Updated on 2021/12/16

写真a

 
SAWA Yoshihiko
 
Organization
Medicine, Dentistry and Pharmaceutical Sciences Professor
Position
Professor
Contact information
メールアドレス
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Degree

  • (BLANK) ( Hokkaido University )

Research Interests

  • 免疫学

  • 血管学

  • Anatomy

  • Immunology

  • Microcirculation

  • 解剖学

Research Areas

  • Life Science / Oral biological science

Education

  • Hokkaido University   歯学研究科   歯学基礎系

    - 1995

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    Country: Japan

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  • Hokkaido University   歯学部   歯学科

    - 1991

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    Country: Japan

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Research History

  • Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences   Deparment of Oral Function & Anatomy   Professor

    2017.7

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  • 福岡歯科大学歯学部(2013より口腔歯学部)   教授(2011より講座主任、2016年よりアニマルセンター長)

    2005.7 - 2017.6

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  • 北海道大学大学院歯学研究科   助教授

    2004.4 - 2005.6

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  • 北海道大学大学院歯学研究科   助教授

    2000.4 - 2004.3

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  • 北海道大学歯学部   助教授

    2000.2 - 2000.3

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  • 北海道大学歯学部   講師

    1999.4 - 2000.1

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  • エドワード・ハインズJr在郷軍人病院(シカゴ)   文部省在外研究員(若手)

    1998.10 - 1999.9

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  • 北海道大学歯学部   助手

    1995.5 - 1999.3

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  • 北海道大学歯学部   研究生

    1995.4 - 1995.5

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  • 北大歯学部 助手

    1995 - 1999

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Professional Memberships

  • アメリカ臨床解剖学会

    2009.6

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  • 日本分子生物学会

    2009.5

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  • 日本癌学会

    2009.5

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  • 日本リンパ学会

    1995.5

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  • 日本微小循環学会(平成20年より評議員)

    1995.5

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  • International Association for Dental Research

    1995.5

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  • 歯科基礎医学会(平成12年より評議員)

    1995.5

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  • 日本解剖学会(平成12年より評議員)

    1995.5

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Committee Memberships

  • 科学研究費委員会(医歯薬学III)   専門委員・スタート支援  

    2017   

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  • 科学研究費委員会(医歯薬学III)   専門委員・スタート支援  

    2016   

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  • 科学研究費委員会(医歯薬学III)   専門委員・スタート支援  

    2014   

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  • 科学研究費委員会(医歯薬学III)   専門委員・スタート支援  

    2012   

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Papers

  • Maxillofacial morphological characteristics in growing orthodontic patients with non‐syndromic oligodontia Reviewed

    Taiki Suyama, Hiroyuki Ishikawa, Sachio Tamaoki, Remi Higa, Shunsuke Takata, Yoshihiko Sawa

    Orthodontics & Craniofacial Research   2021.12

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    Authorship:Last author   Publishing type:Research paper (scientific journal)   Publisher:Wiley  

    DOI: 10.1111/ocr.12548

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    Other Link: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/ocr.12548

  • Overexpression of SGLT2 in the kidney of a P. gingivalis LPS-induced diabetic nephropathy mouse model. Reviewed International journal

    Koichiro Kajiwara, Yoshihiko Sawa

    BMC Nephrology   22 ( 1 )   287 - 287   2021.8

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

    BACKGROUND: The overexpression of sodium-glucose cotransporter 2 (SGLT2) in diabetic kidneys has been reported. It has also been established that the diabetic glomerular endothelium expresses the toll-like receptors TLR2 and TLR4. The present study aims to examine the renal SGLT2 induction by the TLR2/4 ligand Porphyromonas (P.) gingivalis lipopolysaccharide (Pg-LPS) in mouse diabetic nephropathy. METHODS: Immunohistochemical study and tissue RT-PCR analyses were performed on mouse kidneys in streptozotocin (STZ)-induced diabetic ICR mice (STZ-ICR), in healthy ICR mice administered Pg-LPS (LPS-ICR), and in diabetic ICR mouse kidneys with Pg-LPS-induced nephropathy (LPS-STZ). RESULTS: In the quantitative analysis of blood sugar levels, the mean time to reach 600 mg/dl was shorter in the LPS-STZ than in the STZ-ICR kidneys. The rise in blood glucose levels was significantly steeper in the LPS-STZ than in the STZ-ICR kidneys. According to these data the LPS-STZ model suggests a marked glucose intolerance. The expression of SGLT2 was significantly stronger in the whole of the renal parenchyma of the LPS-STZ than in the LPS-ICR or in the STZ-ICR. The expression of SGLT2 was observed both in the renal tubules and around the renal tubules, and in the glomeruli of the LPS-STZ kidneys. In the analysis by tissue real-time PCR and cell ELISA, the expression of the SGLT2 gene and protein was significantly stronger in the LPS-STZ than in the LPS-ICR or in the STZ-ICR. There were no differences in the renal SGLT2 production in the LPS-ICR and the STZ-ICR kidneys. CONCLUSIONS: Abnormally high renal expression of SGLT2 occurs in diabetic kidneys with P. gingivalis LPS. Periodontitis may be an exacerbating factor in diabetic nephropathy as well as in diabetes.

    DOI: 10.1186/s12882-021-02506-8

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  • Expression of SARS-CoV-2 entry factors in human oral tissue. Reviewed International journal

    Yoshihiko Sawa, Soichiro Ibaragi, Tatsuo Okui, Junro Yamashita, Tetsuro Ikebe, Hiroyuki Harada

    Journal of Anatomy   238 ( 6 )   1341 - 1354   2021.6

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

    The distribution of cells expressing SARS-CoV-2 entry factor angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) in human oral tissues were tested. The investigation was conducted with normal flesh tissue and paraffin-embedded specimens. The ACE2 and TMPRSS2 expression was detected with all subjects in the normal mucosa of the keratinized stratified squamous epithelia of the tongue and non-keratinized stratified squamous epithelia of the lip and cheek. It was found that ACE2 is expressed in the cytoplasm and on the cell membrane mainly in the stratum granulosum of the epithelia while the TMPRSS2 is strongly expressed on the cell membrane mainly in the stratum granulosum and stratum spinosum, but not in the stratum basale. Antibodies' reactions for ACE2 and TMPRSS2 were not observed in the nuclei or keratin layer. The expression of ACE2 and TMPRSS2 in the oral epithelia appears to be general, and the expression was also observed in the mucous and serous acini of the labial glands. The SARS-CoV-2 may transiently attach to the oral mucosa and the minor salivary glands which are present under all of the oral mucosa. The oral cavity can be considered an important organ for SARS-CoV-2 attachment and may provide a preventive medical avenue to guard against COVID-19 by preventing saliva from scattering.

    DOI: 10.1111/joa.13391

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  • Immunohistochemical study for the expression of leukocyte adhesion molecules, and FGF23 and ACE2 in P. gingivalis LPS-induced diabetic nephropathy. Reviewed International journal

    Koichiro Kajiwara, Yoshihiko Sawa, Takahiro Fujita, Sachio Tamaoki

    BMC Nephrology   22 ( 1 )   3 - 3   2021.1

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

    OBJECTIVE: The present study aims to examine the expression of leukocyte adhesion molecules and renal metabolic factors in diabetic mouse kidneys with periodontal pathogen Pg-LPS-induced nephropathy. BACKGROUND: We recently reported that the glomerular endothelium expresses toll-like receptor (TLR)2 and TLR4 in diabetic environments and TLR2/4 ligand Porphyromonas (P.) gingivalis lipopolysaccharides (Pg-LPS) induce nephropathy in diabetic mice. It is thought that Pg-LPS promotes the chronic inflammation with the overexpression of leukocyte adhesion molecules and renal-specific metabolic enzymes by the recognition of Pg-LPS via TLR in the diabetic kidneys. There have been no reports of the effects of periodontopathic bacteria on the expression of leukocyte adhesion molecules and the accumulation of physiologically active substances in the kidney. METHODS: The immunohistochemical investigation was performed on diabetic mouse kidney with Pg-LPS-induced nephropathy with glomerulosclerosis in glomeruli. RESULTS: There were no vessels which expressed vascular cell adhesion molecule-1 (VCAM-1), E-selectin, or fibroblast growth factor (FGF) 23 in streptozotocin (STZ)-induced diabetic ICR mice (STZ-ICR), or in healthy ICR mice administered Pg-LPS (LPS-ICR). However, in diabetic ICR mouse kidneys with Pg-LPS-induced nephropathy (LPS-STZ) the expression of VCAM-1 and the accumulation of FGF23 were observed in renal tubules and glomeruli, and the expression of E-selectin was observed in renal parenchyma and glomeruli. The angiotensin-converting enzyme 2 (ACE2) was detected in the proximal tubules but not in other regions of ICR, STZ-ICR, or LPS-ICR. In LPS-STZ ACE2 was detected both in renal tubules as well as in glomeruli. The Mac-1 and podoplanin-positive cells increased in the renal parenchyma with diabetic condition and there was the distribution of a large number of Mac-1-positive cells in LPS-STZ. CONCLUSIONS: The Pg-LPS may induce diabetic renal inflammation such as glomerulosclerosis and tubulitis with infiltration of Mac-1/podoplanin positive macrophages via glomerular overexpression of VCAM-1 and E-selectin, resulting in accumulation of both ACE2 and FGF23 which were unmetabolized with the inflammation-induced kidney damage under the diabetic condition. Periodontitis may be a critical factor in the progress of nephropathy in diabetic patients.

    DOI: 10.1186/s12882-020-02203-y

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  • Cancellation of the Calcification in Cultured Osteoblasts by CLEC-2

    Takenori Kanai, Yoshihiko Sawa, Yoshiaki Sato

    Journal of Hard Tissue Biology   30 ( 1 )   53 - 62   2021

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    Authorship:Corresponding author   Publisher:Society for Hard Tissue Regenerative Biology  

    DOI: 10.2485/jhtb.30.53

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  • Effect of bisphosphonates on healing of tooth extraction wounds in infectious osteomyelitis of the jaw Reviewed International journal

    Junro Yamashita, Naruhiko Sawa, Yoshihiko Sawa, Shoji Miyazono

    Bone   143   115611 - 115611   2020.8

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

    OBJECTIVES: Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) and infectious osteomyelitis of the jaw (OMJ) in antiresorptive-naïve patients are different disease entities. Although osteoclast inhibition is at the center of the pathogenesis of ARONJ, the role of osteoclast inhibition in infectious OMJ is unknown. The objective of this study was to determine the effect of bisphosphonate osteoclast inhibition in infectious OMJ. METHODS: Osteomyelitis was induced in mice by S. aureus inoculation. The establishment of OMJ was verified by the culture of bone marrow samples obtained from the mandible. Infected animals received either zoledronic acid (ZA) or saline starting at week-2. Treated animals along with non-infected animals underwent tooth extractions at week-4 post-infection. Healing was assessed every week using in vivo micro-computed tomography and intraoral photos. Animals were euthanized at week-8 and cervical lymph nodes were assessed for lymphatic and blood vessels. RESULTS: Tooth extraction wounds did not heal in animals with OMJ. These wounds were characterized by incomplete soft tissue coverage, sporadic bone fill in the sockets, and inflammatory cell accumulation in the connective tissue at 4 weeks after tooth extractions. Conversely, the majority of tooth extraction wounds in the infected animals treated with ZA had improved healing with better bone fill than even non-infected control animals. Consistently, atrophic lymphatic vessels were noted in the draining lymph nodes in animals with OMJ. However, infected animals treated with ZA had lymphatic vessels that were unaltered and showed a similar appearance to those in non-infected control animals. CONCLUSION: ZA treatment promoted wound healing in the jaw with infectious osteomyelitis. Clearly, antiresorptive therapy is contraindicated in patients with ARONJ. However, our finding suggests that osteoclast inhibition is potentially an effectual remedy for infectious OMJ in antiresorptive-naïve patients.

    DOI: 10.1016/j.bone.2020.115611

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  • Alternating Differentiation and Dedifferentiation between Mature Osteoblasts and Osteocytes Reviewed International journal

    Sawa N, Fujimoto H, Sawa Y, Yamashita J

    Scientific Reports   25;9 ( 1 )   13842 - 21788   2019.9

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    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    DOI: 10.1038/s41598-020-78856-4

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  • Maxillofacial morphological factors related to acceleration of maxillary growth attributed to facial mask treatment: a structural superimposition study. Reviewed International journal

    Takashi S Kajii, Yui Sakaguchi, Yoshihiko Sawa, Sachio Tamaoki

    Progress in orthodontics   20 ( 1 )   2 - 2   2019.1

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    BACKGROUND: Anatomical textbooks mention that the contact between the pterygoid process and the palatine's pyramidal process is not a "suture" but "conjugation.".The aim was to evaluate the maxillofacial morphological factor responding most to the orthopedic force of facial mask treatment, using the structural superimposition analysis. METHODS: Thirty-one girls with Angle Class III malocclusion treated using a facial mask (FM group) and 11 girls with pseudo-Class III malocclusion (pseudo-III group) were examined. Lateral cephalograms at pre- and posttreatment were analyzed to evaluate maxillofacial changes. Cephalometric structural superimposition analysis originating with Björk and Skieller was also performed. RESULTS: In the FM group, a multiple linear regression model showed that maxillary sutural growth was significantly associated with counter-clockwise rotation of the maxilla and treatment changes in the anteroposterior distance from the pterygomaxillary fissure to the maxillary anterior alveolus, not changes in the distance from the nasion to the maxillary anterior alveolus. CONCLUSIONS: Structural superimposition analysis showed that counter-clockwise rotation of the maxilla and changes in the distance from the pterygomaxillary fissure to the maxillary anterior alveolus responded most to the orthopedic force of facial mask treatment. The analysis implicated that the pterygoid fissure-palatine's pyramidal process conjugation responds most to facial mask treatment among maxillofacial sutures and conjugation, and that the difference in the response induces maxillary counter-clockwise rotation.

    DOI: 10.1186/s40510-018-0254-9

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  • LpMab-23-recognizing cancer-type podoplanin is a novel predictor for a poor prognosis of early stage tongue cancer Reviewed International journal

    Akihiro Miyazaki, Hiromi Nakai, Tomoko Sonoda, Yoshihiko Hirohashi, Mika K. Kaneko, Yukinari Kato, Yoshihiko Sawa, Hiroyoshi Hiratsuka

    Oncotarget   9 ( 30 )   21156 - 21165   2018.4

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Impact Journals LLC  

    Purpose: We report that the reactivity of a novel monoclonal antibody LpMab-23 for human cancer-type podoplanin (PDPN) is a predictor for a poor prognosis of tongue cancer. Patients and Methods: The association between LpMab-23-recognizing cancertype PDPN expression and clinical/pathological features were analyzed on 60 patients with stage I and II tongue cancer treated with transoral resection of the primary tumor. Results: In the mode of invasion, the LpMab-23-dull/negative cases were significantly larger in cases with low-grade malignancies and without late cervical lymph node metastasis, than in cases with high-grade malignancies and the metastasis. In the high-grade malignant cases, LpMab-23-positive cases were significantly larger than LpMab-23-dull/negative cases. The Kaplan-Meier curves of the five-year metastasis-free survival rate (MFS) were significantly lower in the LpMab-23 positive patients than in LpMab-23 dull/negative patients. The LpMab-23- dull/negative cases showed the highest MFS in all of the clinical/pathological features and particularly, the MFS of the LpMab-23 positive cases decreased to less than 60% in the first year. In the Cox proportional hazard regression models a comparison of the numbers of LpMab-23 dull/negative with positive cases showed the highest hazard ratio with statistical significance in all of the clinical/pathological features. Conclusions: LpMab-23 positive cases may be considered to present a useful predictor of poor prognosis for early stage tongue cancer.

    DOI: 10.18632/oncotarget.24986

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  • Expression and dynamics of podoplanin in cultured osteoblasts with mechanostress and mineralization stimulus Reviewed

    Tomohiro Takenawa, Takenori Kanai, Tetsuya Kitamura, Yoshitaka Yoshimura, Yoshihiko Sawa, Junichiro Iida

    Acta Histochemica et Cytochemica   51 ( 1 )   41 - 52   2018

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Japan Society of Histochemistry and Cytochemistry  

    This study investigates the significance of the expression and dynamics of podoplanin in mechanostress and mineralization in cultured murine osteoblasts. Podoplanin increased in osteoblasts subjected to straining in non-mineralization medium, suggesting that the mechanostress alone is a podoplanin induction factor. In osteoblasts subjected to vertical elongation straining in the mineralization medium, the mRNA amounts of podoplanin, osteopontin, and osteocalcin were significantly larger than those in cells not subjected to straining, suggesting that mechanostress is the cause of a synergistic effect in the expression of these proteins. In osteoblasts in the mineralization medium, significant increases in osteocalcin mRNA occurred earlier in cells subjected to straining than in the cells not subjected to straining, suggesting that the mechanostress is a critical factor to enhance the expression of osteocalcin. Western blot and ELISA analysis showed increased podoplanin production in osteoblasts with longer durations of straining. There was significantly less mineralization product in osteoblasts with antibodies for podoplanin, osteopontin, and osteocalcin. There was also less osteopontin and osteocalcin produced in osteoblasts with anti-podoplanin. These findings suggest that mechanostress induces the production of podoplanin in osteoblasts and that podoplanin may play a role in mineralization in cooperation with bone-associated proteins.

    DOI: 10.1267/ahc.17031

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  • The promotion of nephropathy by Porphyromonas gingivalis lipopolysaccharide via toll-like receptors Reviewed International journal

    Koichiro Kajiwara, Shunsuke Takata, Thao T. To, Kenyo Takara, Yuji Hatakeyama, Sachio Tamaoki, Richard Peters Darveau, Hiroyuki Ishikawa, Yoshihiko Sawa

    Diabetology and Metabolic Syndrome   9 ( 1 )   73 - 73   2017.9

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:BioMed Central Ltd.  

    Background: Recently, we reported that toll-like receptor (TLR)2 and TLR4 localized on the glomerular endothelium in the glomeruli of streptozotocin (STZ)-induced type 1 diabetic mice and high fat diet feed-induced type 2 diabetic mice, and that periodontal pathogen Porphyromonas gingivalis LPS (Pg-LPS) administration lowered the survival rate of diabetic mice. The present study aims to examine the effect of TLR4 blocking on the suppression of Pg-LPS-induced diabetic nephropathy. Methods: The survival rate and morphological/biochemical features for streptozotocin-induced diabetic mice with Pg-LPS and TLR4 blocker eritoran administration were investigated by reporter gene assay, urine and blood analysis, immunohistochemistry, and real time-PCR. Results and Conclusions: All of the diabetic mice administered Pg-LPS were euthanized within the survival period of almost all of the diabetic mice. The blood urea nitrogen and creatinine, expression of TLR2 and TGF-b, and type 1 collagen accumulation, in the diabetic mice increased significantly with the Pg-LPS administration. In spite of the limited TLR4 activation with Pg-LPS, the TLR4 blocker eritoran decreased blood urea nitrogen and creatinine, and raised the survival rate of the Pg-LPS-administered diabetic mice slightly. The high expression levels of TLR2, TGF-b, and type 1 collagen in Pg-LPS-administered diabetic mice decreased with eritoran. Nuclear STAT3 which enhances TLR2 expression was detected in the TLR2-expressing glomeruli of diabetic mice. The TLR2 and STAT3 gene expression increased by the Pg-LPS administration but decreased with eritoran. These may suggest that Pg-LPS-induced diabetic nephropathy is mainly dependent on TLR2 signaling on glomerular endothelial cells, and that TLR4 blocker eritoran may play a role to slow the progress of diabetic nephropathy.

