Therapeutic benefits of factors derived from stem cells from human exfoliated deciduous teeth for radiation-induced mouse xerostomia

Radiation therapy for head and neck cancers is frequently associated with adverse effects on the surrounding normal tissue. Irreversible damage to radiation-sensitive acinar cells in the salivary gland (SG) causes severe radiation-induced xerostomia (RIX). Currently, there are no effective drugs for treating RIX. We investigated the efficacy of treatment with conditioned medium derived from stem cells from human exfoliated deciduous teeth (SHED-CM) in a mouse RIX model. Intravenous administration of SHED-CM, but not fibroblast-CM (Fibro-CM), prevented radiation-induced cutaneous ulcer formation (p < 0.0001) and maintained SG function (p < 0.0001). SHED-CM treatment enhanced the expression of multiple antioxidant genes in mouse RIX and human acinar cells and strongly suppressed radiation-induced oxidative stress. The therapeutic effects of SHED-CM were abolished by the superoxide dismutase inhibitor diethyldithiocarbamate (p < 0.0001). Notably, quantitative liquid chromatography-tandem mass spectrometry shotgun proteomics of SHED-CM and Fibro-CM identified eight proteins activating the endogenous antioxidant system, which were more abundant in SHED-CM than in Fibro-CM (p < 0.0001). Neutralizing antibodies against those activators reduced antioxidant activity of SHED-CM (anti-PDGF-D; p = 0.0001, anti-HGF; p = 0.003). Our results suggest that SHED-CM may provide substantial therapeutic benefits for RIX primarily through the activation of multiple antioxidant enzyme genes in the target tissue.


Idiopathic First Bite Syndrome Well-Treated with the Japanese Herbal Medicine Kakkonto: Analysis of Heart Rate Variability.


Inhibition of JAK-STAT Signaling by Baricitinib Reduces Interferon-γ-Induced CXCL10 Production in Human Salivary Gland Ductal Cells.


シェーグレン症候群の病態形成におけるCXCL10の役割

シェーグレン症候群の病態形成におけるCXCL10の役割

Sjögren's syndrome (SS) is a common autoimmune disease characterized by the destruction of acinar structure by marked lymphocytic infiltrates in the salivary and lacrimal glands, resulting in sicca symptoms. Gene expression profiling of lip salivary glands (LSGs) shows that C-X-C motif chemokine 10 (CXCL10) expression is upregulated in patients with primary SS (pSS). CXCL10 and its receptor, C-X-C receptor 3 (CXCR3), contribute to the pathogenesis of SS. We investigated the clinical significance of CXCL10 and CXCR3 in the autoimmune lesions of pSS and the molecular mechanisms of CXCL10 upregulation in the salivary gland cells. CXCL10 showed particularly intense staining in LSG ductal cells from pSS patients. CXCR3 expression was detected primarily in CD163+ macrophages. The number of CXCR3+CD163+ macrophages was inversely correlated with the severity of LSG inflammatory lesions. Our in vitro experiments demonstrated that human salivary gland ductal (NS-SV-DC) cells produced higher levels of CXCL10 than acinar (NS-SV-AC) cells. Furthermore, NS-SV-DC and NS-SV-AC cells had different regulators of CXCL10 enhancement: interferon (IFN)-γ had more potential than IFN-α, tumor necrosis factor (TNF)-α, and interleukin (IL)1-β in the induction of CXCL10 production in NS-SV-DC cells, whereas TNF-α had the potential to induce CXCL10 production in NS-SV-AC cells. Our results suggest that CXCL10 overexpression in salivary glands is mainly caused by IFN-γ-stimulated salivary gland ductal cells. The enhanced production of CXCL10 by ductal cell IFN-γ results in the migration of CXCR3+ immune cells. CXCL10 plays an important role in SS pathogenesis, and CXCL10 regulation may be useful in the treatment of SS patients.

The Japanese Journal of Tissue Culture Society for Dental Research


PLAG1 enhances the stemness profiles of acinar cells in normal human salivary glands in a cell type-specific manner.

Details of the histogenesis of salivary gland tumors are largely unknown. The oncogenic role of PLAG1 in the salivary gland has been demonstrated in vivo. Herein, we demonstrate PLAG1 roles in the acinar and ductal cells of normal human salivary glands to clarify the early events that occur during the histogenesis of salivary gland tumors. Normal salivary gland cells with acinar and ductal phenotypes were transfected with PLAG1 plasmid DNA. Subsequently, PLAG1 overexpressed and mock cells were examined by cell proliferation, transwell migration, and salisphere formation assays. Differentiation and salivary and pluripotent stem cell marker expression levels were evaluated by quantitative reverse transcription-polymerase chain reaction and immunofluorescence. Alterations in transcriptional expressions were investigated via cap analysis of gene expression with gene-enrichment and functional annotation analysis. PLAG1 promoted cell proliferation and transwell migration in the acinar and ductal cells, and markedly enhanced the stemness profiles and luminal cell-like profiles in acinar cells; the stemness profiles were partially increased in the ductal cells. PLAG1 enhanced the stemness profiles in the acinar cells of normal human salivary glands in a cell type-specific manner. Thus, it may be involved in salivary gland tumorigenesis by increasing the stemness character of the normal salivary gland cells.


Primary Glossodynia Well-Treated with Triple-Drug Combination: A Case Series

三剤併用が奏効した一次性舌痛症の3例

Primary glossodynia is characterized by abnormal sensations such as tongue pain without pathological changes and is not fully understood. Primary glossodynia is reported to be associated with neurophathic pain. We describe the cases of 3 patients(2 males, 1 female, mean age 54.3 years, range 42-79 years) with primary glossodynia that was treated with the concomitant medication of pregabalin (50-300mg/day), tramadol hydrochloride/acetaminophen tablets (37.5/325-150/1,300mg/day), and powdered processed aconite roots (0.5-1.5mg/day). This medication remarkably relieved the patients primary glossodynia and promoted health-reated quality of life of them. Significant adverse events did not occur in any of the cases.<br>This concomitant medication may be useful for the treatment of primary glossodynia.

一次性舌痛症は舌に痛みなどの異常感を訴えるものの，器質的または精神的要因のいずれも見出せないものとされる．近年，本症と神経障害性疼痛との関連が論じられている．今般，われわれはプレガバリン，トラマドール塩酸塩/アセトアミノフェン配合錠および加工附子末製剤の三剤併用が奏効した本症の3例を経験したので，その概要を報告する．患者は男性2名，女性1名，年齢42∼79歳(平均54.3歳)であった．全例に対してこれら三剤を併用した．痛みは緩解し，健康関連QOLも向上した．特記すべき有害事象は認められなかった．本症に対するこれら三剤併用の有用性が示唆された．


MMP-9 inhibition suppresses interferon-γ-induced CXCL10 production in human salivary gland ductal cells.

Gene expression profiling of lip salivary gland (LSG) has shown that C-X-C motif chemokine 10 (CXCL10) and matrix metalloproteinase 9 (MMP9) expression is upregulated in primary Sjögren's syndrome (pSS) patients. Although CXCL10 and MMP-9 are both associated with pSS pathogenesis, the potential relationship between these two factors has not been investigated. In this study, we used LSG sections from pSS patients and human salivary gland cell lines to investigate the relationship between CXCL10 and MMP-9. Immunofluorescence analyses revealed that CXCL10 and MMP-9 were co-expressed in the LSG of pSS patients, particularly in expanded ductal cells. Furthermore, RT-qPCR analyses on human salivary gland ductal NS-SV-DC cells confirmed that CXCL10 expression was induced by interferon (IFN)-γ, whereas that of MMP9 was stimulated by IFN-α, tumor necrosis factor-α, and interleukin-1β. Remarkably, MMP-9 inhibition in IFN-γ-stimulated NS-SV-DC cells significantly decreased CXCL10 mRNA and secreted protein levels. Further analyses established that MMP-9 inhibition in IFN-γ-stimulated NS-SV-DC cells decreased STAT1 phosphorylation and hence suppressed IFN-γ signaling. Collectively, these results suggest that in addition to its reported role in the destruction of acinar structures, MMP-9 is involved in the IFN-γ-induced production of CXCL10 in pSS lesions. We believe that our findings open the door to the development of novel treatments for pSS, based on the modulation of MMP-9 activity.


Management of tooth extraction in a patient with ELANE gene mutation-induced cyclic neutropenia: A case report.

