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Frontiers in Immunology 2024Glioblastoma (GBM) accounts for approximately half of all malignant brain tumors, and it remains lethal with a five-year survival of less than 10%. Despite the immense... (Review)
Review
Glioblastoma (GBM) accounts for approximately half of all malignant brain tumors, and it remains lethal with a five-year survival of less than 10%. Despite the immense advancements in the field, it has managed to evade even the most promising therapeutics: immunotherapies. The main reason is the highly spatiotemporally heterogeneous and immunosuppressive GBM tumor microenvironment (TME). Accounting for this complex interplay of TME-driven immunosuppression is key to developing effective therapeutics. This review will explore the immunomodulatory role of the extracellular matrix (ECM) by establishing its contribution to the TME as a key mediator of immune responses in GBM. This relationship will help us elucidate therapeutic targets that can be leveraged to develop and deliver more effective immunotherapies.
Topics: Humans; Glioblastoma; Brain Neoplasms; Immunotherapy; Immunosuppression Therapy; Extracellular Matrix; Tumor Microenvironment
PubMed: 38380331
DOI: 10.3389/fimmu.2024.1336476 -
Tissue & Cell Apr 2024High-temperature requirement A1 (HtrA1), a multidomain serine protease acting on Extracellular matrix (ECM) rearrangement, is also secreted by osteoblasts and...
High-temperature requirement A1 (HtrA1), a multidomain serine protease acting on Extracellular matrix (ECM) rearrangement, is also secreted by osteoblasts and osteoclasts. Recent and conflicting literature highlights HtrA1's role as a controller of bone remodeling, proposing it as a possible target for pathologies with unbalanced bone resorption, like Osteoporosis (OP). To add knowledge on this molecule function in bone physiopathology, here we compared HtrA1 distribution in the ECM of healthy (H) and OP bone tissue, also examining its localization in the sites of new bone formation. HtrA1 was homogeneously expressed in the mature bone ECM of H tissue showing a 55.6 ± 16.4% of the stained area, with a significant (p=0.0001) decrease in OP percentage stained area (21.1 ± 13.1). Moreover, HtrA1 was present in the endosteum and cells involved in osteogenesis, mainly in those "entrapped" in woven bone, whereas osteocytes in mature lamellar bone were negative. Based on our previous observation in OP tissue of a significantly increased expression of Decorin and Osteocalcin, both involved in bone mineralization and remodeling and equally substrates for HtrA1, we speculate that HtrA1 by controlling the proper amount of Decorin and Osteocalcin favors normal bone maturation and mineralization. Besides, we suggest that late-osteoblasts and pre-osteocytes secrete HtrA1 in the adjacent matrix whilst proceeding with their maturation and that HtrA1 expression is further modified during the remodeling from woven to the lamellar bone. Overall, our data suggest HtrA1 as a positive regulator of bone matrix formation and maturation: its reduced expression in mature OP bone, affecting protein content and distribution, could hamper correct bone remodeling and mineralization.
Topics: Humans; Osteocalcin; Serine Proteases; Bone Matrix; Decorin; High-Temperature Requirement A Serine Peptidase 1; Serine Endopeptidases; Bone and Bones; Extracellular Matrix; Osteoporosis
PubMed: 38367326
DOI: 10.1016/j.tice.2024.102329 -
European Review For Medical and... Jan 2024The primary aim of this study was to investigate the serum levels of decorin, a small leucine-rich proteoglycan, in women diagnosed with polycystic ovary syndrome (PCOS)...
OBJECTIVE
The primary aim of this study was to investigate the serum levels of decorin, a small leucine-rich proteoglycan, in women diagnosed with polycystic ovary syndrome (PCOS) and concurrently presenting with moderate to severe acne vulgaris.
PATIENTS AND METHODS
Sixty patients with acne vulgaris symptoms, subsequently diagnosed with PCOS according to the revised Rotterdam criteria, were enrolled in the study. Acne severity was assessed using the acne global severity scale (AGSS), with patients fitting AGSS category 4 (moderate) and 5 (severe) grouped into two separate cohorts of 30 individuals each. The moderate acne group comprised patients with few inflammatory lesions and a minor nodule alongside predominantly non-inflammatory lesions, whereas the severe group contained patients with multiple nodules and a mix of non-inflammatory and inflammatory lesions. A control group of twenty healthy women without acne vulgaris or PCOS was also established. The study measured serum testosterone, follicle-stimulating hormone (FSH), Luteinizing Hormone (LH), and insulin levels, and calculated insulin resistance via the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) formula. Quantitative sandwich enzyme immunoassay was employed to determine decorin levels from venous blood samples.
