify the role of hsp60 in T-cell responses in periodontitis, we examined the proliferative response of peripheral blood mononuclear cells (PBMC), as well as the cytokine profile and T-cell clonality, for periodontitis patients and controls following stimulation with recombinant human hsp60 and Porphyromonas gingivalis GroEL. To confirm the infiltration of hsp60-reactive T-cell clones into periodontitis lesions, nucleotide sequences within complementarity-determining region 3 of the T-cell receptor (TCR) beta-chain were compared between hsp60-reactive peripheral blood T cells and periodontitis lesion-infiltrating T cells. Periodontitis patients demonstrated significantly higher proliferative responses of PBMC to human hsp60, but not to P. gingivalis GroEL, than control subjects. The response was inhibited by anti-major histocompatibility complex class II antibodies. Analysis of the nucleotide sequences of the TCR demonstrated that human hsp60-reactive T-cell clones and periodontitis lesion-infiltrating T cells have the same receptors, suggesting that hsp60-reactive T cells accumulate in periodontitis lesions. Analysis of the cytokine profile demonstrated that hsp60-reactive PBMC produced significant levels of gamma interferon (IFN-gamma) in periodontitis patients, whereas P. gingivalis GroEL did not induce any skewing toward a type1 or type2 cytokine profile. In control subjects no significant expression of IFN-gamma or interleukin 4 was induced. These results suggest that periodontitis patients have human hsp60-reactive T cells with a type 1 cytokine profile in their peripheral blood T-cell pools.

    DOI: 10.1128/IAI.70.5.2492-2501.2002

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  • Self-heat shock protein 60 induces tumour necrosis factor-α in monocyte-derived macrophage: Possible role in chronic inflammatory periodontal disease 査読

    K. Ueki, K. Tabeta, H. Yoshie, K. Yamazaki

    Clinical and Experimental Immunology   127 ( 1 )   72 - 77   2002年

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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 LTD  

    Heat shock protein 60 (hsp60) has been increasingly recognized as an important molecule in infectious and autoimmune diseases. We have demonstrated previously that serum antibodies to both human hsp60 and Porphyromonas gingivalis GroEL were elevated in periodontitis patients compared with healthy subjects. In order to clarify the relative importance of hsp60 in the inflammatory response in periodontal disease, the stimulatory effect of human and bacterial hsp60 on the production of tumour necrosis factor-α (TNF-α) was examined in phorbol myristate acetate (PMA)-stimulated THP-1 cells. As bacterial hsp60s, recombinant P. gingivalis and Actinobacillus actinomycetemcomitans GroEL was used. Human hsp60 but not P. gingivalis or A. actinomycetemcomitans GroEL demonstrated stimulatory activity similar to lipopolysaccharide (LPS) derived from the bacteria. The activity of hsp60 was inhibited by anti-CD14 and anti-Toll-like receptor 4 (TLR4) antibodies, suggesting that both CD14 and TLR4 mediate hsp60 signalling. Immunohistochemical analysis demonstrated that hsp60 is abundantly expressed in periodontitis lesions. Therefore, it is postulated that periodontopathic bacteria stimulate the cells in the periodontium to up-regulate the expression of hsp60, which in turn may stimulate macrophage and possibly other cells to produce proinflammatory cytokines. These mechanisms may be involved in the chronicity and tissue destruction of periodontal disease.

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  • Interleukin-10 gene promoter polymorphism in Japanese patients with adult and early-onset periodontitis 査読

    Kazuhisa Yamazaki, Kouichi Tabeta, Takako Nakajima, Yutaka Ohsawa, Kaoru Ueki, Harue Itoh, Hiromasa Yoshie

    Journal of Clinical Periodontology   28 ( 9 )   828 - 832   2001年

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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:MUNKSGAARD INT PUBL LTD  

    Background: IL-10 is an anti-inflammatory cytokine, which may modulate disease expression in chronic inflammatory periodontal disease. 3 dimorphic polymorphisms within the IL-10 gene promoter have recently been identified and appear to influence regulation of its expression. Aim: The aim of the present study was to investigate whether the promoter polymorphisms are associated with adult periodontitis (AP) and generalized early-onset periodontitis (G-EOP). Methods: Genomic DNA was obtained from 34 AP patients, 18 G-EOP patients and 52 controls. The promoter region between -506 and -1140 was amplified by polymerase chain reaction, and polymorphisms were detected by nucleotide sequencing. Results: The haplotype frequencies in Japanese were quite different from those of Caucasian and were even slightly different from those of southern Chinese with systemic lupus erythematosus. We found no significant difference in allele or haplotype frequencies between patients and controls. Conclusions: IL-10 production may be regulated within the complex cytokine network in chronic inflammatory periodontal disease, rather than the gene polymorphisms. © Munksgaard, 2001.

    DOI: 10.1034/j.1600-051x.2001.028009828.x

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  • Characterization of serum antibody to Actinobacillus actinomycetemcomitans GroEL-like protein in periodontitis patients and healthy subjects 査読

    K. Tabeta, H. Yoshie, K. Yamazaki

    Oral Microbiology and Immunology   16 ( 5 )   290 - 295   2001年

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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:MUNKSGAARD INT PUBL LTD  

    Recent evidence suggests that molecular mimicry between bacterial and human heat shock protein 60 (hsp60) is involved in various conditions of autoimmune and infectious diseases. Many periodontopathic bacteria have been reported to express GroEL-like protein that is homologous to human hsp60. In this study, the presence of antibodies to the hsp60 of Actinobacillus actinomycetemcomitans in the sera of periodontitis patients and periodontally healthy control subjects was evaluated by enzyme-linked immunosorbent assay using a recombinant A. actinomycetemcomitans GroEL as an antigen. Furthermore, their cross-reactivity with Escherichia coli GroEL and Mycobacterium bovis BCG hsp65 was examined. The mean values of antibody were 0.624 (range 0.088-1.113) and 0.728 (range 0.217-1.296) in control subjects and periodontitis patients, respectively. The antibody levels to A. actinomycetemcomitans after absorption with E. coli GroEL and M. bovis BCG clearly decreased in both control subjects and periodontitis patients. The remaining antibody levels to A. actinomycetemcomitans GroEL after absorption with M. bovis BCG hsp65 were higher than those with E. coli GroEL, indicating higher cross-reactivity with E. coli GroEL. These results suggest that not only periodontitis patients but also periodontally healthy subjects may be infected with A. actinomycetemcomitans but that the part of the antibody could be derived from the cross-reactivity with E. coli GroEL. Any relationship of the antibody to the disease, however, remains to be determined.

