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  • 1. Arkhammar, P
    et al.
    Juntti-Berggren, L
    Larsson, O
    Welsh, M
    Nånberg, Eewa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Sjöholm, A
    Köhler, M
    Berggren, P O
    Protein kinase C modulates the insulin secretory process by maintaining a proper function of the beta-cell voltage-activated Ca2+ channels.1994In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 269, no 4, p. 2743-2749Article in journal (Refereed)
    Abstract [en]

    In the present study an attempt was made to further elucidate the molecular mechanisms whereby protein kinase C (PKC) modulates the beta-cell stimulus-secretion coupling. Regulation of Ca2+ channel activity, [Ca2+]i, and insulin release were investigated in both normal pancreatic mouse beta-cells and in similar beta-cells deprived of PKC activity. [Ca2+]i was measured with the intracellular fluorescent Ca2+ indicator fura-2 and the Ca2+ channel activity was estimated by the whole cell configuration of the patch-clamp technique. To reveal the various isoenzymes of PKC present in the mouse beta-cell, proteins were separated by one-dimensional gel electrophoresis and Western blotting was performed. The production of inositol phosphates was measured by ion-exchange chromatography and insulin release was measured radioimmunologically. Acute stimulation with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate resulted in suppression of both the carbamylcholine-induced increase in [Ca2+]i and production of inositol 1,4,5-trisphosphate. Under these conditions the increase in [Ca2+]i in response to glucose was similar to that found in control cells. When beta-cells were deprived of PKC, by exposure to 200 nM 12-O-tetradecanoylphorbol-13-acetate for 24-48 h, there was an enhanced response to carbamylcholine. This response constituted increases in both the [Ca2+]i signal and production of inositol 1,4,5-trisphosphate. Interestingly, cells with down-regulated PKC activity responded more slowly to glucose stimulation, when comparing the initial increase in [Ca2+]i, than control cells. On the other hand, the maximal increase in [Ca2+]i was similar whether or not PKC was present. Moreover, PKC down-regulated cells exhibited a significant reduction of maximal whole cell Ca2+ currents, a finding that may explain the altered kinetics with regard to the [Ca2+]i increase in response to the sugar. Both the alpha and beta 1 forms of the PKC isoenzymes were present in the mouse beta-cell and were also subjected to PKC down-regulation. Hence, either of these isoenzymes or both may be involved in the modulation of phospholipase C and Ca2+ channel activity. Since insulin release under physiological conditions is critically dependent on Ca(2+)-influx through the voltage-gated L-type Ca2+ channels, the kinetics of hormone release was expected to demonstrate a similar delay as that of the [Ca2+]i increase. Although not as pronounced, such a delay was indeed also observed in the onset of insulin release. There was, however, no effect on the total amounts of hormone released.(ABSTRACT TRUNCATED AT 400 WORDS)

  • 2. Arvidsson, A K
    et al.
    Rupp, E
    Nånberg, Eewa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Downward, J
    Rönnstrand, L
    Wennström, S
    Schlessinger, J
    Heldin, C H
    Claesson-Welsh, L
    Tyr-716 in the platelet-derived growth factor beta-receptor kinase insert is involved in GRB2 binding and Ras activation.1994In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 14, no 10, p. 6715-26Article in journal (Refereed)
    Abstract [en]

    Ligand stimulation of the platelet-derived growth factor (PDGF) beta-receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation of the intracellular part of the receptor. The autophosphorylated tyrosine residues mediate interactions with downstream signal transduction molecules and thereby initiate different signalling pathways. A pathway leading to activation of the GTP-binding protein Ras involves the adaptor molecule GRB2. Here we show that Tyr-716, a novel autophosphorylation site in the PDGF beta-receptor kinase insert, mediates direct binding of GRB2 in vitro and in vivo. In a panel of mutant PDGF beta-receptors, in which Tyr-716 and the previously known autophosphorylation sites were individually mutated, only PDGFR beta Y716F failed to bind GRB2. Furthermore, a synthetic phosphorylated peptide containing Tyr-716 bound GRB2, and this peptide specifically interrupted the interaction between GRB2 and the wild-type receptor. In addition, the Y716(P) peptide significantly decreased the amount of GTP bound to Ras in response to PDGF in permeabilized fibroblasts as well as in porcine aortic endothelial cells expressing transfected PDGF beta-receptors. The mutant PDGFR beta Y716F still mediated activation of mitogen-activated protein kinases and an increased DNA synthesis in response to PDGF, indicating that multiple signal transduction pathways transduce mitogenic signals from the activated PDGF beta-receptor.

  • 3.
    Bornehag, Carl-Gustaf
    et al.
    Karlstad University, Faculty of Social and Life Sciences, Department of Health and Environmental Sciences.
    Moniruzzaman, Syed
    Karlstad University, Faculty of Social and Life Sciences, Department of Health and Environmental Sciences.
    Larsson, Malin
    Karlstad University, Faculty of Social and Life Sciences, Department of Health and Environmental Sciences.
    Boman Lindström, Cecilia
    Karlstad University, Faculty of Social and Life Sciences, Department of Health and Environmental Sciences.
    Hasselgren, Mikael
    Centre for Clinical Research, County Council of Värmland, Karlstad.
    Bodin, Anna
    Centre for Clinical Research, County Council of Värmland, Karlstad.
    von Kobyletzki, Laura B.
    Centre for Clinical Research, County Council of Värmland, Karlstad.
    Carlstedt, Fredrik
    Centre for Clinical Research, County Council of Värmland, Karlstad.
    Lundin, Fredrik
    Centre for Clinical Research, County Council of Värmland, Karlstad.
    Nånberg, Eewa
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Jönsson, Bo A. G.
    Division of Occupational and Environmental Medicine, Lund University.
    Sigsgaard, Torben
    Department of Public Health, Unit of Environmental and Occupational Medicine, University of Aarhus, Denmark.
    Janson, Staffan
    Karlstad University, Faculty of Social and Life Sciences, Department of Health and Environmental Sciences.
    The SELMA study: a birth cohort study in Sweden following more than 2000 mother-child pairs2012In: Paediatric and Perinatal Epidemiology, ISSN 0269-5022, E-ISSN 1365-3016, Vol. 26, no 5, p. 456-467Article in journal (Refereed)
    Abstract [en]

    Background:  This paper describes the background, aim and study design for the Swedish SELMA study that aimed to investigate the importance of early life exposure during pregnancy and infancy to environmental factors with a major focus on endocrine disrupting chemicals for multiple chronic diseases/disorders in offspring.

    Methods:  The cohort was established by recruiting women in the 10th week of pregnancy. Blood and urine from the pregnant women and the child and air and dust from home environment from pregnancy and infancy period have been collected. Questionnaires were used to collect information on life styles, socio-economic status, living conditions, diet and medical history.

    Results:  Of the 8394 reported pregnant women, 6658 were invited to participate in the study. Among the invited women, 2582 (39%) agreed to participate. Of the 4076 (61%) non-participants, 2091 women were invited to a non-respondent questionnaire in order to examine possible selection bias. We found a self-selection bias in the established cohort when compared with the non-participant group, e.g. participating families did smoke less (14% vs. 19%), had more frequent asthma and allergy symptoms in the family (58% vs. 38%), as well as higher education among the mothers (51% vs. 36%) and more often lived in single-family houses (67% vs. 60%).

    Conclusions:  These findings indicate that the participating families do not fully represent the study population and thus, the exposure in this population. However, there is no obvious reason that this selection bias will have an impact on identification of environmental risk factors.

  • 4. Burgess, G M
    et al.
    Dooley, R K
    McKinney, J S
    Nånberg, Eewa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Putney, J W
    Further studies on the interactions between the calcium mobilization and cyclic AMP pathways in guinea pig hepatocytes.1986In: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 30, no 4, p. 315-20Article in journal (Refereed)
    Abstract [en]

    Isoproterenol (50 nM) potentiated the effects of angiotensin (1-50 nM) on 86Rb efflux and 45Ca efflux from guinea pig hepatocytes. This effect occurred in the presence or absence of extracellular Ca2+ and required the simultaneous presence of both isoproterenol and angiotensin. Neither the divalent cationophore, A23187, nor 4 beta-phorbol dibutyrate could substitute for angiotensin. The effects of isoproterenol were greatest with submaximal concentrations of angiotensin, whereas maximal concentrations of angiotensin were affected little. Isoproterenol did not substantially increase the formation of [3H]inositol triphosphate or the ratio of isomers [3H]inositol 1,4,5-trisphosphate and [3H]inositol 1,3,4-trisphosphate formed in response to angiotensin. Isoproterenol also enhanced the phase of Ca2+ mobilization involving Ca2+ entry which is consistent with the previously proposed functional linkage between receptor-regulated Ca2+ release and Ca2+ entry. These findings suggest that isoproterenol may act by increasing the sensitivity of the endoplasmic reticulum to the Ca2+-releasing action of inositol 1,4,5-trisphosphate.

