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Platelet integrin

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https://www.readbyqxmd.com/read/28819447/targeting-activated-platelets-a-unique-and-potentially-universal-approach-for-cancer-imaging
#1
May Lin Yap, James D McFadyen, Xiaowei Wang, Nicholas A Zia, Jan David Hohmann, Melanie Ziegler, Yu Yao, Alan Pham, Matthew Harris, Paul S Donnelly, P Mark Hogarth, Geoffrey A Pietersz, Bock Lim, Karlheinz Peter
Rationale The early detection of primary tumours and metastatic disease is vital for successful therapy and is contingent upon highly specific molecular markers and sensitive, non-invasive imaging techniques. We hypothesized that the accumulation of activated platelets within tumours is a general phenomenon and thus represents a novel means for the molecular imaging of cancer. Here we investigate a unique single chain antibody (scFv), which specifically targets activated platelets, as a novel biotechnological tool for molecular imaging of cancer...
2017: Theranostics
https://www.readbyqxmd.com/read/28815933/an-%C3%AE-iib-%C3%AE-3-antagonist-prevents-thrombosis-without-causing-fc%C3%AE-riia-mediated-thrombocytopenia
#2
Yu-Ju Kuo, Ying-Ru Chen, Chun-Chieh Hsu, Hui-Chin Peng, Tur-Fu Huang
BACKGROUND: Thrombocytopenia, a common side effect of Arg-Gly-Asp (RGD)-mimetic antiplatelet drugs, is associated with drug-dependent antibodies (DDAbs) that recognize conformation-altered integrin αIIb β3 . OBJECTIVE: To explore the correlation between αIIb β3 binding epitopes and induction of DDAb binding to conformation-altered αIIb β3 , we examined whether two purified disintegrins TMV-2 and TMV-7 with distinct binding motifs that have different effects on induction of αIIb β3 conformational change and platelet aggregation in the presence of AP2, an IgG1 inhibitory monoclonal antibody (mAb) raised against αIIb β3 ...
August 16, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28808266/in-silico-analysis-of-glanzmann-variants-of-calf-1-domain-of-%C3%AE-iib%C3%AE-3-integrin-revealed-dynamic-allosteric-effect
#3
Matthieu Goguet, Tarun Jairaj Narwani, Rachel Petermann, Vincent Jallu, Alexandre G de Brevern
Integrin αIIbβ3 mediates platelet aggregation and thrombus formation. In a rare hereditary bleeding disorder, Glanzmann thrombasthenia (GT), αIIbβ3 expression / function are impaired. The impact of deleterious missense mutations on the complex structure remains unclear. Long independent molecular dynamics (MD) simulations were performed for 7 GT variants and reference structure of the Calf-1 domain of αIIb. Simulations were analysed using a structural alphabet to describe local protein conformations. Common and flexible regions as well as deformable zones were observed in all the structures...
August 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28799653/kindlin-2-interacts-with-endothelial-adherens-junctions-to-support-vascular-barrier-integrity
#4
Elzbieta Pluskota, Kamila M Bledzka, Katarzyna Bialkowska, Dorota Szpak, Dmitry A Soloviev, Sidney Jones, Dmitriy Verbovetskiy, Edward F Plow
Endothelial cells (EC) establish a physical barrier between the blood and surrounding tissue. Impairment of this barrier can occur during inflammation, ischemia or sepsis and cause severe organ dysfunction. Kindlin-2, primarily recognized as a focal adhesion protein in EC, was not anticipated to have a role in vascular barrier. We tested the role of Kindlin-2 in regulating vascular integrity using several different approaches to decrease Kindlin-2 levels in EC. Reduced levels of Kindlin-2 in Kindlin-2(+/-) mice, aortic endothelial cells (MAECs) from these(-) mice, and human umbilical ECs (HUVEC) treated with Kindlin-2 siRNA showed enhanced basal and Platelet Activating Factor (PAF) or lipopolysaccharide-stimulated vascular leakage compared to wild-type (WT) counterparts...
August 11, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28794070/integrin-%C3%AE-iib%C3%AE-3-outside-in-signaling
#5
Tom N Durrant, Marion T van den Bosch, Ingeborg Hers
Integrin αIIbβ3 is a highly abundant heterodimeric platelet receptor that can transmit information bidirectionally across the plasma membrane, and plays a critical role in hemostasis and thrombosis. Upon platelet activation, inside-out signaling pathways increase the affinity of αIIbβ3 for fibrinogen and other ligands. Ligand binding and integrin clustering subsequently stimulate outside-in signaling, which initiates and amplifies a range of cellular events driving essential platelet processes such as spreading, thrombus consolidation and clot retraction...
