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  • 201. Sun, Jiao
    et al.
    Lou, Xudan
    Wang, Haidong
    Sollazzo, Alice
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Harms-Ringdahl, Mats
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Skog, Sven
    He, Ellen
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Serum 8-hydroxy-2'-deoxyguanosine (8-oxo-dG) levels are elevated in diabetes patients2015In: International Journal of Diabetes in Developing Countries, ISSN 0973-3930, E-ISSN 1998-3832, Vol. 35, no 3, p. 368-373Article in journal (Refereed)
    Abstract [en]

    The increased oxidative stress in diabetes is known to contribute to the development of diabetes. We investigate whether serum 8-hydro-2'-deoxyguanosine (8-oxo-dG) is associated with diabetes at the time of first diagnosis and evaluate whether it can be used as a reliable biomarker for the oxidative stress in diabetes. The study was designed as a case control study with two groups: patient with diabetes and control. The diabetes group consisted of a total of 28 patients consulting the hospital for the first time and definitely diagnosed for diabetes, and the control group was composed of 65 healthy subjects. Serum 8-oxo-dG was measured by a competitive enzyme-linked immunosorbent assay (ELISA) kit, specially developed to minimize cross-reaction of 8-oxo-dG antibody with serum guanosine. The average serum 8-oxo-dG levels in patients with diabetes and controls were 0.72 +/- 0.41 and 0.24 +/- 0.14 ng/mL, respectively, statistically significant (p < 0.001). The 8-oxo-dG value was significantly higher in women with diabetes, compared with men with diabetes (p = 0.028). The sensitivity and the specificity of the 8-oxo-dG ELISA assay were 0.80 and 0.96, respectively, and the ROC value was 0.93. This study suggests that increased oxidative stress has an important role in the pathogenesis of diabetes. Serum 8-oxo-dG may be a useful clinical biomarker for the early diagnosis of stress-related diseases, e.g. diabetes and its management.

  • 202.
    Söderberg, Emilia
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Hessle, Viktoria
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    von Euler, Anne
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Visa, Neus
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Profilin is associated with transcriptionally active genes2012In: Nucleus, ISSN 1949-1034, E-ISSN 1949-1042, Vol. 3, no 3, p. 290-299Article in journal (Refereed)
    Abstract [en]

    We have raised antibodies against the profilin of Chironomus tentans to study the location of profilin relative to chromatin and to active genes in salivary gland polytene chromosomes. We show that a fraction of profilin is located in the nucleus, where profilin is highly concentrated in the nucleoplasm and at the nuclear periphery. Moreover, profilin is associated with multiple bands in the polytene chromosomes. By staining salivary glands with propidium iodide, we show that profilin does not co-localize with dense chromatin. profilin associates instead with protein-coding genes that are transcriptionally active, as revealed by co-localization with hnRNP and snRNP proteins. We have performed experiments of transcription inhibition with actinomycin D and we show that the association of profilin with the chromosomes requires ongoing transcription. however, the interaction of profilin with the gene loci does not depend on RNA. Our results are compatible with profilin regulating actin polymerization in the cell nucleus. however, the association of actin with the polytene chromosomes of C. tentans is sensitive to RNase, whereas the association of profilin is not, and we propose therefore that the chromosomal location of profilin is independent of actin.

  • 203. Tedesco, Sara
    et al.
    Bayat, Narges
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Danielsson, Gabriela
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Buque, Xabier
    Aspichueta, Patricia
    Fresnedo, Olatz
    Cristoabl, Susana
    Proteomic and lipidomic analysis of primary mouse hepatocytes exposed tometal and metal oxide nanoparticles2015In: Journal of Integrated Omics, ISSN 2182-0287, Vol. 5, no 1Article in journal (Refereed)
    Abstract [en]

