Yoshihiro Matsukawa, Natsumi Ikumi, Yoshiki Hamada, Noriyuki Seta, Keiko Aota, Masayuki Azuma, Yuh Baba and Satoshi Takada : Internal Medicine for Dental Treatments: Patients with Medical Diseases, --- Immune System Diseases ---, Springer, Jan. 2024.
Kunihiro Otsuka, Hiroyuki Kondo, Shin-ichi Tsukumo, Daisuke Kurotaki, Kei-Ichiro Yasunaga, Aya Ushio, Ruka Nagao, Keiko Aota, Yoshiaki Kitamura, Takaaki Tsunematsu, Hideo Yagita, Naozumi Ishimaru, Junko Morimoto and Koji Yasutomo : A CD4+ T cell-fibroblast crosstalk exacerbates autoimmunity in a mouse model of primary Sjögren disease., Nature Communications, 2026.
(要約)
CD4+ T cells are key drivers of immune-mediated tissue damage and participate in complex cellular interactions that perpetuate chronic inflammation. However, the specific subsets of pathogenic CD4+ T cells and their non-immune cell partners are less well characterized. Here, we use a mouse model of primary Sjögren disease (pSjD) and identify CD153+CD4+ T cells as critical drivers of inflammation during the early stages of autoimmune pathology. We describe a CD153+CD4+ T cell-CD30+ tissue-resident fibroblast interaction that promotes fibroblast proliferation and chemokine secretion, further driving immune cell infiltration and thereby amplifying the autoimmune response. Importantly, deletion of CD153 in CD4+ T cells or neutralization of fibroblast-derived chemokines reduces lymphocytic infiltration and significantly halts autoimmune-like pathology. The CD153-CD30 axis positively correlates with disease severity in human patients. Thus, our results describe a pathogenic, therapeutically targetable CD153+CD4+ T cell-CD30+ fibroblast axis that perpetuates chronic inflammation in pSjD.
Mari Nishida, Kunihiro Otsuka, Ruka Nagao, Shigefumi Matsuzawa, Aya Ushio, Takaaki Tsunematsu, Keiko Aota and Naozumi Ishimaru : Tissue-Specific Expansion of Age-Associated B Cells via IFN-γ and IL-21 Within Salivary Glands in Sjögren Disease., Journal of Immunology Research, 2026, 1, 2026.
(要約)
Sjögren disease (SjD) is an autoimmune disorder that predominantly affects the exocrine glands, and advancing age is recognized as an important risk factor for its development. However, the mechanisms linking age and disease progression remain poorly understood. Age-associated B cells (ABCs), a subset of B cells that increase with age, have been implicated in autoimmune responses, but their role in SjD pathogenesis has not been fully clarified. In this study, we examined labial salivary glands (LSGs) from 44 SjD patients and 11 non-SjD sicca controls. T-bet+ CD20+ ABCs were detected infiltrating the glands in SjD patients, especially in individuals in their 40s-60s, but were rare in non-SjD sicca controls. To investigate the underlying mechanisms, we used a SjD mouse model at various ages. ABCs (CD11b+ CD95+ CD19+) began locally accumulating in the SGs from the mature-adult stage, earlier than in age-matched controls, while remaining low in cervical lymph nodes (cLNs). To explore the drivers of ABC expansion, we examined the factors involved in ABC differentiation, focusing on interleukin-21 (IL-21) and interferon-gamma (IFN-γ). This combination of IL-21 and IFN-γ upregulated T-bet expression on B cells in SjD model mice. In situ hybridization (ISH) and flow cytometric analysis revealed that CD4+ T cells, especially follicular helper T (Tfh)-like cells were a major source of IL-21 in the SGs of mature-adult-SjD mice. Additionally, ABCs themselves showed elevated expression of IFN-γ compared to other immune cells, indicating an autocrine mechanism promoting their expansion. Our findings suggest that ABCs accumulate in the SGs of SjD patients and model mice through IL-21 signaling from CD4+ T cells and autocrine IFN-γ activity. This localized expansion may contribute to autoimmune tissue damage. These results provide new insights into how aging-associated immune changes may drive the development and progression of SjD, offering potential targets for therapeutic intervention.
Hideki Suito, Yuri Oku, Kohichi Kani, Keiko Aota and Naoki Maeda : A Rare Case of Anterior Stafne Bone Cavity in the Mandibular Region, Curēus, 17, 11, e97395, 2025.
(キーワード)
lingual mandibular bone defect / mandibular anterior region / multi-detector computed tomography; / stafne bone cavity / static bone cavity
Seiya Inoue, Masakazu Goto, Satoshi Fujiwara, Takahiro Yoshida, Fuyumi Izaki, Taihei Takeuchi, Hiroyuki Sumitomo, Mariko Aoyama, Hiroaki Toba, Hiromitsu Takizawa, Yasuhiro Hamada, Tetsuya Matsuura, Keiko Aota and Hidenori Takano : Achievements of perioperative assist team medical care in esophageal cancer surgery, Tokushima University Hospital, The Journal of Medical Investigation : JMI, 71, 3,4, 279-285, 2024.
(要約)
Radical esophagectomy is highly invasive and associated with many postoperative complications. A decline in postoperative QOL is a serious issue for patients, and comprehensive perioperative management through multidisciplinary cooperation is necessary. Our institution has established a perioperative assist team (OPERA) to address this need since 2017. This study included 109 patients with esophageal cancer who underwent neoadjuvant chemotherapy and esophagectomy from 2009 to 2018. O group, means OPERA intervention group, included 57 patients, and N group, means Non-OPERA intervention group, included 52 patients. The effects of the OPERA intervention on reducing chemotherapy-related adverse events and improving postoperative outcomes were retrospectively investigated. The OPERA intervention significantly reduced the incidence of chemotherapy-related adverse events (P=0.002). In particular, anorexia and diarrhea, febrile neutropenia were significantly reduced (P<0.001, P=0.002, P=0.025, respectively). Postoperatively, the start date of walking was significantly earlier (P<0.001), the incidence of pneumonia was lower (P=0.022). At the time of postoperative discharge, N group was significantly greater weight loss compared to O group (P=0.002). The 5-year survival rate was longer in O group (P=0.003). The OPERA intervention reduced the incidence of chemotherapy-related adverse events and postoperative complications and helped improved prognosis. J. Med. Invest. 71 : 279-285, August, 2024.
(キーワード)
Humans / Esophageal Neoplasms / 男性 (male) / 女性 (female) / Middle Aged / Aged / Esophagectomy / Retrospective Studies / Hospitals, University / Postoperative Complications / Perioperative Care / Patient Care Team / Neoadjuvant Therapy / 日本 (Japan)
Tetsu Shimane, Kazuyuki Koike, Shigeyuki Fujita, Hiroshi Kurita, Emiko Tanaka Isomura, Daichi Chikazu, Naomi Kanno, Keiichi Sasaki, Satoshi Hino, Hideharu Hibi, Takahiro Koyama, Seiji Nakamura, Takeshi Nomura, Yoshiyuki Mori, Itaru Tojyo, Toshiro Yamamoto, Iku Yamamori, Keiko Aota and Hideki Tanzawa : Positive impact of perioperative oral management on the risk of surgical site infections after abdominal surgery: Sixteen universities in Japan., Medicine, 102, 37, e35066, 2023.
