PubMed

Related Articles Hepatic Abundance and Activity of Androgen and Drug Metabolizing Enzyme, UGT2B17, are Associated with Genotype, Age, and Sex. Drug Metab Dispos. 2018 Mar 30;: Authors: Bhatt DK, Basit A, Zhang H, Gaedigk A, Lee SB, Claw KG, Mehrotra A, Chaudhry AS, Pearce RE, Gaedigk R, Broeckel U, Thornton TA, Nickerson DA, Schuetz EG, Amory J, Leeder JS, Prasad B Abstract The major objective of this study was to investigate association of genetic and non-genetic factors with variability in protein abundance and in vitro activity of the androgen metabolizing enzyme, UGT2B17, in human liver microsomes (n=455). UGT2B17 abundance was quantified by LC-MS/MS proteomics and enzyme activity was determined by using testosterone and dihydrotestosterone as in vitro probe substrates. Genotyping or gene resequencing and mRNA expression were also evaluated. Multivariate analysis was used to test association of UGT2B17 copy number variation, single nucleotide polymorphisms (SNPs), age and sex with its mRNA expression, abundance and activity. UGT2B17 gene copy number and SNPs (rs7436962, rs9996186, rs28374627 and rs4860305) were associated with gene expression, protein levels and androgen glucuronidation rates in a gene-dose dependent manner. UGT2B17 protein (mean ± SD pmol per mg microsomal protein) is sparsely expressed in children below 9 years (0.12 ± 0.24), but profoundly increases from age 9 years to adults (~10 fold) with ~2.6-fold higher abundance in males than females (1.2 vs. 0.47). Association of androgen glucuronidation with UGT2B15 abundance was only observed in the low UGT2B17 expressers. These data can be used to predict variability in the metabolism of UGT2B17 substrates. Drug companies should include UGT2B17 in early phenotyping assays during drug discovery to avoid late clinical failures. PMID: 29602798 [PubMed - as supplied by publisher]

Related Articles Metabolomics and Metabolic Reprogramming in Kidney Cancer. Semin Nephrol. 2018 Mar;38(2):175-182 Authors: Weiss RH Abstract Kidney cancer, or renal cell carcinoma (RCC), is a disease of increasing incidence that commonly is seen in the general practice of nephrology. Despite this state of affairs, this fascinating and highly morbid disease frequently is under-represented, or even absent, from the curriculum of nephrologists in training and generally is underemphasized in national nephrology meetings, both scientific as well as clinical. Although classic concepts in cancer research in general had led to the concept that cancer is a disease resulting from mutations in the control of growth-regulating pathways, reinforced by the discovery of oncogenes, more contemporary research, particularly in kidney cancer, has uncovered changes in metabolic pathways mediated by those same genes that control tumor energetics and biosynthesis. This adaptation of classic biochemical pathways to the tumor's advantage has been labeled metabolic reprogramming. For example, in the case of kidney cancer there exists a near-universal presence of von Hippel-Lindau tumor suppressor (pVHL) inactivation in the most common form, clear cell RCC (ccRCC), leading to activation of hypoxia-relevant and other metabolic pathways. Studies of this and other pathways in clear cell RCC (ccRCC) have been particularly revealing, leading to the concept that ccRCC can itself be considered a metabolic disease. For this reason, the relatively new method of metabolomics has become a useful technique in the study of ccRCC to tease out those pathways that have been reprogrammed by the tumor to its maximum survival advantage. Furthermore, identification of the nodes of such pathways can lead to novel areas for drug intervention in a disease for which such targets are seriously lacking. Further research and dissemination of these concepts, likely using omics techniques, will lead to clinical trials of therapeutics specifically targeted to tumor metabolism, rather than those generally toxic to all proliferating cells. Such novel agents are highly likely to be more effective than existing drugs and to have far fewer adverse effects. This review provides a general overview of the technique of metabolomics and then discusses how it and other omics techniques have been used to further our understanding of the basic biology of kidney cancer as well as to identify new therapeutic approaches. PMID: 29602399 [PubMed - in process]

