PubMed

Related Articles Assessment of l-Asparaginase Pharmacodynamics in Mouse Models of Cancer. Metabolites. 2019 Jan 09;9(1): Authors: Horvath TD, Chan WK, Pontikos MA, Martin LA, Du D, Tan L, Konopleva M, Weinstein JN, Lorenzi PL Abstract l-asparaginase (ASNase) is a metabolism-targeted anti-neoplastic agent used to treat acute lymphoblastic leukemia (ALL). ASNase's anticancer activity results from the enzymatic depletion of asparagine (Asn) and glutamine (Gln), which are converted to aspartic acid (Asp) and glutamic acid (Glu), respectively, in the blood. Unfortunately, accurate assessment of the in vivo pharmacodynamics (PD) of ASNase is challenging because of the following reasons: (i) ASNase is resilient to deactivation; (ii) ASNase catalytic efficiency is very high; and (iii) the PD markers Asn and Gln are depleted ex vivo in blood samples containing ASNase. To address those issues and facilitate longitudinal studies in individual mice for ASNase PD studies, we present here a new LC-MS/MS bioanalytical method that incorporates rapid quenching of ASNase for measurement of Asn, Asp, Gln, and Glu in just 10 µL of whole blood, with limits of detection (s:n ≥ 10:1) estimated to be 2.3, 3.5, 0.8, and 0.5 µM, respectively. We tested the suitability of the method in a 5-day, longitudinal PD study in mice and found the method to be simple to perform with sufficient accuracy and precision for whole blood measurements. Overall, the method increases the density of data that can be acquired from a single animal and will facilitate optimization of novel ASNase treatment regimens and/or the development of new ASNase variants with desired kinetic properties. PMID: 30634463 [PubMed]

18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/01/12PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

23 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/01/11PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

23 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/01/11PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/01/10PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/01/10PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

22 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/01/09PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

22 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/01/09PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

19 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/01/08PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

19 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/01/08PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

BioTransformer: a comprehensive computational tool for small molecule metabolism prediction and metabolite identification. J Cheminform. 2019 Jan 05;11(1):2 Authors: Djoumbou-Feunang Y, Fiamoncini J, Gil-de-la-Fuente A, Greiner R, Manach C, Wishart DS Abstract BACKGROUND: A number of computational tools for metabolism prediction have been developed over the last 20 years to predict the structures of small molecules undergoing biological transformation or environmental degradation. These tools were largely developed to facilitate absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies, although there is now a growing interest in using such tools to facilitate metabolomics and exposomics studies. However, their use and widespread adoption is still hampered by several factors, including their limited scope, breath of coverage, availability, and performance. RESULTS: To address these limitations, we have developed BioTransformer, a freely available software package for accurate, rapid, and comprehensive in silico metabolism prediction and compound identification. BioTransformer combines a machine learning approach with a knowledge-based approach to predict small molecule metabolism in human tissues (e.g. liver tissue), the human gut as well as the environment (soil and water microbiota), via its metabolism prediction tool. A comprehensive evaluation of BioTransformer showed that it was able to outperform two state-of-the-art commercially available tools (Meteor Nexus and ADMET Predictor), with precision and recall values up to 7 times better than those obtained for Meteor Nexus or ADMET Predictor on the same sets of pharmaceuticals, pesticides, phytochemicals or endobiotics under similar or identical constraints. Furthermore BioTransformer was able to reproduce 100% of the transformations and metabolites predicted by the EAWAG pathway prediction system. Using mass spectrometry data obtained from a rat experimental study with epicatechin supplementation, BioTransformer was also able to correctly identify 39 previously reported epicatechin metabolites via its metabolism identification tool, and suggest 28 potential metabolites, 17 of which matched nine monoisotopic masses for which no evidence of a previous report could be found. CONCLUSION: BioTransformer can be used as an open access command-line tool, or a software library. It is freely available at https://bitbucket.org/djoumbou/biotransformerjar/ . Moreover, it is also freely available as an open access RESTful application at www.biotransformer.ca , which allows users to manually or programmatically submit queries, and retrieve metabolism predictions or compound identification data. PMID: 30612223 [PubMed]

