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Interpreting an apoptotic corpse as anti-inflammatory involves a chloride sensing pathway.
Perry JSA, Morioka S, Medina CB, Iker Etchegaray J, Barron B, Raymond MH, Lucas CD, Onengut-Gumuscu S, Delpire E, Ravichandran KS
(2019) Nat Cell Biol 21: 1532-1543
MeSH Terms: Animals, Apoptosis, Biological Transport, Cell Line, Cell Line, Tumor, Chlorides, Humans, Inflammation, Jurkat Cells, Mice, Mice, Inbred C57BL, Oxidative Stress, Phagocytes, Phagocytosis, Signal Transduction, Sodium-Potassium-Chloride Symporters, Transcription, Genetic
Show Abstract · Added March 18, 2020
Apoptotic cell clearance (efferocytosis) elicits an anti-inflammatory response by phagocytes, but the mechanisms that underlie this response are still being defined. Here, we uncover a chloride-sensing signalling pathway that controls both the phagocyte 'appetite' and its anti-inflammatory response. Efferocytosis transcriptionally altered the genes that encode the solute carrier (SLC) proteins SLC12A2 and SLC12A4. Interfering with SLC12A2 expression or function resulted in a significant increase in apoptotic corpse uptake per phagocyte, whereas the loss of SLC12A4 inhibited corpse uptake. In SLC12A2-deficient phagocytes, the canonical anti-inflammatory program was replaced by pro-inflammatory and oxidative-stress-associated gene programs. This 'switch' to pro-inflammatory sensing of apoptotic cells resulted from the disruption of the chloride-sensing pathway (and not due to corpse overload or poor degradation), including the chloride-sensing kinases WNK1, OSR1 and SPAK-which function upstream of SLC12A2-had a similar effect on efferocytosis. Collectively, the WNK1-OSR1-SPAK-SLC12A2/SLC12A4 chloride-sensing pathway and chloride flux in phagocytes are key modifiers of the manner in which phagocytes interpret the engulfed apoptotic corpse.
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Sox6 as a new modulator of renin expression in the kidney.
Saleem M, Hodgkinson CP, Xiao L, Gimenez-Bastida JA, Rasmussen ML, Foss J, Payne AJ, Mirotsou M, Gama V, Dzau VJ, Gomez JA
(2020) Am J Physiol Renal Physiol 318: F285-F297
MeSH Terms: Animals, Arterioles, Blood Pressure, Cell Differentiation, Cell Proliferation, Cells, Cultured, Diet, Sodium-Restricted, Diuretics, Furosemide, Gene Expression Regulation, Juxtaglomerular Apparatus, Male, Mesenchymal Stem Cells, Mice, Inbred C57BL, Mice, Knockout, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Renin, SOXD Transcription Factors, Signal Transduction
Show Abstract · Added August 24, 2020
Juxtaglomerular (JG) cells, major sources of renin, differentiate from metanephric mesenchymal cells that give rise to JG cells or a subset of smooth muscle cells of the renal afferent arteriole. During periods of dehydration and salt deprivation, renal mesenchymal stromal cells (MSCs) differentiate from JG cells. JG cells undergo expansion and smooth muscle cells redifferentiate to express renin along the afferent arteriole. Gene expression profiling comparing resident renal MSCs with JG cells indicates that the transcription factor Sox6 is highly expressed in JG cells in the adult kidney. In vitro, loss of Sox6 expression reduces differentiation of renal MSCs to renin-producing cells. In vivo, Sox6 expression is upregulated after a low-Na diet and furosemide. Importantly, knockout of Sox6 in Ren1d+ cells halts the increase in renin-expressing cells normally seen during a low-Na diet and furosemide as well as the typical increase in renin. Furthermore, Sox6 ablation in renin-expressing cells halts the recruitment of smooth muscle cells along the afferent arteriole, which normally express renin under these conditions. These results support a previously undefined role for Sox6 in renin expression.
