Creatine is physiologically provided equally by diet and by endogenous synthesis from arginine and glycine with successive involvements of arginine glycine amidinotransferase AGAT and ...guanidinoacetate methyl transferase GAMT. A specific plasma membrane transporter, creatine transporter CRTR (SLC6A8), further enables cells to incorporate creatine and through uptake of its precursor, guanidinoacetate, also directly contributes to creatine biosynthesis. Breakthrough in the role of creatine has arisen from studies on creatine deficiency disorders. Primary creatine disorders are inherited as autosomal recessive (mutations affecting GATM for glycine-amidinotransferase, mitochondrial) and GAMT genes) or X-linked (SLC6A8 gene) traits. They have highlighted the role of creatine in brain functions altered in patients (global developmental delay, intellectual disability, behavioral disorders). Creatine modulates GABAergic and glutamatergic cerebral pathways, presynaptic CRTR (SLC6A8) ensuring re-uptake of synaptic creatine. Secondary creatine disorders, addressing other genes, have stressed the extraordinary imbrication of creatine metabolism with many other cellular pathways. This high dependence on multiple pathways supports creatine as a cellular sensor, to cell methylation and energy status. Creatine biosynthesis consumes 40% of methyl groups produced as S-adenosylmethionine, and creatine uptake is controlled by AMP activated protein kinase, a ubiquitous sensor of energy depletion. Today, creatine is considered as a potential sensor of cell methylation and energy status, a neurotransmitter influencing key (GABAergic and glutamatergic) CNS neurotransmission, therapeutic agent with anaplerotic properties (towards creatine kinases creatine–creatine phosphate cycle and creatine neurotransmission), energetic and antioxidant compound (benefits in degenerative diseases through protection against energy depletion and oxidant species) with osmolyte behavior (retention of water by muscle). This review encompasses all these aspects by providing an illustrated metabolic account for brain and body creatine in health and disease, an algorithm to diagnose metabolic and gene bases of primary and secondary creatine deficiencies, and a metabolic exploration by 1H-MRS assessment of cerebral creatine levels and response to therapeutic measures.
•Primary creatine disorders highlight a role of creatine in brain physiology.•SLC6A8 takes part in creatine transport and re-uptake but also in biosynthesis.•Secondary creatine defects stress dependence of creatine metabolism on many pathways.•The high dependence on multiple metabolic pathways supports creatine as a cell sensor.•Creatine is a potential sensor of cell methylation and energy status.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Hepatocellular carcinoma (HCC) is a longstanding issue in clinical practice and metabolic research. New clues in better understanding the pathogenesis of HCC might relate to the metabolic context in ...patients with citrin (aspartate-glutamate carrier 1) deficiency (CD). Because citrin-deficient liver (CDL) is subject to HCC, it represents a unique metabolic model to highlight the mechanisms of HCC promotion, offering different angles of study than the classical metabolic syndrome/obesity/non-alcoholic fatty liver disease (NAFLD)/HCC study axis. In turn, the metabolic features of HCC could shed light on the pathogenesis of CDL. Among these, HCC-induced re-activation of aralar-1 (aspartate-glutamate carrier 2), physiologically not expressed in the adult liver, might take place in CDL, so gene redundancy for mitochondrial aspartate-glutamate carriers would be exploited by the CDL. This proposed (aralar-1 re-activation) and known (citrate/malate cycle) adaptive mechanisms may substitute for the impaired function in CD and are consistent with the clinical remission stage of CD and CD improvement by medium-chain triglycerides (MCT). However, these metabolic adaptive benefits could also promote HCC development. In CD, as a result of PPARα down-regulation, liver mitochondrial fatty acid-derived acetyl-CoA would, like glucose-derived acetyl-CoA, be used for lipid anabolism and fuel nuclear acetylation events which might trigger aralar-1 re-activation as seen in non-CD HCC. A brief account of these metabolic events which might lead to aralar-1 re-activation in CDL is here given. Consistency of this account for CDL events further relies on the protective roles of PPARα and inhibition of mitochondrial and plasma membrane citrate transporters in non-CD HCC.
•SLC25A13 (citrin) and SLC25A12 (aralar-1) are the two aspartate-glutamate carriers.•Patients with citrin deficiency (CD) are treated with medium-chain triglycerides (MCT).•CD is a cause of hepatocellular carcinoma (HCC) and aralar-1 is re-activated in non-CD HCC.•This re-activation might contribute to CD remission stage and disease improvement by MCT.•Whether MCT promote nuclear acetylations, aralar-1 re-activation, and HCC in CD remains unclear.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Metastasis and drug resistance are the major limitations in the survival and management of patients with cancer. This study aimed to identify the mechanisms underlying HT29 colon cancer cell ...chemoresistance acquired after sequential exposure to 5-fluorouracil (5FU), a classical anticancer drug for treatment of epithelial solid tumors. We examined its clinical relevance in a cohort of patients with colon cancer with liver metastases after 5FU-based neoadjuvant chemotherapy and surgery.
