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John H. Griffin - One of the best experts on this subject based on the ideXlab platform.
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skeletal muscle myosin and cardiac myosin attenuate heparin s antithrombin dependent Anticoagulant Activity
Journal of Thrombosis and Haemostasis, 2021Co-Authors: Shravan Morla, John H. Griffin, Hiroshi DeguchiAbstract:BACKGROUND Heparin enhances the ability of the plasma protease inhibitor, antithrombin, to neutralize coagulation factor Xa and thrombin. Skeletal muscle myosin binds unfractionated heparin. OBJECTIVES The aim of this study was to investigate the influence of myosin binding to heparin on antithrombin's Anticoagulant Activity. METHODS Inhibition of factor Xa and thrombin by antithrombin in the presence of different heparins and skeletal muscle myosin or cardiac myosin was studied by measuring inhibition of each enzyme's chromogenic substrate hydrolysis. RESULTS AND CONCLUSIONS Skeletal muscle myosin and cardiac myosin neutralized unfractionated heparin's enhancement of antithrombin's inhibition of purified factor Xa and thrombin. Skeletal muscle myosin also reduced the inhibition of factor Xa and thrombin by antithrombin in the presence of heparan sulfate. These two myosins did not protect factor Xa from antithrombin inhibition when tested in the presence of smaller heparins (eg, low molecular weight heparin, heparin pentasaccharide). This chain length dependence for skeletal muscle myosin's ability to reduce heparin's Anticoagulant Activity might have potential implications for therapy for patients who experience increases in plasma myosin levels (eg, acute trauma patients). In addition to the chain length, the type and extent of sulfation of glycosaminoglycans influenced the ability of skeletal muscle myosin to neutralize the polysaccharide's ability to enhance antithrombin's Activity. In summary, these studies show that skeletal muscle myosin and cardiac myosin can influence antithrombin's Anticoagulant Activity against factor Xa and thrombin, implying that they may significantly influence the hemostatic balance involving bleeding vs clotting.
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activated protein c mutant with minimal Anticoagulant Activity normal cytoprotective Activity and preservation of thrombin activable fibrinolysis inhibitor dependent cytoprotective functions
Journal of Biological Chemistry, 2007Co-Authors: Laurent O Mosnier, Xia V Yang, John H. GriffinAbstract:Abstract Activated protein C (APC) reduces mortality in severe sepsis patients and exhibits beneficial effects in multiple animal injury models. APC Anticoagulant Activity involves inactivation of factors Va and VIIIa, whereas APC cytoprotective activities involve the endothelial protein C receptor and protease-activated receptor-1 (PAR-1). The relative importance of the Anticoagulant Activity of APC versus the direct cytoprotective effects of APC on cells for the in vivo benefits is unclear. To distinguish cytoprotective from the Anticoagulant activities of APC, a protease domain mutant, 5A-APC (RR229/230AA and KKK191-193AAA), was made and compared with recombinant wild-type (rwt)-APC. This mutant had minimal Anticoagulant Activity but normal cytoprotective activities that were dependent on endothelial protein C receptor and protease-activated receptor-1. Whereas Anticoagulantly active rwt-APC inhibited secondary-extended thrombin generation and concomitant thrombin-dependent activation of thrombin activable fibrinolysis inhibitor (TAFI) in plasma, secondary-extended thrombin generation and the activation of TAFI were essentially unopposed by 5A-APC due to its low Anticoagulant Activity. Compared with rwt-APC, 5A-APC had minimal profibrinolytic Activity and preserved TAFI-mediated anti-inflammatory carboxypeptidase activities toward bradykinin and presumably toward the anaphlatoxins, C3a and C5a, which are well known pathological mediators in sepsis. Thus, genetic engineering can selectively alter the multiple activities of APC and provide APC mutants that retain the beneficial cytoprotective effects of APC while diminishing bleeding risk due to reduction in APC's Anticoagulant and APC-dependent profibrinolytic activities.
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Activated protein C variants with normal cytoprotective but reduced Anticoagulant Activity.
