PubMed

Related Articles The flavonoid 4,4'-dimethoxychalcone promotes autophagy-dependent longevity across species. Nat Commun. 2019 Feb 19;10(1):651 Authors: Carmona-Gutierrez D, Zimmermann A, Kainz K, Pietrocola F, Chen G, Maglioni S, Schiavi A, Nah J, Mertel S, Beuschel CB, Castoldi F, Sica V, Trausinger G, Raml R, Sommer C, Schroeder S, Hofer SJ, Bauer MA, Pendl T, Tadic J, Dammbrueck C, Hu Z, Ruckenstuhl C, Eisenberg T, Durand S, Bossut N, Aprahamian F, Abdellatif M, Sedej S, Enot DP, Wolinski H, Dengjel J, Kepp O, Magnes C, Sinner F, Pieber TR, Sadoshima J, Ventura N, Sigrist SJ, Kroemer G, Madeo F Abstract Ageing constitutes the most important risk factor for all major chronic ailments, including malignant, cardiovascular and neurodegenerative diseases. However, behavioural and pharmacological interventions with feasible potential to promote health upon ageing remain rare. Here we report the identification of the flavonoid 4,4'-dimethoxychalcone (DMC) as a natural compound with anti-ageing properties. External DMC administration extends the lifespan of yeast, worms and flies, decelerates senescence of human cell cultures, and protects mice from prolonged myocardial ischaemia. Concomitantly, DMC induces autophagy, which is essential for its cytoprotective effects from yeast to mice. This pro-autophagic response induces a conserved systemic change in metabolism, operates independently of TORC1 signalling and depends on specific GATA transcription factors. Notably, we identify DMC in the plant Angelica keiskei koidzumi, to which longevity- and health-promoting effects are ascribed in Asian traditional medicine. In summary, we have identified and mechanistically characterised the conserved longevity-promoting effects of a natural anti-ageing drug. PMID: 30783116 [PubMed - in process]

Related Articles Health Outcomes, Pathogenesis and Epidemiology of Severe Acute Malnutrition (HOPE-SAM): rationale and methods of a longitudinal observational study. BMJ Open. 2019 Feb 01;9(1):e023077 Authors: Bwakura-Dangarembizi M, Amadi B, Bourke CD, Robertson RC, Mwapenya B, Chandwe K, Kapoma C, Chifunda K, Majo F, Ngosa D, Chakara P, Chulu N, Masimba F, Mapurisa I, Besa E, Mutasa K, Mwakamui S, Runodamoto T, Humphrey JH, Ntozini R, Wells JCK, Manges AR, Swann JR, Walker AS, Nathoo KJ, Kelly P, Prendergast AJ, HOPE-SAM study team Abstract INTRODUCTION: Mortality among children hospitalised for complicated severe acute malnutrition (SAM) remains high despite the implementation of WHO guidelines, particularly in settings of high HIV prevalence. Children continue to be at high risk of morbidity, mortality and relapse after discharge from hospital although long-term outcomes are not well documented. Better understanding the pathogenesis of SAM and the factors associated with poor outcomes may inform new therapeutic interventions. METHODS AND ANALYSIS: The Health Outcomes, Pathogenesis and Epidemiology of Severe Acute Malnutrition (HOPE-SAM) study is a longitudinal observational cohort that aims to evaluate the short-term and long-term clinical outcomes of HIV-positive and HIV-negative children with complicated SAM, and to identify the risk factors at admission and discharge from hospital that independently predict poor outcomes. Children aged 0-59 months hospitalised for SAM are being enrolled at three tertiary hospitals in Harare, Zimbabwe and Lusaka, Zambia. Longitudinal mortality, morbidity and nutritional data are being collected at admission, discharge and for 48 weeks post discharge. Nested laboratory substudies are exploring the role of enteropathy, gut microbiota, metabolomics and cellular immune function in the pathogenesis of SAM using stool, urine and blood collected from participants and from well-nourished controls. ETHICS AND DISSEMINATION: The study is approved by the local and international institutional review boards in the participating countries (the Joint Research Ethics Committee of the University of Zimbabwe, Medical Research Council of Zimbabwe and University of Zambia Biomedical Research Ethics Committee) and the study sponsor (Queen Mary University of London). Caregivers provide written informed consent for each participant. Findings will be disseminated through peer-reviewed journals, conference presentations and to caregivers at face-to-face meetings. PMID: 30782694 [PubMed - in process]

