PubMed

Systemic effects of ionizing radiation at the proteome and metabolome levels in the blood of cancer patients treated with radiotherapy: The influence of inflammation and radiation toxicity. Int J Radiat Biol. 2017 Mar 10;:1-27 Authors: Jelonek K, Pietrowska M, Widlak P Abstract Purpose Blood is the most common replacement tissue used to study systemic responses of organisms to different types of pathological conditions and environmental insults. Local irradiation during cancer radiotherapy induces whole body responses that can be observed at the blood proteome and metabolome levels. Hence, comparative blood proteomics and metabolomics are emerging approaches used in the discovery of radiation biomarkers. These techniques enable the simultaneous measurement of hundreds of molecules and the identification of sets of components that can discriminate different physiological states of the human body. Radiation-induced changes are affected by the dose and volume of irradiated tissues; hence, the molecular composition of blood is a hypothetical source of biomarkers for dose assessment and the prediction and monitoring of systemic responses to radiation. This review will provide a comprehensive overview on the available evidence regarding molecular responses to ionizing radiation detected at the level of the human blood proteome and metabolome. This review focuses on patients exposed to radiation during cancer radiotherapy and emphasizes effects related to radiation-induced toxicity and inflammation. Conclusions Systemic responses to radiation detected at the blood proteome and metabolome levels are primarily related to the intensity of radiation-induced toxicity, including inflammatory responses. Thus, several inflammation-associated molecules can be used to monitor or even predict radiation-induced toxicity. However, these abundant molecular features have a rather limited applicability as universal biomarkers for dose assessment, reflecting the individual predisposition of the immune system and tissue-specific mechanisms involved in radiation-induced damage. PMID: 28281355 [PubMed - as supplied by publisher]

Related Articles Ginsenoside Rg5 attenuates hepatic glucagon response via suppression of succinate-associated HIF-1α induction in HFD-fed mice. Diabetologia. 2017 Mar 09;: Authors: Xiao N, Lou MD, Lu YT, Yang LL, Liu Q, Liu B, Qi LW, Li P Abstract AIMS/HYPOTHESIS: Ginsenosides regulate glucose homeostasis. This study investigated the effect of ginsenoside Rg5 (Rg5) on the hepatic glucagon response, focusing on the regulation of metabolism. METHODS: Mice fed a high-fat diet (HFD) showed increased hepatic glucose production (HGP). We observed the effects of Rg5 on hepatic fatty acid oxidation and glucagon response. The regulation of phosphodiesterase (PDE) 4B by succinate was also investigated in hepatocytes. RESULTS: Rg5 inhibited endogenous glucose production in HFD-fed mice. Rg5 reduced cyclic AMP (cAMP) accumulation and inhibited transcriptional regulation of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) by dephosphorylation of the cAMP response element-binding transcription factor in the liver, demonstrating the inhibitory effect on hepatic glucagon response. HFD feeding increased succinate accumulation in the liver due to the reversal of succinate dehydrogenase activation and triggered hypoxia-inducible factor-1α (HIF-1α) induction. Succinate prevented cAMP degradation by inactivating PDE4B, thereby increasing cAMP accumulation in response to glucagon. Knockdown of HIF-1α with small interfering RNA diminished the effect of succinate, indicating that HIF-1α was essential for succinate to inactivate PDE4B. Rg5 inhibited succinate accumulation in hepatocytes by combating fatty acid oxidation, and thus reduced cAMP accumulation by blocking succinate/HIF-1α induction. Rg5 reduced HGP as a consequence of the inhibition of the glucagon response. CONCLUSIONS/INTERPRETATION: Succinate acted as a metabolic signal to enhance the hepatic glucagon response. Rg5 reduced hepatic succinate accumulation by combating fatty acid oxidation and attenuated the hepatic glucagon response by suppressing succinate/HIF-1α induction, suggesting that succinate-associated HIF-1α induction in hepatocytes might be a therapeutic target in the treatment of diabetes. PMID: 28280902 [PubMed - as supplied by publisher]

