Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 100
Filtrar
1.
Cell ; 158(1): 9-10, 2014 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-24995972

RESUMO

The pyruvate dehydrogenase complex (PDC) catalyzes the conversion of pyruvate into acetyl-CoA, a critical step in metabolism. Sutendra et al. now demonstrate that PDC can translocate from the mitochondria to the nucleus to provide acetyl-CoA necessary for histone acetylation, suggesting a new pathway for mitochondrial-nuclear communication.


Assuntos
Acetilcoenzima A/biossíntese , Núcleo Celular/metabolismo , Complexo Piruvato Desidrogenase/metabolismo , Humanos
2.
Cell ; 149(1): 49-62, 2012 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-22401813

RESUMO

Decremental loss of PTEN results in cancer susceptibility and tumor progression. PTEN elevation might therefore be an attractive option for cancer prevention and therapy. We have generated several transgenic mouse lines with PTEN expression elevated to varying levels by taking advantage of bacterial artificial chromosome (BAC)-mediated transgenesis. The "Super-PTEN" mutants are viable and show reduced body size due to decreased cell number, with no effect on cell size. Unexpectedly, PTEN elevation at the organism level results in healthy metabolism characterized by increased energy expenditure and reduced body fat accumulation. Cells derived from these mice show reduced glucose and glutamine uptake and increased mitochondrial oxidative phosphorylation and are resistant to oncogenic transformation. Mechanistically we find that PTEN elevation orchestrates this metabolic switch by regulating PI3K-dependent and -independent pathways and negatively impacting two of the most pronounced metabolic features of tumor cells: glutaminolysis and the Warburg effect.


Assuntos
PTEN Fosfo-Hidrolase/metabolismo , Transdução de Sinais , Animais , Tamanho Corporal , Contagem de Células , Proliferação de Células , Respiração Celular , Metabolismo Energético , Camundongos , Camundongos Transgênicos , Mitocôndrias/metabolismo , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo
3.
Am J Physiol Gastrointest Liver Physiol ; 325(6): G539-G555, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37847725

RESUMO

The small intestine requires energy to exert its important role in nutrient uptake and barrier function. Pigs are an important source of food and a model for humans. Young piglets and infants can suffer from periods of insufficient food intake. Whether this functionally affects the small intestinal epithelial cell (IEC) metabolic capacity and how this may be associated with an increased vulnerability to intestinal disease is unknown. We therefore performed a 48-h fasting intervention in young piglets. After feeding a standard weaning diet for 2 wk, 6-wk-old piglets (n = 16/group) were fasted for 48 h, and midjejunal IECs were collected upon euthanasia. Functional metabolism of isolated IECs was analyzed with the Seahorse XF analyzer and gene expression was assessed using RNA-sequencing. Fasting decreased the mitochondrial and glycolytic function of the IECs by 50% and 45%, respectively (P < 0.0001), signifying that overall metabolic function was decreased. The RNA-sequencing results corroborated our functional metabolic measurements, showing that particularly pathways related to mitochondrial energy production were decreased. Besides oxidative metabolic pathways, decreased cell-cycle progression pathways were most regulated in the fasted piglets, which were confirmed by 43% reduction of Ki67-stained cells (P < 0.05). Finally, the expression of barrier function genes was reduced upon fasting. In conclusion, we found that the decreased IEC energy metabolic function in response to fasting is supported by a decreased gene expression of mitochondrial pathways and is likely linked to the observed decreased intestinal cell proliferation and barrier function, providing insight into the vulnerability of piglets, and infants, to decreased food intake.NEW & NOTEWORTHY Fasting is identified as one of the underlying causes potentiating diarrhea development, both in piglets and humans. With this study, we demonstrate that fasting decreases the metabolism of intestinal epithelial cells, on a functional and transcriptional level. Transcriptional and histological data also show decreased intestinal cell proliferation. As such, fasting-induced intestinal energy shortage could contribute to intestinal dysfunction upon fasting.


