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Scientific Reports Jun 2023Glioblastoma, a malignant tumor, has no curative treatment. Recently, mitochondria have been considered a potential target for treating glioblastoma. Previously, we...
Glioblastoma, a malignant tumor, has no curative treatment. Recently, mitochondria have been considered a potential target for treating glioblastoma. Previously, we reported that agents initiating mitochondrial dysfunction were effective under glucose-starved conditions. Therefore, this study aimed to develop a mitochondria-targeted treatment to achieve normal glucose conditions. This study used U87MG (U87), U373, and patient-derived stem-like cells as well as chloramphenicol (CAP) and 2-deoxy-D-glucose (2-DG). We investigated whether CAP and 2-DG inhibited the growth of cells under normal and high glucose concentrations. In U87 cells, 2-DG and long-term CAP administration were more effective under normal glucose than high-glucose conditions. In addition, combined CAP and 2-DG treatment was significantly effective under normal glucose concentration in both normal oxygen and hypoxic conditions; this was validated in U373 and patient-derived stem-like cells. 2-DG and CAP acted by influencing iron dynamics; however, deferoxamine inhibited the efficacy of these agents. Thus, ferroptosis could be the underlying mechanism through which 2-DG and CAP act. In conclusion, combined treatment of CAP and 2-DG drastically inhibits cell growth of glioblastoma cell lines even under normal glucose conditions; therefore, this treatment could be effective for glioblastoma patients.
Topics: Humans; Glioblastoma; Ferroptosis; Chloramphenicol; Glucose; Deoxyglucose
PubMed: 37380755
DOI: 10.1038/s41598-023-37483-5 -
Journal of Natural Medicines Jul 2014Penta-O-galloyl-D-glucose (PGG) is a simple hydrolysable tannin in plants. PGG exists in two anomeric forms, α-PGG and β-PGG. While β-PGG can be found in a wide... (Review)
Review
Penta-O-galloyl-D-glucose (PGG) is a simple hydrolysable tannin in plants. PGG exists in two anomeric forms, α-PGG and β-PGG. While β-PGG can be found in a wide variety of plants, α-PGG is rather rare in nature. Numerous studies with β-PGG revealed a wide variety of biological activities, such as anti-microbial and anti-cancer functions. Until recently, studies with α-PGG were limited by the lack of its availability. Since the development of an efficient chemical synthesis of the compound, several investigations have revealed its anti-diabetic, anti-cancer, and anti-platelet-coagulation functions. Based on structure-activity-relationship (SAR) studies with α-PGG, a variety of α-PGG-related novel compounds were synthesized and some of them have been shown to possess promising therapeutic activities. In this review, the authors will survey and evaluate the biological functions of PGG with a focus on α-PGG and its derivatives.
Topics: Animals; Antineoplastic Agents; Deoxyglucose; Humans; Hydrolyzable Tannins; Hypoglycemic Agents; Structure-Activity Relationship
PubMed: 24532420
DOI: 10.1007/s11418-014-0823-2 -
Proceedings of the National Academy of... Aug 2021The amino acid and oligopeptide transporter Solute carrier family 15 member A4 (SLC15A4), which resides in lysosomes and is preferentially expressed in immune cells,...
The amino acid and oligopeptide transporter Solute carrier family 15 member A4 (SLC15A4), which resides in lysosomes and is preferentially expressed in immune cells, plays critical roles in the pathogenesis of lupus and colitis in murine models. Toll-like receptor (TLR)7/9- and nucleotide-binding oligomerization domain-containing protein 1 (NOD1)-mediated inflammatory responses require SLC15A4 function for regulating the mechanistic target of rapamycin complex 1 (mTORC1) or transporting L-Ala-γ-D-Glu-meso-diaminopimelic acid, IL-12: interleukin-12 (Tri-DAP), respectively. Here, we further investigated the mechanism of how SLC15A4 directs inflammatory responses. Proximity-dependent biotin identification revealed glycolysis as highly enriched gene ontology terms. Fluxome analyses in macrophages indicated that SLC15A4 loss causes insufficient biotransformation of pyruvate to the tricarboxylic acid cycle, while increasing glutaminolysis to the cycle. Furthermore, SLC15A4 was required for M1-prone metabolic change and inflammatory IL-12 cytokine productions after TLR9 stimulation. SLC15A4 could be in close proximity to AMP-activated protein kinase (AMPK) and mTOR, and SLC15A4 deficiency impaired TLR-mediated AMPK activation. Interestingly, SLC15A4-intact but not SLC15A4-deficient macrophages became resistant to fluctuations in environmental nutrient levels by limiting the use of the glutamine source; thus, SLC15A4 was critical for macrophage's respiratory homeostasis. Our findings reveal a mechanism of metabolic regulation in which an amino acid transporter acts as a gatekeeper that protects immune cells' ability to acquire an M1-prone metabolic phenotype in inflammatory tissues by mitigating metabolic stress.
