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https://www.readbyqxmd.com/read/28705384/the-shedding-protease-adam17-physiology-and-pathophysiology
#1
REVIEW
Friederike Zunke, Stefan Rose-John
The disintegrin metalloprotease ADAM17 has been a matter of intense studies aiming to unravel structure, function and regulation of protease expression, maturation and activity. In this review, we summarize data on the physiological role of ADAM17 in health and disease. Here we provide an overview of ADAM17 substrates, mouse models of ADAM17-deficiencies and discuss recent findings of ADAM17 function in the immune system and central nervous system as well as in cancer. Whereas ADAM17 function in EGF-R-, in Interleukin-6 (IL-6)- and in TNFα-biology has been shown to play a decisive role in regulation of the immune system as well as cancer development, the role of ADAM17 in the central nervous system and neurodegeneration still remains elusive...
July 10, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28703301/the-xenoestrogens-biphenol-a-and-nonylphenol-differentially-regulate-metalloprotease-mediated-shedding-of-egfr-ligands
#2
Paulina Urriola-Muñoz, Xue Li, Thorsten Maretzky, David R McIlwain, Tak W Mak, Juan G Reyes, Carl P Blobel, Ricardo D Moreno
The xenoestrogens Bisphenol-A (BPA) and Nonylphenol (NP) are endocrine disruptors used in the plastic polymer industry to manufacture different products for human use. Previous studies have suggested a role of these compounds in the shedding of signaling molecules, such as tumor necrosis factor α (TNF- α). The aim of this work was to evaluate the effect of BPA and NP on the sheddase ADAM17 and its newly discovered regulators iRhom1 and iRhom2 in the release of EGFR-ligands. We report that BPA and NP can stimulate the release of the ADAM17-substrates HB-EGF and TGF- α...
July 13, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28675418/the-soluble-interleukin-6-receptor-advanced-therapeutic-options-in-inflammation
#3
Stefan Rose-John
IL-6 binds to IL-6R and the complex of IL-6 and IL-6R associates with the receptor subunit gp130, which initiates signaling. gp130 is expressed on all cells. The IL-6R is cleaved by the ADAM17 generating a soluble IL-6R (sIL-6R). The sIL-6R binds IL-6 and the complex of IL-6 and sIL-6R binds to gp130 even on cells, which do not express IL-6R. This process, which has been called IL-6 trans-signaling, increases the spectrum of target cells for IL-6. We generated a protein, sgp130Fc, which inhibits IL-6 trans-signaling without affecting IL-6 classic signaling...
July 4, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28671983/isoflurane-promotes-phagocytosis-of-apoptotic-neutrophils-through-ampk-mediated-adam17-mer-signaling
#4
Xueke Du, Chunling Jiang, Yang Lv, Randal O Dull, You-Yang Zhao, David E Schwartz, Guochang Hu
A patient's recovery from lung inflammatory injury or development of multi-system organ failure is determined by the host's ability to resolve inflammation and repair tissue damage, both of which require the clearance of apoptotic neutrophils by macrophages (efferocytosis). Here, we investigated the effects of isoflurane on macrophage efferocytosis and resolution of lung inflammatory injury. Treatment of murine bone marrow-derived macrophages (BMDMs) or alveolar macrophages with isoflurane dramatically enhanced phagocytosis of apoptotic neutrophils...
2017: PloS One
https://www.readbyqxmd.com/read/28637950/adam17-regulates-tnf-%C3%AE-expression-upon-lipopolysaccharide-stimulation-in-oral-keratinocytes
#5
Aya Hirayama, Shuji Awano, Yuji Seta, Toshihiro Ansai
A disintegrin and metalloprotease 17 (ADAM17) is a tumor necrosis factor (TNF)-converting enzyme and was first identified as the enzyme that cleaves the prodomain of TNF-α, a proinflammatory cytokine that plays a central role in immune regulation and a variety of inflammatory responses in destructive periodontal disease. The aim of the present study was to verify the presence of ADAM17 in the gingival epithelium and elucidate its involvement in the release of TNF-αin oral keratinocytes. Immunohistochemical analyses of ADAM17 were performed in gingival tissues obtained from patients and in human oral keratinocytes (HOKs)...
