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Epilepsy Research Jul 20232-deoxy-D-glucose (2DG) is a glucose analog and reversible inhibitor of glycolysis with anticonvulsant and antiepileptic effects in multiple seizure models. 2DG at a...
2-deoxy-D-glucose (2DG) is a glucose analog and reversible inhibitor of glycolysis with anticonvulsant and antiepileptic effects in multiple seizure models. 2DG at a dose of 250 mg/kg intraperitoneally (IP) delays progression of repeated seizures evoked by kindling in rats when administered 30 min prior to twice daily kindling stimulation. As toxicological studies have demonstrated that repeated daily oral administration of 2DG at doses of 60-375 mg/kg/day in rats induces dose-dependent, reversible cardiac myocyte vacuolation, it was of interest to determine if 2DG also slowed kindling progression when administered at or below doses causing cardiac toxicity and at various time points after evoked seizures. We found that: (1) 2DG slowed kindling progression nearly 2-fold when administered at a dose of 37.5 mg/kg given IP 30 min prior to kindling stimulation, and (2) 2DG 37.5 mg/kg IP also slowed kindling progression when given immediately after, and for as long as 10 min after evoked (kindled) seizures. These observations suggest potential clinical usefulness of post-seizure administration of 2DG to reduce seizure clusters and long-term consequences of repeated seizures at human equivalent doses that are likely to be safe and well tolerated in patients.
Topics: Rats; Humans; Animals; Glucose; Seizures; Kindling, Neurologic; Anticonvulsants; Deoxyglucose
PubMed: 37263021
DOI: 10.1016/j.eplepsyres.2023.107169 -
Neurochemical Research Nov 2020The isoform of glucose-6-phosphatase in liver, G6PC1, has a major role in whole-body glucose homeostasis, whereas G6PC3 is widely distributed among organs but has... (Review)
Review
The isoform of glucose-6-phosphatase in liver, G6PC1, has a major role in whole-body glucose homeostasis, whereas G6PC3 is widely distributed among organs but has poorly-understood functions. A recent, elegant analysis of neutrophil dysfunction in G6PC3-deficient patients revealed G6PC3 is a neutrophil metabolite repair enzyme that hydrolyzes 1,5-anhydroglucitol-6-phosphate, a toxic metabolite derived from a glucose analog present in food. These patients exhibit a spectrum of phenotypic characteristics and some have learning disabilities, revealing a potential linkage between cognitive processes and G6PC3 activity. Previously-debated and discounted functions for brain G6PC3 include causing an ATP-consuming futile cycle that interferes with metabolic brain imaging assays and a nutritional role involving astrocyte-neuron glucose-lactate trafficking. Detailed analysis of the anhydroglucitol literature reveals that it competes with glucose for transport into brain, is present in human cerebrospinal fluid, and is phosphorylated by hexokinase. Anhydroglucitol-6-phosphate is present in rodent brain and other organs where its accumulation can inhibit hexokinase by competition with ATP. Calculated hexokinase inhibition indicates that energetics of brain and erythrocytes would be more adversely affected by anhydroglucitol-6-phosphate accumulation than heart. These findings strongly support the paradigm-shifting hypothesis that brain G6PC3 removes a toxic metabolite, thereby maintaining brain glucose metabolism- and ATP-dependent functions, including cognitive processes.
Topics: Animals; Brain; Deoxyglucose; Enzyme Inhibitors; Glucose-6-Phosphatase; Hexokinase; Hexosephosphates; Humans; Neuroprotection; Phosphorylation; Protein Isoforms
PubMed: 32815045
DOI: 10.1007/s11064-020-03113-z -
European Journal of Immunology Sep 2015Cellular metabolism is emerging as a key determinant of T-lymphocyte differentiation and function. While this new paradigm has been primarily characterized in murine...
Cellular metabolism is emerging as a key determinant of T-lymphocyte differentiation and function. While this new paradigm has been primarily characterized in murine systems, research is now characterizing a role for different aspects of cellular metabolism in controlling human T-lymphocyte biology. In this issue of the European Journal of Immunology, Renner et al. [Eur. J. Immunol. 2015. 45: 2504-2516] analyze the glycolytic and mitochondrial activity of activated human CD4(+) and CD8(+) T cells, and correlate it to T-cell function. The authors show that although neither glucose deprivation nor mitochondrial restriction affects cytokine production, the glycolytic inhibitor 2-deoxyglucose severely affects T-cell function.
Topics: CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Deoxyglucose; Glucose; Humans; Mitochondria; T-Lymphocyte Subsets
PubMed: 26256443
DOI: 10.1002/eji.201545885 -
The Review of Diabetic Studies : RDS Jun 20221,5-anhydroglucitol (1,5-AG) is a biomarker of acute hyperglycemia in diabetology and also in cardiodiabetology. It is used to monitor fluctuating glucose levels. 1,5-AG...
