PubMed

Hepatic accumulation of S-Adenosylmethionine in hamsters with non-alcoholic-fatty liver disease associated to metabolic syndrome under selenium and vitamin E deficiency. Clin Sci (Lond). 2017 Nov 09;: Authors: Del Bas JM, Rodríguez B, Puiggròs F, Mariné S, Rodríguez MA, Moriña D, Armengol L, Caimari A, Arola L Abstract Progression of non-alcoholic fatty liver disease (NAFLD) in the context of metabolic syndrome (MetS) is only partially explored due to the lack of preclinical models. In order to study the alterations in hepatic metabolism that accompany this condition, we developed a model of MetS accompanied by the onset of steatohepatitis (NASH) by challenging golden hamsters with a high fat diet low in vitamin E and selenium (HFD), since combined deficiency results in hepatic necroinflammation in rodents. Metabolomics and transcriptomics integrated analyses of livers revealed an unexpected accumulation of hepatic S-Adenosylmethionine (SAM) when compared with healthy livers likely due to diminished methylation reactions and repression of GNMT. SAM plays a key role in the maintenance of cellular homeostasis and cell cycle control. In agreement, analysis of overrepresented transcription factors revealed a central role of c-myc and c-Jun pathways accompanied by negative correlations between SAM concentration, MYC expression and AMPK phosphorylation. These findings point to a drift of cell cycle control towards senescence in livers of HFD animals, which could explain the onset of NASH in this model. In contrast, hamsters with NAFLD induced by a conventional high fat diet did not show SAM accumulation, suggesting a key role of selenium and vitamin E in SAM homeostasis. In conclusion, our results suggest that progression of NAFLD in the context of MetS can take place even in a situation of hepatic SAM excess and that selenium and vitamin E status might be considered in current therapies against NASH based on SAM supplementation. PMID: 29122967 [PubMed - as supplied by publisher]

Gender-related metabolomics and lipidomics: From experimental animal models to clinical evidence. J Proteomics. 2017 Nov 06;: Authors: Audano M, Maldini M, De Fabiani E, Mitro N, Caruso D Abstract Lipidomics and metabolomics have emerged as important tools for the characterization of specific physiological and pathological traits. The selection of the analytical approaches and the choice of a targeted rather than an untargeted strategy in metabolomics find their reasons in the driving hypothesis of the study, sample features and instrumental availability. Moreover, in the last years, -omics approaches have found their application in the study of sex-related dimorphism. In this review, lipidomic and metabolomic analyses are presented in a biomedical perspective. Here, we provide an updated overview covering recent applications of metabolomics and lipidomics in the area of sex-related differences in human and preclinical models. Experimental evidence underlines that sex is one of the most relevant biological variables significantly influencing metabolomic and lipidomic profiles. This knowledge can be exploited for the identification of novel sex-specific biomarkers and innovative targets relevant for gender medicine. PMID: 29122727 [PubMed - as supplied by publisher]

Identification of serum metabolites associated with obesity and traditional risk factors for metabolic disease in Chinese adults. Nutr Metab Cardiovasc Dis. 2017 Oct 03;: Authors: Wang SM, Yang RY, Wang M, Ji FS, Li HX, Tang YM, Chen WX, Dong J Abstract BACKGROUND AND AIMS: Obesity is a major worldwide health problem and is often associated with many metabolic diseases. Levels of several serum-specific metabolites may be altered in patients with these metabolic diseases. We aimed to investigate the associations of serum metabolite levels with obesity and traditional risk factors for metabolic disease in Chinese individuals. METHODS AND RESULTS: Six-hundred Chinese individuals undergoing annual physical exams were recruited and categorized into overweight/obese and control groups (1:1 ratio). We simultaneously quantified the serum lysophosphatidylcholine (LPC), branched-chain amino acids (BCAA), aromatic amino acids (AAA), 25-hydroxyvitamin D, glutamine (Gln), glutamic acid (Glu), and Gln/Glu ratio levels using our previously established targeted serum metabolomic method. The overweight/obesity group had significantly higher levels of BCAA, AAA, and Glu, as well as lower levels of unsaturated LPC, Gln, and Gln/Glu, than the control group. Correlation analyses revealed significant and positive relationships of saturated LPC, BCAA, AAA, and Glu with blood pressure, glucose, triglycerides, apolipoprotein B, and high-sensitivity C-reactive protein, while unsaturated LPC, Gln, Gln/Glu, and 25-hydroxyvitamin D exhibited an opposite trend. In the multifactor logistic regression model, low unsaturated LPC and Gln/Glu, as well as high BCAA and AAA levels, were found to be independent risk factors for obesity; the odds ratios (95% confidence interval) of the highest quartile compared to the lowest quartile were 0.241 (0.139-0.417), 0.436 (0.252-0.755), 3.944 (2.094-7.430), and 2.357 (1.274-4.361) (P < 0.01), respectively. CONCLUSION: LPC, BCAA, AAA, and Gln/Glu are significantly related to obesity development and risk factors of some metabolic diseases. PMID: 29122443 [PubMed - as supplied by publisher]

