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  • 1.
    Andersson, Erik
    et al.
    Örebro University, School of Medical Sciences.
    Bergemalm, Daniel
    Örebro University, School of Medical Sciences.
    Kruse, Robert
    Örebro University, School of Medical Sciences.
    D'Amato, M.
    Department of Medicine, Karolinska Institutet Solna, Stockholm, Sweden.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences.
    Inflammatory biomarkers in serum discriminate Crohn's disease and ulcerative colitis from healthy controls2016In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 10, no Suppl. 1, p. S86-S87Article in journal (Other academic)
  • 2.
    Andersson, Erik
    et al.
    Örebro University, School of Medical Sciences.
    Bergemalm, Daniel
    Örebro University, School of Medical Sciences. Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Kruse, Robert
    Örebro University, School of Medical Sciences.
    Neumann, Gunter
    School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    D'Amato, Mauro
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; BioDonostia Health Research Institute, San Sebastian, Spain; IKERBASQUE Basque Foundation for Science, Bilbao, Spain.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Subphenotypes of inflammatory bowel disease are characterized by specific serum protein profiles2017In: PLOS ONE, E-ISSN 1932-6203, Vol. 12, no 10, article id e0186142Article in journal (Refereed)
    Abstract [en]

    Objective: Genetic and immunological data indicate that inflammatory bowel disease (IBD) are characterized by specific inflammatory protein profiles. However, the serum proteome of IBD is still to be defined. We aimed to characterize the inflammatory serum protein profiles of Crohn's disease (CD) and ulcerative colitis (UC), using the novel proximity extension assay.

    Methods: A panel of 91 inflammatory proteins were quantified in a discovery cohort of CD (n = 54), UC patients (n = 54), and healthy controls (HCs; n = 54). We performed univariate analyses by t-test, with false discovery rate correction. A sparse partial least-squares (sPLS) approach was used to identify additional discriminative proteins. The results were validated in a replication cohort.

    Results: By univariate analysis, 17 proteins were identified with significantly different abundances in CD and HCs, and 12 when comparing UC and HCs. Additionally, 64 and 45 discriminant candidate proteins, respectively, were identified with the multivariate approach. Correspondingly, significant cross-validation error rates of 0.12 and 0.19 were observed in the discovery cohort. Only FGF-19 was identified from univariate comparisons of CD and UC, but 37 additional discriminant candidates were identified using the multivariate approach. The observed cross-validation error rate for CD vs. UC remained significant when restricting the analyses to patients in clinical remission. Using univariate comparisons, 16 of 17 CD-associated proteins and 8 of 12 UC-associated proteins were validated in the replication cohort. The area under the curve for CD and UC was 0.96 and 0.92, respectively, when the sPLS model from the discovery cohort was applied to the replication cohort.

    Conclusions: By using the novel PEA method and a panel of inflammatory proteins, we identified proteins with significantly different quantities in CD patients and UC patients compared to HCs. Our data highlight the potential of the serum IBD proteome as a source for identification of future diagnostic biomarkers.

  • 3.
    Bang, Charlotte Sahlberg
    et al.
    Örebro University, School of Health Sciences.
    Demirel, Isak
    Örebro University, School of Medical Sciences.
    Kruse, Robert
    Örebro University, School of Medical Sciences.
    Persson, Katarina
    Örebro University, School of Medical Sciences.
    Global gene expression profiling and antibiotic susceptibility after repeated exposure to the carbon monoxide-releasing molecule-2 (CORM-2) in multidrug-resistant ESBL-producing uropathogenic Escherichia coli2017In: PLOS ONE, E-ISSN 1932-6203, Vol. 12, no 6, article id e0178541Article in journal (Refereed)
    Abstract [en]

    Treatment of urinary tract infections is today a challenge due to the increasing prevalence of multidrug-resistant ESBL-producing uropathogenic Escherichia coli (UPEC). There is an urgent need for new treatment strategies for multidrug-resistant UPEC and preferably with targets that have low potential for development of resistance. Carbon monoxide-releasing molecules (CORMs) are novel and potent antibacterial agents. The present study examines the transcriptomic targets of CORM-2 in a multidrug-resistant ESBL-producing UPEC isolate in response to a single exposure to CORM-2 and after repeated exposure to CORM-2. The bacterial viability and minimal inhibitory concentration (MIC) were also examined after repeated exposure to CORM-2. Microarray analysis revealed that a wide range of processes were affected by CORM-2, including a general trend of down-regulation in energy metabolism and biosynthesis pathways and up-regulation of the SOS response and DNA repair. Several genes involved in virulence (ibpB), antibiotic resistance (marAB, mdtABC) and biofilm formation (bhsA, yfgF) were up-regulated, while some genes involved in virulence (kpsC, fepCEG, entABE), antibiotic resistance (evgA) and biofilm formation (artIP) were down-regulated. Repeated exposure to CORM-2 did not alter the gene expression patterns, the growth inhibitory response to CORM-2 or the MIC values for CORM-2, cefotaxime, ciprofloxacin and trimethoprim. This study identifies several enriched gene ontologies, modified pathways and single genes that are targeted by CORM-2 in a multidrug-resistant UPEC isolate. Repeated exposure to CORM-2 did not change the gene expression patterns or fold changes and the susceptibility to CORM-2 remained after repeated exposure.

  • 4.
    Bang, Charlotte Sahlberg
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Kruse, Robert
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Demirel, Isak
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Önnberg, Anna
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Dept Lab Med, Örebro University Hospital, Örebro, Sweden.
    Söderquist, Bo
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital. Dept Lab Med, Örebro University Hospital, Örebro, Sweden.
    Persson, Katarina
    Örebro University, School of Medicine, Örebro University, Sweden.
    Multiresistant uropathogenic extended-spectrum β-lactamase (ESBL)-producing Escherichia coli are susceptible to the carbon monoxide releasing molecule-2 (CORM-2).2014In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 66, p. 29-35Article in journal (Refereed)
    Abstract [en]

    Carbon monoxide (CO) releasing molecules (CO-RMs) have been shown to inhibit growth of commensal Escherichia coli (E. coli). In the present study we examined the effect of CORM-2 on uropathogenic E. coli (UPEC) that produces extended-spectrum β-lactamase (ESBL). Viability experiments showed that CORM-2 inhibited the growth of several different ESBL-producing UPEC isolates and that 500 μM CORM-2 had a bactericidal effect within 4 h. The bactericidal effect of CORM-2 was significantly more pronounced than the effect of the antibiotic nitrofurantoin. CORM-2 demonstrated a low level of cytotoxicity in eukaryotic cells (human bladder epithelial cell line 5637) at the concentrations and time-points where the antibacterial effect was obtained. Real-time RT-PCR studies of different virulence genes showed that the expression of capsule group II kpsMT II and serum resistance traT was reduced and that some genes encoding iron acquisition systems were altered by CORM-2. Our results demonstrate that CORM-2 has a fast bactericidal effect against multiresistant ESBL-producing UPEC isolates, and also identify some putative UPEC virulence factors as targets for CORM-2. CO-RMs may be candidate drugs for further studies in the field of finding new therapeutic approaches for treatment of uropathogenic ESBLproducing E. coli.

  • 5.
    Bazov, Igor
    et al.
    Örebro University, School of Medical Sciences.
    Kruse, Robert
    Örebro University, School of Medical Sciences.
    Bergemalm, Daniel
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Gastroenterology.
    Eriksson, Carl
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Gastroenterology.
    Hedin, C. R.
    Karolinska Institutet, Department of Medicine, Solna, Stockholm, Sweden; Karolinska University Hospital, Gastroenterology unit, Department of Gastroenterology, Dermatovenereology and Rheumatology, Stockholm, Sweden.
    Carlson, M.
    Uppsala University, Department of Medical Sciences, Uppsala, Sweden.
    van Nieuwenhoven, Michiel
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Gastroenterology.
    Keita, Å. V.
    Linköping University, Department of Biomedical and Clinical Sciences, Linköping, Sweden.
    Magnusson, M. K.
    University of Gothenburg, Sahlgrenska Academy, Department of Microbiology and Immunology, Institute of Biomedicine, Gothenburg, Sweden.
    Almer, S.
    Karolinska Institutet, Department of Medicine, Solna, Stockholm, Sweden; Karolinska university hospital, Gastroenterology unit, Department of Gastroenterology, Dermatovenereology and Rheumatology, Stockholm, Sweden.
    Strid, H.
    Södra Älvsborgs Hospital, Department of Internal Medicine, Borås, Sweden.
    Mathisen, C. Bache-Wiig
    Oslo University Hospital, Department of Gastroenterology, Oslo, Norway; University of Oslo, Institute of Clinical Medicine, Oslo, Norway.
    Bengtsson, M. B.
    Vestfold Hospital Trust, Department of Gastroenterology, Tønsberg, Norway.
    Aabrekk, T. Bergene
    University of Oslo, Institute of Clinical Medicine, Oslo, Norway; Vestfold Hospital Trust, Department of Gastroenterology, Tønsberg, Norway.
    Medhus, A. W.
    Oslo University Hospital, Department of Gastroenterology, Oslo, Norway; University of Oslo, Institute of Clinical Medicine, Oslo, Norway.
    Detlie, T. E.
    Akershus University Hospital, Department of Gastroenterology, Lørenskog, Norway; University of Oslo, Insititute of Clinical Medicine, Oslo, Norway.
    Frigstad, S. O.
    Vestre Viken Hospital Trust- Bærum Hospital, Department of Internal Medicine, Bærum, Norway.
    Huppertz-Hauss, G.
    Telemark Hospital Trust, Skien, Department of Gastroenterology, Skien, Norway.
    Opheim, R.
    Oslo University Hospital, Department of Gastroenterology, Oslo, Norway; University of Oslo, Institute of Health and Society, Oslo, Norway.
    Ricanek, P.
    Akershus University Hospital, Department of Gastroenterology, Lørenskog, Norway; Lovisenberg Diaconal Hospital, Department of Gastroenterology, Oslo, Norway.
    Kristensen, V. A.
    Oslo University Hospital, Department of Gastroenterology, Oslo, Norway; Lovisenberg Diaconal Hospital, Unger-Vetlesen Institute, Oslo, Norway .
    Salihovic, Samira
    Örebro University, School of Medical Sciences.
    D'Amato, M.
    Karolinska Institutet, Clinical Epidemiology Division, Department of Medicine Solna, Stockholm, Sweden; IKERBASQUE, Basque Foundation for Science, Bilbao, Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Bilbao, Spain.
    Öhman, L.
    University of Gothenburg, Sahlgrenska Academy, Department of Microbiology and Immunology, Institute of Biomedicine, Gothenburg, Sweden.
    Söderholm, J. D.
    Linköping University, Department of Biomedical and Clinical Sciences, Linköping, Sweden.
    Lindqvist, C. M.
    Örebro University, School of Medical Sciences, Faculty of Medicine and Health, Örebro, Sweden.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Høivik, M. L.
    Oslo University Hospital, Department of Gastroenterology, Oslo, Norway; University of Oslo, Institute of Clinical Medicine, Oslo, Norway.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology.
    A novel serum protein signature as biomarker for Inflammatory Bowel Disease: A diagnostic performance and prediction modelling study using data from two independent inception cohorts2023In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 17, no Suppl. 1, p. I314-I315, article id P154Article in journal (Other academic)
  • 6.
    Berg von Linde, Maria
    et al.
    Department of Cardiology, Faculty of Health, Örebro University, Örebro, Sweden.
    Johansson, Karin
    Örebro University Hospital. Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Department of Cardiothoracic and Vascular Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; University Health Care Research Center, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Samano, Ninos
    Örebro University Hospital. Örebro University, School of Medical Sciences. Department of Cardiothoracic and Vascular Surgery.
    Friberg, Örjan
    Department of Cardiothoracic and Vascular Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Frøbert, Anne Mette
    Department of Chemistry and Bioscience, Faculty of Engineering and Science, Aalborg University, Aalborg, Denmar.
    Fröbert, Ole
    Örebro University, School of Medical Sciences. Department of Cardiology.
    Expression of Paracrine Effectors in Human Adipose-Derived Mesenchymal Stem Cells Treated With Plasma From Brown Bears (Ursus arctos)2021In: Clinical and Translational Science, ISSN 1752-8054, E-ISSN 1752-8062, Vol. 14, no 1, p. 317-325Article in journal (Refereed)
    Abstract [en]