Cyclic neutropenia (CyN) is a rare hematological disease, and patients with CyN often experience an early onset of severe periodontitis and are forced to undergo tooth extraction. Here, we report a case of a patient with CyN who showed different periodicity and oscillations of neutrophil count compared with her mother, despite sharing the same novel genetic mutation. A 17-year-old Japanese girl who had been diagnosed with CyN shortly after birth presented to our hospital with a complaint of mobility of her teeth and gingivitis. Upon presentation, an intraoral examination was performed and revealed redness and swelling of the marginal and attached gingiva. Radiographs revealed extreme resorption of the alveolar bone and apical lesions in her mandibular lateral incisors. The patient's hematologic data demonstrated a lack of blood neutrophils (0/μL). The patient had no history of dental extraction, and her mother also had a history of CyN. The patient was diagnosed with severe periodontitis that was associated with CyN. Gene testing showed a novel heterozygous mutation in exon 4 of the ELANE gene (c.538delC, p.Leu180Ser fsX11). Based on the clinical findings, we planned to extract the patient's mandibular lateral incisors. Although the tooth extraction was scheduled considering the cyclic variation in neutrophil count, the patient's neutrophil count was 0/μL on the day before the planned extraction. Therefore, granulocyte-colony stimulating factor (G-CSF) was administered to increase the patient's neutrophil count. On the day of the patient's admission for the tooth extraction, she presented with fever (body temperature, 38.5°C), tonsillitis, and stomatitis. The extraction was subsequently delayed, and the patient was administered antibiotics and G-CSF for 4 days. At this time, the neutrophil count increased to 750/μL, and the tooth extraction was carried out safely. The postoperative course was uneventful, and the healing process at the extraction site was excellent. There is a possibility that the periodicity and oscillations of neutrophil count may change with growth in patients with CyN. Therefore, it is important to frequently examine and treat patients with fluctuating neutrophil levels for the management of invasive dental treatment in patients with CyN.


Effectiveness of Kampo Medicines against Intractable Stomatitis: A Mini-Review

International Journal of Medical and Dental Sciences


Oral Lichen Planus Well-Treated with Kampo Medicines: Two Case Reports

IOSR Journal of Dental and Medical Sciences


A Case of Well-Managed Sarcoidosis with Cardiac Autonomic Dysfunction during Dental Therapy: Significance of Heart Rate Variability Analysis.


Concomitant Pregabalin and Tramadol Hydrochloride/Acetaminophen Formulation Relieved Neuropathic Itch of Gingiva: A Case Report.


CCL22-Producing Resident Macrophages Enhance T Cell Response in Sjögren's Syndrome.

Macrophages (MΦs) are critical regulators of immune response and serve as a link between innate and acquired immunity. The precise mechanism of involvement of tissue-resident MΦs in the pathogenesis of autoimmune diseases is not clear. Here, using a murine model for Sjögren's syndrome (SS), we investigated the role of tissue-resident MΦs in the onset and development of autoimmunity. Two unique populations of CD11b and CD11b resident MΦs were observed in the target tissue of the SS model. Comprehensive gene expression analysis of chemokines revealed effective production of CCL22 by the CD11b MΦs. CCL22 upregulated the migratory activity of CD4 T cells by increasing CCR4, a receptor of CCL22, on T cells in the SS model. In addition, CCL22 enhanced IFN-γ production of T cells of the SS model, thereby suggesting that CCL22 may impair the local immune tolerance in the target organ of the SS model. Moreover, administration of anti-CCL22 antibody suppressed autoimmune lesions in the SS model. Finally, histopathological analysis revealed numerous CCL22-producing MΦs in the minor salivary gland tissue specimens of the SS patients. CCL22-producing tissue-resident MΦs may control autoimmune lesions by enhancing T cell response in the SS model. These results suggest that specific chemokines and their receptors may serve as novel therapeutic or diagnostic targets for SS.


A Case of Well-Managed Fibromyalgia with Autonomic Dysfunction during Dental Therapy: Significance of Heart Rate Variability Analysis


Distinct Regulation of CXCL10 Production by Cytokines in Human Salivary Gland Ductal and Acinar Cells.

CXCL10, a CXC chemokine induced by interferon-gamma [IFN-γ], has been observed in a wide variety of chronic inflammatory disorders and autoimmune conditions. Although CXCL10 is known to be overexpressed in the salivary glands of individuals with primary Sjögren's syndrome (pSS), it is unclear which cells produce CXCL10 under what types of stimulations. Here, we investigated the precise molecular mechanisms by which CXCL10 was produced in human salivary gland ductal (NS-SV-DC) and acinar (NS-SV-AC) cell lines. Our results demonstrated that NS-SV-DC cells produced higher levels of CXCL10 compared to NS-SV-AC cells. In addition, our findings demonstrated that the regulator of the enhancement of CXCL10 was different between NS-SV-DC and NS-SV-AC cells, i.e., interferon-gamma (IFN-γ) had more potential than interferon-alpha (IFN-α), tumor necrosis factor (TNF)-α, and interleukin (IL)1-β in the induction of CXCL10 production in NS-SV-DC cells, whereas TNF-α had potential to induce CXCL10 production in NS-SV-AC cells. A Western blot analysis demonstrated that IFN-γ enhanced the production of CXCL10 via both the JAK/STAT1 pathway and the NF-κB pathway in NS-SV-DC cells, whereas TNF-α enhanced the production of CXCL10 via the NF-κB pathway in NS-SV-AC cells. The results of study suggest that the CXCL10 overexpression in the salivary glands is caused mainly by IFN-γ-stimulated salivary gland ductal cells. The enhanced production of CXCL10 by IFN-γ from ductal cells may result in the inflammation of pSS lesions.


Inverse correlation between the number of CXCR3+ macrophages and the severity of inflammatory lesions in Sjögren's syndrome salivary glands: a pilot study

Mechanisms underlying immune cells' recruitment and activation into the inflammatory lesions of lip salivary glands (LSGs) from primary Sjögren's syndrome (pSS) patients are incompletely understood. Chemokines play pivotal roles in these processes, so we investigated the clinical significance of chemokine receptor CXCR3 and its ligands in the autoimmune lesions of pSS. We histologically determined the grade of LSG samples from 22 patients with pSS and subjected the samples to immunofluorescence analysis to determine the expressions of CXCR3 and its ligands: CXCL9, CXCL10, and CXCL11. To identify the immune cells expressing CXCR3 in the LSGs, we performed double immunofluorescence analysis using antibodies against CD3 (pan-T cells), CD80 (M1 macrophages), CD163 (M2 macrophages), and CD123 (plasmacytoid dendritic cells: pDCs). The relationship between the grade of lymphocytic infiltration and the number of positively stained cells was analyzed by Spearman's rank correlation test. The expressions of CXCL9 and CXCL10 showed particularly intense staining in the LSG samples' ductal cells. The CXCR3 expression was detected mainly in CD80 and CD163 macrophages. The number of CXCR3 CD163 macrophages inversely correlated with the LSG inflammatory lesions' severity (rs = -0.777, P < 0.001). Our results suggest that the enhanced production of CXCL9 and CXCL10 from ductal cells results in the CXCR3 macrophages' migration. There was an inverse correlation between these two parameters: that is, the number of CXCR3 CD163 macrophages decreased as the lymphocytic infiltration grade increased. Although CXCR3 is expressed in all of the innate immune cells, CXCR3 CD163 M2 macrophages may contribute to the anti-inflammatory functions in pSS lesions.


一次性舌痛症における唾液アミラーゼ活性測定の試み

一次性舌痛症における唾液アミラーゼ活性測定の試み

Journal of Japanese Society for Evidence and the Dental Professional


Recurrent Aphthous Stomatitis Well-Treated with Inchinkoto: Two Case Reports


Docetaxel・γ-tocotrienol併用療法による口腔癌移植ヌードマウス腫瘍への抗腫瘍効果の検討．

The Japanese Journal of Tissue Culture Society for Dental Research


Cepharanthine inhibits IFN--induced CXCL10 by suppressing the JAK2/STAT1 signal pathway in human salivary gland ductal cells

Cepharanthine, a biscolaurine alkaloid isolated from the plant Stephania cephalantha Hayata, has been reported to have potent anti-inflammatory properties. Here, we investigated the effects of cepharanthine on the expression of CXCL10 (a CXC chemokine induced by interferon-gamma [IFN-γ] that has been observed in a wide variety of chronic inflammatory disorders and autoimmune conditions) in IFN-γ-treated human salivary gland cell lines. We observed that IFN-γ-induced CXCL10 production in NS-SV-DC cells (a human salivary gland ductal cell line), but not in NS-SV-AC cells (a human salivary gland acinar cell line). Cepharanthine inhibited the IFN-γ-induced CXCL10 production in NS-SV-DC cells. A Western blot analysis showed that cepharanthine prevented the phosphorylation of JAK2 and STAT1, but did not interfere with the NF-κB pathway. Moreover, cepharanthine inhibited the IFN-γ-mediated chemotaxis of Jurkat T cells. These results suggest that cepharanthine suppresses IFN-γ-induced CXCL10 production via the inhibition of the JAK2/STAT1 signaling pathway in human salivary gland ductal cells. Our findings also indicate that cepharanthine could inhibit the chemotaxis of Jurkat T cells by reducing CXCL10 production.


