PubMed

Application of Metabolomics in the Study of Natural Products. Nat Prod Bioprospect. 2018 Jun 29;: Authors: Zhao Q, Zhang JL, Li F Abstract LC-MS-based metabolomics could have a major impact in the study of natural products, especially in its metabolism, toxicity and activity. This review highlights recent applications of metabolomics approach in the study of metabolites and toxicity of natural products, and the understanding of their effects on various diseases. Metabolomics has been employed to study the in vitro and in vivo metabolism of natural compounds, such as osthole, dehydrodiisoeugenol, and myrislignan. The pharmacological effects of natural compounds and extracts were determined using metabolomics technology combined with diseases models in animal, including osthole and nutmeg extracts. It has been demonstrated that metabolomics is a powerful technology for the investigation of xenobiotics-induced toxicity. The metabolism of triptolide and its hepatotoxicity were discussed. LC-MS-based metabolomics has a great potential in the druggability of natural products. The application of metabolomics should be broadened in the field of natural products in the future. PMID: 29959744 [PubMed - as supplied by publisher]

Overoptimism in cross-validation when using partial least squares-discriminant analysis for omics data: a systematic study. Anal Bioanal Chem. 2018 Jun 29;: Authors: Rodríguez-Pérez R, Fernández L, Marco S Abstract Advances in analytical instrumentation have provided the possibility of examining thousands of genes, peptides, or metabolites in parallel. However, the cost and time-consuming data acquisition process causes a generalized lack of samples. From a data analysis perspective, omics data are characterized by high dimensionality and small sample counts. In many scenarios, the analytical aim is to differentiate between two different conditions or classes combining an analytical method plus a tailored qualitative predictive model using available examples collected in a dataset. For this purpose, partial least squares-discriminant analysis (PLS-DA) is frequently employed in omics research. Recently, there has been growing concern about the uncritical use of this method, since it is prone to overfitting and may aggravate problems of false discoveries. In many applications involving a small number of subjects or samples, predictive model performance estimation is only based on cross-validation (CV) results with a strong preference for reporting results using leave one out (LOO). The combination of PLS-DA for high dimensionality data and small sample conditions, together with a weak validation methodology is a recipe for unreliable estimations of model performance. In this work, we present a systematic study about the impact of the dataset size, the dimensionality, and the CV technique used on PLS-DA overoptimism when performance estimation is done in cross-validation. Firstly, by using synthetic data generated from a same probability distribution and with assigned random binary labels, we have obtained a dataset where the true classification rate (CR) is 50%. As expected, our results confirm that internal validation provides overoptimistic estimations of the classification accuracy (i.e., overfitting). We have characterized the CR estimator in terms of bias and variance depending on the internal CV technique used and sample to dimensionality ratio. In small sample conditions, due to the large bias and variance of the estimator, the occurrence of extremely good CRs is common. We have found that overfitting peaks when the sample size in the training subset approaches the feature vector dimensionality minus one. In these conditions, the models are neither under- or overdetermined with a unique solution. This effect is particularly intense for LOO and peaks higher in small sample conditions. Overoptimism is decreased beyond this point where the abundance of noisy produces a regularization effect leading to less complex models. In terms of overfitting, our study ranks CV methods as follows: Bootstrap produces the most accurate estimator of the CR, followed by bootstrapped Latin partitions, random subsampling, K-Fold, and finally, the very popular LOO provides the worst results. Simulation results are further confirmed in real datasets from mass spectrometry and microarrays. PMID: 29959482 [PubMed - as supplied by publisher]

