2021/04/08 更新

写真a

ヤマモト タダシ
山本 直史
YAMAMOTO Tadashi
所属
医歯薬学域 准教授
職名
准教授

学位

  • 博士(歯学) ( 岡山大学 )

研究分野

  • ライフサイエンス / 保存治療系歯学

 

論文

  • Isolation and identification of the antimicrobial substance included in tempeh using Rhizopus stolonifer NBRC 30816 for fermentation 査読

    Masahiro Ito, Takashi Ito, Hideyuki Aoki, Koshi Nishioka, Tsugumi Shiokawa, Hiroko Tada, Yuki Takeuchi, Nobuyuki Takeyasu, Tadashi Yamamoto, Shogo Takashiba

    International Journal of Food Microbiology325   2020年7月

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    掲載種別:研究論文(学術雑誌)  

    © 2020 The Authors In this study, we focus on the antimicrobial properties of tempeh, a soybean fermented food, against oral bacteria. Tempeh showed antimicrobial activity against dental caries pathogenic bacterium Streptococcus mutans at a final concentration of 1 mg/mL. An antimicrobial substance contained in tempeh was present in the 100 kDa or greater fraction generated by ultrafiltration, but it was found not to be proteinaceous by native-PAGE, SDS-PAGE and protein degradation tests. Next, when the fraction was purified with an ODS column, the 80% and 100% methanol eluates showed antimicrobial activity against S. mutans. The 100% methanol eluate was further subjected to a 2nd column purification, and isolation of the target was confirmed by HPLC. When the isolated material was analyzed by ESI-MS, the m/z was 279.234. Further analysis by Raman spectroscopy revealed a peak similar to linoleic acid. This substance also possessed antimicrobial properties equivalent to linoleic acid.

    DOI: 10.1016/j.ijfoodmicro.2020.108645

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  • High Mobility Group Box 1 Expression in Oral Inflammation and Regeneration 査読

    Keisuke Yamashiro, Hidetaka Ideguchi, Hiroaki Aoyagi, Chiaki Yoshihara-Hirata, Anna Hirai, Risa Suzuki-Kyoshima, Yao Zhang, Hidenori Wake, Masahiro Nishibori, Tadashi Yamamoto, Shogo Takashiba

    Frontiers in Immunology11   2020年7月

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    © Copyright © 2020 Yamashiro, Ideguchi, Aoyagi, Yoshihara-Hirata, Hirai, Suzuki-Kyoshima, Zhang, Wake, Nishibori, Yamamoto and Takashiba. High mobility group box 1 (HMGB1) is a non-histone DNA-binding protein of about 30 kDa. It is released from a variety of cells into the extracellular milieu in response to inflammatory stimuli and acts on specific cell-surface receptors, such as receptors for advanced glycation end-products (RAGE), Toll-like receptor (TLR)2, TLR4, with or without forming a complex with other molecules. HMGB1 mediates various mechanisms such as inflammation, cell migration, proliferation, and differentiation. On the other hand, HMGB1 enhances chemotaxis acting through the C-X-C motif chemokine ligand (CXCL)12/C-X-C chemokine receptor (CXCR)4 axis and is involved in regeneration. In the oral cavity, high levels of HMGB1 have been detected in the gingival tissue from periodontitis and peri-implantitis patients, and it has been shown that secreted HMGB1 induces pro-inflammatory cytokine expression, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, which prolong inflammation. In contrast, wound healing after tooth extraction or titanium dental implant osseointegration requires an initial acute inflammation, which is regulated by secreted HMGB1. This indicates that secreted HMGB1 regulates angiogenesis and bone remodeling by osteoclast and osteoblast activation and promotes bone healing in oral tissue repair. Therefore, HMGB1 can prolong inflammation in the periodontal tissue and, conversely, can regenerate or repair damaged tissues in the oral cavity. In this review, we highlight the role of HMGB1 in the oral cavity by comparing its function and regulation with its function in other diseases. We also discuss the necessity for further studies in this field to provide more specific scientific evidence for dentistry.

    DOI: 10.3389/fimmu.2020.01461

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  • The fungal metabolite (+)-terrein abrogates osteoclast differentiation via suppression of the RANKL signaling pathway through NFATc1 査読 国際誌

    Saki Nakagawa, Kazuhiro Omori, Masaaki Nakayama, Hiroki Mandai, Satoshi Yamamoto, Hiroya Kobayashi, Hidefumi Sako, Kyosuke Sakaida, Hiroshi Yoshimura, Satoki Ishii, Soichiro Ibaragi, Kimito Hirai, Keisuke Yamashiro, Tadashi Yamamoto, Seiji Suga, Shogo Takashiba

    International Immunopharmacology83   106429 - 106429   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    © 2020 The Authors Pathophysiological bone resorption is commonly associated with periodontal disease and involves the excessive resorption of bone matrix by activated osteoclasts. Receptor activator of nuclear factor (NF)-κB ligand (RANKL) signaling pathways have been proposed as targets for inhibiting osteoclast differentiation and bone resorption. The fungal secondary metabolite (+)-terrein is a natural compound derived from Aspergillus terreus that has previously shown anti-interleukin-6 properties related to inflammatory bone resorption. However, its effects and molecular mechanism of action on osteoclastogenesis and bone resorption remain unclear. In the present study, we showed that 10 µM synthetic (+)-terrein inhibited RANKL-induced osteoclast formation and bone resorption in a dose-dependent manner and without cytotoxicity. RANKL-induced messenger RNA expression of osteoclast-specific markers including nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), the master regulator of osteoclastogenesis, cathepsin K, tartrate-resistant acid phosphatase (Trap) was completely inhibited by synthetic (+)-terrein treatment. Furthermore, synthetic (+)-terrein decreased RANKL-induced NFATc1 protein expression. This study revealed that synthetic (+)-terrein attenuated osteoclast formation and bone resorption by mediating RANKL signaling pathways, especially NFATc1, and indicated the potential effect of (+)-terrein on inflammatory bone resorption including periodontal disease.

    DOI: 10.1016/j.intimp.2020.106429

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  • Evaluation of the simulator with automatic irrigation control system designed for countermeasures of internal contamination in dental unit water lines 査読

    Keisuke Okubo, Takashi Ito, Kentaro Okamoto, Ichiro Yamamoto, Hajime Mizutani, Yusuke Kawata, Yasuyoshi Shiota, Masahiro Ito, Shin Nakamura, Masako Tai, Tadashi Yamamoto, Shogo Takashiba

    Heliyon6 ( 6 )   2020年6月

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    掲載種別:研究論文(学術雑誌)  

    © 2020 The Author(s) The prevention of nosocomial infections is an imperative task. The dental chair unit (DCU) is an indispensable device used in dental treatment. However, it is known that the dental unit water line (DUWL) can become contaminated with biofilm, consisting mainly of heterotrophic bacteria (HB). Recently, the International Organization for Standardization specified the methods for testing DUWL contamination management. On these grounds, a simulator reproducing DUWL was prepared to standardize the examination method of the DUWL contamination. Objectives: To evaluate the reproducibility of the DUWL simulator, monitor the DUWL contamination states, and test the efficacy of a commercial decontaminant for DUWL. Methods: The DUWL simulator was assembled by a DCU manufacturing company. The simulator's DUWL was filled with tap water (TW), and left for approximately one year. Neutral electrolyzed water (NEW) was used as a decontaminant for DUWL. Both TW and NEW were passed through DUWL in a timely manner simulating daily dental treatment. Water was sampled from the air turbine hand piece weekly for 4 weeks and used for HB culture. Contamination status was evaluated by measuring bacterial adenosine triphosphate release and by culturing on Reasoner's 2A medium. Results: The DUWL released contaminated water had a bacterial count of over 6 × 104 cfu/mL. After passing NEW through DUWL for 1 week, the count drastically decreased to its basal level and remained steady for 4 weeks. However, TW showed no effect on DUWL decontamination throughout the examination periods. Conclusions: The DUWL simulator could be useful to examine the efficacy of the decontaminant for DUWL and development of new methods in DUWL contamination management.

    DOI: 10.1016/j.heliyon.2020.e04132

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  • Functionalized Graphene Oxide Shields Tooth Dentin from Decalcification 査読

    M. Z.I. Nizami, Y. Nishina, T. Yamamoto, Y. Shinoda-Ito, S. Takashiba

    Journal of Dental Research99 ( 2 ) 182 - 188   2020年2月

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    掲載種別:研究論文(学術雑誌)  

    © International & American Associations for Dental Research 2019. This in vitro study assessed the efficacy of functionalized graphene oxide (f-GO) nanocomposites on the decalcification of dentin, because dental caries of the root surface is becoming one of the new problems in aged society. Hydroxyapatite plates (HAP) and dentin slices were coated with f-GO nanocomposites by comparing them to silver diamine fluoride as a positive control, then treated with decalcification solutions such as ethylenediaminetetraacetic acid and citrate at 37°C for 24 h. Scanning electron microscopy (SEM) revealed significant protection of the surface morphology of HAP and dentin. On the other hand, a cariogenic Streptococcus mutans growth was inhibited by f-GO nanocomposites. In addition, cytotoxicity of them to epithelial cells was much less than that of povidone-iodine, which is commonly used for oral disinfectant. We synthesized 5 different f-GO nanocomposites such as GO–silver (Ag), GO-Ag–calcium fluoride (CaF2), GO-CaF2, GO-zinc, and GO–tricalcium phosphate (Ca3(PO4)2). They were standardized by evaluating under SEM, transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), thermogravimetry analysis (TGA), and Raman spectra after being synthesized in an aseptic technique. The abilities of GO-Ag, GO-Ag-CaF2, and GO-CaF2 nanocomposites were most preventive for decalcification. In addition, GO-Ag and GO-Ag-CaF2 almost completely inhibited S. mutans growth. However, they did not exhibit cytotoxicity to epithelial cells except at the highest concentration (0.1 w/v%) of GO-Ag and GO-Ag-CaF2. Furthermore, these f-GO nanocomposites exhibited less or no discoloration of dentin, although commonly used silver diamine fluoride causes discoloration of dentin to black. Thus, these f-GO nanocomposites are useful to protect dental caries on the tooth root that becomes a social problem in aged society.

    DOI: 10.1177/0022034519894583

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  • Induction of migration of periodontal ligament cells by selective regulation of integrin subunits 査読

    Mari Kawamura, Tadashi Yamamoto, Keisuke Yamashiro, Shinsuke Kochi, Chiaki Yoshihara-Hirata, Hidetaka Ideguchi, Hiroaki Aoyagi, Kazuhiro Omori, Shogo Takashiba

    Journal of Cellular and Molecular Medicine23 ( 2 ) 1211 - 1223   2020年2月

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    掲載種別:研究論文(学術雑誌)  

    © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. The recruitment of tissue-resident stem cells is important for wound regeneration. Periodontal ligament cells (PDL cells) are heterogeneous cell populations with stemness features that migrate into wound sites to regenerate periodontal fibres and neighbouring hard tissues. Cell migration is regulated by the local microenvironment, coordinated by growth factors and the extracellular matrix (ECM). Integrin-mediated cell adhesion to the ECM provides essential signals for migration. We hypothesized that PDL cell migration could be enhanced by selective expression of integrins. The migration of primary cultured PDL cells was induced by platelet-derived growth factor-BB (PDGF-BB). The effects of blocking specific integrins on migration and ECM adhesion were investigated based on the integrin expression profiles observed during migration. Up-regulation of integrins α3, α5, and fibronectin was identified at distinct localizations in migrating PDL cells. Treatment with anti-integrin α5 antibodies inhibited PDL cell migration. Treatment with anti-integrin α3, α3-blocking peptide, and α3 siRNA significantly enhanced cell migration, comparable to treatment with PDGF-BB. Furthermore, integrin α3 inhibition preferentially enhanced adhesion to fibronectin via integrin α5. These findings indicate that PDL cell migration is reciprocally regulated by integrin α3-mediated inhibition and α5-mediated promotion. Thus, targeting integrin expression is a possible therapeutic strategy for periodontal regeneration.

