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  • 1.
    Ali, Imran
    et al.
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Julin, Bettina
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Glynn, Anders
    The National Food Agency, Uppsala, Sweden.
    Högberg, Johan
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Berglund, Marika
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Johansson, Jan-Erik
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden; Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden; Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Giovannucci, Edward
    Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston MA, United States; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston MA, United States; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA, United States.
    Wolk, Alicja
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Stenius, Ulla
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Åkesson, Agneta
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Exposure to polychlorinated biphenyls and prostate cancer: population-based prospective cohort and experimental studies2016In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 37, no 12, p. 1144-1151Article in journal (Refereed)
    Abstract [en]

    Polychlorinated biphenyls (PCBs) are highly persistent environmental pollutants and are undesirable components of our daily food. PCBs are classified as human carcinogens, but the evidence for prostate cancer is limited and available data are inconsistent. We explored the link between non-dioxin-like PCB and grade of prostate cancer in a prospective cohort as well as in cell experiments. A population-based cohort of 32496 Swedish men aged 45-79 years was followed prospectively through 1998-2011, to assess the association between validated estimates of dietary PCB exposure and incidence of prostate cancer by grade (2789 cases, whereof 1276 low grade, 756 intermediate grade, 450 high grade) and prostate cancer mortality (357 fatal cases). In addition, we investigated a non-dioxin-like PCB153-induced cell invasion and related markers in normal prostate stem cells (WPE-stem) and in three different prostate cancer cell lines (PC3, DU145 and 22RV1) at exposure levels relevant to humans. After multivariable-adjustment, dietary PCB exposure was positively associated with high-grade prostate cancer, relative risk (RR) 1.35 [95% confidence interval (CI): 1.03-1.76] and with fatal prostate cancer, RR 1.43 (95% CI: 1.05-1.95), comparing the highest tertile with the lowest. We observed no association with low or intermediate grade of prostate cancer. Cell invasion and related markers, including MMP9, MMP2, Slug and Snail, were significantly increased in human prostate cancer cells as well as in prostate stem cells after exposure to PCB153. Our findings both from the observational and experimental studies suggest a role of non-dioxin-like PCB153 in the development of high-grade and fatal prostate cancer.

  • 2.
    Barbarroja, Nuria
    et al.
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
    Rodriguez-Cuenca, Sergio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Nygren, Heli
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Camargo, Antonio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Lipids and Atherosclerosis Research Unit, Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
    Pirraco, Ana
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, Porto, Portugal.
    Relat, Joana
    Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain.
    Cuadrado, Irene
    Departamento de Farmacología, Universidad Complutense de Madrid, Madrid, Spain.
    Pellegrinelli, Vanessa
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Medina-Gomez, Gema
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Lopez-Pedrera, Chary
    Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
    Tinahones, Francisco J.
    CIBER in Physiopathology of Obesity and Nutrition (CB06/03), Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigación Biomédica de Málaga, Hospital Virgen de la Victoria, Malaga, Spain.
    Symons, J. David
    College of Health, University of Utah, Salt Lake City UT, United States; Division of Endocrinology, Metabolism, and Diabetes, University of Utah, Salt Lake City UT, United States.
    Summers, Scott A.
    Program in Cardiovascular and Metabolic Disorders, Duke-National University, Singapore Graduate Medical School, Singapore, Singapore.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Vidal-Puig, Antonio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Increased dihydroceramide/ceramide ratio mediated by defective expression of degs1 impairs adipocyte differentiation and function2015In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 4, p. 1180-1192Article in journal (Refereed)
    Abstract [en]

    Adipose tissue dysfunction is an important determinant of obesity-associated, lipid-induced metabolic complications. Ceramides are well-known mediators of lipid-induced insulin resistance in peripheral organs such as muscle. DEGS1 is the desaturase catalyzing the last step in the main ceramide biosynthetic pathway. Functional suppression of DEGS1 activity results in substantial changes in ceramide species likely to affect fundamental biological functions such as oxidative stress, cell survival, and proliferation. Here, we show that degs1 expression is specifically decreased in the adipose tissue of obese patients and murine models of genetic and nutritional obesity. Moreover, loss-of-function experiments using pharmacological or genetic ablation of DEGS1 in preadipocytes prevented adipogenesis and decreased lipid accumulation. This was associated with elevated oxidative stress, cellular death, and blockage of the cell cycle. These effects were coupled with increased dihydroceramide content. Finally, we validated in vivo that pharmacological inhibition of DEGS1 impairs adipocyte differentiation. These data identify DEGS1 as a new potential target to restore adipose tissue function and prevent obesity-associated metabolic disturbances.

  • 3.
    Basic, Vladimir
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Molecular mechanisms mediating development of pulmonary cachexia in COPD2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cigarette smoking (CS) represents the main causative agent underlying development and progress of COPD. Recently, involvement of CS in the pathogenesis of COPDassociated muscle abnormalities is becoming increasingly evident. Nevertheless, involved triggers and underlying mechanisms remain largely unknown. This study was conceived in order to examine effects of cigarette smoke exposure on skeletal muscle morphology, vascular supply and function. For this purpose, we have specifically designed murine COPD/emphysema model and gastrocnemius muscle was examined, while in vitro experiments were conducted using murine C2C12 skeletal muscle myocytes.

    In addition to the mild emphysematous changes present in the lungs of CS-exposed mice, our results demonstrated evident signs of muscle atrophy reflected by decreased fiber cross-sectional area, profound fiber size variation and reduced body mass. Furthermore, we have observed impairment in terminal myogenesis and lower number of myonuclei in skeletal muscles of CS-exposed animals despite evident activation of muscle repair process. Additionally, our results demonstrate capillary rarefaction in skeletal muscles of CS-exposed animals which was associated with deregulation of hypoxia-angiogenesis signaling, reduced levels of angiogenic factors such as HIF1-α and VEGF and enhanced expression of VHL and its partner proteins PHD2 and Ube2D1. The results of our in-vitro experiments demonstrated that VHL and its ubiquitination machinery can be synergistically regulated by TNF and hypoxia consequentially impairing angiogenic potential of skeletal muscle myocytes. Finally, we have shown that CS elicits chronic ER stress in murine skeletal muscles which is associated with activation of ERAD and apoptotic pathways as mirrored by elevated expression of Usp19, caspase 12 and caspase 3 in skeletal muscles of CSexposed animals. Moreover, molecular and morphological alterations in CS-exposed mice resulted in impairment of muscle function as reflected by their impaired exercise capacity.

    Taken together, from our results it is evident that cigarette smoke exposure elicits set of morphological, vascular and functional changes highly resembling those observed in COPD. Additionally, CS induces wide range of molecular alterations and signaling pathway deregulations suggesting profound effects of cigarette smoke exposure on skeletal muscle cell homeostasis.

    List of papers
    1. Exposure to cigarette smoke induces overexpression of von Hippel-Lindau tumor suppressor in mouse skeletal muscle
    Open this publication in new window or tab >>Exposure to cigarette smoke induces overexpression of von Hippel-Lindau tumor suppressor in mouse skeletal muscle
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    2012 (English)In: American Journal of Physiology - Lung cellular and Molecular Physiology, ISSN 1040-0605, E-ISSN 1522-1504, Vol. 303, no 6, p. L519-L527Article in journal (Refereed) Published
    Abstract [en]

    Cigarette smoke (CS) is a well established risk factor in the development of chronic obstructive pulmonary disease (COPD). In contrast, the extent to which CS exposure contributes to the development of the systemic manifestations of COPD, such as skeletal muscle dysfunction and wasting remains largely unknown. Decreased skeletal muscle capillarization has been previously reported in early stages of COPD and might play an important role in the development of COPD-associated skeletal muscle abnormalities. To investigate the effects of chronic CS exposure on skeletal muscle capillarization and exercise tolerance a mouse model of CS exposure was used. The129/SvJ mice were exposed to CS for 6 months, and the expression of putative elements of the hypoxia-angiogenic signaling cascade as well as muscle capillarization were studied. Additionally, functional tests assessing exercise tolerance/endurance were performed in mice. Compared to controls, skeletal muscles from CS-exposed mice exhibited significantly enhanced expression of von Hippel-Lindau tumor suppressor (VHL), ubiquitin-conjugating enzyme E2D1 (UBE2D1) and prolyl hydroxylase-2 (PHD2). In contrast, hypoxia-inducible factor-1 (HIF1-α) and vascular endothelial growth factor (VEGF) expression was reduced. Furthermore, reduced muscle fiber cross-sectional area, decreased skeletal muscle capillarization, and reduced exercise tolerance were also observed in CS-exposed animals. Taken together, the current results provide evidence linking chronic CS exposure and induction of VHL expression in skeletal muscles leading towards impaired hypoxia-angiogenesis signal transduction, reduced muscle fiber cross-sectional area and decreased exercise tolerance.

    Place, publisher, year, edition, pages
    Bethesda, USA: American Physiological Society, 2012
    Keywords
    Capillaries, chronic obstructive pulmonary disease, hypoxia inducible factor-1 alpha, pulmonary cachexia syndrome, vascular endothelial growth factor
    National Category
    Medical and Health Sciences Physiotherapy
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-24177 (URN)10.1152/ajplung.00007.2012 (DOI)000309109300005 ()22842216 (PubMedID)2-s2.0-84866418091 (Scopus ID)
    Funder
    NIH (National Institute of Health)
    Note

    Funding Agencies:

    Olle Engkvist Byggmastare Fund, Sweden

    NIEHS Environmental Health Science Center grant 

    Available from: 2012-07-31 Created: 2012-07-31 Last updated: 2018-05-09Bibliographically approved
    2. Chronic cigarette smoke exposureimpairs skeletal muscle regenerative capacity in murineCOPD/emphysema model.
    Open this publication in new window or tab >>Chronic cigarette smoke exposureimpairs skeletal muscle regenerative capacity in murineCOPD/emphysema model.
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Cigarette smoke (CS) is a well established risk factor in the development of COPD and irreversible airflow limitation. In contrast, the extent to which CS exposure contributes to development of peripheral skeletal muscle dysfunction and wasting remains largely unknown. Decline in skeletal muscle regenerative capacity has been previously reported in COPD patients.

    Methods: To investigate effects of chronic CS exposure on skeletal muscle regenerative capacity, 129/SvJ mice were exposed to CS for 6 months. The expression levels of myogenin, Jarid2, Znf496, Notch1, Pax7, Fgf1 and Myh3, which are known to regulate skeletal muscle myogenesis, were studied. Additionally, number of fibers with central nuclei, myonuclei number and mean fiber cross-sectional area were assessed.

    Results: Compared to controls, skeletal muscles from CS-exposed mice exhibited significantly decreased expression of Jarid2, coupled with enhanced expression of Znf496, Notch1, Pax7, Fgf1 and Myh3. Expression of myogenin, a marker of terminally differentiated myofibers, was reduced. Furthermore, reduced muscle fiber crosssectional area, increased number of fibers with central nuclei and reduced myonuclei number were also observed in CS-exposed animals.

    Conclusions: Taken together, current results provide evidence linking chronic CS exposure and an ongoing damage/repair process as well as impaired regenerative capacity in skeletal muscles of CS-exposed mice.

    Keywords
    cigarette smoke, chronic obstructive pulmonary disease, skeletal muscle dysfunction, skeletal muscle regeneration
    National Category
    Otorhinolaryngology
    Research subject
    Oto-Rhino-Laryngology
    Identifiers
    urn:nbn:se:oru:diva-38189 (URN)
    Note

    Funding and support:

    Olle Engkvist Byggmästare Fund,

    Åke WibergFoundation, Sweden

    and the research funds of the Department of Medicine,Danderyd Hospital, Stockholm(to S.M.A-H),

    Örebro university grant to doctoralsstudents (We thank the Developmental Studies Hybridoma Bank (DSHB, Universityof Iowa, IA, USA)) for antibody against Pax7

    Available from: 2014-10-27 Created: 2014-10-27 Last updated: 2017-10-17Bibliographically approved
    3. TNF stimulation induces VHL overexpression and impairs angiogenic potential in skeletal muscle myocytes
    Open this publication in new window or tab >>TNF stimulation induces VHL overexpression and impairs angiogenic potential in skeletal muscle myocytes
    2014 (English)In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 34, no 1, p. 228-236Article in journal (Refereed) Published
    Abstract [en]

    Decreased skeletal muscle capillarization is considered to significantly contribute to the development of pulmonary cachexia syndrome (PCS) and progressive muscle wasting in several chronic inflammatory diseases, including chronic obstructive pulmonary disease (COPD). It is unclear to which extent the concurrent presence of systemic inflammation contributes to decreased skeletal muscle capillarization under these conditions. The present study was designed to examine in vitro the effects of the pro-inflammatory cytokine, tumor necrosis factor (TNF), on the regulation of hypoxia-angiogenesis signal transduction and capillarization in skeletal muscles. For this purpose, fully differentiated C2C12 skeletal muscle myocytes were stimulated with TNF and maintained under normoxic or hypoxic conditions. The expression levels of the putative elements of the hypoxia-angiogenesis signaling cascade were examined using qPCR, western blot analysis and immunofluorescence. Under normoxic conditinos, TNF stimulation increased the protein expression of anti-angiogenic von-Hippel Lindau (VHL), prolyl hydroxylase (PHD)2 and ubiquitin conjugating enzyme 2D1 (Ube2D1), as well as the total ubiquitin content in the skeletal muscle myocytes. By contrast, the expression levels of hypoxia-inducible factor 1‑α (HIF1-α) and those of its transcriptional targets, vascular endothelial growth factor (VEGF)A and glucose transporter 1 (Glut1), were markedly reduced. In addition, hypoxia increased the expression of the VHL transcript and further elevated the VHL protein expression levels in C2C12 myocytes following TNF stimulation. Consequently, an impaired angiogenic potential was observed in the TNF-stimulated myocytes during hypoxia. In conclusion, TNF increases VHL expression and disturbs hypoxia-angiogenesis signal transduction in skeletal muscle myocytes. The current findings provide a mechanism linking systemic inflammation and impaired angiogenesis in skeletal muscle. This is particularly relevant to further understanding the mechanisms mediating muscle wasting and cachexia in patients with chronic inflammatory diseases, such as COPD.

