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  • 101.
    Asif, Sana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Ekdahl, Kristina N
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Linnæus Center of Biomaterials Chemistry, Linnæus University, SE-391 82 Kalmar, Sweden.
    Fromell, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Gustafson, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Barnkirurgi.
    Barbu, Andreea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Le Bland, Katarina
    Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Karolinska Institute, and Hematology and Regenerat ive Medicine Centre at Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.
    Nilsson, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Teramura, Yuji
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Department of Bioengineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
    Heparinization of cell surfaces with short pepetide-conjugated PEG-lipid regulates thromboinflammation in thransplantation of human MSCs and hepatocytes2016Inngår i: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 35, s. 194-205Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Infusion of therapeutic cells into humans is associated with immune responses, including thromboinflammation, which result in a large loss of transplanted cells\ To address these problems, heparinization of the cell surfaces was achieved by a cell-surface modification technique using polyethylene glycol conjugated phospholipid (PEG-lipid) derivatives. A short heparin-binding peptide was conjugated to the PEG-lipid for immobilization of heparin conjugates on the surface of human mesenchymal stem cells (hMSCs) and human hepatocytes. Here three kinds of heparin-binding peptides were used for immobilizing heparin conjugates and examined for the antithrombogenic effects on the cell surface. The heparinized cells were incubated in human whole blood to evaluate their hemocompatibility by measuring blood parameters such as platelet count, coagulation markers, complement markers, and Factor Xa activity. We found that one of the heparin-binding peptides did not show cytotoxicity after the immobilization with heparin conjugates. The degree of binding of the heparin conjugates on the cell surface (analyzed by flow cytometer) depended on the ratio of the active peptide to control peptide. For both human MSCs and hepatocytes in whole-blood experiments, no platelet aggregation was seen in the heparin conjugate-immobilized cell group vs. the controls (non-coated cells or control peptide). Also, the levels of thrombin-antithrombin complex (TAT), C3a, and sC5b-9 were significantly lower than those of the controls, indicating a lower activation of coagulation and complement. Factor Xa analysis indicated that the heparin conjugate was still active on the cell surface at 24 h post-coating. It is possible to immobilize heparin conjugates onto hMSC and human hepatocyte surfaces and thereby protect the cell surfaces from damaging thromboinflammation. Statement of Signigficance We present a promising approach to enhance the biocompatibility of therapeutic cells. Here we used short peptide-conjugated PEG-lipid for cell surface modification and heparin conjugates for the coating of human hepatocytes and MSCs. We screened the short peptides to find higher affinity for heparinization of cell surface and performed hemocompatibility assay of heparinized human hepatocytes and human MSCs in human whole blood. Using heparin-binding peptide with higher affinity, not only coagulation activation but also complement activation was significantly suppressed. Thus, it was possible to protect human hepatocytes and human MSCs from the attack of thromboinflammatory activation, which can contribute to the improvement graft survival.

  • 102.
    Atuma, C
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Engstrand, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för fysiologi.
    Holm, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för fysiologi.
    Helicobacter pylori extracts reduce gastric mucosal blood flow by a nitric oxide-independent but mast cell- and platelet-activating factor receptor-dependent pathway in rats1999Inngår i: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 34, nr 12, s. 1183-1189Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: We have previously shown that water extracts from Helicobacter pylori reduce gastric mucosal blood flow by approximately 15%. It has also been suggested that H. pylori can inhibit endogenous nitric oxide (NO) biosynthesis. Our aim was to examine whether the reduction in blood flow induced by H. pylori is the direct consequence of an NO synthase inhibition and the possible involvement of mast cell degranulation.

    METHODS: A water extract was produced from wildtype strain 88-23. The extract was applied on the exteriorized gastric corporal mucosa in inactin-anesthetized rats, after removing as much as possible of the mucus layer, during intravital microscopy. Blood flow was measured with laser-Doppler flowmetry.

    RESULTS: In rats pretreated with the NO synthase inhibitor N-nitro-L-arginine there was a 19% +/- 6% reduction in blood flow 40 min after application of the extract, and a 27% +/- 9% reduction after another 20 min with saline. The reduction was abolished by concomitant pretreatment with the mast cell stabilizer ketotifen or the platelet-activating factor (PAF) receptor antagonist WEB2086.

    CONCLUSION: The reduction in mucosal blood flow induced by the extract was probably mediated through an acute inflammatory response involving mast cell degranulation with consequent PAF secretion. The effect on blood flow was not the result of a decrease in vascular tone due to an inhibition of endogenous NO biosynthesis.

  • 103.
    Azarbayjani, Faranak
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. 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.
    Danielsson, Bengt R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Increased susceptibility to phenytoin teratogenicity: Excessive generation of reactive oxygen species or impaired antioxidant defense?2006Inngår i: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 99, nr 4, s. 305-311Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Phenytoin is a human and animal teratogen. Accumulating evidence suggests that the teratogenicity is associated with a potential of phenytoin to cause embryonic cardiac arrhythmia and resultant generation of toxic reactive oxygen species via hypoxia-reoxygenation mechanisms. The A/J mouse is more susceptible to phenytoin teratogenicity than other mouse strains. The aim of this study was to investigate whether A/J mice have other antioxidant enzyme activities than C57BL/6J and CD-1 mice. Also, strain differences in phenytoin effects on embryonic heart rate and rhythm were determined. Another objective was to determine whether a spin trapping agent with capacity to capture reactive oxygen species alter the developmental toxicity of phenytoin. Treatment with this agent resulted in a marked decrease in phenytoin teratogenicity, which supports the idea that reactive oxygen species are important mediators for the teratogenic action of phenytoin. The A/J mice embryos were most susceptible to the adverse cardiac effects of phenytoin and had the highest activity of superoxide dismutase and glutathione peroxidase, while the activity of catalase was the same in embryos of the three different strains. The high activities of antioxidant enzymes in the A/J stain indicate that the sensitivity to develop malformations is caused by excessive arrhythmia-related generation of reactive oxygen species rather than impaired antioxidant defense.

  • 104. Bakke-McKellep, A. M.
    et al.
    Refstie, S.
    Stefansson, S. O.
    Vanthanouvong, Viengphet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Roomans, Godfried
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Hemre, G. -I
    Krogdahl, Å.
    Effects of dietary soybean meal and photoperiod cycle on osmoregulation following seawater exposure in Atlantic salmon smolts2006Inngår i: Journal of Fish Biology, ISSN 0022-1112, E-ISSN 1095-8649, Vol. 69, nr 5, s. 1396-1426Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Atlantic salmon Salmo salar juveniles were fed either fishmeal-based diets (FM) or diets in which soybean meal (SBM) partly replaced the FM from first feeding on. The fish were kept at continuous daylight during the juvenile stage. During the last 3 weeks before reaching 100 g body mass, all fish were subjected to 12L:12D. Starting at 100 g body mass, groups of 60 fish from each feeding background were subjected to continuous light for 12 weeks (short winter), or a square-wave photoperiod cycle to stimulate parr to smolt transformation with 8L:16D during the first 6 weeks, and then continuous light during the last 6 weeks (long winter). After the 12 weeks, 20 fish from each treatment were subjected to 0, 24 or 96 h seawater exposure at a water salinity of 34. Hypo-osmoregulatory ability at seawater exposure was assessed by mortality, intestinal pathology, plasma ion concentrations and osmolality, gill Na+/K+-ATPase activity and element concentrations in the cytoplasm of distal intestinal enterocytes using X-ray microanalysis. The hypo-osmoregulatory capacity was higher in fish kept at short winter than at long winter, apparently due to more rapid development of gill Na+/K+-ATPase activity. Fish fed SBM suffered typical soybean meal-induced histological alterations of the distal intestine and apparent reductions in digestive function in the more proximal gastrointestinal regions. The net osmoregulatory capacity of these fish was maintained, as indicated by higher gill Na+/K+-ATPase activity and lower plasma Na+, Ca2+ and osmolality compared to the FM-fed fish. Thus, feeding SBM did not impair the hypo-osmoregulatory ability of the Atlantic salmon following seawater exposure.