Related Articles Lipid quantitation and metabolomics data from vitamin E-deficient and -sufficient zebrafish embryos from 0 to 120 hours-post-fertilization. Data Brief. 2017 Apr;11:432-441 Authors: McDougall M, Choi J, Kim HK, Bobe G, Stevens JF, Cadenas E, Tanguay R, Traber MG Abstract The data herein is in support of our research article by McDougall et al. (2017) [1], in which we used our zebrafish model of embryonic vitamin E (VitE) deficiency to study the consequences of VitE deficiency during development. Adult 5D wild-type zebrafish (Danio rerio), fed defined diets without (E-) or with VitE (E+, 500 mg RRR-α-tocopheryl acetate/kg diet), were spawned to obtain E- and E+ embryos that we evaluated using metabolomics and specific lipid analyses (each measure at 24, 48, 72, 120 hours-post-fertilization, hpf), neurobehavioral development (locomotor responses at 96 hpf), and rescue strategies. Rescues were attempted using micro-injection into the yolksac using VitE (as a phospholipid emulsion containing d6-α-tocopherol at 0 hpf) or D-glucose (in saline at 24 hpf). PMID: 28280764 [PubMed - in process]

Related Articles Metabolic fate of glucose and candidate signaling and excess-fuel detoxification pathways in pancreatic β-cells. J Biol Chem. 2017 Mar 09;: Authors: Mugabo Y, Zhao S, Lamontagne J, Al-Mass A, Peyot ML, Corkey BE, Joly E, Madiraju SR, Prentki M Abstract Glucose metabolism promotes insulin secretion in β-cells via metabolic coupling factors that are incompletely defined. Moreover, chronically elevated glucose causes β-cell dysfunction, but little is known about how cells handle excess fuels to avoid toxicity. Here we sought to determine which among the candidate pathways and coupling factors best correlates with glucose-stimulated insulin secretion (GSIS), define the fate of glucose in the β-cell, and identify pathways possibly involved in excess-fuel detoxification. We exposed isolated rat islets for 1 h to increasing glucose concentrations and measured various pathways and metabolites. Glucose oxidation, oxygen consumption, and ATP production correlated well with GSIS and saturated at 16 mM glucose. However, glucose utilization, glycerol release, triglyceride and glycogen contents, free fatty acid (FFA) content and release, and cholesterol and cholesterol esters increased linearly up to 25 mM glucose. Besides being oxidized, glucose was mainly metabolized via glycerol production and release and lipid synthesis (particularly FFA, triglycerides, and cholesterol), whereas glycogen production was comparatively low. Using targeted metabolomics in INS-1(832/13) cells, we found that several metabolites correlated well with GSIS, in particular, some Krebs cycle intermediates, malonyl-CoA, and lower ADP levels. Glucose dose dependently increased the dihydroxyacetone phosphate/glycerol 3-phosphate ratio in INS1(832/13) cells, indicating a more oxidized state of NAD in the cytosol upon glucose stimulation. Overall, the data support a role for accelerated oxidative mitochondrial metabolism, anaplerosis, and malonyl-CoA/lipid signaling in β-cell metabolic signaling and suggest that a decrease in ADP levels is important in GSIS. The results also suggest that excess-fuel detoxification pathways in β-cells possibly comprise glycerol and FFA formation and release extracellularly and the diversion of glucose carbons to triglycerides and cholesterol esters. PMID: 28280244 [PubMed - as supplied by publisher]