五苓散と加工附子末製剤の併用が奏効した三叉神経痛の1例

五苓散と加工附子末製剤の併用が奏効した三叉神経痛の1例


徳島大学病院歯科診療所を受診したHIV感染症患者の臨床統計的検討

徳島大学病院歯科診療所を受診したHIV感染症患者の臨床統計的検討

Journal of Japanese Society of Dentistry for Medically Compromised Patient


肺癌手術における周術期口腔機能管理の術後肺炎予防効果

肺癌手術における周術期口腔機能管理の術後肺炎予防効果

The Journal of the Japanese Association for Chest Surgery


外科診療におけるチーム医療の現況と展望 4．周術期の口腔ケア-食道癌，肺癌手術における周術期口腔機能管理-


Treatment with the Biscoclaurine Alkaloid Cepharanthin Significantly Increases Salivary Selection in Primary Sjögren's Syndrome Patients


A Case Series of Xerostomia Treated with Kampo Medicines: Assessment of Health-Related Quality of Life Based on the Japanese Version of the Short Form-8 Health Survey


Orofacial Pain Well-Treated with Triple-Drug Combination : A Case Series

三剤併用が奏効した口腔顔面痛の3例


Usability Survey on New Oral Care Products, Pepti-Sal Series

新規口腔ケア製品「ペプチサルシリーズ」の使用感に関する調査


Awareness of oral health management in outpatients undergoing chemotherapy

外来化学療法患者の口腔健康管理に対する認識


口腔ならびに呼吸器症状を呈した歯科用金属によるアレルギーの1例

口腔ならびに呼吸器症状を呈した歯科用金属によるアレルギーの1例


Effects of perioperative oral management in thoracoscopic lung lobectomy : Retrospective study

胸腔鏡下肺葉切除術における周術期口腔機能管理の効果に関する検討―後ろ向き研究―


Current Status and Effectiveness of Perioperative Oral Health Care Management for Lung Cancer and Esophageal Cancer Patients

肺癌・食道癌の周術期における口腔ケアの現状とその効果

The Japanese Journal of Thoracic Surgery


Significance of Time-Domain Measurements of Heart Rate Variability in Burning Mouth Syndrome

IOSR Journal of Dental and Medical Sciences


口腔異常感覚に対して白虎加人参湯が奏効した1症例

口腔異常感覚に対して白虎加人参湯が奏効した1症例


A Case of Well-Managed Idiopathic Autonomic Neuropathy during Dental Therapy: Significance of Heart Rate Variability Analysis


Low-intensity pulsed ultrasound rescues insufficient salivary secretion in autoimmune sialadenitis.

These results suggest that LIPUS upregulates expression of AQP5 and inhibits TNF- production. Thus, LIPUS may restore secretion by inflamed salivary glands. It may synergistically activate negative feedback of NF-B signaling in response to inflammatory stimulation. Collectively, LIPUS might be a new strategic therapy for xerostomia in autoimmune sialadenitis with SS.

TNF-α stimulation of NS-SV-AC and NS-SV-DC cells resulted in a significant decrease in cell number and net fluid secretion rate (p < 0.01), whereas LIPUS treatment abolished them (p < 0.05). The expression changes of AQP5 and TNF-α were also inhibited in LIPUS treatment by blocking the NF-κB pathway. Furthermore, we found that mRNA expression of A20, a negative feedback regulator, was significantly increased by LIPUS treatment after TNF-α or interleukin 1β stimulation (NS-SV-AC, p < 0.01; NS-SV-DC, p < 0.05). In vivo LIPUS exposure to MRL/lpr mice exhibited a significant increase in both salivary flow and AQP5 expression by reducing inflammation in salivary glands (p < 0.01).


Cerebellopontine Angle Mass Mimicking Lingual Nerve Injury after Dental Implant Placement: A Case Report.

This is a rare case report of a cerebellopontine angle (CPA) mass mimicking lingual nerve injury after a dental implant placement. Lingual nerve injury is a common complication following dental implant placement. CPA masses are likely to cause symptomatic trigeminal neuralgia, and thus can mimic and be easily confused with oral diseases. We experienced a case of CPA mass mimicking lingual nerve injury after dental implant placement. The patient was a 57-year-old Japanese female and complained of glossalgia. She underwent dental implant placement in the mandible before visiting our clinic. Panoramic x-ray radiography revealed no abnormalities; the salivary flow rate by gum test was 7.0 ml/10 min. She was diagnosed with lingual nerve injury and secondary burning mouth syndrome. Vitamin B12 and oral moisturizer did not provide relief; furthermore, numbness in the lower lip emerged. A Semmes Weinstein test demonstrated elevation of her sensitivity threshold. Finally, magnetic resonance imaging revealed a 20-mm-diameter mass in the CPA. The patient is now being followed under conservative management. Our experience underscores the importance of including CPA mass in the differential diagnosis of dental diseases. This article is protected by copyright. All rights reserved.


対応に苦慮した口腔異常感覚に対して五苓散が奏効した1症例

対応に苦慮した口腔異常感覚に対して五苓散が奏効した1症例


Pregabalin Relieved Gingival Pruritus Associated with Oral Dysesthesia: A Case Report


Study on Health-Related Quality of Life in Patients with Primary Glossodynia : Using the Japanese Version of the MOS 36-Item Short-Form Health Survey Version 2

一次性舌痛症に関する健康関連QOLの調査-MOS 36-Item Short-Form Health Survey Version 2日本語版を用いて-

Primary glossodynia is characterized by abnormal sensations such as tongue pain without pathological changes and is not fully understood. The Japanese version of the MOS 36-item short-form health survey version 2 (SF-36v2) is a questionnaire to measure health-related quality of life (HRQoL) in various diseases. We studied HRQoL in 26 primary glossodynia patients who self-completed the SF-36v2. The mean scores on the SF-36v2 subscales in our female patients were significantly lower than the national norms. Furthermore, those in the elderly female patients were significantly lower than those in the middle-aged ones. Conditions of primary glossodynia in the elderly patients were complicated by physical and mental factors; psychosocial supports should be required for their care in addition to pain control. Our study of HRQoL in primary glossodynia patients using the SF-36v2 was shown to be meaningful for understanding primary glossodynia and establishing goals for its care.

一次性舌痛症は舌痛を訴えるものの確たる要因を見出せず，未だ十分な理解には達していない．MOS 36-Item Short-Form Health Survey Version 2 (SF-36v2)日本語版は健康関連QOL(Health-Related Quality of Life)の尺度である．今般，われわれはSF-36v2日本語版を用いて本疾患に関する健康関連QOLを調査した．2007年1月から2014年12月までに徳島大学病院口腔内科を受診した一次性舌痛症患者26名を対象とした．女性は男性と比較して，総じてSF-36v2下位尺度のスコアが低下し，高齢者では顕著であった．本疾患の病態は加齢によって複雑化し，高齢者に対する治療目標は疼痛だけに固執せず，心理・社会的問題に対する配慮も要すると考えられた．SF-36v2日本語版による健康関連QOLの調査は本疾患の理解と治療目標の設定において有意義であった．

Journal of Japanese Society of Oral Medicine


A Case Series of Burning Mouth Syndrome Treated with Stellate Ganglion Near-Infrared Irradiation: Assessment of HealthRelated Quality of Life Based on the Japanese Version of the MOS 36-Item Short-Form Health Survey Version 2


Well-Managed Postural Orthostatic Tachycardia Syndrome during Dental Therapy and Analysis of Heart Rate Variability: A Case Report


Interleukin-6/STAT pathway is responsible for the induction of gene expression of REG Ia, a new auto-antigen in Sjogren's syndrome patients, in salivary duct epithelial cells.


Oral management of patients with chronic kidney diseases in the Tokushima University Hospital

徳島大学病院における慢性腎臓病患者の口腔管理について


徳島県下の地域歯科診療所における病院・施設への往診/訪問歯科診療の現状

徳島県下の地域歯科診療所における病院・施設への往診/訪問歯科診療の現状

Journal of Shikoku Public Health Society


γ-tocotrienol prevents 5-FU-induced reactive oxygen species production in human oral keratinocytes through the stabilization of 5-FU-induced activation of Nrf2

Chemotherapy induced oral mucositis is a common adverse event in patients with oral squamous cell carcinoma, and is initiated through a variety of mechanisms, including the generation of reactive oxygen species (ROS). In this study, we examined the preventive effect of γ tocotrienol on the 5 FU induced ROS production in human oral keratinocytes (RT7). We treated RT7 cells with 5 FU and γ tocotrienol at concentrations of 10 µg/ml and 10 nM, respectively. When cells were treated with 5 FU alone, significant growth inhibition was observed as compared to untreated cells. This inhibition was, in part, due to the ROS gene rated by 5 FU treatment, because N acetyl cysteine (NAC), a ROS scavenger, significantly ameliorated the growth of RT7 cells. γ tocotrienol showed no cytotoxic effect on the growth of RT7 cells. Simultaneous treatment of cells with these agents resulted in the significant recovery of cell growth, owing to the suppression of ROS generation by γ tocotrienol. Whereas 5 FU stimulated the expression of NF E2 related factor 2 (Nrf2) protein in the nucleus up to 12 h after treatment of RT7 cells, γ tocotrienol had no obvious effect on the expression of nuclear Nrf2 protein. Of note, the combined treatment with both agents stabilized the 5 FU induced nuclear Nrf2 protein expression until 24 h after treatment. In addition, expression of Nrf2 dependent antioxidant genes, such as heme oxygenase 1 (HO 1) and NAD(P)H:quinone oxidoreductase 1 (NQO 1), was significantly augmented by treatment of cells with both agents. These findings suggest that γ tocotrienol could prevent 5 FU induced ROS generation by stabilizing Nrf2 activation, thereby leading to ROS detoxification and cell survival in human oral keratinocytes.


