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Platelet Syk

Kazuo Furukawa, Ichiro Fuse, Yuriko Iwakura, Hidekazu Sotoyama, Osamu Hanyu, Hiroyuki Nawa, Hirohito Sone, Nobuyuki Takei
BACKGROUND: Brain-derived neurotrophic factor (BDNF) exerts beneficial effects not only on diabetic neuropathies but also on cardiovascular injury. There is argument regarding the levels of serum BDNF in patients with diabetes mellitus (DM). Because BDNF in peripheral blood is rich in platelets, this may represent dysregulation of BDNF release from platelets. Here we focused on advanced glycation end products (AGEs), which are elevated in patients with DM and have adverse effects on cardiovascular functions...
February 8, 2017: Cardiovascular Diabetology
Tor Henrik Tvedt, Ina Nepstad, Øystein Bruserud
Midostaurin is a multikinase inhibitor that inhibits receptor tyrosine kinases (Flt3, CD117/c-kit, platelet-derived growth factor receptor, vascular endothelial growth factor receptor 2) as well as non-receptor tyrosine kinases (Frg, Src, Syk, Protein kinase C). Combination of midostaurin with conventional intensive chemotherapy followed by one year maintenance monotherapy was recently reported to improve the survival of acute myeloid leukemia (AML) patients with Flt3 mutations. Areas covered: Relevant publications were identified through literature searches in the PubMed database...
December 28, 2016: Expert Opinion on Investigational Drugs
A J Unsworth, N Kriek, A P Bye, K Naran, T Sage, G D Flora, J M Gibbins
: Essentials peroxisome proliferator-activated receptor γ (PPARγ) agonists inhibit platelet function. PPARγ agonists negatively regulate outside-in signaling via integrin αIIbβ3. PPARγ agonists disrupt the interaction of Gα13 with integrin β3. This is attributed to an upregulation of protein kinase A activity. SUMMARY: Background Agonists for the peroxisome proliferator-activated receptor (PPARγ) have been shown to have inhibitory effects on platelet activity following stimulation by GPVI and GPCR agonists...
November 29, 2016: Journal of Thrombosis and Haemostasis: JTH
Kevin Reppschläger, Jeanne Gosselin, Carol A Dangelmaier, Dafydd H Thomas, Nick Carpino, Steven E McKenzie, Satya P Kunapuli, Alexander Y Tsygankov
Protein-tyrosine phosphatase TULA-2 has been shown to regulate receptor signaling in several cell types, including platelets. Platelets are critical for maintaining vascular integrity; this function is mediated by platelet aggregation in response to recognition of the exposed basement membrane collagen by the GPVI receptor, which is non-covalently associated with the signal-transducing FcRγ polypeptide chain. Our previous studies suggested that TULA-2 plays an important role in negatively regulating signaling through GPVI-FcRγ and indicated that the tyrosine-protein kinase Syk is a key target of the regulatory action of TULA-2 in platelets...
October 21, 2016: Journal of Biological Chemistry
Daniela Semeniak, Rebecca Kulawig, David Stegner, Imke Meyer, Silke Schwiebert, Hendrik Bösing, Beate Eckes, Bernhard Nieswandt, Harald Schulze
Collagen receptors GPVI (also known as GP6) and integrin α2β1 are highly expressed on blood platelets and megakaryocytes, their immediate precursors. After vessel injury, subendothelial collagen becomes exposed and induces platelet activation to prevent blood loss. Collagen types I and IV are thought to have opposite effects on platelet biogenesis, directing proplatelet formation (PPF) towards the blood vessels to prevent premature release within the marrow cavity. We used megakaryocytes lacking collagen receptors or treated megakaryocytes with blocking antibodies, and could demonstrate that collagen-I-mediated inhibition of PPF is specifically controlled by GPVI...
September 15, 2016: Journal of Cell Science
Andrew J Long, Erik Sampson, Richard W McCarthy, Christopher M Harris, Marc Barnard, Dan Shi, Donna Conlon, Robert Caldwell, David Honor, Neil Wishart, Michael Hoemann, Lori Duggan, Douglas Fritz, Christopher Stedman, Elizabeth O'Connor, Igor Mikaelian, Annette Schwartz
Spleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase that is an important signaling enzyme downstream of immunoreceptors containing an intracellular immunoreceptor tyrosine activating motif (ITAM). These receptors encompass a wide variety of biological functions involved in autoimmune disease pathogenesis. There has been considerable interest in the development of inhibitors of the Syk pathway for the treatment of rheumatoid arthritis and systemic lupus erythematosus. We report that Syk inhibition mechanistically caused peri-islet hemorrhages and fibrin deposition in the rat pancreas and that this finding is due to a homeostatic functional defect in platelets...
October 2016: Toxicologic Pathology
Jessica Ryan, John Kanellis, Kate Blease, Frank Y Ma, David J Nikolic-Paterson
Ischemia/reperfusion (I/R) injury is an important cause of acute and chronic renal failure. Neutrophils and macrophages, by integrin-based recruitment, play a key role in renal I/R injury. Integrin-based activation of spleen tyrosine kinase (Syk) contributes to myeloid cell adhesion to activated endothelial cells in vitro; however, whether Syk is required for myeloid cell recruitment and tubular damage in I/R injury is unknown. Therefore, we investigated the function of Syk in mouse I/R injury using two different approaches...
