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1.
Hyperpolarized [U‐2H,U‐13C]Glucose reports on glycolytic and pentose phosphate pathway activity in EL4 tumors and glycolytic activity in yeast cells
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Kerstin N. Timm Johannes Hartl Markus A. Keller De‐En Hu Mikko I. Kettunen Tiago B. Rodrigues Markus Ralser Kevin M. Brindle 《Magnetic resonance in medicine》2015,74(6):1543-1547
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Ana C Mendes M Madalena Caldeira Claudia Silva Shawn C Burgess Matthew E Merritt Filipe Gomes Cristina Barosa Teresa C Delgado Fatima Franco Pedro Monteiro Luis Providencia John G Jones 《Magnetic resonance in medicine》2006,56(5):1121-1125
Menthol glucuronide was isolated from the urine of a healthy 70-kg female subject following ingestion of 400 mg of peppermint oil and 6 g of 99% [U-(13)C]glucose. Glucuronide (13)C-excess enrichment levels were 4-6% and thus provided high signal-to-noise ratios (SNRs) for confident assignment of (13)C-(13)C spin-coupled multiplet components within each (13)C resonance by (13)C NMR. The [U-(13)C]glucuronide isotopomer derived via direct pathway conversion of [U-(13)C]glucose to [U-(13)C]UDP-glucose was resolved from [1,2,3-(13)C(3)]- and [1,2-(13)C(2)]glucuronide isotopomers derived via Cori cycle or indirect pathway metabolism of [U-(13)C]glucose. In a second study, a group of four overnight-fasted patients (63 +/- 10 kg) with severe heart failure were given peppermint oil and infused with [U-(13)C]glucose for 4 hr (14 mg/kg prime, 0.12 mg/kg/min constant infusion) resulting in a steady-state plasma [U-(13)C]glucose enrichment of 4.6% +/- 0.6%. Menthol glucuronide was harvested and glucuronide (13)C-isotopomers were analyzed by (13)C NMR. [U-(13)C]glucuronide enrichment was 0.6% +/- 0.1%, and the sum of [1,2,3-(13)C(3)] and [1,2-(13)C(2)]glucuronide enrichments was 0.9% +/- 0.2%. From these data, flux of plasma glucose to hepatic UDPG was estimated to be 15% +/- 4% that of endogenous glucose production (EGP), and the Cori cycle accounted for at least 32% +/- 10% of GP. 相似文献
3.
Rudolph Willem Monique Biesemans Franois Kayser Willy J. Malaise 《Magnetic resonance in medicine》1994,31(3):259-267
Tumoral pancreatic islet cells of the RIN5mF line were incubated for 120 min in media prepared in 2H2O and containing D -[1-13C]glucose, and D -[2-13C]glucose, and D -[6-13C]glucose. The generation of C2- and C3- deuterated lactic acid was assessed by 13C NMR. The interpretation of experimental results suggests that a) the efficiency of deuteration on the C1 of D-fructose 6-phosphate does not exceed about 47% and 4% in the phosphoglucoisomerase and phosphomannoisomerase reactions, respectively; b) approximately 38% of the molecules of D -glyceraldehyde 3-phosphate generated from D -glucose escape deuteration in the sequence of reactions catalyzed by triose phosphate isomerase and aldolase; and c) about 41% of the molecules of pyruvate generated by glycolysis are immediately converted to lactate, the remaining 59% of pyruvate molecules undergoing first a single or double back-and-forth interconversion with L -alanine. It is proposed that this methodological approach, based on high resolution 13C NMR spectroscopy, may provide novel information on the regulation of back-and-forth interconversion of glycolytic intermediates in intact cells as modulated, for instance, by enzyme-to-enzyme tunneling. 相似文献
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Robin A de Graaf Peter B Brown Graeme F Mason Douglas L Rothman Kevin L Behar 《Magnetic resonance in medicine》2003,49(1):37-46
Localized, water-suppressed (1)H-[(13)C]-NMR spectroscopy was used to detect (13)C-label accumulation in cerebral metabolites following the intravenous infusion of [1,6-(13)C(2)]-glucose (Glc). The (1)H-[(13)C]-NMR method, based on adiabatic RF pulses, 3D image-selected in vivo spectroscopy (ISIS) localization, and optimal shimming, yielded high-quality (1)H-[(13)C]-NMR spectra with optimal NMR sensitivity. As a result, the (13)C labeling of [4-(13)C]-glutamate (Glu) and [4-(13)C]-glutamine (Gln) could be detected from relatively small volumes (100 microL) with a high temporal resolution. The formation of [n-(13)C]-Glu, [n-(13)C]-Gln (n = 2 or 3), [2-(13)C]-aspartate (Asp), [3-(13)C]-Asp, [3-(13)C]-alanine (Ala), and [3-(13)C]-lactate (Lac) was also observed to be reproducible. The (13)C-label incorporation curves of [4-(13)C]-Glu and [4-(13)C]-Gln provided direct information on metabolic pathways. Using a two-compartment metabolic model, the tricarboxylic acid (TCA) cycle flux was determined as 0.52 +/- 0.04 micromol/min/g, while the glutamatergic neurotransmitter flux equaled 0.25 +/- 0.05 micromol/min/g, in good correspondence with previously determined values. 相似文献
6.
