PubMed

Metabolite profile of a mouse model of Charcot-Marie-Tooth type 2D neuropathy: implications for disease mechanisms and interventions. Biol Open. 2016 Jun 10; Authors: Bais P, Beebe K, Morelli KH, Currie ME, Norberg SN, Evsikov AV, Miers KE, Seburn KL, Guergueltcheva V, Kremensky I, Jordanova A, Bult CJ, Burgess RW Abstract Charcot-Marie-Tooth disease encompasses a genetically heterogeneous class of heritable polyneuropathies that result in axonal degeneration in the peripheral nervous system. Charcot-Marie-Tooth type 2D neuropathy (CMT2D) is caused by dominant mutations in glycyl tRNA synthetase (GARS). Mutations in the mouse Gars gene result in a genetically and phenotypically valid animal model of CMT2D. How mutations in GARS lead to peripheral neuropathy remains controversial. To identify putative disease mechanisms, we compared metabolites isolated from the spinal cord of Gars mutant mice and their littermate controls. A profile of altered metabolites that distinguish the affected and unaffected tissue was determined. Ascorbic acid was decreased fourfold in the spinal cord of CMT2D mice, but was not altered in serum. Carnitine and its derivatives were also significantly reduced in spinal cord tissue of mutant mice, whereas glycine was elevated. Dietary supplementation with acetyl-L-carnitine improved gross motor performance of CMT2D mice, but neither acetyl-L-carnitine nor glycine supplementation altered the parameters directly assessing neuropathy. Other metabolite changes suggestive of liver and kidney dysfunction in the CMT2D mice were validated using clinical blood chemistry. These effects were not secondary to the neuromuscular phenotype, as determined by comparison with another, genetically unrelated mouse strain with similar neuromuscular dysfunction. However, these changes do not seem to be causative or consistent metabolites of CMT2D, because they were not observed in a second mouse Gars allele or in serum samples from CMT2D patients. Therefore, the metabolite 'fingerprint' we have identified for CMT2D improves our understanding of cellular biochemical changes associated with GARS mutations, but identification of efficacious treatment strategies and elucidation of the disease mechanism will require additional studies. PMID: 27288508 [PubMed - as supplied by publisher]

Systematic Molecular Phenotyping: A Path Towards Precision Emergency Medicine? Acad Emerg Med. 2016 Jun 11; Authors: Limkakeng AT, Monte A, Kabrhel C, Puskarich M, Heitsch L, Tsalik EL, Shapiro NI Abstract Precision medicine is an emerging approach to disease treatment and prevention that considers variability in patient genes, environment, and lifestyle. However, little has been written about how such research impacts emergency care. Recent advances in analytical techniques have made it possible to characterize patients in a more comprehensive and sophisticated fashion at the molecular level, promising highly individualized diagnosis and treatment. Among these techniques are various systematic molecular phenotyping analyses (e.g., genomics, transcriptomics, proteomics, and metabolomics). Although a number of emergency physicians use such techniques in their research, widespread discussion of these approaches has been lacking in the emergency care literature and many emergency physicians may be unfamiliar with them. In this article, we briefly review the underpinnings of such studies, note how they already impact acute care, discuss areas in which they might soon be applied, and identify challenges in translation to the emergency department. While such techniques hold much promise, it is unclear whether the obstacles to translating their findings to the emergency department will be overcome in the near future. Such obstacles include validation, cost, turnaround time, user interface, decision support, standardization, and adoption by end users. This article is protected by copyright. All rights reserved. PMID: 27288269 [PubMed - as supplied by publisher]

