PubMed

Related Articles Nitrogen mustard-induced corneal injury involves the sphingomyelin-ceramide pathway. Ocul Surf. 2017 Nov 09;: Authors: Charkoftaki G, Jester J, Thompson D, Vasiliou V Abstract PURPOSE: Nitrogen mustard (NM), which simulates the effects of sulfur mustard (SM), is a potent vesicant known to cause irreversible corneal damage. This study investigates the mechanisms by which NM induces corneal damage by examining the impact of NM exposure on the morphology and lipidome of the cornea. METHODS: Intact ex vivo rabbit eyes were placed in serum-free DMEM organ culture. NM (0, 1, 2.5, 5 or 10 mg/ml) was applied to the central cornea for 5, 10 or 15 min using a 5 mm filter disk and subsequently rinsed with DMEM. Corneas were then cultured for 3, 24, or 48 h before being fixed for morphological analysis or for 24 h before being snap- frozen for lipidomic analysis. RESULTS: No morphological changes were detected 3 h after NM exposure. Twenty-four h after exposure, 1 mg/ml NM caused erosion of the corneal epithelium, but no damage to the underlying stroma. Damage caused by 2.5 mg/ml NM extended almost two thirds through the corneal stroma, while 5 mg/ml completely penetrated the corneal stroma. Analtered lipid profile occurred 24 h after corneas were exposed to NM. Specific sphingomyelins, ceramides, and diacylglycerols were increased up to 9-, 60- and 10-fold, respectively. CONCLUSIONS: NM induces concentration- and exposure time-dependent damage to the cornea that increases in severity over time. Alterations in the sphingomyelin-ceramidepathway may contribute to the damaging effects of NM exposure. PMID: 29129753 [PubMed - as supplied by publisher]

Related Articles MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD(+) consumption. Nat Struct Mol Biol. 2017 Nov;24(11):902-910 Authors: Marjanović MP, Hurtado-Bagès S, Lassi M, Valero V, Malinverni R, Delage H, Navarro M, Corujo D, Guberovic I, Douet J, Gama-Perez P, Garcia-Roves PM, Ahel I, Ladurner AG, Yanes O, Bouvet P, Suelves M, Teperino R, Pospisilik JA, Buschbeck M Abstract Histone variants are structural components of eukaryotic chromatin that can replace replication-coupled histones in the nucleosome. The histone variant macroH2A1.1 contains a macrodomain capable of binding NAD(+)-derived metabolites. Here we report that macroH2A1.1 is rapidly induced during myogenic differentiation through a switch in alternative splicing, and that myotubes that lack macroH2A1.1 have a defect in mitochondrial respiratory capacity. We found that the metabolite-binding macrodomain was essential for sustained optimal mitochondrial function but dispensable for gene regulation. Through direct binding, macroH2A1.1 inhibits basal poly-ADP ribose polymerase 1 (PARP-1) activity and thus reduces nuclear NAD(+) consumption. The resultant accumulation of the NAD(+) precursor NMN allows for maintenance of mitochondrial NAD(+) pools that are critical for respiration. Our data indicate that macroH2A1.1-containing chromatin regulates mitochondrial respiration by limiting nuclear NAD(+) consumption and establishing a buffer of NAD(+) precursors in differentiated cells. PMID: 28991266 [PubMed - indexed for MEDLINE]

Related Articles Volatile organic compounds in gastrointestinal stromal tumour tissue originating from patient-derived xenografts. J Breath Res. 2017 Jun 29;11(3):037101 Authors: Wawrzyniak R, Woźniak A, Gebreyohannes YK, Dykcik B, Schöffski P, Markuszewski MJ Abstract Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract and localize mainly in the stomach or small intestine. The metabolomic signatures of GISTs driven by different KIT gene mutations remain undiscovered and unexplored. The main aim of this pilot study was to determine and compare metabolomic profiles in GIST xenograft models with different genetic backgrounds. Metabolomic profiling using gas chromatography coupled with mass spectrometry followed by univariate and multivariate statistical analyses was applied to select metabolites that differentiated the GIST models studied. The significant differences observed in the metabolites were mainly derived from glycolysis, the citric acid cycle and glutamine and lipid metabolism. The obtained results may suggest variable metabolomic signatures of tumours, possibly related to the different underlying, specific KIT gene mutations and with potential implications for the biological behaviour and natural course of this rare disease. This study constitutes a proof of concept in GISTs and reveals the potential of the metabolomic approach in orphan malignancies. PMID: 28416775 [PubMed - indexed for MEDLINE]

