Updated on 2021/04/11

写真a

 
NONAKA Yukari
 
Organization
Academic Assembly Institute of Medicine and Dentistry SHIGAKU KEIRETU Assistant Professor
Graduate School of Medical and Dental Sciences Oral Life Science Oral Biological Science Assistant Professor
Title
Assistant Professor
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Degree

  • 博士(歯学) ( 2011.9   新潟大学 )

Research Interests

  • 分子生物学

  • 免疫学

  • 歯周病学

  • 細菌学

Research Areas

  • Life Science / Conservative dentistry  / 歯周病学

Research History (researchmap)

  • Niigata University   Graduate School of Medical and Dental Sciences   Assistant Professor

    2019.4

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  • Niigata University   Graduate School of Medical and Dental Sciences   Special researcher of the Japan Society for the Promotion of Science

    2017.4 - 2019.3

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  • Niigata University   Medical and Dental Hospital

    2013.8 - 2017.3

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  • 新潟大学医歯学総合研究科   研究員

    2013.4 - 2013.7

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  • 米国カリフォルニア州立大学サンディエゴ校   博士研究員

    2011.11 - 2013.3

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Research History

  • Niigata University   Graduate School of Medical and Dental Sciences Oral Life Science Oral Biological Science   Assistant Professor

    2019.4

  • Niigata University   University Medical and Dental Hospital Dental Health Periodontics

    2016.6 - 2017.3

  • Niigata University   University Medical and Dental Hospital Dental Health Periodontics

    2013.8 - 2016.5

  • Niigata University   Graduate School of Medical and Dental Sciences Oral Life Science Oral Biological Science   Researcher

    2011.9 - 2013.7

Education

  • Niigata University   Graduate School of Medical and Dental Sciences  

    2008.4 - 2011.9

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  • Niigata University   Faculty of Dentistry   School of Dentistry

    2001.4 - 2007.3

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Professional Memberships

  • JAPANESE ASSOCIATION FOR DENTAL RESEARCH

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  • NIIGATA DENTAL SOCIETY

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  • International Association for Dental Research

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  • THE JAPANESE SOCIETY OF CONSERVATIVE DENTISTRY

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  • Japanese Society for Evidence and the Dental Professional

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  • 日本再生医療学会

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  • JAPANESE SOCIETY OF PERIODONTOLOGY

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Qualification acquired

  • Dentist

  • 日本歯周病学会認定 歯周病認定医

  • 日本歯科保存学会 歯科保存治療認定医

 

Papers

  • Epithelial TRPV1 channels: Expression, function, and pathogenicity in the oral cavity. Reviewed International journal

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

    Journal of oral biosciences62 ( 3 ) 235 - 241   2020.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    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.

    DOI: 10.1016/j.job.2020.05.005

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  • Nutritional supplements and periodontal disease prevention—Current understanding Reviewed

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

    Current oral health reports ( 7 ) 154 - 164   2020.3

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  • A bacterial metabolite induces Nrf2-mediated anti-oxidative responses in gingival epithelial cells by activating the MAPK signaling pathway. Reviewed International journal

    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 biology110   104602 - 104602   2020.2

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    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.

    DOI: 10.1016/j.archoralbio.2019.104602

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  • Rice peptide with amino acid substitution inhibits biofilm formation by Porphyromonas gingivalis and Fusobacterium nucleatum. Reviewed

        2020

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  • Ingestion of Porphyromonas gingivalis exacerbates colitis via intestinal epithelial barrier disruption in mice Reviewed

    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   2020

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  • Antimicrobial function of the polyunsaturated fatty acid KetoC in an experimental model of periodontitis. Reviewed International journal

    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 periodontology90 ( 12 ) 1470 - 1480   2019.12

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    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.

    DOI: 10.1002/JPER.19-0130

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  • A peptide derived from rice inhibits alveolar bone resorption via suppression of inflammatory cytokine production. Reviewed International journal

    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 periodontology90 ( 10 ) 1160 - 1169   2019.10

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    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.