ALG6-CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioral and limb anomalies. J Inherit Metab Dis. 2016 Jun 10; Authors: Morava E, Tiemes V, Tiel C, Seta N, de Lonlay P, de Klerk H, Mulder M, Rubio-Gozalbo E, Visser G, van Hasselt P, Horovitz DD, de Souza CF, Schwartz IV, Green A, Al-Owain M, Uziel G, Sigaudy S, Chabrol B, van Spronsen FJ, Steinert M, Komini E, Wurm D, Bevot A, Ayadi A, Huijben K, Dercksen M, Witters P, Jaeken J, Matthijs G, Lefeber DJ, Wevers RA Abstract INTRODUCTION: Alpha-1,3-glucosyltransferase congenital disorder of glycosylation (ALG6-CDG) is a congenital disorder of glycosylation. The original patients were described with hypotonia, developmental disability, epilepsy, and increased bleeding tendency. METHODS: Based on Euroglycan database registration, we approached referring clinicians and collected comprehensive data on 41 patients. RESULTS: We found hypotonia and developmental delay in all ALG6-CDG patients and epilepsy, ataxia, proximal muscle weakness, and, in the majority of cases, failure to thrive. Nine patients developed intractable seizures. Coagulation anomalies were present in <50 % of cases, without spontaneous bleedings. Facial dysmorphism was rare, but seven patients showed missing phalanges and brachydactyly. Cyclic behavioral change, with autistic features and depressive episodes, was one of the most significant complaints. Eleven children died before the age of 4 years due to protein losing enteropathy (PLE), sepsis, or seizures. The oldest patient was a 40 year-old Dutch woman. The most common pathogenic protein alterations were p.A333V and p.I299Del, without any clear genotype-phenotype correlation. DISCUSSION: ALG6-CDG has been now described in 89 patients, making it the second most common type of CDG. It has a recognizable phenotype and a primary neurologic presentation. PMID: 27287710 [PubMed - as supplied by publisher]

Metabolic characterization of the natural progression of chronic hepatitis B. Genome Med. 2016;8(1):64 Authors: Schoeman JC, Hou J, Harms AC, Vreeken RJ, Berger R, Hankemeier T, Boonstra A Abstract BACKGROUND: Worldwide, over 350 million people are chronically infected with the hepatitis B virus (HBV) and are at increased risk of developing progressive liver diseases. The confinement of HBV replication to the liver, which also acts as the central hub for metabolic and nutritional regulation, emphasizes the interlinked nature of host metabolism and the disease. Still, the metabolic processes operational during the distinct clinical phases of a chronic HBV infection-immune tolerant, immune active, inactive carrier, and HBeAg-negative hepatitis phases-remains unexplored. METHODS: To investigate this, we conducted a targeted metabolomics approach on serum to determine the metabolic progression over the clinical phases of chronic HBV infection, using patient samples grouped based on their HBV DNA, alanine aminotransferase, and HBeAg serum levels. RESULTS: Our data illustrate the strength of metabolomics to provide insight into the metabolic dysregulation experienced during chronic HBV. The immune tolerant phase is characterized by the speculated viral hijacking of the glycerol-3-phosphate-NADH shuttle, explaining the reduced glycerophospholipid and increased plasmalogen species, indicating a strong link to HBV replication. The persisting impairment of the choline glycerophospholipids, even during the inactive carrier phase with minimal HBV activity, alludes to possible metabolic imprinting effects. The progression of chronic HBV is associated with increased concentrations of very long chain triglycerides together with citrulline and ornithine, reflective of a dysregulated urea cycle peaking in the HBV envelope antigen-negative phase. CONCLUSIONS: The work presented here will aid in future studies to (i) validate and understand the implication of these metabolic changes using a thorough systems biology approach, (ii) monitor and predict disease severity, as well as (iii) determine the therapeutic value of the glycerol-3-phosphate-NADH shuttle. PMID: 27286979 [PubMed - as supplied by publisher]

