References of "Hiller, Karsten 50001985"
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See detailDistinct metabolomic signature in cerebrospinal fluid in early parkinson's disease: Early Parkinson'S CSF Metabolic Signature
Trezzi, Jean-Pierre UL; Galozzi, Sara; Jäger, Christian UL et al

in Movement Disorders (2017)

Objective: The purpose of this study was to profile cerebrospinal fluid (CSF) from early-stage PD patients for disease-related metabolic changes and to determine a robust biomarker signature for early ... [more ▼]

Objective: The purpose of this study was to profile cerebrospinal fluid (CSF) from early-stage PD patients for disease-related metabolic changes and to determine a robust biomarker signature for early-stage PD diagnosis. Methods: By applying a non-targeted and mass spectrometry-driven approach, we investigated the CSF metabolome of 44 early-stage sporadic PD patients yet without treatment (DeNoPa cohort). We compared all detected metabolite levels with those measured in CSF of 43 age- and gender-matched healthy controls. After this analysis, we validated the results in an independent PD study cohort (T€ubingen cohort). Results: We identified that dehydroascorbic acid levels were significantly lower and fructose, mannose, and threonic acid levels were significantly higher (P <.05) in PD patients when compared with healthy controls. These changes reflect pathological oxidative stress responses, as well as protein glycation/glycosylation reactions in PD. Using a machine learning approach based on logistic regression, we successfully predicted the origin (PD patients vs healthy controls) in a second (n518) as well as in a third and completely independent validation set (n536). The biomarker signature is composed of the three markers—mannose, threonic acid, and fructose—and allows for sample classification with a sensitivity of 0.790 and a specificity of 0.800. Conclusion: We identified PD-specific metabolic changes in CSF that were associated with antioxidative stress response, glycation, and inflammation. Our results disentangle the complexity of the CSF metabolome to unravel metabolome changes related to earlystage PD. The detected biomarkers help understanding PD pathogenesis and can be applied as biomarkers to increase clinical diagnosis accuracy and patient care in early-stage PD. [less ▲]

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See detailErythritol is a pentose-phosphate pathway metabolite and associated with adiposity gain in young adults
Hootman, Katie C.; Trezzi, Jean-Pierre UL; Kraemer, Lisa UL et al

in Proceedings of the National Academy of Sciences of the United States of America (2017)

Metabolomic markers associated with incident central adiposity gain were investigated in young adults. In a 9-mo prospective study of university freshmen (n = 264). Blood samples and anthropometry ... [more ▼]

Metabolomic markers associated with incident central adiposity gain were investigated in young adults. In a 9-mo prospective study of university freshmen (n = 264). Blood samples and anthropometry measurements were collected in the first 3 d on campus and at the end of the year. Plasma from individuals was pooled by phenotype [incident central adiposity, stable adiposity, baseline hemoglobin A1c (HbA1c) > 5.05%, HbA1c < 4.92%] and assayed using GC-MS, chromatograms were analyzed using MetaboliteDetector software, and normalized metabolite levels were compared using Welch’s t test. Assays were repeated using freshly prepared pools, and statistically significant metabolites were quantified in a targeted GC-MS approach. Isotope tracer studies were performed to determine if the potential marker was an endogenous human metabolite in men and in whole blood. Participants with incident central adiposity gain had statistically significantly higher blood erythritol [P < 0.001, false discovery rate (FDR) = 0.0435], and the targeted assay revealed 15-fold [95% confidence interval (CI): 13.27, 16.25] higher blood erythritol compared with participants with stable adiposity. Participants with baseline HbA1c > 5.05% had 21-fold (95% CI: 19.84, 21.41) higher blood erythritol compared with participants with lower HbA1c (P < 0.001, FDR = 0.00016). Erythritol was shown to be synthesized endogenously from glucose via the pentose-phosphate pathway (PPP) in stable isotope-assisted ex vivo blood incubation experiments and through in vivo conversion of erythritol to erythronate in stable isotope-assisted dried blood spot experiments. Therefore, endogenous production of erythritol from glucose may contribute to the association between erythritol and obesity observed in young adults. [less ▲]

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See detailGlutathione Primes T Cell Metabolism for Inflammation
Mak, Tak W.; Grusdat, Melanie; Duncan, Gordon S. et al

in Immunity (2017), 46(4), 675-689

Activated T cells produce reactive oxygen species (ROS), which trigger the antioxidative glutathione (GSH) response necessary to buffer rising ROS and prevent cellular damage. We report that GSH is ... [more ▼]

