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  • 51.
    Andersson, AK
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sandler, S
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Melatonin protects against streptozotocin, but notinterleukin-1beta-induced damage of rodent pancreatic beta-cells.2001Inngår i: J Pineal Res, Vol. 30, s. 157-Artikkel i tidsskrift (Fagfellevurdert)
  • 52.
    Andersson, Annika K.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Role of Inducible Nitric Oxide Synthase and Melatonin in Regulation of β-cell Sensitivity to Cytokines2003Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The mechanisms of β-cell destruction leading to type 1 diabetes are complex and not yet fully understood, but infiltration of the islets of Langerhans by autoreactive immune cells is believed to be important. Activated macrophages and T-cells may then secrete cytokines and free radicals, which could selectively damage the β-cells. Among the cytokines, IL-1β, IFN-γ and TNF-α can induce expression of inducible nitric synthase (iNOS) and cyclooxygenase-2. Subsequent nitric oxide (NO) and prostaglandin E2 (PGE2) formation may impair islet function.

    In the present study, the ability of melatonin (an antioxidative and immunoregulatory hormone) to protect against β-cell damage induced by streptozotocin (STZ; a diabetogenic and free radical generating substance) or IL-1β exposure was examined. In vitro, melatonin counteracted STZ- but not IL-1β-induced islet suppression, indicating that the protective effect of melatonin is related to interference with free radical generation and DNA damage, rather than NO synthesis. In vivo, non-immune mediated diabetes induced by a single dose of STZ was prevented by melatonin.

    Furthermore, the effects of proinflammatory cytokines were examined in islets obtained from mice with a targeted deletion of the iNOS gene (iNOS -/- mice) and wild-type controls. The in vitro data obtained show that exposure to IL-1β or (IL-1β + IFN-γ) induce disturbances in the insulin secretory pathway, which were independent of NO or PGE2 production and cell death. Initially after addition, in particular IL-1β seems to be stimulatory for the insulin secretory machinery of iNOS –/- islets, whereas IL-1β acts inhibitory after a prolonged period. Separate experiments suggest that the stimulatory effect of IL-1β involves an increased gene expression of phospholipase D1a/b. In addition, the formation of new insulin molecules appears to be affected, since IL-1β and (IL-1β + IFN-γ) suppressed mRNA expression of both insulin convertase enzymes and insulin itself.

    Delarbeid
    1. Melatonin protects against streptozotocin, but not Interleukin-1β-induced damage of rodent pancreatic β-cells
    Åpne denne publikasjonen i ny fane eller vindu >>Melatonin protects against streptozotocin, but not Interleukin-1β-induced damage of rodent pancreatic β-cells
    2001 Inngår i: J. Pineal Res., ISSN 0742-3098, Vol. 30, nr 3, s. 157-165Artikkel i tidsskrift (Fagfellevurdert) Published
    Identifikatorer
    urn:nbn:se:uu:diva-90711 (URN)
    Tilgjengelig fra: 2003-09-03 Laget: 2003-09-03bibliografisk kontrollert
    2. Cytokine-induced inhibition of insulin release from mouse pancreatic β-cells deficient in inducible nitric oxide synthase
    Åpne denne publikasjonen i ny fane eller vindu >>Cytokine-induced inhibition of insulin release from mouse pancreatic β-cells deficient in inducible nitric oxide synthase
    2001 Inngår i: Biochem. Biophys. Res. Commun., ISSN 0006-291, Vol. 281, nr 2, s. 396-403Artikkel i tidsskrift (Fagfellevurdert) Published
    Identifikatorer
    urn:nbn:se:uu:diva-90712 (URN)
    Tilgjengelig fra: 2003-09-03 Laget: 2003-09-03bibliografisk kontrollert
    3. Cytokine-induced prostaglandin E2 formation is reduced from mouse pancreatic islets deficient in inducible nitric oxide synthase
    Åpne denne publikasjonen i ny fane eller vindu >>Cytokine-induced prostaglandin E2 formation is reduced from mouse pancreatic islets deficient in inducible nitric oxide synthase
    (engelsk)Manuskript (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-90713 (URN)
    Tilgjengelig fra: 2003-09-03 Laget: 2003-09-03 Sist oppdatert: 2018-01-13
    4. Role of phospholipase D, insulin and proinsulin convertase gene expression in altered insulin secretion from β-cells deficient in inducible nitric oxide synthase following IL-1β and IFN-γ exposure
    Åpne denne publikasjonen i ny fane eller vindu >>Role of phospholipase D, insulin and proinsulin convertase gene expression in altered insulin secretion from β-cells deficient in inducible nitric oxide synthase following IL-1β and IFN-γ exposure
    Manuskript (Annet vitenskapelig)
    Identifikatorer
    urn:nbn:se:uu:diva-90714 (URN)
    Tilgjengelig fra: 2003-09-03 Laget: 2003-09-03 Sist oppdatert: 2010-01-13bibliografisk kontrollert
  • 53.
    Andersson, Annika K
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Börjesson, Andreas
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sandgren, Johanna
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sandler, Stellan
    Cytokines affect PDX-1 expression, insulin and proinsulin secretion from iNOS deficient murine islets.2005Inngår i: Mol Cell Endocrinol, ISSN 0303-7207, Vol. 240, nr 1-2, s. 50-7Artikkel i tidsskrift (Fagfellevurdert)
  • 54.
    Andersson, Annika K.
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Börjesson, Andreas
    Sandler, Stellan
    Role of phospholipase D, insulin and proinsulin convertase gene expression in altered insulin secretion from β-cells deficient in inducible nitric oxide synthase following IL-1β and IFN-γ exposureManuskript (Annet vitenskapelig)
  • 55.
    Andersson, Annika K.
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Flodström, Malin
    Sandler, Stellan
    Cytokine-induced inhibition of insulin release from mouse pancreatic β-cells deficient in inducible nitric oxide synthase2001Inngår i: Biochem. Biophys. Res. Commun., ISSN 0006-291, Vol. 281, nr 2, s. 396-403Artikkel i tidsskrift (Fagfellevurdert)
  • 56.
    Andersson, Annika K.
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sandler, Stellan
    Melatonin protects against streptozotocin, but not Interleukin-1β-induced damage of rodent pancreatic β-cells2001Inngår i: J. Pineal Res., ISSN 0742-3098, Vol. 30, nr 3, s. 157-165Artikkel i tidsskrift (Fagfellevurdert)
  • 57.
    Andersson, Annika K.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Thorvaldson, Lina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Carlsson, Carina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sandler, Stellan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Cytokine-induced PGE2 formation is reduced from iNOS deficient murine islets2004Inngår i: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 220, nr 1-2, s. 21-29Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cytokines may be involved in islet destruction during Type 1 diabetes. Exposure to interleukin-1beta (IL-1beta) or IL-1beta plus interferon-gamma (IFN-gamma) of rodent islets induces expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Subsequent formation of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) may impair beta-cell function. Using iNOS deficient (iNOS -/-) islets, we have further investigated the relation between NO formation and PGE(2) induction. We found that iNOS -/- islets responded with a reduced PGE(2) formation following IL-1beta or (IL-1beta + IFN-gamma) treatment compared to wild-type (wt) islets, while COX-2 mRNA or protein content were unchanged. By the addition of an NO donor together with IL-1beta, PGE(2) formation could be stimulated from iNOS -/- islets. We conclude that the lowered capacity of PGE(2) formation observed from cytokine exposed iNOS -/- islets is due to a decreased stimulation of PGE(2) formation by the COX-2 enzyme in the absence of NO, rather then differences in expressed COX-2 protein.