2017: Biomedical Research
https://www.readbyqxmd.com/read/28631723/pharmacogenetic-biomarkers-of-response-in-crohn-s-disease
#6
REVIEW
T M Linares-Pineda, M Cañadas-Garre, A Sánchez-Pozo, M Á Calleja-Hernández
Crohn's disease (CD) is a chronic condition, which affects the immune system. It can also affect any part of the digestive tract and be associated with external manifestations. The causes of the disease remain unknown, although it seems to be the result of a combination of factors, such as genetic predisposition, environment, lifestyle and the composition of the microbiota, among others. The treatment protocol begins with a change in eating and smoking habits, and is continued with different lines of treatment, including corticosteroids, immunomodulators and biologic therapy (infliximab and adalimumab), which have shown differences in response among patients, especially with biologic treatment...
June 20, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28624437/the-plasma-membrane-penultimate-regulator-of-adam-sheddase-function
#7
REVIEW
Karina Reiss, Sucharit Bhakdi
BACKGROUND: ADAM10 and ADAM17 are the best characterized members of the ADAM (A Disintegrin and Metalloproteinase) - family of transmembrane proteases. Both are involved diverse physiological and pathophysiological processes. ADAMs are known to be regulated by posttranslational mechanisms. However, emerging evidence indicates that the plasma membrane with its unique dynamic properties may additionally play an important role in controlling sheddase function. SCOPE OF REVIEW: Membrane events that could contribute to regulation of ADAM-function are summarized...
June 14, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28571693/molecular-insights-into-the-multilayered-regulation-of-adam17-the-role-of-the-extracellular-region
#8
REVIEW
Joachim Grötzinger, Inken Lorenzen, Stefan Düsterhöft
In contrast to many other signalling mechanisms shedding of membrane-anchored proteins is an irreversible process. A Disintegrin And Metalloproteinase (ADAM) 17 is one of the major sheddases involved in a variety of physiological and pathophysiological processes including regeneration, differentiation, and cancer progression. Due to its central role in signalling the shedding activity of ADAM17 is tightly regulated, especially on the cell surface, where shedding events take place. The activity of ADAM17 can be subdivided into a catalytic activity and the actual shedding activity...
May 29, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28570994/targeting-adam17-inhibits-human-colorectal-adenocarcinoma-progression-and-tumor-initiating-cell-frequency
#9
Joseph Dosch, Elizabeth Ziemke, Shanshan Wan, Kathryn Luker, Theodore Welling, Karin Hardiman, Eric Fearon, Suneetha Thomas, Matthew Flynn, Jonathan Rios-Doria, Robert Hollingsworth, Ronald Herbst, Elaine Hurt, Judith Sebolt-Leopold
ADAM17 (a disintegrin and metalloproteinase 17)/TACE (TNFα converting enzyme) has emerged as a potential therapeutic target in colorectal cancer (CRC) and other cancers, due in part to its role in regulating various tumor cell surface proteins and growth factors and cytokines in the tumor microenvironment. The emergence of MEDI3622, a highly potent and specific antibody-based ADAM17 inhibitor, has allowed testing of the concept that targeting ADAM17 may be an important new therapeutic approach for CRC patients...
May 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28554668/anti-tumor-effects-of-a-human-mouse-cross-reactive-anti-adam17-antibody-in-a-pancreatic-cancer-model-in-vivo
#10
Jie Ye, Shun Ming Yuen, Gillian Murphy, Ruiyu Xie, Hang Fai Kwok
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of tumor amongst all human cancers due to late diagnosis and resistant to treatment with chemotherapy and radiation. Preclinical and clinical studies have revealed that ErbB family for example epidermal growth factor receptor (EGFR) is a validated molecular target for pancreatic cancer prevention and therapy. The ErbB signaling cascade is regulated by a member of the ADAM (a disintegrin and metalloprotease) family, namely ADAM17, by enzymatic cleavage of precursor ligands into soluble cytokines and growth factors...
