scholarly journals Transient Activation of Hedgehog Signaling Inhibits Cellular Senescence and Inflammation in Radiated Swine Salivary Glands through Preserving Resident Macrophages

2021 ◽  
Vol 22 (24) ◽  
pp. 13493
Author(s):  
Liang Hu ◽  
Conglin Du ◽  
Zi Yang ◽  
Yang Yang ◽  
Zhao Zhu ◽  
...  
Keyword(s):  
Salivary Glands ◽  
Cellular Senescence ◽  
Hedgehog Signaling ◽  
Swine Model ◽  
M2 Macrophage ◽  
Parotid Glands ◽  
P53 Signaling ◽  
Transient Activation ◽  
Radiation Induced ◽  
Gland Function

Salivary gland function is commonly and irreversibly damaged by radiation therapy for head and neck cancer. This damage greatly decreases the patient’s quality of life and is difficult to remedy. Previously, we found that the transient activation of Hedgehog signaling alleviated salivary hypofunction after radiation in both mouse and pig models through the inhibition of radiation-induced cellular senescence that is mediated by resident macrophages in mouse submandibular glands. Here we report that in swine parotid glands sharing many features with humans, the Hedgehog receptor PTCH1 is mainly expressed in macrophages, and levels of PTCH1 and multiple macrophage markers are significantly decreased by radiation but recovered by transient Hedgehog activation. These parotid macrophages mainly express the M2 macrophage marker ARG1, while radiation promotes expression of pro-inflammatory cytokine that is reversed by transient Hedgehog activation. Hedgehog activation likely preserves parotid macrophages after radiation through inhibition of P53 signaling and consequent cellular senescence. Consistently, VEGF, an essential anti-senescence cytokine downstream of Hedgehog signaling, is significantly decreased by radiation but recovered by transient Hedgehog activation. These findings indicate that in the clinically-relevant swine model, transient Hedgehog activation restores the function of irradiated salivary glands through the recovery of resident macrophages and the consequent inhibition of cellular senescence and inflammation.

scholarly journals Eight-Week Consumption of High-Sucrose Diet Has a Pro-Oxidant Effect and Alters the Function of the Salivary Glands of Rats

Nutrients ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 1530 ◽  
Author(s):  
Mateusz Maciejczyk ◽  
Jan Matczuk ◽  
Małgorzata Żendzian-Piotrowska ◽  
Wiesława Niklińska ◽  
Katarzyna Fejfer ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Oxidative Damage ◽  
Salivary Glands ◽  
Redox Balance ◽  
Control Group ◽  
Parotid Glands ◽  
Sucrose Diet ◽  
High Sucrose Diet ◽  
Gland Function ◽  
High Sucrose

A high-sucrose diet (HSD) is widely known for its cariogenic effects and promotion of obesity, insulin resistance, type 2 diabetes, and cancer. However, the impact of the HSD diet on the salivary gland function as well as the level of salivary oxidative stress is still unknown and requires evaluation. Our study is the first to determine both redox balance and oxidative injury in the parotid and submandibular glands of rats fed the HSD diet compared to the control group. We have demonstrated that uric acid concentration and the activity of superoxide dismutase and peroxidase varied significantly in both the submandibular and parotid glands of HSD rats vs. the control group. However, enhanced oxidative damage to proteins, lipids, and DNA (increase in advanced glycation end products, advanced oxidation protein products, 4-hydroxynonenal, and 8-hydroxy-2’-deoxyguanosine) was observed only in the parotid glands of HSD rats. Moreover, the HSD diet also reduced the total protein content and amylase activity in both types of salivary glands and decreased the stimulated salivary flow rate. To sum up, an HSD diet reduces salivary gland function and disturbs the redox balance of the parotid as well as submandibular salivary glands. However, the parotid glands are more vulnerable to both antioxidant disturbances and oxidative damage.

scholarly journals Cellular senescence contributes to radiation-induced hyposalivation by affecting the stem/progenitor cell niche

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Xiaohong Peng ◽  
Yi Wu ◽  
Uilke Brouwer ◽  
Thijmen van Vliet ◽  
Boshi Wang ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Cellular Senescence ◽  
Progenitor Cell ◽  
Tissue Degeneration ◽  
Cycle Arrest ◽  
Radiation Induced ◽  
Secretory Phenotype ◽  
Cell Niche ◽  
Gland Function ◽  
Formation Efficiency

Abstract Radiotherapy for head and neck cancer is associated with impairment of salivary gland function and consequent xerostomia, which has a devastating effect on the quality of life of the patients. The mechanism of radiation-induced salivary gland damage is not completely understood. Cellular senescence is a permanent state of cell cycle arrest accompanied by a secretory phenotype which contributes to inflammation and tissue deterioration. Genotoxic stresses, including radiation-induced DNA damage, are known to induce a senescence response. Here, we show that radiation induces cellular senescence preferentially in the salivary gland stem/progenitor cell niche of mouse models and patients. Similarly, salivary gland-derived organoids show increased expression of senescence markers and pro-inflammatory senescence-associated secretory phenotype (SASP) factors after radiation exposure. Clearance of senescent cells by selective removal of p16Ink4a-positive cells by the drug ganciclovir or the senolytic drug ABT263 lead to increased stem cell self-renewal capacity as measured by organoid formation efficiency. Additionally, pharmacological treatment with ABT263 in mice irradiated to the salivary glands mitigates tissue degeneration, thus preserving salivation. Our data suggest that senescence in the salivary gland stem/progenitor cell niche contributes to radiation-induced hyposalivation. Pharmacological targeting of senescent cells may represent a therapeutic strategy to prevent radiotherapy-induced xerostomia.