  • 5.
    Bölling, Anette
    et al.
    Norwegian Institute of Public Health, Norway.
    Holme, Jörn
    Norwegian Institute of Public Health, Norway.
    Bornehag, Carl-Gustaf
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Nygaard, Unni C
    Norwegian Institute of Public Health, Norway.
    Bertelsen, Randi
    Norwegian Institute of Public Health, Norway.
    Nånberg, Eewa
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Bodin, Johanna
    Norwegian Institute of Public Health, Norway.
    Sakhi, Amrit Kaur
    Norwegian Institute of Public Health, Norway.
    Thomsen, Cathrine
    Norwegian Institute of Public Health, Norway.
    Becher, Rune
    Norwegian Institute of Public Health, Norway.
    Pulmonary phthalate exposure and asthma: Is PPAR a plausible mechanistic link?2013In: EXCLI Journal, ISSN 1611-2156, E-ISSN 1611-2156, Vol. 12, p. 733-759Article in journal (Refereed)
    Abstract [en]

    Due to their extensive use as plasticisers in numerous consumer products, phthalates have become ubiquitous environmental contaminants. An increasing number of epidemiological studies suggest that exposure to phthalates may be associated with worsening or development of airway diseases. Peroxisome Proliferation Activated Receptors (PPAR)s, identified as important targets for phthalates in early studies in rodent liver, have been suggested as a possible mechanistic link. In this review we discuss the likelihood of an involvement of PPARs in asthma development and exacerbation due to pulmonary phthalate exposure. First, we go through the literature on indoor air levels of phthalates and pulmonary phthalate kinetics. These data are then used to estimate the pulmonary phthalate levels due to inhalation exposure. Secondly, the literature on phthalate-induced activation or modulation of PPARs is summarized. Based on these data, we discuss whether pulmonary phthalate exposure is likely to cause PPAR activation, and if this is a plausible mechanism for adverse effects of phthalates in the lung. It is concluded that the pulmonary concentrations of some phthalates may be sufficient to cause a direct activation of PPARs. Since PPARs mainly mediate antiinflammatory effects in the lungs, a direct activation is not a likely molecular mechanism for adverse effects of phthalates. However, possible modulatory effects of phthalates on PPARs deserve further investigation, including partial antagonist effects and/or cross talk with other signalling pathways. Moreover other mechanisms, including interactions between phthalates and other receptors, could also contribute to possible adverse pulmonary effects of phthalates.

  • 6. Connolly, E
    et al.
    Nånberg, Eewa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Nedergaard, J
    Na+-dependent, alpha-adrenergic mobilization of intracellular (mitochondrial) Ca2+ in brown adipocytes.1984In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 141, no 1, p. 187-193Article in journal (Refereed)
    Abstract [en]

    The existence and significance of a hormone-sensitive, rapidly mobilizable intracellular pool of Ca2+ in hamster brown-fat cells was investigated with 45Ca2+-labelling techniques. It was shown that such a pool existed and was probably located within the abundant mitochondria. It was rapidly mobilized by norepinephrine (median effective concentration 50 nM) through alpha-adrenergic mechanisms. The mobilization of Ca2+ from the intracellular stores (mitochondria) required the presence of extracellular Na+, but not of Ca2+, K+ or Mg2+. It is concluded that the experiments are in agreement with a hypothesis linking the mobilization of intracellular Ca2+ pools with an alpha-adrenergically-induced increase in plasma membrane Na+ permeability (observed as a membrane depolarization), and a subsequent activation of the mitochondrial Na+/Ca2+ exchange, leading to mobilization of mitochondrial Ca2+ and the mediation of alpha-adrenergic effects as a result of an elevated cytosolic Ca2+ level.

  • 7. Connolly, E
    et al.
    Nånberg, Eewa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Nedergaard, J
    Norepinephrine-induced Na+ influx in brown adipocytes is cyclic AMP-mediated.1986In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 261, no 31, p. 14377-14385Article in journal (Refereed)
    Abstract [en]

    To examine the involvement of Na+ ions in adrenergic responses in brown adipose tissue, a method is described for measuring Na+ influx into isolated brown adipocytes, using short (30 s) incubations with 22Na+, followed by a two-step centrifugation recovery procedure. Using this method, a clear norepinephrine-stimulated accumulation of intracellular 22Na+ was observed, which was enhanced by the addition of ouabain, was insensitive to amiloride (a Na+/H+ exchange blocker), and could not be mimicked by the total removal of oxygen from the incubation medium. The norepinephrine-stimulated Na+ influx was dose-dependent for the hormone with an EC50 of 250 nM, was blocked by the beta-antagonist propranolol but not by the alpha 1-antagonist prazosin, and could be induced by adrenergic agonists with the order of potency: isoproterenol greater than norepinephrine greater than phenylephrine, indicating a beta-receptor-mediated process. The Na+ influx was found to be cAMP-dependent since it could be induced by both theophylline (a phosphodiesterase inhibitor) and forskolin (an adenylate cyclase activator), but it was independent of other known cellular cAMP-dependent responses since neither addition of fatty acid substrates (octanoate or palmitate), nor of the mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxyphenyl-hydrazone could induce the phenomenon, despite having significant stimulatory effects on cellular respiration. Furthermore, total respiratory inhibition with rotenone, or total oxygen depletion of the medium with dithionite, did not prevent the normal norepinephrine-induced Na+ influx. The possibility that this beta-mediated norepinephrine-stimulated Na+ influx plays an important physiological role in brown adipose tissue activity is discussed, perhaps as one of the, as yet undefined, signals initiating tissue growth in the chronically beta-stimulated tissue of animals facing long-term increases in thermogenic demands.

  • 8. Eriksson, A
    et al.
    Nånberg, Eewa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Rönnstrand, L
    Engström, U
    Hellman, U
    Rupp, E
    Carpenter, G
    Heldin, C H
    Claesson-Welsh, L
    Demonstration of functionally different interactions between phospholipase C-gamma and the two types of platelet-derived growth factor receptors.1995In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 270, no 13, p. 7773-7781Article in journal (Refereed)
    Abstract [en]

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

  • 9. Fagerström, S
    et al.
    Påhlman, S
    Gestblom, C
    Nånberg, Eewa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Protein kinase C-epsilon is implicated in neurite outgrowth in differentiating human neuroblastoma cells.1996In: Cell growth & differentiation, ISSN 1044-9523, Vol. 7, no 6, p. 775-785Article in journal (Refereed)
    Abstract [en]

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

  • 10. Fagerström, S
    et al.
    Påhlman, S
    Nånberg, Eewa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Protein kinase C-dependent tyrosine phosphorylation of p130cas in differentiating neuroblastoma cells.1998In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 273, no 4, p. 2336-2343Article in journal (Refereed)
    Abstract [en]

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

  • 11.
    Fjaeraa Alfredsson, Christina
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Nånberg, Eewa
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Effect of ellagic acid on proliferation, cell adhesion and apoptosis in SH-SY5Y human neuroblastoma cells2009In: Biomedicine and Pharmacotherapy, ISSN 0753-3322, E-ISSN 1950-6007, Vol. 63, no 4, p. 254-261Article in journal (Refereed)
    Abstract [en]

    Ellagic acid, a polyphenolic compound found in berries, fruits and nuts, has been shown to possess growth-inhibiting and apoptosis promoting activities in cancer cell lines in vitro. The objective of this study was to investigate the effect of ellagic acid in human neuroblastoma SH-SY5Y cells. In cultures of SH-SY5Y cells incubated with ellagic acid, time- and concentration-dependent inhibitory effects on cell number were demonstrated.Ellagic acid induced cell detachment, decreased cell viability and induced apoptosis as measured by DNA strand breaks. Ellagic acid-induced alterations in cell cycle were also observed. Simultaneous treatment with all-trans retinoic acid did not rescue the cells from ellagic acid effects. Furthermore, the results suggested that pre-treatment with all-trans retinoic acid to induce differentiation and cell cycle arrest did not rescue the cells from ellagic acid-induced cell death.

