48,692 research outputs found

    Relacionando a autofagia e o metabolismo nas células dendríticas plasmacitóides

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    Autophagy is a cellular housekeeping mechanism that degrades long-lived redundant and malfunctioning cellular components. It has a vital role in the immune system, not only for being directly involved in the elimination of pathogens, but also through the functional regulation of immune cells, including dendritic cells (DCs). DCs are phagocytic, antigen presenting cells, which connect the innate response with adaptive immunity, by priming naïve T cells and directing the ensuing polarization. Plasmacytoid DCs (pDCs) are a subpopulation of DC specialized in the rapid production of type I interferon, making them particularly relevant in antiviral responses. Their activation and functional response appear to be strongly dependent on the autophagic flux, which led us to investigate if cellular metabolism could play a role in the regulation of pDC autophagy and, thus, in their function. To that end, a pDC cell line (CAL-1) was treated with three different autophagy inhibitors: Spautin-1, VPS34-IN1 and Bafilomycin A1, followed by Western blot analysis of LC3 lipidation, to confirm autophagy inhibition, and 1H NMR metabolomics. The three drugs efficiently inhibited autophagy and affected the cellular metabolism in a significant manner. Interestingly, the effects of the different inhibitors on the cells metabolic profile were very different. Bafilomycin A1 had the least impact on the cells, while Spautin-1 and VPS34-IN1 had a stronger influence on metabolism, albeit in different directions. While Spautin-1 stimulated glycolysis, impaired the TCA cycle, decreased the levels of amino acids, and increased the levels of branch-chained ketoacids, suggesting mTORC1 activation, VPS34-IN1 caused opposite variations, which suggested AMPK activation. As for Bafilomycin A1, it appeared to induce early endoplasmic reticulum (ER) stress responses, with a mild increase in amino acids, uridine nucleotides, ATP, and NAD+. Overall, this work demonstrated the metabolic responses of pDC cells to autophagy inhibition to be highly dependent on the specific inhibitor considered, raising new questions about the molecular targets and mechanisms involved. Their improved understanding in the future will be key to advance knowledge on pDC biology and functional behaviour.A autofagia é um mecanismo que ajuda na manutenção celular, decompondo componentes celulares desgastos, redundantes ou defeituosos. No sistema imunitário, autofagia desempenha um papel vital, não só estando diretamente envolvida na eliminação de agentes patogénicos, mas também através da regulação funcional das células imunes, incluindo as células dendríticas (DCs). As DCs são células fagocíticas, apresentadoras de antigénios, e incluem uma subpopulação especializada na produção de interferão do tipo I, as células dendríticas plasmacitóides (pDCs), especialmente relevantes na resposta antiviral. A ativação e resposta funcional das pDCs parece ser fortemente dependente do fluxo autofágico, o que nos levou a investigar o possível papel do metabolismo celular na regulação da autofagia e da função destas células. Para esse fim, uma linha celular de pDCs (CAL-1) foi tratada com diferentes inibidores da autofagia: Spautin-1, VPS34-IN1 ou Bafilomicina A1, seguido da análise da lipidação de LC3 por Western blot, para confirmar a inibição da autofagia e análise metabolómica por RMN-1H. Os três compostos inibiram eficazmente a autofagia e alteraram o metabolismo significativamente. No entanto, os seus efeitos foram bastante diferentes. A Bafilomicina A1 foi a que teve o menor impacto nas células, enquanto a Spautin-1 e o VPS34-IN1 tiveram uma maior influência no metabolismo, embora em direções diferentes. A Spautin-1 estimulou a glicólise, inibiu o ciclo do TCA, diminuiu os níveis de aminoácidos e aumentou os níveis de cetoácidos de cadeia ramificada, sugerindo a ativação de mTORC1, enquanto o VPS34-IN1 produziu variações opostas que sugeriram ativação da AMPK. Quanto à Bafilomicina A1, a assinatura metabólica foi consistente com a indução inicial de stress do retículo endoplasmático, consistindo num aumento moderado de aminoácidos, nucleótidos de uridina, ATP e NAD+. Em suma, este trabalho demonstrou uma forte dependência da resposta metabólica das CAL-1 em relação ao inibidor de autofagia considerado, levantando-se novas hipóteses sobre os alvos e mecanismos moleculares envolvidos, cuja compreensão aprofundada permitirá, futuramente, fazer avançar o conhecimento sobre a biologia e o comportamento funcional das pDCs.Mestrado em Bioquímic

    O impacto da sinalização de cálcio nos astrócitos na função cortico-límbica e no comportamento

