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The glucagon-like peptide-1 receptor in the ventromedial hypothalamus reduces short-term food intake in male mice by regulating nutrient sensor activity.
Burmeister MA, Brown JD, Ayala JE, Stoffers DA, Sandoval DA, Seeley RJ, Ayala JE
(2017) Am J Physiol Endocrinol Metab 313: E651-E662
MeSH Terms: Acetyl-CoA Carboxylase, Adenylate Kinase, Animals, Body Composition, CHO Cells, Cricetulus, Dose-Response Relationship, Drug, Eating, Exenatide, Food, Glucagon-Like Peptide-1 Receptor, Glycolysis, Homeostasis, Male, Mice, Mice, Inbred C57BL, Peptides, Sensation, TOR Serine-Threonine Kinases, Venoms, Ventromedial Hypothalamic Nucleus
Show Abstract · Added October 23, 2017
Pharmacological activation of the glucagon-like peptide-1 receptor (GLP-1R) in the ventromedial hypothalamus (VMH) reduces food intake. Here, we assessed whether suppression of food intake by GLP-1R agonists (GLP-1RA) in this region is dependent on AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR). We found that pharmacological inhibition of glycolysis, and thus activation of AMPK, in the VMH attenuates the anorectic effect of the GLP-1R agonist exendin-4 (Ex4), indicating that glucose metabolism and inhibition of AMPK are both required for this effect. Furthermore, we found that Ex4-mediated anorexia in the VMH involved mTOR but not acetyl-CoA carboxylase, two downstream targets of AMPK. We support this by showing that Ex4 activates mTOR signaling in the VMH and Chinese hamster ovary (CHO)-K1 cells. In contrast to the clear acute pharmacological impact of the these receptors on food intake, knockdown of the VMH conferred no changes in energy balance in either chow- or high-fat-diet-fed mice, and the acute anorectic and glucose tolerance effects of peripherally dosed GLP-1RA were preserved. These results show that the VMH GLP-1R regulates food intake by engaging key nutrient sensors but is dispensable for the effects of GLP-1RA on nutrient homeostasis.
Copyright © 2017 the American Physiological Society.
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21 MeSH Terms
Defining the complex phenotype of severe systemic loxoscelism using a large electronic health record cohort.
Robinson JR, Kennedy VE, Doss Y, Bastarache L, Denny J, Warner JL
(2017) PLoS One 12: e0174941
MeSH Terms: Adolescent, Animals, Bilirubin, Brown Recluse Spider, Case-Control Studies, Child, Cross-Sectional Studies, Disseminated Intravascular Coagulation, Electronic Health Records, Female, Hemoglobins, Hemolysis, Humans, L-Lactate Dehydrogenase, Male, Phenotype, Retrospective Studies, Spider Bites, Spider Venoms, Survival Analysis, Young Adult
Show Abstract · Added November 8, 2017
OBJECTIVE - Systemic loxoscelism is a rare illness resulting from the bite of the recluse spider and, in its most severe form, can lead to widespread hemolysis, coagulopathy, and death. We aim to describe the clinical features and outcomes of the largest known cohort of individuals with moderate to severe loxoscelism.
METHODS - We performed a retrospective, cross sectional study from January 1, 1995, to December 31, 2015, at a tertiary-care academic medical center, to determine individuals with clinical records consistent with moderate to severe loxoscelism. Age-, sex-, and race-matched controls were compared. Demographics, clinical characteristics, laboratory measures, and outcomes of individuals with loxoscelism are described. Case and control groups were compared with descriptive statistics and phenome-wide association study (PheWAS).
RESULTS - During the time period, 57 individuals were identified as having moderate to severe loxoscelism. Of these, only 33% had an antecedent spider bite documented. Median age of individuals diagnosed with moderate to severe loxoscelism was 14 years old (IQR 9.0-24.0 years). PheWAS confirmed associations of systemic loxoscelism with 29 other phenotypes, e.g., rash, hemolytic anemia, and sepsis. Hemoglobin level dropped an average of 3.1 g/dL over an average of 2.0 days (IQR 2.0-6.0). Lactate dehydrogenase and total bilirubin levels were on average over two times their upper limit of normal values. Eighteen individuals of 32 tested had a positive direct antiglobulin (Coombs') test. Mortality was 3.5% (2/57 individuals).
