-
Journal of Neuroscience Research Nov 2017Metabolic abnormalities found in epileptogenic tissue provide considerable evidence of brain hypometabolism, while major risk factors for acquired epilepsy all share...
Metabolic abnormalities found in epileptogenic tissue provide considerable evidence of brain hypometabolism, while major risk factors for acquired epilepsy all share brain hypometabolism as one common outcome, suggesting that a breakdown of brain energy homeostasis may actually precede epileptogenesis. However, a causal link between deficient brain energy metabolism and epilepsy initiation has not been yet established. To address this issue we developed an in vivo model of chronic energy hypometabolism by daily intracerebroventricular (i.c.v.) injection of the nonmetabolizable glucose analog 2-deoxy-D-glucose (2-DG) and also investigated acute effects of 2-DG on the cellular level. In hippocampal slices, acute glycolysis inhibition by 2-DG (by about 35%) led to contrasting effects on the network: a downregulation of excitatory synaptic transmission together with a depolarization of neuronal resting potential and a decreased drive of inhibitory transmission. Therefore, the potential acute effect of 2-DG on network excitability depends on the balance between these opposing pre- and postsynaptic changes. In vivo, we found that chronic 2-DG i.c.v. application (estimated transient inhibition of brain glycolysis under 14%) for a period of 4 weeks induced epileptiform activity in initially healthy male rats. Our results suggest that chronic inhibition of brain energy metabolism, characteristics of the well-established risk factors of acquired epilepsy, and specifically a reduction in glucose utilization (typically observed in epileptic patients) can initiate epileptogenesis. © 2017 Wiley Periodicals, Inc.
Topics: Animals; Brain; Deoxyglucose; Energy Metabolism; Epilepsy; Glycolysis; Injections, Intraventricular; Male; Mice; Organ Culture Techniques; Rats; Rats, Sprague-Dawley
PubMed: 28150440
DOI: 10.1002/jnr.24019 -
The American Journal of Clinical... Jan 2022Dicarbonyls are highly reactive compounds and major precursors of advanced glycation end products (AGEs). Both dicarbonyls and AGEs are associated with development of...
BACKGROUND
Dicarbonyls are highly reactive compounds and major precursors of advanced glycation end products (AGEs). Both dicarbonyls and AGEs are associated with development of age-related diseases. Dicarbonyls are formed endogenously but also during food processing. To what extent dicarbonyls from the diet contribute to circulating dicarbonyls and AGEs in tissues is unknown.
OBJECTIVES
To examine cross-sectional associations of dietary dicarbonyl intake with plasma dicarbonyl concentrations and skin AGEs.
METHODS
In 2566 individuals of the population-based Maastricht Study (age: 60 ± 8 y, 50% males, 26% with type 2 diabetes), we estimated habitual intake of the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) by combining FFQs with our dietary dicarbonyl database of MGO, GO, and 3-DG concentrations in > 200 commonly consumed food products. Fasting plasma concentrations of MGO, GO, and 3-DG were measured by ultra-performance liquid chromatography-tandem mass spectrometry. Skin AGEs were measured as skin autofluorescence (SAF), using the AGE Reader. Associations of dietary dicarbonyl intake with their respective plasma concentrations and SAF (all standardized) were examined using linear regression models, adjusted for age, sex, potential confounders related to cardiometabolic risk factors, and lifestyle.
RESULTS
Median intake of MGO, GO, and 3-DG was 3.6, 3.5, and 17 mg/d, respectively. Coffee was the main dietary source of MGO, whereas this was bread for GO and 3-DG. In the fully adjusted models, dietary MGO was associated with plasma MGO (β: 0.08; 95% CI: 0.02, 0.13) and SAF (β: 0.12; 95% CI: 0.07, 0.17). Dietary GO was associated with plasma GO (β: 0.10; 95% CI: 0.04, 0.16) but not with SAF. 3-DG was not significantly associated with either plasma 3-DG or SAF.
