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Genes Dec 2019Musculocontractural Ehlers-Danlos Syndome (mcEDS) is a type of EDS caused by biallelic pathogenic variants in the gene for carbohydrate sulfotransferase 14/dermatan... (Review)
Review
Musculocontractural Ehlers-Danlos Syndome (mcEDS) is a type of EDS caused by biallelic pathogenic variants in the gene for carbohydrate sulfotransferase 14/dermatan 4--sulfotransferase 1 (/, mcEDS-), or in the gene for dermatan sulfate epimerase (, mcEDS-). Thus far, 41 patients from 28 families with mcEDS- and five patients from four families with mcEDS- have been described in the literature. Clinical features comprise multisystem congenital malformations and progressive connective tissue fragility-related manifestations. This review outlines recent advances in understanding the pathophysiology of mcEDS. Pathogenic variants in or lead to reduced activities of relevant enzymes, resulting in a negligible amount of dermatan sulfate (DS) and an excessive amount of chondroitin sulfate. Connective tissue fragility is presumably attributable to a compositional change in the glycosaminoglycan chains of decorin, a major DS-proteoglycan in the skin that contributes to collagen fibril assembly. Collagen fibrils in affected skin are dispersed in the papillary to reticular dermis, whereas those in normal skin are regularly and tightly assembled. Glycosaminoglycan chains are linear in affected skin, stretching from the outer surface of collagen fibrils to adjacent fibrils; glycosaminoglycan chains are curved in normal skin, maintaining close contact with attached collagen fibrils. Homozygous () mice have been shown perinatal lethality, shorter fetal length and vessel-related placental abnormalities. Milder phenotypes in mcEDS- might be related to a smaller fraction of decorin DS, potentially through residual DSE activity or compensation by DSE2 activity. These findings suggest critical roles of DS and DS-proteoglycans in the multisystem development and maintenance of connective tissues, and provide fundamental evidence to support future etiology-based therapies.
Topics: Antigens, Neoplasm; Chondroitin Sulfates; DNA-Binding Proteins; Dermatan Sulfate; Ehlers-Danlos Syndrome; Female; Humans; Male; Neoplasm Proteins; Pedigree; Phenotype; Sulfotransferases
PubMed: 31905796
DOI: 10.3390/genes11010043 -
Journal of Clinical Medicine Mar 2020The outcome of patients with hepatocellular carcinoma (HCC) is still poor. Decorin is a small leucine-rich proteoglycan, which exerts antiproliferative and...
The outcome of patients with hepatocellular carcinoma (HCC) is still poor. Decorin is a small leucine-rich proteoglycan, which exerts antiproliferative and antiangiogenic properties in vitro. We aimed to investigate the associations of decorin with physical function and prognosis in patients with HCC. We enrolled 65 patients with HCC treated with transcatheter arterial chemoembolization (median age, 75 years; female/male, 25/40). Serum decorin levels were measured using enzyme-linked immunosorbent assays; patients were classified into the High or Low decorin groups by median levels. Associations of decorin with physical function and prognosis were evaluated by multivariate correlation and Cox regression analyses, respectively. Age and skeletal muscle indices were not significantly different between the High and Low decorin groups. In the High decorin group, the 6-min walking distance was significantly longer than the Low decorin group and was significantly correlated with serum decorin levels ( = 0.2927, = 0.0353). In multivariate analysis, the High decorin group was independently associated with overall survival (hazard ratio 2.808, 95% confidence interval 1.016-8.018, = 0.0498). In the High decorin group, overall survival rate was significantly higher than in the Low decorin group (median 732 days vs. 463 days, = 0.010). In conclusion, decorin may be associated with physical function and prognosis in patients with HCC.
PubMed: 32231160
DOI: 10.3390/jcm9040936 -
Ginekologia Polska 2020Preeclampsia (PE) is a pregnancy complication caused by typically limited proliferation, apoptosis, migration, and invasion of extra-trophoblast cells. Decorin (DCN) is...
OBJECTIVES
Preeclampsia (PE) is a pregnancy complication caused by typically limited proliferation, apoptosis, migration, and invasion of extra-trophoblast cells. Decorin (DCN) is a decidua-derived transforming growth factor (TGF)-binding proteoglycan which exerts multiple physiological functions such as collagen fibrillogenesis, myogenesis, angiostasis, and restraining placental invasiveness by adversely regulate proliferation, migration, and invasiveness of human extravillous trophoblast cells. Preeclampsia is mainly classified as early- and late-onset PE according to the timing of the disease onset. In the present study, we aimed to investigate the DCN levels in early-onset PE (EOPE, < 34 weeks) and late-onset severe PE (LOPE, ≥ 34 weeks) and uncomplicated pregnancies.
