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Platelet Syk

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https://www.readbyqxmd.com/read/29670076/cathelicidins-prime-platelets-to-mediate-arterial-thrombosis-and-tissue-inflammation
#1
Joachim Pircher, Thomas Czermak, Andreas Ehrlich, Clemens Eberle, Erik Gaitzsch, Andreas Margraf, Jochen Grommes, Prakash Saha, Anna Titova, Hellen Ishikawa-Ankerhold, Konstantin Stark, Tobias Petzold, Thomas Stocker, Ludwig T Weckbach, Julia Novotny, Markus Sperandio, Bernhard Nieswandt, Alberto Smith, Hanna Mannell, Barbara Walzog, David Horst, Oliver Soehnlein, Steffen Massberg, Christian Schulz
Leukocyte-released antimicrobial peptides contribute to pathogen elimination and activation of the immune system. Their role in thrombosis is incompletely understood. Here we show that the cathelicidin LL-37 is abundant in thrombi from patients with acute myocardial infarction. Its mouse homologue, CRAMP, is present in mouse arterial thrombi following vascular injury, and derives mainly from circulating neutrophils. Absence of hematopoietic CRAMP in bone marrow chimeric mice reduces platelet recruitment and thrombus formation...
April 18, 2018: Nature Communications
https://www.readbyqxmd.com/read/29616043/lineage-specific-analysis-of-syk-function-in-autoantibody-induced-arthritis
#2
Tamás Németh, Krisztina Futosi, Kata Szilveszter, Olivér Vilinovszki, Levente Kiss-Pápai, Attila Mócsai
Autoantibody production and autoantibody-mediated inflammation are hallmarks of a number of autoimmune diseases. The K/BxN serum-transfer arthritis is one of the most widely used models of the effector phase of autoantibody-induced pathology. Several hematopoietic lineages including neutrophils, platelets, and mast cells have been proposed to contribute to inflammation and tissue damage in this model. We have previously shown that the Syk tyrosine kinase is critically involved in the development in K/BxN serum-transfer arthritis and bone marrow chimeric experiments indicated that Syk is likely involved in one or more hematopoietic lineages during the disease course...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29472360/immobilized-fibrinogen-activates-human-platelets-through-gpvi
#3
Pierre H Mangin, Marie-Blanche Onselaer, Nicolas Receveur, Nicolas Le Lay, Alexander T Hardy, Clare Wilson, Ximena Sanchez, Stephane Loyau, Arnaud Dupuis, Amir K Babar, Jeanette Lc Miller, Helen Philippou, Craig E Hughes, Andrew B Herr, Robert As Ariëns, Diego Mezzano, Martine Jandrot-Perrus, Christian Gachet, Steve P Watson
GPVI, a major platelet activation receptor for collagen and fibrin, is considered as a particularly promising safe antithrombotic target. In this study, we show that human GPVI signals upon platelet adhesion to fibrinogen. Full spreading of human platelets on fibrinogen is abolished in platelets from GPVI-deficient patients suggesting that fibrinogen activates platelets through GPVI. While mouse platelets fail to spread on fibrinogen, human-GPVI-transgenic mouse platelets show full spreading and increased Ca2+ signalling through the tyrosine kinase Syk...
February 22, 2018: Haematologica
https://www.readbyqxmd.com/read/29470443/structure-antiplatelet-activity-relationships-of-novel-ruthenium-ii-complexes-investigation-of-its-molecular-targets
#4
Chih-Hsuan Hsia, Thanasekaran Jayakumar, Joen-Rong Sheu, Shin-Yi Tsao, Marappan Velusamy, Chih-Wei Hsia, Duen-Suey Chou, Chao-Chien Chang, Chi-Li Chung, Themmila Khamrang, Kao-Chang Lin
The regulation of platelet function by pharmacological agents that modulate platelet signaling has proven to be a positive approach to the prevention of thrombosis. Ruthenium complexes are fascinating for the development of new drugs, as they possess numerous chemical and biological properties. The present study aims to evaluate the structure-activity relationship (SAR) of newly synthesized ruthenium (II) complexes, TQ-1, TQ-2 and TQ-3 in agonists-induced washed human platelets. Silica gel column chromatography, aggregometry, immunoblotting, NMR, and X-ray analyses were performed in this study...
February 22, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29297721/mucor-circinelloides-induces-platelet-aggregation-through-integrin-%C3%AE-iib%C3%AE-3-and-fc%C3%AE-riia
#5
Harlene Ghuman, Alicia Shepherd-Roberts, Stephanie Watson, Malou Zuidscherwoude, Steve P Watson, Kerstin Voelz
Thrombosis is a hallmark of the fatal fungal infection mucormycosis. Yet, the platelet activation pathway in response to mucormycetes is unknown. In this study we determined the platelet aggregation potential of Mucor circinelloides (M. circinelloides) NRRL3631, characterized the signaling pathway facilitating aggregation in response to fungal spores, and identified the influence of the spore developmental stage upon platelet aggregation potential. Using impedance and light-transmission aggregometry, we showed that M...
