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Allan r brasier

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https://www.readbyqxmd.com/read/29694891/selective-antagonists-of-the-bronchiolar-epithelial-nf-%C3%AE%C2%BAb-bromodomain-containing-protein-4-pathway-in-viral-induced-airway-inflammation
#1
Bing Tian, Zhiqing Liu, Jun Yang, Hong Sun, Yingxin Zhao, Maki Wakamiya, Haiying Chen, Erik Rytting, Jia Zhou, Allan R Brasier
The mechanisms by which the mammalian airway detects invading viral pathogens to trigger protective innate neutrophilic inflammation are incompletely understood. We observe that innate activation of nuclear factor κB (NF-κB)/RelA transcription factor indirectly activates atypical BRD4 histone acetyltransferase (HAT) activity, RNA polymerase II (Pol II) phosphorylation, and secretion of neutrophilic chemokines. To study this pathway in vivo, we developed a conditional knockout of RelA in distal airway epithelial cells; these animals have reduced mucosal BRD4/Pol II activation and neutrophilic inflammation to viral patterns...
April 24, 2018: Cell Reports
https://www.readbyqxmd.com/read/29649741/discovery-of-potent-and-selective-brd4-inhibitors-capable-of-blocking-tlr3-induced-acute-airway-inflammation
#2
Zhiqing Liu, Bing Tian, Haiying Chen, Pingyuan Wang, Allan R Brasier, Jia Zhou
A series of diverse small molecules have been designed and synthesized through structure-based drug design by taking advantage of fragment merging and elaboration approaches. Compounds ZL0420 (28) and ZL0454 (35) were identified as potent and selective BRD4 inhibitors with nanomolar binding affinities to bromodomains (BDs) of BRD4. Both of them can be well docked into the acetyl-lysine (KAc) binding pocket of BRD4, forming key interactions including the critical hydrogen bonds with Asn140 directly and Tyr97 indirectly via a H2 O molecule...
May 10, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29593031/central-role-of-the-nf%C3%AE%C2%BAb-pathway-in-the-scgb1a1-expressing-epithelium-in-mediating-respiratory-syncytial-virus-induced-airway-inflammation
#3
Bing Tian, Jun Yang, Yingxin Zhao, Teodora Ivanciuc, Hong Sun, Maki Wakamiya, Roberto P Garofalo, Allan R Brasier
Lower respiratory tract infection with respiratory syncytial virus (RSV) produces profound inflammation. Despite an understanding of the role of adaptive immunity in RSV infection, the identity of the major sentinel cells initially triggering inflammation is controversial. Here we evaluate the role of nonciliated secretoglobin ( Scgb1a1 )-expressing bronchiolar epithelial cells in RSV infection. Knock-in mice expressing a tamoxifen (TMX)-inducible Cre recombinase (CreERTM ) from the Scgb1a1 locus were crossed with mice that harbor a RelA conditional allele ( RelAfl ), with loxP sites flanking exons 5-8 of the Rel homology domain...
March 28, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29452288/repetitive-tlr3-activation-in-the-lung-induces-skeletal-muscle-adaptations-and-cachexia
#4
Ted G Graber, Brandy L Rawls, Bing Tian, William J Durham, Camille R Brightwell, Allan R Brasier, Blake B Rasmussen, Christopher S Fry
Due to immunosenescence, older adults are particularly susceptible to lung-based viral infections, with increased severity of symptoms in those with underlying chronic lung disease. Repeated respiratory viral infections produce lung maladaptations, accelerating pulmonary dysfunction. Toll like 3 receptor (TLR3) is a membrane protein that senses exogenous double-stranded RNA to activate the innate immune response to a viral infection. Polyinosinic-polycytidylic acid [poly(I:C)] mimics double stranded RNA and has been shown to activate TLR3...
June 2018: Experimental Gerontology
https://www.readbyqxmd.com/read/29402958/cell-fate-in-antiviral-response-arises-in-the-crosstalk-of-irf-nf-%C3%AE%C2%BAb-and-jak-stat-pathways
#5
Maciej Czerkies, Zbigniew Korwek, Wiktor Prus, Marek Kochańczyk, Joanna Jaruszewicz-Błońska, Karolina Tudelska, Sławomir Błoński, Marek Kimmel, Allan R Brasier, Tomasz Lipniacki
The innate immune system processes pathogen-induced signals into cell fate decisions. How information is turned to decision remains unknown. By combining stochastic mathematical modelling and experimentation, we demonstrate that feedback interactions between the IRF3, NF-κB and STAT pathways lead to switch-like responses to a viral analogue, poly(I:C), in contrast to pulse-like responses to bacterial LPS. Poly(I:C) activates both IRF3 and NF-κB, a requirement for induction of IFNβ expression. Autocrine IFNβ initiates a JAK/STAT-mediated positive-feedback stabilising nuclear IRF3 and NF-κB in first responder cells...
