PubMed

Related Articles The Effect of Chinese Herbal Medicine Formula mKG on Allergic Asthma by Regulating Lung and Plasma Metabolic Alternations. Int J Mol Sci. 2017 Mar 10;18(3): Authors: Yu M, Jia HM, Cui FX, Yang Y, Zhao Y, Yang MH, Zou ZM Abstract Asthma is a chronic inflammatory disorder of the airway and is characterized by airway remodeling, hyperresponsiveness, and shortness of breath. Modified Kushen Gancao Formula (mKG), derived from traditional Chinese herbal medicines (TCM), has been demonstrated to have good therapeutic effects on experimental allergic asthma. However, its anti-asthma mechanism remains currently unknown. In the present work, metabolomics studies of biochemical changes in the lung tissue and plasma of ovalbumin (OVA)-induced allergic asthma mice with mKG treatment were performed using ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Partial least squares-discriminate analysis (PLS-DA) indicated that the metabolic perturbation induced by OVA was reduced after mKG treatment. A total of twenty-four metabolites involved in seven metabolic pathways were identified as potential biomarkers in the development of allergic asthma. Among them, myristic acid (L3 or P2), sphinganine (L6 or P4), and lysoPC(15:0) (L12 or P16) were detected both in lung tissue and plasma. Additionally, l-acetylcarnitine (L1), thromboxane B2 (L2), 10-HDoHE (L10), and 5-HETE (L11) were first reported to be potential biomarkers associated with allergic asthma. The treatment of mKG mediated all of those potential biomarkers except lysoPC(15:0) (P16). The anti-asthma mechanism of mKG can be achieved through the comprehensive regulation of multiple perturbed biomarkers and metabolic pathways. PMID: 28287417 [PubMed - in process]

Related Articles Metabolic map of osthole and its effect on lipids. Xenobiotica. 2017 Mar 13;:1-38 Authors: Zhao Q, Li XM, Liu HN, Gonzalez FJ, Li F Abstract 1. Osthole, a coumarin compound from plants, is a promising agent for the treatment of metabolic diseases, including hyperglycemia, fatty liver, and cancers. Studies indicate that the peroxisome proliferator-activated receptors (PPAR) α and γ are involved in the pharmacological effects of osthole. The in vitro and in vivo metabolism of osthole, and its biological activity are not completely understood. 2. In this study, UPLC-ESI-QTOFMS-based metabolomics was used to determine the metabolic pathway of osthole and its influence on the levels of endogenous metabolites. Forty-one osthole metabolites, including twenty-three novel metabolites, were identified and structurally elucidated from its metabolism in vitro and in vivo. Recombinant cytochrome P450s (CYPs) screening showed that CYP3A4 and CYP3A5 were the primary enzymes contributing to osthole metabolism. 3. More importantly, osthole was able to decrease the levels of lysophosphatidylethanolamine and lysophosphatidylcholine in the plasma, which explains in part its modulatory effects on metabolic diseases. 4. This study gives the insights about the metabolic pathways of osthole in vivo, including hydroxylation, glucuronidation, and sulfation. Furthermore, the levels of the lipids regulated by osthole indicated its potential effects on adipogenesis. These data contribute to the understanding of the disposition and pharmacological activity of osthole in vivo. PMID: 28287022 [PubMed - as supplied by publisher]