January 3, 2018: Platelets
https://www.readbyqxmd.com/read/29296791/fibrin-and-d-dimer-bind-to-monomeric-gpvi
#6
Marie-Blanche Onselaer, Alexander T Hardy, Clare Wilson, Ximena Sanchez, Amir K Babar, Jeanette L C Miller, Callum N Watson, Stephanie K Watson, Arkadiusz Bonna, Helen Philippou, Andrew B Herr, Diego Mezzano, Robert A S Ariëns, Steve P Watson
Fibrin has recently been shown to activate platelets through the immunoglobulin receptor glycoprotein VI (GPVI). In the present study, we show that spreading of human platelets on fibrin is abolished in patients deficient in GPVI, confirming that fibrin activates human platelets through the immunoglobulin receptor. Using a series of proteolytic fragments, we show that D-dimer, but not the E fragment of fibrin, binds to GPVI and that immobilized D-dimer induces platelet spreading through activation of Src and Syk tyrosine kinases...
August 22, 2017: Blood Advances
https://www.readbyqxmd.com/read/29295843/gpvi-signaling-is-compromised-in-newly-formed-platelets-after-acute-thrombocytopenia-in-mice
#7
Shuchi Gupta, Deya Cherpokova, Markus Spindler, Martina Morowski, Markus Bender, Bernhard Nieswandt
At sites of vascular injury, exposed subendothelial collagens trigger platelet activation and thrombus formation by interacting with the immunoreceptor tyrosine-based activation motif (ITAM)-coupled glycoprotein VI (GPVI) on the platelet surface. Platelets are derived from the cytoplasm of megakaryocytes (MKs), which extend large proplatelets into bone marrow (BM) sinusoids that are then released into the bloodstream, where final platelet sizing and maturation occurs. The mechanisms that prevent activation of MKs and forming proplatelets in the collagen-rich BM environment remain largely elusive...
March 8, 2018: Blood
https://www.readbyqxmd.com/read/29286055/midostaurin-for-the-treatment-of-adult-patients-with-newly-diagnosed-acute-myeloid-leukemia-that-is-flt3-mutation-positive
#8
REVIEW
J S Garcia, M E Percival
Midostaurin is a multitargeted tyrosine kinase inhibitor (TKI) that potently inhibits activated fms-related tyrosine kinase 3 (FLT3) in the nanomolar range and other kinases including platelet-derived growth factor receptors α (PDGFR- α) and β (PDGFR- β), cyclin-dependent kinase, proto-oncogene tyrosine-protein kinase Src, tyrosine-protein kinase Fgr, spleen tyrosine kinase (Syk), KIT proto-oncogene receptor tyrosine kinase and the major vascular endothelial growth factor receptor (VEGFR). Activating mutations in FLT3, which is one of the more common acute myeloid leukemia (AML) mutations, particularly those that result in an FLT3-ITD (internal tandem duplication) mutation, confer poor prognosis and represent a therapeutic target...
October 2017: Drugs of Today
https://www.readbyqxmd.com/read/28967793/fostamatinib-for-persistent-chronic-adult-immune-thrombocytopenia
#9
Adrian Newland, Eun-Ju Lee, Vickie McDonald, James B Bussel
Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by phagocytosis and destruction of autoantibody-coated platelets via spleen tyrosine kinase (Syk)-mediated signal transduction in macrophages. Effectiveness of existing therapies varies, and even leading treatments (e.g., IVIg, splenectomy, rituximab, thrombopoietic agents) do not provide optimal management for a substantial number of patients with chronic ITP. Fostamatinib disodium is an orally-bioavailable investigational agent being developed for treatment of primary persistent/chronic adult ITP...
January 2018: Immunotherapy
https://www.readbyqxmd.com/read/28943410/loss-of-reelin-protects-mice-against-arterial-thrombosis-by-impairing-integrin-activation-and-thrombus-formation-under-high-shear-conditions
#10
Nina Sarah Gowert, Irena Krüger, Meike Klier, Lili Donner, Friederike Kipkeew, Michael Gliem, Nicholas J Bradshaw, David Lutz, Sabrina Köber, Harald Langer, Sebastian Jander, Kerstin Jurk, Michael Frotscher, Carsten Korth, Hans H Bock, Margitta Elvers
Reelin is a secreted glycoprotein and essential for brain development and plasticity. Recent studies provide evidence that Reelin modifies platelet actin cytoskeletal dynamics. In this study we sought to dissect the contribution of Reelin in arterial thrombus formation. Here we analyzed the impact of Reelin in arterial thrombosis ex vivo and in vivo using Reelin deficient (reeler) and wildtype mice. We found that Reelin is secreted upon platelet activation and mediates signaling via glycoprotein (GP)Ib, the amyloid precursor protein (APP) and apolipoprotein E receptor 2 (ApoER2) to induce activation of Akt, extracellular signal-regulated kinase (Erk), SYK and Phospholipase Cγ2...