Related Articles Genome-Wide Association Studies of Metabolite Concentrations (mGWAS): Relevance for Nephrology. Semin Nephrol. 2018 Mar;38(2):151-174 Authors: Köttgen A, Raffler J, Sekula P, Kastenmüller G Abstract Metabolites are small molecules that are intermediates or products of metabolism, many of which are freely filtered by the kidneys. In addition, the kidneys have a central role in metabolite anabolism and catabolism, as well as in active metabolite reabsorption and/or secretion during tubular passage. This review article illustrates how the coupling of genomics and metabolomics in genome-wide association analyses of metabolites can be used to illuminate mechanisms underlying human metabolism, with a special focus on insights relevant to nephrology. First, genetic susceptibility loci for reduced kidney function and chronic kidney disease (CKD) were reviewed systematically for their associations with metabolite concentrations in metabolomics studies of blood and urine. Second, kidney function and CKD-associated metabolites reported from observational studies were interrogated for metabolite-associated genetic variants to generate and discuss complementary insights. Finally, insights originating from the simultaneous study of both blood and urine or by modeling intermetabolite relationships are summarized. We also discuss methodologic questions related to the study of metabolite concentrations in urine as well as among CKD patients. In summary, genome-wide association analyses of metabolites using metabolite concentrations quantified from blood and/or urine are a promising avenue of research to illuminate physiological and pathophysiological functions of the kidney. PMID: 29602398 [PubMed - in process]

Related Articles A Systems-Level View of Renal Metabolomics. Semin Nephrol. 2018 Mar;38(2):142-150 Authors: Rhee EP Abstract The measurement of select circulating metabolites such as creatinine, glucose, and cholesterol are integral to clinical medicine, with implications for diagnosis, prognosis, and treatment. Metabolomics studies in nephrology research seek to build on this paradigm, with the goal to identify novel markers and causal participants in the pathogenesis of kidney disease and its complications. This article reviews three themes pertinent to this goal. Each is rooted in long-established principles of human physiology, with recent updates enabled by metabolomics and other tools. First, the kidney has a broad and heterogeneous impact on circulating metabolites, with progressive loss of kidney function resulting in a multitude of small molecule alterations. Second, an increasing number of circulating metabolites have been shown to possess functional roles, in some cases acting as ligands for specific G-protein-coupled receptors. Third, circulating metabolites traffic through varied, and sometimes complex, interorgan circuits. Taken together, these themes emphasize the importance of viewing renal metabolomics at the systems level, recognizing the diverse origins and physiologic effects of blood metabolites. However, how to synthesize these themes and how to establish clinical relevance remain uncertain and will require further investigation. PMID: 29602397 [PubMed - in process]

Related Articles Lipidomics and Biomarker Discovery in Kidney Disease. Semin Nephrol. 2018 Mar;38(2):127-141 Authors: Afshinnia F, Rajendiran TM, Wernisch S, Soni T, Jadoon A, Karnovsky A, Michailidis G, Pennathur S Abstract Technological advances in mass spectrometry-based lipidomic platforms have provided the opportunity for comprehensive profiling of lipids in biological samples and shown alterations in the lipidome that occur in metabolic disorders. A lipidomic approach serves as a powerful tool for biomarker discovery and gaining insight to molecular mechanisms of disease, especially when integrated with other -omics platforms (ie, transcriptomics, proteomics, and metabolomics) in the context of systems biology. In this review, we describe the workflow commonly applied to the conduct of lipidomic studies including important aspects of study design, sample preparation, biomarker identification and quantification, and data processing and analysis, as well as crucial considerations in clinical applications. We also review some recent studies of the application of lipidomic platforms that highlight the potential of lipid biomarkers and add to our understanding of the molecular basis of kidney disease. PMID: 29602396 [PubMed - in process]