Exposure of Methicillin-Resistant Staphylococcus aureus to Low Levels of the Antibacterial THAM-3ΦG Generates a Small Colony Drug-Resistant Phenotype. Sci Rep. 2018 Jun 29;8(1):9850 Authors: Weaver AJ, Peters TR, Tripet B, Van Vuren A, Rakesh, Lee RE, Copié V, Teintze M Abstract This study investigated resistance against trishexylaminomelamine trisphenylguanide (THAM-3ΦG), a novel antibacterial compound with selective microbicidal activity against Staphylococcus aureus. Resistance development was examined by culturing methicillin resistant S. aureus (MRSA) with sub-lethal doses of THAM-3ΦG. This quickly resulted in the formation of normal (WT) and small colonies (SC) of S. aureus exhibiting minimal inhibitory concentrations (MICs) 2× and 4× greater than the original MIC. Continuous cell passaging with increasing concentrations of THAM-3ΦG resulted in an exclusively SC phenotype with MIC >64 mg/L. Nuclear magnetic resonance (NMR)-based metabolomics and multivariate statistical analysis revealed three distinct metabolic profiles for THAM-3ΦG treated WT, untreated WT, and SC (both treated and untreated). The metabolome patterns of the SC sample groups match those reported for other small colony variants (SCV) of S. aureus. Supplementation of the SCV with menadione resulted in almost complete recovery of growth rate. This auxotrophism was corroborated by NMR analysis revealing the absence of menaquinone production in the SCV. In conclusion, MRSA rapidly acquires resistance to THAM-3ΦG through selection of a slow-growing menaquinone auxotroph. This study highlights the importance of evaluating and monitoring resistance to novel antibacterials during development. PMID: 29959441 [PubMed - in process]

Increased nuclear DNA damage precedes mitochondrial dysfunction in peripheral blood mononuclear cells from Huntington's disease patients. Sci Rep. 2018 Jun 29;8(1):9817 Authors: Askeland G, Dosoudilova Z, Rodinova M, Klempir J, Liskova I, Kuśnierczyk A, Bjørås M, Nesse G, Klungland A, Hansikova H, Eide L Abstract Huntington's disease (HD) is a progressive neurodegenerative disorder primarily affecting the basal ganglia and is caused by expanded CAG repeats in the huntingtin gene. Except for CAG sizing, mitochondrial and nuclear DNA (mtDNA and nDNA) parameters have not yet proven to be representative biomarkers for disease and future therapy. Here, we identified a general suppression of genes associated with aerobic metabolism in peripheral blood mononuclear cells (PBMCs) from HD patients compared to controls. In HD, the complex II subunit SDHB was lowered although not sufficiently to affect complex II activity. Nevertheless, we found decreased level of factors associated with mitochondrial biogenesis and an associated dampening of the mitochondrial DNA damage frequency in HD, implying an early defect in mitochondrial activity. In contrast to mtDNA, nDNA from HD patients was four-fold more modified than controls and demonstrated that nDNA integrity is severely reduced in HD. Interestingly, the level of nDNA damage correlated inversely with the total functional capacity (TFC) score; an established functional score of HD. Our data show that PBMCs are a promising source to monitor HD progression and highlights nDNA damage and diverging mitochondrial and nuclear genome responses representing early cellular impairments in HD. PMID: 29959348 [PubMed - in process]

Supplementation with resveratrol as Polygonum cuspidatum Sieb. et Zucc. extract induces changes in the excretion of urinary markers associated to aging in rats. Fitoterapia. 2018 Jun 26;: Authors: Peron G, Dall'Acqua S, Sut S Abstract An UPLC-HR-MS metabolomics approach was used to study the effects of a 49-days oral supplementation with Polygonum cuspidatum extract in healthy rats. Multivariate analysis allowed to observe significant differences in the excretion of several markers between treated animals and control group. Among the others, the amounts of N-methyl-2-pyridone-5-carboxamide (2PY) and phenylacetylglycine (PAG) were reduced in the treated group compared to control. These compounds have been previously considered as markers of aging. Furthermore, the excretion of 3-hydroxysebacic acid and 4,6-dihydroxyquinoline was also changed following supplementation, although not significantly. Despite the relatively short time of treatment (7 weeks), the significant changes in the urinary levels of aging markers observed at day 49 suggests a potential role of this type of studies as a new approach in the evaluation of the anti-aging effects of plant extracts. PMID: 29959053 [PubMed - as supplied by publisher]

