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Marta Stolarczyk, Guido Veit, Andrea Schnur, Mieke Veltman, Gergely L Lukacs, Bob J Scholte
The EGFR/ADAM17 signaling pathway mediates the shedding of growth factors and secretion of cytokines, and is involved in chronic inflammation and tissue remodeling. Since these are hallmarks of cystic fibrosis (CF) lung disease, we hypothesized that CFTR deficiency enhances EGFR/ADAM17 activity in human bronchial epithelial cells. In CFBE41o- cells lacking functional CFTR (iCFTR-) cultured at air-liquid interface (ALI) we found enhanced ADAM17-mediated shedding of the EGFR ligand amphiregulin (AREG) compared to genetically identical cells with induced CFTR expression (iCFTR+)...
December 14, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
Sebastian Krossa, Axel J Scheidig, Joachim Grötzinger, Inken Lorenzen
A Disintegrin and Metalloprotease 17 (ADAM17) can cause the fast release of growth factors and inflammatory mediators from the cell surface. Its activity has to be turned on which occurs by various stimuli. The active form can be inactivated by a structural change in its ectodomain, related to the pattern of the formed disulphide bridges. The switch-off is executed by protein disulfide isomerases (PDIs) that catalyze an isomerization of two disulfide bridges and thereby cause a disulfide switch. We demonstrate that the integrity of the CGHC-motif within the active site of PDIs is indispensable...
January 18, 2018: Scientific Reports
Daniela Granato, Rute A P Costa, Rebeca Kawahara, Sami Yokoo, Annelize Aragao, Romenia Domingues, Bianca Pauletti, Rodrigo Honorato, Juliana Fattori, Ana Figueira, Paulo Oliveira, Silvio Consonni, Denise Castro Fernandes, Francisco Rafael Martins Laurindo, Hinrich Hansen, Adriana F Paes Leme
A Disintegrin And Metalloprotease 17 (ADAM17) modulates signaling events by releasing surface protein ectodomains such as TNFα and the EGFR-ligands. We have previously characterized cytoplasmic thioredoxin-1 (Trx-1) as a partner of ADAM17 cytoplasmic domain. Combining discovery and targeted proteomic approaches, we uncovered that Trx-1 negatively regulates ADAM17 by direct and indirect effect. We performed cell-based assays with synthetic peptides and site-directed mutagenesis and we demonstrated that the interaction interface of Trx-1 and ADAM17 is important for the negative regulation of ADAM17 activity...
January 15, 2018: Antioxidants & Redox Signaling
Wilbur M Song, Satoru Joshita, Yingyue Zhou, Tyler K Ulland, Susan Gilfillan, Marco Colonna
Alzheimer's disease (AD) is a neurodegenerative disease that causes late-onset dementia. The R47H variant of the microglial receptor TREM2 triples AD risk in genome-wide association studies. In mouse AD models, TREM2-deficient microglia fail to proliferate and cluster around the amyloid-β plaques characteristic of AD. In vitro, the common variant (CV) of TREM2 binds anionic lipids, whereas R47H mutation impairs binding. However, in vivo, the identity of TREM2 ligands and effect of the R47H variant remain unknown...
January 10, 2018: Journal of Experimental Medicine
Justin B Schaal, Thorsten Maretzky, Dat Q Tran, Patti A Tran, Prasad Tongaonkar, Carl P Blobel, André J Ouellette, Michael E Selsted
Theta-defensins (θ-defensins) are macrocyclic peptides expressed exclusively in granulocytes and selected epithelia of Old World monkeys.  They contribute to anti-pathogen host defense responses by directly killing a diverse range of microbes.  Of note, θ-defensins also modulate microbe-induced inflammation by affecting the production of soluble tumor necrosis factor (sTNF) and other proinflammatory cytokines.  Here, we report that natural rhesus macaque θ-defensin (RTD) isoforms regulate sTNF cellular release by inhibiting TNF alpha converting enzyme (TACE; also known as a disintegrin and metalloprotease 17; ADAM17), the primary pro-TNF sheddase...
January 9, 2018: Journal of Biological Chemistry
Sarah L Dombernowsky, Jeanette Schwarz, Jacob Samsøe-Petersen, Reidar Albrechtsen, Kim B Jensen, Gary Thomas, Marie Kveiborg
PACS-2 is a multifunctional sorting protein that mediates cell homeostasis. We recently identified PACS-2 in a functional genome-wide siRNA screen for novel regulators of the metalloproteinase ADAM17, the main sheddase for ligands of the ErbB receptor family. Of note, we showed that Pacs2-/- mice have significantly reduced EGFR activity and proliferative index in the intestinal epithelium. As EGFR signaling is highly mitogenic for intestinal epithelial stem cells, and plays essential roles in intestinal epithelial regeneration and tumor development, we have now examined the role of PACS-2 in these processes...
