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REZOAGLI, EMANUELE. "Optimization of the Therapeutic Potential of Umbilical Cord-Mesenchymal Stem Cells for Staphylococcus Aureus Induced Pneumonia." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2020. http://hdl.handle.net/10281/263058.
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Introduzione: la sindrome da distress respiratorio acuto (ARDS) rappresenta il 10% di tutti i ricoveri in terapia intensiva e il 23% dei pazienti ventilati meccanicamente. Le cause più comuni di ARDS includono polmonite e sepsi. Ad oggi non esiste alcun trattamento per l'ARDS. Le cellule staminali mesenchimali (MSC) stanno emergendo come un trattamento promettente dell'ARDS per tre motivi: proprietà immunomodulatorie; antimicrobiche e di rigenerazione tissutale. Uno dei motivi per cui le MSC non sono ancora utilizzate nella terapi dell’ARDS in clinica è dovuto alla variabilità di risposta biologica. Un potenziale strategia per ottimizzarne l’azione è la preattivazione per-trattamento. Ad oggi, non sono disponibili informazioni sul ruolo delle MSC nel trattamento delle ARDS polmonare indotta da batteri Gram +. S. aureus è un batterio Gram + associato a più del 40% di casi di polmonite nosocomiale e con tassi di mortalità>50%.
Obiettivi 1. Caratterizzare l'espressione delle citochine delle MSC da cordone ombelicale (UC) e il ruolo del loro mezzo di coltura su una linea cellulare monocitica umana; 2. stabilire un nuovo modello di polmonite batterica gram + usando un ceppo di S. aureus da isolato umano; valutare 3. il potenziale ruolo terapeutico di UC-MSC con e senza preattivazione (serie 1) e 4. di UC-MSC preattivate a basso dosaggio (serie 2) nel trattamento di ARDS indotta da S. aureus nel ratto.
Metodi: Gli esperimenti in vitro hanno quantificato il profilo pro/antiinfiammatorio delle citochine derivanti da UC-MSC naïve e preattivate con citomix (TNF-α; IL-1β; e IFN- γ [50 ng / mL ciascuno]) tramite ELISA. Modelli di lesione cellulare in vitro sono stati sviluppati. Cellule THP-1 sono state trattate con mezzo di coltura da MSC per determinarne l'espressione e l'effetto sulla fagocitosi. Ratti (Sprague Dawley) maschi adulti sono stati utilizzati per gli esperimenti. Gli animali sono stati sottoposti a instillazione intratracheale di S. aureus Newman per indurre la ARDS polmonare. Nella serie 1, gli animali sono stati randomizzati, entro 2 ore dall'infezione, alla somministrazione endovenosa di: (1) veicolo (soluzione salina tamponata con fosfato (PBS)); (2) 1x107 / kg di UC-MSC; e (3) 1x107 / kg di UC-MSC pre-attivati per 24 ore. Nella serie 2, abbiamo randomizzato gli animali alla somministrazione endovenosa di: (1) veicolo (soluzione salina tamponata con fosfato (PBS)); (2) 2x106 / kg e (3) 5x106 / kg di UC-MSC pre-attivate per 24 ore con citomix (TNF-α; IL-1β; e IFN- γ [50 ng / mL ciascuno]). I confronti tra i gruppi sono stati testati per le differenze nella carica batterica e nella conta dei globuli bianchi nel lavaggio broncoalveolare (BAL) e in parametri fisiologici a 48h dal danno.
Risultati: le cellule preattivate esprimono un profilo pro/antiinfiammatorio differente rispetto alle UC-MSC naïve in vitro. L'instillazione endotracheale di S. aureus Newman ha indotto il primo modello di ARDS nel ratto usando un tale ceppo batterico. Le UC-MSC naïve hanno trattato parzialmente la lesione polmonare. Al contrario, la preattivazione di UC-MSC con cytomix per 24 ore ha permesso di aumentare significativamente la clearance batterica, ridurre gli infiltrati di cellule polmonari e migliorare l'ossigenazione (PaO2/FiO2 medio>300 (FiO2=1) (serie 1). Questi risultati sono stati confermati nella serie 2, in cui le UC-MSC preattivate hanno dimostrato il loro ruolo terapeutico nella attenuazione dell'ALI anche a basse dosi (2x106/kg).
Conclusioni: la terapia con UC-MSC preattivate ha ridotto la gravità dell'ARDS indotta da S. aureus anche a bassa dose di 2x106 / kg come visibile dalla riduzione della carica batterica e degli infiltrati di cellule infiammatorie polmonari e migliorando compliance respiratoria e ossigenazione arteriosa. L'uso di UC-MSC pre-attivate può rappresentare un trattamento potenzialmente rilevante nell’ARDS polmonare indotta da gram+.Introduction: Acute respiratory distress syndrome accounts for 10% of all ICU admissions and 23% of all mechanically ventilated patients. The most common causes of ARDS include pneumonia and sepsis. There remains currently no specific treatment for ARDS. Mesenchymal stem cells (MSCs) are emerging as a promising strategy for the treatment of ARDS for three main reasons: immune-modulatory properties, anti-microbial effects and tissue regeneration capabilities. With all of these listed qualities, why aren’t MSCs a current therapy in patients with ARDS? One reason for this, is that MSCs present a strong biological variability in-vivo. A possible approach to overcoming this in-consistency in the potential of MSCs is to prime them before administration. No information is available on the role of MSCs in the treatment of pulmonary ARDS induced by Gram positive bacteria. Staphylococcus aureus Newman is a clinically relevant Gram positive bacterium which is associated with >40% health care pneumonia cases and with mortality rates of >50%. Objectives 1. To characterize the cytokine expression of umbilical cord (UC) MSCs and the role of conditioned media on a human monocytic cell line; 2. to establish a new model of gram positive bacterial pneumonia using a clinically relevant strain of S. Aureus from a human isolate; to evaluate 3. the potential therapeutic role of naïve and preactivated UC-MSCs (Series 1) and 4. of low dose preactivated UC-MSCs (Series 2) freshly harvested from culture in the treatment of acute lung injury in a new model of Rodent S. aureus–induced ARDS. Methods: Cellular assays involved cytokine expression of naïve and preactivated UC-MSCs with cytomix (TNF-α; IL-1β; and IFN- γ [50 ng/mL each]) was measured using ELISA. In-vitro chemical and inflammatory injury assays were carried out. THP-1 cells were treated with conditioned media from primed and naïve MSCs to determine cytokine expression and effect on percentage phagocytosis. Adult male Sprague Dawley rats were used for in-vivo experiments. Animals underwent intratracheal instillation of S. aureus Newman to induce pulmonary ARDS. In series 1, animals were randomized, within 2 hours post infection, to intravenous administration of: (1) vehicle (phosphate buffered saline (PBS)); (2) 1x107/kg fresh UC-MSCs; and (3) 1x107/kg fresh UC-MSCs preactivated for 24 hours. In series 2, we randomized animals, within 2 hours post infection, to intravenous administration of: (1) vehicle (phosphate buffered saline (PBS)); (2) 2x106/kg and (3) 5x106/kg fresh UC-MSCs preactivated for 24 hours with cytomix (TNF-α; IL-1β; and IFN- γ [50 ng/mL each]). Comparisons among the groups were tested for differences in bacterial load and white blood cell count in the bronchoalveolar lavage (BAL), and arterial oxygenation after 48 hours. Results: Primed UC-MSCs variably expressed a different pro/anti-inflammatory profile compared to naïve UC-MSCs in vitro. Endotracheal instillation of S. aureus Newman induced the first model of ARDS in rats using such a bacterium strain. Fresh naïve UC-MSCs did not treat the lung injury. In contrast, the preactivation of fresh UC-MSCs with cytomix for 24 hours allowed to significantly increase the pulmonary bacterial clearance, reduce the lung cell infiltrates and to improve oxygenation with an average PaO2/FiO2 ratio above 300 at an FiO2 of 1.0 (series 1). These results were confirmed in series 2, where preactivated UC-MSCs demonstrated their therapeutic role in the decrease of ALI even at the low dose of 2x106/kg. Conclusions: Fresh preactivated UC-MSCs therapy decreased the severity of S. aureus induced ARDS even at the low dose of 2x106/kg by the reduction of bacterial load and white blood cell infiltrates into the lungs, and leading to the increase of arterial oxygenation. The use of preactivated UC-MSCs may represent a potential clinically relevant treatment of acute lung injury in patients with gram positive induced ARDS.
