Alterations In Salivary Glands Research Articles

Pathway Analysis of Transcriptional Alterations in the Salivary Gland Following Radiation Exposure

Radiation-induced xerostomia (RIX) is the subjective condition of dry mouth caused by radiation therapy to the head and neck and a result of hyposalivation and altered sialochemistry. Our long-term goal is to develop novel approaches to improve salivary function after radiation therapy. To better understand the molecular alterations induced by radiation in the salivary glands, we performed transcriptional profiling aimed at describing acute and long-term alterations in the murine salivary glands induced by radiation to better design effective regenerative therapies. The submandibular gland (SMG) of male C57Bl/6 mice received 15 Gy in a single fraction using a small animal image-guided irradiator. The mice were followed for 90 days. Saliva was collected at baseline and 7, 60 and 90 days after radiation. Salivary glands were collected for histology 3, 7, 60, and 90 days after radiation. The tissues were analyzed using a multiplex analysis platform processed with the murine whole transcriptome panel to investigate changes in gene expression over time. Using the multiplex analysis platform software, 96 regions of interest corresponding to acini, ducts, and granular convoluted tubules (GCTs) were delineated and gene expression was assessed separately in each area. To confirm the identified alterations, SMG tissue was histologically evaluated for fibrosis (masons tri-chrome), mucin (alcian blue), and amylase (α-amylase). Alterations in the immune microenvironment (CD19, CD3, and F4/80) and salivary gland stem cells (MIST1, SCA, Sox2, and c-Kit) were assessed by immunohistochemistry. Radiation resulted in a significant decrease in salivary production compared to nonirradiated controls (p-value = 0.03). The analysis of the transcriptional pathway identified early alterations in cell communication, DNA damage, and the immune response. Protein metabolism and extracellular matrix remodeling were up-regulated at later time points. Histological evaluation of tissues showed an increase in glandular structure disorganization over time, with a decrease in the size and distribution of the acinar compartments throughout the gland (mean area stained: No RT = 25.81% vs 90d RT = 19.98%, p-value = 0.005). There was an increase in periductal fibrosis within the tissue after 60 days compared to controls. Acutely, there was an increase in the expression of MIST1 and macrophages (mean area stained: No RT = 14.8% vs 7d RT = 18.76%, p-value = 0.0004) within the SMG that had resolved by the 60- and 90-day time points. The results implicate macrophage alterations in radiation-induced salivary gland damage and provide valuable mechanistic insight guiding potential approaches to intervene in RIX. We are pursuing cell therapy-based approaches to prevent and repair damage caused by radiation in order to improve the lives of our patients.

Ultra-High-Frequency Ultrasonography of Labial Glands in Pediatric Sjögren's Disease: A Preliminary Study.

Sjögren's disease (SD) is a chronic autoimmune disease primarily affecting lacrimal and salivary glands. The diagnosis of pediatric SD mostly relies on clinical suspect, resulting in a significant diagnostic delay. Recently, ultrahigh-frequency ultrasound (UHFUS) of labial glands has been proposed as a diagnostic method in adults with suspected SD. Until now, there have been no studies about UHFUS in pediatric diagnostic work-up. The aim of the study was to evaluate the potential role of UHFUS of minor salivary glands in pediatric SD. Consecutive pediatric patients with a diagnosis of pediatric SD seen at AOU Meyer IRCSS were evaluated. Intraoral UHFUS scan of the lip mucosa was performed with Vevo MD equipment, using a 70 MHz probe with a standardized protocol and the images were independently reviewed by two operators. Lip salivary glands were assessed by using a four-grade semiquantitative scoring system for parenchymal alteration and vascularization. Twelve patients were included. When applying UHFUS to this cohort of patients, all patients showed a UHFUS grade of ≥1 with 8/12 showing a mild glandular alteration (i.e., grade 1), 2/12 a moderate glandular alteration (i.e., grade 2) and finally 2/12 a severe glandular alteration (i.e., grade 3). Moderate intraglandular vascularization was seen in 9/12, with only 3/12 showing mild intraglandular vascularization. Due to limited size of the sample, the relationship between histological findings, autoantibodies status and UHFUS grade could not be performed. This preliminary study seems to report UHFUS as feasibility technique to identify salivary gland alterations in children with a clinical suspect of SD.

Salivary Calcium Level and Its Correlation with Salivary pH, Salivary Volume, and Calcium Intake in Hypertensive Female Patients with Different Blood Sugar Levels.

