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Salivary gland dysfunction is a common side effect of cancer treatments. Salivary function plays key roles in critical daily activities. Consequently, changes in salivary function can profoundly impair quality of life for cancer patients. We discuss salivary gland anatomy and physiology to understand how anticancer therapies such as chemotherapy, bone marrow transplantation, immunotherapy, and radiation therapy impair salivary function. We discuss approaches to quantify xerostomia in the clinic, including the advantages and limitations of validated quality-of-life instruments and approaches to directly measuring salivary function. Current and emerging approaches to treat cancer therapy-induced dry mouth are presented using radiation-induced salivary dysfunction as a model. Limitations of current sialagogues and salivary analogues are presented. Emerging approaches, including cellular and gene therapy and novel pharmacologic approaches, are described.

Purpose: A MASCC/ISOO Clinical Practice Statement (CPS) is aimed at generating a concise tool for clinicians that concentrates practical information needed for the management of oral complications of cancer patients. This CPS is focused on the clinical assessment of salivary gland hypofunction and xerostomia in cancer patients., Methods: This CPS was developed based on a critical evaluation of the literature followed by a structured discussion of a group of leading experts, members of the Oral Care Study Group of MASCC/ISOO. The information is presented in the form of succinct bullets and tables to generate a short manual about the best standard of care., Results: The objective assessment of saliva secretion involves an extra- and intra-oral clinical examination while the subjective assessment involves eliciting information on the patient's complaint of xerostomia and its impact on daily functioning. This CPS summarizes the common investigator- and patient-reported instruments used in clinical practice for assessing salivary gland hypofunction and xerostomia in cancer patients., Conclusion: There is a range of tools to assess salivary gland function in patients undergoing cancer therapy, patients recovering from cancer therapy, or cancer survivors. Clinicians should ideally conduct both objective and subjective measurements to ensure a clear understanding about the status of the patients in order to provide the most appropriate treatment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Although dry mouth is a relatively common condition, salivary flow is not routinely measured in dental clinical practice. Moreover, existing data regarding the use of the modified Schirmer test (MST) for the screening of dry mouth has not been summarized. This systematic review and meta-analysis, conducted in accordance with the PRISMA guidelines, aimed to determine whether the modified Schirmer test can be used to identify dry mouth. The databases of PubMed, Scopus, ScienceDirect, and CENTRAL (CRD42023393843) were systematically searched to retrieve articles published until 9th November 2023. Among the 343 original articles retrieved, six met the inclusion criteria. A total of 1150 patients, comprising 710 (61.7%) women and 440 (38.3%) men (mean age, 47.1 ± 7.3 years), were included. The meta-analysis revealed a weak correlation coefficient of r ¯ $\bar{r}$  = 0.42 (95% Cl: 0.29-0.55) between MST and the unstimulated salivary flow rate. Therefore, while the MST might offer a simple and accessible alternative for initial screening in the future, especially in non-specialized settings, its variability in sensitivity and specificity, along with an actual lack of standardization, necessitates cautious interpretation. Further studies are necessary before recommending the test in clinical routine., (© 2024 The Authors. European Journal of Oral Sciences published by John Wiley & Sons Ltd on behalf of Scandinavian Division of the International Association for Dental Research.)

A declined salivary gland function is commonly observed in elderly people. Advanced glycation end products (AGEs) are believed to contribute to the pathogenesis of aging. Although physical exercise is shown to increase various organ functions in human and experimental models, it is not known whether it has a similar effect in the salivary glands. In the present study, we evaluated the AGEs burden in the salivary gland in the aging process and the protective effect of physical exercise on age-related salivary hypofunction. To accelerate the aging process, rats were peritoneally injected with D-galactose for 6 weeks. Young control rats and d-galactose-induced aging rats in the old group were not exercised. The rats in the physical exercise group ran on a treadmill (12 m/min, 60 min/day, 3 days/week for 6 weeks). The results showed that the salivary flow rate and total protein levels in the saliva of the d-galactose-induced aging rats were reduced compared to those of the young control rats. Circulating AGEs in serum and secreted AGEs in saliva increased with d-galactose-induced aging. AGEs also accumulated in the salivary glands of these aging rats. The salivary gland of aging rats showed increased reactive oxygen species (ROS) generation, loss of acinar cells, and apoptosis compared to young control mice. However, physical exercise suppressed all of these age-related salivary changes. Overall, physical exercise could provide a beneficial option for age-related salivary hypofunction.

Salivary gland dysfunction (SGD) induced by chemo- and radiotherapy for head and neck cancer (HNC) has always been a difficult problem in modern medicine. The quality of life of a large number of HNC patients is severely impaired by SGD such as xerostomia and dysphagia. In recent years, several studies have found that acupuncture can improve patients' salivary secretion, but it has not yet been approved as an alternative therapy for SGD. For this reason, we collected the clinical study reports on acupuncture in the treatment of SGD induced by chemo- and radiotherapy in HNC patients in the past 20 years, and analyzed and discussed the advantages and disadvantages of these studies with respect to tumor types, group setting, intervention modality, acupoints selection, outcome evaluation, and safety. We believed that acupuncture is beneficial for SGD, but the existing objective evidence is insufficient to support its effectiveness. Therefore, improving the Standards for Reporting Interventions in Clinical Trials of Acupuncture, selecting the optimal combination of acupoints through scientific and rigorous study design, and exploring the potential mechanism of acupuncture in the treatment of diseases combined with the meridian theory may be effective ways to promote the acceptance of acupuncture as an alternative therapy for SGD in future. The significance of this review is to provide a reference for researchers to carry out high-quality clinical trials of acupuncture in the treatment of SGD in future from the perspective of the combination of modern medicine and traditional Chinese medicine., (© 2021 American Association for Anatomy.)

Objective: Early diagnosis is critical to reduce long-term disability in patients with JIA by ensuring prompt treatment. The aim of this cross-sectional study was to evaluate the salivary gland function in JIA, addressing specifically oligoarticular (JIA1) and polyarticular (JIA2) subtypes, compared with healthy controls. This may contribute to the identification of salivary risk indicators of the disease that may help diagnosis at an early stage or even before the onset of other clinical evidence., Methods: Twenty-eight patients with JIA1, 28 patients with JIA2, according to the ILAR criteria, and 28 healthy controls (C) were included in the study. Exclusion criteria were any concurrent medical condition. Data on medication, dietary and oral hygiene habits were collected using a questionnaire. All patients underwent oral examination and saliva measurement., Results: While stimulated salivary flow rate (SFR) was significantly lower in JIA1 compared with JIA2 and C (P < 0.001), both salivary buffer capacity and pH were similar in the two JIA groups but statistically different from C (P = 0.002 and P = 0.010, respectively). Children with very low SFR (<3.5 ml) exhibited a 16-fold higher likelihood of being affected by JIA1 rather than JIA2 (P = 0.003), while no association was observed between low flow rate and JIA subtype (P = 0.744)., Conclusion: These preliminary data suggest impairment of salivary gland function as a risk indicator for JIA1 with no association with dietary habits and drug intake., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

This randomized placebo-controlled trial evaluates the impact of photobiomodulation (PBMT) on the salivary flow and biochemistry of patients with chronic kidney disease (CKD) on hemodialysis. Forty-four patients on hemodialysis self-responded two questionnaires for oral health and salivary gland function perception. The subjects were evaluated for function of salivary glands and randomly allocated to two groups: PBMT group (three irradiations at 808 nm, 100 mW, 142 J/cm 2 , and 4 J per site); and placebo group. Patients were submitted to non-stimulated and stimulated sialometry and after the treatment at baseline and 14 days. Salivary volume and biochemical of the saliva were analyzed. At baseline, most subjects had self-perception of poor oral health (52.6%) and salivary dysfunction (63.1%). Clinical exam revealed that 47.3% of subjects presented dry mucosa. PBMT promoted increase of the non-stimulated (p = 0.027) and stimulated saliva (p = 0.014) and decrease of urea levels in both non-stimulated (p = 0.0001) and stimulated saliva (p = 0.0001). No alteration was detected in total proteins and calcium analysis. Patients with kidney disease can present alteration in flow, concentrations, and composition of saliva, affecting oral health, but our findings suggest that PBMT is effective to improve hyposalivation and urea levels in saliva of patients with CKD., (© 2021. Springer-Verlag London Ltd., part of Springer Nature.)

