Publications by authors named "Takashi Takata"

146 Publications

FK866 Protects Human Dental Pulp Cells against Oxidative Stress-Induced Cellular Senescence.

Antioxidants (Basel) 2021 Feb 10;10(2). Epub 2021 Feb 10.

Department of Dental Pharmacology, School of Dentistry, Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Korea.

FK866 possesses various functional properties, such as anti-angiogenic, anti-cancer, and anti-inflammatory activities. We previously demonstrated that premature senescence of human dental pulp cells (hDPCs) was induced by hydrogen peroxide (HO). The present study aimed to investigate whether HO-induced premature senescence of hDPCs is affected by treatment with FK866. We found that FK866 markedly inhibited the senescent characteristics of hDPCs after exposure to HO, as revealed by an increase in the number of senescence-associated β-galactosidase (SA-β-gal)-positive hDPCs and the upregulation of the p21 and p53 proteins, which acts as molecular indicators of cellular senescence. Moreover, the stimulatory effects of HO on cellular senescence are associated with oxidative stress induction, such as excessive ROS production and NADPH consumption, telomere DNA damage induction, and upregulation of senescence-associated secretory phenotype factors (IL-1β, IL-6, IL-8, COX-2, and TNF-α) as well as NF-κB activation, which were all blocked by FK866. Thus, FK866 might antagonize HO-induced premature senescence of hDPCs, acting as a potential therapeutic antioxidant by attenuating oxidative stress-induced pathologies in dental pulp, including inflammation and cellular senescence.
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http://dx.doi.org/10.3390/antiox10020271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916510PMC
February 2021

Anti-inflammatory effect of glycyrrhizin with Equisetum arvense extract.

Odontology 2020 Nov 3. Epub 2020 Nov 3.

Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.

Periodontal disease is the most prevalent infectious disease, and inflammatory mediators play critical roles in its progression. Therefore, controlling pro-inflammatory cytokine production, especially at initial disease stages, is essential to maintaining gingival and periodontal health. Glycyrrhizin (GL) has an anti-inflammatory effect and has been added to toothpaste and mouth rinse to prevent periodontal disease. However, there is a maximum dose for the use of GL. The aim of the present study is to screen plant extracts which can effectively enhance the effects of GL. The effects of extracts from six different plants on GL-suppressed TNF-α expression in Aggregatibacter actinomycetemcomitans (A.a.)-LPS-stimulated human oral keratinocytes (RT7) were examined. Results demonstrated that Equisetum arvense (EA) extract had the strongest additive effect on the suppression of TNF-α by GL at both mRNA and protein levels. In addition, GL downregulated the production of TNF-α by suppressing NF-κB p65 phosphorylation, but not JNK or p38 phosphorylation. In contrast, EA decreased JNK phosphorylation but not NF-κB p65 or p38 phosphorylation. The combination of GL and EA effectively attenuated A.a.-LPS-induced phosphorylation of NF-κB p65 and JNK. Furthermore, an LPS-induced periodontitis rat model showed that GL with EA supplementation significantly downregulated TNF-α mRNA in the gingival tissue. These results indicate that EA can suppress A.a.-LPS-induced pro-inflammatory cytokine production by inhibiting JNK activation and can promote the anti-inflammatory effects of GL. Our findings suggest that a combination of GL and EA may improve the development of new oral hygiene products aimed at enhancing periodontal health.
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http://dx.doi.org/10.1007/s10266-020-00563-3DOI Listing
November 2020

Identification of regulatory mRNA and microRNA for differentiation into cementoblasts and periodontal ligament cells.

J Periodontal Res 2021 Jan 14;56(1):69-82. Epub 2020 Aug 14.

Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

Objective: Periodontitis causes periodontal tissue destruction and results in physiological tooth dysfunction. Therefore, periodontal regeneration is ideal therapy for periodontitis. Mesenchymal stem cells (MSCs) are useful for periodontal regenerative therapy as they can differentiate into periodontal cells; however, the underlying regulatory mechanism is unclear. In this study, we attempted to identify regulatory genes involved in periodontal cell differentiation and clarify the differentiation mechanism for effective periodontal regenerative therapy.

Background: The cementum and periodontal ligament play important roles in physiological tooth function. Therefore, cementum and periodontal ligament regeneration are critical for periodontal regenerative therapy. Mesenchymal stem cell transplantation can be a common periodontal regenerative therapy because these cells have multipotency and self-renewal ability, which induces new cementum or periodontal ligament formation. Moreover, MSCs can differentiate into cementoblasts. Cementoblast- or periodontal ligament cell-specific proteins have been reported; however, it is unclear how these proteins are regulated. MicroRNA (miRNA) can also act as a key regulator of MSC function. Therefore, in this study, we identified regulatory genes involved in cementoblast or periodontal cell differentiation and commitment.

Methods: Human MSCs (hMSCs), cementoblasts (HCEM), and periodontal ligament cells (HPL cells) were cultured, and mRNA or miRNA expression was evaluated. Additionally, cementoblast-specific genes were overexpressed or suppressed in hMSCs and their expression levels were investigated.

Results: HCEM and HPL cells expressed characteristic genes, of which we focused on ets variant 1 (ETV1), miR-628-5p, and miR-383 because ETV1 is a differentiation-related transcription factor, miR-628-5p was the second-highest expressed gene in HCEM and lowest expressed gene in HPL cells, and miR-383 was the highest expressed gene in HCEM. miR-628-5p and miR-383 overexpression in hMSCs regulated ETV1 mRNA expression, and miR-383 overexpression downregulated miR-628-5p expression. Moreover, miR-383 suppression decreased miR-383 expression and enhanced ETV1 mRNA expression, but miR-383 suppression also decreased miR-628-5p. Furthermore, silencing of ETV1 expression in hMSCs regulated miR-628-5p and miR-383 expression. Concerning periodontal cell commitment, miR-628-5p, miR-383, and ETV1 regulated the expression of HCEM- or HPL cell-related genes by adjusting the expression of these miRNAs.

Conclusion: HCEM and HPL cells show characteristic mRNA and miRNA profiles. In particular, these cells have specific miR-383, miR-628-5p, and ETV1 expression patterns, and these genes interact with each other. Therefore, miR-383, miR-628-5p, and ETV1 are key genes involved in cementogenesis or HPL cell differentiation.
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http://dx.doi.org/10.1111/jre.12794DOI Listing
January 2021

Porphyromonas gingivalis, a cause of preterm birth in mice, induces an inflammatory response in human amnion mesenchymal cells but not epithelial cells.

