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  • 1.
    Asfaw Idosa, Berhane
    Örebro University, School of Medical Sciences.
    Inflammasome polymorphisms and the Inflammatory Response to Bacterial Infections2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    NLRP3 inflammasome; a key component of the innate immune system, can be activated by a number of pathogens and other threats of the body. Activation of the NLRP3 inflammasome triggers caspase-1 mediated maturationof IL-1β and IL-18. Polymorphisms Q705K and C10X are two gene variants of the NLRP3 inflammasome that combined or per se have been associated with higher risk and severity of chronic inflammation and excessive production of IL-1β. Host genetic factors have been found an important determinants of susceptibility of infectious diseases and disease outcome. The aims of this thesis were to investigate the association between polymorphisms Q705K and C10X with bacterial infections and the inflammatory response, moreover to determine the inflammasome activation state in healthy carriers of these polymorphisms. The data of the thesis show higher levels of IL-1β and IL-33 in healthy carriers of combined polymorphisms of Q705K and C10X as compared to non-carrier controls. This may provide individuals with combined polymorphisms a more robust innate immune response against pathogens, but could also lead to the onset of chronic inflammation, and excessive inflammation during acute infection. In addition, individuals with C10X polymorphism per se showed association with the presence of bacteremia as compared withhealthy blood donors. No association was found in severely ill patients with negative blood culture bottle. In addition, the results show that LOS of N. meningitidis is responsible for the priming and activating steps of the inflammasome. The non-LOS components were found to contribute to the priming step. A higher inflammatory response to N. meningitidis was found in individuals who were non-carriers of the polymorphisms than individuals with the Q705K and C10X per se or combined regardless of the strain of bacteria. Taken together, the gene variations of the NLRP3 inflammasome are of importance in explaining inter-individual variation in susceptibility to infectious diseases.

    List of papers
    1. Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the NLRP3 inflammasome
    Open this publication in new window or tab >>Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the NLRP3 inflammasome
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    2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10Article in journal (Refereed) Published
    Abstract [en]

    Background: The NLRP3 inflammasome has been recognized as one of the key components of the innate immunity by sensing a diversity of insults. Inflammasome activation results in the maturation of the pro-inflammatory cytokines interleukin (IL)-1 beta and IL-18. Increased production of IL-1 beta is found in patients with gain-of-function polymorphisms in genes encoding the NLRP3 inflammasome. Since approximately 5% of the Swedish population are heterozygote carriers of these combined gene variants, their impact on inflammasome status and a relationship on disease development is therefore highly relevant to study. The present study investigates levels of inflammasome-produced cytokines as a measure of inflammasome activation in healthy individuals carrying Q705K polymorphism in the NLRP3 gene combined with C10X in the CARD8 gene.

    Materials and Methods: Genotyping of 1006 healthy blood donors was performed for the polymorphisms Q705K in the NLRP3 and C10X in the CARD8 genes. IL-1 beta, IL-18, IL-33, as well as a number of other pro-inflammatory cytokines, were analyzed by Luminex or ELISA in plasma from individuals carrying the polymorphisms and in age and gender matched non-carrier controls.

    Results & Discussion: The prevalence of the polymorphisms was in line with previous studies. Plasma levels of IL-1 beta and IL-33 were elevated among carriers of combined Q705K+C10X polymorphisms compared to controls, whereas no difference was found for IL-18 and the other cytokines measured. Moreover, carriers of C10X or Q705K per se had similar plasma levels of IL-1 beta as non-carriers. These data suggest that the combined polymorphisms create inflammasomes with increased basal activation state, which might provide a more favourable innate immune response. In spite of this, it could also represent the mechanisms by which the inflammatory loop is triggered into a long-term inflammatory phenotype.

    Place, publisher, year, edition, pages
    Public Library of Science (PLoS), 2013
    National Category
    Medical and Health Sciences
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-35447 (URN)10.1371/journal.pone.0075457 (DOI)000325483600018 ()24098386 (PubMedID)2-s2.0-84884894455 (Scopus ID)
    Funder
    Swedish Research Council, ES: K2010-57X-21435-01-3
    Note

    Funding Agencies:

    Research committee of the County Council of Örebro

    Nyckelfonden at Örebro University Hospital

    Sund's Foundation for Rheumatic Research

    King Gustaf V Memorial Foundation

    Available from: 2014-06-19 Created: 2014-06-19 Last updated: 2019-06-14Bibliographically approved
    2. C10X polymorphism in the CARD8 gene is associated with bacteraemia
    Open this publication in new window or tab >>C10X polymorphism in the CARD8 gene is associated with bacteraemia
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    2014 (English)In: Immunity, inflammation and disease, E-ISSN 2050-4527, Vol. 2, no 1, p. 13-20Article in journal (Refereed) Published
    Abstract [en]

    The NLRP3 inflammasome is an intracellular multi-protein complex that triggers caspase-1 mediated maturation of interleukin-1β (IL-1β); one of the most potent mediators of inflammation and a major cytokine produced during severe infections, like sepsis. However, the excessive cytokine levels seem to stage for tissue injury and organ failure, and high levels of IL-1β correlates with severity and mortality of sepsis. Instead, recent data suggest caspase-1 to function as a guardian against severe infections. CARD8 has been implied to regulate the synthesis of IL-1β via interaction to caspase-1. In recent years, polymorphism of CARD8 (C10X) per se or in combination with NLRP3 (Q705K) has been implicated with increased risk of inflammation. The aim was to investigate the correlation of these polymorphisms with severe blood stream infection. Human DNA was extracted from blood culture bottles that were found to be positive for microbial growth (i.e. patients with bacteraemia). Polymorphisms Q705K in the NLRP3 gene and C10X in the CARD8 gene were genotyped using TaqMan genotyping assay. The results were compared to healthy controls and to samples from patients with negative cultures. The polymorphism C10X was significantly over-represented among patients with bacteraemia as compared to healthy controls, whereas patients with negative blood culture were not associated with a higher prevalence. No association was observed with polymorphism Q705K of NLRP3 in either group of patients. Patients carrying polymorphism C10X in the CARD8 gene are at increased risk of developing bacteraemia and severe inflammation.

    Place, publisher, year, edition, pages
    West Sussex, UK: John Wiley & Sons, 2014
    Keywords
    Bacteraemia, blood culture, gene variants, infection, inflammasomes, inflammation, innate immunity, leukocytes, polymorphisims, sepsis
    National Category
    Clinical Laboratory Medicine Microbiology in the medical area Immunology in the medical area
    Identifiers
    urn:nbn:se:oru:diva-42421 (URN)10.1002/iid3.14 (DOI)25400921 (PubMedID)
    Available from: 2015-02-05 Created: 2015-02-05 Last updated: 2018-11-30Bibliographically approved
    3. LOS-dependent Neisseria meningitidis-induced caspase-1 activation in human neutrophils
    Open this publication in new window or tab >>LOS-dependent Neisseria meningitidis-induced caspase-1 activation in human neutrophils
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-51769 (URN)
    Available from: 2016-08-24 Created: 2016-08-23 Last updated: 2018-01-10Bibliographically approved
    4. Human gene variants that regulate the NLRP3 activity limit the production of Neisseria meningitidis-induced IL-1β and IL-18
    Open this publication in new window or tab >>Human gene variants that regulate the NLRP3 activity limit the production of Neisseria meningitidis-induced IL-1β and IL-18
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-51776 (URN)
    Available from: 2016-08-24 Created: 2016-08-24 Last updated: 2018-01-10Bibliographically approved
  • 2.
    Asfaw Idosa, Berhane
    et al.
    Örebro University, School of Medical Sciences.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences.
    Kelly, Anne
    Karolinska University Hospital, Stockholm, Sweden.
    Fredlund, Hans
    Örebro University, School of Medical Sciences.
    Persson, Alexander
    Örebro University, School of Medical Sciences.
    Särndahl, Eva
    Örebro University, School of Medical Sciences.
    Human gene variants that regulate the NLRP3 activity limit the production of Neisseria meningitidis-induced IL-1β and IL-18Manuscript (preprint) (Other academic)
  • 3.
    Asfaw Idosa, Berhane
    et al.
    Örebro University, School of Medical Sciences.
    Persson, Alexander
    Örebro University, School of Medical Sciences.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences.
    Demirel, Isak
    Örebro University, School of Medical Sciences.
    Fredlund, Hans
    Örebro University, School of Medical Sciences.
    Särndahl, Eva
    Örebro University, School of Medical Sciences.
    Kelly, Anne
    Karolinska University Hospital, Stockholm, Sweden.
    LOS-dependent Neisseria meningitidis-induced caspase-1 activation in human neutrophilsManuscript (preprint) (Other academic)
  • 4.
    Fernberg, Ulrika
    Örebro University, School of Medical Sciences.
    Arterial stiffness and risk factors for cardiovascular disease in young adults2019Doctoral thesis, comprehensive summary (Other academic)
  • 5.
    Ganda Mall, John-Peter
    Örebro University, School of Medical Sciences.
    Non-digestible Polysaccharides and Intestinal Barrier Function: specific focus on its efficacy in elderly and patients with Crohn’s disease2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A large number of elderly suffer from gastrointestinal (GI) symptoms such as constipation and diarrhoea. The underlying mechanisms of age-acquired GI symptoms are not well studied but are necessary to clarify in order to recommend the right treatment. Non-digestible polysaccharides (NPS) are dietary fibres that could have beneficial effects on the intestinal immune system and barrier function, although their efficacy needs to be evaluated. Paper I showed that elderly with GI symptoms have significantly higher small intestinal permeability than a general elderly population, along with a stronger association to psychological distress. In Paper II we performed a randomised controlled trial with a general population of elderly that consumed either placebo, the NPS’s arabinoxylan or oat β-glucan for a period of 6 weeks. No protective effects were observed related to indomethacin-induced intestinal hyperpermeability, inflammatory markers, or self-reported health if compared to placebo. Paper III showed that stimulation with a yeast-derived β-glucan significantly attenuated Compound (C) 48/80-induced hyperpermeability in colonic biopsies from elderly with GI symptoms mounted in Ussing chambers, but not in young healthy adults. Arabinoxylan attenuated only C48/80-induced transcellular permeability in elderly but both paracellular and transcellular permeability in young healthy adults. Paper IV showed that the same yeast-derived β-glucan from paper III could cross the epithelium of ileal tissues from patients with Crohn’s disease (CD) and non-CD controls, mounted in Ussing chambers, and attenuate C48/80-induced hyperpermeability. In conclusion, we found that elderly with GI symptoms display a deteriorated barrier function and that administration of selective NPS can have beneficial effect on intestinal permeability in selective populations.

    List of papers
    1. Are self-reported gastrointestinal symptoms among older adults associated with increased intestinal permeability and psychological distress?
    Open this publication in new window or tab >>Are self-reported gastrointestinal symptoms among older adults associated with increased intestinal permeability and psychological distress?
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    2018 (English)In: BMC Geriatrics, ISSN 1471-2318, E-ISSN 1471-2318, Vol. 18, no 1, article id 75Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Despite the substantial number of older adults suffering from gastrointestinal (GI) symptoms little is known regarding the character of these complaints and whether they are associated with an altered intestinal barrier function and psychological distress. Our aim was to explore the relationship between self-reported gut health, intestinal permeability and psychological distress among older adults.

    METHODS: Three study populations were included: 1) older adults with GI symptoms (n = 24), 2) a group of older adults representing the general elderly population in Sweden (n = 22) and 3) senior orienteering athletes as a potential model of healthy ageing (n = 27). Questionnaire data on gut-health, psychological distress and level of physical activity were collected. Intestinal permeability was measured by quantifying zonulin in plasma. The level of systemic and local inflammation was monitored by measuring C-reactive protein (CRP), hydrogen peroxide in plasma and calprotectin in stool samples. The relationship between biomarkers and questionnaire data in the different study populations was illustrated using a Principal Component Analysis (PCA).

    RESULTS: Older adults with GI symptoms displayed significantly higher levels of both zonulin and psychological distress than both general older adults and senior orienteering athletes. The PCA analysis revealed a separation between senior orienteering athletes and older adults with GI symptoms and showed an association between GI symptoms, psychological distress and zonulin.

    CONCLUSIONS: Older adults with GI symptoms express increased plasma levels of zonulin, which might reflect an augmented intestinal permeability. In addition, this group suffer from higher psychological distress compared to general older adults and senior orienteering athletes. This relationship was further confirmed by a PCA plot, which illustrated an association between GI symptoms, psychological distress and intestinal permeability.

    Place, publisher, year, edition, pages
    BioMed Central, 2018
    Keywords
    Older adults; Gastrointestinal symptoms; Intestinal barrier function; Psychological distress
    National Category
    Geriatrics
    Identifiers
    urn:nbn:se:oru:diva-66053 (URN)10.1186/s12877-018-0767-6 (DOI)000428260300001 ()29554871 (PubMedID)2-s2.0-85044174344 (Scopus ID)
    Funder
    Knowledge Foundation, 20110225
    Note

    Funding Agencies:

    Bo Rydins stiftelse  F0514 

    Faculty of Medicine and Health at Örebro University  

    Diarrheal Disease Research Centre, Linköping University  

    Available from: 2018-03-27 Created: 2018-03-27 Last updated: 2018-08-20Bibliographically approved
    2. Effects of dietary fibres on indomethacin-induced intestinal permeability in elderly: A randomised placebo controlled parallel clinical trial
    Open this publication in new window or tab >>Effects of dietary fibres on indomethacin-induced intestinal permeability in elderly: A randomised placebo controlled parallel clinical trial
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Identifiers
    urn:nbn:se:oru:diva-66863 (URN)
    Available from: 2018-05-04 Created: 2018-05-04 Last updated: 2018-05-04Bibliographically approved
    3. Differential effects of dietary fibres on colonic barrier function in elderly individuals with gastrointestinal symptoms
    Open this publication in new window or tab >>Differential effects of dietary fibres on colonic barrier function in elderly individuals with gastrointestinal symptoms
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Identifiers
    urn:nbn:se:oru:diva-66866 (URN)
    Available from: 2018-05-04 Created: 2018-05-04 Last updated: 2018-05-04Bibliographically approved
    4. A β-Glucan-Based Dietary Fiber Reduces Mast Cell-Induced Hyperpermeability in Ileum From Patients With Crohn's Disease and Control Subjects
    Open this publication in new window or tab >>A β-Glucan-Based Dietary Fiber Reduces Mast Cell-Induced Hyperpermeability in Ileum From Patients With Crohn's Disease and Control Subjects
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    2017 (English)In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 24, no 1, p. 166-178Article in journal (Refereed) Published
    Abstract [en]

    Background: Administration of β-glucan has shown immune-enhancing effects. Our aim was to investigate whether β-glucan could attenuate mast cell (MC)-induced hyperpermeability in follicle-associated epithelium (FAE) and villus epithelium (VE) of patients with Crohn's disease (CD) and in noninflammatory bowel disease (IBD)-controls. Further, we studied mechanisms of β-glucan uptake and effects on MCs in vitro.

    Methods: Segments of FAE and VE from 8 CD patients and 9 controls were mounted in Ussing chambers. Effects of the MC-degranulator compound 48/80 (C48/80) and yeast-derived β-1,3/1,6 glucan on hyperpermeability were investigated. Translocation of β-glucan and colocalization with immune cells were studied by immunofluorescence. Caco-2-cl1- and FAE-cultures were used to investigate β-glucan-uptake using endocytosis inhibitors and HMC-1.1 to study effects on MCs.

    Results: β-glucan significantly attenuated MC-induced paracellular hyperpermeability in CD and controls. Transcellular hyperpermeability was only significantly attenuated in VE. Baseline paracellular permeability was higher in FAE than VE in both groups, P<0.05, and exhibited a more pronounced effect by C48/80 and β-glucan P<0.05. No difference was observed between CD and controls. In vitro studies showed increased passage, P<0.05, of β-glucan through FAE-culture compared to Caco-2-cl1. Passage was mildly attenuated by the inhibitor methyl-β-cyclodextrin. HMC-1.1 experiments showed a trend to decreasing MC-degranulation and levels of TNF-α but not IL-6 by β-glucan. Immunofluorescence revealed more β-glucan-uptake and higher percentage of macrophages and dendritic cells close to β-glucan in VE of CD compared to controls.

    Conclusions: We demonstrated beneficial effects of β-glucan on intestinal barrier function and increased β-glucan-passage through FAE model. Our results provide important and novel knowledge on possible applications of β-glucan in health disorders and diseases characterized by intestinal barrier dysfunction.

    Place, publisher, year, edition, pages
    Lippincott-Raven Publishers, 2017
    Keywords
    Crohn’s disease, intestinal permeability, β-glucan
    National Category
    Gastroenterology and Hepatology
    Identifiers
    urn:nbn:se:oru:diva-63994 (URN)10.1093/ibd/izx002 (DOI)000427524400018 ()29272475 (PubMedID)
    Funder
    Swedish Foundation for Strategic Research , RB13-016Swedish Research Council, 2014-02537
    Note

    Funding Agency:

    LIONS research foundation

    Available from: 2018-01-09 Created: 2018-01-09 Last updated: 2018-08-13Bibliographically approved
  • 6.
    Ganda Mall, John-Peter
    et al.
    Örebro University, School of Medical Sciences.
    Fart, Frida
    Örebro University, School of Medical Sciences.
    Sabet, Julia
    Örebro University, School of Medical Sciences.
    Lindqvist, Carl-Mårten
    Örebro University, School of Medical Sciences.
    Keita, Åsa V.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Brummer, Robert J.
    Örebro University, School of Medical Sciences.
    Schoultz, Ida
    Örebro University, School of Medical Sciences.
    Effects of dietary fibres on indomethacin-induced intestinal permeability in elderly: A randomised placebo controlled parallel clinical trialManuscript (preprint) (Other academic)
  • 7.
    Ganda Mall, John-Peter
    et al.
    Örebro University, School of Medical Sciences.
    Löfvendahl, Lisa
    Örebro University, School of Medical Sciences.
    Brummer, Robert Jan
    Örebro University, School of Medical Sciences.
    Keita, Åsa V.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Schoultz, Ida
    Örebro University, School of Medical Sciences.
    Differential effects of dietary fibres on colonic barrier function in elderly individuals with gastrointestinal symptomsManuscript (preprint) (Other academic)
  • 8.
    Greis, Christina
    et al.
    Örebro University, Department of Natural Sciences.
    Karlsson, Stefan
    Örebro University, Department of Natural Sciences.
    Düker, Anders
    Örebro University, Department of Natural Sciences.
    Pettersson, Håkan
    Radiofysikavdelningen, O-centrum US, Universitetssjukhuset, Linköping, Sweden .
    Allard, Bert
    Örebro University, Department of Natural Sciences.
    Determination of plutonium in environmental samples with quadrupole ICP-MS2008In: Journal of Radioanalytical and Nuclear Chemistry, ISSN 0236-5731, E-ISSN 1588-2780, Vol. 275, no 1, p. 55-70Article in journal (Refereed)
    Abstract [en]

    A method for rapid determination of plutonium isotopes in environmental samples with ultrasonic nebulisation and quadrupole ICP-MS detection was established. Techniques for sample dissolution, pre-concentration and chemical separation were evaluated and the optimal scheme outlined. Comparisons with α-spectrometry and high resolution ICP-MS confirmed the suitability of the method when applied to different environmental matrices within the global fallout concentration range in the northern hemisphere as well as more contaminated sites. Operational detection limits were 0.5–1.5 fg/l for fresh waters and 0.03–0.1 ng/kg for lake sediments and saline marsh sediments.

