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Journal of Nuclear Medicine : Official... Aug 2021
Topics: Fluorodeoxyglucose F18; Humans; Inflammation; Middle Aged; Positron-Emission Tomography
PubMed: 33893189
DOI: 10.2967/jnumed.121.262446 -
Psychological Medicine Aug 2023Impaired brain metabolism may be central to schizophrenia pathophysiology, but the magnitude and consistency of metabolic dysfunction is unknown. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Impaired brain metabolism may be central to schizophrenia pathophysiology, but the magnitude and consistency of metabolic dysfunction is unknown.
METHODS
We searched MEDLINE, PsychINFO and EMBASE between 01/01/1980 and 13/05/2021 for studies comparing regional brain glucose metabolism using FDG-PET, in schizophrenia/first-episode psychosis controls. Effect sizes (Hedges ) were pooled using a random-effects model. Primary measures were regional absolute and relative CMRGlu in frontal, temporal, parietal and occipital lobes, basal ganglia and thalamus.
RESULTS
Thirty-six studies (1335 subjects) were included. Frontal absolute glucose metabolism (Hedge's = -0.74 ± 0.54, = 0.01; = 67%) and metabolism relative to whole brain ( = -0.44 ± 0.34, = 0.01; = 55%) were lower in schizophrenia controls with moderate heterogeneity. Absolute frontal metabolism was lower in chronic ( = -1.18 ± 0.73) first-episode patients ( = -0.09 ± 0.88) and controls. Medicated patients showed frontal hypometabolism relative to controls (-1.04 ± 0.26) while metabolism in drug-free patients did not differ significantly from controls. There were no differences in parietal, temporal or occipital lobe or thalamic metabolism in schizophrenia controls. Excluding outliers, absolute basal ganglia metabolism was lower in schizophrenia controls (-0.25 ± 0.24, = 0.049; = 5%). Studies identified reporting voxel-based morphometry measures of absolute FDG uptake (eight studies) were also analysed using signed differential mapping analysis, finding lower FDG uptake in the left anterior cingulate gyrus ( = -4.143; = 0.007) and the left inferior orbital frontal gyrus ( = -4.239; = 0.02) in schizophrenia.
CONCLUSIONS
We report evidence for hypometabolism with large effect sizes in the frontal cortex in schizophrenia without consistent evidence for alterations in other brain regions. Our findings support the hypothesis of hypofrontality in schizophrenia.
Topics: Humans; Glucose; Schizophrenia; Fluorodeoxyglucose F18; Brain; Positron-Emission Tomography
PubMed: 35730361
DOI: 10.1017/S003329172200174X -
PLoS Genetics Jul 2020Yeast and fast-growing human tumor cells share metabolic similarities in that both cells use fermentation of glucose for energy and both are highly sensitive to the...
Yeast and fast-growing human tumor cells share metabolic similarities in that both cells use fermentation of glucose for energy and both are highly sensitive to the glucose analog 2-deoxyglucose. Spontaneous mutations in S. cerevisiae that conferred resistance to 2-deoxyglucose were identified by whole genome sequencing. Missense alleles of the HXK2, REG1, GLC7 and SNF1 genes were shown to confer significant resistance to 2-deoxyglucose and all had the potential to alter the activity and or target selection of the Snf1 kinase signaling pathway. All three missense alleles in HXK2 resulted in significantly reduced catalytic activity. Addition of 2DG promotes endocytosis of the glucose transporter Hxt3. All but one of the 2DG-resistant strains reduced the 2DG-mediated hexose transporter endocytosis by increasing plasma membrane occupancy of the Hxt3 protein. Increased expression of the DOG (deoxyglucose) phosphatases has been associated with resistance to 2-deoxyglucose. Expression of both the DOG1 and DOG2 mRNA was elevated after treatment with 2-deoxyglucose but induction of these genes is not associated with 2DG-resistance. RNAseq analysis of the transcriptional response to 2DG showed large scale, genome-wide changes in mRNA abundance that were greatly reduced in the 2DG resistant strains. These findings suggest the common adaptive response to 2DG is to limit the magnitude of the response. Genetic studies of 2DG resistance using the dominant SNF1-G53R allele in cells that are genetically compromised in both the endocytosis and DOG pathways suggest that at least one more mechanism for conferring resistance to this glucose analog remains to be discovered.
