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https://www.readbyqxmd.com/read/29777684/repositioning-of-anti-cancer-drug-candidate-azd7762-to-an-anti-allergic-drug-suppressing-ige-mediated-mast-cells-and-allergic-responses-via-the-inhibition-of-lyn-and-fyn
#1
Young Hwan Park, Do Kyun Kim, Hyun Woo Kim, Hyuk Soon Kim, Dajeong Lee, Min Bum Lee, Keun Young Min, Jimo Koo, Su Jeong Kim, Changhee Kang, Young Mi Kim, Hyung Sik Kim, Wahn Soo Choi
Mast cells are critical effector cells in IgE-mediated allergic responses. The aim of this study was to investigate the anti-allergic effects of 3-[(aminocarbonyl)amino]-5-(3-fluorophenyl)-N-(3S)-3-piperidinyl-2-thiophenecarboxamide (AZD7762) in vitro and in vivo. AZD7762 inhibited the antigen-stimulated degranulation from RBL-2H3 (IC50 , ∼ 27.9 nM) and BMMCs (IC50 , ∼ 99.3 nM) in a dose-dependent manner. AZD7762 also inhibited the production of TNF-α and IL-4. As the mechanism of its action, AZD7762 inhibited the activation of Syk and its downstream signaling proteins, such as Linker of activated T cells (LAT), phospholipase (PL) Cγ1, Akt, and mitogen-activated protein (MAP) kinases (Erk1 / 2, p38, and JNK) in mast cells...
May 16, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29763550/selective-inhibition-of-the-myeloid-src-family-kinase-fgr-potently-suppresses-aml-cell-growth-in-vitro-and-in-vivo
#2
Mark C Weir, Sherry T Shu, Ravi K Patel, Sabine Hellwig, Li Chen, Li Tan, Nathanael S Gray, Thomas E Smithgall
Acute myelogenous leukemia (AML) is the most common hematologic malignancy in adults, and is often associated with constitutive tyrosine kinase signaling. These pathways involve the non-receptor tyrosine kinases Fes, Syk and the three Src-family kinases expressed in myeloid cells (Fgr, Hck, and Lyn). In this study, we report remarkable anti-AML efficacy of an N-phenylbenzamide kinase inhibitor, TL02-59. This compound potently suppressed the proliferation of bone marrow samples from twenty of twenty-six AML patients, with a striking correlation between inhibitor sensitivity and expression levels of the myeloid Src family kinases Fgr, Hck, and Lyn...
May 15, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29748439/autologous-t-cell-activation-fosters-abt-199-resistance-in-chronic-lymphocytic-leukemia-rationale-for-a-combined-therapy-with-syk-inhibitors-and-anti-cd20-moabs
#3
Esteban Enrique Elías, María Belén Almejún, Ana Colado, Gregorio Cordini, Maricef Vergara-Rubio, Enrique Podaza, Denise Risnik, María Cabrejo, Horacio Fernández-Grecco, Raimundo Fernando Bezares, María Del Rosario Custidiano, Julio César Sánchez-Ávalos, Ángeles Vicente, Gonzalo Martín Garate, Mercedes Borge, Mirta Giordano, Romina Gamberale
No abstract text is available yet for this article.
May 10, 2018: Haematologica
https://www.readbyqxmd.com/read/29746940/nlrp3-inflammasome-is-involved-in-the-recognition-of-paracoccidioides-brasiliensis-by-human-dendritic-cells-and-in-the-induction-of-th17-cells
#4
Lívia Furquim de Castro, Larissa Nara Alegrini Longhi, Munir Regini Paião, Amauri da Silva Justo Júnior, Marcelo Bispo de Jesus, Maria Heloisa de Souza Lima Blotta, Ronei Luciano Mamoni
OBJECTIVES: To investigate the involvement of NLRP3 in the effector functions of human dendritic cells (DCs) in response to Paracoccidioides brasiliensis yeast cells (Pb) and to evaluate its role in the modulation of the adaptive immune response. METHODS: DCs were differentiated from purified peripheral blood monocytes and analyzed in relation to the participation of TLR-2, dectin-1, and Syk in Pb recognition, as well as, the indirect mechanisms (Reactive Oxygen Species production, endosome acidification, or K+ efflux) involved in NLRP3 inflammasome activation after the stimulus with Pb...
