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  • 1.
    Elmabsout, Ali Ateia
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sundman, Eva
    Karikas, George
    Törmä, Hans
    Olofsson, Peder S.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Simvastatin and rosuvastatin inhibit CYP26B1-mediated retinoid catabolismManuscript (preprint) (Other academic)
  • 2.
    Fransén, Karin
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Franzén, Petra
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Magnuson, Anders
    Örebro University Hospital, Örebro, Sweden.
    Elmabsout, Ali
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Nyhlin, Nils
    Örebro University Hospital.
    Wickbom, Anna
    Örebro University Hospital, Örebro, Sweden.
    Curman, Bengt
    Örebro University Hospital, Örebro, Sweden.
    Törkvist, Leif
    Karolinska University Hospital, Stockholm, Sweden.
    D'Amato, Mauro
    Karolinska University Hospital, Stockholm, Sweden.
    Bohr, Johan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Halfvarson, Jonas
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital.
    Polymorphism in the retinoic acid metabolizing enzyme CYP26B1 and the development of Crohn's disease2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8, p. e72739-Article in journal (Refereed)
    Abstract [en]

    Several studies suggest that Vitamin A may be involved in the pathogenesis of inflammatory bowel disease (IBD), but the mechanism is still unknown. Cytochrome P450 26 B1 (CYP26B1) is involved in the degradation of retinoic acid and the polymorphism rs2241057 has an elevated catabolic function of retinoic acid, why we hypothesized that the rs2241057 polymorphism may affect the risk of Crohn's disease (CD) and Ulcerative Colitis (UC). DNA from 1378 IBD patients, divided into 871 patients with CD and 507 with UC, and 1205 healthy controls collected at Örebro University Hospital and Karolinska University Hospital were analyzed for the CYP26B1 rs2241057 polymorphism with TaqMan® SNP Genotyping Assay followed by allelic discrimination analysis. A higher frequency of patients homozygous for the major (T) allele was associated with CD but not UC compared to the frequency found in healthy controls. A significant association between the major allele and non-stricturing, non-penetrating phenotype was evident for CD. However, the observed associations reached borderline significance only, after correcting for multiple testing. We suggest that homozygous carriers of the major (T) allele, relative to homozygous carriers of the minor (C) allele, of the CYP26B1 polymorphism rs2241057 may have an increased risk for the development of CD, which possibly may be due to elevated levels of retinoic acid. Our data may support the role of Vitamin A in the pathophysiology of CD, but the exact mechanisms remain to be elucidated.

  • 3.
    Fransén, Karin
    et al.
    Örebro University, School of Medical Sciences.
    Johansson, Madelaine
    Örebro University.
    Prenkert, Malin
    Örebro University, School of Health Sciences.
    Doktoranders upplevelse av nyttan med den obligatoriska forskarutbildningskursen Allmänvetenskaplig forskningsmetodik i medicinsk vetenskap vid Örebro universitet2016Conference paper (Other academic)
  • 4.
    Fransén, Karin
    et al.
    Örebro University, School of Medical Sciences.
    Paramel Varghese, Geena
    Örebro University, School of Medical Sciences.
    Jansson, J.H.
    Skellefteå Hospital, Skellefteå, Sweden; Umeå University Hospital, Umeå, Sweden.
    Eriksson, P.
    Karolinska University Hospital , Karolinska Institutet, Stockholm, Sweden.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Molecular genetic aspects of the NLRP3 inflammasome in cardiovascular disease2016Conference paper (Refereed)
  • 5.
    Göthlin Eremo, Anna
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Tina, Elisabet
    Örebro University Hospital, Örebro, Sweden.
    Kruse, Robert
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Wegman, Pia
    Linköping University Hospital, Linköping, Sweden.
    Repsilber, Dirk
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Montgomery, Scott
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, UK .
    Sollie, Tomas
    Örebro University Hospital, Örebro, Sweden.
    Wingren, Sten
    Örebro University, School of Medicine, Örebro University, Sweden.
    Gene expression profiles in breast tumors from tamoxifen treated patients with and without distant recurrenceManuscript (preprint) (Other academic)
  • 6.
    Göthlin Eremo, Anna
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Tina, Elisabet
    Örebro University Hospital.
    Wegman, Pia
    Linköping University Hospital.
    Stål, Olle
    Linköping University.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fornander, Tommy
    Karolinska University Hospital, Karolinska Institute; Regional Cancer Center Stockholm-Gotland,.
    Wingren, Sten
    Örebro University, School of Medicine, Örebro University, Sweden.
    HER4 tumor expression in breast cancer patients randomized to treatment with or without tamoxifenManuscript (preprint) (Other (popular science, discussion, etc.))
  • 7.
    Göthlin Eremo, Anna
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Tina, Elisabet
    Örebro University Hospital. Clinical Research Centre, Örebro University Hospital, Örebro, Sweden.
    Wegman, Pia
    Department of Clinical Genetics, University Hospital, Linköping, Sweden.
    Stål, Olle
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fornander, Tommy
    Department of Oncology, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden; Regional Cancer Center Stockholm-Gotland, Stockholm, Sweden.
    Wingren, Sten
    Örebro University, School of Medicine, Örebro University, Sweden.
    HER4 tumor expression in breast cancer patients randomized to treatment with or without tamoxifen2015In: International Journal of Oncology, ISSN 1019-6439, Vol. 47, no 4, p. 1311-1320Article in journal (Refereed)
    Abstract [en]

