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The Journal of Physiology Jun 2016Studies over the past four decades have established that Ca(2+) is a critical factor in control of salivary gland function and have led to identification of the critical... (Review)
Review
Studies over the past four decades have established that Ca(2+) is a critical factor in control of salivary gland function and have led to identification of the critical components of this process. The major ion transport mechanisms and ion channels that are involved in fluid secretion have also been established. The key event in activation of fluid secretion is an increase in [Ca(2+) ]i triggered by inositol 1,4,5-trisphosphate (IP3 )-induced release of Ca(2+) from ER via the IP3 receptor (IP3 R). IP3 Rs determine the site of initiation and the pattern of the [Ca(2+) ]i signal in the cell. However, Ca(2+) entry into the cell is required to sustain the elevation of [Ca(2+) ]i and fluid secretion and is mediated by the store-operated Ca(2+) entry (SOCE) mechanism. Orai1, TRPC1, TRPC3 and STIM1 have been identified as critical components of SOCE in these cells. Cells finely tune the generation and amplification of [Ca(2+) ]i signals for regulation of cell function. An important emerging area is the concept that unregulated [Ca(2+) ]i signals in cells can directly cause cell damage, dysfunction and disease. Alternatively, aberrant [Ca(2+) ]i signals can also amplify and increase the rates of cell damage. Such defects in Ca(2+) signalling have been described in salivary glands in conjunction with radiation-induced loss of salivary gland function as well as in the salivary defects associated with the autoimmune exocrinopathy Sjögren's syndrome. Such defects have been associated with altered function or expression of key Ca(2+) signalling components, such as STIM proteins and TRP channels. These studies offer new avenues for examining the mechanisms underlying the disease and development of novel clinical targets and therapeutic strategies.
Topics: Animals; Calcium Channels; Calcium Signaling; Humans; Salivary Glands; Sjogren's Syndrome
PubMed: 26592972
DOI: 10.1113/JP271143 -
International Journal of Molecular... Feb 2020AQP5 plays an important role in the salivary gland function. The and protein for aquaporin 5 (AQP5) are expressed in the acini from embryonic days E13-16 and E17-18,... (Review)
Review
AQP5 plays an important role in the salivary gland function. The and protein for aquaporin 5 (AQP5) are expressed in the acini from embryonic days E13-16 and E17-18, respectively and for entire postnatal days. Ligation-reopening of main excretory duct induces changes in the AQP5 level which would give an insight for mechanism of regeneration/self-duplication of acinar cells. The AQP5 level in the submandibular gland (SMG) decreases by chorda tympani denervation (CTD) via activation autophagosome, suggesting that its level in the SMG under normal condition is maintained by parasympathetic nerve. Isoproterenol (IPR), a β-adrenergic agonist, raised the levels of membrane AQP5 protein and its in the parotid gland (PG), suggesting coupling of the AQP5 dynamic and amylase secretion-restoration cycle. In the PG, lipopolysaccharide (LPS) is shown to activate mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signalings and potentially downregulate AQP5 expression via cross coupling of activator protein-1 (AP-1) and NF-κB. In most species, Ser-156 and Thr-259 of AQP5 are experimentally phosphorylated, which is enhanced by cAMP analogues and forskolin. cAMP-dependent phosphorylation of AQP5 does not seem to be markedly involved in regulation of its intracellular trafficking but seems to play a role in its constitutive expression and lateral diffusion in the cell membrane. Additionally, Ser-156 phosphorylation may be important for cancer development.
Topics: Animals; Aquaporin 5; Gene Expression Regulation; Humans; Phosphorylation; Protein Processing, Post-Translational; Salivary Gland Diseases; Salivary Glands; Ubiquitination
PubMed: 32053992
DOI: 10.3390/ijms21041182 -
Genesis (New York, N.Y. : 2000) May 2018Salivary glands are responsible for maintaining the health of the oral cavity and are routinely damaged by therapeutic radiation for head and neck cancer as well as by... (Review)
Review
Salivary glands are responsible for maintaining the health of the oral cavity and are routinely damaged by therapeutic radiation for head and neck cancer as well as by autoimmune diseases such as Sjögren's syndrome. Regenerative approaches based on the reactivation of endogenous stem cells or the transplant of exogenous stem cells hold substantial promise in restoring the structure and function of these organs to improve patient quality of life. However, these approaches have been hampered by a lack of knowledge on the identity of salivary stem cell populations and their regulators. In this review we discuss our current knowledge on salivary stem cells and their regulators during organ development, homeostasis and regeneration. As increasing evidence in other systems suggests that progenitor cells may be a source of cancer, we also review whether these same salivary stem cells may also be cancer initiating cells.
