Activation of mTOR coincides with autophagy during ligation-induced atrophy in the rat submandibular gland.
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ABSTRACT:
SUBMITTER: Silver N
PROVIDER: S-EPMC2948542 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ATP-sensitive K(+) (K(ATP)) channel subunits were investigated in rat submandibular gland (SMG). RT-PCR detected the presence of mRNA transcripts of the Kir6.1, Kir6.2, SUR2A, and SUR2B in the SMG, whereas SUR1 mRNA was barely detected. Western blot analysis provided the evidence that these four K(ATP) channel subunits are expressed in rat SMG. Immunostaining detected that these four K(ATP) channel subunits are widely distributed, with different intensities, in myoepithelial cells, epithelial cells of intercalated ducts, granular convoluted tubules, striated ducts, and excretory ducts. Immunofluorescence double staining showed that Kir6.1 and Kir6.2 colocalized with SUR2A in the myoepithelial cells, granular convoluted tubules, striated ducts, and excretory ducts. Kir6.1 and Kir6.2 also colocalized with SUR2B, mainly in the duct system, e.g., the granular convoluted tubules, striated ducts, and excretory ducts. Taken together, these results indicate that the K(ATP) channels in SMG may consist of Kir6.1, Kir6.2, SUR2A, and SUR2B, with various combinations of colocalization with each other, and may play important roles in rat SMG during salivary secretion.
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Project description:Transient receptor potential vanilloid subtype 4 (TRPV4) is a ligand-gated nonselective cation channel that participates in the transduction of mechanical and osmotic stimuli in different tissues. TRPV4 is activated by endogenous arachidonic acid metabolites, 4?-phorbol-12,13 didecanoate, GSK1016790A, moderate heat, and mechanical stress. TRPV4 is expressed in the salivary glands, but its expression pattern and function are poorly understood. The aim of this study was to evaluate the functional role of TRPV4 channels in the mouse submandibular gland. Using RT-PCR and Western blot analysis, we detected expression of TRPV4 message and protein, respectively, in the submandibular gland. Immunolocalization studies showed that TRPV4 targeted to the basolateral membrane of mouse submandibular gland acinar cells. Pharmacological TRPV4 activation using the selective agonist GSK1016790A caused Ca(2+) influx in isolated acinar cells in a basal-to-apical wave. Consistent with these observations, GSK1016790A elicited salivation in the perfused submandibular gland that was dependent on extracellular Ca(2+). In summary, we report that activation of TRPV4 channels induced Ca(2+) influx and salivation and, thus, may contribute a novel nonadrenergic, noncholinergic secretion pathway in the mouse submandibular gland.
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Project description:Adiponectin and adiponectin receptors (AdipoR1/2) are expressed in various tissues and are involved in the regulation of multiple functions such as energy metabolism and inflammatory responses. However, the effect of adiponectin and AdipoRs in submandibular glands has not been fully evaluated. In the present study, we found that mRNA and protein of both adiponectin and AdipoR1/2 were expressed in rat submandibular glands and in the SMG-C6 cell line, as evidenced by RT-PCR and Western blot analysis. Immunofluorescence staining showed that adiponectin was diffused in the cytoplasm, while AdipoR1/2 was concentrated in the membrane of acinar cells. Saliva flow was significantly increased by full length adiponectin (fAd) or globular adiponectin (gAd) perfusion in isolated rat submandibular glands. 5-Aminoimidazole-4-carboxamide-1-4-ribofuranoside (AICAR), an adenosine monophosphate activated protein kinase (AMPK) activator, also increased saliva secretion. fAd, gAd, and AICAR all increased the average width of apical tight junctions in perfused submandibular glands, and decreased transepithelial electrical resistance (TER) in SMG-C6 cells, suggesting that adiponectin promoted secretion by modulating paracellular permeability. fAd and gAd increased p-AMPK levels, while AraA, an AMPK antagonist, abolished fAd- and gAd-induced changes in secretion, tight junction ultrastructure, and TER. Moreover, both AdipoR1 and AdipoR2 were required for fAd- or gAd-induced p-AMPK and TER responses, suggesting from their inhibition following AdipoR1 or AdipoR2 knockdown, and co-knockdown of AdipoRs by RNA interference. Our results suggest that adiponectin functions as a promoter of salivary secretion in rat submandibular glands via activation of AdipoRs, AMPK, and paracellular permeability.
