ß-Adrenergic signaling induces Notch-mediated salivary gland progenitor cell control.

ß-Adrenergic signaling blockade is a mainstay of hypertension management. One percent of patients taking ß-blockers develop reduced salivary gland (SG) function. Here we investigate the role of SG progenitor cells in ß-blocker-induced hyposalivation, using human SG organoid cultures (SGOs). Compared with control SGs, initial low SG progenitor cell yield from patients taking ß-blockers was observed. When passaged, these SGOs recovered self-renewal and upregulated Notch pathway expression. Notch signaling was downregulated in situ in ß-adrenergic receptor-expressing luminal intercalated duct (ID) cells of patients taking ß-blockers. Control SGOs treated with ß-adrenergic agonist isoproterenol demonstrated increased proportion of luminal ID SGO cells with active Notch signaling. Control SGOs exposed to isoproterenol differentiated into more mature SGOs (mSGOs) expressing markers of acinar cells. We propose that ß-blocker-induced Notch signaling reduction in luminal ID cells hampers their ability to proliferate and differentiate into acinar cells, inducing a persistent hyposalivation in some patients taking ß-blocking medication.

Cholinergic crisis caused by ingesting topical carpronium chloride solution: A case report.

A cholinergic crisiss is a state characterized by excess acetylcholine owing to the ingestion of cholinesterase inhibitors or cholinergic agonists. We report the first case of a cholinergic crisis after the ingestion of a carpronium chloride solution, a topical solution used to treat alopecia, seborrhea sicca, and vitiligo. An 81-year-old woman with no prior medical history was transported to our emergency department because the patient had disturbance of consciousness after ingesting three bottles of FUROZIN® solution (90 mL, 4500 mg as carpronium chloride). A family member who found the patient called for emergency medical services (EMS) personnel, who contacted the patient ten minutes after ingestion. The patient's Glasgow Coma Scale score was 12 (E4V3M5), and vital signs were as follows: blood pressure, 80/40 mmHg; heart rate, 40 beats/min. The patient vomited repeatedly in the ambulance. On arrival to the ED, the patient's systolic blood pressure and heart rate temporarily decreased to 80 mmHg and 40 beats/min, respectively. Seventy-eight minutes after ingestion, gastric lavage was performed. The patient's symptoms, which included excess salivation, sweating, and hot flush, improved 24 h after ingestion, and the patient's vital signs stabilized without atropine or vasopressors. On the second day of admission, the patient was examined by a psychiatrist and discharged without suicidal ideation. Carpronium chloride has a chemical structure similar to that of acetylcholine; therefore, it exhibits both cholinergic and local vasodilatory activities. There is limited information on the pharmacokinetics of ingested carpronium chloride; therefore, physicians should be made aware that ingesting a carpronium chloride solution may cause a cholinergic crisis.

Gemigliptin suppresses salivary dysfunction in streptozotocin-induced diabetic rats.

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.

Ethanol binge drinking during pregnancy and its effects on salivary glands of offspring rats: oxidative stress, morphometric changes and salivary function impairments.

OBJECTIVES: To investigate the biochemical and morphological effects of ethanol (EtOH) binge drinking during pregnancy on parotid glands (PG), submandibular glands (SMG), and saliva of offspring rats. METHODS: Pregnant Wistar rats (n = 8) were exposed to EtOH consumption (3 g/kg/day - 20 % w/v) for three consecutive days. The saliva of 40-day-old offspring rats was collected to determine amylase activity and total protein concentration. PG and SMG were collected to performe oxidative biochemistry, morphometric and immunohistochemistry analyses (Student's t-test, p < .05). RESULTS: EtOH consumption during pregnancy significantly decreased the total protein concentration and decreased amylase activity. In the PG, the EtOH group showed increased lipid peroxidation and decreased antioxidant capacity against peroxyl. In the SMG, the EtOH group showed increased lipid peroxidation and NOx metabolite levels. PG exposed to EtOH showed a decrease of acini, ducts, and total parenchymal area. SMG exposed to EtOH showed an increase in the total stromal area. The expression of CK-19 and Vimentin were found not different between groups. CONCLUSIONS: For the first time, a three-day EtOH binge-drinking protocol during pregnancy is associated with oxidative stress and morphometric alterations in the salivary glands of offspring rats and with the functional reduction of the main salivary enzyme (amylase). CLINICAL RELEVANCE: EtOH consumption during pregnancy altered the morphology and physiology of the salivary glands of offspring rats.

Sialorrhea in Parkinson's Disease.