    DOI: 10.1186/s13098-017-0271-8

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  • Morphological study of tooth development in podoplanin-deficient mice Reviewed International journal

    Kenyo Takara, Naoki Maruo, Kyoko Oka, Chiaki Kaji, Yuji Hatakeyama, Naruhiko Sawa, Yukinari Kato, Junro Yamashita, Hiroshi Kojima, Yoshihiko Sawa

    PLOS ONE   12 ( 2 )   e0171912   2017.2

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:PUBLIC LIBRARY SCIENCE  

    Podoplanin is a mucin-type highly O-glycosylated glycoprotein identified in several somatyic cells: podocytes, alveolar epithelial cells, lymphatic endothelial cells, lymph node stromal fibroblastic reticular cells, osteocytes, odontoblasts, mesothelial cells, glia cells, and others. It has been reported that podoplanin-RhoA interaction induces cytoskeleton relaxation and cell process stretching in fibroblastic cells and osteocytes, and that podoplanin plays a critical role in type I alveolar cell differentiation. It appears that podoplanin plays a number of different roles in contributing to cell functioning and growth by signaling. However, little is known about the functions of podoplanin in the somatic cells of the adult organism because an absence of podoplanin is lethal at birth by the respiratory failure. In this report, we investigated the tooth germ development in podoplanin-knockout mice, and the dentin formation in podoplanin-conditional knockout mice having neural crest-derived cells with deficiency in podoplanin by the Wnt1 promoter and enhancer-driven Cre recombinase: Wnt1-Cre; Pdpn(Delta/Delta) mice. In the Wnt1-Cre; Pdpn(Delta/Delta)mice, the tooth and alveolar bone showed no morphological abnormalities and grow normally, indicating that podoplanin is not critical in the development of the tooth and bone.

    DOI: 10.1371/journal.pone.0171912

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  • Effects of a chemically synthesized leucine-rich amelogenin peptide (csLRAP) on chondrogenic and osteogenic cells Reviewed

    Yuko Matsuda, Yuji Hatakeyama, Kazuki Nakashima, Naoko Kamogashira, Junko Hatakeyama, Sachio Tamaoki, Yoshihiko Sawa, Hiroyuki Ishikawa

    Journal of Hard Tissue Biology   26 ( 1 )   51 - 60   2017

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    Amelogenin is one of the enamel matrices secreted by ameloblasts and is known to have at least 15 alternative mRNA splicing isoforms. The leucine rich amelogenin peptide (LRAP) is one of most abundant amelogenin isoforms and numerous studies have shown that amelogenin peptides including LRAP, are expressed in cartilage and bone. Lysosome-associated membrane protein-1 (LAMP-1) has been identified as amelogenin binding partner, however, the mechanism of action for LRAP in chondrogenesis or osteogenesis is still unclear. This study aimed to assay the effect of chemically synthesized LRAP (csLRAP) on chondrogenic or osteogenic differentiation with the involvement of LAMP-1. The csLRAP used in this study was generated by F-moc solid phase chemistry based on the mouse LRAP amino acid sequence and was added to the culture medium of the chondrogenic cells, ATDC5 and the osteoblast cells, MC3T3-E1. Both chondrogenic and osteoblast cells, in which an immunopositive reaction to LAMP-1 antibody was observed by immunocytochemistry, showed significant suppression in cell number in the presence of csLRAP at 10 μg/ml compared to that in control, but this effect was rescued in the presence of LAMP-1 antibody. On the other hand, the intensity of alcian blue staining in chondrogenic cells and alizarin red staining in osteoblast cells was significantly increased in the presence of csLRAP at a dose of 10 μg/ml after 4 weeks culture, and this effect was suppressed in the presence LAMP-1 antibody. Moreover, the chondrogenic or osteogenic differentiation marker genes including Sox9, Type II Collagen, Type X Collagen, Runx2, Alkaline Phosphatase, and Type I Collagen, were upregulated in the presence of csLRAP after one week of culture and were suppressed in the presence of LAMP-1 antibody. These results suggest that csLRAP could promote osteogenic and chondrogenic differentiation in vitro, and that LAMP-1 may be involved in the differentiation and proliferation of these cells.

    DOI: 10.2485/jhtb.26.51

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  • Novel Monoclonal Antibody LpMab-17 Developed by CasMab Technology Distinguishes Human Podoplanin from Monkey Podoplanin. Reviewed International journal

    Yukinari Kato, Satoshi Ogasawara, Hiroharu Oki, Ryusuke Honma, Michiaki Takagi, Yuki Fujii, Takuro Nakamura, Noriko Saidoh, Hazuki Kanno, Mitsuo Umetsu, Satoshi Kamata, Hiroshi Kubo, Mitsuhiro Yamada, Yoshihiko Sawa, Kei-Ichi Morita, Hiroyuki Harada, Hiroyoshi Suzuki, Mika Kato Kaneko

    Monoclonal antibodies in immunodiagnosis and immunotherapy   35 ( 2 )   109 - 16   2016.4

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    Podoplanin (PDPN) is a type-I transmembrane sialoglycoprotein, which possesses a platelet aggregation-stimulating (PLAG) domain in its N-terminus. Among the three PLAG domains, O-glycan on Thr52 of PLAG3 is critical for the binding with C-type lectin-like receptor-2 (CLEC-2) and is essential for platelet-aggregating activity of PDPN. Although many anti-PDPN monoclonal antibodies (mAbs) have been established, almost all mAbs bind to PLAG domains. We recently established CasMab technology to produce mAbs against membranous proteins. Using CasMab technology, we produced a novel anti-PDPN mAb, LpMab-17, which binds to non-PLAG domains. LpMab-17 clearly detected endogenous PDPN of cancer cells and normal cells in Western-blot, flow cytometry, and immunohistochemistry. LpMab-17 recognized glycan-deficient PDPN in flow cytometry, indicating that the interaction between LpMab-17 and PDPN is independent of its glycosylation. The minimum epitope of LpMab-17 was identified as Gly77-Asp82 of PDPN using enzyme-linked immunosorbent assay. Of interest, LpMab-17 did not bind to monkey PDPN, whereas the homology is 94% between human PDPN and monkey PDPN, indicating that the epitope of LpMab-17 is unique compared with the other anti-PDPN mAbs. The combination of different epitope-possessing mAbs could be advantageous for the PDPN-targeting diagnosis or therapy.

    DOI: 10.1089/mab.2015.0077

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  • Differentiation of Apical Bud Cells in a Newly Developed Apical Bud Transplantation Model Using GFP Transgenic Mice as Donor. Reviewed International journal

    Naoki Maruo, Ryuji Sakagami, Yasunori Yoshinaga, Kazuhiko Okamura, Yoshihiko Sawa

    PLoS one   11 ( 3 )   e0150766   2016

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    Rodent mandibular incisors have a unique anatomical structure that allows teeth to grow throughout the lifetime of the rodent. This report presents a novel transplantation technique for studying the apical bud differentiation of rodent mandibular incisors. Incisal apical end tissue with green fluorescent protein from transgenic mouse was transplanted to wild type mice, and the development of the transplanted cells were immunohistologically observed for 12 weeks after the transplantation. Results indicate that the green fluorescent apical end tissue replaced the original tissue, and cells from the apical bud differentiated and extended toward the incisal edge direction. The immunostaining with podoplanin also showed that the characteristics of the green fluorescent tissue were identical to those of the original. The green fluorescent cells were only found in the labial side of the incisor up to 4 weeks. After 12 weeks, however, they were also found in the lingual side. Here the green fluorescent cementocyte-like cells were only present in the cementum close to the dentin surface. This study suggests that some of the cells that form the cellular cementum come from the apical tissue including the apical bud in rodent incisors.

    DOI: 10.1371/journal.pone.0150766

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  • Intermittent Administration of Parathyroid Hormone Ameliorates Periapical Lesions in Mice Reviewed International journal

    Masato Otawa, Ryuichiro Tanoue, Hirofumi Kido, Yoshihiko Sawa, Junro Yamashita

    JOURNAL OF ENDODONTICS   41 ( 5 )   646 - 651   2015.5

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    Introduction: Intermittent administration of parathy raid hormone (PTH) promotes oral osseous wound healing and protects against ligature-induced alveolar bone loss. However, its therapeutic value on periapical periodontitis is unknown. The goal of this study was to determine the effect of intermittent PTH administration on the progression of periapical periodontitis. Methods: Seven lymphotoxin alpha deficient mice received pulp exposures of mandibular first and second molars. Exposed pulp in the right mandible was covered with plaque-contaminated fibrin, whereas exposed pulp in the left mandible was left open. After 4 weeks, the perk apical tissues were examined to determine the effect of plaque-contaminated fibrin to induce periapical lesions. Fourteen mice received pulp exposure covered with plaque-contaminated fibrin. PTH (40 Ag/kg/d) was administered intermittently to half of the mice for 3 weeks beginning 1 week after pulp exposure. The remaining half received saline injections as the vehicle control. At sacrifice, mandibles and tibiae were harvested and processed for histologic examination. Evaluation of neutrophils and blood vessels was performed after staining with immunofluorescence, and periradicular bone was histomorphometrically analyzed. Results: The exposed pulp covered with plaque-contaminated fibrin resulted in significantly larger periapical lesions compared with the control. Intermittent PTH administration reduced the size of periapical lesions significantly. Significantly less neutrophil infiltration around the root apex was found in PTH-treated animals compared with the control. Conclusions: PTH treatment suppressed periapical inflammation by reducing neutrophil infiltration and protected against tissue destruction by periapical periodontitis.

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  • マウス下顎切歯歯胚の幹細胞におけるSox2およびOct4の発現 Reviewed

    丸尾 直樹, 岡村 和彦, 沢 禎彦, 坂上 竜資

    Journal of Oral Biosciences Supplement   2014   160 - 160   2014.9

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  • Expression of Toll-Like Receptor 2 in Glomerular Endothelial Cells and Promotion of Diabetic Nephropathy by Porphyromonas gingivalis Lipopolysaccharide Reviewed International journal

    Yoshihiko Sawa, Shunsuke Takata, Yuji Hatakeyama, Hiroyuki Ishikawa, Eichi Tsuruga

    PLOS ONE   9 ( 5 )   e97165   2014.5

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    The toll-like receptor (TLR) has been suggested as a candidate cause for diabetic nephropathy. Recently, we have reported the TLR4 expression in diabetic mouse glomerular endothelium. The study here investigates the effects of the periodontal pathogen Porphyromonas gingivalis lipopolysaccharide (LPS) which is a ligand for TLR2 and TLR4 in diabetic nephropathy. In laser-scanning microscopy of glomeruli of streptozotocin-and a high fat diet feed-induced type I and type II diabetic mice, TLR2 localized on the glomerular endothelium and proximal tubule epithelium. The TLR2 mRNA was detected in diabetic mouse glomeruli by in situ hybridization and in real-time PCR of the renal cortex, the TLR2 mRNA amounts were larger in diabetic mice than in non-diabetic mice. All diabetic mice subjected to repeated LPS administrations died within the survival period of all of the diabetic mice not administered LPS and of all of the non-diabetic LPS-administered mice. The LPS administration promoted the production of urinary protein, the accumulation of type I collagen in the glomeruli, and the increases in IL-6, TNF-alpha, and TGF-beta in the renal cortex of the glomeruli of the diabetic mice. It is thought that blood TLR ligands like Porphyromonas gingivalis LPS induce the glomerular endothelium to produce cytokines which aid glomerulosclerosis. Periodontitis may promote diabetic nephropathy.

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  • Microfibril-associated glycoprotein-1 controls human ciliary zonule development in vitro. Reviewed

    Takahiro Fujita, Eichi Tsuruga, Kaori Yamanouchi, Yoshihiko Sawa, Hiroyuki Ishikawa

    Acta histochemica et cytochemica   47 ( 1 )   11 - 7   2014.2

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    The ciliary zonule in the eye, also known as Zinn's zonule, is composed of oxytalan fibers, which are bundles of microfibrils consisting mainly of fibrillin-1. However, it is still unclear which of the microfibril-associated molecules present in the ciliary zonule controls oxytalan fibers. Microfibril-associated glycoprotein-1 (MAGP-1) is the only microfibril-associated molecule identified in the human ciliary zonule. In the present study, we used siRNA against MAGP-1 in cultures of human non-pigmented ciliary epithelial cells to examine the extracellular deposition and appearance of fibrillin-1 employing Western blotting and immunofluorescence. MAGP-1 suppression led to a reduction of fibrillin-1 deposition. Immunofluorescence also confirmed that RNAi-mediated down-regulation of MAGP-1 led to suppression of fiber development. These results suggest that MAGP-1 plays a crucial role in the extracellular deposition of fibrillin-1 during formation of the human ciliary zonule.

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  • Distribution of podoplanin-expressing cells in the mouse nervous systems. Reviewed

    Miwa Tomooka, Chiaki Kaji, Hiroshi Kojima, Yoshihiko Sawa

    Acta histochemica et cytochemica   46 ( 6 )   171 - 7   2013.12

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    Podoplanin is a mucin-type glycoprotein which was first identified in podocytes. Recently, podoplanin has been successively reported as a marker for brain and peripheral nerve tumors, however, the distribution of podoplanin-expressing cells in normal nerves has not been fully investigated. This study aims to examine the podoplanin-expressing cell distribution in the mouse head and nervous systems. An immunohistochemical study showed that the podoplanin-positive areas in the mouse peripheral nerve and spinal cord are perineurial fibroblasts, satellite cells in the dorsal root ganglion, glia cells in the ventral and dorsal horns, and schwann cells in the ventral and dorsal roots; in the cranial meninges the dura mater, arachnoid, and pia mater; in the eye the optic nerve, retinal pigment epithelium, chorioidea, sclera, iris, lens epithelium, corneal epithelium, and conjunctival epithelium. In the mouse brain choroid plexus and ependyma were podoplanin-positive, and there were podoplanin-expressing brain parenchymal cells in the nuclei and cortex. The podoplanin-expressing cells were astrocyte marker GFAP-positive and there were no differences in the double positive cell distribution of several portions in the brain parenchyma except for the fornix. The results suggest that podoplanin may play a common role in nervous system support cells and eye constituents.

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  • Leucine Rich Amelogenin Peptideによる軟骨形成の誘導

    畠山 純子, 畠山 雄次, 松本 典祥, 春名 千英子, 諸冨 孝彦, 泉 利雄, 沢 禎彦, 笹野 泰之, 阿南 壽

    日本歯科保存学雑誌   56 ( 6 )   560 - 569   2013.12

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    目的:アメロジェニンスプライシングバリアントの一つであるleucine rich amelogenin peptide(LRAP)は,破骨細胞と骨芽細胞の成熟,歯根膜細胞の遊走および増殖を促進するシグナルペプチドとして示唆されている.近年,軟骨にアメロジェニンの発現が報告されている.しかし,LRAPが軟骨形成に関与するかについての詳細は不明である.本研究の目的は,軟骨形成におけるLRAPの機能を明らかにすることである.材料と方法:C57BL6/CrSlcマウスの胎生10日齢の肢芽を摘出後,トリプシン/コラゲナーゼ処理により細胞を分離し,マイクロマスカルチャーを行った.ブタリコンビナントLRAP(マウスLRAPと〜85%の相同性,Dr.Gibson(ペンシルバニア大学,USA)より供与)と陽性コントロールとしてマウスリコンビナントGrowth Differentiation Factor-5(GDF-5,R & D Systems,USA)を,1,10,100ng/mlずつ培地に添加した.培養開始2,4,6日後にアルシアンブルー染色を行った.24,48時間後にBrdU assayを行い,細胞の増殖を確認した.12,24,48時間後にRNAを抽出し,軟骨のマーカーであるSox9,II型コラーゲン(Col2a1)およびAggrecanの半定量的RT-PCRを行った.有意差検定にはANOVAとBonferroni's post hoc testを用いた.結果:添加24・48時間後で,LRAP添加0.1,1,10ng/mlのいずれにおいても,濃度依存的にBrdU陽性細胞がコントロール群と比較して有意に増加していた.コントロール群では添加2日後にアルシアンブルー染色陽性結節の出現がみられ,培養期間が長くなると陽性結節の染色性が増加したが,LRAPおよびGDF-5を添加した群では,濃度依存的・培養期間依存的にアルシアンブルーの染色性が強くなった.LRAP添加群では,24・48時間後にSox9の遺伝子発現が,また48時間後にCol2a1およびAggrecanの遺伝子発現上昇がコントロール群と比較して有意に上昇した.結論:これらの知見は,アメロジェニンスプライシングバリアントの一つであるLRAPが,軟骨形成を促進していることを示唆している.(著者抄録)

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  • Quantitative evaluation of myofibroblast apoptosis during wound healing in rat palate after post-operative administration of basic fibroblast growth factor (bFGF). International journal

    Yuichiro Hata, Hiroyuki Ishikawa, Takeshi Ueki, Takashi S Kajii, Sachio Tamaoki, Eichi Tsuruga, Yoshihiko Sawa, Kunihisa Taniguchi

    Acta odontologica Scandinavica   71 ( 6 )   1501 - 7   2013.11

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    OBJECTIVE: Excessive wound contraction apparently inhibits maxillary growth; thus, myofibroblast apoptosis needs to be accelerated in mucoperiosteal denudation after palatoplasty. The aim of this study was to evaluate myofibroblast apoptosis during wound healing in mucoperiosteal denudation of rat palates immediately after post-operative administration of basic fibroblast growth factor (bFGF). MATERIALS AND METHODS: A total of 100 male Wistar rats aged 20 days were divided into control, scar, sham and bFGF groups (n = 25 each). In the scar, sham and bFGF groups, mucoperiosteum was removed from the palate and fibrin glue was applied to the exposed bone surface immediately after surgery. In the bFGF group, 10 μL of 2 μg/μL bFGF solution was injected into the operated area beneath the fibrin glue. At 2, 5, 7, 14 and 28 days post-operatively, myofibroblast apoptosis during the wound healing process was investigated by double immunofluorescence staining. The apoptotic area of myofibroblasts was measured using image software. RESULTS: In the bFGF group, at 2 days, apoptosis of myofibroblasts in the lamina propria and submucosa was marked, as compared with the other three groups and apoptosis of myofibroblasts was scarcely seen at 5 days. At 5 and 7 days, the apoptotic area of myofibroblasts in the bFGF group was statistically significantly smaller when compared to the scar and sham groups. CONCLUSION: The results confirmed that bFGF injection immediately after surgery accelerated apoptosis of myofibroblasts in mucoperiosteal denudation of rats. This may reduce maxillary growth retardation due to excessive wound contraction.

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  • Altered dynamics in the renal lymphatic circulation of type 1 and type 2 diabetic mice.

    Takanobu Uchiyama, Shunsuke Takata, Hiroyuki Ishikawa, Yoshihiko Sawa

    Acta histochemica et cytochemica   46 ( 2 )   97 - 104   2013.4

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    The dynamics of the renal lymphatic circulation in diabetic nephropathy is not fully elucidated. The present study evaluated the effect of diabetic nephropathy on the renal lymphatic circulation in streptozotocin (STZ)-induced type 1 diabetic mice (ICR-STZ) and in type 2 diabetic KK/Ta mice which were fed a high fat diet (KK/Ta-HF). The diabetic mouse kidneys developed edema because of the nephropathy. In control mice renal lymphatic vessels distributed in the cortex but rarely in the medulla while in ICR-STZ and KK/Ta-HF mice, there were many lymphatic vessels with small lumen in both cortex and medulla. Total numbers and areas of renal blood vessels in the diabetic mice were similar to those in the controls while the total numbers and areas of renal lymphatic vessels were larger in diabetic mice than in the controls. There were statistically significant differences in the numbers of lymphatic vessels with diameters of 50-100 µm between the ICR-STZ and the control ICR mice, and in the numbers of lymphatic capillaries with diameters smaller than 50 µm between the KK/Ta-HF and the control KK/Ta mice. The diabetic nephropathy may induce the lymphangiogenesis or result in at least the renal lymphatic vessel expansion.