Background: The salivary gland neoplasm of unknown malignant potential (SUMP) category reflects the cytomorphologic overlap and complexity of reporting salivary gland cytology in the Milan system. It includes neoplasms for which a diagnosis of a specific entity cannot be made and, more importantly, for which a carcinoma cannot be entirely excluded. For risk stratification, the subcategorization of SUMP based on the predominant cell type is recommended. This study was aimed at evaluating the risk of neoplasm (RON) and the risk of malignancy (ROM) of the basaloid and oncocytic subtypes of the SUMP category., Methods: A retrospective analysis of 482 salivary gland fine-needle aspirations from 2012 to 2019 resulted in 48 SUMP cases. The cytology of these cases was reviewed and reclassified as the basaloid or oncocytic subtype. Surgical follow-up was available for 36 cases. The RON and ROM for each subtype were calculated., Results: The RON and ROM were 100% and 23%, respectively, for monomorphic basaloid tumors and 88% and 58.8%, respectively, for monomorphic oncocytic tumors. The ROM for basaloid tumors was 8.3% without matrix/with minimal matrix and 60% with an nonfibrillary matrix. The ROM for oncocytic tumors was 50% without a cystic background and 60% with a cystic or mucinous background. The difference was not statistically significant for either of the subgroups., Conclusions: Even though statistically not significant in our study, the differential ROMs within the oncocytic and basaloid subgroups help in the risk stratification of SUMP cases. Further subcategorization based on the stroma and background helps in limiting the differential diagnosis but does not necessarily add to the value of the risk stratification., (© 2021 American Cancer Society.)

Hashimoto's thyroiditis (HT) is one of the most common autoimmune diseases. It is suggested that, in addition to thyroid gland dysfunction, HT is responsible for impaired secretion from the salivary glands. The aim of this study was to evaluate the extent of symptoms of salivary gland dysfunction. We also assessed the relationship between the levels of selected cytokines, chemokines, and growth factors in unstimulated whole saliva (UWS) and the rate of UWS secretion and symptoms of xerostomia in HT patients. The study group consisted of 25 female patients diagnosed with Hashimoto's disease in its spontaneous euthyroid state who had never received hormonal treatment. In more than half of the examined patients, we observed the level of UWS secretion below 0.2 mL/min, indicating impaired secretory function of the salivary glands. Moreover, we demonstrated that the clinical symptoms of salivary gland dysfunction worsen with disease duration. Nevertheless, the inflammatory changes occurring in these glands are independent of general inflammation in the course of HT. Our results clearly indicate an abnormal profile of cytokines, chemokines, and growth factors in the UWS of HT euthyroid women as well as the fact that concentrations of IL-6 and IL-1 as well as INF- γ , TNF- α , and IL-12 may be potential biomarkers for salivary gland dysfunction in the course of HT. Furthermore, salivary IL-12 (p40) may be helpful in assessing the progression of autoimmunity-related inflammation in the course of HT. In conclusion, secretory dysfunction of the salivary glands is closely related to autoimmunity-related inflammation in the course of HT, which leads to objective and subjective symptoms of dry mouth., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 K. Morawska et al.)

Xerostomia and salivary gland hypofunction are prevalent conditions in older people and may adversely influence the intake of certain foods, notably fruit and vegetables. Here, we aimed to investigate whether xerostomia and salivary gland hypofunction were associated with a lower intake of fruit and vegetables. The study included 621 community-dwelling adults, mean age 75⋅2 ± 6⋅4 years, 58⋅9 % female, who had participated in the Copenhagen City Heart Study follow-up, and undergone interviews regarding food intake (preceding month), oral and general health (xerostomia, taste alterations, diseases, medication, alcohol consumption and smoking), clinical oral examination and measurements of unstimulated and chewing-stimulated whole saliva flow rates. The average total energy intake (8⋅4 ± 2⋅7 MJ) and protein energy percentage (14⋅8 ± 3⋅1 %) were slightly below recommendations. The average fruit (234⋅7 ± 201⋅2 g/d) and vegetables (317⋅3 ± 157⋅4 g/d) intakes were within recommendations. Xerostomia and hyposalivation were more prevalent in women than in men (16⋅4 v . 7⋅1 %, P < 0⋅001 and 40⋅7 v. 27⋅5 %, P < 0⋅001). Multiple linear regression analyses revealed that older age ( β -0⋅009, se 0⋅003, P = 0⋅005), smoking ( β -0⋅212, se 0⋅060, P = 0⋅0005) and wearing complete dentures/being partially or fully edentulous ( β -0⋅141, se 0⋅048, P = 0⋅003), but neither xerostomia nor salivary flow rates were associated with an inadequate fruit and vegetable intake, after adjustment for covariates. Older age, smoking, tooth loss and denture-wearing were stronger determinants of low fruit and vegetable intakes than xerostomia and salivary hypofunction supporting the importance of dietary counselling and maintenance of oral health and an adequate masticatory performance., (© The Author(s) 2021.)

Scope: This study aims to evaluate the therapeutic efficacy and mechanisms of Lycium barbarum polysaccharide (LBP) in primary Sjögren's syndrome (pSS)., Methods and Results: Non-obese diabetic mice (the pSS model) are randomly divided into four groups: Low dose LBP (LBP.L, 5 mg kg -1  d -1 ), high dose LBP (10 mg kg -1  d -1 ), low dose interleukin (IL)-2 (25 000 IU/d), and control (saline water). Drugs were treated for 12 weeks. LBP.L significantly reduces the salivary gland inflammation compared with the control group (histological score p LBP.L vs Control  = 0.019; foci number: p LBP.L vs Control  = 0.038). LBP.L also remarkably reduces the effector follicular helper T (Tfh) cells and the CD4 + IL-17A + helper T (Th17) cells in both spleen and cervical lymph node (cLN) cells. Additionally, the ratios of regulatory T cell (Treg)/Tfh cells and Treg/Th17 cells are substantially increased in mice treated with LBP.L in both spleen and cLNs. LBP also inhibits Th17 and Tfh cells and markedly increases the Treg/Tfh ratio in human peripheral blood mononuclear cells., Conclusion: LBP.L inhibits the progression of pSS in mice, associated with modulation of T cell differentiation., (© 2021 Wiley-VCH GmbH.)

Patients with diabetes commonly experience hyposalivation, which induces discomfort in eating, swallowing, dryness, smell, and speaking, as well as increases the incidence of periodontal disease. Dipeptidyl peptidase-4 (DPP4) inhibitors are frequently used as antidiabetic drugs that lower glucose levels by utilizing similar mechanisms; however, additional protective functions of each gliptin have been discovered. In this study, the protective roles of gemigliptin, a DPP4 inhibitor, against salivary dysfunction under diabetic conditions were investigated. Streptozotocin-induced diabetic rats received gemigliptin 10 mg/kg or 100 mg/kg via oral gavage for 3 weeks. The weights of salivary gland tissues, saliva secretion, and antioxidant capacity in salivary glands were reduced after diabetes induction, but were significantly preserved following gemigliptin treatment. In salivary gland analysis, expression of apoptotic proteins, as well as amylase and aquaporin-5 (AQP5) protein expression, were increased following gemigliptin treatment. Furthermore, the number of TUNEL-positive cells decreased after gemigliptin treatment. Therefore, gemigliptin has protective roles against salivary dysfunction observed in diabetes, mediated via antioxidant, anti-apoptotic, and salivary secretion mechanisms. These results may help in selecting a suitable drug for patients with diabetes experiencing salivary dysfunction., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

A severe consequence of radiation therapy in patients with head and neck cancer is persistent salivary gland hypofunction which causes xerostomia and oral infections. We previously showed that irradiation (IR) of salivary glands in mice triggers initial transient increases in mitochondrial reactive oxygen species (ROS mt ), mitochondrial [Ca 2+ ] ([Ca 2+ ] mt ), and activated caspase-3 in acinar cells. In contrast, loss of salivary secretion is persistent. Herein we assessed the role of ROS mt in radiation-induced irreversible loss of salivary gland function. We report that treatment of mice with the mitochondrial-targeted antioxidant, MitoTEMPO, resulted in almost complete protection of salivary gland secretion following either single (15 Gy) or fractionated (5 × 3 Gy) doses of irradiation. Salivary gland cells isolated from MitoTEMPO-treated, irradiated, mice displayed significant attenuation of the initial increases in ROS mt , ([Ca 2+ ] mt , and activated caspase-3 as compared to cells from irradiated, but untreated, animals. Importantly, MitoTEMPO treatment prevented radiation-induced decrease in STIM1, consequently protecting store-operated Ca 2+ entry which is critical for saliva secretion. Together, these findings identify the initial increase in ROS mt , that is induced by irradiation, as a critical driver of persistent salivary gland hypofunction. We suggest that the mitochondrially targeted antioxidant, MitoTEMPO, can be potentially important in preventing IR-induced salivary gland dysfunction.

