In Vivo Anticoagulant and Antithrombic Activity of Depolymerized Glycosaminoglycan from <i>Apostichopus japonicus</i> and Dynamic Effect–Exposure Relationship in Rat Plasma
Glycosaminoglycan from <i>Apostichopus japonicus</i> (AHG) and its depolymerized fragments (DAHGs) are anticoagulant fucosylated chondroitin sulfate. The aim of this study was to further evaluate the anticoagulant and antithrombic activity of AHG and DAHGs, as well as reveal the dynamic...
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MDPI AG
2022-10-01
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| Series: | Marine Drugs |
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| Online Access: | https://www.mdpi.com/1660-3397/20/10/631 |
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| author | Han Wang Dandan He Linlin Duan Lv Lv Qun Gao Yuanhong Wang Shuang Yang Zhihua Lv |
| author_facet | Han Wang Dandan He Linlin Duan Lv Lv Qun Gao Yuanhong Wang Shuang Yang Zhihua Lv |
| author_sort | Han Wang |
| collection | DOAJ |
| description | Glycosaminoglycan from <i>Apostichopus japonicus</i> (AHG) and its depolymerized fragments (DAHGs) are anticoagulant fucosylated chondroitin sulfate. The aim of this study was to further evaluate the anticoagulant and antithrombic activity of AHG and DAHGs, as well as reveal the dynamic relationship between exposure and effect in vivo. The results demonstrated that AHG100 (Mw~100 kDa), DAHG50 (Mw~50 kDa), and DAHG10 (Mw~10 kDa) exhibited potent anticoagulant activity by inhibiting intrinsic factor Xase complex (FXase) as well as antithrombin-dependent factor IIa (FIIa) and factor Xa (FXa). These glycosaminoglycans markedly prevented thrombosis formation and thrombin-induced platelet aggregation in a dose- and molecular weight-dependent manner in vitro and in vivo. The further bleeding time measurement indicated that DAHG10 exhibited obviously lower hemorrhage risks than native AHG100. Following oral administration, DAHG10 could be absorbed into blood, further dose-dependently prolonging activated partial thromboplastin time (APTT) and thrombin time (TT) as well as inhibiting FXa and FIIa partially through FXase. Anticoagulant activity was positively associated with plasma concentration following oral administration of DAHG10. Our study proposed a new point of view to understand the correlation between effects and exposure of fucosylated chondroitin sulfate as an effective and safe oral antithrombotic agent. |
| first_indexed | 2024-03-09T19:54:22Z |
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| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-03-09T19:54:22Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-ad7eda0055f246e68b967bc45c1477172023-11-24T01:01:15ZengMDPI AGMarine Drugs1660-33972022-10-01201063110.3390/md20100631In Vivo Anticoagulant and Antithrombic Activity of Depolymerized Glycosaminoglycan from <i>Apostichopus japonicus</i> and Dynamic Effect–Exposure Relationship in Rat PlasmaHan Wang0Dandan He1Linlin Duan2Lv Lv3Qun Gao4Yuanhong Wang5Shuang Yang6Zhihua Lv7Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaGlycosaminoglycan from <i>Apostichopus japonicus</i> (AHG) and its depolymerized fragments (DAHGs) are anticoagulant fucosylated chondroitin sulfate. The aim of this study was to further evaluate the anticoagulant and antithrombic activity of AHG and DAHGs, as well as reveal the dynamic relationship between exposure and effect in vivo. The results demonstrated that AHG100 (Mw~100 kDa), DAHG50 (Mw~50 kDa), and DAHG10 (Mw~10 kDa) exhibited potent anticoagulant activity by inhibiting intrinsic factor Xase complex (FXase) as well as antithrombin-dependent factor IIa (FIIa) and factor Xa (FXa). These glycosaminoglycans markedly prevented thrombosis formation and thrombin-induced platelet aggregation in a dose- and molecular weight-dependent manner in vitro and in vivo. The further bleeding time measurement indicated that DAHG10 exhibited obviously lower hemorrhage risks than native AHG100. Following oral administration, DAHG10 could be absorbed into blood, further dose-dependently prolonging activated partial thromboplastin time (APTT) and thrombin time (TT) as well as inhibiting FXa and FIIa partially through FXase. Anticoagulant activity was positively associated with plasma concentration following oral administration of DAHG10. Our study proposed a new point of view to understand the correlation between effects and exposure of fucosylated chondroitin sulfate as an effective and safe oral antithrombotic agent.https://www.mdpi.com/1660-3397/20/10/631<i>Apostichopus japonicus</i>glycosaminoglycanantithromboticoral anticoagulanteffect–exposure relationship |
| spellingShingle | Han Wang Dandan He Linlin Duan Lv Lv Qun Gao Yuanhong Wang Shuang Yang Zhihua Lv In Vivo Anticoagulant and Antithrombic Activity of Depolymerized Glycosaminoglycan from <i>Apostichopus japonicus</i> and Dynamic Effect–Exposure Relationship in Rat Plasma Marine Drugs <i>Apostichopus japonicus</i> glycosaminoglycan antithrombotic oral anticoagulant effect–exposure relationship |
| title | In Vivo Anticoagulant and Antithrombic Activity of Depolymerized Glycosaminoglycan from <i>Apostichopus japonicus</i> and Dynamic Effect–Exposure Relationship in Rat Plasma |
| title_full | In Vivo Anticoagulant and Antithrombic Activity of Depolymerized Glycosaminoglycan from <i>Apostichopus japonicus</i> and Dynamic Effect–Exposure Relationship in Rat Plasma |
| title_fullStr | In Vivo Anticoagulant and Antithrombic Activity of Depolymerized Glycosaminoglycan from <i>Apostichopus japonicus</i> and Dynamic Effect–Exposure Relationship in Rat Plasma |
| title_full_unstemmed | In Vivo Anticoagulant and Antithrombic Activity of Depolymerized Glycosaminoglycan from <i>Apostichopus japonicus</i> and Dynamic Effect–Exposure Relationship in Rat Plasma |
| title_short | In Vivo Anticoagulant and Antithrombic Activity of Depolymerized Glycosaminoglycan from <i>Apostichopus japonicus</i> and Dynamic Effect–Exposure Relationship in Rat Plasma |
| title_sort | in vivo anticoagulant and antithrombic activity of depolymerized glycosaminoglycan from i apostichopus japonicus i and dynamic effect exposure relationship in rat plasma |
| topic | <i>Apostichopus japonicus</i> glycosaminoglycan antithrombotic oral anticoagulant effect–exposure relationship |
| url | https://www.mdpi.com/1660-3397/20/10/631 |
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