    Adipose-derived mesenchymal stem cells (ADSCs) are promising candidates for novel cell therapeutic applications. Hibernating brown bears sustain tissue integrity and function via unknown mechanisms, which might be plasma borne. We hypothesized that plasma from hibernating bears may increase the expression of favorable factors from human ADSCs. In an experimental study, ADSCs from patients with ischemic heart disease were treated with interventional media containing plasma from hibernating and active bears, respectively, and with control medium. Extracted RNA from the ADSCs was sequenced using next generation sequencing. Statistical analyses of differentially expressed genes were performed using fold change analysis, pathway analysis, and gene ontology. As a result, we found that genes associated with inflammation, such as IGF1, PGF, IL11, and TGFA, were downregulated by > 10-fold in ADSCs treated with winter plasma compared with control. Genes important for cardiovascular development, ADM, ANGPTL4, and APOL3, were upregulated in ADSCs when treated with winter plasma compared with summer plasma. ADSCs treated with bear plasma, regardless if it was from hibernating or active bears, showed downregulation of IGF1, PGF, IL11, INHBA, IER3, and HMOX1 compared with control, suggesting reduced cell growth and differentiation. This can be summarized in the conclusion that plasma from hibernating bears suppresses inflammatory genes and activates genes associated with cardiovascular development in human ADSCs. Identifying the involved regulator(s) holds therapeutic potential.

  • 7.
    Bergemalm, Daniel
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Sapnara, Maria
    Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden; Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Hultgren Hörnquist, Elisabeth
    Örebro University, School of Medical Sciences.
    Elevated fecal peptidase D at onset of colitis in Galphai2(-/-) mice, a mouse model of IBD2017In: PLOS ONE, E-ISSN 1932-6203, Vol. 12, no 3, article id e0174275Article in journal (Refereed)
    Abstract [en]

    Background: The identification of novel fecal biomarkers in inflammatory bowel disease (IBD) is hampered by the complexity of the human fecal proteome. On the other hand, in experimental mouse models there is probably less variation. We investigated the fecal protein content in mice to identify possible biomarkers and pathogenic mechanisms.

    Methods: Fecal samples were collected at onset of inflammation in Galphai2(-/-) mice, a well-described spontaneous model of chronic colitis, and from healthy littermates. The fecal proteome was analyzed by two-dimensional electrophoresis and quantitative mass spectrometry and results were then validated in a new cohort of mice.

    Results: As a potential top marker of disease, peptidase D was found at a higher ratio in Galphai24mouse feces relative to controls (fold change 27; p = 0.019). Other proteins found to be enriched in Gai2(-/-) mice were mainly pancreatic proteases, and proteins from plasma and blood cells. A tendency of increased calprotectin, subunit S100-A8, was also observed (fold change 21; p = 0.058). Proteases are potential activators of inflammation in the gastrointestinal tract through their interaction with the proteinase-activated receptor 2 (PAR2). Accordingly, the level of PAR2 was found to be elevated in both the colon and the pancreas of Galphai24- mice at different stages of disease.

    Conclusions: These findings identify peptidase D, an ubiquitously expressed intracellular peptidase, as a potential novel marker of colitis. The elevated levels of fecal proteases may be involved in the pathogenesis of colitis and contribute to the clinical phenotype, possibly by activation of intestinal PAR2.

  • 8.
    Carstens, Adam
    et al.
    Örebro University, School of Medical Sciences. Department of Internal Medicine, Ersta Hospital, Stockholm, Sweden; Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Björkqvist, Olle
    Örebro University, School of Medical Sciences. Department of Gastroenterology.
    Lindqvist, Carl Mårten
    Örebro University, School of Medical Sciences.
    Rangel, I.
    Department of Internal Medicine, Ersta Hospital, Stockholm, Sweden.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Eriksson, Carl
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Gastroenterology.
    Bergemalm, Daniel
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Gastroenterology.
    Bresso, F.
    Division of Gastroenterology, Department of Gastroenterology, Dermatology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden.
    Strid, H.
    Department of Internal Medicine, Södra Älvsborgs Hospital, Borås, Sweden.
    Hjortswang, H.
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Keita, Å.
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Magnusson, M. K.
    Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Hedin, C.
    Karolinska Institutet, Department of Medicine Solna, Stockholm, Sweden; Karolinska University Hospital, Gastroenterology unit, Department of Gastroenterology, Dermatovenereology and Rheumatology, Stockholm, Sweden.
    Kruse, Robert
    Örebro University, School of Medical Sciences.
    Engstrand, L.
    Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Solna, Sweden.
    Carlson, M.
    Department of Medical Sciences, Gastroenterology Research Group, Uppsala University, Uppsala, Sweden.
    Söderholm, J.
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Department of Surgery, Linköping University, Linköping, Sweden.
    Öhman, L.
    Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology.
    Gut microbiota associated with treatment outcome to biological treatment in inflammatory bowel diseaseManuscript (preprint) (Other academic)
  • 9.
    Chelslín, Felix
    et al.
    Örebro University, School of Medical Sciences.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Östling, Hanna
    Örebro University, School of Medical Sciences. Department of Women's Health.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Paediatrics.
    Differential microRNA expression in placentas of small-for-gestational age neonates with and without exposure to poor maternal gestational weight gain2021In: Journal of Perinatal Medicine, ISSN 0300-5577, E-ISSN 1619-3997, Vol. 49, no 5, p. 632-635Article in journal (Refereed)
  • 10.
    Chelslín, Felix
    et al.
    Örebro University, School of Medical Sciences. University Health Care Research Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. University Health Care Research Centre.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Inflammatory Response and Infection Susceptibility Centre (iRiSC) and X-HiDE Consortium, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Smoking during pregnancy is associated with the placental proteome2023In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 119, article id 108409Article in journal (Refereed)
    Abstract [en]

    Maternal smoking during pregnancy (MSDP) is a significant risk factor for the development of foetal, neonatal, and childhood morbidities. We hypothesized that infants exposed to MSDP have a distinct proteomic expression in their term placentas compared to infants without such an exposure. A total of 39 infants exposed (cord blood cotinine levels of >1ng/ml) and 44 infants not exposed to MSDP were included in the study. Women with chronic disease, body mass index of >30, or a history of uterine surgery were excluded. Total proteome abundance was analysed with quantitative mass spectrometry. For univariate analysis of differences in placental protein levels between groups, ANOVA with multiple testing corrections by the Benjamini-Hochberg method was used. For multivariate analysis, we used principal component analysis, partial least squares, lasso, random forest, and neural networks. The univariate analyses showed four differentially abundant proteins (PXDN, CYP1A1, GPR183, and KRT81) when heavy and moderate smoking groups were compared to non-smokers. With the help of machine learning, we found that an additional six proteins (SEPTIN3, CRAT, NAAA, CD248, CADM3, and ZNF648) were discriminants of MSDP. The placental abundance of these ten proteins together explained 74.1% of the variation in cord blood cotinine levels (p = 0.002). Infants exposed to MSDP showed differential abundance of proteins in term placentas. We report differential placental abundance of several proteins for the first time in the setting of MSDP. We believe that these findings supplement the current understanding of how MSDP affects the placental proteome.

  • 11.
    Demirel, Isak
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Kruse, Robert
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Önnberg, Anna
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Persson, Katarina
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Antibiotic-induced filamentation of extended spectrum beta lactamase (ESBL)-producing uropathogenic E. coli alters host cell responses during an in vitro infectionManuscript (preprint) (Other academic)
    Abstract [en]

    Inadequate and delayed antibiotic treatment of extended spectrum beta-lactamase (ESBL)- producing isolates have been associated with increased mortality of affected patients. The purpose of this study was to compare the host response of human renal epithelial cells and polymorphonuclear leukocyte (PMN) cells when infected by ESBL-producing uropathogenic E. coli (UPEC) isolates in the presence or absence of ineffective antibiotics.

    The renal epithelial cell line A498 and PMN cells were stimulated with ESBLproducing UPEC isolates in the presence or absence of three different antibiotics (trimetoprim, ceftibuten and ciprofloxacin). Host cell responses were evaluated as release of cytokines (IL-6, IL-8), reactive oxygen species (ROS), ATP and endotoxins. Bacterial morphology and PMNphagocytosis were evaluated by microscopy.