Assuntos
Jejum , Intestino Delgado , Humanos , Animais , Suínos , Intestino Delgado/metabolismo , Desmame , Proliferação de Células , RNA/metabolismo , Mucosa Intestinal/metabolismo
4.
Radiology ; 307(2): e220989, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36648348

RESUMO

Background The human cerebellum has a large, highly folded cortical sheet. Its visualization is important for various disorders, including multiple sclerosis and spinocerebellar ataxias. The derivation of the cerebellar cortical surface in vivo is impeded by its high foliation. Purpose To image the cerebellar cortex, including its foliations and lamination, in less than 20 minutes, reconstruct the cerebellocortical surface, and extract cortical measures with use of motion-corrected, high-spatial-resolution 7.0-T MRI. Materials and Methods In this prospective study, conducted between February 2021 and July 2022, healthy participants underwent an examination with either a 0.19 × 0.19 × 0.5-mm3, motion-corrected fast low-angle shot (FLASH) sequence (14.5 minutes) or a whole-cerebellum 0.4 × 0.4 × 0.4-mm3, motion-corrected magnetization-prepared 2 rapid gradient-echo (MP2RAGE) sequence (18.5 minutes) at 7.0 T. Four participants underwent an additional FLASH sequence without motion correction. FLASH and MP2RAGE sequences were used to visualize the cerebellar cortical layers, derive cerebellar gray and white matter segmentations, and examine their fidelity. Quantitative measures were compared using repeated-measures analyses of variance or paired t tests. Results Nine participants (median age, 36 years [IQR, 25-42 years; range, 21-62 years]; five women) underwent examination with the FLASH sequence. Nine participants (median age, 37 years [IQR, 34-42 years; range, 25-62 years]; five men) underwent examination with the MP2RAGE sequence. A susceptibility difference between the expected location of the granular and molecular cerebellar layers was visually detected in the FLASH data in all participants. The segmentations derived from the whole-cerebellum MP2RAGE sequence showed the characteristic anatomic features of the cerebellum, like the transverse fissures and splitting folds. The cortical surface area (median, 949 cm2 [IQR, 825-1021 cm2]) was 1.8 times larger, and the cortical thickness (median, 0.88 mm [IQR, 0.81-0.93 mm]) was five times thinner than previous in vivo estimates and closer to ex vivo reference data. Conclusion In vivo imaging of the cerebellar cortical layers and surface and derivation of quantitative measures was feasible in a clinically acceptable acquisition time with use of motion-corrected 7.0-T MRI. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Dietrich in this issue.


Assuntos
Esclerose Múltipla , Substância Branca , Masculino , Humanos , Feminino , Adulto , Estudos Prospectivos , Imageamento por Ressonância Magnética/métodos , Cerebelo/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Esclerose Múltipla/diagnóstico por imagem , Encéfalo/anatomia & histologia
5.
Mol Genet Metab ; 140(3): 107694, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37708665

RESUMO

Creatine transporter deficiency (CTD), caused by pathogenic variants in SLC6A8, is the second most common cause of X-linked intellectual disability. Symptoms include intellectual disability, epilepsy, and behavioral disorders and are caused by reduced cerebral creatine levels. Targeted treatment with oral supplementation is available, however the treatment efficacy is still being investigated. There are clinical and theoretical indications that heterozygous females with CTD respond better to supplementation treatment than hemizygous males. Unfortunately, heterozygous females with CTD often have more subtle and uncharacteristic clinical and biochemical phenotypes, rendering diagnosis more difficult. We report a new female case who presented with learning disabilities and seizures. After determining the diagnosis with molecular genetic testing confirmed by proton magnetic resonance spectroscopy (1H-MRS), the patient was treated with supplementation treatment including creatine, arginine, and glycine. After 28 months of treatment, the patient showed prominent clinical improvement and increased creatine levels in the brain. Furthermore, we provide a review of the 32 female cases reported in the current literature including a description of phenotypes, genotypes, diagnostic approaches, and effects of supplementation treatment. Based on this, we find that supplementation treatment should be tested in heterozygous female patients with CTD, and a prospective treatment underlines the importance of diagnosing these patients. The diagnosis should be suspected in a broad clinical spectrum of female patients and can only be made by molecular genetic testing. 1H-MRS of cerebral creatine levels is essential for establishing the diagnosis in females, and especially valuable when assessing variants of unknown significance.


Assuntos
Encefalopatias Metabólicas Congênitas , Deficiência Intelectual , Deficiência Intelectual Ligada ao Cromossomo X , Masculino , Humanos , Feminino , Deficiência Intelectual/genética , Creatina , Encefalopatias Metabólicas Congênitas/diagnóstico , Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/tratamento farmacológico , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Deficiência Intelectual Ligada ao Cromossomo X/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Proteínas do Tecido Nervoso
6.
Int J Mol Sci ; 24(4)2023 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-36835625