(要約)
Surgical site infections (SSI) are associated with increased morbidity and mortality rates. This study aimed to investigate the ability of perioperative oral management (POM) to reduce the risk of SSI in abdominal surgery Real-world data collected from 16 university hospitals in Japan were reviewed. The medical records of consecutive 2782 patients (1750 men and 1032 women) who underwent abdominal surgery under general anesthesia at 16 university hospitals were retrospectively reviewed. Detailed information about SSI was assessed and compared between patients with and without POM in univariate and multivariate analyses. SSI were observed in 275 patients (incidence rate:9.9%), and POM was administered to 778 patients (28.0%). Univariate analyses revealed that diabetes mellitus, Eastern Cooperative Oncology Group performance status, American Society of Anesthesiologists classification, surgical site, preoperative Prognostic Nutritional Index score, POM, extent of surgery, operation time, and intraoperative blood loss were significantly associated with postoperative SSI (Chi-square or Mann-Whitney U test, P < .01). Multivariate analysis revealed that POM had significant preventive effects against postoperative SSI (estimate: -0.245, standard error: 0.080, P < .01). Surgical site, American Society of Anesthesiologists classification, and operation time were also significant and independent clinical predictors of SSI. The analysis of real-world data from 16 university hospitals revealed that, regardless of the content and degree of the problem, the addition of POM has significant beneficial effects in reducing the risk of SSI in patients who undergo abdominal surgery. Medical records from each hospital and data from the Health Care Payment Fund were collected and analyzed retrospectively.
(キーワード)
Male / Humans / Female / Surgical Wound Infection / Japan / Retrospective Studies / Universities / Hospitals, University
Tetsu Shimane, Kazuyuki Koike, Shigeyuki Fujita, Hiroshi Kurita, Emiko Tanaka Isomura, Daichi Chikazu, Naomi Kanno, Keiichi Sasaki, Satoshi Hino, Hideharu Hibi, Takahiro Koyama, Seiji Nakamura, Takeshi Nomura, Yoshiyuki Mori, Itaru Tojyo, Toshiro Yamamoto, Iku Yamamori, Keiko Aota and Hideki Tanzawa : Positive impact of perioperative oral management on the risk of surgical site infections after abdominal surgery: Sixteen universities in Japan., Medicine, 102, 37, e35066, 2023.
(要約)
Surgical site infections (SSI) are associated with increased morbidity and mortality rates. This study aimed to investigate the ability of perioperative oral management (POM) to reduce the risk of SSI in abdominal surgery Real-world data collected from 16 university hospitals in Japan were reviewed. The medical records of consecutive 2782 patients (1750 men and 1032 women) who underwent abdominal surgery under general anesthesia at 16 university hospitals were retrospectively reviewed. Detailed information about SSI was assessed and compared between patients with and without POM in univariate and multivariate analyses. SSI were observed in 275 patients (incidence rate:9.9%), and POM was administered to 778 patients (28.0%). Univariate analyses revealed that diabetes mellitus, Eastern Cooperative Oncology Group performance status, American Society of Anesthesiologists classification, surgical site, preoperative Prognostic Nutritional Index score, POM, extent of surgery, operation time, and intraoperative blood loss were significantly associated with postoperative SSI (Chi-square or Mann-Whitney U test, P < .01). Multivariate analysis revealed that POM had significant preventive effects against postoperative SSI (estimate: -0.245, standard error: 0.080, P < .01). Surgical site, American Society of Anesthesiologists classification, and operation time were also significant and independent clinical predictors of SSI. The analysis of real-world data from 16 university hospitals revealed that, regardless of the content and degree of the problem, the addition of POM has significant beneficial effects in reducing the risk of SSI in patients who undergo abdominal surgery. Medical records from each hospital and data from the Health Care Payment Fund were collected and analyzed retrospectively.
S Supriya, R Ushikoshi-Nakayama, T Yamazaki, D Omagari, Keiko Aota, H Inoue, N Matsumoto and I Saito : Effects of polyphenols in non-centrifugal cane sugar on saliva secretion: in vitro and in vivo experiments and a randomized controlled trial, Journal of Clinical Biochemistry and Nutrition, 2, 72, 171-182, 2023.
(要約)
This study examined the bioactivities and mechanisms of the non-centrifugal cane sugar polyphenols saponarin, schaftoside, and isoschaftoside in the salivary gland and their effects on salivation. In acute isolated C57BL/6N mouse submandibular gland cells, these polyphenols led to a higher increase in intracellular calcium after stimulation with the muscarinic agonist carbachol. Stimulation of these cells with polyphenols enhanced ATP production, aquaporin-5 translocation to the plasma membrane and eliminated intracellular reactive oxygen species generated by HO. In addition, phosphorylation of endothelial nitric oxide synthase and increased nitric oxide production in vascular endothelial cells were observed. administration of these polyphenols to C57BL/6N male mice resulted in significantly increased blood flow (saponarin, = 0.040; isoschaftoside, = 0.010) and salivation (saponarin, = 0.031). A randomized controlled trial showed that intake of non-centrifugal cane sugar significantly increased saliva secretion compared with placebo ( = 0.003). These data suggest that non-centrifugal cane sugar polyphenols affect several pathways that support salivation and increase saliva secretion by enhancing vasodilation. Hence, non-centrifugal cane sugar polyphenols can be expected to maintain saliva secretion and improve reduced saliva flow.
Fumiya Kano, Noboru Hashimoto, Yao Liu, Linze Xia, Takaaki Nishihara, Wakana Oki, Keita Kawarabayashi, Noriko Mizusawa, Keiko Aota, Takayoshi Sakai, Masayuki Azuma, Hideharu Hibi, Tomonori Iwasaki, Tsutomu Iwamoto, Nobuyasu Horimai and Akihito Yamamoto : Therapeutic benefits of factors derived from stem cells from human exfoliated deciduous teeth for radiation-induced mouse xerostomia, Scientific Reports, 13, 1, 2706-2719, 2023.
(要約)
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.
【Introduction】The survival rate in patients with HIV infection and acquired immunodeficiency syndrome (AIDS) has been improved dramatically due to the advances in anti-HIV drug therapy, while aging-associated complications become a critical issue. The incidence of sudden occurrence of AIDS without prior detection of HIV infection, so called ``Ikinari AIDS'', still remains high. 【Objective】We retrospectively analyzed the incidence and clinical characteristics of HIV/AIDS patients in both Tokushima University Hospital and Tokushima Prefectural Central Hospital. 【Results】Eighty four patients (74 males and 10 females) with a median age of 39 years old (range 16 - 85) were enrolled. Thirty-four patients (40.5%) were diagnosed with ``Ikinari AIDS'' from 2001 to 2020. All 4 patients were diagnosed with ``Ikinari AIDS'' after 2020. AIDS-defining illnesses were diagnosed as follows ; pneumocystis pneumonia in 21 cases, CMV infection in 8 cases and candidiasis in 6 cases. All patients over 60 years old were suffered from AIDS. Other complications included syphilis in 17 cases, hepatitis B infection in 12 and herpes zoster in 7. 【Discussion/Conclusion】In Tokushima, the incidence rate of ``Ikinari AIDS'' appeared to be higher than that of national average. COVID - 19 pandemic hampered the public health care services of awareness-raising activity for HIV infection and telephone consultations about HIV, which may become more lease asymptomatic HIV patients without diagnosis. For early diagnosis of HIV/AIDS, it is becoming more important to share information to make early screening of HIV infection among medical staffs, such as medical doctors, dentists, nurses, pharmacists and MSWs.
Sjögren's syndrome (SS) is a chronic autoimmune disease involving the salivary and lacrimal glands. Expression of interferon (IFN)-related molecules and C-X-C motif chemokine ligand 10 (CXCL10) is upregulated in labial salivary glands (LSGs) of patients with primary SS (pSS). CXCL10 plays a role in SS pathogenesis via immune-cell accumulation. In various inflammatory diseases, including pSS, the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is activated; moreover, in pSS, the JAK/STAT pathway is associated with CXCL10 production in the LSG tissues. Here, we evaluated potential JAK inhibitor, Baricitinib, as therapeutic agents for pSS by analyzing LSGs of patients with pSS and immortalized normal human salivary gland cell lines, namely NS-SV-DC, and NS-SV-AC. Immunohistochemical analysis revealed strong expression of phosphorylated JAK1 and JAK2 in the ductal epithelial cells of LSGs of patients with pSS. Additionally, phosphorylated JAK2 was observed in several immune cells infiltrating around the ductal epithelium. Baricitinib, a selective JAK1/2 inhibitor, significantly inhibited IFN-γ-induced CXCL10 expression as well as CXCL10 protein levels in an immortalized normal human salivary gland ductal cell (NS-SV-DC) line. Additionally, western blotting showed that baricitinib suppressed the IFN-γ-induced phosphorylation of STAT1 and STAT3. In this review, based on these aforementioned fi ndings, we discussed the potential of JAK inhibitors as new therapeutic agents for pSS. JAK inhibitors may be useful in the treatment of patients with pSS.
