Abstract
Fucosylated chondroitin sulfate (fCS) from sea cucumber Isostichopus badionotus (fCS-Ib) with a chondroitin sulfate type E (CSE) backbone and 2,4-O-sulfo fucose branches has shown excellent anticoagulant activity although has also show severe adverse effects. Depolymerization represents an effective method to diminish this polysaccharide’s side effects. The present study reports a modified controlled Fenton system for degradation of fCS-Ib and the anticoagulant activity of the resulting fragments. Monosaccharides and nuclear magnetic resonance (NMR) analysis of the resulting fragments indicate that no significant chemical changes in the backbone of fCS-Ib and no loss of sulfate groups take place during depolymerization. A reduction in the molecular weight of fCS-Ib should result in a dramatic decrease in prolonging activated partial thromboplastin time and thrombin time. A decrease in the inhibition of thrombin (FIIa) by antithromin III (AT III) and heparin cofactor II (HCII), and the slight decrease of the inhibition of factor X activity, results in a significant increase of anti-factor Xa (FXa)/anti-FIIa activity ratio. The modified free-radical depolymerization method enables preparation of glycosaminoglycan (GAG) oligosaccharides suitable for investigation of clinical anticoagulant application.
Highlights
Fucosylated chondroitin sulfate from sea cucumber has attracted increasing attention due to its potential therapeutic application, such as anti-human immunodeficiency virusactivity [1], attenuation of renal fibrosis through a P-selectin-mediated mechanism [2], inhibition of tumor metastasis [3], and anti-hyperlipidemia activity [4]
Chemical compositional analysis indicated after the oxidation, the monosaccharide composition of the Fucosylated chondroitin sulfate (fCS)-Ib remained unchanged (Table 2), suggesting that backbone chain of depolymeirized products still kept a typical chondroitin sulfate structure and oxidative depolymerization of fCS resulted no obvious loss of fucose branches, the key factor for the anticoagulant and antithrombotic activity of the fCSs
The depolymerization conditions were optimized and the results indicated that lower pH, higher concentration of hydrogen peroxide and reaction temperature and longer time can increase the depolymerization efficiency
Summary
Fucosylated chondroitin sulfate (fCS) from sea cucumber has attracted increasing attention due to its potential therapeutic application, such as anti-human immunodeficiency virus (anti-HIV). The small scale degradation of fCS using a combination of hydrazine and nitrous acid [11] and 60 Co irradiation [12] are effective for backbone depolymerization without loss of the fucose branches, which are a key functional group required for anticoagulation [13] These methods are difficult to scale-up because they use toxic chemicals or radioactive 60 Co. Acid-catalyzed hydrolysis and free-radical depolymerization are efficient ways for the large-scale preparation of low molecular fCSs [14]. First isolated from the sea cucumber, Isostichopus badionotus [18,19], fCS shows an activated partial thromboplastin time (APTT) of 183 IU/mg This fCS shows substantial antithrombin III (AT III) and heparin cofactor II HCII-mediated inhibition thrombin (FIIa) and factor. The anticoagulant activities of the resulting fCS fragments were evaluated, using APTT, and thrombin time (TT), prothrombin time (PT), inhibition of FIIa by HCII and AT FXa by AT, with aims to investigate the anticoagulant mechanism
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