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.

Effectiveness of salivary stimulation using xylitol-malic acid tablets as coadjuvant treatment in patients with gastro-oesophageal reflux disease: early findings

BACKGROUND: Besides dental erosion syndrome, other oral syndromes could benefit from the stimulation of salivary secretion, in patients with gastrooesophageal reflux disease (GORD). Our aims is evaluate the improvement of oral extraoesophageal manifestations in patients with GORD using xylitol–malic acid tablets to stimulate salivary secretion. Material and METHODS: The effectiveness of salivary stimulation using xylitol–malic acid tablets (as a supplement to omeprazole 40 mg/day) was assessed in a clinical trial (n = 14) lasting six months with patients with prior positive pH-metry, through GORD extra-oesophageal clinical signs, GerdQ and RDQ questionnaires, odontological variables, basal salivary secretion, stimulated salivary secretion, pH and buffer capacity, mucosal erythema index and dental wear. Statistics: chi-square (Haberman post-hoc), ANOVA, and Mann-Whitney U; variables between visits were evaluated with McNemar’s Student’s t and Wilcoxon tests; p < 0.05. RESULTS: 100% of patients not taking xylitol–malic acid presented xerostomia, but only 14.3% of patients taking xylitol–malic acid (p < 0.01) did. The mean saliva-buffer capacity at the last visit for patients not taking xylitol–malic acid was 2.14 ± 0.38, versus 2.71 ± 0.49 for patients taking xylitol–malic acid (p < 0.05). Retro-sternal burning (p < 0.05), heartburn (p < 0.05) and regurgitation (p < 0.05) were also reduced. CONCLUSIONS: Xylitol-malic acid tablets improve quality of life among patients with GORD, by reducing dry mouth, increasing saliva buffering and reducing heartburn, retro-sternal burning and regurgitation

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The effect of sublingual atropine sulfate on clozapine-induced hypersalivation: a multicentre, randomised placebo-controlled trial.

BACKGROUND: Hypersalivation and drooling are commonly reported in clozapine-treated patients. Current management strategies have been evaluated using subjective measures. Many case reports describe the successful use of atropine in the treatment of the condition. AIMS: To measure the effect and safety of sublingual atropine on nocturnal unstimulated saliva secretion. Secondary aims were to evaluate the patient's satisfaction with the atropine effect on hypersalivation (or sialorrhea), drooling, and sleep. METHOD: Twenty-one clozapine-treated patients with hypersalivation, or drooling, were randomised to take a single 600-µg dose of sublingual atropine drops or a matching placebo. The saliva secretion was measured over 5 min at baseline and 2 h after the administration of the study medication. RESULTS: Sublingual atropine reduced the saliva secretion significantly more than the placebo (mean difference = - 57.21%, 95% CI: - 104.30, - 10.11, P = 0.02). A significant decrease in standing pulse rate was recorded in the participants in the atropine group (- 5.8 (- 9.54, - 2.15), P = 0.002). Subjectively, more patients in the atropine group found their pillow to have less saliva the following morning and found their sleep to be better. CONCLUSIONS: Sublingual atropine drops significantly reduces nocturnal unstimulated clozapine-induced saliva secretion. More research is required to compare the effect of sublingual atropine with other anticholinergic medications and different dosage forms. TRIAL REGISTRATION: ACTRN12618000051246.

Salivary dysfunction caused by medication usage.

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.

Mechanism of cAMP-PKA Signaling Pathway Mediated by Shaoyao Gancao Decoction () on Regulation of Aquaporin 5 and Muscarinic Receptor 3 Levels in Sjögren's Syndrome.

