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]

Related Articles Anti-CTLA-4 immunotherapy: uncoupling toxicity and efficacy. Cell Res. 2018 Mar 28;: Authors: Pol J, Kroemer G PMID: 29593340 [PubMed - as supplied by publisher]

Related Articles Nonhuman primate breath volatile organic compounds associate with developmental programming and cardio-metabolic status. J Breath Res. 2018 Mar 29;: Authors: Bishop AC, Libardoni M, Choudary A, Misra BB, Lange K, Bernal J, Nijland M, Li C, Olivier M, Nathanielsz PW, Cox LA Abstract Rodent and nonhuman primate (NHP) studies indicate that developmental programming by reduced perinatal nutrition negatively impacts life course cardio-metabolic health. We have developed a baboon model in which we feed control mothers (CON) ad libitum while nutrient restricted mothers are fed 70% of ad libitum global feed in pregnancy and lactation. Offspring of nutrient restricted mothers are intrauterine growth restricted (IUGR) at term. By 3.5 years IUGR baboons showed signs of insulin resistance, indicating a pre-diabetic phenotype, in contrast to healthy CON offspring. We hypothesized that a novel breath analysis approach would provide markers of the altered cardio-metabolic state in a non-invasive manner. Here we assess whether exhaled breath volatile organic compounds (VOCs) collected from this unique cohort of juvenile baboons with documented cardio-metabolic dysfunction resulting from in utero programming can be detected from their breath signatures. Breath was collected from male and female CON and IUGR baboons at 4.8±0.2 years (human equivalent ~13 years). Breath VOCs were quantified using a two-dimensional gas chromatography mass spectrometer (2D GC-MS). Two-way ANOVA, on 76 biologically relevant VOCs identified 27 VOCs (p&lt;0.05) with altered abundances between groups (sex, birthweight, and sex x birthweight). The 27 VOCs included 2-pentanone, 2-octanone, 2,5,5 trimethyl-1-hexene and 2,2-dimethyl-undecane, which have not previously been associated with cardio-metabolic disease. Unsupervised principal component analysis of these VOCs could discriminate the four defined clusters defining males, females, CON and IUGR. This study, which is the first to assess quantifiable breath signatures associated with cardio-metabolic programing for any model of IUGR, demonstrates the translational value of this unique model to identify metabolites of programmed cardio-metabolic dysfunction in breath signatures. Future studies are required to validate the translatability of these findings to humans. PMID: 29593130 [PubMed - as supplied by publisher]

Related Articles Genetic defects in SAPK signalling, chromatin regulation, vesicle transport and CoA-related lipid metabolism are rescued by rapamycin in fission yeast. Open Biol. 2018 Mar;8(3): Authors: Sajiki K, Tahara Y, Villar-Briones A, Pluskal T, Teruya T, Mori A, Hatanaka M, Ebe M, Nakamura T, Aoki K, Nakaseko Y, Yanagida M Abstract Rapamycin inhibits TOR (target of rapamycin) kinase, and is being used clinically to treat various diseases ranging from cancers to fibrodysplasia ossificans progressiva. To understand rapamycin mechanisms of action more comprehensively, 1014 temperature-sensitive (ts) fission yeast (Schizosaccharomyces pombe) mutants were screened in order to isolate strains in which the ts phenotype was rescued by rapamycin. Rapamycin-rescued 45 strains, among which 12 genes responsible for temperature sensitivity were identified. These genes are involved in stress-activated protein kinase (SAPK) signalling, chromatin regulation, vesicle transport, and CoA- and mevalonate-related lipid metabolism. Subsequent metabolome analyses revealed that rapamycin upregulated stress-responsive metabolites, while it downregulated purine biosynthesis intermediates and nucleotide derivatives. Rapamycin alleviated abnormalities in cell growth and cell division caused by sty1 mutants (Δsty1) of SAPK. Notably, in Δsty1, rapamycin reduced greater than 75% of overproduced metabolites (greater than 2× WT), like purine biosynthesis intermediates and nucleotide derivatives, to WT levels. This suggests that these compounds may be the points at which the SAPK/TOR balance regulates continuous cell proliferation. Rapamycin might be therapeutically useful for specific defects of these gene functions. PMID: 29593117 [PubMed - in process]

Related Articles Dilated Cardiomyopathy and Premature Ovarian Failure Unveiling Propionic Aciduria. Clin Chem. 2018 Apr;64(4):752-754 Authors: Grotto S, Sudrié-Arnaud B, Drouin-Garraud V, Nafeh-Bizet C, Chadefaux-Vekemans B, Gobin S, Bekri S, Tebani A PMID: 29592908 [PubMed - in process]