The Pocket-4-Life project, bioavailability and beneficial properties of the bioactive compounds of espresso coffee and cocoa-based confectionery containing coffee: study protocol for a randomized cross-over trial. Trials. 2017 Nov 09;18(1):527 Authors: Mena P, Tassotti M, Martini D, Rosi A, Brighenti F, Del Rio D Abstract BACKGROUND: Coffee is an important source of bioactive compounds, including caffeine, phenolic compounds (mainly chlorogenic acids), trigonelline, and diterpenes. Several studies have highlighted the preventive effects of coffee consumption on major cardiometabolic diseases, but the impact of coffee dosage on markers of cardiometabolic risk is not well understood. Moreover, the pool of coffee-derived circulating metabolites and the contribution of each metabolite to disease prevention still need to be evaluated in real-life settings. The aim of this study will be to define the bioavailability and beneficial properties of coffee bioactive compounds on the basis of different levels of consumption, by using an innovative experimental design. The contribution of cocoa-based products containing coffee to the pool of circulating metabolites and their putative bioactivity will also be investigated. METHODS: A three-arm, crossover, randomized trial will be conducted. Twenty-one volunteers will be randomly assigned to consume three treatments in a random order for 1 month: 1 cup of espresso coffee/day, 3 cups of espresso coffee/day, and 1 cup of espresso coffee plus 2 cocoa-based products containing coffee twice per day. The last day of each treatment, blood and urine samples will be collected at specific time points, up to 24 hours following the consumption of the first product. At the end of each treatment the same protocol will be repeated, switching the allocation group. Besides the bioavailability of the coffee/cocoa bioactive compounds, the effect of the coffee/cocoa consumption on several cardiometabolic risk factors (anthropometric measures, blood pressure, inflammatory markers, trimethylamine N-oxide, nitric oxide, blood lipids, fasting indices of glucose/insulin metabolism, DNA damage, eicosanoids, and nutri-metabolomics) will be investigated. DISCUSSION: Results will provide information on the bioavailability of the main groups of phytochemicals in coffee and on their modulation by the level of consumption. Findings will also show the circulating metabolites and their bioactivity when coffee consumption is substituted with the intake of cocoa-based products containing coffee. Finally, the effect of different levels of 1-month coffee consumption on cardiometabolic risk factors will be elucidated, likely providing additional insights on the role of coffee in the protection against chronic diseases. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03166540 . Registered on May 21, 2017. PMID: 29121975 [PubMed - in process]

Transcriptomics, metabolomics and histology indicate that high-carbohydrate diet negatively affects the liver health of blunt snout bream (Megalobrama amblycephala). BMC Genomics. 2017 Nov 09;18(1):856 Authors: Prisingkorn W, Prathomya P, Jakovlić I, Liu H, Zhao YH, Wang WM Abstract BACKGROUND: Global trend of the introduction of high levels of relatively cheap carbohydrates to reduce the amount of costly protein in the aquatic animal feed production has affected the aquaculture of an economically important cyprinid fish, blunt snout bream (Megalobrama amblycephala). This dietary shift has resulted in increased prevalence of metabolic disorders, often causing economic losses. High dietary intake of carbohydrates, associated with obesity, is one of the major causes of non-alcoholic fatty liver disease (NAFLD) in humans. RESULTS: We have conducted an eight-week feeding trial to better understand how a high-carbohydrate diet (HCBD) affects the liver health in this fish. Hepatosomatic index and lipid content were significantly (P < 0.05) higher in the HCBD group. Histology results also suggested pathological changes in the livers of HCBD group, with excessive lipid accumulation and indication of liver damage. Metabolomics and serum biochemistry analyses showed that a number of metabolites indicative of liver damage were increased in the HCBD group. This group also exhibited low levels of betaine, which is a metabolite crucial for maintaining the healthy liver functions. Transcriptomic and qPCR analyses indicated that HCBD had a strong impact on the expression of a large number of genes associated with the NAFLD and insulin signalling pathways, which may lead to the development of insulin resistance in hepatocytes, pathological liver changes, and eventually the NAFLD. CONCLUSIONS: Transcriptomics, metabolomics and histology results all indicate early symptoms of liver damage. However whether these would actually lead to the development of NAFLD after a longer period of time, remains inconclusive. Additionally, a very high number of upregulated genes in the HCBD group associated with several neurodegenerative diseases is a strong indication of neurodegenerative changes caused by the high-carbohydrate diet in blunt snout bream. This suggests that fish might present a good model to study neurodegenerative changes associated with high-carbohydrate diet in humans. PMID: 29121861 [PubMed - in process]

