PubMed

Related Articles A Preliminary Investigation of NSCL/P Plasma and Urine in Guizhou Province in China Using NMR-Based Metabonomics. Cleft Palate Craniofac J. 2013 Sep;50(5):603-9 Authors: Lei HG, Hong L, Kun SJ, Hai YX, Dong WY, Ke Z, Ping X, Hao C Abstract Objective : To assess the feasibility of metabonomics in clinical studies. This is a pilot study introducing nuclear magnetic resonance (NMR)-based metabonomics to elucidate and compare the metabolism of patients with nonsyndromic cleft lip and/or palate (NSCL/P) and children without orofacial clefts. Methods : High-resolution (1)H NMR spectroscopy was performed on plasma and urine samples obtained from NSCL/P and healthy children. The (1)H NMR spectra were further analyzed with principal component analysis. Results : Compared to the control group, the level of low-molecular-weight metabolites in plasma such as asparagine was higher in NSCL/P patients, while arginine, lysine, acetate, lactate, proline, glutamine, pyruvate, creatinine, choline, and β-glucose were lower. The carnitine, citrate, and formate excretion in urine appeared to be higher in the healthy children, while the NSCL/P group excreted higher concentrations of aspartic acid and phenylalanine in urine. Conclusion : The present study clearly demonstrated the great potential of NMR-based metabonomics in elucidating NSCL/P plasma metabolism and the possible application of this technology in clinical diagnosis and screening. PMID: 22612714 [PubMed - indexed for MEDLINE]

Related Articles LC/MS-based metabolomics strategy to assess the amelioration effects of ginseng total saponins on memory deficiency induced by simulated microgravity. J Pharm Biomed Anal. 2016 Apr 1;125:329-338 Authors: Feng L, Yue XF, Chen YX, Liu XM, Wang LS, Cao FR, Wang Q, Liao YH, Pan RL, Chang Q Abstract Microgravity-induced memory deficiency seriously affects learning and memory ability of the astronaut during spaceflight, with few effective countermeasures. Panax ginseng C. A. Mey. has been used as a nootropic herb for thousands of years in Asian countries. Saponins are recognized as its major active components. Previous studies have shown that ginseng saponins offer protection against memory deficits caused by various factors. Nevertheless, the underlying mechanisms of their nootropic effects are still largely unknown. In this study, we evaluated the memory-improving effects of ginseng total saponins (GTS) on simulated microgravity hindlimb-unloaded rats using a metabolomics approach. After being exposed to a 7-days hindlimb unloading (HU), variations of plasmatic and hippocampal metabolic profiles of rats with and without GTS intervention were examined by a liquid chromatography-mass spectrometry (LC-MS) based untargeted metabolomics method. Subsequently, 8 hippocampal neurotransmitters were determined using a LC-MS/MS method. Finally, a LC-MS/MS based targeted metabolomics was performed to validate biomarkers found in the untargeted analysis. Besides, to support the metabolomics results, passive avoidance (PA) test, Nissl staining, and plasmatic corticosterone (CORT) levels determination were performed. The results showed that HU could lead to variations of 7 neurotransmitters and significantly different plasmatic and hippocampal metabolic profiles. GTS could restore most of the imbalanced neurotransmitters, especially glutamic acid and acetylcholine, and correct the levels of various disturbed learning and memory relevant biomarkers such as asparagine, phenylalanine, tyrosine, tryptophan, and choline. In addition, GTS could markedly ameliorate HU-induced memory deficiency, protect hippocampal neurons from damage, and down-regulate elevated CORT levels. In conclusion, GTS exhibits memory-improving effects mainly through regulating the metabolism of amino acids, neurotransmitters, choline, kynurenine, and sphingolipids. The findings of this study not only can deepen our understanding of the underlying molecular mechanisms of MG-induced memory disorders, but also provide scientific evidence for choosing ginseng as a countermeasure against MG-induced memory deficiency. PMID: 27100700 [PubMed - as supplied by publisher]

