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  • 1.
    Aho, Vilma
    et al.
    Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
    Ollila, Hanna M
    Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Genomics and Biomarkers Unit, Institute for Molecular Medicine FIMM, National Institute for Health and Welfare, Helsinki, Finland; Department of Psychiatry, Helsinki University Hospital, University of Helsinki, Helsinki, Finland; Stanford University Center for Sleep Sciences, Palo Alto CA, United States.
    Kronholm, Erkki
    Department of Chronic Disease Prevention, Population Studies Unit, National Institute for Health and Welfare, Turku, Finland.
    Bondia-Pons, Isabel
    VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center A/S, Gentofte, Denmark.
    Soininen, Pasi
    Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
    Kangas, Antti J
    Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland.
    Hilvo, Mika
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Seppälä, Ilkka
    Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere, School of Medicine, Tampere, Finland.
    Kettunen, Johannes
    Genomics and Biomarkers Unit, Institute for Molecular Medicine FIMM, National Institute for Health and Welfare, Helsinki, Finland; Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
    Oikonen, Mervi
    Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
    Raitoharju, Emma
    Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere, School of Medicine, Tampere, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center A/S, Gentofte, Denmark.
    Kähönen, Mika
    Department of Clinical Physiology, University of Tampere, Tampere University Hospital, Tampere, Finland.
    Viikari, Jorma S A
    Department of Medicine, University of Turku, Turku, Finland; Division of Medicine, Turku University Hospital, Turku, Finland.
    Härmä, Mikko
    Brain and Work Research Centre, Finnish Institute of Occupational Health, Helsinki, Finland.
    Sallinen, Mikael
    Brain and Work Research Centre, Finnish Institute of Occupational Health, Helsinki, Finland; Agora Center, University of Jyväskylä, Jyväskylä, Finland.
    Olkkonen, Vesa M
    Minerva Foundation Institute for Medical Research, Helsinki, Finland; Institute of Biomedicine, Anatomy, University of Helsinki, Helsinki, Finland.
    Alenius, Harri
    Unit of Excellence for Immunotoxicology, Finnish Institute of Occupational Health, Helsinki, Finland.
    Jauhiainen, Matti
    Genomics and Biomarkers Unit, Institute for Molecular Medicine FIMM, National Institute for Health and Welfare, Helsinki, Finland.
    Paunio, Tiina
    Genomics and Biomarkers Unit, Institute for Molecular Medicine FIMM, National Institute for Health and Welfare, Helsinki, Finland; Department of Psychiatry, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
    Lehtimäki, Terho
    Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere, School of Medicine, Tampere, Finland.
    Salomaa, Veikko
    Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
    Orešič, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center A/S, Gentofte, Denmark.
    Raitakari, Olli T
    Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
    Ala-Korpela, Mika
    Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland; Oulu University Hospital, Oulu, Finland; Computational Medicine, School of Social and Community Medicine, Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
    Porkka-Heiskanen, Tarja
    Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
    Prolonged sleep restriction induces changes in pathways involved in cholesterol metabolism and inflammatory responses2016In: Scientific Reports, E-ISSN 2045-2322, Vol. 6, article id 24828Article in journal (Refereed)
    Abstract [en]

    Sleep loss and insufficient sleep are risk factors for cardiometabolic diseases, but data on how insufficient sleep contributes to these diseases are scarce. These questions were addressed using two approaches: an experimental, partial sleep restriction study (14 cases and 7 control subjects) with objective verification of sleep amount, and two independent epidemiological cohorts (altogether 2739 individuals) with questions of sleep insufficiency. In both approaches, blood transcriptome and serum metabolome were analysed. Sleep loss decreased the expression of genes encoding cholesterol transporters and increased expression in pathways involved in inflammatory responses in both paradigms. Metabolomic analyses revealed lower circulating large HDL in the population cohorts among subjects reporting insufficient sleep, while circulating LDL decreased in the experimental sleep restriction study. These findings suggest that prolonged sleep deprivation modifies inflammatory and cholesterol pathways at the level of gene expression and serum lipoproteins, inducing changes toward potentially higher risk for cardiometabolic diseases.

  • 2.
    Ahonen, Linda
    et al.
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Jäntti, Sirkku
    Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
    Suvitaival, Tommi
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Theilade, Simone
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Risz, Claudia
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Kostiainen, Risto
    Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
    Rossing, Peter
    Steno Diabetes Center Copenhagen, Gentofte, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Targeted Clinical Metabolite Profiling Platform for the Stratification of Diabetic Patients2019In: Metabolites, ISSN 2218-1989, E-ISSN 2218-1989, Vol. 9, no 9, article id E184Article in journal (Refereed)
    Abstract [en]

    Several small molecule biomarkers have been reported in the literature for prediction and diagnosis of (pre)diabetes, its co-morbidities, and complications. Here, we report the development and validation of a novel, quantitative method for the determination of a selected panel of 34 metabolite biomarkers from human plasma. We selected a panel of metabolites indicative of various clinically-relevant pathogenic stages of diabetes. We combined these candidate biomarkers into a single ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method and optimized it, prioritizing simplicity of sample preparation and time needed for analysis, enabling high-throughput analysis in clinical laboratory settings. We validated the method in terms of limits of detection (LOD) and quantitation (LOQ), linearity (R2), and intra- and inter-day repeatability of each metabolite. The method's performance was demonstrated in the analysis of selected samples from a diabetes cohort study. Metabolite levels were associated with clinical measurements and kidney complications in type 1 diabetes (T1D) patients. Specifically, both amino acids and amino acid-related analytes, as well as specific bile acids, were associated with macro-albuminuria. Additionally, specific bile acids were associated with glycemic control, anti-hypertensive medication, statin medication, and clinical lipid measurements. The developed analytical method is suitable for robust determination of selected plasma metabolites in the diabetes clinic.

    Download full text (pdf)
    Targeted Clinical Metabolite Profiling Platform for the Stratification of Diabetic Patients
  • 3.
    Alijagic, Andi
    et al.
    Örebro University, School of Science and Technology. Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Scherbak, Nikolai
    Örebro University, School of Science and Technology.
    Kotlyar, Oleksandr
    Örebro University, School of Science and Technology.
    Karlsson, Patrik
    Örebro University, School of Science and Technology.
    Wang, Xuying
    KTH Royal Institute of Technology, Department of Chemistry, Division of Surface and Corrosion Science, SE-100 44 Stockholm, Sweden.
    Odnevall, Inger
    KTH Royal Institute of Technology, Department of Chemistry, Division of Surface and Corrosion Science, SE-100 44 Stockholm, Sweden; AIMES-Center for the Advancement of Integrated Medical and Engineering Sciences at Karolinska Institutet and KTH Royal Institute of Technology, SE-100 44 Stockholm, Sweden; Department of Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    Benada, Oldřich
    Institute of Microbiology of the Czech Academy of Sciences, 140 00 Prague, Czech Republic.
    Amiryousefi, Ali
    Örebro University, School of Medical Sciences.
    Andersson, Lena
    Örebro University, School of Medical Sciences. Örebro University Hospital. Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, SE-701 82 Örebro, Sweden; Department of Occupational and Environmental Medicine, Örebro University Hospital, Örebro, Sweden.
    Persson, Alexander
    Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, SE-701 82 Örebro, Sweden .
    Felth, Jenny
    Uddeholms AB, SE-683 85 Hagfors, Sweden.
    Andersson, Henrik
    Uddeholms AB, SE-683 85 Hagfors, Sweden.
    Larsson, Maria
    Örebro University, School of Science and Technology.
    Hedbrant, Alexander
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, SE-701 82 Örebro, Sweden.
    Salihovic, Samira
    Örebro University, School of Medical Sciences. Man-Technology-Environment Research Center (MTM), Örebro University, SE-701 82 Örebro, Sweden; Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, SE-701 82 Örebro, Sweden.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Särndahl, Eva
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, SE-701 82 Örebro, Sweden.
    Engwall, Magnus
    Örebro University, School of Science and Technology.
    A Novel Nanosafety Approach Using Cell Painting, Metabolomics, and Lipidomics Captures the Cellular and Molecular Phenotypes Induced by the Unintentionally Formed Metal-Based (Nano)Particles2023In: Cells, E-ISSN 2073-4409, Vol. 12, no 2, article id 281Article in journal (Refereed)
    Abstract [en]

    Additive manufacturing (AM) or industrial 3D printing uses cutting-edge technologies and materials to produce a variety of complex products. However, the effects of the unintentionally emitted AM (nano)particles (AMPs) on human cells following inhalation, require further investigations. The physicochemical characterization of the AMPs, extracted from the filter of a Laser Powder Bed Fusion (L-PBF) 3D printer of iron-based materials, disclosed their complexity, in terms of size, shape, and chemistry. Cell Painting, a high-content screening (HCS) assay, was used to detect the subtle morphological changes elicited by the AMPs at the single cell resolution. The profiling of the cell morphological phenotypes, disclosed prominent concentration-dependent effects on the cytoskeleton, mitochondria, and the membranous structures of the cell. Furthermore, lipidomics confirmed that the AMPs induced the extensive membrane remodeling in the lung epithelial and macrophage co-culture cell model. To further elucidate the biological mechanisms of action, the targeted metabolomics unveiled several inflammation-related metabolites regulating the cell response to the AMP exposure. Overall, the AMP exposure led to the internalization, oxidative stress, cytoskeleton disruption, mitochondrial activation, membrane remodeling, and metabolic reprogramming of the lung epithelial cells and macrophages. We propose the approach of integrating Cell Painting with metabolomics and lipidomics, as an advanced nanosafety methodology, increasing the ability to capture the cellular and molecular phenotypes and the relevant biological mechanisms to the (nano)particle exposure.

  • 4.
    Alves, Marina Amaral
    et al.
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Lamichhane, Santosh
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Dickens, Alex
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    McGlinchey, Aidan J
    Örebro University, School of Medical Sciences.
    Ribeiro, Henrique C.
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Sen, Partho
    Örebro University, School of Medical Sciences. Örebro University Hospital. Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Wei, Fang
    Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, Wuhan, P. R. China.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Systems biology approaches to study lipidomes in health and disease2021In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, ISSN 1388-1981, E-ISSN 1879-2618, Vol. 1866, no 2, article id 158857Article, review/survey (Refereed)
    Abstract [en]

    Lipids have many important biological roles, such as energy storage sources, structural components of plasma membranes and as intermediates in metabolic and signaling pathways. Lipid metabolism is under tight homeostatic control, exhibiting spatial and dynamic complexity at multiple levels. Consequently, lipid-related disturbances play important roles in the pathogenesis of most of the common diseases. Lipidomics, defined as the study of lipidomes in biological systems, has emerged as a rapidly-growing field. Due to the chemical and functional diversity of lipids, the application of a systems biology approach is essential if one is to address lipid functionality at different physiological levels. In parallel with analytical advances to measure lipids in biological matrices, the field of computational lipidomics has been rapidly advancing, enabling modeling of lipidomes in their pathway, spatial and dynamic contexts. This review focuses on recent progress in systems biology approaches to study lipids in health and disease, with specific emphasis on methodological advances and biomedical applications.

  • 5.
    Andersson, Linda
    et al.
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Cinato, Mathieu
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Mardani, Ismena
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Miljanovic, Azra
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Arif, Muhammad
    Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, Sweden.
    Koh, Ara
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Precision Medicine, School of Medicine, Sungkyunkwan University (SKKU), Suwon, Republic of Korea.
    Lindbom, Malin
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Laudette, Marion
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Bollano, Entela
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Omerovic, Elmir
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Klevstig, Martina
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Henricsson, Marcus
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Fogelstrand, Per
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Swärd, Karl
    Department of Experimental Medical Science, Lund University, Lund, Sweden.
    Ekstrand, Matias
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Levin, Max
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Wikström, Johannes
    Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Doran, Stephen
    Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Sinisalu, Lisanna
    Örebro University, School of Science and Technology.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Bioscience Centre, University of Turku, Turku, Finland.
    Tivesten, Åsa
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Adiels, Martin
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Bergo, Martin O.
    Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden.
    Proia, Richard
    National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD, USA.
    Mardinoglu, Adil
    Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK.
    Jeppsson, Anders
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Borén, Jan
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Levin, Malin C.
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking2021In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 42, no 43, p. 4481-4492Article in journal (Refereed)
    Abstract [en]

    AIMS: Cardiac injury and remodelling are associated with the rearrangement of cardiac lipids. Glycosphingolipids are membrane lipids that are important for cellular structure and function, and cardiac dysfunction is a characteristic of rare monogenic diseases with defects in glycosphingolipid synthesis and turnover. However, it is not known how cardiac glycosphingolipids regulate cellular processes in the heart. The aim of this study is to determine the role of cardiac glycosphingolipids in heart function.

    METHODS AND RESULTS: Using human myocardial biopsies, we showed that the glycosphingolipids glucosylceramide and lactosylceramide are present at very low levels in non-ischaemic human heart with normal function and are elevated during remodelling. Similar results were observed in mouse models of cardiac remodelling. We also generated mice with cardiomyocyte-specific deficiency in Ugcg, the gene encoding glucosylceramide synthase (hUgcg-/- mice). In 9- to 10-week-old hUgcg-/- mice, contractile capacity in response to dobutamine stress was reduced. Older hUgcg-/- mice developed severe heart failure and left ventricular dilatation even under baseline conditions and died prematurely. Using RNA-seq and cell culture models, we showed defective endolysosomal retrograde trafficking and autophagy in Ugcg-deficient cardiomyocytes. We also showed that responsiveness to β-adrenergic stimulation was reduced in cardiomyocytes from hUgcg-/- mice and that Ugcg knockdown suppressed the internalization and trafficking of β1-adrenergic receptors.