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  • Case of autoimmune hepatitis with markedly enlarged hepatoduodenal ligament lymph nodes. International journal

    Hideki Fujii, Naoki Ohnishi, Kazuho Shimura, Masafumi Sakamoto, Tohru Ohkawara, Yoshihiko Sawa, Koichi Nishida, Yasuo Ohkawara, Tatsuro Kobata, Kanji Yamaguchi, Yoshito Itoh

    World journal of gastroenterology   19 ( 11 )   1834 - 40   2013.3

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    Autoimmune hepatitis (AIH) is a necroinflammatory liver disease of unknown etiology. The disease is characterized histologically by interface hepatitis, biochemically by increased aspartate aminotransferase and alanine aminotransferase levels, and serologically by increased autoantibodies and immunoglobulin G levels. Here we discuss AIH in a previously healthy 37-year-old male with highly elevated serum levels of soluble interleukin-2 receptor and markedly enlarged hepatoduodenal ligament lymph nodes (HLLNs, diameter, 50 mm). Based on these observations, the differential diagnoses were AIH, lymphoma, or Castleman's disease. Liver biopsy revealed the features of interface hepatitis without bridging fibrosis along with plasma cell infiltration which is the typical characteristics of acute AIH. Lymph node biopsy revealed lymphoid follicles with inflammatory lymphocytic infiltration; immunohistochemical examination excluded the presence of lymphoma cells. Thereafter, he was administered corticosteroid therapy: after 2 mo, the enlarged liver reached an almost normal size and the enlarged HLLNs reduced in size. We could not find AIH cases with such enlarged lymph nodes (diameter, 50 mm) in our literature review. Hence, we speculate that markedly enlarged lymph nodes observed in our patient may be caused by a highly activated, humoral immune response in AIH.

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  • Expression of Toll-Like Receptor 4 in Glomerular Endothelial Cells under Diabetic Conditions.

    Shunsuke Takata, Yoshihiko Sawa, Takanobu Uchiyama, Hiroyuki Ishikawa

    Acta histochemica et cytochemica   46 ( 1 )   35 - 42   2013.2

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    Diabetic conditions promote glomerulosclerosis by mesangial cells but the mechanisms are not fully elucidated. The present study evaluated the expression of toll-like receptor 4 in glomerular endothelial cells in the streptozotocin (STZ)-induced type 1 diabetic mouse (ICR-STZ) and the type 2 diabetic KK/TaJcl mouse which were fed a high fat diet feed (KK/Ta-HF). In the ICR-STZ and KK/Ta-HF almost glomeruli were immunostained with anti-TLR4 but there was no glomerulus immunostained by ani-TLR4 in the control ICR and KK/Ta. Laser-scanning confocal microscopy showed that the TLR4-positive region did not coincide with the podoplanin-positive region but coincide with the PECAM-1- and VE-cadherin-positive regions in the glomeruli of the ICR-STZ and KK/Ta-HF. The in situ hybridization showed that almost signals for TLR4 mRNA were present in the glomerulus of the ICR-STZ and KK/Ta-HF to a stronger extent than in the control ICR and KK/Ta. These suggest that glomerular endothelial cells usually express the TLR4 gene and hyperglycemia in the diabetic condition induces the TLR4 protein expression in the glomerular capillary endothelial cells. Cytokine productions through the TLR signaling pathway in glomerular endothelial cells may allow mesangial cells to produce extracellular matrix proteins in the diabetic milieu.

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  • Matrix Metalloproteinase-2 Degrades Fibrillin-1 and Fibrillin-2 of Oxytalan Fibers in the Human Eye and Periodontal Ligaments In Vitro Reviewed

    Megumi Kawagoe, Eichi Tsuruga, Kyoko Oka, Yoshihiko Sawa, Hiroyuki Ishikawa

    ACTA HISTOCHEMICA ET CYTOCHEMICA   46 ( 5 )   153 - 159   2013

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    Oxytalan fibers are distributed in the eye and periodontal ligaments (PDL). The ciliary zonule, known as Zinn's zonule, in the eye is composed of oxytalan fibers, which are bundles of microfibrils consisting mainly of fibrillin-1 and fibrillin-2. As turnover of oxytalan fibers is slow during life, their degradation mechanism remains unclarified. This study was performed to examine degradation pattern of fibrillin-1 and fibrillin-2 by experimental MMP activation. We cultured human non-pigmented ciliary epithelial cells (HNPCEC) and PDL fibroblasts for 7 days, then treated them with concanavalin A to activate matrix metalloproteinase (MMP)-2, and examined the degradation of fibrillin-1 and fibrillin-2 for 72 hr using immunofluorescence. At 7 days of HNPCEC culture, fibrillin-1-positive fibers were observed, some of which merged with fibrillin-2. After MMP-2 activation, fibrillin-1-positive fibers became thin and disappeared by 72 hr, while fibrillin-2-positive fibers disappeared almost completely within 24 hr. At 7 days of PDL fibroblast culture, fibrillin-1-positive fibers were mostly merged with fibrillin-2. After MMP-2 activation, fibrillin-1-positive fibers became thin by 24 hr and had almost disappeared by 48 hr, while fibrillin-2-positive fibers decreased constantly after 24 hr. A MMP-2 inhibitor completely suppressed these degradations. These results suggest that the patterns of fibrillin-1 and fibrillin-2 degradation differ between the eye and the PDL, possibly reflecting the sensitivity of fibrillin-1 and fibrillin-2 of each type of oxytalan fiber against MMP-2.

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  • Latent transforming growth factor-β binding protein 2 negatively regulates coalescence of oxytalan fibers induced by stretching stress Reviewed International journal

    Eichi Tsuruga, Kyoko Oka, Yuji Hatakeyama, Keitaro Isokawa, Yoshihiko Sawa

    Connective Tissue Research   53 ( 6 )   521 - 527   2012.12

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    Oxytalan fibers are extracellular matrix components consisting of pure microfibrils. However, the mechanism whereby oxytalan fibers develop is not fully understood. We have previously reported that in human periodontal ligament (PDL) fibroblasts subjected to stretching stress, bundles of oxytalan fibers coalesce under the control of fibulin-5. Latent transforming growth factor-β binding protein 2 (LTBP-2) is known to bind to fibulin-5. The purpose of this study was to clarify the role of LTBP-2 in the coalescence of oxytalan fibers. We subjected PDL fibroblasts to stretching in order to examine the effects of LTBP-2 on the coalescence of oxytalan fibers in cell/matrix layers. Interaction of LTBP-2 with fibulin-5 was examined by immunoprecipitation assay, and changes in LTBP-2 deposition upon stretching were investigated by Western blotting and immunofluorescence assays. We used small interfering RNA against LTBP-2 in PDL cell culture and examined the appearance of oxytalan fibers on the basis of immunofluorescence. Stretching induced coalescence of oxytalan fibers, but did not affect LTBP-2 expression. The amount of extracellularly deposited LTBP-2 was decreased by about 70% as a result of stretching, compared with the control. LTBP-2 interacted with fibulin-5 on the fibers, and stretching decreased the amount of the LTBP-2 interacted with fibulin-5 by about 60%. Oxytalan fiber coalescence did not occur when LTBP-2 was suppressed by about 95%, whereas it occurred when LTBP-2 was suppressed by about 40%, fibulin-5 being colocalized with oxytalan fibers. These results suggest that LTBP-2, in response to tension stress, may negatively control the function of fibulin-5, thereby modulating the mechanism of oxytalan fiber coalescence. Copyright © Informa Healthcare USA, Inc.

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  • Cellular turnover in epithelial rests of Malassez in the periodontal ligament of the mouse molar Reviewed International journal

    Kyoko Oka, Masakazu Morokuma, Kyoko Imanaka-Yoshida, Yoshihiko Sawa, Keitaro Isokawa, Masaki J Honda

    European Journal of Oral Sciences   120 ( 6 )   484 - 494   2012.12

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    Fragments of Hertwig's epithelial root sheath persist in the periodontal ligament (PDL) in small clusters known as epithelial rests of Malassez (ERM). It is generally agreed that ERM are maintained as a quiescent and exclusively dental epithelial cluster in PDL. However, we speculate that homeostasis and cellular turnover underlies cluster maintenance. We also hypothesize that the fate of ERM clusters - diminishing or remaining - might be regulated via the presence or absence of epithelial stem cells therein. Histological analysis of aging mouse molar PDL showed that ERM clusters gradually increase in size with increasing age. Immunocytochemistry and cell culture revealed that ERM clusters contained Ki67-positive cells and were able to expand when brought in culture. The TdT-mediated biotin-dUTP nick-end labeling (TUNEL) procedure also detected signs of apoptosis. Finally, we identified putative epithelial stem cells in the clusters by 5-bromo-2′-deoxyuridine (BrdU) pulse-chase experiments and immunohistochemistry, using the stem-cell marker leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5). The results suggest that ERM clusters are maintained in the PDL, via cellular turnover, throughout life. © 2012 Eur J Oral Sci.

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  • Chimeric anti-podoplanin antibody suppresses tumor metastasis through neutralization and antibody-dependent cellular cytotoxicity Reviewed International journal

    Mika Kato Kaneko, Akiko Kunita, Shinji Abe, Yuta Tsujimoto, Masashi Fukayama, Kaoru Goto, Yoshihiko Sawa, Yasuhiko Nishioka, Yukinari Kato

    Cancer Science   103 ( 11 )   1913 - 1919   2012.11

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    Podoplanin is a platelet aggregation-inducing factor associated with tumor metastasis, malignant progression, and cancer stem cells. We produced a rat-human chimeric anti-podoplanin mAb, NZ-8, from rat anti-podoplanin mAb (NZ-1). Although both NZ-1 and NZ-8 possess high binding affinities and high neutralizing activities of platelet aggregation, the antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity of NZ-8 were much higher than NZ-1. Furthermore, both NZ-1 and NZ-8 inhibited the growth of podoplanin-expressing tumors in vivo. Both NZ-1 and NZ-8 also suppressed hematogenous metastasis of podoplanin-expressing tumors. These results suggest that anti-podoplanin mAbs suppressed hematogenous metastasis by both neutralization and antibody-dependent cellular cytotoxicity/complement-dependent cytotoxicity activities. Targeting therapy to podoplanin-expressing tumors should be useful as a novel immunotherapy. © 2012 Japanese Cancer Association.

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  • Intracellular interaction of EMILIN-1 with fibrillin-1 in human periodontal ligament cells Reviewed

    Yuka Nakatomi, Eichi Tsuruga, Yoshinori Yamauchi, Megumi Kawagoe, Kaori Yamanouchi, Kazuki Nakashima, Yoshihiko Sawa, Hiroyuki Ishikawa

    Orthodontic Waves   71 ( 2 )   66 - 69   2012.6

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    The elastic system fibers comprise oxytalan, elaunin and elastic fibers, differing in their relative microfibril and elastin contents. Human periodontal ligaments (PDLs) contain oxytalan fibers (pure microfibrils), which are composed mainly of fibrillin-1, the major component of microfibrils. We recently demonstrated that EMILIN-1, located at the interface between elastin and microfibrils, controls the amount of fibrillin-1 assembly in PDL fibroblast cell/matrix layers [8], although the mechanism involved was unclear. We subjected cultured PDL fibroblasts to immunofluorescence and immunoprecipitation assays in order to examine the intracellular interaction of EMILIN-1 with fibrillin-1. Immunofluorescence showed that EMILIN-1 was colocalized with fibrillin-1, both inside and outside the cells. Additionally, EMILIN-1 formed a complex with fibrillin-1 in the intracellular fraction. These results suggest that EMILIN-1 may form complexes with fibrillin-1 in cellular vesicles, thus contributing effectively to the initial assembly of pericellular fibrillin-1 during the process of oxytalan fiber formation. © 2012 Elsevier Ltd and the Japanese Orthodontic Society.

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  • The expression of podoplanin and classic cadherins in the mouse brain Reviewed International journal

    Chiaki Kaji, Miwa Tomooka, Yukinari Kato, Hiroshi Kojima, Yoshihiko Sawa

    Journal of Anatomy   220 ( 5 )   435 - 446   2012.5

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    Podoplanin is a transmembrane glycoprotein indirectly linked to classic cadherins through ezrin-actin networks. Recently, the overexpression of podoplanin in high-grade malignancy brain tumors has been reported. The aim of this study was to investigate the expression of podoplanin and classic cadherins in the mouse brain. Immunohistochemistry showed that podoplanin was expressed on ependymal cells and choroid plexus epithelial cells at the ventricle side of the cell surface and at the cell-cell junctions, and on retinal pigment epithelial cells and in the pia mater
    P-cadherin between choroid plexus epithelial cells and endothelial cells at the basement membrane side of cell surface, and between retinal pigment epithelial cells
    VE-cadherin on the PECAM-1 positive-choroid plexus endothelial cells of the fibrovascular core
    and N-cadherin on the cell surface and at the cell-cell junctions of ependymal cells, and in the pia mater. The regions expressing podoplanin, P-cadherin, and VE-cadherin did not coincide. In real-time PCR analysis, the amounts of podoplanin and P- and N-cadherin mRNA were larger in the ventricular wall with choroid plexus than in the abdominal aorta and cerebrum. In the RT-PCR analysis, the intensities of amplicon for VE-cadherin mRNA were the same for the abdominal aorta, cerebrum, and ventricular wall with the choroid plexus, suggesting that mouse ependymal cells, choroid plexus epithelial cells, and glial cells under the pia mater have the ability to express podoplanin and P- and N-cadherins. Glial cells and retinal pigment epithelial cells may create barriers by podoplanin and classic cadherins as a rate-determining step for transmission of blood components. © 2012 The Authors. Journal of Anatomy © 2012 Anatomical Society.

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  • Factors associated with the overall survival of elderly patients with hepatocellular carcinoma. International journal

    Hideki Fujii, Yoshito Itoh, Naoki Ohnishi, Masafumi Sakamoto, Tohru Ohkawara, Yoshihiko Sawa, Koichi Nishida, Yasuo Ohkawara, Kanji Yamaguchi, Masahito Minami, Takeshi Okanoue

    World journal of gastroenterology   18 ( 16 )   1926 - 32   2012.4

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    AIM: To identify the factors associated with overall survival of elderly patients with hepatocellular carcinoma (HCC). METHODS: A total of 286 patients with HCC (male/female: 178/108, age: 46-100 years), who were diagnosed and treated by appropriate therapeutic procedures between January 2000 and December 2010, were enrolled in this study. Patients were stratified into two groups on the basis of age: Elderly (≥ 75 years old) and non-elderly (< 75 years old). Baseline clinical characteristics as well as cumulative survival rates were then compared between the two groups. Univariate and multivariate analyses were used to identify the factors associated with prolonged overall survival of patients in each group. Cumulative survival rates in the two groups were calculated separately for each modified Japan Integrated Stage score (mJIS score) category by the Kaplan-Meier method. In addition, we compared the cumulative survival rates of elderly and non-elderly patients with good hepatic reserve capacity (≤ 2 points as per mJIS). RESULTS: In the elderly group, the proportion of female patients, patients with absence of hepatitis B or hepatitis C viral infection, and patients with coexisting extrahepatic comorbid illness was higher (56.8% vs 31.1%, P < 0.001; 27.0% vs 16.0%, P = 0.038; 33.8% vs 22.2%, P = 0.047; respectively) than that in the non-elderly group. In the non-elderly group, the proportion of hepatitis B virus (HBV)-infected patients was higher than that in the elderly group (9.4% vs 0%, P = 0.006). The cumulative survival rates in the elderly group were 53.7% at 3 years and 32.9% at 5 years, which were equivalent to those in the non-elderly group (55.9% and 39.4%, respectively), as shown by a log-rank test (P = 0.601). In multivariate analysis, prolonged survival was significantly associated with the extent of liver damage and stage (P < 0.001 and P < 0.001, respectively), but was not associated with patient age. However, on individual evaluation of factors in both groups, stage was significantly (P < 0.001) associated with prolonged survival. Regarding mJIS scores of ≤ 2, the rate of female patients with this score was higher in the elderly group when compared to that in the non-elderly group (P = 0.012) and patients ≥ 80 years of age tended to demonstrate shortened survival. CONCLUSION: Survival of elderly HCC patients was associated with liver damage and stage, but not age, except for patients ≥ 80 years with mJIS score ≤ 2.

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  • Roles of Collagen and Periostin Expression by Cranial Neural Crest Cells during Soft Palate Development Reviewed International journal

    Kyoko Oka, Masaki J. Honda, Eichi Tsuruga, Yuji Hatakeyama, Keitaro Isokawa, Yoshihiko Sawa

    Journal of Histochemistry and Cytochemistry   60 ( 1 )   57 - 68   2012.1

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    The tissue in the palatal region can be divided into the hard and the soft palates, each having a specialized function such as occlusion, speech, or swallowing. Therefore, an understanding of the mechanism of palatogenesis in relation to the function of each region is important. However, in comparison with the hard palate, there is still a lack of information about the mechanisms of soft palate development. In this study, the authors investigated the contribution of cranial neural crest (CNC) cells to development of both hard and soft palates. They also demonstrated a unique pattern of periostin expression during soft palate development, which was closely related to that of collagen type I (Col I) in palatine aponeurosis. Furthermore, organ culture analysis showed that exogenous transforming growth factor-β (TGF-β) induced the expression of both periostin and Col I. These novel patterns of expression in the extracellular matrix (ECM) induced by CNC cells suggest that these cells may help to determine the character of both the hard and soft palates through ECM induction. TGF-β signaling appears to be one of the mediators of Col I and periostin expression in the formation of functional structures during soft palate development. © The Histochemical Society 2012.

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  • Immunohistochemical examination of novel rat monoclonal antibodies against mouse and human podoplanin Reviewed

    Chiaki Kaji, Yuta Tsujimoto, Mika Kato Kaneko, Yukinari Kato, Yoshihiko Sawa

    Acta Histochemica et Cytochemica   45 ( 4 )   227 - 237   2012

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    This study aims to develop new monoclonal antibodies (mAbs) against mouse and human podoplanin. Rats were immunized with synthetic peptides, corresponding to amino acids 38-51 of mouse podoplanin or human podoplanin which is 100% homologous to the same site of monkey podoplanin
    anti-mouse podoplanin mAb PMab-1 (IgG2a) and anti-human mAb NZ-1.2 (IgG2a) were established. In immunocytochemistry, the mouse melanoma B16-F10 and mouse podoplanin (mPDPN)-expressed CHO transfectant were stained by PMab-1
    human lymphatic endothelial cells (LEC) and human podoplanin (hPDPN)-expressed squamous cell carcinoma HSC3 transfectant, were stained by NZ-1.2. Western-blot analysis detected an about 40-kDa protein in CHO-mPDPN and B16-F10 by PMab-1, and in HSC3-hPDPN and LEC by NZ-1.2. In frozen sections, PMab-1 reacted with mouse kidney, pulmonary alveoli, pulmonary pleura, and salivary gland myoepithelial cells while NZ-1.2 reacted to the human salivary gland myoepithelial cells. The immunostaining of paraffin-embedded sections also showed the reaction of PMab-1 or NZ-1.2 to the mouse or monkey kidney glomerulus, pulmonary alveoli, and lung lymphatic vessels. These results indicate that the two novel rat mAbs to the mouse and human/monkey podoplanin are useful for Western-blot and immunostaining of somatic tissues on paraffin-embedded sections as well as frozen sections. © 2012 The Japan Society of Histochemistry and Cytochemistry.

