PubMed

Related Articles Development and validation of an updated computational model of Streptomyces coelicolor primary and secondary metabolism. BMC Genomics. 2018 Jul 04;19(1):519 Authors: Amara A, Takano E, Breitling R Abstract BACKGROUND: Streptomyces species produce a vast diversity of secondary metabolites of clinical and biotechnological importance, in particular antibiotics. Recent developments in metabolic engineering, synthetic and systems biology have opened new opportunities to exploit Streptomyces secondary metabolism, but achieving industry-level production without time-consuming optimization has remained challenging. Genome-scale metabolic modelling has been shown to be a powerful tool to guide metabolic engineering strategies for accelerated strain optimization, and several generations of models of Streptomyces metabolism have been developed for this purpose. RESULTS: Here, we present the most recent update of a genome-scale stoichiometric constraint-based model of the metabolism of Streptomyces coelicolor, the major model organism for the production of antibiotics in the genus. We show that the updated model enables better metabolic flux and biomass predictions and facilitates the integrative analysis of multi-omics data such as transcriptomics, proteomics and metabolomics. CONCLUSIONS: The updated model presented here provides an enhanced basis for the next generation of metabolic engineering attempts in Streptomyces. PMID: 29973148 [PubMed - in process]

Related Articles Comparative Metabolomic and Proteomic Analyses Reveal the Regulation Mechanism Underlying MeJA-Induced Bioactive Compound Accumulation in Cutleaf Groundcherry ( Physalis angulata L.) Hairy Roots. J Agric Food Chem. 2018 Jun 27;66(25):6336-6347 Authors: Zhan X, Liao X, Luo X, Zhu Y, Feng S, Yu C, Lu J, Shen C, Wang H Abstract Cutleaf groundcherry ( Physalis angulata L.) is an annual plant with a number of medicinal ingredients. However, studies about the secondary metabolism of P. angulata are very limited. An integrated metabolome and proteome approach was used to reveal the variations in the metabolism associated with bioactive compounds under methyl-jasmonate (MeJA) treatment. Application of MeJA to the hairy roots could significantly increase the accumulation of most active ingredients. A targeted approach confirmed the variations in physalins D and H between MeJA treatment and the controls. Increases in the levels of a number of terpenoid backbone biosynthesis and steroid biosynthesis related enzymes, cytochrome P450 monooxygenases and 3β-hydroxysterioid dehydrogenase might provide a potential explanation for the MeJA-induced active ingredient synthesis. Our results may contribute to a deeper understanding of the regulation mechanism underlying the MeJA-induced active compound accumulation in P. angulata. PMID: 29874907 [PubMed - indexed for MEDLINE]

Related Articles Mitochondrial Perturbation Contributing to Cognitive Decline in Streptozotocin-Induced Type 1 Diabetic Rats. Cell Physiol Biochem. 2018;46(4):1668-1682 Authors: Zhou Y, Lian S, Zhang J, Lin D, Huang C, Liu L, Chen Z Abstract BACKGROUND/AIMS: Mitochondrial perturbation is a well-established cause of cognitive decline, but as yet it is unclear how mitochondria-associated neuronal abnormalities in type 1 diabetic (T1DM) brain contribute to cognitive decline. METHODS: The streptozotocin (STZ)-induced mouse model of T1DM was used. The Morris water maze test was applied to assess the effect of T1DM on learning and memory. We detected changes in mitochondrial morphology, function and dynamics. Furthermore, we employed metabolomic analysis to reveal the underlying mechanisms of mitochondrial perturbation which contribute to cognitive decline. RESULTS: Our results show that T1DM impairs mitochondrial dynamics, morphology and function in neurons, associated with a decline in cognitive ability. Metabolomic analyses revealed that T1DM mainly affects metabolic pathways involved in mitochondrial energy failure and impairs the antioxidative system. CONCLUSION: These results lay the basis for understanding the underlying mitochondria-associated causes of T1DM-associated cognitive decline and may provide a potential treatment strategy for this condition in future. PMID: 29694977 [PubMed - indexed for MEDLINE]