Metabolomics study of renal fibrosis and intervention effects of total aglycone extracts of Scutellaria baicalensis in unilateral ureteral obstruction rats. J Ethnopharmacol. 2016 Jun 7; Authors: Fang J, Wang W, Sun S, Wang Y, Li Q, Lu X, Qiu M, Zhang Y Abstract ETHNOPHARMACOLOGICAL RELEVANCE: Scutellariae Radix (Scutellaria baicalensis Georgi) is a well-known traditional Chinese medicine (TCM) which mainly contains flavonoids. Our previous studies have demonstrated that total aglycone extracts of Scutellaria Baicalensis (TAES) can improve kidney disease in rats. AIM OF THE STUDY: To investigate the renal fibrosis (RF) pathogenesis and TAES treatment mechanism in unilateral ureteral obstruction (UUO) rats, using a metabolomics approach based on gas chromatography-mass spectrometry (GC/MS). METHODS: Rats with RF were divided into 6 groups with rats subjected to sham operation as normal control. The effects of TAES on some RF closely related parameters in UUO rats were investigated. A metabolomics method, based on GC/MS, was developed to monitor metabolic alterations in urine. Multivariate data analysis was utilized to identify biomarkers potentially associated with RF and the anti-RF activity of TAES. Ontology-based enrichment analysis by BiNChE and pathway analysis by MetPA aid in the interpretation of difference metabolites. RESULTS: After ten days of treatment, the parameters of renal function begin returning to normal, and the abnormal high expressions of genes associated with extracellular matrix (ECM) were relived. In the metabolomics study, metabolic perturbations induced by UUO were reversed after treatment and TAES showed a dose-dependent therapy effect on RF, meanwhile, 18 potential biomarkers associated with RF were identified. Enrichment analysis of metabolites shows an over representation of mostly alkane-alpha, omega-diamine and alpha, omega-dicarboxylic acid, and these biomarkers are primarily involved in Glycine, serine and threonine metabolism, Retinol metabolism, Arginine and proline metabolism and Fructose and mannose metabolism. CONCLUSIONS: Our findings indicate that TAES have positive effects on UUO-induced RF in rats, meanwhile, metabolomics method coupled with metabolites enrichment analysis is a useful tool for revealing the pathogenesis of diseases and action mechanism of TCM on the whole body. PMID: 27286917 [PubMed - as supplied by publisher]

Potential Health Benefits and Metabolomics of Camel Milk by GC-MS and ICP-MS. Biol Trace Elem Res. 2016 Jun 11; Authors: Ahamad SR, Raish M, Ahmad A, Shakeel F Abstract None of the research reports reveals the metabolomics and elemental studies on camel milk. Recent studies showed that camel milk possesses anticancer and anti-inflammatory activity. Metabolomics and elemental studies were carried out in camel milk which showed us the pathways and composition that are responsible for the key biological role of camel milk. Camel milk was dissolved in methanol and chloroform fraction and then vortexed and centrifuged. Both the fractions were derivatized by N,O-bis-(trimethylsilyl)trifluoroacetamide (BSTFA) and TMCS after nitrogen purging and analyzed by GC-MS. Camel milk was also analyzed by ICP-MS after microwave digestion. We found that higher alkanes and fatty acids are present in the chloroform fraction and amino acids, sugars and fatty acid derivatives are present in aqueous fractions. All the heavy metals like As, Pb, Cd, Co, Cu, and Ni were in the safe limits in terms of maximum daily intake of these elements. Na, K, Mg, and Ca were also present in the safe limits in terms of maximum daily intake of these elements. These results suggested that the camel milk drinking is safe and there is no health hazard. The present data of GC-MS and ICP-MS correlate the activities related to camel milk. PMID: 27286716 [PubMed - as supplied by publisher]

HORSE SPECIES SYMPOSIUM: Canine intestinal microbiology and metagenomics: From phylogeny to function. J Anim Sci. 2016 Jun;94(6):2247-2261 Authors: Guard BC, Suchodolski JS Abstract Recent molecular studies have revealed a complex microbiota in the dog intestine. Convincing evidence has been reported linking changes in microbial communities to acute and chronic gastrointestinal inflammation, especially in canine inflammatory bowel disease (IBD). The most common microbial changes observed in intestinal inflammation are decreases in the bacterial phyla Firmicutes (i.e., Lachnospiraceae, Ruminococcaceae, and ) and Bacteroidetes, with concurrent increases in Proteobacteria (i.e., ). Due to the important role of microbial-derived metabolites for host health, it is important to elucidate the metabolic consequences of gastrointestinal dysbiosis and physiological pathways implicated in specific disease phenotypes. Metagenomic studies have used shotgun sequencing of DNA as well as phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) to characterize functional changes in the bacterial metagenome in gastrointestinal disease. Furthermore, wide-scale and untargeted measurements of metabolic products derived by the host and the microbiota in intestinal samples allow a better understanding of the functional alterations that occur in gastrointestinal disease. For example, changes in bile acid metabolism and tryptophan catabolism recently have been reported in humans and dogs. Also, metabolites associated with the pentose phosphate pathway were significantly altered in chronic gastrointestinal inflammation and indicate the presence of oxidative stress in dogs with IBD. This review focuses on the advancements made in canine metagenomics and metabolomics and their implications in understanding gastrointestinal disease as well as the development of better treatment approaches. PMID: 27285902 [PubMed - as supplied by publisher]