  • 58.
    Andersson, Annika K.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Thorvaldson, Lina
    Carlsson, Carina
    Sandler, Stellan
    Cytokine-induced prostaglandin E2 formation is reduced from mouse pancreatic islets deficient in inducible nitric oxide synthaseManuskript (Annet vitenskapelig)
  • 59.
    Andersson, Arne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Department of Medical Cell Biology: Annual Report 20072008Collection/Antologi (Annet (populærvitenskap, debatt, mm))
  • 60.
    Andersson, Arne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Department of Medical Cell Biology: Annual Report 20082009Collection/Antologi (Annet (populærvitenskap, debatt, mm))
  • 61.
    Andersson, Arne
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Bohman, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Borg, L. A. Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Paulsson, Johan F.
    Schultz, Sebastian W.
    Westermark, Gunilla T.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Amyloid deposition in transplanted human pancreatic islets: a conceivable cause of their long-term failure2008Inngår i: Experimental diabetes research, ISSN 1687-5214, Vol. 2008, s. 562985-Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Following the encouraging report of the Edmonton group, there was a rejuvenation of the islet transplantation field. After that, more pessimistic views spread when long-term results of the clinical outcome were published. A progressive loss of the beta-cell function meant that almost all patients were back on insulin therapy after 5 years. More than 10 years ago, we demonstrated that amyloid deposits rapidly formed in human islets and in mouse islets transgenic for human IAPP when grafted into nude mice. It is, therefore, conceivable to consider amyloid formation as one potential candidate for the long-term failure. The present paper reviews attempts in our laboratories to elucidate the dynamics of and mechanisms behind the formation of amyloid in transplanted islets with special emphasis on the impact of long-term hyperglycemia.

  • 62.
    Andersson, Arne
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Börjesson, Joey Lau
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Operating in an era of impact factor mania2015Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, nr 2, s. 124-131Artikkel i tidsskrift (Annet vitenskapelig)
  • 63.
    Andersson, Arne
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Institutionen för medicinska vetenskaper.
    Carlsson, Carina
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Olsson, Richard
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Nordin, Astrid
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Johansson, Magnus
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Palm, Fredrik
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Tyrberg, Björn
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Källskog, Örjan
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Tillman, Linda
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Welsh, NIls
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Mattsson, Göran
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Jansson, Leif
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Promoting islet cell function after transplantation2004Inngår i: Cell Biochem Biophys, nr 40 (3 Suppl), s. 55-64Artikkel i tidsskrift (Fagfellevurdert)
  • 64.
    Andersson, Arne
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Eriksson, Ulf J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Jansson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sandler, Stellan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Welsh, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Welsh, Nils
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Claes Hellerström: a friendly islet explorer2007Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 50, nr 2, s. 4 p following 496-Artikkel i tidsskrift (Fagfellevurdert)
  • 65.
    Andersson, Arne
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Lau Börjesson, Joey
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Scholarly publishing threatened?2016Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967Artikkel i tidsskrift (Annet vitenskapelig)
  • 66.
    Andersson, Arne
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Ronquist, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    A substantial increase of the impact factor2012Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 117, nr 4, s. 353-354Artikkel i tidsskrift (Fagfellevurdert)
  • 67.
    Andersson, Arne
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Ronquist, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Lessons from the recent Journal Citation Report figures2010Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 115, nr 3, s. 161-162Artikkel i tidsskrift (Fagfellevurdert)
  • 68.
    Andersson, C
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Dragomir, A
    Hjelte, L
    Roomans, GM
    CFTR) activity in nasal epithelial cells from cystic fibrosis patients with severe genotypes2002Inngår i: Clin Sci., Vol. 103, s. 417-424Artikkel i tidsskrift (Fagfellevurdert)
  • 69.
    Andersson, C
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Dragomir, A
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Hjelte, L
    Roomans, GM
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Cystic fibrosis transmembrane conductance regulator (CFTR) activity innasal epithelial cells from cystic fibrosis patients with severegenotypes.2002Inngår i: Clin Sci (Lond), Vol. 103, s. 417-Artikkel i tidsskrift (Fagfellevurdert)
  • 70.
    Andersson, C
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Gaston, B
    Roomans, GM
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    S-Nitrosoglutathione induces functional DeltaF508-CFTR in airwayepithelial cells.2002Inngår i: Biochem Biophys Res Commun, Vol. 297, s. 552-Artikkel i tidsskrift (Fagfellevurdert)
  • 71.
    Andersson, C
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Roomans, G M
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Activation of F508 CFTR in a cystic fibrosis respiratory epithelial cell line by 4-phenylbutyrate, genistein and CPX.2000Inngår i: Eur Respir J, Vol. 15, s. 937-Artikkel i tidsskrift (Fagfellevurdert)
  • 72.
    Andersson, C
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Roomans, GM
    Activation of CFTR by genistein in human airway epithelial cell linesManuskript (Annet vitenskapelig)
  • 73.
    Andersson, C
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Roomans, GM
    Activation of deltaF508 CFTR in a cystic fibrosis respiratory epithelial cell line by 4-phenylbutyrate, genistein and CPX2000Inngår i: Eur Respir J., Vol. 15, nr 5, s. 937-41Artikkel i tidsskrift (Fagfellevurdert)
  • 74.
    Andersson, C
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Roomans, GM
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Determination of chloride efflux by X-ray microanalysis versus MQAE-fluorescence2002Inngår i: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 59, nr 6, s. 531-355Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The importance of chloride channels for the cell is demonstrated by a number of serious human diseases that are due to mutations in chloride channels. The most well-known of these diseases is cystic fibrosis. Investigations into the mechanisms of the disease and possible treatments require the study of chloride fluxes at the level of individual cells. The present study compares two methods for studies of chloride transport: X-ray microanalysis and MQAE fluorescence with image analysis. As an experimental system, the cAMP-activated chloride channel in cultured respiratory epithelial cells was chosen. Both methods showed that stimulation with the cAMP-elevating agents forskolin and IBMX decreased the chloride content of the cells by about 20-27%. Inducing a driving force for chloride by replacing extracellular chloride by nitrate resulted in a chloride efflux that was significantly increased in the presence of forskolin and IBMX. This study shows that X-ray microanalysis and MQAE fluorescence are adequate and comparable methods for measuring cAMP-dependent chloride transport in individual cells.

  • 75.
    Andersson, C
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Roomans, GM
    S-Nitrosoglutathione induces functional ?F508-CFTR in airway epithelial cells2002Inngår i: Biochem Biophys Res Commun., Vol. 297, s. 552-557Artikkel i tidsskrift (Fagfellevurdert)
  • 76.
    Andersson, C
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Servetnyk, J
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Roomans, GM
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Activation of CFTR by genistein in human airway epithelial cell lines2003Inngår i: Biochem Biophys Res Commun, Vol. 308, s. 518-Artikkel i tidsskrift (Fagfellevurdert)
  • 77.
    Andersson, Charlotte
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Towards Pharmacological Treatment of Cystic Fibrosis2002Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    S-nitrosogluthatione is an endogenous substance, present at decreased levels in the lungs of CF patients and was recently found to induce mature CFTR in airway epithelial CF cell lines. We show that S-nitrosoglutathione in physiological concentrations increases the presence of ΔF508 CFTR in the cell membrane and induces cAMP dependent chloride transport in cystic fibrosis airway epithelial cells. The properties of S-nitrosoglutathione include other potential benefits for the CF patient and make this agent an interesting candidate for pharmacological treatment of CF that needs to be further evaluated.

