PubMed

Topic model-based mass spectrometric data analysis in cancer biomarker discovery studies. BMC Genomics. 2016;17 Suppl 4:545 Authors: Wang M, Tsai TH, Di Poto C, Ferrarini A, Yu G, Ressom HW Abstract BACKGROUND: A fundamental challenge in quantitation of biomolecules for cancer biomarker discovery is owing to the heterogeneous nature of human biospecimens. Although this issue has been a subject of discussion in cancer genomic studies, it has not yet been rigorously investigated in mass spectrometry based proteomic and metabolomic studies. Purification of mass spectometric data is highly desired prior to subsequent analysis, e.g., quantitative comparison of the abundance of biomolecules in biological samples. METHODS: We investigated topic models to computationally analyze mass spectrometric data considering both integrated peak intensities and scan-level features, i.e., extracted ion chromatograms (EICs). Probabilistic generative models enable flexible representation in data structure and infer sample-specific pure resources. Scan-level modeling helps alleviate information loss during data preprocessing. We evaluated the capability of the proposed models in capturing mixture proportions of contaminants and cancer profiles on LC-MS based serum proteomic and GC-MS based tissue metabolomic datasets acquired from patients with hepatocellular carcinoma (HCC) and liver cirrhosis as well as synthetic data we generated based on the serum proteomic data. RESULTS: The results we obtained by analysis of the synthetic data demonstrated that both intensity-level and scan-level purification models can accurately infer the mixture proportions and the underlying true cancerous sources with small average error ratios (<7 %) between estimation and ground truth. By applying the topic model-based purification to mass spectrometric data, we found more proteins and metabolites with significant changes between HCC cases and cirrhotic controls. Candidate biomarkers selected after purification yielded biologically meaningful pathway analysis results and improved disease discrimination power in terms of the area under ROC curve compared to the results found prior to purification. CONCLUSIONS: We investigated topic model-based inference methods to computationally address the heterogeneity issue in samples analyzed by LC/GC-MS. We observed that incorporation of scan-level features have the potential to lead to more accurate purification results by alleviating the loss in information as a result of integrating peaks. We believe cancer biomarker discovery studies that use mass spectrometric analysis of human biospecimens can greatly benefit from topic model-based purification of the data prior to statistical and pathway analyses. PMID: 27535232 [PubMed - in process]

Related Articles Preface. Adv Clin Chem. 2016;74:xi Authors: Makowski GS PMID: 27117665 [PubMed - indexed for MEDLINE]

Silibinin inhibits hypoxia-induced HIF-1α-mediated signaling, angiogenesis and lipogenesis in prostate cancer cells: In vitro evidence and in vivo functional imaging and metabolomics. Mol Carcinog. 2016 Aug 17; Authors: Deep G, Kumar R, Nambiar DK, Jain AK, Ramteke AM, Serkova NJ, Agarwal C, Agarwal R Abstract Hypoxia is associated with aggressive phenotype and poor prognosis in prostate cancer (PCa) patients suggesting that PCa growth and progression could be controlled via targeting hypoxia-induced signaling and biological effects. Here, we analyzed silibinin (a natural flavonoid) efficacy to target cell growth, angiogenesis and metabolic changes in human PCa, LNCaP and 22Rv1 cells under hypoxic condition. Silibinin treatment inhibited the proliferation, clonogenicity and endothelial cells tube formation by hypoxic (1% O2 ) PCa cells. Interestingly, hypoxia promoted a lipogenic phenotype in PCa cells via activating acetyl-Co A carboxylase (ACC) and fatty acid synthase (FASN) that was inhibited by silibinin treatment. Importantly, silibinin treatment strongly decreased hypoxia-induced HIF-1α expression in PCa cells together with a strong reduction in hypoxia-induced NADPH oxidase (NOX) activity. HIF-1α overexpression in LNCaP cells significantly increased the lipid accumulation and NOX activity; however, silibinin treatment reduced HIF-1α expression, lipid levels, clonogenicity and NOX activity even in HIF-1α overexpressing LNCaP cells. In vivo, silibinin feeding (200 mg/kg body weight) to male nude mice with 22Rv1 tumors, specifically inhibited tumor vascularity (measured by dynamic contrast-enhanced MRI) resulting in tumor growth inhibition without directly inducing necrosis (as revealed by diffusion-weighted MRI). Silibinin feeding did not significantly affect tumor glucose uptake measured by FDG-PET; however, reduced the lipid synthesis measured by quantitative (1) H-NMR metabolomics. IHC analyses of tumor tissues confirmed that silibinin feeding decreased proliferation and angiogenesis as well as reduced HIF-1α, FASN and ACC levels. Together, these findings further support silibinin usefulness against PCa through inhibiting hypoxia-induced signaling. This article is protected by copyright. All rights reserved. PMID: 27533043 [PubMed - as supplied by publisher]

