PubMed

Related Articles Inhibitory effects of endogenous linoleic acid and glutaric acid on the renal glucuronidation of berberrubine in mice and on recombinant human UGT1A7, 1AB, and 1A9. Mol Pharmacol. 2018 Jan 19;: Authors: Yang N, Li S, Yan C, Sun R, He J, Xie Y, Peng Y, Wang G, Aa J Abstract Berberrubine (BRB) has a strong lipid-lowering effect and can be extensively metabolized into berberrubine-9-O-β-D-glucuronide (BRBG) in vivo. Recently, pharmacokinetics studies showed that the production of BRBG was significantly decreased in the urine of mice fed with a high fat diet (HFD), indicating a decreased glucuronidation capacity. Based on the UGT isoform identification, hepatic and renal microsomal incubation, glucuronidation was examined to suggest the metabolism of BRB in liver and kidneys. The results showed that the renal UGT activity for metabolizing BRB markedly decreased, which may be highly related to the decreased expression and activity of renal Ugt1a7c. Surprisingly, in vitro studies revealed neither BRB nor BRBG inhibited the renal UGT activity. By employing an integrated strategy of metabolomics and pharmacokinetics, we identified and confirmed for the first time the inhibitory effect of some potential endogenous molecules on the renal glucuronidation of C57BL/6J mice, such as glutaric acid and linoleic acid. By employing recombinant human UGTs, we found that glutaric acid and linoleic acid efficiently affect the activity of recombinant human UGT1A7, 1A9 and 1A8 at their normal or abnormal physiological levels in vivo. Glutaric acid (2 mM) markedly inhibited the activity of UGT1A7 by 89.4% and UGT1A9 by 32.8%. The inhibition rates reached 99.3% for UGT1A9, 48.3% for UGT1A7, and 46.8% for UGT1A8 with linoleic acid at 200 μM. It has been suggested that the endogenous molecules have the potential to affect the efficiency of glucuronidation, which might be a key factor contributing to individual differences in drug metabolism. PMID: 29351921 [PubMed - as supplied by publisher]

Related Articles EDC IMPACT: Molecular effects of developmental FM 550 exposure in Wistar rat placenta and fetal forebrain. Endocr Connect. 2018 Jan 19;: Authors: Baldwin KR, Horman B, Phillips AL, McRitchie SL, Watson S, Deese-Spruill J, Jima D, Sumner S, Stapleton H, Patisaul H Abstract Firemaster 550 (FM 550) is a flame retardant (FR) mixture that has become one of the most commonly used FRs in foam-based furniture and baby products. Human exposure to this commercial mixture, comprised of brominated and organophosphate components, is widespread. We have repeatedly shown that developmental exposure can lead to sex-specific behavioral effects in rats. Accruing evidence of endocrine disruption and potential neurotoxicity have raised concerns regarding the neurodevelopmental effects of FM 550 exposure, but the specific mechanisms of action remains unclear. Additionally, we observed significant, and in some cases sex-specific, accumulation of FM 550 in placental tissue following gestational exposure. Because the placenta is an important source of hormones and neurotransmitters for the developing brain, it may be a critical target of toxicity to consider in the context of developmental neurotoxicity. Using a mixture of targeted and exploratory approaches, the goal of the present study was to identify possible mechanisms of action in the developing forebrain and placenta. Wistar rat dams were orally exposed to FM 550 (0, 300, or 1,000 µg/day;) for 10 days during gestation and placenta and fetal forebrain tissue collected for analysis. In placenta, evidence of endocrine, inflammatory, and neurotransmitter signaling pathway disruption was identified. Notably, 5-HT turnover was reduced in placental tissue and fetal forebrains indicating that 5-HT signaling between the placenta and the embryonic brain may be disrupted. These findings demonstrate that environmental contaminants, like FM 550, have the potential to impact the developing brain by disrupting normal placental functions. PMID: 29351906 [PubMed - as supplied by publisher]