February 5, 2018: Nature Communications
https://www.readbyqxmd.com/read/28874504/proteome-analysis-of-hypoxic-glioblastoma-cells-reveals-sequential-metabolic-adaptation-of-one-carbon-metabolic-pathways
#6
Kangling Zhang, Pei Xu, James L Sowers, Daniel F Machuca, Barsam Mirfattah, Jason Herring, Hui Tang, Yan Chen, Bing Tian, Allan R Brasier, Lawrence C Sowers
Rapidly proliferating tumors are exposed to a hypoxic microenvironment because of their density, high metabolic consumption, and interruptions in blood flow because of immature angiogenesis. Cellular responses to hypoxia promote highly malignant and metastatic behavior, as well as a chemotherapy-resistant state. To better understand the complex relationships between hypoxic adaptations and cancer progression, we studied the dynamic proteome responses of glioblastoma cells exposed to hypoxia via an innovative approach: quantification of newly synthesized proteins using heavy stable-isotope arginine labeling combined with accurate assessment of cell replication by quantification of the light/heavy arginine ratio of peptides in histone H4...
November 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28819550/effects-of-storage-temperature-on-airway-exosome-integrity-for-diagnostic-and-functional-analyses
#7
Rosario Maroto, Yingxin Zhao, Mohammad Jamaluddin, Vsevolod L Popov, Hongwang Wang, Madumali Kalubowilage, Yueqing Zhang, Jonathan Luisi, Hong Sun, Christopher T Culbertson, Stefan H Bossmann, Massoud Motamedi, Allan R Brasier
Background : Extracellular vesicles contain biological molecules specified by cell-type of origin and modified by microenvironmental changes. To conduct reproducible studies on exosome content and function, storage conditions need to have minimal impact on airway exosome integrity. Aim : We compared surface properties and protein content of airway exosomes that had been freshly isolated vs. those that had been treated with cold storage or freezing. Methods : Mouse bronchoalveolar lavage fluid (BALF) exosomes purified by differential ultracentrifugation were analysed immediately or stored at +4°C or -80°C...
2017: Journal of Extracellular Vesicles
https://www.readbyqxmd.com/read/28818856/deletion-of-nf-%C3%AE%C2%BAb-rela-in-angiotensin-ii-sensitive-mesenchymal-cells-blocks-aortic-vascular-inflammation-and-abdominal-aortic-aneurysm-formation
#8
Talha Ijaz, Hong Sun, Irina V Pinchuk, Dianna M Milewicz, Ronald G Tilton, Allan R Brasier
OBJECTIVE: Infusion of angiotensin II (Ang II) induces extracellular matrix remodeling and inflammation resulting in abdominal aortic aneurysms (AAAs) in normolipidemic mice. Although Ang II activates mesenchymal cells in the media and adventitia to become fibrogenic, the sentinel role of this mesenchymal population in modulating the inflammatory response and aneurysms is not known. We test the hypothesis that these fibrogenic mesenchymal cells play a critical role in Ang II-induced aortic wall vascular inflammation and AAA formation...
October 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28798252/pollen-induced-oxidative-dna-damage-response-regulates-mirnas-controlling-allergic-inflammation
#9
Leopoldo Aguilera-Aguirre, Wenging Hao, Lang Pan, Xiaoxue Li, Alfredo Saavedra-Molina, Attila Bacsi, Zsolt Radak, Sanjiv Sur, Allan R Brasier, Xueqing Ba, Istvan Boldogh
A mucosal oxidative burst is a hallmark response to pollen exposure that promotes allergic inflammatory responses. Reactive species constituents of oxidative stress signal via the modification of cellular molecules including nucleic acids. One of the most abundant forms of oxidative genomic base damage is 8-oxo-7,8-dihydroguanine (8-oxoG), which is removed from DNA by 8-oxoguanine DNA glycosylase 1 (OGG1). OGG1 in complex with 8-oxoG acts as a GDP-GTP exchange factor and induces acute inflammation; however, the mechanism(s) by which OGG1 signaling regulates allergic airway inflammation is not known...