K Takamatsu, J Tanaka, R Katada, K Azuma, I Takakura, Keiko Aota, T Kamatani, T Shirota, S Inoue and K Mishima : Aging-associated stem/progenitor cell dysfunction in the salivary glands of mice, Experimental Cell Research, 409, 1, 112889, 2022.
(要約)
Although stem cell aging leads to a decline in tissue homeostasis and regenerative capacity, it remains unclear whether salivary gland stem cell function changes during this process. However, the salivary glands are gradually replaced by connective tissue during aging. Here, we show a decline in the stem cell ability of CD133-positive stem/progenitor cells in the salivary glands of aged mice. The CD133-positive cells were isolated from young, adult, and aged mice. The number of CD133-positive cells was significantly decreased in aged mice. They also showed a lower sphere formation capacity compared to young and adult mice. RNA sequencing revealed that CD133-positive cells in aged mice exhibited lower gene expression of several aging-related genes, including FoxO3a, than those in young and adult mice. Salivary gland cells infected with a recombinant lentivirus encoding the FoxO3a gene showed a reduction in oxidative stress induced by hydrogen peroxide compared with those infected with a control virus. Thus, FoxO3a may inhibit stem cell aging via oxidative stress.
【Introduction】Congenital hemophilia is a category of hemorrhagic disease caused by a genetic defect in the production of coagulation factors. It is treated by administering regular coagulation factor injections on an ongoing basis. Hemophilia is a hereditary illness, often causing social and psychological problems as a result of the disease. To analyze the objective effects of hemophilia, we conducted a retrospective analysis in Tokushima University Hospital. 【Result】All 23 cases were men between the ages of20and72. Hemophilia A was present in17cases, and hemophilia B was present in six. Nineteen out of 23 cases were severe, and the others were intermediate. Medical assessments were conducted at pediatrics in seven cases and hematology in 16 cases. Adoption of the self-injection technique was not realized in five cases. Seventeen cases were complicated by hemophilic arthropathy, seven with human immunodeficiency virus(HIV), and 12 with hepatitis C virus. Eight participants were unemployed, and17were unmarried. 【Discussion】 Many adult hemophilia patients still visit pediatrics in our hospital. Hemophilia in the period of growth between adolescence and young adulthood is often accompanied by life-altering events such as entering higher education, marriage, and work experience. Therefore, collaboration among professionals of multiple occupations, such as doctors, nurses, pharmacists, medical social workers, and clinical psychologists, is essential. Furthermore, there are many cases of HIV and hepatitis C virus infections complicating hemophilia study due to the stigma surrounding HIV-tainted blood. 【Conclusion】It is imperative that we establish a long-term, sustainable, and multi-disciplinary transitional care and medical support system for patients and their families.
Shin-ichi Yamada, Kazuyuki Koike, Emiko Isomura Tanaka, Daichi Chikazu, Kenji Yamagata, Masahiro Iikubo, Satoshi Hino, Hideharu Hibi, Kouji Katsura, Seiji Nakamura, Takeshi Nomura, Yoshiyuki Mori, Itaru Tojyo, Narisato Kanamura, Iku Yamamori, Keiko Aota, Shigeyuki Fujita, Hideki Tanzawa and Hiroshi Kurita : The effects of perioperative oral management on perioperative serum albumin levels in patients treated surgically under general anesthesia : A multicenter retrospective analysis in Japan, Medicine, 100, 10, e25119, 2021.
(要約)
The purpose of the present study was to investigate the efficacy of perioperative oral managements (POMs) on perioperative nutritional conditions in patients undergoing surgery with general anesthesia. Medical records were retrospectively reviewed and the effects of POMs were investigated based on a large number of cases using a multicenter analysis. The profile of serum albumin levels was assessed and compared between patients with and without POMs using the multivariate analysis. Seventeen Eleven thousand and one hundred sixty patients (4,873 males and 6,287 females) were reviewed. Of these, 2710 patients (24.3%) had undergone POMs. The results of a multivariate analysis revealed the significant positive effect of POMs on perioperative serum albumin level (change between at admission and discharge, (Estimate: 0.022, standard error: 0.012, P < .0001). Patient gender, age, surgical site, performance status, the American Society of Anesthesiologists (ASA) physical status classification, operation time, amount of blood loss, and serum albumin level at admission were also significant predictors. Adjusted multivariate analysis of the effects of POMs on perioperative change of serum albumin level in all subjects reveled the significance of POMs intervention (estimate: 0.022, standard error: 0.012, P < .0001). These results suggest that POMs exerts significant positive effects on perioperative serum albumin levels in patients underwent surgery under general anesthesia.
(キーワード)
oral care / perioperative oral management / serum albumin / surgery
Shin-Ichi Yamada, Kazuyuki Koike, Tanaka Emiko Isomura, Daichi Chikazu, Kenji Yamagata, Masahiro Iikubo, Satoshi Hino, Hideharu Hibi, Kouji Katsura, Seiji Nakamura, Takeshi Nomura, Yoshiyuki Mori, Itaru Tojyo, Narisato Kanamura, Iku Yamamori, Keiko Aota, Shigeyuki Fujita, Hideki Tanzawa and Hiroshi Kurita : The effects of perioperative oral management on perioperative serum albumin levels in patients treated surgically under general anesthesia: A multicenter retrospective analysis in Japan., Medicine, 100, 10, E25119, 2021.
(要約)
The purpose of the present study was to investigate the efficacy of perioperative oral managements (POMs) on perioperative nutritional conditions in patients undergoing surgery with general anesthesia. Medical records were retrospectively reviewed and the effects of POMs were investigated based on a large number of cases using a multicenter analysis. The profile of serum albumin levels was assessed and compared between patients with and without POMs using the multivariate analysis. Seventeen Eleven thousand and one hundred sixty patients (4,873 males and 6,287 females) were reviewed. Of these, 2710 patients (24.3%) had undergone POMs. The results of a multivariate analysis revealed the significant positive effect of POMs on perioperative serum albumin level (change between at admission and discharge, (Estimate: 0.022, standard error: 0.012, P < .0001). Patient gender, age, surgical site, performance status, the American Society of Anesthesiologists (ASA) physical status classification, operation time, amount of blood loss, and serum albumin level at admission were also significant predictors. Adjusted multivariate analysis of the effects of POMs on perioperative change of serum albumin level in all subjects reveled the significance of POMs intervention (estimate: 0.022, standard error: 0.012, P < .0001). These results suggest that POMs exerts significant positive effects on perioperative serum albumin levels in patients underwent surgery under general anesthesia.
(キーワード)
Adult / Anesthesia, General / Female / Humans / Japan / Male / Middle Aged / Oral Hygiene / Perioperative Care / Perioperative Period / Postoperative Complications / Retrospective Studies / Risk Factors / Serum Albumin, Human / Surgical Procedures, Operative / Treatment Outcome
Keiko Aota, Tomoko Yamanoi, Kohichi Kani, Shinji Ono, Yukihiro Momota and Masayuki Azuma : Inhibition of JAK-STAT Signaling by Baricitinib Reduces Interferon-γ-Induced CXCL10 Production in Human Salivary Gland Ductal Cells., Inflammation, 44, 1, 206-216, 2021.