Do linear logistic model analyses of volatile biomarkers in exhaled breath of cystic fibrosis patients reliably indicate Pseudomonas aeruginosa infection? J Breath Res. 2016;10(3):036013 Authors: Španěl P, Sovová K, Dryahina K, Doušová T, Dřevínek P, Smith D Abstract Non-invasive breath analysis has been used to search for volatile biomarkers of lungs and airways infection by Pseudomonas aeruginosa, PA, in cystic fibrosis patients. The exhaled breath of 20 PA-infected patients and 38 PA-negative patients was analysed using selected ion flow tube mass spectrometry, SIFT-MS. Special attention was given to the positive identification and accurate quantification of 16 volatile compounds (VOCs) as assured by the detailed consideration of their analytical ion chemistry occurring in the SIFT-MS reactor. However, the diagnostic sensitivity and specificity of the concentrations of any of the 16 compounds taken individually were found to be low. But when a linear combination of the concentrations of all 16 VOCs was used to construct an optimised receiver operating characteristics (ROC) curve using a linear logistic model, the diagnostic separation of PA-infected patients relative to the PA-negative patients was apparently good in terms of the derived sensitivity (89%), specificity (86%), and the area under the ROC curve is 0.91. Four compounds were revealed by the linear logistic model as significant, viz. malondialdehyde, isoprene, phenol and acetoin. The implications of these results to PA detection in the airways are assessed. Whilst such a metabolomics approach to optimise the ROC curve is widely used in breath analysis, it can lead to misleading indications. Therefore, we conclude that the results of the linear logistic model analyses are of limited immediate clinical value. The identified compounds should rather be considered as a stimulus for further independent studies involving larger patient cohorts. PMID: 27532768 [PubMed - as supplied by publisher]

Autophagy induction for the treatment of cancer. Autophagy. 2016 Aug 17;:0 Authors: Pietrocola F, Pol J, Vacchelli E, Baracco EE, Levesque S, Castoldi F, Chiara Maiuri M, Madeo F, Kroemer G Abstract Cancer can be viewed in 2 rather distinct ways, namely (i) as a cell-autonomous disease in which malignant cells have escaped control from cell-intrinsic barriers against proliferation and dissemination or (ii) as a systemic disease that involves failing immune control of aberrant cells. Since macroautophagy/autophagy generally increases the fitness of cells as well as their resistance against endogenous or iatrogenic (i.e., relating to illness due to medical intervention) stress, it has been widely proposed that inhibition of autophagy would constitute a valid strategy for sensitizing cancer cells to chemotherapy or radiotherapy. Colliding with this cell-autonomous vision, however, we found that immunosurveillance against transplantable, carcinogen-induced or genetically engineered cancers can be improved by pharmacologically inducing autophagy with caloric restriction mimetics. This positive effect depends on autophagy induction in cancer cells and is mediated by alterations in extracellular ATP metabolism, namely increased release of immunostimulatory ATP and reduced adenosine-dependent recruitment of immunosuppressive regulatory T cells into the tumor bed. The combination of autophagy inducers and chemotherapeutic agents is particularly efficient in reducing cancer growth through the stimulation of CD8(+) T lymphocyte-dependent anticancer immune responses. PMID: 27532519 [PubMed - as supplied by publisher]