Related Articles Metabolomic signatures of low birthweight: Pathways to insulin resistance and oxidative stress. PLoS One. 2018;13(3):e0194316 Authors: Metrustry SJ, Karhunen V, Edwards MH, Menni C, Geisendorfer T, Huber A, Reichel C, Dennison EM, Cooper C, Spector T, Jarvelin MR, Valdes AM Abstract Several studies suggest that low birthweight resulting from restricted intrauterine growth can leave a metabolic footprint which may persist into adulthood. To investigate this, we performed metabolomic profiling on 5036 female twins, aged 18-80, with weight at birth information available from the TwinsUK cohort and performed independent replication in two additional cohorts. Out of 422 compounds tested, 25 metabolites associated with birthweight in these twins, replicated in 1951 men and women from the Hertfordshire Cohort Study (HCS, aged 66) and in 2391 men and women from the North Finland Birth 1986 cohort (NFBC, aged 16). We found distinct heterogeneity between sexes and, after adjusting for multiple tests and heterogeneity, two metabolites were reproducible overall (propionylcarnitine and 3-4-hydroxyphenyllactate). Testing women only, we found other metabolites associated with lower birthweight from the meta-analysis of the three cohorts (2-hydroxy-butyric acid and γ-glutamylleucine). Higher levels of all these metabolites can be linked to insulin resistance, oxidative stress or a dysfunction of energy metabolism, suggesting that low birthweight in both twins and singletons are having an impact on these pathways in adulthood. PMID: 29566009 [PubMed - indexed for MEDLINE]

Related Articles Stereoselective Total Synthesis of Macrophage-Produced Prohealing 14,21-Dihydroxy Docosahexaenoic Acids. J Org Chem. 2018 01 05;83(1):154-166 Authors: Nishimura K, Sakaguchi T, Nanba Y, Suganuma Y, Morita M, Hong S, Lu Y, Jun B, Bazan NG, Arita M, Kobayashi Y Abstract Synthesis of 14S,21R- and 14S,21S-dihydroxy-DHA (diHDHA) among the four possible stereoisomers of 14,21-diHDHA was studied. Methyl (R)-lactate (>97% ee), selected as a C20-C22 fragment (DHA numbering), was converted to the C17-C22 phosphonium salt, which was subjected to a Wittig reaction with racemic C16-aldehyde of the C12-C16 part with the TMS and TBS-oxy groups at C12 and C14, yielding the C12-C22 derivative with 14R/S and 21R chirality. Kinetic resolution using Sharpless asymmetric epoxidation of the TBS-deprotected allylic alcohol with l-(+)-DIPT/Ti(O-i-Pr)4 afforded 14S-epoxy alcohol and 14R-allylic alcohol with >99% diastereomeric excess (de) for both. The CN group was introduced to the epoxy alcohol by reaction with Et2AlCN. The 14R-allylic alcohol was also converted to the nitrile via Mitsunobu inversion. Reduction of the nitrile with DIBAL afforded the key aldehyde corresponding to the C11-C22 moiety. The Wittig reaction of this aldehyde with a phosphonium salt of the remaining C1-C10 part followed by functional group manipulation gave 14S,21R-diHDHA. Similarly, ethyl (S)-lactate (>99% ee) was converted to 14S,21S-diHDHA. The chiral LC-UV-MS/MS analysis demonstrated that each of these two 14,21-diHDHAs synthesized using the presented total organic synthesis was highly stereoselective and identical to the macrophage-produced counterpart. PMID: 29224348 [PubMed - indexed for MEDLINE]

