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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
Two-week administration of engineered Escherichia coli establishes persistent resistance to diet-induced obesity even without antibiotic pre-treatment.
Dosoky NS, Chen Z, Guo Y, McMillan C, Flynn CR, Davies SS
(2019) Appl Microbiol Biotechnol 103: 6711-6723
MeSH Terms: Acyltransferases, Animals, Anti-Bacterial Agents, Anti-Obesity Agents, Arabidopsis, Diet, High-Fat, Disease Models, Animal, Escherichia coli, Humans, Metabolic Engineering, Mice, Obesity, Phosphatidylethanolamines, Plant Proteins, Probiotics, Recombinant Proteins, Treatment Outcome
Show Abstract · Added July 17, 2019
Adverse alterations in the composition of the gut microbiota have been implicated in the development of obesity and a variety of chronic diseases. Re-engineering the gut microbiota to produce beneficial metabolites is a potential strategy for treating these chronic diseases. N-acyl-phosphatidylethanolamines (NAPEs) are a family of bioactive lipids with known anti-obesity properties. Previous studies showed that administration of Escherichia coli Nissle 1917 (EcN) engineered with Arabidopsis thaliana NAPE synthase to produce NAPEs imparted resistance to obesity induced by a high-fat diet that persisted after ending their administration. In prior studies, mice were pre-treated with ampicillin prior to administering engineered EcN for 8 weeks in drinking water. If use of antibiotics and long-term administration are required for beneficial effects, implementation of this strategy in humans might be problematic. Studies were therefore undertaken to determine if less onerous protocols could still impart persistent resistance and sustained NAPE biosynthesis. Administration of engineered EcN for only 2 weeks without pre-treatment with antibiotics sufficed to establish persistent resistance. Sustained NAPE biosynthesis by EcN was required as antibiotic treatment after administration of the engineered EcN markedly attenuated its effects. Finally, heterologous expression of human phospholipase A/acyltransferase-2 (PLAAT2) in EcN provided similar resistance to obesity as heterologous expression of A. thaliana NAPE synthase, confirming that NAPEs are the bioactive mediator of this resistance.
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17 MeSH Terms
Chronic Intermittent Ethanol and Acute Stress Similarly Modulate BNST CRF Neuron Activity via Noradrenergic Signaling.
Snyder AE, Salimando GJ, Winder DG, Silberman Y
(2019) Alcohol Clin Exp Res 43: 1695-1701
MeSH Terms: Adrenergic Neurons, Animals, Corticotropin-Releasing Hormone, Ethanol, Excitatory Amino Acid Antagonists, Gene Knock-In Techniques, Glutamic Acid, Kynurenic Acid, Male, Membrane Potentials, Mice, Norepinephrine, Picrotoxin, Propranolol, Restraint, Physical, Septal Nuclei, Substance Withdrawal Syndrome
Show Abstract · Added March 30, 2020
BACKGROUND - Relapse is a critical barrier to effective long-term treatment of alcoholism, and stress is often cited as a key trigger to relapse. Numerous studies suggest that stress-induced reinstatement to drug-seeking behaviors is mediated by norepinephrine (NE) and corticotropin-releasing factor (CRF) signaling interactions in the bed nucleus of the stria terminalis (BNST), a brain region critical to many behavioral and physiologic responses to stressors. Here, we sought to directly examine the effects of NE on BNST CRF neuron activity and determine whether these effects may be modulated by chronic intermittent EtOH (CIE) exposure or a single restraint stress.
METHODS - Adult male CRF-tomato reporter mice were treatment-naïve, or either exposed to CIE for 2 weeks or to a single 1-hour restraint stress. Effects of application of exogenous NE on BNST CRF neuron activity were assessed via whole-cell patch-clamp electrophysiological techniques.
RESULTS - We found that NE depolarized BNST CRF neurons in naïve mice in a β-adrenergic receptor (AR)-dependent mechanism. CRF neurons from CIE- or stress-exposed mice had significantly elevated basal resting membrane potential compared to naïve mice. Furthermore, CIE and stress individually disrupted the ability of NE to depolarize CRF neurons, suggesting that both stress and CIE utilize β-AR signaling to modulate BNST CRF neurons. Neither stress nor CIE altered the ability of exogenous NE to inhibit evoked glutamatergic transmission onto BNST CRF neurons as shown in naïve mice, a mechanism previously shown to be α-AR-dependent.
CONCLUSIONS - Altogether, these findings suggest that stress and CIE interact with β-AR signaling to modulate BNST CRF neuron activity, potentially disrupting the α/β-AR balance of BNST CRF neuronal excitability. Restoration of α/β-AR balance may lead to novel therapies for the alleviation of many stress-related disorders.
© 2019 by the Research Society on Alcoholism.