    In the presence of ceftibuten, 2 out of 3 examined ESBL-isolates changed their morphology into a filamentous form. The presence of ceftibuten enhanced IL-6, IL-8 and ROS-production from host cells, but only from cells stimulated by the filamentous isolates. The bacterial supernatant and not the filamentous bacteria per se was responsible for the increased release of IL-6, IL-8 and ROS. Increased endotoxin and ATP levels were found in the bacterial supernatants from filamentous isolates. Apyrase decreased IL-6 secretion from A498 cells and polymyxin B abolished the increased ROS production from PMN cells. PMN were able to inhibit the bacterial growth of some ESBL-isolates in the presence of ceftibuten. In conclusion, antibiotic-induced filamentation of ESBL-producing UPEC isolates and the associated release of ATP and endotoxins can alter the host cell response in the urinary tract.

  • 12.
    Demirel, Isak
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Kruse, Robert
    Örebro University, School of Medicine, Örebro University, Sweden.
    Önnberg, Anna
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Persson, Katarina
    Örebro University, School of Medicine, Örebro University, Sweden.
    Ceftibuten-induced filamentation of extended spectrum beta lactamase (ESBL)-producing uropathogenic Escherichia coli alters host cell responses during an in vitro infection2015In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 78, p. 52-62Article in journal (Refereed)
    Abstract [en]

    Inadequate and delayed antibiotic treatment of extended spectrum beta-lactamase (ESBL)-producing isolates have been associated with increased mortality of affected patients. The purpose of this study was to compare the host response of human renal epithelial cells and polymorphonuclear leucocyte (PMN) cells when infected by ESBL-producing uropathogenic Escherichia coli (UPEC) isolates in the presence or absence of ineffective antibiotics.

    The renal epithelial cell line A498 and PMN cells were stimulated with ESBL-producing UPEC isolates in the presence or absence of three different antibiotics (trimetoprim, ceftibuten and ciprofloxacin). Host cell responses were evaluated as release of cytokines (IL-6, IL-8), reactive oxygen species (ROS), ATP and endotoxins. Bacterial morphology and PMN phagocytosis were evaluated by microscopy.

    In the presence of ceftibuten, 2 out of 3 examined ESBL-isolates changed their morphology into a filamentous form. The presence of ceftibuten enhanced IL-6, IL-8 and ROS-production from host cells, but only from cells stimulated by the filamentous isolates. The bacterial supernatant and not the filamentous bacteria per se was responsible for the increased release of IL-6, IL-8 and ROS. Increased endotoxin and ATP levels were found in the bacterial supernatants from filamentous isolates. Apyrase decreased IL-6 secretion from A498 cells and polymyxin B abolished the increased ROS-production from PMN cells. PMN were able to inhibit the bacterial growth of some ESBL-isolates in the presence of ceftibuten.

    In conclusion, antibiotic-induced filamentation of ESBL-producing UPEC isolates and the associated release of ATP and endotoxins can alter the host cell response in the urinary tract.

  • 13.
    Demirel, Isak
    et al.
    Örebro University, School of Medical Sciences.
    Persson, Alexander
    Örebro University, School of Medical Sciences.
    Brauner, Annelie
    Division of Clinical Microbiology, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Särndahl, Eva
    Örebro University, School of Medical Sciences.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Persson, Katarina
    Örebro University, School of Medical Sciences.
    Activation of NLRP3 by uropathogenic Escherichia coli is associated with IL-1β release and regulation of antimicrobial properties in human neutrophils2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 21837Article in journal (Refereed)
    Abstract [en]

    The NLRP3 inflammasome and IL-1β have recently been linked to the severity of uropathogenic Escherichia coli (UPEC)-mediated urinary tract infection (UTI). However, not much is known about the contribution of NLRP3 to the antimicrobial properties of neutrophils and the release of IL-1β during UPEC infection. The purpose of this study was to elucidate the mechanisms behind UPEC-induced IL-1β release from human neutrophils, and to investigate the contribution of the NLRP3 inflammasome in neutrophil-mediated inhibition of UPEC growth. We found that the UPEC strain CFT073 increased the expression of NLRP3 and increased caspase-1 activation and IL-1β release from human neutrophils. The IL-1β release was mediated by the NLRP3 inflammasome and by serine proteases in an NF-κB-and cathepsin B-dependent manner. The UPEC virulence factors α-hemolysin, type-1 fimbriae and p-fimbriae were all shown to contribute to UPEC mediated IL-1β release from neutrophils. Furthermore, inhibition of caspase-1 and NLRP3 activation increased neutrophil ROS-production, phagocytosis and the ability of neutrophils to suppress UPEC growth. In conclusion, this study demonstrates that UPEC can induce NLRP3 and serine protease-dependent release of IL-1β from human neutrophils and that NLRP3 and caspase-1 can regulate the antimicrobial activity of human neutrophils against UPEC.

  • 14.
    Demirel, Isak
    et al.
    Örebro University, School of Medical Sciences.
    Persson, Alexander
    Örebro University, School of Medical Sciences.
    Brauner, Annelie
    Department of Microbiology, Tumor and Cell Biology, Division of Clinical Microbiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Särndahl, Eva
    Örebro University, School of Medical Sciences.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Persson, Katarina
    Örebro University, School of Medical Sciences.
    Activation of the NLRP3 Inflammasome Pathway by Uropathogenic Escherichia coli Is Virulence Factor-Dependent and Influences Colonization of Bladder Epithelial Cells2018In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 8, article id 81Article in journal (Refereed)
    Abstract [en]

    The NLRP3 inflammasome and IL-1 beta release have recently been suggested to be important for the progression of urinary tract infection (UTI). However, much is still unknown regarding the interaction of UPEC and the NLRP3 inflammasome. The purpose of this study was to elucidate what virulence factors uropathogenic Escherichia coil (UPEC) use to modulate NLRP3 inflammasome activation and subsequent IL-1 beta release and the role of NLRP3 for UPEC colonization of bladder epithelial cells. The bladder epithelial cell line 5637, CRISPR/Cas9 generated NLRP3, caspase-1 and mesotrypsin deficient cell lines and transformed primary bladder epithelial cells (HBLAK) were stimulated with UPEC isolates and the non-pathogenic MG1655 strain. We found that the UPEC strain CFT073, but not MG1655, induced an increased caspase-1 activity and IL-1 beta release from bladder epithelial cells. The increase was shown to be mediated by et-hemolysin activation of the NLRP3 inflammasome in an NE-kappa B-independent manner. The effect of-hemolysin on IL-1 beta release was biphasic, initially suppressive, later inductive. Furthermore, the phase-locked type-1-fimbrial ON variant of CFT073 inhibited caspase-1 activation and IL-1 beta release. In addition, the ability of CFT073 to adhere to and invade NLRP3 deficient cells was significantly reduced compare to wild-type cells. The reduced colonization of NLRP3-deficient cells was type-1 fimbriae dependent. In conclusion, we found that the NLRP3 inflammasome was important for type-1 fimbriae-dependent colonization of bladder epithelial cells and that both type-1 fimbriae and alpha-hemolysin can modulate the activity of the NLRP3 inflammasome.

  • 15.
    Demirel, Isak
    et al.
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre.
    Rangel, Ignacio
    Örebro University, School of Medical Sciences.
    Petersson, Ulrika
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Persson, Katarina
    Örebro University, School of Medical Sciences. Faculty of Medicine and Health, Inflammatory Response and Infection Susceptibility Centre, Örebro University, Örebro, Sweden.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Faculty of Medicine and Health, Inflammatory Response and Infection Susceptibility Centre, Örebro University, Örebro, Sweden; Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Transcriptional Alterations of Virulence-Associated Genes in Extended Spectrum Beta-Lactamase (ESBL)-Producing Uropathogenic Escherichia coli during Morphologic Transitions Induced by Ineffective Antibiotics2017In: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 8, article id 1058Article in journal (Refereed)
    Abstract [en]

    It is known that an ineffective antibiotic treatment can induce morphological shifts in uropathogenic Escherichia coli (UPEC) but the virulence properties during these shifts remain to be studied. The present study examines changes in global gene expression patterns and in virulence factor-associated genes in an extended spectrum beta-lactamase (ESBL)-producing UPEC (ESBL019) during the morphologic transitions induced by an ineffective antibiotic and in the presence of human primary bladder epithelial cells. Microarray results showed that the different morphological states of ESBL019 had significant transcriptional alterations of a large number of genes (Transition; 7%, Filamentation; 32%, and Reverted 19% of the entities on the array). All three morphological states of ESBL019 were associated with a decreased energy metabolism, altered iron acquisition systems and altered adhesion expression. In addition, genes associated with LPS synthesis and bacterial motility was also altered in all the morphological states. Furthermore, the transition state induced a significantly higher release of TNF-alpha from bladder epithelial cells compared to all other morphologies, while the reverted state was unable to induce INF-alpha release. Our findings show that the morphological shifts induced by ineffective antibiotics are associated with significant transcriptional virulence alterations in ESBL-producing UPEC, which may affect survival and persistence in the urinary tract.

  • 16.
    Demirel, Isak
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Säve, Susanne
    School of Natural Sciences, Linnaeus University, Kalmar, Sweden.
    Kruse, Robert
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Persson, Katarina
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Expression of suppressor of cytokine signalling 3 (SOCS3) in human bladder epithelial cells infected with uropathogenic Escherichia coli2013In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 121, no 2, p. 158-167Article in journal (Refereed)
    Abstract [en]

    Suppressor of cytokine signalling (SOCS) proteins inhibit pro-inflammatory signalling mediated by Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) pathways. To evade the immune response some pathogens appear to modify the host SOCS proteins. Uropathogenic Escherichia coli (UPEC) are able to subvert the host response evoked by bladder epithelial cells, but the mechanisms are not fully understood. The objective of this study was to investigate whether UPEC can modify the host SOCS and STAT3 response. Real time RT-PCR studies demonstrated an increased SOCS1 and SOCS3 expression in the isolated human bladder epithelial cell lines (RT-4 and 5637) in response to cytokines. UPEC strain IA2 increased SOCS3, but not SOCS1, mRNA levels with a peak at 6 h after infection. The increase of SOCS3 was confirmed at the protein level by Western blotting. The UPEC strain IA2 caused a time-dependent decrease in the phosphorylation of STAT3. This study demonstrates that UPEC are able to affect SOCS3 and STAT3 signalling in human uroepithelial cells. The finding that UPEC are able to induce mediators involved in suppression of host cytokine signalling may help to elucidate how UPEC may circumvent the host response during urinary tract infection.