    DOI: 10.1111/jcmm.14023

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  • Antimicrobial and antibiofilm effects of abietic acid on cariogenic Streptococcus mutans 査読

    Yuki Ito, Takashi Ito, Keisuke Yamashiro, Fumi Mineshiba, Kimito Hirai, Kazuhiro Omori, Tadashi Yamamoto, Shogo Takashiba

    Odontology108 ( 1 ) 57 - 65   2020年1月

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    掲載種別:研究論文(学術雑誌)  

    © 2019, The Society of The Nippon Dental University. Dental caries is a type of oral microbiome dysbiosis and biofilm infection that affects oral and systemic conditions. For healthy life expectancy, natural bacteriostatic products are ideal for daily and lifetime use as anti-oral infection agents. This study aimed to evaluate the inhibitory effects of abietic acid, a diterpene derived from pine rosin, on the in vitro growth of cariogenic bacterial species, Streptococcus mutans. The effective minimum inhibitory concentration of abietic acid was determined through observation of S. mutans growth, acidification, and biofilm formation. The inhibitory effects of abietic acid on the bacterial membrane were investigated through the use of in situ viability analysis and scanning electron microscopic analysis. Cytotoxicity of abietic acid was also examined in the context of several human cell lines using tetrazolium reduction assay. Abietic acid was found to inhibit key bacterial growth hallmarks such as colony forming ability, adenosine triphosphate activity (both planktonic and biofilm), acid production, and biofilm formation. Abietic acid was identified as bacteriostatic, and this compound caused minimal damage to the bacterial membrane. This action was different from that of povidone-iodine or cetylpyridinium chloride. Additionally, abietic acid was significantly less cytotoxic compared to povidone-iodine, and it exerted lower toxicity towards epithelial cells and fibroblasts compared to that against monocytic cells. These data suggest that abietic acid may prove useful as an antibacterial and antibiofilm agent for controlling S. mutans infection.

    DOI: 10.1007/s10266-019-00456-0

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  • Microbiome composition comparison in oral and atherosclerotic plaque from patients with and without periodontitis 査読

    Daichi Isoshima, Keisuke Yamashiro, Kazuyuki Matsunaga, Makoto Taniguchi, Takehiro Matsubara, Shuta Tomida, Shinzo Ota, Michiyoshi Sato, Yutaka Shimoe, Tatsuo Kohriyama, Zulema Arias, Kazuhiro Omori, Tadashi Yamamoto, Shogo Takashiba

    Odontology   2020年

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    掲載種別:研究論文(学術雑誌)  

    © 2020, The Society of The Nippon Dental University. There is no conclusive evidence regarding a causal relationship between periodontitis and atherosclerosis. In this study, we examined the microbiome in the oral cavity and atheromatous plaques from atherosclerosis patients with or without periodontitis to investigate the role of oral bacteria in the formation of atheromatous plaques. We chose four patients with and without periodontitis, who had undergone carotid endarterectomy. Bacterial samples were extracted from the tongue surface, from periodontal pocket (during the oral examination), and from the atheromatous plaques (APs). We investigated the general and oral conditions from each patient and performed next-generation sequencing (NGS) analysis for all bacterial samples. There were no significant differences between both groups concerning general conditions. However, the microbiome patterns of the gingival pocket showed differences depending on the absence or presence of periodontitis, while those of the tongue surface were relatively similar. The microbiome pattern of the atheromatous plaques was entirely different from that on the tongue surface and gingival pocket, and oral bacteria were seldom detected. However, the microbiome pattern in atheromatous plaques was different in the presence or absence of periodontitis. These results suggested that oral bacteria did not affect the formation of atheromatous plaques directly.

    DOI: 10.1007/s10266-020-00524-w

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  • Acceleration of bone regeneration of horizontal bone defect in rats using collagen-binding basic fibroblast growth factor combined with collagen scaffolds 査読 国際誌

    Shin Nakamura, Takashi Ito, Kentaro Okamoto, Takehiko Mima, Kentaro Uchida, Yasir D. Siddiqui, Masahiro Ito, Masako Tai, Keisuke Okubo, Keisuke Yamashiro, Kazuhiro Omori, Tadashi Yamamoto, Osamu Matsushita, Shogo Takashiba

    Journal of Periodontology90 ( 9 ) 1043 - 1052   2019年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    © 2019 The Authors. Journal of Periodontology published by Wiley Periodicals, Inc. on behalf of American Academy of Periodontology Background: Basic fibroblast growth factor (bFGF) has been applied for periodontal regeneration. However, the application depends on bone defect morphology because bFGF diffuses rapidly from defect sites. In a previous study, collagen-binding bFGF (CB-bFGF) has been shown to enhance bone formation by collagen-anchoring in the orthopedic field. The aim of this study is to demonstrate the efficacy of CB-bFGF with collagen scaffolds in bone regeneration of horizontal bone defect. Methods: Cell proliferation activity and collagen binding activity of CB-bFGF was confirmed by WST-8 assay and collagen binding assay, respectively. The retention of CB-bFGF in the collagen sheet (CS) was measured by fluorescence imaging. The rat horizontal alveolar bone defect model was employed to investigate the efficacy of CB-bFGF with collagen powder (CP). After 4 and 8 weeks, the regenerative efficacy was evaluated by microcomputed tomography, histological, and immunohistochemical analyses. Results: CB-bFGF had a comparable proliferation activity to bFGF and a collagen binding activity. CB-bFGF was retained in CS longer than bFGF. At 8 weeks postoperation, bone volume, bone mineral content, and new bone area in CB-bFGF/CP group were significantly increased compared with those in other groups. Furthermore, epithelial downgrowth was significantly suppressed in CB-bFGF/CP group. At 4 weeks, the numbers of osteocalcin, proliferating cell nuclear antigen, and osteopontin-positive cells at the regeneration site in CB-bFGF/CP group were greater than those in other groups. Conclusions: CB-bFGF/CP effectively promoted bone regeneration of horizontal bone defect possibly by sustained release of bFGF. The potential of CB-bFGF composite material for improved periodontal regeneration in vertical axis was shown.

    DOI: 10.1002/JPER.18-0674

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  • Effectiveness and safety of low-concentrated ozonized water for the reduction of contamination in dental unit water lines 査読

    Keisuke Okubo, Takashi Ito, Yasuyoshi Shiota, Yusuke Kawata, Tadashi Yamamoto, Shogo Takashiba

    Heliyon5 ( 8 ) e02306   2019年8月

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    掲載種別:研究論文(学術雑誌)  

    © 2019 The Authors Contamination of dental unit waterlines (DUWL) with heterotrophic bacteria can cause problems in immune compromised patients (aged, tumor and organ transplantation-patients). We focused on the use of low-concentrated ozonized water (OZW) as the biofilm formation restraint system for DUWL. Here, we examined the effects of low-concentrated OZW on the growth of bacteria and related biofilm formation and harmfulness to dental unit components (DUCs) in vitro. Objectives: To evaluate the bactericidal effects of OZW on biofilms in DUWL and DUC in vitro. Methods: Low-concentrated OZW (0.4 mg/L) was generated using an OZS-PTDX generator. Heterotrophic bacterial biofilms in old DUWL tubes and Candia albicans solution (control microbe) were treated with OZW for 1 h with gentle agitation before static culturing for 96 h in Reasoner's 2A liquid media. The control solutions were 0.1% cetylpyridinium chloride (CPC), chlorinated tap water (TW), and phosphate-buffered saline (PBS). Adenosine triphosphate (ATP) amounts of the microbes were measured and the biofilms of these microbes were observed using scanning electron microscopy (SEM). Moreover, surfaces of DUC soaked in OZW and TW were observed by SEM. Results: The OZW reduced ATP levels in microbes to 50% compared to TW and PBS treatment, although CPC reduced it below detection limits. SEM observation revealed deformation of microbes cultured with OZW, whereas no changes were seen on DUC surfaces. Conclusions: Low-concentrated OZW is bactericidal against heterotrophic bacteria biofilms and it is not harmful to DUC, suggesting that it might be useful in preventing DUWL contamination.

    DOI: 10.1016/j.heliyon.2019.e02306

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  • Molecular imaging assessment of periodontitis lesions in an experimental mouse model 査読

    Hidetaka Ideguchi, Keisuke Yamashiro, Tadashi Yamamoto, Masayuki Shimoe, Shoichi Hongo, Shinsuke Kochi, Chiaki Yoshihara-Hirata, Hiroaki Aoyagi, Mari Kawamura, Shogo Takashiba

    Clinical Oral Investigations23 ( 2 ) 821 - 827   2019年2月

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

    © 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Objective: We aimed to evaluate molecular imaging as a novel diagnostic tool for mice periodontitis model induced by ligature and Porphyromonas gingivalis (Pg) inoculation. Materials and methods: Twelve female mice were assigned to the following groups: no treatment as control group (n = 4); periodontitis group induced by ligature and Pg as Pg group (n = 4); and Pg group treated with glycyrrhizinic acid (GA) as Pg + GA group (n = 4). All mice were administered a myeloperoxidase (MPO) activity-specific luminescent probe and observed using a charge-coupled device camera on day 14. Image analysis on all mice was conducted using software to determine the signal intensity of inflammation. Additionally, histological and radiographic evaluation for periodontal inflammation and bone resorption at the site of periodontitis, and quantitative enzyme-linked immunosorbent assay (ELISA) were conducted on three mice for each group. Each experiment was performed three times. Results: Levels of serum IgG antibody against P. gingivalis were significantly higher in the Pg than in the Pg + GA group. Histological analyses indicated that the number of osteoclasts and neutrophils were significantly lower in the Pg + GA than in the Pg group. Micro-CT image analysis indicated no difference in bone resorption between the Pg and Pg + GA groups. The signal intensity of MPO activity was detected on the complete craniofacial image; moreover, strong signal intensity was localized specifically at the periodontitis site in the ex vivo palate, with group-wise differences. Conclusions: Molecular imaging analysis based on MPO activity showed high sensitivity of detection of periodontal inflammation in mice. Clinical relevance: Molecular imaging analysis based on MPO activity has potential as a diagnostic tool for periodontitis.