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17 MeSH Terms
Administration of N-Acyl-Phosphatidylethanolamine Expressing Bacteria to Low Density Lipoprotein Receptor Mice Improves Indices of Cardiometabolic Disease.
May-Zhang LS, Chen Z, Dosoky NS, Yancey PG, Boyd KL, Hasty AH, Linton MF, Davies SS
(2019) Sci Rep 9: 420
MeSH Terms: Animals, Cardiovascular Diseases, Escherichia coli, Fatty Acids, Gastrointestinal Microbiome, Liver, Liver Cirrhosis, Mice, Phosphatidylethanolamines, Receptors, LDL, Triglycerides
Show Abstract · Added January 30, 2019
Obesity increases the risk for cardiometabolic diseases. N-acyl phosphatidylethanolamines (NAPEs) are precursors of N-acylethanolamides, which are endogenous lipid satiety factors. Incorporating engineered bacteria expressing NAPEs into the gut microbiota retards development of diet induced obesity in wild-type mice. Because NAPEs can also exert anti-inflammatory effects, we hypothesized that administering NAPE-expressing bacteria to low-density lipoprotein receptor (Ldlr) mice fed a Western diet would improve various indices of cardiometabolic disease manifested by these mice. NAPE-expressing E. coli Nissle 1917 (pNAPE-EcN), control Nissle 1917 (pEcN), or vehicle (veh) were given via drinking water to Ldlr mice for 12 weeks. Compared to pEcN or veh treatment, pNAPE-EcN significantly reduced body weight and adiposity, hepatic triglycerides, fatty acid synthesis genes, and increased expression of fatty acid oxidation genes. pNAPE-EcN also significantly reduced markers for hepatic inflammation and early signs of fibrotic development. Serum cholesterol was reduced with pNAPE-EcN, but atherosclerotic lesion size showed only a non-significant trend for reduction. However, pNAPE-EcN treatment reduced lesion necrosis by 69% indicating an effect on preventing macrophage inflammatory death. Our results suggest that incorporation of NAPE expressing bacteria into the gut microbiota can potentially serve as an adjuvant therapy to retard development of cardiometabolic disease.
1 Communities
4 Members
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11 MeSH Terms
Modification by isolevuglandins, highly reactive γ-ketoaldehydes, deleteriously alters high-density lipoprotein structure and function.
May-Zhang LS, Yermalitsky V, Huang J, Pleasent T, Borja MS, Oda MN, Jerome WG, Yancey PG, Linton MF, Davies SS
(2018) J Biol Chem 293: 9176-9187
MeSH Terms: Aldehydes, Animals, Apolipoprotein A-I, Apolipoprotein A-II, Cells, Cultured, Cholesterol, Female, Humans, Hyperlipoproteinemia Type II, Ketones, Lipid Metabolism, Lipids, Lipoproteins, HDL, Macrophages, Male, Mice, Mice, Inbred C57BL, Phosphatidylethanolamines
Show Abstract · Added August 3, 2018
Cardiovascular disease risk depends on high-density lipoprotein (HDL) function, not HDL-cholesterol. Isolevuglandins (IsoLGs) are lipid dicarbonyls that react with lysine residues of proteins and phosphatidylethanolamine. IsoLG adducts are elevated in atherosclerosis. The consequences of IsoLG modification of HDL have not been studied. We hypothesized that IsoLG modification of apoA-I deleteriously alters HDL function. We determined the effect of IsoLG on HDL structure-function and whether pentylpyridoxamine (PPM), a dicarbonyl scavenger, can preserve HDL function. IsoLG adducts in HDL derived from patients with familial hypercholesterolemia ( = 10, 233.4 ± 158.3 ng/mg) were found to be significantly higher than in healthy controls ( = 7, 90.1 ± 33.4 pg/mg protein). Further, HDL exposed to myeloperoxidase had elevated IsoLG-lysine adducts (5.7 ng/mg protein) compared with unexposed HDL (0.5 ng/mg protein). Preincubation with PPM reduced IsoLG-lysine adducts by 67%, whereas its inactive analogue pentylpyridoxine did not. The addition of IsoLG produced apoA-I and apoA-II cross-links beginning at 0.3 molar eq of IsoLG/mol of apoA-I (0.3 eq), whereas succinylaldehyde and 4-hydroxynonenal required 10 and 30 eq. IsoLG increased HDL size, generating a subpopulation of 16-23 nm. 1 eq of IsoLG decreased HDL-mediated [H]cholesterol efflux from macrophages via ABCA1, which corresponded to a decrease in HDL-apoA-I exchange from 47.4% to only 24.8%. This suggests that IsoLG inhibits apoA-I from disassociating from HDL to interact with ABCA1. The addition of 0.3 eq of IsoLG ablated HDL's ability to inhibit LPS-stimulated cytokine expression by macrophages and increased IL-1β expression by 3.5-fold. The structural-functional effects were partially rescued with PPM scavenging.
© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
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4 Members
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18 MeSH Terms
Cross-Species Alterations in Synaptic Dopamine Regulation After Chronic Alcohol Exposure.
Siciliano CA, Karkhanis AN, Holleran KM, Melchior JR, Jones SR
(2018) Handb Exp Pharmacol 248: 213-238
MeSH Terms: Alcohol Drinking, Alcoholism, Animals, Dopamine, Ethanol, Humans, Mice, Rats
Show Abstract · Added March 30, 2020
Alcohol use disorders are a leading public health concern, engendering enormous costs in terms of both economic loss and human suffering. These disorders are characterized by compulsive and excessive alcohol use, as well as negative affect and alcohol craving during abstinence. Extensive research has implicated the dopamine system in both the acute pharmacological effects of alcohol and the symptomology of alcohol use disorders that develop after extended alcohol use. Preclinical research has shed light on many mechanisms by which chronic alcohol exposure dysregulates the dopamine system. However, many of the findings are inconsistent across experimental parameters such as alcohol exposure length, route of administration, and model organism. We propose that the dopaminergic alterations driving the core symptomology of alcohol use disorders are likely to be relatively stable across experimental settings. Recent work has been aimed at using multiple model organisms (mouse, rat, monkey) across various alcohol exposure procedures to search for commonalities. Here, we review recent advances in our understanding of the effects of chronic alcohol use on the dopamine system by highlighting findings that are consistent across experimental setting and species.
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Muscarinic M receptors modulate ethanol seeking in rats.
Berizzi AE, Perry CJ, Shackleford DM, Lindsley CW, Jones CK, Chen NA, Sexton PM, Christopoulos A, Langmead CJ, Lawrence AJ
(2018) Neuropsychopharmacology 43: 1510-1517
MeSH Terms: Animals, Conditioning, Operant, Corpus Striatum, Cues, Drug-Seeking Behavior, Ethanol, Imidazoles, Indoles, Locomotion, Male, Microinjections, Rats, Receptor, Muscarinic M5, Self Administration, Sucrose, Varenicline
Show Abstract · Added March 18, 2020
Despite the cost to both individual and society, alcohol use disorders (AUDs) remain a major health risk within society, and both relapse and heavy drinking are still poorly controlled with current medications. Here we demonstrate for the first time that a centrally active and selective negative allosteric modulator for the rat M muscarinic acetylcholine receptor (mAChR), ML375, decreases ethanol self-administration and attenuates cue-induced reinstatement of ethanol seeking in ethanol-preferring (iP) rats. Importantly, ML375 did not affect sucrose self-administration or general locomotor activity indicative of a selective effect on ethanol seeking. Based on the expression profile of M mAChRs in the brain and the distinct roles different aspects of the dorsal striatum have on long-term and short-term ethanol use, we studied whether intra-striatal microinjection of ML375 modulated ethanol intake in rats. We show in iP rats with an extensive history of ethanol intake that intra-dorsolateral (DL), but not intra-dorsomedial, striatal injections of ML375 reduced ethanol self-administration to a similar extent as the nicotinic acetylcholine receptor ligand varenicline, which has preclinical and clinical efficacy in reducing the reinforcing effects of ethanol. These data implicate the DL striatum as a locus for the effects of cholinergic-acting drugs on ethanol seeking in rats with a history of long-term ethanol use. Accordingly, we demonstrate in rats that selectively targeting the M mAChR can modulate both voluntary ethanol intake and cue-induced ethanol seeking and thereby provide direct evidence that the M mAChR is a potential novel target for pharmacotherapies aimed at treating AUDs.
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Dietary Fatty Acids Control the Species of N-Acyl-Phosphatidylethanolamines Synthesized by Therapeutically Modified Bacteria in the Intestinal Tract.
Dosoky NS, Guo L, Chen Z, Feigley AV, Davies SS
(2018) ACS Infect Dis 4: 3-13
MeSH Terms: Acyltransferases, Animals, Bacteria, Biomarkers, Biosynthetic Pathways, Chromatography, Liquid, Diet, Fatty Acids, Gastrointestinal Microbiome, Lipid Metabolism, Liver, Male, Mice, Phosphatidylethanolamines, Tandem Mass Spectrometry, Temperature
Show Abstract · Added July 17, 2019
Engineering the gut microbiota to produce specific beneficial metabolites represents an important new potential strategy for treating chronic diseases. Our previous studies with bacteria engineered to produce N-acyl-phosphatidylethanolamines (NAPEs), the immediate precursors of the lipid satiety factors N-acyl-ethanolamides (NAEs), found that colonization of these bacteria inhibited development of obesity in C57BL/6J mice fed a high fat diet. Individual NAE species differ in their bioactivities. Intriguingly, colonization by our engineered bacteria resulted in increased hepatic N-stearoyl-ethanolamide (C18:0NAE) levels despite the apparent inability of these bacteria to biosynthesize its precursor N-stearoyl-phosphatidylethanolamine (C18:0NAPE) in vitro. We therefore sought to identify the factors that allowed C18:0NAPE biosynthesis by the engineered bacteria after colonization of the intestinal tract. We found that the species of NAPE biosynthesized by engineered bacteria depends on the species of dietary fatty acids available in the intestine, suggesting a simple method to fine-tune the therapeutic effects of modified microbiota.