This study aimed to evaluate the salivary calcium level and its correlation with salivary pH, salivary volume, and calcium intake in hypertensive female patients with different blood sugar levels. This cross-sectional study included 49 female subjects with hypertension. Subjects were divided into three groups based on the HbA1c test: normal, prediabetes, and diabetes. Unstimulated whole saliva was collected using the spitting method. Salivary calcium levels were evaluated using an Atomic Absorption Spectrophotometer. Salivary pH was obtained using a universal indicator pH paper test. Calcium intake was assessed by a semi-quantitative food frequency questionnaire. The Kruskal-Wallis test was used to compare salivary parameters and total calcium intake within study groups. Spearman rank correlation and multiple regression analysis were used to evaluate the correlation between salivary calcium levels and all variables in the study. No significant difference in salivary calcium, volume, pH, and total calcium intake was observed within the study groups. However, a significant correlation was found between salivary calcium levels and salivary pH in hypertensive females with normal blood glucose levels. Moreover, salivary calcium levels have a significant correlation with systolic blood pressure in prediabetes and diabetes groups. This study found a decrease in all salivary parameters (calcium, pH, and volume) as well as a low calcium intake in hypertensive females, despite no significant difference found in groups with different blood glucose levels. Blood glucose levels appeared to be a confounder in the relationship between salivary calcium with salivary pH and systolic blood pressure.

The efficacy of Origanum majorana nanocubosomal systems in ameliorating submandibular salivary gland alterations in streptozotocin-induced diabetic rats

Diabetes mellitus is a challenging health problem. Salivary gland dysfunction is one of its complications. Current treatments possess numerous adverse effects. Therefore, herbal extracts have emerged as a promising approach for safe and effective treatment. However, they are required in large doses to achieve the desired effect. Accordingly, Origanum majorana extract (OE) was incorporated into nano-sized systems to enhance its biological effects at lower dosages. OE was standardized against rosmarinic acid (RA) and then loaded into nano-cubosomal (NC) systems via a 23 full-factorial design. Two optimum nano-systems at different drug loads (2.08 or 1.04 mg-RA/mL) were selected and assessed in vivo to compare their effects in streptozotocin-induced diabetic rats against conventional OE (2.08 mg-RA/mL). Blood glucose was evaluated weekly. Submandibular salivary glands were processed for histopathological examination and nuclear factor-erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), and p38-MAPK gene expression analysis. NC systems were successfully prepared and optimized where the optimum systems showed nano-sized vesicles (210.4–368.3 nm) and high zeta potential values. In vivo results showed a significant lower blood glucose in all treated groups, with an exceptional reduction with NC formulations. Marked histopathological improvement was observed in all OE-treated groups, with OE-NC4 (2.08 mg-RA/mL) demonstrating the best features. This was supported by RT-PCR; where the OE-NC4 group recorded the highest mean value of Nrf2 and the least mean values of Keap1 and p38-MAPK, followed by OE-NC3 and OE groups. In conclusion, OE-loaded NC enhanced the anti-hyperglycemic effect of OE and ameliorated diabetic gland alterations compared to conventional OE. Thus, cubosomal nano-systems could be anticipated as potential carriers for the best outcome with OE.

Covid-19 and oral diseases: Crosstalk, synergy or association?

SummaryThe coronavirus disease 2019 (Covid‐19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) that clinically affects multiple organs of the human body. Cells in the oral cavity express viral entry receptor angiotensin‐converting enzyme 2 that allows viral replication and may cause tissue inflammation and destruction. Recent studies have reported that Covid‐19 patients present oral manifestations with multiple clinical aspects. In this review, we aim to summarise main signs and symptoms of Covid‐19 in the oral cavity, its possible association with oral diseases, and the plausible underlying mechanisms of hyperinflammation reflecting crosstalk between Covid‐19 and oral diseases. Ulcers, blisters, necrotising gingivitis, opportunistic coinfections, salivary gland alterations, white and erythematous plaques and gustatory dysfunction were the most reported clinical oral manifestations in patients with Covid‐19. In general, the lesions appear concomitant with the loss of smell and taste. Multiple reports show evidences of necrotic/ulcerative gingiva, oral blisters and hypergrowth of opportunistic oral pathogens. SARS‐CoV‐2 exhibits tropism for endothelial cells and Covid‐19‐mediated endotheliitis can not only promote inflammation in oral tissues but can also facilitate virus spread. In addition, elevated levels of proinflammatory mediators in patients with Covid‐19 and oral infectious disease can impair tissue homeostasis and cause delayed disease resolution. This suggests potential crosstalk of immune‐mediated pathways underlying pathogenesis. Interestingly, few reports suggest recurrent herpetic lesions and higher bacterial growth in Covid‐19 subjects, indicating SARS‐CoV‐2 and oral virus/bacteria interaction. Larger cohort studies comparing SARS‐CoV‐2 negative and positive subjects will reveal oral manifestation of the virus on oral health and its role in exacerbating oral infection.