    CONCLUSIONS: Our findings suggest that cardiac glycosphingolipids are required to maintain β-adrenergic signalling and contractile capacity in cardiomyocytes and to preserve normal heart function.

  • 6.
    Aura, Anna-Marja
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Mattila, Ismo
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Espoo, Finland.
    Gopalacharyulu, Peddinti
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Bounsaythip, Catherine
    University of Helsinki, Helsinki, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland.
    Oksman-Caldentey, Kirsi-Marja
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Drug metabolome of the simvastatin formed by human intestinal microbiota in vitro2011In: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 7, no 2, p. 437-446Article in journal (Refereed)
    Abstract [en]

    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.

  • 7.
    Aura, Anna-Marja
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Mattila, Ismo
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Hyötyläinen, Tuulia
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Gopalacharyulu, Peddinti
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Cheynier, Veronique
    Sciences Pour l'œNologie, Institut national de la recherche agronomique (INRA), Montpellier, France.
    Souquet, Jean-Marc
    Sciences Pour l'œNologie, Institut national de la recherche agronomique (INRA), Montpellier, France.
    Bes, Magali
    Unité Expérimentale de Pech Rouge, Institut national de la recherche agronomique (INRA), Gruissan, France.
    Le Bourvellec, Carine
    Sécurité et Qualité des Produits d'Origine Végétale, Institut national de la recherche agronomique (INRA), Avignon, France.
    Guyot, Sylvain
    Cidricoles et Biotransformation des Fruits et Légumes, Institut national de la recherche agronomique (INRA), Le Rheu, France.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Characterization of microbial metabolism of Syrah grape products in an in vitro colon model using targeted and non-targeted analytical approaches2013In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 52, no 2, p. 833-846Article in journal (Refereed)
    Abstract [en]

    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.

  • 8.
    Blanc, Mélanie
    et al.
    Örebro University, School of Science and Technology.
    Alfonso, Sebastien
    MARBEC, Univ. Montpellier, CNRS, Ifremer, IRD, Route de Maguelone, Palavas-les-Flots, France; COISPA Tecnologia & Ricerca, Stazione Sperimentale per lo Studio delle Risorse del Mare, Italy.
    Begout, Marie-Laure
    MARBEC, Univ. Montpellier, CNRS, Ifremer, IRD, Route de Maguelone, Palavas-les-Flots, France.
    Barrachina, Celia
    MGX, Univ. Montpellier, CNRS, INSERM, Université Montpellier 2, Montpellier, France.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Keiter, Steffen H.
    Cousin, Xavier
    MARBEC, Univ. Montpellier, CNRS, Ifremer, IRD, Route de Maguelone, Palavas-les-Flots, France; Université Paris-Saclay, AgroParisTech, INRAE, GABI, Domaine de Vilvert, Jouy-en-Josas, France.
    An environmentally relevant mixture of polychlorinated biphenyls (PCBs) and polybrominated diphenylethers (PBDEs) disrupts mitochondrial function, lipid metabolism and neurotransmission in the brain of exposed zebrafish and their unexposed F2 offspring2021In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 754, article id 142097Article in journal (Refereed)
    Abstract [en]

    Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are persistent organic pollutants still present in aquatic environments despite their total or partial ban. Previously, we observed that an environmentally realistic mixture of these compounds affects energy balance, growth, and reproduction in exposed zebrafish (F0), and behavior in their unexposed offspring (F1-F4). In the present work, we performed lipidomic and transcriptomic analyses on brains of zebrafish (F0-F2) from exposed and control lineages to identify molecular changes that could explain the observed phenotypes. The use of both technologies highlighted that F0 zebrafish displayed impaired mitochondrial function and lipid metabolism regulation (depletion in triacylglycerols and phospholipids) which can explain disruption of energy homeostasis. A subset of the regulated biological pathways related to energetic metabolism and neurotransmission were inherited in 12. In addition, there were increasing effects on epigenetic pathways from the F0 to the F2 generation. Altogether, we show that the effects of an environmental exposure to PCBs and PBDEs on energetic metabolism as well as neurotransmission extend over 2 generations of zebrafish, possibly due to transgenerational epigenetic inheritance.

  • 9.
    Blanc, Mélanie
    et al.
    Örebro University, School of Science and Technology.
    Alfonso, Sébastien
    MARBEC, Univ. Montpellier, CNRS, Ifremer, IRD, Palavasles- Flots, France; COISPA Tecnologia & Ricerca, Stazione Sperimentale per lo Studio delle Risorse del Mare, Bari, Italy.
    Bégout, Marie-Laure
    MARBEC, Univ. Montpellier, CNRS, Ifremer, IRD, Palavasles- Flots, France.
    Barrachina, Célia
    MGX, Univ. Montpellier, CNRS, INSERM, Université Montpellier 2, Montpellier, France.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Keiter, Steffen
    Örebro University, School of Science and Technology.
    Cousin, Xavier
    MARBEC, Univ. Montpellier, CNRS, Ifremer, IRD, Palavasles- Flots, France; Université Paris-Saclay, AgroParisTech, INRAE, GABI, Domaine de Vilvert, Jouy-en-Josas, France.
    An environmentally relevant mixture of polychlorinated biphenyls (PCBs) and polybrominated diphenylethers (PBDEs) disrupts mitochondrial function, lipid metabolism and neurotransmission in exposed zebrafish and their unexposed F2 offspringManuscript (preprint) (Other academic)
  • 10.
    Blanc, Mélanie
    et al.
    Örebro University, School of Science and Technology.
    Cormier, Bettie
    Örebro University, School of Science and Technology. University of Bordeaux, EPOC UMR CNRS 5805, Pessac, France.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Krauss, Martin
    Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany.
    Scherbak, Nikolai
    Örebro University, School of Science and Technology. Örebro Life Science Centre, School of Science and Technology, Örebro University, Örebro, Sweden.
    Cousin, Xavier
    MARBEC, Univ. Montpellier, CNRS, Ifremer, IRD, Palavas-les-Flots, France; Univ. Paris-Saclay, AgroParisTech, INRAE, GABI, Jouy-en-Josas, France.
    Keiter, Steffen
    Örebro University, School of Science and Technology.
    Multi- and transgenerational effects following early-life exposure of zebrafish to permethrin and coumarin 47: impact on growth, fertility, behavior and lipid metabolismManuscript (preprint) (Other academic)
  • 11.
    Blanc, Mélanie
    et al.
    Örebro University, School of Science and Technology.
    Cormier, Bettie
    Örebro University, School of Science and Technology. University of Bordeaux, EPOC UMR CNRS, Pessac, France .
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Krauss, Martin
    Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany.
    Scherbak, Nikolai
    Örebro University, School of Science and Technology. Orebro Life Science Centre.
    Cousin, Xavier
    MARBEC, Univ. Montpellier, CNRS, Ifremer, IRD, Palavas-les-Flots, France; Univ. Paris-Saclay, AgroParisTech, INRAE, GABI, Jouy-en-Josas, France.
    Keiter, Steffen
    Örebro University, School of Science and Technology.
    Multi- and transgenerational effects following early-life exposure of zebrafish to permethrin and coumarin 47: Impact on growth, fertility, behavior and lipid metabolism2020In: Ecotoxicology and Environmental Safety, ISSN 0147-6513, E-ISSN 1090-2414, Vol. 205, article id 111348Article in journal (Refereed)
    Abstract [en]

    Transgenerational effects induced by environmental stressors are a threat to ecosystems and human health. However, there is still limited observation and understanding of the potential of chemicals to influence life outcomes over several generations. In the present study, we investigated the effects of two environmental contaminants, coumarin 47 and permethrin, on exposed zebrafish (FO) and their progeny (F1-F3). Coumarin 47 is commonly found in personal care products and dyes, whereas permethrin is used as a domestic and agricultural pyrethroid insecticide/insect repellent. Zebrafish (F0) were exposed during early development until 28 days post-fertilization and their progeny (F1-F3) were bred unexposed. On one hand, the effects induced by coumarin 47 suggest no multigenerational toxicity. On the other hand, we found that behavior of zebrafish larvae was significantly affected by exposure to permethrin in F1 to F3 generations with some differences depending on the concentration. This suggests persistent alteration of the neural or neuromuscular function. In addition, lipidomic analyses showed that permethrin treatment was partially correlated with lysophosphatidylcholine levels in zebrafish, an important lipid for neurodevelopment. Overall, these results stress out one of the most widely used pyrethroids can trigger long-term, multi- and possibly transgenerational changes in the nervous system of zebrafish. These neurobehavioral changes echo the effects observed under direct exposure to high concentrations of permethrin and therefore call for more research on mechanisms underlying effect inheritance.

  • 12.
    Bondia-Pons, Isabel
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland; Department of Food Science and Physiology, University of Navarra, Pamplona, Spain.
    Maukonen, Johanna
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Mattila, Ismo
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Rissanen, Aila
    Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.
    Saarela, Maria
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Kaprio, Jaakko
    Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; National Institute for Health and Welfare, Helsinki, Finland.
    Hakkarainen, Antti
    Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland.
    Lundbom, Jesper
    Department of Radiology, Hospital District of Helsinki and Uusimaa (HUS) Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland.
    Lundbom, Nina
    Department of Radiology, Hospital District of Helsinki and Uusimaa (HUS) Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Pietiläinen, Kirsi H.
    Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Metabolome and fecal microbiota in monozygotic twin pairs discordant for weight: a Big Mac challenge2014In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 9, p. 4169-4179Article in journal (Refereed)
    Abstract [en]

    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.

  • 13.
    Bondia-Pons, Isabel
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland; Department of Food Science and Physiology, Research Building, University of Navarra, Pamplona, Spain.
    Pöhö, Päivi
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Bozzetto, Lutgarda
    Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
    Vetrani, Claudia
    Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
    Patti, Lidia
    Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
    Aura, Anna-Marja
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Annuzzi, Giovanni
    Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Rivellese, Angela Albarosa
    Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Isoenergetic diets differing in their n-3 fatty acid and polyphenol content reflect different plasma and HDL-fraction lipidomic profiles in subjects at high cardiovascular risk2014In: Molecular Nutrition & Food Research, ISSN 1613-4125, E-ISSN 1613-4133, Vol. 58, no 9, p. 1873-1882Article in journal (Refereed)
    Abstract [en]

    SCOPE: Dysregulation of lipid homeostasis is related to multiple major healthcare problems. The aim of this study was to investigate the effects of n-3 fatty acid (FA) and polyphenol rich diets on plasma and HDL fraction lipidomic profiles in subjects at high cardiovascular risk.

    METHODS AND RESULTS: Ultra performance LC coupled to quadrupole TOF/MS mass spectrometry global lipidomic profiling was applied to plasma and HDL fraction from an 8 wk randomized intervention with four isoenergetic diets, differing in their natural n-3 FA and polyphenols content, in 78 subjects with a high BMI, abdominal obesity, and at least one other feature of the metabolic syndrome. Dependency network analysis showed a different pattern of associations between lipidomics, dietary, and clinical variables after the dietary interventions. The most remarkable associations between variables were observed after the diet high in n-3 FA and polyphenols, as the inverse association between gallic acid intake and LDL cholesterol levels, which was indirectly associated with a HDL cluster exclusively comprised lysophospholipids.

    CONCLUSION: This is the first human randomized controlled trial showing direct and indirect associations with lipid molecular species and clinical variables of interest in the evaluation of the metabolic syndrome after diets naturally rich in polyphenols.

  • 14.
    Bowden, John A.
    et al.
    Marine Biochemical Sciences Group, Chemical Sciences Division, Hollings Marine Laboratory, National Institute of Standards and Technology, Charleston SC, USA.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Hollings Marine Laboratory, Marine Biochemical Sciences Group, National Institute of Standards and Technology, Charleston SC, United States; Division of Laboratory Sciences, Centers for Disease Control and Prevention, Atlanta GA, United States.
    Zhou, Senlin
    Department of Chemistry and Biochemistry, Wayne State University, Detroit MI, USA.
    Harmonizing Lipidomics: NIST Interlaboratory Comparison Exercise for Lipidomics using Standard Reference Material 1950 Metabolites in Frozen Human Plasma2017In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 58, no 12, p. 2275-2288Article in journal (Refereed)
    Abstract [en]

    As the lipidomics field continues to advance, self-evaluation within the community is critical. Here, we performed an interlaboratory comparison exercise for lipidomics using Standard Reference Material (SRM) 1950 Metabolites in Frozen Human Plasma, a commercially available reference material. The interlaboratory study comprised 31 diverse laboratories, with each lab using a different lipidomics workflow. A total of 1527 unique lipids were measured across all laboratories, and consensus location estimates and associated uncertainties were determined for 339 of these lipids measured at the sum composition level by five or more participating laboratories. These evaluated lipids detected in SRM 1950 serve as community-wide benchmarks for intra- and inter-laboratory quality control and method validation. These analyses were performed using non-standardized laboratory-independent workflows. The consensus locations were also compared to a previous examination of SRM 1950 by the LIPID MAPS consortium. While the central theme of the interlaboratory study was to provide values to help harmonize lipids, lipid mediators, and precursor measurements across the community, it was also initiated to stimulate a discussion regarding areas in need of improvement.