    DOI: 10.1002/JPER.18-0630

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  • The anti-inflammatory effect of 10-oxo-trans-11-octadecenoic acid (KetoC) on RAW 264.7 cells stimulated with Porphyromonas gingivalis lipopolysaccharide. Reviewed

    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   2018.4

  • The TRPA1 ion channel is expressed in CD4+T cells and restrains T-cell-mediated colitis through inhibition of TRPV1 Reviewed

    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

    GUT66 ( 9 ) 1584 - 1596   2017.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:BMJ PUBLISHING GROUP  

    Objective Transient receptor potential ankyrin-1 (TRPA1) and transient receptor potential vanilloid-1 (TRPV1) are calcium (Ca2+)-permeable ion channels mostly known as pain receptors in sensory neurons. However, growing evidence suggests their crucial involvement in the pathogenesis of IBD. We explored the possible contribution of TRPA1 and TRPV1 to T-cell-mediated colitis.
    Design We evaluated the role of Trpa1 gene deletion in two models of experimental colitis (ie, interleukin-10 knockout and T-cell-adoptive transfer models). We performed electrophysiological and Ca2+ imaging studies to analyse TRPA1 and TRPV1 functions in CD4+ T cells. We used genetic and pharmacological approaches to evaluate TRPV1 contribution to the phenotype of Trpa1 -/-CD4+ T cells. We also analysed TRPA1 and TRPV1 gene expression and TRPA1(+)TRPV1(+) T cell infiltration in colonic biopsies from patients with IBD.
    Results We identified a protective role for TRPA1 in T-cell-mediated colitis. We demonstrated the functional expression of TRPA1 on the plasma membrane of CD4+ T cells and identified that Trpa1 -/-CD4+ T cells have increased T-cell receptor-induced Ca2+ influx, activation profile and differentiation into Th1-effector cells. This phenotype was abrogated upon genetic deletion or pharmacological inhibition of the TRPV1 channel in mouse and human CD4+ T cells. Finally, we found differential regulation of TRPA1 and TRPV1 gene expression as well as increased infiltration of TRPA1(+)TRPV1(+) T cells in the colon of patients with IBD.
    Conclusions Our study indicates that TRPA1 inhibits TRPV1 channel activity in CD4+ T cells, and consequently restrains CD4+ T-cell activation and colitogenic responses. These findings may therefore have therapeutic implications for human IBD.

    DOI: 10.1136/gutjnl-2015-310710

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  • The ion channel TRPV1 regulates the activation and proinflammatory properties of CD4(+) T cells Reviewed

    Samuel Bertin, Yukari Aoki-Nonaka, Petrus Rudolf de Jong, Lilian L. Nohara, Hongjian Xu, Shawna R. Stanwood, Sonal Srikanth, Jihyung Lee, Keith To, Lior Abramson, Timothy Yu, Tiffany Han, Ranim Touma, Xiangli Li, Jose M. Gonzalez-Navajas, Scott Herdman, Maripat Corr, Guo Fu, Hui Dong, Yousang Gwack, Alessandra Franco, Wilfred A. Jefferies, Eyal Raz

    NATURE IMMUNOLOGY15 ( 11 ) 1055 - 1063   2014.11

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    TRPV1 is a Ca2+-permeable channel studied mostly as a pain receptor in sensory neurons. However, its role in other cell types is poorly understood. Here we found that TRPV1 was functionally expressed in CD4+ T cells, where it acted as a non-store-operated Ca2+ channel and contributed to T cell antigen receptor (TCR)-induced Ca2+ influx, TCR signaling and T cell activation. In models of T cell-mediated colitis, TRPV1 promoted colitogenic T cell responses and intestinal inflammation. Furthermore, genetic and pharmacological inhibition of TRPV1 in human CD4+ T cells recapitulated the phenotype of mouse Trpvl(-/-) CD4+ T cells. Our findings suggest that inhibition of TRPV1 could represent a new therapeutic strategy for restraining proinflammatory T cell responses.

    DOI: 10.1038/ni.3009

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  • The Role of Distinct T Cell Subsets in Periodontitis- Studies from Humans and Rodent Models. Reviewed

    Okui T, Aoki-Nonaka Y, Nakajima T, Yamazaki K

    Curr Oral Health Rep.1 ( 2 ) 114 - 123   2014.6

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

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

    JOURNAL OF PERIODONTAL RESEARCH49 ( 1 ) 69 - 76   2014.2

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

    DOI: 10.1111/jre.12080

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

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

    LIPIDS IN HEALTH AND DISEASE11   121   2012.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:BIOMED CENTRAL LTD  

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

    DOI: 10.1186/1476-511X-11-121

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  • Oral infection with Porphyromonas gingivalis and systemic cytokine profile in C57BL/6.KOR-ApoEshl mice Reviewed

