Compendium of the most significant studies with reference to properties, intake, effects.

Morla S. Glycosaminoglycans and Glycosaminoglycan Mimetics in Cancer and Inflammation. Int J Mol Sci. 2019 Apr 22;20(8):1963. doi: 10.3390/ijms20081963.

Abstract. Glycosaminoglycans (GAGs) are a class of biomolecules expressed virtually on all mammalian cells and usually covalently attached to proteins, forming proteoglycans. They are present not only on the cell surface, but also in the intracellular milieu and extracellular matrix. GAGs interact with multiple ligands, both soluble and insoluble, and modulate an important role in various physiological and pathological processes including cancer, bacterial and viral infections, inflammation, Alzheimer's disease, and many more. Considering their involvement in multiple diseases, their use in the development of drugs has been of significant interest in both academia and industry. Many GAG-based drugs are being developed with encouraging results in animal models and clinical trials, showcasing their potential for development as therapeutics. In this review, the role GAGs play in both the development and inhibition of cancer and inflammation is presented. Further, advancements in the development of GAGs and their mimetics as anti-cancer and anti-inflammatory agents are discussed.

Griffin KL, Fischer BM, Kummarapurugu AB, Zheng S, Kennedy TP, Rao NV, Foster WM, Voynow JA. 2-O, 3-O-desulfated heparin inhibits neutrophil elastase-induced HMGB-1 secretion and airway inflammation. Am J Respir Cell Mol Biol. 2014 Apr;50(4):684-9. doi: 10.1165/rcmb.2013-0338RC. 

Abstract. Neutrophil elastase (NE) is a major inflammatory mediator in cystic fibrosis (CF) that is a robust predictor of lung disease progression. NE directly causes airway injury via protease activity, and propagates persistent neutrophilic inflammation by up-regulation of neutrophil chemokine expression. Despite its key role in the pathogenesis of CF lung disease, there are currently no effective antiprotease therapies available to patients with CF. Although heparin is an effective antiprotease and anti-inflammatory agent, its anticoagulant activity prohibits its use in CF, due to risk of pulmonary hemorrhage. In this report, we demonstrate the efficacy of a 2-O, 3-O-desulfated heparin (ODSH), a modified heparin with minimal anticoagulant activity, to inhibit NE activity and to block NE-induced airway inflammation. Using an established murine model of intratracheal NE-induced airway inflammation, we tested the efficacy of intratracheal ODSH to block NE-generated neutrophil chemoattractants and NE-triggered airway neutrophilic inflammation. ODSH inhibited NE-induced keratinocyte-derived chemoattractant and high-mobility group box 1 release in bronchoalveolar lavage. ODSH also blocked NE-stimulated high-mobility group box 1 release from murine macrophages in vitro, and inhibited NE activity in functional assays consistent with prior reports of antiprotease activity. In summary, this report suggests that ODSH is a promising antiprotease and anti-inflammatory agent that may be useful as an airway therapy in CF.

Borsig L, Wang L, Cavalcante MC, Cardilo-Reis L, Ferreira PL, Mourão PA, Esko JD, Pavão MS. Selectin blocking activity of a fucosylated chondroitin sulfate glycosaminoglycan from sea cucumber. Effect on tumor metastasis and neutrophil recruitment. J Biol Chem. 2007 May 18;282(20):14984-91. doi: 10.1074/jbc.M610560200. 

Abstract. Heparin is an excellent inhibitor of P- and L-selectin binding to the carbohydrate determinant, sialyl Lewis(x). As a consequence of its anti-selectin activity, heparin attenuates metastasis and inflammation. Here we show that fucosylated chondroitin sulfate (FucCS), a polysaccharide isolated from sea cucumber composed of a chondroitin sulfate backbone substituted at the 3-position of the beta-D-glucuronic acid residues with 2,4-disulfated alpha-L-fucopyranosyl branches, is a potent inhibitor of P- and L-selectin binding to immobilized sialyl Lewis(x) and LS180 carcinoma cell attachment to immobilized P- and L-selectins. Inhibition occurs in a concentration-dependent manner. Furthermore, FucCS was 4-8-fold more potent than heparin in the inhibition of the P- and L-selectin-sialyl Lewis(x) interactions. No inhibition of E-selectin was observed. FucCS also inhibited lung colonization by adenocarcinoma MC-38 cells in an experimental metastasis model in mice, as well as neutrophil recruitment in two models of inflammation (thioglycollate-induced peritonitis and lipopolysaccharide-induced lung inflammation). Inhibition occurred at a dose that produces no significant change in plasma activated partial thromboplastin time. Removal of the sulfated fucose branches on the FucCS abolished the inhibitory effect in vitro and in vivo. Overall, the results suggest that invertebrate FucCS may be a potential alternative to heparin for blocking metastasis and inflammatory reactions without the undesirable side effects of anticoagulant heparin.

Siddiqui N, Oshima K, Hippensteel JA. Proteoglycans and glycosaminoglycans in central nervous system injury. Am J Physiol Cell Physiol. 2022 Jul 1;323(1):C46-C55. doi: 10.1152/ajpcell.00053.2022.