Blood, 2004Co-Authors: Laurent O Mosnier, Andrew J Gale, Subramanian Yegneswaran, John H. GriffinAbstract:Recombinant activated protein C (APC), a well-defined Anticoagulant enzyme, reduced mortality in severe sepsis patients in a phase 3 trial. However, 2 potent Anticoagulants, antithrombin III and recombinant tissue factor pathway inhibitor, failed to do so, implying the physiologic relevance of APC's less well-defined anti-inflammatory and antiapoptotic activities. Recombinant APC therapy conveys an increased risk of serious bleeding complications due to APC Anticoagulant Activity. To generate recombinant APC variants with reduced risk of bleeding due to reduced Anticoagulant Activity, we dissected APC's Anticoagulant Activity from its cytoprotective Activity by site-directed mutagenesis. Using staurosporine-induced endothelial cell apoptosis assays, we show here that Ala mutations (RR229/230AA and KKK191_ 193AAA) in 2 APC surface loops that severely reduce Anticoagulant Activity result in 2 APC variants that retain normal antiapoptotic Activity that requires protease activated receptor-1 and endothelial cell protein C receptor. Thus, it is possible to reduce Anticoagulant Activity while preserving antiapoptotic Activity of recombinant APC variants. We suggest that therapeutic use of such APC variants may reduce serious bleeding risks while providing the beneficial effects of APC acting directly on cells.
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Cardiolipin enhances protein C pathway Anticoagulant Activity.
Blood cells molecules & diseases, 2000Co-Authors: José A. Fernández, Kazuhisa Kojima, Jari Petäjä, Tilman M. Hackeng, John H. GriffinAbstract:Abstract ABSTRACT: The Anticoagulant Activity of activated protein C (APC) was studied using factor Xa-1-stage assays of both the procoagulant and Anticoagulant activities of phospholipid vesicles containing phosphatidylserine or cardiolipin as active phospholipids. In the absence of APC, phosphatidylserine vesicles showed higher procoagulant Activity than cardiolipin vesicles whereas cardiolipin vesicles supported APC-dependent Anticoagulant Activity better than phosphatidylserine vesicles. Enhancement of APC Anticoagulant Activity in plasma by cardiolipin was markedly stimulated by the APC cofactor protein S. In purified reaction mixtures, cardiolipin in phospholipid vesicles dose-dependently enhanced APC Anticoagulant Activity. This effect of cardiolipin was partially dependent on protein S, and immunoblotting studies showed that cardiolipin enhanced the APC-mediated cleavage of the factor Va heavy chain at Arg506 and Arg306. In solid-phase binding assays, increasing amounts of cardiolipin in multicomponent phospholipid vesicles increased the affinity for protein S and to a lesser extent APC. These data are consistent with the hypothesis that cardiolipin stimulates the Anticoagulant protein C pathway by increasing the affinity of phospholipid surfaces for protein S:APC and by enhancing inactivation of factor Va by APC due to cleavages at Arg506 and Arg306 in factor Va. Based on this, it is further hypothesized that anti-cardiolipin or anti-oxidized cardiolipin antibodies may be thrombogenic because they inhibit phospholipid-dependent expression of the Anticoagulant protein C pathway.
Keizo Umegaki - One of the best experts on this subject based on the ideXlab platform.
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Trans-Resveratrol Enhances the Anticoagulant Activity of Warfarin in a Mouse Model
Journal of atherosclerosis and thrombosis, 2016Co-Authors: Tsuyoshi Chiba, Yuka Kimura, Sachina Suzuki, Tomoki Tatefuji, Keizo UmegakiAbstract:Resveratrol is a popular ingredient in dietary supplements. Some patients concomitantly use dietary supplements and medicines in Japan. In the present study, we determined whether trans-resveratrol and melinjo (Gnetum gnemon L.) seed extract (MSE), which contains resveratrol dimers, interacted with drugs using a mouse model. Male C57BL/6J mice were fed experimental diets containing 0.005%, 0.05%, or 0.5% (w/w) trans-resveratrol or MSE for 1 or 12 weeks. The expression of liver cytochrome P-450 (CYP) mRNA and Activity of liver microsomal CYP were measured. To determine the influence of resveratrol or MSE on drug efficacy, the Anticoagulant Activity of warfarin was examined in mice that were fed diets containing trans-resveratrol or MSE for 12 weeks. When the mice were fed experimental diets for 1 week, none of the doses of trans-resveratrol and MSE affected body weight, liver weight, or plasma AST and ALT levels. Trans-resveratrol also did not affect CYP1A1, CYP1A2, CYP2C, or CYP3A activities. In contrast, 0.5% MSE slightly increased CYP1A1 Activity. When the mice were fed experimental diets for 12 weeks, 0.05% trans-resveratrol increased CYP1A1, CYP2C, and CYP3A activities, whereas 0.5% MSE suppressed CYP3A Activity. Under these conditions, 0.5% trans-resveratrol enhanced the Anticoagulant Activity of warfarin, although CYP2C Activity increased. However, MSE did not affect the Anticoagulant Activity of warfarin. The 0.05% trans-resveratrol did not interact with warfarin in a mouse model, whereas 0.5% trans-resveratrol may have enhanced the Anticoagulant Activity of warfarin.
