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Journal of Family Medicine and Primary... Aug 2023Versican is a chondroitin sulphate proteoglycan with raised expression at site of inflammation, and uterine fibroids are associated with local inflammation. Hence, this...
OBJECTIVE
Versican is a chondroitin sulphate proteoglycan with raised expression at site of inflammation, and uterine fibroids are associated with local inflammation. Hence, this study aimed to estimate serum Versican levels in pre-menopausal women with uterine fibroids to evaluate its diagnostic efficiency.
MATERIALS AND METHODS
This case-control study included forty uterine fibroid cases and 40 healthy controls. Cases clinically evaluated with USG findings, that is number, location of fibroid and volume calculated by prolate ellipse formula a × b × c × 0.523 (a - height, b - width, c - depth). Biochemical investigations, that is serum Versican levels, were estimated by ELISA with total cholesterol, HDLc and LDLc. Triglycerides by fully automated chemistry analysers. Serum biochemical parameters were compared and correlated with volume of fibroid. Area under receiver operating characteristic curve was calculated along with cut-off value to determine diagnostic potential of Versican, differentiating women with fibroids.
RESULTS
In the present study, patients with fibroids had decreased levels of serum Versican (79.43 ± 18.60) as compared to healthy controls (101.81 ± 28.24, < 0.001). There was a statistically significant negative correlation ( = - 0. 307, = 0.04) between serum Versican level and volume of fibroid. Area under ROC was 0.726 (95% CI: 0.616-0.836; = 0.001). The best cut-off value for serum Versican level was 96.90 ng/ml with 90% sensitivity and 48% specificity.
CONCLUSION
Serum Versican levels were found significantly lower in women with fibroid with a negative correlation with volume of fibroid uterus. Furthermore, extensive study would help in substantiating diagnostic potential of serum Versican in fibroid uterus patients.
PubMed: 37767449
DOI: 10.4103/jfmpc.jfmpc_320_23 -
PloS One 2021Versican is a large proteoglycan in the extracellular matrix. During embryonic stages, it plays a crucial role in the development of cartilage, heart, and dermis....
Versican is a large proteoglycan in the extracellular matrix. During embryonic stages, it plays a crucial role in the development of cartilage, heart, and dermis. Previously, we reported that Prx1-Vcan conditional knockout mice, lacking Vcan expression in mesenchymal condensation areas of the limb bud, show the impaired joint formation and delayed cartilage development. Here, we investigated their phenotype in adults and found that they develop swelling of the knee joint. Histologically, their newborn joint exhibited impaired formation of both anterior and posterior cruciate ligaments. Immunostaining revealed a decrease in scleraxis-positive cells in both articular cartilage and ligament of Prx1-Vcan knee joint, spotty patterns of type I collagen, and the presence of type II collagen concomitant with the absence of versican expression. These results suggest that versican expression during the perinatal period is required for cruciate ligaments' formation and that its depletion affects joint function in later ages.
Topics: Animals; Animals, Newborn; Anterior Cruciate Ligament; Basic Helix-Loop-Helix Transcription Factors; Cartilage, Articular; Chondrogenesis; Collagen Type I; Collagen Type II; Knee Joint; Mice; Mice, Knockout; Phenotype; Posterior Cruciate Ligament; Versicans
PubMed: 33886644
DOI: 10.1371/journal.pone.0250366 -
Journal of Cardiovascular Development... Aug 2021A bicuspid aortic valve (BAV) is the most common cardiac malformation, found in 0.5% to 2% of the population. BAVs are present in approximately 50% of patients with... (Review)
Review
A bicuspid aortic valve (BAV) is the most common cardiac malformation, found in 0.5% to 2% of the population. BAVs are present in approximately 50% of patients with severe aortic stenosis and are an independent risk factor for aortic aneurysms. Currently, there are no therapeutics to treat BAV, and the human mutations identified to date represent a relatively small number of BAV patients. However, the discovery of BAV in an increasing number of genetically modified mice is advancing our understanding of molecular pathways that contribute to BAV formation. In this study, we utilized the comparison of BAV phenotypic characteristics between murine models as a tool to advance our understanding of BAV formation. The collation of murine BAV data indicated that excess versican within the provisional extracellular matrix (P-ECM) is a common factor in BAV development. While the percentage of BAVs is low in many of the murine BAV models, the remaining mutant mice exhibit larger and more amorphous tricuspid AoVs, also with excess P-ECM compared to littermates. The identification of common molecular characteristics among murine BAV models may lead to BAV therapeutic targets and biomarkers of disease progression for this highly prevalent and heterogeneous cardiovascular malformation.