RESUMO

Biomarkers are important in the assessment of health and disease, but are poorly studied in still healthy individuals with a (potential) different risk for metabolic disease. This study investigated, first, how single biomarkers and metabolic parameters, functional biomarker and metabolic parameter categories, and total biomarker and metabolic parameter profiles behave in young healthy female adults of different aerobic fitness and, second, how these biomarkers and metabolic parameters are affected by recent exercise in these healthy individuals. A total of 102 biomarkers and metabolic parameters were analysed in serum or plasma samples from 30 young, healthy, female adults divided into a high-fit (V̇O2peak ≥ 47 mL/kg/min, N = 15) and a low-fit (V̇O2peak ≤ 37 mL/kg/min, N = 15) group, at baseline and overnight after a single bout of exercise (60 min, 70% V̇O2peak). Our results show that total biomarker and metabolic parameter profiles were similar between high-fit and low-fit females. Recent exercise significantly affected several single biomarkers and metabolic parameters, mostly related to inflammation and lipid metabolism. Furthermore, functional biomarker and metabolic parameter categories corresponded to biomarker and metabolic parameter clusters generated via hierarchical clustering models. In conclusion, this study provides insight into the single and joined behavior of circulating biomarkers and metabolic parameters in healthy females, and identified functional biomarker and metabolic parameter categories that may be used for the characterisation of human health physiology.


Assuntos
Consumo de Oxigênio , Aptidão Física , Adulto , Humanos , Feminino , Aptidão Física/fisiologia , Consumo de Oxigênio/fisiologia , Exercício Físico/fisiologia , Nível de Saúde , Biomarcadores
7.
Am J Physiol Endocrinol Metab ; 322(2): E141-E153, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35001658

RESUMO

Analyzing metabolism of peripheral blood mononuclear cells (PBMCs) can possibly serve as a cellular metabolic read-out for lifestyle factors and lifestyle interventions. However, the impact of PBMC composition on PBMC metabolism is not yet clear, neither is the differential impact of a longer-term lifestyle factor versus a short-term lifestyle intervention. We investigated the effect of aerobic fitness level and a recent exercise bout on PBMC metabolism in females. PBMCs from 31 young female adults divided into a high-fit (V̇o2peak ≥ 47 mL/kg/min, n = 15) and low-fit (V̇o2peak ≤ 37 mL/kg/min, n = 16) groups were isolated at baseline and overnight after a single bout of exercise (60 min, 70% V̇o2peak). Oxygen consumption rate (OCR) and glycolytic rate (GR) were measured using extracellular flux (XF) assays and PBMC subsets were characterized using fluorescence-activated cell sorting (FACS). Basal OCR, FCCP-induced OCR, spare respiratory capacity, ATP-linked OCR, and proton leak were significantly higher in high-fit than in low-fit females (all P < 0.01), whereas no significant differences in glycolytic rate (GR) were found (all P > 0.05). A recent exercise bout did not significantly affect GR or OCR parameters (all P > 0.05). The overall PBMC composition was similar between high-fit and low-fit females. Mitochondrial PBMC function was significantly higher in PBMCs from high-fit than from low-fit females, which was unrelated to PBMC composition and not impacted by a recent bout of exercise. Our study reveals a link between PBMC metabolism and levels of aerobic fitness, increasing the relevance of PBMC metabolism as a marker to study the impact of lifestyle factors on human health.NEW & NOTEWORTHY Mitochondrial metabolism was significantly higher in PBMCs from high-fit than from low-fit females. This was unrelated to PBMC composition and not impacted by a recent bout of exercise. Our study reveals a link between PBMC metabolism and levels of aerobic fitness, increasing the relevance of PBMC metabolism as a marker to study the impact of lifestyle factors on human health.


Assuntos
Exercício Físico/fisiologia , Espaço Extracelular/metabolismo , Leucócitos Mononucleares/metabolismo , Mitocôndrias/metabolismo , Consumo de Oxigênio/fisiologia , Resistência Física/fisiologia , Prótons , Adolescente , Adulto , Feminino , Citometria de Fluxo/métodos , Glicólise/fisiologia , Humanos , Leucócitos Mononucleares/classificação , Estilo de Vida , Adulto Jovem
8.
Magn Reson Med ; 88(3): 1198-1211, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35576128