Related Articles Systems analysis of ethanol production in the genetically engineered cyanobacterium Synechococcus sp. PCC 7002. Biotechnol Biofuels. 2017;10:56 Authors: Kopka J, Schmidt S, Dethloff F, Pade N, Berendt S, Schottkowski M, Martin N, Dühring U, Kuchmina E, Enke H, Kramer D, Wilde A, Hagemann M, Friedrich A Abstract BACKGROUND: Future sustainable energy production can be achieved using mass cultures of photoautotrophic microorganisms, which are engineered to synthesize valuable products directly from CO2 and sunlight. As cyanobacteria can be cultivated in large scale on non-arable land, these phototrophic bacteria have become attractive organisms for production of biofuels. Synechococcus sp. PCC 7002, one of the cyanobacterial model organisms, provides many attractive properties for biofuel production such as tolerance of seawater and high light intensities. RESULTS: Here, we performed a systems analysis of an engineered ethanol-producing strain of the cyanobacterium Synechococcus sp. PCC 7002, which was grown in artificial seawater medium over 30 days applying a 12:12 h day-night cycle. Biosynthesis of ethanol resulted in a final accumulation of 0.25% (v/v) ethanol, including ethanol lost due to evaporation. The cultivation experiment revealed three production phases. The highest production rate was observed in the initial phase when cells were actively growing. In phase II growth of the producer strain stopped, but ethanol production rate was still high. Phase III was characterized by a decrease of both ethanol production and optical density of the culture. Metabolomics revealed that the carbon drain due to ethanol diffusion from the cell resulted in the expected reduction of pyruvate-based intermediates. Carbon-saving strategies successfully compensated the decrease of central intermediates of carbon metabolism during the first phase of fermentation. However, during long-term ethanol production the producer strain showed clear indications of intracellular carbon limitation. Despite the decreased levels of glycolytic and tricarboxylic acid cycle intermediates, soluble sugars and even glycogen accumulated in the producer strain. The changes in carbon assimilation patterns are partly supported by proteome analysis, which detected decreased levels of many enzymes and also revealed the stress phenotype of ethanol-producing cells. Strategies towards improved ethanol production are discussed. CONCLUSIONS: Systems analysis of ethanol production in Synechococcus sp. PCC 7002 revealed initial compensation followed by increasing metabolic limitation due to excessive carbon drain from primary metabolism. PMID: 28286551 [PubMed]

Related Articles Lipid response patterns in acute phase paediatric Plasmodium falciparum malaria. Metabolomics. 2017;13(4):41 Authors: Orikiiriza J, Surowiec I, Lindquist E, Bonde M, Magambo J, Muhinda C, Bergström S, Trygg J, Normark J Abstract INTRODUCTION: Several studies have observed serum lipid changes during malaria infection in humans. All of them were focused at analysis of lipoproteins, not specific lipid molecules. The aim of our study was to identify novel patterns of lipid species in malaria infected patients using lipidomics profiling, to enhance diagnosis of malaria and to evaluate biochemical pathways activated during parasite infection. METHODS: Using a multivariate characterization approach, 60 samples were representatively selected, 20 from each category (mild, severe and controls) of the 690 study participants between age of 0.5-6 years. Lipids from patient's plasma were extracted with chloroform/methanol mixture and subjected to lipid profiling with application of the LCMS-QTOF method. RESULTS: We observed a structured plasma lipid response among the malaria-infected patients as compared to healthy controls, demonstrated by higher levels of a majority of plasma lipids with the exception of even-chain length lysophosphatidylcholines and triglycerides with lower mass and higher saturation of the fatty acid chains. An inverse lipid profile relationship was observed when plasma lipids were correlated to parasitaemia. CONCLUSIONS: This study demonstrates how mapping the full physiological lipid response in plasma from malaria-infected individuals can be used to understand biochemical processes during infection. It also gives insights to how the levels of these molecules relate to acute immune responses. PMID: 28286460 [PubMed - in process]

Related Articles Earwax: A neglected body secretion or a step ahead in clinical diagnosis? A pilot study. J Proteomics. 2017 Mar 09;: Authors: Shokry E, de Oliveira AE, Avelino MA, de Deus MM, Filho NR Abstract This work combines the advantages of volatile metabolites profiling as a young growing research field with a non-invasive sampling technique using earwax "a neglected body secretion" for detection and monitoring of biomarkers for diabetes mellitus (types 1 and 2). Earwax samples were collected from 26 diabetic patients of both types, analyzed by headspace gas chromatography mass spectrometry and confronted to the volatile earwax composition of 33 healthy individuals. Data mining analysis was conducted using different models to discriminate the healthy individuals from the diabetic patients and to discriminate between both types of diabetes as well. The model with the best discriminating ability was found to be partial least squares discriminant analysis (PLS-DA) after variable selection. The 6 most important biomarkers were ethanol, acetone, methoxyacetone, hydroxyurea, isobutyraldehyde, and acetic acid. The multivariate model constructed was validated using a test data set and was able to correctly predict all the samples. The receiver operating characteristic (ROC) curves were built for the 6 variables for diabetes types 1 and 2 diagnoses. Among the 6 variables selected, methoxyacetone was the only biomarker able solely to perfectly discriminate between diabetes types 1 and 2. The method is simple, non-invasive, accurate, and highly accepted by patients. SIGNIFICANCE: Our method involves a volatolomic approach by headspace gas chromatography coupled with mass spectrometry as a single analytical technique combined with multivariate data analysis to detect biomarkers of diabetes in earwax samples. Our method was able to discriminate with high accuracy between 33 healthy controls and 26 diabetic patients as well as its types (1 and 2). Our method employing earwax, a "neglected biological matrix" not only has the advantage of non-invasive sampling but also overcomes the limitations of the applied procedures in other biological samples, involving no or minimum sample pretreatment, no external contamination and utilizing a simple sample collection technique. PMID: 28286320 [PubMed - as supplied by publisher]