    The global analysis of the cellular lipid and protein content upon exposure to metal and metal oxide nanoparticles (NPs) can provide an overview of the possible impact of exposure. Proteomic analysis has been applied to understand the nanoimpact however the relevance of the alteration on the lipidic profile has been underestimated. In our study, primary mouse hepatocytes were treated with ultra-small (US) TiO2-USNPs as well as ZnO-NPs, CuO-NPs and Ag-NPs. The protein extracts were analysed by 2D-DIGE and quantified by imaging software and the selected differentially expressed proteins were identified by nLC-ESI-MS/MS. In parallel, lipidomic analysis of the samples was performed using thin layer chromatography (TLC) and analyzed by imaging software. Our findings show an overall ranking of the nanoimpact at the cellular and molecular level: TiO2-USNPs<ZnO-NPs<Ag-NPs<CuO-NPs. CuO-NPs and Ag-NPs were cytotoxic while ZnO-NPs and CuO-NPs had oxidative capacity. TiO2-USNPs did not have oxidative capacity and were not cytotoxic.  The most common cellular impact of the exposure was the down-regulation of proteins. The proteins identified were involved in urea cycle, lipid metabolism, electron transport chain, metabolism signaling, cellular structure and we could also identify nuclear proteins. CuO-NPs exposure decreased phosphatidylethanolamine and phosphatidylinositol and caused down-regulation of electron transferring protein subunit beta. Ag-NPs exposure caused increased of total lipids and triacylglycerol and decrease of sphingomyelin. TiO2-USNPs also caused decrease of sphingomyelin as well as up-regulation of ATP synthase and electron transferring protein alfa. ZnO-NPs affected the proteome in a concentration-independent manner with down-regulation of RNA helicase.  ZnO-NPs exposure did not affect the cellular lipids. To our knowledge this work represents the first integrated proteomic and lipidomic approach to study the effect of NPs exposure to primary mouse hepatocytes in vitro.

  • 204. Theuri, G.
    et al.
    Dallner, Gustav
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Brismar, K.
    Tekle, Michael
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Effects of lifestyle on plasma levels of the IGF system and the antioxidants coenzyme Q10 and vitamin E in Kenyan rural and urban populations2013In: Growth Hormone & IGF Research, ISSN 1096-6374, E-ISSN 1532-2238, Vol. 23, no 3, p. 68-75Article in journal (Refereed)
    Abstract [en]

    Objective: Overnight fasting blood plasma insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-1 (IGFBP-1), coenzyme Q10, (CoQ) vitamin E and plasma lipids were compared between a semi-nomadic Samburu population and relatively urbanized cohorts from Nairobi, Kenya. Research design and methods: 143 middle aged subjects without known diabetes were included. IGF-I and IGFBP-1 were analyzed by RIA, and CoQ and vitamin E by HPLC. Plasma lipid levels were analyzed by standard laboratory methods routinely used in the clinics. Results: The age adjusted IGF-I serum levels were low in the Samburu male and female populations, ranging from 0 to -4 IGFSD-score (SDS), and a minor part of the investigated population reaching as low as -5 and -7 SDS. The Nairobi cohorts showed significantly higher values reaching from -2.5 to + 1 SDS (P<0.0001). The nomadic Samburu population showed fasting IGFBP-1 values ranging from 30-100 mu g/l, while that of the urbanized Nairobi cohorts was considerably lower (25-60 mu g/l) (P<0.0001). CoQ concentrations of the Nairobi cohorts were 1.5-2.0 nmol/ml similar to the levels found in several European countries. The Samburu population on the other hand showed extremely high CoQ values ranging from 2 to 9 nmol/ml (P<0.0001). Vitamin E levels of the Nairobi group were low (5-20 nmol/ml), but the Samburu population had even lower levels ranging from 3 to 15 nmol/ml (P<0.0001). Plasma lipid levels such as cholesterol, triglycerides, LDL/HDL, ApoB/ApoA ratios as well as BMI and weight were significantly higher in the Nairobi population (P<0.0001). Conclusions: Low IGF-I and high IGFBP-1 levels of the Samburu cohorts indicate malnutrition. High lipid levels of the Nairobi cohorts indicate that these groups have several risk factors for cardiovascular diseases and diabetes type2.

  • 205.
    Tsarouhas, Vasilios
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Yao, Liqun
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Samakovlis, Christos
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Src kinases and ERK activate distinct responses to Stitcher receptor tyrosine kinase signaling during wound healing in Drosophila2014In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 127, no 8, p. 1829-1839Article in journal (Refereed)
    Abstract [en]

    Metazoans have evolved efficient mechanisms for epidermal repair and survival following injury. Several cellular responses and key signaling molecules that are involved in wound healing have been identified in Drosophila, but the coordination of cytoskeletal rearrangements and the activation of gene expression during barrier repair are poorly understood. The Ret-like receptor tyrosine kinase (RTK) Stitcher (Stit, also known as Cad96Ca) regulates both re-epithelialization and transcriptional activation by Grainy head (Grh) to induce restoration of the extracellular barrier. Here, we describe the immediate downstream effectors of Stit signaling in vivo. Drk (Downstream of receptor kinase) and Src family tyrosine kinases bind to the same docking site in the Stit intracellular domain. Drk is required for the full activation of transcriptional responses but is dispensable for re-epithelialization. By contrast, Src family kinases (SFKs) control both the assembly of a contractile actin ring at the wound periphery and Grh-dependent activation of barrier-repair genes. Our analysis identifies distinct pathways mediating injury responses and reveals an RTK-dependent activation mode for Src kinases and their central functions during epidermal wound healing in vivo.

