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Chest Feb 2012This article describes the pharmacology of approved parenteral anticoagulants. These include the indirect anticoagulants, unfractionated heparin (UFH),... (Comparative Study)
Comparative Study Review
This article describes the pharmacology of approved parenteral anticoagulants. These include the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid, as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin, factor Xa, and other clotting enzymes. Heparin also binds to cells and plasma proteins other than antithrombin causing unpredictable pharmacokinetic and pharmacodynamic properties and triggering nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis. LMWHs have greater inhibitory activity against factor Xa than thrombin and exhibit less binding to cells and plasma proteins than heparin. Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and are associated with a lower risk of nonhemorrhagic side effects. LMWHs can be administered once daily or bid by subcutaneous injection, without coagulation monitoring. Based on their greater convenience, LMWHs have replaced UFH for many clinical indications. Fondaparinux, a synthetic pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to antithrombin. Therefore, fondaparinux-associated HIT or osteoporosis is unlikely to occur. Fondaparinux exhibits complete bioavailability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fixed doses, without coagulation monitoring. Three additional parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to heparin in patients with HIT.
Topics: Antithrombins; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Dose-Response Relationship, Drug; Evidence-Based Medicine; Fibrinolytic Agents; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudins; Humans; Infusions, Intravenous; Peptide Fragments; Pipecolic Acids; Polysaccharides; Practice Guidelines as Topic; Recombinant Proteins; Societies, Medical; Sulfonamides; Thrombin; Thrombosis; United States
PubMed: 22315264
DOI: 10.1378/chest.11-2291 -
Glycoconjugate Journal Jun 2017Mast cells contain granules packed with a mixture of proteins that are released on degranulation. The proteoglycan serglycin carries an array of glycosaminoglycan (GAG)... (Review)
Review
Mast cells contain granules packed with a mixture of proteins that are released on degranulation. The proteoglycan serglycin carries an array of glycosaminoglycan (GAG) side chains, sometimes heparin, sometimes chondroitin or dermatan sulphate. Tight packing of granule proteins is dependent on the presence of serglycin carrying these GAGs. The GAGs of mast cells were most intensively studied in the 1970s and 1980s, and though something is known about the fine structure of chondroitin sulphate and dermatan sulphate in mast cells, little is understood about the composition of the heparin/heparan sulphate chains. Recent emphasis on the analysis of mast cell heparin from different species and tissues, arising from the use of this GAG in medicine, lead to the question of whether variations within heparin structures between mast cell populations are as significant as variations in the mix of chondroitins and heparins.
Topics: Animals; Carbohydrate Conformation; Carbohydrate Sequence; Cell Degranulation; Cells, Cultured; Chondroitin Sulfates; Cytoplasmic Granules; Dermatan Sulfate; Heparin; Humans; Mast Cells; Peptide Hydrolases; Protein Binding; Proteoglycans; Structure-Activity Relationship; Vesicular Transport Proteins
PubMed: 27900574
DOI: 10.1007/s10719-016-9749-0 -
Macromolecular Bioscience Mar 2022Cartilage is a connective tissue which a limited capacity for healing and repairing. In this context, osteoarthritis (OA) disease may be developed with high prevalence...
Cartilage is a connective tissue which a limited capacity for healing and repairing. In this context, osteoarthritis (OA) disease may be developed with high prevalence in which the use of scaffolds may be a promising treatment. In addition, three-dimensional (3D) bioprinting has become an emerging additive manufacturing technology because of its rapid prototyping capacity and the possibility of creating complex structures. This study is focused on the development of nanocellulose-alginate (NC-Alg) based bioinks for 3D bioprinting for cartilage regeneration to which it is added chondroitin sulfate (CS) and dermatan sulfate (DS). First, rheological properties are evaluated. Then, sterilization effect, biocompatibility, and printability on developed NC-Alg-CS and NC-Alg-DS inks are evaluated. Subsequently, printed scaffolds are characterized. Finally, NC-Alg-CS and NC-Alg-DS inks are loaded with murine D1-MSCs-EPO and cell viability and functionality, as well as the chondrogenic differentiation ability are assessed. Results show that the addition of both CS and DS to the NC-Alg ink improves its characteristics in terms of rheology and cell viability and functionality. Moreover, differentiation to cartilage is promoted on NC-Alg-CS and NC-Alg-DS scaffolds. Therefore, the utilization of MSCs containing NC-Alg-CS and NC-Alg-DS scaffolds may become a feasible tissue engineering approach for cartilage regeneration.