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  • Analysis of single nucleotide polymorphisms in the 5′-flanking region of tumor necrosis factor-alpha gene in Japanese patients with early-onset periodontitis 査読

    M. Endo, H. Tai, K. Tabeta, T. Kobayashi, K. Yamazaki, H. Yoshie

    Journal of Periodontology   72 ( 11 )   1554 - 1559   2001年

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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 ACAD PERIODONTOLOGY  

    Background: Early-onset periodontitis (EOP) is considered to have a genetic basis, which has not been clearly defined. The tumor necrosis factor-alpha (TNF-α) gene polymorphism as one of the genetic factors may influence the expression of several chronic inflammatory diseases. The aim of the present study was to evaluate whether the polymorphisms in the 5′-flanking region of the TNF-α gene are associated with Japanese EOP patients. Methods: Forty-six Japanese, generalized EOP (G-EOP) patients and 104 Japanese healthy subjects were identified according to established clinical criteria. Twenty healthy subjects were analyzed by nucleotide sequence to screen polymorphisms of the 5′-flanking region of the TNF-α gene. Then, all subjects were analyzed by polymerase chain reaction and sequence-specific oligonucleotide probe (SSOP) methods. Results: We determined 5 single nucleotide polymorphisms at positions -1031 (T/C), -863 (C/A), -857 (C/T), -308 (G/A), and -238 (G/A) in the 5′-flanking region of the TNF-α gene. There were no significant differences in the genotype and allele frequency when we compared G-EOP patients to healthy subjects. Because the frequency of polymorphic alleles at positions -308 and -238 was very low in this study population, we demonstrated the existence of 4 detected haplotypes and 6 detected genotypes concerning 3 single nucleotide polymorphisms (-1031, -863, and -857). The frequency of the H1/H3 (TCC/TCT)-detected genotype tended to decrease in G-EOP patients compared to healthy subjects, but was not statistically significant. Conclusion: These findings suggest there is no significant association between polymorphisms in the 5′-flanking region of the TNF-α gene and susceptibility to G-EOP in Japanese patients.

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  • Toll-like receptors confer responsiveness to lipopolysaccharide from Porphyromonas gingivalis in human gingival fibroblasts 査読

    Kouich Tabeta, Kazuhisa Yamazaki, Sachiko Akashi, Kensuke Miyake, Hidefumi Kumada, Toshio Umemoto, Hiromasa Yoshie

    Infection and Immunity   68 ( 6 )   3731 - 3735   2000年6月

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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 MICROBIOLOGY  

    Gingival fibroblasts produce proinflammatory cytokines in response to lipopolysaccharide (LPS) from periodontopathic bacteria. Recently it has become evident that the human homologue of Drosophila Toll can transduce intracellular signaling by LPS stimulation. Toll-like receptors (TLRs) have been identified in myeloid cells; however, their role in nonmyeloid cells such as gingival fibroblasts has not been fully elucidated. Here, we report that human gingival fibroblasts constitutively express TLR2 and TLR4 and that their levels of expression are increased by stimulation with LPS from Porphyromonas gingivalis. Upregulated expression of interleukin-6 gene and protein in fibroblasts stimulated with LPS is inhibited by anti-TLR4 antibody. These findings suggest that TLRs may confer responsiveness to LPS in gingival fibroblasts.

    DOI: 10.1128/IAI.68.6.3731-3735.2000

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  • Elevated humoral immune response to heat shock protein 60 (hsp60) family in periodontitis patients 査読 国際誌

    K. Tabeta, Kazuhisa Yamazaki, H. Hotokezaka, H. Yoshie, K. Hara

    Clinical and Experimental Immunology   120 ( 2 )   285 - 293   2000年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The presence of antibodies to the 60-kD human and Porphyromonas gingivalis GroEL hsp60 in the sera and inflamed gingival tissues of periodontitiS patients was examined. In order to obtain the antigens, recombinant plasmids carrying human hsp60 and P. gingivalis GroEL genes were constructed and expressed as histidine-tagged recombinant proteins. Immunoreactivities of these proteins were confirmed by MoAbs specific to mammalian hsp60 and cross-reactive with both mammalian and bacterial hsp60. Western blot analysis clearly demonstrated that the number of periodontitis patients showing a positive response to P. gingivalis GroEL was higher than the number of periodontally healthy subjects. Furthermore, anti-P. gingivalis GroEL antibody was detected in all samples of gingival tissue extracts. For human hsp60, a higher frequency of seropositivity was found in the periodontitis patients than in the healthy subjects. In addition, the periodontitis patients demonstrated stronger reactivity compared with the healthy subjects. Quantitative analysis of serum antibodies by ELISA also demonstrated that the levels of antibodies in the sera of patients were significantly higher than those of control subjects. In the gingival tissue extracts, seven out of 10 patients demonstrated a positive response to human hsp60 and tso of these demonstrated strong positivity. Affinity-purified serum antibodies to human hsp60 and P. gingivalis GroEL from selected patients reacted with P. gingivalis GroEL and human hsp60, respectively, suggesting cross-reactivity of antibodies. These results suggest that molecular mimicry between GroEL of the periodontopathic bacterium P. gingivalis and autologous human hsp60 may play some role in immune mechanisms in periodontitis.