Activated T cells produce reactive oxygen species (ROS), which trigger the antioxidative glutathione (GSH) response necessary to buffer rising ROS and prevent cellular damage. We report that GSH is essential for T cell effector functions through its regulation of metabolic activity. Conditional gene targeting of the catalytic subunit of glutamate cysteine ligase (Gclc) blocked GSH production specifically in murine T cells. Gclc-deficient T cells initially underwent normal activation but could not meet their increased energy and biosynthetic requirements. GSH deficiency compromised the activation of mammalian target of rapamycin-1 (mTOR) and expression of NFAT and Myc transcription factors, abrogating the energy utilization and Myc-dependent metabolic reprogramming that allows activated T cells to switch to glycolysis and glutaminolysis. In vivo, T-cell-specific ablation of murine Gclc prevented autoimmune disease but blocked antiviral defense. The antioxidative GSH pathway thus plays an unexpected role in metabolic integration and reprogramming during inflammatory T cell responses. [less ▲]

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See detailStable Isotope-Assisted Evaluation of Different Extraction Solvents for Untargeted Metabolomics of Plants
Doppler, Maria; Kluger, Bernhard; Bueschl, Christoph et al

in International Journal of Molecular Sciences (2016)

The evaluation of extraction protocols for untargeted metabolomics approaches is still difficult. We have applied a novel stable isotope-assisted workflow for untargeted LC-HRMS-based plant metabolomics ... [more ▼]

The evaluation of extraction protocols for untargeted metabolomics approaches is still difficult. We have applied a novel stable isotope-assisted workflow for untargeted LC-HRMS-based plant metabolomics , which allows for the first time every detected feature to be considered for method evaluation. The efficiency and complementarity of commonly used extraction solvents, namely 1 + 3 (v/v) mixtures of water and selected organic solvents (methanol, acetonitrile or methanol/acetonitrile 1 + 1 (v/v)), with and without the addition of 0.1% (v/v) formic acid were compared. Four different wheat organs were sampled, extracted and analysed by LC-HRMS. Data evaluation was performed with the in-house-developed MetExtract II software and R. With all tested solvents a total of 871 metabolites were extracted in ear, 785 in stem, 733 in leaf and 517 in root samples, respectively. Between 48% (stem) and 57% (ear) of the metabolites detected in a particular organ were found with all extraction mixtures, and 127 of 996 metabolites were consistently shared between all extraction agent/organ combinations. In aqueous methanol, acidification with formic acid led to pronounced pH dependency regarding the precision of metabolite abundance and the number of detectable metabolites, whereas extracts of acetonitrile-containing mixtures were less affected. Moreover, methanol and acetonitrile have been found to be complementary with respect to extraction efficiency. Interestingly, the beneficial properties of both solvents can be combined by the use of a water-methanol-acetonitrile mixture for global metabolite extraction instead of aqueous methanol or aqueous acetonitrile alone. [less ▲]

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See detailLacaScore: a novel plasma sample quality control tool based on ascorbic acid and lactic acid levels
Trezzi, Jean-Pierre UL; Bulla, Alexandre; Bellora, Camille et al

in Metabolomics : Official journal of the Metabolomic Society (2016), 12(96),

Introduction Metabolome analysis is complicated by the continuous dynamic changes of metabolites in vivo and ex vivo. One of the main challenges in metabolomics is the robustness and reproducibility of ... [more ▼]

Introduction Metabolome analysis is complicated by the continuous dynamic changes of metabolites in vivo and ex vivo. One of the main challenges in metabolomics is the robustness and reproducibility of results, partially driven by pre-analytical variations. Objectives The objective of this study was to analyse the impact of pre-centrifugation time and temperature, and to determine a quality control marker in plasma samples. Methods Plasma metabolites were measured by gas chromatography-mass spectrometry (GC–MS) and analysed with the MetaboliteDetector software. The metabolites, which were the most labile to pre-analytical variations, were further measured by enzymatic assays. A score was calculated for their use as quality control markers. Results The pre-centrifugation temperature was shown to be critical in the stability of plasma samples and had a significant impact on metabolite concentration profiles. In contrast, pre-centrifugation delay had only a minor impact. Based on the results of this study, whole blood should be kept on wet ice and centrifuged within maximum 3 h as a prerequisite for preparing EDTA plasma samples fit for the purpose of metabolome analysis. Conclusions We have established a novel blood sample quality control marker, the LacaScore, based on the ascorbic acid to lactic acid ratio in plasma, which can be used as an indicator of the blood pre-centrifugation conditions, and hence the suitability of the sample for metabolome analyses. This method can be applied in research institutes and biobanks, enabling assessment of the quality of their plasma sample collections. [less ▲]