  • 15.
    Brial, François
    et al.
    UMRS 1124 INSERM, Université de Paris Descartes, Paris, France.
    Chilloux, Julien
    Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
    Nielsen, Trine
    Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Kobenhavn, Denmark.
    Vieira-Silva, Sara
    Laboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.
    Falony, Gwen
    Laboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.
    Andrikopoulos, Petros
    Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK; National Heart & Lung Institute, Section of Genomic & Environmental Medicine, Imperial College London, London, UK.
    Olanipekun, Michael
    Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK; National Heart & Lung Institute, Section of Genomic & Environmental Medicine, Imperial College London, London, UK.
    Hoyles, Lesley
    Department of Biosciences, Nottingham Trent University, Nottingham, UK.
    Djouadi, Fatima
    Centre de Recherche des Cordeliers, Université Paris Descartes, Paris, France; Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Paris, France.
    Neves, Ana L.
    Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
    Rodriguez-Martinez, Andrea
    Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
    Mouawad, Ghiwa Ishac
    UMRS 1124 INSERM, Université de Paris Descartes, Paris, France.
    Pons, Nicolas
    Metagenopolis, INRAE, Paris, Île-de-France, France.
    Forslund, Sofia
    Forslund Lab, Max Delbrück Centrum für Molekulare Medizin Experimental and Clinical Research Center, Berlin, Berlin, Germany.
    Le-Chatelier, Emmanuelle
    Metagenopolis, INRAE, Paris, Île-de-France, France.
    Le Lay, Aurélie
    UMRS 1124 INSERM, Université de Paris Descartes, Paris, France.
    Nicholson, Jeremy
    Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
    Hansen, Torben
    Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Kobenhavn, Denmark.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Clément, Karine
    INSERM, U1166, team 6 Nutriomique, Université Pierre et Marie Curie-Paris 6, Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France.
    Oresic, Matej
    Örebro University, School of Medical Sciences.
    Bork, Peer
    Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
    Ehrlich, Stanislav Dusko
    Metagenopolis, INRAE, Paris, Île-de-France, France; Center for Host Microbiome Interactions, King's College London Dental Institute, London, UK.
    Raes, Jeroen
    Laboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium; Center for Microbiology, Vlaams Instituut voor Biotechnologie, Leuven, Belgium.
    Pedersen, Oluf Borbye
    Laboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium; Center for Microbiology, Vlaams Instituut voor Biotechnologie, Leuven, Belgium.
    Gauguier, Dominique
    UMRS 1124 INSERM, Université de Paris Descartes, Paris, France.
    Dumas, Marc-Emmanuel
    Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK; National Heart & Lung Institute, Section of Genomic & Environmental Medicine, Imperial College London, London, UK; McGill Genome Centre & Department of Human Genetics, McGill University, Montréal, Québec, Canada; European Genomics Institute for Diabetes, INSERM U1283, CNRS UMR8199, Institut Pasteur de Lille, Lille University Hospital, Unversity of Lille, Lille, France.
    Human and preclinical studies of the host-gut microbiome co-metabolite hippurate as a marker and mediator of metabolic health2021In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 70, no 11, p. 2105-2114Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Gut microbial products are involved in regulation of host metabolism. In human and experimental studies, we explored the potential role of hippurate, a hepatic phase 2 conjugation product of microbial benzoate, as a marker and mediator of metabolic health.

    DESIGN: In 271 middle-aged non-diabetic Danish individuals, who were stratified on habitual dietary intake, we applied 1H-nuclear magnetic resonance (NMR) spectroscopy of urine samples and shotgun-sequencing-based metagenomics of the gut microbiome to explore links between the urine level of hippurate, measures of the gut microbiome, dietary fat and markers of metabolic health. In mechanistic experiments with chronic subcutaneous infusion of hippurate to high-fat-diet-fed obese mice, we tested for causality between hippurate and metabolic phenotypes.

    RESULTS: In the human study, we showed that urine hippurate positively associates with microbial gene richness and functional modules for microbial benzoate biosynthetic pathways, one of which is less prevalent in the Bacteroides 2 enterotype compared with Ruminococcaceae or Prevotella enterotypes. Through dietary stratification, we identify a subset of study participants consuming a diet rich in saturated fat in which urine hippurate concentration, independently of gene richness, accounts for links with metabolic health. In the high-fat-fed mice experiments, we demonstrate causality through chronic infusion of hippurate (20 nmol/day) resulting in improved glucose tolerance and enhanced insulin secretion.

    CONCLUSION: Our human and experimental studies show that a high urine hippurate concentration is a general marker of metabolic health, and in the context of obesity induced by high-fat diets, hippurate contributes to metabolic improvements, highlighting its potential as a mediator of metabolic health.

  • 16.
    Castillo, S.
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Mattila, I.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Miettinen, J.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Hyötyläinen, Tuulia
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Data analysis tool for comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry2011In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 83, no 8, p. 3058-3067Article in journal (Refereed)
    Abstract [en]

    Data processing and identification of unknown compounds in comprehensive two-dimensional gas chromatography combined with time-of-flight mass spectrometry (GC x GC/TOFMS) analysis is a major challenge, particularly when large sample sets are analyzed. Herein, we present a method for efficient treatment of large data sets produced by GC x GC/TOFMS implemented as a freely available open source software package, Guineu. To handle large data sets and to efficiently utilize all the features available in the vendor software (baseline correction, mass spectral deconvolution, peak picking, integration, library search, and signal-to-noise filtering), data preprocessed by instrument software are used as a starting point for further processing. Our software affords alignment of the data, normalization, data filtering, and utilization of retention indexes in the verification of identification as well as a novel tool for automated group-type identification of the compounds. Herein, different features of the software are studied in detail and the performance of the system is verified by the analysis of a large set of standard samples as well as of a large set of authentic biological samples, including the control samples. The quantitative features of our GC x GC/TOFMS methodology are also studied to further demonstrate the method performance and the experimental results confirm the reliability of the developed procedure. The methodology has already been successfully used for the analysis of several thousand samples in the field of metabolomics.

  • 17.
    Castro Alves, Victor
    et al.
    Örebro University, School of Science and Technology.
    Kalbina, Irina
    Örebro University, School of Science and Technology.
    Nilsen, Asgeir
    Örebro University, School of Hospitality, Culinary Arts & Meal Science.
    Mats, Aronsson
    Svegro AB, Svartsjö, Sweden.
    Rosenqvist, Eva
    Section of Crop Sciences, Institute of Plant and Environmental Sciences, University of Copenhagen, Tåstrup, Denmark.
    Jansen, Marcel A K
    School of Biological, Earth and Environmental Sciences, Environmental Research Institute, University College Cork, North Mall, Cork, Ireland.
    Qian, Minjie
    School of Science and Technology, Örebro University, Örebro, Sweden.
    Öström, Åsa
    Örebro University, School of Hospitality, Culinary Arts & Meal Science.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Strid, Åke
    Örebro University, School of Science and Technology.
    Integration of non-target metabolomics and sensory analysis unravels vegetable plant metabolite signatures associated with sensory quality: A case study using dill (Anethum graveolens)2021In: Food Chemistry, ISSN 0308-8146, E-ISSN 1873-7072, Vol. 344, article id 128714Article in journal (Refereed)
    Abstract [en]

    Using dill (Anethum graveolens L.) as a model herb, we revealnovel associations between metabolite profile and sensory quality, by integrating non-target metabolomics with sensory data. Low night temperatures and exposure to UV-enriched light was used to modulate plant metabolism, thereby improving sensory quality. Plant age is a crucial factor associated with accumulation of dill ether and α-phellandrene, volatile compounds associated with dill flavour. However, sensory analysis showed that neither of these compounds has any strong association with dill taste. Rather, amino acids alanine, phenylalanine, glutamic acid, valine, and leucine increased in samples exposed to eustress and were positively associated with dill and sour taste. Increases in amino acids and organic acids changed the taste from lemon/grass to a more bitter/pungent dill-related taste. Our approach reveals a novel approach to establish links between effects of eustressors on sensory quality, and may be applicable to a broad range of crops.

    Download full text (pdf)
    Integration of non-target metabolomics and sensory analysis unravels vegetable plant metabolite signatures associated with sensory quality: A case study using dill (Anethum graveolens)
  • 18.
    Castro Alves, Victor
    et al.
    Örebro University, School of Science and Technology.
    Kalbina, Irina
    Örebro University, School of Science and Technology.
    Öström, Åsa
    Örebro University, School of Hospitality, Culinary Arts & Meal Science.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Strid, Åke
    Örebro University, School of Science and Technology.
    The taste of UV light: Using sensomics to improve horticultural quality2020In: UV4Plants Bulletin, ISSN 2343-323X, no 1, p. 5p. 39-43Article in journal (Refereed)
    Abstract [en]

    Greenhouse horticulture is in its broad definition the production of plant products within, under or sheltered by structures that provide protection against biotic and/or abiotic stress. In greenhouses, horticultural crops can grow protected from infectious agents and adverse weather conditions, allowing off-season, year-round production. However, greenhouse production often comes with a trade-off, which is a skewed light environment with a lack of UV light. 

    In some instances, the blockage of UV by greenhouse glass and plastic covers is beneficial from a commercial perspective, especially on tropical latitudes where plants can often encounter higher UV levels, which may impair plant growth and nutrient absorption (Krause et al. 1999; Verdaguer et al. 2017). On the other hand, reduced UV inside greenhouses may reduce the synthesis of metabolites associated with crop protection against biotic and abiotic stress, such as flavonoids, terpenoids and alkaloids (Yang et al. 2018). This reduction in the amount of protective compounds may not be seen as an important limitation in a protected environment, but these metabolic changes caused by reduced UV exposure may in fact negatively impact on product quality. For example, it is possible to improve of the aroma and taste of greenhouse tomato by exposing plants to low levels of supplementary UV light (Dzakovich et al. 2016).

    Download full text (pdf)
    The taste of UVlight: using sensomics to improve horticultural quality
  • 19.
    Castro Alves, Victor
    et al.
    Örebro University, School of Science and Technology.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Lipidomics in nutrition research2022In: Current opinion in clinical nutrition and metabolic care, ISSN 1363-1950, E-ISSN 1473-6519, Vol. 25, no 5, p. 311-318Article, review/survey (Refereed)
    Abstract [en]

    PURPOSE OF REVIEW: This review focuses on the recent findings from lipidomics studies as related to nutrition and health research.

    RECENT FINDINGS: Several lipidomics studies have investigated malnutrition, including both under- and overnutrition. Focus has been both on the early-life nutrition as well as on the impact of overfeeding later in life. Multiple studies have investigated the impact of different macronutrients in lipidome on human health, demonstrating that overfeeding with saturated fat is metabolically more harmful than overfeeding with polyunsaturated fat or carbohydrate-rich food. Diet rich in saturated fat increases the lipotoxic lipids, such as ceramides and saturated fatty-acyl-containing triacylglycerols, increasing also the low-density lipoprotein aggregation rate. In contrast, diet rich in polyunsaturated fatty acids, such as n-3 fatty acids, decreases the triacylglycerol levels, although some individuals are poor responders to n-3 supplementation.

    SUMMARY: The results highlight the benefits of lipidomics in clinical nutrition research, also providing an opportunity for personalized nutrition. An area of increasing interest is the interplay of diet, gut microbiome, and metabolome, and how they together impact individuals' responses to nutritional challenges.

  • 20.
    Dickens, Alex M.
    et al.
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Borgan, Faith
    Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK.
    Laurikainen, Heikki
    Department of Psychiatry, University of Turku, Turku, Finland; Turku PET Centre, Turku University Hospital, Turku, Finland.
    Lamichhane, Santosh
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Marques, Tiago
    Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK.
    Rönkkö, Tuukka
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Veronese, Mattia
    Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK.
    Lindeman, Tuomas
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Howes, Oliver
    Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK.
    Hietala, Jarmo
    Department of Psychiatry, University of Turku, Turku, Finland; Turku PET Centre, Turku University Hospital, Turku, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Links between central CB1-receptor availability and peripheral endocannabinoids in patients with first episode psychosis2020In: NPJ schizophrenia, E-ISSN 2334-265X, Vol. 6, no 1, article id 21Article in journal (Refereed)
    Abstract [en]

    There is an established, link between psychosis and metabolic abnormalities, such as altered glucose metabolism and dyslipidemia, which often precede the initiation of antipsychotic treatment. It is known that obesity-associated metabolic disorders are promoted by activation of specific cannabinoid targets (endocannabinoid system (ECS)). Our recent data suggest that there is a change in the circulating lipidome at the onset of first episode psychosis (FEP). With the aim of characterizing the involvement of the central and peripheral ECSs, and their mutual associations; here, we performed a combined neuroimaging and metabolomic study in patients with FEP and healthy controls (HC). Regional brain cannabinoid receptor type 1 (CB1R) availability was quantified in two, independent samples of patients with FEP (n = 20 and n = 8) and HC (n = 20 and n = 10), by applying three-dimensional positron emission tomography, using two radiotracers, [11C]MePPEP and [18F]FMPEP-d2. Ten endogenous cannabinoids or related metabolites were quantified in serum, drawn from these individuals during the same imaging session. Circulating levels of arachidonic acid and oleoylethanolamide (OEA) were reduced in FEP individuals, but not in those who were predominantly medication free. In HC, there was an inverse association between levels of circulating arachidonoyl glycerol, anandamide, OEA, and palmitoyl ethanolamide, and CB1R availability in the posterior cingulate cortex. This phenomenon was, however, not observed in FEP patients. Our data thus provide evidence of cross talk, and dysregulation between peripheral endocannabinoids and central CB1R availability in FEP.