Related Articles Traditional and novel tools to probe the mitochondrial metabolism in health and disease. Wiley Interdiscip Rev Syst Biol Med. 2017 Mar;9(2): Authors: Zhang Y, Avalos JL Abstract Mitochondrial metabolism links energy production to other essential cellular processes such as signaling, cellular differentiation, and apoptosis. In addition to producing adenosine triphosphate (ATP) as an energy source, mitochondria are responsible for the synthesis of a myriad of important metabolites and cofactors such as tetrahydrofolate, α-ketoacids, steroids, aminolevulinic acid, biotin, lipoic acid, acetyl-CoA, iron-sulfur clusters, heme, and ubiquinone. Furthermore, mitochondria and their metabolism have been implicated in aging and several human diseases, including inherited mitochondrial disorders, cardiac dysfunction, heart failure, neurodegenerative diseases, diabetes, and cancer. Therefore, there is great interest in understanding mitochondrial metabolism and the complex relationship it has with other cellular processes. A large number of studies on mitochondrial metabolism have been conducted in the last 50 years, taking a broad range of approaches. In this review, we summarize and discuss the most commonly used tools that have been used to study different aspects of the metabolism of mitochondria: ranging from dyes that monitor changes in the mitochondrial membrane potential and pharmacological tools to study respiration or ATP synthesis, to more modern tools such as genetically encoded biosensors and trans-omic approaches enabled by recent advances in mass spectrometry, computation, and other technologies. These tools have allowed the large number of studies that have shaped our current understanding of mitochondrial metabolism. WIREs Syst Biol Med 2017, 9:e1373. doi: 10.1002/wsbm.1373 For further resources related to this article, please visit the WIREs website. PMID: 28067471 [PubMed - indexed for MEDLINE]

Related Articles Forthcoming Challenges in Mycotoxins Toxicology Research for Safer Food-A Need for Multi-Omics Approach. Toxins (Basel). 2017 Jan 04;9(1): Authors: Dellafiora L, Dall'Asta C Abstract The presence of mycotoxins in food represents a severe threat for public health and welfare, and poses relevant research challenges in the food toxicology field. Nowadays, food toxicologists have to provide answers to food-related toxicological issues, but at the same time they should provide the appropriate knowledge in background to effectively support the evidence-based decision-making in food safety. Therefore, keeping in mind that regulatory actions should be based on sound scientific findings, the present opinion addresses the main challenges in providing reliable data for supporting the risk assessment of foodborne mycotoxins. PMID: 28054977 [PubMed - indexed for MEDLINE]

Related Articles Early Cord Metabolite Index and Outcome in Perinatal Asphyxia and Hypoxic-Ischaemic Encephalopathy. Neonatology. 2016;110(4):296-302 Authors: Ahearne CE, Denihan NM, Walsh BH, Reinke SN, Kenny LC, Boylan GB, Broadhurst DI, Murray DM Abstract BACKGROUND: A 1H-NMR-derived metabolomic index based on early umbilical cord blood alterations of succinate, glycerol, 3-hydroxybutyrate and O-phosphocholine has shown potential for the prediction of hypoxic-ischaemic encephalopathy (HIE) severity. OBJECTIVE: To evaluate whether this metabolite score can predict 3-year neurodevelopmental outcome in infants with perinatal asphyxia and HIE, compared with current standard biochemical and clinical markers. METHODS: From September 2009 to June 2011, infants at risk of perinatal asphyxia were recruited from a single maternity hospital. Cord blood was drawn and biobanked at delivery. Neonates were monitored for development of encephalopathy both clinically and electrographically. Neurodevelopmental outcome was assessed at 36-42 months using the Bayley Scales of Infant and Toddler Development, ed. III (BSID-III). Death and cerebral palsy were also considered as abnormal end points. RESULTS: Thirty-one infants had both metabolomic analysis and neurodevelopmental outcome at 36-42 months. No child had a severely abnormal BSID-III result. The metabolite index significantly correlated with outcome (ρ2 = 0.30, p < 0.01), which is robust to predict both severe outcome (area under the receiver operating characteristic curve: 0.92, p < 0.01) and intact survival (0.80, p = 0.01). There was no correlation between the index score and performance in the individual BSID-III subscales (cognitive, language, motor). CONCLUSIONS: The metabolite index outperformed other standard biochemical markers at birth for prediction of outcome at 3 years, but was not superior to EEG or the Sarnat score. PMID: 27486995 [PubMed - indexed for MEDLINE]