OBJECTIVE: To investigate the mechanism of cAMP-PKA signaling pathway mediated by Chinese medicine formula Shaoyao Gancao Decoction (, SGD) on the regulation of aquaporin 5 (AQP5) and muscarinic receptor 3 (M3R) levels in Sjögren's syndrome (SS). METHODS: Of the 30 mice, 5 were randomly selected as control, and others were used for creating SS model. After successful modeling, mice were randomly divided into 5 groups (n=5 per group) and intragastrically administered with saline (8 mL/kg), pilocarpine (1.4 mg/kg), or low, medium and high doses SGD (0.14, 0.21, 0.35 g/kg Radix paeoniae with 0.01 g/kg Radix glycyrrhizae, respectively) for 6 weeks. Human labial gland acinar cells were treated with pilocarpine or varying doses of SGD with saline as the placebo. Hematoxylin and eosin staining was used to observe the histopathological changes of the submandibular glands of mice. The serum levels of anti-SS antigen A (SS-A), anti-SS antigen B (SS-B), M3R, and α-fodrin in submandibular glands of mice were measured by enzyme-linked immunosorbent assay. Immunofluorescence staining was used to observe the spatial localization of AQP5 and M3R in acinar cells. Reverse transcriptase polymerase chain reaction and Western blot were used to detect the expressions of PKA, cAMP, Epac1, AQP5, M3R, nuclear factor kappa-B (NF-κB), and tumor necrosis factor (TNF)-α in submandibular gland tissues and cells of each group. RESULTS: Compared to normal mice, body weight, 5-min salivary secretion, 30-min secretion of tears and breakup time of tear film of model mice decreased at 1-6 weeks after immunization (all P<0.05), whereas water intake increased (all P<0.05). In the model group, glands of the submandibular glands showed atrophy, accompanied by acini of different sizes, decreased numbers and loose arrangement, with catheter dilatation and different degrees of lymphocyte infiltration. Conditions of mice in SGD groups were improved. The positive expression of AQP5 and M3R were higher in the acinar cells treated with all doses SGD compared to the normal group; serum levels of SS-A, SS-B, and α-fodrin were lower, and that of M3R was higher in all doses SGD treated animals than the model or pilocarpine treated ones (all P<0.05). Compared to the model and pilocarpine groups, the mRNA and protein levels of NF-κB and TNF-α were lower in mice or cells treated with medium or high-dose SGD (all P<0.05), while those of PKA, Epac1, AQP5 and M3R were higher (all P<0.05). CONCLUSION: SGD can improve symptoms of SS by regulating the cAMP-PKA signaling pathway and increasing AQP5 and M3R levels.

Antiemetic Effects of Cannabinoid Agonists in Nonhuman Primates.

Attenuating emesis elicited by both disease and medical treatments of disease remains a critical public health challenge. Although cannabinergic medications have been used in certain treatment-resistant populations, Food and Drug Administration-approved cannabinoid antiemetics are associated with undesirable side effects, including cognitive disruption, that limit their prescription. Previous studies have shown that a metabolically stable analog of the endocannabinoid anandamide, methanandamide (mAEA), may produce lesser cognitive disruption than that associated with the primary psychoactive constituent in cannabis, Δ9-tetrahydrocannabinol (Δ9-THC), raising the possibility that endocannabinoids may offer a therapeutic advantage over currently used medications. The present studies were conducted to evaluate this possibility by comparing the antiemetic effects of Δ9-THC (0.032-0.1 mg/kg) and mAEA (3.2-10.0 mg/kg) against nicotine- and lithium chloride (LiCl)-induced emesis and prodromal hypersalivation in squirrel monkeys. Pretreatment with 0.1 mg/kg Δ9-THC blocked nicotine-induced emesis and reduced hypersalivation in all subjects and blocked LiCl-induced emesis and reduced hypersalivation in three of four subjects. Pretreatment with 10 mg/kg mAEA blocked nicotine-induced emesis in three of four subjects and LiCl-induced emesis in one of four subjects and reduced both nicotine- and LiCl-induced hypersalivation. Antiemetic effects of Δ9-THC and mAEA were reversed by rimonabant pretreatment, providing verification of cannabinoid receptor type 1 mediation. These studies systematically demonstrate for the first time the antiemetic effects of cannabinoid agonists in nonhuman primates. Importantly, although Δ9-THC produced superior antiemetic effects, the milder cognitive effects of mAEA demonstrated in previous studies suggest that it may provide a favorable treatment option under clinical circumstances in which antiemetic efficacy must be balanced against side effect liability. SIGNIFICANCE STATEMENT: Emesis has significant evolutionary value as a defense mechanism against ingested toxins; however, it is also one of the most common adverse symptoms associated with both disease and medical treatments of disease. The development of improved antiemetic pharmacotherapies has been impeded by a paucity of animal models. The present studies systematically demonstrate for the first time the antiemetic effects of the phytocannabinoid Δ9-tetrahydrocannabinol and endocannabinoid analog methanandamide in nonhuman primates.

Ixeris dentata and Lactobacillus gasseri Extracts Improve Salivary Secretion Capability in Diabetes-Associated Dry Mouth Rat Model.