We show that a clonal 5F31 cell population, resistant to 1 μmol/L 5FU, express a typical cancer stem cell-like phenotype and enter into a reversible quiescent G0 state upon reexposure to higher 5FU concentrations. These quiescent cells overexpressed the tyrosine kinase c-Yes that became activated and membrane-associated upon 5FU exposure. This enhanced signaling pathway induced the dissociation of the Yes/YAP (Yes-associated protein) molecular complex and depleted nuclear YAP levels. Consistently, YES1 silencing decreased nuclear YAP accumulation and induced cellular quiescence in 5F31 cells cultured in 5FU-free medium. Importantly, YES1 and YAP transcript levels were higher in liver metastases of patients with colon cancer after 5FU-based neoadjuvant chemotherapy. Moreover, the YES1 and YAP transcript levels positively correlated with colon cancer relapse and shorter patient survival (P < 0.05 and P < 0.025, respectively).
We identified c-Yes and YAP as potential molecular targets to eradicate quiescent cancer cells and dormant micrometastases during 5FU chemotherapy and resistance and as predictive survival markers for colon cancer.
Apart from the oncometabolite succinate, little studies have appeared on extra-mitochondrial pathways in Succinate Dehydrogenase (SDH) genetic deficiency. The role of NADH/NAD+ redox status and ...dependent pathways was recently emphasized. Therein, fatty acid (FA) metabolism data were collected here in 30 patients with a loss of function (LOF) variant in one SDHx gene (either with a pheochromocytoma/paraganglioma (PPGL) or asymptomatic) and in 22 wild-type SDHx controls (with PPGL or asymptomatic). Blood acylcarnitines in two patients, peroxisomal biomarkers, very long-chain saturated FA (VLCFA), and C20 to C24 n-3 polyunsaturated fatty acids (PUFA), in all patients were measured by mass spectrometry. Preliminary data showed elevated even and odd long- and very long-chain acylcarnitines in two patients with a SDHB variant. In the whole series, no abnormalities were observed in biomarkers of peroxisomal β-oxidation (C27-bile acids, VLCFAs and phytanic/pristanic acids) in SDHx patients. However, an increased hexaene to pentaene PUFA ratio (TetraHexaenoic Acid + DocosaHexaenoic Acid/n-3 DocosaPentaenoic Acid + EicosaPentaenoic Acid) was noticed in patients with SDHC/SDHD variants vs patients with SDHA/SDHB variants or controls, suggesting a higher degree of unsaturation of PUFAs. Within the group with a SDHx variant, Eicosapentaenoate/Tetracosahexaenoate ratio, as an empiric index of shortening/elongation balance, discriminated patients with PPGL from asymptomatic ones. Present findings argue for stimulated elongation of saturated FAs, changes in shortening/elongation balance and desaturation rates of C20–C24 PUFAs in SDH-deficient patients with PPGL. Overall, oxidation of NADH sustained by these pathways might reflect or impact glycolytic NAD+ recycling and hence tumor proliferation.
•Unsaturation of serum C20–C24 PUFAs is higher in patients with SDHC/D germline variant.•Serum EPA/THA ratio increases in patients with germline SDHx variant and paraganglioma.•This suggests higher Fatty Acid desaturase and elongase activities in SDH deficiency.•Both biochemical pathways increase cytosolic NAD + recycling.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Introduction
Reprogramming of cellular metabolism is now a hallmark of tumorigenesis. In recent years, research on pancreatic neuroendocrine tumors (pNETs) has focused on genetic and epigenetic ...modifications and related signaling pathways, but few studies have been devoted to characterizing the metabolic profile of these tumors. In this review, we thoroughly investigate the metabolic pathways in pNETs by analyzing the transcriptomic and metabolomic data available in the literature.
Methodology
We retrieved and downloaded gene expression profiles from all publicly available gene set enrichments (GSE43797, GSE73338, and GSE117851) to compare the differences in expressed genes based on both the stage and MEN1 mutational status. In addition, we conducted a systematic review of metabolomic data in NETs.
Results
By combining transcriptomic and metabolomic approaches, we have identified a distinctive metabolism in pNETs compared with controls without pNETs. Our analysis showed dysregulations in the one-carbon, glutathione, and polyamine metabolisms, fatty acid biosynthesis, and branched-chain amino acid catabolism, which supply the tricarboxylic acid cycle. These targets are implicated in pNET cell proliferation and metastasis and could also have a prognostic impact. When analyzing the profiles of patients with or without metastasis, or with or without MEN1 mutation, we observed only a few differences due to the scarcity of published clinical data in the existing research. Consequently, further studies are now necessary to validate our data and investigate these potential targets as biomarkers or therapeutic solutions, with a specific focus on pNETs.