    Place, publisher, year, edition, pages
    Spandidos Publications, 2014
    National Category
    Medical Biotechnology
    Research subject
    Medical Disability Research
    Identifiers
    urn:nbn:se:oru:diva-35141 (URN)10.3892/ijmm.2014.1776 (DOI)000338178000027 ()24820910 (PubMedID)2-s2.0-84902649801 (Scopus ID)
    Available from: 2014-05-25 Created: 2014-05-25 Last updated: 2018-06-07Bibliographically approved
    4. Cigarette smoke exposure up-regulates Ubiquitin specific protease 19 in murine skeletal muscles as an adaptive response to prolonged ER stress
    Open this publication in new window or tab >>Cigarette smoke exposure up-regulates Ubiquitin specific protease 19 in murine skeletal muscles as an adaptive response to prolonged ER stress
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Enhanced protein degradation via ubiquitin proteolytic system (UPS) was demonstrated to play an important role in the pathogenesis of cachexia syndrome and muscle wasting in patients with COPD and animal models of the disease. The role of cigarette smoke (CS) exposure in eliciting these abnormalities remains largely unknown. Usp19 is a member of UPS suggested to be involved in progressive muscle wasting in different catabolic conditions. However, factors regulating Usp19 expression, activity and correlation/s with CS-induced muscle atrophy remainunclear.

    Methods: To address these questions, 129 SvJ mice were exposed to cigarette smoke for 6 months and the gastrocnemius muscles were collected. Expression levels of Usp19 as well as pivotal mediators of ER stress response have been studied using PCR, qPCR, western blot and immunofluorescence. Factors regulating muscle Usp19 expression were studied using in-silico analysis of Usp19 promoter as well as by stimulating C2C12 myocytes with different inducers of ER stress including hypoxia, TNF and tunicamycin. Finally, Usp19 expression was depleted in C2C12 myocytes using specific Usp19 siRNA quadriplex and the expression of pivotal myogenic regulators were analyzed.

    Results: Usp19 mRNA expression was enhanced in skeletal muscles of CS-exposed mice. Concurrently, ER stress-associated Caspase 12 and Caspase 3 were activated in the CS-exposed group. Analysis of Usp19 promoter sequence revealed binding sites for ER stress response transcription factors such as HSF, STRE1 and AML1-α. Exposure of C2C12 myocytes to tunicamycin but not hypoxia elevated expression levels of Usp19. TNFstimulation elevated Usp19 protein expression but inhibited its RNA transcription in a dose- and time-dependent manner. Finally, Usp19 overexpression in tunicamycin-treated myocytes was accompanied by reduced expression of myosin heavy chain and tropomyosin and their levels were increased after knocking down Usp19 in C2C12 myocytes.

    Conclusions: In summary, our data demonstrated elevated expression of Usp19 in skeletal muscles of CS-exposed 129 SvJ mice. Moreover, Usp19 overexpression was associated with muscle adaptations to ER stress and suppression of myogenesis. Taken together; our results might provide further insight into molecular mechanisms underlying development and progression of skeletal muscle abnormalities in response to chronic cigarette smoke exposure.

    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-38194 (URN)
    Available from: 2014-10-27 Created: 2014-10-27 Last updated: 2017-10-17Bibliographically approved
    5. The periodontal pathogen Porphyromonas gingivalis changes the gene expression in vascular smooth muscle cells involving the TGFbeta/Notch signalling pathway and increased cell proliferation
    Open this publication in new window or tab >>The periodontal pathogen Porphyromonas gingivalis changes the gene expression in vascular smooth muscle cells involving the TGFbeta/Notch signalling pathway and increased cell proliferation
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    2013 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 14, p. 770-Article in journal (Refereed) Published
    Abstract [en]

    Background: Porphyromonas gingivalis is a gram-negative bacterium that causes destructive chronic periodontitis. In addition, this bacterium is also involved in the development of cardiovascular disease. The aim of this study was to investigate the effects of P. gingivalis infection on gene and protein expression in human aortic smooth muscle cells (AoSMCs) and its relation to cellular function.

    Results: AoSMCs were exposed to viable P. gingivalis for 24 h, whereafter confocal fluorescence microscopy was used to study P. gingivalis invasion of AoSMCs. AoSMCs proliferation was evaluated by neutral red assay. Human genome microarray, western blot and ELISA were used to investigate how P. gingivalis changes the gene and protein expression of AoSMCs. We found that viable P. gingivalis invades AoSMCs, disrupts stress fiber structures and significantly increases cell proliferation. Microarray results showed that, a total of 982 genes were identified as differentially expressed with the threshold log2 fold change >|1| (adjust p-value <0.05). Using bioinformatic data mining, we demonstrated that up-regulated genes are enriched in gene ontology function of positive control of cell proliferation and down-regulated genes are enriched in the function of negative control of cell proliferation. The results from pathway analysis revealed that all the genes belonging to these two categories induced by P. gingivalis were enriched in 25 pathways, including genes of Notch and TGF-beta pathways.

    Conclusions: This study demonstrates that P. gingivalis is able to invade AoSMCs and stimulate their proliferation. The activation of TGF-beta and Notch signaling pathways may be involved in the bacteria-mediated proliferation of AoSMCs. These findings further support the association between periodontitis and cardiovascular diseases.

    Keywords
    Porphyromonas gingivalis, Aortic smooth muscle cells, Proliferation, Gene expression profiling
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:oru:diva-33287 (URN)10.1186/1471-2164-14-770 (DOI)000328639800002 ()24209892 (PubMedID)2-s2.0-84887327838 (Scopus ID)
    Funder
    Swedish Research Council, 2008-2459Swedish Heart Lung Foundation, 2011-0632
    Note

    Funding Agency: Foundation of Olle Engkvist; Foundation of Mats Kleberg (se även Forskningsfinansiär)

    Available from: 2014-01-24 Created: 2014-01-24 Last updated: 2018-01-11Bibliographically approved
  • 4.
    Bilbija, Dusan
    et al.
    University of Oslo, Oslo, Norway.
    Elmabsout, Ali Ateia
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sagave, Julia
    University of Oslo, Oslo, Norway.
    Haugen, Fred
    University of Oslo, Oslo, Norway.
    Bastani, Nasser
    Departments of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Dahl, Christen Peder
    University of Oslo, Oslo, Norway; Department of Cardiology, Oslo University Hospital, Oslo, Norway .
    Gullestad, Lars
    University of Oslo, Oslo, Norway; Department of Cardiology, Oslo University Hospital, Oslo, Norway.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Blomhoff, Rune
    Departments of Nutrition, Institute of Basic Medical Sciences, Oslo University, Oslo, Norway.
    Valen, Guro
    University of Oslo, Oslo, Norway.
    Expression of retinoic acid target genes in coronary artery disease2014In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 33, no 3, p. 677-86Article in journal (Refereed)
    Abstract [en]

    Coronary atherosclerosis can lead to myocardial infarction, and secondarily to post-infarct remodelling and heart failure. Retinoic acid (RA) influences cell proliferation. We hypothesized that RA could influence gene expression and proliferation of cardiovascular cells. Left ventricular biopsies from patients with end-stage heart failure due to coronary artery disease (CAD) or dilated cardiomyopathy were investigated for the content of RA metabolites using liquid chromatography mass spectrometry (LC-MS/MS), and compared with healthy donors. All-trans retinoic acid (ATRA) was increased in the hearts of CAD patients. Gene expression (quantitative PCR) of RA target genes was not influenced in failing hearts, but was increased in the hearts of patients with CAD undergoing open heart surgery. The expression of RA target genes was increased in atherosclerotic lesions from carotid arteries compared to healthy arteries. Stimulation of cardiomyocytes, cardiofibroblasts, smooth muscle cells and endothelial cells with ATRA increased the gene expression of the key enzymes. Cardiofibroblast and smooth muscle cell proliferation were reduced by ATRA, which increased endothelial cell proliferation. Coronary artery disease leads to increased expression of RA target genes. ATRA accumulated in the failing human heart. All investigated cell types present in the heart had induced expression of RA target genes when stimulated with ATRA, which also influenced cell proliferation.

  • 5.
    Bilbija, Dusan
    et al.
    Department of Physiology, University of Oslo, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Haugen, Fred
    Department of Physiology, University of Oslo, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Sagave, Julia
    Department of Physiology, University of Oslo, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Baysa, Anton
    Department of Physiology, University of Oslo, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Bastani, Nasser
    Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway .
    Levy, Finn Olav
    Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Division of Biomedicine, Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Blomhoff, Rune
    Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway .
    Valen, Guro
    Department of Physiology, University of Oslo, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Retinoic acid signalling is activated in the postischemic heart and may influence remodelling2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9, article id e44740Article in journal (Refereed)
    Abstract [en]

    Background: All-trans retinoic acid (atRA), an active derivative of vitamin A, regulates cell differentiation, proliferation and cardiac morphogenesis via transcriptional activation of retinoic acid receptors (RARs) acting on retinoic acid response elements (RARE).We hypothesized that the retinoic acid (RA) signalling pathway is activated in myocardial ischemia and postischemic remodelling.

    Methods and Findings: Myocardial infarction was induced through ligating the left coronary artery in mice. In vivo cardiac activation of the RARs was measured by imaging RARE-luciferase reporter mice, and analysing expression of RAR target genes and proteins by real time RT-PCR and western blot. Endogenous retinoids in postinfarcted hearts were analysed by triple-stage liquid chromatography/tandem mass spectrometry. Cardiomyocytes (CM) and cardiofibroblasts (CF) were isolated from infarcted and sham operated RARE luciferase reporter hearts and monitored for RAR activity and expression of target genes. The effect of atRA on CF proliferation was evaluated by EdU incorporation. Myocardial infarction increased thoracic RAR activity in vivo (p<0.001), which was ascribed to the heart through ex vivo imaging (p = 0.002) with the largest signal 1 week postinfarct. This was accompanied by increased cardiac gene and protein expression of the RAR target genes retinol binding protein 1 (p = 0.01 for RNA, p = 0,006 for protein) and aldehyde dehydrogenase 1A2 (p = 0.04 for RNA, p = 0,014 for protein), while gene expression of cytochrome P450 26B1 was downregulated (p = 0.007). Concomitantly, retinol accumulated in the infarcted zone (p = 0.02). CM and CF isolated from infarcted hearts had higher luminescence than those from sham operated hearts (p = 0.02 and p = 0.008). AtRA inhibited CF proliferation in vitro (p = 0.02).

    Conclusions: The RA signalling pathway is activated in postischemic hearts and may play a role in regulation of damage and repair during remodelling.

  • 6.
    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.

  • 7. Brooks, Andrew J
    et al.
    Johansson, Magnus
    John, Anna V
    Xu, Yibin
    Jans, David A
    Vasudevan, Subhash G
    The interdomain region of dengue NS5 protein that binds to the viral helicase NS3 contains independently functional importin beta 1 and importin alpha/beta-recognized nuclear localization signals2002In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 277, no 39, p. 36399-36407Article in journal (Refereed)
    Abstract [en]

    Dengue virus NS5 protein is a multifunctional RNA-dependent RNA polymerase that is essential for virus replication. We have shown previously that the 37- amino acid interdomain spacer sequence (residues (369)X(2)KKX(14)KKKX(11)RKX(3)405) of Dengue2 NS5 contains a functional nuclear localization signal (NLS). In this study, beta-galactosidase fusion proteins carrying point mutations of the positively charged residues or truncations of the interdomain linker region (residues 369-389 or residues 386-405) were analyzed for nuclear import and importin binding activities to show that the N-terminal part of the linker region (residues 369-389, a/bNLS) is critical for nuclear localization and is recognized with high affinity by the conventional NLS-binding importin alpha/beta heterodimeric nuclear import receptor. We also show that the importin beta-binding site (residues 320-368, bNLS) adjacent to the a/bNLS, previously identified by yeast two-hybrid analysis, is functional as an NLS, recognized with high affinity by importin beta, and able to target beta-galactosidase to the nucleus. Intriguingly, the bNLS is highly conserved among Dengue and related flaviviruses, implying a general role for the region and importin beta in the infectious cycle.

  • 8.
    Bugaytsova, Jeanna A.
    et al.
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Björnham, Oscar
    Department of Applied Physics and Electronics, Umeå University, Umeå, Sweden; Swedish Defence Research Agency, Umeå, Sweden.
    Chernov, Yevgen A.
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Gideonsson, Pär
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Henriksson, Sara
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden; Umeå Core Facil Electron Microscopy UCEM, Umeå University, Umeå, Sweden.
    Mendez, Melissa
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Sjöström, Rolf
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Mahdavi, Jafar
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden; School of Life Sciences, CBS, University of Nottingham, Nottingham, United Kingdom.
    Shevtsova, Anna
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Ilver, Dag
    Department of Medical Biochemistry and Cell Biology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Acreo Swedish ICT AB, Gothenburg, Sweden.
    Moonens, Kristof
    Structural and Molecular Microbiology, VIB Department of Structural Biology, Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium .
    Quintana-Hayashi, Macarena P.
    Department of Medical Biochemistry and Cell Biology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Moskalenko, Roman
    Department of Pathology, Medical Institute, Sumy State University, Sumy, Ukraine.
    Aisenbrey, Christopher
    Department of Chemistry, Umeå University, Umeå, Sweden; Inst Chim, Univ Strasbourg, Strasbourg, France.
    Bylund, Göran
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Schmidt, Alexej
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden; Dept Med Biosci, Umeå Univ, Umeå, Sweden.
    Åberg, Anna
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Brännström, Kristoffer
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Königer, Verena
    Max von Pettenkofer Institute of Hygiene and Medical Microbiology, LMU Munich, Munich, Germany.
    Vikström, Susanne
    Department of Medical Biochemistry and Biophysics & Faculty Science and Technology, Umeå University, Umeå, Sweden.
    Rakhimova, Lena
    Department of Chemistry, Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Hofer, Anders
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Ögren, Johan
    Department of Odontology, Umeå University, Umeå, Sweden.
    Liu, Hui
    Department of Medicine, USUHS, Bethesda MD, United States.
    Goldman, Matthew D.
    Department of Pediatrics, USUHS, Bethesda MD, United States.
    Whitmire, Jeannette M.
    Department of Microbiology and Immunology, USUHS, Bethesda MD, United States.
    Ådén, Jörgen
    Department of Chemistry, Umeå University, Umeå, Sweden.
    Younson, Justine
    Dental Institute, King's College London, London, United Kingdom.
    Kelly, Charles G.
    Dental Institute, King's College London, London, United Kingdom.
    Gilman, Robert H.
    Department of International Health, John Hopkins School of Public Health, Baltimore MD, United States.
    Chowdhury, Abhijit
    Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education & Research, Kolkata, India.
    Mukhopadhyay, Asish K.
    Division of Bacteriology, National Institute of Cholera and Enteric Diseases, Kolkata, India.
    Nair, G. Balakrish
    Translational Health Science and Technology Institute, Haryana, India; WHO Research Policy & Cooperation Unit, New Delhi, India.
    Papadakos, Konstantinos S.
    Hellenic Pasteur Institute, Athens, Greece; Department of Translational Medicine, Wallenberg Lab, Lund University, Malmö, Sweden.
    Martinez-Gonzalez, Beatriz
    Hellenic Pasteur Institute, Athens, Greece.
    Sgouras, Dionyssios N.
    Hellenic Pasteur Institute, Athens, Greece.
    Engstrand, Lars
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Sci Life Lab, Solna, Sweden.
    Unemo, Magnus
    Örebro University Hospital. Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Danielsson, Dan
    Örebro University Hospital. Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Suerbaum, Sebastian
    Max von Pettenkofer Institute of Hygiene and Medical Microbiology, LMU Munich, Munich, Germany ; Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover, Germany; German Center for Infection Research (DZIF), Munich, Germany.
    Oscarson, Stefan
    Centre for Synthesis and Chemical Biology, School of Chemistry, University College Dublin, Dublin, Ireland.
    Morozova-Roche, Ludmilla A.
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Olofsson, Anders
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Gröbner, Gerhard
    Department of Chemistry, Umeå University, Umeå, Sweden.
    Holgersson, Jan
    Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden.
    Esberg, Anders
    Department of Odontology, Umeå University, Umeå, Sweden.
    Strömberg, Nicklas
    Department of Odontology, Umeå University, Umeå, Sweden.
    Landström, Maréne
    Max von Pettenkofer Institute of Hygiene and Medical Microbiology, LMU Munich, Munich, Germany.
    Eldridge, Angela M.
    Department of Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento CA, United States; Genentech Inc, Vacaville CA, USA.
    Chromy, Brett A.
    Department of Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento CA, United States ; Singulex Inc, Alameda CA, USA.
    Hansen, Lori M.
    Departments of Medical Microbiology and Immunology, Center for Comparative Medicine, University of California Davis, Davis CA, United States.
    Solnick, Jay V.
    Departments of Medical Microbiology and Immunology, Center for Comparative Medicine, University of California, Davis CA, United States; California National Primate Research Center, University of California, Davis CA, USA .
    Lindén, Sara K.
    Department of Medical Biochemistry and Cell Biology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Haas, Rainer
    Max von Pettenkofer Institute of Hygiene and Medical Microbiology, LMU Munich, Munich, Germany; German Center for Infection Research (DZIF), Munich, Germany .
    Dubois, Andre
    Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda MD, United States.
    Merrell, D. Scott
    Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda MD, United States.
    Schedin, Staffan
    Department of Applied Physics and Electronics, Umeå University, Umeå, Sweden.
    Remaut, Han
    Structural and Molecular Microbiology, VIB Department of Structural Biology, Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium .
    Arnqvist, Anna
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Berg, Douglas E.
    Department of Medicine, University of California San Diego, La Jolla CA, United States.
    Borén, Thomas
    Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
    Helicobacter pylori adapts to chronic infection and gastric disease via ph-responsive baba-mediated adherence2017In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 21, no 3, p. 376-389, article id S1931-3128(17)30075-6Article in journal (Refereed)
    Abstract [en]