  • 12.
    Fjæraa Alfredsson, Christina
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013).
    Ding, Menglei
    Karlstad University, Faculty of Health, Science and Technology (starting 2013).
    Liang, Qiu-Li
    Karlstad University, Faculty of Health, Science and Technology (starting 2013).
    Sundström, Birgitta
    Karlstad University, Faculty of Technology and Science.
    Nånberg, Eewa
    Karlstad University, Faculty of Health, Science and Technology (starting 2013).
    Ellagic acid induces a dose- and time-dependent depolarization of mitochondria and activation of caspase-9 and -3 in human neuroblastoma cells2014In: Biomedicine and Pharmacotherapy, ISSN 0753-3322, E-ISSN 1950-6007, Vol. 68, no 1, p. 129-135Article in journal (Refereed)
    Abstract [en]

    The polyphenol ellagic acid is found in many natural food sources and has been proposed as a candidate compound for clinical applications due to its anti-oxidative capacity and as a potential anti-tumorigenic compound. The objective of the present study was to evaluate the sensitivity to and possible apoptosis mechanism induced by ellagic acid in neuronal tumor cells. As a model the human neuroblastoma SH-SY5Y cell line was used. The methods applied were bright field and phase contrast microscopy, XTT- and LDH-assays, western blot, and flow cytometric analysis of DNA degradation and mitochondrial membrane potential. Ellagic acid treatment was found to induce a reduction in cell number preceded by alterations of the mitochondrial membrane potential and activation of caspase-9 and -3, DNA-fragmentation and cell death by apoptosis. The apoptotic cell death studied was not due to anoikis since it was significant in the adherent fraction of the cells. We conclude that ellagic acid induces dose- and time-dependent apoptosis, at least partly by the mitochondrial pathway, in an embryonal neuronal tumor cell system. This finding is in agreement with previously reported data on adult carcinoma cells thus suggesting a more general effect of ellagic acid on tumor cells.

  • 13.
    Fjæraa Alfredsson, Christina
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
    Rendel, Filip
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
    Liang, Qui-Li
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
    Sundström, Birgitta E
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
    Nånberg, Eewa
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
    Altered sensitivity to ellagic acid in neuroblastoma cells undergoing differentiation with 12-0-tetradecanoylphorbol-13-acetate and all-trans retinoic acid2015In: Biomedicine and Pharmacotherapy, ISSN 0753-3322, E-ISSN 1950-6007, Vol. 76, p. 39-45Article in journal (Refereed)
    Abstract [en]

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

  • 14.
    Fjæraa Alfredsson, Christina
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
    Rendel, Filip
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
    Sundström, Birgitta E
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
    Nånberg, Eewa
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
    Proliferation in morphologically differentiated SH-SY5Y human neuroblastoma cellsManuscript (preprint) (Other academic)
  • 15.
    Guo, Jing
    et al.
    Normal University, Wuhan.
    Han, Bing
    Normal University, Wuhan.
    Qin, Longjuan
    Normal University, Wuhan.
    Li, Bing
    Normal University, Wuhan.
    You, Huihui
    Normal University, Wuhan.
    Yang, Jiwen
    Normal University, Wuhan.
    Liu, Dandan
    Normal University, Wuhan.
    Wei, Chenxi
    Normal University, Wuhan.
    Nånberg, Eewa
    Karlstad University, Faculty of Social and Life Sciences, Department of Health and Environmental Sciences.
    Bornehag, Carl-Gustaf
    Karlstad University, Faculty of Social and Life Sciences, Department of Health and Environmental Sciences.
    Yang, Xu
    Normal University, Wuhan.
    Pulmonary toxicity and adjuvant effect of di-(2-exylhexyl) phthalate in ovalbumin-immunized BALB/c mice2012In: PloS one, ISSN 1932-6203, Vol. 7, no 6, p. e39008-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Asthma is a complex pulmonary inflammatory disease, which is characterized by airway hyperresponsiveness, variable airflow obstruction and inflammation in the airways. The majority of asthma is allergic asthma, which is a disease caused by type I hypersensitivity mediated by IgE. Exposures to a number of environmental chemicals are suspected to lead to asthma, one such pollutant is di-(2-ethylheyl) phthalate (DEHP). DEHP is a manufactured chemical that is commonly added in plastic products to make them flexible. Epidemiological studies have revealed a positive association between DEHP exposure and asthma prevalence.

    METHODOLOGY/PRINCIPAL FINDINGS: The present study was aimed to determine the underlying role of DEHP exposure in airway reactivity, especially when combined with allergen exposure. The biomarkers include pulmonary histopathology, airway hyperresponsiveness (lung function), IgE, IL-4, IFN-γ and eosinophils. Healthy balb/c mice were randomly divided into eight exposure groups (n = 8 each): (1) saline control, (2) 30 µg/(kg•d) DEHP, (3) 300 µg/(kg•d) DEHP, (4) 3000 µg/(kg•d) DEHP, and (5) ovalbumin (OVA)-sensitized group, (6) OVA-combined with 30 µg/(kg•d) DEHP, (7) OVA-combined with 300 µg/(kg•d) DEHP, and (8) OVA-combined with 3000 µg/(kg•d) DEHP. Experimental tests were conducted after 52-day DEHP exposure and subsequently one week of challenge with aerosolized OVA. The principal findings include: (1) Strong postive associations exist between OVA-combined DEHP exposure and serum total IgE (T-IgE), as well as histological findings. These positive associations show a dose-dependent low dose sensitive effect of DEHP. (2) IL-4, eosinophil recruitment and lung function are also indicators for adjuvant effect of DEHP.

    CONCLUSIONS/SIGNIFICANCE: Our results suggest that except the significant changes of immunological and inflammatory biomarkers (T-IgE, IL-4, IFN-γ and eosinophils), the pulmonary histological (histopathological examination) and physiological (lung function) data also support that DEHP may promote and aggravate allergic asthma by adjuvant effect.

  • 16.
    Karlsson, Sofia
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Nånberg, Eewa
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Fjaeraa Alfredsson, Christina
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Wijkander, Jonny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
    Ellagic acid inhibits lipopolysaccharide-induced expression of enzymesinvolved in the synthesis of prostaglandin E2 in human monocytes2010In: British Journal of Nutrition, ISSN 0007-1145, E-ISSN 1475-2662, Vol. 103, p. 1102-1109Article in journal (Refereed)
    Abstract [en]

    Ellagic acid, a natural polyphenol found in certain fruits, nuts and vegetables, has in recent years been the subject of intense research within the fields of cancer and inflammation. Pain, fever and swelling, all typical symptoms of inflammation, are ascribed to elevated levels of PGE(2). In the present study, we have investigated the effects of ellagic acid on PGE(2) release and on prostaglandin-synthesising enzymes in human monocytes. Ellagic acid was found to inhibit Ca ionophore A23187-, phorbol myristate acetate- and opsonised zymosan-induced release of PGE(2) from monocytes pre-treated with the inflammatory agent lipopolysaccharide. Ellagic acid suppressed the lipopolysaccharide-induced increase in protein expression of cyclo-oxygenase-2 (COX-2), microsomal PGE synthase-1 (mPGEs-1) and cytosolic phospholipase A(2)alpha (cPLA(2)alpha), while it had no effect on the constitutively expressed COX-1 protein. Ellagic acid had no apparent inhibitory effect on these enzymes when the activities were determined in cell-free assays. We conclude that the inhibitory effect of ellagic acid on PGE(2) release from monocytes is due to a suppressed expression of COX-2, mPGEs-1 and cPLA(2)alpha, rather than a direct effect on the activities of these enzymes.

  • 17.
    Karlsson, Sofia
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Nånberg, Eewa
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Fjaeraa, Christina
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Wijkander, Jonny
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Ellagic acid inhibits lipopolysaccharide-inducted expressions of enzymes involved in the synthesis of prostaglandin E2 in human monocytes2010In: British Journal of Nutrition, ISSN 0007-1145, E-ISSN 1475-2662, Vol. 103, no 8, p. 1102-1109Article in journal (Refereed)
  • 18. Lavenius, E
    et al.
    Gestblom, C
    Johansson, I
    Nånberg, Eewa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Påhlman, S
    Transfection of TRK-A into human neuroblastoma cells restores their ability to differentiate in response to nerve growth factor.1995In: Cell growth & differentiation, ISSN 1044-9523, Vol. 6, no 6, p. 727-736Article in journal (Refereed)
    Abstract [en]

    Human neuroblastoma cell lines frequently express the TRK-A proto-oncogene and bind nerve growth factor (NGF) but do not differentiate when exposed to NGF. Transient transfection of an exogenous TRK-A gene into SH-SY5Y and LA-N-5 neuroblastoma cells restored the ability of these tumor cells to differentiate with NGF. Stable TRK-A-transfected SH-SY5Y cell clones were isolated, and they responded to NGF by autophosphorylation of p140trk-A, c-fos induction, morphological differentiation, and increased expression of two neuronal marker genes, neuropeptide tyrosine and GAP-43. In phorbol ester-induced differentiated wild-type cells, TRK-A expression was increased with no change in NGF responsiveness. Thus, the restoration of the NGF-induced differentiation pathway by exogenous TRK-A presents a system of NGF-responsive human cultured cells and focuses attention on the trk-A protein and its function or malfunction in neuroblastoma.