Related Articles Serum lipid profile discriminates patients with early lung cancer from healthy controls. Lung Cancer. 2017 Oct;112:69-74 Authors: Ros-Mazurczyk M, Jelonek K, Marczyk M, Binczyk F, Pietrowska M, Polanska J, Dziadziuszko R, Jassem J, Rzyman W, Widlak P Abstract OBJECTIVES: The role of a low-dose computed tomography lung cancer screening remains a matter of controversy due to its low specificity and high costs. Screening complementation with blood-based biomarkers may allow a more efficient pre-selection of candidates for imaging tests or discrimination between benign and malignant chest abnormalities detected by low-dose computed tomography (LD-CT). We searched for a molecular signature based on a serum lipid profile distinguishing individuals with early lung cancer from healthy participants of the lung cancer screening program. MATERIALS AND METHODS: Blood samples were collected from 100 patients with early stage lung cancer (including 31 screen-detected cases) and from a matched group of 300 healthy participants of the lung cancer screening program. MALDI-ToF mass spectrometry was used to analyze the molecular profile of lipid-containing organic extract of serum samples in the 320-1000Da range. RESULTS: Several components of the serum lipidome were detected, with abundances discriminating patients with early lung cancer from high-risk smokers. An effective cancer classifier was built with an area under the curve of 0.88. Corresponding negative predictive value was 98% and a positive predictive value was 42% when the classifier was tuned for maximum negative predictive value. Furthermore, the downregulation of a few lysophosphatidylcholines (LPC18:2, LPC18:1 and LPC18:0) in samples from cancer patients was confirmed using a complementary LC-MS approach (a reasonable cancer discrimination was possible based on LPC18:2 alone with 25% total weighted error of classification). CONCLUSIONS: Lipid-based serum signature showed potential usefulness in discriminating early lung cancer patients from healthy individuals. PMID: 29191603 [PubMed - indexed for MEDLINE]

Related Articles Hepatocytes of Wistar and Sprague Dawley rats differ significantly in their central metabolism. J Cell Biochem. 2018 Jan;119(1):909-917 Authors: Garg R, Heinzle E, Noor F Abstract Wistar and Sprague-Dawley (SD) rats are most commonly used experimental rats. They have similar genetic background and are therefore, not discriminated in practical research. In this study, we compared metabolic profiles of Wistar and SD rat hepatocytes from middle (6 months) and old (23 months) age groups. Principle component analysis (PCA) on the specific uptake and production rates of amino acids, glucose, lactate and urea indicated clear differences between Wistar and SD rat hepatocytes. SD rat hepatocytes showed higher uptake rates of various essential and non-essential amino acids, particularly in early culture phases (0-12 h) compared to later phases (12-24 h). SD hepatocytes seem to be more sensitive to isolation procedure and in vitro culture requiring more amino acids for cellular maintenance and repair. Major differences between Wistar and SD rat hepatocytes were observed for glucose and branched chain amino acid metabolism. We conclude that the observed differences in the central carbon metabolism of isolated hepatocytes from these two rats should be considered when using one or the other rat type in studies on metabolic effects or diseases such as diabetes or obesity. PMID: 28671274 [PubMed - indexed for MEDLINE]

Related Articles Isolation of Low-Abundant Bacteroidales in the Human Intestine and the Analysis of Their Differential Utilization Based on Plant-Derived Polysaccharides. Front Microbiol. 2018;9:1319 Authors: Tan H, Zhao J, Zhang H, Zhai Q, Chen W Abstract Bacteroidales are the most abundant Gram-negative bacteria flourished in the human intestine with great underlying benefits to be discovered and developed as the next-generation probiotics. However, the traditional isolation method limits the mining of low-abundant species. In this study, modified selective medium was established using xylan as the sole carbohydrate source to enrich low-abundant species such as Prevotella copri and Bacteroides xylanisolvens from healthy human fecal samples. The growth rate, transcriptomics, and metabolomics profiles of the enriched low-abundant species were then evaluated. The considerable upregulated genes encoding xylan-associated hydrolysis and transportation, along with the increased xylose production detected in the culture of the enriched Bacteroidales strains based on xylan, were considered as positive proof of the feasibility of the modified methodology. PMID: 29971058 [PubMed]