  • 105.
    Barbu, A
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Welsh, N
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Saldeen, J
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Cytokine-induced apoptosis and necrosis are preceded by disruption of themitochondrial membrane potential (Deltapsi(m)) in pancreatic RINm5F cells:prevention by Bcl-2.2002Inngår i: Mol Cell Endocrinol, Vol. 190, s. 75-Artikkel i tidsskrift (Fagfellevurdert)
  • 106. Barbu, Andrea R
    et al.
    Welsh, Nils
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Gene Therapy2010Inngår i: Textbook of Diabetes / [ed] Richard I. G. Holt, Clive Cockram, Allan Flyvbjerg, Barry J. Goldstein, Wiley-Blackwell , 2010, 4th edition, s. 1064-1069Kapittel i bok, del av antologi (Annet vitenskapelig)
  • 107.
    Barbu, Andreea
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    In vitro studies of B-cell death and survival: Modulation by adenoviral vectors and Bcl-2 overexpression2004Inngår i: Acta Universitatis Upsaliensis, Vol. 1320Annet (Annet vitenskapelig)
  • 108.
    Barbu, Andreea
    et al.
    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.
    Sandberg, Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Quach, My
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    The use of hydrogen gas clearance for blood flow measurements in single endogenous and transplanted pancreatic islets2015Inngår i: Microvascular Research, ISSN 0026-2862, E-ISSN 1095-9319, Vol. 97, s. 124-129Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The blood perfusion of pancreatic islets is regulated independently from that of the exocrine pancreas, and is of importance for multiple aspects of normal islet function, and probably also during impaired glucose tolerance. Single islet blood flow has been difficult to evaluate due to technical limitations. We therefore adapted a hydrogen gas washout technique using microelectrodes to allow such measurements. Platinum micro-electrodes monitored hydrogen gas clearance from individual endogenous and transplanted islets in the pancreas of male Lewis rats and in human and mouse islets implanted under the renal capsule of male athymic mice. Both in the rat endogenous pancreatic islets as well as in the intra-pancreatically transplanted islets, the vascular conductance and blood flow values displayed a highly heterogeneous distribution, varying by factors 6-10 within the same pancreas. The blood flow of human and mouse islet grafts transplanted in athymic mice was approximately 30% lower than that in the surrounding renal parenchyma. The present technique provides unique opportunities to study the islet vascular dysfunction seen after transplantation, but also allows for investigating the effects of genetic and environmental perturbations on islet blood flow at the single islet level in vivo. (C) 2014 The Authors. Published by Elsevier Inc.

  • 109.
    Barbu, Andreea
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Bodin, Bbirgitta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Källskog, Örjan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin diabetes och metabolism.
    Sandberg, Monica
    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.
    Jansson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Blood flow in endogenous and transplanted pancreatic islets in anesthetized rats: Effects of lactate and pyruvate2012Inngår i: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 41, nr 8, s. 1263-1271Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: The objective of this study was to evaluate the effects of exogenously administered lactate and pyruvate on blood perfusion in endogenous and transplanted islets. METHODS: Anesthetized Wistar-Furth rats were given lactate or pyruvate intravenously, and regional blood perfusion was studied 3 or 30 minutes later with a microsphere technique. Separate rats received a 30-minute infusion of pyruvate or lactate into the portal vein before blood flow measurements. We also administered these substances to islet-implanted rats 4 weeks after transplantation and measured graft blood flow with laser Doppler flowmetry. The expression of monocarboxylate transporter 1 and lactate dehydrogenase A was analyzed. RESULTS: The expression of monocarboxylate transporter 1 and lactate dehydrogenase A was markedly up-regulated in transplanted as compared with endogenous islets. Administration of pyruvate, but not lactate, increased mesenteric blood flow after 3 minutes. Pyruvate decreased mesenteric blood flow after 30 minutes, whereas lactate decreased only islet blood flow. These responses were absent in transplanted animals. A continuous intraportal infusion of lactate or pyruvate increased selectively islet blood flow but did not affect blood perfusion of transplanted islets. CONCLUSIONS: Lactate and pyruvate affect islet blood flow through effects mediated by interactions between the liver and the nervous system. Such a response can help adjust the release of islet hormones during excess substrate concentrations.

  • 110.
    Barbu, Andreea
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Lejonklou, Margareta H
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Skogseid, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Progranulin Stimulates Proliferation of Mouse Pancreatic Islet Cells and Is Overexpressed in the Endocrine Pancreatic Tissue of an MEN1 Mouse Model2016Inngår i: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 45, nr 4, s. 533-540Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: Progranulin (PGRN) promotes cell growth and cell cycle progression in several cell types and contributes to tumorigenesis in diverse cancers. We have recently reported PGRN expression in islets and tumors developed in an MEN1 transgenic mouse. Here we sought to investigate PGRN expression and regulation after exposure to hypoxia as well as its effects on pancreatic islet cells and neuroendocrine tumors (NETs) in MEN1 mice.

    METHODS: Gene and protein expression were analyzed by quantitative polymerase chain reaction, immunohistochemistry, and Western blot. We also investigated PGRN expression in samples from patients carrying pancreatic NETs associated or not with the multiple endocrine neoplasia 1 syndrome, using enzyme-linked immunosorbent assay and immunohistochemistry analysis.

    RESULTS: Progranulin is upregulated in tumors and islets of the MEN1 mouse as well as in the serum of patients with pancreatic NETs associated with glucagonoma syndrome. In normal mice islets and pancreatic tumors, PGRN expression was strongly potentiated by hypoxia. Progranulin promotes cell proliferation in islet cells and βTC-6 cells, a process paralleled by activation of the mitogen-activated protein kinase signaling cascade.

    CONCLUSIONS: Our findings identify PGRN as an effective inducer of pancreatic islet cell proliferation and a possible important factor for pancreatic endocrine tumor development.

  • 111.
    Barbu, Andreea
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Persdotter Hedlund, Gabriella
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Lind, Jenny
    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.
    Pref-1 and adipokine expression inadipose tissues of GK And Zucker rats2009Inngår i: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 299, nr 2, s. 163-171Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In view of the central role of preadipocyte factor-1, adiponectin and leptin in white adipose tissue function, the aim of the present study was to analyze the mRNA expression of these proteins and of the inflammatory markers interleukin-6 and tumor necrosis factor-α in visceral and subcutaneous fat pads of rats with different metabolic disorders.

    We demonstrated highly divergent expression of preadipocyte factor-1, upregulated expression of adiponectin, interleukin-6 and TNF-α mRNA in adipose tissues of the diabetic Goto Kakizaki rat compared to the obese Zucker rat. This was correlated to an increased number of large adipocytes and serum levels of adiponectin. Furthermore, in all four strains studied (as above plus Wistar Furth and Zucker Lean), significant heterogeneity was evident in adipokine expression within specific adipose tissues previously defined as belonging to the visceral or subcutaneous fat depots.

    These results suggest that significantly increased levels of inflammation and redistribution of adipocyte size are mechanisms contributing to the development of type 2 diabetes in the GK rat.

  • 112.
    Barbu, Andreea R
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Akusjärvi, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Welsh, Nils
    Adenoviral-induced islet cell cytotoxicity is not counteracted by Bcl-2 overexpression2002Inngår i: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 8, nr 11, s. 733-741Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The ability to transfer immunoregulatory, cytoprotective, or anti-apoptotic genes into pancreatic islet cells may allow enhanced resistance against the autoimmune destruction of these cells in type 1 diabetes. We describe here an inducible transduction system for expression of the anti-apoptotic bcl-2 gene in insulin-producing cells as a potential tool for protecting against beta-cell death.