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See detailMetabolic Profiling as Well as Stable Isotope Assisted Metabolic and Proteomic Analysis of RAW 264.7 Macrophages Exposed to Ship Engine Aerosol Emissions: Different Effects of Heavy Fuel Oil and Refined Diesel Fuel.
Sapcariu, Sean UL; Kanashova, Tamara; Dilger, Marco et al

in PloS one (2016), 11(6), 0157964

Exposure to air pollution resulting from fossil fuel combustion has been linked to multiple short-term and long term health effects. In a previous study, exposure of lung epithelial cells to engine ... [more ▼]

Exposure to air pollution resulting from fossil fuel combustion has been linked to multiple short-term and long term health effects. In a previous study, exposure of lung epithelial cells to engine exhaust from heavy fuel oil (HFO) and diesel fuel (DF), two of the main fuels used in marine engines, led to an increased regulation of several pathways associated with adverse cellular effects, including pro-inflammatory pathways. In addition, DF exhaust exposure was shown to have a wider response on multiple cellular regulatory levels compared to HFO emissions, suggesting a potentially higher toxicity of DF emissions over HFO. In order to further understand these effects, as well as to validate these findings in another cell line, we investigated macrophages under the same conditions as a more inflammation-relevant model. An air-liquid interface aerosol exposure system was used to provide a more biologically relevant exposure system compared to submerged experiments, with cells exposed to either the complete aerosol (particle and gas phase), or the gas phase only (with particles filtered out). Data from cytotoxicity assays were integrated with metabolomics and proteomics analyses, including stable isotope-assisted metabolomics, in order to uncover pathways affected by combustion aerosol exposure in macrophages. Through this approach, we determined differing phenotypic effects associated with the different components of aerosol. The particle phase of diluted combustion aerosols was found to induce increased cell death in macrophages, while the gas phase was found more to affect the metabolic profile. In particular, a higher cytotoxicity of DF aerosol emission was observed in relation to the HFO aerosol. Furthermore, macrophage exposure to the gas phase of HFO leads to an induction of a pro-inflammatory metabolic and proteomic phenotype. These results validate the effects found in lung epithelial cells, confirming the role of inflammation and cellular stress in the response to combustion aerosols. [less ▲]

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See detailLoss of DJ-1 impairs antioxidant response by altered glutamine and serine metabolism
Meiser, Johannes UL; Delcambre, Sylvie UL; Wegner, André UL et al

in Neurobiology of disease (2016), 89

The oncogene DJ-1 has been originally identified as a suppressor of PTEN. Further on, loss-of-function mutations have been described as a causative factor in Parkinson's disease (PD). DJ-1 has an ... [more ▼]

The oncogene DJ-1 has been originally identified as a suppressor of PTEN. Further on, loss-of-function mutations have been described as a causative factor in Parkinson's disease (PD). DJ-1 has an important function in cellular antioxidant responses, but its role in central metabolism of neurons is still elusive. We applied stable isotope assisted metabolic profiling to investigate the effect of a functional loss of DJ-1 and show that DJ-1 deficient neuronal cells exhibit decreased glutamine influx and reduced serine biosynthesis. By providing precursors for GSH synthesis, these two metabolic pathways are important contributors to cellular antioxidant response. Down-regulation of these pathways, as a result of loss of DJ-1 leads to an impaired antioxidant response. Furthermore, DJ-1 deficient mouse microglia showed a weak but constitutive pro-inflammatory activation. The combined effects of altered central metabolism and constitutive activation of glia cells raise the susceptibility of dopaminergic neurons towards degeneration in patients harboring mutated DJ-1. Our work reveals metabolic alterations leading to increased cellular instability and identifies potential new intervention points that can further be studied in the light of novel translational medicine approaches. [less ▲]

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See detailDual loss of succinate dehydrogenase (SDH) and complex I activity is necessary to recapitulate the metabolic phenotype of SDH mutant tumors
Lorendeau, Doriane; Rinaldi, Gianmarco; Boon, Ruben et al

in Metabolic Engineering (2016)

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See detailAnalysis of mitochondrial metabolism in situ: Combining stable isotope labeling with selective permeabilization
Nonnenmacher, Yannic; Palorini, Roberta; d’ Herouël, Aymeric Fouquier et al

in Metabolic Engineering (2016)

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See detailMetabolic Profiling and Quantification of Neurotransmitters in Mouse Brain by Gas Chromatography-Mass Spectrometry: Metabolic Profiling of Neurotransmitters by GC-MS
Jäger, Christian UL; Hiller, Karsten UL; Buttini, Manuel UL

in Auwerx, Johan; Ackerman, Susan L.; Brown, Stephen D. (Eds.) et al Current Protocols in Mouse Biology (2016)