The serum metabolomics signature of Type 2 Diabetes is obscured in Alzheimer's Disease. Am J Physiol Endocrinol Metab. 2017 Dec 26;: Authors: Morris JK, Piccolo BD, Shankar K, Thyfault JP, Adams SH Abstract There is evidence for systemic metabolic impairment in Alzheimer's disease (AD), and Type 2 Diabetes (T2D) increases AD risk. Although studies analyzing blood metabolomics signatures have shown differences between cognitively healthy (CH) and AD subjects, these signatures have not been compared to individuals with T2D. We utilized untargeted analysis platforms (primary metabolism and complex lipids) to characterize the serum metabolome of 126 overnight fasted elderly subjects classified into 4 groups based upon AD status (CH or AD) and T2D status (Nondiabetic [ND] or T2D). Cognitive diagnosis groups were a priori weighted equally with T2D subjects. We hypothesized that AD subjects would display a similar metabolic profile to cognitively normal elderly individuals with T2D. However, partial least squared-discriminant analysis (PLS-DA) modelling resulted in poor classification across the four groups (< 50% classification accuracy of test subjects). Binary classification of AD vs. CH was poor, but binary classification of T2D vs. ND was good, providing >79.5% and >76.9% classification accuracy for held-out samples using primary metabolism and complex lipids, respectively). When modeling was limited to CH subjects, T2D discrimination improved for the primary metabolism platform (>89.5%) and remained accurate for complex lipids (>73% accuracy). Greater abundances of glucose, fatty acids (C20:2), and phosphatidylcholines and lower abundances of glycine, maleimide, octanol and tryptophan, cholesterol esters, phosphatidylcholines, and sphingomyelins were identified in CH subjects with T2D relative to those without T2D. In contrast, T2D was not accurately discriminated within AD subjects. Results herein suggest that AD may obscure the typical metabolic phenotype of T2D. PMID: 29351484 [PubMed - as supplied by publisher]

Heart in Lack of Oxygen? A Revisited Method to Improve Cardiac Performance Ex Vivo. Am J Physiol Heart Circ Physiol. 2017 Dec 15;: Authors: Ruiz M, Comtois P PMID: 29351474 [PubMed - as supplied by publisher]

Characterization of the proteome and lipidome profiles of human lung cells after low dose and chronic exposure to multiwalled carbon nanotubes. Nanotoxicology. 2018 Jan 19;:1-15 Authors: Phuyal S, Kasem M, Knittelfelder O, Sharma A, Fonseca DM, Vebraite V, Shaposhnikov S, Slupphaug G, Skaug V, Zienolddiny S Abstract The effects of long-term chronic exposure of human lung cells to multi-walled carbon nanotubes (MWCNT) and their impact upon cellular proteins and lipids were investigated. Since the lung is the major target organ, an in vitro normal bronchial epithelial cell line model was used. Additionally, to better mimic exposure to manufactured nanomaterials at occupational settings, cells were continuously exposed to two non-toxic and low doses of a MWCNT for 13-weeks. MWCNT-treatment increased ROS levels in cells without increasing oxidative DNA damage and resulted in differential expression of multiple anti- and pro-apoptotic proteins. The proteomic analysis of the MWCNT-exposed cells showed that among more than 5000 identified proteins; more than 200 were differentially expressed in the treated cells. Functional analyses revealed association of these differentially regulated proteins to cellular processes such as cell death and survival, cellular assembly, and organization. Similarly, shotgun lipidomic profiling revealed accumulation of multiple lipid classes. Our results indicate that long-term MWCNT-exposure of human normal lung cells at occupationally relevant low-doses may alter both the proteome and the lipidome profiles of the target epithelial cells in the lung. PMID: 29350075 [PubMed - as supplied by publisher]