Related Articles Vitamin C in Cancer: A Metabolomics Perspective. Front Physiol. 2018;9:762 Authors: Park S, Ahn S, Shin Y, Yang Y, Yeom CH Abstract There is an ongoing interest in cellular antioxidants and oxidants as well as cellular mechanisms underlying their effects. Several reports suggest that vitamin C (L-ascorbic acid) functions as a pro-oxidant with selective toxicity against specific types of tumor cells. In addition, reduced glutathione plays an emerging role in reducing oxidative stress due to xenobiotic toxins such as metals and oxidants associated with diseases such as cancer, cardiovascular disease, and stroke. High-dose intravenous vitamin C and intravenous glutathione have been used as complementary, alternative, and adjuvant medicines. Here, we review the molecular mechanisms underlying the regulation of oxidation/reduction systems, focusing on the altered metabolomics profile in cancer cells following treatment with pharmacological vitamin C. This review focuses on the role of vitamin C in energy metabolism in terms of adenosine triphosphate, cysteine, and reduced glutathione levels, affecting cancer cell death. PMID: 29971019 [PubMed]

Related Articles The CoLoMoTo Interactive Notebook: Accessible and Reproducible Computational Analyses for Qualitative Biological Networks. Front Physiol. 2018;9:680 Authors: Naldi A, Hernandez C, Levy N, Stoll G, Monteiro PT, Chaouiya C, Helikar T, Zinovyev A, Calzone L, Cohen-Boulakia S, Thieffry D, Paulevé L Abstract Analysing models of biological networks typically relies on workflows in which different software tools with sensitive parameters are chained together, many times with additional manual steps. The accessibility and reproducibility of such workflows is challenging, as publications often overlook analysis details, and because some of these tools may be difficult to install, and/or have a steep learning curve. The CoLoMoTo Interactive Notebook provides a unified environment to edit, execute, share, and reproduce analyses of qualitative models of biological networks. This framework combines the power of different technologies to ensure repeatability and to reduce users' learning curve of these technologies. The framework is distributed as a Docker image with the tools ready to be run without any installation step besides Docker, and is available on Linux, macOS, and Microsoft Windows. The embedded computational workflows are edited with a Jupyter web interface, enabling the inclusion of textual annotations, along with the explicit code to execute, as well as the visualization of the results. The resulting notebook files can then be shared and re-executed in the same environment. To date, the CoLoMoTo Interactive Notebook provides access to the software tools GINsim, BioLQM, Pint, MaBoSS, and Cell Collective, for the modeling and analysis of Boolean and multi-valued networks. More tools will be included in the future. We developed a Python interface for each of these tools to offer a seamless integration in the Jupyter web interface and ease the chaining of complementary analyses. PMID: 29971009 [PubMed]

Related Articles The Modulatory Properties of Li-Ru-Kang Treatment on Hyperplasia of Mammary Glands Using an Integrated Approach. Front Pharmacol. 2018;9:651 Authors: Wei S, Qian L, Niu M, Liu H, Yang Y, Wang Y, Zhang L, Zhou X, Li H, Wang R, Li K, Zhao Y Abstract Background: Li-Ru-Kang (LRK) has been used in the treatment of hyperplasia of mammary glands (HMG) for several decades and can effectively improve clinical symptoms. This study aims to investigate the mechanism by which LRK intervenes in HMG based on an integrated approach that combines metabolomics and network pharmacology analyses. Methods: The effects of LRK on HMG induced by estrogen-progesterone in rats were evaluated by analyzing the morphological and pathological characteristics of breast tissues. Moreover, UPLC-QTOF/MS was performed to explore specific metabolites potentially affecting the pathological process of HMG and the effects of LRK. Pathway analysis was conducted with a combination of metabolomics and network pharmacology analyses to illustrate the pathways and network of LRK-treated HMG. Results: Li-Ru-Kang significantly improved the morphological and pathological characteristics of breast tissues. Metabolomics analyses showed that the therapeutic effect of LRK was mainly associated with the regulation of 10 metabolites, including prostaglandin E2, phosphatidylcholine, leukotriene B4, and phosphatidylserine. Pathway analysis indicated that the metabolites were related to arachidonic acid metabolism, glycerophospholipid metabolism and linoleic acid metabolism. Moreover, principal component analysis showed that the metabolites in the model group were clearly classified, whereas the metabolites in the LRK group were between those in the normal and model groups but closer to those in the normal group. This finding indicated that these metabolites may be responsible for the effects of LRK. The therapeutic effect of LRK on HMG was possibly related to the regulation of 10 specific metabolites. In addition, we further verified the expression of protein kinase C alpha (PKCα), a key target predicted by network pharmacology analysis, and showed that LRK could significantly improve the expression of PKCα. Conclusion: Our study successfully explained the modulatory properties of LRK treatment on HMG using metabolomics and network pharmacology analyses. This systematic method can provide methodological support for further understanding the complex mechanism underlying HMG and possible traditional Chinese medicine (TCM) active ingredients for the treatment of HMG. PMID: 29971006 [PubMed]

