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Search Results: 1 - 10 of 325348 matches for " Tejvir S. Khurana "
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Expression Profiling Reveals Novel Hypoxic Biomarkers in Peripheral Blood of Adult Mice Exposed to Chronic Hypoxia
Matias Mosqueira, Gabriel Willmann, Ulrike Zeiger, Tejvir S. Khurana
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0037497
Abstract: Hypoxia induces a myriad of changes including an increase in hematocrit due to erythropoietin (EPO) mediated erythropoiesis. While hypoxia is of importance physiologically and clinically, lacunae exist in our knowledge of the systemic and temporal changes in gene expression occurring in blood during the exposure and recovery from hypoxia. To identify these changes expression profiling was conducted on blood obtained from cohorts of C57Bl-10 wild type mice that were maintained at normoxia (NX), exposed for two weeks to normobaric chronic hypoxia (CH) or two weeks of CH followed by two weeks of normoxic recovery (REC). Using stringent bioinformatic cut-offs (0% FDR, 2 fold change cut-off), 230 genes were identified and separated into four distinct temporal categories. Class I) contained 1 transcript up-regulated in both CH and REC; Class II) contained 202 transcripts up-regulated in CH but down-regulated after REC; Class III) contained 9 transcripts down-regulated both in CH and REC; Class IV) contained 18 transcripts down-regulated after CH exposure but up-regulated after REC. Profiling was independently validated and extended by analyzing expression levels of selected genes as novel biomarkers from our profile (e.g. spectrin alpha-1, ubiquitin domain family-1 and pyrroline-5-carboxylate reductase-1) by performing qPCR at 7 different time points during CH and REC. Our identification and characterization of these genes define transcriptome level changes occurring during chronic hypoxia and normoxic recovery as well as novel blood biomarkers that may be useful in monitoring a variety of physiological and pathological conditions associated with hypoxia.
Ventilatory Chemosensory Drive Is Blunted in the mdx Mouse Model of Duchenne Muscular Dystrophy (DMD)
Matias Mosqueira, Santhosh M. Baby, Sukhamay Lahiri, Tejvir S. Khurana
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0069567
Abstract: Duchenne Muscular Dystrophy (DMD) is caused by mutations in the DMD gene resulting in an absence of dystrophin in neurons and muscle. Respiratory failure is the most common cause of mortality and previous studies have largely concentrated on diaphragmatic muscle necrosis and respiratory failure component. Here, we investigated the integrity of respiratory control mechanisms in the mdx mouse model of DMD. Whole body plethysmograph in parallel with phrenic nerve activity recordings revealed a lower respiratory rate and minute ventilation during normoxia and a blunting of the hypoxic ventilatory reflex in response to mild levels of hypoxia together with a poor performance on a hypoxic stress test in mdx mice. Arterial blood gas analysis revealed low PaO2 and pH and high PaCO2 in mdx mice. To investigate chemosensory respiratory drive, we analyzed the carotid body by molecular and functional means. Dystrophin mRNA and protein was expressed in normal mice carotid bodies however, they are absent in mdx mice. Functional analysis revealed abnormalities in Dejours test and the early component of the hypercapnic ventilatory reflex in mdx mice. Together, these results demonstrate a malfunction in the peripheral chemosensory drive that would be predicted to contribute to the respiratory failure in mdx mice. These data suggest that investigating and monitoring peripheral chemosensory drive function may be useful for improving the management of DMD patients with respiratory failure.