August 2016: American Journal of Pathology
Marjolein Meinders, Mark Hoogenboezem, Maaike R Scheenstra, Iris M De Cuyper, Petros Papadopoulos, Tamás Németh, Attila Mócsai, Timo K van den Berg, Taco W Kuijpers, Laura Gutiérrez
During hematopoiesis, transcriptional programs are essential for the commitment and differentiation of progenitors into the different blood lineages. GATA1 is a transcription factor expressed in several hematopoietic lineages and essential for proper erythropoiesis and megakaryopoiesis. Megakaryocyte-specific genes, such as GP1BA, are known to be directly regulated by GATA1. Mutations in GATA1 can lead to dyserythropoietic anemia and pseudo gray-platelet syndrome. Selective loss of Gata1 expression in adult mice results in macrothrombocytopenia with platelet dysfunction, characterized by an excess of immature megakaryocytes...
2016: PloS One
Judith M M van Eeuwijk, David Stegner, David J Lamb, Peter Kraft, Sarah Beck, Ina Thielmann, Friedemann Kiefer, Barbara Walzog, Guido Stoll, Bernhard Nieswandt
OBJECTIVE: Ischemic stroke, which is mainly caused by thromboembolic occlusion of brain arteries, is the second leading cause of death and disability worldwide with limited treatment options. The platelet collagen receptor glycoprotein VI (GPVI) is a key player in arterial thrombosis and a critical determinant of stroke outcome, making its signaling pathway an attractive target for pharmacological intervention. The spleen tyrosine kinase (Syk) is an essential signaling mediator downstream of not only GPVI but also other platelet and immune cell receptors...
June 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
Karen P Fong, Hua Zhu, Lisa M Span, David T Moore, Kyungchul Yoon, Ryo Tamura, Hang Yin, William F DeGrado, Joel S Bennett
αIIbβ3 activation in platelets is followed by activation of the tyrosine kinase c-Src associated with the carboxyl terminus of the β3 cytosolic tail. Exogenous peptides designed to interact with the αIIb transmembrane (TM) domain activate single αIIbβ3 molecules in platelets by binding to the αIIb TM domain and causing separation of the αIIbβ3 TM domain heterodimer. Here we asked whether directly activating single αIIbβ3 molecules in platelets using the designed peptide anti-αIIb TM also initiates αIIbβ3-mediated outside-in signaling by causing activation of β3-associated c-Src...
May 27, 2016: Journal of Biological Chemistry
Callum N Watson, Steven W Kerrigan, Dermot Cox, Ian R Henderson, Steve P Watson, Mònica Arman
Gram-negative Escherichia coli cause diseases such as sepsis and hemolytic uremic syndrome in which thrombotic disorders can be found. Direct platelet-bacterium interactions might contribute to some of these conditions; however, mechanisms of human platelet activation by E. coli leading to thrombus formation are poorly understood. While the IgG receptor FcγRIIA has a key role in platelet response to various Gram-positive species, its role in activation to Gram-negative bacteria is poorly defined. This study aimed to investigate the molecular mechanisms of human platelet activation by E...
September 2016: Platelets
Sudipta Biswas, Liang Xin, Soumya Panigrahi, Alejandro Zimman, Hua Wang, Valentin P Yakubenko, Tatiana V Byzova, Robert G Salomon, Eugene A Podrez
A prothrombotic state and increased platelet reactivity are common in dyslipidemia and oxidative stress. Lipid peroxidation, a major consequence of oxidative stress, generates highly reactive products, including hydroxy-ω-oxoalkenoic acids that modify autologous proteins generating biologically active derivatives. Phosphatidylethanolamine, the second most abundant eukaryotic phospholipid, can also be modified by hydroxy-ω-oxoalkenoic acids. However, the conditions leading to accumulation of such derivatives in circulation and their biological activities remain poorly understood...
May 26, 2016: Blood
Gang Liu, Wen Xie, Ao-Di He, Xing-Wen Da, Ming-Lu Liang, Guang-Qiang Yao, Ji-Zhou Xiang, Cun-Ji Gao, Zhang-Yin Ming
SCOPE: Propolis is thought to help prevent thrombotic and related cardiovascular diseases in humans. Chrysin, a bioflavonoids compound found in high levels in propolis and in honey, has been reported to possess antiplatelet activity. However, the mechanism by which it inhibits platelet function is unclear. METHODS AND RESULTS: The effects of chrysin on agonist-activated platelet-aggregation, granule-secretion, and integrin αIIbβ3 activation were examined. Its effects on the phosphorylation of Akt, GSK3β, MAPKs, and several proteins of the glycoprotein VI (GPVI) signaling pathway were also studied on collaged-activated platelets...