    MATERIALS AND METHODS: Isolated pancreatic rat islet cells or rat insulinoma (RINm5F) cells were transduced using a progesterone antagonist (RU 486) inducible adenoviral vector system, expressing the bcl-2 gene. Bcl-2 overexpression was measured by Western blot assays and flow cytometry analysis. Following exposure to cytokines or to the mitochondrial uncoupler FCCP, cell survival was determined using fluorescence and electron microscopy, and a colorimetric assay (2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]- 2H-tetrazolium-5-carboxanilide [XTT]-based) for cell viability. The mitochondrial membrane potential ((m)) was assessed using the lipophilic cationic membrane potential-sensitive dye JC-1.

    RESULTS: The adenoviral gene transfer system induced Bcl-2 expression in more than 70% of beta-cells and the protein expression levels were successfully regulated in response to varying concentrations of progesterone antagonist RU 486. Exposure of islet cells to proinflammatory cytokines IL-1beta, TNF-alpha, and IFN-gamma, or to the mitochondrial uncoupler FCCP resulted in disruption of the mitochondrial membrane potential ((m)) and beta-cell death. Bcl-2 overexpression stabilized (m) and prevented cell death in RINm5F cells but not in islet cells. In addition, prolonged in vitro culture revealed adenoviral-induced islet cell necrosis.

    CONCLUSIONS: The RU 486-regulated adenoviral system can achieve an efficient control of gene transfer at relatively low doses of the adenoviral vector. However, Bcl-2 overexpression in islet cells did not prevent adenoviral- or cytokine-induced toxicity, suggesting that the specific death pathway involved in adenoviral toxicity in beta-cells may bypass the mitochondrial permeability transition event.

  • 113.
    Barbu, Andreea R
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Akusjärvi, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Welsh, Nils
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Adenoviral-mediated transduction of human pancreatic islets: importance of adenoviral genome for cell viability and association with a deficient antiviral response2005Inngår i: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 146, nr 5, s. 2406-2414Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    As adenoviral vectors are extensively used for genetic manipulation of insulin-producing cells in vitro, there is an increasing need to evaluate their effects on the function, morphology, and viability of transduced pancreatic islets. In the present study we observed that specific adenoviral genotypes, carrying E4 and E1/E3 deletions, correlate with differential induction of necrosis in pancreatic islet cells. In particular, the adenovirus death protein encoded from the E3 region of the adenoviral genome was able to modulate the changes induced in the morphology and viability of the transduced cells. We also propose a putative role for the transcriptional regulator pIX. Although human islet cells showed an increased resistance in terms of viral concentrations required for the induction of cell toxicity, our results showed that they were unable to build up an efficient antiviral response after transduction and that their survival was dependent on the exogenous addition of alpha-interferon. An intact and fully functional beta-cell is crucial for the successful application of gene therapy approaches in type 1 diabetes, and therefore, the implications of our findings need to be considered when designing vectors for gene transfer into pancreatic beta-cells.

  • 114.
    Barbu, Andreea R.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Bodin, Birgitta
    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.
    Welsh, Nils
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    A perfusion protocol for highly efficient transduction of intact pancreatic islets of Langerhans2006Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 49, nr 10, s. 2388-2391Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Successful gene transfer to pancreatic islets might be a powerful tool for dissecting the biological pathways involved in the functional impairment and destruction of beta cells in type 1 diabetes. In the long run, such an approach may also prove useful for promoting islet graft survival after transplantation in diabetic patients. However, efficient genetic modification of primary insulin-producing cells is limited by the specific compact structure of the pancreatic islet. We present here a whole-pancreas perfusion-based transduction procedure for genetic modification of intact pancreatic islets.

    We used flow cytometry analysis and confocal microscopy to evaluate the efficiency of in vitro and perfusion-based transduction protocols that use adenoviral and lentiviral vectors expressing green fluorescent protein. Islet cell viability was assessed by fluorescence microscopy and beta cell function was determined via glucose-stimulated insulin secretion.

    In intact rat and human pancreatic islets, adenoviral and lentiviral vectors mediated gene transfer to about 30% of cells, but they did not reach the inner cellular mass within the islet core. Using the whole-pancreas perfusion protocol, we demonstrate that at least in rodent models the centrally located insulin-producing cells can be transduced with high efficiency, while preserving the structural integrity of the islet. Moreover, islet cell viability and function are not impaired by this procedure.

    These results support the view that perfusion-based transduction protocols may significantly improve the yield of successfully engineered primary insulin-producing cells for diabetes research.

  • 115.
    Barbu, Andreea R
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Welsh, Nils
    Saldeen, Johan
    Cytokine-induced apoptosis and necrosis are preceded by disruption of the mitochondrial membrane potential in pancreatic RINm5F cells: prevention by Bcl-22002Inngår i: Molecular and Cellular Endocrinology, Vol. 190, s. 75-82Artikkel i tidsskrift (Fagfellevurdert)
  • 116.
    Barbu, Andreea Roxana
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    In vitro Studies of β-cell Death and Survival. Modulation by Adenoviral Vectors and Bcl-2 Overexpression2004Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Type 1 diabetes is a multifactorial disease resulting from the selective destruction of insulin-producing β-cells within the pancreatic islets of Langerhans. The mechanisms of β-cell death are not fully understood but cytokines are important mediators of this process. In the present study we found that the combination of IL-1β, TNF-α and IFN-γ induced a nitric oxide-dependent disruption of the mitochondrial membrane potential in rat insulin-producing RINm5F-cells, which seems to be a necessary event for both RINm5F-cell apoptosis and necrosis. The antiapoptotic protein Bcl-2 was able to prevent cellular death in RINm5F cells, most probably by counteracting the mitochondrial permeability transition. These results pointed out the potential of such antiapoptotic genes as gene therapy tools, to allow enhanced resistance against autoimmune destruction of β-cells in type 1 diabetes. For this purpose we used a progesterone-antagonist (RU 486)-inducible gene transfer system to achieve an efficient and controlled Bcl-2 overexpression in primary rat β-cells. However, in our experience, prolonged in vitro culture revealed adenoviral-induced islet cell necrosis, a process that was not prevented by Bcl-2 overexpression. Moreover, we observed that specific adenoviral genotypes correlate with differential induction of necrosis in both human and rat pancreatic islet cells. Although human islet cells showed an increased resistance in terms of viral concentrations required for the induction of cell-toxicity, our results showed that they were unable to build up an efficient antiviral response following infection and that their survival was dependent on the exogenous addition of α-interferon.

    In conclusion, adenoviral techniques for overexpression of antiapoptotic proteins in insulin-producing cells may provide useful tools against β-cell directed autoimmune destruction. However, understanding the specific interactions of the viral gene products with cellular proteins and how they are involved in β-cell death regulation is fundamental for an efficient and safe application of gene therapy approaches to type 1 diabetes.

    Delarbeid
    1. Cytokine-induced apoptosis and necrosis are preceded by disruption of the mitochondrial membrane potential in pancreatic RINm5F cells: prevention by Bcl-2
    Åpne denne publikasjonen i ny fane eller vindu >>Cytokine-induced apoptosis and necrosis are preceded by disruption of the mitochondrial membrane potential in pancreatic RINm5F cells: prevention by Bcl-2
    2002 Inngår i: Molecular and Cellular Endocrinology, Vol. 190, s. 75-82Artikkel i tidsskrift (Fagfellevurdert) Published
    Identifikatorer
    urn:nbn:se:uu:diva-91301 (URN)
    Tilgjengelig fra: 2004-02-03 Laget: 2004-02-03bibliografisk kontrollert
    2. Adenoviral-induced islet cell cytotoxicity is not counteracted by Bcl-2 overexpression
    Åpne denne publikasjonen i ny fane eller vindu >>Adenoviral-induced islet cell cytotoxicity is not counteracted by Bcl-2 overexpression
    2002 (engelsk)Inngår i: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 8, nr 11, s. 733-741Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND: The ability to transfer immunoregulatory, cytoprotective, or anti-apoptotic genes into pancreatic islet cells may allow enhanced resistance against the autoimmune destruction of these cells in type 1 diabetes. We describe here an inducible transduction system for expression of the anti-apoptotic bcl-2 gene in insulin-producing cells as a potential tool for protecting against beta-cell death.