A high dose of isoniazid disturbs endobiotic homeostasis in mouse liver. Drug Metab Dispos. 2016 Aug 16; Authors: Li F, Wang P, Liu K, Tarrago MG, Lu J, Chini EN, Ma X Abstract Overdose of isoniazid (INH), an anti-tuberculosis drug, can be life-threatening because of neurotoxicity. In clinical practice for management of INH overdose and acute toxicity, the potential of INH-induced hepatotoxicity is also considered. However, the biochemical basis of acute INH toxicity in the liver remains elusive. In the current study, we used an untargeted metabolomic approach to explore the acute effects of INH on endobiotic homeostasis in mouse liver. We found that overdose of INH resulted in accumulation of oleoyl-L-carnitine and linoleoyl-L-carnitinein the liver, indicating mitochondrial dysfunction. We also revealed the interactions between INH and fatty acyl-CoAs by identifying INH-fatty acid amides. In addition, we found that overdose of INH led to the accumulation of heme and oxidized nicotinamide adenine dinucleotide (NAD) in the liver. We also identified an INH and NAD adduct in the liver. In this adduct, the nicotinamide moiety in NAD was replaced by INH. Furthermore, we illustrated that overdose of INH depleted vitamin B6 in the liver and blocked vitamin B6-dependent cystathionine degradation. These data suggest that INH interacts with multiple biochemical pathways in the liver during acute poisoning caused by INH overdose. PMID: 27531952 [PubMed - as supplied by publisher]

Short-term beef consumption promotes systemic oxidative stress, TMAO formation and inflammation in rats, and dietary fat content modulates these effects. Food Funct. 2016 Aug 17; Authors: Van Hecke T, Jakobsen LM, Vossen E, Guéraud F, De Vos F, Pierre F, Bertram HC, De Smet S Abstract A high consumption of red and/or processed meat is associated with a higher risk to develop several chronic diseases in which oxidative stress, trimethylamine-N-oxide (TMAO) and/or inflammation are involved. We aimed to elucidate the effect of white (chicken) vs. red (beef) meat consumption in a low vs. high dietary fat context (2 × 2 factorial design) on oxidative stress, TMAO and inflammation in Sprague-Dawley rats. Higher malondialdehyde (MDA) concentrations were found in gastrointestinal contents (up to 96% higher) and colonic tissues (+8.8%) of rats fed the beef diets (all P < 0.05). The lean beef diet resulted in lower blood glutathione, higher urinary excretion of the major 4-hydroxy-nonenal metabolite, and higher plasma C-reactive protein, compared to the other dietary treatments (all P < 0.05). Rats on the fat beef diet had higher renal MDA (+24.4% compared to all other diets) and heart MDA (+12.9% compared to lean chicken) and lower liver vitamin E (-26.2% compared to lean chicken) (all P < 0.05). Rats on the fat diets had lower plasma vitamin E (-23.8%), lower brain MDA (-6.8%) and higher plasma superoxide dismutase activity (+38.6%), higher blood glutathione (+16.9%) (all P < 0.05) and tendency to higher ventral prostate MDA (+14.5%, P = 0.078) and prostate weight (+18.9%, P = 0.073), compared to rats on the lean diets. Consumption of the beef diets resulted in higher urinary trimethylamine (4.5-fold) and TMAO (3.7-fold) concentrations (P < 0.001), compared to the chicken diets. In conclusion, consumption of a high beef diet may stimulate gastrointestinal and/or systemic oxidative stress, TMAO formation and inflammation, depending on the dietary fat content and composition. PMID: 27531020 [PubMed - as supplied by publisher]

GC-TOF/MS-based metabolomic strategy for combined toxicity effects of deoxynivalenol and zearalenone on murine macrophage ANA-1 cells. Toxicon. 2016 Aug 13; Authors: Ji J, Pi F, Zhang S, Sun C, Sun J, Wang X, Zhang Y, Sun X Abstract The actual health risk from exposure to combined mycotoxins is unknown, and few studies have focused on changes to cellular biological systems (e.g., metabolomics) caused by combined mycotoxic effects. To evaluate the combined mycotoxic effects of deoxynivalenol (DON) and zearalenone (ZEN) on the level of cellular biological systems, gas chromatographic, time-of-flight mass spectroscopy (GC-TOF/MS) of the complete murine macrophage ANA-1 cell metabolome was implemented in this study. Using optimized chromatography and mass spectrometry parameters, the metabolites detected by GC-TOF/MS were identified and processed using multivariate statistical analysis, including principal component analysis (PCA) and orthogonal projection on latent-structures discriminant analysis (OPLS-DA). The metabolite sets were screened for further pathway analysis under rules of t-test (P) value < 0.05, VIP value > 1, and similarity value > 500. The mainly interfered metabolism pathways were categorized into two dominant types: amino acid metabolism and glycometabolism. Four metabolites, palmitic acid, 1-monopalmitin, ribose-5-phosphate and 2-deoxy-D-galactose, occur only under combined "DON + ZEN" treatment, indicating abnormal metabolism in ANA-1 cells. The metabolic state of ANA-1 cells under induction by combined "DON + ZEN" illustrates that DON may inhibit the estrogenic effects of ZEN. Thus, the combined effect of "DON + ZEN" may exacerbate toxicity in the pentose phosphate pathway, while palmitic acid metabolism is likely a new pathway effected by the combination, "DON + ZEN." PMID: 27530666 [PubMed - as supplied by publisher]

