24 research outputs found
An improved method for the determination of S-Carboxymethyl-L-cysteine in biological fluids with precolumn derivatization and on-line clean-up
Alfuzosin: A Comparison of the Steady-State Pharmacokinetics of Two Dosages in Middle-Aged and Elderly Healthy Male Volunteers
Rapid and Sensitive LC–MS–MS Method for the Simultaneous Estimation of Alfuzosin and Dutasteride in Human Plasma
An Improved Narrow-Bore LC Method for Quantification of Alfuzosin in Pharmaceutical Formulations
Development and Evaluation of Compression Coating Gastro-Floating Tablet of Alfuzosin Hydrochloride for Zero-Order Controlled Release
Eliminating Solid Phase Extraction with Large-Volume Injection LC/MS/MS: Analysis of Illicit and Legal Drugs and Human Urine Indicators in US Wastewaters
Phosphoinositide 3-Kinase p110β Regulates Integrin αIIbβ3 Avidity and the Cellular Transmission of Contractile Forces*
Phosphoinositide (PI) 3-kinase (PI3K) signaling processes play an important role in regulating the adhesive function of integrin αIIbβ3, necessary for platelet spreading and sustained platelet aggregation. PI3K inhibitors are effective at reducing platelet aggregation and thrombus formation in vivo and as a consequence are currently being evaluated as novel antithrombotic agents. PI3K regulation of integrin αIIbβ3 activation (affinity modulation) primarily occurs downstream of Gi-coupled and tyrosine kinase-linked receptors linked to the activation of Rap1b, AKT, and phospholipase C. In the present study, we demonstrate an important role for PI3Ks in regulating the avidity (strength of adhesion) of high affinity integrin αIIbβ3 bonds, necessary for the cellular transmission of contractile forces. Using knock-out mouse models and isoform-selective PI3K inhibitors, we demonstrate that the Type Ia p110β isoform plays a major role in regulating thrombin-stimulated fibrin clot retraction in vitro. Reduced clot retraction induced by PI3K inhibitors was not associated with defects in integrin αIIbβ3 activation, actin polymerization, or actomyosin contractility but was associated with a defect in integrin αIIbβ3 association with the contractile cytoskeleton. Analysis of integrin αIIbβ3 adhesion contacts using total internal reflection fluorescence microscopy revealed an important role for PI3Ks in regulating the stability of high affinity integrin αIIbβ3 bonds. These studies demonstrate an important role for PI3K p110β in regulating the avidity of high affinity integrin αIIbβ3 receptors, necessary for the cellular transmission of contractile forces. These findings may provide new insight into the potential antithrombotic properties of PI3K p110β inhibitors