1,5-anhydroglucitol (1,5-AG) is a biomarker of acute hyperglycemia in diabetology and also in cardiodiabetology. It is used to monitor fluctuating glucose levels. 1,5-AG is a monosaccharide that is biochemically similar to D-glucose and originates from the nutrition. The presence of 1,5-AG in blood and tissue is nearly constant due to reabsorption in the renal proximal tubule. In acute hyperglycemia, renal reabsorption is inhibited by glucose and 1,5- AG is excreted in the urine, while its serum level decreases rapidly. 1,5-AG reflects glucose excursions over 1-3 days to 2 weeks. In this regard, low levels of serum 1,5-AG can be a clinical marker of short- term glycemic derangements such as postprandial hyperglycemia, which is an important risk factor for the pathogenesis of coronary artery disease (CAD) as low levels of 1,5-AG reflect severe plaque calcification in CAD and correlate with high-density lipoprotein cholesterol (HDL-C) levels. For these reasons, 1,5-AG may also be a marker for atherosclerosis; in fact an even better marker than HbA1c or fructosamine which are normally used. 1,5-AG may also be a predictor of cardiovascular disease, left ventricular dysfunction after acute coronary syndrome (ACS), and mortality after ACS. This articles reviews the current knowledge on 1,5-AG related to its use as predictor for cardiovascular events.
Topics: Acute Coronary Syndrome; Biomarkers; Blood Glucose; Coronary Artery Disease; Deoxyglucose; Glycated Hemoglobin; Humans; Hyperglycemia
PubMed: 35831937
DOI: 10.1900/RDS.2022.18.68 -
Journal of Neuroscience Research Nov 2017Succinylation of proteins is widespread, modifies both the charge and size of the molecules, and can alter their function. For example, liver mitochondrial proteins have...
Succinylation of proteins is widespread, modifies both the charge and size of the molecules, and can alter their function. For example, liver mitochondrial proteins have 1,190 unique succinylation sites representing multiple metabolic pathways. Succinylation is sensitive to both increases and decreases of the NAD -dependent desuccinylase, SIRT5. Although the succinyl group for succinylation is derived from metabolism, the effects of systematic variation of metabolism on mitochondrial succinylation are not known. Changes in succinylation of mitochondrial proteins following variations in metabolism were compared against the mitochondrial redox state as estimated by the mitochondrial NAD /NADH ratio using fluorescent probes. The ratio was decreased by reduced glycolysis and/or glutathione depletion (iodoacetic acid; 2-deoxyglucose), depressed tricarboxylic acid cycle activity (carboxyethyl ester of succinyl phosphonate), and impairment of electron transport (antimycin) or ATP synthase (oligomycin), while uncouplers of oxidative phosphorylation (carbonyl cyanide m-chlorophenyl hydrazine or tyrphostin) increased the NAD /NADH ratio. All of the conditions decreased succinylation. In contrast, reducing the oxygen from 20% to 2.4% increased succinylation. The results demonstrate that succinylation varies with metabolic states, is not correlated to the mitochondrial NAD /NADH ratio, and may help coordinate the response to metabolic challenge.
Topics: Animals; Cell Line, Tumor; Deoxyglucose; Mice; Mitochondrial Proteins; NAD; Organophosphonates; Oxidation-Reduction; Oxidative Phosphorylation; Succinates; Succinic Acid
PubMed: 28631845
DOI: 10.1002/jnr.24103 -
Current Protocols May 2021The liver is central in maintaining glucose homeostasis. Indeed, impaired hepatic glucose uptake has been implicated in the development of hyperglycemia in type II...
The liver is central in maintaining glucose homeostasis. Indeed, impaired hepatic glucose uptake has been implicated in the development of hyperglycemia in type II diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). However, current approaches to evaluate glucose mobilization rely on indirect measurements that do not provide spatial and temporal information. Here, we describe confocal-based intravital microscopy (IVM) of the liver that allows the identification of hepatocyte spatial organization and glucose transport. Specifically, we describe a method to fluorescently label hepatic landmarks to identify different compartments within the liver. In addition, we outline an in vivo fluorescent glucose uptake assay to quantitatively measure glucose mobilization in space and time. These protocols allow direct investigation of hepatic glycemic control and can be further applied to murine models of liver disease. © Published 2021. This article is a U.S. Government work and is in the public domain in the USA. Basic Protocol 1: Mouse surgical procedure and positioning for liver intravital imaging Basic Protocol 2: Fluorescent labeling and intravital imaging of mouse hepatic compartments Basic Protocol 3: Mouse hepatic glucose uptake assay and intravital imaging analysis.