Related Articles Age-related changes in skeletal muscle composition: A pilot nuclear magnetic resonance spectroscopy study in mice. Exp Gerontol. 2017 Mar 07;: Authors: Sobolev AP, Mannina L, Costanzo M, Cisterna B, Malatesta M, Zancanaro C Abstract The composition of skeletal muscle was investigated in the quadriceps and gastrocnemius muscle of 13-month-old (n=15) and 23-month-old (n=19) mice by means of high-resolution nuclear magnetic resonance (NMR) spectroscopy. Muscle specimens were dissected out, frozen in liquid nitrogen and extracted in chloroform/methanol, and proton NMR spectra of the resulting aqueous and organic fractions were obtained at 600MHz. Several metabolites were unambiguously identified and quantified. Multivariate ANOVA (factor: age, muscle, age×muscle) showed a significant main effect of age (P=0.031) on the amount of muscle metabolites, suggesting that the aging process affects the composition of skeletal muscle. Univariate tests showed significant differences for lactate, acetate, taurine, and uridine in 13- and 23-month-old mice. A trend for the effect of muscle (quadriceps vs. gastrocnemius; P=0.128) was also found. No significant muscle x age interaction was present. When the same data were used in principal component analysis, the first two principal components separated muscles (quadriceps and gastrocnemius) and ages (13- and 23-month-old), explaining 66.7% of total variance. The results of this pilot study show that high-resolution NMR spectroscopy is able to detect age-associated changes in skeletal muscle metabolites, thereby paving the way to future detailed metabolomics investigation in sarcopenia of aging. PMID: 28286172 [PubMed - as supplied by publisher]

Related Articles The inhibition of UDP-glucuronosyltransferases (UGTs) by tetraiodothyronine (T4) and triiodothyronine (T3). Xenobiotica. 2017 Mar 13;:1-18 Authors: Chen DW, Du Z, Zhang CZ, Zhang WH, Cao YF, Sun HZ, Zhu ZT, Yang K, Liu YZ, Zhao ZW, Fu ZW, Gu WQ, Yu Y, Fang ZZ Abstract 1. UDP-glucuronosyltransferases (UGTs) are important drug-metabolizing enzymes (DMEs) catalyzing the glucuronidation elimination of various xenobiotics and endogenous substances. Endogenous substances are important regulators for the activity of various UGT isoforms. Triiodothyronine (T3) and thyroxine (T4) are important thyroid hormones essential for normal cellular differentiation and growth. The present study aims to elucidate the inhibition behavior of T3 and T4 on the activity of UGT isoforms. 2. In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was used to screen the inhibition potential of triiodothyronine (T3) and thyroxine (T4) on the activity of various UGT isoforms. Initial screening results showed that T4 exerted stronger inhibition potential than T3 on the activity of various UGT isoforms at 100 μM. Inhibition kinetics was determined for the inhibition of T4 on the representative UGT isoforms, including UGT1A1, -1A3, -1A7, -1A8, -1A10, and -2B7. The results showed that T4 competitively inhibited the activity of UGT1A1, -1A3, -1A7, 1A10, and -2B7, and noncompetitively inhibited the activity of UGT1A8. The inhibition kinetic parameters were calculated to be 1.5, 2.4, 11, 9.6, 4.8, and 3.0 μM for UGT1A1, -1A3, -1A7, -1A8, -1A10, and -2B7, respectively. In silico docking method was employed to demonstrate why T4 exerted stronger inhibition than T3 towards UGT1A1. Stronger hydrogen bonds and hydrophobic interaction between T4 and activity cavity of UGT1A1 than T3 contributed to stronger inhibition of T4 towards UGT1A1. 3. In conclusion, more clinical monitoring should be given for the patients with the elevation of T4 level due to stronger inhibition of UGT isoforms-catalyzed metabolism of drugs or endogenous substances by T4. PMID: 28285550 [PubMed - as supplied by publisher]