Placenta 2020 09 18;99:21-26. Epub 2020 Jul 18.

Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences and Health Sciences, Hiroshima University, Hiroshima, Japan. Electronic address:

Introduction: Inflammation and infection, including dental infectious diseases, are factors that can induce preterm birth. We previously reported that mice with dental Porphyromonas gingivalis infection could be used as a model of preterm birth. In this model, cyclooxygenase (COX)-2 and interleukin (IL)-1β levels are increased, and P. gingivalis colonies are observed in the fetal membrane. However, the mechanism underlying fetal membrane inflammation remains unknown. Therefore, we investigated the immune responses of human amnion to P. gingivalis in vitro.

Methods: Epithelial and mesenchymal cells were isolated from human amnion using trypsin and collagenase, and primary cell cultures were obtained. Confluent cells were stimulated with P. gingivalis lipopolysaccharide (P.g-LPS) or P. gingivalis. mRNA expressions of IL-1β, IL-8, IL-6 and COX-2, protein expressions of nuclear factor (NF)-κB pathway components and culture medium levels of prostaglandin E were evaluated.

Results: Following stimulation with 1 μg/mL P.g-LPS, the mRNA expression levels of IL-1β, IL-8, IL-6 and COX-2 in mesenchymal cells were increased 5.9-, 3.3-, 4.2- and 3.1-fold, respectively. Similarly, the expression levels of IL-1β, IL-8, IL-6 and COX-2 in mesenchymal cells were increased by 7.6-, 8.2-, 13.4- and 9.3-fold, respectively, after coculture with P. gingivalis. Additionally, stimulation with P.g-LPS or P. gingivalis resulted in the activation of NF-κB signaling and increased production of IL-1β and prostaglandin E. In contrast, no significant changes were observed in epithelial cells.

Discussion: Our findings suggest that mesenchymal cells might mediate the inflammatory responses to P. gingivalis and P.g-LPS, thereby producing inflammation that contributes to the induction of preterm birth.
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http://dx.doi.org/10.1016/j.placenta.2020.07.016DOI Listing
September 2020

Bovine lactoferrin enhances osteogenesis through Smad2/3 and p38 MAPK activation.

J Oral Biosci 2020 06 25;62(2):147-154. Epub 2020 May 25.

Department of Oral and Maxillofacial Pathobiology, Hiroshima University Institute of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553 1-2-3, Japan. Electronic address:

Objectives: Lactoferrin (LF) possesses diverse biological functions. We previously reported that bovine LF (bLF) attenuates lipopolysaccharide-induced bone resorption in osteoblasts. In addition to its ability to inhibit osteoclastogenesis, bLF has been implicated in stimulating bone formation. However, the molecular mechanisms of bLF in bone cell anabolism remain unclear. Here, we tried to analyse the molecular mechanisms involved in osteogenesis in the presence of bLF.

Methods: Alkaline phosphatase activity, Runx2 activity, gene expression, and Alizarin red staining were analyzed to evaluate the osteogenic differentiation status. The expression of the Smads and mitogen-activated protein kinase (MAPK) signaling molecules was analyzed via western blotting. Ex vivo organ cultures of mouse calvariae were performed to evaluate the effect of bLF on bone regeneration.

Results: bLF enhanced the osteoblastic differentiation of mesenchymal stem cells through activation of Smad2/3 and p38 MAPK, which increased the transcriptional activity of Runx2. bLF treatment also enhanced osteoblastic differentiation and mineralized nodule formation of osteoblast-lineage cells, and repaired bone defects ex vivo. Moreover, inhibition of Smad2/3 or p38 MAPK signaling reduced the anabolic effects of bLF. Together, these results suggested that bLF is a potent osteogenic factor, which mediates its function via activation of the Smad2/3 and p38 MAPK signaling pathways.

Conclusions: Here, we described a novel function of bLF and its signal transduction mechanisms in osseous tissue. Along with inhibiting osteoclastogenesis, bLF may limit further osteoclast formation and contribute to bone mass enlargement. Thus, bLF represents a potentially valuable therapeutic agent for bone regeneration and destructive bone diseases.
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http://dx.doi.org/10.1016/j.job.2020.05.001DOI Listing
June 2020

Odontogenic infection by Porphyromonas gingivalis exacerbates fibrosis in NASH via hepatic stellate cell activation.

Sci Rep 2020 03 5;10(1):4134. Epub 2020 Mar 5.

Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Odontogenic infection of Porphyromonas gingivalis (P.g.), a major periodontal pathogen, exacerbates pathological progression of non-alcoholic steatohepatitis (NASH). In this study, we aimed to clarify the detailed mechanism in which P.g. induced hepatic stellate cells (HSCs; key effector cells in liver fibrosis) activation. In the liver of high fat diet-induced NASH mouse model with P.g. odontogenic infection, immunolocalization of P.g. was detected. The number of hepatic crown-like structure, which was macrophage aggregation and related to liver fibrosis, was drastically increased and fibrosis area was also increased through upregulating immunoexpression of Phosphorylated Smad2 (key signaling molecule of TGF-β1) and Galectin-3. P.g.-secreted trypsin-like enzyme [gingipain; an activator of protease-activated receptor 2 (PAR2)] stimulated HSC proliferation and differentiation through Smad and ERK signaling induced by TGF-β1 produced from HSCs with P.g.-infection. Further, Galectin-3 produced from HSCs with P.g. infection and P.g.-derived LPS/lipoprotein stimulation stabilized TGFβ-receptor II resulting in increasing sensitivity for TGF-β1, finally leading to HSC differentiation via activating Smad and ERK signaling. In addition to them, hepatocytes (main component cells of liver) contributed to HSC activation through TGF-β1 and Galectin-3 production in paracrine manner. Collectively, P.g.-odontogenic infection exacerbates fibrosis of NASH by HSC activation through TGF-β1 and Gal-3 production from HSCs and hepatocytes.
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http://dx.doi.org/10.1038/s41598-020-60904-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058079PMC
March 2020

Visfatin Induces Senescence of Human Dental Pulp Cells.

Cells 2020 01 12;9(1). Epub 2020 Jan 12.

Department of Dental Pharmacology, BK21 PLUS Project, School of Dentistry, Pusan National University, Yangsan 50612, Korea.