    The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease.

  • 9.
    Caesar, Robert
    et al.
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
    Nygren, Heli
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Orešič, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center A/S, Gentofte, Denmark.
    Bäckhed, Fredrik
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
    Interaction between dietary lipids and gut microbiota regulates hepatic cholesterol metabolism2016In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 57, no 3, p. 474-481Article in journal (Refereed)
    Abstract [en]

    The gut microbiota influences many aspects of host metabolism. We have previously shown that the presence of a gut microbiota remodels lipid composition. Here we investigated how interaction between gut microbiota and dietary lipids regulates lipid composition in the liver and plasma, and gene expression in the liver. Germ-free and conventionally raised mice were fed a lard or fish oil diet for 11 weeks. We performed lipidomics analysis of the liver and serum and microarray analysis of the liver. As expected, most of the variation in the lipidomics dataset was induced by the diet, and abundance of most lipid classes differed between mice fed lard and fish oil. However, the gut microbiota also affected lipid composition. The gut microbiota increased hepatic levels of cholesterol and cholesteryl esters in mice fed lard, but not in mice fed fish oil. Serum levels of cholesterol and cholesteryl esters were not affected by the gut microbiota. Genes encoding enzymes involved in cholesterol biosynthesis were downregulated by the gut microbiota in mice fed lard and were expressed at a low level in mice fed fish oil independent of microbial status. In summary, we show that gut microbiota-induced regulation of hepatic cholesterol metabolism is dependent on dietary lipid composition.

  • 10. Ellencrona, Karin
    et al.
    Syed, Asim
    Johansson, Magnus
    Flavivirus NS5 associates with host-cell proteins zonula occludens-1 (ZO-1) and regulating synaptic membrane exocytosis-2 (RIMS2) via an internal PDZ binding mechanism2009In: Biological chemistry (Print), ISSN 1431-6730, E-ISSN 1437-4315, Vol. 390, no 4, p. 319-323Article in journal (Refereed)
    Abstract [en]

    Dengue virus (DENV) and tick-borne encephalitis virus (TBEV) are flaviviruses, which can cause lethal hemorrhagic fever and encephalitis, respectively. Here, we demonstrate that the TBEV-NS5 and DENV-NS5 proteins use an internal binding mechanism to target human PDZ proteins. TBEV-NS5 has high affinity to regulating synaptic membrane exocytosis-2 (RIMS2) and Scribble, whereas DENV-NS5 binds primarily to the tight junction protein zonula occludens-1 (ZO-1). Targeting of TBEV-NS5 to the plasma membrane is stabilised by ZO-1; however, DENV-NS5 co-localises with ZO-1 in the nucleus. These interactions have potential important roles in the ability of flaviviruses to manipulate cell proliferation, junction permeability and the interferon pathways.

  • 11.
    Elmabsout, Ali Ateia
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Kumawat, Ashok K.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Saenz-Méndez, Patricia
    Computational Chemistry and Biology Group, Facultad de Química, UdelaR, Montevideo, Uruguay.
    Krivospitskaya, Olesya
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sävenstrand, Helena
    Örebro University, School of Science and Technology.
    Olofsson, Peder S.
    Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Stockholm, Sweden; Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset NY, United States of America.
    Eriksson, Leif A.
    Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden.
    Strid, Åke
    Örebro University, School of Science and Technology.
    Valen, Guro
    Department of Physiology, Institute of Basic Medical Science and Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Törmä, Hans
    Department of Medical Sciences, Dermatology and Venereology, Uppsala University, Uppsala, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Cloning and functional studies of a splice variant of CYP26B1 expressed in vascular cells2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, article id e36839Article in journal (Refereed)
    Abstract [en]

    Background: All-trans retinoic acid (atRA) plays an essential role in the regulation of gene expression, cell growth and differentiation and is also important for normal cardiovascular development but may in turn be involved in cardiovascular diseases, i.e. atherosclerosis and restenosis. The cellular atRA levels are under strict control involving several cytochromes P450 isoforms (CYPs). CYP26 may be the most important regulator of atRA catabolism in vascular cells. The present study describes the molecular cloning, characterization and function of atRA-induced expression of a spliced variant of the CYP26B1 gene.

    Methodology/Principal Findings: The coding region of the spliced CYP26B1 lacking exon 2 was amplified from cDNA synthesized from atRA-treated human aortic smooth muscle cells and sequenced. Both the spliced variant and full length CYP26B1 was found to be expressed in cultured human endothelial and smooth muscle cells, and in normal and atherosclerotic vessel. atRA induced both variants of CYP26B1 in cultured vascular cells. Furthermore, the levels of spliced mRNA transcript were 4.5 times higher in the atherosclerotic lesion compared to normal arteries and the expression in the lesions was increased 20-fold upon atRA treatment. The spliced CYP26B1 still has the capability to degrade atRA, but at an initial rate one-third that of the corresponding full length enzyme. Transfection of COS-1 and THP-1 cells with the CYP26B1 spliced variant indicated either an increase or a decrease in the catabolism of atRA, probably depending on the expression of other atRA catabolizing enzymes in the cells.

    Conclusions/Significance: Vascular cells express the spliced variant of CYP26B1 lacking exon 2 and it is also increased in atherosclerotic lesions. The spliced variant displays a slower and reduced degradation of atRA as compared to the fulllength enzyme. Further studies are needed, however, to clarify the substrate specificity and role of the CYP26B1 splice variant in health and disease.

  • 12.
    Elvers, Margitta
    et al.
    Medizinische Klinik III, Dept. of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany.
    Grenegård, Magnus
    Faculty of Health Sciences, Department of Medicine and Health, Division of Drug Research/Pharmacology, University of Linköping, Linköping, Sweden.
    Khoshjabinzadeh, Hanieh
    Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, University of Linköping, Linköping, Sweden.
    Münzer, Patrick
    Department of Physiology, Eberhard Karls University, Tübingen, Germany.
    Borst, Oliver
    Medizinische Klinik III, Dept. of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany; Department of Physiology, Eberhard Karls University, Tübingen, Germany.
    Tian, Huasong
    Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, USA.
    Di Paolo, Gilbert
    Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, USA.
    Lang, Florian
    Department of Physiology, Eberhard Karls University, Tübingen, Germany.
    Gawaz, Meinrad
    Medizinische Klinik III, Dept. of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany.
    Lindahl, Tomas L
    Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, Linköping University, Linköping, Sweden.
    Fälker, Knut
    Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, Linköping University, Linköping, Sweden.
    A novel role for phospholipase D as an endogenous negative regulator of platelet sensitivity2012In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 24, no 9, p. 1743-52Article in journal (Refereed)
    Abstract [en]

    Platelet aggregation, secretion and thrombus formation play a critical role in primary hemostasis to prevent excessive blood loss. On the other hand, uncontrolled platelet activation leads to pathological thrombus formation resulting in myocardial infarction or stroke. Stimulation of heterotrimeric G-proteins by soluble agonists or immunoreceptor tyrosine based activation motif-coupled receptors that interact with immobilized ligands such as the collagen receptor glycoprotein (GP) VI lead to the activation of phospholipases that cleave membrane phospholipids to generate soluble second messengers. Platelets contain the phospholipases (PL) D1 and D2 which catalyze the hydrolysis of phosphatidylcholine to generate the second messenger phosphatidic acid (PA). The production of PA is abrogated by primary alcohols that have been widely used for the analysis of PLD-mediated processes. However, it is not clear if primary alcohols effectively reduce PA generation or if they induce PLD-independent cellular effects. In the present study we made use of the specific PLD inhibitor 5-fluoro-2-indolyl des-chlorohalopemide (FIPI) and show for the first time, that FIPI enhances platelet dense granule secretion and aggregation of human platelets. Further, FIPI has no effect on cytosolic Ca(2+) activity but needs proper Rho kinase signaling to mediate FIPI-induced effects on platelet activation. Upon FIPI treatment the phosphorylation of the PKC substrate pleckstrin was prominently enhanced suggesting that FIPI affects PKC-mediated secretion and aggregation in platelets. Similar effects of FIPI were observed in platelets from mouse wild-type and Pld1(-/-) mice pointing to a new role for PLD2 as a negative regulator of platelet sensitivity.

  • 13. Elwood, Chelsea N.
    et al.
    Chew, Ben H.
    Seney, Shannon
    Jass, Jana
    Örebro University, School of Science and Technology.
    Denstedt, John D.
    Cadieux, Peter A.
    Triclosan Inhibits Uropathogenic Escherichia coli-Stimulated Tumor Necrosis Factor-α Secretion in T24 Bladder Cells in Vitro2007In: Journal of endourology, ISSN 0892-7790, E-ISSN 1557-900X, Vol. 21, no 10, p. 1217-1222Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Triclosan is an antimicrobial agent commonly used in consumer and medical products that inhibits bacterial fatty acid synthesis. In addition to its bactericidal effects, sublethal concentrations of triclosan reduce local inflammation, inhibit the growth of bacterial uropathogens, induce membrane stress, and inhibit P-fimbrial expression in uropathogenic Escherichia coli (UPEC). We tested whether sublethal concentrations of triclosan could reduce the adherence of UPEC to bladder and kidney cells and reduce the amount of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) produced by these cells during bacterial challenge in vitro. MATERIALS AND METHODS: Assays of bacterial growth, adhesion, and intracellularization were performed using UPEC GR12 incubated for 4 hours on monolayers of human T24 bladder cells or A498 kidney cells with various sublethal concentrations of triclosan. The expression profile of TNF-alpha from bladder cells was evaluated using ELISA. RESULTS: No significant decreases were observed in the adherence or invasion percentages of UPEC GR12 with either cell line when treated with sublethal amounts of triclosan. However, treatment with triclosan 0.5 microg/mL led to a significant decrease in the total number of UPEC GR12 recovered from T24 monolayers (P < 0.05). Importantly, a reduction in the expression of TNF-alpha by T24 cells was shown when UPEC GR12 was treated with triclosan (P < 0.05). CONCLUSIONS: Sublethal concentrations of triclosan did not inhibit the adhesion or intracellularization of UPEC into kidney or bladder cell lines but did significantly reduce the amount of TNF-alpha secreted by bladder cells. Therefore, the use of triclosan on ureteral stents may prove clinically beneficial, not only by inhibiting bacterial survival and growth within the urinary tract, but by reducing local inflammation as well.

  • 14.
    Eriksson, Katarina
    et al.
    Department of Obstetrics and Gynecology, Ålands Centralsjukhus, Mariehamn, Finland; Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköpings University, Linköping, Sweden.
    Adolfsson, Annsofie
    Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköpings University, Linköping, Sweden; Department of Obstetrics and Gynecology, Kärnsjukhuset, Skövde, Sweden; School of Life Sciences, University of Skövde, Skövde, Sweden.
    Forsum, Urban
    Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköpings University, Linköping, Sweden.
    Larsson, Per-Göran
    Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköpings University, Linköping, Sweden; Department of Obstetrics and Gynecology, Kärnsjukhuset, Skövde, Sweden; School of Life Sciences, University of Skövde, Skövde, Sweden.
    The prevalence of BV in the population on the Åland Islands during a 15-year period2010In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 118, no 11, p. 903-908Article in journal (Refereed)
    Abstract [en]

    The aim of the study was to describe the prevalence and age distribution of bacterial vaginosis (BV) during an observation period of 15 years in a population study with cross-sectional samples of adult women living on the Åland Islands. The Åland Islands form an archipelago in the Baltic Sea and are a province of Finland. Every fifth year, specific age groups in the adult female population are invited to participate in a screening program for early diagnosis of cervical cancer using a papanicolaou (PAP)-stained vaginal smear. Women in the age groups of 20, 25, 30, 35, 40, 45, 50, 55, and 60 years are called each year. BV diagnosis of the PAP-stained smears uses the classification according to Nugent. The PAP-stained smears from the screening program of cervical cancer 1993, 1998, 2003, and 2008 were used in this study. A total of 3456 slides were investigated and 271 women could be followed for the 15-year observation period. The prevalence of BV declined from 15.6% in 1993 to 8.6% in 2008. The highest prevalence occurred among the age groups of 35 and 50 years. Among the 271 women who could be followed for the 15-year observation period, two-third showed normal/intermediate flora and one-third were infected with BV at least once. As this is a cross-sectional population study spanning 15 years, the prevalence of BV in the female adult population of the Åland Islands can be estimated. The prevalence has declined between 1993 and 2008 from 15.6% to 8.6%.