Current Status and Problems Regarding the Perioperative Oral Function Management in the Tokushima University Hospital

徳島大学病院における周術期口腔機能管理の現状と課題

It has been shown that oral hygiene affects the onset of perioperative complications. The usefulness of perioperative oral function management aiming at the outbreak decrease in treatment complications and an early discharge was recognized. As a result, perioperative oral function management fee was founded at revision of medical service fees in Fiscal year 2012. In this clinical study, we evaluated the implementation of perioperative oral function management in Tokushima University Hospital. We examined 781 patients, including 563 patients for surgery and 218 patients for chemotherapy and radiotherapy. The mean age of patients was 58.8 ± 12.4 years old. The implementation rate of perioperative oral function management was 9.7% in the patients of surgery, and 17.4% in those of chemotherapy and radiotherapy. The highly required medical department was neurosurgery in the patients of surgery, and hematology in those of chemotherapy and radiotherapy. The mean number of tooth present was 21.3 ± 7.1 in the patients of surgery, and 19.8 ± 7.2 in those chemotherapy and radiotherapy. The rate of dental treatment was required in 40.5% of total patients who received surgery, and in 51.4% of patients who received chemotherapy and radiotherapy.The rate of patients who received denture treatment attained to 11.9% of the whole patients receiving surgery, and 13.3% of patients receiving chemotherapy and radiotherapy. It was revealed that there were many patients required potential demands in perioperative oral function management, and that there were many patients who need dental or denture treatment. We would like to develop perioperative oral function management by the interprofessional collaboration in health and social care.7月発行だが，6月号である．


口腔癌担癌ヌードマウスに対するdocetaxelおよびγ-tocotrienolの併用による抗腫瘍効果の検討


徳島大学病院脳卒中センターにおける口腔管理の意義について

徳島大学病院脳卒中センターにおける口腔管理の意義について


High-Wattage Pulsed Irradiation of Linearly Polarized Near-Infrared Light to Stellate Ganglion Area for Burning Mouth Syndrome

The purpose of this study was to apply high-wattage pulsed irradiation of linearly polarized near-infrared light to the stellate ganglion area for burning mouth syndrome (BMS) and to assess the efficacy of the stellate ganglion area irradiation (SGR) on BMS using differential time-/frequency-domain parameters (D parameters). Three patients with BMS received high-wattage pulsed SGR; the response to SGR was evaluated by visual analogue scale (VAS) representing the intensity of glossalgia and D parameters used in heart rate variability analysis. High-wattage pulsed SGR significantly decreased the mean value of VAS in all cases without any adverse event such as thermal injury. D parameters mostly correlated with clinical condition of BMS. High-wattage pulsed SGR was safe and effective for the treatment of BMS; D parameters are useful for assessing efficacy of SGR on BMS.


Orthostatic Dysregulation during Postural Change on the Dental Chair and Intraoperative Monitoring by Heart Rate Variability Analysis.

This is the first case report of orthostatic dysregulation (OD) manifested during postural change on the dental chair and intraoperatively monitored by heart rate variability (HRV) analysis. OD-associated autonomic dysfunction is induced by postural changes and easily leads to disturbance in circulatory dynamics; however, most dental practices have not yet realized the importance of managing OD. We measured autonomic activity in a patient with OD during dental therapy and assessed the clinical significance of HRV analysis for OD. The patient was a 17-year-old Japanese female. She was diagnosed with impacted wisdom teeth and had no previous history of a distinct systemic disease. A surgical procedure to extract the teeth was safely performed under both local anesthesia and sedation with nitrous oxide and midazolam. After the surgery, her postural change to sitting induced orthostatic hypotension. HRV variables showed parasympathetic dominance due to the upright position. Subsequently, her posture was returned to supine, and atropine sulfate administration for the immediate treatment of OD returned her blood pressure to normal levels. HRV variables showed relative sympathetic dominance due to an atropine-derived parasympathetic blockade. HRV analysis revealed OD-associated autonomic dysfunction and should become a standard tool for safe and secure dental management of OD.


いわゆる病病連携による障害者歯科医療連携が奏功した集学的歯科治療について

いわゆる病病連携による障害者歯科医療連携が奏功した集学的歯科治療について


A Case of Malignant Lymphoma of the Mandible Diagnosed by Coincidentally-Developed Mental Hypoesthesia after Dental Implant Placement

インプラント埋入後に生じたオトガイ神経麻痺が契機となり診断に至った下顎骨悪性リンパ腫の1例

We present a case of malignant lymphoma of the mandible diagnosed by coincidentally-developed mental hypoesthesia after placement of a dental implant. A 60-year old woman who underwent dental implant placement by a dental practitioner visited our hospital because of postoperative mental hypoesthesia. Orthopantomography and CT revealed perforated bone defects at the posterior molar and ramus region of the mandible, but could not demonstrate a causal relationship between the implantation and the hypoesthesia. In blood test results, the values of sIL-2R and LDH were abnormally elevated. A tumor arising from soft tissue around the molar region was biopsied, and a diagnosis of diffuse large B-cell lymphoma was confirmed histopathologically. This tumor was treated at the Department of Hematology by the R-CHOP chemotherapy regimen, resulting in complete remission of the tumor, and masticatory function was adequately restored using dental implants. It was concluded that early detection and rapid cure are the key to maintaining oral function.

Journal of Japanese Society of Oral Implantology

日本口腔インプラント学会誌


一次性舌痛症における手掌部発汗の発現-皮膚水分量測定の有用性について-

一次性舌痛症における手掌部発汗の発現-皮膚水分量測定の有用性について-

日本歯科人間ドック学会誌

日本歯科人間ドック学会誌


A case of acquired hemophilia A incidentally diagnosed on postoperative bleeding after tooth extraction

抜歯後の止血困難をきっかけに発見された後天性血友病Aの1例

Acquired hemophilia A is a rare disease. It is caused by the acquirement of factor VIII inhibitor. We report a case of acquired hemophilia A incidentally diagnosed on bleeding after tooth extraction. A 75-yearold woman referred to our hospital because of bleeding after tooth extraction. Hematological examination revealed a prolonged activated partial thromboplastin time (APTT) and decreased coagulation activity of factor VIII. In addition, a high level of factor VIII inhibitor was detected. Therefore, our patient was given a diagnosis of acquired hemophilia A. The patient was admitted to our hospital and received corticosteroids and bypass hemostasis using recombinant coagulation factor VII. On hospital day 42, APTT and factor VIII activity returned to the normal range. Moreover, factor VIII inhibitor disappeared. The patient was discharged and is being treated at a local general hospital.

Japanese Journal of Oral & Maxillofacial Surgery


Targeting TNF- suppresses the production of MMP-9 in human salivary gland cells.

Tumour necrosis factor- (TNF-) is a pleiotropic cytokine that plays an essential role in inflammation and apoptosis. Our previous study suggested that TNF--induced activation of matrix metalloproteinase-9 (MMP-9) resulted in the destruction of acinar tissue in the salivary glands of patients with Sjögren's syndrome (SS) via disruption of the acinar cell-basement membrane. Recently, a wide array of biological agents has been designed to inhibit TNF, including etanercept and adalimumab. In this study, we demonstrate the suppressive effect of anti-TNF agents on TNF--induced MMP-9 production in NS-AV-AC, an immortalized human salivary gland acinar cell line. NS-AV-AC cells were treated with etanercept or adalimumab after TNF- treatment. MMP-9 production and enzymatic activity were, respectively, visualized by real-time PCR and ELISA assay, and evaluated by gelatin zymography, and apoptosis was evaluated by DNA fragmentation assay. TNF- induced the production of MMP-9 in NS-SV-AC cells. However, this production was greatly inhibited by treatment with etanercept or adalimumab. In addition, TNF--induced DNA fragmentation was prevented by treatment with etanercept or adalimumab. These results may indicate that anti-TNF agents would have therapeutic efficacy for preventing destruction of the acinar structure in the salivary glands of patients with SS.


Prevention of the destruction of acinar structure in patients with Sjogren's syndrome : Clinicopathological study on the effectiveness of cepharanthin

Sjogren症候群患者の唾液腺腺房構造破壊阻止 : セファランチンの有効性に関する臨床病理学的研究

Sjögren's syndrome (SS) is characterized by the eventual total replacement of the acinar structure by marked infiltration of lymphocytes into the salivary and lacrimal glands. We previously demonstrated that tumor necrosis factor-α (TNF-α) induced matrix metalloproteinase-9 (MMP-9) production by the stimulating transcription factor, nuclear factor-κB (NF-κB), in human salivary gland acinar cells and that cepharanthin, a biscoclaurine alkaloid, prevented the activation of TNF-α-induced NF-κB activity. In addition, we have shown that cepharanthin prevented the destruction of acinar tissues in murine SS. Thus, in this study, we investigated the clinicopathological effect of cepharanthin on the patients with SS.
Ten patients with a diagnosis of primary SS were enrolled in this study. They were treated with cepharanthin for three months, followed by the evaluation of salivary production, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anti-SS-A antibody, anti-SS-B antibody, pathological examination of labial salivary gland biopsy specimens, and the symptom of drymouth.
Average salivary production was 4.25ml/10minutes before the study. This average production increased to 6.46ml/10minutes after the study. There were no remarkable changes in CRP, ESR, anti-SS-A antibody and anti-SS-B antibody. In pathological findings, although the decreases in infiltration of lymphocytes were observed in 5 out of 5 cases, the reduction of destruction of acinar structures was clearly detected in 5 cases. Improvement of symptom of drymouth was detected in 7 out of 10 cases.
These observations suggest that cepharanthin treatment might provide an efficient and useful therapeutic approach for countering the destruction of acinar tissue in salivary glands of patients with SS.

