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Uncovering matrix effects on lipid analyses in MALDI imaging mass spectrometry experiments.
Perry WJ, Patterson NH, Prentice BM, Neumann EK, Caprioli RM, Spraggins JM
(2020) J Mass Spectrom 55: e4491
MeSH Terms: 2-Naphthylamine, Acetophenones, Animals, Fourier Analysis, Gentisates, Lipids, Liver, Mice, Phosphatidylcholines, Phosphatidylethanolamines, Principal Component Analysis, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Show Abstract · Added January 22, 2020
The specific matrix used in matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) can have an effect on the molecules ionized from a tissue sample. The sensitivity for distinct classes of biomolecules can vary when employing different MALDI matrices. Here, we compare the intensities of various lipid subclasses measured by Fourier transform ion cyclotron resonance (FT-ICR) IMS of murine liver tissue when using 9-aminoacridine (9AA), 5-chloro-2-mercaptobenzothiazole (CMBT), 1,5-diaminonaphthalene (DAN), 2,5-Dihydroxyacetophenone (DHA), and 2,5-dihydroxybenzoic acid (DHB). Principal component analysis and receiver operating characteristic curve analysis revealed significant matrix effects on the relative signal intensities observed for different lipid subclasses and adducts. Comparison of spectral profiles and quantitative assessment of the number and intensity of species from each lipid subclass showed that each matrix produces unique lipid signals. In positive ion mode, matrix application methods played a role in the MALDI analysis for different cationic species. Comparisons of different methods for the application of DHA showed a significant increase in the intensity of sodiated and potassiated analytes when using an aerosol sprayer. In negative ion mode, lipid profiles generated using DAN were significantly different than all other matrices tested. This difference was found to be driven by modification of phosphatidylcholines during ionization that enables them to be detected in negative ion mode. These modified phosphatidylcholines are isomeric with common phosphatidylethanolamines confounding MALDI IMS analysis when using DAN. These results show an experimental basis of MALDI analyses when analyzing lipids from tissue and allow for more informed selection of MALDI matrices when performing lipid IMS experiments.
© 2019 John Wiley & Sons, Ltd.
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12 MeSH Terms
Prevention of DNA damage in Barrett's esophageal cells exposed to acidic bile salts.
Bhardwaj V, Horvat A, Korolkova O, Washington MK, El-Rifai W, Dikalov SI, Zaika AI
(2016) Carcinogenesis 37: 1161-1169
MeSH Terms: Acetophenones, Acids, Adenocarcinoma, Antioxidants, BRCA1 Protein, Barrett Esophagus, Bile Acids and Salts, Cell Line, Tumor, DNA Damage, DNA Repair, Esophageal Neoplasms, Gastric Acid, Gastroesophageal Reflux, Humans, Reactive Oxygen Species
Show Abstract · Added March 26, 2019
Esophageal adenocarcinoma (EA) is one of the fastest rising tumors in the USA. The major risk factor for EA is gastroesophageal reflux disease (GERD). During GERD, esophageal cells are exposed to refluxate which contains gastric acid frequently mixed with duodenal bile. This may lead to mucosal injury and Barrett's metaplasia (BE) that are important factors contributing to development of EA. In this study, we investigated DNA damage in BE cells exposed to acidic bile salts and explored for potential protective strategies. Exposure of BE cells to acidic bile salts led to significant DNA damage, which in turn, was due to generation of reactive oxygen species (ROS). We found that acidic bile salts induce a rapid increase in superoxide radicals and hydrogen peroxide, which were determined using electron paramagnetic resonance spectroscopy and Amplex Red assay. Analyzing a panel of natural antioxidants, we identified apocynin to be the most effective in protecting esophageal cells from DNA damage induced by acidic bile salts. Mechanistic analyses showed that apocynin inhibited ROS generation and increases the DNA repair capacity of BE cells. We identified BRCA1 and p73 proteins as apocynin targets. Downregulation of p73 inhibited the protective effect of apocynin. Taken together, our results suggest potential application of natural compounds such as apocynin for prevention of reflux-induced DNA damage and GERD-associated tumorigenesis.
© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381): a novel molecular probe.
