Abstract 280: Increased Metabolite Levels of Glycolysis and Pentose Phosphate Pathway in Rabbit Atherosclerotic Arteries and Hypoxic Macrophage

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Atsushi Yamashita ◽  
Yan Zhao ◽  
Yunosuke Matsuura ◽  
Kazuaki Yamasaki ◽  
Sayaka Moriguchi-Goto ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Pentose Phosphate Pathway ◽  
Nuclear Translocation ◽  
Tricarboxylic Acid Cycle ◽  
Pentose Phosphate ◽  
Plasminogen Activator Inhibitor 1 ◽  
Hexokinase Ii ◽  
Femoral Arteries ◽  
Metabolic Systems ◽  
18F Fdg

Aims: Inflammation and possibly hypoxia largely affect glucose utilization in atherosclerotic arteries, which could alter many metabolic systems. However, metabolic changes in atherosclerotic plaques remain unknown. The present study aims to identify changes in metabolic systems relative to glucose uptake and hypoxia in rabbit atherosclerotic arteries and cultured macrophages. Methods: Macrophage-rich or smooth muscle cell (SMC)-rich neointima was created by balloon injury in the iliac-femoral arteries of rabbits fed with a 0.5% cholesterol diet or a conventional diet. THP-1 macrophages stimulated with lipopolysaccharides (LPS) and interferon-γ (INFγ) were cultured under normoxic and hypoxic conditions. We evaluated comprehensive arterial and macrophage metabolism by performing metabolomic analyses using capillary electrophoresis-time of flight mass spectrometry. We evaluated glucose uptake and its relationship to vascular hypoxia using 18F-fluorodeoxyglucose (18F-FDG) and pimonidazole, a marker of hypoxia. Results: The levels of many metabolites increased in the iliac-femoral arteries with macrophage-rich neointima, compared with those that were not injured and those with SMC-rich neointima (glycolysis, 4 of 9; pentose phosphate pathway, 4 of 6; tricarboxylic acid cycle, 4 of 6; nucleotides, 10 of 20). The uptake of 18F-FDG in arterial walls measured by autoradiography positively correlated with macrophage- and pimonidazole-immunopositive areas (r = 0.76, and r = 0.59 respectively; n = 69 for both; p < 0.0001). Pimonidazole immunoreactivity was closely localized with the nuclear translocation of hypoxia inducible factor-1α and hexokinase II expression in macrophage-rich neointima. The levels of glycolytic (8 of 8) and pentose phosphate pathway (4 of 6) metabolites increased in LPS and INFγ stimulated macrophages under hypoxic but not normoxic condition. Plasminogen activator inhibitor-1 protein levels in the supernatant were closely associated with metabolic pathways in the macrophages. Conclusion: Infiltrative macrophages in atherosclerotic arteries might affect metabolic systems, and hypoxia but not classical activation might augment glycolytic and pentose phosphate pathways in macrophages.

Metabolism of glucose-14C, pyruvate-14C, and mannitol-14C by Melampsora lini. II. Conversion to soluble products

1968 ◽  
Vol 46 (4) ◽  
pp. 453-460 ◽  
Author(s):  
D. Mitchell ◽  
Michael Shaw
Keyword(s):  
Pentose Phosphate Pathway ◽  
Tricarboxylic Acid Cycle ◽  
Rust Fungus ◽  
Tca Cycle ◽  
Tricarboxylic Acid ◽  
Pentose Phosphate ◽  
Soluble Carbohydrates ◽  
Melampsora Lini ◽  
Carbohydrate Fraction ◽  
The Tca Cycle

Mycelium of the flax rust fungus (Melampsora lini (Pers.) Lév.), grown on flax cotyledons in tissue culture, had a mean [Formula: see text]of 4.1 and a mean C6/C1 ratio of 0.14, measured after 4 hours in radioactive glucose. The C6/C1 ratio increased with time and also after treatment with 10−5 M 2,4-dinitrophenol. The relative labelling of the (80%) ethanol-soluble carbohydrates, and organic and amino acid fractions after incubation with glucose-1-, -2-, or -6-14C also indicated preferential release of C1 as 14CO2. Trehalose (unknown A) was tentatively identified in the carbohydrate fraction and was mildly radioactive after incubation of the mycelium with labelled glucose for 3 hours. The principal radioactive products of glucose in this fraction were two unknowns, B and C, which were tentatively identified as mannitol and arabitol. The labelling patterns were consistent with their formation from intermediates of the pentose phosphate pathway. The distribution of radioactivity derived from glucose in alanine, glutamate, and aspartate also indicated that hexose or triose units formed in the pentose phosphate pathway were converted to pyruvate, which either gave rise to alanine or was further oxidized in the tricarboxylic acid cycle. Incubation with pyruvate-1-, -2-, or -3-14C for 3 hours gave rise to 14CO2 and labelled alanine, glutamate, and aspartate in a manner consistent with the operation of the TCA cycle. Mannitol-1-6-14C was not metabolized to any appreciable extent in this period, but did give rise to 14CO2 and to several unidentified compounds in the carbohydrate fraction.