May 7, 2018: Journal of Infection
https://www.readbyqxmd.com/read/29739316/a-genome-wide-survey-of-mutations-in-the-jurkat-cell-line
#5
Louis Gioia, Azeem Siddique, Steven R Head, Daniel R Salomon, Andrew I Su
BACKGROUND: The Jurkat cell line has an extensive history as a model of T cell signaling. But at the turn of the 21st century, some expression irregularities were observed, raising doubts about how closely the cell line paralleled normal human T cells. While numerous expression deficiencies have been described in Jurkat, genetic explanations have only been provided for a handful of defects. RESULTS: Here, we report a comprehensive catolog of genomic variation in the Jurkat cell line based on whole-genome sequencing...
May 8, 2018: BMC Genomics
https://www.readbyqxmd.com/read/29712773/chronic-lymphocytic-leukemia-derived-il-10-suppresses-antitumor-immunity
#6
Sara S Alhakeem, Mary K McKenna, Karine Z Oben, Sunil K Noothi, Jacqueline R Rivas, Gerhard C Hildebrandt, Roger A Fleischman, Vivek M Rangnekar, Natarajan Muthusamy, Subbarao Bondada
Chronic lymphocytic leukemia (CLL) patients progressively develop an immunosuppressive state. CLL patients have more plasma IL-10, an anti-inflammatory cytokine, than healthy controls. In vitro human CLL cells produce IL-10 in response to BCR cross-linking. We used the transgenic Eμ-T cell leukemia oncogene-1 ( TCL1 ) mouse CLL model to study the role of IL-10 in CLL associated immunosuppression. Eμ-TCL mice spontaneously develop CLL because of a B cell-specific expression of the oncogene, TCL1. Eμ- TCL1 mouse CLL cells constitutively produce IL-10, which is further enhanced by BCR cross-linking, CLL-derived IL-10 did not directly affect survival of murine or human CLL cells in vitro...
April 30, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29689251/deregulated-psgl-1-expression-in-b-cells-and-dendritic-cells-may-be-implicated-in-human-systemic-sclerosis-development
#7
Javier Silván, Rafael González-Tajuelo, Esther Vicente-Rabaneda, Alicia Pérez-Frías, Marina Espartero-Santos, Antonio Muñoz-Cañejas, Elena García-Lorenzo, Carlos Gamallo, Santos Castañeda, Ana Urzainqui
Systemic sclerosis (SSc) is an autoimmune disorder with high morbidity and mortality, difficult early diagnosis and without curative treatment. PSGL-1 is a leukocyte receptor whose deficiency in mice promotes an SSc-like disease. ADAM8, a metalloprotease that cleaves PSGL-1, is implicated in inflammatory processes. Our goal was to evaluate whether PSGL-1 and ADAM8 contribute to the pathogenesis of human SSc. We found that patients with SSc presented increased PSGL-1 expression on monocytes, dendritic cells (DCs) and T cells, and decreased expression of PSGL-1 on B cells...
April 21, 2018: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29677469/multidomain-control-over-tec-kinase-activation-state-tunes-the-t-cell-response
#8
Amy H Andreotti, Raji E Joseph, James M Conley, Janet Iwasa, Leslie J Berg
Signaling through the T cell antigen receptor (TCR) activates a series of tyrosine kinases. Directly associated with the TCR, the SRC family kinase LCK and the SYK family kinase ZAP-70 are essential for all downstream responses to TCR stimulation. In contrast, the TEC family kinase ITK is not an obligate component of the TCR cascade. Instead, ITK functions as a tuning dial, to translate variations in TCR signal strength into differential programs of gene expression. Recent insights into TEC kinase structure have provided a view into the molecular mechanisms that generate different states of kinase activation...