May 26, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28512108/clinical-relevance-and-role-of-neuronal-at1-receptors-in-adam17-mediated-ace2-shedding-in-neurogenic-hypertension
#11
Jiaxi Xu, Srinivas Sriramula, Huijing Xia, Lisa Moreno-Walton, Frank Culicchia, Oliver Domenig, Marko Poglitsch, Eric Lazartigues
RATIONALE: Neurogenic hypertension is characterized by an increase in sympathetic activity and often resistance to drug treatments. We previously reported that it is also associated with a reduction of angiotensin-converting enzyme type 2 (ACE2) and an increase in a disintegrin and metalloprotease 17 (ADAM17) activity in experimental hypertension. In addition, while multiple cells within the central nervous system have been involved in the development of neurogenic hypertension, the contribution of ADAM17 has not been investigated...
June 23, 2017: Circulation Research
https://www.readbyqxmd.com/read/28487846/ectodomain-shedding-by-adam17-its-role-in-neutrophil-recruitment-and-the-impairment-of-this-process-during-sepsis
#12
REVIEW
Hemant K Mishra, Jing Ma, Bruce Walcheck
Neutrophils are specialized at killing bacteria and are recruited from the blood in a rapid and robust manner during infection. A cascade of adhesion events direct their attachment to the vascular endothelium and migration into the underlying tissue. A disintegrin and metalloproteinase 17 (ADAM17) functions in the cell membrane of neutrophils and endothelial cells by cleaving its substrates, typically in a cis manner, at an extracellular site proximal to the cell membrane. This process is referred to as ectodomain shedding and it results in the downregulation of various adhesion molecules and receptors, and the release of immune regulating factors...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/28486700/dysregulation-of-the-adam17-notch-signalling-pathways-in-endometriosis-from-oxidative-stress-to-fibrosis
#13
Iñaki González-Foruria, Pietro Santulli, Sandrine Chouzenoux, Francisco Carmona, Charles Chapron, Frédéric Batteux
STUDY QUESTION: Is oxidative stress associated with the A disintegrin and metalloproteases (ADAM) metallopeptidase domain 17 (ADAM17)/Notch signalling pathway and fibrosis in the development of endometriosis? SUMMARY ANSWER: Oxidative stress is correlated with hyperactivation of the ADAM17/Notch signalling pathway and a consequent increase in fibrosis in patients with endometriosis. WHAT IS KNOWN ALREADY: It is nowadays accepted that oxidative stress plays an important role in the onset and progression of endometriosis...
May 9, 2017: Molecular Human Reproduction
https://www.readbyqxmd.com/read/28473444/role-of-adipose-tissue-endothelial-adam17-in-age-related-coronary-microvascular-dysfunction
#14
Huijuan Dou, Attila Feher, Alec C Davila, Maritza J Romero, Vijay S Patel, Vinayak M Kamath, Monika Beck Gooz, R Daniel Rudic, Rudolf Lucas, David J Fulton, Neal L Weintraub, Zsolt Bagi
OBJECTIVE: A disintegrin and metalloproteinase ADAM17 (tumor necrosis factor-α [TNF]-converting enzyme) regulates soluble TNF levels. We tested the hypothesis that aging-induced activation in adipose tissue (AT)-expressed ADAM17 contributes to the development of remote coronary microvascular dysfunction in obesity. APPROACH AND RESULTS: Coronary arterioles (CAs, ≈90 µm) from right atrial appendages and mediastinal AT were examined in patients (aged: 69±11 years, BMI: 30...
June 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28442704/discovery-of-an-enzyme-and-substrate-selective-inhibitor-of-adam10-using-an-exosite-binding-glycosylated-substrate
#15
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
#16
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
#17
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
#18
Aroa Baragaño Raneros, Alfredo Minguela Puras, Ramon M Rodriguez, Enrique Colado, Teresa Bernal, Eduardo Anguita, Adela Vasco Mogorron, Alberto Chaparro Gil, Jose Ramon Vidal-Castiñeira, 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)...
May 9, 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
#19
Takatsugu Ishimoto, Keisuke Miyake, Tannistha Nandi, Masakazu Yashiro, Nobuyuki Onishi, Kie Kyon Huang, Lin Suling Joyce, 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), which 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 gastric cancer (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
#20
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
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