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

Alveolar bone loss caused by periodontal disease eventually leads to tooth loss. Periodontal ligament stem cells (PDLSCs) are the tissue-specific cells for maintaining and repairing the periodontal ligament, cementum, and alveolar bone. Here, we investigated the role of erythropoietin receptor (EPOR), which regulates the microenvironment-modulating function of mesenchymal stem cells, in PDLSC-based periodontal therapy. We isolated PDLSCs from patients with chronic periodontal disease and healthy donors, referred to as PD-PDLSCs and Cont-PDLSCs, respectively. PD-PDLSCs exhibited reduced potency of periodontal tissue regeneration and lower expression of EPOR compared to Cont-PDLSCs. EPOR-silencing suppressed the potency of Cont-PDLSCs mimicking PD-PDLSCs, whereas EPO-mediated EPOR activation rejuvenated the reduced potency of PD-PDLSCs. Furthermore, we locally transplanted EPOR-silenced and EPOR-activated PDLSCs into the gingiva around the teeth of ligament-induced periodontitis model mice and demonstrated that EPOR in PDLSCs participated in the regeneration of the periodontal ligament, cementum, and alveolar bone in the ligated teeth. The EPOR-mediated paracrine function of PDLSCs maintains periodontal immune suppression and bone metabolic balance via osteoclasts and osteoblasts in the periodontitis model mice. Taken together, these results suggest that EPOR signaling is crucial for PDLSC-based periodontal regeneration and paves the way for the development of novel options for periodontal therapy.

DOI： 10.1038/s41598-024-57361-y

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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：Biochemistry and Biophysics Reports  

Introduction & objectives: Stem cell therapy for regenerative medicine has been sincerely investigated, but not still popular although some clinical trials show hopeful results. This therapy is suggested to be a representative candidate such as bone defect due to the accident, iatrogenic resection oncological tumor, congenital disease, and severe periodontitis in oral region. Recently, the Bio-3D printer “Regenova®” has been introduced as an innovative three-dimensional culture system, equipped scaffold-free bio-assembling techniques without any biomaterials. Therefore, we expected a mount of bone defect could be repaired by the structure established from this Bio-3D printer using osteogenic potential stem cells. Material & methods: The gingival tissue (1x1 mm) was removed from the distal part of the lower wisdom tooth of the patients who agreed our study. Human Gingival Mesenchymal Stem Cells (hGMSCs) were isolated from this tissue and cultured, since we confirmed the characteristics such as facile isolation and accelerated proliferation, further, strong potential of osteogenic-differentiation. Spheroids were formed using hGMSC in 96-well plates designed for low cell adhesion. The size of the spheroids was measured, and fluorescent immunostaining was employed to verify the expression of stem cell and apoptosis marker, and extracellular matrix. Following four weeks of bone differentiation, μCT imaging was performed. Calcification was confirmed by alizarin red and von Kossa staining. Fluorescent immunostaining was utilized to assess the expression of markers indicative of advanced bone differentiation. Results: We have established and confirmed the spheroids (∼600 μm in diameter) constructed from human GMSCs (hGMSCs) still maintain stem cell potentials and osteogenic differentiation abilities from the results that CD73 and not CD34 were expressed as stem cell positive and negative marker, respectively. These spheroids were pilled up like cylindal shape to the “Kenzan” platform of Bio-3D printer and cultured for 7days. The cylindal structure originated from compound spheroids were tried to differentiate into bone four weeks with osteogenic induction medium. The calcification of bio-3D printed bone-like structures was confirmed by alizarin red and Von Kossa staining. In addition, μCT analysis revealed that the HU (Hounsfield Unit) of the calcified structures was almost identical to that of trabecular bone. Immunofluorescent staining detected osteocalcin expression, a late-stage bone differentiation marker. Conclusion: For the first time, we have achieved the construction of a scaffold-free, bone-like luminal structure through the assembly of spheroids comprised of this hGMSCs. This success is sure to be close to the induction of clinical application against regenerative medicine especially for bone defect disease.

DOI： 10.1016/j.bbrep.2024.101656

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記述言語：英語  

Aim. The present study evaluated the therapeutic effects of luteolin in alleviating pulpitis of dental pulp- (DP-) derived microvesicles (MVs) via the inhibition of protein kinase R- (PKR-) mediated inflammation. Methodology. Proteomic analysis of immortalized human dental pulp (DP-1) cell-derived MVs was performed to identify PKR-associated molecules. The effect of luteolin on PKR phosphorylation in DP-1 cells and the expression of tumor necrosis factor-α (TNF-α) in THP-1 macrophage-like cells were validated. The effect of luteolin on cell proliferation was compared with that of chemical PKR inhibitors (C16 and 2-AP) and the unique commercially available sedative guaiacol-parachlorophenol. In the dog experimental pulpitis model, the pulps were treated with (1) saline, (2) guaiacol-parachlorophenol, and (3) luteolin. Sixteen teeth from four dogs were extracted, and the pulp tissues were analyzed using hematoxylin and eosin staining. Immunohistochemical staining was performed to analyze the expression of phosphorylated PKR (pPKR), myeloperoxidase (MPO), and CD68. Experimental endodontic-periodontal complex lesions were established in mouse molar through a silk ligature and simultaneous MV injection. MVs were prepared from DP-1 cells with or without pretreatment with 2-AP or luteolin. A three-dimensional microcomputed tomography analysis was performed on day 7 (n=6). Periodontal bone resorption volumes were calculated for each group (nonligated–ligated), and the ratio of bone volume to tissue volume was measured. Results. Proteomic analysis identified an endogenous PKR activator, and a protein activator of interferon-induced PKR, also known as PACT, was included in MVs. Luteolin inhibited the expressions of pPKR in DP-1 cells and TNF-α in THP-1 cells with the lowest suppression of cell proliferation. In the dog model of experimental pulpitis, luteolin treatment suppressed the expression of pPKR-, MPO-, and CD68-positive cells in pulp tissues, whereas guaiacol-parachlorophenol treatment caused coagulative necrosis and disruption. In a mouse model of endodontic-periodontal complex lesions, luteolin treatment significantly decreased MV-induced alveolar bone resorption. Conclusion. Luteolin is an effective and safe compound that inhibits PKR activation in DP-derived MVs, enabling pulp preservation.

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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：BioMed Research International  

Aim. The present study evaluated the therapeutic effects of luteolin in alleviating pulpitis of dental pulp- (DP-) derived microvesicles (MVs) via the inhibition of protein kinase R- (PKR-) mediated inflammation. Methodology. Proteomic analysis of immortalized human dental pulp (DP-1) cell-derived MVs was performed to identify PKR-associated molecules. The effect of luteolin on PKR phosphorylation in DP-1 cells and the expression of tumor necrosis factor-α (TNF-α) in THP-1 macrophage-like cells were validated. The effect of luteolin on cell proliferation was compared with that of chemical PKR inhibitors (C16 and 2-AP) and the unique commercially available sedative guaiacol-parachlorophenol. In the dog experimental pulpitis model, the pulps were treated with (1) saline, (2) guaiacol-parachlorophenol, and (3) luteolin. Sixteen teeth from four dogs were extracted, and the pulp tissues were analyzed using hematoxylin and eosin staining. Immunohistochemical staining was performed to analyze the expression of phosphorylated PKR (pPKR), myeloperoxidase (MPO), and CD68. Experimental endodontic-periodontal complex lesions were established in mouse molar through a silk ligature and simultaneous MV injection. MVs were prepared from DP-1 cells with or without pretreatment with 2-AP or luteolin. A three-dimensional microcomputed tomography analysis was performed on day 7 (n=6). Periodontal bone resorption volumes were calculated for each group (nonligated-ligated), and the ratio of bone volume to tissue volume was measured. Results. Proteomic analysis identified an endogenous PKR activator, and a protein activator of interferon-induced PKR, also known as PACT, was included in MVs. Luteolin inhibited the expressions of pPKR in DP-1 cells and TNF-α in THP-1 cells with the lowest suppression of cell proliferation. In the dog model of experimental pulpitis, luteolin treatment suppressed the expression of pPKR-, MPO-, and CD68-positive cells in pulp tissues, whereas guaiacol-parachlorophenol treatment caused coagulative necrosis and disruption. In a mouse model of endodontic-periodontal complex lesions, luteolin treatment significantly decreased MV-induced alveolar bone resorption. Conclusion. Luteolin is an effective and safe compound that inhibits PKR activation in DP-derived MVs, enabling pulp preservation.

