Validation of a routine gas chromatography mass spectrometry method for 2-hydroxyglutarate quantification in human serum as a screening tool for detection of idh mutations

Fernández-Galán, Esther; Massana, Núria; Parra‐Robert, Marina; Hidalgo, Susana; Casals, Gregori; Esteve, Jordi; Jiménez, Wladimiro

doi:10.1016/j.jchromb.2018.02.038

Cited by 14 publications

(11 citation statements)

References 16 publications

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“…All solvent fractions containing isolated lipids were dried under nitrogen stream and transesterified (FAME) with 0.5 M NAOH and boron trifluoride (Sigma Aldrich, Saint Louis, USA, B1252) in methanol. GC–MS analyses of FAME were performed on a Shimadzu GCMS QP2010 Ultra instrument (Kyoto, Japan) as previously described 88 . Briefly, final extracts were injected in spitless mode (valve opened at 1 min) into the gas chromatograph interfaced with a mass selective detector.…”

Section: Methodsmentioning

confidence: 99%

Cerium oxide nanoparticles display antilipogenic effect in rats with non-alcoholic fatty liver disease

Carvajal

Perramón

Oró

et al. 2019

Sci Rep

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Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, ranging from steatosis to non-alcoholic steatohepatitis (NASH). Recently, cerium oxide nanoparticles (CeO 2 NPs) have emerged as a new antioxidant agent with hepatoprotective properties in experimental liver disease. The aim of the current investigation was to elucidate whether CeO 2 NPs display beneficial effects in an experimental model of NAFLD.Therefore, fifteen Wistar rats were subjected to a methionine and choline deficient diet (MCDD) for 6 weeks and intravenously treated with CeO 2 NP or vehicle during the weeks three and four of the diet. The effect of CeO 2 NPs on serum biochemistry, hepatic steatosis, inflammation, fatty acid content and expression of reactive oxygen species (ROS) and lipid metabolism related genes was assessed. MCDD fed rats showed increased inflammation, enhanced hepatic lipid accumulation of both saturated and unsaturated fatty acids (FAs) and overexpression of genes related to fatty liver and ROS metabolism. Treatment with CeO 2 NPs was able to reduce the size and content of hepatocyte lipid droplets, the hepatic concentration of triglyceride- and cholesterol ester-derived FAs and the expression of several genes involved in cytokine, adipokine and chemokine signaling pathways. These findings suggest that CeO 2 NPs could be of beneficial value in NAFLD.

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Section: Methodsmentioning

confidence: 99%

Cerium oxide nanoparticles display antilipogenic effect in rats with non-alcoholic fatty liver disease

Carvajal

Perramón

Oró

et al. 2019

Sci Rep

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“…D-2HG has been shown to be highly elevated (up to 100-fold) not only in the IDH-mutant tumor cells but also in the tumor microenvironment [21] as well as serum [22] and cerebrospinal fluid [23]. The possibility of D-2HG detection in those biofluids (using mass spectrometry) [23][24][25] as well as in the tumor tissue (using MRI) [26] provides a valuable tool for non-invasive diagnostics and proved to be more robust in terms of prognostic value. Mammalian target of rapamycin (mTOR) holds a key role in cellular metabolism regulating mitochondrial oxygen consumption [37], glucose uptake [38], and nutrient utilization [39] by dictating the expression and or activity of metabolic enzymes [40].…”

Section: D-2hg In the Tumor Microenvironmentmentioning

confidence: 99%

Immunometabolic Regulation of Anti-Tumor T-Cell Responses by the Oncometabolite D-2-Hydroxyglutarate

Mougiakakos¹

2019

Immunometabolism

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Since the discovery of gain-of-function mutations in the tricarboxylic acid (TCA) cycle enzyme isocitrate dehydrogenase (IDH) and the resulting accumulation of the metabolite D-2-hydroxyglutarate (D-2HG) in several tumor entities (such as glioma, acute myeloid leukemia (AML), and cholangiocarcinoma) about 10 years ago research has focused on the tumor cell-intrinsic consequences. D-2HG acting as an oncometabolite was shown to promote proliferation, anoikis, tumorigenesis, and differentiation block of hematopoietic cells in an autocrine fashion. Although the prognostic value of the different types of IDH mutations remains controversial the development of inhibitors against mutated IDH is flourishing. On the other hand, serum levels of D-2HG proved to be a more robust adverse prognostic marker in AML and glioma. Surprisingly, until recently only few studies on the paracrine effects of this oncometabolite on the tumor microenvironment with particular focus on the innate or adaptive immunity were available. Now, three recent publications focused on the paracrine effects of tumorderived D-2HG on T-cells in the context of AML and glioma. It was shown that T-cells are capable of efficiently taking up D-2HG in vitro, which was mirrored by 2HG-enriched T-cells exclusively found in samples from patients with IDH-mutated AML and glioma. Furthermore, all three studies describe an impairment of T-cell activation (although to different extents). The published effects could be at least partly attributed to metabolic alterations evoked by D-2HG influencing amongst others mTOR signaling, Hif-1α protein stability, the balance between aerobic glycolysis and oxidative phosphorylation, and the abundance of ATP (with according changes of AMPK activation). In the context of glioma it was further shown that IDH mutations and high D-2HG levels lead to reduced T-cell migration and consequently lowered T-cell infiltration at the tumor site. Moreover, two of the studies showed an increased frequency of FoxP3 + Tregs. Nevertheless, effects on downstream mechanisms and consequences have been differently addressed in the independent studies, and taken together the findings shed more light on the potentially targetable sites for

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“…Liquid chromatography-tandem mass spectrometry (LC-MS/MS) 18,19 and gas chromatography-tandem mass spectrometry (GC-MS/MS) 20,21 are often used to assess the extracellular concentrations of L-2-HG. These common methods are, at present, time consuming, expensive to perform, and require highly skilled personnel.…”

Section: Introductionmentioning

confidence: 99%

A fluorescent l-2-hydroxyglutarate biosensor

Kang

Zhang

Gao

et al. 2020

Preprint

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Abstractl-2-Hydroxyglutarate (l-2-HG) plays important roles in diverse physiological processes, such as carbon starvation response, tumorigenesis, and hypoxic adaptation. Despite its importance and intensively studied metabolism, regulation of l-2-HG metabolism remains poorly understood and a regulator specifically responded to l-2-HG has never been identified. Based on the genomic neighborhood analysis of the gene encoding l-2-HG oxidase (LhgO), LhgR, which represses the transcription of lhgO, was identified in Pseudomonas putida W619 in this study. LhgR was demonstrated to recognize l-2-HG as its specific effector molecule, and this allosteric transcription factor was then used as a biorecognition element for construction of l-2-HG-sensing FRET sensor. The newly developed l-2-HG sensor can conveniently monitor the concentrations of l-2-HG in various biological samples. In addition to bacterial l-2-HG generation during carbon starvation, biological functions of the l-2-HG dehydrogenase and hypoxia induced l-2-HG accumulation were also revealed by using the l-2-HG sensor in human cells.

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Validation of a routine gas chromatography mass spectrometry method for 2-hydroxyglutarate quantification in human serum as a screening tool for detection of idh mutations

Cited by 14 publications

References 16 publications

Cerium oxide nanoparticles display antilipogenic effect in rats with non-alcoholic fatty liver disease

Cerium oxide nanoparticles display antilipogenic effect in rats with non-alcoholic fatty liver disease

Immunometabolic Regulation of Anti-Tumor T-Cell Responses by the Oncometabolite D-2-Hydroxyglutarate

A fluorescent l-2-hydroxyglutarate biosensor

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