Researcher basic information

• 博士(歯学), 新潟大学

• https://researchmap.jp/takahashi-n?lang=en

• https://orcid.org/0000-0001-8952-7260
• https://jglobal.jst.go.jp/detail?JGLOBAL_ID=201801013251111386
• https://www.den.hokudai.ac.jp/hozon2/perio.html

• 80722842

• https://orcid.org/0000-0001-8952-7260

• 201801013251111386

• 歯周病学
• 分子生物学
• 免疫学
• 細菌学
• 骨再生医療

• Life Science, Conservative dentistry

• Bachelor's degree program, School of Dental Medicine
• Doctoral (PhD) degree program, Graduate school of Dental Medicine

Research activity information

• May 2026, 日本歯周病学会, 日本歯周病学会奨励賞
  本杉 駿弥, 高橋 直紀
• May 2025, 日本歯周病学会, 歯周組織再生医学優秀発表賞
  植田優太;高橋直紀
• Nov. 2024, 日本歯科保存学会, 優秀ポスター賞,
  本杉駿弥、高橋直紀
• Oct. 2023, 日本歯周病学会, 日本歯周病学会学学術賞
  高橋直紀
• Oct. 2022, 日本歯科保存学会, 優秀ポスター賞
  高橋 直紀
• Sep. 2022, 日本歯周病学会, 日本歯周病学会学会誌賞
  高橋 直紀
• Oct. 2020, 日本歯周病学会, 日本歯周病学会奨励賞
  原 実生;高橋直紀
• Nov. 2018, オーラルサイエンス研究会, 優秀発表賞
  高橋 直紀
• Oct. 2017, 国際歯科研究学会, JADR / GC学術奨励賞
  原 実生;高橋直紀
• Jun. 2017, 日本歯科保存学会, 日本歯科保存学会奨励賞
  高橋 直紀
• May 2017, 日本歯周病学会, 日本歯周病学会奨励賞
  高橋 直紀
• Oct. 2015, 国際歯科研究学会, JADR/GC学術奨励賞
  高橋 直紀
• Oct. 2010, 日本歯科保存学会, デンツプライ賞
  高橋 直紀

