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https://www.readbyqxmd.com/read/28442704/discovery-of-an-enzyme-and-substrate-selective-inhibitor-of-adam10-using-an-exosite-binding-glycosylated-substrate
#1
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 5, 2016: Scientific Reports
https://www.readbyqxmd.com/read/28414309/tumor-derived-fibulin-3-activates-pro-invasive-nf-%C3%AE%C2%BAb-signaling-in-glioblastoma-cells-and-their-microenvironment
#2
M S Nandhu, A Kwiatkowska, V Bhaskaran, J Hayes, B Hu, M S Viapiano
Molecular profiling of glioblastomas has revealed the presence of key signaling hubs that contribute to tumor progression and acquisition of resistance. One of these main signaling mechanisms is the nuclear factor-kappa B (NF-κB) pathway, which integrates multiple extracellular signals into transcriptional programs for tumor growth, invasion and maintenance of the tumor-initiating population. We show here that an extracellular protein released by glioblastoma cells, fibulin-3, drives oncogenic NF-κB in the tumor and increases NF-κB activation in peritumoral astrocytes...
April 17, 2017: Oncogene
https://www.readbyqxmd.com/read/28413487/vandetanib-and-adam-inhibitors-synergistically-attenuate-the-pathological-migration-of-ebv-infected-retinal-pigment-epithelial-cells-by-regulating-the-vegf-mediated-mapk-pathway
#3
Daejin Kim, Hyun-Suk Ko, Ga Bin Park, Dae Young Hur, Yeong Seok Kim, Jae Wook Yang
The extracellular signals induced by vascular endothelial growth factor (VEGF) are implicated in choroidal neovascularization (CNV) and thus, are associated with vision-limiting complications in the human retina. Vandetanib is an oral anticancer drug that selectively inhibits the activities of VEGF receptor and epidermal growth factor receptor tyrosine kinase; however, the effects of vandetanib on VEGF in retinal pigment epithelial (RPE) cells have not yet been studied. In the present study, a combined treatment of vandetanib and a disintegrin and metalloproteinase (ADAM) protein inhibitors were used to assess the regulation of Epstein-Barr virus (EBV)-infected ARPE19 cells (ARPE19/EBV) migration as a model of CNV...
April 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28404876/increasing-timp3-expression-by-hypomethylating-agents-diminishes-soluble-mica-micb-and-ulbp2-shedding-in-acute-myeloid-leukemia-facilitating-nk-cell-mediated-immune-recognition
#4
Aroa Baragaño Raneros, Alfredo Minguela Puras, Ramon M Rodriguez, Enrique Colado, Teresa Bernal, Eduardo Anguita, Adela Vasco Mogorron, Alberto Chaparro Gil, Vidal-Castiñeira Jr, Leonardo Márquez-Kisinousky, Paula Díaz Bulnes, Amelia Martinez Marin, Maria Carmen García Garay, Beatriz Suarez-Alvarez, Carlos Lopez-Larrea
Acute myeloid leukemia (AML) is a disease with great morphological and genetic heterogeneity, which complicates its prognosis and treatment. The hypomethylating agents azacitidine (Vidaza®, AZA) and decitabine (Dacogen®, DAC) have been approved for the treatment of AML patients, but their mechanisms of action are poorly understood. Natural killer (NK) cells play an important role in the recognition of AML blasts through the interaction of the activating NKG2D receptor with its ligands (NKG2DL: MICA/B and ULBPs1-3)...
March 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28390866/activation-of-transforming-growth-factor-beta-1-signaling-in-gastric-cancer-associated-fibroblasts-increases-their-motility-via-expression-of-rhomboid-5-homolog-2-and-ability-to-induce-invasiveness-of-gastric-cancer-cells
#5
Takatsugu Ishimoto, Keisuke Miyake, Tannistha Nandi, Masakazu Yashiro, Nobuyuki Onishi, Kie Kyon Huang, Suling Joyce Lin, Ramnarayanan Kalpana, Su Ting Tay, Yuka Suzuki, Byoung Chul Cho, Daisuke Kuroda, Kota Arima, Daisuke Izumi, Masaaki Iwatsuki, Yoshifumi Baba, Eiji Oki, Masayuki Watanabe, Hideyuki Saya, Kosei Hirakawa, Hideo Baba, Patrick Tan
BACKGROUND & AIMS: Fibroblasts that interact with cancer cells are called cancer-associated fibroblasts (CAFs)-they promote progression of different tumor types. We investigated the characteristics and functions of CAFs in diffuse-type gastric cancers (DGCs) by analyzing features of their genome and gene expression patterns. METHODS: We isolated CAFs and adjacent non-cancer fibroblasts (NFs) from 110 GC tissues from patients who underwent gastrectomy in Japan from 2008 through 2016...