  • 9.
    Günaltay, Sezin
    Örebro University, School of Medical Sciences.
    Dysregulated mucosal immune responses in microscopic colitis patients2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC) is a common cause of chronic watery diarrhea. The diagnosis relies on typical histopathological changes observed upon microscopic examination. The studies in this thesis investigated innate and adaptive immune responses in the colonic mucosa of MC patients, also comparing patients with active disease (CC and LC) and histopathologically in remission (CC/LC-HR). We first analyzed expression of interleukin-1/Toll-like receptor (IL-1/TLR) signaling regulators in MC patients (Paper I). Our results showed enhanced IRAK-M, microRNA-146a, -155 and -21 expressions, whereas IL-37 gene expression was reduced in CC and LC patients as compared to non-inflamed controls. These results suggest different pathophysiological mechanisms in MC patients. The mixed inflammatory cell infiltrations seen in the lamina propria of MC patients might be a result of dysregulated expression of chemotactic mediators. In Paper II, we showed that MC patients display mainly an increased expression of chemokines and chemokine receptors in active disease as compared to noninflamed controls. In Paper III, we examined if the decreased IL-37 expression seen in Paper I could mediate the upregulation of chemokines seen in Paper II. We showed that a relatively small reduction in the ability of epithelial cells to produce IL-37 results in mainly increased chemokine expressions in a pattern similar to the findings in Paper II. In order to understand the nature of infiltrating T cells commonly observed in MC patients, we analyzed the T cell receptor (TCR) β chains in colonic biopsies of MC patients (Paper IV). Our results showed significant differences in TCRβ repertoire, which suggests selectively expanded T cell clones in active MC and histopathologically in remission patients. Altogether, these results i) increase the knowledge of MC pathogenesis by showing changes in TLR signaling regulators, enhanced chemokine and their receptor expressions involved in a mixed immune cell infiltrations and selectively expanded T cell clones in CC and LC patients, as well as in histopathological remission ii) might potentially increase the possibility of more target-specific therapies based on IL-37 induction, chemokines or chemokine receptor inhibitions, or hindering T cell infiltration according to TCR clonality.

    List of papers
    1. Differential expression of interleukin-1/Toll-like receptor signaling regulators in microscopic and ulcerative colitis
    Open this publication in new window or tab >>Differential expression of interleukin-1/Toll-like receptor signaling regulators in microscopic and ulcerative colitis
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    2014 (English)In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 20, no 34, p. 12249-12259Article in journal (Refereed) Published
    Abstract [en]

    AIM: To investigate Toll-like receptor (TLR) signaling regulators in microscopic and ulcerative colitis patients.

    METHODS: Total RNA and microRNA were isolated from fresh frozen colonic biopsies of non-inflamed controls and patients with active or in-remission collagenous colitis (CC), lymphocytic colitis (LC), or ulcerative colitis (UC). We compared expressions of interleukin-1 receptor-associated kinase (IRAK)-2, IRAK-M, interleukin (IL)-37, microRNA (miR)-146a, miR-155, and miR-21 using quantitative real time reverse transcription polymerase chain reaction.

    RESULTS: IRAK-M expression was increased in LC patients with active disease in histopathological remission (LC-HR; P = 0.02) and UC patients (P = 0.01), but no differences in IRAK-2 expression were detected compared to controls. miR-146a, -155 and -21 expressions were increased in LC-HR (P = 0.04, 0.07, and 0.004) and UC (P = 0.02, 0.04 and 0.03) patients. miR-146a and miR-21 expressions were significantly enhanced in UC patients compared to UC remission (UC-R; P = 0.01 and 0.04). Likewise, active CC patients showed significantly increased expression of miR-155 (P = 0.003) and miR-21 (P = 0.006). IL-37 expression was decreased in both CC (P = 0.03) and LC (P = 0.04) patients with a similar trend in UC patients but not statistically significant, whilst it was increased in UC-R patients compared to controls (P = 0.02) and active UC (P = 0.001).

    CONCLUSION: The identification of differentially expressed miRNAs, IL-37, and IRAK-M suggests different pathophysiologic mechanisms in various disease stages in LC, CC, and UC. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

    Place, publisher, year, edition, pages
    WJG Press, 2014
    Keywords
    Interleukin-37, MicroRNA, Lymphocytic colitis, Collagenous colitis, Ulcerative colitis
    National Category
    Gastroenterology and Hepatology
    Identifiers
    urn:nbn:se:oru:diva-37676 (URN)10.3748/wjg.v20.i34.12249 (DOI)000341719100033 ()2-s2.0-84909606787 (Scopus ID)
    Note

    Funding Agencies:

    Research Committee of Örebro County Council

    Örebro University

    Available from: 2014-10-13 Created: 2014-10-13 Last updated: 2019-03-26Bibliographically approved
    2. Enhanced levels of chemokines and their receptors in the colon of microscopic colitis patients indicate mixed immune cell recruitment
    Open this publication in new window or tab >>Enhanced levels of chemokines and their receptors in the colon of microscopic colitis patients indicate mixed immune cell recruitment
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    2015 (English)In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, article id 132458Article in journal (Refereed) Published
    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.

    National Category
    Cell and Molecular Biology Immunology in the medical area
    Research subject
    Immunology
    Identifiers
    urn:nbn:se:oru:diva-44605 (URN)10.1155/2015/132458 (DOI)000353128700001 ()2-s2.0-84928473938 (Scopus ID)
    Note

    Funding Agencies:

    Örebro University Hospital Research Foundation (Nyckelfonden)

    Research Committee, Orebro County Council

    Örebro University

    Available from: 2015-05-12 Created: 2015-05-12 Last updated: 2018-06-30Bibliographically approved
    3. Reduced Il-37 production increases the spontaneous chemokine expressions in colon epithelial cells
    Open this publication in new window or tab >>Reduced Il-37 production increases the spontaneous chemokine expressions in colon epithelial cells
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-47897 (URN)
    Available from: 2016-02-02 Created: 2016-02-02 Last updated: 2018-01-10Bibliographically approved
    4. Oligoclonal T cell receptor repertoire in colonic biopsies of microscopic and ulcerative colitis patients
    Open this publication in new window or tab >>Oligoclonal T cell receptor repertoire in colonic biopsies of microscopic and ulcerative colitis patients
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-47898 (URN)
    Available from: 2016-02-02 Created: 2016-02-02 Last updated: 2018-01-10Bibliographically approved
  • 10.
    Günaltay, Sezin
    et al.
    Örebro University, School of Medical Sciences.
    Ghiboub, Mohammed
    Amsterdam university.
    Hultgren, Olof
    Örebro University, School of Medical Sciences.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medical Sciences.
    Reduced Il-37 production increases the spontaneous chemokine expressions in colon epithelial cellsManuscript (preprint) (Other academic)
  • 11.
    Günaltay, Sezin
    et al.
    Örebro University, School of Medical Sciences.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Helenius, Gisela
    Örebro University, School of Medical Sciences.
    Nyhlin, Nils
    Örebro University, School of Medical Sciences.
    Bohr, Johan
    Örebro University, School of Health Sciences.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medical Sciences.
    Oligoclonal T cell receptor repertoire in colonic biopsies of microscopic and ulcerative colitis patientsManuscript (preprint) (Other academic)
  • 12.
    Hagberg, Jessika
    Örebro University, School of Science and Technology.
    Analysis of brominated dioxins and furans by high resolution gas chromatography/high resolution mass spectrometry2009In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1216, no 3, p. 376-384Article, review/survey (Refereed)
    Abstract [en]

    This article reviews the available literature on the analysis of brominated dibenzo-p dioxins and furans(PBDD/Fs) by high resolution gas chromatography/high resolution mass spectrometry (HRGC/HRMS).Sample extraction and clean up, injection techniques, chromatographic separation, labelled standardsand QA/QC works are discussed. Furthermore, full separation of PBDD/Fs from polybrominated diphenylethers (PBDEs) during clean up and control of possible chromatographic interference of PBDEs duringinstrumental analysis as well as possible actions to further enhance the quality of published data arediscussed in detail.

  • 13.
    Isaksson, Helena
    Örebro University, School of Medical Sciences.
    Clinical studies of RNA as a prognostic and diagnostic marker for disease2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Technologies for RNA detection are evolving rapidly and gives an op-portunity for discovery of new markers for early detection of complex diseases. Today in clinical work we rely on signs and symptoms in com-bination with the measurement of protein levels for diagnosis. The quick turnaround time of mRNA synthesis may provide an earlier diagnostic signal than protein-based biomarkers assays, in acute dramatic condi-tions such as acute mesenteric ischemia (AMI), for early detection of cancer, as prognostic tool in cancer treatment and as an aid in difficult diagnosis of unknown origin.

    The main goals of this thesis was to apply a whole genome approach to study different complex diseases to evaluate the applicability of RNA as a diagnostic or prognostic marker for disease, preferably from an easily accessible source such as peripheral blood. This was investigated in an animal model with induced AMI, a cohort of ovarian cancer patients and in a single-patient study of a girl with a severe inflammatory syn-drome.

    Through this thesis we have gained insight into how gene expression is regulated in ischemic intestinal tissue.

    We found that a peripheral blood test can distinguish between ovarian cancer patients with or without residual tumour mass after surgery with the help of expression analysis of six genes. We also found that gene expressions of three genes can predict overall survival in peripheral whole blood from ovarian cancer patients. And that gene expression profiles indeed can significantly distinguish between two groups of high and low risk ovarian cancer. In the single-patient study, we tried but failed to device a successful treatment before it was too late. Neverthe-less, the things we learned and the case studies that were published may serve as a diagnostic tool for clinicians facing similar syndromes.

    List of papers
    1. Altered mRNA Expression due to Acute Mesenteric Ischaemia in a Porcine Model
    Open this publication in new window or tab >>Altered mRNA Expression due to Acute Mesenteric Ischaemia in a Porcine Model
    Show others...
    2011 (English)In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 41, no 2, p. 281-287Article in journal (Refereed) Published
    Abstract [en]

    Introduction: Messenger RNA (mRNA) changes in the small intestine in response to acute mesenteric ischaemia (AMI) could offer novel diagnostic possibilities, but have not been described. The aim was to characterize the mRNA response to experimental AMI. Materials and methods: Twelve pigs underwent catheterisation of the superior mesenteric artery with injection of polivinylalcohol embolisation particles or sodium chloride. Laparotomy and intestinal tissue sampling were performed. Microarray analysis was performed using the GeneChip (R) whole porcine genome array. Results: Seven down-regulated cellular pathways were associated with protein, lipid and carbohydrate metabolism. Seventeen up-regulated pathways were associated with inflammatory and immunological activity, regulation of extracellular matrix and decreased cellular proliferation. Thrombospondin (THS), monocyte chemoattractant protein 1(MCP-1) and gap junction alpha 1(GJA-1) were consistently up-regulated in all embolised pigs. Genes encoding earlier proposed biomarkers for AMI were up-regulated, such as lactate dehydrogenase and creatine kinase, or down-regulated, such as intestinal fatty acid binding protein and glutathione S-transferase. Conclusion: This study describes the intestinal tissue response on a gene expression level to AMI. THS, MCP-1 and GJA-1 were consistently up-regulated by ischaemia, whereas earlier proposed biomarkers for AMI were not. Gene expression may not be directly linked to the use of the corresponding proteins as potential clinical biomarkers. (C) 2010 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

    National Category
    Medical and Health Sciences
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-18783 (URN)10.1016/j.ejvs.2010.09.012 (DOI)000288469000022 ()21095140 (PubMedID)2-s2.0-79651475389 (Scopus ID)
    Available from: 2011-09-29 Created: 2011-09-29 Last updated: 2019-03-29Bibliographically approved
    2. Whole blood RNA expression profiles in ovarian cancer patients with or without residual tumors after primary cytoreductive surgery
    Open this publication in new window or tab >>Whole blood RNA expression profiles in ovarian cancer patients with or without residual tumors after primary cytoreductive surgery
    2012 (English)In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 27, no 5, p. 1331-1335Article in journal (Refereed) Published
    Abstract [en]

    Significant improvements in the treatment results of ovarian cancer have been achieved during the last decades, but further improvements require additional methods identifying signs of the disease and its biological behavior, preferably by a simple blood test. We hypothesized that peripheral blood leukocytes may express genes that carry such clinical information. Therefore, we studied the relative gene expressions of 168 cancer- and metastasis-specific genes in blood samples from ovarian cancer patients with different prognoses after primary cytoreductive surgery. Total RNA was extracted from whole blood and the relative gene expression profile of 168 genes were analyzed using real-time qPCR assays. Two groups of patients were analyzed; one group with residual tumor mass after primary surgery, and one group where the tumor was macroscopically radically resected, resulting in no visible tumor mass left behind. The group with the remaining tumor mass after surgery showed significantly different gene expression profiles compared to the group with no remaining tumor mass. Differences were noted for the metastasis associated 1 family, member 2 gene (MTA2), the TNF, alpha-catenin, interleukin 1 beta, the KiSS-1 metastasis suppressor and the matrix metalloproteinase 10 genes. All genes were downregulated with a fold-change between 1.15 to 1.57; there were no upregulated genes. Thus, a signature of genes involved in metastasis, invasion and inflammation was found to be significantly downregulated in native unstimulated blood leukocytes from ovarian cancer patients with a poor prognosis. Preoperatively it may serve as a guide to the biology of the tumor and postoperatively in the optimization of adjuvant treatment of ovarian cancer patients.

    Place, publisher, year, edition, pages
    Athens, Greece: Spandidos Publications Ltd., 2012
    Keywords
    Seropapillary ovarian cancer, residual tumor, leukocyte gene expression, whole blood RNA expression
    National Category
    Medical and Health Sciences Cancer and Oncology
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-23093 (URN)10.3892/or.2012.1680 (DOI)000302202600005 ()22322362 (PubMedID)2-s2.0-84858269622 (Scopus ID)
    Note

    Funding Agencies:

    Lions' Cancer Research Foundation 

    Research Committee of Orebro County Council 

    Available from: 2012-05-31 Created: 2012-05-31 Last updated: 2019-03-29Bibliographically approved
    3. Whole genome expression profiling of blood cells in ovarian cancer patients: prognostic impact of the CYP1B1, MTSS1, NCALD, and NOP14 genes
    Open this publication in new window or tab >>Whole genome expression profiling of blood cells in ovarian cancer patients: prognostic impact of the CYP1B1, MTSS1, NCALD, and NOP14 genes
    2014 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 5, no 12, p. 4040-4049Article in journal (Refereed) Published
    Abstract [en]

    Ovarian cancer patients with different tumor stages and cell differentiation might be distinguished from each other by gene expression profiles in whole blood cell mRNA by the Affymetrix Human Gene 1.0 ST Array. We also examined if there is any association with other clinical variables, response to therapy, and residual tumor burden after surgery. Patients were divided into two groups, one with poor prognosis, advanced stage and poorly differentiated tumors (n = 22), and one group with good prognosis, early stage and well-to medium differentiated tumors (n = 11). Six genes were found to be differentially expressed: the PDIA3, LYAR, NOP14, NCALD and MTSS1 genes were down-regulated and the CYP1B1 gene expression was up-regulated in the poor prognosis group, all with p value <0.05, adjusted for mass comparison. In survival analyses, CYP1B1, MTSS1, NCALD and NOP14 remained significantly different (p<0.05). Patient groups did not differ in any transcript related to acute phase or immune responses. This minimal gene expression signature of prognostic ovarian cancer-related genes opens up an avenue for more practicable monitoring of ovarian cancer patients by simple peripheral blood tests, which may evolve into a tool to guide selection of curative and postoperative supportive therapies.

    Place, publisher, year, edition, pages
    Impact press, 2014
    Keywords
    ovarian cancer, whole genome profiling, prognosis, mRNA, NCALD, MTSS1, PDA3, CYP1B1, NOP14, LYAR
    National Category
    Cancer and Oncology
    Research subject
    Oncology
    Identifiers
    urn:nbn:se:oru:diva-36179 (URN)000339055200007 ()24961659 (PubMedID)2-s2.0-84905090787 (Scopus ID)
    Note

    Funding Agencies:

    Research Committee of Örebro County Council

    Foundation for Gynecological Oncology, Örebro

    Lions' Cancer Research Foundation, Uppsala-Örebro

    Available from: 2014-09-02 Created: 2014-08-28 Last updated: 2019-03-29Bibliographically approved
    4. Tissue zinc levels in a child with hypercalprotectinaemia and hyperzincaemia: a case report and a review of the literature
    Open this publication in new window or tab >>Tissue zinc levels in a child with hypercalprotectinaemia and hyperzincaemia: a case report and a review of the literature
    2012 (English)In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 72, no 1, p. 34-38Article, review/survey (Refereed) Published
    Abstract [en]

    Background: A girl suffering from a rare syndrome of unknown aetiology, termed hypercalprotectinaemia, was evaluated for tissue zinc status, because calprotectin is a protein which chelates Zn at multiple binding-sites, which might have affected the distribution of Zn in her body.