  • 15.
    Fernández de la Cruz, Lorena
    et al.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Rydell, Mina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Runeson, Bo Sigurd
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian M.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington IN, USA.
    Brander, Gustaf
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Rück, Christian
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul S.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Mataix-Cols, David
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Suicide in obsessive-compulsive disorder: a population-based study of 36 788 Swedish patients2017In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 22, no 11, p. 1626-1632Article in journal (Refereed)
    Abstract [en]

    The risk of death by suicide in individuals with obsessive-compulsive disorder (OCD) is largely unknown. Previous studies have been small and methodologically flawed. We analyzed data from the Swedish national registers to estimate the risk of suicide in OCD and identify the risk and protective factors associated with suicidal behavior in this group. We used a matched case-cohort design to estimate the risk of deaths by suicide and attempted suicide in individuals diagnosed with OCD, compared with matched general population controls (1:10). Cox regression models were used to study predictors of suicidal behavior. We identified 36 788 OCD patients in the Swedish National Patient Register between 1969 and 2013. Of these, 545 had died by suicide and 4297 had attempted suicide. In unadjusted models, individuals with OCD had an increased risk of both dying by suicide (odds ratio (OR)=9.83 (95% confidence interval (CI), 8.72-11.08)) and attempting suicide (OR=5.45 (95% CI, 5.24-5.67)), compared with matched controls. After adjusting for psychiatric comorbidities, the risk was reduced but remained substantial for both death by suicide and attempted suicide. Within the OCD cohort, a previous suicide attempt was the strongest predictor of death by suicide. Having a comorbid personality or substance use disorder also increased the risk of suicide. Being a woman, higher parental education and having a comorbid anxiety disorder were protective factors. We conclude that patients with OCD are at a substantial risk of suicide. Importantly, this risk remains substantial after adjusting for psychiatric comorbidities. Suicide risk should be carefully monitored in patients with OCD.

  • 16.
    Fälker, Knut
    et al.
    Department of Clinical and Experimental Medicine, University of Linköping, University Hospital, Linköping, Sweden.
    Haglund, Linda
    Department of Medical and Health Sciences, University of Linköping, University Hospital, Linköping, Sweden.
    Gunnarsson, Peter
    Department of Medical and Health Sciences, University of Linköping, University Hospital, Linköping, Sweden.
    Nylander, Martina
    Department of Clinical and Experimental Medicine, University of Linköping, University Hospital, Linköping, Sweden.
    Lindahl, Tomas L
    Department of Clinical and Experimental Medicine, University of Linköping, University Hospital, Linköping, Sweden.
    Grenegård, Magnus
    Department of Medical and Health Sciences, University of Linköping, University Hospital, Linköping, Sweden.
    Protease-activated receptor 1 (PAR1) signalling desensitization is counteracted via PAR4 signalling in human platelets2011In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 436, no 2, p. 469-480Article in journal (Refereed)
    Abstract [en]

    PARs (protease-activated receptors) 1 and 4 belong to the family of G-protein-coupled receptors which induce both G(α12/13) and G(αq) signalling. By applying the specific PAR1- and PAR4-activating hexapeptides, SFLLRN and AYPGKF respectively, we found that aggregation of isolated human platelets mediated via PAR1, but not via PAR4, is abolished upon homologous receptor activation in a concentration- and time-dependent fashion. This effect was not due to receptor internalization, but to a decrease in Ca²⁺ mobilization, PKC (protein kinase C) signalling and α-granule secretion, as well as to a complete lack of dense granule secretion. Interestingly, subthreshold PAR4 activation rapidly abrogated PAR1 signalling desensitization by differentially reconstituting these affected signalling events and functional responses, which was sufficient to re-establish aggregation. The lack of ADP release and P2Y₁₂ receptor-induced G(αi) signalling accounted for the loss of the aggregation response, as mimicking G(αi/z) signalling with 2-MeS-ADP (2-methylthioadenosine-5'-O-diphosphate) or epinephrine (adrenaline) could substitute for intermediate PAR4 activation. Finally, we found that the re-sensitization of PAR1 signalling-induced aggregation via PAR4 relied on PKC-mediated release of both ADP from dense granules and fibrinogen from α-granules. The present study elucidates further differences in human platelet PAR signalling regulation and provides evidence for a cross-talk in which PAR4 signalling counteracts mechanisms involved in PAR1 signalling down-regulation.

  • 17.
    Fälker, Knut
    et al.
    Martin-Luther-University, Halle-Wittenberg, Halle, Germany .
    Lange, Danica
    Martin-Luther-University, Halle-Wittenberg, Halle, Germany .
    Presek, Peter
    Martin-Luther-University, Halle-Wittenberg, Halle, Germany .
    ADP secretion and subsequent P2Y12 receptor signalling play a crucial role in thrombin-induced ERK2 activation in human platelets2004In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 92, no 1, p. 114-23Article in journal (Refereed)
    Abstract [en]

    Stimulating human platelets with thrombin induces the activation of the extracellular signal-regulated kinase 2 (ERK2). We demonstrate that this effect is highly dependent on ADP secretion and P2Y12 receptor signalling. AR-C69931MX (10 microM), a specific antagonist of the Gi-coupled P2Y12 ADP receptor, inhibits ERK2 activation induced by thrombin. Antagonists of the Gq-coupled P2Y1 ADP receptor, A3P5P (500 microM) and MRS2179 (100 microM), have no effect. ADP and its more potent analogue 2-methylthio-ADP alone (both up to 100 microM) do not induce ERK2 activation. Furthermore, we show that the inhibitory effect of AR-C69931MX on ERK2 activation induced by 0.1 U/ml thrombin as well as on platelet aggregation can be bypassed by epinephrine (1 and 10 microM), whereas epinephrine alone has no effect. Epinephrine acts on platelets mainly via alpha(2A)-adrenergic receptors, which, like P2Y12 receptors, couple to inhibitory G proteins. In addition, 2-methylthio-ADP as well as epinephrine provoke ERK2 activation at a thrombin concentration that alone has no detectable effect (0.05 U/ml). Thromboxane A2 (TXA2), which, like ADP, is released by activated platelets, acts as a positive feedback mediator. Stimulating the Gq-coupled TXA2 -receptor with U46619 (10 microM), which leads to ADP secretion and P2Y12 receptor-dependent platelet aggregation, also induces P2Y12-related ERK2 activation. The inhibition of U46619-induced ERK2 activation and platelet aggregation by AR-C69931MX are also rescued by epinephrine. Pretreatment with aspirin inhibits ERK2 activation induced by 0.1 U/ml thrombin, but has no effect at high concentrations of thrombin. The combination of U46619 and thrombin, at concentrations which alone have no effect, provokes ERK2 activation, suggesting that thrombin and released TXA2 act synergistically. Our data indicate that both primary signalling through Gq, which evokes ADP secretion, as well as subsequent coupling via Gi by the P2Y12 receptor are required for ERK2 activation.

  • 18.
    Fälker, Knut
    et al.
    Martin-Luther-University Halle-Wittenberg, Faculty of Medicine, Department of Pharmacology and Toxicology, Halle, Germany .
    Lange, Danica
    Martin-Luther-University Halle-Wittenberg, Faculty of Medicine, Department of Pharmacology and Toxicology, Halle, Germany .
    Presek, Peter
    Martin-Luther-University Halle-Wittenberg, Faculty of Medicine, Department of Pharmacology and Toxicology, Halle, Germany .
    P2Y12 ADP receptor-dependent tyrosine phosphorylation of proteins of 27 and 31 kDa in thrombin-stimulated human platelets2005In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 93, no 5, p. 880-888Article in journal (Refereed)
    Abstract [en]

    In thrombin-stimulated human platelets several proteins undergo rapid and transient changes in tyrosine phosphorylation. We demonstrate that a set of proteins of 27, 29, 31, 34, and 39 kDa is affected by released ADP and P2Y12 receptor signaling during platelet activation. AR-C69931MX, an antagonist of the Gi(2)-coupled P2Y12 ADP receptor, inhibits initial tyrosine phosphorylation of p27 and p31 and prevents subsequent dephosphorylation of p29, p34, and p39. Antagonists of the Gq-coupled P2Y1 ADP receptor have no effect. Precluding integrin alpha(IIb)beta(3) outside-in signaling with RGDS or S1197 does not affect the increase in tyrosine phosphorylation of the set of proteins but inhibits their subsequent dephosphorylation. Besides the ADP analogue 2-MeS-ADP, other platelet agonists such as collagen and the TXA(2)-mimetic U46619 also induce p27 and p31 tyrosine phosphorylation in a P2Y12 receptor-dependent manner. Tyrosine phosphorylation of p27 and p31 in response to collagen, but not thrombin, is prevented by aspirin and the TXA(2) receptor antagonist SQ29548, indicating that the effect of collagen strongly relies on TXA(2) signaling. Furthermore, epinephrine, acting via inhibitory Gz-coupled alpha(2A)-adrenoceptors, bypasses the inhibitory effect of AR-C69931MX on thrombin-induced p27 and p31 tyrosine phosphorylation. Finally, we demonstrate that tyrosine phosphorylation of p27 and p31 downstream of P2Y12 receptors is due to the inhibition of adenylyl cyclase but not phosphoinositide 3-kinase (PI 3-K) activation. Elevating cAMP levels with PGI(2) or forskolin precludes thrombin-induced p27 and p31 tyrosine phosphorylation. Moreover, direct inhibition of adenylyl cyclase by SQ22536 reverses the effect of AR-C69931MX. Our data indicate that the observed changes in tyrosine phosphorylation are the result of both primary Gq signaling, initiating the release of ADP, as well as subsequent P2Y12 receptor-mediated Gi coupling.

  • 19.
    Gunaltay, Sezin
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Kumawat, Ashok Kumar
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Institute of Infection, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, United Kingdom.
    Nyhlin, Nils
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Bohr, Johan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Tysk, Curt
    Örebro University Hospital. Division of Gastroenterology, Department of Medicine, Örebro University, Örebro, Sweden.
    Hultgren, Olof
    Örebro University Hospital.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden.
    Enhanced levels of chemokines and their receptors in the colon of microscopic colitis patients indicate mixed immune cell recruitment2015In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, article id 132458Article in journal (Refereed)
    Abstract [en]

    Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC), is a common cause of chronic diarrhea. Various immune cell infiltrations in the epithelium and lamina propria are seen in MC immunopathology. We compared gene and protein expressions of different immune cell attracting chemokines and their receptors in colon biopsies from MC patients in active disease or histopathological remission (CC/LC-HR) with controls, using qRT-PCR and Luminex, respectively. CC and LC patients with active disease demonstrated a mixed chemokine profile with significantly enhanced gene and/or protein expressions of the chemokines CCL2, CCL3, CCL4, CCL5, CCL7, CCL22, CXCL8, CXCL9, CXCL10, CXCL11, and CX(3)CL1 and the receptors CCR2, CCR3, CCR4, CXCR1, CXCR2, and CX(3)CR1. Enhanced chemokine/chemokine receptor gene and protein levels in LC-HR patients were similar to LC patients, whereas CC-HR patients demonstrated almost normalized levels. These findings expand the current understanding of the involvement of various immune cells in MC immunopathology and endorse chemokines as potential diagnostic markers as well as therapeutic candidates. Moreover, this study further supports the hypothesis that CC and LC are two different entities due to differences in their immunoregulatory responses.

  • 20.
    Hahn-Strömberg, Victoria
    et al.
    Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
    Askari, Shlear
    Department of Clinical Research, Örebro University Hospital, Örebro, Sweden.
    Ahmad, Abrar
    Department of Clinical Research, Örebro University Hospital, Örebro, Sweden.
    Befekadu, Rahel
    Örebro University, School of Medical Sciences. Department of Clinical Research, Örebro University Hospital, Örebro, Sweden.
    Nilsson, Torbjörn K.
    Division of Clinical Chemistry, Department of Medical Biosciences, Umeå University, Umeå, Sweden.
    Expression of claudin 1, claudin 4, and claudin 7 in colorectal cancer and its relation with CLDN DNA methylation patterns2017In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 39, no 4, article id 697569Article in journal (Refereed)
    Abstract [en]

    Altered claudin expression has been described in colon, prostatic, ovarian, and breast carcinoma. However, the role of epigenetic modifications in these genes and their role in colorectal cancer is unknown. We aimed our study to investigate whether claudin protein expression and methylation of CLDN can influence the tumorigenesis of colorectal cancer. A total of 31 patients diagnosed with colorectal carcinoma was used in this study. Immunohistochemical staining was used to study protein expression in both tumor and the adjacent nonneoplastic mucosa of claudin 1, 4, and 7. To detect the DNA methylation pattern of CLDN1, 4, and 7, genomic DNA was extracted from both the tumor and the adjacent nonneoplastic mucosa. Methylation analysis was carried out using bisulfite pyrosequencing. Cell membrane staining intensity of all claudins was found significantly lower in colorectal cancer tissues when compared to paired normal mucosa (p ≤ 0.001). For claudin 4, the percentage of cells staining positively was also significantly reduced (p = 0.04). In normal mucosa, cytoplasm showed no staining for claudins in any patient, whereas in paired colorectal cancer tissues, significant cytoplasmic staining appeared both for claudin 1 (p = 0.04) and claudin 4 (p = 0.01). Tumor samples were significantly hypomethylated in CLDN1 (p < 0.05). In conclusion, our results show that CLDN1 is significantly hypomethylated in tumor samples and that the membrane staining intensity for claudin 1, 4, and 7 is significantly lower in colorectal cancer tissues than in adjacent nonneoplastic tissue. Colorectal cancer cells showed dystopic cytoplasmic location of claudins.

  • 21.
    Hahn-Strömberg, Victoria
    et al.
    Örebro University, School of Health and Medical Sciences.
    Edvardsson, Henrik
    Bodin, Lennart
    Franzén, Lennart
    Disturbed expression of E-cadherin, beta-catenin and tight junction proteins in colon carcinoma is unrelated to growth pattern and genetic polymorphisms2008In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 116, no 4, p. 253-262Article in journal (Refereed)
    Abstract [en]

    Adhesion proteins are responsible for the structural integrity of epithelial tissue and in tumors this integrity is often lost, resulting in a disorganization of the tissue. In the present study the complexity of the invasive front of colon carcinomas was correlated with cell adhesion protein expression and with polymorphisms in their genes. A complexity index was constructed from 32 colon carcinomas using computer-assisted morphometry estimating fractal dimension and tumor cell clusters followed by tree analysis. Immunohistochemical staining of beta-catenin, E-cadherin, occludin and claudin 2 was used for assessment of protein expression. Genetic screening of tissue from the tumor invasion front with laser microdissection was performed using SSCP and DNA sequencing. Adhesion protein distribution was significantly disturbed in most carcinomas. A single mutation in the gene of beta-catenin was found but there was no correlation between protein expression and genetic polymorphism. Nor was there any correlation between the complexity of the invasive border and protein distribution or genetic alterations. The results indicate that the complexity of colon carcinoma invasion is not dependent on genetic derangements in the genes of adhesion proteins or the protein distribution. Rather, aberrations in the function of other proteins related to the adhesive proteins could be responsible.