Related Articles Plasma Ceramides, Mediterranean Diet, and Incident Cardiovascular Disease in the PREDIMED Trial. Circulation. 2017 Mar 09;: Authors: Wang DD, Toledo E, Hruby A, Rosner BA, Willett WC, Sun Q, Razquin C, Zheng Y, Ruiz-Canela M, Guasch-Ferré M, Corella D, Gómez-Gracia E, Fiol M, Estruch R, Ros E, Lapetra J, Fitó M, Aros F, Serra-Majem L, Lee CH, Clish CB, Liang L, Salas-Salvadó J, Martínez-González MA, Hu FB Abstract Background -Although in vitro studies and investigations in animal models and small clinical populations have suggested that ceramides may represent an intermediate link between over-nutrition and certain pathological mechanisms underlying cardiovascular disease (CVD), no prospective studies have investigated the association between plasma ceramides and risk of CVD. Methods -The study population consisted of 980 participants from the PREDIMED trial, including 230 incident cases of CVD and 787 randomly selected participants at baseline (including 37 overlapping cases), followed for up to 7.4 years. Participants were randomized to a Mediterranean diet (MedDiet) supplemented with extra-virgin olive oil, a MedDiet supplemented with nuts, or a control diet. Plasma ceramide concentrations were measured on a liquid chromatography tandem mass spectrometry metabolomics platform. The primary outcome was a composite of non-fatal acute myocardial infarction, non-fatal stroke, or cardiovascular death. Hazard Ratios (HRs) were estimated with weighted Cox regression models, using Barlow weights to account for the case-cohort design. Results -The multivariable HRs [95% confidence interval (CI)] comparing the extreme quartiles of plasma concentrations of C16:0, C22:0, C24:0 and C24:1 ceramides were 2.39 (1.49-3.83, Ptrend <0.001), 1.91 (1.21-3.01, Ptrend =0.003), 1.97 (1.21-3.01, Ptrend =0.004), and 1.73 (1.09-2.74, Ptrend=0.011), respectively. The ceramide score, calculated as a weighted sum of concentrations of four ceramides, was associated with a 2.18-fold higher risk of CVD across extreme quartiles (HR =2.18, 95% CI, 1.36-3.49, Ptrend <0.001). The association between baseline ceramide score and incident CVD varied significantly by treatment groups (Pinteraction =0.010). Participants with a higher ceramide score and assigned to either of the two active intervention arms of the trial showed similar CVD risk to those with a lower ceramide score, whereas participants with a higher ceramide score and assigned to the control arm presented significantly higher CVD risk. Changes in ceramide concentration were not significantly different between MedDiet and control groups during the first year of follow-up. Conclusions -Our study documented a novel positive association between baseline plasma ceramide concentrations and incident CVD. In addition, a Mediterranean dietary intervention may mitigate potential deleterious effects of elevated plasma ceramide concentrations on CVD. Clinical Trial Registration -http://www.isrctn.com/ Identifier: ISRCTN35739639. PMID: 28280233 [PubMed - as supplied by publisher]

Related Articles Prebiotic milk oligosaccharides prevent development of obese phenotype, impairment of gut permeability and microbial dysbiosis in high-fat fed mice. Am J Physiol Gastrointest Liver Physiol. 2017 Mar 09;:ajpgi.00427.2016 Authors: Hamilton MK, Ronveaux CC, Rust BM, Newman JW, Hawley M, Barile D, Mills DA, Raybould HE Abstract Microbial dysbiosis and increased intestinal permeability is a target for prevention or reversal of weight gain in high-fat (HF) diet-induced obesity (DIO). Prebiotic milk oligosaccharides (MO) have been shown to benefit the host intestine, but have not been used in DIO. We hypothesized that supplementation with bovine MO would prevent the deleterious effect of HF diet on the gut microbiota and intestinal permeability, and attenuate development of the obese phenotype. C57BL/6 mice were fed a control diet (LF), HF (40% fat/kcal), or HF + prebiotic (6%/Kg BMO or inulin) for 1, 3 or 6 weeks. Gut microbiota and intestinal permeability were assessed in the ileum, cecum and colon. Addition of BMO to the HF diet significantly attenuated weight gain, decreased adiposity and decreased caloric intake; inulin supplementation also lowered weight gain and adiposity, but this did not reach significance. BMO and inulin completely abolished the HF diet-induced increase in paracellular and transcellular permeability in the small and large intestine. Both BMO and inulin increased abundance of beneficial microbes Bifidobacterium and Lactobacillus in the ileum. However, inulin supplementation altered phylogenetic diversity and decreased species richness. We conclude that addition of BMO to the HF diet completely prevented increases in intestinal permeability and microbial dysbiosis and was partially effective to prevent weight gain in DIO. PMID: 28280143 [PubMed - as supplied by publisher]

Related Articles Metabolomics approach to chemical diversity of the Mediterranean marine sponge Agelas oroides. Nat Prod Res. 2017 Feb 06;:1-8 Authors: Sauleau P, Moriou C, Al Mourabit A Abstract The Mediterranean marine sponge Agelas oroides is known to contain a large quantity of oroidin, a deterrent, antifouling and antibiofilm pyrrole-2-aminoimidazole. In contrast with other tropical specimens, the chemical composition of Mediterranean Agelas oroides is surprisingly relatively poor in other related metabolites. In the course of finding novel marine natural products, LC-MS based metabolomics study of the Mediterranean Agelas oroides, however, revealed that next to the major compound oroidin, the sponge contains in fact a great diversity of known pyrrole-imidazole alkaloids in minute amounts. Here, we describe identification of 13 known oroidin class alkaloids along with one new monobromoagelaspongin (24). Five betaines and one amine were also identified from the aqueous fraction. One of those compounds (-)-equinobetaine B (30) was found to be an enantiomer of the known natural product (+)-equinobetaine B. PMID: 28278683 [PubMed - as supplied by publisher]