Systems proteomics of liver mitochondria function. Science. 2016 Jun 10;352(6291):aad0189 Authors: Williams EG, Wu Y, Jha P, Dubuis S, Blattmann P, Argmann CA, Houten SM, Amariuta T, Wolski W, Zamboni N, Aebersold R, Auwerx J Abstract Recent improvements in quantitative proteomics approaches, including Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS), permit reproducible large-scale protein measurements across diverse cohorts. Together with genomics, transcriptomics, and other technologies, transomic data sets can be generated that permit detailed analyses across broad molecular interaction networks. Here, we examine mitochondrial links to liver metabolism through the genome, transcriptome, proteome, and metabolome of 386 individuals in the BXD mouse reference population. Several links were validated between genetic variants toward transcripts, proteins, metabolites, and phenotypes. Among these, sequence variants in Cox7a2l alter its protein's activity, which in turn leads to downstream differences in mitochondrial supercomplex formation. This data set demonstrates that the proteome can now be quantified comprehensively, serving as a key complement to transcriptomics, genomics, and metabolomics--a combination moving us forward in complex trait analysis. PMID: 27284200 [PubMed - in process]

'Nothing of chemistry disappears in biology': the Top 30 damage-prone endogenous metabolites. Biochem Soc Trans. 2016 Jun 15;44(3):961-71 Authors: Lerma-Ortiz C, Jeffryes JG, Cooper AJ, Niehaus TD, Thamm AM, Frelin O, Aunins T, Fiehn O, de Crécy-Lagard V, Henry CS, Hanson AD Abstract Many common metabolites are intrinsically unstable and reactive, and hence prone to chemical (i.e. non-enzymatic) damage in vivo Although this fact is widely recognized, the purely chemical side-reactions of metabolic intermediates can be surprisingly hard to track down in the literature and are often treated in an unprioritized case-by-case way. Moreover, spontaneous chemical side-reactions tend to be overshadowed today by side-reactions mediated by promiscuous ('sloppy') enzymes even though chemical damage to metabolites may be even more prevalent than damage from enzyme sloppiness, has similar outcomes, and is held in check by similar biochemical repair or pre-emption mechanisms. To address these limitations and imbalances, here we draw together and systematically integrate information from the (bio)chemical literature, from cheminformatics, and from genome-scale metabolic models to objectively define a 'Top 30' list of damage-prone metabolites. A foundational part of this process was to derive general reaction rules for the damage chemistries involved. The criteria for a 'Top 30' metabolite included predicted chemical reactivity, essentiality, and occurrence in diverse organisms. We also explain how the damage chemistry reaction rules ('operators') are implemented in the Chemical-Damage-MINE (CD-MINE) database (minedatabase.mcs.anl.gov/#/top30) to provide a predictive tool for many additional potential metabolite damage products. Lastly, we illustrate how defining a 'Top 30' list can drive genomics-enabled discovery of the enzymes of previously unrecognized damage-control systems, and how applying chemical damage reaction rules can help identify previously unknown peaks in metabolomics profiles. PMID: 27284066 [PubMed - in process]