  • 17.
    Folkesson, Mattias
    et al.
    Örebro University, School of Health Sciences.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Kadi, Fawzi
    Örebro University, School of Health Sciences.
    HSP27 is not mandatory for the hypertrophy of human skeletal muscle cellsManuscript (preprint) (Other academic)
  • 18.
    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)
  • 19.
    Jensen-Waern, M.
    et al.
    Department of Clinical Sciences, Section of Comparative Medicine, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Kruse, Robert
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Lundgren, T.
    Division of Transplantation Surgery, CLINTEC, Karolinska Institutet, Stockholm, Sweden.
    Oral immunosuppressive medication for growing pigs in transplantation studies2012In: Laboratory Animals, ISSN 0023-6772, E-ISSN 1758-1117, Vol. 46, no 2, p. 148-151Article in journal (Refereed)
    Abstract [en]

    Immunosuppressive (IS) medication is needed to avoid graft rejection in porcine transplantation models. An ideal IS therapy should have no side-effects, but increased susceptibility to infections, disturbed intestinal microflora and toxic effects on organs and tissues are commonly reported. The aim of the present study was to design an IS protocol with tacrolimus and mycophenolic acid to be used for maintenance therapy in the post-transplant period. An eligible whole blood trough value for tacrolimus was 5-15 mu g/L. Conventional specific pathogen-free pigs were fitted with an indwelling catheter under general anaesthesia, and after the acclimatization period three groups were formed: group A (n = 4) received 0.15 mg/kg body weight (BW) twice daily tacrolimus and 500 mg twice daily mycophenolic acid; group B (n = 4) received 0.3 mg/kg BW twice daily tacrolimus and 500 mg twice daily mycophenolic acid; group C (n = 2) did not receive any medication. Daily clinical examinations and analyses of blood concentrations of tacrolimus and glucose were performed. Total and differential white blood cell counts, enzyme activities, bilirubin and electrolyte concentrations were measured every fourth day. At the end of the experiment, the pigs were killed with an overdose of pentobarbital intravenously and a necropsy was performed immediately. All animals seemed to tolerate the IS treatment well. No alterations in their clinical state of health were observed throughout the study and daily weight gain was similar for the three groups. The necropsy did not reveal any pathological findings related to medication. The study showed that 0.25 mg/kg BW twice daily tacrolimus and 500 mg twice daily mycophenolic acid would be an appropriate maintenance dosage for conventional pigs.

  • 20.
    Juzenas, Simonas
    et al.
    Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany; Institute of Biotechnology, Life Science Centre, Vilnius University, Vilnius, Lithuania.
    Hübenthal, Matthias
    Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany; Department of Dermatology, Quincke Research Center, University Hospital Schleswig-Holstein, Kiel, Germany.
    Lindqvist, Carl Mårten
    Örebro University, School of Medical Sciences. Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Steiert, Tim Alexander
    Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
    Degenhardt, Frauke
    Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
    Schulte, Dominik
    Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Medicine I, University Hospital of Schleswig-Holstein, Kiel, Germany; Institute of Diabetes and Clinical Metabolic Research, Kiel University, Kiel, Germany.
    Nikolaus, Susanna
    Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.
    Zeissig, Sebastian
    Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany; Center for Regenerative Therapies Dresden (CRTD), Technische Universität (TU) Dresden, Dresden, Germany.
    Bergemalm, Daniel
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Almer, Sven
    Department of Medicine, Karolinska Institutet, Solna, and Division of Gastroenterology, Karolinska University Hospital, Stockholm, Sweden.
    Hjortswang, Henrik
    Department of Gastroenterology and Hepatology, Linköping University, Linköping, Sweden; Department of Health, Medicine, and Caring Sciences, Linköping University, Linköping, Sweden.
    Bresso, Francesca
    Department of Medicine, Karolinska Institutet, Solna, and Division of Gastroenterology, Karolinska University Hospital, Stockholm, Sweden.
    Strüning, Nina
    Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.
    Kupcinskas, Juozas
    Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.
    Keller, Andreas
    Chair for Clinical Bioinformatics, Saarland University, Saarbrücken, Germany; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
    Lieb, Wolfgang
    Institute of Epidemiology, Christian-Albrechts-University of Kiel, Kiel, Germany.
    Rosenstiel, Philip
    Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
    Schreiber, Stefan
    Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany; Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.
    D'Amato, Mauro
    Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology.
    Hemmrich-Stanisak, Georg
    Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
    Franke, Andre
    Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany; University Hospital of Schleswig-Holstein (UKSH), Kiel Campus, Kiel, Germany .
    Detailed transcriptional landscape of peripheral blood points to increased neutrophil activation in treatment-naïve inflammatory bowel disease2022In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 16, no 7, p. 1097-1109Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a chronic relapsing disorder of the gastrointestinal tract, which generally manifests as Crohn's disease (CD) or ulcerative colitis (UC). These subtypes are heterogeneous in terms of disease location and histological features, while sharing common clinical presentation, genetic associations and thus, common immune regulatory pathways.

    METHODS: Using miRNA and mRNA coupled transcriptome profiling and systems biology approaches, we report a comprehensive analysis of blood transcriptomes from treatment-naïve (n=110) and treatment-exposed (n=177) IBD patients as well as symptomatic- (n=65) and healthy controls (n=95).

    RESULTS: Broadly, the peripheral blood transcriptomes of CD and UC patients were similar. However, there was an extensive gene deregulation in the blood of IBD patients, while only a slight deregulation in symptomatic controls, when compared with healthy controls. The deregulated mRNAs and miRNAs are mainly involved in the innate immunity and are especially enriched in neutrophil activation-related pathways. Oxidative phosphorylation and neutrophil activation-related modules were found to be differentially co-expressed among treatment-naïve IBD as compared to healthy controls. In the deregulated neutrophil activation-related co-expression module, the IL1B was identified as the central gene. The co-expression levels among IL1B and chemosensing receptor (CXCR1/2 and FPR1/2) genes were reduced in the blood of IBD patients when compared with healthy controls.

    CONCLUSIONS: Immune dysregulation seen in peripheral blood transcriptomes of treatment-naïve IBD patients is mainly driven by neutrophil activation.

  • 21.
    Kruse, Robert
    et al.
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital. Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Clinical Research Centre (KFC), Örebro University Hospital, Örebro, Sweden.
    Demirel, Isak
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Säve, Susanne
    School of Natural Sciences, Linnaeus University, Kalmar, Sweden.
    Persson, Katarina
    Örebro University, School of Medicine, Örebro University, Sweden. Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    IL-8 and global gene expression analysis define a key role of ATP in renal epithelial cell responses induced by uropathogenic bacteria2014In: Purinergic Signalling Purinergic Signalling, ISSN 1573-9538, E-ISSN 1573-9546, Vol. 10, no 3, p. 499-508Article in journal (Refereed)
    Abstract [en]

    The recent recognition of receptor-mediated ATP signalling as a pathway of epithelial pro-inflammatory cytokine release challenges the ubiquitous role of the TLR4 pathway during urinary tract infection. The aim of this study was to compare cellular responses of renal epithelial cells infected with uropathogenic Escherichia coli (UPEC) strain IA2 to stimulation with ATP-gamma-S. A498 cells were infected or stimulated in the presence or absence of apyrase, that degrades extracellular ATP, or after siRNA-mediated knockdown of ATP-responding P2Y(2) receptors. Cellular IL-8 release and global gene expression were analysed. Both IA2 and A498 cells per se released ATP, which increased during infection. IA2 and ATP-gamma-S caused a similar to 5-fold increase in cellular release of IL-8 and stimulations performed in the presence of apyrase or after siRNA knockdown of P2Y(2) receptors resulted in attenuation of IA2-mediated IL-8 release. Microarray results show that both IA2 and ATP-gamma-S induced marked changes in gene expression of renal cells. Thirty-six genes were in common between both stimuli, and many of these are key genes belonging to classical response pathways of bacterial infection. Functional analysis shows that 88 biological function-annotated cellular pathways were identical between IA2 and ATP-gamma-S stimuli. Results show that UPEC-induced release of IL-8 is dependent on P2Y(2) signalling and that cellular responses elicited by UPEC and ATP-gamma-S have many identical features. This indicates that renal epithelial responses elicited by bacteria could be mediated by bacteria- or host-derived ATP, thus defining a key role of ATP during infection.

  • 22.
    Kruse, Robert
    et al.
    Örebro University, School of Medical Sciences. Clinical Sciences, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
    Dutta, P. C.
    Department of Food Science, Uppsala BioCenter, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Morrell, J. M.
    Division of Reproduction, Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Colloid centrifugation removes seminal plasma and cholesterol from boar spermatozoa2011In: Reproduction, Fertility and Development, ISSN 1031-3613, E-ISSN 1448-5990, Vol. 23, no 7, p. 858-65Article in journal (Refereed)
    Abstract [en]

    The objective of the present study was to investigate the effect of Single-Layer Centrifugation (SLC) on boar spermatozoa, namely the effect of removal of seminal plasma proteins and cholesterol from the surface of spermatozoa. The presence of porcine seminal plasma proteins I and II (PSP-I/PSP-II) before and after SLC was studied using immunofluorescence, whereas the removal of cholesterol was shown qualitatively by thin-layer chromatography (TLC). Finally, the integrity of the sperm plasma membrane was observed by electron microscopy. It was shown that the seminal plasma proteins PSP-I and -II were removed from spermatozoa during SLC but could be restored by adding seminal plasma to the SLC-selected sperm samples. Some cholesterol was also lost from the spermatozoa during SLC but the plasma membrane itself appeared to be morphologically intact. Further studies are underway to examine the relevance of these findings to boar sperm cryopreservation and sperm fertility.

  • 23.
    Kruse, Robert
    et al.
    Department of Clinical Sciences, Section for Comparative Physiology and Medicine, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Essén-Gustavsson, Birgitta
    Department of Clinical Sciences, Section for Comparative Physiology and Medicine, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Fossum, Caroline
    2Department of Molecular Biosciences, Section of Veterinary Immunology and Virology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Jensen-Waern, Marianne
    Department of Clinical Sciences, Section for Comparative Physiology and Medicine, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Blood concentrations of the cytokines IL-1beta, IL-6, IL-10, TNF-alpha and IFN-gamma during experimentally induced swine dysentery2008In: Acta Veterinaria Scandinavica, ISSN 0044-605X, E-ISSN 1751-0147, Vol. 50, article id 32Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Knowledge of the cytokine response at infection with Brachyspira hyodysenteriae can help understanding disease mechanism involved during swine dysentery. Since this knowledge is still limited the aim of the present study was to induce dysentery experimentally in pigs and to monitor the development of important immunoregulatory cytokines in blood collected at various stages of the disease.