Partially 13C-labeled mouse tissue as reference for LC-MS based untargeted metabolomics. Anal Biochem. 2018 Jun 26;: Authors: Dethloff F, Bueschl C, Heumann H, Schuhmacher R, Turck CW Abstract The inclusion of stable isotope-labeled reference standards in the sample is an established method for the detection and relative quantification of metabolic features in untargeted metabolomics. In order to quantify as many metabolites as possible, the reference should ideally include the same metabolites in their stable isotope-labeled form as the sample under investigation. We present here an attempt to use partially 13C-labeled mouse material as internal standard for relative metabolite quantification of mouse and human samples in untargeted metabolomics. We fed mice for 14 days with a13C-labeled Ralstonia eutropha based diet. Tissue and blood amino acids from these mice showed 13C enrichment levels that ranged from 6% to 75%. We used MetExtract II software to automatically detect native and labeled peak pairs in an untargeted manner. In a dilution series and with the implementation of a correction factor, partially 13C-labeled mouse plasma resulted in accurate relative quantification of human plasma amino acids using liquid chromatography coupled to mass spectrometry, The coefficient of variation for the relative quantification is reduced from 27% without internal standard to 10% with inclusion of partially 13C-labeled internal standard. We anticipate the method to be of general use for the relative metabolite quantification of human specimens. PMID: 29958846 [PubMed - as supplied by publisher]

2-hydroxycaproate predicts cardiovascular mortality in patients with atherosclerotic disease. Atherosclerosis. 2018 Jun 12;: Authors: Cardellini M, Ballanti M, Davato F, Cardolini I, Guglielmi V, Rizza S, Pecchioli C, Casagrande V, Mavilio M, Porzio O, Legramante JM, Ippoliti A, Farcomeni A, Sbraccia P, Menghini R, Dumas MED, Kappel BA, Federici M Abstract BACKGROUND AND AIMS: We aimed to identify novel biomarkers for cardiovascular mortality through a non-targeted metabolomics approach in patients with established atherosclerotic disease from the Tor Vergata Atherosclerosis Registry (TVAR). METHODS: We compared the serum baseline metabolome of 19 patients with atherosclerosis suffering from cardiovascular death during follow-up with the baseline serum metabolome of 20 control patients matched for age, gender, body mass index (BMI) and atherosclerotic disease status, who survived during the observation period. RESULTS: Three metabolites were significantly different in the cardiovascular mortality (CVM) group compared to controls: 2-hydroxycaproate, gluconate and sorbitol. 2-hydroxycaproate (otherwise known as alpha hydroxy caproate) was also significantly correlated with time to death. The metabolites performed better when combined together rather than singularly on the identification of CVM status. CONCLUSIONS: Our analysis led to identify few metabolites potentially amenable of translation into the clinical practice as biomarkers for specific metabolic changes in the cardiovascular system in patients with established atherosclerotic disease. PMID: 29958653 [PubMed - as supplied by publisher]

16 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 2018/06/30PubMed 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.

16 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 2018/06/30PubMed 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 2018/06/29PubMed 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.

Related Articles Analyses of the genetic diversity and protein expression variation of the acyl: CoA medium-chain ligases, ACSM2A and ACSM2B. Mol Genet Genomics. 2018 Jun 14;: Authors: van der Sluis R Abstract Benzoate (found in milk and widely used as preservative), salicylate (present in fruits and the active component of aspirin), dietary polyphenols produced by gut microbiota, metabolites from organic acidemias, and medium-chain fatty acids (MCFAs) are all metabolised/detoxified by the glycine conjugation pathway. Xenobiotics are first activated to an acyl-CoA by the mitochondrial xenobiotic/medium-chain fatty acid: CoA ligases (ACSMs) and subsequently conjugated to glycine by glycine N-acyltransferase (GLYAT). The MCFAs are activated to acyl-CoA by the ACSMs before entering mitochondrial β-oxidation. This two-step enzymatic pathway has, however, not been thoroughly investigated and the biggest gap in the literature remains the fact that studies continuously characterise the pathway as a one-step reaction. There are no studies available on the interaction/competition of the various substrates involved in the pathway, whilst very little research has been done on the ACSM ligases. To identify variants/haplotypes that should be characterised in future detoxification association studies, this study assessed the naturally observed sequence diversity and protein expression variation of ACSM2A and ACSM2B. The allelic variation, haplotype diversity, Tajima's D values, and phylogenetic analyses indicated that ACSM2A and ACSM2B are highly conserved. This confirmed an earlier hypothesis that the glycine conjugation pathway is highly conserved and essential for life as it maintains the CoA and glycine homeostasis in the liver mitochondria. The protein expression analyses showed that ACSM2A is the predominant transcript in liver. Future studies should investigate the effect of the variants identified in this study on the substrate specificity of these proteins. PMID: 29948332 [PubMed - as supplied by publisher]