(要約)
Sjögren's syndrome (SS) is a chronic autoimmune disease targeting salivary and lacrimal glands. C-X-C motif chemokine ligand 10 (CXCL10) expression is upregulated in lip salivary glands (LSGs) of primary SS (pSS) patients, and CXCL10 involved in SS pathogenesis via immune-cell accumulation. Moreover, interferon (IFN)-γ enhances CXCL10 production via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. We investigated the effects of baricitinib, a selective JAK1/2 inhibitor, on both IFN-γ-induced CXCL10 production and immune-cell chemotaxis. We used immunohistochemical staining to determine the expression levels and localization of JAK1 and JAK2 in LSGs of SS patients (n = 12) and healthy controls (n = 3). We then evaluated the effect of baricitinib in an immortalized normal human salivary gland ductal (NS-SV-DC) cell line. Immunohistochemical analysis of LSGs from pSS patients revealed strong JAK1 and JAK2 expression in ductal and acinar cells, respectively. Baricitinib significantly inhibited IFN-γ-induced CXCL10 expression as well as the protein levels in an immortalized human salivary gland ductal-cell clone in a dose-dependent manner. Additionally, western blot analysis showed that baricitinib suppressed the IFN-γ-induced phosphorylation of STAT1 and STAT3, with a stronger effect observed in the case of STAT1. It also inhibited IFN-γ-mediated chemotaxis of Jurkat T cells. These results suggested that baricitinib suppressed IFN-γ-induced CXCL10 expression and attenuated immune-cell chemotaxis by inhibiting JAK/STAT signaling, suggesting its potential as a therapeutic strategy for pSS.
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.
Keiko Aota, Tomoko Yamanoi, Kohichi Kani, Shinji Ono, Yukihiro Momota and Masayuki Azuma : Inhibition of JAK-STAT Signaling by Baricitinib Reduces Interferon- -Induced CXCL10 Production in Human Salivary Gland Ductal Cells, Inflammation, 44, 1, 206-216, 2020.
(要約)
Sj gren's syndrome (SS) is a chronic autoimmune disease targeting salivary and lacrimal glands. C-X-C motif chemokine ligand 10 (CXCL10) expression is upregulated in lip salivary glands (LSGs) of primary SS (pSS) patients, and CXCL10 involved in SS pathogenesis via immune-cell accumulation. Moreover, interferon (IFN)- enhances CXCL10 production via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. We investigated the effects of baricitinib, a selective JAK1/2 inhibitor, on both IFN- -induced CXCL10 production and immune-cell chemotaxis. We used immunohistochemical staining to determine the expression levels and localization of JAK1 and JAK2 in LSGs of SS patients (n=12) and healthy controls (n=3). We then evaluated effect of baricitinib in an immortalized normal human salivary gland ductal (NS-SV-DC) cell line. Immunohistochemical analysis of LSGs from pSS patients revealed strong JAK1 and JAK2 expression in ductal and acinar cells, respectively. Baricitinib significantly inhibited IFN- -induced CXCL10 expression as well as the protein levels in an immortalized human salivary gland ductal-cell clone in a dose-dependent manner. Additionally, western blot analysis showed that baricitinib suppressed the IFN- -induced phosphorylation of STAT1 and STAT3, with a stronger effect observed in case of STAT1. It also inhibited IFN- -mediated chemotaxis of Jurkat T cells. These results suggested that baricitinib suppressed IFN- -induced CXCL10 expression and attenuated immune-cell chemotaxis by inhibiting JAK/STAT signaling, suggesting its potential as a therapeutic strategy for pSS.
Yuriko Goto, Miho Ibi, Hirotaka Sato, Junichi Tanaka, Rika Yasuhara, Keiko Aota, Masayuki Azuma, Toshiyuki Fukada, Kenji Mishima and Tarou Iri : PLAG1 enhances the stemness profiles of acinar cells in normal human salivary glands in a cell type-specific manner, Journal of Oral Biosciences, 62, 1, 99-106, 2020.
(要約)
Objectives: 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 the roles of PLAG1 in the acinar and ductal cells of normal human salivary glands in an attempt to clarify the early events that occur during the histogenesis of salivary gland tumors. Methods: Normal salivary gland cells with acinar- (NS-SV-AC) and ductal- (NS-SV-DC) phenotypes were transfected with PLAG1 plasmid DNA. Subsequently, the PLAG1 overexpressed and mock cells were examined by cell proliferation, transwell migration, and salisphere formation assays. The expression levels of salivary and pluripotent stem cell markers and differentiation markers were evaluated by quantitative real-time polymerase chain reaction and immunofluorescence. Alterations in transcriptional expressions were investigated via cap analysis of gene expression with gene-enrichment and functional annotation analysis. Results: 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. Conclusion: 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.
Yuriko Goto, Miho Ibi, Hirotaka Sato, Junichi Tanaka, Rika Yasuhara, Keiko Aota, Masayuki Azuma, Toshiyuki Fukada, Kenji Mishima and Tarou Irie : PLAG1 enhances the stemness profiles of acinar cells in normal human salivary glands in a cell type-specific manner., Journal of Oral Biosciences, 62, 1, 99-106, 2020.
(要約)
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.
Keiko Aota, Shinji Ono, Tomoko Yamanoi, Kohichi Kani, Yukihiro Momota and Masayuki Azuma : MMP-9 inhibition suppresses interferon-γ-induced CXCL10 production in human salivary gland ductal cells., Inflammation, 42, 6, 2148-2158, 2019.
(要約)
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.
Keiko Aota, Kohichi Kani, Tomoko Yamanoi, Yukihiro Momota, Masami Ninomiya, Hiromichi Yumoto and Masayuki Azuma : Management of tooth extraction in a patient with ELANE gene mutation-induced cyclic neutropenia, Medicine, 98, 39, e17372, 2019.
(要約)
Introduction: 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. Patient concerns: 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/ L). The patient had no history of dental extraction, and her mother also had a history of CyN. Diagnoses: 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). Interventions: 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/ L 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/ L, and the tooth extraction was carried out safely. Outcomes: The postoperative course was uneventful, and the healing process at the extraction site was excellent. Conclusion: 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.
Keiko Aota, Kohichi Kani, Tomoko Yamanoi, Yukihiro Momota, Masami Ninomiya, Hiromichi Yumoto and Masayuki Azuma : Management of tooth extraction in a patient with ELANE gene mutation-induced cyclic neutropenia: A case report., Medicine, 98, 39, e17372, 2019.
(要約)
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.
Keiko Aota, Shinji Ono, Tomoko Yamanoi, Kohichi Kani, Yukihiro Momota and Masayuki Azuma : MMP-9 Inhibition Suppresses Interferon- -Induced CXCL10 Production in Human Salivary Gland Ductal Cells, Inflammation, 42, 6, 2148-2158, 2019.
(要約)
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 up-regulated in primary Sj gren'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)- , whereas that of MMP9 was stimulated by IFN- , tumor necrosis factor- , and interleukin 1 . Remarkably, MMP-9 inhibition in IFN- -stimulated NS-SV-DC cells significantly decreased CXCL10 mRNA and secreted protein levels. Further analyses established that MMP-9 inhibition in IFN- -stimulated NS-SV-DC cells decreased STAT1 phosphorylation and hence suppressed IFN- 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- -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.
Yukihiro Momota, Keiko Aota, Hideyuki Takano, Kohichi Kani and Masayuki Azuma : Concomitant Pregabalin and Tramadol Hydrochloride/Acetaminophen Formulation Relieved Neuropathic Itch of Gingiva: A Case Report., IOSR Journal of Dental and Medical Sciences, 17, 12, 68-71, 2018.
Aya Ushio, Rieko Arakaki, Kunihiro Ohtsuka, Akiko Yamada, Takaaki Tsunematsu, Yasusei Kudo, Keiko Aota, Masayuki Azuma and Naozumi Ishimaru : CCL22-Producing Resident Macrophages Enhance T Cell Response in Sjögren's Syndrome., Frontiers in Immunology, 9, 2594, 2018.
(要約)
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.