Topics: Alginates; Animals; Bioprinting; Cartilage; Chondroitin; Dermatan Sulfate; Mice; Printing, Three-Dimensional; Regeneration; Tissue Engineering; Tissue Scaffolds
PubMed: 35029035
DOI: 10.1002/mabi.202100435 -
Genes Feb 2023Musculocontractural Ehlers-Danlos syndrome (mcEDS) is a subtype of EDS caused by mutations in the gene for carbohydrate sulfotransferase 14 () (mcEDS-) or dermatan... (Review)
Review
Musculocontractural Ehlers-Danlos syndrome (mcEDS) is a subtype of EDS caused by mutations in the gene for carbohydrate sulfotransferase 14 () (mcEDS-) or dermatan sulfate epimerase () (mcEDS-). These mutations induce loss of enzymatic activity in D4ST1 or DSE and disrupt dermatan sulfate (DS) biosynthesis. The depletion of DS causes the symptoms of mcEDS, such as multiple congenital malformations (e.g., adducted thumbs, clubfeet, and craniofacial characteristics) and progressive connective tissue fragility-related manifestations (e.g., recurrent dislocations, progressive talipes or spinal deformities, pneumothorax or pneumohemothorax, large subcutaneous hematomas, and/or diverticular perforation). Careful observations of patients and model animals are important to investigate pathophysiological mechanisms and therapies for the disorder. Some independent groups have investigated gene-deleted () and mice as models of mcEDS- and mcEDS-, respectively. These mouse models exhibit similar phenotypes to patients with mcEDS, such as suppressed growth and skin fragility with deformation of the collagen fibrils. Mouse models of mcEDS- also show thoracic kyphosis, hypotonia, and myopathy, which are typical complications of mcEDS. These findings suggest that the mouse models can be useful for research uncovering the pathophysiology of mcEDS and developing etiology-based therapy. In this review, we organize and compare the data of patients and model mice.
Topics: Animals; Mice; Dermatan Sulfate; Sulfotransferases; Ehlers-Danlos Syndrome; Skin; Extracellular Matrix
PubMed: 36833362
DOI: 10.3390/genes14020436 -
Arteriosclerosis, Thrombosis, and... Jun 2018The glycosaminoglycans (GAGs) heparan sulfate, dermatan sulfate, and heparin are important anticoagulants that inhibit clot formation through interactions with... (Review)
Review
The glycosaminoglycans (GAGs) heparan sulfate, dermatan sulfate, and heparin are important anticoagulants that inhibit clot formation through interactions with antithrombin and heparin cofactor II. Unfractionated heparin, low-molecular-weight heparin, and heparin-derived drugs are often the main treatments used clinically to handle coagulatory disorders. A wide range of proteins have been reported to bind and neutralize these GAGs to promote clot formation. Such neutralizing proteins are involved in a variety of other physiological processes, including inflammation, transport, and signaling. It is clear that these interactions are important for the control of normal coagulation and influence the efficacy of heparin and heparin-based therapeutics. In addition to neutralization, the anticoagulant activities of GAGs may also be regulated through reduced synthesis or by degradation. In this review, we describe GAG neutralization, the proteins involved, and the molecular processes that contribute to the regulation of anticoagulant GAG activity.