Related Articles Astilbin from Engelhardtia chrysolepis enhances intestinal barrier functions in Caco-2 cell monolayers. Eur J Pharmacol. 2017 Jun 05;804:46-51 Authors: Nakahara T, Nishitani Y, Nishiumi S, Yoshida M, Azuma T Abstract Astilbin, which is one of polyphenolic compounds isolated from the leaves of Engelhardtia chrysolepis HANCE (Chinese name, huang-qui), is available as the effective component in food and cosmetics because of its anti-oxidant and anti-inflammatory effects. The tight junction (TJ) proteins, which protect the body from foreign substances, are related to adhesion between a cell and a cell. Previously, the enhancement of TJ's functions induced by aglycones of flavonoids has been demonstrated, but the effects of the glycosides such as astilbin have not been observed yet. In this study, we investigated the effects of astilbin on the TJ's functions, and human colon carcinoma Caco-2 cell monolayers were used to evaluate the effects of astilbin on transepithelial electrical resistance (TER) value and the mRNA and proteins expressions of TJ-related molecules. Astilbin increased the TER value, mRNA expression levels of claudin-1 and ZO-2, and protein expression levels of occludin and ZO-2 in Caco-2 cells. Astilbin also increased the TER value in Caco-2 cells co-stimulated with TNF-α plus IFN-γ, and moreover upregulated the protein expression of TJ-related molecules in Caco-2 cells co-treated with TNF-α plus IFN-γ. These results suggest that astilbin can enhance the expressions of TJ-related molecules, leading to upregulation of the barrier functions in the intestinal cells. PMID: 28327343 [PubMed - indexed for MEDLINE]

Related Articles Obp56h Modulates Mating Behavior in Drosophila melanogaster. G3 (Bethesda). 2016 Oct 13;6(10):3335-3342 Authors: Shorter JR, Dembeck LM, Everett LJ, Morozova TV, Arya GH, Turlapati L, St Armour GE, Schal C, Mackay TF, Anholt RR Abstract Social interactions in insects are driven by conspecific chemical signals that are detected via olfactory and gustatory neurons. Odorant binding proteins (Obps) transport volatile odorants to chemosensory receptors, but their effects on behaviors remain poorly characterized. Here, we report that RNAi knockdown of Obp56h gene expression in Drosophila melanogaster enhances mating behavior by reducing courtship latency. The change in mating behavior that results from inhibition of Obp56h expression is accompanied by significant alterations in cuticular hydrocarbon (CHC) composition, including reduction in 5-tricosene (5-T), an inhibitory sex pheromone produced by males that increases copulation latency during courtship. Whole genome RNA sequencing confirms that expression of Obp56h is virtually abolished in Drosophila heads. Inhibition of Obp56h expression also affects expression of other chemoreception genes, including upregulation of lush in both sexes and Obp83ef in females, and reduction in expression of Obp19b and Or19b in males. In addition, several genes associated with lipid metabolism, which underlies the production of cuticular hydrocarbons, show altered transcript abundances. Our data show that modulation of mating behavior through reduction of Obp56h is accompanied by altered cuticular hydrocarbon profiles and implicate 5-T as a possible ligand for Obp56h. PMID: 27558663 [PubMed - indexed for MEDLINE]

Co-culture of Marine Invertebrate-Associated Bacteria and Interdisciplinary Technologies Enable Biosynthesis and Discovery of a New Antibiotic, Keyicin. ACS Chem Biol. 2017 Nov 09;: Authors: Adnani N, Chevrette M, Adibhatla SN, Zhang F, Yu Q, Braun DR, Nelson J, Simpkins SW, McDonald BR, Myers CL, Piotrowski JS, Thompson CJ, Currie CR, Li L, Rajski SR, Bugni TS Abstract Advances in genomics and metabolomics have made clear in recent years that microbial biosynthetic capacities on Earth far exceed previous expectations. This is attributable, in part, to the realization that most microbial natural product (NP) producers harbor biosynthetic machineries not readily amenable to classical laboratory fermentation conditions. Such "cryptic" or dormant biosynthetic gene clusters (BGCs) encode for a vast assortment of potentially new antibiotics and, as such, have become extremely attractive targets for activation under controlled laboratory conditions. We report here that co-culturing of a Rhodococcus sp. and a Micromonospora sp. affords keyicin, a new and otherwise unattainable bis-nitroglycosylated anthracycline whose mechanism of action (MOA) appears to deviate from those of other anthracyclines. The structure of keyicin was elucidated using high resolution MS and NMR technologies, as well as detailed molecular mod-eling studies. Sequencing of the keyicin BGC (within the Micromonospora genome) enabled both structural and genomic comparisons to other anthracycline-producing systems informing efforts to characterize keyicin. The new NP was found to be selectively active against Gram-positive bacteria including both Rhodococcus sp. and Mycobacterium sp. E. coli-based chemical genomics studies revealed that keyicin's MOA, in contrast to many other anthracyclines, does not invoke nucleic acid damage. PMID: 29121465 [PubMed - as supplied by publisher]

