| 1. |
- Ahola-Erkkilä, Sofia, et al.
(författare)
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Ketogenic diet slows down mitochondrial myopathy progression in mice
- 2010
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Ingår i: Human Molecular Genetics. - : Elsevier. - 0964-6906 .- 1460-2083. ; 19:10, s. 1974-1984
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial dysfunction is a major cause of neurodegenerative and neuromuscular diseases of adult age and of multisystem disorders of childhood. However, no effective treatment exists for these progressive disorders. Cell culture studies suggested that ketogenic diet (KD), with low glucose and high fat content, could select against cells or mitochondria with mutant mitochondrial DNA (mtDNA), but proper patient trials are still lacking. We studied here the transgenic Deletor mouse, a disease model for progressive late-onset mitochondrial myopathy, accumulating mtDNA deletions during aging and manifesting subtle progressive respiratory chain (RC) deficiency. We found that these mice have widespread lipidomic and metabolite changes, including abnormal plasma phospholipid and free amino acid levels and ketone body production. We treated these mice with pre-symptomatic long-term and post-symptomatic shorter term KD. The effects of the diet for disease progression were followed by morphological, metabolomic and lipidomic tools. We show here that the diet decreased the amount of cytochrome c oxidase negative muscle fibers, a key feature in mitochondrial RC deficiencies, and prevented completely the formation of the mitochondrial ultrastructural abnormalities in the muscle. Furthermore, most of the metabolic and lipidomic changes were cured by the diet to wild-type levels. The diet did not, however, significantly affect the mtDNA quality or quantity, but rather induced mitochondrial biogenesis and restored liver lipid levels. Our results show that mitochondrial myopathy induces widespread metabolic changes, and that KD can slow down progression of the disease in mice. These results suggest that KD may be useful for mitochondrial late-onset myopathies.
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| 2. |
- Aura, Anna-Marja, et al.
(författare)
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Characterization of microbial metabolism of Syrah grape products in an in vitro colon model using targeted and non-targeted analytical approaches
- 2013
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Ingår i: European Journal of Nutrition. - : Springer Berlin/Heidelberg. - 1436-6207 .- 1436-6215. ; 52:2, s. 833-846
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Syrah red grapes are used in the production of tannin-rich red wines. Tannins are high molecular weight molecules, proanthocyanidins (PAs), and poorly absorbed in the upper intestine. In this study, gut microbial metabolism of Syrah grape phenolic compounds was investigated.METHODS: Syrah grape pericarp was subjected to an enzymatic in vitro digestion model, and red wine and grape skin PA fraction were prepared. Microbial conversion was screened using an in vitro colon model with faecal microbiota, by measurement of short-chain fatty acids by gas chromatography (GC) and microbial phenolic metabolites using GC with mass detection (GC-MS). Red wine metabolites were further profiled using two-dimensional GC mass spectrometry (GCxGC-TOFMS). In addition, the effect of PA structure and dose on conversion efficiency was investigated by GC-MS.RESULTS: Red wine exhibited a higher degree of C1-C3 phenolic acid formation than PA fraction or grape pericarp powders. Hydroxyphenyl valeric acid (flavanols and PAs as precursors) and 3,5-dimethoxy-4-hydroxybenzoic acid (anthocyanin as a precursor) were identified from the red wine metabolite profile. In the absence of native grape pericarp or red wine matrix, the isolated PAs were found to be effective in the dose-dependent inhibition of microbial conversions and short-chain fatty acid formation.CONCLUSIONS: Metabolite profiling was complementary to targeted analysis. The identified metabolites had biological relevance, because the structures of the metabolites resembled fragments of their grape phenolic precursors or were in agreement with literature data.
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| 3. |
- Aura, Anna-Marja, et al.