Plasma metabolites associated with type 2 diabetes in a Swedish population: a case-control study nested in a prospective cohort. Diabetologia. 2018 Jan 18;: Authors: Shi L, Brunius C, Lehtonen M, Auriola S, Bergdahl IA, Rolandsson O, Hanhineva K, Landberg R Abstract AIMS/HYPOTHESIS: The aims of the present work were to identify plasma metabolites that predict future type 2 diabetes, to investigate the changes in identified metabolites among individuals who later did or did not develop type 2 diabetes over time, and to assess the extent to which inclusion of predictive metabolites could improve risk prediction. METHODS: We established a nested case-control study within the Swedish prospective population-based Västerbotten Intervention Programme cohort. Using untargeted liquid chromatography-MS metabolomics, we analysed plasma samples from 503 case-control pairs at baseline (a median time of 7 years prior to diagnosis) and samples from a subset of 187 case-control pairs at 10 years of follow-up. Discriminative metabolites between cases and controls at baseline were optimally selected using a multivariate data analysis pipeline adapted for large-scale metabolomics. Conditional logistic regression was used to assess associations between discriminative metabolites and future type 2 diabetes, adjusting for several known risk factors. Reproducibility of identified metabolites was estimated by intra-class correlation over the 10 year period among the subset of healthy participants; their systematic changes over time in relation to diagnosis among those who developed type 2 diabetes were investigated using mixed models. Risk prediction performance of models made from different predictors was evaluated using area under the receiver operating characteristic curve, discrimination improvement index and net reclassification index. RESULTS: We identified 46 predictive plasma metabolites of type 2 diabetes. Among novel findings, phosphatidylcholines (PCs) containing odd-chain fatty acids (C19:1 and C17:0) and 2-hydroxyethanesulfonate were associated with the likelihood of developing type 2 diabetes; we also confirmed previously identified predictive biomarkers. Identified metabolites strongly correlated with insulin resistance and/or beta cell dysfunction. Of 46 identified metabolites, 26 showed intermediate to high reproducibility among healthy individuals. Moreover, PCs with odd-chain fatty acids, branched-chain amino acids, 3-methyl-2-oxovaleric acid and glutamate changed over time along with disease progression among diabetes cases. Importantly, we found that a combination of five of the most robustly predictive metabolites significantly improved risk prediction if added to models with an a priori defined set of traditional risk factors, but only a marginal improvement was achieved when using models based on optimally selected traditional risk factors. CONCLUSIONS/INTERPRETATION: Predictive metabolites may improve understanding of the pathophysiology of type 2 diabetes and reflect disease progression, but they provide limited incremental value in risk prediction beyond optimal use of traditional risk factors. PMID: 29349498 [PubMed - as supplied by publisher]

Lysosome-targeting agents in cancer therapy. Oncotarget. 2017 Dec 22;8(68):112168-112169 Authors: Kroemer G, Galluzzi L Abstract Despite considerable efforts from multiple laboratories worldwide, highly specific inhibitors of autophagy for clinical use are not yet available. Lysosomal inhibitors are being employed instead, in spite of multiple limitations that are summarized herein. PMID: 29348815 [PubMed]

Metabolite profiling of fermented ginseng extracts by gas chromatography mass spectrometry. J Ginseng Res. 2018 Jan;42(1):57-67 Authors: Park SE, Seo SH, Lee KI, Na CS, Son HS Abstract Background: Ginseng contains many small metabolites such as amino acids, fatty acids, carbohydrates, and ginsenosides. However, little is known about the relationships between microorganisms and metabolites during the entire ginseng fermentation process. We investigated metabolic changes during ginseng fermentation according to the inoculation of food-compatible microorganisms. Methods: Gas chromatography mass spectrometry (GC-MS) datasets coupled with the multivariate statistical method for the purpose of latent-information extraction and sample classification were used for the evaluation of ginseng fermentation. Four different starter cultures (Saccharomyces bayanus, Bacillus subtilis, Lactobacillus plantarum, and Leuconostoc mesenteroide) were used for the ginseng extract fermentation. Results: The principal component analysis score plot and heat map showed a clear separation between ginseng extracts fermented with S. bayanus and other strains. The highest levels of fructose, maltose, and galactose in the ginseng extracts were found in ginseng extracts fermented with B. subtilis. The levels of succinic acid and malic acid in the ginseng extract fermented with S. bayanus as well as the levels of lactic acid, malonic acid, and hydroxypruvic acid in the ginseng extract fermented with lactic acid bacteria (L. plantarum and L. mesenteroide) were the highest. In the results of taste features analysis using an electronic tongue, the ginseng extracts fermented with lactic acid bacteria were significantly distinguished from other groups by a high index of sour taste probably due to high lactic acid contents. Conclusion: These results suggest that a metabolomics approach based on GC-MS can be a useful tool to understand ginseng fermentation and evaluate the fermentative characteristics of starter cultures. PMID: 29348723 [PubMed]