  • 21.
    Dickens, Alex M.
    et al.
    Turku Bioscience Center, University of Turku and Åbo Akademi University, Turku, Finland.
    Sen, Partho
    Turku Bioscience Center, University of Turku and Åbo Akademi University, Turku, Finland.
    Kempton, Matthew J.
    Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Barrantes-Vidal, Neus
    Departament de Psicologia Clínica i de la Salut, Universitat Autònoma de Barcelona, Fundació Sanitària Sant Pere Claver, Spanish Mental Health Research Network, Barcelona, Spain.
    Iyegbe, Conrad
    Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Nordentoft, Merete
    Mental Health Center Copenhagen and Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Mental Health Center Glostrup, Mental Health Services in the Capital Region of Copenhagen, University of Copenhagen, Glostrup, Denmark.
    Pollak, Thomas
    Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Riecher-Rössler, Anita
    University Psychiatric Hospital, Basel, Switzerland.
    Ruhrmann, Stephan
    Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany.
    Sachs, Gabriele
    Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
    Bressan, Rodrigo
    Lab Interdisciplinar Neurociências Clínicas, Departimento Psiquiatria, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
    Krebs, Marie-Odile
    University of Paris, Groupe Hospitalier Universitaire Paris Sainte-Anne, Centre d'Évaluation Pour Jeunes Adultes et Adolescents, Institut National de la Santé et de la Recherche Médicale, Institut de Psychiatrie, Paris, France.
    Amminger, G. Paul
    Centre for Youth Mental Health, University of Melbourne, Parkville, Victoria, Australia.
    de Haan, Lieuwe
    Department of Psychiatry, Amsterdam University Medical Center, Faculty of Behavioural and Movement Sciences, Vrije Universiteit, Amsterdam, The Netherlands.
    van der Gaag, Mark
    Department of Clinical Psychology and EMGO+ Institute for Health and Care Research, Faculty of Behavioural and Movement Sciences, Vrije Universiteit, Amsterdam, The Netherlands; Department of Psychosis Research, Parnassia Psychiatric Institute, The Hague, The Netherlands.
    Valmaggia, Lucia
    Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Bioscience Center, University of Turku and Åbo Akademi University, Turku, Finland.
    McGuire, Philip
    Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Dysregulated Lipid Metabolism Precedes Onset of Psychosis2021In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 89, no 3, p. 288-297Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A key clinical challenge in the management of individuals at clinical high risk for psychosis (CHR) is that it is difficult to predict their future clinical outcomes. Here, we investigated if the levels of circulating molecular lipids are related to adverse clinical outcomes in this group.

    METHODS: Serum lipidomic analysis was performed in 263 CHR individuals and 51 healthy control subjects, who were then clinically monitored for up to 5 years. Machine learning was used to identify lipid profiles that discriminated between CHR and control subjects, and between subgroups of CHR subjects with distinct clinical outcomes.

    RESULTS: At baseline, compared with control subjects, CHR subjects (independent of outcome) had higher levels of triacylglycerols with a low acyl carbon number and a double bond count, as well as higher levels of lipids in general. CHR subjects who subsequently developed psychosis (n = 50) were distinguished from those that did not (n = 213) on the basis of lipid profile at baseline using a model with an area under the receiver operating curve of 0.81 (95% confidence interval = 0.69-0.93). CHR subjects who became psychotic had lower levels of ether phospholipids than CHR individuals who did not (p < .01).

    CONCLUSIONS: Collectively, these data suggest that lipidomic abnormalities predate the onset of psychosis and that blood lipidomic measures may be useful in predicting which CHR individuals are most likely to develop psychosis.

  • 22.
    Dickens, Alex Mountfort
    et al.
    Turku Centre for Biotechnology, University of Turku, Turku, Finland .
    Posti, Jussi P.
    Division of Clinical Neurosciences, Department of Rehabilitation and Brain Trauma, Turku University Hospital, Turku, Finland; Department of Neurology, University of Turku, Turku, Finland; Division of Clinical Neurosciences, Department of Neurosurgery, Turku University Hospital, Turku, Finland .
    Takala, Riikka Sk.
    Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, Turku, Finland .
    Ala-Seppälä, Henna Maria
    Department of Neurology,University of Turku, Turku, Finland .
    Mattila, Ismo
    Steno Diabetes Center AS, Gentofte, Denmark.
    Coles, Jonathan Coles
    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Frantzén, Janek
    Division of Clinical Neurosciences, Department of Rehabilitation and Brain Trauma, Turku University Hospital, Turku, Finland; Department of Neurology, University of Turku, Turku, Finland; Division of Clinical Neurosciences, Department of Neurosurgery,Turku University Hospital, Turku, Finland .
    Hutchinson, Peter John
    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Katila, Ari J.
    Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, Turku, Finland.
    Kyllönen, Anna
    Department of Neurology, University of Turku, Turku, Finland .
    Maanpää, Henna-Riikka
    Division of Clinical Neurosciences, Turku University Hospital, Turku, Finland.
    Newcombe, Virginia
    Division of Anaesthesia, Addenbrookes Hospital, University of Cambridge, Cambridge, United Kingdom of Great Britain and Norther Ireland.
    Outtrim, Joanne
    Division of Anaesthesia, Addenbrookes Hospital, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Tallus, Jussi
    Division of Anaesthesia, Addenbrooke's Hospital, Hills Road, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Carpenter, Keri
    Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Menon, David
    Head, Division of Anaesthesia, Addenbrooke's Hospital, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Tenovuo, Olli
    Division of Clinical Neurosciences, Department of Neurosurgery, Turku University Hospital, Turku, Finland; Department of Neurology, University of Turku, Turku, Finland .
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Centre for Biotechnology, University of Turku, Turku, Finland.
    Serum Metabolites Associated with Computed TomographyFindings after Traumatic Brain Injury2018In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 22, p. 2673-2683Article in journal (Refereed)
    Abstract [en]

    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.

  • 23.
    Djekic, Demir
    et al.
    Örebro University, School of Medical Sciences. Department of Cardiology.
    Pinto, Rui
    Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Henein, Michael
    Department of Public Health and Clinical Medicine, Umeå University and Heart Centre, Umeå, Sweden; Molecular and Clinic Research Institute, St George University, London, UK; Institute of Environment, Health and Physical Sciences, Brunel University, London, UK.
    Serum untargeted lipidomic profiling reveals dysfunction of phospholipid metabolism in subclinical coronary artery disease2019In: Vascular Health and Risk Management, ISSN 1176-6344, E-ISSN 1178-2048, Vol. 15, p. 123-135Article in journal (Refereed)
    Abstract [en]

    Purpose: Disturbed metabolism of cholesterol and triacylglycerols (TGs) carries increased risk for coronary artery calcification (CAC). However, the exact relationship between individual lipid species and CAC remains unclear. The aim of this study was to identify disturbances in lipid profiles involved in the calcification process, in an attempt to propose potential biomarker candidates.

    Patients and methods: We studied 70 patients at intermediate risk for coronary artery disease who had undergone coronary calcification assessment using computed tomography and Agatston coronary artery calcium score (CACS). Patients were divided into three groups: with no coronary calcification (NCC; CACS: 0; n=26), mild coronary calcification (MCC; CACS: 1-250; n=27), or severe coronary calcification (SCC; CACS: >250; n=17). Patients' serum samples were analyzed using liquid chromatography-mass spectrometry in an untargeted lipidomics approach.

    Results: We identified 103 lipids within the glycerolipid, glycerophospholipid, sphingolipid, and sterol lipid classes. After false discovery rate correction, phosphatidylcholine (PC)(16:0/20:4) in higher levels and PC(18:2/18:2), PC(36:3), and phosphatidylethanolamine(20:0/18:2) in lower levels were identified as correlates with SCC compared to NCC. There were no significant differences in the levels of individual TGs between the three groups; however, clustering the lipid profiles showed a trend for higher levels of saturated and monounsaturated TGs in SCC compared to NCC. There was also a trend for lower TG (49:2), TG(51:1), TG(54:5), and TG(56:8) levels in SCC compared to MCC.

    Conclusion: In this study we investigated the lipidome of patients with coronary calcification. Our results suggest that the calcification process may be associated with dysfunction in autophagy. The lipidomic biomarkers revealed in this study may aid in better assessment of patients with subclinical coronary artery disease.

  • 24.
    Djekic, Demir
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Cardiology.
    Shi, Lin
    School of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an, China; Division of Food and Nutrition Science, Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
    Calais, Fredrik
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Cardiology.
    Carlsson, Frida
    Division of Food and Nutrition Science, Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
    Landberg, Rikard
    Division of Food and Nutrition Science, Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden; Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Fröbert, Ole
    Örebro University, School of Medical Sciences. Department of Cardiology.
    Effects of a Lacto-Ovo-Vegetarian Diet on the Plasma Lipidome and Its Association with Atherosclerotic Burden in Patients with Coronary Artery Disease-A Randomized, Open-Label, Cross-over Study2020In: Nutrients, E-ISSN 2072-6643, Vol. 12, no 11, article id E3586Article in journal (Refereed)
    Abstract [en]

    A vegetarian diet has been associated with a lower risk of coronary artery disease (CAD). Plasma triacylglycerols, ceramides, and phosphatidylcholines may improve prediction of recurrent coronary events. We sought to investigate effects of a lacto-ovo-vegetarian diet (VD) on plasma lipidome in CAD patients and simultaneously assess associations of plasma lipids with the extent of coronary atherosclerotic burden. We analyzed 214 plasma lipids within glycerolipid, sphingolipid, and sterol lipid classes using lipidomics from a randomized controlled, crossover trial comprising 31 CAD patients on standard medical therapy. Subjects completed a four-week intervention with VD and isocaloric meat diet (MD), separated by a four-week washout period. The VD increased levels of 11 triacylglycerols and lowered 7 triacylglycerols, 21 glycerophospholipids, cholesteryl ester (18:0), and ceramide (d18:1/16:0) compared with MD. VD increased triacylglycerols with long-chain polyunsaturated fatty acyls while decreased triacylglycerols with saturated fatty acyls, phosphatidylcholines, and sphingomyelins than MD. The Sullivan extent score (SES) exhibited on coronary angiograms were inversely associated with triacylglycerols with long-chain unsaturated fatty acyls. Phosphatidylcholines that were lower with VD were positively associated with SES and the total number of stenotic lesions. The VD favorably changed levels of several lipotoxic lipids that have previously been associated with increased risk of coronary events in CAD patients.

  • 25.
    Fan, Yong
    et al.
    Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.
    Støving, René Klinkby
    Center for Eating Disorders, Odense University Hospital, and Research Unit for Medical Endocrinology, Mental Health Services in the Region of Southern Denmark, Open Patient data Explorative Network (OPEN) and Clinical Institute, University of Southern Denmark, Odense, Denmark.
    Berreira Ibraim, Samar
    Université Paris-Saclay, INRAE, MGP, Jouy-en-Josas, France.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Thirion, Florence
    Université Paris-Saclay, INRAE, MGP, Jouy-en-Josas, France.
    Arora, Tulika
    Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.
    Lyu, Liwei
    Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark; Department of Medicine, University of Copenhagen and Herlev-Gentofte University Hospital, Copenhagen, Denmark.
    Stankevic, Evelina
    Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.
    Hansen, Tue Haldor
    Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.
    Déchelotte, Pierre
    INSERM U1073 Research Unit and TargEDys, Rouen University, Rouen, France.
    Sinioja, Tim
    Örebro University, School of Science and Technology.
    Ragnarsdottir, Oddny
    School of Science and Technology, Örebro University, Örebro, Sweden.
    Pons, Nicolas
    Université Paris-Saclay, INRAE, MGP, Jouy-en-Josas, France.
    Galleron, Nathalie
    Université Paris-Saclay, INRAE, MGP, Jouy-en-Josas, France.
    Quinquis, Benoît
    Université Paris-Saclay, INRAE, MGP, Jouy-en-Josas, France.
    Levenez, Florence
    Université Paris-Saclay, INRAE, MGP, Jouy-en-Josas, France.
    Roume, Hugo
    Université Paris-Saclay, INRAE, MGP, Jouy-en-Josas, France.
    Falony, Gwen
    Laboratory of Molecular bacteriology, Department of Microbiology and Immunology, Rega Institute Ku Leuven, Leuven, Belgium; Center for Microbiology, VIB, Leuven, Belgium; Institute of Medical Microbiology and Hygiene and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Institute of Molecular Biology (IMB), Mainz, Germany.
    Vieira-Silva, Sara
    Laboratory of Molecular bacteriology, Department of Microbiology and Immunology, Rega Institute Ku Leuven, Leuven, Belgium; Center for Microbiology, VIB, Leuven, Belgium; Institute of Medical Microbiology and Hygiene and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Institute of Molecular Biology (IMB), Mainz, Germany.
    Raes, Jeroen
    Laboratory of Molecular bacteriology, Department of Microbiology and Immunology, Rega Institute Ku Leuven, Leuven, Belgium; Center for Microbiology, VIB, Leuven, Belgium.
    Clausen, Loa
    Department of Child and Adolescent Psychiatry, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark.
    Telléus, Gry Kjaersdam
    Unit for Psychiatric Research, Aalborg University Hospital, Aalborg, Denmark; Department of Communication and Psychology, The Faculty of Social Sciences and Humanities, Aalborg University, Aalborg, Denmark.
    Bäckhed, Fredrik
    Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark; The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Clinical Physiology, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Ehrlich, S. Dusko
    Université Paris-Saclay, INRAE, MGP, Jouy-en-Josas, France; Department of Clinical and Movement Neurosciences, University College London, London, UK.
    Pedersen, Oluf
    Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark; Department of Medicine, University of Copenhagen and Herlev-Gentofte University Hospital, Copenhagen, Denmark.
    The gut microbiota contributes to the pathogenesis of anorexia nervosa in humans and mice2023In: Nature Microbiology, E-ISSN 2058-5276, Vol. 8, no 5, p. 787-802Article in journal (Refereed)
    Abstract [en]