Adipocyte Expression of SLC19A1 Links DNA Hypermethylation to Adipose Tissue Inflammation and Insulin Resistance. J Clin Endocrinol Metab. 2017 Nov 07;: Authors: Petrus P, Bialesova L, Checa A, Kerr A, Naz S, Bäckdahl J, Gracia A, Toft S, Dahlman-Wright K, Hedén P, Dahlman I, Wheelock CE, Arner P, Mejhert N, Gao H, Rydén M Abstract Context: Insulin resistance (IR) is promoted by a chronic low-grade inflammation in white adipose tissue (WAT). The latter may be regulated through epigenetic mechanisms such as DNA-methylation. The one carbon cycle (1CC) is a central metabolic process governing DNA-methylation. Objective: To identify adipocyte-expressed 1CC genes linked to WAT inflammation, IR and their causal role. Design: Cohort study. Setting: Outpatient academic clinic. Participants: Obese and non-obese subjects. Methods: Gene expression and DNA-methylation arrays were performed in subcutaneous WAT and isolated adipocytes. In in vitro differentiated human adipocytes, gene knockdown was achieved by siRNA and analyses included microarray, qPCR, DNA-methylation by ELISA and pyrosequencing, protein secretion by ELISA, targeted metabolomics, luciferase reporter and thermal shift assays. Main outcome measures: Effects on adipocyte inflammation. Results: In adipocytes from obese individuals, global DNA hypermethylation associated positively with gene expression of pro-inflammatory pathways. Among 1CC-genes, IR in vivo and pro-inflammatory gene expression in WAT were most strongly and inversely associated with SLC19A1, a gene encoding a membrane folate carrier. SLC19A1 knockdown in human adipocytes perturbed intracellular 1CC-metabolism, induced global DNA hypermethylation and increased expression of pro-inflammatory genes. Several CpG loci linked SLC19A1 to inflammation; validation studies were focused on the chemokine CCL2 where methylation in the promoter (cg12698626) regulated CCL2 expression and CCL2 secretion through altered transcriptional activity. Conclusions: Reduced SLC19A1 expression in human adipocytes induces DNA hypermethylation resulting in increased expression of specific pro-inflammatory genes including CCL2. This constitutes an epigenetic mechanism that may link dysfunctional adipocytes to WAT inflammation and IR. PMID: 29121255 [PubMed - as supplied by publisher]

Effects of four different antihypertensive drugs on plasma metabolomic profiles in patients with essential hypertension. PLoS One. 2017;12(11):e0187729 Authors: Hiltunen TP, Rimpelä JM, Mohney RP, Stirdivant SM, Kontula KK Abstract OBJECTIVE: In order to search for metabolic biomarkers of antihypertensive drug responsiveness, we measured >600 biochemicals in plasma samples of subjects participating in the GENRES Study. Hypertensive men received in a double-blind rotational fashion amlodipine, bisoprolol, hydrochlorothiazide and losartan, each as a monotherapy for one month, with intervening one-month placebo cycles. METHODS: Metabolomic analysis was carried out using ultra high performance liquid chromatography-tandem mass spectrometry. Full metabolomic signatures (the drug cycles and the mean of the 3 placebo cycles) became available in 38 to 42 patients for each drug. Blood pressure was monitored by 24-h recordings. RESULTS: Amlodipine (P values down to 0.002), bisoprolol (P values down to 2 x 10-5) and losartan (P values down to 2 x 10-4) consistently decreased the circulating levels of long-chain acylcarnitines. Bisoprolol tended to decrease (P values down to 0.002) the levels of several medium- and long-chain fatty acids. Hydrochlorothiazide administration was associated with an increase of plasma uric acid level (P = 5 x 10-4) and urea cycle metabolites. Decreases of both systolic (P = 0.06) and diastolic (P = 0.04) blood pressure after amlodipine administration tended to associate with a decrease of plasma hexadecanedioate, a dicarboxylic fatty acid recently linked to blood pressure regulation. CONCLUSIONS: Although this systematic metabolomics study failed to identify circulating metabolites convincingly predicting favorable antihypertensive response to four different drug classes, it provided accumulating evidence linking fatty acid metabolism to human hypertension. PMID: 29121091 [PubMed - in process]