Related Articles Study the therapeutic mechanism of Amomum compactum in gentamicin-induced acute kidney injury rat based on a back propagation neural network algorithm. J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Jan 01;1040:81-88 Authors: Wang X, Chen H, Chang C, Jiang M, Wang X, Xu L Abstract Acute kidney injury (AKI) is a major global public health problems, as it causes high morbidity and serious injury to renal function. However, the etiology for AKI is not very clear. In this study, a serum metabolite profile analysis was performed to identify potential biomarkers for gentamicin-induced AKI and to investigate the mechanism of action of Amomum compactum (AC) used for treatment. A metabonomics approach by ultra-performance liquid chromatography together with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was applied to perform the analysis. Back propagation (BP) neural network models were established for classifying data from the control, model, and AC-treated groups. Accuracy rate for classification was 91.7% in positive ion mode and 87.5% in negative ion mode. By orthogonal partial least squares discriminant analysis (OPLS-DA), 29 metabolites were identified as potential biomarkers of gentamicin-induced AKI. Most of them are related to phospholipid metabolism. After treatment with AC, the levels of sphingomyelin, sphingosine, phytosphingosine, and arachidonic acid were restored to normal. The results indicate that AC plays a protective role in rats with gentamicin-induced AKI via regulation of the phospholipid metabolic pathway. In this work, early biomarkers of AKI has been identified and underlying therapeutic mechanism of AC has been understood, therefore, AC can be further investigated and tested for clinical application. PMID: 27978472 [PubMed - indexed for MEDLINE]

Related Articles Can stable isotope mass spectrometry replace ‎radiolabelled approaches in metabolic studies? Plant Sci. 2016 Aug;249:59-69 Authors: Batista Silva W, Daloso DM, Fernie AR, Nunes-Nesi A, Araújo WL Abstract Metabolic pathways and the key regulatory points thereof can be deduced using isotopically labelled substrates. One prerequisite is the accurate measurement of the labeling pattern of targeted metabolites. The subsequent estimation of metabolic fluxes following incubation in radiolabelled substrates has been extensively used. Radiolabelling is a sensitive approach and allows determination of total label uptake since the total radiolabel content is easy to detect. However, the incubation of cells, tissues or the whole plant in a stable isotope enriched environment and the use of either mass spectrometry or nuclear magnetic resonance techniques to determine label incorporation within specific metabolites offers the possibility to readily obtain metabolic information with higher resolution. It additionally also offers an important complement to other post-genomic strategies such as metabolite profiling providing insights into the regulation of the metabolic network and thus allowing a more thorough description of plant cellular function. Thus, although safety concerns mean that stable isotope feeding is generally preferred, the techniques are in truth highly complementary and application of both approaches in tandem currently probably provides the best route towards a comprehensive understanding of plant cellular metabolism. PMID: 27297990 [PubMed - indexed for MEDLINE]

