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Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Associated with Carbonic Anhydrase Inhibitors: Epidemiology, Genetics, and Insights into Mechanisms.
Trubiano JA, Ostrov DA, Phillips EJ
(2019) J Allergy Clin Immunol Pract 7: 2854-2856
MeSH Terms: Carbonic Anhydrase Inhibitors, Carbonic Anhydrases, Humans, Stevens-Johnson Syndrome
Added March 30, 2020
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4 MeSH Terms
Perfusion controls muscle glucose uptake by altering the rate of glucose dispersion in vivo.
McClatchey PM, Williams IM, Xu Z, Mignemi NA, Hughey CC, McGuinness OP, Beckman JA, Wasserman DH
(2019) Am J Physiol Endocrinol Metab 317: E1022-E1036
MeSH Terms: 4-Chloro-7-nitrobenzofurazan, Animals, Blood Flow Velocity, Carbon Radioisotopes, Deoxyglucose, Dextrans, Glucose, Hypoglycemic Agents, Insulin, Intravital Microscopy, Mice, Microcirculation, Microspheres, Muscle, Skeletal, Ultrasonography
Show Abstract · Added March 30, 2020
These studies test, using intravital microscopy (IVM), the hypotheses that perfusion effects on insulin-stimulated muscle glucose uptake (MGU) are ) capillary recruitment independent and ) mediated through the dispersion of glucose rather than insulin. For , capillary perfusion was visualized before and after intravenous insulin. No capillary recruitment was observed. For , mice were treated with vasoactive compounds (sodium nitroprusside, hyaluronidase, and lipopolysaccharide), and dispersion of fluorophores approximating insulin size (10-kDa dextran) and glucose (2-NBDG) was measured using IVM. Subsequently, insulin and 2[C]deoxyglucose were injected and muscle phospho-2[C]deoxyglucose (2[C]DG) accumulation was used as an index of MGU. Flow velocity and 2-NBDG dispersion, but not perfused surface area or 10-kDa dextran dispersion, predicted phospho-2[C]DG accumulation. For , microspheres of the same size and number as are used for contrast-enhanced ultrasound (CEU) studies of capillary recruitment were visualized using IVM. Due to their low concentration, microspheres were present in only a small fraction of blood-perfused capillaries. Microsphere-perfused blood volume correlated to flow velocity. These findings suggest that ) flow velocity rather than capillary recruitment controls microvascular contributions to MGU, ) glucose dispersion is more predictive of MGU than dispersion of insulin-sized molecules, and ) CEU measures regional flow velocity rather than capillary recruitment.
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15 MeSH Terms
Glutamine-451 Confers Sensitivity to Oxidative Inhibition and Heme-Thiolate Sulfenylation of Cytochrome P450 4B1.
Albertolle ME, Song HD, Wilkey CJ, Segrest JP, Guengerich FP
(2019) Chem Res Toxicol 32: 484-492
MeSH Terms: Animals, Aryl Hydrocarbon Hydroxylases, Glutamine, Heme, Molecular Dynamics Simulation, Mutagenesis, Site-Directed, Oxidation-Reduction, Rabbits, Sulfenic Acids, Sulfhydryl Compounds
Show Abstract · Added March 26, 2019
Human cytochrome P450 (P450) family 4 enzymes are involved in the metabolism of fatty acids and the bioactivation of carcinogenic arylamines and toxic natural products, e.g., 4-ipomeanol. These and other drug-metabolizing P450s are redox sensitive, showing a loss of activity resulting from preincubation with HO and recovery with mild reducing agents [Albertolle, M. W., et al. (2017) J. Biol. Chem. 292, 11230-11242]. The inhibition is due to sulfenylation of the heme-thiolate ligand, as determined by chemopreoteomics and spectroscopy. This phenomenon may have implications for chemical toxicity and observed disease-drug interactions, in which the decreased metabolism of P450 substrates occurs in patients with inflammatory diseases (e.g., influenza and autoimmunity). Human P450 1A2 was determined to be redox insensitive. To determine the mechanism underlying the differential redox sensitivity, molecular dynamics (MD) simulations were employed using the crystal structure of rabbit P450 4B1 (Protein Data Bank entry 5T6Q ). In simulating either the thiolate (Cys-S) or the sulfenic acid (Cys-SOH) at the heme ligation site, MD revealed Gln-451 in either an "open" or "closed" conformation, respectively, between the cytosol and heme-thiolate cysteine. Mutation to either an isosteric leucine (Q451L) or glutamate (Q451E) abrogated the redox sensitivity, suggesting that this "open" conformation allows for reduction of the sulfenic acid and religation of the thiolate to the heme iron. In summary, MD simulations suggest that Gln-451 in P450 4B1 adopts conformations that may stabilize and protect the heme-thiolate sulfenic acid; mutating this residue destabilizes the interaction, producing a redox insensitive enzyme.