Untargeted metabolomics reveals specific withanolides and fatty acyl glycoside as tentative metabolites to differentiate organic and conventional Physalis peruviana fruits. Food Chem. 2018 Apr 01;244:120-127 Authors: Llano SM, Muñoz-Jiménez AM, Jiménez-Cartagena C, Londoño-Londoño J, Medina S Abstract The agronomic production systems may affect the levels of food metabolites. Metabolomics approaches have been applied as useful tool for the characterization of fruit metabolome. In this study, metabolomics techniques were used to assess the differences in phytochemical composition between goldenberry samples produced by organic and conventional systems. To verify that the organic samples were free of pesticides, individual pesticides were analyzed. Principal component analysis showed a clear separation of goldenberry samples from two different farming systems. Via targeted metabolomics assays, whereby carotenoids and ascorbic acid were analyzed, not statistical differences between both crops were found. Conversely, untargeted metabolomics allowed us to identify two withanolides and one fatty acyl glycoside as tentative metabolites to differentiate goldenberry fruits, recording organic fruits higher amounts of these compounds than conventional samples. Hence, untargeted metabolomics technology could be suitable to research differences on phytochemicals under different agricultural management practices and to authenticate organic products. PMID: 29120759 [PubMed - in process]

A Microbiomic Analysis in African Americans with Colonic Lesions Reveals Streptococcus sp.VT162 as a Marker of Neoplastic Transformation. Genes (Basel). 2017 Nov 09;8(11): Authors: Brim H, Yooseph S, Lee E, Sherif Z, Abbas M, Laiyemo AO, Varma S, Torralba M, Dowd SE, Nelson KE, Pathmasiri W, Sumner S, de Vos W, Liang Q, Yu J, Zoetendal E, Ashktorab H Abstract Increasing evidence suggests a role of the gut microbiota in colorectal carcinogenesis (CRC). To detect bacterial markers of colorectal cancer in African Americans a metabolomic analysis was performed on fecal water extracts. DNA from stool samples of adenoma and healthy subjects and from colon cancer and matched normal tissues was analyzed to determine the microbiota composition (using 16S rDNA) and genomic content (metagenomics). Metagenomic functions with discriminative power between healthy and neoplastic specimens were established. Quantitative Polymerase Chain Reaction (q-PCR) using primers and probes specific to Streptococcus sp. VT_162 were used to validate this bacterium association with neoplastic transformation in stool samples from two independent cohorts of African Americans and Chinese patients with colorectal lesions. The metabolomic analysis of adenomas revealed low amino acids content. The microbiota in both cancer vs. normal tissues and adenoma vs. normal stool samples were different at the 16S rRNA gene level. Cross-mapping of metagenomic data led to 9 markers with significant discriminative power between normal and diseased specimens. These markers identified with Streptococcus sp. VT_162. Q-PCR data showed a statistically significant presence of this bacterium in advanced adenoma and cancer samples in an independent cohort of CRC patients. We defined metagenomic functions from Streptococcus sp. VT_162 with discriminative power among cancers vs. matched normal and adenomas vs. healthy subjects' stools. Streptococcus sp. VT_162 specific 16S rDNA was validated in an independent cohort. These findings might facilitate non-invasive screening for colorectal cancer. PMID: 29120399 [PubMed]

Related Articles Nuclear magnetic resonance spectroscopy as a new approach for improvement of early diagnosis and risk stratification of prostate cancer. J Zhejiang Univ Sci B. 2017 Nov.;18(11):921-933 Authors: Yang B, Liao GQ, Wen XF, Chen WH, Cheng S, Stolzenburg JU, Ganzer R, Neuhaus J Abstract Prostate cancer (PCa) is the second most common male cancer worldwide and the fifth leading cause of death from cancer in men. Early detection and risk stratification is the most effective way to improve the survival of PCa patients. Current PCa biomarkers lack sufficient sensitivity and specificity to cancer. Metabolite biomarkers are evolving as a new diagnostic tool. This review is aimed to evaluate the potential of metabolite biomarkers for early detection, risk assessment, and monitoring of PCa. Of the 154 identified publications, 27 and 38 were original papers on urine and serum metabolomics, respectively. Nuclear magnetic resonance (NMR) is a promising method for measuring concentrations of metabolites in complex samples with good reproducibility, high sensitivity, and simple sample processing. Especially urine-based NMR metabolomics has the potential to be a cost-efficient method for the early detection of PCa, risk stratification, and monitoring treatment efficacy. PMID: 29119730 [PubMed - in process]