Upregulation of Pentose Phosphate Pathway and Preservation of Tricarboxylic Acid Cycle Flux after Experimental Brain Injury

2005 ◽  
Vol 22 (10) ◽  
pp. 1052-1065 ◽  
Author(s):  
Brenda L. Bartnik ◽  
Richard L. Sutton ◽  
Masamichi Fukushima ◽  
Neil G. Harris ◽  
David A. Hovda ◽  
...  
Keyword(s):  
Brain Injury ◽  
Pentose Phosphate Pathway ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Pentose Phosphate ◽  
Acid Cycle

scholarly journals The pentose phosphate pathway constitutes a major metabolic hub in pathogenic Francisella

2021 ◽  
Vol 17 (8) ◽  
pp. e1009326
Author(s):  
Héloise Rytter ◽  
Anne Jamet ◽  
Jason Ziveri ◽  
Elodie Ramond ◽  
Mathieu Coureuil ◽  
...  
Keyword(s):  
Pentose Phosphate Pathway ◽  
Metabolic Pathways ◽  
Pathogenic Bacteria ◽  
Metabolic Networks ◽  
Tricarboxylic Acid Cycle ◽  
Sulfur Metabolism ◽  
Time Lapse ◽  
Pentose Phosphate ◽  
Francisella Novicida

Metabolic pathways are now considered as intrinsic virulence attributes of pathogenic bacteria and thus represent potential targets for antibacterial strategies. Here we focused on the role of the pentose phosphate pathway (PPP) and its connections with other metabolic pathways in the pathophysiology of Francisella novicida. The involvement of the PPP in the intracellular life cycle of Francisella was first demonstrated by studying PPP inactivating mutants. Indeed, we observed that inactivation of the tktA, rpiA or rpe genes severely impaired intramacrophage multiplication during the first 24 hours. However, time-lapse video microscopy demonstrated that rpiA and rpe mutants were able to resume late intracellular multiplication. To better understand the links between PPP and other metabolic networks in the bacterium, we also performed an extensive proteo-metabolomic analysis of these mutants. We show that the PPP constitutes a major bacterial metabolic hub with multiple connections to glycolysis, the tricarboxylic acid cycle and other pathways, such as fatty acid degradation and sulfur metabolism. Altogether our study highlights how PPP plays a key role in the pathogenesis and growth of Francisella in its intracellular niche.

scholarly journals Maximum activities of key enzymes of glycolysis, glutaminolysis, pentose phosphate pathway and tricarboxylic acid cycle in normal, neoplastic and suppressed cells

1990 ◽  
Vol 265 (2) ◽  
pp. 503-509 ◽  
Author(s):  
M Board ◽  
S Humm ◽  
E A Newsholme
Keyword(s):  
Pyruvate Kinase ◽  
Pentose Phosphate Pathway ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Pentose Phosphate ◽  
Neoplastic Cells ◽  
Acid Cycle ◽  
Key Enzymes ◽  
Metastatic Cells ◽  
Tumorigenic Cells

