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ADAM17

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https://www.readbyqxmd.com/read/28063160/elevated-semaphorin5a-in-systemic-lupus-erythematosus-is-in-association-with-disease-activity-and-lupus-nephritis
#1
Yan Du, Xinyu Wu, Mo Chen, Wenwen Wang, Weihong Xv, Lv Ye, Di Wu, Jing Xue, Wenjia Sun, Judong Luo, Huaxiang Wu
OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by extensive immune response including over-activation of T and B cells development of pathogenic autoantibodies, organ damage induced by the formation and deposition of immune complex, and the abnormal elevation of type I interferon. Semaphorin5A (Sema5A), is essentially involved in immune cell regulation and also implicated in the pathogenesis of autoimmune disorders. We aimed to evaluate the role of Sema5A in patients with SLE...
January 7, 2017: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/28062509/adam17-deficiency-promotes-atherosclerosis-by-enhanced-tnfr2-signaling-in-mice
#2
Alexandros Nicolaou, Zhen Zhao, Bernd H Northoff, Kristina Sass, Andreas Herbst, Alexander Kohlmaier, Athena Chalaris, Christian Wolfrum, Christian Weber, Sabine Steffens, Stefan Rose-John, Daniel Teupser, Lesca M Holdt
OBJECTIVE: ADAM17 (a disintegrin and metalloproteinase 17) is a sheddase releasing different types of membrane-bound proteins, including adhesion molecules, cytokines, and their receptors as well as inflammatory mediators. Because these substrates modulate important mechanisms of atherosclerosis, we hypothesized that ADAM17 might be involved in the pathogenesis of this frequent disease. APPROACH AND RESULTS: Because Adam17-knockout mice are not viable, we studied the effect of Adam17 deficiency on atherosclerosis in Adam17 hypomorphic mice (Adam17(ex/ex)), which have low residual Adam17 expression...
December 22, 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28060820/proteolytic-origin-of-the-soluble-human-il-6r-in-vivo-and-a-decisive-role-of-n-glycosylation
#3
Steffen Riethmueller, Prasath Somasundaram, Johanna C Ehlers, Chien-Wen Hung, Charlotte M Flynn, Juliane Lokau, Maria Agthe, Stefan Düsterhöft, Yijue Zhu, Joachim Grötzinger, Inken Lorenzen, Tomas Koudelka, Kosuke Yamamoto, Ute Pickhinke, Rielana Wichert, Christoph Becker-Pauly, Marisa Rädisch, Alexander Albrecht, Markus Hessefort, Dominik Stahnke, Carlo Unverzagt, Stefan Rose-John, Andreas Tholey, Christoph Garbers
Signaling of the cytokine interleukin-6 (IL-6) via its soluble IL-6 receptor (sIL-6R) is responsible for the proinflammatory properties of IL-6 and constitutes an attractive therapeutic target, but how the sIL-6R is generated in vivo remains largely unclear. Here, we use liquid chromatography-mass spectrometry to identify an sIL-6R form in human serum that originates from proteolytic cleavage, map its cleavage site between Pro-355 and Val-356, and determine the occupancy of all O- and N-glycosylation sites of the human sIL-6R...
January 2017: PLoS Biology
https://www.readbyqxmd.com/read/28059830/2-deoxy-d-glucose-suppresses-the-migration-and-reverses-the-drug-resistance-of-colon-cancer-cells-through-adam-expression-regulation
#4
Ga B Park, Yoon H Chung, Daejin Kim
Cancer cell resistance to chemotherapy is associated with a poor prognosis. The compound 2-deoxy-D-glucose (2-DG) enhances the effect of chemotherapy against cancer cells lines in vitro and in vivo. However, its effect on the epithelial to mesenchymal transition (EMT) in drug-resistant cancer cells has not been fully elucidated. In this study, we investigated whether treatment of 5-fluorouracil or oxaliplatin-resistant colorectal cancer (CRC) cells with 2-DG suppressed their migratory activity and enhanced their susceptibility to chemotherapy...