Gentry PR, Kokubo M, Bridges TM, Cho HP, Smith E, Chase P, Hodder PS, Utley TJ, Rajapakse A, Byers F, Niswender CM, Morrison RD, Daniels JS, Wood MR, Conn PJ, Lindsley CW
(2014) ChemMedChem 9: 1677-82
MeSH Terms: Acetophenones, Animals, Drug Evaluation, Preclinical, Half-Life, Humans, Isoxazoles, Molecular Probes, Muscarinic Antagonists, Protein Binding, Rats, Receptor, Muscarinic M5
Show Abstract · Added February 19, 2015
Of the five G-protein-coupled muscarinic acetylcholine receptors (mAChRs; M1-M5), M5 is the least explored and understood due to a lack of mAChR subtype-selective ligands. We recently performed a high-throughput functional screen and identified a number of weak antagonist hits that are selective for the M5 receptor. Here, we report an iterative parallel synthesis and detailed molecular pharmacologic profiling effort that led to the discovery of the first highly selective, central nervous system (CNS)-penetrant M5-orthosteric antagonist, with sub-micromolar potency (hM5 IC50=450 nM, hM5 Ki=340 nM, M1-M4 IC50>30 μM), enantiospecific inhibition, and an acceptable drug metabolism and pharmacokinetics (DMPK) profile for in vitro and electrophysiology studies. This compound will be a powerful tool and molecular probe for the further investigation into the role of M5 in addiction and other diseases.
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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11 MeSH Terms
Molecular imaging reveals rapid reduction of endothelial activation in early atherosclerosis with apocynin independent of antioxidative properties.
Khanicheh E, Qi Y, Xie A, Mitterhuber M, Xu L, Mochizuki M, Daali Y, Jaquet V, Krause KH, Ruggeri ZM, Kuster GM, Lindner JR, Kaufmann BA
(2013) Arterioscler Thromb Vasc Biol 33: 2187-92
MeSH Terms: APOBEC-1 Deaminase, Acetophenones, Animals, Anti-Inflammatory Agents, Antioxidants, Aortic Diseases, Atherosclerosis, Biomarkers, Blotting, Western, Contrast Media, Cytidine Deaminase, Disease Models, Animal, Endothelium, Vascular, Enzyme Inhibitors, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microbubbles, Molecular Imaging, NADPH Oxidases, Oxidative Stress, Phenotype, Platelet Adhesiveness, Platelet Glycoprotein GPIb-IX Complex, Receptors, LDL, Superoxides, Time Factors, Ultrasonography, Interventional, Vascular Cell Adhesion Molecule-1
Show Abstract · Added August 29, 2013
OBJECTIVE - Antioxidative drugs continue to be developed for the treatment of atherosclerosis. Apocynin is an nicotinamide adenine dinucleotide phosphate oxidase inhibitor with anti-inflammatory properties. We used contrast-enhanced ultrasound molecular imaging to assess whether short-term apocynin therapy in atherosclerosis reduces vascular oxidative stress and endothelial activation
APPROACH AND RESULTS - Genetically modified mice with early atherosclerosis were studied at baseline and after 7 days of therapy with apocynin (4 mg/kg per day IP) or saline. Contrast-enhanced ultrasound molecular imaging of the aorta was performed with microbubbles targeted to vascular cell adhesion molecule 1 (VCAM-1; MB(V)), to platelet glycoprotein Ibα (MB(Pl)), and control microbubbles (MB(Ctr)). Aortic vascular cell adhesion molecule 1 was measured using Western blot. Aortic reactive oxygen species generation was measured using a lucigenin assay. Hydroethidine oxidation was used to assess aortic superoxide generation. Baseline signal for MBV (1.3 ± 0.3 AU) and MB(Pl )(1.5 ± 0.5 AU) was higher than for MBCtr (0.5 ± 0.2 AU; P<0.01). In saline-treated animals, signal did not significantly change for any microbubble agent, whereas short-term apocynin significantly (P<0.05) reduced vascular cell adhesion molecule 1 and platelet signal (MBV: 0.3 ± 0.1; MBPl: 0.4 ± 0.1; MBCtr: 0.3 ± 0.2 AU; P=0.6 between agents). Apocynin reduced aortic vascular cell adhesion molecule 1 expression by 50% (P<0.05). However, apocynin therapy did not reduce reactive oxygen species content, superoxide generation, or macrophage content.
