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The Dihydroxy Metabolite of the Teratogen Thalidomide Causes Oxidative DNA Damage.
Wani TH, Chakrabarty A, Shibata N, Yamazaki H, Guengerich FP, Chowdhury G
(2017) Chem Res Toxicol 30: 1622-1628
MeSH Terms: Catalase, DNA Cleavage, DNA Damage, Free Radical Scavengers, HEK293 Cells, Hep G2 Cells, Human Umbilical Vein Endothelial Cells, Humans, Microscopy, Fluorescence, Plasmids, Poly(ADP-ribose) Polymerases, Reactive Oxygen Species, Teratogens, Thalidomide
Show Abstract · Added March 14, 2018
Thalidomide [α-(N-phthalimido)glutarimide] (1) is a sedative and antiemetic drug originally introduced into the clinic in the 1950s for the treatment of morning sickness. Although marketed as entirely safe, more than 10 000 babies were born with severe birth defects. Thalidomide was banned and subsequently approved for the treatment of multiple myeloma and complications associated with leprosy. Although known for more than 5 decades, the mechanism of teratogenicity remains to be conclusively understood. Various theories have been proposed in the literature including DNA damage and ROS and inhibition of angiogenesis and cereblon. All of the theories have their merits and limitations. Although the recently proposed cereblon theory has gained wide acceptance, it fails to explain the metabolism and low-dose requirement reported by a number of groups. Recently, we have provided convincing structural evidence in support of the presence of arene oxide and the quinone-reactive intermediates. However, the ability of these reactive intermediates to impart toxicity/teratogenicity needs investigation. Herein we report that the oxidative metabolite of thalidomide, dihydroxythalidomide, is responsible for generating ROS and causing DNA damage. We show, using cell lines, the formation of comet (DNA damage) and ROS. Using DNA-cleavage assays, we also show that catalase, radical scavengers, and desferal are capable of inhibiting DNA damage. A mechanism of teratogenicity is proposed that not only explains the DNA-damaging property but also the metabolism, low concentration, and species-specificity requirements of thalidomide.
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14 MeSH Terms
Bridging Translation by Improving Preclinical Study Design in AKI.
de Caestecker M, Humphreys BD, Liu KD, Fissell WH, Cerda J, Nolin TD, Askenazi D, Mour G, Harrell FE, Pullen N, Okusa MD, Faubel S, ASN AKI Advisory Group
(2015) J Am Soc Nephrol 26: 2905-16
MeSH Terms: Acetylcysteine, Acute Kidney Injury, Animals, Contrast Media, Disease Models, Animal, Erythropoietin, Free Radical Scavengers, Humans, Research Design, Sodium Bicarbonate, Translational Medical Research
Show Abstract · Added February 22, 2016
Despite extensive research, no therapeutic interventions have been shown to prevent AKI, accelerate recovery of AKI, or reduce progression of AKI to CKD in patients. This failure in translation has led investigators to speculate that the animal models being used do not predict therapeutic responses in humans. Although this issue continues to be debated, an important concern that has not been addressed is whether improvements in preclinical study design can be identified that might also increase the likelihood of translating basic AKI research into clinical practice using the current models. In this review, we have taken an evidence-based approach to identify common weaknesses in study design and reporting in preclinical AKI research that may contribute to the poor translatability of the findings. We focused on use of N-acetylcysteine or sodium bicarbonate for the prevention of contrast-induced AKI and use of erythropoietin for the prevention of AKI, two therapeutic approaches that have been extensively studied in clinical trials. On the basis of our findings, we identified five areas for improvement in preclinical study design and reporting. These suggested and preliminary guidelines may help improve the quality of preclinical research for AKI drug development.
Copyright © 2015 by the American Society of Nephrology.
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11 MeSH Terms
5'-O-Alkylpyridoxamines: Lipophilic Analogues of Pyridoxamine Are Potent Scavengers of 1,2-Dicarbonyls.