Related Articles The Warburg Effect in Diabetic Kidney Disease. Semin Nephrol. 2018 Mar;38(2):111-120 Authors: Zhang G, Darshi M, Sharma K Abstract Diabetic kidney disease (DKD) is the leading cause of morbidity and mortality in diabetic patients. Defining risk factors for DKD using a reductionist approach has proven challenging. Integrative omics-based systems biology tools have shed new insights in our understanding of DKD and have provided several key breakthroughs for identifying novel predictive and diagnostic biomarkers. In this review, we highlight the role of the Warburg effect in DKD and potential regulating factors such as sphingomyelin, fumarate, and pyruvate kinase muscle isozyme M2 in shifting glucose flux from complete oxidation in mitochondria to the glycolytic pathway and its principal branches. With the development of highly sensitive instruments and more advanced automatic bioinformatics tools, we believe that omics analyses and imaging techniques will focus more on singular-cell-level studies, which will allow in-depth understanding of DKD and pave the path for personalized kidney precision medicine. PMID: 29602394 [PubMed - in process]

GreenCut protein CPLD49 of Chlamydomonas reinhardtii associates with thylakoid membranes and is required for cytochrome b6 f complex accumulation. Plant J. 2018 Mar 30;: Authors: Wittkopp TM, Saroussi S, Yang W, Johnson X, Kim RG, Heinnickel ML, Russell JJ, Phuthong W, Dent RM, Broeckling CD, Peers G, Lohr M, Wollman FA, Niyogi KK, Grossman AR Abstract The GreenCut encompasses a suite of nucleus-encoded proteins with orthologs among green lineage organisms (plants, green algae), but that are absent or poorly conserved in non-photosynthetic/heterotrophic organisms. In Chlamydomonas reinhardtii, CPLD49 (Conserved in Plant Lineage and Diatoms49) is an uncharacterized GreenCut protein that is critical for maintaining normal photosynthetic function. We demonstrate that a cpld49 mutant has impaired photoautotrophic growth under high light conditions. The mutant exhibits a nearly 90% reduction in the level of the cytochrome b6 f complex (Cytb6 f), which impacts linear and cyclic electron transport, but does not compromise the ability of the strain to perform state transitions. Furthermore, CPLD49 strongly associates with thylakoid membranes where it may be part of a membrane protein complex with another GreenCut protein, CPLD38; a mutant null for CPLD38 also impacts Cytb6 f complex accumulation. We investigated several potential functions of CPLD49, with some suggested by protein homology. Our findings are congruent with the hypothesis that CPLD38 and CPLD49 are part of a novel thylakoid membrane complex that primarily modulates accumulation, but also impacts the activity of the Cytb6 f complex. Based on motifs of CPLD49 and the activities of other CPLD49-like proteins, we suggest a role for this putative dehydrogenase in the synthesis of a lipophilic thylakoid membrane molecule that influences the assembly and activity of Cytb6 f. This article is protected by copyright. All rights reserved. PMID: 29602195 [PubMed - as supplied by publisher]

Food safety using NMR-based metabolomics: Assessment of the Atlantic bluefin tuna, Thunnus thynnus, from the Mediterranean Sea. Food Chem Toxicol. 2018 Mar 27;: Authors: Cappello T, Giannetto A, Parrino V, De Marco G, Mauceri A, Maisano M Abstract Seafood is a valuable component of human diet because of its nutritional properties. The Atlantic bluefin tuna Thunnus thynnus is a scombroid fish highly appreciated as seafood worldwide. Being a top pelagic predator, concerns have been raised over human health risks due to its consumption. Therefore, herein it was comprehensively evaluated the health status and potential metabolite shifts between sexes of bluefin tuna from the Mediterranean Sea, proved to bioaccumulate environmental obesogens, namely polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) at hepatic level. To this aim, nuclear magnetic resonance (NMR)-based metabolomics was applied on liver of post-spawning tuna. Findings from this study pointed out that hepatic bioaccumulation of PCBs and OCPs induced differential metabolic disturbances between sexes, attributable to the reproductive stage at which tuna were caught. Alterations were mainly found in energy-producing metabolic pathways (with changes in acetate, acetoacetate, malonate, and lactate), amino acid (with changes in BCAA, alanine, sarcosine, and tyrosine), and lipid (with changes in choline and phosphocholine) metabolism, with activation of fatty acids biosynthesis and ketogenesis in male tuna. Overall, according to the current European legislation on maximum levels of contaminants in seafood, the consumption of bluefin tuna does not represent a risk for human health. PMID: 29601848 [PubMed - as supplied by publisher]