Related Articles Combined Gene Expression and RNAi Screening to Identify Alkylation Damage Survival Pathways from Fly to Human. PLoS One. 2016;11(4):e0153970 Authors: Zanotto-Filho A, Dashnamoorthy R, Loranc E, de Souza LH, Moreira JC, Suresh U, Chen Y, Bishop AJ Abstract Alkylating agents are a key component of cancer chemotherapy. Several cellular mechanisms are known to be important for its survival, particularly DNA repair and xenobiotic detoxification, yet genomic screens indicate that additional cellular components may be involved. Elucidating these components has value in either identifying key processes that can be modulated to improve chemotherapeutic efficacy or may be altered in some cancers to confer chemoresistance. We therefore set out to reevaluate our prior Drosophila RNAi screening data by comparison to gene expression arrays in order to determine if we could identify any novel processes in alkylation damage survival. We noted a consistent conservation of alkylation survival pathways across platforms and species when the analysis was conducted on a pathway/process level rather than at an individual gene level. Better results were obtained when combining gene lists from two datasets (RNAi screen plus microarray) prior to analysis. In addition to previously identified DNA damage responses (p53 signaling and Nucleotide Excision Repair), DNA-mRNA-protein metabolism (transcription/translation) and proteasome machinery, we also noted a highly conserved cross-species requirement for NRF2, glutathione (GSH)-mediated drug detoxification and Endoplasmic Reticulum stress (ER stress)/Unfolded Protein Responses (UPR) in cells exposed to alkylation. The requirement for GSH, NRF2 and UPR in alkylation survival was validated by metabolomics, protein studies and functional cell assays. From this we conclude that RNAi/gene expression fusion is a valid strategy to rapidly identify key processes that may be extendable to other contexts beyond damage survival. PMID: 27100653 [PubMed - as supplied by publisher]

Related Articles Childhood obesity: a systems medicine approach. Front Biosci (Landmark Ed). 2016;21:1061-1075 Authors: Stone WL, Schetzina K, Stuart C Abstract Childhood obesity and its sequelae are a major public health problem in both the USA and globally. This review will focus on a systems medicine approach to obesity. Systems medicine is an integrative approach utilizing the vast amount of data garnered from "omics" technology and integrating these data with conventional pathophysiology as well as diverse environmental factors such as diet, exercise, community dynamics and the intestinal microbiome. Omics technology includes genomics, epigenomics, metagenomics, metabolomics and proteomics. In addition to unraveling etiology, the goals of a systems medicine approach are to provide actionable and evidenced-based clinical approaches. In the case of childhood obesity, an additional goal is characterizing measureable risk factors/biomarkers for obesity at the earliest possible age and devising age-appropriate optimal intervention strategies. It is also important to establish the age at which interventions could be critical. As discussed below, it is possible that some of the pathophysiological and epigenetic changes resulting from childhood obesity could become more irreversible the longer the obesity remains untreated. PMID: 27100491 [PubMed - as supplied by publisher]

Related Articles Proteomics and Metabolomics Analyses to Elucidate the Desulfurization Pathway of Chelatococcus sp. PLoS One. 2016;11(4):e0153547 Authors: Bordoloi NK, Bhagowati P, Chaudhuri MK, Mukherjee AK Abstract Desulfurization of dibenzothiophene (DBT) and alkylated DBT derivatives present in transport fuel through specific cleavage of carbon-sulfur (C-S) bonds by a newly isolated bacterium Chelatococcus sp. is reported for the first time. Gas chromatography-mass spectrometry (GC-MS) analysis of the products of DBT degradation by Chelatococcus sp. showed the transient formation of 2-hydroxybiphenyl (2-HBP) which was subsequently converted to 2-methoxybiphenyl (2-MBP) by methylation at the hydroxyl group of 2-HBP. The relative ratio of 2-HBP and 2-MBP formed after 96 h of bacterial growth was determined at 4:1 suggesting partial conversion of 2-HBP or rapid degradation of 2-MBP. Nevertheless, the enzyme involved in this conversion process remains to be identified. This production of 2-MBP rather than 2-HBP from DBT desulfurization has a significant metabolic advantage for enhancing the growth and sulfur utilization from DBT by Chelatococcus sp. and it also reduces the environmental pollution by 2-HBP. Furthermore, desulfurization of DBT derivatives such as 4-M-DBT and 4, 6-DM-DBT by Chelatococcus sp. resulted in formation of 2-hydroxy-3-methyl-biphenyl and 2-hydroxy -3, 3/- dimethyl-biphenyl, respectively as end product. The GC and X-ray fluorescence studies revealed that Chelatococcus sp. after 24 h of treatment at 37°C reduced the total sulfur content of diesel fuel by 12% by per gram resting cells, without compromising the quality of fuel. The LC-MS/MS analysis of tryptic digested intracellular proteins of Chelatococcus sp. when grown in DBT demonstrated the biosynthesis of 4S pathway desulfurizing enzymes viz. monoxygenases (DszC, DszA), desulfinase (DszB), and an NADH-dependent flavin reductase (DszD). Besides, several other intracellular proteins of Chelatococcus sp. having diverse biological functions were also identified by LC-MS/MS analysis. Many of these enzymes are directly involved with desulfurization process whereas the other enzymes/proteins support growth of bacteria at an expense of DBT. These combined results suggest that Chelatococcus sp. prefers sulfur-specific extended 4S pathway for deep-desulphurization which may have an advantage for its intended future application as a promising biodesulfurizing agent. PMID: 27100386 [PubMed - as supplied by publisher]