Metastasis and drug resistance are major problems in cancer chemotherapy. The purpose of this work was to analyze the molecular mechanisms underlying the invasive potential of drug-resistant colon ...carcinoma cells. Cellular models included the parental HT-29 cell line and its drug-resistant derivatives selected after chronic treatment with either 5-fluorouracil, methotrexate, doxorubicin, or oxaliplatin. Drug-resistant invasive cells were compared with noninvasive cells using cDNA microarray, quantitative reverse transcription-PCR, flow cytometry, immunoblots, and ELISA. Functional and cellular signaling analyses were undertaken using pharmacologic inhibitors, function-blocking antibodies, and silencing by retrovirus-mediated RNA interference. 5-Fluorouracil- and methotrexate-resistant HT-29 cells expressing an invasive phenotype in collagen type I and a metastatic behavior in immunodeficient mice exhibited high expression of the chemokine receptor CXCR4. Macrophage migration-inhibitory factor (MIF) was identified as the critical autocrine CXCR4 ligand promoting invasion in drug-resistant colon carcinoma HT-29 cells. Silencing of CXCR4 and impairing the MIF-CXCR4 signaling pathways by ISO-1, pAb FL-115, AMD-3100, monoclonal antibody 12G5, and BIM-46187 abolished this aggressive phenotype. Induction of CXCR4 was associated with the upregulation of two genes encoding transcription factors previously shown to control CXCR4 expression (HIF-2alpha and ASCL2) and maintenance of intestinal stem cells (ASCL2). Enhanced CXCR4 expression was detected in liver metastases resected from patients with colon cancer treated by the standard FOLFOX regimen. Combination therapies targeting the CXCR4-MIF axis could potentially counteract the emergence of the invasive metastatic behavior in clonal derivatives of drug-resistant colon cancer cells.
Sodium lactate has been shown to improve hemodynamics and avoid fluid overload. The objective of this study was to confirm a beneficial effect on fluid balance with sodium lactate infusion and to ...specify whether the advantage of lactate is related to a negative chloride balance, its particular metabolism, or simply its energy load.
This was an interventional, randomized, open-label, controlled experimental study. Fifteen female "large white" pigs (2 months old) were challenged with intravenous infusion of Escherichia coli endotoxin. Three groups of five animals were randomly assigned to receive different fluids: a treatment group received sodium lactate 11.2% (SL group); an isotonic control group received 0.9% NaCl (NC group); and a hypertonic control group, with the same amount of osmoles and sodium as the SL group, received sodium bicarbonate 8.4% (SB group). In order to provide the same energy load in the three groups, control groups were perfused with an equivalent energy supply. Statistical analysis was performed with non-parametric tests and the Dunn correction for multiple comparisons at p < 0.05.
Fluid and chloride balance, hemodynamics, oxygenation markers, and microcirculatory parameters were measured over a 5-h period. Cumulative fluid balance was significantly lower in the SL group (550 (415-800) mL; median (interquartile range)) compared to the NC group (1100 (920-1640) mL, p = 0.01) and the SB group (935 (790-1220) mL, p = 0.03). Hemodynamics, cardiac efficiency, and microcirculation were significantly enhanced in the SL group, resulting in a significant improvement in oxygen delivery (SL group 417 (305-565) mL/min/m
at 300 min versus the NC (207 (119-272) mL/min/m
, p = 0.01) and the SB (278, (211-315) mL/min/m
, p = 0.03) groups). Oxygenation markers (arterial oxygen partial pressure (PaO
)/inspired oxygen fraction (FiO
), mixed venous oxygen saturation (SvO
), and venoarterial carbon dioxide tension difference (Pv-aCO
) were enhanced with sodium lactate infusion. Chloride balance was equivalent in both hypertonic groups and significantly reduced compared to the NC group.
Sodium lactate infusion improves fluid balance and hemodynamics. The advantage of lactate does not seem to be explained by its energy load or by the induced negative chloride balance with subsequent water movements.
CLINICAL HISTORY AND BACKGROUND A 22-month-old boy with no medical history, born from consanguineous parents, was referred to the pediatric emergency department for respiratory distress, recurrent ...vomiting, hepatomegaly, and asthenia in the context of acute otitis media. First-line blood analyses showed acidosis (pH 7.00; reference, 7.37-7.43), normal lactate (1.8 mmol/L; reference, 0.5-2.2 mmol/L), decreased bicarbonate (3.1 mmol/L; reference, 22-26 mmol/L), abnormal base excess (-26 mmol/L; reference, -2 to +2 mmol/L), hyperketonemia (Abbott Diabetes Care Freestyle Optium Neo, 4.6 mmol/L; threshold, 0.06 mmol/ L), hyperammonemia (99 ^mol/L; reference, 15-55 ^mol/L), and blood glucose of 2.3 mmol/L (reference, 1.65-5.50 mmol/L). ...an amino acid profile will reveal an important increase of alloisoleucine, pointing to an isoleucine catabolism disorder because alloisoleucine is alternatively built up when isoleucine accumulates.
PDF
