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  • 1.
    Adolfsson, Emma
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Friberg, Örjan
    Department of Cardiothoracic Surgery, Faculty of Health, Örebro University, Örebro, Sweden.
    Samano, Ninos
    Örebro University Hospital. Örebro University, School of Medical Sciences. Department of Cardiothoracic Surgery.
    Fröbert, Ole
    Örebro University, School of Medical Sciences. Department of Cardiology.
    Johansson, Karin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine.
    Bone marrow- and adipose tissue-derived mesenchymal stem cells from donors with coronary artery disease: growth, yield, gene expression and the effect of oxygen concentration2020In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 80, no 4, p. 318-326Article in journal (Refereed)
    Abstract [en]

    Mesenchymal stem cells (MSCs) for cardiovascular cell therapy are procured from different sources including bone marrow and adipose tissue. Differently located MSCs differ in growth potential, differentiation ability and gene expression when cultured in vitro, and studies show different healing abilities for different MSC subgroups. In this study, bone marrow derived MSCs (BMSCs) and adipose tissue derived MSCs (ADSCs) from six human donors with coronary artery disease were compared for growth potential and expression of target genes (Angpt1, LIF, HGF, TGF-β1 and VEGF-A) in response to exposure to 1% and 5% O2, for up to 48 h. We found greater growth of ADSCs compared to BMSCs. ADSCs expressed higher levels of Angpt1, LIF and TGF-β1 and equal levels of VEGF-A and HGF as BMSCs. In BMSCs, exposure to low oxygen resulted in upregulation of TGF-β1, whereas other target genes were unaffected. Upregulation was only present at 1% O2. In ADSCs, LIF was upregulated in both oxygen concentrations, whereas Angpt1 was upregulated only at 1% O2. Different response to reduced oxygen culture conditions is of relevance when expanding cells in vitro prior to administration. These findings indicate ADSCs as better suited for cardiovascular cell therapy compared to BMSCs.

  • 2.
    Ahlberg, Emelie
    et al.
    Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Al-Kaabawi, Ahmed
    Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Thune, Rebecka
    Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Simpson, Melanie Rae
    Department of Public Health and Nursing, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
    Pedersen, Sindre Andre
    Library Section for Research Support, Data and Analysis, NTNU University Library, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
    Cione, Erika
    Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Cosenza, Italy.
    Jenmalm, Maria Christina
    Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Tingö, Lina
    Örebro University, School of Medical Sciences. Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Nutrition-Gut-Brain Interactions Research Centre, School of Medical Sciences, Örebro University, Örebro, Sweden; Food and Health Programme, Örebro University, Örebro, Sweden.
    Breast milk microRNAs: Potential players in oral tolerance development2023In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1154211Article, review/survey (Refereed)
    Abstract [en]

    Breast milk is an essential source of nutrition and hydration for the infant. In addition, this highly complex biological fluid contains numerous immunologically active factors such as microorganisms, immunoglobulins, cytokines and microRNAs (miRNAs). Here, we set out to predict the function of the top 10 expressed miRNAs in human breast milk, focusing on their relevance in oral tolerance development and allergy prevention in the infant. The top expressed miRNAs in human breast milk were identified on basis of previous peer-reviewed studies gathered from a recent systematic review and an updated literature search. The miRNAs with the highest expression levels in each study were used to identify the 10 most common miRNAs or miRNA families across studies and these were selected for subsequent target prediction. The predictions were performed using TargetScan in combination with the Database for Annotation, Visualization and Integrated Discovery. The ten top expressed miRNAs were: let-7-5p family, miR-148a-3p, miR-30-5p family, miR-200a-3p + miR-141-3p, miR-22-3p, miR-181-5p family, miR-146b-5p, miR-378a-3p, miR-29-3p family, miR-200b/c-3p and miR-429-3p. The target prediction identified 3,588 potential target genes and 127 Kyoto Encyclopedia of Genes and Genomes pathways; several connected to the immune system, including TGF-b and T cell receptor signaling and T-helper cell differentiation. This review highlights the role of breast milk miRNAs and their potential contribution to infant immune maturation. Indeed, breast milk miRNAs seem to be involved in several pathways that influence oral tolerance development.

  • 3.
    Ahlberg, Emelie
    et al.
    Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Jenmalm, Maria C.
    Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Tingö, Lina
    Örebro University, School of Medical Sciences. Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Evaluation of five column-based isolation kits and their ability to extract miRNA from human milk2021In: Journal of Cellular and Molecular Medicine (Print), ISSN 1582-1838, E-ISSN 1582-4934, Vol. 25, no 16, p. 7973-7979Article in journal (Refereed)
    Abstract [en]

    MicroRNA can be found in various body fluids, including breast milk. MicroRNA may be transferred from mother to infant via breast milk and potentially regulate the development of the infant's immune system on a post-transcriptional level. This study aimed to determine the microRNA extraction efficiency of five RNA extraction kits from human skim milk samples. Their efficiency was determined by comparing microRNA concentrations, total RNA yield and purity. Furthermore, hsa-miR-148a-3p expression and the recovery of an exogenous control, cel-miR-39-3p, were quantified using qPCR. Each kit extracted different amounts of microRNA and total RNA, with one kit tending to isolate the highest amount of both RNA species. Based on these results, the extraction kit ReliaPrep™ miRNA Cell and Tissue Miniprep System from Promega was found to be the most appropriate kit for microRNA extraction from human skim milk. Moreover, further research is needed to establish a standardized protocol for microRNA extraction from breast milk.

  • 4.
    Ali, Imran
    et al.
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Julin, Bettina
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Glynn, Anders
    The National Food Agency, Uppsala, Sweden.
    Högberg, Johan
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Berglund, Marika
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Johansson, Jan-Erik
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden; Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden; Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Giovannucci, Edward
    Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston MA, United States; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston MA, United States; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA, United States.
    Wolk, Alicja
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Stenius, Ulla
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Åkesson, Agneta
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Exposure to polychlorinated biphenyls and prostate cancer: population-based prospective cohort and experimental studies2016In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 37, no 12, p. 1144-1151Article in journal (Refereed)
    Abstract [en]

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

  • 5.
    Alijagic, Andi
    et al.
    Örebro University, School of Science and Technology. Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Scherbak, Nikolai
    Örebro University, School of Science and Technology.
    Kotlyar, Oleksandr
    Örebro University, School of Science and Technology.
    Karlsson, Patrik
    Örebro University, School of Science and Technology.
    Wang, Xuying
    KTH Royal Institute of Technology, Department of Chemistry, Division of Surface and Corrosion Science, SE-100 44 Stockholm, Sweden.
    Odnevall, Inger
    KTH Royal Institute of Technology, Department of Chemistry, Division of Surface and Corrosion Science, SE-100 44 Stockholm, Sweden; AIMES-Center for the Advancement of Integrated Medical and Engineering Sciences at Karolinska Institutet and KTH Royal Institute of Technology, SE-100 44 Stockholm, Sweden; Department of Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    Benada, Oldřich
    Institute of Microbiology of the Czech Academy of Sciences, 140 00 Prague, Czech Republic.
    Amiryousefi, Ali
    Örebro University, School of Medical Sciences.
    Andersson, Lena
    Örebro University, School of Medical Sciences. Örebro University Hospital. Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, SE-701 82 Örebro, Sweden; Department of Occupational and Environmental Medicine, Örebro University Hospital, Örebro, Sweden.
    Persson, Alexander
    Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, SE-701 82 Örebro, Sweden .
    Felth, Jenny
    Uddeholms AB, SE-683 85 Hagfors, Sweden.
    Andersson, Henrik
    Uddeholms AB, SE-683 85 Hagfors, Sweden.
    Larsson, Maria
    Örebro University, School of Science and Technology.
    Hedbrant, Alexander
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, SE-701 82 Örebro, Sweden.
    Salihovic, Samira
    Örebro University, School of Medical Sciences. Man-Technology-Environment Research Center (MTM), Örebro University, SE-701 82 Örebro, Sweden; Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, SE-701 82 Örebro, Sweden.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Repsilber, Dirk
    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, SE-701 82 Örebro, Sweden.
    Engwall, Magnus
    Örebro University, School of Science and Technology.
    A Novel Nanosafety Approach Using Cell Painting, Metabolomics, and Lipidomics Captures the Cellular and Molecular Phenotypes Induced by the Unintentionally Formed Metal-Based (Nano)Particles2023In: Cells, E-ISSN 2073-4409, Vol. 12, no 2, article id 281Article in journal (Refereed)
    Abstract [en]

    Additive manufacturing (AM) or industrial 3D printing uses cutting-edge technologies and materials to produce a variety of complex products. However, the effects of the unintentionally emitted AM (nano)particles (AMPs) on human cells following inhalation, require further investigations. The physicochemical characterization of the AMPs, extracted from the filter of a Laser Powder Bed Fusion (L-PBF) 3D printer of iron-based materials, disclosed their complexity, in terms of size, shape, and chemistry. Cell Painting, a high-content screening (HCS) assay, was used to detect the subtle morphological changes elicited by the AMPs at the single cell resolution. The profiling of the cell morphological phenotypes, disclosed prominent concentration-dependent effects on the cytoskeleton, mitochondria, and the membranous structures of the cell. Furthermore, lipidomics confirmed that the AMPs induced the extensive membrane remodeling in the lung epithelial and macrophage co-culture cell model. To further elucidate the biological mechanisms of action, the targeted metabolomics unveiled several inflammation-related metabolites regulating the cell response to the AMP exposure. Overall, the AMP exposure led to the internalization, oxidative stress, cytoskeleton disruption, mitochondrial activation, membrane remodeling, and metabolic reprogramming of the lung epithelial cells and macrophages. We propose the approach of integrating Cell Painting with metabolomics and lipidomics, as an advanced nanosafety methodology, increasing the ability to capture the cellular and molecular phenotypes and the relevant biological mechanisms to the (nano)particle exposure.

  • 6.
    Andjelkov, N.
    et al.
    Department of Orthopedics, Västmanlands Regional Hospital, Västerås, Sweden; Centre for Clinical Research, Uppsala University, Västmanlands Regional Hospital, Västerås, Sweden; Department of Orthopaedics, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Riyadh, H.
    Department of Orthopedics, Västmanlands Regional Hospital, Västerås, Sweden.
    Ivarsson, Mikael
    Örebro University, School of Health Sciences.
    Kacarevic-Popovic, Z.
    Department of Radiation Chemistry and Physics, Vinca Institute of Nuclear Sciences, University of Belgrade, Belgrade, Serbia.
    Krstic, J.
    Department of Radiation Chemistry and Physics, Vinca Institute of Nuclear Sciences, University of Belgrade, Belgrade, Serbia.
    Wretenberg, Per
    Örebro University, School of Medical Sciences.
    The enhancement of cartilage regeneration by use of a chitosan-based scaffold in a 3D model of microfracture in vitro: a pilot evaluation2021In: Journal of experimental orthopaedics, E-ISSN 2197-1153, Vol. 8, no 1, article id 12Article in journal (Refereed)
    Abstract [en]

    Purpose: Even though various types of scaffolds have been used lately as a complement to microfracture, the exact mechanism of reported cartilage repair improvement when using scaffolds is still unclear. In this study, an effort has been made to identify the specific effects that scaffolds may have on the cells of reparation when using this technique.