    METHODS: Ten conventional pigs (~23 kg) were orally inoculated with Brachyspira hyodysenteriae B204T. Eight animals developed muco-haemorrhagic diarrhoea with impaired general body condition. Blood was sampled before inoculation and repeatedly during acute dysentery and recovery periods and cytokine levels of IL-1beta, IL-6, Il-10, TNF-alpha and IFN-gamma were measured by ELISA.

    RESULTS: IL-1beta was increased at the beginning of the dysentery period and coincided with the appearance of Serum amyloid A and clinical signs of disease. TNF-alpha increased in all animals after inoculation, with a peak during dysentery, and IL-6 was found in 3 animals during dysentery and in the 2 animals that did not develop clinical signs of disease. IL-10 was found in all sick animals during the recovery period. IFN-gamma was not detected on any occasion.

    CONCLUSION: B. hyodysenteriae inoculation induced production of systemic levels of IL-1beta during the dysentery period and increased levels of IL-10 coincided with recovery from dysentery.

  • 24.
    Kruse, Robert
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Säve, Susanne
    School of Health and Medical Sciences, Clinical Research Center (KFC), Örebro University Hospital, Örebro, Sweden; School of Natural Sciences, Linnaeus University (SS), Kalmar, Sweden.
    Persson, Katarina
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. School of Health and Medical Sciences, Clinical Research Center (KFC), Örebro University Hospital, Örebro, Sweden; School of Natural Sciences, Linnaeus University (SS), Kalmar, Sweden.
    Adenosine triphosphate induced P2Y(2) receptor activation induces proinflammatory cytokine release in uroepithelial cells2012In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 188, no 6, p. 2419-2425Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 25.
    Lundström, Maria Ling
    et al.
    Department of Medical Sciences, Gastroenterology Research Group, Uppsala University, Uppsala, Sweden.
    Peterson, Christer
    Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden.
    Lampinen, Maria
    Department of Medical Sciences, Gastroenterology Research Group, Uppsala University, Uppsala, Sweden.
    Hedin, Charlotte R. H.
    Karolinska Institute, Department of Medicine Solna, Stockholm, Sweden; Karolinska University Hospital, Gastroenterology Unit, Department of Gastroenterology, Dermatovenereology and Rheumatology, Stockholm, Sweden.
    Keita, Åsa V.
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Kruse, Robert
    Örebro University, School of Medical Sciences. iRiSC - Inflammatory Response and Infection Susceptibility Centre and Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Magnusson, Maria K.
    Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Lindqvist, Carl Mårten
    Örebro University, School of Medical Sciences.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    D'Amato, Mauro
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Institute, Solna, Sweden; Department of Medicine and Surgery, LUM University, Casamassima, Italy; Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
    Hjortswang, Henrik
    Division of Gastroenterology and Hepatology, Department of Clinical and Experimental Science, Linköping University, Linköping, Sweden.
    Strid, Hans
    Department of Internal Medicine, Södra Älvsborgs Hospital, Borås, Sweden.
    Rönnblom, Anders
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Söderholm, Johan D.
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Department of Surgery, Linköping University, Linköping, Sweden.
    Öhman, Lena
    Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Venge, Per
    Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Carlson, Marie
    Department of Medical Sciences, Gastroenterology Research Group, Uppsala University, Uppsala, Sweden.
    Faecal biomarkers of neutrophil and eosinophil origin reflect the response to biological therapy and corticosteroids in patients with IBD2023In: Clinical and Translational Gastroenterology, E-ISSN 2155-384X, Vol. 14, no 8, article id e00605Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Faecal calprotectin (FC) is a non-invasive tool for examining response to biologics in inflammatory bowel disease (IBD), but its performance in relation to other novel faecal markers of various cellular origins is unknown.

    METHODS: We performed a prospective multicentre cohort study and included patients with active IBD who provided a faecal sample at initiation of biological therapy. Levels of FC, myeloperoxidase (MPO), human neutrophil lipocalin (HNL), and eosinophil-derived neurotoxin (EDN) were analysed and related to clinical remission status at 3 months. Changes in levels of markers at 3 months were calculated and the impact of concomitant use of corticosteroids at baseline was estimated.

    RESULTS: In patients achieving clinical remission (n=27), a decrease in levels of FC (p=0.005), MPO (p<0.001), HNL (p<0.001) and EDN (p<0.001) was observed, whereas no significant decrease was seen in patients not achieving remission (n=39). There was a significant difference in the change in the level of MPO (p=0.01) and HNL (p=0.02) between patients achieving clinical remission compared with those who did not, but changes in FC and EDN could not differentiate between these groups. Patients with concomitant systemic corticosteroids at inclusion had lower levels of HNL (p=0.01) and EDN (p<0.001) at baseline, compared with patients without corticosteroids.

    CONCLUSION: Faecal MPO, HNL, and EDN are all promising biomarkers for assessing the treatment outcome of biologics in patients with IBD. Faecal levels of EDN and HNL are significantly affected by corticosteroids indicating a greater sensitivity to the effects of corticosteroids compared with FC and MPO.

  • 26.
    Mathisen, C. Bache-Wiig
    et al.
    Oslo University Hospital, Department of Gastroenterology, Oslo, Norway; University of Oslo, Institute of Clinical Medicine, Oslo, Norway.
    Nyström, N.
    Uppsala Univeristy Hospital, Department of Women's and Children's health, Uppsala, Sweden.
    Bazov, Igor
    Örebro University, School of Medical Sciences.
    Andersen, S.
    Vestfold Hospital trust, Department of Pediatrics, Tønsberg, Norway.
    Olbjørn, C.
    Akershus University Hospital, Department of Pediatric and Adolescent Medicine, Lørenskog, Norway.
    Perminow, G.
    Oslo University Hospital, Department of Pediatric Medicine, Oslo, Norway.
    Kristensen, V. A.
    Oslo University Hospital, Department of Gastroenterology, Oslo, Norway; Lovisenberg Diaconal Hospital, Unger-Vetlesen Institute, Oslo, Norway.
    Opheim, R.
    Oslo University Hospital, Department of Gastroenterology, Oslo, Norway; University of Oslo, Faculty of Medicine, Oslo, Norway .
    Ricanek, P.
    Lovisenberg Diaconal Hospital, Department of Gastroenterology, Oslo, Norway; Akershus University Hospital, Department of Gastroenterology, Lørenskog, Norway.
    D'Amato, M.
    Karolinska Institutet, Clinical Epidemiology Division, Department of Medicine Solna, Stockholm, Sweden; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain; CIC bioGUNE - BRTA, Gastrointestinal Genetics Lab, Derio, Spain.
    Carlson, M.
    Uppsala University, Department of Medical Sciences, Uppsala, Sweden.
    Hedin, C. R.
    Karolinska Institute, Department of Medicine Solna, Stockholm, Sweden; Karolinska University Hospital, Gastroenterology unit, Department of Gastroenterology, Dermatovenereology and Rheumatology, Oslo, Sweden.
    Keita, Å. V.
    Linköping University, Department of Biomedical and Clinical Sciences, Linköping, Sweden.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Lindqvist, C. M.
    Örebro University, School of Medical Sciences, Faculty of Medicine and Health, Örebro, Sweden.
    Magnusson, M. K.
    University of Gothenburg, Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, Gothenburg, Sweden.
    Salihovic, Samira
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre.
    Söderholm, J. D.
    Linköping University, Department of Biomedical and Clinical Sciences, Linköping, Sweden.
    Öhman, L.
    University of Gothenburg, Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, Gothenburg, Sweden.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Høivik, M. L.
    Oslo University Hospital, Department of Gastroenterology, Oslo, Norway; University of Oslo, Institute of Clinical Medicine, Oslo, Norway.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology.
    A novel diagnostic serum protein signature for paediatric Inflammatory Bowel Disease: A discovery and validation study in two independent inception cohorts2023In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 17, no Suppl. 1, p. I71-I73, article id DOP11Article in journal (Other academic)
  • 27.
    Moraes Holst, Luiza
    et al.
    Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology.
    Carlson, Marie
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Hedin, Charlotte
    Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Lindqvist, Carl Mårten
    Örebro University, School of Medical Sciences.
    Bergemalm, Daniel
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Gastroenterology.
    Almér, Sven
    Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Bresso, Francesca
    Karolinska University Hospital, Gastroenterology Unit, Department of Gastroenterology, Dermatovenereology and Rheumatology, Stockholm, Sweden.
    Ling Lundström, Maria
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    D'Amato, Mauro
    Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain; Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain.
    Keita, Åsa
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Hjortswang, Henrik
    Department of Clinical and Experimental Science, Linköping University, Linköping, Sweden.
    Söderholm, Johan
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Sundin, Johanna
    Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, Gothenburg, Sweden.
    Törnblom, Hans
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Simrén, Magnus
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    Strid, Hans
    Department of Internal Medicine, Södra Älvsborg Hospital, Borås, Sweden.
    Magnusson, Maria K.
    Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Öhman, Lena
    Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Downregulated Mucosal Autophagy, Alpha Kinase-1 and IL-17 Signaling Pathways in Active and Quiescent Ulcerative Colitis2022In: Clinical and Experimental Gastroenterology, E-ISSN 1178-7023, Vol. 15, p. 129-144Article in journal (Refereed)
    Abstract [en]

    Background: Improved mucosal immune profiling in active and quiescent colonic inflammatory bowel disease (IBD) is needed to develop therapeutic options for treating and preventing flares. This study therefore aimed to provide a comprehensive mucosal characterization with emphasis on immunological host response of patients with active ulcerative colitis (UC active), UC during remission (UC remission) and active colonic Crohn's disease (CD active).

    Methods: Colonic biopsies from 47 study subjects were collected for gene expression and pathway analyses using the NanoString host-response panel, including 776 genes and 56 immune-related pathways.

    Results: The majority of mucosal gene expression and signaling pathway scores were increased in active IBD (n=27) compared to healthy subjects (n=10). However, both active IBD and UC remission (n=10) demonstrated decreased gene expression and signaling pathway scores related to autophagy, alpha kinase-1 and IL-17 signaling pathways compared to healthy subjects. Further, UC remission was characterized by decreased scores of several signaling pathways linked to homeostasis along with increased mononuclear cell migration pathway score as compared to healthy subjects. No major differences in the colonic mucosal gene expression between CD active (n=7) and UC (n=20) active were observed.

