PubMed

Host metabolic responses to Plasmodium falciparum infections evaluated by (1)H NMR metabolomics. Mol Biosyst. 2016 Aug 22; Authors: Sengupta A, Ghosh S, Das BK, Panda A, Tripathy R, Pied S, Ravindran B, Pathak S, Sharma S, Sonawat HM Abstract The human malarial parasite Plasmodium falciparum causes the most severe forms of malarial infections, which include cerebral malaria and various organ dysfunctions amongst adults in India. So far no dependable clinical descriptor is available that can distinguish cerebral malaria from other symptomatically similar diseases such as sepsis and encephalitis. This study aims at evaluating the differential metabolic features of plasma samples from P. falciparum patients with varying severities, and patients suffering from symptomatically similar diseases. (1)H Nuclear Magnetic Resonance (NMR) based metabolic profiling of the plasma of the infected individuals and the control population was performed. The differences in the plasma profiles were evaluated through multivariate statistical analyses. The results suggest malaria-specific elevation of plasma lipoproteins. Such an increase was absent in control populations. In addition, cerebral malaria patients exhibited a decrease in plasma glycoproteins; such a reduction was not observed in malarial patients without cerebral symptoms. The data presented here indicates that the metabolism and/or transport of the plasma lipids is specifically perturbed by malarial infections. The differential perturbation of the plasma glycoprotein levels in cerebral malaria patients may have important implications in the diagnosis of cerebral malaria. PMID: 27546486 [PubMed - as supplied by publisher]

The Pentose Phosphate Pathway Regulates the Circadian Clock. Cell Metab. 2016 Aug 17; Authors: Rey G, Valekunja UK, Feeney KA, Wulund L, Milev NB, Stangherlin A, Ansel-Bollepalli L, Velagapudi V, O'Neill JS, Reddy AB Abstract The circadian clock is a ubiquitous timekeeping system that organizes the behavior and physiology of organisms over the day and night. Current models rely on transcriptional networks that coordinate circadian gene expression of thousands of transcripts. However, recent studies have uncovered phylogenetically conserved redox rhythms that can occur independently of transcriptional cycles. Here we identify the pentose phosphate pathway (PPP), a critical source of the redox cofactor NADPH, as an important regulator of redox and transcriptional oscillations. Our results show that genetic and pharmacological inhibition of the PPP prolongs the period of circadian rhythms in human cells, mouse tissues, and fruit flies. These metabolic manipulations also cause a remodeling of circadian gene expression programs that involves the circadian transcription factors BMAL1 and CLOCK, and the redox-sensitive transcription factor NRF2. Thus, the PPP regulates circadian rhythms via NADPH metabolism, suggesting a pivotal role for NADPH availability in circadian timekeeping. PMID: 27546460 [PubMed - as supplied by publisher]

Quantitative phosphoproteomics reveals the role of the AMPK plant ortholog SnRK1 as a metabolic master regulator under energy deprivation. Sci Rep. 2016;6:31697 Authors: Nukarinen E, Nägele T, Pedrotti L, Wurzinger B, Mair A, Landgraf R, Börnke F, Hanson J, Teige M, Baena-Gonzalez E, Dröge-Laser W, Weckwerth W Abstract Since years, research on SnRK1, the major cellular energy sensor in plants, has tried to define its role in energy signalling. However, these attempts were notoriously hampered by the lethality of a complete knockout of SnRK1. Therefore, we generated an inducible amiRNA::SnRK1α2 in a snrk1α1 knock out background (snrk1α1/α2) to abolish SnRK1 activity to understand major systemic functions of SnRK1 signalling under energy deprivation triggered by extended night treatment. We analysed the in vivo phosphoproteome, proteome and metabolome and found that activation of SnRK1 is essential for repression of high energy demanding cell processes such as protein synthesis. The most abundant effect was the constitutively high phosphorylation of ribosomal protein S6 (RPS6) in the snrk1α1/α2 mutant. RPS6 is a major target of TOR signalling and its phosphorylation correlates with translation. Further evidence for an antagonistic SnRK1 and TOR crosstalk comparable to the animal system was demonstrated by the in vivo interaction of SnRK1α1 and RAPTOR1B in the cytosol and by phosphorylation of RAPTOR1B by SnRK1α1 in kinase assays. Moreover, changed levels of phosphorylation states of several chloroplastic proteins in the snrk1α1/α2 mutant indicated an unexpected link to regulation of photosynthesis, the main energy source in plants. PMID: 27545962 [PubMed - in process]