    Methods: Measurement of serum, urine, hair and nail zinc (Zn) concentration, complemented with measurement of total Zn in ultrafiltrates of plasma.

    Results: Her serum Zn concentration was 105-133 mu mol/L. Zn levels in her hair (102 mu g/g), nail (90 mu g/g) and urine (3-12 mu mol/L; 20-80 mu g/dL) were all at the lower end of the reference intervals described in the sparse literature. Zn concentrations in ultrafiltrates of plasma were below the detection limit (<100 nmol/L). Thus, the elevated serum Zn did not translate into a similarly increased level of Zn in any of the tissues tested, nor in free Zn concentrations. Instead it appeared to be a result of Zn being chelated to binder proteins, most probably calprotectin.

    Conclusion: Her grossly elevated serum calprotectin concentration is probably able to raise circulating total Zn concentrations without raising ionized concentrations, but this Zn remains confined to the circulating blood as well as to excreted body fluids, particularly faeces.

    Place, publisher, year, edition, pages
    London, United Kingdom: Informa Healthcare, 2012
    Keywords
    Tissue zinc, zinc excretion, calprotectin, inflammation, growth retardation
    National Category
    Medical Biotechnology Clinical Laboratory Medicine
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-21627 (URN)10.3109/00365513.2011.623177 (DOI)000299283700005 ()22017170 (PubMedID)2-s2.0-84856056036 (Scopus ID)
    Available from: 2012-02-14 Created: 2012-02-14 Last updated: 2019-03-29Bibliographically approved
    5. Whole genome microarray expression analysis in blood leucocytes identifies pathways linked to signs and symptoms of a patient with hypercalprotectinaemia and hyperzincaemia
    Open this publication in new window or tab >>Whole genome microarray expression analysis in blood leucocytes identifies pathways linked to signs and symptoms of a patient with hypercalprotectinaemia and hyperzincaemia
    Show others...
    2018 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 191, no 2, p. 240-251Article in journal (Refereed) Published
    Abstract [en]

    A child, 2 years with the "hypercalprotectinemia with hyperzincemia" clinical syndrome presented with atypical symptoms and signs, notably persistent fever of around 38°C, thrombocythaemia of >700 x 10(9) /L, and a predominance of persistent intestinal symptoms. In an effort to find a cure by identifying the dysregulated pathways we analyzed whole-genome mRNA expression by the Affymetrix HG U133 PLUS 2.0 array on three occasions 3 to 5 months apart. Major upregulation was demonstrated for the JAK/STAT pathway including in particular CD177, S100A8, S100A9, and S100A12, accounting for the thrombocytosis; a large number of interleukins, their receptors, and activators, accounting for the febrile apathic state; and the HMBG1 gene, possibly accounting for part of the intestinal symptoms. These results show that gene expression array technology may assist the clinician in the diagnostic workup of individual patients with suspected syndromal states of unknown origin, and the expression data can guide the selection of optimal treatment directed at the identified target pathways.

    Place, publisher, year, edition, pages
    Wiley-Blackwell Publishing Inc., 2018
    Keywords
    expression array, fever, hypercalprotectinaemia, hyperzincaemia, thrombocytaemia
    National Category
    Medical Genetics Immunology in the medical area
    Identifiers
    urn:nbn:se:oru:diva-61444 (URN)10.1111/cei.13064 (DOI)000419624200012 ()28984903 (PubMedID)
    Available from: 2017-11-02 Created: 2017-11-02 Last updated: 2019-03-29Bibliographically approved
  • 14.
    Jayaprakash, Kartheyaene
    Örebro University, School of Medical Sciences.
    Monocyte and Neutrophil Inflammatory Responses to the Periodontopathogen Porphyromonas gingivalis2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Periodontitis is one of the most common adult infections. Duing bacteremia in healthy individuals or patients with chronic periodontitis, a number of oral bacteria such as Porphyromonas gingivalis encounter inflammatory cells in the blood eg. platelets, neutrophils and monocytes. Although several studies have suggested an association between periodontitis and cardiovascular diseases, the infection and inflammatory mechanisms are poorly understood. Hence, the aim of this thesis was to elucidate the mechanisms that are involved in P. gingivalis interaction with blood leukocytes, in order to further understand the molecular pathogenesis that renders periodontitis as a risk factor for several systemic conditions. We have demonstrated that P. gingivalis induces ROS production in neutrophils, THP1 cells and in whole blood, through activation of pattern recognition receptors, such as toll-like receptors, nuclear oligomerizing domains and protease- activated receptors. Besides, we have also shown that monocytes secrete IL-1β and CXCL8 in response to P. gingivalis. Both these cytokines prime neutrophils, endothelial cells and other vascular cells in an autocrine and paracrine manner. P. gingivalis has a plethora of virulence factors of which gingipains are very unique. In addition to activating inflammatory signalling pathways in cells, gingipains also regulate CXCL8 and IL-1β, thereby curtailing the host defence strategies. We demonstrated that oxidized LDL, but not native LDL, induces IL-1β release and CD36 expression on THP1 cells. Furthermore, LDL mildly modifies P. gingivalis-induced inflammatory responses as well as CD36 expression in THP1 cells. We also observed that P. gingivalis is eliminated mainly by phagocytosis in neutrophils. In summary, these studies clarify the mechanisms of interaction between P. gingivalis and leukocytes, which can increase the understanding of the pathogenesis of periodontitis and associated systemic disorders.

    List of papers
    1. Gingipains from Porphyromonas gingivalis play a significant role in induction and regulation of CXCL8 in THP-1 cells
    Open this publication in new window or tab >>Gingipains from Porphyromonas gingivalis play a significant role in induction and regulation of CXCL8 in THP-1 cells
    2014 (English)In: BMC Microbiology, ISSN 1471-2180, E-ISSN 1471-2180, Vol. 14, article id 193Article in journal (Refereed) Published
    Abstract [en]

    Background: Porphyromonas gingivalis is an important bacterial etiological agent involved in periodontitis. The bacterium expresses two kinds of cysteine proteases called gingipains: arginine gingipains (RgpA/B) and lysine gingipain (Kgp). This study evaluated the interaction between P. gingivalis and THP-1 cells, a widely used monocytic cell line, in vitro with a focus on CXCL8 at the gene and protein levels and its fate thereafter in cell culture supernatants. THP-1 cells were stimulated with viable and heat-killed wild-type strains ATCC 33277 or W50 or viable isogenic gingipain mutants of W50, E8 (Rgp mutant) or K1A (Kgp mutant), for 24 hours.

    Results: ELISA and qPCR results show an elevated CXCL8 expression and secretion in THP-1 cells in response to P. gingivalis, where the heat-killed ATCC33277 and W50 induced higher levels of CXCL8 in comparison to their viable counterparts. Furthermore, the Kgp-deficient mutant K1A caused a higher CXCL8 response compared to the Rgp-deficient E8. Chromogenic quantification of lipopolysaccharide (LPS) in supernatant showed no significant differences between viable and heat killed bacteria except that W50 shed highest levels of LPS. The wild-type strains secreted relatively more Rgp during the co-culture with THP-1 cells. The CXCL8 degradation assay of filter-sterilized supernatant from heat-killed W50 treated cells showed that Rgp was most efficient at CXCL8 hydrolysis. Of all tested P. gingivalis strains, adhesion and internalization in THP-1 cells was least conspicuous by Rgp-deficient P. gingivalis (E8), as demonstrated by confocal imaging.

    Conclusions: W50 and its Kgp mutant K1A exhibit a higher immunogenic and proteolytic function in comparison to the Rgp mutant E8. Since K1A differs from E8 in the expression of Rgp, it is rational to conclude that Rgp contributes to immunomodulation in a more dynamic manner in comparison to Kgp. Also, W50 is a more virulent strain when compared to the laboratory strain ATCC33277.

    Place, publisher, year, edition, pages
    BioMed Central, 2014
    Keywords
    Porphyromonas gingivalis, THP-1 cells, Gingipains, Mutants, CXCL8 degradation
    National Category
    Microbiology
    Research subject
    Microbiology
    Identifiers
    urn:nbn:se:oru:diva-36171 (URN)10.1186/1471-2180-14-193 (DOI)000339837900001 ()
    Funder
    Swedish Heart Lung Foundation
    Note

    Funding Agencies:

    Foundation of Olle Engkvist

    Knowledge Foundation

    Available from: 2014-09-03 Created: 2014-08-28 Last updated: 2019-06-14Bibliographically approved
    2. PKC, ERK/p38 MAP kinases and NF-κB targeted signalling plays a crucial role in expression and release of IL-1β and CXCL8 in Porphyromonas gingivalis infected monocytes
    Open this publication in new window or tab >>PKC, ERK/p38 MAP kinases and NF-κB targeted signalling plays a crucial role in expression and release of IL-1β and CXCL8 in Porphyromonas gingivalis infected monocytes
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-49455 (URN)
    Available from: 2016-03-22 Created: 2016-03-22 Last updated: 2018-01-10Bibliographically approved
    3. Porphyromonas gingivalis induced release of reactive oxygen species and interleukin-1 beta and the effects of low density lipoproteins in monocytes and whole blood
    Open this publication in new window or tab >>Porphyromonas gingivalis induced release of reactive oxygen species and interleukin-1 beta and the effects of low density lipoproteins in monocytes and whole blood
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-49456 (URN)
    Available from: 2016-03-22 Created: 2016-03-22 Last updated: 2018-01-10Bibliographically approved
    4. The role of phagocytosis, oxidative burst and neutrophil extracellular traps in the interaction between neutrophils and the periodontal pathogen Porphyromonas gingivalis
    Open this publication in new window or tab >>The role of phagocytosis, oxidative burst and neutrophil extracellular traps in the interaction between neutrophils and the periodontal pathogen Porphyromonas gingivalis
    2015 (English)In: Molecular Oral Microbiology, ISSN 2041-1006, E-ISSN 2041-1014, Vol. 30, no 5, p. 361-375Article in journal (Refereed) Published
    Abstract [en]

    Neutrophils are regarded as the sentinel cells of innate immunity and are found in abundance within the gingival crevice. Discovery of neutrophil extracellular traps (NETs) within the gingival pockets prompted us to probe the nature of the interactions of neutrophils with the prominent periopathogen Porphyromonas gingivalis. Some of the noted virulence factors of this Gram-negative anaerobe are gingipains: arginine gingipains (RgpA/B) and lysine gingipain (Kgp). The aim of this study was to evaluate the role of gingipains in phagocytosis, formation of reactive oxygen species, NETs and CXCL8 modulation by using wild-type strains and isogenic gingipain mutants. Confocal imaging showed that gingipain mutants K1A (Kgp) and E8 (RgpA/B) induced extracellular traps in neutrophils, whereas ATCC33277 and W50 were phagocytosed. The viability of both ATCC33277 and W50 dwindled as the result of phagocytosis and could be salvaged by cytochalasin D, and the bacteria released high levels of lipopolysaccharide in the culture supernatant. Porphyromonas gingivalis induced reactive oxygen species and CXCL8 with the most prominent effect being that of the wild-type strain ATCC33277, whereas the other wild-type strain W50 was less effective. Quantitative real-time polymerase chain reaction revealed a significant CXCL8 expression by E8. All the tested P.gingivalis strains increased cytosolic free calcium. In conclusion, phagocytosis is the primary neutrophil response to P.gingivalis, although NETs could play an accessory role in infection control. Although gingipains do not seem to directly regulate phagocytosis, NETs or oxidative burst in neutrophils, their proteolytic properties could modulate the subsequent outcomes such as nutrition acquisition and survival by the bacteria.

    Keywords
    neutrophils, neutrophil extracellular traps, periodontitis, phagocytosis, reactive oxygen species
    National Category
    Dentistry
    Identifiers
    urn:nbn:se:oru:diva-46034 (URN)10.1111/omi.12099 (DOI)000361007200003 ()25869817 (PubMedID)2-s2.0-84941023684 (Scopus ID)
    Funder
    Swedish Heart Lung FoundationSwedish Research Council
    Note

    Funding Agency:

    Foundation of Olle Engkvist

    Available from: 2015-10-07 Created: 2015-10-07 Last updated: 2017-12-01Bibliographically approved
  • 15.
    Jayaprakash, Kartheyaene
    et al.
    Örebro University, School of Medical Sciences.
    Demirel, Isak
    Örebro University, School of Medical Sciences.
    Gunaltay, Sezin
    Örebro University, School of Medical Sciences.
    Khalaf, Hazem
    Örebro University, School of Medical Sciences.
    Bengtsson, Torbjörn
    Örebro University, School of Medical Sciences.
    PKC, ERK/p38 MAP kinases and NF-κB targeted signalling plays a crucial role in expression and release of IL-1β and CXCL8 in Porphyromonas gingivalis infected monocytesManuscript (preprint) (Other academic)
  • 16.
    Jayaprakash, Kartheyaene
    et al.
    Örebro University, School of Medical Sciences.
    Demirel, Isak
    Örebro University, School of Medical Sciences.
    Khalaf, Hazem
    Örebro University, School of Medical Sciences.
    Bengtsson, Torbjörn
    Örebro University, School of Medical Sciences.
    Porphyromonas gingivalis induced release of reactive oxygen species and interleukin-1 beta and the effects of low density lipoproteins in monocytes and whole bloodManuscript (preprint) (Other academic)
  • 17.
    Joukamo, Laura
    et al.
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Lankinen, Maria
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Schwab, Ursula
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Soininen, Pasi
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Kangas, Antti J.
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Kolehmainen, Marjukka
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Paananen, Jussi
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Poutanen, Kaisa
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Mykkänen, Hannu
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Seppänen-Laakso, Tuulikki
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Gylling, Helena
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Oresic, Matej
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Ala-Korpela, Mika
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Uusitupa, Matti
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Rasvainen kala muokkaa HDL-hiukkaskokoa ja lipidipitoisuuksia [Fatty fish modifies HDL particle size and lipid concentrations]2013In: Duodecim, ISSN 0012-7183, E-ISSN 2242-3281, Vol. 129, no 24, p. 2661-2670Article in journal (Refereed)
    Abstract [fi]

    BACKGROUND: We investigated with 1HNMR-spectroscopy the effects of habitual fatty fish intake on serum lipiprotein profiles in persons with features of metabolic syndrome.

    MATERIAL AND METHODS: The participants (n = 105) were randomized into three diet intervention groups. The groups were given different dietary instructions.

    RESULTS: Increased intake of fatty fish had a significant (p < 0.05) increasing effect on the amount of large HDL-lipoprotein subclasses and their lipids.

    CONCLUSIONS: Frequent intake of fatty fish may have beneficial effects on HDL-metabolism beyond that assumed to be related to its serum concentrations.

  • 18.
    Kardeby, Caroline
    Örebro University, School of Medical Sciences.
    Studies of platelet signalling and endothelial cell responses using unique synthetic drugs2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Haemostasis is a complex and tightly regulated process which protects us from bleeding. Platelets are essential for maintained haemostasis. Under normal conditions platelets are calmed by antithrombotic substances release by the endothelium. During vascular injury, the platelets will activate and form a haemostatic plug to prevent bleeding. Inflammatory processes like atherosclerosis can disturb the haemostatic balance and lead to severe consequences like myocardial infarction and stroke. Inhibition of platelets and coagulation are common treatments to prevent unwanted blood clot formation. There is a great need for increased knowledge on the mechanisms of thrombosis and characterisation of new substances with possible therapeutic potential. This thesis used unique synthetic drugs to study platelet signalling and endothelial responses. Paper I showed that both sulfated polysaccharides from seaweed and synthetic glycopolymers which mimic their chemical properties caused platelet activation.

    Paper II elucidated the molecular mechanism underlying platelet activation by sulfated glycopolymers and polysaccharides. We found that human platelet activation took place via the Platelet endothelial aggregation receptor 1 (PEAR1), while mouse platelet activation was mainly via C-type lectin-like receptor 2. Aggregation was supported by Glycoprotein Ibα in both species.

    Paper III showed the effect of synthetic glycopolymers and natural polysaccharides on cultured human endothelial cells. We found that both the glycopolymers and polysaccharides caused a proinflammatory response after 24h.

    In Paper IV, the effect of a synthetic purine analogue with a nitrate ester motif was studied. We found that the purine analogue reduced platelet functions by inhibiting Rho-associated protein kinase (ROCK).

    This thesis describes unique synthetic drugs that can be used for further studies of the mechanisms underlying the biological processes of thrombosis and inflammation. The synthetic glycopolymers can be used to further elucidate the physiological role of PEAR1, a potential future therapeutic target.

    List of papers
    1. Fucoidan-Mimetic Glycopolymers as Tools for Studying Molecular and Cellular Responses in Human Blood Platelets
    Open this publication in new window or tab >>Fucoidan-Mimetic Glycopolymers as Tools for Studying Molecular and Cellular Responses in Human Blood Platelets
    Show others...
    2017 (English)In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 17, no 2, article id UNSP 1600257Article in journal (Refereed) Published
    Abstract [en]

    The marine sulfated polysaccharide fucoidan displays superior ability to induce platelet aggregation compared to other sulfated polysaccharides. As such, it is an attractive tool for studying molecular and cellular responses in activated platelets. The heterogeneous structure, however, poses a problem in such applications. This study describes the synthesis of sulfated α-l-fucoside-pendant poly(methacryl amides) with homogeneous structures. By using both thiol-mediated chain transfer and reversible addition-fragmentation chain transfer polymerization techniques, glycopolymers with different chain lengths are obtained. These glycopolymers show platelet aggregation response and surface changes similar to those of fucoidan, and cause platelet activation through intracellular signaling as shown by extensive protein tyrosine phosphorylation. As the platelet activating properties of the glycopolymers strongly mimic those of fucoidan, this study concludes these fucoidan-mimetic glycopolymers are unique tools for studying molecular and cellular responses in human blood platelets.

