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Spleen tyrosine kinase

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https://www.readbyqxmd.com/read/27906453/syk-inhibition-blocks-airway-constriction-and-protects-from-th2-induced-airway-inflammation-and-remodeling-in-mice
#1
Christoph Tabeling, Julia Herbert, Andreas C Hocke, David Lamb, Lutz Wollin, Klaus Erb, Ekaterina Boiarina, Hesam Movassagh, Jörg Scheffel, Jan M Doehn, Stefan Hippenstiel, Marcus Maurer, Abdelilah S Gounni, Wolfgang M Kuebler, Norbert Suttorp, Martin Witzenrath
BACKGROUND: Spleen tyrosine kinase (Syk) is an intracellular non-receptor tyrosine kinase, which has been implicated as central immune modulator promoting allergic airway inflammation. Syk inhibition has been proposed as a new therapeutic approach in asthma. However, the direct effects of Syk inhibition on airway constriction independent of allergen sensitization remain elusive. METHODS: Spectral confocal microscopy of human and murine lung tissue was performed to localize Syk expression...
December 1, 2016: Allergy
https://www.readbyqxmd.com/read/27903679/the-bruton-s-tyrosine-kinase-btk-inhibitor-acalabrutinib-demonstrates-potent-on-target-effects-and-efficacy-in-two-mouse-models-of-chronic-lymphocytic-leukemia
#2
Sarah E M Herman, Arnau Montraveta, Carsten U Niemann, Helena Mora-Jensen, Michael Gulrajani, Fanny Krantz, Rose Mantel, Lisa L Smith, Fabienne McClanahan, Bonnie Harrington, Dolors Colomer, Todd Covey, John C Byrd, Raquel Izumi, Allard Kaptein, Roger Ulrich, Amy Johnson, Brian J Lannutti, Adrian Wiestner, Jennifer A Woyach
PURPOSE: Acalabrutinib (ACP-196) is a novel, potent, and highly selective BTK inhibitor, which binds covalently to Cys481 in the ATP-binding pocket of BTK. We sought to evaluate the anti-tumor effects of acalabrutinib treatment in two established mouse models of chronic lymphocytic leukemia (CLL). EXPERIMENTAL DESIGN: Two distinct mouse models were used, the TCL1 adoptive transfer model where leukemic cells from Eμ-TCL1 transgenic mice are transplanted into C57BL/6 mice, and the human NSG primary CLL xenograft model...
November 30, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27899962/new-emerging-therapies-in-the-management-of-chronic-lymphocytic-leukemia
#3
Xiao-Lin Li, Ci-Xian Zhang
Chronic lymphocytic leukemia (CLL) is considered incurable despite advances in management strategies. New drugs targeting cell pathways are currently being developed for the efficient management of CLL. Various strategies involving different targets have been developed, or are currently in the developing stage. A search was conducted in the electronic database PubMed, for pre-clinical as well as clinically controlled trials reporting various strategies against CLL currently under investigation. Novel strategies included use of antibodies, small cell inhibitors, such as spleen tyrosine kinase, LYN, cyclin-dependent kinase, and histone deacetylase inhibitors...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27894895/molecular-characterization-and-expression-analysis-of-olive-flounder-paralichthys-olivaceus-phospholipase-c-gamma-1-and-gamma-2
#4
Soo Ji Woo, Hyae In Jo, Hyung Ho Lee, Joon Ki Chung
Phospholipase C gamma 1 and gamma 2 (PLCG1 and PLCG2) are influential in modulating Ca(2+) and diacylglycerol, second messengers involved in tyrosine kinase-dependent signaling, including growth factor activation. Here, we used RACE (rapid amplification of cDNA ends) to clone cDNA encoding PLCG1 (PoPLCG1) and PLCG2 (PoPLCG2) in the olive flounder (Paralichthys olivaceus). The respective 1313 and 1249 amino acid sequences share high identity with human PLCG1 and PLCG2, and contain the following domains: pleckstrin homology (PH), EF-hand, catalytic X and Y, Src homology 2 (SH2), Src homology 3 (SH3), and C2...
