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https://www.readbyqxmd.com/read/27913761/best-practices-in-the-treatment-of-early-cystic-fibrosis-lung-disease
#1
REVIEW
Marijke Proesmans
For many years, management of cystic fibrosis (CF) lung disease was focused on symptomatic treatment of chronic lung infection, which is characterized by cough and sputum production, leading to progressive lung damage. With increasing survival and better knowledge of the pathogenesis of CF lung disease, it has become clear that treatment has to start very early because lung damage occurs in young patients, often before obvious symptoms appear. The arrival of new cystic fibrosis transmembrane conductance-regulator (CFTR)-correcting therapies will bring more opportunities to prevent the disease, apart from only treating chronic lung infection...
December 2, 2016: Therapeutic Advances in Respiratory Disease
https://www.readbyqxmd.com/read/27913277/specific-stabilization-of-cftr-by-phosphatidylserine
#2
Ellen Hildebrandt, Netaly Khazanov, John C Kappes, Qun Dai, Hanoch Senderowitz, Ina L Urbatsch
The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR, ABCC7) is a plasma membrane chloride ion channel in the ABC transporter superfamily. CFTR is a key target for cystic fibrosis drug development, and its structural elucidation would advance those efforts. However, the limited in vivo and in vitro stability of the protein, particularly its nucleotide binding domains, has made structural studies challenging. Here we demonstrate that phosphatidylserine uniquely stimulates and thermally stabilizes the ATP hydrolysis function of purified human CFTR...
November 29, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27912062/atomic-structure-of-the-cystic-fibrosis-transmembrane-conductance-regulator
#3
Zhe Zhang, Jue Chen
The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel evolved from the ATP-binding cassette (ABC) transporter family. In this study, we determined the structure of zebrafish CFTR in the absence of ATP by electron cryo-microscopy to 3.7 Å resolution. Human and zebrafish CFTR share 55% sequence identity, and 42 of the 46 cystic-fibrosis-causing missense mutational sites are identical. In CFTR, we observe a large anion conduction pathway lined by numerous positively charged residues...
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27904687/high-fructose-causes-cardiac-hypertrophy-via-mitochondrial-signaling-pathway
#4
Yan-Bo Zhang, Yan-Hai Meng, Shuo Chang, Rong-Yuan Zhang, Chen Shi
High fructose diet can cause cardiac hypertrophy and oxidative stress is a key mediator for myocardial hypertrophy. Disruption of cystic fibrosis transmembrane conductance regulator (CFTR) leads to oxidative stress. This study aims to reveal mitochondrial oxidative stress-related signaling pathway in high fructose-induced cardiac hypertrophy. Mice were fed high fructose to develop cardiac hypertrophy. Fructose and H2O2 were used to induce cardiomyocyte hypertrophy in vitro. Mitochondria-targeted antioxidant SkQ1 was applied to investigate the possible role of mitochondrial reactive oxygen species (ROS)...
2016: American Journal of Translational Research
https://www.readbyqxmd.com/read/27898234/lumacaftor-ivacaftor-treatment-of-patients-with-cystic-fibrosis-heterozygous-for-f508del-cftr
#5
Steven M Rowe, Susanna A McColley, Ernst Rietschel, Xiaolei Li, Scott C Bell, Michael W Konstan, Gautham Marigowda, David Waltz, Michael P Boyle
RATIONALE: Lumacaftor/ivacaftor treatment (≤28 days) in patients with cystic fibrosis (CF) heterozygous for F508del-CFTR did not improve lung function. OBJECTIVES: To evaluate an optimized lumacaftor/ivacaftor dosing regimen with longer duration in a cohort of patients heterozygous for F508del-CFTR. METHODS: Patients age ≥18 years with a confirmed CF diagnosis and percent predicted forced expiratory volume in 1 second (ppFEV1) of 40 to 90 were randomized to lumacaftor/ivacaftor (400 mg/250 mg every 12 hours) or placebo daily for 56 days...