Dental pulp plays an important role in the health of teeth. The aging of teeth is strongly related to the senescence of dental pulp cells. A novel adipokine, visfatin, is closely associated with cellular senescence. However, little is known about the effect of visfatin on the senescence of human dental pulp cells (hDPCs). Here, it was found that in vivo visfatin levels in human dental pulp tissues increase with age and are upregulated in vitro in hDPCs during premature senescence activated by HO, suggesting a correlation between visfatin and senescence. In addition, visfatin knockdown by small interfering RNA led to the reduction in hDPC senescence; however, treatment with exogenous visfatin protein induced the senescence of hDPCs along with increased NADPH consumption, which was reversed by FK866, a chemical inhibitor of visfatin. Furthermore, visfatin-induced senescence was associated with both the induction of telomere damage and the upregulation of senescence-associated secretory phenotype (SASP) factors as well as NF-κB activation, which were all inhibited by FK866. Taken together, these results demonstrate, for the first time, that visfatin plays a pivotal role in hDPC senescence in association with telomere dysfunction and the induction of SASP factors.
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http://dx.doi.org/10.3390/cells9010193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017355PMC
January 2020

The transition of tissue inhibitor of metalloproteinases from -4 to -1 induces aggressive behavior and poor patient survival in dedifferentiated liposarcoma via YAP/TAZ activation.

Carcinogenesis 2019 Oct;40(10):1288-1297

Department of Oral and Maxillofacial Pathobiology, Basic Life Science, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Liposarcoma (LS) is the most common soft-tissue sarcoma. Dedifferentiated liposarcoma (DDLS) shows more aggressive biological behavior than that of well-differentiated liposarcoma (WDLS), so advanced therapeutic agents based on molecular mechanism are urgently needed. Here we show that tissue inhibitors of metalloproteinases (TIMPs) from TIMP-1 to TIMP-4 are differently expressed and regulate yes-associated protein (YAP)/transcriptional co-activator with PDZ binding motif (TAZ) in LS. Database analysis showed high TIMP-1 expression in DDLS patients correlating with poor prognosis, but high TIMP-4 expression in WDLS patients with better prognosis. Stable TIMP-1 knockdown inactivated YAP/TAZ and inhibited proliferation, colony formation and migration in DDLS cells, which was rescued by a constitutive active YAP. However, stable overexpression of TIMP-1 showed the opposite in WDLS cells. Stable TIMP-4 knockdown activated YAP/TAZ and promoted proliferation and migration in WDLS cells, which was suppressed by YAP/TAZ inhibitor (verteporfin) or knockdown of YAP/TAZ. Recombinant TIMP-4 showed opposite results in DDLS cells. These results indicate that dedifferentiation in LS shifts the expression of TIMPs from type 4 to type 1, inducing more aggressive behavior and poor prognosis through YAP/TAZ activation, which can be prognostic markers and therapeutic targets for LS patients.
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http://dx.doi.org/10.1093/carcin/bgz023DOI Listing
October 2019

Baicalin Promotes Osteogenic Differentiation of Human Cementoblast Lineage Cells Via the Wnt/β Catenin Signaling Pathway.

Curr Pharm Des 2018 ;24(33):3980-3987

Department of Orthodontics and Craniofacial Development Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.

Background: Baicalin constitutes a natural bioactive flavonoid extracted from Scutellaria baicalensis Georgi that mediates bone formation. However, the biological functions of baicalin in cementoblasts remain unclear. The purpose of this study was to examine the effects of baicalin on osteogenic differentiation of human cementoblast (HCEM) cells.

Methods: HCEM cells were cultured and treated with 0, 0.01, 0.1 or 1 µM baicalin. Alkaline phosphatase (ALP) and runt-related transcription factor 2 (Runx2) mRNA and protein levels were examined by real-time polymerase chain reaction and western blot analysis, respectively. Cell mineralization was assessed using Alizarin red staining. Glycogen synthase kinase-3 beta (GSK3β) phosphorylation was measured in 1 µM baicalin-treated HCEM cells with or without the Wnt signaling pathway inhibitor, DKK-1 using ELISA and western blotting.

Results: The protein levels of ALP and Runx2 and the intensity of Alizarin red staining were enhanced by baicalin in a dose-dependent manner compared to that of the non-treated control. The ratio of phosphorylated to total GSK3β increased in the presence of baicalin but was reduced by the addition of DKK-1. Treatment of HCEMs with baicalin up-regulated mRNA levels of ALP and Runx2, which were reduced by DKK-1. In addition, the protein levels of ALP and Runx2, ALP activity, and calcium deposition were also enhanced by baicalin, and these parameters were inhibited by DKK-1.

Conclusion: Baicalin enhanced osteogenic differentiation of HCEM cells through the Wnt/beta catenin signaling pathway which may be useful for periodontal tissue regeneration.
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http://dx.doi.org/10.2174/1381612824666181116103514DOI Listing
November 2019

Effects of interleukin-1β on human follicular dendritic cell-secreted protein gene expression in periodontal ligament cells.

J Oral Sci 2018 ;60(4):601-610

Department of Periodontology, Nihon University School of Dentistry at Matsudo.

Follicular dendritic cell-secreted protein (FDC-SP) is expressed in FDCs, human periodontal ligament (HPL) cells, and junctional epithelium. To evaluate the effects of interleukin-1 beta (IL-1β) on FDC-SP gene expression in immortalized HPL cells, FDC-SP mRNA and protein levels in HPL cells following stimulation by IL-1β were measured by real-time polymerase chain reaction and Western blotting. Luciferase (LUC), gel mobility shift, and chromatin immunoprecipitation (ChIP) analyses were performed to study the interaction between transcription factors and promoter regions in the human FDC-SP gene. IL-1β (1 ng/mL) induced the expression of FDC-SP mRNA and protein levels at 3 h, and reached maximum levels at 12 h. IL-1β increased LUC activities of constructs (-116FDCSP - -948FDCSP) including the FDC-SP gene promoter. Transcriptional inductions by IL-1β were partially inhibited by 3-base-pair (3-bp) mutations in the Yin Yang 1 (YY1), GATA, CCAAT-enhancer-binding protein2 (C/EBP2), or C/EBP3 in the -345FDCSP. IL-1β-induced -345FDCSP activities were inhibited by protein kinase A, tyrosine-kinase, mitogen-activated protein kinase (MEK)1/2, and PI3-kinase inhibitors. The results of gel shift and ChIP assays revealed that YY1, GATA, and C/EBP-β interacted with the YY1, GATA, C/EBP2, and C/EBP3 elements that were increased by IL-1β. These studies demonstrate that IL-1β increases FDC-SP gene transcription in HPL cells by targeting YY1, GATA, C/EBP2, and C/EBP3 in the human FDC-SP gene promoter.
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http://dx.doi.org/10.2334/josnusd.17-0473DOI Listing
May 2019

Molecular mechanisms underlying the inhibitory effects of bovine lactoferrin on osteosarcoma.