A fast and sensitive procedure to determine the turnover of the H2 hydrogen of lactate and quantify its (2)H-enrichment by (1)H NMR is illustrated using C6 cells metabolizing (3-(13)C) lactate in 50% (2)H(2)O (vol/vol). (2)H substitution of the lactate H2 hydrogen resulted in two easily detectable transformations of the vicinal H3 doublet resonance: 1) the formation of an H3 singlet due to the disappearance of the homonuclear coupling to H2 ((3)J(betaH-alphaH) = 7.0 Hz), and 2) an upfield isotopic shift derived from the vicinal (2)H2 substitution (Delta(3) = -0.007 ppm). Only those lactate molecules that have passed through the cell cytosol experience these effects, since H2 deuteration involves lactate dehydrogenase activity and NAD((2)H). Thus, analysis of the observed shifted and unshifted H3 lactate resonances from the incubation medium allows the discrimination of the perprotonated (3-(13)C) lactate added as substrate, and the (3-(13)C, 2-(2)H) lactate recycled to the incubation medium after passage through the cytosol. 相似文献
7.
Localized proton NMR observation of [3-13C]lactate in stroke after [1-13C]glucose infusion. 总被引:1,自引:0,他引:1
D L Rothman A M Howseman G D Graham O A Petroff G Lantos P B Fayad L M Brass G I Shulman R G Shulman J W Prichard 《Magnetic resonance in medicine》1991,21(2):302-307
To assess whether elevated lactate in stable stroke is being actively produced from blood glucose localized 1H NMR stimulated echo spectra were obtained from a patient in the region of a 32-day-old cortical infarct before and 60-100 min after infusion of [1-13C]glucose. Prior to the infusion the spectrum from the region of the infarct contained an elevated resonance from C3 lactate and a greatly reduced resonance from N-acetyl groups relative to an unaffected contralateral region. After the infusion two additional resonances were observed at 62 and -64 Hz relative to the unlabeled resonance of C3 lactate which were assigned on the basis of chemical shift and relative intensity to [3-13C]lactate. The [3-13C]lactate fractional enrichment in the infarct region was measured to be 32% which is within error one-half the average [1-13C]plasma glucose enrichment during the postinfusion NMR measurement. The result suggests that the stroke lactate pool was completely derived from infused glucose. 相似文献
8.
Mikko I. Kettunen De‐en Hu Timothy H. Witney Rebekah McLaughlin Ferdia A. Gallagher Sarah E. Bohndiek Sam E. Day Kevin M. Brindle 《Magnetic resonance in medicine》2010,63(4):872-880
Measurements of the conversion of hyperpolarized [1‐13C]pyruvate into lactate, in the reaction catalyzed by lactate dehydrogenase, have shown promise as a metabolic marker for the presence of disease and response to treatment. However, it is unclear whether this represents net flux of label from pyruvate to lactate or exchange of isotope between metabolites that are close to chemical equilibrium. Using saturation and inversion transfer experiments, we show that there is significant exchange of label between lactate and pyruvate in a murine lymphoma in vivo. The rate constants estimated from the magnetization transfer experiments, at specific points during the time course of label exchange, were similar to those obtained by fitting the changes in peak intensities during the entire exchange time course to a kinetic model for two‐site exchange. These magnetization transfer experiments may therefore provide an alternative and more rapid way of estimating flux between pyruvate and lactate to serial measurements of pyruvate and lactate 13C peak intensities following injection of hyperpolarized [1‐13C]pyruvate. Magn Reson Med 63:872–880, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
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Jason A. Koutcher Alan A. Alfieri Cornelia Matei Kristen L. Meyer James C. Street Daniel S. Martin 《Magnetic resonance in medicine》1996,36(6):887-892
6-aminonicotinamide (6AN) has been shown to enhance radio-sensitivity in vitro, although previous in vivo studies failed to show an effect. 31P NMR spectra were obtained by using a one-dimensional chemical shift imaging technique on a first generation transplant of the CD8FI spontaneous mammary carcinoma tumor model. Spectra were obtained both before and 10 h after treatment with 6AN (20 mg/kg). Changes in pH, nucleoside triphosphate/inorganic phosphate, and phosphocreatine/inorganic phosphate measured at 10 h post-6AN were not significant. A new peak was detected 10 h post-6AN, which was assigned to 6-phosphogluconate (6PG), indicating inhibition of the pentose phosphate pathway (PPP). Based on the spectral data demonstrating inhibition of the PPP at 10 h post-6AN, tumor-bearing mice were irradiated (15 Gy × 3 fractions) on Days 1, 10 or 11, and 21 10 h after administration of 6-aminonicotinamide (20 mg/kg). Tumor-bearing mice receiving 6AN alone (20 mg/kg × 3), radiation alone (15 Gy × 3), or saline were also studied. Tumor growth delay studies indicated that 6AN alone induced a small but significant tumor growth delay (4.3 ± 0.8 days). Radiation alone induced a tumor growth delay of 34.5 ± 2.7 days. Treatment with 6AN followed by radiation induced a tumor growth delay of 57.0 ± 3.8 days. This was significantly greater than the TGD values for treatment with 6AN alone or radiation (P < 0.01). No complete regressions were noted after treatment with 6AN or radiation alone. Concomitant therapy with 6AN plus radiation yielded 6/28 complete regressions (21%), which was significantly greater than radiation (P < 0.05) or 6AN alone (P < 0.01) on this mammary carcinoma. 相似文献
10.
