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Analysis of biomarkers and metabolic pathways in patients with unstable angina based on ultra‑high‑performance liquid chromatography‑quadrupole time‑of‑flight mass spectrometry.
Liu, Y, Li, Y, Zhang, T, Zhao, H, Fan, S, Cai, X, Liu, Y, Li, Z, Gao, S, Li, Y, et al
Molecular medicine reports. 2020;(5):3862-3872
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Abstract
Unstable angina (UA) is a coronary disease with a high mortality and morbidity worldwide. The present study aimed to use non‑invasive techniques to identify urine biomarkers in patients with UA, so as to provide more information for the early diagnosis and treatment of the disease. Based on metabolomics, urine samples from 28 patients with UA and 28 healthy controls (HCs) were analyzed using ultra‑high‑performance liquid chromatography‑quadrupole time‑of‑flight mass spectrometry (UPLC‑Q‑TOF/MS). A total of 16 significant biomarkers that could distinguish between patients with UA and HCs, including D‑glucuronic acid, creatinine, succinic acid and N‑acetylneuraminic acid, were identified. The major metabolic pathways associated with UA were subsequently analyzed by non‑targeted metabolomics. The results demonstrated that amino acid and energy metabolism, fatty acid metabolism, purine metabolism and steroid hormone biosynthetic metabolism may serve important roles in UA. The results of the current study may provide a theoretical basis for the early diagnosis of UA and novel treatment strategies for clinicians. The trial was registered with the Chinese Clinical Trial Registration Center (registration no. ChiCTR‑ROC‑17013957) at Tianjin University of Traditional Chinese Medicine.
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A reverse metabolic approach to weaning: in silico identification of immune-beneficial infant gut bacteria, mining their metabolism for prebiotic feeds and sourcing these feeds in the natural product space.
Michelini, S, Balakrishnan, B, Parolo, S, Matone, A, Mullaney, JA, Young, W, Gasser, O, Wall, C, Priami, C, Lombardo, R, et al
Microbiome. 2018;(1):171
Abstract
BACKGROUND Weaning is a period of marked physiological change. The introduction of solid foods and the changes in milk consumption are accompanied by significant gastrointestinal, immune, developmental, and microbial adaptations. Defining a reduced number of infections as the desired health benefit for infants around weaning, we identified in silico (i.e., by advanced public domain mining) infant gut microbes as potential deliverers of this benefit. We then investigated the requirements of these bacteria for exogenous metabolites as potential prebiotic feeds that were subsequently searched for in the natural product space. RESULTS Using public domain literature mining and an in silico reverse metabolic approach, we constructed probiotic-prebiotic-food associations, which can guide targeted feeding of immune health-beneficial microbes by weaning food; analyzed competition and synergy for (prebiotic) nutrients between selected microbes; and translated this information into designing an experimental complementary feed for infants enrolled in a pilot clinical trial ( http://www.nourishtoflourish.auckland.ac.nz/ ). CONCLUSIONS In this study, we applied a benefit-oriented microbiome research strategy for enhanced early-life immune health. We extended from "classical" to molecular nutrition aiming to identify nutrients, bacteria, and mechanisms that point towards targeted feeding to improve immune health in infants around weaning. Here, we present the systems biology-based approach we used to inform us on the most promising prebiotic combinations known to support growth of beneficial gut bacteria ("probiotics") in the infant gut, thereby favorably promoting development of the immune system.
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A pharmaco-metabolomics approach in a clinical trial of ALS: Identification of predictive markers of progression.
Blasco, H, Patin, F, Descat, A, Garçon, G, Corcia, P, Gelé, P, Lenglet, T, Bede, P, Meininger, V, Devos, D, et al
PloS one. 2018;(6):e0198116
Abstract
There is an urgent and unmet need for accurate biomarkers in Amyotrophic Lateral Sclerosis. A pharmaco-metabolomics study was conducted using plasma samples from the TRO19622 (olesoxime) trial to assess the link between early metabolomic profiles and clinical outcomes. Patients included in this trial were randomized into either Group O receiving olesoxime (n = 38) or Group P receiving placebo (n = 36). The metabolomic profile was assessed at time-point one (V1) and 12 months (V12) after the initiation of the treatment. High performance liquid chromatography coupled with tandem mass spectrometry was used to quantify 188 metabolites (Biocrates® commercial kit). Multivariate analysis based on machine learning approaches (i.e. Biosigner algorithm) was performed. Metabolomic profiles at V1 and V12 and changes in metabolomic profiles between V1 and V12 accurately discriminated between Groups O and P (p<5×10-6), and identified glycine, kynurenine and citrulline/arginine as the best predictors of group membership. Changes in metabolomic profiles were closely linked to clinical progression, and correlated with glutamine levels in Group P and amino acids, lipids and spermidine levels in Group O. Multivariate models accurately predicted disease progression and highlighted the discriminant role of sphingomyelins (SM C22:3, SM C24:1, SM OH C22:2, SM C16:1). To predict SVC from SM C24:1 in group O and SVC from SM OH C22:2 and SM C16:1 in group P+O, we noted a median sensitivity between 67% and 100%, a specificity between 66.7 and 71.4%, a positive predictive value between 66 and 75% and a negative predictive value between 70% and 100% in the test sets. This proof-of-concept study demonstrates that the metabolomics has a role in evaluating the biological effect of an investigational drug and may be a candidate biomarker as a secondary outcome measure in clinical trials.