    MATERIALS AND METHODS: Isolated pancreatic rat islet cells or rat insulinoma (RINm5F) cells were transduced using a progesterone antagonist (RU 486) inducible adenoviral vector system, expressing the bcl-2 gene. Bcl-2 overexpression was measured by Western blot assays and flow cytometry analysis. Following exposure to cytokines or to the mitochondrial uncoupler FCCP, cell survival was determined using fluorescence and electron microscopy, and a colorimetric assay (2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]- 2H-tetrazolium-5-carboxanilide [XTT]-based) for cell viability. The mitochondrial membrane potential ((m)) was assessed using the lipophilic cationic membrane potential-sensitive dye JC-1.

    RESULTS: The adenoviral gene transfer system induced Bcl-2 expression in more than 70% of beta-cells and the protein expression levels were successfully regulated in response to varying concentrations of progesterone antagonist RU 486. Exposure of islet cells to proinflammatory cytokines IL-1beta, TNF-alpha, and IFN-gamma, or to the mitochondrial uncoupler FCCP resulted in disruption of the mitochondrial membrane potential ((m)) and beta-cell death. Bcl-2 overexpression stabilized (m) and prevented cell death in RINm5F cells but not in islet cells. In addition, prolonged in vitro culture revealed adenoviral-induced islet cell necrosis.

    CONCLUSIONS: The RU 486-regulated adenoviral system can achieve an efficient control of gene transfer at relatively low doses of the adenoviral vector. However, Bcl-2 overexpression in islet cells did not prevent adenoviral- or cytokine-induced toxicity, suggesting that the specific death pathway involved in adenoviral toxicity in beta-cells may bypass the mitochondrial permeability transition event.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-91302 (URN)12520090 (PubMedID)
    Tilgjengelig fra: 2004-02-03 Laget: 2004-02-03 Sist oppdatert: 2017-12-14bibliografisk kontrollert
    3. Adenoviral-mediated transduction of human pancreatic islets: importance of adenoviral genome for cell viability and association with a deficient antiviral response
    Åpne denne publikasjonen i ny fane eller vindu >>Adenoviral-mediated transduction of human pancreatic islets: importance of adenoviral genome for cell viability and association with a deficient antiviral response
    2005 (engelsk)Inngår i: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 146, nr 5, s. 2406-2414Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    As adenoviral vectors are extensively used for genetic manipulation of insulin-producing cells in vitro, there is an increasing need to evaluate their effects on the function, morphology, and viability of transduced pancreatic islets. In the present study we observed that specific adenoviral genotypes, carrying E4 and E1/E3 deletions, correlate with differential induction of necrosis in pancreatic islet cells. In particular, the adenovirus death protein encoded from the E3 region of the adenoviral genome was able to modulate the changes induced in the morphology and viability of the transduced cells. We also propose a putative role for the transcriptional regulator pIX. Although human islet cells showed an increased resistance in terms of viral concentrations required for the induction of cell toxicity, our results showed that they were unable to build up an efficient antiviral response after transduction and that their survival was dependent on the exogenous addition of alpha-interferon. An intact and fully functional beta-cell is crucial for the successful application of gene therapy approaches in type 1 diabetes, and therefore, the implications of our findings need to be considered when designing vectors for gene transfer into pancreatic beta-cells.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-91303 (URN)10.1210/en.2004-1667 (DOI)15705772 (PubMedID)
    Tilgjengelig fra: 2004-02-03 Laget: 2004-02-03 Sist oppdatert: 2017-12-14bibliografisk kontrollert
  • 117.
    Barbu, Andreea
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Welsh, Nils
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Diabetes Mellitus: Gene Therapy2007Inngår i: ENCYCLOPEDIA OF LIFE SCIENCES, John Wiley & Sons , 2007Kapittel i bok, del av antologi (Annet (populærvitenskap, debatt, mm))
    Abstract [en]

    Gene therapy in diabetes mellitus can be defined as transfer of DNA to somatic cells in order to understand, treat or prevent the disease. For many gene therapy strategies in the treatment of diabetes, successful transduction of insulin producing cells is a prerequisite. Therefore, much effort is currently directed in developing efficient and non-toxic vectors for gene transfer in pancreatic insulin producing beta-cell. If available, these gene therapy tools could prevent the autoimmune beta-cell destruction in type 1 diabetes by protecting the remaining beta-cell mass in newly diagnosed diabetics or in prediabetic individuals at a high risk of becoming diabetic. Such an approach may also prove useful for promoting islet graft survival after transplantation in diabetic patients. Alternatively, attempts are being made to genetically engineer cells to become artificial beta-cells. Such cells could conceivably compensate for the lost endogenous beta-cell mass and restore a regulated insulin secretion.

  • 118.
    Barbu, Andreea
    et al.
    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.
    Lipofection of insulin-producing RINm5F cells: methodological improvements2007Inngår i: Journal of liposome research, ISSN 0898-2104, E-ISSN 1532-2394, Vol. 17, nr 2, s. 49-62Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cationic lipid/DNA-complexes have been widely used as gene transfer vectors because they are less toxic and immunogenic than viral vectors. The aim of the present study was to improve and characterize lipofection of an insulin-producing cell line. We compared the transfection efficiency of seven commercially available lipid formulations (Lipotaxi, SuperFect, Fugene, TransFast, Dosper, GenePORTER and LipofectAMINE) by flow cytometry analysis of GFP-expression. In addition, we have determined the influences of centrifugation, serum and a nuclear localization signal peptide on the lipofection efficiency. We observed that two lipid formulations, GenePORTER and LipofectAMINE, were able to promote efficient gene transfer in RINm5F cells. However, GenePORTER exhibited the important advantage of being able to transfect cells in the presence of serum and with less cytotoxicity than LipofectAMINE. LipofectAMINE-induced RINm5F cell death could partially be counteracted by TPA, forskolin or fumonisin β1. Finally, both centrifugation and a nuclear localization signal peptide increased transfection efficiency.

  • 119.
    Barbu, Andreea
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Welsh, Nils
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    The use of tetrazolium salt-based methods for determination of islet cell viability in response to cytokines: a cautionary note.2004Inngår i: Diabetologia, nr 47, s. 2042-2043Artikkel i tidsskrift (Fagfellevurdert)
  • 120.
    Barg, Sebastian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Copello, J A
    Fleischer, S
    Different interactions of cardiac and skeletal muscle ryanodine receptors with FK-506 binding protein isoforms1997Inngår i: American Journal of Physiology, ISSN 0002-9513, E-ISSN 2163-5773, Vol. 272, nr 5 Pt 1, s. C1726-C1733Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In the present study, we compare functional consequences of dissociation and reconstitution of binding proteins FKBP12 and FKBP12.6 with ryanodine receptors from cardiac (RyR2) and skeletal muscle (RyR1). The skeletal muscle RyR1 channel became activated on removal of endogenously bound FKBP12, consistent with previous reports. Both FKBP12 and FKBP12.6 rebind to FKBP-depleted RyR1 and restore its quiescent channel behavior by altering ligand sensitivity, as studied by single-channel recordings in planar lipid bilayers, and macroscopic behavior of the channels (ryanodine binding and net energized Ca2- uptake). By contrast, removal of FKBP12.6 from the cardiac RyR2 did not modulate the function of the channel using the same types of assays as for RyR1. FKBP12 or FKBP12.6 had no effect on channel activity of FKBP12.6-depleted cardiac RyR2, although FKBP12.6 rebinds. Our studies reveal important differences between the two ryanodine receptor isoforms with respect to their functional interaction with FKBP12 and FKBP12.6.