Amarnath V, Amarnath K, Avance J, Stec DF, Voziyan P
(2015) Chem Res Toxicol 28: 1469-75
MeSH Terms: Biocatalysis, Electron Spin Resonance Spectroscopy, Free Radical Scavengers, Free Radicals, Glucose, Horseradish Peroxidase, Hydrophobic and Hydrophilic Interactions, Membrane Proteins, Molecular Conformation, Muramidase, Pyridoxamine, Pyruvaldehyde, Spectrophotometry, Ultraviolet, Superoxide Dismutase
Show Abstract · Added June 9, 2017
Pyridoxamine (PM) is a prospective drug for the treatment of diabetic complications. In order to make zwitterionic PM more lipophilic and improve its tissue distribution, PM derivatives containing medium length alkyl groups on the hydroxymethyl side chain were prepared. The synthesis of these alkylpyridoxamines (alkyl-PMs) starting from pyridoxine offers high yields and is amenable to bulk preparations. Interestingly, alkyl-PMs were found to react with methylglyoxal (MGO), a major toxic product of glucose metabolism and autoxidation, several orders of magnitude faster than PM. This suggests the formation of nonionic pyrido-1,3-oxazine as the key step in the reaction of PM with MGO. Since the primary target of MGO in proteins is the guanidine side chain of arginine, alkyl-PMs were shown to be more effective than PM in reducing the modification of N-α-benzoylarginine by MGO. Alkyl-PMs in the presence of MGO also protected the enzymatic activity of lysozyme that contains several arginine residues next to its active site. Alkyl-PMs can be expected to trap MGO and other toxic 1,2-carbonyl compounds more effectively than PM, especially in lipophilic tissue environments, thus protecting macromolecules from functional damage. This suggests potential therapeutic uses for alkyl-PMs in diabetes and other diseases characterized by the elevated levels of toxic dicarbonyl compounds.
1 Communities
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14 MeSH Terms
Even free radicals should follow some rules: a guide to free radical research terminology and methodology.
Forman HJ, Augusto O, Brigelius-Flohe R, Dennery PA, Kalyanaraman B, Ischiropoulos H, Mann GE, Radi R, Roberts LJ, Vina J, Davies KJ
(2015) Free Radic Biol Med 78: 233-5
MeSH Terms: Animals, Antioxidants, Fluorescent Dyes, Free Radical Scavengers, Free Radicals, Humans, Lipid Peroxidation, Reactive Nitrogen Species, Reactive Oxygen Species, Terminology as Topic, Thiobarbituric Acid Reactive Substances
Show Abstract · Added February 15, 2016
Free radicals and oxidants are now implicated in physiological responses and in several diseases. Given the wide range of expertise of free radical researchers, application of the greater understanding of chemistry has not been uniformly applied to biological studies. We suggest that some widely used methodologies and terminologies hamper progress and need to be addressed. We make the case for abandonment and judicious use of several methods and terms and suggest practical and viable alternatives. These changes are suggested in four areas: use of fluorescent dyes to identify and quantify reactive species, methods for measurement of lipid peroxidation in complex biological systems, claims of antioxidants as radical scavengers, and use of the terms for reactive species.
Copyright © 2014 Elsevier Inc. All rights reserved.
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11 MeSH Terms
Reduction of reactive oxygen species prevents hypoxia-induced CREB depletion in pulmonary artery smooth muscle cells.