    Genistein was found to increase the chloride efflux in both normal and ΔF508 cells without stimulation of cAMP elevating agents and without prior treatment with phenylbutyrate. Genistein, in concentrations close to those that can be detected in plasma after a high soy diet, could induce chloride efflux in cells with the ΔF508 CFTR mutation and its possible use in the treatment of CF should therefore be further investigated.

    Studies on nasal epithelial cells from CF patients showed cAMP dependent chloride efflux in some of the patients with severe genotypes. This may complicate in vitro evaluation of clinical treatment of these patients. The presence of cAMP dependent chloride transport did not necessarily lead to a milder phenotype. Other factors than CFTR may influence the clinical development of the disease.

    Cystic fibrosis (CF) is the most common monogenetic disease among Caucasians. A defective cAMP regulated chloride channel (cystic fibrosis transmembrane conductance regulator, CFTR) in epithelial cells leads to viscous mucus, bacterial infections, inflammation and tissue damage in the lungs that cause death in 95% of the cystic fibrosis patients. There is no cure for the disease although existing treatment has dramatically prolonged the life expectancy. The aim of this thesis was to study pharmacological agents for their ability to restore the cellular deficiency in CF airway epithelial cells. X-ray microanalysis, MQAE fluorescence and immunocytochemistry were used to evaluate the effects.

    Delarbeid
    1. Activation of deltaF508 CFTR in a cystic fibrosis respiratory epithelial cell line by 4-phenylbutyrate, genistein and CPX
    Åpne denne publikasjonen i ny fane eller vindu >>Activation of deltaF508 CFTR in a cystic fibrosis respiratory epithelial cell line by 4-phenylbutyrate, genistein and CPX
    2000 Inngår i: Eur Respir J., Vol. 15, nr 5, s. 937-41Artikkel i tidsskrift (Fagfellevurdert) Published
    Identifikatorer
    urn:nbn:se:uu:diva-89966 (URN)
    Tilgjengelig fra: 2002-10-11 Laget: 2002-10-11bibliografisk kontrollert
    2. Activation of CFTR by genistein in human airway epithelial cell lines
    Åpne denne publikasjonen i ny fane eller vindu >>Activation of CFTR by genistein in human airway epithelial cell lines
    Manuskript (Annet vitenskapelig)
    Identifikatorer
    urn:nbn:se:uu:diva-89967 (URN)
    Tilgjengelig fra: 2002-10-11 Laget: 2002-10-11 Sist oppdatert: 2010-01-13bibliografisk kontrollert
    3. S-Nitrosoglutathione induces functional ?F508-CFTR in airway epithelial cells
    Åpne denne publikasjonen i ny fane eller vindu >>S-Nitrosoglutathione induces functional ?F508-CFTR in airway epithelial cells
    2002 Inngår i: Biochem Biophys Res Commun., Vol. 297, s. 552-557Artikkel i tidsskrift (Fagfellevurdert) Published
    Identifikatorer
    urn:nbn:se:uu:diva-89968 (URN)
    Tilgjengelig fra: 2002-10-11 Laget: 2002-10-11bibliografisk kontrollert
    4. Determination of chloride efflux by X-ray microanalysis versus MQAE-fluorescence
    Åpne denne publikasjonen i ny fane eller vindu >>Determination of chloride efflux by X-ray microanalysis versus MQAE-fluorescence
    2002 (engelsk)Inngår i: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 59, nr 6, s. 531-355Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The importance of chloride channels for the cell is demonstrated by a number of serious human diseases that are due to mutations in chloride channels. The most well-known of these diseases is cystic fibrosis. Investigations into the mechanisms of the disease and possible treatments require the study of chloride fluxes at the level of individual cells. The present study compares two methods for studies of chloride transport: X-ray microanalysis and MQAE fluorescence with image analysis. As an experimental system, the cAMP-activated chloride channel in cultured respiratory epithelial cells was chosen. Both methods showed that stimulation with the cAMP-elevating agents forskolin and IBMX decreased the chloride content of the cells by about 20-27%. Inducing a driving force for chloride by replacing extracellular chloride by nitrate resulted in a chloride efflux that was significantly increased in the presence of forskolin and IBMX. This study shows that X-ray microanalysis and MQAE fluorescence are adequate and comparable methods for measuring cAMP-dependent chloride transport in individual cells.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-89969 (URN)10.1002/jemt.10234 (DOI)12467030 (PubMedID)
    Tilgjengelig fra: 2002-10-11 Laget: 2002-10-11 Sist oppdatert: 2017-12-14bibliografisk kontrollert
    5. Assessment of chloride secretion in human nasal epithelial cells by X-ray microanalysis
    Åpne denne publikasjonen i ny fane eller vindu >>Assessment of chloride secretion in human nasal epithelial cells by X-ray microanalysis
    2001 Inngår i: J Microsc., Vol. 203, nr 3, s. 277-84Artikkel i tidsskrift (Fagfellevurdert) Published
    Identifikatorer
    urn:nbn:se:uu:diva-89970 (URN)
    Tilgjengelig fra: 2002-10-11 Laget: 2002-10-11bibliografisk kontrollert
    6. CFTR) activity in nasal epithelial cells from cystic fibrosis patients with severe genotypes
    Åpne denne publikasjonen i ny fane eller vindu >>CFTR) activity in nasal epithelial cells from cystic fibrosis patients with severe genotypes
    2002 Inngår i: Clin Sci., Vol. 103, s. 417-424Artikkel i tidsskrift (Fagfellevurdert) Published
    Identifikatorer
    urn:nbn:se:uu:diva-89971 (URN)
    Tilgjengelig fra: 2002-10-11 Laget: 2002-10-11bibliografisk kontrollert
  • 78. Andersson, Charlotte
    et al.
    Dragomir, Anca
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Hjelte, Lena
    Roomans, Godfried M.
    Cystic fibrosis transmembrane conductance regulator (CFTR) activity in nasal epithelial cells from cystic fibrosis patients with severe genotypes.2002Inngår i: Clinical Science, Vol. 103, s. 417-424Artikkel i tidsskrift (Fagfellevurdert)
  • 79.
    Andersson, Charlotte
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Servetnyk, Zhanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Roomans, Godfried M
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Activation of CFTR by genistein in human airway epithelial cell lines2003Inngår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 308, nr 3, s. 518-522Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cystic fibrosis (CF) is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel expressed in epithelial cells. The effects of genistein and 4-phenylbutyrate (PBA) on CFTR were studied in three human airway epithelial cell lines expressing wild-type or DeltaF508 CFTR: Calu-3, CFSMEo-, and CFBE41o- cells. The cells were loaded with the fluorescent dye N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE) and chloride efflux was studied. Forskolin and 3-isobutyl-1-methylxanthine (IBMX) induced chloride efflux in Calu-3 cells but not in CF lines. Genistein (2.5-50 microM) alone was able to induce chloride efflux in all cell lines. Genistein did not enhance the effect of forskolin and IBMX. PBA had little or no effect on genistein-induced chloride efflux. The effect of genistein seen at low concentrations makes genistein interesting for possible pharmacological treatment of CF, since it is known that similar concentrations can be obtained in plasma by a soy-rich diet.