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See detailThe role of HIF-1 in oncostatin M-dependent metabolic reprogramming of hepatic cells.
Battello, Nadia UL; Zimmer, Andreas David UL; Goebel, Carole et al

in Cancer & metabolism (2016), 4

BACKGROUND: Hypoxia and inflammation have been identified as hallmarks of cancer. A majority of hepatocellular carcinomas are preceded by hepatitis B- or C-related chronic infections suggesting that liver ... [more ▼]

BACKGROUND: Hypoxia and inflammation have been identified as hallmarks of cancer. A majority of hepatocellular carcinomas are preceded by hepatitis B- or C-related chronic infections suggesting that liver cancer development is promoted by an inflammatory microenvironment. The inflammatory cytokine oncostatin M (OSM) was shown to induce the expression of hypoxia-inducible factor-1 alpha (HIF-1 alpha) under normoxic conditions in hepatocytes and hepatoma cells. HIF-1 alpha is known to orchestrate the expression of numerous genes, many of which code for metabolic enzymes that play key roles in the adaptation of cellular metabolism to low oxygen tension. RESULTS: Here, we show that OSM-induced upregulation of HIF-1 alpha reprograms cellular metabolism in three clones of the human hepatocyte cell line PH5CH (PH5CH1, PH5CH7, and PH5CH8) towards a hypoxia-like metabolic phenotype but has no significant effect on cellular metabolism of HepG2 and JHH-4 hepatoma cells. Although we observed only minor changes in glucose uptake and lactate secretion in PH5CH8 upon OSM treatment, we identified more pronounced changes in intracellular fluxes based on stable isotope labeling experiments. In particular, glucose oxidation in the tricarboxylic acid (TCA) cycle is reduced through pyruvate dehydrogenase kinase 1 (PDK1)-mediated inhibition of the pyruvate dehydrogenase complex, thereby reducing the oxidative TCA cycle flux. As a result of the impaired mitochondrial glucose and glutamine oxidation, the reductive isocitrate dehydrogenase flux was increased. CONCLUSIONS: We provide evidence that connects the inflammatory mediator OSM to a hypoxia-like metabolic phenotype. In the human hepatocyte cell line PH5CH, OSM-mediated upregulation of HIF-1 alpha and PDK1 can induce hypoxia-like metabolic changes, although to a lesser extent than hypoxia itself. Since PDK1 is overexpressed in several cancers, it might provide a causal link between chronic inflammation and malignant cellular transformation. [less ▲]

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See detailProtein Kinase A Activation Promotes Cancer Cell Resistance to Glucose Starvation and Anoikis.
Palorini, Roberta; Votta, Giuseppina; Pirola, Yuri et al

in PLoS genetics (2016), 12(3), 1005931

Cancer cells often rely on glycolysis to obtain energy and support anabolic growth. Several studies showed that glycolytic cells are susceptible to cell death when subjected to low glucose availability or ... [more ▼]

Cancer cells often rely on glycolysis to obtain energy and support anabolic growth. Several studies showed that glycolytic cells are susceptible to cell death when subjected to low glucose availability or to lack of glucose. However, some cancer cells, including glycolytic ones, can efficiently acquire higher tolerance to glucose depletion, leading to their survival and aggressiveness. Although increased resistance to glucose starvation has been shown to be a consequence of signaling pathways and compensatory metabolic routes activation, the full repertoire of the underlying molecular alterations remain elusive. Using omics and computational analyses, we found that cyclic adenosine monophosphate-Protein Kinase A (cAMP-PKA) axis activation is fundamental for cancer cell resistance to glucose starvation and anoikis. Notably, here we show that such a PKA-dependent survival is mediated by parallel activation of autophagy and glutamine utilization that in concert concur to attenuate the endoplasmic reticulum (ER) stress and to sustain cell anabolism. Indeed, the inhibition of PKA-mediated autophagy or glutamine metabolism increased the level of cell death, suggesting that the induction of autophagy and metabolic rewiring by PKA is important for cancer cellular survival under glucose starvation. Importantly, both processes actively participate to cancer cell survival mediated by suspension-activated PKA as well. In addition we identify also a PKA/Src mechanism capable to protect cancer cells from anoikis. Our results reveal for the first time the role of the versatile PKA in cancer cells survival under chronic glucose starvation and anoikis and may be a novel potential target for cancer treatment. [less ▲]