Keiko Aota, Kohichi Kani, Tomoko Yamanoi, Koh-ichi Nakashiro, Naozumi Ishimaru and Masayuki Azuma : Distinct Regulation of CXCL10 Production by Cytokines in Human Salivary Gland Ductal and Acinar Cells., Inflammation, 41, 4, 1172-1181, 2018.
(要約)
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.
Keiko Aota, Tomoko Yamanoi, Kohichi Kani, Koh-ichi Nakashiro, Naozumi Ishimaru and Masayuki Azuma : Inverse correlation between the number of CXCR3+ macrophages and the severity of inflammatory lesions in Sjögren's syndrome salivary glands: a pilot study, Journal of Oral Pathology & Medicine, 47, 7, 710-718, 2018.
(要約)
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.
Keiko Aota, Tomoko Yamanoi, Kohichi Kani, Koh-ichi Nakashiro, Naozumi Ishimaru and Masayuki Azuma : Inverse correlation between the number of CXCR3+ macrophages and the severity of inflammatory lesions in Sj gren's syndrome salivary glands : A pilot study, Journal of Oral Pathology & Medicine, 47, 7, 710-718, 2018.
(要約)
Background: Mechanisms underlying immune cells' recruitment and activation into the inflammatory lesions of lip salivary glands (LSGs) from primary Sj gren'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. Methods: We histologically determined the grade of LSG samples from 22 pSS patients 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 macrophage), 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. Results: 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). Conclusions: 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: i.e., 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.
Keiko Aota, Tomoko Yamanoi, Kohichi Kani and Masayuki Azuma : Cepharanthine inhibits IFN--induced CXCL10 by suppressing the JAK2/STAT1 signal pathway in human salivary gland ductal cells, Inflammation, 41, 1, 50-58, 2018.
(要約)
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.
Keiko Aota, Tomoko Yamanoi, Kohichi Kani and Masayuki Azuma : Cepharanthine Inhibits IFN- -Induced CXCL10 by Suppressing the JAK2/STAT1 Signal Pathway in Human Salivary Gland Ductal Cells, Inflammation, 41, 1, 50-58, 2017.
(要約)
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- ] that has been observed in a wide variety of chronic inflammatory disorders and autoimmune conditions) in IFN- -treated human salivary gland cell lines. We observed that IFN- 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- -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- B pathway. Moreover, cepharanthine inhibited the IFN- -mediated chemotaxis of Jurkat T cells. These results suggest that cepharanthine suppresses IFN- -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.
Tomoko Yamanoi, Keiko Aota, Yukihiro Momota and Masayuki Azuma : Treatment with the Biscoclaurine Alkaloid Cepharanthin Significantly Increases Salivary Selection in Primary Sjögren's Syndrome Patients, Journal of Oral Health and Biosciences, 29, 2, 39-48, 2017.
Yukihiro Momota, Hideyuki Takano, Kohichi Kani, Fumihiro Matsumoto, Keiko Aota, Tomoko Yamanoi, 高瀬 奈緒, Yuki Miyamoto, Shinji Ono, Shigemasa Tomioka and Masayuki Azuma : 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, Oral Science in Japan, 2017, 79-82, 2017.
Yukihiro Momota, Hideyuki Takano, Kohichi Kani, Fumihiro Matsumoto, Keiko Aota, Yamanoi Tomoko, Kondo Chika, Takase Nao, Miyamoto Yuki, Shigemasa Tomioka and Masayuki Azuma : Significance of Time-Domain Measurements of Heart Rate Variability in Burning Mouth Syndrome, IOSR Journal of Dental and Medical Sciences, 15, 1, 25-33, 2016.
46.
Fumihiro Matsumoto, Yukihiro Momota, Hideyuki Takano, Keiko Aota, Kohichi Kani, Chika Kondo, Tomoko Yamanoi, Nao Takase, Yuki Miyamoto, Shinji Ono, Yoshiko Yamamura and Hidehiko Hosoki : Severe Posterior Open Bite by Posterior Folding of the Retrodiscal Tissue: A Case Report, IOSR Journal of Dental and Medical Sciences, 14, 10, 27-31, 2015.
(キーワード)
Magnetic resonance image / Posterior folding of the retrodiscal tissue / Posterior open bite / Pumping manipulation technique / Temporomandibular joint
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．
(キーワード)
一次性舌痛症 / 健康関連QOL / SF-36v2 / primary glossodynia / health-related quality of life / MOS 36-item short-from health survey version 2
Yukihiro Momota, Hideyuki Takano, Kohichi Kani, Fumihiro Matsumoto, Keiko Aota, Tomoko Yamanoi, Chika Kondo, Nao Takase, Yuki Miyamoto, Shigemasa Tomioka and Masayuki Azuma : 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, IOSR Journal of Dental and Medical Sciences, 14, 6, 39-43, 2015.
Hideyuki Takano, Yukihiro Momota, Kohichi Kani, Keiko Aota, Yoshiko Yamamura, Yamanoi Tomoko and Masayuki Azuma : γ-tocotrienol prevents 5-FU-induced reactive oxygen species production in human oral keratinocytes through the stabilization of 5-FU-induced activation of Nrf2, International Journal of Oncology, 46, 4, 1453-1460, 2015.
(要約)
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.
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．
Yukihiro Momota, Kohichi Kani, Hideyuki Takano, Fumihiro Matsumoto, Keiko Aota, Daisuke Takegawa, Yamanoi Tomoko, Kondo Chika, Shigemasa Tomioka and Masayuki Azuma : High-Wattage Pulsed Irradiation of Linearly Polarized Near-Infrared Light to Stellate Ganglion Area for Burning Mouth Syndrome, Case Reports in Dentistry, 2014.
(要約)
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.
Keiko Aota and Masayuki Azuma : Targeting TNF- suppresses the production of MMP-9 in human salivary gland cells, Archives of Oral Biology, 58, 12, 1761-1768, 2013.
(要約)
Objective: Tumor 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 Sj gren 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. Materials and Methods: 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. Results: 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. Conclusions: 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.
Keiko Aota and Masayuki Azuma : Targeting TNF- suppresses the production of MMP-9 in human salivary gland cells., Archives of Oral Biology, 58, 12, 1761-1768, 2013.
(要約)
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.
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. <br>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. <br>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. <br>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.
Yukihiro Momota, Hideyuki Takano, Kohichi Kani, Fumihiro Matsumoto, Katsumi Motegi, Keiko Aota, Yoshiko Yamamura, Mayuko Omori, Shigemasa Tomioka and Masayuki Azuma : Frequency analysis of heart rate variability: a useful assessment tool of linearly polarized near-infrared irradiation to stellate ganglion area for burning mouth syndrome., Pain Medicine, 14, 3, 351-357, 2013.
(要約)
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.
(キーワード)
Adult / Aged / Aged, 80 and over / Autonomic Nervous System Diseases / Burning Mouth Syndrome / Female / Heart Rate / Humans / Male / Middle Aged / Stellate Ganglion / Treatment Outcome
Kohichi Kani, Yukihiro Momota, Michito Harada, Yoshiko Yamamura, Keiko Aota, Tomoko Yamanoi, Hideyuki Takano, Katsumi Motegi and Masayuki Azuma : 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., International Journal of Oncology, 42, 1, 75-82, 2013.
(要約)
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.
Yoshiko Yamamura, Katsumi Motegi, Kohichi Kani, Hideyuki Takano, Yukihiro Momota, Keiko Aota, Tomoko Yamanoi and Masayuki Azuma : TNF-a inhibits aquaporin 5 expression in human salivary gland acinar cells via suppression of histone H4 acetylation., Journal of Cellular and Molecular Medicine, 16, 8, 1766-1775, 2012.
(要約)
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.
Yoshiko Yamamura, Keiko Aota, T Yamanoi, Kohichi Kani, H Takano, Yukihiro Momota, Katsumi Motegi and Masayuki Azuma : DNA demethylating agent decitabine increases AQP5 expression and restores salivary function., Journal of Dental Research, 91, 6, 612-617, 2012.