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  • Selective expansion of T cells in gingival lesions of patients with chronic inflammatory periodontal disease 査読

    Kazuhisa Yamazaki, T. Nakajima, Y. Ohsawa, K. Tabeta, H. Yoshie, K. Sakurai, G. J. Seymour

    Clinical and Experimental Immunology   120 ( 1 )   154 - 161   2000年

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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 SCIENCE LTD  

    Chronic inflammatory periodontal diseases are characterized by a cellular infiltrate and are similar in many respects to other chronic inflammatory diseases. While periodontopathic bacteria have been recognized as the principal causative agent and the immune response to these bacteria is thought to be responsible for the tissue destruction, the full aetiological spectrum is still incompletely understood. In addition to many cell types such as polymorphonuclear leucocytes and macrophages, T cells have been implicated in pathogenesis and are considered to have regulatory roles in progression of the disease. Based on our recent studies demonstrating biased expression of several Vβ families in periodontitis tissues, the aim of this study was to characterize further the T cells relevant to the disease process by reverse transcription-polymerase chain reaction-single-strand conformation polymorphism (RT-PCRSSCP) and subsequent nucleotide sequence analysis of complementarity-determining region 3 (CDR3) of the TCR β-chain. In spite of the likely involvement of numerous bacteria, the present study has clearly shown the oligoclonality of infiltrating T cells in periodontitis lesions in contrast to low clonality of peripheral blood T cells as evidenced by the appearance of distinct bands in gingival tissue samples and smear pattern of peripheral blood on SSCP gels. These were confirmed by the DNA sequencing of the CDR3 of Vβ16 of selected samples. The analysis of deduced amino acid sequences demonstrated amino acid motifs in the CDR3 region of the periodontitis lesion-derived sequences from each patient. The results indicate that gingival tissue-infiltrating T cells recognizing a limited number of antigens or epitopes are involved in the disease process.

    DOI: 10.1046/j.1365-2249.2000.01179.x

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    その他リンク: http://orcid.org/0000-0002-7019-1872

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MISC

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講演・口頭発表等

  • シンポジウム 歯周炎における血中バイオロジカルマーカーの意義と可能性

    多部田 康一

    第58回春季日本歯周病学会学術大会  2016年 

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  • シンポジウム Mechanisms Linking Periodontitis to Atherosclerotic Diseases

    多部田 康一

    7th International Symposium.Kyudai Oral Bioscience シンポジウム  2013年 

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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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  • シンポジウム 歯周炎と動脈硬化性疾患の関連メカニズム-炎症と血清脂質プロファイルの変化-.

    多部田 康一

    第10回口腔医科学フロンティア学術集会  2012年 

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    会議種別:口頭発表(招待・特別)  

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  • シンポジウム Mechanisms Linking Periodontitis to Atherosclerotic Diseases-Oral infection and lipid metabolism

    多部田 康一

    60th Annual Meeting of Japanese Association dor Dental Research  2012年 

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  • シンポジウムII 歯周炎と動脈硬化性疾患 -関連メカニズムの解析- 招待

    多部田 康一

    第52回秋季日本歯周病学会学術大会 シンポジウム  2009年 

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  • シンポジウム TLR signaling and its regulation: 3D, a novel mutation that confers defective sensing by Toll-like receptor 3,7,9 招待

    多部田 康一

    第34回日本免疫学会総会・学術集会 シンポジウム  2005年12月 

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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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  • シンポジウム 感染・免疫研究のフロンティア 自然免疫における核酸抗原認識 -新たな分子 Unc93b1 の関与- 招待

    多部田 康一

    第48回歯科基礎医学会学術大会 シンポジウム  2005年 

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産業財産権

  • 自己免疫疾患および関連疾患の処置のための組成物および方法

    ブルース・ビュートラー, 多部田 康一

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    出願人:ザ スクリップス リサーチ インスティテュート

    出願番号:特願2007-558217  出願日:2006年3月

    公表番号:特表2008-531057  公表日:2008年8月

    J-GLOBAL

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受賞

  • 日本歯科保存学会奨励賞

    2002年  

    多部田 康一

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  • 財団法人上原記念生命科学財団 リサーチフェローシップ

    2002年  

    多部田 康一

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  • 日本歯周病学会奨励賞

    2002年  

    多部田 康一

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共同研究・競争的資金等の研究

  • MPN武装細菌による口腔マイクロバイオームの再構築

    研究課題/領域番号:23K18357

    2023年6月 - 2025年3月

    制度名:科学研究費助成事業

    研究種目:挑戦的研究(萌芽)

    提供機関:日本学術振興会

    多部田 康一, 江島 広貴, 野中 由香莉, 高橋 直紀, 中島 麻由佳

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    配分額:6500000円 ( 直接経費:5000000円 、 間接経費:1500000円 )

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  • Backpackを応用したセルバインディングDDSの開発―新規歯周治療モダリティ

    研究課題/領域番号:23H03079

    2023年4月 - 2026年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    多部田 康一, 岩尾 康範, 野中 由香莉, 高橋 直紀, 中島 麻由佳, 池田 真由美

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    配分額:18850000円 ( 直接経費:14500000円 、 間接経費:4350000円 )

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  • DEL-1による口腔組織修復および再生機構の解明

    研究課題/領域番号:22H03267

    2022年4月 - 2025年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    前川 知樹, 土門 久哲, 多部田 康一, 寺尾 豊, 高橋 直紀

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    配分額:17680000円 ( 直接経費:13600000円 、 間接経費:4080000円 )