CONCLUSIONS - Short-term treatment with apocynin in atherosclerosis reduces endothelial cell adhesion molecule expression. This change in endothelial phenotype can be detected by molecular imaging before any measurable decrease in macrophage content and is not associated with a detectable change in oxidative burden.
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31 MeSH Terms
Increased ANG II sensitivity following recovery from acute kidney injury: role of oxidant stress in skeletal muscle resistance arteries.
Phillips SA, Pechman KR, Leonard EC, Friedrich JL, Bian JT, Beal AG, Basile DP
(2010) Am J Physiol Regul Integr Comp Physiol 298: R1682-91
MeSH Terms: Acetophenones, Acute Kidney Injury, Animals, Antioxidants, Arteries, Cyclic N-Oxides, Hydrogen Peroxide, Male, Muscle, Skeletal, NADPH Oxidases, Nitric Oxide Synthase Type III, Oxidants, Oxidative Stress, Rats, Rats, Sprague-Dawley, Reperfusion Injury, Spin Labels, Superoxides, Vascular Resistance, Vasoconstrictor Agents
Show Abstract · Added March 6, 2020
Ischemia-reperfusion (I/R)-induced acute kidney injury (AKI) results in prolonged impairment of peripheral (i.e., nonrenal) vascular function since skeletal muscle resistance arteries derived from rats 5 wk post-I/R injury, show enhanced responses to ANG II stimulation but not other constrictors. Because vascular superoxide increases ANG II sensitivity, we hypothesized that peripheral responsiveness following recovery from AKI was attributable to vascular oxidant stress. Gracilis arteries (GA) isolated from post-I/R rats (approximately 5 wk recovery) showed significantly greater superoxide levels relative to sham-operated controls, as detected by dihydroeithidium, which was further augmented by acute ANG II stimulation in vitro. Hydrogen peroxide measured by dichlorofluorescein was not affected by ANG II. GA derived from postischemic animals manifested significantly greater constrictor responses in vitro to ANG II than GA from sham-operated controls. The addition of the superoxide scavenging reagent Tempol (10(-5) M) normalized the response to values similar to sham-operated controls. Apocynin (10(-6) M) and endothelial denudation nearly abrogated all ANG II-stimulated constrictor activity in GA from post-AKI rats, suggesting an important role for an endothelial-derived source of peripheral oxidative stress. Apocynin treatment in vivo abrogated GA oxidant stress and attenuated ANG II-induced pressor responses post-AKI. Interestingly, gene expression studies in GA vessels indicated a paradoxical reduction in NADPH oxidase subunit and AT(1)-receptor genes and no effect on several antioxidant genes. Taken together, this study demonstrates that AKI alters peripheral vascular responses by increasing oxidant stress, likely in the endothelium, via an undefined mechanism.
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Age-accelerated atherosclerosis correlates with failure to upregulate antioxidant genes.
Collins AR, Lyon CJ, Xia X, Liu JZ, Tangirala RK, Yin F, Boyadjian R, Bikineyeva A, Praticò D, Harrison DG, Hsueh WA
(2009) Circ Res 104: e42-54
MeSH Terms: Acetophenones, Aging, Animals, Antioxidants, Atherosclerosis, Diabetes Mellitus, Diet, Atherogenic, Eating, Enzyme Inhibitors, Gene Expression Profiling, Gene Expression Regulation, Gene Knockout Techniques, Humans, Insulin Resistance, Metabolic Syndrome, Mice, Mice, Knockout, Obesity, Oligonucleotide Array Sequence Analysis, Oxidative Stress, Receptors, LDL
Show Abstract · Added July 20, 2014
Excess food intake leads to obesity and diabetes, both of which are well-known independent risk factors for atherosclerosis, and both of which are growing epidemics in an aging population. We hypothesized that aging enhances the metabolic and vascular effects of high fat diet (HFD) and therefore examined the effect of age on atherosclerosis and insulin resistance in lipoprotein receptor knockout (LDLR(-/-)) mice. We found that 12-month-old (middle-aged) LDLR(-/-) mice developed substantially worse metabolic syndrome, diabetes, and atherosclerosis than 3-month-old (young) LDLR(-/-) mice when both were fed HFD for 3 months, despite similar elevations in total cholesterol levels. Microarray analyses were performed to analyze the mechanism responsible for the marked acceleration of atherosclerosis in middle-aged mice. Chow-fed middle-aged mice had greater aortic expression