April 5, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28387913/nivolumab-effectively-inhibit-platinum-resistant-ovarian-cancer-cells-via-induction-of-cell-apoptosis-and-inhibition-of-adam17-expression
#6
L-M Sun, Y-C Liu, W Li, S Liu, H-X Liu, L-W Li, R Ma
OBJECTIVE: Nivolumab is an anti-PD-1 (anti-programmed death-1) monoclonal antibody. It has achieved an overall response rate of 17% in Phase 1 clinical trial for patient with platinum-resistant ovarian cancer (PROC). However, its underlying mechanism has not been fully explored yet. The aim of the study is to investigate the efficiency of nivolumab to inhibit PROC cells and its possible mechanism. MATERIALS AND METHODS: Firstly, methylthiazolyl tetrazolium bromide (MTT) assay was performed to determine the IC50 values of cisplatin in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells...
March 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28351660/tweak-fn14-activation-contributes-to-the-pathogenesis-of-bullous-pemphigoid
#7
Yale Liu, Lingling Peng, Liang Li, Chengfei Liu, Xiao Hu, Shengxiang Xiao, Yumin Xia
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) participates in various cellular effects by engaging its receptor of fibroblast growth factor inducible 14 (Fn14). Increased levels of soluble TWEAK are associated with systemic autoimmunity in patients with lupus erythematosus, rheumatoid arthritis or dermatomyositis. However, the role of TWEAK in bullous pemphigoid (BP) remains unknown. In this study, we found an elevated serum level of TWEAK and a positive correlation between serum TWEAK and anti-BP180 antibodies...
March 25, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28350885/glutamate-dependent-ectodomain-shedding-of-neuregulin-1-type-ii-precursors-in-rat-forebrain-neurons
#8
Yuriko Iwakura, Ran Wang, Naoko Inamura, Kazuaki Araki, Shigeki Higashiyama, Nobuyuki Takei, Hiroyuki Nawa
The neurotrophic factor neuregulin 1 (NRG1) regulates neuronal development, glial differentiation, and excitatory synapse maturation. NRG1 is synthesized as a membrane-anchored precursor and is then liberated by proteolytic processing or exocytosis. Mature NRG1 then binds to its receptors expressed by neighboring neurons or glial cells. However, the molecular mechanisms that govern this process in the nervous system are not defined in detail. Here we prepared neuron-enriched and glia-enriched cultures from embryonic rat neocortex to investigate the role of neurotransmitters that regulate the liberation/release of NRG1 from the membrane of neurons or glial cells...
2017: PloS One
https://www.readbyqxmd.com/read/28297575/selective-inhibition-of-adam17-efficiently-mediates-glycoprotein-ib%C3%AE-retention-during-ex-vivo-generation-of-human-induced-pluripotent-stem-cell-derived-platelets
#9
Shinji Hirata, Takahiko Murata, Daisuke Suzuki, Sou Nakamura, Ryoko Jono-Ohnishi, Hidenori Hirose, Akira Sawaguchi, Satoshi Nishimura, Naoshi Sugimoto, Koji Eto
Donor-independent platelet concentrates for transfusion can be produced in vitro from induced pluripotent stem cells (iPSCs). However, culture at 37°C induces ectodomain shedding on platelets of glycoprotein Ibα (GPIbα), the von Willebrand factor receptor critical for adhesive function and platelet lifetime in vivo, through temperature-dependent activation of a disintegrin and metalloproteinase 17 (ADAM17). The shedding can be suppressed by using inhibitors of panmetalloproteinases and possibly of the upstream regulator p38 mitogen-activated protein kinase (p38 MAPK), but residues of these inhibitors in the final platelet products may be accompanied by harmful risks that prevent clinical application...
