Language：English   Publisher：(一社)日本癌学会  

researchmap

Language：English   Publisher：(一社)日本癌学会  

researchmap

Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Current periodontal treatment focuses on the mechanical removal of the source of infection, such as bacteria and their products, and there is no approach to control the host inflammatory response that leads to tissue destruction. In order to control periodontal inflammation, we have previously reported the optimization of (+)-terrein synthesis methods and the inhibitory effect of (+)-terrein on osteoclast differentiation in vitro. However, the pharmacological effect of (+)-terrein in vivo in the periodontitis model is still unknown. In this study, we investigated the effect of synthetic (+)-terrein on inflammatory bone resorption using a ligature-induced periodontitis mouse model. Synthetic (+)-terrein (30 mg/kg) was administered intraperitoneally twice a week to the mouse periodontitis model. The control group was treated with phosphate buffer. One to two weeks after the induction of periodontitis, the periodontal tissues were harvested for radiological evaluation (micro-CT), histological evaluation (HE staining and TRAP staining), and the evaluation of inflammatory cytokine production in the periodontal tissues and serum (quantitative reverse-transcription PCR, ELISA). The synthetic (+)-terrein-treated group suppressed alveolar bone resorption and the number of osteoclasts in the periodontal tissues compared to the control group (p < 0.05). In addition, synthetic (+)-terrein significantly suppressed both mRNA expression of TNF-α in the periodontal tissues and the serum concentration of TNF-α (both p < 0.05). In conclusion, we have demonstrated that synthetic (+)-terrein abrogates alveolar bone resorption via the suppression of TNF-α production and osteoclast differentiation in vivo. Therefore, we could expect potential clinical effects when using (+)-terrein on inflammatory bone resorption, including periodontitis.

DOI： 10.3390/jof9030314

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Current periodontal treatment focuses on the mechanical removal of the source of infection, such as bacteria and their products, and there is no approach to control the host inflammatory response that leads to tissue destruction. In order to control periodontal inflammation, we have previously reported the optimization of (+)-terrein synthesis methods and the inhibitory effect of (+)-terrein on osteoclast differentiation in vitro. However, the pharmacological effect of (+)-terrein in vivo in the periodontitis model is still unknown. In this study, we investigated the effect of synthetic (+)-terrein on inflammatory bone resorption using a ligature-induced periodontitis mouse model. Synthetic (+)-terrein (30 mg/kg) was administered intraperitoneally twice a week to the mouse periodontitis model. The control group was treated with phosphate buffer. One to two weeks after the induction of periodontitis, the periodontal tissues were harvested for radiological evaluation (micro-CT), histological evaluation (HE staining and TRAP staining), and the evaluation of inflammatory cytokine production in the periodontal tissues and serum (quantitative reverse-transcription PCR, ELISA). The synthetic (+)-terrein-treated group suppressed alveolar bone resorption and the number of osteoclasts in the periodontal tissues compared to the control group (p < 0.05). In addition, synthetic (+)-terrein significantly suppressed both mRNA expression of TNF-α in the periodontal tissues and the serum concentration of TNF-α (both p < 0.05). In conclusion, we have demonstrated that synthetic (+)-terrein abrogates alveolar bone resorption via the suppression of TNF-α production and osteoclast differentiation in vivo. Therefore, we could expect potential clinical effects when using (+)-terrein on inflammatory bone resorption, including periodontitis.

DOI： 10.3390/jof9030314

PubMed

researchmap

Language：Japanese   Publisher：(NPO)日本歯周病学会  

researchmap

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Porphyromonas gingivalis is commonly known as one of the major pathogens contributing to periodontitis, and its persistent infection may increase the risk for the disease. The proinflammatory mediators, including IL-6, TNF-α, and cyclooxygenase-2 (COX-2)/PGE2, are closely associated with progression of periodontitis. In this study, we focused on the cysteine protease "gingipains," lysine-specific gingipain, arginine-specific gingipain (Rgp) A, and RgpB, produced by P. gingivalis, and used the wild-type strain and several gene-deletion mutants (rgpA, rgpB, kgp, and fimA) to elucidate the involvement of gingipains in COX-2 expression and PGE2 production. We infected human monocytes, which are THP-1 cells and primary monocytes, with these bacterial strains and found that gingipains were involved in induction of COX-2 expression and PGE2 production. We have shown that the protease activity of gingipains was crucial for these events by using gingipain inhibitors. Furthermore, activation of ERK1/2 and IκB kinase was required for gingipain-induced COX-2 expression/PGE2 production, and these kinases activated two transcription factors, c-Jun/c-Fos (AP-1) and NF-κB p65, respectively. In particular, these data suggest that gingipain-induced c-Fos expression via ERK is essential for AP-1 formation with c-Jun, and activation of AP-1 and NF-κB p65 plays a central role in COX-2 expression/PGE2 production. Thus, we show the (to our knowledge) novel finding that gingipains with the protease activity from P. gingivalis induce COX-2 expression and PGE2 production via activation of MEK/ERK/AP-1 and IκB kinase/NF-κB p65 in human monocytes. Hence it is likely that gingipains closely contribute to the inflammation of periodontal tissues.

