Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 2944

Publication Record

Connections

Preparation, preliminary pharmacokinetic and brain targeting study of metformin encapsulated W/O/W composite submicron emulsions promoted by borneol.
Hong L, Li X, Bao Y, Duvall CL, Zhang C, Chen W, Peng C
(2019) Eur J Pharm Sci 133: 160-166
MeSH Terms: Animals, Bornanes, Brain, Drug Compounding, Drug Delivery Systems, Drug Liberation, Emulsions, Female, Hypoglycemic Agents, Male, Metformin, Rats, Sprague-Dawley
Show Abstract · Added April 10, 2019
Metformin hydrochloride (Met) is the first-line drug to treat type 2 diabetes and has shown high efficiency in reducing Alzheimer's disease in recent studies. Herein, a borneol W/O/W composite submicron emulsion containing Met (B-Met-W/O/W SE) was prepared, expecting longer in-vivo circulation time, better bioavailability and brain targeting of Met drug. In the optimized formulation, the mean droplets size, polydispersity index and encapsulation efficiency of the composite were 386.5 nm, 0.219 and 87.26%, respectively. FTIR analysis confirmed that Met interacted with carriers in B-Met-W/O/W SE. Compared with Met free drug, in-vitro release of Met in B-Met-W/O/W SE delivery system was much slower. In pharmacokinetic studies in rats, the AUC, MRT and t of the B-Met-W/O/W SE system were respectively 1.27, 2.49 and 4.02-fold higher than Met free drug system. The drug-targeting index of B-Met-W/O/W SE system to the brain tissue was also higher than that of Met free drug system and Met-W/O/W SE system. These results indicated that B-Met-W/O/W SE drug delivery system is a promising candidate in treating clinical Alzheimer's disease.
Copyright © 2019 Elsevier B.V. All rights reserved.
0 Communities
1 Members
0 Resources
12 MeSH Terms
Glutamate-oxaloacetate transaminase activity promotes palmitate lipotoxicity in rat hepatocytes by enhancing anaplerosis and citric acid cycle flux.
Egnatchik RA, Leamy AK, Sacco SA, Cheah YE, Shiota M, Young JD
(2019) J Biol Chem 294: 3081-3090
MeSH Terms: Animals, Aspartate Aminotransferases, Cell Death, Cell Line, Citric Acid Cycle, Extracellular Space, Glutamine, Hepatocytes, Ketoglutaric Acids, Male, Oxidative Stress, Oxygen, Palmitates, Rats, Rats, Sprague-Dawley
Show Abstract · Added March 28, 2019
Hepatocyte lipotoxicity is characterized by aberrant mitochondrial metabolism, which predisposes cells to oxidative stress and apoptosis. Previously, we reported that translocation of calcium from the endoplasmic reticulum to mitochondria of palmitate-treated hepatocytes activates anaplerotic flux from glutamine to α-ketoglutarate (αKG), which subsequently enters the citric acid cycle (CAC) for oxidation. We hypothesized that increased glutamine anaplerosis fuels elevations in CAC flux and oxidative stress following palmitate treatment. To test this hypothesis, primary rat hepatocytes or immortalized H4IIEC3 rat hepatoma cells were treated with lipotoxic levels of palmitate while modulating anaplerotic pathways leading to αKG. We found that culture media supplemented with glutamine, glutamate, or dimethyl-αKG increased palmitate lipotoxicity compared with media that lacked these anaplerotic substrates. Knockdown of glutamate-oxaloacetate transaminase activity significantly reduced the lipotoxic effects of palmitate, whereas knockdown of glutamate dehydrogenase (Glud1) had no effect on palmitate lipotoxicity. C flux analysis of H4IIEC3 cells co-treated with palmitate and the pan-transaminase inhibitor aminooxyacetic acid confirmed that reductions in lipotoxic markers were associated with decreases in anaplerosis, CAC flux, and oxygen consumption. Taken together, these results demonstrate that lipotoxic palmitate treatments enhance anaplerosis in cultured rat hepatocytes, causing a shift to aberrant transaminase metabolism that fuels CAC dysregulation and oxidative stress.
© 2019 Egnatchik et al.
0 Communities
1 Members
0 Resources
15 MeSH Terms
Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.