Related Articles Effects of dietary fat on gut microbiota and faecal metabolites, and their relationship with cardiometabolic risk factors: a 6-month randomised controlled-feeding trial. Gut. 2019 Feb 19;: Authors: Wan Y, Wang F, Yuan J, Li J, Jiang D, Zhang J, Li H, Wang R, Tang J, Huang T, Zheng J, Sinclair AJ, Mann J, Li D Abstract OBJECTIVE: To investigate whether diets differing in fat content alter the gut microbiota and faecal metabolomic profiles, and to determine their relationship with cardiometabolic risk factors in healthy adults whose diet is in a transition from a traditional low-fat diet to a diet high in fat and reduced in carbohydrate. METHODS: In a 6-month randomised controlled-feeding trial, 217 healthy young adults (aged 18-35 years; body mass index <28 kg/m2; 52% women) who completed the whole trial were included. All the foods were provided during the intervention period. The three isocaloric diets were: a lower-fat diet (fat 20% energy), a moderate-fat diet (fat 30% energy) and a higher-fat diet (fat 40% energy). The effects of the dietary interventions on the gut microbiota, faecal metabolomics and plasma inflammatory factors were investigated. RESULTS: The lower-fat diet was associated with increased α-diversity assessed by the Shannon index (p=0.03), increased abundance of Blautia (p=0.007) and Faecalibacterium (p=0.04), whereas the higher-fat diet was associated with increased Alistipes (p=0.04), Bacteroides (p<0.001) and decreased Faecalibacterium (p=0.04). The concentration of total short-chain fatty acids was significantly decreased in the higher-fat diet group in comparison with the other groups (p<0.001). The cometabolites p-cresol and indole, known to be associated with host metabolic disorders, were decreased in the lower-fat diet group. In addition, the higher-fat diet was associated with faecal enrichment in arachidonic acid and the lipopolysaccharide biosynthesis pathway as well as elevated plasma proinflammatory factors after the intervention. CONCLUSION: Higher-fat consumption by healthy young adults whose diet is in a state of nutrition transition appeared to be associated with unfavourable changes in gut microbiota, faecal metabolomic profiles and plasma proinflammatory factors, which might confer adverse consequences for long-term health outcomes. TRIAL REGISTRATION NUMBER: NCT02355795; Results. PMID: 30782617 [PubMed - as supplied by publisher]

Related Articles A Comprehensive LC-QTOF-MS Metabolic Phenotyping Strategy: Application to Alkaptonuria. Clin Chem. 2019 Feb 19;: Authors: Norman BP, Davison AS, Ross GA, Milan AM, Hughes AT, Sutherland H, Jarvis JC, Roberts NB, Gallagher JA, Ranganath LR Abstract BACKGROUND: Identification of unknown chemical entities is a major challenge in metabolomics. To address this challenge, we developed a comprehensive targeted profiling strategy, combining 3 complementary liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) techniques and in-house accurate mass retention time (AMRT) databases established from commercial standards. This strategy was used to evaluate the effect of nitisinone on the urinary metabolome of patients and mice with alkaptonuria (AKU). Because hypertyrosinemia is a known consequence of nitisinone therapy, we investigated the wider metabolic consequences beyond hypertyrosinemia. METHODS: A total of 619 standards (molecular weight, 45-1354 Da) covering a range of primary metabolic pathways were analyzed using 3 liquid chromatography methods-2 reversed phase and 1 normal phase-coupled to QTOF-MS. Separate AMRT databases were generated for the 3 methods, comprising chemical name, formula, theoretical accurate mass, and measured retention time. Databases were used to identify chemical entities acquired from nontargeted analysis of AKU urine: match window theoretical accurate mass ±10 ppm and retention time ±0.3 min. RESULTS: Application of the AMRT databases to data acquired from analysis of urine from 25 patients with AKU (pretreatment and after 3, 12, and 24 months on nitisinone) and 18 HGD -/- mice (pretreatment and after 1 week on nitisinone) revealed 31 previously unreported statistically significant changes in metabolite patterns and abundance, indicating alterations to tyrosine, tryptophan, and purine metabolism after nitisinone administration. CONCLUSIONS: The comprehensive targeted profiling strategy described here has the potential of enabling discovery of novel pathways associated with pathogenesis and management of AKU. PMID: 30782595 [PubMed - as supplied by publisher]