    消化管の最前線である口腔は,歯や骨といった硬組織,さらに粘膜組織,口腔腺によって構成されるユニークな湿潤環境下にあり,外的刺激および口腔内細菌群の刺激に晒されている.一つの完結された臓器(口腔臓器)であり,構成組織が協調して機能している.口腔は栄養摂取に伴う食物粉砕過程で,口腔粘膜の損傷を受けやすいという特徴をもつが,皮膚や腸管などのバリア組織と比較して,迅速かつ瘢痕を伴わない創傷治癒能力をもつ.しかしながら,口腔粘膜の優れた治癒および環境への適応能力は加齢とともに低下し,歯を支える周囲組織の炎症・歯周炎による歯の脱落や口腔癌等の発症を伴う. 申請者は,口腔が特異的にもつこれらの粘膜修復および機能維持にDEL-1が必須の役割を担うことを明らかにしてきた.しかし,DEL-1の作用を解析する上で,口腔は複雑な細菌叢や多種の細胞・組織から構成されており,未同定な細胞の存在も示唆されていることから,DEL-1の標的は口腔組織を構成する多様な細胞種に及ぶことが考えられ,解析に困難が予測される.これまでの口腔医学は,横断的な研究が主であり,一つの完結した臓器として口腔が捉えられていなかったため,口腔局所で得られた結果は口腔だけに適応するものになっていた.口腔を臓器として捉える本申請研究によって,口腔粘膜バリア破綻や修復エラーが起因となる疾患の病態理解と,予防・治療法の確立に繋がるのみならず,DEL-1の機能を生かした骨再生医療への展開が可能となる.そこで本年度は,DEL-1による組織修復促進機構の解明および空間的遺伝子発現解析およびシングルセル解析をもちいた口腔組織における細胞間ネットワーク解明による口腔組織幹細胞の候補探索およびDEL-1が組織修復に与える影響解析をおこなった.

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  • 嚥下された歯周病原細菌による腸管恒常性破綻機構の解明

    研究課題/領域番号:22K09961

    2022年4月 - 2025年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    高橋 直紀, 多部田 康一, 谷口 浩二

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    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

    様々な外来病原因子に晒される腸管粘膜は,生体防御の最前線として宿主-微生物間の均衡を保つことで、腸管の恒常性維持に重要な役割を果たしている.その恒常性の破綻によって局所での炎症誘導や組織損傷が引き起こされる結果,炎症性腸疾患(潰瘍性大腸炎・クローン病)や大腸がんへと発展することが知られている。
    大腸がん研究においては,細菌や宿主細胞,非細胞成分から構成されるがん組織周囲における特徴的ながん微小環境が病態形成・進展に大きく関与することが報告されている。主要な歯周病原細菌のひとつであるF. nucleatumは,大腸がん関連細菌として数多くの報告があるが、他の歯周病原細菌によるがん微小環境への影響の詳細は明らかでない.
    そこで本課題の目的は、実験的大腸がんモデルマウスを確立して、各種歯周病原細菌の影響とそのメカニズムをin vivoとin vitroで解析することで、口腔細菌を標的とした新たな大腸がん予防法やリスク診断への発展応用を将来的に目指すことである.
    今年度は実験的大腸炎モデルのひとつである、大腸起炎物質デキストラン硫酸ナトリウム溶液 (DSS) と化学発癌剤アゾキシメタン (AOM) を併用したDSS/AOM誘導性大腸がんモデルマウスの確立を行った。DSSおよびAOMの濃度・投与期間の至適化を行い、免疫染色方法や分子生物学手法を用いて、その重症度の評価系も確立した。

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  • 口腸連関における大腸がんリスクとなる潜在的粘膜親和性Pathobiont検索

    研究課題/領域番号:21K19592

    2021年7月 - 2023年3月

    制度名:科学研究費助成事業 挑戦的研究(萌芽)

    研究種目:挑戦的研究(萌芽)

    提供機関:日本学術振興会

    多部田 康一, 寺井 崇二, 谷口 浩二, 佐藤 裕樹, 高橋 直紀

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    配分額:6500000円 ( 直接経費:5000000円 、 間接経費:1500000円 )

    これまでの口腔-腸管連関研究から,歯周病原細菌と大腸がんの関連が示唆されている.口腔が消化管への細菌供給源として機能し,嚥下された口腔細菌による腸内細菌叢の破綻 (Dysbiosis) が,新規ペリオドンタルメディスン病因論として定説化しつつある.その一方で異所性感染することで初めて病原性を発現する病原性片利共生菌“Pathobiont” が口腔内に存在することが近年明らかとなっている.胃がんにおけるピロリ菌のように,特定の細菌が強力な発がん因子であったことから,腸管へ異所性感染することで発がんに関与する細菌が口腔内に存在する可能性がある.本研究課題では,新しい口腔-大腸がん連関のリスクとなる“Pathobiont”に注目し,臨床検体を用いた解析から候補Pathobiontを探索することを目的とする.具体的には,大腸がん患者において口腔試料および腸管試料を採取し,メタゲノム解析を実施予定であり,現在患者リクルートおよび検体採取を継続的に実施している.