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Central EP3 (E Prostanoid 3) Receptors Mediate Salt-Sensitive Hypertension and Immune Activation.
Xiao L, Itani HA, do Carmo LS, Carver LS, Breyer RM, Harrison DG
(2019) Hypertension 74: 1507-1515
MeSH Terms: Adaptive Immunity, Analysis of Variance, Animals, Biomarkers, Biopsy, Needle, Brain, Dinoprostone, Disease Models, Animal, Female, Flow Cytometry, Hypertension, Immunohistochemistry, Male, Mice, Mice, Inbred C57BL, NG-Nitroarginine Methyl Ester, Random Allocation, Real-Time Polymerase Chain Reaction, Receptors, Prostaglandin E, EP3 Subtype, Sodium, Dietary
Show Abstract · Added December 3, 2019
We recently identified a pathway underlying immune activation in hypertension. Proteins oxidatively modified by reactive isoLG (isolevuglandin) accumulate in dendritic cells (DCs). PGE (Prostaglandin E2) has been implicated in the inflammation associated with hypertension. We hypothesized that PGE via its EP (E prostanoid) 3 receptor contributes to DC activation in hypertension. EP3 mice and wild-type littermates were exposed to sequential hypertensive stimuli involving an initial 2-week exposure to the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester hydrochloride in drinking water, followed by a 2-week washout period, and a subsequent 4% high-salt diet for 3 weeks. In wild-type mice, this protocol increased systolic pressure from 123±2 to 148±8 mm Hg (<0.05). This was associated with marked renal inflammation and a striking accumulation of isoLG adducts in splenic DCs. However, the increases in blood pressure, renal T-cell infiltration, and DC isoLG formation were completely prevented in EP3 mice. Similar protective effects were also observed in wild-type mice that received intracerebroventricular injection of a lentiviral vector encoding shRNA targeting the EP3 receptor. Further, in vitro experiments indicated that PGE also acts directly on DCs via its EP1 receptors to stimulate intracellular isoLG formation. Together, these findings provide new insight into how EP receptors in both the central nervous system and peripherally on DCs promote inflammation in salt-induced hypertension.
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20 MeSH Terms
Cryo-EM structures of the human cation-chloride cotransporter KCC1.
Liu S, Chang S, Han B, Xu L, Zhang M, Zhao C, Yang W, Wang F, Li J, Delpire E, Ye S, Bai XC, Guo J
(2019) Science 366: 505-508
MeSH Terms: Amino Acid Sequence, Animals, Binding Sites, Cryoelectron Microscopy, HEK293 Cells, Humans, Ion Transport, Mice, Molecular Dynamics Simulation, Oocytes, Protein Domains, Protein Multimerization, Protein Structure, Quaternary, Sequence Alignment, Sodium-Potassium-Chloride Symporters, Symporters, Xenopus laevis
Show Abstract · Added March 18, 2020
Cation-chloride cotransporters (CCCs) mediate the coupled, electroneutral symport of cations with chloride across the plasma membrane and are vital for cell volume regulation, salt reabsorption in the kidney, and γ-aminobutyric acid (GABA)-mediated modulation in neurons. Here we present cryo-electron microscopy (cryo-EM) structures of human potassium-chloride cotransporter KCC1 in potassium chloride or sodium chloride at 2.9- to 3.5-angstrom resolution. KCC1 exists as a dimer, with both extracellular and transmembrane domains involved in dimerization. The structural and functional analyses, along with computational studies, reveal one potassium site and two chloride sites in KCC1, which are all required for the ion transport activity. KCC1 adopts an inward-facing conformation, with the extracellular gate occluded. The KCC1 structures allow us to model a potential ion transport mechanism in KCCs and provide a blueprint for drug design.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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17 MeSH Terms
Combining Salt Doping and Matrix Sublimation for High Spatial Resolution MALDI Imaging Mass Spectrometry of Neutral Lipids.
