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Cureus Jan 2023Hurler syndrome (HS) belongs to the category of mucopolysaccharidosis (MPS), a spectrum of rare genetic disorders of the mucopolysaccharides metabolism. This syndrome is...
Hurler syndrome (HS) belongs to the category of mucopolysaccharidosis (MPS), a spectrum of rare genetic disorders of the mucopolysaccharides metabolism. This syndrome is due to a defect in α-iduronidase, an enzyme responsible for the degradation of the glycosaminoglycans (GAGs) heparin and dermatan sulfate. Intra and extracellular accumulation of these non-metabolized substances may lead to multisystemic dysfunction, with severe stomatognathic involvement that may often need treatment. The aim of this article is to present the heterogeneity of orofacial and radiographic findings observed in two patients with HS with long-term follow-up, who were referred to our Stomatology department.
PubMed: 36741627
DOI: 10.7759/cureus.33313 -
Microbiology Spectrum Jan 2023Porcine circovirus type 2 (PCV2) is associated with several economically important diseases that are described as PCV2-associated diseases (PCVADs). PCV2 is replicating...
Porcine circovirus type 2 (PCV2) is associated with several economically important diseases that are described as PCV2-associated diseases (PCVADs). PCV2 is replicating in lymphoblasts, and PCV2 particles are taken up by monocytes without effective replication or complete degradation. Glycosaminoglycans (GAGs) have been demonstrated to be important receptors for PCV2 binding and entry in T-lymphocytes and continuous cell lines. The objective of this study was to determine whether differences exist in viral uptake and outcome among six PCV2 strains from different disease outbreaks in primary porcine monocytes: Stoon-1010 (PCV2a; PMWS), 1121 (PCV2a; abortion), 1147 (PCV2b; PDNS), 09V448 (PCV2d-1; PCVAD with high viral load in lymphoid tissues [PCVAD]), DE222-13 (PCV2d-2; PCVAD), and 19V245 (PCV2d-2; PCVAD). The uptake of PCV2 in peripheral blood monocytes was different among the PCV2 strains. A large number of PCV2 particles were found in the monocytes for Stoon-1010, DE222-13, and 19V245, while a low number was found for 1121, 1147, and 09V448. Competition with, and removal of GAGs on the cell surface, demonstrated an important role of chondroitin sulfate (CS) and dermatan sulfate (DS) in PCV2 entry into monocytes. The mapping of positively/negatively charged amino acids exposed on the surface of PCV2 capsids revealed that their number and distribution could have an impact on the binding of the capsids to GAGs, and the internalization into monocytes. Based on the distribution of positively charged amino acids on PCV2 capsids, phosphacan was hypothesized, and further demonstrated, as an effective candidate to mediate virus attachment to, and internalization in, monocytes. PCV2 is present on almost every pig farm in the world and is associated with a high number of diseases (PCV2-associated diseases [PCVADs]). It causes severe economic losses. Although vaccination is successfully applied in the field, there are still a lot of unanswered questions on the pathogenesis of PCV2 infections. This article reports on the uptake difference of various PCV2 strains by peripheral blood monocytes, and reveals the mechanism of the strong viral uptake ability of monocytes of Piétrain pigs. We further demonstrated that: (i) GAGs mediate the uptake of PCV2 particles by monocytes, (ii) positively charged three-wings-windmill-like amino acid patterns on the capsid outer surface are activating PCV2 uptake, and (iii) phosphacan is one of the potential candidates for PCV2 internalization. These results provide new insights into the mechanisms involved in PCVAD and contribute to a better understanding of PCV2 evolution. This may lead to the development of resistant pigs.
PubMed: 36719220
DOI: 10.1128/spectrum.03805-22 -
Diagnostics (Basel, Switzerland) Dec 2022Mucopolysaccharidosis (MPS) is a group of disorders caused by the reduced or absent activity of enzymes involved in the glycosaminoglycans (GAGs) degradation; the... (Review)
Review
Mucopolysaccharidosis (MPS) is a group of disorders caused by the reduced or absent activity of enzymes involved in the glycosaminoglycans (GAGs) degradation; the consequence is the progressive accumulation of the substrate (dermatan, heparan, keratan or chondroitin sulfate) in the lysosomes of cells belonging to several tissues. The rarity, the broad spectrum of manifestations, the lack of strict genotype-phenotype association, and the progressive nature of MPS make diagnosing this group of conditions challenging. Musculoskeletal involvement represents a common and prominent feature of MPS. Joint and bone abnormalities might be the main clue for diagnosing MPS, especially in attenuated phenotypes; therefore, it is essential to increase the awareness of these conditions among the pediatric rheumatology and orthopedic communities since early diagnosis and treatment are crucial to reduce the disease burden of these patients. Nowadays, enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) are available for some MPS types. We describe the musculoskeletal characteristics of MPS patients through a literature review of MPS cases misdiagnosed as having rheumatologic or orthopedic conditions.
PubMed: 36611367
DOI: 10.3390/diagnostics13010075 -
Investigative Ophthalmology & Visual... Dec 2022The sclera is believed to biomechanically influence eye size, facilitating the excessive axial elongation that occurs during myopigenesis. Here, we test the hypothesis...