Journal of The Japanese Stomatological Society


A case of oral, pharyngeal, esophageal, and gastric ulcer in a patient with primary macroglobulinemia showing remission by treatment with rituximab

リツキシマブの投与によって生じた口腔・上部消化管潰瘍の1例


口腔白板症の臨床病理学的検討-悪性化に関する臨床病理学的指標について-

口腔白板症の臨床病理学的検討-悪性化に関する臨床病理学的指標について-

Journal of Japanese Society for Evidence and the Dental Professional


Current state of request for Oral Care in the Tokushima University Hospital

徳島大学病院内の口腔ケア依頼状況


Frequency analysis of heart rate variability: a useful assessment tool of linearly polarized near-infrared irradiation to stellate ganglion area for burning mouth syndrome.

Burning mouth syndrome (BMS) is characterized by the following subjective complaints without distinct organic changes: burning sensation in mouth or chronic pain of tongue. BMS is also known as glossodynia; both terms are used equivalently in Japan. Although the real cause of BMS is still unknown, it has been pointed out that BMS is related to some autonomic abnormality, and that stellate ganglion near-infrared irradiation (SGR) corrects the autonomic abnormality. Frequency analysis of heart rate variability (HRV) is expected to be useful for assessing autonomic abnormality. This study investigated whether frequency analysis of HRV could reveal autonomic abnormality associated with BMS, and whether autonomic changes were corrected after SGR. Eight subjects received SGR; the response to SGR was assessed by frequency analysis of HRV. No significant difference of autonomic activity concerning low-frequency (LF) norm, high-frequency (HF) norm, and low-frequency/high-frequency (LF/HF) was found between SGR effective and ineffective groups. Therefore, we proposed new parameters: differential normalized low frequency (D LF norm), differential normalized high frequency (D HF norm), and differential low-frequency/high-frequency (D LF/HF), which were defined as differentials between original parameters just before and after SGR. These parameters as indexes of responsiveness of autonomic nervous system (ANS) revealed autonomic changes in BMS, and BMS seems to be related to autonomic instability rather than autonomic imbalance. Frequency analysis of HRV revealed the autonomic instability associated with BMS and enabled tracing of autonomic changes corrected with SGR. It is suggested that frequency analysis of HRV is very useful in follow up of BMS and for determination of the therapeutic efficacy of SGR.


γ-tocotrienol enhances the chemosensitivity of human oral cancer cells to docetaxel through the down regulation of the expression of NF-kB-regulated anti-apoptotic gene products.

Taxanes, including docetaxel, are widely used for the treatment of squamous cell carcinoma of the head and neck. However, the gastrointestinal toxicity of docetaxel has limited its high-dose clinical use. In this study, we examined the synergistic anticancer effects of combined low-dose docetaxel and γ-tocotrienol treatment on human oral cancer (B88) cells. We treated B88 cells with docetaxel and γ-tocotrienol at concentrations of 0.5 nM and 50 µM, respectively. When cells were treated with either agent alone at a low dose, no significant cytotoxic effect was observed. However, the simultaneous treatment of cells with both agents almost completely suppressed cell growth. Whereas docetaxel stimulated the expression of nuclear factor-κB (NF-κB) p65 protein in B88 cells, γ-tocotrienol slightly inhibited the expression of constitutive nuclear p65 protein. Of note, the combined treatment with both agents inhibited docetaxel-induced nuclear p65 protein expression. Electrophoretic mobility shift assay (EMSA) revealed that the simultaneous treatment with these agents suppressed the NF-κB DNA binding activity in B88 cells. In addition, γ-tocotrienol downregulated the docetaxel-induced expression of NF-κB-regulated gene products associated with the inhibition of apoptosis. Furthermore, the activation of initiator caspases, caspases-8 and -9, and the effector caspase, caspase-3, was detected following treatment with both agents. Finally, apoptosis was also clearly observed as demonstrated by the cleavage of poly(ADP-ribose) polymerase (PARP) and nuclear fragmentation through the activation of caspase-3 by combined treatment with docetaxel and γ-tocotrienol. These findings suggest that the combination treatment with these agents may provide enhanced therapeutic response in oral cancer patients, while avoiding the toxicity associated with high-dose β-tubulin stabilization monotherapy.


イムノクロマト法による口腔カンジダ症迅速診断の臨床的有用性

イムノクロマト法による口腔カンジダ症迅速診断の臨床的有用性


精神科神経科入院患者の口腔環境評価と専門的口腔ケアの有用性について

精神科神経科入院患者の口腔環境評価と専門的口腔ケアの有用性について


徳島大学病院精神科神経科入院患者に対する口腔ケアの意義

徳島大学病院精神科神経科入院患者に対する口腔ケアの意義


Adrenergic urticaria and glossalgia induced by stress during dental therapy and monitored by heart variability analysis: A case report

Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology


Clinical Statistics of Patients with Lingual Abnormalities Including Glossalgia -Clinical Characteristics of Glossodynia-

舌痛などの舌症状を主訴とする患者の臨床統計学的検討—舌痛症の特異性についてー.

Purpose: There are many kinds of diseases that can cause glossalgia, and it is not always easy to determine the differential diagnosis. Therefore, establishment of screening procedures for organic factors of glossalgia is important to obtain the correct diagnosis. We statistically analyzed the findings in patients with various lingual abnormalities. Methods: Patients were 104 persons consisted of 12 males and 92 females. Medical history taking, intraoral and extraoral examinarion, panoramic x-ray radiography, blood examination, culture, and salivation test were performed. It was also determined whether local analgesic or nonsteroidal anti-inflammatory drug relieved the pain or not. Results: Glossalgia-related diseases consisted of oral candidiasis, xerostomia, glossitis, glossodynia and other diseases. The major part of oral candidiasis lacked a change in organic appearance. Concerning xerostomia, a sense of thirst was also lacking. Local analgesic or nonsteroidal anti-inflammatory drug showed a limited effect on glossodynia. The prevalence of taste disorder or hypozincemia in glossodynia was less than that in other diseases. On the other hand the prevalence of palm sweating in glossodynia was greater than that in other diseases. Conclusions: Culture and salivation test were necessary for the diagnosis of either oral candidiasis without a change in organic appearance or xerostomia without a sense of thirst. If these examinations were not performed, these cases might be diagnosed as glossodynia. The presence of pain on tongue tip and the absence of food-induced pain or oppressive pain were specific findings of glossodynia. Lingual mucous damage could not be directly correlated with pathology of glossodynia judging from the nature of glossalgia and the result of analgesic effects. Taste disorder and hypozincemia were found to be nonspecific findings of glossodynia. It was suggested that glossodynia is related to dysautonomia, and palm sweating is a specific finding of glossodynia.

目的:舌痛の器質的要因をスクリーニングする系統的診断システムを提案し，本法によって診断された舌痛関連疾患を検討する．方法:2007年1月から2009年12月までに舌痛などの舌症状を主訴としてで徳島大学病院歯科口腔外科を受診した患者104名(男性12名，女性92名，平均68歳2か月)を臨床統計学的に検討した．病歴聴取，口腔内・外診査，パノラマエックス線検査，血液検査，培養検査および唾液分泌検査を行った．局所麻酔薬と非ステロイド性抗炎症薬の効果も確認した．結果:原因疾患は口腔カンジダ症，口腔乾燥症，舌炎，舌痛症などであった．器質的変化や自覚症状の乏しい口腔カンジダ症や口腔乾燥症が認められた．舌痛症の多くは舌尖に発現し，食餌性刺激による誘発痛や圧痛が認められないものが多く，局所麻酔薬や非ステロイド系抗炎症薬の効果も乏しかった．舌痛症における味覚異常や低亜鉛血症の発現頻度は低く，手掌部発汗が高頻度に認められた．結論:培養検査や唾液分泌検査が不可欠であり，器質的変化や自覚症状の乏しい口腔カンジダ症や口腔乾燥症は舌痛症と診断される可能性があった．舌尖部疼痛を有し，食餌性刺激による誘発痛や圧痛がないことが舌痛症特異的な所見と考えられ，その病態に舌粘膜障害の関与は否定的であった．味覚障害や低亜鉛血症は舌痛症特異的な所見ではなかった．手掌部発汗は舌痛症特異的な所見と考えられ，その病態に自律神経異常の関与が示唆された．


Rapidly-Enlarged and Ruptured Submucous Hematoma of Soft and Hard Palate during Anticoagulation Therapy with Warfarin : A Case Report

ワルファリン療法中に急速に増大・破裂した軟硬口蓋粘膜下血腫の1例

We present a case of rapidly-enlarged and ruptured submucous hematoma of soft and hard palate during warfarin therapy.
The Patient was a 76-year old man. He suddenly had palatal swelling and difficulty in breathing while eating, and was brought to us by ambulance. He has been receiving warfarin therapy and treatments for paroxysmal atrial fibrillation, diabetes mellitus and high blood pressure. On blood examination normocytic anemia was diagnosed. Blood coagulation test demonstrated an elevated value (1.52) of PT-INR. The mucous membrane was exfoliated from both soft and hard palate without abnormalities in either respiratory or circulatory status. Immediately, suturing of the mucosa to the submucosal tissue was performed along with astriction.
Emphasis should be on soft and hard palatine submucous hematoma as an oral bleeding complication associated with warfarin therapy.