DOI： 10.1155/2024/8864513

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Drug-induced gingival overgrowth (DIGO), induced by certain immunosuppressive drugs, antihypertensive agents, and antiepileptic drugs, may contribute to the formation of deeper periodontal pockets and intractableness in periodontitis. To date, multiple factors such as enhanced matrix production, inflammation, and reduced matrix degradation might be involved in the pathogenesis of DIGO. We have previously reported that SPOCK-1, a heparan sulfate proteoglycan, could affect gingival thickening by promoting epithelial-to-mesenchymal transition (EMT) in gingival keratinocytes. However, few studies have investigated whether a combination of these factors enhances the DIGO phenotype in animal models. Therefore, we investigated whether SPOCK-1, periodontal inflammation, and cyclosporin-A (CsA) could cooperatively promote gingival overgrowth. We first confirmed that Spock-1 overexpressing (Spock1-Tg) mice showed significantly thicker gingiva and greater alveolar bone loss than WT mice in response to ligature-induced experimental periodontitis. DIGO was induced by the combination of CsA administration and experimental periodontitis was significantly enhanced in Spock1-Tg mice compared to that in WT mice. Ligature-induced alveolar bone loss in CsA-treated Spock1-Tg mice was also significantly greater than that in CsA-treated WT mice, while being accompanied by an increase in Rankl and Col1a1 levels and a reduction in matrix metalloprotease expression. Lastly, SPOCK-1 promoted RANKL-induced osteoclast differentiation in both human peripheral blood mononuclear cells and murine macrophages, while peritoneal macrophages from Spock1-Tg mice showed less TNFα and IL-1β secretion than WT mice in response to Escherichia coli lipopolysaccharide. These results suggest that EMT, periodontal inflammation, and subsequent enhanced collagen production and reduced proteinase production contribute to CsA-induced DIGO pathogenesis.

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

Drug-induced gingival overgrowth (DIGO), induced by certain immunosuppressive drugs, antihypertensive agents, and antiepileptic drugs, may contribute to the formation of deeper periodontal pockets and intractableness in periodontitis. To date, multiple factors such as enhanced matrix production, inflammation, and reduced matrix degradation might be involved in the pathogenesis of DIGO. We have previously reported that SPOCK-1, a heparan sulfate proteoglycan, could affect gingival thickening by promoting epithelial-to-mesenchymal transition (EMT) in gingival keratinocytes. However, few studies have investigated whether a combination of these factors enhances the DIGO phenotype in animal models. Therefore, we investigated whether SPOCK-1, periodontal inflammation, and cyclosporin-A (CsA) could cooperatively promote gingival overgrowth. We first confirmed that Spock-1 overexpressing (Spock1-Tg) mice showed significantly thicker gingiva and greater alveolar bone loss than WT mice in response to ligature-induced experimental periodontitis. DIGO was induced by the combination of CsA administration and experimental periodontitis was significantly enhanced in Spock1-Tg mice compared to that in WT mice. Ligature-induced alveolar bone loss in CsA-treated Spock1-Tg mice was also significantly greater than that in CsA-treated WT mice, while being accompanied by an increase in Rankl and Col1a1 levels and a reduction in matrix metalloprotease expression. Lastly, SPOCK-1 promoted RANKL-induced osteoclast differentiation in both human peripheral blood mononuclear cells and murine macrophages, while peritoneal macrophages from Spock1-Tg mice showed less TNFα and IL-1β secretion than WT mice in response to Escherichia coli lipopolysaccharide. These results suggest that EMT, periodontal inflammation, and subsequent enhanced collagen production and reduced proteinase production contribute to CsA-induced DIGO pathogenesis.

DOI： 10.3389/fphys.2023.1298813

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記述言語：日本語   出版者・発行元：(NPO)日本歯科保存学会  

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記述言語：日本語   出版者・発行元：(NPO)日本歯科保存学会  

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記述言語：その他   掲載種別：研究論文（学術雑誌）  

DOI： 10.1177/00220345231181539

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1177/00220345231181539

記述言語：日本語   出版者・発行元：(NPO)日本歯科保存学会  

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記述言語：英語  

Periodontal disease is an infectious disease that affects many people worldwide. Disease progression destroys the alveolar bone and causes tooth loss. We have previously shown that alymphoplasia (aly/aly) mice harboring a loss-of-function mutation in the map3k14 gene, which is involved in p100 to p52 processing of the alternative NF-κB pathway, exhibited mild osteopetrosis due to decreased number of osteoclasts, suggesting the alternative NF-κB pathway as a potential drug target for the amelioration of bone disease. In the present study, wild-type (WT) and aly/aly mice were subjected to silk ligation to establish a periodontitis model. Alveolar bone resorption was suppressed in aly/aly mice by decreased numbers of osteoclasts in the alveolar bone in comparison to WT mice. Furthermore, the expression of receptor activator of NF-κB ligand (RANKL) and TNFα (cytokines involved in osteoclast induction in periligative gingival tissue) was decreased. When primary osteoblasts (POBs) and bone marrow cells (BMCs) derived from WT and aly/aly mice were prepared and co-cultured, osteoclasts were induced from WT-derived BMCs, regardless of the origin of the POBs, but hardly formed from aly/aly mouse-derived BMCs. Furthermore, the local administration of an NIK inhibitor, Cpd33, inhibited osteoclast formation and thereby inhibited alveolar bone resorption in the periodontitis model. Therefore, the NIK-mediated NF-κB alternative pathway can be a therapeutic target for periodontal disease.

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記述言語：英語   出版者・発行元：Frontiers in Immunology  

Periodontal disease is an infectious disease that affects many people worldwide. Disease progression destroys the alveolar bone and causes tooth loss. We have previously shown that alymphoplasia (aly/aly) mice harboring a loss-of-function mutation in the map3k14 gene, which is involved in p100 to p52 processing of the alternative NF-κB pathway, exhibited mild osteopetrosis due to decreased number of osteoclasts, suggesting the alternative NF-κB pathway as a potential drug target for the amelioration of bone disease. In the present study, wild-type (WT) and aly/aly mice were subjected to silk ligation to establish a periodontitis model. Alveolar bone resorption was suppressed in aly/aly mice by decreased numbers of osteoclasts in the alveolar bone in comparison to WT mice. Furthermore, the expression of receptor activator of NF-κB ligand (RANKL) and TNFα (cytokines involved in osteoclast induction in periligative gingival tissue) was decreased. When primary osteoblasts (POBs) and bone marrow cells (BMCs) derived from WT and aly/aly mice were prepared and co-cultured, osteoclasts were induced from WT-derived BMCs, regardless of the origin of the POBs, but hardly formed from aly/aly mouse-derived BMCs. Furthermore, the local administration of an NIK inhibitor, Cpd33, inhibited osteoclast formation and thereby inhibited alveolar bone resorption in the periodontitis model. Therefore, the NIK-mediated NF-κB alternative pathway can be a therapeutic target for periodontal disease.

DOI： 10.3389/fimmu.2023.1179007

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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：Diabetes  

Insulin resistance and hyperglycemia are risk factors for periodontitis and poor wound healing in diabetes, which have been associated with selective loss of insulin- activation of the PI3K/Akt pathway in the gingiva. This study showed that insulin resistance in the mouse gingiva due to selective deletion of smooth muscle and fibroblast insulin receptor (SMIRKO mice) or systemic metabolic changes induced by high fat diet (HFD) in HFD-fed mice exacerbated periodontitis-induced alveolar bone loss, preceded by delayed neutrophil and monocyte recruitment and impaired bacterial clearance compared to their respective controls. The immunocytokines, CXCL1, CXCL2, MCP-1, TNFα, IL-1β and IL-17A exhibited delayed maximal expression in the gingiva of male SMIRKO and HFD-fed mice compared to controls. Targeted overexpression of CXCL1 in the gingiva by adenovirus normalized neutrophil and monocyte recruitment and prevented bone loss in both mouse models of insulin resistance. Mechanistically, insulin enhanced bacterial lipopolysaccharide-induced CXCL1 production in mouse and human gingival fibroblasts (GFs), via Akt pathway and NF-κB activation, which were reduced in GFs from SMIRKO and HFD-fed mice. These results provided the first report that insulin signaling can enhance endotoxin induced CXCL1 expression to modulate neutrophil recruitment, suggesting CXCL1 as a new therapeutic direction for periodontitis or wound healing in diabetes.