CONCLUSION - Systemic loxoscelism is a rare but devastating process with only a minority of patients recalling the toxic exposure; hemolysis reaches a peak at 2 days after admission, with some cases taking more than a week before recovery. In endemic areas, suspicion for systemic loxoscelism should be high in individuals, especially children and younger adults, presenting with a cutaneous ulcer and hemolysis or coagulopathy, even in the absence of a bite exposure history.
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21 MeSH Terms
Toxins and pharmacologically active compounds from species of the family Bufonidae (Amphibia, Anura).
Rodríguez C, Rollins-Smith L, Ibáñez R, Durant-Archibold AA, Gutiérrez M
(2017) J Ethnopharmacol 198: 235-254
MeSH Terms: Amphibian Venoms, Animals, Biological Products, Bufonidae, Humans, Magnetic Resonance Spectroscopy, Mass Spectrometry, Medicine, Traditional, Species Specificity, Toxins, Biological
Show Abstract · Added April 18, 2017
ETHNOPHARMACOLOGICAL RELEVANCE - Among amphibians, 15 of the 47 species reported to be used in traditional medicines belong to the family Bufonidae, which demonstrates their potential in pharmacological and natural products research. For example, Asian and American tribes use the skin and the parotoid gland secretions of some common toads in the treatment of hemorrhages, bites and stings from venomous animals, skin and stomach disorders, as well as several types of cancers.
OVERARCHING OBJECTIVE - In addition to reviewing the occurrence of chemical constituents present in the family Bufonidae, the cytotoxic and biomedical potential of the active compounds produced by different taxa are presented.
METHODOLOGY - Available information on bioactive compounds isolated from species of the family Bufonidae was obtained from ACS Publications, Google, Google Scholar, Pubmed, Sciendirect and Springer. Papers written in Chinese, English, German and Spanish were considered.
RESULTS - Recent reports show more than 30% of amphibians are in decline and some of bufonid species are considered to be extinct. For centuries, bufonids have been used as traditional folk remedies to treat allergies, inflammation, cancer, infections and other ailments, highlighting their importance as a prolific source for novel drugs and therapies. Toxins and bioactive chemical constituents from skin and parotid gland secretions of bufonid species can be grouped in five families, the guanidine alkaloids isolated and characterized from Atelopus, the lipophilic alkaloids isolated from Melanophryniscus, the indole alkaloids and bufadienolides known to be synthesized by species of bufonids, and peptides and proteins isolated from the skin and gastrointestinal extracts of some common toads. Overall, the bioactive secretions of this family of anurans may have antimicrobial, protease inhibitor and anticancer properties, as well as being active at the neuromuscular level.
CONCLUSION - In this article, the traditional uses, toxicity and pharmacological potential of chemical compounds from bufonids have been summarized. In spite of being reported to be used to treat several diseases, neither extracts nor metabolites from bufonids have been tested in such illness like acne, osteoporosis, arthritis and other illnesses. However, the cytotoxicity of these metabolites needs to be evaluated on adequate animal models due to the limited conditions of in vitro assays. Novel qualitative and quantitative tools based on MS spectrometry and Nuclear Magnetic Resonance spectroscopy is now available to study the complex secretions of bufonids.
Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.
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10 MeSH Terms
The Hypothalamic Glucagon-Like Peptide 1 Receptor Is Sufficient but Not Necessary for the Regulation of Energy Balance and Glucose Homeostasis in Mice.