Related Articles Shifts in the Gut Metabolome and Clostridium difficile Transcriptome throughout Colonization and Infection in a Mouse Model. mSphere. 2018 Mar-Apr;3(2): Authors: Fletcher JR, Erwin S, Lanzas C, Theriot CM Abstract Antibiotics alter the gut microbiota and decrease resistance to Clostridium difficile colonization; however, the mechanisms driving colonization resistance are not well understood. Loss of resistance to C. difficile colonization due to antibiotic treatment is associated with alterations in the gut metabolome, specifically, with increases in levels of nutrients that C. difficile can utilize for growth in vitro. To define the nutrients that C. difficile requires for colonization and pathogenesis in vivo, we used a combination of mass spectrometry and RNA sequencing (RNA Seq) to model the gut metabolome and C. difficile transcriptome throughout an acute infection in a mouse model at the following time points: 0, 12, 24, and 30 h. We also performed multivariate-based integration of the omics data to define the signatures that were most important throughout colonization and infection. Here we show that amino acids, in particular, proline and branched-chain amino acids, and carbohydrates decrease in abundance over time in the mouse cecum and that C. difficile gene expression is consistent with their utilization in vivo. This was also reinforced by the multivariate-based integration of the omics data where we were able to discriminate the metabolites and transcripts that support C. difficile physiology between the different time points throughout colonization and infection. This report illustrates how important the availability of amino acids and other nutrients is for the initial stages of C. difficile colonization and progression of disease. Future studies identifying the source of the nutrients and engineering bacteria capable of outcompeting C. difficile in the gut will be important for developing new targeted bacterial therapeutics. IMPORTANCE Clostridium difficile is a bacterial pathogen of global significance that is a major cause of antibiotic-associated diarrhea. Antibiotics deplete the indigenous gut microbiota and change the metabolic environment in the gut to one favoring C. difficile growth. Here we used metabolomics and transcriptomics to define the gut environment after antibiotics and during the initial stages of C. difficile colonization and infection. We show that amino acids, in particular, proline and branched-chain amino acids, and carbohydrates decrease in abundance over time and that C. difficile gene expression is consistent with their utilization by the bacterium in vivo. We employed an integrated approach to analyze the metabolome and transcriptome to identify associations between metabolites and transcripts. This highlighted the importance of key nutrients in the early stages of colonization, and the data provide a rationale for the development of therapies based on the use of bacteria that specifically compete for nutrients that are essential for C. difficile colonization and disease. PMID: 29600278 [PubMed - in process]

Related Articles Coagulation cascade and complement system in systemic lupus erythematosus. Oncotarget. 2018 Mar 13;9(19):14862-14881 Authors: Liang Y, Xie SB, Wu CH, Hu Y, Zhang Q, Li S, Fan YG, Leng RX, Pan HF, Xiong HB, Ye DQ Abstract This study was conducted to (1) characterize coagulation cascade and complement system in systemic lupus erythematosus (SLE); (2) evaluate the associations between coagulation cascade, complement system, inflammatory response and SLE disease severity; (3) test the diagnostic value of a combination of D-dimer and C4 for lupus activity. Transcriptomics, proteomics and metabolomics were performed in 24 SLE patients and 24 healthy controls. The levels of ten coagulations, seven complements and three cytokines were measured in 112 SLE patients. Clinical data were collected from 2025 SLE patients. The analysis of multi-omics data revealed the common links for the components of coagulation cascade and complement system. The results of ELISA showed coagulation cascade and complement system had an interaction effect on SLE disease severity, this effect was pronounced among patients with excess inflammation. The analysis of clinical data revealed a combination of D-dimer and C4 provided good diagnostic performance for lupus activity. This study suggested that coagulation cascade and complement system become 'partners in crime', contributing to SLE disease severity and identified the diagnostic value of D-dimer combined with C4for lupus activity. PMID: 29599912 [PubMed]