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  • ウェアラブルデバイスを用いた咀嚼行動変容と歯周病改善による糖尿病コントロール

    研究課題/領域番号:21H03129

    2021年4月 - 2025年3月

    制度名:科学研究費助成事業 基盤研究(B)

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    堀 一浩, 多部田 康一, 小野 高裕, 曽根 博仁, 高橋 直紀

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    配分額:17290000円 ( 直接経費:13300000円 、 間接経費:3990000円 )

    近年,咀嚼と全身の健康との関連が報告されているが,咀嚼能力と咀嚼行動(咀嚼回数やスピード)のいずれが全身の健康と関連するのかは不明瞭なままである.特に,医科で注目されている咀嚼行動に関しては,これまでアンケートによる主観的な評価にとどまっており,実効的なツールが無いことから,効果的な咀嚼行動変容を促すことができずにいた.そこで,我々は耳に掛けるだけで客観的に咀嚼行動のモニタリングが可能なウェアラブルデバイスの開発に携わってきた.本検討課題では,このデバイスを使用して成人期におけるにおける咀嚼能率と咀嚼回数,および全身との関連を明らかとし,行動変容アルゴリズムを用いて効果的な咀嚼行動変容を促すことにより,その改善効果を検討する.
    本年は,72名の対象者におにぎり1つ(100g)を摂取してもらい,その際の咀嚼回数,食事時間・咀嚼スピード・一口当たり咀嚼回数などを測定し,その後の経時的血糖値を計測した.さらに,対象者の身長体重測定,血液検査,口腔機能測定を行い,その関連について検討した.その結果,咀嚼回数は体重やBMI・腹囲と負の相関がみられ,経時的血糖変化曲線下面積(AUC)とは正の相関がみられた.また,摂取時間は咀嚼回数との相関が高く,体重・BMIとの負の相関がみられた.さらに,取り込み回数は体重・BMI・空腹時血糖と負の相関がみられた.一方で,一口当たりの咀嚼回数や咀嚼能率は体重やBMIとは相関を認めなかったが,経時血糖AUCとは正の相関を認めた.また,おにぎり咀嚼回数の中央値(234.5回)で被験者をよく噛む群とあまり咬まない群の2群に分けて比較したところ,体重,BMIには有意に差が見られ,あまり咬まない群は肥満の傾向が認められた.また,経時的血糖曲線におけるAUCの比較では,よく咬む群の方が有意に高い値となった.

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  • ジペプチジルペプチダーゼを標的とした新規歯周病医薬開発

    研究課題/領域番号:21K09913

    2021年4月 - 2024年3月

    制度名:科学研究費助成事業 基盤研究(C)

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    野中 由香莉, 田中 信忠, 日高 興士, 多部田 康一

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

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  • 歯周病原細菌感染症としての精神疾患発症機構の解明

    研究課題/領域番号:21H03109

    2021年4月 - 2024年3月

    制度名:科学研究費助成事業 基盤研究(B)

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    照沼 美穂, 多部田 康一, 飯田 和泉

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    配分額:17550000円 ( 直接経費:13500000円 、 間接経費:4050000円 )

    歯周病は口腔内感染症の一つであり、グラム陰性嫌気性菌であるPorphyromonas gingivalis菌(Pg菌)を含むいくつかの口腔内細菌が炎症を惹起することで発症すると考えられている。アルツハイマー病(AD)、パーキンソン病、うつ病などの精神・神経疾患は、脳の炎症所見である神経炎症が認められる疾患であり、感染症の1つである歯周病との関連性が報告されてきた。しかし、歯周病原細菌感染による脳疾患発症の病態生理学的な分子機序の解明は十分になされていない。最近、AD患者の脳からPg菌の16s rRNAやPg菌産生タンパク質分解酵素ジンジパインが検出された (Dominy et al, Science Advances, 2019)。口腔内細菌は、歯科治療や歯磨きなどでも血液中に侵入し、菌血症を発症させることから、本研究では、「血管内に侵入したPg菌は脳に作用する」との仮説を立て、検証を行うこととした。中でも、精神疾患との関連性を明らかにするために、ストレス反応の中枢であり、摂食行動や睡眠、性行動などの本能行動を司る視床下部に着目し研究を行う予定である。
    本年度は、尾静脈に投与したPg菌の追跡を行うために、細菌の生存時間について、経時的に解析をした。また、Pg菌の投与回数による脳の炎症反応の変化を、様々な部位において解析した。同時に、食欲や体重の変化の有無、基本的な行動解析を行い、マウスの健康状態を確認した。
    これらの研究により、Pg菌がどのような脳部位で著明な炎症反応を起こすかが明らかとなった。

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  • Therapeutic biofilmによる歯周病・根面う蝕治療アプローチの転換

    研究課題/領域番号:19K22705

    2019年6月 - 2021年3月

    制度名:科学研究費助成事業 挑戦的研究(萌芽)

    研究種目:挑戦的研究(萌芽)

    提供機関:日本学術振興会

    多部田 康一, 野中 由香莉, 寺尾 豊, 藤本 啓二, 高橋 直紀

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    配分額:6500000円 ( 直接経費:5000000円 、 間接経費:1500000円 )

    本研究では,歯周・う蝕治療の基本概念である『バイオフィルムの徹底排除』から『Therapeutic biofilmの作為的形成』へと発想を逆転することにより,歯周病および根面う蝕の発症・進行の制御に挑戦する。両疾病の原因となる細菌プラークはバイオフィルムとして薬剤抵抗性を持ち, 治療においては機械的除去が必要である。しかしセルフケア困難な部位にバイオフィルムを作らせないことは不可能であり,既存の治療法は限界に至ったと考える。そこで,本研究は既存概念を転換して,Therapeutic biofilmの概念創生に向けた探索を行う挑戦的研究である。
    In vitro におけるTherapeutic biofilmの創製および機能評価を目標とし,その予備実験として,キトサン被覆リポソームを用い,歯周病原細菌由来バイオフィルムへの影響を検討した。代表的な歯周病原細菌であるPorphyromonas gingivalis, Fusobacterium nucleatum の培養液に上記リポソームを添加し,バイオフィルム形成に対する抑制効果を検討した。バイオフィルム形成量の評価にはクリスタルバイオレット染色を用いた。
    その結果,キトサン被覆リポソームを高濃度で添加するといずれの菌においてもバイオフィルム形成が一定量抑制される可能性が示唆された。すなわち,抗菌物質未含有のリポナノカプセルによっても,菌叢の変化が生じる可能性が示された。これらの抑制メカニズムについては今後更なる検討が必要である。また、口腔内の常在菌を含めた各種細菌に対する影響について今後解析を予定している。