Lijing Xin Vladimír Mlynárik Bernard Lanz Hanne Frenkel Rolf Gruetter 《Magnetic resonance in medicine》2010,64(2):334-340
Full signal intensity 1H‐[13C] NMR spectroscopy, combining a preceding 13C‐editing block based on an inversion BISEP (B1‐insensitive spectral editing pulse) with a spin‐echo coherence–based localization, was developed and implemented at 14.1 T. 13C editing of the proposed scheme was achieved by turning on and off the 13C adiabatic full passage in the 13C‐editing block to prepare inverted and noninverted 13C‐coupled 1H coherences along the longitudinal axis prior to localization. The novel 1H‐[13C] NMR approach was applied in vivo under infusion of the glia‐specific substrate [2‐13C] acetate. Besides a ~50% improvement in sensitivity, spectral dispersion was enhanced at 14.1 T, especially for J‐coupled metabolites such as glutamate and glutamine. A more distinct spectral structure at 1.9–2.2 ppm(parts per million) was observed, e.g., glutamate C3 showed a doublet pattern in both simulated 1H spectrum and in vivo 13C‐edited 1H NMR spectra. Besides 13C time courses of glutamate C4 and glutamine C4, the time courses of glutamate C3 and glutamine C3 obtained by 1H‐[13C] NMR spectroscopy were reported for the first time. Such capability should greatly improve the ability to study neuron‐glial metabolism using 1H‐observed 13C‐edited NMR spectroscopy. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
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Ralph E. Hurd Yi‐Fen Yen Dirk Mayer Albert Chen David Wilson Susan Kohler Robert Bok Daniel Vigneron John Kurhanewicz James Tropp Daniel Spielman Adolf Pfefferbaum 《Magnetic resonance in medicine》2010,63(5):1137-1143
Formulation, polarization, and dissolution conditions were developed to obtain a stable hyperpolarized solution of [1‐13C]‐ethyl pyruvate. A maximum tolerated concentration and injection rate were determined, and 13C spectroscopic imaging was used to compare the uptake of hyperpolarized [1‐13C]‐ethyl pyruvate relative to hyperpolarized [1‐13C]‐pyruvate into anesthetized rat brain. Hyperpolarized [1‐13C]‐ethyl pyruvate and [1‐13C]‐pyruvate metabolic imaging in normal brain is demonstrated and quantified in this feasibility and range‐finding study. Magn Reson Med 63:1137–1143, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
12.
Clinical utility of (13)C MRS is limited by cost and long examination times. Three 1-(13)C glucose infusion protocols-a high-dose i.v., low-dose i.v., and oral administration of 1-(13)C glucose-were compared on a GE 1.5T MR scanner. Resolution and sensitivity were sufficient to identify (13)C glucose (1alpha and 1beta), glutamate (C1-C4), glutamine (C1-C4), aspartate (C2 and C3), lactate, alanine, and bicarbonate in brain spectra. The three protocols were efficacious, as measured by cerebral enrichment of 1-(13)C glucose (62%, 42%, and 38%) and its principal metabolite, 4-(13)C glutamate (13%, 11%, and 16%), respectively. Intravenous infusion of 1-(13)C glucose 0.23 g/kg body weight (low dose) provides equivalent information at one third the cost of previous regimes. Magn Reson Med 46:39-48, 2001. 相似文献
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Gilles Bloch Laurence Jouvensal Pierre G. Carlier 《Magnetic resonance in medicine》1995,34(3):353-358
1H NMR simultaneous editing of 13C-coupled and 13C-uncoupled methyl protons resonance, using the selection of double quantum coherences by a gradient pulse, was analyzed in vitro and demonstrated in situ on the hindlimb of an exercised rat model postmortem. In vitro calibration showed agreement with theoretical analysis. High-resolution NMR of muscle extract confirmed the accuracy of the lactate 13C-enrichment calculated using the in situ NMR data and the calibration factor obtained in vitro. 相似文献
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16.