Biochem Biophys Res Commun 2019 01 10;508(3):946-952. Epub 2018 Dec 10.

Department of Oral & Maxillofacial Pathobiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan. Electronic address:

Osteosarcoma (OS) is one the most common primary malignancies of the bone in children and young adults with high metastasis. The use of non-toxic naturally derived compounds is one of present strategies in OS therapy to reduce secondary effects and chemo-resistance. Lactoferrin (LF), a transferrin protein derived from milk, currently appears to be an anticancer agent. However, its suppressive effects on OS have not been fully investigated. Therefore, we aimed to examine the molecular mechanism underlying the inhibitory effects of bovine LF (bLF) on OS. OS cell lines (NOS1, U2OS, MG63, and 143B) and an osteoblastic (ST2) were treated with bLF. Effects of bLF on OS-cell proliferation and migration were examined by proliferation and wound-healing assays. Expression levels of low-density-lipoprotein-receptor-related protein 1 (LRP1) and cytokines including interleukin-1 beta (IL-1β), IL-6, and receptor-activator of nuclear factor kappa-Β ligand (RANKL) were measured using western blotting. Osteoclast formation was examined by co-culture of 143B, ST2, and bone marrow cells. We found that bLF down-regulated IL-1β, IL-6, and RANKL expression and suppressed phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 in 143B cells; bLF also drastically suppressed 143B-activated RANKL production in ST2 cells. This may have contributed to the reduction in the number of differentiated osteoclasts. Taken together, these data reveal that bLF down-regulates NF-κB to attenuate proliferation, migration, and bone resorption in OS and the OS-microenvironment. This study provides new findings and the precise underlying mechanisms of the inhibitory effects of bLF on OS. bLF can be a possible therapeutic agent for OS patients.
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http://dx.doi.org/10.1016/j.bbrc.2018.11.204DOI Listing
January 2019

Bovine lactoferrin reverses programming of epithelial-to-mesenchymal transition to mesenchymal-to-epithelial transition in oral squamous cell carcinoma.

Biochem Biophys Res Commun 2018 12 8;507(1-4):142-147. Epub 2018 Nov 8.

Department of Oral & Maxillofacial Pathobiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan. Electronic address:

Epithelial-to-mesenchymal transition (EMT) is a biological process of invasion and metastasis in cancers, including in oral squamous cell carcinoma (OSCC). However, an effective anticancer drug that directly targets EMT has not yet been discovered. Therefore, we aimed to investigate the repressive effects of bovine lactoferrin (bLF) on EMT to achieve mesenchymal-to-epithelial transition (MET) in OSCC. OSCC cell lines, HOC313 (EMT-induced) and SCCVII (without EMT induction), were treated with bLF. The effects of bLF on EMT in OSCC were identified histologically by haematoxylin and eosin staining and observed morphologically and immunohistochemically using an anti-E-cadherin antibody. Expression levels of E-cadherin and vimentin were investigated using RT-PCR and western blotting. Immuno-expression of E-cadherin was examined in vivo in tumour tissues of C3H/HeN mice, transplanted with SCCVII cells, with or without bLF administration. We found that bLF changed the spindle-like mesenchymal cells to cuboidal-like epithelial cells and enhanced the affinity of membrane-bound E-cadherin in HOC313 cells. The transformation of EMT-MET in HOC313 cells was confirmed by the upregulation of E-cadherin and suppression of vimentin. Moreover, bLF suppressed TWIST expression through downregulation of ERK1/2 phosphorylation. Additionally, the inhibition tumour cell infiltration and increase in E-cadherin expression were observed in xenografts of the mice orally administered with bLF. Thus, based on the results from in vitro and in vivo studies, we concluded that bLF caused the restoration of epithelial properties through MET. Importantly, this finding is novel and is the first report indicating that bLF inhibited EMT and induced MET in OSCC, suggesting that bLF may provide a novel therapeutic strategy in OSCC.
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http://dx.doi.org/10.1016/j.bbrc.2018.10.193DOI Listing
December 2018

Detection of MAPK/ERK pathway proteins and KRAS mutations in adenomatoid odontogenic tumors.

Oral Dis 2019 Mar 7;25(2):481-487. Epub 2018 Nov 7.

Division of Anatomical and Cellular Pathology, Department of Pathology, Iwate Medical University, Morioka, Japan.

Objective: This study aimed to assess the frequency of KRAS mutation and its association with the presence of the MAPK/ERK signaling pathway proteins in adenomatoid odontogenic tumors.

Study Design: Paraffin-embedded tissue samples from nine cases of adenomatoid odontogenic tumor were used. Genomic DNA was extracted from each sample; in one case, genetic mutations in 50 cancer-associated genes were examined by next-generation sequencing. Hotspot mutations in the RAS family were analyzed by Luminex assay using the remaining eight cases. Subsequently, immunohistochemistry for KRAS, CRAF, BRAF, EGFR, ERK, MEK, and BRAFV600E was performed.

Results: A KRAS G12D missense mutation was detected in the DNA sequence of the tumor cells, but it was not detected in the stromal tissue. KRAS G12V and KRAS G12R mutations were detected in two and four cases, respectively. For immunohistochemistry, all the cases were EGFR, KRAS, BRAF, CRAF positive, one case was ERK negative,and one case was MEK and ERK negative, all the other remaining cases were MEK and ERK positive.

Conclusion: KRAS mutation at codon 12 and the presence of MAPK/ERK pathway proteins were detected suggesting their association with tumorigenesis of adenomatoid odontogenic tumors.
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http://dx.doi.org/10.1111/odi.12989DOI Listing
March 2019

Inhibitory effect of IFITM5 on cementoblast differentiation is associated with Wnt signaling.

Acta Biochim Biophys Sin (Shanghai) 2018 Nov;50(11):1176-1179

Division in Anatomy and Developmental Biology, Department of Oral Biology, Oral Science Research Center, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, Korea.

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http://dx.doi.org/10.1093/abbs/gmy113DOI Listing
November 2018

Fetal Membrane Inflammation Induces Preterm Birth Via Toll-Like Receptor 2 in Mice With Chronic Gingivitis.

Reprod Sci 2019 07 17;26(7):869-878. Epub 2018 Sep 17.