1. Maximal activities of some key enzymes of glycolysis, the pentose phosphate pathway, the tricarboxylic acid cycle and glutaminolysis were measured in homogenates from a variety of normal, neoplastic and suppressed cells. 2. The relative activities of hexokinase and 6-phosphofructokinase suggest that, particularly in neoplastic cells, in which the capacity for glucose transport is high, hexokinase could approach saturation in respect to intracellular glucose; consequently, hexokinase and phosphofructokinase could play an important role in the regulation of glycolytic flux in these cells. 3. The activity of pyruvate kinase is considerably higher in tumorigenic cells than in non-tumorigenic cells and higher in metastatic cells than in tumorigenic cells: for non-tumorigenic cells the activities range from 28.4 to 574, for tumorigenic cells from 899 to 1280, and for metastatic cells from 1590 to 1627 nmol/min per mg of protein. 4. The ratio of pyruvate kinase activity to 2 x phosphofructokinase activity is very high in neoplastic cells. The mean is 22.4 for neoplastic cells, whereas for muscle from 60 different animals it is only 3.8. 5. Both citrate synthase and isocitrate dehydrogenase activities are present in non-neoplastic and neoplastic cells, suggesting that the full complement of tricarboxylic-acid-cycle enzymes are present in these latter cells. 6. In neoplastic cells, the activity of glutaminase is similar to or greater than that of hexokinase, which suggests that glutamine may be as important as glucose for energy generation in these cells.

scholarly journals MicroRNA-Mediated Metabolic Reprograming in Renal Cancer

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1825 ◽  
Author(s):  
Bogusławska ◽  
Popławski ◽  
Alseekh ◽  
Koblowska ◽  
Iwanicka-Nowicka ◽  
...  
Keyword(s):  
Renal Cancer ◽  
Pentose Phosphate Pathway ◽  
Cancer Metabolism ◽  
Target Genes ◽  
Tricarboxylic Acid Cycle ◽  
Cell Cancer ◽  
Pentose Phosphate ◽  
Metabolic Reprogramming ◽  
Gas Chromatography Mass Spectrometry ◽  
Arginine Metabolism

Metabolic reprogramming is one of the hallmarks of renal cell cancer (RCC). We hypothesized that altered metabolism of RCC cells results from dysregulation of microRNAs targeting metabolically relevant genes. Combined large-scale transcriptomic and metabolic analysis of RCC patients tissue samples revealed a group of microRNAs that contribute to metabolic reprogramming in RCC. miRNAs expressions correlated with their predicted target genes and with gas chromatography-mass spectrometry (GC-MS) metabolome profiles of RCC tumors. Assays performed in RCC-derived cell lines showed that miR-146a-5p and miR-155-5p targeted genes of PPP (the pentose phosphate pathway) (G6PD and TKT), the TCA (tricarboxylic acid cycle) cycle (SUCLG2), and arginine metabolism (GATM), respectively. miR-106b-5p and miR-122-5p regulated the NFAT5 osmoregulatory transcription factor. Altered expressions of G6PD, TKT, SUCLG2, GATM, miR-106b-5p, miR-155-5p, and miR-342-3p correlated with poor survival of RCC patients. miR-106b-5p, miR-146a-5p, and miR-342-3p stimulated proliferation of RCC cells. The analysis involving >6000 patients revealed that miR-34a-5p, miR-106b-5p, miR-146a-5p, and miR-155-5p are PanCancer metabomiRs possibly involved in global regulation of cancer metabolism. In conclusion, we found that microRNAs upregulated in renal cancer contribute to disturbed expression of key genes involved in the regulation of RCC metabolome. miR-146a-5p and miR-155-5p emerge as a key “metabomiRs” that target genes of crucial metabolic pathways (PPP (the pentose phosphate pathway), TCA cycle, and arginine metabolism).

scholarly journals Biochemical adaptation in rat liver in response to marginal oxygen toxicity

1971 ◽  
Vol 125 (2) ◽  
pp. 439-447 ◽  
Author(s):  
R. R. Gorman ◽  
J. P. Jordan ◽  
J. B. Simmons ◽  
D. P. Clarkson
Keyword(s):  
Sea Level ◽  
Pentose Phosphate Pathway ◽  
Tricarboxylic Acid Cycle ◽  
Oxygen Toxicity ◽  
Liver Glycogen ◽  
Tricarboxylic Acid ◽  
Pentose Phosphate ◽  
Acid Cycle ◽  
Biochemical Adaptation ◽  
Glucose 6 Phosphate Dehydrogenase