  • 22.
    Hogh, K-Lynn N.
    et al.
    Northern Medical Program, University of Northern British Columbia, Prince George BC, Canada.
    Craig, Michael N.
    Northern Medical Program, University of Northern British Columbia, Prince George BC, Canada.
    Uy, Christopher E.
    Northern Medical Program, University of Northern British Columbia, Prince George BC, Canada.
    Nygren, Heli
    VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center A/S, Gentofte, Denmark.
    Asadi, Ali
    Department of Cellular and Physiological Sciences and Faculty of Medicine, University of British Columbia, Vancouver BC, Canada.
    Speck, Madeline
    Child and Family Research Institute, Vancouver BC, Canada.
    Fraser, Jordie D.
    Rudecki, Alexander P.
    Northern Medical Program, University of Northern British Columbia, Prince George BC, Canada.
    Baker, Robert K.
    Department of Cellular and Physiological Sciences and Faculty of Medicine, University of British Columbia, Vancouver BC, Canada.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center A/S, Gentofte, Denmark.
    Gray, Sarah L.
    Northern Medical Program, University of Northern British Columbia, Prince George BC, Canada.
    Overexpression of PPARγ specifically in pancreatic β-cells exacerbates obesity-induced glucose intolerance, reduces β-cell mass, and alters islet lipid metabolism in male mice2014In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 155, no 10, p. 3843-3852Article in journal (Refereed)
    Abstract [en]

    The contribution of peroxisomal proliferator-activated receptor (PPAR)-γ agonism in pancreatic β-cells to the antidiabetic actions of thiazolidinediones has not been clearly elucidated. Genetic models of pancreatic β-cell PPARγ ablation have revealed a potential role for PPARγ in β-cell expansion in obesity but a limited role in normal β-cell physiology. Here we overexpressed PPARγ1 or PPARγ2 specifically in pancreatic β-cells of mice subjected to high-fat feeding using an associated adenovirus (β-PPARγ1-HFD and β-PPARγ2-HFD mice). We show β-cell-specific PPARγ1 or PPARγ2 overexpression in diet-induced obese mice exacerbated obesity-induced glucose intolerance with decreased β-cell mass, increased islet cell apoptosis, and decreased plasma insulin compared with obese control mice (β-eGFP-HFD mice). Analysis of islet lipid composition in β-PPARγ2-HFD mice revealed no significant changes in islet triglyceride content and an increase in only one of eight ceramide species measured. Interestingly β-PPARγ2-HFD islets had significantly lower levels of lysophosphatidylcholines, lipid species shown to enhance insulin secretion in β-cells. Gene expression profiling revealed increased expression of uncoupling protein 2 and genes involved in fatty acid transport and β-oxidation. In summary, transgenic overexpression of PPARγ in β-cells in diet-induced obesity negatively impacts whole-animal carbohydrate metabolism associated with altered islet lipid content, increased expression of β-oxidative genes, and reduced β-cell mass.

  • 23.
    Huppertz, Berthold
    et al.
    Institute of Cell Biology, Histology and Embryology, Centre of Molecular Medicine, Medical University of Graz, Graz, Austria.
    Gauster, Martin
    Institute of Cell Biology, Histology and Embryology, Centre of Molecular Medicine, Medical University of Graz, Graz, Austria.
    Orendi, Kristina
    Institute of Cell Biology, Histology and Embryology, Centre of Molecular Medicine, Medical University of Graz, Graz, Austria.
    König, Julia
    Institute of Cell Biology, Histology and Embryology, Centre of Molecular Medicine, Medical University of Graz, Graz, Austria.
    Moser, Gerit
    Institute of Cell Biology, Histology and Embryology, Centre of Molecular Medicine, Medical University of Graz, Graz, Austria.
    Oxygen as modulator of trophoblast invasion2009In: Journal of Anatomy, ISSN 0021-8782, E-ISSN 1469-7580, Vol. 215, no 1, p. 14-20Article in journal (Refereed)
    Abstract [en]

    At the time of blastocyst implantation the uterine spiral arteries have already undergone morphological changes in the absence of any extravillous trophoblast invasion. Only 2 weeks after implantation, extravillous trophoblast cells develop and come into first contact with decidual tissues. Invading through the decidual interstitium, extravillous trophoblasts potentially reach and transform spiral arteries into uteroplacental arteries. Spiral arterial erosion starts at about mid-first trimester, whereas flow of maternal blood into the intervillous space is continuously established only at the beginning of the second trimester. One key regulator of the number of extravillous trophoblasts is oxygen. The steep gradient in oxygen concentration within the first trimester placenta is diminished with the onset of maternal blood flow. This gradient is used by the trophoblast to generate a large number of invasive cells to adapt the arterial vasculature in the placental bed to the growing needs of the fetus. Changes in oxygen concentrations or other factors leading to alterations in the rates of proliferation and/or apoptosis of extravillous trophoblast clearly impact on the remodelling of the vessels. The respective consequences of a failure in trophoblast invasion are growth restrictions of the baby and perhaps other pregnancy complications.

  • 24.
    Hyötyläinen, Tuulia
    et al.
    Örebro University, School of Science and Technology. Department of Chemistry.
    Ahonen, Linda
    Steno Diabetes Center A/S, Gentofte, Denmark .
    Pöhö, Päivi
    Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
    Oresic, Matej
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Lipidomics in biomedical research-practical considerations2017In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1862, no 8, p. 800-803Article in journal (Refereed)
    Abstract [en]

    Lipids have many central physiological roles including as structural components of cell membranes, energy storage sources and intermediates in signaling pathways. Lipid-related disturbances are known to underlie many diseases and their co-morbidities. The emergence of lipidomics has empowered researchers to study lipid metabolism at the cellular as well as physiological levels at a greater depth than was previously possible. The key challenges ahead in the field of lipidomics in medical research lie in the development of experimental protocols and in silico techniques needed to study lipidomes at the systems level. Clinical questions where lipidomics may have an impact in healthcare settings also need to be identified, both from the health outcomes and health economics perspectives. This article is part of a Special Issue entitled: BBALIP_Lipidomics Opinion Articles edited by Sepp Kohlwein.

  • 25.
    Hyötyläinen, Tuulia
    et al.
    Steno Diabetes Center, Gentofte, Denmark; Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland.
    Orešič, Matej
    Steno Diabetes Center, Gentofte, Denmark; Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland.
    Bioanalytical techniques in nontargeted clinical lipidomics2016In: Bioanalysis, ISSN 1757-6180, E-ISSN 1757-6199, Vol. 8, no 4, p. 351-364Article in journal (Refereed)
    Abstract [en]

    Lipidomic analysis aims at comprehensive characterization of molecular lipids in biological systems. Due to the central role of lipid metabolism in many devastating diseases, lipidomics is being increasingly applied in biomedical research. Over the past years, advances in analytical techniques and bioinformatics enabled increasingly comprehensive and accurate coverage of lipids both in tissues and biofluids, yet many challenges remain. This review highlights recent progress in the domain of analytical lipidomics, with main emphasis on non-targeted methodologies for large scale clinical applications, as well as discusses some of the key challenges and opportunities in this field.

  • 26.
    Jatta, Ken
    et al.
    Örebro University, School of Health and Medical Sciences.
    Eliason, Gabriella
    Örebro University, School of Health and Medical Sciences.
    Portela-Gomes, Guida M.
    Grimelius, Lars
    Caro, Oscar
    Nilholm, Lennart
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences.
    Piehl-Aulin, Karin
    Örebro University, School of Health and Medical Sciences.
    Abdel-Halim, Samy M.
    Örebro University, School of Health and Medical Sciences.
    Overexpression of von Hippel-Lindau protein in skeletal muscles of patients with chronic obstructive pulmonary disease2009In: Journal of Clinical Pathology, ISSN 0021-9746, E-ISSN 1472-4146, Vol. 62, no 1, p. 70-76Article in journal (Refereed)
    Abstract [en]

    Background/aim: A Significant number of patients with chronic obstructive pulmonary disease (COPD) exhibit skeletal muscle wasting and decreased capillary area formation which have been correlated to increased mortality. The current study aimed to determine the molecular mechanisms mediating decreased capillary formation in COPD.

    Methods: Twenty-four COPD patients and twelve matching controls were recruited. COPD patients were divided into mild, moderate and severe groups according to GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria. Skeletal muscle biopsies were obtained from the tibialis anterior muscle. Fibre typing and capillary formation together with messenger RNA (mRNA) expression of hypoxia-inducible factors (HIF-1á and HIF-3á ), vascular endothelial growth factors (VEGF-A, -B and -C isoforms) and von Hippel Lindau (VHL) were determined. VHL expression and localization was further studied by immunohistochemistry.

    Results: Skeletal muscle capillary formation was significantly decreased with ascending disease severity. Compared to controls, a tendency to mRNA overexpression of HIF-1á, HIF-3á and VEGF isoforms was observed at mild and moderate COPD that decreased at the severe stage. By contrast, skeletal muscle biopsies from COPD patients exhibited significant overexpression of VHL both on the mRNA and protein levels by immunohistochemistry. VHL protein was further determined to be localized to satellite cells.

    Conclusions: Overexpression of VHL was identified in the skeletal muscle of patients with COPD. Increased VHL activity may exert a negative impact on transducing the hypoxic signal and may contribute to decreased capillarization in skeletal muscles of patients with COPD.

  • 27. Johansson, Magnus
    et al.
    Brooks, A J
    Jans, D A
    Vasudevan, S G
    A small region of the dengue virus-encoded RNA-dependent RNA polymerase, NS5, confers interaction with both the nuclear transport receptor importin-beta and the viral helicase, NS32001In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 82, no Pt 4, p. 735-745Article in journal (Refereed)
    Abstract [en]

    The dengue virus RNA-dependent RNA polymerase, NS5, and the protease/helicase, NS3, are multidomain proteins that have been shown to interact both in vivo and in vitro. A hyperphosphorylated form of NS5 that does not interact with NS3 has been detected in the nuclei of virus-infected cells, presumably as the result of the action of a functional nuclear localization sequence within the interdomain region of NS5 (residues 369-405). In this study, it is shown by using the yeast two-hybrid system that the C-terminal region of NS3 (residues 303-618) interacts with the N-terminal region of NS5 (residues 320-368). Further, it is shown that this same region of NS5 is also recognized by the cellular nuclear import receptor importin-beta. The interaction between NS5 and importin-beta and competition by NS3 with the latter for the same binding site on NS5 were confirmed by pull-down assays. The direct interaction of importin-beta with NS5 has implications for the mechanism by which this normally cytoplasmic protein may be targetted to the nucleus.

  • 28.
    Junker, Johan P.E.
    et al.
    Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA; Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Lönnqvist, Susanna
    Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Plastic Surgery, County of Östergötland, Linköping, Sweden.
    Rakar, Jonathan
    Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Plastic Surgery, County of Östergötland, Linköping, Sweden.
    Karlsson, Lisa K.
    Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Plastic Surgery, County of Östergötland, Linköping, Sweden.
    Grenegård, Magnus
    Department of Medical and Health Sciences, University Hospital of Linköping, Linköping, Sweden.
    Kratz, Gunnar
    Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Plastic Surgery, County of Östergötland, Linköping, Sweden.
    Differentiation of human dermal fibroblasts towards endothelial cells2013In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436, Vol. 85, no 3, p. 67-77Article in journal (Refereed)
    Abstract [en]

    The ultimate goal of vascular tissue engineering is the production of functional grafts for clinical use. Difficulties acquiring autologous endothelial cells have motivated the search for alternative cell sources. Differentiation of dermal fibroblasts towards several mesenchymal lineages as well as endothelial cells has been proposed. The aim of the present study was to investigate the endothelial differentiation capacity of human dermal fibroblasts on a gene expression, protein expression and functional physiological level. Endothelial differentiation of fibroblasts was induced by culturing cells in 30% human serum, but not in fetal calf serum. Expression of proteins and genes relevant for endothelial function and differentiation was increased after induction. Furthermore, fibroblasts exposed to 30% human serum displayed increased uptake of low-density lipoprotein and formation of capillary-like networks. The results of this study may have an impact on cell sourcing for vascular tissue engineering, and the development of methods for vascularization of autologous tissue engineered constructs.

  • 29. Kaminsky, Zachary A.
    et al.
    Tang, Thomas
    Wang, Sun-Chong
    Ptak, Carolyn
    Oh, Gabriel H. T.
    Wong, Albert H. C.
    Feldcamp, Laura A.
    Virtanen, Carl
    Halfvarson, Jonas
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences.
    McRae, Allan F.
    Visscher, Peter M.
    Montgomery, Grant W.
    Gottesman, Irving I.
    Martin, Nicholas G.
    Petronis, Art
    DNA methylation profiles in monozygotic and dizygotic twins2009In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 41, no 2, p. 240-245Article in journal (Refereed)
    Abstract [en]

    Twin studies have provided the basis for genetic and epidemiological studies in human complex traits. As epigenetic factors can contribute to phenotypic outcomes, we conducted a DNA methylation analysis in white blood cells (WBC), buccal epithelial cells and gut biopsies of 114 monozygotic (MZ) twins as well as WBC and buccal epithelial cells of 80 dizygotic (DZ) twins using 12K CpG island microarrays. Here we provide the first annotation of epigenetic metastability of approximately 6,000 unique genomic regions in MZ twins. An intraclass correlation (ICC)-based comparison of matched MZ and DZ twins showed significantly higher epigenetic difference in buccal cells of DZ co-twins (P = 1.2 x 10(-294)). Although such higher epigenetic discordance in DZ twins can result from DNA sequence differences, our in silico SNP analyses and animal studies favor the hypothesis that it is due to epigenomic differences in the zygotes, suggesting that molecular mechanisms of heritability may not be limited to DNA sequence differences.