November 29, 2016: Annals of the American Thoracic Society
https://www.readbyqxmd.com/read/27897275/an-ex-vivo-model-contributing-to-the-diagnosis-and-evaluation-of-new-drugs-in-cystic-fibrosis
#6
A M Di Lullo, M Scorza, F Amato, M Comegna, V Raia, L Maiuri, G Ilardi, E Cantone, G Castaldo, M Iengo
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. About 2000 mutations have been described so far. We setup an ex vivo model of human nasal epithelial cells (HNECs) to study CF patients testing the effect of novel mutations and molecular therapies. We performed the sampling (by brushing), followed by culture and analysis of HNECs using a series of molecular techniques. We performed 50 brushings from CF patients and controls...
November 29, 2016: Acta Otorhinolaryngologica Italica
https://www.readbyqxmd.com/read/27895116/correctors-and-potentiators-rescue-function-of-the-truncated-w1282x-cftr-translation-product
#7
Peter M Haggie, Puay-Wah Phuan, Joseph-Anthony Tan, Haijin Xu, Radu G Avramescu, Doranda Perdomo, Lorna Zlock, Dennis W Nielson, Walter E Finkbeiner, Gergely L Lukacs, Alan S Verkman
W1282X is the fifth most common CFTR mutation that causes cystic fibrosis. Here, we investigated the utility of a small molecule corrector / potentiator strategy, as used for ΔF508-CFTR, to produce functional rescue of the truncated translation product of the W1282X mutation, CFTR1281, without the need for read-through. In transfected cell systems, certain potentiators and correctors including VX-809 and VX-770 increased CFTR1281 activity. To identify novel correctors and potentiators with potentially greater efficacy on CFTR1281, functional screens were done of ~30,000 synthetic small molecules and drugs/nutraceuticals in CFTR1281-transfected cells...
November 28, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27891704/isoflavone-genistein-inhibits-estrogen-induced-chloride-and-bicarbonate-secretory-mechanisms-in-the-uterus-in-rats
#8
Asma Chinigarzadeh, Kamarulzaman Karim, Sekaran Muniandy, Naguib Salleh
We hypothesized that genistein could affect the chloride (Cl(-) ) and bicarbonate (HCO3(-) ) secretory mechanisms in uterus. Ovariectomized female rats were given estradiol or estradiol plus progesterone with 25, 50, or 100 mg/kg/day genistein. Following completion of the treatment, uterine fluid Cl(-) and HCO3(-) concentrations were determined by in vivo uterine perfusion. Uteri were subjected for molecular biological analysis (Western blot, qPCR, and immunohistochemistry) to detect levels of expression of Cystic Fibrosis transmembrane regulator (CFTR), Cl(-) /HCO3(-) exchanger (SLC26a6), Na(+) /HCO3(-) cotransporter (SLC4a4), and estrogen receptor (ER)-α and β...
November 28, 2016: Journal of Biochemical and Molecular Toxicology
https://www.readbyqxmd.com/read/27890909/symptoms-mimicking-sj%C3%A3-gren-syndrome-in-a-heterozygous-carrier-of-cftr-deltaf508-mutation
#9
Marta Domżalska, Zbigniew Zdrojewski, Natalia Buda, Anna Masiak, Jolanta Szade, Grzegorz Romanowicz
No abstract text is available yet for this article.
November 28, 2016: Polskie Archiwum Medycyny Wewnętrznej
https://www.readbyqxmd.com/read/27888566/functional-expression-of-g-protein-coupled-receptor-30-in-immature-rat-epididymal-epithelium
#10
Xiaonian Cao, Jiehong Huang, Geng Zhang, Wulin Zuo, Chongfeng Lan, Qing Sun, Dengliang Yang, Dongdong Gao, Christopher H K Cheng, Wen-Liang Zhou
The aim of this study is to investigate the functional role of G protein-coupled receptor 30 (GPR30) in the epididymis. We found that GPR30 is expressed in the epithelium of the immature rat epididymis and is involved in chloride secretion into the caudal epididymis lumen. The short-circuit current (Isc) experiments showed that in primary cultured caudal epididymis epithelium, activation of GPR30 by its specific agonist G1 induced a mono-phasic current increase, and G15, the specific antagonist of GPR30, could completely inhibit the current induced by G1...
