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      Marine Non-Glycosaminoglycan Sulfated Glycans as Potential Pharmaceuticals

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          Abstract

          Sulfated fucans (SFs) and sulfated galactans (SGs) are currently the marine non-glycosaminoglycan (GAG) sulfated glycans most studied in glycomics. These compounds exhibit therapeutic effects in several pathophysiological systems such as blood coagulation, thrombosis, neovascularization, cancer, inflammation, and microbial infections. As analogs of the largely employed GAGs and due to some limitations of the GAG-based therapies, SFs and SGs comprise new carbohydrate-based therapeutics available for clinical studies. Here, the principal structural features and the major mechanisms of action of the SFs and SGs in the above-mentioned pathophysiological systems are presented. Discussion is also given on the current challenges and the future perspectives in drug development of these marine glycans.

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          Most cited references82

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          Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization.

          The crystal structure of a dimeric 2:2:2 FGF:FGFR:heparin ternary complex at 3 A resolution has been determined. Within each 1:1 FGF:FGFR complex, heparin makes numerous contacts with both FGF and FGFR, thereby augmenting FGF-FGFR binding. Heparin also interacts with FGFR in the adjoining 1:1 FGF:FGFR complex to promote FGFR dimerization. The 6-O-sulfate group of heparin plays a pivotal role in mediating both interactions. The unexpected stoichiometry of heparin binding in the structure led us to propose a revised model for FGFR dimerization. Biochemical data in support of this model are also presented. This model provides a structural basis for FGFR activation by small molecule heparin analogs and may facilitate the design of heparin mimetics capable of modulating FGF signaling.
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            Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation.

            Cancer metastasis consists of a sequential series of events, and the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are recognized as critical events for metastasis of carcinomas. A current area of focus is the histopathological similarity between primary and metastatic tumors, and MET at sites of metastases has been postulated to be part of the process of metastatic tumor formation. Here, we summarize accumulating evidence from experimental studies that directly supports the role of MET in cancer metastasis, and we analyze the main mechanisms that regulate MET or reverse EMT in carcinomas. Given the critical role of MET in metastatic tumor formation, the potential to effectively target the MET process at sites of metastasis offers new hope for inhibiting metastatic tumor formation.
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              Heparin and heparan sulfate: structure and function.

              This review covers the structure and function of heparin and heparan sulfate glycosaminoglycans. Their chemical structures are discussed, including recently developed methods for sequencing picomole to nanomole quantities of heparin- and heparan sulfate-derived oligosaccharides. The biosynthesis of heparin and heparan sulfate is reviewed as it relates to their diverse and varied structures, and their biological activities and functions are discussed. The literature up to August 2001 is reviewed, and 208 references are cited.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Pharmaceuticals (Basel)
                Pharmaceuticals (Basel)
                pharmaceuticals
                Pharmaceuticals
                MDPI
                1424-8247
                10 December 2015
                December 2015
                : 8
                : 4
                : 848-864
                Affiliations
                Program of Glycobiology, Institute of Medical Biochemistry Leopoldo de Meis, University Hospital Clementino Fraga Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil; E-Mail: pominvh@ 123456bioqmed.ufrj.br or vhpomin@ 123456gmail.com ; Tel.: +55-21-3938-2939; Fax: +55-21-3938-2090
                Article
                pharmaceuticals-08-00848
                10.3390/ph8040848
                4695813
                26690451
                79e4236d-dcdc-43b5-90e0-f38f87d9bf65
                © 2015 by the author; licensee MDPI, Basel, Switzerland.

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

                History
                : 09 October 2015
                : 08 December 2015
                Categories
                Review

                angiogenesis,cancer,coagulation,inflammation,marine glycans,microbial infection,sulfated fucans,sulfated galactans,thrombosis

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