Related Articles Metabolomics: From liver chiromancy to personalized precision medicine in advanced chronic liver disease. World J Hepatol. 2018 Mar 27;10(3):371-378 Authors: Procopet B, Fischer P, Farcau O, Stefanescu H Abstract Currently there is a lack of accurate biomarkers for diagnosis and prognosis in advanced liver diseases. Either the occurrence of first decompensation, or diagnosis of acute on chronic liver failure, severe alcoholic hepatitis, or hepatocellular carcinoma (HCC), none of the available biomarkers are satisfactory. Metabolomics is the newest of omics, being much closer than the others to the actual phenotype and pathologic changes that characterizes a certain condition. It deals with a much wider spectrum of low molecular weight bio-compounds providing a powerful platform for discovering novel biomarkers and biochemical pathways to improve diagnostic, prognostication and therapy. Until now metabolomics was applied in a wide spectrum of liver conditions, but the findings were contradictory. This review proposes a synthesis of the existing evidences of metabolomics use in advanced chronic liver diseases, decompensated liver cirrhosis, severe alcoholic hepatitis and HCC. PMID: 29599900 [PubMed]

Related Articles Gas chromatography-time of flight/mass spectrometry-based metabonomics of changes in the urinary metabolic profile in osteoarthritic rats. Exp Ther Med. 2018 Mar;15(3):2777-2785 Authors: Jiang H, Liu J, Qin XJ, Chen YY, Gao JR, Meng M, Wang Y, Wang T Abstract The aim of the present study was to explore changes in the urinary metabolic spectrum in rats with knee osteoarthritis, using gas chromatography-time of flight/mass spectrometry (GC-TOF/MS) to determine the metabonomic disease pathogenesis. Sprague-Dawley rats were randomly divided into the control and model groups (n=8/group), and 20 µl of 4% papain and 0.03 M L-cysteine was injected into the right knee on days 1, 3 and 7 to establish the knee osteoarthritis model. Following 14 days, urine was collected over 12 h and cartilage ultrastructural damage was assessed by hematoxylin-eosin staining. GC-TOF/MS, combined with principal component analysis, partial least squares discriminant modeling and orthogonal partial least squares discriminant modeling, was used to analyze the changes in the metabolic spectrum trajectory and to identify potential biomarkers and their related metabolic pathways. Compared with the control group, the synovial cell lining of the knee joint exhibited proliferation, inflammatory cell infiltration and collagen fiber hyperplasia in the knee osteoarthritis group. A total of 23 potential biomarkers were identified, including alanine, α-ketoglutarate, asparagine, maltose and glutamine. Furthermore, metabolomic pathogenesis of osteoarthritis may be related to disorders of amino acid metabolism, energy metabolism, fatty acid metabolism, vitamin B6 metabolism and nucleic acid metabolism. PMID: 29599826 [PubMed]

Related Articles Prospecting for Microelement Function and Biosafety Assessment of Transgenic Cereal Plants. Front Plant Sci. 2018;9:326 Authors: Yu X, Luo Q, Huang K, Yang G, He G Abstract Microelement contents and metabolism are vitally important for cereal plant growth and development as well as end-use properties. While minerals phytotoxicity harms plants, microelement deficiency also affects human health. Genetic engineering provides a promising way to solve these problems. As plants vary in abilities to uptake, transport, and accumulate minerals, and the key enzymes acting on that process is primarily presented in this review. Subsequently, microelement function and biosafety assessment of transgenic cereal plants have become a key issue to be addressed. Progress in genetic engineering of cereal plants has been made with the introduction of quality, high-yield, and resistant genes since the first transgenic rice, corn, and wheat were born in 1988, 1990, and 1992, respectively. As the biosafety issue of transgenic cereal plants has now risen to be a top concern, many studies on transgenic biosafety have been carried out. Transgenic cereal biosafety issues mainly include two subjects, environmental friendliness and end-use safety. Different levels of gene confirmation, genomics, proteomics, metabolomics and nutritiomics, absorption, metabolism, and function have been investigated. Also, the different levels of microelement contents have been measured in transgenic plants. Based on the motivation of the requested biosafety, systematic designs, and analysis of transgenic cereal are also presented in this review paper. PMID: 29599791 [PubMed]