Related Articles Multigenerational metabolic profiling in the Michigan PBB registry. Environ Res. 2019 Feb 13;172:182-193 Authors: Walker DI, Marder ME, Yano Y, Terrell M, Liang Y, Barr DB, Miller GW, Jones DP, Marcus M, Pennell KD Abstract Although polychlorinated biphenyls and polybrominated biphenyls are no longer manufactured the United States, biomonitoring in human populations show that exposure to these pollutants persist in human tissues. The objective of this study was to identify metabolic variations associated with exposure to 2,2'4,4',5,5'-hexabromobiphenyl (PBB-153) and 2,2'4,4',5,5'-hexachlorobiphenyl (PCB-153) in two generations of participants enrolled in the Michigan PBB Registry (http://pbbregistry.emory.edu/). Untargeted, high-resolution metabolomic profiling of plasma collected from 156 individuals was completed using liquid chromatography with high-resolution mass spectrometry. PBB-153 and PCB-153 levels were measured in the same individuals using targeted gas chromatography-tandem mass spectrometry and tested for dose-dependent correlation with the metabolome. Biological response to these exposures were evaluated using identified endogenous metabolites and pathway enrichment. When compared to lipid-adjusted concentrations for adults in the National Health and Nutrition Examination Survey (NHANES) for years 2003-2004, PCB-153 levels were consistent with similarly aged individuals, whereas PBB-153 concentrations were elevated (p<0.0001) in participants enrolled in the Michigan PBB Registry. Metabolic alterations were correlated with PBB-153 and PCB-153 in both generations of participants, and included changes in pathways related to catecholamine metabolism, cellular respiration, essential fatty acids, lipids and polyamine metabolism. These pathways were consistent with pathophysiological changes observed in neurodegenerative disease and included previously identified metabolomic markers of Parkinson's disease. To determine if the metabolic alterations detected in this study are replicated other cohorts, we evaluated correlation of PBB-153 and PCB-153 with plasma fatty acids measured in NHANES. Both pollutants showed similar associations with fatty acids previously linked to PCB exposure. Thus, the results from this study show metabolic alterations correlated with PBB-153 and PCB-153 exposure can be detected in human populations and are consistent with health outcomes previously reported in epidemiological and mechanistic studies. PMID: 30782538 [PubMed - as supplied by publisher]

22 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/02/20PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Hepatic differentiation of human pluripotent stem cells by developmental stage-related metabolomics products. Differentiation. 2019 Jan 28;105:54-70 Authors: Bandi S, Tchaikovskaya T, Gupta S Abstract Endogenous cell signals regulate tissue homeostasis and are significant for directing the fate of stem cells. During liver development, cytokines released from various cell types are critical for stem/progenitor cell differentiation and lineage expansions. To determine mechanisms in these stage-specific lineage interactions, we modeled potential effects of soluble signals derived from immortalized human fetal liver parenchymal cells on stem cells, including embryonic and induced pluripotent stem cells. For identifying lineage conversion and maturation, we utilized conventional assays of cell morphology, gene expression analysis and lineage markers. Molecular pathway analysis used functional genomics approaches. Metabolic properties were analyzed to determine the extent of hepatic differentiation. Cell transplantation studies were performed in mice with drug-induced acute liver failure to elicit benefits in hepatic support and tissue regeneration. These studies showed signals emanating from fetal liver cells induced hepatic differentiation in stem cells. Gene expression profiling and comparison of regulatory networks in immature and mature hepatocytes revealed stem cell-derived hepatocytes represented early fetal-like stage. Unexpectedly, differentiation-inducing soluble signals constituted metabolomics products and not proteins. In stem cells exposed to signals from fetal cells, mechanistic gene networks of upstream regulators decreased pluripotency, while simultaneously inducing mesenchymal and epithelial properties. The extent of metabolic and synthetic functions in stem cell-derived hepatocytes was sufficient for providing hepatic support along with promotion of tissue repair to rescue mice in acute liver failure. During this rescue, paracrine factors from transplanted cells contributed in stimulating liver regeneration. We concluded that hepatic differentiation of pluripotent stem cells with metabolomics products will be significant for developing therapies. The differentiation mechanisms involving metabolomics products could have an impact on advancing recruitment of stem/progenitor cells during tissue homeostasis. PMID: 30776728 [PubMed - as supplied by publisher]