    Methods: A 3‑D model in vitro, representing microfracture and containing both chondrocytes and bone marrow‑derived cells in different experimental conditions was made, and the cells were cultured for eight weeks. Subse‑quently, the constructs containing our 3‑D model were removed from the cell culture medium, fixed in paraffin and analyzed with immunohistochemistry.

    Results: Bone marrow – derived cells migrated to the upper compartment of the construct through a perforated nylon membrane containing both enzymatically digested‑ and non‑digested particulated cartilage. The histological sections were stained with hematoxylin, eosin, S‑100, SOX‑9, Gomori, and procollagen type I and II. When minced cartilage wasn’t pretreated with collagenase, exclusively bone‑derived cells have created new extracellular matrix as showed by the histological analysis.

    Conclusions: In this model of microfracture, bone‑derived cells but not chondrocytes have shown to have an active role in new cartilage formation without predigestion with collagenase. Moreover, it seems that the addition of a chitosan‑based scaffold may lead to the improvement of a new cartilage matrix synthesis and integration. This effect hasn’t been seen without the use of scaffold or when a fibrin‑ or a collagen‑based scaffold have been used.

  • 7.
    Arnsrud Godtman, Rebecka
    et al.
    Department of Urology, Institute of Clinical Sciences, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Hallsberg, Lena
    Department of Surgery, Institute of Clinical Sciences, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Löf-Öhlin, Zarah
    Örebro University, School of Medical Sciences. Örebro University Hospital. The Clinical Research Laboratory.
    Peeker, Ralph
    Department of Urology, Institute of Clinical Sciences, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Delbro, Dick
    Örebro University, School of Medical Sciences.
    Constitutive expression of inducible nitric oxide synthase in healthy rat urothelium?2021In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 55, no 6, p. 493-497Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Contrasting findings have been reported regarding a possible constitutive expression of inducible nitric oxide synthase (iNOS) in a normal mammalian bladder. The current study was designed to further investigate such putative iNOS expression.

    MATERIALS AND METHODS: The experiments were conducted with paraffin-embedded archival material from the urinary bladder of 6 normal, male Sprague-Dawley rats. In addition, two normal female mice (C57BL/6) were sacrificed and the urinary bladders were harvested. The occurrence of iNOS mRNA was examined by the RNAScope in situ hybridization method. Protein expression of iNOS and 3-nitrotyrosine (the latter used as an indicator of oxidative stress) was investigated by immunohistochemistry.

    RESULTS: No expression of iNOS mRNA was observed in the bladder tissue. iNOS protein and 3-nitrotyrosine were strongly expressed in the urothelium. iNOS was also expressed perinuclearly in the detrusor.

    CONCLUSIONS: Although the RNAScope methodology could not demonstrate mRNA for iNOS in the normal urinary bladder, the results by immunohistochemistry strongly suggest the occurrence of iNOS in particular, in the urothelium. Positive reactivity for 3-nitrotyrosine may indicate ongoing oxidative stress of the urothelium. The finding of perinuclear iNOS immunoreactivity could suggest an intracrine signaling function by iNOS to the nucleus.

  • 8.
    Asghar, Naveed
    et al.
    Örebro University, School of Medical Sciences.
    Jaafar, Rita
    Örebro University, School of Medical Sciences.
    Lindqvist, Carl Mårten
    Örebro University, School of Medical Sciences.
    Ljunberg, Karl
    Eurocine Vaccines AB, Solna, Sweden.
    Johansson, Magnus
    Örebro University, School of Medical Sciences.
    Design, rescue, and characterization of Langat virus infectious clone by next generation sequencing2023Conference paper (Other academic)
    Abstract [en]

    Tick-borne encephalitis (TBE) is one of the most important tick-transmitted diseases in Europe and Asia. TBE virus (TBEV) infections cause mild flu-like symptoms that may lead to severe neurological disorders. The incidence of TBE cases in Sweden has increase remarkably over the last decades. There is no specific antiviral treatment available against TBEV and vaccination remains the best protective measure. The currently available TBE vaccines require repeated injections for long-term immunity and vaccine failure can occur in some patients due to poor immunogenicity in the elderly. 

    Live attenuated viral vaccines are known to provide long-term immunity with fewer doses whereas the commercial TBE vaccines are based on single surface protein of the virus. We aim to develop a modified live attenuated TBE vaccine based on Langat virus (LGTV). LGTV is a naturally attenuated strain of TBEV. We aim to weaken the virus further by introducing modifications within LGTV genome. In this study we have successfully designed and rescued infectious clones of LGTV using RNA and DNA based strategies. We passaged these infections clones in cell culture and performed next generation sequencing to study similarity of rescued viruses to the parental LGTV sequence and their stability in cell culture. 

    Note: Visit my poster to discuss the results of next generation sequencing analysis and rescue strategies for LGTV infectious clones. 

  • 9.
    Aye, Cho-Cho
    et al.
    The Department of Cellular and Molecular Physiology, Institute of Translational Medicine, The University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
    Hammond, Dean E.
    The Department of Cellular and Molecular Physiology, Institute of Translational Medicine, The University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
    Rodriguez-Cuenca, Sergio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, UK.
    Doherty, Mary K.
    Division of Biomedical Sciences, Centre for Health Science, University of the Highlands and Islands, Old Perth Road, Inverness IV2 3JH, UK.
    Whitfield, Phillip D.
    Division of Biomedical Sciences, Centre for Health Science, University of the Highlands and Islands, Old Perth Road, Inverness IV2 3JH, UK; Glasgow Polyomics, College of Medical, Veterinary and Life Sciences, Garscube Campus, University of Glasgow, Glasgow G61 1BD, UK.
    Phelan, Marie M.
    Centre for Nuclear Magnetic Resonance, Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
    Yang, Chenjing
    The Department of Cellular and Molecular Physiology, Institute of Translational Medicine, The University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
    Perez-Perez, Rafael
    Instituto de Investigación, Hospital Universitario 12 de Octubre, Avda. de Córdoba s/n, 28041 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U723, 28029 Madrid, Spain.
    Li, Xiaoxin
    The Department of Cellular and Molecular Physiology, Institute of Translational Medicine, The University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
    Diaz-Ramos, Angels
    Institute for Research in Biomedicine, C/Baldiri Reixac 10, 08028 Barcelona, Spain.
    Peddinti, Gopal
    Technical Research Centre of Finland, 02044 Espoo, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Technical Research Centre of Finland, 02044 Espoo, Finland; Turku Centre for Biotechnology, University of Turku and Abo Akademi University, 20520 Turku, Finland.
    Vidal-Puig, Antonio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, UK; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
    Zorzano, Antonio
    Institute for Research in Biomedicine, C/Baldiri Reixac 10, 08028 Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain; Department de Bioquimica i Biomedicina, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain.
    Ugalde, Cristina
    Instituto de Investigación, Hospital Universitario 12 de Octubre, Avda. de Córdoba s/n, 28041 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U723, 28029 Madrid, Spain.
    Mora, Silvia
    The Department of Cellular and Molecular Physiology, Institute of Translational Medicine, The University of Liverpool, Crown Street, Liverpool L69 3BX, UK; Department de Bioquimica i Biomedicina, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain.
    CBL/CAP Is Essential for Mitochondria Respiration Complex I Assembly and Bioenergetics Efficiency in Muscle Cells2023In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 24, no 4, article id 3399Article in journal (Refereed)
    Abstract [en]

    CBL is rapidly phosphorylated upon insulin receptor activation. Mice whole body CBL depletion improved insulin sensitivity and glucose clearance; however, the precise mechanisms remain unknown. We depleted either CBL or its associated protein SORBS1/CAP independently in myocytes and assessed mitochondrial function and metabolism compared to control cells. CBL- and CAP-depleted cells showed increased mitochondrial mass with greater proton leak. Mitochondrial respiratory complex I activity and assembly into respirasomes were reduced. Proteome profiling revealed alterations in proteins involved in glycolysis and fatty acid degradation. Our findings demonstrate CBL/CAP pathway couples insulin signaling to efficient mitochondrial respiratory function and metabolism in muscle.

  • 10.
    Barbarroja, Nuria
    et al.
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
    Rodriguez-Cuenca, Sergio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Nygren, Heli
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Camargo, Antonio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Lipids and Atherosclerosis Research Unit, Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
    Pirraco, Ana
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, Porto, Portugal.
    Relat, Joana
    Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain.
    Cuadrado, Irene
    Departamento de Farmacología, Universidad Complutense de Madrid, Madrid, Spain.
    Pellegrinelli, Vanessa
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Medina-Gomez, Gema
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Lopez-Pedrera, Chary
    Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
    Tinahones, Francisco J.
    CIBER in Physiopathology of Obesity and Nutrition (CB06/03), Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigación Biomédica de Málaga, Hospital Virgen de la Victoria, Malaga, Spain.
    Symons, J. David
    College of Health, University of Utah, Salt Lake City UT, United States; Division of Endocrinology, Metabolism, and Diabetes, University of Utah, Salt Lake City UT, United States.
    Summers, Scott A.
    Program in Cardiovascular and Metabolic Disorders, Duke-National University, Singapore Graduate Medical School, Singapore, Singapore.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Vidal-Puig, Antonio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Increased dihydroceramide/ceramide ratio mediated by defective expression of degs1 impairs adipocyte differentiation and function2015In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 4, p. 1180-1192Article in journal (Refereed)
    Abstract [en]

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

  • 11.
    Basic, Vladimir
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Molecular mechanisms mediating development of pulmonary cachexia in COPD2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

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

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

    Funding Agencies:

    Olle Engkvist Byggmastare Fund, Sweden

    NIEHS Environmental Health Science Center grant 

    Available from: 2012-07-31 Created: 2012-07-31 Last updated: 2024-01-03Bibliographically approved
    2. Chronic cigarette smoke exposureimpairs skeletal muscle regenerative capacity in murineCOPD/emphysema model.
    Open this publication in new window or tab >>Chronic cigarette smoke exposureimpairs skeletal muscle regenerative capacity in murineCOPD/emphysema model.
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