    The human epidermal growth factor receptor (HER) 4 is a relative of HER2 and has been associated to endocrine breast cancer and prediction of tamoxifen response. In addition to PI3K/Akt and MAPK pathway activation, ligand binding to HER4 triggers proteolytic cleavage and release of an intracellular receptor domain (4ICD) with signaling properties. The aim of the present study was to analyze HER4 protein expression and intracellular localization in breast cancer tissue from patients randomized to treatment with or without adjuvant tamoxifen. To investigate HER4 expression and localization in response to estradiol (E2) and 4-hydroxytamoxifen (4-OHT) exposure, we also performed in vitro studies. Cytoplasmic, nuclear and membrane expression of HER4 protein was evaluated by immunohistochemical staining in tumor tissue from 912 breast cancer patients. Three different breast epithelia cancer cell lines were exposed to E2 and 4-OHT and mRNA expression was analyzed using qPCR. Further, nuclear and cytoplasmic proteins were separated and analyzed with western blotting. We found an association between nuclear HER4 protein expression and ER-positivity (P=0.004). Furthermore, significant association was found between cytoplasmic HER4 and ER-negativity (P<0.0005), PgR-negativity (P<0.0005), tumor size >20 mm (P=0.001) and HER2-negativity (P=0.008). However, no overall significance of HER4 on recurrence-free survival was found. After E2 exposure, HER4 mRNA and protein expression had decreased in two cell lines in vitro yet no changes in nuclear or cytoplasmic protein fractions were seen. In conclusion, nuclear HER4 seem to be co-located with ER, however, we did not find support for overall HER4 expression in independently predicting response of tamoxifen treatment. The possible influence of separate isoforms was not tested and future studies may further evaluate HER4 significance.

  • 8.
    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)
  • 9.
    Kardeby, Caroline
    et al.
    Örebro University, School of Medical Sciences.
    Paramel Varghese, Geena
    Örebro University, School of Medical Sciences.
    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.
    Koufaki, Maria
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Fransén, Karin
    Örebro University, School of Medical Sciences.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition2019In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 857, article id 172428Article in journal (Refereed)
    Abstract [en]

    Natural purines like ATP, ADP and adenosine have crucial roles in platelet physiology. This knowledge has been significant in drug development and today ADP receptor antagonists are widely used for prevention of thrombotic events following myocardial infarction and ischaemic stroke.

