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      Galactosaminoglycans: Medical Applications and Drawbacks

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          Abstract

          Galactosaminoglycans (GalAGs) are sulfated glycans composed of alternating N-acetylgalactosamine and uronic acid units. Uronic acid epimerization, sulfation patterns and fucosylation are modifications observed on these molecules. GalAGs have been extensively studied and exploited because of their multiple biomedical functions. Chondroitin sulfates (CSs), the main representative family of GalAGs, have been used in alternative therapy of joint pain/inflammation and osteoarthritis. The relatively novel fucosylated chondroitin sulfate (FCS), commonly found in sea cucumbers, has been screened in multiple systems in addition to its widely studied anticoagulant action. Biomedical properties of GalAGs are directly dependent on the sugar composition, presence or lack of fucose branches, as well as sulfation patterns. Although research interest in GalAGs has increased considerably over the three last decades, perhaps motivated by the parallel progress of glycomics, serious questions concerning the effectiveness and potential side effects of GalAGs have recently been raised. Doubts have centered particularly on the beneficial functions of CS-based therapeutic supplements and the potential harmful effects of FCS as similarly observed for oversulfated chondroitin sulfate, as a contaminant of heparin. Unexpected components were also detected in CS-based pharmaceutical preparations. This review therefore aims to offer a discussion on (1) the current and potential therapeutic applications of GalAGs, including those of unique features extracted from marine sources, and (2) the potential drawbacks of this class of molecules when applied to medicine.

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          Autoimmune heparin-induced thrombocytopenia.

          Autoimmune heparin-induced thrombocytopenia (aHIT) indicates the presence in patients of anti-platelet factor 4 (PF4)-polyanion antibodies that are able to activate platelets strongly even in the absence of heparin (heparin-independent platelet activation). Nevertheless, as seen with serum obtained from patients with otherwise typical heparin-induced thrombocytopenia (HIT), serum-induced platelet activation is inhibited at high heparin concentrations (10-100 IU mL-1heparin). Furthermore, upon serial dilution, aHIT serum will usually show heparin-dependent platelet activation. Clinical syndromes associated with aHIT include: delayed-onset HIT, persisting HIT, spontaneous HIT syndrome, fondaparinux-associated HIT, heparin 'flush'-induced HIT, and severe HIT (platelet count of < 20 × 109 L-1) with associated disseminated intravascular coagulation (DIC). Recent studies have implicated anti-PF4 antibodies that are able to bridge two PF4 tetramers even in the absence of heparin, probably facilitated by non-heparin platelet-associated polyanions (chondroitin sulfate and polyphosphates); nascent PF4-aHIT-IgG complexes recruit additional heparin-dependent HIT antibodies, leading to the formation of large multimolecular immune complexes and marked platelet activation. aHIT can persist for several weeks, and serial fibrin, D-dimer, and fibrinogen levels, rather than the platelet count, may be helpful for monitoring treatment response. Although standard anticoagulant therapy for HIT ought to be effective, published experience indicates frequent failure of activated partial thromboplastin time (APTT)-adjusted anticoagulants (argatroban, bivalirudin), probably because of underdosing in the setting of HIT-associated DIC, known as 'APTT confounding'. Thus, non-APTT-adjusted therapies with drugs such as danaparoid and fondaparinux, or even direct oral anticoagulants, such as rivaroxaban or apixaban, are suggested therapies, especially for long-term management of persisting HIT. In addition, emerging data indicate that high-dose intravenous immunoglobulin can interrupt HIT antibody-induced platelet activation, leading to rapid platelet count recovery.
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            Glycosaminoglycans: key players in cancer cell biology and treatment.

            Glycosaminoglycans are natural heteropolysaccharides that are present in every mammalian tissue. They are composed of repeating disaccharide units that consist of either sulfated or non-sulfated monosaccharides. Their molecular size and the sulfation type vary depending on the tissue, and their state either as part of proteoglycan or as free chains. In this regard, glycosaminoglycans play important roles in physiological and pathological conditions. During recent years, cell biology studies have revealed that glycosaminoglycans are among the key macromolecules that affect cell properties and functions, acting directly on cell receptors or via interactions with growth factors. The accumulated knowledge regarding the altered structure of glycosaminoglycans in several diseases indicates their importance as biomarkers for disease diagnosis and progression, as well as pharmacological targets. This review summarizes how the fine structural characteristics of glycosaminoglycans, and enzymes involved in their biosynthesis and degradation, are involved in cell signaling, cell function and cancer progression. Prospects for glycosaminoglycan-based therapeutic targeting in cancer are also discussed. © 2012 The Authors Journal compilation © 2012 FEBS.
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              Glycomics hits the big time.

              Cells run on carbohydrates. Glycans, sequences of carbohydrates conjugated to proteins and lipids, are arguably the most abundant and structurally diverse class of molecules in nature. Recent advances in glycomics reveal the scope and scale of their functional roles and their impact on human disease. Copyright © 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                01 August 2019
                August 2019
                : 24
                : 15
                : 2803
                Affiliations
                [1 ]Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677-1848, USA
                [2 ]Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677-1848, USA
                [3 ]Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-590, Brazil
                [4 ]Imperial College, Department of Medicine, Burlington Danes Building, Du Cane Road, London W12 0NN, UK
                Author notes
                [* ]Correspondence: vpomin@ 123456olemiss.edu
                Author information
                https://orcid.org/0000-0002-5015-8880
                Article
                molecules-24-02803
                10.3390/molecules24152803
                6696379
                31374852
                bedbfe16-e805-413d-862b-084e802d6b03
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 19 June 2019
                : 30 July 2019
                Categories
                Review

                carbohydrate-based drug discovery,chondroitin sulfate,dermatan sulfate,fucosylated chondroitin sulfate,galactosaminoglycans

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