RESULTS
While age, body mass index (BMI), serum FSH, LH, testosterone, and HOMA-IR values demonstrated similarity between the moderate and severe acne cohorts, comparisons between the control and both acne groups (AGSS-4 and AGSS-5) revealed significantly elevated values in the latter, excluding age, BMI, and FSH. Importantly, the serum decorin levels in both acne groups were substantially higher than in controls. A significant positive correlation was observed between serum decorin levels and both HOMA-IR (r=7.88, p<0.01) and testosterone (r=0.813, p<0.01).
CONCLUSIONS
This study suggests that elevated circulating decorin levels play a pivotal role in the manifestation of acne vulgaris in women with PCOS.
Topics: Female; Humans; Polycystic Ovary Syndrome; Decorin; Insulin Resistance; Luteinizing Hormone; Follicle Stimulating Hormone; Testosterone; Body Mass Index; Acne Vulgaris; Insulin
PubMed: 38305592
DOI: 10.26355/eurrev_202401_35044 -
Cardiology in the Young Feb 2024Proteomics may help discover novel biomarkers and underlying mechanisms for cardiovascular disease. This could be useful for childhood cancer survivors as they show an...
INTRODUCTION
Proteomics may help discover novel biomarkers and underlying mechanisms for cardiovascular disease. This could be useful for childhood cancer survivors as they show an increased risk of cardiovascular disease. The aim of this study was to investigate circulating cardiovascular proteins in young adult survivors of childhood cancer and their relationship to previously reported subclinical cardiovascular disease.
METHODS
Ninety-two cardiovascular proteins were measured in 57 childhood cancer survivors and in 52 controls. For proteins that were significantly different between childhood cancer survivors and controls, we performed correlations between protein levels and measures of peripheral arterial stiffness (carotid distensibility and stiffness index, and augmentation index) and endothelial dysfunction (reactive hyperemia index).
RESULTS
Leptin was significantly higher in childhood cancer survivors compared to controls (normalized protein expression units: childhood cancer survivors 6.4 (1.5) versus 5.1 (1.7), p < 0.0000001) after taking multiple tests into account. Kidney injury molecule-1, MER proto-oncogene tyrosine kinase, selectin P ligand, decorin, alpha-1-microglobulin/bikunin precursor protein, and pentraxin 3 showed a trend towards group differences (p < 0.05). Among childhood cancer survivors, leptin was associated with anthracycline treatment after adjustment for age, sex, and body mass index (p < 0.0001). Higher leptin correlated with lower carotid distensibility after adjustment for age, sex, body mass index, and treatments with radiotherapy and anthracyclines (p = 0.005).
CONCLUSION
This proteomics approach identified that leptin is higher in young asymptomatic adult survivors of childhood cancer than in healthy controls and is associated with adverse vascular changes. This could indicate a role for leptin in driving the cardiovascular disease burden in this population.
PubMed: 38305049
DOI: 10.1017/S1047951124000076 -
Cornea May 2024The aims of this study were to construct a mesenchymal stem cell (MSC)-laden in situ-forming hydrogel and study its effects on preventing corneal stromal opacity.
PURPOSE
The aims of this study were to construct a mesenchymal stem cell (MSC)-laden in situ-forming hydrogel and study its effects on preventing corneal stromal opacity.
METHODS
The native gellan gum was modified by high temperature and pressure, and the rabbit bone marrow MSCs were encapsulated before adding Ca 2+ to initiate cross-linking. The effects of the hydrogel on 3D culture and gene expression of the rabbit bone marrow MSCs were observed in vitro. Then, the MSC-hydrogel was used to repair corneal stromal injury in New Zealand white rabbits within 28 days postoperation.