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    Tese de doutoramento em Ciências da SaúdeOs astrócitos desempenham múltiplas funções desde a homeostasia cerebral ao controlo e processamento da atividade sináptica. Eles integram sinais neuronais por elevações complexas de cálcio (Ca2+) com impacto na comunicação neurónio-astrócito. As elevações de Ca2+ nos astrócitos podem ser divididas em dois tipos: globais (presentes no soma e principais processos) e/ou focais (presentes nos microdomínios). Apesar de estar descrito que as elevações globais de Ca2+ nos astrócitos podem modular a comunicação sináptica, continuam por esclarecer quais os mecanismos moleculares envolvidos. Desta forma, urge uma caracterização comportamental, estrutural e molecular detalhada para compreender esses mecanismos. Nesta tese, utilizámos o modelo de murganho que apresenta a deleção constitutiva do receptor 2 do inositol 1,4,5-trifosfato (IP3R2 KO), no qual as elevações globais de Ca2+ nos astrócitos estão ausentes. Na primeira parte deste trabalho (Capítulo 2) demonstramos que os murganhos IP3R2 KO têm um desenvolvimento somático e neurológico normal. Em seguida, a caracterização comportamental deste modelo transgénico (Capítulo 3) revelou que os murganhos IP3R2 KO apresentam uma melhoria do desempenho cognitivo em tarefas dependentes do hipocampo. Identificámos o factor de transcrição Foxo1 como modulador da expressão de genes específicos de astrócitos, responsáveis pela regulação do citoesqueleto e de espinhas dendríticas. A sobre-expressão do FOXO1 em astrócitos do hipocampo de murganho C57BL/6J foi suficiente para mimetizar a melhoria cognitiva verificada no modelo IP3R2 KO. Este resultado levou-nos a avaliar o papel da sinalização global de Ca2+ no contexto da depressão, uma doença que afeta comportamento dependente das regiões cortico-límbicas (Capítulo 4). Os murganhos IP3R2 KO apresentam uma surpreendente resiliência ao efeito ansiogénico do stress crónico. Por fim, explorámos o papel da sinalização de Ca2+ nos astrócitos no envelhecimento cognitivo (Capítulo 5). Os nossos resultados demonstram uma preservação do desempenho cognitivo em murganhos IP3R2 KO envelhecidos, caracterizado por alteração do rácio neurónio/astrócito e por refinamento dendrítico dos neurónios da camada V do córtex pré-frontal. Em suma, este trabalho contribuiu para uma melhor compreensão do papel da sinalização global de Ca2+ nos astrócitos desde o desenvolvimento até ao envelhecimento, num contexto de saúde e doença. Os resultados revelaram um alvo terapêutico específico em astrócitos com potencial aplicação em contextos de depressão e envelhecimento cognitivo.Astrocytes are responsible for distinct functions ranging from brain homeostasis to the modulation of synaptic functioning. They integrate neuronal signals by complex calcium (Ca2+) elevations that control intracellular mechanisms that in turn drive the neuron-astrocyte dialogue, modulating the activity of cells and networks. It is now recognized that Ca2+ elevations in astrocytes appear spatially distributed in global (soma and main processes) and/or focal regions (microdomains). Although it is observed that global astrocytic Ca2+ signaling contributes to synaptic communication, its role in circuit computation and behavioral performance is still poorly understood. A detailed behavioral, structural and molecular characterization should provide us with putative mechanisms underlying the roles of astrocytic Ca2+. In this thesis, we took advantage of the inositol 1,4,5-trisphosphate receptor type 2 knockout (IP3R2 KO) mouse model, which lacks global Ca2+ signaling in astrocytes. In the first part of this work (Chapter 2), we demonstrate that IP3R2 KO mice retain a normal developmental maturation, as compared with WT littermates. Next, a detailed behavioral characterization of this mouse model (Chapter 3) showed that IP3R2 KO mice display enhanced cognitive performance in hippocampal-dependent tasks. We found Foxo1 as the most active transcription factor controlling the increased expression of astrocyte-specific genes related with fine cytoskeleton modulation and spinogenesis, which could underlie the cognitive enhancement observed. Moreover, specific overexpression of FOXO1 in hippocampal astrocytes of C57BL/6J mice was enough to recapitulate the enhanced fear memory observed in IP3R2 KO mice. This striking observation prompted us to test the role of global Ca2+ signaling in the context of depression, which affects cortico-limbic regions (Chapter 4). IP3R2 KO mice present an unexpected resilience to the installation of stress effects, namely translated into an increased self-care and a reduced anxious-like phenotype. Finally, we explored the role of astrocytic Ca2+ signaling in cortico-limbic performance in aged mice that display cognitive decline (Chapter 5). We observed a preserved cognitive performance in aged IP3R2 KO mice, an altered neuron/astrocyte ratio and a dendritic refinement of mPFC neurons. Overall, this work contributed to a better understanding on the role of global astrocytic Ca2+ signaling from development to aging, both in a health and disease context. We found a putative astrocyte-specific therapeutic target that could be used to prevent depression- and aging-related deficits.The work presented in this thesis was performed in the Life and Health Sciences Research Institute (ICVS), at the School of Medicine, University of Minho. Financial support was provided by a PhD grant (SFRH/BD/101298/2014 to SGG), FCT Investigator grants (IF/00328/2015 to JO, IF/01079/2014 to LP) and PTDC/MED-NEU/31417/2017 from the FCT – Foundation for Science and Technology, by BIAL Foundation grants (207/14 to JO and 427/14 to LP), by Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013); FEDER Funds, through the Competitiveness Factors Operational Programme (COMPETE), and The National Fund, through the FCT (POCI-01-0145-FEDER-007038)