CONCLUSIONS
Higher habitual intake of dietary MGO and GO, but not 3-DG, was associated with higher corresponding plasma concentrations. Higher intake of MGO was also associated with higher SAF. These results suggest dietary absorption of MGO and GO. Biological implications of dietary absorption of MGO and GO need to be determined. The study has been approved by the institutional medical ethical committee (NL31329.068.10) and the Minister of Health, Welfare and Sports of the Netherlands (Permit 131088-105234-PG).
Topics: Aged; Chromatography, Liquid; Cross-Sectional Studies; Deoxyglucose; Diabetes Mellitus, Type 2; Diet; Diet Surveys; Dietary Exposure; Fasting; Female; Glycation End Products, Advanced; Glyoxal; Humans; Linear Models; Male; Mass Spectrometry; Middle Aged; Netherlands; Optical Imaging; Pyruvaldehyde; Skin
PubMed: 34625788
DOI: 10.1093/ajcn/nqab329 -
Food Chemistry Mar 2022Glucose is a primary source of energy used in most organisms. Thus, development of reliable approaches to measure intracellular glucose uptake is an important research...
Glucose is a primary source of energy used in most organisms. Thus, development of reliable approaches to measure intracellular glucose uptake is an important research issue. 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-d-glucose (2-NBDG), as a fluorescent glucose derivative, has been widely used to track intracellular glucose uptake by fluorescence imaging and measuring in mammalian cells. However, the avoid-less cross-interference of intrinsic autofluorescence background and tested fluorescent compounds limits its ability to provide trustworthy information on intracellular glucose uptake. By the extraction, separation and detection of 2-NBDG, a simple, sensitive and accurate HPLC-FLD method was established and validated for the measurement of intracellular glucose uptake in HepG2 cells. The developed method has been employed successfully to assess the glucose uptake activity of anti-diabetic drugs and fluorescent natural products. A fit-for-purpose partial validation was further performed for quantification and comparison of glucose uptake in AML12, LO2 hepatocytes, L6 myoblasts and 3T3-L1 preadipocytes.
Topics: 3T3-L1 Cells; 4-Chloro-7-nitrobenzofurazan; Animals; Biological Transport; Chromatography, High Pressure Liquid; Deoxyglucose; Fluorescent Dyes; Glucose; Mice
PubMed: 34624783
DOI: 10.1016/j.foodchem.2021.131218 -
Physiology & Behavior Jan 2023Inflammation is linked to motivational deficits seen in depression and other disorders. Lipopolysaccharide (LPS) induces an inflammatory response and impairs motivated...
Inflammation is linked to motivational deficits seen in depression and other disorders. Lipopolysaccharide (LPS) induces an inflammatory response and impairs motivated behavior in humans and rodents. It has been suggested that inflammation can shift metabolic needs to functions that warrant more response to the perceived threat (e.g., fighting infection), therefore altering aspects of motivation. Animal models have been developed to assess alterations in motivated behavior by giving the animal the option to work (i.e., lever press) for a highly palatable food reward vs. approaching and consuming a freely available, albeit less preferred, food. This model was used to determine if administration of 2-deoxy-D-glucose (2DG), a substance that inhibits glucose uptake and glycolysis, could reverse the motivational deficits induced by LPS in rats. A food preference/intake task was also conducted to see if LPS affected intake of the highly palatable vs. less palatable foods when both are freely available. It was hypothesized that 2-DG would reverse the motivational deficits caused by LPS and there would be no effect on food preference/intake of the highly palatable food. Results showed that 2-DG significantly reversed LPS effects at the lowest dose, while methylphenidate did not. The food intake/preference tests showed that LPS significantly decreased food intake of both foods but did not alter preference for the highly palatable food compared to vehicle. These results suggest that in addition to having effects on exertion of effort during instrumental behavior, LPS also has direct effects on primary food motivation.