PURPOSE
The sclera is believed to biomechanically influence eye size, facilitating the excessive axial elongation that occurs during myopigenesis. Here, we test the hypothesis that the sclera will be remodeled and exhibit altered biomechanics in the mouse model of form-deprivation (FD) myopia, accompanied by altered retinoid concentrations, a potential signaling molecule involved in the process.
METHODS
Male C57 Bl/6J mice were subjected to unilateral FD (n = 44 eyes), leaving the contralateral eye untreated (contra; n = 44). Refractive error and ocular biometry were measured in vivo prior to and after 1 or 3 weeks of FD. Ex vivo measurements were made of scleral biomechanical properties (unconfined compression: n = 24), scleral sulfated glycosaminoglycan (sGAG) content (dimethylmethylene blue: n = 18, and immunohistochemistry: n = 22), and ocular all-trans retinoic acid (atRA) concentrations (retina and RPE + choroid + sclera, n = 24). Age-matched naïve controls were included for some outcomes (n = 32 eyes).
RESULTS
Significant myopia developed after 1 (-2.4 ± 1.1 diopters [D], P < 0.001) and 3 weeks of FD (-4.1 ± 0.7 D, P = 0.025; mean ± standard deviation). Scleral tensile stiffness and permeability were significantly altered during myopigenesis (stiffness = -31.4 ± 12.7%, P < 0.001, and permeability = 224.4 ± 205.5%, P < 0.001). Total scleral sGAG content was not measurably altered; however, immunohistochemistry indicated a sustained decrease in chondroitin-4-sulfate and a slower decline in dermatan sulfate. The atRA increased in the retinas of eyes form-deprived for 1 week.
CONCLUSIONS
We report that biomechanics and GAG content of the mouse sclera are altered during myopigenesis. All scleral outcomes generally follow the trends found in other species and support a retina-to-sclera signaling cascade underlying mouse myopigenesis.
Topics: Male; Mice; Animals; Sclera; Sensory Deprivation; Myopia; Choroid; Retina; Disease Models, Animal
PubMed: 36512347
DOI: 10.1167/iovs.63.13.13 -
Polymers Nov 2022Glycosaminoglycans (GAGs) are a heterogeneous family of linear polysaccharides which are composed of a repeating disaccharide unit. They are also linked to core proteins... (Review)
Review
Glycosaminoglycans (GAGs) are a heterogeneous family of linear polysaccharides which are composed of a repeating disaccharide unit. They are also linked to core proteins to form proteoglycans (PGs). GAGs/PGs are major components of the cell surface and the extracellular matrix (ECM), and they display critical roles in development, normal function, and damage response in the body. Some properties (such as expression quantity, molecular weight, and sulfation pattern) of GAGs may be altered under pathological conditions. Due to the close connection between these properties and the function of GAGs/PGs, the alterations are often associated with enormous changes in the physiological/pathological status of cells and organs. Therefore, these GAGs/PGs may serve as marker molecules of disease. This review aimed to investigate the structural alterations and roles of GAGs/PGs in a range of diseases, such as atherosclerosis, cancer, diabetes, neurodegenerative disease, and virus infection. It is hoped to provide a reference for disease diagnosis, monitoring, prognosis, and drug development.
PubMed: 36433141
DOI: 10.3390/polym14225014 -
Journal of Clinical Medicine Oct 2022Systemic sclerosis (SSc) is a chronic connective tissue disease characterized by immune system dysfunction, vasculopathy, and progressive fibrosis of the skin and...
Systemic sclerosis (SSc) is a chronic connective tissue disease characterized by immune system dysfunction, vasculopathy, and progressive fibrosis of the skin and internal organs, resulting from excessive accumulation of extracellular matrix (ECM) elements, including collagen and proteoglycans (PGs). An uncontrolled PG proliferation, caused by disturbances in their metabolism in tissues, is most likely reflected in the quantitative changes of their components, i.e., glycosaminoglycans (GAGs), in body fluids. Therefore, the aim of this study was to quantify the different types of GAGs in the blood and urine of systemic sclerosis patients. Chondroitin/dermatan sulfates (CS/DS) and heparan sulfates/heparin (HS/H) were quantified by hexuronic acid assay and electrophoretic fractionation, while hyaluronic acid (HA) and keratan sulfates were evaluated using ELISA tests. In turn, individual urinary GAGs were determined using the Blyscan™ Sulfated Glycosaminoglycan Assay Kit. Our results showed that the plasma concentrations of CS/DS, HS/H, HA, and KS in systemic sclerosis patients were significantly higher compared with those in healthy subjects. In the case of urine measurements, we have found that in SSc patients, CS/DC concentrations were significantly higher, while HA concentrations were significantly lower compared with the values observed in the urine of healthy subjects. Importantly, the found by us correlations between plasma keratan sulfate levels and both the duration of the disease and the severity of skin lesions, as expressed by the Rodnan scale, seems to suggest this GAG as a potential marker in assessing disease progression and activity. In addition, a level of urinary excretion of all types of GAGs due to their high positive correlation with uACR, may be a valuable complementary test in the diagnosis of early renal dysfunction in the course of SSc.