    DOI: 10.1007/s00784-018-2510-2

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  • Resolvin D2 induces resolution of periapical inflammation and promotes healing of periapical lesions in rat periapical periodotitis 査読

    Yasir Dilshad Siddiqui, Kazuhiro Omori, Takashi Ito, Keisuke Yamashiro, Shin Nakamura, Kentaro Okamoto, Mitsuaki Ono, Tadashi Yamamoto, Thomas E.Van Dyke, Shogo Takashiba

    Frontiers in Immunology10 ( FEB ) 307   2019年

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    掲載種別:研究論文(学術雑誌)  

    © 2019 Frew. Periapical periodontitis results from pulpal infection leading to pulpal necrosis and resorption of periapical bone. The current treatment is root canal therapy, which attempts to eliminate infection and necrotic tissue. But, in some cases periapical inflammation doesn't resolve even after treatment. Resolvins belongs to a large family of specialized pro-resolving lipid mediators that actively resolves inflammation signaling via specific receptors. Resolvin D2 (RvD2), a metabolite of docosahexaenoic acid (DHA), was tested as an intracanal medicament in rats in vivo. Mechanism was evaluated in rat primary dental pulp cells (DPCs) in vitro. The results demonstrate that RvD2 reduces inflammatory cell infiltrate, periapical lesion size, and fosters pulp like tissue regeneration and healing of periapical lesion. RvD2 enhanced expression of its receptor, GPR18, dentin matrix acidic phosphoprotein 1 (DMP1) and mineralization in vivo and in vitro. Moreover, RvD2 induces phosphorylation of Stat3 transcription factor in dental pulp cells. We conclude that intracanal treatment with RvD2 resolves inflammation and promoting calcification around root apex and healing of periapical bone lesions. The data suggest that RvD2 induces active resolution of inflammation with pulp-like tissue regeneration after root canal infection and thus maybe suitable for treating periapical lesions.

    DOI: 10.3389/fimmu.2019.00307

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  • Fungal metabolite (+)-terrein suppresses IL-6/sIL-6R-induced CSF1 secretion by inhibiting JAK1 phosphorylation in human gingival fibroblasts 査読 国際誌

    Satoshi Yamamoto, Kazuhiro Omori, Hiroki Mandai, Masaaki Nakayama, Saki Nakagawa, Hiroya Kobayashi, Tadashi Kunimine, Hiroshi Yoshimura, Kyosuke Sakaida, Hidefumi Sako, Soichiro Ibaragi, Tadashi Yamamoto, Hiroshi Maeda, Seiji Suga, Shogo Takashiba

    Heliyon4 ( 11 ) e00979   2018年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    © 2018 The Authors Control of bacterial infection-induced inflammatory responses is one of the effective therapeutic approaches of periodontal diseases. Natural products such as lipid mediators and metabolites from microorganisms have been used for decreasing inflammation. We previously reported that (+)-terrein inhibited activation of STAT3 and ERK1/2 in interleukin-6 (IL-6) signaling cascade, leading to prevent vascular endothelial growth factor (VEGF) secretion in human gingival fibroblasts (HGFs). However, little is still known about the role of (+)-terrein on inflammatory responses. In this study, we provided the possibility of novel action that (+)-terrein inhibits activation of Janus-activated kinase 1 (JAK1), which has a central function in IL-6 signaling cascade, and alters expression of mRNAs and proteins induced by IL-6/soluble IL-6 receptor (sIL-6R) stimulation in HGFs. First, we performed PCR array to examine IL-6/sIL-6R-induced mRNA expression, and then expression of mRNA and protein of colony stimulating factor-1 (CSF1) and VEGF were clearly determined by quantitative RT-PCR and ELISA, respectively. Treatment with (+)-terrein suppressed expression of mRNA and protein of CSF1 and VEGF by IL-6/sIL-6R stimulation. Next, to test the effect of (+)-terrein on IL-6/sIL-6R signaling cascade, we demonstrated whether (+)-terrein affects phosphorylation of JAK1 and its downstream proteins, Akt and SHP-2. Western blotting revealed that (+)-terrein inhibited IL-6/sIL-6R-induced phosphorylation of JAK1, Akt, and SHP-2. Therefore, (+)-terrein suppresses IL-6/sIL-6R-induced expression of CSF1 and VEGF via inhibition of JAK1, Akt, and SHP-2. Based on our results, we suggest that (+)-terrein is a candidate compound for anti-inflammatory effect associated with IL-6 signaling.

    DOI: 10.1016/j.heliyon.2018.e00979

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  • HMGB1-induced inflammatory response promotes bone healing in murine tooth extraction socket 査読

    Hiroaki Aoyagi, Keisuke Yamashiro, Chiaki Hirata-Yoshihara, Hidetaka Ideguchi, Mutsuyo Yamasaki, Mari Kawamura, Tadashi Yamamoto, Shinsuke Kochi, Hidenori Wake, Masahiro Nishibori, Shogo Takashiba

    Journal of Cellular Biochemistry119 ( 7 ) 5481 - 5490   2018年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley-Liss Inc.  

    © 2018 Wiley Periodicals, Inc. High mobility group box 1 (HMGB1) is a non-histone DNA-binding protein that is secreted into the extracellular milieu in response to inflammatory stimuli. The secreted HMGB1 has been suggested to mediate various inflammatory diseases. However, it is still unknown whether HMGB1 is involved in a healing process in the tooth extraction socket, the tissue containing gingival epithelium, and alveolar bone that is exposed to oral bacteria. In this study, we constructed a murine tooth extraction model with anti-HMGB1 neutralization antibody administration and observed the inflammatory response and bone healing process in tooth extraction sockets by molecular imaging of myeloperoxidase (MPO) activity, histological analysis, and quantitative RT-PCR. The translocation of HMGB1 from the nucleus to the cytoplasm in gingival epithelial cells and inflammatory cells was inhibited by anti-HMGB1 antibody administration. The MPO activity around the tooth extraction socket was significantly reduced, and the numbers of CD31- and CD68-positive cells were significantly lower in the anti-HMGB1 antibody treatment samples than in the control samples. The TRAP-positive cells, osteocalcin positive cells, and the neoplastic bone area were significantly lower in anti-HMGB1 antibody treatment samples than in control samples. The expression levels of IL-1β and VEGF-A were also decreased in anti-HMGB1 antibody treatment samples compared to that in control samples. Secreted HMGB1 induced initial acute inflammation and inflammatory cells recruitment after tooth extraction. HMGB1 was associated with angiogenesis and bone remodeling by osteoclast and osteoblast activation and promoted bone healing in the tooth extraction socket.

    DOI: 10.1002/jcb.26710

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  • Anti-HMGB1 neutralizing antibody attenuates periodontal inflammation and bone resorption in a murine periodontitis model 査読

    Chiaki Yoshihara-Hirata, Keisuke Yamashiro, Tadashi Yamamoto, Hiroaki Aoyagi, Hidetaka Ideguchi, Mari Kawamura, Risa Suzuki, Mitsuaki Ono, Hidenori Wake, Masahiro Nishibori, Shogo Takashiba

    Infection and Immunity86 ( 5 )   2018年5月

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

    © 2018 American Society for Microbiology. High mobility group box 1 (HMGB1) is a non-histone DNA-binding protein that is secreted into the extracellular milieu in response to inflammatory stimuli. The secreted HMGB1 mediates various inflammatory diseases, including periodontitis; however, the underlying mechanisms of HMGB1-induced periodontal inflammation are not completely understood. Here, we examined whether anti-HMGB1 neutralizing antibody inhibits periodontal progression and investigated the molecular pathology of HMGB1 in vitro and in vivo. In vitro analysis indicated that HMGB1, granulocytemacrophage colony-stimulating factor (GM-CSF), and interleukin-1β (IL-1β) were secreted in response to tumor necrosis factor-α (TNF-α) stimuli in human gingival epithelial cells (HGECs) and human monocytic leukemia cells (THP-1) treated with phorbol myristate acetate. Increased levels of GM-CSF and IL-1β were observed in the conditioned media from TNF-α-stimulated HGECs and THP-1 in vitro. Simultaneous stimulation with TNF-α and anti-HMGB1 antibody significantly decreased TNF-α- induced inflammatory cytokine secretion. Experimental periodontitis was induced in mice using Porphyromonas gingivalis-soaked ligatures. The extracellular translocation was confirmed in gingival epithelia in the periodontitis model mice by immunofluorescence analysis. Systemic administration of anti-HMGB1 neutralizing antibody significantly inhibited translocation of HMGB1. The anti-HMGB1 antibody inhibited periodontal inflammation, expression of IL-1β and C-X-C motif chemokine ligand 1 (CXCL1), migration of neutrophils, and bone resorption, shown by bioluminescence imaging of myeloperoxidase activity, quantitative reverse transcription-PCR (RT-PCR), and micro-computed tomography analysis. These findings indicate that HMGB1 is secreted in response to inflammatory stimuli caused by periodontal infection, which is crucial for the initiation of periodontitis, and the anti-HMGB1 antibody attenuates the secretion of a series of inflammatory cytokines, consequently suppressing the progression of periodontitis.

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  • Correction to: Expression of optineurin isolated from rat-injured dental pulp and the effects on inflammatory signals in normal rat kidney cells (Odontology, (2018), 106, 2, (135-144), 10.1007/s10266-017-0314-5) 査読

    Kyoko Senoo, Keisuke Yamashiro, Tadashi Yamamoto, Fumio Myokai, Mari Kawamura, Shogo Takashiba

    Odontology106 ( 2 ) 223   2018年4月

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    掲載種別:研究論文(学術雑誌)  

    © 2017, The Society of The Nippon Dental University. In the original publication of the article, one of the author name was published incorrectly as “Keisuke Yamashairo” and correct name should be “Keisuke Yamashiro”.

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  • Expression of optineurin isolated from rat-injured dental pulp and the effects on inflammatory signals in normal rat kidney cells 査読

    Kyoko Senoo, Keisuke Yamashiro, Tadashi Yamamoto, Fumio Myokai, Mari Kawamura, Shogo Takashiba

    Odontology106 ( 2 ) 135 - 144   2018年4月

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

    © 2017, The Society of The Nippon Dental University. We previously isolated rat 14.7K-interacting protein-2 (rFIP-2) from the rat-wounded pulp. The protein, homologous to human FIP-2, is known as optineurin and was initially identified as a novel tumor necrosis factor-α (TNF-α)-inducible protein, and more recently, as an autophagy receptor. However, the biological role of optineurin in dental pulp remains elusive. We hypothesized that optineurin has a crucial role in regulating molecular processes during pulp inflammatory responses induced by TNF-α. We examined the kinetics of optineurin expression in pulp inflammation. Optineurin localization and expression were examined using rat pulp fibroblasts. The cells were treated with pharmacological inhibitors for TNF-α-induced inflammatory signals or with hydrogen peroxide as apoptotic stimuli. Stable optineurin-knockdown cells (OPTN-KD cells) were established by transfecting normal rat kidney cells with a vector expressing optineurin-specific small interfering RNA. Cell proliferation and the profiles of cytokines and intracellular signaling molecules were examined using OPTN-KD cells stimulated by TNF-α. Optineurin was localized in the cytoplasm and then translocated into the nucleus upon apoptotic stimuli. Optineurin expression was increased by TNF-α and decreased by a specific inhibitor of c-Jun N-terminal kinase. The OPTN-KD cells secreted smaller amounts of monocyte chemotactic protein-1 (MCP-1) and intracellular MCP-1 mRNA, and cell proliferation was significantly increased. Apoptosis-related signaling molecules were downregulated in OPTN-KD cells. These results demonstrated that optineurin is a crucial molecule mediated by TNF-α, which induces the production of inflammatory factors and apoptosis signaling, suggesting the presence of signaling interactions between optineurin and a transcription factor for MCP-1.