Burmeister MA, Ayala JE, Smouse H, Landivar-Rocha A, Brown JD, Drucker DJ, Stoffers DA, Sandoval DA, Seeley RJ, Ayala JE
(2017) Diabetes 66: 372-384
MeSH Terms: Animals, Body Composition, Diet, High-Fat, Eating, Energy Metabolism, Exenatide, Gene Knockdown Techniques, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Glucose, Glucose Tolerance Test, Homeostasis, Hypothalamus, Incretins, Liraglutide, Male, Mice, Neurons, Paraventricular Hypothalamic Nucleus, Peptides, Pro-Opiomelanocortin, Venoms, Weight Gain
Show Abstract · Added October 23, 2017
Pharmacological activation of the hypothalamic glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) promotes weight loss and improves glucose tolerance. This demonstrates that the hypothalamic GLP-1R is sufficient but does not show whether it is necessary for the effects of exogenous GLP-1R agonists (GLP-1RA) or endogenous GLP-1 on these parameters. To address this, we crossed mice harboring floxed Glp1r alleles to mice expressing Nkx2.1-Cre to knock down Glp1r expression throughout the hypothalamus (GLP-1RKD). We also generated mice lacking Glp1r expression specifically in two GLP-1RA-responsive hypothalamic feeding nuclei/cell types, the paraventricular nucleus (GLP-1RKD) and proopiomelanocortin neurons (GLP-1RKD). Chow-fed GLP-1RKD mice exhibited increased food intake and energy expenditure with no net effect on body weight. When fed a high-fat diet, these mice exhibited normal food intake but elevated energy expenditure, yielding reduced weight gain. None of these phenotypes were observed in GLP-1RKD and GLP-1RKD mice. The acute anorectic and glucose tolerance effects of peripherally dosed GLP-1RA exendin-4 and liraglutide were preserved in all mouse lines. Chronic liraglutide treatment reduced body weight in chow-fed GLP-1RKD mice, but this effect was attenuated with high-fat diet feeding. In sum, classic homeostatic control regions are sufficient but not individually necessary for the effects of GLP-1RA on nutrient homeostasis.
© 2017 by the American Diabetes Association.
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23 MeSH Terms
Development of a reliable automated screening system to identify small molecules and biologics that promote human β-cell regeneration.
Aamodt KI, Aramandla R, Brown JJ, Fiaschi-Taesch N, Wang P, Stewart AF, Brissova M, Powers AC
(2016) Am J Physiol Endocrinol Metab 311: E859-E868
MeSH Terms: Activins, Adenosine, Adenosine A2 Receptor Agonists, Adenosine-5'-(N-ethylcarboxamide), Adult, Automation, Cell Culture Techniques, Cell Proliferation, Drug Evaluation, Preclinical, Erythropoietin, Exenatide, Female, GABA Agents, Harmine, Humans, Incretins, Insulin-Secreting Cells, Male, Middle Aged, Monoamine Oxidase Inhibitors, Myostatin, Nucleosides, Peptides, Platelet-Derived Growth Factor, Prolactin, Regeneration, Serotonin, Serotonin Receptor Agonists, Vasodilator Agents, Venoms, Young Adult, gamma-Aminobutyric Acid
Show Abstract · Added April 26, 2017
Numerous compounds stimulate rodent β-cell proliferation; however, translating these findings to human β-cells remains a challenge. To examine human β-cell proliferation in response to such compounds, we developed a medium-throughput in vitro method of quantifying adult human β-cell proliferation markers. This method is based on high-content imaging of dispersed islet cells seeded in 384-well plates and automated cell counting that identifies fluorescently labeled β-cells with high specificity using both nuclear and cytoplasmic markers. β-Cells from each donor were assessed for their function and ability to enter the cell cycle by cotransduction with adenoviruses encoding cell cycle regulators cdk6 and cyclin D3. Using this approach, we tested 12 previously identified mitogens, including neurotransmitters, hormones, growth factors, and molecules, involved in adenosine and Tgf-1β signaling. Each compound was tested in a wide concentration range either in the presence of basal (5 mM) or high (11 mM) glucose. Treatment with the control compound harmine, a Dyrk1a inhibitor, led to a significant increase in Ki-67 β-cells, whereas treatment with other compounds had limited to no effect on human β-cell proliferation. This new scalable approach reduces the time and effort required for sensitive and specific evaluation of human β-cell proliferation, thus allowing for increased testing of candidate human β-cell mitogens.
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32 MeSH Terms
Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels.