December 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28888895/regulation-of-platelet-activation-and-thrombus-formation-by-reactive-oxygen-species
#11
Jianlin Qiao, Jane F Arthur, Elizabeth E Gardiner, Robert K Andrews, Lingyu Zeng, Kailin Xu
Reactive oxygen species (ROS) are generated within activated platelets and play an important role in regulating platelet responses to collagen and collagen-mediated thrombus formation. As a major collagen receptor, platelet-specific glycoprotein (GP)VI is a member of the immunoglobulin (Ig) superfamily, with two extracellular Ig domains, a mucin domain, a transmembrane domain and a cytoplasmic tail. GPVI forms a functional complex with the Fc receptor γ-chain (FcRγ) that, following receptor dimerization, signals via an intracellular immunoreceptor tyrosine-based activation motif (ITAM), leading to rapid activation of Src family kinase signaling pathways...
April 2018: Redox Biology
https://www.readbyqxmd.com/read/28878675/inhibition-of-collagen-induced-platelet-aggregation-by-the-secobutanolide-secolincomolide-a-from-lindera-obtusiloba-blume
#12
Sang-Hyuk Jung, Joo-Hui Han, Hyun-Soo Park, Jung-Jin Lee, Seo Young Yang, Young Ho Kim, Kyung-Sun Heo, Chang-Seon Myung
Atherothrombosis is one of the main underlying cause of cardiovascular diseases. In addition to treating atherothrombosis with antithrombotic agents, there is growing interest in the role of natural food products and biologically active ingredients for the prevention and treatment of cardiovascular diseases. This study aimed to investigate the effect of secolincomolide A (3) isolated from Lindera obtusiloba Blume on platelet activity and identify possible signaling pathways. In our study, the antiplatelet activities of 3 were measured by collagen-induced platelet aggregation and serotonin secretion in freshly isolated rabbit platelets...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28855423/plant-based-food-cyanidin-3-glucoside-modulates-human-platelet-glycoprotein-vi-signaling-and-inhibits-platelet-activation-and-thrombus-formation
#13
Yanling Yao, Yanqiu Chen, Reheman Adili, Thomas McKeown, Pingguo Chen, Guangheng Zhu, Dan Li, Wenhua Ling, Heyu Ni, Yan Yang
Background: Platelets play an important role in hemostasis, thrombosis, and atherosclerosis. Glycoprotein VI (GPVI) is a major platelet receptor that interacts with exposed collagen on injured vessel walls. Our previous studies have shown that anthocyanins (a type of natural plant pigment) attenuate platelet function; however, whether anthocyanins affect collagen-induced GPVI signaling remains unknown. Objective: The objective of this study was to explore the effects of cyanidin-3-glucoside (Cy-3-g, one of the major bioactive compounds in anthocyanins) on platelet activation and thrombosis and the GPVI signaling pathway...
October 2017: Journal of Nutrition
https://www.readbyqxmd.com/read/28842683/a-novel-ruthenium-ii-derived-organometallic-compound-tq-6-potently-inhibits-platelet-aggregation-ex-vivo-and-in-vivo-studies
#14
Chih-Hsuan Hsia, Marappan Velusamy, Joen-Rong Sheu, Themmila Khamrang, Thanasekaran Jayakumar, Wan-Jung Lu, Kuan-Hung Lin, Chao-Chien Chang
Arterial thrombosis plays a key role in cardiovascular diseases. Hence, developing more effective antithrombotic agents is necessary. We designed a ruthenium (II)-derived complex, [Ru(η(6)-cymene)2-(1H-benzoimidazol-2-yl)-quinoline Cl]BF4 (TQ-6), as a new antiplatelet drug. TQ-6 (0.3 µM) exhibited extremely strong inhibitory activity against platelet aggregation, Src, and Syk phosphorylation stimulated by agonists in human platelets. In collagen-activated platelets, TQ-6 also inhibited ATP-release, [Ca(+2)]i, P-selectin expression, FITC-PAC-1 binding, and hydroxyl radical formation, as well as the phosphorylation of phospholipase Cγ2, protein kinase C, mitogen-activated protein kinases, and Akt...
