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https://www.readbyqxmd.com/read/28195723/drug-discovery-targeting-bromodomain-containing-protein-4-brd4
#1
Zhiqing Liu, Pingyuan Wang, Haiying Chen, Eric A Wold, Bing Tian, Allan R Brasier, Jia Zhou
BRD4, the most extensively studied member of BET family, is an epigenetic regulator that localizes to DNA via binding acetylated histones and controls the expression of therapeutically important gene regulatory networks through recruiting 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, etc...
February 14, 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
#2
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
#3
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/bromodomain-containing-4-brd4-couples-nf%C3%AE%C2%BAb-rela-with-airway-inflammation-and-the-irf-rig-i-amplification-loop-in-respiratory-syncytial-virus-infection
#4
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 NFκB/RelA. BRD4 is functionally required for expression of the NFκB-dependent inflammatory gene regulatory network (GRN), including the IFN Response Factor (IRFs)-1 and -7 that mediate a cross-talk pathway for RIG-I upregulation...
January 11, 2017: Journal of Virology
https://www.readbyqxmd.com/read/27975232/qualification-and-verification-of-protein-biomarker-candidates
#5
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
https://www.readbyqxmd.com/read/27975229/introduction-to-clinical-proteomics
#6
John E Wiktorowicz, Allan R Brasier
Within the context of this section, biomarkers are defined as a panel of proteins and peptides that are predictive of the risk for developing a pathological condition. It is important to note here that the use of the descriptor 'panel' is purposeful in that single "biomarkers" are rarely sufficient to permit accurate prediction of a pathological condition. More specifically, the primary application of a biomarker panel is that it serves as a molecular indicator of the severity of a disease or its early response to treatment...
2016: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/27911568/nf%C3%AE%C2%BAb-mediates-mesenchymal-transition-remodeling-and-pulmonary-fibrosis-in-response-to-chronic-inflammation-by-viral-rna-patterns
#7
Bing Tian, Igor Patrikeev, Lorenzo Ochoa, Gracie Vargas, KarryAnne K Belanger, Julia Litvinov, Istvan Boldogh, Bill T Ameredes, Massoud Motamedi, Allan R Brasier
Airway remodeling is resultant of a complex multi-cellular response associated with a progressive decline of pulmonary function in patients with chronic airway disease. Here, repeated infections with respiratory viruses are linked with airway remodeling through largely unknown mechanisms. Although acute activation of the Toll like receptor (TLR)3 pathway by extracellular poly(I:C) induces innate signaling through the NFkB transcription factor in human small airway epithelial cells (hSAECs), prolonged (repetitive or tonic) poly(I:C) stimulation produces chronic stress fiber formation, mesenchymal transition and activation of a fibrotic program...
December 2, 2016: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/27793799/brd4-mediates-nf-%C3%AE%C2%BAb-dependent-epithelial-mesenchymal-transition-and-pulmonary-fibrosis-via-transcriptional-elongation
#8
Bing Tian, Yingxin Zhao, Hong Sun, Yueqing Zhang, Jun Yang, Allan R Brasier
Chronic epithelial injury triggers a TGF-β-mediated cellular transition from normal epithelium into a mesenchymal-like state that produces subepithelial fibrosis and airway remodeling. Here we examined how TGF-β induces the mesenchymal cell state and determined its mechanism. We observed that TGF-β stimulation activates an inflammatory gene program controlled by the NF-κB/RelA signaling pathway. In the mesenchymal state, NF-κB-dependent immediate-early genes accumulate euchromatin marks and processive RNA polymerase...
