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The Toxicology of Native Fucosylated Glycosaminoglycans and the Safety of Their Depolymerized Products as Anticoagulants.

ABSTRACT: Fucosylated glycosaminoglycan (FG) from sea cucumber is a potent anticoagulant by inhibiting intrinsic coagulation tenase (iXase). However, high-molecular-weight FGs can activate platelets and plasma contact system, and induce hypotension in rats, which limits its application. Herein, we found that FG from T. ananas (TaFG) and FG from H. fuscopunctata (HfFG) at 4.0 mg/kg (i.v.) could cause significant cardiovascular and respiratory dysfunction in rats, even lethality, while their depolymerized products had no obvious side effects. After injection, native FG increased rat plasma kallikrein activity and levels of the vasoactive peptide bradykinin (BK), consistent with their contact activation activity, which was assumed to be the cause of hypotension in rats. However, the hemodynamic effects of native FG cannot be prevented by the BK receptor antagonist. Further study showed that native FG induced in vivo procoagulation, thrombocytopenia, and pulmonary embolism. Additionally, its lethal effect could be prevented by anticoagulant combined with antiplatelet drugs. In summary, the acute toxicity of native FG is mainly ascribed to pulmonary microvessel embolism due to platelet aggregation and contact activation-mediated coagulation, while depolymerized FG is a safe anticoagulant candidate by selectively targeting iXase.

SUBMITTER: Lin L

PROVIDER: S-EPMC8467514 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Oligosaccharides from depolymerized fucosylated glycosaminoglycan: Structures and minimum size for intrinsic factor Xase complex inhibition.

Project description:Fucosylated glycosaminoglycan (FG), a structurally complex glycosaminoglycan found up to now exclusively in sea cucumbers, has distinct anticoagulant properties, notably a strong inhibitory activity of intrinsic factor Xase complex (FXase). Knowledge of the FG structures could facilitate the development of a clinically effective intrinsic FXase inhibitor for anticoagulant drugs. Here, a new fucosylated glycosaminoglycan was obtained from the widely traded sea cucumber Bohadschia argus The precise structure was deduced as {→4)-[l-Fuc3S4S-α-(1→3)-]-d-GlcA-β-(1→3)-d-GalNAc4S6S-β-(1} through analysis of its chemical properties and homogeneous oligosaccharides purified from its β-eliminative depolymerized products. The B. argus FG with mostly 3,4-di-O-sulfated fucoses expands our knowledge on FG structural types. This β-elimination process, producing oligosaccharides with well-defined structures, is a powerful tool for analyzing the structure of complex FGs. Among these oligosaccharides, an octasaccharide displayed potent FXase inhibitory activity. Compared with oligosaccharides with various degrees of polymerization (3n and 3n - 1), our analyses reveal that the purified octasaccharide is the minimum structural unit responsible for the potent selective FXase inhibition, because the d-talitol in the nonsaccharide is unnecessary. The octasaccharide with 2,4-di-O-sulfated fucoses is more potent than that of one with 3,4-di-O-sulfated fucoses. Thus, sulfation patterns can play an important role in the inhibition of intrinsic factor Xase complex.

| S-EPMC6130965 | biostudies-literature

Precise Structure and Anticoagulant Activity of Fucosylated Glycosaminoglycan from Apostichopus japonicus: Analysis of Its Depolymerized Fragments.

Project description:Apostichopus japonicus is one of the most economically important species in sea cucumber aquaculture in China. Fucosylated glycosaminoglycan from A. japonicus (AjFG) has shown multiple pharmacological activities. However, results from studies on the structure of AjFG are still controversial. In this study, the deaminative depolymerization method that is glycosidic bond-selective was used to prepare the depolymerized products from AjFG (dAjFG), and then a series of purified oligosaccharide fragments such as tri-, hexa-, nona-, and dodecasaccharides were obtained from dAjFG by gel permeation chromatography. The 1D/2D NMR and ESI-MS spectrometry analyses showed that these oligosaccharides had the structural formula of l-FucS-α1,3-d-GlcA-β1,3-{d-GalNAc4S6S-β1,4-[l-FucS-α1,3-]d-GlcA-β1,3-}n-d-anTal-diol4S6S (n = 0, 1, 2, 3; FucS represents Fuc2S4S, Fuc3S4S, or Fuc4S). Thus, the unambiguous structure of native AjFG can be rationally deduced: it had the backbone of {-4-d-GlcA-β1,3-d-GalNAc4S6S-β1-}n, which is similar to chondroitin sulfate E, and each d-GlcA residue in the backbone was branched with a l-FucS monosaccharide at O-3. Bioactivity assays confirmed that dAjFG and nonasaccharides and dodecasaccharides from AjFG had potent anticoagulant activity by intrinsic FXase inhibition while avoiding side effects such as FXII activation and platelet aggregation.

