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学者姓名:王栋
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BACKGROUND:FXIa (coagulation factor XIa) is considered as a promising antithrombotic target with reduced hemorrhagic liabilities. The objective of this study was to identify a small-molecule inhibitor of FXIa as a potential low-hemorrhagic anticoagulant.METHODS:A high-throughput virtual screening was conducted using a drug repurposing library with the catalytic domain of FXIa as the bait. The identified inhibitor's anticoagulant activity was evaluated in vitro and in both arterial and venous murine thrombotic models. The dependency of the inhibitor on FXIa was further examined using FXI-/- mice. Hemorrhagic risks were subsequently evaluated in models of both localized and major bleeding.RESULTS:Virtual screening led to the identification of montelukast, a commonly used antiasthmatic drug, as a potent and specific FXIa inhibitor (half maximal inhibitory concentration of 0.17 mu mol/L). MK exhibited anticoagulant effects comparable to those of 2 mostly prescribed anticoagulants (warfarin and apixaban) in both arterial and venous thrombotic models. Notably, in stark contrast to the pronounced hemorrhagic risks of warfarin and apixaban, MK did not measurably increase the tendency of localized or major bleeding. Furthermore, MK did not prolong the time to arterial thrombotic occlusion in FXI-/- mice, while effectively inhibited arterial occlusion induced by the reinfusion of recombinant FXIa, confirming that MK's anticoagulant activity is mediated by plasma FXIa. Additionally, MK ameliorated inflammation levels and mitigated pulmonary microthrombus formation in a septic mouse model. Moreover, combination therapy with MK enhanced the antithrombotic effects of antiplatelets without an obvious increase of hemorrhage.CONCLUSIONS:This proof-of-concept study suggests the potent low-hemorrhage antithrombotic effect of MK by targeting FXIa and unveiling a new therapeutic application of MK.
Keyword :
anticoagulants anticoagulants factor XI factor XI mice mice montelukast montelukast thrombosis thrombosis
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GB/T 7714 | Zhou, Yang , Wang, Dong , Wu, Juhong et al. Discovery of the Low-Hemorrhagic Antithrombotic Effect of Montelukast by Targeting FXIa in Mice [J]. | ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY , 2025 , 45 (4) : e150-e162 . |
MLA | Zhou, Yang et al. "Discovery of the Low-Hemorrhagic Antithrombotic Effect of Montelukast by Targeting FXIa in Mice" . | ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 45 . 4 (2025) : e150-e162 . |
APA | Zhou, Yang , Wang, Dong , Wu, Juhong , Qi, Yingying , Song, Meiru , Yao, Huiqiao et al. Discovery of the Low-Hemorrhagic Antithrombotic Effect of Montelukast by Targeting FXIa in Mice . | ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY , 2025 , 45 (4) , e150-e162 . |
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In our previous studies of Cr-coated Zr alloy cladding, models for the oxidation and degradation of Cr coating and for the oxidation and phase transformation of Zr alloy have been established. On these foundations, oxygen flux models for Cr-Zr non-eutectic and eutectic conditions are developed in this paper, enabling a comprehensive simulation of the oxidation processes of Cr-coated Zr alloy. The models are validated through oxidation experiments under isothermal and temperature ramp conditions, showing good agreement with the experimental data. The models can effectively simulate the processes where, under non-eutectic conditions, oxygen atoms first dissolve into the prior beta-Zr matrix after coating degradation, followed by the formation of alpha-Zr(O) and eventually ZrO2. For conditions with eutectic reaction, model assumption of immediate complete coating failure could lead to overestimation of substrate oxidation extent at low heating rates. This prediction deviation decreases as heating rate increases.
Keyword :
Cr-coated Zr alloy Cr-coated Zr alloy Diffusion Diffusion High-temperature oxidation High-temperature oxidation Model development Model development Oxygen flux Oxygen flux
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GB/T 7714 | Wang, Dong , Wu, Shihao , Lu, Kai et al. High-temperature oxidation of accident tolerant Cr-coated Zr alloy cladding: Model development and validation [J]. | JOURNAL OF NUCLEAR MATERIALS , 2025 , 606 . |
MLA | Wang, Dong et al. "High-temperature oxidation of accident tolerant Cr-coated Zr alloy cladding: Model development and validation" . | JOURNAL OF NUCLEAR MATERIALS 606 (2025) . |
APA | Wang, Dong , Wu, Shihao , Lu, Kai , Zhang, Yapei , Su, G. H. , Liu, Xi . High-temperature oxidation of accident tolerant Cr-coated Zr alloy cladding: Model development and validation . | JOURNAL OF NUCLEAR MATERIALS , 2025 , 606 . |
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