Topics: Humans; Rats; Animals; Motivation; Lipopolysaccharides; Choice Behavior; Rats, Sprague-Dawley; Deoxyglucose; Reward; Inflammation
PubMed: 36283457
DOI: 10.1016/j.physbeh.2022.114005 -
The Journal of Biological Chemistry May 2017Here we report the use of a fluorescein-tagged peroxisomal targeting sequence peptide (F-PTS1, acetyl-C{K(FITC)}GGAKL) for investigating pH regulation of glycosomes in...
Here we report the use of a fluorescein-tagged peroxisomal targeting sequence peptide (F-PTS1, acetyl-C{K(FITC)}GGAKL) for investigating pH regulation of glycosomes in live procyclic form When added to cells, this fluorescent peptide is internalized within vesicular structures, including glycosomes, and can be visualized after 30-60 min. Using F-PTS1 we are able to observe the pH conditions inside glycosomes in response to starvation conditions. Previous studies have shown that in the absence of glucose, the glycosome exhibits mild acidification from pH 7.4 ± 0.2 to 6.8 ± 0.2. Our results suggest that this response occurs under proline starvation as well. This pH regulation is found to be independent from cytosolic pH and requires a source of Na ions. Glycosomes were also observed to be more resistant to external pH changes than the cytosol; placement of cells in acidic buffers (pH 5) reduced the pH of the cytosol by 0.8 ± 0.1 pH units, whereas glycosomal pH decreases by 0.5 ± 0.1 pH units. This observation suggests that regulation of glycosomal pH is different and independent from cytosolic pH regulation. Furthermore, pH regulation is likely to work by an active process, because cells depleted of ATP with 2-deoxyglucose and sodium azide were unable to properly regulate pH. Finally, inhibitor studies with bafilomycin and EIPA suggest that both V-ATPases and Na/H exchangers are required for glycosomal pH regulation.
Topics: Adenosine Triphosphate; Amiloride; Animals; Cytosol; Deoxyglucose; Digitonin; Glucose; Homeostasis; Hydrogen-Ion Concentration; Macrolides; Microbodies; Microscopy, Fluorescence; Potassium; Proline; Protein Domains; Protozoan Proteins; Sodium Azide; Trypanosoma brucei brucei
PubMed: 28348078
DOI: 10.1074/jbc.M117.784173 -
Nuclear Medicine Communications Mar 2022The aim of the study was to construct and validate 18F-fluorodeoxyglucose (18F-FDG) PET-based radiomics nomogram and use it to predict N2-3b lymph node metastasis in...
OBJECTIVE
The aim of the study was to construct and validate 18F-fluorodeoxyglucose (18F-FDG) PET-based radiomics nomogram and use it to predict N2-3b lymph node metastasis in Chinese patients with gastric cancer (GC).
METHODS
A total of 127 patients with pathologically confirmed GC who underwent preoperative 18F-FDG PET/CT imaging between January 2014 and September 2020 were enrolled as subjects in this study. We use the LIFEx software to extract PET radiomic features. A radiomics signature (Rad-score) was developed with the least absolute shrinkage and selection operator algorithm. Then a prediction model, which incorporated the Rad-score and independent clinical risk factors, was constructed and presented with a radiomics nomogram. Receiver operating characteristic (ROC) analysis was used to assess the performance of Rad-score and the nomogram. Finally, decision curve analysis (DCA) was applied to evaluate the clinical usefulness of the nomogram.
RESULTS
The PET Rad-score, which includes four selected features, was significantly related to pN2-3b (all P < 0.05). The prediction model, which comprised the Rad-score and carcinoembryonic antigen (CEA) level, showed good calibration and discrimination [area under the ROC curve: 0.81(95% confidence interval: 0.74-0.89), P < 0.001)]. The DCA also indicated that the prediction model was clinically useful.
CONCLUSION
This study presents a radiomics nomogram consisting of a radiomics signature based on PET images and CEA level that can be conveniently used for personalized prediction of high-risk N2-3b metastasis in Chinese GC patients.
Topics: Fluorodeoxyglucose F18
PubMed: 34954765
DOI: 10.1097/MNM.0000000000001523 -
Food Chemistry Aug 20193-Deoxyglucosone (3-DG) is a metabolite from sugar degradation obtained by the Maillard reaction. It is an important precursor compound in Strecker reactionism that...