    Anorexia nervosa (AN) is an eating disorder with a high mortality. About 95% of cases are women and it has a population prevalence of about 1%, but evidence-based treatment is lacking. The pathogenesis of AN probably involves genetics and various environmental factors, and an altered gut microbiota has been observed in individuals with AN using amplicon sequencing and relatively small cohorts. Here we investigated whether a disrupted gut microbiota contributes to AN pathogenesis. Shotgun metagenomics and metabolomics were performed on faecal and serum samples, respectively, from a cohort of 77 females with AN and 70 healthy females. Multiple bacterial taxa (for example, Clostridium species) were altered in AN and correlated with estimates of eating behaviour and mental health. The gut virome was also altered in AN including a reduction in viral-bacterial interactions. Bacterial functional modules associated with the degradation of neurotransmitters were enriched in AN and various structural variants in bacteria were linked to metabolic features of AN. Serum metabolomics revealed an increase in metabolites associated with reduced food intake (for example, indole-3-propionic acid). Causal inference analyses implied that serum bacterial metabolites are potentially mediating the impact of an altered gut microbiota on AN behaviour. Further, we performed faecal microbiota transplantation from AN cases to germ-free mice under energy-restricted feeding to mirror AN eating behaviour. We found that the reduced weight gain and induced hypothalamic and adipose tissue gene expression were related to aberrant energy metabolism and eating behaviour. Our 'omics' and mechanistic studies imply that a disruptive gut microbiome may contribute to AN pathogenesis.

  • 26.
    Fang, Wei
    et al.
    Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, Wuhan, Hubei, PR China.
    Santosh, Lamichhane
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, Wuhan, Hubei, PR China; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Lipidomes in health and disease: Analytical strategies and considerations2019In: TrAC. Trends in analytical chemistry, ISSN 0165-9936, E-ISSN 1879-3142, Vol. 120, article id 115664Article, review/survey (Refereed)
    Abstract [en]

    Lipidomics is a rapidly-growing field which focuses on global characterization of lipids at molecular and systems levels. As small changes in the concentrations of lipids may have important physiological consequences, much attention in the field has recently been paid to more accurate quantitation and identification of lipids. Community-wide efforts have been initiated, aiming to develop best practices for lipidomic analyses and reporting of lipidomic data. Nevertheless, current approaches for comprehensive analysis of lipidomes have some inherent challenges and limitations. Additionally, there is, currently, limited knowledge concerning the impacts of various external and internal exposures on lipid levels. In this review, we discuss the recent progress in lipidomics analysis, with a primary focus on analytical approaches, as well as on the different sources of variation in quantifying lipid levels, both technical and biological.

    Download full text (pdf)
    Lipidomes in health and disease: Analytical strategies and considerations
  • 27.
    Fart, Frida
    et al.
    Örebro University, School of Medical Sciences.
    Salihovic, Samira
    Örebro University, School of Medical Sciences. Örebro University, School of Science and Technology.
    McGlinchey, Aidan J
    Örebro University, School of Medical Sciences.
    Gareau, Melanie G.
    Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA, USA.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Schoultz, Ida
    Örebro University, School of Medical Sciences.
    Perfluoroalkyl substances are increased in patients with late-onset ulcerative colitis and induce intestinal barrier defects ex vivo in murine intestinal tissue2021In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 56, no 11, p. 1286-1295Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Environmental factors are strongly implicated in late-onset of inflammatory bowel disease. Here, we investigate whether high levels of perfluoroalkyl substances are associated with (1) late-onset inflammatory bowel disease, and (2) disturbances of the bile acid pool. We further explore the effect of the specific perfluoroalkyl substance perfluorooctanoic acid on intestinal barrier function in murine tissue.

    METHODS: Serum levels of perfluoroalkyl substances and bile acids were assessed by ultra-performance liquid chromatography coupled to a triple-quadrupole mass spectrometer in matched samples from patients with ulcerative colitis (n = 20) and Crohn's disease (n = 20) diagnosed at the age of ≥55 years. Age and sex-matched blood donors (n = 20), were used as healthy controls. Ex vivo Ussing chamber experiments were performed to assess the effect of perfluorooctanoic acid on ileal and colonic murine tissue (n = 9).

    RESULTS: The total amount of perfluoroalkyl substances was significantly increased in patients with ulcerative colitis compared to healthy controls and patients with Crohn's disease (p < .05). Ex vivo exposure to perfluorooctanoic acid induced a significantly altered ileal and colonic barrier function. The distribution of bile acids, as well as the correlation pattern between (1) perfluoroalkyl substances and (2) bile acids, differed between patient and control groups.

    DISCUSSION: Our results demonstrate that perfluoroalkyl substances levels are increased in patients with late-onset ulcerative colitis and may contribute to the disease by inducing a dysfunctional intestinal barrier.

  • 28.
    Fart, Frida
    et al.
    Örebro University, School of Medical Sciences.
    Salihovic, Samira
    Örebro University, School of Medical Sciences.
    McGlinchey, Aidan J
    Örebro University, School of Medical Sciences.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Schoultz, Ida
    Örebro University, School of Medical Sciences.
    Per- and polyfluoroalkyl substances (PFAS) are significantly increased in patients with late-onset of ulcerative colitis2020In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 14, no Suppl. 1, p. S138-S139Article in journal (Other academic)
  • 29.
    Foerster, Jana
    et al.
    Department of Epidemiology, German Institute of Human Nutrition Potsdam–Rehbruecke, Nuthetal, Germany.
    Hyötyläinen, Tuulia
    Systems Medicine, Steno Diabetes Centre, Gentofte, Denmark.
    Oresic, Matej
    Systems Medicine, Steno Diabetes Centre, Gentofte, Denmark.
    Nygren, Heli
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Boeing, Heiner
    Department of Epidemiology, German Institute of Human Nutrition Potsdam–Rehbruecke, Nuthetal, Germany.
    Serum Lipid and Serum Metabolite Components in relation to anthropometric parameters in EPIC-Potsdam participants2015In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 64, no 10, p. 1348-58Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/AIM: Lipidomic and metabolomic techniques become more and more important in human health research. Recent developments in analytical techniques enable the investigation of high amounts of substances. The high numbers of metabolites and lipids that are detected with among others mass spectrometric techniques challenge in most cases the statistical processes to bring out stable and interpretable results. This study targets to use the novel non-established statistical method treelet transform (TT) to investigate high numbers of metabolites and lipids and to compare the results with the established method principal component analysis (PCA). Serum lipid and metabolite profiles are investigated regarding their association to anthropometric parameters associated to obesity.

    METHODS: From 226 participants of the EPIC (European Prospective Investigation into Cancer and Nutrition)-Potsdam study blood samples were investigated with an untargeted metabolomics approach regarding serum metabolites and lipids. Additionally, participants were surveyed anthropometrically to assess parameters of obesity, such as body mass index (BMI), waist-to-hip-ratio (WHR) and body fat mass. TT and PCA are used to generate treelet components (TCs) and factors summarizing serum metabolites and lipids in new, latent variables without too much loss of information. With partial correlations TCs and factors were associated to anthropometry under the control for relevant parameters, such as sex and age.

    RESULTS: TT with metabolite variables (p=121) resulted in 5 stable and interpretable TCs explaining 18.9% of the variance within the data. PCA on the same variables generated 4 quite complex, less easily interpretable factors explaining 37.5% of the variance. TT on lipidomic data (p=353) produced 3 TCs as well as PCA on the same data resulted in 3 factors; the proportion of explained variance was 17.8% for TT and 39.8% for PCA. In both investigations TT ended up with stable components that are easier to interpret than the factors from the PCA. In general, the generated TCs and factors were similar in their structure when the factors are considered regarding the original variables loading high on them. Both TCs and factors showed associations to anthropometric measures.

    CONCLUSIONS: TT is a suitable statistical method to generate summarizing, latent variables in data sets with more variables than observations. In the present investigation it resulted in similar latent variables compared to the established method of PCA. Whereby less variance is explained by the summarizing constructs of TT compared to the factors of PCA, TCs are easier to interpret. Additionally the resulting TCs are quite stable in bootstrap samples.

  • 30.
    Frank, Elisabeth
    et al.
    Biomax Informatics AB, Planegg, Germany.
    Maier, Dieter
    Biomax Informatics AB, Planegg, Germany.
    Pajula, Juha
    VTT Technical Research Centre of Finland Ltd., Tampere, Finland.
    Suvitaival, Tommi
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Borgan, Faith
    Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK.
    Butz-Ostendorf, Markus
    Biomax Informatics AB, Planegg, Germany.
    Fischer, Alexander
    Philips GmbH Innovative Technologies, Aachen, Germany.
    Hietala, Jarmo
    Department of Psychiatry, University of Turku, Turku, Finland; Turku PET Centre, Turku University Hospital, Turku, Finland.
    Howes, Oliver
    Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. Department of Chemistry, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Janssen, Joost
    Child and Adolescent Psychiatry Department, School of Medicine, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Investigación Sanitaria del Hospital Gregorio Marañón (IISGM), Madrid, Spain.
    Laurikainen, Heikki
    Department of Psychiatry, University of Turku, Turku, Finland; Turku PET Centre, Turku University Hospital, Turku, Finland.
    Moreno, Carmen
    Child and Adolescent Psychiatry Department, School of Medicine, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Investigación Sanitaria del Hospital Gregorio Marañón (IISGM), Madrid, Spain.
    Suvisaari, Jaana
    National Institute for Health and Welfare (THL), Helsinki, Finland.
    Van Gils, Mark
    VTT Technical Research Centre of Finland Ltd.,Tampere, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Centre for Biotechnology, University of Turku, Turku, Finland; Åbo Akademi University, Turku, Finland.
    Platform for systems medicine research and diagnostic applications in psychotic disorders - The METSY project2018In: European psychiatry, ISSN 0924-9338, E-ISSN 1778-3585, Vol. 50, p. 40-46Article in journal (Refereed)
    Abstract [en]

    Psychotic disorders are associated with metabolic abnormalities including alterations in glucose and lipid metabolism. A major challenge in the treatment of psychosis is to identify patients with vulnerable metabolic profiles who may be at risk of developing cardiometabolic co-morbidities. It is established that both central and peripheral metabolic organs use lipids to control energy balance and regulate peripheral insulin sensitivity. The endocannabinoid system, implicated in the regulation of glucose and lipid metabolism, has been shown to be dysregulated in psychosis. It is currently unclear how these endocannabinoid abnormalities relate to metabolic changes in psychosis. Here we review recent research in the field of metabolic co-morbidities in psychotic disorders as well as the methods to study them and potential links to the endocannabinoid system. We also describe the bioinformatics platforms developed in the EU project METSY for the investigations of the biological etiology in patients at risk of psychosis and in first episode psychosis patients. The METSY project was established with the aim to identify and evaluate multi-modal peripheral and neuroimaging markers that may be able to predict the onset and prognosis of psychiatric and metabolic symptoms in patients at risk of developing psychosis and first episode psychosis patients. Given the intrinsic complexity and widespread role of lipid metabolism, a systems biology approach which combines molecular, structural and functional neuroimaging methods with detailed metabolic characterisation and multi-variate network analysis is essential in order to identify how lipid dysregulation may contribute to psychotic disorders. A decision support system, integrating clinical, neuropsychological and neuroimaging data, was also developed in order to aid clinical decision making in psychosis. Knowledge of common and specific mechanisms may aid the etiopathogenic understanding of psychotic and metabolic disorders, facilitate early disease detection, aid treatment selection and elucidate new targets for pharmacological treatments.