DOI： 10.2337/db22-1014

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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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 日本臨床歯周病学会  

DOI： 10.57303/tjacp.40.2_43

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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：Archives of Biochemistry and Biophysics  

A well-tuned inflammatory response is crucial for an effective immune process. Nuclear factor-kappa B (NF-κB) is a key mediator of inflammatory and innate immunity responses, and its dysregulation is closely associated with immune-related diseases. MicroRNAs (miRNAs) are important inflammation modulators. However, miRNA-regulated mechanisms that implicate NF-κB activity are not fully understood. This study aimed to identify a potential miRNA that could modulate the dysregulated NF-κB signaling during inflammation. We identified miR-582-5p that was significantly downregulated in inflamed murine adipose tissues and RAW264.7 cells. S-phase kinase-associated protein 1 (SKP1), a core component of an E3 ubiquitin ligase that regulates the NF-κB pathway, was proposed as a biological target of miR-582-5p by using TargetScan. The binding of miR-582-5p to a 3'-untranslated region site on Skp1 was confirmed using a dual-luciferase reporter assay; in addition, transfection with a miR-582-5p mimic suppressed SKP1 expression in RAW264.7 cells. Importantly, exogenous miR-582-5p attenuated the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 through suppressing the degradation of the NF-κB inhibitor alpha, followed by the nuclear translocation of NF-κB. Therefore, exogenously applied miR-582-5p can attenuate the NF-κB signaling pathway via targeting Skp1; this provides a prospective therapeutic strategy for treating inflammatory and immune diseases.

DOI： 10.1016/j.abb.2022.109501

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DOI： 10.3389/icell.2022.1061216

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

The expression profiles of exosomal microRNAs (miRNAs) are regulated by the microenvironment, and appropriate priming with mesenchymal stem cells (MSCs) is one of the strategies to enhance the paracrine potency of MSCs. Our previous work demonstrated that exosomes from tumor necrosis factor (TNF)-α-primed human gingiva-derived MSCs (GMSCs) could be a therapeutic tool against periodontitis, and that TNFα-inducible exosomal miR-1260b is essential for the inhibition of alveolar bone loss. However, the precise molecular mechanism underlying miR-1260b-mediated inhibition of osteoclastogenesis is not yet fully understood. Here, we found that the activating transcription factor (ATF)-6β, a novel miR-1260b-targeting gene, is critical for the regulation of osteoclastogenesis under endoplasmic reticulum (ER) stress. An experimental periodontal mouse model demonstrated that induction of ER stress was accompanied by enhanced ATF6β expression, and local administration of miR-1260b and ATF6β siRNA using polyethylenimine nanoparticles (PEI-NPs) significantly suppressed the periodontal bone resorption. In periodontal ligament (PDL) cells, the ER stress inducer, tunicamycin, enhanced the expression of the receptor activator of NF-κB ligand (RANKL), while miR-1260b-mediated downregulation of ATF6β caused RANKL inhibition. Furthermore, the secretome from miR-1260b/ATF6β-axis-activated PDL cells inhibited osteoclastogenesis in human CD14+ peripheral blood-derived monocytes. These results indicate that the miR-1260b/ATF6β axis mediates the regulation of ER stress, which may be used as a novel therapeutic strategy to treat periodontal disease.

DOI： 10.3389/fcell.2022.1061216

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記述言語：日本語   出版者・発行元：(NPO)日本歯科保存学会  

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

Aims: Pancreatic β-cell apoptosis may be involved in the onset and progression of type 2 diabetes mellitus, although its mechanism remains unclear. We previously demonstrated that macrophage-derived interferon (IFN) β induced X-linked inhibitor of apoptosis–associated factor 1 (XAF1) expression in β-cells and accelerated β-cell apoptosis in vitro. Here, we explored the effects of XAF1 on β-cell function and progression of diabetes in vivo. Methods: Pancreatic β-cell-selective XAF1 overexpressing (Xaf1 Tg) mice were generated. Xaf1 Tg mice and their wild-type (WT) littermates were fed either a normal diet or a 40% or 60% high-fat diet (HFD). The effects of β-cell XAF1 on β-cell apoptosis and exacerbation of diabetes were investigated. Results: Palmitic acid induced IFNβ expression in macrophages, and HFD intake promoted macrophage infiltration in pancreatic islets, both of which cooperatively upregulated XAF1 expression in mouse islets. Furthermore, HFD-fed Xaf1 Tg mice demonstrated increased β-cell apoptosis, lowered insulin expression, and impaired glucose tolerance compared with WT mice fed the same diet. These effects were more pronounced in the 60%HFD group than in the 40%HFD group. Conclusions: Pancreatic β-cell XAF1 expression was enhanced via HFD-induced, macrophage-derived IFNβ, which promoted β-cell apoptosis and led to a reduction in insulin secretion and progression of diabetes. To our knowledge, this is the first report to demonstrate an association between pancreatic β-cell XAF1 overexpression and exacerbation of diabetes, thus providing insight into the mechanism of β-cell mass reduction in diabetes.

DOI： 10.1007/s00592-022-01930-y

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その他リンク： https://link.springer.com/article/10.1007/s00592-022-01930-y/fulltext.html

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  

Immunoregulatory properties of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) are promising. Gingival tissue-derived MSCs (GMSCs) have unique immunoregulatory capacity and secrete large amounts of EVs. Recent findings suggest that priming MSCs with inflammatory stimuli is an effective strategy for cell-free therapy. However, the precise mechanism by which the contents of EVs are customized has not been fully elucidated. Here, we show that EVs derived from GMSCs primed with a combination of two pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interferon-α (IFN-α), synergistically promote anti-inflammatory M2 macrophage polarization by increasing the expression of cluster of differentiation 73 (CD73) and CD5 molecule-like (CD5L). Expression of CD73 by TNF-α/IFN-α stimulation was transcriptionally upregulated by the activation of mammalian target of rapamycin signaling and nuclear translocation of hypoxia-inducible factor 1α in GMSCs. TNF-α/IFN-α treatment also significantly increased the expression of CD5L mRNA via the transcription factor DNA-binding protein inhibitor ID3 and liver X receptor. Interestingly, exosomal CD5L is a prerequisite for the synergistic effect of EVs-mediated M2 macrophage polarization. These results indicate that combined pre-licensing with TNF-α and IFN-α in GMSCs is ideal for enhancing the anti-inflammatory function of EVs, which contributes to the establishment of a therapeutic tool.

DOI： 10.1038/s41598-022-17692-0

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   出版者・発行元：(NPO)日本歯科保存学会  

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記述言語：日本語   出版者・発行元：(NPO)日本歯科保存学会  

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出版者・発行元：Lasers in Dental Science  

Introduction: Dental caries and apical periodontitis are ones of the most prevalent chronic diseases and involve infection by cariogenic and endodontic bacteria. It can be said that the most required to cure is disinfection. We hypothesized that NB-UVB could be used for intraoral disinfection without affecting cells, and that it could be used in combination with TiO2 to disinfect complex root canals. The objectives were to investigate the effects of UV on dental pulp cells and oral bacteria and to evaluate the enhancement effect of a photocatalyst on bactericidal effects of UV irradiation. Methods: UV irradiation devices of UVB (310, 285 nm) and UVC (265 nm) were prepared. Cell proliferation and cytotoxicity assays after UV irradiation were performed using human dental pulp cells. The antibacterial activity of UV irradiation was investigated in Streptococcus mutans, Staphylococcus aureus, Enterococcus faecalis, Actinomyces naeslundii, Porphyromonas gingivalis, and Fusobacterium nucleatum. A curved simulated root canal with plastic training block was used to evaluate the effect of combined UV and TiO2 treatment. Data were analyzed by one-way ANOVA (p < 0.05) followed by Tukey’s post hoc tests (p < 0.05). Results: Human dental pulp cell proliferation was decreased by 265 nm, 285 nm, and 310 nm UV irradiation, although 310 nm UV irradiation did not show cytotoxic effects on these cells. Oral bacterial growth was suppressed following UV irradiation at 285 nm and 265 nm. Viability of all bacteria significantly decreased with UV irradiation. In the curved simulated root canal, viability of E. faecalis in UV irradiation at 285 nm with long taper fibers was significantly decreased in the 300 s irradiation group. E. faecalis proliferation was inhibited by combined UV irradiation and TiO2 application with long taper fibers in the curved simulated root canal. Conclusions: The wavelength of UVB and UVC showed bactericidal effects on oral bacteria including caries-related bacteria and apical periodontitis–related bacteria while NB-UVB did not. UVB with longer fibers was more effective in disinfection on E. faecalis in curved simulated root canal, and the combined use of photocatalyst further improved the disinfection effect.

