PubMed

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]

Related Articles Astilbin from Engelhardtia chrysolepis enhances intestinal barrier functions in Caco-2 cell monolayers. Eur J Pharmacol. 2017 Jun 05;804:46-51 Authors: Nakahara T, Nishitani Y, Nishiumi S, Yoshida M, Azuma T Abstract Astilbin, which is one of polyphenolic compounds isolated from the leaves of Engelhardtia chrysolepis HANCE (Chinese name, huang-qui), is available as the effective component in food and cosmetics because of its anti-oxidant and anti-inflammatory effects. The tight junction (TJ) proteins, which protect the body from foreign substances, are related to adhesion between a cell and a cell. Previously, the enhancement of TJ's functions induced by aglycones of flavonoids has been demonstrated, but the effects of the glycosides such as astilbin have not been observed yet. In this study, we investigated the effects of astilbin on the TJ's functions, and human colon carcinoma Caco-2 cell monolayers were used to evaluate the effects of astilbin on transepithelial electrical resistance (TER) value and the mRNA and proteins expressions of TJ-related molecules. Astilbin increased the TER value, mRNA expression levels of claudin-1 and ZO-2, and protein expression levels of occludin and ZO-2 in Caco-2 cells. Astilbin also increased the TER value in Caco-2 cells co-stimulated with TNF-α plus IFN-γ, and moreover upregulated the protein expression of TJ-related molecules in Caco-2 cells co-treated with TNF-α plus IFN-γ. These results suggest that astilbin can enhance the expressions of TJ-related molecules, leading to upregulation of the barrier functions in the intestinal cells. PMID: 28327343 [PubMed - indexed for MEDLINE]

Related Articles Obp56h Modulates Mating Behavior in Drosophila melanogaster. G3 (Bethesda). 2016 Oct 13;6(10):3335-3342 Authors: Shorter JR, Dembeck LM, Everett LJ, Morozova TV, Arya GH, Turlapati L, St Armour GE, Schal C, Mackay TF, Anholt RR Abstract Social interactions in insects are driven by conspecific chemical signals that are detected via olfactory and gustatory neurons. Odorant binding proteins (Obps) transport volatile odorants to chemosensory receptors, but their effects on behaviors remain poorly characterized. Here, we report that RNAi knockdown of Obp56h gene expression in Drosophila melanogaster enhances mating behavior by reducing courtship latency. The change in mating behavior that results from inhibition of Obp56h expression is accompanied by significant alterations in cuticular hydrocarbon (CHC) composition, including reduction in 5-tricosene (5-T), an inhibitory sex pheromone produced by males that increases copulation latency during courtship. Whole genome RNA sequencing confirms that expression of Obp56h is virtually abolished in Drosophila heads. Inhibition of Obp56h expression also affects expression of other chemoreception genes, including upregulation of lush in both sexes and Obp83ef in females, and reduction in expression of Obp19b and Or19b in males. In addition, several genes associated with lipid metabolism, which underlies the production of cuticular hydrocarbons, show altered transcript abundances. Our data show that modulation of mating behavior through reduction of Obp56h is accompanied by altered cuticular hydrocarbon profiles and implicate 5-T as a possible ligand for Obp56h. PMID: 27558663 [PubMed - indexed for MEDLINE]

Co-culture of Marine Invertebrate-Associated Bacteria and Interdisciplinary Technologies Enable Biosynthesis and Discovery of a New Antibiotic, Keyicin. ACS Chem Biol. 2017 Nov 09;: Authors: Adnani N, Chevrette M, Adibhatla SN, Zhang F, Yu Q, Braun DR, Nelson J, Simpkins SW, McDonald BR, Myers CL, Piotrowski JS, Thompson CJ, Currie CR, Li L, Rajski SR, Bugni TS Abstract Advances in genomics and metabolomics have made clear in recent years that microbial biosynthetic capacities on Earth far exceed previous expectations. This is attributable, in part, to the realization that most microbial natural product (NP) producers harbor biosynthetic machineries not readily amenable to classical laboratory fermentation conditions. Such "cryptic" or dormant biosynthetic gene clusters (BGCs) encode for a vast assortment of potentially new antibiotics and, as such, have become extremely attractive targets for activation under controlled laboratory conditions. We report here that co-culturing of a Rhodococcus sp. and a Micromonospora sp. affords keyicin, a new and otherwise unattainable bis-nitroglycosylated anthracycline whose mechanism of action (MOA) appears to deviate from those of other anthracyclines. The structure of keyicin was elucidated using high resolution MS and NMR technologies, as well as detailed molecular mod-eling studies. Sequencing of the keyicin BGC (within the Micromonospora genome) enabled both structural and genomic comparisons to other anthracycline-producing systems informing efforts to characterize keyicin. The new NP was found to be selectively active against Gram-positive bacteria including both Rhodococcus sp. and Mycobacterium sp. E. coli-based chemical genomics studies revealed that keyicin's MOA, in contrast to many other anthracyclines, does not invoke nucleic acid damage. PMID: 29121465 [PubMed - as supplied by publisher]