Related Articles Prophylactic ketamine alters nucleotide and neurotransmitter metabolism in brain and plasma following stress. Neuropsychopharmacology. 2018 Mar 29;: Authors: McGowan JC, Hill C, Mastrodonato A, LaGamma CT, Kitayev A, Brachman RA, Narain NR, Kiebish MA, Denny CA Abstract Recently, we have shown that ketamine given prior to stress exposure protects against the development of depressive-like behavior in mice. These data suggest that it may be possible to prevent the induction of affective disorders before they develop by administering prophylactic pharmaceuticals, a relatively nascent and unexplored strategy for psychiatry. Here, we performed metabolomics analysis of brain and plasma following prophylactic ketamine treatment in order to identify markers of stress resilience enhancement. We administered prophylactic ketamine in mice to buffer against fear expression. Following behavioral analyses, untargeted metabolomic profiling was performed on both hemispheres of the prefrontal cortex (PFC) and the hippocampus (HPC), and plasma. We found that prophylactic ketamine attenuated learned fear. Eight metabolites were changed in the PFC and HPC upon ketamine treatment. Purine and pyrimidine metabolism were most significantly changed in the HPC, PFC, and, interestingly, plasma of mice two weeks after prophylactic administration. Moreover, most precursors to inhibitory neurotransmitters were increased whereas precursors to excitatory neurotransmitters were decreased. Strikingly, these long-term metabolomic changes were not observed when no stressor was administered. Our results suggest that prophylactic treatment differentially affects purine and pyrimidine metabolism and neurotransmission in brain and plasma following stress, which may underlie the long-lasting resilience to stress induced by a single injection of ketamine. These data may provide novel targets for prophylactic development, and indicate an interaction effect of prophylactic ketamine and stress. To our knowledge, this is the first study that identifies metabolomic alterations and biomarker candidates for prophylactic ketamine efficacy in mice. PMID: 29599484 [PubMed - as supplied by publisher]

Related Articles Protein fermentation in the gut; implications for intestinal dysfunction in humans, pigs and poultry. Am J Physiol Gastrointest Liver Physiol. 2018 Mar 29;: Authors: Gilbert MS, Ijssennagger N, Kies AK, van Mil SWC Abstract The amount of dietary protein is associated with intestinal disease in different vertebrate species. In humans, this is exemplified by the association between high protein intake and fermentation metabolite concentrations in patients with inflammatory bowel disease. In production animals, dietary protein intake is associated with post-weaning diarrhea in piglets and with the occurrence of wet litter in poultry. The underlying mechanisms by which dietary protein contributes to intestinal problems remain largely unknown. Fermentation of undigested protein in the hindgut results in formation of fermentation products including short-chain fatty acids (SCFA), branched-chain fatty acids (BCFA), ammonia, phenolic and indolic compounds, biogenic amines, hydrogen sulfide and nitric oxide. Here, we review the mechanisms by which these metabolites may cause intestinal disease. Studies addressing how different metabolites induce epithelial damage rely mainly on cell culture studies and occasionally on mice or rat models. Often, contrasting results were reported. The direct relevance of such studies for human, pig and poultry gut health is therefore questionable and does not suffice for the development of interventions to improve gut health. We discuss a road-map to improve our understanding of gut metabolites and microbial species associated with intestinal health in humans and production animals, and to determine whether these metabolite/bacterial networks cause epithelial damage. The outcomes of these studies will dictate proof-of-principle studies to eliminate specific metabolites and or bacterial strains and will provide the basis for interventions aiming to improve gut health. PMID: 29597354 [PubMed - as supplied by publisher]