    Place, publisher, year, edition, pages
    Weinheim, Germany: Wiley-VCH Verlagsgesellschaft, 2017
    Keywords
    biological applications of polymers; biomimetic; radical polymerization; reversible addition fragmentation chain transfer; structure-property relations
    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Identifiers
    urn:nbn:se:oru:diva-52179 (URN)10.1002/mabi.201600257 (DOI)000394592600012 ()27616165 (PubMedID)2-s2.0-84987653303 (Scopus ID)
    Note

    Funding Agency:

    AFA Insurance, VR Treatments of the Future grant

    Available from: 2016-09-21 Created: 2016-09-14 Last updated: 2019-05-06Bibliographically approved
    2. Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα
    Open this publication in new window or tab >>Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα
    Show others...
    2019 (English)In: Blood advances, ISSN 2473-9529, Vol. 3, no 3, p. 275-287Article in journal (Refereed) Published
    Abstract [en]

    Fucoidans are sulfated fucose-based polysaccharides that activate platelets and have pro- and anticoagulant effects; thus, they may have therapeutic value. In the present study, we show that 2 synthetic sulfated α-l-fucoside-pendant glycopolymers (with average monomeric units of 13 and 329) and natural fucoidans activate human platelets through a Src- and phosphatidylinositol 3-kinase (PI3K)-dependent and Syk-independent signaling cascade downstream of the platelet endothelial aggregation receptor 1 (PEAR1). Synthetic glycopolymers and natural fucoidan stimulate marked phosphorylation of PEAR1 and Akt, but not Syk. Platelet aggregation and Akt phosphorylation induced by natural fucoidan and synthetic glycopolymers are blocked by a monoclonal antibody to PEAR1. Direct binding of sulfated glycopolymers to epidermal like growth factor (EGF)-like repeat 13 of PEAR1 was shown by avidity-based extracellular protein interaction screen technology. In contrast, synthetic glycopolymers and natural fucoidans activate mouse platelets through a Src- and Syk-dependent pathway regulated by C-type lectin-like receptor 2 (CLEC-2) with only a minor role for PEAR1. Mouse platelets lacking the extracellular domain of GPIbα and human platelets treated with GPIbα-blocking antibodies display a reduced aggregation response to synthetic glycopolymers. We found that synthetic sulfated glycopolymers bind directly to GPIbα, substantiating that GPIbα facilitates the interaction of synthetic glycopolymers with CLEC-2 or PEAR1. Our results establish PEAR1 as the major signaling receptor for natural fucose-based polysaccharides and synthetic glycopolymers in human, but not in mouse, platelets. Sulfated α-l-fucoside-pendant glycopolymers are unique tools for further investigation of the physiological role of PEAR1 in platelets and beyond.

    Place, publisher, year, edition, pages
    American Society of Hematology, 2019
    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Hematology
    Identifiers
    urn:nbn:se:oru:diva-72478 (URN)10.1182/bloodadvances.2018024950 (DOI)000458442500007 ()30700416 (PubMedID)2-s2.0-85060943358 (Scopus ID)
    Funder
    Knowledge Foundation
    Note

    Funding Agencies:

    BHF  PG/16/53/32242  RG/13/18/30563 

    Deutsche Forschungsgemeinschaft  DFG: Eb 177/14-1 

    Fonds voor Wetenschappelijk Onderzoek Vlaanderen grant  G0A6514N 

    Available from: 2019-02-14 Created: 2019-02-14 Last updated: 2019-06-18Bibliographically approved
    3. Sulfated glycopolymers and polysaccharides regulate inflammation-related proteins in human vascular endothelial cells
    Open this publication in new window or tab >>Sulfated glycopolymers and polysaccharides regulate inflammation-related proteins in human vascular endothelial cells
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Identifiers
    urn:nbn:se:oru:diva-74033 (URN)
    Available from: 2019-05-06 Created: 2019-05-06 Last updated: 2019-05-06Bibliographically approved
    4. A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition
    Open this publication in new window or tab >>A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Identifiers
    urn:nbn:se:oru:diva-74034 (URN)
    Available from: 2019-05-06 Created: 2019-05-06 Last updated: 2019-05-06Bibliographically approved
  • 19.
    Kardeby, Caroline
    et al.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Paramel Varghese, Geena
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Pournara, Dimitra
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Fotopoulou, Theano
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Koufaki, Maria
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Fransén, Karin
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Grenegård, Magnus
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibitionManuscript (preprint) (Other academic)
  • 20.
    Kardeby, Caroline
    et al.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Sirsjö, Allan
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Ljungberg, Liza
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Grenegård, Magnus
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Sulfated glycopolymers and polysaccharides regulate inflammation-related proteins in human vascular endothelial cellsManuscript (preprint) (Other academic)
  • 21.
    Karpanen, Terhi
    et al.
    Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki and Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; .
    Bry, Maija
    Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki and Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Ollila, Hanna M.
    Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki and Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Seppänen-Laakso, Tuulikki
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Liimatta, Erkki
    Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland.
    Leskinen, Hanna
    Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
    Kivelä, Riikka
    Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki and Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Helkamaa, Teemu
    Institute of Biomedicine, Department of Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Merentie, Mari
    A.I. Virtanen Institute, Department of Biotechnology and Molecular Medicine, University of Kuopio, Kuopio, Finland.
    Jeltsch, Michael
    Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki and Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Paavonen, Karri
    Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki and Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Andersson, Leif C.
    Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland.
    Mervaala, Eero
    Institute of Biomedicine, Department of Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Hassinen, Ilmo E.
    Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland.
    Ylä-Herttuala, Seppo
    A.I. Virtanen Institute, Department of Biotechnology and Molecular Medicine, University of Kuopio, Kuopio, Finland.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Alitalo, Kari
    Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki and Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Overexpression of vascular endothelial growth factor-B in mouse heart alters cardiac lipid metabolism and induces myocardial hypertrophy2008In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 103, no 9, p. 1018-1026Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor (VEGF)-B is poorly angiogenic but prominently expressed in metabolically highly active tissues, including the heart. We produced mice expressing a cardiac-specific VEGF-B transgene via the alpha-myosin heavy chain promoter. Surprisingly, the hearts of the VEGF-B transgenic mice showed concentric cardiac hypertrophy without significant changes in heart function. The cardiac hypertrophy was attributable to an increased size of the cardiomyocytes. Blood capillary size was increased, whereas the number of blood vessels per cell nucleus remained unchanged. Despite the cardiac hypertrophy, the transgenic mice had lower heart rate and blood pressure than their littermates, and they responded similarly to angiotensin II-induced hypertension, confirming that the hypertrophy does not compromise heart function. Interestingly, the isolated transgenic hearts had less cardiomyocyte damage after ischemia. Significantly increased ceramide and decreased triglyceride levels were found in the transgenic hearts. This was associated with structural changes and eventual lysis of mitochondria, resulting in accumulation of intracellular vacuoles in cardiomyocytes and increased death of the transgenic mice, apparently because of mitochondrial lipotoxicity in the heart. These results suggest that VEGF-B regulates lipid metabolism, an unexpected function for an angiogenic growth factor.

  • 22.
    Koikkalainen, Juha R.
    et al.
    VTT Technical Research Centre of Finland, Tampere, Finland .
    Antila, Margareta
    Helsinki Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland.
    Lötjönen, Jyrki M. P.
    VTT Technical Research Centre of Finland, Tampere, Finland.
    Heliö, Tiina
    Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
    Lauerma, Kirsi
    Helsinki Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland.
    Kivistö, Sari M.
    Helsinki Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland.
    Sipola, Petri
    Department of Radiology, Kuopio University Hospital, Kuopio, Finland.
    Kaartinen, Maija A.
    Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
    Kärkkäinen, Satu T. J.
    Department of Medicine, Kuopio University Hospital, Kuopio, Finland.
    Reissell, Eeva
    Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
    Kuusisto, Johanna
    Department of Medicine, Kuopio University Hospital, Kuopio, Finland.
    Laakso, Markku
    Department of Medicine, Kuopio University Hospital, Kuopio, Finland.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland .
    Nieminen, Markku S.
    Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
    Peuhkurinen, Keijo J.
    Department of Medicine, Kuopio University Hospital, Kuopio, Finland.
    Early familial dilated cardiomyopathy: identification with determination of disease state parameter from cine MR image data2008In: Radiology, ISSN 0033-8419, E-ISSN 1527-1315, Vol. 249, no 1, p. 88-96Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To characterize early changes in cardiac anatomy and function for lamin A/C gene (LMNA) mutation carriers by using magnetic resonance (MR) imaging and to develop tools to analyze and visualize the findings.

    MATERIALS AND METHODS: The ethical review board of the institution approved the study, and informed written consent was obtained. The patient group consisted of 12 subjects, seven women (mean age, 36 years; age range, 18-54 years) and five men (mean age, 28 years; age range, 18-39 years) of Finnish origin, who were each heterozygotes with one LMNA mutation that may cause familial dilated cardiomyopathy (DCM). All the subjects were judged to be healthy with transthoracic echocardiography. The control group consisted of 14 healthy subjects, 11 women (mean age, 41 years; range, 23-54 years) and three men (mean age, 45 years; range, 34-57 years), of Finnish origin. Cine steady state free precession MR imaging was performed with a 1.5-T system. The volumes, wall thickness, and wall motion of both left ventricle (LV) and right ventricle were assessed. A method combining multiple MR image parameters was used to generate a global cardiac function index, the disease state parameter (DSP). A visual fingerprint was generated to assess the severity of familial DCM.

    RESULTS: The mean DSP of the patient group (0.69 +/- 0.15 [standard deviation]) was significantly higher than that of the control group (0.32 +/- 0.13) (P = .00002). One subject had an enlarged LV.

    CONCLUSION: Subclinical familial DCM was identified by determination of the DSP with MR imaging, and this method might be used to recognize familial DCM at an early stage.

  • 23.
    Kolak, Maria
    et al.
    Atherosclerosis Research Unit, Department of Medicine, King Gustaf V. Research Institute, Karolinska Institutet, Stockholm, Sweden.
    Westerbacka, Jukka
    Division of Diabetes, Department of Medicine, University of Helsinki, Helsinki, Finland.
    Velagapudi, Vidya R.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Wågsäter, Dick
    Atherosclerosis Research Unit, Department of Medicine, King Gustaf V. Research Institute, Karolinska Institutet, Stockholm, Sweden.
    Yetukuri, Laxman
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Makkonen, Janne
    Division of Diabetes, Department of Medicine, University of Helsinki, Helsinki, Finland; Minerva Medical Research Institute, Helsinki, Finland.
    Rissanen, Aila
    Obesity Research Unit, University of Helsinki, Helsinki, Finland.
    Häkkinen, Anna-Maija
    Department of Oncology, University of Helsinki, Helsinki, Finland.
    Lindell, Monica
    Atherosclerosis Research Unit, Department of Medicine, King Gustaf V. Research Institute, Karolinska Institutet, Stockholm, Sweden.
    Bergholm, Robert
    Division of Diabetes, Department of Medicine, University of Helsinki, Helsinki, Finland; Minerva Medical Research Institute, Helsinki, Finland.
    Hamsten, Anders
    Atherosclerosis Research Unit, Department of Medicine, King Gustaf V. Research Institute, Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Per
    Atherosclerosis Research Unit, Department of Medicine, King Gustaf V. Research Institute, Karolinska Institutet, Stockholm, Sweden.
    Fisher, Rachel M.
    Atherosclerosis Research Unit, Department of Medicine, King Gustaf V. Research Institute, Karolinska Institutet, Stockholm, Sweden.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Yki-Järvinen, Hannele
    Atherosclerosis Research Unit, Department of Medicine, King Gustaf V. Research Institute, Karolinska Institutet, Stockholm, Sweden; Division of Diabetes, Department of Medicine, University of Helsinki, Helsinki, Finland.
    Adipose tissue inflammation and increased ceramide content characterize subjects with high liver fat content independent of obesity2007In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 56, no 8, p. 1960-1968Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: We sought to determine whether adipose tissue is inflamed in individuals with increased liver fat (LFAT) independently of obesity.

    RESEARCH DESIGN AND METHODS: A total of 20 nondiabetic, healthy, obese women were divided into normal and high LFAT groups based on their median LFAT level (2.3 +/- 0.3 vs. 14.4 +/- 2.9%). Surgical subcutaneous adipose tissue biopsies were studied using quantitative PCR, immunohistochemistry, and a lipidomics approach to search for putative mediators of insulin resistance and inflammation. The groups were matched for age and BMI. The high LFAT group had increased insulin (P = 0.0025) and lower HDL cholesterol (P = 0.02) concentrations.

    RESULTS: Expression levels of the macrophage marker CD68, the chemokines monocyte chemoattractant protein-1 and macrophage inflammatory protein-1alpha, and plasminogen activator inhibitor-1 were significantly increased, and those of peroxisome proliferator-activated receptor-gamma and adiponectin decreased in the high LFAT group. CD68 expression correlated with the number of macrophages and crown-like structures (multiple macrophages fused around dead adipocytes). Concentrations of 154 lipid species in adipose tissue revealed several differences between the groups, with the most striking being increased concentrations of triacylglycerols, particularly long chain, and ceramides, specifically Cer(d18:1/24:1) (P = 0.01), in the high LFAT group. Expression of sphingomyelinases SMPD1 and SMPD3 were also significantly increased in the high compared with normal LFAT group.

    CONCLUSIONS: Adipose tissue is infiltrated with macrophages, and its content of long-chain triacylglycerols and ceramides is increased in subjects with increased LFAT compared with equally obese subjects with normal LFAT content. Ceramides or their metabolites could contribute to adverse effects of long-chain fatty acids on insulin resistance and inflammation.

  • 24.
    Koskela, Anita
    et al.
    Clinical Research Center, University Hospital, Örebro, Sweden; Örebro Life Science Center, University Hospital Örebro, Örebro, Sweden.
    Engström, Kristina
    Department of Otolaryngology, Örebro University Hospital, Örebro, Sweden.
    Hakelius, Malin
    Department of Surgical Sciences, Plastic Surgery Unit, Uppsala University, Uppsala, Sweden.
    Nowinski, Daniel
    Department of Surgical Sciences, Plastic Surgery Unit, Uppsala University, Uppsala, Sweden.
    Ivarsson, Mikael
    Clinical Research Center, Örebro University Hospital, Örebro, Sweden; Örebro Life Science Center, University Hospital Örebro, Örebro, Sweden.
    Regulation of fibroblast gene expression by keratinocytes in organotypic skin culture provides possible mechanisms for the antifibrotic effect of reepithelialization.2010In: Wound Repair and Regeneration, ISSN 1067-1927, E-ISSN 1524-475X, Vol. 18, no 5, p. 452-459Article in journal (Refereed)
    Abstract [en]

    To investigate the mechanisms behind the antifibrotic effect associated with epidermal regeneration, the expression of 12 fibroblast genes important for the modulation of the extracellular matrix (ECM), as well as α-smooth muscle actin, was studied in a keratinocyte-fibroblast organotypic skin culture model. The study was performed over time during epidermal generation and in the presence or absence of the profibrotic factor transforming growth factor-β. the Presence of epidermal differentiation markers in the model was essentially coherent with that of native skin. Fibroblast gene expression was analyzed with real-time polymerase chain reaction after removal of the epidermal layer. After 2 days of air-exposed culture, 11 out of the 13 genes studied were significantly regulated by keratinocytes in the absence or presence of transforming growth factor-β. The regulation of connective tissue growth factor, collagen I and III, fibronectin, plasmin system regulators, matrix metalloproteinases and their inhibitors as well as α-smooth muscle actin was consistent with a suppression of ECM formation or contraction. Overall, the results support a view that keratinocytes regulate fibroblasts to act catabolically on the ECM in epithelialization processes. This provides possible mechanisms for the clinical observations that reepithelialization and epidermal wound coverage counteract excessive scar formation.

  • 25.
    Koskela von Sydow, Anita
    Örebro University, School of Medical Sciences.
    Regulation of fibroblast activity by keratinocytes, TGF-β and IL-1α: studies in two- and three dimensional in vitro models2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Dysregulated wound healing is commonly associated with excessive fibrosis. Connective tissue growth factor (CTGF/CCN2) is characteristically overexpressed in fibrotic diseases and stimulated by transforming growth factor-β (TGF-β) in dermal fibroblasts. Reepithelialisation and epidermal wound coverage counteract excessive scar formation. We have previously shown that interleukin-1α (IL-1α) derived from keratinocytes conteracts TGF-β-stimulated CTGF-expression. The aim of this thesis was to further explore the effects of keratinocytes and IL-1α on gene and protein expression, as well as pathways, in TGF-β stimulated fibroblasts. Fibroblasts were studied in vitro by conventional two dimensional cell culture models and in a three dimensional keratinocyte-fibroblast organotypic skin culture model.

    The results showed that IL-1 suppresses basal and TGF-β-induced CTGF mRNA and protein, involving a possible TAK1 mechanism. Keratinocytes regulate the expression of fibroblast genes important for the turnover of the extracellular matrix. Most of the genes analysed (11/13) were regulated by TGF-β and counter regulated by keratinocytes. The overall results support a view that keratinocytes regulate fibroblasts to act catabolically (anti-fibrotic) on the extracellular matrix.

    Transcriptional microarray and gene set enrichment analysis showed that antagonizing effects of IL-1α on TGF-β were much more prominent than the synergistic effects. The most confident of these pathways was the interferon signaling, which were inhibited by TGF-β and activated by IL-1α. A proteomics study confirmed that IL-1α preferentially conteracts TGF-β effects. Six new fibroblast proteins involved in synthesis/ regulation were identified, being regulated by TGF-β and antagonized by IL-1α. Pathway analysis confirmed counter-regulation of interferon signaling by the two cytokines. These findings have implications for understanding the role of fibroblasts for inflammatory responses and development of fibrosis in the skin.