September 2016: Molecular Nutrition & Food Research
M Keegan Delaney, Kyungho Kim, Brian Estevez, Zheng Xu, Aleksandra Stojanovic-Terpo, Bo Shen, Masuko Ushio-Fukai, Jaehyung Cho, Xiaoping Du
OBJECTIVE: Reactive oxygen species (ROS) are known to regulate platelet activation; however, the mechanisms of ROS production during platelet activation remain unclear. Platelets express different isoforms of nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidases (NOXs). Here, we investigated the role of NOX1 and NOX2 in ROS generation and platelet activation using NOX1 and NOX2 knockout mice. APPROACH AND RESULTS: NOX1(-/Y) platelets showed selective defects in G-protein-coupled receptor-mediated platelet activation induced by thrombin and thromboxane A2 analog U46619, but were not affected in platelet activation induced by collagen-related peptide, a glycoprotein VI agonist...
May 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
Lan Wang, Jie Yin, Xuefei Wang, Miaomiao Shao, Fangfang Duan, Weicheng Wu, Peike Peng, Jing Jin, Yue Tang, Yuanyuan Ruan, Yihong Sun, Jianxin Gu
BACKGROUND & AIMS: C-type lectin-like receptor 2 (CLEC2) is a transmembrane receptor expressed on platelets and several hematopoietic cells. CLEC2 regulates platelet aggregation and the immune response. We investigated its expression and function in normal and transformed gastric epithelial cells from human tissues. METHODS: We performed tissue microarray analyses of gastric carcinoma samples collected from 96 patients who underwent surgery at Zhongshan Hospital of Fudan University in Shanghai, China and performed real-time polymerase chain reaction assays from an independent group of 60 patients; matched nontumor gastric mucosa tissues were used as the control...
May 2016: Gastroenterology
Lorena Buitrago, Bhanu Kanth Manne, Pierrette Andre, Steven McKenzie, Satya Kunapuli
No abstract text is available yet for this article.
July 2016: Platelets
Christophe Vandenbriele, Yi Sun, Maarten Criel, Katrien Cludts, Soetkin Van Kerckhoven, Benedetta Izzi, Thomas Vanassche, Peter Verhamme, Marc F Hoylaerts
UNLABELLED: Dextran sulfate (DxS; Mr 500 kD) induces fibrinogen receptor (αIIbβ3) activation via CLEC-2/Syk signaling and via a Syk-independent SFK/PI3K/Akt-dependent tyrosine kinase pathway in human and murine platelets. The platelet surface receptor, responsible for the DxS-induced Syk-independent Akt-activation, has hitherto not been identified. We found that DxS elicited a concentration-dependent aggregation of human platelets resulting from direct PEAR1 activation by DxS. Blocking the PEAR1 receptor, in combination with a selective Syk-inhibitor, completely abrogated the DxS-driven platelet aggregation...
June 2016: Platelets
Joanne L Dunster, Francoise Mazet, Michael J Fry, Jonathan M Gibbins, Marcus J Tindall
We present a data-driven mathematical model of a key initiating step in platelet activation, a central process in the prevention of bleeding following Injury. In vascular disease, this process is activated inappropriately and causes thrombosis, heart attacks and stroke. The collagen receptor GPVI is the primary trigger for platelet activation at sites of injury. Understanding the complex molecular mechanisms initiated by this receptor is important for development of more effective antithrombotic medicines. In this work we developed a series of nonlinear ordinary differential equation models that are direct representations of biological hypotheses surrounding the initial steps in GPVI-stimulated signal transduction...
November 2015: PLoS Computational Biology
I V Byelinska, O V Lynchak, S M Tsyvinska, V K Rybalchenko
The effect of the protein kinases inhibitor maleimide derivative (MI-1, 1-(4-Cl-benzyl)-3-Cl-4-(CF3-phenylamino)-1H-pyrrole-2,5-dione), inhibitor of VEGF-R1,2,3, FGF-R1, EGF-R(h), PDK1, Src(h), Syk(h), YES, ZAP70 et al. with antineoplastic activity, on blood cells parameters of rats after chronic exposure has been studied. Administration of MI-1 at doses 0.027 and 2.7 mg/kg (suppress colon carcinogenesis) for 20 and 26 weeks does not affect the morphofunctional state of red blood cells in healthy rats. This is confirmed by the lack of differences in the concentration of hemoglobin in blood, red blood cells count, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration, hematocrit and mean corpuscular volume, and the number of reticulocytes in blood after 20 and 26 weeks of exposure compared with the control group...
2015: Fiziolohichnyĭ Zhurnal
Bing Wu, Yan Wei, Qian Zhang
Immune thrombocytopenia (ITP) is caused by platelet autoantibodies and T-cell dysregulation. Both platelets and their precursor megakaryocytes may be targeted leading to platelet destruction and insufficient production. Current treatments for ITP, including corticosteroids, rituximab, splenectomy and TPO receptor agonists can not reverse the disease process and can be limited by their side effects including infection and thrombosis. New methods, such as anti-CD154 antibody, FcγRIIb and Syk (spleen tyrosine kinase) inhibitor, can target at certain key steps in the disease process, showing the potential to limite systemic side effects and to decrease the morbidity and mortality of ITP patients...
August 2015: Zhongguo Shi Yan Xue Ye Xue za Zhi
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