    Diagnostic profiling of MDSCs in sepsis

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    With 50 million cases and 11 million deaths per year, sepsis is one of the leading causes of death worldwide. Sepsis is caused by a dysregulated host response to an infection, which consists of concurrent inflammatory and immunosuppressive reactions. Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells characterized by their immunosuppressive properties, rising in inflammatory diseases. MDSCs are subdivided into polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs) based on their relationship with mature PMNs and monocytes. It is unknown how their level varies over time in human sepsis. We hypothesized that MDSCs have diagnostic and prognostic potential in sepsis patients. In this thesis, we aimed to illustrate the dynamic profile of MDSCs in critically ill patients in relation to sepsis severity, secondary infections, and mortality. Four study cohorts were used: 1) healthy subjects infused with endotoxin, 2) non-infectious, critically ill patients without antibiotic therapy (PIPOVAP study), 3) hospitalized coronavirus 2019 (COVID-19) patients and, 4) sepsis patients with multi-organ dysfunction syndrome (MODS) (INCLASS study). Serial samples of peripheral blood were used to quantify MDSCs by flow cytometry and FlowSOM to avoid gating biases. M-MDSCs were defined as HLA-DRlow monocytes, and PMN-MDSCs as CD16low granulocytes. Furthermore, we quantified up to 49 cytokines by multiplex bead assay, and analysed the functionality of monocytes and dendritic cells (DCs) in ex vivo stimulated whole blood by intracellular cytokine staining and flow cytometry. Endotoxin infusion in healthy subjects induced a quick, massive, and transient accumulation of MDSCs in peripheral blood. PMN-MDSCs increased 40-fold to reach up to 43% of all granulocytes 6-8 hours after infusion. M-MDSCs increased 10-fold 8 hours after endotoxin infusion comprising more than half of total monocytes. After 24 hours, PMN-MDSCs and M-MDSCs returned to baseline levels. In patients enrolled in the PIPOVAP, COVID-19, and INCLASS studies, the blood concentration of PMN-MDSCs and M-MDSCs were high at study inclusion and correlated to disease severity. In the PIPOVAP study, high levels of M-MDSCs also correlated to the development of secondary gram-negative infections. High MDSCs were associated with mortality in non-infectious critically ill patients (PIPOVAP), but with survival in sepsis patients with MODS (INCLASS). MDSCs correlated with the concentrations of blood cytokines, chemokines, and growth factors in the PIPOVAP and COVID-19 studies. Finally, 3 months after the COVID-19 diagnosis, irrespective of initial disease severity, MDSCs were back to normal levels whilst the production of cytokines by blood cells was still largely affected. Altogether, we report that MDSCs quickly rise during endotoxemia and are associated with sepsis severity. Thus, MDSCs might represent valuable tools to screen vulnerable patients in the intensive care. Additionally, we show for the first time that a high level of MDSCs is associated with improved outcomes in a subset of extremely ill sepsis patients with MODS. Overall, MDSCs may represent sepsis biomarkers and targets of therapy. To pursue clinical development, the quantification method of MDSCs in patients need to be standardized, and the function and plasticity of MDSCs during sepsis should be further explored. -- Avec 50 millions de cas et 11 millions de décès par an, le sepsis est l'une des principales causes de décès dans le monde. Le sepsis est causé par une réponse dérégulée de l'hôte en réponse à une infection, qui consiste en des réactions inflammatoires et immunosuppressives concomitantes. Les cellules suppressives d'origine myéloïde (MDSCs) sont des cellules myéloïdes immatures caractérisées par leurs propriétés immunosuppressives. Les MDSCs sont subdivisées en MDSCs polymorphonucléaires (PMN- MDSCs) et MDSCs monocytaires (M-MDSCs) en fonction de leur relation avec les PMNs et monocytes matures. L’évolution des MDSCs au cours d’un sepsis humain est très peu documentée. Pour combler cette lacune, dans