3 Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Inflammation is associated with preterm birth. We previously described a mouse model of chronic inflammation-induced preterm birth after dental infection. The aim of this study was to employ this model system to investigate the mechanisms through which enhanced uterine contractility induces preterm birth. Messenger RNA (mRNA) encoding contraction-associated proteins, such as oxytocin receptors, was measured at various gestational time points by real-time polymerase chain reaction (PCR). Spontaneous and oxytocin-induced uterine contractile activity at gestational day 18 was assessed using a tissue organ bath. The expression levels of Toll-like receptor 2 (TLR2), TLR4, cyclooxygenase (COX)-2, nuclear factor-kappa B (NF-κB) p65, and p38 mitogen-activated protein kinase (MAPK) on gestational day 18 were also determined by real-time PCR or Western blotting. Messenger RNA encoding contraction-associated proteins was increased at gestational day 18, and the spontaneous contractile activity (1.6-fold greater area under the contraction curve) and sensitivity to oxytocin (EC: 8.8 nM vs 2.2 nM) were enhanced in the group compared to those in the control group. In the group, COX-2 mRNA expression was not elevated in the placenta or myometrium but was upregulated 2.3-fold in the fetal membrane. The TLR2 mRNA levels in the fetal membrane were 2.7-fold higher in the group, whereas TLR4 levels were not elevated. Activation of the NF-κB p65 and p38 MAPK pathways was enhanced in the fetal membrane of the group. Thus, in mice with chronic dental infection, TLR2-induced inflammation in the fetal membrane leads to upregulation of uterine contractility, leading to preterm birth.
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http://dx.doi.org/10.1177/1933719118792097DOI Listing
July 2019

Interaction between N-cadherin and decoy receptor-2 regulates apoptosis in head and neck cancer.

Oncotarget 2018 Jul 31;9(59):31516-31530. Epub 2018 Jul 31.

Department of Oral and Maxillofacial Pathobiology, Basic Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

N-cadherin is a neural cell adhesion molecule that aberrantly occurs in head and neck cancers to promote cancer cell growth. However, the underlying mechanisms remain unclear. Here we report that N-cadherin increases cancer cell growth by inhibiting apoptosis. Apoptosis eliminates old, unnecessary, and unhealthy cells. However, tumor cells have the ability of avoiding apoptosis that increases cancer cell growth. Recent studies have found that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in tumor cells by reacting with four distinct cell surface receptors: TRAIL-R1 (DR-4), TRAIL-R2 (DR-5), TRAIL-R3 (DcR-1), and TRAIL-R4 (DcR-2). Among these TRAIL receptors, the death receptors DR-4 and DR-5 transmit apoptotic signals owing to the death domain in the intracellular portion. Conversely, the decoy receptors DcR-1 and DcR-2 lack a complete intracellular portion, so neither can transmit apoptotic signals. DcR-1 or DcR-2 overexpression suppresses TRAIL-induced apoptosis. In this study, N-cadherin overexpression increased DcR-2 expression and decreased DR-5 expression. In contrast, knockdown of N-cadherin expression upregulated DR-5 expression and downregulated DcR-2 expression. A significantly positive relationship between N-cadherin and DcR-2 expression was also found in HNSCC specimens. Those specimens with a lower apoptotic index showed a higher expression of N-cadherin and/or DcR-2. In addition, we demonstrated that N-cadherin interacts directly with DcR-2. Notably, DcR-2 induces cancer cell survival through the cleavage of caspases and PARP by activating MAPK/ERK pathway and suppressing NF-kB/ p65 phosphorylation, which has a very important role in resistance to chemotherapy.
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http://dx.doi.org/10.18632/oncotarget.25846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6101147PMC
July 2018

Pathogenesis of primordial odontogenic tumour based on tumourigenesis and odontogenesis.

Oral Dis 2018 Oct 10;24(7):1226-1234. Epub 2018 Jul 10.

Division of Clinical Pathology, Department of Oral and Maxillofacial Reconstructive Surgery, School of Dentistry, Iwate Medical University, Morioka, Japan.

Objective: Primordial odontogenic tumour (POT) is a rare benign mixed epithelial and mesenchymal odontogenic tumour. POT is composed of dental papilla-like tissue covered with cuboidal to columnar epithelium that resembles to inner and outer enamel epithelium of the enamel organ without dental hard tissue formation. The aim of this study was to examine pathogenesis of POT based on tumourigenesis and odontogenesis.

Subjects And Methods: Six cases of POT were submitted for study. DNA analysis and transcriptome analysis were performed by next-generation sequencing. Expression of amelogenin, ameloblastin and dentin sialophosphoprotein (DSPP) was examined by immunohistochemistry.

Results: There were no gene mutations detected in any of analysed 151 cancer- and 42 odontogenesis-associated genes. Enamel protein-coding genes of Amelx, Ambn and Enam, and dentin protein-coding genes of Col1a1, Dspp, Nes and Dmp1 were expressed, whereas expression of dentinogenesis-associated genes of Bglap, Ibsp and Nfic was negative or very weak suggesting inhibition of dentin formation in POT after odontoblast differentiation. Immunoreactivity of amelogenin, ameloblastin and DSPP was detected in POT.

Conclusions: Pathogenesis of POT is considered to be genetically different from other odontogenic tumours. It is suggested that inhibition of enamel and dentin formation in POT is due to defects in dentin formation process.
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http://dx.doi.org/10.1111/odi.12914DOI Listing
October 2018

Comparison of the bone regeneration ability between stem cells from human exfoliated deciduous teeth, human dental pulp stem cells and human bone marrow mesenchymal stem cells.

Biochem Biophys Res Commun 2018 03;497(3):876-882

Department of Orthodontics and Craniofacial Developmental Biology, Division of Dental Sciences, Biomedical Sciences Major, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.

Cleft lip and palate is the most common congenital anomaly in the orofacial region. Autogenous iliac bone graft, in general, has been employed for closing the bone defect at the alveolar cleft. However, such iliac bone graft provides patients with substantial surgical and psychological invasions. Consequently, development of a less invasive method has been highly anticipated. Stem cells from human exfoliated deciduous teeth (SHED) are a major candidate for playing a significant role in tissue engineering and regenerative medicine. The aim of this study was to elucidate the nature of bone regeneration by SHED as compared to that of human dental pulp stem cells (hDPSCs) and bone marrow mesenchymal stem cells (hBMSCs). The stems cells derived from pulp tissues and bone marrow were transplanted with a polylactic-coglycolic acid barrier membrane as a scaffold, for use in bone regeneration in an artificial bone defect of 4 mm in diameter in the calvaria of immunodeficient mice. Three-dimensional analysis using micro CT and histological evaluation were performed. Degree of bone regeneration with SHED relative to the bone defect was almost equivalent to that with hDPSCs and hBMSCs 12 weeks after transplantation. The ratio of new bone formation relative to the pre-created bone defect was not significantly different among groups with SHED, hDPSCs and hBMSCs. In addition, as a result of histological evaluation, SHED produced the largest osteoid and widely distributed collagen fibers compared to hDPSCs and hBMSCs groups. Thus, SHED transplantation exerted bone regeneration ability sufficient for the repair of bone defect. The present study has demonstrated that SHED is one of the best candidate as a cell source for the reconstruction of alveolar cleft due to the bone regeneration ability with less surgical invasion.
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http://dx.doi.org/10.1016/j.bbrc.2018.02.156DOI Listing
March 2018

Galectin-3 Plays an Important Role in Preterm Birth Caused by Dental Infection of Porphyromonas gingivalis.