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  • フレイルとAMRの課題に対応する食品由来機能ペプチドを素材とした歯周病医薬開発

    研究課題/領域番号:19H03829

    2019年4月 - 2023年3月

    制度名:科学研究費助成事業 基盤研究(B)

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    多部田 康一, 野中 由香莉, 寺尾 豊, 藤本 啓二, 高橋 直紀, 谷口 正之

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    配分額:17160000円 ( 直接経費:13200000円 、 間接経費:3960000円 )

    コメ由来のAmyⅠ-1-18ペプチドおよびそのアミノ酸置換体は浮遊状態のPorphyromonas gingivalisに抗菌活性を示す(Taniguchi M et.al., Biopolymers, 2015)。しかし,これらのペプチドがバイオフィルムを制御し,歯周病治療に有効であるかどうかは明らかではない。そこで,本年度は,AmyⅠ-1-18および同ペプチドのアミノ酸置換体G12Rが歯周病原細菌のバイオフィルムに及ぼす影響について解析した。
    まず初めに,代表的な歯周病原細菌であるP. gingivalisおよびFusobacterium nucleatumの培養液に,これらのペプチドを添加し,バイオフィルム量をクリスタルバイオレット染色にて評価した。その結果,両ペプチドはP. gingivalisおよびF. nucleatumのバイオフィルム形成を阻害した。また,AmyⅠ-1-18と比較してG12Rは,両菌株に対し,より低濃度でバイオフィルム形成を阻害した。
    次に,これらのペプチドの抗菌メカニズムを明らかとするため,MICおよびMBCを測定すると,AmyⅠ-1-18ペプチドはP. gingivalisに対して静菌的に,F. nucleatumに対しては殺菌的に作用することが示された。一方,G12Rはいずれの菌に対しても,AmyⅠ-1-18ペプチドよりも強力な殺菌的作用を示した。また,propidium iodide染色を用いて,各ペプチドによる細胞膜傷害性を調べたところ,G12R投与群では,膜透過性の亢進が示唆された。
    以上より,AmyⅠ-1-18およびG12Rペプチドは,歯周病原細菌のバイオフィルム形成を阻害した。アミノ酸置換体であるG12Rは歯周病原細菌に対する細胞膜傷害能の強化により,強い殺菌作用を示すことが明らかとなった。

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  • 口腔-腸管連関の新展開:嚥下された歯周病原細菌は腸炎を悪化させるか?

    研究課題/領域番号:19K10126

    2019年4月 - 2022年3月

    制度名:科学研究費助成事業 基盤研究(C)

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    高橋 直紀, 多部田 康一, 片倉 響子

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    歯周医学の新規病因論のひとつとして、嚥下された歯周病原細菌が腸内細菌叢を攪乱することで全身性に悪影響をおよぼすという「口腔」と「腸管」の連関が近年注目されている。しかしながら、潰瘍性大腸炎をはじめとする炎症性腸疾患に対する口腔細菌の直接的な影響は不明である。そこで本研究は、嚥下された口腔細菌が炎症性腸疾患におよぼす影響とそのメカニズムについて、実験的腸炎モデルマウスを中心に明らかにすることである。その関係が明らかとなれば口腔内プロバイオティクス・プレバイオティクスを用いた炎症性腸疾患の予防や治療につながることが期待される。
    まず、in vivoにおいてはデキストラン硫酸ナトリウム(DSS)誘導性の実験的腸炎モデルマウスの確立を行った。試適濃度を決定する目的で、8-10週齢のC57BL/6マウスに各種濃度DSSを5-7日間飲水投与行った。腸炎重症度の評価は、体重の経時的変化や便の性状、腸管組織における炎症性サイトカイン産生や腸管の組織像から比較検討した。試適濃度における腸炎モデルマウス確立後、主要な歯周病原細菌を経口投与し、未投与群との重症度の比較を行い、Porphyromonas gingivalis投与によって腸炎が重症化することが確認された。in vitroにおいては腸管上皮細胞をPorphyromonas gingivalis菌体にて刺激することで、上皮バリア関連タンパクが変化することを確認した。

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  • コメ由来ペプチド素材を用いた口腔ケアアプリケーションと歯周病ペプチド医薬の開発

    研究課題/領域番号:16K15845

    2016年4月 - 2019年3月

    制度名:科学研究費助成事業 挑戦的萌芽研究

    研究種目:挑戦的萌芽研究

    提供機関:日本学術振興会

    多部田 康一, 谷口 正之

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    配分額:3380000円 ( 直接経費:2600000円 、 間接経費:780000円 )

    本研究においては,コメαアミラーゼ由来のAmyΙ-1-18ペプチドに着目し,歯周病に対する抑制能とその作用機序を明らかにすることを目的とした.AmyΙ-1-18ペプチドは,炎症性サイトカイン産生の抑制を介してマウス歯周炎モデルにおいて歯槽骨吸収を阻害した. さらに,AmyΙ-1-18ペプチドは,マクロファージにおいてLPSおよびIL-1βによって誘導される炎症性サイトカインを抑制した. AmyΙ-1-18ペプチドは抗炎症性作用によって,歯周病を抑制することが明らかとなった.この研究の成果により,新規歯周病医薬開発の基礎となるデータが得られた.