Topics: Adult Stem Cells; Animals; Cell Differentiation; Humans; Neoplasms; Regeneration; Salivary Glands
PubMed: 29663717
DOI: 10.1002/dvg.23211 -
Colombia Medica (Cali, Colombia) Dec 2018Obesity has reached pandemic proportions in recent years. Not only adults suffer from the disease, but increasingly children and young people. One of the main causes of... (Review)
Review
Obesity has reached pandemic proportions in recent years. Not only adults suffer from the disease, but increasingly children and young people. One of the main causes of overweight and obesity is excessive food intake, in particular heavily processed carbohydrates. Obesity alters multiple organs, including the salivary glands, bringing functional alterations with it. Among researchers, the relation between obesity and tooth decay, periodontal disease and xerostomia is being debated. More and more scientific reports are drawing attention to the changes in the microflora of the oral cavity during obesity. All changes are closely related to the morphological and functional alterations of the salivary glands. This article review presents the current points of view regarding the impact of obesity on the health of the salivary glands, and how changes their functions influence other structures in the oral cavity.
Topics: Adolescent; Adult; Child; Dental Caries; Humans; Obesity; Pediatric Obesity; Periodontal Diseases; Salivary Gland Diseases; Salivary Glands; Xerostomia
PubMed: 30700921
DOI: 10.25100/cm.v49i3.3919 -
Journal of Dental Research Aug 2015Autophagy is a catabolic process that has been shown to have a role in many cellular processes including the removal of excessive or damaged proteins and protein... (Review)
Review
Autophagy is a catabolic process that has been shown to have a role in many cellular processes including the removal of excessive or damaged proteins and protein aggregates. The salivary glands play a critical role in oral health, and their secretory capacity may be critically intertwined with the autophagic process. This review describes the role of autophagy activation in normal salivary gland homeostasis and during the glandular stress responses of therapeutic radiation, ductal ligation, autoimmunity, and salivary gland adenoid cystic carcinoma.
Topics: Animals; Autoimmune Diseases; Autophagy; Carcinoma, Adenoid Cystic; Disease Models, Animal; Homeostasis; Humans; Ligation; Salivary Gland Neoplasms; Salivary Glands; Sirolimus; Stress, Physiological
PubMed: 26092378
DOI: 10.1177/0022034515590796 -
Ear, Nose, & Throat Journal Aug 2020The pathogenesis and molecular basis of salivary gland tumors (SGT) are not well understood. We investigated the expression of receptor activator of nuclear factor κB...
OBJECTIVES
The pathogenesis and molecular basis of salivary gland tumors (SGT) are not well understood. We investigated the expression of receptor activator of nuclear factor κB (RANK) and RANK ligand (RANKL) in benign and malignant SGTs and their relationship with clinicopathological features.
METHODS
Fifty malignant and 38 benign SGTs were analyzed in this study. We evaluated the correlation between RANK and RANKL expression and benign and malignant tumors, as well as the correlation between clinicopathological prognostic parameters and RANK and RANKL expression.
RESULTS
Receptor activator of nuclear factor κB was positive in 82% (41) malignant SGTs and in 34.2% (13) benign SGTs. Receptor activator of nuclear factor κB ligand was expressed in 28% (14) malignant and 5.3% (2) benign tumors. Receptor activator of nuclear factor κB and RANKL expression were significantly different between benign and malignant SGTs ( < .001, = .006, respectively). However, a relationship was not found between positive expression of RANK or RANKL and clinicopathological features.
CONCLUSIONS
In our study, RANK and RANKL expression was found to be higher in malignant SGTs compared to benign SGTs and RANK was more sensitive than RANKL. In addition, RANK and RANKL expression was higher in some malignant histological subtypes. Based on these results, we think that RANK and RANKL expression in SGTs and its potential as a target for treatment should continue to be investigated.
