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Publication Record


Perfusion controls muscle glucose uptake by altering the rate of glucose dispersion in vivo.
McClatchey PM, Williams IM, Xu Z, Mignemi NA, Hughey CC, McGuinness OP, Beckman JA, Wasserman DH
(2019) Am J Physiol Endocrinol Metab 317: E1022-E1036
MeSH Terms: 4-Chloro-7-nitrobenzofurazan, Animals, Blood Flow Velocity, Carbon Radioisotopes, Deoxyglucose, Dextrans, Glucose, Hypoglycemic Agents, Insulin, Intravital Microscopy, Mice, Microcirculation, Microspheres, Muscle, Skeletal, Ultrasonography
Show Abstract · Added March 30, 2020
These studies test, using intravital microscopy (IVM), the hypotheses that perfusion effects on insulin-stimulated muscle glucose uptake (MGU) are ) capillary recruitment independent and ) mediated through the dispersion of glucose rather than insulin. For , capillary perfusion was visualized before and after intravenous insulin. No capillary recruitment was observed. For , mice were treated with vasoactive compounds (sodium nitroprusside, hyaluronidase, and lipopolysaccharide), and dispersion of fluorophores approximating insulin size (10-kDa dextran) and glucose (2-NBDG) was measured using IVM. Subsequently, insulin and 2[C]deoxyglucose were injected and muscle phospho-2[C]deoxyglucose (2[C]DG) accumulation was used as an index of MGU. Flow velocity and 2-NBDG dispersion, but not perfused surface area or 10-kDa dextran dispersion, predicted phospho-2[C]DG accumulation. For , microspheres of the same size and number as are used for contrast-enhanced ultrasound (CEU) studies of capillary recruitment were visualized using IVM. Due to their low concentration, microspheres were present in only a small fraction of blood-perfused capillaries. Microsphere-perfused blood volume correlated to flow velocity. These findings suggest that ) flow velocity rather than capillary recruitment controls microvascular contributions to MGU, ) glucose dispersion is more predictive of MGU than dispersion of insulin-sized molecules, and ) CEU measures regional flow velocity rather than capillary recruitment.
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15 MeSH Terms
Utility of [F]FSPG PET to Image Hepatocellular Carcinoma: First Clinical Evaluation in a US Population.
Kavanaugh G, Williams J, Morris AS, Nickels ML, Walker R, Koglin N, Stephens AW, Washington MK, Geevarghese SK, Liu Q, Ayers D, Shyr Y, Manning HC
(2016) Mol Imaging Biol 18: 924-934
MeSH Terms: Acetates, Adult, Aged, Amino Acid Transport System y+, Carbon Radioisotopes, Carcinoma, Hepatocellular, Female, Glutamates, Glutamic Acid, Humans, Liver Neoplasms, Male, Middle Aged, Positron-Emission Tomography, Radiopharmaceuticals, Sequence Analysis, RNA, Tissue Array Analysis
Show Abstract · Added April 6, 2017
PURPOSE - Non-invasive imaging is central to hepatocellular carcinoma (HCC) diagnosis; however, conventional modalities are limited by smaller tumors and other chronic diseases that are often present in patients with HCC, such as cirrhosis. This pilot study evaluated the feasibility of (4S)-4-(3-[F]fluoropropyl)-L-glutamic acid ([F]FSPG) positron emission tomography (PET)/X-ray computed tomography (CT) to image HCC. [F]FSPG PET/CT was compared to standard-of-care (SOC) magnetic resonance imaging (MRI) and CT, and [C]acetate PET/CT, commonly used in this setting. We report the largest cohort of HCC patients imaged to date with [F]FSPG PET/CT and present the first comparison to [C]acetate PET/CT and SOC imaging. This study represents the first in a US HCC population, which is distinguished by different underlying comorbidities than non-US populations.
PROCEDURES - x transporter RNA and protein levels were evaluated in HCC and matched liver samples from The Cancer Genome Atlas (n = 16) and a tissue microarray (n = 83). Eleven HCC patients who underwent prior MRI or CT scans were imaged by [F]FSPG PET/CT, with seven patients also imaged with [C]acetate PET/CT.
