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Rafael S. Glycosaminoglycans GAGs are complex carbohydrates that are expressed ubiquitously and abundantly on the cell surface and in the extracellular matrix ECM. The extraordinary structural diversity of GAGs enables them to interact with a wide variety of biological molecules. Through these interactions, GAGs modulate various biological processes, such as cell adhesion, proliferation and migration, ECM assembly, tissue repair, coagulation, and immune responses, among many others.
Studies during the last several decades have indicated that GAGs also interact with microbial pathogens. GAG—pathogen interactions affect most, if not all, the key steps of microbial pathogenesis, including host cell attachment and invasion, cell—cell transmission, systemic dissemination and infection of secondary organs, and evasion of host defense mechanisms. These observations indicate that GAG—pathogen interactions serve diverse functions that affect the pathogenesis of infectious diseases.
GAGs play numerous functions in the ECM to regulate mechanical properties of a tissue: cell proliferation, cell adhesion, growth factor aling, immune cell function, and collagen structure. The structural and functional diversity of GAGs is regulated by the sugar composition of the GAG, size of the GAG chains, degree of sulfation, and the ability to bind collagen and other proteins.
In the cervix, GAG composition and abundance change dramatically during pregnancy and parturition. Although total sulfated GAG levels are constant, it remains to be determined if there are regulated changes in sulfated GAGs bound to specific proteoglycans that may influence proteoglycan function.
Transcripts encoding the core protein of proteoglycans such as versican, decorin, biglycan, and fibromodulin are abundant and constant in the human and murine cervix through pregnancy and parturition. Table 1. Preterm birth induced on gestation day Untreated day 15 cervix averages: wet weight The day of cervical plug is deated as gestation day 0.
GAGs are a diverse class of linear polysaccharides consisting of repeating disaccharide units that contain at least one deoxyamino sugar. GAGs represent a large of polymers with ificant chemical and structural differences that arise from the patterns of disaccharide building blocks e.
They can regulate many biological processes through their interactions with numerous effector proteins. The diversity of GAG structures and their biological roles are too numerous to detail in this chapter; 1 however, the structure and functions of a series of representative GAGs are illustrated in Table 5. Table 5. Structure of representative GAGs and their function Kirsten G. Malmos, Daniel E. Otzen, in Bio-nanoimaging Glycosaminoglycans GAGs different types of gags been known since the s to co-localize with amyloid deposits, yet many questions remain unanswered with regard to their interactions with amyloid.
This chapter focuses on the molecular and biophysical aspects of these interactions. The interactions between GAGs and protein are believed to be mainly electrostatic in nature, involving GAG sulfate moieties which are proposed to bind the basic amino acids in a stoichiometric fashion, leaving the mature complex electrically neutral.
It remains unclear whether GAGs protect the cell from toxic oligomers formed prior to the mature fibrils or rather increase the formation of aggregated species, leading to increased toxicity. Besides accelerating fibrillation in amyloidogenic proteins, GAGs have also been found to induce amyloid formation in non-amyloidogenic proteins as a possible storage-and-release switch. Thus, GAG-amyloid interactions may be both beneficial and pathologic. Clearly, there is scope for more research to address these intriguing molecular aspects. Caliari, B. Harley, in Comprehensive Biomaterials GAGs are long, different types of gags disaccharide units that are linked to protein cores to form proteoglycans Figure 2.
These properties are responsible for the high compressive modulus and excellent resistance to repeated deformation seen in GAG-rich tissues such as articular cartilage. Figure 2. Shaker A. Paul J. Glycosaminoglycans GAGs are carbohydrates that have desirable therapeutic effects on pathologic thrombosis, neovascularization, cancer, and inflammation. The most commonly used GAGs in clinical practice are heparin, chondroitin sulfate, and keratin sulfate, but these compounds have ificant disadvantages .
Non-GAG sulfated glycans now are also available. Examples of these are marine sulfated fucans SFs and sulfated galactans SGs. The SFs or SGs harvested from invertebrates and red algae are, compared to GAGs, homogeneous in terms of monosaccharide backbone constitution and patterns of sulfation.
Effects of the marine sulfated glycans that may be shown to be clinically advantageous are their development as anti-coagulant alternatives to heparin, particularly in those settings in which heparin is suboptimally effective or inactive. These sulfated glycans are a basis for defining the structure-activity relationships SARs of the family. Table 6. Biological effects of natural glycosaminoglycan from animals and marine sources. Inhibition activities on growth factors necessary for cell differentiation and neovascularization.