cette thèse nous avons analysé l’expression des MDSCs dans le sang en regard de la sévérité du sepsis et de paramètres immunologiques. Quatre études de cohortes ont été utilisées: 1) des sujets sains perfusés avec de l'endotoxine, un composant de bactéries gram-négatives qui permet de mimer une infection bactérienne (étude endotoxin), 2) des patients non infectieux, hospitalisés aux soins intensifs (SI) (étude PIPOVAP), 3) des patients coronavirus 2019 hospitalisés (étude COVID-19) et 4) des patients sepsis présentant un syndrome de défaillance multiviscérale associé à une mortalité d’environ ~70% (étude INCLASS). Des échantillons sériels de sang périphérique ont été collectés pour quantifier les MDSCs. En outre, nous avons mesuré une cinquantaine de cytokines, chimiokines et facteurs de croissances et analysé la fonctionnalité des globules blancs du sang complet. La perfusion d'endotoxine chez des sujets sains induisait une accumulation rapide, massive (pouvant aller jusqu’à 30-40% de tous les globules blancs) et transitoire de MDSCs. Après 24 heures, les MDSCs étaient revenus à un taux normal. Les MDSCs étaient élevées chez les patients inclus dans les études PIPOVAP, COVID-19 et INCLASS. Cette augmentation corrélait avec la gravité de la maladie et, dans l'étude PIPOVAP, avec le développement d'infections nosocomiales. Des taux élevés de MDSCs étaient associés à la mortalité chez les patients non-infectieux hospitalisés aux SI. Par contre, une accumulation de MDSCs était associée à un devenir favorable chez les patients sepsis ayant développé un syndrome de défaillance multiviscérale. Finalement, chez les patients COVID-19 ré-analysés 3 mois après leur hospitalisation, les MDSCs étaient normales alors que certains dysfonctionnements immunitaires étaient détectés. Ceux-ci qui pourraient être associés au syndrome de « COVID long ». En résumé, nous rapportons que les MDSCs augmentent rapidement et fortement dans le sang d’individus exposés à un composant de bactérie, et qu’elles sont associées à la sévérité du sepsis. Ainsi, les MDSCs ont un potentiel diagnostique et pronostique chez les patients atteints de sepsis. Par ailleurs, les MDSCs pourraient représenter des cibles d’immunothérapie, d’autant plus que des traitements ciblant les MDSCs sont actuellement testées dans le cadre de cancers. -- The immune system protects the human body against infections caused by microorganisms, like viruses and bacteria. White blood cells are one important part of the immune system. White blood cells kill invading organisms as well as warn and activate other white blood cells to increase host defences. However, sometimes the immune system does not respond appropriately to an infection, or it cannot control it. When that happens, white blood cells injure tissues through collateral damage while trying to contain the infection. This can lead to organ failure, which is associated with a high mortality rate. When this happens, it is called sepsis. With 50 million cases and 11 million deaths per year, sepsis is a global health priority. During sepsis, white blood cells can respond too strongly, stop functioning, or even repress the function of other cells. This is called immunosuppression. Immunosuppression can cause long-term effects in recovered sepsis patients, such as the development of new infections and heart diseases. In this thesis, we were interested in a particular type of white blood cells called myeloid-derived suppressor cells (MDSCs). MDSCs restrict the function of other white blood cells. In short, they are immunosuppressive. Healthy people have very few MDSCs, but patients with inflammatory diseases such as cancer, have high levels of MDSCs. How fast MDSCs respond after an infection, and what type of impact these cells have during sepsis are largely unknown. We aimed to give an in-depth view of the dynamics of MDSCs in conditions of inflammation and infection. We set up four studies to address our aim. Blood was collected from individuals at different time intervals to measure MDSCs and other immune parameters. The first study was with healthy volunteers who were injected with bacterial compounds, which trigger