    Recent studies have shown that a purine analogue bearing nitrate ester group (denoted MK128) has anti-inflammatory effects probably due to its ability to donate nitric oxide (NO). However, other pharmacological mechanisms may contribute to the observed effect. The aim of the present study was to establish the anti-platelet activity and elucidate the underlying molecular mechanism(s) of the purine analogue MK128.

    We found that MK128 reduced aggregation and secretion induced by the thrombin receptor agonist SFLLRN and nearly abolished aggregation and secretion induced by thromboxane A2 (TxA2) and collagen receptor agonists. The inhibition took place despite blockage of the NO/cGMP signalling system. Furthermore, interaction between MK128 and platelet purinergic receptors did not explain the observed inhibition. Instead, we found that MK128 concentration-dependently inhibited Rho-associated kinase (ROCK), which led to decreased ROCK-dependent myosin phosphatase target subunit (MYPT)-1 phosphorylation and suppression of platelet functional responses.

  • 10.
    Nixon Tangi, Tebeng
    et al.
    Department of Clinical Medicine, School of Health and Medical Science, Örebro University, Örebro, Sweden.
    Elmabsout, Ali Ateia
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Role of NLRP3 and CARD8 in the regulation of TNF-α induced IL-1β release in vascular smooth muscle cells2012In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 30, no 3, p. 697-702Article in journal (Refereed)
    Abstract [en]

    Interleukin (IL)-1β is known to be activated by the inflammasome. Inflammasome activities depend on a plethora of moieties including NLRP3 and CARD8, which have been reported to be associated with several inflammatory diseases. Aortic smooth muscle cells (AOSMCs) were transfected with siRNA targeting the NLRP3 and CARD8 genes, followed by tumor necrosis factor-α (TNF-α) treatment. We found that TNF-α induces IL-1β, IL-1Ra and NLRP3 genes but not CARD8. Silencing of the NLRP3 gene significantly decreased IL-1β expression and release, the IL-1Ra expression showed a borderline non-significant increment, while CARD8 knockdown did not affect the IL-1β and IL-1Ra mRNA expression or IL-1β protein release. Our results suggest that mainly NLRP3 plays a role in the regulation of IL-1β expression and release in AOSMC and could be a potential future target for the treatment of atherosclerosis and other inflammatory diseases.

  • 11.
    Paramel, Geena
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Folkersen, Lasse
    Atherosclerosis Research Unit, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Strawbridge, Rona J.
    Atherosclerosis Research Unit, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Elmabsout, Ali
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Särndahl, Eva
    Örebro University, School of Medicine, Örebro University, Sweden.
    Lundman, Pia
    Division of Cardiovascular Medicine, Department of Clinical Sciences, Karolinska Institutet, Danderyd University Hospital, Stockholm, Sweden.
    Jansson, Jan-Håkan
    Department of Internal Medicine, Skellefteå Hospital, Umeå, Sweden; Department of Internal Medicine, Umeå University Hospital, Umeå, Sweden.
    Hansson, Göran K.
    Experimental Cardiovascular Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation2013In: Clinical Science, ISSN 0143-5221, E-ISSN 1470-8736, Vol. 125, no 8, p. 401-407Article in journal (Refereed)
    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.

  • 12.
    Paramel, Geena
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Hurtig-Wennlöf, Anita
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Jansson, Jan-Håkan
    Department of Internal Medicine, Skellefteå Hospital and Umeå University Hospital.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Q705K variant in NLRP3 gene confers protection against myocardial infarction in female individuals2013In: Biomedical Reports, ISSN 2049-9434, Vol. 1, no 6, p. 879-882Article in journal (Refereed)
    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.

  • 13.
    Paramel, Geena
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Role of genetic alterations in the NLRP3 and CARD8 genes in health and disease2015In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, article id 846782Article in journal (Refereed)
    Abstract [en]

    The complexity of a common inflammatory disease is influenced by multiple genetic and environmental factors contributing to the susceptibility of disease. Studies have reported that these exogenous and endogenous components may perturb the balance of innate immune response by activating the NLRP3 inflammasome. The multimeric NLRP3 complex results in the caspase-1 activation and the release of potent inflammatory cytokines, like IL-1β. Several studies have been performed on the association of the genetic alterations in genes encoding NLRP3 and CARD8 with the complex diseases with inflammatory background, like inflammatory bowel disease, cardiovascular diseases, rheumatoid arthritis, and type 1 diabetes. The aim of the present review is therefore to summarize the literature regarding genetic alterations in these genes and their association with health and disease.