Dufresne M, Patterson NH, Norris JL, Caprioli RM
(2019) Anal Chem 91: 12928-12934
MeSH Terms: Animals, Benzoates, Brain, Cerebrosides, Image Processing, Computer-Assisted, Lipids, Mice, Phospholipids, Sodium Chloride, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Show Abstract · Added October 15, 2019
The combination of sodium salt doping of a tissue section along with the sublimation of the matrix 2,5-dihydrobenzoic acid (DHB) was found to be an effective coating for the simultaneous detection of neutral lipids and phospholipids using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry in positive ionization mode. Lithium, sodium, and potassium acetate were initially screened for their ability to cationize difficult to analyze neutral lipids such as cholesterol esters, cerebrosides, and triglycerides directly from a tissue section. The combination of sodium salt and DHB sublimation was found to be an effective cation/matrix combination for detection of neutral lipids. Further experimental optimizations revealed that sodium carbonate or sodium phosphate followed by DHB sublimation increases the signal intensity of the neutral lipids studied depending on the specific lipid family and tissue type by 10-fold to 140-fold compared with that of previously published methods. Application of sodium carbonate tissue doping and DHB sublimation resulted in crystal sizes ≤2 μm. We were thus able to image a mouse brain cerebellum at a high spatial resolution and detected 37 cerebrosides in a single run using a MALDI-TOF instrument. The combination of sodium doping and DHB sublimation offer a targeted and sensitive approach for the detection of neutral lipids that do not typically ionize well under normal MALDI conditions.
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10 MeSH Terms
High dietary salt-induced dendritic cell activation underlies microbial dysbiosis-associated hypertension.
Ferguson JF, Aden LA, Barbaro NR, Van Beusecum JP, Xiao L, Simmons AJ, Warden C, Pasic L, Himmel LE, Washington MK, Revetta FL, Zhao S, Kumaresan S, Scholz MB, Tang Z, Chen G, Reilly MP, Kirabo A
(2019) JCI Insight 5:
MeSH Terms: Adolescent, Adoptive Transfer, Adult, Angiotensin II, Animals, Aorta, Bacteria, Blood Pressure, CD11c Antigen, Colon, Cytokines, Dendritic Cells, Disease Models, Animal, Dysbiosis, Female, Gastrointestinal Microbiome, Humans, Hypertension, Inflammation, Lipids, Lymph Nodes, Male, Mice, Mice, Inbred C57BL, Middle Aged, Myeloid Cells, Peyer's Patches, RNA, Ribosomal, 16S, Sodium Chloride, Sodium Chloride, Dietary, Young Adult
Show Abstract · Added March 3, 2020
Excess dietary salt contributes to inflammation and hypertension via poorly understood mechanisms. Antigen presenting cells including dendritic cells (DCs) play a key role in regulating intestinal immune homeostasis in part by surveying the gut epithelial surface for pathogens. Previously, we found that highly reactive γ-ketoaldehydes or isolevuglandins (IsoLGs) accumulate in DCs and act as neoantigens, promoting an autoimmune-like state and hypertension. We hypothesized that excess dietary salt alters the gut microbiome leading to hypertension and this is associated with increased immunogenic IsoLG-adduct formation in myeloid antigen presenting cells. To test this hypothesis, we performed fecal microbiome analysis and measured blood pressure of healthy human volunteers with salt intake above or below the American Heart Association recommendations. We also performed 16S rRNA analysis on cecal samples of mice fed normal or high salt diets. In humans and mice, high salt intake was associated with changes in the gut microbiome reflecting an increase in Firmicutes, Proteobacteria and genus Prevotella bacteria. These alterations were associated with higher blood pressure in humans and predisposed mice to vascular inflammation and hypertension in response to a sub-pressor dose of angiotensin II. Mice fed a high salt diet exhibited increased intestinal inflammation including the mesenteric arterial arcade and aorta, with a marked increase in the B7 ligand CD86 and formation of IsoLG-protein adducts in CD11c+ myeloid cells. Adoptive transfer of fecal material from conventionally housed high salt-fed mice to germ-free mice predisposed them to increased intestinal inflammation and hypertension. These findings provide novel insight into the mechanisms underlying inflammation and hypertension associated with excess dietary salt and may lead to interventions targeting the microbiome to prevent and treat this important disease.