white blood cells mimicking bacterial sepsis. We observed that MDSC levels rise strongly 2 hours after infusion and remained high until 8 hours after the injection. MDSCs returned to normal levels after 24 hours. This tells us that MDSCs are very fast responders when the host is triggered by a bacterial compound. In the second study, we tested critically ill patients in the Intensive Care Unit (ICU) without an infection. We noticed that patients with high levels of MDSCs were more likely to become infected and to die. We assume that MDSCs suppressed the function of anti-microbial white blood cells, increasing the risks of infection. In the third study, we looked at COVID-19 patients. COVID-19 patients can develop sepsis, which is one of the reasons why some must be hospitalized. Patients admitted to the ICU had more MDSCs than patients who did not require admission to the ICU. In the fourth study, we analysed severe sepsis patients with multiple organ dysfunctions. Patients with high levels of MDSCs were more likely to survive. Most likely, MDSCs were beneficial in these severe patients because MDSCs were counterbalancing the otherwhite blood cells that were overreacting and damaging. To conclude, this thesis shows 1) how MDSCs are modulated during sepsis, and 2) that MDSCs can be helpful or hurtful depending on the degree of sepsis severity. We propose to use MDSCs as signals of sepsis severity, and possibly as targets of therapy as currently tested in cancer patients. -- Le système immunitaire protège notre organisme contre les infections par les bactéries et les virus. Les globules blancs présents dans le sang sont des éléments vitaux du système immunitaire car ils peuvent tuer les bactéries et les virus. Par ailleurs ils activent d'autres globules blancs, augmentent les défenses de l'hôte, et confèrent la mémoire immunitaire protégeant de réinfections. Il arrive que le système immunitaire ne réponde pas de façon appropriée ou ne peut pas contrôler l’infection. Dans ce cas, les globules blancs peuvent causer des dommages collatéraux aux tissus. Cela peut entraîner une défaillance d’organe, associée à un taux de mortalité élevé. C'est ce qu'on appelle un sepsis. Avec 50 millions de cas et 11 millions de décès par an, le sepsis est une priorité sanitaire mondiale. Lors d’un sepsis, les globules blancs peuvent cesser de fonctionner ou empêcher le fonctionnement d'autres cellules. C'est ce qu'on appelle l'immunosuppression. Elle peut avoir des effets à long terme chez les patients ayant guéris d’un sepsis, comme le développement d’infections et ou de maladies cardiaques. Dans cette thèse, nous nous sommes intéressés aux globules blancs appelés cellules myéloïdes suppressives (MDSCs). Les MDSCs restreignent la fonction des autres globules blancs, elles sont donc immunosuppressives. Les personnes en bonne santé, contrairement à celles atteintes de maladies inflammatoires y compris le cancer, ont très peu de MDSCs dans leur sang. Très peu étant connu quant à l’implication des MDSCs dans le sepsis, notre objectif était de fournir une analyse approfondie de la dynamique des MDSCs dans des conditions d'infection. Nous avons mis en place quatre études pour répondre à notre objectif. Le sang a été prélevé à intervalles réguliers pour mesurer les MDSCs et d'autres paramètres immunologiques. La première étude portait sur des volontaires sains recevant une injection d’un morceau de bactérie simulant un sepsis à bactérie. Les MDSCs augmentaient rapidement, fortement, et transitoirement revenant à un niveau normal 24 heures après l’injection. Dans la deuxième étude, nous avons testé des patients sans infection, admis aux soins intensifs (SI). Nous avons remarqué que les patients avec beaucoup de MDSCs développaient plus d’infections nosocomiales, dont des infections mortelles. Nous pensons que les MDSCs supprimaient la fonction des globules blancs antimicrobiens, augmentant les risques d'infection. Dans la troisième étude, nous avons examiné des patients atteints de COVID-19. Les patients COVID-19 admis aux SI avaient plus de MDSCs que ceux n’ayant pas besoin d'être admis aux SI. Dans la quatrième étude, nous avons analysé