  • 206. van den Brand, Dirk
    et al.
    Gorris, Mark A. J.
    van Asbeck, Alexander H.
    Palmen, Emma
    Ebisch, Inge
    Dolstra, Harry
    Hällbrink, Mattias
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Massuger, Leon F. A. G.
    Brock, Roland
    Peptide-mediated delivery of therapeutic mRNA in ovarian cancer2019In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 141, p. 180-190Article in journal (Refereed)
    Abstract [en]

    Ovarian cancer is the most lethal gynecological malignancy in the developed world. In spite of intensive research, the mortality has hardly decreased over the past twenty years. This necessitates the exploration of novel therapeutic modalities. Transient protein expression through delivery of mRNA is emerging as a highly promising option. In contrast to gene therapy there is no risk of integration into the genome. Here, we explore the expression of mRNA in models of ovarian cancer of increasing complexity. The cell-penetrating peptide (CPP) PepFect 14 (PF14) was used to formulate CPP-mRNA nanoparticles. Efficient expression of a reporter protein was achieved in two-dimensional tissue cultures and in three-dimensional cancer cell spheroids. PF14 nano particles greatly outperformed a lipid-based transfection agent in vivo, leading to expression in various cell types of tumor associated tissue. Protein expression was restricted to the peritoneal cavity. Messenger RNA expression across different cell types was confirmed in primary ovarian cancer explants. As ovarian cancer is confined to the peritoneal cavity in most cases, the results create the basis for applications in which the tumor microenviron-ment is transiently modified through protein expression.

  • 207.
    Vintermist, Anna
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Chromatin remodelling of ribosomal genes - be bewitched by B-WICH2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Transcription of the ribosomal genes accounts for the majority of transcription in the cell due to the constant high demand for ribosomes. The number of proteins synthesized correlates with an effective ribosomal biogenesis, which is regulated by cell growth and proliferation. In the work presented in this thesis, we have investigated the ribosomal RNA genes 45S and 5S rRNA, which are transcribed by RNA Pol I and RNA Pol III, respectively.

    The focus of this work is the chromatin remodelling complex B-WICH, which is composed of WSTF, the ATPase SNF2h and NM1. We have studied in particular its role in ribosomal gene transcription. We showed in Study I that B-WICH is required to set the stage at rRNA gene promoters by remodelling the chromatin into an open, transcriptionally active configuration. This results in the binding of histone acetyl transferases to the genes and subsequent histone acetylation, which is needed for ribosomal gene activation. Study II investigated the role of B-WICH in transcription mediated by RNA polymerase III. We showed that B-WICH is essential to create an accessible chromatin atmosphere at 5S rRNA genes, which is compatible with the results obtained in Study 1. In this case, however, B-WICH operates as a licensing factor for c-Myc and the Myc/Max/Mxd network. Study III confirmed the importance and the function of the B-WICH complex as an activator of ribosomal genes. We demonstrated that B-WICH is important for the remodelling of the rDNA chromatin into an active, competent state in response to extracellular stimuli, and that the association of the B-WICH complex to the rRNA gene promoter is regulated by proliferative and metabolic changes in cells.

    The work presented in this thesis has confirmed that the B-WICH complex is an important regulator and activator of Pol I and Pol III transcription. We conclude that B-WICH is essential for remodelling the rDNA chromatin into a transcriptionally active state, as required for efficient ribosomal gene transcription.