  • 19. Lavenius, E
    et al.
    Parrow, V
    Nånberg, Eewa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Påhlman, S
    Basic FGF and IGF-I promote differentiation of human SH-SY5Y neuroblastoma cells in culture.1994In: Growth Factors, ISSN 0897-7194, E-ISSN 1029-2292, Vol. 10, no 1, p. 29-39Article in journal (Refereed)
    Abstract [en]

    Phorbolester-triggered differentiation of SH-SY5Y neuroblastoma cells requires serum and a prolonged activation of protein kinase C (PKC). Under serum-free conditions development of a mature phenotype requires phorbolester in combination with a member of either the insulin-like growth factor (IGF) or the platelet-derived growth factor family. Here we report that basic and acidic fibroblast growth factor (FGF) and epidermal growth factor, but not nerve growth factor, synergistically potentiate phorbolester-induced differentiation. Alone these factors induced a mitogenic response which varied in magnitude, with basic FGF and IGF-I being the two most potent mitogens. However, a combination of basic FGF and IGF-I induced differentiation as judged by morphology and the increase in growth associated protein (GAP-43) and neuropeptide tyrosine mRNA levels. In contrast to the phenotype obtained in the presence of phorbolester, bFGF and IGF-I-treated SH-SY5Y cells retained their capacity to proliferate. Finally, in these cells, the phosphorylation of the endogenous PKC substrate, myristoylated alanine-rich C-kinase substrate (MARCKS), was slightly increased during several days, suggesting an involvement of PKC in the bFGF and IGF-I-induced differentiation.

  • 20. Lopez-Rivas, A
    et al.
    Mendoza, S A
    Nånberg, Eewa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Sinnett-Smith, J
    Rozengurt, E
    Ca2+-mobilizing actions of platelet-derived growth factor differ from those of bombesin and vasopressin in Swiss 3T3 mouse cells.1987In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 84, no 16, p. 5768-5772Article in journal (Refereed)
    Abstract [en]

    Addition of the mitogenic peptides bombesin and vasopressin to quiescent Swiss 3T3 mouse cells increased the cytosolic Ca2+ concentration without any measurable delay. In contrast, there was a significant lag period (16 +/- 1.2 s) before platelet-derived growth factor (PDGF) increased cytosolic Ca2+ concentration. This lag was not diminished at high concentrations of either porcine or human PDGF. Similar results were obtained in 3T3 cells loaded with quin-2 or fura-2. The differences in the effects of bombesin, vasopressin, and PDGF on Ca2+ movements were also substantiated by measurements of 45Ca2+ efflux and of cellular 45Ca2+ content. Activation of protein kinase C by phorbol esters inhibited Ca2+ mobilization induced by either bombesin or vasopressin. In contrast, phorbol esters had no effect on PDGF-induced cytosolic Ca2+ concentration increase or acceleration of 45Ca2+ efflux. Finally, bombesin and vasopressin caused a rapid increase in the production of inositol 1,4,5-trisphosphate and inositol 1,3,4-trisphosphate, whereas PDGF, even at a saturating concentration, exerted only a small effect. These results indicate that the signal transduction pathways activated by PDGF that lead to Ca2+ mobilization can be distinguished from those utilized by bombesin and vasopressin.

  • 21.
    Ma, Ping
    et al.
    China.
    Liu, Xudong
    China.
    Wu, Jiliang
    China.
    Yan, Biao
    China.
    Zhang, Yuchao
    China.
    Lu, Yu
    Wu, Yang
    Liu, Chao
    China.
    Guo, Junhui
    China.
    Nanberg, Eewa
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
    Bornehag, Carl Gustaf
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
    Yang, Xu
    Cognitive deficits and anxiety induced by diisononyl phthalate in mice and the neuroprotective effects of melatonin2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 14676Article in journal (Refereed)
    Abstract [en]

    Diisononyl phthalate (DINP) is a plasticizer that is frequently used as a substitute for other plasticizers whose use is prohibited in certain products. In vivo studies on the neurotoxicity of DINP are however, limited. This work aims to investigate whether DINP causes neurobehavioral changes in mice and to provide useful advice on preventing the occurrence of these adverse effects. Behavioral analysis showed that oral administration of 20 or 200â mg/kg/day DINP led to mouse cognitive deficits and anxiety. Brain histopathological observations, immunohistochemistry assays (cysteine-aspartic acid protease 3 [caspase-3], glial fibrillary acidic protein [GFAP]), oxidative stress assessments (reactive oxygen species [ROS], glutathione [GSH], superoxide dismutase [SOD] activities, 8-hydroxy-2-deoxyguanosine [8-OH-dG] and DNA-protein crosslinks [DPC]), and assessment of inflammation (tumor necrosis factor alpha [TNF-Crossed D sign°[ and interleukin-1 beta [IL-1β]) of mouse brains showed that there were histopathological alterations in the brain and increased levels of oxidative stress, and inflammation for these same groups. However, some of these effects were blocked by administration of melatonin (50â mg/kg/day). Down-regulation of oxidative stress was proposed to explain the neuroprotective effects of melatonin. The data suggests that DINP could cause cognitive deficits and anxiety in mice, and that melatonin could be used to avoid these adverse effects.

  • 22. Mehmet, H
    et al.
    Nånberg, Eewa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Lehmann, W
    Murray, M J
    Rozengurt, E
    Early signals in the mitogenic response of Swiss 3T3 cells: a comparative study of purified PDGF homodimers.1990In: Growth Factors, ISSN 0897-7194, E-ISSN 1029-2292, Vol. 3, no 2, p. 83-95Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor (PDGF) occurs as three dimeric isoforms, AA, BB, and AB. Two distinct receptor subunits, alpha and beta, have been identified which bind either all three isoforms of PDGF (alpha) or PDGF-BB only (beta). Here, we have compared the effect of purified PDGF homodimers on the early intracellular signaling events and mitogenesis in Swiss 3T3 cells, which possess equivalent numbers of the alpha and beta subunits. Both PDGF-AA and PDGF-BB stimulated receptor phosphorylation, inositol phosphate formation, activation of protein kinase C, calcium mobilization, EGF receptor transmodulation, sodium uptake, arachidonic acid release, cyclic AMP accumulation, and c-fos induction in a comparable, dose-dependent manner (half-maximal values for all these response were in the 2-10 ng/ml range for both homodimers). At high concentrations of PDGF (greater than 10 ng/ml), the BB homodimer effect on early membrane and cytosolic signals was 20-30% greater than PDGF-AA, reflecting the greater number of available binding sites for PDGF-BB. DNA synthesis studies indicated that PDGF-AA and PDGF-BB were potent mitogens for Swiss 3T3 cells, displaying identical dose-response effects. Moreover, the mitogenic activities of both homodimers were equally potentiated in the presence of insulin. These results indicate that both PDGF-AA and PDGF-BB stimulate the full complement of molecular responses required for the synergistic interactions mediating long-term mitogenesis. We conclude that alpha and beta receptor subunits do not differ in their ability to transduce PDGF-mediated signals leading to DNA synthesis in Swiss 3T3 cells.

  • 23. Nedergaard, J
    et al.
    Connolly, E
    Nånberg, Eewa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Mohell, N
    A possible physiological role of the Na+/Ca2+ exchange mechanism of brown-fat mitochondria in the mediation of alpha 1-adrenergic signals.1984In: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 12, no 3, p. 393-396Article in journal (Refereed)
  • 24.
    Nånberg, Eewa
    et al.
    Karlstad University, Faculty of Technology and Science, Department of Chemistry and Biomedical Sciences.
    Bornehag, Carl-Gustaf
    Karlstad University, Faculty of Social and Life Sciences, Department of Health and Environmental Sciences.
    Phthalate exposure and asthma in children2010In: International Journal of Andrology, ISSN 0105-6263, E-ISSN 1365-2605, Vol. 33, no 2, p. 333-345Article in journal (Refereed)
    Abstract

    During the last decades more than 100 000 new chemicals have been introduced to the environment. Many of these new chemicals and many common consumer products that include these have been shown to be toxic in animal studies and an increasing body of evidence suggests that they are also impacting human health. Among the suspect chemicals, the endocrine disrupting chemicals (EDCs) are of particular concern. One such chemical group is the phthalates, used in soft poly vinyl chloride (PVC) material and in a huge number of consumer products. During the same period of time that the prevalence of these modern chemicals has increased, there has been a remarkable increase in several chronic illnesses, including asthma and allergy in children. In this article we outline the scientific knowledge on phthalate exposure for asthma and airway diseases in children by examining epidemiological and experimental peer review data for potential explanatory mechanisms. Epidemiological data point to a possible correlation between phthalate exposure and asthma and airway diseases in children. Experimental studies present support for an adjuvant effect on basic mechanisms in allergic sensitization by several phthalates. Despite variations in the experimental design and reported result in the individual studies, a majority of published reports have identified adjuvant effects on Th2 differentiation, production of Th2 cytokines and enhanced levels of Th2 promoted immunoglobulins (mainly IgG1 but also IgE) in mice. A limited amount of data do also suggest phthalate-induced enhancement of mast cell degranulation and eosinophilic infiltration which are important parts in the early inflammation phase. Thus, some of the early key mechanisms in the pathology of allergic asthma could possibly be targeted by phthalate exposure. But the important questions of clinical relevance of real life exposure and identification of molecular targets that can explain interactions largely remain to be answered