• Impact of electrode distance, axial position, and energization time on cauterization of root canal isthmuses using high-frequency current
  Ahmed Saud Alkuwaykibi; Tsutomu Sugaya; Mohammed Katib Alruwaili; Naoki Takahashi
  Clinical Oral Investigations, 03 Jun. 2026
  Scientific journal
• A DPP inhibitor suppresses periodontitis via antibacterial effect targeting Porphyromonas gingivalis.
  Yukari Aoki-Nonaka; Yukako Minato; Koushi Hidaka; Yuko Warita; Daiki Ando; Hnin Yu Lwin; Aoi Matsugishi-Nasu; Naoki Takahashi; Akihiro Nakamura; Wataru Ogasawara; Mizuki Sekiya; Yasumitsu Sakamoto; Koichi Tabeta
  Scientific reports, 08 May 2026, [International Magazine]
  English, Scientific journal, Porphyromonas gingivalis is the most common periodontal pathogen. P. gingivalis dipeptidyl peptidase 7 (PgDPP7) belongs to a new class of serine peptidases, family S46. S46 peptidases are absent in mammals. Therefore, these enzymes are promising targets for novel antibacterial agents. In this study, inhibitors were designed based on the cocrystal structures of valyl-tyrosine and phenylalanyl-tyrosine, which bind to the active centers of DPP7 derived from bacteria, and dipeptide derivatives that inhibit PgDPP7 were obtained. The active compound KGDI-109, the first peptidyl inhibitor of S46 peptidases, exerted an inhibitory effect against P. gingivalis growth at a minimum inhibitory concentration of 1.56 µM. In C57BL/6 N male mice with induced periodontitis, the oral administration of KGDI-109 significantly suppressed alveolar bone resorption and reduced the amount of P. gingivalis in the oral cavity, indicating that the DPP inhibitor suppresses periodontal disease by its antibacterial activity. This dipeptide derivative did not inhibit the growth of other oral bacteria, and its antibacterial action was presumed to target bacteria possessing DPP, particularly P. gingivalis. Furthermore, KGDI-109 may be more effective than azithromycin in maintaining the gut microbial diversity and reducing adverse health effects. KGDI-109 can be a novel treatment for periodontal diseases targeting P. gingivalis.
• The Efficacy of Sodium Hypochlorite in Combination with Hyaluronic Acid as an Adjunct to Non-Surgical Periodontal Treatment: A Systematic Review.
  Qonita Feria; Inggrid Ratna Sari Soegiharto; Nanda Denia Astika Putri; Yohana Hutapea; Naoki Takahashi; Benso Sulijaya; Dewi Ayuningtyas
  Antibiotics (Basel, Switzerland), 15, 5, 24 Apr. 2026, [International Magazine]
  English, Scientific journal, Objective: The purpose of this systematic review is to evaluate the available scientific literature on the effectiveness of combining sodium hypochlorite and cross-linked hyaluronic acid (xHyA) as an adjunct to non-surgical periodontal treatment. Materials and Methods: Five electronic databases were searched. The study was traced using the PRISMA criteria and publications from ProQuest, Google Scholar, Springer Nature, Scopus, and PubMed. The randomized study was examined using the Cochrane Risk of Bias 2 (RoB) tool and two case series studies were reviewed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist. Results: The systematic review included four studies (two RCT and two case series). Across the included studies, the adjunctive use of sodium hypochlorite/amino acid gel and cross-linked hyaluronic acid (xHyA) following subgingival instrumentation was associated with improvements in clinical periodontal parameters. Probing pocket depth (PPD) reduction ranged from 1.5 to 5.8 mm, clinical attachment level (CAL) gain ranged from 1.5 to 5.3 mm, and bleeding on probing (BOP) reduction ranged from 57.5% to 65.6%. The improvements were generally more pronounced in deeper periodontal pockets. Minor variations in intervention protocols were observed among studies. Conclusions: The adjunctive use of sodium hypochlorite and cross-linked hyaluronic acid in non-surgical periodontal therapy may be associated with improvements in clinical periodontal parameters, including PPD, CAL, and BOP, particularly in deep pockets. However, the available evidence is limited and heterogeneous, with small sample sizes and short follow-up durations. Therefore, these findings should be interpreted with caution, and further well-designed long-term studies are required.
• The favorable role of recombinant collagen peptide in periosteal cell-derived osteoregeneration
  Tran Thi Thuy Diep; Naoki Takahashi; Takahiro Tsuzuno; Shunya Motosugi; Yuta Ueda; Aoi Yamada; Yukari Aoki-Nonaka; Masaki Nagata; Koichi Tabeta
  Regenerative Therapy, Mar. 2026
  Scientific journal
• Ferulic acid suppresses Porphyromonas gingivalis biofilm formation via the inhibition of autoinducer-2 production and receptor activity
  Daiki Ando; Hnin Yu Lwin; Yukari Aoki-Nonaka; Aoi Matsugishi-Nasu; Yukako Minato; Yuko Warita; Naoki Takahashi; Koichi Tabeta
  Archives of Oral Biology, Oct. 2025, [Peer-reviewed]
  Scientific journal
• Biological stress response to scaling and root planing and subgingival scaling with Er:YAG laser: A pilot study
  保苅 崇大; 野中 由香莉; 濃野 要; 杉原 俊太郎; 新井 恭子; 鎗田 将史; 宮沢 春菜; 山本 裕子; 佐藤 友則; 高橋 直紀; 小松 康高; 小牧 基浩; 多部田 康一; 両⻆ 俊哉
  日本歯周病学会会誌, 67, 3, 111, 121, Japanese Society of Periodontology, 30 Sep. 2025, [Peer-reviewed]
  Scientific journal
• Antimicrobial and antibiofilm effects of a leucine-substituted rice peptide against Porphyromonas gingivalis and Fusobacterium nucleatum.
  Yukari Aoki-Nonaka; Aoi Matsugishi-Nasu; Hnin Yu Lwin; Yukako Minato; Daiki Ando; Yuko Warita; Naoki Takahashi; Koichi Tabeta
  Microbial pathogenesis, 108052, 108052, 18 Sep. 2025, [Peer-reviewed], [International Magazine]
  English, Scientific journal, The aim of this study to elucidate the antibacterial and antibiofilm effects of a leucine-substituted peptide against periodontal pathogen. N3L peptide was designed as a leucine-substituted variant of the rice-derived AmyI-1-18 peptide. Subsequently, the minimum inhibitory concentration and minimum bactericidal concentration of N3L against Porphyromonas gingivalis and Fusobacterium nucleatum were determined. Furthermore, its membrane permeability was investigated by propidium iodide (PI) staining. Moreover, the effects of N3L on the gene expression of virulence factors were analyzed by reverse transcriptase quantitative polymerase chain reaction. The biofilm amount was assessed by crystal violet staining to analyze the biofilm control ability of N3L peptide. N3L demonstrated bactericidal activity against P. gingivalis and F. nucleatum, with notably enhanced antimicrobial activity against P. gingivalis compared with the parent peptide AmyI-1-18. PI staining indicated that N3L showed bacterial membrane permeability against P. gingivalis and F. nucleatum. Moreover, N3L significantly downregulated the expression levels of fimA, rgpA, rgpB, and kgp in P. gingivalis and fadA in F. nucleatum. This peptide also significantly inhibited biofilm formation and reduced established biofilms of P. gingivalis and F. nucleatum. The leucine-substituted rice peptide N3L, with its hydrophobicity and α-helix content higher than those of AmyI-1-18, showed enhanced antimicrobial and antibiofilm activities through membrane disruption and modulation of gene expressions related to adherence and metabolism. The leucine-substituted rice peptide N3L showed enhanced antimicrobial and antibiofilm activities against P. gingivalis and F. nucleatum.
• RORγt Inhibition Reduces Protumor Inflammation and Decreases Tumor Growth in Experimental Models of Lung Cancer
  Miki Yamada-Hara; Lauren Amaya; Zhihe Wang; Ji Won Byun; Naoki Takahashi; Sunandini Sharma; Han Chang; Arisachi Tanaka; Liping Zeng; Zahra Malakoutikhah; Sneha Ganguly; Minh-Chau Vu; Matt Levin; David Schwartz; Jack Heath; Scott Herdman; Maripat Corr; Eyal Raz; Samuel Bertin
  Cancer Immunology Research, 02 Sep. 2025, [Peer-reviewed]
  Scientific journal
• Analysis of the Effect of Human Type I Collagen-Derived Peptide on Bone Regenerative Capacity and Comparison with Various Collagen Materials In Vivo
  Tatsunori Asakura; Tran Thi Thuy Diep; Yuta Ueda; Aoi Yamada; Takahiro Tsuzuno; Naoki Takahashi; Masayuki Miyata; Koichi Tabeta; Masaki Nagata; Ken Matsuda
  Medicina, 02 Jan. 2025, [Peer-reviewed]
  Scientific journal
• Patients with periodontitis exhibit persistent dysbiosis of the gut microbiota and distinct serum metabolome.
  Eiji Miyauchi; Kyoko Yamazaki; Yuuri Tsuboi; Takako Nakajima; Shigeru Ono; Kentaro Mizuno; Naoki Takahashi; Kentaro Imamura; Hidetoshi Morita; Nobuaki Miura; Shujiro Okuda; Jun Kikuchi; Nobuo Sasaki; Hiroshi Ohno; Kazuhisa Yamazaki
  Journal of oral microbiology, 17, 1, 2499284, 2499284, 2025, [Peer-reviewed], [International Magazine]
  English, Scientific journal, OBJECTIVES: Animal studies suggest that periodontopathic bacteria induce gut dysbiosis and related pathology, possibly connecting periodontitis to non-oral diseases. However, the effects on the gut ecosystem in periodontitis patients are not fully understood. METHODS: We conducted a comprehensive analysis of the salivary and gut microbiota using 16S rRNA sequencing in periodontitis patients before and after treatment, comparing them to healthy participants. Serum metabolites were also analyzed. RESULTS: Periodontitis patients showed high alpha diversity in both salivary and gut microbiota with a strong correlation. Significant differences were also observed in the gut microbiota composition between patients before treatment and healthy participants, irrespective of the ectopic colonization of periodontitis-associated bacteria in the gut. Co-abundance group analysis demonstrated that the gut microbiota of healthy participants was enriched with short-chain fatty acid producers. Changes in the gut microbiota coincided with alterations in the serum metabolite profile. While periodontal therapy improved salivary microbiota, it did not significantly affect gut microbiota. CONCLUSIONS: Gut dysbiosis of periodontitis patients may impact systemic metabolite profiles. Given that periodontal therapy alone did not substantially improve the gut microbiota, adjunctive strategies targeting the gut microbiome may be effective in reducing the risk of periodontitis-associated diseases.
• Enrichment of Porphyromonas gingivalis in colonic mucosa-associated microbiota and its enhanced adhesion to epithelium in colorectal carcinogenesis: Insights from in vivo and clinical studies.
  Shunya Motosugi; Naoki Takahashi; Shuhei Mineo; Keisuke Sato; Takahiro Tsuzuno; Yukari Aoki-Nonaka; Nao Nakajima; Kazuya Takahashi; Hiroki Sato; Haruna Miyazawa; Koji Taniguchi; Shuji Terai; Koichi Tabeta
  PloS one, 20, 3, e0320383, 2025, [Peer-reviewed], [International Magazine]
  English, Scientific journal, OBJECTIVES: The oral-gut axis is believed to play a role in the pathogenesis of colorectal cancer (CRC). Previous studies have demonstrated the transmission of oral microbiota to the gut, disrupting gut microbial balance and creating a protumorigenic microenvironment conducive to CRC progression. Fusobacterium nucleatum is a putative periodontal pathogen recognized as a specific bacterium that promotes CRC development. However, the possible involvement of other periodontal pathogens in CRC is poorly understood. This study aimed to explore the effects of ingested periodontal pathogens on experimental CRC in mice and elucidate the underlying mechanisms. METHODS: In this study, experimental colitis-induced CRC mouse models were used. The mice were orally administered periodontal pathogens (Porphyromonas gingivalis and Prevotella intermedia) three times a week during the experimental period. The CRC severity between the P. gingivalis-treated and P. intermedia-treated groups was compared. Lumen-associated microbiota (LAM) and mucosa-associated microbiota (MAM) were analyzed in both mouse and human samples. In vitro studies were conducted using intestinal epithelial cells to explore the possible mechanisms by which the periodontal pathogens affect the CRC development. RESULTS: The P. gingivalis-treated group exhibited significantly increased CRC severity compared to the other groups among azoxymethane/dextran sodium sulfate (AOM/DSS)-induced mouse models. The LAM and MAM exhibited distinct bacterial compositions, and P. gingivalis was enriched more in MAM than in LAM. In vitro adhesion assays revealed that P. gingivalis had higher adhesive capacity to intestinal epithelial cells than P. intermedia and indicated the possible involvement of gingipains in such a capacity. CONCLUSION: P. gingivalis is enriched in MAM, and its subsequent adhesion to intestinal epithelial cells is potentially involved in the progression of CRC.
• Allyl isothiocyanate suppressed periodontal tissue destruction in mice via bacteriostatic and anti-inflammatory activities against Porphyromonas gingivalis
  Yukako Minato; Yukari Aoki-Nonaka; Hnin Yu Lwin; Daiki Ando; Yuko Warita; Aoi Matsugishi-Nasu; Takumi Hiyoshi; Naoki Takahashi; Koichi Tabeta
  Archives of Oral Biology, Jan. 2025, [Peer-reviewed]
  Scientific journal
• In Vivo Bioluminescence Imaging of Tumor Progression in the Lewis Lung Carcinoma Orthotopic Mouse Model: A Comparison Between the Tail Vein Injection and Intranasal Instillation Methods.
  Miki Yamada-Hara; Naoki Takahashi; Ji Won Byun; Liping Zeng; Zhihe Wang; Arisachi Tanaka; Zahra Malakoutikhah; Tomoko Hayashi; Nicholas J G Webster; Eyal Raz; Samuel Bertin
  Current protocols, 4, 12, e70071, Dec. 2024, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Metastasis remains a leading cause of cancer-related mortality, yet its study has been constrained by the lack of reliable animal models that faithfully replicate this complex process. Syngeneic models for studying lung cancer metastasis are limited, with the Lewis lung carcinoma (LLC) model being the most commonly employed. The conventional LLC orthotopic model involves injecting LLC cells intravenously (i.v.) via the tail vein into syngeneic C57BL/6 mice. However, this model has significant drawbacks, such as tumor development in multiple anatomical sites, incomplete lung tumor penetrance, and challenges in monitoring lung tumor growth. This article highlights the advantages of using luciferase-expressing LLC cells combined with bioluminescence imaging (BLI) to quantify tumor progression in live animals. We demonstrate that both white- and black-furred C57BL/6 mice can be used for BLI. Finally, we propose that intranasal (i.n.) instillation of LLC cells offers a valuable alternative to the traditional i.v. tail vein injection method, particularly for its simplicity and improved reproducibility. Although the LLC i.n. model does not recapitulate the metastasis process via the blood vascular route, it is an effective model for studying tumor seeding within the lungs and is particularly useful for analyzing the impact of the lung microenvironment on tumor initiation and progression. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Lewis lung carcinoma intravenous injection method Support Protocol: In vivo bioluminescence imaging Basic Protocol 2: Lewis lung carcinoma intranasal instillation method.
• Characterization of the cellular heterogeneity and bone regenerative potential of cultured human periosteal cells
  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, Dec. 2023, [Peer-reviewed]
  Scientific journal
• Osteoclastogenesis Inhibitor and Antioxidant Properties of Konjac Glucomannan in a Periodontitis Mice Model: An In Vivo Study
  Edlyn Dwiputri; Kartika Dhipta Lestari; Geraldi Hartono Kurniawan Tan; Benso Sulijaya; Yuniarti Soeroso; Sri Lelyati C. Masulili; Naoki Takahashi; Koichi Tabeta; Fatimah Maria Tadjoedin
  International Journal of Dentistry, 31 Oct. 2023, [Peer-reviewed]
  Scientific journal
• Exploring the Antibacterial Potential of Konjac Glucomannan in Periodontitis: Animal and In Vitro Studies
  Kartika Dhipta Lestari; Edlyn Dwiputri; Geraldi Hartono Kurniawan Tan; Benso Sulijaya; Yuniarti Soeroso; Natalina Natalina; Nadhia Anindhita Harsas; Naoki Takahashi
  Medicina, 06 Oct. 2023, [Peer-reviewed]
  Scientific journal
• Probiotics and metabolites regulate the oral and gut microbiome composition as host modulation agents in periodontitis: A narrative review
  Fathia Agzarine Deandra; Ketherin Ketherin; Rieska Rachmasari; Benso Sulijaya; Naoki Takahashi
  Heliyon, 9, 2, e13475, Feb. 2023, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Periodontitis is defined as an oral bacterial dysbiosis-induced persistent inflammation on dental supporting tissue resulting in periodontal tissue breakdown and alveolar bone destruction. The disease is initiated by the interaction between periodontopathogens and the host immune system. Its development and severity can be associated with several systemic diseases, such as cardiovascular disease (CVD), diabetes mellitus, and rheumatoid arthritis (RA). Moreover, the latest research has suggested that the oral and gut microbiome hypothesis lays the oral and systemic connection mechanism. Bacterial homeostasis and restoration in the oral cavity and intestine become therapeutics concepts. Concerning the treatment of periodontitis, a local inflammatory condition, prolonged systemic administration of antibiotics is no longer recommended due to bacterial resistance issues. Probiotics and several bioactive metabolites have been widely investigated to address the needs of host modulation therapy in periodontitis. Evidence suggests that the use of probiotics helps downregulate the inflammation process through the regulation of toll-like receptor 4 (TLR4) and the production of fatty acid, targeting reactive oxygen species (ROS). In brief, several herbals have anti-inflammatory properties by inhibiting pro-inflammatory cytokines and mediators, including mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB). Consistently, improvement of periodontal pocket depth (PPD) and gingival index (GI) was seen in a group given melatonin as an adjunct treatment. In all, this review will highlight host modulation agents regarding periodontitis therapy, plausible mechanisms on how probiotics and metabolites work on periodontal restoration, and their reported studies. Limitations given by published studies will be elaborated, while future directions will be proposed.
• Quantitative Visualization of Two-Phase Acoustic Streaming Emitted from Ultrasonic Scaler
  Takayuki Yamagata; Kota Kato; Naoki Takahashi; Syuhei Mineo; Koichi Tabeta
  Journal of Flow Control, Measurement & Visualization, 10, 03, 87, 97, Scientific Research Publishing, Inc., 08 Jul. 2022, [Peer-reviewed]
  Scientific journal
• Soybean peptide inhibits the biofilm of periodontopathic bacteria via bactericidal activity
  Hnin Yu Lwin; Yukari Aoki-Nonaka; Aoi Matsugishi; Naoki Takahashi; Takumi Hiyoshi; Koichi Tabeta
  Archives of Oral Biology, 142, 105497, 105497, Elsevier BV, Jul. 2022, [Peer-reviewed], [International Magazine]
  English, Scientific journal, 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.
• Laminin Isoforms in Human Dental Pulp: Lymphatic Vessels Express Laminin-332, and Schwann Cell-Associated Laminin-211 Modulates CD163 Expression of M2-like Macrophages.
  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, 29 Dec. 2021, [Peer-reviewed], [International Magazine]
  English, Scientific journal, 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.
• 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, Frontiers Media {SA}, 11 Oct. 2021, [Peer-reviewed]
  Scientific journal
• 歯周病原細菌による消化器がん発症・進行メカニズム
  高橋 直紀; 多部田 康一
  日本歯周病学会会誌, 63, 3, 151, 157, (NPO)日本歯周病学会, Sep. 2021
  Japanese
• Rice bran-derived protein fractions enhance sulforaphane-induced anti-oxidative activity in gingival epithelial cells.
  Shuhei Mineo; Naoki Takahashi; Miki Yamada-Hara; Takahiro Tsuzuno; Yukari Aoki-Nonaka; Koichi Tabeta
  Archives of oral biology, 129, 105215, 105215, 24 Jul. 2021, [Peer-reviewed], [International Magazine]
  English, Scientific journal, 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.
• Ingestion of Porphyromonas gingivalis exacerbates colitis via intestinal epithelial barrier disruption in mice.
  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, Apr. 2021, [Peer-reviewed], [International Magazine]
  English, Scientific journal, 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.
• Effects of Erythromycin on Osteoclasts and Bone Resorption via DEL-1 Induction in Mice
  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, 10, 3, 312, 312, MDPI AG, 17 Mar. 2021, [Peer-reviewed]
  Scientific journal, 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.
• 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, 766170, 766170, 2021, [Peer-reviewed], [International Magazine]
  English, Scientific journal, 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.
• Rice peptide with amino acid substitution inhibits biofilm formation by Porphyromonas gingivalis and Fusobacterium nucleatum.
  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, Jan. 2021, [Peer-reviewed], [International Magazine]
  English, Scientific journal, 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 AmyI-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 AmyI-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, AmyI-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 α-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.
• Erythromycin inhibits neutrophilic inflammation and mucosal disease by upregulating DEL-1.
  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 Ι Alexaki; Triantafyllos Chavakis; Yutaka Terao; George Hajishengallis
