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BMC Oral Health Mar 2021ADAMTS expression can be associated with several inflammatory processes, and has been correlated with tumorigenesis of some neoplasms, but its participation in the...
BACKGROUND
ADAMTS expression can be associated with several inflammatory processes, and has been correlated with tumorigenesis of some neoplasms, but its participation in the development of periapical lesions has not been investigated. Therefore, our objective was to verify the expression of ADAMTS-1, versican and pEGFR in Periapical Granuloma (PG) and in the Radicular Cyst (RC) since they are the most common lesions of the periapex.
METHODS
25 samples of RC and 10 of PG were used. As a control, 10 samples of inflammatory fibrous hyperplasia (IFH) and 10 of dental follicle (DF) were used. The expression of these proteins was investigated using immunohistochemistry.
RESULTS
In the epithelium of RC, IFH and DF, the expression of ADAMTS-1 was greater in DF than in RC (p < .001). Versicano showed greater expression in IFH than in RC, DF than in RC (p < .001). pEGFR showed greater expression in IFH and RC than in DF (p < .01 and p < .05, respectively). In connective tissue, ADAMTS-1 expression was greater in PG and RC than in IFH and DF (p < .001). Versicano showed greater expression in PG, RC and IFH compared to DF (p < .001). In pEGFR there was a higher expression in PG when compared to RC, IFH and DF (p < .001). Greater immunostaining occurred in the RC than in the DF (p < .001).
CONCLUSIONS
Our results suggest that the studied proteins may participate in the pathogenesis of PG and RC, through the interaction of these proteins, in the remodeling of the ECM (versican) by ADAMTS-1, producing bioactive fragments, which could activate EGFR, contributing to the formation, growth and maintenance of injuries.
Topics: ErbB Receptors; Humans; Immunohistochemistry; Periapical Granuloma; Radicular Cyst; Versicans
PubMed: 33676487
DOI: 10.1186/s12903-021-01462-x -
Respiratory Research Nov 2023Lung fibrosis is a major concern in severe COVID-19 patients undergoing mechanical ventilation (MV). Lung fibrosis frequency in post-COVID syndrome is highly variable...
BACKGROUND
Lung fibrosis is a major concern in severe COVID-19 patients undergoing mechanical ventilation (MV). Lung fibrosis frequency in post-COVID syndrome is highly variable and even if the risk is proportionally small, many patients could be affected. However, there is still no data on lung extracellular matrix (ECM) composition in severe COVID-19 and whether it is different from other aetiologies of ARDS.
METHODS
We have quantified different ECM elements and TGF-β expression in lung tissue of 28 fatal COVID-19 cases and compared to 27 patients that died of other causes of ARDS, divided according to MV duration (up to six days or seven days or more). In COVID-19 cases, ECM elements were correlated with lung transcriptomics and cytokines profile.
RESULTS
We observed that COVID-19 cases presented significant increased deposition of collagen, fibronectin, versican, and TGF-β, and decreased decorin density when compared to non-COVID-19 cases of similar MV duration. TGF-β was precociously increased in COVID-19 patients with MV duration up to six days. Lung collagen was higher in women with COVID-19, with a transition of upregulated genes related to fibrillogenesis to collagen production and ECM disassembly along the MV course.
CONCLUSIONS
Fatal COVID-19 is associated with an early TGF-β expression lung environment after the MV onset, followed by a disordered ECM assembly. This uncontrolled process resulted in a prominent collagen deposition when compared to other causes of ARDS. Our data provides pathological substrates to better understand the high prevalence of pulmonary abnormalities in patients surviving COVID-19.
Topics: Humans; Female; Pulmonary Fibrosis; COVID-19; Extracellular Matrix; Collagen; Lung; Transforming Growth Factor beta; Respiratory Distress Syndrome
PubMed: 37964271
DOI: 10.1186/s12931-023-02555-7 -
Phytomedicine : International Journal... Jul 2023Proteoglycans (PGs) accumulation and inflammation are two interactional pathological processes of atherosclerosis (AS). Up to now, there is no ideal drug for decreasing...