Radiation therapy for head and neck cancer causes damage to the surrounding salivary glands, resulting in salivary gland hypofunction and xerostomia. Current treatments do not provide lasting restoration of salivary gland function following radiation; therefore, a new mechanistic understanding of the radiation-induced damage response is necessary for identifying therapeutic targets. The purpose of the present study was to investigate the metabolic phenotype of radiation-induced damage in parotid salivary glands by integrating transcriptomic and metabolomic data. Integrated data were then analyzed to identify significant gene-metabolite interactions. Mice received a single 5 Gy dose of targeted head and neck radiation. Parotid tissue samples were collected 5 days following treatment for RNA sequencing and metabolomics analysis. Altered metabolites and transcripts significantly converged on a specific region in the metabolic reaction network. Both integrative pathway enrichment using rank-based statistics and network analysis highlighted significantly coordinated changes in glutathione metabolism, energy metabolism (TCA cycle and thermogenesis), peroxisomal lipid metabolism, and bile acid production with radiation. Integrated changes observed in energy metabolism suggest that radiation induces a mitochondrial dysfunction phenotype. These findings validated previous pathways involved in the radiation-damage response, such as altered energy metabolism, and identified robust signatures in salivary glands, such as reduced glutathione metabolism, that may be driving salivary gland dysfunction.

The tick Rhipicephalus sanguineus sensu lato has great medical and veterinary importance, mainly because the ability to transmit many diseases, causing harm to pets but also risks to public health. The blood spoliation and transmission of pathogens occur because of the immunosuppressive action of these ticks' saliva, a potent mixture of bioactive substances that is secreted by the salivary glands, one of the organs responsible for their biological success, and hence the target of studies for their control. Ozone has promise for use as an alternative acaricide, due to its proven efficiency in controlling agricultural and food pests, besides posing no risk of environmental contamination or to animal and human health. Therefore, this study evaluated the acaricidal potential of exposure of females of R. sanguineus s.l. to ozonated water at many concentrations and analysed the morphophysiological alterations of the salivary glands, employing histological and light microscopic techniques. The results demonstrated that the ozonated water at the concentrations investigated caused severe alterations in the salivary glands, bringing a new perspective for control of R. sanguineus s.l., through an ecologically correct method due to the absence of harm to non-target organisms and the environment., (© 2020 The Royal Entomological Society.)

Chronic heart failure (HF) is an important clinical, social, and economic problem. A key role in HF progression is played by oxidative stress. Free oxygen radicals, formed under the conditions of hypoxia and reperfusion, participate in myocardial stunning and other forms of post-reperfusion damage. HF patients also suffer from disorders connected with saliva secretion. However, still little is known about the mechanisms that impair the secretory function of salivary glands in these patients. In the presented study, we were the first to compare the antioxidant barrier, protein glycoxidation, and nitrosative/nitrative stress in non-stimulated (non-stimulated whole saliva (NWS)) and stimulated (SWS) saliva of HF patients. The study included 50 HF patients with normal saliva (NS) secretion ( n = 27) and hyposalivation (HS) ( n = 23), as well as an age- and gender-matched control group ( n = 50). We demonstrated that, in NWS of HF patients with HS, the concentration of low-molecular-weight non-enzymatic antioxidants decreased (↓total polyphenols, ↓ascorbic acid, ↓reduced glutathione, ↓albumin) compared to HF patients with normal saliva (NS) secretion, as well as the control group (except albumin). We also observed increased content of protein glycoxidation products (↑dityrosine, ↑kynurenine, ↑glycophore) in NWS and SWS of HF patients with HS compared to healthy controls. Interestingly, the content of dityrosine, N-formylkynurenine, and glycophore in NWS was also significantly higher in HF patients with HS compared to those with NS secretion. The concentration of NO was considerably lower, while the levels of peroxynitrite and nitrotyrosine were significantly higher in NWS and SWS of HF subjects with HS compared to the controls. Salivary gland dysfunction occurs in patients with chronic HF with the submandibular salivary glands being the least efficient. Oxidative/nitrosative stress may be one of the mechanisms responsible for the impairment of salivary gland secretory function in HF patients.

Salivary secretory disorders are life-disrupting pathologic conditions with a high prevalence, especially in the geriatric population. Both patients and clinicians frequently feel helpless and get frustrated by the currently available therapeutic strategies, which consist mainly of palliative managements. Accordingly, to unravel the underlying mechanisms and to develop effective and curative strategies, several animal models have been developed and introduced. Experimental findings from these models have contributed to answer biological and biomedical questions. This review aims to provide various methodological considerations used for the examination of pathological fundamentals in salivary disorders using animal models and to summarize the obtained findings. The information provided in this review could provide plausible solutions for overcoming salivary disorders and also suggest purpose-specific experimental animal systems.

Background: Although ulcerative colitis primarily involves the colon, extra-intestinal manifestations are common and oral and dental complaints are no exception., Objective: This study aims at evaluating oral and dental health problems and salivary function and composition in ulcerative colitis patients and its correlation with disease activity., Methods: Xerostomia Inventory score, (unstimulated/stimulated) salivary flow rates, salivary amylase and mucin/ Mucin 5B levels, self-reported oral and dental complaints, the oral health related quality of life, Simple Clinical Colitis Activity Index and inflammatory bowel disease-specific health related quality of life were determined., Results: The cohort consisted of 51 ulcerative colitis patients. Hyposalivation was experienced by 16% of patients under resting conditions and 24% under chewing-stimulated conditions. Xerostomia was not correlated with salivary flow rates. Disease activity did not influence salivary amylase and Mucin 5B concentrations. The Xerostomia Inventory score was correlated with the Simple Clinical Colitis Activity Index ( p  = 0.042) and inflammatory bowel disease-specific health related quality of life ( p  = 0.001). Most reported oral health problems were halitosis (29%) and aphthae (28%). Frequently reported dental problems were cavities (35%) and gum problems (31%). Patients with active disease experienced significantly more oral and dental complaints. The number of oral problems was positively correlated with the Simple Clinical Colitis Activity Index ( p  = 0.045) and negatively correlated with the inflammatory bowel disease-specific health related quality of life ( p  = 0.005)., Conclusion: The subjective feeling of a dry mouth (xerostomia) is related to disease activity and disease activity-associated quality of life in ulcerative colitis patients, whereas the objective saliva secretion rate is not. Oral and dental health problems are frequently observed in patients with ulcerative colitis, especially during active disease.

Background: An important side effect of radioactive iodine (RAI) therapy in patients treated for papillary thyroid cancer (PTC) is chronic sialadenitis. Neck ultrasonography (US) easily recognizes radioiodine-induced salivary gland abnormalities. The objectives of this study were to determine the prevalence of US-detected sialadenitis caused by RAI and to identify the risk factors associated with this damage. Methods: This nonconcurrent cohort study includes all PTC-operated patients who were treated with RAI between 2007 and 2017 and were systematically evaluated with preoperative and follow-up neck US that included targeted exploration of the major salivary glands. Patients with pre-existing salivary gland diseases were excluded. The anatomical damage (diminished glandular volume, wavy contours, hypoechogenicity, and heterogeneity) was qualitatively assessed and compared with the preoperative study. RAI activity, sex, age, and preparation method were evaluated as risk factors using univariate and multivariate analyses with logistic regression. Results: Enrolled in this study were 570 patients who received a median RAI activity of 3700 MBq (100 mCi). On US, we found 143 patients (25.1%) with damage in at least one of their salivary glands: all had parotid damage (77 bilaterally) and 14 (9.8%) also had submandibular gland damage (7 of them bilaterally). The multivariate analysis indicated that the risk of sialadenitis was significantly ( p  < 0.01) correlated with both RAI activity and sex (14.1% of males vs. 28.5% of females). However, the main risk factor was RAI activity; no injury was detected in 156 patients who received 1110 MBq (30 mCi) and 1850 MBq (50 mCi) of RAI. In the groups of patients receiving 3700 MBq (100 mCi), 5550 MBq (150 mCi) and ≥7400 MBq (≥200 mCi), atrophy was found in 21%, 46.9%, and 77.7% of patients, respectively. Age and preparation method were not related to an increased risk of atrophy in this study. Conclusions: Chronic sialadenitis is common and affects approximately one fourth of patients who receive 3700 MBq (100 mCi) or higher RAI activity. The main risk factor for this injury is the total RAI activity administered. By using the lowest effective activity possible, irreversible anatomical damage in salivary glands can be minimized. US is an excellent tool to diagnose post-RAI atrophy.