PubMed: 34436234
DOI: 10.3390/jcdd8080092 -
Frontiers in Immunology 2022Increasing evidence has revealed an important role of versican (VCAN) on various aspects of cancer progression. Here, we assessed the impact of VCAN expression on...
BACKGROUND
Increasing evidence has revealed an important role of versican (VCAN) on various aspects of cancer progression. Here, we assessed the impact of VCAN expression on prognosis and the response to adjuvant therapy and immunotherapy in patients with gastric cancer (GC).
METHODS
Four independent cohorts containing 1353 patients with GC, were utilized to investigate the effect of VCAN expression on prognosis and response to adjuvant therapy in GC. Two cohorts treated with immune checkpoint blockades were included to assess the predict value of VCAN expression on response to immunotherapy. Moreover, the bulk RNA-seq and single-cell RNA-seq data were analyzed to illustrate the role of VCAN in tumor microenvironment. Clinical outcomes of patient subgroups were compared by Kaplan-Meier curves with the log-rank test.
RESULT
High VCAN expression was associated with poor prognosis for patients with GC. Compared with patients with high VCAN expression, patients with low VCAN expression benefited more from adjuvant chemotherapy and adjuvant chemoradiotherapy. Moreover, patients with high VCAN expression tended to be resistant to immunotherapy, and VCAN could serve as a promising indicator for predicting the response to immunotherapy. VCAN tumors showed a specific microenvironment with more cancer associated fibroblasts infiltration and significant enrichment of stromal relevant signaling pathways.
CONCLUSION
VCAN could predict the response to adjuvant chemotherapy, adjuvant chemoradiotherapy and immunotherapy in GC, and designing new medicine target to VCAN might be an effective way to improve the efficacy of several treatment options for GC.
Topics: Humans; Immunotherapy; Prognosis; Stomach Neoplasms; Tumor Microenvironment; Versicans
PubMed: 36203562
DOI: 10.3389/fimmu.2022.960570 -
Cell Death & Disease Jan 2024The global burden of colorectal cancer (CRC) has rapidly increased in recent years. Dysregulated cholesterol homeostasis facilitated by extracellular matrix (ECM)...
The global burden of colorectal cancer (CRC) has rapidly increased in recent years. Dysregulated cholesterol homeostasis facilitated by extracellular matrix (ECM) remodeling transforms the tumor microenvironment. Collagen I, a major with ECM component is highly expressed in colorectal tumors with infiltrative growth. Although oxysterol binding protein (OSBP)-related proteins accommodate tumorigenesis, OSBPL2, which is usually involved in deafness, is not associated with CRC progression. Therefore, we aimed to investigate the pathological function of OSBPL2 and identify the molecular link between ECM-Collagen I and OSBPL2 in CRC to facilitate the development of new treatments for CRC. OSBPL2 predicted a favorable prognosis in stage IV CRC and substantially repressed Collagen I-induced focal adhesion, migration, and invasion. The reduction of OSBPL2 activated ERK signaling through the VCAN/AREG/EREG axis during CRC growth, while relying on PARP1 via ZEB1 in CRC metastasis. OSBPL2 defect supported colorectal tumor growth and metastasis, which were suppressed by the ERK and PARP1 inhibitors SCH772984 and AG14361, respectively. Overall, our findings revealed that the Collagen I-induced loss of OSBPL2 aggravates CRC progression through VCAN-mediated ERK signaling and the PARP1/ZEB1 axis. This demonstrates that SCH772984 and AG14361 are reciprocally connective therapies for OSBPL2 CRC, which could contribute to further development of targeted CRC treatment.