des patients atteints de sepsis grave présentant une défaillance de plusieurs organes. Ceux avec beaucoup de MDSCs avaient un pronostique plus favorable. Nous pensons que, dans ce contexte particulièrement sévère (environ 70% des patients décédaient), les MDSCs contrebalançaient la réponse excessive de globules blancs et les dommages collatéraux subséquents. Pour conclure, cette thèse décrit comment les MDSCs sont modulées pendant un sepsis, et que les MDSCs peuvent être utiles ou néfastes selon le degré de sévérité des patients infectés. Les MDSCs pourraient être utilisées comme indicateur de gravité du sepsis, et éventuellement comme cibles de traitements tels que ceux ciblant les MDSCs testés actuellement chez les patients cancéreux. -- Het lichaam wordt door zijn eigen immuunsysteem beschermd tegen indringers zoals virussen en bacteriën. Witte bloedcellen spelen daarbij een belangrijke rol. Ze doden indringers en waarschuwen en activeren andere witte bloedcellen om de afweer te versterken. Soms reageren de witte bloedcellen te sterk of krijgen ze de infectie niet onder controle. In een poging de infectie te bestrijden beschadigen witte bloedcellen dan de weefsels. Deze weefselschade kan leiden tot uitval van organen. De kans op overlijden is hierbij groot. Dit ernstige ziektebeeld wordt sepsis genoemd. Jaarlijks ontwikkelen wereldwijd ongeveer 50 miljoen mensen sepsis waarvan er 11 miljoen overlijden. Na een doorgemaakte sepsis is er kans op langdurige gezondheidsproblemen, zoals bijvoorbeeld nieuwe infecties en hartaandoeningen. Dit komt doordat tijdens sepsis, witte bloedcellen niet alleen te sterk reageren, maar ook stoppen met functioneren en de functie van andere cellen onderdrukken. Dit laatste wordt immunosuppressie genoemd en kan lang aanhouden nadat patiënten van sepsis hersteld zijn. In dit proefschrift onderzochten we een bepaald type witte bloedcel, namelijk “myeloid-derived suppressor cells” (MDSC's). MDSC's onderdrukken de functie van andere witte bloedcellen en werken dus immunosuppressief. In tegenstelling tot gezonde mensen hebben patiënten met ontstekingsziekten zoals kanker of auto-immuunziekten veel MDSC’s. Het is echter nog onbekend hoe snel MDSC’s reageren op een infectie en welke rol zij spelen tijdens sepsis. We hebben vier onderzoeken uitgevoerd om hierin meer inzicht te krijgen. De eerste studie betrof gezonde vrijwilligers die stukjes van bacteriën toegediend kregen. Dit activeert witte bloedcellen en is daarom vergelijkbaar met bacteriële sepsis. We constateerden dat de MDSC-waarden in het bloed 2 uur na toediening sterk stegen en vervolgens verhoogd bleven tot 8 uur na toediening. Na 24 uur keerden MDSC-waarden terug naar normaal. Hieruit kunnen we concluderen dat MDSC's zeer snel reageren wanneer het lichaam wordt geïnfecteerd door een bacterie. De tweede studie betrof ernstig zieke patiënten die initieel geen infectie hadden op de intensive care (IC). In deze groep zagen we dat patiënten met hoge MDSC-waarden een grotere kans hadden om een infectie te ontwikkelen en hierdoor te overlijden. Waarschijnlijk onderdrukten MDSC's de functie van andere infectie-bestrijdende witte bloedcellen, waardoor het infectierisico toenam. De derde studie betrof COVID-19-patiënten. Sommige COVID-19-patiënten ontwikkelen sepsis en moeten worden opgenomen in het ziekenhuis. Wij constateerden dat COVID-19-patiënten die op de IC waren opgenomen, meer MDSC's hadden dan patiënten die op de verpleegafdeling konden blijven. Ten slotte, onderzochten we in vierde studie patiënten met ernstige sepsis bij wie meerdere organen waren uitgevallen. Hier constateerden we dat patiënten met hoge MDSC-waarden een grotere overlevingskans hadden. Hoogstwaarschijnlijk waren MDSC's beschermend bij deze ernstig zieke patiënten omdat MDSC’s de te hevig reagerende witte bloedcellen onder controle brachten. Concluderend toont dit proefschrift hoe MDSC’s zich gedragen tijdens sepsis, en dat MDSC’s therapeutisch of ziekmakend kunnen werken, afhankelijk van de mate van ontsteking in het lichaam. MDSC-waarden kunnen in de toekomst mogelijk gebruikt worden als maat voor ernst van sepsis, en als aangrijpingspunt voor medicatie