April 26, 2018: Annual Review of Immunology
https://www.readbyqxmd.com/read/29673901/the-role-of-syk-in-peripheral-t-cells
#9
Jeoung-Eun Park, Sirshendu Majumdar, David D Brand, Edward F Rosloniec, Ae-Kyung Yi, John M Stuart, Andrew H Kang, Linda K Myers
The aim of this study was to understand how Syk affects peripheral T cell function. T cells from Syk-/- chimeric mice and DR1 Sykfl/fl CD4cre conditional mice gave strong CD3-induced Th1, Th2, and Th17 cytokine responses. However, an altered peptide ligand (APL) of human CII (256-276) with two substitutions (F263N, E266D), also called A12, elicited only Th2 cytokine responses from Sykfl/fl T cells but not Sykfl/fl- CD4cre T cells. Western blots revealed a marked increase in the phosphorylation of Syk, JNK and p38 upon A12/DR1 activation in WT or Sykfl/fl T cells but not in Sykfl/fl CD4-cre cells...
April 16, 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/29669390/editorial-title-lessons-learned-from-a-failed-clinical-trial
#10
EDITORIAL
E F A Leijten, T R D J Radstake, K A Reedquist
Spleen tyrosine kinase (Syk), through its capacity to promote the pathogenic activation of B lymphocytes, myeloid cells, osteoclasts, and stromal fibroblast-like synoviocytes, has been subject to intense translational and clinical scrutiny as a potential therapeutic target in rheumatoid arthritis (RA) (1). Initial phase II clinical trials with the Syk inhibitor fostamatinib showed promising effectivity in treating RA patients that had displayed inadequate responses to methotrexate (2,3). However, concerns were raised of drug-dependent adverse effects in these studies, and fostamatinib did not improve disease in RA patients failing other biologic agents (4)...
April 18, 2018: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/29668708/dectin-1-2-induced-autocrine-pge2-signaling-licenses-dendritic-cells-to-prime-th2-responses
#11
Maria M M Kaisar, Manuel Ritter, Carlos Del Fresno, Hulda S Jónasdóttir, Alwin J van der Ham, Leonard R Pelgrom, Gabriele Schramm, Laura E Layland, David Sancho, Clarissa Prazeres da Costa, Martin Giera, Maria Yazdanbakhsh, Bart Everts
The molecular mechanisms through which dendritic cells (DCs) prime T helper 2 (Th2) responses, including those elicited by parasitic helminths, remain incompletely understood. Here, we report that soluble egg antigen (SEA) from Schistosoma mansoni, which is well known to drive potent Th2 responses, triggers DCs to produce prostaglandin E2 (PGE2), which subsequently-in an autocrine manner-induces OX40 ligand (OX40L) expression to license these DCs to drive Th2 responses. Mechanistically, SEA was found to promote PGE2 synthesis through Dectin-1 and Dectin-2, and via a downstream signaling cascade involving spleen tyrosine kinase (Syk), extracellular signal-regulated kinase (ERK), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase 1 and 2 (COX-1 and COX-2)...
April 18, 2018: PLoS Biology
https://www.readbyqxmd.com/read/29625466/narrow-spectrum-kinase-inhibitors-demonstrate-promise-for-the-treatment-of-dry-eye-disease-and-other-ocular-inflammatory-disorders
#12
Suzanne Hagan, Matthew C T Fyfe, Boatemaa Ofori-Frimpong, Katherine Oliver, Martyn R Foster, Sameer Sirohi, Yemisi Solanke, Michael Doughty, Adele Rowley, Mike Taylor, Steve Webber, Claire A Walshe
Purpose: The purpose of this study is to determine the potential of narrow spectrum kinase inhibitors (NSKIs) to treat inflammatory eye disorders. Methods: Human conjunctival epithelial (HCE) cells were retrieved from subjects via impression cytology. Real-time quantitative PCR (qPCR) was performed on HCE cells to determine gene expression of NSKI kinase targets and proinflammatory cytokines in dry eye disease (DED) patients versus healthy controls. qPCR also assessed p38α expression in hyperosmolar-treated Chang conjunctival epithelial cells...