of multiple antioxidant genes than chow-fed young mice, including glutathione peroxidase-1 and -4, catalase, superoxide dismutase-2, and uncoupling protein-2. Aortic expression of these enzymes markedly increased in young mice fed HFD but decreased or only modestly increased in middle-aged mice fed HFD, despite the fact that systemic oxidative stress and vascular reactive oxygen species generation, measured by plasma F2alpha isoprostane concentration (systemic) and dihydroethidium conversion and p47phox expression (vascular), were greater in middle-aged mice fed HFD. Thus, the mechanism for the accelerated vascular injury in older LDLR(-/-) mice was likely the profound inability to mount an antioxidant response. This effect was related to a decrease in vascular expression of 2 key transcriptional pathways regulating the antioxidant response, DJ-1 and forkhead box, subgroup O family (FOXOs). Treatment of middle-aged mice fed HFD with the antioxidant apocynin attenuated atherosclerosis, whereas treatment with the insulin sensitizer rosiglitazone attenuated both metabolic syndrome and atherosclerosis. Both treatments decreased oxidative stress. A novel effect of rosiglitazone was to increase expression of Nrf2 (nuclear factor [erythroid-derived 2]-like 2), a downstream target of DJ-1 contributing to enhanced expression of vascular antioxidant enzymes. This investigation underscores the role of oxidative stress when multiple atherosclerotic risk factors, particularly aging, converge on the vessel wall and emphasizes the need to develop effective strategies to inhibit oxidative stress to protect aging vasculature.
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21 MeSH Terms
Bone morphogenic protein-4 induces hypertension in mice: role of noggin, vascular NADPH oxidases, and impaired vasorelaxation.
Miriyala S, Gongora Nieto MC, Mingone C, Smith D, Dikalov S, Harrison DG, Jo H
(2006) Circulation 113: 2818-25
MeSH Terms: Acetophenones, Acetylcholine, Animals, Aorta, Thoracic, Apolipoproteins E, Bone Morphogenetic Protein 4, Bone Morphogenetic Proteins, Calcimycin, Carrier Proteins, Diet, Atherogenic, Endothelium, Vascular, Enzyme Activation, Humans, Hyperlipoproteinemia Type II, Hypertension, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, NADPH Oxidases, Nitroglycerin, Recombinant Fusion Proteins, Superoxides, Vasodilator Agents
Show Abstract · Added February 17, 2016
BACKGROUND - Recent in vitro studies have shown that disturbed flow and oxidative conditions induce the expression of bone morphogenic proteins (BMPs 2 and 4) in cultured endothelial cells. BMPs can stimulate superoxide production and inflammatory responses in endothelial cells, raising the possibility that BMPs may play a role in vascular diseases such as hypertension and atherosclerosis. In this study, we examined the hypothesis that BMP4 would induce hypertension in intact animals by increasing superoxide production from vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and an impairment of vasodilation responses.
METHODS AND RESULTS - BMP4 infusion by osmotic pumps increased systolic blood pressure in a time- and dose-dependent manner in both C57BL/6 mice (from 101 to 125 mm Hg) and apolipoprotein E-null mice (from 107 to 146 mm Hg) after 4 weeks. Cotreatment with the BMP antagonist noggin or the NADPH oxidase inhibitor apocynin completely blocked the BMP4 effect. In addition, BMP4 infusion stimulated aortic NADPH oxidase activity and impaired vasorelaxation, both of which were prevented either by coinfusing noggin or by treating the isolated aortas with apocynin. BMP4, however, did not cause significant changes in maximum relaxation induced by the endothelium-independent vasodilator nitroglycerin. Remarkably, BMP4 infusion failed to stimulate aortic NADPH oxidases, increase blood pressure, and impair vasodilation responses in p47phox-deficient mice.
CONCLUSIONS - These results suggest that BMP4 infusion induces hypertension in mice in a vascular NADPH oxidase-dependent manner and the subsequent endothelial dysfunction. We suggest that BMP4 is a novel mediator of endothelial dysfunction and hypertension and that noggin and its analogs could be used as therapeutic agents for treating vascular diseases.
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24 MeSH Terms
Angiopoietin-1-induced angiogenesis is modulated by endothelial NADPH oxidase.