Sialorrhea, or excessive saliva beyond the margin of the lip, is a common problem in many neurological diseases. Previously, sialorrhea has been underrecognized in Parkinson's disease (PD) patients. Despite this, many patients rank sialorrhea as one of the most debilitating complaints of Parkinson's disease. Previous treatment for sialorrhea has been suboptimal and has been plagued by significant side effects that are bothersome and can be dangerous in patients with a concurrent neurodegenerative disease. This review sought to review the anatomy, function, and etiology of sialorrhea in PD. It then sought to examine the evidence for the different treatments of sialorrhea in PD, and further examined newer evidence for safety and efficacy in minimally invasive treatment such as botulinum toxin.

Immune checkpoint inhibitors can affect any organ, including the salivary glands. A case of Sjögren's syndrome (SjS) induced by nivolumab for the treatment of gastric cancer is herein presented. Nivolumab treatment caused marked tumor shrinkage, but xerostomia developed after two cycles. It took 3 months after symptom onset to confirm the diagnosis of SjS. Prednisolone and pilocarpine hydrochloride did not relieve the symptoms. SjS is a relatively rare immune-related adverse event that might sometimes be overlooked. Since SjS can severely impair a patient's quality of life, oncologists should not miss any signs of salivary gland hypofunction and cooperate with specialists for SjS.

Objectives: This study was conducted to investigate the dose-response characteristics of radioiodine on salivary glands and to investigate the mechanism responsible for radioiodine-induced salivary glands toxicity., Methods: Twenty-four mice were divided into six groups: 0, 0.05, 0.10, 0.20, 0.40, and 0.80 mCi/20 g mouse, administered orally. Mortalities were noted 12 months after radioiodine administration. Body weights, gland weights, salivary lag times, flow rates, and changes in 99m Tc pertechnetate were recorded. Histopathological changes and mRNA expressions were also evaluated, and immunohistochemical analysis and apoptotic assays were performed., Results: Survival rates, body weights, gland weights, and flow rates decreased, and lag times increased on increasing radioiodine dose. Animals administered radioiodine showed acinar atrophy, striated duct dilations, and lymphocytic infiltration in glands and irregular destruction of epithelial surfaces of tongue. The uptake and excretion of 99m Tc pertechnetate were impaired by radioiodine. Immunohistochemical analysis showed that numbers of salivary epithelial, myoepithelial, and endothelial cells decreased and that numbers of ductal cells increased with radioiodine dose. Oxidative stress biomarker levels increased; reactive oxygen species scavenger levels decreased; and numbers of apoptotic cells increased in animals exposed to higher radioiodine doses., Conclusion: These dose-related, long-term effects on salivary gland should be taken into account when determining radioiodine doses., Level of Evidence: NA Laryngoscope, 130:2173-2178, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Tight junction (TJ) plays an important role in regulating paracellular fluid transport in salivary glands; however, little is known about the involvement of TJs in diabetes salivary glands. This study aimed to investigate the alterations of TJs and their possible contribution in diabetes-induced hyposalivation. Here, we observed that the morphologies of submandibular glands (SMGs) were impaired, characterized by enlarged acini accumulation with giant secretory granules, which were significantly reduced in atrophic ducts in SMGs of db/db mice, a spontaneous model of type-2 diabetes. However, the secretory granules were increased and scattered in the acini of diabetes parotid glands (PGs). Other ultrastructural damages including swollen mitochondria, expansive endoplasmic reticulum, and autophagosomes were observed in the diabetes group. The levels of TJ proteins including claudin-1 (Cldn1) and claudin-3 (Cldn3) were increased, whereas those of claudin-4 (Cldn4), occludin (Ocln), and zonula occludens-1 (ZO-1) were decreased in SMGs of db/db mice. Higher Cldn1 and Cldn3 and lower claudin-10 (Cldn10) and Ocln levels were observed in PGs of diabetes mice. Taken together, the structures of SMGs and PGs were impaired in diabetes mice, and the disruption of TJ integrity in both SMGs and PGs may contribute to diabetes-induced hyposalivation., (© 2020 Anatomical Society.)

A considerable number of patients arriving in dental offices are being treated with ongoing medication for a variety of chronic diseases. As a result, dentists must be familiar with the potential side effects these therapeutic agents may have on the tissues of the oral cavity, and in particular on the salivary gland. Salivary gland function may be altered by a wide range of medications, leading to effects such as xerostomia, hyposalivation, hypersalivation or even swelling of the glands. These disorders can cause a variety of other health complications. This review will focus on the most common groups of drugs responsible for salivary gland dysfunction, including psychoactive drugs, antidepressants, antipsychotics, antihypertensives, and antihistamines.

Objective: Salivary flow rate exerts an essential impact on the development and progression of dental erosion. In this work, the experimental dental erosion in non-obese diabetic (NOD) mice with reduced salivary flow rate was induced, and the erosive effect of acidic drinks on their dentition was studied. Material and methods: Three acidic drinks (sports drink, cola light drink and sugar containing cola drink) were given to adult NOD mice (groups: N  = 11) as the only drink for 6 weeks. Two control groups were included; wild type and NOD control (groups: N  = 9). Experimental and control (water) teeth were dissected out and observed by scanning electron microscopy (SEM). Mandibular first molars were subsequently embedded in Epon, ground transversely, observed again by SEM, and the enamel thickness and tooth height were measured. Results: Mandibular molars were considerably more eroded than maxillary molars. The erosive process started at the top of the cusps and subsequently extended in the cervical, mesio-distal, and pulpal direction. Erosive lesions were evident in increased succession from sports drink, cola light to cola drink exposed mandibular molars, with the lingual tooth height being approximately 23%, 26%, and 37% lower, respectively, compared to the control. The lingual enamel was approximately 48% thinner in sports drink molars and 62% thinner in cola light molars. In cola drink molars, the lingual enamel was totally eroded, and significant erosion of dentine was evident. Conclusion: Reduced salivary flow, together with a high consumption of acidic drinks, results in severe erosion of NOD mice molars.

Background: Treatment for most patients with head and neck cancers includes ionizing radiation with or without chemotherapy. This treatment causes irreversible damage to salivary glands in the irradiation field accompanied by a loss of fluid-secreting acinar cells and a considerable decrease of saliva secretion. There is currently no adequate conventional treatment for this condition. In recent years, we developed an effective culture method to enhance the anti-inflammatory and vasculogenic phenotypes of peripheral blood mononuclear cells (PBMNCs), and such effectively conditioned PBMNC (E-MNC) therapy has shown promising improvements to the function of radiation-injured salivary glands in preclinical studies. However, the safety and effect of E-NMC therapy have yet assessed in human. The objective of this ongoing first-in-man study is to assess the safety, tolerability, and in part the efficacy of E-MNC therapy for treating radiation-induced xerostomia., Methods/design: This phase 1 first-in-man study is an open-label, single-center, two-step dose escalation study. A total of 6 patients, who had no recurrence of head and neck cancer over 5 years following radiation therapy and suffered from radiation-induced xerostomia, will receive a transplantation of E-NMCs derived from autologous PBMNCs to a submandibular gland. The duration of the intervention will be 1 year. To analyze the recovery of salivary secretion, a gum test will be performed. To analyze the recovery of atrophic salivary glands, computed tomography (CT), and magnetic resonance imaging (MRI) of salivary glands will be conducted. The primary endpoint is the safety of the protocol. The secondary endpoints are the changes from baseline in whole saliva secretion and salivary gland atrophy., Discussion: This will be the first clinical study of regenerative therapy using E-MNCs for patients with severe radiation-induced xerostomia. The results of this study are expected to contribute to developing the low-invasive cell-based therapy for radiation-induced xerostomia., Trial Registration: This study was registered with the Japan Registry of Clinical Trials (http://jrct.niph.go.jp) as jRCTb070190057.