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  • Fibrillin-1 and Fibrillin-2 Are Essential for Formation of Thick Oxytalan Fibers in Human Nonpigmented Ciliary Epithelial Cells In Vitro Reviewed International journal

    Kaori Yamanouchi, Eichi Tsuruga, Kyoko Oka, Yoshihiko Sawa, Hiroyuki Ishikawa

    CONNECTIVE TISSUE RESEARCH   53 ( 1 )   14 - 20   2012

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    The ciliary zonule, also known as Zinn's zonule, is composed of oxytalan fibers. However, the mechanism by which epithelial cells in the ciliary body form these fibers in not fully understood. We examined human nonpigmented ciliary epithelial cells to determine the appearance and amount of oxytalan fibers in terms of positivity for their major components, fibrillin-1 and fibrillin-2. Examination of fibrillin-1 and fibrillin-2 expression by immunofluorescence revealed that thin fibers positive for fibrillin-1 on Day 2 changed to thick fibers by Day 8. The fibers positive for fibrillin-2 appeared on the thick fibrillin-1-positive fibers after Day 4. Northern blot analysis revealed that the level of fibrillin-1 did not change markedly, while induction of fibrillin-2 gene was evident on Day 5. Western blot analysis showed that fibrillin-1 deposition increased gradually, while that of fibrillin-2 increased markedly from Day 5 to Day 8. Fibrillin-1 suppression did not lead to the formation of fibrillin-2-positive thick fibers, whereas fibrillin-2 suppression led to the formation of fibrillin-1-positive thin fibers, but not thick fibers. These results suggest that both fibrillin-1 and fibrillin-2 are essential for the formation of thick oxytalan fibers in the ciliary zonule and are informative for clarifying the mechanism of homeostasis of the ocular matrix.

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  • Immunohistochemical and immunocytochemical localization of amylase in rat parotid glands and von Ebner's glands by ion etching-immunoscanning electron microscopy Reviewed

    Junko Yahiro, Tetsuichiro Inai, Akihito Tsutsui, Atsuko Sato, Toshikazu Nagato, Kunihisa Taniguchi, Eichi Tsuruga, Yoshihiko Sawa

    Acta Histochemica et Cytochemica   44 ( 5 )   201 - 212   2011.8

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    The distribution of amylase in rat parotid glands and von Ebner's glands was examined using ion etching-immunoscanning electron microscopy, which enables both light and electron microscopic observations of identical semi-thin resin sections immunolabeled with anti-α- amylase and immunogold in association with silver enhancement. At the light microscopic level, most acinar secretory granules (SG) and striated duct secretions of parotid glands were strongly stained dark brown. In von Ebner's glands, acinar SG and duct secretions were weakly to strongly stained light to dark brown. At the electron microscopic level, labeling was observed as bright gold-silver particles. The labeling intensity of acinar SG of parotid glands was higher than that of von Ebner's glands. In parotid glands, weak labeling of SG in transitional cells between acini and intercalated ducts, very weak labeling of SG in intercalated ducts, and strong labeling of striated duct secretions were observed. In von Ebner's glands, the secretions and some SG of interlobular ducts were strongly labeled compared to those of intralobular ducts and SG of acini. Less amylase was synthesized in von Ebner's acini compared to parotid acini, whereas von Ebner's ducts may secrete significantly more amylase to modify saliva than parotid ducts. © 2011 The Japan Society of Histochemistry and Cytochemistry.

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  • Establishment of a novel monoclonal antibody SMab-1 specific for IDH1-R132S mutation Reviewed International journal

    Mika Kato Kaneko, Wei Tian, Shingo Takano, Hiroyuki Suzuki, Yoshihiko Sawa, Yasukazu Hozumi, Kaoru Goto, Kentaro Yamazaki, Chifumi Kitanaka, Yukinari Kato

    Biochemical and Biophysical Research Communications   406 ( 4 )   608 - 613   2011.3

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    Isocitrate dehydrogenase 1 (IDH1) mutations, which are early and frequent genetic alterations in gliomas, are specific to a single codon in the conserved and functionally important Arginine 132 (R132) in IDH1. We earlier established a monoclonal antibody (mAb), IMab-1, which is specific for R132H-containing IDH1 (IDH1-R132H), the most frequent IDH1 mutation in gliomas. To establish IDH1-R132S-specific mAb, we immunized mice with R132S-containing IDH1 (IDH1-R132S) peptide. After cell fusion using Sendai virus envelope, IDH1-R132S-specific mAbs were screened in ELISA. One mAb, SMab-1, reacted with the IDH1-R132S peptide, but not with other IDH1 mutants. Western-blot analysis showed that SMab-1 reacted only with the IDH1-R132S protein, not with IDH1-WT protein or IDH1 mutants, indicating that SMab-1 is IDH1-R132S-specific. Furthermore, SMab-1 specifically stained the IDH1-R132S-expressing glioblastoma cells in immunocytochemistry and immunohistochemistry, but did not react with IDH1-WT or IDH1-R132H-containing glioblastoma cells. We newly established an anti-IDH1-R132S-specific mAb SMab-1 for use in diagnosis of mutation-bearing gliomas. © 2011 Elsevier Inc.

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  • Stretch stimuli increase fibulin-5/EMILIN-1 complex on oxytalan fibers in human periodontal ligament cells Reviewed

    Kazuki Nakashima, Eichi Tsuruga, Yuka Nakatomi, Yoshinori Yamauchi, Yuichiro Hata, Sachio Tamaoki, Yoshihiko Sawa, Hiroyuki Ishikawa

    Orthodontic Waves   70 ( 1 )   15 - 20   2011.3

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    Periodontal ligaments (PDLs) are continuously exposed to various functional forces, such as tooth movement and occlusal loading. Human PDLs comprise elastic system fibers as well as collagen fibers. The elastic system fibers in turn comprise oxytalan, elaunin and elastic fibers, which differ in their relative microfibril and elastin contents. Human PDLs contain oxytalan fibers (pure microfibrils), which are composed mainly of fibrillin-1 (the major component of microfibrils). We have previously reported that bundles of oxytalan fibers in cultured PDL cells coalesce in response to mechanical strain, and that this coalescence is controlled by fibulin-5. However, the relationship between fibulin-5 and other fibrillin-1-binding molecules is unclear. In the present study we investigated whether fibulin-5 and EMILIN-1 (both of which are fibrillin-1-binding molecules) contribute to the formation of oxytalan fibers upon exposure to mechanical strain. We subjected PDL cells to stretching in order to examine the role of fibulin-5 and EMILIN-1 in the formation of oxytalan fibers in cell/matrix layers. We examined the relationship between fibulin-5 and EMILIN-1 in PDL cell cultures using immunofluorescence and immunoprecipitation assay. Immunofluorescence showed that fibulin-5 and EMILIN-1 were colocalized on fibrillin-1-positive oxytalan fibers. Fibulin-5 formed a complex with EMILIN-1, and stretching increased the amount of this complex relative to cells that were not subjected to stretching. These results suggest that the expression of the fibulin-5/EMILIN-1 complex is upregulated in response to tension strain, and may control the formation of oxytalan fibers in PDLs. © 2010 Japanese Orthodontic Society.

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  • EMILIN-1 regulates the amount of oxytalan fiber formation in periodontal ligaments in vitro Reviewed International journal

    Yuka Nakatomi, Eichi Tsuruga, Kazuki Nakashima, Yoshihiko Sawa, Hiroyuki Ishikawa

    Connective Tissue Research   52 ( 1 )   30 - 35   2011.2

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    The elastic system fibers comprise oxytalan, elaunin, and elastic fibers, differing in their relative microfibril and elastin contents. Among them, human periodontal ligament (PDL) contains only oxytalan fibers (pure microfibrils). Elastin microfibril interface-located protein-1 (EMILIN-1) is localized at the interface between microfibrils and elastin. We hypothesized that EMILIN-1 may contribute to the formation of oxytalan fibers. We used a small interfering RNA (siRNA) for EMILIN-1 in PDL cell culture to examine the extracellular deposition of fibrillin-1 (the major component of microfibrils). EMILIN-1 was labeled on microfibrils positive for fibrillin-1 and was colocalized with fibrillin-1 upon immunoprecipitation assay. EMILIN-1 suppression reduced the level of fibrillin-1 deposition to 23 of the control, and this was responsible for the diminution of fibrillin-1 deposition revealed by immunofluorescence. These results suggest that EMILIN-1 may regulate the formation of oxytalan fibers and play a role in their homeostasis. © 2011 Informa Healthcare USA, Inc.

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  • Expression of podoplanin and classical cadherins in salivary gland epithelial cells of klotho-deficient mice Reviewed

    Ikuko Amano, Yuri Imaizumi, Chiaki Kaji, Hiroshi Kojima, Yoshihiko Sawa

    Acta Histochemica et Cytochemica   44 ( 6 )   267 - 276   2011

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    We have recently shown that salivary gland myoepithelial cells express podoplanin. Podoplanin indirectly binds the actin filament network which links classical cadherins. The study here is aimed to investigate the expression of podoplanin and cadherins on salivary gland myoepithelial cells and the changes in the aging cells using klotho-deficient (kl/kl) mice. The submandibular glands of kl/kl mouse lack granular ducts which express klotho in wild type mice, suggesting that klotho may be a gene responsible for granular duct development. Although aging resulted in growth suppression of myoepithelial cells because of the sparse distribution of the cells in kl/kl mouse salivary glands, the expression of podoplanin and Ecadherin was shown in aging myoepithelial cells. It is thought that podoplanin participates in the actin-E-cadherin networks which are maintained in aging myoepithelial cells. It was also shown that granular ducts were filled with P-cadherin, and that the P-cadherin amount was larger in the wild type mouse submandibular glands than in the sublingual and parotid glands of wild type mouse, and in the submandibular glands of kl/kl mouse. These findings suggest that the granular duct is an organ secreting soluble P-cadherin into the saliva. © 2011 The Japan Society of Histochemistry and Cytochemistry.

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  • The effect of valproic Acid on mesenchymal pluripotent cell proliferation and differentiation in extracellular matrices. International journal

    Yuji Hatakeyama, Junko Hatakeyama, Atsushi Takahashi, Kyoko Oka, Eichi Tsuruga, Tetsuichiro Inai, Yoshihiko Sawa

    Drug target insights   5   1 - 9   2011

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    Valproic acid (2-n-propylpentanoic acid, VPA) is a widely used antiepileptic and anticonvulsant drug. Previous studies have reported that VPA effects osteogenesis in vivo and in vitro, yet it remains unclear whether VPA promotes cell differentiation of osteoblasts derived from mesenchymal cells. The purpose of this study was to clarify the effect of VPA on undifferentiated pluripotent mesenchymal cell proliferation and differentiation into osteoblasts while analyzing the impact of the absence or presence of extracellular matrices (ECMs). Mouse mesenchymal cells were cultured on non-coated plastic, type I collagen-coated, and fibronectin-coated plates in the absence or presence of VPA. A cell proliferation assay was performed in which modified formazan dye content was analyzed and proliferation nuclear antigen (PCNA)-positive cells were counted at various concentrations of VPA. A high concentration of VPA did not clearly alter cell morphology, but large numbers of stress fibers were observed in these cells and the cell proliferation ratio was decreased with positive PCNA counts. In the presence of matrices, the cell proliferation ratio decreased at low VPA concentrations compared with the ratio obtained in the absence of these ECMs. On the other hand, VPA promoted osteoblastic differentiation in the presence of type I collagen. These findings indicate that for undifferentiated mesenchymal cells, VPA promotes a decrease in the cell proliferation rate in the presence of ECMs and promotes osteoblastic differentiation, both of which could provide insight into additional mechanisms of osteoblastic cell differentiation caused by VPA.

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  • Immunoelectron microscopic study of podoplanin localization in mouse salivary gland myoepithelium Reviewed

    Minoru Hata, Ikuko Amano, Eichi Tsuruga, Hiroshi Kojima, Yoshihiko Sawa

    Acta Histochemica et Cytochemica   43 ( 2 )   77 - 82   2010

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    We have recently reported that salivary gland cells express the lymphatic endothelial cell marker podoplanin. The present study was aimed to immunohistochemically investigate the expression of the myoepithelial cell marker α-smooth muscle actin (SMA) on podoplaninpositive cells in mouse parotid and sublingual glands, and to elucidate podoplanin localization in salivary gland myoepithelial cells by immunoelectron microscopic study. The distribution of myoepithelial cells expressing podoplanin and α-SMA was examined by immunofluorescent staining, and the localization of reaction products of anti-podoplanin antibody was investigated by pre-embedded immunoelectron microscopic method. In immunohistochemistry, the surfaces of both the mucous acini terminal portion and ducts were covered by a number of extensive myoepithelial cellular processes expressing podoplanin, and the immunostaining level with anti-podoplanin antibody to myoepithelial cells completely coincided with the immunostaining level with anti-α-SMA antibody. These findings suggest that podoplanin is a salivary gland myoepithelial cell antigen, and that the detection level directly reflects the myoepithelial cell distribution. In immunoelectron microscopic study, a number of reaction products with anti-podoplanin antibody were found at the Golgi apparatus binding to the endoplasmic reticulum in the cytoplasm of myoepithelial cells between sublingual gland acinar cells, and were also found at the myoepithelial cell membrane. These findings suggest that salivary gland myoepithelial cells constantly produce podoplanin and glycosylate at the Golgi apparatus, and transport them to the cell membrane. Podoplanin may be involved in maintaining the homeostasis of myoepithelial cells through its characteristic as a mucin-type transmembrane glycoprotein. © 2010 The Japan Society of Histochemistry and Cytochemistry.

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  • Immunohistochemical examination on the distribution of cells expressed lymphatic endothelial marker podoplanin and LYVE-1 in the mouse tongue tissue Reviewed

    Yuya Noda, Ikuko Amano, Minoru Hata, Hiroshi Kojima, Yoshihiko Sawa

    Acta Histochemica et Cytochemica   43 ( 2 )   61 - 68   2010

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    The clinical study for lingual disease requires the detailed investigation of the lingual lymphatic network and lymphatic marker-positive cells. Recently, it has been reported that several tissue cells and leukocytes express lymphatic markers, LYVE-1 and podoplanin. This study was aimed to clarify the lingual distribution of cells expressing LYVE-1 and podoplanin. In the mouse tongue, podoplanin is expressed in nerve sheaths, lingual gland myoepithelial cells, and lymphatic vessels. LYVE-1 is expressed in the macrophage marker Mac-1-positive cells as well as lymphatic vessels, while factor-VIII was detected in only blood endothelial cells. α-SMA was detected in vascular smooth muscle and myoepithelial cells. Therefore, identification of lymphatic vessels in lingual glands, the combination of LYVE-1 and factor-VIII, or LYVE-1 and Mac-1 is useful because myoepithelial cells express podoplanin and α-SMA. The immunostaining of factor-VIII on lymphatic vessels was masked by the immunostaining to LYVE-1 or podoplanin because lymphatic vessels express factor-VIII to a far lesser extent than blood vessels. Therefore, except for the salivary glands, the combination of podoplanin and α-SMA, or factor-VIII is useful to identify lymphatic vessels and blood vessels with smooth muscle, or blood capillaries. © 2010 The Japan Society of Histochemistry and Cytochemistry.

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  • Immunohistochemical examination for the distribution of podoplanin-expressing cells in developing mouse molar tooth germs Reviewed

    Yuri Imaizumi, Ikuko Amano, Eichi Tsuruga, Hiroshi Kojima, Yoshihiko Sawa

    Acta Histochemica et Cytochemica   43 ( 5 )   115 - 121   2010

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    We recently reported the expression of podoplanin in the apical bud of adult mouse incisal tooth. This study was aimed to investigate the distribution of podoplanin-expressing cells in mouse tooth germs at several developing stages. At the bud stage podoplanin was expressed in oral mucous epithelia and in a tooth bud. At the cap stage podoplanin was expressed on inner and outer enamel epithelia but not in mesenchymal cells expressing the neural crest stem cell marker nestin. At the early bell stage nestin and podoplanin were expressed in cervical loop and odontoblasts. At the root formation stage both nestin and podoplanin were weakly expressed in odontoblasts generating radicular dentin. Podoplanin expression was also found in the Hertwig epithelial sheath. These results suggest that epithelial cells of developing tooth germ acquire the ability to express nestin, and that tooth germ epithelial cells maintain the ability to express podoplanin in oral mucous epithelia. The expression of podoplanin in odontoblasts was induced as tooth germ development advanced, but was suppressed with the completion of the primary dentin, suggesting that podoplanin may be involved in the cell growth of odontoblasts. Nestin may function as an intermediate filament that binds podoplanin in odontoblasts. © 2010 The Japan Society of Histochemistry and Cytochemistry.

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  • Fibulin-4 and -5, but not Fibulin-2, are Associated with Tropoelastin Deposition in Elastin-Producing Cell Culture Reviewed

    Yoshinori Yamauchi, Eichi Tsuruga, Kazuki Nakashima, Yoshihiko Sawa, Hiroyuki Ishikawa

    Acta Histochemica et Cytochemica   43 ( 6 )   131 - 138   2010

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    201E0l aTshteic J sapyasnte Smo cfiibeteyr so fc oHnisstioscth oefm misitcrryo afinbdri lCs ya-nd tropoelastin. During development, microfibrils act as a template on which tropoelastin is deposited. Fibrillin-1 is the major component of microfibrils. It is not clear whether elastic fiber-associated molecules, such as fibulins, contribute to tropoelastin deposition. Among the fibulin family, fibulin-2, -4 and -5 are capable of binding to tropoelastin and fibrillin-1. In the present study, we used the RNA interference (RNAi) technique to establish individual gene-specific knockdown of fibulin-2, -4 and -5 in elastin-producing cells (human gingival fibroblasts
    HGF). We then examined the extracellular deposition of tropoelastin using immunofluorescence. RNAi-mediated downregulation of fibulin-4 and -5 was responsible for the diminution of tropoelastin deposition. Suppression of fibulin-5 appeared to inhibit the formation of fibrillin-1 microfibrils, while that of fibulin-4 did not. Similar results to those for HGF were obtained with human dermal fibroblasts. These results suggest that fibulin-4 and -5 may be associated in different ways with the extracellular deposition of tropoelastin during elastic fiber formation in elastinproducing cells in culture. © 2010 The Japan Society of Histochemistry and Cytochemistry.

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  • Fibulin-5 contributes to microfibril assembly in human periodontal ligament cells Reviewed

    Yutaka Hisanaga, Kazuki Nakashima, Eichi Tsuruga, Yuka Nakatomi, Yuji Hatakeyama, Hiroyuki Ishikawa, Yoshihiko Sawa

    Acta Histochemica et Cytochemica   42 ( 5 )   151 - 157   2009.10

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    The elastic system fibers comprise oxytalan, elaunin and elastic fibers, which differ in their relative microfibril and elastin content. Human periodontal ligaments (PDL) contain only oxytalan fibers (pure microfibrils) among them. Since fibulin-5 regulates the organization of elastic fibers to link the fibers to cells, we hypothesized that fibulin-5 may contribute to the formation of oxytalan fibers. We used siRNA for fibulin-5 in PDL cell culture to examine the extracellular deposition of fibrillin-1 and -2, which are the major components of microfibrils. Fibulin-5 was labeled on microfibrils positive for fibrillin-1 and -2. Fibulin-5 suppression reduced the level of fibrillin-1 and -2 deposition to 60% of the control level. These results suggest that fibulin-5 may control the formation of oxytalan fibers, and play a role in the homeostasis of oxytalan fibers. © 2009 The Japan Society of Histochemistry and Cytochemistry.