Dry mouth, hyposalivation, or xerostomia is a significant problem in diabetic patients; however, there has been no way to relieve these symptoms. This study's aim was to evaluate the effects of Ixeris dentata (IXD) in combination with lactobacillus extract on the salivation rate in diabetes-induced dry mouth, and its mechanism was also investigated. In the streptozotocin (STZ)-induced diabetes model, the dry mouth condition was established as a model. Here, rats were treated with water or IXD through the sublingual spray, and subsequently treated with or without a spray of lactobacillus extract. In diabetes condition, the salivary flow rate, amylase activity, and aquaporin-5 and Na+/H+ exchanger (NHE-1) expressions were markedly decreased, whereas they were more significantly recovered in the sequential treatment of IXD-lactobacillus extract than in each single treatment. Furthermore, oxidative stress and its related ER stress response were especially regulated in the IXD/lactobacillus extract condition, where the following anti-oxidative enzymes, glutathione assay (GSH: GSSG) ratio, superoxide dismutase (SOD), and glutathione peroxidase (GPx), were involved. This study suggests that the combination of IXD and lactobacillus would be a potential alternative medicine against diabetes-induced hyposalivation and xerostomia.

Suppression of high-mobility group box 1 ameliorates xerostomia in a Sjögren syndrome-triggered mouse model.

Xerostomia is a self-conscious symptom. High-mobility group box 1 (HMGB1) promotes pro-inflammatory effects in many diseases. This study aimed to clarify the role of HMGB1 in Sjögren syndrome (SS)-triggered xerostomia. Nonobese diabetic (NOD)/Ltj mice were used to establish an SS-triggered xerostomia model. The results showed that saliva production was decreased and anti-Sjögren syndrome B (anti-SSB) level was increased in SS. PCR, Western blot, and immunohistochemistry experiments indicated that the HMGB1 and aquaporin 5 (AQP5) levels were enhanced and diminished in SS compared with those in the control, respectively. While the mice were treated with anti-HMGB1, xerostomia was reversed due to the elevated saliva production and reduced anti-SSB level. In addition, it was found that the inhibition of HMGB1 restrained the toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) axis activation. The TLR4 and p-IκB levels were alleviated, while the IκBα and NF-κB p65 levels were augmented. The NF-κB p65 binding activity was attenuated via the electrophoretic mobility shift assay (EMSA) after anti-HMGB1 treatment. Moreover, the repression of HMGB1 facilitated the expression of AQP5. These findings demonstrate that suppression of HMGB1 ameliorates SS-triggered xerostomia via suppressing the HMGB1/TLR4/NF-κB signaling pathway and upregulating AQP5 expression.

Patient-related outcomes in Sjögren syndrome treated with stimulants of salivary secretion: Randomized clinical trial.

OBJECTIVES: To investigate the impact of gustatory stimulants of salivary secretion (GSSS) on Sjögren's syndrome patients' self-perception of xerostomia, oral health-related quality of life (OHRQoL) and salivary secretion. METHODS: A total of 110 Sjögren's syndrome patients were randomly allocated to be treated with either a malic acid lozenge or a citric acid mouthwash and then crossed over. Before and after the interventions, the Xerostomia Inventory 5 (SXI-5-PL) and the Oral Health Impact Profile (OHIP-14-PT) questionnaires (both in the Portuguese language) were administered to patients. Unstimulated, mechanical and gustatory-stimulated salivary flows were determined. Repeated measures and between-subject analyses were performed. Statistical significance was set at 5%. RESULTS: After the intervention and within each group, both GSSS elicited a reduction in the SXI-5-PL and OHIP-14-PT scores and an increase in salivary output, significant in the malic acid lozenge group. The malic acid treatment resulted in a greater effect size and percentage improvement than citric acid mouthwash. The malic acid lozenge also produced a significant greater salivary output than the citric acid rising solution. CONCLUSIONS: In Sjögren's syndrome patients, lozenges containing malic acid increased saliva production and xerostomia relief, resulting in improved quality of life.

Zn2+ stimulates salivary secretions via metabotropic zinc receptor ZnR/GPR39 in human salivary gland cells.