January 2, 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/28056193/reduced-cd62l-expression-on-t-cells-and-increased-soluble-cd62l-levels-predict-molecular-response-to-tyrosine-kinase-inhibitor-therapy-in-early-chronic-phase-chronic-myelogenous-leukemia
#5
Sieghart Sopper, Satu Mustjoki, Deborah White, Timothy Hughes, Peter Valent, Andreas Burchert, Bjørn T Gjertsen, Günther Gastl, Matthias Baldauf, Zlatko Trajanoski, Frank Giles, Andreas Hochhaus, Thomas Ernst, Thomas Schenk, Jeroen J W M Janssen, Gert J Ossenkoppele, Kimmo Porkka, Dominik Wolf
Purpose Immunologic surveillance of minimal residual disease in chronic myelogenous leukemia (CML) may be relevant for long-term control or cure of CML. Little is known about immune-modulatory effects of nilotinib in vivo, potentially predicting response to therapy. Patients and Methods A prospective and comprehensive flow cytometry-based immunomonitoring program paralleled the ENEST1st clinical study, investigating 52 nilotinib-naïve patients with chronic-phase CML. Data were verified in independent validation cohorts...
January 10, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28053235/inactivation-of-rab11a-gtpase-in-macrophages-facilitates-phagocytosis-of-apoptotic-neutrophils
#6
Chunling Jiang, Zheng Liu, Rong Hu, Lulong Bo, Richard D Minshall, Asrar B Malik, Guochang Hu
The timely and efficient clearance of apoptotic neutrophils by macrophages (efferocytosis) is required for the resolution of inflammation and tissue repair, but the regulatory mechanisms remain unclear. In this study, we investigated the role of the small GTPase Ras-related protein in brain (Rab)11a in regulating efferocytosis, and on this basis the resolution of inflammatory lung injury. We observed that apoptotic neutrophil feeding induced a rapid loss of Rab11a activity in bone marrow-derived macrophages and found that depletion of Rab11a in macrophages by small interfering RNA dramatically increased the phagocytosis of apoptotic neutrophils compared with control cells...
January 4, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28049760/a-study-of-tnf-pathway-activation-in-schizophrenia-and-bipolar-disorder-in-plasma-and-brain-tissue
#7
Eva Zsuzsanna Hoseth, Thor Ueland, Ingrid Dieset, Rebecca Birnbaum, Joo Heon Shin, Joel Edward Kleinman, Thomas Michael Hyde, Ragni Helene Mørch, Sigrun Hope, Tove Lekva, Aurelija Judita Abraityte, Annika E Michelsen, Ingrid Melle, Lars Tjelta Westlye, Torill Ueland, Srdjan Djurovic, Pål Aukrust, Daniel R Weinberger, Ole Andreas Andreassen
OBJECTIVE: A proinflammatory imbalance in the tumor necrosis factor (TNF) system may contribute to the pathogenesis of schizophrenia (SCZ) and bipolar disorders (BDs) and related comorbidities. We investigated the relative distribution of TNF-related molecules in blood and dorsolateral prefrontal cortex (DLPFC) in these disorders. METHOD: We measured plasma levels of TNF, soluble TNF receptor 1 (sTNFR1), soluble TNF receptor 2 (sTNFR2), and a disintegrin and metalloprotease-17 (ADAM17) using enzyme immunoassays and calculated the TNF/sTNFRs ratio (TNF/sTNFR1+sTNFR2) in a sample of 816 SCZ and BD spectrum patients and 624 healthy controls (HCs)...