Metabolic and antioxidant profiles of herbal infusions and decoctions. Food Chem. 2016 Nov 15;211:963-71 Authors: Fotakis C, Tsigrimani D, Tsiaka T, Lantzouraki DZ, Strati IF, Makris C, Tagkouli D, Proestos C, Sinanoglou VJ, Zoumpoulakis P Abstract This study implements NMR metabolomics and spectrophotometric studies (Folin-Ciocalteu, FRAP, ABTS) to infusions and decoctions of ten plant species in order to assess and compare the metabolic and antioxidant profiles for each botanical family. Multivariate and univariate data analyses highlighted the differences among the samples and pinpointed specific classes of compounds for each plant species as well as infusions and decoctions. The identified phenolic compounds by NMR, as well as the antioxidant profile, framed a trend of increased values in infusions compared to the decoctions. Moreover, the infusion procedure positively affected the extractability of the phenolic compounds compared to decoctions. The highest total phenolic content was found in Mentha spicata, while the lowest in Matricaria chamomilla preparations, irrespective of the preparation method. The preparation time for the decoctions was examined showing that the 15min preparations were generally found richer in phenolics and of higher antioxidant capacity. PMID: 27283718 [PubMed - in process]

New integrative computational approaches unveil the Saccharomyces cerevisiae pheno-metabolomic fermentative profile and allow strain selection for winemaking. Food Chem. 2016 Nov 15;211:509-20 Authors: Franco-Duarte R, Umek L, Mendes I, Castro CC, Fonseca N, Martins R, Silva-Ferreira AC, Sampaio P, Pais C, Schuller D Abstract During must fermentation by Saccharomyces cerevisiae strains thousands of volatile aroma compounds are formed. The objective of the present work was to adapt computational approaches to analyze pheno-metabolomic diversity of a S. cerevisiae strain collection with different origins. Phenotypic and genetic characterization together with individual must fermentations were performed, and metabolites relevant to aromatic profiles were determined. Experimental results were projected onto a common coordinates system, revealing 17 statistical-relevant multi-dimensional modules, combining sets of most-correlated features of noteworthy biological importance. The present method allowed, as a breakthrough, to combine genetic, phenotypic and metabolomic data, which has not been possible so far due to difficulties in comparing different types of data. Therefore, the proposed computational approach revealed as successful to shed light into the holistic characterization of S. cerevisiae pheno-metabolome in must fermentative conditions. This will allow the identification of combined relevant features with application in selection of good winemaking strains. PMID: 27283661 [PubMed - in process]

Different metabolic responses to PI3K inhibition in NSCLC cells harboring wild-type and G12C mutant KRAS. Oncotarget. 2016 Jun 6; Authors: Caiola E, Brunelli L, Marabese M, Broggini M, Lupi M, Pastorelli R Abstract KRAS mutations in non-small-cell lung cancer (NSCLC) patients are considered a negative predictive factor and indicate poor response to anticancer treatments. KRAS mutations lead to activation of the PI3K/akt/mTOR pathway, whose inhibition remains a challenging clinical target. Since the PI3K/akt/mTOR pathway and KRAS oncogene mutations all have roles in cancer cell metabolism, we investigated whether the activity of PI3K/akt/mTOR inhibitors (BEZ235 and BKM120) in cells harboring different KRAS status is related to their metabolic effect. Isogenic NSCLC cell clones expressing wild-type (WT) and mutated (G12C) KRAS were used to determine the response to BEZ235 and BKM120. Metabolomics analysis indicated the impairment of glutamine in KRAS-G12C and serine metabolism in KRAS-WT, after pharmacological blockade of the PI3K signaling, although the net effect on cell growth, cell cycle distribution and caspase activation was similar. PI3K inhibitors caused autophagy in KRAS-WT, but not in KRAS-G12C, where there was a striking decrease in ammonia production, probably a consequence of glutamine metabolism impairment.These findings lay the grounds for more effective therapeutic combinations possibly distinguishing wild-type and mutated KRAS cancer cells in NSCLC, exploiting their different metabolic responses to PI3K/akt/mTOR inhibitors. PMID: 27283493 [PubMed - as supplied by publisher]