November 25, 2016: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/27837109/characterization-of-the-syk-dependent-t-cell-signaling-response-to-an-altered-peptide
#5
Jeoung-Eun Park, Jeffrey A Rotondo, David L Cullins, David D Brand, Ae-Kyung Yi, John M Stuart, Andrew H Kang, Linda K Myers
Rheumatoid arthritis is an autoimmune disorder characterized by T cell dysregulation. We have shown that an altered peptide ligand (A9) activates T cells to use an alternate signaling pathway that is dependent on FcRγ and spleen tyrosine kinase, resulting in downregulation of inflammation. In the experiments described in this study, we have attempted to determine the molecular basis of this paradox. Three major Src family kinases found in T cells (Lck, Fyn, and Lyn) were tested for activation following stimulation by A9/I-A(q) Unexpectedly we found they are not required for T cell functions induced by A9/I-A(q), nor are they required for APL stimulation of cytokines...
December 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27825101/dynamic-contributions-of-p-and-e-selectins-to-%C3%AE-2-integrin-induced-neutrophil-transmigration
#6
Yixin Gong, Yan Zhang, Shiliang Feng, Xiaofeng Liu, Shouqin Lü, Mian Long
Leukocyte transendothelial migration is a key step in their recruitment to sites of inflammation. However, synergic regulation of endothelium-expressed selectins on leukocyte transmigration remains unclear. In this study, an in vitro model was developed to investigate the dynamic contributions of P- and E-selectin to polymorphonuclear (PMN) cell transmigration under static conditions. Human umbilical vein endothelial cells (HUVECs) were treated with LPS for 4 or 12 h to induce different expression of selectins and intercellular adhesion molecule (ICAM)-1...
October 6, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/27822175/keyhole-limpet-hemocyanin-induces-innate-immunity-via-syk-and-erk-phosphorylation
#7
Kyoko Yasuda, Hideki Ushio
Hemocyanin is an extracellular respiratory protein containing copper in hemolymph of invertebrates, such as Mollusk and Arthropod. Keyhole limpet hemocyanin (KLH) is one of hemocyanins and has many years of experience for vaccine developments and immunological studies in mammals including human. However, the association between KLH and the immune systems, especially the innate immune systems, remains poorly understood. The aim of this study is to clarify the direct effects of KLH on the innate immune systems...
2016: EXCLI journal
https://www.readbyqxmd.com/read/27795434/clec5a-mediated-enhancement-of-the-inflammatory-response-in-myeloid-cells-contributes-to-influenza-pathogenicity-in-vivo
#8
Ooiean Teng, Szu-Ting Chen, Tsui-Ling Hsu, Sin Fun Sia, Suzanne Cole, Sophie A Valkenburg, Tzu-Yun Hsu, Jian Teddy Zheng, Wenwei Tu, Roberto Bruzzone, Joseph Sriyal Malik Peiris, Shie-Liang Hsieh, Hui-Ling Yen
: Human infections with influenza viruses exhibit mild to severe clinical outcome as a result of complex virus-host interactions. Induction of inflammatory mediators via pattern recognition receptors may dictate subsequent host responses for pathogen clearance and tissue damage. We identified that human C-type lectin member 5A (CLEC5A) interacts with the hemagglutinin protein of influenza viruses expressed on lentiviral pseudoparticles through lectin screening. Silencing CLEC5A gene expression, blocking influenza-CLEC5A interactions with anti-CLEC5A antibodies, or dampening CLEC5A-mediated signaling using a spleen tyrosine kinase inhibitor consistently reduced the levels of pro-inflammatory cytokines produced by human macrophages without affecting the replication of influenza A viruses of different subtypes...