PML at Mitochondria-Associated Membranes Is Critical for the Repression of Autophagy and Cancer Development. Cell Rep. 2016 Aug 18; Authors: Missiroli S, Bonora M, Patergnani S, Poletti F, Perrone M, Gafà R, Magri E, Raimondi A, Lanza G, Tacchetti C, Kroemer G, Pandolfi PP, Pinton P, Giorgi C Abstract The precise molecular mechanisms that coordinate apoptosis and autophagy in cancer remain to be determined. Here, we provide evidence that the tumor suppressor promyelocytic leukemia protein (PML) controls autophagosome formation at mitochondria-associated membranes (MAMs) and, thus, autophagy induction. Our in vitro and in vivo results demonstrate how PML functions as a repressor of autophagy. PML loss promotes tumor development, providing a growth advantage to tumor cells that use autophagy as a cell survival strategy during stress conditions. These findings demonstrate that autophagy inhibition could be paired with a chemotherapeutic agent to develop anticancer strategies for tumors that present PML downregulation. PMID: 27545895 [PubMed - as supplied by publisher]

Fructose during pregnancy provokes fetal oxidative stress: The key role of the placental heme oxygenase-1. Mol Nutr Food Res. 2016 Aug 22; Authors: Rodrigo S, Rodríguez L, Otero P, Panadero MI, García A, Barbas C, Roglans N, Ramos S, Goya L, Laguna JC, Álvarez-Millán JJ, Bocos C Abstract SCOPE: One of the features of metabolic syndrome caused by liquid fructose intake is an impairment of redox status. We have investigated whether maternal fructose ingestion modifies the redox status in pregnant rats and their fetuses. METHODS AND RESULTS: Fructose (10% wt/vol) in the drinking water of rats throughout gestation, leads to maternal hepatic oxidative stress. However, this change was also observed in glucose-fed rats and, in fact, both carbohydrates produced a decrease in antioxidant enzyme activity. Surprisingly, mothers fed carbohydrates displayed low plasma lipid oxidation. In contrast, fetuses from fructose-fed mothers showed elevated levels of plasma lipoperoxides versus fetuses from control or glucose-fed mothers. Interestingly, a clearly augmented oxidative stress was observed in placenta of fructose-fed mothers, accompanied by a lower expression of the transcription factor Nuclear factor-erythroid 2-related factor-2 (Nrf2) and its target gene, heme oxygenase-1 (HO-1), a potent antioxidant molecule. Moreover, histone deacetylase 3 (HDAC3) which has been proposed to upregulate HO-1 expression by stabilizing Nrf2, exhibited a diminished expression in placenta of fructose-supplemented mothers. CONCLUSIONS: Maternal fructose intake provoked an imbalanced redox status in placenta and a clear diminution of HO-1 expression, which could be responsible for the augmented oxidative stress found in their fetuses. This article is protected by copyright. All rights reserved. PMID: 27545118 [PubMed - as supplied by publisher]

Integrated application of transcriptomics and metabolomics yields insights into population-asynchronous ovary development in Coilia nasus. Sci Rep. 2016;6:31835 Authors: Xu G, Du F, Li Y, Nie Z, Xu P Abstract Populations of Coilia nasus demonstrate asynchronous ovarian development, which severely restricts artificial breeding and large-scale cultivation. In this study, we used a combination of transcriptomic and metabolomic methods to identify the key signaling pathways and genes regulation affecting ovarian development. We identified 565 compounds and generated 47,049 unigenes from ovary tissue. Fifteen metabolites and 830 genes were significantly up-regulated, while 27 metabolites and 642 genes were significantly down-regulated from stage III to stage IV of ovary development. Meanwhile, 31 metabolites and 1,932 genes were significantly up-regulated, and four metabolites and 764 genes were down-regulated from stage IV to stage V. These differentially expressed genes and metabolites were enriched by MetScape. Forty-three and 50 signaling pathways had important functions from stage III-IV and from stage IV-V in the ovary, respectively. Among the above signaling pathways, 39 played important roles from ovarian stage III-V, including "squalene and cholesterol biosynthesis", "steroid hormone biosynthesis", and "arachidonate metabolism and prostaglandin formation" pathways which may thus have key roles in regulating asynchronous development. These results shed new light on our understanding of the mechanisms responsible for population-asynchronous development in fish. PMID: 27545088 [PubMed - in process]