BACKGROUND
Proteoglycans (PGs) accumulation and inflammation are two interactional pathological processes of atherosclerosis (AS). Up to now, there is no ideal drug for decreasing these pathological changes. Gua Lou Er Chen decoction (GED) has been used to treat AS for several years. However, if GED could treat AS through reducing PGs accumulation and inflammation remains unknown.
PURPOSE
This study was designed to illustrate whether GED could attenuate AS by reducing chondroitin sulphate proteoglycan (CSPG) expressions and alleviating inflammation.
METHODS
In vivo study, apolipoprotein E-deficient mice were fed a high-fat diet to induce AS. In vitro study, oxidised low-density lipoprotein (ox-LDL) and tumour necrosis factor (TNF)-α were used to induce proteoglycans accumulation and inflammation changes of vascular smooth muscle cells (VSMCs) and RAW264.7 macrophages. Oil Red O was used to stain mouse aortic lipid plaque. Haematoxylin eosin staining was used to assess the pathological changes of aortic valve and thoracic aorta. Specialised kits were used to identify blood lipids and sGAGs. Immunofluorescence and immunohistochemistry was used to identify aortic valve CSPG and versican. Western blotting, enzyme-linked immunosorbent assay and quantitative reverse transcription-polymerase chain reaction were used to measure versican, interleukin (IL)-6, TNF-α, and chondroitin sulphate (CS) synthetase expressions. CCK-8 was used to measure the cells proliferation.
RESULTS
In vivo experiments revealed that GED significantly improved hyperlipidemia, lowered lipid plaque deposition in the aorta, and increased plaque stability of AS mice. In addition, further studies revealed that GED lowered the sGAGs, CSPG, and versican levels and down-regulated CS synthetase and inflammatory factor expressions. In vitro experiments revealed that GED decreased TNF-α expression in the RAW264.7 macrophage supernatant stimulated by ox-LDL; decreased versican, CS-related synthetase, and IL-6 expressions; reduced VSMC proliferation stimulated by ox-LDL; down-regulated sGAG and versican expressions of VSMCs stimulated by TNF-α.
CONCLUSION
Our results demonstrated that GED could attenuate AS by reducing hyperlipidemia, hyper-expression of CSPG, and inflammation. This study might provide a novel insight into the development of innovative drug for AS.
Topics: Mice; Animals; Tumor Necrosis Factor-alpha; Versicans; Atherosclerosis; Plaque, Atherosclerotic; Inflammation; Lipoproteins, LDL; Interleukin-6; Lipids; Hyperlipidemias
PubMed: 37094421
DOI: 10.1016/j.phymed.2023.154811 -
Molecular Cancer Sep 2022Chimeric antigen receptor (CAR) T-cell therapy using brexucabtagene autoleucel (BA) induces remission in many patients with mantle cell lymphoma (MCL), and BA is the...
BACKGROUND
Chimeric antigen receptor (CAR) T-cell therapy using brexucabtagene autoleucel (BA) induces remission in many patients with mantle cell lymphoma (MCL), and BA is the only CAR T-cell therapy approved by the FDA for MCL. However, development of relapses to BA is recognized with poor patient outcomes. Multiple CAR T-cell therapies have been approved for other lymphomas and the resistance mechanisms have been investigated. However, the mechanisms underlying BA relapse in MCL have not been investigated and whether any previously reported resistance mechanisms apply to BA-relapsed patients with MCL is unknown.
METHODS
To interrogate BA resistance mechanisms in MCL, we performed single-cell RNA sequencing on 39 longitudinally collected samples from 15 BA-treated patients, and multiplex cytokine profiling on 80 serial samples from 20 patients.