    List of papers
    1. Inhibition of Connective Tissue Growth Factor/CCN2 Expression in Human Dermal Fibroblasts by Interleukin-1 alpha and beta
    Open this publication in new window or tab >>Inhibition of Connective Tissue Growth Factor/CCN2 Expression in Human Dermal Fibroblasts by Interleukin-1 alpha and beta
    Show others...
    2010 (English)In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 110, no 5, p. 1226-1233Article in journal (Refereed) Published
    Abstract [en]

    Connective tissue growth factor (CTGF/CCN2) is a matricellular protein induced by transforming growth factor (TGF)-beta and intimately involved with tissue repair and overexpressed in various fibrotic conditions We previously showed that keratmocytes in vitro downregulate TGF-beta-induced expression of CTGF in fibroblasts by an interleukin (IL)-1 alpha-dependent mechanism. Here, we investigated further the mechanisms of this downregulation by both IL-1 alpha and beta Human dermal fibroblasts and NIH 3T3 cells were treated with IL-1 alpha or beta in presence or absence of TGF-beta 1. IL-1 suppressed basal and TGF-beta-induced CTGF mRNA and protein expression. IL-1 alpha and beta inhibited TGF-beta-stimulated CTGF promoter activity, and the activity of a synthetic minimal promoter containing Smad 3-binding CAGA elements Furthermore. IL-1 alpha and beta inhibited TGF-beta-stimulated Smad 3 phosphorylation, possibly linked to an observed increase in Smad 7 mRNA expression. In addition. RNA interference suggested that TGF-beta activated kinase1 (TAK1) is necessary for IL-1 inhibition of TGF-beta-stimulated CTGF expression. These results add to the understanding of how the expression of CTGF in human dermal fibroblasts is regulated, which in turn may have implications for the pathogenesis of fibrotic conditions involving the skin. J. Cell Biochem. 110: 1226-1233, 2010. (C) 2010 Wiley-Liss. Inc

    Keywords
    interleukin-1, connective tissue growth factor, transforming growth factor-beta, smad 3, tak1
    National Category
    Cell Biology Biochemistry and Molecular Biology
    Research subject
    Cell Research
    Identifiers
    urn:nbn:se:oru:diva-28379 (URN)10.1002/jcb.22637 (DOI)000280435900021 ()20544797 (PubMedID)2-s2.0-77954894569 (Scopus ID)
    Available from: 2013-03-26 Created: 2013-03-14 Last updated: 2018-04-24Bibliographically approved
    2. Regulation of fibroblast gene expression by keratinocytes in organotypic skin culture provides possible mechanisms for the antifibrotic effect of reepithelialization.
    Open this publication in new window or tab >>Regulation of fibroblast gene expression by keratinocytes in organotypic skin culture provides possible mechanisms for the antifibrotic effect of reepithelialization.
    Show others...
    2010 (English)In: Wound Repair and Regeneration, ISSN 1067-1927, E-ISSN 1524-475X, Vol. 18, no 5, p. 452-459Article in journal (Refereed) Published
    Abstract [en]

    To investigate the mechanisms behind the antifibrotic effect associated with epidermal regeneration, the expression of 12 fibroblast genes important for the modulation of the extracellular matrix (ECM), as well as α-smooth muscle actin, was studied in a keratinocyte-fibroblast organotypic skin culture model. The study was performed over time during epidermal generation and in the presence or absence of the profibrotic factor transforming growth factor-β. the Presence of epidermal differentiation markers in the model was essentially coherent with that of native skin. Fibroblast gene expression was analyzed with real-time polymerase chain reaction after removal of the epidermal layer. After 2 days of air-exposed culture, 11 out of the 13 genes studied were significantly regulated by keratinocytes in the absence or presence of transforming growth factor-β. The regulation of connective tissue growth factor, collagen I and III, fibronectin, plasmin system regulators, matrix metalloproteinases and their inhibitors as well as α-smooth muscle actin was consistent with a suppression of ECM formation or contraction. Overall, the results support a view that keratinocytes regulate fibroblasts to act catabolically on the ECM in epithelialization processes. This provides possible mechanisms for the clinical observations that reepithelialization and epidermal wound coverage counteract excessive scar formation.

    Place, publisher, year, edition, pages
    The Wound Healing Society, 2010
    National Category
    Other Basic Medicine
    Identifiers
    urn:nbn:se:oru:diva-48462 (URN)10.1111/j.1524-475X.2010.00605.x (DOI)000282263500004 ()20731800 (PubMedID)2-s2.0-77956625499 (Scopus ID)
    Available from: 2016-02-22 Created: 2016-02-22 Last updated: 2018-05-02Bibliographically approved
    3. IL-1α Counteract TGF-β Regulated Genes and Pathways in Human Fibroblasts
    Open this publication in new window or tab >>IL-1α Counteract TGF-β Regulated Genes and Pathways in Human Fibroblasts
    Show others...
    2016 (English)In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 117, no 7, p. 1622-1632Article in journal (Refereed) Published
    Abstract [en]

    Dysregulated wound healing is commonly associated with excessive fibrosis. Connective tissue growth factor (CTGF/CCN2) is characteristically overexpressed in fibrotic diseases and stimulated by transforming growth factor-β (TGF-β) in dermal fibroblasts. We previously showed that interleukin-1 (IL-1α) counteracts TGF-β-stimulated CTGF mRNA and protein expression in these cells. The aim of this study was to explore the effects of IL-1α on further genes and pathways in TGF-β regulated fibroblasts. Transcriptional microarray and multiple comparison analysis showed that the antagonizing effects of IL-1α was much more prominent than the synergistic effects, both with respect to number of genes and extent of changes in gene expression. Moreover, comparing canonical pathways by gene set enrichment analysis and the Ingenuity Pathway Analysis tool revealed that IL-1α counteracted TGF-β in the top six most confident pathways regulated by both cytokines. Interferon and IL-1 signaling, as well as two pathways involved in apoptosis signaling were suppressed by TGF-β and activated by IL-1α. Pathways involving actin remodeling and focal adhesion dynamics were activated by TGF-β and suppressed by IL-1α. Analyzing upstream regulators in part corroborate the comparison of canonical pathways and added cell cycle regulators as another functional group regulated by IL-1α. Finally, gene set enrichment analysis of fibrosis-related genes indicated that IL-1 moderately counteracts the collective effect of TGF-β on these genes. Microarray results were validated by qPCR. Taken together, the results indicate prominent antagonistic effects of IL-1α on TGF-β regulated interferon signaling, as well as on a wide variety of other genes and pathways in fibroblasts. This article is protected by copyright. All rights reserved.

    Place, publisher, year, edition, pages
    Hoboken, USA: Wiley-Blackwell, 2016
    Keywords
    Connective tissue growth factor, transforming growth factor-beta, interleukin-1, interferon, fibroblast, fibrosis and ingenuity pathway analysis
    National Category
    Other Basic Medicine Cell Biology Biochemistry and Molecular Biology
    Research subject
    Cell Research
    Identifiers
    urn:nbn:se:oru:diva-48463 (URN)10.1002/jcb.25455 (DOI)000375916800014 ()26629874 (PubMedID)2-s2.0-84964773875 (Scopus ID)
    Note

    Funding Agencies:

    Örebro County Council Research Committee of the Örebro University Hospital OLL-550071

    Nyckelfonden AE56340

    Available from: 2016-02-22 Created: 2016-02-22 Last updated: 2019-03-26Bibliographically approved
    4. IL-1α counteracts TGF-β regulated protein expression in human dermal fibroblasts
    Open this publication in new window or tab >>IL-1α counteracts TGF-β regulated protein expression in human dermal fibroblasts
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Identifiers
    urn:nbn:se:oru:diva-48464 (URN)
    Available from: 2016-02-22 Created: 2016-02-22 Last updated: 2018-01-10Bibliographically approved
  • 26.
    Koskela von Sydow, Anita
    et al.
    Örebro University, School of Health Sciences.
    Janbaz, Chris
    Department of Plastic and Reconstructive Surgery Clinic, School of Medical Science, Örebro University SE 70182, Örebro, Sweden.
    Bergemalm, Daniel
    Örebro University, School of Health Sciences. Department of Internal Medicine, Division of Gastroenterology.
    Ivarsson, Mikael
    Örebro University, School of Health Sciences.
    IL-1α counteracts TGF-β regulated protein expression in human dermal fibroblastsManuscript (preprint) (Other academic)
  • 27.
    Koskela von Sydow, Anita
    et al.
    Department of Clinical Research Laboratory, Örebro University Hospital, Örebro, Sweden.
    Janbaz, Chris
    Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Department of Plastic and Reconstructive Surgery, Örebro University Hospital, Örebro, Sweden .
    Kardeby, Caroline
    Örebro University, School of Medical Sciences.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Ivarsson, Mikael
    Örebro University, School of Health Sciences.
    IL-1α Counteract TGF-β Regulated Genes and Pathways in Human Fibroblasts2016In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 117, no 7, p. 1622-1632Article in journal (Refereed)
    Abstract [en]

    Dysregulated wound healing is commonly associated with excessive fibrosis. Connective tissue growth factor (CTGF/CCN2) is characteristically overexpressed in fibrotic diseases and stimulated by transforming growth factor-β (TGF-β) in dermal fibroblasts. We previously showed that interleukin-1 (IL-1α) counteracts TGF-β-stimulated CTGF mRNA and protein expression in these cells. The aim of this study was to explore the effects of IL-1α on further genes and pathways in TGF-β regulated fibroblasts. Transcriptional microarray and multiple comparison analysis showed that the antagonizing effects of IL-1α was much more prominent than the synergistic effects, both with respect to number of genes and extent of changes in gene expression. Moreover, comparing canonical pathways by gene set enrichment analysis and the Ingenuity Pathway Analysis tool revealed that IL-1α counteracted TGF-β in the top six most confident pathways regulated by both cytokines. Interferon and IL-1 signaling, as well as two pathways involved in apoptosis signaling were suppressed by TGF-β and activated by IL-1α. Pathways involving actin remodeling and focal adhesion dynamics were activated by TGF-β and suppressed by IL-1α. Analyzing upstream regulators in part corroborate the comparison of canonical pathways and added cell cycle regulators as another functional group regulated by IL-1α. Finally, gene set enrichment analysis of fibrosis-related genes indicated that IL-1 moderately counteracts the collective effect of TGF-β on these genes. Microarray results were validated by qPCR. Taken together, the results indicate prominent antagonistic effects of IL-1α on TGF-β regulated interferon signaling, as well as on a wide variety of other genes and pathways in fibroblasts. This article is protected by copyright. All rights reserved.

  • 28.
    Lamichhane, Santosh
    et al.
    Turku Bioscience, University of Turku and Åbo Akademi University, Turku, Finland.
    Kemppainen, Esko
    Turku Bioscience, University of Turku and Åbo Akademi University, Turku, Finland.
    Trošt, Kajetan
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Siljander, Heli
    Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Program Unit, University of Helsinki, Helsinki, Finland.
    Hyöty, Heikki
    Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland; Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland.
    Ilonen, Jorma
    Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland; Clinical Microbiology, Turku University Hospital, Turku, Finland.
    Toppari, Jorma
    Institute of Biomedicine, Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland; Department of Pediatrics, Turku University Hospital, Turku, Finland.
    Veijola, Riitta
    Department of Pediatrics, PEDEGO Research Unit, Medical Research Centre, University of Oulu, Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland; Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Knip, Mikael
    Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Program Unit, University of Helsinki, Helsinki, Finland; Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland; Folkhälsan Research Center, Helsinki, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Bioscience, University of Turku and Åbo Akademi University, Turku, Finland; .
    Circulating metabolites in progression to islet autoimmunity and type 1 diabetes2019In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: Metabolic dysregulation may precede the onset of type 1 diabetes. However, these metabolic disturbances and their specific role in disease initiation remain poorly understood. In this study, we examined whether children who progress to type 1 diabetes have a circulatory polar metabolite profile distinct from that of children who later progress to islet autoimmunity but not type 1 diabetes and a matched control group.

    METHODS: We analysed polar metabolites from 415 longitudinal plasma samples in a prospective cohort of children in three study groups: those who progressed to type 1 diabetes; those who seroconverted to one islet autoantibody but not to type 1 diabetes; and an antibody-negative control group. Metabolites were measured using two-dimensional GC high-speed time of flight MS.

    RESULTS: In early infancy, progression to type 1 diabetes was associated with downregulated amino acids, sugar derivatives and fatty acids, including catabolites of microbial origin, compared with the control group. Methionine remained persistently upregulated in those progressing to type 1 diabetes compared with the control group and those who seroconverted to one islet autoantibody. The appearance of islet autoantibodies was associated with decreased glutamic and aspartic acids.

    CONCLUSIONS/INTERPRETATION: Our findings suggest that children who progress to type 1 diabetes have a unique metabolic profile, which is, however, altered with the appearance of islet autoantibodies. Our findings may assist with early prediction of the disease.

  • 29.
    Lelliott, Christopher J.
    et al.
    Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom; AstraZeneca R&D, Mölndal, Sweden .
    Medina-Gomez, Gema
    Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom .
    Petrovic, Natasa
    The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden .
    Kis, Adrienn
    Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom .
    Feldmann, Helena M.
    The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden .
    Bjursell, Mikael
    AstraZeneca R&D, Mölndal, Sweden .
    Parker, Nadeene
    Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom .
    Curtis, Keira
    Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom .
    Campbell, Mark
    Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom .
    Hu, Ping
    Division of Cardiology, University of Utah, Salt Lake City, Utah, United States of America .
    Zhang, Dongfang
    Division of Cardiology, University of Utah, Salt Lake City, Utah, United States of America .
    Litwin, Sheldon E.
    Division of Cardiology, University of Utah, Salt Lake City, Utah, United States of America .
    Zaha, Vlad G.
    Division of Endocrinology, Metabolism, and Diabetes and Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, Utah, United States of America .
    Fountain, Kimberly T.
    Division of Endocrinology, Metabolism, and Diabetes and Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, Utah, United States of America .
    Boudina, Sihem
    Division of Endocrinology, Metabolism, and Diabetes and Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, Utah, United States of America .
    Jimenez-Linan, Mercedes
    Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom .
    Blount, Margaret
    Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom .
    Lopez, Miguel
    Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom .
    Meirhaeghe, Aline
    INSERM, Institut Pasteur de Lille, Lille Cedex, France .
    Bohlooly-Y, Mohammad
    AstraZeneca R&D, Mölndal, Sweden .
    Storlien, Leonard
    AstraZeneca R&D, Mölndal, Sweden .
    Strömstedt, Maria
    AstraZeneca R&D, Mölndal, Sweden .
    Snaith, Michael
    AstraZeneca R&D, Mölndal, Sweden .
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland .
    Abel, E. Dale
    Division of Endocrinology, Metabolism, and Diabetes and Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, Utah, United States of America .
    Cannon, Barbara
    The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden .
    Vidal-Puig, Antonio
    Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom .
    Ablation of PGC-1beta results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance2006In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 4, no 11, article id e369Article in journal (Refereed)
    Abstract [en]

    The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1beta (PGC-1beta) has been implicated in important metabolic processes. A mouse lacking PGC-1beta (PGC1betaKO) was generated and phenotyped using physiological, molecular, and bioinformatic approaches. PGC1betaKO mice are generally viable and metabolically healthy. Using systems biology, we identified a general defect in the expression of genes involved in mitochondrial function and, specifically, the electron transport chain. This defect correlated with reduced mitochondrial volume fraction in soleus muscle and heart, but not brown adipose tissue (BAT). Under ambient temperature conditions, PGC-1beta ablation was partially compensated by up-regulation of PGC-1alpha in BAT and white adipose tissue (WAT) that lead to increased thermogenesis, reduced body weight, and reduced fat mass. Despite their decreased fat mass, PGC1betaKO mice had hypertrophic adipocytes in WAT. The thermogenic role of PGC-1beta was identified in thermoneutral and cold-adapted conditions by inadequate responses to norepinephrine injection. Furthermore, PGC1betaKO hearts showed a blunted chronotropic response to dobutamine stimulation, and isolated soleus muscle fibres from PGC1betaKO mice have impaired mitochondrial function. Lack of PGC-1beta also impaired hepatic lipid metabolism in response to acute high fat dietary loads, resulting in hepatic steatosis and reduced lipoprotein-associated triglyceride and cholesterol content. Altogether, our data suggest that PGC-1beta plays a general role in controlling basal mitochondrial function and also participates in tissue-specific adaptive responses during metabolic stress.

  • 30.
    Logotheti, Marianthi
    Örebro University, School of Medical Sciences.
    Integration of functional genomics and data mining methodologies in the study of bipolar disorder and schizophrenia2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Bipolar disorder and schizophrenia are two severe psychiatric disorders characterized by a complex genetic basis, coupled to the influence of environmental factors. In this thesis, functional genomic analysis tools were used for the study of the underlying pathophysiology of these disorders, focusing on gene expression and function on a global scale with the application of high-throughput methods. Datasets from public databases regarding transcriptomic data of postmortem brain and skin fibroblast cells of patients with either schizophrenia or bipolar disorder were analyzed in order to identify differentially expressed genes. In addition, fibroblast cells of bipolar disorder patients obtained from the Biobank of the Neuropsychiatric Research Laboratory of Örebro University were cultured, RNA was extracted and used for microarray analysis. In order to gain deeper insight into the biological mechanisms related to the studied psychiatric disorders, the differentially expressed gene lists were subjected to pathway and target prioritization analysis, using proprietary tools developed by the group of Metabolic Engineering and Bioinformatics, of the National Hellenic Research Foundation, thus indicating various cellular processes as significantly altered. Many of the molecular processes derived from the analysis of the postmortem brain data of schizophrenia and bipolar disorder were also identified in the skin fibroblast cells. Additionally, through the use of machine learning methods, gene expression data from patients with schizophrenia were exploited for the identification of a subset of genes with discriminative ability between schizophrenia and healthy control subjects. Interestingly, a set of genes with high separating efficiency was derived from fibroblast gene expression profiling. This thesis suggests the suitability of skin fibroblasts as a reliable model for the diagnostic evaluation of psychiatric disorders and schizophrenia in particular, through the construction of promising machine-learning based classification models, exploiting gene expression data from peripheral tissues.