Medication Associated Salivary Gland Alterations– Assessment of risk

Brief Background Medication Associated Salivary Gland Alterations (MASGA) are a common set of adverse events (AE) associated with many common medications. There are a few reports of the risk of MASGA with medication. Materials and Methods Using whole database approach, the Food and Drug Administration Adverse Event Reporting System (FAERS) of the United States of America was searched for MASGA. Common alterations and drugs associated were assessed for the Reporting Odds Ratio, as mentioned in pharmacovigilance researches. Results In the time phase considered, there were in all 16996785 AE reported in the FAERs database. Of this 68624 were related to MASGA with Dry Mouth and hypersecretion being most common. Anti-psychotic drugs predominated the hypersecretion spectrum with clozapine having a ROR of 58.04 followed by Haloperidol (25.29). Among the drugs that caused SG enlargement, potassium iodide (1335.32) and Oxyphenbutazone (696.58) had the highest ROR. Non-specific description of altered saliva was seen with high ROR in haloperidol and enoxaparin sodium (14.22). Summary and Conclusions Odds Ratio of drugs causing MASGA are. chronic medication such as those given for non-communicable, life style diseases and psychiatric medications known to cause MASGA. Key Words Salivary Alterations, Xerostomia, Salivary gland enlargement, Adverse Events, Pharmacovigilance

Synaptotagmin-1 overexpression under inflammatory conditions affects secretion in salivary glands from Sjögren's syndrome patients

Sjögren's syndrome (SS) is an autoimmune exocrinopathy associated with severe secretory alterations by disruption of the glandular architecture integrity, which is fundamental for a correct function and localization of the secretory machinery. Syt-1, PI(4,5)P2 and Ca2+ are significant factors controlling exocytosis in different secretory cells, the Ca2+ role being the most studied. Salivary acinar cells from SS-patients show a defective agonist-regulated intracellular Ca2+ release together with a decreased IP3R expression level, and this condition may explain a reduced water release. However, there are not reports where Syt-1, PI(4,5)P2 and Ca2+ in acinar cells of SS patients had been studied. In the present study, we analyzed the expression and/or localization of Syt-1 and PI(4,5)P2 in acinar cells of labial salivary gland biopsies from SS-patients and control individuals. Also, we evaluated whether the overexpression of Syt-1 and the loss of cell polarity induced by TNF-α or loss of interaction between acinar cell and basal lamina, alters directionality of the exocytosis process, Ca2+ signaling and α-amylase secretion in a 3D-acini model stimulated with cholinergic or β-adrenergic agonists. In addition, the correlation between Syt-1 protein levels and clinical parameters was evaluated. The results showed an increase of Syt-1 mRNA and protein levels, and a high number of co-localization points of Syt-1/STX4 and PI(4,5)P2/Ezrin in the acinar basolateral region of LSG from SS-patients. With regard to 3D-acini, Syt-1 overexpression increased exocytosis in the apical pole compared to control acini. TNF-α stimulation increased exocytic events in the basal pole, which was further enhanced by Syt-1 overexpression. Additionally, altered acinar cell polarity affected Ca2+ signaling and amylase secretion. Overexpression of Syt-1 was associated with salivary gland alterations revealing that the secretory dysfunction in SS-patients is linked to altered expression and/or localization of secretory machinery components together with impaired epithelial cell polarity. These findings provide a novel insight on the pathological mechanism implicated in ectopic secretory products to the extracellular matrix of LSG from SS-patients, which might initiate inflammation.

A comparison of conventional and diffusion-weighted magnetic resonance imaging in the diagnosis of sialadenitis and pleomorphic adenoma

The aim of this study was to compare the efficacy of conventional magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) in correctly identifying the presence of disease in the major salivary glands and correctly distinguish sialadenitis from pleomorphic adenoma. Twenty-one patients diagnosed with unilateral sialadenitis or pleomorphic adenoma were selected. The nonaffected contralateral glands were also analyzed. T1- and T2-weighted MRI and DWI were obtained using spin-echo pulse sequences with a 1.5 Tesla MRI device. The diagnostic performance of 3 observers was evaluated for detection of salivary gland alterations and differentiation between sialadenitis and pleomorphic adenoma based on evaluation of MRI in comparison with DWI. Intra-and interobserver reliability ranged from 0.86 to 0.94. DWI demonstrated greater sensitivity and accuracy values compared with MRI for both detection of disease and differentiation of sialadenitis from pleomorphic adenoma, with specificity values that were greater than or equal to those of MRI. DWI yielded significantly higher diagnostic odds ratios compared with MRI for both identification of disease and differentiation between lesions. DWI demonstrated better diagnostic performance in the detection of alterations in the salivary glands and in differentiating between sialadenitis and pleomorphic adenoma compared with conventional T1 and T2-weighted MRI.

