Click
here to close Hello! We notice that
you are using Internet Explorer, which is not supported by Echinobase
and may cause the site to display incorrectly. We suggest using a
current version of Chrome,
FireFox,
or Safari.
Mar Drugs
2018 Aug 30;169:. doi: 10.3390/md16090304.
Show Gene links
Show Anatomy links
Anticoagulant and Antithrombotic Properties of Three Structurally Correlated Sea Urchin Sulfated Glycans and Their Low-Molecular-Weight Derivatives.
Vasconcelos AA
,
Sucupira ID
,
Guedes AL
,
Queiroz IN
,
Frattani FS
,
Fonseca RJ
,
Pomin VH
.
Abstract
The anticoagulant and antithrombotic properties of three structurally correlated sea urchin-derived 3-linked sulfated α-glycans and their low molecular-weight derivatives were screened comparatively through various in vitro and in vivo methods. These methods include activated partial thromboplastin time, the inhibitory activity of antithrombin over thrombin and factor Xa, venous antithrombosis, the inhibition of platelet aggregation, the activation of factor XII, and bleeding. While the 2-sulfated fucan from Strongylocentrotus franciscanus was observed to be poorly active in most assays, the 4-sulfated fucan from Lytechinus variegatus, the 2-sulfated galactan from Echinometra lucunter and their derivatives showed multiple effects. All marine compounds showed no capacity to activate factor XII and similar low bleeding tendencies regardless of the dose concentrations used to achieve the highest antithrombotic effect observed. The 2-sulfated galactan showed the best combination of results. Our work improves the background about the structure-function relationship of the marine sulfated glycans in anticoagulation and antithrombosis. Besides confirming the negative effect of the 2-sulfated fucose and the positive effect of the 2-sulfated galactose on anticoagulation in vitro, our results also demonstrate the importance of this set of structural requirements on antithrombosis in vivo, and further support the involvement of high-molecular weight and 4-sulfated fucose in both activities.
Figure 1. Structural representation (AâC), polyacrylamide gel electrophoresis (PAGE) (D) and 1H-13C dept-heteronuclear single quantum coherence (HSQC) spectra (EâL) of the three structurally correlated sea urchin sulfated glycans. Their structures are the 3-linked 4-sulfated α-fucan from Lytechinus variegatus (A), the 3-linked 2-sulfated α-fucan from Strongylocentrotus franciscanus (B), and the 3-linked 2-sulfated α-galactan from Echinometra lucunter (C). The molecular weight (MW) ranges of the native sulfated glycans, of their low-MW derivatives and of the standards unfractionated heparin (UFH) (MW~16 kDa) and low molecular-weight heparin (LMWH) (MW ~ 8 kDa) are comparatively analyzed through PAGE (D). The 1H-13C dept-HSQC spectra were recorded for UFH (E), L.v (F), S.f. (G), E.l. (H), LMWH (I), L.v. hd (J), S.f. hd (K), and E.l. hd (L). While cross-peaks from CH and CH3 (in-phase) are shown in blue, those from CH2 (anti-phase) are shown in red. In panels (E) and (I), peaks labeled with (A) and (I) stand for glucosamine and iduronate, respectively. In panel (FâH) and(JâL), (A) stands for the sulfated units and (B) stands for the desulfated units.
Figure 2. Anticoagulant properties of the native sea urchin sulfated glycans (A,C,E) and their low-MW derivatives (B,D,F) screened by aPTT (A,B) and by AT-mediated IIa (C,D) and Xa (E,F) inhibition.
Figure 3. Antithrombotic properties of the native sea urchin sulfated glycans (A,B) and their low-MW derivatives (C), in venous model of thrombosis, (A) and platelet aggregation (B,C).
Figure 4. Effects of the native sea urchin sulfated glycans (A, and solid circles in panel C) and low-MW derivatives (B, and open circles in panel C) in assays of factor XII activation (A,B) and bleeding tendency (C).
Ahmed,
Heparin induced thrombocytopenia: diagnosis and management update.
2007, Pubmed
Ahmed,
Heparin induced thrombocytopenia: diagnosis and management update.
2007,
Pubmed
Alves,
Sulfated polysaccharides from the egg jelly layer are species-specific inducers of acrosomal reaction in sperms of sea urchins.
1997,
Pubmed
,
Echinobase
Baroletti,
Heparin-induced thrombocytopenia.
2006,
Pubmed
Becker,
Conformation of sulfated galactan and sulfated fucan in aqueous solutions: implications to their anticoagulant activities.