Topics: Humans; Benzodiazepines; Azulenes; Collagen Type I; Colorectal Neoplasms; Tumor Microenvironment; Zinc Finger E-box-Binding Homeobox 1; Receptors, Steroid; Versicans; Poly (ADP-Ribose) Polymerase-1
PubMed: 38267463
DOI: 10.1038/s41419-024-06468-1 -
The Journal of Biological Chemistry Nov 2021A disintegrin-like and metalloprotease domain with thrombospondin type 1 motifs (ADAMTS)8 is a secreted protease, which was recently implicated in pathogenesis of...
A disintegrin-like and metalloprotease domain with thrombospondin type 1 motifs (ADAMTS)8 is a secreted protease, which was recently implicated in pathogenesis of pulmonary arterial hypertension (PAH). However, the substrate repertoire of ADAMTS8 and regulation of its activity are incompletely understood. Although considered a proteoglycanase because of high sequence similarity and close phylogenetic relationship to the proteoglycan-degrading proteases ADAMTS1, 4, 5, and 15, as well as tight genetic linkage with ADAMTS15 on human chromosome 11, its aggrecanase activity was reportedly weak. Several post-translational factors are known to regulate ADAMTS proteases such as autolysis, inhibition by endogenous inhibitors, and receptor-mediated endocytosis, but their impacts on ADAMTS8 are unknown. Here, we show that ADAMTS8 undergoes autolysis at six different sites within its spacer domain. We also found that in contrast to ADAMTS4 and 5, ADAMTS8 levels were not regulated through low-density lipoprotein receptor-related protein 1 (LRP1)-mediated endocytosis. Additionally, ADAMTS8 lacked significant activity against the proteoglycans aggrecan, versican, and biglycan. Instead, we found that ADAMTS8 cleaved osteopontin, a phosphoprotein whose expression is upregulated in PAH. Multiple ADAMTS8 cleavage sites were identified using liquid chromatography-tandem mass spectrometry. Osteopontin cleavage by ADAMTS8 was efficiently inhibited by TIMP-3, an endogenous inhibitor of ADAMTS1, 4, and 5, as well as by TIMP-2, which has no previously reported inhibitory activity against other ADAMTS proteases. These differences in post-translational regulation and substrate repertoire differentiate ADAMTS8 from other family members and may help to elucidate its role in PAH.
Topics: ADAMTS Proteins; HEK293 Cells; Humans; Osteopontin; Protein Processing, Post-Translational; Proteoglycans; Proteolysis; Pulmonary Arterial Hypertension; Tissue Inhibitor of Metalloproteinase-3
PubMed: 34687701
DOI: 10.1016/j.jbc.2021.101323 -
Matrix Biology : Journal of the... Mar 2021Little is known about extracellular matrix (ECM) contributions to formation of the earliest cell lineages in the embryo. Here, we show that the proteoglycan versican and...
Little is known about extracellular matrix (ECM) contributions to formation of the earliest cell lineages in the embryo. Here, we show that the proteoglycan versican and glycosaminoglycan hyaluronan are associated with emerging Flk1 hematoendothelial progenitors at gastrulation. The mouse versican mutant Vcan lacks yolk sac vasculature, with attenuated yolk sac hematopoiesis. CRISPR/Cas9-mediated Vcan inactivation in mouse embryonic stem cells reduced vascular endothelial and hematopoietic differentiation within embryoid bodies, which generated fewer blood colonies, and had an impaired angiogenic response to VEGF. Hyaluronan was severely depleted in Vcan embryos, with corresponding upregulation of the hyaluronan-depolymerase TMEM2. Conversely, hyaluronan-deficient mouse embryos also had vasculogenic suppression but with increased versican proteolysis. VEGF and Indian hedgehog, crucial vasculogenic factors, utilized the versican-hyaluronan matrix, specifically versican chondroitin sulfate chains, for binding. Versican-hyaluronan ECM is thus an obligate requirement for vasculogenesis and primitive hematopoiesis, providing a vasculogenic factor-enriching microniche for Flk1 progenitors from their origin at gastrulation.