    Atypical developmental trajectories of white matter microstructure in prenatal alcohol exposure: Preliminary evidence from neurite orientation dispersion and density imaging

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    IntroductionFetal alcohol spectrum disorder (FASD), a life-long condition resulting from prenatal alcohol exposure (PAE), is associated with structural brain anomalies and neurobehavioral differences. Evidence from longitudinal neuroimaging suggest trajectories of white matter microstructure maturation are atypical in PAE. We aimed to further characterize longitudinal trajectories of developmental white matter microstructure change in children and adolescents with PAE compared to typically-developing Controls using diffusion-weighted Neurite Orientation Dispersion and Density Imaging (NODDI).Materials and methodsParticipants: Youth with PAE (n = 34) and typically-developing Controls (n = 31) ages 8–17 years at enrollment. Participants underwent formal evaluation of growth and facial dysmorphology. Participants also completed two study visits (17 months apart on average), both of which involved cognitive testing and an MRI scan (data collected on a Siemens Prisma 3 T scanner). Age-related changes in the orientation dispersion index (ODI) and the neurite density index (NDI) were examined across five corpus callosum (CC) regions defined by tractography.ResultsWhile linear trajectories suggested similar overall microstructural integrity in PAE and Controls, analyses of symmetrized percent change (SPC) indicated group differences in the timing and magnitude of age-related increases in ODI (indexing the bending and fanning of axons) in the central region of the CC, with PAE participants demonstrating atypically steep increases in dispersion with age compared to Controls. Participants with PAE also demonstrated greater increases in ODI in the mid posterior CC (trend-level group difference). In addition, SPC in ODI and NDI was differentially correlated with executive function performance for PAE participants and Controls, suggesting an atypical relationship between white matter microstructure maturation and cognitive function in PAE.DiscussionPreliminary findings suggest subtle atypicality in the timing and magnitude of age-related white matter microstructure maturation in PAE compared to typically-developing Controls. These findings add to the existing literature on neurodevelopmental trajectories in PAE and suggest that advanced biophysical diffusion modeling (NODDI) may be sensitive to biologically-meaningful microstructural changes in the CC that are disrupted by PAE. Findings of atypical brain maturation-behavior relationships in PAE highlight the need for further study. Further longitudinal research aimed at characterizing white matter neurodevelopmental trajectories in PAE will be important

    Mushroom β-glucan and polyphenol formulations as natural immunity boosters and balancers: nature of the application

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    Mushrooms are experiencing a kind of renaissance as a part of the contemporary human diet. These valuable organisms are more than food, they fi t in perfectly as a novel market group known as nutra-mycoceuticals. Immune-balancing mushroom dietary fibers and secondary metabolites such as polyphenols are the main focus of the healthcare industry. Wellness and cosmetic companies are increasingly using mushroom extracts rich in these ingredients. This review considers the basic molecular immunomodulatory mechanisms of action of the most commonly used mushroom dietary fibers, β-glucans. The literature data on their bioavailability, metabolic transformations, preclinical and human clinical research, and safety are discussed. Immunomodulatory mechanisms of polyphenol ingredients are also considered. These molecules present great potential in the design of the new immunity balancer formulations according to their widespread structural diversity. Finally, we draw attention to the perspectives of modern trends in mushroom nutraceutical and cosmeceutical formulations to strengthen and balance immunity

    Pathogenesis and treatment of chronic rhinosinusitis from the perspective of sinonasal epithelial dysfunction

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    BackgroundChronic rhinosinusitis (CRS) is a clinical syndrome primarily characterized by long-term mucosal inflammation of the nasal cavity and sinuses. The pathogenesis of CRS is still unclear due to its high heterogeneity. A number of studies have recently focused on the sinonasal epithelium. Thus, there has been a quantum leap in awareness of the role of the sinonasal epithelium, which is now understood as an active functional organ rather than simply an inert mechanical barrier. Undoubtedly, epithelial dysfunction plays a vital role in the onset and development of CRS.ObjectiveIn this article, we discuss the potential contribution of sinonasal epithelium dysfunction to CRS pathogenesis and explore a few current and developing therapeutic options targeting the sinonasal epithelium.ResultsImpaired mucociliary clearance (MCC) and an abnormal sinonasal epithelial barrier are usually considered to be the main causative factors in CRS. Epithelial-derived bioactive substances, such as cytokines, exosomes, and complements, play a vital role in the regulation of innate and adaptive immunity and contribute to the pathophysiological alterations of CRS. The phenomena of epithelial–mesenchymal transition (EMT), mucosal remodeling, and autophagy observed in CRS offer some novel insights into the pathogenesis of this disease. In addition, existing treatment options targeting disorder of sinonasal epithelium can help to relieve the main symptoms associated with CRS to some extent.ConclusionThe presence of a normal epithelium is fundamental for maintaining homeostasis in the nasal and paranasal sinuses. Here, we describe various aspects of the sinonasal epithelium and highlight the contributions of epithelial dysfunction to CRS pathogenesis. Our review provides sound evidence of the need for in-depth study of the pathophysiological alterations of this disease and for the development of novel epithelium-targeting alternative treatments