Sci Rep 2018 02 12;8(1):2867. Epub 2018 Feb 12.

Department of Oral and Maxillofacial Pathobiology, School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan.

Dental infection is risk for preterm birth (PTB) through unclear mechanisms. We established a dental infection-induced PTB mouse model, in which Porphyromonas gingivalis (P.g.) induced PTB by 2 days. We analysed pathogenic factors contributing to PTB and their effects on trophoblasts in vitro. TNF-α, IL-8, and COX-2 were upregulated in P.g.-infected placenta. Galectin-3 (Gal-3), an immune regulator, was significantly upregulated in placenta, amniotic fluid, and serum. In vitro, P.g.-lipopolysaccharide (P.g.-LPS) increased TNF-α and Gal-3 in trophoblasts via NF-κB/MAPK signalling. Gal-3 inhibition significantly downregulated P.g.-LPS-induced TNF-α production. TNF-α upregulated Gal-3. Gal-3 also increased cytokines and Gal-3 through NF-κB/MAPK signalling. Moreover, Gal-3 suppressed CD-66a expression at the maternal-foetal interface. Co-stimulation with Gal-3 and P.g.-LPS upregulated cytokine levels, while Gal-3 plus Aggregatibacter actinomycetemcomitans (A.a.)- or Escherichia coli (E. coli)-LPS treatment downregulated them, indicating the critical role of Gal-3 especially in P.g. dental infection-induced PTB. P.g.-dental infection induced PTB, which was associated with Gal-3-dependent cytokine production. New therapies and/or diagnostic systems targeting Gal-3 may reduce PTB.
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http://dx.doi.org/10.1038/s41598-018-21072-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809409PMC
February 2018

Molecular mechanism of inhibitory effects of bovine lactoferrin on the growth of oral squamous cell carcinoma.

PLoS One 2018 30;13(1):e0191683. Epub 2018 Jan 30.

Department of Oral & Maxillofacial Pathobiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Background: Lactoferrin (LF), a member of the transferrin family, recently has been demonstrated to have anticancer effects on various cancers including oral squamous cell carcinoma (OSCC). However, little is known about the underlying mechanisms of its effects on OSCC. Therefore, we aimed to investigate the mechanism of the suppressive effects of bovine LF (bLF) on the growth of OSCC cells.

Methods: In the current study, HSC2, HSC3, HSC4 and normal human oral keratinocytes (RT7) cell lines were tested with bLF 1, 10, and 100 μg/ml. The effects and detail mechanisms of bLF on proliferation and apoptosis of cells were investigated using flow cytometry and western blotting.

Results: We found that bLF (1, 10, and 100 μg/ml) induced activation of p53, a tumor suppressor gene, is associated with the induction of cell cycle arrest in G1/S phase and apoptosis in OSCC. Moreover, bLF downregulated the phosphorylation of Akt and activated suppressor of cytokine signaling 3 (SOCS3), thereby attenuating multiple signaling pathways including mTOR/S6K and JAK/STAT3. Interestingly, we revealed that bLF exerted its effect selectively against HSC3 but not on RT7 via different effects on the phosphorylation status of NF-κB and Akt.

Conclusion: This is the first report showing that bLF selectively suppresses proliferation through mTOR/S6K and JAK/STAT3 pathways and induction of apoptosis in OSCC. This study provides important new findings, which might be useful in the prevention and treatment of OSCC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191683PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790278PMC
March 2018

Roles of VEGF-Flt-1 signaling in malignant behaviors of oral squamous cell carcinoma.

PLoS One 2017 17;12(11):e0187092. Epub 2017 Nov 17.

Department of Oral and Maxillofacial Pathobiology, School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Background: Vascular endothelial growth factor (VEGF) is a highly specific signaling protein for vascular endothelial cells that plays a critical role in tumor growth and invasion through angiogenesis, and may contribute to cell migration and activation of pre-osteoclasts, osteoclasts and some tumor cells.

Objectives: We aimed to clarify the detailed roles of VEGF-Flt-1 signaling in bone invasion of oral squamous cell carcinoma (OSCC) cells.

Results: Forty-two (42) of 54 cases with gingival SCC (77.8%) strongly expressed VEGF, and had a significantly increased number of Flt-1+ osteoclasts (p<0.01) and more aggressive bone invasion (p<0.05). PlGF, a ligand of Flt-1, induced osteoclastogenesis in single culture of bone marrow cells (BMCs), and inhibition of Flt-1-signaling by VEGF tyrosine kinase inhibitor and It's down stream (Akt and ERK1/2) inhibitos reduced osteoclastogenesis in PlGF-stimulated BMCs (p<0.01). In molecular level, PlGF stimulation significantly upregulated RANKL expression in Flt-1-expressing HSC2 cells via phosphorylation of Akt and ERK1/2. In the co-culture of VEGF-producing HSC2 cells and BMCs, number of TRAP-positive osteoclasts markedly increased (p<0.01). The osteoclastogenesis was significantly inhibited by RANKL-neutralizing antibody (p<0.01) as well as by VEGF tyrosine kinase inhibitor (p<0.01) and it's downstream (Akt and ERK1/2) inhibitors (p<0.01, p<0.05, respectively).

Conclusion: VEGF-Flt-1 signaling induces osteoclastogenesis in OSCC through two possible ways: 1) VEGF produced from OSCC cells can directly stimulate the Flt-1 pathway in preosteoclasts to induce migration to future bone resorbing area and differentiation into osteoclasts, and 2) VEGF-Flt-1 signaling upregulates RANKL expression in OSCC cells, which indirectly leads to osteoclast differentiation. Therefore, blocking of the VEGF-Flt-1 signaling may help inhibit bone invasion of OSCC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187092PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5693288PMC
December 2017

Central mucoepidermoid carcinoma arising from glandular odontogenic cyst confirmed by analysis of MAML2 rearrangement: A case report.