Topics: Animals; Anticoagulants; Binding Sites; Blood Coagulation; Dermatan Sulfate; Glycosaminoglycans; Heparin; Heparin Antagonists; Heparitin Sulfate; Humans; Protein Binding
PubMed: 29674476
DOI: 10.1161/ATVBAHA.118.311102 -
Genes Feb 2023Dermatan sulfate (DS) and its proteoglycans are essential for the assembly of the extracellular matrix and cell signaling. Various transporters and biosynthetic enzymes... (Review)
Review
Dermatan sulfate (DS) and its proteoglycans are essential for the assembly of the extracellular matrix and cell signaling. Various transporters and biosynthetic enzymes for nucleotide sugars, glycosyltransferases, epimerase, and sulfotransferases, are involved in the biosynthesis of DS. Among these enzymes, dermatan sulfate epimerase (DSE) and dermatan 4--sulfotranserase (D4ST) are rate-limiting factors of DS biosynthesis. Pathogenic variants in human genes encoding DSE and D4ST cause the musculocontractural type of Ehlers-Danlos syndrome, characterized by tissue fragility, joint hypermobility, and skin hyperextensibility. DS-deficient mice exhibit perinatal lethality, myopathy-related phenotypes, thoracic kyphosis, vascular abnormalities, and skin fragility. These findings indicate that DS is essential for tissue development as well as homeostasis. This review focuses on the histories of DSE as well as D4ST, and their knockout mice as well as human congenital disorders.
Topics: Pregnancy; Female; Humans; Animals; Mice; Dermatan Sulfate; Ehlers-Danlos Syndrome; Phenotype; Sulfotransferases; Racemases and Epimerases
PubMed: 36833436
DOI: 10.3390/genes14020509 -
Marine Drugs Dec 2023Glycosaminoglycans (GAGs) with unique structures from marine animals show intriguing pharmacological activities and negligible biological risks, providing more options...
Glycosaminoglycans (GAGs) with unique structures from marine animals show intriguing pharmacological activities and negligible biological risks, providing more options for us to explore safer agents. The swim bladder is a tonic food and folk medicine, and its GAGs show good anticoagulant activity. In this study, two GAGs, CMG-1.0 and GMG-1.0, were extracted and isolated from the swim bladder of and . The physicochemical properties, precise structural characteristics, and anticoagulant activities of these GAGs were determined for the first time. The analysis results of the CMG-1.0 and GMG-1.0 showed that they were chondroitin sulfate (CS)/dermatan sulfate (DS) hybrid chains with molecular weights of 109.3 kDa and 123.1 kDa, respectively. They were mainly composed of the repeating disaccharide unit of -{IdoA-α1,3-GalNAc-β1,4-}- (DS-A). The DS-B disaccharide unit of -{IdoA-α1,3-GalNAc-β1,4-}- also existed in both CMG-1.0 and GMG-1.0. CMG-1.0 had a higher proportion of CS-O disaccharide unit -{-GlcA-β1,3-GalNAc-β1,4-}- but a lower proportion of CS-E disaccharide unit -{-GlcA-β1,3-GalNAc-β1,4-}- than GMG-1.0. The disaccharide compositions of the GAGs varied in a species-specific manner. Anticoagulant activity assay revealed that both CMG-1.0 and GMG-1.0 had potent anticoagulant activity, which can significantly prolong activated partial thromboplastin time. GMG-1.0 also can prolong the thrombin time. CMG-1.0 showed no intrinsic tenase inhibition activity, while GMG-1.0 can obviously inhibit intrinsic tenase with EC of 58 nM. Their significantly different anticoagulant activities may be due to their different disaccharide structural units and proportions. These findings suggested that swim bladder by-products of fish processing of these two marine organisms may be used as a source of anticoagulants.
Topics: Animals; Chondroitin Sulfates; Dermatan Sulfate; Urinary Bladder; Glycosaminoglycans; Anticoagulants; Disaccharides
PubMed: 38276647
DOI: 10.3390/md22010009 -
The Journal of Histochemistry and... Dec 2012The ability of chondroitin/dermatan sulfate (CS/DS) to convey biological information is enriched by the presence of iduronic acid. DS-epimerases 1 and 2 (DS-epi1 and 2),... (Review)
Review
The ability of chondroitin/dermatan sulfate (CS/DS) to convey biological information is enriched by the presence of iduronic acid. DS-epimerases 1 and 2 (DS-epi1 and 2), in conjunction with DS-4-O-sulfotransferase 1, are the enzymes responsible for iduronic acid biosynthesis and will be the major focus of this review. CS/DS proteoglycans (CS/DS-PGs) are ubiquitously found in connective tissues, basement membranes, and cell surfaces or are stored intracellularly. Such wide distribution reflects the variety of biological roles in which they are involved, from extracellular matrix organization to regulation of processes such as proliferation, migration, adhesion, and differentiation. They play roles in inflammation, angiogenesis, coagulation, immunity, and wound healing. Such versatility is achieved thanks to their variable composition, both in terms of protein core and the fine structure of the CS/DS chains. Excellent reviews have been published on the collective and individual functions of each CS/DS-PG. This short review presents the biosynthesis and functions of iduronic acid-containing structures, also as revealed by the analysis of the DS-epi1- and 2-deficient mouse models.