  • 80.
    Andersson, Charlotte
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Zhang, Ai-Ling
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Roomans, Godfried M
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Ca2+ mobilization in the human submandibular duct cell line A253.2000Inngår i: Cell Biol Int, Vol. 24, s. 273-Artikkel i tidsskrift (Fagfellevurdert)
  • 81.
    Andersson, K.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Shebani, E. B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Makeeva, N.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Roomans, G. M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Servetnyk, Z.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Corticosteroids and Montelukast: Effects on Airway Epithelial and Human Umbilical Vein Endothelial Cells2010Inngår i: Lung, ISSN 0341-2040, E-ISSN 1432-1750, Vol. 188, nr 3, s. 209-216Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Our primary objective was to investigate the possible contribution of controller medications to asthmatic airway remodeling, by (1) comparing the apoptotic and necrotic effects of several corticosteroids and montelukast on cultured airway human bronchial surface epithelial (16HBE) and submucosal (Calu3) cells; (2) measuring epithelial shedding potential and desmosome length in response to a cytokine challenge, with or without co-administered corticosteroids; and (3) studying corticosteroids and montelukast effects on inter-cellular adhesion molecule (ICAM) expression in both 16HBE and human umbilical vein endothelial cells (HUVEC). For this purpose, apoptosis, necrosis, and ICAM expression were quantified by flow cytometry, with 16HBE cells sensitive to both the apoptotic and necrotic effects of dexamethasone and montelukast; Calu3 cells sensitive only to budesonide. Transmission electron microscopy revealed decreased desmosome length in the presence of cytokines (TNF-alpha and INF-gamma), with corticosteroids counteracting this reduction. Dexamethasone, beclomethasone, and montelukast decreased versus increased ICAM-1 expression in airway epithelial cells and HUVEC, respectively. For conclusions, bronchial surface epithelial and submucosal cells exhibit a different sensitivity profile toward dexamethasone, budesonide, and montelukast, with corticosteroids preventing cytokineinduced desmosomal damage in 16HBE cells. The studied drugs led to increased ICAM-1 expression in endothelium, potentially facilitating inflammatory cell migration into lung tissue.

  • 82. Andrèn, A
    et al.
    Sjöquist, M
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Tegelberg, A
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    Effects on blood pressure after treatment of obstructive sleep apnoea with a mandibular advancement appliance - a three-year follow-up2009Inngår i: Journal of Oral Rehabilitation, ISSN 0305-182X, E-ISSN 1365-2842, Vol. 36, nr 10, s. 719-725Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    P>Obstructive sleep apnoea (OSA) is a highly prevalent sleep disorder; it affects 4% of males and 2% of females. Hypertension has been shown to occur in 28-57% of OSA patients. There is a steady increase in evidence linking OSA to long-term cardiovascular morbidity including hypertension. The purpose of this study was to investigate whether mandibular advancement oral appliance (OA) treatment of OSA affects the patient's blood pressure (BP) in a 3-month and a 3-year perspective. Twenty-nine consecutive patients, with verified OSA defined as apnoea index (AI) > 5 per hour and/or apnoea/hypopnoea index (AHI) >= 10 per hour, received an OA as treatment. BP was measured on three occasions; before treatment, after 3 months of treatment, and after 3 years of treatment. BP was measured with an electronic blood pressure monitor. The treatment effect of OA was measured after 3 months by repeated somnographic registration while the patient was wearing the OA. A treatment response was defined as AHI < 10; this was achieved in 25 of 29 patients (86%) at the 3-month evaluation. Significant reductions in blood pressure were attained between baseline and the 3-month evaluation (P < 0 center dot 001) and these changes remained at the 3-year follow-up in both systolic BP of -15 center dot 4 +/- 18 center dot 7 mm Hg and diastolic BP of -10 center dot 3 +/- 10 center dot 0 mm Hg. OA therapy reduced blood pressure in both a 3-month and a 3-year perspective in patients with OSA.

  • 83.
    Ankarcrona, M.
    et al.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Ctr Alzheimer Res, Huddinge, Sweden..
    Winblad, B.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Ctr Alzheimer Res, Huddinge, Sweden..
    Monteiro, C.
    Skaggs Inst Chem Biol, Dept Chem, La Jolla, CA 92037 USA.;Scripps Res Inst, Dept Mol & Expt Med, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA..
    Fearns, C.
    Skaggs Inst Chem Biol, Dept Chem, La Jolla, CA 92037 USA.;Scripps Res Inst, Dept Mol & Expt Med, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA..
    Powers, E. T.
    Skaggs Inst Chem Biol, Dept Chem, La Jolla, CA 92037 USA..
    Johansson, J.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Ctr Alzheimer Res, Huddinge, Sweden..
    Westermark, Gunilla T.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Presto, J.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Ctr Alzheimer Res, Huddinge, Sweden..
    Ericzon, B. -G
    Karolinska Univ Hosp, Div Transplantat Surg, Stockholm, Sweden.
    Kelly, J. W.
    Skaggs Inst Chem Biol, Dept Chem, La Jolla, CA 92037 USA.;Scripps Res Inst, Dept Mol & Expt Med, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA..
    Current and future treatment of amyloid diseases2016Inngår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 280, nr 2, s. 177-202Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    There are more than 30 human proteins whose aggregation appears to cause degenerative maladies referred to as amyloid diseases or amyloidoses. These disorders are named after the characteristic cross--sheet amyloid fibrils that accumulate systemically or are localized to specific organs. In most cases, current treatment is limited to symptomatic approaches and thus disease-modifying therapies are needed. Alzheimer's disease is a neurodegenerative disorder with extracellular amyloid -peptide (A) fibrils and intracellular tau neurofibrillary tangles as pathological hallmarks. Numerous clinical trials have been conducted with passive and active immunotherapy, and small molecules to inhibit A formation and aggregation or to enhance A clearance; so far such clinical trials have been unsuccessful. Novel strategies are therefore required and here we will discuss the possibility of utilizing the chaperone BRICHOS to prevent A aggregation and toxicity. Type 2 diabetes mellitus is symptomatically treated with insulin. However, the underlying pathology is linked to the aggregation and progressive accumulation of islet amyloid polypeptide as fibrils and oligomers, which are cytotoxic. Several compounds have been shown to inhibit islet amyloid aggregation and cytotoxicity in vitro. Future animal studies and clinical trials have to be conducted to determine their efficacy in vivo. The transthyretin (TTR) amyloidoses are a group of systemic degenerative diseases compromising multiple organ systems, caused by TTR aggregation. Liver transplantation decreases the generation of misfolded TTR and improves the quality of life for a subgroup of this patient population. Compounds that stabilize the natively folded, nonamyloidogenic, tetrameric conformation of TTR have been developed and the drug tafamidis is available as a promising treatment. Read more articles from the symposium: Amyloid - a multifaceted player in human health and disease.

  • 84.
    Annerén, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Dual role of the tyrosine kinase GTK and the adaptor protein SHB in β-cell growth: enhanced β-cell replication after 60% pancreatectomy and increased sensitivity to streptozotocin2002Inngår i: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 1479-6805, Vol. 172, nr 1, s. 145-153Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Transgenic CBA mice expressing either the tyrosine kinase GTK (gut tyrosine kinase) or the adaptor protein SHB (Src homology 2 protein of beta-cells) under the control of the rat insulin promoter exhibited an increased beta-cell mass, but also elevated cytokine-induced islet cell death compared with control mice. To further investigate the importance of GTK and SHB for beta-cell death and proliferation, these mice were subjected to a 60% partial pancreatectomy (Px) or a sham-operation and beta-cell replication was determined by autoradiographic detection of [(3)H]thymidine incorporation into islet cells positively stained for insulin. The Px-operated control mice exhibited a moderate and insignificant increase in beta-cell replication 4 days after Px compared with the sham-operated mice (0.27+/-0.08% vs 0.08+/-0.02%). In contrast, the Px-induced beta-cell proliferation was significantly increased in both the GTK- and SHB-transgenic mice compared with the corresponding sham-treated animals (0.64+/-0.12% vs 0.11+/-0.04% and 0.44+/-0.11% vs 0.09+/-0.04% respectively). This effect was dependent on intracellular signal transduction pathways activated or enhanced by GTK and SHB overexpression, since the proliferation of acinar cells, located in the vicinity of the islets, was equal in the transgenic and control mice. GTK- and SHB-transgenic mice, treated with a sub-diabetogenic dose of the beta-cell toxin streptozotocin (STZ) on day 0 and subjected to a glucose tolerance test on day 3, exhibited an impaired glucose tolerance in comparison with the STZ-treated control mice. Pretreatment with STZ blunted the regenerative response to Px in the transgenic mice. Furthermore, the SHB-transgenic islets were significantly more damaged with respect to beta-cell loss, compared with the islets of the control mice. Previous and present data suggest a dual role of GTK and SHB for beta-cell growth: whereas these proteins increase the beta-cell mass and induce beta-cell proliferation after 60% Px, SHB and GTK also enhance beta-cell death under certain stressful conditions.