Pathol Int 2018 Jan 13;68(1):31-35. Epub 2017 Nov 13.

Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Central mucoepidermoid carcinoma (MEC) poses a diagnostic challenge because of its rarity and histological overlap with glandular odontogenic cyst (GOC). In MEC of both salivary glands and jaws, MAML2 arrangement has been well known as the specific gene alteration. We report a case of central MEC arising from GOC diagnosed by MAML2 fusion gene. A 57-year-old male presented a multilocular cystic lesion in left molar region of the mandible. Histopathologically, multiple cysts lined by thin cuboidal or non-keratinized squamous epithelium with small duct-like structures, mucous cells and ciliated cells were present. It was diagnosed as GOC. The recurrent lesion after nine years showed the proliferation of many cystic and solid nests composed of epidermoid, mucous and intermediated cells. Nested PCR revealed CRTC3-MAML2 fusion gene in the recurrent lesion, but not in the primary one. Similarly, MAML-2 rearrangement by FISH analysis was positive in the recurrent lesion, while negative for the primary one, thus confirming the diagnosis of central MEC arising from GOC. Analysis of MAML2 rearrangement can be used as a supportive evidence to distinguish central MEC from GOC.
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http://dx.doi.org/10.1111/pin.12609DOI Listing
January 2018

Inhibition of DMH-DSS-induced colorectal cancer by liposomal bovine lactoferrin in rats.

Oncol Lett 2017 Nov 15;14(5):5688-5694. Epub 2017 Sep 15.

Department of Health Sciences, Prefectural University of Hiroshima, Minami, Hiroshima 734-8558, Japan.

Bovine lactoferrin (bLF) is a multifunctional protein with anti-inflammatory, antibacterial, antiviral, anti-tumour and immunoregulatory effects. The present study was conducted to evaluate the anti-inflammatory and anti-tumour effects of liposomal bLF (LbLF) in a 1,2-dimethylhydrazine (DMH)/dextran sulphate sodium (DSS)-induced model of carcinogenesis in F344 rats. F344 rats were randomly divided into three groups: Control (water), 500 or 1,000 mg/kg/day LbLF; additionally, the rats were injected with DMH (20 mg/kg) once per week for 8 consecutive weeks, after one week of drinking water containing 1% DSS. All rats were sacrificed at 25 weeks. The tissues were examined for the presence of aberrant crypt foci (ACF) and subjected to histopathological analysis. Additionally, human colon cancer cells were utilised to investigate the effect of LbLF on proliferation and inflammation. Rats from the 500 and 1,000 mg/kg/day LbLF groups harboured significantly fewer colon ACF, adenomas and adenocarcinomas than the rats from the control group. Lastly, it was demonstrated that LbLF inhibits cell growth and TNF-α mRNA expression. These data support the hypothesis that LbLF affects colorectal carcinogenesis by suppressing inflammation and cell proliferation in rats.
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http://dx.doi.org/10.3892/ol.2017.6976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661379PMC
November 2017

Bio-implant as a novel restoration for tooth loss.

Sci Rep 2017 08 7;7(1):7414. Epub 2017 Aug 7.

Division in Anatomy and Developmental Biology, Department of Oral Biology, Oral Science Research Center, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, Korea.

A dental implant is used to replace a missing tooth. Fixing the implant in its natural position requires the engineering of a substantial amount of conformal bone growth inside the implant socket, osseointegration. However, this conventional implant attachment does not include the periodontal ligament (PDL), which has a fundamental role in cushioning high mechanical loads. As a result, tooth implants have a shorter lifetime than the natural tooth and have a high chance of infections. We have engineered a "bio-implant" that provides a living PDL connection for titanium implants. The bio-implant consists of a hydroxyapatite coated titanium screw, ensheathed in cell sheets made from immortalized human periodontal cells. Bio-implants were transplanted into the upper first molar region of a tooth-extraction mouse model. Within 8 weeks the bio-implant generated fibrous connective tissue, a localised blood vessel network and new bone growth fused into the alveolar bone socket. The study presents a bio-implant engineered with human cells, specialised for the root connection, and resulted in the partial reconstruction of a naturalised tooth attachment complex (periodontium), consisting of all the principal tissue types, cementum, PDL and alveolar bone.
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http://dx.doi.org/10.1038/s41598-017-07819-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5547161PMC
August 2017

Involvement of Porphyromonas gingivalis in the progression of non-alcoholic fatty liver disease.

J Gastroenterol 2018 Feb 24;53(2):269-280. Epub 2017 Jul 24.

Department of Gastroenterology and Metabolism, Division of Frontier Medical Science, Programs for Biomedical Research Graduate School of Biomedical Science, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Background And Aims: The risk factors in the progression of nonalcoholic fatty liver disease (NAFLD) have not been fully clarified. Porphyromonas gingivalis (P.g) has been considered to be a confounding risk factor for systemic diseases. We aimed to evaluate the effect of P.g infection on risk of progression to NASH.

Methods: (1) Serum IgG antibody titers against P.g fimbriae (fimA) in 200 biopsy-proven NAFLD patients were measured by ELISA and compared with histological findings. (2) C57BL/6J mice were fed a control diet (CD) or high-fat diet (HFD) with or without P.g-odontogenic infection and analyzed histologically. Mouse livers were analyzed using CE-TOFMS and LC-TOFMS.

Results: (1) A significant correlation between fibrosis progression and antibody titers against P.g possessing fimA type 4 was identified (P = 0.0081). Multivariate analysis identified older age and type 4 P.g-positivity as risk factors for advanced fibrosis. (2) Fibrosis and steatosis were more severe in HFD P.g(+) mice compared with HFD P.g(-) mice. In metabolome analysis, fatty acid metabolism was significantly disrupted with HFD in P.g-infected mouse livers. Monounsaturated/saturated fatty acid ratios were significantly higher in the HFD P.g(+) group than in the HFD P.g(-) group (P < 0.05). Moreover, expression levels of SCD1 and ELOVL6 were significantly reduced.

Conclusions: These results suggest that P.g infection is an important risk factor for pathological progression in NAFLD. Increase in the monounsaturated/saturated fatty acid ratio may be an important change that facilitates progression of NAFLD.
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http://dx.doi.org/10.1007/s00535-017-1368-4DOI Listing
February 2018

New tumour entities in the 4th edition of the World Health Organization Classification of Head and Neck tumours: odontogenic and maxillofacial bone tumours.

Virchows Arch 2018 Mar 3;472(3):331-339. Epub 2017 Jul 3.

