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Spleen tyrosine kinase

Yuhang Zhou, Shaji Abraham, Stephanie Renna, Leonard C Edelstein, Carol A Dangelmaier, Alexander Y Tsygankov, Satya P Kunapuli, Paul F Bray, Steven E McKenzie
OBJECTIVE: The objective of this study is to investigate the role of T-cell ubiquitin ligand-2 (TULA-2) in the platelet Fc receptor for IgG IIA (FcγRIIA) pathway and in the pathogenesis of heparin-induced thrombocytopenia (HIT). APPROACH AND RESULTS: HIT is a life-threatening thrombotic disease in which IgG antibodies against the heparin-platelet factor 4 complex activate platelets via FcγRIIA. We reported previously differential expression of TULA-2 in human population was linked to FcγRIIA responsiveness...
October 20, 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
JoAnn Trial, Lawrence A Potempa, Mark L Entman
The participation of C-reactive protein (CRP) in host defense against microorganisms has been well described. More controversial has been its role in chronic conditions such as cardiovascular disease. Our recent publications explain the reasons for some of the confusion concerning CRP as a risk factor for disease and whether it is pro-inflammatory or anti-inflammatory. We found that two isoforms of CRP, pentameric (pCRP) and monomeric (mCRP), on microparticles (MPs), were not measureable by standard clinical assays...
2016: Inflammation and Cell Signaling
Kenta Fujimoto, Takehiro Motowaki, Naoya Tamura, Yasuaki Aratani
Myeloperoxidase (MPO), a major component of neutrophils, catalyzes the production of hypochlorous acid from hydrogen peroxide and chloride anion. Phagocytosis is a critical event induced by neutrophils for host defense and inflammation. Interestingly, we found that MPO-deficient (MPO(-/-)) neutrophils engulfed larger amounts of zymosan than wild-type neutrophils. Blocking of the CD11b subunit of complement receptor 3 (CR3) as well as inhibition of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK) dramatically reduced zymosan phagocytosis...
October 4, 2016: Free Radical Research
Maninder Kaur, Om Silakari
The clinical efficacy of multiple kinase inhibitors has caught the interest of Pharmaceutical and Biotech researchers to develop potential drugs with multi-kinase inhibitory activity for complex diseases. In the present work, we attempted to identify dual inhibitors of. Syk and JAK3, keys players in immune signaling, by developing ideal pharmacophores integrating Ligand based pharmacophore models (LBPMs) and Structure based pharmacophore models (SBPMs), thereby projecting the optimum pharmacophoric required for inhibition of both the kinases...
September 28, 2016: Journal of Biomolecular Structure & Dynamics
Milton Pereira, Panagiotis Tourlomousis, John Wright, Tom P Monie, Clare E Bryant
Interleukin-1β (IL-1β) is a proinflammatory cytokine required for host control of bacterial infections, and its production must be tightly regulated to prevent excessive inflammation. Here we show that caspase recruitment domain-containing protein 9 (CARD9), a protein associated with induction of proinflammatory cytokines by fungi, has a negative role on IL-1β production during bacterial infection. Specifically, in response to activation of the nucleotide oligomerization domain receptor pyrin-domain containing protein 3 (NLRP3) by Salmonella infection, CARD9 negatively regulates IL-1β by fine-tuning pro-IL-1β expression, spleen tyrosine kinase (SYK)-mediated NLRP3 activation and repressing inflammasome-associated caspase-8 activity...
2016: Nature Communications
H Zaouri, H Amarouch, N Elmakrini, N Tazi, N Ismaili, L Benzekri, K Senouci, B Hassam
Mastocytosis is a group of diseases related to abnormal accumulation and proliferation of mast cells in one or more organs. They may be associated with an acquired point mutation and the activation of the receptor tyrosine-kinase c-KIT of CFS (mast cell growth factor). The clinical manifestations are varied and secondary to the release of mast cell mediators and/or infiltration of various organs. There are two main types of mastocytosis: pure cutaneous mastocytosis and systemic mastocytosis when more than two organs are involved in mast cell infiltration (bone marrow, gastrointestinal tract, bone, liver and spleen, lymph nodes)...
September 23, 2016: Archives de Pédiatrie: Organe Officiel de la Sociéte Française de Pédiatrie
Sheikh Fayaz Ahmad, Mushtaq Ahmad Ansari, Ahmed Nadeem, Khairy M A Zoheir, Saleh A Bakheet, Othman A Al-Shabanah, Ammar Cherkess Al Rikabi, Sabry M Attia
Protein tyrosine kinases are key mediators of the signal transduction cascades that control expression of many genes involved in the induction of inflammation caused by arthritis. Here we investigate the effect of the tyrosine kinase inhibitor tyrphostin AG126 on a mouse model of adjuvant-induced arthritis (AIA). We report that when given at 5mg/kg i.p. every 48h from days 0-21, AG126 exerts potent anti-arthritic effects. Further, we investigated the role of AG126 on the key mediators of arthritic inflammation, namely, edema, arthritic score, presence of immunophenotypes including Foxp3(+), CD4(+)Foxp3(+), and CD25(+)Foxp3(+) T regulatory (Treg) cells, as well as pro- and anti-inflammatory mediators...