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10 MeSH Terms
Short-term Optic Disc Cupping Reversal in a Patient With Mild Juvenile Open-angle Glaucoma Due to Early Idiopathic Intracranial Hypertension.
Umfress AC, Mawn LA, Joos KM
(2019) J Glaucoma 28: e53-e57
MeSH Terms: Acetazolamide, Carbonic Anhydrase Inhibitors, Diet, Reducing, Female, Glaucoma, Open-Angle, Humans, Intraocular Pressure, Optic Disk, Optic Nerve Diseases, Pseudotumor Cerebri, Spinal Puncture, Tomography, Optical Coherence, Tonometry, Ocular, Vision Disorders, Visual Acuity, Visual Field Tests, Visual Fields, Young Adult
Show Abstract · Added April 3, 2019
PURPOSE - The purpose of this study was to report a case of optic disc cupping reversal in an adult without significant intraocular pressure-lowering treatment.
PATIENT - A 20-year-old female with a history of mild juvenile open-angle glaucoma who developed subjective blurred vision and a decrease in cupping of her optic discs.
RESULTS - Dilated examination demonstrated decreased cup-to-disc ratios in both eyes with a slight blurring of the disc margin in the right eye. The appearance of both optic discs returned to baseline after weight loss therapy.
CONCLUSIONS - An unexplained reduction of optic nerve cup-to-disc ratio should prompt a workup for other etiologies, such as increased intracranial pressure. Baseline photographs not subjected to computerized scan obsolescence are extremely useful in monitoring the long-term appearance of asymmetric optic discs as an adjunct to the clinical examination.
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18 MeSH Terms
ARNT as a Novel Antifibrotic Target in CKD.
Haase VH
(2019) Am J Kidney Dis 73: 281-284
MeSH Terms: Aryl Hydrocarbon Receptor Nuclear Translocator, Humans, Hypoxia, Kidney Failure, Chronic, Transcription Factors
Added October 28, 2018
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5 MeSH Terms
Graphene oxide polarizes iNKT cells for production of TGFβ and attenuates inflammation in an iNKT cell-mediated sepsis model.
Lee SW, Park HJ, Van Kaer L, Hong S, Hong S
(2018) Sci Rep 8: 10081
MeSH Terms: Animals, Antigens, CD1d, Cell Polarity, Dendritic Cells, Disease Models, Animal, Galactosylceramides, Graphite, Humans, Inflammation, Intraepithelial Lymphocytes, Lymphocyte Activation, Mice, Nanotubes, Carbon, Natural Killer T-Cells, Sepsis, Toll-Like Receptor 4, Transforming Growth Factor beta
Show Abstract · Added March 26, 2019
Graphene oxide (GO) modulates the functions of antigen-presenting cells including dendritic cells (DCs). Although carbon nanotubes affect expression of the MHC class I-like CD1d molecule, whether GO can influence immune responses of CD1d-dependent invariant natural killer T (iNKT) cells remains unclear. Here, we investigated the impact of GO on inflammatory responses mediated by α-galactosylceramide (α-GalCer), an iNKT cell agonist. We found that in vivo GO treatment substantially inhibited the capacity of α-GalCer to induce the iNKT cell-mediated trans-activation of and cytokine production by innate and innate-like cells, including DCs, macrophages, NK cells, and γδ T cells. Such effects of GO on α-GalCer-induced inflammatory responses closely correlated with iNKT cell polarization towards TGFβ production, which also explains the capacity of GO to expand regulatory T cells. Interestingly, the absence of TLR4, a receptor for GO, failed to downregulate, and instead partially enhanced the anti-inflammatory activity of GO against α-GalCer-elicited responses, implying negative effects of TLR4 signaling on the anti-inflammatory properties of GO. By employing an α-GalCer-induced sepsis model, we further demonstrated that GO treatment significantly protected mice from α-GalCer-induced lethality. Taken together, we provide strong evidence that GO holds promise as an adjuvant to modulate iNKT cell responses for immunotherapy.