Radiation-Induced Loss of Salivary Gland Function Is Driven by Cellular Senescence and Prevented by IL6 Modulation

2016 ◽  
Vol 76 (5) ◽  
pp. 1170-1180 ◽  
Author(s):  
Yitzhak Marmary ◽  
Revital Adar ◽  
Svetlana Gaska ◽  
Annette Wygoda ◽  
Alexander Maly ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Cellular Senescence ◽  
Salivary Gland Function ◽  
Radiation Induced ◽  
Gland Function

scholarly journals Sox9+ Cell is Required for Salivary Gland Regeneration after Radiation Damage via Wnt/β-Catenin Pathway

2021 ◽  
Author(s):  
Xiuyun Xu ◽  
Xiong Gan ◽  
Ming Zhang ◽  
Jiaxiang Xie ◽  
Shuang Chen ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Salivary Glands ◽  
Cell Lineage ◽  
Term Treatment ◽  
Sequencing Data ◽  
Long Term Treatment ◽  
Radiation Induced ◽  
Gland Function ◽  
Salivary Gland Regeneration

Abstract Background: Radiotherapy for head and neck cancer can cause serious side effects, including severe damage to the salivary glands, resulting in symptoms such as xerostomia, dental caries, oral infectious and so on. Due to lack of long-term treatment for the symptoms of saliva barren, current research has focused on finding endogenous stem cells that can differentiate into various cell lineage to replace lost tissue and restore function. Results: In our study, we identified Sox9+ cells can differentiate into various salivary epithelial cell lineages under homeostatic conditions. After ablating Sox9+ cells, the salivary glands of irradiated mice showed more severe phenotypes and reduced proliferative capacity. Analysis of online single cell RNA-sequencing data revealed enrichment of the Wnt/β-catenin pathway in Sox9+ cell population. Furthermore, treatment of Wnt/β-catenin inhibitor to irradiated mice inhibited the regenerative capability of Sox9+ cells. Finally, we showed that Sox9+ cells were able to form organoids in vitro and transplanting these organoids into salivary glands after radiation restored part of salivary gland function. Conclusions: In short, our research indicated that regenerative therapy targeting Sox9+ cells is a promising method to solve the radiation induced salivary gland injury.

Partial Purification of a Specific Plasminogen Activator from Porcine Parotid Glands

1974 ◽  
Vol 31 (03) ◽  
pp. 403-414 ◽  
Author(s):  
Terence Cartwright
Keyword(s):  
Nucleic Acid ◽  
Salivary Glands ◽  
Plasminogen Activator ◽  
Protein Interactions ◽  
Partial Purification ◽  
Protein Protein Interactions ◽  
Parotid Glands ◽  
Two Stage ◽  
Preliminary Characterization ◽  
Specific Inhibitors

SummaryA method is described for the extraction with buffers of near physiological pH of a plasminogen activator from porcine salivary glands. Substantial purification of the activator was achieved although this was to some extent complicated by concomitant extraction of nucleic acid from the glands. Preliminary characterization experiments using specific inhibitors suggested that the activator functioned by a similar mechanism to that proposed for urokinase, but with some important kinetic differences in two-stage assay systems. The lack of reactivity of the pig gland enzyme in these systems might be related to the tendency to protein-protein interactions observed with this material.

scholarly journals Investigation of Changes in Saliva in Radiotherapy-Induced Head Neck Cancer Patients

2021 ◽  
Vol 18 (4) ◽  
pp. 1629
Author(s):  
Christina Winter ◽  
Roman Keimel ◽  
Markus Gugatschka ◽  
Dagmar Kolb ◽  
Gerd Leitinger ◽  
...  
Keyword(s):  
Hyaluronic Acid ◽  
Salivary Glands ◽  
Treatment Options ◽  
Chemical Properties ◽  
Head Neck Cancer ◽  
Potential Candidate ◽  
Adhesive Properties ◽  
Whole Saliva ◽  
Radiation Induced ◽  
Unstimulated Whole Saliva