Differential diagnosis between newly diagnosed asthma and chronic obstructive pulmonary disease using exhaled breath condensate metabolomics: a pilot study. Eur Respir J. 2018 Jan 18;: Authors: Maniscalco M, Paris D, Melck DJ, Molino A, Carone M, Ruggeri P, Caramori G, Motta A PMID: 29348154 [PubMed - as supplied by publisher]

Transcriptome and DNA Methylome Analysis in a Mouse Model of Diet-Induced Obesity Predicts Increased Risk of Colorectal Cancer. Cell Rep. 2018 Jan 16;22(3):624-637 Authors: Li R, Grimm SA, Mav D, Gu H, Djukovic D, Shah R, Merrick BA, Raftery D, Wade PA Abstract Colorectal cancer (CRC) tends to occur at older age; however, CRC incidence rates have been rising sharply among young age groups. The increasing prevalence of obesity is recognized as a major risk, yet the mechanistic underpinnings remain poorly understood. Using a diet-induced obesity mouse model, we identified obesity-associated molecular changes in the colonic epithelium of young and aged mice, and we further investigated whether the changes were reversed after weight loss. Transcriptome analysis indicated that obesity-related colonic cellular metabolic switch favoring long-chain fatty acid oxidation happened in young mice, while obesity-associated downregulation of negative feedback regulators of pro-proliferative signaling pathways occurred in older mice. Strikingly, colonic DNA methylome was pre-programmed by obesity at young age, priming for a tumor-prone gene signature after aging. Furthermore, obesity-related changes were substantially preserved after short-term weight loss, but they were largely reversed after long-term weight loss. We provided mechanistic insights into increased CRC risk in obesity. PMID: 29346762 [PubMed - in process]

Reliability of plasma polar metabolite concentrations in a large-scale cohort study using capillary electrophoresis-mass spectrometry. PLoS One. 2018;13(1):e0191230 Authors: Harada S, Hirayama A, Chan Q, Kurihara A, Fukai K, Iida M, Kato S, Sugiyama D, Kuwabara K, Takeuchi A, Akiyama M, Okamura T, Ebbels TMD, Elliott P, Tomita M, Sato A, Suzuki C, Sugimoto M, Soga T, Takebayashi T Abstract BACKGROUND: Cohort studies with metabolomics data are becoming more widespread, however, large-scale studies involving 10,000s of participants are still limited, especially in Asian populations. Therefore, we started the Tsuruoka Metabolomics Cohort Study enrolling 11,002 community-dwelling adults in Japan, and using capillary electrophoresis-mass spectrometry (CE-MS) and liquid chromatography-mass spectrometry. The CE-MS method is highly amenable to absolute quantification of polar metabolites, however, its reliability for large-scale measurement is unclear. The aim of this study is to examine reproducibility and validity of large-scale CE-MS measurements. In addition, the study presents absolute concentrations of polar metabolites in human plasma, which can be used in future as reference ranges in a Japanese population. METHODS: Metabolomic profiling of 8,413 fasting plasma samples were completed using CE-MS, and 94 polar metabolites were structurally identified and quantified. Quality control (QC) samples were injected every ten samples and assessed throughout the analysis. Inter- and intra-batch coefficients of variation of QC and participant samples, and technical intraclass correlation coefficients were estimated. Passing-Bablok regression of plasma concentrations by CE-MS on serum concentrations by standard clinical chemistry assays was conducted for creatinine and uric acid. RESULTS AND CONCLUSIONS: In QC samples, coefficient of variation was less than 20% for 64 metabolites, and less than 30% for 80 metabolites out of the 94 metabolites. Inter-batch coefficient of variation was less than 20% for 81 metabolites. Estimated technical intraclass correlation coefficient was above 0.75 for 67 metabolites. The slope of Passing-Bablok regression was estimated as 0.97 (95% confidence interval: 0.95, 0.98) for creatinine and 0.95 (0.92, 0.96) for uric acid. Compared to published data from other large cohort measurement platforms, reproducibility of metabolites common to the platforms was similar to or better than in the other studies. These results show that our CE-MS platform is suitable for conducting large-scale epidemiological studies. PMID: 29346414 [PubMed - in process]