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

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

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

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

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

    Funding and support:

    Olle Engkvist Byggmästare Fund,

    Åke WibergFoundation, Sweden

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

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

    Available from: 2014-10-27 Created: 2014-10-27 Last updated: 2024-01-03Bibliographically approved
    3. TNF stimulation induces VHL overexpression and impairs angiogenic potential in skeletal muscle myocytes
    Open this publication in new window or tab >>TNF stimulation induces VHL overexpression and impairs angiogenic potential in skeletal muscle myocytes
    2014 (English)In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 34, no 1, p. 228-236Article in journal (Refereed) Published
    Abstract [en]

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

    Place, publisher, year, edition, pages
    Spandidos Publications, 2014
    National Category
    Medical Biotechnology
    Research subject
    Medical Disability Research
    Identifiers
    urn:nbn:se:oru:diva-35141 (URN)10.3892/ijmm.2014.1776 (DOI)000338178000027 ()24820910 (PubMedID)2-s2.0-84902649801 (Scopus ID)
    Available from: 2014-05-25 Created: 2014-05-25 Last updated: 2024-01-03Bibliographically approved
    4. Cigarette smoke exposure up-regulates Ubiquitin specific protease 19 in murine skeletal muscles as an adaptive response to prolonged ER stress
    Open this publication in new window or tab >>Cigarette smoke exposure up-regulates Ubiquitin specific protease 19 in murine skeletal muscles as an adaptive response to prolonged ER stress
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

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

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

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

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

    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-38194 (URN)
    Available from: 2014-10-27 Created: 2014-10-27 Last updated: 2024-01-03Bibliographically approved
    5. The periodontal pathogen Porphyromonas gingivalis changes the gene expression in vascular smooth muscle cells involving the TGFbeta/Notch signalling pathway and increased cell proliferation
    Open this publication in new window or tab >>The periodontal pathogen Porphyromonas gingivalis changes the gene expression in vascular smooth muscle cells involving the TGFbeta/Notch signalling pathway and increased cell proliferation
    Show others...
    2013 (English)In: BMC Genomics, E-ISSN 1471-2164, Vol. 14, p. 770-Article in journal (Refereed) Published
    Abstract [en]

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

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

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

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

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

    Available from: 2014-01-24 Created: 2014-01-24 Last updated: 2024-01-17Bibliographically approved
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  • 12.
    Bettoni, Serena
    et al.
    Lund University - Department of Translational Medicine, Malmö, Sweden.
    Shaughnessy, Jutamas
    Department of Medicine, Division of Infectious Diseases, University of Massachusetts Medical School, Worcester, USA.
    Maziarz, Karolina
    Lund University - Department of Translational Medicine, Malmö, Sweden.
    Ermert, David
    Lund University - Department of Translational Medicine, Malmö, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for STIs, Department of Laboratory Medicine.
    Riesbeck, Kristian
    Lund University - Department of Translational Medicine, Malmö, Sweden.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for STIs, Department of Laboratory Medicine.
    Blom, Anna
    Lund University - Department of Translational Medicine, Malmö, Sweden.
    Ram, Sanjay
    Department of Medicine, Division of Infectious Diseases, University of Massachusetts Medical School, Worcester, USA.
    C4BP-IGM FUSION PROTEIN AS A NOVEL THERAPEUTIC APPROACH TO TREAT NEISSERIA GONORRHOEAE INFECTIONS2019In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 114, p. 470-470Article in journal (Other academic)
  • 13.
    Bilbija, Dusan
    et al.
    University of Oslo, Oslo, Norway.
    Elmabsout, Ali Ateia
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sagave, Julia
    University of Oslo, Oslo, Norway.
    Haugen, Fred
    University of Oslo, Oslo, Norway.
    Bastani, Nasser
    Departments of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Dahl, Christen Peder
    University of Oslo, Oslo, Norway; Department of Cardiology, Oslo University Hospital, Oslo, Norway .
    Gullestad, Lars
    University of Oslo, Oslo, Norway; Department of Cardiology, Oslo University Hospital, Oslo, Norway.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Blomhoff, Rune
    Departments of Nutrition, Institute of Basic Medical Sciences, Oslo University, Oslo, Norway.
    Valen, Guro
    University of Oslo, Oslo, Norway.
    Expression of retinoic acid target genes in coronary artery disease2014In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 33, no 3, p. 677-86Article in journal (Refereed)
    Abstract [en]

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

  • 14.
    Bilbija, Dusan
    et al.
    Department of Physiology, University of Oslo, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Haugen, Fred
    Department of Physiology, University of Oslo, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Sagave, Julia
    Department of Physiology, University of Oslo, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Baysa, Anton
    Department of Physiology, University of Oslo, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Bastani, Nasser
    Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway .
    Levy, Finn Olav
    Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Division of Biomedicine, Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Blomhoff, Rune
    Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway .
    Valen, Guro
    Department of Physiology, University of Oslo, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Retinoic acid signalling is activated in the postischemic heart and may influence remodelling2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 9, article id e44740Article in journal (Refereed)
    Abstract [en]

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

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

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

  • 15.
    Bowden, John A.
    et al.
    Marine Biochemical Sciences Group, Chemical Sciences Division, Hollings Marine Laboratory, National Institute of Standards and Technology, Charleston SC, USA.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Hollings Marine Laboratory, Marine Biochemical Sciences Group, National Institute of Standards and Technology, Charleston SC, United States; Division of Laboratory Sciences, Centers for Disease Control and Prevention, Atlanta GA, United States.
    Zhou, Senlin
    Department of Chemistry and Biochemistry, Wayne State University, Detroit MI, USA.
    Harmonizing Lipidomics: NIST Interlaboratory Comparison Exercise for Lipidomics using Standard Reference Material 1950 Metabolites in Frozen Human Plasma2017In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 58, no 12, p. 2275-2288Article in journal (Refereed)
    Abstract [en]

    As the lipidomics field continues to advance, self-evaluation within the community is critical. Here, we performed an interlaboratory comparison exercise for lipidomics using Standard Reference Material (SRM) 1950 Metabolites in Frozen Human Plasma, a commercially available reference material. The interlaboratory study comprised 31 diverse laboratories, with each lab using a different lipidomics workflow. A total of 1527 unique lipids were measured across all laboratories, and consensus location estimates and associated uncertainties were determined for 339 of these lipids measured at the sum composition level by five or more participating laboratories. These evaluated lipids detected in SRM 1950 serve as community-wide benchmarks for intra- and inter-laboratory quality control and method validation. These analyses were performed using non-standardized laboratory-independent workflows. The consensus locations were also compared to a previous examination of SRM 1950 by the LIPID MAPS consortium. While the central theme of the interlaboratory study was to provide values to help harmonize lipids, lipid mediators, and precursor measurements across the community, it was also initiated to stimulate a discussion regarding areas in need of improvement.

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

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

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

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

  • 18.
    Burm, Rani
    et al.
    Laboratory of Liver Infectious Diseases (LLID), Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
    Maravelia, Panagiota
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ahlen, Gustaf
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ciesek, Sandra
    Institute for Medical Virology, University Hospital, Goethe University, Frankfurt am Main, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany; German Center for Infection Research, DZIF, External partner site, Frankfurt am Main, Germany.
    Caro Perez, Noelia
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Pasetto, Anna
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Urban, Stephan
    Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany.
    Van Houtte, Freya
    Laboratory of Liver Infectious Diseases (LLID), Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
    Verhoye, Lieven
    Laboratory of Liver Infectious Diseases (LLID), Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
    Wedemeyer, Heiner
    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
    Johansson, Magnus
    Örebro University, School of Medical Sciences.
    Frelin, Lars
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Sällberg, Matti
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Meuleman, Philip
    Laboratory of Liver Infectious Diseases (LLID), Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
    Novel prime-boost immune-based therapy inhibiting both hepatitis B and D virus infections.2023In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 72, no 6, p. 1186-1195Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Chronic HBV/HDV infections are a major cause of liver cancer. Current treatments can only rarely eliminate HBV and HDV. Our previously developed preS1-HDAg immunotherapy could induce neutralising antibodies to HBV in vivo and raise HBV/HDV-specific T-cells. Here, we further investigate if a heterologous prime-boost strategy can circumvent T-cell tolerance and preclude HDV superinfection in vivo.

    DESIGN: A DNA prime-protein boost strategy was evaluated for immunogenicity in mice and rabbits. Its ability to circumvent T-cell tolerance was assessed in immunocompetent hepatitis B surface antigen (HBsAg)-transgenic mice. Neutralisation of HBV and HDV was evaluated both in vitro and in immunodeficient human-liver chimeric mice upon adoptive transfer.

    RESULTS: The prime-boost strategy elicits robust HBV/HDV-specific T-cells and preS1-antibodies that can effectively prevent HBV and HDV (co-)infection in vitro and in vivo. In a mouse model representing the chronic HBsAg carrier state, active immunisation primes high levels of preS1-antibodies and HDAg-specific T-cells. Moreover, transfer of vaccine-induced antibodies completely protects HBV-infected human-liver chimeric mice from HDV superinfection.

    CONCLUSION: The herein described preS1-HDAg immunotherapy is shown to be immunogenic and vaccine-induced antibodies are highly effective at preventing HBV and HDV (super)infection both in vitro and in vivo. Our vaccine can complement current and future therapies for the control of chronic HBV and HDV infection.

  • 19.
    Caesar, Robert
    et al.
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
    Nygren, Heli
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Orešič, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center A/S, Gentofte, Denmark.
    Bäckhed, Fredrik
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
    Interaction between dietary lipids and gut microbiota regulates hepatic cholesterol metabolism2016In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 57, no 3, p. 474-481Article in journal (Refereed)
    Abstract [en]

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

  • 20.
    Castro Alves, Victor
    et al.
    Department of Food Science and Experimental Nutrition, University of São Paulo, São Paulo, Brazil.
    Cordenunsi, Beatriz R.
    Food and Nutrition Research Center, University of São Paulo, São Paulo, Brazil; Department of Food Science and Experimental Nutrition, University of São Paulo, São Paulo, Brazil .
    Total Soluble Phenolic Compounds Quantification Is Not As Simple As It Seems2015In: Food Analytical Methods, ISSN 1936-9751, E-ISSN 1936-976X, Vol. 8, no 4, p. 873-884Article in journal (Refereed)
    Abstract [en]

    Despite the important role of total soluble phenoliccompounds (TSPC) in plant and human health, a large numberof studies that have evaluated the TSPC in food matrices didnot consider possible interfering compounds such as solublesugars, ascorbic acid (AA), and other reducing compounds inthe Folin-Ciocalteu (F-C) quantification method. Thus, thepresent study describes steps for the optimization of a meth-odology to extract the TSPC using banana leaves as an exam-ple. In addition, the method was tested using ascorbate oxi-dase (AOX) as a tool to determine and emphasize the impor-tance of the evaluation of AA interference in food productsusing orange juice as an example. The results showed that twoextraction cycles with 80 % acetone and a posterior hexaneextraction cycle to remove the excess of chlorophylls wereable to obtain a good TSPC extraction yield from bananaleaves without extracting compounds that may interfere withthe F-C method. The methodology has proven to be accurate,precise, simple, rapid, and inexpensive. Additionally, an over-estimation of the TSPC levels in AA-rich matrices was provenusing orange juice as an example. Finally, it was demonstratedthat the use of AOX could be a useful and simple tool to verifyand reduce the AA interference. This work proves and em-phasizes the importance of evaluating the yield of the extrac-tion and interferences in the quantification of the TSPC invegetal-derived foods, which are complex matrices thatshould be cautiously evaluated.