Related Articles S-Nitrosylation of Sarcomeric Proteins Depresses Myofilament Ca2+)Sensitivity in Intact Cardiomyocytes. Antioxid Redox Signal. 2015 Nov 1;23(13):1017-34 Authors: Figueiredo-Freitas C, Dulce RA, Foster MW, Liang J, Yamashita AM, Lima-Rosa FL, Thompson JW, Moseley MA, Hare JM, Nogueira L, Sorenson MM, Pinto JR Abstract AIMS: The heart responds to physiological and pathophysiological stress factors by increasing its production of nitric oxide (NO), which reacts with intracellular glutathione to form S-nitrosoglutathione (GSNO), a protein S-nitrosylating agent. Although S-nitrosylation protects some cardiac proteins against oxidative stress, direct effects on myofilament performance are unknown. We hypothesize that S-nitrosylation of sarcomeric proteins will modulate the performance of cardiac myofilaments. RESULTS: Incubation of intact mouse cardiomyocytes with S-nitrosocysteine (CysNO, a cell-permeable low-molecular-weight nitrosothiol) significantly decreased myofilament Ca(2+) sensitivity. In demembranated (skinned) fibers, S-nitrosylation with 1 μM GSNO also decreased Ca(2+) sensitivity of contraction and 10 μM reduced maximal isometric force, while inhibition of relaxation and myofibrillar ATPase required higher concentrations (≥ 100 μM). Reducing S-nitrosylation with ascorbate partially reversed the effects on Ca(2+) sensitivity and ATPase activity. In live cardiomyocytes treated with CysNO, resin-assisted capture of S-nitrosylated protein thiols was combined with label-free liquid chromatography-tandem mass spectrometry to quantify S-nitrosylation and determine the susceptible cysteine sites on myosin, actin, myosin-binding protein C, troponin C and I, tropomyosin, and titin. The ability of sarcomere proteins to form S-NO from 10-500 μM CysNO in intact cardiomyocytes was further determined by immunoblot, with actin, myosin, myosin-binding protein C, and troponin C being the more susceptible sarcomeric proteins. INNOVATION AND CONCLUSIONS: Thus, specific physiological effects are associated with S-nitrosylation of a limited number of cysteine residues in sarcomeric proteins, which also offer potential targets for interventions in pathophysiological situations. PMID: 26421519 [PubMed - indexed for MEDLINE]