Vitamin C for the critically ill: Is the evidence strong enough? Nutrition. 2018 Oct 22;60:185-190 Authors: L Langlois P, Lamontagne F Abstract Vitamin C exhibits interesting properties in the context of critical illness, with benefits described in neurologic, cardiovascular, renal, and hematologic systems, both in in vitro and in animal models. Through direct effects on bacterial replication, immunomodulation, and antioxidant reserve of the organism, vitamin C directly affects the pathophysiological process of sepsis, trauma, burn, and systemic inflammation. Even if several observational trials have linked vitamin C deficiency to worse outcomes, the evidence is not such as to provide us with a distinction between causality effects or simple epiphenomenon, and the current focus is on interventional trials. Pharmacokinetic data suggest that a minimal supplementation of 3 g/d intravenously is required to restore normal serum values in critically ill patients with known deficiency. According to these data, only five trials, including a retrospective analysis, studied pharmacologic dose: three as an antioxidant cocktail and two as monotherapy. The largest trial, conducted in 2002, reported reduced incidence of multiorgan failure and duration of mechanical ventilation. Recently a retrospective analysis reported impressive results after administration of vitamin C, thiamine, and hydrocortisone. The two most recent trials reported improved clinical outcomes, including improved mortality, but contained significant methodological limitations. A recent systematic review did not find clinical benefits with the most-studied low-dose oral supplementation, potentially because of suboptimal or insufficient repletion. Current guidelines do not support the administration of high-dose vitamin C in critically ill patients. Future larger trials are required to support any therapy, but the low cost and safety profile can justify supplementation in the meantime. Metabolomics study will further help understand biological effect. PMID: 30612038 [PubMed - as supplied by publisher]

Metabolomics as a complement to phylogenetics for assessing intraspecific boundaries in the desiccation-tolerant medicinal shrub Myrothamnus flabellifolia (Myrothamnaceae). Phytochemistry. 2019 Jan 03;159:127-136 Authors: Bentley J, Moore JP, Farrant JM Abstract The desiccation-tolerant shrub Myrothamnus flabellifolia has colonised a unique and harsh niche that provides little protection from the elements. It has a wide distribution range in southern Africa, occurring across an environmental gradient that is exceptionally arid in the southwest and highly mesic in the northeast. It is also harvested for use in medicinal preparations, both traditionally and commercially. However, the phytochemical variability of plants from different rainfall regions has not been assessed, nor have the intraspecific relationships been evaluated by means of a rigorously tested phylogeny. The aims of the present study were thus (1) to test a phylogenetic hypothesis for intraspecific relationships in M. flabellifolia; (2) to assess, based on the global metabolomic profiles, whether accessions collected from the three different geographic locations in southern Africa across a rainfall gradient can be differentiated, and if this corroborates the phylogenetic signature; and (3) with the aid of multivariate statistical analysis, identify and evaluate the most significant discriminatory metabolites between the three sampled regions that could act as potential barcodes. The results show that the phylogenetic and metabolomic signatures were congruent, and the metabolomic data were better able to discriminate the different populations collected from the three regions. Several potential barcodes for discriminating the material from the three regions are proposed. Quercetin-rhamnoside and 3-O-methylquercetin, both significant antioxidants, were present at significantly higher quantities in the material from the driest region in the west than from the more mesic regions in the south and east, whereas quercetin-3-O-glucuronide was significantly higher in the latter. A naringenin-like compound or arbutin derivative could discriminate the southern samples from the eastern samples, whereas digalloylglucose differentiated the eastern samples from the southern samples. In summary, the findings of this study imply that the origin of the material should be considered when used in medicinal and cosmetic preparations. PMID: 30611872 [PubMed - as supplied by publisher]

Exploratory metabolomics of nascent metabolic syndrome. J Diabetes Complications. 2018 Dec 10;: Authors: Shim K, Gulhar R, Jialal I Abstract INTRODUCTION: Metabolic syndrome (MetS) is a disorder defined by having three of five features: increased waist circumference (WC), hypertriglyceridemia, decreased high-density lipoprotein-cholesterol, hypertension and an elevated blood glucose (BG). Metabolic Syndrome ( MetS) affects 35% of American adults and significantly increases risk for Atherosclerotic cardiovascular disease (ASCVD) and type-2 diabetes (T2DM). An understanding of the metabolome will help elucidate the pathogenesis of MetS and lead to better management. We hypothesize that the metabolites, gamma-aminobutyric acid (GABA), d-pyroglutamic acid (PGA) and N-acetyl-d-tryptophan (NAT) will be altered in nascent MetS patients without the confounding of ASCVD or T2DM. We also correlated these metabolites with biomarkers of inflammation. PATIENTS AND METHODS: This was an exploratory study of 30 patients with nascent MetS and 20 matched controls undertaken in 2018. Metabolites were evaluated from patient's frozen early morning urine samples and were correlated with biomarkers of inflammation and adipokines. They were assayed by the NIH Western Metabolomics Center using liquid chromatography/mass spectrometry and standardized to urinary creatinine. All patients had normal hepatic and renal function. RESULTS: GABA and PGA levels were significantly increased in MetS patients compared to controls: 2.8-fold and 2.9-fold median increases respectively with p < 0.0001 and p = 0.004, possibly deriving from glutamate. NAT was significantly decreased by 90% in MetS patients compared to controls, p < 0.001. GABA correlates significantly with cardio-metabolic (CM) features including WC, blood pressure systolic (BP-S) while NAT correlated inversely with WC, BP-S, blood glucose (BG) and triglycerides (TG). GABA correlated positively with chemerin, leptin, Fetuin A and endotoxin. NAT correlated inversely with WC, BP-S, BG, TG, high sensitivity C - reactive protein (hsCRP), toll-like receptor-4 (TLR-4), lipopolysaccharide binding protein (LBP), chemerin and retinol binding protein-4 (RBP-4). CONCLUSIONS: We make the novel observation of increased GABA and PGA with decreased NAT in patients with MetS. While GABA and PGA correlates positively with CM features and biomediators of inflammation, the metabolite NAT correlated inversely. Thus, GABA and PGA could contribute to the pro-inflammatory state of MetS while NAT could mitigate this pro-inflammatory response. PMID: 30611573 [PubMed - as supplied by publisher]