  • 31.
    Geng, Dawei
    et al.
    Örebro University, School of Science and Technology.
    Musse, Ayan Au
    School of Science and Technology, Örebro University, Örebro, Sweden.
    Wigh, Viktoria
    School of Science and Technology, Örebro University, Örebro, Sweden.
    Carlsson, Cecilia
    School of Science and Technology, Örebro University, Örebro, Sweden.
    Engwall, Magnus
    Örebro University, School of Science and Technology.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Scherbak, Nikolai
    Örebro University, School of Science and Technology.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Effect of perfluorooctanesulfonic acid (PFOS) on the liver lipid metabolism of the developing chicken embryo2019In: Ecotoxicology and Environmental Safety, ISSN 0147-6513, E-ISSN 1090-2414, Vol. 170, p. 691-698Article in journal (Refereed)
    Abstract [en]

    Perfluorooctanesulfonate (PFOS) is a well-known contaminant in the environment and it has shown to disrupt multiple biological pathways, particularly those related with lipid metabolism. In this study, we have studied the impact of in ovo exposure to PFOS on lipid metabolism in livers in developing chicken embryos using lipidomics for detailed characterization of the liver lipidome. We used an avian model (Gallus gallus domesticus) for in ovo treatment at two levels of PFOS. The lipid profile of the liver of the embryo was investigated by ultra-high performance liquid chromatography combined with quadrupole-time-of-flight mass spectrometry and by gas chromatography mass spectrometry. Over 170 lipids were identified, covering phospholipids, ceramides, di- and triacylglycerols, cholesterol esters and fatty acid composition of the lipids. The PFOS exposure caused dose dependent changes in the lipid levels, which included upregulation of specific phospholipids associated with the phosphatidylethanolamine N-methyltransferase (PEMT) pathway, triacylglycerols with low carbon number and double bond count as well as of lipotoxic ceramides and diacylglycerols. Our data suggest that at lower levels of exposure, mitochondrial fatty acid β-oxidation is suppressed while the peroxisomal fatty acid β -oxidation is increased. At higher doses, however, both β -oxidation pathways are upregulated.

  • 32.
    Greiner, Thomas U.
    et al.
    Department of Molecular and Clinical Medicine, Institute of Medicine, Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Gothenburg, Sweden.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Knip, Mikael
    Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland; Folkhälsan Research Center, Helsinki, Finland; Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
    Bäckhed, Fredrik
    Department of Molecular and Clinical Medicine, Institute of Medicine, Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    The gut microbiota modulates glycaemic control and serum metabolite profiles in non-obese diabetic mice2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 11, article id e110359Article in journal (Refereed)
    Abstract [en]

    Islet autoimmunity in children who later progress to type 1 diabetes is preceded by dysregulated serum metabolite profiles, but the origin of these metabolic changes is unknown. The gut microbiota affects host metabolism and changes in its composition contribute to several immune-mediated diseases; however, it is not known whether the gut microbiota is involved in the early metabolic disturbances in progression to type 1 diabetes. We rederived non-obese diabetic (NOD) mice as germ free to explore the potential role of the gut microbiota in the development of diabetic autoimmunity and to directly investigate whether the metabolic profiles associated with the development of type 1 diabetes can be modulated by the gut microbiota. The absence of a gut microbiota in NOD mice did not affect the overall diabetes incidence but resulted in increased insulitis and levels of interferon gamma and interleukin 12; these changes were counterbalanced by improved peripheral glucose metabolism. Furthermore, we observed a markedly increased variation in blood glucose levels in the absence of a microbiota in NOD mice that did not progress to diabetes. Additionally, germ-free NOD mice had a metabolite profile similar to that of pre-diabetic children. Our data suggest that germ-free NOD mice have reduced glycaemic control and dysregulated immunologic and metabolic responses.

  • 33.
    Grip, Tove
    et al.
    Clinical Sciences/Pediatrics, Umeå University, Umeå, Sweden.
    Dyrlund, Thomas S.
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Ahonen, Linda
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Domellöf, Magnus
    Clinical Sciences/Pediatrics, Umeå University, Umeå, Sweden.
    Hernell, Olle
    Clinical Sciences/Pediatrics, Umeå University, Umeå, Sweden.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. Department of Chemistry.
    Knip, Mikael
    Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; Folkhälsan Research Institute, Helsinki, Finland.
    Lönnerdal, Bo
    Department of Nutrition, University of California, Davis, United States.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Centre for Biotechnology, University of Turku and Åbo Academy University, Turku, Finland.
    Timby, Niklas
    Clinical Sciences/Pediatrics, Umeå University, Umeå, Sweden.
    Serum, plasma and erythrocyte membrane lipidomes in infants fed formula supplemented with bovine milk fat globule membranes2018In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 84, no 5, p. 726-732Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Supplementation of formula with bovine milk fat globule membranes has been shown to narrow the gap in immunological and cognitive development between breast-fed and formula-fed infants.

    METHOD: In a double-blinded randomized controlled trial 160 formula-fed infants received an experimental formula (EF), supplemented with bovine milk fat globule membranes, or standard formula until 6 months of age. A breast-fed reference group was recruited. Lipidomic analyses were performed on plasma and erythrocyte membranes at 6 months and on serum at 4 and 12 months of age.

    RESULTS: At 6 months of age, we observed a significant separation in the plasma lipidome between the two formula groups, mostly due to differences in concentrations of sphingomyelins (SM), phosphatidylcholines (PC), and ceramides, and in the erythrocyte membrane lipidome, mostly due to SMs, PEs and PCs. Already at 4 months, a separation in the serum lipidome was evident where SMs and PCs contributed. The separation was not detected at 12 months.

    CONCLUSIONS: The effect of MFGM supplementation on the lipidome is likely part of the mechanisms behind the positive cognitive and immunological effects of feeding the EF previously reported in the same study population.

  • 34.
    Götz, Alexandra
    et al.
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Tyynismaa, Henna
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Euro, Liliya
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Ellonen, Pekka
    Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
    Hyötyläinen, Tuulia
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Ojala, Tiina
    Department of Pediatric Cardiology, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.
    Hämäläinen, Riikka H
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Tommiska, Johanna
    Institute of Biomedicine, Department of Physiology, University of Helsinki, Helsinki, Finland; Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland g.
    Raivio, Taneli
    Institute of Biomedicine, Department of Physiology, University of Helsinki, Helsinki, Finland; Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland.
    Karikoski, Riitta
    Department of Pathology, University of Helsinki, Helsinki, Finland; Helsinki University Central Hospital, Helsinki, Finland.
    Tammela, Outi
    Pediatric Research Centre, Tampere University Hospital, Tampere, Finland.
    Simola, Kalle O J
    Genetics Outpatient Clinic, Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
    Paetau, Anders
    Department of Pathology, University of Helsinki, Helsinki, Finland; Helsinki University Central Hospital, Helsinki, Finland.
    Tyni, Tiina
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland; Department of Pediatric Neurology, Helsinki University Central Hospital, Helsinki, Finland.
    Suomalainen, Anu
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
    Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy2011In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 88, no 5, p. 635-642Article in journal (Refereed)
    Abstract [en]

    Infantile cardiomyopathies are devastating fatal disorders of the neonatal period or the first year of life. Mitochondrial dysfunction is a common cause of this group of diseases, but the underlying gene defects have been characterized in only a minority of cases, because tissue specificity of the manifestation hampers functional cloning and the heterogeneity of causative factors hinders collection of informative family materials. We sequenced the exome of a patient who died at the age of 10 months of hypertrophic mitochondrial cardiomyopathy with combined cardiac respiratory chain complex I and IV deficiency. Rigorous data analysis allowed us to identify a homozygous missense mutation in AARS2, which we showed to encode the mitochondrial alanyl-tRNA synthetase (mtAlaRS). Two siblings from another family, both of whom died perinatally of hypertrophic cardiomyopathy, had the same mutation, compound heterozygous with another missense mutation. Protein structure modeling of mtAlaRS suggested that one of the mutations affected a unique tRNA recognition site in the editing domain, leading to incorrect tRNA aminoacylation, whereas the second mutation severely disturbed the catalytic function, preventing tRNA aminoacylation. We show here that mutations in AARS2 cause perinatal or infantile cardiomyopathy with near-total combined mitochondrial respiratory chain deficiency in the heart. Our results indicate that exome sequencing is a powerful tool for identifying mutations in single patients and allows recognition of the genetic background in single-gene disorders of variable clinical manifestation and tissue-specific disease. Furthermore, we show that mitochondrial disorders extend to prenatal life and are an important cause of early infantile cardiac failure.

  • 35.
    Ha, V. T.
    et al.
    National Institute of Chemistry, Ljubljana, Slovenia.
    Lainscek, D.
    National Institute of Chemistry, Ljubljana, Slovenia.
    Gesslbauer, B.
    University of Graz, Graz, Austria.
    Jarc, E.
    Jozef Stefan Institute, Ljubljana, Slovenia.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Ilc, N.
    University of Ljubljana, Ljubljana, Slovenia.
    Lakota, K.
    University Medical Centre Ljubljana, Ljubljana, Slovenia.
    Tomsic, M.
    University Medical Centre Ljubljana, Ljubljana, Slovenia.
    van de Loo, F. A.
    Radboud University Medical Center, Nijmegen, Netherlands.
    Bochkov, V.
    University of Graz, Graz, Austria.
    Petan, T.
    Jozef Stefan Institute, Ljubljana, Slovenia.
    Jerala, R.
    National Institute of Chemistry, Ljubljana, Slovenia.
    Keber, M. Mancek
    National Institute of Chemistry, Ljubljana, Slovenia.
    Synergy between 15-lipoxygenase and secreted PLA2 promotes inflammation by formation of TLR4 agonists from extracellular vesicles2021In: FEBS Open Bio, E-ISSN 2211-5463, Vol. 11, no Suppl. 1, p. 480-480Article in journal (Other academic)
    Abstract [en]

    Damage assoiated molecular patterns (DAMPs) are endogenous ligands that induce innate immune response, thus promoting sterile inflammation. During oxidative stress, stress-derived EVs (stressEVs) were found to activate Toll-like receptor 4 (TLR4), but the activating ligands were not fully determined. Additionally, several enzymes such as 15-lipoxygenase (15-LO) and secreted phospholipase A2 (sPLA2) are induced during inflammation and were suggested to promote DAMP formation. Stress-EVs were produced from HEK293 exposed to 10uM A23187 and isolated with ultracentrifugation. 20:4 lysoPI was oxidized for 10 min with 15-LO. SynEVs were prepared from phospholipids (PLs), oxidized with 15-LO and hydrolyzed with sPLA2. Activity was measured by qPCR and ELISA on wt and KO cells. Ox 20:4 lysoPI was analyzed by MS. sPLA2 activity was measured in synovial fluid from patients using fluorometric assay. K/BxN serum transfer induced arthritis model on wt and TLR4 KO mice(C57Bl/6 mice) with sPLA2-IIA injection was performed. StressEVs released after oxidative stress were found to activate TLR4with a gene profile different from agonist lipopolysaccharide. StressEVs, 15-LO oxidized synEVs, but only 15-LO oxidized lysoPLs activated cytokine expression through TLR4/MD-2.Hydroxy, hydroperoxy and keto products of 20:4 lysoPI oxidation were determined by MS and they activated the same gene pattern as stressEVs. Furthermore, sPLA2 activity, which we detected in the SF from patients, promoted formation of TLR4 agonists after 15-LO oxidation. Injection of sPLA2-IIA into mice promoted K/BxN serum induced arthritis in TLR4-dependent manner. Both 15-LO and sPLA2 are induced during inflammation, therefore these results imply the role of oxidized lysoPLs in stressEVs in promoting sterile inflammation through TLR4 signaling. The formation of TLR4 agonists is enzyme driven so it provides an opportunity for therapy without compromising innate immunity against pathogens (Ha VT. et al., PNAS 2020).

  • 36.
    Ha, Van Thai
    et al.
    Department of Synthetic Biology and Immunology, National Institute of Chemistry, Ljubljana, Slovenia; Graduate School of Biomedicine, University of Ljubljana, Ljubljana, Slovenia.
    Lainšček, Duško
    Department of Synthetic Biology and Immunology, National Institute of Chemistry, Ljubljana, Slovenia; Excellent NMR Future Innovation for Sustainable Technologies (EN-FIST), Centre of Excellence, Ljubljana, Slovenia.
    Gesslbauer, Bernd
    Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria.
    Jarc-Jovičić, Eva
    Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Ljubljana, Slovenia.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Ilc, Nejc
    Faculty of Computer and Information Science, University of Ljubljana, Ljubljana, Slovenia.
    Lakota, Katja
    Department of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia; Faculty of Mathematics, Natural Science and Information Technologies, University of Primorska, Koper, Slovenia.
    Tomšič, Matija
    Department of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
    van de Loo, Fons A. J.
    Department of Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
    Bochkov, Valery
    Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria.
    Petan, Toni
    Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Ljubljana, Slovenia.
    Jerala, Roman
    Department of Synthetic Biology and Immunology, National Institute of Chemistry, Ljubljana, Slovenia; Excellent NMR Future Innovation for Sustainable Technologies (EN-FIST), Centre of Excellence, Ljubljana, Slovenia.
    Manček-Keber, Mateja
    Department of Synthetic Biology and Immunology, National Institute of Chemistry, Ljubljana, Slovenia; Excellent NMR Future Innovation for Sustainable Technologies (EN-FIST), Centre of Excellence, Ljubljana, Slovenia.
    Synergy between 15-lipoxygenase and secreted PLA(2) promotes inflammation by formation of TLR4 agonists from extracellular vesicles2020In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 117, no 41, p. 25679-25689Article in journal (Refereed)
    Abstract [en]

    Damage-associated endogenous molecules induce innate immune response, thus making sterile inflammation medically relevant. Stress-derived extracellular vesicles (stressEVs) released during oxidative stress conditions were previously found to activate Toll-like receptor 4 (TLR4), resulting in expression of a different pattern of immune response proteins in comparison to lipopolysaccharide (LPS), underlying the differences between pathogen-induced and sterile inflammation. Here we report that synergistic activities of 15-lipoxygenase (15-LO) and secreted phospholipase A2 (sPLA2) are needed for the formation of TLR4 agonists, which were identified as lysophospholipids (lysoPLs) with oxidized unsaturated acyl chain. Hydroxy, hydroperoxy, and keto products of 2-arachidonoyl-lysoPI oxidation by 15-LO were identified by mass spectrometry (MS), and they activated the same gene pattern as stressEVs. Extracellular PLA2 activity was detected in the synovial fluid from rheumatoid arthritis and gout patients. Furthermore, injection of sPLA2 promoted K/BxN serum-induced arthritis in mice, whereby ankle swelling was partially TLR4 dependent. Results confirm the role of oxidized lysoPL of stressEVs in sterile inflammation that promotes chronic diseases. Both 15-LO and sPLA2 enzymes are induced during inflammation, which opens the opportunity for therapy without compromising innate immunity against pathogens.