Drug Discovery for Duchenne Muscular Dystrophy via Utrophin Promoter Activation Screening
Catherine Moorwood, Olga Lozynska, Neha Suri, Andrew D. Napper, Scott L. Diamond, Tejvir S. Khurana
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026169
Abstract: Background Duchenne muscular dystrophy (DMD) is a devastating muscle wasting disease caused by mutations in dystrophin, a muscle cytoskeletal protein. Utrophin is a homologue of dystrophin that can functionally compensate for its absence when expressed at increased levels in the myofibre, as shown by studies in dystrophin-deficient mice. Utrophin upregulation is therefore a promising therapeutic approach for DMD. The use of a small, drug-like molecule to achieve utrophin upregulation offers obvious advantages in terms of delivery and bioavailability. Furthermore, much of the time and expense involved in the development of a new drug can be eliminated by screening molecules that are already approved for clinical use. Methodology/Principal Findings We developed and validated a cell-based, high-throughput screening assay for utrophin promoter activation, and used it to screen the Prestwick Chemical Library of marketed drugs and natural compounds. Initial screening produced 20 hit molecules, 14 of which exhibited dose-dependent activation of the utrophin promoter and were confirmed as hits. Independent validation demonstrated that one of these compounds, nabumetone, is able to upregulate endogenous utrophin mRNA and protein, in C2C12 muscle cells. Conclusions/Significance We have developed a cell-based, high-throughput screening utrophin promoter assay. Using this assay, we identified and validated a utrophin promoter-activating drug, nabumetone, for which pharmacokinetics and safety in humans are already well described, and which represents a lead compound for utrophin upregulation as a therapy for DMD.
Translational Regulation of Utrophin by miRNAs
Utpal Basu, Olga Lozynska, Catherine Moorwood, Gopal Patel, Steve D. Wilton, Tejvir S. Khurana
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0029376
Abstract: Background Utrophin is the autosomal homolog of dystrophin, the product of the Duchenne Muscular Dystrophy (DMD) locus. Its regulation is of therapeutic interest as its overexpression can compensate for dystrophin's absence in animal models of DMD. The tissue distribution and transcriptional regulation of utrophin have been characterized extensively, and more recently translational control mechanisms that may underlie its complex expression patterns have begun to be identified. Methodology/Principal Findings Using a variety of bioinformatic, molecular and cell biology techniques, we show that the muscle isoform utrophin-A is predominantly suppressed at the translational level in C2C12 myoblasts. The extent of translational inhibition is estimated to be ~99% in C2C12 cells and is mediated by both the 5′- and 3′-UTRs of the utrophin-A mRNA. In this study we identify five miRNAs (let-7c, miR-150, miR-196b, miR-296-5p, miR-133b) that mediate the repression, and confirm repression by the previously identified miR-206. We demonstrate that this translational repression can be overcome by blocking the actions of miRNAs, resulting in an increased level of utrophin protein in C2C12 cells. Conclusions/Significance The present study has identified key inhibitory mechanisms featuring miRNAs that regulate utrophin expression, and demonstrated that these mechanisms can be targeted to increase endogenous utrophin expression in cultured muscle cells. We suggest that miRNA-mediated inhibitory mechanisms could be targeted by methods similar to those described here as a novel strategy to increase utrophin expression as a therapy for DMD.
Chronic Hypoxia Impairs Muscle Function in the Drosophila Model of Duchenne's Muscular Dystrophy (DMD)
Matias Mosqueira,Gabriel Willmann,Hannele Ruohola-Baker,Tejvir S. Khurana
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013450
Abstract: Duchenne's muscular dystrophy (DMD) is a severe progressive myopathy caused by mutations in the DMD gene leading to a deficiency of the dystrophin protein. Due to ongoing muscle necrosis in respiratory muscles late-stage DMD is associated with respiratory insufficiency and chronic hypoxia (CH). To understand the effects of CH on dystrophin-deficient muscle in vivo, we exposed the Drosophila model for DMD (dmDys) to CH during a 16-day ascent to the summit of Mount Denali/McKinley (6194 meters above sea level). Additionally, dmDys and wild type (WT) flies were also exposed to CH in laboratory simulations of high altitude hypoxia. Expression profiling was performed using Affymetrix GeneChips? and validated using qPCR. Hypoxic dmDys differentially expressed 1281 genes, whereas the hypoxic WT flies differentially expressed 56 genes. Interestingly, a number of genes (e.g. heat shock proteins) were discordantly regulated in response to CH between dmDys and WT. We tested the possibility that the disparate molecular responses of dystrophin-deficient tissues to CH could adversely affect muscle by performing functional assays in vivo. Normoxic and CH WT and dmDys flies were challenged with acute hypoxia and time-to-recover determined as well as subjected to climbing tests. Impaired performance was noted for CH-dmDys compared to normoxic dmDys or WT flies (rank order: Normoxic-WT ≈ CH-WT> Normoxic-dmDys> CH-dmDys). These data suggest that dystrophin-deficiency is associated with a disparate, pathological hypoxic stress response(s) and is more sensitive to hypoxia induced muscle dysfunction in vivo. We hypothesize that targeting/correcting the disparate molecular response(s) to hypoxia may offer a novel therapeutic strategy in DMD.