Related Articles Secondary metabolites from the endophytic fungus Talaromyces pinophilus. Nat Prod Res. 2017 Feb 28;:1-8 Authors: Vinale F, Nicoletti R, Lacatena F, Marra R, Sacco A, Lombardi N, d'Errico G, Digilio MC, Lorito M, Woo SL Abstract Endophytic fungi have a great influence on plant health and growth, and are an important source of bioactive natural compounds. Organic extracts obtained from the culture filtrate of an endophytic strain of Talaromyces pinophilus isolated from strawberry tree (Arbutus unedo) were studied. Metabolomic analysis revealed the presence of three bioactive metabolites, the siderophore ferrirubin, the platelet-aggregation inhibitor herquline B and the antibiotic 3-O-methylfunicone. The latter was the major metabolite produced by this strain and displayed toxic effects against the pea aphid Acyrthosiphon pisum (Homoptera Aphidiidae). This toxicity represents an additional indication that the widespread endophytic occurrence of T. pinophilus may be related to a possible role in defensive mutualism. Moreover, the toxic activity on aphids could promote further study on 3-O-methylfunicone, or its derivatives, as an alternative to synthetic chemicals in agriculture. PMID: 28278635 [PubMed - as supplied by publisher]

Related Articles Omics markers of the red cell storage lesion and metabolic linkage. Blood Transfus. 2017 Mar;15(2):137-144 Authors: D'alessandro A, Nemkov T, Reisz J, Dzieciatkowska M, Wither MJ, Hansen KC Abstract The introduction of omics technologies in the field of Transfusion Medicine has significantly advanced our understanding of the red cell storage lesion. While the clinical relevance of such a lesion is still a matter of debate, quantitative and redox proteomics approaches, as well quantitative metabolic flux analysis and metabolic tracing experiments promise to revolutionise our understanding of the role of blood processing strategies, inform the design and testing of novel additives or technologies (such as pathogen reduction), and evaluate the clinical relevance of donor and recipient biological variability with respect to red cell storability and transfusion outcomes. By reviewing existing literature in this rapidly expanding research endeavour, we highlight for the first time a correlation between metabolic markers of the red cell storage age and protein markers of haemolysis. Finally, we introduce the concept of metabolic linkage, i.e. the appreciation of a network of highly correlated small molecule metabolites which results from biochemical constraints of erythrocyte metabolic enzyme activities. For the foreseeable future, red cell studies will advance Transfusion Medicine and haematology by addressing the alteration of metabolic linkage phenotypes in response to stimuli, including, but not limited to, storage additives, enzymopathies (e.g. glucose 6-phosphate dehydrogenase deficiency), hypoxia, sepsis or haemorrhage. PMID: 28263171 [PubMed - indexed for MEDLINE]

Related Articles Elucidating the Rimosamide-Detoxin Natural Product Families and Their Biosynthesis Using Metabolite/Gene Cluster Correlations. ACS Chem Biol. 2016 12 16;11(12):3452-3460 Authors: McClure RA, Goering AW, Ju KS, Baccile JA, Schroeder FC, Metcalf WW, Thomson RJ, Kelleher NL Abstract As microbial genome sequencing becomes more widespread, the capacity of microorganisms to produce an immense number of metabolites has come into better view. Utilizing a metabolite/gene cluster correlation platform, the biosynthetic origins of a new family of natural products, the rimosamides, were discovered. The rimosamides were identified in Streptomyces rimosus and associated with their NRPS/PKS-type gene cluster based upon their high frequency of co-occurrence across 179 strains of actinobacteria. This also led to the discovery of the related detoxin gene cluster. The core of each of these families of natural products contains a depsipeptide bond at the point of bifurcation in their unusual branched structures, the origins of which are definitively assigned to nonlinear biosynthetic pathways via heterologous expression in Streptomyces lividans. The rimosamides were found to antagonize the antibiotic activity of blasticidin S against Bacillus cereus. PMID: 27809474 [PubMed - indexed for MEDLINE]