March 1, 2018: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29616019/the-syk-coupled-c-type-lectin-receptors-dectin-2-and-dectin-3-are-involved-in-paracoccidioides-brasiliensis-recognition-by-human-plasmacytoid-dendritic-cells
#13
Nycolas Willian Preite, Claudia Feriotti, Dhêmerson Souza de Lima, Bruno Borges da Silva, Antônio Condino-Neto, Alessandra Pontillo, Vera Lúcia Garcia Calich, Flávio Vieira Loures
Plasmacytoid dendritic cells (pDCs), which have been extensively studied in the context of the immune response to viruses, have recently been implicated in host defense mechanisms against fungal infections. Nevertheless, the involvement of human pDCs during paracoccidioidomycosis (PCM), a fungal infection endemic to Latin America, has been scarcely studied. However, pDCs were found in the cutaneous lesions of PCM patients, and in pulmonary model of murine PCM these cells were shown to control disease severity...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29537660/tyrosine-kinase-syk-is-a-potential-therapeutic-target-for-liver-fibrosis
#14
Chen Qu, Dandan Zheng, Sai Li, Yingjun Liu, Anna Lidofsky, Jacinta A Holmes, Jianning Chen, Lu He, Lan Wei, Yadi Liao, Hui Yuan, Qimeng Jin, Zelong Lin, Qiaoting Hu, Yuchuan Jiang, Mengxian Tu, Xijun Chen, Weiming Li, Wenyu Lin, Bryan C Fuchs, Raymond T Chung, Jian Hong
Spleen tyrosine kinase (SYK) plays a critical role in immune cell signaling pathways and has been reported as a novel biomarker for human hepatocellular carcinoma (HCC). We sought to investigate the mechanism by which SYK promotes liver fibrosis and to evaluate SYK as a therapeutic target for liver fibrosis. We evaluated the cellular localization of SYK and the association between SYK expression and liver fibrogenesis in normal, HBV-infected, HCV-infected and non-alcoholic steatohepatitis (NASH) liver tissue (n=36, 127, 22 and 30, respectively)...
March 14, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29472360/immobilized-fibrinogen-activates-human-platelets-through-glycoprotein-vi
#15
Pierre H Mangin, Marie-Blanche Onselaer, Nicolas Receveur, Nicolas Le Lay, Alexander T Hardy, Clare Wilson, Ximena Sanchez, Stéphane 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
Glycoprotein VI, a major platelet activation receptor for collagen and fibrin, is considered a particularly promising, safe antithrombotic target. In this study, we show that human glycoprotein VI signals upon platelet adhesion to fibrinogen. Full spreading of human platelets on fibrinogen was abolished in platelets from glycoprotein VI- deficient patients suggesting that fibrinogen activates platelets through glycoprotein VI. While mouse platelets failed to spread on fibrinogen, human-glycoprotein VI-transgenic mouse platelets showed full spreading and increased Ca2+ signaling through the tyrosine kinase Syk...