3-Deoxyglucosone (3-DG) is a metabolite from sugar degradation obtained by the Maillard reaction. It is an important precursor compound in Strecker reactionism that directly leads to known beer aging indicators and can influence the final sensory beer quality. However, the conditions of 3-DG formation in the malting process have not yet been described. To investigate the reaction pathways of 3-DG formation, we varied the composition of reactants (sugars, amino acids) by using different malting modification levels (germination time 5-7 d; steeping degree 42-45%; germination temperature 12-14 °C); final kilning temperature (60 °C to 100 °C). After its derivatization with ortho-phenylenediamine, we analyzed 3-DG with HPLC-UV. 3-DG concentration was between 5 and 120 µmol/100 g dry weight. The formation of 3-DG increased for high malt modification levels and high final kilning temperature. The abundant formation of 3-DG in the malting process is already comparable to the occurred brewing process concentration.
Topics: Amino Acids; Beer; Chromatography, High Pressure Liquid; Deoxyglucose; Food Handling; Maillard Reaction; Monosaccharides; Phenylenediamines; Spectrophotometry, Ultraviolet; Temperature
PubMed: 31000036
DOI: 10.1016/j.foodchem.2019.03.144 -
Journal of Reproductive Immunology Sep 2023The proper invasion of trophoblasts is crucial for embryo implantation and placental development, which is helpful to establish a correct maternal-fetal relationship....
The proper invasion of trophoblasts is crucial for embryo implantation and placental development, which is helpful to establish a correct maternal-fetal relationship. Trophoblasts can produce a large amount of lactate through aerobic glycolysis during early pregnancy. Lactate creates a low pH microenvironment around the embryo to help uterine tissue decompose and promote the invasion of trophoblasts. The purpose of this study is to reveal the the potential mechanism of aerobic glycolysis regulating the invasiveness of trophoblasts by investigating the effect of 2-Deoxy-D-glucose (2-DG), a glycolysis inhibitor, on the biological function of HTR-8/SVneo trophoblast cells, the expressions of epithelial mesenchymal transformation (EMT) markers and invasion-related factors. 2-DG could inhibit the aerobic glycolysis of trophoblasts and decrease the activity of trophoblasts in a dose-dependent manner. Moreover, 2-DG inhibited the EMT of HTR-8/SVneo cells, down-regulated the expression of invasion-related factors matrix metalloproteinase 2/9 (MMP2/9) and up-regulated the expression of tissue inhibitor of matrix metalloproteinases 1/2 (TIMP1/2), thus inhibiting cell migration and invasion. This paper provides a foundation in the significance of aerobic glycolysis of trophoblasts in the process of invasion, and also provides ideas and insights for the promotion of embryo implantation.
Topics: Humans; Pregnancy; Female; Trophoblasts; Placenta; Matrix Metalloproteinase 2; Signal Transduction; Cell Line; Deoxyglucose; Lactates; Cell Movement
PubMed: 37487312
DOI: 10.1016/j.jri.2023.104123 -
British Journal of Pharmacology Mar 2019The pathogenic mechanism of autosomal dominant polycystic kidney disease (ADPKD) is unclear. Similar to tumour cells, polycystic kidney cells are primarily dependent on...
BACKGROUND AND PURPOSE
The pathogenic mechanism of autosomal dominant polycystic kidney disease (ADPKD) is unclear. Similar to tumour cells, polycystic kidney cells are primarily dependent on aerobic glycolysis for ATP production. Compared with rodents, miniature pigs are more similar to humans. This study is the first time to investigate the effects of the combination of metformin and 2-deoxyglucose (2DG) in a pig model of chronic progressive ADPKD.
EXPERIMENTAL APPROACH
A miniature pig ADPKD model was established by inducible deletion of the PKD1 gene. Blood, urine and kidney biopsy specimens were collected for analysis at specific times. The renal vesicle index was analysed by three-dimensional reconstruction of CT scans. Markers of the mammalian target of rapamycin (mTOR) and ERK signalling pathways and associated metabolism were detected by Western blots and colorimetry.