(要約)
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.
Generalized herpes zoster with widely disseminated cutaneous lesions is caused by varicella-zoster virus (VZV) viremia. We report on a patient who received treatment for recurrent gingival cancer of the maxilla and had generalized herpes zoster with Ramsay Hunt syndrome.<br> A 59-year-old woman was given a diagnosis of upper gingival cancer (T3N1M0) and underwent partial maxillectomy and total neck dissection on the left side. Although a recurrent tumor was treated with chemoradiation and boron neutron capture therapy, it extended into the ethmoidal sinus and the parapharyngeal space. She had a fever of 38.5 C while she stayed at home for a while, and disseminated skin eruption appeared 3 days later. After another 3 days, herpes zoster around the pinna, facial paralysis, and hearing difficulty developed.<br> She had not recently contacted patients with VZV infection, and had antibodies against VZV at the onset of the skin lesions. VZV antigen was also demonstrated in a specimen of the skin lesions. Generalized herpes zoster and Ramsay Hunt syndrome were diagnosed. She was treated with acyclovir and -globulin and recovered without complications.
Hiroyuki Nakano, Tetsuei Miki, Keiko Aota, Tetsuro Sumi, Ken Matsumoto and Yoshiaki Yura : Garré's Osteomyelitis of the Mandible Caused by an Infected Wisdom Tooth, Oral Science International, 5, 2, 150-154, 2008.
(キーワード)
Garré's Osteomyelitis / mandible / tooth-germ of a wisdom tooth
Oral malignant melanomas were clinically studied in 10 patients treated at the Department of Oral and Maxillofacial Surgery If, Osaka University Graduate School of Dentistry, and the Departments of Dentistry and Oral Surgery, of Tenri Hospital and of Higashiosaka City General Hospital from 1987 through 2003.<BR>The subjects were 9 men and 1 woman aged from 43 to 82 years. The tumor location was the maxillary gingiva in 5 patients, the hard palatein 2, the lower gingiva in 2, and the buccal mucosa in 1. Two patients were in Stage I, 7 in Stage II, and 1 in Stage III. As for the histological invasion grade, 1 patient was in Level I, 3 in Level II, and 4 in Level III. Tumors were removed surgically in 8 patients, 6 of whom received chemotherapy after operation. The other 2 patients received either carbon ion radiotherapy or chemotherapy alone.<BR>Six patients died of distant metastasis. Distant metastasis occurred frequently in patients with deeply infiltrating tumors and/or multiple cervical metastatic lymph nodes. The histological invasion level and the number of metastatic regional lymph nodes may be useful for predicting the outcomes of patients with oral malignant melanoma.
(キーワード)
malignant melanoma / oral region / 謔ェ諤ァ鮟定牡閻ォ / 蜿」閻秘�伜沺
Fumi Ogawa, Hiroo Takaoka, Soichi Iwai, Keiko Aota and Yoshiaki Yura : Combined oncolytic virotherapy with herpes simplex virus for oral squamous cell carcinoma, Anticancer Research, 28, 6 A, 3637-3645, 2008.
(要約)
The effect of dual infection with herpes simplex virus type 1 (HSV-1) mutants on human oral squamous cell carcinoma (SCC) cells was examined. Human oral SCC cells were infected with gamma1(34.5) gene-deficient HSV-1 R849 and HSV-1 HF that has multiple mutations and induces cell fusion. Cell viability was measured by LDH release assay. Athymic mice were injected with oral SCC cells into the buccal region to induce subcutaneous tumors. Oral SCC cells were infected with R849, followed by infection with R849 or HF. Virus production was elevated by both strains of HSV-1. Although the release of LDH from R849-infected cells was increased by secondary infection with R849 or HF, the effect of HF was more remarkable. When nude mouse tumors were treated with R849, HF, R849+R849, or R849+HF, treatment with R849+HF was the most effective. These results suggest that fusion-inducing virus HF enhances the oncolytic ability of gamma1(34.5) gene-deficient HSV-1 and provides a rationale for using fusogenic viruses as enhancing agents
Masayuki Azuma, Keiko Aota, Tetsuya Tamatani, Katsumi Motegi, Tsuyoshi Yamashita, Yuki Ashida, Yoshio Hayashi and Mitsunobu Sato : Suppression of tumor necrosis factor α-induced matrix metalloproteinase 9 production in human salivary gland acinar cells by cepharanthine occurs via down-regulation of nuclear factor κB: A possible therapeutic agent for preventing the destruction of the acinar structure in the salivary glands of Sjögren's syndrome patients, Arthritis and Rheumatism, 46, 6, 1585-1594, 2002.
(要約)
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.
Keiko Aota, Masayuki Azuma, Tetsuya Tamatani, Tsuyoshi Yamashita, Yuki Ashida and Mitsunobu Sato : Stable inhibition of NF-κB in salivary gland cells does not enhance sensitivity to TNF-α-induced apoptosis due to upregulation of TRAF-1 expression, Experimental Cell Research, 276, 1, 111-119, 2002.
(要約)
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.
Tetsuya Tamatani, Masayuki Azuma, Keiko Aota, Tsuyoshi Yamashita, Takashi Bando and Mitsunobu Sato : Enhanced IκB kinase activity is responsible for the augmented activity of NF-κB in human head and neck carcinoma cells, Cancer Letters, 171, 2, 165-172, 2001.
(要約)
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.
(キーワード)
Head and neck carcinoma / IκB-α / IκB-α kinase / NF-κB
M. Azuma, T. Yamashita, Keiko Aota, T. Tamatani and M. Sato : 5-Fluorouracil suppression of NF-kappa;B is mediated by the inhibition of Ikappa;B kinase activity in human salivary gland cancer cells, Biochemical and Biophysical Research Communications, 282, 1, 292-296, 2001.
(要約)
We have recently shown that 5-Fluorouracil (5-FU) suppresses the transcription factor NF-kappaB in human salivary gland cancer cells (cl-1) by mediating upregulation of IkappaB-alpha expression. However, the precise mechanism involved in this action has not yet been elucidated. IkappaB kinases (IKK-alpha and IKK-beta) are the key components of the IKK complex that mediates activation of NF-kappaB in response to external stimuli such as cytokines. In addition, NF-kappaB-inducing kinase (NIK) and mitogen-activated protein kinase kinase kinase 1 (MEKK-1), both of which are the upstream kinases for the IKKs, interact with and activate the IKKs. Thus, we investigated the molecular mechanisms involved in the suppression of NF-kappaB by 5-FU. Although 5-FU did not affect the expression levels of IKKs, NIK, or MEKK-1, IKK activity in cl-1 cells was suppressed at both 6 h and 12 h after treatment with 2 microgram/ml 5-FU. Moreover, when cells were treated with various concentrations of 5-FU for 12 h, the concentration of 2 microgram/ml efficiently inhibited the IKK activity as compared to 1, 5, or 10 microgram/ml. The expression of Fas-associated death domain-like interleukin 1-converting enzyme-inhibitory protein (FLIP), which acts as an inhibitor of an initiator caspase (caspase-8), was down-regulated by 5-FU treatment in cl-1 cells. Apoptosis, as evidenced by cleavage of poly(ADP-ribose) polymerase through the action of an executioner caspase (caspase-3), was also clearly observed. Thus, these results suggest that 5-FU induction of apoptosis in cl-1 cells may be mediated by suppression of NF-kappaB via inhibition of IKK activity.
K. Motegi, M. Azuma, Keiko Aota, T. Yamashita, T. Tamatani, K. Harada, H. Yoshida and M. Sato : Effect of a mutant form of IκB-α on 5-fluorouracil-induced apoptosis in transformed human salivary gland cells, Oral Oncology, 37, 2, 185-192, 2001.
