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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/27902465/gene-and-microrna-modulation-upon-trabectedin-treatment-in-a-human-intrahepatic-cholangiocarcinoma-paired-patient-derived-xenograft-and-cell-line
#2
Caterina Peraldo Neia, Giuliana Cavalloni, Giovanna Chiorino, Paola Ostano, Massimo Aglietta, Francesco Leone
Intrahepatic cholangiocarcinoma (ICC) is an aggressive and lethal malignancy with limited therapeutic options. Trabectedin has a high antitumor activity in preclinical models of biliary tract carcinoma (BTC), being a promising alternative treatment. Here, we studied the effect of trabectedin at transcriptomic level on an ICC patient derived xenograft (PDX) and on the derived cell line, MT-CHC01. Further, putative targets of trabectedin were explored in the in vitro model. In vitro, trabectedin inhibited genes involved in protein modification, neurogenesis, migration, and motility; it induced the expression of genes involved in keratinization, tissues development, and apoptotic processes...
November 24, 2016: Oncotarget
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/27899526/dynamic-pre-bcr-homodimers-fine-tune-autonomous-survival-signals-in-b-cell-precursor-acute-lymphoblastic-leukemia
#4
M Frank Erasmus, Ksenia Matlawska-Wasowska, Ichiko Kinjyo, Avanika Mahajan, Stuart S Winter, Li Xu, Michael Horowitz, Diane S Lidke, Bridget S Wilson
The pre-B cell receptor (pre-BCR) is an immature form of the BCR critical for early B lymphocyte development. It is composed of the membrane-bound immunoglobulin (Ig) heavy chain, surrogate light chain components, and the signaling subunits Igα and Igβ. We developed monovalent quantum dot (QD)-labeled probes specific for Igβ to study the behavior of pre-BCRs engaged in autonomous, ligand-independent signaling in live B cells. Single-particle tracking revealed that QD-labeled pre-BCRs engaged in transient, but frequent, homotypic interactions...
November 29, 2016: Science Signaling
https://www.readbyqxmd.com/read/27895176/the-syk-nfat-il-2-pathway-in-dendritic-cells-is-required-for-optimal-sterile-immunity-elicited-by-alum-adjuvants
#5
Hanif Javanmard Khameneh, Adrian W S Ho, Roberto Spreafico, Heidi Derks, Hazel Q Y Quek, Alessandra Mortellaro
Despite a long history and extensive usage of insoluble aluminum salts (alum) as vaccine adjuvants, the molecular mechanisms underpinning Ag-specific immunity upon vaccination remain unclear. Dendritic cells (DCs) are crucial initiators of immune responses, but little is known about the molecular pathways used by DCs to sense alum and, in turn, activate T and B cells. In this article, we show that alum adjuvanticity requires IL-2 specifically released by DCs, even when T cell secretion of IL-2 is intact. We demonstrate that alum, as well as other sterile particulates, such as uric acid crystals, induces DCs to produce IL-2 following initiation of actin-mediated phagocytosis that leads to Src and Syk kinase activation, Ca(2+) mobilization, and calcineurin-dependent activation of NFAT, the master transcription factor regulating IL-2 expression...
November 28, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27890932/il-10-production-by-cll-cells-is-enhanced-in-the-anergic-ighv-mutated-subset-and-associates-with-reduced-dna-methylation-of-the-il10-locus
#6
S Drennan, A D'Avola, Y Gao, C Weigel, E Chrysostomou, A J Steele, T Zenz, C Plass, P W Johnson, A P Williams, G Packham, F K Stevenson, C C Oakes, F Forconi
Chronic lymphocytic leukemias (CLL) with unmutated (U-CLL) or mutated (M-CLL) IGHV have variable features of immunosuppression, possibly influenced by those CLL cells activated to produce IL-10. The two subsets differ in their levels of anergy, defined by low surface IgM levels/signaling capacity, and in their DNA methylation profile, particularly variable in M-CLL. We have now found that levels of IL-10 produced by activated CLL cells were highly variable. Levels were higher in M-CLL than in U-CLL and correlated with anergy...
