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Hans Deckmyn - One of the best experts on this subject based on the ideXlab platform.
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identification of a small molecule that modulates platelet glycoprotein ib von willebrand Factor Interaction
Journal of Biological Chemistry, 2012Co-Authors: Katleen Broos, Mieke Trekels, Rani Alphonsa Jose, Jonas Demeulemeester, Aline Vandenbulcke, Nele Vandeputte, Tom Venken, Brecht Egle, Wim M De Borggraeve, Hans DeckmynAbstract:The von Willebrand Factor (VWF) A1-glycoprotein (GP) Ibα Interaction is of major importance during thrombosis mainly at sites of high shear stress. Inhibitors of this Interaction prevent platelet-dependent thrombus formation in vivo, without major bleeding complications. However, the size and/or protein nature of the inhibitors currently in development limit oral bioavailability and clinical development. We therefore aimed to search for a small molecule protein-protein Interaction inhibitor interfering with the VWF-GPIbα binding. After determination of putative small molecule binding pockets on the surface of VWF-A1 and GPIbα using site-finding algorithms and molecular dynamics, high throughput molecular docking was performed on both binding partners. A selection of compounds showing good in silico docking scores into the predicted pockets was retained for testing their in vitro effect on VWF-GPIbα complex formation, by which we identified a compound that surprisingly stimulated the VWF-GPIbα binding in a ristocetin coFactor ELISA and increased platelet adhesion in whole blood to collagen under arterial shear rate but in contrast inhibited ristocetin-induced platelet aggregation. The selected compound adhering to the predicted binding partner GPIbα could be confirmed by saturation transfer difference NMR spectroscopy. We thus clearly identified a small molecule that modulates VWF-GPIbα binding and that will now serve as a starting point for further studies and chemical modifications to fully characterize the Interaction and to manipulate specific activity of the compound.
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characterization of murine anti glycoprotein ib monoclonal antibodies that differentiate between shear induced and ristocetin botrocetin induced glycoprotein ib von willebrand Factor Interaction
Haemostasis, 2000Co-Authors: Nancy Cauwenberghs, Dominique Baruch, Nadine Ajzenberg, S Vauterin, Marc Hoylaerts, Paul Declerck, Hans DeckmynAbstract:Platelet adhesion to vascular subendothelium under conditions of high shear stress is mediated by the platelet glycoprotein (GP) Ib-von Willebrand Factor (vWF) Interaction. The aim of this study was to characterize the murine monoclonal antibodies (MoAbs) 27A10 and 28E6, both raised against purified GPIb. The MoAb 27A10 is a potent inhibitor of shear-induced platelet adhesion to collagen type I in a flow chamber at shear rates of 1,300 and 2,700 s–1. 20 μg/ml of MoAb 27A10, furthermore, could completely block shear-induced aggregation in a modified Couette viscometer at shear rates of 1,000 and 4,000 s–1. On the other hand, MoAb 27A10 had a negligible effect on botrocetin-induced GPIb-vWF binding and is only a poor inhibitor of the ristocetin-dependent Interaction. In contrast, MoAb 28E6 did abolish both the ristocetin- and botrocetin-induced GPIb-vWF binding, whereas it did not block the shear-induced Interaction. Thus, we identify here two anti-GPIb MoAbs 27A10 and 28E6 that either preferentially inhibit the shear-induced or the ristocetin/botrocetin-induced platelet-vWF Interaction. With these tools it should be possible to more clearly define the mechanisms by which platelets bind to vWF in vivo.
Leonard I. Garfinkel - One of the best experts on this subject based on the ideXlab platform.
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A monomeric von Willebrand Factor fragment, Leu-504--Lys-728, inhibits von Willebrand Factor Interaction with glycoprotein Ib-IX [corrected].