(要約)
Increasing evidence indicates that transcription factor NF-kappaB may play a role in cell survival, and that some chemotherapeutic agents activate NF-kappaB, while inhibition of NF-kappaB renders cells sensitive to these drugs. 5-Fluorouracil (5-FU) exerts its cytotoxic effect through the induction of apoptosis. However, it still remains uncertain whether 5-FU treatment in combination with the inhibition of NF-kappaB largely exerts an anti-proliferative effect on the growth of neoplastic human salivary gland cells. Thus, we investigated whether NF-kappaB suppression in transformed human salivary gland (NS-SV-AC) cells leads to a marked reduction in cell growth in response to 5-FU treatment. Our results demonstrated that under unstimulated conditions, the ability of cell growth in the super-repressor form of IkappaB-alpha (srIkappaB-alpha) cDNA-transfected cell clones (ACMT-6 and -7) was significantly lower than that in the empty vector-transfected cell clone (ACpRc-1). In addition, the growth inhibition caused by 5-FU was greatly enhanced in ACMT-6 and -7 as compared to ACpRc-1. Based on fractional inhibition analysis, this growth inhibition was due to an additive effect of both inhibitors. Electrophoretic mobility shift assay revealed that NF-kappaB activity in these cell clones was not affected by treatment with 5-FU. Accordingly, our data provide evidence that the combination of 5-FU and NF-kappaB suppression cooperatively functions in the growth inhibition of NS-SV-AC cells.
Masayuki Azuma, Keiko Aota, Tetsuya Tamatani, Katsumi Motegi, Tsuyoshi Yamashita, Kouji Harada, Yoshio Hayashi and Mitsunobu Sato : Suppression of tumor necrosis factor α-induced matrix metalloproteinase 9 production by the introduction of a super-repressor form of inhibitor of nuclear factor κBα complementary DNA into immortalized human salivary gland acinar cells: Prevention of the destruction of the acinar structure in sjogren's syndrome salivary glands, Arthritis and Rheumatism, 43, 8, 1756-1767, 2000.
(要約)
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.
Keiko Aota, Masayuki Azuma, Tsuyoshi Yamashita, Tetsuya Tamatani, Katsumi Motegi, Naozumi Ishimaru, Yoshio Hayashi and Mitsunobu Sato : 5-fluorouracil induces apoptosis through the suppression of NF-κB activity in human salivary gland cancer cells, Biochemical and Biophysical Research Communications, 273, 3, 1168-1174, 2000.
(要約)
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.
Masayuki Azuma, Katsumi Motegi, Keiko Aota, Tsuyoshi Yamashita, Hideo Yoshida and Mitsunobu Sato : TGF-β1 inhibits NF-κB activity through induction of IκB-α expression in human salivary gland cells: A possible mechanism of growth suppression by TGF-β1, Experimental Cell Research, 250, 1, 213-222, 1999.
(要約)
Transforming growth factor (TGF)-beta is the prototype of a large superfamily of signaling molecules involved in the inhibition of proliferation of multiple epithelial cell types. Although accumulated evidence indicates the mechanisms of the antimitogenic effect of TGF-beta in a variety of cell types, the signal transduction mechanism underlying the regulation of NF-kappaB transcription factor by TGF-beta is largely unknown. Because NF-kappaB is not only involved in inflammatory responses but also mediates cell growth, we have investigated the effect of TGF-beta1 on the activity of NF-kappaB and the role of the inhibitory IkappaB-alpha protein in the growth of the human salivary gland cell clones NS-SV-AC, HSGc, and cl-1. NF-kappaB, which is usually maintained in an inactive state by protein-protein interaction with IkappaB, was found to be constitutively active in salivary gland cell lines. Upon treatment of cell clones with TGF-beta1, the NF-kappaB activity in NS-SV-AC and HSGc, but not in cl-1, which lacks the expression of TGF-beta type II receptor, was suppressed. In NS-SV-AC and HSGc, this inhibition was mediated by the induction of IkappaB-alpha at the mRNA and protein levels. The blocking of NF-kappaB subunit with a specific antisense oligonucleotide reduced the growth rate of all of the cell clones, including cl-1. Introduction of a mutated form of IkappaB-alpha cDNA into NS-SV-AC suppressed the growth rate of this cell clone. These results indicate that TGF-beta1 downregulates NF-kappaB activity through the induction of IkappaB-alpha expression in human salivary gland cells and that inhibition of NF-kappaB activity suppresses the growth rate of these cells.
Masayuki Azuma, Katsumi Motegi, Keiko Aota, Yoshio Hayashi and Mitsunobu Sato : Role of cytokines in the destruction of acinar structure in Sjogren's syndrome salivary glands, Laboratory Investigation; a Journal of Technical Methods and Pathology, 77, 3, 269-280, 1997.
(要約)
Our aim in the present study was to understand the mechanism whereby specific destruction of acinar but not ductal structure occurs in salivary glands in Sjögren's syndrome (SS). Thus, we examined the effects of cytokines including TNF-alpha and IL-1 beta on the proteolytic activity of cultured normal human salivary gland cell clones, because degradation of the basement membrane by proteolytic enzymes leads to the disruption of acinar or ductal structure in salivary glands. Simian virus 40 (SV40)-immortalized normal human salivary gland cell clones with ductal (NS-SV-DC) or acinar (NS-SV-AC) phenotype were treated either with TNF-alpha or IL-1 beta alone or with a combination of both, and then proteolytic activity was examined. Although cytokine-treated NS-SV-AC demonstrated high matrix metalloproteinase-2 (MMP-2) activity at both protein and mRNA levels, no remarkable increase in MMP-2 activity was detected in NS-SV-DC. Expression of tissue inhibitor of metalloproteinase-2 (TIMP-2), a specific inhibitor of MMP-2, was similarly inhibited by cytokines in these cell clones. Thus, the net balance estimated by MMP-2/TIMP-2 suggested enhanced proteolysis in cytokine-treated NS-SV-AC and, to a much lesser extent, in NS-SV-DC. To examine whether enhanced expression of MMP-2 occurred in acinar cells of SS salivary glands, we carried out an immunohistochemical study using SS salivary gland tissues. This study indicated that acinar cells adjacent to the lymphocytic infiltrate exhibited enhanced expression of MMP-2 compared with those distant from infiltrated lymphocytes or with those in normal salivary glands. By Northern blot analysis, NS-SV-DC and NS-SV-AC expressed receptor mRNA for both cytokines. The signal-dependent activation of the transcription factor NF-kappa B was observed only in NS-SV-AC. I kappa B-alpha, a specific inhibitor of NF-kappa B, was down-regulated by treatment with cytokines in NS-SV-AC. However, the expression of I kappa B-alpha protein was not detected in NS-SV-DC at the basal level. Treatment of NS-SV-AC with calpain inhibitor-I restored the expression of I kappa B-alpha protein in cytokine-treated cells, thus leading to the inhibition of NF-kappa B activation. Reverse transcriptase-PCR analysis confirmed that there was a marked reduction in I kappa B-alpha mRNA expression in NS-SV-DC as compared to that in NS-SV-AC. As such, it seems likely that there is a relationship between the activation of MMP-2 and the activity of NF-kappa B, and that the NF-kappa B/I kappa B-alpha complex is not a signal mediator involved in cytokine-induced suppression of TIMP-2. These observations, therefore, indicate that the divergent response to cytokines in each constituent cell of salivary gland may result in the histopathologic manifestation of SS.
Keiko Aota : Medical and Oral Care in the 21st Century by the Department of Oral Medicine, --- A novel Therapeutic Strategy for Dry Mouth on the Basis of Molecular Mechanisms Involved in the Onset of the Disease ---, Journal of Oral Health and Biosciences, 36, 2, 13-21, 2024.