DOI： 10.1007/s41547-021-00145-8

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記述言語：その他   掲載種別：研究論文（学術雑誌）  

DOI： 10.1155/2021/5548760

記述言語：その他   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/jcb.29903

記述言語：その他   掲載種別：研究論文（学術雑誌）  

DOI： 10.1136/bmjdrc-2020-001871

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/jcm10061165

記述言語：その他   掲載種別：研究論文（学術雑誌）  

Mesenchymal stem cell (MSC)–derived exosome plays a central role in the cell-free therapeutics involving MSCs and the contents can be customized under disease-associated microenvironments. However, optimal MSC-preconditioning to enhance its therapeutic potential is largely unknown. Here, we show that preconditioning of gingival tissue-derived MSCs (GMSCs) with tumor necrosis factor-alpha (TNF-α) is ideal for the treatment of periodontitis. TNF-α stimulation not only increased the amount of exosome secreted from GMSCs, but also enhanced the exosomal expression of CD73, thereby inducing anti-inflammatory M2 macrophage polarization. The effect of GMSC-derived exosomes on inflammatory bone loss were examined by ligature-induced periodontitis model in mice. Local injection of GMSC-derived exosomes significantly reduced periodontal bone resorption and the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, and these effects were further enhanced by preconditioning of GMSCs with TNF-α. Thus, GMSC-derived exosomes also exhibited anti-osteoclastogenic activity. Receptor activator of NF-κB ligand (RANKL) expression was regulated by Wnt5a in periodontal ligament cells (PDLCs), and exosomal miR-1260b was found to target Wnt5a-mediated RANKL pathway and inhibit its osteoclastogenic activity. These results indicate that significant ability of the TNF-α-preconditioned GMSC-derived exosomes to regulate inflammation and osteoclastogenesis paves the way for establishment of a therapeutic approach for periodontitis.

DOI： 10.1016/j.actbio.2020.12.046

記述言語：その他   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/intimm/dxaa066

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/jcm10040723

記述言語：その他   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s13340-020-00465-3

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-020-66660-z

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/jcm9113754

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbrep.2020.100757

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3389/fimmu.2020.00709

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbrc.2020.09.129

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/cas.14204

記述言語：英語   掲載種別：研究論文（学術雑誌）  

It is well known that dental pulp tissue can evoke some of the most severe acute inflammation observed in the human body. We found that dental pulp cells secrete a factor that induces tumor necrosis factor-α production from macrophages, and designated this factor, dental pulp cell-derived powerful inducer of TNF-α (DPIT). DPIT was induced in dental pulp cells and transported to recipient cells via microvesicles. Treatment of dental pulp cells with a PKR inhibitor markedly suppressed DPIT activity, and weak interferon signals were constitutively activated inside the cells. In recipient macrophages, stimulation with DPIT-containing supernatants from pulp cells resulted in activation of both nuclear factor-κB and MAP kinases like JNK and p38. Proteomics analyses revealed that many stress granule-related proteins were present in supernatants from dental pulp cells as well as microvesicle marker proteins like GAPDH, β-actin, HSPA8, HSPB1, HSPE1, and HSPD1. Furthermore, giant molecule AHNAK and PKR were detected in microvesicles derived from dental pulp cells, and gene silencing of AHNAK in dental pulp cells led to reduced DPIT activity. Thus, it appeared that the core protein of DPIT was PKR, and that PKR was maintained in an active state in stress granule aggregates with AHNAK and transported via microvesicles. The activity of DPIT for TNF-α induction was far superior to that of gram-negative bacterial endotoxin. Therefore, we, report for the first time, that active PKR is transported via microvesicles as stress granule aggregates and induces powerful inflammatory signals in macrophages.

DOI： 10.1038/s41598-019-40046-2

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12986-019-0372-5

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s13098-019-0454-6

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.celrep.2019.02.066

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1128/MRA.01641-18

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-018-21183-6

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3892/br.2018.1066

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Metabolic endotoxemia has been implicated in the pathogenesis of type 2 diabetes. In addition to adipose tissue inflammation, inflammatory cell infiltration is also observed in islets, although its effect on islets is largely unknown. We hypothesized that macrophage infiltration into islets leads to impairment of α or β cell function, which ultimately act to exacerbate the pathophysiology of diabetes. Gene expression in a murine α cell line, αTC1, and β cell line, βTC6, was investigated by DNA microarray after co-culturing the cells with a murine macrophage cell line, RAW 264.7, in the presence or absence of bacterial endotoxin. Among the genes showing highly upregulated expression, genes specifically upregulated only in β cells were evaluated to determine the roles of the gene products on the cellular function of β cells. In both α and β cells, expression of type I interferon-responsive genes was highly upregulated upon endotoxin stimulation. Among these genes, expression of the X-linked inhibitor of apoptosis (Xiap)-associated factor 1 (Xaf1) gene, which is associated with the induction of apoptosis, was specifically enhanced in β cells by endotoxin stimulation. This upregulation appeared to be mediated by macrophage-derived interferon β (IFNβ), as endotoxin-stimulated macrophages produced higher amounts of IFNβ, and exogenous addition of IFNβ into βTC6 cultures resulted in increased Xaf1 protein production and cleaved caspase 3, which accelerated β-cell apoptosis. Macrophages activated by metabolic endotoxemia infiltrated into islets and produced IFNβ, which induced β-cell apoptosis by increasing the expression of Xaf1.

DOI： 10.1055/s-0043-121467

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbrc.2017.12.136

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbrc.2017.11.069

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0188670

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.archoralbio.2017.08.005

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.intimp.2017.06.006

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/jdi.12633

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.imbio.2017.05.001

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.metabol.2017.01.006

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.numecd.2016.11.008

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/08820139.2016.1238925

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jim.2016.11.012

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/cre2.48

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12903-017-0337-x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/jre.12353

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bone.2016.09.003

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/srep38697

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/cbin.10652

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Interleukin-17A (IL-17A) is known to induce inflammatory responses and to be involved in the pathogenesis of not only autoimmune diseases, but also several metabolic and infectious diseases. In this study, IL-17A is shown to induce IL-6 expression in 3T3-L1 mature adipocytes. Interestingly, we found that IL-17A synergistically amplified TNFα-induced secretion of IL-6 and upregulation of IL-17RA expression in 3T3-L1 adipocytes. Its synergistic effects on IL-6 production were inhibited by pre-treatment with inhibitors of IκBα and JNK. Furthermore, IL-17A cooperatively enhanced LPS-mediated IL-6 production in 3T3-L1 adipocytes co-cultured with RAW264.7 macrophages. In addition, IL-17A also enhanced CCL20 production in 3T3-L1 adipocytes stimulated with TNFα or co-cultured with LPS-stimulated RAW macrophages. In high-fat diet-fed mouse epididymal adipose tissues, IL-17RA and RORγt mRNA levels were significantly increased and the serum level of CCL20 was also upregulated. Taken together, these data show that, in adipose tissues, IL-17A contributes to exacerbating insulin resistance-enhancing IL-6 production and promotes the infiltration of Th17 cells in cooperation with TNFα; these findings represent a novel hypothesis for the association between IL-17A-producing cells and type 2 diabetes.

DOI： 10.1016/j.bbrc.2016.06.049

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10753-016-0333-3

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/femspd/ftw003

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/jcp.25087

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Periodontitis is a chronic inflammatory disorder caused by specific bacteria residing in the biofilm, particularly Porphyromonas gingivalis (Pg). Sprouty2 (Spry2) functions as a negative regulator of the fibroblast growth factor (FGF) signaling pathway. We previously demonstrated that sequestration of Spry2 induced proliferation and osteogenesis in osteoblastic cells by basic FGF (bFGF) and epidermal growth factor (EGF) stimulation in vitro, but diminished cell proliferation in gingival epithelial cells. In addition, Spry2 knockdown in combination with bFGF and EGF stimulation increases periodontal ligament cell proliferation and migration accompanied by prevention of osteoblastic differentiation. In this study, we investigated the mechanisms through which Spry2 depletion by interferon (IFN) γ and Pg lipopolysaccharide (LPS) stimulation affected the physiology of macrophages in vitro. Transfection of macrophages with Spry2 small-interfering RNA (siRNA) promoted the expression of genes characteristic of M2 alternative activated macrophages, induced interleukin (IL)-10 expression, and enhanced arginase activity, even in cells stimulated with IFNγ and Pg LPS. In addition, we found that phosphoinositide 3-kinase (PI3K) and AKT activation by Spry2 downregulation enhanced efferocytosis of apoptotic cells by increasing Rac1 activation and decreasing nuclear factor kappa B (NFkB) p65 phosphorylation but not signal transducer and activator of transcription 1 (STAT1) phosphorylation. Collectively, our results suggested that topical administration of Spry2 inhibitors may efficiently resolve inflammation in periodontal disease as macrophage-based anti-inflammatory immunotherapy and may create a suitable environment for periodontal wound healing. These in vitro findings provide a molecular basis for new therapeutic approaches in periodontal tissue regeneration.