MATERIAL AND METHODS
In this case-control study, serum samples were obtained from 21 pregnant women with EOPE and 29 pregnant women with LOPE, as well as from 38 healthy controls (n = 12 early-onset controls and n = 26 late-onset controls) with uncomplicated pregnancies.
RESULTS
The mean DCN level was statistically significantly higher in the early-onset PE controls than late-onset PE controls (p = 0.040). Although the mean DCN level was higher in the early-onset PE controls than EOPE and LOPE groups, it did not reach statistical significance (p = 0.119 and p = 0.117, respectively).
CONCLUSIONS
Although DCN has been thought to play a role in the pathophysiology of PE, our study results show that DCN is not a useful predictive marker of EOPE and LOPE. Further large-scale studies are needed to draw a definitive conclusion.
Topics: Adolescent; Adult; Biomarkers; Case-Control Studies; Decorin; Female; Humans; Pre-Eclampsia; Predictive Value of Tests; Pregnancy; Pregnancy Trimesters; Prenatal Diagnosis; Prospective Studies; Young Adult
PubMed: 32495932
DOI: 10.5603/GP.2020.0050 -
International Journal of Molecular... May 2024Corneal neovascularization can impair vision and result in a poor quality of life. The pathogenesis involves a complex interplay of angiogenic factors, notably vascular... (Review)
Review
Corneal neovascularization can impair vision and result in a poor quality of life. The pathogenesis involves a complex interplay of angiogenic factors, notably vascular endothelial growth factor (VEGF). This review provides a comprehensive overview of potential therapies for corneal neovascularization, covering tissue inhibitors of metalloproteinases (TIMPs), transforming growth factor beta (TGF-β) inhibitors, interleukin-1L receptor antagonist (IL-1 Ra), nitric oxide synthase (NOS) isoforms, galectin-3 inhibitors, retinal pigment epithelium-derived factor (PEDF), platelet-derived growth factor (PDGF) receptor inhibitors, and surgical treatments. Conventional treatments include anti-VEGF therapy and laser interventions, while emerging therapies such as immunosuppressive drugs (cyclosporine and rapamycin) have been explored. Losartan and decorin are potential antifibrotic agents that mitigate TGF-β-induced fibrosis. Ocular nanosystems are innovative drug-delivery platforms that facilitate the targeted release of therapeutic agents. Gene therapies, such as small interfering RNA and antisense oligonucleotides, are promising approaches for selectively inhibiting angiogenesis-related gene expression. Aganirsen is efficacious in reducing the corneal neovascularization area without significant adverse effects. These multifaceted approaches underscore the corneal neovascularization management complexity and highlight ideas for enhancing therapeutic outcomes. Furthermore, the importance of combination therapies and the need for further research to develop specific inhibitors while considering their therapeutic efficacy and potential adverse effects are discussed.
Topics: Humans; Corneal Neovascularization; Animals; Genetic Therapy; Angiogenesis Inhibitors; Transforming Growth Factor beta
PubMed: 38791518
DOI: 10.3390/ijms25105479 -
Life (Basel, Switzerland) Dec 2021Diabetic retinopathy (DR) is a microvascular complication of diabetes in the retina. Chronic hyperglycemia damages retinal microvasculature embedded into the...
Diabetic retinopathy (DR) is a microvascular complication of diabetes in the retina. Chronic hyperglycemia damages retinal microvasculature embedded into the extracellular matrix (ECM), causing fluid leakage and ischemic retinal neovascularization. Current treatment strategies include intravitreal anti-vascular endothelial growth factor (VEGF) or steroidal injections, laser photocoagulation, or vitrectomy in severe cases. However, treatment may require multiple modalities or repeat treatments due to variable response. Though DR management has achieved great success, improved, long-lasting, and predictable treatments are needed, including new biomarkers and therapeutic approaches. Small-leucine rich proteoglycans, such as decorin, constitute an integral component of retinal endothelial ECM. Therefore, any damage to microvasculature can trigger its antifibrotic and antiangiogenic response against retinal vascular pathologies, including DR. We conducted a cross-sectional study to examine the association between aqueous humor (AH) decorin levels, if any, and severity of DR. A total of 82 subjects (26 control, 56 DR) were recruited. AH was collected and decorin concentrations were measured using an enzyme-linked immunosorbent assay (ELISA). Decorin was significantly increased in the AH of DR subjects compared to controls ( = 0.0034). AH decorin levels were increased in severe DR groups in ETDRS and Gloucestershire classifications. Decorin concentrations also displayed a significant association with visual acuity (LogMAR) measurements. In conclusion, aqueous humor decorin concentrations were found elevated in DR subjects, possibly due to a compensatory response to the retinal microvascular changes during hyperglycemia.