Lipidomics biomarker studies: Errors, limitations, and the future. Biochem Biophys Res Commun. 2018 Mar 26;: Authors: Wood PL, Cebak JE Abstract Lipidomics is an ever-expanding subfield of metabolomics that surveys 3000 to 5000 individual lipids across more than 56 lipid subclasses, including lipid peroxidation products. Unfortunately, there exists a large number of publications with poor quality data obtained with unit mass resolution leading to many lipid misidentifications. This is further complicated by poor scientific oversight with regard to recognition of isobar issues, sample collection, and sample storage issues that inexplicably requires more detailed attention. Inadvertent or intentional obfuscation of relative quantification data represented as absolute quantification is a subtle but profound difference that may readers outside of the field may not realize, therefore, instigating disservice and unnecessary distrust in the scientific community. These issues need to be addressed aggressively as high quality data are essential for the translation of biomarker research to clinical practice. PMID: 29596837 [PubMed - as supplied by publisher]

Variations in gut microbiota and fecal metabolic phenotype associated with Fenbendazole and Ivermectin Tablets by 16S rRNA gene sequencing and LC/MS-based metabolomics in Amur tiger. Biochem Biophys Res Commun. 2018 Mar 26;: Authors: He F, Zhai J, Zhang L, Liu D, Ma Y, Rong K, Xu Y, Ma J Abstract BACKGROUND: The Amur tiger is one of the most endangered species in the world, and the healthy population of captive Amur tigers assists the recovery of the wild population. Gut microbes have been shown to be important for human disease and health, but little research exists regarding the microbiome of Amur tigers in captivity. METHODS: In this study, we used an integrated approach of 16S rRNA gene sequencing combined with ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS)-based metabolomics to analyze the effects of Fenbendazole and Ivermectin Tablets on the gut microbiota and fecal metabolic phenotype of the Amur tiger. RESULTS: The relative abundances of the bacterial genera Collinsella, Clostridium XI and Megamonas were decreased, whereas those of Escherichia and Clostridium sensu stricto were increased in experimental Amur tigers compared with those in normal controls. Meanwhile, distinct changes in the fecal metabolic phenotype of the experimental Amur tigers were also found, including lower levels of acrylic acid, acetoacetate and catechol and higher amounts of 5,6-dihydrouracil, adenine hydrochloride hydrate and galactitol. Moreover, the differentially abundant gut microbes were substantially associated with the altered fecal metabolites, especially the bacteria in the Firmicutes and Actinomycetes, which were involved in the metabolism of 5,6-dihydrouracil, 6-phospho-d-gluconate and 1-methylnicotinamide. CONCLUSION: Our results indicate for the first time that Fenbendazole and Ivermectin Tablets not only disturb the gut microbiota at the abundance level but also alter the metabolic homeostasis of the Amur tiger. PMID: 29596832 [PubMed - as supplied by publisher]

Differential Mobility Spectrometry (DMS) Reveals the Elevation of Urinary Acetylcarnitine in Non-Human Primates (NHPs) Exposed to Radiation. J Mass Spectrom. 2018 Mar 29;: Authors: Vera NB, Chen Z, Pannkuk E, Laiakis EC, Fornace AJ, Erion DM, Coy SL, Pfefferkorn JA, Vouros P Abstract Acetylcarnitine has been identified as one of several urinary biomarkers indicative of radiation exposure in adult rhesus macaque monkeys (non-human primates, NHPs). Previous work has demonstrated an up-regulated dose-response profile in a balanced male/female NHP cohort1 . As a contribution toward the development of metabolomics-based radiation biodosimetry in human populations and other applications of acetylcarnitine screening, we have developed a quantitative, high-throughput method for the analysis of acetylcarnitine. We employed the Sciex SelexIon DMS-MS/MS QTRAP 5500 platform coupled to flow injection analysis (FIA), thereby allowing for fast analysis times of less than 0.5 minutes per injection with no chromatographic separation. Ethyl acetate is used as a DMS modifier to reduce matrix chemical background. We have measured NHP urinary acetylcarnitine from the male cohorts that were exposed to the following radiation levels: control, 2 Gy, 4 Gy, 6 Gy, 7 Gy and 10 Gy. Biological variability, along with calibration accuracy of the FIA-DMS-MS/MS method, indicate LOQ of 20 μM, with observed biological levels on the order of 600 μM and control levels near 10 μM. There is an apparent onset of intensified response in the transition from 6 Gy to 10 Gy. The results demonstrate that FIA-DMS-MS/MS is a rapid, quantitative technique that can be utilized for the analysis of urinary biomarker levels for radiation biodosimetry. PMID: 29596720 [PubMed - as supplied by publisher]