RESULTS - x transporter RNA and protein levels were elevated in HCC samples compared to background liver. Over 50 % of low-grade HCCs and ~70 % of high-grade tumors exceeded background liver protein expression. [F]FSPG PET/CT demonstrated a detection rate of 75 %. [F]FSPG PET/CT also identified an HCC devoid of typical MRI enhancement pattern. Patients scanned with [F]FSPG and [C]acetate PET/CT exhibited a 90 and 70 % detection rate, respectively. In dually positive tumors, [F]FSPG accumulation consistently resulted in significantly greater tumor-to-liver background ratios compared with [C]acetate PET/CT.
CONCLUSIONS - [F]FSPG PET/CT is a promising modality for HCC imaging, and larger studies are warranted to examine [F]FSPG PET/CT impact on diagnosis and management of HCC. [F]FSPG PET/CT may also be useful for phenotyping HCC tumor metabolism as part of precision cancer medicine.
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17 MeSH Terms
Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents.
Scarlett JM, Rojas JM, Matsen ME, Kaiyala KJ, Stefanovski D, Bergman RN, Nguyen HT, Dorfman MD, Lantier L, Wasserman DH, Mirzadeh Z, Unterman TG, Morton GJ, Schwartz MW
(2016) Nat Med 22: 800-6
MeSH Terms: Adipose Tissue, Animals, Blood Glucose, Blotting, Western, Body Composition, Brain, Carbon Radioisotopes, Deoxyglucose, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Diet, High-Fat, Disease Models, Animal, Ependymoglial Cells, Fibroblast Growth Factor 1, Forkhead Box Protein O1, Glucose Tolerance Test, Heart, Heat-Shock Proteins, Hyperglycemia, Hypothalamus, Injections, Intraventricular, Liver, Male, Mice, Mice, Knockout, Mice, Obese, Molecular Chaperones, Muscle, Skeletal, Myocardium, Neoplasm Proteins, Proto-Oncogene Proteins c-fos, Rats, Rats, Zucker, Real-Time Polymerase Chain Reaction, Receptor, Insulin, Remission Induction
Show Abstract · Added May 16, 2019
Type 2 diabetes (T2D) is among the most common and costly disorders worldwide. The goal of current medical management for T2D is to transiently ameliorate hyperglycemia through daily dosing of one or more antidiabetic drugs. Hypoglycemia and weight gain are common side effects of therapy, and sustained disease remission is not obtainable with nonsurgical approaches. On the basis of the potent glucose-lowering response elicited by activation of brain fibroblast growth factor (FGF) receptors, we explored the antidiabetic efficacy of centrally administered FGF1, which, unlike other FGF peptides, activates all FGF receptor subtypes. We report that a single intracerebroventricular injection of FGF1 at a dose one-tenth of that needed for antidiabetic efficacy following peripheral injection induces sustained diabetes remission in both mouse and rat models of T2D. This antidiabetic effect is not secondary to weight loss, does not increase the risk of hypoglycemia, and involves a novel and incompletely understood mechanism for increasing glucose clearance from the bloodstream. We conclude that the brain has an inherent potential to induce diabetes remission and that brain FGF receptors are potential pharmacological targets for achieving this goal.
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36 MeSH Terms
Relationship between impulsivity, prefrontal anticipatory activation, and striatal dopamine release during rewarded task performance.