January 3, 2017: Schizophrenia Bulletin
https://www.readbyqxmd.com/read/28004780/adam17-egfr-axis-promotes-transglutaminase-dependent-skin-barrier-formation-through-phosholipase-c-%C3%AE-1-and-protein-kinase-c-pathways
#8
Cristina Wolf, Yawen Qian, Matthew A Brooke, David P Kelsell, Claus-Werner Franzke
The vitally important skin barrier is formed by extensive cross-linking activity of transglutaminases (TGs) during terminal epidermal differentiation. We have previously shown that epidermal deficiency of a disintegrin and metalloproteinase 17 (ADAM17), the principal EGFR ligand sheddase, results in postnatal skin barrier defects in mice due to impeded TG activity. However, the mechanism by which ADAM17/EGFR signalling maintains TG activity during epidermal differentiation remains elusive. Here we demonstrate that ADAM17-dependent EGFR signalling promotes TG activity in keratinocytes committed to terminal differentiation by direct induction of TG1 expression...
December 22, 2016: Scientific Reports
https://www.readbyqxmd.com/read/28004058/contrasting-effects-of-myeloid-and-endothelial-adam17-on-atherosclerosis-development
#9
Emiel P C van der Vorst, Zhen Zhao, Martina Rami, Lesca M Holdt, Daniel Teupser, Sabine Steffens, Christian Weber
No abstract text is available yet for this article.
December 22, 2016: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/27993561/loss-of-smooth-muscle-cell-disintegrin-and-metalloproteinase-17-transiently-suppresses-angiotensin-ii-induced-hypertension-and-end-organ-damage
#10
Mengcheng Shen, Jude Morton, Sandra T Davidge, Zamaneh Kassiri
Hypertension is associated with hypertrophy and hyperplasia of smooth muscle cells (SMCs). Disintegrin and metalloproteinase 17 (ADAM17) is a membrane-bound enzyme reported to mediate SMC hypertrophy through activation of epidermal growth factor receptor (EGFR). We investigated the role of ADAM17 in Ang II-induced hypertension and end-organ damage. VSMC was isolated from mice with intact ADAM17 expression (Adam17(f/f)) or lacking ADAM17 in the SMC (Adam17(f/f)/Cre(Sm22)). Human VSMCs were isolated from the aorta of donors, and ADAM17 deletion was achieved by siRNA transfection...
December 16, 2016: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/27991559/shedding-of-neurexin-3%C3%AE-ectodomain-by-adam10-releases-a-soluble-fragment-that-affects-the-development-of-newborn-neurons
#11
Erika Borcel, Magda Palczynska, Marine Krzisch, Mitko Dimitrov, Giorgio Ulrich, Nicolas Toni, Patrick C Fraering
Neurexins are transmembrane synaptic cell adhesion molecules involved in the development and maturation of neuronal synapses. In the present study, we report that Nrxn3β is processed by the metalloproteases ADAM10, ADAM17, and by the intramembrane-cleaving protease γ-secretase, producing secreted neurexin3β (sNrxn3β) and a single intracellular domain (Nrxn3β-ICD). We further completed the full characterization of the sites at which Nrxn3β is processed by these proteases. Supporting the physiological relevance of the Nrxn3β processing, we demonstrate in vivo a significant effect of the secreted shedding product sNrxn3β on the morphological development of adult newborn neurons in the mouse hippocampus...
December 19, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27982031/harnessing-the-natural-inhibitory-domain-to-control-tnf%C3%AE-converting-enzyme-tace-activity-in-vivo
#12
Eitan Wong, Tal Cohen, Erez Romi, Maxim Levin, Yoav Peleg, Uri Arad, Avraham Yaron, Marcos E Milla, Irit Sagi
Dysregulated activity of A Disintegrin And Metalloproteinase 17 (ADAM17)/TNFα Converting Enzyme (TACE) is associated with inflammatory disorders and cancer progression by releasing regulatory membrane-tethered proteins like TNFα, IL6R and EGFR ligands. Although specific inhibition of TACE is thought to be a viable strategy for inflammatory disorders and for malignancies treatment, the generation of effective inhibitors in vivo has been proven to be challenging. Here we report on the development of a protein inhibitor that leverages the endogenous modulator of TACE...
