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https://www.readbyqxmd.com/read/28927525/alpha-1-antitrypsin-deficiency-genetic-variations-clinical-manifestations-and-therapeutic-interventions
#1
REVIEW
Younis Mohammad Hazari, Arif Bashir, Mudasir Habib, Samirul Bashir, Huma Habib, M Abul Qasim, Naveed Nazir Shah, Ehtishamul Haq, Jeffrey Teckman, Khalid Majid Fazili
Alpha-1-antitrypsin (AAT) is an acute phase secretory glycoprotein that inhibits neutrophil proteases like elastase and is considered as the archetype of a family of structurally related serine-protease inhibitors termed serpins. Serum AAT predominantly originates from liver and increases three to five fold during host response to tissue injury and inflammation. The AAT deficiency is unique among the protein-misfolding diseases in that it causes target organ injury by both loss-of-function and gain-of-toxic function mechanisms...
July 2017: Mutation Research
https://www.readbyqxmd.com/read/28883796/functions-of-nqo1-in-cellular-protection-and-coq10-metabolism-and-its-potential-role-as-a-redox-sensitive-molecular-switch
#2
REVIEW
David Ross, David Siegel
NQO1 is one of the two major quinone reductases in mammalian systems. It is highly inducible and plays multiple roles in cellular adaptation to stress. A prevalent polymorphic form of NQO1 results in an absence of NQO1 protein and activity so it is important to elucidate the specific cellular functions of NQO1. Established roles of NQO1 include its ability to prevent certain quinones from one electron redox cycling but its role in quinone detoxification is dependent on the redox stability of the hydroquinone generated by two-electron reduction...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28854829/profile-of-the-proaxsis-active-neutrophil-elastase-immunoassay-for-precision-medicine-in-chronic-respiratory-disease
#3
Holly R Keir, Christopher J Fong, Alison J Dicker, James D Chalmers
Neutrophil elastase (NE) is a 29kDa serine protease released from the azurophilic granules of neutrophils. It may be directly involved in the pathogenesis and disease progression in cystic fibrosis, bronchiectasis and COPD through the degradation of airway elastin and by impairing host defence. Areas covered: Measurement of NE activity has emerged as a promising biomarker strategy in inflammatory lung disease. The authors review studies where NE activity has been linked with clinical outcomes such as lung function decline, exacerbation frequency or other cross-sectional and longitudinal markers of disease severity...
September 7, 2017: Expert Review of Molecular Diagnostics
https://www.readbyqxmd.com/read/28596972/targets-of-neutrophil-influx-and-weaponry-therapeutic-opportunities-for-chronic-obstructive-airway-disease
#4
REVIEW
Carina Kärrman Mårdh, James Root, Mohib Uddin, Kristina Stenvall, Anna Malmgren, Kostas Karabelas, Matthew Thomas
Neutrophils are important effector cells of antimicrobial immunity in an acute inflammatory response, with a primary role in the clearance of extracellular pathogens. However, in respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), there is excessive infiltration and activation of neutrophils, subsequent production of reactive oxygen species, and release of serine proteases, matrix metalloproteinases, and myeloperoxidase-resulting in collateral damage as the cells infiltrate into the tissue...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/27982104/pharmacological-and-genetic-reappraisals-of-protease-and-oxidative-stress-pathways-in-a-mouse-model-of-obstructive-lung-diseases
#5
Tsuyoshi Shuto, Shunsuke Kamei, Hirofumi Nohara, Haruka Fujikawa, Yukihiro Tasaki, Takuya Sugahara, Tomomi Ono, Chizuru Matsumoto, Yuki Sakaguchi, Kasumi Maruta, Ryunosuke Nakashima, Taisei Kawakami, Mary Ann Suico, Yoshitaka Kondo, Akihito Ishigami, Toru Takeo, Ken-Ichiro Tanaka, Hiroshi Watanabe, Naomi Nakagata, Kohei Uchimura, Kenichiro Kitamura, Jian-Dong Li, Hirofumi Kai
Protease-antiprotease imbalance and oxidative stress are considered to be major pathophysiological hallmarks of severe obstructive lung diseases including chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF), but limited information is available on their direct roles in the regulation of pulmonary phenotypes. Here, we utilized βENaC-transgenic (Tg) mice, the previously established mouse model of severe obstructive lung diseases, to produce lower-mortality but pathophysiologically highly useful mouse model by backcrossing the original line with C57/BL6J mice...