Related Articles Non-targeted analysis of unexpected food contaminants using LC-HRMS. Anal Bioanal Chem. 2018 Mar 29;: Authors: Kunzelmann M, Winter M, Åberg M, Hellenäs KE, Rosén J Abstract A non-target analysis method for unexpected contaminants in food is described. Many current methods referred to as "non-target" are capable of detecting hundreds or even thousands of contaminants. However, they will typically still miss all other possible contaminants. Instead, a metabolomics approach might be used to obtain "true non-target" analysis. In the present work, such a method was optimized for improved detection capability at low concentrations. The method was evaluated using 19 chemically diverse model compounds spiked into milk samples to mimic unknown contamination. Other milk samples were used as reference samples. All samples were analyzed with UHPLC-TOF-MS (ultra-high-performance liquid chromatography time-of-flight mass spectrometry), using reversed-phase chromatography and electrospray ionization in positive mode. Data evaluation was performed by the software TracMass 2. No target lists of specific compounds were used to search for the contaminants. Instead, the software was used to sort out all features only occurring in the spiked sample data, i.e., the workflow resembled a metabolomics approach. Procedures for chemical identification of peaks were outside the scope of the study. Method, study design, and settings in the software were optimized to minimize manual evaluation and faulty or irrelevant hits and to maximize hit rate of the spiked compounds. A practical detection limit was established at 25 μg/kg. At this concentration, most compounds (17 out of 19) were detected as intact precursor ions, as fragments or as adducts. Only 2 irrelevant hits, probably natural compounds, were obtained. Limitations and possible practical use of the approach are discussed. PMID: 29594430 [PubMed - as supplied by publisher]

Related Articles Identification of Metabolomic Biomarkers for Endometrial Cancer and Its Recurrence after Surgery in Postmenopausal Women. Front Endocrinol (Lausanne). 2018;9:87 Authors: Audet-Delage Y, Villeneuve L, Grégoire J, Plante M, Guillemette C Abstract Endometrial cancer (EC) is the most frequent gynecological cancer in developed countries. Most EC occurs after menopause and is diagnosed as endometrioid (type I) carcinomas, which exhibit a favorable prognosis. In contrast, non-endometrioid (type II) carcinomas such as serous tumors have a poor prognosis. Our goal was to identify novel blood-based markers associated with EC subtypes and recurrence after surgery in postmenopausal women. Using mass spectrometry-based untargeted metabolomics, we examined preoperative serum metabolites among control women (n = 18) and those with non-recurrent (NR) and recurrent (R) cases of type I endometrioid (n = 24) and type II serous (n = 12) carcinomas. R and NR cases were similar with respect to pathological characteristics, body mass index, and age. A total of 1,592 compounds were analyzed including 14 different lipid classes. When we compared EC cases with controls, 137 metabolites were significantly different. A combination of spermine and isovalerate resulted in an age-adjusted area under the receiver-operating characteristic curve (AUCadj) of 0.914 (P < 0.001) for EC detection. The combination of 2-oleoylglycerol and TAG42:2-FA12:0 allowed the distinction of R cases from NR cases with an AUCadj of 0.901 (P < 0.001). Type I R cases were also characterized by much lower levels of bile acids and elevated concentrations of phosphorylated fibrinogen cleavage peptide, whereas type II R cases displayed higher levels of ceramides. The findings from our pilot study provide a detailed metabolomics study of EC and identify putative serum biomarkers for defining clinically relevant risk groups. PMID: 29593653 [PubMed]