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  • Modulation of microenvironment for controlling the fate of periodontal ligament cells: the role of Rho/ROCK signaling and cytoskeletal dynamics 査読

    Tadashi Yamamoto, Yuki Ugawa, Mari Kawamura, Keisuke Yamashiro, Shinsuke Kochi, Hidetaka Ideguchi, Shogo Takashiba

    Journal of Cell Communication and Signaling12 ( 1 ) 369 - 378   2018年3月

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    記述言語:英語   出版者・発行元:Springer Netherlands  

    © 2017, The International CCN Society. Cells behave in a variety of ways when they perceive changes in their microenvironment; the behavior of cells is guided by their coordinated interactions with growth factors, niche cells, and extracellular matrix (ECM). Modulation of the microenvironment affects the cell morphology and multiple gene expressions. Rho/Rho-associated coiled-coil-containing protein kinase (ROCK) signaling is one of the key regulators of cytoskeletal dynamics and actively and/or passively determines the cell fate, such as proliferation, migration, differentiation, and apoptosis, by reciprocal communication with the microenvironment. During periodontal wound healing, it is important to recruit the residential stem cells into the defect site for regeneration and homeostasis of the periodontal tissue. Periodontal ligament (PDL) cells contain a heterogeneous fibroblast population, including mesenchymal stem cells, and contribute to the reconstruction of tooth-supporting tissues. Therefore, bio-regeneration of PDL cells has been the ultimate goal of periodontal therapy for decades. Recent stem cell researches have shed light on intrinsic ECM properties, providing paradigm shifts in cell fate determination. This review focuses on the role of ROCK activity and the effects of Y-27632, a specific inhibitor of ROCK, in the modulation of ECM-microenvironment. Further, it presents the current understanding of how Rho/ROCK signaling affects the fate determination of stem cells, especially PDL cells. In addition, we have also discussed in detail the underlying mechanisms behind the reciprocal response to the microenvironment.

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  • Effects of Lectins on initial attachment of cariogenic Streptococcus mutans 査読

    Takashi Ito, Yasuhiro Yoshida, Yasuyoshi Shiota, Yuki Ito, Tadashi Yamamoto, Shogo Takashiba

    Glycoconjugate Journal35 ( 1 ) 41 - 51   2018年2月

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

    © 2017, Springer Science+Business Media, LLC. Oral bacteria initiate biofilm formation by attaching to tooth surfaces via an interaction of a lectin-like bacterial protein with carbohydrate chains on the pellicle. This study aimed to find naturally derived lectins that inhibit the initial attachment of a cariogenic bacterial species, Streptococcus mutans (S. mutans), to carbohydrate chains in saliva in vitro. Seventy kinds of lectins were screened for candidate motifs that inhibit the attachment of S. mutans ATCC 25175 to a saliva-coated culture plate. The inhibitory effect of the lectins on attachment of the S. mutans to the plates was quantified by crystal violet staining, and the biofilm was observed under a scanning electron microscope (SEM). Surface plasmon resonance (SPR) analysis was performed to examine the binding of S. mutans to carbohydrate chains and the binding of candidate lectins to carbohydrate chains, respectively. Moreover, binding assay between the biotinylated-lectins and the saliva components was conducted to measure the lectin binding. Lectins recognizing a salivary carbohydrate chain, Galβ1-3GalNAc, inhibited the binding of S. mutans to the plate. In particular, Agaricus bisporus agglutinin (ABA) markedly inhibited the binding. This inhibition was confirmed by SEM observation. SPR analysis indicated that S. mutans strongly binds to Galβ1-3GalNAc, and ABA binds to Galβ1-3GalNAc. Finally, the biotinylated Galβ1-3GalNAc-binding lectins including ABA demonstrated marked binding to the saliva components. These results suggest that ABA lectin inhibited the attachment of S. mutans to Galβ1-3GalNAc in saliva and ABA can be useful as a potent inhibitor for initial attachment of oral bacteria and biofilm formation.

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  • IS1598 (IsPg4) distributed to abscess-forming strains of Porphyromonas gingivalis may enhance virulence through upregulation of nrdD-like gene expression 査読

    Norihiro Sonoi, Hiroshi Maeda, Toshimitsu Murauchi, Tadashi Yamamoto, Kazuhiro Omori, Susumu Kokeguchi, Koji Naruishi, Shogo Takashiba

    New Microbiologica41 ( 1 ) 52 - 60   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Luigi Ponzio e figlio Editori  

    ©2018 by EDIMES-Edizioni Internazionali Srl. All rights reserved. An insertion sequence, IS1598 (IsPg4) has been found in virulent strains of Porphyromonas gingivalis in a murine abscess model. The present study was performed to investigate the effects of genetic rearrangements by IS1598 on the phenotypic characteristics of the virulent strains. For this purpose, we searched for a common insertion site of IS1598 among the virulent strains. Through cloning and database search, a common insertion site was identified beside an nrdD-like gene in the virulent FDC 381, W83 and W50 strains. In this region, predicted promoters of the nrdD-like gene and IS1598 are located in tandem, and accumulation of nrdD-like gene mRNA was 5-fold higher in virulent strains (W83, W50, FDC 381) than avirulent strains (ATCC33277, SU63, SUNY1021, ESO59 without IS1598). The role of the nrdD-like gene in virulence of P. gingivalis was investigated by constructing a nrdD-deficient mutant. In the murine abscess model, the parental W83 strain produced necrotic abscesses, while the nrdD-deficient mutant had almost lost this ability. Insertion of IS1598 into the nrdD-like gene promoter region may be related to the phenotypic differences in virulence among P. gingivalis strains through upregulation of the expression of this gene.

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  • Aggregatibacter actinomycetemcomitans regulates the expression of integrins and reduces cell adhesion via integrin α5 in human gingival epithelial cells. 査読

    Kochi S, Yamashiro K, Hongo S, Yamamoto T, Ugawa Y, Shimoe M, Kawamura M, Hirata-Yoshihara C, Ideguchi H, Maeda H, Takashiba S

    Molecular and cellular biochemistry436 ( 1-2 ) 39 - 48   2017年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Assessment of pathogenesis of infective endocarditis by plasma IgG antibody titer test against periodontal bacteria. 査読

    Isoshima D, Yamashiro K, Matsunaga K, Shinobe M, Nakanishi N, Nakanishi I, Omori K, Yamamoto T, Takashiba S

    Clinical case reports5 ( 10 ) 1580 - 1586   2017年10月

  • Rho-kinase regulates extracellular matrix-mediated osteogenic differentiation of periodontal ligament cells 査読

    Yuki Ugawa, Tadashi Yamamoto, Mari Kawamura, Keisuke Yamashiro, Masayuki Shimoe, Kazuya Tomikawa, Shoichi Hongo, Hiroshi Maeda, Shogo Takashiba

    CELL BIOLOGY INTERNATIONAL41 ( 6 ) 651 - 658   2017年6月

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

    The periodontal ligament (PDL) cells contain heterogeneous mesenchymal cell populations, which have the ability to differentiate into cells that produce adjacent mineralized tissues and abundant extracellular matrix (ECM). ECM is essential not only for the homeostasis of the periodontal tissue, but also for controlling the differentiation of the PDL cells. The process of differentiation involves mechanotransduction, which links the ECM to the cytoskeleton. The present study investigated the roles of Rho-associated coiled-coil containing protein kinase (ROCK) signaling, a crucial regulator of the cytoskeleton, during ECM-mediated osteogenic differentiation of PDL cells in vitro. The PDL cells were isolated from human periodontal ligaments of extracted teeth and cultured in osteogenic medium with or without Y-27632, a pharmacological inhibitor of ROCK. ECMcoated plates were used for ECM-mediated differentiation. The osteogenic phenotype was evaluated at different time points by real-time RT-PCR for the gene encoding alkaline phosphatase (ALP) and an ALP activity assay. The effects of ROCK on cytoskeletal changes and ECM synthesis were examined by immunofluorescence analysis. Y-27632 significantly inhibited ALP at the mRNA and protein activity levels in the late stage of differentiation; concomitantly, the actin filament content and the extracellular levels of collagen-I and fibronectin were markedly decreased by Y-27632. Exogenous collagen-I and fibronectin temporally increased ALP activity, with fibronectin showing a more pronounced effect. Importantly, ECM-mediated differentiation was almost completely inhibited by Y-27632. These findings indicated that ECM-mediated differentiation is dependent on ROCK signaling, and ROCK signaling contributes to the establishment of the ECM microenvironment for PDL cell differentiation.

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  • Smad2 overexpression enhances adhesion of gingival epithelial cells 査読

    Shoichi Hongo, Tadashi Yamamoto, Keisuke Yamashiro, Masayuki Shimoe, Kazuya Tomikawa, Yuki Ugawa, Shinsuke Kochi, Hidetaka Ideguchi, Hiroshi Maeda, Shogo Takashiba

    ARCHIVES OF ORAL BIOLOGY71   46 - 53   2016年11月

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

    Objective: Gingival epithelial cells play an important role in preventing the initiation of periodontitis, by their hemidesmosomal adhesion to the tooth root surface. Adhesion requires integrin-extracellular matrix (ECM) interactions that are intricately regulated by transforming growth factor-beta (TGF-beta) signaling. However, the mechanisms underlying the interplay between adhesion molecules and TGF-beta, especially the respective roles of Smad2 and Smad3, remain elusive. In this study, we examined the effects of Smad overexpression on gingival epithelial cell adhesion and expression profiles of integrin and ECM-related genes.
    Methods: Human gingival epithelial cells immortalized by the SV40 T-antigen were transfected with Smad2- and Smad3-overexpression vectors. A cell adhesion assay involving fluorescence detection of attached cells was performed using the ArrayScan imaging system. Real-time PCR was performed to examine the kinetics of integrin and ECM gene expression. In vitro and in vivo localization of adhesion molecules was examined by immunofluorescence analysis.
    Results: By using SB431542, a specific inhibitor of the TGF-beta type I receptor, Smad2/3 signaling was confirmed to be dominant in TGF-beta 1-induced cell adhesion. The Smad2-transfectant demonstrated higher potency for cell adhesion and integrin expression (alpha 2, alpha 5, beta 4, and beta 6) than the Smad3-transfectant, whereas little or no change in ECM expression was observed in either transfectant. Moreover, the gingival epithelium of transgenic mice that overexpressed Smad2 driven by the keratin 14 promoter showed increased integrin alpha 2 expression.
    Conclusion: These findings indicate the crucial role of Smad2 in increased adhesion of gingival epithelial cells via upregulation of integrin alpha 2. (C) 2016 Elsevier Ltd. All rights reserved.

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  • Osteogenic differentiation regulated by Rho-kinase in periodontal ligament cells 査読

    Tadashi Yamamoto, Yuki Ugawa, Keisuke Yamashiro, Masayuki Shimoe, Kazuya Tomikawa, Shoichi Hongo, Shinsuke Kochi, Hidetaka Ideguchi, Hiroshi Maeda, Shogo Takashiba

    DIFFERENTIATION88 ( 2-3 ) 33 - 41   2014年9月

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

    The periodontal ligament is a multifunctional soft connective tissue, which functions not only as a cushion supporting the teeth against occlusal force, but is also a source of osteogenic cells that can regenerate neighboring hard tissues. Periodontal ligament cells (PDL cells) contain heterogeneous cell populations, including osteogenic cell progenitors. However, the precise mechanism underlying the differentiation process remains elusive. Cell differentiation is regulated by the local biochemical and mechanical microenvironment that can modulate gene expression and cell morphology by altering actin cytoskeletal organization mediated by Rho-associated, coiled-coil containing protein kinase (ROCK). To determine its role in PDL cell differentiation, we examined the effects of ROCK on cytoskeletal changes and kinetics of gene expression during osteogenic differentiation. PDL cells were isolated from human periodontal ligament on extracted teeth and cultured in osteogenic medium for 14 days. Y-27632 was used for ROCK inhibition assay. Osteogenic phenotype was determined by monitoring alkaline phosphatase (ALP) activity and calcium deposition by Alizarin Red staining. ROCK-induced cytoskeletal changes were examined by immunofluorescence analysis of F-actin and myosin light chain 2 (MLC2) expression. Real-time PCR was performed to examine the kinetics of osteogenic gene expression. F-actin and phospho-MLC2 were markedly induced during osteogenic differentiation, which coincided with upregulation of ALP activity and mineralization. Subsequent inhibition assay indicated that Y-27632 significantly inhibited F-actin and phospho-MLC2 expression in a dose dependent manner with concomitant partial reversal of the PDL cell osteogenic phenotype. PCR array analysis of osteogenic gene expression indicated that extracellular matrix genes, such as fibronectin 1, collagen type I and Ill, and biglycan, were significantly downregulated by Y27632. These findings indicated crucial effects of ROCK in cytoskeletal reorganization and differentiation of PDL cells toward osteogenic cells. ROCK contributes to induction of osteogenic differentiation by synergistic increases in extracellular matrix gene expression in PDL cells. (C) 2014 International Society of Differentiation, Published by Elsevier B.V. All rights reserved.