DOI： 10.1002/iid3.99

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Resistin-like molecule β (RELMβ) reportedly has multiple functions including local immune responses in the gut. In this study, we investigated the possible contribution of RELMβ to non-alcoholic steatohepatitis (NASH) development. First, RELMβ knock-out (KO) mice were shown to be resistant to methionine-choline deficient (MCD) diet-induced NASH development. Since it was newly revealed that Kupffer cells in the liver express RELMβ and that RELMβ expression levels in the colon and the numbers of RELMβ-positive Kupffer cells were both increased in this model, we carried out further experiments using radiation chimeras between wild-type and RELMβ-KO mice to distinguish between the contributions of RELMβ in these two organs. These experiments revealed the requirement of RELMβ in both organs for full manifestation of NASH, while deletion of each one alone attenuated the development of NASH with reduced serum lipopolysaccharide (LPS) levels. The higher proportion of lactic acid bacteria in the gut microbiota of RELMβ-KO than in that of wild-type mice may be one of the mechanisms underlying the lower serum LPS level the former. These data suggest the contribution of increases in RELMβ in the gut and Kupffer cells to NASH development, raising the possibility of RELMβ being a novel therapeutic target for NASH.

DOI： 10.1038/srep20157

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/srep19286

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/odi.12369

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/naika.104.1907

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/oby.21127

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s13098-015-0047-y

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.archoralbio.2015.05.013

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/jcb.25014

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Dipeptidyl peptidase IV (DPPIV) expression in visceral adipose tissue is reportedly increased in obese patients, suggesting an association of DPP-IV with inflammation. In this study, first, lipopolysaccharide (LPS)- or palmitateinduced elevations of inflammatory cytokine mRNA expressions in RAW264.7 macrophages were shown to be significantly suppressed by coincubation with a DPP-IV inhibitor, anagliptin (10 μM), despite low DPP-IV expression in the RAW264.7 cells. Regarding the molecular mechanism, LPS-induced degradation of IκBα and phosphorylations of p65, JNK, and p38, as well as NF- κB and AP-1 promoter activities, were revealed to be suppressed by incubation with anagliptin, indicating suppressive effects of anagliptin on both NF- κB and AP-1 signaling pathways. Anagliptin also acted on 3T3-L1 adipocytes, weakly suppressing the inflammatory cytokine expressions induced by LPS and TNFα. When 3T3-L1 and RAW cells were cocultured and stimulated with LPS, the effects of anagliptin on the suppression of cytokine expressions in 3T3-L1 adipocytes were more marked and became evident at the 10 μM concentration. Anti-inflammatory effects of anagliptin were also observed in vivo on the elevated hepatic and adipose expressions and serum concentrations of inflammatory cytokines in association with the suppression of hepatic NF- κB transcriptional activity in LPS-infused mice. Taking these observations together, the anti-inflammatory properties of anagliptin may be beneficial in terms of preventing exacerbation of diabetes and cardiovascular events.

DOI： 10.1152/ajpendo.00553.2014

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1152/ajpgi.00198.2014

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1155/2015/897971

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0112490

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00520-014-2432-8

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jebdp.2014.04.017

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/omi.12046

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/ndt/gft449

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Macrophage infiltration in the adipose tissue, and the interaction with adipocytes, is well documented to be involved in fat inflammation and obesity-associated complications. In this study, we isolated IκB kinase ε (IKKε) as a key adipocyte factor that is potentially affected by interaction with macrophages in adipose tissue in vivo. We showed that IKKε mRNA expression levels in white adipose tissue were increased in both genetic and diet-induced obese mouse. Furthermore, IKKε mRNA expression was decreased by the administration of vitamin B6, an anti-inflammatory vitamin, and that IKKε expression levels in adipose tissue were closely correlated with the numbers of infiltrating macrophages. In a co-culture system, we showed that IKKaε expression in adipocytes was upregulated by interaction with activated macrophages. This study provides novel insight into IKKε, which is involved in adipose tissue inflammation during the development of obesity.

DOI： 10.1080/09168451.2014.925776

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s11010-014-2290-1

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/adj.12177

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/omi.12051

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.5551/jat.21055

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1152/ajpgi.00225.2013

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0078129

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/j.1532-2149.2013.00289.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE - : Resistin-like molecule (RELM) β is a secretory protein homologous to resistin and reportedly contributes to local immune response regulation in gut and bronchial epithelial cells. However, we found that activated macrophages also express RELMβ and thus investigated the role of RELMβ in the development of atherosclerosis. APPROACH AND RESULTS - : It was demonstrated that foam cells in atherosclerotic lesions of the human coronary artery abundantly express RELMβ. RELMβ knockout ( ^-/-) and wild-type mice were mated with apolipoprotein E-deficient background mice. RELMβ^-/- apolipoprotein E-deficient mice exhibited less lipid accumulation in the aortic root and wall than RELMβ^+/+ apolipoprotein E-deficient mice, without significant changes in serum lipid parameters. In vitro, RELMβ^-/- primary cultured peritoneal macrophages (PCPMs) exhibited weaker lipopolysaccharide- induced nuclear factor-κB classical pathway activation and inflammatory cytokine secretion than RELMβ^+/+, whereas stimulation with RELMβ upregulated inflammatory cytokine expressions and increased expressions of many lipid transporters and scavenger receptors in PCPMs. Flow cytometric analysis revealed inflammatory stimulation-induced RELMβ in F4/80(+) CD11c(+) PCPMs. In contrast, the expressions of CD11c and tumor necrosis factor were lower in RELMβ^-/- PCPMs, but both were restored by stimulation with recombinant RELMβ. CONCLUSIONS - : RELMβ is abundantly expressed in foam cells within plaques and contributes to atherosclerosis development via lipid accumulation and inflammatory facilitation.

DOI： 10.1161/ATVBAHA.113.301546

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1074/jbc.M113.485730

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbrc.2013.03.029

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.diabres.2013.01.028

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0061931

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.diabres.2012.11.002

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1365-2591.2012.02095.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.4161/adip.21837

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.4161/adip.21837

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1365-2591.2012.02074.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1074/jbc.M112.397133

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.orcp.2012.05.005

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.archoralbio.2012.03.005

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1177/1753425910393370

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1161/ATVBAHA.111.234559

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Macrophages are integrated into adipose tissues and interact with adipocytes in obese subjects, thereby exacerbating adipose insulin resistance. This study aimed to elucidate the molecular mechanism underlying the insulin-sensitizing effect of the angiotensin II receptor blocker (ARB) valsartan, as demonstrated in clinical studies. Insulin signaling, i.e., insulin receptor substrate-1 and Akt phosphorylations, in 3T3-L1 adipocytes was impaired markedly by treatment with tumor necrosis factor-α (TNFα) or in the culture medium of lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages, and valsartan had no effects on these impairments. However, in contrast, when cocultured with RAW 264.7 cells using a transwell system, the LPS-induced insulin signaling impairment in 3T3-L1 adipocytes showed almost complete normalization with coaddition of valsartan. Furthermore, valsartan strongly suppressed LPS-induced productions of cytokines such as interleukin (IL)-1β, IL-6, and TNFα with nuclear factor-κB activation and c-Jun NH ₂-terminal kinase phosphorylation in RAW 264.7 and primary murine macrophages. Very interestingly, this effect of valsartan was also observed in THP-1 cells treated with angiotensin II type 1 (AT1) siRNA or a peroxisome proliferator-activated receptor-γ (PPARγ) antagonist as well as macrophages from AT1a receptor-knockout mice. We conclude that valsartan suppresses the inflammatory response of macrophages, albeit not via PPARγ or the AT1a receptor. This suppression appears to secondarily improve adipose insulin resistance.

DOI： 10.1152/ajpendo.00324.2011

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/1617-9625-10-3

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/1617-9625-9-12

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00520-010-0923-9

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1074/jbc.M110.206904

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.metabol.2010.07.034

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1152/ajpcell.00416.2010

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/labinvest.2010.128

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1074/jbc.M110.137836

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00520-009-0789-x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.orcp.2010.02.002

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.diabres.2009.10.011

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1902/jop.2009.090461

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1177/0022034509339889

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00520-008-0532-z

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1600-0765.2008.01097.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/ijo.2008.153

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/jcp.21517

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00520-008-0470-9

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Single nucleotide polymorphisms (SNPs) in the 5′ flanking region of IL12RB2 are frequently detected in lepromatous leprosy patients, and may be possible immunogenetic factors that reduce transcriptional activity of the IL-12Rβ2 gene in Jurkat T cells. This study determined the functional effects of these SNPs on NK-cell activity, including IFN-γ production and IL-12Rβ2 gene expression. Reporter gene assays using the NK cell line NK3.3 revealed that transcriptional activities of the variant haplotypes were significantly higher in the NK cell line, in contrast to our previous results in Jurkat T cells. IFN-γ production in activated T cells from donors was significantly lower than in cells from donors without the variant SNPs, while NK cells with these SNPs produced significantly higher amounts of IFN-γ. These results suggest that these SNPs in IL12RB2 have differential effects on cellular activation of T cells and NK cells.