Enhanced Isotopic Ratio Outlier Analysis (IROA) Peak Detection and Identification with Ultra-High Resolution GC-Orbitrap/MS: Potential Application for Investigation of Model Organism Metabolomes. Metabolites. 2018 Jan 18;8(1): Authors: Qiu Y, Moir RD, Willis IM, Seethapathy S, Biniakewitz RC, Kurland IJ Abstract Identifying non-annotated peaks may have a significant impact on the understanding of biological systems. In silico methodologies have focused on ESI LC/MS/MS for identifying non-annotated MS peaks. In this study, we employed in silico methodology to develop an Isotopic Ratio Outlier Analysis (IROA) workflow using enhanced mass spectrometric data acquired with the ultra-high resolution GC-Orbitrap/MS to determine the identity of non-annotated metabolites. The higher resolution of the GC-Orbitrap/MS, together with its wide dynamic range, resulted in more IROA peak pairs detected, and increased reliability of chemical formulae generation (CFG). IROA uses two different 13C-enriched carbon sources (randomized 95% 12C and 95% 13C) to produce mirror image isotopologue pairs, whose mass difference reveals the carbon chain length (n), which aids in the identification of endogenous metabolites. Accurate m/z, n, and derivatization information are obtained from our GC/MS workflow for unknown metabolite identification, and aids in silico methodologies for identifying isomeric and non-annotated metabolites. We were able to mine more mass spectral information using the same Saccharomyces cerevisiae growth protocol (Qiu et al. Anal. Chem 2016) with the ultra-high resolution GC-Orbitrap/MS, using 10% ammonia in methane as the CI reagent gas. We identified 244 IROA peaks pairs, which significantly increased IROA detection capability compared with our previous report (126 IROA peak pairs using a GC-TOF/MS machine). For 55 selected metabolites identified from matched IROA CI and EI spectra, using the GC-Orbitrap/MS vs. GC-TOF/MS, the average mass deviation for GC-Orbitrap/MS was 1.48 ppm, however, the average mass deviation was 32.2 ppm for the GC-TOF/MS machine. In summary, the higher resolution and wider dynamic range of the GC-Orbitrap/MS enabled more accurate CFG, and the coupling of accurate mass GC/MS IROA methodology with in silico fragmentation has great potential in unknown metabolite identification, with applications for characterizing model organism networks. PMID: 29346327 [PubMed]

A metabolomics study reveals enhanced inhibition and metabolic dysregulation in E. coli induced by Lactobacillus acidophilus fermented black tea extract. J Agric Food Chem. 2018 Jan 18;: Authors: Yang K, Duley M, Zhu J Abstract This study examined the ability of Lactobacillus acidophilus (LA) to ferment black tea extract (BTE), and the enhancement of Escherichia coli cellular uptake of phenolic compounds when this bacteria was incubated with fermented BTE. The inhibitory effects of BTE to E. coli bacteria, with and w/o fermentation, were compared. Several intracellular phenolic compounds, as well as metabolic profiles of E. coli with and w/o treatments, were also determined using a HPLC-MS/MS-based approach. Our results showed that out of three concentrations from the non-fermented BTE treatment, only the extract from the 25 mg/ml tea leaves solution could inhibit E. coli survival, while LA fermented BTE extract from 5, 10 and 25 mg/mL tea leaves solutions all inhibited E. coli growth significantly. Intracellular concentration of (+)-catechin-3-gallate/ (-)-epicatechin-3-gallate and (+)-catechin / (-)-epicatechin were significantly higher when E. coli was treated with fermented BTE in comparison to non-fermented BTE. Scanning electron microscopy (SEM) images indicated that the intracellular phenolic compounds inhibited E. coli growth by increasing endogenous oxidative stress. Metabolic profiles of E. coli were also investigated to understand their metabolic response when treated with BTE, and significant metabolic changes of E. coli were observed. Metabolic profile data were further analyzed using partial least square-discriminant analysis (PLS-DA) to distinguish the fermented BTE treatment group from the control group and the non-fermented BTE treatment group. The results indicated a large-scale E. coli metabolic dysregulation induced by the fermented BTE. Our findings showed that LA fermentation can be an efficient approach to enhance phenolic inhibition of bacterial cells through increased endogenous oxidative stress and dysregulated metabolic activities. PMID: 29345909 [PubMed - as supplied by publisher]