Metabolomics and Gene Expression Analysis Reveal Down-regulation of the Citric Acid (TCA) Cycle in Non-diabetic CKD Patients. EBioMedicine. 2017 Oct 31;: Authors: Hallan S, Afkarian M, Zelnick LR, Kestenbaum B, Sharma S, Saito R, Darshi M, Barding G, Raftery D, Ju W, Kretzler M, Sharma K, de Boer IH Abstract Chronic kidney disease (CKD) is a public health problem with very high prevalence and mortality. Yet, there is a paucity of effective treatment options, partly due to insufficient knowledge of underlying pathophysiology. We combined metabolomics (GCMS) with kidney gene expression studies to identify metabolic pathways that are altered in adults with non-diabetic stage 3-4 CKD versus healthy adults. Urinary excretion rate of 27 metabolites and plasma concentration of 33 metabolites differed significantly in CKD patients versus controls (estimate range-68% to +113%). Pathway analysis revealed that the citric acid cycle was the most significantly affected, with urinary excretion of citrate, cis-aconitate, isocitrate, 2-oxoglutarate and succinate reduced by 40-68%. Reduction of the citric acid cycle metabolites in urine was replicated in an independent cohort. Expression of genes regulating aconitate, isocitrate, 2-oxoglutarate and succinate were significantly reduced in kidney biopsies. We observed increased urine citrate excretion (+74%, p=0.00009) and plasma 2-oxoglutarate concentrations (+12%, p=0.002) in CKD patients during treatment with a vitamin-D receptor agonist in a randomized trial. In conclusion, urinary excretion of citric acid cycle metabolites and renal expression of genes regulating these metabolites were reduced in non-diabetic CKD. This supports the emerging view of CKD as a state of mitochondrial dysfunction. PMID: 29128444 [PubMed - as supplied by publisher]

Investigation of novel metabolites potentially involved in the pathogenesis of coronary heart disease using a UHPLC-QTOF/MS-based metabolomics approach. Sci Rep. 2017 Nov 10;7(1):15357 Authors: Li Y, Zhang D, He Y, Chen C, Song C, Zhao Y, Bai Y, Wang Y, Pu J, Chen J, Yang Y, Dou K Abstract Coronary heart disease (CHD) is associated with complex metabolic disorders, but its molecular aetiology remains unclear. Using a novel nontargeted metabolomics approach, we explored the global metabolic perturbation profile for CHD. Blood samples from 150 patients with severe obstructive CHD and 150 angiographically normal controls were collected. Metabolic fingerprinting was performed by ultra-high performance liquid chromatography coupled to quadruple time-of-flight mass spectrometry (UHPLC-QTOF/MS) technique. After adjusting for CHD traditional risk factors and metabolic batch, a comprehensive list of 105 metabolites was found to be significantly altered in CHD patients. Among the metabolites identified, six metabolites were discovered to have the strongest correlation with CHD after adjusting for multiple testing: palmitic acid (β = 0.205; p < 0.0001), linoleic acid (β = 0.133; p < 0.0001), 4-pyridoxic acid (β = 0.142; p < 0.0001), phosphatidylglycerol (20:3/2:0) (β = 0.287; p < 0.0001), carnitine (14:1) (β = 0.332; p < 0.0001) and lithocholic acid (β = 0.224; p < 0.0001); of these, 4-pyridoxic acid, lithocholic acid and phosphatidylglycerol (20:3/2:0) were, to the best of our knowledge, first reported in this study. A logistic regression model further quantified their positive independent correlations with CHD. In conclusion, this study surveyed a broad panel of nontargeted metabolites in Chinese CHD populations and identified novel metabolites that are potentially involved in CHD pathogenesis. PMID: 29127404 [PubMed - in process]