Topics: 4-Chloro-7-nitrobenzofurazan; Animals; Deoxyglucose; Fluorescent Dyes; Glucose; Hepatocytes; Imaging, Three-Dimensional; Intravital Microscopy; Liver; Mice
PubMed: 34033261
DOI: 10.1002/cpz1.139 -
Journal of Nephrology Aug 2017Autosomal dominant polycystic kidney disease (ADPKD) is an inherited renal disease characterized by bilateral renal cyst formation. ADPKD is one of the most common rare... (Review)
Review
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited renal disease characterized by bilateral renal cyst formation. ADPKD is one of the most common rare disorders, accounting for ~10% of all patients with end-stage renal disease (ESRD). ADPKD is a chronic disorder in which the gradual expansion of cysts that form in a minority of nephrons eventually causes loss of renal function due to the compression and degeneration of the surrounding normal parenchyma. Numerous deranged pathways have been identified in the cyst-lining epithelia, prompting the design of potential therapies. Several of these potential treatments have proved effective in slowing down disease progression in pre-clinical animal studies, while only one has subsequently been proven to effectively slow down disease progression in patients, and it has recently been approved for therapy in Europe, Canada and Japan. Among the affected cellular functions and pathways, recent investigations have described metabolic derangement in ADPKD as a major trait offering additional opportunities for targeted therapies. In particular, increased aerobic glycolysis (the Warburg effect) has been described as a prominent feature of ADPKD kidneys and its inhibition using the glucose analogue 2-deoxy-D-glucose (2DG) proved effective in slowing down disease progression in preclinical models of the disease. At the same time, previous clinical experiences have been reported with 2DG, showing that this compound is well tolerated in humans with minimal and reversible side effects. In this work, we review the literature and speculate that 2DG could be a good candidate for a clinical trial in humans affected by ADPKD.
Topics: Animals; Deoxyglucose; Disease Models, Animal; Disease Progression; Glycolysis; Humans; Kidney; Kidney Failure, Chronic; Polycystic Kidney, Autosomal Dominant; Renal Agents; Translational Research, Biomedical; Treatment Outcome
PubMed: 28390001
DOI: 10.1007/s40620-017-0395-9 -
Molecules (Basel, Switzerland) Sep 2022Viral infection almost invariably causes metabolic changes in the infected cell and several types of host cells that respond to the infection. Among metabolic changes,... (Review)
Review
Viral infection almost invariably causes metabolic changes in the infected cell and several types of host cells that respond to the infection. Among metabolic changes, the most prominent is the upregulated glycolysis process as the main pathway of glucose utilization. Glycolysis activation is a common mechanism of cell adaptation to several viral infections, including noroviruses, rhinoviruses, influenza virus, Zika virus, cytomegalovirus, coronaviruses and others. Such metabolic changes provide potential targets for therapeutic approaches that could reduce the impact of infection. Glycolysis inhibitors, especially 2-deoxy-D-glucose (2-DG), have been intensively studied as antiviral agents. However, 2-DG's poor pharmacokinetic properties limit its wide clinical application. Herein, we discuss the potential of 2-DG and its novel analogs as potent promising antiviral drugs with special emphasis on targeted intracellular processes.
Topics: Antiviral Agents; COVID-19; Deoxyglucose; Glucose; Glycolysis; Humans; Mannose; SARS-CoV-2; Zika Virus; Zika Virus Infection
PubMed: 36144664
DOI: 10.3390/molecules27185928 -
Histochemistry and Cell Biology Apr 2017
Topics: Animals; Cytoskeletal Proteins; Deoxyglucose; Epithelial-Mesenchymal Transition; Golgi Apparatus; Humans; Membrane Proteins; Podocytes
PubMed: 28285336
DOI: 10.1007/s00418-017-1552-x -
Microbes and Infection 2023Viral infection treatment is a difficult task due to its complex structure and metabolism. Additionally, viruses can alter the metabolism of host cells, mutate, and...
Viral infection treatment is a difficult task due to its complex structure and metabolism. Additionally, viruses can alter the metabolism of host cells, mutate, and readily adjust to harsh environments. Coronavirus stimulates glycolysis, weakens mitochondrial activity, and impairs infected cells. In this study, we investigated the efficacy of 2-DG in inhibiting coronavirus-induced metabolic processes and antiviral host defense systems, which have not been explored so far. 2-Deoxy-d-glucose (2-DG), a molecule restricting substrate availability, has recently gained attention as a potential antiviral drug. The results revealed that 229E human coronavirus promoted glycolysis, producing a significant increase in the concentration of fluorescent 2-NBDG, a glucose analog, particularly in the infected host cells. The addition of 2-DG decreased its viral replication and suppressed infection-induced cell death and cytopathic effects, thereby improving the antiviral host defense response. It was also observed that administration of low doses of 2-DG inhibited glucose uptake, indicating that 2-DG consumption in virus-infected host cells was mediated by high-affinity glucose transporters, whose levels were amplified upon coronavirus infection. Our findings indicated that 2-DG could be a potential drug to improve the host defense system in coronavirus-infected cells.
Topics: Humans; Deoxyglucose; Virulence; Glycolysis; Glucose; Coronavirus; Antiviral Agents
PubMed: 37178787
DOI: 10.1016/j.micinf.2023.105150