Related Articles Preferential Extracellular Generation of the Active Parkinsonian Toxin MPP+ by Transporter-Independent Export of the Intermediate MPDP+. Antioxid Redox Signal. 2015 Nov 1;23(13):1001-16 Authors: Schildknecht S, Pape R, Meiser J, Karreman C, Strittmatter T, Odermatt M, Cirri E, Friemel A, Ringwald M, Pasquarelli N, Ferger B, Brunner T, Marx A, Möller HM, Hiller K, Leist M Abstract AIMS: 1-Methyl-4-phenyl-tetrahydropyridine (MPTP) is among the most widely used neurotoxins for inducing experimental parkinsonism. MPTP causes parkinsonian symptoms in mice, primates, and humans by killing a subpopulation of dopaminergic neurons. Extrapolations of data obtained using MPTP-based parkinsonism models to human disease are common; however, the precise mechanism by which MPTP is converted into its active neurotoxic metabolite, 1-methyl-4-phenyl-pyridinium (MPP(+)), has not been fully elucidated. In this study, we aimed to address two unanswered questions related to MPTP toxicology: (1) Why are MPTP-converting astrocytes largely spared from toxicity? (2) How does MPP(+) reach the extracellular space? RESULTS: In MPTP-treated astrocytes, we discovered that the membrane-impermeable MPP(+), which is generally assumed to be formed inside astrocytes, is almost exclusively detected outside of these cells. Instead of a transporter-mediated export, we found that the intermediate, 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP(+)), and/or its uncharged conjugate base passively diffused across cell membranes and that MPP(+) was formed predominately by the extracellular oxidation of MPDP(+) into MPP(+). This nonenzymatic extracellular conversion of MPDP(+) was promoted by O2, a more alkaline pH, and dopamine autoxidation products. INNOVATION AND CONCLUSION: Our data indicate that MPTP metabolism is compartmentalized between intracellular and extracellular environments, explain the absence of toxicity in MPTP-converting astrocytes, and provide a rationale for the preferential formation of MPP(+) in the extracellular space. The mechanism of transporter-independent extracellular MPP(+) formation described here indicates that extracellular genesis of MPP(+) from MPDP is a necessary prerequisite for the selective uptake of this toxin by catecholaminergic neurons. PMID: 26413876 [PubMed - indexed for MEDLINE]

Related Articles Combination of transcriptomic and metabolomic analyses reveals a JAZ repressor in the jasmonate signaling pathway of Salvia miltiorrhiza. Sci Rep. 2015;5:14048 Authors: Ge Q, Zhang Y, Hua WP, Wu YC, Jin XX, Song SH, Wang ZZ Abstract Jasmonates (JAs) are plant-specific key signaling molecules that respond to various stimuli and are involved in the synthesis of secondary metabolites. However, little is known about the JA signal pathway, especially in economically significant medicinal plants. To determine the functions of novel genes that participate in the JA-mediated accumulation of secondary metabolites, we examined the metabolomic and transcriptomic signatures from Salvia miltiorrhiza. For the metabolome, 35 representative metabolites showing significant changes in rates of accumulation were extracted and identified. We also screened out 2131 differentially expressed unigenes, of which 30 were involeved in the phenolic secondary metabolic pathway, while 25 were in the JA biosynthesis and signal pathways. Among several MeJA-induced novel genes, SmJAZ8 was selected for detailed functional analysis. Transgenic plants over-expressing SmJAZ8 exhibited a JA-insensitive phenotype, suggesting that the gene is a transcriptional regulator in the JA signal pathway of S. miltiorrhiza. Furthermore, this transgenic tool revealed that JAZ genes have novel function in the constitutive accumulation of secondary metabolites. Based on these findings, we propose that the combined strategy of transcriptomic and metabolomic analyses is valuable for efficient discovery of novel genes in plants. PMID: 26388160 [PubMed - indexed for MEDLINE]

Quantitative, equal carbon response HSQC experiment, QEC-HSQC. J Magn Reson. 2016 Aug 9;271:34-39 Authors: Mäkelä V, Helminen J, Kilpeläinen I, Heikkinen S Abstract Quantitative NMR has become increasingly useful and popular in recent years, with many new and emerging applications in metabolomics, quality control, reaction monitoring and other types of mixture analysis. While sensitive and simple to acquire, the low resolving power of 1D (1)H NMR spectra can be a limiting factor when analyzing complex mixtures. This drawback can be solved by observing a different type of nuclei offering improved resolution or with multidimensional experiments, such as HSQC. In this paper, we present a novel Quantitative, Equal Carbon HSQC (QEC-HSQC) experiment providing an equal response across different type of carbons regardless of the number of attached protons, in addition to an uniform response over a wide range of (1)JCH couplings. This enables rapid quantification and integration over multiple signals without the need for complete resonance assignments and simplifies the integration of overlapping signals. PMID: 27543809 [PubMed - as supplied by publisher]