Related Articles Probiotic Strain Bifidobacterium animalis subsp. lactis CECT 8145 Reduces Fat Content and Modulates Lipid Metabolism and Antioxidant Response in Caenorhabditis elegans. J Agric Food Chem. 2016 May 04;64(17):3462-72 Authors: Martorell P, Llopis S, González N, Chenoll E, López-Carreras N, Aleixandre A, Chen Y, Karoly ED, Ramón D, Genovés S Abstract Recently, microbial changes in the human gut have been proposed as a possible cause of obesity. Therefore, modulation of microbiota through probiotic supplements is of great interest to support obesity therapeutics. The present study examines the functional effect and metabolic targets of a bacterial strain, Bifidobacterium animalis subsp. lactis CECT 8145, selected from a screening in Caenorhabditis elegans. This strain significantly reduced total lipids (40.5% ± 2.4) and triglycerides (27.6% ± 0.5), exerting antioxidant effects in the nematode (30% ± 2.8 increase in survival vs control); activities were also preserved in a final food matrix (milk). Furthermore, transcriptomic and metabolomic analyses in nematodes fed with strain CECT 8145 revealed modulation of the energy and lipid metabolism, as well as the tryptophan metabolism (satiety), as the main metabolic targets of the probiotic. In conclusion, our study describes for the first time a new B. animalis subsp. lactis strain, CECT 8145, as a promising probiotic for obesity disorders. Furthermore, the data support future studies in obesity murine models. PMID: 27054371 [PubMed - indexed for MEDLINE]

Related Articles Microdialysis measurements of equine lamellar perfusion and energy metabolism in response to physical and pharmacological manipulations of blood flow. Equine Vet J. 2016 Nov;48(6):756-764 Authors: Medina-Torres CE, Underwood C, Pollitt CC, Castro-Olivera EM, Hodson MP, Richardson DW, van Eps AW Abstract REASONS FOR PERFORMING STUDY: A suitable method for evaluating lamellar perfusion changes and their metabolic consequences is currently lacking. OBJECTIVES: To examine perfusion changes in lamellar tissue using serial microdialysis measurements of urea clearance and energy metabolites. STUDY DESIGN: Randomised, controlled (within subject) experimental trial. METHODS: Nine Standardbred horses were instrumented with microdialysis probes in the foot lamellar tissue and skin (over the tail base). Urea (20 mmol/l) was added to the perfusate and its clearance was used to estimate local perfusion. Samples were collected every 15 min for a 1 h control period, then during application of a distal limb tourniquet, during periods when norepinephrine or potassium chloride (KCl) were included in both skin and lamellar perfusates, and after systemic (intravenous) acetylpromazine. Dialysate concentrations of glucose, lactate, pyruvate and urea were measured and lactate:glucose (L:G) and lactate:pyruvate (L:P) ratios calculated. Values were compared with pre-intervention baseline and also between simultaneous skin and lamellar samples using nonparametric statistical methods. RESULTS: Lamellar glucose decreased and lactate, urea, L:G and L:P increased significantly with tourniquet application, without significant changes in skin dialysate values. Lamellar and skin glucose decreased and L:G increased significantly during norepinephrine infusion, but mild increases in urea were not significant at either site. KCl caused significant decreases in lamellar and skin L:G, and an increase in skin glucose, but did not affect urea clearance. Acetylpromazine caused profound decreases in lamellar glucose and L:P, with increased L:G and pyruvate, but did not affect urea clearance or any skin dialysate values. CONCLUSIONS: Significant changes in microdialysis urea clearance only occurred with severe lamellar hypoperfusion. However, changes in dialysate metabolite concentrations reflected less profound fluctuations in perfusion. This method may be useful for examining lamellar perfusion and energy balance during laminitis development and for the evaluation of vasoactive therapeutics. PMID: 26500146 [PubMed - indexed for MEDLINE]

Related Articles A Review on the Effect of Drying on Antioxidant Potential of Fruits and Vegetables. Crit Rev Food Sci Nutr. 2016 Jul 29;56 Suppl 1:S110-29 Authors: Kamiloglu S, Toydemir G, Boyacioglu D, Beekwilder J, Hall RD, Capanoglu E Abstract The role of antioxidants in human nutrition has gained increased interest, especially due to their associated health beneficial effects for a number of chronic diseases, including cardiovascular diseases and certain types of cancer. Fruits and vegetables are perishable and difficult to preserve as fresh products. Dried fruits and vegetables can be easily stored, transported at relatively low cost, have reduced packing costs, and their low water content delays microbial spoilage. Air-, freeze-, microwave- and sun-drying are among the most thoroughly studied drying methods. This review provides an overview of recent findings on the effects of different drying techniques on major antioxidants of fruits and vegetables. In particular, changes in ascorbic acid, carotenoids, flavonoids, phenolic acids, total phenolics, and antioxidant activity are discussed in detail. PMID: 26191781 [PubMed - indexed for MEDLINE]