High spatiotemporal resolution bSSFP imaging of hyperpolarized [1‐13C]pyruvate and [1‐13C]lactate with spectral suppression of alanine and pyruvate‐hydrate
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Eugene Milshteyn Cornelius von Morze Jeremy W. Gordon Zihan Zhu Peder E.Z. Larson Daniel B. Vigneron 《Magnetic resonance in medicine》2018,80(3):1048-1060
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Eunsook S. Jin John G. Jones Shawn C. Burgess Matthew E. Merritt A. Dean Sherry Craig R. Malloy 《Magnetic resonance in medicine》2005,53(6):1479-1483
A recently introduced tracer, [3,4‐13C2]glucose, was compared to the widely used tracer, [6,6‐2H2]glucose, for measurement of whole‐body glucose turnover. The rate of glucose production (GP) was measured in rats after primed infusions of [3,4‐13C2]glucose, [6,6‐2H2]glucose, or both tracers simultaneously followed by a constant infusion of tracer(s) over 90 min. Blood glucose was purified and converted into monoacetone glucose for analysis by 13C NMR (for [3,4‐13C2]glucose) or 1H and 2H NMR (for [6,6‐2H2]glucose). The values of GP measured during infusion of each single tracer were not significantly different. In rats infused with both tracers simultaneously, GP was identical as reported by each tracer, 42 ± 4 μmol/kg/min. Since 2H and 13C enrichment in glucose is typically much less than 2% for in vivo studies, [3,4‐13C2]glucose does not interfere with measurements of 13C or 2H enrichment patterns and therefore is valuable when multiple metabolic pathways are being evaluated simultaneously. Magn Reson Med 53:1479–1483, 2005. © 2005 Wiley‐Liss, Inc. 相似文献
18.
Lactate dehydrogenase (LDH, EC 1.1.1.27) catalyzes an exchange reaction between pyruvate and lactate. It is demonstrated here that this reaction is sufficiently fast to cause a significant magnetization (saturation) transfer effect when the 13C resonance of pyruvate is saturated by a continuous-wave (CW) RF pulse. Infusion of [2-(13)C]glucose was used to allow labeling of pyruvate C2 at 207.9 ppm to determine the pseudo first-order rate constant of the unidirectional lactate-->pyruvate flux in vivo. During systemic administration of GABAA receptor antagonist bicuculline, this pseudo first-order rate constant was determined to be 0.08+/-0.01 s-1 (mean+/-SD, N=4) in halothane-anesthetized adult rat brains. In 9L and C6 rat glioma models, the 13C saturation transfer effect of the LDH reaction was also detected in vivo. Our results demonstrate that the 13C magnetization transfer effect of the LDH reaction may be useful as a novel marker for utilizing noninvasive in vivo MRS to study many physiological and pathological conditions, such as cancer. 相似文献
19.
Lijing Xin Hanne Frenkel Vladimír Mlynárik Florence D. Morgenthaler Rolf Gruetter 《Magnetic resonance in medicine》2009,61(2):260-266
Despite obvious improvements in spectral resolution at high magnetic field, the detection of 13C labeling by 1H‐[13C] NMR spectroscopy remains hampered by spectral overlap, such as in the spectral region of 1H resonances bound to C3 of glutamate (Glu) and glutamine (Gln), and C6 of N‐acetylaspartate (NAA). The aim of this study was to develop, implement, and apply a novel 1H‐[13C] NMR spectroscopic editing scheme, dubbed “selective Resonance suppression by Adiabatic Carbon Editing and Decoupling single‐voxel STimulated Echo Acquisition Mode” (RACED‐STEAM). The sequence is based on the application of two asymmetric narrow‐transition‐band adiabatic RF inversion pulses at the resonance frequency of the 13C coupled to the protons that need to be suppressed during the mixing time (TM) period, alternating the inversion band downfield and upfield from the 13C resonance on odd and even scans, respectively, thus suppressing the detection of 1H resonances bound to 13C within the transition band of the inversion pulse. The results demonstrate the efficient suppression of 1H resonances bound to C3 of Glu and Gln, and C4 of Glu, which allows the 1H resonances bound to C6 of NAA and C4 of Gln to be revealed. The measured time course of the resolved labeling into NAA C6 with the new scheme was consistent with the slow turnover of NAA. Magn Reson Med 61:260–266, 2009. © 2009 Wiley‐Liss, Inc. 相似文献