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: Harvey R Gralnick, Laurie P. Mckeown, Sybil B. Williams, Henry C. Krutzsch, Amon Pinet, Wendy Kramer, Marian Gorecki, Leonard I. GarfinkelAbstract:Abstract von Willebrand Factor Interaction with glycoprotein Ib alpha (GPIb alpha) plays a critical role in the initial phase of platelet adhesion at high shear rates, and it may also play a role in platelet thrombus formation in partially occluded arteries. Previous studies have indicated that two peptides, Cys-474--Pro-488 (peptide 153) and Ser-692--Pro-708 (peptide 154), inhibit von Willebrand Factor--GPIb alpha Interaction. We have expressed a recombinant fragment of von Willebrand Factor, Leu-504--Lys-728 [corrected], with a single intrachain disulfide bond linking residues Cys-509--Cys-695 and examined its ability to inhibit von Willebrand Factor--GPIb alpha Interactions and platelet adhesion at high shear forces. This recombinant fragment, named VCL, inhibits ristocetin-induced, botrocetin-induced, and asialo-von Willebrand Factor-induced platelet aggregation and binding to platelets at an IC50 = 0.011-0.260 microM, significantly lower than the IC50 of peptide 153 or 154, IC50 = 86-700 microM. Peptides 153 and 154 did not result in any inhibition of platelet adhesion (IC50 greater than 500 microM). In contrast, VCL inhibited 50% of platelet adhesion at 0.94 microM and at 7.6 microM inhibited greater than 80% of platelet adhesion to human umbilical artery subendothelium at high shear forces. VCL inhibited the contact and spreading of platelets and also caused a marked decrease in thrombus formation. These studies indicate that VCL may be an effective antithrombotic agent in preventing arterial thrombus formation in areas of high shear force.
Yuandong Peng - One of the best experts on this subject based on the ideXlab platform.
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platelet glycoprotein ibβ ix mediates glycoprotein ibα localization to membrane lipid domain critical for von willebrand Factor Interaction at high shear
Journal of Biological Chemistry, 2011Co-Authors: Hongquan Geng, Jose A Lopez, Yali Ran, Yuandong PengAbstract:The localization of the platelet glycoprotein GP Ib-IX complex (GP Ibα, GP Ibβ, and GP IX) to membrane lipid domain, also known as glycosphingolipid-enriched membranes (GEMs or raft) lipid domain, is essential for the GP Ib-IX complex mediated platelet adhesion to von Willebrand Factor (vWf) and subsequent platelet activation. To date, the mechanism for the complex association with the GEMs remains unclear. Although the palmitate modifications of GP Ibβ and GP IX were thought to be critical for the complex presence in the GEMs, we found that the removal of the putative palmitoylation sites of GP Ibβ and GP IX had no effects on the localization of the GP Ib-IX complex to the GEMs. Instead, the disruption of GP Ibα disulfide linkage with GP Ibβ markedly decreased the amount of the GEM-associated GP Ibα without altering the GEM association of GP Ibβ and GP IX. Furthermore, partial dissociation with the GEMs greatly inhibited GP Ibα Interaction with vWf at high shear instead of in static condition or under low shear stress. Thus, for the first time, we demonstrated that GP Ibβ/GP IX mediates the disulfide-linked GP Ibα localization to the GEMs, which is critical for vWf Interaction at high shear.
B H Hameed - One of the best experts on this subject based on the ideXlab platform.
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effect of preparation conditions of oil palm fronds activated carbon on adsorption of bentazon from aqueous solutions
Journal of Hazardous Materials, 2010Co-Authors: J M Salman, B H HameedAbstract:Oil palm fronds (OPF) were used to prepare activated carbon (PFAC) using physiochemical activation method, which consisted of potassium hydroxide (KOH) treatment and carbon dioxide gasification. The effects of the preparation variables, which were activation temperature, activation time and chemical impregnation ratios (KOH: char by weight), on the carbon yield and bentazon removal were investigated. Based on the central composite design (CCD), two Factor Interaction (2FI) and quadratic models were, respectively, employed to correlate the PFAC preparation variables to the bentazon removal and carbon yield. From the analysis of variance (ANOVA), the most influential Factor on each experimental design response was identified. The optimum conditions for preparing activated carbon from OPF were found as follows: activation temperature of 850 °C, activation time of 1 h and KOH:char ratio of 3.75:1. The predicted and experimental results for removal of bentazon and yield of PFAC were 99.85%, 20.5 and 98.1%, 21.6%, respectively.