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

    JOURNAL OF PERIODONTAL RESEARCH47 ( 3 ) 402 - 408   2012.6

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

    DOI: 10.1111/j.1600-0765.2011.01441.x

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

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

    ARCHIVES OF ORAL BIOLOGY57 ( 6 ) 820 - 829   2012.6

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:PERGAMON-ELSEVIER SCIENCE LTD  

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

    DOI: 10.1016/j.archoralbio.2011.11.008

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  • The Presence of IL-17(+)/FOXP3(+) Double-positive Cells in Periodontitis Reviewed

    T. Okui, Y. Aoki, H. Ito, T. Honda, K. Yamazaki

    JOURNAL OF DENTAL RESEARCH91 ( 6 ) 574 - 579   2012.6

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:SAGE PUBLICATIONS INC  

    Increasing evidence suggests that distinct inflammatory cytokines convert forkhead box protein P3 (FOXP3(+)) regulatory T-cells (Tregs) into IL-17-producing cells (Th17 cells) in vitro. However, this functional plasticity has not been examined in the pathogenesis of periodontal disease. In this study, we analyzed the IL-17A(+)FOXP3(+) cells present in periodontitis lesions to determine the association between Treg conversion and the pathogenesis of periodontitis. The immunohistochemical analysis of gingival tissues demonstrated that the numbers of Th17 cells (IL-17A(+)FOXP3(-)) and Tregs (IL-17A(-)FOXP3(+)) were greater in periodontitis lesions than in gingivitis lesions. We further identified a small number of IL-17A(+)FOXP3(+) cells in periodontitis lesions but not in gingivitis lesions. The flow cytometry analysis of CD4(+) T-cell lines established from gingival tissues and the peripheral blood of periodontitis patients showed that the proportion of Tregs was reduced and the proportion of IL-17A(+)FOXP3(+) cells among all FOXP3(+) cells was elevated in gingival tissue T-cell lines relative to the proportions in peripheral blood T-cell lines. Our findings indicate that Treg-Th17 conversion may occur in periodontitis lesions. Further studies addressing the role of Treg conversion during inflammatory responses against periodontopathic bacteria are needed.

    DOI: 10.1177/0022034512446341

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  • Chronic Oral Infection with Porphyromonas gingivalis Accelerates Atheroma Formation by Shifting the Lipid Profile Reviewed

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

    PLOS ONE6 ( 5 ) e20240   2011.5

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

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  • Analysis of immunostimulatory activity of Porphyromonas gingivalis fimbriae conferred by Toll-like receptor 2 Reviewed

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

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS398 ( 1 ) 86 - 91   2010.7

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Bacterial fimbriae are an important pathogenic factor. It has been demonstrated that fimbrial protein encoded by fimA gene (FimA fimbriae) of Porphyromonas gingivalis not only contributes to the abilities of bacterial adhesion and invasion to host cells, but also strongly stimulates host innate immune responses. However, FimA fimbriae separated from P. gingivalis ATCC 33277 using a gentle procedure showed very weak proinflammatory activity compared with previous reports. Therefore, in the present study, biological characteristics of FimA fimbriae were further analyzed in terms of proinflammatory activity in macrophages. Macrophages differentiated from THP-1 cells were stimulated with native, heat-denatured, or either proteinase- or lipoprotein lipase-treated FimA fimbriae of P. gingivalis ATCC 33277. Stimulating activities of these FimA fimbriae were evaluated by TNF-alpha-inducing activity in the macrophages. To clarify the mode of action of FimA fimbriae, anti-Toll-like receptor (TLR) 2 blocking antibody was added prior to stimulation. Weak stimulatory activity of native FimA fimbriae was enhanced by heat treatment and low-dose proteinase K treatment. Higher dose of proteinase K treatment abrogated this up-regulation. The activity of treated FimA fimbriae was suppressed by anti-TLR2 antibody, and more substantially by lipoprotein lipase treatment. These results suggest that lipoproteins or lipopeptides associated with FimA fimbriae could at least in part account for signaling via TLR2 and subsequent TNF-alpha production in macrophages. (C) 2010 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.bbrc.2010.06.040

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  • Elevated expression of IL-17 and IL-12 genes in chronic inflammatory periodontal disease Reviewed

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

    CLINICA CHIMICA ACTA395 ( 1-2 ) 137 - 141   2008.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:ELSEVIER SCIENCE BV  

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

    DOI: 10.1016/j.cca.2008.06.003

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Books

  • 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

    クインテッセンス出版  2020.10  ( ISBN:9784781207735

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    Total pages:318p   Language:Japanese

    CiNii Books

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MISC

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Awards

  • IADR/Unilever Hatton Divisional Award

    2012.6  

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  • デンツプライ賞

    2011.10  

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  • BD Japan Young Investigator’s Travel Award.