November 28, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27890918/2-hydroxy-3-methoxybenzoic-acid-attenuates-mast-cell-mediated-allergic-reaction-in-mice-via-modulation-of-the-fc%C3%AE%C2%B5ri-signaling-pathway
#7
Yeon-Yong Kim, In-Gyu Je, Min Jong Kim, Byeong-Cheol Kang, Young-Ae Choi, Moon-Chang Baek, Byungheon Lee, Jin Kyeong Choi, Hae Ran Park, Tae-Yong Shin, Soyoung Lee, Seung-Bin Yoon, Sang-Rae Lee, Dongwoo Khang, Sang-Hyun Kim
Mast cells are important effector cells in immunoglobulin (Ig) E-mediated allergic reactions such as asthma, atopic dermatitis and rhinitis. Vanillic acid, a natural product, has shown anti-oxidant and anti-inflammatory activities. In the present study, we investigated the anti-allergic inflammatory effects of ortho-vanillic acid (2-hydroxy-3-methoxybenzoic acid, o-VA) that was a derivative of vanillic acid isolated from Amomum xanthioides. In mouse anaphylaxis models, oral administration of o-VA (2, 10, 50 mg/kg) dose-dependently attenuated ovalbumin-induced active systemic anaphylaxis and IgE-mediated cutaneous allergic reactions such as hypothermia, histamine release, IgE production and vasodilation; administration of o-VA also suppressed the mast cell degranulator compound 48/80-induced anaphylaxis...
November 28, 2016: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/27889356/role-of-ptx3-in-corneal-epithelial-innate-immunity-against-aspergillus-fumigatus-infection
#8
Jie Zhang, Guiqiu Zhao, Jing Lin, Chengye Che, Cui Li, Nan Jiang, Liting Hu, Qian Wang
Pentraxin3 (PTX3), a member of long pentraxin family, plays a non-redundant role in human humoral innate immunity. However, whether PTX3 is expressed by corneal epithelial cells and its role during corneal fungi infection has not yet been investigated. To identify the presence of PTX3 in cornea, the possible mechanisms involved in its expression, and also the effects on corneal anti-fungi innate immune response, clinic human corneal tissues and cultured human corneal epithelial cells (HCECs) were resorted. PTX3 mRNA and protein were detected in corneal samples and cultured HCECs, which was significantly up-regulated after exposing to Aspergillus fumigatus (A...
November 23, 2016: Experimental Eye Research
https://www.readbyqxmd.com/read/27888629/inhibition-of-bcr-signaling-using-the-syk-inhibitor-tak-659-prevents-stroma-mediated-signaling-in-chronic-lymphocytic-leukemia-cells
#9
Noelia Purroy, Júlia Carabia, Pau Abrisqueta, Leire Egia, Meritxell Aguiló, Cecilia Carpio, Carles Palacio, Marta Crespo, Francesc Bosch
Proliferation and survival of chronic lymphocytic leukemia (CLL) cells depend on microenvironmental signals coming from lymphoid organs. One of the key players involved in the crosstalk between CLL cells and the microenvironment is the B-cell receptor (BCR). Syk protein, a tyrosine kinase essential for BCR signaling, is therefore a rational candidate for targeted therapy in CLL. Against this background, we tested the efficacy of the highly specific Syk inhibitor TAK-659 in suppressing the favorable signaling derived from the microenvironment...