    Crosstalk of Inflammatory Cytokines within the Breast Tumor Microenvironment

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    Several immune and immunocompetent cells, including dendritic cells, macrophages, adipocytes, natural killer cells, T cells, and B cells, are significantly correlated with the complex discipline of oncology. Cytotoxic innate and adaptive immune cells can block tumor proliferation, and others can prevent the immune system from rejecting malignant cells and provide a favorable environment for tumor progression. These cells communicate with the microenvironment through cytokines, a chemical messenger, in an endocrine, paracrine, or autocrine manner. These cytokines play an important role in health and disease, particularly in host immune responses to infection and inflammation. They include chemokines, interleukins (ILs), adipokines, interferons, colony-stimulating factors (CSFs), and tumor necrosis factor (TNF), which are produced by a wide range of cells, including immune cells, such as macrophages, B-cells, T-cells, and mast cells, as well as endothelial cells, fibroblasts, a variety of stromal cells, and some cancer cells. Cytokines play a crucial role in cancer and cancer-related inflammation, with direct and indirect effects on tumor antagonistic or tumor promoting functions. They have been extensively researched as immunostimulatory mediators to promote the generation, migration and recruitment of immune cells that contribute to an effective antitumor immune response or pro-tumor microenvironment. Thus, in many cancers such as breast cancer, cytokines including leptin, IL-1B, IL-6, IL-8, IL-23, IL-17, and IL-10 stimulate while others including IL-2, IL-12, and IFN-γ, inhibit cancer proliferation and/or invasion and enhance the body’s anti-tumor defense. Indeed, the multifactorial functions of cytokines in tumorigenesis will advance our understanding of cytokine crosstalk pathways in the tumor microenvironment, such as JAK/STAT, PI3K, AKT, Rac, MAPK, NF-κB, JunB, cFos, and mTOR, which are involved in angiogenesis, cancer proliferation and metastasis. Accordingly, targeting and blocking tumor-promoting cytokines or activating and amplifying tumor-inhibiting cytokines are considered cancer-directed therapies. Here, we focus on the role of the inflammatory cytokine system in pro- and anti-tumor immune responses, discuss cytokine pathways involved in immune responses to cancer and some anti-cancer therapeutic applications

    IDO1 and inflammatory neovascularization: bringing new blood to tumor-promoting inflammation

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    In parallel with the genetic and epigenetic changes that accumulate in tumor cells, chronic tumor-promoting inflammation establishes a local microenvironment that fosters the development of malignancy. While knowledge of the specific factors that distinguish tumor-promoting from non-tumor-promoting inflammation remains inchoate, nevertheless, as highlighted in this series on the ‘Hallmarks of Cancer’, it is clear that tumor-promoting inflammation is essential to neoplasia and metastatic progression making identification of specific factors critical. Studies of immunometabolism and inflamometabolism have revealed a role for the tryptophan catabolizing enzyme IDO1 as a core element in tumor-promoting inflammation. At one level, IDO1 expression promotes immune tolerance to tumor antigens, thereby helping tumors evade adaptive immune control. Additionally, recent findings indicate that IDO1 also promotes tumor neovascularization by subverting local innate immunity. This newly recognized function for IDO1 is mediated by a unique myeloid cell population termed IDVCs (IDO1-dependent vascularizing cells). Initially identified in metastatic lesions, IDVCs may exert broader effects on pathologic neovascularization in various disease settings. Mechanistically, induction of IDO1 expression in IDVCs by the inflammatory cytokine IFNγ blocks the antagonistic effect of IFNγ on neovascularization by stimulating the expression of IL6, a powerful pro-angiogenic cytokine. By contributing to vascular access, this newly ascribed function for IDO1 aligns with its involvement in other cancer hallmark functionalities, (tumor-promoting inflammation, immune escape, altered cellular metabolism, metastasis), which may stem from an underlying role in normal physiological functions such as wound healing and pregnancy. Understanding the nuances of how IDO1 involvement in these cancer hallmark functionalities varies between different tumor settings will be crucial to the future development of successful IDO1-directed therapies

    Multiple functions and regulatory network of miR-150 in B lymphocyte-related diseases

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    MicroRNAs (miRNAs) play vital roles in the post-transcriptional regulation of gene expression. Previous studies have shown that miR-150 is a crucial regulator of B cell proliferation, differentiation, metabolism, and apoptosis. miR-150 regulates the immune homeostasis during the development of obesity and is aberrantly expressed in multiple B-cell-related malignant tumors. Additionally, the altered expression of MIR-150 is a diagnostic biomarker of various autoimmune diseases. Furthermore, exosome-derived miR-150 is considered as prognostic tool in B cell lymphoma, autoimmune diseases and immune-mediated disorders, suggesting miR-150 plays a vital role in disease onset and progression. In this review, we summarized the miR-150-dependent regulation of B cell function in B cell-related immune diseases
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