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  • Stretching stimulates fibulin-5 expression and controls microfibril bundles in human periodontal ligament cells Reviewed

    K. Nakashima, E. Tsuruga, Y. Hisanaga, H. Ishikawa, Y. Sawa

    Journal of Periodontal Research   44 ( 5 )   622 - 627   2009.10

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    Background and Objective: The elastic fiber system comprises oxytalan, elaunin and elastic fibers, differing in their relative microfibril and elastin contents. Human periodontal ligaments contain oxytalan fibers (pure microfibrils). Periodontal ligaments are continuously exposed to various functional forces, such as tooth movement and occlusal loading. We have reported that bundles of microfibrils coalesce in response to mechanical strain in cultured periodontal ligament fibroblasts, as assessed in terms of their positivity for fibrillin-1 (the major component of microfibrils). However, the mechanism of microfibril coalescence is unclear. We hypothesized that the fibrillin-1-binding molecule, fibulin-5, contributes to oxytalan fiber formation under mechanical stra Material and Methods: We subjected periodontal ligament fibroblasts to stretching in order to examine the effects of fibulin-5 on the formation of oxytalan fibers in cell/matrix layers. We transfected periodontal ligament cells with small interference RNA for fibulin-5, then examined oxytalan fibers using immunofluorescence and electron microscopy. Results: Immunofluorescence showed that fibrillin-1-positive microfibrils coalesced as a result of stretching, compared with cells that were not subjected to stretching. Fibulin-5 colocalized on fibrillin-1-positive microfibrils. Stretching increased fibulin-5 gene expression and protein deposition. Immunofluorescence and immunogold electron microscopy analysis revealed that fibulin-5 suppression inhibited the coalescence of microfibrils under stretching conditions. Conclusion: These results suggest that fibulin-5 up-regulated in response to tension strain may control the formation of microfibril bundles in periodontal ligament. © 2008 Blackwell Munksgaard.

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  • Integrin αvβ3 regulates microfibril assembly in human periodontal ligament cells Reviewed

    E. Tsuruga, A. Sato, T. Ueki, K. Nakashima, Y. Nakatomi, H. Ishikawa, T. Yajima, Y. Sawa

    Tissue and Cell   41 ( 2 )   85 - 89   2009

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    Fibrillin-1 is the major structural component of extracellular microfibrils. However, the mechanism by which extracellular fibrillin-1 assembles into microfibrils is not fully understood. Fibrillin-1 contains the Arg-Gly-Asp (RGD) motif, which may allow binding to RGD-recognizing integrins. We hypothesized that integrin αvβ3 on the cell surface of human periodontal ligament (PDL) fibroblasts may influence fibrillin-1 assembly into cell/matrix layers. We treated PDL fibroblasts with an integrin αvβ3-specific antagonist to examine fibrillin-1 assembly. Western blotting and immunofluorescence analysis showed that treatment with the integrin αvβ3 antagonist at 5 μM clearly abolished fibrillin-1 deposition. These results provide for the first time evidence that integrin αvβ3 regulates extracellular assembly of fibrillin-1, thereby modulating cell-mediated homeostasis of microfibrils. © 2008 Elsevier Ltd. All rights reserved.

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  • Expression of podoplanin in the mouse tooth germ and apical bud cells Reviewed

    Yoshihiko Sawa, Kana Iwasawa, Hiroyuki Ishikawa

    Acta Histochemica et Cytochemica   41 ( 5 )   121 - 126   2008.10

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    This study was designed to investigate the distribution of cells expressing podoplanin in the mouse tooth bud. Podoplanin expression was detected in enamel epithelia of the cervical loop at cell-cell contacts strongly, and weakly on the loosely aggregated stellate reticulum in the center and the neighboring stratum intermedium. Odontoblasts exhibited intense podoplanin expression at the junction with predentin while no expression was detected in the enamel organ containing ameloblasts. These results suggest that proliferating inner and outer enamel epithelia express podoplanin but that the expression is suppressed in the differentiated epithelia containing ameloblasts. On the other hand the podoplanin expression occurs in the differentiating odontoblasts and the expression is sustained in differentiated odontoblasts, indicating that odontoblasts have the strong ability to express podoplanin. In cultured apical bud cells podoplanin was detected at cell-cell contacts. In real-time PCR analysis the amount of podoplanin mRNA of the apical buds was 2-fold compared with the amount of kidney used as a positive control. These findings indicate that apical bud cells have the strong ability to express the podoplanin gene. Podoplanin is a mucin-type glycoprotein negatively charged by extensive O-glycosylation and a high content of sialic acid, which expresses the adhesive property. The podoplanin may contribute to form odontoblastic fiber or function as the anchorage to the tooth development and in proliferating epithelial cells of cervical loop and apical bud. © 2008 The Japan Society of Histochemistry and Cytochemistry.

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  • Induction of ICAM-1 and VCAM-1 on the mouse lingual lymphatic endothelium with TNF-α Reviewed

    Kana Iwasawa, Takeshi Kameyama, Hiroyuki Ishikawa, Yoshihiko Sawa

    Acta Histochemica et Cytochemica   41 ( 5 )   115 - 120   2008.10

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    This study investigated the TNF-α-induced ICAM-1 and VCAM-1 expression on mouse lingual lymphatic vessels. All podoplanin-positive lymphatic vessels expressed PECAM-1. In the lamina propria mucosae of TNF-α-treated tongue, almost all initial lymphatics expressed ICAM-1. There were initial lymphatics with the VCAM-1 expression and also the vessels without the expression. In the tunica muscularis of TNF-α-treated tongue, collecting lymphatic vessels expressed ICAM-1, but rarely expressed VCAM-1 whereas blood vessels simultaneously expressed ICAM-1 and VCAM-1. The ICAM-1-positive rate increased with TNF-α to 75% from 10% on initial lymphatics, and to 40% from 0% on collecting lymphatic vessels while it increased to 90% from 45% on blood vessels. The VCAM-1-positive rate increased with TNF-α to 30% from 0% on initial lymphatics, and to 5% from 0% on collecting lymphatic vessels while it increased to 75% from 5% on blood vessels. These findings suggest that the lingual lymphatic endothelium has the ability to express ICAM-1, and VCAM-1 to a lesser extent than the ICAM-1 induction with TNF-α, and that the ICAM-1 and VCAM-1 induction predominantly occurs in the initial lymphatics compared with collecting lymphatic vessels. © 2008 The Japan Society of Histochemistry and Cytochemistry.

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  • Expression of podoplanin in the mouse salivary glands Reviewed International journal

    Minoru Hata, Takeshi Ueki, Atsuko Sato, Hiroshi Kojima, Yoshihiko Sawa

    Archives of Oral Biology   53 ( 9 )   835 - 841   2008.9

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    Objective: Podoplanin is one of the most highly expressed lymphatic-specific genes. Here, we report the distribution of cells expressing podoplanin in mouse salivary glands. Design: We immunohistochemically investigated the distribution of cells expressing podoplanin in mouse major salivary glands by laser-scanning microscopy. The expression of endothelial cell marker PECAM-1 was tested to discriminate lymphatic endothelium from salivary gland cells, and myoepithelial cells were identified by an antibody for P-cadherin. Results: The podoplanin expression was rarely found in acini of the parotid gland but clearly found at the basal portion of acini in the submandibular and sublingual glands. The number of portion reacted with anti-podoplanin is greater in the sublingual gland than in the submandibular gland. The expression was also found at the basal portion of ducts in all major salivary glands. The P-cadherin expression was rarely found in acini of the parotid gland but found in acini of the sublingual gland and on ducts in parotid and sublingual glands, corresponding to the area of podoplanin expression. Conclusions: It was suggested that the acinar and myoepithelial cells in the salivary glands have the ability to express podoplanin, and that the expression may be concerned with the mucous saliva excretion. © 2008 Elsevier Ltd. All rights reserved.

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  • Leukocyte adhesion molecule and chemokine production through lipoteichoic acid recognition by toll-like receptor 2 in cultured human lymphatic endothelium Reviewed International journal

    Yoshihiko Sawa, Eichi Tsuruga, Kana Iwasawa, Hiroyuki Ishikawa, Shigemitsu Yoshida

    Cell and Tissue Research   333 ( 2 )   237 - 252   2008.8

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    We have recently reported that the human lymphatic endothelium has toll-like receptor 4 (TLR4)-mediated lipopolysaccharide recognition mechanisms that induce the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Although ligand engagement with TLR2 enables activation of the MyD88-dependent pathway similarly to TLR4, whether TLR2 ligands such as lipoteichoic acid (LTA) trigger the activation of lymphatic endothelium remains unclear. This study has been designed to investigate the expression dynamics of LTA-induced leukocyte adhesion molecules and chemokines in cultured human lymphatic endothelium (LEC). Reverse transcription/polymerase chain reaction (RT-PCR) and real-time quantitative PCR analyses have shown that LEC usually expresses TLR2 and increases TLR2 gene expression on LTA treatment. Indeed, LTA-treated LEC increases the expression of E-selectin, ICAM-1, and VCAM-1 but does not alter the gene expression of ICAM-2, ICAM-3, junctional adhesion molecule-1 (JAM-1), JAM-3, or platelet endothelial cell adhesion molecule-1 (PECAM-1). The expression of LTA-induced E-selectin, ICAM-1, and VCAM-1 in LEC is suppressed by anti-TLR2 but not by anti-TLR4 and is also suppressed by TLR2-specific short interfering RNA (siRNA) but not by siRNA for TLR4. The expression of CCL2, CCL5, and CCL20 (Cys-Cys motif chemokines) and of CXCL1, CXCL3, CXCL5, CXCL6, and CXCL8 (Cys-X-Cys motif chemokines) was induced in LEC with LTA. These data suggest that the human lymphatic endothelial phenotype has TLR2-mediated LTA-recognition mechanisms, resulting in increased expression of inflammatory leukocyte adhesion molecules and phagocyte-attractive chemokines. The human lymphatic endothelium may thus function to collect leukocytes from tissues into lymphatic vessels by means of immunologically functional molecules. © 2008 Springer-Verlag.

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  • The expression of E-selectin and chemokines in the cultured human lymphatic endothelium with lipopolysaccharides Reviewed International journal

    Yoshihiko Sawa, Eichi Tsuruga

    Journal of Anatomy   212 ( 5 )   654 - 663   2008.5

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    This study investigated the expression of selectins and chemokines in cultured human lymphatic endothelial cells stimulated with lipopolysaccharides. In microarray, vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 gene expressions in the lymphatic endothelium with lipopolysaccharides did not change at 0.5 h but increased two- to three-fold at 12 h, whereas E-selectin increased 10-fold at 0.5 h and 68-fold at 12 h compared with untreated cells. The E-selectin mRNA and protein increased in the lymphatic endothelial cells with lipopolysaccharides at more than two-fold levels compared with human umbilical vein endothelial cells. Induction of Cys-Cys chemokine ligand 2, 3, 5, 7, 8 and 20 mRNAs in the lymphatic endothelial cells with lipopolysaccharides was detected in microarray and real-time PCR. The Cys-Cys chemokine ligand 2, 5 and 20 mRNA amounts in cells with high concentration lipopolysaccharides were larger in the lymphatic endothelial cells than in human umbilical vein endothelial cells. The Cys-Cys chemokine ligand 3 and 8 mRNAs were not detected in human umbilical vein endothelial cells. Induction of Cys-X-Cys chemokine ligand 1, 3, 5, 6 and 8 mRNAs was detected in the lymphatic endothelial cells with lipopolysaccharides. The Cys-X-Cys chemokine ligand 3, 5 and 8 mRNA amounts in cells with high concentration lipopolysaccharides were larger in the lymphatic endothelial cells than in human umbilical vein endothelial cells. In conclusion, it was demonstrated that the cultured human lymphatic endothelial cells express E-selectin and phagocyte-attractive chemokine genes. © 2008 The Authors Journal compilation © 2008 Anatomical Society of Great Britain and Ireland.

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  • Expression of junctional adhesion molecules on the human lymphatic endothelium Reviewed International journal

    Takeshi Ueki, Kana Iwasawa, Hiroyuki Ishikawa, Yoshihiko Sawa

    MICROVASCULAR RESEARCH   75 ( 2 )   269 - 278   2008.3

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    Human lymphatic vessels express several leukocyte adhesion molecules. The study here investigated the expression of three junctional adhesion molecules (JAM) which are a newly reported glycoprotein family of adhesion molecules on human lymphatic endothelium. In this study, JAM-1 and JAM-3 but not JAM-2 were detected in cultured human neonatal dermal lymphatic endothelial cells (LEC) at the gene and protein levels by microarray, RT-PCR, real-time PCR, and immunohistochemical analysis. The JAM-I and JAM-3 expression was not altered in the TNF-alpha-treated LEC or in the untreated cells. In human tissue, the expression of JAM-1, and the expression of JAM-1, JAM-2, and JAM-3 were observed in collecting lymphatic vessels of uninflamed small intestine, and in initial lymphatics of inflamed tongue and uninflamed gingival tissue. It is thought that JAM-2 mRNA could be produced in mature vascular endothelium but not in cultured cells, and that human intestinal and oral lymphatic vessels usually express JAM-1, JAM-2, and JAM-3. There were initial lymphatics simultaneously expressing JAM-1, JAM-2, and JAM-3 in the mucosal connective tissue papillae of gingival tissue. The three JAM expressions on the lymphatic endothelium may contribute to both seal the cell-cell contact at interendothelial junctions and also allow lymphocytes to transmigrate into lymphatic vessels from tissue, independent of inflammatory cytokines. (c) 2007 Elsevier Inc. All rights reserved.

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  • LPS-induced IL-6, IL-8, VCAM-1, and ICAM-1 expression in human lymphatic endothelium Reviewed International journal

    Yoshihiko Sawa, Takeshi Ueki, Minoru Hata, Kana Iwasawa, Eichi Tsuruga, Hiroshi Kojima, Hiroyuki Ishikawa, Shigemitsu Yoshida

    Journal of Histochemistry and Cytochemistry   56 ( 2 )   97 - 109   2008.2

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    We have previously reported the TLR4 expression in human intestinal lymphatic vessels. In the study here, microarray analysis showed the expression of the TLR4, MD-2, CD14, MyD88, TIRAP, TRAM, IRAK1, and TRAF6 genes in cultured human neonatal dermal lymphatic microvascular endothelial cells (LEC). The microarray analysis also showed that LEC expressed genes of IL-6, IL-8, VCAM-1, and ICAM-1, and the real-time quantitative PCR analysis showed that mRNA production was increased by lipopolysaccharide (LPS). The LPS-induced IL-6, IL-8, VCAM-1, and ICAM-1 production in LEC was suppressed by the introduction of TLR4-specific small interfering RNA, and also by anti-TLR4, nobiletin, and CAPE pretreatment. These findings suggest that LEC has TLR4-mediated LPS recognition mechanisms that involve at least activation of NF-κB, resulting in increased expression of IL-6, IL-8, VCAM-1, and ICAM-1. Both the LPS effect on the gene expression and also the suppression by nobiletin and CAPE pre-treatment on the protein production were larger in IL-6 and in VCAM-1 than in IL-8 and in ICAM-1 in LEC. The signal transduction of NF-κB and AP-1-dependent pathway may be more critical for the expression of IL-6 and VCAM-1 than that of IL-8 and ICAM-1 in LEC. © The Histochemical Society, Inc.

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  • Effects of bFGF on suppression of collagen type I accumulation and scar tissue formation during wound healing after mucoperiosteal denudation of rat palate Reviewed International journal

    Wookjin Choi, Hitoshi Kawanabe, Yoshihiko Sawa, Kunihisa Taniguchi, Hiroyuki Ishikawa

    ACTA ODONTOLOGICA SCANDINAVICA   66 ( 1 )   31 - 37   2008

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    Objective. The purpose of this study was to evaluate the effect of basic fibroblast growth factor (bFGF) on collagen changes after mucoperiosteal denudation of rat palate. Material and methods. A total of 36 male Wistar rats were divided into control, scar, sham, and bFGF groups. In the scar, sham, and bFGF groups, lateral palatal mucoperiosteum was excised to form scar tissue on the palate. In the bFGF group, bFGF solution was injected into the operated area 1 week postoperatively. At 6 weeks postoperatively, the distribution of collagen type I and the 3-dimensional structure of collagen fibers were investigated under immunofluorescent and scanning electron microscopy. Result. In the bFGF group, weakly immunostained submucosa was clearly distinguishable from the strongly immunostained cervical periodontal ligament and gingiva. Collagen fibers running from submucosal tissue into the surface of underlying palatal bone comprised loosely arranged collagen fibrils. Lumen structures in collagen fibers resembled those in the control group. Conclusion. Administration of bFGF for suppression of collagen type I generation could suppress scar tissue formation and reduce connective strength with adjacent teeth and palatal bone.

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  • Effects of TNF-alpha on leukocyte adhesion molecule expressions in cultured human lymphatic endothelium Reviewed International journal

    Yoshihiko Sawa, Yukitaka Sugimoto, Takeshi Ueki, Hiroyuki Ishikawa, Atuko Sato, Toshikazu Nagato, Shigemitsu Yoshida

    JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY   55 ( 7 )   721 - 733   2007.7

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    TNF-alpha alters leukocyte adhesion molecule expression of cultured endothelial cells like human umbilical vein endothelial cells (HUVEC). This study was designed to investigate the changes in vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and platelet endothelial cell adhesion molecule-1 (PECAM-1) expression with TNF-alpha stimulation in cultured human neonatal dermal lymphatic endothelial cells (HNDLEC). The real-time quantitative PCR analysis on HNDLEC showed that TNF-alpha. treatment leads to increases of VCAM-1 and ICAM-1 mRNAs to the 10.8- and 48.2-fold levels of untreated cells and leads to a reduction of PECAM-1 mRNA to the 0.42-fold level of untreated cells. Western blot and immunohistochemical analysis showed that TNF-a leads to VCAM-1 and ICAM-1 expressions that were inhibited by antiserum to human TNF receptor or by AP-1 inhibitor nobiletin. In flow cytometry analysis, the number of VCAM-1- and ICAM-1-positive cells increased, and PECAM-1-positive cells decreased with TNF-alpha treatment. Regarding protein amounts produced in cells and amounts expressed on the cell surface, VCAM-1 and ICAM-1 increased in HNDLEC and HUVEC, and PECAM-1 decreased in HNDLEC in a TNF-a concentration-dependent manner. VCAM-1, ICAM-1, and PECAM-1 protein amounts in TNF-alpha-stimulated cells were lower in HNDLEC than in HUVEC. This suggests that the lymphatic endothelium has the TNF-alpha-induced signaling pathway, resulting in increased VCAM-1 and ICAM-1 expression to a weaker extent than blood endothelium and PECAM-1 reduction to a stronger extent than blood endothelium.

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  • [A case of recrudescent groove pancreatitis, which was in remission by proximal gastrectomy with vagotomy for gastric cancer].