DOI： 10.4049/jimmunol.2100866

PubMed

researchmap

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

DOI： 10.1111/1348-0421.12944

PubMed

researchmap

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/1348-0421.12944

Language：English   Publishing type：Research paper (scientific journal)  

Tuberculosis is a communicable disease caused by Mycobacterium tuberculosis which primarily infects macrophages and establishes intracellular parasitism. A mycobacterial virulence factor Zn2+ metalloprotease 1 (Zmp1) is known to suppress interleukin (IL)-1β production by inhibiting caspase-1 resulting in phagosome maturation arrest. However, the molecular mechanism of caspase-1 inhibition by Zmp1 is still elusive. Here, we identified GRIM-19 (also known as NDUFA13), an essential subunit of mitochondrial respiratory chain complex I, as a novel Zmp1-binding protein. Using the CRISPR/Cas9 system, we generated GRIM-19 knockout murine macrophage cell line J774.1 and found that GRIM-19 is essential for IL-1β production during mycobacterial infection as well as in response to NLRP3 inflammasome-activating stimuli such as extracellular ATP or nigericin. We also found that GRIM-19 is required for the generation of mitochondrial reactive oxygen species and NLRP3-dependent activation of caspase-1. Loss of GRIM-19 or forced expression of Zmp1 resulted in a decrease in mitochondrial membrane potential. Our study revealed a previously unrecognized role of GRIM-19 as an essential regulator of NLRP3 inflammasome and a molecular mechanism underlying Zmp1-mediated suppression of IL-1β production during mycobacterial infection.

DOI： 10.1096/fj.202101074RR

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Mycobacterium tuberculosis, the causative agent of tuberculosis, possess flavin-dependent thymidylate synthase, ThyX. Since thyX is absent in humans and was shown to be essential for M. tuberculosis normal growth, ThyX is thought to be an attractive novel TB drug target. This study assessed thyX essentiality in Mycobacterium bovis BCG strains using CRISPR interference based gene silencing and found that thyX is not essential in an M. bovis BCG Tokyo derivative strain. A thyX deletion mutant strain was successfully constructed from that strain, which reinforces the non-essentiality of thyX under a certain genetic background.

DOI： 10.1111/1348-0421.12944

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1096/fj.202101074RR.

researchmap

Language：Japanese   Publisher：岡山歯学会  

J-GLOBAL

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/1348-0421.12944.

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Osteoporosis is a common disease characterized by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. Severe bone loss due to osteoporosis triggers pathological fractures and consequently decreases the daily life activity and quality of life. Therefore, prevention of osteoporosis has become an important issue to be addressed. We have reported that the fungal secondary metabolite (+)-terrein (TER), a natural compound derived from Aspergillus terreus, has shown receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation by suppressing nuclear factor of activated T-cell 1 (NFATc1) expression, a master regulator of osteoclastogenesis. TER has been shown to possess extensive biological and pharmacological benefits; however, its effects on bone metabolism remain unclear. In this study, we investigated the effects of TER on the femoral bone metabolism using a mouse-ovariectomized osteoporosis model (OVX mice) and then on RANKL signal transduction using mouse bone marrow macrophages (mBMMs). In vivo administration of TER significantly improved bone density, bone mass, and trabecular number in OVX mice (p < 0.01). In addition, TER suppressed TRAP and cathepsin-K expression in the tissue sections of OVX mice (p < 0.01). In an in vitro study, TER suppressed RANKL-induced phosphorylation of PKCα/βII, which is involved in the expression of NFATc1 (p < 0.05). The PKC inhibitor, GF109203X, also inhibited RANKL-induced osteoclastogenesis in mBMMs as well as TER. In addition, TER suppressed the expression of osteoclastogenesis-related genes, such as Ocstamp, Dcstamp, Calcr, Atp6v0d2, Oscar, and Itgb3 (p < 0.01). These results provide promising evidence for the potential therapeutic application of TER as a novel treatment compound against osteoporosis.

DOI： 10.3389/fphar.2021.674366

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Microbiology Society  

Mycobacterium avium subspecies hominissuis (MAH) is a pathogen that causes various non-tuberculous mycobacterial diseases in humans and animals worldwide. Among the genus, MAH is characterized by relatively slow growth. Here, we isolated a rapidly growing variant of the MAH 104 strain. The variant strain (named N104) exhibited an enhanced growth rate and higher motility compared to the parent MAH 104 strain (P104). Whole-genome sequencing analysis of N104 revealed the loss of the stop codon of MAV_RS14660 due to a single nucleotide replacement, resulting in the substitution of the codon for tryptophan. Notably, exclusion of the stop codon ligated the open reading frames and caused the fusion of two adjacent proteins. A revertant parent strain, in which a mutation was introduced to restore the stop codon, revealed that elimination of the stop codon in MAV_RS14660 was responsible for the N104 phenotype. Furthermore, we analysed the phenotypes of the parent and mutated strains by determining the functions of the MAV_RS14660 and MAV_RS14655 coding regions flanking the stop codon. The mutant strains, expected to express a fusion protein, exhibited increased resistance to antimicrobial drugs and exogenous copper toxicity compared to that of the parent strains. These findings suggest that the fusion of the MAV_RS14660- and MAV_RS14655-encoding regions in the mutant N104 strain could be related to the modified functions of these intrinsic proteins.

DOI： 10.1099/mic.0.001007.

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Mycobacterium avium subspecies hominissuis (MAH) is a pathogen that causes various non-tuberculous mycobacterial diseases in humans and animals worldwide. Among the genus, MAH is characterized by relatively slow growth. Here, we isolated a rapidly growing variant of the MAH 104 strain. The variant strain (named N104) exhibited an enhanced growth rate and higher motility compared to the parent MAH 104 strain (P104). Whole-genome sequencing analysis of N104 revealed the loss of the stop codon of MAV_RS14660 due to a single nucleotide replacement, resulting in the substitution of the codon for tryptophan. Notably, exclusion of the stop codon ligated the open reading frames and caused the fusion of two adjacent proteins. A revertant parent strain, in which a mutation was introduced to restore the stop codon, revealed that elimination of the stop codon in MAV_RS14660 was responsible for the N104 phenotype. Furthermore, we analysed the phenotypes of the parent and mutated strains by determining the functions of the MAV_RS14660 and MAV_RS14655 coding regions flanking the stop codon. The mutant strains, expected to express a fusion protein, exhibited increased resistance to antimicrobial drugs and exogenous copper toxicity compared to that of the parent strains. These findings suggest that the fusion of the MAV_RS14660- and MAV_RS14655-encoding regions in the mutant N104 strain could be related to the modified functions of these intrinsic proteins.