December 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27802588/gene-profiles-in-a-smoke-induced-copd-mouse-lung-model-following-treatment-with-mesenchymal-stem-cells
#6
You-Sun Kim, Nurdan Kokturk, Ji-Young Kim, Sei Won Lee, Jaeyun Lim, Soo Jin Choi, Wonil Oh, Yeon-Mok Oh
Mesenchymal stem cells (MSCs) effectively reduce airway inflammation and regenerate the alveolus in cigarette- and elastase-induced chronic obstructive pulmonary disease (COPD) animal models. The effects of stem cells are thought to be paracrine and immune-modulatory because very few stem cells remain in the lung one day after their systemic injection, which has been demonstrated previously. In this report, we analyzed the gene expression profiles to compare mouse lungs with chronic exposure to cigarette smoke with non-exposed lungs...
October 2016: Molecules and Cells
https://www.readbyqxmd.com/read/27564672/delivery-of-alpha-1-antitrypsin-to-airways
#7
Matthias Griese, Gerhard Scheuch
Treatment with exogenous alpha-1 antitrypsin (AAT), a potent serine protease inhibitor, was developed originally for chronic obstructive pulmonary disease associated with AAT deficiency; however, other lung conditions involving neutrophilic inflammation and proteolytic tissue injury related to neutrophil elastase and other serine proteases may also be considered for AAT therapy. These conditions include bronchiectasis caused by primary ciliary dyskinesia, cystic fibrosis, and other diseases associated with an increased free elastase activity in the airways...
August 2016: Annals of the American Thoracic Society
https://www.readbyqxmd.com/read/27564666/alpha-1-antitrypsin-investigations-using-animal-models-of-emphysema
#8
Kevin Ni, Karina A Serban, Chanan Batra, Irina Petrache
Animal models of disease help accelerate the translation of basic science discoveries to the bedside, because they permit experimental interrogation of mechanisms at relatively high throughput, while accounting for the complexity of an intact organism. From the groundbreaking observation of emphysema-like alveolar destruction after direct instillation of elastase in the lungs to the more clinically relevant model of airspace enlargement induced by chronic exposure to cigarette smoke, animal models have advanced our understanding of alpha-1 antitrypsin (AAT) function...
August 2016: Annals of the American Thoracic Society
https://www.readbyqxmd.com/read/27564662/well-known-and-less-well-known-functions-of-alpha-1-antitrypsin-its-role-in-chronic-obstructive-pulmonary-disease-and-other-disease-developments
#9
Sabina Janciauskiene, Tobias Welte
Alpha-1 antitrypsin (A1AT) is an acute-phase protein, and is best known as an inhibitor of the serine proteases, specifically, neutrophil elastase, proteinase 3, and cathepsin G. The discovery of the connection between inherited A1AT deficiency and emphysema resulted in the concept of a proteinase-antiproteinase imbalance to explain the pathogenic mechanisms of chronic obstructive pulmonary disease, as well as the concomitant development of augmentation therapy with plasma-purified human A1AT. This proteinase-antiproteinase imbalance concept has been difficult to prove, as no single mechanism can account for the complex pathology of chronic obstructive pulmonary disease...
August 2016: Annals of the American Thoracic Society
https://www.readbyqxmd.com/read/27515817/novel-rna-binding-activity-of-nqo1-promotes-serpina1-mrna-translation
#10
Andrea Di Francesco, Clara Di Germanio, Amaresh C Panda, Phu Huynh, Robert Peaden, Ignacio Navas-Enamorado, Paul Bastian, Elin Lehrmann, Alberto Diaz-Ruiz, David Ross, David Siegel, Jennifer L Martindale, Michel Bernier, Myriam Gorospe, Kotb Abdelmohsen, Rafael de Cabo
NAD(P)H: quinone oxidoreductase (NQO1) is essential for cell defense against reactive oxidative species, cancer, and metabolic stress. Recently, NQO1 was found in ribonucleoprotein (RNP) complexes, but NQO1-interacting mRNAs and the functional impact of such interactions are not known. Here, we used ribonucleoprotein immunoprecipitation (RIP) and microarray analysis to identify comprehensively the subset of NQO1 target mRNAs in human hepatoma HepG2 cells. One of its main targets, SERPINA1 mRNA, encodes the serine protease inhibitor α-1-antitrypsin, A1AT, which is associated with disorders including obesity-related metabolic inflammation, chronic obstructive pulmonary disease (COPD), liver cirrhosis and hepatocellular carcinoma...