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Changes in Plasma Acylcarnitine and Lysophosphatidylcholine Levels Following a High-Fructose Diet: A Targeted Metabolomics Study in Healthy Women.
Gonzalez-Granda, A, Damms-Machado, A, Basrai, M, Bischoff, SC
Nutrients. 2018;(9)
Abstract
BACKGROUND The consumption of high amounts of fructose is associated with metabolic diseases. However, the underlying mechanisms are largely unknown. OBJECTIVE To determine the effects of high fructose intake on plasma metabolomics. STUDY DESIGN We enrolled 12 healthy volunteers (six lean and six obese women, age 24⁻35 years) in a crossover intervention study. All participants carried out three diets: (1) low fructose (<10 g/day); (2) high fructose (100 g/day) from natural food sources (fruit); and (3) high fructose (100 g/day) from high fructose syrup (HFS). OUTCOME MEASURES The primary outcome was changes in plasma metabolites measured by targeted metabolomics. RESULTS High compared to low fructose diets caused a marked metabolite class separation, especially because of changes in acylcarnitine and lysophosphatidylcholine levels. Both high fructose diets resulted in a decrease in mean acylcarnitine levels in all subjects, and an increase in mean lysophosphatidylcholine and diacyl-phosphatidylcholine levels in obese individuals. Medium chain acylcarnitines were negatively correlated with serum levels of liver enzymes and with the fatty liver index. DISCUSSION The metabolic shifts induced by high fructose consumption suggest an inhibition of mitochondrial β-oxidation and an increase in lipid peroxidation. The effects tended to be more pronounced following the HFS than the fruit diet.
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Interventional left atrial appendage closure may affect metabolism of essential amino acids and bioenergetic efficacy.
Rusnak, J, Behnes, M, Saleh, A, Fastner, C, Sattler, K, Barth, C, Wenke, A, Sartorius, B, Mashayekhi, K, Hoffmann, U, et al
International journal of cardiology. 2018;:125-131
Abstract
BACKGROUND Interventional closure of left atrial appendage (LAAC) represents an alternative for stroke prevention in patients with non-valvular atrial fibrillation. Whether LAAC may affect metabolomic pathways has not been investigated yet. This study evaluates the impact of LAAC on the metabolism of essential amino acids, kynurenine and creatinine. METHODS Peripheral blood samples of prospectively enrolled patients undergoing successful LAAC were taken before (T0) and 6 months after (T1, mid-term follow-up). Targeted metabolomic profiling was performed using electrospray ionization liquid chromatography-mass spectrometry (ESI-LC-MS/MS) and MS/MS measurements focusing on metabolism of essential amino acids. RESULTS 44 patients with non-valvular AF (mean CHA2DS2-VASc score 4, mean HAS-BLED score 4) were enrolled. Changes in metabolites of essential amino acids, myocardial contraction and bioenergetic efficacy, such as phenylalanine (percentage change 8.2%, p = 0.006), tryptophan (percentage change 20.3%, p = 0.0006), tyrosine (percentage change 20.2%, p = 0.0001), creatinine (percentage change 7.2%, p > 0.05) and kynurenine (percentage change 8.3%, p = 0.0239) were found at mid-term follow-up. CONCLUSIONS LAAC may affect the metabolism of essential amino acids and bioenergetic efficacy. ClinicalTrials.gov Identifier: NCT02985463.
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Effect of masticatory stimulation on the quantity and quality of saliva and the salivary metabolomic profile.