  JCI insight, 5, 15, 30 Jun. 2020, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Macrolide antibiotics exert anti-inflammatory effects; however, little is known regarding their immunomodulatory mechanisms. In this study, using two distinct mouse models of mucosal inflammatory disease (LPS-induced acute lung injury and ligature-induced periodontitis), we demonstrated that the anti-inflammatory action of erythromycin (ERM) is mediated through upregulation of the secreted homeostatic protein 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 Del1-deficient mice. By interacting with the growth hormone secretagogue receptor (GHSR) and activating JAK2 in human lung microvascular endothelial cells, ERM induced C/EBPβ-dependent DEL-1 transcription, which was mediated by MAPK p38. Moreover, ERM reversed IL-17-induced inhibition of DEL-1 transcription, in a manner that was not only dependent on JAK2 but also on PI3K/AKT signaling. As DEL-1 levels are severely reduced in inflammatory conditions and with aging, the ability of ERM to upregulate DEL-1 may be a novel approach for the treatment of inflammatory and aging-related diseases.
• Epithelial TRPV1 channels: Expression, function, and pathogenicity in the oral cavity.
  Naoki Takahashi; Takahiro Tsuzuno; Shuhei Mineo; Miki Yamada-Hara; Yukari Aoki-Nonaka; Koichi Tabeta
  Journal of oral biosciences, 62, 3, 235, 241, 13 Jun. 2020, [Peer-reviewed], [International Magazine]
  English, Scientific journal, 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. HIGHLIGH: t: 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.
• Nutritional Supplements and Periodontal Disease Prevention—Current Understanding
  Yukari Aoki-Nonaka; Aoi Matsugishi; Hnin Yu Lwin; Naoki Takahashi; Koichi Tabeta
  Current Oral Health Reports, 7, 2, 154, 164, Springer Science and Business Media LLC, Jun. 2020, [Peer-reviewed]
  Scientific journal
• Lactobacillus-Derived Bioactive Metabolites for the Regulation of Periodontal Health: Evidences to Clinical Setting.
  Benso Sulijaya; Naoki Takahashi; Kazuhisa Yamazaki
  Molecules (Basel, Switzerland), 25, 9, 29 Apr. 2020, [Peer-reviewed], [International Magazine]
  English, Scientific journal, BACKGROUND: Gut microbiota plays a pivotal role in regulating host metabolism that affects the systemic health. To date, several studies have confirmed the fact that microbiota interacts with host, modulating immunity, controlling the homeostasis environment, and maintaining systemic condition. Recent studies have focused on the protective function of poly unsaturated fatty acids, 10-oxo-trans-11-oxadecenoic acid (KetoC) and 10-hydroxy-cis-12-octadecenoic acid (HYA), generated by gut microbiota on periodontal disease. Nevertheless, the mechanism remains unclear as investigations are limited to in vivo and in vitro studies. In this present review, we found that the administration of metabolites, KetoC and HYA, by a probiotic gut microbiota Lactobacillus plantarum from linoleic acid is found to inhibit the oxidation process, possess an antimicrobial function, and prevent the inflammation. These findings suggest the promising use of functional lipids for human health. CONCLUSION: Protective modalities of bioactive metabolites may support periodontal therapy by suppressing bacterial dysbiosis and regulating periodontal homeostasis in the clinical setting.
• M2 Phenotype Macrophages Colocalize with Schwann Cells in Human Dental Pulp
  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, 002203451989495, 002203451989495, {SAGE} Publications, 08 Mar. 2020, [Peer-reviewed]
  English, Scientific journal
• 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
  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, (NPO)日本歯科保存学会, Feb. 2020, [Peer-reviewed]
  Japanese
• A bacterial metabolite induces Nrf2-mediated anti-oxidative responses in gingival epithelial cells by activating the MAPK signaling pathway.
  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, Feb. 2020, [Peer-reviewed], [International Magazine]
  English, Scientific journal, 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.
• Antimicrobial function of the polyunsaturated fatty acid KetoC in an experimental model of periodontitis.
  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, Dec. 2019, [Peer-reviewed], [International Magazine]
  English, Scientific journal, 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 (109 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.
• A peptide derived from rice inhibits alveolar bone resorption via suppression of inflammatory cytokine production.
  Yukari Aoki-Nonaka; Koichi Tabeta; Mai Yokoji; Aoi Matsugishi; Yumi Matsuda; Naoki Takahashi; Benso Sulijaya; Hisanori Domon; Yutaka Terao; Masayuki Taniguchi; Kazuhisa Yamazaki
  Journal of periodontology, 90, 10, 1160, 1169, Oct. 2019, [Peer-reviewed], [International Magazine]
  English, Scientific journal, BACKGROUND: Periodontitis is an inflammatory disease that results in alveolar bone resorption due to inflammatory cytokine production induced by bacterial antigens such as lipopolysaccharides (LPS). Here, the preventive effect of the Amyl-1-18 peptide derived from rice in an experimental model of periodontitis and the effect on the anti-inflammatory response were assessed. METHODS: Alveolar bone resorption, gene transcription of proinflammatory cytokines in the gingiva, and the endotoxin level in the oral cavity were evaluated after oral administration of the Amyl-1-18 peptide for 14 days using a ligature-induced periodontitis model in mice. Additionally, murine macrophages were incubated with LPS of Escherichia coli or Porphyromonas gingivalis in the presence of Amyl-1-18 to analyze the suppressive effects of Amyl-1-18 on the cell signaling pathways associated with proinflammatory cytokine production, including inflammasome activities. RESULTS: Oral administration of Amyl-1-18 suppressed alveolar bone resorption and gene transcription of interleukin (il)6 in the gingiva of the periodontitis model, and decreased endotoxin levels in the oral cavity, suggesting modulation of periodontal inflammation by inhibition of endotoxin activities in vivo. Also, Amyl-1-18 suppressed IL-6 production induced by LPS and recombinant IL-1β in macrophages in vitro but had no effect on inflammasome activity. CONCLUSIONS: The Amyl-1-18 peptide from rice inhibited alveolar bone destruction in mouse periodontitis model via suppressing inflammatory cytokine production induced by LPS. It was suggested that Amyl-1-18 peptide has anti-inflammatory property against LPS, not only by neutralization of LPS and subsequent inhibition of nuclear factor-κB signaling but also by inhibition of the IL-1R-related signaling cascade.
• Host modulation therapy using anti-inflammatory and antioxidant agents in periodontitis: A review to a clinical translation.
  Benso Sulijaya; Naoki Takahashi; Kazuhisa Yamazaki
  Archives of oral biology, 105, 72, 80, Sep. 2019, [Peer-reviewed], [International Magazine]
  English, Scientific journal, OBJECTIVE: To highlight the shifting paradigm of periodontitis, describe mechanism of periodontal bone destruction, and propose an updated host modulation therapy (HMT) strategy. To add further clinical relevance, related studies investigating the efficacy of several HMT agents in periodontitis will be discussed. DESIGN: Literature searches were conducted from articles published in PubMed using keywords "periodontal disease AND periodontitis AND host modulation therapy AND anti-inflammatory AND antioxidant", and then the findings were comprehensively summarized and elaborated. RESULT: Accumulating evidence indicates that periodontitis is no longer defined solely as a pathogen-induced disease; rather, it is now recognized as a consequence of uncontrolled immune response and oxidative stress leading to periodontal tissue damage. Although periodontopathic bacteria initiate the disease, inflammation and oxidative stress were reported to be the main causes for the severity of tissue destruction. Thus, since the concept of periodontitis has shifted, our approach to its management needs to be adjusted to accommodate the latest paradigm. Nowadays, the modulation of inflammation and oxidative stress is considered a target of HMT. HMT agents, such as probiotics, anti-inflammatory drugs, anti-chemokines, lipid mediators, and bio-active fatty acids, have been extensively investigated for their remarkable functions in modulating the immune response and providing antioxidant effects. CONCLUSION: Findings from in vitro, in vivo, and human studies frequently demonstrate positive association by the administration of HMT in periodontitis. HMT strategy targeted on anti-inflammatory and antioxidant in periodontitis might serve as an excellent therapeutic approach to reach the level of clinical benefit.
• Nutrition as Adjunct Therapy in Periodontal Disease Management.
  Sulijaya B; Takahashi N; Yamazaki K; Yamazaki K
  Current Oral Health Reports., 6, 2, 61, 69, Springer Science and Business Media LLC, Jun. 2019, [Peer-reviewed]
  English, Scientific journal
• Aggregatibacter actinomycetemcomitans induces detachment and death of human gingival epithelial cells and fibroblasts via elastase release following leukotoxin-dependent neutrophil lysis.
  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, Mar. 2019, [Peer-reviewed], [International Magazine]
  English, Scientific journal, 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.
• Corrigendum to "Indirect regulation of PCSK9 gene in inflammatory response by Porphyromonas gingivalis infection" [Heliyon 5 (1) (January 2019) e01111].
  Yokoji-Takeuchi M; Tabeta K; Takahashi N; Arimatsu K; Miyazawa H; Matsuda-Matsukawa Y; Sato K; Yamada M; Yamazaki K
  Heliyon, 5, 2, e01210, Feb. 2019, [Peer-reviewed]
  English
• Indirect regulation of PCSK9 gene in inflammatory response by Porphyromonas gingivalis infection.
  Mai Yokoji-Takeuchi; Koichi Tabeta; Naoki Takahashi; Kei Arimatsu; Haruna Miyazawa; Yumi Matsuda-Matsukawa; Keisuke Sato; Miki Yamada; Kazuhisa Yamazaki
  Heliyon, 5, 1, e01111, Jan. 2019, [Peer-reviewed], [International Magazine]
  English, Scientific journal, 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-α 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-β-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.
• β2-Microglobulin and Neutrophil Gelatinase-Associated Lipocalin, Potential Novel Urine Biomarkers in Periodontitis: A Cross-Sectional Study in Japanese.
  Mayuka Nakajima; Michihiro Hosojima; Koichi Tabeta; Sayuri Miyauchi; Miki Yamada-Hara; Naoki Takahashi; Haruna Miyazawa; Yumi Matsuda-Matsukawa; Keisuke Sato; Noriko Sugita; Yasutaka Komatsu; Tomomi Ishikawa; Kazuhiro Akiishi; Kazuhisa Yamazaki; Kiminori Kato; Akihiko Saito; Hiromasa Yoshie
  International journal of dentistry, 2019, 1394678, 1394678, 2019, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Objectives: Several serum biomarkers have been reported to increase in periodontitis patients as possible mediators linking periodontal inflammation to systemic diseases. However, the relationship between periodontitis and urine biomarkers is still unclear. The aim of this cross-sectional study was to investigate potential urine biomarkers of periodontitis in a Japanese population. Materials and Methods: This study included 108 male subjects, and microbiological and clinical parameters were evaluated as a periodontitis marker. The correlation between nine urine biomarkers (typically used to diagnose kidney disease) and periodontal parameters was analyzed. Based on the findings, β2-microglobulin (β2-MG) and neutrophil gelatinase-associated lipocalin (NGAL) were selected for comparison and multivariate regression analysis, and the Kruskal-Wallis test followed by Bonferroni correction was used to identify differences in their concentrations between the three periodontitis groups (severe, moderate, and no/mild periodontitis). Results: β2-MG and NGAL exhibited a significant correlation with clinical parameters of periodontitis. The prevalence of clinical parameters such as bleeding on probing and number of sites with probing depth (PD) ≥ 6 mm were greater in the β2-MG high group (≥300 μg/g creatinine) than in the normal group (P=0.017 and 0.019, respectively). Multivariate regression analysis indicated that the number of sites with PD ≥ 6 mm was independently associated with urine β2-MG. Moreover, the number of sites with the clinical attachment level (CAL) ≥ 6 mm was greater in the NGAL high group (highest quartile) (P=0.041). Multivariate regression analysis showed that the number of sites with CAL ≥ 6 mm was associated independently with urine NGAL. Finally, β2-MG was significantly higher in the severe periodontitis subjects compared to the no/mild periodontitis subjects. Conclusion: The significant association between urine β2-MG or NGAL and periodontitis was revealed. These biomarkers can potentially be used to screen for or diagnose periodontitis. This trial is registered with the UMIN Clinical Trials Registry UMIN000013485.
• Gingival epithelial barrier: regulation by beneficial and harmful microbes.
  Naoki Takahashi; Benso Sulijaya; Miki Yamada-Hara; Takahiro Tsuzuno; Koichi Tabeta; Kazuhisa Yamazaki
  Tissue barriers, 7, 3, e1651158, 2019, [Peer-reviewed], [International Magazine]
  English, Scientific journal, 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.
• A bacterial metabolite ameliorates periodontal pathogen-induced gingival epithelial barrier disruption via GPR40 signaling
  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, Nature Publishing Group, 01 Dec. 2018, [Peer-reviewed]
  English, Scientific journal
• Increased serum PCSK9, a potential biomarker to screen for periodontitis, and decreased total bilirubin associated with probing depth in a Japanese community survey
  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, Blackwell Munksgaard, 01 Jun. 2018, [Peer-reviewed]
  English, Scientific journal
• The anti-inflammatory effect of 10-oxo-trans-11-octadecenoic acid (KetoC) on RAW 264.7 cells stimulated with Porphyromonas gingivalis lipopolysaccharide.
  Sulijaya B; Takahashi N; Yamada M; Yokoji M; Sato K; Aoki-Nonaka Y; Nakajima T; Kishino S; Ogawa J; Yamazaki K
  Journal of periodontal research, 53, 5, 777, 784, Wiley, Apr. 2018, [Peer-reviewed]
  Scientific journal
• Aggravation of collagen-induced arthritis by orally administered Porphyromonas gingivalis through modulation of the gut microbiota and gut immune system
  Keisuke Sato; Naoki Takahashi; Tamotsu Kato; Yumi Matsuda; Mai Yokoji; Miki Yamada; Takako Nakajima; Naoki Kondo; Naoto Endo; Reiko Yamamoto; Yuichiro Noiri; Hiroshi Ohno; Kazuhisa Yamazaki
  Scientific Reports, 7, 1, 6955, Nature Publishing Group, 01 Dec. 2017, [Peer-reviewed]
  English, Scientific journal
• The TRPA1 ion channel is expressed in CD4+T cells and restrains T-cell-mediated colitis through inhibition of TRPV1
  Samuel Bertin; Yukari Aoki-Nonaka; Jihyung Lee; Petrus R. de Jong; Peter Kim; Tiffany Han; Timothy Yu; Keith To; Naoki Takahashi; Brigid S. Boland; John T. Chang; Samuel B. Ho; Scott Herdman; Maripat Corr; Alessandra Franco; Sonia Sharma; Hui Dong; Armen N. Akopian; Eyal Raz
  GUT, 66, 9, 1584, 1596, Sep. 2017, [Peer-reviewed]
  English, Scientific journal
• An ENU-induced splice site mutation of mouse Col1a1 causing recessive osteogenesis imperfecta and revealing a novel splicing rescue
  Tabeta, K.; Du, X.; Arimatsu, K.; Yokoji, M.; Takahashi, N.; Amizuka, N.; Hasegawa, T.; Crozat, K.; Maekawa, T.; Miyauchi, S.; Matsuda, Y.; Ida, T.; Kaku, M.; Hoebe, K.; Ohno, K.; Yoshie, H.; Yamazaki, K.; Moresco, E.M.Y.; Beutler, B.
  Scientific Reports, 7, 1, 11717, 2017, [Peer-reviewed]
  Scientific journal
• Ligature-induced periodontitis in mice induces elevated levels of circulating interleukin-6 but shows only weak effects on adipose and liver tissues
  Y. Matsuda; T. Kato; N. Takahashi; M. Nakajima; K. Arimatsu; T. Minagawa; K. Sato; H. Ohno; K. Yamazaki
  JOURNAL OF PERIODONTAL RESEARCH, 51, 5, 639, 646, Oct. 2016, [Peer-reviewed]
  English, Scientific journal
• Brazilian propolis mitigates impaired glucose and lipid metabolism in experimental periodontitis in mice
  Mayuka Nakajima; Kei Arimatsu; Takayoshi Minagawa; Yumi Matsuda; Keisuke Sato; Naoki Takahashi; Takako Nakajima; Kazuhisa Yamazaki
  BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE, 16, 1, 329, Aug. 2016, [Peer-reviewed]
  English, Scientific journal
• Neuronal TRPV1 activation regulates alveolar bone resorption by suppressing osteoclastogenesis via CGRP
  Naoki Takahashi; Yumi Matsuda; Keisuke Sato; Petrus R. de Jong; Samuel Bertin; Koichi Tabeta; Kazuhisa Yamazaki
  SCIENTIFIC REPORTS, 6, 29294, Jul. 2016, [Peer-reviewed]
  English, Scientific journal
• ERK5 signalling rescues intestinal epithelial turnover and tumour cell proliferation upon ERK1/2 abrogation
  Petrus R. de Jong; Koji Taniguchi; Alexandra R. Harris; Samuel Bertin; Naoki Takahashi; Jen Duong; Alejandro D. Campos; Garth Powis; Maripat Corr; Michael Karin; Eyal Raz
  NATURE COMMUNICATIONS, 7, 11551, May 2016, [Peer-reviewed]
  English, Scientific journal
• Resveratrol suppresses the inflammatory responses of human gingival epithelial cells in a SIRT1 independent manner
  T. Minagawa; T. Okui; N. Takahashi; T. Nakajima; K. Tabeta; S. Murakami; K. Yamazaki
  JOURNAL OF PERIODONTAL RESEARCH, 50, 5, 586, 593, Oct. 2015, [Peer-reviewed]
  English, Scientific journal
• Oral Administration of P. gingivalis Induces Dysbiosis of Gut Microbiota and Impaired Barrier Function Leading to Dissemination of Enterobacteria to the Liver
  Mayuka Nakajima; Kei Arimatsu; Tamotsu Kato; Yumi Matsuda; Takayoshi Minagawa; Naoki Takahashi; Hiroshi Ohno; Kazuhisa Yamazaki
  PLOS ONE, 10, 7, e0134234, Jul. 2015, [Peer-reviewed]
  English, Scientific journal
• TRPM8 on mucosal sensory nerves regulates colitogenic responses by innate immune cells via CGRP
  P. R. de Jong; N. Takahashi; M. Peiris; S. Bertin; J. Lee; M. G. Gareau; A. Paniagua; A. R. Harris; D. S. Herdman; M. Corr; L. A. Blackshaw; E. Raz
  MUCOSAL IMMUNOLOGY, 8, 3, 491, 504, May 2015, [Peer-reviewed]
  English, Scientific journal
• Epithelial TRPV1 Signaling Accelerates Gingival Epithelial Cell Proliferation
  N. Takahashi; Y. Matsuda; H. Yamada; K. Tabeta; T. Nakajima; S. Murakami; K. Yamazaki
  JOURNAL OF DENTAL RESEARCH, 93, 11, 1141, 1147, Nov. 2014, [Peer-reviewed]
  English, Scientific journal
• Ion channel TRPV1-dependent activation of PTP1B suppresses EGFR-associated intestinal tumorigenesis
  Petrus R. de Jong; Naoki Takahashi; Alexandra R. Harris; Jihyung Lee; Samuel Bertin; James Jeffries; Michael Jung; Jen Duong; Amy I. Triano; Jongdae Lee; Yaron Niv; David S. Herdman; Koji Taniguchi; Chang-Whan Kim; Hui Dong; Lars Eckmann; Stephanie M. Stanford; Nunzio Bottini; Maripat Corr; Eyal Raz
  JOURNAL OF CLINICAL INVESTIGATION, 124, 9, 3793, 3806, Sep. 2014, [Peer-reviewed]
  English, Scientific journal
• Relationship between serum antibody titres to Porphyromonas gingivalis and hs-CRP levels as inflammatory markers of periodontitis
  Hirotaka Miyashita; Tomoyuki Honda; Tomoki Maekawa; Naoki Takahashi; Yukari Aoki; Takako Nakajima; Koichi Tabeta; Kazuhisa Yamazaki
  ARCHIVES OF ORAL BIOLOGY, 57, 6, 820, 829, Jun. 2012, [Peer-reviewed]
  English, Scientific journal
• Porphyromonas gingivalis lipopolysaccharide induces miR-146a without altering the production of inflammatory cytokines
  Tomoyuki Honda; Naoki Takahashi; Sayuri Miyauchi; Kazuhisa Yamazaki
  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 420, 4, 918, 925, Apr. 2012, [Peer-reviewed]
  English, Scientific journal
• Effect of interleukin-17 on the expression of chemokines in gingival epithelial cells
  Naoki Takahashi; Takafumi Okui; Koichi Tabeta; Kazuhisa Yamazaki
  EUROPEAN JOURNAL OF ORAL SCIENCES, 119, 5, 339, 344, Oct. 2011, [Peer-reviewed]
  English, Scientific journal
• Chronic Oral Infection with Porphyromonas gingivalis Accelerates Atheroma Formation by Shifting the Lipid Profile
  Tomoki Maekawa; Naoki Takahashi; Koichi Tabeta; Yukari Aoki; Hirotaka Miyashita; Sayuri Miyauchi; Haruna Miyazawa; Takako Nakajima; Kazuhisa Yamazaki
  PLOS ONE, 6, 5, e20240, May 2011, [Peer-reviewed]
  English, Scientific journal
• Elevated Antibody Titers to Porphyromonas gingivalis as a Possible Predictor of Ischemic Vascular Disease: Results from the Tokamachi-Nakasato Cohort Study
  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, [Peer-reviewed]
  English, Scientific journal
• Interleukin-1 receptor-associated kinase-M in gingival epithelial cells attenuates the inflammatory response elicited by Porphyromonas gingivalis
  N. Takahashi; T. Honda; H. Domon; T. Nakajima; K. Tabeta; K. Yamazaki
  JOURNAL OF PERIODONTAL RESEARCH, 45, 4, 512, 519, Aug. 2010, [Peer-reviewed]
  English, Scientific journal
• Periodontitis-associated up-regulation of systemic inflammatory mediator level may increase the risk of coronary heart disease
  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, Feb. 2010, [Peer-reviewed]
  English, Scientific journal
• 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
  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, [Peer-reviewed]
  English, Scientific journal
• Up-regulation of the endoplasmic reticulum stress-response in periodontal disease
  Hisanori Domon; Naoki Takahashi; Tomoyuki Honda; Takako Nakajima; Koichi Tabeta; Yoshimitsu Abiko; Kazuhisa Yamazaki
  CLINICA CHIMICA ACTA, 401, 1-2, 134, 140, Mar. 2009, [Peer-reviewed]
  English, Scientific journal
• Elevated expression of IL-17 and IL-12 genes in chronic inflammatory periodontal disease
  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, 395, 1-2, 137, 141, Sep. 2008, [Peer-reviewed]
  English, Scientific journal
• 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, (公社)日本歯科医師会, Aug. 2008
  Japanese