  • 208.
    Vintermist, Anna
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology.
    Böhm, Stefanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology.
    Sadeghifar, Fatemeh
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology.
    Louvet, Emilie
    Mansén, Anethe
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology.
    Percipalle, Pergiorgio
    Östlund Farrants, Ann-Kristin
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology.
    The Chromatin Remodelling Complex B-WICH Changes the Chromatin Structure and Recruits Histone Acetyl-Transferases to Active rRNA Genes2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 4, article id e19184Article in journal (Refereed)
    Abstract [en]

    The chromatin remodelling complex B-WICH, which comprises the William syndrome transcription factor (WSTF), SNF2h, and nuclear myosin 1 (NM1), is involved in regulating rDNA transcription, and SiRNA silencing of WSTF leads to a reduced level of 45S pre-rRNA. The mechanism behind the action of B-WICH is unclear. Here, we show that the B-WICH complex affects the chromatin structure and that silencing of the WSTF protein results in a compaction of the chromatin structure over a 200 basepair region at the rRNA promoter. WSTF knock down does not show an effect on the binding of the rRNA-specific enhancer and chromatin protein UBF, which contributes to the chromatin structure at active genes. Instead, WSTF knock down results in a reduced level of acetylated H3-Ac, in particular H3K9-Ac, at the promoter and along the gene. The association of the histone acetyl-transferases PCAF, p300 and GCN5 with the promoter is reduced in WSTF knock down cells, whereas the association of the histone acetyl-transferase MOF is retained. A low level of H3-Ac was also found in growing cells, but here histone acetyl-transferases were present at the rDNA promoter. We propose that the B-WICH complex remodels the chromatin structure at actively transcribed rRNA genes, and this allows for the association of specific histone acetyl-transferases.

  • 209.
    Vintermist, Anna
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Guo, Yuan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Rolicka, Anna
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sadeghifar, Fatemeh
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Östlund Farrants, Ann-Kristin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The chromatin remodelling complex B-WICH is required for transcriptional activation by glucose stimulationManuscript (preprint) (Other academic)
  • 210.
    von Essen, Gabriella
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The effect of various dietary fatty acids on adaptive thermogenesis2014Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Recently it has been revealed that brown adipose tissue (BAT) is present in adult humans and not, as thought before, only in infants and rodents. BAT, with a main function to generate heat, is also involved in energy metabolism by an adaptive response to eating, referred to as diet-induced thermogenesis (DIT). When activated, BAT has a large capacity to dissipate energy, therefore being an interesting player in counteracting obesity. The aim of this review was to examine whether dietary fatty acids may have effects on BAT. There are at least 20 different dietary fatty acids containing 4 to 22 carbons. Depending on length and amount of double bonds, the fatty acids have different properties and effects on BAT. In summary, dietary short-chain fatty acids and medium-chain fatty acids have the largest effect on BAT, with a substantial anti-obesity impact. Long-chain fatty acids and conjugated fatty acids have weaker effects; however they show browning in WAT and decreased visceral fat pad sizes, but possibly need long-term duration to be effective. Nonetheless, for BAT to stay active, it has to be constantly activated, indicating a continual requirement for adequate fatty acids to be more or less chronic to obtain thermogenic effects.

    Enclosed in this thesis are the following papers:

    Paper I: Significant diet-induced thermogenesis in wild-type but not in UCP1-ablated mice

    Paper II: No obesity protection from cold-recruited brown adipose tissue, when mice are transferred to thermoneutrality

    Paper III: Replacing long-chain triglycerides with medium-chain triglycerides abolishes diet-induced obesity

  • 211. von Walden, Ferdinand
    et al.
    Casagrande, Vandre
    Farrants, Ann-Kristin Östlund
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Cell Biology.
    Nader, Gustavo A.
    Mechanical loading induces the expression of a Pol I regulon at the onset of skeletal muscle hypertrophy2012In: American Journal of Physiology - Cell Physiology, ISSN 0363-6143, E-ISSN 1522-1563, Vol. 302, no 10, p. c1523-C1530Article in journal (Refereed)
    Abstract [en]

    von Walden F, Casagrande V, Ostlund Farrants AK, Nader GA. Mechanical loading induces the expression of a Pol I regulon at the onset of skeletal muscle hypertrophy. Am J Physiol Cell Physiol 302: C1523-C1530, 2012. First published March 7, 2012; doi:10.1152/ajpcell.00460.2011.-The main goal of the present study was to investigate the regulation of ribosomal DNA (rDNA) gene transcription at the onset of skeletal muscle hypertrophy. Mice were subjected to functional overload of the plantaris by bilateral removal of the synergist muscles. Mechanical loading resulted in muscle hypertrophy with an increase in rRNA content. rDNA transcription, as determined by 45S pre-rRNA abundance, paralleled the increase in rRNA content and was consistent with the onset of the hypertrophic response. Increased transcription and protein expression of c-Myc and its downstream polymerase I (Pol I) regulon (POL1RB, TIF-1A, PAF53, TTF1, TAF1C) was also consistent with the increase in rRNA. Similarly, factors involved in rDNA transcription, such as the upstream binding factor and the Williams syndrome transcription factor, were induced by mechanical loading in a corresponding temporal fashion. Chromatin immunoprecipitation revealed that these factors, together with Pol I, were enriched at the rDNA promoter. This, in addition to an increase in histone H3 lysine 9 acetylation, demonstrates that mechanical loading regulates rRNA synthesis by inducing a gene expression program consisting of a Pol I regulon, together with accessory factors involved in transcription and chromatin remodeling at the rDNA promoter. Altogether, these data indicate that transcriptional and epigenetic mechanisms take place in the regulation of ribosome production at the onset of muscle hypertrophy.

