Review of genes potentially related to hyposecretion in male non-obese diabetic (NOD) mice,a Sjögren's syndrome model

BackgroundSjögren's syndrome (SS) is known to cause dry eyes and mouth due to inflammation of the lacrimal and salivary glands. However, some reports imply that other factors trigger dry eyes and mouth. We previously investigated various factors using RNA-sequencing analysis of lacrimal glands from male non-obese diabetic (NOD) mice, an SS model. In this review, we described (1) the exocrine features of male and female NOD mice, (2) the up- and down-regulated genes in the lacrimal glands of male NOD mice as revealed by our RNA-sequencing data, and (3) comparisons between these genes and data in the Salivary Gland Gene Expression Atlas.HighlightsMale NOD mice exhibit a steady worsening of lacrimal hyposecretion and dacryoadenitis, whereas females exhibit a complex pathophysiological condition that includes diabetic disease, salivary hyposecretion, and sialadenitis. Ctss, an up-regulated gene, is a potential inducer of lacrimal hyposecretion and is also expressed in salivary glands. Two other up-regulated genes, Ccl5 and Cxcl13, may worsen the inflammation of SS in both the lacrimal and salivary glands. The genes Esp23, Obp1a, and Spc25 were detected as down-regulated, but judging the relationship between these genes and hyposecretion is difficult as only limited information is available. Another down-regulated gene, Arg1, is involved in lacrimal hyposecretion, and it also has the potential to cause salivary hyposecretion in NOD mice.ConclusionIn NOD mice, males may be better than females at evaluating the pathophysiology of SS. Some regulated genes revealed by our RNA-sequencing data might be potential therapeutic targets for SS.     

Histamine deficiency inhibits lymphocyte infiltration in the submandibular gland of aged mice via increased anti-aging factor Klotho

ObjectivesHistidine decarboxylase (HDC), a histamine synthase, is expressed in various tissues and is induced by proinflammatory cytokines such as TNFα. As they age, C57BL/6 mice show auto-antibody deposition and lymphocyte infiltration into various tissues, including salivary glands. However, the mechanism underlying cell infiltration and the change in HDC expression in salivary glands with aging remain unclear. Thus, we aimed to elucidate the relationship between histamine and inflammaging.MethodsWe investigated the change in histology and HDC expression in the major salivary glands (parotid, submandibular, and sublingual) of 6-week- and 9-month-old wild-type mice. We also determined the histological changes, cytokine expression, and anti-aging factor Klotho in the salivary glands of 9-month-old wild-type and HDC-deficient (HDC-KO) mice.ResultsCell infiltration was observed in the submandibular gland of 9-month-old wild-type mice. Although most cells infiltrating the submandibular glands were CD3-positive and B220-positive lymphocytes, CD11c-positive and F4/80-positive monocyte lineages were also detected. HDC, TNFα, and IL-1β mRNA expression increased in the submandibular gland of 9-month-old wild-type mice. The expression of PPARγ, an anti-inflammatory protein, declined in 9-month-old wild-type mice, and Klotho expression increased in 9-month-old HDC-KO mice. Immunohistochemistry showed that Klotho-positive cells disappeared in the submandibular gland of 9-month-old wild-type mice, while Klotho was detected in all salivary glands in HDC-KO mice of the same age.ConclusionOur findings demonstrate the multifunctionality of histamine and can aid in the development of novel therapeutic methods for inflammatory diseases such as Sjogren's syndrome and age-related dysfunctions.     