Related Articles Application of molecular tools to elucidate the microbiota of seafood. J Appl Microbiol. 2018 Jan 18;: Authors: de Almeida Rodrigues P, Ferrari RG, Conte Junior CA Abstract The aim of this review is to present the methodologies currently applied to identify microbiota and pathogens transmitted to humans through seafood consumption, focusing on molecular techniques and pointing out their importance, advantages, disadvantages, and applicability. Knowledge of available techniques allows researchers to identify which technique best fits their expectations. With such discernment, it will be possible to infer which disadvantages will be present and, therefore, not interfering with the final result. Two methodologies can be employed for this purpose, dependent and independent cultures. However, the culture-dependent has certain limitations that can be solved through the independent cultivation techniques, such as PCR, PFGE and NGS, especially through the sequencing of the 16S rRNA region, providing a complete view of microbial diversity. These have revolutionized microbiological knowledge, mainly because they allow for the identification of uncultivable microorganisms, which represent a substantial portion of total microorganisms, making it possible to elucidate not yet described taxa which may display pathogenic potential, besides quantifying microbial communities, microbiota genetics, translated proteins and produced metabolites. In addition, transcriptomic and metabolomics techniques also allow for the evaluation of possible impacts that microbial communities may create in their environment, as well as the determination of potential pathogenicity to humans. This article is protected by copyright. All rights reserved. PMID: 29345036 [PubMed - as supplied by publisher]

Related Articles Effluent and serum protein N-glycosylation is associated with inflammation and peritoneal membrane transport characteristics in peritoneal dialysis patients. Sci Rep. 2018 Jan 17;8(1):979 Authors: Ferrantelli E, Farhat K, Ederveen ALH, Reiding KR, Beelen RHJ, van Ittersum FJ, Wuhrer M, Dotz V Abstract Mass spectrometric glycomics was used as an innovative approach to identify biomarkers in serum and dialysate samples from peritoneal dialysis (PD) patients. PD is a life-saving treatment worldwide applied in more than 100,000 patients suffering from chronic kidney disease. PD treatment uses the peritoneum as a natural membrane to exchange waste products from blood to a glucose-based solution. Daily exposure of the peritoneal membrane to these solutions may cause complications such as peritonitis, fibrosis and inflammation which, in the long term, lead to the failure of the treatment. It has been shown in the last years that protein N-glycosylation is related to inflammatory and fibrotic processes. Here, by using a recently developed MALDI-TOF-MS method with linkage-specific sialic acid derivatisation, we showed that alpha2,6-sialylation, especially in triantennary N-glycans from peritoneal effluents, is associated with critical clinical outcomes in a prospective cohort of 94 PD patients. Moreover, we found an association between the levels of presumably immunoglobulin-G-related glycans as well as galactosylation of diantennary glycans with PD-related complications such as peritonitis and loss of peritoneal mesothelial cell mass. The observed glycomic changes point to changes in protein abundance and protein-specific glycosylation, representing candidate functional biomarkers of PD and associated complications. PMID: 29343697 [PubMed - in process]