Shi CH, Rubel C, Soss SE, Sanchez-Hodge R, Zhang S, Madrigal SC, Ravi S, McDonough H, Page RC, Chazin WJ, Patterson C, Mao CY, Willis MS, Luo HY, Li YS, Stevens DA, Tang MB, Du P, Wang YH, Hu ZW, Xu YM, Schisler JC
(2018) PLoS Genet 14: e1007664
MeSH Terms: Animals, Behavior, Animal, CRISPR-Cas Systems, Cognition, Disease Models, Animal, Female, Humans, Male, Mice, Mice, Inbred C57BL, Models, Molecular, Motor Activity, Mutagenesis, Site-Directed, Phenotype, Point Mutation, Protein Domains, Protein Multimerization, Rats, Rats, Sprague-Dawley, Spinocerebellar Ataxias, Ubiquitin-Protein Ligases
Show Abstract · Added March 26, 2019
CHIP (carboxyl terminus of heat shock 70-interacting protein) has long been recognized as an active member of the cellular protein quality control system given the ability of CHIP to function as both a co-chaperone and ubiquitin ligase. We discovered a genetic disease, now known as spinocerebellar autosomal recessive 16 (SCAR16), resulting from a coding mutation that caused a loss of CHIP ubiquitin ligase function. The initial mutation describing SCAR16 was a missense mutation in the ubiquitin ligase domain of CHIP (p.T246M). Using multiple biophysical and cellular approaches, we demonstrated that T246M mutation results in structural disorganization and misfolding of the CHIP U-box domain, promoting oligomerization, and increased proteasome-dependent turnover. CHIP-T246M has no ligase activity, but maintains interactions with chaperones and chaperone-related functions. To establish preclinical models of SCAR16, we engineered T246M at the endogenous locus in both mice and rats. Animals homozygous for T246M had both cognitive and motor cerebellar dysfunction distinct from those observed in the CHIP null animal model, as well as deficits in learning and memory, reflective of the cognitive deficits reported in SCAR16 patients. We conclude that the T246M mutation is not equivalent to the total loss of CHIP, supporting the concept that disease-causing CHIP mutations have different biophysical and functional repercussions on CHIP function that may directly correlate to the spectrum of clinical phenotypes observed in SCAR16 patients. Our findings both further expand our basic understanding of CHIP biology and provide meaningful mechanistic insight underlying the molecular drivers of SCAR16 disease pathology, which may be used to inform the development of novel therapeutics for this devastating disease.
0 Communities
1 Members
0 Resources
MeSH Terms
Nanotechnology Enabled Modulation of Signaling Pathways Affects Physiologic Responses in Intact Vascular Tissue.
Hocking KM, Evans BC, Komalavilas P, Cheung-Flynn J, Duvall CL, Brophy CM
(2019) Tissue Eng Part A 25: 416-426
MeSH Terms: Actin Cytoskeleton, Actins, Animals, Blood Vessels, Calcium, Gene Silencing, Heat-Shock Proteins, Humans, Micelles, Muscle Contraction, Muscle, Smooth, Nanoparticles, Nanotechnology, Peptides, Polymerization, RNA, Small Interfering, Rats, Signal Transduction, Static Electricity
Show Abstract · Added April 10, 2019
IMPACT STATEMENT - Subarachnoid hemorrhage (SAH) is associated with vasospasm that is refractory to traditional vasodilators, and inhibition of vasospasm after SAH remains a large unmet clinical need. SAH causes changes in the phosphorylation state of the small heat shock proteins (HSPs), HSP20 and HSP27, in the vasospastic vessels. In this study, the levels of HSP27 and HSP20 were manipulated using nanotechnology to mimic the intracellular phenotype of SAH-induced vasospasm, and the effect of this manipulation was tested on vasomotor responses in intact tissues. This work provides insight into potential therapeutic targets for the development of more effective treatments for SAH induced vasospasm.
0 Communities
1 Members
0 Resources
19 MeSH Terms
Retrograde Degenerative Signaling Mediated by the p75 Neurotrophin Receptor Requires p150 Deacetylation by Axonal HDAC1.