DOI： 10.1099/mic.0.001007

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.job.2020.09.007

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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.

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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

PubMed

researchmap

Language：Japanese   Publisher：日本細菌学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Okayama University  

The periodontal pathogen Porphyromonas gingivalis shows colonial pigmentation on blood agar and produces gingipains (Kgp, RgpA, and RgpB), cysteine proteases involved in an organism's virulence and pigmentation. We showed previously that deletion of the PGN_0300 gene abolished the pigmentation activity and reduced the proteolytic activity of gingipains. The role of the PGN_0297 gene, which consists of an operon with the PGN_0300 gene, is unclear. Herein we examined the effect of PGN_0297 gene deletion on the pigmentation and proteolytic activities and transcriptional levels of gingipains. A PGN_0297 gene deletion mutant (ΔPGN_0297) did not exhibit the pigmentation. The proteolytic activity of the gingipains was decreased in the culture supernatant and on the cell surface of ΔPGN_0297. The mutant ΔPGN_0297 failed to attenuate Akt phosphorylation at Thr308 and Ser473, but both phosphorylations were attenuated in the wild-type and its complementation strain. The deletion of PGN_0297 gene did not substantially affect the transcriptional levels of the gingipain genes kgp, rgpA, and rgpB. Taken together, these results indicate that PGN_0297 is closely involved in the secretion and maturation of gingipains.

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

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 (sIL6R) stimulation in HGFs. First, we performed PCR array to examine IL-6/sIL6R-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

Web of Science

researchmap

Language：English   Publisher：Japanese Association for Oral Biology  

Background Porphyromonas gingivalis is s major oral bacterium closely associated with periodontal diseases including periodontitis and directly affects host cellular signaling. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway plays multiple roles in various cell functions including cell survival and glucose metabolism. In this review, we describe the effect of gingipains on the PI3K/Akt signaling pathway in P. gingivalis infection. Highlight Gingipains inactivate PI3K and Akt in gingival epithelial cells infected with P. gingivalis. These events occur independently of invasion of this organism into the cells and are required for the enzymatic activity of gingipains. Furthermore, 3-Phosphoinositide-dependent protein kinase-1 (PDK1) failed to translocate to the plasma membrane from the cytosol following PI3K inactivation. Additionally, dephosphorylation of Akt downstream proteins, including glycogen synthase kinase 3 (GSK3), mammalian target of rapamycin (mTOR), and Bad, occurs in parallel with the dysregulation of PI3K/PDK1/Akt cascades. Conclusion This review describes the biological characterization of gingipains, which inactivate PI3K and Akt, and disorder the PI3K/Akt signaling pathway. Hence, gingipains may decrease cellular physiological functions, eventually disrupting the gingival epithelium and causing development of periodontal diseases.

DOI： 10.1016/j.job.2017.05.003

Web of Science

Scopus

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC MICROBIOLOGY  

The oral Gram-negative anaerobic bacterium Porphyromonas gingivalis is an important pathogen involved in chronic periodontitis. Among its virulence factors, the major extracellular proteinases, Arg-gingipain and Lys-gingipain, are of interest given their abilities to degrade host proteins and process other virulence factors. Gingipains possess C-terminal domains (CTDs) and are translocated to the cell surface or into the extracellular milieu by the type IX secretion system (T9SS). Gingipains contribute to the colonial pigmentation of the bacterium on blood agar. In this study, Omp17, the PGN_0300 gene product, was found in the outer membrane fraction. A mutant lacking Omp17 did not show pigmentation on blood agar and showed reduced proteolytic activity of the gingipains. CTD-containing proteins were released from bacterial cells without cleavage of the CTDs in the omp17 mutant. Although synthesis of the anionic polysaccharide (A-LPS) was not affected in the omp17 mutant, the processing of and A-LPS modification of CTD-containing proteins was defective. PorU, a C-terminal signal peptidase that cleaves the CTDs of other CTD-containing proteins, was not detected in any membrane fraction of the omp17 mutant, suggesting that the defective maturation of CTD-containing proteins by impairment of Omp17 is partly due to loss of function of PorU. In the mouse subcutaneous infection experiment, the omp17 mutant was less virulent than the wild type. These results suggested that Omp17 is involved in P. gingivalis virulence.

DOI： 10.1128/IAI.01308-15

Web of Science

PubMed

researchmap

Language：Japanese   Publisher：(一社)歯科基礎医学会  

researchmap

Language：Japanese   Publisher：(一社)歯科基礎医学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Society for Biochemistry and Molecular Biology Inc.  

Background: The significance of gingipains on the PI3K/Akt signaling pathway is poorly understood.Results: The inactivation of PI3K and Akt was induced by P. gingivalis, which was associated with gingipains.Conclusion: Gingipains are critical for suppressing the PI3K/Akt signaling pathway via extracellular proteolysis independent of P. gingivalis invasion. Significance: This study shows the first evidence that the gingipains negatively regulate the PI3K/Akt signaling pathway.