Related Articles Uremic Solute-Aryl Hydrocarbon Receptor-Tissue Factor Axis Associates with Thrombosis after Vascular Injury in Humans. J Am Soc Nephrol. 2018 Jan 17;: Authors: Kolachalama VB, Shashar M, Alousi F, Shivanna S, Rijal K, Belghasem ME, Walker J, Matsuura S, Chang GH, Gibson CM, Dember LM, Francis JM, Ravid K, Chitalia VC Abstract Individuals with CKD are particularly predisposed to thrombosis after vascular injury. Using mouse models, we recently described indoxyl sulfate, a tryptophan metabolite retained in CKD and an activator of tissue factor (TF) through aryl hydrocarbon receptor (AHR) signaling, as an inducer of thrombosis across the CKD spectrum. However, the translation of findings from animal models to humans is often challenging. Here, we investigated the uremic solute-AHR-TF thrombosis axis in two human cohorts, using a targeted metabolomics approach to probe a set of tryptophan products and high-throughput assays to measure AHR and TF activity. Analysis of baseline serum samples was performed from 473 participants with advanced CKD from the Dialysis Access Consortium Clopidogrel Prevention of Early AV Fistula Thrombosis trial. Participants with subsequent arteriovenous thrombosis had significantly higher levels of indoxyl sulfate and kynurenine, another uremic solute, and greater activity of AHR and TF, than those without thrombosis. Pattern recognition analysis using the components of the thrombosis axis facilitated clustering of the thrombotic and nonthrombotic groups. We further validated these findings using 377 baseline samples from participants in the Thrombolysis in Myocardial Infarction II trial, many of whom had CKD stage 2-3. Mechanistic probing revealed that kynurenine enhances thrombosis after vascular injury in an animal model and regulates thrombosis in an AHR-dependent manner. This human validation of the solute-AHR-TF axis supports further studies probing its utility in risk stratification of patients with CKD and exploring its role in other diseases with heightened risk of thrombosis. PMID: 29343519 [PubMed - as supplied by publisher]

Related Articles Mass-spectrometric profiling of cerebrospinal fluid reveals metabolite biomarkers for CNS involvement in varicella zoster virus reactivation. J Neuroinflammation. 2018 Jan 17;15(1):20 Authors: Kuhn M, Sühs KW, Akmatov MK, Klawonn F, Wang J, Skripuletz T, Kaever V, Stangel M, Pessler F Abstract BACKGROUND: Varicella zoster virus (VZV) reactivation spans the spectrum from uncomplicated segmental herpes zoster to life-threatening disseminated CNS infection. Moreover, in the absence of a small animal model for this human pathogen, studies of pathogenesis at the organismal level depend on analysis of human biosamples. Changes in cerebrospinal fluid (CSF) metabolites may reflect critical aspects of host responses and end-organ damage in neuroinfection and neuroinflammation. We therefore applied a targeted metabolomics screen of CSF to three clinically distinct forms of VZV reactivation and infectious and non-infectious disease controls in order to identify biomarkers for CNS involvement in VZV reactivation. METHODS: Metabolite profiles were determined by targeted liquid chromatography-mass spectrometry in CSF from patients with segmental zoster (shingles, n = 14), facial nerve zoster (n = 16), VZV meningitis/encephalitis (n = 15), enteroviral meningitis (n = 10), idiopathic Bell's palsy (n = 11), and normal pressure hydrocephalus (n = 15). RESULTS: Concentrations of 88 metabolites passing quality assessment clearly separated the three VZV reactivation forms from each other and from the non-infected samples. Internal cross-validation identified four metabolites (SM C16:1, glycine, lysoPC a C26:1, PC ae C34:0) that were particularly associated with VZV meningoencephalitis. SM(OH) C14:1 accurately distinguished facial nerve zoster from Bell's palsy. Random forest construction revealed even more accurate classifiers (signatures comprising 2-4 metabolites) for most comparisons. Some of the most accurate biomarkers correlated only weakly with CSF leukocyte count, indicating that they do not merely reflect recruitment of inflammatory cells but, rather, specific pathophysiological mechanisms. Across all samples, only the sum of hexoses and the amino acids arginine, serine, and tryptophan correlated negatively with leukocyte count. Increased expression of the metabolites associated with VZV meningoencephalitis could be linked to processes relating to neuroinflammation/immune activation, neuronal signaling, and cell stress, turnover, and death (e.g., autophagy and apoptosis), suggesting that these metabolites might sense processes relating to end-organ damage. CONCLUSIONS: The results provide proof-of-concept for the value of CSF metabolites as (1) disease-associated signatures suggesting pathophysiological mechanisms, (2) degree and nature of neuroinflammation, and (3) biomarkers for diagnosis and risk stratification of VZV reactivation and, likely, neuroinfections due to other pathogens. TRIAL REGISTRATION: Not applicable (non-interventional study). PMID: 29343258 [PubMed - in process]