Localization of phospholipid-related signal molecules in salivary glands of rodents: A review

BackgroundIn the 1950s, Hokin conducted initial studies on phosphoinositide turnover/cycle in salivary glandular cells. From these studies, the idea emerged that receptor-mediated changes in intramembranous levels of phosphoinositides represent an early step in the stimulus-response pathway. Based on this idea and the general view that knowledge of the exact localization of a given endogenous molecule in cells in situ is important for understanding its functional significance, we have reviewed available information about the localization of several representative phosphoinositide-signaling molecules in the salivary glands in situ in mice.HighlightWe focused on phosphatidylinositol 4-kinase, phosphatidylinositol 4 phosphate 5-kinase α, β, γ, phospholipase Cβ, muscarinic cholinoceptors 1 and 3, diacylglycerol kinase ζ, phospholipase D1 and 2, ADP-ribosylation factor 6 and its exchange factors for Arf6, and cannabinoid receptors. These molecules individually exhibit differential localization in a spatiotemporal manner in the exocrine glands, making it possible to deduce their functional significance, such as their involvement in secretion and cell differentiation.ConclusionAlthough phosphoinositide-signaling molecules whose in situ localization in glandular cells has been clarified are still limited, the obtained information on their localization suggests that their functional significance is more valuable in glandular ducts than in acini. It thus suggests the necessity of greater attention to the ducts in their physio-pharmacological analyses. The purpose of this review is to encourage more in situ localization studies of phosphoinositide-signaling molecules with an aim to further understand their possible involvement in the pathogenesis of salivary gland diseases.     

Adipose-derived mesenchymal stem cells promote salivary duct regeneration via a paracrine effect

ObjectivesThe self-regeneration of exocrine tissues, including salivary glands, is limited and their regeneration mechanism has not yet been fully elucidated. Here we identify the role of adipose-derived mesenchymal stem cells (AMSCs) in salivary gland regeneration.MethodsAMSCs expressing mesenchymal stem cell markers were applied to a submandibular gland injury model and the mechanism of salivary gland repair and regeneration was analyzed.ResultsTransplanted green fluorescent protein (GFP)-labeled AMSCs grew tightly together and promoted ductal regeneration in the regenerative nodule, with slight infiltration of nonspecific immune cells. A comprehensive gene analysis through RNA-sequencing revealed increased expression of bone morphogenetic protein (BMP), transforming growth factor (TGF), and Wnt in AMSC-transplanted regenerative nodules. The factors released from AMSCs scavenge hydrogen peroxidase-induced reactive oxygen species (ROS) through Wnt promoter activity in vitro. Furthermore, AMSC-conditioned medium recovered the growth of the hydrogen peroxidase-damaged primordium of the submandibular gland culture ex vivo.ConclusionsThese results suggest that AMSC-released factors scavenge ROS and maintain salivary gland repair and regeneration via paracrine effects. Thus, AMSCs could be a practical and applicable tool for use in salivary gland regeneration.     

Hypertriglyceridemia-induced brain-derived neurotrophic factor in rat submandibular glands

ObjectivesSalivary glands produce brain-derived neurotrophic factor (BDNF), which increases plasma BDNF content. Salivary BDNF influences the hippocampus and enhances anxiety-like behaviors. Dyslipidemia affects the brain, promoting depression and anxiety-like behaviors. This study was performed to investigate whether hypertriglyceridemia influences salivary BDNF expression.MethodsHypertriglyceridemia was induced in rats by high-fat diet intake for 10 weeks. BDNF protein levels in the saliva and submandibular glands were measured using enzyme-linked immunosorbent assay (ELISA). Bdnf mRNA levels in the submandibular gland were determined using real-time polymerase chain reaction.ResultsA hypertriglyceridemia rat model was established. Body weight did not differ between the control and hypertriglyceridemia groups. Bdnf mRNA and protein expression was increased in the submandibular gland in the hypertriglyceridemia group compared to the control group. BDNF expression was also significantly increased in the saliva of the hypertriglyceridemia group.ConclusionsThis is first study to show that hypertriglyceridemia induces BDNF expression in the rat submandibular gland and suggests that salivary BDNF is associated with lipid metabolism.     