Zn2+ is a divalent cation that is essential for many biological activities, as it influences many ion channels and enzymatic activities. Zn2+ can evoke G-protein-coupled receptor signaling via activation of the metabotropic zinc receptor ZnR/GPR39. In spite of evidence suggesting the presence of ZnR/GPR39 in salivary gland cells, there has been no evidence of ZnR/GPR39-mediated modulation of salivary gland function. Here we characterized the role of ZnR/GPR39 in human submandibular gland cells. A 0.25% ZnCl2 solution evoked secretion of unstimulated and stimulated whole saliva in humans. We found that ZnR/GPR39 is expressed in human submandibular glands and HSG cells. Zn2+ increased cytosolic Ca2+ concentration ([Ca2+]i) in a concentration-dependent manner. Muscarinic antagonist had no effect on Zn2+-induced [Ca2+]i increase, which was completely blocked by the phospholipase C-ß inhibitor. As with muscarinic agonist, Zn2+ also induced the translocation of aquaporin-5 (AQP-5) to the plasma membrane, which was drastically decreased in ZnR/GPR39-knockdown cells. These data suggest that the metabotropic Zn2+ receptor ZnR/GPR39 can modulate salivary secretion in human submandibular gland cells independent of muscarinic or histamine receptor signaling.

[Therapy of sialorrhea with botulinum toxin]. / Therapie der Sialorrhoe mit Botulinumtoxin.

The most important salivary glands are the paired parotid and submandibular glands. Adults produce 1 to 1.5 liters of saliva which are then regularly swallowed. When the act of swallowing is disturbed, salivation occurs. More rarely, the cause can be found in increased saliva production, for example, when caused through medication. Sialorrhea impairs the quality of life substantially and is frequently often socially stigmatizing. Therapy includes conservative measures such as functional dysphagia therapy, oral or transdermal application of anticholinergics, as well as, in selected cases, radiation and surgical measures. Over the last 20 years local injection of botulinum toxin has been successfully applied in the treatment of this condition. With approval of this therapy by the European agencies, this measure will become the therapy of choice for pronounced therapy-resistant sialorrhea.

Effect of ingesting yogurt fermented with Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1 on influenza virus-bound salivary IgA in elderly residents of nursing homes: a randomized controlled trial.

Objective: The purpose of this study was to clarify the influence of consuming yogurt fermented with Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1 (1073R-1-yogurt) on influenza virus-bound salivary immunoglobulin A (IgA) levels, in the elderly residents of nursing homes. Methods: A double-blind, parallel-group, randomized controlled trial was conducted with 96 elderly volunteers residing in 2 nursing homes. During the trial, participants consumed 100 g of 1073R-1-yogurt every morning for 12 weeks, whereas the control participants consumed yogurt fermented with a different Lactobacillus strain (control yogurt). Saliva was collected before the trial and after 4, 8 and 12 weeks of yogurt ingestion. Results: Our data indicated that consumption of 1073R-1-yogurt affected influenza A virus subtype H3N2-bound IgA levels in saliva (p = .001). In addition, saliva flow rate and total IgA levels increased in response to the yogurt intake period in both the 1073R-1 and control yogurt groups (p = .04). Conclusions: Our study suggests that continuous daily ingestion of 1073R-1-yogurt may help prevent infection with influenza A virus subtype H3N2 in elderly subjects with weakened immunity, by increasing the production of influenza A virus subtype of H3N2-bound salivary IgA.

Study on the salivation effect of encapsulated food products containing Sichuan pepper oil.

Sichuan pepper is a plant belonging to the genus Zanthoxylum and family rue. To evaluate whether Sichuan pepper oil boosts saliva secretion using an encapsulated food product containing the oil in subjects presenting with mouth dryness. We evaluated subjective symptoms that changed with a decrease in salivary secretion in the subjects by evaluating the number of Candida colonies and by conducting interviews. The study results demonstrated that salivary secretion increased by 39.4% ± 37.6% after single ingestion of the product, and an additional 8.7% ± 13.2% and 6.3% ± 31.2% following continuous ingestion over 2 and 4 weeks, respectively. These findings suggested that the product rapidly promotes and maintains salivation. Regarding the proliferation of Candida colonies in subjects with mouth dryness, a negative correlation was observed between Candida colony number and salivary secretion quantity. Additionally, interviews revealed that subjective symptoms, such as mouth dryness, discomfort and pain in the mouth, difficulty swallowing the saliva, and feeling of stickiness in the mouth, improved shortly after single ingestion of the product, and mouth dryness was reduced by continuous consumption of the product. These findings indicated that the product studied promotes rapid salivary secretion, is effective in reducing the number of oral Candida colonies, and improves subjective symptoms such as mouth dryness.

GPR55 controls functional differentiation of self-renewing epithelial progenitors for salivation.