The importance of relative humidity and trophic resources in governing ecological niche of the invasive carabid beetle Merizodus soledadinus in the Kerguelen archipelago. J Insect Physiol. 2016 Aug 13; Authors: Ouisse T, Bonte D, Lebouvier M, Hendrickx F, Renault D Abstract Comprehensive studies to identify species-specific drivers of survival to environmental stress, reproduction, growth, and recruitment are vital to gaining a better understanding of the main ecological factors shaping species habitat distribution and dispersal routes. The present study performed a field-based assessment of habitat distribution in the invasive carabid beetle Merizodus soledadinus for the Kerguelen archipelago. The results emphasised humid habitats as a key element of the insect's realised niche. In addition, insects faced food and water stress during dispersal events. We evaluated quantitatively how water availability and trophic resources governed the spatial distribution of this invasive predatory insect at Îles Kerguelen. Food and water stress survival durations [in 100%, 70%, and 30% relative humidity (RH) conditions] and changes in a set of primary metabolic compounds (metabolomics) were determined. Adult M. soledadinus supplied with water ad libitum were highly tolerant to prolonged starvation (LT50 = 51.7 ± 6.2 d). However, food-deprived insect survival decreased rapidly in moderate (70% RH, LT50 = 30.37 ± 1.39 h) and low (30% RH, LT50 = 13.03 ± 0.48 h) RH conditions. Consistently, body water content decreased rapidly in insects exposed to 70% and 30% RH. Metabolic variation evidenced the effects of food deprivation in control insects (exposed to 100% RH), which exhibited a progressive decline of most glycolytic sugars and tricarboxylic acid cycle intermediates. Most metabolite levels were elevated levels during the first few hours of exposure to 30% and 70% RH. Augmented alanine and lactate levels suggested a shift to anaerobic metabolism. Simultaneously, peaks in threonine and glycolytic sugars pointed to metabolic disruption and a progressive physiological breakdown in dehydrating individuals. Overall, the results of our study indicate that the geographic distribution of M. soledadinus populations is highly dependent on habitat RH and water accessibility. PMID: 27530305 [PubMed - as supplied by publisher]

Inflammation in adult women with a history of child maltreatment: The involvement of mitochondrial alterations and oxidative stress. Mitochondrion. 2016 Aug 13; Authors: Boeck C, Koenig AM, Schury K, Geiger ML, Karabatsiakis A, Wilker S, Waller C, Gündel H, Fegert JM, Calzia E, Kolassa IT Abstract The experience of maltreatment during childhood is associated with chronic low-grade inflammation in adulthood. However, the molecular mechanisms underlying this pro-inflammatory phenotype remain unclear. Mitochondria were recently found to principally coordinate inflammatory processes via both inflammasome activation and inflammasome-independent pathways. To this end, we hypothesized that alterations in immune cell mitochondrial functioning and oxidative stress might be at the interface between the association of maltreatment experiences during childhood and inflammation. We analyzed pro-inflammatory biomarkers (levels of C-reactive protein, cytokine secretion by peripheral blood mononuclear cells (PBMC) in vitro, PBMC composition, lysophosphatidylcholine levels), serum oxidative stress levels (arginine:citrulline ratio, l-carnitine and acetylcarnitine levels) and mitochondrial functioning (respiratory activity and density of mitochondria in PBMC) in peripheral blood samples collected from 30 women (aged 22-44years) with varying degrees of maltreatment experiences in form of abuse and neglect during childhood. Exposure to maltreatment during childhood was associated with an increased ROS production, higher levels of oxidative stress and an increased mitochondrial activity in a dose-response relationship. Moreover, the increase in mitochondrial activity and ROS production were positively associated with the release of pro-inflammatory cytokines by PBMC. Decreased serum levels of lysophosphatidylcholines suggested higher inflammasome activation with increasing severity of child maltreatment experiences. Together these findings offer preliminary evidence for the association of alterations in immune cell mitochondrial functioning, oxidative stress and the pro-inflammatory phenotype observed in individuals with a history of maltreatment during childhood. The results emphasize that the early prevention of child abuse and neglect warrants more attention, as the experience of maltreatment during childhood might have life-long consequences for physical health. PMID: 27530300 [PubMed - as supplied by publisher]