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  • Overexpression of Smad2 inhibits proliferation of gingival epithelial cells 査読

    M. Shimoe, T. Yamamoto, N. Shiomi, K. Tomikawa, S. Hongo, K. Yamashiro, T. Yamaguchi, H. Maeda, S. Takashiba

    JOURNAL OF PERIODONTAL RESEARCH49 ( 3 ) 290 - 298   2014年6月

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

    Background and Objective
    Spatiotemporal inhibition of apical migration and proliferation of gingival epithelium are significant factors involved in periodontal regeneration. Transforming growth factor beta (TGF-beta) is important in multiple aspects of wound healing, and Smad2, a downstream transcription factor of TGF-beta, has an inhibitory effect on re-epithelialization during gingival wound healing. Therefore, we investigated the effects on migration and proliferation status, and intra/extracellular signaling regulated by Smad2 overexpression in gingival epithelial cells.
    Material and Methods
    Gingival epithelial cells were isolated from the palatal gingival tissue of transgenic mice overexpressing Smad2 driven by the Keratin14 promoter. Smad2 expression was identified by western blotting and immunofluorescence analysis. Scratch assay and 5-bromo-2 '-deoxyuridine staining were performed to assess cell migration and proliferation. To inactivate TGF-beta type I receptor, the cultures were supplemented with SB431542. Secreted TGF-beta was quantified by ELISA. Smad2 target gene expression was examined by real-time RT-PCR and in vivo immunofluorescence analysis of gingival junctional epithelium.
    Results
    Smad2-overexpressing cells were confirmed to have significant phosphorylated Smad2 in the nucleus. Scratch assay and 5-bromo-2 '-deoxyuridine staining indicated that Smad2-overexpressing cells showed no significant differences in migration, but had reduced proliferation rates compared to wild-type controls. SB431542 significantly inhibited Smad2 phosphorylation, which coincided with restoration of the proliferation rate in Smad2-overexpressing cells. ELISA of TGF-beta release did not show any differences between genotypes. The cell cycle inhibitors, p15 and p21, showed significant upregulation in Smad2-overexpressing cells compared to wild-type controls. Moreover, junctional epithelium of the transgenic mice showed increased expression of P-Smad2, p15 and p21.
    Conclusion
    The signaling activation triggered by overexpression of Smad2 was dependent on TGF-beta type I receptor, and the activated Smad2 increased p15 and p21 expression, responsible for inhibiting cell cycle entry, resulting in antiproliferative effects on gingival epithelial cells. Understanding of Smad2-induced signaling would be useful for possible clinical application to regulate gingival epithelial downgrowth.

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  • Serum antibody response to group II chaperonin from Methanobrevibacter oralis and human chaperonin CCT 査読

    Kimito Hirai, Hiroshi Maeda, Kazuhiro Omori, Tadashi Yamamoto, Susumu Kokeguchi, Shogo Takashiba

    PATHOGENS AND DISEASE68 ( 1 ) 12 - 19   2013年6月

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

    Both group I (HSP60) and group II (CCT) chaperonins are targets of autoantibodies. Autoimmune reactions to HSP60 have been well characterized, while immune reactions to group II chaperonin have not been clarified. Methanobrevibacter oralis is a suspected periodontal pathogen with group II chaperonin. In this study, serum responses to M.oralis chaperonin, human HSP60, and CCT subunits were examined using sera from patients with periodontitis and autoimmune diseases. In comparison with healthy controls, periodontitis patients showed significantly higher responses to CCT4 and CCT8 on dot blot analysis. Signals for CCT3 and CCT8 in autoimmune disease patients were significantly higher than in controls. Significant differences were also demonstrated by Western blotting in anti-CCT4 response in both patient groups. All subjects showed strong reactivity to M.oralis chaperonin and faint signals to human HSP60. Autoantibodies were raised against CCT rather than HSP60; and CCT3, CCT4, and CCT8 were shown to be the main targets. Host immune systems may be frequently exposed to chaperonins of Archaea in various habitats. Although further studies of the cross-reactivity between M.oralis chaperonin and human CCT are required, anti-CCT autoantibodies may be involved in the pathogenesis of periodontitis and autoimmune diseases.

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  • Medical microbiological approach to Archaea in oral infectious diseases 査読

    Hiroshi Maeda, Kimito Hirai, Junji Mineshiba, Tadashi Yamamoto, Susumu Kokeguchi, Shogo Takashiba

    Japanese Dental Science Review49 ( 2 ) 72 - 78   2013年5月

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    記述言語:英語  

    Recent advances in molecular biological techniques have yielded large amounts of information regarding the oral microflora. The microbiological communities were shown to be more diverse than previously thought and to include a number of previously uncharacterized microorganisms. The range of research targets of microorganisms associated with oral diseases has been expanded to include these unknown or uncharacterized organisms. These organisms include the Archaea. A series of recent reports suggested these microorganisms to be potential pathogens involved in periodontitis and apical periodontitis mainly based on the detection frequency or their increased numbers in diseased sites in association with the severity or symptoms of disease. However, it cannot be concluded that Archaea are oral pathogens based on such circumstantial evidence. Further studies are required to investigate the potential pathogenic mechanisms of action of these organisms. This will require investigation of the antigenic properties of the Archaea and synergism with other established oral pathogens. Especially, studies of the host immune response will provide insight into the medical impact of Archaea as suspected pathogens. © 2013 Japanese Association for Dental Science.

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  • Smad2 Decelerates Re-epithelialization during Gingival Wound Healing 査読

    K. Tomikawa, T. Yamamoto, N. Shiomi, M. Shimoe, S. Hongo, K. Yamashiro, T. Yamaguchi, H. Maeda, S. Takashiba

    JOURNAL OF DENTAL RESEARCH91 ( 8 ) 764 - 770   2012年8月

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

    During periodontal regeneration, inhibition of gingival downgrowth is necessary to promote migration of mesenchymal cells into the defects. Transforming growth factor (TGF)-beta is a pleiotropic cytokine that has numerous cell functions, including regulation of epithelial growth. Recent studies have shown that Smad2, a downstream transcription factor of TGF-beta, plays crucial roles in wound healing in the epithelia. Therefore, we investigated the effects of Smad2 overexpression on re-epithelialization of gingival wounds. Transgenic mice overexpressing smad2 driven by the keratin 14 promoter (k14-smad2) were confirmed to have significant Smad2 phosphorylation in gingival basal epithelia. Punch wounds were made in the palatal gingiva, and wound healing was assessed histologically for 7 days. Re-epithelialization was significantly retarded on day 2, while collagen deposition was enhanced on day 7 in k14-smad2 compared with wild-type mice. Moreover, expression of keratin 16 (K16), an indicator of keratinocyte migration, was significantly inhibited in wound-edge keratinocytes in k14-smad2. The inhibition of K16 coincided with the induction of Smad2 in the corresponding epithelia, while BrdU incorporation was unaffected. These results indicated that Smad2 has inhibitory effects in regulating keratinocyte migration during gingival wound healing. TGF-beta/Smad2 signaling mediating alteration of K16 expression must be tightly regulated during periodontal regeneration.

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  • The promotional effect of IL-22 on mineralization activity of periodontal ligament cells 査読

    Nahoko Kato-Kogoe, Toshihiro Nishioka, Mutsuki Kawabe, Fusa Kataoka, Koji Yamanegi, Naoko Yamada, Masaki Hata, Tadashi Yamamoto, Keiji Nakasho, Masahiro Urade, Nobuyuki Terada, Hideki Ohyama

    CYTOKINE59 ( 1 ) 41 - 48   2012年7月

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

    Objectives: Interleukin (IL)-22 acts on non-immune cells to induce anti-microbial responses, protection from tissue damage, and enhance cell regeneration. However, little is known about the involvement of IL-22 in periodontal biology. This study investigated the biological effects of IL-22 on periodontal ligament (PDL) cells as part of studies to assess the involvement of IL-22 in periodontal disease.
    Materials and methods: Gene expression levels of IL-22 and its receptors in PDL cells and gingival tissue samples were evaluated by real-time PCR. Proliferative responses and mineralized-matrix forming activities of PDL cells were examined in the presence and absence of IL-22.
    Results: In contrast to the expression of IL-22 receptors detected in PDL tissues and their cell lines, gingival tissues showed modest or no gene expressions of IL-22. The production of several cytokines including IL-11, IL-8 and CCL2 was upregulated by IL-22 treatment of PDL cells in a dose-dependent manner. IL-22 treatment had no effect on the proliferative response in PDL cells. Meanwhile, IL-22 precipitated mineralized nodule formation and induced gene expressions of RUNX2,MSX2 and osteocalcin in PDL cells, suggesting that IL-22 enhances the mineralized matrix-forming activities of PDL cells.
    Conclusion: IL-22 has the potential to promote mineralizing activity in PDL cells and to develop appropriate regenerative therapy. (C) 2012 Elsevier Ltd. All rights reserved.

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  • Chronic periodontitis with multiple risk factor syndrome: a case report. 査読

    Shimoe M, Yamamoto T, Iwamoto Y, Shiomi N, Maeda H, Nishimura F, Takashiba S

    Journal of the International Academy of Periodontology13 ( 2 ) 40 - 47   2011年7月

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  • Rapid detection of mecA and spa by the loop-mediated isothermal amplification (LAMP) method. 査読

    Koide Y, Maeda H, Yamabe K, Naruishi K, Yamamoto T, Kokeguchi S, Takashiba S

    Letters in applied microbiology50 ( 4 ) 386 - 392   2010年4月

  • Highly expressed genes in a rough-colony-forming phenotype of Aggregatibacter actinomycetemcomitans: implication of a mip-like gene for the invasion of host tissue 査読

    Takemasa Maeda, Hiroshi Maeda, Kokoro Yamabe, Junji Mineshiba, Ichiro Tanimoto, Tadashi Yamamoto, Koji Naruishi, Susumu Kokeguchi, Shogo Takashiba

    FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY58 ( 2 ) 226 - 236   2010年3月

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

    Aggregatibacter actinomycetemcomitans, a potent pathogen of periodontitis, typically grows as a rough and adherent colony on primary isolated cultures. The colony transforms into a smooth phenotype during repeated subculture. In this study, we aimed to identify highly expressed genes in the rough-colony-forming phenotype for isolation of host-induced genes. Using a cDNA-subtractive hybridization technique, three genes, homologous to a macrophage infectivity potentiator gene (mip), peroxiredoxin gene (prx) and outer membrane protein gene (ompA), were identified. The expression levels of these genes in the rough-colony-forming phenotype were 4-10-fold higher as compared with the smooth-colony-forming phenotype. Attention was focused on the mip-like gene, and a recombinant protein and a deficient mutant were constructed. The recombinant protein reacted with sera from patients with periodontitis, suggesting the production of the Mip-like protein in periodontal lesions. Viable quantitative invasion assay demonstrated that the viable cell counts of the wild-type strain that invaded HeLa cells were more than fourfold as compared with the mip-deficient mutant. The expression of the mip-like gene, prx-like gene and ompA-like gene may be enhanced in the host, and the mip-like gene may play an important role in the infection of A. actinomycetemcomitans, especially in its invasion of the epithelium.