October 2016: Molecular Immunology
Beibei Ni, Jun Hu, Dianke Chen, Li Li, Daici Chen, Jianping Wang, Lei Wang
Spleen tyrosine kinase (SYK) has been reported as a potential tumor suppressor in colorectal cancer (CRC). However, the role of alternative splicing of SYK in carcinogenesis remains unclear. In the present study, SYK isoforms were overexpressed in the human CRC HCT 116 cell line using lentiviral expression vectors to investigate the biological functions of full length SYK [SYK(L)] and short form SYK [SYK(S)] in CRC. Real-time cellular analysis and the 5-ethynyl-2-deoxyuridine assay were used to detect the effects of SYK(L) and SYK(S) on cell proliferation...
September 2016: Oncology Letters
Neil S Garton, Michael D Barker, Rob P Davis, Clement Douault, Edward Hooper-Greenhill, Emma Jones, Huw D Lewis, John Liddle, Dave Lugo, Scott McCleary, Alex G S Preston, Cesar Ramirez-Molina, Margarete Neu, Tracy J Shipley, Don O Somers, Robert J Watson, David M Wilson
The optimisation of the azanaphthyridine series of Spleen Tyrosine Kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over hERG activity. A good pharmacokinetic profile was achieved by modification of the pKa. Morpholine compound 32 is a potent SYK inhibitor showing moderate selectivity, good oral bioavailability and good efficacy in the rat Arthus model but demonstrated a genotoxic potential in the Ames assay...
October 1, 2016: Bioorganic & Medicinal Chemistry Letters
Hyoung-Min Han, Seung-Ju Kim, Jong-Sik Kim, Bum Hoi Kim, Hai Woong Lee, Yong Tae Lee, Kyung-Hwa Kang
Artemisia argyi Folium has been used to treat skin diseases, including eczema and dermatitis, in South Korean medicine. The present study investigated the curative effects of Artemisia argyi Folium extract (AAFE) on 2,4‑dinitrochlorobenzene (DNCB)‑induced atopic dermatitis (AD)‑like skin lesions in a BALB/c mouse model. Briefly, the dorsal skin of the BALB/c mice was sensitized three times with DNCB, whereas the ears were challenged twice. Repeated treatment with DNCB induced AD‑like lesions. The effects of AAFE on AD‑like lesions were evaluated by clinical observation, histopathological analysis, immunohistochemistry and enzyme‑linked immunosorbent assay...
October 2016: Molecular Medicine Reports
Long Hang, Arthur M Blum, Sangeeta Kumar, Joseph F Urban, Makedonka Mitreva, Timothy G Geary, Armando Jardim, Mary M Stevenson, Clifford A Lowell, Joel V Weinstock
Helminthic infections modulate host immunity and may protect people in less-developed countries from developing immunological diseases. In a murine colitis model, the helminth Heligmosomoides polygyrus bakeri prevents colitis via induction of regulatory dendritic cells (DCs). The mechanism driving the development of these regulatory DCs is unexplored. There is decreased expression of the intracellular signaling pathway spleen tyrosine kinase (Syk) in intestinal DCs from H. polygyrus bakeri-infected mice. To explore the importance of this observation, it was shown that intestinal DCs from DC-specific Syk(-/-) mice were powerful inhibitors of murine colitis, suggesting that loss of Syk was sufficient to convert these cells into their regulatory phenotype...
October 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Ze-Quan Mo, Man Yang, Hai-Qing Wang, Yang Xu, Mian-Zhi Huang, Guo-Feng Lao, Yan-Wei Li, An-Xing Li, Xiao-Chun Luo, Xue-Ming Dan
B cell antigen receptor (BCR) plays a crucial role in B cell development and antibody production. It comprises membrane immunoglobulin non-covalently associated with CD79a/CD79b heterodimer. After B cell activation, initial extracellular signals are transduced by BCR complex and amplified by two protein tyrosine kinases, LYN and SYK, which then trigger various pathways. In the present study, we cloned grouper genes for BCR accessory molecules, EcCD79a (669 bp) and EcCD79b (639 bp), as well as two protein tyrosine kinases, EcLYN (1482 bp) and EcSYK (1854 bp)...
October 2016: Fish & Shellfish Immunology
Jeffrey C Howard, Angelique Florentinus-Mefailoski, Peter Bowden, William Trimble, Sergio Grinstein, John G Marshall
The binding and activation of macrophages by microscopic aggregates of oxLDL in the intima of the arteries may be an important step towards atherosclerosis leading to heart attack and stroke. Microbeads coated with oxLDL were used to activate, capture and isolate the oxLDL receptor complex from the surface of live cells. Analysis of the resulting tryptic peptides by liquid chromatography and tandem mass spectrometry revealed the Spleen Tyrosine Kinase (SYK), and many of SYK's known interaction network including Fc receptors (FCGR2A, FCER1G and FCGR1A) Toll receptor 4 (TLR4), receptor kinases like EGFRs, as well as RNA binding and metabolism proteins...
