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Liang Gao, Gülce Sila Gülcüler, Lieke Golbach, Helena Block, Alexander Zarbock, Ana Martin-Villalba
Integrin activation is crucial for regulation of leukocyte rolling, adhesion and trans-vessel migration during inflammation and occurs by engagement of myeloid cells through factors presented by inflamed vessels. However, endothelial-dependent mechanisms of myeloid cell recruitment are not fully understood. Here we show using an autoperfused flow chamber assay of whole blood neutrophils and intravital microscopy of the inflamed cremaster muscle that CD95 mediates leukocyte slow rolling, adhesion and transmigration upon binding of CD95-ligand (CD95L) that is presented by endothelial cells...
October 20, 2016: ELife
Jesus Duque-Afonso, Chiou-Hong Lin, Kyuho Han, Michael C Wei, Jue Feng, Jason Kurzer, Corina Schneidawind, Stephen H K Wong, Michael C Bassik, Michael L Cleary
There is limited understanding of how signaling pathways are altered by oncogenic fusion transcription factors that drive leukemogenesis. To address this, we interrogated activated signaling pathways in a comparative analysis of mouse and human leukemias expressing the fusion protein E2A-PBX1, which is present in 5-7% of pediatric and 50% of pre-B-cell receptor (preBCR+) acute lymphocytic leukemia (ALL). In this study, we describe remodeling of signaling networks by E2A-PBX1 in pre-B-ALL which result in hyperactivation of the key oncogenic effector enzyme PLCγ2...
October 7, 2016: Cancer Research
X Chen, Q Lv, Y Liu, W Deng
Although the role of PLCγ2 in apoptotic response has been reported, too little is known about whether PLCγ2 induces liver cell apoptosis during liver regeneration. Therefore, this study firstly packaged Ad-PLCγ2 recombinant adenovirus and primarily evaluated its effect on apoptosis of rat liver cell BRL-3A in vitro. Following ten days of co-transfection of pHBAd-MCMV-GFP-PLCγ2 and pHBAd-BHG into HEK293 cells, viral cytopathic effect (CPE) was apparent. Following three rounds of amplification, tissue culture infectious dose 50 (TCID50) assay showed that the titer value reached 1×1010 PFU/mL...
September 30, 2016: Cellular and Molecular Biology
Krisztina Futosi, Attila Mócsai
Neutrophils play a critical role in antimicrobial host defense, but their improper activation also contributes to inflammation-induced tissue damage. Therefore, understanding neutrophil biology is important for the understanding, diagnosis, and therapy of both infectious and inflammatory diseases. Neutrophils express a large number of cell-surface receptors that sense extracellular cues and trigger various functional responses through complex intracellular signaling pathways. During the last several years, we and others have shown that tyrosine kinases play a critical role in those processes...
September 2016: Immunological Reviews
Claudia Walliser, Elisabeth Hermkes, Anja Schade, Sebastian Wiese, Julia Deinzer, Marc Zapatka, Laurent Désiré, Daniel Mertens, Stephan Stilgenbauer, Peter Gierschik
Mutations in the gene encoding phospholipase C-γ2 (PLCγ2) have been shown to be associated with resistance to targeted therapy of chronic lymphocytic leukemia (CLL) with the Bruton's tyrosine kinase inhibitor ibrutinib. The fact that two of these mutations, R665W and L845F, imparted upon PLCγ2 an ∼2-3-fold ibrutinib-insensitive increase in the concentration of cytosolic Ca(2+) following ligation of the B cell antigen receptor (BCR) led to the assumption that the two mutants exhibit constitutively enhanced intrinsic activity...
October 14, 2016: Journal of Biological Chemistry
Nili Dezorella, Ben-Zion Katz, Mika Shapiro, Aaron Polliack, Chava Perry, Yair Herishanu
: In the last decade, the B-cell receptor has emerged as a pivotal stimulus in chronic lymphocytic leukemia pathogenesis, and a very feasible therapeutic target. The B-cell receptor responsiveness in chronic lymphocytic leukemia cells is heterogeneous among patients and correlates with aggressiveness of the disease. Here we show, for the first time, that SLP76, a key scaffold protein in T-cell receptor signaling, is ectopically expressed in chronic lymphocytic leukemia cells, with variable levels among patients, and correlates positively with unmutated immunoglobulin heavy chain variable gene mutational status and ZAP-70 expression...