A Ser252Trp substitution in mouse FGFR2 results in hyperplasia of embryonic salivary gland parenchyma

ObjectivesMutations in the fibroblast growth factor receptor 2 (FGFR2) gene are responsible for several severe forms of craniosynostotic disorders, such as Apert and Crouzon syndromes. Patients with craniosynostotic disorders caused by a mutation in Fgfr2 present with several clinical symptoms, including hypersalivation. Here we used a transgenic mouse model of Apert syndrome (Fgfr2^+/S252W mice) to evaluate the morphology of the submandibular glands at embryonic day 15.5 (E15.5), the time point reported to mark the start of lumen formation.MethodsFgfr2^+/S252W mice were generated by crossing ACTB-Cre^+/+ and Fgfr2^+/Neo-S252W mice. After measuring body weight, the submandibular glands were collected at E15.5. H&E staining, immunostaining, and RT-qPCR were performed to investigate the development of the submandibular gland.ResultsThe number of ducts and acini in Fgfr2^+/S252W mice was significantly higher than in control littermates; however, lumen formation was not affected. The mRNA expression of Fgf1, Fgfr1, Mmp2, Bmp4, Bmp7, Dusp6, and Etv5 in Fgfr2^+/S252W mice was significantly higher compared to control littermates. Immunoreactivity for FGF3, FGF1, BMP4, and F4/80 was detected in the parenchyma of Fgfr2^+/S252W mice. The area of apoptotic cells stained with TUNEL in Fgfr2^+/S252W mice was significantly larger than that of the control littermates.ConclusionsThese results suggested that increased FGFR1 signaling and apoptosis in the submandibular glands of Fgfr2^+/S252W mice occurred at E15.5, leading to parenchymal hyperplasia. This study demonstrated that a Ser252Trp substitution in mouse FGFR2 resulted in hyperplasia of the submandibular gland parenchyma during development.     

Responses of salivary glands to intake of soft diet

BackgroundModernization has made individuals prefer processed and cooked foods (soft food), but this eating habit may have negative effects on the oral cavity. However, laboratory animals fed with soft diet are commonly used in an attempt to clarify this issue, and various oral tissues, including the salivary glands have been examined. In this review, we summarize the findings of previous studies concerning the responses of salivary glands to daily intake of soft diet.HighlightThe weight of the parotid glands decreased in rodents fed with soft diet (liquid or powder). In atrophic parotid glands, acinar cell shrinkage is histologically observed and the DNA content is reduced, showing that the atrophy is caused by a decrease in the size and number of acinar cells. Immunohistochemical examinations showed that the decrease in the acinar cell number was induced by suppression of acinar cell proliferation and acceleration of apoptosis. The atrophic parotid glands recovered following a change from soft to pellet diet. Other salivary glands, such as the submandibular, sublingual, and palatine glands, responded only slightly to the soft diet feeding.ConclusionAccumulated research data showed that a soft diet negatively affects the parotid glands much more than other salivary glands and that atrophic parotid glands are able to recover by switching to a hard diet. Therefore, it should be emphasized that good eating habits are important for not only digestion but also the health of oral tissues, including the salivary glands.     

Salivary factors related to caries in pregnancy: A systematic review and meta-analysis

BackgroundThe authors of this meta-analysis aimed to assess saliva-related caries risk factors, including calcium and phosphate, hydrogen ion concentration, buffer capacity, Streptococcus mutans and Lactobacillus counts, flow rate, and decayed, missing and filled teeth index in each trimester during pregnancy.Types of Studies ReviewedThe authors searched electronic databases up to July 1, 2019. Eligible observational studies were included. The authors assessed the quality of the included studies by using the Joanna Briggs Institute scale. To estimate the effects of pregnancy, standardized mean differences with 95% confidence intervals were pooled using the random-effects model. Subgroup analysis and meta-regression were used to explore heterogeneity. Publication bias was assessed using Begg and Egger tests.ResultsTwenty-nine studies were included in the meta-analysis, representing 1,230 pregnant women in the case groups and 715 in the control groups (nonpregnant women). The results showed that salivary calcium concentration decreased in the third trimester, salivary phosphate decreased in the second and third trimesters, saliva hydrogen ion concentration decreased in the first and third trimesters, stimulated saliva flow rate increased in the third trimester, and salivary S mutans count increased in the second and third trimesters. In addition, the results showed that saliva calcium, phosphate, S mutans, and buffer capacity amounts had changed from the first trimester to the third.Conclusions and Practical ImplicationsIn the third trimester, most salivary factors related to caries change and can increase the risk of developing caries in the future. Interventions and screening for caries prevention in pregnancy should start in the first or second trimesters.     