  • 21.
    Chau, Michael
    et al.
    Division of Pediatric Endocrinology and Center for Molecular Medicine, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden; Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
    Dou, Zelong
    Division of Pediatric Endocrinology and Center for Molecular Medicine, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Baroncelli, Marta
    Division of Pediatric Endocrinology and Center for Molecular Medicine, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Landman, Ellie B.
    Division of Pediatric Endocrinology and Center for Molecular Medicine, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Bendre, Ameya
    Division of Pediatric Endocrinology and Center for Molecular Medicine, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Kanekiyo, Masaru
    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
    Gkourogianni, Alexandra
    Division of Pediatric Endocrinology and Center for Molecular Medicine, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Barnes, Kevin
    Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA..
    Ottosson, Lars
    Division of Pediatric Endocrinology and Center for Molecular Medicine, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Division of Pediatric Endocrinology and Center for Molecular Medicine, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden; Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA; Department of Pediatrics, University Hospital, Örebro, Sweden.
    The synovial microenvironment suppresses chondrocyte hypertrophy and promotes articular chondrocyte differentiation2022In: NPJ Regenerative medicine, E-ISSN 2057-3995, Vol. 7, no 1, article id 51Article in journal (Refereed)
    Abstract [en]

    During the development of the appendicular skeleton, the cartilaginous templates undergo hypertrophic differentiation and remodels into bone, except for the cartilage most adjacent to joint cavities where hypertrophic differentiation and endochondral bone formation are prevented, and chondrocytes instead form articular cartilage. The mechanisms that prevent hypertrophic differentiation and endochondral bone formation of the articular cartilage have not been elucidated. To explore the role of the synovial microenvironment in chondrocyte differentiation, osteochondral allografts consisting of articular cartilage, epiphyseal bone, and growth plate cartilage from distal femoral epiphyses of inbred Lewis rats expressing enhanced green fluorescent protein from a ubiquitous promoter were transplanted either in inverted or original (control) orientation to matching sites in wildtype littermates, thereby allowing for tracing of transplanted cells and their progenies. We found that no hypertrophic differentiation occurred in the growth plate cartilage ectopically placed at the joint surface. Instead, the transplanted growth plate cartilage, with time, remodeled into articular cartilage. This finding suggests that the microenvironment at the articular surface inhibits hypertrophic differentiation and supports articular cartilage formation. To explore this hypothesis, rat chondrocyte pellets were cultured with and without synoviocyte-conditioned media. Consistent with the hypothesis, hypertrophic differentiation was inhibited and expression of the articular surface marker lubricin (Prg4) was dramatically induced when chondrocyte pellets were exposed to synovium- or synoviocyte-conditioned media, but not to chondrocyte- or osteoblast-conditioned media. Taken together, we present evidence for a novel mechanism by which synoviocytes, through the secretion of a factor or factors, act directly on chondrocytes to inhibit hypertrophic differentiation and endochondral bone formation and promote articular cartilage formation. This mechanism may have important implications for articular cartilage development, maintenance, and regeneration.

  • 22.
    Deane, Colleen S.
    et al.
    Department of Sport and Health Sciences, College of Life and Environmental Sciences, University of Exeter, UK.
    Ames, Ryan M.
    Living Systems Institute, University of Exeter, Exeter, UK.
    Phillips, Bethan E.
    MRC ‐ ARUK Centre of Research Excellence and National Institute of Health Research, Biomedical Research Centre, Postgraduate Entry Medical School, Royal Derby Hospital Centre, School of Medicine, University of Nottingham, Derby, UK.
    Weedon, Michael N.
    Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
    Willis, Craig R. G.
    Department of Sport and Health Sciences, College of Life and Environmental Sciences, University of Exeter, UK.
    Boereboom, Catherine
    MRC ‐ ARUK Centre of Research Excellence and National Institute of Health Research, Biomedical Research Centre, Postgraduate Entry Medical School, Royal Derby Hospital Centre, School of Medicine, University of Nottingham, Derby, UK.
    Abdulla, Haitham
    MRC ‐ ARUK Centre of Research Excellence and National Institute of Health Research, Biomedical Research Centre, Postgraduate Entry Medical School, Royal Derby Hospital Centre, School of Medicine, University of Nottingham, Derby, UK.
    Bukhari, Syed S. I.
    MRC ‐ ARUK Centre of Research Excellence and National Institute of Health Research, Biomedical Research Centre, Postgraduate Entry Medical School, Royal Derby Hospital Centre, School of Medicine, University of Nottingham, Derby, UK.
    Lund, Jonathan N.
    Department of Surgery, Postgraduate Entry Medical School, Royal Derby Hospital Centre, School of Medicine, University of Nottingham, Derby, UK.
    Williams, John P.
    MRC ‐ ARUK Centre of Research Excellence and National Institute of Health Research, Biomedical Research Centre, Postgraduate Entry Medical School, Royal Derby Hospital Centre, School of Medicine, University of Nottingham, Derby, UK.
    Wilkinson, Daniel J.
    MRC ‐ ARUK Centre of Research Excellence and National Institute of Health Research, Biomedical Research Centre, Postgraduate Entry Medical School, Royal Derby Hospital Centre, School of Medicine, University of Nottingham, Derby, UK.
    Smith, Kenneth
    MRC ‐ ARUK Centre of Research Excellence and National Institute of Health Research, Biomedical Research Centre, Postgraduate Entry Medical School, Royal Derby Hospital Centre, School of Medicine, University of Nottingham, Derby, UK.
    Gallagher, Iain J.
    Faculty of Health Sciences and Sport, University of Stirling, Stirling, UK.
    Kadi, Fawzi
    Örebro University, School of Health Sciences.
    Szewczyk, Nathaniel J.
    MRC ‐ ARUK Centre of Research Excellence and National Institute of Health Research, Biomedical Research Centre, Postgraduate Entry Medical School, Royal Derby Hospital Centre, School of Medicine, University of Nottingham, Derby, UK.
    Atherton, Philip J.
    MRC ‐ ARUK Centre of Research Excellence and National Institute of Health Research, Biomedical Research Centre, Postgraduate Entry Medical School, Royal Derby Hospital Centre, School of Medicine, University of Nottingham, Derby, UK.
    Etheridge, Timothy
    Department of Sport and Health Sciences, College of Life and Environmental Sciences, University of Exeter, UK.
    The acute transcriptional response to resistance exercise: impact of age and contraction mode2019In: Aging, ISSN 1945-4589, E-ISSN 1945-4589, Vol. 11, no 7, p. 2111-2126Article in journal (Refereed)
    Abstract [en]

    Optimization of resistance exercise (RE) remains a hotbed of research for muscle building and maintenance. However, the interactions between the contractile components of RE (i.e. concentric (CON) and eccentric (ECC)) and age, are poorly defined. We used transcriptomics to compare age-related molecular responses to acute CON and ECC exercise. Eight young (21 +/- 1 y) and eight older (70 +/- 1 y) exercise-naive male volunteers had vastus lateralis biopsies collected at baseline and 5 h post unilateral CON and contralateral ECC exercise. RNA was subjected to next-generation sequencing and differentially expressed (DE) genes tested for pathway enrichment using Gene Ontology (GO). The young transcriptional response to CON and ECC was highly similar and older adults displayed moderate contraction-specific profiles, with no GO enrichment. Age-specific responses to ECC revealed 104 DE genes unique to young, and 170 DE genes in older muscle, with no GO enrichment. Following CON, 15 DE genes were young muscle-specific, whereas older muscle uniquely expressed 147 up-regulated genes enriched for cell adhesion and blood vessel development, and 28 down-regulated genes involved in mitochondria! respiration, amino acid and lipid metabolism. Thus, older age is associated with contraction-specific regulation often without clear functional relevance, perhaps reflecting a degree of stochastic age-related dysregulation.

  • 23.
    Dou, Zelong
    et al.
    Division of Pediatric Endocrinology and Center for Molecular Medicine, L8:01, Department of Women’s and Children’s Health, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Chau, Michael
    Division of Pediatric Endocrinology and Center for Molecular Medicine, L8:01, Department of Women’s and Children’s Health, Karolinska Institutet and University Hospital, Stockholm, Sweden; Department of Orthopedic Surgery, University of Minnesota, Minneapolis-St. Paul MN, United States.
    Muder, Daniel
    Department of Surgical Sciences, Uppsala University, Uppsala, Sweden ; Department of Orthopedics, Falu Lasarett, Falun, Sweden.
    Vedung, Torbjörn
    Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; Elisabeth Hospital, Aleris Healthcare, Uppsala, Sweden .
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Division of Pediatric Endocrinology and Center for Molecular Medicine, L8:01, Department of Women’s and Children’s Health, Karolinska Institutet and University Hospital, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
    Optimized protocols for in situ hybridization, immunohistochemistry, and immunofluorescence on skeletal tissue2021In: Acta Histochemica, ISSN 0065-1281, E-ISSN 1618-0372, Vol. 123, no 5, article id 151747Article in journal (Refereed)
    Abstract [en]

    Assessment of gene and protein expression in tissue sections is instrumental in medical research. However, this is often challenging to perform on skeletal tissues that require prolonged decalcification and have poor adhesion to slides. In this study, we optimized selected steps of in situ hybridization (ISH), immunohistochemistry (IHC), and immunofluorescence (IF) for formalin fixed and decalcified skeletal tissues. Sections from distal femur of 6-, 8- and 14-week-old rats injected with BrdU with or without a hemizygous eGFP transgene expressed under the control of a ubiquitous promotor were used. We report that proteinase K digestion is critical for the sensitivity of ISH, as concentrations that were too strong and too mild both resulted in loss of signal. In addition, intensified RNase A digestion removed nonspecific riboprobe-mRNA hybrids. Furthermore, enzymatic antigen retrieval using proteinase K provided more consistent results in IHC and can therefore be a useful alternative to heat induced epitope retrieval (HIER) for skeletal tissues where such treatment often damages the morphology. A mild proteinase K digestion also improved IF detection of GFP and worked well for double labeling IF of GFP and osteocalcin on frozen sections of formalin fixed and decalcified rat bones while maintaining morphology. In summary, this study provides strategies to improve protocols for enzymatic digestion in ISH, IHC, and IF for skeletal tissues and also demonstrates the importance of careful optimization and validation with the use of these techniques.