Topics: Animals; Biocatalysis; Bipolar Disorder; Carbohydrate Epimerases; Dermatan Sulfate; Ehlers-Danlos Syndrome; Humans; Iduronic Acid; Mice; Mice, Knockout; Molecular Structure; Neoplasms; Sulfotransferases
PubMed: 22899863
DOI: 10.1369/0022155412459857 -
International Journal of Molecular... Mar 2022Pleiotrophin (PTN) is a neurotrophic factor that participates in the development of the embryonic central nervous system (CNS) and neural stem cell regulation by means...
Pleiotrophin (PTN) is a neurotrophic factor that participates in the development of the embryonic central nervous system (CNS) and neural stem cell regulation by means of an interaction with sulfated glycosaminoglycans (GAGs). Chondroitin sulfate (CS) is the natural ligand in the CNS. We have previously studied the complexes between the tetrasaccharides used here and MK (Midkine) by ligand-observed NMR techniques. The present work describes the interactions between a tetrasaccharide library of synthetic models of CS-types and mimetics thereof with PTN using the same NMR transient techniques. We have concluded that: (1) global ligand structures do not change upon binding, (2) the introduction of lipophilic substituents in the structure of the ligand improves the strength of binding, (3) binding is weaker than for MK, (4) STD-NMR results are compatible with multiple binding modes, and (5) the replacement of GlcA for IdoA is not relevant for binding. Then we can conclude that the binding of CS derivatives to PTN and MK are similar and compatible with multiple binding modes of the same basic conformation.
Topics: Carrier Proteins; Chondroitin Sulfates; Cytokines; Dermatan Sulfate; Ligands; Oligosaccharides
PubMed: 35328448
DOI: 10.3390/ijms23063026 -
The Journal of Biological Chemistry Aug 2018During the biosynthesis of chondroitin/dermatan sulfate (CS/DS), a variable fraction of glucuronic acid is converted to iduronic acid through the activities of two...
During the biosynthesis of chondroitin/dermatan sulfate (CS/DS), a variable fraction of glucuronic acid is converted to iduronic acid through the activities of two epimerases, dermatan sulfate epimerases 1 (DS-epi1) and 2 (DS-epi2). Previous studies indicated that without association with other enzymes, DS-epi1 activity produces structures that have only a few adjacent iduronic acid units. , concomitant with epimerization, dermatan 4--sulfotransferase 1 (D4ST1) sulfates the GalNAc adjacent to iduronic acid. This sulfation facilitates DS-epi1 activity and enables the formation of long blocks of sulfated iduronic acid-containing domains, which can be major components of CS/DS. In this report, we used recombinant enzymes to confirm the concerted action of DS-epi1 and D4ST1. Confocal microscopy revealed that these two enzymes colocalize to the Golgi, and FRET experiments indicated that they physically interact. Furthermore, FRET, immunoprecipitation, and cross-linking experiments also revealed that DS-epi1, DS-epi2, and D4ST1 form homomers and are all part of a hetero-oligomeric complex where D4ST1 directly interacts with DS-epi1, but not with DS-epi2. The cooperation of DS-epi1 with D4ST1 may therefore explain the processive mode of the formation of iduronic acid blocks. In conclusion, the iduronic acid-forming enzymes operate in complexes, similar to other enzymes active in glycosaminoglycan biosynthesis. This knowledge shed light on regulatory mechanisms controlling the biosynthesis of the structurally diverse CS/DS molecule.
Topics: Animals; Antigens, Neoplasm; COS Cells; Chlorocebus aethiops; DNA-Binding Proteins; Dermatan Sulfate; Humans; Iduronic Acid; Neoplasm Proteins; Recombinant Proteins; Sulfotransferases
PubMed: 29976758
DOI: 10.1074/jbc.RA118.003875