    List of papers
    1. A Comparative Genomic Study in Schizophrenic and in Bipolar Disorder Patients, Based on Microarray Expression Profiling Meta-Analysis
    Open this publication in new window or tab >>A Comparative Genomic Study in Schizophrenic and in Bipolar Disorder Patients, Based on Microarray Expression Profiling Meta-Analysis
    Show others...
    2013 (English)In: Scientific World Journal, ISSN 1537-744X, E-ISSN 1537-744X, Vol. 2013, no 685917, p. 1-14, article id 685917Article in journal (Refereed) Published
    Abstract [en]

    Schizophrenia affecting almost 1% and bipolar disorder affecting almost 3%-5% of the global population constitute two severe mental disorders. The catecholaminergic and the serotonergic pathways have been proved to play an important role in the development of schizophrenia, bipolar disorder, and other related psychiatric disorders. The aim of the study was to perform and interpret the results of a comparative genomic profiling study in schizophrenic patients as well as in healthy controls and in patients with bipolar disorder and try to relate and integrate our results with an aberrant amino acid transport through cell membranes. In particular we have focused on genes and mechanisms involved in amino acid transport through cell membranes from whole genome expression profiling data. We performed bioinformatic analysis on raw data derived from four different published studies. In two studies postmortem samples from prefrontal cortices, derived from patients with bipolar disorder, schizophrenia, and control subjects, have been used. In another study we used samples from postmortem orbitofrontal cortex of bipolar subjects while the final study was performed based on raw data from a gene expression profiling dataset in the postmortem superior temporal cortex of schizophrenics. The data were downloaded from NCBI's GEO datasets

    Place, publisher, year, edition, pages
    New York, USA: Hindawi Publishing Corporation, 2013
    National Category
    Medical and Health Sciences
    Research subject
    Biomedicine; Psychiatry
    Identifiers
    urn:nbn:se:oru:diva-42590 (URN)10.1155/2013/685917 (DOI)000316470600001 ()23554570 (PubMedID)2-s2.0-84876539074 (Scopus ID)
    Available from: 2015-02-11 Created: 2015-02-11 Last updated: 2018-05-26Bibliographically approved
    2. Gene Expression Analysis of Fibroblasts from Patients with Bipolar Disorder
    Open this publication in new window or tab >>Gene Expression Analysis of Fibroblasts from Patients with Bipolar Disorder
    Show others...
    2015 (English)In: Journal of Neuropsychopharmacology & Mental Health, ISSN 2472-095X, Vol. 1, no 1, p. 1-9, article id 1000103Article in journal (Refereed) Published
    Abstract [en]

    Bipolar disorder is a severe, lifelong psychiatric disease. The main underlying pathophysiology of the disease is still incomprehensible. Various studies have suggested that many genes of small impact in combination with environmental factors contribute to the expression of the disease. In this study comparative transcriptomic profiling to characterize skin fibroblasts’ gene expression of bipolar disorder patients compared to healthy controls has been performed. Skin fibroblast cells from bipolar disorder patients (n=10) and marched healthy controls (n=5) have been cultured. RNA was extracted and then hybridized onto Illumina Human HT-12 v4 Expression BeadChips. Differentially expressed genes between bipolar disorder samples and healthy controls were identified by performing unequal t-test on log 2 transformed expression values. The resulting gene list was obtained by setting the p-value threshold to 0.05 and by removing genes that presented a fold change ≥ |0.5| (in log 2 scale). We concluded to 457 differentially expressed genes. Among them 127 showed an upregulation and 330 were downregulated. Τhe expression alterations of selected genes were validated by quantitative real-time polymerase chain reaction. In order to derive better insight into the biological mechanisms related to the differentially expressed genes, the lists of significant genes were subjected to pathway analysis and target prioritization indicating various processes such as calcium ion homeostasis, positive regulation of apoptotic process and cellular response to retinoic acid.

    Place, publisher, year, edition, pages
    OMICS International, 2015
    Keywords
    Skin fibroblasts, Bbipolar disorder, transcriptome, psychiatric diseases, pathway analysis, microarrays
    National Category
    Medical and Health Sciences Psychiatry
    Research subject
    Psychiatry; Molecular Medicine (Genetics and Pathology); Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-47705 (URN)10.4172/jnpmh.1000103 (DOI)
    Available from: 2016-01-20 Created: 2016-01-20 Last updated: 2018-07-02Bibliographically approved
    3. Studying Microarray Gene Expression Data of Schizophrenic Patients for Derivation of a Diagnostic Signature through the Aid of Machine Learning
    Open this publication in new window or tab >>Studying Microarray Gene Expression Data of Schizophrenic Patients for Derivation of a Diagnostic Signature through the Aid of Machine Learning
    Show others...
    2016 (English)In: Biometrics & Biostatistics International Journal, ISSN 2378-315X, Vol. 4, no 5, article id 00106Article in journal (Refereed) Published
    Abstract [en]

    Schizophrenia is a complex psychiatric disease that is affected by multiple genes, some of which could be used as biomarkers for specific diagnosis of the disease. In this work, we explore the power of machine learning methodologies for predicting schizophrenia, through the derivation of a biomarker gene signature for robust diagnostic classification purposes. Postmortem brain gene expression data from the anterior prefrontal cortex of schizophrenia patients were used as training data for the construction of the classifiers. Several machine learning algorithms, such as support vector machines, random forests, and extremely randomized trees classifiers were developed and their performance was tested. After applying the feature selection method of support vector machines recursive feature elimination a 21-gene model was derived. Using these genes for developing classification models, the random forests algorithm outperformed all examined algorithms achieving an area under the curve of 0.98 and sensitivity of 0.89, discriminating schizophrenia from healthy control samples with high efficiency. The 21-gene model that was derived from the feature selection is suggested for classifying schizophrenic patients, as it was successfully applied on an independent dataset of postmortem brain samples from the superior temporal cortex, and resulted in a classification model that achieved an area under the curve score of 0.91. Additionally, the functional analysis of the statistically significant genes indicated many mechanisms related to the immune system.

    Place, publisher, year, edition, pages
    MedCrave, 2016
    Keywords
    Classification, Schizophrenia, Machine learning, Gene expression, Microarray studies, Support vector machines, Adaboost
    National Category
    Other Basic Medicine
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-53536 (URN)
    Note

    DOI 10.15406/bbij.2016.04.00106

    Available from: 2016-11-17 Created: 2016-11-17 Last updated: 2018-04-27Bibliographically approved
    4. Development and validation of a skin fibroblast biomarker profile for schizophrenic patients
    Open this publication in new window or tab >>Development and validation of a skin fibroblast biomarker profile for schizophrenic patients
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-53538 (URN)
    Available from: 2016-11-17 Created: 2016-11-17 Last updated: 2018-01-13Bibliographically approved
  • 31.
    Logotheti, Marianthi
    et al.
    Örebro University, School of Medical Sciences. Metabolic Engineering and Bioinformatics Group, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
    Pilalis, Eleftherios
    Metabolic Engineering and Bioinformatics Group, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; e-NIOS Applications PC, Athens, Greece .
    Venizelos, Nikolaos
    Örebro University, School of Health Sciences.
    Kolisis, Fragiskos
    Laboratory of Biotechnology, School of Chemical Engineering, National Technical University of Athens, Athens, Greece.
    Chatziioannou, Aristotelis
    Metabolic Engineering and Bioinformatics Group, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; e-NIOS Applications PC, Athens, Greece .
    Development and validation of a skin fibroblast biomarker profile for schizophrenic patientsManuscript (preprint) (Other academic)
  • 32.
    Logotheti, Marianthi
    et al.
    Örebro University, School of Medical Sciences. Metabolic Engineering and Bioinformatics Group, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
    Pilalis, Eleftherios
    Metabolic Engineering and Bioinformatics Group, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; e-NIOS Applications PC, Athens, Greece .
    Venizelos, Nikolaos
    Neuropsychiatric Research Laboratory, Faculty of Medicine and Health, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Kolisis, Fragiskos
    Laboratory of Biotechnology, School of Chemical Engineering, National Technical University of Athens, Athens, Greece.
    Chatziioannou, Aristotelis
    Metabolic Engineering and Bioinformatics Group, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; e-NIOS Applications PC, Athens, Greece .
    Studying Microarray Gene Expression Data of Schizophrenic Patients for Derivation of a Diagnostic Signature through the Aid of Machine Learning2016In: Biometrics & Biostatistics International Journal, ISSN 2378-315X, Vol. 4, no 5, article id 00106Article in journal (Refereed)
    Abstract [en]

    Schizophrenia is a complex psychiatric disease that is affected by multiple genes, some of which could be used as biomarkers for specific diagnosis of the disease. In this work, we explore the power of machine learning methodologies for predicting schizophrenia, through the derivation of a biomarker gene signature for robust diagnostic classification purposes. Postmortem brain gene expression data from the anterior prefrontal cortex of schizophrenia patients were used as training data for the construction of the classifiers. Several machine learning algorithms, such as support vector machines, random forests, and extremely randomized trees classifiers were developed and their performance was tested. After applying the feature selection method of support vector machines recursive feature elimination a 21-gene model was derived. Using these genes for developing classification models, the random forests algorithm outperformed all examined algorithms achieving an area under the curve of 0.98 and sensitivity of 0.89, discriminating schizophrenia from healthy control samples with high efficiency. The 21-gene model that was derived from the feature selection is suggested for classifying schizophrenic patients, as it was successfully applied on an independent dataset of postmortem brain samples from the superior temporal cortex, and resulted in a classification model that achieved an area under the curve score of 0.91. Additionally, the functional analysis of the statistically significant genes indicated many mechanisms related to the immune system.

  • 33.
    Löfstedt, Håkan
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Westerlund, Jessica
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Graff, Pål
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bryngelsson, Ing-Liss
    Department of Occupational and Environmental Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Mölleby, Göte
    Department of Occupational and Environmental Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Olin, Anna-Carin
    Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Eriksson, Kåre
    Umeå University, Umeå, Sweden.
    Westberg, Håkan
    Örebro University, School of Science and Technology.
    Respiratory and ocular symptoms among employees at Swedish indoor swimming poolsManuscript (preprint) (Other academic)
  • 34.
    Medina-Gomez, Gema
    et al.
    Department of Clinical Biochemistry, Histopathology, University of Cambridge/Addenbrooke's Hospital, Cambridge, United Kingdom .
    Gray, Sarah L.
    Department of Clinical Biochemistry, Histopathology, University of Cambridge/Addenbrooke's Hospital, Cambridge, United Kingdom .
    Yetukuri, Laxman
    Technical Research Centre of Finland (VTT), Espoo, Finland .
    Shimomura, Kenju
    University Laboratory of Physiology, University of Oxford, Oxford, United Kingdom .
    Virtue, Sam
    Department of Clinical Biochemistry, Histopathology, University of Cambridge/Addenbrooke's Hospital, Cambridge, United Kingdom .
    Campbell, Mark
    Department of Clinical Biochemistry, Histopathology, University of Cambridge/Addenbrooke's Hospital, Cambridge, United Kingdom .
    Curtis, R. Keira
    Department of Clinical Biochemistry, Histopathology, University of Cambridge/Addenbrooke's Hospital, Cambridge, United Kingdom .
    Jimenez-Linan, Mercedes
    Department of Clinical Biochemistry, Histopathology, University of Cambridge/Addenbrooke's Hospital, Cambridge, United Kingdom .
    Blount, Margaret
    Department of Clinical Biochemistry, Histopathology, University of Cambridge/Addenbrooke's Hospital, Cambridge, United Kingdom .
    Yeo, Giles S. H.
    Department of Clinical Biochemistry, Histopathology, University of Cambridge/Addenbrooke's Hospital, Cambridge, United Kingdom .
    Lopez, Miguel
    Department of Clinical Biochemistry, Histopathology, University of Cambridge/Addenbrooke's Hospital, Cambridge, United Kingdom .
    Seppänen-Laakso, Tuulikki
    Technical Research Centre of Finland (VTT), Espoo, Finland .
    Ashcroft, Frances M.
    University Laboratory of Physiology, University of Oxford, Oxford, United Kingdom .
    Oresic, Matej
    Technical Research Centre of Finland (VTT), Espoo, Finland .
    Vidal-Puig, Antonio
    Department of Clinical Biochemistry, Histopathology, University of Cambridge/Addenbrooke's Hospital, Cambridge, United Kingdom .
    PPAR gamma 2 prevents lipotoxicity by controlling adipose tissue expandability and peripheral lipid metabolism2007In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 3, no 4, article id e64Article in journal (Refereed)
    Abstract [en]

    Peroxisome proliferator activated receptor gamma 2 (PPARg2) is the nutritionally regulated isoform of PPARg. Ablation of PPARg2 in the ob/ob background, PPARg2(-/-) Lep(ob)/Lep(ob) (POKO mouse), resulted in decreased fat mass, severe insulin resistance, beta-cell failure, and dyslipidaemia. Our results indicate that the PPARg2 isoform plays an important role, mediating adipose tissue expansion in response to positive energy balance. Lipidomic analyses suggest that PPARg2 plays an important antilipotoxic role when induced ectopically in liver and muscle by facilitating deposition of fat as relatively harmless triacylglycerol species and thus preventing accumulation of reactive lipid species. Our data also indicate that PPARg2 may be required for the beta-cell hypertrophic adaptive response to insulin resistance. In summary, the PPARg2 isoform prevents lipotoxicity by (a) promoting adipose tissue expansion, (b) increasing the lipid-buffering capacity of peripheral organs, and (c) facilitating the adaptive proliferative response of beta-cells to insulin resistance.

  • 35.
    Medina-Gomez, Gema
    et al.
    Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
    Virtue, Sam
    Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
    Lelliott, Christopher
    Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
    Boiani, Romina
    Institute of Normal Human Morphology, Faculty of Medicine, Ancona University, Ancona, Italy .
    Campbell, Mark
    Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
    Christodoulides, Constantinos
    Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
    Perrin, Christophe
    Centre National de la Recherche Scientifique, Paul Sabatier University, Toulouse, France .
    Jimenez-Linan, Mercedes
    Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
    Blount, Margaret
    Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
    Dixon, John
    Paradigm Therapeutics, Cambridge, U.K.
    Zahn, Dirk
    Paradigm Therapeutics, Cambridge, U.K.
    Thresher, Rosemary R.
    Paradigm Therapeutics, Cambridge, U.K.
    Aparicio, Sam
    Paradigm Therapeutics, Cambridge, U.K.
    Carlton, Mark
    Paradigm Therapeutics, Cambridge, U.K.
    Colledge, William H.
    Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
    Kettunen, Mikko I.
    Department of Biochemistry, University of Cambridge, Cambridge, U.K..
    Seppänen-Laakso, Tuulikki
    VTT: Technical Research Centre of Finland, VTT Biotechnology, Espoo, Finland.
    Sethi, Jaswinder K.
    Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
    O'Rahilly, Stephen
    Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
    Brindle, Kevin
    Department of Biochemistry, University of Cambridge, Cambridge, U.K..
    Cinti, Saverio
    Institute of Normal Human Morphology, Faculty of Medicine, Ancona University, Ancona, Italy .
    Oresic, Matej
    VTT: Technical Research Centre of Finland, VTT Biotechnology, Espoo, Finland.
    Burcelin, Remy
    Centre National de la Recherche Scientifique, Paul Sabatier University, Toulouse, France .
    Vidal-Puig, Antonio
    Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
    The link between nutritional status and insulin sensitivity is dependent on the adipocyte-specific peroxisome proliferator-activated receptor-gamma2 isoform2005In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 54, no 6, p. 1706-1716Article in journal (Refereed)
    Abstract [en]

    The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) is critically required for adipogenesis. PPARgamma exists as two isoforms, gamma1 and gamma2. PPARgamma2 is the more potent adipogenic isoform in vitro and is normally restricted to adipose tissues, where it is regulated more by nutritional state than PPARgamma1. To elucidate the relevance of the PPARgamma2 in vivo, we generated a mouse model in which the PPARgamma2 isoform was specifically disrupted. Despite similar weight, body composition, food intake, energy expenditure, and adipose tissue morphology, male mice lacking the gamma2 isoform were more insulin resistant than wild-type animals when fed a regular diet. These results indicate that insulin resistance associated with ablation of PPARgamma2 is not the result of lipodystrophy and suggests a specific role for PPARgamma2 in maintaining insulin sensitivity independently of its effects on adipogenesis. Furthermore, PPARgamma2 knockout mice fed a high-fat diet did not become more insulin resistant than those on a normal diet, despite a marked increase in their mean adipocyte cell size. These findings suggest that PPARgamma2 is required for the maintenance of normal insulin sensitivity in mice but also raises the intriguing notion that PPARgamma2 may be necessary for the adverse effects of a high-fat diet on carbohydrate metabolism.

  • 36.
    Medina-Gomez, Gema
    et al.
    University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK.
    Yetukuri, Laxman
    VTT Technical Research Centre of Finland, Finland.
    Velagapudi, Vidya
    VTT Technical Research Centre of Finland, Finland.
    Campbell, Mark
    University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK.
    Blount, Margaret
    University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK.
    Jimenez-Linan, Mercedes
    Department of Histopathology, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK.
    Ros, Manuel
    University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Finland.
    Vidal-Puig, Antonio
    University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK.
    Adaptation and failure of pancreatic beta cells in murine models with different degrees of metabolic syndrome2009In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 2, no 11-12, p. 582-592Article in journal (Refereed)
    Abstract [en]

    The events that contribute to the expansion of beta-cell mass and enhanced beta-cell function in insulin-resistant states have not been elucidated fully. Recently, we showed that beta-cell adaptation failed dramatically in adult, insulin-resistant POKO mice, which contrasts with the appropriate expansion of beta cells in their ob/ob littermates. Thus, we hypothesised that characterisation of the islets in these mouse models at an early age should provide a unique opportunity to: (1) identify mechanisms involved in sensing insulin resistance at the level of the beta cells, (2) identify molecular effectors that contribute to increasing beta-cell mass and function, and (3) distinguish primary events from secondary events that are more likely to be present at more advanced stages of diabetes. Our results define the POKO mouse as a model of early lipotoxicity. At 4 weeks of age, it manifests with inappropriate beta-cell function and defects in proliferation markers. Other well-recognised pathogenic effectors that were observed previously in 16-week-old mice, such as increased reactive oxygen species (ROS), macrophage infiltration and endoplasmic reticulum (ER) stress, are also present in both young POKO and young ob/ob mice, indicating the lack of predictive power with regards to the severity of beta-cell failure. Of interest, the relatively preserved lipidomic profile in islets from young POKO mice contrasted with the large changes in lipid composition and the differences in the chain length of triacylglycerols in the serum, liver, muscle and adipose tissue in adult POKO mice. Later lipotoxic insults in adult beta cells contribute to the failure of the POKO beta cell. Our results indicate that the rapid development of insulin resistance and beta-cell failure in POKO mice makes this model a useful tool to study early molecular events leading to insulin resistance and beta-cell failure. Furthermore, comparisons with ob/ob mice might reveal important adaptive mechanisms in beta cells with either therapeutic or diagnostic potential.