  • 37.
    Hartonen, Minna
    et al.
    VTT Technical Research Centre of Finland, Helsiniki, Finland.
    Mattila, Ismo
    VTT Technical Research Centre of Finland, Helsiniki, Finland.
    Ruskeepää, Anna-Liisa
    VTT Technical Research Centre of Finland, Helsiniki, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Helsiniki, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Helsiniki, Finland.
    Characterization of cerebrospinal fluid by comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry2013In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1293, p. 142-149, article id S0021-9673(13)00567-0Article in journal (Refereed)
    Abstract [en]

    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.

  • 38.
    Havula, Essi
    et al.
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland; Department of Biosciences, University of Helsinki, Helsinki, Finland.
    Teesalu, Mari
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland; Department of Biosciences, University of Helsinki, Helsinki, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Espoo, Finland.
    Seppälä, Heini
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland; Department of Biosciences, University of Helsinki, Helsinki, Finland.
    Hasygar, Kiran
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland; Department of Biosciences, University of Helsinki, Helsinki, Finland.
    Auvinen, Petri
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Sandmann, Thomas
    German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Hietakangas, Ville
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland; Department of Biosciences, University of Helsinki, Helsinki, Finland.
    Mondo/ChREBP-Mlx-regulated transcriptional network is essential for dietary sugar tolerance in Drosophila2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 4, article id e1003438Article in journal (Refereed)
    Abstract [en]

    Sugars are important nutrients for many animals, but are also proposed to contribute to overnutrition-derived metabolic diseases in humans. Understanding the genetic factors governing dietary sugar tolerance therefore has profound biological and medical significance. Paralogous Mondo transcription factors ChREBP and MondoA, with their common binding partner Mlx, are key sensors of intracellular glucose flux in mammals. Here we report analysis of the in vivo function of Drosophila melanogaster Mlx and its binding partner Mondo (ChREBP) in respect to tolerance to dietary sugars. Larvae lacking mlx or having reduced mondo expression show strikingly reduced survival on a diet with moderate or high levels of sucrose, glucose, and fructose. mlx null mutants display widespread changes in lipid and phospholipid profiles, signs of amino acid catabolism, as well as strongly elevated circulating glucose levels. Systematic loss-of-function analysis of Mlx target genes reveals that circulating glucose levels and dietary sugar tolerance can be genetically uncoupled: Krüppel-like transcription factor Cabut and carbonyl detoxifying enzyme Aldehyde dehydrogenase type III are essential for dietary sugar tolerance, but display no influence on circulating glucose levels. On the other hand, Phosphofructokinase 2, a regulator of the glycolysis pathway, is needed for both dietary sugar tolerance and maintenance of circulating glucose homeostasis. Furthermore, we show evidence that fatty acid synthesis, which is a highly conserved Mondo-Mlx-regulated process, does not promote dietary sugar tolerance. In contrast, survival of larvae with reduced fatty acid synthase expression is sugar-dependent. Our data demonstrate that the transcriptional network regulated by Mondo-Mlx is a critical determinant of the healthful dietary spectrum allowing Drosophila to exploit sugar-rich nutrient sources.

  • 39.
    Helle, Anne
    et al.
    Laboratory of Analytical Chemistry, Department of Chemistry, University of Helsinki, Helsinki, Finland.
    Hirsjärvi, Samuli
    Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
    Peltonen, Leena
    Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
    Hirvonen, Jouni
    Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
    Wiedmer, Susanne K.
    Laboratory of Analytical Chemistry, Department of Chemistry, University of Helsinki, Helsinki, Finland.
    Hyötyläinen, Tuulia
    Quantitative Biology and Bioinformatics, VTT Technical Research Centre of Finland, Espoo, Finland.
    Novel, dynamic on-line analytical separation system for dissolution of drugs from poly(lactic acid) nanoparticles2010In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 51, no 1, p. 125-130Article in journal (Refereed)
    Abstract [en]

    A novel method for investigating drug release in a dynamic manner from nanoparticles including, but not limited to, biodegradable poly(lactic acid) (PLA) is reported. The PLA nanoparticles were prepared by the nanoprecipitation method. Two poorly soluble drugs, beclomethasone dipropionate (BDP) and indomethacin, were encapsulated into PLA nanoparticles, and their dissolution from the nanoparticles were followed in a dynamic way. The on-line method comprised a short column (vessel) packed with the PLA nanoparticles, on-line connected to an analytical liquid chromatographic column via a multiport switching valve equipped with two loops. The system allowed monitoring of the drug release profiles in real time, and the conditions for the drug release could be precisely controlled and easily changed. The effects of solvent composition and temperature on the rate of dissolution of the drugs from the PLA nanoparticles were investigated. The system proved to be linear for the drugs tested over the concentration range 10-3000 ng (n = 6, R(2) = 0.999 and 0.997 for indomethacin and beclomethasone, respectively) and repeatable (RSD of peak areas <0.5%). The recoveries of the dissolution study were quantitative (120 and 103% for indomethacin and beclomethasone, respectively).

  • 40.
    Hernández-Alvarez, María Isabel
    et al.
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain; Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain.
    Sebastián, David
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
    Vives, Sara
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Ivanova, Saška
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
    Bartoccioni, Paola
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; CIBERER, Instituto de Salud Carlos III, Madrid, Spain.
    Kakimoto, Pamela
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departamento de Bioquímica, Instituto de Química, Universidad de São Paulo, São Paulo, Brazil.
    Plana, Natalia
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Veiga, Sónia R.
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departamento de Bioquímica, Instituto de Química, Universidad de São Paulo, São Paulo, Brazil.
    Hernández, Vanessa
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Vasconcelos, Nuno
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Peddinti, Gopal
    VTT Technical Research Center of Finland, Espoo, Finland.
    Adrover, Anna
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Jové, Mariona
    Department of Experimental Medicine, University of Lleida-Lleida Biomedical Research Institute (UdL-IRBLleida), Lleida, Spain.
    Pamplona, Reinald
    Department of Experimental Medicine, University of Lleida-Lleida Biomedical Research Institute (UdL-IRBLleida), Lleida, Spain.
    Gordaliza-Alaguero, Isabel
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
    Calvo, Enrique
    Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain.
    Cabré, Noemí
    Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; Universitat Rovira i Virgili, Department of Medicine and Surgery, Reus, Spain; Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Reus, Spain.
    Castro, Rui
    Research Institute for Medicines (iMed.ULisboa), and Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal.
    Kuzmanic, Antonija
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Boutant, Marie
    Nestlé Institute of Health Sciences SA, Lausanne, Switzerland.
    Sala, David
    Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Oresic, Matej
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Fort, Joana
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBERER, Instituto de Salud Carlos III, Madrid, Spain.
    Errasti-Murugarren, Ekaitz
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Rodrígues, Cecilia M. P.
    Research Institute for Medicines (iMed.ULisboa), and Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal.
    Orozco, Modesto
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Joven, Jorge
    Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; Universitat Rovira i Virgili, Department of Medicine and Surgery, Reus, Spain; Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Reus, Spain.
    Cantó, Carles
    Nestlé Institute of Health Sciences SA, Lausanne, Switzerland.
    Palacin, Manuel
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBERER, Instituto de Salud Carlos III, Madrid, Spain.
    Fernández-Veledo, Sonia
    Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain; Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain.
    Vendrell, Joan
    Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain; Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain; Universitat Rovira i Virgili, Tarragona, Spain.
    Zorzano, Antonio
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
    Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease2019In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 177, no 4, p. 881-895.e17Article in journal (Refereed)
    Abstract [en]

    Non-alcoholic fatty liver is the most common liver disease worldwide. Here, we show that the mitochondrial protein mitofusin 2 (Mfn2) protects against liver disease. Reduced Mfn2 expression was detected in liver biopsies from patients with non-alcoholic steatohepatitis (NASH). Moreover, reduced Mfn2 levels were detected in mouse models of steatosis or NASH, and its re-expression in a NASH mouse model ameliorated the disease. Liver-specific ablation of Mfn2 in mice provoked inflammation, triglyceride accumulation, fibrosis, and liver cancer. We demonstrate that Mfn2 binds phosphatidylserine (PS) and can specifically extract PS into membrane domains, favoring PS transfer to mitochondria and mitochondrial phosphatidylethanolamine (PE) synthesis. Consequently, hepatic Mfn2 deficiency reduces PS transfer and phospholipid synthesis, leading to endoplasmic reticulum (ER) stress and the development of a NASH-like phenotype and liver cancer. Ablation of Mfn2 in liver reveals that disruption of ER-mitochondrial PS transfer is a new mechanism involved in the development of liver disease.

  • 41.
    Herzig, Merja
    et al.
    Faculty of Nuclear Sciences and Physical Engineering, Department of Nuclear Chemistry, Czech Technical University in Prague, Prague, Czech Republic; Radiochemistry Unit, Faculty of Science, Department of Chemistry, University of Helsinki, Helsinki, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. ´.
    Vettese, Gianni F.
    Radiochemistry Unit, Faculty of Science, Department of Chemistry, University of Helsinki, Helsinki, Finland.
    Law, Gareth T. W.
    Radiochemistry Unit, Faculty of Science, Department of Chemistry, University of Helsinki, Helsinki, Finland.
    Vierinen, Taavi
    Radiochemistry Unit, Faculty of Science, Department of Chemistry, University of Helsinki, Helsinki, Finland.
    Bomberg, Malin
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Altering environmental conditions induce shifts in simulated deep terrestrial subsurface bacterial communities-Secretion of primary and secondary metabolites2023In: Environmental Microbiology, ISSN 1462-2912, E-ISSN 1462-2920Article in journal (Refereed)
    Abstract [en]

    The deep terrestrial subsurface (DTS) harbours a striking diversity of microorganisms. However, systematic research on microbial metabolism, and how varying groundwater composition affects the bacterial communities and metabolites in these environments is lacking. In this study, DTS groundwater bacterial consortia from two Fennoscandian Shield sites were enriched and studied. We found that the enriched communities from the two sites consisted of distinct bacterial taxa, and alterations in the growth medium composition induced changes in cell counts. The lack of an exogenous organic carbon source (ECS) caused a notable increase in lipid metabolism in one community, while in the other, carbon starvation resulted in low overall metabolism, suggesting a dormant state. ECS supplementation increased CO2 production and SO4 2- utilisation, suggesting activation of a dissimilatory sulphate reduction pathway and sulphate-reducer-dominated total metabolism. However, both communities shared common universal metabolic features, most probably involving pathways needed for the maintenance of cell homeostasis (e.g., mevalonic acid pathway). Collectively, our findings indicate that the most important metabolites related to microbial reactions under varying growth conditions in enriched DTS communities include, but are not limited to, those linked to cell homeostasis, osmoregulation, lipid biosynthesis and degradation, dissimilatory sulphate reduction and isoprenoid production.

  • 42.
    Hilvo, Mika
    et al.
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Denkert, Carsten
    Institute of Pathology, Berlin, Germany.
    Lehtinen, Laura
    Bio and Process Technology, VTT Technical Research Centre of Finland, Turku, Finland.
    Müller, Berit
    Institute of Pathology, Berlin, Germany.
    Brockmöller, Scarlet
    Institute of Pathology, Berlin, Germany.
    Seppänen-Laakso, Tuulikki
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Budczies, Jan
    Institute of Pathology, Berlin, Germany.
    Bucher, Elmar
    Bio and Process Technology, VTT Technical Research Centre of Finland, Turku, Finland.
    Yetukuri, Laxman
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Castillo, Sandra
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Berg, Emilia
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Nygren, Heli
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Sysi-Aho, Marko
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Griffin, Julian L.
    Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
    Fiehn, Oliver
    Genome Center, University of California, Davis CA, United States.
    Loibl, Sibylle
    German Breast Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
    Richter-Ehrenstein, Christiane
    cBreast Cancer Center, Charité University Hospital, Berlin, Germany.
    Radke, Cornelia
    Institute of Pathology, DRK Klinikum Berlin Köpenick, Berlin, Germany.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Kallioniemi, Olli
    Bio and Process Technology, VTT Technical Research Centre of Finland, Turku, Finland.
    Iljin, Kristiina
    Bio and Process Technology, VTT Technical Research Centre of Finland, Turku, Finland.
    Oresic, Matej
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Novel theranostic opportunities offered by characterization of altered membrane lipid metabolism in breast cancer progression2011In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 71, no 9, p. 3236-45Article in journal (Refereed)
    Abstract [en]

    Activation of lipid metabolism is an early event in carcinogenesis and a central hallmark of many cancers. However, the precise molecular composition of lipids in tumors remains generally poorly characterized. The aim of the present study was to analyze the global lipid profiles of breast cancer, integrate the results to protein expression, and validate the findings by functional experiments. Comprehensive lipidomics was conducted in 267 human breast tissues using ultraperformance liquid chromatography/ mass spectrometry. The products of de novo fatty acid synthesis incorporated into membrane phospholipids, such as palmitate-containing phosphatidylcholines, were increased in tumors as compared with normal breast tissues. These lipids were associated with cancer progression and patient survival, as their concentration was highest in estrogen receptor-negative and grade 3 tumors. In silico transcriptomics database was utilized in investigating the expression of lipid metabolism related genes in breast cancer, and on the basis of these results, the expression of specific proteins was studied by immunohistochemistry. Immunohistochemical analyses showed that several genes regulating lipid metabolism were highly expressed in clinical breast cancer samples and supported also the lipidomics results. Gene silencing experiments with seven genes [ACACA (acetyl-CoA carboxylase α), ELOVL1 (elongation of very long chain fatty acid-like 1), FASN (fatty acid synthase), INSIG1 (insulin-induced gene 1), SCAP (sterol regulatory element-binding protein cleavage-activating protein), SCD (stearoyl-CoA desaturase), and THRSP (thyroid hormone-responsive protein)] indicated that silencing of multiple lipid metabolism-regulating genes reduced the lipidomic profiles and viability of the breast cancer cells. Taken together, our results imply that phospholipids may have diagnostic potential as well as that modulation of their metabolism may provide therapeutic opportunities in breast cancer treatment.