  • 30.
    Ketola, Kirsi
    et al.
    Medical Biotechnology, VTT Technical Research Centre of Finland, Espoo, Finland; University of Turku, Turku, Finland.
    Hilvo, Mika
    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.
    Vuoristo, Anu
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Ruskeepää, Anna Liisa
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland.
    Kallioniemi, Olli Pekka
    Medical Biotechnology, VTT Technical Research Centre of Finland, Espoo, Finland; University of Turku, Turku, Finland; Institute for Molecular Medicine, Finland (FIMM), University of Helsinki, Helsinki, Finland.
    Iljin, Kristiina
    Medical Biotechnology, VTT Technical Research Centre of Finland, Espoo, Finland; University of Turku, Turku, Finland.
    Salinomycin inhibits prostate cancer growth and migration via induction of oxidative stress2012In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 106, no 1, p. 99-106Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We have shown that a sodium ionophore monensin inhibits prostate cancer cell growth. A structurally related compound to monensin, salinomycin, was recently identified as a putative cancer stem cell inhibitor.

    METHODS: The growth inhibitory potential of salinomycin was studied in a panel of prostate cells. To get insights into the mechanism of action, a variety of assays such as gene expression and steroid profiling were performed in salinomycin-exposed prostate cancer cells.

    RESULTS: Salinomycin inhibited the growth of prostate cancer cells, but did not affect non-malignant prostate epithelial cells. Salinomycin impacted on prostate cancer stem cell functions as evidenced by reduced aldehyde dehydrogenase activity and the fraction of CD44(+) cells. Moreover, salinomycin reduced the expression of MYC, AR and ERG, induced oxidative stress as well as inhibited nuclear factor-κB activity and cell migration. Furthermore, profiling steroid metabolites revealed increased levels of oxidative stress-inducing steroids 7-ketocholesterol and aldosterone and decreased levels of antioxidative steroids progesterone and pregnenolone in salinomycin-exposed prostate cancer cells.

    CONCLUSION: Our results indicate that salinomycin inhibits prostate cancer cell growth and migration by reducing the expression of key prostate cancer oncogenes, inducing oxidative stress, decreasing the antioxidative capacity and cancer stem cell fraction.

  • 31.
    Kruse, Robert
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Säve, Susanne
    School of Health and Medical Sciences, Clinical Research Center (KFC), Örebro University Hospital, Örebro, Sweden; School of Natural Sciences, Linnaeus University (SS), Kalmar, Sweden.
    Persson, Katarina
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. School of Health and Medical Sciences, Clinical Research Center (KFC), Örebro University Hospital, Örebro, Sweden; School of Natural Sciences, Linnaeus University (SS), Kalmar, Sweden.
    Adenosine triphosphate induced P2Y(2) receptor activation induces proinflammatory cytokine release in uroepithelial cells2012In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 188, no 6, p. 2419-2425Article in journal (Refereed)
    Abstract [en]

    Purpose: We characterized and identified the uroepithelial P2 receptor responsible for adenosine triphosphate mediated release of the cytokines interleukin-8 and 6.

    Materials and Methods: The human renal epithelial cell line A498 (ATCC™) was cultured and stimulated with different purinergic agonists with or without prior inhibition with different antagonists or signaling pathway inhibitors. Supernatant was analyzed for interleukin-8 and 6 by enzyme-linked immunosorbent assay. P2 receptor mRNA expression was assessed by real-time reverse transcriptase-polymerase chain reaction. The candidate receptor was knocked down with siRNA technology. Interleukin-8 and 6 responses were measured after purinergic stimulation of knocked down cells.

    Results: ATP and ATP-γ-S (Roche Diagnostics, Mannheim, Germany) were equipotent as inducers of interleukin-8 and 6 release. Agonist profile experiments using different P2 receptor agonists indicated that P2Y(2) was the main contributor to this release, although P2Y(11) and P2X(7) activation could not be excluded. Signaling pathway experiments showed that interleukin-8 release involved phospholipase C and inositol trisphosphate mediated signaling, indicating a P2Y receptor subtype. Antagonist experiments indicated P2Y(2) as the responsible receptor. Gene expression analysis of P2 receptors showed that strong expression of P2Y(2) receptor and subsequent knockdown of P2Y(2) receptor mRNA for 72 and 96 hours abrogated interleukin-8 and 6 release after purinergic stimulation with adenosine triphosphate-γ-S.

    Conclusions: Interleukin-8 and 6 release after purinergic stimulation in uroepithelial A498 cells is mediated through P2Y(2) receptor activation.

  • 32.
    Kumawat, Ashok Kumar
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Nyhlin, Nils
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Wickbom, Anna
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Bohr, Johan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Hultgren, Olof
    Örebro University Hospital. Department of Microbiology and Immunology, Örebro University Hospital, Örebro, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden.
    An In Vitro Model to Evaluate the Impact of the Soluble Factors from the Colonic Mucosa of Collagenous Colitis Patients on T Cells: Enhanced Production of IL-17A and IL-10 from Peripheral CD4(+) T Cells2014In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, article id 879843Article in journal (Refereed)
    Abstract [en]

    Soluble factors from intestinal mucosal cells contribute to immune homeostasis in the gut. We have established an in vitro model to investigate the regulatory role of soluble factors from inflamed intestinal mucosa of collagenous colitis (CC) patients in the differentiation of T cells. Peripheral blood CD4(+) T cells from healthy donors were polyclonally activated in the presence of conditioned medium (CM) generated from denuded biopsies (DNB) or isolated lamina propria mononuclear cells (LPMCs) from mucosal biopsies from CC patients compared to noninflamed controls, to determine proliferation and secretion of cytokines involved in T-cell differentiation. Compared to controls, we observed significantly increased production of the proinflammatory cytokines IFN-gamma, IL-17A, IL-6, and IL-1 beta and the anti-inflammatory cytokines IL-4 and IL-10 in the presence of CC-DNB-CM. The most pronounced effect of CC-LPMC-CM on peripheral CD4(+) T cells was a trend towards increased production of IL-17A and IL-10. A trend towards reduced inhibition of T-cell proliferation was noted in the presence of CC-DNB-CM. In conclusion, our in vitro model reveals implications of soluble factors from CC colonic mucosa on peripheral T cells, enhancing their production of both pro-and anti-inflammatory cytokines.

  • 33.
    Lamichhane, Santosh
    et al.
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Sen, Partho
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Dickens, Alex M.
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Bertram, Hanne Christine
    Department of Food Science, Aarhus University, Aarslev, Denmark.
    Gut metabolome meets microbiome: A methodological perspective to understand the relationship between host and microbe2018In: Methods, ISSN 1046-2023, E-ISSN 1095-9130, Vol. 149, p. 3-12Article in journal (Refereed)
    Abstract [en]

    It is well established that gut microbes and their metabolic products regulate host metabolism. The interactions between the host and its gut microbiota are highly dynamic and complex. In this review we present and discuss the metabolomic strategies to study the gut microbial ecosystem. We highlight the metabolic profiling approaches to study faecal samples aimed at deciphering the metabolic product derived from gut microbiota. We also discuss how metabolomics data can be integrated with metagenomics data derived from gut microbiota and how such approaches may lead to better understanding of the microbial functions. Finally, the emerging approaches of genome-scale metabolic modelling to study microbial co-metabolism and host-microbe interactions are highlighted.

  • 34.
    Lehtinen, Laura
    et al.
    Medical Biotechnology, VTT Technical Research Centre of Finland, Turku, Finland; Centre for Biotechnology, University of Turku, Turku, Finland.
    Vainio, Paula
    Medical Biotechnology, VTT Technical Research Centre of Finland, Turku, Finland; Centre for Biotechnology, University of Turku, Turku, Finland.
    Wikman, Harriet
    Institute of Tumour Biology, Centre of Experimental Medicine, University Medical Centre, Hamburg-Eppendorf, Germany.
    Reemts, Johannes
    Institute of Tumour Biology, Centre of Experimental Medicine, University Medical Centre, Hamburg-Eppendorf, Germany.
    Hilvo, Mika
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Issa, Rana
    Institute of Pathology, University Medical Centre, Hamburg-Eppendorf, Germany.
    Pollari, Sirkku
    Medical Biotechnology, VTT Technical Research Centre of Finland, Turku, Finland; Centre for Biotechnology, University of Turku, Turku, Finland.
    Brandt, Burkhard
    Institute of Clinical Chemistry, Schleswig-Holstein University Hospital, Kiel, Germany.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland.
    Pantel, Klaus
    Institute of Tumour Biology, Centre of Experimental Medicine, University Medical Centre, Hamburg-Eppendorf, Germany.
    Kallioniemi, Olli
    Medical Biotechnology, VTT Technical Research Centre of Finland, Turku, Finland; Centre for Biotechnology, University of Turku, Turku, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
    Iljin, Kristiina
    Medical Biotechnology, VTT Technical Research Centre of Finland, Turku, Finland; Centre for Biotechnology, University of Turku, Turku, Finland.
    15-Hydroxyprostaglandin dehydrogenase associates with poor prognosis in breast cancer, induces epithelial-mesenchymal transition, and promotes cell migration in cultured breast cancer cells2012In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 226, no 4, p. 674-686Article in journal (Refereed)
    Abstract [en]

    Breast cancer is the most frequent cancer and the leading cause of cancer-related deaths in women worldwide. The prognosis of breast cancer is tightly correlated with the degree of spread beyond the primary tumour. Arachidonic acid (AA) and prostaglandin E(2) (PGE(2)) are known to regulate tumour metastasis enabling epithelial-mesenchymal transition (EMT). However, the detailed role of 15-hydroxyprostaglandin dehydrogenase (HPGD), the key enzyme degrading prostaglandin E(2) , remains unclear in breast cancer. Here, we show that HPGD mRNA is overexpressed in a subset of clinical breast cancers compared to normal breast tissue samples and that high HPGD mRNA expression associates with poor prognosis. Immunohistochemical staining of primary breast cancer and lymph node metastasis tissue samples confirmed high HPGD protein expression in 20% of the samples, as well as associated HPGD expression with aggressive characteristics, such as increased risk of disease relapse and shorter disease-free survival. Results from cultured cells indicated abundant HPGD expression in highly metastatic breast cancer cells, and impairment of HPGD expression using RNA interference led to a significant decrease in transforming growth factor-β signalling, in cellular arachidonic acid levels as well as in cell migration. Furthermore, gene expression microarray analysis followed by quantitative RT-PCR validation showed that HPGD silencing decreased aryl hydrocarbon receptor signalling and induced mesenchymal-epithelial transition. In conclusion, our results indicate that HPGD is highly expressed in metastatic and aggressive breast cancer and promotes EMT and migration in breast cancer cells.

  • 35.
    Lui, Julian C.
    et al.
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Collaborative Research Centers (CRC),National Institutes of Health, Bethesda MD, USA.
    Garrison, Presley
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Collaborative Research Centers (CRC), National Institutes of Health, Bethesda MD, USA.
    Nguyen, Quang
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Collaborative Research Centers (CRC), National Institutes of Health, Bethesda MD, USA.
    Ad, Michal
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Collaborative Research Centers (CRC), National Institutes of Health, Bethesda MD, USA.
    Keembiyehetty, Chithra
    Genomic Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda MD, USA.
    Chen, Weiping
    Genomic Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda MD, USA.
    Jee, Youn Hee
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Collaborative Research Centers (CRC), National Institutes of Health, Bethesda MD, USA.
    Landman, Ellie
    Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; University Hospital, Stockholm, Sweden.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. University Hospital, Örebro, Sweden; Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; University Hospital, Stockholm, Sweden.
    Barnes, Kevin M.
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Collaborative Research Centers (CRC), National Institutes of Health, Bethesda, Maryland, USA.
    Baron, Jeffrey
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Collaborative Research Centers (CRC), National Institutes of Health, Bethesda MD, USA.
    EZH1 and EZH2 promote skeletal growth by repressing inhibitors of chondrocyte proliferation and hypertrophy2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 13685Article in journal (Refereed)
    Abstract [en]

    Histone methyltransferases EZH1 and EZH2 catalyse the trimethylation of histone H3 at lysine 27 (H3K27), which serves as an epigenetic signal for chromatin condensation and transcriptional repression. Genome-wide associated studies have implicated EZH2 in the control of height and mutations in EZH2 cause Weaver syndrome, which includes skeletal overgrowth. Here we show that the combined loss of Ezh1 and Ezh2 in chondrocytes severely impairs skeletal growth in mice. Both of the principal processes underlying growth plate chondrogenesis, chondrocyte proliferation and hypertrophy, are compromised. The decrease in chondrocyte proliferation is due in part to derepression of cyclin-dependent kinase inhibitors Ink4a/b, while ineffective chondrocyte hypertrophy is due to the suppression of IGF signalling by the increased expression of IGF-binding proteins. Collectively, our findings reveal a critical role for H3K27 methylation in the regulation of chondrocyte proliferation and hypertrophy in the growth plate, which are the central determinants of skeletal growth.

  • 36.
    Lång, Anna
    et al.
    Linköpings Universitet.
    Palmebäck Wegman, Pia
    Örebro University, School of Health and Medical Sciences.
    Wingren, Sten
    Örebro University, School of Health and Medical Sciences.
    The significance of MDM2 SNP309 and p53 Arg72Pro in young women with breast cancer2009In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 22, no 3, p. 575-579Article in journal (Refereed)
    Abstract [en]

    The p53 protein and its regulator MDM2 is central to tumorigenesis by directing cells to undergo cell cycle arrest and/or apoptosis in response to DNA damage or other stress signals. The genes encoding these proteins contain nucleotide variation (p53 codon 72, MDM2 SNP309) that influences cellular response. We examined the p53 codon 72 and MDM2 SNP309 to determine their implication with age of disease onset and risk of breast cancer in young women (≤36 years). No risk of breast cancer was observed for the genotypes of p53 and MDM2, however, a tendency (P=0.15) towards increased risk of early onset breast cancer was observed in carriers of two or more Pro and/or G alleles. We further calculated the influence on age at diagnosis. Cases were grouped according to the number of G and Pro alleles (0, 1, 2 or 3-4) and age at diagnosis. A significant trend towards decreased age at diagnosis with increased number of risk alleles was found (P=0.013). Our results suggest that p53 codon 72 and MDM2 SNP309 may be implicated in early onset breast cancer.