ワルファリン療法中に急速に増大・破裂した軟硬口蓋粘膜下血腫の1例を経験した．
症例は76歳，男性．食事中，急に口蓋が腫脹し，呼吸困難を訴え救急搬送された．発作性心房細動，糖尿病，高血圧症でワルファリン療法中であった．正球性貧血とPT-INR値は1.52を呈した．呼吸・循環動態に異常なく，軟硬口蓋粘膜が広範に剥離していたが，圧迫止血後，粘膜弁を縫合閉鎖した．
症例は留意すべき口腔の出血性合併症であった．

Journal of Japanese Society of Oral Medicine


A case of odontoameloblastoma arising in the maxilla

上顎に発生した歯牙エナメル上皮腫の1例

Odontoameloblastoma is a rare odontogenic tumor, in which dentin and enamel are formed. Histologically, odontoameloblastoma is similar to ameloblastoma. We report a case of odontoameloblastoma arising in the maxilla.<br>A 12-year-old boy complained of swelling and pain at the incisor region on the left side of the maxilla and visited our department. Computed tomography showed a unilocular radiolucency, in which many calcified bodies were observed around the impacted canine. The clinical diagnosis was an odontogenic tumor, and the lesion was extirpated under general anesthesia. Histopathological examination of the resected specimens showed the presence of hard tissues, enamel, and dentin, accompanied by an enamel organ. Consequently, the tumor was diagnosed to be an odontoameloblastoma. There has been no evidence of recurrence for 3.5 years after the operation.

Japanese Journal of Oral & Maxillofacial Surgery


TNF-a inhibits aquaporin 5 expression in human salivary gland acinar cells via suppression of histone H4 acetylation.

Sjögren's syndrome is a systemic autoimmune disease characterized by reductions in salivary and lacrimal secretions. The mechanisms underlying these reductions remain unclear. We have previously shown that TNF-α plays an important role in the destruction of acinar structures. Here we examined TNF-α's function in the expression of aquaporin (AQP) 5 in human salivary gland acinar cells. Immortalized human salivary gland acinar (NS-SV-AC) cells were treated with TNF-α, and then the expression levels of AQP5 mRNA and protein were analysed. In addition, the mechanisms underlying the reduction of AQP5 expression by TNF-α treatment were investigated. TNF-α-treatment of NS-SV-AC cells significantly suppressed the expression levels of AQP5 mRNA and protein, and reduced the net fluid secretion rate. We examined the expression and activation levels of DNA methyltransferases (Dnmts) in NS-SV-AC cells treated with TNF-α. However, no significant changes were observed in the expression or activation levels of Dnmt1, Dnmt3a or Dnmt3b. Although we also investigated the role of NF-κB activity in the TNF-α-induced suppression of AQP5 expression in NS-SV-AC cells, we detected similar TNF-α suppression of AQP5 expression in non-transfected cells and in a super-repressor form of IκBα cDNA-transfected cell clones. However, interestingly, chromatin immunoprecipitation analysis demonstrated a remarkable decrease in levels of acetylated histone H4 associated with the AQP5 gene promoter after treatment with TNF-α in NS-SV-AC cells. Therefore, our results may indicate that TNF-α inhibition of AQP5 expression in human salivary gland acinar cells is due to the epigenetic mechanism by suppression of acetylation of histone H4.

Journal of Cellular and Molecular Medicine


DNA demethylating agent decitabine increases AQP5 expression and restores salivary function.

Xerostomia is the symptom of oral dryness resulting most frequently, but not exclusively, from salivary gland hypofunction. Because the prevalence of xerostomia may increase with age, it has multiple oral health consequences in aging populations. In the present study, we demonstrate that the in vivo administration of 5-aza-2'-deoxycytidine (5-Aza-CdR; decitabine), a DNA demethylating agent, to the murine aging model C57BL/6CrSlc mice (24 wks old) increased the volumes of salivary flow compared with those of control mice. Western blot analysis and immunohistochemical staining demonstrated the augmented expression of AQP5 protein in the salivary glands of 5-Aza-CdR-treated mice compared with those of control mice. In addition, AQP5 protein expression levels in 5-Aza-CdR-treated old mice (27 wks old) were much higher than those in untreated and young mice (6 wks old). Global methylation levels in the salivary glands were significantly lower in the 5-Aza-CdR-treated mice than in the untreated mice. Moreover, the induction of demethylation in the AQP5 promoter of 5-Aza-CdR-treated mice was stronger than in the control mice. Analysis of our data therefore suggests that a DNA demethylating agent may be a useful drug for restoring hyposalivation in elderly individuals, thereby leading to the resolution of xerostomia.


副オトガイ孔を走行する神経様組織の捻除により口唇感覚異常が改善した症候性三叉神経痛の1例-神経学的検査の有用性について-

Journal of Japanese Society for Evidence and the Dental Professional


真菌培養検査におけるカンジダの検出に影響する臨床的要因の検討ー口腔乾燥の関連についてー


Cepharanthin-enhanced radiosensitivity through the inhibition of radiation-induced nuclear factor-kappaB activity in human oral squamous cell carcinoma cells.

We have already demonstrated that human head and neck cancer cells have significantly enhanced levels of transcription factor nuclear factor (NF)-kappaB activity compared to their normal counterparts, suggesting that NF-kappaB plays an important role in the development of head and neck cancer. However, it has been reported that chemotherapeutic agents and radiation activate NF-kappaB activity in cancer cells, thus making the cells radioresistant and chemoresistant. In addition, we have shown that the suppression of NF-kappaB activity enhanced apoptosis in oral squamous cell carcinoma cells. In this study, we examined whether cepharanthin-induced inhibition of NF-kappaB activity enhances radiosensitivity in human oral carcinoma cells. Cepharanthin is a biscoclaurine alkaloid extracted from the roots of Stephania cepharantha hayata, and is widely used in Japan for the treatment of patients with leucopenia, nasal allergy, and venomous snakebites. gamma-irradiation (IR) induces NF-kappaB activity in oral carcinoma cells through the activation of upstream molecules, including Akt and IkappaB kinase. However, a luciferase assay revealed that cepharanthin suppresses IR-induced NF-kappaB activity in oral squamous cell carcinoma cells, thereby enhancing the radio-sensitivity. Western blot analysis showed an enhanced cleavage of poly-(ADP-ribose) polymerase protein in carcinoma cells by both cepharanthin treatment and IR exposure compared to IR or cepharanthin alone. In an in vivo study, B88 cells were s.c. inoculated into the backs of nude mice. Tumor-bearing nude mice received either cepharanthin, IR alone, or a combination of cepharanthin and IR. The combined treatment suppressed tumor growth significantly more than either cepharanthin or IR alone. Cepharanthin inhibited the production of IR-induced IL-6 and IL-8, which are downstream targets of NF-kappaB. In quantitative real-time RT-PCR, IR also induced the expression of anti-apoptotic proteins [cellular inhibitor of apoptosis protein (cIAP)-1 and -2] in carcinoma cells. Treatment of cancer cells with cepharanthin combined with exposure to IR decreased cIAP-1 and -2 mRNA expression. These findings suggested that the combination of radiotherapy and cepharanthin could enhance radiosensitivity in the treatment of human oral cancer.


Cepharanthin,a biscoclaurine alkaloid,prevents destruction of acinar tissues in murine Sjogren's syndrome.

Our previous study suggested that suppression by cepharanthin of tumor necrosis factor-a (TNF-a)-induced matrix metalloproteinase-9 (MMP-9) could prevent destruction of the acinar structure in the salivary glands of patients with Sjögren's syndrome (SS). In this study, we observed that in vivo administration of cepharanthin prevented severe damage to acinar tissues in the murine model of human SS. Cepharanthin was intraperitoneally administered to thymectomized female NFS/sld mice. Inflammatory lesions in the salivary and lacrimal glands were then examined histologically. Expression of phosphorylated IkB-a, MMP-9, and type IV collagen was analyzed immunohistochemically. The apoptotic cell death of acinar cells was determined. Although extensive mononuclear cell infiltration and destruction of acinar tissue in salivary and lacrimal glands were observed in control mice, significant improvement of these lesions was evident in mice treated with cepharanthin. Immunohistochemical analysis revealed that p65, phosphorylated IkB-a, and MMP-9 were more strongly stained in the acinar cells of control mice than in cepharanthin-treated mice. Although no staining for type IV collagen was observed in the acinar tissues of control mice, continuity of staining for type IV collagen was observed in acinar tissues of cepharanthin-treated mice. Destruction of acinar tissues was attributed to the induction of apoptosis, suggesting that cepharanthin inhibits apoptosis by suppressing phosphorylation of IkB-a, followed by prevention of MMP-9 activation. Our findings suggest that cepharanthin may be a promising agent for use in preventing destruction of acinar tissues in murine SS.