2007,
Pubmed
Cinelli,
Expression of two different sulfated fucans by females of Lytechinus variegatus may regulate the seasonal variation in the fertilization of the sea urchin.
2007,
Pubmed
,
Echinobase
Clark,
Cerebral hemorrhagic risk of aspirin or heparin therapy with thrombolytic treatment in rabbits.
1991,
Pubmed
Fanikos,
Adverse drug events in hospitalized cardiac patients.
2007,
Pubmed
Fonseca,
Effects of polysaccharides enriched in 2,4-disulfated fucose units on coagulation, thrombosis and bleeding. Practical and conceptual implications.
2009,
Pubmed
,
Echinobase
Fonseca,
Effects of oversulfated and fucosylated chondroitin sulfates on coagulation. Challenges for the study of anticoagulant polysaccharides.
2010,
Pubmed
Fonseca,
Slight differences in sulfation of algal galactans account for differences in their anticoagulant and venous antithrombotic activities.
2008,
Pubmed
Fonseca,
Fucosylated chondroitin sulfate as a new oral antithrombotic agent.
2006,
Pubmed
,
Echinobase
Fonseca,
Improved anticoagulant effect of fucosylated chondroitin sulfate orally administered as gastro-resistant tablets.
2017,
Pubmed
,
Echinobase
Herbert,
Importance of platelets in experimental venous thrombosis in the rat.
1992,
Pubmed
Mannucci,
Old and new anticoagulant drugs: a minireview.
2011,
Pubmed
Melo,
An algal sulfated galactan has an unusual dual effect on venous thrombosis due to activation of factor XII and inhibition of the coagulation proteases.
2008,
Pubmed
Moore,
Serious adverse drug events reported to the Food and Drug Administration, 1998-2005.
2007,
Pubmed
Mulloy,
Pharmacology of Heparin and Related Drugs.
2016,
Pubmed
Pereira,
Is there a correlation between structure and anticoagulant action of sulfated galactans and sulfated fucans?
2002,
Pubmed
Pereira,
A 2-sulfated, 3-linked alpha-L-galactan is an anticoagulant polysaccharide.
2002,
Pubmed
,
Echinobase
Pomin,
Medical Gains of Chondroitin Sulfate Upon Fucosylation.
2015,
Pubmed
,
Echinobase
Pomin,
Selective cleavage and anticoagulant activity of a sulfated fucan: stereospecific removal of a 2-sulfate ester from the polysaccharide by mild acid hydrolysis, preparation of oligosaccharides, and heparin cofactor II-dependent anticoagulant activity.
2005,
Pubmed
,
Echinobase
Pomin,
A Dilemma in the Glycosaminoglycan-Based Therapy: Synthetic or Naturally Unique Molecules?
2015,
Pubmed
Pomin,
Marine Non-Glycosaminoglycan Sulfated Glycans as Potential Pharmaceuticals.
2015,
Pubmed
Pomin,
Fucanomics and galactanomics: current status in drug discovery, mechanisms of action and role of the well-defined structures.
2012,
Pubmed
Pomin,
Holothurian fucosylated chondroitin sulfate.
2014,
Pubmed
,
Echinobase
Pomin,
Anticoagulant motifs of marine sulfated glycans.
2014,
Pubmed
Pomin,
Dual and antagonic therapeutic effects of sulfated glycans.
2016,
Pubmed
Queiroz,
Oligosaccharides from the 3-linked 2-sulfated alpha-L-fucan and alpha-L-galactan show similar conformations but different dynamics.
2016,
Pubmed
Queiroz,
Impact of sulfation pattern on the conformation and dynamics of sulfated fucan oligosaccharides as revealed by NMR and MD.
2015,
Pubmed
,
Echinobase
Quinderé,
Is the antithrombotic effect of sulfated galactans independent of serpin?
2014,
Pubmed
Ramirez-Lassepas,
Heparin therapy for stroke: hemorrhagic complications and risk factors for intracerebral hemorrhage.
1984,
Pubmed
Raskob,
Thrombosis: a major contributor to global disease burden.
2014,
Pubmed
Spyropoulos,
Brave new world: the current and future use of novel anticoagulants.
2008,
Pubmed
Vilela-Silva,
Structure of the sulfated alpha-L-fucan from the egg jelly coat of the sea urchin Strongylocentrotus franciscanus: patterns of preferential 2-O- and 4-O-sulfation determine sperm cell recognition.
1999,
Pubmed
,
Echinobase
WESSLER,
Biologic assay of a thrombosis-inducing activity in human serum.
1959,
Pubmed