Variation patterns in the content of glycosides during green tea manufacturing by a modification-specific metabolomics approach: Enzymatic reaction promoting an increase in the glycosidically bound volatiles at the pan firing stage. Food Chem. 2019 May 01;279:80-87 Authors: Li P, Zhu Y, Lu M, Yang C, Xie D, Tan J, Peng Q, Zhang Y, Ni D, Dai W, Lin Z Abstract The glycosides are presumed to influence the quality of green tea but the molecular mechanism behind remains unclear. To elucidate the contribution of glycosides to the flavor formation of green tea, changes of both glycosidically bound non-volatiles (GBNVs) and glycosidically bound volatiles (GBVs) during the manufacturing of green tea were investigated using a modification-specific metabolomics method. A total of 64 glycosides (47 GBNVs and 17 GBVs) were identified and their contents mainly changed during the pan firing and drying stages of green tea manufacturing. Notably, the contents of GBVs significantly increased by 1.12-4.46-fold during pan firing. Correlation analysis showed that the GBVs contents were negatively related to the contents of volatiles and glucose. Model experiments revealed that enzymatic synthesis contributed to the increase in the content of GBVs during the pan firing. This comprehensive study on the glycosides changes revealed the molecular bases for GBVs increments during the pan firing. PMID: 30611515 [PubMed - in process]

Untargeted LC-MS based 13C labelling provides a full mass balance of deoxynivalenol and its degradation products formed during baking of crackers, biscuits and bread. Food Chem. 2019 May 01;279:303-311 Authors: Stadler D, Lambertini F, Bueschl C, Wiesenberger G, Hametner C, Schwartz-Zimmermann H, Hellinger R, Sulyok M, Lemmens M, Schuhmacher R, Suman M, Berthiller F, Krska R Abstract Deoxynivalenol (DON) is considered to be one of the most important contaminants in cereals and food commodities produced thereof. So far it is not clear i) to which extent DON is degraded during baking and ii) if a degradation results in reduced toxicity. We have elucidated the fate of DON during baking of crackers, biscuits and bread, which were produced from fortified dough and processed under pilot plant conditions. Untargeted stable isotope assisted liquid chromatography (LC) high resolution mass spectrometry was used to determine all extractable degradation products. Targeted LC - tandem mass spectrometry based quantification revealed that DON was partially degraded to isoDON (1.3-3.9%), norDON B (0.2-0.9%) and norDON C (0.3-1.2%). A DON degradation of 6% (crackers), 5% (biscuits) and 2% (bread), respectively, was observed. In vitro translation experiments indicate that isoDON is less toxic than DON. PMID: 30611495 [PubMed - in process]

Comparison of phenolic compounds profile and antioxidant properties of different sweet cherry (Prunus avium L.) varieties. Food Chem. 2019 May 01;279:260-271 Authors: Acero N, Gradillas A, Beltran M, García A, Muñoz Mingarro D Abstract In the present work, three Spanish local varieties of Prunus avium (L.), as well as two foreign varieties were studied. The content of total phenols, flavonoids, anthocyanins, glucose and fructose of methanolic extracts from ripe fruits of each variety were analysed. A phytochemical profile of these cultivars was performed by UHPLC-qTOF-MS. The employed chromatographic method allowed a clear and rapid separation of the three main phenolic compound groups present in the extracts: hydroxycinnamic acids, anthocyanins and flavonoids. In addition, the extracts DPPH radical scavenging ability, as well as their capacity to affect xanthine/xanthine oxidase system, were determined. Finally, variations in ROS intracellular concentrations in HepG2 cell line cultures treated with cherry extracts were measured through DCFH-DA assay. All extracts showed a significant inhibitory effect on the xanthine/xanthine oxidase system. Differences between in vitro and in cell culture results evidence the interaction among the phenolic compounds of the extract. PMID: 30611489 [PubMed - in process]