(författare)
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Drug metabolome of the simvastatin formed by human intestinal microbiota in vitro
- 2011
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Ingår i: Molecular Biosystems. - : Royal Society of Chemistry. - 1742-206X .- 1742-2051. ; 7:2, s. 437-446
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Tidskriftsartikel (refereegranskat)abstract
- The human colon contains a diverse microbial population which contributes to degradation and metabolism of food components. Drug metabolism in the colon is generally poorly understood. Metabolomics techniques and in vitro colon models are now available which afford detailed characterization of drug metabolites in the context of colon metabolism. The aim of this work was to identify novel drug metabolites of Simvastatin (SV) by using an anaerobic human in vitro colon model at body temperature coupled with systems biology platform, excluding the metabolism of the host liver and intestinal epithelia. Comprehensive two-dimensional gas chromatography with a time-of-flight mass spectrometry (GC×GC-TOFMS) was used for the metabolomic analysis. Metabolites showing the most significant differences in the active faecal suspension were elucidated in reference with SV fragmentation and compared with controls: inactive suspension or buffer with SV, or with active suspension alone. Finally, time courses of selected metabolites were investigated. Our data suggest that SV is degraded by hydrolytic cleavage of methylbutanoic acid from the SV backbone. Metabolism involves demethylation of dimethylbutanoic acid, hydroxylation/dehydroxylation and β-oxidation resulting in the production of 2-hydroxyisovaleric acid (3-methyl-2-hydroxybutanoic acid), 3-hydroxybutanoic acid and lactic acid (2-hydroxypropanoic acid), and finally re-cyclisation of heptanoic acid (possibly de-esterified and cleaved methylpyranyl arm) to produce cyclohexanecarboxylic acid. Our study elucidates a pathway of colonic microbial metabolism of SV as well as demonstrates the applicability of the in vitro colon model and metabolomics to the discovery of novel drug metabolites from drug response profiles.
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| 4. |
- Bondia-Pons, Isabel, et al.
(författare)
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Metabolome and fecal microbiota in monozygotic twin pairs discordant for weight : a Big Mac challenge
- 2014
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Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 28:9, s. 4169-4179
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Tidskriftsartikel (refereegranskat)abstract
- Postprandial responses to food are complex, involving both genetic and environmental factors. We studied postprandial responses to a Big Mac meal challenge in monozygotic co-twins highly discordant for body weight. This unique design allows assessment of the contribution of obesity, independent of genetic liability. Comprehensive metabolic profiling using 3 analytical platforms was applied to fasting and postprandial serum samples from 16 healthy monozygotic twin pairs discordant for weight (body mass index difference >3 kg/m(2)). Nine concordant monozygotic pairs were examined as control pairs. Fecal samples were analyzed to assess diversity of the major bacterial groups by using 5 different validated bacterial group specific denaturing gradient gel electrophoresis methods. No differences in fecal bacterial diversity were detected when comparing co-twins discordant for weight (ANOVA, P<0.05). We found that within-pair similarity is a dominant factor in the metabolic postprandial response, independent of acquired obesity. Branched chain amino acids were increased in heavier as compared with leaner co-twins in the fasting state, but their levels converged postprandially (paired t tests, FDR q<0.05). We also found that specific bacterial groups were associated with postprandial changes of specific metabolites. Our findings underline important roles of genetic and early life factors in the regulation of postprandial metabolite levels.
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| 5. |
- Bondia-Pons, Isabel, et al.