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31 MeSH Terms
Nasal saline irrigation: a clinical update.
Succar EF, Turner JH, Chandra RK
(2019) Int Forum Allergy Rhinol 9: S4-S8
MeSH Terms: Chronic Disease, Humans, Hygiene, Nasal Lavage, Practice Guidelines as Topic, Rhinitis, Saline Solution, Sinusitis, Sodium Chloride
Show Abstract · Added July 23, 2020
BACKGROUND - Nasal saline irrigation (NSI) plays an important role in the treatment of chronic rhinosinusitis (CRS). It is a beneficial low-risk treatment that serves an adjunctive function in the medical and surgical management of CRS. NSI is hypothesized to function by thinning mucous, improving mucociliary clearance, decreasing edema, and reducing antigen load in the nasal and sinus cavities. Although its use in CRS is nearly universal, significant variety exists with regard to delivery volume, delivery pressure, frequency of use, duration of use, composition, and hygiene recommendations. Evidence is limited regarding the most optimal methods of NSI delivery. In addition, use of NSI has recently come under increasing scrutiny due to potential associations with cases of primary amebic meningoencephalitis.
METHODS - In this review we provide a clinical update summarizing use of NSI for treatment of CRS, including current recommendations for use, and data regarding overall efficacy, available delivery devices, solution composition, and hygiene.
RESULTS - Current evidence and recommendations for nasal saline delivery methods, composition, and hygiene are presented.
CONCLUSION - The most recent consensus statements and Cochrane Review recommend the use of NSI for CRS based on a preponderance of lower level evidence. A conclusion regarding the optimal method of delivery and solution composition cannot be drawn based on the current literature.
© 2019 ARS-AAOA, LLC.
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Electrophysiologic and molecular mechanisms of a frameshift NPPA mutation linked with familial atrial fibrillation.
Menon A, Hong L, Savio-Galimberti E, Sridhar A, Youn SW, Zhang M, Kor K, Blair M, Kupershmidt S, Darbar D
(2019) J Mol Cell Cardiol 132: 24-35
MeSH Terms: Action Potentials, Animals, Atrial Fibrillation, Atrial Natriuretic Factor, Electrophysiological Phenomena, Frameshift Mutation, Heart Atria, Humans, Membrane Potentials, Mice, Mice, Transgenic, Myocytes, Cardiac, NAV1.5 Voltage-Gated Sodium Channel
Show Abstract · Added June 14, 2019
A frameshift (fs) mutation in the natriuretic peptide precursor A (NPPA) gene, encoding a mutant atrial natriuretic peptide (Mut-ANP), has been linked with familial atrial fibrillation (AF) but the underlying mechanisms by which the mutation causes AF remain unclear. We engineered 2 transgenic (TG) mouse lines expressing the wild-type (WT)-NPPA gene (H-WT-NPPA) and the human fs-Mut-NPPA gene (H-fsMut-NPPA) to test the hypothesis that mice overexpressing the human NPPA mutation are more susceptible to AF and elucidate the underlying electrophysiologic and molecular mechanisms. Transthoracic echocardiography and surface electrocardiography (ECG) were performed in H-fsMut-NPPA, H-WT-NPPA, and Non-TG mice. Invasive electrophysiology, immunohistochemistry, Western blotting and patch clamping of membrane potentials were performed. To examine the role of the Mut-ANP in ion channel remodeling, we measured plasma cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activity in the 3 groups of mice. In H-fsMut-NPPA mice mean arterial pressure (MAP) was reduced when compared to H-WT-NPPA and Non-TG mice. Furthermore, injection of synthetic fs-Mut-ANP lowered the MAP in H-WT-NPPA and Non-TG mice while synthetic WT-ANP had no effect on MAP in the 3 groups of mice. ECG characterization revealed significantly prolonged QRS duration in H-fsMut-NPPA mice when compared to the other two groups. Trans-Esophageal (TE) atrial pacing of H-fsMut-NPPA mice showed increased AF burden and AF