Control and regulation of S-Adenosylmethionine biosynthesis by the regulatory β subunit and quinolone-based compounds. FEBS J. 2019 Feb 18;: Authors: Panmanee J, Bradley-Clarke J, Mato JM, O'Neill PM, Antonyuk SV, Hasnain SS Abstract Methylation is an underpinning process of life and provides control for biological processes such as DNA synthesis, cell growth and apoptosis. Methionine Adenosyltransferases (MAT) produce the cellular methyl donor, S-Adenosylmethionine (SAMe). Dysregulation of SAMe level is a relevant event in many diseases, including cancers such as hepatocellular carcinoma and colon cancer. In addition, mutation of Arg264 in MATα1 causes isolated persistent hypermethioninemia, which is characterized by low activity of the enzyme in liver and high level of plasma methionine. In mammals, MATα1/α2 and MATβV1/V2 are the catalytic and the major form of regulatory subunits respectively. A gating loop comprising residues 113-131 is located beside the active site of catalytic subunits (MATα1/α2) and provides controlled access to the active site. Here, we provide evidence of how the gating loop facilitates the catalysis and define some of the key elements that control the catalytic efficiency. Mutation of several residues of MATα2 including Gln113, Ser114 and Arg264 lead to partial or total loss of enzymatic activity, demonstrating their critical role in catalysis. The enzymatic activity of the mutated enzymes is restored to varying degree upon complex formation with MATβV1 or MATβV2, endorsing its role as an allosteric regulator of MATα2 in response to the levels of methionine or SAMe. Finally, the protein-protein interacting surface formed in MATα2:MATβ complexes is explored to demonstrate that several quinolone-based compounds modulate the activity of MATα2 and its mutants, providing a rational for chemical design/intervention responsive to the level of SAMe in the cellular environment. This article is protected by copyright. All rights reserved. PMID: 30776190 [PubMed - as supplied by publisher]

Gene Expression Studies and Targeted Metabolomics Reveal Disturbed Serine, Methionine, and Tyrosine Metabolism in Early Hypertensive Nephrosclerosis. Kidney Int Rep. 2019 Feb;4(2):321-333 Authors: Øvrehus MA, Bruheim P, Ju W, Zelnick LR, Langlo KA, Sharma K, de Boer IH, Hallan SI Abstract Introduction: Hypertensive nephrosclerosis is among the leading causes of end-stage renal disease, but its pathophysiology is poorly understood. We wanted to explore early metabolic changes using gene expression and targeted metabolomics analysis. Methods: We analyzed gene expression in kidneys biopsied from 20 patients with nephrosclerosis and 31 healthy controls with an Affymetrix array. Thirty-one amino acids were measured by liquid chromatography coupled with mass spectrometry (LC-MS) in urine samples from 62 patients with clinical hypertensive nephrosclerosis and 33 age- and sex-matched healthy controls, and major findings were confirmed in an independent cohort of 45 cases and 15 controls. Results: Amino acid catabolism and synthesis were strongly underexpressed in hypertensive nephrosclerosis (13- and 7-fold, respectively), and these patients also showed gene expression patterns indicating decreased fatty acid oxidation (12-fold) and increased interferon gamma (10-fold) and cellular defense response (8-fold). Metabolomics analysis revealed significant distribution differences in 11 amino acids in hypertensive nephrosclerosis, among them tyrosine, phenylalanine, dopamine, homocysteine, and serine, with 30% to 70% lower urine excretion. These findings were replicated in the independent cohort. Integrated gene-metabolite pathway analysis showed perturbations of renal dopamine biosynthesis. There were also significant differences in homocysteine/methionine homeostasis and the serine pathway, which have strong influence on 1-carbon metabolism. Several of these disturbances could be interconnected through reduced regeneration of tetrahydrofolate and tetrahydrobiopterin. Conclusion: Early hypertensive nephrosclerosis showed perturbations of intrarenal biosynthesis of dopamine, which regulates natriuresis and blood pressure. There were also disturbances in serine/glycine and methionine/homocysteine metabolism, which may contribute to endothelial dysfunction, atherosclerosis, and renal fibrosis. PMID: 30775629 [PubMed]