  • 37.
    Mackey, Abigail L.
    et al.
    Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M, Bispebjerg Hospital, Copenhagen, Denmark; Department of Biomedical Sciences, Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Rasmussen, Lotte K.
    Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M, Bispebjerg Hospital, Copenhagen, Denmark.
    Kadi, Fawzi
    Örebro University, School of Health Sciences.
    Schjerling, Peter
    Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M, Bispebjerg Hospital, Copenhagen, Denmark.
    Helmark, Ida C.
    Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M, Bispebjerg Hospital, Copenhagen, Denmark.
    Ponsot, Elodie
    Örebro University, School of Health Sciences.
    Aagaard, Per
    Department of Sports Science and Clinical Biomechanics, Muscle Research Cluster, University of Southern Denmark, Odense, Denmark.
    Durigan, João Luiz Q.
    Physical Therapy Division, University of Brasília, Brasília, Brazil.
    Kjaer, Michael
    Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M, Bispebjerg Hospital, Copenhagen, Denmark; Department of Biomedical Sciences, Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Activation of satellite cells and the regeneration of human skeletal muscle are expedited by ingestion of nonsteroidal anti-inflammatory medication2016In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 30, no 6, p. 2266-2281Article in journal (Refereed)
    Abstract [en]

    With this study we investigated the role of nonsteroidal anti-inflammatory drugs (NSAIDs) in human skeletal muscle regeneration. Young men ingested NSAID [1200 mg/d ibuprofen (IBU)] or placebo (PLA) daily for 2 wk before and 4 wk after an electrical stimulation-induced injury to the leg extensor muscles of one leg. Muscle biopsies were collected from the vastus lateralis muscles before and after stimulation (2.5 h and 2, 7, and 30 d) and were assessed for satellite cells and regeneration by immunohistochemistry and real-time RT-PCR, and we also measured telomere length. After injury, and compared with PLA, IBU was found to augment the proportion of ActiveNotch1(+) satellite cells at 2 d [IBU, 29 ± 3% vs. PLA, 19 ± 2% (means ± sem)], satellite cell content at 7 d [IBU, 0.16 ± 0.01 vs. PLA, 0.12 ± 0.01 (Pax7(+) cells/fiber)], and to expedite muscle repair at 30 d. The PLA group displayed a greater proportion of embryonic myosin(+) fibers and a residual ∼2-fold increase in mRNA levels of matrix proteins (all P < 0.05). Endomysial collagen was also elevated with PLA at 30 d. Minimum telomere length shortening was not observed. In conclusion, ingestion of NSAID has a potentiating effect on Notch activation of satellite cells and muscle remodeling during large-scale regeneration of injured human skeletal muscle.-Mackey, A. L., Rasmussen, L. K., Kadi, F., Schjerling, P., Helmark, I. C., Ponsot, E., Aagaard, P., Durigan, J. L. Q., Kjaer, M. Activation of satellite cells and the regeneration of human skeletal muscle are expedited by ingestion of nonsteroidal anti-inflammatory medication.

  • 38.
    Melik, Wessam
    et al.
    School of Life Sciences, Södertörn University, Huddinge, Sweden.
    Ellencrona, Karin
    School of Life Sciences, Södertörn University, Huddinge, Sweden.
    Wigerius, Michael
    School of Life Sciences, Södertörn University, Huddinge, Sweden; Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax NS, Canada.
    Hedström, Christer
    School of Life Sciences, Södertörn University, Huddinge, Sweden.
    Elväng, Annelie
    School of Life Sciences, Södertörn University, Huddinge, Sweden.
    Johansson, Magnus
    Örebro University, School of Medicine, Örebro University, Sweden. School of Life Sciences, Södertörn University, Huddinge, Sweden.
    Two PDZ binding motifs within NS5 have roles in Tick-borne encephalitis virus replication2012In: Virus Research, ISSN 0168-1702, E-ISSN 1872-7492, Vol. 169, no 1, p. 54-62Article in journal (Refereed)
    Abstract [en]

    The flavivirus genus includes important human neurotropic pathogens like Tick-borne encephalitis virus (TBEV) and West-Nile virus (WNV). Flavivirus replication occurs at replication complexes, where the NS5 protein provides both RNA cap methyltransferase and RNA-dependent RNA polymerase activities. TBEVNS5 contains two PDZ binding motifs (PBMs) important for specific targeting of human PDZ proteins including Scribble, an association important for viral down regulation of cellular defense systems and neurite outgrowth. To determine whether the PBMs of TBEVNS5 affects virus replication we constructed a DNA based sub-genomic TBEV replicon expressing firefly luciferase. The PBMs within NS5 were mutated individually and in concert and the replicons were assayed in cell culture. Our results show that the replication rate was impaired in all mutants, which indicates that PDZ dependent host interactions influence TBEV replication. We also find that the C-terminal PBMs present in TBEVNS5 and WNVNS5 are targeting various human PDZ domain proteins. TBEVNS5 has affinity to Zonula occludens-2 (ZO-2), GIAP C-terminus interacting protein (GIPC), calcium/calmodulin-dependent serine protein kinase (CASK), glutamate receptor interacting protein 2, (GRIP2) and Interleukin 16 (IL-16). A different pattern was observed for WNVNS5 as it associate with a broader repertoire of putative host PDZ proteins.

  • 39.
    Mohlin, Camilla
    et al.
    Department of Chemistry and Biomedicine, Linnaeus University, Kalmar, Sweden.
    Delbro, Dick
    Örebro University, School of Medical Sciences.
    Kvanta, Anders
    Department of Clinical Neuroscience, Section for Ophthalmology and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden.
    Johansson, Kjell
    Department of Science, Kristianstad University, Kristianstad, Sweden.
    Evaluation of Congo Red Staining in Degenerating Porcine Photoreceptors In Vitro: Protective Effects by Structural and Trophic Support2018In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 66, no 9, p. 631-641Article in journal (Refereed)
    Abstract [en]

    Congo red (CR) is a histological stain used for the detection of extracellular amyloids mediating various neurodegenerative diseases. Given that damaged photoreceptors appear to degenerate similarly to other nerve cells, CR staining was evaluated in experimentally injured porcine retina. CR staining appeared mostly as discrete cytosolic deposits with no obvious plaque formation during the investigated time period. Increases of CR labeling coincided temporally with the known accumulation of mislocalized opsins and increases of cell death. Coculture, either with human retinal pigment epithelium (ARPE) or human neural progenitor (ReN) cells, was accompanied by a significant reduction of CR labeling. Of particular interest was the reduction of CR labeling in cone photoreceptors, which are important for the perception of color and fine details and afflicted in age-related macular degeneration (AMD). Electron microscopy revealed inclusions in the inner segment, cell body, and occasionally synaptic terminals of photoreceptor cells in cultured specimens. Closer examinations indicated the presence of different types of inclusions resembling protein aggregates as well as inclusion bodies. The current results indicate that injury-related response resulted in accumulation of CR deposits in photoreceptor cells, and that trophic and/or structural support attenuated this response.

  • 40.
    Mohlin, Camilla
    et al.
    Faculty of Health and Life Science, Linnaeus Center of Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden.
    Sandholm, Kerstin
    Faculty of Health and Life Science, Linnaeus Center of Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden.
    Kvanta, Anders
    Department of Clinical Neuroscience, Section for Ophthalmology and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden.
    Ekdahl, Kristina N.
    Faculty of Health and Life Science, Linnaeus Center of Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden; Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala, Sweden.
    Johansson, Kjell
    Örebro University, School of Medical Sciences.
    A model to study complement involvement in experimental retinal degeneration2018In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 123, no 1, p. 28-42Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The complement system (CS) plays a role in the pathogenesis of a number of ocular diseases, including diabetic retinopathy (DR), glaucoma, uveitis, and age-related macular degeneration (AMD). Given that many of the complex eye-related degenerative diseases have limited treatment opportunities, we aimed to mimic the in vivo retinal degenerative process by developing a relevant co-culture system.

    METHOD AND MATERIALS: The adult porcine retina was co-cultured with the spontaneously arising human retinal pigment epithelial cells-19 (ARPE-19).

    RESULTS: Inflammatory activity was found after culture and included migrating microglial cells, gliosis, cell death, and CS activation (demonstrated by a minor increase in the secreted anaphylotoxin C3a in co-culture). CS components, including C1q, C3, C4, soluble C5b-9, and the C5a receptor, were expressed in the retina and/or ARPE cells after culture. C1q, C3, and CS regulators such as C4 binding protein (C4BP), factor H (CFH), and factor I (CFI) were secreted after culture.

    DISCUSSION: Thus, our research indicates that this co-culturing system may be useful for investigations of the CS and its involvement in experimental neurodegenerative diseases.

  • 41.
    Moulder, Robert
    et al.
    Turku Centre for Biotechnology, University of Turku, Turku, Finland; Åbo Akademi University, Turku, Finland.
    Lönnberg, Tapio
    Turku Centre for Biotechnology, University of Turku, Turku, Finland; Åbo Akademi University, Turku, Finland; National Graduate School in Computational Biology, Bioinformatics and Biometry, Helsinki, Finland.
    Elo, Laura L.
    Turku Centre for Biotechnology, University of Turku, Turku, Finland; Åbo Akademi University, Turku, Finland; National Graduate School in Computational Biology, Bioinformatics and Biometry, Helsinki, Finland; Department of Mathematics, University of Turku, Turku, Finland.
    Filén, Jan-Jonas
    Turku Centre for Biotechnology, University of Turku, Turku, Finland; Åbo Akademi University, Turku, Finland; National Graduate School in Informational and Structural Biology, Turku, Finland.
    Rainio, Eeva
    Turku Centre for Biotechnology, University of Turku, Turku, Finland; Åbo Akademi University, Turku, Finland.
    Corthals, Garry
    Turku Centre for Biotechnology, University of Turku, Turku, Finland; Åbo Akademi University, Turku, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland.
    Nyman, Tuula A.
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
    Aittokallio, Tero
    Department of Mathematics, University of Turku, Turku, Finland.
    Lahesmaa, Riitta
    Turku Centre for Biotechnology, University of Turku, Turku, Finland; Åbo Akademi University, Turku, Finland.
    Quantitative proteomics analysis of the nuclear fraction of human CD4+ cells in the early phases of IL-4-induced Th2 differentiation2010In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 9, no 9, p. 1937-1953Article in journal (Refereed)
    Abstract [en]

    We used stable isotope labeling with 4-plex iTRAQ (isobaric tags for relative and absolute quantification) reagents and LC-MS/MS to investigate proteomic changes in the nucleus of activated human CD4(+) cells during the early stages of Th2 cell differentiation. The effects of IL-4 stimulation upon activated naïve CD4(+) cells were measured in the nuclear fractions from 6 and 24 h in three biological replicates, each using pooled cord blood samples derived from seven or more individuals. In these analyses, in the order of 800 proteins were detected with two or more peptides and quantified in three biological replicates. In addition to consistent differences observed with the nuclear localization/expression of established human Th2 and Th1 markers, there were changes that suggested the involvement of several proteins either only recently reported or otherwise not known in this context. These included SATB1 and among the novel changes detected and validated an IL-4-induced increase in the level of YB1. This unique data set from human cord blood CD4(+) T cells details an extensive list of protein determinations that compares with and complements previous data determined from the Jurkat cell nucleus.

  • 42.
    Nilsson, Torbjörn K.
    et al.
    Department of Medical Biosciences/Clinical Chemistry, Umeå University, Umeå, Sweden.
    Hurtig-Wennlöf, Anita
    Örebro University, School of Health Sciences.
    Sjöström, Michael
    Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden.
    Herrmann, Wolfgang
    Department of Clinical Chemistry and Laboratory Medicine, Saarland University Hospital, Homburg, Germany.
    Obeid, Rima
    Department of Clinical Chemistry and Laboratory Medicine, Saarland University Hospital, Homburg, Germany.
    Owen, Jennifer R.
    Nutrition Research Institute, University of North Carolina, Chapel Hill, USA.
    Zeisel, Steven
    Nutrition Research Institute, University of North Carolina, Chapel Hill, USA; Department of Nutrition, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA.
    Plasma 1-carbon metabolites and academic achievement in 15-yr-old adolescents2016In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 30, no 4, p. 1683-1688Article in journal (Refereed)
    Abstract [en]

    Academic achievement in adolescents is correlated with 1-carbon metabolism (1-CM), as folate intake is positively related and total plasma homocysteine (tHcy) negatively related to academic success. Because another 1-CM nutrient, choline is essential for fetal neurocognitive development, we hypothesized that choline and betaine could also be positively related to academic achievement in adolescents. In a sample of 15-yr-old children (n = 324), we measured plasma concentrations of homocysteine, choline, and betaine and genotyped them for 2 polymorphisms with effects on 1-CM, methylenetetrahydrofolate reductase (MTHFR) 677C>T, rs1801133, and phosphatidylethanolamine N-methyltransferase (PEMT), rs12325817 (G>C). The sum of school grades in 17 major subjects was used as an outcome measure for academic achievement. Lifestyle and family socioeconomic status (SES) data were obtained from questionnaires. Plasma choline was significantly and positively associated with academic achievement independent of SES factors (paternal education and income, maternal education and income, smoking, school) and of folate intake (P = 0.009, R-2 = 0.285). With the addition of the PEMT rs12325817 polymorphism, the association value was only marginally changed. Plasma betaine concentration, tHcy, and the MTHFR 677C>T polymorphism did not affect academic achievement in any tested model involving choline. Dietary intake of choline is marginal in many adolescents and may be a public health concern.

  • 43.
    Nylander, M
    et al.
    Cardiovascular Inflammation Research Centre, Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, Sweden; Deparment of Medical and Health Science, Division of Pharmacology, Linköping University, Sweden; Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, University Hospital, Linköping, Sweden.
    Lindahl, T L
    Cardiovascular Inflammation Research Centre, Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, Sweden.
    Bengtsson, Torbjörn
    Deparment of Medical and Health Science, Division of Pharmacology, Linköping University, Sweden.
    Grenegård, M
    Deparment of Medical and Health Science, Division of Pharmacology, Linköping University, Sweden.
    The periodontal pathogen Porphyromonas gingivalis sensitises human blood platelets to epinephrine2008In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 19, no 5, p. 352-358Article in journal (Refereed)
    Abstract [en]

    Recent studies indicate connections between periodontitis and atherothrombosis, and the periodontal pathogen Porphyromonas gingivalis has been found within atherosclerotic lesions. P. gingivalis-derived proteases, designated gingipains activate human platelets, probably through a "thrombin-like" activity on protease-activated receptors (PARs). However, the potential interplay between P. gingivalis and other physiological platelet activators has not been investigated. The aim of this study was to elucidate consequences and mechanisms in the interaction between P. gingivalis and the stress hormone epinephrine. By measuring changes in light transmission through platelet suspensions, we found that P. gingivalis provoked aggregation, whereas epinephrine alone never had any effect. Intriguingly, pre-treatment of platelets with a low, sub-threshold number of P. gingivalis (i.e. a density that did not directly provoke platelet aggregation) resulted in a marked aggregation response when epinephrine was added. This synergistic action was not inhibited by the cyclooxygenas inhibitor aspirin. Furthermore, fura-2-measurements revealed that epinephrine caused an intracellular Ca(2+) mobilization in P. gingivalis pre-treated platelets, whereas epinephrine alone had no effect. Inhibition of the arg-specific gingipains, but not the lys-specific gingipains, abolished the aggregation and the Ca(2+) response provoked by epinephrine. Similar results were achieved by separate blockage of platelet alpha(2)-adrenergic receptors and PARs. In conclusion, the present study shows that a sub-threshold number of P. gingivalis sensitizes platelets to epinephrine. We suggest that P. gingivalis-derived arg-specific gingipains activates a small number of PARs on the surface of the platelets. This leads to an unexpected Ca(2+) mobilization and a marked aggregation response when epinephrine subsequently binds to the alpha(2)-adrenergic receptor. The present results are consistent with a direct connection between periodontitis and stress, and describe a novel mechanism that may contribute to pathological platelet activation.