Enhanced radiosensitization by cepharanthin in human oral squamous carcinoma cells : Inhibition of NF-κB as a molecular target

口腔扁平上皮癌細胞に対するセファランチンによる放射線感受性増強作用 : 分子標的NF-κBの抑制

Journal of The Japanese Stomatological Society


Expression of aquaporin-5 in and fluid secretion from immortalized human salivary gland ductal cells by treatment with 5-aza-2'-deoxycytidine: a possibility for improvement of xerostomia in patients with Sjögren's syndrome.

The aim of the present study was to investigate the possibility that ductal cells, which preferentially survive and/or proliferate in Sjögren's syndrome (SS) salivary glands of patients with SS, could acquire the functional expression of membrane water channel aquaporin-5 (AQP5). Thus, in this study, we demonstrate that an immortalized normal human salivary gland ductal cell (NS-SV-DC) line, lacking the expression of AQP5, acquires AQP5 gene expression in response to treatment with 5-aza-2'-deoxycytidine (5-Aza-CdR), a DNA demethylating agent. Confocal microscopic analysis revealed the localization of AQP5 expression mainly at the apical and lateral sides of the plasma membrane. The expressed AQP5 protein was functionally active because AQP5 expression resulted in a significant increase in the osmotically directed net fluid rate across monolayers of NS-SV-DC cells. By the analysis of bisulfite sequencing of CpG islands in the AQP5 promoter, hypermethylation within the consensus Sp1-binding sites was commonly observed in parental cell clones, whereas demethylation at the CGs, one in the second consensus Sp1 element and the other outside of the third consensus Sp1 element in the AQP5 promoter, was detected in NS-SV-DC cells after treatment with 5-Aza-CdR. By analyzing the luciferase activity of transfected AQP5 promoter vectors, it became evident that demethylation at the CGs cooperatively functions between these two sites to induce AQP5 expression. Our data, therefore, suggest that treatment of ductal cells with 5-Aza-CdR could result in the expression of the AQP5 gene, thereby leading to increased fluid secretion from ductal cells in SS salivary glands.

Laboratory Investigation; a Journal of Technical Methods and Pathology


Enhanced radiosensitization and chemosensitization in NF-κB-suppressed human oral cancer cells via the inhibition of g-irradiation- and 5-FU-induced production of IL-6 and IL-8

We examined the mechanisms underlying the enhancement of radiosensitivity and chemosensitivity to gamma-irradiation (IR) and 5-Fluorouracil (5-FU) in human oral carcinoma cells (B88) in which NF-kappaB activity was constitutively suppressed. Three super-repressor form of IkappaBalpha cDNA-transfected cell (B88mI) clones and 1 empty vector-transfected cell clone (B88neo) have been established. We found that the tumor-forming ability in nude mice of B88mI clones was significantly lower than that of B88 or B88neo. This suppressed ability in tumorigenicity was attributed to the down-regulation of the expression of interleukin (IL)-1alpha, IL-6, IL-8, vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9 in B88mI cell clones as compared to that in B88 or B88neo. IR and 5-FU induced a much greater degree of apoptosis, as evidenced by flow cytometry analysis and annexin V staining, in B88mI cell clones than in B88 or B88neo. When tumor-bearing nude mice were treated with IR or 5-FU, the suppression of tumor growth was significantly augmented in B88mI cell clones as compared to that in B88 or B88neo. ELISA analysis indicated that although a remarkable increase in production of IL-6 and IL-8 was observed in B88 and B88neo after in vitro exposure to IR or treatment with 5-FU, radiotherapy and chemotherapy-induced production of these cytokines was significantly suppressed in B88mI cell clones. These findings suggest that production of angiogenic factors and growth factors in response to radiotherapy and chemotherapy is a principal mechanism of inducible radioresistance and chemoresistance in human oral cancers, and establish the inhibition of NF-kappaB as a rational approach to improve conventional radiotherapy and chemotherapy outcomes.


Cisplatin induces apoptosis in oral squamous carcinoma cells by the mitochondria-mediated but not the NF-kB-suppressed pathway

Cisplatin (CDDP) is a potent DNA-damaging anticancer agent, and its cytotoxic action is exerted by the induction of apoptosis. However, activation of the transcription factor NF-kappaB results in protection against apoptosis. We examined the molecular mechanisms involved in the induction of apoptosis by CDDP as regards both suppression of NF-kappaB and activation of caspases. Human oral squamous carcinoma cells (B88) were employed in this study. We found that CDDP treatment affected neither NF-kappaB activity nor the expression levels of antiapoptotic proteins, including TRAF-1, TRAF-2, and cFLIP, in B88 cells. However, two apoptosome molecules, cytochrome c and Apaf-1, were significantly augmented in the cytoplasm by CDDP treatment. Further, the activation of caspase-9 and caspase-3, downstream molecules leading to mitochondria-mediated apoptosis, were detected after treatment with CDDP. Finally, apoptosis was also clearly observed, as evidenced by cleavage of PARP through the activation of caspase-3. These findings suggest that CDDP exerts its apoptotic action by the mitochondria-mediated activation of caspases but not by the activation of caspases due to the inhibition of NF-kappaB activity that follows the suppression of antiapoptotic proteins.


Suppression of TNF-α-induced MMP 9 production in human salivary gland acinar cells by cepharanthine occurs via down-regulation of NFκB --- A possible therapeutic agent for preventing the destruction of the acinar structure in the salivary glands of Sjögren's syndrome patients

Our previous results suggested that suppression of tumor necrosis factor alpha (TNFalpha)-induced matrix metalloproteinase 9 (MMP-9) could prevent the destruction of acinar tissue in the salivary glands of patients with Sjögren's syndrome (SS). The present study was undertaken to investigate the effect of cepharanthine on the suppression of TNFalpha-induced MMP-9 production in NS-SV-AC, an SV40-immortalized normal human acinar cell clone. After pretreatment with or without cepharanthine, NS-SV-AC cells were treated with TNFalpha alone or with a combination of TNFalpha and cepharanthine. The expression of MMP-9 was then examined at the protein and messenger RNA levels. In addition, the effect of cepharanthine on the morphogenetic behavior of NS-SV-AC cells cultured on type IV collagen-coated dishes in the presence of TNFalpha was examined. Although TNFalpha induced the production of MMP-9 in NS-SV-AC cells, this production was greatly suppressed when cells were pretreated with cepharanthine, followed by treatment with both TNFalpha and cepharanthine. In addition, cepharanthine suppressed the TNFalpha-stimulated NF-kappaB activity by partly preventing the degradation of IkappaBalpha protein in NS-SV-AC cells. When NS-SV-AC cells were seeded on type IV collagen-coated dishes in the presence of both TNFalpha and plasmin, type IV collagen interaction with the cells was lost and the cells entered apoptosis. However, pretreatment with cepharanthine restored the aberrant in vitro morphogenesis of the NS-SV-AC cells. These results may indicate a molecular mechanism by which cepharanthine is able to protect against the destruction of the acinar structure in salivary glands from patients with SS.


Stable inhibition of NF-kB in salivary gland cells does not enhance sensitivity to TNF-a-induced apoptosis due to upregulation of TRAF-1 expression

The transcription factor NF-kappa B inhibits the apoptotic response induced by TNF-alpha. However, in salivary gland cell clones (ACMT-6 and ACMT-7) in which NF-kappa B activation was suppressed by introduction of a super-repressor form of I kappa B-alpha cDNA, TNF-alpha did not cause apoptosis. Thus, to investigate the molecular mechanism involved in the unresponsiveness of these cell clones to TNF-alpha-induced apoptosis, we examined the effect of TNF-alpha on the expression of antiapoptotic proteins, including TNF receptor-associated factor (TRAF)-1, TRAF-2, cellular inhibitor of apoptosis protein (cIAP)-1, and cIAP-2. Here we show that expression of TRAF-1 was commonly detected by treatment with TNF-alpha in ACMT-6, ACMT-7, and an empty vector-transfected cell clone (ACpRc-1) and that downregulation of TRAF-1 protein by either treatment with an antisense oligonucleotide or introduction of an antisense plasmid resulted in the induction of apoptosis in these cell clones. Our results, therefore, suggest that one of the mechanisms by which cells acquire resistance to TNF-alpha-induced apoptosis is a TNF-alpha induction of TRAF-1.


Enhanced IkB kinase activity is responsible for the augmented activity of NF-_B in human head and neck carcinoma cells

The nuclear transcription factor kappaB (NF-kappaB) plays an important role in the development and progression of cancers. However, the mechanism by which cancer cells in the head and neck region acquire high NF-kappaB activity has not yet been clarified. In this study, we examined the NF-kappaB binding activity and the expression of the signal-transduction-related proteins of NF-kappaB in head and neck carcinoma cell lines. These cancer cells showed significantly higher NF-kappaB binding activity than normal oral epithelial and salivary gland cells. We also demonstrated the increased phosphorylation and degradation of IkappaB-alpha protein in cancer cells. Thus, enhanced NF-kappaB activity in cancer cells is attributable to the rapid phosphorylation and degradation of IkappaB-alpha protein. To further elucidate the mechanism involved in this phenomenon, we analyzed both the expression levels of upstream kinases (IkappaB kinase- (IKK-) alpha, IKK-beta, IKK-gamma, and NF-kappaB-inducing kinase (NIK)) and the IKK activity in cells. Although there was no significant difference in the expression levels of NIK, IKK-beta, or IKK-gamma in cancer cell lines compared to those in normal cells, increased expression of IKK-alpha protein was observed in cancer cells. In addition, IKK activity was significantly augmented in cancer cells as compared to normal cells. Thus, our results suggest that enhanced NF-kappaB activity in head and neck cancer cells may be due to the augmentation of IKK activity.


