scholarly journals Choline Acetyltransferase Induces the Functional Regeneration of the Salivary Gland in Aging SAMP1/Kl -/- Mice

2021 ◽  
Vol 22 (1) ◽  
pp. 404
Author(s):  
Nguyen Khanh Toan ◽  
Nguyen Chi Tai ◽  
Soo-A Kim ◽  
Sang-Gun Ahn
Keyword(s):  
Salivary Gland ◽  
Choline Acetyltransferase ◽  
Salivary Flow ◽  
Salivary Secretion ◽  
Functional Markers ◽  
Tooth Structure ◽  
Saliva Secretion ◽  
Gland Function ◽  
The Impact

Salivary gland dysfunction induces salivary flow reduction and a dry mouth, and commonly involves oral dysfunction, tooth structure deterioration, and infection through reduced salivation. This study aimed to investigate the impact of aging on the salivary gland by a metabolomics approach in an extensive aging mouse model, SAMP1/Klotho -/- mice. We found that the salivary secretion of SAMP1/Klotho -/- mice was dramatically decreased compared with that of SAMP1/Klotho WT (+/+) mice. Metabolomics profiling analysis showed that the level of acetylcholine was significantly decreased in SAMP1/Klotho -/- mice, although the corresponding levels of acetylcholine precursors, acetyl-CoA and choline, increased. Interestingly, the mRNA and protein expression of choline acetyltransferase (ChAT), which is responsible for catalyzing acetylcholine synthesis, was significantly decreased in SAMP1/Klotho -/- mice. The overexpression of ChAT induced the expression of salivary gland functional markers (α–amylase, ZO-1, and Aqua5) in primary cultured salivary gland cells from SAMP1/Klotho +/+ and -/- mice. In an in vivo study, adeno-associated virus (AAV)-ChAT transduction significantly increased saliva secretion compared with the control in SAMP1/Klotho -/- mice. These results suggest that the dysfunction in acetylcholine biosynthesis induced by ChAT reduction may cause impaired salivary gland function

scholarly journals Localized Delivery of Amifostine Enhances Salivary Gland Radioprotection

2018 ◽  
Vol 97 (11) ◽  
pp. 1252-1259 ◽  
Author(s):  
J.J. Varghese ◽  
I.L. Schmale ◽  
D. Mickelsen ◽  
M.E. Hansen ◽  
S.D. Newlands ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Side Effects ◽  
Cellular Level ◽  
Systemic Administration ◽  
Therapeutic Window ◽  
Saliva Secretion ◽  
Life Issues ◽  
Localized Delivery ◽  
Gland Function

Radiotherapy for head and neck cancers commonly causes damage to salivary gland tissue, resulting in xerostomia (dry mouth) and numerous adverse medical and quality-of-life issues. Amifostine is the only Food and Drug Administration–approved radioprotective drug used clinically to prevent xerostomia. However, systemic administration of amifostine is limited by severe side effects, including rapid decrease in blood pressure (hypotension), nausea, and a narrow therapeutic window. In this study, we demonstrate that retroductal delivery of amifostine and its active metabolite, WR-1065, to murine submandibular glands prior to a single radiation dose of 15 Gy maintained gland function and significantly increased acinar cell survival. Furthermore, in vivo stimulated saliva secretion was maintained in retrograde-treated groups at levels significantly higher than irradiated-only and systemically treated groups. In contrast to intravenous injections, retroductal delivery of WR-1065 or amifostine significantly attenuated hypotension. We conclude that localized delivery to salivary glands markedly improves radioprotection at the cellular level, as well as mitigates the adverse side effects associated with systemic administration. These results support the further development of a localized delivery system that would be compatible with the fractionated dose regimen used clinically.

scholarly journals Mitochondria-targeted antioxidant protects against irradiation-induced salivary gland hypofunction

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xibao Liu ◽  
Krishna P. Subedi ◽  
Changyu Zheng ◽  
Indu Ambudkar
Keyword(s):  
Salivary Gland ◽  
Caspase 3 ◽  
Salivary Secretion ◽  
Initial Increase ◽  
Oral Infections ◽  
Saliva Secretion ◽  
Salivary Gland Secretion ◽  
Radiation Induced ◽  
Salivary Gland Hypofunction ◽  
Gland Function

AbstractA 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 (ROSmt), mitochondrial [Ca2+] ([Ca2+]mt), and activated caspase-3 in acinar cells. In contrast, loss of salivary secretion is persistent. Herein we assessed the role of ROSmt 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 ROSmt, ([Ca2+]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 Ca2+ entry which is critical for saliva secretion. Together, these findings identify the initial increase in ROSmt, 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.

scholarly journals Disease-Induced Changes in Salivary Gland Function and the Composition of Saliva