Pathak A, Stanley EM, Hickman FE, Wallace N, Brewer B, Li D, Gluska S, Perlson E, Fuhrmann S, Akassoglou K, Bronfman F, Casaccia P, Burnette DT, Carter BD
(2018) Dev Cell 46: 376-387.e7
MeSH Terms: Animals, Axonal Transport, Axons, Dynactin Complex, Histone Deacetylase 1, Microtubule-Associated Proteins, Neurons, Rats, Sprague-Dawley, Receptor, Nerve Growth Factor
Show Abstract · Added March 27, 2019
During development, neurons undergo apoptosis if they do not receive adequate trophic support from tissues they innervate or when detrimental factors activate the p75 neurotrophin receptor (p75NTR) at their axon ends. Trophic factor deprivation (TFD) or activation of p75NTR in distal axons results in a retrograde degenerative signal. However, the nature of this signal and the regulation of its transport are poorly understood. Here, we identify p75NTR intracellular domain (ICD) and histone deacetylase 1 (HDAC1) as part of a retrograde pro-apoptotic signal generated in response to TFD or ligand binding to p75NTR in sympathetic neurons. We report an unconventional function of HDAC1 in retrograde transport of a degenerative signal and its constitutive presence in sympathetic axons. HDAC1 deacetylates dynactin subunit p150, which enhances its interaction with dynein. These findings define p75NTR ICD as a retrograde degenerative signal and reveal p150 deacetylation as a unique mechanism regulating axonal transport.
Copyright © 2018 Elsevier Inc. All rights reserved.
0 Communities
2 Members
0 Resources
MeSH Terms
Discovery, Characterization, and Effects on Renal Fluid and Electrolyte Excretion of the Kir4.1 Potassium Channel Pore Blocker, VU0134992.
Kharade SV, Kurata H, Bender AM, Blobaum AL, Figueroa EE, Duran A, Kramer M, Days E, Vinson P, Flores D, Satlin LM, Meiler J, Weaver CD, Lindsley CW, Hopkins CR, Denton JS
(2018) Mol Pharmacol 94: 926-937
MeSH Terms: Animals, Binding Sites, Diuretics, Electrolytes, HEK293 Cells, Humans, Male, Models, Molecular, Molecular Docking Simulation, Molecular Structure, Mutagenesis, Site-Directed, Potassium Channels, Inwardly Rectifying, Rats, Small Molecule Libraries, Substrate Specificity
Show Abstract · Added April 10, 2019
The inward rectifier potassium (Kir) channel Kir4.1 () carries out important physiologic roles in epithelial cells of the kidney, astrocytes in the central nervous system, and stria vascularis of the inner ear. Loss-of-function mutations in lead to EAST/SeSAME syndrome, which is characterized by epilepsy, ataxia, renal salt wasting, and sensorineural deafness. Although genetic approaches have been indispensable for establishing the importance of Kir4.1 in the normal function of these tissues, the availability of pharmacological tools for acutely manipulating the activity of Kir4.1 in genetically normal animals has been lacking. We therefore carried out a high-throughput screen of 76,575 compounds from the Vanderbilt Institute of Chemical Biology library for small-molecule modulators of Kir4.1. The most potent inhibitor identified was 2-(2-bromo-4-isopropylphenoxy)--(2,2,6,6-tetramethylpiperidin-4-yl)acetamide (VU0134992). In whole-cell patch-clamp electrophysiology experiments, VU0134992 inhibits Kir4.1 with an IC value of 0.97 M and is 9-fold selective for homomeric Kir4.1 over Kir4.1/5.1 concatemeric channels (IC = 9 M) at -120 mV. In thallium (Tl) flux assays, VU0134992 is greater than 30-fold selective for Kir4.1 over Kir1.1, Kir2.1, and Kir2.2; is weakly active toward Kir2.3, Kir6.2/SUR1, and Kir7.1; and is equally active toward Kir3.1/3.2, Kir3.1/3.4, and Kir4.2. This potency and selectivity profile is superior to Kir4.1 inhibitors amitriptyline, nortriptyline, and fluoxetine. Medicinal chemistry identified components of VU0134992 that are critical for inhibiting Kir4.1. Patch-clamp electrophysiology, molecular modeling, and site-directed mutagenesis identified pore-lining glutamate 158 and isoleucine 159 as critical residues for block of the channel. VU0134992 displayed a large free unbound fraction () in rat plasma ( = 0.213). Consistent with the known role of Kir4.1 in renal function, oral dosing of VU0134992 led to a dose-dependent diuresis, natriuresis, and kaliuresis in rats. Thus, VU0134992 represents the first in vivo active tool compound for probing the therapeutic potential of Kir4.1 as a novel diuretic target for the treatment of hypertension.
Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.
0 Communities
1 Members
0 Resources
MeSH Terms
Brief exposure to obesogenic diet disrupts brain dopamine networks.
Barry RL, Byun NE, Williams JM, Siuta MA, Tantawy MN, Speed NK, Saunders C, Galli A, Niswender KD, Avison MJ
(2018) PLoS One 13: e0191299
MeSH Terms: Amphetamine, Animals, Brain, Diet, High-Fat, Dopamine, Insulin, Male, Neostriatum, Nerve Net, Obesity, Rats, Rats, Sprague-Dawley, Receptors, Dopamine D2, Signal Transduction, Time Factors
Show Abstract · Added April 11, 2019
OBJECTIVE - We have previously demonstrated that insulin signaling, through the downstream signaling kinase Akt, is a potent modulator of dopamine transporter (DAT) activity, which fine-tunes dopamine (DA) signaling at the synapse. This suggests a mechanism by which impaired neuronal insulin receptor signaling, a hallmark of diet-induced obesity, may contribute to impaired DA transmission. We tested whether a short-term (two-week) obesogenic high-fat (HF) diet could reduce striatal Akt activity, a marker of central insulin, receptor signaling and blunt striatal and dopaminergic network responsiveness to amphetamine (AMPH).
METHODS - We examined the effects of a two-week HF diet on striatal DAT activity in rats, using AMPH as a probe in a functional magnetic resonance imaging (fMRI) assay, and mapped the disruption in AMPH-evoked functional connectivity between key dopaminergic targets and their projection areas using correlation and permutation analyses. We used phosphorylation of the Akt substrate GSK3α in striatal extracts as a measure of insulin receptor signaling. Finally, we confirmed the impact of HF diet on striatal DA D2 receptor (D2R) availability using [18F]fallypride positron emission tomography (PET).
RESULTS - We found that rats fed a HF diet for only two weeks have reductions in striatal Akt activity, a marker of decreased striatal insulin receptor signaling and blunted striatal responsiveness to AMPH. HF feeding also reduced interactions between elements of the mesolimbic (nucleus accumbens-anterior cingulate) and sensorimotor circuits (caudate/putamen-thalamus-sensorimotor cortex) implicated in hedonic feeding. D2R availability was reduced in HF-fed animals.
CONCLUSION - These studies support the hypothesis that central insulin signaling and dopaminergic neurotransmission are already altered after short-term HF feeding. Because AMPH induces DA efflux and brain activation, in large part via DAT, these findings suggest that blunted central nervous system insulin receptor signaling through a HF diet can impair DA homeostasis, thereby disrupting cognitive and reward circuitry involved in the regulation of hedonic feeding.
0 Communities
1 Members
0 Resources
MeSH Terms
Organization of afferents to the orbitofrontal cortex in the rat.
Murphy MJM, Deutch AY
(2018) J Comp Neurol 526: 1498-1526
MeSH Terms: Afferent Pathways, Animals, Basolateral Nuclear Complex, Biogenic Monoamines, Cholera Toxin, HEK293 Cells, Humans, Male, Mediodorsal Thalamic Nucleus, Mesencephalon, Prefrontal Cortex, Rats, Rats, Sprague-Dawley, Stilbamidines, Transfection, Tyrosine 3-Monooxygenase
Show Abstract · Added April 2, 2019
The prefrontal cortex (PFC) is usually defined as the frontal cortical area receiving a mediodorsal thalamic (MD) innervation. Certain areas in the medial wall of the rat frontal area receive a MD innervation. A second frontal area that is the target of MD projections is located dorsal to the rhinal sulcus and often referred to as the orbitofrontal cortex (OFC). Both the medial PFC and OFC are comprised of a large number of cytoarchitectonic regions. We assessed the afferent innervation of the different areas of the OFC, with a focus on projections arising from the mediodorsal thalamic nucleus, the basolateral nucleus of the amygdala, and the midbrain dopamine neurons. Although there are specific inputs to various OFC areas, a simplified organizational scheme could be defined, with the medial areas of the OFC receiving thalamic inputs, the lateral areas of the OFC being the recipient of amygdala afferents, and a central zone that was the target of midbrain dopamine neurons. Anterograde tracer data were consistent with this organization of afferents, and revealed that the OFC inputs from these three subcortical sites were largely spatially segregated. This spatial segregation suggests that the central portion of the OFC (pregenual agranular insular cortex) is the only OFC region that is a prefrontal cortical area, analogous to the prelimbic cortex in the medial prefrontal cortex. These findings highlight the heterogeneity of the OFC, and suggest possible functional attributes of the three different OFC areas.