Radioiodine (RI) therapy is known to cause salivary gland (SG) dysfunction. The effects of antioxidants on RI-induced SG damage have not been well described. This study was performed to investigate the radioprotective effects of alpha lipoic acid (ALA) administered prior to RI therapy in a mouse model of RI-induced sialadenitis. Four-week-old female C57BL/6 mice were divided into four groups ( n = 10 per group): group I, normal control; group II, ALA alone (100 mg/kg); group III, RI alone (0.01 mCi/g body weight, orally); and group IV, ALA + RI (ALA at 100 mg/kg, 24 h and 30 min before RI exposure at 0.01 mCi/g body weight). The animals in these groups were divided into two subgroups and euthanized at 30 or 90 days post-RI treatment. Changes in salivary 99m Tc pertechnetate uptake and excretion were tracked by single-photon emission computed tomography. Salivary histological examinations and TUNEL assays were performed. The 99m Tc pertechnetate excretion level recovered in the ALA treatment group. Salivary epithelial (aquaporin 5) cells of the ALA + RI group were protected from RI damage. The ALA + RI group exhibited more mucin-containing parenchyma and less fibrotic tissues than the RI only group. Fewer apoptotic cells were observed in the ALA + RI group compared to the RI only group. Pretreatment with ALA before RI therapy is potentially beneficial in protecting against RI-induced salivary dysfunction.

Candida species are common in the human oral microbiota and may cause oral candidiasis (OC) when the microbiota equilibrium is disturbed. Immunosuppressed individuals are susceptible to oral infections as individuals with Down syndrome (IDS) due to particularities of their mouth morphoanatomy, saliva and comorbidities. This study aimed to analyze the molecular epidemiology of Candida spp. from the oral cavity of IDS and their relatives. A case-control study with 80 IDS and 80 non-syndromic (non-DS) was evaluated by oral swab collection for culture on Sabouraud dextrose agar, selection of yeast colonies to Gram staining and culturing on chromogenic media. DNA extraction was performed with the phenol/chloroform method for screening of 6 Candida species medically important in PCR, applying SPSS for statistics. We confirmed four species in 46 IDS without use of antimicrobials (57.54%), with a high prevalence of C. albicans/Ca (93.48%/43) and 3 C. glabrata/Cg (6.52%), being 25 of these IDS (31.25%) colonized by species other than C. albicans: Ca + Cg (16), Ca + C. tropicalis/Ct (7) and Ca + C. krusei/Ck (2). Only 10 non-DS were colonized by one species (11.25%): 6 C. albicans, 2 C. glabrata, 1 C. tropicalis and 1 C. krusei. Previous OC was reported by 39 IDS (48.75%), being 33 positives for Candida spp. (84.61%) and 17 with active OC (21.25%). Five non-DS reported OC previously and had no active lesions. Behavioral changes and buccal health programs directed to IDS may help prevent OC and its recurrence, providing information on oral hygiene for self-care.

Background: Primary Sjögren’s syndrome is a chronic inflammatory autoimmune disease. Minor salivary gland biopsy is the gold standard for the diagnosis of primary Sjögren’s syndrome. Superb microvascular imaging, power Doppler ultrasound, and color Doppler of the salivary glands represent non-invasive, non-irradiating modality for evaluating the vascularity of the salivary glands in the diagnosis and follow-up of primary Sjögren’s syndrome., Aims: To evaluate the efficacy of superb microvascular imaging and vascularity index in salivary glands for the sonographic diagnosis of primary Sjögren’s syndrome., Study Design: Prospective case-control study., Methods: Twenty participants with primary Sjögren’s syndrome and 20 healthy subjects were included in the study. Both parotid glands and submandibular glands were evaluated by superb microvascular imaging, power Doppler ultrasound, and color Doppler. The diagnostic accuracy of superb microvascular imaging was compared using these techniques., Results: In the patient group, the vascularity index values of superb microvascular imaging in parotid glands and submandibular glands were 3.5±1.66, 5.06±1.94, respectively. While the same values were 1.0±0.98 and 2.44±1.34 in the control group (p≤0.001). In the patient group, the vascularity index values of power Doppler ultrasound in parotid glands and submandibular glands were 1.3±1.20 and 2.59±1.82, respectively. While the same values were 0.3±0.32 and 0.85±0.68 in the control group (p≤0.001). The superb microvascular imaging vascularity index cut-off value for the diagnosis of primary Sjögren’s syndrome in parotid glands that maximizes the accuracy was 1.85 (area under the curve: 0.906; 95% confidence interval: 0.844, 0.968), and its sensitivity and specificity were 87.5% and 72.5%, respectively. While the superb microvascular imaging vascularity index cut-off value for the diagnosis of primary Sjögren’s syndrome in submandibular gland that maximizes the accuracy was 3.35 (area under the curve: 0.873; 95% confidence interval: 0.800, 0.946), its sensitivity and specificity were 82.5% and 70%, respectively., Conclusion: Superb microvascular imaging with high reproducibility of the vascularity index has a higher sensitivity and specificity than the power Doppler ultrasound in the diagnosis of primary Sjögren’s syndrome. It can be a noninvasive technique in the diagnosis of primary Sjögren’s syndrome when used with clinical, laboratory and other imaging methods.

Purpose: To investigate the value of diffusion-weighted imaging (DWI) in assessing dynamic changes of major salivary gland function during follow-up post radiotherapy (RT) in nasopharyngeal carcinoma (NPC) patients., Materials and Methods: 31 consecutive patients with pathologically confirmed NPC scheduled for RT underwent six routine follow-up MRI examinations including DWI sequence prior to (pre-RT) and 1, 3, 6, 9, and 12 months post RT. Mean apparent diffusion coefficient (ADC) values of bilateral parotid glands (PGs) and submandibular glands (SMGs) were measured. Objective measurement of salivary flow rate (SFR) under unstimulated (uSFR) and stimulated conditions (sSFR) as well as subjective xerostomia assessment according to a patient-rated questionnaire were conducted before each MRI. Variance analysis was used to evaluate dynamic changes of ADC, SFR and xerostomia questionnaire summary scores (XQ-sum) at different timepoints and the correlation between ADC and XQ-sum. Pearson's correlation test was used to evaluate the correlations between pre- and post-RT changes of ADC (ΔADC) and SFR (ΔSFR) or mean RT dose., Results: At each timepoint, ADCs of PGs were significantly lower than of SMGs, uSFR was significantly lower than sSFR. For both PGs and SMGs, ADC post-RT were all higher than ADC pre-RT , with significant differences. ADC 1m-post-RT initially increased and changed little to ADC 3m-post-RT , ADC 6m-post-RT , ADC 9m-post-RT , and ADC 12m-post-RT , then gradually declined over time. The dynamic change trends of SFR were negatively paralleled to those of ADC, while that of XQ-sum was similar. Dose-response relationships were detected between salivary gland mean RT dose and ΔADC. In PGs, negative correlations between ΔsSFR 9m-post-RT and ΔADC 9m-post-RT , and ΔsSFR 12m-post-RT and ΔADC 12m-post-RT were detected. In SMGs, negative correlations between ΔsSFR 12m-post-RT and ΔADC 12m-post-RT , and ΔuSFR 12m-post-RT and ΔADC 12m-post-RT were also detected. The ADCs of patients with severe subjective xerostomia were significantly higher, while patients with moderate subjective xerostomia presented a tendency toward higher ADCs compared to those with mild xerostomia from 6 to 12 months post RT., Conclusion: As part of routine follow-up MRI in NPC patients, DWI might be a promising modality for follow-up assessing the dynamic changes of major salivary gland function and might be more powerful in the late post-RT period.

