Keiko Aota's research while affiliated with The University of Tokushima and other places

Aim Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease that affects exocrine glands. CXCL10 production from salivary gland ductal cells via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway has been suggested to be involved in glandular inflammation in pSS. We aimed to investigate JAK1, JAK2, phosphorylated JAK1, and phosphorylated JAK2 expression in labial salivary gland (LSG) tissues from patients with pSS to evaluate the potential of JAK inhibitors as therapeutic agents for pSS. Methods Immunohistochemical analysis was performed using LSG tissues of patients with pSS (n = 10), non‐SS patients (n = 5), and healthy controls (n = 5). The LSG sections were scored to determine the expression levels of JAK1, JAK2, phosphorylated JAK1, and phosphorylated JAK2 in the ductal and acinar epithelium. Results In acinar epithelial cells of LSG tissues, JAK1, JAK2, and phosphorylated JAK1 expression was significantly lower in patients with pSS than in the controls. Significantly high expression of phosphorylated JAK1 and phosphorylated JAK2 was observed in the ductal epithelial cells of patients with pSS. However, there was no significant association between phosphorylated JAK1 or JAK2 expression levels and inflammation degree. Furthermore, immunofluorescence analysis revealed JAK2 phosphorylation in many CD3 ⁺ T cells infiltrating the LSG tissues. Conclusions The results suggest JAK2 activation in both ductal epithelial cells and infiltrating CD3 ⁺ T cells in LSG tissues of patients with pSS. JAK inhibitors may be effective therapeutic agents for pSS by regulating both chemokine production from salivary gland cells and effector T cell activation.

Patients with immune system diseases, such as Rheumatoid arthritis (RA), collagen disease and allergic disease, often develop oral lesions and visit the dentist. Some oral lesions may be complications of the disease itself, or others may be caused by drugs used to treat the disease. Oral lesions may also lead to the diagnosis of immune system diseases. Therefore, dentists need to acquire knowledge of diagnosis and treatment of these diseases that possibly cause oral lesions. In this chapter, we explain RA, collagen diseases including Systemic lupus erythematosus, Systemic sclerosis, Polymyositis/Dermatomyositis. Sjögren’s syndrome, Mikulicz’s disease and Behçet’s disease, and allergic disease.

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.

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.

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 H2O2. In addition, phosphorylation of endothelial nitric oxide synthase and increased nitric oxide production in vascular endothelial cells were observed. In vivo administration of these polyphenols to C57BL/6N male mice resulted in significantly increased blood flow (saponarin, p = 0.040; isoschaftoside, p = 0.010) and salivation (saponarin, p = 0.031). A randomized controlled trial showed that intake of non-centrifugal cane sugar significantly increased saliva secretion compared with placebo (p = 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.

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease that affects exocrine glands, such as salivary and lacrimal glands. The Janus kinase (JAK) /signal transducer and activator of transcription (STAT) pathway are activated in various inflammatory diseases including pSS. This study aimed to investigate the expression of JAK1, JAK2, phosphorylated JAK1, and phosphorylated JAK2 in labial salivary gland (LSG) tissues from patients with pSS to evaluate the potential of JAK inhibitors as therapeutic agents for pSS. Immunohistochemical analysis was performed using LSG tissues of patients with pSS (n=10), non-SS (n=5), and healthy controls (n=5). In acinar epithelial cells, JAK1, JAK2, and phosphorylated JAK1 were expressed at significantly lower levels in LSG tissues of patients with pSS than in healthy controls. Significantly higher expression of phosphorylated JAK1 and phosphorylated JAK2 was observed in the ductal epithelial cells of patients with pSS compared to the controls. However, there was no significant association between the expression levels of phosphorylated JAK1 or JAK2 and the degree of inflammation. In addition, immunofluorescence analysis revealed JAK2 phosphorylation in many CD3 + T cells infiltrating the LSG tissues. These results suggested the activation of JAK/STAT signaling in both the ductal epithelial cells and the infiltrating CD3 + T cells in the LSG tissues of patients with pSS. Therefore, JAK inhibitors may be effective therapeutic agents for pSS by regulating both effector T cells and target cells.

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.

Background: Surgical site infections (SSI) are associated with increased morbidity and mortality. The purpose of this study was to investigate the ability of perioperative oral management (POM) to reduce the risk of SSI in abdominal surgery. Real-world data collected from 16 Japanese university hospital was reviewed. Methods: The medical records of consecutive 2,782 patients (1,750 men and 1,032 women) who underwent abdominal surgery under general anesthesia in 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. Results: SSI were observed in 275 patients (incidence rate: 9.9%) and POM was delivered in 778 patients (28.0%). Univariate analyses revealed that diabetes mellitus, Eastern Cooperative Oncology Group (ECOG) performance status, the American Society of Anesthesiologists (ASA) classification, the surgical site, the preoperative Prognostic Nutritional Index score, POM, the extent of surgery, the operation time, and the amount of intraoperative blood loss were significantly associated with postoperative SSI (Chi-square or Mann-Whitney U-test, p <0.01). The multivariate analysis revealed that POM had significant preventative effects against postoperative SSI (estimate: -0.245, standard error: 0.080, p <0.01). The surgical site, the ASA classification, and the operation time were also significant and independent clinical predictors of SSI. Conclusion: The analysis of real-world data from 16 university hospitals revealed that, regardless of the content and degree of the problem, addition of POM has significant beneficial effects in reducing the risk of SSI in patients who undergo abdominal surgery.

Background: Postoperative surgical site infections (SSI) can be major complications, which can prolong postoperative treatment. Perioperative oral management (POM) was first covered by Japanese national health insurance system in 2012, and patients that are scheduled to undergo major surgical treatment receive dental and oral management during the perioperative period. Objectives: The purpose of the present study was to investigate the ability of POM to prevent perioperative SSI in patients undergoing abdominal surgery. Methods: The patients’ medical records were retrospectively reviewed, and the effects of POM were investigated in a multicenter analysis involving many cases. Detailed information about SSI was assessed and compared between patients with and without POM in univariate and multivariate analyses. Results: In total, the cases of 2,782 patients (1,750 males 1,032 females) were reviewed. Of these, POM was performed in 778 patients (28.0%). Univariate analyses revealed that diabetes mellitus, Eastern Cooperative Oncology Group (ECOG) performance status, the American Society of Anesthesiologists (ASA) classification, the surgical site, the preoperative Prognostic Nutritional Index score, POM, the extent of surgery, the operation time, and the amount of intraoperative blood loss were significantly associated with postoperative SSI (Chi-square or Mann-Whitney U-test, p <0.01). The multivariate analysis revealed that POM had significant preventative effects against postoperative SSI (estimate: -0.245, standard error: 0.080, p <0.01). The surgical site, the ASA classification, and the operation time were also significant and independent clinical predictors of SSI. Conclusion: This study suggests that POM helps to prevent SSI in patients that undergo abdominal surgery.

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.