    Conclusion: This study indicates that autophagy, alpha kinase-1 and IL-17 signaling pathways are persistently downregulated in UC irrespective of disease activity. Further, UC patients in remission present a unique mucosal environment, potentially preventing patients from reaching and sustaining true homeostasis. These findings may enable better comprehension of the remitting and relapsing pattern of colonic IBD and guide future treatment and prevention of flares.

  • 28.
    Nikaein, Niloofar
    et al.
    Örebro University, School of Medical Sciences.
    Tuerxun, Kaya
    Örebro University, School of Medical Sciences.
    Cedersund, Gunnar
    Örebro University, School of Medical Sciences. Center for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden.
    Eklund, Daniel
    Örebro University, School of Medical Sciences.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Särndahl, Eva
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Nånberg, Eewa
    Örebro University, School of Health Sciences. Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Thonig, Antje
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Persson, Alexander
    School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Nyman, Elin
    Department of Biomedical engineering, Linköping University, Linköping, Sweden.
    Mathematical models disentangle the role of IL-10 feedbacks in human monocytes upon proinflammatory activation2023In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 299, no 10, article id 105205Article in journal (Refereed)
    Abstract [en]

    Inflammation is one of the vital mechanisms through which the immune system responds to harmful stimuli. During inflammation, pro and anti-inflammatory cytokines interplay to orchestrate fine-tuned, dynamic immune responses. The cytokine interplay governs switches in the inflammatory response and dictates the propagation and development of the inflammatory response. Molecular pathways underlying the interplay are complex, and time-resolved monitoring of mediators and cytokines is necessary as a basis to study them in detail. Our understanding can be advanced by mathematical models which enable to analyze the system of interactions and their dynamical interplay in detail. We, therefore, used a mathematical modeling approach to study the interplay between prominent pro and anti-inflammatory cytokines with a focus on tumor necrosis factor (TNF) and interleukin 10 (IL-10) in lipopolysaccharide (LPS)-primed primary human monocytes. Relevant time-resolved data were generated by experimentally adding or blocking IL-10 at different time points. The model was successfully trained and could predict independent validation data and was further used to perform simulations to disentangle the role of IL-10 feedbacks during an acute inflammatory event. We used the insight to obtain a reduced predictive model including only the necessary IL-10-mediated feedbacks. Finally, the validated reduced model was used to predict early IL-10 - TNF switches in the inflammatory response. Overall, we gained detailed insights into fine-tuning of inflammatory responses in human monocytes and present a model for further use in studying the complex and dynamic process of cytokine-regulated acute inflammation.

  • 29.
    Persson, Katarina
    et al.
    Örebro University, School of Medical Sciences.
    Petersson, Ulrika
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Johansson, Charlotte
    School of Health Sciences, Örebro University, Örebro, Sweden.
    Demirel, Isak
    Örebro University, School of Medical Sciences.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Transcriptional alterations in bladder epithelial cells in response to infection with different morphological states of uropathogenic Escherichia coli2022In: Scientific Reports, E-ISSN 2045-2322, Vol. 12, no 1, article id 486Article in journal (Refereed)
    Abstract [en]

    Uropathogenic Escherichia coli (UPEC) may undergo a cyclic cascade of morphological alterations that are believed to enhance the potential of UPEC to evade host responses and re-infect host cell. However, knowledge on the pathogenic potential and host activation properties of UPEC during the morphological switch is limited. Microarray analysis was performed on mRNA isolated from human bladder epithelial cells (HBEP) after exposure to three different morphological states of UPEC (normal coliform, filamentous form and reverted form). Cells stimulated with filamentous bacteria showed the lowest number of significant gene alterations, although the number of enriched gene ontology classes was high suggesting diverse effects on many different classes of host genes. The normal coliform was in general superior in stimulating transcriptional activity in HBEP cells compared to the filamentous and reverted form. Top-scored gene entities activated by all three morphological states included IL17C, TNFAIP6, TNF, IL20, CXCL2, CXCL3, IL6 and CXCL8. The number of significantly changed canonical pathways was lower in HBEP cells stimulated with the reverted form (32 pathways), than in cells stimulated with the coliform (83 pathways) or filamentous bacteria (138 pathways). A host cell invasion assay showed that filamentous bacteria were unable to invade bladder cells, and that the number of intracellular bacteria was markedly lower in cells infected with the reverted form compared to the coliform. In conclusion, the morphological state of UPEC has major impact on the host bladder response both when evaluating the number and the identity of altered host genes and pathways.

  • 30.
    Sahlberg Bang, Charlotte
    et al.
    Örebro University, School of Medical Sciences. iRiSC - Inflammatory Responses and Infection Susceptibility Centre, Örebro University, Örebro, Sweden; iRiSC - Inflammatory Responses and Infection Susceptibility Centre, Örebro University Hospital, Örebro, Sweden.
    Kruse, Robert
    Örebro University, School of Medical Sciences. iRiSC - Inflammatory Responses and Infection Susceptibility Centre, Örebro University, Örebro, Sweden; iRiSC - Inflammatory Responses and Infection Susceptibility Centre, Örebro University Hospital, Örebro, Sweden.
    Johansson, Kjell
    Örebro University, School of Medical Sciences.
    Persson, Katarina
    Örebro University, School of Medical Sciences. iRiSC - Inflammatory Responses and Infection Susceptibility Centre, Örebro University, Örebro, Sweden; iRiSC - Inflammatory Responses and Infection Susceptibility Centre, Örebro University Hospital, Örebro, Sweden.
    Carbon monoxide releasing molecule-2 (CORM-2) inhibits growth of multidrug-resistant uropathogenic Escherichia coli in biofilm and following host cell colonization2016In: BMC Microbiology, E-ISSN 1471-2180, Vol. 16, no 1, article id 64Article in journal (Refereed)
    Abstract [en]

    Increased resistance to antimicrobial agents is a characteristic of many bacteria growing in biofilms on for example indwelling urinary catheters or in intracellular bacterial reservoirs. Biofilm-related infections caused by multidrug-resistant bacteria, such as extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, are a major challenge. The aim of this study was to investigate if a carbon monoxide-releasing molecule (CORM-2) has antibacterial effects against ESBL-producing uropathogenic E. coli (UPEC) in the biofilm mode of growth and following colonization of host bladder epithelial cells.

    Results

    The effect of CORM-2 was examined on bacteria grown within an established biofilm (biofilm formed for 24 h on plastic surface) by a live/dead viability staining assay. CORM-2 (500 μM) exposure for 24 h killed approximately 60 % of the ESBL-producing UPEC isolate. A non-ESBL-producing UPEC isolate and the E. coli K-12 strain TG1 were also sensitive to CORM-2 exposure when grown in biofilms. The antibacterial effect of CORM-2 on planktonic bacteria was reduced and delayed in the stationary growth phase compared to the exponential growth phase. In human bladder epithelial cell colonization experiments, CORM-2 exposure for 4 h significantly reduced the bacterial counts of an ESBL-producing UPEC isolate.

    Conclusion

    This study shows that CORM-2 has antibacterial properties against multidrug-resistant UPEC under biofilm-like conditions and following host cell colonization, which motivate further studies of its therapeutic potential.

  • 31.
    Sahlberg Bang, Charlotte
    et al.
    Örebro University, School of Medical Sciences.
    Kruse, Robert
    Örebro University, School of Medical Sciences.
    Persson, Katarina
    Örebro University, School of Medical Sciences.
    Global gene expression profiling and antibiotic susceptibility after repeated exposure to the carbon monoxide-releasing molecule-2 (CORM-2) in multidrug-resistant ESBL-producing uropathogenic Escherichia coliManuscript (preprint) (Other academic)
  • 32.
    Salihovic, Samira
    et al.
    Örebro University, School of Medical Sciences.
    Nyström, N.
    Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden.
    Mathisen, C. Bache-Wiig
    Department of Gastroenterology, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
    Andersen, S.
    Department of Pediatrics, Vestfold Hospital trust, Tønsberg, Norway.
    Olbjørn, C.
    Department of Pediatrics and Adolescent Medicine, Akershus University Hospital, Lørenskog, Norway.
    Perminow, G.
    Department of Pediatric Medicine, Oslo University Hospital, Oslo, Norway.
    Opheim, R.
    Department of Gastroenterology- Oslo University Hospital and Faculty of Medicine, University of Oslo, Oslo, Norway.
    Detlie, T. E.
    Department of Gastroenterology, Akershus University Hospital and Institute of Clinical Medicine, University of Oslo, Lørenskog, Norway.
    Huppertz-Hauss, G.
    Department of Gastroenterology, Telemark Hospital Trust, Skien, Norway.
    Bazov, Igor
    Örebro University, School of Medical Sciences.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Lindqvist, C. M.
    School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Hedin, C. R. H.
    Department of Medicine Solna and Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Carlson, M.
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Öhman, L.
    Department of Microbiology and Immunology and Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Magnusson, M.
    Department of Microbiology and Immunology and Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Keita, Å. V.
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Söderholm, J. D.
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    D'Amato, M.
    Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Oresic, Matej
    Örebro University, School of Medical Sciences.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Hoivik, M. L.
    Department of Gastroenterology, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology.
    Identification and validation of a lipidomic signature as a novel diagnostic biomarker of paediatric Inflammatory Bowel Disease2023In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 17, no Suppl. 1, p. I76-I77, article id DOP14Article in journal (Other academic)
  • 33.
    Scherbak, Nikolai
    et al.
    Örebro University, School of Science and Technology.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Inflammatory Response and Infection Susceptibility Center (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Nyström, Thomas
    Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset, Stockholm, Sweden.
    Jendle, Johan
    Örebro University, School of Medical Sciences.
    Glimepiride Compared to Liraglutide Increases Plasma Levels of miR-206, miR-182-5p, and miR-766-3p in Type 2 Diabetes Mellitus: A Randomized Controlled Trial (Diabetes Metab J 2023;47:668-81)2023In: Diabetes & metabolism journal, ISSN 2233-6079, E-ISSN 2233-6087, Vol. 47, no 6, p. 882-883Article in journal (Refereed)
  • 34.
    Scherbak, Nikolai N.
    et al.
    Örebro University, School of Science and Technology.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory, Inflammatory Response and Infection Susceptibility Center (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset, Stockholm, Sweden.
    Nyström, Thomas
    School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Jendle, Johan
    Örebro University, School of Medical Sciences.
    Glimepiride Compared to Liraglutide Increases Plasma Levels of miR-206, miR-182-5p, and miR-766-3p in Type 2 Diabetes Mellitus: A Randomized Controlled Trial2023In: Diabetes & metabolism journal, ISSN 2233-6079, E-ISSN 2233-6087, Vol. 47, no 5, p. 668-681Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Diabetes is a chronic disease with several long-term complications. Several glucose-lowering drugs are used to treat type 2 diabetes mellitus (T2DM), e.g., glimepiride and liraglutide, in which both having different modes of action. Circulating microRNAs (miRNAs) are suggested as potential biomarkers that are associated with the disease development and the effects of the treatment. In the current study we evaluated the effect of glimepiride, liraglutide on the expression of the circulating miRNAs.