  • 121.
    Barg, Sebastian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Gandasi, Nikhil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Quantitative analysis of t-SNARE and Ca2+-channel clusters near secretory granules2010Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 53, nr Suppl. 1, s. S46-S46Artikkel i tidsskrift (Annet vitenskapelig)
  • 122.
    Barg, Sebastian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Gucek, Alenka
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    How Kiss-and-Run Can Make Us Sick: SOX4 Puts a Break on the Pore2016Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, nr 7, s. 1791-1793Artikkel i tidsskrift (Annet vitenskapelig)
  • 123.
    Barg, Sebastian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Knowles, M. K.
    Chen, X.
    Midorikawa, M.
    Almers, Wolfhard
    Syntaxin clusters assemble reversibly at sites of secretory granules in live cells2010Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, nr 48, s. 20804-20809Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Syntaxin resides in the plasma membrane, where it helps to catalyze membrane fusion during exocytosis. The protein also forms clusters in cell-free and granule-free plasma-membrane sheets. We imaged the interaction between syntaxin and single secretory granules by two-color total internal reflection microscopy in PC12 cells. Syntaxin-GFP assembled in clusters at sites where single granules had docked at the plasma membrane. Clusters were intermittently present at granule sites, as syntaxin molecules assembled and disassembled in a coordinated fashion. Recruitment to granules required the N-terminal domain of syntaxin, but not the entry of syntaxin into SNARE complexes. Clusters facilitated exocytosis and disassembled once exocytosis was complete. Syntaxin cluster formation defines an intermediate step in exocytosis.

  • 124.
    Barg, Sebastian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Olofsson, Charlotta S
    Schriever-Abeln, Jenny
    Wendt, Anna
    Gebre-Medhin, Samuel
    Renström, Erik
    Rorsman, Patrik
    Delay between fusion pore opening and peptide release from large dense-core vesicles in neuroendocrine cells2002Inngår i: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 33, nr 2, s. 287-299Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Peptidergic neurotransmission is slow compared to that mediated by classical neurotransmitters. We have studied exocytotic membrane fusion and cargo release by simultaneous capacitance measurements and confocal imaging of single secretory vesicles in neuroendocrine cells. Depletion of the readily releasable pool (RRP) correlated with exocytosis of 10%-20% of the docked vesicles. Some remaining vesicles became releasable after recovery of RRP. Expansion of the fusion pore, seen as an increase in luminal pH, occurred after approximately 0.3 s, and peptide release was delayed by another 1-10 s. We conclude that (1) RRP refilling involves chemical modification of vesicles already in place, (2) the release of large neuropeptides via the fusion pore is negligible and only proceeds after complete fusion, and (3) sluggish peptidergic transmission reflects the time course of vesicle emptying.

  • 125.
    Basu, Samar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Hellberg, A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Ulus, A. T.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Westman, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Karacagil, Sadettin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Biomarkers of free radical injury during spinal cord ischemia2001Inngår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 508, nr 1, s. 36-38Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Plasma and urinary levels of 8-iso-PGF(2alpha) and 15-keto-dihydro-PGF(2alpha) were analysed at baseline and during the ischemia-reperfusion period in experimental spinal cord ischemia. A significant and immediate increase of 8-iso-PGF(2alpha) in plasma at the start and up to 60 min, and in the urine at 90-150 min following ischemia indicate an association of oxidative injury. The inflammatory response indicator 15-keto-dihydro-PGF(2alpha) in plasma increased significantly at the start and up to 60 min after ischemia. No such increase was seen in animals with no spinal cord ischemia. Thus, free radical mediated and cyclooxygenase catalysed products of arachidonic acid are increased during spinal cord ischemia as a consequence of oxidative injury and inflammation.

  • 126.
    Becirovic Agic, Mediha
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Jönsson, Sofia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Hultström, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Quantitative trait loci associated with angiotensin II and high-salt diet induced acute decompensated heart failure in Balb/CJ mice2019Inngår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 51, nr 7, s. 279-289Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genetic background of different mouse strains determines their susceptibility to disease. We have previously shown that Balb/CJ and C57BL/6J mice develop cardiac hypertrophy to the same degree when treated with a combination of angiotensin II and high-salt diet (ANG II+ Salt). but only Balb/CJ show impaired cardiac function associated with edema development and substantial mortality. We hypothesized that the different response to ANG II +Salt is due to the different genetic backgrounds of Balb/CJ and C57BL/6J. To address this we performed quantitative trait locus (QTL) mapping of second filial generation (F2) of mice derived from a backcross between Balb/CJ and first filial generation (Fl) of mice. Cardiac function was measured with echocardiography, glomerular filtration rate using FITC-inulin clearance, fluid and electrolyte balance in metabolic cages, and blood pressure with tail-cuff at baseline and on the fourth day of treatment with ANG II+Salt. A total of nine QTLs were found to be linked to different phenotypes in ANG II + Salt-treated F2 mice. A QTL on chromosome 3 was linked to cardiac output. and a QTL on chromosome 12 was linked to isovolumic relaxation time. QTLs on chromosome 2 and 3 were linked to urine excretion and sodium excretion. Eight genes located at the different QTLs contained coding nonsynonymous SNPs published in the mouse genome database that differ between Balb/CJ and C57BL/6J. In conclusion. ANG II+Salt-induced acute decompensation in Balb/CJ is genetically linked to several QTLs, indicating a multifaceted phenotype. The present study identified potential candidate genes that may represent important pathways in acute decompensated heart failure.