(författare)
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Postprandial differences in the plasma metabolome of healthy Finnish subjects after intake of a sourdough fermented endosperm rye bread versus white wheat bread
- 2011
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Ingår i: Nutrition Journal. - : BioMed Central. - 1475-2891 .- 1475-2891. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The mechanism behind the lowered postprandial insulin demand observed after rye bread intake compared to wheat bread is unknown. The aim of this study was to use the metabolomics approach to identify potential metabolites related to amino acid metabolism involved in this mechanism.METHODS: A sourdough fermented endosperm rye bread (RB) and a standard white wheat bread (WB) as a reference were served in random order to 16 healthy subjects. Test bread portions contained 50 g available carbohydrate. In vitro hydrolysis of starch and protein were performed for both test breads. Blood samples for measuring glucose and insulin concentrations were drawn over 4 h and gastric emptying rate (GER) was measured. Changes in the plasma metabolome were investigated by applying a comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry metabolomics platform (GC × GC-TOF-MS).RESULTS: Plasma insulin response to RB was lower than to WB at 30 min (P = 0.004), 45 min (P = 0.002) and 60 min (P < 0.001) after bread intake, and plasma glucose response was significantly higher at time point 90 min after RB than WB intake (P = 0.045). The starch hydrolysis rate was higher for RB than WB, contrary to the in vitro protein digestibility. There were no differences in GER between breads. From 255 metabolites identified by the metabolomics platform, 26 showed significant postprandial relative changes after 30 minutes of bread intake (p and q values < 0.05). Among them, there were changes in essential amino acids (phenylalanine, methionine, tyrosine and glutamic acid), metabolites involved in the tricarboxylic acid cycle (alpha-ketoglutaric, pyruvic acid and citric acid) and several organic acids. Interestingly, the levels of two compounds involved in the tryptophan metabolism (picolinic acid, ribitol) significantly changed depending on the different bread intake.CONCLUSIONS: A single meal of a low fibre sourdough rye bread producing low postprandial insulin response brings in several changes in plasma amino acids and their metabolites and some of these might have properties beneficial for health.
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| 6. |
- Dickens, Alex Mountfort, et al.
(författare)
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Serum Metabolites Associated with Computed TomographyFindings after Traumatic Brain Injury
- 2018
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Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 35:22, s. 2673-2683
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Tidskriftsartikel (refereegranskat)abstract
- There is a need to rapidly detect patients with traumatic brain injury (TBI) who require head computed tomography (CT). Given the energy crisis in the brain following TBI, we hypothesized that serum metabolomics would be a useful tool for developing a set of biomarkers to determine the need for CT and to distinguish between different types of injuries observed. Logistic regression models using metabolite data from the discovery cohort (n=144, Turku, Finland) were used to distinguish between patients with traumatic intracranial findings and negative findings on head CT. The resultant models were then tested in the validation cohort (n=66, Cambridge, UK). The levels of glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 were also quantified in the serum from the same patients. Despite there being significant differences in the protein biomarkers in patients with TBI, the model that determined the need for a CT scan validated poorly (AUC=0.64: Cambridge patients). However, using a combination of six metabolites (two amino acids, three sugar derivatives and one ketoacid) it was possible to discriminate patients with intracranial abnormalities on CT and patients with a normal CT (AUC=0.77 in Turku patients and AUC=0.73 in Cambridge patients). Furthermore, a combination of three metabolites could distinguish between diffuse brain injuries and mass lesions (AUC=0.87 in Turku patients and AUC=0.68 in Cambridge patients). This study identifies a set of validated serum polar metabolites, which associate with the need for a CT scan. Additionally, serum metabolites can also predict the nature of the brain injury. These metabolite markers may prevent unnecessary CT scans, thus reducing the cost of diagnostics and radiation load.
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| 7. |
- Hartonen, Minna, et al.
(författare)
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Characterization of cerebrospinal fluid by comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry
- 2013
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Ingår i: Journal of Chromatography A. - : Elsevier BV. - 0021-9673 .- 1873-3778. ; 1293, s. 142-149
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Tidskriftsartikel (refereegranskat)abstract
- Comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (GC×GC-TOFMS) was applied in the quantification and identification of organic compounds in patient-matched human cerebrospinal fluid (CSF) and serum samples. Concentrations of 21 amino and hydroxyl acids varied from 0.04 to 77ng/μl in CSF and from 0.1 to 84ng/μl in serum. In total, 91 metabolites out of over 1200 detected were identified based on mass spectra and retention indices. The other metabolites were identified at the functional group level. The main metabolites detected in CSF were sugar and amino acid derivatives. The CSF and serum had clearly distinct metabolic profiles, with larger biological variation in the serum than in CSF. The GC×GC-TOFMS allowed detection and identification of several metabolites that have not been previously detected in CSF.