Impaired mitochondria and intracellular calcium transients in the salivary glands of obese rats.

Long-term consumption of a high-fat diet (HFD) causes not only obese-insulin resistance, but is also associated with mitochondrial dysfunction in several organs. However, the effect of obese-insulin resistance on salivary glands has not been investigated. We hypothesized that obese-insulin resistance induced by HFD impaired salivary gland function by reducing salivation, increasing inflammation, and fibrosis, as well as impairing mitochondrial function and calcium transient signaling. Male Wistar rats (200-220 g) were fed either a ND or an HFD (n = 8/group) for 16 weeks. At the end of week 16, salivary flow rates, metabolic parameters, and plasma oxidative stress were determined. Rats were then sacrificed and submandibular glands were removed to determine inflammation, fibrosis, apoptosis, mitochondrial function and dynamics, and intracellular calcium transient signaling. Long-term consumption of an HFD caused obese-insulin resistance and increased oxidative stress, fibrosis, inflammation, and apoptosis in the salivary glands. In addition, impaired mitochondrial function, as indicated by increased mitochondrial reactive oxygen species, mitochondrial membrane depolarization, and mitochondrial swelling in salivary glands and impaired intracellular calcium regulation, as indicated by a reduced intracellular calcium transient rising rate, decay rates, and amplitude of salivary acinar cells, were observed in HFD-fed rats. However, salivary flow rate and level of aquaporin 5 protein were not different between both groups. Although HFD consumption did not affect salivation, it caused obese-insulin resistance, leading to pathophysiological alteration of salivary glands, including impaired intracellular calcium transients, increased oxidative stress and inflammation, and salivary mitochondrial dysfunction.

Morphological alterations in salivary glands of Rhipicephalus sanguineus ticks (Acari: Ixodidae) exposed to neem seed oil with known azadirachtin concentration

Neem (Azadirachta indica) has attracted the attention of researchers worldwide due to its repellent properties and recognized effects on the morphology and physiology of arthropods, including ticks. Therefore, this study aimed to demonstrate the effects of neem seed oil enriched with azadirachtin on salivary glands of Rhipicephalus sanguineus ticks, targets of great veterinary interest because of their ability to transmit pathogens to dogs. For this, R. sanguineus semi-engorged females were subjected to treatment with neem seed oil, with known azadirachtin concentrations (200, 400 and 600ppm). After dissection, salivary glands were collected and evaluated through morphological techniques in light microscopy, confocal scanning laser microscopy and transmission electron microscopy, so that the possible relation between neem action and further impairment in these ectoparasites feed performance could be established. Neem oil demonstrated a clear dose-dependent effect in the analyzed samples. The agranular (type I) and granular acini (types II and III) showed, particularly in individuals treated with the highest concentrations of the product, cells with irregular shape, intense cytoplasmic disorganization and vacuolation, dilation of rough endoplasmic reticulum lumen, besides alterations in mitochondrial intermembrane space. These morphological damages may indicate modifications in salivary glands physiology, demonstrating the harmful effects of compounds present in neem oil on ticks. These results reinforce the potential of neem as an alternative method for controlling R. sanguineus ticks, instead of synthetic acaricides.

Salivary exoglycosidases in gestational diabetes

As exoglycosidases have been described as potential markers of salivary gland pathology, we decided to check the possibility of the use of these enzymes in the detection of salivary gland involvement in gestational diabetes. For this purpose diabetic pregnant women were compared to pregnant and non-pregnant healthy women. The activities of total HEX as well as GLU in the saliva were determined in duplicate according to Marciniak et al. The activities of GAL, FUC, and MAN in the saliva were determined in duplicate according to Zwierz et al. It was found that the specific activities of exoglycosidases in the saliva of diabetic pregnant women significantly increased in comparison to healthy pregnant and non-pregnant women. Increased specific activity of exoglycosidases suggests that gestational diabetes provokes structural/functional alterations in salivary glands and changes in the salivary glycoconjugates metabolism.

