scholarly journals Human Prostate Cancer Is Characterized by an Increase in Urea Cycle Metabolites

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1814 ◽  
Author(s):  
Andras Franko ◽  
Yaping Shao ◽  
Martin Heni ◽  
Jörg Hennenlotter ◽  
Miriam Hoene ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Urea Cycle ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Human Prostate Cancer ◽  
Acid Cycle ◽  
Lower Survival Rate ◽  
Nfκb Pathway ◽  
Cancer Tissues

Despite it being the most common incident of cancer among men, the pathophysiological mechanisms contributing to prostate cancer (PCa) are still poorly understood. Altered mitochondrial metabolism is postulated to play a role in the development of PCa. To determine the key metabolites (which included mitochondrial oncometabolites), benign prostatic and cancer tissues of patients with PCa were analyzed using capillary electrophoresis and liquid chromatography coupled with mass spectrometry. Gene expression was studied using real-time PCR. In PCa tissues, we found reduced levels of early tricarboxylic acid cycle metabolites, whereas the contents of urea cycle metabolites including aspartate, argininosuccinate, arginine, proline, and the oncometabolite fumarate were higher than that in benign controls. Fumarate content correlated positively with the gene expression of oncogenic HIF1α and NFκB pathways, which were significantly higher in the PCa samples than in the benign controls. Furthermore, data from the TCGA database demonstrated that prostate cancer patients with activated NFκB pathway had a lower survival rate. In summary, our data showed that fumarate content was positively associated with carcinogenic genes.

scholarly journals Endogenous 2-oxoacids differentially regulate expression of oxygen sensors

2004 ◽  
Vol 380 (2) ◽  
pp. 419-424 ◽  
Author(s):  
Clifton Lee DALGARD ◽  
Huasheng LU ◽  
Ahmed MOHYELDIN ◽  
Ajay VERMA
Keyword(s):  
Gene Expression ◽  
Nuclear Translocation ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Oxygen Sensors ◽  
Dependent Manner ◽  
Acid Cycle ◽  
Disease States ◽  
The Stability ◽  
Regulated Gene Expression

Adaptations to change in oxygen availability are crucial for survival of multi-cellular organisms and are also implicated in several disease states. Such adaptations rely upon gene expression regulated by the heterodimeric transcription factors HIFs (hypoxia-inducible factors). Enzymes that link changes in oxygen tensions with the stability and transcriptional activity of HIFs are considered as oxygen sensors. These enzymes are oxygen-, iron- and 2-oxoglutarate-dependent dioxygenases that hydroxylate key proline and asparagine residues in HIFα subunits. The constitutive inhibitory action of these enzymes on HIFs is relieved by hypoxia and by agents that displace iron or 2-oxoglutarate. Two of the enzymes, HPH (HIF prolyl hydroxylase)-1 and HPH-2, are known to be inducible by hypoxia in a HIF-dependent manner. This suggests the existence of a novel feedback loop for adjusting hypoxia-regulated gene expression. We have recently shown that HIF-1α stability, HIF-1 nuclear translocation and HIF-mediated gene expression in human glioma cell lines can be stimulated by pyruvate independently of hypoxia. In the present study we show that the endogenous 2-oxoacid oxaloacetate can also activate HIF-mediated gene expression. Pyruvate and oxaloacetate treatment of cells also up-regulates HPH-1 and HPH-2, but not HPH-3 or the HIF asparaginyl hydroxylase FIH-1 (factor inhibiting HIF). Regulation of HIF-1 and the expression of HPH homologue genes can thus be influenced by specific glycolytic and tricarboxylic acid cycle metabolites. These findings may underlie important interactions between oxygen homoeostasis, glycolysis, the tricarboxylic acid cycle and gluconeogenesis.

scholarly journals Neisseria meningitidis Uses Sibling Small Regulatory RNAs To Switch from Cataplerotic to Anaplerotic Metabolism

mBio ◽  
2017 ◽  
Vol 8 (2) ◽  
Author(s):  
Yvonne Pannekoek ◽  
Robert A. G. Huis in ‘t Veld ◽  
Kim Schipper ◽  
Sandra Bovenkerk ◽  
Gertjan Kramer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Neisseria Meningitidis ◽  
Tricarboxylic Acid Cycle ◽  
Regulation Of Gene Expression ◽  
Stringent Response ◽  
Tricarboxylic Acid ◽  
Metabolic Adaptation ◽  
Acid Cycle ◽  
Small Regulatory Rnas ◽  
Regulatory Rnas

