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neutrophil substrate

Youssef Z Wadghiri, Dung Minh Hoang, Anita Leporati, Matthew J Gounis, Aurora Rodríguez-Rodríguez, Mary L Mazzanti, John P Weaver, Ajay K Wakhloo, Peter Caravan, Alexei A Bogdanov
Progress in clinical development of magnetic resonance imaging (MRI) substrate-sensors of enzymatic activity has been slow partly due to the lack of human efficacy data. We report here a strategy that may serve as a shortcut from bench to bedside. We tested ultra high-resolution 7T MRI (µMRI) of human surgical histology sections in a 3-year IRB approved, HIPAA compliant study of surgically clipped brain aneurysms. µMRI was used for assessing the efficacy of MRI substrate-sensors that detect myeloperoxidase activity in inflammation...
May 16, 2018: Scientific Reports
C M Scholte, D C Nelson, M Garcia, S B Linden, T H Elsasser, S Kahl, Y Qu, K M Moyes
Mastitis is the leading cause of antimicrobial use on dairy farms. The potential for antimicrobial resistance has led to the examination of alternative strategies for controlling mastitis. One such alternative is PlyC, a potent peptidoglycan hydrolase derived from the streptococcal C1 bacteriophage that causes targeted lysis of the cell wall of Streptococcus uberis. At a concentration of 1.0 μg/mL, recombinant PlyC can induce lytic activity, suggesting that a low dose may successfully eliminate infection. We evaluated the dose effect of PlyC (1-50 µg/mL) on cytotoxicity and oxidative response on bovine blood polymorphonuclear leukocytes (PMN) obtained from 12 healthy, mid-lactation primiparous dairy cows...
May 2, 2018: Journal of Dairy Science
Michael Thorpe, Zhirong Fu, Gurdeep Chahal, Srinivas Akula, Jukka Kervinen, Lawrence de Garavilla, Lars Hellman
Human neutrophils express at least four active serine proteases, cathepsin G, N-elastase, proteinase 3 and neutrophil serine protease 4 (NSP4). They have all been extensively studied due to their importance in neutrophil biology and immunity. However, their extended cleavage specificities have never been determined in detail. Here we present a detailed cleavage specificity analysis of human cathepsin G (hCG). The specificity was determined by phage display analysis and the importance of individual amino acids in and around the cleavage site was then validated using novel recombinant substrates...
2018: PloS One
Mamatha Kunder, V Lakshmaiah, A V Moideen Kutty
Dengue fever (DF) is characterized by systemic inflammatory response including neutrophil activation leading to uncontrolled elastase activity. This study was aimed to measure the activity of plasma neutrophil elastase (NE), its endogenous inhibitors α1 -antitrypsin (α1 -AT) and α2 -macroglobulin (α2 -MG) and elastase in complex with α1 -AT (NE-α1 -AT complex) in DF. 50 dengue patients [39 DF and 11 dengue hemorrhagic fever (DHF)] and 52 healthy subjects were included in the study. NE was measured using N -succinyl-tri-alanine- p -nitroanilide as substrate...
April 2018: Indian Journal of Clinical Biochemistry: IJCB
Jeong Yoon Kim, Yan Wang, Zia Uddin, Yeong Hun Song, Zuo Peng Li, Janar Jenis, Ki Hun Park
Flemingia philippinensis has been used throughout history to cure rheumatism associated with neutrophil elastase (NE). In this study, we isolated sixteen NE inhibitory flavonoids (1-16), including the most potent and abundant prenyl isoflavones (1-9), from the F. philippinensis plant. These prenyl isoflavones (2, 3, 5, 7, and 9) competitively inhibited NE, with IC50 values of 1.3-12.0 μM. In addition, they were reversible, simple, slow-binding inhibitors according to their respective parameters. Representative compound 3 had an IC50  = 1...
March 23, 2018: Bioorganic Chemistry
Paulo C Maffía, Diego Guerrieri, Ximena Villalonga, Fiorella Caro, Sonia Gómez, Nancy Tateosian, Betiana P Bogado, Mercedes L Sánchez, Nella Ambrosi, Eduardo Chuluyan
Secretory Leukocyte Proteinase Inhibitor (SLPI) is an antiinflammatory peptide that blocks the activity of serine proteases, primarily the neutrophil elastase. In an attempt to direct the activity of SLPI on inflamed sites, a chimera consisting of the transglutaminase II substrate domain of trappin 2 (cementoin), and the mature SLPI protein was constructed. Cell attachment and biological activity were compared between SLPI and this chimera. By using whole cell ELISA, fluorescence microscopy and flow cytometry assays we observed that the cementoin-SLPI fusion protein (FP) but not SLPI attached to a human lung epithelial cell line and monocytes...
March 28, 2018: Scientific Reports
Sarah L King, Christoffer K Goth, Ulrich Eckhard, Hiren Jitendra Joshi, Amalie D Haue, Sergey Vakhrushev, Katrine Schjoldager, Christopher M Overall, Hans H Wandall
Proteolytic processing is an irreversible post-translational modification functioning as a ubiquitous regulator of cellular activity. Protease activity is tightly regulated via control of gene expression, enzyme and substrate compartmentalization, zymogen activation, enzyme inactivation, and substrate availability. Emerging evidence suggests that proteolysis can also be regulated by substrate glycosylation and that glycosylation of individual sites on a substrate can decrease, or in rare cases, increase its sensitivity to proteolysis...