Related Articles Integrated Network Pharmacology and Metabolomics Analysis of the Therapeutic Effects of Zi Dian Fang on Immune Thrombocytopenic Purpura. Front Pharmacol. 2018;9:597 Authors: Li Y, Li Y, Lu W, Li H, Wang Y, Luo H, Wu Y, Dong W, Bai G, Zhang Y Abstract Current hormone-based treatments for immune thrombocytopenic purpura (ITP) are associated with potentially serious adverse reactions. Zi Dian Fang (ZDF) is a multi-target Traditional Chinese Medicine (TCM) used to treat both the symptoms and root causes of ITP, with fewer side effects than hormone-based treatments. This study analysis of the therapeutic effects of ZDF on ITP from three aspects: platelet proliferation, immunoregulation, and inflammation. After detection of 52 chemical constituents of ZDF by UPLC-Q-TOF/MS, The main targets and pathways affected by ZDF were screened by network pharmacology and verified by Western blot and ELISA. Meanwhile, metabolomics analysis were applied to a mouse model of ITP to identify and screen endogenous terminal metabolites differentially regulated by ZDF. Integrated network pharmacology and metabolomics analysis of the therapeutic effects of ZDF on ITP may be as follows: ZDF counteracts ITP symptoms mainly by inhibiting Ras/MAPKs (Ras/Mitogen-activated protein kinases) pathway, and the expression of upstream protein (Ras) and downstream protein (p-ERK, p-JNK, p-p38) were inhibited, which affects the content of effect index associated with proliferation (Thrombopoietin, TPO; Granulocyte-macrophage colony stimulating factor, GM-CSF), inflammation (Tumor necrosis factor-α, TNF-α; Interleukin-6, IL-6), immune (Interleukin-2, IL-2; Interferon-gamma, IFN-γ; Interleukin-4, IL-4), so that the body's arginine, Δ12-prostaglandin j2 (Δ12-PGJ2), 9-cis-Retinoic Acid, sphingosine-1-phosphate (S1P), oleic acid amide and other 12 endogenous metabolites significantly changes. Considering the established safety profile, the present study suggests ZDF may be a useful alternative to hormone-based therapies for the treatment of ITP. PMID: 29971001 [PubMed]

Related Articles Consequences of blunting the mevalonate pathway in cancer identified by a pluri-omics approach. Cell Death Dis. 2018 Jul 03;9(7):745 Authors: Goulitquer S, Croyal M, Lalande J, Royer AL, Guitton Y, Arzur D, Durand S, Le Jossic-Corcos C, Bouchereau A, Potin P, Akoka S, Antignac JP, Krempf M, Ferchaud-Roucher V, Giraudeau P, Corcos L Abstract We have previously shown that the combination of statins and taxanes was a powerful trigger of HGT-1 human gastric cancer cells' apoptosis1. Importantly, several genes involved in the "Central carbon metabolism pathway in cancer", as reported in the Kyoto Encyclopedia of Genes and Genomes, were either up- (ACLY, ERBB2, GCK, MYC, PGM, PKFB2, SLC1A5, SLC7A5, SLC16A3,) or down- (IDH, MDH1, OGDH, P53, PDK) regulated in response to the drug association. In the present study, we conducted non-targeted metabolomics and lipidomics analyses by complementary methods and cross-platform initiatives, namely mass spectrometry (GC-MS, LC-MS) and nuclear magnetic resonance (NMR), to analyze the changes resulting from these treatments. We identified several altered biochemical pathways involved in the anabolism and disposition of amino acids, sugars, and lipids. Using the Cytoscape environment with, as an input, the identified biochemical marker changes, we distinguished the functional links between pathways. Finally, looking at the overlap between metabolomics/lipidomics and transcriptome changes, we identified correlations between gene expression modifications and changes in metabolites/lipids. Among the metabolites commonly detected by all types of platforms, glutamine was the most induced (6-7-fold), pointing to an important metabolic adaptation of cancer cells. Taken together, our results demonstrated that combining robust biochemical and molecular approaches was efficient to identify both altered metabolic pathways and overlapping gene expression alterations in human gastric cancer cells engaging into apoptosis following blunting the cholesterol synthesis pathway. PMID: 29970880 [PubMed - in process]

