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Mar Drugs
2021 Aug 27;199:. doi: 10.3390/md19090487.
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The Toxicology of Native Fucosylated Glycosaminoglycans and the Safety of Their Depolymerized Products as Anticoagulants.
Lin L
,
Li S
,
Gao N
,
Wang W
,
Zhang T
,
Yang L
,
Yang X
,
Luo D
,
Ji X
,
Zhao J
.
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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.
Figure 1. The chemical structures of TaFG and HfFG.
Figure 2. Rat typical arterial pressure response after treatment. Data were recorded by a multi-channel physiological signal-collecting instrument before and after treatment. Arrows indicate the administration of the test compound. Representative graphs are shown, n ≥ 8.
Figure 3. Effects of FG on rat arterial pressure. Effects of different polysaccharides on rat blood pressure (a). Effects of different doses of HfFG on rat blood pressure (b). After the 10-min adaptation period, rats were treated with a single intravenous bolus of the test compound. The arterial pressure and heart rate were detected for 10 min before and 30 min after treatment. Arrows indicate the administration of the test compound. Mean ± SEM, n ≥ 8. Abbreviation: AP, arterial pressure.
Figure 4. Effect of HfFG (i.v.) on rat left ventricular pressure (upper) and electrocardiogram (below). Data were recorded by a multi-channel physiological signal-collecting instrument before and after treatment. For the left ventricular pressure, different time scales were shown. For the electrocardiogram, different time points (A–D) in the left ventricular pressure recording were shown, time scale of (A–D) was 80 ms/div. Arrows indicate the administration of the test compound. Representative graphs are shown, n ≥ 8.
Figure 5. Effects of HfFG (i.v.) on rat ECG and the respiratory wave. Data were recorded by a multi-channel physiological signal-collecting instrument before and after treatment. HfFG was at 4.0 mg/kg and arrows indicate the administration of the test compound. Representative graph is shown and the experiment was repeated three times. Abbreviation: ECG, electrocardiogram.
Figure 6. Amidolytic activity (a) and levels of BK (b), C3a (c), and C5a (d) in rat plasmas. Amidolytic activity was detected by the chromogenic substrate method and the concentrations of BK, C3a, and C5a were determined by ELISA kits. For each parameter, the value was compared with that of the control (vehicle) group. * p ≤ 0.05, ** p ≤ 0.01, and *** p ≤ 0.001, two-tail t-test. Each sample was measured in duplicates and results were expressed as mean ± SEM, n = 3. Abbreviation: BK, bradykinin.
Figure 7. Rat pulmonary microvessel embolism induced by native FGs. Rat were i.v. injected with TaFG (4.0 mg/kg), HfFG (4.0 mg/kg), dHG-5 (6.7 mg/kg), or the vehicle and after 5 min the lung was collected for histopathological assays. Experiments were conducted in triplicates and represented results are shown.
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