Related Articles Imaging of Endogenous Metabolites of Plant Leaves by Mass Spectrometry Based on Laser Activated Electron Tunneling. Sci Rep. 2016 Apr 07;6:24164 Authors: Huang L, Tang X, Zhang W, Jiang R, Chen D, Zhang J, Zhong H Abstract A new mass spectrometric imaging approach based on laser activated electron tunneling (LAET) was described and applied to analysis of endogenous metabolites of plant leaves. LAET is an electron-directed soft ionization technique. Compressed thin films of semiconductor nanoparticles of bismuth cobalt zinc oxide were placed on the sample plate for proof-of-principle demonstration because they can not only absorb ultraviolet laser but also have high electron mobility. Upon laser irradiation, electrons are excited from valence bands to conduction bands. With appropriate kinetic energies, photoexcited electrons can tunnel away from the barrier and eventually be captured by charge deficient atoms present in neutral molecules. Resultant unpaired electron subsequently initiates specific chemical bond cleavage and generates ions that can be detected in negative ion mode of the mass spectrometer. LAET avoids the co-crystallization process of routinely used organic matrix materials with analyzes in MALDI (matrix assisted-laser desorption ionization) analysis. Thus uneven distribution of crystals with different sizes and shapes as well as background peaks in the low mass range resulting from matrix molecules is eliminated. Advantages of LAET imaging technique include not only improved spatial resolution but also photoelectron capture dissociation which produces predictable fragment ions. PMID: 27053227 [PubMed - indexed for MEDLINE]

Related Articles Targeting the Enterohepatic Bile Acid Signaling Induces Hepatic Autophagy via a CYP7A1-AKT-mTOR Axis in Mice. Cell Mol Gastroenterol Hepatol. 2017 Mar;3(2):245-260 Authors: Wang Y, Ding Y, Li J, Chavan H, Matye D, Ni HM, Chiang JY, Krishnamurthy P, Ding WX, Li T Abstract BACKGROUND & AIMS: Hepatic cholesterol accumulation and autophagy defects contribute to hepatocyte injury in fatty liver disease. Bile acid synthesis is a major pathway for cholesterol catabolism in the liver. This study aims to understand the molecular link between cholesterol and bile acid metabolism and hepatic autophagy activity. METHODS: The effects of cholesterol and cholesterol 7α-hydroxylase (CYP7A1) expression on autophagy and lysosome function were studied in cell models. The effects and mechanism of disrupting enterohepatic bile acid circulation on hepatic autophagy were studied in mice. RESULTS: The results first showed differential regulation of hepatic autophagy by free cholesterol and cholesterol ester, whereby a modest increase of cellular free cholesterol, but not cholesterol ester, impaired lysosome function and caused marked autolysosome accumulation. We found that CYP7A1 induction, either by cholestyramine feeding in mice or adenovirus-mediated CYP7A1 expression in hepatocytes, caused strong autophagy induction. Mechanistically, we showed that CYP7A1 expression markedly attenuated growth factor/AKT signaling activation of mechanistic target of rapamycin (mTOR), but not amino acid signaling to mTOR in vitro and in vivo. Metabolomics analysis further found that CYP7A1 induction not only decreased hepatic cholesterol but also altered phospholipid and sphingolipid compositions. Collectively, these results suggest that CYP7A1 induction interferes with growth factor activation of AKT/mTOR signaling possibly by altering membrane lipid composition. Finally, we showed that cholestyramine feeding restored impaired hepatic autophagy and improved metabolic homeostasis in Western diet-fed mice. CONCLUSIONS: This study identified a novel CYP7A1-AKT-mTOR signaling axis that selectively induces hepatic autophagy, which helps improve hepatocellular integrity and metabolic homeostasis. PMID: 28275691 [PubMed - in process]