Related Articles Combining Targeted Metabolites Analysis and Transcriptomics to Reveal Chemical Composition Difference and Underlying Transcriptional Regulation in Maca (Lepidium Meyenii Walp.) Ecotypes. Genes (Basel). 2018 Jul 03;9(7): Authors: Chen Q, Li M, Wang C, Li Z, Xu J, Zheng Q, Liu P, Zhou H Abstract Maca (Lepidium meyenii Walp.) is a traditional Andean crop with great potential for various sanitarian and medical functions, which is attracting increased research attention. The majority of previous Maca studies were focused on biochemistry and pharmacodynamics, while the genetic basis of its unique characteristics lagged due to a lack of genome information. The authors perform gas chromatography-mass spectrometry (GC/MS) analysis in the hypocotyls of three Maca ecotypes and identify 79 compounds. Among them, 62 compounds have distinct profiles among Maca ecotypes. To reveal the underlying regulatory mechanism of the chemical composition differences, de novo transcriptome sequencing is performed and the transcription profiles of three Maca ecotypes are comparatively analyzed. Functional analysis indicates several key pathways, including “starch and sucrose metabolism,” “phenylpropanoid biosynthesis,” “phenylalanine metabolism” and “plant-pathogen interaction,” are involved in regulating the chemical compositions of Maca. Combining metabolomics and transcriptomics analysis indicates transcription factors such as MYB and WRKY and mediators such as protein kinase and bifunctional inhibitors might be critical regulators of chemical composition in Maca. The transcriptome reference genome and differentially expressed genes (DEGs) obtained in this study might serve as an initial step to illustrate the genetic differences in nutrient component, secondary metabolites content, medicinal function and stress resistance in Maca. PMID: 29970867 [PubMed]

Related Articles Visualizing Energy Charge in Breast Carcinoma Tissues by MALDI Mass-spectrometry Imaging Profiles of Low-molecular-weight Metabolites. Anticancer Res. 2018 Jul;38(7):4267-4272 Authors: Torata N, Kubo M, Miura D, Ohuchida K, Mizuuchi Y, Fujimura Y, Hayakawa E, Kai M, Oda Y, Mizumoto K, Hashizume M, Nakamura M Abstract BACKGROUND/AIM: Metabolomics is widely used for biomarker discovery, but conventional mass-spectrometry extraction procedures lose the spatial localization of metabolites. In this study, we directly analyzed breast carcinoma tissues embedded in frozen tissue microarrays (fTMAs) using MALDI mass-spectrometry imaging (MALDI-MSI). MATERIALS AND METHODS: A total of 119 breast tissues (84 carcinoma and 35 normal) were used. MSI data were extracted from each tissue. RESULTS: Overall, 185 of 1,915 peaks which were commonly detected in 60% of target areas were subjected to further analysis. One hundred and fifty-two peaks of carcinoma showed significantly higher intensity than normal. Comparing metabolite profiles from carcinoma and normal tissues, energy charge (EC) and the sum of adenosine phosphate compound (AXP) indicated significantly higher intensities in cancerous tissues than normal. But comparisons of EC and AXP among lymph node metastasis, tumor size and tumor subtypes indicated no significant differences. CONCLUSION: Breast carcinoma tissues had higher EC and AXP values than normal. MALDI-MSI could be a tool for characterizing breast carcinoma. PMID: 29970560 [PubMed - in process]