Okuma, N, Saita, M, Hoshi, N, Soga, T, Tomita, M, Sugimoto, M, Kimoto, K
PloS one. 2017;(8):e0183109
Abstract
BACKGROUND This study characterized the changes in quality and quantity of saliva, and changes in the salivary metabolomic profile, to understand the effects of masticatory stimulation. METHODS Stimulated and unstimulated saliva samples were collected from 55 subjects and salivary hydrophilic metabolites were comprehensively quantified using capillary electrophoresis-time-of-flight mass spectrometry. RESULTS In total, 137 metabolites were identified and quantified. The concentrations of 44 metabolites in stimulated saliva were significantly higher than those in unstimulated saliva. Pathway analysis identified the upregulation of the urea cycle and synthesis and degradation pathways of glycine, serine, cysteine and threonine in stimulated saliva. A principal component analysis revealed that the effect of masticatory stimulation on salivary metabolomic profiles was less dependent on sample population sex, age, and smoking. The concentrations of only 1 metabolite in unstimulated saliva, and of 3 metabolites stimulated saliva, showed significant correlation with salivary secretion volume, indicating that the salivary metabolomic profile and salivary secretion volume were independent factors. CONCLUSIONS Masticatory stimulation affected not only salivary secretion volume, but also metabolite concentration patterns. A low correlation between the secretion volume and these patterns supports the conclusion that the salivary metabolomic profile may be a new indicator to characterize masticatory stimulation.
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Statin Effects on Metabolic Profiles: Data From the PREVEND IT (Prevention of Renal and Vascular End-stage Disease Intervention Trial).
Kofink, D, Eppinga, RN, van Gilst, WH, Bakker, SJL, Dullaart, RPF, van der Harst, P, Asselbergs, FW
Circulation. Cardiovascular genetics. 2017;(6)
Abstract
BACKGROUND Statins lower cholesterol by inhibiting HMG-CoA reductase, the rate-limiting enzyme of the metabolic pathway that produces cholesterol and other isoprenoids. Little is known about their effects on metabolite and lipoprotein subclass profiles. We, therefore, investigated the molecular changes associated with pravastatin treatment compared with placebo administration using a nuclear magnetic resonance-based metabolomics platform. METHODS AND RESULTS We performed metabolic profiling of 231 lipoprotein and metabolite measures in the PREVEND IT (Prevention of Renal and Vascular End-stage Disease Intervention Trial) study, a placebo-controlled randomized clinical trial designed to test the effects of pravastatin (40 mg once daily) on cardiovascular risk. Metabolic profiles were assessed at baseline and after 3 months of treatment. Pravastatin lowered low-density lipoprotein cholesterol (change in SD units [95% confidence interval]: -1.01 [-1.14, -0.88]), remnant cholesterol (change in SD units [95% confidence interval]: -1.03 [-1.17, -0.89]), and apolipoprotein B (change in SD units [95% confidence interval]: -0.98 [-1.11, -0.86]) with similar effect magnitudes. In addition, pravastatin globally lowered levels of lipoprotein subclasses, with the exception of high-density lipoprotein subclasses, which displayed a more heterogeneous response pattern. The lipid-lowering effect of pravastatin was accompanied by selective changes in lipid composition, particularly in the cholesterol content of very-low-density lipoproteinparticles. In addition, pravastatin reduced levels of several fatty acids but had limited effects on fatty acid ratios. CONCLUSIONS These randomized clinical trial data demonstrate the widespread effects of pravastatin treatment on lipoprotein subclass profiles and fatty acids. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT03073018.
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Urinary 6β-Hydroxycortisol/Cortisol Ratio Most Highly Correlates With Midazolam Clearance Under Hepatic CYP3A Inhibition and Induction in Females: A Pharmacometabolomics Approach.
Shin, KH, Ahn, LY, Choi, MH, Moon, JY, Lee, J, Jang, IJ, Yu, KS, Cho, JY
The AAPS journal. 2016;(5):1254-1261
Abstract
Endogenous metabolites of cytochrome P450 (CYP3A) are useful in predicting drug-drug interactions between in vivo CYP3A inhibitors and inducers for clinical applications of CYP3A substrate drugs. This study aimed to develop predictable markers of the magnitude of hepatic CYP3A induction and inhibition in healthy female subjects using pharmacometabolomics. Twelve female subjects received midazolam during three study phases: 1 mg midazolam (control phase), 1 mg midazolam after pretreatment with 400 mg ketoconazole once daily for 4 days (CYP3A inhibition phase), and 2.5 mg midazolam after pretreatment with 600 mg rifampicin once daily for 10 days (CYP3A induction phase). Throughout the study, blood samples were collected 24 h after midazolam administration and urine samples at 12-h intervals during the 24 h before and after midazolam administration for the analysis of endogenous steroid metabolites. A statistical model was generated to predict midazolam clearance using measurements of endogenous metabolites associated with the inhibition and induction of CYP3A. Mean midazolam clearance decreased to ∼20% of control levels during the inhibition phase and increased more than 2-fold during the induction phase. Of the urine and plasma metabolites measured, the 6β-hydroxycortisol/cortisol ratio was most significantly correlated with midazolam clearance during hepatic CYP3A inhibition and induction. Our results suggest that the urinary 6β-hydroxycortisol/cortisol ratio is the best predictor of hepatic CYP3A activity under both maximal inhibition and maximal induction. Furthermore, the predictive model including 6β-hydroxycortisol/cortisol as a covariate could be applied to predict the magnitude of CYP3A-mediated drug interactions.