2021 ◽  
pp. 002203452110048
Author(s):  
G.B. Proctor ◽  
A.M. Shaalan
Keyword(s):  
Salivary Gland ◽  
Sjögren Syndrome ◽  
Healthy Population ◽  
Sjogren Syndrome ◽  
Salivary Gland Function ◽  
Salivary Gland Dysfunction ◽  
Gland Function ◽  
And Function ◽  
The Impact ◽  
Saliva Composition

Although the physiological control of salivary secretion has been well studied, the impact of disease on salivary gland function and how this changes the composition and function of saliva is less well understood and is considered in this review. Secretion of saliva is dependent upon nerve-mediated stimuli, which activate glandular fluid and protein secretory mechanisms. The volume of saliva secreted by salivary glands depends upon the frequency and intensity of nerve-mediated stimuli, which increase dramatically with food intake and are subject to facilitatory or inhibitory influences within the central nervous system. Longer-term changes in saliva secretion have been found to occur in response to dietary change and aging, and these physiological influences can alter the composition and function of saliva in the mouth. Salivary gland dysfunction is associated with different diseases, including Sjögren syndrome, sialadenitis, and iatrogenic disease, due to radiotherapy and medications and is usually reported as a loss of secretory volume, which can range in severity. Defining salivary gland dysfunction by measuring salivary flow rates can be difficult since these vary widely in the healthy population. However, saliva can be sampled noninvasively and repeatedly, which facilitates longitudinal studies of subjects, providing a clearer picture of altered function. The application of omics technologies has revealed changes in saliva composition in many systemic diseases, offering disease biomarkers, but these compositional changes may not be related to salivary gland dysfunction. In Sjögren syndrome, there appears to be a change in the rheology of saliva due to altered mucin glycosylation. Analysis of glandular saliva in diseases or therapeutic interventions causing salivary gland inflammation frequently shows increased electrolyte concentrations and increased presence of innate immune proteins, most notably lactoferrin. Altering nerve-mediated signaling of salivary gland secretion contributes to medication-induced dysfunction and may also contribute to altered saliva composition in neurodegenerative disease.

scholarly journals Radiation Produces Irreversible Chronic Dysfunction in the Submandibular Glands of the Rat

2012 ◽  
Vol 6 (1) ◽  
pp. 8-13 ◽  
Author(s):  
C De la Cal ◽  
J Fernández-Solari ◽  
CE Mohn ◽  
JP Prestifilippo ◽  
A Pugnaloni ◽  
...  
Keyword(s):  
Single Dose ◽  
Salivary Gland ◽  
Ionizing Radiation ◽  
Salivary Secretion ◽  
Maximal Response ◽  
Chronic Effect ◽  
Post Irradiation ◽  
Gland Function ◽  
High Doses ◽  
Rat Salivary Gland

The exposure to high doses of ionizing radiation during radiotherapy results in severe morphological and functional alterations of the salivary glands, such as xerostomia. In the present study we investigated the chronic effect of a single radiation dose of 15 Gray (Gy) limited to head and neck on rat salivary gland function (salivary secretion and gland mass) and histology. Results indicate that norepinephrine (NE)-induced salivary secretion was reduced significantly at 30, 90, 180 and 365 days after the administration of a single dose of 15 Gy of ionizing radiation compared to non-irradiated animals. The maximal secretory response was reduced by 33% at 30 and 90 days post irradiation. Interestingly, a new fall in the salivary response to NE was observed at 180 days and was maintained at 365 days post irradiation, showing a 75% reduction in the maximal response. The functional fall of the salivary secretion observed at 180 days post irradiation was not only associated with a reduction of gland mass but also to an alteration of the epithelial architecture exhibiting a changed proportion of ducts and acini, loss of eosinophilic secretor granular material, and glandular vacuolization and fibrosis. On the basis of the presented results, we conclude that ionizing radiation produces irreversible and progressive alterations of submandibular gland (SMG) function and morphology that leads to a severe salivary hypo-function.

scholarly journals Inhibition of Alk signaling promotes the induction of human salivary-gland-derived organoids

2020 ◽  
Vol 13 (9) ◽  
pp. dmm045054 ◽  
Author(s):  
Shohei Yoshimoto ◽  
Junko Yoshizumi ◽  
Hiromasa Anzai ◽  
Koichiro Morishita ◽  
Kazuhiko Okamura ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Fungal Infections ◽  
Disease Model ◽  
Good Health ◽  
Functional Changes ◽  
Human Salivary Gland ◽  
Saliva Secretion ◽  
Tnf Α

