The Toxicology of Native Fucosylated Glycosaminoglycans and the Safety of Their Depolymerized Products as Anticoagulants
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...
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| Format: | Article |
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MDPI AG
2021-08-01
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| Series: | Marine Drugs |
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| Online Access: | https://www.mdpi.com/1660-3397/19/9/487 |
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| author | Lisha Lin Sujuan Li Na Gao Weili Wang Taocui Zhang Lian Yang Xingzhi Yang Dan Luo Xu Ji Jinhua Zhao |
| author_facet | Lisha Lin Sujuan Li Na Gao Weili Wang Taocui Zhang Lian Yang Xingzhi Yang Dan Luo Xu Ji Jinhua Zhao |
| author_sort | Lisha Lin |
| collection | DOAJ |
| description | 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 <i>T. ananas</i> (TaFG) and FG from <i>H. fuscopunctata</i> (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. |
| first_indexed | 2024-03-10T07:30:21Z |
| format | Article |
| id | doaj.art-cd485cb766d4467f9906bd73a8550cbb |
| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-03-10T07:30:21Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-cd485cb766d4467f9906bd73a8550cbb2023-11-22T13:58:32ZengMDPI AGMarine Drugs1660-33972021-08-0119948710.3390/md19090487The Toxicology of Native Fucosylated Glycosaminoglycans and the Safety of Their Depolymerized Products as AnticoagulantsLisha Lin0Sujuan Li1Na Gao2Weili Wang3Taocui Zhang4Lian Yang5Xingzhi Yang6Dan Luo7Xu Ji8Jinhua Zhao9State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, ChinaState Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, ChinaSchool of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan 430074, ChinaState Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, ChinaState Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, ChinaState Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, ChinaState Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, ChinaCollege of Traditional Chinese Medicine, Yunnan University of Chinese Medicine, Kunming 650201, ChinaSchool of Chemical Science and Technology, Yunnan University, Kunming 650201, ChinaSchool of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan 430074, ChinaFucosylated 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 <i>T. ananas</i> (TaFG) and FG from <i>H. fuscopunctata</i> (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.https://www.mdpi.com/1660-3397/19/9/487fucosylated glycosaminoglycananticoagulantplatelet aggregationcontact activationhypotensionpulmonary embolism |
| spellingShingle | Lisha Lin Sujuan Li Na Gao Weili Wang Taocui Zhang Lian Yang Xingzhi Yang Dan Luo Xu Ji Jinhua Zhao The Toxicology of Native Fucosylated Glycosaminoglycans and the Safety of Their Depolymerized Products as Anticoagulants Marine Drugs fucosylated glycosaminoglycan anticoagulant platelet aggregation contact activation hypotension pulmonary embolism |
| title | The Toxicology of Native Fucosylated Glycosaminoglycans and the Safety of Their Depolymerized Products as Anticoagulants |
| title_full | The Toxicology of Native Fucosylated Glycosaminoglycans and the Safety of Their Depolymerized Products as Anticoagulants |
| title_fullStr | The Toxicology of Native Fucosylated Glycosaminoglycans and the Safety of Their Depolymerized Products as Anticoagulants |
| title_full_unstemmed | The Toxicology of Native Fucosylated Glycosaminoglycans and the Safety of Their Depolymerized Products as Anticoagulants |
| title_short | The Toxicology of Native Fucosylated Glycosaminoglycans and the Safety of Their Depolymerized Products as Anticoagulants |
| title_sort | toxicology of native fucosylated glycosaminoglycans and the safety of their depolymerized products as anticoagulants |
| topic | fucosylated glycosaminoglycan anticoagulant platelet aggregation contact activation hypotension pulmonary embolism |
| url | https://www.mdpi.com/1660-3397/19/9/487 |
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