Related Articles Data representing two separate LC-MS methods for detection and quantification of water-soluble and fat-soluble vitamins in tears and blood serum. Data Brief. 2017 Apr;11:316-330 Authors: Khaksari M, Mazzoleni LR, Ruan C, Kennedy RT, Minerick AR Abstract Two separate liquid chromatography (LC)-mass spectrometry (MS) methods were developed for determination and quantification of water-soluble and fat-soluble vitamins in human tear and blood serum samples. The water-soluble vitamin method was originally developed to detect vitamins B1, B2, B3 (nicotinamide), B5, B6 (pyridoxine), B7, B9 and B12 while the fat-soluble vitamin method detected vitamins A, D3, 25(OH)D3, E and K1. These methods were then validated with tear and blood serum samples. In this data in brief article, we provide details on the two LC-MS methods development, methods sensitivity, as well as precision and accuracy for determination of vitamins in human tears and blood serum. These methods were then used to determine the vitamin concentrations in infant and parent samples under a clinical study which were reported in "Determination of Water-Soluble and Fat-Soluble Vitamins in Tears and Blood Serum of Infants and Parents by Liquid Chromatography/Mass Spectrometry DOI:10.1016/j.exer.2016.12.007 [1]". This article provides more details on comparison of vitamin concentrations in the samples with the ranges reported in the literature along with the medically accepted normal ranges. The details on concentrations below the limits of detection (LOD) and limits of quantification (LOQ) are also discussed. Vitamin concentrations were also compared and cross-correlated with clinical data and nutritional information. Significant differences and strongly correlated data were reported in [1]. This article provides comprehensive details on the data with slight differences or slight correlations. PMID: 28275666 [PubMed - in process]

Related Articles Metabolic profiling of body fluids and multivariate data analysis. MethodsX. 2017;4:95-103 Authors: Trezzi JP, Jäger C, Galozzi S, Barkovits K, Marcus K, Mollenhauer B, Hiller K Abstract Metabolome analyses of body fluids are challenging due pre-analytical variations, such as pre-processing delay and temperature, and constant dynamical changes of biochemical processes within the samples. Therefore, proper sample handling starting from the time of collection up to the analysis is crucial to obtain high quality samples and reproducible results. A metabolomics analysis is divided into 4 main steps: 1) Sample collection, 2) Metabolite extraction, 3) Data acquisition and 4) Data analysis. Here, we describe a protocol for gas chromatography coupled to mass spectrometry (GC-MS) based metabolic analysis for biological matrices, especially body fluids. This protocol can be applied on blood serum/plasma, saliva and cerebrospinal fluid (CSF) samples of humans and other vertebrates. It covers sample collection, sample pre-processing, metabolite extraction, GC-MS measurement and guidelines for the subsequent data analysis. Advantages of this protocol include: •Robust and reproducible metabolomics results, taking into account pre-analytical variations that may occur during the sampling process•Small sample volume required•Rapid and cost-effective processing of biological samples•Logistic regression based determination of biomarker signatures for in-depth data analysis. PMID: 28275554 [PubMed - in process]

Related Articles A member of the gut mycobiota modulates host purine metabolism exacerbating colitis in mice. Sci Transl Med. 2017 Mar 08;9(380): Authors: Chiaro TR, Soto R, Zac Stephens W, Kubinak JL, Petersen C, Gogokhia L, Bell R, Delgado JC, Cox J, Voth W, Brown J, Stillman DJ, O'Connell RM, Tebo AE, Round JL Abstract The commensal microbiota has an important impact on host health, which is only beginning to be elucidated. Despite the presence of fungal, archaeal, and viral members, most studies have focused solely on the bacterial microbiota. Antibodies against the yeast Saccharomyces cerevisiae are found in some patients with Crohn's disease (CD), suggesting that the mycobiota may contribute to disease severity. We report that S. cerevisiae exacerbated intestinal disease in a mouse model of colitis and increased gut barrier permeability. Transcriptome analysis of colon tissue from germ-free mice inoculated with S. cerevisiae or another fungus, Rhodotorula aurantiaca, revealed that S. cerevisiae colonization affected the intestinal barrier and host metabolism. A fecal metabolomics screen of germ-free animals demonstrated that S. cerevisiae colonization enhanced host purine metabolism, leading to an increase in uric acid production. Treatment with uric acid alone worsened disease and increased gut permeability. Allopurinol, a clinical drug used to reduce uric acid, ameliorated colitis induced by S. cerevisiae in mice. In addition, we found a positive correlation between elevated uric acid and anti-yeast antibodies in human sera. Thus, yeast in the gut may be able to potentiate metabolite production that negatively affects the course of inflammatory bowel disease. PMID: 28275154 [PubMed - in process]