DOI： 10.1074/jbc.M114.591610

Scopus

PubMed

researchmap

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Porphyromonas gingivalis has been implicated as a major pathogen in the development and progression of chronic periodontitis. P. gingivalis biofilm formation in the subgingival crevice plays an important role in the ability of the bacteria to tolerate stress signals outside the cytoplasmic membrane. Some bacteria use a distinct subfamily of sigma factors to regulate their extracytoplasmic functions (the ECF subfamily). The objective of this study was to determine if P. gingivalis ECF sigma factors affect P. gingivalis biofilm formation. METHODS: To elucidate the role of ECF sigma factors in P. gingivalis, chromosomal mutants carrying a disruption of each ECF sigma factor-encoding gene were constructed. Bacterial growth curves were measured by determining the turbidity of bacterial cultures. The quantity of biofilm growing on plates was evaluated by crystal violet staining. RESULTS: Comparison of the growth curves of wild-type P. gingivalis strain 33277 and the ECF mutants indicated that the growth rate of the mutants was slightly lower than that of the wild-type strain. The PGN_0274- and PGN_1740-defective mutants had increased biofilm formation compared with the wild-type (p < 0.001); however, the other ECF sigma factor mutants or the complemented strains did not enhance biofilm formation. CONCLUSION: These results suggest that PGN_0274 and PGN_1740 play a key role in biofilm formation by P. gingivalis.

DOI： 10.1186/1472-6831-15-4

PubMed

researchmap

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

We report here the construction of a plasmid vector designed for the efficient electrotransformation of the periodontal pathogen Porphyromonas gingivalis. The novel Escherichia coli-Bacteroides/P. gingivalis shuttle vector, designated pTIO-1, is based on the 11.0-kb E. coli-Bacteroides conjugative shuttle vector, pVAL-1 (a pB8-51 derivative). To construct pTIO-1, the pB8-51 origin of replication and erythromycin resistance determinant of pVAL-1 were cloned into the E. coli cloning vector pBluescript II SK(-) and non-functional regions were deleted. pTIO-1 has an almost complete multiple cloning site from pBluescript II SK(-). The size of pTIO-1 is 4.5 kb, which is convenient for routine gene manipulation. pTIO-1 was introduced into P. gingivalis via electroporation, and erythromycin-resistant transformants carrying pTIO-1 were obtained. We characterized the transformation efficiency, copy number, host range, stability, and insert size capacity of pTIO-1. An efficient plasmid electrotransformation of P. gingivalis will facilitate functional analysis and expression of P. gingivalis genes, including the virulence factors of this bacterium. (C) 2014 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.mimet.2014.07.032

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.mimet.2014.07.032.

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Society for Microbiology  

ABSTRACT

Periodontitis is an inflammatory disease of polymicrobial origin affecting the tissues supporting the tooth. The oral anaerobic bacterium Porphyromonas gingivalis , which is implicated as an important pathogen for chronic periodontitis, triggers a series of host inflammatory responses that promote the destruction of periodontal tissues. Among the virulence factors of P. gingivalis , hemoglobin receptor protein (HbR) is a major protein found in culture supernatants. In this study, we investigated the roles of HbR in the production of inflammatory mediators. We found that HbR induced interleukin-8 (IL-8) production in the human gingival epithelial cell line Ca9-22. p38 mitogen-activated protein kinase (MAPK) and extracellular signal-related kinase 1/2 (Erk1/2) were activated in HbR-stimulated Ca9-22 cells. Inhibitors of p38 MAPK (SB203580) and Erk1/2 (PD98059) blocked HbR-induced IL-8 production. Additionally, HbR stimulated the translocation of NF-κB-p65 to the nucleus, consistent with enhancement of IL-8 expression by activation of the NF-κB pathway. In addition, small interfering RNA (siRNA) targeting activating transcription factor 2 (ATF-2) or cyclic AMP-response element-binding protein (CREB) inhibited HbR-induced IL-8 production. Moreover, pretreatment with SB203580 and PD98059 reduced HbR-induced phosphorylation of CREB and ATF-2, respectively. Combined pretreatment with an inhibitor of NF-κB (BAY11-7082) and SB203580 was more efficient in inhibiting the ability of HbR to induce IL-8 production than pretreatment with either BAY11-7082 or SB203580 alone. Thus, in Ca9-22 cells, the direct activation of p38 MAPK and Erk1/2 by HbR caused the activation of the transcription factors ATF-2, CREB, and NF-κB, thus resulting in the induction of IL-8 production.

DOI： 10.1128/iai.01140-12

researchmap

Language：Japanese   Publisher：(一社)歯科基礎医学会  

researchmap

Language：Japanese   Publisher：(一社)歯科基礎医学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER/PLENUM PUBLISHERS  

Using endoscopic biopsies, gastric mucosal expression levels of interleukin (IL)-1 beta, IL-6, IL-8, and tumor necrosis factor-alpha (TNF-alpha) messenger RNA (mRNA) and microRNAs (miRNAs) that were differentially expressed in association with Helicobacter pylori were assessed by quantitative reverse-transcriptase polymerase chain reaction. Among the H. pylori-positive mucosa, 17 out of 29 miRNAs had significant correlations with at least one of the four proinflammatory cytokines in expression. Among the 17 miRNAs, 15 were associated with the degree of neutrophil infiltration and, more prominently, the degree of mononuclear cell infiltration, according to the updated Sydney system. Persistent H. pylori infection may affect the mucosal expression profiles of miRNAs via chronic inflammation mediated by proinflammatory cytokines. There were significant positive correlations between certain miRNAs including the microRNA-200 family and IL-1 beta, IL-6, or TNF-alpha mRNA in H. pylori-negative gastric mucosa. Underscoring the causal association between miRNAs and proinflammatory cytokines may provide insights into the pathogenesis of H. pylori-associated gastritis linking to gastric carcinogenesis.