Topics: 4-Chloro-7-nitrobenzofurazan; Animals; Cell Differentiation; Cell Line; Dendritic Cells; Deoxyglucose; Energy Metabolism; Gene Expression Regulation; Gene Silencing; Humans; Macrophages; Membrane Transport Proteins; Mice; Mice, Knockout; Nerve Tissue Proteins; Oligodeoxyribonucleotides
PubMed: 34385317
DOI: 10.1073/pnas.2100295118 -
Epilepsy & Behavior : E&B Mar 20232-deoxy-D-glucose (2DG) is a glucose analog differing from glucose only by removal of an oxygen atom at the 2 position, which prevents the isomerization of... (Review)
Review
2-deoxy-D-glucose (2DG) is a glucose analog differing from glucose only by removal of an oxygen atom at the 2 position, which prevents the isomerization of glucose-6-phosphate to fructose-6-phosphate, and thereby reversibly inhibits glycolysis. PET studies of regional brain glucose utilization positron-emitting 18F-2DG demonstrate that brain regions generating seizures have diminished glucose utilization during interictal conditions, but rapidly transition to markedly increased glucose delivery and utilization during seizures, particularly in status epilepticus (SE). 2-deoxy-D-glucose has acute antiseizure actions in multiple in vivo and in vitro seizure models, including models of SE induced by the chemo convulsants pilocarpine and kainic acid, suggesting that focal enhanced delivery of 2DG to ictal brain circuits is a potential novel anticonvulsant intervention for the treatment of SE.
Topics: Humans; Deoxyglucose; Status Epilepticus; Seizures; Glucose; Glycolysis; Pilocarpine
PubMed: 36804714
DOI: 10.1016/j.yebeh.2023.109108 -
In Vivo (Athens, Greece) 20231,5-Anhydro-d-fructose (1,5-AF, saccharide) and 1,5-anhydro-d-glucitol (1,5-AG) converted from 1,5-AF via the glycemic pathway have health benefits. However, this...
BACKGROUND/AIM
1,5-Anhydro-d-fructose (1,5-AF, saccharide) and 1,5-anhydro-d-glucitol (1,5-AG) converted from 1,5-AF via the glycemic pathway have health benefits. However, this metabolism has not been sufficiently elucidated. To clarify the in vivo metabolism of 1,5-AF to 1,5-AG, porcine (blood kinetics) and human (urinary excretion) studies were conducted.
MATERIALS AND METHODS
Microminipigs were administrated 1,5-AF orally or intravenously. Blood samples were obtained to analyse the kinetics of 1,5-AF and 1,5-AG. Urine samples were collected from human subjects who had orally ingested 1,5-AF, and the amounts of 1,5-AF and 1,5-AG excreted in the urine were analysed.
RESULTS
In blood kinetics analysis, the time to the maximum concentration of 1,5-AF after intravenous administration was 0.5 h, whereas 1,5-AF was not observed after oral administration. The times to the maximum concentration of 1,5-AG after intravenous and oral administration were 1.5 h and 2 h, respectively. In urinary excretion, the concentration of 1,5-AG in urine rapidly increased after the administration of 1,5-AF, peaked at 2 h, whereas 1,5-AF was not detected.
CONCLUSION
1,5-AF was rapidly metabolized to 1.5-AG in vivo in swine and human.
Topics: Humans; Animals; Swine; Sorbitol; Deoxyglucose; Fructose
PubMed: 37103066
DOI: 10.21873/invivo.13176 -
Physiological Research May 2018Reactive dicarbonyls stimulate production of advanced glycation endproducts, increase oxidative stress and inflammation and contribute to the development of vascular...