The influence of periodontal status and serum biomarkers on salivary leptin levels in systemic lupus erythematosus patients

ObjectiveThis study aimed to investigate the influence of periodontal status, clinical data, and serum markers on salivary leptin levels in patients with systemic lupus erythematosus (SLE).MethodsA case–control study was conducted with 38 patients with SLE and 29 healthy controls. Periodontal data included periodontal probing depth (PPD), clinical attachment level (CAL), and gingival bleeding on probing (BOP). Stimulated saliva samples were collected to analyze salivary leptin levels. Clinical and serum data were collected from the SLE group. Statistical analysis included the t-test, Mann–Whitney test, Spearman correlation coefficient, and a structural equation model.ResultsThe SLE group had a lower salivary leptin level than the control group (P = 0.002). The model revealed that SLE had an inverse and independent effect on salivary leptin (standardized estimate =  ? 0.289, P = 0.023). Moreover, salivary leptin level negatively correlated with the serum levels of triglyceride, creatinine, and leukocytes, positively correlated with the serum total cholesterol, but was not significantly correlated with the periodontal status.ConclusionThese findings suggest that patients with SLE have a lower salivary leptin level. In addition, the level of salivary leptin does not appear to be related to periodontal status in patients with SLE.     

Saliva diagnostics: Salivaomics,saliva exosomics,and saliva liquid biopsy

BackgroundEach day, humans produce approximately 0.5 through 1.5 liters of saliva, a biofluid that is rich in biological omic constituents. Our lack of understanding how omic biomarkers migrate from diseased tissue to the saliva has impeded the clinical translation of saliva testing. Although such biomarkers must be conveyed via the vascular and lymphatic systems to the salivary glands, the molecular mechanisms that underlie this transport remain unclear. Although COVID-19 highlighted the need for rapid and reliable testing for infectious diseases, it represents only one of the many health conditions that potentially can be diagnosed using a saliva sample.Types of Studies ReviewedThe authors discuss salivaomics, saliva exosomics, and the mechanisms on which saliva diagnostics are based and introduce a novel electrochemical sensing technology that may be exploited for saliva liquid biopsy.ResultsThe utility of saliva for screening for lung cancer is under investigation. Saliva testing may be used to stratify patients, monitor treatment response, and detect disease recurrence. The authors also highlight the landscapes of saliva-based SARS-CoV-2 testing and ultrashort cell-free DNA and outline how these fields are likely to evolve in the near future.Practical ImplicationsBreakthroughs in the study of saliva research, therefore, will facilitate clinical deployment of saliva-based testing.     

Efficacy of oscillating rotating versus side-to-side powered toothbrushes on plaque and gingival index reduction: A systematic review

BackgroundThe authors conducted a systematic review to assess the efficacy of oscillating rotating (OR) versus side-to-side (SS) powered toothbrushes on plaque and gingival index reduction.MethodsThe authors searched 3 electronic databases and the gray literature for randomized clinical trials in which investigators compared OR with SS powered toothbrushes. Two authors independently screened the studies, performed data abstraction, and assessed the risk of bias. The authors used random-effects model meta-analyses to pool results across trials and the Grading of Recommendations Assessment, Development and Evaluation approach to rate the certainty of evidence.ResultsThis systematic review included 24 trials in which researchers enrolled a total of 2,998 patients. There was moderate-certainty evidence that SS toothbrushes may result in little to no difference in plaque index reduction from baseline to 4 weeks compared with OR toothbrushes (standardized mean difference, 0.02; 95% confidence interval, –0.46 to 0.42). There was moderate-certainty evidence that SS toothbrushes may result in little to no difference in gingival index reduction from baseline to 4 weeks compared with OR toothbrushes (standardized mean difference, 0.13; 95% confidence interval, –0.47 to 0.22). There was moderate-quality evidence suggesting little to no difference in adverse events.ConclusionsThe evidence does not suggest the superiority of either OR or SS toothbrushes for plaque or gingival index reduction.Practical ImplicationsClinicians and patients considering the use of either of these toothbrushes are unlikely to observe more benefits with one type versus the other.     