1. Hepatic glucose 6-phosphate dehydrogenase activity was increased in rats exposed to 5lb/in2 (equivalent to 27000ft), 100% O2 when compared with control animals in a 14.7lb/in2 (sea level), air environment. Glyceraldehyde 3-phosphate dehydrogenase, isocitrate dehydrogenase, and succinate dehydrogenase were not affected by the 5lb/in2, 100% O2 environment. 2. Animals exposed to the hyperoxic environment consumed food, expired CO2 and gained weight at the same rate as normoxic control animals. Additionally, blood glucose and liver glycogen concentrations were unchanged in the hyperoxic animals. The only readily apparent physiological difference in the hyperoxic animals was a decreased haematocrit. 3. The increase in glucose 6-phosphate dehydrogenase was eliminated by the injection of actinomycin D or cycloheximide. 4. Expiration of 14CO2 from [1-14C]glucose was approximately the same in hyperoxic and normoxic rats. However, 14CO2 expiration from [6-14C]glucose was markedly decreased in the animals exposed to the hyperoxic environment. 5. Calculations of the relative importance of the pentose phosphate pathway versus the tricarboxylic acid cycle plus glycolysis indicated that the livers from animals in the 5lb/in2, 100% O2 environment metabolized twice as much carbohydrate by way of the pentose phosphate pathway as did those from the sea-level air control animals. 6. In livers of rats exposed to 5lb/in2, 100% O2 the concentrations of pyruvate, citrate and 2-oxoglutarate were increased, that of isocitrate was slightly elevated, whereas the concentrations of succinate, fumarate and malate were decreased. 7. An inactivation of both tricarboxylic acid cycle lipoate-containing dehydrogenases, pyruvate and 2-oxoglutarate, under hyperoxic conditions is proposed. 8. The adaptive significance of the induction of glucose 6-phosphate dehydrogenase and the resultant production of NADPH under hyperoxic conditions is discussed.

scholarly journals Dual metabolomic profiling uncovers Toxoplasma manipulation of the host metabolome and the discovery of a novel parasite metabolic capability

2018 ◽  
Author(s):  
William J. Olson ◽  
David Stevenson ◽  
Daniel Amador-Noguez ◽  
Laura J. Knoll
Keyword(s):  
Pentose Phosphate Pathway ◽  
Time Course ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Pentose Phosphate ◽  
Acid Cycle ◽  
Obligate Intracellular ◽  
Host Parasite ◽  
Host Metabolism ◽  
Sedoheptulose Bisphosphatase

AbstractThe obligate intracellular parasite Toxoplasma gondii is auxotrophic for several key metabolites and must scavenge these from the host. It is unclear how Toxoplasma manipulates host metabolism for its overall growth rate and non-essential metabolites. To address this question, we measured changes in the joint host-parasite metabolome over a time course of infection. Host and parasite transcriptomes were simultaneously generated to determine potential changes in metabolic enzyme levels. Toxoplasma infection increased activity in multiple metabolic pathways, including the tricarboxylic acid cycle, the pentose phosphate pathway, glycolysis, amino acid synthesis, and nucleotide metabolism. Our analysis indicated that changes in some pathways, such as the tricarboxylic acid cycle, derive from the parasite, while changes in others, like the pentose phosphate pathway, were host and parasite driven. Further experiments led to the discovery of a Toxoplasma enzyme, sedoheptulose bisphosphatase, which funnels carbon from glycolysis into ribose synthesis through a energetically driven dephosphorylation reaction. This second route for ribose synthesis resolves a conflict between the Toxoplasma tricarboxylic acid cycle and pentose phosphate pathway, which are both NADP+ dependent. During periods of high energetic and ribose need, the competition for NADP+ could result in lethal redox imbalances. Sedoheptulose bisphosphatase represents a novel step in Toxoplasma central carbon metabolism that allows Toxoplasma to satisfy its ribose demand without using NADP+. Sedoheptulose bisphosphatase is not present in humans, highlighting its potential as a drug target.Author SummaryThe obligate intracellular parasite Toxoplasma is commonly found among human populations worldwide and poses severe health risks to fetuses and individuals with AIDS. While some treatments are available they are limited in scope. A possible target for new therapies is Toxoplasma’s limited metabolism, which makes it heavily reliant in its host. In this study, we generated a joint host/parasite metabolome to better understand host manipulation by the parasite and to discover unique aspects of Toxoplasma metabolism that could serve as the next generation of drug targets. Metabolomic analysis of Toxoplasma during an infection time course found broad activation of host metabolism by the parasite in both energetic and biosynthetic pathways. We discovered a new Toxoplasma enzyme, sedoheptulose bisphosphatase, which redirects carbon from glycolysis into ribose synthesis. Humans lack sedoheptulose bisphosphatase, making it a potential drug target. The wholesale remodeling of host metabolism for optimal parasite growth is also of interest, although the mechanisms behind this host manipulation must be further studied before therapeutic targets can be identified.

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