Topics: Aged; Biomarkers, Tumor; Female; Gene Expression; Humans; Immunohistochemistry; Male; Middle Aged; Neoplasm Grading; Prognosis; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Salivary Gland Neoplasms; Salivary Glands; Sensitivity and Specificity; Tumor Burden
PubMed: 32525717
DOI: 10.1177/0145561320930640 -
Clinical and Experimental Rheumatology Dec 2023Wide variety in salivary gland 18F-FDG-uptake is observed in the general population. A general consensus about the usefulness of 18F-FDG-PET/CT to detect salivary gland...
OBJECTIVES
Wide variety in salivary gland 18F-FDG-uptake is observed in the general population. A general consensus about the usefulness of 18F-FDG-PET/CT to detect salivary gland inflammatory conditions, such as in primary Sjögren's syndrome (pSS), is not yet clear. This study aimed to investigate whether there are differences in uptake of 18F-FDG in salivary glands among two autoimmune groups [pSS, giant cell arteritis (GCA)] and a non-autoimmune group (lung cancer).
METHODS
PSS patients aged ≥50 years who underwent 18F-FDG-PET/CT were included and age-matched with GCA patients and a non-autoimmune control group (lung cancer patients). Scans were visually evaluated and quantitative analysis was performed by measuring standardised uptake values (SUV) within salivary glands and lacrimal glands. For GCA patients, arteries in the vicinity of the parotid and submandibular gland were assessed for positivity.
RESULTS
PSS patients did not show increased 18F-FDG-uptake in the parotid or submandibular gland, compared to the other two groups. For the tubarial gland, significantly higher SUVmax was found in the pSS patient group. Interestingly, GCA patients had significantly higher SUVmax in the submandibular gland than the other two groups. Visual 18F-FDG-positivity of cranial arteries related to the parotid and submandibular glands was associated with significantly higher SUVmax in salivary glands of GCA patients.
CONCLUSIONS
Although 18F-FDG-uptake was not increased in parotid and submandibular glands of pSS patients, increased 18F-FDG-uptake in tubarial glands of pSS patients might indicate a role for these glands in pSS. Furthermore, parotid and submandibular glands may be affected by local vasculitis in GCA.
Topics: Humans; Sjogren's Syndrome; Fluorodeoxyglucose F18; Positron Emission Tomography Computed Tomography; Giant Cell Arteritis; Salivary Glands; Parotid Gland; Submandibular Gland; Lung Neoplasms
PubMed: 38079331
DOI: 10.55563/clinexprheumatol/8qt9me -
Rheumatology (Oxford, England) May 2022The involvement of salivary glands in primary SS (pSS) can be assessed in different ways: histopathology, salivary flow and ultrasonography. To understand the relative...
OBJECTIVE
The involvement of salivary glands in primary SS (pSS) can be assessed in different ways: histopathology, salivary flow and ultrasonography. To understand the relative value of these different approaches, it is crucial to understand the relationship between them. As we routinely perform these three modalities in the parotid gland for disease evaluation, our aim was to investigate the construct validity between these modalities in one and the same gland.
METHODS
Consecutive sicca patients underwent a multidisciplinary diagnostic workup including parotid gland biopsy, collection of parotid gland-specific saliva and parotid gland ultrasonography. Patients who were classified as pSS according to the ACR-EULAR criteria were included. Construct validity was assessed using Spearman's correlation coefficients.
RESULTS
The 41 included pSS patients completed a full workup within a mean time interval of 2.6 months. Correlations between histopathological features and stimulated parotid salivary flow were fair (ρ = -0.123 for focus score and ρ = -0.259 for percentage of CD45+ infiltrate). Likewise, poor correlations were observed between stimulated parotid salivary flow and parotid ultrasonography (ρ = -0.196). Moderate to good associations were found between the histopathological items focus score and the percentage of CD45+ infiltrate, with parotid US scores (total US score: ρ = 0.510 and ρ = 0.560; highest for homogeneity: ρ = 0.574 and ρ = 0.633).