August 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28775078/tlr2-plays-a-key-role-in-platelet-hyperreactivity-and-accelerated-thrombosis-associated-with-hyperlipidemia
#15
Sudipta Biswas, Alejandro Zimman, Detao Gao, Tatiana V Byzova, Eugene A 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 the accumulation in the circulation of a specific group of oxidized phospholipids (oxPCCD36) that are ligands for the platelet pattern recognition receptor CD36...
September 29, 2017: Circulation Research
https://www.readbyqxmd.com/read/28705934/g-q-pathway-regulates-proximal-c-type-lectin-like-receptor-2-clec-2-signaling-in-platelets
#16
COMPARATIVE STUDY
Rachit Badolia, Vaishali Inamdar, Bhanu Kanth Manne, Carol Dangelmaier, Johannes A Eble, Satya P Kunapuli
Platelets play a key role in the physiological hemostasis or pathological process of thrombosis. Rhodocytin, an agonist of the C-type lectin-like receptor-2 (CLEC-2), elicits powerful platelet activation signals in conjunction with Src family kinases (SFKs), spleen tyrosine kinase (Syk), and phospholipase γ2 (PLCγ2). Previous reports have shown that rhodocytin-induced platelet aggregation depends on secondary mediators such as thromboxane A2 (TxA2) and ADP, which are agonists for G-protein-coupled receptors (GPCRs) on platelets...
September 1, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28663280/megakaryocytic-smad4-regulates-platelet-function-through-syk-and-rock2-expression
#17
Yanhua Wang, Lirong Jiang, Xi Mo, Yu Lan, Xiao Yang, Xinyi Liu, Jian Zhang, Li Zhu, Junling Liu, Xiaolin Wu
Smad4, a key transcription factor in the transforming growth factor-β signaling pathway, is involved in a variety of cell physiologic and pathologic processes. Here, we characterized megakaryocyte/platelet-specific Smad4 deficiency in mice to elucidate its effect on platelet function. We found that megakaryocyte/platelet-specific loss of Smad4 caused mild thrombocytopenia and significantly extended first occlusion time and tail bleeding time in mice. Smad4-deficient platelets showed reduced agonist-induced platelet aggregation...
September 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28598382/syk-activity-is-dispensable-for-platelet-gp1b-ix-v-signaling
#18
Rachit Badolia, John C Kostyak, Carol Dangelmaier, Satya P Kunapuli
The binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein 1b-IX (GP1b-IX) leads to activation of platelets. GP1b was shown to signal via the FcRγ-ITAM (Fc Receptor γ-Immunoreceptor tyrosine-based activation motif) pathway, activating spleen tyrosine kinase (Syk) and other tyrosine kinases. However, there have been conflicting reports regarding the role of Syk in GP1b signaling. In this study, we sought to resolve these conflicting reports and clarify the role of Syk in VWF-induced platelet activation...
June 9, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28391340/targeting-the-tyrosine-kinase-signalling-pathways-for-treatment-of-immune-mediated-glomerulonephritis-from-bench-to-bedside-and-beyond
#19
REVIEW
Terry King-Wing Ma, Stephen P McAdoo, Frederick Wai Keung Tam
Glomerulonephritis (GN) affects patients of all ages and is an important cause of morbidity and mortality. Non-selective immunosuppressive drugs have been used in immune-mediated GN but often result in systemic side effects and occasionally fatal infective complications. There is increasing evidence from both preclinical and clinical studies that abnormal activation of receptor and non-receptor tyrosine kinase signalling pathways are implicated in the pathogenesis of immune-mediated GN. Activation of spleen tyrosine kinase (SYK), Bruton's tyrosine kinase (BTK), platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR) and discoidin domain receptor 1 (DDR1) have been demonstrated in anti-GBM disease...
January 1, 2017: Nephrology, Dialysis, Transplantation
https://www.readbyqxmd.com/read/28336561/mice-lacking-the-inhibitory-collagen-receptor-lair-1-exhibit-a-mild-thrombocytosis-and-hyperactive-platelets
#20
Christopher W Smith, Steven G Thomas, Zaher Raslan, Pushpa Patel, Maxwell Byrne, Marie Lordkipanidzé, Danai Bem, Linde Meyaard, Yotis A Senis, Steve P Watson, Alexandra Mazharian
OBJECTIVE: Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is a collagen receptor that belongs to the inhibitory immunoreceptor tyrosine-based inhibition motif-containing receptor family. It is an inhibitor of signaling via the immunoreceptor tyrosine-based activation motif-containing collagen receptor complex, glycoprotein VI-FcRγ-chain. It is expressed on hematopoietic cells, including immature megakaryocytes, but is not detectable on platelets. Although the inhibitory function of LAIR-1 has been described in leukocytes, its physiological role in megakaryocytes and in particular in platelet formation has not been explored...
May 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
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