SERUM metabolomics of acute lymphoblastic leukaemia and acute myeloid leukaemia for probing biomarker molecules. Hematol Oncol. 2016 Jun 10; Authors: Musharraf SG, Siddiqui AJ, Shamsi T, Naz A Abstract Acute leukaemia (AL) is a critical neoplasm of white blood cells. Diagnosing AL requires bone marrow puncture procedure, which many patients do not consent to for it is invasive. Hence sensitive and specific early diagnostic biomarkers are essential for non-invasive diagnosis, new therapeutics and improving the disease prognosis. To differentiate the metabolic alterations associated with acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML), we investigated serum of ALL and AML patients in comparison with two controls using gas chromatography coupled with triple quadrupole tandem mass spectrometry and multivariate statistical analysis. Twenty seven out of 1425 metabolites were found differentiative among ALL, AML, aplastic anaemia (APA) patients and healthy control using p-value ≤ 0.001. ALL is the most dissimilar group from other three groups as in hierarchical clustering showed 72.1% dissimilarity. Model generation using PLSDA gave an overall accuracy of 91.9%. This study helps in metabolic fingerprinting of control and disease serum at high significance levels and could be used for early diagnosing of AL. Based on pathways analysis, fatty acid metabolism is deregulated in patients with AL and may represent an underlying metabolic pathway associated with disease progression. Copyright © 2016 John Wiley & Sons, Ltd. PMID: 27283238 [PubMed - as supplied by publisher]

(1)H-NMR based metabolomics reveals a pedoclimatic metabolic imprinting in ready to drink carrot juices. J Agric Food Chem. 2016 Jun 9; Authors: Tomassini A, Sciubba F, Di Cocco ME, Capuani G, Delfini M, Aureli W, Miccheli A Abstract Carrots are usually consumed as such or processed into many different products. Carrot juice is a popular beverage consumed throughout the world and is attracting more attention due to its nutritional value, being a natural source of bioactive compounds. Ready-to-drink carrot juices produced in the same factory, were analyzed by 1H Nuclear Magnetic Resonance (NMR) spectroscopy. The juices were obtained from carrots roots of the same cultivar grown in three different geographical areas in Italy. More than 30 metabolites have been identified and quantified and the data were analyzed by univariate ANOVA and multivariate analyses. A geographical-dependent clear clustering was observed and the metabolic profiles were related to the different pedoclimatic conditions. The proposed phytoprofiling approach could be employed on industrial scale in order to evaluate finished products in relation to different sites of supply of the raw material thus improving both the quality and the uniformity of the juices. PMID: 27281439 [PubMed - as supplied by publisher]

Serum-Based Oxylipins Are Associated with Outcomes in Primary Prevention Implantable Cardioverter Defibrillator Patients. PLoS One. 2016;11(6):e0157035 Authors: Zhang Y, Guallar E, Blasco-Colmenares E, Harms AC, Vreeken RJ, Hankemeier T, Tomaselli GF, Cheng A Abstract INTRODUCTION: Individuals with systolic heart failure are at risk of ventricular arrhythmias and all-cause mortality. Little is known regarding the mechanisms underlying these events. We sought to better understand if oxylipins, a diverse class of lipid metabolites derived from the oxidation of polyunsaturated fatty acids, were associated with these outcomes in recipients of primary prevention implantable cardioverter defibrillators (ICDs). METHODS: Among 479 individuals from the PROSE-ICD study, baseline serum were analyzed and quantitatively profiled for 35 known biologically relevant oxylipin metabolites. Associations with ICD shocks for ventricular arrhythmias and all-cause mortality were evaluated using Cox proportional hazards models. RESULTS: Six oxylipins, 17,18-DiHETE (HR = 0.83, 95% CI 0.70 to 0.99 per SD change in oxylipin level), 19,20-DiHDPA (HR = 0.79, 95% CI 0.63 to 0.98), 5,6-DiHETrE (HR = 0.73, 95% CI 0.58 to 0.91), 8,9-DiHETrE (HR = 0.76, 95% CI 0.62 to 0.95), 9,10-DiHOME (HR = 0.81, 95% CI 0.65 to 1.00), and PGF1α (HR = 1.33, 95% CI 1.04 to 1.71) were associated with the risk of appropriate ICD shock after multivariate adjustment for clinical factors. Additionally, 4 oxylipin-to-precursor ratios, 15S-HEPE / FA (20:5-ω3), 17,18-DiHETE / FA (20:5-ω3), 19,20-DiHDPA / FA (20:5-ω3), and 5S-HEPE / FA (20:5-ω3) were positively associated with the risk of all-cause mortality. CONCLUSION: In a prospective cohort of patients with primary prevention ICDs, we identified several novel oxylipin markers that were associated with appropriate shock and mortality using metabolic profiling techniques. These findings may provide new insight into the potential biologic pathways leading to adverse events in this patient population. PMID: 27281224 [PubMed - as supplied by publisher]