Reactive dicarbonyls stimulate production of advanced glycation endproducts, increase oxidative stress and inflammation and contribute to the development of vascular complications. We measured concentrations of dicarbonyls - methylglyoxal (MG), glyoxal (GL) and 3-deoxyglucosone (3-DG) - in the heart and kidney of a model of metabolic syndrome - hereditary hypertriglyceridemic rats (HHTg) and explored its modulation by metformin. Adult HHTg rats were fed a standard diet with or without metformin (300 mg/kg b.w.) and dicarbonyl levels and metabolic parameters were measured. HHTg rats had markedly elevated serum levels of triacylglycerols (p<0.001), FFA (p<0.01) and hepatic triacylglycerols (p<0.001) along with increased concentrations of reactive dicarbonyls in myocardium (MG: p<0.001; GL: p<0.01; 3-DG: p<0.01) and kidney cortex (MG: p<0.01). Metformin treatment significantly reduced reactive dicarbonyls in the myocardium (MG: p<0.05, GL: p<0.05, 3-DG: p<0.01) along with increase of myocardial concentrations of reduced glutathione (p<0.01) and glyoxalase 1 mRNA expression (p<0.05). Metformin did not have any significant effect on dicarbonyls, glutathione or on glyoxalase 1 expression in kidney cortex. Chronically elevated hypertriglyceridemia was associated with increased levels of dicarbonyls in heart and kidney. Beneficial effects of metformin on reactive dicarbonyls and glyoxalase in the heart could contribute to its cardioprotective effects.
Topics: Animals; Deoxyglucose; Diet; Glutathione; Glyoxal; Hypertriglyceridemia; Hypoglycemic Agents; Lactoylglutathione Lyase; Male; Metformin; Myocardium; Pyruvaldehyde; Rats; Rats, Wistar; Stress, Physiological
PubMed: 29137475
DOI: 10.33549/physiolres.933606 -
Biochimie Apr 2022A characteristic of cancer cells is increased glucose uptake and glycolysis for energy production and hydroperoxide detoxification due to mitochondrial dysfunction....
A characteristic of cancer cells is increased glucose uptake and glycolysis for energy production and hydroperoxide detoxification due to mitochondrial dysfunction. Thus, inhibition of glucose uptake and glycolysis represent smart novel therapy. We used 2-deoxyglucose (2DG) as a glycolysis inhibitor and acarbose (ACA), a specific alpha-glucosidase inhibitor, to decrease glucose uptake. Mice bearing mammary adenocarcinoma tumors were treated by 2DG and/or ACA. Relative tumor volume, tumor growth inhibition rate, relative body weight, glucose concentration, hexokinase-1 protein level by ELISA, pyruvate, and ATP (glycolysis products), reactive oxygen species (ROS), total glutathione T-GSH, apoptosis, and histopathology were measured in treated and untreated groups. Our results showed that combination therapy inhibited tumor volume and increased tumor growth inhibition rate, body weight reduction, decreasing glucose level, HK-1 level, and inhibition of glycolysis products. In addition, combination therapy induced oxidative stress, increase ROS, and decrease T-GSH. Furthermore, immunohistochemistry examination showed the broader area of apoptosis in breast cancer treated by combination agents. In conclusion, our result revealed that the novel combination inhibits glycolysis and glucose uptake and induced oxidative stress and apoptosis.
Topics: Acarbose; Animals; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Deoxyglucose; Female; Glucose; Glycolysis; Humans; Mice; Oxidative Stress
PubMed: 35066100
DOI: 10.1016/j.biochi.2022.01.007 -
IUBMB Life Mar 2017Glycolytic inhibitors are of interest therapeutically as they are effective against cancers that display increased glycolytic rate and mitochondrial defects.... (Review)
Review
Glycolytic inhibitors are of interest therapeutically as they are effective against cancers that display increased glycolytic rate and mitochondrial defects. 2-Deoxyglucose (2-DG) is one such glycolytic inhibitor and was identified to be a competitive inhibitor of glucose. Studies from past few decades have shown that the mechanism of action of 2-DG is complex involving several metabolic and signaling pathways. Budding yeast Saccharomyces cerevisiae and fission yeast Schizosaccharomyces pombe are two important models for studying metabolism, cell cycle and cell signaling. These two unicellular eukaryotes are Crabtree positive yeasts exhibiting a metabolism similar to that of cancer cells. Effects of 2-DG in yeast is of interest owing to these similarities and hence yeasts have emerged as ideal model organisms to study the mode of action and resistance to 2-DG. In this review, we summarize the studies on biological effect and resistance to 2-DG in budding and fission yeasts and give an insight into its possible mechanism of action as models for understanding cancer metabolism and drugs affecting cancer progression. © 2017 IUBMB Life, 69(3):137-147, 2017.