December 1, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/27756845/oxidized-guanine-base-lesions-function-in-8-oxoguanine-dna-glycosylase-1-mediated-epigenetic-regulation-of-nuclear-factor-%C3%AE%C2%BAb-driven-gene-expression
#9
Lang Pan, Bing Zhu, Wenjing Hao, Xianlu Zeng, Spiros A Vlahopoulos, Tapas K Hazra, Muralidhar L Hegde, Zsolt Radak, Attila Bacsi, Allan R Brasier, Xueqing Ba, Istvan Boldogh
A large percentage of redox-responsive gene promoters contain evolutionarily conserved guanine-rich clusters; guanines are the bases most susceptible to oxidative modification(s). Consequently, 7,8-dihydro-8-oxoguanine (8-oxoG) is one of the most abundant base lesions in promoters and is primarily repaired via the 8-oxoguanine DNA glycosylase-1 (OOG1)-initiated base excision repair pathway. In view of a prompt cellular response to oxidative challenge, we hypothesized that the 8-oxoG lesion and the cognate repair protein OGG1 are utilized in transcriptional gene activation...
December 2, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27662828/generation-and-characterization-of-a-novel-transgenic-mouse-harboring-conditional-nuclear-factor-kappa-b-rela-knockout-alleles
#10
Talha Ijaz, Maki Wakamiya, Hong Sun, Adrian Recinos, Ronald G Tilton, Allan R Brasier
BACKGROUND: Nuclear Factor-Kappa B (NF-kB) is a family of transcription factors that are important in embryonic development, inflammation, epithelial-to-mesenchymal transition and cancer. The 65 kDa RelA subunit is the major transcriptional activator of the NF-kB pathways. Whole-body deficiency of RelA leads to massive apoptosis of liver hepatocytes and death in utero. To study the role of RelA in physiology and in disease states in a manner that circumvents this embryonic lethal phenotype, we have generated a mouse with RelA conditional knockout (CKO) alleles containing loxP sites that are deleted by activated Cre recombinase...
September 23, 2016: BMC Developmental Biology
https://www.readbyqxmd.com/read/27635260/s-nitrosylation-proteome-profile-of-peripheral-blood-mononuclear-cells-in-human-heart-failure
#11
Sue-Jie Koo, Heidi M Spratt, Kizhake V Soman, Susan Stafford, Shivali Gupta, John R Petersen, Maria P Zago, Muge N Kuyumcu-Martinez, Allan R Brasier, John E Wiktorowicz, Nisha Jain Garg
Nitric oxide (NO) protects the heart against ischemic injury; however, NO- and superoxide-dependent S-nitrosylation (S-NO) of cysteines can affect function of target proteins and play a role in disease outcome. We employed 2D-GE with thiol-labeling FL-maleimide dye and MALDI-TOF MS/MS to capture the quantitative changes in abundance and S-NO proteome of HF patients (versus healthy controls, n = 30/group). We identified 93 differentially abundant (59-increased/34-decreased) and 111 S-NO-modified (63-increased/48-decreased) protein spots, respectively, in HF subjects (versus controls, fold-change | ≥1...
2016: International Journal of Proteomics
https://www.readbyqxmd.com/read/27624997/palmitoyl-carnitine-production-by-blood-cells-associates-with-the-concentration-of-circulating-acyl-carnitines-in-healthy-overweight-women
#12
Maria Chondronikola, Rabia Asghar, Xiaojun Zhang, Edgar L Dillon, William J Durham, Zhanpin Wu, Craig Porter, Maria Camacho-Hughes, Yingxin Zhao, Allan R Brasier, Elena Volpi, Melinda Sheffield-Moore, Nicola Abate, Labros Sidossis, Demidmaa Tuvdendorj
BACKGROUND: Circulating acyl-carnitines (acyl-CNTs) are associated with insulin resistance (IR) and type 2 diabetes (T2D) in both rodents and humans. However, the mechanisms whereby circulating acyl-CNTs are increased in these conditions and their role in whole-body metabolism remains unknown. The purpose of this study was to determine if, in humans, blood cells contribute in production of circulating acyl-CNTs and associate with whole-body fat metabolism. METHODS AND RESULTS: Eight non-diabetic healthy women (age: 47 ± 19 y; BMI: 26 ± 1 kg·m(-2)) underwent stable isotope tracer infusion and hyperinsulinemic-euglycemic clamp study to determine in vivo whole-body fatty acid flux and insulin sensitivity...