Replication of LC-MS untargeted lipidomics results in patients with calcific coronary disease: An interlaboratory reproducibility study. Int J Cardiol. 2016 Aug 2;222:1042-1048 Authors: Djekic D, Pinto R, Vorkas PA, Henein MY Abstract BACKGROUND: Recently a lipidomics approach was able to identify perturbed fatty acyl chain (FAC) and sphingolipid moieties that could stratify patients according to the severity of coronary calcification, a form of subclinical atherosclerosis. Nevertheless, these findings have not yet been reproduced before generalising their application. The aim of this study was to evaluate the reproducibility of lipidomics approaches by replicating previous lipidomic findings in groups of patients with calcific coronary artery disease (CCAD). METHODS: Patients were separated into the following groups based on their calcium score (CS); no calcification (CS: 0; n=26), mild calcification (CS: 1-250; n=27) and severe calcification (CS: >250; n=17). Two serum samples were collected from each patient and used for comparative analyses by 2 different laboratories, in different countries and time points using liquid chromatography coupled to mass spectrometry untargeted lipidomics methods. RESULTS: Six identical metabolites differentiated patients with severe coronary artery calcification from those with no calcification were found by both laboratories independently. Additionally, relative intensities from the two analyses demonstrated high correlation coefficients. Phosphatidylcholine moieties with 18-carbon FAC were identified in lower intensities and 20:4 FAC in higher intensities in the serum of diseased group. Moreover, 3 common sphingomyelins were detected. CONCLUSION: This is the first interlaboratory reproducibility study utilising lipidomics applications in general and specifically in patients with CCAD. Lipid profiling applications in patients with CCAD are very reproducible in highly specialised and experienced laboratories and could be applied in clinical practice in order to spare patients diagnostic radiation. PMID: 27543723 [PubMed - as supplied by publisher]

Comparison of collection methods for fecal samples for discovery metabolomics in epidemiological studies. Cancer Epidemiol Biomarkers Prev. 2016 Aug 19; Authors: Loftfield E, Vogtmann E, Sampson JN, Moore SC, Nelson H, Knight R, Chia N, Sinha R Abstract BACKGROUND: The gut metabolome may be associated with incidence and progression of numerous diseases. The composition of the gut metabolome can be captured by measuring metabolite levels in the feces. However, there is little data describing the effect of fecal sample collection methods on metabolomic measures. METHODS: We collected fecal samples from eighteen volunteers using four methods: no solution, 95% ethanol, fecal occult blood test (FOBT) cards, and fecal immunochemical test (FIT). One set of samples was frozen after collection (day 0), and for 95% ethanol, FOBT, and FIT, a second set was frozen after 96 hours at room temperature. We evaluated 1) technical reproducibility within sample replicates, 2) stability after 96 hours at room temperature for 95% ethanol, FOBT, and FIT, and 3) concordance of metabolite measures with the putative "gold standard," day 0 samples without solution. RESULTS: Intraclass correlation coefficients (ICC) estimating technical reproducibility were high for replicate samples for each collection method. ICCs estimating stability at room temperature were high for 95% ethanol and FOBT (median ICC>0.87) but not FIT (median ICC=0.52). Similarly, Spearman correlation coefficients (rs) estimating metabolite concordance with the "gold standard" were higher for 95% ethanol (median rs=0.82) and FOBT (median rs=0.70) than for FIT (median rs=0.40). CONCLUSIONS: Metabolomic measurements appear reproducible and stable in fecal samples collected with 95% ethanol or FOBT. Concordance with the "gold standard" is highest with 95% ethanol and acceptable with FOBT. IMPACT: Future epidemiologic studies should collect feces using 95% ethanol or FOBT if interested in studying fecal metabolomics. PMID: 27543620 [PubMed - as supplied by publisher]