July 21, 2016: Haematologica
A Hamasy, Q Wang, K E M Blomberg, D K Mohammad, L Yu, M Vihinen, A Berglöf, C I E Smith
Irreversible Bruton tyrosine kinase (BTK) inhibitors, ibrutinib and acalabrutinib have demonstrated remarkable clinical responses in multiple B-cell malignancies. Acquired resistance has been identified in a sub-population of patients in which mutations affecting BTK predominantly substitute cysteine 481 in the kinase domain for catalytically active serine, thereby ablating covalent binding of inhibitors. Activating substitutions in the BTK substrate phospholipase Cγ2 (PLCγ2) instead confers resistance independent of BTK...
June 10, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Omri Matalon, Sophia Fried, Aviad Ben-Shmuel, Maor H Pauker, Noah Joseph, Danielle Keizer, Marina Piterburg, Mira Barda-Saad
Natural killer (NK) cells discriminate between healthy cells and virally infected or transformed self-cells by tuning activating and inhibitory signals received through cell surface receptors. Inhibitory receptors inhibit NK cell function by recruiting and activating the tyrosine phosphatase Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-1 (SHP-1) to the plasma membrane. However, to date, the guanine nucleotide exchange factor VAV1 is the only direct SHP-1 substrate identified in NK cells...
2016: Science Signaling
Alok Kumar Verma, Akanksha Sharma, Sandeep Kumar, Rinkesh Kumar Gupta, Dinesh Kumar, Kriti Gupta, B H Giridhar, Mukul Das, Premendra D Dwivedi
Chickpea (CP), a legume of the family Fabaceae, is an important nutrient-rich food providing protein, essential amino acids, vitamins, dietary fibre, and minerals. Unfortunately, several IgE-binding proteins in CP have been detected that are responsible for allergic manifestations in sensitized population. Therefore, the prevalence of CP induced allergy prompted us towards purification, characterization and allergenicity assessment of a major ∼26kDa protein from chickpea crude protein extract (CP-CPE). Purification of CP 26kDa protein was done using a combination of fractionation and anion exchange chromatography...
June 2016: Molecular Immunology
Anja Schade, Claudia Walliser, Martin Wist, Jennifer Haas, Petra Vatter, Johann M Kraus, Davide Filingeri, George Havenith, Hans A Kestler, Joshua D Milner, Peter Gierschik
Deletions in the gene encoding signal-transducing inositol phospholipid-specific phospholipase C-γ2 (PLCγ2) are associated with the novel human hereditary disease PLAID (PLCγ2-associated antibody deficiency and immune dysregulation). PLAID is characterized by a rather puzzling concurrence of augmented and diminished functions of the immune system, such as cold urticaria triggered by only minimal decreases in temperature, autoimmunity, and immunodeficiency. Understanding of the functional effects of the genomic alterations at the level of the affected enzyme, PLCγ2, is currently lacking...
September 2016: Cellular Signalling
Doori Park, Chan-Won Park, YoungJin Choi, Jingjing Lin, Dong-Hyun Seo, Han-Sung Kim, Soo Young Lee, In-Cheol Kang
Small molecule-inhibition targeting protein-protein interaction (PPI) is now recognized as an emerging and challenging area in drug design. We developed a novel interactive drug discovery methodology known as Protein Chip technology (ProteoChip) as a cutting-edge PPI assay system applicable for unique PPI-targeting therapeutics integrated with computer-aided drug design (CADD). Here, we describe a novel small molecular PPI inhibitor, IPS-02001, which the blocks integrin αvβ3-osteopontin interface a novel PPI inhibitor identified by the interactive methodology of both ProteoChip- and CADD-based PPI assay...
May 5, 2016: Biomaterials
Leen Moens, Alisa Kane, Stuart G Tangye
Immunological memory is characterized by the rapid reactivation of memory B cells that produce large quantities of high-affinity antigen-specific antibodies. This contrasts the response of naïve B cells, and the primary immune response, which is much slower and of lower affinity. Memory responses are critical for protection against infectious diseases and form the basis of most currently available vaccines. Although we have known about the phenomenon of long-lived memory for centuries, the biochemical differences underlying these diverse responses of naïve and memory B cells is incompletely resolved...