Topics: Deoxyglucose; Endocytosis; Energy Metabolism; Gene Expression Regulation, Fungal; Glucose; Glucose Transport Proteins, Facilitative; Hexokinase; Humans; Mutation; Phosphoric Monoester Hydrolases; Protein Phosphatase 1; Protein Serine-Threonine Kinases; RNA, Messenger; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Signal Transduction; Whole Genome Sequencing
PubMed: 32673313
DOI: 10.1371/journal.pgen.1008484 -
Biomedicine & Pharmacotherapy =... Sep 2019Sites of infection and inflammation can be misleading in oncology PET/CT imaging because these areas commonly show F-FDG activity. Caution in the interpretation must be... (Review)
Review
Sites of infection and inflammation can be misleading in oncology PET/CT imaging because these areas commonly show F-FDG activity. Caution in the interpretation must be taken to avoid the misdiagnosis of malignancy. Utilization of both CT findings as well as patient history can help differentiate benign infectious and inflammatory processes from malignancy, although occasionally additional work-up may be required. This article discusses the mechanism of F-FDG uptake in infection and inflammation with illustrative examples.
Topics: Animals; Fluorodeoxyglucose F18; Humans; Infections; Inflammation; Neoplasms; Positron Emission Tomography Computed Tomography
PubMed: 31334700
DOI: 10.1016/j.biopha.2019.109168 -
Journal of Pharmacological Sciences Sep 2021We investigated the effect of 3-methyladenine (3MA), a class III phosphatidylinositol 3-kinase (PI3K)-blocking autophagy inhibitor, on cancer cell death induced by...
We investigated the effect of 3-methyladenine (3MA), a class III phosphatidylinositol 3-kinase (PI3K)-blocking autophagy inhibitor, on cancer cell death induced by simultaneous inhibition of glycolysis by 2-deoxyglucose (2DG) and mitochondrial respiration by rotenone. 2DG/rotenone reduced ATP levels and increased mitochondrial superoxide production, causing mitochondrial swelling and necrotic death in various cancer cell lines. 2DG/rotenone failed to increase proautophagic beclin-1 and autophagic flux in melanoma cells despite the activation of AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin complex 1 (mTORC1). 3MA, but not autophagy inhibition with other PI3K and lysosomal inhibitors, attenuated 2DG/rotenone-induced mitochondrial damage, oxidative stress, ATP depletion, and cell death, while antioxidant treatment mimicked its protective action. The protection was not mediated by autophagy upregulation via class I PI3K/Akt inhibition, as it was preserved in cells with genetically inhibited autophagy. 3MA increased AMPK and mTORC1 activation in energy-stressed cells, but neither AMPK nor mTORC1 inhibition reduced its cytoprotective effect. 3MA reduced JNK activation, and JNK pharmacological/genetic suppression mimicked its mitochondria-preserving and cytoprotective activity. Therefore, 3MA prevents energy stress-triggered cancer cell death through autophagy-independent mechanisms possibly involving JNK suppression and decrease of oxidative stress. Our results warrant caution when using 3MA as an autophagy inhibitor.
Topics: AMP-Activated Protein Kinases; Adenine; Animals; Autophagy; Cell Death; Deoxyglucose; JNK Mitogen-Activated Protein Kinases; Mechanistic Target of Rapamycin Complex 1; Melanoma; Melanoma, Experimental; Mice, Inbred C57BL; Mitochondria; Mitochondrial Swelling; Necrosis; Oxidative Stress; Phosphatidylinositol 3-Kinases; Rotenone; Mice
PubMed: 34294367
DOI: 10.1016/j.jphs.2021.06.003 -
Journal of Neurophysiology Apr 20192-Deoxy-d-glucose (2DG), a glucose analog that inhibits glycolysis, has acute and chronic antiepileptic effects. We evaluated 2DG's acute effects on synaptic and...