• 人工足場材料に対するヒト培養骨膜細胞の生物学的応答性の解析
  植田 優太; 高橋 直紀; 都野 隆博; 永田 昌毅; 本杉 駿弥; 山田 葵; Tran Diep; Tran Khoa; 小林 航大; 馬場 水彩妃; 原 実生; 多部田 康一, 日本歯周病学会会誌, 67, 秋季特別, 139, 139, Oct. 2025
  (NPO)日本歯周病学会, Japanese
• 歯周病原細菌の気管内噴霧投与による肺炎誘導能の検討
  馬場 水彩妃; 原 実生; 都野 隆博; 峯尾 修平; 本杉 駿弥; 植田 優太; 小林 航大; 高橋 直紀; 多部田 康一, 日本歯周病学会会誌, 67, 秋季特別, 154, 154, Oct. 2025
  (NPO)日本歯周病学会, Japanese
• セメント質過形成を伴う広汎型重度慢性歯周炎患者に包括的歯周治療を行った一症例
  高橋 直紀; 多部田 康一, 日本歯周病学会会誌, 66, 春季特別, 147, 147, Apr. 2024
  (NPO)日本歯周病学会, Japanese
• 歯周炎患者におけるSRPおよびEr:YAGレーザー応用による歯石除去時の生体応答の検討
  保苅 崇大; 両角 俊哉; 野中 由香莉; 濃野 要; 小松 康高; 杉原 俊太郎; 山本 裕子; 宮沢 春菜; 鎗田 将史; 新井 恭子; 佐藤 友則; 高橋 直紀; 小牧 基浩; 多部田 康一, 日本歯周病学会会誌, 66, 春季特別, 140, 140, Apr. 2024
  (NPO)日本歯周病学会, Japanese
• Porphyromonas gingivalisが実験的大腸がんモデルマウスに及ぼす影響とそのメカニズムの解析
  本杉駿弥; 高橋直紀; 都野隆博; 峯尾修平; DIEP Tran Thi Thuy; 植田優太; 多部田康一, 新潟歯学会雑誌, 54, 2, 2024
• フェルラ酸によるP.gingivalisバイオフィルム阻害作用の検討
  安藤大樹; LWIN Hnin Yu; 野中由香莉; 松岸葵; 湊裕佳子; 割田悠子; 高橋直紀; 多部田康一, 新潟歯学会雑誌, 54, 2, 2024
• Optical Coherence Tomographyを用いた培養骨膜シートの厚みと骨形成能の関連性の検討
  植田優太; 高橋直紀; 都野隆博; 永田昌毅; 本杉駿弥; 山田葵; TRAN Diep; 泉健次; 多部田康一, 日本歯周病学会会誌(Web), 66, 2024
• 歯周炎患者におけるSRPおよびEr:YAGレーザー応用による歯石除去時の生体応答の検討
  保苅崇大; 両角俊哉; 両角俊哉; 野中由香莉; 濃野要; 小松康高; 杉原俊太郎; 山本裕子; 宮沢春菜; 鎗田将史; 新井恭子; 佐藤友則; 高橋直紀; 小牧基浩; 多部田康一, 日本歯周病学会会誌(Web), 66, 2024
• 顎骨由来培養骨膜細胞のheterogeneity解析と骨形成能への関与
  高橋直紀; 都野隆博; 永田昌毅; 植田優太; 本杉駿弥; 山田葵; TRAN Diep; 中田光; 多部田康一, 日本再生医療学会総会(Web), 23rd, 2024
• 【歯周病の新分類対応 アップデート・ザ・ペリオ～超高齢社会へのアプローチ～】(2章)歯周基本治療 超高齢社会における高齢者・有病者への対応
  高橋 直紀, DENTAL DIAMOND, 48, 6, 84, 85, Apr. 2023
  (株)デンタルダイヤモンド社, Japanese
• ヒト培養骨膜細胞におけるin vitro造腫瘍性の検討
  都野隆博; 都野隆博; 永田昌毅; 高橋直紀; 多部田康一; 中田光, 日本再生医療学会総会(Web), 22nd, 2023
• ヒト歯周炎組織におけるTRPV1発現とその制御機構の解析
  水口舞依; 高橋直紀; 本杉駿弥; 峯尾修平; 都野隆博; 多部田康一, 日本歯周病学会会誌(Web), 65, 2023
• Prevention of aerosol diffusion generated from ultrasonic scaler by suction devices
  高橋直紀; 山縣貴幸; 峯尾修平; 加藤光太; 多部田康一, 日本歯科保存学会学術大会プログラムおよび講演抄録集(Web), 155th, 2021
• 超音波スケーラーから発生するエアロゾル特性と口腔内外吸引装置の拡散防止効果 2)-小粒径エアロゾルの粒径分布とその吸引効果の検討-
  高橋直紀; 峯尾修平; 多部田康一, 日本歯周病学会会誌(Web), 63, 2021
• 超音波スケーラーから発生するエアロゾル特性と口腔内外吸引装置による拡散防止効果 1)-感水試験紙を用いた飛散方向および距離の検討-
  峯尾修平; 高橋直紀; 多部田康一, 日本歯周病学会会誌(Web), 63, 2021
• Characteristics of Aerosols Generated from an Ultrasonic Scaling Device and Prevention of Diffusion by Intra- and Extraoral Suction Devices
  高橋直紀; 山縣貴幸; 峯尾修平; 加藤光太; 多部田康一, 日本歯周病学会会誌(Web), 63, 4, 2021
• Periodontal disease exacerbates NAFLD via dysbiosis of gut microbiota
  山崎恭子; 山崎恭子; 中島麻由佳; 竹内麻衣; 原実生; 都野隆博; 都野隆博; 松岸葵; 松岸葵; 松川由実; 佐藤圭祐; 高橋直紀; 多部田康一; 坪井裕理; 菊地淳; 加藤完; 大野博司; 山崎和久, 腸内細菌学雑誌, 34, 2, 2020
• 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(Web), 62, 2020
• ヒト歯肉上皮細胞における抗酸化ストレス応答を増強する食物由来ペプチドの探索
  峯尾修平; 高橋直紀; 都野隆博; 都野隆博; 野中由香莉; 多部田康一, 新潟歯学会雑誌, 50, 2, 116, 117, 2020
  新潟歯学会, Japanese
• Porphyromonas gingivalis経口投与は腸内細菌の変化を介してNAFLD病態に影響を与える
  山崎恭子; 山崎恭子; 中島麻由佳; 竹内麻衣; 原実生; 原実生; 都野隆博; 都野隆博; 松岸葵; 松岸葵; 松川由実; 佐藤圭祐; 高橋直紀; 多部田康一; 山崎和久, 新潟歯学会雑誌, 50, 2, 116, 116, 2020
  新潟歯学会, Japanese
• Porphyromonas gingivalisがNASH病態形成に与える影響の解析
  山崎恭子; 山崎恭子; 中島麻由佳; 中島麻由佳; 竹内麻衣; 竹内麻衣; 原(山田)実生; 原(山田)実生; 都野隆博; 都野隆博; 松岸葵; 松岸葵; 松川(松田; 由美; 佐藤圭祐; 高橋直紀; 多部田康一; 山崎和久, 日本歯周病学会会誌(Web), 61, 春季特別, 125, 125, 01 May 2019
  (NPO)日本歯周病学会, Japanese
• 歯周炎患者における腸内細菌叢の解析
  山崎恭子; 山崎恭子; 中島貴子; 宮沢春菜; 宮沢春菜; 伊藤晴江; 佐藤圭祐; 佐藤圭祐; 原実生; 原実生; 竹内麻衣; 竹内麻衣; 高橋直紀; 森田英利; 須田亙; 服部正平; 山崎和久, 腸内細菌学雑誌, 33, 2, 116, 116, Apr. 2019
  (公財)日本ビフィズス菌センター, Japanese
• 歯周炎患者唾液細菌叢が腸内細菌叢に与える影響の解析
  山崎恭子; 山崎恭子; 中島貴子; 宮澤春菜; 佐藤圭祐; 高橋直紀; 原実生; 原実生; 竹内麻衣; 山崎和久, 日本歯周病学会会誌(Web), 61, 2019
• Aggregatibacter actinomycetemcomitansによる歯周炎重症化メカニズムの解析
  日吉巧; 日吉巧; 土門久哲; 土門久哲; 前川知樹; 前川知樹; 前川知樹; 永井康介; 田村光; 田村光; 田村光; 高橋直紀; 吉田明弘; 寺尾豊; 多部田康一, 日本歯周病学会会誌(Web), 61, 2019
• 歯周組織再生療法および歯周形成外科治療を行った広汎型重度慢性歯周炎患者の一症例
  高橋直紀; 多部田康一, 日本歯周病学会会誌(Web), 61, 2019
• Porphyromonas gingivalis口腔投与がDSS誘導性実験的腸炎におよぼす影響の解析
  都野隆博; 都野隆博; 高橋直紀; 竹内麻衣; 原実生; 中島麻由佳; 多部田康一; 山崎和久, 日本歯周病学会会誌(Web), 61, 2019
• 実験的腸炎モデルマウスにおけるPorphyromonas gingivalisによる腸炎増悪のメカニズムの解析
  都野隆博; 都野隆博; 高橋直紀; 竹内麻衣; 原実生; 多部田康一; 山崎和久, 日本歯周病学会会誌(Web), 61, 2019
• 下顎前歯歯肉退縮に対して両側歯冠乳頭弁移動改良法を用いて根面被覆を行った1症例
  高橋直紀; 都野隆博; 竹内麻衣; 多部田康一, 日本歯科保存学会学術大会プログラムおよび講演抄録集(Web), 150th, 2019
• Porphyromonas gingivalisがNASH病態を進行させるメカニズムの解析
  山崎恭子; 山崎恭子; 中島麻由佳; 竹内麻衣; 原実生; 原実生; 都野隆博; 都野隆博; 松岸葵; 松岸葵; 松川由実; 佐藤圭祐; 高橋直紀; 多部田康一; 山崎和久, 日本歯科保存学会学術大会プログラムおよび講演抄録集(Web), 151st, 2019
• Porphyromonas gingivalisが腸管上皮バリア機能へ及ぼす影響の解析
  都野隆博; 都野隆博; 高橋直紀; 竹内麻衣; 原実生; 中島麻由佳; 多部田康一; 山崎和久, 日本歯科保存学会学術大会プログラムおよび講演抄録集(Web), 150th, 2019
• P.gingivalis感染におけるPCSK9産生の誘導機構
  横地麻衣; 横地麻衣; 多部田康一; 高橋直紀; 高橋直紀; 宮澤春菜; 松田由実; 佐藤圭祐; 山田実生; 山田実生; SULIJAYA Benso; SULIJAYA Benso; 山崎和久, 新潟歯学会雑誌, 48, 2, 110, 110, 15 Dec. 2018
  新潟歯学会, Japanese
• 口腔細菌の脂質代謝に由来する機能性脂肪酸HYAは歯肉上皮バリア機能を強化することで歯周炎の発症を抑制する
  山田実生; 山田実生; 高橋直紀; 高橋直紀; 松田由実; 佐藤圭祐; 横地麻衣; 横地麻衣; SULIJAYA Benso; SULIJAYA Benso; 多部田康一; 山崎和久, 新潟歯学会雑誌, 48, 2, 110‐111, 111, 15 Dec. 2018
  新潟歯学会, Japanese
• 広汎型重度慢性歯周炎患者において歯周組織再生療法と局所矯正治療により改善を認めた一症例
  両角俊哉; 両角俊哉; 保苅崇大; 野村隆; 久保田健彦; 小松康高; 高橋直紀; 奥田一博; 三辺正人; 吉江弘正; 吉江弘正, 日本歯周病学会会誌(Web), 60, 春季特別, 150, 150, 01 May 2018
  (NPO)日本歯周病学会, Japanese
• 広汎型重度慢性歯周炎患者において歯周組織再生療法と局所矯正治療により改善を認めた一症例
  両角 俊哉; 保苅 崇大; 野村 隆; 久保田 健彦; 小松 康高; 高橋 直紀; 奥田 一博; 三辺 正人; 吉江 弘正, 日本歯周病学会会誌, 60, 春季特別, 150, 150, May 2018
  (NPO)日本歯周病学会, Japanese
• Aggregatibacter actinomycetemcomitansによる歯周組織破壊メカニズムの解析
  日吉 巧; 土門 久哲; 永井 康介; 前川 知樹; 高橋 直紀; 米澤 大輔; 田村 光; 吉田 明弘; 寺尾 豊; 吉江 弘正, 日本歯周病学会会誌, 60, 春季特別, 128, 128, May 2018
  (NPO)日本歯周病学会, Japanese
• 新規機能性脂肪酸の歯肉上皮細胞における抗酸化ストレス作用の検討
  横地麻衣; 横地麻衣; 高橋直紀; 高橋直紀; 高橋直紀; 松田由実; 松田由実; 山田実生; 山田実生; SULIJAYA Benso; SULIJAYA Benso; 多部田康一; 多部田康一; 中島貴子; 山崎和久, 日本歯周病学会会誌(Web), 60, 2018
• 新規機能性脂肪酸の歯肉上皮細胞における抗酸化ストレス作用の検討
  横地麻衣; 横地麻衣; 高橋直紀; 高橋直紀; 松田由実; 山田実生; 山田実生; SULIJAYA Benso; SULIJAYA Benso; 多部田康一; 山崎和久, 新潟歯学会雑誌, 48, 2, 2018
• Porphyromonas gingivalis口腔投与のコラーゲン誘導性関節炎増悪メカニズムの解析
  佐藤圭祐; 高橋直紀; 中島麻由佳; 松田由実; 山田実生; 横地麻衣; 中島貴子; 山崎和久, 日本歯科保存学会学術大会プログラムおよび講演抄録集(Web), 147th, 56 (WEB ONLY), 56, 25 Oct. 2017
  (NPO)日本歯科保存学会, Japanese
• 歯周炎患者腸内細菌叢における口腔内由来細菌の比率
  山崎恭子; 中島貴子; 高橋直紀; 宮澤春菜; 皆川高嘉; 佐藤圭祐; 伊藤晴江; 山崎和久, 日本歯科保存学会学術大会プログラムおよび講演抄録集(Web), 147th, 88 (WEB ONLY), 88, 25 Oct. 2017
  (NPO)日本歯科保存学会, Japanese
• 文献と臨床の橋わたし 口腔と全身の相互作用(第3回)口腔 : 腸管連関から考える歯周病と全身の関連
  山崎 和久; 高橋 直紀; 中島 貴子, 日本歯科評論, 77, 9, 161, 164, Sep. 2017
  ヒョーロン・パブリッシャーズ, Japanese
• 歯周炎患者における腸内細菌叢の解析
  中島貴子; 中島貴子; 高橋直紀; 高橋直紀; 高橋直紀; 皆川高嘉; 皆川高嘉; 宮沢春菜; 宮沢春菜; 伊藤晴江; 伊藤晴江; 佐藤圭祐; 佐藤圭祐; 山崎和久, 日本歯周病学会会誌(Web), 59, 春季特別, 129, 129, 18 Apr. 2017
  (NPO)日本歯周病学会, Japanese
• Porphyromonas gingivalis口腔投与のコラーゲン誘導性関節炎増悪メカニズムの解析
  佐藤圭祐; 佐藤圭祐; 高橋直紀; 高橋直紀; 中島麻由佳; 中島麻由佳; 松田由実; 松田由実; 山田実生; 山田実生; 横地麻衣; 横地麻衣; 多部田康一; 中島貴子; 山崎和久, 新潟歯学会雑誌, 46, 2, 116, 116, 20 Dec. 2016
  新潟歯学会, Japanese
• 細菌抗原によるPCSK9産生の誘導機構
  横地麻衣; 横地麻衣; 多部田康一; 宮澤春菜; 野中由香莉; 高橋直紀; 松田由実; 松田由実; 佐藤圭祐; 佐藤圭祐; 山田実生; 山田実生; 伊藤晴江; 中島貴子; 山崎和久, 日本歯科保存学会学術大会プログラムおよび講演抄録集(Web), 145th, ROMBUNNO.P94 (WEB ONLY), 145, 13 Oct. 2016
  (NPO)日本歯科保存学会, Japanese
• 口腔細菌脂質代謝に由来する機能性脂肪酸HYAは歯肉上皮バリア機能の低下を抑制する
  山田実生; 山田実生; 高橋直紀; 高橋直紀; 高橋直紀; 松田由実; 松田由実; 佐藤圭祐; 佐藤圭祐; 横地麻衣; 横地麻衣; 多部田康一; 多部田康一; 中島貴子; 山崎和久, 日本歯周病学会会誌(Web), 58, 112, 09 Sep. 2016
  Japanese
• カプサイシン受容体TRPV1の活性化が歯槽骨吸収におよぼす影響
  高橋直紀; 高橋直紀; 松田由実; 松田由実; 佐藤圭祐; 佐藤圭祐; 多部田康一; 山崎和久; 前田健康, 日本歯周病学会会誌(Web), 58, 124, 09 Sep. 2016
  Japanese
• 実験的歯周炎モデルマウスの歯槽骨吸収におけるTRPV1チャネルタンパクの関与
  高橋直紀; 松田由実; 佐藤圭祐; 多部田康一; 前田健康; 山崎和久, 日本歯科医師会雑誌, 69, 5, 487, 487, 10 Aug. 2016