RESULTS
The short-chain gellan gum solution has a very low viscosity (<0.1 Pa·s) that is ideal for encapsulating cells. Moreover, mRNA expressions of 3D-cultured MSCs coding for corneal stromal components (decorin, lumican, and keratocan) were upregulated (by 127.8, 165.5, and 25.4 times, respectively) ( P < 0.05) on day 21 in vitro and were verified by Western blotting results. For the in vivo study, the corneal densitometry of the experimental group was (20.73 ± 1.85) grayscale units which was lower than the other groups ( P < 0.05). The MSC-hydrogel downregulated mRNA expression coding for fibrosis markers (α-smooth muscle actin, vimentin, collagen type 5-α1, and collagen type 1-α1) in the rabbit corneal stroma. Furthermore, some of the 5-ethynyl-2'-deoxyuridine (EdU)-labeled MSCs integrated into the upper corneal stroma and expressed keratocyte-specific antigens on day 28 postoperation.
CONCLUSIONS
The short-chain gellan gum allows MSCs to slowly release to the corneal stromal defect and prevent corneal stromal opacity. Some of the implanted MSCs can integrate into the corneal stroma and differentiate into keratocytes.
Topics: Animals; Rabbits; Hydrogels; Cornea; Corneal Stroma; Corneal Keratocytes; Mesenchymal Stem Cells; Corneal Opacity; Corneal Injuries; Collagen; RNA, Messenger
PubMed: 38289027
DOI: 10.1097/ICO.0000000000003475 -
Molecular & Cellular Proteomics : MCP Mar 2024Glioblastoma (GBM) is the most aggressive brain tumor and different efforts have been employed in the search for new drugs and therapeutic protocols for GBM....
Glioblastoma (GBM) is the most aggressive brain tumor and different efforts have been employed in the search for new drugs and therapeutic protocols for GBM. Epitranscriptomics has shed light on new druggable Epigenetic therapies specifically designed to modulate GBM biology and behavior such as Histone Deacetylase inhibitors (iHDAC). Although the effects of iHDAC on GBM have been largely explored, there is a lack of information on the underlaying mechanisms HDAC-dependent that modulate the repertoire of GBM secreted molecules focusing on the set of Extracellular Matrix (ECM) associated proteins, the Matrisome, that may impact the surrounding tumor microenvironment. To acquire a better comprehension of the impacts of HDAC activity on the GBM Matrisome, we studied the alterations on the Matrisome-associated ECM regulators, Core Matrisome ECM glycoproteins, ECM-affiliated proteins and Proteoglycans upon HDAC inhibition in vitro as well as their relationship with glioma pathophysiological/clinical features and angiogenesis. For this, U87MG GBM cells were treated for with iHDAC or vehicle (control) and the whole secretome was processed by Mass Spectrometry NANOLC-MS/MS. In silico analyses revealed that proteins associated to the Angiogenic Matrisome (AngioMatrix), including Decorin, ADAM10, ADAM12 and ADAM15 were differentially regulated in iHDAC versus control secretome. Interestingly, genes coding for the Matrisome proteins differentially regulated were found mutated in patients and were correlated to glioma pathophysiological/clinical features. In vitro functional assays, using HBMEC endothelial cells exposed to the secretome of control or iHDAC treated GBM cells, coupled to 2D and 3D GBM cell culture system, showed impaired migratory capacity of endothelial cells and disrupted tubulogenesis in a Fibronectin and VEGF independent fashion. Collectively, our study provides understanding of epigenetic mechanisms HDAC-dependent to key Matrisomal proteins that may contribute to identify new druggable Epigenetic therapies or gliomagenesis biomarkers with relevant implications to improve therapeutic protocols for this malignancy.
Topics: Humans; Glioblastoma; Histone Deacetylases; Endothelial Cells; Tandem Mass Spectrometry; Extracellular Matrix; Glioma; Epigenesis, Genetic; Extracellular Matrix Proteins; Brain Neoplasms; Tumor Microenvironment; Membrane Proteins; ADAM Proteins
PubMed: 38272115
DOI: 10.1016/j.mcpro.2024.100722 -
Frontiers in Endocrinology 2023This study analyzes the levels of peripheral blood placental growth factor (PLGF), body mass index (BMI), decorin (DCN), lactate dehydrogenase (LDH), uric acid (UA), and...