  • 25.
    Nånberg, Eewa
    et al.
    The Wenner-Gren Institute, University of Stockholm.
    Connolly, E
    Nedergaard, J
    Presence of a Ca2+-dependent K+ channel in brown adipocytes. Possible role in maintenance of alpha 1-adrenergic stimulation.1985In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 844, no 1, p. 42-49Article in journal (Refereed)
    Abstract [en]

    We have previously demonstrated mobilization of Ca2+ in and efflux of Rb+ (K+) from isolated hamster brown adipocytes as a consequence of norepinephrine stimulation. We have now investigated the adrenoceptor subtype specificity of these responses and found them both to be of the alpha 1-subtype. Further, we have found that the Rb+ (K+) efflux was dependent upon a primary Ca2+ mobilization event in response to the alpha 1-adrenergic stimulation, since the Rb+ efflux could also be demonstrated by the addition of the Ca2+ ionophore A23187 to the cells. The norepinephrine- and A23187-stimulated Rb+ effluxes were both inhibited by the Ca2+-dependent K+-channel blocker apamin. Apamin also significantly attenuated Ca2+ mobilization in cells in response to a submaximal concentration of norepinephrine. We conclude that alpha 1-adrenergic stimulation of brown fat cells leads to a mobilization of intracellular Ca2+ which, in itself or via other mechanisms, leads to an increase in cytosolic Ca2+ concentration which, in turn, activates a Ca2+-dependent K+ channel, leading to a K+ release from these cells. A possible role for this channel to sustain and augment the response to alpha 1-adrenergic stimulation is discussed.

  • 26.
    Nånberg, Eewa
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Morris, C
    Higgins, T
    Vara, F
    Rozengurt, E
    Fibroblast growth factor stimulates protein kinase C in quiescent 3T3 cells without Ca2+ mobilization or inositol phosphate accumulation.1990In: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 143, no 2, p. 232-242Article in journal (Refereed)
    Abstract [en]

    To elucidate the transmembrane signalling processes initiated by fibroblast growth factor (FGF), we have studied the effect of recombinant basic FGF (bFGF) on various early events associated with mitogenesis in Swiss 3T3 fibroblasts. bFGF, at mitogenic concentrations, neither induced Ca2+ mobilization from intracellular stores nor increased the accumulation of inositol phosphates. In contrast, bFGF stimulated the phosphorylation of the Mr 80,000 (80K) cellular protein which is a major substrate of protein kinase C. This effect was potentiated by the diacylglycerol kinase inhibitor R59022. Two-dimensional polyacrylamide gel electrophoresis and phosphopeptide mapping showed that the 80K phosphoproteins generated in response to bFGF, bombesin, and phorbol 12,13-dibutyrate were indistinguishable. Down-regulation of protein kinase C prevented bFGF stimulation of 80K phosphorylation. Other protein kinase C-dependent early events such as transmodulation of the epidermal growth factor receptor, cytoplasmic alkalinization, inhibition of vasopressin induced increase in cytosolic [Ca2+], and enhancement of cAMP accumulation in response to forskolin were also induced by bFGF. Similar results were obtained when bFGF was added to quiescent cultures of tertiary mouse embryo fibroblasts. We conclude that bFGF stimulates protein kinase C through a signal transduction pathway distinct from inositol phospholipid turnover and Ca2+ mobilization.

  • 27.
    Nånberg, Eewa
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Nedergaard, J
    Alpha 1-adrenergic inositol trisphosphate production in brown adipocytes is Na+ dependent.1987In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 930, no 3, p. 438-445Article in journal (Refereed)
    Abstract [en]

    In order to investigate the ionic requirements for inositol trisphosphate production, brown adipocytes were prelabelled with myo-[3H]inositol and the formation of inositol trisphosphates and inositol bisphosphates as a consequence of alpha 1-adrenergic stimulation was monitored. Omission of Ca2+ from the incubation medium diminished the norepinephrine-induced increase in inositol trisphosphate levels, but it would seem that this reduction can be fully accounted for by a decreased level of the 'inactive' isomer inositol 1,3,4-trisphosphate. Omission of Na+ fully abolished the norepinephrine-induced inositol trisphosphate response. However, it was observed that the presence of Li+ in the incubation medium could fully reconstitute the ability of the cells to yield the early response of inositol trisphosphate production; Li+ could, however, not substitute for Na+ in the entire alpha 1-adrenergic cellular pathway. It was concluded that the Na+-dependent step is found in the coupling mechanism between the alpha 1-receptor and the activation of the phosphodiesterase responsible for inositol trisphosphate production. Thus, all events in the alpha 1-adrenergic pathway which are consequences of IP3 production should appear to be Na+-dependent in these cells.

  • 28.
    Nånberg, Eewa
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Nedergaard, J
    Cannon, B
    Alpha-adrenergic effects on 86Rb+ (K+) potentials and fluxes in brown fat cells.1984In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 804, no 3, p. 291-300Article in journal (Refereed)
    Abstract [en]

    Net K+ fluxes in isolated hamster brown fat cells were studied by the use of the K+ analogue 86Rb+. In isolated cells, cold-stored overnight to diminish K+ gradients, an equilibrium 86Rb+ (K+) clearance value of 27 microliter/million cells was obtained after 30 min incubation at 37 degrees C. This corresponds to a 10-fold K+ gradient over the plasma membrane, and a K+ potential of about -60 mV. The attainment of this equilibrium was dependent upon the presence of Na+ in the extracellular medium, and the uptake was fully inhibited by the (Na+ + K+)-ATPase inhibitor ouabain. Ouabain had, however, no significant acute effect on the maximal rate of thermogenesis achieved after norepinephrine stimulation of the cells, but if the restoration of ionic equilibrium was inhibited by ouabain in prolonged incubations, a decreased thermogenesis was observed. This was probably due to the low cytosolic K+ content then encountered, and the resulting inhibition of lipolysis. The addition of norepinephrine to cells in which 86Rb+ (K+) equilibrium had been attained resulted in a rapid efflux of 86Rb+ and the establishment of a new equilibrium value, at about 65% of the unstimulated value. This corresponds to a decrease in K+ potential of about 15 mV. The effect of norepinephrine was stereospecific and reversible, and had an EC50 value of about 10 nM. As catecholamine effects were much more sensitive to phentolamine than to propranolol, the adrenergically-induced efflux was classified as predominantly alpha-adrenergic. It is suggested that the norepinephrine-induced K+ efflux is due to a (probably Ca2+-mediated) opening of K+ channels in the cell membrane, and that this effect occurs secondarily to the alpha-adrenergically induced membrane depolarization (and increase in cytosolic Ca2+). The increased PK over the cell membrane would counteract further depolarization, and the K+ gradient would then approach the Nernst equilibrium under the new steady-state conditions.

  • 29.
    Nånberg, Eewa
    et al.
    Department of Metabolic Research, The Wenner-Gren Insitute, University of Stockholm.
    Putney, J
    Alpha 1-adrenergic activation of brown adipocytes leads to an increased formation of inositol polyphosphates.1986In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 195, no 1-2, p. 319-22Article in journal (Refereed)
    Abstract [en]

    alpha 1-Adrenergic activation of isolated brown adipocytes causes a rapid mobilization of intracellular Ca2+. The cells also respond with an increased turnover of inositol lipids. The present work demonstrates that alpha 1-adrenergic stimulation of brown adipocytes results in phospholipase C-mediated breakdown of phosphatidylinositol bisphosphate to form inositol trisphosphate. The rate of appearance of inositol trisphosphate is sufficiently rapid for it to mediate or contribute to Ca2+ mobilization in these cells.

  • 30.
    Nånberg, Eewa
    et al.
    Imperial Cancer Research Fund, London, UK.
    Rozengurt, E
    Temporal relationship between inositol polyphosphate formation and increases in cytosolic Ca2+ in quiescent 3T3 cells stimulated by platelet-derived growth factor, bombesin and vasopressin.1988In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 7, no 9, p. 2741-7Article in journal (Refereed)
    Abstract [en]

    We determined the temporal relationship between the formation of inositol phosphates and increase in cytosolic [Ca2+] elicited by bombesin, vasopressin and platelet-derived growth factor (PDGF) in quiescent Swiss 3T3 cells. These responses were measured under identical conditions. Bombesin caused a rapid increase in inositol 1,4,5-trisphosphate which coincided with the increase in cytosolic [Ca2+]. This was followed by a slower but marked increase in inositol 1,3,4-trisphosphate and inositol-bisphosphate. Vasopressin elicited a similar sequence of events. In sharp contrast, highly purified porcine PDGF induced increases in cytosolic [Ca2+] and inositol 1,4,5-trisphosphate that were temporally uncoupled: detectable inositol polyphosphate formation occurred after Ca2+ mobilization from intracellular stores. The same temporal dissociation was observed when a recombinant v-sis product was used instead of porcine PDGF. However, PDGF was as effective as bombesin in stimulating the formation of inositol phosphates after 5-10 min of incubation. The data suggest that PDGF increases cytosolic [Ca2+] via a different signal transduction pathway from that utilized by bombesin and vasopressin. These findings have important implications for understanding the signal transduction pathway activated by PDGF.