    DOI: 10.1111/j.1574-695X.2009.00624.x

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  • Rapid detection of mecA and spa by the loop-mediated isothermal amplification (LAMP) method 査読

    山本直史

    Letters in Applied Microbiology58 ( 2 ) 226 - 236   2010年

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  • Oligonucleotide array analysis of cyclic tension-responsive genes in human periodontal ligament fibroblasts 査読

    Keisuke Yamashiro, Fumio Myokai, Koichi Hiratsuka, Tadashi Yamamoto, Kyoko Senoo, Hideo Arai, Fusanori Nishimura, Yoshimitsu Abiko, Shogo Takashiba

    INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY39 ( 5 ) 910 - 921   2007年

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

    Mechanical stress results in differential gene expression that is critical to convert the stimulus into biochemical signals. Under physiological stress such as occlusal force, human periodontal ligament fibroblasts (HPLF) are associated with homeostasis of periodontal tissues however the changes in response to mechanotransduction remain uncharacterized. We hypothesized that cyclic tension-responsive (CT) genes may be used to identify a set of fundamental pathways of mechanotransduction. Our goal was to catalogue CT genes in cultured HPLE HPLF were subjected to cyclic tension up to 16 h, and total RNA was isolated from both tension-loaded and static HPLE The oligonucleotide arrays analysis revealed significant changes of mRNA accumulation for 122 CT genes, and their kinetics were assigned by the K-means clustering methods. Ingenuity Pathway Analysis was completed for HPLF mechanotransduction using 50 CT genes. This analysis revealed that cyclic tension immediately down-regulated all nuclear transcription factors except v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS) reacting as an early responsive gene. In turn, transcription factors such as tumor protein p53 binding protein 2 (TP53BP2), and extra-nuclear molecules such as adrenergic receptor beta 2 (ADRB2) were up-regulated after 1-2 h, which may result in fundamental HPLF functions to adapt to cyclic tension. Subsequent inhibition assays using Y27632, a pharmacologic inhibitor of Rho-associated kinase (ROCK), suggested that HPLF has both ROCK-dependent and ROCK-independent CT genes. Mechanical stress was found to effect the expression of numerous genes, in particular, expression of an early responsive gene; FOS initiates alteration of HPLF behaviors to control homeostasis of the periodontal ligament. (C) 2007 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.biocel.2007.01.015

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  • Inhibition of SMAD2 expression prevents murine palatal fusion 査読

    N Shiomi, XM Cui, T Yamamoto, T Saito, CF Shuler

    DEVELOPMENTAL DYNAMICS235 ( 7 ) 1785 - 1793   2006年7月

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

    Transforming growth factor (TGF)-beta 3 is known to regulate the disappearance of murine medial edge epithelium (MEE) during palatal fusion. Our previous studies showed that SMAD2, a TGF-beta signaling mediator, was expressed and phosphorylated primarily in the MEE and that SMAD2 phosphorylation in the MEE was temporospatially regulated by TGF-beta 3. The goal of this study was to examine the requirement for SMAD2 to complete the developmental events necessary for palatal fusion. SMAD2 expression was inhibited with Smad2 siRNA transfection into palatal tissues in vitro. The results showed that Smad2 siRNA transfection resulted in the maintenance of MEE cells in the palatal midline. Western blot and immunofluorescence analyses confirmed that the endogenous SAUD2 and phospho-SMAD2 levels were reduced following siRNA transfection. The SMAD3 level was not altered by the Smad2 siRNA transfection. The persistence of the MEE and the decreased SMAD2/phospho-SMAD2 levels were coincident with increased MEE cell proliferation. Addition of exogenous TGF-beta 3 increased p-SMAD2 level but not the total SMAD2 level. Therefore, exogenous TGF-beta 3 was not able to induce p-SMAD2 enough to rescue the palatal phenotype in the Smad2 siRNA group. The results indicated that the endogenous SMAD2 level is crucial in the regulation of disappearance of MEE during palatal fusion.

    DOI: 10.1002/dvdy.20819

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  • Effect of N '-nitrosonornicotine (NNN) on murine palatal fusion in vitro 査読

    T Saito, XM Cui, T Yamamoto, N Shiomi, P Bringas, CF Shuler

    TOXICOLOGY207 ( 3 ) 475 - 485   2005年2月

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

    Maternal smoking has been linked to an increased risk for orofacial clefts. N'-nitrosonornicotine (NNN) is one of the tobacco-specific nitrosamines that has been shown to be Linked to the deleterious effects of tobacco and could be linked to the formation of cleft palate birth defects. The effect of NNN on palatal fusion was examined using an in vitro organ culture model of palatal development. The organ cultures were exposed to NNN (0.0 1, 0. 1, 1, 10 and 100 mM) and the effects on palatal development characterized at defined points. Palatal fusion was evaluated at embryonic day 13 (E 13) + 72 h by characterizing the remaining medial edge epithelium (MEE) and determining the extent of fusion compared to controls. The NNN-treated group (I MM) had more MEE remaining in the palatal midline than the untreated group at E 13 + 72 h (P < 0.05). Changes in cell proliferation in the MEE resulting from NNN exposure were examined by BrdU incorporation in replicating DNA. Changes in the pattern of MEE cell death were examined by TUNEL. BrdU incorporation and TUNEL staining showed that the NNN (1 mM)-treated palates had more MEE cell proliferation and less apoptosis than the untreated-palates at E 13 + 24 h (P < 0.05). The mechanism altered by NNN was further evaluated by characterizations of extracellular signal-regulated kinase (ERK) 1/2, p38 and c-jun amino-terminal kinase (INK). NNN at I mM induced ERK1/2 phosphorylation, but reduced p38 phosphorylation (P<0.05, P< 0.01, respectively) in the MEE. The results suggest that NNN inhibited palatal fusion by effects on cell proliferation and MEE cell death. © 2004 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.tox.2004.10.015

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  • Overexpression of Smad2 in Tgf-beta 3-null mutant mice rescues cleft palate 査読

    XM Cui, N Shiomi, JC Chen, T Saito, T Yamamoto, Y Ito, P Bringas, Y Chat, CF Shuler

    DEVELOPMENTAL BIOLOGY278 ( 1 ) 193 - 202   2005年2月

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

    Transforming growth factor (TGF)-beta3 is an important contributor to the regulation of medial edge epithelium (MEE) disappearance during palatal fusion. SMAD2 phosphorylation in the MEE has been shown to be directly regulated by TGF-beta3. No phospho-SMAD2 was identified in the MEE in Tgf-beta3-null mutant mice (Tgf-beta(-1-)), which was correlated with the persistence of the MEE and failure of palatal fusion. In the present study, the cleft palate phenotype in Tgf-beta3(-/-) mice was rescued by overexpression of a Smad2 transgene in Keratin 14-synthesizing MEE cells following mating Tgf-beta3 heterozygous mice with Keratin 14 promoter directed Smad2 transgenic mice (K14-Smad2). Success of the rescue could be attributed to the elevated phospho-SMAD2 level in the MEE, demonstrated by two indirect evidences. The rescued palatal fusion in Tgf-beta3(-/-)/K14-Smad2 mice, however, never proceeded to the junction of primary and secondary palates and the most posterior border of the soft palate, despite phospho-SMAD2 expression in these regions at the same level as in the middle portion of the secondary palate. The K14-Smad2 transgene was unable to restore all the functional outcomes of TGF-beta3. This may indicate an anterior-posterior patterning in the palatal shelves with respect to TGF-beta3 signaling and the mechanism of secondary palatal fusion. (C) 2004 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.ydbio.2004.10.023

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  • Identification of genes differentially regulated in rat alveolar bone wound healing by subtractive hybridization 査読

    T Ohira, F Myokai, N Shiomi, K Yamashiro, T Yamamoto, Y Murayama, H Arai, F Nishimura, S Takashiba

    JOURNAL OF DENTAL RESEARCH83 ( 7 ) 546 - 551   2004年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R  

    Periodontal healing requires the participation of regulatory molecules, cells, and scaffold or matrix. Here, we hypothesized that a certain set of genes is expressed in alveolar bone wound healing. Reciprocal subtraction gave 400 clones from the injured alveolar bone of Wistar rats. Identification of 34 genes and analysis of their expression in injured tissue revealed several clusters of unique gene regulation patterns, including the up-regulation at 1 wk of cytochrome c oxidase regulating electron transfer and energy metabolism, presumably occurring at the site of inflammation; up-regulation at 2.5 wks of pro-alpha-2 type I collagen involving the formation of a connective tissue structure; and up-regulation at 1 and 2 wks and down-regulation at 2.5 and 4 wks of ubiquitin carboxyl-terminal hydrolase 13 involving cell cycle, DNA repair, and stress response. The differential expression of genes may be associated with the processes of inflammation, wound contraction, and formation of a connective tissue structure.

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  • Role of ERK1/2 signaling during EGF-induced inhibition of palatal fusion 査読

    T Yamamoto, XM Cui, CF Shuler

    DEVELOPMENTAL BIOLOGY260 ( 2 ) 512 - 521   2003年8月

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

    During mammalian palatal fusion, the medial edge epithelial (MEE) cells must stop DNA synthesis prior to the initial contact of opposing palatal shelves and thereafter selectively disappear from the midline. Exogenous EGF has been shown to inhibit the cessation of DNA synthesis and induce cleft palate; however, the precise intracellular mechanism has not been determined. We hypothesized that EGF signaling acting via ERK1/2 would maintain MEE DNA synthesis and cell proliferation and consequently inhibit the process of palatal fusion. Palatal shelves from E13 mouse embryos were maintained in organ cultures and stimulated with EGF. EGF-treated palates failed to fuse with intact MEE and had significant ERK1/2 phosphorylation. Both EGF-induced ERK1/2 phosphorylation and BrdU-incorporation were localized in the nucleus of MEE cells. Subsequent inhibition assays using U0126, a specific inhibitor of ERK1/2 phosphorylation, were conducted. U0126 inhibited EGF-induced ERK1/2 phosphorylation in a dose-dependent manner and consequently MEE cells stopped proliferation. The threshold of ERK1/2 inactivation to stop MEE DNA synthesis coincides with the level required to rescue the EGF-induced cleft palate phenotype. These results indicate that EGF-induced inhibition of palatal fusion is dependent on nuclear ERK1/2 activation and that this mechanism must be tightly regulated during normal palatal fusion. (C) 2003 Elsevier Inc. All rights reserved.