  • 44. Olsson, G. M.
    et al.
    Montgomery, Scott M.
    Örebro University, School of Health and Medical Sciences.
    Alm, J.
    Family conditions and dietary control in phenylketonuria2007In: Journal of Inherited Metabolic Disease, ISSN 0141-8955, E-ISSN 1573-2665, Vol. 30, no 5, p. 708-715Article in journal (Refereed)
    Abstract [en]

    Objective This investigation is an attempt to describe coping with phenylketonuria (PKU) in order to understand some aspects underlying good compliance. Methods The coping concept was applied to PKU in two questionnaires. Self- and parental ratings were combined with assessments of phenylalanine levels and the severity of the disease. All Swedish patients with PKU born in 1980–91, a total of 53 children and youths with their parents, were invited to participate in the study and 41 (77%) of them did so. Results The patients turned out to have good compliance with the diet. The main result was that patients with separated or divorced parents were more likely to have higher phenylalanine levels and this association was not diminished by adjustment for the potential confounding factors. Conclusion Patients’ need for support must be judged individually according to different family conditions.

  • 45.
    Osman, Abdimajid
    et al.
    Clinical and Experimental Medicine, Department of Clinical Chemistry, Linköping University, Linköping, Sweden.
    Fälker, Knut
    Clinical and Experimental Medicine, Department of Clinical Chemistry, Linköping University, Linköping, Sweden.
    Characterization of human platelet microRNA by quantitative PCR coupled with an annotation network for predicted target genes2011In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 22, no 6, p. 433-41Article in journal (Refereed)
    Abstract [en]

    Platelets are anucleate blood cells that play a crucial role in thrombosis and hemostasis. Despite their lack of nuclear DNA, platelets contain significant amounts of microRNA (miRNA) that may have vital functions in post-transcriptional gene regulation. Here, we combined comprehensive miRNA expression profiling by quantitative PCR with target prediction analysis for the most abundant miRNAs in human platelets. A network composed of predicted platelet miRNA target genes was then constructed, using annotations available in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. In addition, we evaluated possible differences in miRNA levels between resting and thrombin-stimulated platelets. We identified 281 transcripts, including 228 mature miRNAs and 53 minor miRNAs (or miR*), of which six miRNAs (miR-15 a, miR-339-3 p, miR-365, miR-495, miR-98, and miR-361-3 p) were up- or down-regulated in activated human platelets (P ≤ 0.001). A redundancy-reduced network was established that encompassed 246 genes in five statistically significant functional clusters representing platelet miRNA regulating pathways. Comparison of the 246 network genes with the platelet mRNA expression data available at ArrayExpress database confirmed that most of these genes (89%) are expressed in human platelets. In conclusion, this work affirms a recent microarray study reporting a wide-spread existence of miRNAs in human platelets. Further, we observed that thrombin stimulation was associated with altered levels of some miRNAs in platelets. The proposed functional network, combining computational prediction analysis with annotations from experimental observations, may in addition provide some information about probable miRNA target pathways in human platelets.

  • 46.
    Palm, Eleonor
    et al.
    Örebro University, School of Medical Sciences.
    Demirel, Isak
    Örebro University, School of Medical Sciences.
    Bengtsson, Torbjörn
    Örebro University, School of Medical Sciences.
    Khalaf, Hazem
    Örebro University, School of Medical Sciences.
    The role of toll-like and protease-activated receptors and associated intracellular signaling in Porphyromonas gingivalis-infected gingival fibroblasts2017In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 125, no 2, p. 157-169Article in journal (Refereed)
    Abstract [en]

    Porphyromonas gingivalis, which is considered a keystone agent in periodontitis, has evolved elaborate mechanisms to grow and survive in a hostile milieu. The gingival fibroblast is the major cell type in the gingiva and is considered to be important in the periodontitis-associated inflammation. As a part of the innate immune response, they produce cytokines such as CXCL8 and interleukin (IL)-6 which are believed to contribute to the destruction of the tooth-supporting tissues. This study investigates how the expression of protease-activated receptors (PAR1, PAR2) and toll-like receptors (TLR2, TLR4) changes with P. gingivalis exposure and how silencing of one receptor affects the expression of the other receptors. The importance of protein kinase C (PKC) and p38 in the regulation of CXCL8 and IL-6 was also examined. Receptors were knockdown with small-interfering RNA. PKC or p38 was blocked prior to stimulation with P. gingivalis. Fibroblasts were able to compensate for PAR1 knockdown with increased expression of PAR2. PKC and p38 were involved in the regulation of P. gingivalis-induced CXCL8 and IL-6. Our results indicate that PAR1 and PAR2 could be implicated in periodontitis and that PKC and P38 play a role in the inflammatory response in P. gingivalis-infected gingival fibroblasts.

  • 47.
    Paramel Varghese, Geena
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Zhang, Boxi
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Khalaf, Hazem
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Ljungberg, Liza U.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Medicine, Örebro University, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Poryphyromonas gingivalis induces IL-1β in aortic smooth muscle cells: possible role of gingipains?Manuscript (preprint) (Other academic)
  • 48.
    Pietiläinen, Kirsi H
    et al.
    Department of Medicine, Division of Internal Medicine, Department of Psychiatry, Obesity Research Unit, Helsinki University Central Hospital, Helsinki, Finland; Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland; Institute for Molecular Medicine Finland, Helsinki, Finland.
    Róg, Tomasz
    Department of Physics, Tampere University of Technology, Tampere, Finland.
    Seppänen-Laakso, Tuulikki
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Virtue, Sam
    Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
    Gopalacharyulu, Peddinti
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Tang, Jing
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Rodriguez-Cuenca, Sergio
    Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
    Maciejewski, Arkadiusz
    Department of Physics, Tampere University of Technology, Tampere, Finland; Department of Computational Biophysics and Bioinformatics, Jagiellonian University, Kraków, Poland.
    Naukkarinen, Jussi
    Department of Medical Genetics, University of Helsinki, Helsinki, Finland; Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.
    Ruskeepää, Anna-Liisa
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Niemelä, Perttu S
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Yetukuri, Laxman
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Tan, Chong Yew
    Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
    Velagapudi, Vidya
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Castillo, Sandra
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Nygren, Heli
    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.
    Rissanen, Aila
    Department of Medicine, Division of Internal Medicine, Department of Psychiatry, Obesity Research Unit, Helsinki University Central Hospital, Helsinki, Finland.
    Kaprio, Jaakko
    Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland; Institute for Molecular Medicine Finland, Helsinki, Finland; Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.
    Yki-Järvinen, Hannele
    Division of Diabetes, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
    Vattulainen, Ilpo
    Department of Physics, Tampere University of Technology, Tampere, Finland; Department of Applied Physics, School of Science and Technology, Aalto University, Espoo, Finland; MEMPHYS-Center for Biomembrane Physics, University of Southern Denmark, Odense, Denmark.
    Vidal-Puig, Antonio
    Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
    Oresic, Matej
    Institute for Molecular Medicine Finland, Helsinki, Finland; VTT Technical Research Centre of Finland, Espoo, Finland.
    Association of lipidome remodeling in the adipocyte membrane with acquired obesity in humans2011In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 9, no 6, article id e1000623Article in journal (Refereed)
    Abstract [en]

    Identification of early mechanisms that may lead from obesity towards complications such as metabolic syndrome is of great interest. Here we performed lipidomic analyses of adipose tissue in twin pairs discordant for obesity but still metabolically compensated. In parallel we studied more evolved states of obesity by investigating a separated set of individuals considered to be morbidly obese. Despite lower dietary polyunsaturated fatty acid intake, the obese twin individuals had increased proportions of palmitoleic and arachidonic acids in their adipose tissue, including increased levels of ethanolamine plasmalogens containing arachidonic acid. Information gathered from these experimental groups was used for molecular dynamics simulations of lipid bilayers combined with dependency network analysis of combined clinical, lipidomics, and gene expression data. The simulations suggested that the observed lipid remodeling maintains the biophysical properties of lipid membranes, at the price, however, of increasing their vulnerability to inflammation. Conversely, in morbidly obese subjects, the proportion of plasmalogens containing arachidonic acid in the adipose tissue was markedly decreased. We also show by in vitro Elovl6 knockdown that the lipid network regulating the observed remodeling may be amenable to genetic modulation. Together, our novel approach suggests a physiological mechanism by which adaptation of adipocyte membranes to adipose tissue expansion associates with positive energy balance, potentially leading to higher vulnerability to inflammation in acquired obesity. Further studies will be needed to determine the cause of this effect.

  • 49.
    Prieur, Xavier
    et al.
    Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Institut du Thorax, Institut National de la Santé et de la Recherche Médicale U915, Nantes, France.
    Mok, Crystal Y. L.
    Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Velagapudi, Vidya R
    Technical Research Centre of Finland (VTT), Espoo, Finland.
    Núñez, Vanessa
    Department of Regenerative Cardiology, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
    Fuentes, Lucía
    Department of Regenerative Cardiology, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
    Montaner, David
    Department of Bioinformatics and Genomics, Functional Genomics Node (INB) at CIPF, Centro de Investigación Príncipe Felipe (CIFP), Valencia, Spain.
    Ishikawa, Ko
    Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Camacho, Alberto
    Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Barbarroja, Nuria
    Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    O'Rahilly, Stephen
    Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Sethi, Jaswinder K
    Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Dopazo, Joaquin
    Department of Regenerative Cardiology, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Technical Research Centre of Finland (VTT), Espoo, Finland.
    Ricote, Mercedes
    Department of Regenerative Cardiology, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
    Vidal-Puig, Antonio
    Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice2011In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, no 3, p. 797-809Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Obesity-associated insulin resistance is characterized by a state of chronic, low-grade inflammation that is associated with the accumulation of M1 proinflammatory macrophages in adipose tissue. Although different evidence explains the mechanisms linking the expansion of adipose tissue and adipose tissue macrophage (ATM) polarization, in the current study we investigated the concept of lipid-induced toxicity as the pathogenic link that could explain the trigger of this response.

    RESEARCH DESIGN AND METHODS: We addressed this question using isolated ATMs and adipocytes from genetic and diet-induced murine models of obesity. Through transcriptomic and lipidomic analysis, we created a model integrating transcript and lipid species networks simultaneously occurring in adipocytes and ATMs and their reversibility by thiazolidinedione treatment.

    RESULTS: We show that polarization of ATMs is associated with lipid accumulation and the consequent formation of foam cell-like cells in adipose tissue. Our study reveals that early stages of adipose tissue expansion are characterized by M2-polarized ATMs and that progressive lipid accumulation within ATMs heralds the M1 polarization, a macrophage phenotype associated with severe obesity and insulin resistance. Furthermore, rosiglitazone treatment, which promotes redistribution of lipids toward adipocytes and extends the M2 ATM polarization state, prevents the lipid alterations associated with M1 ATM polarization.

    CONCLUSIONS: Our data indicate that the M1 ATM polarization in obesity might be a macrophage-specific manifestation of a more general lipotoxic pathogenic mechanism. This indicates that strategies to optimize fat deposition and repartitioning toward adipocytes might improve insulin sensitivity by preventing ATM lipotoxicity and M1 polarization.

  • 50.
    Ragnarsson, Eva G. E.
    et al.
    Department of Pharmacy, Uppsala University, Uppsala.
    Schoultz, Ida
    Division of Surgery, Department of Clinical and Experimental Medicine, Linköping University, Linköping.
    Gullberg, Elisabet
    Department of Pharmacy, Uppsala University, Uppsala; Division of Surgery, Department of Clinical and Experimental Medicine, Linköping University, Linköping.
    Carlsson, Anders H.
    Division of Surgery, Department of Clinical and Experimental Medicine, Linköping University, Linköping.
    Tafazoli, Farideh
    Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Lerm, Maria
    Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Magnusson, Karl-Eric
    Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Söderholm, Johan D.
    Division of Surgery, Department of Clinical and Experimental Medicine, Linköping University, Linköping.
    Artursson, Per
    Department of Pharmacy, Uppsala University, Uppsala.
    Yersinia pseudotuberculosis induces transcytosis of nanoparticles across human intestinal villus epithelium via invasin-dependent macropinocytosis2008In: Laboratory Investigation, ISSN 0023-6837, E-ISSN 1530-0307, Vol. 88, no 11, p. 1215-26Article in journal (Refereed)
    Abstract [en]

    Crohn's disease is characterized by a defect in intestinal barrier function, where bacteria are considered the most important inflammation-driving factor. Enteric bacteria, including E. coli and Yersinia spp, affect tight junctions in enterocytes, but little is known about bacterial effects on the transcellular pathway. Our objective was to study the short-term effects of Y. pseudotuberculosis on uptake of nanoparticles across human villus epithelium. Monolayers of human colon epithelium-derived Caco-2 cells and biopsies of normal human ileum were studied after 2 h exposure to Y. pseudotuberculosis expressing (inv+) or lacking (inv-) the bacterial adhesion molecule, invasin. Transepithelial transport of fluorescent nanoparticles (markers of transcytosis) was quantified by flow cytometry, and mechanisms explored by using inhibitors of endocytosis. Epithelial expressions of beta1-integrin and particle uptake pathways were studied by confocal microscopy. The paracellular pathway was assessed by electrical resistance (TER), mannitol flux, and expression of tight junction proteins occludin and caludin-4 by confocal microscopy. Inv+ Y. pseudotuberculosis adhered to the apical surface of epithelial cells and induced transcytosis of exogenous nanoparticles across Caco-2 monolayers (30-fold increase, P<0.01) and ileal mucosa (268+/-47% of control; P<0.01), whereas inv bacteria had no effect on transcytosis. The transcytosis was concentration-, particle size- and temperature-dependent, and possibly mediated via macropinocytosis. Y. pseudotuberculosis also induced apical expression of beta1-integrin on epithelial cells. A slight drop in TER was seen after exposure to inv+ Y. pseudotuberculosis, whereas mannitol flux and tight junction protein expression was unchanged. In summary, Y. pseudotuberculosis induced apical expression of beta1-integrin and stimulated uptake of nanoparticles via invasin-dependent transcytosis in human intestinal epithelium. Our findings suggest that bacterial factors may initiate transcytosis of luminal exogenous particles across human ileal mucosa, thus presenting a novel mechanism of intestinal barrier dysfunction.

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