Bridging the gap between comprehensive extraction protocols in plant metabolomics studies and method validation. Anal Chim Acta. 2016 Sep 7;935:136-50 Authors: Bijttebier S, Van der Auwera A, Foubert K, Voorspoels S, Pieters L, Apers S Abstract It is vital to pay much attention to the design of extraction methods developed for plant metabolomics, as any non-extracted or converted metabolites will greatly affect the overall quality of the metabolomics study. Method validation is however often omitted in plant metabolome studies, as the well-established methodologies for classical targeted analyses such as recovery optimization cannot be strictly applied. The aim of the present study is to thoroughly evaluate state-of-the-art comprehensive extraction protocols for plant metabolomics with liquid chromatography-photodiode array-accurate mass mass spectrometry (LC-PDA-amMS) by bridging the gap with method validation. Validation of an extraction protocol in untargeted plant metabolomics should ideally be accomplished by validating the protocol for all possible outcomes, i.e. for all secondary metabolites potentially present in the plant. In an effort to approach this ideal validation scenario, two plant matrices were selected based on their wide versatility of phytochemicals: meadowsweet (Filipendula ulmaria) for its polyphenols content, and spicy paprika powder (from the genus Capsicum) for its apolar phytochemicals content (carotenoids, phytosterols, capsaicinoids). These matrices were extracted with comprehensive extraction protocols adapted from literature and analysed with a generic LC-PDA-amMS characterization platform that was previously validated for broad range phytochemical analysis. The performance of the comprehensive sample preparation protocols was assessed based on extraction efficiency, repeatability and intermediate precision and on ionization suppression/enhancement evaluation. The manuscript elaborates on the finding that none of the extraction methods allowed to exhaustively extract the metabolites. Furthermore, it is shown that depending on the extraction conditions enzymatic degradation mechanisms can occur. Investigation of the fractions obtained with the different extraction methods revealed a low resolving power for phytochemicals for all methods. Nevertheless, an overall good repeatability was observed for all extraction methods, which is essential to allow direct comparison between samples. In summary, no single procedure outperforms the others and compromises will have to be made during method selection. PMID: 27543023 [PubMed - in process]

Uncovering the benefits of fluctuating thermal regimes on cold tolerance of drosophila flies by combined metabolomic and lipidomic approach. Biochim Biophys Acta. 2016 Aug 16; Authors: Colinet H, Renault D, Javal M, Berková P, Šimek P, Koštál V Abstract When exposed to constant low temperatures (CLTs), insects often suffer from cumulative physiological injuries that can severely compromise their fitness and survival. Yet, mortality can be considerably lowered when the cold stress period is interrupted by periodic warm interruption(s), referred to as fluctuating thermal regimes, FTRs. In this study, we have shown that FTRs strongly promoted cold tolerance of Drosophila melanogaster adults. We then assessed whether this marked phenotypic shift was associated with detectable physiological changes, such as synthesis of cryoprotectants and/or membrane remodeling. To test these hypotheses, we conducted two different time-series Omics analyzes in adult flies submitted to CLTs vs. FTRs: metabolomics (GC/MS) and lipidomics (LC/ESI/MS) targeting membrane phospholipids. We observed increasing levels in several polyhydric alcohols (arabitol, erythritol, sorbitol, mannitol, glycerol), sugars (fructose, mannose) and amino acids (serine, alanine, glutamine) in flies under CLT. Prolonged exposure to low temperature was also associated with a marked deviation of metabolic homeostasis and warm interruptions as short as 2h were sufficient to periodically return the metabolic system to functionality. Lipidomics revealed an increased relative proportion of phosphatidylethanolamines and a shortening of fatty acyl chains in flies exposed to cold, likely to compensate for the ordering effect of low temperature on membranes. We found a remarkable correspondence in the time-course of changes between the metabolic and phospholipids networks, both suggesting a fast homeostatic regeneration during warm intervals under FTRs. In consequence, we suggest that periodic opportunities to restore system-wide homeostasis contribute to promote cold tolerance under FTRs. PMID: 27542540 [PubMed - as supplied by publisher]