1H NMR metabolomics of plasma unveils liver dysfunction in dengue patients. J Virol. 2016 Jun 8; Authors: El-Bacha T, Struchiner CJ, Cordeiro MT, Almeida FC, de Azevedo Marques ET, Da Poian AT Abstract Dengue, due to its global burden, is the most important arthropod-born flavivirus disease and early detection lowers fatality rates to below 1%. Since the metabolic resources crucial for viral replication are provided by host cells, detecting changes in the metabolic profile associated with disease pathogenesis could help identifying markers of prognostic and diagnostic importance. We applied (1)H NMR exploratory metabolomics to study longitudinal changes in plasma metabolites in a cohort in Recife, Brazil. To gain statistical power, we used innovative paired multivariate analyzes to discriminate individuals with dengue fever (DF; mild) and dengue hemorrhagic fever (DHF; severe) presenting primary and secondary infection and subjects with non-specific infection (ND). Our results showed that a decrease in plasma LDL and VLDL discriminated dengue-infected from ND subjects and also those subjects with severe infection presented an even decrease in lipoproteins concentration when compared to subjects with mild infection. These results add to the ongoing discussion that manipulation of lipid metabolism is crucial for DENV replication and infection. In addition, a decrease in plasma glutamine was characteristic of DENV infection and disease severity and an increase in plasma acetate discriminated subjects with DF and DHF from ND-subjects. Several other metabolites showed to be altered in DENV infection and the implications of these alterations are discussed. We hypothesize that these changes in plasma metabolome are suggestive of liver dysfunction and could provide insights into the underlying molecular mechanisms of dengue pathogenesis and could help discriminating individuals at risk to develop severe infection and to predict disease outcome. IMPORTANCE: Dengue virus infection, due to its global burden, is the most important mosquito-born viral disease. There is no specific treatment for dengue disease and early detection lowers fatality rates to below 1%. In this study we observed the effects of dengue virus infection on the profile of small molecules in the blood of patients with mild and severe infection. Variations in the profile of these small molecules reflect the replication of dengue virus in different tissues and the extent of tissue damage during infection. The results of this study showed that the molecules that changed the most were VLDL and LDL lipoproteins and amino acids. We proposed that these changes reflect liver dysfunction and also that they can be used to discriminate subjects with mild and severe dengue infection. PMID: 27279613 [PubMed - as supplied by publisher]

Screening of Indian Lingzhi or Reishi Medicinal Mushroom, Ganoderma lucidum (Agaricomycetes): A UPC2-SQD-MS Approach. Int J Med Mushrooms. 2016;18(2):177-89 Authors: Bhardwaj A, Srivastava M, Pal M, Sharma YK, Bhattacharya S, Tulsawani R, Sugadev R, Misra K Abstract Oriental medicinal mushroom Ganoderma lucidum has been widely used for the promotion of health and longevity owing to its various bioactive constituents. Therefore, comprehending metabolomics of different G. lucidum parts could be of paramount importance for investigating their pharmacological properties. Ultra-performance convergence chromatography (UPC2) along with mass spectrometry (MS) is an emerging technique that has not yet been applied for metabolite profiling of G. lucidum. This study has been undertaken to establish metabolomics of the aqueous extracts of mycelium (GLM), fruiting body (GLF), and their mixture (GLMF) using ultra-performance convergence chromatography single quadrupole mass spectrometry (UPC2-SQD-MS). Aqueous extracts of G. lucidum prepared using an accelerated solvent extraction technique have been characterized for their mycochemical activities in terms of total flavonoid content, 1,1-diphenyl-2-picryl-hydrazyl scavenging activity, and ferric ion reducing antioxidant power. The UPC2-SQD-MS technique has been used for the first time for metabolite profiling of G. lucidum on a Princeton Diol column (4.6 × 250 mm; 5 µm) using supercritical CO2 (solvent) and 20 mM ammonium acetate in methanol (co-solvent). In the present study, UPC2-SQD-MS was found to be a rapid, efficient, and high-throughput analytical technique, whose coupling to principal component analysis (PCA) and phytochemical evaluation could be used as a powerful tool for elucidating metabolite diversity between mycelium and fruiting body of G. lucidum. PCA showed a clear distinction in the metabolite compositions of the samples. Mycochemical studies revealed that overall GLF possessed better antioxidant properties among the aqueous extracts of G. lucidum. PMID: 27279539 [PubMed - in process]

