3 research outputs found
Immunometabolic regulation of atherosclerosis
No full textIschaemic heart disease and stroke are the most common causes of death in the world, both diseases being manifestations of atherosclerotic cardiovascular disease. Atherosclerosis is a slow process initialized by the retention and accumulation of cholesterol rich lipoproteins in the innermost layer of the artery wall. Activation of an inflammatory response with the recruitment of immune cells lead to a buildup of plaques in the vessel. Both innate immune cells, most prominently macrophages, and adaptive immune cells play important roles in all stages of the development of atherosclerosis.Metabolism is intimately linked with atherosclerosis development. Systemically increased levels of metabolites such as cholesterol and glucose are known risk factors for atherosclerosis. The metabolism in the microenvironment of the atherosclerotic plaque shape the immune response and influence disease progression. Immune cell metabolism of glucose and amino acids have been suggested as possible targets for future therapy. While modern therapies are effective at reducing known risk factors such as hyperlipidemia, considerable risk remains and few therapies for atherosclerosis target the underlying inflammatory mechanisms that drive the disease.In Paper I the effect of indoleamine 2,3-dioxygenase (IDO) mediated tryptophan metabolism on atherosclerosis was investigated. Pharmacological inhibition of IDO with 1-methyl- tryptophan resulted in increased atherosclerotic burden in mice. Furthermore, in vitro data showed that the expression of pro-inflammatory molecules was increased on smooth muscle cells upon IDO inhibition. Treatment with the downstream tryptophan metabolite 3-hydroxyanthranilic acid (3-HAA) reversed both the in vivo and in vitro effects of IDO inhibition.The effects of 3-HAA on lipoprotein metabolism was studied in Paper II. Activity of the transcription factor sterol response element binding protein 2 (SREBP2) was decreased when HepG2 hepatoma cells were treated with 3-HAA. Mice treated with the pharmacological inhibitor of the 3-HAA degrading enzyme 3-HAA oxygenase had less atherosclerotic plaque size and lower plasma lipids. In vitro experiments also showed 3-HAA to be a potent inhibitor of the inflammasome in macrophages.In Paper III we showed that the metabolism of tryptophan is altered in human atherosclerotic disease. Patients with symptoms had an impaired metabolism of tryptophan to kynurenic acid, a metabolite that can induce anti-inflammatory responses, possibly via aryl hydrocarbon receptor activation. In Paper IV we demonstrate that the small molecule dichloroacetate (DCA), a known inhibitor of glycolysis, reduces atherosclerosis lesion size, plasma lipids and reprograms the immune system towards an anti-inflammatory phenotype. We also show that DCA is a potent inhibitor of inflammasome production of IL-1β.List of scientific papersI. Polyzos K, Ovchinnikova O, Berg M, Baumgartner R, Agardh H, Pirault J, Gisterå A, Assinger A, Laguna Fernandez A, Bäck M, Hansson GK, Ketelhuth DFJ. Inhibition of indoleamine 2,3-dioxygenase promotes vascular inflammation and increases atherosclerosis in Apoe-/- mice. Cardiovasc Res. 2015;106(2):295-302. https://doi.org/10.1093/cvr/cvv100 II. Berg M*, Polyzos KA*, Agardh H, Baumgartner R, Forteza MJ, Kareinen I, Gisterå A, Bottcher G, Hurt-Camejo E, Hansson GK, Ketelhuth DFJ. 3-Hydroxyanthralinic acid Metabolism Controls the Hepatic Srebp/Lipoprotein axis, Inhibits Inflammasome Activation in Macrophages, and Decreases Atherosclerosis in LDLR-/- Mice. Cardiovasc Res. 2019 Oct 7;cvz258. *Equal contribution. https://doi.org/10.1093/cvr/cvz258 III. Baumgartner R*, Berg M*, Matic L, Polyzos KP, Forteza MJ, Hjorth SA, Schwartz TW, Paulson- Berne G, Hansson GK, Hedin U, Ketelhuth DFJ. Evidence that deviation of the Kynurenine Pathway decreases kynurenic acid production and aryl hydrocarbon receptor signaling and aggravates atherosclerotic disease in humans. *Equal contribution. [Accepted] https://doi.org/10.1111/joim.13142 IV. Forteza MJ, Berg M, Baumgartner R, Kareinen I, Beccaria Casagrande F, Hedin U, Zhang S, Vuckovic I, Dzeja PP, Polyzos KA, Trauelsen M, Schwartz TW, Dib L, Herrmann J, Matic L, Monaco C, Ketelhuth DFJ. Pyruvate dehydrogenase kinase links glycolysis with succinate/GPR91 signalling to regulate vascular inflammation and atherosclerosis. [Manuscript]</p
Patch-clamp studies of macroscopic and single-channel currents in mouse neuroblastoma cells.