Unique Francisella Phosphatidylethanolamine Acts as a Potent Anti-Inflammatory Lipid. J Innate Immun. 2018 Jul 03;:1-15 Authors: Ireland R, Schwarz B, Nardone G, Wehrly TD, Broeckling CD, Chiramel AI, Best SM, Bosio CM Abstract Virulent Francisella tularensis subsp. tularensis (Ftt) is a dynamic, intracellular, bacterial pathogen. Its ability to evade and rapidly suppress host inflammatory responses is considered a key element for its profound virulence. We previously established that Ftt lipids play a role in inhibiting inflammation, but we did not determine the lipid species mediating this process. Here, we show that a unique, abundant, phosphatidylethanolamine (PE), present in Francisella, contributes to driving the suppression of inflammatory responses in human and mouse cells. Acyl chain lengths of this PE, C24: 0 and C10: 0, were key to the suppressive capabilities of Francisella PE. Addition of synthetic PE 24: 0-10: 0 resulted in the accumulation of PE in host cells for up to 24 h of incubation, and recapitulated the inhibition of inflammatory responses observed with native Ftt PE. Importantly, this novel PE significantly inhibited inflammatory responses driven by a medically and globally important flavivirus, dengue fever virus. Thus, targeting these lipids and/or the pathways that they manipulate represents a new strategy to combat immunosuppression engendered by Ftt, but they also show promise as a novel therapeutic intervention for significant viral infections. PMID: 29969788 [PubMed - as supplied by publisher]

Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics. Sci Rep. 2018 Jul 03;8(1):10056 Authors: Nagy-Szakal D, Barupal DK, Lee B, Che X, Williams BL, Kahn EJR, Ukaigwe JE, Bateman L, Klimas NG, Komaroff AL, Levine S, Montoya JG, Peterson DL, Levin B, Hornig M, Fiehn O, Lipkin WI Abstract The pathogenesis of ME/CFS, a disease characterized by fatigue, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever, irritable bowel syndrome (IBS), and lymphadenopathy, is poorly understood. We report biomarker discovery and topological analysis of plasma metabolomic, fecal bacterial metagenomic, and clinical data from 50 ME/CFS patients and 50 healthy controls. We confirm reports of altered plasma levels of choline, carnitine and complex lipid metabolites and demonstrate that patients with ME/CFS and IBS have increased plasma levels of ceramide. Integration of fecal metagenomic and plasma metabolomic data resulted in a stronger predictive model of ME/CFS (cross-validated AUC = 0.836) than either metagenomic (cross-validated AUC = 0.745) or metabolomic (cross-validated AUC = 0.820) analysis alone. Our findings may provide insights into the pathogenesis of ME/CFS and its subtypes and suggest pathways for the development of diagnostic and therapeutic strategies. PMID: 29968805 [PubMed - in process]

Metabolomic and lipidomic analysis of the effect of pioglitazone on hepatic steatosis in a rat model of obese type 2 diabetes. Br J Pharmacol. 2018 Jul 02;: Authors: Yang H, Suh DH, Kim DH, Jung ES, Liu KH, Lee CH, Park CY Abstract BACKGROUND AND PURPOSE: Thiazolidinediones, acting as peroxisome proliferator-activated receptor gamma ligands, reduce hepatic steatosis in humans and animals. However, the underlying mechanism of this action remains unclear. The purpose of this study was to investigate changes in hepatic metabolites and lipids in response to treatment with the thiazolidinedione pioglitazone in an animal model of obese type 2 diabetes. EXPERIMENTAL APPROACH: Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats were orally administered either vehicle (control) or pioglitazone (30 mg·kg-1 ) and fed a high-fat diet (60 kcal % fat) for 12 weeks. Hepatic metabolites were analyzed via metabolomic and lipidomic analyses. Gene expression and phospholipase A2 (PLA2 ) activity were analyzed in pioglitazone and control rat livers. KEY RESULTS: OLETF rats that received pioglitazone showed decreased fat accumulation and improvement of lipid profiles in the liver compared to control rats. Pioglitazone treatment significantly altered levels of hepatic metabolites, including free fatty acids, lysophosphatydylcholines, and phosphatidylcholines in the liver. In addition, pioglitazone significantly reduced the expression of genes involved in hepatic de novo lipogenesis and fatty acid uptake and transport, whereas genes related to fatty acid oxidation were up-regulated. Gene expression and enzyme activity of PLA2 , which hydrolyzes phosphatidylcholines to release lysophosphatydylcholines and free fatty acids, were significantly decreased in the livers of pioglitazone-treated rats compared to control rats. CONCLUSION AND IMPLICATIONS: Our results present evidence for the ameliorative effect of pioglitazone on hepatic steatosis, largely due to the regulation of lipid metabolism, including fatty acids, lysophosphatydylcholines, phosphatidylcholines, and related gene-expression patterns. PMID: 29968381 [PubMed - as supplied by publisher]