Related Articles Maternal PCaaC38:6 is Associated With Preterm Birth - a Risk Factor for Early and Late Adverse Outcome of the Offspring. Kidney Blood Press Res. 2016 Apr 22;41(3):250-257 Authors: Li J, Lu YP, Reichetzeder C, Kalk P, Kleuser B, Adamski J, Hocher B Abstract BACKGROUND/AIMS: Preterm birth (PTB) and low birth weight (LBW) significantly influence mortality and morbidity of the offspring in early life and also have long-term consequences in later life. A better understanding of the molecular mechanisms of preterm birth could provide new insights regarding putative preventive strategies. Metabolomics provides a powerful analytic tool to readout complex interactions between genetics, environment and health and may serve to identify relevant biomarkers. In this study, the association between 163 targeted maternal blood metabolites and gestational age was investigated in order to find candidate biomarkers for PTB. METHODS: Five hundred twenty-three women were included into this observational study. Maternal blood was obtained before delivery. The concentration of 163 maternal serum metabolites was measured by flow injection tandem mass spectrometry. To find putative biomarkers for preterm birth, a three-step analysis was designed: bivariate correlation analysis followed by multivariable regression analysis and a comparison of mean values among gestational age groups. RESULTS: Bivariate correlation analysis showed that 2 acylcarnitines (C16:2, C2), 1 amino acids (xLeu), 8 diacyl-PCs (PCaaC36:4, PCaaC38:4, PCaaC38:5, PCaaC38:6, PCaaC40:4, PCaaC40:5, PCaaC40:6, PCaaC42:4), and 1 Acylalkyl-PCs (PCaeC40:5) were inversely correlated with gestational age. Multivariable regression analysis confounded for PTB history, maternal body mass index (BMI) before pregnancy, systolic blood pressure at the third trimester, and maternal body weight at the third trimester, showed that the diacyl-PC PCaaC38:6 was the only metabolite inversely correlated with gestational age. CONCLUSIONS: Maternal blood concentrations of PCaaC38:6 are independently associated with gestational age. PMID: 27100327 [PubMed - as supplied by publisher]

Related Articles The biochemical origins of the surface-enhanced Raman spectra of bacteria: a metabolomics profiling by SERS. Anal Bioanal Chem. 2016 Apr 21; Authors: Premasiri WR, Lee JC, Sauer-Budge A, Théberge R, Costello CE, Ziegler LD Abstract The dominant molecular species contributing to the surface-enhanced Raman spectroscopy (SERS) spectra of bacteria excited at 785 nm are the metabolites of purine degradation: adenine, hypoxanthine, xanthine, guanine, uric acid, and adenosine monophosphate. These molecules result from the starvation response of the bacterial cells in pure water washes following enrichment from nutrient-rich environments. Vibrational shifts due to isotopic labeling, bacterial SERS spectral fitting, SERS and mass spectrometry analysis of bacterial supernatant, SERS spectra of defined bacterial mutants, and the enzymatic substrate dependence of SERS spectra are used to identify these molecular components. The absence or presence of different degradation/salvage enzymes in the known purine metabolism pathways of these organisms plays a central role in determining the bacterial specificity of these purine-base SERS signatures. These results provide the biochemical basis for the development of SERS as a rapid bacterial diagnostic and illustrate how SERS can be applied more generally for metabolic profiling as a probe of cellular activity. Graphical Abstract Bacterial typing by metabolites released under stress. PMID: 27100230 [PubMed - as supplied by publisher]

Related Articles Omics profiling in precision oncology. Mol Cell Proteomics. 2016 Apr 20; Authors: Yu KH, Snyder M Abstract Cancer causes significant morbidity and mortality worldwide, and is the area most targeted in precision medicine. Recent development of high-throughput methods enables detailed omics analysis of the molecular mechanisms underpinning tumor biology. These studies have identified clinically actionable mutations, gene and protein expression patterns associated with prognosis, and provided further insights into the molecular mechanisms indicative of cancer biology and new therapeutics strategies such as immunotherapy. In this review, we summarize the techniques used for tumor omics analysis, recapitulate the key findings in cancer omics studies, and point to areas requiring further research on precision oncology. PMID: 27099341 [PubMed - as supplied by publisher]