Klemm DJ, Majka SM, Crossno JT, Psilas JC, Reusch JE, Garat CV
(2011) J Cardiovasc Pharmacol 58: 181-91
MeSH Terms: Animals, Blotting, Western, Cell Culture Techniques, Cell Hypoxia, Cell Movement, Cell Proliferation, Cells, Cultured, Cyclic AMP Response Element-Binding Protein, Free Radical Scavengers, Hydrogen Peroxide, Hypertension, Pulmonary, Hypoxia, Male, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Pulmonary Artery, RNA, Small Interfering, Rats, Rats, Inbred WKY
Show Abstract · Added August 4, 2015
Hypoxia-induced pulmonary arterial hypertension (PAH) is a deadly disease characterized by progressive remodeling and persistent vasoconstriction of the pulmonary arterial system. Remodeling of the pulmonary artery (PA) involves smooth muscle cell (SMC) proliferation, hypertrophy, migration, and elevated extracellular matrix (ECM) production elicited by mitogens and oxidants produced in response to hypoxic insult. We previously reported that the transcription factor cAMP response element binding protein (CREB) is depleted in medial PA SMCs in remodeled, hypertensive vessels in rats or calves exposed to chronic hypoxia. In culture, CREB loss can be induced in PA SMCs by exogenous oxidants or platelet-derived growth factor. Forced depletion of CREB with small interfering RNA (siRNA) in PA SMCs is sufficient to induce their proliferation, hypertrophy, migration, dedifferentiation, and ECM production. This suggests that oxidant and/or mitogen-induced loss of CREB in medial SMCs is, in part, responsible for PA thickening. Here, we tested whether oxidant scavengers could prevent the loss of CREB in PA SMCs and inhibit SMC proliferation, migration, and ECM production using in vitro and in vivo models. Exposure of PA SMCs to hypoxia induced hydrogen peroxide (H2O2) production and loss of CREB. Treatment of SMCs with exogenous H2O2 or a second oxidant, Sin-1, elicited CREB depletion under normoxic conditions. Exogenous H2O2 also induced SMC proliferation, migration, and increased elastin levels as did forced depletion of CREB. In vivo, hypoxia-induced thickening of the PA wall was suppressed by the superoxide dismutase mimetic, Tempol, which also prevented the loss of CREB in medial SMCs. Tempol also reduced hypoxia-induced SMC proliferation and elastin deposition in the PA. The data indicate that CREB levels in the arterial wall are regulated in part by oxidants produced in response to hypoxia and that CREB plays a crucial role in regulating SMC phenotype and PA remodeling.
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19 MeSH Terms
Preparation and investigation of vitamin B6-derived aminopyridinol antioxidants.
Serwa R, Nam TG, Valgimigli L, Culbertson S, Rector CL, Jeong BS, Pratt DA, Porter NA
(2010) Chemistry 16: 14106-14
MeSH Terms: Amino Alcohols, Aminopyridines, Antioxidants, Free Radical Scavengers, Humans, Lipid Peroxidation, Molecular Structure, Oxidation-Reduction, Vitamin B 6, alpha-Tocopherol
Show Abstract · Added May 29, 2014
3-Pyridinols bearing amine substitution para to the hydroxylic moiety have previously been shown to inhibit lipid peroxidation more effectively than typical phenolic antioxidants, for example, α-tocopherol. We report here high-yielding, large-scale syntheses of mono- and bicyclic aminopyridinols from pyridoxine hydrochloride (i.e., vitamin B(6)). This approach provides straightforward, scaleable access to novel, potent, molecular scaffolds whose antioxidant properties have been investigated in homogeneous solutions and in liposomal vesicles. These molecular aggregates mimic cell membranes that are the targets of oxidative damage in vivo.
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1 Members
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10 MeSH Terms
Action of 6-amino-3-pyridinols as novel antioxidants against free radicals and oxidative stress in solution, plasma, and cultured cells.