DOI： 10.1007/s10875-011-9626-3

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

researchmap

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

Chemokine CXC ligand 13 (CXCL13) and CXC receptor type 5 (CXCR5) are constitutively expressed in tertiary lymphoid follicles where the CXCL13/CXCR5 system regulates B lymphocytes homing. In this study, we sought to examine CXCL13 expression in the H. pylori-infected and -uninfected gastric mucosa and to elucidate the implication in the pathogenesis of HAG in humans.Using endoscopic biopsies taken from the gastric antrum of 29 subjects infected with Helicobacter pylori and 22 uninfected subjects, mucosal CXCL13 mRNA and protein levels were measured by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively.The CXCL13 expression levels were significantly more elevated in H. pylori-positive patients than uninfected ones. The CXCL13 expression levels correlated with the degree of chronic gastritis and bacterial colonization. Immunohistochemistry and in vitro infection assay showed that CXCL13 was not produced by the gastric epithelium, but the alpha-smooth muscle antigen expressing mesenchymal cells were the possible source of CXCL13 within H. pylori-infected gastric mucosa. CXCR5 immunostaining was seen in the CD20-positive lymphoid aggregates.The enhanced induction of CXCL13 may be involved in the pathogenesis of H. pylori-associated gastritis.

DOI： 10.1007/s10620-011-1717-8

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

researchmap

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

Helicobacter pylori vacuolating cytotoxin, VacA, stimulates apoptosis via a mitochondria-dependent pathway. VacA induces apoptosis via activation of the pro-apoptotic B-cell lymphoma (Bcl)-2 family proteins, Bcl-2-associated X protein (Bax) and Bcl-2 homologous antagonist/killer (Bak), while the implication of such pro-survival Bcl-2 family members as Bcl-2 and Bcl-X-L in the VacA-induced apoptosis remains unknown. Signal transduction and activator of transcription 3 (STAT3) is a pivotal transcription factor that upregulates Bcl-2 and Bcl-X-L.This study was conducted to elicit the implication of STAT3 and pro-survival Bcl-2 and Bcl-X-L in the intrinsic apoptosis.Immunoblot and reverse transcriptase real-time polymerase chain reaction (RT-PCR) were employed to assess the cellular expression of STAT3, Bcl-2, and Bcl-X-L in response to purified VacA in gastric adenocarcinoma cell lines. VacA-induced apoptosis was quantitated morphologically following knockdown by each specific small interfering RNA (siRNA) or in the presence of pharmacological inhibitors.VacA reduced STAT3, Bcl-2, and Bcl-X-L expression in a dose-dependent manner. Knockdown of STAT3, Bcl-2, and Bcl-X-L by siRNA induced apoptosis to a similar extent in the case of sufficient VacA inoculation. The VacA-mediated reduction of STAT3 expression was independent of cellular vacuolization, since a vacuolar-type ATPase inhibitor, bafilomycin A1, did not inhibit VacA-induced reduction of STAT3, Bcl-2, and Bcl-X-L expression. Instead, a c-JUN NH2-terminal kinase (JNK) inhibitor, SP600125, restored the VacA-induced reduction of STAT3 expression to the basal level.VacA-induced apoptosis may be, in part, implicated in the reduction of STAT3 linking to the downregulation of Bcl-2 and Bcl-X-L, in association with JNK activity.

DOI： 10.1007/s10620-010-1420-1

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

CiNii Article

researchmap

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

CiNii Article

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Helicobacterpylori VacA induces multiple effects on susceptible cells, including vacuolation, mitochondrial damage, inhibition of cell growth, and enhanced cyclooxygenase-2 expression. To assess the ability of H. pylori to modulate the production of inflammatory mediators, we examined the mechanisms by which VacA enhanced IL-8 production by promonocytic U937 cells, which demonstrated the greatest VacA-induced IL-8 release of the cells tested. Inhibitors of p38 MAPK (SB203580), ERK1/2 (PD98059), IKBa ((E)-3-(4-methylphenyisulfonyl)-2-propenenitrile), Ca2+ entry (SKF96365), and intracellular Ca 21 channels (dantrolene) blocked VacA-induced IL-8 production. Furthermore, an intracellular Ca2+ chelator (BAPTA-AM), which inhibited VacA-activated p38 MAPK, caused a dose-dependent reduction in VacA-induced IL-8 secretion by U937 cells, implying a role for intracellular Ca 21 in mediating activation of MAPK and the canonical NF-kappa B pathway. VacA stimulated translocation of NF-kappa Bp65 to the nucleus, consistent with enhancement of IL-8 expression by activation of the NF-kappa B pathway. In addition, small interfering RNA of activating transcription factor (ATF)-2 or CREB, which is a p38MAPK substrate and binds to the AP-1 site of the IL-8 promoter, inhibited VacA-induced IL-8 production. VacA activated an IL-8 promoter containing an NF-IL-6 site, but not a mutated AP-1 or NF-kappa B site, suggesting direct involvement of the ATF-2/CREB binding region or NF-kappa B-binding regions in VacA-induced IL-8 promoter activation. Thus, in U937 cells, VacA directly increases IL-8 production by activation of the p38 MAPK via intracellular Ca2+ release, leading to activation of the transcription factors, ATF-2, CREB, and NF-kappa B.