September 2016: Immunology and Cell Biology
Zhao Yin, Hai-Jiang Xu, Xia-Li Yao, Gang Liu, Chun-Jie Nie, Han Wei, Cai Li, Ming-Lu Liang, Zhang-Yin Ming, Xiao-Jian Zhang
AIMS: It has been proven that carbon nanoparticles or diesel exhaust particles stimulate platelet activation. However, the effect of fine particle matter (PM2.5 ) on platelet activation remains unknown, which motivates this study. METHODS: PM2.5 samples were collected in an urban area of Zhengzhou, China. To study the morphological characteristics and the mass concentrations of trace elements of PM2.5 samples, a filed-emission scanning electron microscope, the Image-J software, and an inductively coupled plasma mass spectrometry were used...
April 4, 2016: Environmental Toxicology
Anthony S L Chan, Winnie W I Lau, Aydan C H Szeto, Jiuling Wang, Yung H Wong
CXCL8 (also known as interleukin-8 or IL-8) is a proinflammatory chemokine that not only modulates the inflammatory and immune responses, but whose upregulation is often associated with diseases including various types of cancer. Although numerous ligands for G protein-coupled receptors (GPCRs) have been shown to stimulate the production of CXCL8, the specificity of the G protein signal remains undefined. By expressing the constitutively active Gα subunits in HEK293 cells, CXCL8 production was herein demonstrated to be most effectively stimulated by Gαq family members, while those of Gαs and Gα12 elicited much weaker activities, and Gαi being totally ineffective...
September 25, 2016: Journal of Molecular Biology
Tamás Németh, Krisztina Futosi, Cassian Sitaru, Jürgen Ruland, Attila Mócsai
Neutrophils are terminally differentiated cells with limited transcriptional activity. The biological function of their gene expression changes is poorly understood. CARD9 regulates transcription during antifungal immunity but its role in sterile inflammation is unclear. Here we show that neutrophil CARD9 mediates pro-inflammatory chemokine/cytokine but not lipid mediator release during non-infectious inflammation. Genetic deficiency of CARD9 suppresses autoantibody-induced arthritis and dermatitis in mice...
2016: Nature Communications
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
Nicholas Steven Archer, Dongli Liu, Jan Shaw, Garry Hannan, Konsta Duesing, Russell Keast
Variability in human taste perception is associated with both genetic and environmental factors. The influence of taste receptor expression on this variability is unknown, in part, due to the difficulty in obtaining human oral tissue that enables quantitative expression measures of taste genes. In a comparison of six current techniques (Oragene RNeasy Kit, Isohelix swab, Livibrush cytobrush, tongue saliva, cheek saliva collection, and fungiform papillae biopsy), we identify the fungiform papillae biopsy is the optimal sampling technique to analyse human taste gene expression...
2016: PloS One
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
Hirotake Ichise, Taeko Ichise, Nobuaki Yoshida
Phospholipase Cγ2 (PLCγ2)-deficient mice exhibit misconnections of blood and lymphatic vessels, and male infertility. However, the cell type responsible for vascular partitioning and the mechanism for male infertility remain unknown. Accordingly, we generated a mouse line that conditionally expresses endogenous Plcg2 in a Cre/loxP recombination-dependent manner, and found that Tie2-Cre- or Pf4-Cre-driven reactivation of Plcg2 rescues PLCγ2-deficient mice from the vascular phenotype. By contrast, male mice rescued from the vascular phenotype exhibited epididymal sperm granulomas...
2016: PloS One
Osamu Tadokoro, Hiroshi Ando, Ichiro Kawahara, Naokazu Asanuma, Masayo Okumura, Junichi Kitagawa, Eiji Kondo, Hiroshi Yagasaki
Previous studies have found a few intralingual ganglionic cells that were immunoreactive to vasoactive intestinal polypeptide (VIP) in the frog. A recent study reported a large number of such cells, and the possibility of the release of substance P (SP) from these. The aim of the present study was to investigate the distribution, origin, and colocalization of VIP- and SP- immunoreactive nerves in the tongue of the bullfrog, R. catesbeiana. In addition, the study also examined the colocalization of SP and phospholipase Cβ2 (PLCβ2 ) in the tongue and jugular ganglion...
July 2016: Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology
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