Omata Y, Saito Y, Yoshida Y, Jeong BS, Serwa R, Nam TG, Porter NA, Niki E
(2010) Free Radic Biol Med 48: 1358-65
MeSH Terms: 1-Methyl-4-phenylpyridinium, Animals, Antioxidants, Cytoprotection, Fatty Acids, Unsaturated, Free Radical Scavengers, Glutamic Acid, Lipid Peroxidation, Oxidation-Reduction, Oxidative Stress, Oxidopamine, PC12 Cells, Pyridones, Rats, alpha-Tocopherol
Show Abstract · Added May 29, 2014
Free radical-mediated lipid peroxidation has been implicated in the pathogenesis of various diseases. Lipid peroxidation products are cytotoxic and they modify proteins and DNA bases, leading eventually to degenerative disorders. Various synthetic antioxidants have been developed and assessed for their capacity to inhibit lipid peroxidation and oxidative stress induced by free radicals. In this study, the capacity of novel 6-amino-2,4,5-trimethyl-3-pyridinols for scavenging peroxyl radicals, inhibiting plasma lipid peroxidation in vitro, and preventing cytotoxicity induced by glutamate, 6-hydroxydopamine, 1-methyl-4-phenylpyridium (MPP(+) ), and hydroperoxyoctadecadienoic acid was assessed. It was found that they exerted higher reactivity toward peroxyl radicals and more potent activity for inhibiting the above oxidative stress than alpha-tocopherol, the most potent natural antioxidant, except against the cytotoxicity induced by MPP(+). These results suggest that the novel 6-amino-3-pyridinols may be potent antioxidants against oxidative stress.
Copyright 2010 Elsevier Inc. All rights reserved.
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15 MeSH Terms
Selective gamma-ketoaldehyde scavengers protect Nav1.5 from oxidant-induced inactivation.
Nakajima T, Davies SS, Matafonova E, Potet F, Amarnath V, Tallman KA, Serwa RA, Porter NA, Balser JR, Kupershmidt S, Roberts LJ
(2010) J Mol Cell Cardiol 48: 352-9
MeSH Terms: Action Potentials, Aldehydes, Amines, Cell Line, Free Radical Scavengers, Humans, Ion Channel Gating, Kinetics, NAV1.5 Voltage-Gated Sodium Channel, Oxidants, Oxidative Stress, Sodium Channels, tert-Butylhydroperoxide
Show Abstract · Added June 1, 2013
The cardiac sodium channel (SCN5A, Na(V)1.5) is a key determinant of electrical impulse conduction in cardiac tissue. Acute myocardial infarction leads to diminished sodium channel availability, both because of decreased channel expression and because of greater inactivation of channels already present. Myocardial infarction leads to significant increases in reactive oxygen species and their downstream effectors including lipoxidation products. The effects of reactive oxygen species on Na(V)1.5 function in whole hearts can be modeled in cultured myocytes, where oxidants shift the availability curve of I(Na) to hyperpolarized potentials, decreasing cardiac sodium current at the normal activation threshold. We recently examined potential mediators of the oxidant-induced inactivation and found that one specific lipoxidation product, the isoketals, recapitulated the effects of oxidant on sodium currents. Isoketals are highly reactive gamma-ketoaldehydes formed by the peroxidation of arachidonic acid that covalently modify the lysine residues of proteins. We now confirm that exposure to oxidants induces lipoxidative modification of Na(V)1.5 and that the selective isoketal scavengers block voltage-dependent changes in sodium current by the oxidant tert-butylhydroperoxide, both in cells heterologously expressing Na(V)1.5 and in a mouse cardiac myocyte cell line (HL-1). Thus, inhibition of this lipoxidative modification pathway is sufficient to protect the sodium channel from oxidant induced inactivation and suggests the potential use of isoketal scavengers as novel therapeutics to prevent arrhythmogenesis during myocardial infarction.
Copyright 2009 Elsevier Ltd. All rights reserved.
1 Communities
5 Members
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13 MeSH Terms
The delivery of superoxide dismutase encapsulated in polyketal microparticles to rat myocardium and protection from myocardial ischemia-reperfusion injury.