RESUMO

PURPOSE: Accuracy investigation of volumetric navigators for motion correction, with emphasis on geometric EPI distortions at ultrahigh field. METHODS: High-resolution Dixon images were collected in different head positions and reconstructed to water, fat, T2 *, and B0 maps. Resolution reduction was performed, and the T2 * and B0 maps were used to apply effects of TE and EPI distortions to simulate various volumetric water and fat navigators. Registrations of the simulated navigators were compared with registrations of the original high-resolution images. RESULTS: Increased accuracy was observed with increased spatial resolution for non-EPI navigators. When using EPI, the distortions had a negative effect on registration accuracy, which was most noticeable for high-resolution navigators. Parallel imaging helped to alleviate those caveats to a certain extent, and 5-fold acceleration gave close to similar accuracy to non-EPI in most cases. Shortening the TE by partial Fourier sampling was shown to be mostly beneficial, except for water navigators with long readout durations. The EPI blip direction had an influence on navigator accuracy, and positive blip gradient polarities (yielding mostly image stretching frontally) typically gave the best accuracy for water navigators, whereas no clear recommendation could be made for fat navigators. Generally, fat EPI navigators had lower accuracy than water EPI navigators with otherwise similar parameters. CONCLUSIONS: Echo planar imaging has been widely used for MRI navigators, but the induced distortions reduce navigator accuracy at ultrahigh field. This study can help protocol optimization and guide the complex tradeoff between resolution and EPI acceleration in navigator parameter setup.


Assuntos
Artefatos , Imagem Ecoplanar , Encéfalo , Imagem Ecoplanar/métodos , Interpretação de Imagem Assistida por Computador/métodos , Processamento de Imagem Assistida por Computador/métodos , Água
9.
Magn Reson Med ; 88(1): 71-82, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35344600

RESUMO

PURPOSE: Single-voxel MRS (SV MRS) requires robust volume localization as well as optimized crusher and phase-cycling schemes to reduce artifacts arising from signal outside the volume of interest. However, due to local magnetic field gradients (B0 inhomogeneities), signal that was dephased by the crusher gradients during acquisition might rephase, leading to artifacts in the spectrum. Here, we analyzed this mechanism, aiming to identify the source of signals arising from unwanted coherence pathways (spurious signals) in SV MRS from a B0 map. METHODS: We investigated all possible coherence pathways associated with imperfect localization in a semi-localized by adiabatic selective refocusing (semi-LASER) sequence for potential rephasing of signals arising from unwanted coherence pathways by a local magnetic field gradient. We searched for locations in the B0 map where the signal dephasing due to external (crusher) and internal (B0 ) field gradients canceled out. To confirm the mechanism, SV-MR spectra (TE = 31 ms) and 3D-CSI data with the same volume localization as the SV experiments were acquired from a phantom and 2 healthy volunteers. RESULTS: Our analysis revealed that potential sources of spurious signals were scattered over multiple locations throughout the brain. This was confirmed by 3D-CSI data. Moreover, we showed that the number of potential locations where spurious signals could originate from monotonically decreases with crusher strength. CONCLUSION: We proposed a method to identify the source of spurious signals in SV 1 H MRS using a B0 map. This can facilitate MRS sequence design to be less sensitive to experimental artifacts.


Assuntos
Artefatos , Imageamento por Ressonância Magnética , Encéfalo/diagnóstico por imagem , Humanos , Campos Magnéticos , Imageamento por Ressonância Magnética/métodos , Imagens de Fantasmas
10.
NMR Biomed ; 35(12): e4801, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35833462

RESUMO

In a standard spin echo, the time evolution due to homonuclear couplings is not reversed, leading to echo time (TE)-dependent modulation of the signal amplitude and signal loss in the case of overlapping multiplet resonances. This has an adverse effect on quantification of several important metabolites such as glutamate and glutamine. Here, we propose a J-refocused variant of the sLASER sequence (J-sLASER) to improve quantification of J-coupled metabolites at ultrahigh field (UHF). The use of the sLASER sequence is particularly advantageous at UHF as it minimizes chemical shift displacement error and results in relatively homogenous refocusing. We simulated the MRS signal from brain metabolites over a broad range of TE values with sLASER and J-sLASER, and showed that the signal of J-coupled metabolites was increased with J-sLASER with TE values up to ~80 ms. We further simulated "brain-like" spectra with both sequences at the shortest TE available on our scanner. We showed that, despite the slightly longer TE, the J-sLASER sequence results in significantly lower Cramer-Rao lower bounds (CRLBs) for J-coupled metabolites compared with those obtained with sLASER. Following phantom validation, we acquired spectra from two brain regions in 10 healthy volunteers (age 38 ± 15 years) using both sequences. We showed that using J-sLASER results in a decrease of CRLBs for J-coupled metabolites. In particular, we measured a robust ~38% decrease in the mean CRLB (glutamine) in parietal white matter and posterior cingulate cortex (PCC). We further showed, in 10 additional healthy volunteers (age 34 ± 15 years), that metabolite quantification following two separate acquisitions with J-sLASER in the PCC was repeatable. The improvement in quantification of glutamine may in turn improve the independent quantification of glutamate, the main excitatory neurotransmitter in the brain, and will simultaneously help to track possible modulations of glutamine, which is a key player in the glutamatergic cycle in astrocytes.