  • 212.
    Wagner, Nicole
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Krohne, Georg
    LEM-domain proteins: New insights into lamin-interacting proteins2007In: International Review of Cytology, ISSN 0074-7696, E-ISSN 2163-5854, Vol. 261, p. 1-+Article, review/survey (Refereed)
    Abstract [en]

    LEM-domain proteins present a growing family of nonrelated inner nuclear membrane and intranuclear proteins, including emerin, MAN1, LEM2, several alternatively spliced isoforms of LAP2, and various uncharacterized proteins in higher eukaryotes as well as the Drosophila-specific proteins otefin and Bocksbeutel. LEM-domain proteins are involved in diverse cellular processes including replication and cell cycle control, chromatin organization and nuclear assembly, the regulation of gene expression and signaling pathways, as well as retroviral infection. Genetic analyses in different model organisms reveal new insights into the various functions of LEM-domain proteins, lamins, and their involvement in laminopathic diseases. All these findings as well as previously proposed ideas and models have been summarized to broaden our view of this exciting protein family.

  • 213.
    Waluk, Dominik Paweł
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Biosynthesis and physiological functions of N-acyl amino acids2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    N-acyl amino acids are lipid signalling molecules that have recently been identified in biological systems. These lipids are structurally related to the endocannabinoids, although they do not activate cannabinoid receptors. In 2001, N-arachidonoyl glycine was the first signalling lipid in this group to be identified in bovine and rat brain and since then, about 50 novel N-acyl amino acids have been identified in mammalian systems. These N-acyl amino acids are involved in regulating pain processes, are anti-inflammatory and regulate body temperature, but the metabolic pathways for production and metabolism remain poorly understood.

    This thesis focussed on the identification of pathways for production and regulation of N-acyl amino acids, in particular N-acyl glycines, and in identifying physiological functions for N-acyl amino acids (particularly N-acyl taurines). Our results identified an enzymatic pathway for production of N-acyl glycines in human and we identified that the human glycine N-acyltransferase-like 2 (hGLYATL2) conjugates (amidates) medium- and long-chain, saturated and unsaturated acyl-CoAs with glycine, to produce N-acyl glycines, with the preferential production of N-oleoyl glycine. Furthermore, we have characterized two other members of the gene family of glycine N-acyltransferases (GLYATs) in human, the hGLYATL1 and hGLYATL3 that may be involved in the production of N-acyl amino acids.

    As N-acyl glycines are bioactive signalling molecules, it is likely their production requires a rapid on/off switch. The post-translational modification of proteins can result in enzyme regulation, without the need for transcriptional regulation. We have identified that hGLYATL2 is regulated by acetylation/deacetylation on lysine 19, and using mutation analysis, we show that deacetylation of lysine 19 is important for full enzyme activity.

    The physiological functions of N-acyl amino acids are not well studied to date. In this thesis, we have identified that N-arachidonoyl taurine and N-oleoyl taurine trigger insulin secretion by increasing the calcium flux in pancreatic b-cells via the activation of transient receptor potential vanilloid subfamily 1 (TRPV1).

    This work on N-acyl amino acids has led us to identify new pathways and physiological functions for these lipid signalling molecules, which advances our knowledge of the importance of these lipids in mammalian systems.