No full textCells from the clonal cell line N1E115, a mouse tumour of sympathetic origin, differentiate both morphologically and electrophysiologically when cultured in medium containing dimethylsulphoxide. This technique was used to obtain cells for electrophysiological recording. Macroscopic currents were measured using the whole-cell patch-clamp technique and two currents, one thought to be carried mainly by sodium ions and one mainly by potassium ions, were identified. The kinetics of the potassium current, which are voltage dependent, suggested that this was a delayed rectifier. A single-channel current which was selective for potassium ions was recorded using the cell-attached patch-clamp recording technique. The channel was thought to be the unitary current correlate of the macroscopic potassium current on the basis of its activation kinetics. The channel was shown to have two open states of different conductance, one having approximately two-thirds the conductance of the other. The single-channel kinetics were measured and it was shown that the open time distribution of the channel, the latency to its first opening after a voltage step and the relative times spent in each of the two open states are voltage dependent. The amplitude of these currents was reduced by application of tetraethylammonium ions to the extracellular face of the membrane patch and the concentration- and voltage-dependence of this block were investigated. Two further unitary currents were identified using the excised patch-clamp recording technique: a calcium-activated non-selective cation current and a calcium-activated potassium current. The conductance and voltage-dependence of both currents were investigated
Gestão da evidenciação ambiental
No full textTese (doutorado) - Universidade Federal de Santa Catarina, Centro Tecnológico, Programa de Pós-Graduação em Engenharia de Produção, Florianópolis, 2011No contexto atual, a preocupação com a divulgação dos impactos ambientais gerados por empresas do setor elétrico tem impulsionado pesquisas científicas sobre evidenciação ambiental. Também se observa que movimentos sociais e normativos têm pressionado as empresas deste setor a melhorar seus níveis de divulgação sobre desempenho ambiental. Neste contexto gestores de meio ambiente dessas empresas necessitam meios que os auxiliem a gerenciar e melhorar o desempenho das informações divulgadas. A revisão de literatura revela também que: (i) o contexto da evidenciação é singular (muda de empresa para empresa); (ii) as empresas necessitam gerenciar e avaliar um conjunto de informações sobre desempenho da gestão ambiental para prestar contas aos diferentes stakeholders; (iii) a evidenciação ambiental representa uma das estratégias usadas pelas empresas para procurar a aceitação da sociedade, a fim de preservar a imagem de um negócio legítimo; (iv) a evidenciação ambiental está conectada a diversos sistemas da organização, e não apenas à gestão ambiental; e (v) o processo de gestão da evidenciação ambiental permite aperfeiçoamentos que justificam esta pesquisa. Assim, para contribuir com o espectro teórico e metodológico da evidenciação ambiental, esta tese norteia-se pela pergunta: Como promover a gestão da evidenciação ambiental da empresa Eletrosul S.A.?. Para responder esta pergunta, o objetivo do trabalho consiste em propor uma ferramenta multicritério de apoio à decisão para a empresa Eletrosul S.A., com vistas a promover a gestão da evidenciação ambiental. Para alcançar os objetivos da pesquisa, foi realizado um estudo de caso, utilizando como instrumento de intervenção a Metodologia Multicritério de Apoio à Decisão Construtivista - MCDA-C. Esta metodologia foi selecionada, por permitir a construção do conhecimento no decisor sobre a evidenciação ambiental e apoiar decisões gerenciais. Os resultados encontrados possibilitaram: (i) identificar a evidenciação ambiental sob a ótica de gestão, (ii) desenvolver, através da metodologia MCDA-C, um processo de avaliação de desempenho capaz de: identificar 928 critérios, organizar esses critérios em cinco modelos, mensurar a partir de escalas ordinais e cardinais, integrar e gerenciar os critérios e subcritérios identificados, organizados e mensurado com a finalidade de gerar diagnóstico sistêmico da situação e promover ações de aperfeiçoamento, e, por fim, (iii) construir um instrumento de apoio à decisão para a empresa Eletrosul S.A. Como pesquisas futuras, verifica-se a oportunidade de aprofundar estudos sobre avaliação externa da evidenciação ambiental, adaptação do modelo MED para outras empresas do setor elétrico e utilização do processo estruturado para construir modelos de gestão da evidenciação ambiental para empresas de outros setores