Topics: Animals; CRISPR-Cas Systems; Cell Differentiation; Cells, Cultured; Extracellular Matrix; Hedgehog Proteins; Hematopoiesis; Hyaluronic Acid; Membrane Proteins; Mice; Mouse Embryonic Stem Cells; Stem Cell Niche; Up-Regulation; Vascular Endothelial Growth Factor Receptor-2; Versicans
PubMed: 33454424
DOI: 10.1016/j.matbio.2021.01.002 -
Critical Care (London, England) Feb 2021Biomarkers can be used to detect the presence of endothelial and/or alveolar epithelial injuries in case of ARDS. Angiopoietin-2 (Ang-2), soluble intercellular adhesion...
BACKGROUND
Biomarkers can be used to detect the presence of endothelial and/or alveolar epithelial injuries in case of ARDS. Angiopoietin-2 (Ang-2), soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), P-selectin and E-selectin are biomarkers of endothelial injury, whereas the receptor for advanced glycation end-products (RAGE) reflects alveolar epithelial injury. The aims of this study were to evaluate whether the plasma concentration of the above-mentioned biomarkers was different 1) in survivors and non-survivors of COVID-19-related ARDS and 2) in COVID-19-related and classical ARDS.
METHODS
This prospective study was performed in two COVID-19-dedicated Intensive Care Units (ICU) and one non-COVID-19 ICU at Ferrara University Hospital. A cohort of 31 mechanically ventilated patients with COVID-19 ARDS and a cohort of 11 patients with classical ARDS were enrolled. Ang-2, ICAM-1, VCAM-1, P-selectin, E-selectin and RAGE were determined with a bead-based multiplex immunoassay at three time points: inclusion in the study (T1), after 7 ± 2 days (T2) and 14 ± 2 days (T3). The primary outcome was to evaluate the plasma trend of the biomarker levels in survivors and non-survivors. The secondary outcome was to evaluate the differences in respiratory mechanics variables and gas exchanges between survivors and non-survivors. Furthermore, we compared the plasma levels of the biomarkers at T1 in patients with COVID-19-related ARDS and classical ARDS.
RESULTS
In COVID-19-related ARDS, the plasma levels of Ang-2 and ICAM-1 at T1 were statistically higher in non-survivors than survivors, (p = 0.04 and p = 0.03, respectively), whereas those of P-selectin, E-selectin and RAGE did not differ. Ang-2 and ICAM-1 at T1 were predictors of mortality (AUROC 0.650 and 0.717, respectively). At T1, RAGE and P-selectin levels were higher in classical ARDS than in COVID-19-related ARDS. Ang-2, ICAM-1 and E-selectin were lower in classical ARDS than in COVID-19-related ARDS (all p < 0.001).
CONCLUSIONS
COVID-19 ARDS is characterized by an early pulmonary endothelial injury, as detected by Ang-2 and ICAM-1. COVID-19 ARDS and classical ARDS exhibited a different expression of biomarkers, suggesting different pathological pathways. Trial registration NCT04343053 , Date of registration: April 13, 2020.
Topics: Aged; Antigens, Neoplasm; Area Under Curve; Biomarkers; COVID-19; Cohort Studies; E-Selectin; Female; Humans; Intensive Care Units; Intercellular Adhesion Molecule-1; Lung Injury; Male; Middle Aged; Mitogen-Activated Protein Kinases; P-Selectin; Prospective Studies; ROC Curve; Respiration, Artificial; Respiratory Distress Syndrome; Versicans; Vesicular Transport Proteins
PubMed: 33608030
DOI: 10.1186/s13054-021-03499-4 -
Genes Nov 2022Fluoroquinolone antibiotics are associated with increased risk of tendinopathy and tendon rupture, which can occur well after cessation of treatment. We have previously...