Topics: Animals; Antimetabolites, Antineoplastic; Cell Line, Tumor; Deoxyglucose; Drug Screening Assays, Antitumor; Energy Metabolism; Humans; Neoplasms; Schizosaccharomyces
PubMed: 28093891
DOI: 10.1002/iub.1599 -
Biochemical Pharmacology Dec 2020Most malignant cells display increased glucose absorption and metabolism compared to surrounding tissues. This well-described phenomenon results from a metabolic... (Review)
Review
Most malignant cells display increased glucose absorption and metabolism compared to surrounding tissues. This well-described phenomenon results from a metabolic reprogramming occurring during transformation, that provides the building blocks and supports the high energetic cost of proliferation by increasing glycolysis. These features led to the idea that drugs targeting glycolysis might prove efficient in the context of cancer treatment. One of these drugs, 2-deoxyglucose (2-DG), is a synthetic glucose analog that can be imported into cells and interfere with glycolysis and ATP generation. Its preferential targeting to sites of cell proliferation is supported by the observation that a derived molecule, 2-fluoro-2-deoxyglucose (FDG) accumulates in tumors and is used for cancer imaging. Here, we review the toxicity mechanisms of this drug, from the early-described effects on glycolysis to its other cellular consequences, including inhibition of protein glycosylation and endoplasmic reticulum stress, and its interference with signaling pathways. Then, we summarize the current data on the use of 2-DG as an anti-cancer agent, especially in the context of combination therapies, as novel 2-DG-derived drugs are being developed. We also show how the use of 2-DG helped to decipher glucose-signaling pathways in yeast and favored their engineering for biotechnologies. Finally, we discuss the resistance strategies to this inhibitor that have been identified in the course of these studies and which may have important implications regarding a medical use of this drug.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Clinical Trials as Topic; Deoxyglucose; Drug Resistance, Neoplasm; Glucose; Glycolysis; Humans
PubMed: 32890467
DOI: 10.1016/j.bcp.2020.114213 -
Current Protein & Peptide Science 2020Skeletal muscle is the largest organ in the body and constitutes almost 40% of body mass. It is also the primary site of insulin-mediated glucose uptake, and skeletal... (Review)
Review
Skeletal muscle is the largest organ in the body and constitutes almost 40% of body mass. It is also the primary site of insulin-mediated glucose uptake, and skeletal muscle insulin resistance, that is, diminished response to insulin, is characteristic of Type 2 diabetes (T2DM). One of the foremost reasons posited to explain the etiology of T2DM involves the modification of proteins by dicarbonyl stress due to an unbalanced metabolism and accumulations of dicarbonyl metabolites. The elevated concentration of dicarbonyl metabolites (i.e., glyoxal, methylglyoxal, 3-deoxyglucosone) leads to DNA and protein modifications, causing cell/tissue dysfunctions in several metabolic diseases such as T2DM and other age-associated diseases. In this review, we recapitulated reported effects of dicarbonyl stress on skeletal muscle and associated extracellular proteins with emphasis on the impact of T2DM on skeletal muscle and provided a brief introduction to the prevention/inhibition of dicarbonyl stress.
Topics: Deoxyglucose; Diabetes Mellitus, Type 2; Extracellular Matrix Proteins; Gene Expression Regulation; Glycation End Products, Advanced; Glyoxal; Humans; Insulin; Insulin Resistance; Isoenzymes; Lactoylglutathione Lyase; Muscle, Skeletal; Oxidative Stress; Protein Carbonylation; Pyruvaldehyde; Signal Transduction
PubMed: 31746292
DOI: 10.2174/1389203720666191119100759