OBJECTIVE
This study analyzes the levels of peripheral blood placental growth factor (PLGF), body mass index (BMI), decorin (DCN), lactate dehydrogenase (LDH), uric acid (UA), and clinical indicators of patients with preeclampsia (PE), and establishes a predictive risk model of PE, which can provide a reference for early and effective prediction of PE.
METHODS
81 cases of pregnant women with PE who had regular prenatal checkups and delivered in Jinshan Branch of Shanghai Sixth People's Hospital from June 2020 to December 2022 were analyzed, and 92 pregnant women with normal pregnancies who had their antenatal checkups and delivered at the hospital during the same period were selected as the control group. Clinical data and peripheral blood levels of PLGF, DCN, LDH, and UA were recorded, and the two groups were subjected to univariate screening and multifactorial logistic regression analysis. Based on the screening results, the diagnostic efficacy of PE was evaluated using the receiver operating characteristic (ROC) curve. Risk prediction nomogram model was constructed using language. The Bootstrap method (self-sampling method) was used to validate and produce calibration plots; the decision curve analysis (DCA) was used to assess the clinical benefit rate of the model.
RESULTS
There were statistically significant differences in age, pre-pregnancy BMI, gestational weight gain, history of PE or family history, family history of hypertension, gestational diabetes mellitus, and history of renal disease between the two groups (P < 0.05). The results of multifactorial binary logistic stepwise regression revealed that peripheral blood levels of PLGF, DCN, LDH, UA, and pre-pregnancy BMI were independent influences on the occurrence of PE (P < 0.05). The area under the curve of PLGF, DCN, LDH, UA levels and pre-pregnancy BMI in the detection of PE was 0.952, with a sensitivity of 0.901 and a specificity of 0.913, which is better than a single clinical diagnostic indicator. The results of multifactor analysis were constructed as a nomogram model, and the mean absolute error of the calibration curve of the modeling set was 0.023, suggesting that the predictive probability of the model was generally compatible with the actual value. DCA showed the predictive model had a high net benefit in the range of 5% to 85%, suggesting that the model has clinical utility value.
CONCLUSION
The occurrence of PE is related to the peripheral blood levels of PLGF, DCN, LDH, UA and pre-pregnancy BMI, and the combination of these indexes has a better clinical diagnostic value than a single index. The nomogram model constructed by using the above indicators can be used for the prediction of PE and has high predictive efficacy.
Topics: Pregnancy; Humans; Female; Pre-Eclampsia; Body Mass Index; L-Lactate Dehydrogenase; Placenta Growth Factor; Uric Acid; China; Decorin
PubMed: 38260145
DOI: 10.3389/fendo.2023.1297731 -
JCI Insight Jan 2024Lupus nephritis (LN) is a pathologically heterogenous autoimmune disease linked to end-stage kidney disease and mortality. Better therapeutic strategies are needed as...
Lupus nephritis (LN) is a pathologically heterogenous autoimmune disease linked to end-stage kidney disease and mortality. Better therapeutic strategies are needed as only 30%-40% of patients completely respond to treatment. Noninvasive biomarkers of intrarenal inflammation may guide more precise approaches. Because urine collects the byproducts of kidney inflammation, we studied the urine proteomic profiles of 225 patients with LN (573 samples) in the longitudinal Accelerating Medicines Partnership in RA/SLE cohort. Urinary biomarkers of monocyte/neutrophil degranulation (i.e., PR3, S100A8, azurocidin, catalase, cathepsins, MMP8), macrophage activation (i.e., CD163, CD206, galectin-1), wound healing/matrix degradation (i.e., nidogen-1, decorin), and IL-16 characterized the aggressive proliferative LN classes and significantly correlated with histological activity. A decline of these biomarkers after 3 months of treatment predicted the 1-year response more robustly than proteinuria, the standard of care (AUC: CD206 0.91, EGFR 0.9, CD163 0.89, proteinuria 0.8). Candidate biomarkers were validated and provide potentially treatable targets. We propose these biomarkers of intrarenal immunological activity as noninvasive tools to diagnose LN and guide treatment and as surrogate endpoints for clinical trials. These findings provide insights into the processes involved in LN activity. This data set is a public resource to generate and test hypotheses and validate biomarkers.