PubMed: 34947953
DOI: 10.3390/life11121421 -
Aging May 2021Desmoplasia in the extracellular matrix (ECM) is one of the hallmarks of pancreatic cancer (PC), a virtually incurable disease. Decorin, a classical small leucine-rich...
Desmoplasia in the extracellular matrix (ECM) is one of the hallmarks of pancreatic cancer (PC), a virtually incurable disease. Decorin, a classical small leucine-rich proteoglycan found in the ECM, was upregulated in PC tissue samples according to the data of TCGA. However, decorin plays a protective role in the ECM. So it is necessary to study the roles of decorin in the progression of PC. A significantly upregulated expression of decorin was observed in the PC tissue samples compared with the normal tissues. However, there was no considerable difference in the level of expression of decorin during different pathological stages, which was supported by the immunoblot analysis. Western blot showed a higher expression of decorin A in the para-carcinoma tissue than in the cancerous tissue but the expression of decorin B, C, and D was elevated in the cancerous tissue. The results of the MTT and scratch wound healing assays revealed an elevated proliferation ability and migration rate in decorin B-overexpressing cells but were inhibited in the decorin A-overexpressing cells. Overexpression of decorin A significantly elevated the expression of the apoptosis-related genes and Decorin B-overexpression elevated proliferation-related genes. All the results showed that decorin B played important roles in the promoting of PC.
Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Decorin; Disease Progression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Models, Biological; Pancreatic Neoplasms
PubMed: 34021540
DOI: 10.18632/aging.203060 -
BioRxiv : the Preprint Server For... Aug 2023The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These...
The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These tumor-host interactions are often affected by soluble bioactive molecules such as proteoglycans. Decorin, an archetypical small leucine-rich proteoglycan primarily expressed by stromal cells, affects cancer growth in its soluble form by interacting with several receptor tyrosine kinases (RTK). Overall, decorin leads to a context-dependent and protracted cessation of oncogenic RTK activity by attenuating their ability to drive a pro-survival program and to sustain a pro-angiogenic network. Through an unbiased transcriptomic analysis using deep RNAseq, we discovered that decorin downregulated a cluster of tumor-associated genes involved in lymphatic vessel development when systemically delivered to mice harboring breast carcinoma allografts. We found that Lyve1 and Podoplanin, two established markers of lymphatic vessels, were markedly suppressed at both the mRNA and protein levels and this suppression correlated with a significant reduction in tumor lymphatic vessels. We further discovered that soluble decorin, but not its homologous proteoglycan biglycan, inhibited lymphatic vessel sprouting in an 3D model of lymphangiogenesis. Mechanistically, we found that decorin interacted with VEGFR3, the main lymphatic RTK, and its activity was required for the decorin-mediated block of lymphangiogenesis. Finally, we discovered that Lyve1 was in part degraded via decorin-evoked autophagy in a nutrient- and energy-independent manner. These findings implicate decorin as a new biological factor with anti-lymphangiogenic activity and provide a potential therapeutic agent for curtailing breast cancer growth and metastasis.
PubMed: 37693608
DOI: 10.1101/2023.08.28.555187 -
American Journal of Physiology. Cell... Dec 2022Proteoglycans consist of a core protein substituted with one or more glycosaminoglycan (GAG) chains and execute versatile functions during many physiological and... (Review)
Review
Proteoglycans consist of a core protein substituted with one or more glycosaminoglycan (GAG) chains and execute versatile functions during many physiological and pathological processes. The biosynthesis of GAG chains is a complex process that depends on the concerted action of a variety of enzymes. Central to the biosynthesis of heparan sulfate (HS) and chondroitin sulfate/dermatan sulfate (CS/DS) GAG chains is the formation of a tetrasaccharide linker region followed by biosynthesis of HS or CS/DS-specific repeating disaccharide units, which then undergo modifications and epimerization. The importance of these biosynthetic enzymes is illustrated by several severe pleiotropic disorders that arise upon their deficiency. The Ehlers-Danlos syndromes (EDS) constitute a special group among these disorders. Although most EDS types are caused by defects in fibrillar types I, III, or V collagen, or their modifying enzymes, a few rare EDS types have recently been linked to defects in GAG biosynthesis. Spondylodysplastic EDS (spEDS) is caused by defective formation of the tetrasaccharide linker region, either due to β4GalT7 or β3GalT6 deficiency, whereas musculocontractural EDS (mcEDS) results from deficiency of D4ST1 or DS-epi1, impairing DS formation. This narrative review highlights the consequences of GAG deficiency in these specific EDS types, summarizes the associated phenotypic features and the molecular spectrum of reported pathogenic variants, and defines the current knowledge on the underlying pathophysiological mechanisms based on studies in patient-derived material, in vitro analyses, and animal models.