Related Articles Simultaneous quantification of cardiovascular disease related metabolic risk factors using liquid chromatography tandem mass spectrometry in human serum. J Chromatogr B Analyt Technol Biomed Life Sci. 2016 Jan 15;1009-1010:144-51 Authors: Wang M, Yang R, Dong J, Zhang T, Wang S, Zhou W, Li H, Zhao H, Zhang L, Wang S, Zhang C, Chen W Abstract Recent observations from metabonomic studies have consistently found that branched-chain amino acids (BCAAs), aromatic amino acids (AAAs), glutamine (Gln), glutamic acid (Glu), Gln/Glu ratio, carnitine, and several species of acylcarnitines and lysophosphatidylcholines (LPCs) are possible risk factors for metabolic diseases such as diabetes mellitus (DM) and cardiovascular diseases (CVD). We described here a simple and reliable method for simultaneous quantification of these metabolic risk factors by liquid chromatography tandem mass spectrometry (LC-MS/MS). Serum samples were extracted with isopropanol, and the extracted metabolites were separated by hydrophilic interaction liquid chromatography (HILIC) and detected with electrospary ionization (ESI) inpositive ion mode with multiple reaction monitor (MRM) mode. All the metabolites were effectively separated within 5.5min. Analytical recoveries were in the range of 92.8-106.9%, with an average of 100.6%. The intra- run and total imprecisions for the measurement of these metabolites were 1.2-3.8% and 1.5-7.4%, respectively. Serum concentrations of the metabolites were analyzed in 123 apparently healthy volunteers. Significant associations between the metabolites and traditional CVD risk factors were observed. The newly developed LC-MS/MS method was simple, precise, and accurate and can be used as an efficient tool in CVD research and studies. PMID: 26735710 [PubMed - indexed for MEDLINE]

Related Articles Metabonomic study of the effects of different acupuncture directions on therapeutic efficacy. J Chromatogr B Analyt Technol Biomed Life Sci. 2016 Jan 15;1009-1010:87-95 Authors: Ju L, Wen Y, Yin J, Deng S, Zheng J, Wang L, Deng H, Hou Z, Zhao X, He S, Huang L, Zhang C, Tian G, Meng Z, Li Y Abstract Posterior circulation ischemia (PCI) is a common clinical ischemic cerebrovascular disease that can endanger the lives of patients in severe cases. Our previous research found that needling the Fengchi (GB20) acupoint presents a significant effect on PCI and that different acupuncture directions can exert different effects. To investigate the biological mechanism of acupuncture directions, rapid resolution liquid chromatography coupled with quadrupole time-of-flight mass spectrometry-based metabonomic techniques are used to analyze the metabolic profiles of urine samples. The urine samples were obtained from 30 healthy control subjects, 60 PCI patients before and after treatment of different acupuncture directions. Six metabolites, including LPE (22:6), estrone, uric acid, vanillylmandelic acid, N-acetyl-l-tyrosine, and 4-hydroxyphenylacetylglutamine were identified as potential biomarkers of acupuncture treatment of PCI. Acupuncture treatment of PCI patients significantly changed the levels of these potential biomarkers. Moreover, different acupuncture directions showed different effects on the contents of these biomarkers. These results strongly support the belief that acupuncture direction performs an important function in acupuncture intervention. The findings provide new insights into the mechanism of acupuncture treatment and reveal that acupuncture manipulation results in various curative. PMID: 26708629 [PubMed - indexed for MEDLINE]