2-Deoxy-d-glucose (2DG), a glucose analog that inhibits glycolysis, has acute and chronic antiepileptic effects. We evaluated 2DG's acute effects on synaptic and membrane properties of CA3 pyramidal neurons in vitro. 2DG (10 mM) had no effects on spontaneously occurring postsynaptic currents (PSCs) in 3.5 mM extracellular potassium concentration ([K]). In 7.5 mM [K], 2DG significantly reduced the frequency of epileptiform bursting and the charge carried by postsynaptic currents (PSCs) with a greater effect on inward excitatory compared with outward inhibitory charge (71% vs. 40%). In 7.5 mM [K] and bicuculline, 2DG reduced significantly the excitatory charge by 67% and decreased the frequency but not amplitude of excitatory PSCs between bursts. In 7.5 mM [K], 2DG reduced pharmacologically isolated inhibitory PSC frequency without a change in amplitude. The frequency but not amplitude of inward miniature PSCs was reduced when 2DG was applied in 7.5 mM [K] before bath application of TTX, but there was no effect when 2DG was applied after TTX, indicating a use-dependent uptake of 2DG was required for its actions at a presynaptic locus. 2DG did not alter membrane properties of CA3 neurons except for reducing the slow afterhyperpolarization in 3.5 but not 7.5 mM [K]. The reduction in frequency of spontaneous and inward miniature PSCs in elevated [K] indicates a presynaptic mechanism of action. 2DG effects required use-dependent uptake and suggest an important role for glycolysis in neuronal metabolism and energetics in states of high neural activity as occur during abnormal network synchronization and seizures. NEW & NOTEWORTHY 2-Deoxy-d-glucose (2DG) is a glycolytic inhibitor and suppresses epileptiform activity acutely and has chronic antiepileptic effects. The mechanisms of the acute effects are not well delineated. In this study, we show 2DG suppressed abnormal network epileptiform activity without effecting normal synaptic network activity or membrane properties. The effects appear to be use dependent and have a presynaptic locus of action. Inhibition of glycolysis is a novel presynaptic mechanism to limit abnormal neuronal network activity and seizures.
Topics: Animals; Bicuculline; CA3 Region, Hippocampal; Deoxyglucose; Epilepsy; Glycolysis; Neurons; Potassium; Rats; Rats, Sprague-Dawley; Synaptic Potentials; Tetrodotoxin
PubMed: 30673364
DOI: 10.1152/jn.00723.2018 -
European Journal of Nuclear Medicine... Dec 2021
Topics: Fluorodeoxyglucose F18; Humans; Positron-Emission Tomography; Radiopharmaceuticals
PubMed: 33515054
DOI: 10.1007/s00259-021-05214-5 -
Molecular Biology of the Cell Oct 2022Endothelia determine blood-to-tissue solute delivery, yet glucose transit is poorly understood. To illuminate mechanisms, we tracked [H]-2-deoxyglucose (2-DG) in human...
Endothelia determine blood-to-tissue solute delivery, yet glucose transit is poorly understood. To illuminate mechanisms, we tracked [H]-2-deoxyglucose (2-DG) in human adipose-tissue microvascular endothelial cells. 2-DG uptake was largely facilitated by the glucose transporters GLUT1 and GLUT3. Once in the cytosol, >80% of 2-DG became phosphorylated and ∼20% incorporated into glycogen, suggesting that transported glucose is readily accessible to cytosolic enzymes. Interestingly, a fraction of intracellular 2-DG was released over time (15-20% over 30 min) with slower kinetics than for uptake, involving GLUT3. In contrast to intracellular 2-DG, the released 2-DG was largely unphosphorylated. Glucose release involved endoplasmic reticulum-resident translocases/phosphatases and was stimulated by adrenaline, consistent with participation of glycogenolysis and glucose dephosphorylation. Surprisingly, the fluorescent glucose derivative 2-NBD-glucose (2-NBDG) entered cells largely via fluid phase endocytosis and exited by recycling. 2-NBDG uptake was insensitive to GLUT1/GLUT3 inhibition, suggesting poor influx across membranes. 2-NBDG recycling, but not 2-DG efflux, was sensitive to N-ethyl maleimide. In sum, by utilizing radioactive and fluorescent glucose derivatives, we identified two parallel routes of entry: uptake into the cytosol through dedicated glucose transporters and endocytosis. This reveals the complex glucose handling by endothelial cells that may contribute to glucose delivery to tissues.