Metabolomics and neuroanatomical evaluation of post-mortem changes in the hippocampus. Brain Struct Funct. 2017 Mar 11;: Authors: Gonzalez-Riano C, Tapia-González S, García A, Muñoz A, DeFelipe J, Barbas C Abstract Understanding the human brain is the ultimate goal in neuroscience, but this is extremely challenging in part due to the fact that brain tissue obtained from autopsy is practically the only source of normal brain tissue and also since changes at different levels of biological organization (genetic, molecular, biochemical, anatomical) occur after death due to multiple mechanisms. Here we used metabolomic and anatomical techniques to study the possible relationship between post-mortem time (PT)-induced changes that may occur at both the metabolomics and anatomical levels in the same brains. Our experiments have mainly focused on the hippocampus of the mouse. We found significant metabolomic changes at 2 h PT, whereas the integrity of neurons and glia, at the anatomical/ neurochemical level, was not significantly altered during the first 5 h PT for the majority of histological markers. PMID: 28285370 [PubMed - as supplied by publisher]

Diseases of the Synaptic Vesicle: A Potential New Group of Neurometabolic Disorders Affecting Neurotransmission. Semin Pediatr Neurol. 2016 Nov;23(4):306-320 Authors: Cortès-Saladelafont E, Tristán-Noguero A, Artuch R, Altafaj X, Bayès A, García-Cazorla A Abstract The general concept of inborn error of metabolism is currently evolving into the interface between classical biochemistry and cellular biology. Basic neuroscience is providing increasing knowledge about the mechanisms of neurotransmission and novel related disorders are being described. There is a necessity of updating the classic concept of "inborn error of neurotransmitters (NT)" that considers mainly defects of synthesis and catabolism and transport of low weight NT molecules. Monogenic defects of the synaptic vesicle (SV), and especially those affecting the SV cycle are a potential new group of NT disorders since they end up in abnormal NT turnover and release. The most common clinical manifestations include epilepsy, intellectual disability, autism and movement disorders, and are in the continuum symptoms of synaptopathies. Interestingly, brain malformations and neurodegenerative conditions are also present within SV diseases. Metabolomics, proteomics, and other -omic techniques probably will provide biomarkers and contribute to therapeutic targets in the future. PMID: 28284392 [PubMed - in process]

Candida krusei form mycelia along agar surfaces towards each other and other Candida species. BMC Microbiol. 2017 Mar 11;17(1):60 Authors: Fleischmann J, Broeckling CD, Lyons S Abstract BACKGROUND: Candida krusei has been known to exhibit communal interactions such as pellicle formation and crawling out of nutritional broth. We noticed another possible interaction on agar surfaces, where C. krusei yeast cells formed mycelia along agar surfaces toward each other. We report here the results of experiments to study this interaction. RESULTS: When C.krusei yeast cells are plated in parallel streaks, they form mycelia along agar surfaces toward other yeasts. They also detect the presence of Candida albicans and Candida glabrata across agar surfaces, while the latter two react neither to their own kind, nor to C. krusei. Secreted molecule(s) are likely involved as C.krusei does not react to heat killed C. krusei. Timing and rate of mycelia formation across distances suggests that mycelia start forming when a secreted molecule(s) on agar surface reaches a certain concentration. We detected farnesol, tyrosol and tryptophol molecules that may be involved with mycelial formation, on the agar surfaces between yeast streaks. Unexpectedly the amounts detected between streaks were significantly higher than would have expected from additive amounts of two streaks. All three Candida species secreted these molecules. When tested on agar surface however, none of these molecules individually or combined induced mycelia formation by C. krusei. CONCLUSIONS: Our data confirms another communal interaction by C. krusei, manifested by formation of mycelia by yeast cells toward their own kind and other yeasts on agar surfaces. We detected secretion of farnesol, tyrosol and tryptophol by C. krusei but none of these molecules induced this activity on agar surface making it unlikely that they are the ones utilized by this yeast for this activity. PMID: 28284180 [PubMed - in process]