Related Articles Recent advances in the metabolomic study of bladder cancer. Expert Rev Proteomics. 2019 Feb 16;: Authors: Amara CS, Vantaku V, Lotan Y, Putluri N Abstract INTRODUCTION: Metabolomics is a chemical process, involving the characterization of metabolites and cellular metabolism. Recent studies indicate that numerous metabolic pathways are altered in bladder cancer (BLCA), providing potential targets for improved detection and possible therapeutic intervention. We review recent advances in metabolomics related to BLCA and identify various metabolites that may serve as potential biomarkers for BLCA. Areas covered. In this review, we describe the latest advances in defining the BLCA metabolome and discuss the possible clinical utility of metabolic alterations in BLCA tissues, serum, and urine. In addition, we focus on the metabolic alterations associated with tobacco smoke and racial disparity in BLCA. Expert commentary. Metabolomics is a powerful tool which can shed new light on BLCA development and behavior. Key metabolites may serve as possible markers of BLCA. However, prospective validation will be needed to incorporate these markers into clinical care. PMID: 30773067 [PubMed - as supplied by publisher]

Omega-3 fatty acid-derived mediators that control inflammation and tissue homeostasis. Int Immunol. 2019 Feb 17;: Authors: Ishihara T, Yoshida M, Arita M Abstract Omega-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid, docosapentaenoic acid and docosahexaenoic acid, display a wide range of beneficial effects in humans and animals. Many of the biological functions of PUFAs are mediated via bioactive metabolites produced by fatty acid oxygenases such as cyclooxygenases, lipoxygenases and cytochrome P450 monooxygenases. Liquid chromatography-tandem mass spectrometry-based mediator lipidomics revealed a series of novel bioactive lipid mediators derived from omega-3 PUFAs. Here, we describe recent advances on omega-3 PUFA-derived mediators, mainly focusing on their enzymatic oxygenation pathway, and their biological functions in controlling inflammation and tissue homeostasis. PMID: 30772915 [PubMed - as supplied by publisher]

Circulating anthocyanin metabolites mediate vascular benefits of blueberries: insights from randomized controlled trials, metabolomics, and nutrigenomics. J Gerontol A Biol Sci Med Sci. 2019 Feb 16;: Authors: Rodriguez-Mateos A, Istas G, Boschek L, Feliciano RP, Mills CE, Boby C, Gomez-Alonso S, Milenkovic D, Heiss C Abstract Potential health benefits of blueberries may be due to vascular effects of anthocyanins which predominantly circulate in blood as phenolic acid metabolites. We investigated which role blueberry anthocyanins and circulating metabolites play in mediating improvements in vascular function and explore potential mechanisms using metabolomics and nutrigenomics. Purified anthocyanins exerted a dose-dependent improvement of endothelial function in healthy humans, as measured by flow-mediated dilation (FMD). The effects were similar to those of blueberries containing similar amounts of anthocyanins while control drinks containing fiber, minerals, or vitamins had no significant effect. Daily 1-month blueberry consumption increased FMD and lowered 24h-ambulatory-systolic-blood-pressure. Of the 63 anthocyanin plasma metabolites quantified, 14 and 17 correlated with acute and chronic FMD improvements, respectively. Injection of these metabolites improved FMD in mice. Daily blueberry consumption led to differential expression (>1.2-fold) of 608 genes and 3 microRNAs, with Mir-181c showing a 13-fold increase in peripheral blood mononuclear cells. Patterns of 13 metabolites were independent predictors of gene expression changes and pathway enrichment analysis revealed significantly modulated biological processes involved in cell adhesion, migration, immune response, and cell differentiation. Our results identify anthocyanin metabolites as major mediators of vascular bioactivities of blueberries and changes of cellular gene programs. PMID: 30772905 [PubMed - as supplied by publisher]

Untargeted Metabolomics and Inflammatory Markers Profiling in Children With Crohn's Disease and Ulcerative Colitis-A Preliminary Study. Inflamm Bowel Dis. 2019 Feb 17;: Authors: Daniluk U, Daniluk J, Kucharski R, Kowalczyk T, Pietrowska K, Samczuk P, Filimoniuk A, Kretowski A, Lebensztejn D, Ciborowski M Abstract BACKGROUND: Metabolic profiling might be used to identify disease biomarkers. The aim of our study was to determine the usefulness of untargeted metabolomics analysis to detect differences in serum metabolites between newly diagnosed and untreated pediatric patients with Crohn's disease (CD) or ulcerative colitis (UC) in comparison with a control group (Ctr). Moreover, we investigated the potential of profiling metabolomics and inflammatory markers to improve the noninvasive diagnosis of CD and UC in children. METHODS: Metabolic fingerprinting of serum samples was estimated with liquid chromatography coupled with mass spectrometry in children with CD (n = 9; median age, 14 years), UC (n = 10; median age, 13.5 years), and controls (n = 10; median age, 12.5 years). RESULTS: The majority of chemically annotated metabolites belonged to phospholipids and were downregulated in CD and UC compared with the Ctr. Only 1 metabolite, lactosylceramide 18:1/16:0 (LacCer 18:1/16:0), significantly discriminated CD from UC patients. Interestingly, combining LacCer 18:1/16:0 with other inflammatory markers resulted in a significant increase in the area under the curve with the highest specificity and sensitivity. CONCLUSIONS: Using serum untargeted metabolomics, we have shown that LacCer 18:1/16:0 is a very unique metabolite for CD patients. PMID: 30772902 [PubMed - as supplied by publisher]