Topics: Animals; Dermatan Sulfate; Sulfotransferases; Ehlers-Danlos Syndrome; Collagen; Proteoglycans
PubMed: 35993517
DOI: 10.1152/ajpcell.00127.2022 -
Molecules (Basel, Switzerland) Jul 2020Search for new cardioprotective therapies is of great importance since no cardioprotective drugs are available on the market. In line with this need, several natural...
Search for new cardioprotective therapies is of great importance since no cardioprotective drugs are available on the market. In line with this need, several natural biomolecules have been extensively tested for their potential cardioprotective effects. Previously, we have shown that biglycan, a member of a diverse group of small leucine-rich proteoglycans, enhanced the expression of cardioprotective genes and decreased ischemia/reperfusion-induced cardiomyocyte death via a TLR-4 dependent mechanism. Therefore, in the present study we aimed to test whether decorin, a small leucine-rich proteoglycan closely related to biglycan, could exert cardiocytoprotection and to reveal possible downstream signaling pathways. Methods: Primary cardiomyocytes isolated from neonatal and adult rat hearts were treated with 0 (Vehicle), 1, 3, 10, 30 and 100 nM decorin as 20 h pretreatment and maintained throughout simulated ischemia and reperfusion (SI/R). In separate experiments, to test the mechanism of decorin-induced cardio protection, 3 nM decorin was applied in combination with inhibitors of known survival pathways, that is, the NOS inhibitor L-NAME, the PKG inhibitor KT-5823 and the TLR-4 inhibitor TAK-242, respectively. mRNA expression changes were measured after SI/R injury. Results: Cell viability of both neonatal and adult cardiomyocytes was significantly decreased due to SI/R injury. Decorin at 1, 3 and 10 nM concentrations significantly increased the survival of both neonatal and adult myocytes after SI/R. At 3nM (the most pronounced protective concentration), it had no effect on apoptotic rate of neonatal cardiac myocytes. No one of the inhibitors of survival pathways (L-NAME, KT-5823, TAK-242) influenced the cardiocytoprotective effect of decorin. MYND-type containing 19 (Zmynd19) and eukaryotic translation initiation factor 4E nuclear import factor 1 (Eif4enif1) were significantly upregulated due to the decorin treatment. In conclusion, this is the first demonstration that decorin exerts a direct cardiocytoprotective effect possibly independent of NO-cGMP-PKG and TLR-4 dependent survival signaling.
Topics: Animals; Cardiotonic Agents; Cell Survival; Decorin; Myocardial Reperfusion Injury; Myocytes, Cardiac; Rats; Rats, Wistar; Signal Transduction
PubMed: 32731559
DOI: 10.3390/molecules25153426 -
Frontiers in Cell and Developmental... 2020The ocular surface, which forms the interface between the eye and the external environment, includes the cornea, corneoscleral limbus, the conjunctiva and the accessory... (Review)
Review
The ocular surface, which forms the interface between the eye and the external environment, includes the cornea, corneoscleral limbus, the conjunctiva and the accessory glands that produce the tear film. Glycosaminoglycans (GAGs) and proteoglycans (PGs) have been shown to play important roles in the development, hemostasis and pathology of the ocular surface. Herein we review the current literature related to the distribution and function of GAGs and PGs within the ocular surface, with focus on the cornea. The unique organization of ECM components within the cornea is essential for the maintenance of corneal transparency and function. Many studies have described the importance of GAGs within the epithelial and stromal compartment, while very few studies have analyzed the ECM of the endothelial layer. Importantly, GAGs have been shown to be essential for maintaining corneal homeostasis, epithelial cell differentiation and wound healing, and, more recently, a role has been suggested for the ECM in regulating limbal stem cells, corneal innervation, corneal inflammation, corneal angiogenesis and lymphangiogenesis. Reports have also associated genetic defects of the ECM to corneal pathologies. Thus, we also highlight the role of different GAGs and PGs in ocular surface homeostasis, as well as in pathology.
PubMed: 32903857
DOI: 10.3389/fcell.2020.00731