Related Articles Serum apolipoprotein A2 isoforms in autoimmune pancreatitis. Biochem Biophys Res Commun. 2018 03 11;497(3):903-907 Authors: Kobayashi T, Sato Y, Nishiumi S, Yagi Y, Sakai A, Shiomi H, Masuda A, Okaya S, Kutsumi H, Yoshida M, Honda K Abstract Recently, apolipoprotein A2 (apoA2) isoforms have been reported as candidate serum/plasma biomarkers of pancreatic cancer. However, the distribution of apoA2 isoforms in patients with autoimmune pancreatitis (AIP) has not been investigated yet. In this study, we evaluated the distribution of serum apoA2 isoforms; i.e., homodimer apoA2-ATQ/ATQ, heterodimer apoA2-ATQ/AT, and homodimer apoA2-AT/AT, in AIP patients and healthy volunteers (HV) using enzyme-linked immunosorbent assays, and the clinical characteristics and serum levels of each apoA2 isoform in 32 AIP patients and 38 HV were investigated. The calculated apoA2-ATQ/AT levels of the AIP patients were significantly lower than those of the HV, which agreed with results obtained for patients with pancreatic cancer. Interestingly, most of the AIP patients exhibited high levels of apoA2-ATQ along with low levels of apoA2-AT, indicating that the processing of the C-terminal regions of apoA2 dimer was inhibited in the AIP patients. This specific distribution of serum apoA2 isoforms might provide important information about the disease states of AIP patients and aid the differential diagnosis of AIP versus pancreatic cancer. PMID: 29481802 [PubMed - indexed for MEDLINE]

Related Articles Genome-wide methylome and chromatin interactome identify abnormal enhancer to be risk factor of breast cancer. Oncotarget. 2017 Jul 04;8(27):44705-44719 Authors: Wang Y, Hao DP, Li JJ, Wang L, Di LJ Abstract Enhancer is critical cis regulatory elements in gene expression. To understand whether and how the aberrant enhancer activation may contribute to cancer risk, the differentially methylated enhancers (eDMRs) in normal and malignant breast tissues were identified and analyzed. By incorporating genome-wide chromatin interaction, integrated analysis of eDMRs and target gene expression identified 1,272 enhancer-promoter pairs. Surprisingly, two functionally distinct groups of genes were identified in these pairs, one showing better correlation to enhancer methylation (eRGs) and the other showing better correlation to promoter methylation (pRGs), and the former group is functionally enriched with cancer related genes. Moreover, enhancer methylation based clustering of breast cancer samples is capable of discriminating basal breast cancer from other subtypes. By correlating enhancer methylation status to patient survival, 345 enhancers show the impact on the disease outcome and the majority of their target genes are important regulators of cell survival pathways including known cancer related genes. Together, these results suggest reactivation of enhancers in cancer cells has the add-on effect and contributes to cancer risk in combination. PMID: 28621677 [PubMed - indexed for MEDLINE]

Related Articles BioContainers: an open-source and community-driven framework for software standardization. Bioinformatics. 2017 Aug 15;33(16):2580-2582 Authors: da Veiga Leprevost F, Grüning BA, Alves Aflitos S, Röst HL, Uszkoreit J, Barsnes H, Vaudel M, Moreno P, Gatto L, Weber J, Bai M, Jimenez RC, Sachsenberg T, Pfeuffer J, Vera Alvarez R, Griss J, Nesvizhskii AI, Perez-Riverol Y Abstract Motivation: BioContainers (biocontainers.pro) is an open-source and community-driven framework which provides platform independent executable environments for bioinformatics software. BioContainers allows labs of all sizes to easily install bioinformatics software, maintain multiple versions of the same software and combine tools into powerful analysis pipelines. BioContainers is based on popular open-source projects Docker and rkt frameworks, that allow software to be installed and executed under an isolated and controlled environment. Also, it provides infrastructure and basic guidelines to create, manage and distribute bioinformatics containers with a special focus on omics technologies. These containers can be integrated into more comprehensive bioinformatics pipelines and different architectures (local desktop, cloud environments or HPC clusters). Availability and Implementation: The software is freely available at github.com/BioContainers/. Contact: yperez@ebi.ac.uk. PMID: 28379341 [PubMed - indexed for MEDLINE]