Inhibition activities on selectins necessary for cell migration, attachment, and adhesion. Inhibition of l-selectin during leukocyte recruitment and rolling. Inhibition of binding of free chemokines to infiltrated leukocytes in inflamed tissues. Completion with hydrolase activity during ECM processing necessary to enhance leukocyte transmigration. Marine sulfated glycans may be less active or inactive in this context.
Some natural glycosaminoglycans possess anti-coagulant activities and others are devoid of such activities. Marine non-glycosaminoglycan sulfated glycans as potential pharmaceuticals. Pharmaceuticals ;8 4 — Used under the terms and conditions of the Creative Commons Attribution .
GAGs are negatively charged polysaccharides of differing degrees of complexity that mediate many biological functions. GAGs are long, linear and highly negatively charged polysaccharides and consist of a backbone of repeating disaccharide units generally formed by a uronic acid and a glycosamine residue.
The many biological characteristics of GAGs also make them valuable molecules for incorporation into matrices. For instance, HS is able to bind and modulate bioactive components like growth factors, cytokines and proteases, which are essential for basic cellular phenomena like cell adhesion, growth differentiation and activation, and implicate a role for GAGs in wound healing, inflammation, tissue morphogenesis and homeostasis.
The incorporation of GAGs into a biomatrix promotes angiogenesis, tissue regeneration, reduces foreign body reactions and preserves matrix integrity in vivo e. Jing Pan, Therefore, a ificant increase in circulating GAGs in cancer patients might not be detectable by plasma glucosamine and galactosamine quantification. To test this idea, GAGs were isolated from plasmas of four normal controls and four lung cancer patients.
We found that the galactosamine level of plasma GAGs Fig. These data suggest that galactosamine and glucosamine quantifications either from plasma or from purified plasma GAGs are valid in developing lung cancer diagnosis biomarkers.
Plasma galactosamine and glucosamine quantification. An aliquot of GAGs purified from normal control or patient plasmas was hydrolyzed and derivatized. The fluorescent derivatives are separated by the reversed-phase HPLC and then quantified. Both GAGs and mucins have a tightly controlled circulation concentration due to the presence of multiple hepatic clearance receptors. It is unknown how the high level of GAGs is maintained in lung cancer plasmas or whether dermatan sulfate made by endothelial cells or GAGs made by the cancer cells contribute to the activated contact systems observed in our studies.
The relative contributions of mucins or proteoglycan GAGs to the activation of cancer plasma contact systems are also unknown.
The answers to these questions may lead to novel cancer prevention and treatment targets. Download as PDF. Set alert. About this. View chapter Purchase book. Polymers in Biology and Medicine E. Glycosaminoglycans and Fibrillar Polymorphism Kirsten G. Otzen, in Bio-nanoimagingAbstract Glycosaminoglycans GAGs have been known since the s to co-localize with amyloid deposits, yet many questions remain unanswered with regard to their interactions with amyloid.
Biologically Inspired and Biomolecular Materials S. Harley, in Comprehensive Biomaterials2. Davis, different types of gags Anti-Angiogenesis Strategies in Cancer TherapeuticsMarine Nonglycosaminoglycan Sulfated Glycans Glycosaminoglycans GAGs are carbohydrates that have desirable therapeutic effects on pathologic thrombosis, neovascularization, cancer, and inflammation.
Biological effects of natural glycosaminoglycan from animals and marine sources Anti-angiogenesis and anti-cancer - Inhibition activities on growth factors necessary for cell differentiation and neovascularization - Inhibition activities on selectins necessary for cell migration, attachment, and adhesion Anti-inflammation - Inhibition of l-selectin during leukocyte recruitment and rolling - Inhibition of chemokine functions in leukocyte activation - Decreased extravasation of activated leukocytes - Inhibition of binding of free chemokines to infiltrated leukocytes in inflamed tissues - Completion with hydrolase activity during ECM processing necessary to enhance leukocyte transmigration.
Artificial biomaterials for urological tissue engineering W. Anticoagulant Stabilization of mast cell tryptases Modulation of mast cell chymases Regulation of the inflammatory response Remodeling of the airway wall in asthma Interaction with cytokines, chemokines, and interleukins — Morphogenesis, development, and organogenesis Coreceptors for receptor tyrosinekinases Prevention of inflammation Immune modulation Maintenance of the structure and function of cartilage Cartilage shock-absorbing properties Regulation of cell adhesion to the ECM Tissue hydration Antiadhesive to cell attachment Abundant airway secretion Stabilization of connective tissue Organization of ECM Hydration and water homeostasis Receptor-mediated aling Morphogenesis and tissue homeostasisRegulation of the inflammatory response Tissue remodeling Cellular migration and phagocytosisDifferent types of gags
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