  • 127.
    Becirovic Agic, Mediha
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Jönsson, Sofia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Isackson, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Tveitarås, Maria K.
    Department of Biomedicine, University of Bergen, Bergen, Norway.
    Skogstrand, Trude
    Department of Biomedicine, University of Bergen, Bergen, Norway.
    Karlsen, Tine V.
    Department of Biomedicine, University of Bergen, Bergen, Norway.
    Lidén, Åsa
    Department of Biomedicine, University of Bergen, Bergen, Norway.
    Leh, Sabine
    Department of Pathology, Haukeland university Hospital, Bergen, Norway, and Department of Clinical Medicine, University of Bergen, Bergen, Norway.
    Ericsson, Madelene
    Department of Medical Biosciences, Umeå University, Umeå, Sweden.
    Nilsson, Stefan K.
    Department of Medical Biosciences, Umeå University, Umeå, Sweden.
    Reed, Rolf K.
    Department of Biomedicine, University of Bergen, Bergen, Norway.
    Hultström, Micahel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Angiotensin II and salt-induced decompensation in Balb/CJ mice is associated with genetic differences in glutathione transferase activityManuskript (preprint) (Annet vitenskapelig)
  • 128.
    Becirovic-Agic, Mediha
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Hultström, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Release of a contractile factor and reduced nitric oxide from isolated pulmonary resistance vessels from BalB/CJ mice cause higher reactivity to angiotensin II compared to C57BL/6JManuskript (preprint) (Annet vitenskapelig)
  • 129.
    Becirovic-Agic, Mediha
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Jönsson, Sofia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Hultström, Mediha
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Quantitative Trait Loci (QTL) associated with angiotensin II and high-salt diet induced acute decompensation in Balb/CJ miceManuskript (preprint) (Annet vitenskapelig)
  • 130.
    Becirovic-Agic, Mediha
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Jönsson, Sofia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Tveitarås, Maria K.
    Skogstrand, Trude
    Karlsen, Tine Veronica
    Lidén, Åsa
    Leh, Sabine
    Ericsson, Madelene
    Nilsson, Stefan K.
    Reed, Rolf K.
    Hultström, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi. Department of Biomedicine, University of Bergen, Bergen, Norway.
    Time course of decompensation after angiotensin II and high-salt diet in Balb/CJ mice suggests pulmonary hypertension-induced cardiorenal syndrome2019Inngår i: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 316, nr 5, s. R563-R570Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The genetic background of a mouse strain determines its susceptibility to disease. C57BL/6J and Balb/CJ are two widely used inbred mouse strains that we found react dramatically differently to angiotensin II and high-salt diet (ANG II + Salt). Balb/CJ show increased mortality associated with anuria and edema formation while C57BL/6J develop arterial hypertension but do not decompensate and die. Clinical symptoms of heart failure in Balb/CJ mice gave the hypothesis that ANG II + Salt impairs cardiac function and induces cardiac remodeling in male Balb/CJ but not in male C57BL/6J mice. To test this hypothesis, we measured cardiac function using echocardiography before treatment and every day for 7 days during treatment with ANG II + Salt. Interestingly, pulsed wave Doppler of pulmonary artery flow indicated increased pulmonary vascular resistance and right ventricle systolic pressure in Balb/CJ mice, already 24 h after ANG II + Salt treatment was started. In addition, Balb/CJ mice showed abnormal diastolic filling indicated by reduced early and late filling and increased isovolumic relaxation time. Furthermore, Balb/CJ exhibited lower cardiac output compared with C57BL/6J even though they retained more sodium and water, as assessed using metabolic cages. Left posterior wall thickness increased during ANG II + Salt treatment but did not differ between the strains. In conclusion, ANG II + Salt treatment causes early restriction of pulmonary flow and reduced left ventricular filling and cardiac output in Balb/CJ, which results in fluid retention and peripheral edema. This makes Balb/CJ a potential model to study the adaptive capacity of the heart for identifying new disease mechanisms and drug targets.

  • 131.
    Becriovic Agic, Mediha
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Jönsson, Sofia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Hultström, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Genetic association of oxidative stress and fluid accumulation makes Balb/CJ mice more sensitive to decompensated heart failure2017Inngår i: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 61, nr 8, s. 963-964Artikkel i tidsskrift (Annet vitenskapelig)
  • 132.
    Becriovic-Agic, Mediha
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Susceptibility to Acute Decompensated Heart Failure in Two Common Mouse Strains2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Heart failure is a clinical syndrome characterized by an inability of the heart to meet oxygen demands of the body. During the initial stage of heart failure development compensatory mechanisms are activated to help the heart sustain proper function. Over time these compensatory mechanisms become inadequate resulting in decompensation. Acute decompensated heart failure is characterized by rapidly escalating heart failure symptoms, such as dyspnea and congestion, which require urgent treatment. The pathophysiology of decompensation and role of genetic background on this process is not completely understood.  The aim of this thesis was to investigate the role of genetic background on susceptibility to develop acute decompensated heart failure.

    Balb/CJ and C57BL/6J mice are two common mouse strains that we found have different susceptibility to angiotensin II and high-salt diet (AngII+Salt) induced decompensation. Balb/CJ treated with AngII+Salt develop massive edema associated with anuria and high mortality within 4-6 days of treatment, while C57BL/6J mice do not. Due to the clinical symptoms of heart failure we hypothesized that Balb/CJ develop acute decompensated heart failure, and that the genetic background of this strain is responsible for the increased susceptibility to heart failure. AngII+Salt increased pulmonary and systemic vascular resistance, reduced left ventricle filling, and increased sodium and water retention in Balb/CJ mice. Increased pulmonary vascular resistance correlated with a higher angiotensin II response in isolated pulmonary arteries from Balb/CJ compared to C57BL/6J. Cardiac output was lower in Balb/CJ than C57BL/6J during AngII+Salt treatment even though they retained more sodium and water. This indicated that AngII+Salt impairs cardiac function in Balb/CJ mice. Oxidative stress was shown to play a role in AngII+Salt induced acute decompensation since treatment with an antioxidant reduced oxidative stress but impaired cardiac function and increased mortality in both strains. A linkage study was performed to reveal genes that are with high probability related to AngII+Salt induced decompensation in Balb/CJ mice. Quantative trait loci (QTLs) on chromosome 3 and 12 were linked to cardiac dysfunction and QTLs on chromosome 2 and 3 were linked to sodium and fluid balance. Foxo1 was found to be one of candidate genes for further study.

    Taken together, the data in this thesis shows that genetic background does play a large role in the development of acute decompensated heart failure. It reveals several candidate genes that could be studied in the setting of acute decompensated heart failure. Finally, it describes a new mouse model that could potentially be used for studying the pathophysiology of decompensation and identifying new drug targets.

    Delarbeid
    1. Time course of decompensation after angiotensin II and high-salt diet in Balb/CJ mice suggests pulmonary hypertension-induced cardiorenal syndrome
    Åpne denne publikasjonen i ny fane eller vindu >>Time course of decompensation after angiotensin II and high-salt diet in Balb/CJ mice suggests pulmonary hypertension-induced cardiorenal syndrome
    Vise andre…
    2019 (engelsk)Inngår i: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 316, nr 5, s. R563-R570Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The genetic background of a mouse strain determines its susceptibility to disease. C57BL/6J and Balb/CJ are two widely used inbred mouse strains that we found react dramatically differently to angiotensin II and high-salt diet (ANG II + Salt). Balb/CJ show increased mortality associated with anuria and edema formation while C57BL/6J develop arterial hypertension but do not decompensate and die. Clinical symptoms of heart failure in Balb/CJ mice gave the hypothesis that ANG II + Salt impairs cardiac function and induces cardiac remodeling in male Balb/CJ but not in male C57BL/6J mice. To test this hypothesis, we measured cardiac function using echocardiography before treatment and every day for 7 days during treatment with ANG II + Salt. Interestingly, pulsed wave Doppler of pulmonary artery flow indicated increased pulmonary vascular resistance and right ventricle systolic pressure in Balb/CJ mice, already 24 h after ANG II + Salt treatment was started. In addition, Balb/CJ mice showed abnormal diastolic filling indicated by reduced early and late filling and increased isovolumic relaxation time. Furthermore, Balb/CJ exhibited lower cardiac output compared with C57BL/6J even though they retained more sodium and water, as assessed using metabolic cages. Left posterior wall thickness increased during ANG II + Salt treatment but did not differ between the strains. In conclusion, ANG II + Salt treatment causes early restriction of pulmonary flow and reduced left ventricular filling and cardiac output in Balb/CJ, which results in fluid retention and peripheral edema. This makes Balb/CJ a potential model to study the adaptive capacity of the heart for identifying new disease mechanisms and drug targets.