Assuntos
Ácido Glutâmico , Glutamina , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Glutamina/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Limite de Detecção , Ácido Glutâmico/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo
11.
NMR Biomed ; 35(10): e4771, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35577344

RESUMO

The increased signal-to-noise ratio (SNR) and chemical shift dispersion at high magnetic fields (≥7 T) have enabled neuro-metabolic imaging at high spatial resolutions. To avoid very long acquisition times with conventional magnetic resonance spectroscopic imaging (MRSI) phase-encoding schemes, solutions such as pulse-acquire or free induction decay (FID) sequences with short repetition time and inner volume selection methods with acceleration (echo-planar spectroscopic imaging [EPSI]), have been proposed. With the inner volume selection methods, limited spatial coverage of the brain and long echo times may still impede clinical implementation. FID-MRSI sequences benefit from a short echo time and have a high SNR per time unit; however, contamination from strong extra-cranial lipid signals remains a problem that can hinder correct metabolite quantification. L2-regularization can be applied to remove lipid signals in cases with high spatial resolution and accurate prior knowledge. In this work, we developed an accelerated two-dimensional (2D) FID-MRSI sequence using an echo-planar readout and investigated the performance of lipid suppression by L2-regularization, an external crusher coil, and the combination of these two methods to compare the resulting spectral quality in three subjects. The reduction factor of lipid suppression using the crusher coil alone varies from 2 to 7 in the lipid region of the brain boundary. For the combination of the two methods, the average lipid area inside the brain was reduced by 2% to 38% compared with that of unsuppressed lipids, depending on the subject's region of interest. 2D FID-EPSI with external lipid crushing and L2-regularization provides high in-plane coverage and is suitable for investigating brain metabolite distributions at high fields.


Assuntos
Imagem Ecoplanar , Prótons , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Imagem Ecoplanar/métodos , Humanos , Lipídeos/química , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética/métodos
12.
Mov Disord ; 37(3): 479-489, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35114035

RESUMO

BACKGROUND: Parkinson's disease (PD) causes a loss of neuromelanin-positive, noradrenergic neurons in the locus coeruleus (LC), which has been implicated in nonmotor dysfunction. OBJECTIVES: We used "neuromelanin sensitive" magnetic resonance imaging (MRI) to localize structural disintegration in the LC and its association with nonmotor dysfunction in PD. METHODS: A total of 42 patients with PD and 24 age-matched healthy volunteers underwent magnetization transfer weighted (MTw) MRI of the LC. The contrast-to-noise ratio of the MTw signal (CNRMTw ) was used as an index of structural LC integrity. We performed slicewise and voxelwise analyses to map spatial patterns of structural disintegration, complemented by principal component analysis (PCA). We also tested for correlations between regional CNRMTw and severity of nonmotor symptoms. RESULTS: Mean CNRMTw of the right LC was reduced in patients relative to controls. Voxelwise and slicewise analyses showed that the attenuation of CNRMTw was confined to the right mid-caudal LC and linked regional CNRMTw to nonmotor symptoms. CNRMTw attenuation in the left mid-caudal LC was associated with the orthostatic drop in systolic blood pressure, whereas CNRMTw attenuation in the caudal most portion of right LC correlated with apathy ratings. PCA identified a bilateral component that was more weakly expressed in patients. This component was characterized by a gradient in CNRMTw along the rostro-caudal and dorso-ventral axes of the nucleus. The individual expression score of this component reflected the overall severity of nonmotor symptoms. CONCLUSION: A spatially heterogeneous disintegration of LC in PD may determine the individual expression of specific nonmotor symptoms such as orthostatic dysregulation or apathy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.