August 9, 2017: Blood
https://www.readbyqxmd.com/read/28790378/hypoxia-impairs-agonist-induced-integrin-%C3%AE-iib%C3%AE-3-activation-and-platelet-aggregation
#6
Klytaimnistra Kiouptsi, Stepan Gambaryan, Elena Walter, Ulrich Walter, Kerstin Jurk, Christoph Reinhardt
Under ischemic conditions, tissues are exposed to hypoxia. Although human physiology, to a certain extent, can adapt to hypoxic conditions, the impact of low oxygen levels on platelet function is unresolved. Therefore, we explored how reduction of atmospheric oxygen levels to 1% might affect agonist-induced aggregation and static adhesion of isolated human platelets. We uncovered that isolated, washed human platelets exposed to hypoxic conditions show reduced thrombin receptor-activating peptide-6 (TRAP-6) and convulxin-induced aggregation...
August 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28783171/the-pdgfr%C3%AE-laminin-b1-keratin-19-cascade-drives-tumor-progression-at-the-invasive-front-of-human-hepatocellular-carcinoma
#7
O Govaere, M Petz, J Wouters, Y-P Vandewynckel, E J Scott, B Topal, F Nevens, C Verslype, Q M Anstee, H Van Vlierberghe, W Mikulits, T Roskams
Human hepatocellular carcinomas (HCCs) expressing the biliary/hepatic progenitor cell marker keratin 19 (K19) have been linked with a poor prognosis and exhibit an increase in platelet-derived growth factor receptor α (PDGFRα) and laminin beta 1 (LAMB1) expression. PDGFRα has been reported to induce de novo synthesis of LAMB1 protein in a Sjogren syndrome antigen B (La/SSB)-dependent manner in a murine metastasis model. However, the role of this cascade in human HCC remains unclear. This study focused on the functional role of the PDGFRα-La/SSB-LAMB1 pathway and its molecular link to K19 expression in human HCC...
August 7, 2017: Oncogene
https://www.readbyqxmd.com/read/28775078/tlr2-plays-a-key-role-in-platelet-hyperreactivity-and-accelerated-thrombosis-associated-with-hyperlipidemia
#8
Sudipta Biswas, Alejandro Zimman, Detao Gao, Tatiana Byzova, Eugene Podrez
Rationale: Platelet hyperreactivity, which is common in many pathological conditions, is associated with increased atherothrombotic risk. The mechanisms leading to platelet hyperreactivity are complex and not yet fully understood. Objective: Platelet hyperreactivity and accelerated thrombosis, specifically in dyslipidemia, have been mechanistically linked to accumulation in the circulation of a specific group of oxidized phospholipids (oxPCCD36) that are ligands for the platelet pattern-recognition receptor CD36...
August 3, 2017: Circulation Research
https://www.readbyqxmd.com/read/28762304/identification-of-two-novel-mutations-in-rasgrp2-affecting-platelet-caldag-gefi-expression-and-function-in-patients-with-bleeding-diathesis
#9
Teresa Sevivas, José María Bastida, David S Paul, Eva Caparros, Verónica Palma-Barqueros, Margarida Coucelo, Dalila Marques, Francisca Ferrer-Marín, José Ramón González-Porras, Vicente Vicente, Jesús María Hernández-Rivas, Steve P Watson, María Luisa Lozano, Wolfgang Bergmeier, José Rivera
The RASGRP2 gene encodes the Ca(2+) and DAG-regulated guanine nucleotide exchange factor I (CalDAG-GEFI), which plays a key role in integrin activation in platelets and neutrophils. We here report two new RASGRP2 variants associated with platelet dysfunction and bleeding in patients. The homozygous patients had normal platelet and neutrophil counts and morphology. Platelet phenotyping showed: prolonged PFA-100 closure times; normal expression of major glycoprotein receptors; severely reduced platelet aggregation response to ADP and collagen (both patients); aggregation response to PAR1 and arachidonic acid markedly impaired in one patient; PMA-induced aggregation unaffected; platelet secretion, clot retraction, and spreading minimally affected...
August 1, 2017: Platelets
https://www.readbyqxmd.com/read/28760385/platelet-factor-xi-intracellular-localization-and-mrna-splicing-following-platelet-activation
#10
M Zucker, H Hauschner, U Seligsohn, N Rosenberg
BACKGROUND: The structure and function of platelet factor XI (FXI) protein and the presence of F11 mRNA in platelets are controversial. Although platelets are anucleated cells they contain spliceosome components and pre-mRNAs. Three platelet proteins have been demonstrated to be spliced upon platelet activation. OBJECTIVE: To determine whether FXI is also spliced upon activation and to discern the localization of FXI in platelets. METHODS: Localization of FXI in platelets was assessed by confocal immunofluorescence staining...