RESULTS
We demonstrate that after BA relapse, the proportion of T cells, especially cytotoxic T cells (CTLs), decreased among non-tumor cells, while the proportion of myeloid cells correspondingly increased. TIGIT, LAG3, and CD96 were the predominant checkpoint molecules expressed on exhausted T cells and CTLs; only TIGIT was significantly increased after relapse. CTLs expanded during remission, and then contracted during relapse with upregulated TIGIT expression. Tumor cells also acquired TIGIT expression after relapse, leading to the enhanced interaction of tumor cell TIGIT with monocyte CD155/PVR. In myeloid cells, post-relapse HLA-II expression was reduced relative to pretreatment and during remission. Myeloid-derived suppressor cells (MDSCs) were enriched after relapse with elevated expression of activation markers, including CLU (clusterin) and VCAN (versican). Extracellular chemokines (CCL4, CXCL9, CXCL13), soluble checkpoint inhibitors (sPD-L1, sTIM3, s4-1BB), and soluble receptors (sIL-2R, sTNFRII) were decreased during remission but elevated after relapse.
CONCLUSIONS
Our data demonstrate that multiple tumor-intrinsic and -extrinsic factors are associated with T-cell suppression and BA relapse. Among these, TIGIT appears to be the central player given its elevated expression after BA relapse in not only CTLs but also MCL cells. The acquisition of TIGIT expression on tumor cells is MCL-specific and has not been reported in other CAR T-treated diseases. Together, our data suggest that co-targeting TIGIT may prevent CAR T relapses and thus promote long-term progression-free survival in MCL patients.
Topics: Adult; Antigens, CD; Clusterin; Cytokines; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Receptors, Chimeric Antigen; Receptors, Immunologic; T-Lymphocytes; Versicans
PubMed: 36163179
DOI: 10.1186/s12943-022-01655-0 -
Frontiers in Oncology 2019Versican and tumor-associated macrophages (TAMs) are involved in growth and metastases in several cancers. Here, we investigated the potential role of versican, a matrix...
Versican and tumor-associated macrophages (TAMs) are involved in growth and metastases in several cancers. Here, we investigated the potential role of versican, a matrix proteoglycan, and its correlation with TAMs infiltrates in different stages of two different breast cancer models: spontaneous canine mammary gland carcinomas and the murine 4T1 breast cancer model. The stromal versican expression was correlated with TAMs accumulation in tumors with an advanced stage from spontaneous canine mammary carcinoma samples. Versican expression in mice, identified in late stages of tumor progression, was associated to a high number of peri-tumoral infiltrating TAMs. Indeed, TAMs were related to a pro-inflammatory and pro-angiogenic state in the primary tumor. Furthermore, TAMs accumulation was related to versican expression in the lungs and an increased number of pulmonary metastatic nodules with pulmonary mechanical dysfunction, which was due to leukocyte influx in the airways and elevated growth factor levels in the microenvironment. Thus, we suggest that versican and TAMs as attractive targets for breast cancer therapy.
PubMed: 31334111
DOI: 10.3389/fonc.2019.00577 -
Methods in Molecular Biology (Clifton,... 2023Proteoglycans (PGs) are non-fibrillar extracellular matrix (ECM) molecules composed by a protein core and glycosaminoglycan (GAG) chains. These molecules are present in...
Proteoglycans (PGs) are non-fibrillar extracellular matrix (ECM) molecules composed by a protein core and glycosaminoglycan (GAG) chains. These molecules are present in all tissues playing essential structural, biomechanical, and biological roles. In addition, PGs can regulate cell behavior due to their versatility and ability to interact with other ECM molecules, growth factors, and cells. The distribution of PGs can be evaluated by histochemical and immunohistochemical methods. Histochemical methods aimed to provide a useful overview of the presence and distribution pattern of certain groups of PGs. In contrast, immunohistochemical procedures aimed the identification of highly specific target molecules. In this chapter we described Alcian Blue, Safranin O, and Toluidine Blue histochemical methods for the screening of PGs in tissue sections. Finally, we describe the immunohistochemical procedures for specific identification of PGs (decorin, biglycan, and versican) in formaldehyde-fixed and paraffin-embedded tissues.
Topics: Alcian Blue; Biglycan; Chondroitin Sulfate Proteoglycans; Decorin; Extracellular Matrix Proteins; Formaldehyde; Glycosaminoglycans; Tolonium Chloride; Versicans
PubMed: 36152244
DOI: 10.1007/978-1-0716-2675-7_7 -
Matrix Biology Plus Dec 2023Cardiac fibrosis is a central pathological feature in several cardiac diseases, but the underlying molecular players are insufficiently understood. The extracellular...