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optimization of basic dye removal by oil palm fibre based activated carbon using response surface methodology
Journal of Hazardous Materials, 2008Co-Authors: B H Hameed, I A W Tan, A L AhmadAbstract:Abstract Oil palm fibre was used to prepare activated carbon using physiochemical activation method which consisted of potassium hydroxide (KOH) treatment and carbon dioxide (CO2) gasification. The effects of three preparation variables: the activation temperature, activation time and chemical impregnation (KOH:char) ratio on methylene blue (MB) uptake from aqueous solutions and activated carbon yield were investigated. Based on the central composite design (CCD), a quadratic model and a two Factor Interaction (2FI) model were respectively developed to correlate the preparation variables to the MB uptake and carbon yield. From the analysis of variance (ANOVA), the significant Factors on each experimental design response were identified. The optimum activated carbon prepared from oil palm fibre was obtained by using activation temperature of 862 °C, activation time of 1 h and chemical impregnation ratio of 3.1. The optimum activated carbon showed MB uptake of 203.83 mg/g and activated carbon yield of 16.50%. The equilibrium data for adsorption of MB on the optimum activated carbon were well represented by the Langmuir isotherm, giving maximum monolayer adsorption capacity as high as 400 mg/g at 30 °C.
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optimization of preparation conditions for activated carbons from coconut husk using response surface methodology
Chemical Engineering Journal, 2008Co-Authors: I A W Tan, A L Ahmad, B H HameedAbstract:Abstract Coconut husk was used to prepare activated carbon using physiochemical activation method, consisted of potassium hydroxide (KOH) treatment and carbon dioxide (CO 2 ) gasification. The effects of the preparation variables which were activation temperature, activation time and chemical impregnation (KOH:char) ratio on the adsorption capacity on methylene blue dye and carbon yield were investigated. Based on the central composite design (CCD), a two Factor Interaction (2FI) model and a quadratic model were respectively developed to correlate the preparation variables to the adsorption capacity and yield. From the analysis of variance (ANOVA), the most influential Factor on each experimental design response was identified. The predicted adsorption capacity and yield after process optimization was found to agree satisFactory with the experimental values. The optimum conditions for preparing activated carbon from coconut husk were found as follows: activation temperature of 816 °C, activation time of 1 h and KOH:char ratio of 3.9.
Michael C Berndt - One of the best experts on this subject based on the ideXlab platform.
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regulation of glycoprotein ib ix von willebrand Factor Interaction by camp dependent protein kinase mediated phosphorylation at ser 166 of glycoprotein ibβ
Journal of Biological Chemistry, 2002Co-Authors: Richard Bodnar, Michael C BerndtAbstract:The platelet receptor for von Willebrand Factor (VWF), glycoprotein (GP) Ib-IX, mediates initial platelet adhesion and activation. It is known that the cytoplasmic domain of GPIbbeta is phosphorylated at Ser(166) by cAMP-dependent protein kinase (PKA). To understand the physiological role of GPIbbeta phosphorylation, a GPIb-IX mutant replacing Ser(166) of GPIbbeta with alanine (S166A) and a deletion mutant lacking residues 166-181 of GPIbbeta (Delta165) were constructed. These mutants, expressed in Chinese hamster ovary (CHO) cells, showed an enhanced VWF-binding function compared with wild type GPIb-IX. Treatment of CHO cells expressing wild type GPIb-IX with a PKA inhibitor, PKI, reduced Ser(166) phosphorylation and also enhanced VWF binding to GPIb-IX. Furthermore, cells expressing S166A or Delta165 mutants showed a significantly enhanced adhesion to immobilized VWF under flow conditions. Consistent with the studies in CHO cells, treatment of platelets with PKI enhanced VWF binding to platelets. In contrast, a PKA stimulator, forskolin, reduced VWF binding and VWF-induced platelet agglutination, which was reversed by PKI. Thus, PKA-mediated phosphorylation of GPIbbeta at Ser(166) negatively regulates VWF binding to GPIb-IX and is one of the mechanisms by which PKA mediates platelet inhibition.