May 2018: Haematologica
https://www.readbyqxmd.com/read/29459869/fc%C3%A2%C2%B5-receptor-promotes-the-survival-and-activation-of-marginal-zone-b-cells-and-protects-mice-against-bacterial-sepsis
#16
Jun Liu, Hanying Zhu, Jiawen Qian, Ermeng Xiong, Lumin Zhang, Yan-Qing Wang, Yiwei Chu, Hiromi Kubagawa, Takeshi Tsubata, Ji-Yang Wang
The marginal zone B cells (MZB) are located at the interface between the circulation and lymphoid tissue and as a gatekeeper play important roles in both innate and adaptive immune responses. We have previously found that MZB are significantly reduced in mice deficient in the IgM Fc receptor (FcμR) but how FcμR regulates the development and function of MZB remains unknown. In this study, we found that both marginal zone precursor (MZP) and MZB were decreased in FcμR -/- mice. The reduction of MZP and MZB was not due to impaired proliferation of these cells but rather due to their increased death...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29440271/phosphorylated-immunoreceptor-tyrosine-based-activation-motifs-and-integrin-cytoplasmic-domains-activate-spleen-tyrosine-kinase-via-distinct-mechanisms
#17
Lina Antenucci, Vesa P Hytönen, Jari Ylänne
Spleen tyrosine kinase (Syk) is involved in cellular adhesion and also in the activation and development of hematopoietic cells. Syk activation induced by genomic rearrangement has been linked to certain T-cell lymphomas, and Syk inhibitors have been shown to prolong survival of patients with B-cell lineage malignancies. Syk is activated either by its interaction with a double-phosphorylated immunoreceptor tyrosine-based activation motif (pITAM), which induces rearrangements in the Syk structure, or by the phosphorylation of specific tyrosine residues...
March 30, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29401630/tetrandrine-attenuates-the-bone-erosion-in-collagen-induced-arthritis-rats-by-inhibiting-osteoclastogenesis-via-spleen-tyrosine-kinase
#18
Yugai Jia, Yumeng Miao, Mengfan Yue, Mei Shu, Zhifeng Wei, Yue Dai
Tetrandrine, a bisbenzylisoquinoline alkaloid, was previously demonstrated to attenuate inflammation and cartilage destruction in the ankles of mice with collagen-induced arthritis (CIA). Here, we explored the underlying mechanism by which tetrandrine prevented arthritis-induced bone erosion by focusing on the differentiation and function of osteoclasts. We found that daily administration of tetrandrine (30 mg/kg) markedly reduced the bone damage and decreased the number of osteoclasts in CIA rats. In vitro, tetrandrine inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis at the early stage and reduced the expressions of osteoclast-related marker genes...
January 30, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29386201/cd301b-mgl2-mononuclear-phagocytes-orchestrate-autoimmune-cardiac-valve-inflammation-and-fibrosis
#19
Lee A Meier, Jennifer L Auger, Brianna J Engelson, Hannah M Cowan, Elise R Breed, Mayra I Gonzalez-Torres, Joshua D Boyer, Mayank Verma, Aubyn Marath, Bryce A Binstadt
Background -Valvular heart disease (VHD) is common and affects the mitral valve (MV) most frequently. Despite the prevalence of mitral valve disease (MVD), the cellular and molecular pathways that initiate and perpetuate it are not well understood. Methods -K/B.g7 T cell receptor (TCR) transgenic mice spontaneously develop systemic autoantibody-associated autoimmunity, leading to fully-penetrant fibro-inflammatory MVD and arthritis. We used multiparameter flow cytometry, intracellular cytokine staining, and immunofluorescent staining to characterize the cells in inflamed K/B...
January 31, 2018: Circulation
https://www.readbyqxmd.com/read/29372378/syk-targeted-dendritic-cell-mediated-cytotoxic-t-lymphocytes-enhance-the-effect-of-immunotherapy-on-retinoblastoma
#20
Xuemei Chen, Patricia Elena Kunda, Jianwei Lin, Meiling Zhou, Jinghan Huang, Huqin Zhang, Tao Liu
PURPOSE: Retinoblastoma (RB) is the most common primary intraocular tumor in children. Chemotherapy is currently the main method of RB treatment. Unfortunately, RB often becomes chemoresistant and turns lethal. Here, we used in vitro cell immunotherapy to explore whether adoptive immunotherapy could be used as a potential treatment for RB. We focused on spleen tyrosine kinase (SYK), which is significantly upregulated in RB cells and serves as a marker for RB cells. METHODS: Using lentiviruses, we genetically modified dendritic cells (DCs) to express and present the SYK peptide antigen to cytotoxic T lymphocytes (CTLs) in vitro...
April 2018: Journal of Cancer Research and Clinical Oncology
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