  • 37.
    Minehira, Kaori
    et al.
    Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA, USA; Department of Physiology, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
    Young, Stephen G.
    Department of Medicine, University of California, Los Angeles, CA, USA.
    Villanueva, Claudio J
    Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA, USA.
    Yetukuri, Laxman
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Hellerstein, Mark K.
    Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA.
    Farese, Robert V.
    Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA, USA.
    Horton, Jay D
    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
    Preitner, Frederic
    Department of Physiology, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
    Thorens, Bernard
    Department of Physiology, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
    Tappy, Luc
    Department of Physiology, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
    Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice2008In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 49, no 9, p. 2038-2044Article in journal (Refereed)
    Abstract [en]

    The liver secretes triglyceride-rich VLDLs, and the triglycerides in these particles are taken up by peripheral tissues, mainly heart, skeletal muscle, and adipose tissue. Blocking hepatic VLDL secretion interferes with the delivery of liver-derived triglycerides to peripheral tissues and results in an accumulation of triglycerides in the liver. However, it is unclear how interfering with hepatic triglyceride secretion affects adiposity, muscle triglyceride stores, and insulin sensitivity. To explore these issues, we examined mice that cannot secrete VLDL [due to the absence of microsomal triglyceride transfer protein (Mttp) in the liver]. These mice exhibit markedly reduced levels of apolipoprotein B-100 in the plasma, along with reduced levels of triglycerides in the plasma. Despite the low plasma triglyceride levels, triglyceride levels in skeletal muscle were unaffected. Adiposity and adipose tissue triglyceride synthesis rates were also normal, and body weight curves were unaffected. Even though the blockade of VLDL secretion caused hepatic steatosis accompanied by increased ceramides and diacylglycerols in the liver, the mice exhibited normal glucose tolerance and were sensitive to insulin at the whole-body level, as judged by hyperinsulinemic euglycemic clamp studies. Normal hepatic glucose production and insulin signaling were also maintained in the fatty liver induced by Mttp deletion. Thus, blocking VLDL secretion causes hepatic steatosis without insulin resistance, and there is little effect on muscle triglyceride stores or adiposity.

  • 38.
    Mollick, Tanzina
    Örebro University, School of Medical Sciences.
    Photoreceptor degeneration, second order neuron remodeling and glia reactivity in an in vivo and in vitro model of retinal neurodegeneration2016Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Photoreceptors have the ability to last during the entire lifespan of an individual. Being the first line of neurons in the visual transduction pathway, their health and maintenance is eminent for proper retinal function. However, photoreceptors are susceptible to neurodegenerative retinal dystrophies. A number of retinal pathologies such as retinitis pigmentosa, age-related amacular degeneration and diabetic retinopathy have been linked to photoreceptor death. Moreover, photoreceptor degeneration has been shown to affect downstream inner nuclear layer cells as well as induce reactive responses from Müller cells and microglia. Since current treatments are ineffective in preventing the degeneration of these neurons, intense research is still underway to discover novel treatment modalities. In this thesis, photoreceptor degeneration was assessed in an in vivo and in vitro model of neurodegeneration. Moreover, a possible mode of preserving these neurons by the use of human neural progenitor cells (hNPCs) was investigated. The in vivo pdgf-bret/ret (platelet derived growth factor-b retention motif knockout) mouse model, which shows severe vascular pathology as a result of detachment of pericytes from the vascular endothelium, was studied during the first postnatal month. In a short time span, i.e. between postnatal day (P)10 and P15, retinopathic features were observed. Photoreceptor degeneration related to cell death, cone outer segment (OS) shortening and synapse disassembly in the outer plexiform layer (OPL) was seen. The second order rod bipolar cells underwent remodeling and the Müller cells became gliotic with increased expression of GFAP (glial fibrillary acidic protein). Microglial cells were also observed to convert to their reactive amoeboid-like phenotype. These features seemed to become more severe in the older P28 mutants. In the in vitro porcine retinal explant model, photoreceptor death significantly increased by 3 days in vitro (div). This was associated with loss of cone OSs, opsin mislocalization and loss of synaptic integrity in the OPL. Horizontal cell death and remodeling was also observed together with a severe gliotic response from the Müller cells. Human neural progenitor cell cocultured explants for 3 div had the ability to preserve photoreceptor survival by means of OS conservation, better opsin trafficking and maintaining synaptic integrity. However, Müller cell gliosis was only mitigated by a decreased density of GFAP immunoreactive Müller cells. In conclusion, both the in vivo and in vitro model of neurodegeneration demonstrate the vulnerability of photoreceptors to various mechanisms of retinal injury. Interestingly, hNPC derived neurotrophic factors had neuroprotective qualities in 3 div porcine retinal explants.

    List of papers
    1. Photoreceptor degeneration, structural remodeling and glial activation: a morphological study on a genetic mouse model for pericyte deficiency
    Open this publication in new window or tab >>Photoreceptor degeneration, structural remodeling and glial activation: a morphological study on a genetic mouse model for pericyte deficiency
    2014 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 279, p. 269-284Article in journal (Refereed) Published
    Abstract [en]

    Interaction between pericytes and endothelial cells via platelet-derived growth factor B (PDGF-B) signaling is critical for the development of the retinal microvasculature. The PDGF-B retention motif controls the spatial distribution range of the growth factor in the vicinity of its producing endothelial cells allowing its recognition by PDGF receptor beta-(PDGFR-beta)-carrying pericytes; this promotes recruitment of pericytes to the vascular basement membrane. Impairment of the PDGF-B signaling mechanism causes development of vascular abnormalities, and in the retina this consequently leads to defects in the neurological circuitry. The vascular pathology in the pdgf-b(ret/ret) (PDGF-B retention motif knockout) mouse retina has been previously reported; our study investigates the progressive neuronal defects and changes in the retinal morphology of this pericyte-deficient mouse model. Immunohistochemical analysis revealed retinal injuries to occur as early as postnatal day (P) 10 with substantial damage progressing from P15 and onward. Vascular abnormalities were apparent from P10, however, prominent neuronal defects were mostly observed from P15, beginning with the compromised integrity of the laminated retinal structure characterized by the presence of rosettes and focally distorted regions. Photoreceptor degeneration was observed by loss of both rod and cone cells, including the disassembly and altered structure of their synaptic terminals. Significant shortening of cone outer segments was observed from P10 and later stages; however, decrease in cone density was only observed at P28. Disorganization and dendrite remodeling of rod bipolar cells also added to the diminished neural and synaptic integrity. Moreover, in response to retinal injuries, Muller and microglial cells were observed to be in the reactive phenotype from P15 and onward. Such a sequence of events indicates that the pdgf-b(ret/ret) mouse model displays a short time frame between P10 and P15, during which the retina shifts to a retinopathic phase by the development of prominently altered morphological features.

    Keywords
    photoreceptor degeneration, cell death, rosette, synapse, microglia, Müller cells
    National Category
    Neurosciences
    Research subject
    Neurology
    Identifiers
    urn:nbn:se:oru:diva-38893 (URN)10.1016/j.neuroscience.2014.09.013 (DOI)000343633800022 ()25224828 (PubMedID)2-s2.0-84907487118 (Scopus ID)
    Note

    Funding Agencies:

    Faculty of Medicine at Örebro University

    Signhild Engkvist Foundation

    Ögonfonden

    Crown Princess Margaretas Committee for the Blind

    Gun and Bertil Stohnes Foundation

    Karolinska Fonder och Stiftelser

    Available from: 2014-11-24 Created: 2014-11-21 Last updated: 2018-01-11Bibliographically approved
    2. Human neural progenitor cells decrease photoreceptor degeneration, normalize opsin distribution and support synapse structure in cultured porcine retina
    Open this publication in new window or tab >>Human neural progenitor cells decrease photoreceptor degeneration, normalize opsin distribution and support synapse structure in cultured porcine retina
    2016 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1646, p. 522-534Article in journal (Refereed) Published
    Abstract [en]

    Retinal neurodegenerative disorders like retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy and retinal detachment decrease retinal functionality leading to visual impairment. The pathological events are characterized by photoreceptor degeneration, synaptic disassembly, remodeling of postsynaptic neurons and activation of glial cells. Despite intense research, no effective treatment has been found for these disorders. The current study explores the potential of human neural progenitor cell (hNPC) derived factors to slow the degenerative processes in adult porcine retinal explants. Retinas were cultured for 3 days with or without hNPCs as a feeder layer and investigated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), immunohistochemical, western blot and quantitative real time-polymerase chain reaction (qRT-PCR) techniques. TUNEL showed that hNPCs had the capacity to limit photoreceptor cell death. Among cone photoreceptors, hNPC coculture resulted in better maintenance of cone outer segments and reduced opsin mislocalization. Additionally, maintained synaptic structural integrity and preservation of second order calbindin positive horizontal cells was also observed. However, Müller cell gliosis only seemed to be alleviated in terms of reduced Müller cell density. Our observations indicate that at 3 days of coculture, hNPC derived factors had the capacity to protect photoreceptors, maintain synaptic integrity and support horizontal cell survival. Human neural progenitor cell applied treatment modalities may be an effective strategy to help maintain retinal functionality in neurodegenerative pathologies. Whether hNPCs can independently hinder Müller cell gliosis by utilizing higher concentrations or by combination with other pharmacological agents still needs to be determined.

    Place, publisher, year, edition, pages
    Amsterdam, Netherlands: Elsevier, 2016
    Keywords
    Photoreceptor degeneration, synapse, opsin, gliosis, neuroprotection
    National Category
    Neurosciences Ophthalmology
    Research subject
    Neurology
    Identifiers
    urn:nbn:se:oru:diva-51995 (URN)10.1016/j.brainres.2016.06.039 (DOI)000381844700059 ()27369448 (PubMedID)2-s2.0-84978831975 (Scopus ID)
    Note

    Funding Agencies:

    Faculty of Natural Sciences at Linnaeus University

    Faculty of Medical Sciences at Örebro University 

    Olle Engkvist Foundation

    Ögonfonden

    Crown Princess Margaretas Committee for the Blind

    Edwin Jordan Foundation

    Available from: 2016-09-07 Created: 2016-09-06 Last updated: 2018-04-27Bibliographically approved
  • 39.
    Nakka, Sravya Sowdamini
    Örebro University, School of Medical Sciences.
    Development of novel tools for prevention and diagnosis of Porphyromonas gingivalis infection and periodontitis2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Periodontitis is a chronic inflammatory disease caused by exaggerated host immune responses to dysregulated microbiota in dental biofilms leading to degradation of tissues and alveolar bone loss. Porphyromonas gingivalis is a major periodontal pathogen and expresses several potent virulence factors. Among these factors, arginine and lysine gingipains are of special importance, both for the bacterial survival/proliferation and the pathological outcome. The major aim of this thesis was to develop and test novel methods for diagnosis and prevention of P. gingivalis infection and periodontitis. In study I, anti-P. gingivalis antibodies were developed in vitro for immunodetection of bacteria in clinical samples using a surface plasmon resonance (SPR)-based biosensor. Specific binding of the antibodies to P. gingivalis was demonstrated in samples of patients with periodontitis and the results were validated using real-time PCR and DNA-DNA checkerboard analysis. In study II, we elucidated the properties and antimicrobial effects of different lactobacillus species and the two-peptide bacteriocin PLNC8 αβ on P. gingivalis. L. plantarum NC8 and 44048 effectively inhibited P. gingivalis growth and pure PLNC8 αβ induced bacterial lysis by damaging P. gingivalis membrane. In study III, we demonstrated that PLNC8 αβ dose-dependently induces proliferation and release of growth factors in gingival epithelial cells (GECs). Furthermore, PLNC8 αβ decreased P. gingivalis-induced cytotoxic effects in GECs but did not alter the effect of gingipains on cytokine expression. In study IV, we elucidated the effects of anti-P. gingivalis antibodies and PLNC8 αβ in regulating cellular responses during P. gingivalis infection. Both antibodies and PLNC8 αβ modulated P. gingivalis-induced expression of growth factors in GECs, however, their effects were diminished when used in combination. The results of this thesis demonstrate a possible role of anti-P. gingivalis antibodies and PLNC8 αβ in prevention and treatment of P. gingivalis infection and periodontitis with no cytotoxic effects on human cells.

    List of papers
    1. Antibodies produced in vitro in the detection of periodontal bacteria by using surface plasmon resonance analysis
    Open this publication in new window or tab >>Antibodies produced in vitro in the detection of periodontal bacteria by using surface plasmon resonance analysis
    Show others...
    2015 (English)In: Clinical and Experimental Dental Research, ISSN 2057-4347, Vol. 1, no 1, p. 32-44Article in journal (Refereed) Published
    Abstract [en]

    Porphyromonas gingivalis (P. gingivalis) is a major etiological agent associated with periodontitis. This study aims to develop antibodies to P. gingivalis in vitro for real-time detection of bacteria in clinical samples. Lymphocytes were isolated from whole blood of patient treated for periodontitis and were stimulated with P. gingivalis ATCC 33277. B-cell maturation to long-living antibody secreting-plasma cells was studied using flow cytometry and immunofluorescence staining. The antibodies developed in vitro were immobilized onto a CM-5 sensor chip of a biosensor to detect the presence of P. gingivalis in the gingival crevicular fluid of patients with periodontitis compared to periodontally healthy controls (n = 30). Surface plasmon resonance (SPR) analysis was performed to evaluate specific interactions of bacteria in samples with the immobilized antibodies. The results of SPR analysis were compared to the detection of P. gingivalis in the samples using DNA–DNA checkerboard hybridization technique. A clear and distinct change in lymphocyte morphology upon stimulation with P. gingivalis was observed. Anti-P. gingivalis antibodies secreted by CD38+ plasma cells showed the presence of all the four IgG subclasses. The results of DNA–DNA checkerboard analysis were in agreement with that of SPR analysis for the detection of P. gingivalis in patient samples. Furthermore, incubation with anti-P. gingivalis attenuated the bacterial response in SPR. The in vitro method for antibody production developed during this study could be used for an efficient real-time detection of periodontitis, and the attenuating effects of in vitro antibodies suggest their role in passive immunization to prevent periodontitis and their associated risk factors.

    Place, publisher, year, edition, pages
    Wiley-Blackwell, 2015
    Keywords
    Antibodies, B-cell, plasma cell, periodontitis, P. gingivalis, surface plasmon resonance
    National Category
    Microbiology in the medical area
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-46728 (URN)10.1002/cre2.6 (DOI)000216889200006 ()2-s2.0-84986898105 (Scopus ID)
    Funder
    Knowledge Foundation
    Available from: 2015-11-24 Created: 2015-11-23 Last updated: 2018-04-07Bibliographically approved
    2. Antibacterial effects of Lactobacillus and bacteriocin PLNC8 αβ on the periodontal pathogen Porphyromonas gingivalis
    Open this publication in new window or tab >>Antibacterial effects of Lactobacillus and bacteriocin PLNC8 αβ on the periodontal pathogen Porphyromonas gingivalis
    Show others...
    2016 (English)In: BMC Microbiology, ISSN 1471-2180, E-ISSN 1471-2180, Vol. 16, no 1, article id 188Article in journal (Refereed) Published
    Abstract [en]

    Background: The complications in healthcare systems associated with antibiotic-resistant microorganisms have resulted in an intense search for new effective antimicrobials. Attractive substances from which novel antibiotics may be developed are the bacteriocins. These naturally occurring peptides are generally considered to be safe and efficient at eliminating pathogenic bacteria. Among specific keystone pathogens in periodontitis, Porphyromonas gingivalis is considered to be the most important pathogen in the development and progression of chronic inflammatory disease. The aim of the present study was to investigate the antimicrobial effects of different Lactobacillus species and the two-peptide bacteriocin PLNC8 αβ on P. gingivalis.

    Results: Growth inhibition of P. gingivalis was obtained by viable Lactobacillus and culture media from L. plantarum NC8 and 44048, but not L. brevis 30670. The two-peptide bacteriocin from L. plantarum NC8 (PLNC8 αβ) was found to be efficient against P. gingivalis through binding followed by permeabilization of the membranes, using Surface plasmon resonance analysis and DNA staining with Sytox Green. Liposomal systems were acquired to verify membrane permeabilization by PLNC8 αβ. The antimicrobial activity of PLNC8 αβ was found to be rapid (1 min) and visualized by TEM to cause cellular distortion through detachment of the outer membrane and bacterial lysis.

    Conclusion: Soluble or immobilized PLNC8 αβ bacteriocins may be used to prevent P. gingivalis colonization and subsequent pathogenicity, and thus supplement the host immune system against invading pathogens associated with periodontitis.