November 15, 2016: Analytical Biochemistry
Sang Jae Lee, Jang-Sik Choi, Byeong-Gu Han, Hyoun Sook Kim, Ho-Juhn Song, Jaekyoo Lee, Seungyoon Nam, Sung-Ho Goh, Jung-Ho Kim, Jong Sung Koh, Byung Il Lee
: Spleen tyrosine kinase (SYK) is a cytosolic nonreceptor protein tyrosine kinase that mediates key signal transduction pathways following the activation of immune cell receptors. SYK regulates cellular events induced by the B-cell receptor and Fc receptors with high intrinsic activity. Furthermore, SYK has been regarded as an attractive target for the treatment of autoimmune diseases and cancers. Here, we report the crystal structures of SYK in complex with seven newly developed inhibitors (G206, G207, O178, O194, O259, O272, and O282) to provide structural insights into which substituents of the inhibitors and binding regions of SYK are essential for lead compound optimization...
October 2016: FEBS Journal
Terry King-Wing Ma, Stephen P McAdoo, Frederick Wai-Keung Tam
Spleen tyrosine kinase (Syk), a 72 kDa cytoplasmic non-receptor protein-tyrosine kinase, plays an important role in signal transduction in a variety of cell types. Ever since its discovery in the early 1990s, there has been accumulating evidence to suggest a pathogenic role of Syk in various allergic disorders, autoimmune diseases and malignancies. Additionally, there is emerging data from both pre-clinical and clinical studies that Syk is implicated in the pathogenesis of proliferative glomerulonephritis (GN), including anti-glomerular basement membrane disease, anti-neutrophil cytoplasmic antibody-associated GN, lupus nephritis and immunoglobulin A nephropathy (IgAN)...
2016: Nephron
Qifeng Sun, Chuanliang Peng, Bo Cong, Yingtao Hao, Jiazhong Guo, Yunpeng Zhao, Xiaogang Zhao
BACKGROUND AND AIMS: Lung cancer has become one of the most dangerous malignant tumors in the world nowadays, whose pathogenesis is complex involving multi-genes and multi-elements. This study aims to investigate the values of spleen tyrosine kinase (Syk) and vascular endothelial growth factor-C (VEGF-C) in lymphangiogenesis and metastasis of lung adenocarcinoma A549 cells. MATERIALS AND METHODS: The pcDNA3.1-VEGF-C and pLNCX-syk were constructed and transfected into A549 cells...
April 2016: Journal of Cancer Research and Therapeutics
Naeem K Patil, Julia K Bohannon, Liming Luan, Yin Guo, Benjamin Fensterheim, Antonio Hernandez, Jingbin Wang, Edward R Sherwood
INTRODUCTION: Sepsis is a leading cause of death among severely burned patients. Burn injury disrupts the protective skin barrier and causes immunological dysfunction. In our previous studies, we found that burn injury and wound infection causes a significant decline in lymphocyte populations, implying adaptive immune system dysfunction. In the present study, we examined the effect of treatment with Fms like tyrosine kinase-3 Ligand (Flt3L) on T cell phenotype and function in a model of burn wound sepsis...
July 21, 2016: Shock
Louise Boye, Iain Welsby, Lisbeth Drozd Lund, Stanislas Goriely, Hanne Frøkiaer
Lactobacillus acidophilus induces a potent interferon-β (IFN-β) response in dendritic cells (DCs) by a Toll-like receptor 2 (TLR2) -dependent mechanism, in turn leading to strong interleukin-12 (IL-12) production. In the present study, we investigated the involvement of different types of endocytosis in the L. acidophilus-induced IFN-β and IL-12 responses and how TLR2 or TLR4 ligation by lipopolysaccharide and Pam3/4CSK4 influenced endocytosis of L. acidophilus and the induced IFN-β and IL-12 production...
November 2016: Immunology
M Kaur, O Silakari
Owing to the complex pathophysiology of autoimmune disorders, it is very challenging to develop successful treatment strategies. Single-target agents are not desired therapeutics for such multi-factorial disorders. Considering the current need for the treatment of complex autoimmune disorders, dual inhibitors of Syk and PI3Kδ have been designed using ligand and structure-based molecular modelling strategies. In the present work, structure and ligand-based pharmacophore modelling was implemented for a varied set of Syk and PI3Kδ inhibitors...
June 2016: SAR and QSAR in Environmental Research
Cynthia J Koziol-White, Yanlin Jia, Gretchen A Baltus, Philip R Cooper, Dennis M Zaller, Michael A Crackower, Erich E Sirkowski, Steven Smock, Alan B Northrup, Blanca E Himes, Stephen E Alves, Reynold A Panettieri
BACKGROUND AND PURPOSE: Asthma manifests as a heterogeneous syndrome characterized by airway obstruction, inflammation and hyper-reactivity (AHR). Spleen tyrosine kinase (Syk) mediates allergen-induced mast cell degranulation, a central component of allergen-induced inflammation and AHR. However, the role of Syk in IgE-mediated constriction of human small airways remains unknown. In this study, we addressed whether selective inhibition of Syk attenuates IgE-mediated constriction and mast cell mediator release in human small airways...
July 15, 2016: British Journal of Pharmacology
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