December 1, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28726418/quantitative-assessment-of-the-effects-of-trypsin-digestion-methods-on-affinity-purification-mass-spectrometry-based-protein-protein-interaction-analysis
#10
Yueqing Zhang, Hong Sun, Jing Zhang, Allan R Brasier, Yingxin Zhao
Affinity purification-mass spectrometry (AP-MS) has become the method of choice for discovering protein-protein interactions (PPIs) under native conditions. The success of AP-MS depends on the efficiency of trypsin digestion and the recovery of the tryptic peptides for MS analysis. Several different protocols have been used for trypsin digestion of protein complexes in AP-MS studies, but no systematic studies have been conducted on the impact of trypsin digestion conditions on the identification of PPIs. Here, we used NFκB/RelA and Bromodomain-containing protein 4 (BRD4) as baits and test five distinct trypsin digestion methods (two using "on-beads," three using "elution-digestion" protocols)...
August 4, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28714690/selective-affinity-enrichment-of-nitrotyrosine-containing-peptides-for-quantitative-analysis-in-complex-samples
#11
Yingxin Zhao, Yueqing Zhang, Hong Sun, Rosario Maroto, Allan R Brasier
Protein tyrosine nitration by oxidative and nitrate stress is important in the pathogenesis of many inflammatory or aging-related diseases. Mass spectrometry analysis of protein nitrotyrosine is very challenging because the non-nitrated peptides suppress the signals of the low-abundance nitrotyrosine (NT) peptides. No validated methods for enrichment of NT-peptides are currently available. Here we report an immunoaffinity enrichment of NT-peptides for proteomics analysis. The effectiveness of this approach was evaluated using nitrated protein standards and whole-cell lysates in vitro...
August 4, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28666081/major-histocompatibility-complex-class-ii-alleles-influence-induction-of-pathogenic-antiphospholipid-antibodies-in-a-mouse-model-of-thrombosis
#12
Elizabeth Papalardo, Zurina Romay-Penabad, Rohan Willis, Premkumar Christadoss, Ana Laura Carrera-Marin, Elba Reyes-Maldonado, Rajani Rudrangi, Silvana Alfieri-Papalardo, Ethel Garcia-Latorre, Miri Blank, Silvia Pierangeli, Allan R Brasier, Emilio B Gonzalez
OBJECTIVE: Both environmental and genetic factors are important in the development of antiphospholipid antibodies (aPL) in patients with antiphospholipid syndrome (APS). Currently, the only available data on predisposing genetic factors have been obtained from epidemiologic studies, without mechanistic evidence. Therefore, we studied the influence of major histocompatibility complex (MHC) class II alleles on the production of aPL in a mouse model of APS. METHODS: Three groups of mice, MHC class II-deficient (MHCII-/- ) mice, MHCII-/- mice transgenic for human HLA-DQ6 (DQ6), DQ8, or DR4 alleles, and the corresponding wild-type (WT) mouse strains were immunized; half were immunized with human β2 -glycoprotein I (β2 GPI), and the other half were immunized with control ovalbumin (OVA) protein...
October 2017: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/28583369/innate-mechanism-of-pollen-and-cat-dander-induced-oxidative-stress-and-dna-damage-in-the-airways
#13
Koa Hosoki, David Redding, Toshiko Itazawa, Anirban Chakraborty, Nisha Tapryal, Sun Qian, Huibin Qi, Leopoldo Aguilera-Aguirre, Allan R Brasier, Veeranki Sreenivas Phani, Tapas K Hazra, Istvan Boldogh, Sanjiv Sur
No abstract text is available yet for this article.
June 2, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28581456/epigenetic-silencing-of-irf1-dysregulates-type-iii-interferon-responses-to-respiratory-virus-infection-in-epithelial-to-mesenchymal-transition
#14
Jun Yang, Bing Tian, Hong Sun, Roberto P Garofalo, Allan R Brasier
Chronic oxidative injury produced by airway disease triggers a transforming growth factor-β (TGF-β)-mediated epigenetic reprogramming known as the epithelial-mesenchymal transition (EMT). We observe that EMT silences protective mucosal interferon (IFN)-I and III production associated with enhanced rhinovirus (RV) and respiratory syncytial virus (RSV) replication. Mesenchymal transitioned cells are defective in inducible interferon regulatory factor 1 (IRF1) expression by occluding RelA and IRF3 access to the promoter...
