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.

In Vivo and Clinical Studies of Sea Cucumber-Derived Bioactives for Human Health and Nutrition From 2012-2021

“…Notably, a recent study reported that 4.0 mg/kg (i.v.) of FGs (derived from Thelenota ananas and Holothuria fuscopunctata) could cause significant cardiovascular and respiratory dysfunction in rats which was mainly ascribed to pulmonary microvessel embolism due to platelet aggregation and contact activation-mediated coagulation, while their depolymerized products (dTaFG13 and dHG-5) had no obvious side effects (Lin et al, 2021). Yin et al (2021) purified the Compounds 5 from the depolymerized natural Glycosaminoglycans of sea cucumber Thelenota ananas and tested its anticoagulant activity in mice and antithrombotic activity in rat model.…”

Glycosaminoglycan-like sulfated polysaccharides from Vibrio diabolicus bacterium: Semi-synthesis and characterization

“…Sulfated polysaccharides employed for some applications can cause in some cases adverse effects, that are associated with high molecular weight sulfated species (Fonseca et al, 2010;Lin et al 2021), Therefore, HE800 EPS produced by V. diabolicus HE800 fermentation under controlled conditions, was partially depolymerized through a H 2 O 2 -mediated free radical reaction to give a LMW HE800 EPS (approx. 24 kDa, Table 1) before any sulfate group insertion.…”

Prospective bacterial and fungal sources of hyaluronic acid: A review

“…GAGs are involved in various biological processes, such as cell signaling [1] and extracellular matrix assembly. Due to their unique biological properties, there has been a burgeoning interest in glycosaminoglycans for medical use as coating materials for anti-inflammatory agents [2] , [3] and anticoagulants [4] , [5] . A review about the development of GAG applications in medicine and pharmacy has been published recently [6] .…”