September 6, 2016: Clinical Nutrition: Official Journal of the European Society of Parenteral and Enteral Nutrition
https://www.readbyqxmd.com/read/27619163/cytokine-amplification-and-macrophage-effector-functions-in-aortic-inflammation-and-abdominal-aortic-aneurysm-formation
#13
COMMENT
Talha Ijaz, Ronald G Tilton, Allan R Brasier
On April 29, 2015, Son and colleagues published an article entitled "Granulocyte macrophage colony-stimulating factor (GM-CSF) is required for aortic dissection/intramural haematoma" in Nature Communications. The authors observed that the heterozygous Kruppel-like transcription factor 6 (KLF6) deficiency or absence of myeloid-specific KLF6 led to upregulation of macrophage GM-CSF expression, promoted the development of aortic hematoma/dissection, and stimulated abdominal aortic aneurysm (AAA) formation when the vessel wall was subjected to an inflammatory stimulus...
August 2016: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/27535058/respiratory-syncytial-virus-infection-triggers-epithelial-hmgb1-release-as-a-damage-associated-molecular-pattern-promoting-a-monocytic-inflammatory-response
#14
Yashoda M Hosakote, Allan R Brasier, Antonella Casola, Roberto P Garofalo, Alexander Kurosky
: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infant and elderly populations worldwide. Currently, there is no efficacious vaccine or therapy available for RSV infection. The molecular mechanisms underlying RSV-induced acute airway disease and associated long-term consequences remain largely unknown; however, experimental evidence suggests that the lung inflammatory response plays a fundamental role in the outcome of RSV infection. High-mobility group box 1 (HMGB1) is a nuclear protein that triggers inflammation when released from activated immune or necrotic cells and drives the pathogenesis of various infectious agents...
November 1, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27530234/measurement-of-histone-methylation-dynamics-by-one-carbon-metabolic-isotope-labeling-and-high-energy-collisional-dissociation-methylation-signature-ion-detection
#15
Hui Tang, Bing Tian, Allan R Brasier, Lawrence C Sowers, Kangling Zhang
Accumulating evidence suggests that cellular metabolites and nutrition levels control epigenetic modifications, including histone methylation. However, it is not currently possible to measure the metabolic control of histone methylation. Here we report a novel detection method to monitor methyl transfer from serine to histones through the one-carbon metabolic pathway, using stable-isotope labeling and detection of lysine methylation signature ions generated in high-energy-dissociation (HCD) tandem mass spectrometry...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27461979/integrative-proteomic-analysis-reveals-reprograming-tumor-necrosis-factor-signaling-in-epithelial-mesenchymal-transition
#16
Yingxin Zhao, Bing Tian, Rovshan G Sadygov, Yueqing Zhang, Allan R Brasier
UNLABELLED: The airway epithelium is a semi-impermeable barrier whose disruption by growth factor reprogramming is associated with chronic airway diseases of humans. Transforming growth factor beta (TGFβ)-induced epithelial mesenchymal transition (EMT) plays important roles in airway remodeling characteristic of idiopathic lung fibrosis, asthma and chronic obstructive pulmonary disease (COPD). Inflammation of the airways leads to airway injury and tumor necrosis factor alpha (TNFα) plays an important pro-inflammatory role...