    Hideki Aragane, Hideki Fujii, Takaharu You, Atuhiro Morita, Morimichi Miyazaki, Kiyoshi Morita, Tohru Ohkawara, Shinji Fukumitu, Yoshihiko Sawa, Yasuo Ohkawara

    Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology   103 ( 5 )   537 - 42   2006.5

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    This report describes our experience with a 60 year old male who suffered from a recrudescence of groove pancreatitis. He had been treated by conservative medication therapy by proton pump inhibitor used for therapy of duodenal ulcer, and was in remission. During a follow-up one year later, endoscopy revealed gastric cancer, for which a proximal gastrectomy and vagotomy were performed. The patient continues to remain in remission for the groove pancreatitis. Our experience with the clinical course of this disease, in which treatment for duodenal ulcer was used effectively, offers new insights into the progression and therapy of groove pancreatitis.

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  • Intracellular distribution of desmoplakin in human odontoblasts Reviewed International journal

    Y Sawa, S Kuroshima, Y Yamaoka, S Yoshida

    JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY   53 ( 9 )   1099 - 1108   2005.9

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    Coexpression of desmosomal proteins and vimentin has been reported in a specific mesenchymal phenotype. This study investigated the expression of vimentin-binding desmosomal proteins in human dental pulp fibroblasts (DPF) and odontoblasts. The dental pulp has no cells expressing desmocollin (DSC) 1-3, desmoglein (DSG) 1-3, junction plakoglobin (JUP), or desmoplakin (DPK) 1 and 2 except for odontoblasts expressing DPK. A confocal image by laser-scanning microscopy demonstrated the diffuse distribution of DPK in the cytoplasm throughout the odontoblast processes. In culture, the mRNA expression of JUP and DPK1, but not DSC1-3 and DSG1-3, was detected in all DPF clones tested and also in odontoblast-like cells (OB) expressing osteocalcin and dentin sialophosphoprotein mRNAs established in the differentiation medium. The DPF having the potential to differentiate into OB expressed vimentin, but not DPK before culturing in the differentiation medium, whereas OB expressed vimentin-binding DPK1. These results suggest that DPF usually expresses DPK1 mRNA, and that the DPK1 production and the bonding of vimentin to DPK1 occur in DPF with the differentiation into odontoblasts.

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  • Expression of cys-cys chemokine ligand 21 on human gingival lymphatic vessels Reviewed International journal

    S Kuroshima, Y Sawa, Y Yamaoka, K Notani, S Yoshida, N Inoue

    TISSUE & CELL   36 ( 2 )   121 - 127   2004.4

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    The cys-cys (C-C) chemokine ligand 21 is a member of the C-C chemokines that constitute a group of heparin-binding cytokines with a pattern of four or six conserved cysteines. The CCL21 is known to be expressed in secondary lymphoid tissues, however it has rarely been reported for the expression on peripheral lymphatic vessels in somatic tissue. Here we investigated the expression of CCL21 on lymphatic vessels identified by anti-desmoplakin in uninflamed and inflamed human gingiva. In uninflamed tissue the expression of CCL21 was detected on lymphatic vessels in gingiva. In uninflamed gingiva the expression of CCL21 was detected on all lymphatic capillaries of the mucosal connective tissue papillae. There were two types of collecting lymphatic vessels in the lamina propria mucosae expressing CCL21 strongly or very weakly. In inflamed gingiva no expression of CCL21 was detected on lymphatic vessels. In all tissue sections no blood vessels expressing CCL21 were observed. These results may suggest that the expression of CCL21 is predominantly induced in the peripheral lymphatic endothelium of the uninflamed mucosal microcirculation, and that under inflamed conditions a reduction of CCL21 occurs in lymphatic endothelium. (C) 2003 Elsevier Ltd. All rights reserved.

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  • Reduction of alkaline phosphatase activity in aged human osteogenic periodontal ligament fibroblasts exhibiting short telomeres Reviewed International journal

    Y Sawa, Y Yamaoka, S Kuroshima, S Yoshida

    CELL AND TISSUE RESEARCH   315 ( 3 )   331 - 337   2004.3

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    The osteogenic cell type of human periodontal ligament fibroblasts (PDLF) undergoes senescence at finite population doubling numbers unrelated to donor ages. This study investigated telomere lengths of osteogenic PDLF from differently aged donors and alterations of the osteoblast-like properties in the aged PDLF with short telomeres. Telomere lengths of osteogenic PDLF were biased towards long or short among all 15- to 51-year-old individuals, and did not show a normal distribution by Pearson's test or a correlation to donor age by simple regression analysis. In osteogenic PDLF, senescence-associated beta-galactosidase was expressed in 78.5% of cells in the clones with short telomeres (mean 3.02 kbp), and in 9.4% of cells in the clones with long telomeres (mean 13.06 kbp). These results suggest that human periodontium comprises aged osteogenic PDLF without correlation to age. Osteogenic PDLF with long telomeres strongly expressed alkaline phosphatase (ALPase) activity whereas cells with short telomeres expressed ALPase activity to a weaker extent. Total activity of ALPase in the clones of osteogenic PDLF with long telomeres was significantly higher than that in the clones with short telomeres. The produced amounts of both osteopontin and osteocalcin in the clones of osteogenic PDLF with long telomeres were slightly but statistically significantly smaller than those in the clones with short telomeres. These findings suggest that aged osteogenic PDLF reduce the expression of ALPase activity but that there is not a critical alteration in bone-associated protein production. Aged osteogenic PDLF may impair the ability to induce ALPase-dependent calcification.

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  • Expression of Toll-like receptors 2 and 4 on human intestinal lymphatic vessels Reviewed International journal

    S Kuroshima, Y Sawa, T Kawamoto, Y Yamaoka, K Notani, S Yoshida, N Inoue

    Microvascular Research   67 ( 1 )   90 - 95   2004.1

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    The Toll-like receptor (TLR) is a part of the innate immune system sensing pathogen-associated molecular patterns (PAMPs). Recently, TLRs 2 and 4 have been demonstrated for the ligand engagements, which result in the induction of cytokines. Here we investigated the expression of TLRs 2 and 4 on lymphatic vessels producing cys-cys chemokine ligand 21 (CCL21) in the human small intestine. The specificity of antibodies to TLRs was tested on a human monocyte leukemia cell line, umbilical vein endothelial cells (HUVEC), and periodontal ligament fibroblasts (PDLF) with the examination for the TLR gene expression by the reverse transcription-polymerase chain reaction (RT-PCR), and lymphatic vessels were identified by antibodies for platelet-endothelial cell adhesion molecule-1 (PECAM-1) and desmoplakin. The expression of CCL21 was not clearly detected on collecting lymphatic vessels in the submucosa while it was generally observed on the central lacteals of villi and lymphatic capillaries in the lamina propria mucosae. The reaction of antibodies to TLRs 2 and 4 was also not clearly detected on collecting lymphatic vessels in the submucosa and central lacteals of villi, but generally observed on lymphatic capillaries expressing CCL21 in the lamina propria mucosae of tissue where the expression of CCL21 and TLRs was not clearly observed in blood vessels. These may suggest that the expression of CCL21, and TLRs 2 and 4 is predominantly induced in the peripheral lymphatic endothelium of the small intestinal microcirculation. The lymphatic endothelium may contribute to allow dendritic cells to home into secondary lymphoid tissue through the expression of TLRs, the ligand engagements of which result in the induction of chemokines. (C) 2003 Elsevier Inc. All rights reserved.

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  • Plastic casts and confocal laser scanning microscopy applied to the observation of enamel tubules in the red Kangaroo (Macropus rufus).

    Masatsugu Suzuki, Natsumi Ushijima, Ayako Kohno, Yoshihiko Sawa, Shigemitsu Yoshida, Mitsuo Sekikawa, Noriyuki Ohtaishi

    Anatomical science international   78 ( 1 )   53 - 61   2003.3

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    Scanning electron microscopy for plastic casts and confocal laser scanning microscopy for Villanueva bone-stained ground sections were used together to observe enamel tubules in red kangaroo molars. Although the tubular structures such as terminals, bends, expansions, splits, divergences and rejoinings in this species were within the variations of marsupial species, their morphological characteristics were demonstrated with extremely clear and persuasive images. Thus, the combined observations of plastic casts by scanning electron microscopy and Villanueva bone-stain sections by confocal laser scanning microscopy were found to be of value for the investigation of enamel tubules and tubular structures in other hard tissues.

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  • Production of colony-stimulating factor in human dental pulp fibroblasts Reviewed

    Y Sawa, Y Horie, Y Yamaoka, N Ebata, T Kim, S Yoshida

    JOURNAL OF DENTAL RESEARCH   82 ( 2 )   96 - 100   2003.2

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    Class II major histocompatilibity complex (MHC)-expressing cells are usually distributed in dental pulp, and it was postulated that the colony-stimulating factor (CSF) derived from dental pulp fibroblasts contributes to the migration of class II MHC-expressing cells into pulp tissue. This study aimed to investigate the CSF production of human dental pulp fibroblasts. In pulp tissue sections, granulocyte (G)-CSF was detected from normal teeth, while G-CSF, macrophage (M)-CSF, and granulocyte-macrophage (GM)-CSF were detected from teeth with dentinal caries. In cultured dental pulp fibroblasts, G-CSF was detected by immunostaining, immunoprecipitation, and ELISA, and mRNAs of G-CSF, M-CSF, and GM-CSF were detected by RT-PCR. The dental pulp fibroblasts cultured with TNF-alpha were found to increase the G-CSF expression and to produce M-CSF and GM-CSF. These findings suggest that dental pulp fibroblasts usually produce G-CSF. In the presence of TNF-alpha, dental pulp fibroblast express M-CSF and GM-CSF.

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  • Cultured periodontal ligament fibroblasts express diverse connexins Reviewed International journal

    Y Yamaoka, Y Sawa, N Ebata, N Ibuki, S Yoshida

    TISSUE & CELL   34 ( 6 )   375 - 380   2002.12

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    Recent studies have suggested multiple functions of periodontal ligament fibroblasts (PDLFs) which may relate to the permeability of gap junctions composed of various types of connexins (Cxs). At present, 15 types of Cxs are known to exist, and six of their antibodies, anti-Cx26, Cx32, Cx37, Cx40, Cx43, and Cx45 are commercially available. This study aims to examine which types of Cxs are expressed in cultured PDLFs by an immunohistochemical method, western blotting, and RT-PCR.
    The study confirmed the expressions of Cx32, Cx40, Cx43, and Cx45 in PDLFs, while Cx26 and Cx37 were not detected. Considering previous reports, Cx32 may relate to the secretory function, and Cx40 and Cx45 to the contractile function of PDLFs, however, a function for Cx43 has not been specified. In the immunohistochemical examination, different localizations of Cx40/43 and Cx32/45 were established. The former were observed punctately, suggesting that a large part of Cx40/43 may exist in the cell membrane and construct gap junctions. In contrast, the latter were observed uniformly in all the cells, indicating that they are present both in the cell membrane and in the cytoplasm of the cells. (C) 2002 Elsevier Science Ltd. All rights reserved.

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  • Different expressions of connexin 43 and 32 in the fibroblasts of human dental pulp Reviewed

    N Ibuki, Y Yamaoka, Y Sawa, T Kawasaki, S Yoshida

    TISSUE & CELL   34 ( 3 )   170 - 176   2002.6

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    The expression and localization of gap junctional proteins connexin (Cx) 26, 32, and 43 was examined in human dental pulp. Dental pulp tissues were obtained from human third molars immediately after extraction. Some pulp tissues were used for cell culture, and the rest for histological observations. Immunostaining for cultured dental pulp fibroblasts (DPFs) showed that Cx32 and 43 were expressed in human DPFs, and proteins corresponding to 27 (Cx32) and 43 kDa (Cx43) were identified by Western blot analysis. Immunostaining for tissue sections showed that the expression of Cx32 and 43 was observed in the entire region of the pulp and further strong expression of Cx32 was established beneath the cell-rich zone. Considering the close relationship between Cx types and cell functions, the results indicate that DPFs beneath the cell-rich zone may have specific, Cx32-related functions. The cell rich zone is thought to contain progenitor odontoblasts that can be induced to differentiate into mature odontoblasts in response to wounding. Therefore, it may be hypothesized that DPFs just beneath the cell-rich zone produce proteins and induce odontoblast differentiation from the cells in the cell-rich zone. (C) 2002 Elsevier Science Ltd. All rights reserved.

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  • Immunoelectron microscopic study of PECAM-1 expression on lymphatic endothelium of the human tongue Reviewed

    N Ebata, Y Sawa, Y Nodasaka, Y Yamaoka, S Yoshida, Y Totsuka

    TISSUE & CELL   33 ( 3 )   211 - 218   2001.6

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    The expression of platelet-endothelial cell adhesion molecule-1 (PECAM-1) on lymphatic and blood vessels of the human tongue was examined with fluorescence and transmission electron microscopy (TEM), The study used anti-desmoplakins antiserum for light microscopic identification of the lymphatic vessels, plus a pre-embedding immunogold electron microscopic technique for TEM observations. Before making TEM observations, cryostat serial sections were immunostained with anti-desmoplakins or anti-PECAM-l and then embedded. Semithin sections from each cryostat section were photographed under a light microscope and compared in order to identify the lymphatic vessels expressing PECAM-1. In fluorescence microscopy, PECAM-1 expression on lymphatic vessels was weaker than that on blood vessels, TEM observations showed that PECAM-1 expression on the blood vessels was observed only on the luminal surface of the endothelium. In lymphatic vessels, PECAM-1 expression was found both on the luminal and abluminal surfaces of the endothelium. The density of the PECAM-1 reaction products was lower in lymphatic vessels than in blood vessels. The density of PECAM-1 reaction products on the luminal surface of lymphatic vessels was higher than on the abluminal surfaces. The results suggest that blood vessels are more active than lymphatic vessels in leukocyte migration. The expression of PECAM-1 on the abluminal surface of lymphatic endothelium may allow leukocytes to adhere to the endothelium and interact in their migration from tissue into lymphatic vessels. (C) 2001 Harcourt Publishers Ltd.

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  • Desmoplakin as a specific marker of lymphatic vessels Reviewed

    N Ebata, Y Nodasaka, Y Sawa, Y Yamaoka, S Makino, Y Totsuka, S Yoshida

    MICROVASCULAR RESEARCH   61 ( 1 )   40 - 48   2001.1

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

    The usefulness of immunostaining with anti-desmoplakin antibody for light microscopic identification of lymphatic vessels was examined in cryostat sections of the human tongue. The results were compared with laminin, 5'-nucleotidase (5'-Nase), and factor VIII staining. Immunoelectron microscopic observation was also performed to confirm that the vessels reacting with anti-desmoplakin were lymphatic vessels. Under the immunoelectron microscopic, the vessels reacting with anti-desmoplakin showed ultrastructural features characteristic of lymphatic vessels: thin endothelial walls, no or incomplete basal lamina, open junctions, and overlapping endothelium. In general, lymphatic vessels identified by anti-desmoplakin reacted strongly with 5'-Nase, but showed weak or no reactivity with anti-laminin and anti-factor VIII. Blood vessels showed no reactivity with anti-desmoplakin, but reacted strongly with anti-laminin and anti-factor VIII. However, some blood and lymphatic vessels showed intermediate reactivity with anti-laminin, anti-factor VIII, and 5'-Nase. It was difficult to identify these as blood or lymphatic vessels only by the reactivity differences. The results indicate that anti-desmoplakin antibody specifically distinguishes lymphatic vessels and is useful for studying the fine distribution of lymphatic vessels under light microscopy. (C) 2000 Academic Press.

    DOI: 10.1006/mvre.2000.2280

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  • Double expressions of connexin 43 and 32 in human periodontal ligament fibroblasts Reviewed

    Y Yamaoka, Y Sawa, N Ebata, N Ibuki, S Yoshida, T Kawasaki

    TISSUE & CELL   32 ( 4 )   328 - 335   2000.8

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

    The expressions of connexin 43 and 32 in cultured and intact human periodontal ligament fibroblasts (PDLFs) were examined using immunohistochemical methods, and western blot analysis was conducted with anti-connexin 43 and 32 in cultured PDLFs. The PDLFs both in cultured cells and tissue sections reacted with anti-connexin 43 and 32, and western blot analysis showed bands of approximately 43 kD and 27 kD reacted with anti-connexin 43 and 32 respectively, suggesting the existence of gap junctions in human PDLFs, In cultured PDLFs there were no reaction products of connexin 43 when the cells were not in contact with adjacent cells, but reaction products were increasingly observed with increases in cell-cell contacts. Different from connexin 43, the reaction products of connexin 32 were found in the cytoplasm, regardless of whether the cells were or were not in contact with adjacent cells. Further, the reaction activity of connexin 32 varied among PDLFs; some were strong, some moderate, and some weak. The expressions of connexin 43 and 32 in human PDLFs are suggested to be related to the regulation of two different functions of the PDLFs. (C) 2000 Harcourt Publishers Ltd.

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  • Desmosomal proteins in cultured and intact human periodontal ligament fibroblasts Reviewed

    Y Yamaoka, Y Sawa, N Ebata, S Yoshida, T Kawasaki

    TISSUE & CELL   31 ( 6 )   605 - 609   1999.12

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

    This study examined the kinds of desmosomal proteins in the human periodontal ligament fibroblasts (PDLFs), The PDLFs obtained from young and older patients were cultured and the amounts of desmosomal proteins were measured by ELISA with antibodies to desmoplakins, desmogleins, and desmocollins. Cultured cells and tissue sections of the human periodontal ligament were immunostained with the same antibodies. Expression of desmosomal proteins in the PDLFs was clearly demonstrated both by ELISA and the immunohistochemical studies, suggesting the existence of desmosome-like junctions in the PDLFs, The junctions are considered to protect gap junctions in the PDLFs against cell transformation caused by cell contraction, which may relate to tooth eruption and repair of periodontal tissue, and/or strong occlusal forces, Statistically significant differences (P&lt;0.0001) in the expression of desmoplakins and desmogleins between younger and older patients were observed in this study, (C) 1999 Harcourt Publishers Ltd.

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  • Transcriptional activation of mRNA of intercellular adhesion molecule 1 and induction of its cell surface expression in normal human gingival fibroblasts by Mycoplasma salivarium and Mycoplasma fermentans Reviewed

    L Dong, KI Shibata, Y Sawa, A Hasebe, Y Yamaoka, S Yoshida, T Watanabe

    INFECTION AND IMMUNITY   67 ( 6 )   3061 - 3065   1999.6

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

    Lipoproteins in the cell membranes of both Mycoplasma salivarium and Mycoplasma fermentans were demonstrated to trigger the transcription of intercellular adhesion molecule-1 mRNA in normal fibroblasts isolated from human gingival tissue and to induce its cell surface expression by a mechanism distinct from that of Escherichia call lipopolysaccharide. The lipid moiety of the lipoproteins was suggested to play a key role in the expression of the activity.

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  • Lymphatic endothelium of the human tongue expresses multiple leukocyte adhesion molecules Reviewed

    N Ebata, Y Sawa, Y Ashikaga, Y Yamaoka, M Suzuki, Totsuka, V, S Yoshida

    TISSUE & CELL   31 ( 1 )   34 - 38   1999.2

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

    The expression of leukocyte adhesion molecules on lymphatic vessels of the human tongue was examined using histochemical and immunohistochemical methods. Three different types of lymphatic vessels were distinguished: type I vessels expressed intercellular adhesion molecule-1 (ICAM-1), platelet-endothelial cell adhesion molecule-1 (PECAM-1), and endothelial cell-selectin (ELAM-1); type II vessels expressed ICAM-1 and PECAM-1; and type III vessels expressed PECAM-1 only, The lymphatic vessels located very close to the oral epithelium (lymphatic capillaries) and the other lymphatic vessels near the oral epithelium were type I. The lymphatic vessels in the submucosal connective tissue (collecting lymphatic vessels) were type II and type III. The results suggest that there may be functional differences in the lymphatic endothelium, where lymphatic capillaries are more active than collecting lymphatic vessels in lymphocyte migration from tissue into the lymphatic vessels.