Related Articles Lipid biomarkers and long-term risk of cancer in the Women's Health Study. Am J Clin Nutr. 2016 Apr 20; Authors: Chandler PD, Song Y, Lin J, Zhang S, Sesso HD, Mora S, Giovannucci EL, Rexrode KE, Moorthy MV, Li C, Ridker PM, Lee IM, Manson JE, Buring JE, Wang L Abstract BACKGROUND: Lipid biomarkers, such as HDL-cholesterol concentrations, have been shown to have positive, inverse, and null associations with total, breast, and colorectal cancer risks. Studies of novel lipid biomarkers, such as apolipoprotein A-I (apo A-I) and apolipoprotein B-100 (apo B-100), and cancer risk have been sparse, to our knowledge. OBJECTIVES: We evaluated the prospective association of total, breast, colorectal, and lung cancers and cancer mortality with circulating lipid biomarkers in 15,602 female health professionals in the Women's Health Study (aged ≥45 y, free of cardiovascular disease and cancer, and without hormone replacement therapy or lipid-lowering medications at baseline). DESIGN: Cox regression models estimated HRs of cancer endpoints (19 y median follow-up) across quartiles 1 (reference) to 4 of each lipid biomarker after adjustment for cancer risk factors. RESULTS: Confirmed cases included 2163 incident cancer cases (864 breast, 198 colorectal, and 190 lung cancers) and 647 cancer deaths. Total cancer risk was significantly lower in the highest quartile of apo A-I (adjusted HR: 0.79; 95% CI: 0.70, 0.90;P-trend = 0.0008) and HDL cholesterol (HR: 0.85; 95% CI: 0.75, 0.97;P-trend = 0.01). For site-specific cancers, significant associations included colorectal cancer risk with HDL cholesterol (HR: 0.63; 95% CI; 0.41, 0.98;P-trend = 0.03), triglycerides (HR: 1.86; 95% CI: 1.17, 2.97;P-trend = 0.02), and apo B-100 (HR: 1.60; 95% CI: 1.03, 2.49;P-trend = 0.006) and lung cancer risk with HDL cholesterol (HR: 0.59; 95% CI: 0.38, 0.93;P-trend = 0.01). LDL cholesterol was not significantly associated with risk of total cancer or any site-specific cancers. In time-dependent models that were adjusted for the use of a lipid-lowering medication after baseline, these associations remained. CONCLUSIONS: Lipids were associated with total, lung, and colorectal cancer risks in women. Lifestyle interventions for heart-disease prevention, which reduce apo B-100 or raise HDL cholesterol, may be associated with reduced cancer risk. The Women's Health Study was registered atclinicaltrials.govasNCT00000479. PMID: 27099252 [PubMed - as supplied by publisher]

Related Articles Plasma acylcarnitines and risk of cardiovascular disease: effect of Mediterranean diet interventions. Am J Clin Nutr. 2016 Apr 20; Authors: Guasch-Ferré M, Zheng Y, Ruiz-Canela M, Hruby A, Martínez-González MA, Clish CB, Corella D, Estruch R, Ros E, Fitó M, Dennis C, Morales-Gil IM, Arós F, Fiol M, Lapetra J, Serra-Majem L, Hu FB, Salas-Salvadó J Abstract BACKGROUND: Previous studies have suggested that metabolite profiles of elevated acylcarnitines were associated with increased risk of cardiovascular disease (CVD) in populations with established coronary disease. However, to our knowledge, this association has not been evaluated in the context of primary cardiovascular prevention. OBJECTIVES: We evaluated the association between 28 plasma acylcarnitine species and risk of incident CVD and the potential modifying effect of Mediterranean diet (MedDiet) interventions. DESIGN: We measured plasma acylcarnitines with the use of high-throughput liquid chromatography-tandem mass spectrometry at baseline and after 1 y of follow-up, both individually and classified into short-, medium-, or long-chain scores, in a case-cohort study within the Prevención con Dieta Mediterránea (PREDIMED) study, which is a randomized Mediterranean dietary intervention for primary cardiovascular prevention. A randomly selected subcohort (n= 751) and all available incident CVD cases (n= 229) after 4.8 y of follow-up were included in the current study. RESULTS: After adjustment for age, sex, body mass index, and other CVD risk factors, participants in the highest quartile of baseline short- and medium-chain acylcarnitines had a higher risk of CVD than did participants in the lowest quartile [HRs: 1.80 (95% CI: 1.11, 2.91;P-trend 0.01) and 1.55 (95% CI: 1.01, 2.48;P-trend = 0.04), respectively]. Increased short-chain acylcarnitines after 1 y were associated with higher risks of total CVD and stroke. Participants with higher baseline concentrations of short-, medium-, and long-chain acylcarnitines who were randomly assigned to the control group had a higher risk of CVD than did subjects with lower concentrations of acylcarnitines who were assigned to the MedDiet group. CONCLUSIONS: Our data support the conclusion that metabolite profiles characterized by elevated concentrations of acylcarnitines are independently associated with risks of total CVD and stroke alone in participants at high risk of CVD. MedDiet interventions may mitigate the adverse associations shown between higher concentrations of acylcarnitines and CVD. This trial was registered atwww.controlled-trials.comasISRCTN35739639. PMID: 27099249 [PubMed - as supplied by publisher]