ABSTRACTHyposalivation and xerostomia are the cause of several morbidities, such as dental caries, painful mucositis, oral fungal infections, sialadenitis and dysphagia. For these reasons, preservation of normal saliva secretion is critical for the maintenance of functionally normal oral homeostasis and for keeping good health. Several strategies for restoring salivary gland function have been reported, from different points of view, based on the use of salivary-gland-derived epithelial stem/progenitor cells and tissue engineering approaches to induce organoids that mimic in vivo salivary glands. In this study, we clarified that inhibition of activin receptor-like kinase (Alk) signaling was essential for the induction of human salivary-gland-derived organoids, and demonstrated the usefulness of such organoids as an inflammatory disease model. In inflammatory conditions like sialadenitis, in general, pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α, also known as TNF) are upregulated, but their function is still unclear. In our established human salivary-gland-derived organoid culture system, we successfully induced organoid swelling by stimulation with carbachol, a non-selective cholinergic agonist, and forskolin, an activator of cystic fibrosis transmembrane conductance regulator (CFTR). Furthermore, we found that this organoid swelling was inhibited by TNF-α. From these results, we could clarify the inhibitory function of TNF-α on saliva secretion in vitro. Thus, our established human salivary-gland-derived organoids would be useful for in vitro analyses of the morphological and functional changes involved in salivary gland dysfunctions in several research fields, such as pathobiology, inflammation and regenerative medicine.This article has an associated First Person interview with the first author of the paper.

scholarly journals Salivary Gland Dysfunction in Stroke Patients Is Associated with Increased Protein Glycoxidation and Nitrosative Stress

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Mateusz Maciejczyk ◽  
Piotr Gerreth ◽  
Anna Zalewska ◽  
Katarzyna Hojan ◽  
Karolina Gerreth
Keyword(s):  
Oxidative Stress ◽  
Salivary Gland ◽  
Nitrosative Stress ◽  
Salivary Secretion ◽  
Protein Glycation ◽  
Control Group ◽  
Stroke Patients ◽  
Saliva Secretion ◽  
Whole Saliva ◽  
Salivary Gland Hypofunction

Stroke is one of the leading causes of disability and death worldwide. Despite intensive medical care, many of the complaints directly threatening the patient’s life marginalize their dental needs after the stroke. Recent studies indicate reduced saliva secretion in stroke patients in addition to the increased incidence of caries and periodontal disease. Since oxidative stress plays a vital role in the pathogenesis of salivary gland hypofunction and neurodegenerative disorders (including stroke), this is the first to evaluate the relationship between salivary gland activity and protein glycoxidation and nitrosative damage. The content of glycation and protein oxidation products and nitrosative stress was assessed in nonstimulated (NWS) and stimulated (SWS) whole saliva of stroke patients with normal salivary secretion and hyposalivation (reduced saliva production). The study included 30 patients in the stroke’s subacute phase and 30 healthy controls matched by age and sex. We have shown that stroke patients with hyposalivation show increased contents of protein glycation (↑Amadori products and ↑advanced glycation end products), glycoxidation (↑dityrosine), and nitration (↑nitrotyrosine) products compared to stroke cases with normal salivary secretion and control group. Interestingly, higher oxidative/nitrosative stress was found in NWS, which strongly correlates with salivary flow rate, total protein content, and salivary amylase activity. Such relationships were not observed in the control group. Summarizing, oxidative and nitrosative stress may be one of the mechanisms responsible for the impairment of saliva secretion in stroke patients. However, extraglandular sources of salivary oxidative stress in stroke patients cannot be excluded. Further studies to assess salivary gland hypofunction in stroke cases are necessary.

scholarly journals VIRUS AS A CAUSE OF SALIVARY GLAND DISEASES

2019 ◽  
Vol 6 (1) ◽  
pp. 37
Author(s):  
Etis Duhita Rahayuningtyas ◽  
Riani Setiadhi
Keyword(s):  
Salivary Gland ◽  
Viral Infection ◽  
Salivary Glands ◽  
Salivary Flow ◽  
Salivary Secretion ◽  
Coxsackie Virus ◽  
Parasympathetic Nerves ◽  
Barr Virus ◽  
Salivary Gland Diseases ◽  
Simplex Virus

Background: Enlargement in the extraoral region with the absence of abnormal dental and periodontal structures are sometimes seen in dental practice, sometimes followed by xerostomia. Enlargement of the acute nonsuppurative salivary glands has been associated with several types of viruses. The purpose of this paper is to review salivary gland diseases associated with non-HIV and HIV viral infections.Discussion: Non-HIV viruses which were detected in the salivary glands including Paramyxovirus, cytomegalovirus (CMV), Hepatitis C virus (HCV), human papilloma viruses (HPV), Epstein-Barr virus (EBV), human herpes simplex virus (HHSV-8), and coxsackie virus. HIV-associated salivary gland disease typically presents with xerostomia and/or intraglandular lymph nodes, and diffuse infiltrative lymphocytosis syndrome (DILS). The most common viral infection conditions in salivary gland disorders are mumps and HIV. Enlargement and inflammation of the glandular structures will affects the control of salivary secretion by nerves. Parasympathetic nerves block conducted signals to the salivary glands, so the salivary flow isdecreased.Conclusion: There is association between viral infection and diseases of thesalivary gland. By knowing sequelae viruses on the salivary gland, dentists are expected to understand the clinical condition and therapeutic that should be given to the patients.