November 24, 2016: Oncotarget
https://www.readbyqxmd.com/read/27871362/actin-is-an-evolutionarily-conserved-damage-associated-molecular-pattern-that-signals-tissue-injury-in-drosophila-melanogaster
#10
Naren Srinivasan, Oliver Gordon, Susan Ahrens, Anna Franz, Safia Deddouche, Probir Chakravarty, David Phillips, Ali A Yunus, Michael K Rosen, Rita S Valente, Luis Teixeira, Barry Thompson, Marc S Dionne, Will Wood, Caetano Reis E Sousa
Damage associated molecular patterns (DAMPs) are released by dead cells and can trigger sterile inflammation and, in vertebrates, adaptive immunity. Actin is a DAMP detected in mammals by the receptor, DNGR-1, expressed by dendritic cells (DCs). DNGR-1 is phosphorylated by Src-family kinases and recruits the tyrosine kinase Syk to promote DC cross-presentation of dead cell-associated antigens. Here we report that actin is also a DAMP in invertebrates that lack DCs and adaptive immunity. Administration of actin to Drosophila melanogaster triggers a response characterised by selective induction of STAT target genes in the fat body through the cytokine Upd3 and its JAK/STAT-coupled receptor, Domeless...
November 22, 2016: ELife
https://www.readbyqxmd.com/read/27851983/osteopontin-inhibition-of-mir-129-3p-enhances-il-17-expression-and-monocyte-migration-in-rheumatoid-arthritis
#11
Chun-Hao Tsai, Shan-Chi Liu, Yu-Han Wang, Chen-Ming Su, Chien-Chung Huang, Chin-Jung Hsu, Chih-Hsin Tang
BACKGROUND: Osteopontin (OPN) is an important proinflammatory cytokine in rheumatoid arthritis (RA). Levels of OPN have been shown to be significantly correlated with interleukin-17 (IL-17) production and expression of Th17 cells in the synovial fluid of RA patients. Here, we investigated the role of OPN in monocyte migration, IL-17 production and osteoblasts. METHODS: OPN and IL-17 expression profiles in osteoarthritis (OA) and RA synovial fluid were determined by enzyme-linked immunosorbent assay (ELISA)...
November 13, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27845194/human-albumin-attenuates-excessive-innate-immunity-via-inhibition-of-microglial-mincle-syk-signaling-in-subarachnoid-hemorrhage
#12
Yi Xie, Hongquan Guo, Liumin Wang, Lili Xu, Xiaohao Zhang, Linjie Yu, Qian Liu, Yunzi Li, Nana Zhao, Nan Zhao, Ruidong Ye, Xinfeng Liu
Subarachnoid hemorrhage (SAH) is a devastating subtype of stroke. Microglial macrophage-inducible C-type lectin (Mincle) receptor launches microglial innate immunity after SAH, and thereby achieves a key step of early cerebral injury in SAH. We previously revealed albumin could improve long-term neurological outcomes after SAH. In this study, we examined the role of microglia-mediated innate immunity in the salutary effects of albumin. SAH was induced by endovascular perforation in rats. We found that albumin can significantly mitigate early neurovascular dysfunction of SAH rats...
November 10, 2016: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/27837109/characterization-of-the-syk-dependent-t-cell-signaling-response-to-an-altered-peptide
#13
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/27822175/keyhole-limpet-hemocyanin-induces-innate-immunity-via-syk-and-erk-phosphorylation
#14
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/27807193/ptpn22-is-a-critical-regulator-of-fc%C3%AE-receptor-mediated-neutrophil-activation
#15
Sonja Vermeren, Katherine Miles, Julia Y Chu, Donald Salter, Rose Zamoyska, Mohini Gray
Neutrophils act as a first line of defense against bacterial and fungal infections, but they are also important effectors of acute and chronic inflammation. Genome-wide association studies have established that the gene encoding the protein tyrosine phosphatase nonreceptor 22 (PTPN22) makes an important contribution to susceptibility to autoimmune disease, notably rheumatoid arthritis. Although PTPN22 is most highly expressed in neutrophils, its function in these cells remains poorly characterized. We show in this article that neutrophil effector functions, including adhesion, production of reactive oxygen species, and degranulation induced by immobilized immune complexes, were reduced in Ptpn22(-/-) neutrophils...