Related Articles Metabolomics profiling reveals the mechanism of increased pneumocandin B0 production by comparing mutant and parent strains. J Ind Microbiol Biotechnol. 2018 Jun 14;: Authors: Song P, Yuan K, Qin T, Zhang K, Ji XJ, Ren L, Guan R, Wen J, Huang H Abstract Metabolic profiling was used to discover mechanisms of increased pneumocandin B0 production in a high-yield strain by comparing it with its parent strain. Initially, 79 intracellular metabolites were identified, and the levels of 15 metabolites involved in six pathways were found to be directly correlated with pneumocandin B0 biosynthesis. Then by combining the analysis of key enzymes, acetyl-CoA and NADPH were identified as the main factors limiting pneumocandin B0 biosynthesis. Other metabolites, such as pyruvate, α-ketoglutaric acid, lactate, unsaturated fatty acids and previously unreported metabolite γ-aminobutyric acid were shown to play important roles in pneumocandin B0 biosynthesis and cell growth. Finally, the overall metabolic mechanism hypothesis was formulated and a rational feeding strategy was implemented that increased the pneumocandin B0 yield from 1821 to 2768 mg/L. These results provide practical and theoretical guidance for strain selection, medium optimization, and genetic engineering for pneumocandin B0 production. PMID: 29948195 [PubMed - as supplied by publisher]

Related Articles Imaging and the completion of the omics paradigm in breast cancer. Radiologe. 2018 Jun 08;: Authors: Leithner D, Horvat JV, Ochoa-Albiztegui RE, Thakur S, Wengert G, Morris EA, Helbich TH, Pinker K Abstract Within the field of oncology, "omics" strategies-genomics, transcriptomics, proteomics, metabolomics-have many potential applications and may significantly improve our understanding of the underlying processes of cancer development and progression. Omics strategies aim to develop meaningful imaging biomarkers for breast cancer (BC) by rapid assessment of large datasets with different biological information. In BC the paradigm of omics technologies has always favored the integration of multiple layers of omics data to achieve a complete portrait of BC. Advances in medical imaging technologies, image analysis, and the development of high-throughput methods that can extract and correlate multiple imaging parameters with "omics" data have ushered in a new direction in medical research. Radiogenomics is a novel omics strategy that aims to correlate imaging characteristics (i. e., the imaging phenotype) with underlying gene expression patterns, gene mutations, and other genome-related characteristics. Radiogenomics not only represents the evolution in the radiology-pathology correlation from the anatomical-histological level to the molecular level, but it is also a pivotal step in the omics paradigm in BC in order to fully characterize BC. Armed with modern analytical software tools, radiogenomics leads to new discoveries of quantitative and qualitative imaging biomarkers that offer hitherto unprecedented insights into the complex tumor biology and facilitate a deeper understanding of cancer development and progression. The field of radiogenomics in breast cancer is rapidly evolving, and results from previous studies are encouraging. It can be expected that radiogenomics will play an important role in the future and has the potential to revolutionize the diagnosis, treatment, and prognosis of BC patients. This article aims to give an overview of breast radiogenomics, its current role, future applications, and challenges. PMID: 29947931 [PubMed - as supplied by publisher]