CONCLUSION
Although pSS-associated ultrasonographic findings did correlate with histopathological features, the three modalities that evaluate salivary gland involvement assess different (or at best partly related) constructs. Therefore histopathology, salivary flow and ultrasonography are complementary measurements and cannot directly replace each other in the workup of pSS.
Topics: Humans; Parotid Gland; Saliva; Salivary Glands; Sjogren's Syndrome; Ultrasonography
PubMed: 34672336
DOI: 10.1093/rheumatology/keab781 -
Cellular and Molecular Life Sciences :... Apr 2021The mammalian salivary gland develops as a highly branched structure designed to produce and secrete saliva. This review focuses on research conducted on mammalian... (Review)
Review
The mammalian salivary gland develops as a highly branched structure designed to produce and secrete saliva. This review focuses on research conducted on mammalian salivary gland development, particularly on the differentiation of acinar, ductal, and myoepithelial cells. We discuss recent studies that provide conceptual advances in the understanding of the molecular mechanisms of salivary gland development. In addition, we describe the organogenesis of submandibular glands (SMGs), model systems used for the study of SMG development, and the key signaling pathways as well as cellular processes involved in salivary gland development. The findings from the recent studies elucidating the identity of stem/progenitor cells in the SMGs, and the process by which they are directed along a series of cell fate decisions to form functional glands, are also discussed. Advances in genetic tools and tissue engineering strategies will significantly increase our knowledge about the mechanisms by which signaling pathways and cells establish tissue architecture and function during salivary gland development, which may also be conserved in the growth and development of other organ systems. An increased knowledge of organ development mechanisms will have profound implications in the design of therapies for the regrowth or repair of injured tissues. In addition, understanding how the processes of cell survival, expansion, specification, movement, and communication with neighboring cells are regulated under physiological and pathological conditions is critical to the development of future treatments.
Topics: Animals; Cell Differentiation; Humans; Organogenesis; Salivary Glands; Signal Transduction; Stem Cells
PubMed: 33449148
DOI: 10.1007/s00018-020-03741-2 -
Frontiers in Immunology 2023Assessing labial salivary gland exocrinopathy is a cornerstone in primary Sjögren's syndrome. Currently this relies on the histopathologic diagnosis of focal...
INTRODUCTION
Assessing labial salivary gland exocrinopathy is a cornerstone in primary Sjögren's syndrome. Currently this relies on the histopathologic diagnosis of focal lymphocytic sialadenitis and computing a focus score by counting lym=phocyte foci. However, those lesions represent advanced stages of primary Sjögren's syndrome, although earlier recognition of primary Sjögren's syndrome and its effective treatment could prevent irreversible damage to labial salivary gland. This study aimed at finding early biomarkers of primary Sjögren's syndrome in labial salivary gland combining metabolomics and machine-learning approaches.
METHODS
We used a standardized targeted metabolomic approach involving high performance liquid chromatography coupled with mass spectrometry among newly diagnosed primary Sjögren's syndrome (n=40) and non- primary Sjögren's syndrome sicca (n=40) participants in a prospective cohort. A metabolic signature predictive of primary Sjögren's syndrome status was explored using linear (logistic regression with elastic-net regularization) and non-linear (random forests) machine learning architectures, after splitting the data set into training, validation, and test sets.
RESULTS
Among 126 metabolites accurately measured, we identified a discriminant signature composed of six metabolites with robust performances (ROC-AUC = 0.86) for predicting primary Sjögren's syndrome status. This signature included the well-known immune-metabolite kynurenine and five phospholipids (LysoPC C28:0; PCaa C26:0; PCaaC30:2; PCae C30:1, and PCaeC30:2). It was split into two main components: the first including the phospholipids was related to the intensity of lymphocytic infiltrates in salivary glands, while the second represented by kynurenine was independently associated with the presence of anti-SSA antibodies in participant serum.
CONCLUSION
Our results reveal an immuno-lipidomic signature in labial salivary gland that accurately distinguishes early primary Sjögren's syndrome from other causes of sicca symptoms.
Topics: Humans; Sjogren's Syndrome; Prospective Studies; Kynurenine; Salivary Glands; Salivary Glands, Minor
PubMed: 37520535
DOI: 10.3389/fimmu.2023.1205616