Related Articles Metabolomics: Challenges and Opportunities in Systems Biology Studies. Methods Mol Biol. 2018;1702:327-336 Authors: Casadei L, Valerio M, Manetti C Abstract Metabolomics has the capability of providing predisposition, diagnostic, prognostic, and therapeutic biomarker profiles of individual patients, since a large number of metabolites can be measured in an unbiased manner from biological samples. In this setting, (1)H-Nuclear Magnetic Resonance (NMR) spectroscopy of biofluids such as plasma, urine, and fecal water offers the opportunity to identify patterns of biomarker changes that reflects the physiological or pathological status of an individual patient.In this chapter, we show as a metabolomics study can be used to diagnose a disease, classifying patients as healthy or as pathological taking into account individual variability. PMID: 29119513 [PubMed - in process]

Related Articles Exposure to intrauterine inflammation alters metabolomic profiles in the amniotic fluid, fetal and neonatal brain in the mouse. PLoS One. 2017;12(10):e0186656 Authors: Brown AG, Tulina NM, Barila GO, Hester MS, Elovitz MA Abstract INTRODUCTION: Exposure to prenatal inflammation is associated with diverse adverse neurobehavioral outcomes in exposed offspring. The mechanism by which inflammation negatively impacts the developing brain is poorly understood. Metabolomic profiling provides an opportunity to identify specific metabolites, and novel pathways, which may reveal mechanisms by which exposure to intrauterine inflammation promotes fetal and neonatal brain injury. Therefore, we investigated whether exposure to intrauterine inflammation altered the metabolome of the amniotic fluid, fetal and neonatal brain. Additionally, we explored whether changes in the metabolomic profile from exposure to prenatal inflammation occurs in a sex-specific manner in the neonatal brain. METHODS: CD-1, timed pregnant mice received an intrauterine injection of lipopolysaccharide (50 μg/dam) or saline on embryonic day 15. Six and 48 hours later mice were sacrificed and amniotic fluid, and fetal brains were collected (n = 8/group). Postnatal brains were collected on day of life 1 (n = 6/group/sex). Global biochemical profiles were determined using ultra performance liquid chromatography/tandem mass spectrometry (Metabolon Inc.). Statistical analyses were performed by comparing samples from lipopolysaccharide and saline treated animals at each time point. For the P1 brains, analyses were stratified by sex. RESULTS/CONCLUSIONS: Exposure to intrauterine inflammation induced unique, temporally regulated changes in the metabolic profiles of amniotic fluid, fetal brain and postnatal brain. Six hours after exposure to intrauterine inflammation, the amniotic fluid and the fetal brain metabolomes were dramatically altered with significant enhancements of amino acid and purine metabolites. The amniotic fluid had enhanced levels of several members of the (hypo) xanthine pathway and this compound was validated as a potential biomarker. By 48 hours, the number of altered biochemicals in both the fetal brain and the amniotic fluid had declined, yet unique profiles existed. Neonatal pups exposed to intrauterine inflammation have significant alterations in their lipid metabolites, in particular, fatty acids. These sex-specific metabolic changes within the newborn brain offer an explanation regarding the sexual dimorphism of certain psychiatric and neurobehavioral disorders associated with exposure to prenatal inflammation. PMID: 29049352 [PubMed - indexed for MEDLINE]

Related Articles Methionine metabolism is essential for SIRT1-regulated mouse embryonic stem cell maintenance and embryonic development. EMBO J. 2017 Nov 02;36(21):3175-3193 Authors: Tang S, Fang Y, Huang G, Xu X, Padilla-Banks E, Fan W, Xu Q, Sanderson SM, Foley JF, Dowdy S, McBurney MW, Fargo DC, Williams CJ, Locasale JW, Guan Z, Li X Abstract Methionine metabolism is critical for epigenetic maintenance, redox homeostasis, and animal development. However, the regulation of methionine metabolism remains unclear. Here, we provide evidence that SIRT1, the most conserved mammalian NAD(+)-dependent protein deacetylase, is critically involved in modulating methionine metabolism, thereby impacting maintenance of mouse embryonic stem cells (mESCs) and subsequent embryogenesis. We demonstrate that SIRT1-deficient mESCs are hypersensitive to methionine restriction/depletion-induced differentiation and apoptosis, primarily due to a reduced conversion of methionine to S-adenosylmethionine. This reduction markedly decreases methylation levels of histones, resulting in dramatic alterations in gene expression profiles. Mechanistically, we discover that the enzyme converting methionine to S-adenosylmethionine in mESCs, methionine adenosyltransferase 2a (MAT2a), is under control of Myc and SIRT1. Consistently, SIRT1 KO embryos display reduced Mat2a expression and histone methylation and are sensitive to maternal methionine restriction-induced lethality, whereas maternal methionine supplementation increases the survival of SIRT1 KO newborn mice. Our findings uncover a novel regulatory mechanism for methionine metabolism and highlight the importance of methionine metabolism in SIRT1-mediated mESC maintenance and embryonic development. PMID: 29021282 [PubMed - indexed for MEDLINE]