Related Articles Leveraging increased cytoplasmic nucleoside kinase activity to target mtDNA and oxidative phosphorylation in AML. Blood. 2017 Mar 10;: Authors: Liyanage SU, Hurren R, Voisin V, Bridon G, Wang X, Xu C, MacLean N, Siriwardena TP, Gronda M, Yehudai D, Sriskanthadevan S, Avizonis D, Shamas-Din A, Minden MD, Bader GD, Laposa R, Schimmer AD Abstract Mitochondrial DNA (mtDNA) biosynthesis requires replication factors and adequate nucleotide pools from the mitochondria and cytoplasm. We performed gene expression profiling analysis of 542 human AML samples and identified 55% with upregulated mtDNA biosynthesis pathway expression compared to normal hematopoietic cells. Genes that support mitochondrial nucleotide pools, including mitochondrial nucleotide transporters and a subset of cytoplasmic nucleoside kinases, were also increased in AML compared to normal hematopoietic samples. Knockdown of cytoplasmic nucleoside kinases reduced mtDNA levels in AML cells, demonstrating their contribution in maintaining mtDNA. To assess cytoplasmic nucleoside kinase pathway activity, we employed a nucleoside analog 2'3'-dideoxycytidine (ddC), which is phosphorylated to the activated anti-metabolite, 2'3'-dideoxycytidine triphosphate (ddCTP) by cytoplasmic nucleoside kinases. ddC is a selective inhibitor of the mitochondrial DNA polymerase, POLG. ddC was preferentially activated in AML cells compared to normal hematopoietic progenitor cells. ddC treatment inhibited mtDNA replication, oxidative phosphorylation, and induced cytotoxicity in a panel of AML cell lines. Furthermore, ddC preferentially inhibited mtDNA replication in a subset of primary human leukemia cells and selectively targeted leukemia cells while sparing normal progenitors cells. In animal models of human AML, treatment with ddC decreased mtDNA, electron transport chain proteins, and induced tumor regression without toxicity. ddC also targeted leukemic stem cells in secondary AML xenotransplantation assays. Thus, AML cells have increased cytidine nucleoside kinase activity that regulates mtDNA biogenesis and can be leveraged to selectively target oxidative phosphorylation in AML. PMID: 28283480 [PubMed - as supplied by publisher]

Related Articles Global metabolome changes induced by cyanobacterial blooms in three representative fish species. Sci Total Environ. 2017 Mar 07;: Authors: Sotton B, Paris A, Le Manach S, Blond A, Lacroix G, Millot A, Duval C, Qiao Q, Catherine A, Marie B Abstract Cyanobacterial blooms induce important ecological constraints for aquatic organisms and strongly impact the functioning of aquatic ecosystems. In the past decades, the effects of the cyanobacterial secondary metabolites, so called cyanotoxins, have been extensively studied in fish. However, many of these studies have used targeted approaches on specific molecules, which are thought to react to the presence of these specific cyanobacterial compounds. Since a few years, untargeted metabolomic approaches provide a unique opportunity to evaluate the global response of hundreds of metabolites at a glance. In this way, our study provides the first utilization of metabolomic analyses in order to identify the response of fish exposed to bloom-forming cyanobacteria. Three relevant fish species of peri-urban lakes of the European temperate regions were exposed for 96h either to a microcystin (MC)-producing or to a non-MC-producing strain of Microcystis aeruginosa and metabolome changes were characterized in the liver of fish. The results suggest that a short-term exposure to those cyanobacterial biomasses induces metabolome changes without any response specificity linked to the fish species considered. Candidate metabolites are involved in energy metabolism and antioxidative response, which could potentially traduce a stress response of fish submitted to cyanobacteria. These results are in agreement with the already known information and could additionally bring new insights about the molecular interactions between cyanobacteria and fish. PMID: 28283295 [PubMed - as supplied by publisher]