  • 31.
    Nånberg, Eewa
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Westermark, B
    Platelet-derived growth factor increases the turnover of GTP/GDP on ras in permeabilized fibroblasts.1993In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 268, no 24, p. 18187-18194Article in journal (Refereed)
    Abstract [en]

    The potent mitogen platelet-derived growth factor (PDGF) induced a rapid increase in Ras.GTP in permeabilized human and murine fibroblasts. The effect was initiated by both PDGF-AA acting exclusively through PDGF alpha-receptors, and by PDGF-BB interacting with both alpha- and beta-type receptors. The dose-response curves suggest that both receptor types mediate the response. PDGF-dependent Ras activation, measured as increased formation of Ras.GTP, was rapid and reversible. At 37 degrees C the effect had a duration of around 10 min. The PDGF-dependent increase in Ras.GTP was followed by a simultaneous increase in Ras.GDP. Under no experimental condition could a relative increase in Ras.GTP be detected. 0.5 microM GDP and 0.5 microM GTP were equally potent competing for the formation of Ras.[alpha-32P]GTP upon PDGF stimulation. Furthermore, when the basal nucleotide exchange rate on Ras was elevated by omission of Mg2+ from the medium, PDGF had no further effect on the formation of Ras.GTP. We therefore conclude that PDGF activates Ras through a mechanism leading to an increased nucleotide exchange on Ras.

  • 32. Olsson, A K
    et al.
    Nånberg, Eewa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    A functional role for ERK in gene induction, but not in neurite outgrowth in differentiating neuroblastoma cells.2001In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 265, no 1, p. 21-30Article in journal (Refereed)
    Abstract [en]

    The human neuroblastoma cell line SH-SY5Y can differentiate into a functional sympathetic neuronal phenotype when treated with low concentrations of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) in the presence of serum or defined growth factors. When TrkA is introduced into the cells, NGF also induces differentiation. In both cases, protein kinase C (PKC) is pivotal for induction and maintenance of the differentiated phenotype. We have recently shown that PKC activity is needed to enable the MAPK ERK to accumulate in the nucleus of SH-SY5Y cells and hence activate transcription. To find out whether this could be one reason for the PKC dependency in the differentiation process we have investigated the role of ERK during neuronal differentiation of these cells. The results show that ERK was needed for full upregulation of the neuronal marker genes NPY and GAP-43. However, ERK activity was not necessary for TPA-induced neurite formation. Neither was activation of ERK sufficient to promote neurite outgrowth. The results clearly show that there was no correlation between nuclear ERK activity, measured as SRE transactivation, and neurite formation in TPA-differentiated SH-SY5Y neuroblastoma cells.

  • 33. Olsson, A K
    et al.
    Vadhammar, K
    Nånberg, Eewa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Activation and protein kinase C-dependent nuclear accumulation of ERK in differentiating human neuroblastoma cells.2000In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 256, no 2, p. 454-467Article in journal (Refereed)
    Abstract [en]

    The human neuroblastoma cell line SH-SY5Y is a well characterized model for sympathetic neuronal differentiation in vitro. Several differentiation protocols exist, one of which, the addition of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) in the presence of serum, has been thoroughly studied. Wild-type SH-SY5Y cells are unresponsive to nerve growth factor (NGF), but cells transfected with the high-affinity NGF receptor TrkA (SH-SY5Y/TrkA) differentiate in response to NGF. In the present study, we have addressed the existence of a differentiation-specific mode of activation and subcellular distribution of the extracellular signal-regulated kinases ERK1 and ERK2 in SH-SY5Y/wt and SH-SY5Y/TrkA. Both TPA and NGF induced a sustained activation and nuclear accumulation of ERK that was accompanied by transactivation of a serum response element (SRE)-driven reporter and of the c-fos gene. However, activation and nuclear accumulation of ERK were not sufficient to induce neuronal differentiation in SH-SY5Y, as demonstrated by the response to TPA in serum-free cultures. Nuclear accumulation but not activation of ERK was demonstrated to require active protein kinase C (PKC). The effect of specific PKC inhibitors on subcellular distribution of ERK and ERK-dependent transcription suggests a functional role for PKC in the regulation of nuclear ERK activity in SH-SY5Y neuroblastoma cells.

  • 34. Parrow, V
    et al.
    Fagerström, S
    Meyerson, G
    Nånberg, Eewa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Påhlman, S
    Protein kinase C-alpha and -epsilon are enriched in growth cones of differentiating SH-SY5Y human neuroblastoma cells.1995In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 41, no 6, p. 782-791Article in journal (Refereed)
    Abstract [en]

    SH-SY5Y cells differentiate into neuronal-like cells and express marker proteins like growth-associated protein (GAP-43) and neuropeptide tyrosine when treated with a low concentration (16 nM) of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) in the presence of growth factors or serum. Both control and differentiated cells expressed protein kinase C-alpha (PKC-alpha), PKC-epsilon, and PKC-zeta as revealed by Western blot analyses, but the subcellular distribution of the three isoforms was not uniform, indicating specific localized functions of the enzymes. In growth cones prepared from differentiating cells PKC-alpha and PKC-epsilon were enriched. In contrast, PKC-zeta was more evenly distributed within the differentiating cell. Cells treated with a high concentration of TPA (1.6 microM) differentiate poorly and continue to proliferate. In those cells, PKC-alpha and PKC-epsilon were found to be down-regulated while PKC-zeta remained present. Thus, down-regulation of PKC-alpha and PKC-epsilon appears to be incompatible with neuronal differentiation of SH-SY5Y cells. These cells also differentiate when treated with a combination of basic fibroblast growth factor and insulin-like growth factor I. Growth cones isolated from such cells are also enriched in PKC-alpha and PKC-epsilon, but not in PKC-zeta. Based on the subcellular distribution of PKC-alpha and epsilon, and that PKC substrates like GAP-43 and pp60c-src are enriched in SH-SY5Y growth cones, a role during neurite growth is suggested.

  • 35.
    Parrow, Vendela
    et al.
    Department of Pathology, University Hospital, Uppsala.
    Nånberg, Eewa
    Department of Biochemistry and Pharmacy, Åbo Akademi University, Finland.
    Heikkilä, Jari
    Department of Biochemistry and Pharmacy, Åbo Akademi University, Finland.
    Hammerling, Ulf
    Department of Pathology, University Hospital, Uppsala.
    Påhlman, Sven
    Department of Pathology, University Hospital, Uppsala.
    Protein kinase C remains functionally active during TPA induced neuronal differentiation of SH-SY5Y human neuroblastoma cells1992In: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 152, no 3, p. 536-44Article in journal (Refereed)
    Abstract [en]

    SH-SY5Y human neuroblastoma cells can be induced to differentiate into a neuronal phenotype by treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA). In other cell systems, TPA treatment frequently leads to down-regulation of protein kinase C (PKC). However, we now report that TPA-treated and non-treated SH-SY5Y cells express PKC-alpha, but not PKC-beta and PKC-gamma, mRNA. Furthermore, only a slight down-regulation of the PKC-alpha protein could be seen during prolonged treatment with 16 nM TPA, the concentration giving optimal differentiation. In contrast, a higher concentration of TPA (1.6 microM) results in a poor neuronal differentiation and a complete down-regulation of PKC-alpha. PKC-alpha was rapidly translocated to the particulate fraction and remained membrane bound for at least 4 days during treatment with 16 nM TPA. In such cells a sustained increased level of the phosphorylated form of a 80,000 Dalton PKC-substrate was found. In addition to this sustained augmented phosphorylation, administration of fresh TPA at day 4 caused a small but reproducible further increased level of phosphorylated substrate. When the PKC activity was measured by the histone phosphorylation assay a substantial fraction of the initial enzyme activity could still be detected after 4 days of TPA treatment. Taken together, the data demonstrate that PKC remains functionally active during TPA induced differentiation of SH-SY5Y cells, which may suggest a continuous role for the enzyme during the differentiation process.