The role of sugar-rich diet and salivary proteins in dental plaque formation and oral health

BackgroundDental plaque is a complex colorless film of bacteria that develops on the surfaces of teeth. Different mechanisms of microbial adhesion to tooth surfaces exist. Both non-specific and specific types of adherence have been anticipated.HighlightThe present review evaluated the effect of sugar-rich diet and salivary proteins on oral hygiene and dental plaque development.ConclusionThe oral microbiota is essential for maintaining and reestablishing a healthy oral cavity. Different types of sugars have different effects on the inhibition and formation of dental plaque. The peptides, proteins, and amino acids secreted by parotid glands in the oral cavity facilitate neutralizing the acidity in dental plaque and preventing dental caries. A properly balanced diet is crucial for both a healthy oral cavity and the oral microbiome.     

Importance of anatomy in dental implant surgery

BackgroundThe knowledge of nerves and vessels in the maxillofacial region, particularly the anatomical structures in the maxilla, mandible, tongue muscles, and salivary glands, is essential for dental surgeons. In addition, the structures in the mandibular canal, palate, and maxillary sinus should be understood well.HighlightThe arteries and nerves in the maxillofacial region were observed in this study. Some variations in the origin of the inferior alveolar artery were found. Notably, the variations in the origin of the inferior alveolar artery from that of the external carotid artery and a double origin of the inferior alveolar artery were observed. Thus, the maxillary artery may originate from the external carotid and stapedial arteries. The following points are important. (1)The greater palatine artery is always located deeper than the greater palatine nerve. (2)The posterior superior alveolar artery often runs through the compact bone of the maxilla. Using CT scans, the canal of the artery can be observed. (3)Variations in origins of the inferior alveolar artery have been observed. The origin of the inferior alveolar nerve may differ depending on the course of the maxillary artery.ConclusionsDental practitioners should, therefore, have a comprehensive knowledge of the anatomy of the maxillofacial region and its variations. Without this knowledge, they should not operate on patients.     

Impact of motivational interviewing on early childhood caries: A systematic review and meta-analysis

BackgroundThe authors aimed to assess the scientific evidence on motivational interviewing for the clinical reduction of early childhood caries compared with traditional dental health education.MethodsSearch terms were selected on the basis of Medical Subject Headings and non–Medical Subject Headings terms. The main key words were motivational interviewing, early childhood caries, and education. Potentially eligible studies involved the clinical assessment of caries rate in children whose parents or caregivers received motivational interviewing as an intervention. The authors assessed the risk of bias using the Cochrane risk-of-bias tool. In March 2019, the authors performed an electronic database search of literature published in English within the following databases: Scopus, Cochrane, PubMed, and Embase.ResultsOf 329 articles retrieved initially, 14 were eligible for inclusion in the systematic review and 3 articles contributed to the meta-analysis. For statistical analysis, the mean difference of continuous data was analyzed at a 95% confidence interval using the random-effects model.ConclusionsOverall, the evidence presented in this review was limited. Although the results of the meta-analysis showed that motivational interviewing is as effective as dental health education in controlling early childhood caries, we need more and better designed and reported interventions to assess its impact on early childhood caries accurately.     