March 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28274635/identification-of-novel-tace-inhibitors-compatible-with-topical-application
#10
Gilles Ouvry, Yaël Berton, Yushma Bhurruth-Alcor, Laetitia Bonnary, Claire Bouix-Peter, Karine Bouquet, Marilyne Bourotte, Sandrine Chambon, Catherine Comino, Benoît Deprez, Denis Duvert, Gwenaëlle Duvert, Feriel Hacini-Rachinel, Craig S Harris, Anne-Pascale Luzy, Arnaud Mathieu, Corinne Millois, Jonathan Pascau, Artur Pinto, Gaëlle Polge, Arnaud Reitz, Kevin Reversé, Carine Rosignoli, Nathalie Taquet, Laurent F Hennequin
Targeting the Tumor Necrosis Factor α signalling with antibodies has led to a revolution in the treatment of psoriasis. Locally inhibiting Tumor Necrosis Factor α Converting Enzyme (TACE or ADAM17) could potentially mimic those effects and help treat mild to moderate psoriasis, without the reported side effect of systemic TACE inhibitors. Efforts to identify new TACE inhibitors are presented here. Enzymatic SAR as well as ADME and physico-chemistry data are presented. This study culminated in the identification of potent enzymatic inhibitors...
February 20, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28264989/characterization-of-the-catalytic-properties-of-the-membrane-anchored-metalloproteinase-adam9-in-cell-based-assays
#11
Thorsten Maretzky, Steven Swendeman, Elin Mogollon, Gisela Weskamp, Umut Sahin, Karina Reiss, Carl P Blobel
ADAM9 (A Disintegrin And Metalloprotease 9) is a membrane-anchored metalloproteinase that has been implicated in pathological retinal neovascularization and in tumor progression. ADAM9 has constitutive catalytic activity in both biochemical and cell-based assays and can cleave several membrane proteins, including epidermal growth factor and Ephrin receptor B4; yet little is currently known about the catalytic properties of ADAM9 and its post-translational regulation and inhibitor profile in cell-based assays...
April 13, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28249164/baff-and-taci-dependent-processing-of-baffr-by-adam-proteases-regulates-the-survival-of-b-cells
#12
Cristian R Smulski, Patrick Kury, Lea M Seidel, Hannah S Staiger, Anna K Edinger, Laure Willen, Maximilan Seidl, Henry Hess, Ulrich Salzer, Antonius G Rolink, Marta Rizzi, Pascal Schneider, Hermann Eibel
B cell activating factor (BAFF) provides B cells with essential survival signals. It binds to three receptors: BAFFR, TACI, and BCMA that are differentially expressed by B cell subsets. BAFFR is early expressed in circulating B cells and provides key signals for further maturation. Here, we report that highly regulated BAFFR processing events modulate BAFF responses. BAFFR processing is triggered by BAFF binding in B cells co-expressing TACI and it is executed by the metalloproteases ADAM10 and ADAM17. The degree of BAFF oligomerization, the expression of ADAM proteins in different B cell subsets, and the activation status of the cell determine the proteases involved in BAFFR processing...
February 28, 2017: Cell Reports
https://www.readbyqxmd.com/read/28245631/role-of-nerve-growth-factor-ngf-and-mirnas-in-epithelial-ovarian-cancer
#13
REVIEW
Rocío Retamales-Ortega, Lorena Oróstica, Carolina Vera, Paula Cuevas, Andrea Hernández, Iván Hurtado, Margarita Vega, Carmen Romero
Ovarian cancer is the eighth most common cancer in women worldwide, and epithelial ovarian cancer (EOC) represents 90% of cases. Nerve growth factor (NGF) and its high affinity receptor tyrosine kinase A receptor (TRKA) have been associated with the development of several types of cancer, including EOC; both NGF and TRKA levels are elevated in this pathology. EOC presents high angiogenesis and several molecules have been reported to induce this process. NGF increases angiogenesis through its TRKA receptor on endothelial cells, and by indirectly inducing vascular endothelial growth factor expression...