    METHODS: The present study is a post hoc trial from a previously randomized control trial comparing liraglutide versus glimepiride both in combination with metformin in subjects with T2DM, and subclinical heart failure. miRNAs were determined in the subjects' serum samples with next generation sequencing. Expression patterns of the circulating miRNAs were analyzed using bioinformatic univariate and multivariate analyses (clinical trial registration: NCT01425580).

    RESULTS: Univariate analyses show that treatment with glimepiride altered expression of three miRNAs in patient serum, miR-206, miR-182-5p, and miR-766-3p. Both miR-182-5p and miR-766-3p were also picked up among the top contributing miRNAs with penalized regularised logistic regressions (Lasso). The highest-ranked miRNAs with respect to Lasso coefficients were miR-3960, miR-31-5p, miR-3613-3p, and miR-378a-3p. Liraglutide treatment did not significantly influence levels of circulating miRNAs.

    CONCLUSION: Present study indicates that glucose-lowering drugs differently affect the expression of circulating miRNAs in serum in individuals with T2DM. More studies are required to investigate possible mechanisms by which glimepiride is affecting the expression of circulating miRNAs.

  • 35.
    Serhan, Charles N.
    et al.
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
    Gupta, Shailendra K.
    Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany.
    Perretti, Mauro
    The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK.
    Godson, Catherine
    Diabetes Complications Research Centre, Conway Institute & School of Medicine, University College Dublin, Belfield, Dublin, Ireland.
    Brennan, Eoin
    Diabetes Complications Research Centre, Conway Institute & School of Medicine, University College Dublin, Belfield, Dublin, Ireland.
    Li, Yongsheng
    Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, China.
    Soehnlein, Oliver
    Department of Physiology and Pharmacology (FyFA), Karolinska Institutet, Stockholm, Sweden; German Center for Cardiovascular Research (DZHK), München, Germany; Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian University, München, Germany.
    Shimizu, Takao
    Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; National Center for Global Health and Medicine, Toyama, Shinjuku-ku, Tokyo, Japan.
    Werz, Oliver
    Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany.
    Chiurchiù, Valerio
    Institute of Translational Pharmacology, National Research Council, Rome, Italy; Laboratory of Resolution of Neuroinflammation, IRCCS Santa Lucia Foundation, Rome, Italy.
    Azzi, Angelo
    School of Graduate Biomedical Pharmacology and Drug Development Program at Tufts University, Boston, MA, USA.
    Dubourdeau, Marc
    Ambiotis, Canal Biotech, Toulouse, France.
    Gupta, Suchi Smita
    Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany.
    Schopohl, Patrick
    Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany.
    Hoch, Matti
    Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany.
    Gjorgevikj, Dragana
    Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany.
    Khan, Faiz M.
    Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany.
    Brauer, David
    Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany.
    Tripathi, Anurag
    CSIR - Indian Institute of Toxicology Research, Lucknow, India.
    Cesnulevicius, Konstantin
    Department of Medical Affairs & Research, Heel GmbH, Baden-Baden, Germany.
    Lescheid, David
    Department of Medical Affairs & Research, Heel GmbH, Baden-Baden, Germany.
    Schultz, Myron
    Department of Medical Affairs & Research, Heel GmbH, Baden-Baden, Germany.
    Särndahl, Eva
    Örebro University, School of Medical Sciences.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Sala, Angelo
    Department of Pharmaceutical Sciences, University of Milan, Milano, and IRIB, C.N.R, Palermo, Italy.
    Haeggström, Jesper Z.
    Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
    Levy, Bruce D.
    Brigham and Women's Hospital, Department of Medicine, Pulmonary and Critical Care Medicine and Harvard Medical School, Boston, MA, USA.
    Filep, János G.
    Department of Pathology and Cell Biology, University of Montreal, Research Center, Maisonneuve-Rosemont Hospital, Montreal, Canada.
    Wolkenhauer, Olaf
    Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany; Stellenbosch Institute for Advanced Study (STIAS), Wallenberg Research Centre at Stellenbosch University, Stellenbosch, South Africa.
    The Atlas of Inflammation Resolution (AIR)2020In: Molecular Aspects of Medicine, ISSN 0098-2997, E-ISSN 1872-9452, Vol. 74, article id 100894Article in journal (Refereed)
    Abstract [en]

    Acute inflammation is a protective reaction by the immune system in response to invading pathogens or tissue damage. Ideally, the response should be localized, self-limited, and returning to homeostasis. If not resolved, acute inflammation can result in organ pathologies leading to chronic inflammatory phenotypes. Acute inflammation and inflammation resolution are complex coordinated processes, involving a number of cell types, interacting in space and time. The biomolecular complexity and the fact that several biomedical fields are involved, make a multi- and interdisciplinary approach necessary. The Atlas of Inflammation Resolution (AIR) is a web-based resource capturing an essential part of the state-of-the-art in acute inflammation and inflammation resolution research. The AIR provides an interface for users to search thousands of interactions, arranged in inter-connected multi-layers of process diagrams, covering a wide range of clinically relevant phenotypes. By mapping experimental data onto the AIR, it can be used to elucidate drug action as well as molecular mechanisms underlying different disease phenotypes. For the visualization and exploration of information, the AIR uses the Minerva platform, which is a well-established tool for the presentation of disease maps. The molecular details of the AIR are encoded using international standards. The AIR was created as a freely accessible resource, supporting research and education in the fields of acute inflammation and inflammation resolution. The AIR connects research communities, facilitates clinical decision making, and supports research scientists in the formulation and validation of hypotheses. The AIR is accessible through https://air.bio.informatik.uni-rostock.de.

  • 36.
    Tuerxun, Kaya
    et al.
    Örebro University, School of Medical Sciences.
    Eklund, Daniel
    Örebro University, School of Medical Sciences.
    Wallgren, Ulrika
    Gustavsbergs Vårdcentral, Gustavsberg, Stockholm, Sweden.
    Dannenberg, Katharina
    Örebro University, School of Medical Sciences.
    Repsilber, Dirk
    School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Kruse, Robert
    Örebro University, School of Medical Sciences.
    Särndahl, Eva
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre, (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Kurland, Lisa
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre, (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Department of Emergency Medicine, Örebro University Hospital, Örebro, Sweden.
    Predicting sepsis using a combination of clinical information and molecular immune markers sampled in the ambulance2023In: Scientific Reports, E-ISSN 2045-2322, Vol. 13, no 1, article id 14917Article in journal (Refereed)
    Abstract [en]

    Sepsis is a time dependent condition. Screening tools based on clinical parameters have been shown to increase the identification of sepsis. The aim of current study was to evaluate the additional predictive value of immunological molecular markers to our previously developed prehospital screening tools. This is a prospective cohort study of 551 adult patients with suspected infection in the ambulance setting of Stockholm, Sweden between 2017 and 2018. Initially, 74 molecules and 15 genes related to inflammation were evaluated in a screening cohort of 46 patients with outcome sepsis and 50 patients with outcome infection no sepsis. Next, 12 selected molecules, as potentially synergistic predictors, were evaluated in combination with our previously developed screening tools based on clinical parameters in a prediction cohort (n = 455). Seven different algorithms with nested cross-validation were used in the machine learning of the prediction models. Model performances were compared using posterior distributions of average area under the receiver operating characteristic (ROC) curve (AUC) and difference in AUCs. Model variable importance was assessed by permutation of variable values, scoring loss of classification as metric and with model-specific weights when applicable. When comparing the screening tools with and without added molecular variables, and their interactions, the molecules per se did not increase the predictive values. Prediction models based on the molecular variables alone showed a performance in terms of AUCs between 0.65 and 0.70. Among the molecular variables, IL-1Ra, IL-17A, CCL19, CX3CL1 and TNF were significantly higher in septic patients compared to the infection non-sepsis group. Combing immunological molecular markers with clinical parameters did not increase the predictive values of the screening tools, most likely due to the high multicollinearity of temperature and some of the markers. A group of sepsis patients was consistently miss-classified in our prediction models, due to milder symptoms as well as lower expression levels of the investigated immune mediators. This indicates a need of stratifying septic patients with a priori knowledge of certain clinical and molecular parameters in order to improve prediction for early sepsis diagnosis.Trial registration: NCT03249597. Registered 15 August 2017.

  • 37.
    Tuerxun, Kaya
    et al.
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health Örebro University, Örebro, Sweden.
    Midtbö, Kristine
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health Örebro University, Örebro, Sweden.
    Särndahl, Eva
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health Örebro University, Örebro, Sweden.
    Vorontsov, Egor
    Proteomics Core Facility, Sahlgrenska Academy University of Gothenburg, Gothenburg, Sweden.
    Karlsson, Roger
    Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy of the University of Gothenburg Sweden; Department of Clinical Microbiology, Sahlgrenska University Hospital, Region Västra Götaland, Sweden; Nanoxis Consulting AB, Gothenburg, Sweden.
    Persson, Alexander
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health Örebro University, Örebro, Sweden.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health Örebro University, Örebro, Sweden; Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Eklund, Daniel
    Faculty of Medicine and Health, School of Medical Sciences Örebro University Örebro Sweden;Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health Örebro University Örebro Sweden.
    Cytokine responses to LPS in reprogrammed monocytes are associated with the transcription factor PU.12022In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 112, no 4, p. 679-692Article in journal (Refereed)
    Abstract [en]

    Myeloid-derived suppressor cells (MDSCs) are functionally immunosuppressive cellsthat arise and expand during extensive inflammatory conditions by increasedhematopoietic output or reprogramming of immune cells. In sepsis, an increase of circulatingMDSCs is associated with adverse outcomes, but unique traits that can beused to identify increased activity of MDSCs are lacking. By using endotoxin toleranceas a model of sepsis-induced monocytic MDSCs (M-MDSC-like cells), this studyaims to identify the mediator and transcriptional regulator profile associated with MMDSCactivity. After analyzing 180 inflammation-associated proteins, a profile of differentiallyexpressed cytokines was found in M-MDSC-like cells versus normal monocytesstimulated with LPS. These cytokines were associated with 5 candidate transcriptionfactors,where particularly PU.1 showed differential expression on both transcriptionaland protein levels in M-MDSC-like cells. Furthermore, inhibition of PU.1led to increased production of CXCL5 and CCL8 in M-MDSC-like cells indicating itsrole in regulating the ability ofM-MDSC-like cells to recruit other immune cells. Takentogether, the study identifies a unique profile in the pattern of immune mediatorsdefining M-MDSC activity upon LPS stimulation, which offers a functional link to theircontribution to immunosuppression.