December 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27941799/inhibition-of-notch-pathway-arrests-pten-deficient-advanced-prostate-cancer-by-triggering-p27-driven-cellular-senescence
#13
Ajinkya Revandkar, Maria Luna Perciato, Alberto Toso, Abdullah Alajati, Jingjing Chen, Hermeto Gerber, Mitko Dimitrov, Andrea Rinaldi, Nicolas Delaleu, Emiliano Pasquini, Rocco D'Antuono, Sandra Pinton, Marco Losa, Letizia Gnetti, Alberto Arribas, Patrick Fraering, Francesco Bertoni, Alain Nepveu, Andrea Alimonti
Activation of NOTCH signalling is associated with advanced prostate cancer and treatment resistance in prostate cancer patients. However, the mechanism that drives NOTCH activation in prostate cancer remains still elusive. Moreover, preclinical evidence of the therapeutic efficacy of NOTCH inhibitors in prostate cancer is lacking. Here, we provide evidence that PTEN loss in prostate tumours upregulates the expression of ADAM17, thereby activating NOTCH signalling. Using prostate conditional inactivation of both Pten and Notch1 along with preclinical trials carried out in Pten-null prostate conditional mouse models, we demonstrate that Pten-deficient prostate tumours are addicted to the NOTCH signalling...
December 12, 2016: Nature Communications
https://www.readbyqxmd.com/read/27929373/tumor-induced-mdsc-act-via-remote-control-to-inhibit-l-selectin-dependent-adaptive-immunity-in-lymph-nodes
#14
Amy W Ku, Jason B Muhitch, Colin A Powers, Michael Diehl, Minhyung Kim, Daniel T Fisher, Anand P Sharda, Virginia K Clements, Kieran O'Loughlin, Hans Minderman, Michelle N Messmer, Jing Ma, Joseph J Skitzki, Douglas A Steeber, Bruce Walcheck, Suzanne Ostrand-Rosenberg, Scott I Abrams, Sharon S Evans
Myeloid-derived suppressor cells (MDSC) contribute to an immunosuppressive network that drives cancer escape by disabling T cell adaptive immunity. The prevailing view is that MDSC-mediated immunosuppression is restricted to tissues where MDSC co-mingle with T cells. Here we show that splenic or, unexpectedly, blood-borne MDSC execute far-reaching immune suppression by reducing expression of the L-selectin lymph node (LN) homing receptor on naïve T and B cells. MDSC-induced L-selectin loss occurs through a contact-dependent, post-transcriptional mechanism that is independent of the major L-selectin sheddase, ADAM17, but results in significant elevation of circulating L-selectin in tumor-bearing mice...
December 8, 2016: ELife
https://www.readbyqxmd.com/read/27923568/noradrenaline-induces-cx3cl1-production-and-release-by-neurons
#15
José L M Madrigal, Javier R Caso, Borja García-Bueno, Irene L Gutiérrez, Juan C Leza
CX3CL1 is a chemokine for which neurons constitute its primary source within the brain. Besides acting as a chemokine, CX3CL1 regulates multiple processes and is known to inhibit microglial activation. Because of this, CX3CL1 is considered as a messenger used by neurons to communicate with microglia. Similarly, the neurotransmitter noradrenaline reduces microglial activation and production of neurotoxic agents. Based on this, the regulation of neuronal CX3CXL1 by noradrenaline was analyzed. In primary cortical neurons, noradrenaline induced the accumulation of CX3CL1 protein and mRNA...