Assessment of the possible ameliorative effect of curcumin nanoformulation on the submandibular salivary gland of alloxan-induced diabetes in a rat model (Light microscopic and ultrastructural study)

BackgroundNowadays, attention is directed to herbal treatments in an attempt to lessen the adverse effects of diabetes. Nanoformulation of curcumin (NC) was shown to enhance stability and water solubility compared to native curcumin.ObjectiveTo examine the effect of different NC concentrations on the histopathological structure of the submandibular salivary gland of diabetic rats.Methods28 rats were divided equally into 4 groups. Group I: Control group, Group II (diabetic), III (diabetic + nanocurcumin low dose), and IV (diabetic + nanocurcumin high dose): Rats of groups II, III and IV were injected with a single dose of alloxan (140 mg/kg) to induce diabetes. After 7 days, groups III and IV were treated for 6 weeks with NC (100 mg/kg/day) for group III, and (200 mg/kg/day) for group IV. Submandibular salivary glands were assessed histologically, immunohistochemically using α smooth muscle actin (α SMA) and ultrastructurally.ResultsDiabetic samples showed destruction of parenchymal elements of the gland, with thick fiber bundles encircling the excretory ducts and minimal reaction for α SMA. Amelioration of the gland's architecture was detected in groups III and IV with reduction of collagen deposition and elevation of positive immunoreactivity to α SMA.ConclusionNC profoundly repaired the induced diabetic histopathological and ultrastructural alterations of the gland in a dose dependent manner.     

Single-cell RNA-sequence of dental epithelium reveals responsible genes of dental anomalies in human

ObjectivesDental anomalies show various symptoms and some of them are accompanied with inherited diseases. However, only a few of responsible genes of dental anomalies are identified. In this study, we aimed to establish a novel strategy for identification of responsible genes of dental anomalies using integration of single-cell RNA-sequence (scRNA-seq) and Online Mendelian Inheritance in Man (OMIM).Materials and methodsSingle cells were isolated from mandibular incisor of post-natal day (P) seven mice and scRNA-seq were performed. Top 20 differentially expressed genes between clusters were identified and used for further analyses. Inherited diseases of differentially expressed genes and their Clinical Synopsis were examined using OMIM.ResultsThe prevalence of inherited disease was 43/80 genes (53.8%) and inherited diseases which associate with dental anomalies were 34/96 diseases (35.4%); 14.6% in enamel abnormality, 4.1% in dentin abnormality, and 16.7% in other abnormality. The prevalence of enamel abnormality was the highest in ameloblast, while that of other abnormality was high in non-ameloblast cell types. Chromosomal mapping of differentially expressed genes indicated that chromosome 4 has “hotspots” of dental anomalies-associated genes.ConclusionThe differentially expressed genes in dental epithelial cells were responsible for inherited disease which shows dental anomalies. The strategy employed in this study will contribute to identify the responsible gene for dental anomalies.     

Association of MMP9, MMP13 and MMP20 genes polymorphism with dental caries: A meta-analysis

ObjectivesGenetic factors can be involved in dental caries as the most common chronic oral diseases. The association between polymorphism of MMP9, MMP13 and MMP20 genes with tooth decay has been studied but contradictory outcomes have been indicated. Thus, a meta-analysis was done to get comprehensive outcomes in this path.Materials and methodsAll articles in English by March 2022 were searched with correlated keywords from known database as PubMed, Scopus, Embase and Web of Science, and the articles were selected in several stages based on exclusion and inclusion criteria. Comprehensive meta-analysis software v.2.0 was used for Meta-analysis.ResultsFinally, 11 related articles were selected for meta-analysis. According to the results, MMP9 and MMP20 polymorphisms were not related with increased susceptibility to caries in the studied models, but in the case of MMP13, a significant association was observed between gene polymorphism and caries risk.ConclusionThe results about MMP13 gene polymorphism showed that guanine G allele and GG genotype have a protective role and decrease the risk of dental caries. It should be noted that, these conclusions could be promoted by studies contain large sample sizes. Finding the genetic factors influencing tooth decay can help increase our current knowledge of caries pathology, predict its occurrence, and target genes at the molecular level to prevent it.