Quantum Chemical Fragment Precursor Tests: Accelerating de novo annotation of tandem mass spectra. Anal Chim Acta. 2017 Dec 01;995:52-64 Authors: Janesko BG, Li L, Mensing R Abstract Tandem mass spectrometry is widely used to assign and distinguish chemical structures in proteomics, metabolomics, lipidomics, and many other areas. Spectral annotation remains a major bottleneck. Our "Quantum Chemical Fragment Precursor Tests" (QC-FPT) approach brings the accuracy and generality of modern quantum chemistry to combinatorial-search-based computer-aided spectral annotation. QC-FPT takes as input the dominant fragment peaks from a particular experiment, and one or more chemically reasonable hypotheses for the precursor ion's three-dimensional structure. The algorithm automatically generates possible precursor ion fragmentations matching the target experimental peaks, uses quantum chemistry calculations (geometry optimization with gas-phase semiempirical or density functional theory calculations) to predict each neutral or charged fragment's structure and energy, and reports the thermodynamically feasible predicted fragment assignments. Applications demonstrate that QC-FPT recovers known spectral annotations, can handle multiple ionization and fragmentation methods and adducts, and can capture some fragment rearrangements. We apply QC-FPT to assign previously unassigned peaks in an experimental LC-ESI-MS(2) spectrum of dimethylarsinothioyl glutathione (Yehiayan et al., Chem. Res. Toxicol. 2014, 27, 754-764), and to a hypothetical experiment distinguishing two isomeric candidates for an "unknown" pesticide's experimental LC-ESI-MS(2) spectrum. Our results suggest QC-FPT is a practical tool to sharpen and refine the chemical intuition of experimentalists engaged in the laborious process of annotating tandem mass spectra. PMID: 29126481 [PubMed - in process]

Optimization of GC/TOF MS analysis conditions for assessing host-gut microbiota metabolic interactions: Chinese rhubarb alters fecal aromatic amino acids and phenol metabolism. Anal Chim Acta. 2017 Dec 01;995:21-33 Authors: Yin S, Guo P, Hai D, Xu L, Shu J, Zhang W, Khan MI, Kurland IJ, Qiu Y, Liu Y Abstract In this paper, an optimized method based on gas chromatography/time-of-flight mass spectrometry (GC-TOFMS) platform has been developed for the analysis of gut microbial-host related co-metabolites in fecal samples. The optimization was performed with proportion of chloroform (C), methanol (M) and water (W) for the extraction of specific metabolic pathways of interest. Loading Bi-plots from the PLS regression model revealed that high concentration of chloroform emphasized the extraction of short chain fatty acids and TCA intermediates, while the higher concentration of methanol emphasized indole and phenyl derivatives. Low level of organic solution emphasized some TCA intermediates but not for indole and phenyl species. The highest sum of the peak area and the distribution of metabolites corresponded to the extraction of methanol/chloroform/water of 225:75:300 (v/v/v), which was then selected for method validation and utilized in our application. Excellent linearity was obtained with 62 reference standards representing different classes of gut microbial-host related co-metabolites, with correlation coefficients (r(2)) higher than 0.99. Limit of detections (LODs) and limit of qualifications (LOQs) for these standards were below 0.9 nmol and 1.6 nmol, respectively. The reproducibility and repeatability of the majority of tested metabolites in fecal samples were observed with RSDs lower than 15%. Chinese rhubarb-treated rats had elevated indole and phenyl species, and decreased levels of polyamine such as putrescine, and several amino acids. Our optimized method has revealed host-microbe relationships of potential importance for intestinal microbial metabolite receptors such as pregnane X receptor (PXR) and aryl hydrocarbon receptor (AHR) activity, and for enzymes such as ornithine decarboxylase (ODC). PMID: 29126478 [PubMed - in process]

Combination of HPLC with organic and inorganic mass spectrometry to study the metabolic response of the clam Scrobicularia plana to arsenic exposure. Electrophoresis. 2017 Nov 10;: Authors: Rodríguez-Moro G, García-Barrera T, Trombini C, Blasco J, Gómez-Ariza JL Abstract Arsenic is a toxic element extensively studied in the marine environment due to differential toxicological effects of inorganic and organic species. In the present work, the bivalve Scrobicularia plana was exposed to As(V) (10 and 100 μg·L(-1) ) for 14 days to evaluate the metabolic perturbations caused by this element. Arsenic speciation and metabolomic analysis were performed in the digestive gland of the bivalve using two complementary analytical platforms based on inorganic and organic mass spectrometry. It has been observed the greater presence of the innocuous specie arsenobetaine produced in this organism as defense mechanism against arsenic toxicity, although significant concentrations of methylated and inorganic arsenic were also present, depending on the level of arsenic in aqueous media. Complementarily, a metabolomic study based on mass spectrometry and statistical discriminant analysis allows a good classification of samples associated to low and high As(V) exposure in relation to controls. About 15 metabolites suffer significant changes of expression by the presence of As(V): amino acids, nucleotides, energy-related metabolites, free fatty acids, phospholipids and triacylglycerides, which can be related to membrane structural and functional damage. In addition, perturbation of the methylation cycle, associated with the increase of homocysteine and methionine was observed, which enhance the methylation of toxic inorganic arsenic to less toxic dimethylarsenic. This article is protected by copyright. All rights reserved. PMID: 29125650 [PubMed - as supplied by publisher]