  • 85.
    Annerén, Cecilia
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    The Tyrosine Kinase GTK: Signal Transduction and Biological Function2001Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Protein tyrosine kinases play an important role in the regulation of various cellular processes such as

    growth, differentiation and survival. GTK, a novel SRC-like cytoplasmic tyrosine kinase, was recently cloned from a mouse insulinoma cell line and the present work was conducted in order to find a biological function of GTK in insulin producing and neuronal cells. It was observed that kinase active GTK-mutants, expressed in RINm5F cells, transferred to the cell nucleus and increased the levels of the cell cycle regulatory protein p27KIP1, reduced cell growth and stimulated glucagon mRNA expression. Furthermore, wild type GTK induces neurite outgrowth in the rat adrenal pheochromocytoma PC12 cell line, through activation of the RAP1-pathway, suggesting a role of GTK for cell differentiation. Studies using transgenic mice, expressing GTK under the control of the rat insulin 1 promoter, demonstrated a dual role of GTK for β-cell growth: Whereas GTK increases the β-cell mass and causes enhanced β-cell proliferation in response to partial pancreatectomy it also induced β-cell death in response to proinflammatory cytokines and impaired the glucose tolerance in mice treated with the β-cell toxin streptozotocin suggesting a possible role of GTK for β-cell destruction in Type 1 diabetes. We have also observed that GTK-transgenic islets and GTK-expressing RINm5F cells exhibit a reduced insulininduced activation of the insulin receptor substrate (IRS-1 and IRS-2)-pathways, partly due to an increased basal activity of these. GTK was found to associate with and phosphorylate the SH2 domain adapter protein SHB, which could explain many of the GTK-dependent effects both in vitro and in vivo. In summary, the present work suggests that the novel tyrosine kinase GTK is involved in various signal transduction pathways, regulating different cellular responses, such as proliferation, differentiation and survival.

    Delarbeid
    1.
    Posten ble ikke funnet. Det kan skyldes at posten ikke lenger er tilgjengelig eller det er feil id i adressefeltet.
    2. Increased cytokine-induced cytotoxicity of pancreatic islet cells from transgenic mice expressing the Src-like tyrosine kinase GTK
    Åpne denne publikasjonen i ny fane eller vindu >>Increased cytokine-induced cytotoxicity of pancreatic islet cells from transgenic mice expressing the Src-like tyrosine kinase GTK
    2001 (engelsk)Inngår i: Mol Med., Vol. 7, s. 301-310Artikkel i tidsskrift (Fagfellevurdert) Published
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-89441 (URN)
    Tilgjengelig fra: 2001-09-25 Laget: 2001-09-25 Sist oppdatert: 2012-12-17
    3. Dual role of the tyrosine kinase GTK and the adaptor protein SHB in β-cell growth: enhanced β-cell replication after 60% pancreatectomy and increased sensitivity to streptozotocin
    Åpne denne publikasjonen i ny fane eller vindu >>Dual role of the tyrosine kinase GTK and the adaptor protein SHB in β-cell growth: enhanced β-cell replication after 60% pancreatectomy and increased sensitivity to streptozotocin
    2002 (engelsk)Inngår i: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 1479-6805, Vol. 172, nr 1, s. 145-153Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Transgenic CBA mice expressing either the tyrosine kinase GTK (gut tyrosine kinase) or the adaptor protein SHB (Src homology 2 protein of beta-cells) under the control of the rat insulin promoter exhibited an increased beta-cell mass, but also elevated cytokine-induced islet cell death compared with control mice. To further investigate the importance of GTK and SHB for beta-cell death and proliferation, these mice were subjected to a 60% partial pancreatectomy (Px) or a sham-operation and beta-cell replication was determined by autoradiographic detection of [(3)H]thymidine incorporation into islet cells positively stained for insulin. The Px-operated control mice exhibited a moderate and insignificant increase in beta-cell replication 4 days after Px compared with the sham-operated mice (0.27+/-0.08% vs 0.08+/-0.02%). In contrast, the Px-induced beta-cell proliferation was significantly increased in both the GTK- and SHB-transgenic mice compared with the corresponding sham-treated animals (0.64+/-0.12% vs 0.11+/-0.04% and 0.44+/-0.11% vs 0.09+/-0.04% respectively). This effect was dependent on intracellular signal transduction pathways activated or enhanced by GTK and SHB overexpression, since the proliferation of acinar cells, located in the vicinity of the islets, was equal in the transgenic and control mice. GTK- and SHB-transgenic mice, treated with a sub-diabetogenic dose of the beta-cell toxin streptozotocin (STZ) on day 0 and subjected to a glucose tolerance test on day 3, exhibited an impaired glucose tolerance in comparison with the STZ-treated control mice. Pretreatment with STZ blunted the regenerative response to Px in the transgenic mice. Furthermore, the SHB-transgenic islets were significantly more damaged with respect to beta-cell loss, compared with the islets of the control mice. Previous and present data suggest a dual role of GTK and SHB for beta-cell growth: whereas these proteins increase the beta-cell mass and induce beta-cell proliferation after 60% Px, SHB and GTK also enhance beta-cell death under certain stressful conditions.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-89442 (URN)10.1677/joe.0.1720145 (DOI)000173471200013 ()11786382 (PubMedID)
    Tilgjengelig fra: 2001-09-25 Laget: 2001-09-25 Sist oppdatert: 2017-12-14bibliografisk kontrollert
    4.
    Posten ble ikke funnet. Det kan skyldes at posten ikke lenger er tilgjengelig eller det er feil id i adressefeltet.
    5. GTK, a Src-related tyrosine kinase, induces nerve growth factor-independent neurite outgrowth in PC12 cells through activation of the Rap1 pathway: Relationship to Shb tyrosine phosphorylation and elevated levels of focal adhesion kinase
    Åpne denne publikasjonen i ny fane eller vindu >>GTK, a Src-related tyrosine kinase, induces nerve growth factor-independent neurite outgrowth in PC12 cells through activation of the Rap1 pathway: Relationship to Shb tyrosine phosphorylation and elevated levels of focal adhesion kinase
    2000 (engelsk)Inngår i: J Biol Chem, Vol. 275, s. 29153-29161Artikkel i tidsskrift (Fagfellevurdert) Published
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-89444 (URN)
    Tilgjengelig fra: 2001-09-25 Laget: 2001-09-25 Sist oppdatert: 2012-12-17
  • 86.
    Annerén, Cecilia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Lindholm, Cecilia K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Kriz, Vitezslav
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Welsh, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    The FRK/RAK-SHB signaling cascade: a versatile signal-transduction pathway that regulates cell survival, differentiation and profileration2003Inngår i: Current molecular medicine, ISSN 1566-5240, E-ISSN 1875-5666, Vol. 3, nr 4, s. 313-324Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Recent experiments have unravelled novel signal transduction pathways that involve the SRC homology 2 (SH2) domain adapter protein SHB. SHB is ubiquitously expressed and contains proline rich motifs, a phosphotyrosine binding (PTB) domain, tyrosine phosphorylation sites and an SH2 domain and serves a role in generating signaling complexes in response to tyrosine kinase activation. SHB mediates certain responses in platelet-derived growth factor (PDGF) receptor-, fibroblast growth factor (FGF) receptor-, neural growth factor (NGF) receptor TRKA-, T cell receptor-, interleukin-2 (IL-2) receptor- and focal adhesion kinase- (FAK) signaling. Upstream of SHB in some cells lies the SRC-like FYN-Related Kinase FRK / RAK (also named BSK / IYK or GTK). FRK / RAK and SHB exert similar effects when overexpressed in rat phaeochromocytoma (PC12) and β-cells, where they both induce PC12 cell differentiation and β-cell proliferation. Furthermore, β-cell apoptosis is augmented by these proteins under conditions that cause β-cell degeneration. The FRK / RAK-SHB responses involve FAK and insulin receptor substrates (IRS) -1 and -2.