ABSTRACT Neisseria meningitidis (the meningococcus) is primarily a commensal of the human oropharynx that sporadically causes septicemia and meningitis. Meningococci adapt to diverse local host conditions differing in nutrient supply, like the nasopharynx, blood, and cerebrospinal fluid, by changing metabolism and protein repertoire. However, regulatory transcription factors and two-component systems in meningococci involved in adaptation to local nutrient variations are limited. We identified novel sibling small regulatory RNAs ( Neisseria metabolic switch regulators [NmsRs]) regulating switches between cataplerotic and anaplerotic metabolism in this pathogen. Overexpression of NmsRs was tolerated in blood but not in cerebrospinal fluid. Expression of six tricarboxylic acid cycle enzymes was downregulated by direct action of NmsRs. Expression of the NmsRs themselves was under the control of the stringent response through the action of RelA. Small sibling regulatory RNAs of meningococci, controlling general metabolic switches, add an exciting twist to their versatile repertoire in bacterial pathogens. IMPORTANCE Regulatory small RNAs (sRNAs) of pathogens are coming to be recognized as highly important components of riboregulatory networks, involved in the control of essential cellular processes. They play a prominent role in adaptation to physiological changes as represented by different host environments. They can function as posttranscriptional regulators of gene expression to orchestrate metabolic adaptation to nutrient stresses. Here, we identified highly conserved sibling sRNAs in Neisseria meningitidis which are functionally involved in the regulation of gene expression of components of the tricarboxylic acid cycle. These novel sibling sRNAs that function by antisense mechanisms extend the so-called stringent response which connects metabolic status to colonization and possibly virulence as well as pathogenesis in meningococci. IMPORTANCE Regulatory small RNAs (sRNAs) of pathogens are coming to be recognized as highly important components of riboregulatory networks, involved in the control of essential cellular processes. They play a prominent role in adaptation to physiological changes as represented by different host environments. They can function as posttranscriptional regulators of gene expression to orchestrate metabolic adaptation to nutrient stresses. Here, we identified highly conserved sibling sRNAs in Neisseria meningitidis which are functionally involved in the regulation of gene expression of components of the tricarboxylic acid cycle. These novel sibling sRNAs that function by antisense mechanisms extend the so-called stringent response which connects metabolic status to colonization and possibly virulence as well as pathogenesis in meningococci.

scholarly journals The Drosophila mitochondrial citrate carrier regulates L-2-hydroxyglutarate accumulation by coupling the tricarboxylic acid cycle with glycolysis

2018 ◽  
Author(s):  
Hongde Li ◽  
Alexander J. Hurlburt ◽  
Jason M. Tennessen
Keyword(s):  
Gene Expression ◽  
Tricarboxylic Acid Cycle ◽  
Lactate Production ◽  
Cellular Metabolism ◽  
Tricarboxylic Acid ◽  
Acid Cycle ◽  
Glucose Catabolism ◽  
Elevated Glucose ◽  
Citrate Carrier ◽  
Citrate Efflux

AbstractThe oncometabolites D- and L-2-hydroxyglutarate (2HG) broadly interfere with cellular metabolism, physiology, and gene expression. A key regulator of 2HG metabolism is the mitochondrial citrate carrier (CIC), which, when mutated, promotes excess D-/L-2HG accumulation. The mechanism by which CIC influences 2HG levels, however, remains unknown. Here we studied the Drosophila gene scheggia (sea), which encodes the fly CIC homolog, to explore the mechanisms linking mitochondrial citrate efflux to L-2HG metabolism. Our findings demonstrate that decreased Drosophila CIC activity results in elevated glucose catabolism and increased lactate production, thereby creating a metabolic environment that inhibits L-2HG degradation.

scholarly journals Metabolomics and transcriptomics profiles reveal the dysregulation of the tricarboxylic acid cycle and related mechanisms in prostate cancer

2018 ◽  
Vol 143 (2) ◽  
pp. 396-407 ◽  
Author(s):  
Yaping Shao ◽  
Guozhu Ye ◽  
Shancheng Ren ◽  
Hai-Long Piao ◽  
Xinjie Zhao ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Acid Cycle

scholarly journals Effects of sevoflurane anesthesia and abdominal surgery on the systemic metabolome: a prospective observational study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yiyong Wei ◽  
Donghang Zhang ◽  
Jin Liu ◽  
Mengchan Ou ◽  
Peng Liang ◽  
...  
Keyword(s):  
Abdominal Surgery ◽  
General Anesthesia ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Metabolic Changes ◽  
Sevoflurane Anesthesia ◽  
Glutamate Metabolism ◽  
Acid Cycle ◽  
Link Type ◽  
The Mean

Abstract Background Metabolic status can be impacted by general anesthesia and surgery. However, the exact effects of general anesthesia and surgery on systemic metabolome remain unclear, which might contribute to postoperative outcomes. Methods Five hundred patients who underwent abdominal surgery were included. General anesthesia was mainly maintained with sevoflurane. The end-tidal sevoflurane concentration (ETsevo) was adjusted to maintain BIS (Bispectral index) value between 40 and 60. The mean ETsevo from 20 min after endotracheal intubation to 2 h after the beginning of surgery was calculated for each patient. The patients were further divided into low ETsevo group (mean − SD) and high ETsevo group (mean + SD) to investigate the possible metabolic changes relevant to the amount of sevoflurane exposure. Results The mean ETsevo of the 500 patients was 1.60% ± 0.34%. Patients with low ETsevo (n = 55) and high ETsevo (n = 59) were selected for metabolomic analysis (1.06% ± 0.13% vs. 2.17% ± 0.16%, P < 0.001). Sevoflurane and abdominal surgery disturbed the tricarboxylic acid cycle as identified by increased citrate and cis-aconitate levels and impacted glycometabolism as identified by increased sucrose and D-glucose levels in these 114 patients. Glutamate metabolism was also impacted by sevoflurane and abdominal surgery in all the patients. In the patients with high ETsevo, levels of L-glutamine, pyroglutamic acid, sphinganine and L-selenocysteine after sevoflurane anesthesia and abdominal surgery were significantly higher than those of the patients with low ETsevo, suggesting that these metabolic changes might be relevant to the amount of sevoflurane exposure. Conclusions Sevoflurane anesthesia and abdominal surgery can impact principal metabolic pathways in clinical patients including tricarboxylic acid cycle, glycometabolism and glutamate metabolism. This study may provide a resource data for future studies about metabolism relevant to general anaesthesia and surgeries. Trial registration www.chictr.org.cn. identifier: ChiCTR1800014327.

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