Related Articles Localization and characterization of CYP76AE2 part of thapsigargin biosynthesis in Thapsia garganica. Plant Physiol. 2017 Mar 08;: Authors: Andersen TB, Martinez-Swatson KA, Rasmussen SA, Boughton BA, Jørgensen K, Andersen-Ranberg J, Nyberg N, Christensen SB, Simonsen HT Abstract The Mediterranean plant Thapsia garganica (dicot, Apiaceae), also known as Deadly carrot, produces the highly toxic compound thapsigargin. This compound is a potent inhibitor of the SERCA calcium pump in mammals, and is of industrial importance as the active moiety of the anticancer drug Mipsagargin, currently in clinical trials. Knowledge of thapsigargin in planta storage and biosynthesis has so far been limited. Here we present the putative second step in thapsigargin biosynthesis, by showing that the cytochrome P450 TgCYP76AE2, transiently expressed in Nicotiana benthamiana, converts epikunzeaol into epidihydrocostunolide. Furthermore, we show that thapsigargin is likely to be stored in secretory ducts in the roots. Transcripts from TgTPS2 (epikunzeaol synthase) and TgCYP76AE2 in roots were only found in the epithelial cells lining these secretory ducts. This emphasizes the involvement of these cells in the biosynthesis of thapsigargin. This study paves the way for the further studies of thapsigargin biosynthesis. PMID: 28275147 [PubMed - as supplied by publisher]

Related Articles Integration of Traditional and Metabolomics Biomarkers Identifies Prognostic Metabolites for Predicting Responsiveness to Nutritional Intervention against Oxidative Stress and Inflammation. Nutrients. 2017 Mar 04;9(3): Authors: Kim YJ, Huh I, Kim JY, Park S, Ryu SH, Kim KB, Kim S, Park T, Kwon O Abstract Various statistical approaches can be applied to integrate traditional and omics biomarkers, allowing the discovery of prognostic markers to classify subjects into poor and good prognosis groups in terms of responses to nutritional interventions. Here, we performed a prototype study to identify metabolites that predict responses to an intervention against oxidative stress and inflammation, using a data set from a randomized controlled trial evaluating Korean black raspberry (KBR) in sedentary overweight/obese subjects. First, a linear mixed-effects model analysis with multiple testing correction showed that four-week consumption of KBR significantly changed oxidized glutathione (GSSG, q = 0.027) level, the ratio of reduced glutathione (GSH) to GSSG (q = 0.039) in erythrocytes, malondialdehyde (MDA, q = 0.006) and interleukin-6 (q = 0.006) levels in plasma, and seventeen NMR metabolites in urine compared with those in the placebo group. A subsequent generalized linear mixed model analysis showed linear correlations between baseline urinary glycine and N-phenylacetylglycine (PAG) and changes in the GSH:GSSG ratio (p = 0.008 and 0.004) as well as between baseline urinary adenine and changes in MDA (p = 0.018). Then, receiver operating characteristic analysis revealed that a two-metabolite set (glycine and PAG) had the strongest prognostic relevance for future interventions against oxidative stress (the area under the curve (AUC) = 0.778). Leave-one-out cross-validation confirmed the accuracy of prediction (AUC = 0.683). The current findings suggest that a higher level of this two-metabolite set at baseline is useful for predicting responders to dietary interventions in subjects with oxidative stress and inflammation, contributing to the emergence of personalized nutrition. PMID: 28273855 [PubMed - in process]

Related Articles Comprehensive Metabolomic Analysis in Blood, Urine, Fat, and Muscle in Men with Metabolic Syndrome: A Randomized, Placebo-Controlled Clinical Trial on the Effects of Resveratrol after Four Months' Treatment. Int J Mol Sci. 2017 Mar 04;18(3): Authors: Korsholm AS, Kjær TN, Ornstrup MJ, Pedersen SB Abstract Resveratrol possesses several beneficial metabolic effects in rodents, while the effects of resveratrol in humans remain unclear. Therefore, we performed a non-targeted comprehensive metabolomic analysis on blood, urine, adipose tissue, and skeletal muscle tissue in middle-aged men with metabolic syndrome randomized to either resveratrol or placebo treatment for four months. Changes in steroid hormones across all four matrices were the most pronounced changes observed. Resveratrol treatment reduced sulfated androgen precursors in blood, adipose tissue, and muscle tissue, and increased these metabolites in urine. Furthermore, markers of muscle turnover were increased and lipid metabolism was affected, with increased intracellular glycerol and accumulation of long-chain saturated, monounsaturated, and polyunsaturated (n3 and n6) free fatty acids in resveratrol-treated men. Finally, urinary derivatives of aromatic amino acids, which mainly reflect the composition of the gut microbiota, were altered upon resveratrol treatment. In conclusion, the non-targeted metabolomics approach applied to four different matrices provided evidence of subtle but robust effects on several metabolic pathways following resveratrol treatment for four months in men with metabolic syndrome-effects that, for the most part, would not have been detected by routine analyses. The affected pathways should be the focus of future clinical trials on resveratrol's effects, and perhaps particularly the areas of steroid metabolism and the gut microbiome. PMID: 28273841 [PubMed - in process]