Chen JX, Zeng H, Lawrence ML, Blackwell TS, Meyrick B
(2006) Am J Physiol Heart Circ Physiol 291: H1563-72
MeSH Terms: Acetophenones, Angiopoietin-1, Animals, Cell Movement, Cells, Cultured, Endothelium, Vascular, Enzyme Inhibitors, Gene Expression Regulation, Enzymologic, Mice, Mice, Knockout, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, NADPH Oxidases, Neovascularization, Physiologic, Oncogene Protein v-akt, Onium Compounds, Phosphorylation, Reactive Oxygen Species, Receptor, TIE-2, Swine
Show Abstract · Added March 5, 2014
Reactive oxygen species (ROS) play a central role in the pathogenesis of many cardiovascular diseases, such as atherosclerosis and hypertension. Endothelial NADPH oxidase is the major source of intracellular ROS. The present study investigated the role of endothelial NADPH oxidase-derived ROS in angiopoietin-1 (Ang-1)-induced angiogenesis. Exposure of porcine coronary artery endothelial cells (PCAECs) to Ang-1 (250 ng/ml) for periods up to 30 min led to a transient and dose-dependent increase in intracellular ROS. Thirty minutes of pretreatment with the NADPH oxidase inhibitors diphenylene iodinium (DPI, 10 microM) and apocynin (200 microM) suppressed Ang-1-stimulated ROS. Pretreatment with either DPI or apocynin also significantly attenuated Ang-1-induced Akt and p44/42 MAPK phosphorylation. In addition, inhibition of NADPH oxidase significantly suppressed Ang-1-induced endothelial cell migration and sprouting from endothelial spheroids. Using mouse heart microvascular endothelial cells from wild-type (WT) mice and mice deficient in the p47(phox) component of NADPH oxidase (p47(phox-/-)), we found that although Ang-1 stimulated intracellular ROS, Akt and p42/44 MAPK phosphorylation, and cell migration in WT cells, the responses were strikingly suppressed in cells from the p47(phox-/-) mice. Furthermore, exposure of aortic rings from p47(phox-/-) mice to Ang-1 demonstrated fewer vessel sprouts than WT mice. Inhibition of the Tie-2 receptor inhibited Ang-1-induced endothelial migration and vessel sprouting. Together, our data strongly suggest that endothelial NADPH oxidase-derived ROS play a critical role in Ang-1-induced angiogenesis.
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20 MeSH Terms
Selective activation of protein kinase C delta in human neutrophils following ischemia reperfusion of skeletal muscle.
Huda R, Vergara LA, Solanki DR, Sherwood ER, Mathru M
(2004) Shock 21: 500-4
MeSH Terms: Acetophenones, Apoptosis, Benzopyrans, Cells, Cultured, Cytosol, Enzyme Activation, Enzyme Inhibitors, Humans, Muscle, Skeletal, Neutrophils, Phosphorylation, Protein Kinase C, Protein Kinase C-delta, Protein Transport, Reperfusion, Reperfusion Injury
Show Abstract · Added October 18, 2015
Circulatory neutrophils are known to be critical mediators of inflammation and oxidative stress during ischemia reperfusion (I/R) injury. Recent studies have shown an important role for protein kinase C (PKC) in neutrophil survival and function. Activation of specific isotypes of PKC are known to be involved in membrane alteration and motility, oxidative phosphorylation, and apoptosis modulation of neutrophils. However, the role of PKC in neutrophil responses to I/R in the clinical setting has not been studied. In this study, we examined the neutrophil activation of PKC induced by tourniquet-controlled I/R of skeletal muscle in humans. We found that I/R rapidly activates and translocates PKC delta, but not any of the classical forms of PKC (alpha or beta) from cytosol to the particulate fraction of neutrophils. Particulate translocation of PKC delta is sustained up to 4 h after reperfusion and is associated with kinase activity. Postreperfusion activation of PKC delta in neutrophils signals proapoptosis, but does not cause immediate cell death (as revealed by neutrophil morphology study and DNA-laddering assay). This study indicates that calcium-independent novel PKC delta (nPKC delta) might be predominantly involved in regulating membrane functions and survival of neutrophils associated with post-I/R-induced inflammatory oxidative stress.
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16 MeSH Terms