April 21, 2017: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/28746873/deletion-of-glut1-and-glut3-reveals-multiple-roles-for-glucose-metabolism-in-platelet-and-megakaryocyte-function
#11
Trevor P Fidler, Robert A Campbell, Trevor Funari, Nicholas Dunne, Enrique Balderas Angeles, Elizabeth A Middleton, Dipayan Chaudhuri, Andrew S Weyrch, E Dale Abel
Anucleate platelets circulate in the blood to facilitate thrombosis and diverse immune functions. Platelet activation leading to clot formation correlates with increased glycogenolysis, glucose uptake, glucose oxidation, and lactic acid production. Simultaneous deletion of glucose transporter (GLUT) 1 and GLUT3 (double knockout [DKO]) specifically in platelets completely abolished glucose uptake. In DKO platelets, mitochondrial oxidative metabolism of non-glycolytic substrates, such as glutamate, increased...
July 25, 2017: Cell Reports
https://www.readbyqxmd.com/read/28744026/integrin-%C3%AE-3-akt-signaling-contributes-to-platelet-induced-hemangioendothelioma-growth
#12
Rui Gu, Xin Sun, Yijie Chi, Qishuang Zhou, Hongkai Xiang, Dale B Bosco, Xinhe Lai, Caixia Qin, Kwok-Fai So, Yi Ren, Xiao-Ming Chen
Hemangioendothelioma (HE) is a type of angiomatous lesions that features endothelial cell proliferation. Understanding the mechanisms orchestrating HE angiogenesis can provide therapeutic insights. It has been shown that platelets can support normal and malignant endothelial cells during angiogenesis. Using the mouse endothelial-derived EOMA cell line as a model of HE, we explored the regulatory effect of platelets. We found that platelets stimulated EOMA proliferation but did not mitigate apoptosis. Furthermore, direct platelet-EOMA cell contact was required and the proliferation was mediated via integrin β3/Akt signaling in EOMA cells...
July 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28743718/twinfilin-2a-is-a-regulator-of-platelet-reactivity-and-turnover-in-mice
#13
Simon Stritt, Sarah Beck, Isabelle C Becker, Timo Vögtle, Markku Hakala, Katrin G Heinze, Xiaoping Du, Markus Bender, Attila Braun, Pekka Lappalainen, Bernhard Nieswandt
Regulated reorganization of the actin cytoskeleton is a prerequisite for proper platelet production and function. Consequently, defects in proteins controlling actin dynamics have been associated with platelet disorders in humans and mice. Twinfilin 2a (Twf2a) is a small actin-binding protein, which inhibits actin filament assembly by sequestering actin monomers and by capping filament barbed ends. Moreover, Twf2a binds heterodimeric capping proteins, but the role of this interaction in cytoskeletal dynamics has remained elusive...
July 25, 2017: Blood
https://www.readbyqxmd.com/read/28742189/novel-endogenous-negative-modulators-of-platelet-function-as-potential-anti-thrombotic-targets
#14
Y-J Li, H-X Zhu, D Zhang, H-C Li, P Ma, L-Y Huang
Platelets are megakaryocyte-derived nuclear-free fragments that participate in cardiovascular diseases including acute myocardial infarction, ischemic stroke, hypertension, and atherosclerosis. At the endothelium damage site, platelets interact with sub-endothelial matrix proteins such as glycoprotein VI/Fc receptor γ-chain (GPVI/FcRγ), G protein-coupled receptor/phospholipase Cγ(β) (GPCR/PLCγ(β)), Rho/RhoK and integrin. The activation of these signaling pathways triggers intracellular calcium increase and causes platelet adhesion, aggregation, granule release and finally thrombus formation...
July 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28739088/trimucrin-an-arg-gly-asp-containing-disintegrin-attenuates-myocardial-ischemia-reperfusion-injury-in-murine-by-inhibiting-platelet-function
#15
Yu-Chun Hung, Yu-Ju Kuo, Shiang-Suo Huang, Tur-Fu Huang
Trimucrin, a novel small-mass Arg-Gly-Asp (RGD)-containing disintegrin, has been demonstrated to possess anti-platelet and anti-inflammatory effect through blockade of platelet αIIbβ3 and phagocyte αvβ3 integrin. In this study, we found that the platelet-rich plasma prepared from trimucrin-treated rats platelet aggregation was diminished in response to adenosine diphosphate (ADP). We tried to determine whether trimucrin is cardioprotective in rats subjected to myocardial ischemia-reperfusion (I-R) injury...