  • 24.
    Dou, Zelong
    et al.
    Division of Pediatric Endocrinology and Center for Molecular Medicine, L8:01, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Muder, Daniel
    Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Baroncelli, Marta
    Division of Pediatric Endocrinology and Center for Molecular Medicine, L8:01, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Bendre, Ameya
    Division of Pediatric Endocrinology and Center for Molecular Medicine, L8:01, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Gkourogianni, Alexandra
    Division of Pediatric Endocrinology and Center for Molecular Medicine, L8:01, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Ottosson, Lars
    Division of Pediatric Endocrinology and Center for Molecular Medicine, L8:01, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Vedung, Torbjörn
    Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; Elisabeth Hospital, Aleris Healthcare, Uppsala, Sweden.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Division of Pediatric Endocrinology and Center for Molecular Medicine, L8:01, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden; School of Medical Sciences, Örebro University Hospital, Örebro, Sweden.
    Rat perichondrium transplanted to articular cartilage defects forms articular-like, hyaline cartilage2021In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 151, article id 116035Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Perichondrium autotransplants have been used to reconstruct articular surfaces destroyed by infection or trauma. However, the role of the transplanted perichondrium in the healing of resurfaced joints have not been investigated.

    DESIGN: Perichondrial and periosteal tissues were harvested from rats hemizygous for a ubiquitously expressed enhanced green fluorescent protein (EGFP) transgene and transplanted into full-thickness articular cartilage defects at the trochlear groove of distal femur in wild-type littermates. As an additional control, cartilage defects were left without a transplant (no transplant control). Distal femurs were collected 3, 14, 56, 112 days after surgery.

    RESULTS: Tracing of transplanted cells showed that both perichondrium and periosteum transplant-derived cells made up the large majority of the cells in the regenerated joint surfaces. Perichondrium transplants contained SOX9 positive cells and with time differentiated into a hyaline cartilage that expanded and filled out the defects with Col2a1-positive and Col1a1-negative chondrocytes and a matrix rich in proteoglycans. At later timepoints the cartilaginous perichondrium transplants were actively remodeled into bone at the transplant-bone interface and at post-surgery day 112 EGFP-positive perichondrium cells at the articular surface were positive for Prg4. Periosteum transplants initially lacked SOX9 expression and despite a transient increase in SOX9 expression and chondrogenic differentiation, remained Col1a1 positive, and were continuously thinning as periosteum-derived cells were incorporated into the subchondral compartment.

    CONCLUSIONS: Perichondrium and periosteum transplanted to articular cartilage defects did not just stimulate regeneration but were themselves transformed into cartilaginous articular surfaces. Perichondrium transplants developed into an articular-like, hyaline cartilage, whereas periosteum transplants appeared to produce a less resilient fibro-cartilage.

  • 25.
    Elander, Nils
    et al.
    Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping, Sweden.
    Söderkvist, Peter
    Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping, Sweden.
    Fransén, Karin
    Örebro University, School of Medical Sciences. Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping, Sweden.
    Matrix metalloproteinase (MMP) -1, -2, -3 and -9 promoter polymorphisms in colorectal cancer2006In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 26, no 1B, p. 791-795, article id 16739355Article in journal (Refereed)
    Abstract [en]

    Background: Matrix metalloproteinases (MMPs) are a group of matrix-degrading proteins implicated in several pathological processes, e.g., invasion and metastasis in malignant diseases such as colorectal cancer (CRC).

    Materials and methods: One hundred and twenty-seven CRC patients and 208 controls were genotyped for MMP-1, -2, -3 and -9 promoter polymorphisms. The genotyping was performed with PCR/primer-extension/DHPLC or PCR/RFLP.

    Results: The MMP-1 2G allele was significantly associated with CRC (p=0.037). No significant association between CRC and MMP-2, -3 or -9 polymorphisms was evident. The analysis of polymorphisms in the clinicopathological subgroups displayed no significant associations.

    Conclusion: The MMP-1 promoter polymorphism seems to affect the susceptibility to CRC, while MMP-2, -3 and -9 polymorphisms appear less likely to have any impact on CRC.

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

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

  • 27.
    Elmabsout, Ali Ateia
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Kumawat, Ashok K.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Saenz-Méndez, Patricia
    Computational Chemistry and Biology Group, Facultad de Química, UdelaR, Montevideo, Uruguay.
    Krivospitskaya, Olesya
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sävenstrand, Helena
    Örebro University, School of Science and Technology.
    Olofsson, Peder S.
    Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Stockholm, Sweden; Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset NY, United States of America.
    Eriksson, Leif A.
    Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden.
    Strid, Åke
    Örebro University, School of Science and Technology.
    Valen, Guro
    Department of Physiology, Institute of Basic Medical Science and Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Törmä, Hans
    Department of Medical Sciences, Dermatology and Venereology, Uppsala University, Uppsala, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Cloning and functional studies of a splice variant of CYP26B1 expressed in vascular cells2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 5, article id e36839Article in journal (Refereed)
    Abstract [en]

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

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

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

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  • 28.
    Elvers, Margitta
    et al.
    Medizinische Klinik III, Dept. of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany.
    Grenegård, Magnus
    Faculty of Health Sciences, Department of Medicine and Health, Division of Drug Research/Pharmacology, University of Linköping, Linköping, Sweden.
    Khoshjabinzadeh, Hanieh
    Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, University of Linköping, Linköping, Sweden.
    Münzer, Patrick
    Department of Physiology, Eberhard Karls University, Tübingen, Germany.
    Borst, Oliver
    Medizinische Klinik III, Dept. of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany; Department of Physiology, Eberhard Karls University, Tübingen, Germany.
    Tian, Huasong
    Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, USA.
    Di Paolo, Gilbert
    Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, USA.
    Lang, Florian
    Department of Physiology, Eberhard Karls University, Tübingen, Germany.
    Gawaz, Meinrad
    Medizinische Klinik III, Dept. of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany.
    Lindahl, Tomas L
    Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, Linköping University, Linköping, Sweden.
    Fälker, Knut
    Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, Linköping University, Linköping, Sweden.
    A novel role for phospholipase D as an endogenous negative regulator of platelet sensitivity2012In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 24, no 9, p. 1743-52Article in journal (Refereed)
    Abstract [en]

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

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

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

  • 30.
    Eriksson, Anders
    et al.
    Ludwig Institute for Cancer Research, Uppsala, Sweden.
    Nånberg, Eewa
    Department of Pathology, University Hospital, Uppsala, Sweden.
    Rönnstrand, Lars
    Ludwig Institute for Cancer Research, Uppsala, Sweden.
    Engström, Ulla
    Ludwig Institute for Cancer Research, Uppsala, Sweden.
    Hellman, Ulf
    Ludwig Institute for Cancer Research, Uppsala, Sweden.
    Rupp, Eva
    Ludwig Institute for Cancer Research, Uppsala, Sweden.
    Carpenter, Graham
    Department of Biochemistry, School of Medicine, Vanderbilt University, Nashville, Tennessee.
    Heldin, Carl-Henrik
    Ludwig Institute for Cancer Research, Uppsala, Sweden.
    Claesson-Welsh, Lena
    Ludwig Institute for Cancer Research, Uppsala, Sweden.
    Demonstration of functionally different interactions between phospholipase C-gamma and the two types of platelet-derived growth factor receptors1995In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 270, no 13, p. 7773-7781Article in journal (Refereed)
    Abstract [en]

    Phosphorylated tyrosine residues in receptor tyrosine kinases serve as binding sites for signal transduction molecules. We have identified two autophosphorylation sites, Tyr-988 and Tyr-1018, in the platelet-derived growth factor (PDGF) alpha-receptor carboxyl-terminal tail, which are involved in binding of phospholipase C-gamma (PLC-gamma). The capacities of the Y988F and Y1018F mutant PDGF alpha-receptors, expressed in porcine aortic endothelial cells, to bind PLC-gamma are 60 and 5% of that of the wild-type receptor, respectively. Phosphorylated but not unphosphorylated peptides containing Tyr-1018 are able to compete with the intact receptor for binding to immobilized PLC-gamma SH2 domains; a phosphorylated Tyr-988 peptide competes 10 times less efficiently. The complex between PLC-gamma and the PDGF alpha-receptor is more stable than that of PLC-gamma and the PDGF beta-receptor. However, PDGF stimulation results in a smaller fraction of tyrosine-phosphorylated PLC-gamma and a smaller accumulation of inositol trisphosphate in cells expressing the alpha-receptor as compared with cells expressing the beta-receptor. We conclude that phosphorylated Tyr-988 and Tyr-1018 in the PDGF alpha-receptor carboxyl-terminal tail bind PLC-gamma, but this association leads to only a relatively low level of tyrosine phosphorylation and activation of PLC-gamma.

  • 31.
    Eriksson, Katarina
    et al.
    Department of Obstetrics and Gynecology, Ålands Centralsjukhus, Mariehamn, Finland; Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköpings University, Linköping, Sweden.
    Adolfsson, Annsofie
    Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköpings University, Linköping, Sweden; Department of Obstetrics and Gynecology, Kärnsjukhuset, Skövde, Sweden; School of Life Sciences, University of Skövde, Skövde, Sweden.
    Forsum, Urban
    Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköpings University, Linköping, Sweden.
    Larsson, Per-Göran
    Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköpings University, Linköping, Sweden; Department of Obstetrics and Gynecology, Kärnsjukhuset, Skövde, Sweden; School of Life Sciences, University of Skövde, Skövde, Sweden.
    The prevalence of BV in the population on the Åland Islands during a 15-year period2010In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 118, no 11, p. 903-908Article in journal (Refereed)
    Abstract [en]

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

  • 32.
    Eriksson, Leif A.
    et al.
    Göteborgs universitet, Göteborg.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Strid, Åke
    Örebro University, School of Science and Technology.
    Tetrazole derivatives as cytochrome p450 inhibitors2019Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    According to the invention there is provided a compound of formula I, wherein Rand Rhave meanings given in the description, which compounds are useful in the treatment of skin disorders and other diseases.