December 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27792904/epstein-barr-virus-latent-membrane-protein-2a-lmp2a-enhances-il-10-production-through-the-activation-of-bruton-s-tyrosine-kinase-and-stat3
#16
Ryan Incrocci, Levi Barse, Amanda Stone, Sai Vagvala, Michael Montesano, Vijay Subramaniam, Michelle Swanson-Mungerson
Previous data demonstrate that Epstein-Barr Virus Latent Membrane Protein 2A (LMP2A) enhances IL-10 to promote the survival of LMP2A-expressing B cell lymphomas. Since STAT3 is an important regulator of IL-10 production, we hypothesized that LMP2A activates a signal transduction cascade that increases STAT3 phosphorylation to enhance IL-10. Using LMP2A-negative and -positive B cell lines, the data indicate that LMP2A requires the early signaling molecules of the Syk/RAS/PI3K pathway to increase IL-10. Additional studies indicate that the PI3K-regulated kinase, BTK, is responsible for phosphorylating STAT3, which ultimately mediates the LMP2A-dependent increase in IL-10...
January 2017: Virology
https://www.readbyqxmd.com/read/27786273/the-nedd4-2-ndfip1-axis-is-a-negative-regulator-of-ige-mediated-mast-cell-activation
#17
Kwok Ho Yip, Natasha Kolesnikoff, Nicholas Hauschild, Lisa Biggs, Angel F Lopez, Stephen J Galli, Sharad Kumar, Michele A Grimbaldeston
Cross-linkage of the high-affinity immunoglobulin E (IgE) receptor (FcɛRI) on mast cells by antigen ligation has a critical role in the pathology of IgE-dependent allergic disorders, such as anaphylaxis and asthma. Restraint of intracellular signal transduction pathways that promote release of mast cell-derived pro-inflammatory mediators is necessary to dampen activation and restore homoeostasis. Here we show that the ligase Nedd4-2 and the adaptor Ndfip1 (Nedd4 family interacting protein 1) limit the intensity and duration of IgE-FcɛRI-induced positive signal transduction by ubiquitinating phosphorylated Syk, a tyrosine kinase that is indispensable for downstream FcɛRI signalosome activity...
October 27, 2016: Nature Communications
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
#18
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/27775869/degradation-of-lignin-%C3%AE-aryl-ether-units-in-arabidopsis-thaliana-expressing-ligd-ligf-and-ligg-from-sphingomonas-paucimobilis-syk-6
#19
Ewelina Mnich, Ruben Vanholme, Paula Oyarce, Sarah Liu, Fachuang Lu, Geert Goeminne, Bodil Jørgensen, Mohammed Saddik Motawie, Wout Boerjan, John Ralph, Peter Ulvskov, Birger Lindberg Møller, Nanna Bjarnholt, Jesper Harholt
Lignin is a major polymer in the secondary plant cell wall and composed of hydrophobic interlinked hydroxyphenylpropanoid units. The presence of lignin hampers conversion of plant biomass into biofuels; plants with modified lignin are therefore being investigated for increased digestibility. The bacterium Sphingomonas paucimobilis produces lignin-degrading enzymes including LigD, LigF and LigG involved in cleaving the most abundant lignin inter-unit linkage, the β-aryl ether bond. In this study, we expressed the LigD, LigF and LigG (LigDFG) genes in Arabidopsis thaliana to introduce post-lignification modifications into the lignin structure...
October 24, 2016: Plant Biotechnology Journal
https://www.readbyqxmd.com/read/27774606/mechanism-involved-in-interleukin-il-21-induced-phagocytosis-in-human-monocytes-and-macrophages
#20
Francis Vallières, Denis Girard D
The interleukin (IL)-21/IL-21 receptor (R) is a promising system to be exploited for the development of therapeutic strategies. Although the biological activities of IL-21 and its cell signaling events have been largely studied in immunocytes, its interaction with human monocytes and macrophages have been neglected. Previously, we reported that IL-21 enhances FcRγ-mediated phagocytosis in human monocytes and in human monocyte-derived macrophages (HMDM) and identified Syk as a novel molecular target of IL-21...
October 24, 2016: Clinical and Experimental Immunology
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