Reddy IA, Pino JA, Weikop P, Osses N, Sørensen G, Bering T, Valle C, Bluett RJ, Erreger K, Wortwein G, Reyes JG, Graham D, Stanwood GD, Hackett TA, Patel S, Fink-Jensen A, Torres GE, Galli A
(2016) Transl Psychiatry 6: e809
MeSH Terms: Animals, Arachidonic Acid, Arachidonic Acids, Cocaine, Dopamine, Dopamine Plasma Membrane Transport Proteins, Dopamine Uptake Inhibitors, Endocannabinoids, Exenatide, Glucagon-Like Peptide-1 Receptor, Glycerides, Homeostasis, Incretins, Mice, Microdialysis, Peptides, Proto-Oncogene Proteins c-fos, Septal Nuclei, Venoms
Show Abstract · Added April 6, 2017
Agonism of the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) has been effective at treating aspects of addictive behavior for a number of abused substances, including cocaine. However, the molecular mechanisms and brain circuits underlying the therapeutic effects of GLP-1R signaling on cocaine actions remain elusive. Recent evidence has revealed that endogenous signaling at the GLP-1R within the forebrain lateral septum (LS) acts to reduce cocaine-induced locomotion and cocaine conditioned place preference, both considered dopamine (DA)-associated behaviors. DA terminals project from the ventral tegmental area to the LS and express the DA transporter (DAT). Cocaine acts by altering DA bioavailability by targeting the DAT. Therefore, GLP-1R signaling might exert effects on DAT to account for its regulation of cocaine-induced behaviors. We show that the GLP-1R is highly expressed within the LS. GLP-1, in LS slices, significantly enhances DAT surface expression and DAT function. Exenatide (Ex-4), a long-lasting synthetic analog of GLP-1 abolished cocaine-induced elevation of DA. Interestingly, acute administration of Ex-4 reduces septal expression of the retrograde messenger 2-arachidonylglycerol (2-AG), as well as a product of its presynaptic degradation, arachidonic acid (AA). Notably, AA reduces septal DAT function pointing to AA as a novel regulator of central DA homeostasis. We further show that AA oxidation product γ-ketoaldehyde (γ-KA) forms adducts with the DAT and reduces DAT plasma membrane expression and function. These results support a mechanism in which postsynaptic septal GLP-1R activation regulates 2-AG levels to alter presynaptic DA homeostasis and cocaine actions through AA.
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19 MeSH Terms
Opposing roles of LTB4 and PGE2 in regulating the inflammasome-dependent scorpion venom-induced mortality.
Zoccal KF, Sorgi CA, Hori JI, Paula-Silva FW, Arantes EC, Serezani CH, Zamboni DS, Faccioli LH
(2016) Nat Commun 7: 10760
MeSH Terms: Animals, Arachidonate 5-Lipoxygenase, Blotting, Western, Carrier Proteins, Celecoxib, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Cyclooxygenase Inhibitors, Dinoprostone, In Vitro Techniques, Indoles, Indomethacin, Inflammasomes, Interleukin-1beta, Leukotriene B4, Lipoxygenase Inhibitors, Macrophages, Macrophages, Peritoneal, Mice, Mice, Knockout, NF-kappa B, NLR Family, Pyrin Domain-Containing 3 Protein, Phosphoproteins, Prostaglandin Antagonists, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Prostaglandin E, EP4 Subtype, Reverse Transcriptase Polymerase Chain Reaction, Scorpion Stings, Scorpion Venoms, Scorpions, Xanthones
Show Abstract · Added May 4, 2017
Tityus serrulatus sting causes thousands of deaths annually worldwide. T. serrulatus-envenomed victims exhibit local or systemic reaction that culminates in pulmonary oedema, potentially leading to death. However, the molecular mechanisms underlying T. serrulatus venom (TsV) activity remain unknown. Here we show that TsV triggers NLRP3 inflammasome activation via K(+) efflux. Mechanistically, TsV triggers lung-resident cells to release PGE2, which induces IL-1β production via E prostanoid receptor 2/4-cAMP-PKA-NFκB-dependent mechanisms. IL-1β/IL-1R actions account for oedema and neutrophil recruitment to the lungs, leading to TsV-induced mortality. Inflammasome activation triggers LTB4 production and further PGE2 via IL-1β/IL-1R signalling. Activation of LTB4-BLT1/2 pathway decreases cAMP generation, controlling TsV-induced inflammation. Exogenous administration confirms LTB4 anti-inflammatory activity and abrogates TsV-induced mortality. These results suggest that the balance between LTB4 and PGE2 determines the amount of IL-1β inflammasome-dependent release and the outcome of envenomation. We suggest COX1/2 inhibition as an effective therapeutic intervention for scorpion envenomation.