    Besides regulating apoptosis, proliferation and differentiation, SHB is also a component of the T cell receptor (TCR) signaling response. In Jurkat T cells, SHB links several signaling components with the TCR and is thus required for IL-2 production. In endothelial cells, SHB both promotes apoptosis under conditions that are anti-angiogenic, but is also required for proper mitogenicity, spreading and tubular morphogenesis. In embryonic stem cells, dominant-negative SHB (R522K) prevents early cavitation of embryoid bodies and reduces differentiation to cells expressing albumin, amylase, insulin and glucagon, suggesting a role of SHB in development.

    In summary, SHB is a versatile signal transduction molecule that produces diverse biological responses in different cell types under various conditions. SHB operates downstream of GTK in cells that express this kinase.

  • 87.
    Annerén, Cecilia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Reedquist, K A
    Bos, J L
    Welsh, M
    GTK, a Src-related tyrosine kinase, induces nerve growth factor-independent neurite outgrowth in PC12 cells through activation of the Rap1 pathway: Relationship to Shb tyrosine phosphorylation and elevated levels of focal adhesion kinase2000Inngår i: J Biol Chem, Vol. 275, s. 29153-29161Artikkel i tidsskrift (Fagfellevurdert)
  • 88.
    Annerén, Cecilia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Welsh, M
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Increased cytokine-induced cytotoxicity of pancreatic islet cells from transgenic mice expressing the Src-like tyrosine kinase GTK2001Inngår i: Mol Med., Vol. 7, s. 301-310Artikkel i tidsskrift (Fagfellevurdert)
  • 89.
    Annerén, Cecilia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Welsh, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    GTK Tyrosine Kinase-induced Alteration of IRS-protein Signalling in Insulin Producing Cells2002Inngår i: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 8, nr 11, s. 705-713Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Insulin receptor substrate proteins (IRS) mediate various effects of insulin, including regulation of glucose homeostasis, cell growth and survival. To understand the underlying mechanisms explaining the effects of the Src-related tyrosine kinase GTK on beta-cell proliferation and survival, insulin-signalling pathways involving IRS-1 and IRS-2 were studied in islet cells and RINm5F cells overexpressing wild-type and two different mutants of the SRC-related tyrosine kinase GTK. MATERIALS AND METHODS: Islets isolated from transgenic mice and RINm5F cells overexpressing wild-type and mutant GTK were analysed for IRS-1, IRS-2, SHB, AKT and ERK phosphorylation/activity by Western blot analysis. RESULTS: RINm5F cells expressing the kinase active mutant Y504F-GTK and islet cells from GTK(Y504F) -transgenic mice exhibited reduced insulin-induced tyrosine phosphorylation of IRS-1 and IRS-2. In RINm5F cells, the diminished IRS-phosphorylation was accompanied by a reduced insulin-stimulated activation of phosphatidylinositol 3-kinase (PI3K), AKT and Extracellular Signal-Regulated Kinase, partly due to an increased basal activity. In addition, increased tyrosine phosphorylation of the SHB SH2 domain-adaptor protein and its association with IRS-2, IRS-1 and focal adhesion kinase was observed in these cells. RINm5F cells overexpressing wild-type GTK also exhibited reduced activation of IRS-2, PI3K and AKT, whereas cells expressing a GTK mutant with lower kinase activity (GTK(Y394F)) exhibited insignificantly altered responses to insulin compared to the mock transfected cells. Moreover, GTK was shown to associate with and phosphorylate SHB in transiently transfected COS-7 cells, indicating that SHB is a specific substrate for GTK. CONCLUSIONS: The results suggest that GTK signals via SHB to modulate insulin-stimulated pathways in beta cells and this may explain previous results showing an increased beta-cell mass in GTK-transgenic mice.

  • 90.
    Annerén, Cecilia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Welsh, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Role of the Bsk/lyk non-receptor tyrosine kinase for the control of growth and hormone production in RINm5F cells2000Inngår i: Growth Factors, ISSN 0897-7194, E-ISSN 1029-2292, Vol. 17, s. 233-247Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Bsk/Iyk, a murine non-receptor-tyrosine kinase which is expressed in fetal and adult islet of Langerhans was previously found to decrease NIH3T3 cell proliferation when expressed as a Y497/504F-mutant. We presently wanted to determine the effects of Bsk/Iyk on the proliferation of insulin producing cells. Cells expressing Bsk/IykY497/504F and Bsk/IykY504F display a decreased proliferation rate and express higher levels of the cell cycle inhibitor p27/Kip1 compared to control cells. These mutants also conferred diminished cell viability in response to INF-gamma and IL-1beta and contain higher levels of glucagon mRNA. Wild-type Bsk/Iyk is mainly localized at the plasma membrane whereas mutant Bsk/Iyk can enter the nucleus. In vitro kinase reactions using an exogenous substrate indicate a complicated mode of regulation of kinase activity by Y497 and Y504 with the latter being homologous to Y527 in pp60c-Src. These findings suggest that Bsk/Iyk might play a role in inhibiting cell proliferation, transducing cytokine-induced cytotoxicity and regulating hormone production of endocrine pancreatic cells.

  • 91.
    Annerén, Cecilia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Welsh, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Jansson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Glucose intolerance and reduced islet blood flow in transgenic mice expressing the FRK tyrosine kinase under the control of the rat insulin promoter2007Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 292, nr 4, s. E1183-E1190Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The FRK tyrosine kinase has previously been shown to transduce β-cell cytotoxic signals in response to cytokines and streptozotocin and to promote β-cell proliferation and an increased β-cell mass. We therefore aimed to further evaluate the effects of overexpression of FRK tyrosine kinase in β-cells. A transgenic mouse expressing kinase-active FRK under control of the insulin promoter (RIP-FRK) was studied with regard to islet endocrine function and vascular morphology. Mild glucose intolerance develops in RIP-FRK male mice of at least 4 mo of age. This effect is accompanied by reduced glucose-stimulated insulin secretion in vivo and reduced second-phase insulin secretion in response to glucose and arginine upon pancreas perfusion. Islets isolated from the FRK transgenic mice display a glucose-induced insulin secretory response in vitro similar to that of control islets. However, islet blood flow per islet volume is decreased in the FRK transgenic mice. These mice also exhibit a reduced islet capillary lumen diameter as shown by electron microscopy. Total body weight and pancreas weight are not significantly affected, but the β-cell mass is increased. The data suggest that long-term expression of active FRK in β-cells causes an in vivo insulin-secretory defect, which may be the consequence of islet vascular abnormalities that yield a decreased islet blood flow.