Related Articles Strain-level dissection of the contribution of the gut microbiome to human metabolic disease. Genome Med. 2016;8(1):41 Authors: Zhang C, Zhao L Abstract The gut microbiota has been linked with metabolic diseases in humans, but demonstration of causality remains a challenge. The gut microbiota, as a complex microbial ecosystem, consists of hundreds of individual bacterial species, each of which contains many strains with high genetic diversity. Recent advances in genomic and metabolomic technologies are facilitating strain-level dissection of the contribution of the gut microbiome to metabolic diseases. Interventional studies and correlation analysis between variations in the microbiome and metabolome, captured by longitudinal sampling, can lead to the identification of specific bacterial strains that may contribute to human metabolic diseases via the production of bioactive metabolites. For example, high-quality draft genomes of prevalent gut bacterial strains can be assembled directly from metagenomic datasets using a canopy-based algorithm. Specific metabolites associated with a disease phenotype can be identified by nuclear magnetic resonance-based metabolomics of urine and other samples. Such multi-omics approaches can be employed to identify specific gut bacterial genomes that are not only correlated with detected metabolites but also encode the genes required for producing the precursors of those metabolites in the gut. Here, we argue that if a causative role can be demonstrated in follow-up mechanistic studies-for example, using gnotobiotic models-such functional strains have the potential to become biomarkers for diagnostics and targets for therapeutics. PMID: 27098841 [PubMed - in process]

Related Articles Comparative effects of dexamethasone and bergenin on chronic bronchitis and their anti-inflammatory mechanisms based on NMR metabolomics. Mol Biosyst. 2016 Apr 21; Authors: Ren X, Ma S, Wang J, Tian S, Fu X, Liu X, Li Z, Zhao B, Wang X Abstract In order to compare the effect of dexamethasone and bergenin on chronic bronchitis and to reveal their anti-inflammatory mechanisms, (1)H NMR-based metabolomics was performed to explore the potential biomarkers of the disease and study the therapeutic mechanisms of the drugs. In this study, 40 Sprague-Dawley male rats were randomly divided into 4 groups, namely control, model, dexamethasone and bergenin groups, with 10 rats in each group. Except for the control group, rats from the other three groups were exposed to tobacco smoke for 1 h d(-1) for 28 days. During the modeling, dexamethasone (0.2 mg kg(-1)) and bergenin (87 mg kg(-1)) were administered orally to dexamethasone or bergenin rats 3 h after exposure every day. On the other hand, control and model rats were intragastrically administered water. According to the results of morphometric analysis of the airway epithelium and the count of white blood cells in the bronchoalveolar lavage fluid (BALF), dexamethasone and bergenin could suppress the infiltration of inflammatory cells, inhibit the secretion of mucus, and reduce white blood cells in BALF. Serum samples from the rats' orbits were collected every week. The metabolic profiles of sera were analyzed by multivariate statistical analyses, including PCA, PLS-DA and OPLS-DA models, and 18 metabolites were identified. The dynamic fluctuations of these biomarkers in sera from different groups were detected. The results suggested that the anti-inflammatory mechanism of dexamethasone may be associated with BCAA metabolism and glycolysis while bergenin could change BCAA metabolism, glycine, serine and threonine metabolism, and glycolysis to treat chronic bronchitis. PMID: 27098339 [PubMed - as supplied by publisher]