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Trans-Resveratrol Enhances the Anticoagulant Activity of Warfarin in a Mouse Model
Journal of atherosclerosis and thrombosis, 2016Co-Authors: Tsuyoshi Chiba, Yuka Kimura, Sachina Suzuki, Tomoki Tatefuji, Keizo UmegakiAbstract:Aim Resveratrol is a popular ingredient in dietary supplements. Some patients concomitantly use dietary supplements and medicines in Japan. In the present study, we determined whether trans-resveratrol and melinjo (Gnetum gnemon L.) seed extract (MSE), which contains resveratrol dimers, interacted with drugs using a mouse model. Methods Male C57BL/6J mice were fed experimental diets containing 0.005%, 0.05%, or 0.5% (w/w) trans-resveratrol or MSE for 1 or 12 weeks. The expression of liver cytochrome P-450 (CYP) mRNA and Activity of liver microsomal CYP were measured. To determine the influence of resveratrol or MSE on drug efficacy, the Anticoagulant Activity of warfarin was examined in mice that were fed diets containing trans-resveratrol or MSE for 12 weeks. Results When the mice were fed experimental diets for 1 week, none of the doses of trans-resveratrol and MSE affected body weight, liver weight, or plasma AST and ALT levels. Trans-resveratrol also did not affect CYP1A1, CYP1A2, CYP2C, or CYP3A activities. In contrast, 0.5% MSE slightly increased CYP1A1 Activity. When the mice were fed experimental diets for 12 weeks, 0.05% trans-resveratrol increased CYP1A1, CYP2C, and CYP3A activities, whereas 0.5% MSE suppressed CYP3A Activity. Under these conditions, 0.5% trans-resveratrol enhanced the Anticoagulant Activity of warfarin, although CYP2C Activity increased. However, MSE did not affect the Anticoagulant Activity of warfarin. Conclusion The 0.05% trans-resveratrol did not interact with warfarin in a mouse model, whereas 0.5% trans-resveratrol may have enhanced the Anticoagulant Activity of warfarin.
Tsuyoshi Chiba - One of the best experts on this subject based on the ideXlab platform.
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Trans-Resveratrol Enhances the Anticoagulant Activity of Warfarin in a Mouse Model
Journal of atherosclerosis and thrombosis, 2016Co-Authors: Tsuyoshi Chiba, Yuka Kimura, Sachina Suzuki, Tomoki Tatefuji, Keizo UmegakiAbstract:Resveratrol is a popular ingredient in dietary supplements. Some patients concomitantly use dietary supplements and medicines in Japan. In the present study, we determined whether trans-resveratrol and melinjo (Gnetum gnemon L.) seed extract (MSE), which contains resveratrol dimers, interacted with drugs using a mouse model. Male C57BL/6J mice were fed experimental diets containing 0.005%, 0.05%, or 0.5% (w/w) trans-resveratrol or MSE for 1 or 12 weeks. The expression of liver cytochrome P-450 (CYP) mRNA and Activity of liver microsomal CYP were measured. To determine the influence of resveratrol or MSE on drug efficacy, the Anticoagulant Activity of warfarin was examined in mice that were fed diets containing trans-resveratrol or MSE for 12 weeks. When the mice were fed experimental diets for 1 week, none of the doses of trans-resveratrol and MSE affected body weight, liver weight, or plasma AST and ALT levels. Trans-resveratrol also did not affect CYP1A1, CYP1A2, CYP2C, or CYP3A activities. In contrast, 0.5% MSE slightly increased CYP1A1 Activity. When the mice were fed experimental diets for 12 weeks, 0.05% trans-resveratrol increased CYP1A1, CYP2C, and CYP3A activities, whereas 0.5% MSE suppressed CYP3A Activity. Under these conditions, 0.5% trans-resveratrol enhanced the Anticoagulant Activity of warfarin, although CYP2C Activity increased. However, MSE did not affect the Anticoagulant Activity of warfarin. The 0.05% trans-resveratrol did not interact with warfarin in a mouse model, whereas 0.5% trans-resveratrol may have enhanced the Anticoagulant Activity of warfarin.