June 5, 2017: Nature Microbiology
https://www.readbyqxmd.com/read/28258195/systematic-analysis-of-cell-type-differences-in-the-epithelial-secretome-reveals-insights-into-the-pathogenesis-of-respiratory-syncytial-virus-induced-lower-respiratory-tract-infections
#15
Yingxin Zhao, Mohammad Jamaluddin, Yueqing Zhang, Hong Sun, Teodora Ivanciuc, Roberto P Garofalo, Allan R Brasier
Lower respiratory tract infections from respiratory syncytial virus (RSV) are due, in part, to secreted signals from lower airway cells that modify the immune response and trigger airway remodeling. To understand this process, we applied an unbiased quantitative proteomics analysis of the RSV-induced epithelial secretory response in cells representative of the trachea versus small airway bronchiolar cells. A workflow was established using telomerase-immortalized human epithelial cells that revealed highly reproducible cell type-specific differences in secreted proteins and nanoparticles (exosomes)...
April 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28195723/drug-discovery-targeting-bromodomain-containing-protein-4
#16
REVIEW
Zhiqing Liu, Pingyuan Wang, Haiying Chen, Eric A Wold, Bing Tian, Allan R Brasier, Jia Zhou
BRD4, the most extensively studied member of the BET family, is an epigenetic regulator that localizes to DNA via binding to acetylated histones and controls the expression of therapeutically important gene regulatory networks through the recruitment of transcription factors to form mediator complexes, phosphorylating RNA polymerase II, and by its intrinsic histone acetyltransferase activity. Disrupting the protein-protein interactions between BRD4 and acetyl-lysine has been shown to effectively block cell proliferation in cancer, cytokine production in acute inflammation, and so forth...
June 8, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28182006/coordinate-activities-of-brd4-and-cdk9-in-the-transcriptional-elongation-complex-are-required-for-tgf%C3%AE-induced-nox4-expression-and-myofibroblast-transdifferentiation
#17
Talha Ijaz, Mohammad Jamaluddin, Yingxin Zhao, Yueqing Zhang, Jayson Jay, Celeste C Finnerty, David N Herndon, Ronald G Tilton, Allan R Brasier
Transdifferentiation of quiescent dermal fibroblasts to secretory myofibroblasts has a central role in wound healing and pathological scar formation. This myofibroblast transdifferentiation process involves TGFβ-induced de novo synthesis of alpha smooth muscle cell actin (αSMA)+ fibers that enhance contractility as well as increased expression of extracellular matrix (ECM) proteins, including collagen and fibronectin. These processes are mediated upstream by the reactive oxygen species (ROS)-producing enzyme Nox4, whose induction by TGFβ is incompletely understood...
February 9, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28145773/reply-protease-plays-a-role-in-ragweed-pollen-induced-neutrophil-recruitment-and-epithelial-barrier-disruption
#18
LETTER
Koa Hosoki, Allan R Brasier, Alexander Kurosky, Istvan Boldogh, Sanjiv Sur
No abstract text is available yet for this article.
February 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/28077651/brd4-couples-nf-%C3%AE%C2%BAb-rela-with-airway-inflammation-and-the-irf-rig-i-amplification-loop-in-respiratory-syncytial-virus-infection
#19
Bing Tian, Jun Yang, Yingxin Zhao, Teodora Ivanciuc, Hong Sun, Roberto P Garofalo, Allan R Brasier
The airway mucosa expresses protective interferon (IFN) and inflammatory cytokines in response to respiratory syncytial virus (RSV) infection. In this study, we examine the role of bromodomain containing 4 (BRD4) in mediating this innate immune response in human small airway epithelial cells. We observe that RSV induces BRD4 to complex with NF-κB/RelA. BRD4 is functionally required for expression of the NF-κB-dependent inflammatory gene regulatory network (GRN), including the IFN response factor 1 (IRF1) and IRF7, which mediate a cross talk pathway for RIG-I upregulation...
March 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/27975232/qualification-and-verification-of-protein-biomarker-candidates
#20
REVIEW
Yingxin Zhao, Allan R Brasier
The importance of biomarkers has long been recognized by the public, scientific community, and industry. Yet despite extensive efforts and funding investments in biomarker discovery, only 109 protein biomarkers in plasma or serum were approved by the US Food and Drug Administration throughout 2008 (Anderson NL. Clin Chem 56:177-185, 2010), and even fewer protein biomarkers are currently used routinely in the clinic. In recent years, the introduction of new protein biomarkers approved by the US Food and Drug Administration has fallen to an average of 1...
2016: Advances in Experimental Medicine and Biology
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