Related Articles [Progress of serum pharmacochemistry of traditional Chinese medicine and further development of its theory and method]. Zhongguo Zhong Yao Za Zhi. 2015 Sep;40(17):3406-12 Authors: Yan GL, Sun H, Zhang AH, Han Y, Wang P, Wu XH, Meng XC, Wang XJ Abstract Serum pharmacochemistry of traditional Chinese medicine (TCM) is designed to screen the efficacy material base of TCMs from the constituents absorbed into the blood after oral administration. The theory and method is in accordance with the effect characteristics of TCMs, and reflects the interaction between the body and the drugs, has become an effective pathway for researching the efficacy material base of TCMs which has been recognized and used widely. In the paper, the previous research contents and methods of the serum pharmacochemistry of TCM were reviewed, and on the basis of the further validity of the special administration form of the TCM formula and the corresponding property to TCM syndrome, the new strategy of serum pharmacochemistry of TCM integrating the metabonomics technologies was put forward. According to the strategy, we take the biological characters of TCM syndrome as a research starting point, taking TCM formula as object, using the metabolic biomarkers of syndromes or disease to evaluate the therapeutic effect of formula and screen the compounds of TCMs in serum which are highly correlated with the metabolic biomarkers through the correlation analysis, and by further biological validation to finally confirm the efficacy material basis of TCMs. Integrating with the systems biology technologies, the theory and method of serum pharmacochemistry of TCM will further develop, and open a new chapter in the interpretation of the theory of TCM. PMID: 26978981 [PubMed - indexed for MEDLINE]

Related Articles Metabolic fingerprinting of Lactobacillus paracasei: a multi-criteria evaluation of methods for extraction of intracellular metabolites. Anal Bioanal Chem. 2015 Aug;407(20):6095-104 Authors: Jäpelt KB, Nielsen NJ, Wiese S, Christensen JH Abstract An untargeted multi-criteria approach was used to select the best extraction method among freeze-thawing in methanol (FTM), boiling ethanol (BE) and chloroform-methanol (CM) for gas chromatography mass spectrometry (GC-MS) metabolic fingerprinting of Lactobacillus paracasei subsp. paracasei (CRL-431®). The following results were obtained: (i) coverage and efficiency, measured by the number of features extracted and the sum of feature intensities, showed that FTM extraction resulted in the largest compound coverage with a total number of features 8.9 × 10(3) ± 0.5 × 10(3), while merely 6.6 × 10(3) ± 0.9 × 10(3) and 7.9 × 10(3) ± 0.8 × 10(3) were detected in BE or CM, respectively; (ii) the similarity of extraction methods, measured by common features, demonstrated that FTM yielded the most complementary information to BE and CM; i.e. 17 and 33 % of the features of FTM extracted were unique compared to CM and BE, respectively; and (iii) a clear-cut separation according to extraction method was demonstrated by assessment of the metabolic fingerprints by pixel-based data analysis. Indications of metabolite degradation were observed under the elevated temperature for BE extraction. A superior coverage of FTM together with a high repeatability over nearly the whole range of GC-amenable compounds makes this the extraction method of choice for metabolic fingerprinting of L. paracasei. PMID: 26022096 [PubMed - indexed for MEDLINE]

Related Articles Comparative metabolic profiling reveals the key role of amino acids metabolism in the rapamycin overproduction by Streptomyces hygroscopicus. J Ind Microbiol Biotechnol. 2015 Jun;42(6):949-63 Authors: Wang B, Liu J, Liu H, Huang D, Wen J Abstract Rapamycin is an important natural macrolide antibiotic with antifungal, immunosuppressive and anticancer activity produced by Streptomyces hygroscopicus. In this study, a mutant strain obtained by ultraviolet mutagenesis displayed higher rapamycin production capacity compared to the wild-type S. hygroscopicus ATCC 29253. To gain insights into the mechanism of rapamycin overproduction, comparative metabolic profiling between the wild-type and mutant strain was performed. A total of 86 metabolites were identified by gas chromatography-mass spectrometry. Pattern recognition methods, including principal component analysis, partial least squares and partial least squares discriminant analysis, were employed to determine the key biomarkers. The results showed that 22 potential biomarkers were closely associated with the increase of rapamycin production and the tremendous metabolic difference was observed between the two strains. Furthermore, metabolic pathway analysis revealed that amino acids metabolism played an important role in the synthesis of rapamycin, especially lysine, valine, tryptophan, isoleucine, glutamate, arginine and ornithine. The inadequate supply of amino acids, or namely "nitrogen starvation" occurred in the mutant strain. Subsequently, the exogenous addition of amino acids into the fermentation medium of the mutant strain confirmed the above conclusion, and rapamycin production of the mutant strain increased to 426.7 mg/L after adding lysine, approximately 5.8-fold of that in the wild-type strain. Finally, the results of real-time PCR and enzyme activity assays demonstrated that dihydrodipicolinate synthase involved with lysine metabolism played vital role in the biosynthesis of rapamycin. These findings will provide a theoretical basis for further improving production of rapamycin. PMID: 25840873 [PubMed - indexed for MEDLINE]