Metabolite Profiling of Peppers of Various Colors Reveals Relationships Between Tocopherol, Carotenoid, and Phytosterol Content. J Food Sci. 2017 Nov 10;: Authors: Kim TJ, Choi J, Kim KW, Ahn SK, Ha SH, Choi Y, Park NI, Kim JK Abstract Peppers are widely consumed in Korea; the varietal development of peppers with increased content of beneficial plant metabolites is, therefore, of considerable interest. This requires a comprehensive understanding of the metabolic profile of pepper plants and the factors affecting this profile. To this end, we determined the content of various metabolites, such as hydrophilic and lipophilic compounds, phenolic acids, carotenoids, and capsaicinoids in peppers of various colors (green, red, pale green, and violet peppers) and in a high-pungency (green) pepper. We also performed principal component analysis (PCA), Pearson's correlation analysis, and hierarchical clustering analysis (HCA) to determine the relationships among these metabolites in peppers. PCA results indicated no significant variances among the 3 sample replicates. The HCA showed correlations between the metabolites resulting from common or closely linked biosynthesis pathways. Our results showed that carotenoids correlated positively with tocopherols and negatively with phytosterols; our findings also indicated a close relationship between the methylerythritol 4-phosphate and mevalonic acid biosynthesis pathways, providing evidence in favor of an earlier hypothesis regarding crosstalk across the chloroplast membrane. We, thus, demonstrate that metabolic profiling combined with multivariate analysis is a useful tool for analyzing metabolic networks. PRACTICAL APPLICATION: A total of 71 metabolites were measured in 5 peppers of different colors. The metabolic profiling with multivariate analysis revealed that tocopherol content had a positive correlation with the carotenoid content and a negative correlation with the phytosterol content. The results of this study may help in breeding programs to produce new germplasm with enhanced nutritional quality. PMID: 29125620 [PubMed - as supplied by publisher]

Early Response Monitoring Following Radiation Therapy by Using [(18)F]FDG and [(11)C]Acetate PET in Prostate Cancer Xenograft Model with Metabolomics Corroboration. Molecules. 2017 Nov 10;22(11): Authors: Chung YH, Tsai CK, Wang CC, Chen HM, Lu KY, Chiu H, Lin YC, Yen TC, Lin G Abstract We aim to characterize the metabolic changes associated with early response to radiation therapy in a prostate cancer mouse model by 2-deoxy-2-[(18)F]fluoro-d-glucose ([(18)F]FDG) and [(11)C]acetate ([(11)C]ACT) positron emission tomography, with nuclear magnetic resonance (NMR) metabolomics corroboration. [(18)F]FDG and [(11)C]ACT PET were performed before and following irradiation (RT, 15Gy) for transgenic adenocarcinoma of mouse prostate xenografts. The underlying metabolomics alterations of tumor tissues were analyzed by using ex vivo NMR. The [(18)F]FDG total lesion glucose (TLG) of the tumor significant increased in the RT group at Days 1 and 3 post-irradiation, compared with the non-RT group (p < 0.05). The [(11)C]ACT maximum standard uptake value (SUVmax) in RT (0.83 ± 0.02) and non-RT groups (0.85 ± 0.07) were not significantly different (p > 0.05). The ex vivo NMR analysis showed a 1.70-fold increase in glucose and a 1.2-fold increase in acetate in the RT group at Day 3 post-irradiation (p < 0.05). Concordantly, the expressions of cytoplasmic acetyl-CoA synthetase in the irradiated tumors was overexpressed at Day 3 post-irradiation (p < 0.05). Therefore, TLG of [(18)F]FDG in vivo PET images can map early treatment response following irradiation and be a promising prognostic indicator in a longitudinal preclinical study. The underlying metabolic alterations was not reflected by the [(11)C]ACT PET. PMID: 29125557 [PubMed - in process]