Round robin study of formalin-fixed paraffin-embedded tissues in mass spectrometry imaging. Anal Bioanal Chem. 2018 Jul 03;: Authors: Buck A, Heijs B, Beine B, Schepers J, Cassese A, Heeren RMA, McDonnell LA, Henkel C, Walch A, Balluff B Abstract Mass spectrometry imaging (MSI) has provided many results with translational character, which still have to be proven robust in large patient cohorts and across different centers. Although formalin-fixed paraffin-embedded (FFPE) specimens are most common in clinical practice, no MSI multicenter study has been reported for FFPE samples. Here, we report the results of the first round robin MSI study on FFPE tissues with the goal to investigate the consequences of inter- and intracenter technical variation on masking biological effects. A total of four centers were involved with similar MSI instrumentation and sample preparation equipment. A FFPE multi-organ tissue microarray containing eight different types of tissue was analyzed on a peptide and metabolite level, which enabled investigating different molecular and biological differences. Statistical analyses revealed that peptide intercenter variation was significantly lower and metabolite intercenter variation was significantly higher than the respective intracenter variations. When looking at relative univariate effects of mass signals with statistical discriminatory power, the metabolite data was more reproducible across centers compared to the peptide data. With respect to absolute effects (cross-center common intensity scale), multivariate classifiers were able to reach on average > 90% accuracy for peptides and > 80% for metabolites if trained with sufficient amount of cross-center data. Overall, our study showed that MSI data from FFPE samples could be reproduced to a high degree across centers. While metabolite data exhibited more reproducibility with respect to relative effects, peptide data-based classifiers were more directly transferable between centers and therefore more robust than expected. Graphical abstract ᅟ. PMID: 29968108 [PubMed - as supplied by publisher]

Higher Concentrations of BCAAs and 3-HIB Are Associated with Insulin Resistance in the Transition from Gestational Diabetes to Type 2 Diabetes. J Diabetes Res. 2018;2018:4207067 Authors: Andersson-Hall U, Gustavsson C, Pedersen A, Malmodin D, Joelsson L, Holmäng A Abstract Aim: Determine the metabolic profile and identify risk factors of women transitioning from gestational diabetes mellitus (GDM) to type 2 diabetes mellitus (T2DM). Methods: 237 women diagnosed with GDM underwent an oral glucose tolerance test (OGTT), anthropometrics assessment, and completed lifestyle questionnaires six years after pregnancy. Blood was analysed for clinical variables (e.g., insulin, glucose, HbA1c, adiponectin, leptin, and lipid levels) and NMR metabolomics. Based on the OGTT, women were divided into three groups: normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and T2DM. Results: Six years after GDM, 19% of subjects had T2DM and 19% IGT. After BMI adjustment, the IGT group had lower HDL, higher leptin, and higher free fatty acid (FFA) levels, and the T2DM group higher triglyceride, FFA, and C-reactive protein levels than the NGT group. IGT and T2DM groups reported lower physical activity. NMR measurements revealed that levels of branched-chain amino acids (BCAAs) and the valine metabolite 3-hydroxyisobyturate were higher in T2DM and IGT groups and correlated with measures of insulin resistance and lipid metabolism. Conclusion: In addition to well-known clinical risk factors, BCAAs and 3-hydroxyisobyturate are potential markers to be evaluated as predictors of metabolic risk after pregnancy complicated by GDM. PMID: 29967793 [PubMed - in process]