    Place, publisher, year, edition, pages
    London, United Kingdom: BioMed Central, 2016
    Keywords
    Periodontitis, P. gingivalis, Lactobacillus, Bacteriocin, PLNC8
    National Category
    Microbiology
    Identifiers
    urn:nbn:se:oru:diva-51749 (URN)10.1186/s12866-016-0810-8 (DOI)000383422500001 ()27538539 (PubMedID)2-s2.0-84982308370 (Scopus ID)
    Funder
    Swedish Heart Lung FoundationKnowledge FoundationMagnus Bergvall Foundation
    Note

    Funding Agency:

    Foundation of Olle Engkvist

    Available from: 2016-08-23 Created: 2016-08-23 Last updated: 2017-11-28Bibliographically approved
    3. Bacteriocin plantaricin NC8 αβ antagonizes Porphyromonas gingivalis infection and induces proliferation of gingival epithelial cells
    Open this publication in new window or tab >>Bacteriocin plantaricin NC8 αβ antagonizes Porphyromonas gingivalis infection and induces proliferation of gingival epithelial cells
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-52858 (URN)
    Available from: 2016-10-06 Created: 2016-10-06 Last updated: 2018-01-14Bibliographically approved
    4. Effects of plantaricin NC8 αβ and antibodies on gingival epithelial cells infected by Porphyromonas gingivalis
    Open this publication in new window or tab >>Effects of plantaricin NC8 αβ and antibodies on gingival epithelial cells infected by Porphyromonas gingivalis
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-52859 (URN)
    Available from: 2016-10-06 Created: 2016-10-06 Last updated: 2018-01-14Bibliographically approved
  • 40.
    Nakka, Sravya Sowdamini
    et al.
    Örebro University, School of Medical Sciences. The Institution for Protein Environmental Affinity Surveys, PEAS Institut AB, Linköping, Sweden.
    Palm, Eleonor
    Örebro University, School of Medical Sciences.
    Bengtsson, Torbjörn
    Örebro University, School of Medical Sciences.
    Khalaf, Hazem
    Örebro University, School of Medical Sciences.
    Bacteriocin plantaricin NC8 αβ antagonizes Porphyromonas gingivalis infection and induces proliferation of gingival epithelial cellsManuscript (preprint) (Other academic)
  • 41.
    Nakka, Sravya Sowdamini
    et al.
    Örebro University, School of Medical Sciences. The Institution for Protein Environmental Affinity Surveys, PEAS Institut AB, Linköping, Sweden.
    Palm, Eleonor
    Örebro University, School of Medical Sciences.
    Nayeri, Fariba
    The Institution for Protein Environmental Affinity Surveys, PEAS Institut AB, Linköping, Sweden; Division of Infectious Diseases, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Medical Sciences.
    Khalaf, Hazem
    Örebro University, School of Medical Sciences.
    Effects of plantaricin NC8 αβ and antibodies on gingival epithelial cells infected by Porphyromonas gingivalisManuscript (preprint) (Other academic)
  • 42.
    Paramel Varghese, Geena
    Örebro University, School of Medical Sciences.
    Innate immunity in human atherosclerosis and myocardial infarction: Role of CARD8 and NLRP32017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Atherosclerosis is complex inflammatory disease of the arterial wall with progressive accumulation of lipids and narrowing of the vessel. Increasing evidence suggest that inflammation plays an important role in plaque stability and often accelerate cardiovascular events such as myocardial infarction (MI). Among the vast number of inflammatory cytokines, IL-1β is known to be a key modulator in vessel wall inflammation and acceleration of the atherosclerotic process. The biologically active IL-1β is regulated by a multiprotein complex known as the NLRP3 inflammasome complex. In this thesis, we have focused on polymorphisms in the NLRP3 and CARD8 genes and their possible association to atherosclerosis and/or MI. We have also investigated the expression of inflammasome components NLRP3 and CARD8 in atherosclerosis and the role of genetic variants for the expression of these genes. The expression of NLRP3, CARD8, ASC, caspase-1, IL-1β, and IL-18 were found significantly upregulated in atherosclerotic lesions compared to normal arteries. Human carotid plaques not only express the NLRP3 inflammasome, but also release IL-1β upon exposure to lipopolysaccharide (LPS), adenosine triphosphate (ATP) and cholesterol crystals, which suggest NLRP3 inflammasome activation in human atherosclerotic lesions. Also, CARD8 was found to be important in the regulation of several inflammatory markers in endothelial cells, like RANTES, IP10 and ICAM-1. We further assessed the potential association of a CARD8 polymorphism and polymorphisms located downstream of the NLRP3 gene to the risk of MI in two independent Swedish cohorts. The CARD8 variant exhibited no association to risk of MI in either of the two cohorts. Some of the minor alleles of NLRP3 variants were associated with increased IL-1β levels and to NLRP3 mRNA levels in peripheral blood monocytic cells (PBMC). Taken together, the present thesis shows that NLRP3 inflammasome activation and increased expression of CARD8 in the atherosclerotic plaque might be possible contributors to the enhanced inflammatory response and leukocyte infiltration in the pathophysiology of atherosclerosis.

    List of papers
    1. NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis
    Open this publication in new window or tab >>NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis
    Show others...
    2016 (English)In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 5, no 5, article id e003031Article in journal (Refereed) Published
    Abstract [en]

    Background: The NLR family, pyrin domain containing 3 (NLRP3) inflammasome is an interleukin (IL)-1β and IL-18 cytokine processing complex that is activated in inflammatory conditions. The role of the NLRP3 inflammasome in the pathogenesis of atherosclerosis and myocardial infarction is not fully understood.

    Methods and Results: Atherosclerotic plaques were analyzed for transcripts of the NLRP3 inflammasome, and for IL-1β release. The Swedish First-ever myocardial Infarction study in Ac-county (FIA) cohort consisting of DNA from 555 myocardial infarction patients and 1016 healthy individuals was used to determine the frequency of 4 single nucleotide polymorphisms (SNPs) from the downstream regulatory region of NLRP3. Expression of NLRP3, Apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1 (CASP1), IL1B, and IL18 mRNA was significantly increased in atherosclerotic plaques compared to normal arteries. The expression of NLRP3 mRNA was significantly higher in plaques of symptomatic patients when compared to asymptomatic ones. CD68-positive macrophages were observed in the same areas of atherosclerotic lesions as NLRP3 and ASC expression. Occasionally, expression of NLRP3 and ASC was also present in smooth muscle cells. Cholesterol crystals and ATP induced IL-1β release from lipopolysaccharide-primed human atherosclerotic lesion plaques. The minor alleles of the variants rs4266924, rs6672995, and rs10733113 were associated with NLRP3 mRNA levels in peripheral blood mononuclear cells but not with the risk of myocardial infarction.

    Conclusions: Our results indicate a possible role of the NLRP3 inflammasome and its genetic variants in the pathogenesis of atherosclerosis.

    Place, publisher, year, edition, pages
    Hoboken, USA: Wiley-Blackwell Publishing Inc., 2016
    Keywords
    Inflammasome, interleukin-1b, myocardial infarction, NLRP3, polymorphism
    National Category
    Cardiac and Cardiovascular Systems
    Research subject
    Cardiology
    Identifiers
    urn:nbn:se:oru:diva-50441 (URN)10.1161/JAHA.115.003031 (DOI)000386711200020 ()27207962 (PubMedID)
    Funder
    Swedish Research Council, 6816 K2012-64X-12233-13-3Swedish Heart Lung Foundation, 20110359Magnus Bergvall Foundation
    Note

    Funding Agencies:

    Center of Excellence for Research on Inflammation and Cardiovascular Disease (CERIC) Linnaeus Center8703

    Foundation for Strategic Research, Uppdrag Besegra Stroke P581/2011-123

    Strategic Cardiovascular Programs of Karolinska Institutet, Stockholm County Council ALF 20110279

    Örebro University

    Sigurd and Elsa Goljes Foundation

    Available from: 2016-05-26 Created: 2016-05-26 Last updated: 2018-09-12Bibliographically approved
    2. Q705K variant in NLRP3 gene confers protection against myocardial infarction in female individuals
    Open this publication in new window or tab >>Q705K variant in NLRP3 gene confers protection against myocardial infarction in female individuals
    Show others...
    2013 (English)In: Biomedical Reports, ISSN 2049-9434, Vol. 1, no 6, p. 879-882Article in journal (Refereed) Published
    Abstract [en]

    Inflammation is a multifaceted process that underlies the pathophysiology of acute myocardial infarction (MI). Variations in the inflammasome‑related NLRP3 gene have been associated with risk for a number of different inflammatory diseases. Therefore, Q705K polymorphism in NLRP3 gene likely confers susceptibility to risk for MI. A First‑ever myocardial Infarction study in Ac‑county (FIA) cohort comprising 555 MI patients and 1,016 controls was used to genotype rs35829419 in the NLRP3 gene by TaqMan single‑nucleotide polymorphism assay. C‑reactive protein (CRP) was measured in the study participants by ELISA. The results showed no significant association between the variant rs35829419 and MI. However, the minor A allele of the rs35829419 polymorphism conferred a protective effect against the risk of developing MI in females. The minor A allele of rs35829419 polymorphism was also associated with increased CRP levels in males. Results of the study suggested a gender‑specific deregulation of NLRP3 gene mediated by rs35829419 polymorphism that confers protection against MI in females but has no effect on MI susceptibility in males. However, the rs35829419 polymorphism was associated with increased CRP levels among the male subjects, thereby demonstrating the possible effect of the Q705K polymorphism in elevating the basal active state of innate immune response.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:oru:diva-35448 (URN)10.3892/br.2013.155 (DOI)
    Available from: 2014-06-19 Created: 2014-06-19 Last updated: 2017-10-18Bibliographically approved
    3. CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation
    Open this publication in new window or tab >>CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation
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    2013 (English)In: Clinical Science, ISSN 0143-5221, E-ISSN 1470-8736, Vol. 125, no 8, p. 401-407Article in journal (Refereed) Published
    Abstract [en]

    Inflammation is a key factor in the development of atherosclerotic coronary artery disease. It is promoted through the inflammasome, a molecular machine that produces IL (interleukin)-1 beta in response to cholesterol crystal accumulation in macrophages. The CARD8 (caspase recruitment domain 8) protein modulates this process by suppressing caspase 1 and the transcription factor NF-kappa B (nuclear factor kappa B). The expression of CARD8 mRNA was examined in atherosclerotic vascular tissue and the impact on MI (myocardial infarction) of a polymorphism in the CARD8 gene determined. CARD8 mRNA was analysed by microarray of human atherosclerotic tissue and compared with transplant donor arterial tissue. Microarray analysis was performed for proximal genes associated with the rs2043211 locus in plaque. The CARD8 rs2043211 polymorphism was analysed by genotyping of two Swedish MI cohorts, FIA (First Myocardial Infarction in Northern Sweden) and SCARF (Stockholm Coronary Atherosclerosis Risk Factor). The CRP (C-reactive protein) level was measured in both cohorts, but the levels of the pro-inflammatory cytokines IL-1 beta, IL-18, TNF (tumour necrosis factor) and MCP-1 (monocyte chemoattractant protein) were measured in sera available from the SCARF cohort. CARD8 mRNA was highly expressed in atherosclerotic plaques compared with the expression in transplant donor vessel (P < 0.00001). The minor allele was associated with lower expression of CARD8 in the plaques, suggesting that CARD8 may promote inflammation. Carriers of the minor allele of the rs2043211 polymorphism also displayed lower circulating CRP and lower levels of the pro-atherosclerotic chemokine MCP-1. However, no significant association could be detected between this polymorphism and MI in the two cohorts. Genetic alterations in the CARD8 gene therefore seem to be of limited importance for the development of MI.

    Place, publisher, year, edition, pages
    London, United Kingdom: Portland Press, 2013
    Keywords
    Caspase activation and recruitment domain 8 (CARD8), cytokines, gene polymorphism, inflammasome, myocardial infarction, rs2043211
    National Category
    Medical and Health Sciences Genetics
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-30985 (URN)10.1042/CS20120572 (DOI)000323852600009 ()23611467 (PubMedID)2-s2.0-84880141884 (Scopus ID)
    Funder
    Swedish Heart Lung FoundationSwedish Research Council, 521-2009-4203 349-2007-8703
    Note

    Funding Agencies:

    Magnus Bergvalls Foundation

    Örebro University

    Available from: 2013-09-27 Created: 2013-09-27 Last updated: 2018-08-27Bibliographically approved
    4. CARD8, a protein of innate immunity regulates the release of inflammatory cytokines in human endothelial cells
    Open this publication in new window or tab >>CARD8, a protein of innate immunity regulates the release of inflammatory cytokines in human endothelial cells
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-54142 (URN)
    Available from: 2016-12-20 Created: 2016-12-20 Last updated: 2018-01-13Bibliographically approved
  • 43.
    Paramel Varghese, Geena
    et al.
    Örebro University, School of Medical Sciences.
    Göthlin Eremo, Anna
    Örebro University Hospital, Örebro, Sweden.
    Ljungberg, Liza
    Örebro University, School of Medical Sciences.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Fransén, Karin
    Örebro University, School of Health Sciences.
    CARD8, a protein of innate immunity regulates the release of inflammatory cytokines in human endothelial cellsManuscript (preprint) (Other academic)
  • 44.
    Pietiläinen, Kirsi H.
    et al.
    Obesity Research Unit, Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland; Department of Medicine, Division of Diabetes, Helsinki University Central Hospital, Helsinki, Finland; Finnish Twin Cohort Study, Department of Public Health, University of Helsinki, Helsinki, Finland .
    Naukkarinen, Jussi
    Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland; Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland .
    Rissanen, Aila
    Obesity Research Unit, Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland .
    Saharinen, Juha
    Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland; Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland.
    Ellonen, Pekka
    Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland; Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland.
    Keränen, Heli
    Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland; Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland.
    Suomalainen, Anu
    Research Program of Molecular Neurology and Department of Neurology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland .
    Götz, Alexandra
    Research Program of Molecular Neurology and Department of Neurology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland .
    Suortti, Tapani
    VTT Technical Research Centre of Finland, Espoo, Finland .
    Yki-Järvinen, Hannele
    Department of Medicine, Division of Diabetes, Helsinki University Central Hospital, Helsinki, Finland .
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland .
    Kaprio, Jaakko
    Finnish Twin Cohort Study, Department of Public Health, University of Helsinki, Helsinki, Finland; Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland .
    Peltonen, Leena
    Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland; Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland; The Wellcome Trust Sanger Institute, Cambridge, United Kingdom; Broad Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America; Lund University, Sweden.
    Global transcript profiles of fat in monozygotic twins discordant for BMI: pathways behind acquired obesity2008In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 5, no 3, article id e51Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The acquired component of complex traits is difficult to dissect in humans. Obesity represents such a trait, in which the metabolic and molecular consequences emerge from complex interactions of genes and environment. With the substantial morbidity associated with obesity, a deeper understanding of the concurrent metabolic changes is of considerable importance. The goal of this study was to investigate this important acquired component and expose obesity-induced changes in biological pathways in an identical genetic background.

    METHODS AND FINDINGS: We used a special study design of "clonal controls," rare monozygotic twins discordant for obesity identified through a national registry of 2,453 young, healthy twin pairs. A total of 14 pairs were studied (eight male, six female; white), with a mean +/- standard deviation (SD) age 25.8 +/- 1.4 y and a body mass index (BMI) difference 5.2 +/- 1.8 kg/m(2). Sequence analyses of mitochondrial DNA (mtDNA) in subcutaneous fat and peripheral leukocytes revealed no aberrant heteroplasmy between the co-twins. However, mtDNA copy number was reduced by 47% in the obese co-twin's fat. In addition, novel pathway analyses of the adipose tissue transcription profiles exposed significant down-regulation of mitochondrial branched-chain amino acid (BCAA) catabolism (p < 0.0001). In line with this finding, serum levels of insulin secretion-enhancing BCAAs were increased in obese male co-twins (9% increase, p = 0.025). Lending clinical relevance to the findings, in both sexes the observed aberrations in mitochondrial amino acid metabolism pathways in fat correlated closely with liver fat accumulation, insulin resistance, and hyperinsulinemia, early aberrations of acquired obesity in these healthy young adults.

    CONCLUSIONS: Our findings emphasize a substantial role of mitochondrial energy- and amino acid metabolism in obesity and development of insulin resistance.

  • 45.
    Pietiläinen, Kirsi H.
    et al.
    Obesity Research Unit, Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland; Department of Medicine, Division of Diabetes, Helsinki University Central Hospital, Helsinki, Finland; Finnish Twin Cohort Study, Department of Public Health, University of Helsinki, Helsinki, Finland.
    Sysi-Aho, Marko
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Rissanen, Aila
    Obesity Research Unit, Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.
    Seppänen-Laakso, Tuulikki
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Yki-Järvinen, Hannele
    Department of Medicine, Division of Diabetes, Helsinki University Central Hospital, Helsinki, Finland.
    Kaprio, Jaakko
    Finnish Twin Cohort Study, Department of Public Health, University of Helsinki, Helsinki, Finland; Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland, .
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Acquired obesity is associated with changes in the serum lipidomic profile independent of genetic effects: a monozygotic twin study2007In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 2, no 2, article id e218Article in journal (Refereed)
    Abstract [en]

    Both genetic and environmental factors are involved in the etiology of obesity and the associated lipid disturbances. We determined whether acquired obesity is associated with changes in global serum lipid profiles independent of genetic factors in young adult monozygotic (MZ) twins. 14 healthy MZ pairs discordant for obesity (10 to 25 kg weight difference) and ten weight concordant control pairs aged 24-27 years were identified from a large population-based study. Insulin sensitivity was assessed by the euglycemic clamp technique, and body composition by DEXA (% body fat) and by MRI (subcutaneous and intra-abdominal fat). Global characterization of lipid molecular species in serum was performed by a lipidomics strategy using liquid chromatography coupled to mass spectrometry. Obesity, independent of genetic influences, was primarily related to increases in lysophosphatidylcholines, lipids found in proinflammatory and proatherogenic conditions and to decreases in ether phospholipids, which are known to have antioxidant properties. These lipid changes were associated with insulin resistance, a pathogonomic characteristic of acquired obesity in these young adult twins. Our results show that obesity, already in its early stages and independent of genetic influences, is associated with deleterious alterations in the lipid metabolism known to facilitate atherogenesis, inflammation and insulin resistance.

  • 46.
    Sahlberg Bang, Charlotte
    Örebro University, School of Medical Sciences.