December 12, 2017: Oncotarget
Stefanie Maurer, Korbinian Nepomuk Kropp, Gerd Klein, Alexander Steinle, Sebastian P Haen, Juliane S Walz, Clemens Hinterleitner, Melanie Märklin, Hans-Georg Kopp, Helmut Rainer Salih
Platelets promote metastasis, among others by coating cancer cells traveling through the blood, which results in protection from NK cell immune-surveillance. The underlying mechanisms, however, remain to be fully elucidated. Here we report that platelet-coating reduces surface expression of NKG2D ligands, in particular MICA and MICB, on tumor cells, which was mirrored by enhanced release of their soluble ectodomains. Similar results were obtained upon exposure of tumor cells to platelet-releasate and can be attributed to the sheddases ADAM10 and ADAM17 that are detectable on the platelet surface and in releasate following activation and at higher levels on platelets of patients with metastasized lung cancer compared with healthy controls...
2018: Oncoimmunology
Alexandros Nicolaou, Bernd H Northoff, Zhen Zhao, Alexander Kohlmaier, Kristina Sass, Stefan Rose-John, Sabine Steffens, Christian Weber, Daniel Teupser, Lesca M Holdt
No abstract text is available yet for this article.
January 2018: Thrombosis and Haemostasis
Christine Sommer, Sindre Lee, Hanne Løvdal Gulseth, Jørgen Jensen, Christian A Drevon, Kåre Inge Birkeland
Context: Plasma soluble leptin receptor (sOb-R) seems protective of gestational and type 2 diabetes in observational studies, but the mechanisms are unknown. sOb-R is formed by ectodomain shedding of membrane-bound leptin receptors (Ob-R), but its associations with mRNA expression is scarcely explored. Objective: To explore associations between plasma levels of sOb-R and 1) insulin sensitivity; 2) mRNA pathways in adipose tissue and skeletal muscle; and 3) mRNA of candidate genes for sOb-R generation in adipose tissue and skeletal muscle...
December 28, 2017: Journal of Clinical Endocrinology and Metabolism
Marcia L Moss, Dmitry Minond
Since its discovery, ADAM17, also known as TNFα converting enzyme or TACE, is now known to process over 80 different substrates. Many of these substrates are mediators of cancer and inflammation. The field of ADAM metalloproteinases is at a crossroad with many of the new potential therapeutic agents for ADAM17 advancing into the clinic. Researchers have now developed potential drugs for ADAM17 that are selective and do not have the side effects which were seen in earlier chemical entities that targeted this enzyme...
2017: Mediators of Inflammation
Haifang Wang, Shuhui Ma, Jing Li, Miaomiao Zhao, Xueping Huo, Jingying Sun, Lijun Sun, Jun Hu, Qinshe Liu
Paeoniflorin (PF), the most abundant active ingredient of traditional Chinese herbal medicine Paeoniae Radix, has been recognized as a potential neuroprotectant due to its remarkable efficacy on mitigating cerebral infarction and preventing the neurodegenerative diseases. However, the precise mechanisms of PF remain incompletely understood. In this study, we first provided evidence for the protective effect of PF on hydrogen peroxide-induced injury on mouse brain microvascular endothelial bEnd.3 cells, and for transactivation of the epidermal growth factor receptor (EGFR) signal induced by PF, suggesting that EGFR transactivation might be involved in the beneficial role of PF...
December 7, 2017: Journal of Cellular Physiology
Kanupriya Singh, Vikrant Piprode, Suhas T Mhaske, Amruta Barhanpukar-Naik, Mohan R Wani
Bone remodeling comprises balanced activities between osteoclasts and osteoblasts, which is regulated by various factors, including hormones and cytokines. We previously reported that IL-3 inhibits osteoclast differentiation and pathological bone loss. IL-3 also enhances osteoblast differentiation and bone formation from mesenchymal stem cells. However, the role of IL-3 in regulation of osteoblast-osteoclast interactions and underlying mechanisms is not yet delineated. In this study, we investigated the role of IL-3 on the regulation of osteoblast-specific molecules, receptor activator of NF-κB ligand (RANKL), and osteoprotegerin (OPG) that modulate bone homeostasis...
December 4, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
Jihyun Kim, Anthony Elias, Taeweon Lee, Patrice Maurel, Haesun A Kim
Tissue inhibitor of metalloproteinase-3 (TIMP-3) inhibits the activities of various metalloproteinases including matrix metalloproteinases and ADAM family proteins. In the peripheral nervous system, ADAM17, also known as TNF-α converting enzyme (TACE), cleaves the extracellular domain of Nrg1 type III, an axonal growth factor that is essential for Schwann cell myelination. The processing by ADAM17 attenuates Nrg1 signaling and inhibits Schwann cell myelination. TIMP-3 targets ADAM17, suggesting a possibility that TIMP-3 may elicit a promyelinating function in Schwann cells by relieving ADAM17-induced myelination block...
November 2017: ASN Neuro
Chun-Gang Zhai, Ye-Yang Xu, Yuan-Yuan Tie, Ya Zhang, Wen-Qiang Chen, Xiao-Ping Ji, Yang Mao, Lei Qiao, Jing Cheng, Qing-Bo Xu, Cheng Zhang
AIMS: Cardiac pressure and humoral factors induce cardiac hypertrophy and fibrosis, which are characterized by increased stiffness, reduced contractility and altered perfusion. Angiotensin II (AngII) is well known to promote this pathology. Angiotensin-converting enzyme (ACE) 2, which cleaves AngII and forms Ang-(1-7), exerts protective anti-hypertrophy and anti-fibrosis effects. A disintegrin and metalloproteinase 17 (ADAM17), a membrane-bound enzyme reported to cleave ACE2, may participate in the pathological process of AngII perfusion-induced heart damage...