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Books

  • ネッター頭頸部・口腔顎顔面の臨床解剖学アトラス

    Norton, Neil Scott, 前田, 健康(Chapter 14 舌)

    エルゼビア・ジャパン,医歯薬出版 (発売)  2018.9  ( ISBN:9784263458266

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    Total pages:xiv, 706p   Language:Japanese

    CiNii Books

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  • 臨床免疫・アレルギー科 特別増刊号 『サイトカインのすべて』

    矢田純一, 宮坂信之( Role: Joint author ,  4.ケモカイン 6) CXCL-6)

    科学評論社  2012.5 

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  • 口腔解剖学 = Oral anatomy

    井出, 吉信, 前田, 健康, 天野, 修, 脇田, 稔, 山下, 靖雄(血管学総論)

    医歯薬出版  2009.11  ( ISBN:9784263456347

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    Total pages:212p   Language:Japanese

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MISC

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Presentations

  • Abnormal expression of SGLT2 in the kidney of a P. gingivalis LPS-induced diabetic nephropathy mouse model

    Kajiwara K, Sawa Y, Fujita T, Tamaoki S

    JADR, WEB  2021 

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    Event date: 2021

    Presentation type:Poster presentation  

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  • An immunohistochemical study on the expression of bioactive molecules in the mouse kidney in P. gingivalis LPS-induced diabetic nephropathy

    Kajiwara K, Sawa Y, Fujita T, Tamaoki S

    JADR  2020 

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    Event date: 2020

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  • Development of scar suppression method applying TGF-β function of microfibril protein

    Fujita T, Kajiwara K, Takara K, Sakagami R, Kojima H, Sawa Y, Tamaoki S

    2019 

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  • Effect of TLR4 inhibitors on porphyromonas gingivalis LPS-induced diabetic nephropathy

    Kajiwara K, Takara K, Fujita T, Kanai T, Sakagami R, Kojima H, Sawa Y, Tamaoki S

    2019 

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  • CLEC-2 suppresses calcification in calvarial osteoblasts

    Takara K, Kajiwara K, Fujita T, Kanai T, Tamaoki S, Sakagami R, Sawa Y, Kojima H

    2019 

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    Event date: 2019

    Presentation type:Poster presentation  

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  • Study for the diabetic nephropathy;promoted by Porphyromonas gingivalis lipopolysaccharide a;the prevension effect by TLR blocker

    Kajiwara K, TakaraK, Takata S, Tamaoki S, Yoshinaga Y, Sawa Y, Sakagami R

    2018 

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    Event date: 2018

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  • Effects of TLR4 blocking on diabetic nephropathy promoted by the Porphyromonas gingivalis lipopolysaccharide.

    Kajiwara K, Takata S, Fujita T, Takara K, Hatakeyama Y, Tamaoki S, Ishikawa H, Sawa Y

    2017 

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  • The expression of podoplanin and bone-associated proteins after mechanical stress.

    Takenawa S, Kim T, Takakusaki Y, SatoY, Iida J, Sawa Y

    IADR  2016 

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    Event date: 2016

    Presentation type:Poster presentation  

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  • Porphyromonas Gingivalis lipopolysaccharide promote diabetic nephropathy through TLR2.

    Kajiwara K, Takata S, Hatakeyama Y, Ishikawa H, Sawa Y

    IADR  2016 

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    Event date: 2016

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  • The morphological investigation of head and neck organs in the systemic podoplanin knockout mice.

    Takara K, Kaji C, Hatakeyama Y, Kojima H, Sawa Y

    2016 

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  • The cytokine inductions in glomerular endothelial cells with Porphyromonas gingivalis lipopolysaccharide through TLR2.

    Takata S, Kajiwara K, Hatakeyama Y, Ishikawa H, Sawa Y

    2016 

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    Event date: 2016

    Presentation type:Poster presentation  

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  • Study for the apical bud differentiation model using green mice.

    Maruo S, Kajiwara K, Ishikawa H, Sawa Y

    IADR  2016 

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    Presentation type:Poster presentation  

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Research Projects

  • 骨破壊腫瘍進展と骨病変形成における細胞内情報伝達系の恒常的活性化機構の解明と制御

    Grant number:21H03111  2021.04 - 2025.03

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

    寺町 順平, 原田 武志, 沢 禎彦, 安倍 正博, 日浅 雅博

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

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  • The study of the normal regulatory mechanism in the alveolar bone by PDPN-dependent mechanosensing

    Grant number:21K10153  2021.04 - 2024.03

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

    金井 壮律, 佐藤 嘉晃, 沢 禎彦, 足利 雄一

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

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  • Study on epidemiological meta-analysis of diabetic nephropathy focusing on complex systems of periodontal disease and intestinal immune disturbance

    Grant number:18H03015  2018.04 - 2021.03

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

    沢 禎彦, 加藤 幸成, 坂上 竜資, 丸濱 功太郎

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    Grant amount:\17550000 ( Direct expense: \13500000 、 Indirect expense:\4050000 )

    歯周病原細菌P. gingivalis由来lipopolysaccharide (LPS)は自然免疫受容体TLR2で宿主に認識されサイトカイン産生を誘導する。P. gingivalis LPSが糖尿病マウスに腎症を起こすこと、TLR2活性型に無効のTLR4阻害剤Eritoran(,83142-1:2013-0162:Eritoran/E5564, Eisai Inc. USA)が、糖尿病マウスのP. gingivalis LPS誘導性腎症の発症を阻止することを報告した。この時、腎症マウスに腸炎が確認され、強力なTLR4リガンドである腸内細菌E. coli LPSの腎循環への侵入が考えられた。そこで、糖尿病環境で血中に入ったP. gingivalisは構造の複雑な糸球体に蓄積し、TLR2経路で腎症を誘発すると同時に糖尿病性フレイルによる腸管免疫の撹乱により下部消化管の大腸菌LPSの腸管通過が腎症に関係すると予想した。現在、P. gingivalis LPS誘導性糖尿病性腎症マウス腎糸球体における白血球接着因子の過剰発現、血中リン濃度の調節を行うFGF23の蓄積、さらに、血圧を負に制御するACE2の近位尿細管brush borderにおける過剰発現まで明らかにした(投稿準備中)。一方アンケート調査では糖尿病で腎症発症以前から歯周病を有する割合が有意に多く腎症合併の一要因となる可能性を示唆する結果が出ており、また高血圧、骨粗しょう症など、血圧調節異常、骨代謝異常を合わせていることが腎症合併の要因となっている可能性を示唆する結果が出ている。さらに、多くの腎症患者でフレイル・大腸過敏症の既往・現病歴があり、腸管免疫とフレイルによる消化管免疫の不調が腎症の進行を助長する可能性が明らかになって来た。

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  • Elucidation of cancer stem cell niche formation mechanisms of CAF derived from oral tissue using Pdpn-cKO mouse

    Grant number:17K19777  2017.06 - 2019.03

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

    SAWA YOSHIHIKO, HATAKEYAMA YUJI

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

    We aim to discover oncoproteins that promote environmental maintenance for metastasis. In this study, we developed mice where fibroblasts can not make podoplanin (cKO mice) and transplanted cancer cells in mice, it was shown that the formation of fibroblasts around transplanted cancer was weaker in cKO than in the normal, and metastasis was significantly reduced in cKO mice. Therefore, we developed an antibody to cancer-type podoplanin that produced in the human oral carcinoma but not in the normal, and investigated tongue cancer, it was shown that metastasis and recurrence were significantly higher in cancer-type podoplanin-positive patients than in the negative, and that the five-year new metastasis-free survival rate was reduced in cancer-type podoplanin-positive patients. We think that the expression of cancer-type podoplanin is useful as a prognostic factor (July 26, 2018 press release, Okayama University).

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  • Podoplanin -dependent bone formation mechanism with orthodontic mechanostress.

    Grant number:15K11333  2015.04 - 2019.03

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

    Kanai Takenori, Takenawa Tomohiro, Sato Yoshiaki

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    Grant amount:\4940000 ( Direct expense: \3800000 、 Indirect expense:\1140000 )

    The expression of podoplanin in cultured osteoblasts subjected to elongation straining was significantly larger than that in cells without straining, and the expression increased with duration of elongation time. The podoplanin mRNA amount in cultured osteoblasts subjected to straining in non-mineralization medium was significantly larger than in unstrained cells in mineralization medium. The cultured osteoblasts increased podoplanin production with longer durations of elongation straining and reached a plateau within 3-5 days. There are significantly less of mineralization products in osteoblasts cultured with antibodies for podoplanin, as well as in cells with both antibodies for osteopontin, and osteocalcin as positive controls. These findings may suggest that mechanostress induces the production of podoplanin, and that podoplanin may contribute to the mineralization in osteoblasts in bone under the circumstances with mechanostress.

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  • Study on control of scar formation after cleft palate with a wound healing model using rat skin

    Grant number:15K11358  2015.04 - 2018.03

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

    Ishikawa Hiroyuki

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    Grant amount:\4810000 ( Direct expense: \3700000 、 Indirect expense:\1110000 )

    Postoperative scar tissue on palates is considered to induce maxillary growth inhibition in cleft lip and palate patients. We characterized the role of TRP channels in the release of TGF-β1 from keratinocytes and the differentiation of fibroblasts to identify possible promising pharmacological approaches to prevent scar formation and contractures. The 3D culture model was made from rat skin seeded on a collagen gel in which dermal fibroblasts had been embedded. Among the TRP channel inhibitors tested, the TRPV2 inhibitors attenuated most potently keratinocyte-dependent and -independent collagen gel contraction due to TGF-β signaling as well as TGF-β1 release from keratinocytes and α-SMA production in myofibroblasts. TRPV2 was expressed in the epidermis and keratinocyte layers of the model. Compounds targeting TRPV2 channels would ameliorate wound contraction through the inhibition of TGF-β1 release and the differentiation of dermal fibroblasts in a culture model.

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  • Elucidation of the pathogenic mechanism of diabetic nephropathy by oral microorganism-derived blood TLR ligand and development for prevention

    Grant number:15H05060  2015.04 - 2018.03

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

    SAWA YOSHIHIKO

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    Grant amount:\17680000 ( Direct expense: \13600000 、 Indirect expense:\4080000 )

    Diabetes is known to increase the possibility of becoming nephropathy when it comes to periodontitis, but the mechanism is not known. In an experiment using diabetic mice, we found that blood vessels of a urine generating device, called glomeruli of the kidney, express 'toll-like receptors' that recognize bacterial components when it comes to diabetes. We also found that injection of periodontal disease pathogen into mucosa of diabetic mouse oral cavity causes nephropathy. It is thought that germs of periodontal disease enter the blood vessels of the oral cavity, go around the body, enter the kidney and bind to the receptor and cause nephropathy. In periodontitis, bacteria easily enter the blood vessel with tooth brushing. For people with diabetes, prevention of periodontitis is considered to prevent the diabetic nephropathy.

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  • Investigation of the influence on oral health of childhood cancer treatment

    Grant number:26860834  2014.04 - 2017.03

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

    Nishimura Sawa, Ishikawa Hiroyuki, Sawa Yoshihiko, Inada Hiroko, Suita Sachiyo

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    Grant amount:\3510000 ( Direct expense: \2700000 、 Indirect expense:\810000 )

    This study aimed to investigate the laterality of tooth formation anomalies in pediatric cancers. The 46 long-term survivors treated for pediatric cancers were divided into two groups to analyze for the incidence of tooth agenesis (TA) and microdonts (MO): a conventional chemotherapy (CC, n=26); a high-dose chemotherapy followed by blood stem cell transplantation (HDC, n=20). It was revealed that anti-cancer chemotherapies induce TA/MO more in maxilla than in mandible symmetrically and HDC is prone to induce asymmetrical TA/MO in mandible. The mandible is a free bone supplied by the inferior alveolar artery whereas the maxilla is a complex supplied by the sphenopalatine artery, posterior and anterior superior alveolar arteries, and greater palatine artery. It is thought that anti-cancer treatments affect tooth buds stronger in maxilla than in mandible based on the blood supply, and the laterality of blood supply may induce the laterality of TA/MO.

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  • The promotion mechanisms of diabetic nephropathy by Porphyromonas gingivalis lipopolysaccharide via toll-like receptors in glomerular endothelial cells.

    Grant number:25670803  2013.04 - 2015.03

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

    SAWA YOSHIHIKO, HATAKEYAMA Yuji, OKA Kyoko

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    Grant amount:\3770000 ( Direct expense: \2900000 、 Indirect expense:\870000 )

    We showed that the glomerulus blood endothelial cells with Diabetes mellitus expressed toll-like receptors (TLRs), and that all of the diabetic mice injected with Porphyromonas gingivalis LPS, which is the ligand of TLRs and the causative agent of periodontitis, died for diabetic nephropathy within all survival periods of non-diabetic mice with the LPS likewise. Diabetic nephropathy might be a cause in oral bacteria entering in the circulation because bacteria easily enter into the blood vessels of the patients with severe periodontitis by toothbrushing. The bacteria entering into the circulation at the intestine go to the liver but at the oral and maxillofacial circulation bacteria anatomically reach to kidney. Now, we began the study to prophylactically inhibit diabetic nephropathy by using the TLR antagonists.

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  • Chimeric PLAG-immunoglobulin protein-induced anti-tumor immune response

    Grant number:23659884  2011 - 2012

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

    SAWA Yoshihiko, KATO Yukinari, TANIGUCHI Kunihisa, TSURUGA Eichi, HATAKEYAMA Yuji, OKA Kyoko

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    Grant amount:\3640000 ( Direct expense: \2800000 、 Indirect expense:\840000 )

    We developed novel rat antibodies specific for human and mouse podoplanin (NZ-1.2, PMab-1) sold by MBL, Imgenex, Sigma, and Millipore. The antibodies suppressed the growth of podoplanin positive tumor cells transplanted under mouse buccal mucosa and the effect enhanced in mice immunized with podoplanin peptide. Podoplanin may useful molecule for immunotherapy of cancer.

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  • Induction of carcinogenesis in oral cancer cells by CLEC2-PLAG complex in the lymphatic microcirculation

    2010 - 2012

    Grant-in-Aid for Scientific Research 

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    Induction of carcinogenesis by CLEC2-PLAG complex

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  • Functional analysis of Rho-GTPase playing the re-arrangement of cytoskeleton in salivary gland epithelial cells

    2010 - 2012

    Grant-in-Aid for Scientific Research 

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    Grant type:Competitive

    Functional of Rho in salivary gland epithelial cells

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  • Role of podoplanin in the differentiation of developmental odontoblasts

    2010 - 2012

    Grant-in-Aid for Scientific Research 

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    Grant type:Competitive

    Role of podoplanin in developmental odontoblasts

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  • リンパ管内微小環境におけるCLEC2-PLAG 複合体の癌性形質誘導に関する研究

    2010 - 2012

    科学研究費補助金 

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    Grant type:Competitive

    悪性腫瘍の転移機構

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  • Effects of alkylating agents to the tooth germ development

    2010 - 2012

    Cooperative Research 

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    Grant type:Competitive

    Alkylating agents diminish tooth germ

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  • 歯胚象牙芽細胞の分化機構で果たす内皮細胞由来シアル酸蛋白の寄与

    2010 - 2012

    科学研究費補助金 

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    Grant type:Competitive

    象牙芽細胞の形態分化

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  • アルキル化剤が歯胚形成に及ぼす影響

    2010 - 2012

    共同研究 

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    Grant type:Competitive

    アルキル化剤は歯胚を欠損させる

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  • 唾液腺筋上皮形態形成におけるRhoGTPaseの役割

    2010 - 2012

    科学研究費補助金 

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    Grant type:Competitive

    唾液腺筋上皮形態形成はRhoが担う

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  • CLEC2-PLAG complex-induced oncogenic transformation in the intra-lymphatic microenvironment

    Grant number:22390345  2010 - 2012

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

    SAWA Yoshihiko, KATO Yukinari, TANIGUCHI Kunihisa, TSURUGA Eichi, KAJIYA Hiroshi, HATAKEYAMA Yuji, OKA Kyoko

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    Grant amount:\19890000 ( Direct expense: \15300000 、 Indirect expense:\4590000 )

    We developed novel antibodies specific for human and mouse podoplanin (PMab-1,NZ-1.2) sold in MBL, Imgenex, Sigma, and Millipore. Immunohistochemical studies on the oral squamous cell carcinoma (SCC) revealed that platelets exist between SCC and lymphatic endothelial cells at the luminal side of lymphatic vessels where SCC attached. The platelets may contribute to the lymphogenous metastasis of SCC. The adhesion activity to human lymphatic endothelial cells was higher in podoplanin-positive SCC than in podoplanin-negative SCC, and the adhesion of SCC was blocked by NZ-1.2. Anti-podoplanin may be useful for the inhibition of the lymphogenous metastasis of SCC.

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  • The basic study of effects of bFGF on control of post-operative scarring in cleft palate surgery

    Grant number:20390526  2008 - 2011

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

    ISHIKAWA Hiroyuki, SAWA Yoshihiko, TSURUGA Eichi, TANIGUCHI Kunihisa, HATA Yuichiro

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    Grant amount:\18850000 ( Direct expense: \14500000 、 Indirect expense:\4350000 )

    The pharmaceutical modulation may reduce unfavorable effects of scarring after cleft palate surgery by the push-back method. This study investigated the effects of local bFGF administration immediately after mucoperiosteal denudation of rat palates on apoptosis in myofibroblasts, collagen changes and dento-alveolar growth during the wound healing. The results showed that bFGF induces rapid reductions in myofibroblasts, suppresses collagen typeIand elastic system fibers generation, and relieves dental arch constriction in the wound healing process after mucoperiosteal denudation of rat palates. These findings suggest that bFGF has the potential to reduce maxillary growth inhibition after cleft palate surgery by modulating the palatal wound healing process.

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  • The Clarification of the expression mechanism of functional molecules on human lymphatic endothelium in oral cavity

    Grant number:18390483  2006 - 2009

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

    YOSHIDA Shigemitsu, ISHISAKI Akira, DOMON Takanori, ASHIKAGA Yuichi, INOUE Kiichiro, KUROSHIMA Shinichiro, SAWA Yoshihiko

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    Grant amount:\17560000 ( Direct expense: \15700000 、 Indirect expense:\1860000 )

    We investigated some proteins which play an important role in the immune system to clarify immune mechanisms via intraoral and extraoral lymphatic vessels. We showed that intraoral lymphatic vessels may differently play site-specific roles in immune systems, and extraoral lymphatic vessels have intracellular networks through these proteins. We discovered that systemic lymphatic vessels contribute to not only substance transport, but also immune mechanisms.