DOI： 10.4049/jimmunol.180.7.5017

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Treatment of AZ-521 cells with Helicobacter pylori VacA increased cyclooxygenase 2 (COX-2) mRNA in a time- and dose-dependent manner. A p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, blocked elevation of COX-2 mRNA levels, whereas PD98059, which blocks the Erk1/2 cascade, partially suppressed the increase. Consistent with involvement of p38 MAPK, VacA-induced accumulation of COX-2 mRNA was reduced in AZ-521 cells overexpressing a dominant-negative p38 MAPK (DN-p38). Phosphatidylinositol- specific phospholipase C, which inhibits VacA-induced p38 MAPK activation, blocked VacA-induced COX-2 expression. In parallel with COX-2 expression, VacA increased prostaglandin E2 (PGE2) production, which was inhibited by SB203580 and NS-398, a COX-2 inhibitor. VacA-induced PGE 2 production was markedly attenuated in AZ-521 cells stably expressing DN-p38. VacA increased transcription of a COX-2 promoter reporter gene and activated a COX-2 promoter containing mutated NF-κB or NF-interleukin-6 sites but not a mutated cis-acting replication element (CRE) site, suggesting direct involvement of the activating transcription factor 2 (ATF-2)/CREB-binding region in VacA-induced COX-2 promoter activation. The reduction of ATF-2 expression in AZ-521 cells transformed with ATF-2-small interfering RNA duplexes resulted in suppression of COX-2 expression. Thus, VacA enhances PGE2 production by AZ-521 cells through induction of COX-2 expression via the p38 MAPK/ATF-2 cascade, leading to activation of the CRE site in the COX-2 promoter. Copyright © 2007, American Society for Microbiology. All Rights Reserved.

DOI： 10.1128/IAI.00500-07

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

researchmap

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

researchmap

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

DOI： 10.1074/jbc.m509404200

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Helicobacter pylori vacuolating cytotoxin, VacA, induces vacuolation in mammalian cell lines. Sequence differences in the middle of VacA molecules define two families, termed m1VacA and m2VacA, which differ in cell specificity. Similar to m1VacA, m2VacA is activated by acid or alkali, which enhances its binding to cells. Immunoprecipitation experiments showed that, in AZ-521 cells, activated m2VacA, similar to m1VacA, binds to two receptor-like protein tyrosine phosphatases, RPTPalpha and RPTPbeta suggesting that activated m2VacA as well as m1VacA may contribute to gastrointestinal disease following H. pylori infection. G401 cells express RPTPalpha, not RPTPbeta, and responded to both m1VacA and m2VacA. HeLa cells likewise expressed RPTPalpha, not RPTPbeta, but, in contrast to other cell lines, responded poorly to m2VacA. m1VacA associated with RPTPalpha of HeLa cells to an extent similar to that in other toxin-sensitive cells, whereas activated m2VacA bound HeLa cell RPTPalpha less well, consistent with its low vacuolating activity against these cells. The molecular mass of RPTPalpha from HeLa cells is less than that of the protein from G401 cells, although their extracellular amino acid sequences are virtually identical, with only two amino acid differences noted. Different post-translational modifications of RPTPalpha in HeLa cells may be responsible for the reduced susceptibility to m2VacA.

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Helicobacter pylori produces a potent exotoxin, VacA, which causes progressive vacuolation as well as gastric injury. Although VacA was able to interact with two receptor-like protein tyrosine phosphatases, RPTPbeta and RPTPalpha, RPTPbeta was found to be responsible for gastric damage caused by VacA. To define the region of RPTPbeta involved in VacA binding, we made mutants of human cDNA RPTPbeta-B, a short receptor form of RPTPbeta. Immunoprecipitation experiments to assess VacA binding to RPTPbeta-B mutants indicated that five residues (QTTQP) at positions 747-751 of the extracellular domain of RPTPbeta-B (which is commonly retained in RPTPbeta-A, a long form of RPTPbeta) play a crucial role in its interaction with VacA, resulting in vacuolation as well as Git-1 phosphorylation. Transfected cells expressing deletion mutant Delta752, which lacks QTTQP, or the double point mutant Delta747 (T748A,T749A) had diminished vacuolation in response to VacA. Treatment of RPTPbeta-B and Delta747 (which have QTTQP at 747-751) with neuraminidase and O-glycosidase diminished their VacA binding, whereas chondroitinase ABC did not have an effect. No inhibitory effect of pleiotrophin, a natural RPTPbeta ligand, on VacA binding to RPTPbeta-B or Delta747 was observed, supporting the conclusion that the extracellular region of RPTPbeta-B responsible for VacA binding is different from that involved in binding pleiotrophin. These data define the region in the RPTPbeta extracellular domain critical for VacA binding, in particular the sequence QTTQP at positions 747-751 with crucial threonines at positions 748 and 749 and are consistent with a role for terminal sialic acids possibly because of threonine glycosylation.

PubMed

researchmap

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

DOI： 10.1074/jbc.m307944200

researchmap

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Persistent Helicobacter pylori colonization in the stomach induces gastritis and peptic ulcer and interferes with ulcer healing. Most strains of H. pylori produce a cytotoxin, VacA, that induces cytoplasmic vacuolation in epithelial cells with structural and functional changes, leading to gastric injury. VacA is known to cause cell death by mitochondrial damage. We hypothesized that VacA might disrupt other signaling pathways; to that end, we examined the effects of VacA on MAPKs to elucidate their role in the abnormalities seen in VacA-treated cells. VacA stimulated phosphorylation of p38 and Erk1/2, but not JNK, in AZ-521 cells. Both phosphorylation and kinase activation of p38 were maximal 10-30 min after addition of VacA and declined thereafter. Treatment with anti-VacA antibody or the p38 inhibitor SB203580 blocked p38 phosphorylation caused by VacA and inhibited VacA-induced phosphorylation of activating transcription factor 2 (ATF-2), which is implicated in transcriptional control of stress-responsive genes. These data indicate that VacA stimulates a p38/ATF-2-mediated signal pathway. However, 10 microM SB203580, which is sufficient to decrease p38 phosphorylation, did not inhibit VacA-induced cellular vacuolation, decrease in mitochondrial membrane potential, or cytochrome c release from mitochondria. These results suggest that VacA-induced activation of p38/ATF-2-mediated signal pathway is independent of cellular vacuolation, decrease in mitochondrial membrane potential, or cytochrome c release from mitochondria caused by VacA. The cytotoxin may thus act independently on several cellular targets, leading to disruption of signaling, regulatory, and metabolic pathways.