Department of Oral & Maxillofacial Pathobiology, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.

The latest (4th) edition of the World Health Organization Classification of Head and Neck tumours has recently been published with a number of significant changes across all tumour sites. In particular, there has been a major attempt to simplify classifications and to use defining criteria which can be used globally in all situations, avoiding wherever possible the use of complex molecular techniques which may not be affordable or widely available. This review summarises the changes in Chapter 8: Odontogenic and maxillofacial bone lesions. The most significant change is the re-introduction of the classification of the odontogenic cysts, restoring this books status as the only text which classifies and defines the full range of lesions of the odontogenic tissues. The consensus group considered carefully the terminology of lesions and were concerned to ensure that the names used properly reflected the best evidence regarding the true nature of specific entities. For this reason, this new edition restores the odontogenic keratocyst and calcifying odontogenic cyst to the classification of odontogenic cysts and rejects the previous terminology (keratocystic odontogenic tumour and calcifying cystic odontogenic tumour) which were intended to suggest that they are true neoplasms. New entities which have been introduced include the sclerosing odontogenic carcinoma and primordial odontogenic tumour. In addition, some previously poorly defined lesions have been removed, including the ameloblastic fibrodentinoma, ameloblastic fibro-odontoma, which are probably developing odontomas, and the odontoameloblastoma, which is not regarded as an entity. Finally, the terminology "cemento" has been restored to cemento-ossifying fibroma and cemento-osseous dysplasias, to properly reflect that they are of odontogenic origin and are found in the tooth-bearing areas of the jaws.
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http://dx.doi.org/10.1007/s00428-017-2182-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886999PMC
March 2018

The fourth edition of the head and neck World Health Organization blue book: editors' perspectives.

Hum Pathol 2017 08 2;66:10-12. Epub 2017 Jun 2.

Department of Pathology HP437, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.

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http://dx.doi.org/10.1016/j.humpath.2017.05.014DOI Listing
August 2017

A case of primordial odontogenic tumor: A new entity in the latest WHO classification (2017).

Pathol Int 2017 Jul 25;67(7):365-369. Epub 2017 May 25.

Department of Oral and Maxillofacial Pathobiology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Primordial odontogenic tumor (POT) is a rare lesion in the jaw which has been included as a new entity of benign mixed epithelial and mesenchymal odontogenic tumour in the latest World Health Organization (WHO) classification (2017). Only seven cases have been reported. It typically occurs in the posterior mandible. We report an additional case of POT in the maxilla of an 8-year-old girl presenting with an asymptomatic buccal enlargement. A well-defined, unilocular, radiolucent lesion was observed radiographically. Histologically, the tumor was mostly composed of loose fibrous connective tissue resembling dental papilla and a single layer of columnar epithelium covering the periphery of the tumor. In part, cords or nests of epithelium were present in the mesenchyme close to the periphery. Nestin, a marker of odontogenic ectomesenchyme, was positive in the mesenchymal tumor cells. We finally diagnosed the lesion as POT considering the possibility of other odontogenic tumors like ameloblastic fibroma or developing odontoma as a differential diagnosis. The patient shows no recurrence after 16 months. This case is the first report from Japan using this novel diagnosis POT after it was recognized and defined in the latest WHO classification.
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http://dx.doi.org/10.1111/pin.12543DOI Listing
July 2017

Bovine lactoferrin reduces extra-territorial facial allodynia/hyperalgesia following a trigeminal nerve injury in the rat.

Brain Res 2017 Aug 29;1669:89-96. Epub 2017 Apr 29.

Department of Orthodontics, Applied Life Sciences, Hiroshima University, Institute of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.

There is an urgent clinical need for an effective therapeutic agent to treat neuropathic pain. This study explored whether intrathecal administration of bovine lactoferrin (bLF), in combination with signal transduction pathway inhibition or an inflammatory cytokine production, results in reduced allodynia/hyperalgesia in the whisker pad area following mental nerve transection (MNT) in rats. Rats were intrathecally infused with bLF, lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS), an antagonist of Toll-like receptor 4 (TLR4), or interleukin (IL)-18 binding protein (BP). bLF attenuated allodynia/hyperalgesia and blocked upregulation of phosphorylated (p)-p38 mitogen-activated protein kinase (MAPK), p-nuclear factor (NF)-κB p65, p-IκB kinase, and IL-18 in the trigeminal subnucleus caudalis (Vc). Microglia expressed p-p38 and astrocytes expressed p-NF-κB p65 in the Vc following MNT. LPS-RS had the same effects as bLF, except for attenuation of p-NF-κB p65. IL-18BP attenuated allodynia/hyperalgesia and IL-18 upregulation in the Vc. These results suggest that bLF suppresses IL-18 production, which is involved in allodynia/hyperalgesia following MNT, by inhibiting TLR4-derived p38 MAPK activation in microglia. Additionally, binding of bLF to tumor necrosis factor receptor-associated factor 6 might result in inhibition of p38 MAPK and NF-κB activation. The findings suggest that bLF could serve as a potent therapeutic agent for neuropathic pain.
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http://dx.doi.org/10.1016/j.brainres.2017.04.015DOI Listing
August 2017

Ameloblastin induces tumor suppressive phenotype and enhances chemosensitivity to doxorubicin via Src-Stat3 inactivation in osteosarcoma.

Sci Rep 2017 01 5;7:40187. Epub 2017 Jan 5.

Department of Oral and Maxillofacial Pathobiology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Ameloblastin (AMBN), the most abundant non-amelogenin enamel matrix protein, plays a role in ameloblast differentiation. Previously, we found that AMBN promoted osteogenic differentiation via the interaction between CD63 and integrin β1, leading to the inactivation of Src; however, how AMBN affects the malignant behavior of osteosarcoma is still unclear. Osteosarcoma affects the bone and is associated with poor prognosis because of the high rate of pulmonary metastases and drug resistance. Here we demonstrated that stable overexpression of AMBN induced apoptosis and suppressed colony formation and cell migration via the inactivation of Src-Stat3 pathway in human osteosarcoma cells. Moreover, AMBN induced chemosensitivity to doxorubicin. Thus, AMBN induced a tumor suppressive phenotype and chemosensitivity to doxorubicin via the AMBN-Src-Stat3 axis in osteosarcoma. Indeed, immunohistochemical expression of AMBN was significantly correlated with better outcome of osteosarcoma patients. Our findings suggest that AMBN can be a new prognostic marker and therapeutic target for osteosarcoma combined with conventional doxorubicin treatment.
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http://dx.doi.org/10.1038/srep40187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5214574PMC
January 2017