  • 214.
    Wang, Yanling
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Fälting, Johanna M.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mattsson, Charlotte L.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Holmström, Therese E.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    In brown adipocytes, adrenergically induced beta(1)-/beta(3)-(G(s))-, alpha(2)-(G(i))- and alpha(1)-(G(q))-signalling to Erk1/2 activation is not mediated via EGF receptor transactivation2013In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 319, no 17, p. 2718-2727Article in journal (Refereed)
    Abstract [en]

    Brown adipose tissue is unusual in that the neurotransmitter norepinephrine influences cell destiny in ways generally associated with effects of classical growth factors: regulation of cell proliferation, of apoptosis, and progression of differentiation. The norepinephrine effects are mediated through G-protein-coupled receptors; further mediation of such stimulation to e.g. Erk1/2 activation is in cell biology in general accepted to occur through transactivation of the EGF receptor (by external or internal pathways). We have examined here the significance of such transactivation in brown adipocytes. Stimulation of mature brown adipocytes with cirazoline (alpha(1)-adrenoceptor coupled via G(q)), clonidine (alpha(2) via G(i)) or CL316243 (beta(3) via G(s)) or via beta(1)-receptors significantly activated Erk1/2. Pretreatment with the EGF receptor kinase inhibitor AG1478 had, remarkably, no significant effect on Erk1/2 activation induced by any of these adrenergic agonists (although it fully abolished EGF-induced Erk1/2 activation), demonstrating absence of EGF receptor-mediated transactivation. Results with brown preadipocytes (cells in more proliferative states) were not qualitatively different. Joint stimulation of all adrenoceptors with norepinephrine did not result in synergism on Erk1/2 activation. AG1478 action on EGF-stimulated Erk1/2 phosphorylation showed a sharp concentration response relationship (IC50 0.3 mu M); a minor apparent effect of AG1478 on norepinephrine-stimulated Erk1/2 phosphorylation showed nonspecific kinetics, implying caution in interpretation of partial effects of AG1478 as reported in other systems. Transactivation of the EGF receptor is clearly not a universal prerequisite for coupling of G-protein coupled receptors to Erk1/2 signalling cascades.

  • 215.
    Wang, Yanling
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sato, Masaaki
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Guo, Yuan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Bengtsson, Tore
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Protein kinase A-mediated cell proliferation in brown preadipocytes is independent of Erk1/2, PI3K and mTOR2014In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 328, no 1, p. 143-155Article in journal (Refereed)
    Abstract [en]

    The physiological agonist norepinephrine promotes cell proliferation of brown preadipocytes during the process of tissue recruitment. In a primary culture system, CAMP mediates these adrenergic effects. In the present study, we demonstrated that, in contrast to other systems where the mitogenic effect of cAMP requires the synergistic action of (serum) growth factors, especially insulin/IGF, the cAMP effect in brown preadipocytes was independent of serum and insulin. Protein kinase A, rather than Epac, mediated the cAMP mitogenic effect. The Erk 1/2 family of MAPK, the PI3K system and the mTOR complexes were all activated by cAMP, but these activations were not necessary for cAMP-induced cell proliferation; a protein kinase C isoform may be involved in mediating cAMP-activated cell proliferation. We conclude that the generally acknowledged cellular mediators for induction of cell proliferation are not involved in this process in the brown preadipocyte system; this conclusion may be of relevance both for examination of mechanisms for induction of brown adipose tissue recruitment but also for understanding the mechanism behind e.g. certain endocrine neoplasias.

  • 216. Whittle, Andrew J.
    et al.
    Carobbio, Stefania
    Martins, Luis
    Slawik, Marc
    Hondares, Elayne
    Jesus Vazquez, Maria
    Morgan, Donald
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Gallego, Rosalia
    Rodriguez-Cuenca, Sergio
    Dale, Martin
    Virtue, Samuel
    Villarroya, Francesc
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Rahmouni, Kamal
    Lopez, Miguel
    Vidal-Puig, Antonio
    BMP8B Increases Brown Adipose Tissue Thermogenesis through Both Central and Peripheral Actions2012In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 149, no 4, p. 871-885Article in journal (Refereed)
    Abstract [en]

    Thermogenesis in brown adipose tissue (BAT) is fundamental to energy balance and is also relevant for humans. Bone morphogenetic proteins (BMPs) regulate adipogenesis, and, here, we describe a role for BMP8B in the direct regulation of thermogenesis. BMP8B is induced by nutritional and thermogenic factors in mature BAT, increasing the response to noradrenaline through enhanced p38MAPK/CREB signaling and increased lipase activity. Bmp8b(-/-) mice exhibit impaired thermogenesis and reduced metabolic rate, causing weight gain despite hypophagia. BMP8B is also expressed in the hypothalamus, and Bmp8b(-/-) mice display altered neuropeptide levels and reduced phosphorylation of AMP-activated protein kinase (AMPK), indicating an anorexigenic state. Central BMP8B treatment increased sympathetic activation of BAT, dependent on the status of AMPK in key hypothalamic nuclei. Our results indicate that BMP8B is a thermogenic protein that regulates energy balance in partnership with hypothalamic AMPK. BMP8B may offer a mechanism to specifically increase energy dissipation by BAT.