Abstract. The brain and spinal cord constitute the central nervous system (CNS), which when injured, can be exceedingly devastating. The mechanistic roles of proteoglycans (PGs) and their glycosaminoglycan (GAG) side chains in such injuries have been extensively studied. CNS injury immediately alters endothelial and extracellular matrix (ECM) PGs and GAGs. Subsequently, these alterations contribute to acute injury, postinjury fibrosis, and postinjury repair. These effects are central to the pathophysiology of CNS injury. This review focuses on the importance of PGs and GAGs in multiple forms of injury including traumatic brain injury, spinal cord injury, and stroke. We highlight the causes and consequences of degradation of the PG and GAG-enriched endothelial glycocalyx in early injury and discuss the pleiotropic roles of PGs in neuroinflammation. We subsequently evaluate the dualistic effects of PGs on recovery: both PG/GAG-mediated inhibition and facilitation of repair. We then report promising therapeutic strategies that may prove effective for repair of CNS injury including PG receptor inhibition, delivery of endogenous, pro-repair PGs and GAGs, and direct degradation of pathological GAGs. Finally, we discuss the importance of two PG- and GAG-containing ECM structures (synapses and perineuronal nets) in CNS injury and recovery.

Afratis N, Gialeli C, Nikitovic D, Tsegenidis T, Karousou E, Theocharis AD, Pavão MS, Tzanakakis GN, Karamanos NK. Glycosaminoglycans: key players in cancer cell biology and treatment. FEBS J. 2012 Apr;279(7):1177-97. doi: 10.1111/j.1742-4658.2012.08529.x.

Abstract. 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.

Sobczak AIS, Pitt SJ, Stewart AJ. Glycosaminoglycan Neutralization in Coagulation Control. Arterioscler Thromb Vasc Biol. 2018 Jun;38(6):1258-1270. doi: 10.1161/ATVBAHA.118.311102.

Abstract. 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. © 2018 The Authors.

Ryan CN, Sorushanova A, Lomas AJ, Mullen AM, Pandit A, Zeugolis DI. Glycosaminoglycans in Tendon Physiology, Pathophysiology, and Therapy. Bioconjug Chem. 2015 Jul 15;26(7):1237-51. doi: 10.1021/acs.bioconjchem.5b00091.

Abstract. Although glycosaminoglycans constitute a minor portion of native tissues, they play a crucial role in various physiological processes, while their abnormal expression is associated with numerous pathophysiologies. Glycosaminoglycans have become increasingly prevalent in biomaterial design for tendon repair, given their low immunogenicity and their inherent capacity to stimulate the regenerative processes, while maintaining resident cell phenotype and function. Further, their incorporation into three-dimensional scaffold conformations significantly improves their mechanical properties, while reducing the formation of peritendinous adhesions. Herein, we discuss the role of glycosaminoglycans in tendon physiology and pathophysiology and the advancements achieved to date using glycosaminoglycan-functionalized scaffolds for tendon repair and regeneration. It is evidenced that glycosaminoglycan functionalization has led to many improvements in tendon tissue engineering and it is anticipated to play a pivotal role in future reparative therapies.

Vynios DH, Karamanos NK, Tsiganos CP. Advances in analysis of glycosaminoglycans: its application for the assessment of physiological and pathological states of connective tissues. J Chromatogr B Analyt Technol Biomed Life Sci. 2002 Dec 5;781(1-2):21-38. doi: 10.1016/s1570-0232(02)00498-1.

Abstract. Glycosaminoglycans are a class of biological macromolecules found mainly in connective tissues as constituents of proteoglycans, covalently linked to their core protein. Hyaluronan is the only glycosaminoglycan present under its single form and possesses the ability to aggregate with the class of proteoglycans termed hyalectans. Proteoglycans are localised both at the extracellular and cellular (cell-surface and intracellular) levels and, via either their glycosaminoglycan chains or their core proteins participate in and regulate several cellular events and (patho)physiological processes. Advances in analytical separational techniques, including high-performance liquid chromatography, capillary electrophoresis and fluorophore assisted carbohydrate electrophoresis, make possible to examine alterations of glycosaminoglycans with respect to their amounts and fine structural features in various pathological conditions, thus becoming applicable for diagnosis. In this review we present the chromatographic and electromigration procedures developed to analyse and characterise glycosaminoglycans. Moreover, a critical evaluation of the biological relevance of the results obtained by the developed methodology is discussed.

Sugahara K, Kitagawa H. Recent advances in the study of the biosynthesis and functions of sulfated glycosaminoglycans. Curr Opin Struct Biol. 2000 Oct;10(5):518-27. doi: 10.1016/s0959-440x(00)00125-1. 

Abstract. Recent cDNA cloning of the glycosyltransferases involved in the synthesis of the sulfated glycosaminoglycan sidechains of proteoglycans has provided important clues to answering long-standing questions concerning the mechanisms of both chain polymerization and the biosynthetic sorting of glucosaminoglycans (heparin/heparan sulfate) and galactosaminoglycans (chondroitin/dermatan sulfate). These biosynthetic mechanisms are crucial to the expression and regulation of the biological functions of glycosaminoglycans in development and pathophysiology.

Ghiselli G, Maccarana M. Drugs affecting glycosaminoglycan metabolism. Drug Discov Today. 2016 Jul;21(7):1162-9. doi: 10.1016/j.drudis.2016.05.010. 

Abstract. ... In this review, we provide a classification of small molecules affecting Glycosaminoglycans GAG metabolism based on their mechanism of action. Furthermore, we present evidence to show that clinically approved drugs affect GAG metabolism and that this could contribute to their therapeutic benefit. Copyright © 2016 Elsevier Ltd.