Assuntos
Neurônios Adrenérgicos , Doença de Parkinson , Neurônios Adrenérgicos/patologia , Humanos , Locus Cerúleo/metabolismo , Imageamento por Ressonância Magnética/métodos , Movimento , Doença de Parkinson/complicações
13.
Eur J Nutr ; 61(1): 329-340, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34338868

RESUMO

PURPOSE: Vitamin B3 provides nicotinamide adenine dinucleotide (NAD+), an essential coenzyme in oxidoreductase reactions. Severe vitamin B3 deficiency leads to the disease Pellagra, while mild vitamin B3 deficiency has been linked to age-related and metabolic diseases. Mild vitamin B3 deficiency is understudied, especially in females. Therefore, we examined how female mice responded to a diet that induced mild vitamin B3 deficiency in male mice. METHODS: Female C57BL/6RccHsd mice were subjected for 18 weeks to a diet without vitamin B3 and low but sufficient tryptophan (0.115%) (0NR) and were compared to control female mice on the same diet with the reference dose of vitamin B3 (30NR, 30 mg nicotinamide riboside/ kg diet). RESULTS: In the female mice, no differences between the two dietary groups were found in liver nicotinamide mononucleotide (NMN) levels, body composition, whole body energy and substrate metabolism measured by indirect calorimetry, or liver triacylglycerol metabolism. Expression of seven genes that previously were shown to respond to mild vitamin B3 deficiency in male white adipose tissue were not differentially expressed between the female dietary groups, neither was insulin sensitivity. CONCLUSION: We concluded that the female 0NR mice were not vitamin B3 deficient; the role of age, sex and health status is discussed. Demonstrated by clear differences between females and males, the latter showing mild deficiency under the same conditions, this study highlights the importance of studying both sexes.


Assuntos
Tecido Adiposo Branco , Niacinamida/deficiência , Deficiência de Vitaminas do Complexo B , Animais , Feminino , Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NAD , Fatores Sexuais , Vitaminas
14.
MAGMA ; 35(6): 943-951, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35511312

RESUMO

OBJECT: Improve shimming capabilities of ultra-high field systems, with addition of an accessible low-complexity B0 shim array for head MRI at 7 T. MATERIALS AND METHODS: An eight channel B0 shim coil array was designed as a tradeoff between shimming improvement and construction complexity, to provide an easy to use shim array that can be employed with the standard 7 T head coil. The array was interfaced using an open-source eight-channel shim amplifier rack. Improvements in field homogeneity for whole-brain and slice-based shimming were compared to standard second-order shimming, and to more complex higher order dynamic shimming and shim arrays with 32 and 48 channels. RESULTS: The eight-channel shim array provided 12% improvement in whole brain static shimming and provided 33% improvement when using slice-based shimming. With this, the eight-channel array performed similar to third-order dynamic shimming (without the need for higher order eddy current compensation). More complex shim arrays with 32 and 48 channels performed better, but require a dedicated RF coil. DISCUSSION: The designed eight-channel shim array provides a low-complexity and low-cost approach for improving B0 field shimming on an ultra-high field system. In both static and dynamic shimming, it provides improved B0 homogeneity over standard shimming.


Assuntos
Encéfalo , Processamento de Imagem Assistida por Computador , Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética , Ondas de Rádio , Software
15.
Neuroimage ; 233: 117922, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33662573

RESUMO

The major inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and the dominant antioxidant glutathione (GSH) both play a crucial role in brain functioning and are involved in several neurodegenerative and psychiatric diseases. Magnetic resonance spectroscopy (MRS) is a unique way to measure these neurometabolites non-invasively, but the measurement is highly sensitive to head movements, and especially in specific patient groups, motion stabilization in MRS could be valuable. Conventional MRS is acquired at relatively short echo times (TE), however, for unambiguous detection of GABA and GSH, spectral editing techniques are typically used. These depend on longer TEs and use frequency selective spectral editing pulses to separate the low-intensity peaks of GABA and GSH from overlapping resonances, but results in further increased motion sensitivity. Low-intensity metabolite peaks are usually edited one-by-one, however, simultaneous editing of multiple metabolites can be achieved using a Hadamard scheme, resulting in a substantial reduction in scan time. To investigate and correct for motion sensitivity in both conventional short-TE MRS (PRESS) and edited MRS (HERMES), we implemented a navigator-based prospective motion correction strategy including reacquisition of corrupted data. PRESS and HERMES spectra were acquired without motion, with motion with correction (repeated twice), and with motion without correction. Results indicate that when sufficient retrospective outlier removal is used, no significant differences in concentration and spectral quality were observed between motion conditions, even without prospective correction. HERMES spectral editing data showed to be more sensitive to motion, as significant differences in metabolite estimates and variability of spectral quality measures were observed for tCr, GABA+ and GSH when only retrospective outlier removal was applied. When using both prospective and retrospective correction, spectral quality was improved to almost the level of the no-motion acquisition. No differences in metabolite ratios for GABA and GSH could be observed when using motion correction. In conclusion, edited MRS showed to be more prone to motion artifacts, and prospective motion correction can restore most of the spectral quality in both conventional and edited MRS.


