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Kardeby, C., Paramel Varghese, G., Pournara, D., Fotopoulou, T., Sirsjö, A., Koufaki, M., . . . Grenegård, M. (2019). A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition. European Journal of Pharmacology, 857, Article ID 172428.
Open this publication in new window or tab >>A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition
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2019 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 857, article id 172428Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Nitric oxide, Platelet inhibitor, Purinergic receptors, Rho associated protein kinase, Thromboxane A2
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:oru:diva-74650 (URN)10.1016/j.ejphar.2019.172428 (DOI)000472711200011 ()31175850 (PubMedID)2-s2.0-85066786586 (Scopus ID)
Funder
Knowledge Foundation
Note

Funding Agency:

Onassis Foundation

Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-11-14Bibliographically approved
Wadensten, T., Nyström, E., Fransén, K., Stenzelius, K., Lindam, A. & Samuelsson, E. (2019). A smartphone app for self-management of urgency and mixed urinary incontinence: a randomized controlled trial. Paper presented at 49th Annual Meeting of the International-Continence-Society (ICS), Gothenburg, Sweden, September 3-6, 2019. Neurourology and Urodynamics, 38(S3), S361-S363
Open this publication in new window or tab >>A smartphone app for self-management of urgency and mixed urinary incontinence: a randomized controlled trial
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2019 (English)In: Neurourology and Urodynamics, ISSN 0733-2467, E-ISSN 1520-6777, Vol. 38, no S3, p. S361-S363Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
John Wiley & Sons, 2019
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:oru:diva-75787 (URN)000477753000250 ()
Conference
49th Annual Meeting of the International-Continence-Society (ICS), Gothenburg, Sweden, September 3-6, 2019
Funder
Forte, Swedish Research Council for Health, Working Life and WelfareThe Kamprad Family Foundation
Note

Funding Agency:

The Region Jämtland Härjedalen

Available from: 2019-08-16 Created: 2019-08-16 Last updated: 2019-08-16Bibliographically approved
Fransén, K., Johansson, M. & Prenkert, M. (2016). Doktoranders upplevelse av nyttan med den obligatoriska forskarutbildningskursen Allmänvetenskaplig forskningsmetodik i medicinsk vetenskap vid Örebro universitet. In: : . Paper presented at NU 2016, Malmö, Sweden, June 15-17, 2016.
Open this publication in new window or tab >>Doktoranders upplevelse av nyttan med den obligatoriska forskarutbildningskursen Allmänvetenskaplig forskningsmetodik i medicinsk vetenskap vid Örebro universitet
2016 (Swedish)Conference paper, Poster (with or without abstract) (Other academic)
National Category
Educational Sciences
Identifiers
urn:nbn:se:oru:diva-52110 (URN)
Conference
NU 2016, Malmö, Sweden, June 15-17, 2016
Available from: 2016-09-09 Created: 2016-09-09 Last updated: 2019-05-21Bibliographically approved
Fransén, K., Paramel Varghese, G., Jansson, J., Eriksson, P. & Sirsjö, A. (2016). Molecular genetic aspects of the NLRP3 inflammasome in cardiovascular disease. In: : . Paper presented at Miami Winter symposium 2016, Miami, Florida, USA, 24-27 Jan., 2016.
Open this publication in new window or tab >>Molecular genetic aspects of the NLRP3 inflammasome in cardiovascular disease
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2016 (English)Conference paper, Poster (with or without abstract) (Refereed)
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:oru:diva-66012 (URN)
Conference
Miami Winter symposium 2016, Miami, Florida, USA, 24-27 Jan., 2016
Available from: 2018-03-22 Created: 2018-03-22 Last updated: 2018-03-23Bibliographically approved
Paramel Varghese, G., Folkersen, L., Strawbridge, R. J., Halvorsen, B., Yndestad, A., Ranheim, T., . . . Sirsjö, A. (2016). NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 5(5), Article ID e003031.
Open this publication in new window or tab >>NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis
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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
Göthlin Eremo, A., Tina, E., Wegman, P., Stål, O., Fransén, K., Fornander, T. & Wingren, S. (2015). HER4 tumor expression in breast cancer patients randomized to treatment with or without tamoxifen. International Journal of Oncology, 47(4), 1311-1320
Open this publication in new window or tab >>HER4 tumor expression in breast cancer patients randomized to treatment with or without tamoxifen
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2015 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 47, no 4, p. 1311-1320Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Athens: Spandidos publications, 2015
Keywords
breast cancer, ErBb4, HER4, randomized patients, tamoxifen
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:oru:diva-45679 (URN)10.3892/ijo.2015.3108 (DOI)000362058300015 ()26238412 (PubMedID)2-s2.0-84941006155 (Scopus ID)
Note