Related Articles Metabolite Profiles in Sepsis: Developing Prognostic Tools Based on the Type of Infection. Crit Care Med. 2016 Apr 19; Authors: Neugebauer S, Giamarellos-Bourboulis EJ, Pelekanou A, Marioli A, Baziaka F, Tsangaris I, Bauer M, Kiehntopf M Abstract OBJECTIVES: Currently used biomarkers insufficiently discriminate between patients with systemic inflammatory response syndrome of non-infectious origin and sepsis. The aim of this study was to identify surrogate markers that distinguish between systemic inflammatory response syndrome and sepsis as well as the underlying type of infection by targeted metabolomics. DESIGN: Retrospective analysis. SETTINGS: Six sites of the Hellenic Sepsis Study Group and at Jena University Hospital. PATIENTS: A total of 406 patients were analyzed: 66 fulfilling criteria for diagnosis of systemic inflammatory response syndrome, 100 for community-acquired pneumonia, 112 for urinary tract infection, 83 for intra-abdominal infection and 45 for bloodstream infection. Patients were divided into test cohort (n = 268) and confirmation cohort (n = 138). INTERVENTIONS: A total of 186 metabolites were determined by liquid chromatography tandem mass spectrometry. MEASUREMENTS AND MAIN RESULTS: Serum concentrations of most acylcarnitines, glycerophospholipids and sphingolipids were altered in sepsis compared to systemic inflammatory response syndrome. A regression model combining the sphingolipid SM C22:3 and the glycerophospholipid lysoPCaC24:0 was discovered for sepsis diagnosis with a sensitivity of 84.1% and specificity of 85.7%. Furthermore, specific metabolites could be used for the discrimination of different types of infection. The glycerophospholipid lysoPCaC26:1 identified patients with community-acquired pneumonia in sepsis or severe sepsis/septic shock. Within severe sepsis/septic shock, patients with bloodstream infection could be discriminated by a decrease of acetylornithine. Changes of metabolites between sepsis and severe sepsis/septic shock also varied according to the underlying type of infection, showing that putrescine, lysoPCaC18:0 and SM C16:1 are associated with unfavorable outcome in community-acquired pneumonia, intra-abdominal infections and bloodstream infections, respectively. CONCLUSIONS: Using a metabolomics approach, single metabolites are identified that allow a good, albeit at about 14% false positive rate of sepsis diagnosis. Additionally, metabolites might be also useful for differentiation and prognosis according to the type of underlying infection. However, confirmation of the findings in ongoing studies is mandatory before they can be applied in the development of novel diagnostic tools for the management of sepsis. PMID: 27097292 [PubMed - as supplied by publisher]

Related Articles Spaceflight Activates Lipotoxic Pathways in Mouse Liver. PLoS One. 2016;11(4):e0152877 Authors: Jonscher KR, Alfonso-Garcia A, Suhalim JL, Orlicky DJ, Potma EO, Ferguson VL, Bouxsein ML, Bateman TA, Stodieck LS, Levi M, Friedman JE, Gridley DS, Pecaut MJ Abstract Spaceflight affects numerous organ systems in the body, leading to metabolic dysfunction that may have long-term consequences. Microgravity-induced alterations in liver metabolism, particularly with respect to lipids, remain largely unexplored. Here we utilize a novel systems biology approach, combining metabolomics and transcriptomics with advanced Raman microscopy, to investigate altered hepatic lipid metabolism in mice following short duration spaceflight. Mice flown aboard Space Transportation System -135, the last Shuttle mission, lose weight but redistribute lipids, particularly to the liver. Intriguingly, spaceflight mice lose retinol from lipid droplets. Both mRNA and metabolite changes suggest the retinol loss is linked to activation of PPARα-mediated pathways and potentially to hepatic stellate cell activation, both of which may be coincident with increased bile acids and early signs of liver injury. Although the 13-day flight duration is too short for frank fibrosis to develop, the retinol loss plus changes in markers of extracellular matrix remodeling raise the concern that longer duration exposure to the space environment may result in progressive liver damage, increasing the risk for nonalcoholic fatty liver disease. PMID: 27097220 [PubMed - as supplied by publisher]