  • 36. Påhlman, S
    et al.
    Hoehner, J C
    Nånberg, Eewa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Hedborg, F
    Fagerström, S
    Gestblom, C
    Johansson, I
    Larsson, U
    Lavenius, E
    Ortoft, E
    Differentiation and survival influences of growth factors in human neuroblastoma.1995In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 31A, no 4, p. 453-458Article in journal (Refereed)
    Abstract [en]

    Human neuroblastoma cell lines are established from high-stage, highly malignant tumours. Despite this and the fact that these tumours are arrested at an early, immature stage, many cell lines have the capacity to undergo neuronal differentiation under proper growth conditions. One such cell line is the noradrenergic SH-SY5Y cell line. These cells can be induced to mature by a variety of modalities, resulting in different mature phenotypes. The use of this cell system as a model to study the stem cell character of neuroblastoma is reviewed and discussed. In particular, we focus on growth factor dependencies in the SH-SY5Y system, and compare that to the normal situation, i.e. growth factor control of sympathetic neuronal and neuroendocrine differentiation during human and rat embryogenesis.

  • 37.
    Rendel, Filip
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Fjaeraa Alfredsson, Christina
    Landstinget i Värmland.
    Bornehag, Carl-Gustaf
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Sundström, Birgitta E.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Nånberg, Eewa
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Effects of Di-Isononyl Phthalate on Neuropeptide Y Expression in Differentiating Human Neuronal Cells2017In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 120, no 3, p. 218-323Article in journal (Refereed)
  • 38. Rosenmüller, T
    et al.
    Rydh, K
    Nånberg, Eewa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Role of phosphoinositide 3OH-kinase in autocrine transformation by PDGF-BB.2001In: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 188, no 3, p. 369-382Article in journal (Refereed)
    Abstract [en]

    Phosphoinositide 3OH-kinases (PI3K) are a family of lipid kinases that activates signalling pathways important for migration, cytoskeletal rearrangements, and cell survival. These processes are important hallmarks in transformation. We have evaluated the functional role of PI3K for development of a transformed morphology and migratory responses of murine fibroblasts (NIH/sis and COL1A1/NIH3T3 cell lines) stimulated in an autocrine fashion by constitutive expression of platelet-derived growth factor-BB (PDGF-BB). We show that prolonged treatment with the specific PI3K inhibitor LY294002, induced a reversion of the transformed morphology, and prevented density-independent growth and focus formation. Functional PI3K was also required for development of the transformed morphology of NIH/sis and COL1A1/NIH3T3. Furthermore, treatment with LY294002 completely perturbed random migration of the cells. In addition our data show that, in the signalling pathways downstream of PI3K, activation of the small GTPase Rac was a prerequisite for the transformation signal. Our data also indicate the presence of a suramin-insensitive PI3K activity. Most likely this was due to the presence of a suramin-insensitive intracellular PDGFR pool that allowed activation of PI3K located in intracellular compartments. In conclusion these data show that intact PI3K activity was required for the morphological alterations and the enhanced migratory response that are hallmarks for PDGF induced autocrine transformation.

  • 39. Rozengurt, E
    et al.
    Erusalimsky, J
    Mehmet, H
    Morris, C
    Nånberg, Eewa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Sinnett-Smith, J
    Signal transduction in mitogenesis: further evidence for multiple pathways.1988In: Cold Spring Harbor Symposia on Quantitative Biology, ISSN 0091-7451, E-ISSN 1943-4456, Vol. 53 Pt 2, p. 945-954Article in journal (Refereed)
  • 40.
    Shu, Huan
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
    Jönsson, Bo A
    Department of Laboratory Medicine, Lund University.
    Larsson, Malin
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
    Nånberg, Eewa
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
    Bornehag, Carl-Gustaf
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
    PVC flooring at home and development of asthma among young children in Sweden, a 10-year follow-up2014In: Indoor Air, ISSN 0905-6947, E-ISSN 1600-0668, Vol. 24, no 3, p. 227-235Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The incidence of asthma and allergy has increased throughout the developed world over the past decades. During the same period of time the use of industrial chemicals such as phthalates, commonly used as plasticizers in polyvinylchloride (PVC) flooring material, has increased.

    AIMS: To investigate if PVC-flooring in the home of children in the age of 1-5 years is associated with the development of asthma in 5-year and 10-year follow-up investigations (n=3,228).

    METHODS: Dampness in Buildings and Health Study (DBH Study) commenced in 2000 in Värmland, Sweden. The current analyses included subjects who answered all baseline and follow-up questionnaires. Logistic regression analyses were applied to questionnaire results.

    RESULTS: Children who had PVC floorings in the bedroom at baseline were more likely to develop doctor diagnosed asthma during the following 10 years period when compared with children living without. There were indications that PVC flooring in the parents' bedrooms were stronger associated with the new cases of doctor diagnosed asthma when compared with child's bedroom.

    CONCLUSIONS: Our results suggest PVC flooring exposure during pregnancy could be a critical period in the development of asthma in children at a later time, prenatal exposure and measurements of phthalate metabolites should be included in the future. This article is protected by copyright. All rights reserved.

  • 41.
    Shu, Huan
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Jönsson, Bo AG
    Lunds Universitet.
    Gennings, Chris
    Icahn School of Medicine at Mount Sinai, USA.
    Svensson, Åke
    Lunds Universitet.
    Nånberg, Eewa
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Lindh, Christian H
    Lunds universitet.
    Knutz, Malin
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Takaro, Tim K.
    Simon Fraser University, Canada.
    Bornehag, Carl-Gustaf
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Temporal Trends of Phthalate Exposures during 2007-2010 in Swedish Pregnant Women2018In: Journal of Exposure Science and Environmental Epidemiology, ISSN 1559-0631, E-ISSN 1559-064X, Vol. 28, no 5, p. 437-447Article in journal (Refereed)
    Abstract [en]

    Background: The general population is exposed to phthalates, a group of chemicals with strong evidence for endocrine disrupting properties, commonly used in a large number of consumer products. Based on published research and evidence compiled by environmental agencies, certain phthalate applications and products have become restricted, leading to an increasing number of “new generation compounds” coming onto the market during recent years replacing older phthalates. Some examples of such newer compounds are di-iso-nonyl phthalate (DiNP), di-iso-decyl phthalate (DiDP), and most recently di-isononyl-cyclohexane-1,2-dicarboxylate (DiNCH). Objectives: In order to evaluate temporal trends in phthalate exposure, first trimester urinary biomarkers of phthalates were measured in the Swedish SELMA study over a period of 2.5 years (2007–2010). Methods: We collected first morning void urine samples around week 10 of pregnancy from 1651 pregnant women. Spot samples were analyzed for 13 phthalate metabolites and one phthalate replacement and least square geometric mean (LSGM) levels of the metabolites were compared between the sampling years when adjusted for potential confounders. Results: All 14 metabolites were detectable in more than 99% of the SELMA subjects. The levels were generally comparable to other studies, but the SELMA subjects showed slightly higher exposure to butyl-benzyl phthalate (BBzP) and di-butyl phthalate (DBP). Di-ethyl-hexyl phthalate (DEHP) metabolites levels decreased while DiNP, DiDP/di-2-propylheptyl phthalate (DPHP), and DiNCH metabolites levels increased during the sampling period. Conclusions: Urinary metabolite levels of the older phthalates and more recently introduced phthalate replacement compound changed during the short sampling period in this Swedish pregnancy cohort. Our results indicate that replacement of phthalates can make an impact on human exposure to these chemicals. During this particularly vulnerable stage of life, phthalate exposures are of particular concern as the impacts, though not immediately noticeable, may increase the risk for health effects later in life.

  • 42.
    Shu, Huan
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Jönsson, Bo
    Lund University.
    Gennings, Chris
    Icahn School of Medicine at Mount Sinai,.
    Lindh, Christian
    Lund University.
    Nånberg, Eewa
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Bornehag, Carl-Gustaf
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013). Icahn School of Medicine at Mount Sinai,.
    PVC flooring at home and uptake of phthalates in pregnant women2019In: Indoor Air, ISSN 0905-6947, E-ISSN 1600-0668, no 1, p. 43-54Article in journal (Other academic)
    Abstract [en]

    Phthalates are used as plasticizers in polyvinyl chloride (PVC) materials and it is known that phthalates may migrate into the surrounding environment and then become a source for human uptake. The aim of the study was to investigate whether residential PVC flooring was related to the urinary levels of phthalate metabolites determined in pregnant women. The data were from the Swedish SELMA study where sampling was conducted during the time period 2007-2010. Spot urine samples from 1674 women at the end of the first trimester were analyzed for 14 metabolites from seven phthalates and one phthalate alternative. Data on flooring material in the kitchen and the parents' bedrooms as well as potential confounders were collected by postal questionnaires at the same time as the urine samples were taken. Multiple regression modeling by least square geometric mean and weighted quantile sum regression was applied to log-transformed and creatinine-adjusted phthalate metabolite concentrations adjusted for potential confounders from questionnaire data. This study has found significantly higher urinary levels of the BBzP metabolite (MBzP) in pregnant women living in homes with PVC flooring as compared to homes with other flooring materials