    2010.8  

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Research Projects

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

    Grant number:19K22705  2019.06 - 2021.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Challenging Research (Exploratory)  Challenging Research (Exploratory)

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

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    Grant amount:\6500000 ( Direct Cost: \5000000 、 Indirect Cost:\1500000 )

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  • Peptide drugs derived from food material for periodontal disease preventing flail and AMR

    Grant number:19H03829  2019.04 - 2023.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

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

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    Grant amount:\17160000 ( Direct Cost: \13200000 、 Indirect Cost:\3960000 )

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  • 緑茶およびワサビ由来成分の抗菌・抗炎症作用による歯周病予防・治療効果の検討

    2019.04 - 2020.03

    本庄国際奨学財団  食と健康研究助成金 

    野中 由香莉

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    Authorship:Principal investigator  Grant type:Competitive

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  • シナモン成分による歯周病抑制効果の検討

    Grant number:18K17043  2018.04 - 2021.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Early-Career Scientists  Grant-in-Aid for Early-Career Scientists

    野中 由香莉

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\4160000 ( Direct Cost: \3200000 、 Indirect Cost:\960000 )

    歯周病の有病率を下げ歯の喪失を防ぐことは、国民の健康寿命の延伸につながる。しかし、薬剤耐性菌の問題から、既存の抗菌薬に代わる歯周病予防・治療薬の開発が必要とされている。これまでに、陽イオンチャネルであるTRPA1チャネルのアゴニストのひとつで、シナモンの主成分であるCinnamaldehydeが、一部の細菌に対する抗菌活性・抗炎症作用を示すことが報告されている。本研究の目的は、Cinnamaldehydeについて、歯周病原細菌に対する抗菌活性や抗炎症作用を明らかとし、新規の歯周病治療薬開発に資することである。
    H30年度は研究計画に従い、代表的な歯周病原細菌であるP. gingivalis、F. nucleatum、P. intermedia、A. actinomycetemcomitansに対するCinnamaldehydeによる抗菌活性を評価した。それぞれの菌に対する最小発育阻止濃度 (MIC)および最小殺菌濃度(MBC)を測定した。いずれの菌に対しても抗菌活性を認めた。また、P. gingivalis、F. nucleatumについてはin vitroにてバイオフィルムを作成し、バイオフィルム形成阻害作用および成熟バイオフィルムに対する除去効果を検討した。その結果、いずれの菌に対してもCinnamaldehydeによるバイオフィルム形成阻害作用を認めた。成熟バイオフィルム除去については、特にP. gingivalisで強くその効果を認めた。
    以上より、Cinnamaldehydeは歯周病原細菌に対し強い抗菌活性を示すとともに、バイオフィルムに対しても除去効果を有することが明らかとなった。

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  • コメ由来抗菌ペプチドの生体防御機能の解明―新規歯周病医薬開発を目指して―

    Grant number:17J40165  2017.04 - 2020.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for JSPS Fellows  Grant-in-Aid for JSPS Fellows

    野中 由香莉

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    Grant amount:\4030000 ( Direct Cost: \3100000 、 Indirect Cost:\930000 )