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Project description:The salivary glands play a central role in the secretion of saliva, whose composition and volume affect oral and overall health. A lesser-explored dimension encompasses the possible changes in salivary gland proteomes in response to fluctuations in sex hormone levels. This study aimed to examine the effects of chronic exposure to testosterone on salivary gland remodeling, particularly focusing on proteomic adaptations. Therefore, male Wistar rats were implanted with subcutaneous testosterone-releasing devices at 14 weeks of age. Their submandibular glands were histologically and molecularly analyzed 47 weeks later. The results underscored a significant increase in gland mass after testosterone exposure, further supported by histologic evidence of granular duct enlargement. Despite increased circulating sex hormones, there was no detectable shift in the tissue levels of estrogen alpha and androgen receptors. GeLC-MS/MS and subsequent bioinformatics identified 308 proteins in the submandibular glands, 12 of which were modulated by testosterone. Of note was the pronounced upregulation of Klk3 and the downregulation of Klk6 and Klk7 after testosterone exposure. Protein-protein interaction analysis with the androgen receptor suggests that Klk3 is a potential target of androgenic signaling, paralleling previous findings in the prostate. This exploratory analysis sheds light on the response of salivary glands to testosterone exposure, providing proteome-level insights into the associated weight and histological changes.
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Project description:The sulphotransferase activity of rat submandibular gland differs markedly from that of testis, kidney and brain. The addition of lipid acceptors and Mn2+ (or Mg2+), which have been shown to enhance sulpholipid formation from adenosine 3'-phosphate 5'-sulphatophosphate in other tissues, has either no effect or inhibits the transfer process.
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Project description:Circadian rhythms are essential for health and regulate various physiological functions. These rhythms are regulated by a negative-feedback loop involving clock genes in the suprachiasmatic nucleus (SCN) and peripheral tissues. The rate of secretion of salivary substances, ions, and water follows a circadian rhythm, however, the relationship between the molecular mechanism of salivary secretion and peripheral circadian rhythm is not yet clear. Anoctamin 1 (ANO1, also known as TMEM16A) and Aquaporin 5 (AQP5) play an important role in the transport of ions and water in the submandibular glands (SGs). We examined the interaction between the rhythmic expression pattern of the clock genes, Ano1 and Aqp5, in rat whole SGs as well as isolated acinar and ductal cells. Circadian rhythmic expression for Bmal1, Per1, Per2, Clock, Cry1, Cry2, Ror?, and Rev-erb? mRNAs, also called the clock genes, was observed in rat SGs by semi-quantitative RT-PCR analysis. We also observed rhythmic patterns in Ano1 and Aqp5 mRNA expression. The expression of ANO1 protein also showed circadian rhythm, as confirmed by western blot analysis. We could not observe any time delay between the peak expression of ANO1 protein and its mRNA. Expression levels of the clock gene mRNAs in the ductal cells was higher than that in acinar cells, however, rhythmic oscillations were observed in both. Our results suggest that SGs have peripheral clocks, and rhythmic expressions of Ano1 and Aqp5 along with the clock genes, may play an important role in the circadian regulation of salivary secretion.
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Project description:1. Serotonin (5-hydroxytryptamine, 5-HT) has been shown to increase cyclic AMP production in dispersed cell aggregates from the major salivary glands of the rat. The goal of the present study was to identify the 5-HT receptor subtypes that mediate these effects in rat submandibular glands (SMG). 2. Among the 5-HT receptor subtypes identified in the rat, 5-HT(4(a,b)), 5-HT(6) and 5-HT(7(a,b,c)) activate adenylyl cyclase (AC). We used subtype specific primers to screen rat SMG by reverse transcription-PCR. Results indicate the presence of mRNA for 5-HT(4(b)) and 5-HT(7(a)) but not for 5-HT(4(a)), 5-HT(6) and 5-HT(7(b,c)). 3. In dispersed SMG cells, 5-carboxyamidotryptamine (5-CT), a 5-HT(7) receptor agonist, stimulated cyclic AMP synthesis with higher potency (EC(50)=27+/-5 nM) but lower efficacy than 5-HT, suggesting a 5-HT(7) component and an additional component in the response to 5-HT. The 5-HT(7) contribution was further supported by antagonism of the 5-CT effect by metergoline, a 5-HT(7) antagonist, which exhibited an affinity (K(i)=50 nM) similar to that obtained at the cloned 5-HT(7) receptor. 4. In the presence of a maximally effective concentration of 5-CT, 5-HT produced an additional increase in cyclic AMP production that was inhibited by the 5-HT(4) receptor antagonist, GR113808, suggesting that the second component of cyclic AMP production is mediated by 5-HT(4) receptors. 5. These findings indicate the presence in rat SMG of both 5-HT(4(b)) and 5-HT(7(a)) receptors positively coupled to AC.