scholarly journals SOURCES OF LARVAL SALIVARY GLAND SECRETION IN THE DIPTERAN CHIRONOMUS TENTANS

1969 ◽  
Vol 40 (1) ◽  
pp. 61-78 ◽  
Author(s):  
D. Doyle ◽  
H. Laufer
Keyword(s):  
Salivary Gland ◽  
De Novo ◽  
Salivary Secretion ◽  
Disc Electrophoresis ◽  
Protein Fractions ◽  
Chironomus Tentans ◽  
Salivary Gland Secretion ◽  
Larval Salivary Gland

The soluble proteins in the hemolymph, the salivary gland, and the salivary secretion of fourth instar Chironomus tentans were examined by disc electrophoresis in acrylamide gels. Of the 11 protein fractions detected in buffered saline extracts of the gland, 10 are present also in the hemolymph. Amino acid isotope incorporation experiments indicate that the protein fractions shared by the salivary gland and the hemolymph are not synthesized in the gland but are synthesized in other larval tissues. Immunochemical studies show that most of these proteins eventually are secreted from the gland. The salivary gland in vivo and in vitro is active in de novo protein synthesis. The protein synthesized tends to form large molecular weight aggregates. As demonstrated by radioautography, at least 80% of this protein is secreted from the 30 large cells forming most of the gland. The proteins synthesized in the salivary gland cannot be detected in the hemolymph. The results of this investigation are consistent with a mechanism of secretion formation involving both de novo synthesis of some secretion proteins and the selective uptake, transport, and secretion of hemal proteins by the salivary gland.

mTOR Inhibition Ablates Cisplatin-Resistant Salivary Gland Cancer Stem Cells

2020 ◽  
pp. 002203452096514
Author(s):  
T. Nakano ◽  
K.A. Warner ◽  
A.E. Oklejas ◽  
Z. Zhang ◽  
C. Rodriguez-Ramirez ◽  
...  
Keyword(s):  
Stem Cells ◽  
Salivary Gland ◽  
Cancer Stem Cells ◽  
Mucoepidermoid Carcinoma ◽  
Salivary Gland Cancer ◽  
Mtor Inhibition ◽  
Platinum Based Chemotherapy ◽  
The Impact

Patients with advanced salivary gland mucoepidermoid carcinoma (MEC) are treated with surgery and radiotherapy, as current systemic therapies are largely ineffective. As such, current treatment frequently leads to poor long-term survival due to locoregional recurrence or metastases. We have shown that salivary gland cancer stem cells (CSCs) are resistant to platinum-based chemotherapy and drive tumor progression. The purpose of this study was to investigate the effect of therapeutic inhibition of mTOR (mechanistic target of rapamycin) on resistance of CSCs to cisplatin, a prototypic platinum-based chemotherapeutic agent. Viability assays determined the effect of several inhibitors of PI3k/mTOR signaling (e.g., temsirolimus, BKM120, AZD8055, PF4708671) and/or cisplatin on survival of human MEC cells. The impact of mTOR inhibitors and/or cisplatin on MEC stemness was examined with salisphere assays, flow cytometry for ALDH/CD44 (CSC markers for MEC), and Western blots for Bmi-1 expression (marker of stem cell self-renewal). Salivary gland MEC patient-derived xenografts were used to examine the effect of cisplatin and/or temsirolimus on CSCs in vivo. We observed that cisplatin induced mTOR and S6K1 phosphorylation, increased the number and size of MEC salispheres, and induced Bmi-1 expression and the fraction of CSCs in MEC models in vitro. Cisplatin also increased the fraction of CSCs in vivo. In contrast, mTOR inhibition (e.g., temsirolimus) blocked cisplatin-induced Bmi-1 expression and salisphere formation in vitro. Remarkably, temsirolimus slowed down tumor growth and decreased the fraction of CSCs ( P < 0.05) even in presence of cisplatin in a short-term in vivo experiment. Collectively, these results demonstrate that therapeutic inhibition of mTOR ablates cytotoxic-resistant CSCs, and they suggest that a combination of an mTOR inhibitor and platinum-based chemotherapy might be beneficial to patients with salivary gland mucoepidermoid carcinoma.

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