Objective: This study aims to analyze the presence of oxidative stress and activity of the antioxidant system in the parotid and submandibular salivary glands of rats with Chronic Kidney Disease (CKD)., Design: Sixteen male wistar rats were divided into two groups (n = 8, each): control rats and rats with CKD. CKD was induced by 5/6 nephrectomy. Blood urea nitrogen and serum creatinine clearance were quantified. Malondialdehyde, superoxide dismutase, glutathione peroxidase, glutathione reductase, catalase, total antioxidant status, ascorbic acid, α-tocopherol, superoxide anion, and hydrogen peroxide concentrations were assessed., Results: In CKD rats, blood urea nitrogen, serum creatinine, and proteinuria concentrations were increased, while creatinine clearance was reduced. In the submandibular gland, superoxide anion concentration was increased significantly (p < 0.05). Hydrogen peroxide and superoxide anion concentrations were reduced in the parotid gland. CKD rats presented increased malondialdehyde concentration, total antioxidant status, superoxide dismutase, and glutathione reductase activities only in the parotid gland (p < 0.05)., Conclusion: Oxidative stress and changes in the antioxidant system were found in the parotid and submandibular salivary glands in an experimental model of CKD induced by 5/6 nephrectomy., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Catalpol is an active ingredient of Rehmanniae Radix, a medical herb used frequently in treating primary Sjogren's Syndrome (pSS). However, no study has assessed the therapeutic effects of catalpol in treating Sjogren's Syndrome. This study aimed to investigate the therapeutic effects of catalpol for pSS by evaluating the water consumption, stimulated salivary flow rates, sialadenitis, T cell subsets and related cytokine levels. Catalpol treated mice had improved stimulated salivary flow rates and water consumption compared to mice from the control group. Catalpol also reduced the lymphocytic infiltration and prevented the formation of ectopic germinal centers. These effects, especially in the catalpol high dose group, were associated with elevated CD4 + CXC-R5 + PD-1 + Foxp3 + T follicular regulatory (Tfr) cells (1.572 % vs 1.118 %, P = 0.0005) and a higher ratio of Tfr cells to T follicular helper (Tfh) cells (2.137 vs 1.541, P = 0.0007). Downregulated levels of IFN-γ and BAFF in serum and submandibular glands were also noted in catalpol treated groups. Our work indicated that catalpol might be a potential drug for treating pSS by regulating the interplay between T and B cells., Competing Interests: Declaration of Competing Interest None of the authors of this manuscript have a financial interest related to this work., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease, with only palliative treatments available. Recent work has suggested that increased bone morphogenetic protein 6 (BMP6) expression could alter cell signaling in the salivary gland (SG) and result in the associated salivary hypofunction. We examined the prevalence of elevated BMP6 expression in a large cohort of pSS patients and tested the therapeutic efficacy of BMP signaling inhibitors in two pSS animal models. Increased BMP6 expression was found in the SGs of 54% of pSS patients, and this increased expression was correlated with low unstimulated whole saliva flow rate. In mouse models of SS, inhibition of BMP6 signaling reduced phosphorylation of SMAD1/5/8 in the mouse submandibular glands, and led to a recovery of SG function and a decrease in inflammatory markers in the mice. The recovery of SG function after inhibition of BMP6 signaling suggests cellular plasticity within the salivary gland and a possibility for therapeutic intervention that can reverse the loss of function in pSS.

AQP5 plays an important role in the salivary gland function. The mRNA and protein for aquaporin 5 (AQP5) are expressed in the acini from embryonic days E13-16 and E17-18, respectively and for entire postnatal days. Ligation-reopening of main excretory duct induces changes in the AQP5 level which would give an insight for mechanism of regeneration/self-duplication of acinar cells. The AQP5 level in the submandibular gland (SMG) decreases by chorda tympani denervation (CTD) via activation autophagosome, suggesting that its level in the SMG under normal condition is maintained by parasympathetic nerve. Isoproterenol (IPR), a β-adrenergic agonist, raised the levels of membrane AQP5 protein and its mRNA in the parotid gland (PG), suggesting coupling of the AQP5 dynamic and amylase secretion-restoration cycle. In the PG, lipopolysaccharide (LPS) is shown to activate mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signalings and potentially downregulate AQP5 expression via cross coupling of activator protein-1 (AP-1) and NF-κB. In most species, Ser-156 and Thr-259 of AQP5 are experimentally phosphorylated, which is enhanced by cAMP analogues and forskolin. cAMP-dependent phosphorylation of AQP5 does not seem to be markedly involved in regulation of its intracellular trafficking but seems to play a role in its constitutive expression and lateral diffusion in the cell membrane. Additionally, Ser-156 phosphorylation may be important for cancer development., Competing Interests: The authors declare no conflict of interest.

Objectives : Autoimmune diseases include a spectrum of disorders in which immune response to the autoantigens leads to tissue damage or dysfunction. Xerostomia, salivary gland dysfunction and lack of saliva are some common symptoms associated with many autoimmune diseases. Methods : In this review study, the meta-analysis technique is used to objectively review the relationship between autoimmune diseases and salivary gland dysfunction. We have searched Medline and Embase and Google Scholar. By Revman 5.3, meta-analysis was performed to investigate the salivary flow rate in both stimulatory and non-stimulatory saliva. The sample size obtained from these studies was 130 people with autoimmune diseases and 100 healthy individuals. Results : The results showed a significant decrease in the level of non-stimulatory saliva in people with autoimmune diseases. Conclusions : A complete and comprehensive understanding of the clinical manifestation of systemic diseases is crucial in early diagnosis of diseases and identifying the mechanisms that develop the disease. Other than xerostomia, there is a significant reduction in salivary flow rate in patients with autoimmune diseases. As saliva plays a very important role in oral health and has significant functions, more attention is needed for monitoring and managing of hyposalivation in autoimmune patients.

Background: Xerostomia caused by radiation-induced salivary glands injury has a considerable impact on patients' quality of life. Nowadays, the existed different methods of evaluating xerostomia in clinical practice there are still some disadvantages and limitations. This study used diffusion-weighted magnetic resonance imaging (DW-MRI) with gustatory stimulation to assess salivary glands function after intensity-modulated radiotherapy (IMRT) in patients with nasopharyngeal carcinoma (NPC)., Methods: DW-MRI was performed in 30 NPC patients and swab method was used to calculate rest and stimulated salivary flow rates (SFR). DW sequence at rest and then repeated ten times during stimulation were obtained. Apparent diffusion coefficients (ADCs) maps of three glands were calculated. Patients before and after RT were recorded as xerostomia and non-xerostomia groups separately. Rest and stimulated ADCs, ADCs increase rates (IRs), time to maximum ADCs (Tmax), ADCs change rates (CRs), rest and stimulated SFR, SFR increase rates (IRs) and SFR change rates (CRs) before and after RT were assessed., Results: The rest and stimulated ADCs of three glands after RT were higher than those before RT (p < 0.001). The rest and stimulated SFR of all salivary glands after RT were lower than those before RT (p < 0.001). A correlation existed between rest ADCs of submandibular glands and rest SFR of submandibular mixed with sublingual glands and full three glands before RT (p = 0.019, p = 0.009), stimulated ADCs and stimulated SFR in parotid glands before RT (p = 0.047). The rest ADCs of parotid glands after RT correlated to XQ scores (p = 0.037)., Conclusions: The salivary glands' ADCs increased after RT both in rest and stimulated state due to the radiation injury and the ADCs correlated with SFR and XQ scores of evaluating the xerostomia in clinical practice.

The Non-obese Diabetic (NOD) mouse model for type I diabetes also develops some features of Sjögren's syndrome (SS). Since the source of the mice and the environment exert a strong influence on diabetes, this study investigated SS development in NOD mice obtained from two vendors. Female NOD mice from The Jackson Laboratory (JAX) and Taconic Biosciences were monitored for blood glucose and pilocarpine-induced salivation. The gut microbiome was analyzed by 16S rRNA sequencing of stool DNA. At euthanasia, serum cytokines and sialoadenitis severity were evaluated. The onset of diabetes was significantly accelerated in JAX mice compared to Taconic mice. Although the gut microbiome between the two groups was distinct, both groups developed sialoadenitis. There was no correlation between the severity of sialoadenitis and reduced saliva production. Instead, salivary gland dysfunction was associated with hyperglycemia and elevation of serum IL1β, IL16, and CXCL13. Our data suggest that inflammatory pathways linked with hyperglycemia are confounding factors for salivary gland dysfunction in female NOD mice, and might not be representative of the mechanisms operative in SS patients. Considering that NOD mice have been used to test numerous experimental therapies for SS, caution needs to be exerted before advancing these therapeutics for human trials.