March 28, 2018: Journal of Biological Chemistry
Svetlana N Pleskova, Ekaterina N Gorshkova, Ruslan N Kriukov
In the process of performing their protective functions, neutrophils can form neutrophil extracellular traps (NETs), consisting of DNA in combination with enzymes and histones. The aim of the study was to determine the dynamics of the formation of NETs under the influence of opsonized Staphylococcus aureus and to determine the morphological features of their development in real time by atomic force microscopy. It was found that the maximum formation of NETs was observed after 3 hours of co-incubation of neutrophils and opsonized S...
March 23, 2018: Journal of Molecular Recognition: JMR
Catherine M Dickinson, Brian W LeBlanc, Muhammad M Edhi, Daithi S Heffernan, Mohd Hafeez Faridi, Vineet Gupta, William G Cioffi, Xian O'Brien, Jonathan S Reichner
Background: Multi-organ failure occurs during critical illness and is mediated in part by destructive neutrophil-to-endothelial interactions. The β2 integrin receptor, CR3 (complement receptor 3; Mac-1; CD11b/CD18), which binds endothelial intercellular adhesion molecule-1 (ICAM-1), plays a key role in promoting the adhesion of activated neutrophils to inflamed endothelia which, when prolonged and excessive, can cause vascular damage. Leukadherin-1 (LA-1) is a small molecule allosteric activator of CR3 and has been shown to promote adhesion of blood neutrophils to inflamed endothelium and restrict tissue infiltration...
2018: Journal of Intensive Care
Emmet A Francis, Volkmar Heinrich
Global bursts in free intracellular calcium (Ca2+ ) are among the most conspicuous signaling events in immune cells. To test the common view that Ca2+ bursts mediate rearrangement of the actin cytoskeleton in response to the activation of G protein-coupled receptors, we combined single-cell manipulation with fluorescence imaging and monitored the Ca2+ concentration in individual human neutrophils during complement-mediated chemotaxis. By decoupling purely chemotactic pseudopod formation from cell-substrate adhesion, we showed that physiological concentrations of anaphylatoxins, such as C5a, induced nonadherent human neutrophils to form chemotactic pseudopods but did not elicit Ca2+ bursts...
March 13, 2018: Science Signaling
J Vincent Edwards, Krystal Fontenot, Falk Liebner, Nicole Doyle Nee Pircher, Alfred D French, Brian D Condon
Nanocellulose has high specific surface area, hydration properties, and ease of derivatization to prepare protease sensors. A Human Neutrophil Elastase sensor designed with a nanocellulose aerogel transducer surface derived from cotton is compared with cotton filter paper, and nanocrystalline cellulose versions of the sensor. X-ray crystallography was employed along with Michaelis-Menten enzyme kinetics, and circular dichroism to contrast the structure/function relations of the peptide-cellulose conjugate conformation to enzyme/substrate binding and turnover rates...
March 13, 2018: International Journal of Molecular Sciences
Angelo A Manfredi, Giuseppe A Ramirez, Patrizia Rovere-Querini, Norma Maugeri
Neutrophils recognize particulate substrates of microbial or endogenous origin and react by sequestering the cargo via phagocytosis or by releasing neutrophil extracellular traps (NETs) outside the cell, thus modifying and alerting the environment and bystander leukocytes. The signals that determine the choice between phagocytosis and the generation of NETs are still poorly characterized. Neutrophils that had phagocytosed bulky particulate substrates, such as apoptotic cells and activated platelets, appear to be "poised" in an unresponsive state...
2018: Frontiers in Immunology
Graeme P Sullivan, Conor M Henry, Danielle M Clancy, Tazhir Mametnabiev, Ekaterina Belotcerkovskaya, Pavel Davidovich, Sylvia Sura-Trueba, Alexander V Garabadzhiu, Seamus J Martin
Sterile inflammation is initiated by molecules released from necrotic cells, called damage-associated molecular patterns (DAMPs). Members of the extended IL-1 cytokine family are important DAMPs, are typically only released through necrosis, and require limited proteolytic processing for activation. The IL-1 family cytokines, IL-36α, IL-36β, and IL-36γ, are expressed as inactive precursors and have been implicated as key initiators of psoriatic-type skin inflammation. We have recently found that IL-36 family cytokines are proteolytically processed and activated by the neutrophil granule-derived proteases, elastase, and cathepsin G...
March 7, 2018: Cell Death & Disease
Larissa A C Carvalho, João P P B Lopes, Gilberto H Kaihami, Railmara P Silva, Alexandre Bruni-Cardoso, Regina L Baldini, Flavia C Meotti
Uric acid is the end product of purine metabolism in humans and is an alternative physiological substrate for myeloperoxidase. Oxidation of uric acid by this enzyme generates uric acid free radical and urate hydroperoxide, a strong oxidant and potentially bactericide agent. In this study, we investigated whether the oxidation of uric acid and production of urate hydroperoxide would affect the killing activity of HL-60 cells differentiated into neutrophil-like cells (dHL-60) against a highly virulent strain (PA14) of the opportunistic pathogen Pseudomonas aeruginosa...