1 Communities
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Chronic ethanol exposure increases inhibition of optically targeted phasic dopamine release in the nucleus accumbens core and medial shell ex vivo.
Melchior JR, Jones SR
(2017) Mol Cell Neurosci 85: 93-104
MeSH Terms: Alcoholism, Animals, Central Nervous System Depressants, Dopamine, Dopaminergic Neurons, Ethanol, Gene Knock-In Techniques, Male, Mice, Mice, Inbred C57BL, Nucleus Accumbens, Optogenetics, Organ Culture Techniques, Receptors, Opioid, kappa, Synaptic Transmission
Show Abstract · Added March 30, 2020
Dopamine signaling encodes reward learning and motivated behavior through modulation of synaptic signaling in the nucleus accumbens, and aberrations in these processes are thought to underlie obsessive behaviors associated with alcohol abuse. The nucleus accumbens is divided into core and shell sub-regions with overlapping but also divergent contributions to behavior. Here we optogenetically targeted dopamine projections to the accumbens allowing us to isolate stimulation of dopamine terminals ex vivo. We applied 5 pulse (phasic) light stimulations to probe intrinsic differences in dopamine release parameters across regions. Also, we exposed animals to 4weeks of chronic intermittent ethanol vapor and measured phasic release. We found that initial release probability, uptake rate and autoreceptor inhibition were greater in the accumbens core compared to the shell, yet the shell showed greater phasic release ratios. Following chronic ethanol, uptake rates were increased in the core but not the shell, suggesting region-specific neuronal adaptations. Conversely, kappa opioid receptor function was upregulated in both regions to a similar extent, suggesting a local mechanism of kappa opioid receptor regulation that is generalized across the nucleus accumbens. These data suggest that dopamine axons in the nucleus accumbens core and shell display differences in intrinsic release parameters, and that ethanol-induced adaptations to dopamine neuron terminal fields may not be homogeneous. Also, chronic ethanol exposure induces an upregulation in kappa opioid receptor function, providing a mechanism for potential over-inhibition of accumbens dopamine signaling which may negatively impact downstream synaptic function and ultimately bias choice towards previously reinforced alcohol use behaviors.
Copyright © 2017 Elsevier Inc. All rights reserved.
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Leptogenic effects of NAPE require activity of NAPE-hydrolyzing phospholipase D.
Chen Z, Zhang Y, Guo L, Dosoky N, de Ferra L, Peters S, Niswender KD, Davies SS
(2017) J Lipid Res 58: 1624-1635
MeSH Terms: Animals, Arabidopsis, Hydrolysis, Leptin, Mice, Phosphatidylethanolamines, Phospholipase D
Show Abstract · Added April 10, 2018
Food intake induces synthesis of -acylphosphatidylethanolamines (NAPEs) in the intestinal tract. While NAPEs exert leptin-like (leptogenic) effects, including reduced weight gain and food intake, the mechanisms by which NAPEs induce these leptogenic effects remain unclear. One key question is whether intestinal NAPEs act directly on cognate receptors or first require conversion to -acylethanolamides (NAEs) by NAPE-hydrolyzing phospholipase D (NAPE-PLD). Previous studies using mice were equivocal because intraperitoneal injection of NAPEs led to nonspecific aversive effects. To avoid the aversive effects of injection, we delivered NAPEs and NAEs intestinally using gut bacteria synthesizing these compounds. Unlike in wild-type mice, increasing intestinal levels of NAPE using NAPE-synthesizing bacteria in mice failed to reduce food intake and weight gain or alter gene expression. In contrast, increasing intestinal NAE levels in mice using NAE-synthesizing bacteria induced all of these effects. These NAE-synthesizing bacteria also markedly increased NAE levels and decreased inflammatory gene expression in omental adipose tissue. These results demonstrate that intestinal NAPEs require conversion to NAEs by the action of NAPE-PLD to exert their various leptogenic effects, so that the reduced intestinal NAPE-PLD activity found in obese subjects may directly contribute to excess food intake and obesity.
Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.
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