    Emneord
    animal model, congestive heart failure, pulmonary hypertension, right-sided heart failure
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-380656 (URN)10.1152/ajpregu.00373.2018 (DOI)000468436400001 ()30840486 (PubMedID)
    Forskningsfinansiär
    Åke Wiberg FoundationSwedish Heart Lung FoundationSwedish Society of MedicineSwedish Society for Medical Research (SSMF)EU, FP7, Seventh Framework Programme
    Merknad

    Title in thesis list of papers: Time-course of decompensation after angiotensin II and high-salt diet in Balb/CJ mice suggests pulmonary hypertension-induced cardiorenal syndrome

    Tilgjengelig fra: 2019-04-01 Laget: 2019-04-01 Sist oppdatert: 2019-06-24bibliografisk kontrollert
    2. Angiotensin II and salt-induced decompensation in Balb/CJ mice is associated with genetic differences in glutathione transferase activity
    Åpne denne publikasjonen i ny fane eller vindu >>Angiotensin II and salt-induced decompensation in Balb/CJ mice is associated with genetic differences in glutathione transferase activity
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-379720 (URN)
    Tilgjengelig fra: 2019-03-20 Laget: 2019-03-20 Sist oppdatert: 2019-04-01
    3. Quantitative Trait Loci (QTL) associated with angiotensin II and high-salt diet induced acute decompensation in Balb/CJ mice
    Åpne denne publikasjonen i ny fane eller vindu >>Quantitative Trait Loci (QTL) associated with angiotensin II and high-salt diet induced acute decompensation in Balb/CJ mice
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-380658 (URN)
    Tilgjengelig fra: 2019-04-01 Laget: 2019-04-01 Sist oppdatert: 2019-04-01
    4. Release of a contractile factor and reduced nitric oxide from isolated pulmonary resistance vessels from BalB/CJ mice cause higher reactivity to angiotensin II compared to C57BL/6J
    Åpne denne publikasjonen i ny fane eller vindu >>Release of a contractile factor and reduced nitric oxide from isolated pulmonary resistance vessels from BalB/CJ mice cause higher reactivity to angiotensin II compared to C57BL/6J
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-380659 (URN)
    Tilgjengelig fra: 2019-04-01 Laget: 2019-04-01 Sist oppdatert: 2019-04-01
  • 133.
    Bedoya, F J
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Flodstrom, M
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Eizirik, D L
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Pyrrolidine dithiocarbamte prevents IL-1-induced nitric oxide synthase mRNA, but not superoxide dismutase mRNA, in insulin producing cells.1995Inngår i: Biochem Biophys Res Commun, Vol. 210, s. 816-Artikkel i tidsskrift (Fagfellevurdert)
  • 134.
    Benda, Birgitta
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Lycke, Nils
    Holstad, Maria
    Institutionen för medicinsk cellbiologi.
    Korsgren, Olle
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Delayed type hypersensitivity-assoaciated cytokines in islet xenotransplantation: limited efficacy of interleukin-2- and tumor necrosis factor-alpha-blockade in interferon-gamma receptor-deficient mic2000Inngår i: Xenotransplantation, Vol. 7, s. 206-Artikkel i tidsskrift (Fagfellevurdert)
  • 135.
    Benedict, Christian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Cedernaes, Jonathan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Nilsson, Emil K
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Hogenkamp, Pleunie S
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Vågesjö, Evelina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Massena, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Pettersson, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Christoffersson, Gustaf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Phillipson, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Broman, Jan-Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Zetterberg, Henrik
    Schiöth, Helgi B
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Acute sleep deprivation increases serum levels of neuron-specific enolase (NSE) and S100 calcium binding protein B (S-100B) in healthy young men2014Inngår i: Sleep, ISSN 0161-8105, E-ISSN 1550-9109, Vol. 37, nr 1, s. 195-198Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    STUDY OBJECTIVES:

    To investigate whether total sleep deprivation (TSD) affects circulating concentrations of neuron-specific enolase (NSE) and S100 calcium binding protein B (S-100B) in humans. These factors are usually found in the cytoplasm of neurons and glia cells. Increasing concentrations of these factors in blood may be therefore indicative for either neuronal damage, impaired blood brain barrier function, or both. In addition, amyloid β (Aβ) peptides 1-42 and 1-40 were measured in plasma to calculate their ratio. A reduced plasma ratio of Aβ peptides 1-42 to 1-40 is considered an indirect measure of increased deposition of Aβ 1-42 peptide in the brain.

    DESIGN:

    Subjects participated in two conditions (including either 8-h of nocturnal sleep [22:30-06:30] or TSD). Fasting blood samples were drawn before and after sleep interventions (19:30 and 07:30, respectively).

    SETTING:

    Sleep laboratory.

    PARTICIPANTS:

    15 healthy young men.

    RESULTS:

    TSD increased morning serum levels of NSE (P = 0.002) and S-100B (P = 0.02) by approximately 20%, compared with values obtained after a night of sleep. In contrast, the ratio of Aβ peptides 1-42 to 1-40 did not differ between the sleep interventions.

    CONCLUSIONS:

    Future studies in which both serum and cerebrospinal fluid are sampled after sleep loss should elucidate whether the increase in serum neuron-specific enolase and S100 calcium binding protein B is primarily caused by neuronal damage, impaired blood brain barrier function, or is just a consequence of increased gene expression in non-neuronal cells, such as leukocytes.

  • 136.
    Berg, Anna-Karin
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Elshebani, Asma
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Andersson, Arne
    Institutionen för medicinsk cellbiologi.
    Frisk, Gun
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    dsRNA formed as an intermediate during Coxsackievirus infection does not induce NO production in a beta-cell line with or without addition of IFN-gamma.2005Inngår i: Biochem Biophys Res Commun, ISSN 0006-291X, Vol. 327, nr 3, s. 780-788Artikkel i tidsskrift (Fagfellevurdert)
  • 137. Bergenholtz, Sa Schoug
    et al.
    Wessman, Per
    Wuttke, Anne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Håkansson, Sebastian
    A case study on stress preconditioning of a Lactobacillus strain prior to freeze-drying2012Inngår i: Cryobiology, ISSN 0011-2240, E-ISSN 1090-2392, Vol. 64, nr 3, s. 152-159Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Freeze-drying of bacterial cells with retained viability and activity after storage requires appropriate formulation, i.e. mixing of physiologically adapted cell populations with suitable protective agents, and control of the freeze-drying process. Product manufacturing may alter the clinical effects of probiotics and it is essential to identify and understand possible factor co-dependencies during manufacturing. The physical solid-state behavior of the formulation and the freeze-drying parameters are critical for bacterial survival and thus process optimization is important, independent of strain. However, the maximum yield achievable is also strain-specific and strain survival is governed by e.g. medium, cell type, physiological state, excipients used, and process. The use of preferred compatible solutes for cross-protection of Lactobacilli during industrial manufacturing may be a natural step to introduce robustness, but knowledge is lacking on how compatible solutes, such as betaine, influence formulation properties and cell survival. This study characterized betaine formulations, with and without sucrose, and tested these with the model lactic acid bacteria Lactobacillus coryniformis Si3. Betaine alone did not act as a lyo-protectant and thus betaine import prior to freeze-drying should be avoided. Differences in protective agents were analyzed by calorimetry, which proved to be a suitable tool for evaluating the characteristics of the freeze-dried end products.

  • 138. Berggren, Per-Olof
    et al.
    Hellerström, Claes
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Reglering av insulinsekretionen2002Inngår i: Diabetes, 2002, s. 38-Kapittel i bok, del av antologi (Annet vitenskapelig)
  • 139.
    Bergman, Hilde-Marlene
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Lindfors, Lina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Kihlberg, Jan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Lanekoff, Ingela
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Metabolite aberrations at early onset of diabetes detected in rat kidney using mass spectrometry imaging2019Inngår i: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 411, nr 13, s. 2809-2816Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Diabetic kidney disease is a serious complication of diabetes that can ultimately lead to end-stage renal disease. The pathogenesis of diabetic kidney disease is complex, and fundamental research is still required to provide a better understanding of the driving forces behind it. We report regional metabolic aberrations from an untargeted mass spectrometry imaging study of kidney tissue using an insulinopenic rat model of diabetes. Diabetes was induced by intravenous injection of streptozotocin, and kidneys were harvested 2weeks thereafter. Imaging was performed using nanospray desorption electrospray ionization connected to a high-mass-resolving mass spectrometer. No histopathological changes were observed in the kidney sections; however, mass spectrometry imaging revealed a significant increase in several 18-carbon unsaturated non-esterified fatty acid species and monoacylglycerols. Notably, these 18-carbon acyl chains were also constituents of several increased diacylglycerol species. In addition, a number of short- and long-chain acylcarnitines were found to be accumulated while several amino acids were depleted. This study presents unique regional metabolic data indicating a dysregulated energy metabolism in renal mitochondria as an early response to streptozotocin-induced type I diabetes.