Related Articles Integrated transcriptomics and metabolomics reveal signatures of lipid metabolism dysregulation in HepaRG liver cells exposed to PCB 126. Arch Toxicol. 2018 Jun 14;: Authors: Mesnage R, Biserni M, Balu S, Frainay C, Poupin N, Jourdan F, Wozniak E, Xenakis T, Mein CA, Antoniou MN Abstract Chemical pollutant exposure is a risk factor contributing to the growing epidemic of non-alcoholic fatty liver disease (NAFLD) affecting human populations that consume a western diet. Although it is recognized that intoxication by chemical pollutants can lead to NAFLD, there is limited information available regarding the mechanism by which typical environmental levels of exposure can contribute to the onset of this disease. Here, we describe the alterations in gene expression profiles and metabolite levels in the human HepaRG liver cell line, a validated model for cellular steatosis, exposed to the polychlorinated biphenyl (PCB) 126, one of the most potent chemical pollutants that can induce NAFLD. Sparse partial least squares classification of the molecular profiles revealed that exposure to PCB 126 provoked a decrease in polyunsaturated fatty acids as well as an increase in sphingolipid levels, concomitant with a decrease in the activity of genes involved in lipid metabolism. This was associated with an increased oxidative stress reflected by marked disturbances in taurine metabolism. A gene ontology analysis showed hallmarks of an activation of the AhR receptor by dioxin-like compounds. These changes in metabolome and transcriptome profiles were observed even at the lowest concentration (100 pM) of PCB 126 tested. A decrease in docosatrienoate levels was the most sensitive biomarker. Overall, our integrated multi-omics analysis provides mechanistic insight into how this class of chemical pollutant can cause NAFLD. Our study lays the foundation for the development of molecular signatures of toxic effects of chemicals causing fatty liver diseases to move away from a chemical risk assessment based on in vivo animal experiments. PMID: 29947894 [PubMed - as supplied by publisher]

Related Articles Altered Plasma Amino Acids and Lipids Associated with Abnormal Glucose Metabolism and Insulin Resistance in Older Adults. J Clin Endocrinol Metab. 2018 Jun 26;: Authors: Semba RD, Gonzalez-Freire M, Moaddel R, Sun K, Fabbri E, Zhang P, Carlson OD, Khadeer M, Chia CW, Salem N, Ferrucci L Abstract Context and Objectives: Glucose metabolism becomes progressively impaired with older age. Fasting glucose and insulin resistance are risk factors for premature death and other adverse outcomes. We aimed to identifying plasma metabolites associated with altered glucose metabolism and insulin resistance in older community-dwelling adults. Participants and Methods: A targeted metabolomics approach was used to identify plasma metabolites associated with impaired fasting plasma glucose, 2-hour plasma glucose on oral glucose tolerance testing, and homeostatic model assessment insulin resistance in 472 participants who participated in the Baltimore Longitudinal Study of Aging, mean (standard deviation) age 70.7 (9.9) years. Results: We measured 143 plasma metabolites. In ordinal logistic regression analyses, using a false discovery rate of 5%, and adjusting for potential confounders: alanine, glutamic acid, and proline were significantly associated with increased odds of abnormal fasting plasma glucose. Phosphatidylcholine (diacyl C34:4, alkyl-acyl C32:1, C32:2, C34:2, C34:3, and C36:3) was associated with decreased odds of abnormal fasting plasma glucose. Glutamic and acid phosphatidylcholine alkyl-acyl C34:2 were associated with increased and decreased odds of 2-hour plasma glucose, respectively. Glutamic acid was associated with increased odds of higher tertiles of HOMA-IR. Glycine, phosphatidylcholine (diacyl C32:0, alkyl-acyl C32:1, C32:2, C34:1, C34:2, C34:3, C36:2, C36:3, C40:5, C40:6, C42:3, C42:4, and C42:5), sphingomyelin C16:0, C24:1, and C26:1, and lysophosphatidylcholine C18:1 were associated with decreased odds of abnormal HOMA-IR. Conclusions: Targeted metabolomics identified four plasma amino acids and sixteen plasma lipid species, primarily containing polyunsaturated fatty acids, that were associated with abnormal glucose metabolism and insulin resistance in older adults. PMID: 29947780 [PubMed - as supplied by publisher]