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Trans-Resveratrol Enhances the Anticoagulant Activity of Warfarin in a Mouse Model
Journal of atherosclerosis and thrombosis, 2016Co-Authors: Tsuyoshi Chiba, Yuka Kimura, Sachina Suzuki, Tomoki Tatefuji, Keizo UmegakiAbstract:Aim Resveratrol is a popular ingredient in dietary supplements. Some patients concomitantly use dietary supplements and medicines in Japan. In the present study, we determined whether trans-resveratrol and melinjo (Gnetum gnemon L.) seed extract (MSE), which contains resveratrol dimers, interacted with drugs using a mouse model. Methods Male C57BL/6J mice were fed experimental diets containing 0.005%, 0.05%, or 0.5% (w/w) trans-resveratrol or MSE for 1 or 12 weeks. The expression of liver cytochrome P-450 (CYP) mRNA and Activity of liver microsomal CYP were measured. To determine the influence of resveratrol or MSE on drug efficacy, the Anticoagulant Activity of warfarin was examined in mice that were fed diets containing trans-resveratrol or MSE for 12 weeks. Results When the mice were fed experimental diets for 1 week, none of the doses of trans-resveratrol and MSE affected body weight, liver weight, or plasma AST and ALT levels. Trans-resveratrol also did not affect CYP1A1, CYP1A2, CYP2C, or CYP3A activities. In contrast, 0.5% MSE slightly increased CYP1A1 Activity. When the mice were fed experimental diets for 12 weeks, 0.05% trans-resveratrol increased CYP1A1, CYP2C, and CYP3A activities, whereas 0.5% MSE suppressed CYP3A Activity. Under these conditions, 0.5% trans-resveratrol enhanced the Anticoagulant Activity of warfarin, although CYP2C Activity increased. However, MSE did not affect the Anticoagulant Activity of warfarin. Conclusion The 0.05% trans-resveratrol did not interact with warfarin in a mouse model, whereas 0.5% trans-resveratrol may have enhanced the Anticoagulant Activity of warfarin.
Lihong Fan - One of the best experts on this subject based on the ideXlab platform.
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Preparation and Anticoagulant Activity of N-succinyl chitosan sulfates.
International journal of biological macromolecules, 2012Co-Authors: Tan Wang, Yue Zhou, Weiguo Xie, Lingyun Chen, Hua Zheng, Lihong FanAbstract:In order to develop a promising substitute for heparin, N-succinyl chitosan (NSC) was chemically modified by sulfating agent N(SO(3)Na)(3), which were synthesized with sodium bisulfite and sodium nitrite in aqueous solution. The N-succinyl chitosan sulfates (NSCS) products were characterized by infrared spectroscopy (FT-IR) and (13)C NMR. The degree of substitution (DS) of NSCS depended on the ratio of sulfating agent to N-succinyl chitosan, reaction temperature, reaction time and pH of sulfation agent. N-succinyl chitosan sulfates with DS of 1.97 were obtained under optimal conditions. The in vitro coagulation assay of NSCS was determined by activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT) assays. The results showed that NSCS obviously prolonged APTT. The Anticoagulant Activity strongly depended on DS, molecular weight (M(w)) and concentration of NSCS. The Anticoagulant Activity of NSCS promoted with the increase of DS and concentration, and NSCS exhibited the best Anticoagulant Activity with the M(w) of 1.37×10(4).