PubMed: 36362582
DOI: 10.3390/jcm11216354 -
International Journal of Molecular... Oct 2022The enzyme N-acetylgalactosamine-4-sulfatase (Arylsulfatase B; ARSB) was originally identified as a lysosomal enzyme which was deficient in Mucopolysaccharidosis VI (MPS... (Review)
Review
The enzyme N-acetylgalactosamine-4-sulfatase (Arylsulfatase B; ARSB) was originally identified as a lysosomal enzyme which was deficient in Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy Syndrome). The newly directed attention to the impact of ARSB in human pathobiology indicates a broader, more pervasive effect, encompassing roles as a tumor suppressor, transcriptional mediator, redox switch, and regulator of intracellular and extracellular-cell signaling. By controlling the degradation of chondroitin 4-sulfate and dermatan sulfate by removal or failure to remove the 4-sulfate residue at the non-reducing end of the sulfated glycosaminoglycan chain, ARSB modifies the binding or release of critical molecules into the cell milieu. These molecules, such as galectin-3 and SHP-2, in turn, influence crucial cellular processes and events which determine cell fate. Identification of ARSB at the cell membrane and in the nucleus expands perception of the potential impact of decline in ARSB activity. The regulation of availability of sulfate from chondroitin 4-sulfate and dermatan sulfate may also affect sulfate assimilation and production of vital molecules, including glutathione and cysteine. Increased attention to ARSB in mammalian cells may help to integrate and deepen our understanding of diverse biological phenomenon and to approach human diseases with new insights.
Topics: Humans; Chondroitin Sulfates; Dermatan Sulfate; Mucopolysaccharidosis VI; N-Acetylgalactosamine-4-Sulfatase; Sulfates
PubMed: 36361933
DOI: 10.3390/ijms232113146 -
Genes Oct 2022Musculocontractural Ehlers-Danlos syndrome (mcEDS) is a subtype of EDS caused by defective dermatan sulfate biosynthesis, characterized by multiple malformations...
Musculocontractural Ehlers-Danlos syndrome (mcEDS) is a subtype of EDS caused by defective dermatan sulfate biosynthesis, characterized by multiple malformations (craniofacial features, ocular and visceral malformations) and progressive cutaneous, skeletal, vascular, and visceral fragility-related manifestations. Repeated dislocations and deformities of the joints due to joint relaxation are observed, causing serious damage to the musculoskeletal system of the whole body; however, the motor function of the upper limbs and the morphology of the bone joints have not been systematically investigated. In this study, we present a detailed and comprehensive report on upper limb lesions of 13 patients with a mean age at the first visit of 21 years. Twelve patients (92.3%) had a history of dislocation. Eleven patients (84.6%) had shoulder dislocations, and two patients (15.4%) had elbow dislocations. Four patients (30.8%) had elbow osteoarthritis, and three patients (23.1%) had distal radioulnar joint (DRUJ) osteoarthritis. The phalanges and metacarpals are thin, and the ratio of medullary cavity of the metacarpal bone decreases with age. As bone and joint deformity progresses, patients with mcEDS should be recommended to receive regular follow-up, including radiology. The present findings suggest an important role for dermatan sulfate in the maintenance of the skeletal system.
Topics: Humans; Young Adult; Adult; Ehlers-Danlos Syndrome; Dermatan Sulfate; Sulfotransferases; Upper Extremity; Osteoarthritis
PubMed: 36360214
DOI: 10.3390/genes13111978 -
Marine Drugs Oct 2022Acute and chronic dermatological injuries need rapid tissue repair due to the susceptibility to infections. To effectively promote cutaneous wound recovery, it is...
Acute and chronic dermatological injuries need rapid tissue repair due to the susceptibility to infections. To effectively promote cutaneous wound recovery, it is essential to develop safe, low-cost, and affordable regenerative tools. Therefore, we aimed to identify the biological mechanisms involved in the wound healing properties of the glycosaminoglycan dermatan sulfate (DS), obtained from ascidian , a marine invertebrate, which in preliminary work from our group showed no toxicity and promoted a remarkable fibroblast proliferation and migration. In this study, 2,4-DS (50 µg/mL)-treated and control groups had the relative gene expression of 84 genes participating in the healing pathway evaluated. The results showed that 57% of the genes were overexpressed during treatment, 16% were underexpressed, and 9.52% were not detected. In silico analysis of metabolic interactions exhibited overexpression of genes related to: extracellular matrix organization, hemostasis, secretion of inflammatory mediators, and regulation of insulin-like growth factor transport and uptake. Furthermore, in C57BL/6 mice subjected to experimental wounds treated with 0.25% 2,4-DS, the histological parameters demonstrated a great capacity for vascular recovery. Additionally, this study confirmed that DS is a potent inducer of wound-healing cellular pathways and a promoter of neovascularization, being a natural ally in the tissue regeneration strategy.
Topics: Animals; Mice; Dermatan Sulfate; Mice, Inbred C57BL; Urochordata; Wound Healing; Natural Resources
PubMed: 36354999
DOI: 10.3390/md20110676