Related Articles Diurnal rhythms in the human urine metabolome during sleep and total sleep deprivation. Sci Rep. 2015;5:14843 Authors: Giskeødegård GF, Davies SK, Revell VL, Keun H, Skene DJ Abstract Understanding how metabolite levels change over the 24 hour day is of crucial importance for clinical and epidemiological studies. Additionally, the association between sleep deprivation and metabolic disorders such as diabetes and obesity requires investigation into the links between sleep and metabolism. Here, we characterise time-of-day variation and the effects of sleep deprivation on urinary metabolite profiles. Healthy male participants (n = 15) completed an in-laboratory study comprising one 24 h sleep/wake cycle prior to 24 h of continual wakefulness under highly controlled environmental conditions. Urine samples were collected over set 2-8 h intervals and analysed by (1)H NMR spectroscopy. Significant changes were observed with respect to both time of day and sleep deprivation. Of 32 identified metabolites, 7 (22%) exhibited cosine rhythmicity over at least one 24 h period; 5 exhibiting a cosine rhythm on both days. Eight metabolites significantly increased during sleep deprivation compared with sleep (taurine, formate, citrate, 3-indoxyl sulfate, carnitine, 3-hydroxyisobutyrate, TMAO and acetate) and 8 significantly decreased (dimethylamine, 4-DTA, creatinine, ascorbate, 2-hydroxyisobutyrate, allantoin, 4-DEA, 4-hydroxyphenylacetate). These data indicate that sampling time, the presence or absence of sleep and the response to sleep deprivation are highly relevant when identifying biomarkers in urinary metabolic profiling studies. PMID: 26450397 [PubMed - indexed for MEDLINE]

Hypertonic saline primes activation of the p53/p21 signaling axis in Human Small Airway Epithelial Cells that prevents inflammation induced by pro-inflammatory cytokines. J Proteome Res. 2016 Aug 16; Authors: Gamboni F, Anderson C, Sanchayita M, Haines J, Nemkov T, Dzieciatkowska M, Jones KL, Hansen KC, D'Alessandro A, Banerjee A Abstract Uncontrolled inflammatory responses underlie the etiology of acute lung injury and acute distress respiratory syndrome, the most common late complications in trauma, the leading cause of death under the age of 59. Treatment with HTS decreases lung injury in clinical trials, rat models of trauma/hemorrhagic shock and inflammation in lung cell lines, though the mechanisms underlying these responses are still incompletely understood. Transcriptomics (RNAseq), proteomics, and U-13C-glucose tracing metabolomics experiments were performed to investigate the mechanisms of cellular responses to HTS treatment in primary Small Airway Epithelial Cells, in presence or absence of inflammatory injury mediated by a cocktail of cytokines (10 ng/ml of IFNγ, IL-1β and TNFα). Modestly hyperosmolar HTS has an anti-inflammatory effect, triggers the p53/p21 signaling axis, deregulates mitochondrial metabolism while inducing minimal apoptosis in response to a second hit by cytokines. Decreased transcription of pro-inflammatory cytokines suggested a role for the tumor suppressor protein p53 in mediating the beneficial effects of the HTS treatment. The anti-inflammatory mechanisms induced by HTS involves p53 gene regulation, promotes cell cycle arrest, prevents ROS formation and mitochondria depolarization. Pharmaceutical targeting of the p53/p21 axis may mimic or reinforce the beneficial effects mediated by HTS when sustained hypertonicity cannot be maintained. PMID: 27529569 [PubMed - as supplied by publisher]

The Role of Plasma and Urine Metabolomics in Identifying New Biomarkers in Severe Newborn Asphyxia: A Study of Asphyxiated Newborn Pigs following Cardiopulmonary Resuscitation. PLoS One. 2016;11(8):e0161123 Authors: Sachse D, Solevåg AL, Berg JP, Nakstad B Abstract BACKGROUND: Optimizing resuscitation is important to prevent morbidity and mortality from perinatal asphyxia. The metabolism of cells and tissues is severely disturbed during asphyxia and resuscitation, and metabolomic analyses provide a snapshot of many small molecular weight metabolites in body fluids or tissues. In this study metabolomics profiles were studied in newborn pigs that were asphyxiated and resuscitated using different protocols to identify biomarkers for subject characterization, intervention effects and possibly prognosis. METHODS: A total of 125 newborn Noroc pigs were anesthetized, mechanically ventilated and inflicted progressive asphyxia until asystole. Pigs were randomized to resuscitation with a FiO2 0.21 or 1.0, different duration of ventilation before initiation of chest compressions (CC), and different CC to ventilation ratios. Plasma and urine samples were obtained at baseline, and 2 h and 4 h after return of spontaneous circulation (ROSC, heart rate > = 100 bpm). Metabolomics profiles of the samples were analyzed by nuclear magnetic resonance spectroscopy. RESULTS: Plasma and urine showed severe metabolic alterations consistent with hypoxia and acidosis 2 h and 4 h after ROSC. Baseline plasma hypoxanthine and lipoprotein concentrations were inversely correlated to the duration of hypoxia sustained before asystole occurred, but there was no evidence for a differential metabolic response to the different resuscitation protocols or in terms of survival. CONCLUSIONS: Metabolic profiles of asphyxiated newborn pigs showed severe metabolic alterations. Consistent with previously published reports, we found no evidence of differences between established and alternative resuscitation protocols. Lactate and pyruvate may have a prognostic value, but have to be independently confirmed. PMID: 27529347 [PubMed - as supplied by publisher]