The intact function of the salivary glands is of utmost importance for oral health. During radiotherapy in patients with head and neck tumors, the salivary glands can be damaged, causing the composition of saliva to change. This leads to xerostomia, which is a primary contributor to oral mucositis. Medications used for protective or palliative treatment often show poor efficacy as radiation-induced changes in the physico-chemical properties of saliva are not well understood. To improve treatment options, this study aimed to carefully examine unstimulated whole saliva of patients receiving radiation therapy and compare it with healthy unstimulated whole saliva. To this end, the pH, osmolality, electrical conductivity, buffer capacity, the whole protein and mucin concentrations, and the viscoelastic and adhesive properties were investigated. Moreover, hyaluronic acid was examined as a potential candidate for a saliva replacement fluid. The results showed that the pH of radiation-induced saliva shifted from neutral to acidic, the osmolality increased and the viscoelastic properties changed due to a disruption of the mucin network and a change in water secretion from the salivary glands. By adopting an aqueous 0.25% hyaluronic acid formulation regarding the lost properties, similar adhesion characteristics as in healthy, unstimulated saliva could be achieved.

scholarly journals Activation of two distinct Sox9-EGFP-expressing intestinal stem cell populations during crypt regeneration after irradiation

2012 ◽  
Vol 302 (10) ◽  
pp. G1111-G1132 ◽  
Author(s):  
Laurianne Van Landeghem ◽  
M. Agostina Santoro ◽  
Adrienne E. Krebs ◽  
Amanda T. Mah ◽  
Jeffrey J. Dehmer ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Populations ◽  
Intestinal Epithelial ◽  
P53 Signaling ◽  
Reporter Mice ◽  
Radiation Induced ◽  
Molecular Phenotypes ◽  
Stem Cell Populations ◽  
Induced Changes

Recent identification of intestinal epithelial stem cell (ISC) markers and development of ISC reporter mice permit visualization and isolation of regenerating ISCs after radiation to define their functional and molecular phenotypes. Previous studies in uninjured intestine of Sox9-EGFP reporter mice demonstrate that ISCs express low levels of Sox9-EGFP (Sox9-EGFP Low), whereas enteroendocrine cells (EEC) express high levels of Sox9-EGFP (Sox9-EGFP High). We hypothesized that Sox9-EGFP Low ISCs would expand after radiation, exhibit enhanced proliferative capacities, and adopt a distinct gene expression profile associated with rapid proliferation. Sox9-EGFP mice were given 14 Gy abdominal radiation and studied between days 3 and 9 postradiation. Radiation-induced changes in number, growth, and transcriptome of the different Sox9-EGFP cell populations were determined by histology, flow cytometry, in vitro culture assays, and microarray. Microarray confirmed that nonirradiated Sox9-EGFP Low cells are enriched for Lgr5 mRNA and mRNAs enriched in Lgr5-ISCs and identified additional putative ISC markers. Sox9-EGFP High cells were enriched for EEC markers, as well as Bmi1 and Hopx, which are putative markers of quiescent ISCs. Irradiation caused complete crypt loss, followed by expansion and hyperproliferation of Sox9-EGFP Low cells. From nonirradiated intestine, only Sox9-EGFP Low cells exhibited ISC characteristics of forming organoids in culture, whereas during regeneration both Sox9-EGFP Low and High cells formed organoids. Microarray demonstrated that regenerating Sox9-EGFP High cells exhibited transcriptomic changes linked to p53-signaling and ISC-like functions including DNA repair and reduced oxidative metabolism. These findings support a model in which Sox9-EGFP Low cells represent active ISCs, Sox9-EGFP High cells contain radiation-activatable cells with ISC characteristics, and both participate in crypt regeneration.

FUNCTIONAL DISORDERSOF THE SALIVARY GLANDS IN PATIENTS WITH COMPRESSION AND DISLOCATION DYSFUNCTION OF THE TEMPOROMANDIBULAR JOINT AND THEIR CORRECTION

2021 ◽  
Vol 74 (7) ◽  
pp. 1695-1698
Author(s):  
Oleg V. Rybalov ◽  
Pavel I. Yatsenko ◽  
Olga Yu. Andriyanova ◽  
Elena S. Ivanytska ◽  
Maria A. Korostashova
Keyword(s):  
Parotid Gland ◽  
Salivary Glands ◽  
Functional State ◽  
Oral Fluid ◽  
Healthy Individuals ◽  
Parotid Glands ◽  
Posterior Teeth ◽  
Fluid Content ◽  
Lower Jaw ◽  
Before And After

The aim: Is to assess the functional state of parotid glands and general secretion in patients with compression, dislocation dysfunction of TMJ, to correct the revealed disorders. Materials and methods: We examined 46 patients with dysfunction of TMJ. Examination included TMJ zonography and salivary glands sonography. We studied the general and parotid secretion, transparency, viscosity, pH of the oral fluid and the secretions of the parotid glands before and after treatment. The treatment of dysfunction and hyposialosis included the repositioning of the articular heads of the lower jaw in the correct anatomical position, the use of a repositioning plate on the posterior teeth at the compression side of the articular head, bougienage of the duct of the parotid gland, administration of 10% magnesium-mineral solution of bischofite into the gland. Results: In patients with TMJ dysfunction, a significant decrease in the oral fluid content was noted before treatment. The saliva transparency was reduced, the viscosity was increased, the pH was slightly acidic. A study, which was carried out a month after completion of the course of treatment showed that all the studied parameters corresponded to those in healthy individuals. Conclusions: The study confirmed that in compression and dislocation dysfunction of TMJ, there are disorders of the functional state of the salivary glands.

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