Related Articles Tracking down protein-protein interactions via a FRET-system using site-specific thiol-labeling. Org Biomol Chem. 2018 Jun 27;: Authors: Söveges B, Imre T, Póti ÁL, Sok P, Kele Z, Alexa A, Kele P, Németh K Abstract Förster resonance energy transfer is among the most popular tools to follow protein-protein interactions. Although limited to certain cases, site-specific fluorescent labeling of proteins via natural functions by means of chemical manipulations can redeem laborious protein engineering techniques. Herein we report on the synthesis of a heterobifunctional tag and its use in site-specific protein labeling studies aiming at exploring protein-protein interactions. The oxadiazole-methylsulfonyl functionality serves as a thiol specific warhead that enables easy and selective installation of fluorescent labels through a bioorthogonal motif. Mitogen activated protein kinase (MAPK14) and its substrate mitogen activated protein kinase activated kinase (MAPKAP2) or its docking motif, a 22 amino acid-long peptide fragment, were labeled with a donor and an acceptor, respectively. Evolution of strong FRET signals upon protein-protein interactions supported the specific communication between the partners. Using an efficient FRET pair allowed the estimation of dissociation constants for protein-protein and peptide-protein interactions (145 nM and 240 nM, respectively). PMID: 29947400 [PubMed - as supplied by publisher]

Related Articles Serum metabolites associate with CT findings following TBI. J Neurotrauma. 2018 Jun 27;: Authors: Dickens AM, Posti JP, Takala RS, Ala-Seppälä HM, Mattila I, Coles JC, Frantzén J, Hutchinson PJ, Katila AJ, Kyllönen A, Maanpää HR, Newcombe V, Outtrim J, Tallus J, Carpenter K, Menon D, Hyotylainen T, Tenovuo O, Oresic M Abstract There is a need to rapidly detect patients with traumatic brain injury (TBI) who require head computed tomography (CT). Given the energy crisis in the brain following TBI, we hypothesized that serum metabolomics would be a useful tool for developing a set of biomarkers to determine the need for CT and to distinguish between different types of injuries observed. Logistic regression models using metabolite data from the discovery cohort (n=144, Turku, Finland) were used to distinguish between patients with traumatic intracranial findings and negative findings on head CT. The resultant models were then tested in the validation cohort (n=66, Cambridge, UK). The levels of glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 were also quantified in the serum from the same patients. Despite there being significant differences in the protein biomarkers in patients with TBI, the model that determined the need for a CT scan validated poorly (AUC=0.64: Cambridge patients). However, using a combination of six metabolites (two amino acids, three sugar derivatives and one ketoacid) it was possible to discriminate patients with intracranial abnormalities on CT and patients with a normal CT (AUC=0.77 in Turku patients and AUC=0.73 in Cambridge patients). Furthermore, a combination of three metabolites could distinguish between diffuse brain injuries and mass lesions (AUC=0.87 in Turku patients and AUC=0.68 in Cambridge patients). This study identifies a set of validated serum polar metabolites, which associate with the need for a CT scan. Additionally, serum metabolites can also predict the nature of the brain injury. These metabolite markers may prevent unnecessary CT scans, thus reducing the cost of diagnostics and radiation load. PMID: 29947291 [PubMed - as supplied by publisher]

Related Articles Human metabolome changes after a single dose of 3,4-methylenedioxymethamphetamine (MDMA) with special focus on steroid metabolism and inflammation processes. J Proteome Res. 2018 Jun 27;: Authors: Boxler MI, Streun GL, Liechti ME, Schmid Y, Kraemer T, Steuer AE Abstract The intake of 3,4-methylenedioxymethamphetamine (MDMA) is known to increase several endogenous substances involved in steroid and inflammation pathways. Untargeted metabolomics screening approaches can determine biochemical changes after drug exposure and can reveal new pathways which might be involved in the pharmacology and toxicology of a drug of abuse. We analyzed plasma samples from a placebo-controlled cross-over study of a single intake of MDMA. Plasma samples from a time point before and three time points after the intake of a single dose of 125 mg MDMA were screened for changes of endogenous metabolites. An untargeted metabolomics approach on a high resolution quadrupole time of flight mass spectrometer coupled to liquid chromatography with two different chromatographic systems (reversed phase and hydrophobic interaction liquid chromatography) was applied. Over 10'000 features of the human metabolome were detected. Hence, 28 metabolites were identified which showed significant changes after administration of MDMA compared to placebo. The analysis revealed an upregulation of cortisol and pregnenolone sulfate four hours after MDMA intake suggesting increased stress and serotonergic activity. Further, calcitriol levels were decreased after the intake of MDMA. Calcitriol is involved in the upregulation of trophic factors which have protective effects on brain dopamine neurons. The inflammation mediators hydroxyeicosatetraenoic acid (HETE), dihydroxyeicosatetraenoic acid (diHETE) and octadecadienoic acid (oxoODE) were found to be upregulated after the intake of MDMA compared to placebo which suggested a stimulation of inflammation pathways. PMID: 29947220 [PubMed - as supplied by publisher]