DOI： 10.1089/jir.2008.0133

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1574-695X.2008.00417.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Goals: The commercially available saliva substitute Oralbalance® has been reported to alleviate symptoms of post-radiotherapy xerostomia in head and neck cancer patients. Oralbalance® may also be effective for xerostomia in patients undergoing hematopoietic cell transplantation (HCT) with high-dose chemotherapy and total-body irradiation. However, HCT patients are severely compromised, and saliva substitute must therefore not promote infection. This study was performed to determine the effects of Oralbalance® on microbial species identified during HCT. Patients and methods: Microbial identification of oral mucosa was performed in 28 patients undergoing HCT. The antimicrobial effects of Oralbalance® against bacteria and fungi detected in the HCT period were examined in vitro. Briefly, bacteria and fungi were spread on agar plates, and 0.1g of Oralbalance® gel was applied (about φ1cm). After incubation at 37°C for 24h, the presence of a transparent zone of inhibition around Oralbalance® was observed. Main results: Not only bacterial species constituting normal flora of the oral mucosa but also those not usually constituting normal flora, e.g., coagulase-negative Staphylococcus, were detected. A transparent zone was observed around Oralbalance® in all bacterial species examined. No transparent zone was observed for Candida albicans, but growth was inhibited in the area where Oralbalance® was applied. Conclusions: Oralbalance® does not facilitate increases in microorganisms in the HCT period. Oral care with Oralbalance® does not promote infection in patients undergoing HCT.

DOI： 10.1007/s00520-007-0391-z

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objectives: The expression of interleukin (IL)-12Rβ2 molecule is a crucial regulatory factor in the T-helper type (Th) 1 differentiation of T cells. To elucidate the role of the cell-mediated immune (CMI) response in the pathogenesis of periodontitis, Japanese periodontal patients were subjected to single nucleotide polymorphism (SNP) analyses of the 5′ flanking region of IL12RB2, whose variants are frequently detected in lepromatous leprosy patients, in which the very weak cellular immune response is caused by low expression of IL-12Rβ2. Material and Methods: The gene polymorphisms of the 5′ flanking region of IL12RB2 were examined in subjects with several types of periodontal disease and in healthy controls. Serum immunoglobulin (Ig) G antibody titres against periodontopathic bacteria were measured and compared in periodontal patients with and without variant alleles of IL12RB2. Results: The frequencies of variant alleles of IL12RB2 were significantly higher in aggressive periodontitis patients as compared with healthy controls or chronic periodontitis patients. Serum IgG titres against all periodontal bacteria examined in subjects carrying variant alleles were higher than those in subjects without variant alleles. Conclusion: IL-12Rβ2 SNPs could be useful as genetic markers to access the susceptibility of the general population to periodontal disease. Low CMI responses or high humoral responses are associated with the pathogenesis of inflammatory periodontal diseases.

DOI： 10.1111/j.1600-051X.2008.01208.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1902/jop.2008.070205

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1600-0765.2007.00985.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/oby.2007.305

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1365-2249.2007.03450.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1177/0968051907082608

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.biocel.2007.01.015

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1600-0757.2006.00171.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1365-4632.2006.02900.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1055/s-2006-954582

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1055/s-2006-949525

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.metabol.2005.08.020

記述言語：英語   掲載種別：研究論文（学術雑誌）  

α2 integrin on fibroblasts is reported to play an important role in the induction of drug-induced gingival overgrowth, which is characterized by excessive accumulation of type I collagen in gingival connective tissue. Silent polymorphism 807 T/C within the α2 integrin gene is associated with high/low α2 integrin expression. The aim of this study was to test the hypothesis that expression of α2 integrin 807 T/C polymorphism correlates with drug-induced gingival overgrowth. A case-control study comparing 136 subjects taking calcium channel blockers (72 with vs. 64 without drug-induced gingival overgrowth) demonstrated that the frequency of the +807 C allele was significantly higher in the case group than in the controls (odds ratio, 3.61; 95% confidence interval, 2.14 - 6.10; P < 0.05). The present findings suggest that the α2 +807 C allele is one of the genetic risk factors for drug-induced gingival overgrowth.

DOI： 10.1177/154405910508401217

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1902/jop.2005.76.11-S.2075

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1177/154405910508400912

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1902/jop.2005.76.7.1211

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Human β-defensin-2 (hBD-2) is an antimicrobial peptide with a broad spectrum of antimicrobial activity against bacteria, yeast and fungi. Here, we analyzed the transcriptional regulation of hBD-2 in cultured human cervical carcinoma (HeLa) cells with or without lipopolysaccharide (LPS). DNA from position -329 to -39 in the hBD-2 promoter region contained the consensus binding sites for transcription factors, one site for nuclear factor for IL-6 expression (NF-IL6) and two sites for nuclear factor-κB (NF-κB). Reporter gene assays for promoter activity revealed that the region had the highest level of responsiveness to LPS. Furthermore, mutations in both of the NF-κB binding sites caused a significant reduction of the responsiveness to LPS, whereas mutation in the NF-IL6 binding site resulted in an elevation of the basal promoter activity. Electrophoretic mobility shift assays demonstrated that LPS induced the binding of HeLa nuclear factors to 60-bp probe containing the two NF-κB binding sites, suggesting that the sites were essential for the binding. Our results suggest that the two NF-κB binding sites contribute to LPS-mediated hBD-2 transcription while the NF-IL6 binding site represses LPS-independent hBD-2 transcription in the HeLa cells.

DOI： 10.1016/j.femsim.2005.01.008

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Individual differences in T cell responsiveness to interleukin 12 (IL-12), resulting from inherited factors, may be responsible for differences in the intensity of cell mediated immune (CMI) responses in patients with leprosy, a disease with a wide clinical spectrum. Aim: Polymorphisms in the 5′ flanking region of the IL12RB2 gene were analysed to determine potential immunogenetic factors affecting CMI responses, using leprosy as a model. Methods: Polymorphisms in the 5′ flanking region of IL12RB2 were examined using direct sequencing techniques, and allele frequencies between patients with lepromatous leprosy and patients with tuberculoid leprosy were compared. The effect of these single nucleotide polymorphisms (SNPs) on IL12RB2 expression was estimated using the dual luciferase reporter gene assay in Jurkat T cells. Results: Several SNPs, including -1035A>G, -1023A>G, -650delG, and -465A>G, were detected within the 5′ flanking region of IL12RB2. The frequency of haplotype 1 (-1035A, -1023A, -650G, -464A) was high in the general Japanese population, but was significantly lower in lepromatous patients compared with tuberculoid patients and healthy controls. Reporter gene assays using Jurkat T cells revealed that all haplotypes carrying one or more SNP exhibited a lower transcriptional activity compared with haplotype 1. Conclusion: SNPs within the 5′ flanking region of IL12RB2 affect the degree of expression of this gene and may be implicated in individual differences in CMI responsiveness to mycobacterial antigens, leading to lepromatous or tuberculoid leprosy.

DOI： 10.1136/jcp.2004.023903

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1399-302X.2004.00203.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.femsim.2004.08.005

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1177/154405910508400306

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1600-0765.2004.00746.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1600-0463.2004.apm11204-0507.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1074/jbc.M311688200

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1055/s-2004-814221

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.lfs.2003.07.018

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.yexmp.2003.09.002

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1177/154405910408300707

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/01.TP.0000085661.52980.95

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/S0928-8244(03)00224-4

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1902/jop.2003.74.8.1231

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The role of human leukocyte antigen (HLA) class II molecules on non-antigen presenting cells has been a matter of controversy. We recently reported that ligation of HLA-DR molecule with anti-HLA-DR antibodies (L243) and/or antigenic peptide/T cell receptor complex resulted in a secretion of several chemokines such as RANTES. In the present study, we aimed to detect putative signal transduction pathway leading to RANTES production from fibroblasts when the DR molecules were ligated with L243. Protein tyrosine kinase inhibitor (GF109203X) suppressed RANTES expression in a dose dependent manner for up to 50% from gingival fibroblasts (GF), while protein kinase C inhibitor (genistein) had no inhibitory effect. Ligation of DR molecules with L243 resulted in tyrosine phosphorylation of 54 kDa cellular protein. Thus, we suspected that either Jun N-terminal kinase-2 (JNK-2) or Src family proteins were involved in HLA-DR-mediated signaling. JNK inhibitor (SP600125), but not Src inhibitor (PP2), suppressed both L243 stimulated RANTES mRNA expression and protein secretion. The maximum inhibition for RANTES production by SP600125 was more than 80%. Additionally, JNK inhibitor nearly completely blocked tumor necrosis factor-α (TNF-α)-induced RANTES production in GF. Furthermore, ligation of GF HLA-DR with L243 induced selective phosphorylation of JNK-2. We concluded that JNK-2 was one of the HLA-DR-mediated signal transduction pathways.