Related Articles Adenine Addition Restores Cell Viability and Butanol Production in Clostridium saccharoperbutylacetonicum N1-4 (ATCC 13564) Cultivated at 37°C. Appl Environ Microbiol. 2017 Apr 01;83(7): Authors: Kiyoshi K, Kawashima S, Nobuki K, Kadokura T, Nakazato A, Suzuki KI, Nakayama S Abstract We have developed butanol-producing consolidated bioprocessing from cellulosic substrates through coculture of cellulolytic clostridia and butanol-producing Clostridium saccharoperbutylacetonicum strain N1-4. However, the butanol fermentation by strain N1-4 (which has an optimal growth temperature of 30°C) is sensitive to the higher cultivation temperature of 37°C; the nature of this deleterious effect remains unclear. Comparison of the intracellular metabolites of strain N1-4 cultivated at 30°C and 37°C revealed decreased levels of multiple primary metabolites (notably including nucleic acids and cofactors) during growth at the higher temperature. Supplementation of the culture medium with 250 mg/liter adenine enhanced both cell growth (with the optical density at 600 nm increasing from 4.3 to 10.2) and butanol production (increasing from 3.9 g/liter to 9.6 g/liter) at 37°C, compared to those obtained without adenine supplementation, such that the supplemented 37°C culture exhibited growth and butanol production approaching those observed at 30°C in the absence of adenine supplementation. These improved properties were based on the maintenance of cell viability. We further showed that adenine supplementation enhanced cell viability during growth at 37°C by maintaining ATP levels and inhibiting spore formation. This work represents the first demonstration (to our knowledge) of the importance of adenine-related metabolism for clostridial butanol production, suggesting a new means of enhancing target pathways based on metabolite levels.IMPORTANCE Metabolomic analysis revealed decreased levels of multiple primary metabolites during growth at 37°C, compared to 30°C, in C. saccharoperbutylacetonicum strain N1-4. We found that adenine supplementation restored the cell growth and butanol production of strain N1-4 at 37°C. The effects of adenine supplementation reflected the maintenance of cell viability originating from the maintenance of ATP levels and the inhibition of spore formation. Thus, our metabolomic analysis identified the depleted metabolites that were required to maintain cell viability. Our strategy, which is expected to be applicable to a wide range of organisms, permits the identification of the limiting metabolic pathway, which can serve as a new target for molecular breeding. The other novel finding of this work is that adenine supplementation inhibits clostridial spore formation. The mechanism linking spore formation and metabolomic status in butanol-producing clostridia is expected to be the focus of further research. PMID: 28130303 [PubMed - indexed for MEDLINE]

Related Articles Metabolic profiling on the effect of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) in MCF-7 cells. Chemosphere. 2017 Oct 31;192:297-304 Authors: Wei J, Xiang L, Yuan Z, Li S, Yang C, Liu H, Jiang Y, Cai Z Abstract Polybrominated diphenyl ethers (PBDEs) are commonly used to prevent the development of fire in various factory products. Due to the adverse effects on human health and the bio-accumulation capacity, PBDEs are considered as one kind of persistent organic pollutants (POPs). BDE-47 is one of the most frequently detected PBDEs congeners in human samples. Although numerous studies have shown the close connection between BDE-47 and human health, few reports were related to breast carcinoma. In the present study, the toxicity mechanism of BDE-47 was investigated by using MCF-7 breast cancer cells. Metabolomics analysis was conducted by using ultra-high performance liquid chromatography coupled with mass spectrometry (UHPLC-MS). Results showed that the toxicity to MCF-7 cells gradually increased when the concentration of BDE-47 exceeded 1 μM in the medium with 1% fetal bovine serum (FBS). It was found that pyrimidine metabolism, purine metabolism and pentose phosphate pathway (PPP) were the most influenced metabolic pathways, and the metabolites in the three metabolic pathways were significantly downregulated. Moreover, the increase of reactive oxygen species (ROS) was detected by using the 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining method. The obtained results suggested that the BDE-47 induced oxidative stress by downregulating the NADPH generation in PPP. The pyrimidine metabolism and purine metabolism might be downregulated by the downregulation of mRNA transcripts. Therefore, BDE-47 could induce oxidative stress by inhibiting PPP and disorder the metabolism of the entire cell subsequently. This research provided evidence for investigating mechanism of the adverse effect of BDE-47 on human health. PMID: 29117588 [PubMed - as supplied by publisher]