October 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/27492524/novel-variants-of-serpin1a-gene-interplay-between-alpha1-antitrypsin-deficiency-and-chronic-obstructive-pulmonary-disease
#11
REVIEW
Arif Bashir, Naveed Nazir Shah, Younis Mohammad Hazari, Mudasir Habib, Samirul Bashir, Nazia Hilal, Mariam Banday, Syed Asrafuzzaman, Khalid Majid Fazili
Alpha1-antitrypsin (AAT) is one of the major circulating anti-protease whose levels in circulation are raised during excessive amount of proteases, especially neutrophil elastase (NE) released during the course of inflammation. Proteolytic attack of NE on peripheral organs, more exclusively on lung parenchyma has severe consequence that may precipitate pulmonary emphysema. Normally, human body has its own molecular and physiological mechanisms to synthesize and regulate the production of anti-protease like AAT to mitigate the extent of inflammatory damage...
August 2016: Respiratory Medicine
https://www.readbyqxmd.com/read/27465595/clickable-4-oxo-%C3%AE-lactam-based-selective-probing-for-human-neutrophil-elastase-related-proteomes
#12
Eduardo F P Ruivo, Lídia M Gonçalves, Luís A R Carvalho, Rita C Guedes, Stefan Hofbauer, José A Brito, Margarida Archer, Rui Moreira, Susana D Lucas
Human neutrophil elastase (HNE) is a serine protease associated with several inflammatory processes such as chronic obstructive pulmonary disease (COPD). The precise involvement of HNE in COPD and other inflammatory disease mechanisms has yet to be clarified. Herein we report a copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC, or 'click' chemistry) approach based on the 4-oxo-β-lactam warhead that yielded potent HNE inhibitors containing a triazole moiety. The resulting structure-activity relationships set the basis to develop fluorescent and biotinylated activity-based probes as tools for molecular functional analysis...
September 20, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27059719/serpine2-deficiency-results-in-lung-lymphocyte-accumulation-and-bronchus-associated-lymphoid-tissue-formation
#13
Siva Kumar Solleti, Sorachai Srisuma, Soumyaroop Bhattacharya, Javier Rangel-Moreno, Kaiser M Bijli, Troy D Randall, Arshad Rahman, Thomas J Mariani
Serine proteinase inhibitor, clade E, member 2 (SERPINE2), is a cell- and extracellular matrix-associated inhibitor of thrombin. Although SERPINE2 is a candidate susceptibility gene for chronic obstructive pulmonary disease, the physiologic role of this protease inhibitor in lung development and homeostasis is unknown. We observed spontaneous monocytic-cell infiltration in the lungs of Serpine2-deficient (SE2(-/-)) mice, beginning at or before the time of lung maturity, which resulted in lesions that resembled bronchus-associated lymphoid tissue (BALT)...
July 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/26850997/n-arylacyl-o-sulfonated-aminoglycosides-as-novel-inhibitors-of-human-neutrophil-elastase-cathepsin-g-and-proteinase-3
#14
Ioana Craciun, Amanda M Fenner, Robert J Kerns
The balance between neutrophil serine proteases (NSPs) and protease inhibitors (PIs) in the lung is a critical determinant for a number of chronic inflammatory lung diseases such as chronic obstructive pulmonary disease, cystic fibrosis and acute lung injury. During activation at inflammatory sites, excessive release of NSPs such as human neutrophil elastase (HNE), proteinase 3 (Pr3) and cathepsin G (CatG), leads to destruction of the lung matrix and continued propagation of acute inflammation. Under normal conditions, PIs counteract these effects by inactivating NSPs; however, in chronic inflammatory lung diseases, there are insufficient amounts of PIs to mitigate damage...
July 2016: Glycobiology
https://www.readbyqxmd.com/read/26671198/cigarette-smoke-extract-treated-mast-cells-promote-alveolar-macrophage-infiltration-and-polarization-in-experimental-chronic-obstructive-pulmonary-disease
#15
Hong Li, Tian Yang, Qian Ning, Feiyan Li, Tianjun Chen, Yan Yao, Zhongmin Sun
OBJECTIVE: Cigarette smoking is the main cause of chronic obstructive pulmonary disease (COPD) and may modulate the immune response of exposed individuals. Mast cell function can be altered by cigarette smoking, but the role of smoking in COPD remains poorly understood. The current study aimed to explore the role of cigarette smoke extract (CSE)-treated mast cells in COPD pathogenesis. METHODS: Cytokine and chemokine expression as well as degranulation of bone marrow-derived mast cells (BMMCs) were detected in cells exposed to immunoglobulin E (IgE) and various doses of CSE...