DOI： 10.1016/S1043-4666(03)00123-6

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objectives: Tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) participate in the establishment of inflammatory lesions in periodontitis. High production of these cytokines may relate to the severity of periodontitis. There have already been several studies examining the association between periodontitis and single nucleotide polymorphisms (SNPs) that affect cytokine productivity. Recently, new SNPs of TNF-α, -1031, -863 and -857, variants of which are observed in a relatively large proportion in Japanese, have been identified. The variant alleles of these SNPs have been suggested to be related to high TNF-α production. For a better understanding of the genetic factors associated with the severity of periodontitis, further analysis including these newly identified SNPs is essential. In addition, previous reports on TNF-α or IL-1β SNPs associated with periodontitis were mainly for Caucasian populations. Therefore, the aim of this study is to examine the association between severe periodontitis in Japanese and the following SNPs: five in the TNF-α gene promoter (-1031, -863, -857, -308, -238) and three in the IL-1β gene (-511, -31, +3953). Material and Methods: A total of 128 Japanese individuals were enrolled in this study. They were 64 patients with severe adult periodontitis and 64 healthy subjects. TNF-α and IL-1β SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism for all subjects. TNF-α and IL-1β production from LPS-stimulated monocytes/macrophages was also measured for 15 healthy male subjects. Results: TNF-α production in TNF-α -1031/ -863 (linkage disequilibrated) or -857 SNP variant allele carriers tended to be elevated, and the frequency of subjects who carried at least one variant allele in TNF-α -1031, -863 or -857 SNPs among severe periodontitis patients was significantly higher than in healthy subjects. Conclusion: Since the frequency of subjects who carried at least one variant allele in TNF-α -1031, -863 or -857 SNPs was higher in periodontitis patients than in healthy subjects, TNF-α -1031, -863 and -857 SNPs appear to be associated with severe adult periodontitis in Japanese populations.

DOI： 10.1034/j.1600-051X.2003.00287.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1053/meta.2003.50001

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1034/j.1600-0765.2003.02607.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1034/j.1600-0765.2003.00602.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

It is generally accepted that obesity is associated with many other multiple-risk factor syndromes such as hypertension, hyperlipidemia, type 2 diabetes mellitus, and periodontal disease. The number of obese people is increasing rapidly in both western and eastern countries. Adipocytes in the adipose tissues of obese people produce large quantities of biologically active molecules such as leptin, an important molecule regulating energy expenditure and body weight. Therefore, adipocyte-derived active molecules, named adipocytokines, are candidate molecules accounting for the close association between obesity and other multiple-risk factor syndromes. The proinflammatory cytokine tumor necrosis factor-α (TNF-α) is produced by adipocytes, and its blood concentration is elevated in obese patients and declines with weight loss. Studies have demonstrated that TNF-α suppresses insulin action via its specific receptor; hence, it exacerbates insulin resistance. In addition to adipocytes, monocytes/macrophages produce large quantities of TNF-α. Thus, TNF-α, produced from monocytic cells due to inflammatory diseases, may have an additive influence on insulin sensitivity to adipocyte-derived TNF-α. Here, we hypothesized that 1) TNF-α produced by the adipose tissues of obese patients acts as a risk factor for periodontal inflammation, and 2) TNF-α produced due to periodontal inflammation may be an additional important factor influencing insulin sensitivity in both obese and type 2 diabetic patients. We believe that this interaction is a possible mechanism accounting for a 2-way relationship between type 2 diabetes and periodontal disease.

DOI： 10.1902/jop.2003.74.1.97

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1177/154405910308200814

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/S0002-9440(10)64483-5

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1006/cyto.2001.0976

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2337/diacare.25.10.1888

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/S0264-410X(01)00354-1

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1902/jop.2001.72.6.774

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1902/jop.2001.72.5.598

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1902/jop.2001.72.4.425

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1034/j.1399-302X.2001.016002073.x

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：英語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：英語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：英語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：英語  

記述言語：英語  

記述言語：日本語   出版者・発行元：(有)科学評論社  

記述言語：日本語   出版者・発行元：(有)科学評論社  

記述言語：英語  

The present narrative review examines the scientific evidence of the biological mechanisms that may link periodontitis and diabetes, as a source of comorbidity. Publications regarding periodontitis and diabetes, in human, animals, and in vitro were screened for their relevance. Periodontal microbiome studies indicate a possible association between altered glucose metabolism in prediabetes and diabetes and changes in the periodontal microbiome. Coinciding with this, hyperglycemia enhances expression of pathogen receptors, which enhance host response to the dysbiotic microbiome. Hyperglycemia also promotes pro-inflammatory response independently or via the advanced glycation end product/receptor for advanced glycation end product pathway. These processes excite cellular tissue destruction functions, which further enhance pro-inflammatory cytokines expression and alteration in the RANKL/osteoprotegerin ratio, promoting formation and activation of osteoclasts. The evidence supports the role of several pathogenic mechanisms in the path of true causal comorbidity between poorly controlled diabetes and periodontitis. However, further research is needed to better understand these mechanisms and to explore other mechanisms.

DOI： 10.1111/prd.12298

記述言語：英語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：英語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

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種別：査読等 

外国語雑誌　査読論文数：10

日本語雑誌　査読論文数：1

種別：大会・シンポジウム等 

参加者数：2,900

種別：学会・研究会等 

種別：学会・研究会等 

種別：大会・シンポジウム等 

参加者数：200

種別：査読等 

外国語雑誌　査読論文数：10

日本語雑誌　査読論文数：1

種別：大会・シンポジウム等 

参加者数：200

種別：大会・シンポジウム等 

参加者数：200

種別：学会・研究会等 

歯髄で炎症が惹起されると急激な炎症が短時間に誘導され、歯髄は数日内に融解壊死を起こすがその機序は不明であった。歯髄細胞から分泌される細胞外微粒子内の活性化シグナル伝達分子がマクロファージからの炎症性サイトカイン産生を誘導することを見出し、この現象が急激な歯髄炎症の原因であることを世界で初めて見出した。

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〔研究目的及び到達目標〕
口腔の健康は咀嚼機能の回復を介した高齢者のQOLの向上に寄与することに加え、認知機能、肥満や糖尿病などの生活習慣病予防、宿主防御機構の恒常性維持など多岐にわたって健康長寿社会の実現に貢献する。さらに、口腔諸組織には幹細胞が豊富に存在し、かつ採取が比較的容易であることから、これらを用いた難治性自己免疫疾患や肝臓病などに対する治療応用の可能性についても注目されつつある。

九州大学歯学研究院は、「口腔の健康から全身の健康を推進する口腔健康科学」、「組織の再生・再建研究」を重点プロジェクトとして位置づけ、本分野における研究を強力に推進し、独創性に富む世界的研究拠点の形成を目指している。また、その達成に向け研究志向大学としての使命を自覚し、①研究マインドを有する学部学生や大学院生の醸成教育の展開、および②次世代リーダーの育成に力を注いでいる。健康長寿の実現を口腔の健康から強力に推進するために、海外の一流の研究者（研究室）と相互訪問・交流（IN-CROSS-OUT）を通じて強固なネットワークを創出して、国際ハブ拠点を目指す。

〔研究計画・方法〕
歯学研究院の掲げる重点プロジェクトによる独創的拠点形成を達成するため、頭脳循環により次世代のリーダー候補者によるプロジェクト研究の水準向上と知的財産の創出を推進する。

口腔健康科学プロジェクトの計画を示す。申請者らは、味覚受容体およびその摂食調節機構の研究において被引用論文数世界第1位（SCOPUS）であり、単一味神経・細胞応答記録など世界オンリーワンの技術を有する（生理学）。新規に発見したPRIP(IP3結合蛋白)とその関連蛋白PP1、PP2Aによる骨代謝/生殖/エネルギー代謝の包括的制御という世界に類をみない独創的な研究を展開中である（生化学）。これらの課題について、味覚・嗅覚における世界でもオンリーワンの研究機関（Monell Center）と、若手研究者を中心に継続的な共同研究を展開することで、栄養の経口摂取を介した肥満・生活習慣病予防、および超高齢者に多くみられる飢餓状態の改善が可能となる。一方、日本人に多い軽微な過体重や肥満を呈する患者の中で、重症の歯周病が合併した場合に惹起される、欧米型肥満類似の慢性炎症病態を解析する極めてユニークな歯周医学研究を展開している（歯周病学）。さらに、こうして活性化された自然免疫機構により、神経障害性疼痛の惹起によるアルツハイマー病の誘導（薬理学）、ミクリッツ病などの唾液線自己免疫疾患を介した高齢者のドライマウス発現（口腔外科学）について、卓越した研究を展開中である。この課題についてはUniversity of Pennsilvania、Harvard University免疫学部門との交流により、臨床免疫学の充実化を図り、最終的にエネルギー代謝研究と融合させることで、neurology、immunogy、endocrinologyを包含する口腔健康科学研究の拠点化を目指す。