Weiland BJ, Heitzeg MM, Zald D, Cummiford C, Love T, Zucker RA, Zubieta JK
(2014) Psychiatry Res 223: 244-52
MeSH Terms: Adult, Anticipation, Psychological, Carbon Radioisotopes, Corpus Striatum, Dopamine, Dopamine Antagonists, Female, Humans, Impulsive Behavior, Income, Magnetic Resonance Imaging, Middle Aged, Neostriatum, Nucleus Accumbens, Positron-Emission Tomography, Prefrontal Cortex, Raclopride, Receptors, Dopamine D2, Receptors, Dopamine D3, Reward, Task Performance and Analysis
Show Abstract · Added April 6, 2017
Impulsivity, and in particular the negative urgency aspect of this trait, is associated with poor inhibitory control when experiencing negative emotion. Individual differences in aspects of impulsivity have been correlated with striatal dopamine D2/D3 receptor availability and function. This multi-modal pilot study used both positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to evaluate dopaminergic and neural activity, respectively, using modified versions of the monetary incentive delay task. Twelve healthy female subjects underwent both scans and completed the NEO Personality Inventory Revised to assess Impulsiveness (IMP). We examined the relationship between nucleus accumbens (NAcc) dopaminergic incentive/reward release, measured as a change in D2/D3 binding potential between neutral and incentive/reward conditions with [(11)C]raclopride PET, and blood oxygen level-dependent (BOLD) activation elicited during the anticipation of rewards, measured with fMRI. Left NAcc incentive/reward dopaminergic release correlated with anticipatory reward activation within the medial prefrontal cortex (mPFC), left angular gyrus, mammillary bodies, and left superior frontal cortex. Activation in the mPFC negatively correlated with IMP and mediated the relationship between IMP and incentive/reward dopaminergic release in left NAcc. The mPFC, with a regulatory role in learning and valuation, may influence dopamine incentive/reward release.
Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
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21 MeSH Terms
Sub-second proton imaging of 13C hyperpolarized contrast agents in water.
Truong ML, Coffey AM, Shchepin RV, Waddell KW, Chekmenev EY
(2014) Contrast Media Mol Imaging 9: 333-41
MeSH Terms: Carbon Radioisotopes, Contrast Media, Humans, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Phantoms, Imaging, Protons, Water
Show Abstract · Added June 10, 2014
Indirect proton detection of (13)C hyperpolarized contrast agents potentially enables greater sensitivity. Presented here is a study of sub-second projection imaging of hyperpolarized (13)C contrast agent addressing the obstacle posed by water suppression for indirect detection in vivo. Sodium acetate phantoms were used to develop and test water suppression and sub-second imaging with frequency-selective RF pulses using spectroscopic and imaging indirect proton detection. A 9.8 mm aqueous solution of (13)C PHIP hyperpolarized 2-hydroxyethyl-(13)C-propionate-d2,3,3 (HEP),

 ~25% was used for demonstration of indirect proton sub-second imaging detection. Balanced 2D FSSFP (fast steady-state free precession) allowed the recording of proton images with a field of view of 64 × 64 mm(2) and spatial resolution 2 × 2 mm(2) with total acquisition time of less than 0.2 s. In thermally polarized sodium 1-(13)C-acetate, (13) C to (1)H polarization transfer efficiency of 45.1% of the theoretically predicted values was observed in imaging detection corresponding to an 11-fold overall sensitivity improvement compared with direct (13)C FSSFP imaging. (13)C to (1)H polarization transfer efficiency of 27% was observed in imaging detection, corresponding to a 3.25-fold sensitivity improvement compared with direct (13)C FSSFP imaging with hyperpolarized HEP. The range of potential applications and limitations of this sub-second and ultra-sensitive imaging approach are discussed.
Copyright © 2014 John Wiley & Sons, Ltd.

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8 MeSH Terms
Facile synthesis of deuterated and [(14) C]labeled analogs of vanillin and curcumin for use as mechanistic and analytical tools.
Gordon ON, Graham LA, Schneider C
(2013) J Labelled Comp Radiopharm 56: 696-9
MeSH Terms: Benzaldehydes, Carbon Radioisotopes, Curcumin, Isotope Labeling, Radiopharmaceuticals
Show Abstract · Added January 20, 2015
Curcumin is a dietary diphenol with antioxidant, antinflammatory, and antitumor activity. We describe facile procedures for the synthesis of [(14) C2 ]curcumin (4 mCi/mmol), [d6 ]curcumin, [d3 ]curcumin, [(13) C5 ]curcumin, and [d6 ]bicyclopentadione, the major oxidative metabolite of curcumin. We also describe synthesis of the labeled building blocks [(14) C]vanillin, [d3 ]vanillin, and [(13) C5 ]acetylacetone. The overall molar yields of the labeled products were 52 ([(14) C]) and 47% ([d3 ]) for vanillin and 25 ([(14) C2 ]) and 27% ([d6 ]) for curcumin. The compounds can be used as radiotracers in biotransformation studies and as isotopic standards for mass spectrometry-based quantification in pharmacokinetic analyses.