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Project description:BackgroundOrgan replacement regenerative therapy based on human adult stem cells may be effective for salivary gland hypofunction. However, the generated tissues are immature because the signaling factors that induce the differentiation of human salivary gland stem cells into salivary glands are unknown.MethodsIsolated human submandibular gland stem/progenitor cells (hSMGepiS/PCs) were characterized and three-dimensionally (3D) cultured to generate organoids and further induced by fibroblast growth factor 10 (FGF10) in vitro. The induced spheres alone or in combination with embryonic day 12.5 (E12.5) mouse salivary gland mesenchyme were transplanted into the renal capsules of nude mice to assess their development in vivo. Immunofluorescence, quantitative reverse transcriptase-polymerase chain reaction, calcium release analysis, western blotting, hematoxylin-eosin staining, Alcian blue-periodic acid-Schiff staining, and Masson's trichrome staining were performed to assess the structure and function of generated tissues in vitro and in vivo.ResultsThe isolated hSMGepiS/PCs could be long-term cultured with a stable genome. The organoids treated with FGF10 [FGF10 (+) group] exhibited higher expression of salivary gland-specific markers; showed spatial arrangement of AQP5+, K19+, and SMA+ cells; and were more sensitive to the stimulation by neurotransmitters than untreated organoids [FGF10 (-) group]. After heterotopic transplantation, the induced cell spheres combined with mouse embryonic salivary gland mesenchyme showed characteristics of mature salivary glands, including a natural morphology and saliva secretion.ConclusionFGF10 promoted the development of the hSMGepiS/PC-derived salivary gland organoids by the expression of differentiation markers, structure formation, and response to neurotransmitters in vitro. Moreover, the hSMGepiS/PCs responded to the niche in mouse embryonic mesenchyme and further differentiated into salivary gland tissues with mature characteristics. Our study provides a foundation for the regenerative therapy of salivary gland diseases.
| S-EPMC7083056 | biostudies-literature
Project description:Salivary glands consist of highly specialized epithelial cells that secrete the fluid, saliva, and/or transport saliva into the oral cavity. Saliva is essential to lubricate the oral cavity for food consumption and to maintain the hygiene of the oral cavity. In this review, we will focus on the formation of the epithelial cell lineage and the cell junctions that are essential for formation of saliva and maintenance of the epithelial barrier between the ducts that transport saliva and the extracellular environment.
| S-EPMC10606785 | biostudies-literature
Project description:BackgroundNUT carcinoma (NUTc) is a rare and aggressive malignant epithelial tumor characterized by rearrangement of the NUT gene on chromosome 15q14.MethodsIn this article, we present the fifth case worldwide of a young woman affected by a NUTc arising from a submandibular gland, presenting as a rapidly evolving mass. She underwent a right scialoadenectomy and received the initial diagnosis of high-grade mucoepidermoid carcinoma. Due to evidence of local recurrence at magnetic resonance imaging 1 month later, a subsequent right radical neck dissection was performed. The patient then sought a second opinion at our cancer center and finally received the correct diagnosis of NUT carcinoma. Given the well-known aggressive behavior of this neoplasm, as well as clinical and radiological features, she underwent adjuvant chemo-radiation (intensity-modulated radiotherapy + concurrent chemotherapy with cisplatin).ResultsAfter a disease-free interval of 2.6 months, a widespread metastatic disease led to rapid deterioration of performance status and patient death in a few weeks after metastatic onset.ConclusionsWe presented a case of NUTc arising from salivary gland aiming to improve the knowledge of this rare malignancy. First, we pointed out that in the setting of rare tumors like salivary gland cancers, the diagnosis should be obtained by expert pathologists, and patients should be referred to tertiary cancer centers for their clinical management. Second, molecular profiling may help to identify possible druggable targets that may be exploited to treat patients suffering from this aggressive malignancy. Sharing the molecular data provided in this case will be useful for further research.
| S-EPMC10728538 | biostudies-literature