PubMed

researchmap

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

DOI： 10.1074/jbc.m300117200

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

CiNii Article

CiNii Books

researchmap

Other Link： http://search.jamas.or.jp/link/ui/2003196659

Language：Japanese

researchmap

Language：Japanese

researchmap

Language：Japanese   Publisher：(一社)歯科基礎医学会  

researchmap

Language：Japanese   Publisher：日本細菌学会  

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)歯科基礎医学会  

researchmap

Language：Japanese   Publisher：(一社)日本病理学会  

researchmap

Language：Japanese   Publisher：日本細菌学会  

researchmap

Language：English   Publisher：日本細菌学会  

researchmap

Language：Japanese   Publisher：日本細菌学会  

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)歯科基礎医学会  

researchmap

Language：Japanese   Publisher：日本細菌学会  

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)歯科基礎医学会  

researchmap

Language：English   Publisher：日本細菌学会  

researchmap

Language：Japanese   Publisher：日本細菌学会  

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：岡山歯学会  

researchmap

Language：Japanese   Publisher：岡山歯学会  

researchmap

Language：Japanese   Publisher：岡山歯学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(NPO)日本歯周病学会  

researchmap

Language：Japanese   Publisher：(一社)歯科基礎医学会  

researchmap

Language：Japanese   Publisher：(一社)歯科基礎医学会  

researchmap

Language：Japanese   Publisher：日本細菌学会  

researchmap

Language：Japanese   Publisher：日本細菌学会  

researchmap

Language：English   Publisher：日本細菌学会  

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：岡山歯学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：岡山歯学会  

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese  

CiNii Article

CiNii Books

researchmap

Other Link： http://search.jamas.or.jp/link/ui/2018320253

Language：Japanese   Publisher：北隆館  

CiNii Article

CiNii Books

researchmap

Language：Japanese   Publisher：日本細菌学会  

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：English  

Porphyromonas gingivalis (P. gingivalis) is a major oral pathogen and associated with periodontal diseases including periodontitis and alveolar bone loss. In this review, we indicate that two virulence factors, which are hemoglobin receptor protein (HbR) and cysteine proteases "gingipains", expressed by P. gingivalis have novel functions on the pathogenicity of P. gingivalis. P. gingivalis produces three types of gingipains and concomitantly several adhesin domains. Among the adhesin domains, hemoglobin receptor protein (HbR), also called HGP15, has the function of induction of interleukin-8 (IL-8) expression in human gingival epithelial cells, indicating the possibility that HbR is associated with P. gingivalis-induced periodontal inflammation. On bacteria-host cells contact, P. gingivalis induces cellular signaling alteration in host cells. Phosphatidylinositol 3-kinase (PI3K) and Akt are well known to play a pivotal role in various cellular physiological functions including cell survival and glucose metabolism in mammalian cells. Recently, we demonstrated that gingipains attenuate the activity of PI3K and Akt, which might have a causal influence on periodontal diseases by chronic infection to the host cells from the speculation of molecular analysis. In this review, we discuss new molecular and biological characterization of the virulence factors from P. gingivalis.

DOI： 10.1016/j.jdsr.2017.06.001

PubMed

researchmap

Language：Japanese  

CiNii Article

CiNii Books

researchmap

Other Link： http://search.jamas.or.jp/link/ui/2017405117

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本結核病学会  

researchmap

Language：Japanese   Publisher：日本細菌学会  

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)歯科基礎医学会  

researchmap

Language：Japanese   Publisher：(一社)歯科基礎医学会  

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Event date： 2022.3.29 - 2022.3.31

Language：Japanese   Presentation type：Poster presentation  

Venue：WEB（オンライン）開催（東京）  

researchmap

Event date： 2022.3.29 - 2022.3.31

Language：Japanese   Presentation type：Poster presentation  

Venue：WEB（オンライン）開催（東京）  

researchmap

Event date： 2021.10.9 - 2021.10.17

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2021.10.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：WEB開催（広島）  

researchmap

Event date： 2021.3.23 - 2021.3.25

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Venue：WEB開催（岡山）  

researchmap

Event date： 2020.11.7

Language：English   Presentation type：Oral presentation (invited, special)  

researchmap

Event date： 2020.9.11 - 2020.10.9

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2020.3.18 - 2020.3.21

Language：English   Presentation type：Poster presentation  

Venue：Washington, D.C. USA  

researchmap

Event date： 2020.2.19 - 2020.2.21

Language：Japanese   Presentation type：Oral presentation (general)  

researchmap

Event date： 2019.11.23 - 2019.11.24

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：米子市文化ホール イベントホール（鳥取・米子）  

researchmap

Event date： 2019.10.25 - 2019.10.26

Language：Japanese   Presentation type：Poster presentation  

Venue：北九州国際会議場および西日本総合展示場（福岡・北九州）  

researchmap

Event date： 2019.10.12 - 2019.10.14

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2019.10.12 - 2019.10.14

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2019.6.7 - 2019.6.8

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：iichiko総合文化センター、ホテル日航大分 オアシスタワー（大分）  