March 1, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/27920432/discovery-of-an-enzyme-and-substrate-selective-inhibitor-of-adam10-using-an-exosite-binding-glycosylated-substrate
#16
Franck Madoux, Daniela Dreymuller, Jean-Phillipe Pettiloud, Radleigh Santos, Christoph Becker-Pauly, Andreas Ludwig, Gregg B Fields, Thomas Bannister, Timothy P Spicer, Mare Cudic, Louis D Scampavia, Dmitriy Minond
ADAM10 and ADAM17 have been shown to contribute to the acquired drug resistance of HER2-positive breast cancer in response to trastuzumab. The majority of ADAM10 and ADAM17 inhibitor development has been focused on the discovery of compounds that bind the active site zinc, however, in recent years, there has been a shift from active site to secondary substrate binding site (exosite) inhibitor discovery in order to identify non-zinc-binding molecules. In the present work a glycosylated, exosite-binding substrate of ADAM10 and ADAM17 was utilized to screen 370,276 compounds from the MLPCN collection...
December 2016: Scientific Reports
https://www.readbyqxmd.com/read/27895032/molecular-pathways-receptor-ectodomain-shedding-in-treatment-resistance-and-monitoring-of-cancer
#17
Miles A Miller, Ryan J Sullivan, Douglas A Lauffenburger
Proteases known as sheddases cleave the extracellular domains of their substrates from the cell surface. The A Disintegrin and Metalloproteinases ADAM10 and ADAM17 are among the most prominent sheddases, being widely expressed in many tissues, frequently over-expressed in cancer, and promiscuously cleaving diverse substrates. It is increasingly clear that the proteolytic shedding of transmembrane receptors impacts pathophysiology and drug response. Receptor substrates of sheddases include the cytokine receptors TNFR1 and IL-6R; the Notch receptors; type-I and -III TGF-β receptors; receptor tyrosine kinases (RTKs) such as HER2, HER4, and VEGFR2; and in particular, MET and TAM-family RTKs AXL and Mer (MerTK)...
November 28, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27878499/therapeutic-potential-of-adam17-modulation-in-gastric-cancer-through-regulation-of-the-egfr-and-tnf-%C3%AE-signalling-pathways
#18
Jinbing Sun, Jianlong Jiang, Kuangyi Lu, Qiao Chen, Danhao Tao, Zhong Chen
A disintegrin and metalloproteinase 17 (ADAM17) is highly expressed in various tumours and affects tumour progression. In this study, ADAM17 expression in 60 gastric cancer and 20 normal gastric mucosal tissues was assessed using immunohistochemistry. ADAM17 expression was higher in gastric cancer tissues than in normal gastric mucosal tissues (P < 0.0005). A significant relationship was identified between ADAM17 expression and the depth of tumour invasion, metastasis, and carcinoma stage. Furthermore, the effects of ADAM17 knockdown on the proliferation, cell invasion, and apoptosis of human gastric carcinoma cells (SGC-7901) were determined...
November 22, 2016: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/27874952/nox1-promotes-colon-cancer-cell-metastasis-via-activation-of-the-adam17-pathway
#19
H-P Wang, X Wang, L-F Gong, W-J Chen, Z Hao, S-W Feng, Y-B Wu, T Ye, Y-K Cai
OBJECTIVE: Reactive oxygen species (ROS) generated by endogenous metabolic enzymes are involved in a variety of pathology processes, including cancer. In particular, superoxide-generating NADPH oxidase 1 (Nox1), a member of Nox enzyme family, is highly expressed in the colon tissue and has been implicated in physiological and pathophysiological states of colon cancer. However, the underlying molecular mechanism of Nox1 in the regulation of colon cancer progression remains largely unknown...
November 2016: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/27869207/erratum-control-of-adam17-activity-by-regulation-of-its-cellular-localisation
#20
Inken Lorenzen, Juliane Lokau, Yvonne Korpys, Mirja Oldefest, Charlotte M Flynn, Ulrike Künzel, Christoph Garbers, Matthew Freeman, Joachim Grötzinger, Stefan Düsterhöft
No abstract text is available yet for this article.
November 21, 2016: Scientific Reports
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