Related Articles Untargeted Metabolomics Reveal Defensome-Related Metabolic Reprogramming in Sorghum bicolor against Infection by Burkholderia andropogonis. Metabolites. 2019 Jan 02;9(1): Authors: Mareya CR, Tugizimana F, Piater LA, Madala NE, Steenkamp PA, Dubery IA Abstract Burkholderia andropogonis is the causal agent of bacterial leaf stripe, one of the three major bacterial diseases affecting Sorghum bicolor. However, the biochemical aspects of the pathophysiological host responses are not well understood. An untargeted metabolomics approach was designed to understand molecular mechanisms underlying S. bicolor⁻B. andropogonis interactions. At the 4-leaf stage, two sorghum cultivars (NS 5511 and NS 5655) differing in disease tolerance, were infected with B. andropogonis and the metabolic changes monitored over time. The NS 5511 cultivar displayed delayed signs of wilting and lesion progression compared to the NS 5655 cultivar, indicative of enhanced resistance. The metabolomics results identified statistically significant metabolites as biomarkers associated with the sorghum defence. These include the phytohormones salicylic acid, jasmonic acid, and zeatin. Moreover, metabolic reprogramming in an array of chemically diverse metabolites that span a wide range of metabolic pathways was associated with the defence response. Signatory biomarkers included aromatic amino acids, shikimic acid, metabolites from the phenylpropanoid and flavonoid pathways, as well as fatty acids. Enhanced synthesis and accumulation of apigenin and derivatives thereof was a prominent feature of the altered metabolomes. The analyses revealed an intricate and dynamic network of the sorghum defence arsenal towards B. andropogonis in establishing an enhanced defensive capacity in support of resistance and disease suppression. The results pave the way for future analysis of the biosynthesis of signatory biomarkers and regulation of relevant metabolic pathways in sorghum. PMID: 30609758 [PubMed]

Related Articles Rac-Mediated Macropinocytosis of Extracellular Protein Promotes Glucose Independence in Non-Small Cell Lung Cancer. Cancers (Basel). 2019 Jan 02;11(1): Authors: Hodakoski C, Hopkins BD, Zhang G, Su T, Cheng Z, Morris R, Rhee KY, Goncalves MD, Cantley LC Abstract Cancer cells can adapt to nutrient poor conditions by rewiring their metabolism and using alternate fuel sources. Identifying these adaptive metabolic pathways may provide novel targets for cancer therapy. Here, we identify a subset of non-small cell lung cancer (NSCLC) cell lines that survive in the absence of glucose by internalizing and metabolizing extracellular protein via macropinocytosis. Macropinocytosis is increased in these glucose independent cells, and is regulated by phosphoinositide 3-kinase (PI3K) activation of Rac-Pak signaling. Furthermore, inhibition of Rac-dependent macropinocytosis blocks glucose-independent proliferation. We find that degradation of internalized protein produces amino acids, including alanine, which generates TCA cycle and glycolytic intermediates in the absence of glucose. In this process, the conversion of alanine to pyruvate by alanine transaminase 2 (ALT2) is critical for survival during glucose starvation. Collectively, Rac driven macropinocytosis of extracellular protein is an adaptive metabolic pathway used by a subset of lung cancers to survive states of glucose deprivation, and may serve as a potential drug target for cancer therapy. PMID: 30609754 [PubMed]

Related Articles Palbociclib and Fulvestrant Act in Synergy to Modulate Central Carbon Metabolism in Breast Cancer Cells. Metabolites. 2019 Jan 02;9(1): Authors: Warth B, Palermo A, Rattray NJW, Lee NV, Zhu Z, Hoang LT, Cai Y, Mazurek A, Dann S, VanArsdale T, Fantin VR, Shields D, Siuzdak G, Johnson CH Abstract The aims of this study were to determine whether combination chemotherapeutics exhibit a synergistic effect on breast cancer cell metabolism. Palbociclib, is a selective inhibitor of cyclin-dependent kinases 4 and 6, and when patients are treated in combination with fulvestrant, an estrogen receptor antagonist, they have improved progression-free survival. The mechanisms for this survival advantage are not known. Therefore, we analyzed metabolic and transcriptomic changes in MCF-7 cells following single and combination chemotherapy to determine whether selective metabolic pathways are targeted during these different modes of treatment. Individually, the drugs caused metabolic disruption to the same metabolic pathways, however fulvestrant additionally attenuated the pentose phosphate pathway and the production of important coenzymes. A comprehensive effect was observed when the drugs were applied together, confirming the combinatory therapy's synergism in the cell model. This study also highlights the power of merging high-dimensional datasets to unravel mechanisms involved in cancer metabolism and therapy. PMID: 30609717 [PubMed]