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17 MeSH Terms
Glycine -methyltransferase deletion in mice diverts carbon flux from gluconeogenesis to pathways that utilize excess methionine cycle intermediates.
Hughey CC, Trefts E, Bracy DP, James FD, Donahue EP, Wasserman DH
(2018) J Biol Chem 293: 11944-11954
MeSH Terms: Animals, Carbon, Citric Acid Cycle, Energy Metabolism, Fatty Liver, Gene Deletion, Gluconeogenesis, Glucose, Glycine N-Methyltransferase, Liver, Male, Metabolic Flux Analysis, Methionine, Mice, Mice, Knockout, S-Adenosylmethionine
Show Abstract · Added March 26, 2019
Glycine -methyltransferase (GNMT) is the most abundant liver methyltransferase regulating the availability of the biological methyl donor, -adenosylmethionine (SAM). Moreover, GNMT has been identified to be down-regulated in hepatocellular carcinoma (HCC). Despite its role in regulating SAM levels and association of its down-regulation with liver tumorigenesis, the impact of reduced GNMT on metabolic reprogramming before the manifestation of HCC has not been investigated in detail. Herein, we used H/C metabolic flux analysis in conscious, unrestrained mice to test the hypothesis that the absence of GNMT causes metabolic reprogramming. GNMT-null (KO) mice displayed a reduction in blood glucose that was associated with a decline in both hepatic glycogenolysis and gluconeogenesis. The reduced gluconeogenesis was due to a decrease in liver gluconeogenic precursors, citric acid cycle fluxes, and anaplerosis and cataplerosis. A concurrent elevation in both hepatic SAM and metabolites of SAM utilization pathways was observed in the KO mice. Specifically, the increase in metabolites of SAM utilization pathways indicated that hepatic polyamine synthesis and catabolism, transsulfuration, and lipogenesis pathways were increased in the KO mice. Of note, these pathways utilize substrates that could otherwise be used for gluconeogenesis. Also, this metabolic reprogramming occurs before the well-documented appearance of HCC in GNMT-null mice. Together, these results indicate that GNMT deletion promotes a metabolic shift whereby nutrients are channeled away from glucose formation toward pathways that utilize the elevated SAM.
© 2018 Hughey et al.
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MeSH Terms
Isotopically nonstationary metabolic flux analysis (INST-MFA): putting theory into practice.
Cheah YE, Young JD
(2018) Curr Opin Biotechnol 54: 80-87
MeSH Terms: Autotrophic Processes, Carbon Isotopes, Isotope Labeling, Metabolic Flux Analysis, Models, Biological, Software
Show Abstract · Added March 14, 2018
Typically, C flux analysis relies on assumptions of both metabolic and isotopic steady state. If metabolism is steady but isotope labeling is not allowed to fully equilibrate, isotopically nonstationary metabolic flux analysis (INST-MFA) can be used to estimate fluxes. This requires solution of differential equations that describe the time-dependent labeling of network metabolites, while iteratively adjusting the flux and pool size parameters to match the transient labeling measurements. INST-MFA holds a number of unique advantages over approaches that rely solely upon steady-state isotope enrichments. First, INST-MFA can be applied to estimate fluxes in autotrophic systems, which consume only single-carbon substrates. Second, INST-MFA is ideally suited to systems that label slowly due to the presence of large intermediate pools or pathway bottlenecks. Finally, INST-MFA provides increased measurement sensitivity to estimate reversible exchange fluxes and metabolite pool sizes, which represents a potential framework for integrating metabolomic analysis with C flux analysis. This review highlights the unique capabilities of INST-MFA, describes newly available software tools that automate INST-MFA calculations, presents several practical examples of recent INST-MFA applications, and discusses the technical challenges that lie ahead.