Akt Deficiency Attenuates Muscle Size and Function but Not the Response to ActRIIB Inhibition
Marcus D. Goncalves,Emidio E. Pistilli,Anthony Balduzzi,Morris J. Birnbaum,Jennifer Lachey,Tejvir S. Khurana,Rexford S. Ahima
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0012707
Abstract: Akt is a critical mediator of developmental skeletal muscle growth. Treatment with a soluble ActRIIB fusion protein (ActRIIB-mFc) increases skeletal muscle mass and strength by inhibiting myostatin and related peptides. Recent in vitro studies have suggested that Akt signaling is necessary for the ability of ActRIIB inhibition to induce muscle hypertrophy. Thus, we hypothesized that mice deficient in either Akt1 or Akt2 would not respond to in vivo inhibition of ActRIIB with ActRIIB-mFc treatment.
Drug-Induced Hemolytic Anemia: A Fatal Complication Further Under-Recognized in Sickle Cell Disease  [PDF]
Monica Khurana, Shekhar S. Raj
Open Journal of Blood Diseases (OJBD) , 2017, DOI: 10.4236/ojbd.2017.73008
Drug-induced immune hemolytic anemia (DIIHA) is commonly attributed to cephalosporins. Ceftriaxone is the most frequently administered cephalosporin in patients with sickle cell disease. We present a pediatric patient with severe DIIHA (hemoglobin < 2 g/dl) who survived. Since DIIHA often goes undiagnosed until late in the course, vigilance of DIIHA minimizes unnecessary diagnostic tests and therapies. DIIHA likely remains under-recognized in all patient subpopulations due to its rarity and overlapping presentations with other conditions. Distinction between exacerbation of chronic hemolysis and new onset of acute hemolysis poses a unique challenge in patients with sickle cell disease. A thorough analysis is warranted to better identify factors within the pediatric sickle cell population that may increase the predisposition for DIIHA, particularly due to ceftriaxone.
Modulus of Lattice-valued Measures
S. S. Khurana
Abstract: Let X be a completely regular Hausdorff space, E a Banach lattice, and m an E-valued countably additive, regular Borel measure on X. Some results about the countable additivity and regularity of the modulus |m | are proved. Also in special cases, it is proved that L1(m)= L1(|m|).
A note on mutiplication operators on K the-Bochner spaces
S. S. Khurana
Abstract: Let (Ω, A, μ) is a finite measure space, E an order continuous Banach function space over μ, X a Banach space and E(X) the K the-Bochner space. A new simple proof is given of the result that a continuous linear operator T E(X) E(X) is a multiplication operator (by a function in L¥) iff T(g f, x* > x) =g T(f), x* > x for every g L¥, f E(X), x X, x* X*.
A note on mutiplication operators on K the-Bochner spaces
S. S. Khurana
Abstract: Let (Ω, A, μ) is a finite measure space, E an order continuous Banach function space over μ, X a Banach space and E(X) the K the-Bochner space. A new simple proof is given of the result that a continuous linear operator T: E(X) E(X) is a multiplication operator (by a function in L¥) iff T(g < f, x* > x) =g < T(f), x* > x for everyg L¥, f E(X), x X, x* X*.
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