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| S-EPMC7278963 | biostudies-literature

Fucosylated glycoproteins and fucosylated glycolipids play opposing roles in cholera intoxication

Project description:Cholera toxin (CT) is the etiological agent of cholera. Here we report that multiple classes of fucosylated glycoconjugates function in CT binding and intoxication of intestinal epithelial cells. In Colo205 cells, knockout of B3GNT5, the enzyme required for synthesis of lacto- and neolacto-series glycosphingolipids (GSLs), reduces CT binding but sensitizes cells to intoxication. Overexpressing B3GNT5 to generate more fucosylated GSLs confers protection against intoxication, indicating that fucosylated GSLs act as decoy receptors for CT. Knockout (KO) of B3GALT5 causes increased production of fucosylated O-linked and N-linked glycoproteins, and leads to increased CT binding and intoxication. Knockout of B3GNT5 in B3GALT5 KO cells eliminates production of fucosylated GSLs but increases intoxication, identifying fucosylated glycoproteins as functional receptors for CT. These findings provide insight into molecular determinants regulating CT sensitivity of host cells.

2024-08-31 | GSE242156 | GEO

Efficacy and safety of novel anticoagulants in the elderly.

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| S-EPMC5067434 | biostudies-other

Bacterial conversion of depolymerized Kraft lignin.

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| S-EPMC6420747 | biostudies-literature

Bacterial conversion of depolymerized Kraft lignin.

Project description:BackgroundLignin is a potential feedstock for microbial conversion into various chemicals. However, the degradation rate of native or technical lignin is low, and depolymerization is needed to obtain reasonable conversion rates. In the current study, base-catalyzed depolymerization-using NaOH (5 wt%)-of softwood Kraft lignin was conducted in a continuous-flow reactor system at temperatures in the range 190-240 °C and residence times of 1 or 2 min. The ability of growth of nine bacterial strains belonging to the genera Pseudomonas and Rhodococcus was tested using the alkaline-treated lignin as a sole carbon source.ResultsPseudomonas fluorescens and Rhodococcus opacus showed the best growth of the tested species on plates with lignin. Further evaluation of P. fluorescens and R. opacus was made in liquid cultivations with depolymerized lignin (DL) at a concentration of 1 g/L. Size exclusion chromatography (SEC) showed that R. opacus consumed most of the available lower molecular weight compounds (approximately 0.1-0.4 kDa) in the DL, but the weight distribution of larger fractions was almost unaffected. Importantly, the consumed compounds included guaiacol-one of the main monomers in the DL. SEC analysis of P. fluorescens culture broth, in contrast, did not show a large conversion of low molecular weight compounds, and guaiacol remained unconsumed. However, a significant shift in molecular weight distribution towards lower average weights was seen.ConclusionsRhodococcus opacus and P. fluorescens were identified as two potential microbial candidates for the conversion/consumption of base-catalyzed depolymerized lignin, acting on low and high molecular weight lignin fragments, respectively. These findings will be of relevance for designing bioconversion of softwood Kraft lignin.

| S-EPMC6123935 | biostudies-literature

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| S-EPMC6213321 | biostudies-literature

Native and non-native host assessment towards metabolic pathway reconstructions of plant natural products.

Project description:Plant-based biopreparations are reasonably priced and are devoid of viral, prion and endotoxin contaminants. However, synthesizing these natural plant products by chemical methods is quite expensive. The structural complexity of plant-derived natural products poses a challenge for chemical synthesis at a commercial scale. Failure of commercial-scale synthesis is the chief reason why metabolic reconstructions in heterologous hosts are inevitable. This review discusses plant metabolite pathway reconstructions experimented in various heterologous hosts, and the inherent challenges involved. Plants as native hosts possess enhanced post-translational modification ability, along with rigorous gene edits, unlike microbes. To achieve a high yield of metabolites in plants, increased cell division rate is one of the requisites. This improved cell division rate will promote cellular homogeneity. Incorporation and maintenance of plant cell synchrony, in turn, can program stable product scale-up.

| S-EPMC8091882 | biostudies-literature

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