Copyright © 2018 Elsevier Ltd. All rights reserved.
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6 MeSH Terms
A Metabolic Basis for Endothelial-to-Mesenchymal Transition.
Xiong J, Kawagishi H, Yan Y, Liu J, Wells QS, Edmunds LR, Fergusson MM, Yu ZX, Rovira II, Brittain EL, Wolfgang MJ, Jurczak MJ, Fessel JP, Finkel T
(2018) Mol Cell 69: 689-698.e7
MeSH Terms: 3-Hydroxyacyl CoA Dehydrogenases, Acetyl Coenzyme A, Acetyl-CoA C-Acyltransferase, Animals, Carbon-Carbon Double Bond Isomerases, Carnitine O-Palmitoyltransferase, Cells, Cultured, Endothelium, Vascular, Enoyl-CoA Hydratase, Epithelial-Mesenchymal Transition, Fatty Acids, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Oxidation-Reduction, Racemases and Epimerases, Signal Transduction, Transforming Growth Factor beta
Show Abstract · Added March 14, 2018
Endothelial-to-mesenchymal transition (EndoMT) is a cellular process often initiated by the transforming growth factor β (TGF-β) family of ligands. Although required for normal heart valve development, deregulated EndoMT is linked to a wide range of pathological conditions. Here, we demonstrate that endothelial fatty acid oxidation (FAO) is a critical in vitro and in vivo regulator of EndoMT. We further show that this FAO-dependent metabolic regulation of EndoMT occurs through alterations in intracellular acetyl-CoA levels. Disruption of FAO via conditional deletion of endothelial carnitine palmitoyltransferase II (Cpt2) augments the magnitude of embryonic EndoMT, resulting in thickening of cardiac valves. Consistent with the known pathological effects of EndoMT, adult Cpt2 mice demonstrate increased permeability in multiple vascular beds. Taken together, these results demonstrate that endothelial FAO is required to maintain endothelial cell fate and that therapeutic manipulation of endothelial metabolism could provide the basis for treating a growing number of EndoMT-linked pathological conditions.
Copyright © 2018 Elsevier Inc. All rights reserved.
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20 MeSH Terms
C Flux Analysis Reveals that Rebalancing Medium Amino Acid Composition can Reduce Ammonia Production while Preserving Central Carbon Metabolism of CHO Cell Cultures.
McAtee Pereira AG, Walther JL, Hollenbach M, Young JD
(2018) Biotechnol J 13: e1700518
MeSH Terms: Amino Acids, Ammonia, Animals, Antibodies, Monoclonal, CHO Cells, Carbon, Cricetulus, Culture Media, Glycosylation, Metabolic Flux Analysis, Recombinant Proteins
Show Abstract · Added March 14, 2018
C metabolic flux analysis (MFA) provides a rigorous approach to quantify intracellular metabolism of industrial cell lines. In this study, C MFA was used to characterize the metabolic response of Chinese hamster ovary (CHO) cells to a novel medium variant designed to reduce ammonia production. Ammonia inhibits growth and viability of CHO cell cultures, alters glycosylation of recombinant proteins, and enhances product degradation. Ammonia production was reduced by manipulating the amino acid composition of the culture medium; specifically, glutamine, glutamate, asparagine, aspartate, and serine levels were adjusted. Parallel C flux analysis experiments determined that, while ammonia production decreased by roughly 40%, CHO cell metabolic phenotype, growth, viability, and monoclonal antibody (mAb) titer were not significantly altered by the changes in media composition. This study illustrates how C flux analysis can be applied to assess the metabolic effects of media manipulations on mammalian cell cultures. The analysis revealed that adjusting the amino acid composition of CHO cell culture media can effectively reduce ammonia production while preserving fluxes throughout central carbon metabolism.
© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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11 MeSH Terms