KEY RESULTS
The three-dimensional reconstruction of CT scans indicated a markedly lower renal vesicle index in the combination therapy group. Each drug intervention group showed a significantly lower serum creatinine and urinary protein/creatinine ratio. This treatment regimen also inhibited the activities of markers of the proliferation-related mTOR and ERK pathways, and the expression of key enzymes involved in glycolysis, as well as reducing the production of ATP and lactic acid.
CONCLUSIONS AND IMPLICATIONS
This study showed that the combination of metformin and 2DG blocked the formation of renal cysts and improved the renal function in ADPKD miniature pigs. Our results indicate that the combination of metformin and 2DG may be a promising therapeutic strategy in human ADPKD.
Topics: Animals; Deoxyglucose; Disease Models, Animal; Drug Therapy, Combination; Kidney; MAP Kinase Signaling System; Metformin; Polycystic Kidney, Autosomal Dominant; Swine; Swine, Miniature; TOR Serine-Threonine Kinases; TRPP Cation Channels
PubMed: 30515768
DOI: 10.1111/bph.14558 -
Circulation Research Apr 2018Current cardiovascular clinical imaging techniques offer only limited assessment of innate immune cell-driven inflammation, which is a potential therapeutic target in...
RATIONALE
Current cardiovascular clinical imaging techniques offer only limited assessment of innate immune cell-driven inflammation, which is a potential therapeutic target in myocardial infarction (MI) and other diseases. Hyperpolarized magnetic resonance (MR) is an emerging imaging technology that generates contrast agents with 10- to 20 000-fold improvements in MR signal, enabling cardiac metabolite mapping.
OBJECTIVE
To determine whether hyperpolarized MR using [1-C]pyruvate can assess the local cardiac inflammatory response after MI.
METHODS AND RESULTS
We performed hyperpolarized [1-C]pyruvate MR studies in small and large animal models of MI and in macrophage-like cell lines and measured the resulting [1-C]lactate signals. MI caused intense [1-C]lactate signal in healing myocardial segments at both day 3 and 7 after rodent MI, which was normalized at both time points after monocyte/macrophage depletion. A near-identical [1-C]lactate signature was also seen at day 7 after experimental MI in pigs. Hyperpolarized [1-C]pyruvate MR spectroscopy in macrophage-like cell suspensions demonstrated that macrophage activation and polarization with lipopolysaccharide almost doubled hyperpolarized lactate label flux rates in vitro; blockade of glycolysis with 2-deoxyglucose in activated cells normalized lactate label flux rates and markedly inhibited the production of key proinflammatory cytokines. Systemic administration of 2-deoxyglucose after rodent MI normalized the hyperpolarized [1-C]lactate signal in healing myocardial segments at day 3 and also caused dose-dependent improvement in IL (interleukin)-1β expression in infarct tissue without impairing the production of key reparative cytokines. Cine MRI demonstrated improvements in systolic function in 2-DG (2-deoxyglucose)-treated rats at 3 months.
CONCLUSIONS
Hyperpolarized MR using [1-C]pyruvate provides a novel method for the assessment of innate immune cell-driven inflammation in the heart after MI, with broad potential applicability across other cardiovascular disease states and suitability for early clinical translation.
Topics: Animals; Carbon Isotopes; Carbon-13 Magnetic Resonance Spectroscopy; Cardiac-Gated Imaging Techniques; Contrast Media; Deoxyglucose; Female; Glycolysis; Lactic Acid; Lipopolysaccharides; Macrophage Activation; Macrophages; Magnetic Resonance Imaging; Magnetic Resonance Imaging, Cine; Mice; Myocardial Infarction; Myocarditis; Myocardium; Pyruvic Acid; RAW 264.7 Cells; Rats; Rats, Wistar; Swine
PubMed: 29440071
DOI: 10.1161/CIRCRESAHA.117.312535