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  • 38.
    Vumma, Ravi
    et al.
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Bang, Charlotte Sahlberg
    Örebro University, School of Health Sciences. iRiSC-Inflammatory Responses and Infection Susceptibility Centre, Örebro University, Örebro, Sweden.
    Kruse, Robert
    Örebro University, School of Medical Sciences. iRiSC-Inflammatory Responses and Infection Susceptibility Centre, Örebro University, Örebro, Sweden.
    Johansson, Kjell
    Örebro University, School of Medical Sciences.
    Persson, Katarina
    Örebro University, School of Medical Sciences. iRiSC-Inflammatory Responses and Infection Susceptibility Centre, Örebro University, Örebro, Sweden.
    Antibacterial effects of nitric oxide on uropathogenic Escherichia coli during bladder epithelial cell colonization-a comparison with nitrofurantoin2016In: Journal of antibiotics (Tokyo. 1968), ISSN 0021-8820, E-ISSN 1881-1469, Vol. 69, no 3, p. 183-186Article in journal (Refereed)
  • 39. Welander, Edward
    et al.
    Åström, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Enonge Fotabe, Leslie
    Kardeby, Caroline
    Örebro University, School of Medical Sciences.
    Tina, Elisabet
    Örebro University, School of Medical Sciences.
    Elgbratt, Kristina
    Örebro University, School of Health Sciences.
    Pourlotfi, Arvid
    Abawi, Akram
    Romild, Alma
    Kruse, Robert
    Örebro University, School of Medical Sciences.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Crafoord, Jakob
    Ahlstrand, Erik
    Örebro University Hospital. Örebro University, School of Medical Sciences.
    Ivarsson, Mikael
    Örebro University, School of Health Sciences.
    Integrated analysis indicates reciprocal immune response dysregulations between bone marrow multipotent stromal cells and granulocytes at the mRNA but not at the protein level in myelofibrosis2018Conference paper (Refereed)
  • 40.
    Zhang, Boxi
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Elmabsout, Ali Ateia
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Khalaf, Hazem
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Basic, Vladimir T.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Jayaprakash, Kartheyaene
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Kruse, Robert
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Medicine, Örebro University, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    The periodontal pathogen Porphyromonas gingivalis changes the gene expression in vascular smooth muscle cells involving the TGFbeta/Notch signalling pathway and increased cell proliferation2013In: BMC Genomics, E-ISSN 1471-2164, Vol. 14, p. 770-Article in journal (Refereed)
    Abstract [en]

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

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

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

  • 41.
    Östling, Hanna
    et al.
    Örebro University, School of Medical Sciences.
    Kruse, Robert
    Örebro University, School of Medical Sciences.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Infants born small-for-gestational age have different placental expression of microRNAs2017In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 88, no Suppl. 1, p. 100-101, article id P1-508Article in journal (Other academic)
  • 42.
    Östling, Hanna
    et al.
    Örebro University, School of Medical Sciences. Department of Obstetrics and Gynecology.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Pediatrics.
    Placental expression of microRNAs in infants born small for gestational age2019In: Placenta, ISSN 0143-4004, E-ISSN 1532-3102, Vol. 81, p. 46-53Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: The molecular mechanisms behind poor foetal growth are not fully known. The aim of this study was to explore global microRNA expression in placentas of infants born small for gestational age (SGA) compared to infants with a normal birth weight (NBW).

    METHODS: Placental biopsies from term infants were identified in a biobank and divided into four groups: infants born SGA with (n = 13) or without (n = 9) exposure to low maternal gestational weight gain (GWG) and infants born with NBWs with (n = 20) or without (n = 26) exposure to low GWG. All women and infants were healthy, and no woman smoked during pregnancy. Only vaginal deliveries were included. Next-generation sequencing was performed with single read sequencing of >9 million reads per sample. Differential microRNA expression was analysed using ANOVA for unequal variances (Welch) with multiple testing corrections through the Benjamini-Hochberg method. A fold change >2 and a corrected p value < 0.05 were considered significant. Adjustments for possible confounding factors were made using a linear regression model.

    RESULTS: A total of 1870 known, mature human microRNAs were detected in the sample. MiR-3679-5p and miR-193b-3p were significantly upregulated, and miR-379-3p, miR-335-3p, miR-4532, miR-519e-3p, miR-3065-5p, and miR-105-5p were significantly downregulated after adjustment for potential confounding factors in SGA infants with normal GWG compared to infants with NBWs and normal GWG.

    DISCUSSION: Infants born unexplained SGA show differential microRNA expression in their placenta. Important pathways for the differentially expressed microRNAs include inflammation and the insulin-IGF system.

  • 43.
    Östling, Hanna
    et al.
    Örebro University, School of Medical Sciences. Department of Obstetrics and Gynaecology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Paediatrics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Backman, Helena
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Obstetrics and Gynaecology.
    Kruse, Robert
    Örebro University, School of Medical Sciences. iRiSC - Inflammatory Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Global microRNA and protein expression in human term placenta2022In: Frontiers in Medicine, E-ISSN 2296-858X, Vol. 9, article id 952827Article in journal (Refereed)
    Abstract [en]

    Introduction: Description of the global expression of microRNAs (miRNAs) and proteins in healthy human term placentas may increase our knowledge of molecular biological pathways that are important for normal fetal growth and development in term pregnancy. The aim of this study was to explore the global expression of miRNAs and proteins, and to point out functions of importance in healthy term placentas.

    Materials and methods: Placental samples (n = 19) were identified in a local biobank. All samples were from uncomplicated term pregnancies with vaginal births and healthy, normal weight newborns. Next-generation sequencing and nano-scale liquid chromatographic tandem mass spectrometry were used to analyse miRNA and protein expression, respectively.

    Results: A total of 895 mature miRNAs and 6,523 proteins were detected in the placentas, of which 123 miRNAs and 346 proteins were highly abundant. The miRNAs were in high degree mapped to chromosomes 19, 14, and X. Analysis of the highly abundant miRNAs and proteins showed several significantly predicted functions in common, including immune and inflammatory response, lipid metabolism and development of the nervous system.

    Discussion: The predicted function inflammatory response may reflect normal vaginal delivery, while lipid metabolism and neurodevelopment may be important processes for the term fetus. The data presented in this study, with complete miRNA and protein findings, will enhance the knowledge base for future research in the field of placental function and pathology.

  • 44.
    Östling, Hanna
    et al.
    Örebro University, School of Medical Sciences. Department of Obstetrics and Gynaecology.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Paediatrics; University Health Care Research Centre.
    Backman, Helena
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Obstetrics and Gynaecology.
    Kruse, Robert
    Örebro University, School of Medical Sciences. iRiSC - Inflammatory Response and Infection Susceptibility Centre; Department of Clinical Research Laboratory.
    Global microRNA and protein expression in human term placenta may improve our understanding of fetal growth2022In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 95, no Suppl. 2, p. 247-247, article id P1-91Article in journal (Other academic)
    Abstract [en]

    Introduction: The placenta is an endocrine organ vital to fetal growth. It has multiple functions: pregnancy maintenance, nutrient and oxygen transport to the fetus, and removal of waste products among other functions. MicroRNAs (miRNAs) and proteins are significant mediators of these functions. A description of their global expression in healthy placenta may increase our understanding of the molecular biological pathways that are important for normal fetal growth and development. The aims of this study were to explore the global expression of both miRNAs and proteins in the same samples of human term healthy placenta and to describe involved pathways.

    Methods: Nineteen term placenta samples from healthy women with uncomplicated pregnancies were identified in a local sample collection. The samples were derived from uncomplicated vaginal deliveries with healthy normal weight new-borns (5 females). Next generation sequencing and nano-scale liquid chromatographic tandem mass spectrometry were used for the analyses of miRNA and protein expression, respectively. Ingenuity Pathway Analysis was used for functional bioinformatics analyses.

    Results: A total of 895 mature miRNAs and 6,523 proteins were detected in the placenta samples, whereof 123 miRNAs and 346 proteins were highly abundant. The miRNAs were in high degree mapped to chromosomes 19, 14 and X. The most abundant proteins served as enzymes (23%), transporters (10%) or transcription regulators (8%). Of the 20 most significant downstream functions for the highly expressed miRNAs and proteins, respectively, eight shared functions were found, namely Cellular function and maintenance, Cell death and survival, Cell-to-cell signaling and interaction, Cellular assembly and organization, Organismal development, Digestive system development and function, Hepatic system development and function, and Inflammatory response.

    Discussion: As far as we know, this is the first study presenting both global miRNA and protein expression in the same placenta sample set from healthy term pregnancies. Two of the chromosomes found to have high presence of miRNA genes in the present study are known to contain placenta-specific miRNA clusters (chromosomes 14 and 19), while chromosome X might have been identified here since it has a higher density of miRNA genes than autosomes. The biological functions for the miRNAs and proteins point at basic cellular actions and clearly illustrate that development is an important task during fetal life. Profound knowledge of miRNA and protein expression in healthy placenta can improve the management of aberrant fetal growth and development.

  • 45.
    Östling, Hanna
    et al.
    Örebro University, School of Medical Sciences. Department of Obstetrics and Gynaecology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Paediatrics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; University Health Care Research Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Backman, Helena
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Obstetrics and Gynaecology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Kruse, Robert
    Örebro University, School of Medical Sciences. iRiSC - Inflammatory Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Global microRNA and protein expression in humanterm placenta may improve our understandingof fetal growth2022In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 95, no 2, p. 247-247, article id P1-91Article in journal (Other academic)
1 - 45 of 45
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