  • 140.
    Bergqvist, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Sundström, Sara
    Karolinska Institutet.
    Dimberg, Lina Y.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Gylfe, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Masucci, Maria G.
    Karolinska Institutet.
    The Hepatitis C Virus Core Protein Modulates T Cell Responses by Inducing Spontaneous and Altering T-cell Receptor-triggered Ca2+ Oscillations2003Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 278, nr 21, s. 18877-18883Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Alterations of cytokine responses are thought to favor the establishment of persistent hepatitis C virus (HCV) infection, enhancing the risk of liver cirrhosis and hepatocellular carcinoma. Expression of the HCV core (C) protein modulates transcription of the IL-2 promoter in T lymphocytes by activating the nuclear factor of activated T lymphocyte (NFAT) pathway. Here we report on the effect of HCV C on Ca2+ signaling, which is essential for activation of NFAT. Expression of HCV C correlated with increased levels of cytosolic Ca2+ and spontaneous Ca2+ oscillations in transfected Jurkat cells. Triggering of the T-cell receptor induced a prolonged Ca2+ response characterized by vigorous high frequent oscillations in a high proportion of the responding cells. This was associated with decreased sizes and accelerated emptying of the intracellular calcium stores. The effect of HCV C on calcium mobilization was not dependent on phospholipase C-1 (PLC-) activity or increased inositol 1,4,5-trisphosphate (IP3) production and did not require functional IP3 receptors, suggesting that insertion of the viral protein in the endoplasmic reticulum membrane may be sufficient to promote Ca2+ leakage with dramatic downstream consequences on the magnitude and duration of the response. Our data suggest that expression of HCV C in infected T lymphocytes may contribute to the establishment of persistent infections by inducing Ca2+ oscillations that regulate both the efficacy and information content of Ca2+ signals and are ultimately responsible for induction of gene expression and functional differentiation.

  • 141.
    Bergsten , Peter
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Calcium dysregulation, insulin release and the pathogenesis of diabetes.2002Inngår i: Advances in Cell Aging and Gerontology, Elsevier Sciences BV , 2002, Vol. 10, s. 147-Kapittel i bok, del av antologi (Annet vitenskapelig)
  • 142.
    Bergsten, J
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Lin, J
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Westerlund, J
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Pulsatile release of insulin: role of cytoplasmic Ca2+ oscillations1998Inngår i: Diabete Metab, Vol. 24, s. 4145-Artikkel i tidsskrift (Fagfellevurdert)
  • 143.
    Bergsten, P
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Glucose-induced pulsatile insulin release from single islets at stable and oscillatory cytoplasmic Ca2+1998Inngår i: Am J Physiol, Vol. 274, s. 796800-Artikkel i tidsskrift (Fagfellevurdert)
  • 144.
    Bergsten, P
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Islet protein profiling2009Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 11, s. 97-117Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Islet protein profiling is defined as generation of extended protein expression data sets from islets or islet cells. Islets from rodent control and animal models of type 1 and type 2 diabetes mellitus and healthy humans and insulin- and glucagon-producing cell lines have been used. Protein profiling entails separation, differential expression determination, identification and expression analysis. Protein/peptide separation is either gel-based or by chromatography. Differential expression is based on comparison of visualized spots/proteins between gels or by sample labelling in gel-free systems. Identification of proteins is made by tryptic fragmentation of proteins, fragment mass determination and mass comparison with protein databases. Analysis of expression data sets interprets the complex protein changes into cellular mechanisms to generate hypotheses. The importance of such protein expression sets to elucidate islet cellular events is evidenced by the observation that only about 50% of the differentially expressed proteins and transcripts showed concordance when measured in parallel. Using protein profiling, different areas related to islet dysfunction in type 1 and type 2 diabetes mellitus have been addressed, including dysfunction induced by elevated levels of glucose and fatty acids and cytokines. Because islets from individuals with type 1 or type 2 diabetes mellitus have not yet been protein profiled, islets from rat (BB-DP) and mouse (NOD, ob/ob, MKR) models of the disease have been used, and mechanisms responsible for islet dysfunction delineated offering avenues of intervention.

  • 145.
    Bergsten, P
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Pathophysiology of impaired pulsatile insulin release2000Inngår i: Diabet Metab Rev, Vol. 16, s. 179191-Artikkel i tidsskrift (Fagfellevurdert)
  • 146.
    Bergsten, P
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Role of oscillations in membrane potential, cytoplasmic Ca2+, andmetabolism for plasma insulin oscillations.2002Inngår i: Diabetes, Vol. 51 Suppl 1, s. S171-Artikkel i tidsskrift (Fagfellevurdert)
  • 147.
    Bergsten, P
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Slow and fast oscillations of cytoplasmic Ca2+ in pancreatic islets correspond to pulsatile insulin release1995Inngår i: Am J Physiol, Vol. 268, s. 282-Artikkel i tidsskrift (Fagfellevurdert)
  • 148.
    Bergsten, P
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Westerlund, J
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Liss, P
    Institutionen för onkologi, radiologi och klinisk immunologi.
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Primary in vivo oscillations of metabolism in the pancreas.2002Inngår i: Diabetes, Vol. 51, s. 699-Artikkel i tidsskrift (Fagfellevurdert)
  • 149.
    Bergsten, P
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Yu, R
    Yu, R
    Kehrl, J
    Levine, M
    Ascorbic acid transport and distribution in human B lymphocytes.1995Inngår i: Arch Biochem Biophys, Vol. 317, s. 208-Artikkel i tidsskrift (Fagfellevurdert)
  • 150.
    Bergsten, Peter
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Aoyagi, K.
    Persson, Erik
    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.
    Appearance of glucose-induced insulin release in fetal rat β-cells1998Inngår i: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 1479-6805, Vol. 158, nr 1, s. 115-120Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Fetal rat pancreatic cells were isolated from pancreatic primordia on days 12-14 of pregnancy and cultured for 48 h in the presence of 5 mmol/l glucose. Insulin accumulation in the medium over the next 24 h was measured. Cultured cells from day 12 fetuses secreted about 1 fmol insulin per pancreas in response to 5 or 15 mmol/l glucose irrespective of whether 1 mmol/l tolbutamide, 400 mumol/l diazoxide, 5 mmol/l theophylline or 10 mmol/l mannoheptulose was present. In contrast, insulin released from day 13 cultured cells increased significantly from 3.0 +/- 0.6 to 6.2 +/- 2.2 fmol per pancreas, when the glucose concentration was raised. Tolbutamide increased, diazoxide and mannoheptulose decreased and theophylline had no effect on insulin release. Even more pronounced effects were found on insulin release from day 14 cultured cells, in which theophylline also increased the release. In addition, insulin release from cells from pregnancy day 14 was 75 +/- 16 amol/min per pancreas when the cells were perifused for 15-20 min in the presence of 5 mmol/l glucose within 3 h of isolation. Increasing the glucose concentration to 15 mmol/l or adding tolbutamide increased, whereas diazoxide decreased, insulin release in the freshly isolated cells. The insulin content of rat pancreata from pregnancy day 13 was 0.06 +/- 0.01 pmol per pancreas and increased approximately 10-fold every second day up to 6.7 +/- 0.9 pmol on day 17 of pregnancy. Between day 17 and 19 the pancreatic insulin content increased about fivefold to 39 +/- 2 pmol. The present data suggest that critical components of the insulin-secretory machinery, including ATP-regulated K+ channels, glucokinase and adenylate cyclase activities, are present in the developing beta-cell earlier than hitherto thought.

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