Repeat dietary administration of an organic acid causes salivary gland alterations

Repeat dietary administration of an organic acid causes salivary gland alterations

Morphological alterations in salivary glands of mice (Mus musculus) submitted to tannin enriched diets: comparison with sialotrophic effects of sympathetic agonists stimulation

In order to study the effects of tannins at histomorphological level, mice were either fed with three structurally different types of tannins (tannic acid, chestnut, and quebracho) or treated with isoproterenol, during 10 days. Acini of parotid and submandibular glands increased significantly, being the increase higher for parotid compared to submandibular glands, and higher in the quebracho compared with the other tannin groups. Sublingual acinar size also increased after tannin consumption, by opposition to isoproterenol-treated animals. The results present evidences that the effects produced by tannins are dependent on their structure.

Xerostomia in Sjögren's syndrome and lupus erythematosus: a comparative histological and immunofluorescence study of minor salivary glands alterations

Xerostomia is a symptom that can be triggered by chronic diseases such as Sjögren's syndrome (SS) and lupus erythematosus (LE). Many authors regard most cases of salivary hypofunction in LE to secondary SS. Others believe that salivary changes in patients with LE might reflect a multisystem presentation of the disease. The present study compared histopathological and direct immunofluorescence (DIF) alterations in salivary glands of patients with xerostomia and diagnosis of LE or SS. Twenty-eight salivary gland biopsies from patients with xerostomia and diagnosed with LE or SS were submitted to histopathological and DIF exams. From the 28 patients, 16 had SS and 12 had LE. In SS, a moderate to intense sialadenitis was detected, with infiltration and destruction of excretory salivary ducts. In LE, mild/moderate sialadenitis with thickening and hyalinization of the ductal basement membrane was observed. DIF revealed that 50% of SS patients presented intercellular ductal IgA deposits, whereas 58% of LE patients showed deposits of IgG in the ductal basement membrane. Alterations in salivary glands of LE patients may be a specific manifestation of the disease (lupus sialadenitis), reflecting its multisystemic presentation, instead of an association of secondary SS and LE.

Sialolithiasis and Poorly Controlled Type 2 Diabetes Mellitus

Sialolithiasis is a common disease of the submandibular glands or its duct but rare in parotids of patients, especially in male adults. The accessory of salivary glands are small, unsheathed masses with a small canaliculi. The irritant factors might be due to inflammation of the inner layer of the canaliculi, that often concomitant to saliva stasis. This process leads to development of calculus that it is related to secretive specificity of the submandibular gland. The essential factor for its calcification is the stagnation of secretory matieral rich in calcium. The accumulation of this material would cause swelling, further obstruction and atrophy until there is widespread inflammation that has been termed sialadenitis. Diabetes mellitus is one of the medically compromised diseases. Although there are many assocaiations between diabetes mellitus and oral health, lack of investigation in this area has been done to study salivary gland alterations. Many diabetic patient complained xerostomia, a decreasing salivary flow and enlargement of the parotid gland due to a compensatory mechanism to xerostomia that has been termed sialadenosis. This review article summarized that there is no relationship between sialolithiasis and poorly controlled type 2 diabetes mellitus.

Parotid gland involvement in advanced AIDS.

This study describes the involvement and the histological alterations found in the parotid glands of 100 patients who died with AIDS. Sex, age, CD4 cell count and clinical history were obtained from the files of 100 patients who died with AIDS. Histological analysis of the parotid glands was performed using H&E, Gomori-Grocott, Ziehl-Neelsen and Mucicarmine. Histological findings were grouped in reactive, infectious, cystic, neoplastic and concomitant lesions. None of the patients presented complaints or symptoms related to salivary gland alterations prior to death. The mean age of the patients and CD4 cell count were 36.4 years and 76.07 cells microliter-1, respectively. Histological alterations of the parotid glands were found in 51% of the patients. The most common alteration was non-specific chronic sialadenitis (29 cases), followed by infectious conditions (22 cases). Mycobacteriosis was the most common infectious disease (10 cases), followed by cytomegalovirus (nine cases), cryptococcosis (three cases) and histoplasmosis (two cases). Lymphoepithelial cysts occurred in six cases, Warthin's tumor and non-Hodgkin Lymphoma in one case each. These results indicate that infection and other lesions in the parotid glands are more frequent than hitherto described in the specialized literature in AIDS patients. Clinicians should consider parotid gland involvement, when evaluating disease extension in advanced AIDS patients.

Saliva and Salivary Gland Alterations in HIV Infection

HIV-1 infection may involve saliva and the salivary glands. The virus may be recovered from the mouth and anti-viral antibodies are found in saliva. Salivary dysfunction after infection ranges from xerostomia to a Sjogren's syndrome-like condition with persistent glandular enlargement and marked secretory hypofunction.