Purpose: To evaluate the preventive effect of parotid gland (PG) massage for PG damage during the I therapy, we prospectively investigated the serum amylase value and salivary gland scintigraphy (SGS) after I therapy., Materials and Methods: One hundred patients with thyroidectomized differentiated thyroid cancer who underwent high-dose I therapy were enrolled in the clinical trial and randomized into 2 groups (PG massage group and nonmassage group). The serum amylase value was obtained before and 24 hours after I therapy, and the SGSs were also taken just before and at 8 months after the I therapy. Change in serum amylase value and SGS was compared between PG massage and nonmassage groups., Results: The difference value of serum amylase was significantly lower in PG massage group than in nonmassage group (P = 0.0052). Worsening of PG function on SGS was observed in 43 (45.3%) of the 95 patients. The incidence rate of PG abnormality on F/U SGS was significantly lower in PG massage group than in nonmassage group (odds ratio, 0.3704; P = 0.0195). In the multiple regression analysis, PG massage significantly affected the abnormality on the 8-month F/U SGS (rpartial = -0.2741, P = 0.0090) after adjusting for clinical variables (age, sex, TNM stage, TSH preparation methods for the I therapy, and I dose)., Conclusions: PG gland massage significantly reduced the incidence rates of salivary gland dysfunction on the 8-month F/U SGS and the level of the serological marker of salivary gland destruction after I therapy. Therefore, PG gland massage could alleviate salivary gland damage related to I therapy.

Oxidative stress plays a crucial role in the salivary gland dysfunction in insulin resistance; however, the cause of increased free radical formation in these conditions is still unknown. Therefore, the aim of the study was to investigate the effect of high-fat diet (HFD) on the mitochondrial respiratory system, prooxidant enzymes, ROS production, and nitrosative/oxidative stress in the submandibular and parotid glands of rats. The experiment was performed on male Wistar rats divided into two groups ( n = 10): control and HFD. The 8-week feeding of HFD affects glucose metabolism observed as significant increase in plasma glucose and insulin as well as HOMA-IR as compared to the control rats. The activity of mitochondrial Complex I and Complex II+III was significantly decreased in the parotid and submandibular glands of HFD rats. Mitochondrial cytochrome c oxidase (COX) activity and the hydrogen peroxide level were significantly increased in the parotid and submandibular glands of the HFD group as compared to those of the controls. HFD rats also showed significantly lower reduced glutathione (GSH) and reduced : oxidized glutathione (GSH : GSSG) ratio, as well as a higher GSSG level in the parotid glands of HFD rats. The activity of NADPH oxidase, xanthine oxidase, and levels of oxidative/nitrosative stress (malonaldehyde, nitric oxide, nitrotyrosine, and peroxynitrite) and inflammation/apoptosis (interleukin-1 β and caspase-3) biomarkers were statistically elevated in the HFD group in comparison to the controls. HFD impairs mitochondrial function in both types of salivary glands by enhancing ROS production, as well as stimulating inflammation and apoptosis. However, free radical production, protein nitration, and lipid peroxidation were more pronounced in the parotid glands of HFD rats.

Objective: This systematic review evaluated the efficacy of immunobiologics for the management of oral disease in Sjögren's syndrome (SS)., Materials and Methods: MEDLINE ® , Embase, Scopus, and the Cochrane Library were searched for evidence on the use of immunobiologics for management of glandular disease in SS. Primary outcomes were xerostomia and salivary gland dysfunction, assessed via visual analogue scales, disease-specific scales for SS, measurement of salivary flow, ultrasound data, and quality of life measures., Results: Seventeen studies (11 randomized controlled trials and 6 observational studies) met inclusion criteria. Rituximab showed efficacy in improving salivary gland function but not xerostomia. Abatacept showed promise in improving both xerostomia and salivary flow. Belimumab exhibited long-term improvement of salivary flow and subjective measures. The novel agent CFZ533 improved both disease activity and patient-reported indexes., Conclusions: There is strong evidence pointing to the efficacy of rituximab in the management of oral disease in SS. Future controlled trials may elucidate the efficacy of belimumab and abatacept. The new drug CFZ533 is a promising alternative for the management of SS and its salivary gland involvement. In considering these agents, the promise of efficacy must be balanced against the harmful effects associated with biologic agents., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.)

Chronic inflammation of the salivary glands from pathologic conditions such as Sjögren's syndrome can result in glandular destruction and hyposalivation. To understand which molecular factors may play a role in clinical cases of salivary gland hypofunction, we developed an aquaporin 5 (AQP5) Cre mouse line to produce genetic recombination predominantly within the acinar cells of the glands. We then bred these mice with the TNF-αglo transgenic line to develop a mouse model with salivary gland-specific overexpression of TNF-α; which replicates conditions seen in sialadenitis, an inflammation of the salivary glands resulting from infection or autoimmune disorders such as Sjögren's syndrome. The resulting AQP5-Cre/TNF-αglo mice display severe inflammation in the salivary glands with acinar cell atrophy, fibrosis, and dilation of the ducts. AQP5 expression was reduced in the salivary glands, while tight junction integrity appeared to be disrupted. The immune dysregulation in the salivary gland of these mice led to hyposalivation and masticatory dysfunction.

Radioiodine (RI) treatment is widely used in patients with differentiated thyroid cancer. However, RI exposure often induces salivary gland (SG) dysfunction. In this study, we investigated the effect of curcumin on RI-induced SG dysfunction in mice. Mice were assigned to one of four groups (n = 6 per group) as follows: normal control, RI only, RI + curcumin, and RI + amifostine group. Salivary flow rate, lag time, and changes in 99m Tc (technetium)-pertechnetate uptake and excretion were measured, and changes in SG morphology and histology were analysed. Salivary epidermal growth factor content, amylase, and superoxide dismutase (SOD) activities were also measured. A terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was performed to assess SG apoptosis, and the expression of apoptosis-related protein was determined by western blotting. The reduced salivary flow rate and prolonged lag time in the RI group was restored by treatment with curcumin or amifostine. In the histological analysis, compared with the RI group, RI + curcumin and RI + amifostine groups had more mucin-rich acini and less periductal fibrosis. Compared with the RI group, RI + curcumin and RI + amifostine groups showed evidence of tissue remodelling, with a greater number of salivary epithelial cells (AQP-5-positive), SG ductal cells (CK18-positive), endothelial cells (CD31-positive), and myoepithelial cells (α-SMA-positive). RI + curcumin and RI + amifostine groups alleviated RI-induced cell death, demonstrating antiapoptotic effect, compared with the RI group. Both SOD activity and the protein expression levels of SOD2 were higher in the RI + curcumin and RI + amifostine groups than in the RI group. Our results demonstrate that curcumin ameliorates RI-induced SG dysfunction in mice., (© 2019 John Wiley & Sons, Ltd.)

Life expectancy has increased as a result of advancements in health care services; thus, maintaining healthy dentition is an important factor in overall health. Furthermore, the growing desire of elderly patients to maintain their teeth has led to an increased need for the performance of complex dental treatment in elderly patients. Root canal therapy is an essential phase of such treatments. Elderly patients may exhibit one or more systemic conditions that require special care, in addition to other changes that occur within the dentition and oral mucosa as a result of aging. These make root canal treatment in elderly patients a great challenge. The aim of this review was to characterize pathologic and physiologic changes in elderly patients that can interfere with root canal treatment procedures, as well as attitudes of elderly patients toward such treatment, guidelines and clinical considerations for management of root canal treatment in elderly patients.

Dry mouth or xerostomia is a frequent medical condition among the polymedicated elderly population. Systemic pilocarpine is included in the first line of pharmacological therapies for xerostomia. However, the efficacy of existing pilocarpine formulations is limited due to its adverse side effects and multiple daily dosages. To overcome these drawbacks, a localized formulation of pilocarpine targeting the salivary glands (SG) was developed in the current study. The proposed formulation consisted of pilocarpine-loaded Poly(lactic- co -glycolic acid) (PLGA)/poly(ethylene glycol) (PEG) nanofiber mats via an electrospinning technique. The nanofiber mats were fully characterized for their size, mesh porosity, drug encapsulation efficiency, and in vitro drug release. Mat biocompatibility and efficacy was evaluated in the SG organ ex vivo, and the expression of proliferation and pro-apoptotic markers at the cellular level was determined. In vivo short-term studies were performed to evaluate the saliva secretion after acute SG treatment with pilocarpine-loaded nanofiber mats, and after systemic pilocarpine for comparison purposes. The outcomes demonstrated that the pilocarpine-loaded mats were uniformly distributed (diameter: 384 ± 124 nm) in a highly porous mesh, and possessed a high encapsulation efficiency (~81%). Drug release studies showed an initial pilocarpine release of 26% (4.5 h), followed by a gradual increase (~46%) over 15 d. Pilocarpine-loaded nanofiber mats supported SG growth with negligible cytotoxicity and normal cellular proliferation and homeostasis. Salivary secretion was significantly increased 4.5 h after intradermal SG treatment with drug-loaded nanofibers in vivo. Overall, this study highlights the strengths of PLGA/PEG nanofiber mats for the localized daily delivery of pilocarpine and reveals its potential for future clinical translation in patients with xerostomia.