Rapid and Sensitive Differentiating Ischemic and Hemorrhagic Strokes by Dried Blood Spot Based Direct Injection Mass Spectrometry Metabolomics Analysis. J Clin Lab Anal. 2016 Jun 9; Authors: Hu Z, Zhu Z, Cao Y, Wang L, Sun X, Dong J, Fang Z, Fang Y, Xu X, Gao P, Hongzhi S Abstract Cerebral infarction (CI) and intracerebral hemorrhage are lethal cerebrovascular diseases, sometimes sharing similar clinical manifestations but with distinct therapeutic strategies. Delayed treatment usually resulted in poor prognosis. A timely diagnosis report is highly warranted especially in emergency. One hundred twenty-nine CI patients, 73 intracerebral hemorrhage (ICH) patients, and 98 controls were enrolled in this study. A direct injection mass spectrometry metabolomics approach was adopted using dried blood spot samples. This targeted metabolomics analysis focused on absolute quantitation of 23 amino acids, 26 carnitine/carnitine esters, and 22 calculated ratios parameters. Compared to the normal control group, CI and ICH showed distinct metabolite changes, respectively. For stroke differentiation, Tyr, C5-OH/C0, Cit, Asn, Pro, Val, Arg/Orn, Leu, and Val/Phe were elevated in the CI group. On the contrary, C5:1, Phe/Tyr, (C0 + C2 + C3 + C16 + C18:1)/Cit, and Met/Leu were of lower levels in the CI group. Using regression model based on some of the above-mentioned parameters, 79.07% of stroke patients from a new set could be definitely confirmed. This study proved the targeted metabolomics analysis was a promising tool for rapid and timely stroke differentiation. PMID: 27278546 [PubMed - as supplied by publisher]

Chemical composition and anti-inflammatory activity of the leaves of Byrsonima verbascifolia. J Nat Med. 2016 Jun 8; Authors: Saldanha AA, do Carmo LF, do Nascimento SB, de Matos NA, de Carvalho Veloso C, Castro AH, De Vos RC, Klein A, de Siqueira JM, Carollo CA, do Nascimento TV, Toffoli-Kadri MC, Soares AC Abstract An ethnopharmacological survey indicates that the genus Byrsonima has some medicinal species that are commonly found in the Brazilian Cerrado and has been used as an anti-inflammatory and for gastroduodenal disorders. The aim of this study was to evaluate the anti-inflammatory and antioxidant activity along with qualitative chemical characterization of the methanolic extract of the leaves of Byrsonima verbascifolia (BvME) obtained by exhaustive percolation. The data from the chemical analyses by liquid chromatography-mass spectrometry led to tentative identification of 42 compounds belonging to proanthocyanidins, galloyl quinic acid derivatives, flavonoids, and triterpene glycoside derivatives. BvME contain flavonoids and show an antioxidative activity. The methanolic extract administered intraperitoneally at doses of 50, 100, or 300 mg/kg showed a significant reduction in paw edema and modulated the neutrophil influx in a mouse model. Furthermore, the anti-edematogenic activity of the extract provided in smaller doses (12.5 and 25 mg/kg) was also demonstrated in a mouse paw edema model. The extract inhibited NO production by macrophages induced by lipopolysaccharide. We presume that the anti-inflammatory effects of BvME are due to a combination of compounds present in B. verbascifolia, including catechins (procyanidins), flavonoids, and triterpene glycosides and that these anti-inflammatory actions should be mediated, at least partly, through the inhibition of NO production. This study supports and validates the ethnopharmacological uses of B. verbascifolia as an anti-inflammatory. PMID: 27278224 [PubMed - as supplied by publisher]

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