episodes when compared with H-WT-NPPA or Non-TG mice. The cardiac Na (NaV1.5) and Ca (CaV1.2/CaV1.3) channel expression and currents (I, I) and action potential durations (APD/APD/APD) were significantly reduced in H-fsMut-NPPA mice while the rectifier K channel current (I) was markedly increased when compared to the other 2 groups of mice. In addition, plasma cGMP levels were only increased in H-fsMut-NPPA mice with a corresponding reduction in plasma cAMP levels and PKA activity. In summary, we showed that mice overexpressing an AF-linked NPPA mutation are more prone to develop AF and this risk is mediated in part by remodeling of the cardiac Na, Ca and K channels creating an electrophysiologic substrate for reentrant AF.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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13 MeSH Terms
Effect of environmental salt concentration on the Helicobacter pylori exoproteome.
Caston RR, Loh JT, Voss BJ, McDonald WH, Scholz MB, McClain MS, Cover TL
(2019) J Proteomics 202: 103374
MeSH Terms: Bacterial Proteins, Dose-Response Relationship, Drug, Gene Expression Regulation, Bacterial, Helicobacter pylori, Proteome, Proteomics, Sodium Chloride, Dietary
Show Abstract · Added July 14, 2019
Helicobacter pylori infection and a high salt diet are each risk factors for gastric cancer. In this study, we tested the hypothesis that environmental salt concentration influences the composition of the H. pylori exoproteome. H. pylori was cultured in media containing varying concentrations of sodium chloride, and aliquots were fractionated and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). We identified proteins that were selectively released into the extracellular space, and we identified selectively released proteins that were differentially abundant in culture supernatants, depending on the environmental salt concentration. We also used RNA-seq analysis to identify genes that were differentially expressed in response to environmental salt concentration. The salt-responsive proteins identified by proteomic analysis and salt-responsive genes identified by RNA-seq analysis were mostly non-concordant, but the secreted toxin VacA was salt-responsive in both analyses. Western blot analysis confirmed that VacA levels in the culture supernatant were increased in response to high salt conditions, and quantitative RT-qPCR experiments confirmed that vacA transcription was upregulated in response to high salt conditions. These results indicate that environmental salt concentration influences the composition of the H. pylori exoproteome, which could contribute to the increased risk of gastric cancer associated with a high salt diet. SIGNIFICANCE: Helicobacter pylori-induced alterations in the gastric mucosa have been attributed, at least in part, to the actions of secreted H. pylori proteins. In this study, we show that H. pylori growth in high salt concentrations leads to increased levels of a secreted VacA toxin. Salt-induced alterations in the composition of the H. pylori exoproteome is relevant to the increased risk of gastric cancer associated with consumption of a high salt diet.
Published by Elsevier B.V.
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7 MeSH Terms
Quantitating excess tissue sodium.
Bhave G
(2019) Clin Sci (Lond) 133: 739-740
MeSH Terms: Biomarkers, Edema, Humans, Ions, Sodium
Show Abstract · Added March 3, 2020
Using changes in tissue [Na] concentration alone as done with Na MRI may not accurately quantitate excess tissue Na, particularly in cellular tissues. However, individually quantitating alterations in tissue Na and water content as possible with ashing studies may still accurately quantitate excess tissue Na in these situations. Furthermore, when tissue [Na] exceeds plasma [Na], excess tissue Na must be present.
© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.
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