  • 92.
    Anvari, Ebrahim
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Fred, Rikard G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Welsh, Nils
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    The H-1-Receptor Antagonist Cetirizine Protects Partially Against Cytokine- and Hydrogen Peroxide-Induced beta-TC6 Cell Death In Vitro2014Inngår i: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 43, nr 4, s. 624-629Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective It has been proposed that the histamine 1 (H-1) receptor not only promotes allergic reactions but also modulates autoimmune diseases, such as type 1 diabetes. In line with this, it has recently been reported that the H-1-receptor antagonist cetirizine can counteract the activation of signals/factors pertinent to the pathogenesis of type 1 diabetes and cytokine-induced beta-cell destruction. Therefore, the overall aim of this study was to determine whether H-1-receptor antagonists affect cytokine-induced beta-cell death and signaling in vitro. Methods The insulin-producing cell line beta-TC6 was exposed to the proinflammatory cytokines interleukin 1 beta(+) interferon gamma, or hydrogen peroxide. The H-1-receptor antagonists desloratadine and cetirizine were added to the cell cultures and cell viability; macrophage inhibitory factor levels, c-Jun N-terminal kinase phosphorylation, c-Jun expression, and beta-catenin levels were analyzed by flow cytometry, real-time polymerase chain reaction, and immunoblotting. Results Cetirizine protected partially against both cytokine- and hydrogen peroxide-induced cell death. This effect was paralleled by an inhibition of cytokine-induced c-Jun N-terminal kinase phosphorylation, c-Jun induction, and a restoration of macrophage inhibitory factor contents. Cetirizine also increased the beta-TC6 cell contents of beta-catenin at basal conditions. Conclusions Our results indicate a protective effect of a specific H-1-receptor antagonist.

  • 93.
    Anvari, Ebrahim
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wang, Xuan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sandler, Stellan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Welsh, Nils
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    The H1-receptor antagonist cetirizine ameliorates high-fat diet-induced glucose intolerance in male C57BL/6 mice, but not diabetes outcome in female non-obese diabetic (NOD) mice2015Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, nr 1, s. 40-46Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. It has been proposed that the histamine 1-receptor (H1-receptor) not only promotes allergic reactions, but also modulates innate immunity and autoimmune reactions. In line with this, we have recently reported that the H1-receptor antagonist cetirizine partially counteracts cytokine-induced beta-cell signaling and destruction. Therefore, the aim of this study was to determine whether cetirizine affects diabetes in NOD mice, a model for human type 1 diabetes, and glucose intolerance in high-fat diet C57BL/6 mice, a model for human glucose intolerance. Methods. Female NOD mice were treated with cetirizine in the drinking water (25 mg/kg body weight) from 9 until 30 weeks of age during which precipitation of diabetes was followed. Male C57BL/6 mice were given a high-fat diet from 5 weeks of age. When the mice were 12 weeks of age cetirizine was given for 2 weeks in the drinking water. The effects of cetirizine were analyzed by blood glucose determinations, glucose tolerance tests, and insulin sensitivity tests. Results. Cetirizine did not affect diabetes development in NOD mice. On the other hand, cetirizine treatment for 1 week protected against high-fat diet-induced hyperglycemia. The glucose tolerance after 2 weeks of cetirizine treatment was improved in high-fat diet mice. We observed no effect of cetirizine on the insulin sensitivity of high-fat diet mice. Conclusion. Our results suggest a protective effect of cetirizine against high-fat diet-induced beta-cell dysfunction, but not against autoimmune beta-cell destruction.

  • 94.
    Anvari, Ebrahim
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wikström, Per
    Walum, Erik
    Welsh, Nils
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    The novel NADPH oxidase 4 inhibitor GLX351322 counteracts glucose intolerance in high-fat diet-treated C57BL/6 mice2015Inngår i: Free radical research, ISSN 1071-5762, E-ISSN 1029-2470, Vol. 49, nr 11, s. 1308-1318Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In type 2 diabetes, it has been proposed that pancreatic beta-cell dysfunction is promoted by oxidative stress caused by NADPH oxidase (NOX) overactivity. Five different NOX enzymes (NOX1-5) have been characterized, among which NOX1 and NOX2 have been proposed to negatively affect beta-cells, but the putative role of NOX4 in type 2 diabetes-associated beta-cell dysfunction and glucose intolerance is largely unknown. Therefore, we presently investigated the importance of NOX4 for high-fat diet or HFD-induced glucose intolerance using male C57BL/6 mice using the new NOX4 inhibitor GLX351322, which has relative NOX4 selectivity over NOX2. In HFD-treated male C57BL/6 mice a two-week treatment with GLX351322 counteracted non-fasting hyperglycemia and impaired glucose tolerance. This effect occurred without any change in peripheral insulin sensitivity. To ascertain that NOX4 also plays a role for the function of human beta-cells, we observed that glucose- and sodium palmitate-induced insulin release from human islets in vitro was increased in response to NOX4 inhibitors. In long-term experiments (1-3 days), high-glucose-induced human islet cell reactive oxygen species (ROS) production and death were prevented by GLX351322. We propose that while short-term NOX4-generated ROS production is a physiological requirement for beta-cell function, persistent NOX4 activity, for example, during conditions of high-fat feeding, promotes ROS-mediated beta-cell dysfunction. Thus, selective NOX inhibition may be a therapeutic strategy in type 2 diabetes.

  • 95.
    Aoyagi, K
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Bergsten, Peter
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Eriksson, Ulf
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Ebendal, Ted
    Institutionen för neurovetenskap.
    Hellerstrom, Claes
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    In vitro regulation of insulin release and biosynthesis of fetal rat pancreatic cells explanted on pregnancy day 16.1997Inngår i: Biol Neonate, Vol. 71, s. 60-68Artikkel i tidsskrift (Fagfellevurdert)
  • 96.
    Aresh, Bejan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Freitag, Fabio B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Perry, Sharn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Blümel, Edda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Lau, Joey
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Franck, Marina C.M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Lagerström, Malin C.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Spinal Cord Interneurons Expressing the Gastrin-Releasing Peptide Receptor Convey Itch Through VGLUT2-Mediated Signaling2017Inngår i: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 158, nr 5, s. 945-961Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Itch is a sensation that promotes the desire to scratch, which can be evoked by mechanical and chemical stimuli. In the spinal cord, neurons expressing the gastrin-releasing peptide receptor (GRPR) have been identified as specific mediators of itch. However, our understanding of the GRPR population in the spinal cord, and thus how these neurons exercise their functions, is limited. For this purpose, we constructed a Cre line designed to target the GRPR population of neurons (Grpr-Cre). Our analysis revealed that Grpr-Cre cells in the spinal cord are predominantly excitatory interneurons that are found in the dorsal lamina, especially in laminae II-IV. Application of the specific agonist gastrin-releasing peptide induced spike responses in 43.3% of the patched Grpr-Cre neurons, where the majority of the cells displayed a tonic firing property. Additionally, our analysis showed that the Grpr-Cre population expresses Vglut2 mRNA, and mice ablated of Vglut2 in Grpr-Cre cells (Vglut2-lox; Grpr-Cre mice) displayed less spontaneous itch and attenuated responses to both histaminergic and nonhistaminergic agents. We could also show that application of the itch-inducing peptide, natriuretic polypeptide B, induces calcium influx in a subpopulation of Grpr-Cre neurons. To summarize, our data indicate that the Grpr-Cre spinal cord neural population is composed of interneurons that use VGLUT2-mediated signaling for transmitting chemical and spontaneous itch stimuli to the next, currently unknown, neurons in the labeled line of itch.