  • 43.
    Hilvo, Mika
    et al.
    Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland Espoo, Espoo, Finland.
    Gade, Stephan
    German Breast Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland Espoo, Espoo, Finland.
    Nekljudova, Valentina
    German Breast Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
    Seppänen-Laakso, Tuulikki
    Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland Espoo, Espoo, Finland.
    Sysi-Aho, Marko
    Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland Espoo, Espoo, Finland.
    Untch, Michael
    Department of Gynecology and Obstetrics, Helios Klinikum Berlin-Buch, Berlin, Germany.
    Huober, Jens
    Department of Gynecology, University of Ulm, Ulm, Germany.
    von Minckwitz, Gunter
    German Breast Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
    Denkert, Carsten
    Department of Gynecology and Obstetrics, Helios Klinikum Berlin-Buch, Berlin, Germany.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland Espoo, Espoo, Finland.
    Loibl, Sibylle
    German Breast Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
    Monounsaturated fatty acids in serum triacylglycerols are associated with response to neoadjuvant chemotherapy in breast cancer patients2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 134, no 7, p. 1725-1733Article in journal (Refereed)
    Abstract [en]

    Changes in cellular lipid metabolism are a common feature in most solid tumors, which occur already in early stages of the tumor progression. However, it remains unclear if the tumor-specific lipid changes can be detected at the level of systemic lipid metabolism. The objective of this study was to perform comprehensive analysis of lipids in breast cancer patient serum samples. Lipidomic profiling using an established analytical platform was performed in two cohorts of breast cancer patients receiving neoadjuvant chemotherapy. The analyses were performed for 142 patients before and after neoadjuvant chemotherapy, and the results before chemotherapy were validated in an independent cohort of 194 patients. The analyses revealed that in general the tumor characteristics are not reflected in the serum samples. However, there was an association of specific triacylglycerols (TGs) in patients' response to chemotherapy. These TGs containing mainly oleic acid (C18:1) were found in lower levels in those patients showing pathologic complete response before receiving chemotherapy. Some of these TGs were also associated with estrogen receptor status and overall or disease-free survival of the patients. The results suggest that the altered serum levels of oleic acid in breast cancer patients are associated with their response to chemotherapy.

  • 44.
    Holster, S.
    et al.
    Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Geng, D.
    Faculty of Business, Science and Engineering, School of Science and Technology, Örebro University, Örebro, Sweden.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Salonen, A.
    Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
    Lindqvist, Carl Mårten
    Örebro University, School of Medical Sciences.
    Rajan, Sukithar K
    Örebro University, School of Medical Sciences.
    De Vos, W. M.
    Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Laboratory of Microbiology, Wageningen University and Research Centre, Wageningen, The Netherlands.
    Brummer, Robert Jan
    Örebro University, School of Medical Sciences.
    König, Julia
    Örebro University, School of Medical Sciences.
    Correlations between microbiota and metabolites after faecal microbiota transfer in irritable bowel syndromeManuscript (preprint) (Other academic)
  • 45.
    Holster, S.
    et al.
    Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Geng, D.
    Faculty of Business, Science and Engineering, School of Science and Technology, Örebro University, Örebro, Sweden.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Salonen, A.
    Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
    Lindqvist, Carl Mårten
    Örebro University, School of Medical Sciences.
    Rajan, Sukithar K
    Örebro University, School of Medical Sciences.
    de Vos, W. M.
    Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Laboratory of Microbiology, Wageningen University and Research Centre, Wageningen, the Netherlands.
    Brummer, Robert Jan
    Örebro University, School of Medical Sciences.
    König, Julia
    Örebro University, School of Medical Sciences.
    Correlations between microbiota and metabolites after faecal microbiota transfer in irritable bowel syndrome2021In: Beneficial Microbes, ISSN 1876-2883, E-ISSN 1876-2891, Vol. 12, no 1, p. 17-30Article in journal (Refereed)
    Abstract [en]

    Faecal microbiota transfer (FMT) consists of the infusion of donor faecal material into the intestine of a patient with the aim to restore a disturbed gut microbiota. In this study, it was investigated whether FMT has an effect on faecal microbial composition, its functional capacity, faecal metabolite profiles and their interactions in 16 irritable bowel syndrome (IBS) patients. Faecal samples from eight different time points before and until six months after allogenic FMT (faecal material from a healthy donor) as well as autologous FMT (own faecal material) were analysed by 16S RNA gene amplicon sequencing and gas chromatography coupled to mass spectrometry (GS-MS). The results showed that the allogenic FMT resulted in alterations in the microbial composition that were detectable up to six months, whereas after autologous FMT this was not the case. Similar results were found for the functional profiles, which were predicted from the phylogenetic sequencing data. While both allogenic FMT as well as autologous FMT did not have an effect on the faecal metabolites measured in this study, correlations between the microbial composition and the metabolites showed that the microbe-metabolite interactions seemed to be disrupted after allogenic FMT compared to autologous FMT. This shows that FMT can lead to altered interactions between the gut microbiota and its metabolites in IBS patients. Further research should investigate if and how this affects efficacy of FMT treatments.

  • 46.
    Holster, Savanne
    et al.
    Örebro University, School of Medical Sciences.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Geng, Dawei
    Science and Engineering, School of Science and Technology, Örebro University, Sweden.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Lindqvist, Carl Mårten
    Örebro University, School of Medical Sciences.
    de Vos, W.
    Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Laboratory of Microbiology, Wageningen University and Research Centre, Wageningen, The Netherlands.
    Brummer, Robert Jan
    Örebro University, School of Medical Sciences.
    König, Julia
    Örebro University, School of Medical Sciences.
    Faecal microbiota transfer in irritable bowel syndrome results inaltered correlations between the gut microbiota and its metabolitesManuscript (preprint) (Other academic)
  • 47.
    Hukkanen, J.
    et al.
    University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland.
    Puurunen, J.
    University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland.
    Hyötyläinen, Tuulia
    Steno Diabetes Center, Gentofte, Denmark.
    Savolainen, M. J.
    University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland.
    Ruokonen, A.
    University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland.
    Morin-Papunen, L.
    University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland.
    Oresic, Matej
    Steno Diabetes Center, Gentofte, Denmark.
    Piltonen, T.
    University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland.
    Tapanainen, J. S.
    University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland; University of Helsinki, Helsinki, Finland; Helsinki University Hospital, Helsinki, Finland.
    The effect of atorvastatin treatment on serum oxysterol concentrations and cytochrome P450 3A4 activity2015In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 80, no 3, p. 473-479Article in journal (Refereed)
    Abstract [en]

    Aims: Atorvastatin is known to both inhibit and induce the cytochrome P450 3A4 (CYP3A4) enzyme in vitro. Some clinical studies indicate that atorvastatin inhibits CYP3A4 but there are no well-controlled longer term studies that could evaluate the inducing effect of atorvastatin. We aimed to determine if atorvastatin induces or inhibits CYP3A4 activity as measured by the 4β-hydroxycholesterol to cholesterol ratio (4βHC : C).

    Methods: In this randomized, double-blind, placebo-controlled 6 month study we evaluated the effects of atorvastatin 20mg day1 (n=15) and placebo (n = 14) on oxysterol concentrations and determined if atorvastatin induces or inhibits CYP3A4 activity as assessed by the 4βHC : C index. The respective 25-hydroxycholesterol and 5α,6α- epoxycholesterol ratios were used as negative controls.

    Results: Treatment with atorvastatin decreased 4βHC and 5α,6α-epoxycholesterol concentrations by 40% and 23%, respectively. The mean 4βHC : C ratio decreased by 13% (0.214 ± 0.04 to 0.182 ± 0.04, P = 0.024, 95% confidence interval (CI) of the difference –0.0595, –0.00483) in the atorvastatin group while no significant change occurred in the placebo group. The difference in change of 4βHC : C between study arms was statistically significant (atorvastatin –0.032, placebo 0.0055, P = 0.020, 95% CI of the difference – 0.069, –0.0067). The ratios of 25-hydroxycholesterol and 5α,6α- epoxycholesterol to cholesterol did not change.

    Conclusions: The results establish atorvastatin as an inhibitor of CYP3A4 activity.

    Furthermore, 4βHC : C is a useful index of CYP3A4 activity, including the

    conditions with altered cholesterol concentrations.

  • 48.
    Hylén, Ulrika
    et al.
    Örebro University, School of Medical Sciences. University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Sweden; Inflammatory Response and Infection Susceptibility Centre, (iRiSC), Örebro University, Örebro, Sweden.
    McGlinchey, Aidan J
    Örebro University, School of Medical Sciences.
    Oresic, Matej
    Örebro University, School of Medical Sciences.
    Bejerot, Susanne
    Örebro University, School of Medical Sciences. University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Sweden; Inflammatory Response and Infection Susceptibility Centre, (iRiSC), Örebro University, Örebro, Sweden.
    Humble, Mats B.
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre, (iRiSC), Örebro University, Örebro, Sweden.
    Särndahl, Eva
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre, (iRiSC), Örebro University, Örebro, Sweden.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Eklund, Daniel
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre, (iRiSC), Örebro University, Örebro, Sweden.
    Potential Transdiagnostic Lipid Mediators of Inflammatory Activity in Individuals With Serious Mental Illness2021In: Frontiers in Psychiatry, E-ISSN 1664-0640, Vol. 12, article id 778325Article in journal (Refereed)
    Abstract [en]

    Mental disorders are heterogeneous and psychiatric comorbidities are common. Previous studies have suggested a link between inflammation and mental disorders. This link can manifest as increased levels of proinflammatory mediators in circulation and as signs of neuroinflammation. Furthermore, there is strong evidence that individuals suffering from psychiatric disorders have increased risk of developing metabolic comorbidities. Our group has previously shown that, in a cohort of low-functioning individuals with serious mental disorders, there is increased expression of genes associated with the NLRP3 inflammasome, a known sensor of metabolic perturbations, as well as increased levels of IL-1-family cytokines. In the current study, we set out to explore the interplay between disease-specific changes in lipid metabolism and known markers of inflammation. To this end, we performed mass spectrometry-based lipidomic analysis of plasma samples from low-functioning individuals with serious mental disorders (n = 39) and matched healthy controls (n = 39). By identifying non-spurious immune-lipid associations, we derived a partial correlation network of inflammatory markers and molecular lipids. We identified levels of lipids as being altered between individuals with serious mental disorders and controls, showing associations between lipids and inflammatory mediators, e.g., osteopontin and IL-1 receptor antagonist. These results indicate that, in low-functioning individuals with serious mental disorders, changes in specific lipids associate with immune mediators that are known to affect neuroinflammatory diseases.

  • 49.
    Hylén, Ulrika
    et al.
    Örebro University, School of Medical Sciences. University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Sweden; Inflammatory Response and Infection Susceptibility Centre, (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Särndahl, Eva
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre, (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Bejerot, Susanne
    Örebro University, School of Medical Sciences. University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Sweden.
    Humble, Mats B.
    Örebro University, School of Medical Sciences.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Eklund, Daniel
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre, (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Salihovic, Samira
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre, (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Man-Technology-Environment Research Center, School of Science and Technology, Örebro University, Sweden.
    Elevated plasma levels of polyamines and kynurenines in individuals with psychiatric disordersManuscript (preprint) (Other academic)
  • 50.
    Hylén, Ulrika
    et al.
    Örebro University, School of Medical Sciences. University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Sweden; Inflammatory Response and Infection Susceptibility Centre, (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Särndahl, Eva
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre, (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Bejerot, Susanne
    Örebro University, School of Medical Sciences. University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Sweden.
    Humble, Mats B.
    Örebro University, School of Medical Sciences.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Salihovic, Samira
    Örebro University, School of Medical Sciences. Man-Technology-Environment Research Center, School of Science and Technology, Örebro University, Sweden.
    Individuals with severe psychiatric disorders display altered pattern of plasma immunometabolitesManuscript (preprint) (Other academic)
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