October 4, 2016: Journal of Proteomics
https://www.readbyqxmd.com/read/27239029/dysregulation-of-rbfox2-is-an-early-event-in-cardiac-pathogenesis-of-diabetes
#17
Curtis A Nutter, Elizabeth A Jaworski, Sunil K Verma, Vaibhav Deshmukh, Qiongling Wang, Olga B Botvinnik, Mario J Lozano, Ismail J Abass, Talha Ijaz, Allan R Brasier, Nisha J Garg, Xander H T Wehrens, Gene W Yeo, Muge N Kuyumcu-Martinez
Alternative splicing (AS) defects that adversely affect gene expression and function have been identified in diabetic hearts; however, the mechanisms responsible are largely unknown. Here, we show that the RNA-binding protein RBFOX2 contributes to transcriptome changes under diabetic conditions. RBFOX2 controls AS of genes with important roles in heart function relevant to diabetic cardiomyopathy. RBFOX2 protein levels are elevated in diabetic hearts despite low RBFOX2 AS activity. A dominant-negative (DN) isoform of RBFOX2 that blocks RBFOX2-mediated AS is generated in diabetic hearts...
June 7, 2016: Cell Reports
https://www.readbyqxmd.com/read/26919708/changes-in-proteome-profile-of-peripheral-blood-mononuclear-cells-in-chronic-chagas-disease
#18
Nisha Jain Garg, Kizhake V Soman, Maria P Zago, Sue-Jie Koo, Heidi Spratt, Susan Stafford, Zinzi N Blell, Shivali Gupta, Julio Nuñez Burgos, Natalia Barrientos, Allan R Brasier, John E Wiktorowicz
Trypanosoma cruzi (Tc) infection causes chagasic cardiomyopathy; however, why 30-40% of the patients develop clinical disease is not known. To discover the pathomechanisms in disease progression, we obtained the proteome signature of peripheral blood mononuclear cells (PBMCs) of normal healthy controls (N/H, n = 30) and subjects that were seropositive for Tc-specific antibodies, but were clinically asymptomatic (C/A, n = 25) or clinically symptomatic (C/S, n = 28) with cardiac involvement and left ventricular dysfunction...
February 2016: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/26586036/myeloid-differentiation-protein-2-facilitates-pollen-and-cat-dander-induced-innate-and-allergic-airway-inflammation
#19
Koa Hosoki, Istvan Boldogh, Leopoldo Aguilera-Aguirre, Qian Sun, Toshiko Itazawa, Tapas Hazra, Allan R Brasier, Alexander Kurosky, Sanjiv Sur
BACKGROUND: The National Health and Nutrition Examination Survey identified several pollens and cat dander as among the most common allergens that induce allergic sensitization and allergic diseases. We recently reported that ragweed pollen extract (RWPE) requires Toll-like receptor 4 (TLR4) to stimulate CXCL-mediated innate neutrophilic inflammation, which in turn facilitates allergic sensitization and airway inflammation. Myeloid differentiation protein 2 (MD2) is a TLR4 coreceptor, but its role in pollen- and cat dander-induced innate and allergic inflammation has not been critically evaluated...
May 2016: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/26581097/improved-detection-of-invasive-pulmonary-aspergillosis-arising-during-leukemia-treatment-using-a-panel-of-host-response-proteins-and-fungal-antigens
#20
Allan R Brasier, Yingxin Zhao, Heidi M Spratt, John E Wiktorowicz, Hyunsu Ju, L Joseph Wheat, Lindsey Baden, Susan Stafford, Zheng Wu, Nicolas Issa, Angela M Caliendo, David W Denning, Kizhake Soman, Cornelius J Clancy, M Hong Nguyen, Michele W Sugrue, Barbara D Alexander, John R Wingard
Invasive pulmonary aspergillosis (IPA) is an opportunistic fungal infection in patients undergoing chemotherapy for hematological malignancy, hematopoietic stem cell transplant, or other forms of immunosuppression. In this group, Aspergillus infections account for the majority of deaths due to mold pathogens. Although early detection is associated with improved outcomes, current diagnostic regimens lack sensitivity and specificity. Patients undergoing chemotherapy, stem cell transplantation and lung transplantation were enrolled in a multi-site prospective observational trial...
2015: PloS One
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