Serum metabolic changes in rats after intragastric administration of dextromethorphan. Biomed Chromatogr. 2016 Aug 15; Authors: Bao S, Zhang J, Lin Z, Su K, Mo J, Hong L, Qian S, Chen L, Sun F, Wen C, Wu Q, Hu L, Lin G, Wang X Abstract Dextromethorphan is recognized as a substance of abuse around the world. An estimated 3.1 million people between the ages of 12 to 25 years (5.3%) misused over-the-counter cough and cold medications in 2006. In this study, we developed a serum metabolomic method by gas chromatography-mass spectrometry (GC-MS) to evaluate the effect of abuse of dextromethorphan on rats. The dextromethorphan treated group rats were given 12, 24 and 48 mg/kg (Low, Medium, High) of dextromethorphan by intragastric administration each day for 3 days. Partial least squares-discriminate analysis (PLS-DA) revealed that intragastric administration of dextromethorphan induced metabolic perturbations. Compared to the control (healthy) group, the level of propanoic acid, urea, heptafluorobutanoic acid, 2-hexyldecanoic acid, butanedioic acid of Low group decreased; propanoic acid, heptafluorobutanoic acid of Medium group decreased, while benzoic acid increased; 2-hexyldecanoic acid, glycerol, butanedioic acid of High group increased. These biomarkers are involved in Citric acid cycle, Urea cycle, Glycerolipid metabolism and Tricarboxylic acid (TCA) cycle. The results indicate that metabolomic method by GC-MS may be useful to elucidate abuse of dextromethorphan. According to the pathological changes of liver at difference dosage, dextromethorphan is not hepatotoxic after intragastric administration of 12, 24 and 48 mg/kg for 3 days. PMID: 27528536 [PubMed - as supplied by publisher]

Early/late-life adversities and behavioural phenotypes: insight into metabolomics, genomics and connectomics. J Intellect Disabil Res. 2016 Sep;60(9):833-4 Authors: Federico A, Verri A, de Vries PJ PMID: 27528383 [PubMed - in process]

Metabolomic analysis reveals altered metabolic pathways in a rat model of gastric carcinogenesis. Oncotarget. 2016 Aug 4; Authors: Gu J, Hu X, Shao W, Ji T, Yang W, Zhuo H, Jin Z, Huang H, Chen J, Huang C, Lin D Abstract Gastric cancer (GC) is one of the most malignant tumors with a poor prognosis. Alterations in metabolic pathways are inextricably linked to GC progression. However, the underlying molecular mechanisms remain elusive. We performed NMR-based metabolomic analysis of sera derived from a rat model of gastric carcinogenesis, revealed significantly altered metabolic pathways correlated with the progression of gastric carcinogenesis. Rats were histologically classified into four pathological groups (gastritis, GS; low-grade gastric dysplasia, LGD; high-grade gastric dysplasia, HGD; GC) and the normal control group (CON). The metabolic profiles of the five groups were clearly distinguished from each other. Furthermore, significant inter-metabolite correlations were extracted and used to reconstruct perturbed metabolic networks associated with the four pathological stages compared with the normal stage. Then, significantly altered metabolic pathways were identified by pathway analysis. Our results showed that oxidative stress-related metabolic pathways, choline phosphorylation and fatty acid degradation were continually disturbed during gastric carcinogenesis. Moreover, amino acid metabolism was perturbed dramatically in gastric dysplasia and GC. The GC stage showed more changed metabolite levels and more altered metabolic pathways. Two activated pathways (glycolysis; glycine, serine and threonine metabolism) substantially contributed to the metabolic alterations in GC. These results lay the basis for addressing the molecular mechanisms underlying gastric carcinogenesis and extend our understanding of GC progression. PMID: 27527852 [PubMed - as supplied by publisher]