1H NMR-based metabolomic analysis of nine organophosphate flame retardants metabolic disturbance in Hep G2 cell line. Sci Total Environ. 2019 Feb 04;665:162-170 Authors: Gu J, Su F, Hong P, Zhang Q, Zhao M Abstract Organophosphate flame retardants (OPFRs) are frequently found in the environment and could be adversely affecting organisms. In fact, nine OPFRs have been shown to cause endocrine disruptions, but information on the metabolism-perturbing properties of these OPFRs remains unclear. In this study, the 1H-nuclear magnetic resonance (NMR) based metabolomic method was applied to evaluate the metabolic disturbances caused by these nine OPFRs. From the analysis of the metabolic phenotypes, we found that TDBPP, TMPP and TPHP could be clustered into one group; TBOEP, TCIPP, TCEP and TEHP could be clustered into another group; and the residual OPFRs could be clustered into another. The classification results agree with the antagonistic activities of glucocorticoid and mineralocorticoid receptors. Then, we found that when HepG2 cells were exposed to TMPP, TPHP and TDBPP, the main metabolic sub-network disturbances focused on metabolism linked with oxidative stress, osmotic pressure equilibrium, and glucocorticoid and mineralocorticoid receptor antagonist activities; this was also true for TNBP and TDCIPP. Meanwhile, the other OPFRs mainly affected oxidative stress and amino acid metabolism. With multivariate statistical analysis, we found many differential metabolites in each group. Notably, Trimethylamine‑N‑oxide (TMAO) was the differential metabolite in six of the tested OPFRs, excluding TMPP, TPHP and TDBPP, and was one of the potential cardiovascular biomarkers. The data provided here could be helpful in gaining a more in-depth understanding of the metabolic disturbances of these nine OPFRs and may offer a new perspective for understanding potential pollutants with endocrine-disrupting effects on host metabolism. PMID: 30772545 [PubMed - as supplied by publisher]

Oxidized alginate hydrogels with the GHK peptide enhance cord blood mesenchymal stem cell osteogenesis: a paradigm for metabolomics-based evaluation of biomaterial design. Acta Biomater. 2019 Feb 14;: Authors: Klontzas ME, Reakasame S, Silva R, Morais JCF, Vernardis S, MacFarlane RJ, Heliotis M, Tsiridis E, Panoskaltsis N, Boccaccini AR, Mantalaris A Abstract Oxidized alginate hydrogels are appealing alternatives to natural alginate due to their favourable biodegradability profiles and capacity to self-crosslink with amine containing molecules facilitating functionalization with extracellular matrix cues, which enable modulation of stem cell fate, achieve highly viable 3-D cultures, and promote cell growth. Stem cell metabolism is at the core of cellular fate (proliferation, differentiation, death) and metabolomics provides global metabolic signatures representative of cellular status, being able to accurately identify the quality of stem cell differentiation. Herein, umbilical cord blood mesenchymal stem cells (UCB MSCs) were encapsulated in novel oxidized alginate hydrogels functionalized with the glycine-histidine-lysine (GHK) peptide and differentiated towards the osteoblastic lineage. The ADA-GHK hydrogels significantly improved osteogenic differentiation compared to gelatin-containing control hydrogels, as demonstrated by gene expression, alkaline phosphatase activity and bone extracellular matrix deposition. Metabolomics revealed the high degree of metabolic heterogeneity in the gelatin-containing control hydrogels, captured the enhanced osteogenic differentiation in the ADA-GHK hydrogels, confirmed the similar metabolism between differentiated cells and primary osteoblasts, and elucidated the metabolic mechanism responsible for the function of GHK. Our results suggest a novel paradigm for metabolomics-guided biomaterial design and robust stem cell bioprocessing. SIGNIFICANCE STATEMENT: Producing high quality engineered bone grafts is important for the treatment of critical sized bone defects. Robust and sensitive techniques are required for quality assessment of tissue-engineered constructs, which result to the selection of optimal biomaterials for bone graft development. Herein, we present a new use of metabolomics signatures in guiding the development of novel oxidised alginate-based hydrogels with umbilical cord blood mesenchymal stem cells and the glycine-histidine-lysine peptide, demonstrating that GHK induces stem cell osteogenic differentiation. Metabolomics signatures captured the enhanced osteogenesis in GHK hydrogels, confirmed the metabolic similarity between differentiated cells and primary osteoblasts, and elucidated the metabolic mechanism responsible for the function of GHK. In conclusion, our results suggest a new paradigm of metabolomics-driven design of biomaterials. PMID: 30772514 [PubMed - as supplied by publisher]

Targeted metabolomics of whole blood using volumetric absorptive microsampling. Talanta. 2019 May 15;197:49-58 Authors: Kok MGM, Nix C, Nys G, Fillet M Abstract Volumetric absorptive microsampling (VAMS) enables the collection of small and accurate quantities of biological fluids. Therefore, this sampling technique is of great interest for volume-limited samples or serial collection of samples. In this study, we examined the potential of VAMS for targeted mass spectrometry (MS)-based metabolomics. The targeted analysis of 36 major metabolites from only 10 μL of whole blood was optimized. A design of experiments was carried out to maximize the extraction of metabolites. Moreover, critical steps in sample preparation and sample analysis were studied and characterized, such as the addition of internal standards to tips of VAMS devices before sample collection. A reversed-phase UHPLC-MS/MS method was used to analyze organic acids, whereas hydrophilic interaction chromatography (HILIC)-MS/MS was selected for the determination of amino acids. Overall, the optimum extraction solvent was acetonitrile-water in a proportion of 60:40 (v/v), providing good recoveries and resulting in the detection of all target metabolites in whole blood with good repeatability (less than 15% RSD on peak area). Furthermore, the stability of the analytes in dried whole blood, which is of critical importance in metabolomics studies, was investigated. The amino and organic acids were stable for at least 4 days when stored at room temperature. This is in contrast to the instability of these compounds in wet blood, thereby showing the great potential of VAMS in metabolomics studies. PMID: 30771966 [PubMed - in process]

A combined targeted/untargeted LC-MS/MS-based screening approach for mammalian cell lines treated with ionic liquids: Toxicity correlates with metabolic profile. Talanta. 2019 May 15;197:472-481 Authors: Sanwald C, Robciuc A, Ruokonen SK, Wiedmer SK, Lämmerhofer M Abstract This work presents the development and validation of a quantitative HILIC UHPLC-ESI-QTOF-MS/MS method for amino acids combined with untargeted metabolic profiling of human corneal epithelial (HCE) cells after treatment with ionic liquids. The work included a preliminary metabotoxicity screening of 14 different ionic liquids, of which 9 carefully selected ionic liquids were chosen for a metabolomics study. This study is focused on the correlation between the toxicity of the ionic liquids and their metabolic profiles. The method development included the comparison of different MS/MS acquisition modes. A sequential window acquisition of all theoretical fragment ion mass spectra (SWATH) method with variable Q1 window widths and narrow Q1 target windows of 5 Da for most of the amino acids was selected as the optimal acquisition mode. Due to the absence of a true blank matrix, 13C,15N-isotopically labelled amino acids were utilized as surrogate calibrants, instead of proteinogenic amino acids. Partial least squares (PLS) analysis of the median effective concentrations (EC50) of 9 selected ionic liquids showed a correlation with their metabolic profile measured by the untargeted screening. PMID: 30771964 [PubMed - in process]

Metabolic shift of Staphylococcus aureus under sublethal dose of methicillin in the presence of glucose. J Pharm Biomed Anal. 2019 Feb 08;167:140-148 Authors: Rutowski J, Zhong F, Xu M, Zhu J Abstract Traditional strategies in developing novel drugs to treat antibiotic-resistant S. aureus have not been very successful to date, therefore, there is an urgent need for creative usage of existing agents that can treat and control S. aureus infection. This study demonstrated that a combination of glucose and a sublethal dose of antibiotic can reduce the survivability of S. aureus in a glucose concentration-dependent manner. Mass spectrometry-based targeted metabolic profiling detected massive metabolic profile shift of both methicillin-susceptible and resistant S. aureus after methicillin and glucose co-treatment. The dramatic alteration of metabolites from these metabolic pathways can be detected when 10 mg/L or higher concentration of glucose were added to methicillin treated culture. Our data also indicated that multiple biochemical metabolic pathways, including pyrimidine metabolism and valine, leucine, and isoleucine degradation showed a significant difference (p < 0.01) in comparison of control groups to glucose treatment groups. Taken together, this pilot study suggested that exogenous glucose in combination with a sublethal dose of antibiotics can disturb the metabolism of both methicillin-susceptible and resistant S. aureus, and enhance the antibiotic bactericidal effect. PMID: 30771647 [PubMed - as supplied by publisher]