Adipocyte Expression of SLC19A1 Links DNA Hypermethylation to Adipose Tissue Inflammation and Insulin Resistance. J Clin Endocrinol Metab. 2017 Nov 07;: Authors: Petrus P, Bialesova L, Checa A, Kerr A, Naz S, Bäckdahl J, Gracia A, Toft S, Dahlman-Wright K, Hedén P, Dahlman I, Wheelock CE, Arner P, Mejhert N, Gao H, Rydén M Abstract Context: Insulin resistance (IR) is promoted by a chronic low-grade inflammation in white adipose tissue (WAT). The latter may be regulated through epigenetic mechanisms such as DNA-methylation. The one carbon cycle (1CC) is a central metabolic process governing DNA-methylation. Objective: To identify adipocyte-expressed 1CC genes linked to WAT inflammation, IR and their causal role. Design: Cohort study. Setting: Outpatient academic clinic. Participants: Obese and non-obese subjects. Methods: Gene expression and DNA-methylation arrays were performed in subcutaneous WAT and isolated adipocytes. In in vitro differentiated human adipocytes, gene knockdown was achieved by siRNA and analyses included microarray, qPCR, DNA-methylation by ELISA and pyrosequencing, protein secretion by ELISA, targeted metabolomics, luciferase reporter and thermal shift assays. Main outcome measures: Effects on adipocyte inflammation. Results: In adipocytes from obese individuals, global DNA hypermethylation associated positively with gene expression of pro-inflammatory pathways. Among 1CC-genes, IR in vivo and pro-inflammatory gene expression in WAT were most strongly and inversely associated with SLC19A1, a gene encoding a membrane folate carrier. SLC19A1 knockdown in human adipocytes perturbed intracellular 1CC-metabolism, induced global DNA hypermethylation and increased expression of pro-inflammatory genes. Several CpG loci linked SLC19A1 to inflammation; validation studies were focused on the chemokine CCL2 where methylation in the promoter (cg12698626) regulated CCL2 expression and CCL2 secretion through altered transcriptional activity. Conclusions: Reduced SLC19A1 expression in human adipocytes induces DNA hypermethylation resulting in increased expression of specific pro-inflammatory genes including CCL2. This constitutes an epigenetic mechanism that may link dysfunctional adipocytes to WAT inflammation and IR. PMID: 29121255 [PubMed - as supplied by publisher]

Effects of four different antihypertensive drugs on plasma metabolomic profiles in patients with essential hypertension. PLoS One. 2017;12(11):e0187729 Authors: Hiltunen TP, Rimpelä JM, Mohney RP, Stirdivant SM, Kontula KK Abstract OBJECTIVE: In order to search for metabolic biomarkers of antihypertensive drug responsiveness, we measured >600 biochemicals in plasma samples of subjects participating in the GENRES Study. Hypertensive men received in a double-blind rotational fashion amlodipine, bisoprolol, hydrochlorothiazide and losartan, each as a monotherapy for one month, with intervening one-month placebo cycles. METHODS: Metabolomic analysis was carried out using ultra high performance liquid chromatography-tandem mass spectrometry. Full metabolomic signatures (the drug cycles and the mean of the 3 placebo cycles) became available in 38 to 42 patients for each drug. Blood pressure was monitored by 24-h recordings. RESULTS: Amlodipine (P values down to 0.002), bisoprolol (P values down to 2 x 10-5) and losartan (P values down to 2 x 10-4) consistently decreased the circulating levels of long-chain acylcarnitines. Bisoprolol tended to decrease (P values down to 0.002) the levels of several medium- and long-chain fatty acids. Hydrochlorothiazide administration was associated with an increase of plasma uric acid level (P = 5 x 10-4) and urea cycle metabolites. Decreases of both systolic (P = 0.06) and diastolic (P = 0.04) blood pressure after amlodipine administration tended to associate with a decrease of plasma hexadecanedioate, a dicarboxylic fatty acid recently linked to blood pressure regulation. CONCLUSIONS: Although this systematic metabolomics study failed to identify circulating metabolites convincingly predicting favorable antihypertensive response to four different drug classes, it provided accumulating evidence linking fatty acid metabolism to human hypertension. PMID: 29121091 [PubMed - in process]