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  • 象牙芽細胞におけるデスモプラキンカイネティクスに関する研究

    Grant number:16659497  2004 - 2005

    日本学術振興会  科学研究費助成事業 萌芽研究  萌芽研究

    沢 禎彦, 吉田 重光, 山岡 雄司

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    Grant amount:\3400000 ( Direct expense: \3400000 )

    本年度は、前年度に報告した以下の事柄に関して追試を行った。すなわち、ヒト歯髄象牙芽細胞におけるデスモゾーム蛋白の発現に関して、
    1.ヒト歯髄象牙芽細胞はデスモプラキン-1、-2、プラコグロビン、デスモコリン-1、-2、-3、デスモグレイン-1、-2、-3のうち、デスモプラキンのみを発現する。
    2.ヒト歯髄におけるプラキンファミリー蛋白の発現はデスモプラキンのみが特異的である。
    3.デスモプラキンは象牙芽細胞の細胞体および細胞突起全体に拡散して発現する。
    4.培養歯髄細胞ならびに象牙芽細胞では、デスモプラキンおよびプラコグロビン遺伝子を発現する。
    5.培養歯髄細胞ならびに象牙芽細胞では、デスモコリン-1、-2、-3およびデスモグレイン-1、-2、-3の遺伝子を発現しない。
    6.培養歯髄細胞ではデスモプラキン蛋白の発現は見られない。
    7.分化培地を用いた培養でオステオカルシンおよびデンチンシアロホスホプロテインの遺伝子発現が陽性となった細胞ではデスモプラキン-1蛋白の発現が見られる。
    8.オステオカルシンおよびデンチンシアロホスホプロテインの遺伝子発現が陽性となった細胞ではデスモプラキン蛋白に対するビメンチンの結合が見られる。
    以上の研究成果は、デスモゾーム蛋白デスモプラキンがヒト歯髄象牙芽細胞の分化マーカーとなる可能性、また象牙芽細胞は通常のデスモゾームを形成しない可能性、さらに象牙芽細胞において、デスモプラキンはビメンチンと結合することで細胞内骨格分子として機能する可能性を示唆するものである。

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  • THE STUDY FOR REGULATION OF THE DEVELOPMENTAL DYNAMICS OF LYMPHATIC SYSTEMS IN HEAD AND NECK, AND FOR THE ADHESION SYSTEMS OF CANCER CELLS TO LYMPHATIC ENDOTHELIUM

    Grant number:14370575  2002 - 2005

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

    YOSHIDA Shigemitsu, SAWA Yoshihiko, SHIBATA Kei-ichiro, YAMAOKA Yuji

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    Grant amount:\13900000 ( Direct expense: \13900000 )

    We have been cleared that the human lymphatic endothelium expresses desmoplakin which is a component of desmosome. In this study, the expression of desmosome-associated proteins ; desmoplakins and plakoglobin in plaque, and desmocollins and desmogleins in core was tested on the oral squamous cell carcinoma (OSCC) in the maxillary antrum and tongue. In the results, 1)lymphatic endothelium in cancer tissues expressed desmoplakins, 2)OSCC in lymphatic vessles overexpressed desmoplakins, and 3)OSCC developed a tendency to lose desmosomal core. In the study for the expression of desmosomal proteins on OSCC cell lines ; HSC2,HSC3,HSC4,HO1myu1,HO1N1,Ca.922,SAS,KB, it was observed that 1)all cell lines did not express desmoglein 1 and 2, 2)KB did not express desmoglein 1-3, 3)all cell lines except for Ca.922 did not express desmocollin 1, 4)HSC4,HO1myu1,HO1N1,SAS rarely express desmocollin 2, 5)all cell lines express desmocollin 3, plakoglobin, and desmoplakin 1 and 2, and 6)in HO1myu1,HO1N1,Ca.922, and SAS, desmoplakin expresses at cell-cell contact but in HSC2,HSC3, and HSC4, desmoplakin diffuses intracellularly. The OSCC may bind to lymphatic vessels with surface exposed desmoplakin overexpressed on cells. Furthermore the OSCC cells in both cell lines and tissues having p53 mutant also intracellulaly overexpressed desmoplakin. The over-expression of desmoplakin may be implicated of the p53 mutation. In the cell growth test for the human neonatal lymphatic endothelial cells (HNDLEC), it was showed that HNDLEC could not proliferate without vascular endothelium growth factor (VEGF) and insulin-like growth factor (IGF). The proliferative test of HNDLEC in co-culture with HSC2,HSC3,HSC4,HO1myul,HO1N1,Ca.922,SAS, and KB, it was suggested that the maintenance of cell viability of HNDLEC is longer in co-culture with HSC3, HO1myu1, SAS than in culture without them. Some OSCC may produce the growth factors which need to the lymphatic angiogenesis.

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  • THE STUDY FOR ADHESION SYSTEMS OF LYMPHOCYTES AND CANCER CELLS TO LYMPHATIC ENDOTHELIUM

    Grant number:12470379  2000 - 2003

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

    SAWA Yoshihiko, YAMAOKA Yuji, YOSHIDA Shigemitsu

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    Grant amount:\15500000 ( Direct expense: \15500000 )

    On the adhesion systems of cancer cells to lymphatic vessels we showed that desmoplakin is a specific marker for lymphatic endothelium (Ebata et al., 2001a, b). We are now investigating whether desmoplakin aids the adhesion of oral squamous cell carcinoma to lymphatic endothelium. On the adhesion systems of lymphocytes to lymphatic vessels we examined the expressions of cys-cys (C-C) chemokine ligand 21 (CCL21) expressing in secondary lymphoid tissues, and of toll-like receptor (TLR)2 and TLR4, using human small intestine. These expressions were not clearly detected on collecting lymphatic vessels but the expression of TLRs 2 and 4 was observed on the central lacteals and lymphatic capillaries expressing CCL21 in the lamina propria mucosae whereas the expression of CCL21 and TLRs was not clearly observed in blood vessels (Kuroshima et al., 2004a). The TLRs sense pathogen-associated molecular patterns (PAMPs) and induce cytokine production. Our results suggests that the expression of CCL21, and TLRs 2 and 4 is predominantly induced in the peripheral lymphatic endothelium of the small intestinal microcirculation, and that the lymphatic endothelium may contribute to allow lymphocytes to home into secondary lymphoid tissue through the expression of TLRs, PAMPs engagements of which result in the chemokine induction. In uninflamed human gingiva the CCL21 expression was detected on all lymphatic capillaries of the mucosal connective tissue papillae while there were two types of collecting lymphatic vessels expressing CCL21 or not. In inflamed gingiva no CCL21 expression was detected on lymphatic vessels. No blood vessels expressed CCL21. These results may suggest that the CCL21 expression is predominantly induced in the peripheral lymphatic endothelium of the uninflamed mucosal microcirculation of gingiva, and that under inflamed conditions a reduction of CCL21 occurs in lymphatic endothelium (Kuroshima et al., 2004b).

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  • 歯根膜組織の老化機構に関する研究

    Grant number:12877301  2000 - 2001

    日本学術振興会  科学研究費助成事業 萌芽的研究  萌芽的研究

    沢 禎彦, 山岡 雄司, 吉田 重光

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    Grant amount:\1800000 ( Direct expense: \1800000 )

    本年度は,ヒト培養歯根膜細胞のテロメア長分析を行った.その結果,1)1回の分裂で切れるテロメア長は150bpで,50-100bp/回という従来の報告とほぼ一致した.2)平均的テロメア長は表皮線維芽細胞の平均的テロメア長である16kbpより短かった.3)ドナー年齢に相関したテロメア短小化は観察されなかった.4)同一のドナー由来の歯根膜組織から,平均3kbpの短いテロメア長を有する株と,平均13kbpの長いテロメア長を有する株が,またその両者をカバーする範囲のテロメア長を示す株が確立された.本結果から,歯根膜線維芽細胞は年齢に相関せず一般的に短いテロメアを有することが示唆され,表皮など他の一般的結合組織繊維芽細胞よりも細胞寿命の短い可能性が考えちれた.
    一方,歯根膜細胞株のあるものは長いテロメアを示したことから,歯根膜におけるテロメラーゼ活性発現型歯根膜幹細胞の存在を考えた.テロメア長を検索した細胞株について,そのテロメラーゼ活性をTRAPアッセイによって測定し,また免疫染色によってテロメラーゼ蛋白発現を検索した.その結果,1)TRPPアッセイでは,典型的なテロメラーゼ活性を示す結果は得られなかったが,細胞株のテロメア長とは関係なく,弱いテロメラーゼ活性の存在を示唆する増幅されたTRAP産物が観察された.2)抗テロメラーゼ抗体陽性の細胞が観察された.以上について,申請者は現在投稿準備中であり,今後,歯根膜幹細胞の探究と分離を試み,培養歯根膜作製への応用を目標とする基盤研究を申請する.

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  • 歯の再植の成否に関与する歯根膜細胞の活性に関する免疫組織化学的研究

    Grant number:11877328  1999 - 2000

    日本学術振興会  科学研究費助成事業 萌芽的研究  萌芽的研究

    吉田 重光, 山岡 雄司, 沢 禎彦, 牧野 修治郎

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    Grant amount:\2000000 ( Direct expense: \2000000 )

    1.ヒト歯根膜組織ならびに培養ヒト線維芽細胞におけるGap junction関連蛋白[connexin(Cx)]の発現を検索した結果,歯根膜線維芽細胞はCx43,Cx32を発現すること,培養細胞においてCx43は細胞の辺縁ならびに核周囲に発現し,Cx32は核以外のすべての部位に広く発現することを報告した[北海道歯学雑誌,2000,vol.21,No.1,Tssue & Cell,2000,32(4)].
    しかしながら,本研究において発現が認められたCxがGap junctionを形成していることに関しては不明であり,免疫電顕的手法を用いた検索が必要であると考えられるため現在Cxの局在に関して検索中である.
    2.ヒト歯根膜組織ならびに培養ヒト線維芽細胞におけるDesmosome関連蛋白の発現を検索した結果,歯根膜線維芽細胞にdesmoplakin, desmogrein, desmocollin Iおよびdesmocollin IIIが存在すること,さらにdesmoplakinとdesmogreinに関しては加齢にともない増加していく可能性があることを報告した[Tissue&Cell,1999,31(6)].これらDesmosome関連蛋白の局在に関して詳細な検討が必要であると考えられたため,培養細胞を免疫電顕によって検索した結果,上記Desmosome関連蛋白ならびにplakoglobinは,細胞膜近傍と分泌顆粒中に存在するものの,培養細胞間にdesmosomeを確認することは出来なかった[北海道歯学雑誌,2000,vol.21,No.1].
    現在ヒト歯根膜組織を免疫電顕的手法にてdesmosomeの存在と上記蛋白の発現部位に関して検索している.

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  • Immuno-histochemical and microbiological study on the relationships between microcirculatory system and immuno-defence system in the dental pulp.

    Grant number:09470389  1997 - 2000

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

    YOSHIDA Shigemitsu, SAWA Yoshihiko, SHIBATA Kenichiro, WATANABE Tsuguo, YAMAOKA Yuji, MAKINO Shujiroh

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    Grant amount:\13500000 ( Direct expense: \13500000 )

    To clarify the relationships between microcirculatory system and immuno-defence system in the dental pulp, we examined human blood and lymphatic vessels immuno-histochemically and microbiologically. The results are summarized as follows :
    1)In general, lymphatic vessels in healthy tissue express PECAM-1 only, but in inflamed tissue, they express PECAM-1, ICAM-1, ICAM-3, and VCAM-1.
    2) In the submandibular lymph node, lymphatic vessels express PECAM-1 and ICAM-1.
    3) In the tongue, lymphatic capillaries close to oral epithelitum express PECAM-1, ICAM-1, and ELAM-1, or PECAM-1 and ICAM-1. However, collecting lymphatic vessels express PECAM-1 only.
    4) Mediation of inflammatory cytokines induce strong expression of PECAM-1, and expression of ICAM-1 on the lymphatic vessels.
    5) Some oral microbial associates induce expression of leukocyte adhesion molecules and production of cytokines in the vascular endothelial cells.
    6) In blood vessels of healthy dental pulp, there are strong expression of PECAM-1 and weak expression of MHC class II, ELAM-1, and ICAM-1.
    7) In blood vessels of inflamed dental pulp, there are strong expression of PFCAM-1, MHC class II, ELAM-1, ICAM-1, ICAM-3, and VCAM-1.
    8) In lymphatic vessels of healthy and inflamed dental pulp, there are strong expression of PECAM-1 and weak expression of ICAM-1.
    9) PECAM-1 expression of the blood vessels was observed only on the luminal surface of the endothelium, but in the lymphatic vessels, it was found both on the luminal and abluminal surfaces of the endothelium.
    10) Expression of desmoplakin is observed only in the lymphatic vessels, but not in the blood vessels, indicating that anti-desmoplakin antibody is useful to discriminate lymphatic vessels from blood vessels.

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  • 口腔粘膜症患の発症機構におけるγδT細胞の関与に関する研究

    Grant number:09877357  1997 - 1998

    日本学術振興会  科学研究費助成事業 萌芽的研究  萌芽的研究

    吉田 重光, 沢 禎彦, 鈴木 正嗣, 柴田 健一郎

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    Grant amount:\1900000 ( Direct expense: \1900000 )

    1. ヒトおよびBALB/cAnNCrjマウスγδT細胞についてのγδT細胞レセプター共通抗原に対する抗体(anti-pan-γδTCR)、およびanti-Vγ4を用いた免疫組織化学的検索
    1) 腸管粘膜やリンパ節の組織切片で観察されるγδT細胞の細胞数と比較して、舌ならびに頬粘膜の組織切片で観察されるγδT細胞の細胞数は顕著に少ない。
    2) TNF-αならびにIFN-γを投与したマウス舌粘膜では健常組織と比較してγδT細胞の増加は見られない。
    3) BCG投与ならびにLPS長期連続投与したマウス舌ではanti-Pan-γδTCR陽性細胞およびVγ4型γδT細胞の両者の増加傾向が見られる。
    2. 扁平苔癖および舌癌から得られた臨床材料についてのanti-pan-γδTCRを用いた検索
    4) 扁平苔癖病巣中心部ではγδT細胞は観察されないものの、病巣辺縁部ではγδT細胞が観察される。
    5) 舌癌では病巣中心部および辺縁部共にγδT細胞は観察されない。
    以上の検索結果は、口腔粘膜に通常存在するγδT細胞の細胞数は腸管粘膜ほど多くないこと、急性炎症には関与しないこと、また粘膜異常の早期に出現し、これに関与する可能性のあることを示すものである。またγδT細胞の分化に関与することが知られているIL-7を長期投与したマウス舌組織切片において、観察されるγδT細胞の細胞数が増加傾向を示すことが観察されたが、このことは口腔粘膜における未分化T前駆細胞の存在を示唆している。

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  • 組織内微小リンパ管の免疫学的機能に関する研究

    Grant number:09771490  1997 - 1998

    日本学術振興会  科学研究費助成事業 奨励研究(A)  奨励研究(A)

    沢 禎彦

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    Grant amount:\2400000 ( Direct expense: \2400000 )

    申請者は平成10年度において以下の事実を明らかにした。1. ヒト健常組織のリンパ管は、白血球接着因子の中で、PECAM-1のみを発現する。2. ヒトリンパ節皮質辺縁には5'-nucleotidase活性とPECAM-1の発現がともに強い活性化リンパ球が観察される。以上1.2.の結果は、ヒトリンパ管内皮細胞がPECAM-1を介してリンパ球と接着する可能性を示すものである。3. CD4+およびCD8+αβ+T細胞が種々のヒト組織内リンパ管に存在する。4. 多数の血管がMHCclassIIを発現しているヒト炎症組織において、ICAM-1,ICAM-3,PECAM-1および
    VCAM-1を発現しているリンパ管が存在する。5. マウスリンパ管は通常ICAM-1を発現しないが、TNF-αおよびIFN-yを腹腔に投与したマウスの腸管膜では、
    ICAM-1を発現しているリンパ管が存在する。
    以上3.4.5.の結果は、リンパ管は通常PECAM-1のみを発現するが、炎症組織内のリンパ管内皮細胞は種々の白血球接着因子を発現すること、その発現は炎症性サイトカイン依存性に増大することを示唆している。
    本研究は、組織内リンパ球の組織からリンパ管内への移動にリンパ管内皮細胞が発現する接着因子が寄与する可能性を示すものである。このことは以後、免疫担当細胞のリンパ循環系のならびに腫瘍のリンパ節転移機構の研究に大きく貢献すると考えられる。

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  • 免疫組織化学的手法による新しいリンパ管同定法の開発

    Grant number:08771558  1996

    日本学術振興会  科学研究費助成事業 奨励研究(A)  奨励研究(A)

    沢 禎彦

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    Grant amount:\1100000 ( Direct expense: \1100000 )

    申請者は,これまで安定した結果の得られるヒト組織内微小リンパ管の特異的同定法が確立されていなかったことから、免疫組織化学的方法を用いたヒトリンパ管特異的同定法を開発し(印刷中)、専門学会に報告した(第42回日本解剖学会東北・北海道連合地方会、平成8年9月、山形。第38回歯科基礎医学会、平成8年10月、横須賀)。本方法は、ヒト胸管内皮細胞の膜蛋白特異的抵抗体が、抗ラミニン抗体で強く染色される血管様構造物に反応を示さず、リンパ管様構造物のみを認識することから確立した、抗体ヒト胸管抗体によるヒトリンパ管特異的免疫染色法である。また、抗ヒト胸管抗体でリンパ管を、さらに抗ラミニン抗体で血管を鑑別染色する二重染色法を確立した。本染色法は次の点で画期的であると思われる。1)反応が特異的であり、且つ通常の固定・染色操作で抗原決定基が失活しないことから、安定した血管が得られること。2)入手の容易な市販の抗体を用いた凍結切片に対する方法であることから、病理検査など一般的方法として有用であること。申請者はこれまでその存在に関して種々の論争のあった、ヒト歯髄リンパ管の光顕的同定を行った(投稿中)。また現在、本方法によって同定した種々の組織内微小リンパ管の内皮細胞について、イムノグロブリンスーパーファミリーの発現を検索し、リンパ管内皮細胞の細胞輸送機能を検討している(投稿準備中)。

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  • Human Anatomy (2021academic year) Concentration  - その他

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  • Anatomy of the Brain (Practice) (2021academic year) Fourth semester  - 月4,月5,月6,月7,金4,金5,金6,金7

  • Structures of locomotor systems (2021academic year) 1st semester  - 水4,水5,水6

  • Applied Anatomy of Head and Neck (2021academic year) Fourth semester  - 月4,月5,月6,月7,金4,金5,金6,金7

  • Human Anatomy (2020academic year) Concentration  - その他

  • splanchnology (2020academic year) Third semester  - 水7

  • Research Presentation in Oral Health and Development (2020academic year) Year-round  - その他

  • Oral Health and Development (2020academic year) Year-round  - その他

  • Research Projects and Practicals:Oral Function and Anatomy I (2020academic year) special  - その他

  • Lecture and Research Projects:Oral Function and Anatomy I (2020academic year) special  - その他

  • Research Projects and Practicals:Oral Function and Anatomy II (2020academic year) special  - その他

  • Lecture and Research Projects:Oral Function and Anatomy II (2020academic year) special  - その他

  • Oral Anatomy (Practice) (2020academic year) Fourth semester  - 月4~7,火4~7,水4~7,木4~7,金4~7

  • Structure of the Nervous System (2020academic year) Second semester  - 火1,火2,火3

  • Introduction to Neurology (2020academic year) Second semester  - 月1,月2,月3

  • Human Body Dissection: Systemic and Regional Anatomy and Applied (2020academic year) Fourth semester  - 月4~7,火4~7,水4~7,木4~7,金4~7

  • Structure of the Vascular System (2020academic year) 1st semester  - 月6,月7

  • Anatomy of the Brain (Practice) (2020academic year) Fourth semester  - 月4,月5,月6,月7,金4,金5,金6,金7

  • Structures of locomotor systems (2020academic year) 1st semester  - 水4,水5,水6

  • Applied Anatomy of Head and Neck (2020academic year) Fourth semester  - 月4,月5,月6,月7,金4,金5,金6,金7

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