Assuntos
Encéfalo/metabolismo , Glutationa/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Movimento (Física) , Ácido gama-Aminobutírico/metabolismo , Adulto , Artefatos , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Espectroscopia de Ressonância Magnética/normas , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Adulto Jovem
16.
NMR Biomed ; 34(5): e4350, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32596978

RESUMO

Magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) allow the chemical analysis of physiological processes in vivo and provide powerful tools in the life sciences and for clinical diagnostics. Excellent homogeneity of the static B0 magnetic field over the object of interest is essential for achieving high-quality spectral results and quantitative metabolic measurements. The experimental minimization of B0 variation is performed in a process called B0 shimming. In this article, we summarize the concepts of B0 field shimming using spherical harmonic shimming techniques, specific strategies for B0 homogenization and crucial factors to consider for implementation and use in both brain and body. In addition, experts' recommendations are provided for minimum requirements for B0 shim hardware and evaluation criteria for the primary outcome of adequate B0 shimming for MRS and MRSI, such as the water spectroscopic linewidth.


Assuntos
Consenso , Imageamento por Ressonância Magnética , Animais , Calibragem , Simulação por Computador , Prova Pericial , Humanos , Campos Magnéticos , Processamento de Sinais Assistido por Computador
17.
J Inherit Metab Dis ; 44(2): 438-449, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32740932

RESUMO

Post-translational protein modifications derived from metabolic intermediates, such as acyl-CoAs, have been shown to regulate mitochondrial function. Patients with a genetic defect in the propionyl-CoA carboxylase (PCC) gene clinically present symptoms related to mitochondrial disorders and are characterised by decreased mitochondrial respiration. Since propionyl-CoA accumulates in PCC deficient patients and protein propionylation can be driven by the level of propionyl-CoA, we hypothesised that protein propionylation could play a role in the pathology of the disease. Indeed, we identified increased protein propionylation due to pathologic propionyl-CoA accumulation in patient-derived fibroblasts and this was accompanied by defective mitochondrial respiration, as was shown by a decrease in complex I-driven respiration. To mimic pathological protein propionylation levels, we exposed cultured fibroblasts, Fao liver cells and C2C12 muscle myotubes to propionate levels that are typically found in these patients. This induced a global increase in protein propionylation and histone protein propionylation and was also accompanied by a decrease in mitochondrial respiration in liver and fibroblasts. However, in C2C12 myotubes propionate exposure did not decrease mitochondrial respiration, possibly due to differences in propionyl-CoA metabolism as compared to the liver. Therefore, protein propionylation could contribute to the pathology in these patients, especially in the liver, and could therefore be an interesting target to pursue in the treatment of this metabolic disease.


Assuntos
Fibroblastos/metabolismo , Metilmalonil-CoA Descarboxilase/genética , Mitocôndrias/genética , Fibras Musculares Esqueléticas/metabolismo , Acidemia Propiônica/genética , Humanos , Fígado/metabolismo , Proteínas de Membrana , Mitocôndrias/enzimologia , Propionatos/metabolismo , Acidemia Propiônica/enzimologia , Processamento de Proteína Pós-Traducional/genética
18.
Mol Cell ; 50(5): 686-98, 2013 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-23746352

RESUMO

Lipid metabolism is tightly controlled by the nutritional state of the organism. Nutrient-rich conditions increase lipogenesis, whereas nutrient deprivation promotes fat oxidation. In this study, we identify the mitochondrial sirtuin, SIRT4, as a regulator of lipid homeostasis. SIRT4 is active in nutrient-replete conditions to repress fatty acid oxidation while promoting lipid anabolism. SIRT4 deacetylates and inhibits malonyl CoA decarboxylase (MCD), an enzyme that produces acetyl CoA from malonyl CoA. Malonyl CoA provides the carbon skeleton for lipogenesis and also inhibits fat oxidation. Mice lacking SIRT4 display elevated MCD activity and decreased malonyl CoA in skeletal muscle and white adipose tissue. Consequently, SIRT4 KO mice display deregulated lipid metabolism, leading to increased exercise tolerance and protection against diet-induced obesity. In sum, this work elucidates SIRT4 as an important regulator of lipid homeostasis, identifies MCD as a SIRT4 target, and deepens our understanding of the malonyl CoA regulatory axis.