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Dy, Eric David. "Development of a cytomic force transducer for experimental mechanobiology." Diss., Restricted to subscribing institutions, 2008. http://proquest.umi.com/pqdweb?did=1750740721&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Fergusson, Ronald John. "Treatment of human lung cancer with interferon and cytoxic agents." Thesis, University of Edinburgh, 1990. http://hdl.handle.net/1842/23889.
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The prognosis for patients with lung cancer remains extremely poor. Newer, more effective treatment regimens are required. In this thesis, the effectiveness of combining human recombinant interferon alpha with various estalished cytotoxic agents was assessed in laboratory models of human lung cancer and a clinical study. The majority of the experimental work was performed on a series of human bronchial carcinoma xenografts established in immune deprived CBA mice. Interferon alone had no cytotoxic effect but appeared to potentiate the activity of various anti-cancer agents in non-small cell tumours. No such effect was seen in two small cell xenografts. Further studies suggested that the dosing schedules of each agent in the combination was important in producing positive effects. The exact mechanisms by which interferon may interact with cytotoxic drugs remains unexplained. It was shown that the results obtained in the xenograft model were not mediated through increased toxicity to the host or by modulation of cell cycle distribution within the tumour cells. Assessment of interferon/drug combinations was also performed using in-vitro models of lung cancer. Significant synergistic interactions were not demonstrated. A pilot clinical study investigating the potential of combined treatment with interferon and Cisplatinum was performed in a group of patients with non-small cell lung cancer. The toxicity of the treatment was predictable and an encouraging response rate was seen.
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Campos, Alexandre Rosa. "Application of proteomics and cytomics in human neutrophils functional studies." reponame:Repositório Institucional da UnB, 2007. http://repositorio.unb.br/handle/10482/1077.
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Dissertação (mestrado)—Universidade de Brasília, Faculdade de Medicina, 2007.Submitted by Luis Felipe Souza (luis_felas@globo.com) on 2008-11-12T17:50:40Z No. of bitstreams: 1 Dissertacao_2007_AlexandreRosa.pdf: 9082399 bytes, checksum: 9fe59d69d2f47fa7ddf981b510013376 (MD5)
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Biomedical research commonly starts by raising a hypothesis to solve a problem. In this context, scientists select the most appropriate method(s) to answer the question and solve a common dilemma. Over the past decade, we have witnessed a revolution of new technologies in molecular biology – the Omics Science. Highscale technologies such as metabolomics, cytomics, genomics and proteomics are changing the way we study complex biological systems. Current approaches to understanding the functional diversity of an organism preferentially strive for a systems biology approach whereby first the phenotypic classification of a specific cytome is achieved prior to an attempt to perform proteomic analysis. In this context, to better understand the features that involve neutrophil activation and programmed cell death in the pathological and healthy states, this study proposes the integration of cell biology approaches such as flow cytometry with a very robust proteomics platform in an attempt to integrate data at the molecular level with phenotypic data of neutrophils. The application of subcellular fractionation method using digitonin detergent extraction to enrich cytosolic proteins from neutrophils was found reproducible, simple to perform, and inexpensive. ________________________________________________________________________________________ ABSTRACT
Pesquisas biomédica comumente começa com a elaboração de uma hipotese para resolver um problema. Nesse contexto, cientistas selecionam o(s) metodo(s) mais apropriado(s) para responder a questão e solucionar um dilema. Nos últimas anos, nós temos testemunhado uma revolução de novas tecnologias em biologia molecular – a ciência -Omica. Tecnologias de alta-escala tais como metabolômica, citômica, genômica e proteômica estão mudando o modo que estudamos sistemas biológicos complexos. Métodos contemporâneos para o entendimento da diversidade funcional em um dado organismo preferencialmente abordam uma visão de biologia de sistemas onde primeiro a classificação fenótipa de um citoma é alcançado antes de uma tentativa de caracterizar o proteoma de tal célula. Dentro desse contexto, e para proporcionar um melhor entendimento dos componentes envolvidos na ativação e morte celular programada dos neutrófilos nos estados patológicos e sano, esse estudo propõe a integração de métodos em biologia celular tal como citometria de fluxo com uma robusta plataforma proteômica em uma tentativa de integrar dados a nível molecular com dados fenótipicos de neutrófilos. Fracionamento subcelular usando um método de extração e enriquecimento de proteínas citosólicas com o detergente digitonina foi otimizado nesse trabalho, e encontrado ser altamente reprodutível, fácil de realizar, e de baixo custo.
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Strzelczyk, Barbara. "Cytokin mRNA profil i perifera mononukleära celler hos barn med födoämnesallergi." Thesis, Umeå universitet, Biomedicinsk laboratorievetenskap, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-58649.
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Helg, Andreas Gabriel. "Allopyranosyl-Nukleinsäure : Synthese, Paarungseigenschaften und Struktur von Guanin-/Cytosin-enthaltenden Oligonukleotiden /." [S.l.] : [s.n.], 1994. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=10464.
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Letort, Gaelle. "Exploration par simulations numériques de l'auto-organisation du cytosquelette sous conditions géométriquement contrôlées." Thesis, Université Grenoble Alpes (ComUE), 2015. http://www.theses.fr/2015GREAS048/document.
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Le cytosquelette joue un rôle essentiel dans de nombreux processus cellulaires (division, adhésion, migration, morphogenèse..). Un de ses principaux constituants, les filaments d'actine, des polymères semi flexibles polarisés, forme des réseaux dont les architectures spécifiques permettent au cytosquelette de réaliser ses fonctions physiologiques. Un enjeu majeur en biologie cellulaire est de comprendre comment les cellules peuvent former une telle variété d'organisations à partir de la même entité de base, les monomères d'actine. Nous avons découvert récemment que limiter la nucléation des filaments d'actine à des géométries définies suffit à contrôler la formation de différentes organisations (Reymann et al, 2010). Néanmoins, les paramètres principaux permettant d'expliquer comment ces contraintes géométriques déterminent l'organisation collective des filaments n'ont pas été identifiés. Pour comprendre les lois physiques régissant ce phénomène, j'ai développé des simulations numériques du système expérimental en utilisant le logiciel Cytosim. J'ai pu ainsi montrer que la géométrie, les interactions stériques entre filaments, leurs propriétés mécaniques, et l'efficacité de la nucléation sont les paramètres clés contrôlant la formation de structures. Cette étude propose une base solide pour comprendre l'organisation cellulaire de l'actine en identifiant un système minimal de composants suffisant pour simuler l'émergence de différentes organisations d'actine (réseau branché, faisceaux de filaments parallèles ou antiparallèles). Avec cet outil, nous pouvons à présent prédire, étant donnée une géométrie de nucléation, quelles structures en émergeront.Nous avons alors combiné nos deux méthodes in-vitro et in-silico pour étudier comment le couplage entre l'architecture des réseaux et leur composition biochimique contrôle la réponse contractile. La connectivité entre les filaments en est un facteur crucial. En effet, un réseau peu connecté se déforme seulement localement, et n'instaure pas de comportement global. Une structure fortement connectée est très rigide, les moteurs moléculaires ne peuvent donc pas la déformer efficacement. La contraction d'une structure n'est donc possible que pour des valeurs de connectivité intermédiaires. L'amplitude de cette contraction est alors déterminée par l'organisation des filaments. Ainsi nous avons pu expliquer comment l'architecture mais aussi la connectivité des réseaux gouverne leur contractilité.Finalement, les microtubules sont aussi des acteurs essentiels aux processus cellulaires. Étant longs et rigides, ils servent de senseurs de la forme cellulaire et organisent les organites. Leur distribution spatiale, facteur majeur pour l'organisation cellulaire, est contrôlée dans un grand nombre de types cellulaires par la position du centrosome, un organite qui nuclée la plupart des microtubules. La capacité du centrosome à trouver le centre de la cellule dans de nombreuses conditions physiologiques est particulièrement étonante. Il peut aussi adopter une position décentrée lors de processus cellulaires spécifiques. Des mécanismes pouvant potentiellement expliquer le positionnement du centrosome ont été proposés (Manneville et al., 2006; Zhu et al, 2010), mais ce phénomène reste dans sa plus grande partie inexpliqué. J'ai utilisé les simulations pour explorer différents mécanismes pouvant le contrôler selon différentes conditions. Ces résultats permettent de disposer d'une base théorique pour présumer des mécanismes intervenant dans un système donné. Ils peuvent aussi permettre de valider ou réfuter des hypothèses sur les phénomènes mis en jeu et aider à l'élaboration de nouveaux systèmes expérimentaux.Les simulations que j'ai développées aident ici à étudier des comportements spécifiques, en apportant de nouveaux éclairages sur les comportements collectifs du cytosquelette. Elles pourraient être utilisées comme un outil prédictif ou adaptées pour l'étude d'autres systèmes expérimentauxThe cytoskeleton plays a crucial role in cellular processes, including cell division, adhesion, migration and morphogenesis. One of its main compenent, the actin filaments, a polarised semi-flexible polymer, contributes to these processes by forming specific collective architectures, whose structural organisations are essential to perform their functions. A major challenge in cell biology is to understand how the cell can form such a variety of organisations by using the same basic entity, the actin monomers. Recently we discovered that limiting actin nucleation to specific regions was sufficient to obtain actin networks with different organization (Reymann et al., 2010). However, our understanding of the general parameters involved in geometrically-driven actin assembly was limited. To understand mechanistically how spatially constraining actin nucleation determines the emergent actin organization, I performed detailed simulations of the actin filament system using Cytosim, a simulation tool dedicated to cytoskeleton system. I found that geometry, actin filaments local interactions, bundle rigidity, and nucleation efficiency are the key parameters controlling the emergent actin architecture. This study sets the foundation for our understanding of actin cellular organization by identifying a reduced set of components that were sufficient to realistically reproduce in silico the emergence of the different types of actin organization (branched actin network, parallel or anti parallel actin bundles). We can now predict for any given nucleation geometry which structures will form.Being able to control the formation of specific structures in-vitro and in-silico, we used the combination of both methods to study how the interplay between actin network architecture and its biochemical composition affects its contractile response. We highlighted the importance of the connectivity between filaments in the structures. Indeed, a loosely connected network cannot have a global behavior, but undergoes only local deformations. A highly connected network will be too rigid to be efficiently deformed by molecular motors. Only for an intermediate range of network connectivity the structures will contract, with an amplitude that depends notably on actin filaments organisation. This work explains how architecture and connectivity govern actin network contractility.Finally, the microtubules are also essential actors of cellular processes. Being long and rigid, they serve as sensors of the cellular shape and can organize the position of organelles in the cytoplasm. Their spatial distribution in the cell is thus a crucial cellular feature. this distribution is determined in a vast number of cell types by the position of the centrosome, an organelle that nucleates the majority of microtubules. Quite strinkingly, the centrosome is able to find the center of the cell in a lot of different physiological conditions, but can nonetheless adopt a decentered position in specific cellular processes. How this positioning is controled is not yet fully understood, but a few potential mechanims have been proposed (Manneville et al., 2006; Zhu et al., 2010). I used the simulations to explore different mechanisms taht can explain the position of the centrosome under different conditions. These results offer theorical considerations as a basis to assess which mechanism might prevail in a specific experimental system and may help to design new experimental setups.The simulations that I developed helped to study some specific behavior, by giving new insights into cytoskeleton collective organisations. These simulations can be further used as predictive tool or adapted to other experimental systems
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Feldhaus, Beatrix. "Periventrikuläre Leukomalazie Untersuchung Cytokin-induzierter Schädigungen von Oligodendrocyten-Vorläuferzellen und Protektion durch Corticoide /." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=968797806.
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Lödige, Inga. "Untersuchungen zur Rolle des Kernexportes des Transkriptionsfaktors STAT1 in der Cytokin-abhängigen Geninduktion." [S.l.] : [s.n.], 2006. http://www.diss.fu-berlin.de/2006/527/index.html.
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Schießer, Stefan. "Synthese neuer Cisplatin-N-Lost-Konjugate und epigenetisch relevanter C5-modifizierter Cytosin Derivate." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-167750.
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Reither, Sabine [Verfasser], and Jörn Erik [Akademischer Betreuer] Walter. "Reprogrammierung von 5-methyl-Cytosin in Säugetieren / Sabine Reither. Betreuer: Jörn Erik Walter." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2011. http://d-nb.info/1051326117/34.
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Herckelrath, Tanja. "Genexpressionsmuster nach Behandlung von Hepatomzellen mit dem Cytokin TGF-beta bzw. mit Tumorpromotoren." [S.l. : s.n.], 2004. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB11482176.
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Sezer, Ömer. "Der Einfluss von Doxycyclin auf die Cytokin- und Lipidmediatorsynthese sowie die Proliferation humaner Leukozyten." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=971468885.
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Schleifer, Grigorij [Verfasser]. "Kardioprotektiver Effekt von Cytosin-Phosphoguanin-Oligonucleotiden in einem murinen "Closed Chest" Modell / Grigorij Schleifer." Bonn : Universitäts- und Landesbibliothek Bonn, 2017. http://d-nb.info/1139119060/34.
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Fleckenstein, Diana Silke. "Charakterisierung Cytokin-induzierter Signaltransduktionswege TNF-Rezeptor assoziierter Faktor 4 (TRAF4) als neuer Ligand der p70S6 Kinase /." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=964293641.
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Haddad, Elias K. "Study of the role of macrophage activation and macrophage derived cytoxic factors in early embryo loss." Thesis, McGill University, 1997. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=42023.
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Using murine models of spontaneous and induced embryo resorption, we have investigated the role of macrophages in the mechanism of early embryo loss. The results showed that macrophage derived nitric oxide was associated with embryo resorption, and that decidual macrophages could be triggered by lipopolysaccharide (LPS) to produce nitric oxide, indicating that the decidual mononuclear cells were primed in situ. Using double immunostaining, we have shown that macrophages were the cellular source of the inducible nitric oxide production. We further showed that embryo abortion can be significantly decreased by inhibiting the production of nitric oxide in vivo. The results presented strongly suggested a role for nitric oxide as an effector molecule in mediating early embryo loss and showed that the in situ activation of decidual macrophages was an early event preceding spontaneous abortion.It is known that interferon-$ gamma$ (IFN-$ gamma$) is the major cytokine responsible for the priming of macrophages and that LPS can trigger primed macrophages to produce nitric oxide. Therefore, the observation that exogenous LPS induced embryo abortion in most strains of pregnant mice suggested that the decidual macrophages have been previously primed in situ. To investigate the role of IFN-$ gamma$ as a potential priming signal for decidual macrophage activation, we studied the effect of the depletion of IFN-$ gamma$ on LPS induced pregnancy loss. The results showed that IFN-$ gamma$ deficient mice were more resistant to LPS induced abortion than control mice. This suggested that IFN-$ gamma$ was essential for the priming of decidual macrophages and that decidual macrophages from IFN-$ gamma$ deficient mice could not be activated when exposed to LPS both in vivo and in vitro. Our results also showed increased IFN-$ gamma$ mRNA expression simultaneously in the same embryos that also expressed elevated iNOS mRNA, a macrophage activation marker. This suggested that macrophage activation, subsequent nitric oxide production, and spontaneous embryo loss could be a consequence of local IFN-$ gamma$ over production.
While LPS serves as an exogenous triggering factor, endogenous TNF-$ alpha$ is known to trigger NO production by primed macrophages. Therefore, we investigated the role of TNF-$ alpha$, as a second signal, in mediating embryo loss. Our studies showed that the frequency of embryos with significantly increased TNF-$ alpha$ mRNA expression corresponded to the incidence of murine embryo abortion. In addition, the results showed that increased TNF-$ alpha$ mRNA was simultaneously expressed with iNOS mRNA suggesting a potential role for TNF-$ alpha$ in the triggering of decidual macrophages.
In summary, we demonstrated the presence of activated decidual macrophages in murine placentas, and that inducible nitric oxide produced by these macrophages was responsible for embryo death. We further showed that IFN-$ gamma$ was responsible for the priming of decidual macrophages, and that the expression of TNF-$ alpha$, a potential secondary signal was associated with decidual macrophage activation, NO production, and subsequent embryo loss.
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Miguel, Lediana Iagalo. "Papel dos mediadores inflamatorios nas propriedades adesivas dos neutrofilos de pacientes com anemia falciforme e os efeitos de drogas moduladoras de nucleotideos ciclicos nesta adesão." [s.n.], 2010. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311499.
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Orientador: Nicola Amanda Conran ZorzettoDissertação (mestrado) - Universidade Estadual de Campinas. Faculdade de Ciencias Medicas
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Resumo: A adesão anormal das células brancas e vermelhas ao endotélio, que desencadeia numa diminuição do fluxo de sangue na microcirculação, é um dos principais fatores envolvidos na iniciação da vaso-oclusão em pacientes falciformes (AF). O estado inflamatório crônico, característico nos pacientes com AF, eleva a circulação de citocinas, as quais podem contribuir significativamente para a ativação e adesão das células vermelhas e brancas ao endotélio. O óxido nítrico (NO) e a via de sinalização dependente em NO têm importante efeito inibidor nas propriedades adesivas de leucócitos. Drogas que aumentem a biodisponibilidade de NO ou que atuem na via de sinalização NO-GMPc podem ser benéficas no tratamento de alguns aspectos da AF. Já é de conhecimento que pacientes com AF apresentam níveis elevados de algumas citocinas presentes no plasma, assim sendo, este estudo teve como objetivo avaliar os efeitos in vitro das citocinas nas propriedades adesivas de neutrófilos e células vermelhas de indivíduos controles e pacientes com AF. Adicionalmente, foram determinados os efeitos de BAY 73-6691, um inibidor da enzima hidrolizante de GMPc, fosfodiesterase 9A (PDE9A) e BAY 41-2272, um ativador de guanilato ciclase, na ausência ou presença da estimulação pelas citocinas na adesão dessas células. Os neutrófilos e as células vermelhas de indivíduos controles e pacientes com AF foram isolados de sangue periférico. A adesão das células à fibronectina foi determinada utilizando o ensaio de adesão estático na presença ou ausência das citocinas IL-8 (10-500ng/ml), TNF-alpha (10-100ng/ml) e GM-CSF (0,1-10ng/ml) e/ou na presença/ausência de BAY 73-6691 (60µM), BAY 41-2272 (60nM) ou DMSO como veículo (0.2%v/v). Como previamente demonstrado, os neutrófilos de pacientes com AF (neutrófilos AF) possuem uma maior capacidade de aderir à FN do que os neutrófilos de indivíduos controle (neutrófilos CON). A estimulação das células in vitro com as três citocinas aumentaram significativamente as adesões à FN dos neutrófilos CON e aumentou ainda mais a adesão dos neutrófilos AF. A incubação de ambos os neutrófilos, CON e AF, com BAY 73-6691, mas não BAY 41-2272, reduziu significativamente as propriedades adesivas à FN; esse evento foi acompanhado por uma diminuição da expressão das moléculas de adesão, L-selectina e CD11b (subunidade Mac-1) na superfície de neutrófilos AF. Além do mais, nas concentrações utilizadas, BAY 73-6691, mas não o BAY 41-2272, diminui significativamente a adesão de neutrófilos CON e AF após estimulação com IL-8, TNF-a e GM-CSF. No entanto, esse evento não foi acompanhado por alterações na expressão da moléculas de adesão na superfície de neutrófilos AF quando estimulados com IL-8. As células vermelhas de indivíduos AF também apresentaram uma maior capacidade de se aderir à FN quando comparadas às células de indivíduos controles. No entanto, ao contrário dos neutrófilos, na presença de IL-8 (10-500ng/ml) e TNF-a (0.1-1µg/ml), não houve alteração das propriedades adesivas dessas células tanto de indivíduos controles quanto das células de pacientes com AF. Além disso, BAY 73-6691 e BAY 41-2272, não alteraram a adesão basal tanto das células vermelhas de controles quanto pacientes com AF. Os principais mediadores inflamatórios, utilizados em concentrações fisiologicamente relevantes, foram capazes de aumentar as propriedades adesivas de neutrófilos, mas não das células vermelhas, de indivíduos controles e AF. Portanto, sugerimos que as citocinas inflamatórias circulantes podem desempenhar um papel na indução das propriedades adesivas dos neutrófilos em pacientes falciformes; em contrapartida, outros fatores além do estímulo inflamatório, podem ser mais importante para induzir a adesão das células vermelhas de pacientes AF. Dados sugerem que agentes que aumentam os níveis de GMPc intracelular podem ser úteis para reduzir as propriedades adesivas de neutrófilos AF, mesmo na presença de um estado inflamatório. PDE9A é altamente expressa pelas células hematopoiéticas e a inibição desta enzima, com conseqüente elevação de GMPc, pode representar um alvo terapêutico para drogas que são tecido/célula específicas, necessitando de mais estudos in vivo e in vitro para a terapêutica de AF
Abstract: The adhesion of both red and white cells to the vessel walls of the microcirculation initiates vaso-occlusion in sickle cell disease (SCD). The chronic inflammatory nature of SCD leads to elevation of circulating cytokines in patients, which may contribute significantly to the activation of red and white cells and their consequent adhesion. Nitric oxide (NO) and the NO-dependent signaling pathway have important inhibitory effects on cellular adhesive properties. Drugs that enhance NO bioavailability or NO-cGMP-dependent signaling may hold potential for treatment of various aspects of SCD. It is known that levels of certain cytokines are augmented in the plasma of SCD individuals; therefore, this study aimed to observe the effect of cytokines, on the in vitro adhesive properties of neutrophils (neu) and red blood cells (RBC) from healthy control (CON) and steady-state SCD (SCD) individuals. Furthermore, the effects of BAY 73-6691, an inhibitor of the cGMP-hydrolyzing enzyme, phosphodiesterase 9A (PDE9A) and BAY 41-2272, a guanylate cylase activator, on non-stimulated and cytokine-stimulated cell adhesion were determined. Neutrophils and red blood cells (RBC) were isolated from the peripheral blood of CON and SCD individuals. Cell adhesion to immobilized fibronectin was assessed using static adhesion assays in the presence or absence of the cytokines, IL-8 (10-500ng/ml), TNF-alpha (10-100ng/ml) and GM-CSF (0,1-10ng/ml) and/or in the presence/absence of BAY 73-6691 (10-60µM), BAY 41-2272 (60nM) or DMSO vehicle (0.2%v/v). As previously demonstrated, SCDneu have a greater capacity to adhere to FN than CONneu. Stimulation of cells in vitro with all three cytokines significantly augmented both CONneu adhesion to FN and further increased SCDneu adhesion. The incubation of both CONneu and SCDneu with BAY 73-6691, but not BAY 41-2272, significantly reduced their adhesions to FN; this was accompanied by a decrease in the expressions of the L-selectin and CD11b (Mac-1-subunit) adhesion molecules on the SCAneu surface. Furthermore, BAY 73-6691, but essentially not BAY 41-2272, significantly inhibited CONneu and SCDneu adhesion stimulated by IL-8, TNF-alpha and GM-CSF. However, this was not accompanied by alterations in adhesion molecule presentation on IL-8-stimulated SCAneu. As previously reported, SCD RBC have a greater capacity to adhere to FN, in vitro, compared to CON RBC. However, in contrast to neutrophils, cytokines IL-8 (10-500ng/ml) and TNF-alpha (0.1-1µg/ml) did not alter the capacities of neither CON RBC nor SCD RBC to adhere to FN. Furthermore, BAY 73-6691 and BAY 41-2272 did not affect either basal CON RBC or SCD RBC adhesion. Key SCD inflammatory mediators were found, at physiologically relevant concentrations, to augment the adhesive properties of neutrophils from control and SCD individuals. Circulating inflammatory cytokines may play a role in the induction of leukocyte adhesive properties in SCD; in contrast factors other than inflammatory stimuli may be more important for induction of SCD RBC adhesion. Data suggest that elevation of intracellular cGMP may be an important approach for reducing SCD leukocyte adhesive properties, even in an inflammatory environment. PDE9A is highly expressed in hematopoietic cells and inhibition of this enzyme, with consequent augmentation of cGMP, may represent a tissue/cell-specific therapeutic drug target worthy of further in vitro and in vivo studies as a therapy for SCD
Mestrado
Ciencias Biomedicas
Mestre em Ciências Médicas
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Schießer, Stefan [Verfasser], and Thomas [Akademischer Betreuer] Carell. "Synthese neuer Cisplatin-N-Lost-Konjugate und epigenetisch relevanter C5-modifizierter Cytosin Derivate / Stefan Schießer. Betreuer: Thomas Carell." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://d-nb.info/1049393198/34.
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Franke, Jeannine C. [Verfasser]. "Das eisenhaltige Cytosin-Analogon Ferropoptosid (N69) induziert Caspase-unabhängige aber ROS-abhängige Apoptose in Melanom-Zellen / Jeannine Constanze Franke." Berlin : Freie Universität Berlin, 2010. http://d-nb.info/1024744167/34.
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Quaas, Meike. "Mechanismus der Hemmung der glucagon-stimulierten Phosphoenolpyruvat-Carboxykinase-1-Genexpression durch das proinflammatorische Cytokin Interleukin 6 in primär kultivierten Rattenhepatozyten." [S.l.] : [s.n.], 2000. http://deposit.ddb.de/cgi-bin/dokserv?idn=961891742.
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Kraemer, Marcus [Verfasser]. "Das cytokin interleukin-1α und der basische Fibroblasten-Wachstumsfaktor: Zwei neue Komponenten der UV-induzierten Signalkette in Saeugerzellen / Marcus Kraemer." Karlsruhe : KIT-Bibliothek, 1991. http://d-nb.info/1155474139/34.
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García, Rico Laura. "Papel de la citómica funcional en el estudio de mecanismos de refractariedad de las neoplasias hematológicas." Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/669537.
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La leucèmia aguda i el mieloma múltiple són neoplàsies hematològiques que tenen una incidència notable en la població, causant una elevada mortalitat anualment. Una de les principals causes de la mortalitat és la refractarietat al tractament i la recaiguda. Tot i els avenços terapèutics, la majoria de pacients experimenta recaigudes o refractarietat, fet que fa que aquestes malalties siguin incurables. La citòmica funcional és una disciplina que permet l’anàlisi multiparamètric de l’heterogeneïtat cel·lular i dels citomes, relacionant la genòmica i la proteòmica amb la dinàmica i funció cel·lular. Aquesta tecnologia podria ser clau per a detectar cèl·lules relacionades amb la refractarietat, ja que permet la manipulació mínima dels espècimens a estudi, així com la mimetització de les condicions fisiològiques. Tot això pot contribuir a detectar de manera més eficient aquestes cèl·lules i a permetre el desenvolupament de noves aproximacions per a l’estudi de la malaltia refractària. L’objectiu de la Tesi Doctoral va residir en desenvolupar nous sistemes alternatius per a estudiar i identificar poblacions cel·lulars relacionades amb la refractarietat al tractament, aplicant aproximacions citòmiques avançades que van permetre realitzar estudis a nivell fenotípic i funcional, amb una pertorbació mínima de l’espècimen. En el primer treball es va desenvolupar una tecnologia basada en citòmica funcional per a determinar l’activitat fosfatasa alcalina en subpoblacions de cèl·lules mare de la leucèmia aguda avaluant-se com a mètode potencial per a detectar subpoblacions associades a una major refractarietat al tractament. En els pacients diagnosticats de leucèmia aguda refractaria, es van determinar poblacions CD34+\/ALPhigh en diferents seguiments que podrien estar associades amb la leucemogènesi al llarg del temps. Per a explorar la significança de l’activitat fosfatasa alcalina en el moment del diagnòstic de leucèmia mieloide aguda, es va realitzar un estudi prospectiu en 43 pacients. Es va demostrar que la detecció de l’activitat fosfatasa alcalina es mostrava com a un factor pronòstic independent de supervivència lliure d’esdeveniments, podent ésser inclosa en l’estratificació de risc actual de la malaltia. En el segon treball, mitjançant la utilització de la citòmica funcional, es va tractar de dissenyar i avaluar una nova metodologia per identificar les cèl·lules supressores d’origen mieloide amb expressió de PD-L1 en pacients amb mieloma múltiple, amb l’objectiu de predir l’èxit de la immunoteràpia amb inhibidors PD-L1. La clau de la metodologia desenvolupada va residir en la utilització de cèl·lules vives i en el propòsit de mimetitzar les condicions fisiològiques, per a tractar de comprendre els mecanismes de regulació del lligand. La combinació de la detecció immunofenotípica de PD-L1 amb l’estimulació cel·lular va revelar diferències en la reactivitat de la molècula en els 35 pacients estudiats. Les diferències observades van suggerir una gran plasticitat estèrica de la molècula que podria contribuir a explicar la gran heterogeneïtat en la resposta a la immunoteràpia. En conclusió, gràcies als treballs desenvolupats en la Tesi Doctoral s’han aportat noves evidències de la importància de la citòmica funcional en l’estudi de la neoplàsia, proporcionant abordatges complementaris a les tecnologies actuals en la comprensió de l’evolució de la malaltia.La leucemia aguda y el mieloma múltiple son neoplasias hematológicas con una incidencia notable en la población y una elevada mortalidad. Una de las principales causas de la mortalidad es la refractariedad al tratamiento y la recaída. A pesar de los grandes avances terapéuticos, la mayoría de pacientes experimenta recaídas o refractariedad, haciendo que estas enfermedades sean incurables. La citómica funcional es una disciplina que permite el análisis multiparamétrico de la heterogeneidad celular y de los citomas, relacionando la genómica y la proteómica con la dinámica y función celular. Esta tecnología podría ser clave para detectar células relacionadas con la refractariedad, permitiendo la manipulación mínima de los especímenes de estudio, así como la mimetización de las condiciones fisiológicas. Todo ello puede contribuir a detectar eficientemente dichas células y a desarrollar nuevas aproximaciones para el estudio de las implicaciones pronósticas y de la predicción de riesgo de recaída o enfermedad refractaria. \r\nEl objetivo de la Tesis Doctoral residió en desarrollar nuevos sistemas alternativos para estudiar e identificar poblaciones celulares refractarias, aplicando aproximaciones citómicas avanzadas que permitían realizar estudios a nivel fenotípico y funcional, con una perturbación mínima del espécimen. En el primer trabajo se desarrolló una tecnología basada en citómica funcional para determinar la actividad fosfatasa alcalina en subpoblaciones de células madre de la leucemia aguda evaluándose como método potencial para detectar subpoblaciones refractarias. En los pacientes diagnosticados de leucemia aguda refractaria, se determinaron poblaciones CD34+\/ALPhigh en distintos seguimientos que podrían estar asociadas con la leucemogénesis a lo largo del tiempo. Para explorar la significancia de la actividad fosfatasa alcalina celular en el momento del diagnóstico de leucemia mieloide aguda, se realizó un estudio prospectivo en 43 pacientes. Se demostró que la detección de la actividad fosfatasa alcalina se mostraba como un factor pronóstico independiente de supervivencia libre de eventos, pudiendo ser incluida en la estratificación de riesgo actual de la enfermedad. En segundo trabajo, mediante la utilización de la citómica funcional, se trató de dise\u00F1ar y evaluar una nueva metodología para identificar las células supresoras de origen mieloide con expresión de PD-L1 en pacientes con mieloma múltiple, con el objetivo predecir el éxito de la inmunoterapia con inhibidores de PD-L1. La clave de la metodología desarrollada residió en la utilización de células vivas y en el propósito de mimetizar las condiciones fisiológicas, para tratar de comprender los mecanismos de regulación del ligando. La combinación de la detección inmunofenotípica de PD-L1 con la estimulación celular reveló diferencias en la reactividad de la molécula en los 35 pacientes estudiados. Las diferencias observadas, sugirieron una gran plasticidad estérica de la molécula que podría contribuir a explicar la gran heterogeneidad en el grado de respuesta a la inmunoterapia. En conclusión, gracias a los trabajos desarrollados en la Tesis Doctoral se han aportado nuevas evidencias de la importancia de la citómica funcional en el estudio de la neoplasia hematológica, proporcionando abordajes complementarios a las tecnologías actuales en la comprensión de la evolución de la enfermedad.
Acute leukemia and multiple myeloma include a group of hematological malignances with a noticeable incidence among the population and causing a high mortality per year. The main causes of this high mortality rate are due to treatment refractoriness and disease relapse. Despite new therapeutic approaches, most patients eventually relapse or show treatment refractoriness and these diseases become still incurables. Functional cytomics is a discipline that allows a multiparametric analysis of the cellular heterogeneity and cytomes, and connects genomics and proteomics with cell dynamics and function. This technology can provide new insights for refractory cells detection due to samples can be minimally manipulated and physiological conditions can be maintained. These characteristics can contribute to a more efficient detection of these cells and to the development of new approaches for prognosis and for the study of relapse or refractoriness risk prediction. The aim and main purpose of the Doctoral Thesis was to develop novel alternative systems to study and to identify cell populations involved in treatment refractoriness in hematological malignances based on advanced cytomic approaches allowing functional and phenotypic studies with a minimal sample perturbation. The first study involved the development of a functional cytomics based technology for a prospective alkaline phosphatase activity determination in acute leukemia stem cells subpopulations and their evaluation as a potential method to detect cell populations associated with a higher treatment refractoriness. CD34+\/ALPhigh cell populations were detected at disease follow up in patients diagnosed with refractory acute leukemia. Our results suggested that CD34+\/ALPhigh cells appeared to sustain leukemogenesis over time. To explore cellular alkaline phosphatase activity significance in acute myeloid leukemia, we performed a prospective study including 43 newly diagnosed patients. Alkaline phosphatase determination at diagnosis appeared to be an independent event-free survival prognostic factor and could be included in current disease risk stratification models. In the second study, we designed and evaluated a novel functional cytomics based methodology to identify myeloid-derived suppressor cells expressing PD-L1 in multiple myeloma patients with the aim to predict immunotherapy targeting PD-1\/PD-L1 checkpoint success. The key point of this methodology was the use of living cells and the maintenance of the physiological conditions. PD-L1 immunophenotyping determination combined with cell stimulation revealed molecular reactivity differences among 35 multiple myeloma patients. Observed differences suggested a great molecular steric plasticity that may contribute to explain heterogeneous immunotherapeutic treatment responses. In conclusion, the studies here developed provide novel evidences about the importance of functional cytomics in the study of hematological malignances. Moreover, these methodologies, in addition to current approaches, may contribute to a better comprehension of disease evolution.
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Zacke, Laura [Verfasser], Roland [Akademischer Betreuer] Nau, Fred [Gutachter] Lühder, and Holger [Gutachter] Reichardt. "Beeinflussung des Verlaufs von Pneumokokken-Meningitis in Mäusen durch Stimulation mit einem Cytosin-Guanin-haltigen Oligonukleotid / Laura Zacke ; Gutachter: Fred Lühder, Holger Reichardt ; Betreuer: Roland Nau." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2020. http://d-nb.info/1204635978/34.
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Nilsson, Sofia. "En samlad bild över nutidens forskning angående immunmodulatoriska effekter av te." Thesis, Linnéuniversitetet, Institutionen för naturvetenskap, NV, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-20797.
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Teblad innehåller en mängd substanser som på olika sätt kan påverka biologiska processer i människan. I föreliggande arbete har en sammanställning gjorts utifrån vetenskapliga artiklar över teets antagna effekter på människans immunsystem .Främst har den mest studerade komponenten i te, epigallocatechin gallate, EGCG, undersökts. De variabler som studerats i immunförsvaret är neutrofiler, tumörnekrosfaktor-α, interferon-γ, interleukin-1β, interleukin-2, interleukin-5, interleukin-6, interleukin-8, interleukin-10 ,interleukin-12, interleukin-13, eikosanoidmetabolismen, lymfocyter, makrofager, dendritiskaceller och T-cellsdifferentiering. Sammafattningsvis föreföll te hämma följande: Neutrofilaktiviteten, TNF-α-bildningen, IFN-γ-aktiviteten, stimuli-inducerad IL-β-bildning, IL-8-aktivering och IL-10-bildning. EGCG visades öka dendritiska cellers apoptos och ändra dedenderitiska cellernas morfologi och minska deras förmüga att stimulera T-cellproliferationen. EGCG-behandling av celler ledde till ökad makrofagaktivitet, ökad produktion av T-regceller kontra andra T-cellslinjer. Tebehandling ökade bildningen av IL-12 ochIL-13. EGCGs effekt på IL-6 var tvetydig; enligt en del artiklar påverkade EGCG ej IL-6, medan det enligt andra artiklar antingen ökade eller minskade IL-6-bildningen. Trots att resultaten ej var entydiga kunde slutsatsen att EGCG (och därmed te) utövade immunsupprimerande effekt dras men att det sannolikt krävs betydligt högre koncentrationer än de som är fysiologiskt uppnåbara (1 μM i plasma och 3 mM i tarmen) genom reguljärt tedrickande för att få en avgörande effekt på människans immunsystem. EGCGs hämmnade effekt på immunsystemet kan dock vara av intresse i högre – farmakologiska – koncentrationer genom att EGCG skulle kunna nyttjas som komplement eller alternativ till för närvarande nyttjade immunförtryckande läkemedel som ciklosporin och glukokortikoider.
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Bosak, Viktoria, Kei Murata, Oliver Bludau, and Michael Brand. "Role of the immune response in initiating central nervous system regeneration in vertebrates." The International Journal of Developmental Biology, 2018. https://tud.qucosa.de/id/qucosa%3A31815.
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The mammalian central nervous system is not able to regenerate neurons lost upon injury. In contrast, anamniote vertebrates show a remarkable regenerative capacity and are able to replace damaged cells and restore function. Recent studies have shown that in naturally regenerating vertebrates, such as zebrafish, inflammation is a key processes required for the initiation of regeneration. These findings are in contrast to many studies in mammals, where the central nervous system has long been viewed as an immune-privileged organ with inflammation considered one of the key negative factors causing lack of neuronal regeneration. In this review, we discuss similarities and differences between naturally regenerating vertebrates, and those with very limited to non-existing regenerative capacity. We will introduce neural stem and progenitor cells in different species and explain how they differ in their reaction to acute injury of the central nervous system. Next, we illustrate how different organisms respond to injuries by activation of their immune system. Important immune cell types will be discussed in relation to their effects on neural stem cell behavior. Finally, we will give an overview on key inflammatory mediators secreted upon injury that have been linked to activation of neural stem cells and regeneration. Overall, understanding how species with regenerative potential couple inflammation and successful regeneration will help to identify potential targets to stimulate proliferation of neural stem cells and subsequent neurogenesis in mammals and may provide targets for therapeutic intervention strategies for neurodegenerative diseases.
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Reis, Corine Santos. "Genotoxic effects of silver nanoparticles on lung cells." Master's thesis, Universidade de Aveiro, 2013. http://hdl.handle.net/10773/13808.
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Mestrado em Biologia AplicadaSilver nanoparticles have increased importance due to their antimicrobial activity, being used in several applications such as in prosthesis, medical devices, food storing and cosmetics. Its increasing manufacturing will reflect in the environment, as for instance in the air, exposing the organism to its potential harmful effects. Altogether, the aim of this work was to evaluate the potential genotoxic effects of polyvinylpyrrolidone coated AgNPs. For that, a human alveolar adenocarcinoma cell line, A549, was exposed to increased concentrations of 0, 50 and 100 μg/mL PVP coated silver nanoparticles, of 10 and 20 nm, for 24h. Both the cytokinesis-block micronucleus cytome assay and the comet assay were used to evaluate the potential genotoxic effects of silver nanoparticles. To validate the cytokinesis-block micronucleus cytome assay, a human bone cell line, MG-63, was exposed to increased concentrations of 20 nm PVP coated silver nanoparticles. In A549 cell line, the comet assay revealed an increase in DNA damage, with increase concentration of silver nanoparticles of 10 nm. By other hand, for 20 nm AgNPs a significant increase in DNA damage was observed only for the lowest concentration (50 μg/mL). The cytokinesis-block micronucleus cytome assay showed a cytostatic effect of silver nanoparticles. In MG-63 cell line it was observed an increase in both micronucleus and nuclear buds for 50 μg/mL, indicating the presence of DNA damage. Altogether, the results suggest that PVP coated silver nanoparticles have the potential to induce DNA damage, dependent on the concentration and the size, and have a cytostatic effect on cells.
As nanopartículas de prata têm grande importância pelas suas propriedades antimicrobianas sendo cada vez mais usadas, por exemplo, no revestimento de próteses, em material médico, no revestimento de embalagens alimentares e em cosmética. A sua crescente manufacturação reflectir-se-á também na sua existência no meio ambiente, como por exemplo, no ar, expondo o organismo aos seus potenciais efeitos prejudiciais. Este trabalho teve como objectivo a avaliação dos possíveis efeitos genotóxicos de nanopartículas de prata revestidas com polivinilpirrolidona. Para isso, usou-se uma linha celular de epitélio pulmonar, A549, que foi exposta a concentrações crescentes de 0, 50 e 100 μg/mL de nanopartículas de prata revestidas com PVP, de 10 e 20 nm, durante 24h. O teste dos micronúcleos por bloqueio da citocinese e o ensaio de cometas foram usados para avaliar os potenciais efeitos genotóxicos das nanopartículas de prata. Para validação do teste dos micronúcleos por bloqueio da citocinese, uma linha celular de osso, MG-63, foi exposta a concentrações crescentes de nanopartículas de prata revestidas com PVP, de 20 nm. Na linha celular A549, o ensaio de cometas revelou um aumento do dano no DNA com o aumento da concentração de nanopartículas de 10 nm. Por outro lado, os resultados obtidos para as nanoparticulas de 20 nm mostraram um aumento significativo da degradação do DNA apenas para a concentração mais baixa (50 μg/mL). O teste dos micronúcleos mostrou um efeito citostático das nanopartículas de prata. Na linha celular MG-63 verificou-se um aumento de micronúcleos e protusões nucleares para a concentração de 50 ug/mL, indicando a presença de dano no DNA. Em conjunto, os resultados sugerem que as nanopartículas de prata revestidas com PVP têm potencial para provocar dano no DNA, dependente da sua concentração e do seu tamanho, e têm um efeito citostático nas células.
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Hillemann, Annett. "Verstärkung des bystander Effektes von Suizidgentherapeutika." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät II, 2005. http://dx.doi.org/10.18452/15450.
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Die vorliegende Arbeit beschäftigt sich mit einem neuartigen proteinbasierten, suizidgentherapeutischen Ansatz zur sicheren und effektiven Behandlung von soliden Tumoren. Verwendet wurden zellpermeable Fusionsproteine auf der Grundlage des bakteriellen Enzyms Cytosin Desaminase, welches spezifisch die Umsetzung der inaktive, nichttoxische Substanz (Prodroge) 5-Fluorcytosin in den hochwirksamen, stark toxischen Wirkstoff 5-Fluoruracil katalysiert. Dieser bewirkt die selektive Zerstörung von Tumorzellen. Durch die Fusion der bakteriellen Cytosin Desaminase (bCD) mit der Sequenz des Zellpermeabilität vermittelnden Peptides HBV-Translokationsmotiv (TLM) des Hepatits B-Virus (HBV) wurden zunächst zellpermeable E.coli Cytosin Desaminase Suizidfusionskonstrukte generiert. Für die bakteriell synthetisierten HBV-TLM-Fusionsproteine konnten eine Hexamerisierung sowie eine spezifische enzymatische Aktivität bei der Umsetzung von Cytosin zu Uracil als strukturelle und funktionelle Voraussetzungen für einen Einsatz in der Suizidgentherapie nachgewiesen werden, die vergleichbar mit dem wt-Protein waren. Bei Versuchen zur Internalisierung der zellpermeablen Fusionsproteine wurde für die Fusionsproteine mit C-terminal fusioniertem HBV-TLM (bCD-HBV-TLM) eine Aufnahme in das Zytoplasma von Hepatomzellen mittels konfokaler Laserscanmikroskopie und differentieller Zellfraktionierung nachgewiesen, nicht jedoch für Fusionsproteine mit N-terminalem HBV-TLM (HBV-TLM-bCD). Die gezeigte Internalisierung des Proteins HBV-TLM-bCD erfolgte effizient und schnell und war unabhängig vom endosomalen Aufnahmeweg. Bei der nachgewiesenen Translokalisation blieb die enzymatische, suizidgentherapeutische Aktivität des zellpermeablen Suizidproteins (HBV-TLM-bCD), d.h. die katalytische Wirkung bei der Umsetzung der Prodroge 5-Fluorcytosin vollständig erhalten, so dass sich dieses Fusionsprotein für einen therapeutischen Einsatz in der Suizidgentherapie eignet. Zusätzlich zur antitumoralen Wirkung können durch einen gezielten, lokal begrenzten therapeutischen Einsatz der vorgestellten zellpermeablen bCD-HBV-TLM-Fusionsproteine starke Nebenwirkungen, wie sie bei einer konventionellen Chemotherapie zu beobachten sind, weitgehend vermieden werden.This work investigates the application of protein based therapeutic suicide enzyme/prodrug approaches providing novel means for both safe and effective local therapeutic regimes in solid tumors. The concept of the used suicide gene therapy system is based mainly on the transfer of the cell permeable bacterial suicide enzyme cytosine deaminase which specifically convert the inactive, non-toxic prodrug 5-fluorocytosine into the toxic metabolite 5-fluorouracil finally executing the efficient destruction of tumor cells. Employing a novel cell permeable peptide, known as the translocation motif (TLM) of hepatitis B virus (HBV), E.coli cytosine deaminase (bCD) suicide fusion proteins were generated. HBV-TLM fusion proteins formed hexamers (as do parental wt bCD) and retained the specific enzymatic activity of cytosine conversion to uracil also being comparable to parental wtbCD protein. However, only bCD-HBV-TLM fusion proteins, but not HBV-TLM-bCD fusion proteins were found to be taken up to the cytoplasm of target hepatoma cells as demonstrated both by confocal laser scanning microscopy and cell fractionation. Uptake of bCD-HBV-TLM worked both efficiently and rapidly and was found to be independent from the endosomal pathway. Since bCD-HBV-TLM fusion proteins completely retained their suicide enzymatic activity in the course of translocation across the plasma membrane their usage as profound inducers of chemo-sensitivity to 5-fluorocytosine strongly is suggested. Future therapeutic local application of cell permeable bCD-HBV-TLM fusion proteins together with a systemic 5-fluorocytosine prodrug application could result in profound antitumor activities without apparent side effects.