Gene-specific DNA methylation may mediate atypical antipsychotic-induced insulin resistance. Bipolar Disord. 2016 Aug 20; Authors: Burghardt KJ, Goodrich JM, Dolinoy DC, Ellingrod VL Abstract OBJECTIVES: Atypical antipsychotics (AAPs) carry a significant risk of cardiometabolic side effects, including insulin resistance. It is thought that the insulin resistance resulting from the use of AAPs may be associated with changes in DNA methylation. We aimed to identify and validate a candidate gene associated with AAP-induced insulin resistance by using a multi-step approach that included an epigenome-wide association study (EWAS) and validation with site-specific methylation and metabolomics data. METHODS: Subjects with bipolar disorder treated with AAPs or lithium monotherapy were recruited for a cross-sectional visit to analyze peripheral blood DNA methylation and insulin resistance. Epigenome-wide DNA methylation was analyzed in a discovery sample (n = 48) using the Illumina 450K BeadChip. Validation analyses of the epigenome-wide findings occurred in a separate sample (n = 72) using site-specific methylation with pyrosequencing and untargeted metabolomics data. Regression analyses were conducted controlling for known confounders in all analyses and a mediation analysis was performed to investigate if AAP-induced insulin resistance occurs through changes in DNA methylation. RESULTS: A differentially methylated probe associated with insulin resistance was discovered and validated in the fatty acyl CoA reductase 2 (FAR2) gene of chromosome 12. Functional associations of this DNA methylation site with untargeted phospholipid-related metabolites were also detected. Our results identified a mediating effect of this FAR2 methylation site on AAP-induced insulin resistance. CONCLUSIONS: Going forward, prospective, longitudinal studies assessing comprehensive changes in FAR2 DNA methylation, expression, and lipid metabolism before and after AAP treatment are required to assess its potential role in the development of insulin resistance. PMID: 27542345 [PubMed - as supplied by publisher]

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MetaboTools: A Comprehensive Toolbox for Analysis of Genome-Scale Metabolic Models. Front Physiol. 2016;7:327 Authors: Aurich MK, Fleming RM, Thiele I Abstract Metabolomic data sets provide a direct read-out of cellular phenotypes and are increasingly generated to study biological questions. Previous work, by us and others, revealed the potential of analyzing extracellular metabolomic data in the context of the metabolic model using constraint-based modeling. With the MetaboTools, we make our methods available to the broader scientific community. The MetaboTools consist of a protocol, a toolbox, and tutorials of two use cases. The protocol describes, in a step-wise manner, the workflow of data integration, and computational analysis. The MetaboTools comprise the Matlab code required to complete the workflow described in the protocol. Tutorials explain the computational steps for integration of two different data sets and demonstrate a comprehensive set of methods for the computational analysis of metabolic models and stratification thereof into different phenotypes. The presented workflow supports integrative analysis of multiple omics data sets. Importantly, all analysis tools can be applied to metabolic models without performing the entire workflow. Taken together, the MetaboTools constitute a comprehensive guide to the intra-model analysis of extracellular metabolomic data from microbial, plant, or human cells. This computational modeling resource offers a broad set of computational analysis tools for a wide biomedical and non-biomedical research community. PMID: 27536246 [PubMed]

Proteomic analysis reveals dynamic regulation of fruit development and sugar and acid accumulation in apple. J Exp Bot. 2016 Aug 17; Authors: Li M, Li D, Feng F, Zhang S, Ma F, Cheng L Abstract Understanding the fruit developmental process is critical for fruit quality improvement. Here, we report a comprehensive proteomic analysis of apple fruit development over five growth stages, from young fruit to maturity, coupled with metabolomic profiling. A tandem mass tag (TMT)-based comparative proteomics approach led to the identification and quantification of 7098 and 6247 proteins, respectively. This large-scale proteomic dataset presents a global view of the critical pathways involved in fruit development and metabolism. When linked with metabolomics data, these results provide new insights into the modulation of fruit development, the metabolism and storage of sugars and organic acids (mainly malate), and events within the energy-related pathways for respiration and glycolysis. We suggest that the key steps identified here (e.g. those involving the FK2, TST, EDR6, SPS, mtME and mtMDH switches), can be further targeted to confirm their roles in accumulation and balance of fructose, sucrose and malate. Moreover, our findings imply that the primary reason for decreases in amino acid concentrations during fruit development is related to a reduction in substrate flux via glycolysis, which is mainly regulated by fructose-bisphosphate aldolase and bisphosphoglycerate mutase. PMID: 27535992 [PubMed - as supplied by publisher]