  (公社)日本歯科医師会, Japanese
• Periodontopathic bacteria increases the risk of rheumatoid arthritis by affecting gut immune system
  K. Sato; N. Takahashi; M. Nakajima; Y. Matsuda; M. Yamada; M. Yokoji; T. Kato; H. Ohno; K. Yamazaki, EUROPEAN JOURNAL OF IMMUNOLOGY, 46, 640, 640, Aug. 2016
  English, Summary international conference
• 結紮誘導歯周炎モデルマウスにおける全身への影響とそのメカニズムの解析
  松田由実; 松田由実; 高橋直紀; 高橋直紀; 中島麻由佳; 中島麻由佳; 佐藤圭祐; 佐藤圭祐; 多部田康一; 中島貴子; 山崎和久, 新潟歯学会雑誌, 46, 1, 48, 48, 20 Jul. 2016
  新潟歯学会, Japanese
• 外傷性咬合により誘導される歯槽骨吸収に対するResveratrolの影響
  松田由実; 松田由実; 皆川高嘉; 皆川高嘉; 高橋直紀; 高橋直紀; 佐藤圭祐; 佐藤圭祐; 横地麻衣; 横地麻衣; 山田実生; 山田実生; 多部田康一; 中島貴子; 山崎和久, 日本歯科保存学会学術大会プログラムおよび講演抄録集(Web), 144th, A7 (WEB ONLY), 27, 01 Jun. 2016
  (NPO)日本歯科保存学会, Japanese
• TRPV1受容体の活性化は神経ペプチド産生を介して歯槽骨吸収を抑制する
  高橋直紀; 高橋直紀; 高橋直紀; 松田由実; 松田由実; 佐藤圭祐; 佐藤圭祐; 多部田康一; 吉江弘正; 山崎和久, 日本歯科保存学会学術大会プログラムおよび講演抄録集(Web), 144th, P7 (WEB ONLY), 65, 01 Jun. 2016
  (NPO)日本歯科保存学会, Japanese
• Porphyromonas gingivalisバイオフィルムは人工胃液耐性を有する
  山本 れいこ; 野杁 由一郎; 高橋 直紀; 山崎 和久; 恵比須 繁之; 林 美加子, BACTERIAL ADHERENCE & BIOFILM, 29, 25, 30, May 2016
  日本バイオフィルム学会, Japanese
• Porphyromonas gingivalis口腔投与のコラーゲン誘導性関節炎増悪メカニズムの解析
  佐藤圭祐; 佐藤圭祐; 高橋直紀; 高橋直紀; 中島麻由佳; 中島麻由佳; 松田由実; 松田由実; 山田実生; 山田実生; 横地麻衣; 横地麻衣; 多部田康一; 中島貴子; 山崎和久, 日本歯周病学会会誌(Web), 58, 春季特別, 116, 116, 18 Apr. 2016
  (NPO)日本歯周病学会, Japanese
• う蝕抑制効果をもつマウスガード材料の開発
  白井 友恵; 荒井 良明; 高橋 直紀; 高嶋 真樹子; 河村 篤志; 永井 康介; 高木 律男, 新潟歯学会雑誌, 45, 2, 109, 109, Dec. 2015
  新潟歯学会, Japanese
• 歯周炎と血液・尿中バイオロジカルマーカーとの関連解析
  中島麻由佳; 中島麻由佳; 多部田康一; 宮内小百合; 杉田典子; 小松康高; 本田朋之; 高橋直紀; 宮澤春菜; 有松圭; 皆川高嘉; 松田由実; 松田由実; 佐藤圭祐; 佐藤圭祐; 山崎和久; 吉江弘正, 日本歯科保存学会学術大会プログラムおよび講演抄録集(Web), 143rd, P126 (WEB ONLY), 197, 01 Nov. 2015
  (NPO)日本歯科保存学会, Japanese
• 歯周組織局所の炎症およびP.gingivalisによる腸内細菌叢の変動が全身に及ぼす影響とその分子機構の比較
  松田由実; 松田由実; 高橋直紀; 高橋直紀; 有松圭; 有松圭; 中島麻由佳; 中島麻由佳; 佐藤圭祐; 佐藤圭祐; 多部田康一; 中島貴子; 山崎和久, 日本歯周病学会会誌(Web), 57, 秋季特別, 129, 129, 17 Aug. 2015
  (NPO)日本歯周病学会, Japanese
• Porphyromonas gingivalisバイオフィルムは人工胃液耐性を有する
  山本 れいこ; 野杁 由一郎; 高橋 直紀; 山崎 和久; 恵比須 繁之; 林 美加子, 日本バイオフィルム学会学術集会プログラム・抄録集, 29回, 28, 28, Jul. 2015
  日本バイオフィルム学会, Japanese
• Porphyromonas gingivalis経口単回投与によるマウス腸内細菌叢の変動
  中島麻由佳; 中島麻由佳; 有松圭; 有松圭; 高橋直紀; 高橋直紀; 皆川高嘉; 皆川高嘉; 松田由実; 松田由実; 佐藤圭祐; 佐藤圭祐; 中島貴子; 多部田康一; 山崎和久, 新潟歯学会雑誌, 45, 1, 26, 27, 19 Jun. 2015
  新潟歯学会, Japanese
• 歯周炎モデルマウスにおける腸内細菌叢の変動と免疫応答への影響
  高橋直紀; 有松圭; 中島麻由佳; 松田由実; 佐藤圭祐; 多部田康一; 中島貴子; 加藤完; 大野博司; 山崎和久, 腸内細菌学雑誌, 29, 2, 91, 91, Apr. 2015
  (公財)日本ビフィズス菌センター, Japanese
• 歯周炎患者におけるPISAと血中マーカーとの関連性
  本田朋之; 本田朋之; 宮沢春菜; 宮沢春菜; 野中由香莉; 野中由香莉; 高橋直紀; 高橋直紀; 多部田康一; 中島貴子; 山崎和久, 日本歯周病学会会誌(Web), 57, 2015
• Porphyromonas gingivalis経口単回投与によるマウス腸内細菌叢の変動
  中島麻由佳; 有松圭; 高橋直紀; 皆川高嘉; 山田ひとみ; 松田由実; 佐藤圭祐; 多部田康一; 中島貴子; 山崎和久, 日本歯科保存学会学術大会プログラムおよび講演抄録集(Web), 141st, B24 (WEB ONLY), 62, 01 Oct. 2014
  (NPO)日本歯科保存学会, Japanese
• 結紮誘導歯周炎モデルマウスにおける全身への影響とその分子機構の解析
  松田由実; 松田由実; 山田ひとみ; 山田ひとみ; 高橋直紀; 高橋直紀; 有松圭; 有松圭; 皆川高嘉; 皆川高嘉; 中島麻由佳; 中島麻由佳; 多部田康一; 中島貴子; 山崎和久, 日本歯周病学会学術大会プログラムおよび講演抄録集, 57th, 2014
• 歯肉上皮細胞におけるカプサイシン受容体TRPV1の発現および機能解析
  高橋直紀; 松田由実; 山田ひとみ; 中島貴子; 多部田康一; 村上伸也; 山崎和久, 日本歯科保存学会学術大会プログラムおよび講演抄録集(Web), 140th, 2014
• 歯周病原細菌誘導性糖・脂質代謝変動に及ぼすPropolisの効果
  中島麻由佳; 中島麻由佳; 有松圭; 有松圭; 高橋直紀; 高橋直紀; 山田ひとみ; 山田ひとみ; 皆川高嘉; 皆川高嘉; 松田由実; 松田由実; 多部田康一; 中島貴子; 山崎和久, 日本歯周病学会学術大会プログラムおよび講演抄録集, 57th, 2014
• ResveratrolはSIRT1非依存的に歯肉上皮細胞の炎症性応答を抑制する
  皆川高嘉; 皆川高嘉; 奥井隆文; 高橋直紀; 高橋直紀; 中島貴子; 多部田康一; 山崎和久, 新潟歯学会雑誌, 44, 2, 2014
• TRPV1 suppresses intestinal tumorigenesis by negatively regulating EGFR signaling
  Petrus R. de Jong; Naoki Takahashi; Alexandra R. Harris; Jihyung Lee; Samuel Bertin; Eyal Raz, CANCER RESEARCH, 73, 8, Apr. 2013
  English, Summary international conference
• 歯肉上皮細胞における新規イオンチャネルの発現解析およびその機能の検討
  高橋直紀; 松田由実; 松田由実; 多部田康一; 山崎和久, 日本歯周病学会学術大会プログラムおよび講演抄録集, 56th, 2013
• 新たな骨形成不全症モデルマウスのフェノタイプ発症機構
  多部田康一; 有松圭; 有松圭; 有松圭; 高橋直紀; 前川知樹; 宮内小百合; 宮内小百合; 宮内小百合; 山崎和久; 山崎和久, 日本歯周病学会学術大会プログラムおよび講演抄録集, 55th, 2012
• TRPV1 signaling modulates EGFR kinase activity in intestinal epithelial cells which inhibits regenerative responses after mucosal injury
  Petrus De Jong; Naoki Takahashi; Samuel Bertin; James Jeffries; Michael Jung; Jen Duong; Amy Triano; Scott Herdman; Hui Dong; Jongdae Lee; Eyal Raz, INFLAMMATORY BOWEL DISEASES, 17, S72, S73, Dec. 2011
  English, Summary international conference
• Porphyromonas gingivalis LPSがmicroRNA発現に及ぼす影響
  本田朋之; 本田朋之; 高橋直紀; 高橋直紀; 奥井隆文; 宮内小百合; 宮内小百合; 中島貴子; 中島貴子; 多部田康一; 山崎和久; 山崎和久, 日本歯科保存学会学術大会プログラムおよび講演抄録集(Web), 135th, 2011
• 新たな視点から口腔疾患を誘因とする難治性疾患を考える 歯周疾患の動脈硬化症リスクに及ぼす影響
  山崎 和久; 多部田 康一; 前川 知樹; 高橋 直紀; 青木 由香莉; 宮下 博考; 宮内 小百合; 米澤 大輔; 本田 朋之; 奥井 隆文; 奥井 桂子; 伊藤 晴江; 中島 貴子, Journal of Oral Biosciences, 52, Suppl, 67, 67, Sep. 2010
  (一社)歯科基礎医学会, Japanese
• 新たな骨形成不全症モデルマウスに見られた選択的スプライシング sealにおけるGT-AGルールの例外
  多部田 康一; 高橋 直紀; 前川 知樹; 山崎 和久; 網塚 憲生, 新潟歯学会雑誌, 40, 1, 79, 81, Jun. 2010
  新潟歯学会, Japanese
• 歯周炎患者におけるPorphyromonas gingivalisに対する抗体価と高感度CRPの関連性
  宮下 博考; 米澤 大輔; 本田 朋之; 奥井 隆文; 奥井 桂子; 前川 知樹; 高橋 直紀; 伊藤 晴江; 中島 貴子; 多部田 康一; 山崎 和久, 新潟歯学会雑誌, 40, 1, 98, 98, Jun. 2010
  新潟歯学会, Japanese
• Porphyromonas gingivalis LPSがmicroRNA発現に及ぼす影響
  本田朋之; 高橋直紀; 高橋直紀; 奥井桂子; 奥井桂子; 奥井隆文; 中島貴子; 中島貴子; 多部田康一; 山崎和久, 日本歯周病学会学術大会プログラムおよび講演抄録集, 53rd, 2010
• ヒト歯肉上皮細胞のケモカイン産生におけるinterleukin(IL)-17の関与-IL-17受容体の発現とその機能解析-
  高橋直紀; 前川知樹; 奥井隆文; 本田朋之; 多部田康一; 中島貴子; 山崎和久, 日本歯周病学会学術大会プログラムおよび講演抄録集, 53rd, 2010
• ヒト歯肉上皮細胞のケモカイン産生におけるinterleukin(IL)-17の関与-IL-17受容体の発現解析とその機能解析-
  高橋直紀; 高橋直紀; 奥井隆文; 中島貴子; 中島貴子; 多部田康一; 山崎和久; 山崎和久, 日本歯科保存学会学術大会プログラムおよび講演抄録集(Web), 133rd, 2010
• 歯周炎患者におけるPorphyromonas gingivalisに対する抗体価と高感度CRPの関連性
  宮下 博考; 米澤 大輔; 本田 朋之; 奥井 隆文; 奥井 桂子[梶田]; 前川 知樹; 高橋 直紀; 伊藤 晴江; 中島 貴子; 多部田 康一; 山崎 和久, 日本歯周病学会会誌, 51, 秋季特別, 99, 99, Sep. 2009
  (NPO)日本歯周病学会, Japanese
• ORAL INFECTION OF PORPHYROMONAS GINGIVALIS INDUCES PRO-ATHEROGENIC CHANGE IN MICE
  K. Yamazaki; T. Maekawa; N. Takahashi; T. Nakajima; K. Tabeta, ATHEROSCLEROSIS SUPPLEMENTS, 10, 2, Jun. 2009
  English, Summary international conference
• 歯周炎の病態は冠動脈血管内皮細胞のEarly growth response-1発現を上昇・誘導し炎症反応を促進させる
  前川 知樹; 高橋 直紀; 本田 朋之; 宮下 博孝; 米澤 大輔; 奥井 隆文; 多部田 康一; 山崎 和久, 新潟歯学会雑誌, 39, 1, 86, 86, Jun. 2009
  新潟歯学会, Japanese
• Porphyromonas gingivalis感染が冠動脈疾患リスクに及ぼす影響 基本健康診査受診者における解析
  米澤 大輔; 宮下 博孝; 前川 知樹; 高橋 直紀; 青木 由香莉; 奥井 隆文; 中島 貴子; 田辺 直仁; 多部田 康一; 山崎 和久, 新潟歯学会雑誌, 39, 1, 87, 87, Jun. 2009
  新潟歯学会, Japanese
• Porphyromonas gingivalis感染が冠動脈疾患リスクに及ぼす影響 基本健康診査受診者における解析
  米澤 大輔; 宮下 博考; 前川 知樹; 高橋 直紀; 青木 由香莉; 奥井 隆文; 中島 貴子; 田辺 直仁; 多部田 康一; 山崎 和久, 日本歯周病学会会誌, 51, 春季特別, 127, 127, Apr. 2009
  (NPO)日本歯周病学会, Japanese
• ヒト歯肉上皮細胞のケモカイン産生におけるIRAK-Mの関与
  高橋直紀; 高橋直紀; 高橋直紀; 本田朋之; 本田朋之; 本田朋之; 奥井隆文; 奥井隆文; 奥井隆文; 土門久哲; 土門久哲; 土門久哲; 吉江弘正; 多部田康一; 山崎和久; 山崎和久, 新潟歯学会雑誌, 39, 1, 2009
• Porphyromonas gingivalis抗原およびIL-6刺激は血管内皮細胞において転写因子Egr-1を介してMCP-1の産生を増強する
  前川知樹; 高橋直紀; 本田朋之; 宮下博考; 多部田康一; 山崎和久, 日本歯科保存学会学術大会プログラムおよび講演抄録集(Web), 131st, 2009
• 歯周炎における小胞体ストレスの関与
  高橋直紀; 高橋直紀; 高橋直紀; 土門久哲; 土門久哲; 土門久哲; 本田朋之; 本田朋之; 本田朋之; 吉江弘正; 安孫子宜光; 多部田康一; 山崎和久; 山崎和久, 日本歯周病学会学術大会プログラムおよび講演抄録集, 51st, 2008
• 歯周炎マウスモデルにおける口腔内感染が血清脂質,大動脈組織の遺伝子発現変化に与える影響-歯周炎が全身に与える影響のエビデンス-
  多部田康一; 前川知樹; 高橋直紀; 梶田桂子; 奥井隆文; 土門久哲; 本田朋之; 伊藤晴江; 中島貴子; 山崎和久, 日本動脈硬化学会総会・学術集会プログラム・抄録集, 40th, 2008
• ヒト歯肉上皮細胞のケモカイン産生におけるIRAK-Mの関与
  高橋直紀; 高橋直紀; 高橋直紀; 本田朋之; 本田朋之; 本田朋之; 奥井隆文; 土門久哲; 土門久哲; 土門久哲; 吉江弘正; 多部田康一; 山崎和久; 山崎和久, 日本歯周病学会学術大会プログラムおよび講演抄録集, 51st, 2008