    DOI: 10.1016/S0012-1606(03)00275-6

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  • Gene profiling in human periodontal ligament fibroblasts by subtractive hybridization 査読

    T Yamamoto, F Myokai, F Nishimura, T Ohira, N Shiomi, K Yamashiro, H Arai, Y Murayama, S Takashiba

    JOURNAL OF DENTAL RESEARCH82 ( 8 ) 641 - 645   2003年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R  

    Genes expressed by human periodontal ligament fibroblasts (HPFs)are likely to be associated with specific functions of the ligament. The aim of this study is to profile genes expressed highly by HPFs. A library (6 x 103 pfu)was constructed, followed by subtraction of HPF cDNAs with human gingival fibroblast (HGF) cDNAs. Reverse-dot hybridization revealed that 33 clones expressed higher levels of specific mRNAs in HPFs than in HGFs. These were mRNAs for known genes including several associated with maturation and differentiation of cells. None had been reported in PFs. One clone, PDL-29 identified as a COX assembly factor, showed much stronger mRNA expression in HPFs than in HGFs in culture. In rat periodontium, however, PDL-29 mRNA expression was similar in PFs and GFs. These results suggest that HPFs express many previously unreported genes associated with maturation and differentiation, but expression can differ in vitro and in vivo.

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  • TGF-beta3–dependent SMAD2 phosphorylation and inhibition of MEE proliferation during palatal fusion 査読

    山本直史

      227 ( 3 ) 387 - 394   2003年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/dvdy.10326

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  • Unique genes induced by mechanical stress in periodontal ligament cells 査読

    F Myokai, M Oyama, F Nishimura, T Ohira, T Yamamoto, H Arai, S Takashiba, Y Murayama

    JOURNAL OF PERIODONTAL RESEARCH38 ( 3 ) 255 - 261   2003年6月

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

    Objectives: The aim of this study is to isolate mechanical stress-induced genes (MSGens) from human periodontal ligament (PDL) cells and to analyze profiles of the mRNA expression of these genes.
    Background: Differential expression of genes in PDL cells under physiological stress such as occlusal force is thought to be orchestrated not only for the remodeling of PDL itself but also for the repair and regeneration of periodontal tissues. However, little is known about the genes expressed in PDL cells under mechanical stress.
    Methods: The cDNA from mechanical stress-applied human PDL cells was subtracted against the cDNA from static control cells. The subtracted cDNA was amplified by polymerase chain reaction (PCR) and cloned for further analysis.
    Results: Among 68 independent clones isolated, 15 contained DNA fragments greater than 250 bp. Reverse Northern analysis revealed a marked induction of MSGen-15 and MSGen-28 mRNA expression in the mechanical stress-applied cells. However, little difference in the magnitude of expression for the other MSGens was detected between the stress-applied cells and the control cells. After nucleotide sequencing and the analysis of homology with known genes, five clones were identified; ribosomal protein S27 (MSGen-9), MRG 15 (MSGen-15), androgen-binding protein (MSGen-18), cathepsin H (MSGen-28), and cytochrome c (MSGen-47). Interestingly, it has been reported that MRG 15 is a novel transcription factor involved in the regulation of cell growth and senescence. The remaining 10 clones, classified into six sequence types, had no significant homology with any known genes.
    Conclusions: These results suggest that many known and unknown genes are expressed in response to mechanical stress in PDL cells, and that a transcription factor, MRG 15, may be responsible for molecular events in PDL cells under mechanical stress.

    DOI: 10.1034/j.1600-0765.2003.00602.x

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MISC

  • 細菌感染度を評価しながら包括的歯周治療を行った広汎型侵襲性歯周炎患者の一症例

    冨川和哉, 河野隆幸, 山本直史, 岩本義博, 下江正幸, 山口知子, 本郷昌一, 宮本学, 前田博史, 高柴正悟

    日本歯周病学会会誌55 ( 4 ) 340 - 348   2013年

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  • 血清抗体価検査を応用して治療した広汎型侵襲性歯周炎患者の15年間の経過

    冨川和哉, 岩本義博, 大江丙午, 新井英雄, 山本直史, 前田博史, 高柴正悟

    日本歯周病学会会誌54 ( 2 ) 193 - 202   2012年6月

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    記述言語:日本語   出版者・発行元:特定非営利活動法人 日本歯周病学会  

    歯周病に対する感受性が高い侵襲性歯周炎患者の治療においては,徹底した感染コントロールを行い,疾患活動性を抑制する事が要求される。近年,歯周病原細菌の感染量や歯周炎の活動性を評価するために,PCR 法を応用した細菌 DNA 検査や血清抗体価検査が活用されるようになってきた。今回報告するのは,好中球貪食能が低下傾向であった広汎型侵襲性歯周炎患者の症例である。患者は 25 歳の女性であり,歯周 基本治療,歯周組織再生療法を含む歯周外科治療,そして最終補綴治療を経て SPT に移行し,初診から 15 年間にわたって,臨床計測値の変化および歯周病原細菌に対する血清 IgG 抗体価の変動をモニタリングしている。これによって,SPT 期間中に歯周組織の破壊が進行した 26 の臨床所見と血清 IgG 抗体価の変動を捉えることができた。26 以外の歯周組織は SPT 期間を通して安定した状態を示していたが,血清 IgG 抗体価は 26 の組織破壊の進行と連動して高値を示した。本症例においては局所的な歯周炎の活動性が血清 IgG 抗体価検査によって評価できたと考える。日本歯周病学会会誌(日歯病誌)54(2):193-202, 2012

    DOI: 10.2329/perio.54.193

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  • ラット創傷歯髄から単離したFIP-2が炎症制御因子と細胞死に与える影響について

    妹尾 京子, 山本 直史, 明貝 文夫, 山城 圭介, 新井 英雄, 西村 英紀, 高柴 正悟

    日本歯科保存学雑誌 = THE JAPANESE JOURNAL OF CONSERVATIVE DENTISTRY50   2007年5月

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    記述言語:日本語  

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  • 培養ヒト歯根膜線維芽細胞における高浸透圧刺激によるsgk発現に関する研究

    明貝 文夫, 妹尾 京子, 山城 圭介, 山本 直史, 小柳津 功介, 新井 英雄, 西村 英紀, 高柴 正悟

    日本歯科保存学雑誌 = THE JAPANESE JOURNAL OF CONSERVATIVE DENTISTRY48 ( 6 ) 939 - 945   2005年12月

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    記述言語:日本語  

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  • 機械的刺激を与えた培養ヒト歯根膜線維芽細胞が発現する遺伝子の網羅的解析

    山城 圭介, 明貝 文夫, 妹尾 京子, 山本 直史, 新井 英雄, 西村 英紀, 高柴 正悟

    日本歯科保存学雑誌 = THE JAPANESE JOURNAL OF CONSERVATIVE DENTISTRY47   2004年10月

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    記述言語:日本語  

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  • Exogenous EGF activates ERK1/2 in murine palatal shelf in vitro.

    T Yamamoto, XM Cui, J Chen, CF Shuler

    JOURNAL OF DENTAL RESEARCH81   A303 - A303   2002年3月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R  

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  • Possible role of serum and glucocorticoid-lnducible kinase during craniofacial-oral-dental development.

    F Myokai, T Ohira, T Yamamoto, K Naruishi, F Nishimura, H Arai, S Takashiba, Y Murayama

    JOURNAL OF DENTAL RESEARCH78 ( 5 ) 1124 - 1124   1999年5月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC DENTAL RESEARCH  

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  • B-13-11 : 10 ヒト歯根膜線維芽細胞が機械的刺激によって発現する特徴的な遺伝子の研究

    明貝 文夫, 太平 泰資, 山本 直史, 峯柴 淳二, 鷲尾 憲文, 成石 浩司, 新井 英雄, 西村 英紀, 高柴 正悟, 村山 洋二

    日本歯周病学会会誌40 ( 0 )   1998年9月

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    記述言語:日本語   出版者・発行元:特定非営利活動法人日本歯周病学会  

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  • ラット硬組織形成過程における糖質コルチコイド誘導性キナーゼ遺伝子(sgk)の発現パターン

    大平 泰資, 明貝 文夫, 成石 浩司, 山本 直史, 新井 英雄, 西村 英紀, 高柴 正悟, 村山 洋二

    日本歯科保存学雑誌41   1998年5月

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    記述言語:日本語  

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  • B-12-11 : 24 歯根膜線維芽細胞が特異的に発現する遺伝子

    山本 直史, 高柴 正悟, 明貝 文夫, 滝川 雅之, 鷲尾 憲文, 西村 英紀, 新井 英雄, 村山 洋二

    日本歯周病学会会誌40 ( 0 )   1998年4月

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    記述言語:日本語   出版者・発行元:特定非営利活動法人日本歯周病学会  

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  • A-16 15 : 20 細胞周期からみた歯根膜線維芽細胞の遊走に関する研究

    淺原 洋士, 西村 英紀, 鷲尾 憲文, 周 幸華, 山本 直史, 新井 英雄, 高柴 正悟, 村山 洋二

    日本歯周病学会会誌38 ( 0 )   1996年3月

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    記述言語:日本語   出版者・発行元:特定非営利活動法人日本歯周病学会  

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共同研究・競争的資金等の研究

  • コラーゲン結合型FGF-2による水平性歯槽骨吸収に対する歯周組織再生療法の開発

    研究課題/領域番号:19H03831  2019年04月 - 2023年03月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    高柴 正悟, 松下 治, 平山 晴子, 山本 直史, 美間 健彦

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    配分額:17030000円 ( 直接経費:13100000円 、 間接経費:3930000円 )

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  • 幹細胞ニッチの制御を目指したインテグリンペプチド療法の開発

    研究課題/領域番号:18K09576  2018年04月 - 2021年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    山本 直史, 小林 寛也, 山城 圭介, 高柴 正悟

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    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

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  • Inflamm-agingを中心とした歯周病,サルコペニア,糖尿病の病態解明

    研究課題/領域番号:18K09598  2018年04月 - 2021年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    小林 寛也, 山本 直史, 山城 圭介, 高柴 正悟

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    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

    サルコペニア予防は高齢者の要介護度を低下させるために重要な課題である。申請者らは,近年提唱されている炎症性老化の概念に着目し,慢性炎症性疾患である歯周病が,筋組織の治癒過程,インスリン抵抗性に及ぼす影響とその制御メカニズムの一端を,老齢マウスを用いた歯周炎モデルに用いて明らかにすることを目的に研究を行なっている。平成30年度に行った研究成果は以下の通りである。
    ①歯周炎/筋損傷モデルマウスの作製:C57BL/6J(健康)とTALLYHO/JngJ(糖尿病)の老齢マウスの第二大臼歯に歯周病原細菌Porphyromonas gingivalis(P.g.)を浸漬させた絹糸を3週間結紮した後に,前脛骨筋に筋損傷を惹起させる塩化バリウムを注射した。
    ②歯槽骨吸収量の定量:小動物用マイクロスX線スキャナを用いて調べた。
    ③マウスの炎症状態のモニタリング:好中球に特異的なミエロペルオキシダーゼ(MPO)活性に反応して発光するXenolight Redject Inflammation Probeを使用したin vivoイメージングシステム(IVIS)を用いて解析した。
    研究を開始した平成30年度は,上記事項に加えて筋損傷後の血清中の炎症性サイトカインを網羅的に解析し,歯周病または糖尿病の有無で発現パターンを比較する予定であったが,まだ開始できていない。理由としては,筋損傷モデルマウスの確立が不完全なためである。引き続きモデルマウスの確立を進めていくが,時間を要するようであれば,確立方法を変更することも検討していく。

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  • 炎症メディエーターHMGB1の歯周炎における機能解明

    研究課題/領域番号:16K20670  2016年04月 - 2018年03月

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    山城 圭介, 青柳 浩明, 井手口 英隆, 高知 信介, 山本 直史, 高柴 正悟, 和氣 秀徳, 西堀 正洋

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    配分額:3900000円 ( 直接経費:3000000円 、 間接経費:900000円 )

    High mobility group box 1(HMGB1)は,DNA結合タンパク質であるが,組織の損傷や壊死によって細胞外へ分泌された場合,炎症メディエーターとして機能する。HMGB1が歯周炎の進行にどのように影響を及ぼすか,その詳細なメカニズムは未だ明らかになっていない。本研究の結果,炎症刺激により歯肉上皮細胞,マクロファージ様細胞からHMGB1が産生されることが明らかとなった。また,歯周炎モデルマウスに抗HMGB1抗体を投与することで,歯周炎による炎症は抑制される。その結果,好中球の遊走,IL-1βの産生などが抑制され,歯周炎による骨吸収が抑制されることが明らかとなった。

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  • インテグリンの活性制御による歯周組織幹細胞の遊走促進:分子リガンド創製への展開

    研究課題/領域番号:26463134  2014年04月 - 2017年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    山本 直史, 高柴 正悟, 畑中 加珠, 下江 正幸

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    配分額:4810000円 ( 直接経費:3700000円 、 間接経費:1110000円 )

    歯根膜細胞は,結合組織付着によるメカニカルな防御機能に加えて,多分化能を有する幹細胞としての機能を有することから,歯根膜細胞の欠損部位への遊走は歯周組織の恒常性維持や再生に重要な役割を果たす。本研究で,Integrin α3は歯根膜細胞の遊走を抑制し,integrin α5は遊走を促進することが明らかになった。とりわけ,integrin α3阻害剤が歯根膜細胞の遊走促進に有効であることが分かった。

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  • 唾液腺体性幹細胞とiPS細胞を用いた唾液腺機能再生に関する研究

    研究課題/領域番号:25463217  2013年04月 - 2014年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    峯柴 淳二, 大森 一弘, 山本 直史, 高柴 正悟

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    配分額:4940000円 ( 直接経費:3800000円 、 間接経費:1140000円 )

    【研究の目的】唾液は,口腔感染制御を含めて口腔内環境を保つ重要な働きを持つ。しかし唾液を分泌する唾液腺は,自己再生能が低く,障害後の機能回復は難しい。我々は,CD49F+細胞がin vitroではINHIBIN βA,INHIBIN βB,FOLLISTATINを発現することを報告している。INHIBINのβ鎖はホモ二量体を構成し,ACTIVIN分子と成る。一方FOLLISTATINは,ACTIVINに特異的に結合し,その受容体への結合を阻害する。本研究は,マウス顎下腺の主排泄導管を結紮後に解除すると顎下腺が再生することを利用し,in vivoにおいて唾液腺組織再生中のCD49F,INHIBIN βA,INHIBIN βB,そしてFOLLISTATINの発現局在の解明を目的とした。
    【研究実施計画および結果】
    マウス顎下腺の片側の排泄導管を血管結紮用クリップで結紮,他方は対照とし,6日後に結紮を解除した。結紮解除1,2,4,8,16日後の顎下腺を摘出し,パラフィン包埋切片作製の後,INHIBIN βA,INHIBIN βB,CD49FそしてFOLLISTATINの局在を免疫組織染色法で検討した。その結果,結紮解除後のどの日数でもINHIBIN βAは染色されず,INHIBIN βBとCD49fは染色された。また,結紮解除後8日目にはFOLLISTATINが染色された。さらに連続切片上で,CD49F,INHIBIN βB,そしてFOLLISTATINが同部位で染色された。以上から,結紮解除後8日目以降の唾液腺組織再生に,CD49F+細胞でのactivin-follistatin相互作用の関与を想定できる。
    以上から本研究を行った結果,マウス顎下腺主排泄導管結紮解除後8日目の導管上皮細胞で,CD49F,INHIBIN βB,FOLLISTATINが発現していることが解明された。

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  • 口腔内感染度からみたビスフォスフォネート系製剤関連顎骨壊死の予防システムの構築

    研究課題/領域番号:23593058  2011年 - 2013年

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    畑中 加珠, 高柴 正悟, 山本 直史, 山城 圭介

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

    がんの骨転移などの治療に使用されるビスフォスフォネート(BP)製剤の投与を受けている患者において、顎骨壊死(ONJ)が発生するという事象が報告されている。岡山大学病院では、腫瘍センターに歯科衛生士を配置し、口腔内のトラブルの実態を調査した。その結果、年々腫瘍センター利用患者および歯科衛生士の面談件数は増えており、3年間で新たに6件のONJを見つけることができた。当院歯周科および口腔外科にてフォローしている。また、他の化学療法患者に口内炎の訴えがある患者が多く見られた。

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  • 歯周組織の細胞周期アトラスの作製

    研究課題/領域番号:23659977  2011年 - 2013年

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究  挑戦的萌芽研究

    山本 直史, 高柴 正悟, 畑中 加珠, 山城 圭介, 山口 知子

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    配分額:3510000円 ( 直接経費:2700000円 、 間接経費:810000円 )

    生細胞の細胞周期の進行をリアルタイムで識別できるトランスジェニックマウス(Fucciマウス)は、歯周組織での時空的な細胞周期の動態を解析するための重要なツールであり,特に未分化な細胞と歯肉上皮の細胞周期の可視化に有用である。これを応用したFucciマウスの歯周病モデルの分子イメージング結果から,歯周組織の炎症期に活性化好中球が産生する一連の活性酵素が,歯周組織構成細胞の細胞周期をG1期で停止させる可能性が示唆された。

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  • 歯肉上皮細胞における増殖因子による細胞接着因子制御のメカニズムの分子生物学的解明

    研究課題/領域番号:22890119  2010年 - 2011年

    日本学術振興会  科学研究費助成事業 研究活動スタート支援  研究活動スタート支援

    山城 圭介, 山本 直史, 高柴 正悟

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    配分額:2977000円 ( 直接経費:2290000円 、 間接経費:687000円 )

    歯周病は歯周病原細菌の感染が原因で起こる慢性炎症で,日本人の約8割が罹患していると言われており,歯の喪失のもっとも大きな原因である。しかし個人差による進行の程度などわからないことも多い。歯肉上皮と歯が接着することは細菌感染に対しての物理的バリアとなっており,接着を強固にすることは歯周病の予防に大変重要であると考えられる。本研究では,歯肉上皮細胞が産生する増殖因子が,細胞接着を制御していると仮説を立てそのメカニズムを調べたものである。

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  • RhoAによる細胞分化機構を応用した歯根膜細胞移植治療のための基礎的研究

    研究課題/領域番号:20592429  2008年 - 2010年

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    山本 直史, 高柴 正悟, 峯柴 淳二, 山城 圭介, 成石 浩司, 塩見 信行, 園山 亘

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

    歯根膜細胞の硬組織形成細胞への分化過程は、RhoA-ROCKシグナルが制御する細胞骨格の性状に依存的であり、その細胞骨格はBMP-4やWnt3aおよびWnt5aなどの硬組織分化に関与する遺伝子発現を制御すると考えられる。一方、RhoAおよびROCKを過剰発現した歯根膜細胞は著しい細胞増殖能の低下を示したことから、歯根膜細胞の分化は、細胞骨格の性状に加えて、種々の増殖因子や細胞外基質の協調制御が重要であると考えられる。

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  • ラット根管治療モデルを用いたラミニンγ2発現動態からみた根尖病巣治癒メカニズム

    研究課題/領域番号:20592226  2008年 - 2010年

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    畑中 加珠, 山本 直史, 高柴 正悟, 下江 正幸, 山口 知子, 成石 浩司, 加古 綾

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    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

    根尖性歯周炎(根尖周囲に骨吸収をきたす炎症性疾患)の治癒過程において遺伝子発現の亢進を報告した細胞外基質ラミニンおよび炎症性サイトカインIL-1αを中心に、骨再生を担う骨芽細胞に対するこれら分子の効果を検討した。IL-1αは骨芽細胞のインテグリンα3発現を亢進し、また、骨芽細胞のラミニンに対する細胞接着性を亢進させたという結果は、根尖病巣の治癒期に病巣部への骨芽細胞の誘導・定着を示唆するものである。

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  • 創傷歯髄から単離した新規遺伝子FIP-2による歯髄炎症のコントロール法の探索

    研究課題/領域番号:18799006  2006年 - 2007年

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    山本 直史

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    配分額:3200000円 ( 直接経費:3200000円 )

    歯髄組織の保存および象牙質の再生を促進するためには,歯髄炎症を分子生物学的アプローチからコントロールすることが有効であると考えられる。本年度は,ラット創傷歯髄から単離した新規遺伝子FIP-2の発現抑制による歯髄炎症のコントロールを目標として,FIP-2が制御する炎症性シグナル分子機構および細胞死への影響を調べた。
    FIP-2に特異的なsiRNAを含む発現ベクターをラット腎臓細胞に遺伝子導入・薬剤選択培養し,FIP-2を発現抑制した細胞株(FIP-2KD)を確立した。FIP-2-KDおよびMockの細胞株をそれぞれ無刺激または過酸化水素にて刺激し,細胞内蛋白の発現変化を抗体アレイで解析し,制御因子の相互関係をIngenuity Signaling Pathways Knowledge Baseを用いてパスウェイ解析を行った。
    Mockに比較してFIP-2-KDでは,一連の細胞増殖因子mitogen activated protein kinase(MAPKS),myelocytosis(MYC),細胞周期制御因子cyclin dependent kinase(CDKS),そしてcell division cycle(CDCS)のシグナルが増強していた。また,細胞死制御因子であるCaspasesのシグナルが減弱していた。一方,過酸化水素で刺激下では,一連の細胞周期制御因子,細胞増殖因子,そして細胞死制御因子の発現が,顕著に抑制されており,DNAの断片化を示すTUNEL陽性細胞はFIP-2-KDにおいて著しく少なかった。
    以上の結果から,FIP-2は,炎症性反応のなかで発現増加し,細胞死を促進させる因子であることが示唆された。FIP-2を局所的に発現抑制することは歯髄の炎症反応の改善に役立つ可能性がある。

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  • 血中エクソソームを標的とした侵襲性歯周炎のナノ診断システムの開発

    国立研究開発法人日本医療研究開発機構(AMED)  2019-20年度 橋渡し研究戦略的推進プログラム シーズA 

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  • 幹細胞ニッチを制御する歯科再生材料の開発

    国立研究開発法人日本医療研究開発機構(AMED)  平成30年度 橋渡し研究戦略的推進プログラム シーズA 

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  • エクソソームによる侵襲性歯周炎患者の病態解析 ~パイロット研究~

    日本歯周病学会  平成29年度 企画調査研究助成 

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担当授業科目

  • 口腔感染・炎症制御学(実習(臨床実習)) (2020年度) 特別  - その他

  • 口腔感染・炎症制御学(講義・演習) (2020年度) 特別  - その他

  • 学際的研究と臨床 (2020年度) 第3学期  - 月1,月2

  • 歯周病態診断・治療学 (2020年度) 第4学期  - 火3,火4

  • 歯周病態診断・治療学 (2020年度) 第4学期  - 火2,火3

  • 歯周病治療専門学(実習(臨床実習)) (2020年度) 特別  - その他

  • 歯周病治療専門学(講義・演習) (2020年度) 特別  - その他

  • 歯髄・歯内病変治療専門学(実習(臨床実習)) (2020年度) 特別  - その他

  • 歯髄・歯内病変治療専門学(講義・演習) (2020年度) 特別  - その他

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