Copyright © 2013 John Wiley & Sons, Ltd.
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5 MeSH Terms
Low-field MRI can be more sensitive than high-field MRI.
Coffey AM, Truong ML, Chekmenev EY
(2013) J Magn Reson 237: 169-174
MeSH Terms: Algorithms, Carbon Radioisotopes, Electromagnetic Fields, Equipment Design, Hydrogen, Image Enhancement, Magnetic Resonance Imaging, Phantoms, Imaging, Signal-To-Noise Ratio
Show Abstract · Added March 5, 2014
MRI signal-to-noise ratio (SNR) is the key factor for image quality. Conventionally, SNR is proportional to nuclear spin polarization, which scales linearly with magnetic field strength. Yet ever-stronger magnets present numerous technical and financial limitations. Low-field MRI can mitigate these constraints with equivalent SNR from non-equilibrium 'hyperpolarization' schemes, which increase polarization by orders of magnitude independently of the magnetic field. Here, theory and experimental validation demonstrate that combination of field independent polarization (e.g. hyperpolarization) with frequency optimized MRI detection coils (i.e. multi-turn coils using the maximum allowed conductor length) results in low-field MRI sensitivity approaching and even rivaling that of high-field MRI. Four read-out frequencies were tested using samples with identical numbers of (1)H and (13)C spins. Experimental SNRs at 0.0475T were ∼40% of those obtained at 4.7T. Conservatively, theoretical SNRs at 0.0475T 1.13-fold higher than those at 4.7T were possible despite an ∼100-fold lower detection frequency, indicating feasibility of high-sensitivity MRI without technically challenging, expensive high-field magnets. The data at 4.7T and 0.0475T was obtained from different spectrometers with different RF probes. The SNR comparison between the two field strengths accounted for many differences in parameters such as system noise figures and variations in the probe detection coils including Q factors and coil diameters.
Copyright © 2013 Elsevier Inc. All rights reserved.
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9 MeSH Terms
Resveratrol potentiates effect of simvastatin on inhibition of mevalonate pathway in human endometrial stromal cells.
Villanueva JA, Sokalska A, Cress AB, Ortega I, Bruner-Tran KL, Osteen KG, Duleba AJ
(2013) J Clin Endocrinol Metab 98: E455-62
MeSH Terms: Acetates, Adult, Anti-Inflammatory Agents, Non-Steroidal, Carbon Radioisotopes, Cholesterol, Drug Synergism, Endometrium, Female, Gene Expression Regulation, Enzymologic, Humans, Hydroxymethylglutaryl CoA Reductases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Mevalonic Acid, Primary Cell Culture, RNA, Messenger, Resveratrol, Simvastatin, Stilbenes, Stromal Cells
Show Abstract · Added May 29, 2014
CONTEXT - Growth of endometriotic lesions in rodent model of endometriosis is inhibited by resveratrol, a natural polyphenol with antiproliferative and antiinflammatory properties, and simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) activity.
OBJECTIVE - The objective of the investigation was to study the mechanism of action of resveratrol and its interactions with simvastatin, focusing on cholesterol biosynthesis and HMGCR gene expression and protein activity in primary cultures of human endometrial stromal (HES) cells.
METHODS - HES cells were obtained from healthy volunteers. Biosynthesis of cholesterol was assessed by measuring the conversion of [(14)C]acetate to [(14)C]cholesterol. HMGCR mRNA transcripts were quantified by real-time PCR, protein expression by Western blot analysis, and enzyme activity by measuring the conversion of [3-(14)C]3-hydroxy-3-methyl-glutaryl-coenzyme A to [(14)C]mevalonic acid lactone in HES cell microsomes.
RESULTS - Resveratrol inhibited cholesterol biosynthesis, HMGCR mRNA, and enzyme activity. Simvastatin inhibited cholesterol biosynthesis and enzyme activity but increased HMGCR mRNA and protein expression. Resveratrol potentiated the inhibitory effects of simvastatin on cholesterol biosynthesis and HMGCR enzyme activity and abrogated the stimulatory effects of simvastatin on HMGCR mRNA transcripts and protein expression.