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Pharmacometabolomics of l-carnitine treatment response phenotypes in patients with septic shock.
Puskarich, MA, Finkel, MA, Karnovsky, A, Jones, AE, Trexel, J, Harris, BN, Stringer, KA
Annals of the American Thoracic Society. 2015;(1):46-56
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Abstract
RATIONALE Sepsis therapeutics have a poor history of success in clinical trials, due in part to the heterogeneity of enrolled patients. Pharmacometabolomics could differentiate drug response phenotypes and permit a precision medicine approach to sepsis. OBJECTIVES To use existing serum samples from the phase 1 clinical trial of l-carnitine treatment for severe sepsis to metabolically phenotype l-carnitine responders and nonresponders. METHODS Serum samples collected before (T0) and after completion of the infusion (T24, T48) from patients randomized to either l-carnitine (12 g) or placebo for the treatment of vasopressor-dependent septic shock were assayed by untargeted (1)H-nuclear magnetic resonance metabolomics. The normalized, quantified metabolite data sets of l-carnitine- and placebo-treated patients at each time point were compared by analysis of variance with post-hoc testing for multiple comparisons. Pathway analysis was performed to statistically rank metabolic networks. MEASUREMENTS AND MAIN RESULTS Thirty-eight metabolites were identified in all samples. Concentrations of 3-hydroxybutyrate, acetoacetate, and 3-hydroxyisovalerate were different at T0 and over time in l-carnitine-treated survivors versus nonsurvivors. Pathway analysis of pretreatment metabolites revealed that synthesis and degradation of ketone bodies had the greatest impact in differentiating l-carnitine treatment response. Analysis of all patients based on pretreatment 3-hydroxybutyrate concentration yielded distinct phenotypes. Using the T0 median 3-hydroxybutyrate level (153 μM), patients were categorized as either high or low ketone. l-Carnitine-treated low-ketone patients had greater use of carnitine as evidenced by lower post-treatment l-carnitine levels. The l-carnitine responders also had faster resolution of vasopressor requirement and a trend toward a greater improvement in mortality at 1 year (P = 0.038) compared with patients with higher 3-hydroxybutyrate. CONCLUSIONS The results of this preliminary study, which were not readily apparent from the parent clinical trial, show a unique metabolite profile of l-carnitine responders and introduce pharmacometabolomics as a viable strategy for informing l-carnitine responsiveness. The approach taken in this study represents a concrete example for the application of precision medicine to sepsis therapeutics that warrants further study.
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LC-MS metabolomics of psoriasis patients reveals disease severity-dependent increases in circulating amino acids that are ameliorated by anti-TNFα treatment.
Kamleh, MA, Snowden, SG, Grapov, D, Blackburn, GJ, Watson, DG, Xu, N, Ståhle, M, Wheelock, CE
Journal of proteome research. 2015;(1):557-66
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Abstract
Psoriasis is an immune-mediated highly heterogeneous skin disease in which genetic as well as environmental factors play important roles. In spite of the local manifestations of the disease, psoriasis may progress to affect organs deeper than the skin. These effects are documented by epidemiological studies, but they are not yet mechanistically understood. In order to provide insight into the systemic effects of psoriasis, we performed a nontargeted high-resolution LC-MS metabolomics analysis to measure plasma metabolites from individuals with mild or severe psoriasis as well as healthy controls. Additionally, the effects of the anti-TNFα drug Etanercept on metabolic profiles were investigated in patients with severe psoriasis. Our analyses identified significant psoriasis-associated perturbations in three metabolic pathways: (1) arginine and proline, (2) glycine, serine and threonine, and (3) alanine, aspartate, and glutamate. Etanercept treatment reversed the majority of psoriasis-associated trends in circulating metabolites, shifting the metabolic phenotypes of severe psoriasis toward that of healthy controls. Circulating metabolite levels pre- and post-Etanercept treatment correlated with psoriasis area and severity index (PASI) clinical scoring (R(2) = 0.80; p < 0.0001). Although the responsible mechanism(s) are unclear, these results suggest that psoriasis severity-associated metabolic perturbations may stem from increased demand for collagen synthesis and keratinocyte hyperproliferation or potentially the incidence of cachexia. Data suggest that levels of circulating amino acids are useful for monitoring both the severity of disease as well as therapeutic response to anti-TNFα treatment.