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Synthesis, characterization, and Anticoagulant Activity of carboxymethyl starch sulfates
Journal of Applied Polymer Science, 2012Co-Authors: Lihong Fan, Yugui Gong, Mi Cao, Song Gao, Yi Sun, Lingyun Chen, Hua Zheng, Weiguo XieAbstract:To develop a renewable and compatible Anticoagulant as potential heparin alternative, carboxymethyl starch sulfate (CMSS) was prepared by the reaction of carboxymethyl starch (CMS) and sulfating reagent [N(SO3Na)3]. The chemical structures of CMS and CMSS were characterized by Fourier transform infrared spectroscopy and 13C nuclear magnetic resonance. The influences of reaction parameters, including the pH of sulfating reagent, the molar ratio of sulfating reagent to CMS, reaction time, and temperature on the degree of substitution of sulfate groups (DS) of CMSS were studied. Meantime, the DS of each CMSS was determined by barium sulfate–glutin nephelometery method. Moreover, the Anticoagulant Activity of CMSS was investigated by the coagulation assays of activated partial thromboplastin time, thrombin time, and prothrombin time. The results revealed that the Anticoagulant Activity of CMSS was closely related to the DS value and concentration. The Anticoagulant Activity was promoted with the increasing of the DS and concentration. The molecular weight (Mw) in measured range had little impact on Anticoagulant Activity in contract to the DS and concentration. In this article, the CMSS with the DS of 1.91, concentration of 75 μg/mL and the Mw of 2.61 × 104 had the best blood Anticoagulant activities. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013
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Synthesis and Anticoagulant Activity of sodium alginate sulfates
Carbohydrate Polymers, 2011Co-Authors: Lihong Fan, Lan Jiang, Yue Zhou, Yuan Shen, Weiguo Xie, Zhong-heng Long, Jinping ZhouAbstract:Abstract Sodium alginate sulfates prepared from sodium alginate through reaction with an uncommon sulfating agent (N (SO 3 Na) 3 ) which was synthesized by sodium bisulfite and sodium nitrite in aqueous solution. The factors that could affect the degree of substitution (DS) of sodium alginate sulfates were investigated in detail. A sodium alginate sulfate with DS of 1.87 was obtained under optimal conditions. The structures of the derivatives were characterized by FTIR and 13 C NMR. FTIR spectra showed the characteristic absorptions of sulfate ester bonds at 1249 cm −1 and 873 cm −1 . The in vitro coagulation assay of human plasma containing the sodium alginate sulfates was determined with respect to activated partial thromboplastin time (APTT), thrombin time (TT) and prothombin time (PT). These activities strongly depended on the DS, molecular weight ( M w ) and the concentration of sodium alginate sulfates. The introduction of sulfate groups to hydroxyl groups greatly prolonged the APTT and TT. Low S% and concentration sodium alginate sulfates showed little Anticoagulant Activity. The high DS and concentration could inhibit the Activity of IIa and Xa to prolong APTT and TT. The low molecular weight resulted in higher anti-factor Xa Activity to promote Anticoagulant Activity. Generally, the introducing of sulfate groups could not increase PT, it had little effect on coagulation factors in the extrinsic pathway.
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influence of functional groups on the in vitro Anticoagulant Activity of chitosan sulfate
Carbohydrate Research, 2003Co-Authors: Ronghua Huang, Jianhong Yang, Lihong FanAbstract:A new method for the chemical modification of chitosan sulfate was used to prepare N-propanoyl-, N-hexanoyl- and N,O-quaternary substituted chitosan sulfate. Structural analysis by elemental analysis, FTIR, 13C NMR, and 1H NMR spectroscopy, and gel-permeation chromatography showed that these methods could conveniently be used for the introduction of functional groups. The influences of the acyl or quaternary groups on the Anticoagulant Activity of the polysaccharides were studied with respect to activated partial thromboplastin time (APTT) thrombin time (TT), and prothrombin time (PT). The propanoyl and hexanoyl groups increased the APTT Activity, and the propanoyl groups also increased the TT Anticoagulant Activity slightly, while the N,O-quaternary chitosan sulfate showed only a slight TT coagulant Activity.