Cardiac fibrosis is a central pathological feature in several cardiac diseases, but the underlying molecular players are insufficiently understood. The extracellular matrix proteoglycan versican is elevated in heart failure and suggested to be a target for treatment. However, the temporal expression and spatial distribution of versican and the versican cleavage fragment containing the neoepitope DPEAAE in cardiac fibrosis remains to be elucidated. In this study, we have examined versican during cardiac fibrosis development in a murine pressure overload model and in patients with cardiomyopathies. We found that versican, mainly the V1 isoform, was expressed immediately after induction of pressure overload, preceding collagen accumulation, and versican protein levels extended from the perivascular region into the cardiac interstitium. In addition, we found increased production of versican by collagen expressing fibroblasts, and that it was deposited extensively in the fibrotic extracellular matrix during pressure overload. In cardiac cell cultures, the expression of versican was induced by the pro-fibrotic transforming growth factor beta and mechanical stretch. Furthermore, we observed that the proteolytic cleavage of versican (DPEAAE fragment) increased in the late phase of fibrosis development during pressure overload. In patients with hypertrophic and dilated cardiomyopathies, we found elevated levels of versican and a positive correlation between versican and collagen mRNA in the heart, as well as increased cleavage of full-length protein. Taken together, the temporal expression profile and the spatial distribution of both the full-length versican and the DPEAAE fragment observed in this study indicates a role for versican in development of cardiac fibrosis.
PubMed: 38076279
DOI: 10.1016/j.mbplus.2023.100135 -
Neurourology and Urodynamics Mar 2021Abnormal extracellular matrix (ECM) changes are correlated with stress urinary incontinence (SUI). The ECM components versican (Vcan) and hyaluronan (HA) play key roles...
PURPOSE
Abnormal extracellular matrix (ECM) changes are correlated with stress urinary incontinence (SUI). The ECM components versican (Vcan) and hyaluronan (HA) play key roles in regulating tissue inflammation and maintaining connective tissue homeostasis. We analyzed the localization and expression of these ECM components in urethral and vaginal tissues from a rat model of urinary incontinence and from human clinical specimens.
METHODS
Nulliparous rats underwent vaginal distension (VD), a rodent model of SUI, or a sham procedure. Tissues were harvested from six rats per group at days 1, 4, and 21 for immunohistochemistry and RNA expression analysis of ECM components. Periurethral vaginal samples from female patients with SUI were also examined.
RESULTS
High-intensity staining for Vcan was observed 1 day after procedure in both control and VD animals. This level of abundance persisted at day 4 in VD compared to control, with concurrent reduced messenger RNA (mRNA) expression of the Vcan-degrading enzymes ADAMTS5 and ADAMTS9 and reduced staining for the Vcan cleavage epitope DPEAAE. Abundance of HA was not different between VD and control, however mRNA expression of the HA synthase Has2 was significantly reduced in VD tissues at day 4. Abundant Vcan staining was observed in 60% of SUI patient samples, which was strongest in regions of disrupted elastin.
CONCLUSION
Reduction of Vcan-degrading enzymes and HA synthases at day 4 postsurgery indicates a potential delay in ECM turnover associated with SUI. Abundant Vcan is associated with inflammation and elastin fiber network disruption, warranting further investigation to determine its role in SUI pathogenesis.
Topics: Animals; Disease Models, Animal; Extracellular Matrix; Female; Humans; Hyaluronic Acid; Middle Aged; Rats; Rats, Sprague-Dawley; Urethra; Urinary Incontinence, Stress; Vagina
PubMed: 33645869
DOI: 10.1002/nau.24635 -
Aging Feb 2023Gastric cancer is the most common malignant tumor of the digestive system. The progression from gastritis to gastric cancer may be related to genetic factors, but the...
OBJECTIVE
Gastric cancer is the most common malignant tumor of the digestive system. The progression from gastritis to gastric cancer may be related to genetic factors, but the specific molecular mechanism remains unclear. Therefore, an in-depth study of the molecular mechanism of gastritis and gastric cancer is significant.
