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| 2. |
- Reinke, SN, et al.
(författare)
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Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study
- 2022
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Ingår i: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 59:6
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Tidskriftsartikel (refereegranskat)abstract
- Asthma is a heterogeneous disease with poorly defined phenotypes. Patients with severe asthma often receive multiple treatments including oral corticosteroids (OCS). Treatment may modify the observed metabotype, rendering it challenging to investigate underlying disease mechanisms. Here, we aimed to identify dysregulated metabolic processes in relation to asthma severity and medication.MethodsBaseline urine was collected prospectively from healthy participants (n=100), patients with mild-to-moderate asthma (n=87) and patients with severe asthma (n=418) in the cross-sectional U-BIOPRED cohort; 12–18-month longitudinal samples were collected from patients with severe asthma (n=305). Metabolomics data were acquired using high-resolution mass spectrometry and analysed using univariate and multivariate methods.ResultsA total of 90 metabolites were identified, with 40 significantly altered (p<0.05, false discovery rate <0.05) in severe asthma and 23 by OCS use. Multivariate modelling showed that observed metabotypes in healthy participants and patients with mild-to-moderate asthma differed significantly from those in patients with severe asthma (p=2.6×10−20), OCS-treated asthmatic patients differed significantly from non-treated patients (p=9.5×10−4), and longitudinal metabotypes demonstrated temporal stability. Carnitine levels evidenced the strongest OCS-independent decrease in severe asthma. Reduced carnitine levels were associated with mitochondrial dysfunction via decreases in pathway enrichment scores of fatty acid metabolism and reduced expression of the carnitine transporter SLC22A5 in sputum and bronchial brushings.ConclusionsThis is the first large-scale study to delineate disease- and OCS-associated metabolic differences in asthma. The widespread associations with different therapies upon the observed metabotypes demonstrate the need to evaluate potential modulating effects on a treatment- and metabolite-specific basis. Altered carnitine metabolism is a potentially actionable therapeutic target that is independent of OCS treatment, highlighting the role of mitochondrial dysfunction in severe asthma.
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| 3. |
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| 4. |
- Dyczynski, M, et al.
(författare)
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Metabolic reprogramming of acute lymphoblastic leukemia cells in response to glucocorticoid treatment
- 2018
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 9:9, s. 846-
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Tidskriftsartikel (refereegranskat)abstract
- Glucocorticoids (GCs) are metabolic hormones with immunosuppressive effects that have proven effective drugs against childhood acute lymphoblastic leukemia (ALL). Yet, the role of metabolic reprogramming in GC-induced ALL cell death is poorly understood. GCs efficiently block glucose uptake and metabolism in ALL cells, but this does not fully explain the observed induction of autophagy and cell death. Here, we have performed parallel time-course proteomics, metabolomics, and isotope-tracing studies to examine in detail the metabolic effects of GCs on ALL cells. We observed metabolic events associated with growth arrest, autophagy, and catabolism prior to onset of apoptosis: nucleotide de novo synthesis was reduced, while certain nucleobases accumulated; polyamine synthesis was inhibited; and phosphatidylcholine synthesis was induced. GCs suppressed not only glycolysis but also entry of both glucose and glutamine into the TCA cycle. In contrast, expression of glutamine-ammonia ligase (GLUL) and cellular glutamine content was robustly increased by GC treatment, suggesting induction of glutamine synthesis, similar to nutrient-starved muscle. Modulating medium glutamine and dimethyl-α-ketoglutarate (dm-αkg) to favor glutamine synthesis reduced autophagosome content of ALL cells, and dm-αkg also rescued cell viability. These data suggest that glutamine synthesis affects autophagy and possibly onset of cell death in response to GCs, which should be further explored to understand mechanism of action and possible sources of resistance.
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| 6. |
- Gallart-Ayala, H., et al.
(författare)
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Data Analysis in Transcriptomics and Metabolomics Clinical Applications
- 2018
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Ingår i: Comprehensive Analytical Chemistry. - : Elsevier. - 9780444640444 ; , s. 613-641
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Bokkapitel (refereegranskat)abstract
- In the last couple of decades, transcriptomics and metabolomics technologies have been used for the simultaneous detection and quantification of hundreds to thousands of transcripts and metabolites in several clinical studies. Depending on the aim of the study or its design, different data analysis methodologies and pipelines have been applied to extract relevant information from these studies and aid in their interpretation. Using selected examples in the clinical context, this chapter reviews some of these data analysis strategies commonly applied to transcriptomics and metabolomics datasets, both separately and in an integrated manner.
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| 7. |
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| 8. |
- Gomez, C, et al.
(författare)
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Metabolomics: a tool to characterize the effect of phthalates and bisphenol A
- 2018
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Ingår i: ENVIRONMENTAL REVIEWS. - : Canadian Science Publishing. - 1208-6053 .- 1181-8700. ; 26:4, s. 351-357
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Forskningsöversikt (övrigt vetenskapligt/konstnärligt)abstract
- The study of physiological disruptions induced upon exposure to a given chemical substance has emerged as a research field. The assessment of the effects of chemical substances at low concentration levels is not always doable using classical toxicological studies. The use of metabolomics approaches integrated with conventional toxicological studies is expected to provide valuable information for risk assessment. This review recapitulates some of the recent publications related to the use of metabolomics to study the effect of bisphenol A (BPA) and phthalates exposure. Mass spectrometry and nuclear magnetic resonance metabolomics approaches revealed the principal metabolic pathways such as amino acids, energy storage compounds, or organic osmolytes were altered. To investigate phthalates and BPA effects is relevant to assist in potential correlations between exposure and adverse human effects and to provide data and evidence for effective regulatory policies and risk exposure assessment.
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| 9. |
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| 10. |
- Reinke, SN, et al.
(författare)
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Metabolomics analysis identifies different metabotypes of asthma severity
- 2017
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Ingår i: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 49:3
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we sought to determine whether asthma has a metabolic profile and whether this profile is related to disease severity.We characterised the serum from 22 healthy individuals and 54 asthmatics (12 mild, 20 moderate, 22 severe) using liquid chromatography–high-resolution mass spectrometry-based metabolomics. Selected metabolites were confirmed by targeted mass spectrometry assays of eicosanoids, sphingolipids and free fatty acids.We conclusively identified 66 metabolites; 15 were significantly altered with asthma (p≤0.05). Levels of dehydroepiandrosterone sulfate, cortisone, cortisol, prolylhydroxyproline, pipecolate and N-palmitoyltaurine correlated significantly (p<0.05) with inhaled corticosteroid dose, and were further shifted in individuals treated with oral corticosteroids. Oleoylethanolamide increased with asthma severity independently of steroid treatment (p<0.001). Multivariate analysis revealed two patterns: 1) a mean difference between controls and patients with mild asthma (p=0.025), and 2) a mean difference between patients with severe asthma and all other groups (p=1.7×10−4). Metabolic shifts in mild asthma, relative to controls, were associated with exogenous metabolites (e.g. dietary lipids), while those in moderate and severe asthma (e.g. oleoylethanolamide, sphingosine-1-phosphate, N-palmitoyltaurine) were postulated to be involved in activating the transient receptor potential vanilloid type 1 (TRPV1) receptor, driving TRPV1-dependent pathogenesis in asthma.Our findings suggest that asthma is characterised by a modest systemic metabolic shift in a disease severity-dependent manner, and that steroid treatment significantly affects metabolism.
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