Related Articles Metabolic fate of glucose in the brain of APP/PS1 transgenic mice at 10 months of age: a 13C NMR metabolomic study. Metab Brain Dis. 2018 Jun 26;: Authors: Zhou Q, Zheng H, Chen J, Li C, Du Y, Xia H, Gao H Abstract Alzheimer's disease (AD) has been associated with the disturbance of brain glucose metabolism. The present study investigates brain glucose metabolism using 13C NMR metabolomics in combination with intravenous [1-13C]-glucose infusion in APP/PS1 transgenic mouse model of amyloid pathology at 10 months of age. We found that brain glucose was significantly accumulated in APP/PS1 mice relative to wild-type (WT) mice. Reductions in 13C fluxes into the specific carbon sites of tricarboxylic acid (TCA) intermediate (succinate) as well as neurotransmitters (glutamate, glutamine, γ-aminobutyric acid and aspartate) from [1-13C]-glucose were also detected in the brain of APP/PS1 mice. In addition, our results reveal that the 13C-enrichments of the C3 of alanine were significantly lower and the C3 of lactate have a tendency to be lower in the brain of APP/PS1 mice than WT mice. Taken together, the development of amyloid pathology could cause a reduction in glucose utilization and further result in decreases in energy and neurotransmitter metabolism as well as the lactate-alanine shuttle in the brain. PMID: 29946959 [PubMed - as supplied by publisher]

Related Articles Pharmacometabolomics reveals a role for histidine, phenylalanine, and threonine in the development of paclitaxel-induced peripheral neuropathy. Breast Cancer Res Treat. 2018 Jun 26;: Authors: Sun Y, Kim JH, Vangipuram K, Hayes DF, Smith EML, Yeomans L, Henry NL, Stringer KA, Hertz DL Abstract PURPOSE: Approximately 25% of breast cancer patients experience treatment delays or discontinuation due to paclitaxel-induced peripheral neuropathy (PN). Currently, there are no predictive biomarkers of PN. Pharmacometabolomics is an informative tool for biomarker discovery of drug toxicity. We conducted a secondary whole blood pharmacometabolomics analysis to assess the association between pretreatment metabolome, early treatment-induced metabolic changes, and the development of PN. METHODS: Whole blood samples were collected pre-treatment (BL), just before the end of the first paclitaxel infusion (EOI), and 24 h after the first infusion (24H) from sixty patients with breast cancer receiving (80 mg/m2) weekly treatment. Neuropathy was assessed at BL and prior to each infusion using the sensory subscale (CIPN8) of the EORTC CIPN20 questionnaire. Blood metabolites were quantified from 1-D-1H-nuclear magnetic resonance spectra using Chenomx® software. Metabolite concentrations were normalized in preparation for Pearson correlation and one-way repeated measures ANOVA with multiple comparisons corrected by false discovery rate (FDR). RESULTS: Pretreatment histidine, phenylalanine, and threonine concentrations were inversely associated with maximum change in CIPN8 (ΔCIPN8) (p < 0.02; FDR ≤ 25%). Paclitaxel caused a significant change in concentrations of 2-hydroxybutyrate, 3-hydroxybutyrate, pyruvate, o-acetylcarnitine, and several amino acids from BL to EOI and/or 24H (p < 0.05; FDR ≤ 25%), although these changes were not associated with ΔCIPN8. CONCLUSIONS: Whole blood metabolomics is a feasible approach to identify potential biomarker candidates of paclitaxel-induced PN. The findings suggest that pretreatment concentrations of histidine, phenylalanine, and threonine may be predictive of the severity of future PN and paclitaxel-induced metabolic changes may be related to disruption of energy homeostasis. PMID: 29946863 [PubMed - as supplied by publisher]