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    Patent
  • 33.
    Fagerström, Sofia
    et al.
    Department of Pathology, University Hospital, Uppsala, Sweden.
    Påhlman, Sven
    Department of Pathology, University Hospital, Uppsala, Sweden.
    Gestblom, Carolina
    Department of Pathology, University Hospital, Uppsala, Sweden.
    Nånberg, Eewa
    Department of Pathology, University Hospital, Uppsala, Sweden.
    Protein kinase C-epsilon is implicated in neurite outgrowth in differentiating human neuroblastoma cells1996In: Cell growth & differentiation, ISSN 1044-9523, Vol. 7, no 6, p. 775-785Article in journal (Refereed)
    Abstract [en]

    A combination of basic fibroblast growth factor (bFGF) and insulin-like growth factor-I (IGF-I) or 16 nM 12-O-tetradecanoylphorbol-13-acetate (TPA) and serum induces human SH-SY5Y neuroblastoma cells to undergo differentiation and acquire a neuronal phenotype. Nerve growth factor (NGF) added to SH-SY5Y cells stably transfected with the NGF-receptor TRK-A (SH-SY5Y/trk) induces a similar differentiated phenotype. SH-SY5Y cells express protein kinase C (PKC)-alpha, PKC-beta I, PKC-epsilon, and PKC-zeta protein, and phorbol ester- or growth factor-induced differentiation results in a sustained activation of PKC. The specific PKC inhibitor GF 109203X blocked TPA- and bFGF-IGF-I-induced neurite outgrowth in wild-type SH-SY5Y cells and NGF-induced neurite outgrowth in SH-SY5Y/trk cells. When added to differentiated cells, GF 109203X caused rapid retraction of growth cone filopodia. In TPA- and bFGF-IGF-I-treated cells, addition of GF 109203X also blocked induced expression of growth associated protein-43 and neuropeptide tyrosine while the increase in expression of these two genes was only slightly affected by the inhibitor in NGF-treated SH-SY5Y/trk cells. Thus, a portion of the NGF-induced phenotypic changes appears not to be mediated via PKC-dependent signaling. A high concentration of TPA (1.6 microM) down regulated PKC-alpha and PKC-beta I almost completely and PKC-epsilon partially in wild-type SH-SY5Y and SH-SY5Y/trk cells. Cells with down-regulated PKC-alpha and PKC-beta I after 1.6 microM TPA treatment still differentiated with growth factors. In these cells, the PKC-epsilon level was restored, and the PKC-epsilon protein was enriched in the growth cones. The 1.6 microM TPA-induced down-regulation of PKC-epsilon was counteracted by bFGF and NGF but not by platelet-derived growth factor or IGF-I. These data indicate that PKC activity is vital for neurite formation, and that the cells can differentiate under conditions when PKC-alpha and PKC-beta I are extensively down regulated. The close correlation between differentiation and presence of PKC-epsilon protein suggests an important function for this isoform during this process.

  • 34.
    Fagerström, Sofia
    et al.
    Department of Laboratory Medicine, Lund University, University Hospital MAS, Malmö.
    Påhlman, Sven
    Department of Laboratory Medicine, Lund University, University Hospital MAS, Malmö.
    Nånberg, Eewa
    Department of Pathology, University Hospital, Uppsala, Sweden.
    Protein kinase C-dependent tyrosine phosphorylation of p130cas in differentiating neuroblastoma cells1998In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 273, no 4, p. 2336-2343Article in journal (Refereed)
    Abstract [en]

    The cell signaling docking protein p130cas became tyrosine-phosphorylated in SH-SY5Y human neuroblastoma cells during induced differentiation with 12-O-tetradecanoylphorbol-13-acetate (TPA) and serum or a combination of basic fibroblast growth factor (bFGF) and insulin-like growth factor-I (IGF-I). The differentiating cells develop a neuronal phenotype with neurites and growth cones and sustained activation of protein kinase C (PKC) and pp60c-src. The TPA-induced p130cas phosphorylation increased within 5 min of stimulation and persisted for at least 4 days, whereas bFGF/IGF-I-induced p130cas phosphorylation was biphasic. However, the increase in tyrosine phosphorylation of p130cas was not restricted to differentiation inducing stimuli. The phosphorylation was blocked by the specific PKC inhibitor GF 109203X, and transient transfection with active PKC-epsilon induced p130cas tyrosine phosphorylation. pp60c-src, known to directly phosphorylate p130cas in other cell systems, was not activated after stimulation with TPA or bFGF/IGF-I for up to 30 min, and the initial p130cas phosphorylation was resistant to the Src family kinase inhibitor herbimycin A. However, in long term stimulated cells, herbimycin A blocked the induced phosphorylation of p130cas. Also, overexpression of src induced phosphorylation of p130cas. p130cas protein and phosphorylated p130cas were present in growth cones isolated from differentiated SH-SY5Y cells. Inhibition of PKC activity in differentiating cells with GF 109203X leads to a rapid retraction of growth cone filopodia, and p130cas phosphorylation decreased transiently (within minutes). Growth cones isolated from these cells were virtually devoid of phosphorylated p130cas. These data suggest a function for p130cas as a PKC downstream target in SH-SY5Y cells and possibly also in their growth cones.

  • 35.
    Fernández de la Cruz, Lorena
    et al.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Rydell, Mina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Runeson, Bo Sigurd
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian M.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington IN, USA.
    Brander, Gustaf
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Rück, Christian
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul S.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Mataix-Cols, David
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Suicide in obsessive-compulsive disorder: a population-based study of 36 788 Swedish patients2017In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 22, no 11, p. 1626-1632Article in journal (Refereed)
    Abstract [en]

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

  • 36.
    Fjæraa Alfredsson, Christina
    et al.
    Biomedical Sciences, Department of Health Sciences, Faculty of Health, Science and Technology, Karlstad University, Karlstad, Sweden.
    Rendel, Filip
    Biomedical Sciences, Department of Health Sciences, Faculty of Health, Science and Technology, Karlstad University, Karlstad, Sweden.
    Liang, Qui-Li
    Biomedical Sciences, Department of Health Sciences, Faculty of Health, Science and Technology, Karlstad University, Karlstad, Sweden.
    Sundström, Birgitta E
    Biomedical Sciences, Department of Health Sciences, Faculty of Health, Science and Technology, Karlstad University, Karlstad, Sweden.
    Nånberg, Eewa
    Biomedical Sciences, Department of Health Sciences, Faculty of Health, Science and Technology, Karlstad University, Karlstad, Sweden.
    Altered sensitivity to ellagic acid in neuroblastoma cells undergoing differentiation with 12-0-tetradecanoylphorbol-13-acetate and all-trans retinoic acid2015In: Biomedicine and Pharmacotherapy, ISSN 0753-3322, E-ISSN 1950-6007, Vol. 76, p. 39-45Article in journal (Refereed)
    Abstract [en]

    Ellagic acid has previously been reported to induce reduced proliferation and activation of apoptosis in several tumor cell lines including our own previous data from non-differentiated human neuroblastoma SH-SY5Y cells. The aim of this study was now to investigate if in vitro differentiation with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate or the vitamin A derivative all-trans retinoic acid altered the sensitivity to ellagic acid in SH-SY5Y cells. The methods used were cell counting and LDH-assay for evaluation of cell number and cell death, flow cytometric analysis of SubG(1)-and TUNEL-analysis for apoptosis and western blot for expression of apoptosis-associated proteins. In vitro differentiation was shown to reduce the sensitivity to ellagic acid with respect to cell detachment, loss of viability and activation of apoptosis. The protective effect was phenotype-specific and most prominent in all-trans retinoic acid-differentiated cultures. Differentiation-dependent up-regulation of Bcl-2 and integrin expression is introduced as possible protective mechanisms. The presented data also point to a positive correlation between proliferative activity and sensitivity to ellagic-acid-induced cell detachment. In conclusion, the presented data emphasize the need to consider degree of neuronal differentiation and phenotype of neuroblastoma cells when discussing a potential pharmaceutical application of ellagic acid in tumor treatment.

  • 37.
    Fjæraa Alfredsson, Christina
    et al.
    Karlstads universitet, Institutionen för hälsovetenskaper (from 2013).
    Rendel, Filip
    Karlstads universitet, Institutionen för hälsovetenskaper (from 2013).
    Sundström, Birgitta E.
    Karlstads universitet, Institutionen för hälsovetenskaper (from 2013).
    Nånberg, Eewa
    Karlstads universitet, Institutionen för hälsovetenskaper (from 2013).
    Proliferation in morphologically differentiated SH-SY5Y human neuroblastoma cellsManuscript (preprint) (Other academic)
  • 38.
    Fransén, Karin
    et al.
    Department of Biomedicine and Surgery, Division of Cell Biology, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Dimberg, Jan
    Department of Biomedicine and Surgery, Division of Cell Biology, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Österström, Anna
    Department of Biomedicine and Surgery, Division of Cell Biology, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Olsson, Anneli
    Söderkvist, Peter
    Department of Biomedicine and Surgery, Division of Cell Biology, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Sirsjö, Allan
    Nitric oxide synthase 2 mRNA expression in relation to p53 and adenomatous polyposis coli mutations in primary colorectal adenocarcinomas2002In: Surgery, ISSN 0039-6060, Vol. 131, no 4, p. 384-392, article id 11935128Article in journal (Refereed)
    Abstract [en]

    Background: The inducible nitric (NO) synthase 2 (NOS2) is upregulated in breast, brain, colon, and gynecological tumors, which indicate that NO may have a role in tumorigenesis. However, little is known about the role and regulation of NOS2 in colorectal carcinomas. Recent in vitro experiments have implicated that NOS2 is downregulated by p53 accumulation. Virtual analysis of the NOS2 promoter showed putative TCF-4/Lef-1 response elements, which indicate a potential regulation of NOS2 expression by activation of the adenomatous polyposis coli (APC)/beta-catenin pathway.

    Methods: NOS2 mRNA expression was investigated in 59 colorectal carcinomas by reverse transcriptase/real-time polymerase chain reaction and related to mutations in the p53, APC, and beta-catenin genes. Presence of NOS2 protein was studied by Western blot, and the localization was studied by immunohistochemistry. Loss of heterozygosity was studied in the region of the NOS2 gene.