December 4, 2017: Journal of Molecular and Cellular Cardiology
Yuki Inoue, Masamitsu Shimazawa, Shinsuke Nakamura, Shinsuke Takata, Yuhei Hashimoto, Hiroshi Izawa, Tomomi Masuda, Kazuhiro Tsuruma, Tomohisa Sakaue, Hironao Nakayama, Shigeki Higashiyama, Hideaki Hara
OBJECTIVE: The incidence of blindness is increasing because of the increase in abnormal ocular neovascularization. Anti-VEGF (vascular endothelial growth factor) therapies have led to good results, although they are not a cure for the blindness. The purpose of this study was to determine what role HB-EGF (heparin-binding epidermal growth factor-like growth factor) plays in ocular angiogenesis. APPROACH AND RESULTS: We examined the role played by HB-EGF in ocular neovascularization in 2 animal models of neovascularization: laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy...
November 30, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
Toshie Yoneyama, Michael Gorry, Miles A Miller, Autumn Gaither-Davis, Yan Lin, Marcia L Moss, Linda G Griffith, Douglas A Lauffenburger, Laura P Stabile, James G Herman, Nikola L Vujanovic
Increases in expression of ADAM10 and ADAM17 genes and proteins have been evaluated, but not validated as cancer biomarkers. Specific enzyme activities better reflect enzyme cellular functions, and might be better biomarkers than enzyme genes or proteins. However, no high throughput assay is available to test this possibility. Recent studies have developed the high throughput real-time proteolytic activity matrix analysis (PrAMA) that integrates the enzymatic processing of multiple enzyme substrates with mathematical-modeling computation...
2017: Journal of Cancer
Dorota Jędroszka, Magdalena Orzechowska, Andrzej K Bednarek
Introduction: Notch signalling, an evolutionarily conserved mechanism of cellular differentiation and tissue remodelling, is frequently deregulated in several human malignancies, including renal cell carcinoma (RCC). However, the prognostic value of individual Notch pathway members in RC subtypes remains indefinable. The present study investigates whether the differential expression of Notch members has a contrary effect on disease-free survival (DFS) in clear cell renal cell carcinoma (KIRC), papillary cell renal cell carcinoma (KIRP) and chromophobe renal cell carcinoma (KICH) patients...
October 2017: Archives of Medical Science: AMS
Prajna Paramita Naik, Subhadip Mukhopadhyay, Prashanta Kumar Panda, Niharika Sinha, Chandan Kanta Das, Rajakishore Mishra, Shankargouda Patil, Sujit Kumar Bhutia
OBJECTIVE: We inspected the relevance of CD44, ABCB1 and ADAM17 in OSCC stemness and deciphered the role of autophagy/mitophagy in regulating stemness and chemoresistance. MATERIAL AND METHODS: A retrospective analysis of CD44, ABCB1 and ADAM17 with respect to the various clinico-pathological factors and their correlation was analysed in sixty OSCC samples. Furthermore, the stemness and chemoresistance were studied in resistant oral cancer cells using sphere formation assay, flow cytometry and florescence microscopy...
November 23, 2017: Cell Proliferation
Jörg C Gerlach, Hubert G Foka, Robert L Thompson, Bruno Gridelli, Eva Schmelzer
Epithelial Cell Adhesion Molecule (EpCAM), or CD326, is a trans-membrane glycoprotein expressed by multiple normal epithelia as well as carcinoma. Human hepatic stem cells and bile duct epithelium of the liver are EpCAM positive. In tumor cell lines, its intracellular domain can be released after cleavage of the extracellular domain. Within the cell nucleus it induces cell proliferation, but cleavage depends on cell contact. Fragments of various lengths have been described in tumor cells. Despite of its described important role in proliferation in tumor cells, there is not much known about the expression and role of EpCAM fragments in primary human liver cells...
November 18, 2017: Journal of Cellular Physiology
Mohan Sobhana Nandhu, Prajna Behera, Vivek Bhaskaran, Sharon L Longo, Lina M Barrera-Arenas, Sadhak Sengupta, Diego J Rodriguez-Gil, E Antonio Chiocca, Mariano S Viapiano
PURPOSE: We sought a novel approach against glioblastomas (GBM) focused on targeting signaling molecules localized in the tumor extracellular matrix (ECM). We investigated fibulin-3, a glycoprotein that forms the ECM scaffold of GBMs and promotes tumor progression by driving Notch and NF-kB signaling. EXPERIMENTAL DESIGN: We used deletion constructs to identify a key signaling motif of fibulin-3. A monoclonal antibody (mAb428.2) was generated against this epitope and extensively validated for specific detection of human fibulin-3...
November 16, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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