GPR55, a lipid-sensing receptor, is implicated in cell cycle control, malignant cell mobilization, and tissue invasion in cancer. However, a physiological role for GPR55 is virtually unknown for any tissue type. Here, we localize GPR55 to self-renewing ductal epithelial cells and their terminally differentiated progeny in both human and mouse salivary glands. Moreover, we find GPR55 expression downregulated in salivary gland mucoepidermoid carcinomas and GPR55 reinstatement by antitumor irradiation, suggesting that GPR55 controls renegade proliferation. Indeed, GPR55 antagonism increases cell proliferation and function determination in quasiphysiological systems. In addition, Gpr55-/- mice present ~50% enlarged submandibular glands with many more granulated ducts, as well as disordered endoplasmic reticuli and with glycoprotein content. Next, we hypothesized that GPR55 could also modulate salivation and glycoprotein content by entraining differentiated excretory progeny. Accordingly, GPR55 activation facilitated glycoprotein release by itself, inducing low-amplitude Ca2+ oscillations, as well as enhancing acetylcholine-induced Ca2+ responses. Topical application of GPR55 agonists, which are ineffective in Gpr55-/- mice, into adult rodent submandibular glands increased salivation and saliva glycoprotein content. Overall, we propose that GPR55 signaling in epithelial cells ensures both the life-long renewal of ductal cells and the continuous availability of saliva and glycoproteins for oral health and food intake.

P2X7 receptor deletion suppresses γ-radiation-induced hyposalivation.

Head and neck cancer treatments typically involve a combination of surgery and radiotherapy, often leading to collateral damage to nearby tissues causing unwanted side effects. Radiation damage to salivary glands frequently leads to irreversible dysfunction by poorly understood mechanisms. The P2X7 receptor (P2X7R) is a ligand-gated ion channel activated by extracellular ATP released from damaged cells as "danger signals." P2X7R activation initiates apoptosis and is involved in numerous inflammatory disorders. In this study, we utilized P2X7R knockout (P2X7R-/-) mice to determine the role of the receptor in radiation-induced salivary gland damage. Results indicate a dose-dependent increase in γ-radiation-induced ATP release from primary parotid gland cells of wild-type but not P2X7R-/- mice. Despite these differences, apoptosis levels are similar in parotid glands of wild-type and P2X7R-/- mice 24-72 h after radiation. However, γ-radiation caused elevated prostaglandin E2 (PGE2) release from primary parotid cells of wild-type but not P2X7R-/- mice. To attempt to uncover the mechanism underlying differential PGE2 release, we evaluated the expression and activities of cyclooxygenase and PGE synthase isoforms. There were no consistent trends in these mediators following radiation that could explain the reduction in PGE2 release in P2X7R-/- mice. Irradiated P2X7R-/- mice have stimulated salivary flow rates similar to unirradiated controls, whereas irradiated wild-type mice have significantly decreased salivary flow rates compared with unirradiated controls. Notably, treatment with the P2X7R antagonist A438079 preserves stimulated salivary flow rates in wild-type mice following γ-radiation. These data suggest that P2X7R antagonism is a promising approach for preventing γ-radiation-induced hyposalivation.

Aspirin Triggered Resolvin D1 reduces inflammation and restores saliva secretion in a Sjögren's syndrome mouse model.

OBJECTIVES: SS is characterized by chronic inflammation of the salivary glands leading to loss of secretory function, thereby suggesting specialized pro-resolving mediators targeting inflammation to be a viable option for treating SS. Previous studies demonstrated that aspirin-triggered resolvin D1 (AT-RvD1) prevents chronic inflammation and enhances saliva secretion in a SS-like mouse model when applied before disease onset. However, this therapy cannot be used in SS patients given that diagnosis occurs post-disease onset and no reliable screening methods exist. Therefore, we examined whether treatment with AT-RvD1 reduces SS-like features in a mouse model post-disease onset. METHODS: Tail vein injections were performed in a SS-like mouse model both with and without AT-RvD1 post-disease onset for 8 weeks, with salivary gland function and inflammatory status subsequently determined. RESULTS: Treatment of a SS-like mouse model with AT-RvD1 post-disease onset restores saliva secretion in both females and males. Moreover, although AT-RvD1 treatment does not reduce the overall submandibular gland lymphocytic infiltration, it does reduce the number of T helper 17 cells within the infiltrates in both sexes. Finally, AT-RvD1 reduces SS-associated pro-inflammatory cytokine gene and protein expression levels in submandibular glands from female but not male mice. CONCLUSION: AT-RvD1 treatment administered post-disease onset reduces T helper 17 cells and successfully restores salivary gland function in a SS mouse model with variable effects noted by sex, thus warranting further examination of both the causes for the sex differences and the mechanisms responsible for the observed treatment effect.