Fluoroquinolone antibiotics are associated with increased risk of tendinopathy and tendon rupture, which can occur well after cessation of treatment. We have previously reported that the fluoroquinolone ciprofloxacin (CPX) reduced proteoglycan synthesis in equine tendon explants. This study aimed to determine the effects of CPX on proteoglycan catabolism and whether any observed effects are reversible. Equine superficial digital flexor tendon explant cultures were treated for 4 days with 1, 10, 100 or 300 µg/mL CPX followed by 8 days without CPX. The loss of [S]-labelled proteoglycans and chemical pool of aggrecan and versican was studied as well as the gene expression levels of matrix-degrading enzymes responsible for proteoglycan catabolism. CPX suppressed [S]-labelled proteoglycan and total aggrecan loss from the explants, although not in a dose-dependent manner, which coincided with downregulation of RNA expression of MMP-9, -13, ADAMTS-4, -5. The suppressed loss of proteoglycans was reversed upon removal of the fluoroquinolone with concurrent recovery of MMP and ADAMTS RNA expression, and downregulated TIMP-2 and upregulated TIMP-1 expression. No changes in MMP-3 expression by CPX was observed at any stage. These findings suggest that CPX suppresses proteoglycan catabolism in tendon, and this is partially attributable to downregulation of matrix-degrading enzymes.
Topics: Animals; Horses; Aggrecans; Ciprofloxacin; Tendons; Fluoroquinolones; Versicans; RNA, Messenger
PubMed: 36553476
DOI: 10.3390/genes13122210 -
Arteriosclerosis, Thrombosis, and... Sep 2020The ductus arteriosus (DA) is a fetal artery connecting the aorta and pulmonary arteries. Progressive matrix remodeling, that is, intimal thickening (IT), occurs in the...
OBJECTIVE
The ductus arteriosus (DA) is a fetal artery connecting the aorta and pulmonary arteries. Progressive matrix remodeling, that is, intimal thickening (IT), occurs in the subendothelial region of DA to bring anatomic DA closure. IT is comprised of multiple ECMs (extracellular matrices) and migrated smooth muscle cells (SMCs). Because glycoprotein fibulin-1 binds to multiple ECMs and regulates morphogenesis during development, we investigated the role of fibulin-1 in DA closure. Approach and Results: Fibulin-1-deficient () mice exhibited patent DA with hypoplastic IT. An unbiased transcriptome analysis revealed that EP4 (prostaglandin E receptor 4) stimulation markedly increased fibulin-1 in DA-SMCs via phospholipase C-NFκB (nuclear factor κB) signaling pathways. Fluorescence-activated cell sorting (FACS) analysis demonstrated that fibulin-1 binding protein versican was derived from DA-endothelial cells (ECs). We examined the effect of fibulin-1 on directional migration toward ECs in association with versican by using cocultured DA-SMCs and ECs. EP4 stimulation promoted directional DA-SMC migration toward ECs, which was attenuated by either silencing fibulin-1 or versican. Immunofluorescence demonstrated that fibulin-1 and versican V0/V1 were coexpressed at the IT of wild-type DA, whereas 30% of versican-deleted mice lacking a hyaluronan binding site displayed patent DA. Fibulin-1 expression was attenuated in the EP4-deficient mouse () DA, which exhibits patent DA with hypoplastic IT, and fibulin-1 protein administration restored IT formation. In human DA, fibulin-1 and versican were abundantly expressed in SMCs and ECs, respectively.
CONCLUSIONS
Fibulin-1 contributes to DA closure by forming an environment favoring directional SMC migration toward the subendothelial region, at least, in part, in combination with EC-derived versican and its binding partner hyaluronan.
Topics: Animals; Calcium-Binding Proteins; Cell Movement; Cells, Cultured; Coculture Techniques; Ductus Arteriosus; Ductus Arteriosus, Patent; Endothelial Cells; Extracellular Matrix; Humans; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Smooth Muscle; NF-kappa B; Organ Culture Techniques; Protein Kinase C; Rats, Wistar; Receptors, Prostaglandin E, EP4 Subtype; Signal Transduction; Type C Phospholipases
PubMed: 32640908
DOI: 10.1161/ATVBAHA.120.314729