October 19, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27789138/synthesis-and-optimization-of-furano-3-2-d-pyrimidines-as-selective-spleen-tyrosine-kinase-syk-inhibitors
#9
Michael Hoemann, Noel Wilson, Maria Argiriadi, David Banach, Andrew Burchat, David Calderwood, Bruce Clapham, Phil Cox, David B Duignan, Don Konopacki, Gagandeep Somal, Anil Vasudevan
A series of furano[3,2-d]pyrimidine Syk inhibitors were synthesized and optimized for their enzyme potency and selectivity versus other kinases. In addition, ADME properties were assessed and compounds were prepared with optimized profiles for in vivo experiments. Compound 23 was identified as having acceptable pharmacokinetic properties and demonstrated efficacy in a rat collagen induced arthritis model.
October 11, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27785737/pharmacokinetics-pharmacodynamics-and-safety-of-entospletinib-a-novel-psyk-inhibitor-following-single-and-multiple-oral-dosing-in-healthy-volunteers
#10
Srini Ramanathan, Julie A Di Paolo, Feng Jin, Lixin Shao, Shringi Sharma, Michelle Robeson, Brian P Kearney
BACKGROUND AND OBJECTIVES: Entospletinib is a selective, reversible, adenosine triphosphate-competitive small-molecule spleen tyrosine kinase (SYK) inhibitor that blocks B cell receptor-mediated signaling and proliferation in B lymphocytes. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of entospletinib in a double-blind, single/multiple ascending dose study in healthy volunteers. METHODS: In sequential cohorts, 120 subjects received entospletinib (25-1200 mg; fasted) as single or twice-daily oral doses for 7 days...
October 26, 2016: Clinical Drug Investigation
https://www.readbyqxmd.com/read/27765766/tula-2-t-cell-ubiquitin-ligand-2-inhibits-the-platelet-fc-receptor-for-igg-iia-fc%C3%AE-riia-signaling-pathway-and-heparin-induced-thrombocytopenia-in-mice
#11
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
https://www.readbyqxmd.com/read/27738646/the-role-of-c-reactive-protein-in-innate-and-acquired-inflammation-new-perspectives
#12
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
https://www.readbyqxmd.com/read/27701922/myeloperoxidase-deficiency-enhances-zymosan-phagocytosis-associated-with-up-regulation-of-surface-expression-of-cd11b-in-mouse-neutrophils
#13
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
https://www.readbyqxmd.com/read/27678281/ligand-based-and-e-pharmacophore-modeling-3d-qsar-and-hierarchical-virtual-screening-to-identify-dual-inhibitors-of-spleen-tyrosine-kinase-syk-and-janus-kinase-3-jak3
#14
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
https://www.readbyqxmd.com/read/27670879/card9-negatively-regulates-nlrp3-induced-il-1%C3%AE-production-on-salmonella-infection-of-macrophages
#15
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...
September 27, 2016: Nature Communications
https://www.readbyqxmd.com/read/27670724/-diffuse-cutaneous-mastocytosis-of-an-infant-a-case-report
#16
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
https://www.readbyqxmd.com/read/27608299/the-tyrosine-kinase-inhibitor-tyrphostin-ag126-reduces-activation-of-inflammatory-cells-and-increases-foxp3-regulatory-t-cells-during-pathogenesis-of-rheumatoid-arthritis
#17
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
https://www.readbyqxmd.com/read/27602108/alternative-splicing-of-spleen-tyrosine-kinase-differentially-regulates-colorectal-cancer-progression
#18
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
https://www.readbyqxmd.com/read/27578246/optimisation-of-a-novel-series-of-potent-and-orally-bioavailable-azanaphthyridine-syk-inhibitors
#19
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
https://www.readbyqxmd.com/read/27571702/ameliorative-effects-of-artemisia-argyi-folium-extract-on-2-4%C3%A2-dinitrochlorobenzene%C3%A2-induced-atopic-dermatitis%C3%A2-like-lesions-in-balb-c-mice
#20
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
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