Related Articles Impact of Prolonged Blood Incubation and Extended Serum Storage at Room Temperature on the Human Serum Metabolome. Metabolites. 2018 Jan 13;8(1): Authors: Kamlage B, Neuber S, Bethan B, González Maldonado S, Wagner-Golbs A, Peter E, Schmitz O, Schatz P Abstract Metabolomics is a powerful technology with broad applications in life science that, like other -omics approaches, requires high-quality samples to achieve reliable results and ensure reproducibility. Therefore, along with quality assurance, methods to assess sample quality regarding pre-analytical confounders are urgently needed. In this study, we analyzed the response of the human serum metabolome to pre-analytical variations comprising prolonged blood incubation and extended serum storage at room temperature by using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) -based metabolomics. We found that the prolonged incubation of blood results in a statistically significant 20% increase and 4% decrease of 225 tested serum metabolites. Extended serum storage affected 21% of the analyzed metabolites (14% increased, 7% decreased). Amino acids and nucleobases showed the highest percentage of changed metabolites in both confounding conditions, whereas lipids were remarkably stable. Interestingly, the amounts of taurine and O-phosphoethanolamine, which have both been discussed as biomarkers for various diseases, were 1.8- and 2.9-fold increased after 6 h of blood incubation. Since we found that both are more stable in ethylenediaminetetraacetic acid (EDTA) blood, EDTA plasma should be the preferred metabolomics matrix. PMID: 29342854 [PubMed]

Related Articles Germline BRCA1 mutation reprograms breast epithelial cell metabolism towards mitochondrial-dependent biosynthesis: evidence for metformin-based "starvation" strategies in BRCA1 carriers. Oncotarget. 2016 Aug 16;7(33):52974-52992 Authors: Cuyàs E, Fernández-Arroyo S, Alarcón T, Lupu R, Joven J, Menendez JA Abstract We hypothesized that women inheriting one germline mutation of the BRCA1 gene ("one-hit") undergo cell-type-specific metabolic reprogramming that supports the high biosynthetic requirements of breast epithelial cells to progress to a fully malignant phenotype. Targeted metabolomic analysis was performed in isogenic pairs of nontumorigenic human breast epithelial cells in which the knock-in of 185delAG mutation in a single BRCA1 allele leads to genomic instability. Mutant BRCA1 one-hit epithelial cells displayed constitutively enhanced activation of biosynthetic nodes within mitochondria. This metabolic rewiring involved the increased incorporation of glutamine- and glucose-dependent carbon into tricarboxylic acid (TCA) cycle metabolite pools to ultimately generate elevated levels of acetyl-CoA and malonyl-CoA, the major building blocks for lipid biosynthesis. The significant increase of branched-chain amino acids (BCAAs) including the anabolic trigger leucine, which can not only promote protein translation via mTOR but also feed into the TCA cycle via succinyl-CoA, further underscored the anabolic reprogramming of BRCA1 haploinsufficient cells. The anti-diabetic biguanide metformin "reversed" the metabolomic signature and anabolic phenotype of BRCA1 one-hit cells by shutting down mitochondria-driven generation of precursors for lipogenic pathways and reducing the BCAA pool for protein synthesis and TCA fueling. Metformin-induced restriction of mitochondrial biosynthetic capacity was sufficient to impair the tumor-initiating capacity of BRCA1 one-hit cells in mammosphere assays. Metabolic rewiring of the breast epithelium towards increased anabolism might constitute an unanticipated and inherited form of metabolic reprogramming linked to increased risk of oncogenesis in women bearing pathogenic germline BRCA1 mutations. The ability of metformin to constrain the production of mitochondrial-dependent biosynthetic intermediates might open a new avenue for "starvation" chemopreventive strategies in BRCA1 carriers. PMID: 27259235 [PubMed - indexed for MEDLINE]

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