Effect of taurine supplementation on hepatic metabolism and alleviation of cadmium toxicity and bioaccumulation in a marine teleost, red sea bream, Pagrus major. Fish Physiol Biochem. 2016 Aug 17; Authors: Hano T, Ito K, Kono K, Ito M, Ohkubo N, Mochida K Abstract This study was performed to unravel the mechanism of the beneficial action of taurine on marine teleost fish, red sea bream (Pagrus major), by analyzing the hepatic metabolism. Moreover, the ameliorative effects of the nutrient against cadmium toxicity and bioaccumulation were further evaluated. The fish were fed a diet containing 0 % (TAU0 %), 0.5 % (TAU0.5 %), or 5.0 % (TAU5.0 %) taurine for 40-55 days (d) and subjected to cadmium acute toxicity and bioaccumulation tests. Taurine deficiency in feed severely affected growth and the hepatic metabolic profiles of the fish, including a remarkable increase in myo-inositol, aspartate, and ß-alanine in the TAU0 % group, which indicates a complementary physiological response to taurine deficiency. For the acute toxicity test, fish were fed the test diets for 55 d and were then exposed to different dose of cadmium ranging from 0 to 5.6 mg/L for 96 h. Fish fed taurine had a higher tolerance to cadmium than those not fed taurine. For the bioaccumulation test, fish were fed the test diets for 40 d and then were chronically exposed to 0.2 mg/L of cadmium for 28 d followed by depuration for 21 d. Cadmium concentrations in the liver and muscle of fish fed TAU5.0 % were significantly lower than those of fish fed TAU0 % for the first 7 d of exposure and the first 7 d of elimination. Our findings suggest a possible mechanism for the beneficial role played by taurine and that the inclusion of taurine in fish aquaculture feed may reduce cadmium contamination of fish intended for human consumption. PMID: 27535560 [PubMed - as supplied by publisher]

Cyclic mononucleotide- and Clr-dependent gene regulation in Sinorhizobium meliloti. Microbiology. 2016 Aug 16; Authors: Krol E, Klaner C, Gnau P, Kaever V, Essen LO, Becker A Abstract To identify physiological processes affected by cAMP in the plant-symbiotic nitrogen-fixing proteobacterium Sinorhizobium meliloti Rm2011, cAMP levels were artificially increased by overexpression of its cognate adenylate/guanylate cyclase gene cyaJ. This resulted in high accumulation of cAMP in the culture supernatant, decreased swimming motility and increased production of succinoglycan, an exopolysaccharide involved in host invasion. Weaker, similar phenotypic changes were induced by overexpression of cyaB and cyaG1. Effects on swimming motility and succinoglycan production were partially dependent on clr encoding a CRP-like protein. Transcriptome profiling of an cyaJ overexpressing strain identified 72 upregulated and 82 downregulated genes. A considerable number of upregulated genes are related to polysaccharide biosynthesis and osmotic stress response. These included succinoglycan biosynthesis genes, genes of the putative polysaccharide synthesis nodP2-exoF3 cluster, and feuN, the first gene of the operon encoding the FeuNPQ regulatory system. Downregulated genes were mostly related to respiration, central metabolism and swimming motility. Promoter-probe studies in presence of externally added cAMP revealed 18 novel Clr-cAMP-regulated genes. Moreover, addition of cGMP into the growth medium also promoted clr-dependent gene regulation. Clr-cAMP/cGMP dependent activation of SMc02178, SMb20906, SMc04190, and SMc00653 promoters was demonstrated in E. coli as heterologous host. These results and in vitro binding of Clr-cAMP and Clr-cGMP to the promoter regions of these genes and SMc00925, SMc01136, and cyaF2, suggest direct gene activation by Clr-cAMP/cGMP. The Clr-binding site (A/C/T)GT(T/C)(T/C/A)C N4 G(G/A)(T/A)ACA, a motif upstream of SMc02178, SMb20906, SMc04190, SMc00925, SMc01136 and cyaF2, was required for Clr cAMP/cGMP-dependent gene activation. PMID: 27535558 [PubMed - as supplied by publisher]