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31 MeSH Terms
Differential CaMKII regulation by voltage-gated calcium channels in the striatum.
Pasek JG, Wang X, Colbran RJ
(2015) Mol Cell Neurosci 68: 234-43
MeSH Terms: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester, Animals, Calcium, Calcium Channel Agonists, Calcium Channel Blockers, Calcium Channels, L-Type, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Chelating Agents, Corpus Striatum, Egtazic Acid, Enzyme Inhibitors, Gene Expression Regulation, In Vitro Techniques, Male, Mice, Mice, Inbred C57BL, Pyrroles, Receptors, Glutamate, Signal Transduction, Spider Venoms
Show Abstract · Added February 15, 2016
Calcium signaling regulates synaptic plasticity and many other functions in striatal medium spiny neurons to modulate basal ganglia function. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a major calcium-dependent signaling protein that couples calcium entry to diverse cellular changes. CaMKII activation results in autophosphorylation at Thr286 and sustained calcium-independent CaMKII activity after calcium signals dissipate. However, little is known about the mechanisms regulating striatal CaMKII. To address this, mouse brain slices were treated with pharmacological modulators of calcium channels and punches of dorsal striatum were immunoblotted for CaMKII Thr286 autophosphorylation as an index of CaMKII activation. KCl depolarization increased levels of CaMKII autophosphorylation ~2-fold; this increase was blocked by an LTCC antagonist and was mimicked by treatment with pharmacological LTCC activators. The chelation of extracellular calcium robustly decreased basal CaMKII autophosphorylation within 5min and increased levels of total CaMKII in cytosolic fractions, in addition to decreasing the phosphorylation of CaMKII sites in the GluN2B subunit of NMDA receptors and the GluA1 subunit of AMPA receptors. We also found that the maintenance of basal levels of CaMKII autophosphorylation requires low-voltage gated T-type calcium channels, but not LTCCs or R-type calcium channels. Our findings indicate that CaMKII activity is dynamically regulated by multiple calcium channels in the striatum thus coupling calcium entry to key downstream substrates.
Copyright © 2015 Elsevier Inc. All rights reserved.
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20 MeSH Terms
Bee venom stirs up buzz in antigen presentation.
Van Kaer L
(2015) J Exp Med 212: 126
MeSH Terms: Animals, Antigen Presentation, Antigens, CD1, Bee Venoms, Humans, Lipids, Skin
Added September 28, 2015
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7 MeSH Terms
Discovery of (S)-2-cyclopentyl-N-((1-isopropylpyrrolidin2-yl)-9-methyl-1-oxo-2,9-dihydro-1H-pyrrido[3,4-b]indole-4-carboxamide (VU0453379): a novel, CNS penetrant glucagon-like peptide 1 receptor (GLP-1R) positive allosteric modulator (PAM).
Morris LC, Nance KD, Gentry PR, Days EL, Weaver CD, Niswender CM, Thompson AD, Jones CK, Locuson CW, Morrison RD, Daniels JS, Niswender KD, Lindsley CW
(2014) J Med Chem 57: 10192-7
MeSH Terms: Allosteric Regulation, Animals, Catalepsy, Central Nervous System Agents, Drug Synergism, Exenatide, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Haloperidol, High-Throughput Screening Assays, Indoles, Insulin, Insulin Secretion, Islets of Langerhans, Male, Mice, Inbred C57BL, Microsomes, Liver, Peptides, Pyrrolidines, Receptors, Glucagon, Structure-Activity Relationship, Venoms
Show Abstract · Added February 16, 2015
A duplexed, functional multiaddition high throughput screen and subsequent iterative parallel synthesis effort identified the first highly selective and CNS penetrant glucagon-like peptide-1R (GLP-1R) positive allosteric modulator (PAM). PAM (S)-9b potentiated low-dose exenatide to augment insulin secretion in primary mouse pancreatic islets, and (S)-9b alone was effective in potentiating endogenous GLP-1R to reverse haloperidol-induced catalepsy.
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22 MeSH Terms