  • 43.
    Shu, Huan
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
    Jönsson, Bo
    Lund University.
    Lindh, Christian
    Lund University.
    Knutz, Malin
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
    Nånberg, Eewa
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
    Svensson, Åke
    Malmö University Hospital.
    Bornehag, Carl Gustaf
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
    PVC flooring in the home is related to urinary levels of phthalates in swedish pregnant women in the selma study2014In: Indoor Air, ISSN 0905-6947, E-ISSN 1600-0668, p. 976-978Article in journal (Refereed)
  • 44.
    Shu, Huan
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Wikstrom, Sverre
    Jonsson, Bo A. G.
    Lindh, Christian H.
    Svensson, Åke
    Nånberg, Eewa
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Bornehag, Carl-Gustaf
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013). Karlstad University, Faculty of Social and Life Sciences, Department of Health and Environmental Sciences.
    Prenatal phthalate exposure was associated with croup in Swedish infants2018In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 107, no 6, p. 1011-1019Article in journal (Refereed)
    Abstract [en]

    Aim: This study examined whether prenatal phthalate exposure was associated with lower or upper airway inflammation in infants. Methods: From 2007 to 2010, we used liquid chromatography-tandem mass spectrometry, adjusted for creatinine, to analyse 14 phthalate metabolites and one phthalate replacement in the urine of 1062 Swedish mothers at a median of 10 weeks of pregnancy. This was used to determine any associations between prenatal phthalate exposure and croup, wheezing or otitis in their offspring until 12 months of age, using logistic regression, adjusted for potential confounders. Results: There were significant associations between phthalate metabolites of butyl-benzyl phthalate (BBzP) and di-ethyl-hexyl phthalate (DEHP) concentrations in maternal prenatal urine and croup in 1062 infants during the first year of life, when adjusted for potential confounders. A dose-response relationship was found between prenatal phthalates exposure and maternal reported croup in the children, with a significant association in boys. There was no clear indication with regard to associations between prenatal phthalate exposure and wheezing or otitis media in the children during the first year of life. Conclusion: Our analysis suggests that exposure to BBzP and DEHP phthalates was associated with maternal reports of croup in infants up to 12 months of age

  • 45.
    Shu, Huan
    et al.
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Wikström, Sverre
    Örebro universitet.
    Jönsson, Bo AG
    Lunds universitet.
    Svensson, Åke
    Lunds universitet.
    Nånberg, Eewa
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Bornehag, Carl-Gustaf
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Prenatal phthalates exposure and the association to infant’s croup in the Swedish SELMA studyManuscript (preprint) (Other academic)
  • 46. Söderholm, H
    et al.
    Olsson, A
    Lavenius, E
    Rönnstrand, L
    Nånberg, Eewa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Activation of Ras, Raf-1 and protein kinase C in differentiating human neuroblastoma cells after treatment with phorbolester and NGF.2001In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 13, no 2, p. 95-104Article in journal (Refereed)
    Abstract [en]

    The human neuroblastoma cell line SH-SY5Y/TrkA differentiates in vitro and acquires a sympathetic phenotype in response to phorbolester (activator of protein kinase C, PKC) in the presence of serum or growth factors, or nerve growth factor (NGF). We have now investigated to what extent phorbolester and NGF cause activation of Ras and Raf-1 and the involvement of PKC in this response in differentiating SH-SY5Y/TrkA cells. NGF stimulated increased accumulation of Ras-GTP and a threefold activation of Raf-1. In contrast, 12-O-tetradecanoylphorbol-13-acetate (TPA) had no effect on the amount of Ras-GTP but led to a smaller activation of Raf-1. NGF caused a limited increase in phosphorylation of Raf-1 compared with TPA, and NGF-induced Raf activity was independent of PKC. Analysis of phosphorylation of the endogenous PKC substrate myristoylated alanine-rich C-kinase substrate (MARCKS), and of subcellular distribution of PKC-alpha, -delta, and -epsilon revealed that NGF only caused a very small activation of PKC in SH-SY5Y/TrkA cells. The results identify Raf-1 as a target for both TPA- and NGF-induced signals in differentiating SH-SY5Y/TrkA cells and demonstrate that signalling to Raf-1 was mediated via distinct mechanisms.

  • 47.
    Tang, Jiaqi
    et al.
    Cent China Normal Univ, Coll Life Sci, Hubei Key Lab Genet Regulat & Integrat Biol, Sect Environm Biomed, Wuhan, Peoples R China..
    Yuan, Ye
    Cent China Normal Univ, Coll Life Sci, Hubei Key Lab Genet Regulat & Integrat Biol, Sect Environm Biomed, Wuhan, Peoples R China..
    Wei, Chenxi
    Cent China Normal Univ, Coll Life Sci, Hubei Key Lab Genet Regulat & Integrat Biol, Sect Environm Biomed, Wuhan, Peoples R China..
    Liao, Xiaomei
    Cent China Normal Univ, Coll Life Sci, Hubei Key Lab Genet Regulat & Integrat Biol, Sect Environm Biomed, Wuhan, Peoples R China..
    Yuan, Junlin
    Cent China Normal Univ, Coll Life Sci, Hubei Key Lab Genet Regulat & Integrat Biol, Sect Environm Biomed, Wuhan, Peoples R China..
    Nånberg, Eewa
    Zhang, Yinping
    Tsinghua Univ, Dept Bldg Sci, Beijing 100084, Peoples R China..
    Bornehag, Carl-Gustaf
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
    Yang, Xu
    Cent China Normal Univ, Coll Life Sci, Hubei Key Lab Genet Regulat & Integrat Biol, Sect Environm Biomed, Wuhan, Peoples R China..
    Neurobehavioral changes induced by di(2-ethylhexyl) phthalate and the protective effects of vitamin E in Kunming mice2015In: Toxicology research, ISSN 2045-452X, Vol. 4, no 4, p. 1006-1015Article in journal (Refereed)
    Abstract [en]

    Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer commonly used in PVC that may leach into the environment, and has been shown to adversely affect the health of humans and animals. We undertook a study to ascertain the neurotoxicity of DEHP in Kunming mice. This study included three rounds of testing. In the first round, Kunming mice were exposed to different concentrations of DEHP (0, 5, 50, 500 mg kg(-1) per day) after which their cognitive ability was assessed using the Morris water maze (MWM) test. The reactive oxygen species (ROS) content in tissue and the malondialdehyde (MDA) content of brains were also measured. In the second round, vitamin E (50 mg kg(-1) per day) was given daily as an anti-oxidant via the intragastric route. Cognitive deficits and locomotor activity, as well as ROS and MDA contents were tested employing the same methods. In the third round, the depressive mood of mice after DEHP exposure (500 mg kg(-1) per day) was measured using the open field test, the tail suspension test, and the forced swim test. The main findings of this study include: (1) a statistical association exists between DEHP oral exposure and spatial learning (DEHP 500 mg kg(-1) per day) and memory (DEHP 50 mg kg(-1) per day) dysfunction as ascertained by an MWM test of Kunming mice. (2) A statistical association was also found between DEHP oral exposure (50 and 500 mg kg(-1) per day) and oxidative stress (ROS and MDA) of mouse brain tissue. (3) Co-administration of vitamin E (50 mg kg(-1) per day) diminishes the elevation of ROS and MDA induced by DEHP (50 mg kg(-1) per day) from significant levels to non-significant levels. (4) Co-administration of vitamin E (50 mg kg(-1) per day) protects against mouse memory dysfunction induced by DEHP (50 mg kg(-1) per day) from being significant to being not significant. (5) In the 5 mg kg(-1) per day DEHP exposure groups, oxidative stress in brain tissue, and neurobehavioral changes were not found. (6) High dose DEHP exposure (500 mg kg(-1) per day) may induce behavioral despair in mice. Conclusions: These data suggest that DEHP is neurotoxic with regard to cognitive ability and locomotor activity.

  • 48. Zachary, I
    et al.
    Millar, J
    Nånberg, Eewa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Higgins, T
    Rozengurt, E
    Inhibition of bombesin-induced mitogenesis by pertussis toxin: dissociation from phospholipase C pathway.1987In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 146, no 2, p. 456-463Article in journal (Refereed)
    Abstract [en]

    Prior incubation of quiescent cultures of Swiss 3T3 cells with pertussis toxin selectively inhibited the stimulation of DNA synthesis induced by peptides of the bombesin family. While pertussis toxin blocked mitogenesis at an early stage in the action of the peptide, the toxin did not impair the rapid stimulation of polyphosphoinositide breakdown, Ca2+ mobilization or activation of protein kinase C promoted by bombesin. Thus, inhibition of bombesin-induced mitogenesis by pertussis toxin can be dissociated from inactivation of the phospholipase C signalling pathway.

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