February 26, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28161636/diallyl-trisulfide-a-chemopreventive-agent-from-allium-vegetables-inhibits-alpha-secretases-in-breast-cancer-cells
#14
Violet A Kiesel, Silvia D Stan
Breast cancer affects one in eight women throughout the course of their lifetime creating a demand for novel prevention strategies against this disease. The Notch signaling pathway is often aberrantly activated in human malignancies including breast cancer. Alpha secretases, including ADAM (A Disintegrin and Metalloprotease) -10 and -17, are proteases that play a key role in the cleavage of cell surface molecules and subsequent ligand-mediated activation of Notch signaling pathway. High expression levels of ADAM10 and 17 have been clinically associated with a lower disease-free survival in breast cancer patients...
February 2, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28160627/interleukin-11-driven-gastric-tumourigenesis-is-independent-of-trans-signalling
#15
Jesse J Balic, Christoph Garbers, Stefan Rose-John, Liang Yu, Brendan J Jenkins
Deregulated gp130-dependent STAT3 signalling by the pleiotropic cytokine interleukin (IL)-11 has been implicated in the pathogenesis of gastric cancer (GC), the third most common cancer worldwide. While the IL-11-gp130-STAT3 signalling axis has traditionally been thought to exclusively use the membrane-bound IL-11 receptor (mIL-11R), recent evidence suggests that mIL-11R can be proteolytically cleaved to generate a soluble form (sIL-11R) which can elicit trans-signalling. Since the role of IL-11 trans-signalling in disease pathogenesis is unknown, here we have employed the IL-11-driven gp130(F/F) spontaneous model of GC to determine whether IL-11 trans-signalling promotes gastric tumourigenesis...
February 1, 2017: Cytokine
https://www.readbyqxmd.com/read/28143719/enhancing-interleukin-6-and-interleukin-11-receptor-cleavage
#16
Juliane Lokau, Marieke Wandel, Christoph Garbers
Proteolytic cleavage of the membrane-bound Interleukin-6 receptor (IL-6R) by the metalloprotease ADAM17 releases an agonistic soluble form of the IL-6R (sIL-6R), which is responsible for the pro-inflammatory trans-signaling branch of the cytokine's activities. This proteolytic step, which is also called ectodomain shedding, is critically regulated by the cleavage site within the IL-6R stalk, because mutations or small deletions within this region are known to render the IL-6R irresponsive towards proteolysis...
January 29, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28122773/adam17-a-molecular-switch-to-control-tnfr2-during-atherogenesis-in-vivo
#17
EDITORIAL
Yiting Jia, Wei Kong
No abstract text is available yet for this article.
February 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28112251/corrigendum-adam17-egfr-axis-promotes-transglutaminase-dependent-skin-barrier-formation-through-phospholipase-c-%C3%AE-1-and-protein-kinase-c-pathways
#18
Cristina Wolf, Yawen Qian, Matthew A Brooke, David P Kelsell, Claus-Werner Franzke
No abstract text is available yet for this article.
January 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28109308/semaphorin-7a-as-a-potential-immune-regulator-and-promising-therapeutic-target-in-rheumatoid-arthritis
#19
Jianmin Xie, Hao Wang
BACKGROUND: Semaphorin 7A (Sema7A) is expressed by several different classes of lymphoid and myeloid cells and is a potent immunomodulator. We examined the role of Sema7A in modulating cellular immune responses and to provide experimental data validating the therapeutic potential of Sema7A in rheumatoid arthritis (RA). METHODS: Soluble Sema7A (sSema7A) levels in the serum and synovial fluid from patients with RA or osteoarthritis, as well as cytokine secretions, were analyzed with an enzyme-linked immunosorbent assay...
January 21, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28107420/the-polyherbal-wattana-formula-displays-anti-amyloidogenic-properties-by-increasing-%C3%AE-secretase-activities
#20
Htut Htut Htoo, Suveerawan Limsuvan, Onusa Thamsermsang, Jean-François Hernandez, Frédéric Checler, Piyarat Govitrapong, Narawut Pakaprot, Pravit Akarasereenont, Bruno Vincent
Alzheimer's disease is characterized by the deposition of insoluble amyloid-β peptides produced from the β-amyloid precursor protein (βAPP). Because α-secretase cleavage by ADAM10 and ADAM17 takes place in the middle of Aβ, its activation is considered as a promising anti-AD therapeutic track. Here we establish that the polyherbal Wattana formula (WNF) stimulates sAPPα production in cells of neuronal and non-neuronal origins through an increase of both ADAM10 and ADAM17 catalytic activities with no modification of BACE1 activity and expression...
2017: PloS One
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