Serine Availability Influences Mitochondrial Dynamics and Function through Lipid Metabolism. Cell Rep. 2018 Mar 27;22(13):3507-3520 Authors: Gao X, Lee K, Reid MA, Sanderson SM, Qiu C, Li S, Liu J, Locasale JW Abstract Cell proliferation can be dependent on the non-essential amino acid serine, and dietary restriction of serine inhibits tumor growth, but the underlying mechanisms remain incompletely understood. Using a metabolomics approach, we found that serine deprivation most predominantly impacts cellular acylcarnitine levels, a signature of altered mitochondrial function. Fuel utilization from fatty acid, glucose, and glutamine is affected by serine deprivation, as are mitochondrial morphological dynamics leading to increased fragmentation. Interestingly, these changes can occur independently of nucleotide and redox metabolism, two known major functions of serine. A lipidomics analysis revealed an overall decrease in ceramide levels. Importantly, supplementation of the lipid component of bovine serum or C16:0-ceramide could partially restore defects in cell proliferation and mitochondrial fragmentation induced by serine deprivation. Together, these data define a role for serine in supporting mitochondrial function and cell proliferation through ceramide metabolism. PMID: 29590619 [PubMed - in process]

1H-NMR-based metabolomics approach reveals metabolic mechanism of (-)-5-hydroxy-equol against hepatocellular carcinoma cells in vitro. J Proteome Res. 2018 Mar 28;: Authors: Gao L, Wang KX, Zhang NN, Li JQ, Qin XM, Wang XL Abstract 1H-NMR-based metabolomics can rapidly detect metabolic shift under various stimulus, thus it facilitated the dissection of the therapeutic mechanisms of compounds. (-)-5-hydroxy-equol is an isoflavone metabolite that be obtained by microbial biotransformation. In the current work, the effect of (‒)-5-hydroxy-equol on hepatocellular carcinoma cells and its mechanism have been explored based on 1H-NMR-based metabolomics approach. Our results revealed that (-)-5-hydroxy-equol can significantly inhibit the proliferation, migration and invasion of SMMC-7721 cells, and inhibit the proliferation of HepG2 cells. Metabolomics revealed that 17 differential metabolites involving in amino acid metabolism and energy metabolism were significantly changed inside and outside of the cells after treatment of (-)-5-hydroxy-equol. Specifically, (-)-5-hydroxy-equol at concentration of 30 μM significantly decreased the concentrations of pyruvate, glutamate and glucose. As glycometabolism is a crucial feature of cancer-specific metabolism, we further verified enzymes and proteins that closely relevant to glycometabolism. Our results indicated that (-)-5-hydroxy-equol modulated glycolysis in HCC through inhibition of activities of hexokinase, phosphofructokinase and pyruvate kinase, and the expression of pyruvate kinase M2. This study revealed that metabolomic analysis integrating with further verifications at the biochemical level can facilitate understanding the anti-HCC mechanisms of (-)-5-hydroxy-equol. PMID: 29589762 [PubMed - as supplied by publisher]

Related Articles Influence of Nutritional Status on the Absorption of Polyphyllin I, an Anticancer Candidate from Paris polyphylla in Rats. Eur J Drug Metab Pharmacokinet. 2018 Mar 28;: Authors: Yu FL, Gong WL, Xu FJ, Wu JW, Shakya S, Zhu H Abstract BACKGROUND AND OBJECTIVES: Protein-calorie malnutrition (PCM) is one of the most suffered complications in cancer patients. Polyphyllin I (PPI), a saponin isolated from rhizome of Paris polyphylla, is a potential candidate in cancer therapy. In this study, the influence of nutritional status on the absorption of PPI in rats was explored after oral administration. METHODS: PCM rats, namely mal-nourished (MN) rats, were induced from well-nourished (WN) rats by caloric restriction protocol. Intestinal absorption of PPI in WN and MN rats was evaluated by pharmacokinetic and intestinal perfusion methods. The potential mechanisms between two groups were investigated on the basis of intestinal permeability, intestinal efflux and PPI's depletions in vivo. The intestinal permeability was analyzed by determining the concentration of paracellular marker transport in serum and the expression of junction proteins in intestine. The intestinal efflux was evaluated through comparing the protein level of P-glycoprotein (P-gp) in intestine, and the depletions of PPI and/or generation of its metabolites in liver and intestines were analyzed by liquid chromatography triple quadrupole mass spectrometry (LC-MS/MS) method. RESULTS: Compared to WN rats, the oral systemic exposure of PPI was significantly increased in MN rats, evidenced by significant enhancement of maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0-60h) by more than 2.51- and 3.71-folds as well as terminal elimination half-life (t1/2) prolonged from to 7.3 to 14.1 h. Further studies revealed that the potential mechanism might be associated with combined contribution of improved intestinal absorption and depressed deglycosylation of PPI in MN rats. Furthermore, enhanced intestinal absorption of PPI was benefited from increased intestinal permeability and decreased intestinal efflux in MN rats. Meanwhile, the former manifested as increased transport of paracellular marker and decreased junction proteins levels, while the later evidenced by reduced P-gp expression. CONCLUSIONS: The oral exposure of PPI was enhanced in MN rats, which suggested that nutritional status alters the absorption of PPI, and thus the dosage of PPI should be modified during the treatment of cancer patient with PCM. PMID: 29589340 [PubMed - as supplied by publisher]