Discovery of Antimalarial Drugs from Streptomycetes Metabolites Using a Metabolomic Approach. J Trop Med. 2017;2017:2189814 Authors: Ahmad SJ, Abdul Rahim MBH, Baharum SN, Baba MS, Zin NM Abstract Natural products continue to play an important role as a source of biologically active substances for the development of new drug. Streptomyces, Gram-positive bacteria which are widely distributed in nature, are one of the most popular sources of natural antibiotics. Recently, by using a bioassay-guided fractionation, an antimalarial compound, Gancidin-W, has been discovered from these bacteria. However, this classical method in identifying potentially novel bioactive compounds from the natural products requires considerable effort and is a time-consuming process. Metabolomics is an emerging "omics" technology in systems biology study which integrated in process of discovering drug from natural products. Metabolomics approach in finding novel therapeutics agent for malaria offers dereplication step in screening phase to shorten the process. The highly sensitive instruments, such as Liquid Chromatography-Mass Spectrophotometry (LC-MS), Gas Chromatography-Mass Spectrophotometry (GC-MS), and Nuclear Magnetic Resonance ((1)H-NMR) spectroscopy, provide a wide range of information in the identification of potentially bioactive compounds. The current paper reviews concepts of metabolomics and its application in drug discovery of malaria treatment as well as assessing the antimalarial activity from natural products. Metabolomics approach in malaria drug discovery is still new and needs to be initiated, especially for drug research in Malaysia. PMID: 29123551 [PubMed]

Targeted mitochondrial therapy using MitoQ shows equivalent renoprotection to angiotensin converting enzyme inhibition but no combined synergy in diabetes. Sci Rep. 2017 Nov 09;7(1):15190 Authors: Ward MS, Flemming NB, Gallo LA, Fotheringham AK, McCarthy DA, Zhuang A, Tang PH, Borg DJ, Shaw H, Harvie B, Briskey DR, Roberts LA, Plan MR, Murphy MP, Hodson MP, Forbes JM Abstract Mitochondrial dysfunction is a pathological mediator of diabetic kidney disease (DKD). Our objective was to test the mitochondrially targeted agent, MitoQ, alone and in combination with first line therapy for DKD. Intervention therapies (i) vehicle (D); (ii) MitoQ (DMitoQ;0.6 mg/kg/day); (iii) Ramipril (DRam;3 mg/kg/day) or (iv) combination (DCoAd) were administered to male diabetic db/db mice for 12 weeks (n = 11-13/group). Non-diabetic (C) db/m mice were followed concurrently. No therapy altered glycaemic control or body weight. By the study end, both monotherapies improved renal function, decreasing glomerular hyperfiltration and albuminuria. All therapies prevented tubulointerstitial collagen deposition, but glomerular mesangial expansion was unaffected. Renal cortical concentrations of ATP, ADP, AMP, cAMP, creatinine phosphate and ATP:AMP ratio were increased by diabetes and mostly decreased with therapy. A higher creatine phosphate:ATP ratio in diabetic kidney cortices, suggested a decrease in ATP consumption. Diabetes elevated glucose 6-phosphate, fructose 6-phosphate and oxidised (NAD+ and NADP+) and reduced (NADH) nicotinamide dinucleotides, which therapy decreased generally. Diabetes increased mitochondrial oxygen consumption (OCR) at complex II-IV. MitoQ further increased OCR but decreased ATP, suggesting mitochondrial uncoupling as its mechanism of action. MitoQ showed renoprotection equivalent to ramipril but no synergistic benefits of combining these agents were shown. PMID: 29123192 [PubMed - in process]

Hepatic accumulation of S-Adenosylmethionine in hamsters with non-alcoholic-fatty liver disease associated to metabolic syndrome under selenium and vitamin E deficiency. Clin Sci (Lond). 2017 Nov 09;: Authors: Del Bas JM, Rodríguez B, Puiggròs F, Mariné S, Rodríguez MA, Moriña D, Armengol L, Caimari A, Arola L Abstract Progression of non-alcoholic fatty liver disease (NAFLD) in the context of metabolic syndrome (MetS) is only partially explored due to the lack of preclinical models. In order to study the alterations in hepatic metabolism that accompany this condition, we developed a model of MetS accompanied by the onset of steatohepatitis (NASH) by challenging golden hamsters with a high fat diet low in vitamin E and selenium (HFD), since combined deficiency results in hepatic necroinflammation in rodents. Metabolomics and transcriptomics integrated analyses of livers revealed an unexpected accumulation of hepatic S-Adenosylmethionine (SAM) when compared with healthy livers likely due to diminished methylation reactions and repression of GNMT. SAM plays a key role in the maintenance of cellular homeostasis and cell cycle control. In agreement, analysis of overrepresented transcription factors revealed a central role of c-myc and c-Jun pathways accompanied by negative correlations between SAM concentration, MYC expression and AMPK phosphorylation. These findings point to a drift of cell cycle control towards senescence in livers of HFD animals, which could explain the onset of NASH in this model. In contrast, hamsters with NAFLD induced by a conventional high fat diet did not show SAM accumulation, suggesting a key role of selenium and vitamin E in SAM homeostasis. In conclusion, our results suggest that progression of NAFLD in the context of MetS can take place even in a situation of hepatic SAM excess and that selenium and vitamin E status might be considered in current therapies against NASH based on SAM supplementation. PMID: 29122967 [PubMed - as supplied by publisher]

Gender-related metabolomics and lipidomics: From experimental animal models to clinical evidence. J Proteomics. 2017 Nov 06;: Authors: Audano M, Maldini M, De Fabiani E, Mitro N, Caruso D Abstract Lipidomics and metabolomics have emerged as important tools for the characterization of specific physiological and pathological traits. The selection of the analytical approaches and the choice of a targeted rather than an untargeted strategy in metabolomics find their reasons in the driving hypothesis of the study, sample features and instrumental availability. Moreover, in the last years, -omics approaches have found their application in the study of sex-related dimorphism. In this review, lipidomic and metabolomic analyses are presented in a biomedical perspective. Here, we provide an updated overview covering recent applications of metabolomics and lipidomics in the area of sex-related differences in human and preclinical models. Experimental evidence underlines that sex is one of the most relevant biological variables significantly influencing metabolomic and lipidomic profiles. This knowledge can be exploited for the identification of novel sex-specific biomarkers and innovative targets relevant for gender medicine. PMID: 29122727 [PubMed - as supplied by publisher]

Identification of serum metabolites associated with obesity and traditional risk factors for metabolic disease in Chinese adults. Nutr Metab Cardiovasc Dis. 2017 Oct 03;: Authors: Wang SM, Yang RY, Wang M, Ji FS, Li HX, Tang YM, Chen WX, Dong J Abstract BACKGROUND AND AIMS: Obesity is a major worldwide health problem and is often associated with many metabolic diseases. Levels of several serum-specific metabolites may be altered in patients with these metabolic diseases. We aimed to investigate the associations of serum metabolite levels with obesity and traditional risk factors for metabolic disease in Chinese individuals. METHODS AND RESULTS: Six-hundred Chinese individuals undergoing annual physical exams were recruited and categorized into overweight/obese and control groups (1:1 ratio). We simultaneously quantified the serum lysophosphatidylcholine (LPC), branched-chain amino acids (BCAA), aromatic amino acids (AAA), 25-hydroxyvitamin D, glutamine (Gln), glutamic acid (Glu), and Gln/Glu ratio levels using our previously established targeted serum metabolomic method. The overweight/obesity group had significantly higher levels of BCAA, AAA, and Glu, as well as lower levels of unsaturated LPC, Gln, and Gln/Glu, than the control group. Correlation analyses revealed significant and positive relationships of saturated LPC, BCAA, AAA, and Glu with blood pressure, glucose, triglycerides, apolipoprotein B, and high-sensitivity C-reactive protein, while unsaturated LPC, Gln, Gln/Glu, and 25-hydroxyvitamin D exhibited an opposite trend. In the multifactor logistic regression model, low unsaturated LPC and Gln/Glu, as well as high BCAA and AAA levels, were found to be independent risk factors for obesity; the odds ratios (95% confidence interval) of the highest quartile compared to the lowest quartile were 0.241 (0.139-0.417), 0.436 (0.252-0.755), 3.944 (2.094-7.430), and 2.357 (1.274-4.361) (P < 0.01), respectively. CONCLUSION: LPC, BCAA, AAA, and Gln/Glu are significantly related to obesity development and risk factors of some metabolic diseases. PMID: 29122443 [PubMed - as supplied by publisher]