  • 14.
    Paramel, Geena
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Uporova, Ludmila
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Halfvarson, Jonas
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Polymorphism in the NLRP3 inflammasome-associated EIF2AK2 gene and inflammatory bowel disease2015In: Molecular Medicine Reports, ISSN 1791-2997, E-ISSN 1791-3004, Vol. 11, no 6, p. 4579-4584Article in journal (Refereed)
    Abstract [en]

    Inflammatory bowel disease (IBD) is the common name for numerous relapsing inflammatory conditions, and is the collective name for Crohn's disease (CD) and ulcerative colitis (UC). The activation of the inflammasome in the pathogenesis of IBD has recently been identified, however the underlying mechanisms remain unclear. An activator of the inflammasome is double-stranded RNA-dependent protein kinase R, also termed EIF2AK2. A genetic alteration in the EIF2AK2 gene has previously been shown to be associated with Alzheimer's disease. The present study genotyped samples from a Swedish cohort of patients with IBD and healthy controls for an EIF2AK2 polymorphism. The rs2254958 polymorphism in the 5'-untranslated region of the EIF2AK2 gene was genotyped by TaqMan® single nucleotide polymorphism genotyping, followed by allelic discrimination. However, no significant association was determined between the rs2254958 polymorphism and the development of IBD, or clinical outcome. In conclusion, the results of the present study suggest that the rs2254958 polymorphism has a limited effect on the onset or progression of IBD.

  • 15.
    Paramel Varghese, Geena
    et al.
    Örebro University, School of Medical Sciences.
    Folkersen, Lasse
    Department of Medicine and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Strawbridge, Rona J.
    Department of Medicine and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Halvorsen, Bente
    Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
    Yndestad, Arne
    Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway.
    Ranheim, Trine
    Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
    Krohg-Sørensen, Kirsten
    Department of Thoracic and Cardiovascular Surgery, Oslo University Hospital Rikshospitalet, Oslo, Norway.
    Skjelland, Mona
    Department of Neurology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
    Espevik, Terje
    Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway.
    Aukrust, Pål
    Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway.
    Lengquist, Mariette
    Department of Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Hedin, Ulf
    Department of Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Jansson, Jan-Håkan
    Department of Internal Medicine, Umeå University Hospital, Umeå, Sweden; Department of Internal Medicine, Skellefteå Hospital, Skellefteå, Sweden.
    Fransén, Karin
    Örebro University, School of Medical Sciences.
    Hansson, Göran K.
    Department of Medicine and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Per
    Department of Medicine and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis2016In: 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)
    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.

  • 16.
    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)
  • 17.
    Paramel Varghese, Geena
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Zhang, Boxi
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Khalaf, Hazem
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Ljungberg, Liza U.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Medicine, Örebro University, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Poryphyromonas gingivalis induces IL-1β in aortic smooth muscle cells: possible role of gingipains?Manuscript (preprint) (Other academic)
  • 18.
    Sahdo, Berolla
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Asfaw Idosa, Berhane
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Eriksson, Per
    Division of Rheumatology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Söderquist, Bo
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital, Region Örebro County, Örebro, Sweden.
    Kelly, Anne
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Särndahl, Eva
    Örebro University, School of Medicine, Örebro University, Sweden.
    Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the NLRP3 inflammasome2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10Article in journal (Refereed)
    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.

  • 19.
    Sahdo, Berolla
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Idosa, Berhane Asfaw
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Eriksson, Per
    Division of Rheumatology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden.
    Söderquist, Bo
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Örebro University Hospital, SE-701 85 Örebro, Sweden.
    Kelly, Anne
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Särndahl, Eva
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro universitetssjukhus, Örebro, Sweden.
    Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the nlrp3 inflammasomeManuscript (preprint) (Other academic)
    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)-1β and IL-18. Increased production of IL-1β 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-1β, 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 noncarrier controls.