© 2018 Wiley Periodicals, Inc.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Evaluation of the novel TSPO radiotracer 2-(7-butyl-2-(4-(2-([F]fluoroethoxy)phenyl)-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide in a preclinical model of neuroinflammation.
Tang D, Fujinaga M, Hatori A, Zhang Y, Yamasaki T, Xie L, Mori W, Kumata K, Liu J, Manning HC, Huang G, Zhang MR
(2018) Eur J Med Chem 150: 1-8
MeSH Terms: Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Fluorine Radioisotopes, Humans, Inflammation, Ischemia, Male, Mice, Molecular Probes, Molecular Structure, Positron-Emission Tomography, Pyrazoles, Pyrimidines, Radioactive Tracers, Radiopharmaceuticals, Rats, Rats, Sprague-Dawley, Receptors, GABA, Structure-Activity Relationship, Tissue Distribution
Show Abstract · Added March 22, 2018
Translocator Protein (18 kDa, TSPO) is regarded as a useful biomarker for neuroinflammation imaging. TSPO PET imaging could be used to understand the role of neuroinflammation in brain diseases and as a tool for evaluating novel therapeutic effects. As a promising TSPO probe, [F]DPA-714 is highly specific and offers reliable quantification of TSPO in vivo. In this study, we further radiosynthesized and evaluated another novel TSPO probe, 2-(7-butyl-2-(4-(2-[F]fluoroethoxy)phenyl)-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide ([F]VUIIS1018A), which features a 700-fold higher binding affinity for TSPO than that of [F]DPA-714. We evaluated the performance of [F]VUIIS1018A using dynamic in vivo PET imaging, radiometabolite analysis, in vitro autoradiography assays, biodistribution analysis, and blocking assays. In vivo study using this probe demonstrated high signal-to-noise ratio, binding potential (BP), and binding specificity in preclinical neuroinflammation studies. Taken together, these findings indicate that [F]VUIIS1018A may serve as a novel TSPO PET probe for neuroinflammation imaging.
Copyright © 2018. Published by Elsevier Masson SAS.
0 Communities
1 Members
0 Resources
21 MeSH Terms
Enhanced Ion Transmission Efficiency up to m/ z 24 000 for MALDI Protein Imaging Mass Spectrometry.
Prentice BM, Ryan DJ, Van de Plas R, Caprioli RM, Spraggins JM
(2018) Anal Chem 90: 5090-5099
MeSH Terms: Animals, Apoproteins, Brain, Ions, Kidney, Molecular Weight, Myoglobin, Proteins, Rats, Signal-To-Noise Ratio, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Ubiquitin
Show Abstract · Added March 22, 2018
The molecular identification of species of interest is an important part of an imaging mass spectrometry (IMS) experiment. The high resolution accurate mass capabilities of Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) have recently been shown to facilitate the identification of proteins in matrix-assisted laser desorption/ionization (MALDI) IMS. However, these experiments are typically limited to proteins giving rise to ions of relatively low m/ z due to difficulties transmitting and measuring large molecular weight ions of low charge states. Herein we have modified the source gas manifold of a commercial MALDI FT-ICR MS to regulate the gas flow and pressure to maximize the transmission of large m/ z protein ions through the ion funnel region of the instrument. By minimizing the contribution of off-axis gas disruption to ion focusing and maximizing the effective potential wall confining the ions through pressure optimization, the signal-to-noise ratios (S/N) of most protein species were improved by roughly 1 order of magnitude compared to normal source conditions. These modifications enabled the detection of protein standards up to m/ z 24 000 and the detection of proteins from tissue up to m/ z 22 000 with good S/N, roughly doubling the mass range for which high quality protein ion images from rat brain and kidney tissue could be produced. Due to the long time-domain transients (>4 s) required to isotopically resolve high m/ z proteins, we have used these data as part of an FT-ICR IMS-microscopy data-driven image fusion workflow to produce estimated protein images with both high mass and high spatial resolutions.
0 Communities
3 Members
0 Resources
12 MeSH Terms