Related Articles Nutrigenomics, the Microbiome, and Gene-Environment Interactions: New Directions in Cardiovascular Disease Research, Prevention, and Treatment: A Scientific Statement From the American Heart Association. Circ Cardiovasc Genet. 2016 Apr 19; Authors: Ferguson JF, Allayee H, Gerszten RE, Ideraabdullah F, Kris-Etherton PM, Ordovás JM, Rimm EB, Wang TJ, Bennett BJ Abstract Cardiometabolic diseases are the leading cause of death worldwide and are strongly linked to both genetic and nutritional factors. The field of nutrigenomics encompasses multiple approaches aimed at understanding the effects of diet on health or disease development, including nutrigenetic studies investigating the relationship between genetic variants and diet in modulating cardiometabolic risk, as well as the effects of dietary components on multiple "omic" measures, including transcriptomics, metabolomics, proteomics, lipidomics, epigenetic modifications, and the microbiome. Here, we describe the current state of the field of nutrigenomics with respect to cardiometabolic disease research and outline a direction for the integration of multiple omics techniques in future nutrigenomic studies aimed at understanding mechanisms and developing new therapeutic options for cardiometabolic disease treatment and prevention. PMID: 27095829 [PubMed - as supplied by publisher]

Related Articles Cytokinin metabolism in maize: Novel evidence of cytokinin abundance, interconversions and formation of a new trans-zeatin metabolic product with a weak anticytokinin activity. Plant Sci. 2016 Jun;247:127-37 Authors: Hluska T, Dobrev PI, Tarkowská D, Frébortová J, Zalabák D, Kopečný D, Plíhal O, Kokáš F, Briozzo P, Zatloukal M, Motyka V, Galuszka P Abstract Cytokinins (CKs) are an important group of phytohormones. Their tightly regulated and balanced levels are essential for proper cell division and plant organ development. Here we report precise quantification of CK metabolites and other phytohormones in maize reproductive organs in the course of pollination and kernel maturation. A novel enzymatic activity dependent on NADP(+) converting trans-zeatin (tZ) to 6-(3-methylpyrrol-1-yl)purine (MPP) was detected. MPP shows weak anticytokinin properties and inhibition of CK dehydrogenases due to their ability to bind to an active site in the opposite orientation than substrates. Although the physiological significance of tZ side-chain cyclization is not anticipated as the MPP occurrence in maize tissue is very low, properties of the novel CK metabolite indicate its potential for utilization in plant in vitro tissue culture. Furthermore, feeding experiments with different isoprenoid CKs revealed distinct preferences in glycosylation of tZ and cis-zeatin (cZ). While tZ is preferentially glucosylated at the N9 position, cZ forms mainly O-glucosides. Since O-glucosides, in contrast to N9-glucosides, are resistant to irreversible cleavage catalyzed by CK dehydrogenases, the observed preference of maize CK glycosyltransferases to O-glycosylate zeatin in the cis-position might be a reason why cZ derivatives are over-accumulated in different maize tissues and organs. PMID: 27095406 [PubMed - in process]

Related Articles Drug target identification using network analysis: Taking active components in Sini decoction as an example. Sci Rep. 2016;6:24245 Authors: Chen S, Jiang H, Cao Y, Wang Y, Hu Z, Zhu Z, Chai Y Abstract Identifying the molecular targets for the beneficial effects of active small-molecule compounds simultaneously is an important and currently unmet challenge. In this study, we firstly proposed network analysis by integrating data from network pharmacology and metabolomics to identify targets of active components in sini decoction (SND) simultaneously against heart failure. To begin with, 48 potential active components in SND against heart failure were predicted by serum pharmacochemistry, text mining and similarity match. Then, we employed network pharmacology including text mining and molecular docking to identify the potential targets of these components. The key enriched processes, pathways and related diseases of these target proteins were analyzed by STRING database. At last, network analysis was conducted to identify most possible targets of components in SND. Among the 25 targets predicted by network analysis, tumor necrosis factor α (TNF-α) was firstly experimentally validated in molecular and cellular level. Results indicated that hypaconitine, mesaconitine, higenamine and quercetin in SND can directly bind to TNF-α, reduce the TNF-α-mediated cytotoxicity on L929 cells and exert anti-myocardial cell apoptosis effects. We envisage that network analysis will also be useful in target identification of a bioactive compound. PMID: 27095146 [PubMed - in process]