The Pocket-4-Life project, bioavailability and beneficial properties of the bioactive compounds of espresso coffee and cocoa-based confectionery containing coffee: study protocol for a randomized cross-over trial. Trials. 2017 Nov 09;18(1):527 Authors: Mena P, Tassotti M, Martini D, Rosi A, Brighenti F, Del Rio D Abstract BACKGROUND: Coffee is an important source of bioactive compounds, including caffeine, phenolic compounds (mainly chlorogenic acids), trigonelline, and diterpenes. Several studies have highlighted the preventive effects of coffee consumption on major cardiometabolic diseases, but the impact of coffee dosage on markers of cardiometabolic risk is not well understood. Moreover, the pool of coffee-derived circulating metabolites and the contribution of each metabolite to disease prevention still need to be evaluated in real-life settings. The aim of this study will be to define the bioavailability and beneficial properties of coffee bioactive compounds on the basis of different levels of consumption, by using an innovative experimental design. The contribution of cocoa-based products containing coffee to the pool of circulating metabolites and their putative bioactivity will also be investigated. METHODS: A three-arm, crossover, randomized trial will be conducted. Twenty-one volunteers will be randomly assigned to consume three treatments in a random order for 1 month: 1 cup of espresso coffee/day, 3 cups of espresso coffee/day, and 1 cup of espresso coffee plus 2 cocoa-based products containing coffee twice per day. The last day of each treatment, blood and urine samples will be collected at specific time points, up to 24 hours following the consumption of the first product. At the end of each treatment the same protocol will be repeated, switching the allocation group. Besides the bioavailability of the coffee/cocoa bioactive compounds, the effect of the coffee/cocoa consumption on several cardiometabolic risk factors (anthropometric measures, blood pressure, inflammatory markers, trimethylamine N-oxide, nitric oxide, blood lipids, fasting indices of glucose/insulin metabolism, DNA damage, eicosanoids, and nutri-metabolomics) will be investigated. DISCUSSION: Results will provide information on the bioavailability of the main groups of phytochemicals in coffee and on their modulation by the level of consumption. Findings will also show the circulating metabolites and their bioactivity when coffee consumption is substituted with the intake of cocoa-based products containing coffee. Finally, the effect of different levels of 1-month coffee consumption on cardiometabolic risk factors will be elucidated, likely providing additional insights on the role of coffee in the protection against chronic diseases. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03166540 . Registered on May 21, 2017. PMID: 29121975 [PubMed - in process]

Transcriptomics, metabolomics and histology indicate that high-carbohydrate diet negatively affects the liver health of blunt snout bream (Megalobrama amblycephala). BMC Genomics. 2017 Nov 09;18(1):856 Authors: Prisingkorn W, Prathomya P, Jakovlić I, Liu H, Zhao YH, Wang WM Abstract BACKGROUND: Global trend of the introduction of high levels of relatively cheap carbohydrates to reduce the amount of costly protein in the aquatic animal feed production has affected the aquaculture of an economically important cyprinid fish, blunt snout bream (Megalobrama amblycephala). This dietary shift has resulted in increased prevalence of metabolic disorders, often causing economic losses. High dietary intake of carbohydrates, associated with obesity, is one of the major causes of non-alcoholic fatty liver disease (NAFLD) in humans. RESULTS: We have conducted an eight-week feeding trial to better understand how a high-carbohydrate diet (HCBD) affects the liver health in this fish. Hepatosomatic index and lipid content were significantly (P < 0.05) higher in the HCBD group. Histology results also suggested pathological changes in the livers of HCBD group, with excessive lipid accumulation and indication of liver damage. Metabolomics and serum biochemistry analyses showed that a number of metabolites indicative of liver damage were increased in the HCBD group. This group also exhibited low levels of betaine, which is a metabolite crucial for maintaining the healthy liver functions. Transcriptomic and qPCR analyses indicated that HCBD had a strong impact on the expression of a large number of genes associated with the NAFLD and insulin signalling pathways, which may lead to the development of insulin resistance in hepatocytes, pathological liver changes, and eventually the NAFLD. CONCLUSIONS: Transcriptomics, metabolomics and histology results all indicate early symptoms of liver damage. However whether these would actually lead to the development of NAFLD after a longer period of time, remains inconclusive. Additionally, a very high number of upregulated genes in the HCBD group associated with several neurodegenerative diseases is a strong indication of neurodegenerative changes caused by the high-carbohydrate diet in blunt snout bream. This suggests that fish might present a good model to study neurodegenerative changes associated with high-carbohydrate diet in humans. PMID: 29121861 [PubMed - in process]