CONCLUSIONS - Resveratrol inhibits key steps of the mevalonate pathway by mechanisms that are partly complementary to and partly comparable with simvastatin via reducing both expression and activity of HMGCR. A combination of resveratrol and simvastatin may be of potential clinical relevance to development new treatments of human endometriosis.
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19 MeSH Terms
Peak antibody production is associated with increased oxidative metabolism in an industrially relevant fed-batch CHO cell culture.
Templeton N, Dean J, Reddy P, Young JD
(2013) Biotechnol Bioeng 110: 2013-24
MeSH Terms: Animals, Antibodies, CHO Cells, Carbon Radioisotopes, Cell Respiration, Cricetulus, Energy Metabolism, Isotope Labeling, Lactates, Metabolic Flux Analysis, Recombinant Proteins
Show Abstract · Added January 23, 2015
Cell metabolism can vary considerably over the course of a typical fed-batch antibody production process. However, the intracellular pathway alterations associated with various phases of growth and antibody production have yet to be fully elucidated using industrially relevant production hosts. Therefore, we performed (13)C labeling experiments and metabolic flux analysis (MFA) to characterize CHO cell metabolism during four separate phases of a fed-batch culture designed to closely represent industrial process conditions. First, we found that peak specific growth rate was associated with high lactate production and minimal TCA cycling. Conversely, we found that lactate metabolism switched from net production to net consumption as the culture transitioned from peak growth to peak antibody production. During the peak antibody production phase, energy was primarily generated through oxidative phosphorylation, which was also associated with elevated oxidative pentose phosphate pathway (oxPPP) activity. Interestingly, as TCA cycling and antibody production reached their peaks, specific growth rate continued to diminish as the culture entered stationary phase. However, TCA cycling and oxPPP activity remained high even as viable cell density began to decline. Overall, we found that a highly oxidative state of metabolism corresponded with peak antibody production, whereas peak cell growth was characterized by a highly glycolytic metabolic state.
Copyright © 2013 Wiley Periodicals, Inc.
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11 MeSH Terms
Enhanced cardiac protein glycosylation (O-GlcNAc) of selected mitochondrial proteins in rats artificially selected for low running capacity.
Johnsen VL, Belke DD, Hughey CC, Hittel DS, Hepple RT, Koch LG, Britton SL, Shearer J
(2013) Physiol Genomics 45: 17-25
MeSH Terms: Absorptiometry, Photon, Analysis of Variance, Animals, Carbon Radioisotopes, Citrate (si)-Synthase, Fatty Acids, Nonesterified, Glucose, Glucose Clamp Technique, Glycosylation, Immunoblotting, Insulin Resistance, Kinetics, Mitochondrial Proteins, Models, Animal, Myocardium, N-Acetylglucosaminyltransferases, Oxidative Phosphorylation, Rats, Rats, Inbred Strains, Running
Show Abstract · Added April 24, 2014
O-linked β-N-acetyl glucosamine (O-GlcNAc) is a posttranslational modification consisting of a single N-acetylglucosamine moiety attached by an O-β-glycosidic linkage to serine and threonine residues of both nuclear and cytosolic proteins. Analogous to phosphorylation, the modification is reversible and dynamic, changing in response to stress, nutrients, hormones, and exercise. Aims of this study were to examine differences in O-GlcNAc protein modification in the cardiac tissue of rats artificially selected for low (LCR) or high (HCR) running capacity. Hyperinsulinemic-euglycemic clamps in conscious animals assessed insulin sensitivity while 2-[(14)C] deoxyglucose tracked both whole body and tissue-specific glucose disposal. Immunoblots of cardiac muscle examined global O-GlcNAc modification, enzymes that control its regulation (OGT, OGA), and specific proteins involved in mitochondrial oxidative phosphorylation. LCR rats were insulin resistant disposing of 65% less glucose than HCR. Global tissue O-GlcNAc, OGT, OGA, and citrate synthase were similar between groups. Analysis of cardiac proteins revealed enhanced O-GlcNAcylation of mitochondrial Complex I, Complex IV, VDAC, and SERCA in LCR compared with HCR. These results are the first to establish an increase in specific protein O-GlcNAcylation in LCR animals that may contribute to progressive mitochondrial dysfunction and the pathogenesis of insulin resistance observed in the LCR phenotype.
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20 MeSH Terms