一方、組織再生・再建プロジェクトにおいて、申請者らは、口腔組織に由来する幹細胞（以下、口腔幹細胞と略す）を用いた顎顔面口腔領域の再生医療研究に留まらず、自己免疫疾患や難治性肝疾患、先天性疾患等を含む全身の難病への臨床応用を目的とした、独創的かつ先端的なトランスレーショナルリサーチを展開し、卓越した実績を挙げつつある（解剖学）。加えて、口腔幹細胞を用いて難病の発症機序を分子/遺伝子レベルで解明・診断し、当該分子を標的とした治療法の開発を試みるユニークな研究を展開しつつある（解剖学、小児歯科学）。また従来の歯周再生治療や歯科インプラント治療の概念を凌駕する、口腔幹細胞を用いたインプラント体への付着性・シーリングの向上を目指す画期的な粘膜治療法の開発を推進している（歯科保存学、補綴学）。これら萌芽期にある口腔幹細胞を基盤とした再生医療の展開と発展のために次世代の若手研究者の育成は急務の課題であり、この取り組みに関して卓越した研究を展開しているUniversity of Southern California、University of Pennsilvania、University of Michiganと共同研究することで、その理論と実践、とりわけトランスレーショナルリサーチの実際を徹底的にマスターさせる。

特に重要な点は単に相互訪問（IN-OUT）するものではなく、若手研究者が世界のトップサイエンティストとの議論と実践を通じて成果を確実に獲得するための交流（CROSS）へとパラダイムシフトさせることである。また、海外の連携研究者を、毎年開催している国際シンポジウム「Kyudai Oral Bioscience」と「味覚嗅覚の分子神経機構」前後に招聘し、共同研究について精査・議論するとともに、派遣若手研究者の成果発表の場として、CROSSの達成度を評価し、次年度の事業計画に生かすとともに将来の国際共同研究のマイルストーンを構築する。これらの取り組みにより若手研究者を刺激し、さらなる意欲の向上を目指す。以上の頭脳循環・交流の取り組みにより九州大学歯学研究院を独創性と先端性に富むプロジェクトを展開する世界トップレベルの歯学研究拠点とする取り組みを推進する。

〔研究目的及び到達目標〕
口腔の健康は咀嚼機能の回復を介した高齢者のQOLの向上に寄与することに加え、認知機能、肥満や糖尿病などの生活習慣病予防、宿主防御機構の恒常性維持など多岐にわたって健康長寿社会の実現に貢献する。さらに、口腔諸組織には幹細胞が豊富に存在し、かつ採取が比較的容易であることから、これらを用いた難治性自己免疫疾患や肝臓病などに対する治療応用の可能性についても注目されつつある。

九州大学歯学研究院は、「口腔の健康から全身の健康を推進する口腔健康科学」、「組織の再生・再建研究」を重点プロジェクトとして位置づけ、本分野における研究を強力に推進し、独創性に富む世界的研究拠点の形成を目指している。また、その達成に向け研究志向大学としての使命を自覚し、①研究マインドを有する学部学生や大学院生の醸成教育の展開、および②次世代リーダーの育成に力を注いでいる。健康長寿の実現を口腔の健康から強力に推進するために、海外の一流の研究者（研究室）と相互訪問・交流（IN-CROSS-OUT）を通じて強固なネットワークを創出して、国際ハブ拠点を目指す。

〔研究計画・方法〕
歯学研究院の掲げる重点プロジェクトによる独創的拠点形成を達成するため、頭脳循環により次世代のリーダー候補者によるプロジェクト研究の水準向上と知的財産の創出を推進する。

口腔健康科学プロジェクトの計画を示す。申請者らは、味覚受容体およびその摂食調節機構の研究において被引用論文数世界第1位（SCOPUS）であり、単一味神経・細胞応答記録など世界オンリーワンの技術を有する（生理学）。新規に発見したPRIP(IP3結合蛋白)とその関連蛋白PP1、PP2Aによる骨代謝/生殖/エネルギー代謝の包括的制御という世界に類をみない独創的な研究を展開中である（生化学）。これらの課題について、味覚・嗅覚における世界でもオンリーワンの研究機関（Monell Center）と、若手研究者を中心に継続的な共同研究を展開することで、栄養の経口摂取を介した肥満・生活習慣病予防、および超高齢者に多くみられる飢餓状態の改善が可能となる。一方、日本人に多い軽微な過体重や肥満を呈する患者の中で、重症の歯周病が合併した場合に惹起される、欧米型肥満類似の慢性炎症病態を解析する極めてユニークな歯周医学研究を展開している（歯周病学）。さらに、こうして活性化された自然免疫機構により、神経障害性疼痛の惹起によるアルツハイマー病の誘導（薬理学）、ミクリッツ病などの唾液線自己免疫疾患を介した高齢者のドライマウス発現（口腔外科学）について、卓越した研究を展開中である。この課題についてはUniversity of Pennsilvania、Harvard University免疫学部門との交流により、臨床免疫学の充実化を図り、最終的にエネルギー代謝研究と融合させることで、neurology、immunogy、endocrinologyを包含する口腔健康科学研究の拠点化を目指す。

一方、組織再生・再建プロジェクトにおいて、申請者らは、口腔組織に由来する幹細胞（以下、口腔幹細胞と略す）を用いた顎顔面口腔領域の再生医療研究に留まらず、自己免疫疾患や難治性肝疾患、先天性疾患等を含む全身の難病への臨床応用を目的とした、独創的かつ先端的なトランスレーショナルリサーチを展開し、卓越した実績を挙げつつある（解剖学）。加えて、口腔幹細胞を用いて難病の発症機序を分子/遺伝子レベルで解明・診断し、当該分子を標的とした治療法の開発を試みるユニークな研究を展開しつつある（解剖学、小児歯科学）。また従来の歯周再生治療や歯科インプラント治療の概念を凌駕する、口腔幹細胞を用いたインプラント体への付着性・シーリングの向上を目指す画期的な粘膜治療法の開発を推進している（歯科保存学、補綴学）。これら萌芽期にある口腔幹細胞を基盤とした再生医療の展開と発展のために次世代の若手研究者の育成は急務の課題であり、この取り組みに関して卓越した研究を展開しているUniversity of Southern California、University of Pennsilvania、University of Michiganと共同研究することで、その理論と実践、とりわけトランスレーショナルリサーチの実際を徹底的にマスターさせる。

特に重要な点は単に相互訪問（IN-OUT）するものではなく、若手研究者が世界のトップサイエンティストとの議論と実践を通じて成果を確実に獲得するための交流（CROSS）へとパラダイムシフトさせることである。また、海外の連携研究者を、毎年開催している国際シンポジウム「Kyudai Oral Bioscience」と「味覚嗅覚の分子神経機構」前後に招聘し、共同研究について精査・議論するとともに、派遣若手研究者の成果発表の場として、CROSSの達成度を評価し、次年度の事業計画に生かすとともに将来の国際共同研究のマイルストーンを構築する。これらの取り組みにより若手研究者を刺激し、さらなる意欲の向上を目指す。以上の頭脳循環・交流の取り組みにより九州大学歯学研究院を独創性と先端性に富むプロジェクトを展開する世界トップレベルの歯学研究拠点とする取り組みを推進する。

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指導大学院生の論文がacta biomaterialia (IF: 7.242)に受理された。

指導中の大学院生の1名が国際歯科学会議（歯科領域で最も権威のある国際学会）におけるハットン賞（優秀研究奨励賞）の最終候補者として日本代表に選ばれ、最終選考会に臨んだ。

指導中の博士課程３年生すべて（４名）が博士課程中間発表において優秀賞を受賞した。

広島大学歯学部、福岡歯科大学歯学部、長崎大学歯学部、福井大学医学部、広島大学大学院で非常勤講師を務めた。

広島大学歯学部、福岡歯科大学歯学部、長崎大学歯学部、福井大学医学部、広島大学大学院で非常勤講師を務めた。

広島大学歯学部、福岡歯科大学歯学部、長崎大学歯学部、福井大学医学部、広島大学大学院で非常勤講師を務めた。

広島大学歯学部、広島大学大学院、長崎大学歯学部、福井大学医学部で非常勤講師を務めた。

広島大学歯学部、岡山大学歯学部、長崎大学歯学部、福井大学医学部で非常勤講師を務めた。

広島大学歯学部、岡山大学歯学部、長崎大学歯学部、福井大学医学部で非常勤講師を務めた。