Related Articles Evening electronic device use: The effects on alertness, sleep and next-day physical performance in athletes. J Sports Sci. 2017 Feb 14;:1-9 Authors: Jones MJ, Peeling P, Dawson B, Halson S, Miller J, Dunican I, Clarke M, Goodman C, Eastwood P Abstract The aim of the present study was to investigate the influence of different types of tasks performed with or without an electronic device (tablet) on pre-sleep alertness, subsequent sleep quality and next-day athletic performance. Eight highly trained netball players attended a sleep laboratory for pre-sleep testing, polysomnographic sleep monitoring and next-day physical performance testing on 5 separate occasions (1 familiarisation and 4 experimental sessions). For 2 h prior to bedtime, athletes completed cognitively stimulating tasks (puzzles) or passive tasks (reading) with or without a tablet. Sleepiness tended to be greater after reading compared to completing puzzles without a tablet (d = 0.80), but not with a tablet. Melatonin concentration increased more so after reading compared to completing puzzles on a tablet (P = 0.02). There were no significant differences in sleep quality or quantity or next-day athletic performance between any of the conditions. These data suggest that using a tablet for 2 h prior to sleep does not negatively affect subsequent sleep or next-day performance in athletes. PMID: 28282750 [PubMed - as supplied by publisher]

Related Articles Can changes in resistance exercise workload influence internal load, countermovement jump performance and the endocrine response? J Sports Sci. 2017 Feb 23;:1-7 Authors: Hiscock DJ, Dawson B, Clarke M, Peeling P Abstract This study examined the influence of differing volume load and intensity (%1 repetition maximum[%1RM]) resistance exercise workouts on session rating of perceived exertion (sRPE) countermovement jump (CMJ) performance and endocrine responses. Twelve participants performed a workout comprising four exercises (bench press, back squat, deadlift and prone bench pull) in randomised order as either power (POW); 3 sets × 6 repetitions at 45%1RM × 3 min inter-set rest, strength (ST); 3 sets × 3 repetitions at 90%1RM × 3 min inter-set rest, or hypertrophy (HYP); 3 sets × 10 repetitions at 70%1RM × 1 min inter-set rest in a randomised-crossover design. CMJ performance and endocrine responses were measured immediately pre-, post-, 12, 24, 48 and 72 h post-exercise. POW sRPE (3.0 ± 1.0) was lower than ST (4.5 ± 1.0) (P = 0.01), and both were lower than HYP (8.5 ± 1.0) (P = 0.01). Duration of CMJ decrement was longer (P ≤ 0.05) for HYP (72 h) compared to POW (12 h) and ST (24 h). Testosterone concentration was greater (P ≤ 0.05) immediately post-exercise in HYP compared to POW and ST. In conclusion, less inter-set rest, greater volume load and intensity (%1RM) may increase sRPE, duration of CMJ performance decrement and testosterone responses in resistance exercise. PMID: 28282743 [PubMed - as supplied by publisher]

Auto-phosphorylation Represses Protein Kinase R Activity. Sci Rep. 2017 Mar 10;7:44340 Authors: Wang D, de Weerd NA, Willard B, Polekhina G, Williams BR, Sadler AJ Abstract The central role of protein kinases in controlling disease processes has spurred efforts to develop pharmaceutical regulators of their activity. A rational strategy to achieve this end is to determine intrinsic auto-regulatory processes, then selectively target these different states of kinases to repress their activation. Here we investigate auto-regulation of the innate immune effector protein kinase R, which phosphorylates the eukaryotic initiation factor 2α to inhibit global protein translation. We demonstrate that protein kinase R activity is controlled by auto-inhibition via an intra-molecular interaction. Part of this mechanism of control had previously been reported, but was then controverted. We account for the discrepancy and extend our understanding of the auto-inhibitory mechanism by identifying that auto-inhibition is paradoxically instigated by incipient auto-phosphorylation. Phosphor-residues at the amino-terminus instigate an intra-molecular interaction that enlists both of the N-terminal RNA-binding motifs of the protein with separate surfaces of the C-terminal kinase domain, to co-operatively inhibit kinase activation. These findings identify an innovative mechanism to control kinase activity, providing insight for strategies to better regulate kinase activity. PMID: 28281686 [PubMed - in process]