Related Articles Colorectal Cancer Detection Using Targeted LC-MS Metabolic Profiling. Methods Mol Biol. 2018;1765:229-240 Authors: Djukovic D, Zhang J, Raftery D Abstract Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies and causes of cancer death. While the mortality rates from CRC have steadily declined, 50,000 individuals in the USA (and many times this number worldwide) still succumb to this illness every year. Early detection of CRC is the most critical need for improving 5-year survival and cure rates. Currently available CRC diagnostic techniques often miss early stage disease such that only 40% of newly diagnosed CRC patients are treated for local disease, Therefore, development of new screening methods that are highly sensitive, specific, noninvasive and easily accessible are critically desired for the early diagnosis and significant reduction in death rate from CRC. In this chapter we describe a targeted LC-MS based metabolic profiling approach used for the discovery of CRC metabolite biomarker candidates, based on highly reproducible hydrophilic interaction liquid chromatography coupled to triple-quadrupole mass spectrometry (HILIC-LC-QQQ-MS). A partial least squares-discriminant analysis (PLS-DA) model was able to differentiate CRC patients from both healthy controls and polyp patients, as well as to distinguish CRC patients based on the cancer stage. PMID: 29589312 [PubMed - in process]

Related Articles Identifying and correcting epigenetics measurements for systematic sources of variation. Clin Epigenetics. 2018;10:38 Authors: Perrier F, Novoloaca A, Ambatipudi S, Baglietto L, Ghantous A, Perduca V, Barrdahl M, Harlid S, Ong KK, Cardona A, Polidoro S, Nøst TH, Overvad K, Omichessan H, Dollé M, Bamia C, Huerta JM, Vineis P, Herceg Z, Romieu I, Ferrari P Abstract Background: Methylation measures quantified by microarray techniques can be affected by systematic variation due to the technical processing of samples, which may compromise the accuracy of the measurement process and contribute to bias the estimate of the association under investigation. The quantification of the contribution of the systematic source of variation is challenging in datasets characterized by hundreds of thousands of features.In this study, we introduce a method previously developed for the analysis of metabolomics data to evaluate the performance of existing normalizing techniques to correct for unwanted variation. Illumina Infinium HumanMethylation450K was used to acquire methylation levels in over 421,000 CpG sites for 902 study participants of a case-control study on breast cancer nested within the EPIC cohort. The principal component partial R-square (PC-PR2) analysis was used to identify and quantify the variability attributable to potential systematic sources of variation. Three correcting techniques, namely ComBat, surrogate variables analysis (SVA) and a linear regression model to compute residuals were applied. The impact of each correcting method on the association between smoking status and DNA methylation levels was evaluated, and results were compared with findings from a large meta-analysis. Results: A sizeable proportion of systematic variability due to variables expressing 'batch' and 'sample position' within 'chip' was identified, with values of the partial R2 statistics equal to 9.5 and 11.4% of total variation, respectively. After application of ComBat or the residuals' methods, the contribution was 1.3 and 0.2%, respectively. The SVA technique resulted in a reduced variability due to 'batch' (1.3%) and 'sample position' (0.6%), and in a diminished variability attributable to 'chip' within a batch (0.9%). After ComBat or the residuals' corrections, a larger number of significant sites (k = 600 and k = 427, respectively) were associated to smoking status than the SVA correction (k = 96). Conclusions: The three correction methods removed systematic variation in DNA methylation data, as assessed by the PC-PR2, which lent itself as a useful tool to explore variability in large dimension data. SVA produced more conservative findings than ComBat in the association between smoking and DNA methylation. PMID: 29588806 [PubMed - in process]