November 26, 2016: Cell Biology International
https://www.readbyqxmd.com/read/27881573/intestinal-na-k-2cl-cotransporter-2-plays-a-crucial-role-in-hyperosmotic-transitions-of-a-euryhaline-teleost
#11
Andrew J Esbaugh, Brett Cutler
Euryhaline fishes, such as the red drum (Sciaenops ocellatus), must quickly transition between hyperosmotic and hypoosmotic physiological strategies. When freshwater individuals transition to seawater they are exposed to increased diffusive water loss and ion gain. To maintain osmoregulatory balance these animals must drink and absorb seawater through the intestine, followed by ion excretion at the gills. The ability of fishes to transition between strategies can limit the magnitude of osmotic shock that can be tolerated...
November 2016: Physiological Reports
https://www.readbyqxmd.com/read/27876591/cystic-fibrosis-and-the-nervous-system
#12
REVIEW
Leah R Reznikov
Cystic Fibrosis (CF) is a life-shortening autosomal recessive disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is an anion channel that conducts bicarbonate and chloride across cell membranes. While defective anion transport across epithelial cells is accepted as the basic defect in CF, many of the features observed in people with CF and organs affected in CF are modulated by the nervous system. This is of interest because CFTR expression has been reported in both the peripheral and central nervous systems, and it is well known that the transport of anions, such as chloride, greatly modulates neuronal excitability...
November 19, 2016: Chest
https://www.readbyqxmd.com/read/27871064/benzopyrimido-pyrrolo-oxazine-dione-cftr-inhibitor-r-bpo-27-for-anti-secretory-therapy-of-diarrheas-caused-by-bacterial-enterotoxins
#13
Onur Cil, Puay-Wah Phuan, Anne Marie Gillespie, Sujin Lee, Lukmanee Tradtrantip, Jianyi Yin, Ming Tse, Nicholas C Zachos, Ruxian Lin, Mark Donowitz, Alan S Verkman
Secretory diarrheas caused by bacterial enterotoxins, including cholera and traveler's diarrhea, remain a major global health problem. Inappropriate activation of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel occurs in these diarrheas. We previously reported that the benzopyrimido-pyrrolo-oxazinedione (R)-BPO-27 inhibits CFTR chloride conductance with low-nanomolar potency. Here, we demonstrate using experimental mouse models and human enterocyte cultures the potential utility of (R)-BPO-27 for treatment of secretory diarrheas caused by cholera and Escherichia coli enterotoxins...
November 8, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/27870250/new-insights-into-interactions-between-the-nucleotide-binding-domain-of-cftr-and-keratin-8
#14
Aiswarya Premchandar, Anna Kupniewska, Arkadiusz Bonna, Grazyna Faure, Tomasz Fraczyk, Ariel Roldan, Brice Hoffmann, Mélanie Faria da Cunha, Harald Herrmann, Gergely L Lukacs, Aleksander Edelman, Michał Dadlez
The intermediate filament protein keratin 8 (K8) interacts with the nucleotide-binding domain 1 (NBD1) of the cystic fibrosis transmembrane regulator (CFTR) with phenylalanine 508 deletion (ΔF508), and this interaction hampers the biogenesis of functional ΔF508-CFTR and its insertion into the plasma membrane. Interruption of this interaction may constitute a new therapeutic target for cystic fibrosis patients bearing the ΔF508 mutation. Here we aimed to determine the binding surface between these two proteins, to facilitate the design of the interaction inhibitors...
November 21, 2016: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/27866192/dietary-genistein-rescues-reduced-basal-chloride-secretion-in-diabetic-jejunum-via-sex-dependent-mechanisms
#15
Shawn Catmull, Faisal Masood, Sydney Schacht, Robert Dolan, Daniel Stegman, Lana Leung, Layla Al-Nakkash
BACKGROUND/AIMS: The goal of this study was to determine the effect of dietary genistein (naturally occurring phytoestrogen) on jejunal secretory function in a clinically relevant model of diabetes and obesity, the leptin-defIcient ob/ob mouse. METHODS: We measured transepithelial short circuit current (Isc), across freshly isolated segments of jejunum from 12-week old male and female ob/ob and lean C57Bl/6J mice fed a genistein diet (600 mg genistein/kg diet) for 4-weeks...