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  • 歯周炎病態形成におけるTRPチャネルを介した神経-骨代謝ネットワークの解明

    研究課題/領域番号:16K11827

    2016年4月 - 2019年3月

    制度名:科学研究費助成事業 基盤研究(C)

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    高橋 直紀, 多部田 康一, 山崎 和久

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    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    歯周炎は歯槽骨の吸収を特徴とする慢性炎症性疾患であり,主要な歯の喪失原因である.近年同定されたTRPV1タンパクは,様々な炎症性疾患に関与することが知られているが,歯周炎への関与はほとんど報告がない.実験的歯周炎モデルマウスにおいて,TRPV1ノックアウトマウスは歯槽骨破壊が亢進することが確認された.そのメカニズムとして,TRPV1の活性化によって産生誘導される神経ペプチドCGRPが破骨細胞分化を抑制することが示唆された.TRPV1アゴニストであるカプサイシンを実験的歯周炎モデルマウスに投与することで歯周炎が抑制された.以上より,TRPV1が歯周炎の病態形成に関与することが示唆された.

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  • 高付加価値型歯周炎ワクチン―DNAオリガミとイミダゾキノリンによるIgA誘導―(国際共同研究強化)

    研究課題/領域番号:15KK0338

    2016年 - 2018年

    制度名:科学研究費助成事業 国際共同研究加速基金(国際共同研究強化)

    研究種目:国際共同研究加速基金(国際共同研究強化)

    提供機関:日本学術振興会

    多部田 康一

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    配分額:14560000円 ( 直接経費:11200000円 、 間接経費:3360000円 )

    唾液中の免疫グロブリン(分泌型IgA抗体)は歯周病などの口腔感染症の予防に役割を果たす。この分泌型IgAを効果的に誘導することは歯周病の予防・治療における一つのアプローチである。本研究においては,ENUマウスミュータジェネシスと呼ばれるマウス遺伝子変異体の遺伝子機能の違いを検出する研究手法により分泌型IgAの産生を制御する遺伝子の検索を行った。その結果,唾液中分泌型IgA量に影響を与える遺伝子変異(Yummy)を検出した。Yummyミューテーションを持つ責任遺伝子のノックアウトマウスが作成された。今後の遺伝子機能解析が予定される。

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  • コメ由来ペプチド素材を用いた口腔ケアアプリケーションと歯周病ペプチド医薬の開発

    2016年 - 2018年

    制度名:挑戦的萌芽研究

    提供機関:科学研究費

    多部田 康一

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    担当区分:研究代表者  資金種別:競争的資金

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  • 歯周炎病態形成におけるTRPチャネルを介した神経-骨代謝ネットワークの解明

    2016年 - 2018年

    制度名:基盤研究(C)

    提供機関:科学研究費

    高橋直紀

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    資金種別:競争的資金

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  • 高付加価値型歯周炎ワクチン―DNAオリガミとイミダゾキノリンによるIgA誘導―

    研究課題/領域番号:15H05052

    2015年4月 - 2018年3月

    制度名:科学研究費助成事業 基盤研究(B)

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    多部田 康一, 寺尾 豊, 高橋 直紀, 山崎 和久

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    配分額:17290000円 ( 直接経費:13300000円 、 間接経費:3990000円 )

    感染症である歯周炎におけるワクチンの有効性は示唆されているが、実際に応用可能なワクチンの開発にはこれまで至っていない。本研究において、粘膜免疫における分泌型IgA産生誘導を焦点に歯周炎ワクチン開発の可能性を検証した。その結果、核酸抗原様化合物であるイミダゾキノリン誘導体を介してケモカイン産生および濾胞性T細胞活性化が誘導され、分泌型IgA産生が促進された。これらのことから、核酸抗原をアジュバンドとした歯周炎ワクチン開発の可能性が示唆された。

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  • 高付加価値型歯周炎ワクチン―DNAオリガミとイミダゾキノリンによるIgA誘導―(国際共同研究強化)

    2015年 - 2018年

    制度名:国際共同研究加速基金(国際共同研究強化)

    提供機関:科学研究費

    多部田 康一

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    担当区分:研究代表者  資金種別:競争的資金

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  • 高付加価値型歯周炎ワクチン―DNAオリガミとイミダゾキノリンによるIgA誘導―

    2015年 - 2017年

    制度名:基盤研究(B)

    提供機関:科学研究費

    多部田 康一

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    担当区分:研究代表者  資金種別:競争的資金

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  • IL-10応答を中心とした歯周病原細菌感染に対する慢性炎症成立機構の基盤解明

    研究課題/領域番号:25463216

    2013年4月 - 2016年3月

    制度名:科学研究費助成事業 基盤研究(C)

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    中島 貴子, 多部田 康一, 伊藤 晴江, 山崎 和久, 山田 ひとみ, 松田 由実

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    配分額:5070000円 ( 直接経費:3900000円 、 間接経費:1170000円 )

    抗炎症性サイトカインIL-10を中心とした歯周炎の発症・進行抑制に対する効果を検討した。ヒト歯周炎患者の歯肉病変部では歯肉炎に比較してIL-10が有意に高いレベルで検出された。マウス絹糸結紮歯周炎モデルにおいて、口腔細菌の増加、歯肉の著明な炎症、歯槽骨吸収と同時に、歯肉でのIL-10発現の上昇を認めた。このモデルにおいて歯肉局所にIL-10を直接投与すると炎症、骨吸収の抑制作用は認められなかったが、腹腔投与すると歯肉の炎症性サイトカインは抑制しないが歯槽骨吸収は抑制傾向が認められた。歯周炎の骨吸収は局所の炎症のみでなく、全身性に制御されていることが示唆された。

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  • IL-10応答を中心とした歯周病原細菌感染に対する慢性炎症成立機構の基盤解明

    2013年 - 2015年

    制度名:基盤研究(C)

    提供機関:科学研究費

    中島貴子

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    資金種別:競争的資金

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  • 加齢により減少する新規細胞外マトリクスの機能解析-組織再生応用への新たな可能性-