Related Articles Treatment Outcome of Combined Continuous Venovenous Hemofiltration and Hemoperfusion in Acute Paraquat Poisoning: A Prospective Controlled Trial. Crit Care Med. 2017 Nov 07;: Authors: Li C, Hu D, Xue W, Li X, Wang Z, Ai Z, Song Y, Liu X, Cheng J, Fan S, Zhao L, Wang L, Mohan C, Peng A Abstract OBJECTIVES: To investigate whether combined continuous venovenous hemofiltration and hemoperfusion among paraquat-poisoned patients would improve survival. DESIGN: Prospective, controlled interventional study over 4 years. SETTING: Single, tertiary, academic medical center. PATIENTS: We recruited patients admitted to Shanghai Tenth People's Hospital within 48 hours after paraquat ingestion. Exclusions were under 14 years old, ingestion of paraquat with other toxicants, pregnant, a history of chronic pulmonary disease, psychosis, hyperthyroidism, or diabetes with impaired liver or renal function. INTERVENTIONS: All patients were assigned to receive continuous venovenous hemofiltration with hemoperfusion therapy (continuous venovenous hemofiltration group) and to receive conventional therapy (conventional group). The study outcomes were death from any cause within 90 days after paraquat ingestion and the frequencies of hypoxia, acute kidney injury, or adverse events. MEASUREMENTS AND MAIN RESULTS: Of the 110 enrolled patients, 59 were assigned to continuous venovenous hemofiltration group and 51 to conventional group. The two groups had similar baseline demographics and clinical features. At 90 days after paraquat ingestion, 19 of 59 patients (32.2%) in the continuous venovenous hemofiltration group and 29 of 51 patients (56.9%) in the conventional group had died (hazard ratio, 0.43; 95% CI, 0.24-0.76; p = 0.004). In multivariable Cox proportional hazard models controlling for baseline characteristics, combined continuous venovenous hemofiltration and hemoperfusion was independently associated with reduced risk of death compared with conventional therapy (adjusted hazard ratio, 0.35; 95% CI, 0.19-0.64; p = 0.001). Patients in the continuous venovenous hemofiltration group, as compared to the conventional group, had a reduced occurrence rate of hypoxia (40.7% vs 72.5%; p = 0.001) and of acute kidney injury (59.3% vs 78.4%; p = 0.03). Hypophosphatemia and thrombocytopenia were more common in the continuous venovenous hemofiltration group (p < 0.05). CONCLUSIONS: In patients with paraquat poisoning, treatment with combined continuous venovenous hemofiltration and hemoperfusion significantly improved 90-day survival rates. PMID: 29116999 [PubMed - as supplied by publisher]

Related Articles Targeted Metabolomics Reveals Abnormal Hepatic Energy Metabolism by Depletion of β-Carotene Oxygenase 2 in Mice. Sci Rep. 2017 Nov 07;7(1):14624 Authors: Wu L, Guo X, Lyu Y, Clarke SL, Lucas EA, Smith BJ, Hildebrand D, Wang W, Medeiros DM, Shen X, Lin D Abstract β-carotene oxygenase 2 (BCO2) is a carotenoid cleavage enzyme located in the inner mitochondrial membrane. Ablation of BCO2 impairs mitochondrial function leading to oxidative stress. Herein, we performed a targeted metabolomics study using ultrahigh performance liquid chromatography-tandem mass spectroscopy and gas chromatography-mass spectroscopy to discriminate global metabolites profiles in liver samples from six-week-old male BCO2 systemic knockout (KO), heterozygous (Het), and wild type (WT) mice fed a chow diet. Principal components analysis revealed distinct differences in metabolites in the livers of KO mice, compared to WT and Het mice. However, no marked difference was found in the metabolites of the Het mouse liver compared to the WT. We then conducted random forest analysis to classify the potential biomarkers to further elucidate the different metabolomics profiles. We found that systemic ablation of BCO2 led to perturbations in mitochondrial function and metabolism in the TCA cycle, amino acids, carnitine, lipids, and bile acids. In conclusion, BCO2 is essential to macronutrient and mitochondrial metabolism in the livers of mice. The ablation of BCO2 causes dysfunctional mitochondria and altered energy metabolism, which further leads to systemic oxidative stress and inflammation. A single functional copy of BCO2 largely rescues the hepatic metabolic homeostasis in mice. PMID: 29116185 [PubMed - in process]