Assuntos
Carboxiliases/metabolismo , Metabolismo dos Lipídeos , Proteínas Mitocondriais/metabolismo , Sirtuínas/metabolismo , Acetilação , Tecido Adiposo Branco/metabolismo , Animais , Dieta , Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos/genética , Lipídeos/biossíntese , Masculino , Camundongos , Camundongos Knockout , Proteínas Mitocondriais/genética , Obesidade/etiologia , Obesidade/metabolismo , Oxirredução , Sirtuínas/genética
19.
Int J Mol Sci ; 22(20)2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34681598

RESUMO

Butyrate is considered the primary energy source of colonocytes and has received wide attention due to its unique health benefits. Insight into the mechanistic effects of butyrate on cellular and metabolic function relies mainly on research in in-vitro-cultured cells. However, cells in culture differ from those in vivo in terms of metabolic phenotype and nutrient availability. For translation, it is therefore important to understand the impact of different nutrients on the effects of butyrate. We investigated the metabolic consequences of butyrate exposure under various culturing conditions, with a focus on the interaction between butyrate and glucose. To investigate whether the effects of butyrate were different between cells with high and low mitochondrial capacity, we cultured HT29 cells under either low- (0.5 mM) or high- (25 mM) glucose conditions. Low-glucose culturing increased the mitochondrial capacity of HT29 cells compared to high-glucose (25 mM) cultured HT29 cells. Long-term exposure to butyrate did not alter mitochondrial bioenergetics, but it decreased glycolytic function, regardless of glucose availability. In addition, both high- and low-glucose-grown HT29 cells showed increased lipid droplet accumulation following long-term butyrate exposure. Acute exposure of cultured cells (HT29 and Caco-2) to butyrate increased their oxygen consumption rate (OCR). A simultaneous decrease in extracellular acidification rate (ECAR) was observed. Furthermore, in the absence of glucose, OCR did not increase in response to butyrate. These results lead us to believe that butyrate itself was not responsible for the observed increase in OCR, but, instead, butyrate stimulated pyruvate flux into mitochondria. Indeed, blocking of the mitochondrial pyruvate carrier prevented a butyrate-induced increase in oxygen consumption. Taken together, our results indicate that butyrate itself is not oxidized in cultured cells but instead alters pyruvate flux and induces lipid accumulation.


Assuntos
Butiratos/farmacologia , Gotículas Lipídicas/metabolismo , Mitocôndrias/efeitos dos fármacos , Ácido Pirúvico/metabolismo , Linhagem Celular Tumoral , Colo/citologia , Colo/efeitos dos fármacos , Colo/metabolismo , Glucose/farmacologia , Glicólise/efeitos dos fármacos , Humanos , Mitocôndrias/metabolismo , Consumo de Oxigênio/efeitos dos fármacos
20.
Magn Reson Med ; 84(3): 1101-1112, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32060951

RESUMO

PURPOSE: To interleave global and local higher order shimming for single voxel MRS. Single voxel MR spectroscopy requires optimization of the B0 field homogeneity in the region of the voxel to obtain a narrow linewidth and provide high data quality. However, the optimization of local higher order fields on a localized MRS voxel typically leads to large field offsets outside that volume. This compromises interleaved MR sequence elements that benefit from global field homogeneity such as water suppression, interleaved MRS-fMRI, and MR motion correction. METHODS: A shimming algorithm was developed to optimize the MRS voxel homogeneity and the whole brain homogeneity for interleaved sequence elements, using static higher order shims and dynamic linear terms (HOS-DLT). Shimming performance was evaluated using 6 brain regions and 10 subjects. Furthermore, the benefits of HOS-DLT was demonstrated for water suppression, MRS-fMRI, and motion corrected MRS using fat-navigators. RESULTS: The HOS-DLT algorithm was shown to improve the whole brain homogeneity compared to an MRS voxel-based shim, without compromising the MRS voxel homogeneity. Improved water suppression over the brain, reduced image distortions in MRS-fMRI, and improved quality of motion navigators were demonstrated using the HOS-DLT method. CONCLUSION: HOS-DLT shimming allowed for both local and global field homogeneity, providing excellent MR spectroscopy data quality, as well as good field homogeneity for interleaved sequence elements, even without the need for dynamic higher order shimming capabilities.


Assuntos
Imageamento por Ressonância Magnética , Água , Algoritmos , Encéfalo/diagnóstico por imagem , Humanos , Espectroscopia de Ressonância Magnética , Movimento (Física)
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA