Abstract Objective This pilot study was designed to determine if metabolic effects in different brain regions (left and right parietal lobes, midbrain) caused by 3 d of food consumption without ...methionine or cysteine could be detected by proton magnetic resonance spectroscopy. Methods Healthy individuals 18 to 36 y old ( n = 8) were studied by magnetic resonance spectroscopy after receiving a diet with adequate sulfur amino acids (SAAs) or with zero SAA for 3 d. Pulse sequences were used to selectively measure glutathione (GSH), and linear combination modeling of spectra was used to measure other high-abundance brain metabolites and expressed relative to creatine (Cr). Results Although dietary SAAs are required to maintain GSH, the 3-d SAA insufficiency resulted in no significant change in GSH/Cr in the three brain regions. Principal component analysis of 16 metabolites measured by linear combination modeling showed that the metabolic pattern in the midbrain, but not in the parietal lobes, was distinguished according to the dietary SAAs. Multivariate statistical analysis showed that the major discriminating factors were signals of glutamate/Cr, (glutamate + glutamine)/Cr, and myoinositol/Cr. Correlation analyses between midbrain metabolites and GSH-related metabolites in plasma showed that midbrain glutamate/Cr had an inverse correlation with plasma cystine. Conclusion The data show that magnetic resonance spectroscopy is a non-invasive tool suitable for nutritional assessment and suggest that nutritional imbalance caused by 3 d of SAA-free food more selectively affects the midbrain than the parietal lobes.
Abstract only
Introduction:
Patients living in neighborhoods with lower socioeconomic status have a greater risk for incident heart failure (HF), more severe symptoms, and increased risk of adverse ...clinical outcomes. We used high resolution metabolomics profiling to identify novel biomarkers associated with neighborhood socioeconomic status (nSES) in patients with HFrEF.
Methods:
The Area Deprivation Index (ADI) was used to characterize nSES in a discovery (n=170) and a validation (n=166) cohort of patients with HFrEF. Targeted and untargeted high-resolution plasma metabolomics profiling coupled with partial least-squares discriminant analysis (PLS-DA) was used to identify metabolites and metabolic pathways uniquely perturbed in patients in the highest tertile of the ADI (indicating lower nSES). Metabolites with a variable importance in projection (VIP)
>
1 entered pathway enrichment analysis.
Results:
Compared to patients in the lower and middle ADI tertiles, patients with HFrEF living in the highest ADI tertile were more likely to be Black, and had higher body mass index and lower ejection fraction (all P
<
0.01). PLS-DA confirmed metabolites that may be associated with worse diet quality in patients in both the discovery and validation cohorts who lived in neighborhoods in the highest ADI tertile, including amino acids and their metabolic products (carnitine, methionine, tryptophan, phenylalanine, valine, phenethylamine, indole), and urate. Moreover, metabolites associated with the human exposome (5-valerolactone, 1-naphthylamine) were also identified. Pathway enrichment analysis revealed branched-chain amino acid metabolism, fatty acid metabolism, and purine metabolism as part of this distinct metabolic signature (
Figure
).
Conclusions:
Patients with HFrEF living in neighborhoods with lower SES have a distinct metabolic signature that may, in part, be related to worse diet quality and more severe HF.
Background:
Small studies have recently suggested that there are specific plasma metabolic signatures in chronic obstructive pulmonary disease (COPD), but there have been no large comprehensive study ...of metabolomic signatures in COPD that also integrate genetic variants.
Materials and Methods:
Fresh frozen plasma from 957 non-Hispanic white subjects in COPDGene was used to quantify 995 metabolites with Metabolon's global metabolomics platform. Metabolite associations with five COPD phenotypes (chronic bronchitis, exacerbation frequency, percent emphysema, post-bronchodilator forced expiratory volume at one second FEV
1
/forced vital capacity FVC, and FEV
1
percent predicted) were assessed. A metabolome-wide association study was performed to find genetic associations with metabolite levels. Significantly associated single-nucleotide polymorphisms were tested for replication with independent metabolomic platforms and independent cohorts. COPD phenotype-driven modules were identified in network analysis integrated with genetic associations to assess gene-metabolite-phenotype interactions.
Results:
Of metabolites tested, 147 (14.8%) were significantly associated with at least 1 COPD phenotype. Associations with airflow obstruction were enriched for diacylglycerols and branched chain amino acids. Genetic associations were observed with 109 (11%) metabolites, 72 (66%) of which replicated in an independent cohort. For 20 metabolites, more than 20% of variance was explained by genetics. A sparse network of COPD phenotype-driven modules was identified, often containing metabolites missed in previous testing. Of the 26 COPD phenotype-driven modules, 6 contained metabolites with significant met-QTLs, although little module variance was explained by genetics.
Conclusion:
A dysregulation of systemic metabolism was predominantly found in COPD phenotypes characterized by airflow obstruction, where we identified robust heritable effects on individual metabolite abundances. However, network analysis, which increased the statistical power to detect associations missed previously in classic regression analyses, revealed that the genetic influence on COPD phenotype-driven metabolomic modules was modest when compared with clinical and environmental factors.
Bone marrow-derived mesenchymal stem cells (BMDMSC) are emerging as a therapeutic modality in various inflammatory disease states, including acute lung injury (ALI). A hallmark of inflammation, and a ...consistent observation in patients with ALI, is a perturbation in the systemic redox environment. However, little is known about the effects of BMDMSC on the systemic redox status. The objective of the present study was to determine whether exogenously infused BMDMSC protect against endotoxin-induced oxidation of plasma cysteine (Cys) and glutathione (GSH) redox states. To determine the effect on the redox state if BMDMSC, mice received endotoxin intraperitoneally (1 mg/kg), followed by intravenous infusion of either 5×105 BMDMSC or an equal volume of saline solution. Control mice received intraperitoneal endotoxin followed by 5×105 lung fibroblasts given intravenously. Cys, cystine (CySS), GSH, and glutathione disulfide (GSSG) concentrations were determined by HPLC. Results showed sequential preservation of plasma Cys and GSH levels in response to BMDMSC infusion. The data show that BMDMSC infusion leads to a more reducing Cys and GSH redox state. The findings are the first to demonstrate that BMDMSC have antioxidant effects in vivo, and add to our understanding of the systemic effects of BMDMSC in lung injury.
Abstract
Although substantial evidence from cell and animal studies, epidemiological studies, and clinical trials supports the chemopreventive effects of aspirin, especially for colorectal cancer, ...the molecular mechanisms are uncertain. Aspirin incorporates two bioactive components in one molecule, a reactive acetyl moiety and a salicylate group, and is well known for its pleotropic effects. Its best-characterized pharmacologic activity is the irreversible acetylation of the cyclooxygenases (COX-1 and COX-2). However, there is evidence for numerous COX-independent mechanisms that could also modify colorectal carcinogenesis. This study applied an untargeted, discovery-based approach (metabolomics) to elucidate the effects of aspirin on low molecular weight molecules in human colon tissue and assess their impact on colorectal carcinogenesis. We utilized normal mucosal tissue biopsies collected at colonoscopy after about 3 years of treatment from a sub-set of N=325 participants in the Aspirin/Folate Polyp Prevention Study, a randomized, placebo-controlled trial of aspirin (81 or 325 mg/day) for the prevention of colorectal adenomas. The global metabolic effects of aspirin were assessed using a high-resolution Thermo Fusion mass spectrometer coupled with dual chromatography and dual ionization (HILIC positive and C18 negative electrospray ionization). Multivariable linear regression was used to identify metabolic features associated with aspirin treatment adjusting for age, sex and race. Multivariable Poisson regression was used to assess associations with adenoma outcomes of metabolic features associated with aspirin treatment. Products of aspirin metabolism (salicylate, salicyluric acid) were identified and statistically significantly increased in post treatment compared to baseline plasma samples confirming aspirin treatment status. After quality control exclusions, N=4,879 and N=5,390 features were included in analyses from the C18 and HILIC columns, respectively, of which N=244 and N=222 were associated with aspirin treatment at a raw P<0.05. At the pathway level, aspirin treatment was most strongly associated with perturbations in prostaglandin/arachidonic acid metabolism and the carnitine shuttle, which is involved in energy metabolism from fatty acids. At the metabolite level, only one feature (tentatively identified as a pterosin compound) was statistically significantly associated with aspirin treatment after FDR adjustment, but it was not associated with adenoma risk. Top features associated with aspirin treatment that were associated with adenoma outcomes included creatinine but are mostly of unknown identity at this time. In conclusion, a non-targeted high-resolution metabolomics approach has the potential to identify key downstream effects of aspirin involved in colorectal chemoprevention.
Citation Format: Elizabeth L. Barry, Karan Uppal, Chunyu Ma, Dean P. Jones, John A. Baron, Veronika Fedirko. High resolution metabolomics of aspirin treatment in colon tissue and adenoma risk: Results from a randomized clinical trial abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 656.
BACKGROUND: α-Linolenic acid (ALA) is associated with a low risk of cardiovascular disease; however, the underlying mechanism is not completely known. OBJECTIVE: The objective was to examine whether ...habitual dietary ALA intake is associated with plasma concentrations of inflammatory biomarkers after control for shared genetic and common environmental factors. DESIGN: We cross-sectionally studied 353 middle-aged male twins. Habitual diet was assessed with the Willett food-frequency questionnaire. Fasting plasma concentrations of interleukin-6 (IL-6) and its soluble receptor (sIL-6R), high-sensitivity C-reactive protein (hsCRP), and tumor necrosis factor-α (TNF-α) were measured. Linear mixed-effect regression analysis was used to partition the overall association into within- and between-pair associations. RESULTS: A 1-g increment in habitual dietary ALA intake was associated with 11.0% lower concentrations of sIL-6R (P = 0.004) but not of IL-6 (P = 0.31), TNF-α (P = 0.16), or hsCRP (P = 0.36) after adjustment for energy intake, nutritional factors, known cardiovascular disease risk factors, and medications. After further control for shared genetic and common environmental factors by comparison of brothers within a twin pair, a twin with a 1-g higher ALA intake was likely to have 10.9% (95% CI: 3.7%, 17.6%; P = 0.004) lower sIL-6R concentrations than his co-twin with a low intake, whereas ALA intake was not significantly associated with plasma concentrations of IL-6, TNF-α, or hsCRP. These results were validated by using 1000 bootstrap samples. CONCLUSIONS: Habitual dietary ALA intake is inversely associated with plasma sIL-6R concentrations independent of shared genetic and common environmental influences. Lowering sIL-6R may be a mechanism underlying the cardioprotective properties of habitual dietary ALA. This study was registered at clinicaltrials.gov as NCT00017836.
Most current studies of reactive oxygen species (ROS) production report globally averaged measurements within the cell; however, ROS can be produced in distinct subcellular locations and have local ...effects in their immediate vicinity. A microfluidic platform for high-throughput single-cell imaging allows mitochondrial ROS production to be monitored as varying in both space and time. Using this systems biology approach, single-cell variability can be viewed within a population. We discuss single-cell monitoring of contributors to mitochondrial redox state-mitochondrial hydrogen peroxide or superoxide-through the use of a small molecule probe or targeted fluorescent reporter protein. Jurkat T lymphoma cells were stimulated with antimycin A and imaged in an arrayed microfluidic device over time. Differences in single-cell responses were observed as a function of both inhibitor concentration and type of ROS measurement used.
Departments of 1 Medicine and 3 Chemistry, Emory University, Atlanta, Georgia; and 2 Department of Industrial Systems and Information Engineering, Korea University, Seoul, South Korea
Submitted 9 ...September 2008
; accepted in final form 13 May 2009
Proton nuclear magnetic resonance ( 1 H-NMR) spectroscopy of plasma provides a global metabolic profiling method that shows promise for clinical diagnostics. However, cross-sectional studies are complicated by a lack of understanding of intraindividual variation, and this limits experimental design and interpretation of data. The present study determined the diurnal variation detected by 1 H NMR spectroscopy of human plasma. Data reduction methods revealed three time-of-day metabolic patterns, which were associated with morning, afternoon, and night. Major discriminatory regions for these time-of-day patterns included the various kinds of lipid signals (-CH 2 - and -CH 2 OCOR), and the region between 3 and 4 ppm heavily overlapped with amino acids that had -CH and -CH 2 . The phasing and duration of time-of-day patterns were variable among individuals, apparently because of individual difference in food processing/digestion and absorption and clearance of macronutrient energy sources (fat, protein, carbohydrate). The times of day that were most consistent among individuals, and therefore most useful for cross-sectional studies, were fasting morning (0830–0930), postprandial afternoon (1430–1630), and nighttime samples (0430–0530). Importantly, the integrated picture of metabolism provided by 1 H-NMR spectroscopy of plasma suggests that this approach is suitable to study complex regulatory processes, including eating patterns/eating disorders, upper gastrointestinal functions (gastric emptying, pancreatic, biliary functions), and absorption/clearance of macronutrients. Hence, 1 H-NMR spectroscopy of plasma could provide a global metabolic tolerance test to assess complex processes involved in disease, including eating disorders and the range of physiological processes causing dysregulation of energy homeostasis.
metabolomics; diurnal variation; eating disorders; gastrointestinal regulation
Address for reprint requests and other correspondence: D. P. Jones, Dept. of Medicine/Pulmonary Division, Whitehead Biomedical Research Bldg., Suite 205P, 615 Michael St., Emory Univ., Atlanta, GA 30322 (e-mail: dpjones{at}emory.edu )
This study presents three feature selection methods for identifying the metabolite features in nuclear magnetic resonance spectra that contribute to the distinction of samples among varying ...nutritional conditions. Principal component analysis, Fisher discriminant analysis, and Partial Least Square Discriminant Analysis (PLS-DA) were used to calculate the importance of individual metabolite feature in spectra. Moreover, an Orthogonal Signal Correction (OSC) filter was used to eliminate unnecessary variations in spectra. We evaluated the presented methods by comparing the ability of classification based on the features selected by each method. The result showed that the best classification was achieved from an OSC-PLS-DA model.
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