ReferenceID 1570
Modulation of human platelet activation and in vivo vascular thrombosis by columbianadin: regulation by integrin αIIbβ3 inside-out but not outside-in signals
J Biomed Sci
BACKGROUND: Columbianadin (CBN) is one of the main coumarin constituents isolated from Angelica pubescens. The pharmacological value of CBN is well demonstrated, especially in the prevention of several cancers and analge
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- Reference Id
- 1570
- Evidence Id
- 18160
- Core Evidence Id
- 18160
- Source Reference Id
- 3144
- Herb2 Reference Id
- HBREF003941
- Subject Paper Key
- HBIN021295_32375785
- Pubmed Id
- 32375785
- Doi
- 10.1186/s12929-020-0619-5
- Paper Title
- Modulation of human platelet activation and in vivo vascular thrombosis by columbianadin: regulation by integrin αIIbβ3 inside-out but not outside-in signals
- Paper Abstract
- BACKGROUND: Columbianadin (CBN) is one of the main coumarin constituents isolated from Angelica pubescens. The pharmacological value of CBN is well demonstrated, especially in the prevention of several cancers and analgesic activity. A striking therapeutic target for arterial thrombosis is inhibition of platelet activation because platelet activation significantly contributes to these diseases. The current study examined the influence of CBN on human platelet activation in vitro and vascular thrombotic formation in vivo. METHODS: Aggregometry, immunoblotting, immunoprecipitation, confocal microscopic analysis, fibrin clot retraction, and thrombogenic animals were used in this study. RESULTS: CBN markedly inhibited platelet aggregation in washed human platelets stimulated only by collagen, but was not effective in platelets stimulated by other agonists such as thrombin, arachidonic acid, and U46619. CBN evidently inhibited ATP release, intracellular ([Ca2+]i) mobilization, and P-selectin expression. It also inhibited the phosphorylation of phospholipase C (PLC)gamma2, protein kinase C (PKC), Akt (protein kinase B), and mitogen-activated protein kinases (MAPKs; extracellular signal-regulated kinase [ERK] 1/2 and c-Jun N-terminal kinase [JNK] 1/2, but not p38 MAPK) in collagen-activated platelets. Neither SQ22536, an adenylate cyclase inhibitor, nor ODQ, a guanylate cyclase inhibitor, reversed the CBN-mediated inhibition of platelet aggregation. CBN had no significant effect in triggering vasodilator-stimulated phosphoprotein phosphorylation. Moreover, it markedly hindered integrin alphaIIbbeta3 activation by interfering with the binding of PAC-1; nevertheless, it had no influences on integrin alphaIIbbeta3-mediated outside-in signaling such as adhesion number and spreading area of platelets on immobilized fibrinogen as well as thrombin-stimulated fibrin clot retraction. Additionally, CBN did not attenuate FITC-triflavin binding or phosphorylation of proteins, such as integrin beta3, Src, and focal adhesion kinase, in platelets spreading on immobilized fibrinogen. In experimental mice, CBN increased the occlusion time of thrombotic platelet plug formation. CONCLUSION: This study demonstrated that CBN exhibits an exceptional activity against platelet activation through inhibition of the PLCgamma2-PKC cascade, subsequently suppressing the activation of Akt and ERKs/JNKs and influencing platelet aggregation. Consequently, this work provides solid evidence and considers that CBN has the potential to serve as a therapeutic agent for the treatment of thromboembolic disorders.
- Journal
- J Biomed Sci
- Publish Year
- 2020
- Experiment Subject
- mouse; human
- Experiment Type
- Animal & Cell Experiment
- Phenotype Related
- Arterial Thrombosis; Cancers; Thromboembolic Disorders
- Paper Title Cn
- Paper Title En
- Modulation of human platelet activation and in vivo vascular thrombosis by columbianadin: regulation by integrin αIIbβ3 inside-out but not outside-in signals
- Bilingual Status
- semi_complete