口腔癌細胞への変異型IkB-a遺伝子導入による抗血管新生作用を介した腫瘍増殖抑制効果


Autoantigen-specific CD4+CD28low T cell subset prevents autoimmune exocrinopathy in murine Sjogren's syndrome

Organ-specific autoimmune exocrinopathy resembling Sjögren's syndrome (SS) that spontaneously develops in NFS/sld mutant mice thymectomized 3 day after birth is dependent on Th1-type CD4+ T cells. We previously reported that a cleavage product of 120-kDa alpha-fodrin may be an important autoantigen in the pathogenesis of SS in both an animal model and the patients. We demonstrate that in an animal model of SS with overt exocrinopathy, a unique CD4+ T cell subset expressing CD28low is dramatically increased in spleen cells before the disease onset, but that the CD4+ T cells of diseased mice were virtually all CD28high. We found that the spleen cells in these mice before the disease onset showed a significant increase in autoantigen-specific T cell proliferation. Analysis of in vitro cytokine production by spleen cells indicated, before the disease onset, severely impaired production of IL-2 and IFN-gamma in the animal model, whereas high levels of IL-4 were observed. Expression of cytokine genes, including IL-4, IL-10, and TGF-beta, was detected in FACS-sorted CD4+CD28low T cells by RT-PCR analysis. Transfer of CD4+CD28low T cells into the animal model actually prevented the development of autoimmune lesions including autoantibody production. These results suggest that a CD4+CD28low T cell subset that is continuously activated by an organ-specific autoantigen may play a regulatory role in the development of organ-specific autoimmune disease in an animal model of SS.


Suppression of tumor necrosis factor-a-induced matrix metalloproteinase-9-production by introduction of a super-repressor form of IkB-cDNA into immotalized human salivary gland acinar cells

We have previously shown that specific enhancement in acinar cells of proteolytic activity induced by tumor necrosis factor alpha (TNFalpha) may be responsible for the destruction of the acinar structure in the salivary glands of patients with Sjögren's syndrome. Because matrix metalloproteinase 9 (MMP-9) is regulated by nuclear factor kappaB (NF-kappaB), we investigated the effect of a super-repressor form of inhibitor of nuclear factor kappaBalpha (srIkappaBalpha) on the suppression of TNFalpha-induced MMP-9 production in acinar cells. Two srIkappaBalpha complementary DNA (cDNA)-transfected acinar cell clones (ACMT-6 and ACMT-7) and 1 empty vector-transfected cell clone (ACpRc-1) were established. After treatment of cell clones with TNFalpha, the expression of MMP-9 was examined. In addition, the effect of TNFalpha on cell growth and the morphogenetic behavior of cell clones cultured on type IV collagen-coated dishes were examined. TNFalpha induced the production of MMP-9 in the ACpRc-1 cell clone, but greatly suppressed MMP-9 production in ACMT-6 and ACMT-7 clones. No apparent cytotoxic effect of TNFalpha treatment was observed in these cell clones. When ACpRc-1 cells were seeded on type IV collagen-coated dishes in the presence of both TNFalpha and plasmin, type IV collagen interaction with the cells was lost and the cells entered apoptosis. However, even when ACMT-6 and ACMT-7 cells were cultured under the same culture conditions as those for ACpRc-1, these cell clones attached to the substrate and grew consistently without showing apoptosis. Conclusion. These observations indicate that suppression of TNFalpha-induced MMP-9 production by the introduction of srIkappaBalpha cDNA corrected the aberrant in vitro morphogenesis of acinar cells grown on type IV collagen.


5-Fluorouracil Induces Apoptosis through the Suppression of NF-κB Activity in Human Salivary Gland Cancer Cells

Activation of the transcription factor NF-kappaB results in protection against apoptosis, and the chemotherapeutic agent 5-Fluorouracil (5-FU) exerts its cytotoxic effect through the induction of apoptosis. Thus, we examined whether 5-FU could induce apoptosis through the suppression of NF-kappaB activity. We found that upon treatment of a human salivary gland cancer cell line (cl-1) with 5-FU, the NF-kappaB activity was suppressed in a time-dependent manner. This inhibition was mediated by a prevention of the degradation of the inhibitory IkappaB-alpha protein. In addition, the expression of TRAF-2 and cIAP-1, which are transcriptionally regulated by NF-kappaB and function as anti-apoptotic molecules through the interruption of caspase pathway, was also inhibited by 5-FU. Finally, the activity of caspase-8 and caspase-3 showed a significant increase in response to 5-FU. By flow cytometric analysis, 5-FU did not affect the expression level of Fas on the cell surface. Thus, our results suggest that one of the molecular mechanisms involved in 5-FU-induced apoptosis in cl-1 cells may be due to the suppression of NF-kappaB activity, resulting in the activation of the pro-apoptotic pathway.

Biochemical and Biophysical Research Communications


Treatment with anti-CD86 costimulatory molecule prevents the autoimmune lesions in murine Sjogren's syndrome (SS) through up-regulated Th2 response


Treatment with anti-CD 86 costimulatory molecule prevents the autoimmune lesions in murine Sjogren's syndrome(SS) through up-regulated Th2 response


慢性GVHDにおける口腔粘膜·口唇腺の免疫組織化学的研究

慢性GVHDにおける口腔粘膜·口唇腺の免疫組織化学的研究


Role of cytokines in the destruction of acinar structure in Sjogren's syndrome salivary glands

Laboratory Investigation; a Journal of Technical Methods and Pathology


Therapy for oral squamous cell carcinoma by tegafur and streptococcal agent OK-432 in combination with radiotherapy : Association of the therapeutic effect with differentiation and apoptosis in the cancer cells

Twenty patients with oral squamous cell carcinoma having mainly stage II or III lesions without distant metastasis, were treated with tegafur and streptococcal agent, OK-432, in combination with radiotherapy. As a consequence, 16 cases among the treated 20 cases showed complete remission by this therapy alone. Especially, we have found that the squamous cell carcinoma arising in non-keratinizing oral epithelium rather than in keratinizing oral epithelium has better response to this therapy. Among the 16 cases with complete remission (CR) by the current therapy, 10 cases were histopathologically diagnosed as well-differentiated squamous cell carcinoma and six cases as moderately differentiated squamous cell carcinoma. When we examined immunohistochemically the expression of various antigens such as proliferating cell nuclear antigen (PCNA), p53 and LeY or the presence of DNA fragmentation by nick-end labelling in the biopsy materials taken at the first visit to our clinic from 20 patients treated with the current therapy, the CR group showed a significantly increased LeY expres-sion level ( p< 0.05) and DNA fragmentation rate (p< 0.05) as compared with the partial response (PR, n= 3) + no change (NC, n= 1) group. On the other hand, the CR group with respect to PCNA expression level was significantly decreased as compared with the PR + NC group ( p< 0.05). From these findings, it can be considered that the therapy for oral squamous cell carcinoma by UFT and OK-432 in combination with radiotherapy is very effective, which may be associated with differentiation or apoptosis in oral squamous carcinoma cells. In addition, we present the clinical findings and results of immunohistochemical staining for the biopsy materials obtained from four CR cases treated with the current therapeutic method.


Role of cytokines of acinar structure in Sjogren's syndrome salivary glands


Expression of vasoactive intestinal polypeptide and amylase in a human parotid gland adenocarcinoma cell line in culture

Journal of the National Cancer Institute


Small cell undifferentiated carcinoma of the minor salivary gland containing exocrine, neuroendocrine, and squamous cells


Induction of cells with acinar cell phenotype including presence of intracellular amylase --- Treatment with 12-O-tetradecanoyl-phorbol-13-acetate in a neoplastic human salivary intercalated duct cell line grown in athymic nude mice


The relation of ras oncogene product p21 expression to clinocopathological status criteria and clinical outcome in squamous cell head and neck cancer


Emergence of differentiated subclones from a human salivary adenocarcinoma cell clone in culture after treatment with sodium butyrate


Expression of epidermal growth factor and transforming growth factor-beta in human salivary gland adenocarcinoma cell line


Intermediate-sized filaments and specific markers in a human salivary gland adenocarcinoma cell line and its nude mouse tumors


Interferon Activity and Its Characterization in the Sera of Patients with Head and Neck Cancer


ヒト唾液腺細胞におけるピロカルピン塩酸塩の AQP5 発現に関する研究

ヒト唾液腺細胞におけるピロカルピン塩酸塩の AQP5 発現に関する研究

The Japanese Journal of Tissue Culture Society for Dental Research


徳島大学病院口腔内科-発足前後5年間における外来・入院患者の臨床統計的観察-

徳島大学病院口腔内科-発足前後5年間における外来・入院患者の臨床統計的観察-

Journal of Japanese Society of Oral Medicine


The primary therapy of oral squamous cell carcinoma by UFT and OK-432 in combination with Radiotherapy

口腔扁平上皮癌に対するUFT,OK-432, 放射線治療を併用した一次治療