Experimental infection of small ruminants with bluetongue virus expressing Toggenburg Orbivirus proteins. Vet Microbiol. 2016 Aug 30;192:145-51 Authors: van Rijn PA, van de Water SG, Maris-Veldhuis MA, van Gennip RG Abstract Bluetongue virus (BTV) is the prototype orbivirus (Reoviridae family, genus Orbivirus) consisting of more than 24 recognized serotypes or neutralization groups. Recently, new BTV serotypes in goats have been found; serotype 25 (Toggenburg Orbivirusor TOV), serotype 26 (KUW2010/02), and serotype 27 from Corsica, France. KUW2010/02 has been isolated in mammalian cells but is not replicating in Culicoides cells. TOVhas been detected in goats but could not been cultured, although TOV has been successfully passed to naïve animals by experimental infection using viremic blood. Genome segments Seg-2[VP2], Seg-6[VP5], Seg-7[VP7], and Seg-10[NS3/NS3a] expressing the respective TOV proteins were incorporated in BTV using reverse genetics, demonstrating that these TOV proteins are functional in BTV replication. Depending on the incorporated TOV proteins, in vitro replication is, however, decreased compared to the ancestor BTV, in particular by TOV-VP5. Sheep and goats were experimentally infected with BTV expressing both outer capsid proteins VP2 and VP5 of TOV, so-named 'TOV-serotyped BTV'. Viremia was not detected in sheep, and hardly detected in goats after infection with TOV-serotyped BTV. Seroconversion by cELISA, however, was detected, suggesting that TOV-serotyped BTV replicates in small ruminants. One goat was coincidentally pregnant, and the fetus was strong PCR-positive in blood samples and several organs, which conclusively demonstrates that TOV-serotyped BTV replicates in vivo. PMID: 27527776 [PubMed - in process]

Clinical and Metabolic Characterization of Lean Caucasian Subjects With Non-alcoholic Fatty Liver. Am J Gastroenterol. 2016 Aug 16; Authors: Feldman A, Eder SK, Felder TK, Kedenko L, Paulweber B, Stadlmayr A, Huber-Schönauer U, Niederseer D, Stickel F, Auer S, Haschke-Becher E, Patsch W, Datz C, Aigner E Abstract OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is closely linked to obesity; however, 5-8% of lean subjects also have evidence of NAFLD. We aimed to investigate clinical, genetic, metabolic and lifestyle characteristics in lean Caucasian subjects with NAFLD. METHODS: Data from 187 subjects allocated to one of the three groups according to body mass index (BMI) and hepatic steatosis on ultrasound were obtained: lean healthy (BMI≤25 kg/m(2), no steatosis, N=71), lean NAFLD (BMI≤25 kg/m(2), steatosis, N=55), obese NAFLD (BMI≥30 kg/m(2), steatosis; N=61). All subjects received a detailed clinical and laboratory examination including oral glucose tolerance test. The serum metabolome was assessed using the Metabolomics AbsoluteIDQ p180 kit (BIOCRATES Life Sciences). Genotyping for single-nucleotide polymorphisms (SNPs) associated with NAFLD was performed. RESULTS: Lean NAFLD subjects had fasting insulin concentrations similar to lean healthy subjects but had markedly impaired glucose tolerance. Lean NAFLD subjects had a higher rate of the mutant PNPLA3 CG/GG variant compared to lean controls (P=0.007). Serum adiponectin concentrations were decreased in both NAFLD groups compared to controls (P<0.001 for both groups) The metabolomics study revealed a potential role for various lysophosphatidylcholines (lyso-PC C18:0, lyso-PC C17:0) and phosphatidylcholines (PCaa C36:3; false discovery rate (FDR)-corrected P-value<0.001) as well as lysine, tyrosine, and valine (FDR<0.001). CONCLUSIONS: Lean subjects with evidence of NAFLD have clinically relevant impaired glucose tolerance, low adiponectin concentrations and a distinct metabolite profile with an increased rate of PNPLA3 risk allele carriage.Am J Gastroenterol advance online publication, 16 August 2016; doi:10.1038/ajg.2016.318. PMID: 27527746 [PubMed - as supplied by publisher]