Related Articles Sex-comparative study of mouse cerebellum physiology under adult-onset hypothyroidism: The significance of GC-MS metabolomic data normalization in meta-analysis. J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Jan 15;1041-1042:158-166 Authors: Maga-Nteve C, Vasilopoulou CG, Constantinou C, Margarity M, Klapa MI Abstract A systematic data quality validation and normalization strategy is an important component of the omic profile meta-analysis, ensuring comparability of the profiles and exclusion of experimental biases from the derived biological conclusions. In this study, we present the normalization methodology applied on the sets of cerebellum gas chromatography-mass spectrometry metabolic profiles of 124days old male and female animals in an adult-onset-hypothyroidism (AOH) mouse model before combining them into a sex-comparative analysis. The employed AOH model concerns the monitoring of the brain physiology of Balb/cJ mice after eight-week administration of 1%w/v KClO4 in the drinking water, initiated on the 60th day of their life. While originating from the same animal study, the tissues of the two sexes were processed and their profiles acquired and analyzed at different time periods. Hence, the previously published profile set of male mice was first re-annotated based on the presently available resources. Then, after being validated as acquired under the same analytical conditions, both profiles sets were corrected for derivatization biases and filtered for low-confidence measurements based on the same criteria. The final normalized 73-metabolite profiles contribute to the currently few available omic datasets of the AOH effect on brain molecular physiology, especially with respect to sex differentiation. Multivariate statistical analysis indicated one (unknown) and three (succinate, benzoate, myristate) metabolites with significantly higher and lower, respectively, cerebellum concentration in the hypothyroid compared to the euthyroid female mice. The respective numbers for the males were two and 24. Comparison of the euthyroid cerebellum metabolic profiles between the two sexes indicated 36 metabolites, including glucose, myo- and scyllo-inositol, with significantly lower concentration in the females versus the males. This implies that the female mouse cerebellum has been conditioned to smaller changes in its metabolic activity with respect to the pathways involving these metabolites compared to the male animals. In conclusion, our study indicated a much subtler AOH effect on the cerebellum metabolic activity of the female compared to the male mice. The leaner metabolic profile of the female mouse cerebellum was suggested as a potential factor contributing to this phenomenon. PMID: 28040659 [PubMed - indexed for MEDLINE]

Related Articles Comparisons of parallel potential biomarkers of 1H-MRS-measured hepatic lipid content in patients with non-alcoholic fatty liver disease. Sci Rep. 2016 Apr 15;6:24031 Authors: Shih KL, Su WW, Chang CC, Kor CT, Chou CT, Chen TY, Wu HM Abstract Non-alcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease. This cross-sectional study aimed to evaluate whether parallel clinical features and serum markers are related to the severity of NAFLD. We enrolled 111 participants with different metabolic syndrome (MetS) scores (zero, n = 22; one, n = 19; two, n = 22; and ≥ three, n = 48) and used 1H-MRS to measure liver fat content. Biochemical profiles and potential biomarkers of NAFLD were measured in fasting plasma. We found that 1H-MRS-measured fat content was significantly associated with MetS score ≥1, endotoxin, and hs-CRP. Ordinal logistic regression analysis revealed that MetS score ≥2 and endotoxin were predictive of NAFLD (1H-MRS > 5%) and that endotoxin, hs-CRP, and malondialdehyde (MDA) were predictive of NAFLD with liver injury (1H-MRS > 9.67%). Endotoxin plus MetS score was shown to be the most accurate predictor of overall NAFLD (AUC = 0.854; (95% CI: 0.785-0.924), P < 0.001), and endotoxin plus hs-CRP and MDA was found to be predictive of NAFLD with liver injury (0.868; (0.801-0.936), P < 0.001). These results suggest that MetS score plus certain serum biomarkers with 1H-MRS findings may hold promise for developing an effective model for monitoring the severity of NAFLD. PMID: 27079922 [PubMed - indexed for MEDLINE]