    Results: The NOS2 mRNA and protein expression were significantly higher in tumors than in control tissue. Immunohistochemistry revealed extensive NOS2 staining in the epithelial cells and, to a minor degree, in leukocytes. Increased NOS2 mRNA expression was found in Dukes' stages A and B compared with the C and D stages. No relationship was found between elevated NOS2 expression and loss of heterozygosity in the later stages according to Dukes' classification or mutations in the p53, APC, or beta-catenin genes.

    Conclusions: Inactivating mutations in the p53 and APC pathways are not the main explanation for the increased NOS2 expression found in colorectal tumors.

  • 39.
    Fransén, Karin
    et al.
    Örebro University, School of Medical Sciences. Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping, Sweden.
    Elander, Nils
    Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping, Sweden.
    Söderkvist, Peter
    Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping, Sweden.
    Nitric oxide synthase 2 (NOS2) promoter polymorphisms in colorectal cancer2005In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 225, no 1, p. 99-103, article id 15922861Article in journal (Refereed)
    Abstract [en]

    Previously, increased expression of nitric oxide synthase 2 (NOS2) in colorectal cancer (CRC) has been identified. The NOS2 gene is transcriptionally regulated, which suggests that polymorphisms in the NOS2 promoter may have a role for CRC development and progression. The genotyping was performed with PCR/RFLP, single strand conformation analysis or MegaBACE genotyping of normal blood DNA from CRC patients and normal healthy controls. However, no significant association between NOS2 polymorphisms and CRC onset or clinical outcome was evident. In conclusion, these results, therefore, suggest that NOS2 promoter polymorphisms have a limited effect on the onset or progression of CRC.

  • 40.
    Fransén, Karin
    et al.
    Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping, Sweden.
    Fenech, Matthew
    Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping, Sweden.
    Fredrikson, Mats
    Division of Occupational and Environmental Medicine, Department of Molecular and Clinical Medicine, Faculty of Health Sciences, University Hospital, Linköping, Sweden.
    Dabrosin, Charlotta
    Division of Gynecologic Oncology, University Hospital, Faculty of Health Sciences, Linköping, Sweden.
    Söderkvist, Peter
    Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping, Sweden.
    Association between ulcerative growth and hypoxia inducible factor-1alpha polymorphisms in colorectal cancer patients2006In: Molecular Carcinogenesis, ISSN 0899-1987, E-ISSN 1098-2744, Vol. 45, no 11, p. 833-840Article in journal (Refereed)
    Abstract [en]

    The hypoxia inducible factor-1alpha (HIF-1alpha) has been found to be involved in several different physiological mechanisms, such as blood-vessel formation, apoptosis, and erythropoiesis. HIF-1alpha is hydroxylated at normoxia and rapidly degraded via the von Hippel-Lindau (VHL)/ubiquitin-proteasome degradation system to prevent angiogenesis. In a previous study, the C1772T (P582S) and the G1790A (A588T) polymorphisms were identified in the human HIF-1alpha gene, which was shown to have a higher transactivating capability in vitro compared to the wild type allele. However, the role for these polymorphisms in vivo is still unclear. In the present investigation, we have therefore studied the role of the two polymorphic variants in the development of colorectal cancer (CRC) with PCR/RFLP (restriction fragment length polymorphism), single strand conformation analysis (SSCA), and immunohistochemistry (IHC). A significant higher-risk was identified between patients heterozygous for the C1772T polymorphism and the more severe ulcerative growth pattern compared to homozygous C1772C wild type tumors (RR = 5.2; 95% CI 1.26-21.6; P = 0.006). This was also verified on the allelic level (RR = 6.5; 95% CI 1.58-26.8; P = 0.001). In addition, patients carrying one or more polymorphic alleles in either the HIF-1alpha C1772T or the G1790A polymorphisms display significant higher risk for the development of ulcerative CRCs (RR = 4.17; 95% CI = 1.33-13.08; P = 0.004). These results suggest that the HIF-1alpha polymorpisms are an important factor for development of a subset of ulcerative intestinal tumors. Future screening of the polymorphic HIF-1alpha allele may therefore be of importance in the selection of treatment strategies of CRC.

  • 41.
    Fransén, Karin
    et al.
    Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping University, Linköping, Sweden .
    Klintenäs, Maria
    Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Österström, Anna
    Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Natural Science and Biomedicine, University College of Health Sciences, Jönköping, Sweden.
    Dimberg, Jan
    Department of Natural Science and Biomedicine, University College of Health Sciences, Jönköping, Sweden.
    Monstein, Hans-Jürg
    Molecular BiologyLaboratory, Strategic Development-LMÖ/IBK, University Hospital, Linköping, Sweden.
    Söderkvist, Peter
    Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas2004In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 25, no 4, p. 527-533, article id 14688025Article in journal (Refereed)
    Abstract [en]

    Colorectal cancer is a multi-step process characterized by a sequence of genetic alterations in cell growth regulatory genes, such as the adenomatous polyposis coli, KRAS, p53 and DCC genes. In the present study mutation analysis was performed with SSCA/direct sequencing of the hot-spot regions in exons 11 and 15 for the BRAF gene and exons 1-2 for the KRAS gene in 130 primary colorectal cancer tumors and correlated with clinico-pathological and mutational data. We also performed mutation analysis of the corresponding conserved regions in the ARAF and RAF-1 genes. Mutations in the BRAF and KRAS genes were found in 11.5 and 40% of the tumors, respectively. One germline exonic and nine germline intronic genetic variants were found in the ARAF and RAF-1 genes. All of the BRAF mutations were located in the kinase domain of the conserved region 3 in exon 15 of the BRAF gene. One novel somatic mutation was also identified in the BRAF gene. The majority of the BRAF mutations were found in colon compared with rectal tumors (P = 0.014). In agreement with others, a statistically significant correlation between BRAF mutations and microsatellite instability could be found. A negative correlation was also evident between mutations in the BRAF and KRAS genes, which supports earlier studies where somatic mutations in these genes are mutually exclusive. Collectively, our results provide support for the idea that activation of the MAP kinase pathway, especially via BRAF and KRAS mutations, is of critical importance for the development of colorectal cancer.

  • 42.
    Fransén, Karin
    et al.
    Örebro University, School of Medical Sciences.
    Pettersson, Carolina
    Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Hurtig-Wennlöf, Anita
    School of Health and Welfare, Jönköping University, Sweden.
    CRP levels are significantly associated with CRP genotype and estrogen use in The Lifestyle, Biomarker and Atherosclerosis (LBA) study2022In: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261, Vol. 22, no 1, article id 170Article in journal (Refereed)
    Abstract [en]

    Background: The C‑reactive protein (CRP) is an important biomarker for atherosclerosis and single nucleotide poly‑morphisms (SNPs) in the CRP locus have been associated with altered CRP levels and associated with risk for cardio‑vascular disease. However, the association between genetic variations in the CRP gene, estrogen use and CRP levels orearly signs of atherosclerosis in young healthy individuals is not fully characterized. We aimed to evaluate the influ‑ence of five genetic variants on both plasma CRP levels and carotid intima‑media thickness (cIMT) values, includingaspects on estrogen containing contraceptive use in females.

    Methods: Genotyping was performed with TaqMan real time PCR and compared with high sensitivity CRP serumlevels in 780 Swedish young, self‑reported healthy individuals. Haplotypes of the SNPs were estimated with the PHASEv 2.1. The cIMT was measured by 12 MHz ultrasound. The contraceptive use was self‑reported.

    Results: Strong associations between CRP and genotype were observed for rs3091244, rs1800947, rs1130864, andrs1205 in women (all p < 0.001). In men, only rs1800947 was associated with CRP (p = 0.029). The independent effectof genotypes on CRP remained significant also after adjustment for established risk factors. Female carriers of the H1/ATGTG haplotype had higher CRP than non‑carriers. This was specifically pronounced in the estrogen‑using group(p < 0.001), and they had also higher cIMT (p = 0.002) than non‑carriers but with a small cIMT difference between thehaplotype groups (0.02 mm). In parallel, a significant correlation between CRP and cIMT in the estrogen using groupwas observed (r = 0.194; p = 0.026).

    Conclusions: Estrogen use, genotypes and haplotypes in the CRP locus are significantly associated with CRP levels.Based on an observed interaction effect between sex/estrogen use and the H1/ATGTG haplotype on CRP, and amarginally thicker cIMT in the estrogen using group, our data suggest that both genotypes and estrogen usage couldbe involved in arterial wall structural differences. The causality between CRP levels and cIMT remains unclear, and theobserved difference in cIMT is not clinically relevant in the present state. Future larger and longitudinal studies mayshed further light on the role of more long‑term estrogen use and early atherosclerosis.

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  • 43.
    Freund-Levi, Yvonne
    et al.
    Section of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet and Department of Geriatrics Karolinska University Hospital Stockholm, Sweden.
    Vedin, Inger
    Division of Haematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital at Huddinge, Stockholm, Sweden.
    Hjorth, Erik
    Division of Neurodegeneration, Department of Neurobiology, Care Sciences & Society, Karolinska Institutet, Stockholm, Sweden.
    Basun, Hans
    Division of Geriatrics, Uppsala University, Uppsala, Sweden; Chaire d'Excellence Program, Department of Biochemistry, Molecular Biology and Nutrition, Universite d'Auvergne, Clermont-Ferrand, France.
    Faxén Irving, Gerd
    Divisions of Clinical Nutrition, Karolinska Institutet, Karolinska University Hospital at Huddinge, Stockholm, Sweden.
    Schultzberg, Marianne
    Division of Neurodegeneration, Department of Neurobiology, Care Sciences & Society, Karolinska Institutet, Stockholm, Sweden.
    Eriksdotter, Maria
    Section of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet and Department of Geriatrics Karolinska University Hospital Stockholm, Sweden.
    Palmblad, Jan
    Division of Haematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital at Huddinge, Stockholm, Sweden.
    Vessby, Bengt
    Clinical Nutrition and Metabolism, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
    Wahlund, Lars-Olof
    Section of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet and Department of Geriatrics Karolinska University Hospital Stockholm, Sweden.
    Cederholm, Tommy
    Clinical Nutrition and Metabolism, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
    Basu, Samar
    Division of Oxidative Stress and Inflammation, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden; Chaire d'Excellence Program, Department of Biochemistry, Molecular Biology and Nutrition, Universite d'Auvergne, Clermont-Ferrand, France.
    Effects of supplementation with omega-3 fatty acids on oxidative stress and inflammation in patients with Alzheimer's disease: the OmegAD study2014In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 42, no 3, p. 823-831Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Oxidative stress and inflammation are two key mechanisms suggested to be involved in the pathogenesis of Alzheimer's disease (AD). Omega-3 fatty acids (ω-3 FAs) found in fish and fish oil have several biological properties that may be beneficial in AD. However, they may also auto-oxidize and induce in vivo lipid peroxidation.