  • 217.
    Wollberg, Patrik
    Stockholm University, Faculty of Science.
    Growth-associated expression of glycolytic isoenzymes in mitogen activated human T lymphocytes1994Doctoral thesis, comprehensive summary (Other academic)
  • 218. Xue, Yuan
    et al.
    Petrovic, Natasa
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Cao, Renhai
    Larsson, Ola
    Lim, Sharon
    Chen, Shaohua
    Feldmann, Helena M.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Liang, Zicai
    Zhu, Zhenping
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Cao, Yihai
    Hypoxia-independent angiogenesis in adipose tissues during cold acclimation.2009In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 9, no 1, p. 99-109Article in journal (Refereed)
    Abstract [en]

    The molecular mechanisms of angiogenesis in relation to adipose tissue metabolism remain poorly understood. Here, we show that exposure of mice to cold led to activation of angiogenesis in both white and brown adipose tissues. In the inguinal depot, cold exposure resulted in elevated expression levels of brown-fat-associated proteins, including uncoupling protein-1 (UCP1) and PGC-1alpha. Proangiogenic factors such as VEGF were upregulated, and endogenous angiogenesis inhibitors, including thrombospondin, were downregulated. In wild-type mice, the adipose tissues became hypoxic during cold exposure; in UCP1(-/-) mice, hypoxia did not occur, but, remarkably, the augmented angiogenesis was unaltered and was thus hypoxia independent. Intriguingly, VEGFR2 blockage abolished the cold-induced angiogenesis and significantly impaired nonshivering thermogenesis capacity. Unexpectedly, VEGFR1 blockage resulted in the opposite effects: increased adipose vascularity and nonshivering thermogenesis capacity. Our findings have conceptual implications concerning application of angiogenesis modulators for treatment of obesity and metabolic disorders.

  • 219.
    Yentrapalli, Ramesh
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Helmholtz Zentrum München.
    Azimzadeh, Omid
    Sriharshan, Arundhathi
    Malinowsky, Katharina
    Merl, Juliane
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Harms-Ringdahl, Mats
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Atkinson, Michael J.
    Becker, Karl-Friedrich
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Tapio, Soile
    The PI3K/Akt/mTOR Pathway Is Implicated in the Premature Senescence of Primary Human Endothelial Cells Exposed to Chronic Radiation2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8, p. e70024-Article in journal (Refereed)
    Abstract [en]

    The etiology of radiation-induced cardiovascular disease (CVD) after chronic exposure to low doses of ionizing radiation is only marginally understood. We have previously shown that a chronic low-dose rate exposure (4.1 mGy/h) causes human umbilical vein endothelial cells (HUVECs) to prematurely senesce. We now show that a dose rate of 2.4 mGy/h is also able to trigger premature senescence in HUVECs, primarily indicated by a loss of growth potential and the appearance of the senescence-associated markers ß-galactosidase (SA-ß-gal) and p21. In contrast, a lower dose rate of 1.4 mGy/h was not sufficient to inhibit cellular growth or increase SA-ß-gal-staining despite an increased expression of p21. We used reverse phase protein arrays and triplex Isotope Coded Protein Labeling with LC-ESI-MS/MS to study the proteomic changes associated with chronic radiation-induced senescence. Both technologies identified inactivation of the PI3K/Akt/mTOR pathway accompanying premature senescence. In addition, expression of proteins involved in cytoskeletal structure and EIF2 signaling was reduced. Age-related diseases such as CVD have been previously associated with increased endothelial cell senescence. We postulate that a similar endothelial aging may contribute to the increased rate of CVD seen in populations chronically exposed to low-dose-rate radiation.