(要約)
Japan became a super-aging society in 2007, and the aging rate is expected to increase further. This rapid aging of the population has impacted the structure of disease. In terms of oral health, this has resulted in an urgent need to shift from conventional ``curative treatment'', which focuses on restoring dental morphology, to ``curative and supportive treatment'', which focuses on restoring oral function in elderly and diseased patients. Diseases treated by the Department of Oral Medicine include oral mucosal diseases, salivary gland diseases (such as dry mouth), inflammatory diseases, neurological diseases, oral psychosomatic disorders, and taste disorders, among others. As many oral diseases are related to systemic diseases, the Department of Oral Medicine is a dental field adjacent to medical science. Therefore, the Department of Oral Medicine is responsible for perioperative oral function management and oral screening prior to the introduction of bone-modifying drugs in collaboration with medical doctors, and it also plays an important role in developing oral management plans according to the patient's disease and condition. The importance of the Department of Oral Medicine will continue to increase further. This review article focuses on dry mouth, a rising issue in the super-aging society, and describes research on developing novel treatments for Sjögren's syndrome (SS). C-X-C motif chemokine ligand 10 (CXCL10) is overexpressed in the labial salivary glands (LSGs) of patients with primary SS (pSS). Studies using human salivary gland cells have demonstrated that CXCL10 is secreted via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway through interferon-γ stimulation in ductal cells. The potential of JAK inhibitors as therapeutic agents for pSS was evaluated by analyzing the LSGs of patients with pSS and immortalized normal human salivary gland cell lines. The results suggested that JAK inhibitors may be effective for treating dry mouth in patients with pSS. Treating dry mouth may improve the quality of life and contribute to a long and healthy life.
Keiko Aota : Medical and Oral Care in the 21st Century by the Department of Oral Medicine : A novel Therapeutic Strategy for Dry Mouth on the Basis of Molecular Mechanisms Involved in the Onset of the Disease, Journal of Oral Health and Biosciences, 36, 2, 13-21, Mar. 2024.
(要約)
Japan became a super-aging society in 2007, and the aging rate is expected to increase further. This rapid aging of the population has impacted the structure of disease. In terms of oral health, this has resulted in an urgent need to shift from conventional urative treatment , which focuses on restoring dental morphology, to urative and supportive treatment , which focuses on restoring oral function in elderly and diseased patients. Diseases treated by the Department of Oral Medicine include oral mucosal diseases, salivary gland diseases (such as dry mouth), inflammatory diseases, neurological diseases, oral psychosomatic disorders, and taste disorders, among others. As many oral diseases are related to systemic diseases, the Department of Oral Medicine is a dental field adjacent to medical science. Therefore, the Department of Oral Medicine is responsible for perioperative oral function management and oral screening prior to the introduction of bone-modifying drugs in collaboration with medical doctors, and it also plays an important role in developing oral management plans according to the patient's disease and condition. The importance of the Department of Oral Medicine will continue to increase further. This review article focuses on dry mouth, a rising issue in the super-aging society, and describes research on developing novel treatments for Sj gren's syndrome (SS). C-X-C motif chemokine ligand 10 (CXCL10) is overexpressed in the labial salivary glands (LSGs) of patients with primary SS (pSS). Studies using human salivary gland cells have demonstrated that CXCL10 is secreted via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway through interferon- stimulation in ductal cells. The potential of JAK inhibitors as therapeutic agents for pSS was evaluated by analyzing the LSGs of patients with pSS and immortalized normal human salivary gland cell lines. The results suggested that JAK inhibitors may be effective for treating dry mouth in patients with pSS. Treating dry mouth may improve the quality of life and contribute to a long and healthy life.
(キーワード)
Department of Oral Medicine / Medical and oral care / dry mouth / Sjテカgren's syndrome
We report about general anesthesia for disabled patients with special needs or young children during dental treatment in Tokushima University Hospital. We have administered ambulatory anesthesia or general anesthesia with short-term hospitalization for the patients. In this report, we showed anesthesia as a behavior management technique and the system for the patients who schedule ambulatory anesthesia in our hospital. We indicated the present situation of dental treatment under general anesthesia and supposed the prospects of dental care for the patients with special needs.
Keiko Aota, Hiroaki Tawara, Mari Nishida, Shinji Ono, Hiroaki Hochi, Kohichi Kani, Yukihiro Momota, Makoto Fukui, Daisuke Hinode and Fumihiko Tsushima : Effect of Perioperative Oral Management on Postoperative Pneumonia: A 16-Year Longitudinal and Department-Specific Analysis, The 6th Annual Meeting of the International Society of Oral Care, Matsumoto, May 2026.
2.
Hideyuki Takano, Makoto Fukui, Natsumi Fujiwara, Yukihiro Momota and Keiko Aota : The usefulness of non-face-to-face clinical practice using smart glasses in dental hygiene student education, The 3rd annual meeting of the International Society of Oral Care, Apr. 2023.
3.
Keiko Aota, Tsuruta Mai, Okamoto Tomomi, Masugi Sachie, Shinji Ono, Kanakawa Hiroko, Hideyuki Takano, Makoto Fukui and Daisuke Hinode : Factors associated with the development of oral mucositis in pharyngeal cancer patients receiving chemoradiotherapy, The 3rd Annual Meeting of the International Society of Oral Care, Apr. 2023.
4.
Keiko Aota : Clinical characteristics of five cases of oral cancer detected by perioperative oral management, The Second Annual Meeting of the International Society of Oral Care, Apr. 2022.
(キーワード)
perioperative oral management / oral cancer
5.
Yukihiro Momota, Hideyuki Takano, Kohichi Kani, Fumihiro Matsumoto, Keiko Aota, N Takase, Hiroko Kanagawa, Tomoko Yamanoi, Yuki Miyamoto, Shigemasa Tomioka and Masayuki Azuma : Intractable Stomatitis Well-Treated with Kampo Medicines: A Case Series, The 13th Asian Congress on Oral and Maxillofacial Surgery, Taipei, Nov. 2018.
6.
Yukihiro Momota, Hideyuki Takano, Kohichi Kani, Fumihiro Matsumoto, Keiko Aota, Tomoko Yamanoi, 高瀬 奈緒, 宮本 由貴, Shinji Ono and Masayuki Azuma : 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, 23rd International Conference on Oral and Maxillofacial Surgery, Hong Kong, Mar. 2017.
Yoshiko Yamamura, Katsumi Motegi, Yukihiro Momota, Keiko Aota, Hideyuki Takano, Kohichi Kani and Masayuki Azuma : A mechanism underlying the constitutive expression of AQP5 in human salivary gland acinar cells, 21st International canference on oral and maxillofacial surgery, Barcelona, Oct. 2013.
10.
Keiko Aota, Yoshiko Yamamura, Mayuko Omori and Masayuki Azuma : Effectiveness of professional oral care for the improvement of oral hygiene in patients with psychiatry neurology., Asean Plus and Tokushima Joint International Conference, Indonesia, Dec. 2012.
11.
Yoshiko Yamamura, Katsumi Motegi, Keiko Aota, Tomoko Yamanoi, Yukihiro Momota and Masayuki Azuma : Mechanism involved in the constitutive expression of AQP5 in human salivary gland acinar cells., Asean Plus and Tokushima Joint International Conference, Indnesia, Dec. 2012.
12.
Yoshiko Yamamura, Keiko Aota, Katsumi Motegi, T Yamanoi, Yukihiro Momota, Hideyuki Takano, Kohichi Kani and Masayuki Azuma : Augmented Expression of Aquaporin 5 in Aging Mice, The 2nd International Joint Symposium on Oral and Dental Sciences in Conjunction with Dental Specialists Seminar, Indonesia, Mar. 2012.
13.
Masayuki Azuma, Katsumi Motegi, Yoshiko Yamamura, Kohichi Kani, Hideyuki Takano, Yukihiro Momota, Keiko Aota and T Yamanoi : TNF-a inhibits aquaporin 5 expression in human salivary gland acinar cells via suppression of histone H4 acetylation., Autoimmunity Congress Asia, 1, 1, 1-5, Singapore, Nov. 2011.