Sialorrhea is often treated with anticholinergic agents, but they can have undesirable side effects such as drowsiness, sedation, and constipation. Effective medication that acts selectively on the salivary glands is needed. We report the case of a patient with sialorrhea who was successfully treated by the combined use of pirenzepine and solifenacin (M1 and M3 muscarinic receptor antagonists, respectively). The patient was a 51-year-old man with mean unstimulated and stimulated salivary flow rates per 10 min of 6.1 mL and 41.7 mL, respectively (both were measured three times). 99m TcO 4- salivary gland scintigraphy revealed characteristic spontaneous saliva secretion without stimulation. He was treated with Scopolia extract, escitalopram, solifenacin succinate, and the combined administration of solifenacin succinate and pirenzepine. A statistically significant decrease was observed from the pre-medication unstimulated and stimulated salivary flow rates only following the combined administration of solifenacin and pirenzepine. The major muscarinic receptor subtype expressed in the salivary glands is M3; however, M1 is also present. A study using knockout mice demonstrated that the presence of either M1 or M3 receptors was sufficient for salivation. Thus, the combined use of selective M1 and M3 antagonists could provide a good treatment option for sialorrhea.

This study assessed the impact of chronic unpredictable mild stress (CUMS) on the structure of mouse salivary glands and the role of musk in alleviating this impact. Forty male albino mice were distributed equally into four groups; control (untreated), CUMS (exposed to CUMS for 4 weeks), CUMS+fluoxetine (FLU) (exposed to CUMS then treated with FLU, CUMS+musk (exposed to CUMS then treated with musk). Behavioral changes and serum corticosterone levels were assessed at the end of the experiment. The submandibular and parotid glands were dissected out and processed for histopathological and immunohistochemical examination using antibodies against alpha smooth muscle actin (ASMA) and brain-derived neurotropic factor (BDNF). Exposure to CUMS significantly (P < 0.001) increased the serum corticosterone level and induced depression. CUMS also induced vacuolation in acinar cells along with a significant (P < 0.001) reduction of ASMA immunoexpression, indicating an effect on myoepithelial cells, and a significant (P < 0.001) increase of BDNF expression in the gland ductal system. Both FLU and musk alleviated the CUMS-induced behavioral, biochemical and histopathological changes in the salivary glands. In conclusion, musk ameliorates stress-induced structural changes in mouse salivary glands. This effect might be mediated through up-regulation of BDNF secretion by the glands.

Salivary glands secrete saliva, a mixture of proteins and fluids, which plays an extremely important role in the maintenance of oral health. Loss of salivary secretion causes a dry mouth condition, xerostomia, which has numerous deleterious consequences including opportunistic infections within the oral cavity, difficulties in eating and swallowing food, and problems with speech. Saliva secretion is regulated by stimulation of specific signaling mechanisms within the acinar cells of the gland. Neurotransmitter-stimulated increase in cytosolic [Ca 2+ ] ([Ca 2+ ] i ) in acinar cells is the primary trigger for salivary fluid secretion from salivary glands, the loss of which is a critical factor underlying dry mouth conditions in patients. The increase in [Ca 2+ ] i regulates multiple ion channel and transport activities that together generate the osmotic gradient which drives fluid secretion across the apical membrane. Ca 2+ entry mediated by the Store-Operated Ca 2+ Entry (SOCE) mechanism provides the essential [Ca 2+ ] i signals to trigger salivary gland fluid secretion. Under physiological conditions depletion of ER-Ca 2+ stores is caused by activation of IP3R by IP3 and this provides the stimulus for SOCE. Core components of SOCE in salivary gland acinar cells are the plasma membrane Ca 2+ channels, Orai1 and TRPC1, and STIM1, a Ca 2+ -sensor protein in the ER, which regulates both channels. In addition, STIM2 likely enhances the sensitivity of cells to ER-Ca 2+ depletion thereby tuning the cellular response to agonist stimulation. Two major, clinically relevant, conditions which cause irreversible salivary gland dysfunction are radiation treatment for head-and-neck cancers and the autoimmune exocrinopathy, Sjögren's syndrome (pSS). However, the exact mechanism(s) that causes the loss of fluid secretion, in either condition, is not clearly understood. A number of recent studies have identified that defects in critical Ca 2+ signaling mechanisms underlie salivary gland dysfunction caused by radiation treatment or Sjögren's syndrome (pSS). This chapter will discuss these very interesting and important studies., (Copyright © 2018. Published by Elsevier B.V.)

80 % of patients suffering from amyotrophic lateral sclerosis present bulbar involvement and 50 % have salivary symptoms, which are often poorly managed. They present either with drooling or thick secretions. This elevates the risk of bronchoaspiration leading to pneumonia, second cause of death in this population. It is hence paramount to treat, while enhancing the patient's quality of life. The first line of treatment is a salivary drying agent such as an atropine-based medication. These treatments have a low adverse effect rate, are reversible and easy to dose. Management of thick secretions is possible with mucolytics. Taking into account the severity of the bulbar involvement, the second line of treatment, once controversial, is salivary gland injections of botulinium toxin., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Sjögren's syndrome (SS) is an inflammatory autoimmune disease that causes hyposecretion in salivary glands. Endothelial tight junctions (TJs) play crucial roles in salivation and barrier function of blood vessels. However, whether the alteration of endothelial TJs were involved in pathogenesis of SS was still unknown. Here, the ultrastructure and function of endothelial TJs in submandibular glands (SMGs) were detected by transmission electron microscopy and in vivo paracellular permeability assay in different aged NOD mouse model for SS. CFSE-labeled lymphocytes were injected into tail vein to trace the infiltration, while claudin-5 expression and distribution were detected by immunofluorescence, qRT-PCR, and western blot. Results showed that the stimulated salivary flow rate was gradually decreased and lymphocytic infiltration was found as age increased in 12- and 21-week-old NOD mice, but not 7-week-old NOD mice. Blood vessels were dilated, while endothelial TJ width and paracellular tracer transport were increased in 12-week-old NOD mice. Moreover, the injected CFSE-labeled lymphocytes were observed in SMGs of 12-week-old NOD mice. Claudin-5 level was increased and relocalized from the apical portion of neighboring endothelial cells to lateral membranes and cytoplasm in 12-week-old NOD mice. Additionally, the alteration of claudin-5 expression and distribution was further confirmed in labial salivary glands and bilateral parotid glands from SS patients. In cultured human microvessel endothelial cell line (HMEC-1), IFN-γ stimulation significantly increased claudin-5 expression. Taken together, we identified that the endothelial TJ barrier was disrupted and contributed to the development of salivary hyposecretion and lymphocytic infiltration in SS., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Hypofunction of the salivary gland causes several life-disrupting side effects such as dental caries, oral candidiasis, loss of taste, and swallowing disorders. No satisfactory therapy has been established to treat salivary hypofunction. Pilocarpine represents a potential treatment for dry mouth due to Sjögren's syndrome (SS). Although subjective improvement was consistently observed with pilocarpine therapy, the mechanism was unclear. In this study, we investigated the mechanism of recovery in salivation following treatment with pilocarpine. We first examined the effectiveness of pilocarpine in SS patients as quantified by the Saxon test and the visual analogue scale average. We found that salivation ability and subjective symptoms improved by continuous administration of pilocarpine. These results demonstrated that long-term medication for dry mouth patients was more effective. However, as the mechanism remained unclear, molecular biological mechanisms were analyzed based on the effects of continuous administration of pilocarpine using model mice. In the molecular biological analysis, continuous administration of pilocarpine was effective in both ICR and SS model mice. Gene and protein expression of muscarinic acetylcholine receptor 3 (M3R) increased in salivary glands following continuous administration of pilocarpine compared with single administration. Therefore, continuous administration of pilocarpine effectively induced M3R expression, thereby activating salivation., (Copyright © 2018 Elsevier Inc. All rights reserved.)