Topics: Deoxyglucose; Endothelial Cells; Epinephrine; Glucose; Glucose Transporter Type 1; Glucose Transporter Type 3; Glycogen; Humans; Maleimides; Phosphoric Monoester Hydrolases
PubMed: 35921166
DOI: 10.1091/mbc.E22-04-0146 -
BioMed Research International 2019The objective of this study was to evaluate the association between salivary 1,5-anhydroglucitol (AG), vitamins A (VA), C (VC), and E (VE), and caries risk in children....
The objective of this study was to evaluate the association between salivary 1,5-anhydroglucitol (AG), vitamins A (VA), C (VC), and E (VE), and caries risk in children. 100 healthy children aged between 6 and 13 years were divided into two equal groups of caries-free (DMFS/dmfs=0) and caries active (DMFS/dmfs>3). Unstimulated midmorning saliva was collected from all the children and the levels of salivary AG and vitamins A, C, and E were measured. Caries risk assessment was done using American Academy of Pediatric Dentistry Caries Assessment Tool. Analysis of salivary AG and vitamins was performed using a commercially available ELISA kit. Low levels of AG were present in caries active and high caries risk groups compared to caries-free and low/medium caries risk groups. This difference is statistically significant (p < 0.05). A strong negative correlation between AG and caries activity was observed in the caries active group. VA was not related to caries activity, while VC and VE displayed a statistically significant correlation (p < 0.05). Similarly, a strong negative correlation was observed between the levels of AG and high caries risk group. Salivary AG, VC, and VE together are related to caries risk in caries active children. These salivary parameters can act as indicator of caries status in children.
Topics: Adolescent; Ascorbic Acid; Child; Dental Caries; Deoxyglucose; Female; Humans; Male; Risk Factors; Saliva; Vitamin A; Vitamin E
PubMed: 30881987
DOI: 10.1155/2019/4503450 -
American Journal of Physiology.... Oct 2022A portion of absorbed dietary triglycerides (TG) is retained in the intestine after the postprandial period, within intracellular and extracellular compartments. This...
A portion of absorbed dietary triglycerides (TG) is retained in the intestine after the postprandial period, within intracellular and extracellular compartments. This pool of TG can be mobilized in response to several stimuli, including oral glucose. The objective of this study was to determine whether oral glucose must be absorbed and metabolized to mobilize TG in rats and whether high-fat feeding, a model of insulin resistance, alters the lipid mobilization response to glucose. Lymph flow, TG concentration, TG output, and apolipoprotein B48 (apoB48) concentration and output were assessed after an intraduodenal lipid bolus in rats exposed to the following intraduodenal administrations 5 h later: saline (placebo), glucose, 2-deoxyglucose (2-DG, absorbed but not metabolized), or glucose + phlorizin (intestinal glucose absorption inhibitor). Glucose alone, but not 2-DG or glucose + phlorizin treatments, stimulated lymph flow, TG output, and apoB48 output compared with placebo. The effects of glucose in high-fat-fed rats were similar to those in chow-fed rats. In conclusion, glucose must be both absorbed and metabolized to enhance lymph flow and intestinal lipid mobilization. This effect is qualitatively and quantitatively similar in high-fat- and chow-fed rats. The precise signaling mechanism whereby enteral glucose enhances lymph flow and mobilizes enteral lipid remains to be determined. Glucose potently enhances mesenteric lymph flow in chow- and high-fat-fed rats. The magnitude of glucose effect on lymph flow is no different in chow- and high-fat-fed rats. Glucose must be absorbed and metabolized to enhance lymph flow and mobilize intestinal lipid.
Topics: Animals; Apolipoprotein B-48; Chylomicrons; Deoxyglucose; Glucose; Lymph; Phlorhizin; Rats; Triglycerides
PubMed: 35916412
DOI: 10.1152/ajpgi.00095.2022