• 歯周病およびインプラント周囲組織の疾患と状態に関する新分類 : アメリカ歯周病学会(AAP)/ヨーロッパ歯周病連盟(EFP)共催2017ワールドワークショップ会議録
  Kornman, Kenneth S.; Tonetti, Maurizio S.; 日本歯周病学会; 日本臨床歯周病学会; 村上, 伸也, 全身疾患および先天的あるいは後天的な疾患・状態による歯周組織の徴候：歯周病およびインプラント周囲の疾患と状態の分類に関する2017年ワールドワークショップ、ワークグループ3のコンセンサスレポート．
  クインテッセンス出版, Oct. 2020, 9784781207735, 318p, Japanese, [Joint work]
• 臨床歯周病学 第3版
  村上, 伸也; 申, 基喆; 齋藤, 淳; 山田, 聡, 1編歯周病の基礎知識 歯周病の原因と症状
  医歯薬出版, Feb. 2020, 9784263458440, xi, 403p, Japanese, [Joint work]
• 文献と臨床の橋わたし 口腔と全身の相互作用(第３回) 口腔-腸管連関から考える歯周病と全身の関連
  高橋 直紀
  日本歯科評論, Sep. 2017, [Joint work]
• 文献と臨床の橋わたし 口腔と全身の相互作用(第２回) 口腔細菌の全身への伝播と口腔感染による全身性サイトカイン上昇
  高橋 直紀
  日本歯科評論, Aug. 2017, [Joint work]
• 文献と臨床の橋わたし 口腔と全身の相互作用(第２回) 歯周病と関連する全身疾患
  高橋 直紀
  日本歯科評論, Jul. 2017, [Joint work]
• 歯周病と全身の健康
  日本歯周病学会, 第1 部 臨床研究 からのエビデンス １）歯周病と血管障害
  医歯薬出版, Apr. 2016, 9784263444696, 116p, Japanese, [Joint work]
• 第Ⅲ編 口腔細菌と疾患 第14章 腸内細菌叢への影響．「バイオテクノロジーシリーズ 腸内細菌・口腔細菌と全身疾患」
  高橋 直紀
  シーエムシー出版, Dec. 2015, [Joint work]

• up-dateシンポジウム：歯周炎と下部消化器疾患 －粘膜関連細菌叢に着目した基礎的・臨床的検討－
  高橋直紀
  第66回歯科基礎医学会学術大会, 03 Nov. 2024
• Exploring the Oral-Gut Axis: The Role of Periodontal Pathogens in Gastrointestinal Diseases
  Naoki Takahashi
  International Collaborative Symposium on Development of Human Resources in Practical Oral Health and Treatment, 31 May 2024, English, Invited oral presentation
• 学会学術賞受賞記念講演：歯肉上皮バリア機能制御を基軸とした新規抗歯周病薬開発の基礎的研究
  高橋直紀
  第67回春季日本歯周病学会学術大会, 25 May 2024, Japanese, Invited oral presentation
• 下部消化器Pathobiontとしての歯周病原細菌P.gingivalis
  高橋直紀
  日本歯科保存学会 2024年度春季学術大会(第160回), 17 May 2024, Japanese, Nominated symposium
• Trip to TRPs: TRP Ion Channels in Periodontitis
  Naoki Takahashi
  2022 IADR/APR General Session, 24 Jun. 2022, English, Public symposium
• Pre-conference workshops: Experimental animal model in periodontal research
  Naoki Takahashi
  15th the International Dental Collaboration of the Mekong River Region (IDCMR), 19 Aug. 2021, English, Nominated symposium
• Neuronal TRPV1 activation prevents alveolar bone resorption via CGRP.
  Naoki Takahashi
  97th General session & Exhibition of the IADR, 22 Jun. 2019, English, Nominated symposium
  [International presentation]
• 歯周病と全身疾患の関連メカニズム―腸 内細菌叢を介する新たな仮説―
  高橋 直紀
  第71回日本口腔科学会学術集会, 26 Apr. 2017, Nominated symposium
  [Domestic Conference]

• THE JAPANESE ACADEMY OF CLINICAL PERIODONTOLOGY
• International Association for Dental Research
• JAPANESE ASSOCIATION FOR DENTAL RESEARCH
• JAPANESE SOCIETY OF PERIODONTOLOGY
• THE JAPANESE SOCIETY OF CONSERVATIVE DENTISTRY
• 日本口腔検査学会
• NIIGATA DENTAL SOCIETY
• 日本再生医療学会

• Development of a Novel Bone Regeneration Modality Based on Periosteum-Derived Matrisome
  Grants-in-Aid for Scientific Research
  01 Apr. 2025 - 31 Mar. 2028
  高橋 直紀; 永田 昌毅; 多部田 康一
  Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 25K13001
• Analysis of the new occlusal trauma diagnosis biomaker by the microRNA of GCF
  Grants-in-Aid for Scientific Research
  01 Apr. 2025 - 31 Mar. 2028
  佐藤 圭祐; 多部田 康一; 野中 由香莉; 高橋 直紀
  Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Niigata University, 25K13031
• Identification of Era Common Bacteria and Factors by Reconstruction of Oral Bacterial Flora
  Grants-in-Aid for Scientific Research
  28 Jun. 2024 - 31 Mar. 2026
  前川 知樹; Rosenkranz Andrea; 高橋 直紀; 米澤 大輔
  Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Research (Exploratory), Niigata University, 24K22180
• Development of new modalities in periodontal treatment using cell binding backpack
  Grants-in-Aid for Scientific Research
  Apr. 2023 - Mar. 2026
  多部田 康一; 中島 麻由佳; 福田 達也; 池田 真由美; 高橋 直紀; 野中 由香莉; 岩尾 康範
  病原細菌量を減少させることは歯周治療の本質であるが，免疫バランスの破綻により炎症性の組織破壊が急速に進行する症例では免疫応答を積極的に調節する新規モダリティが求められる。しかし歯周炎における免疫治療標的選択に関する体系的な理解・見解はなく，また生物学的製剤は取り扱いの煩雑さ，時間・経済的コストの問題から通常の歯周治療において応用できる状況にない。そこで本課題では新規徐放性ドラッグキ ャリアーであるcellular backpack（BP）を用いて免疫細胞の個別制御を行い，免疫治療標的についての俯瞰的検討を行うと共に，次世代歯周治療スキームとしてのCell binding-ドラッグデリバリーシステムを開発することを目的とする。
  R5年度は，マクロファージを標的としたBPを作成した。BP内包薬としてM2型（抗炎症性）マクロファージを誘導することが報告されているIL-4を選択した。作成したIL-4内包BPはマクロファージによる貪食を回避して細胞表面に結合し続けることが確認された。In vitroにおいて，人工的M1環境下においてもIL-4内包BPの結合によりマクロファージがM2フェノタイプを維持することが確認された。
  Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Niigata University, 23K27769
• MPN武装細菌による口腔マイクロバイオームの再構築
  科学研究費助成事業
  30 Jun. 2023 - 31 Mar. 2025
  多部田 康一; 江島 広貴; 野中 由香莉; 高橋 直紀; 中島 麻由佳
  日本学術振興会, 挑戦的研究(萌芽), 新潟大学, 23K18357
• Elucidation of Oral Tissue Repair and Regeneration Mechanisms by DEL-1
  Grants-in-Aid for Scientific Research
  Apr. 2022 - Mar. 2025
  前川 知樹; 土門 久哲; 多部田 康一; 寺尾 豊; 高橋 直紀
  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。すなわち，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。
  本年度は、その中で口腔環境の維持に重要なDEL-1に着目した研究を行った。DEL-1は生体内で常時産生されているタンパク質であるが，その発現は年齢とともに減少する。そこで，生体内にDEL-1を誘導する方法を昨年度に同定し，特に大きくDEL-1発現を誘導することのできる薬剤の選定を行った。薬剤のDEL-1発現の変動を検索すると同時に，老化で問題となる骨についても検索を行った。
  共同研究先から供与された薬剤における破骨細胞抑制効果および骨芽細胞による骨ノジュール形成能をそれぞれ測定した。いくつかの構造体からその効果が高いものを選定するとともに，基礎骨格となる薬剤との比較検討も同時に行った。それにより，選定薬剤のMOAが予測可能となり，生体に安全で，かつ効果の高い構造体を同定することができた。
  また，これら薬剤を使用した実践的な疾患モデルへの効果検討も開始することができた。
  続いて，これら薬剤をより生体に安全に使用できるような処置を加えることとした。共同研究機関とともに，選定された薬剤をマイクロ粒子化することにより，細胞障害を極力減弱することに成功し，緩徐に，かつ効果を増強させることが可能となった。
  Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Niigata University, 23K24525
• Mechanisms of disruption of intestinal homeostasis by swallowed periodontopathogenic bacteria.
  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
  Apr. 2022 - Mar. 2025
  高橋 直紀; 多部田 康一; 谷口 浩二
  Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Niigata University, 22K09961
• 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
  科学研究費助成事業
  Apr. 2021 - Mar. 2025
  堀 一浩; 多部田 康一; 吉村 将悟; 小野 高裕; 曽根 博仁; 村上 和裕; 高橋 直紀
  近年，咀嚼と全身の健康との関連が報告されているが，その詳細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，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．
  本年度は肥満患者を対象に，咀嚼行動変容アルゴリズムをインストールしたbitescanにおける行動変容の効果を検討した．介入期間は３か月とし，介入群は咀嚼行動変容アルゴリズム付きのbitescanを毎食使用した．主要評価項目として，BMIおよび体重の変化率とし，副次評価項目として，おにぎり摂取時の咀嚼行動とした．包含基準・除外基準に適合した73名を解析対象とした．その結果，介入群では，BMIは平均29.4±4.4kg/m2，BMI変化率100.3%，咀嚼回数は340.1±185.5回，咀嚼回数変化率は175.1%であった．対照群では，BMIは平均29.5±3.7kg/m2，BMI変化率99.7%，咀嚼回数は250.8±99.1回，咀嚼回数変化率は171.4%，であった．その結果，介入群・対照群両者ともにBMI，体重において介入前後における有意差は認めなかった．一方で，両群ともに咀嚼行動には有意な違いがみられ，介入前と比べて介入後では，おにぎり摂取時の咀嚼回数は有意に増加した．
  日本学術振興会, 基盤研究(B), 新潟大学, 23K21489
• Peptide drugs derived from food material for periodontal disease preventing flail and AMR
  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
  01 Apr. 2019 - 31 Mar. 2023
  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
  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。
  Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Niigata University, Competitive research funding, 19H03829
• 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
  Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory)
  Jul. 2021 - Mar. 2023
  多部田 康一; 寺井 崇二; 谷口 浩二; 佐藤 裕樹; 高橋 直紀
  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．
  Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Research (Exploratory), Niigata University, 21K19592
• Next step in the oral-gut connection: Do swallowed periodontopathogenic bacteria exacerbate colitis?
  Grants-in-Aid for Scientific Research
  01 Apr. 2019 - 31 Mar. 2022
  Takahashi Naoki
  This study aimed to evaluate the effects of ingested periodontal pathogens on experimental colitis in mice and to elucidate its underlying mechanisms. We found that 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.
  Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Niigata University, 19K10126
• Therapeutic biofilm as a new approach to the treatment of periodontal disease and root caries
  Grants-in-Aid for Scientific Research
  28 Jun. 2019 - 31 Mar. 2021
  Tabeta Koichi
  This study is a challenge to control the onset and progression of periodontal disease and root caries by "artificial formation of therapeutic biofilm". We explored the possibility of creating the concept of a therapeutic biofilm by assimilating nanomedicines into the initial biofilm to create a symbiosis environment (less harmful bacterial flora).
  The conditions for the production of S. mitis biofilm containing liponanocapsules were clarified, indicating the possibility of creating a therapeutic biofilm. The degradation rate of the capsules was measured, suggesting the environmentally responsive degradation of the capsules, induced by the growth of the bacteria and the maturation of the biofilm.
  Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Research (Exploratory), Niigata University, Competitive research funding, 19K22705
• スケーリング後菌血症に対する高齢者生体応答の解析と光治療による予防法の確立
  科学研究費助成事業 基盤研究(C)
  01 Apr. 2017 - 31 Mar. 2021
  両角 俊哉; 高橋 直紀; 小松 康高; 保苅 崇大; 宮沢 春菜
  あらゆる観血処置にともない，一過性の菌血症が発生する。我々はこれまでの一連の研究で，中年期の歯周炎患者において，1) スケーリング・ルートプレーニング（SRP）後に高頻度で菌血症が発生すること，2) 抗菌薬（アジスロマイシン）併用やエルビウムヤグ（Er: YAG）レーザー治療により菌血症の発生を減少または抑制できること，3) 局所薬物配送システム（LDDS）は機械的除去療法前の使用でも歯周ポケット内環境を改善できることなどを報告してきた。一方，免疫力が低下している高齢者においては，菌血症が一過性で終わらず，全身性の高リスクとなる可能性がある。
  そこで，高齢者に適した安全かつ効果的な歯周治療法を確立し，超高齢社会のニーズに応えるべく、本研究では慢性歯周炎を有する高齢者のSRP時に発生する菌血症，それにともなう生体応答の解析，および光治療（Er:YAGレーザー）による菌血症予防の有効性検討を目的とする。
  具体的には、① ハンドスケーラー群：ハンドスケーラーにてSRP実施 ② エルビウムヤグ（Er: YAG）レーザー群：レーザーにて処置 の２群間で、(1) 血清中炎症性メディエイター（高感度CRP、IL-6、IFN-g、TNF-a等） (2) ストレス指標（心拍変動、血中酸素飽和度等） (3) 臨床パラメーター の経時的変化および相関関係を比較解析し、予防対策について検討する。
  現在、上記内容で研究が開始され、進行中である。
  日本学術振興会, 基盤研究(C), 17K11984
• Elucidation of the TRP-TLR interaction in the pathogenesis of inflammatory diseases
  Grants-in-Aid for Scientific Research Fund for the Promotion of Joint International Research (Fostering Joint International Research (A))
  2019 - 2021
  高橋 直紀
  近年同定されたTransient receptor potential (TRP) タンパクは、温度、機械刺激、化学刺激などによって活性化されるユニークなイオンチャネルであり、環境センサーとして全身の臓器や組織に広く発現している。その構造と機能が明らかになるにつれ、このタンパクは細胞機能を制御することで様々な疾患に関連することが報告されている。
  我々はこれまでに実験的歯周炎モデルマウスを用いた検討において、TRPチャネルタンパクスーパーファミリーのひとつであるTRPV1の活性化が歯周炎に対して抑制的に働くことを報告した。その詳細なメカニズムを解析する中で、TRPチャネルタンパクが誘導する細胞内カルシウムシグナリングがToll-like receptor（TLR）を介した自然免疫応答を制御している可能性が確認された。
  その制御メカニズムが明らかとなれば、TRPチャネルをターゲットとした歯周炎の新規予防法・治療法の開発につながるだけでなく、自然免疫応答がトリガーとなる様々な炎症性疾患に対する創薬イノベーションが期待される。
  本年度は、渡航先における自然免疫関連遺伝子改変マウスライブラリーおよび細胞内蛍光バイオイメージング技術を用いた実験の前段階として、これまでに報告されているTRP-TLR相互作用に関する文献的な情報収集と、in vitroにおける予備的な実験を実施した。具体的には、生体防御の最前線で機能する上皮細胞に各種TRPアゴニストで前処理後、TLRリガンドで刺激し、炎症性サイトカイン産生への影響を解析した。
  Japan Society for the Promotion of Science, Fund for the Promotion of Joint International Research (Fostering Joint International Research (A)), Niigata University, 18KK0434
• Interaction Between Neural and Non-Neuronal Cells in the Pathogenesis of Periodontitis.
  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
  01 Apr. 2016 - 31 Mar. 2019
  Takahashi Naoki; Yamazaki Kazuhisa
  However 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 generelated 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 tartrateresistant 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.
  Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Niigata University, 16K11827
• スケーリング後菌血症に対する高齢者生体応答の解析と光治療による予防法の確立
  基盤研究(C)
  2017 - 2019
  両角 俊哉
  日本学術振興会, Competitive research funding
• Vaccines against periodontitis using DNA ORIGAMI and imidazoquinolines
  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
  01 Apr. 2015 - 31 Mar. 2018
  KOICHI TABETA; YAMAZAKI Kazuhisa
  Although the efficacy of vaccines against an infectious disease, periodontitis, has been suggested, it has not been applied in clinical practices. In this study, we examined the possibility of development of a vaccine to prevent/treat periodontitis focusing on induction of secretory IgA production via modulation of mucosal immunity. We found that, chemokine production and follicular T cell activation were induced by imidazoquinoline derivatives which are nucleic acid antigen - like compounds, and secretory IgA production was promoted. These findings suggested the possibility of developing a periodontitis vaccine using nucleic acid antigen as an adjuvant.
  Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Niigata University, 15H05052
• TRPチャネルタンパクによる自然免疫チューニング機構の解明と歯周炎治療への応用
  国際共同研究加速基金(国際共同研究強化(A))
  2018
  高橋 直紀
  日本学術振興会, Principal investigator, Competitive research funding
• The Effect of TRPV1 channel in the pathogenesis of periodontitis.
  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
  01 Apr. 2014 - 31 Mar. 2016
  Takahashi Naoki
  TRPV1, a member of the calcium-permeable thermosensitive transient receptor potential super family, is a sensor of thermal and chemical stimuli. 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.Our results suggest that functional TRPV1 is expressed by GECs and contribute to the regulation of cell proliferation.
  Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (B), Niigata University, 26861808
• 口腔粘膜上皮における新規イオンチャネルの網羅的発現解析とその機能の解明
  科学研究費助成事業 特別研究員奨励費
  01 Apr. 2013 - 31 Mar. 2016
  高橋 直紀
  歯周炎の病態形成におけるTRPチャネルタンパクの影響を検討する目的でin vivoで検討を行った。我々が以前確立した歯牙結紮誘導性歯周炎モデルマウスを用いた。野生型マウスとTRPV1ノックアウトマウスの上顎第二臼歯に絹糸を結紮し、7日後にサンプルを回収した。マイクロCTによる歯槽骨吸収は野生型マウスに比較してTRPV1ノックアウトマウスでは有意に増加していることが確認された。また野生型マウスにTRPV1のアゴニストであるカプサイシンを投与すると歯槽骨吸収が有意に抑制されることが確認された。これらのことより、TRPV1が歯周炎の病態形成に関与する可能性が示唆された。その詳細なメカニズムは今後さらに検討が必要である。
  日本学術振興会, 特別研究員奨励費, 新潟大学, 13J04959
• The role of interactions between IL-17 and periodontopathic bacteria in the pathogenesis of periodontitis
  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
  2011 - 2012
  HONDA Tomoyuki; TAKAHASHI Naoki; MIYAUCHI Sayuri; OKUI Takafumi
  In human gingival epithelial cell lines, Epi4 cells, IL-17 up-regulated inflammatory cytokines and chemokines including CXCL8. IL-17, as well as TNF-α, is involved in the regulation of the innate immune response in gingival epithelial cells. Further studies are needed to examine the roles of interactions among periodontopathic bacteria, IL-17A and IL-17C in the pathogenesis of periodontitis.
  Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (B), Niigata University, 23792470
• Elucidation of immune escape mechanisms by periodontopathic bacteria
  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
  2009 - 2010
  HONDA Tomoyuki; TAKAHASHI Naoki; KAJITA Keiko; OKUI Takafumi
  P.gingivalis stimulation up-regulated the expression of miR-146a in macrophages. Over expression of miR-146a in macrophages attenuated the release of P.gingivalis-induced inflammatory cytokines. Further studies are required to elucidate the exact role of microRNA in periodontal pathogenesis.
  Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (B), Niigata University, 21792112
• Elucidation of immune escape mechanisms by periodontopathic bacteria
  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
  2007 - 2008
  HONDA Tomoyuki; DOMON Hisanori; TAKAHASHI Naoki
  歯周病原因細菌の1つPorphyromonas gingivalis は,免疫による排除機構から逃れ,感染を慢性化させている可能性が考えられる.この細菌のもつ病原因子が歯周組織の構成細胞(マクロファージ,上皮細胞)によって認識される過程においてIRAK-M の発現が高まる.IRAK-M は免疫を抑制する分子の一つとして既に知られているが,歯周組織の細胞においても免疫応答性を低下させ,感染を慢性化させるメカニズムの一端が明らかとなった.
  Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (B), Niigata University, 19791610