Seshadri G, Sy JC, Brown M, Dikalov S, Yang SC, Murthy N, Davis ME
(2010) Biomaterials 31: 1372-9
MeSH Terms: Animals, Drug Carriers, Drug Compounding, Free Radical Scavengers, Microspheres, Myocardial Reperfusion Injury, Rats, Rats, Sprague-Dawley, Superoxide Dismutase, Treatment Outcome
Show Abstract · Added February 17, 2016
Oxidative stress is increased in the myocardium following infarction and plays a significant role in death of cardiac myocytes, leading to cardiac dysfunction. Levels of the endogenous antioxidant Cu/Zn-superoxide dismutase (SOD1) decrease following myocardial infarction. While SOD1 gene therapy studies show promise, trials with SOD1 protein have had little success due to poor pharmacokinetics and thus new delivery vehicles are needed. In this work, polyketal particles, a recently developed delivery vehicle, were used to make SOD1-encapsulated-microparticles (PKSOD). Our studies with cultured macrophages demonstrated that PKSOD treatment scavenges both intracellular and extracellular superoxide, suggesting efficient delivery of SOD1 protein to the inside of cells. In a rat model of ischemia/reperfusion (IR) injury, injection of PKSOD, and not free SOD1 or empty particles was able to scavenge IR-induced excess superoxide 3 days following infarction. In addition, only PKSOD treatment significantly reduced myocyte apoptosis. Further, PKSOD treatment was able to improve cardiac function as measured by acute changes in fractional shortening from baseline echocardiography, suggesting that sustained delivery of SOD1 is critical during the early phase of cardiac repair. These data demonstrate that delivery of SOD1 with polyketals is superior to free SOD1 protein therapy and may have potential clinical implications.
(c) 2009 Elsevier Ltd. All rights reserved.
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10 MeSH Terms
Melanocyte-like cells in the heart and pulmonary veins contribute to atrial arrhythmia triggers.
Levin MD, Lu MM, Petrenko NB, Hawkins BJ, Gupta TH, Lang D, Buckley PT, Jochems J, Liu F, Spurney CF, Yuan LJ, Jacobson JT, Brown CB, Huang L, Beermann F, Margulies KB, Madesh M, Eberwine JH, Epstein JA, Patel VV
(2009) J Clin Invest 119: 3420-36
MeSH Terms: Animals, Arrhythmias, Cardiac, Electrophysiological Phenomena, Free Radical Scavengers, Gene Expression Profiling, Gene Expression Regulation, Enzymologic, Humans, Intramolecular Oxidoreductases, Melanocytes, Mice, Mice, Knockout, Myocardium, Pulmonary Veins, Receptor Protein-Tyrosine Kinases, Receptors, Adrenergic, Receptors, Muscarinic
Show Abstract · Added February 19, 2015
Atrial fibrillation is the most common clinical cardiac arrhythmia. It is often initiated by ectopic beats arising from the pulmonary veins and atrium, but the source and mechanism of these beats remains unclear. The melanin synthesis enzyme dopachrome tautomerase (DCT) is involved in intracellular calcium and reactive species regulation in melanocytes. Given that dysregulation of intracellular calcium and reactive species has been described in patients with atrial fibrillation, we investigated the role of DCT in this process. Here, we characterize a unique DCT-expressing cell population within murine and human hearts that populated the pulmonary veins, atria, and atrioventricular canal. Expression profiling demonstrated that this population expressed adrenergic and muscarinic receptors and displayed transcriptional profiles distinct from dermal melanocytes. Adult mice lacking DCT displayed normal cardiac development but an increased susceptibility to atrial arrhythmias. Cultured primary cardiac melanocyte-like cells were excitable, and those lacking DCT displayed prolonged repolarization with early afterdepolarizations. Furthermore, mice with mutations in the tyrosine kinase receptor Kit lacked cardiac melanocyte-like cells and did not develop atrial arrhythmias in the absence of DCT. These data suggest that dysfunction of melanocyte-like cells in the atrium and pulmonary veins may contribute to atrial arrhythmias.
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16 MeSH Terms