researchmap

Event date： 2019.4.23 - 2019.4.25

Language：Japanese   Presentation type：Poster presentation  

Venue：札幌コンベンションセンター（北海道・札幌）  

researchmap

Event date： 2019.4.23 - 2019.4.25

Language：Japanese   Presentation type：Poster presentation  

Venue：札幌コンベンションセンター（北海道・札幌）  

researchmap

Event date： 2019.4.23 - 2019.4.25

Language：Japanese   Presentation type：Poster presentation  

Venue：札幌コンベンションセンター（北海道・札幌）  

researchmap

Event date： 2018.10.28

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Venue：大阪大学中之島センター佐治敬三メモリアルホール（10階）（大阪）  

researchmap

Event date： 2018.10.6 - 2018.10.7

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：愛媛大学 城北キャンパス グリーンホール  

researchmap

Event date： 2018.9.5 - 2018.9.7

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2018.9.5 - 2018.9.7

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2018.3.27 - 2018.3.29

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2018.3.27 - 2018.3.29

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2018.3.27 - 2018.3.29

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2018.3.14 - 2019.3.16

Presentation type：Oral presentation (general)  

researchmap

Event date： 2017.11.17 - 2017.11.19

Language：English   Presentation type：Oral presentation (invited, special)  

researchmap

Event date： 2017.10.14 - 2017.10.15

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：広島大学 東広島キャンパス 学士会館 2階 レセプションホール  

researchmap

Event date： 2017.10.14 - 2017.10.15

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：広島大学 東広島キャンパス 学士会館 2階 レセプションホール  

researchmap

Event date： 2017.10.14 - 2017.10.15

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：広島大学 東広島キャンパス 学士会館 2階 レセプションホール  

researchmap

Event date： 2017.9.16 - 2017.9.18

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：松本歯科大学キャンパス  

researchmap

Event date： 2017.9.16 - 2017.9.18

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：松本歯科大学キャンパス  

researchmap

Event date： 2017.9.16 - 2017.9.18

Language：Japanese   Presentation type：Oral presentation (general)  

researchmap

Event date： 2017.7.17 - 2017.7.21

Language：English   Presentation type：Poster presentation  

researchmap

Event date： 2017.5.14 - 2017.5.16

Language：English   Presentation type：Oral presentation (general)  

researchmap

Event date： 2017.3.22

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京  

researchmap

Event date： 2017.3.22

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京  

researchmap

Event date： 2017.3.19 - 2017.3.21

Language：Japanese   Presentation type：Poster presentation  

Venue：仙台国際センター展示棟（宮城）  

researchmap

Event date： 2017.3.19 - 2017.3.21

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

researchmap

Event date： 2017.3.19 - 2017.3.21

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2017.3.19 - 2017.3.21

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2016.10.15

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：かがわ国際会議場（香川）  

researchmap

Event date： 2016.10.15

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：かがわ国際会議場（香川）  

researchmap

Event date： 2016.10.15

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：かがわ国際会議場（香川）  

researchmap

Event date： 2016.8.24 - 2016.8.26

Language：English   Presentation type：Poster presentation  

researchmap

Event date： 2016.8.24 - 2016.8.26

Language：Japanese   Presentation type：Oral presentation (invited, special)  

researchmap

Event date： 2016.3.23 - 2016.3.25

Language：Japanese   Presentation type：Poster presentation  

Venue：大阪国際交流センター（大阪）  

researchmap

Event date： 2016.3.23 - 2016.3.25

Language：Japanese   Presentation type：Poster presentation  

Venue：大阪国際交流センター（大阪）  

researchmap

Event date： 2015.10.3 - 2015.10.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：岡山大学鹿田キャンパス 地域医療人育成センターおかやま (MUSCAT CUBE)（岡山）  

researchmap

Event date： 2015.10.3 - 2015.10.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：岡山大学鹿田キャンパス 地域医療人育成センターおかやま (MUSCAT CUBE)（岡山）  

researchmap

Event date： 2015.10.3 - 2015.10.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：岡山大学鹿田キャンパス 地域医療人育成センターおかやま (MUSCAT CUBE)（岡山）  

researchmap

Event date： 2015.10.3 - 2015.10.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：岡山大学鹿田キャンパス 地域医療人育成センターおかやま (MUSCAT CUBE)（岡山）  

researchmap

Event date： 2015.9.11 - 2015.9.13

Language：English   Presentation type：Poster presentation  

researchmap

Event date： 2015.3.26 - 2015.3.28

Language：Japanese   Presentation type：Poster presentation  

researchmap

Event date： 2015.3.26 - 2015.3.28

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Venue：長良川国際会議場（岐阜）  

researchmap

Event date： 2015.3.26 - 2015.3.28

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Venue：長良川国際会議場（岐阜）  

researchmap

Event date： 2015.3.26 - 2015.3.28

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Venue：長良川国際会議場（岐阜）  

researchmap

Event date： 2015.3.26 - 2015.3.28

Language：Japanese   Presentation type：Poster presentation  

Venue：長良川国際会議場（岐阜）  

researchmap

Event date： 2015.2.5

Language：English   Presentation type：Oral presentation (invited, special)  

researchmap

岡山大学・群馬大学との共同研究
真菌代謝産物Terreinの破骨細胞分化抑制とメカニズム解明に関わる実験

"長崎大学大学院医歯薬学総合研究科口腔病原微生物学分野
（中山浩次博士・内藤真理子博士）"

歯周病細菌が産生するプロテアーゼの宿主細胞に対する病原発現機序に関わる研究について、細菌培養・細菌変異株の作製・細菌学的解析・生化学的実験の面から共同研究を継続している。