Sachina Suzuki - One of the best experts on this subject based on the ideXlab platform.
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Trans-Resveratrol Enhances the Anticoagulant Activity of Warfarin in a Mouse Model
Journal of atherosclerosis and thrombosis, 2016Co-Authors: Tsuyoshi Chiba, Yuka Kimura, Sachina Suzuki, Tomoki Tatefuji, Keizo UmegakiAbstract:Resveratrol is a popular ingredient in dietary supplements. Some patients concomitantly use dietary supplements and medicines in Japan. In the present study, we determined whether trans-resveratrol and melinjo (Gnetum gnemon L.) seed extract (MSE), which contains resveratrol dimers, interacted with drugs using a mouse model. Male C57BL/6J mice were fed experimental diets containing 0.005%, 0.05%, or 0.5% (w/w) trans-resveratrol or MSE for 1 or 12 weeks. The expression of liver cytochrome P-450 (CYP) mRNA and Activity of liver microsomal CYP were measured. To determine the influence of resveratrol or MSE on drug efficacy, the Anticoagulant Activity of warfarin was examined in mice that were fed diets containing trans-resveratrol or MSE for 12 weeks. When the mice were fed experimental diets for 1 week, none of the doses of trans-resveratrol and MSE affected body weight, liver weight, or plasma AST and ALT levels. Trans-resveratrol also did not affect CYP1A1, CYP1A2, CYP2C, or CYP3A activities. In contrast, 0.5% MSE slightly increased CYP1A1 Activity. When the mice were fed experimental diets for 12 weeks, 0.05% trans-resveratrol increased CYP1A1, CYP2C, and CYP3A activities, whereas 0.5% MSE suppressed CYP3A Activity. Under these conditions, 0.5% trans-resveratrol enhanced the Anticoagulant Activity of warfarin, although CYP2C Activity increased. However, MSE did not affect the Anticoagulant Activity of warfarin. The 0.05% trans-resveratrol did not interact with warfarin in a mouse model, whereas 0.5% trans-resveratrol may have enhanced the Anticoagulant Activity of warfarin.
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Trans-Resveratrol Enhances the Anticoagulant Activity of Warfarin in a Mouse Model
Journal of atherosclerosis and thrombosis, 2016Co-Authors: Tsuyoshi Chiba, Yuka Kimura, Sachina Suzuki, Tomoki Tatefuji, Keizo UmegakiAbstract:Aim Resveratrol is a popular ingredient in dietary supplements. Some patients concomitantly use dietary supplements and medicines in Japan. In the present study, we determined whether trans-resveratrol and melinjo (Gnetum gnemon L.) seed extract (MSE), which contains resveratrol dimers, interacted with drugs using a mouse model. Methods Male C57BL/6J mice were fed experimental diets containing 0.005%, 0.05%, or 0.5% (w/w) trans-resveratrol or MSE for 1 or 12 weeks. The expression of liver cytochrome P-450 (CYP) mRNA and Activity of liver microsomal CYP were measured. To determine the influence of resveratrol or MSE on drug efficacy, the Anticoagulant Activity of warfarin was examined in mice that were fed diets containing trans-resveratrol or MSE for 12 weeks. Results When the mice were fed experimental diets for 1 week, none of the doses of trans-resveratrol and MSE affected body weight, liver weight, or plasma AST and ALT levels. Trans-resveratrol also did not affect CYP1A1, CYP1A2, CYP2C, or CYP3A activities. In contrast, 0.5% MSE slightly increased CYP1A1 Activity. When the mice were fed experimental diets for 12 weeks, 0.05% trans-resveratrol increased CYP1A1, CYP2C, and CYP3A activities, whereas 0.5% MSE suppressed CYP3A Activity. Under these conditions, 0.5% trans-resveratrol enhanced the Anticoagulant Activity of warfarin, although CYP2C Activity increased. However, MSE did not affect the Anticoagulant Activity of warfarin. Conclusion The 0.05% trans-resveratrol did not interact with warfarin in a mouse model, whereas 0.5% trans-resveratrol may have enhanced the Anticoagulant Activity of warfarin.