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| 8. |
- Hyötyläinen, Tuulia, 1971-, et al.
(författare)
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Genome-scale study reveals reduced metabolic adaptability in patients with non-alcoholic fatty liver disease
- 2016
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Ingår i: Nature Communications. - London, United Kingdom : Nature Publishing Group. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Non-alcoholic fatty liver disease (NAFLD) is a major risk factor leading to chronic liver disease and type 2 diabetes. Here we chart liver metabolic activity and functionality in NAFLD by integrating global transcriptomic data, from human liver biopsies, and metabolic flux data, measured across the human splanchnic vascular bed, within a genome-scale model of human metabolism. We show that an increased amount of liver fat induces mitochondrial metabolism, lipolysis, glyceroneogenesis and a switch from lactate to glycerol as substrate for gluconeogenesis, indicating an intricate balance of exacerbated opposite metabolic processes in glycemic regulation. These changes were associated with reduced metabolic adaptability on a network level in the sense that liver fat accumulation puts increasing demands on the liver to adaptively regulate metabolic responses to maintain basic liver functions. We propose that failure to meet excessive metabolic challenges coupled with reduced metabolic adaptability may lead to a vicious pathogenic cycle leading to the co-morbidities of NAFLD.
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| 9. |
- Hyötyläinen, Tuulia, 1971-, et al.
(författare)
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Metabolomic analysis of polar metabolites in lipoprotein fractions identifies lipoprotein-specific metabolic profiles and their association with insulin resistance
- 2012
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Ingår i: Molecular Biosystems. - : Royal Society of Chemistry. - 1742-206X .- 1742-2051. ; 8:10, s. 2559-2565
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Tidskriftsartikel (refereegranskat)abstract
- While the molecular lipid composition of lipoproteins has been investigated in detail, little is known about associations of small polar metabolites with specific lipoproteins. The aim of the present study was to investigate the profiles of polar metabolites in different lipoprotein fractions, i.e., very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and two sub-fractions of the high-density lipoprotein (HDL). The VLDL, IDL, LDL, HDL(2), and HDL(3) fractions were isolated from serum of sixteen individuals having a broad range of insulin sensitivity and characterized using comprehensive two-dimensional gas chromatography combined with time-of-flight mass spectrometry (GC×GC-TOFMS). The lipoprotein fractions had clearly different metabolite profiles, which correlated with the particle size and surface charge. Lipoprotein-specific associations of individual metabolites with insulin resistance were identified, particularly in VLDL and IDL fractions, even in the absence of such associations in serum. The results indicate that the polar molecules are strongly attached to the surface of the lipoproteins. Furthermore, strong lipoprotein-specific associations of metabolites with insulin resistance, as compared to their serum profiles, indicate that lipoproteins may be a rich source of tissue-specific metabolic biomarkers.
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| 10. |
- Jørgenrud, Benedicte, et al.
(författare)
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The influence of sample collection methodology and sample preprocessing on the blood metabolic profile.
- 2015
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Ingår i: Bioanalysis. - : Future Science Ltd.. - 1757-6180 .- 1757-6199. ; 7:8, s. 991-1006
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Tidskriftsartikel (refereegranskat)abstract
- AIM: Blood serum and plasma have intrinsic differences in their composition and the preprocessing, such as clotting temperature in serum, and storage at room temperature may have further effect on metabolite concentrations.METHODS: The influence of sampling preprocessing on the metabolic profiles in serum and different types of plasma was investigated using liquid chromatography and comprehensive 2D gas chromatography coupled to a mass spectrometer.RESULTS: The profiles of polar metabolites were significantly dependent on the type of the sample, while lipid profiles were similar in serum and different types of plasma. Extended storage of plasma at room temperature resulted in degradation of lipids already after 1 day. Serum clotting at room temperature generally resulted in higher metabolite concentration compared with serum clotting on ice.
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