    歯周病は歯周病原細菌感染によって引き起こされる炎症性の疾患であり、バイオフィルム感染症と位置付けられる。バイオフィルムは、一般に薬剤の浸透に抵抗性を持つ。一方で、抗菌薬の使用制限が国策として決まり、既存の抗菌薬によるバイオフィルム形成阻止が実用化困難となりつつある中で、新たな治療薬の開発が急務である。以上の背景から、食品由来の安全性と抗菌活性を有する上記のコメ由来ペプチドの応用が可能ではないかと考えた。
    コメを原材料としたペプチド素材の歯周病に対する効果について検討を行い、本年度は特にその抗菌作用に着目した。これまでの結果において、代表的な歯周病原細菌であるP. gingivalis に対する抗菌活性が確認できたAmy1-1-18ペプチドと、さらにそのアミノ酸置換体を用いて歯周病原細菌バイオフィルムに対する効果の検証を行った。本研究においては、P. gingivalisおよびF. nucleatumを対象としてバイオフィルムモデルを構築し、ペプチドの抗菌活性について評価を行った。
    結果として、Amy1-1-18ペプチドおよびそのアミノ酸置換体のいくつかは、P. gingivalisおよびF. nucleatumのバイオフィルム形成を阻害することが示された。中でも、Amy1-1-18ペプチドの12番目の塩基配列を置換したペプチドにおいては、F. nucleatumに対して極めて強い抗菌活性を示すことが明らかとなった。さらに、そのメカニズムとして強い膜障害性を有することが示された。以上より、アミノ酸置換によるカチオン性の強化により膜を標的とした抗菌作用が強化されたことが示唆された。また、抗菌活性の選択性がアミノ酸置換で調整できる可能性が示唆された。すなわち、より狭スペクトルで耐性菌が生じにくい新たなバイオフィルム制御医薬としての発展の可能性が示唆された。

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  • Analysis of anti-inflammatory effect of vitaminD against periodonthopathic bacteria

    Grant number:15K20619  2015.03 - 2018.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    NONAKA Yukari

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    Grant amount:\4030000 ( Direct Cost: \3100000 、 Indirect Cost:\930000 )

    Vitamin D is a nutrient involved in maintenance of bone homeostasis. The purpose of this study is to clarify the anti-inflammatory effect of vitamin D against periodontal pathogenic bacterial infection. Active vitamin D, 1,25(OH)2D3 couldn’t suppress the inflammatory response induced by periodontal pathogenic bacterial LPS in macrophages. Furthermore, wound healing assay was performed using Epi4 cells derived from human gingival epithelial cells, but wound healing promoting effect was not observed by addition of active vitamin D.

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  • The Periodontal-Metabolic syndrome etiology via the intestine -the role of TRP channels-

    Grant number:25893079  2013.08 - 2015.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Research Activity start-up  Grant-in-Aid for Research Activity start-up

    NONAKA Yukari

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    Grant amount:\2730000 ( Direct Cost: \2100000 、 Indirect Cost:\630000 )

    Periodontitis as periodontal bacterial infection has been implicated as a risk factor for diabetes, atherosclerotic vascular diseases, and non-alcoholic fatty liver disease. TRP channels are Ca2+ permeable cation channels, which play an important role in the pathogenesis and progression of inflammatory responses and metabolic disorders. The present study has demonstrated that TRPV1 can regulate inflammatory responses and lipid metabolism in the liver. This result suggests that TRP channel may affect the pathological mechanism of systemic diseases caused by periodontitis.

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  • TRPチャネルの免疫調節機能―腸管を介した歯周病原細菌による炎症誘導メカニズムへの関与

    2013.04 - 2014.03

    新潟大学  新潟大学プロジェクト推進経費 

    野中 由香莉

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  • The effect of Treg-Th17 conversion induced by periodontopathicbacteria on osteoclastogenesis.

    Grant number:23792469  2011 - 2012

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    OKUI Takafumi, NONAK Yukari, HONDA Tomoyuki

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    Grant amount:\4160000 ( Direct Cost: \3200000 、 Indirect Cost:\960000 )

    We investigated whether the Treg-Th17 conversion is associated with the pathogenesis of periodontitis. Immunohistological analysis showed that IL-17A+FOXP3+ cells were observed only in periodontitis lesions but not in clinically healthy sites. Next, we established CD4+ T-cell lines from gingival tissues and peripheral blood of periodontitis patients. The proportion of IL-17+FOXP3+ cells in total FOXP3+ cellswas higher in gingival tissue CD4+ T-cell lines compared with peripheral blood CD4+T-cell lines.

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Teaching Experience

  • 歯周病学

    2020
    -
    Now
    機関名:新潟大学

  • 生涯にわたる歯と咬合

    2019
    -
    Now
    機関名:新潟大学

  • 歯科衛生学実習Ⅱ

    2019
    -
    Now
    機関名:新潟大学

  • 臨床実習Ⅱ

    2019
    機関名:新潟大学

  • 臨床実習Ⅲ

    2019
    機関名:新潟大学

  • 臨床予備実習

    2019
    機関名:新潟大学

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