    OBJECTIVE: The objective of this study was to evaluate systemic oxidative stress and inflammatory biomarkers following oral supplementation of dietary ω-3 FA.

    METHODS: Forty patients with moderate AD were randomized to receive 1.7 g DHA (22:6) and 0.6 g EPA (20:5) or placebo for 6 months. Urinary samples were collected before and after supplementation. The levels of the major F2-isoprostane, 8-iso-PGF2α, a consistent in vivo biomarker of oxidative stress, and 15-keto-dihydro-PGF2α, a major metabolite of PGF2α and biomarker of inflammatory response, were measured.

    RESULTS: F2-isoprostane in urine increased in the placebo group after 6 months, but there was no clear difference in treatment effect between supplemented and non-supplemented patients on the urinary levels of F2-isoprostanes and 15-keto-dihydro-PGF2α. At baseline, the levels of 15-keto-dihydro-PGF2α showed negative correlative relationships to ω-3 FAs, and a positive correlation to linoleic acid. 8-iso-PGF2α correlated negatively to the ω-6 FA arachidonic acid.

    CONCLUSION: The findings indicate that supplementation of ω-3 FAs to patients with AD for 6 months does not have a clear effect on free radical-mediated formation of F2-isoprostane or cyclooxygenase-mediated formation of prostaglandin F2α. The correlative relationships to FAs indicate a potential role of FAs in immunoregulation.

  • 44.
    Fälker, Knut
    et al.
    Department of Clinical and Experimental Medicine, University of Linköping, University Hospital, Linköping, Sweden.
    Haglund, Linda
    Department of Medical and Health Sciences, University of Linköping, University Hospital, Linköping, Sweden.
    Gunnarsson, Peter
    Department of Medical and Health Sciences, University of Linköping, University Hospital, Linköping, Sweden.
    Nylander, Martina
    Department of Clinical and Experimental Medicine, University of Linköping, University Hospital, Linköping, Sweden.
    Lindahl, Tomas L
    Department of Clinical and Experimental Medicine, University of Linköping, University Hospital, Linköping, Sweden.
    Grenegård, Magnus
    Department of Medical and Health Sciences, University of Linköping, University Hospital, Linköping, Sweden.
    Protease-activated receptor 1 (PAR1) signalling desensitization is counteracted via PAR4 signalling in human platelets2011In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 436, no 2, p. 469-480Article in journal (Refereed)
    Abstract [en]

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

  • 45.
    Fälker, Knut
    et al.
    Martin-Luther-University, Halle-Wittenberg, Halle, Germany .
    Lange, Danica
    Martin-Luther-University, Halle-Wittenberg, Halle, Germany .
    Presek, Peter
    Martin-Luther-University, Halle-Wittenberg, Halle, Germany .
    ADP secretion and subsequent P2Y12 receptor signalling play a crucial role in thrombin-induced ERK2 activation in human platelets2004In: Thrombosis and Haemostasis, ISSN 0340-6245, E-ISSN 2567-689X, Vol. 92, no 1, p. 114-23Article in journal (Refereed)
    Abstract [en]

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

  • 46.
    Fälker, Knut
    et al.
    Martin-Luther-University Halle-Wittenberg, Faculty of Medicine, Department of Pharmacology and Toxicology, Halle, Germany .
    Lange, Danica
    Martin-Luther-University Halle-Wittenberg, Faculty of Medicine, Department of Pharmacology and Toxicology, Halle, Germany .
    Presek, Peter
    Martin-Luther-University Halle-Wittenberg, Faculty of Medicine, Department of Pharmacology and Toxicology, Halle, Germany .
    P2Y12 ADP receptor-dependent tyrosine phosphorylation of proteins of 27 and 31 kDa in thrombin-stimulated human platelets2005In: Thrombosis and Haemostasis, ISSN 0340-6245, E-ISSN 2567-689X, Vol. 93, no 5, p. 880-888Article in journal (Refereed)
    Abstract [en]

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

  • 47.
    Fälker, Knut
    et al.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Ljungberg, Liza
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Kardeby, Caroline
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Lindkvist, Madelene
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Sirsjö, Allan
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Grenegård, Magnus
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Adrenoceptor α2A signalling countervails the taming effects of synchronous cyclic nucleotide-elevation on thrombin-induced human platelet activation and aggregation2019In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 59, p. 96-109Article in journal (Refereed)
    Abstract [en]

    The healthy vascular endothelium constantly releases autacoids which cause an increase of intracellular cyclic nucleotides to tame platelets from inappropriate activation. Elevating cGMP and cAMP, in line with previous reports, cooperated in the inhibition of isolated human platelet intracellular calcium-mobilization, dense granules secretion, and aggregation provoked by thrombin. Further, platelet alpha granules secretion and, most relevant, integrin αIIaβ3 activation in response to thrombin are shown to be prominently affected by the combined elevation of cGMP and cAMP. Since stress-related sympathetic nervous activity is associated with an increase in thrombotic events, we investigated the impact of epinephrine in this setting. We found that the assessed signalling events and functional consequences were to various extents restored by epinephrine, resulting in full and sustained aggregation of isolated platelets. The restoring effects of epinephrine were abolished by either interfering with intracellular calcium-elevation or with PI3-K signalling. Finally, we show that in our experimental setting epinephrine likewise reconstitutes platelet aggregation in heparinized whole blood, which may indicate that this mechanism could also apply in vivo.

  • 48.
    Grahn, Niclas
    et al.
    Molecular Biology Laboratory - LMC, University Hospital, Linköping, Sweden; Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Laboratory of Human Molecular Genetics, Faculty of Medicine of Sfax, Tunisia.
    Hmani-Aifa, Mounira
    Molecular Biology Laboratory - LMC, University Hospital, Linköping, Sweden; Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Laboratory of Human Molecular Genetics, Faculty of Medicine of Sfax, Tunisia.
    Fransén, Karin
    Molecular Biology Laboratory - LMC, University Hospital, Linköping, Sweden; Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Laboratory of Human Molecular Genetics, Faculty of Medicine of Sfax, Tunisia.
    Söderkvist, Peter
    Molecular Biology Laboratory - LMC, University Hospital, Linköping, Sweden; Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Laboratory of Human Molecular Genetics, Faculty of Medicine of Sfax, Tunisia.
    Monstein, Hans-Jürg
    Molecular Biology Laboratory - LMC, University Hospital, Linköping, Sweden; Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Laboratory of Human Molecular Genetics, Faculty of Medicine of Sfax, Tunisia.
    Molecular identification of Helicobacter DNA present in human colorectal adenocarcinomas by 16S rDNA PCR amplification and pyrosequencing analysis2005In: Journal of Medical Microbiology, ISSN 0022-2615, E-ISSN 1473-5644, Vol. 54, no 11, p. 1031-1035, article id 16192433Article in journal (Refereed)
    Abstract [en]

    Seroepidemiological studies have indicated that Helicobacter pylori infection might be a possible risk factor for colorectal adenocarcinoma (CRC) development. However, limited information is available as to whether or not Helicobacter species are present in CRC tissues. In this study the presence of Helicobacter DNA in 77 CRC biopsies was investigated by means of a Helicobacter species-specific 16S rDNA PCR assay and real-time DNA pyrosequencing of the 16S rDNA variable V3 region. Pyrosequencing revealed the presence of Helicobacter DNA sequences in 21 of 77 biopsy specimens (27%). 16S rDNA sequences corresponding to H. pylori 26695 and H. pylori J99 were most commonly found. Intriguingly, one sequence belonged to Helicobacter mustelae, previously identified in ferrets. No significant correlations were found in the prevalence of Helicobacter DNA between colon and rectum tumour biopsies (P = 0.815), nor between Dukes' classes A/B and C/D (P = 0.262). 16S rDNA PCR amplification combined with pyrosequencing analysis of 16S rDNA variable V3 regions provides a powerful molecular tool to identify Helicobacter species in human biopsy specimens.

  • 49.
    Guaran, Valeria
    et al.
    Bioacoustics Research Laboratory, Department of Neurosciences, University of Padua, Padua, Italy.
    Astolfi, Laura
    Bioacoustics Research Laboratory, Department of Neurosciences, University of Padua, Padua, Italy.
    Castiglione, Alessandro
    ENT Surgery, Department of Neurosciences, University of Padua, Padua, Italy.
    Simoni, Edi
    Bioacoustics Research Laboratory, Department of Neurosciences, University of Padua, Padua, Italy.
    Olivetto, Elena
    Bioacoustics Research Laboratory, Department of Neurosciences, University of Padua, Padua, Italy.
    Galasso, Marco
    Department of Morphology and Embriology, University of Ferrara, Ferrara, Italy.
    Trevisi, Patrizia
    ENT Surgery, Department of Neurosciences, University of Padua, Padua, Italy.
    Busi, Micol
    Department of Audiology, University of Ferrara, Ferrara, Italy.
    Volinia, Stefano
    Department of Morphology and Embriology, University of Ferrara, Ferrara, Italy.
    Martini, Alessandro
    ENT Surgery, Department of Neurosciences, University of Padua, Padua, Italy.
    Association between idiopathic hearing loss and mitochondrial DNA mutations: a study on 169 hearing-impaired subjects2013In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 32, no 4, p. 785-794Article in journal (Refereed)
    Abstract [en]

    Mutations in mitochondrial DNA (mtDNA) have been shown to be an important cause of sensorineural hearing loss (SNHL). In this study, we performed a clinical and genetic analysis of 169 hearing-impaired patients and some of their relatives suffering from idiopathic SNHL, both familial and sporadic. The analysis of four fragments of their mtDNA identified several polymorphisms, the well known pathogenic mutation, A1555G, and some novel mutations in different genes, implying changes in the aminoacidic sequence. A novel sporadic mutation in 12S rRNA (MT-RNR1), not previously reported in the literature, was found in a case of possible aminoglycoside-induced progressive deafness. 

  • 50.
    Gunaltay, Sezin
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Kumawat, Ashok Kumar
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Institute of Infection, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, United Kingdom.
    Nyhlin, Nils
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Bohr, Johan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Tysk, Curt
    Örebro University Hospital. Division of Gastroenterology, Department of Medicine, Örebro University, Örebro, Sweden.
    Hultgren, Olof
    Örebro University Hospital.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden.
    Enhanced levels of chemokines and their receptors in the colon of microscopic colitis patients indicate mixed immune cell recruitment2015In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, article id 132458Article in journal (Refereed)
    Abstract [en]

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

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