Funding Agencies:

Nyckelfonden, Örebro University Hospital, Sweden

Lions Cancer Research Foundation, Region Uppsala - Örebro, Sweden

Stockholm Cancer Society, Sweden

Available from: 2015-08-31 Created: 2015-08-31 Last updated: 2018-07-01Bibliographically approved
Paramel, G., Uporova, L., Halfvarson, J., Sirsjö, A. & Fransén, K. (2015). Polymorphism in the NLRP3 inflammasome-associated EIF2AK2 gene and inflammatory bowel disease. Molecular Medicine Reports, 11(6), 4579-4584
Open this publication in new window or tab >>Polymorphism in the NLRP3 inflammasome-associated EIF2AK2 gene and inflammatory bowel disease
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2015 (English)In: Molecular Medicine Reports, ISSN 1791-2997, E-ISSN 1791-3004, Vol. 11, no 6, p. 4579-4584Article in journal (Refereed) Published
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.

Keywords
EIF2AK2; Inflammasome; NLRP3; Polymorphism; Protein kinase R; Rs2254958
National Category
Medical and Health Sciences Cancer and Oncology
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-41505 (URN)10.3892/mmr.2015.3236 (DOI)000355497100083 ()25607115 (PubMedID)2-s2.0-84924674689 (Scopus ID)
Funder
Swedish Research Council, 521-2011-2764Magnus Bergvall Foundation
Note

Funding Agencies:

Örebro University (Örebro, Sweden)

Bengt Ihre's Foundation

Nanna Svartz's Foundation

Örebro University Hospital Research Foundation

Örebro County Research Foundation

Swedish Foundation for Gastrointestinal Research

Available from: 2015-01-14 Created: 2015-01-14 Last updated: 2017-12-05Bibliographically approved
Paramel, G., Sirsjö, A. & Fransén, K. (2015). Role of genetic alterations in the NLRP3 and CARD8 genes in health and disease. Mediators of Inflammation, Article ID 846782.
Open this publication in new window or tab >>Role of genetic alterations in the NLRP3 and CARD8 genes in health and disease
2015 (English)In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, article id 846782Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
New York: Hindawi Publishing Corporation, 2015
Keywords
NLRP3, inflammasome, polymorphism, CARD8
National Category
Immunology in the medical area
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-42795 (URN)10.1155/2015/846782 (DOI)000350655400001 ()2-s2.0-84924227184 (Scopus ID)
Note

Funding Agencies:

Magnus Bergvalls Foundation

Sigurd and Elsa Goljes Minne (Lindhes Advokatbyrå AB)

Stiftelsen Gamla Tjänarinnor

Available from: 2015-02-19 Created: 2015-02-19 Last updated: 2018-01-11Bibliographically approved
Paramel, G., Folkersen, L., Strawbridge, R. J., Elmabsout, A., Särndahl, E., Lundman, P., . . . Fransén, K. (2013). CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation. Clinical Science, 125(8), 401-407
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
Sahdo, B., Fransén, K., Asfaw Idosa, B., Eriksson, P., Söderquist, B., Kelly, A. & Särndahl, E. (2013). Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the NLRP3 inflammasome. PLoS ONE, 8(10)
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
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ORCID iD: ORCID iD iconorcid.org/0000-0002-9826-0462

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