Topics: Humans; Lupus Nephritis; Proteomics; Proteinuria; Inflammation; Aggression
PubMed: 38258904
DOI: 10.1172/jci.insight.172569 -
International Journal of Molecular... Jan 2024Proteoglycans are differentially expressed in different atherosclerotic plaque phenotypes, with biglycan and decorin characteristic of ruptured plaques and versican and...
Proteoglycans are differentially expressed in different atherosclerotic plaque phenotypes, with biglycan and decorin characteristic of ruptured plaques and versican and hyaluronan more prominent in eroded plaques. Following plaque disruption, the exposure of extracellular matrix (ECM) proteins triggers platelet adhesion and thrombus formation. In this study, the impact of differential plaque composition on platelet function and thrombus formation was investigated. Platelet adhesion, activation and thrombus formation under different shear stress conditions were assessed in response to individual proteoglycans and composites representing different plaque phenotypes. The results demonstrated that all the proteoglycans tested mediated platelet adhesion but not platelet activation, and the extent of adhesion observed was significantly lower than that observed with type I and type III collagens. Thrombus formation upon the rupture and erosion ECM composites was significantly reduced ( < 0.05) compared to relevant collagen alone, indicating that proteoglycans negatively regulate platelet collagen responses. This was supported by results demonstrating that the addition of soluble biglycan or decorin to whole blood markedly reduced thrombus formation on type I collagen ( < 0.05). Interestingly, thrombus formation upon the erosion composite displayed aspirin sensitivity, whereas the rupture composite was intensive to aspirin, having implications for current antiplatelet therapy regimes. In conclusion, differential platelet responses and antiplatelet efficacy are observed on ECM composites phenotypic of plaque rupture and erosion. Proteoglycans inhibit thrombus formation and may offer a novel plaque-specific approach to limit arterial thrombosis.
Topics: Humans; Biglycan; Decorin; Atherosclerosis; Plaque, Atherosclerotic; Extracellular Matrix Proteins; Aspirin; Collagen Type I; Thrombosis
PubMed: 38256024
DOI: 10.3390/ijms25020950 -
Wound Repair and Regeneration :... 2024Hypertrophic scars (HTS) develop from an excessive synthesis of structural proteins like collagen and a decreased expression of proteoglycans such as decorin. Previous...
Hypertrophic scars (HTS) develop from an excessive synthesis of structural proteins like collagen and a decreased expression of proteoglycans such as decorin. Previous research has demonstrated that decorin expression is significantly down-regulated in HTS, deep dermal tissue, and thermally injured tissue, reducing its ability to regulate pro-fibrotic transforming growth factor-beta 1 (TGF-β1) and normal fibrillogenesis. However, treatment of HTS fibroblasts with interferon-alpha 2b (IFN-α2b) has been shown to reduce excessive collagen synthesis and improve HTS by reducing serum TGF-β1 levels. The expression of decorin isoforms in HTS is currently unknown and the effects of TGF-β1 and IFN-α2b on decorin, decorin isoform expression and type 1 collagen are of great interest to our group. Dermal fibroblasts were treated with TGF-β1 and/or IFN-α2b, for 48 h. The expression and secretion of decorin, decorin isoforms and type 1 collagen were quantified with reverse transcription-quantitative polymerase chain reaction, immunofluorescence staining and enzyme-linked immunosorbent assays. The mRNA expression of decorin and each isoform was significantly reduced in HTS fibroblasts relative to normal skin. TGF-β1 decreased the mRNA expression of decorin and decorin isoforms, whereas IFN-α2b showed the opposite effect. IFN-α2b significantly inhibited TGF-β1's effect on the mRNA expression of type I collagen alpha 1 in papillary dermal fibroblasts and overall showed relative effects of inhibiting TGF-β1. These data support that a further investigation into the structural and functional roles of decorin isoforms in HTS pathogenesis is warranted and that IFN-α2b is an important agent in reducing fibrotic outcomes.
Topics: Humans; Cells, Cultured; Cicatrix, Hypertrophic; Collagen; Collagen Type I; Decorin; Fibroblasts; Interferon alpha-2; Interferon-alpha; Protein Isoforms; RNA, Messenger; Transforming Growth Factor beta1; Wound Healing
PubMed: 38243615
DOI: 10.1111/wrr.13155