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See detailDistinct Metabolic States Can Support Self-Renewal and Lipogenesis in Human Pluripotent Stem Cells under Different Culture Conditions
Zhang, Hui; Badur, Mehmet G.; Divakaruni, Ajit S. et al

in Cell Reports (2016), 16(6), 1536--1547

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See detailIsotopologue ratio normalization for non-targeted metabolomics
Weindl, Daniel UL; Wegner, André UL; Jäger, Christian UL et al

in Journal of Chromatography. A (2015), 1389

Robust quantification of analytes is a prerequisite for meaningful metabolomics experiments. In non-targeted metabolomics it is still hard to compare measurements across multiple batches or instruments ... [more ▼]

Robust quantification of analytes is a prerequisite for meaningful metabolomics experiments. In non-targeted metabolomics it is still hard to compare measurements across multiple batches or instruments. For targeted analyses isotope dilution mass spectrometry is used to provide a robust normalization reference. Here, we present an approach that allows for the automated semi-quantification of metabolites relative to a fully stable isotope-labeled metabolite extract. Unlike many previous approaches, we include both identified and unidentified compounds in the data analysis. The internal standards are detected in an automated manner using the non-targeted tracer fate detection algorithm. The ratios of the light and heavy form of these compounds serve as a robust measure to compare metabolite levels across different mass spectrometric platforms. As opposed to other methods which require high resolution mass spectrometers, our methodology works with low resolution mass spectrometers as commonly used in gas chromatography electron impact mass spectrometry (GC–EI-MS)-based metabolomics. We demonstrate the validity of our method by analyzing compound levels in different samples and show that it outperforms conventional normalization approaches in terms of intra- and inter-instrument reproducibility. We show that a labeled yeast metabolite extract can also serve as a reference for mammalian metabolite extracts where complete stable isotope labeling is hard to achieve. [less ▲]

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See detailMetabolome-wide analysis of stable isotope labeling - Is it worth the effort?
Weindl, Daniel UL; Wegner, André UL; Hiller, Karsten UL

in Frontiers in Physiology (2015), 6(344),

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See detailNon-targeted tracer fate detection
Weindl, Daniel UL; Wegner, André UL; Hiller, Karsten UL

in Methods in Enzymology (2015), 561

Stable isotopes have been used to trace atoms through metabolism and quantify metabolic fluxes for several decades. Only recently non-targeted stable isotope labeling approaches have emerged as a powerful ... [more ▼]

Stable isotopes have been used to trace atoms through metabolism and quantify metabolic fluxes for several decades. Only recently non-targeted stable isotope labeling approaches have emerged as a powerful tool to gain biological insights into metabolism. However, the manual detection of isotopic enrichment for a non-targeted analysis is tedious and time consuming. To overcome this limitation, the non-targeted tracer fate detection (NTFD) algorithm for the automated metabolome-wide detection of isotopic enrichment has been developed. NTFD detects and quantifies isotopic enrichment in the form of mass isotopomer distributions (MIDs) in an automated manner, providing the means to trace functional groups, determine MIDs for metabolic flux analysis, or detect tracer-derived molecules in general. Here, we describe the algorithmic background of NTFD, discuss practical considerations for the freely available NTFD software package, and present potential applications of non-targeted stable isotope labeling analysis. [less ▲]

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See detailPreferential extracellular generation of the active parkinsonian toxin MPP+ by transporter-independent export of the intermediate MPDP+
Schildknecht, Stefan; Pape, Regina; Meiser, Johannes et al

in Antioxidants & redox signaling (2015)

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See detailItaconic Acid: The Surprising Role of an Industrial Compound as a Mammalian Antimicrobial Metabolite
Cordes, Thekla; Michelucci, Alessandro UL; Hiller, Karsten UL

in Annual review of nutrition (2015)

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See detailHow metabolites modulate metabolic flux
Wegner, André UL; Meiser, Johannes UL; Weindl, Daniel UL et al

in Current Opinion in Biotechnology (2015), 34

Adaptation to metabolic needs and changing environments is a basic requirement of every living system. These adaptations can be very quick and mild or slower but more drastic. In any case, cells have to ... [more ▼]

Adaptation to metabolic needs and changing environments is a basic requirement of every living system. These adaptations can be very quick and mild or slower but more drastic. In any case, cells have to constantly monitor their metabolic state and requirements.In this article we review general concepts as well as recent advances on how metabolites can regulate metabolic fluxes. We discuss how cells sense metabolite levels and how changing metabolite levels regulate metabolic enzymes on different levels, from specific allosteric regulation to global transcriptional regulation. We thereby focus on local metabolite sensing in mammalian cells and show that several major discoveries have only very recently been made. [less ▲]

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