1H NMR metabolomic analysis of skin and blubber of bottlenose dolphins reveal a functional metabolic dichotomy. Comp Biochem Physiol Part D Genomics Proteomics. 2019 Feb 10;30:25-32 Authors: Misra BB, Mariel RI, Ivonne HG, Emanuel HN, Raúl DG, Cristina CR Abstract The common bottlenose dolphin (Tursiops truncatus) is a carnivorous cetacean thriving in marine environment that is one of the apex predators of the marine food web. They are found in coastal and estuarine ecosystems which are known to be sensitive to environmental impacts. Dolphins are considered sentinel organisms for monitoring the health of coastal marine ecosystems in their role as predators that can bioaccumulate contaminants. Although recent studies have focused on capturing the circulating metabolomes of these mammals, as well as in the context of pollutants and exposures in the marine environment, the skin and blubber are important surface and protective organs that have not been probed for metabolism. Using 1HNMR based metabolomic approach we quantified 51 metabolites belonging to 74 different metabolic pathways in the skin and blubber of stranding bottlenose dolphin samples collected from the Southern Zone coast of Yucatan Peninsula of Mexico. The results indicate that metabolism of skin and blubber metabolism are quantitatively very different. Further, using heat maps and random forest analysis, the results point to unique metabolites that are important classifiers of the tissue-type. The differential metabolic patterns, mainly linking fatty acid metabolism and ketogenic amino acids, seem to constitute a characteristic of blubber, pointing to fat synthesis and deposition. The skin showed several metabolites involved in gluconeogenic pathways, pointing towards active metabolism. The most notable pathways implicated in both tissues included: urea cycle and glutathione metabolism among others. Our 1H NMR metabolomics analysis allowed for the identification of metabolites associated with these organ types, such as pyruvic acid, arginine, ornithine, 2‑hydroxybutyric acid, 3‑hydroxyisobutyric acid, and acetic acid, as discriminatory and classifying metabolites. These results would lead to further understanding of the physiological roles of dolphin skin and blubber metabolism for better efforts in their conservation as well as useful target biopsy tissues for monitoring of dolphin health conditions in marine pollution and ecotoxicology studies. PMID: 30771562 [PubMed - as supplied by publisher]

Breast cancer risk in relation to plasma metabolites among Hispanic and African American women. Breast Cancer Res Treat. 2019 Feb 15;: Authors: Zhao H, Shen J, Moore SC, Ye Y, Wu X, Zanetti KA, Esteva FJ, Tripathy D, Chow WH Abstract PURPOSE: The metabolic etiology of breast cancer has been explored in the past several years using metabolomics. However, most of these studies only included non-Hispanic White individuals. METHODS: To fill this gap, we performed a two-step (discovery and validation) metabolomics profiling in plasma samples from 358 breast cancer patients and 138 healthy controls. All study subjects were either Hispanics or non-Hispanic African Americans. RESULTS: A panel of 14 identified metabolites significantly differed between breast cancer cases and healthy controls in both the discovery and validation sets. Most of these identified metabolites were lipids. In the pathway analysis, citrate cycle (TCA cycle), arginine and proline metabolism, and linoleic acid metabolism pathways were observed, and they significantly differed between breast cancer cases and healthy controls in both sets. From those 14 metabolites, we selected 9 non-correlated metabolites to generate a metabolic risk score. Increased metabolites risk score was associated with a 1.87- and 1.63-fold increased risk of breast cancer in the discovery and validation sets, respectively (Odds ratio (OR) 1.87, 95% Confidence interval (CI) 1.50, 2.32; OR 1.63, 95% CI 1.36, 1.95). CONCLUSIONS: In summary, our study identified metabolic profiles and pathways that significantly differed between breast cancer cases and healthy controls in Hispanic or non-Hispanic African American women. The results from our study might provide new insights on the metabolic etiology of breast cancer. PMID: 30771047 [PubMed - as supplied by publisher]