    2012年

    制度名:新潟大学 プロジェクト 推進経費 ・奨励研究

    提供機関:新潟大学

    多部田 康一

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    担当区分:研究代表者  資金種別:競争的資金

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  • 脂質代謝バランスの揺らぎと歯周疾患のパスウェイ解析

    研究課題/領域番号:23390476

    2011年4月 - 2014年3月

    制度名:科学研究費助成事業 基盤研究(B)

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    山崎 和久, 多部田 康一, 中島 貴子, 土門 久哲, 中山 浩次

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    配分額:19110000円 ( 直接経費:14700000円 、 間接経費:4410000円 )

    本研究課題では歯周病原細菌感染の脂質代謝への影響を解析した。その結果、歯周炎患者において脂質プロフィールが動脈硬化性に変化しているとともに、血中LDLコレステロールの制御に重要なPCSK9が上昇していることが明らかになった。また、マウス実験的歯周炎モデルにおいては、PCSK9をはじめとする脂質代謝制御に関連する遺伝子発現が動脈硬化性に変化するとともに、HDLコレステロールの低下が認められた。これらより、歯周病原細菌感染はコレステロールの排出抑制、LDL受容体の発現上昇による細胞内への取り込みの亢進により動脈硬化を促進することが明らかになった。

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  • 脂質代謝バランスの揺らぎと歯周疾患のパスウェイ解析

    2011年 - 2014年

    制度名:基盤研究(B)

    提供機関:科学研究費

    山崎 和久

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    資金種別:競争的資金

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  • 口腔ー消化管の粘膜免疫システムを介した口腔感染と動脈硬化性疾患の関連機序

    研究課題/領域番号:23593056

    2011年 - 2013年

    制度名:科学研究費助成事業 基盤研究(C)

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    多部田 康一, 山崎 和

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    配分額:5200000円 ( 直接経費:4000000円 、 間接経費:1200000円 )

    本研究は歯周病の原因菌であるPorphyromonas gingivalisを感染させた動脈硬化症マウスモデルを用い、歯周病を想定する口腔感染に起因する消化管における宿主応答が全身の炎症応答と動脈硬化病変の進展に関与するメカニズムを明らかにすることを目的とした。口腔から摂取したPorphyromonas gingivalisは腸管において炎症応答を誘導した。新たな知見として核酸抗原(DNA 抗原、RNA抗原)を認識することのできないUnc93b欠損マウスにおいてはIgAの産生低下が認められた。この結果から消化管を介した免疫応答とIgAの産生において核酸抗原が重要な役割をもつ知見が得られた。

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  • 口腔‐消化管の粘膜免疫システムを介した口腔感染と動脈硬化性疾患の関連機序

    2011年 - 2013年

    制度名:基盤研究(C)

    提供機関:科学研究費

    多部田 康一

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    担当区分:研究代表者  資金種別:競争的資金

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  • 選択的スプライシングにおけるGU(T)-AGルールの例外-新たな骨形成不全症モデルマウスにおける病態発症機構の解明-

    2010年

    制度名:新潟大学 プロジェクト 推進経費 ・奨励研究B

    提供機関:新潟大学

    多部田 康一

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    担当区分:研究代表者  資金種別:競争的資金

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  • レギュラトリー細胞が歯周組織破壊に及ぼす影響-敵か味方か-

    研究課題/領域番号:21390555

    2009年 - 2011年

    制度名:科学研究費助成事業 基盤研究(B)

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    中島 貴子, 山崎 和久, 多部田 康一, 伊藤 晴江, 下野 正基

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    配分額:17810000円 ( 直接経費:13700000円 、 間接経費:4110000円 )

    歯周病原細菌Porphyromonas gingivalisを慢性口腔感染させた歯周炎モデルマウスを用い、抑制性細胞NKT細胞の欠失あるいは活性化が歯周組織破壊に及ぼす影響とメカニズムを解析した。NKT細胞欠損マウスでは歯槽骨吸収は抑制され、NKT活性化マウスでは亢進した。NKT細胞活性化マウスではNKT細胞によるサイトカイン産生はINF-γよりもIL-4産生優位であった。さらに血清中のP. gingivalis特異抗体レベルならびにRANKLレベルの上昇を認めた。これらより、NKT細胞はTh2応答を誘導することにより歯槽骨吸収を促進させることが示唆された。

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  • レギュラトリー細胞が歯周組織破壊に及ぼす影響-敵か味方か-

    2009年 - 2011年

    制度名:基盤研究(B)

    提供機関:科学研究費

    中島 貴子

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    資金種別:競争的資金

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  • 新潟大学 プロジェクト 推進経費 ・奨励研究

    2009年

    提供機関:新潟大学

    多部田 康一

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    担当区分:研究代表者  資金種別:競争的資金

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  • 歯周炎と動脈硬化性疾患の生物学的関連を解明するーインターフェースとなるエイジング

    研究課題/領域番号:20592426

    2008年 - 2010年

    制度名:科学研究費助成事業 基盤研究(C)

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    多部田 康一, 山崎 和久

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    配分額:4550000円 ( 直接経費:3500000円 、 間接経費:1050000円 )

    歯周炎マウスモデルを用いた解析においては、P.gingivalisの口腔内感染が全身的な炎症応答を誘導し、動脈組織における遺伝子発現の変化に加え、血清脂質の動脈硬化症リスクを高める方向への変動も誘導することが示された。動脈硬化性疾患と口腔感染の関連メカニズムとして、口腔感染が脂質代謝変動に寄与する新しい知見が得られた。またエイジングとの関連について検討を継続している。

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  • 歯周炎と動脈硬化性疾患の生物学的関連を解明する-インター フェースとなるエイジング-

    2008年 - 2010年