2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27863009/regulation-of-mrna-turnover-in-cystic-fibrosis-lung-disease
#16
REVIEW
Roopa Biswas, Parameet Kumar, Harvey B Pollard
Cystic fibrosis (CF) is an autosomal recessive disease due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, F508del-CFTR being the most frequent mutation. The CF lung is characterized by a hyperinflammatory phenotype and is regulated by multiple factors that coordinate its pathophysiology. In CF the expression of CFTR as well as proinflammatory genes are regulated at the level of messenger RNA (mRNA) stability, which subsequently affect translation. These mechanisms are mediated by inflammatory RNA-binding proteins as well as small endogenous noncoding microRNAs, in coordination with cellular signaling pathways...
November 13, 2016: Wiley Interdisciplinary Reviews. RNA
https://www.readbyqxmd.com/read/27860385/paranasal-sinus-size-is-decreased-in-cftr-heterozygotes-with-chronic-rhinosinusitis
#17
Joshua B Calton, Pradeep C Koripella, Amanda L Willis, Christopher H Le, Alexander G Chiu, Eugene H Chang
BACKGROUND: Cystic fibrosis (CF) heterozygotes with a single mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are at significantly higher risk to develop chronic rhinosinusitis (CRS). However the reasons why remain unknown. We tested the hypothesis that CFTR heterozygotes would have smaller sinus volumes than healthy controls. To exclude sinus disease as a confounding factor we also assessed paranasal sinus volume in those with CRS, but without known CFTR mutations...
November 17, 2016: International Forum of Allergy & Rhinology
https://www.readbyqxmd.com/read/27854364/deep-interactome-profiling-of-membrane-proteins-by-co-interacting-protein-identification-technology
#18
Sandra Pankow, Casimir Bamberger, Diego Calzolari, Andreas Bamberger, John R Yates
Affinity purification coupled to mass spectrometry (AP-MS) is the method of choice for analyzing protein-protein interactions, but common protocols frequently recover only the most stable interactions and tend to result in low bait yield for membrane proteins. Here, we present a novel, deep interactome sequencing approach called CoPIT (co-interacting protein identification technology), which allows comprehensive identification and analysis of membrane protein interactomes and their dynamics. CoPIT integrates experimental and computational methods for a coimmunoprecipitation (Co-IP)-based workflow from sample preparation for mass spectrometric analysis to visualization of protein-protein interaction networks...
December 2016: Nature Protocols
https://www.readbyqxmd.com/read/27852956/preparation-for-a-first-in-man-lentivirus-trial-in-patients-with-cystic-fibrosis
#19
Eric W F W Alton, Jeffery M Beekman, A Christopher Boyd, June Brand, Marianne S Carlon, Mary M Connolly, Mario Chan, Sinead Conlon, Heather E Davidson, Jane C Davies, Lee A Davies, Johanna F Dekkers, Ann Doherty, Sabrina Gea-Sorli, Deborah R Gill, Uta Griesenbach, Mamoru Hasegawa, Tracy E Higgins, Takashi Hironaka, Laura Hyndman, Gerry McLachlan, Makoto Inoue, Stephen C Hyde, J Alastair Innes, Toby M Maher, Caroline Moran, Cuixiang Meng, Michael C Paul-Smith, Ian A Pringle, Kamila M Pytel, Andrea Rodriguez-Martinez, Alexander C Schmidt, Barbara J Stevenson, Stephanie G Sumner-Jones, Richard Toshner, Shu Tsugumine, Marguerite W Wasowicz, Jie Zhu
We have recently shown that non-viral gene therapy can stabilise the decline of lung function in patients with cystic fibrosis (CF). However, the effect was modest, and more potent gene transfer agents are still required. Fuson protein (F)/Hemagglutinin/Neuraminidase protein (HN)-pseudotyped lentiviral vectors are more efficient for lung gene transfer than non-viral vectors in preclinical models. In preparation for a first-in-man CF trial using the lentiviral vector, we have undertaken key translational preclinical studies...
November 16, 2016: Thorax
https://www.readbyqxmd.com/read/27837011/how-phosphorylation-and-atpase-activity-regulate-anion-flux-through-the-cystic-fibrosis-transmembrane-conductance-regulator-cftr
#20
Matthias Zwick, Cinzia Esposito, Manuel Hellstern, Anna Seelig
No abstract text is available yet for this article.
November 11, 2016: Journal of Biological Chemistry
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