  • 220. Zenius Jespersen, Naja
    et al.
    Juhlin Larsen, Therese
    Peijs, Lone
    Daugaard, Søren
    Homøe, Preben
    Loft, Annika
    de Jong, Jasper
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mathur, Neha
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Klarlund Pedersen, Bente
    Møller, Kirsten
    Scheele, Camilla
    A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans2013In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 17, no 5, p. 798-805Article in journal (Refereed)
    Abstract [en]

    Human brown adipose tissue (BAT) has been detected in adults but was recently suggested to be of brite/beige origin. We collected BAT from the supraclavicular region in 21 patients undergoing surgery for suspected cancer in the neck area and assessed the gene expression of established murine markers for brown, brite/beige, and white adipocytes. We demonstrate that a classical brown expression signature, including upregulation of miR-206, miR-133b, LHX8, and ZIC1 and downregulation of HOXC8 and HOXC9, coexists with an upregulation of two newly established brite/beige markers, TBX1 and TMEM26. A similar mRNA expression profile was observed when comparing isolated human adipocytes from BAT and white adipose tissue (WAT) depots, differentiated in vitro. In conclusion, our data suggest that human BAT might consist of both classical brown and recruitable brite adipocytes, an observation important for future considerations on how to induce human BAT.

  • 221. Zovko, Ana
    et al.
    Novak, Metka
    Hååg, Petra
    Kovalerchick, Dimitry
    Holmlund, Teresa
    Färnegårdh, Katarina
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Ilan, Micha
    Carmeli, Shmuel
    Lewensohn, Rolf
    Viktorsson, Kristina
    Compounds from the marine sponge Cribrochalina vasculum offer a way to target IGF-1R mediated signaling in tumor cells2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 31, p. 50258-50276Article in journal (Refereed)
    Abstract [en]

    In this work two acetylene alcohols, compound 1 and compound 2, which were isolated and identified from the sponge Cribrochalina vasculum, and which showed antitumor effects were further studied with respect to targets and action mechanisms. Gene expression analyses suggested insulin like growth factor receptor (IGF-1R) signaling to be instrumental in controlling anti-tumor efficacy of these compounds in non-small cell lung cancer (NSCLC). Indeed compounds 1 and 2 inhibited phosphorylation of IGF-1R beta as well as reduced its target signaling molecules IRS-1 and PDK1 allowing inhibition of pro-survival signaling. In silico docking indicated that compound 1 binds to the kinase domain of IGF-1R at the same binding site as the well known tyrosine kinase inhibitor AG1024. Indeed, cellular thermal shift assay (CETSA) confirmed that C. vasculum compound 1 binds to IGF-1R but not to the membrane localized tyrosine kinase receptor EGFR. Importantly, we demonstrate that compound 1 causes IGF-1R beta but not Insulin Receptor degradation specifically in tumor cells with no effects seen in normal diploid fibroblasts. Thus, these compounds hold potential as novel therapeutic agents targeting IGF-1R signaling for anti-tumor treatment.

  • 222.
    Öjemalm, Karin
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Watson, Helen R.
    Roboti, Peristera
    Cross, Benedict C. S.
    Warwicker, Jim
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    High, Stephen
    Positional editing of transmembrane domains during ion channel assembly2013In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 126, no 2, p. 464-472Article in journal (Refereed)
    Abstract [en]

    The integration of transmembrane (TM)-spanning regions of many channels and ion transporters is potentially compromised by the presence of polar and charged residues required for biological function. Although the two TMs of the ATP-gated ion channel subunit P2X2 each contain charged/polar amino acids, we found that each TM is efficiently membrane inserted when it is analysed in isolation, and uncovered no evidence for cooperativity between these two TMs during P2X2 integration. However, using minimal N-glycosylation distance mapping, we find that the positioning of TM2 in newly synthesized P2X2 monomers is distinct from that seen in subunits of the high-resolution structures of assembled homologous trimers. We conclude that P2X2 monomers are initially synthesised at the endoplasmic reticulum in a distinct conformation, where the extent of the TM-spanning regions is primarily defined by the thermodynamic cost of their membrane integration at the Sec61 translocon. In this model, TM2 of P2X2 subsequently undergoes a process of positional editing within the membrane that correlates with trimerisation of the monomer, a process requiring specific polar/charged residues in both TM1 and TM2. We postulate that the assembly process offsets any energetic cost of relocating TM2, and find evidence that positional editing of TM2 in the acid-sensing ion channel (ASIC1a) is even more pronounced than that observed for P2X2. Taken together, these data further underline the potential complexities involved in accurately predicting TM domains. We propose that the orchestrated repositioning of TM segments during subunit oligomerisation plays an important role in generating the functional architecture of active ion channels, and suggest that the regulation of this underappreciated biosynthetic step may provide an elegant mechanism for maintaining ER homeostasis.

2345 201 - 222 of 222
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