2015: Inhalation Toxicology
https://www.readbyqxmd.com/read/26369819/development-of-trypsin-like-serine-protease-inhibitors-as-therapeutic-agents-opportunities-challenges-and-their-unique-structure-based-rationales
#16
REVIEW
Guyan Liang, J Phillip Bowen
There has been a revolution in the development of effective, small-molecule anticoagulants and antiplatelet agents. Numerous trypsin-like serine proteases have been under active pursuit as therapeutic targets. Important examples include thrombin, factor VIIa, factor Xa, and β-tryptase with indications ranging from thrombosis and inflammation to asthma and chronic obstructive pulmonary disease (COPD). Trypsin-like serine proteases exhibit a highly similar tertiary folding pattern, especially for the region near the substrate binding pocket that includes the conserved catalytic triad consisting of histidine 57, aspartic acid 102, and serine 195...
2016: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/26341472/antimicrobial-proteins-and-peptides-in-human-lung-diseases-a-friend-and-foe-partnership-with-host-proteases
#17
REVIEW
Fabien Lecaille, Gilles Lalmanach, Pierre-Marie Andrault
Lung antimicrobial proteins and peptides (AMPs) are major sentinels of innate immunity by preventing microbial colonization and infection. Nevertheless bactericidal activity of AMPs against Gram-positive and Gram-negative bacteria is compromised in patients with chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) and asthma. Evidence is accumulating that expression of harmful human serine proteases, matrix metalloproteases and cysteine cathepsins is markedely increased in these chronic lung diseases...
March 2016: Biochimie
https://www.readbyqxmd.com/read/26169056/altered-protease-and-antiprotease-balance-during-a-copd-exacerbation-contributes-to-mucus-obstruction
#18
Shashi Chillappagari, Jenni Preuss, Sebastian Licht, Christian Müller, Poornima Mahavadi, Gaurav Sarode, Claus Vogelmeier, Andreas Guenther, Lutz Nahrlich, Bruce K Rubin, Markus O Henke
BACKGROUND: Proteases have been shown to degrade airway mucin proteins and to damage the epithelium impairing mucociliary clearance. There are increased proteases in the COPD airway but changes in protease-antiprotease balance and mucin degradation have not been investigated during the course of a COPD exacerbation. We hypothesized that increased protease levels would lead to mucin degradation in acute COPD exacerbations. METHODS: We measured neutrophil elastase (NE) and alpha 1 protease inhibitor (A1-PI) levels using immunoblotting, and conducted protease inhibitor studies, zymograms, elastin substrate assays and cigarette smoke condensate experiments to evaluate the stability of the gel-forming mucins, MUC5AC and MUC5B, before and 5-6 weeks after an acute pulmonary exacerbation of COPD (n = 9 subjects)...
2015: Respiratory Research
https://www.readbyqxmd.com/read/26005342/identification-of-a-novel-serpina-1-mutation-causing-alpha-1-antitrypsin-deficiency-in-a-patient-with-severe-bronchiectasis-and-pulmonary-embolism
#19
Katrin Milger, Lesca Miriam Holdt, Daniel Teupser, Rudolf Maria Huber, Jürgen Behr, Nikolaus Kneidinger
Deficiency in the serine protease inhibitor, alpha-1 antitrypsin (AAT), is known to cause emphysema and liver disease. Other manifestations, including airway disease or skin disorders, have also been described. A 44-year-old woman presented to our emergency department with dyspnea and respiratory insufficiency. She had never smoked, and had been diagnosed with COPD 9 years earlier. Three months previously, she had suffered a pulmonary embolism. Chest computed tomography scan revealed severe cystic bronchiectasis with destruction of the lung parenchyma...
2015: International Journal of Chronic Obstructive Pulmonary Disease
https://www.readbyqxmd.com/read/25714719/lytm-proteins-play-a-crucial-role-in-cell-separation-outer-membrane-composition-and-pathogenesis-in-nontypeable-haemophilus-influenzae
#20
Giuseppe Ercoli, Chiara Tani, Alfredo Pezzicoli, Irene Vacca, Manuele Martinelli, Simone Pecetta, Roberto Petracca, Rino Rappuoli, Mariagrazia Pizza, Nathalie Norais, Marco Soriani, Beatrice Aricò
UNLABELLED: LytM proteins belong to a family of bacterial metalloproteases. In Gram-negative bacteria, LytM factors are mainly reported to have a direct effect on cell division by influencing cleavage and remodeling of peptidoglycan. In this study, mining nontypeable Haemophilus influenzae (NTHI) genomes, three highly conserved open reading frames (ORFs) containing a LytM domain were identified, and the proteins encoded by the ORFs were named YebA, EnvC, and NlpD on the basis of their homology with the Escherichia coli proteins...
2015: MBio
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