July 21, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28726538/marked-bleeding-diathesis-in-patients-with-platelet-dysfunction-due-to-a-novel-mutation-in-rasgrp2-encoding-caldag-gefi-p-gly305asp
#16
Emilse Bermejo, Maria F Alberto, David S Paul, Aaron A Cook, Paquita Nurden, Analia Sanchez Luceros, Alan T Nurden, Wolfgang Bergmeier
Congenital platelet function disorders are often the result of defects in critical signal transduction pathways required for platelet adhesion and clot formation. Mutations affecting RASGRP2, the gene encoding the Rap GTPase activator, CalDAG-GEFI, give rise to a novel, and rare, group of platelet signal transduction abnormalities. We here report platelet function studies for two brothers (P1 and P2) expressing a novel variant of RASGRP2, CalDAG-GEFI(p.Gly305Asp). P1 and P2 have a lifelong history of bleeding with severe epistaxis successfully treated with platelet transfusions or rFVIIa...
July 20, 2017: Platelets
https://www.readbyqxmd.com/read/28725968/microglial-mediated-pdgf-cc-activation-increases-cerebrovascular-permeability-during-ischemic-stroke
#17
Enming Joseph Su, Chunzhang Cao, Linda Fredriksson, Ingrid Nilsson, Christina Stefanitsch, Tamara K Stevenson, Juanjuan Zhao, Margret Ragsdale, Yu-Yo Sun, Manuel Yepes, Chia-Yi Kuan, Ulf Eriksson, Dudley K Strickland, Daniel A Lawrence, Li Zhang
Treatment of acute ischemic stroke with the thrombolytic tissue plasminogen activator (tPA) can significantly improve neurological outcomes; however, thrombolytic therapy is associated with an increased risk of intra-cerebral hemorrhage (ICH). Previously, we demonstrated that during stroke tPA acting on the parenchymal side of the neurovascular unit (NVU) can increase blood-brain barrier (BBB) permeability and ICH through activation of latent platelet-derived growth factor-CC (PDGF-CC) and signaling by the PDGF receptor-α (PDGFRα)...
July 19, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28717419/platelet-extracellular-vesicles-induce-a-pro-inflammatory-smooth-muscle-cell-phenotype
#18
Tanja Vajen, Birke J Benedikter, Alexandra C A Heinzmann, Elena M Vasina, Yvonne Henskens, Martin Parsons, Patricia B Maguire, Frank R Stassen, Johan W M Heemskerk, Leon J Schurgers, Rory R Koenen
Extracellular vesicles (EVs) are mediators of cell communication during health and disease, and abundantly released by platelets upon activation or during ageing. Platelet EVs exert modulatory effects on immune and vascular cells. Platelet EVs may modulate the function of vascular smooth muscle cells (SMC). Platelet EVs were isolated from platelet-rich plasma and incubated with SMC in order to assess binding, proliferation, migration and pro-inflammatory phenotype of the cells. Platelet EVs firmly bound to resting SMC through the platelet integrin αIIbβ3, while binding also occurred in a CX3CL1-CX3CR1-dependent manner after cytokine stimulation...
2017: Journal of Extracellular Vesicles
https://www.readbyqxmd.com/read/28714276/human-platelet-lysate-supports-the-formation-of-robust-human-periodontal-ligament-cell-sheets
#19
Bei-Min Tian, Rui-Xin Wu, Chun-Sheng Bi, Xiao-Tao He, Yuan Yin, Fa-Ming Chen
The use of stem cell-derived sheets has become increasingly common in a wide variety of biomedical applications. Although substantial evidence has demonstrated that human platelet lysate (PL) can be used for therapeutic cell expansion, either as a substitute for or as a supplement to xenogeneic fetal bovine serum (FBS), its impact on cell sheet production remains largely unexplored. In this study, we manufactured periodontal ligament stem cell (PDLSC) sheets in vitro by incubating PDLSCs in sheet-induction media supplemented with various ratios of PL and FBS, i...
July 17, 2017: Journal of Tissue Engineering and Regenerative Medicine
https://www.readbyqxmd.com/read/28711718/phospholipase-d1-is-a-regulator-of-platelet-mediated-inflammation
#20
Meike Klier, Nina Sarah Gowert, Sven Jäckel, Christoph Reinhardt, Margitta Elvers
Glycoprotein (GP)Ib is not only required for stable thrombus formation but for platelet-mediated inflammatory responses. Phospholipase (PL)D1 is essential for GPIb-dependent aggregate formation under high shear conditions while nothing is known about PLD1-induced regulation of GPIb in platelet-mediated inflammation and the underlying mechanisms. This study aimed to investigate the relevance of PLD1 for platelet-mediated endothelial and leukocyte recruitment and activation in vitro and in vivo. Pld1(-/-) platelets showed strongly reduced adhesion to TNFα stimulated endothelial cells (ECs) under high shear conditions ex vivo...
July 12, 2017: Cellular Signalling
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