    Results & Discussion: The prevalence of the polymorphisms was in line with previous studies. Plasma levels of IL-1β 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. These data suggest that these combined polymorphisms creates 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.

  • 20.
    Ungerbäck, Jonas
    et al.
    Division of Cell biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Belenki, Dimitri
    Division of Cell biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Jawas ul-Hassan, Aksa
    Division of Cell biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Fredrikson, Mats
    Division of Cell biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Elander, Nils
    Division of Cell biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Verma, Deepti
    Division of Cell biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Söderkvist, Peter
    Division of Cell biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Genetic variation and alterations of genes involved in NFκB/TNFAIP3- and NLRP3-inflammasome signaling affect susceptibility and outcome of colorectal cancer2012In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 33, no 11, p. 2126-2134Article in journal (Refereed)
    Abstract [en]

    Colorectal tumors are continuously exposed to an inflammatory environment, which together with mitogenic signals sustain several cancer hallmarks. Nuclear factor-kappa B (NFκB) is a major regulator of inflammation and variation in NFκB-associated genes could potentially be used as biomarkers to identify patients with increased risk of colorectal cancer (CRC) development, and/or a rapidly progressing disease. In this study, 348 CRC cases and 806 randomly selected healthy individuals from southeastern Sweden were examined with regard to seven polymorphisms in NFκB pathway-associated genes. Log-rank-tests and Cox proportional hazard regression analysis examined the association between the polymorphisms and CRC-specific survival, whereas chi-square tests and logistic regression analysis were used to test for associations between the polymorphisms and CRC susceptibility. Gene expression and loss of heterozygosity analyses of TNFAIP3 were carried out in a subset of tumors to assess its role as a tumor suppressor in CRC. Heterozygous and polymorphic TNFAIP3 (rs6920220), heterozygous NLRP3 (Q705K) and polymorphic NFκB -94 ATTG ins/del genotypes were found to be associated with poorer survival in patients diagnosed with invasive CRC (aHR = 5.2, 95% CI: 2.5-10.9, P < 0.001). TNFAIP3 mRNA levels were significantly decreased in tumors compared with adjacent non-neoplastic mucosa (P < 0.0001) and loss of heterozygosity of 6q23.3 (TNFAIP3) was detected in 17% of cases, whereas only 2.5% of the investigated specimens displayed TNFAIP3 gene mutations. We propose that TNFAIP3 (rs6920220), NLRP3 (Q705K) and NFκB -94 ATTG ins/del polymorphisms are associated with poor survival in patients with advanced CRC and may be used as prognostic markers. Experimental results indicate that TNFAIP3 may act as a tumor suppressor in CRC.

  • 21.
    Wadensten, T.
    et al.
    Department of Public Health and Clinical Medicine, Family Medicine, Umeå University, Sweden.
    Nyström, E.
    Department of Public Health and Clinical Medicine, Unit of Research, Education and Development - Östersund, Umeå University, Sweden.
    Fransén, Karin
    Örebro University, School of Medical Sciences. .Women’s Clinic, Örebro University Hospital, School of Medical Sciences, Örebro University, Sweden.
    Stenzelius, K.
    .Department of Care Sciences, Malmö University, Malmö, Sweden; Skåne University Hospital, Malmö/Lund, Sweden.
    Lindam, A.
    Unit of Research, Education, and Development, Östersund Hospital, Östersund, Sweden.
    Samuelsson, E.
    Department of Public Health and Clinical Medicine, Family Medicine, Umeå University, Sweden.
    A smartphone app for self-management of urgency and mixed urinary incontinence: a randomized controlled trial2019In: Neurourology and Urodynamics, ISSN 0733-2467, E-ISSN 1520-6777, Vol. 38, no S3, p. S361-S363Article in journal (Other academic)
1 - 21 of 21
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