  • 97.
    Arnadottir, M
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Hultberg, B
    Roomans, G M
    Institutionen för medicinsk cellbiologi.
    Serum total homocysteine concentration before anda after renal transplntation.1998Inngår i: Kidney int, Vol. 54, s. 1380-Artikkel i tidsskrift (Fagfellevurdert)
  • 98.
    Ashrafzadeh, Parham
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Exploring Cellular Dynamics: From Vesicle Tethering to Cell Migration2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Cells in the body communicate with each other in order to cooperate efficiently. This communication is in part achieved by regulated secretion of signaling molecules, which when released from a cell may activate receptors present at the plasma membrane of an adjacent cell. Such signals affect both cell fate and behavior. Dysregulated signaling may lead to disease, including cancer. This thesis is focused on how exocytosis and subsequent activation and trafficking of receptors can be regulated, and what the consequences of this regulation may be for cell migration.

    Actin filaments are important transport structures for secretory vesicle trafficking. In Paper 1, actin polymerization was shown to induce formation of ordered lipid domains in the plasma membrane. Accordingly, actin filaments may thus create and stabilize specific membrane domains that enable docking of vesicles containing secretory cargo.

    The RhoGEF FGD5 regulates Cdc42 which can result in cytoskeletal rearrangements. In Paper II, FGD5 was shown to be selectively expressed in blood vessels and required for normal VEGFR2 signaling. FGD5 protected VEGFR2 from proteasome-mediated degradation and was essential for endothelial cells to efficiently respond to chemotactic gradients of VEGFA.

    The exocyst component EXOC7 is essential for tethering secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. In Paper III, EXOC7 was required for trafficking of VEGFR2-containing vesicles to the inner plasma membrane and VEGFR2 presentation at the cell surface.

    The ability of tumor cells to escape the primary tumor and establish metastasis is in part dependent on their capacity to migrate. In Paper IV, a method based on time-lapse microscopy and fluorescent dyes was created to analyze single cancer cell migration in mixed cancer cell cultures, and in particular the influence of different types on neighboring cells was assessed.

    In conclusion, these studies have enhanced our understanding of the mechanisms behind cellular trafficking, and may be applied in the future to develop more specific therapeutics to treat cancer and other diseases associated with abnormal angiogenesis and cellular migration.

    Delarbeid
    1. Actin filaments attachment at the plasma membrane in live cells cause the formation of ordered lipid domains
    Åpne denne publikasjonen i ny fane eller vindu >>Actin filaments attachment at the plasma membrane in live cells cause the formation of ordered lipid domains
    2013 (engelsk)Inngår i: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1828, nr 3, s. 1102-1111Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The relationship between ordered plasma membrane nanodomains, known as lipid rafts, and actin filaments is the focus of this study. Plasma membrane order was followed in live cells at 37°C using laurdan and di-4-ANEPPDHQ to report on lipid packing. Disrupting actin polymerisation decreased the fraction of ordered domains, which strongly argue that unstimulated cells have a basal level of ordered domains. Stabilising actin filaments had the opposite effect and increased the proportion of ordered domains. Decreasing the plasma membrane level of 4-phosphate-inositides lowers the number of attachment points for actin filaments and reduced the proportion of ordered domains. Aggregation of plasma membrane molecules, both lipid raft and non-lipid raft markers, lead to the formation of ordered domains. The increase in ordered domains was correlated with an increase in actin filaments just beneath the plasma membrane. In live cell plasma membrane blebs, which are detached from the underlying actin filaments, the fraction of ordered domains was low and GM1 could not be patched to form ordered domains. We conclude that ordered domains form when actin filaments attach to the plasma membrane. This downplays lipid-lipid interactions as the main driving force behind the formation of ordered membrane domains in vivo, giving greater prominence to membrane-intracellular filament interactions.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-196480 (URN)10.1016/j.bbamem.2012.12.004 (DOI)000315473400021 ()23246974 (PubMedID)
    Tilgjengelig fra: 2013-03-10 Laget: 2013-03-10 Sist oppdatert: 2018-01-11bibliografisk kontrollert
    2. FGD5 sustains vascular endothelial growth factor A (VEGFA) Signaling through inhibition of proteasome-mediated VEGF-receptor 2 degradation
    Åpne denne publikasjonen i ny fane eller vindu >>FGD5 sustains vascular endothelial growth factor A (VEGFA) Signaling through inhibition of proteasome-mediated VEGF-receptor 2 degradation
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-306177 (URN)
    Tilgjengelig fra: 2016-10-25 Laget: 2016-10-25 Sist oppdatert: 2018-02-19
    3. Exocyst complex component 7 (EXOC7) regulates vascular endothelial growth factor receptor 2 (VEGFR2) trafficking to the plasma membrane
    Åpne denne publikasjonen i ny fane eller vindu >>Exocyst complex component 7 (EXOC7) regulates vascular endothelial growth factor receptor 2 (VEGFR2) trafficking to the plasma membrane
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-306178 (URN)
    Tilgjengelig fra: 2016-10-25 Laget: 2016-10-25 Sist oppdatert: 2018-01-14
    4. A tracking strategy for analyzing single cancer cell migration behavior in mixed cancer cell cultures
    Åpne denne publikasjonen i ny fane eller vindu >>A tracking strategy for analyzing single cancer cell migration behavior in mixed cancer cell cultures
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-306561 (URN)
    Tilgjengelig fra: 2016-10-28 Laget: 2016-10-28 Sist oppdatert: 2018-01-14
  • 99.
    Ashrafzadeh, Parham
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Dinic, Jelena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Parmryd, Ingela
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Actin Filaments Attachment to the Plasma Membrane Cause the Formation of Ordered Lipid Domains in Live Cells2014Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, nr 2, s. 706A-706AArtikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    The aim of this study was to investigate the relationship between ordered plasma membrane nanodomains and actin filaments using di-4-ANEPPDHQ and laurdan together with the reagents that affect actin filament dynamics in live Jurkat and primary T cells. The degree of lipid packing can be quantified using polarity sensitive membrane dyes such as laurdan and di-4-ANEPPDHQ. These two dyes display a red shift in their emission peaks for membranes in ld phase relative to lo phase. Laurdan is uncharged and can easily flip between two leaflets of the plasma membrane and we demonstrate that it reports equally on the two leaflets of the plasma membrane.

  • 100.
    Ashrafzadeh, Parham
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Parmryd, Ingela
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Methods applicable to membrane nanodomain studies?2015Inngår i: Essays in Biochemistry, ISSN 0071-1365, E-ISSN 1744-1358, Vol. 57, s. 57-68Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Membrane nanodomains are dynamic liquid entities surrounded by another type of dynamic liquid. Diffusion can take place inside, around and in and out of the domains, and membrane components therefore continuously shift between domains and their surroundings. In the plasma membrane, there is the further complexity of links between membrane lipids and proteins both to the extracellular matrix and to intracellular proteins such as actin filaments. In addition, new membrane components are continuously delivered and old ones removed. On top of this, cells move. Taking all of this into account imposes great methodological challenges, and in the present chapter we discuss some methods that are currently used for membrane nanodomain studies, what information they can provide and their weaknesses.

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