METHODS
We downloaded two gene profiles, GSE2669 and GSE116312, from the Gene Expression Omnibus (GEO) database. This study aims to apply bioinformatics technology to mine differentially expressed genes (DEGs), DEGs annotation, protein-protein interaction (PPI) network creation, and hub gene identification and expression between gastric cancer patients and gastritis patients. Overall survival analysis of hub genes, analysis by comparative toxicogenomics database for hub genes in gastric cancer, THBS2 and VCAN protein expression by immunohistochemistry for gastric cancer and gastritis as well as design of the biological process (BP) neural network was implemented.
RESULTS
The MSLN, SPP1, THBS2, SPARC, FN1, IGFBP7, VCAN were up-regulated in gastric carcinoma samples, while FGA was down-regulated. The protein expression of THBS2 and VCAN in gastric cancer was significantly higher than that in gastritis. VCAN protein expression was positively associated with tumor invasion ( = 0.011) and HER2 overexpression ( = 0.031). Strong correlation among THBS2, VCAN, and gastric cancer based on the BP neural network.
CONCLUSION
THBS2 and VCAN may be potential targets for improving gastric cancer patients' diagnosis and clinical efficacy.
Topics: Humans; Biomarkers, Tumor; Computational Biology; Gene Expression Profiling; Prognosis; Protein Interaction Maps; Stomach Neoplasms; Versicans
PubMed: 36842141
DOI: 10.18632/aging.204520 -
Molecular & Cellular Proteomics : MCP Apr 2022Glioblastoma (GBM) is the most common and malignant primary brain tumor. The extracellular matrix, also known as the matrisome, helps determine glioma invasion,...
Glioblastoma (GBM) is the most common and malignant primary brain tumor. The extracellular matrix, also known as the matrisome, helps determine glioma invasion, adhesion, and growth. Little attention, however, has been paid to glycosylation of the extracellular matrix components that constitute the majority of glycosylated protein mass and presumed biological properties. To acquire a comprehensive understanding of the biological functions of the matrisome and its components, including proteoglycans (PGs) and glycosaminoglycans (GAGs), in GBM tumorigenesis, and to identify potential biomarker candidates, we studied the alterations of GAGs, including heparan sulfate (HS) and chondroitin sulfate (CS), the core proteins of PGs, and other glycosylated matrisomal proteins in GBM subtypes versus control human brain tissue samples. We scrutinized the proteomics data to acquire in-depth site-specific glycoproteomic profiles of the GBM subtypes that will assist in identifying specific glycosylation changes in GBM. We observed an increase in CS 6-O sulfation and a decrease in HS 6-O sulfation, accompanied by an increase in unsulfated CS and HS disaccharides in GBM versus control samples. Several core matrisome proteins, including PGs (decorin, biglycan, agrin, prolargin, glypican-1, and chondroitin sulfate proteoglycan 4), tenascin, fibronectin, hyaluronan link protein 1 and 2, laminins, and collagens, were differentially regulated in GBM versus controls. Interestingly, a higher degree of collagen hydroxyprolination was also observed for GBM versus controls. Further, two PGs, chondroitin sulfate proteoglycan 4 and agrin, were significantly lower, about 6-fold for isocitrate dehydrogenase-mutant, compared to the WT GBM samples. Differential regulation of O-glycopeptides for PGs, including brevican, neurocan, and versican, was observed for GBM subtypes versus controls. Moreover, an increase in levels of glycosyltransferase and glycosidase enzymes was observed for GBM when compared to control samples. We also report distinct protein, peptide, and glycopeptide features for GBM subtypes comparisons. Taken together, our study informs understanding of the alterations to key matrisomal molecules that occur during GBM development. (Data are available via ProteomeXchange with identifier PXD028931, and the peaks project file is available at Zenodo with DOI 10.5281/zenodo.5911810).
Topics: Agrin; Brain; Brain Neoplasms; Chondroitin Sulfate Proteoglycans; Extracellular Matrix; Extracellular Matrix Proteins; Glioblastoma; Glycosaminoglycans; Heparitin Sulfate; Humans
PubMed: 35202840
DOI: 10.1016/j.mcpro.2022.100216