June 2018: Redox Biology
Ghislain Opdenakker, Jo Van Damme, Jan Jeroen Vranckx
Chronic skin wounds, caused by arterial or venous insufficiency or by physical pressure, constitute an increasing medical problem as populations age. Whereas typical wounds are characterized by local inflammation that participates in the healing process, atonic wounds lack inflammatory markers, such as neutrophil infiltration, and generally do not heal. Recently, prominent roles in the immunopathology of chronic wounds were attributed to dysregulations in specific cytokines, chemokines, matrix metalloproteinases (MMPs), and their substrates...
April 2018: Trends in Immunology
Cédric Delporte, Karim Zouaoui Boudjeltia, Paul G Furtmüller, Richard A Maki, Marc Dieu, Caroline Noyon, Monika Soudi, Damien Dufour, Catherine Coremans, Vincent Nuyens, Florence Reye, Alexandre Rousseau, Martine Raes, Nicole Moguilevsky, Michel Vanhaeverbeek, Jean Ducobu, Jean Nève, Bernard Robaye, Luc Vanhamme, Wanda F Reynolds, Christian Obinger, Pierre Van Antwerpen
Protein carbamylation by cyanate is a post-translational modification associated with several (patho)physiological conditions, including cardiovascular disorders. However, the biochemical pathways leading to protein carbamylation are incompletely characterized. This work demonstrates that the heme protein myeloperoxidase (MPO), which is secreted at high concentrations at inflammatory sites from stimulated neutrophils and monocytes, is able to catalyze the two-electron oxidation of cyanide to cyanate and promote the carbamylation of taurine, lysine, and low-density lipoproteins...
April 27, 2018: Journal of Biological Chemistry
Manoj K Pandey, Gregory A Grabowski, Jörg Köhl
The complement system is well appreciated for its role as an important effector of innate immunity that is activated by the classical, lectin or alternative pathway. C5a is one important mediator of the system that is generated in response to canonical and non-canonical C5 cleavage by circulating or cell-derived proteases. In addition to its function as a chemoattractant for neutrophils and other myeloid effectors, C5a and its sister molecule C3a have concerted roles in cell homeostasis and surveillance. Through activation of their cognate G protein coupled receptors, C3a and C5a regulate multiple intracellular pathways within the mitochondria and the lysosomal compartments that harbor multiple enzymes critical for protein, carbohydrate and lipid metabolism...
February 22, 2018: Seminars in Immunology
Javier Pascual, Bärbel U Foesel, Alicia Geppert, Katharina J Huber, Christian Boedeker, Manja Luckner, Gerhard Wanner, Jörg Overmann
A novel slow-growing bacterium, designated strain AW1220T , was isolated from agricultural floodplain soil sampled at Mashare (Kavango region, Namibia) by using a high-throughput cultivation approach. Strain AW1220T was characterized as a Gram-negative, non-motile, rod-shaped bacterium. Occasionally, some cells attained an unusual length of up to 35 µm. The strain showed positive responses for catalase and cytochrome-c oxidase and divided by binary fission and/or budding. The strain had an aerobic chemoorganoheterotrophic metabolism and was also able to grow under micro-oxic conditions...
April 2018: International Journal of Systematic and Evolutionary Microbiology
Fatma H Al-Awadhi, Valerie J Paul, Hendrik Luesch
Three new 3-amino-6-hydroxy-2-piperidone (Ahp)-containing cyclic depsipeptides, named loggerpeptins A-C (1-3), along with molassamide (4), were discovered from a marine cyanobacterium, extending the structural diversity of this prevalent scaffold of cyanobacterial serine protease inhibitors. Molassamide, which contains a 2-amino-butenoic (Abu) unit in the cyclic core, was the most potent and selective analogue against human neutrophil elastase (HNE). Given the growing evidence supporting the role of HNE in breast cancer progression and metastasis, we assessed the cellular effects of compounds 3 and 4 in the context of targeting invasive breast cancer...
April 16, 2018: Chembiochem: a European Journal of Chemical Biology
Nienke W M de Jong, Nicoleta T Ploscariu, Kasra X Ramyar, Brandon L Garcia, Alvaro I Herrera, Om Prakash, Benjamin B Katz, Kevin G Leidal, William M Nauseef, Kok P M van Kessel, Jos A G van Strijp, Brian V Geisbrecht
The heme-containing enzyme myeloperoxidase (MPO) is critical for optimal antimicrobial activity of human neutrophils. We recently discovered that the bacterium Staphylococcus aureus expresses a novel immune evasion protein, called SPIN, that binds tightly to MPO, inhibits MPO activity, and contributes to bacterial survival following phagocytosis. A co-crystal structure of SPIN bound to MPO suggested that SPIN blocks substrate access to the catalytic heme by inserting an N-terminal β-hairpin into the MPO active-site channel...
February 16, 2018: Journal of Biological Chemistry
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