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Jaša, Petr. "Techniky pro získávání dat v genomice." Master's thesis, Vysoké učení technické v Brně. Fakulta informačních technologií, 2007. http://www.nusl.cz/ntk/nusl-412789.
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First of all, this thesis sets itself a goal to introduce some common technics for datamining in genomics and as a next step to implement own algorithm like algorithm BLAST. In the concrete, this work is pointed to sequences of DNA. The DNA sequence contains in itself genetic information, which is template for living organism. For explanation this information can be used number of technics. This paper describes algorithm Fasta and algorithms from BLAST family. With these algorithms, it is possible to gain a lot of important information even about such DNA sequences, where only primary structure is known. Principle of these algorithms is based on alignments of one query sequence, which we want to obtain some information from, with many sequences stored in database. According to result alignment, it is possible to determine many features of the query sequence.
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Becker, Heiko [Verfasser], Irmgard [Gutachter] Schwarte-Waldhoff, and Rolf [Gutachter] Heumann. "Wie verändert der SMAD4-Verlust die Interaktionen zwischen Tumorzellen sowie Matrix und Stroma an der invasiven Front? : Einblicke in mögliche Mechanismen durch umfassende Untersuchungen des Transkriptoms Cytokin-behandelter humaner kolorektaler Tumorzelllinien / Heiko Becker ; Gutachter: Irmgard Schwarte-Waldhoff, Rolf Heumann ; Fakultät für Chemie und Biochemie." Bochum : Ruhr-Universität Bochum, 2013. http://d-nb.info/1148749233/34.
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Boumhras, Mohamed. "Evaluation de la toxicité de moules de 2 sites de la Côte Atlantique Marocaine (Jorf Lasfar et Oualidia) utilisées comme bioindicateurs de contamination : étude in vivo et in vitro sur des rats et des cellules β-pancréatiques murines (MIN-6)." Thesis, Dijon, 2012. http://www.theses.fr/2012DIJOS118/document.
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Des substances toxiques générées par les activités portuaires, urbaines et industrielles sont déversées à certains niveaux du milieu marin côtier marocain. Les mollusques peuvent concentrer les polluants et avoir des effets néfastes sur la santé humaine par l’intermédiaire de la chaîne alimentaire. Malgré le renforcement des mesures de sécurité alimentaire, l’implication de la pollution chimique des aliments dans les troubles métaboliques n’est pas à exclure. Pour prédire l’impact des polluants sur l’écosystème aquatique et sur la santé humaine, le développement d’outils de biosurveillance est nécessaire.Nous avons quantifié les métaux lourds (Cd, Cr et Pb) chez les moules (Mytilus galloprovincialis) issues de la côte atlantique marocaine (site industriel Jorf Lasfar (JL) et site touristique d’Oualidia (OL)) en raison de la proximité d’une plateforme d’extraction de phosphate puis caractérisé leurs profils lipidiques (acides gras, cholestérol, oxystérols, phytostérols et phospholipides). Les extraits lipidiques totaux de moules ont été testés in vivo sur des rats pour déterminer leurs effets sur les paramètres biochimiques plasmatiques et in vitro sur une lignée de cellules β pancréatiques murine (MIN-6) en conditions normo et hyperglycémique. Les effets des extraits de moules JL et OL ont été comparés par rapport à ceux de moules d’origine espagnole (ES) destinées à la consommation en France.Les métaux lourds dans les moules JL dépassent les normes internationales. Les concentrations métalliques dans tous les extraits lipidiques sont à l’état de trace. Les moules JL et OL sont moins riches en acides gras insaturés, plus riches en oxystérols et en phospholipides par rapport aux moules ES, suggérant un stress environnemental. Les extraits lipidiques des moules JL et OL administrés à des rats, ont provoqué une perturbation des paramètres plasmatiques, notamment des taux de glucose, créatinine, triglycérides et transaminases avec une augmentation de cholestérol-HDL. In vitro seuls les extraits lipidiques JL et OL induisent la mort des cellules MIN-6 par un processus non apoptotique. Ce processus est associé à une dépolarisation mitochondriale, une déstabilisation lysosomale et une augmentation de la perméabilité de la membrane cytoplasmique, paramètres mesurés par cytométrie en flux dans une démarche cytomique. Ils provoquent aussi une surproduction de H2O2, une augmentation d’activité catalase, une diminution du glutathion réduit, une peroxydation lipidique et une forte stimulation de la sécrétion d’insuline avec un effet plus marqués en présence des extraits lipidiques JL.Globalement, les lipides de moules JL induisent des effets néfastes in vivo et in vitro par rapport à ceux provenant de OL et ES. Une étude épidémiologique à large échelle dans le contexte des maladies métaboliques pourrait être pertinente chez les populations consommatrices de ces moulesToxic substances generated by various human activities are spilled on different area of the Moroccan coast. Shellfishes can concentrate pollutants and have some adverse effects on human health through the food chain. Despite the strengthening of food safety rules, the involvement of chemical pollution of food on metabolic disorders is not known. To predict the impact of pollutants on the aquatic ecosystem and human health, the development of appropriate biomonitoring tools is required.We quantified heavy metals (Cd, Cr and Pb) in mussels (Mytilus galloprovincialis) from two sites of Moroccan Atlantic coast (industrial site Jorf Lasfar (JL) and touristic site Oualidia (OL)) due to the proximity of a phosphate extraction platform, and further characterized their lipid profiles (fatty acids, cholesterol, oxysterols, phospholipids and phytosterols). Total lipid extracts of mussels were tested in vivo in rats to determine their effects on biochemical plasmatic parameters and in vitro on a β pancreatic murine cell line (MIN-6) in normo-and hyperglycemic conditions. The effects of JL and OL mussel extracts were compared to mussels from Spain (ES) used for human consumption in France. Heavy metals in JL mussels exceed international standard level. Metal concentrations in all lipid extracts are present in small quantity. JL and OL mussels are less enriched in unsaturated fatty acids, oxysterols and contain higher levels of phospholipids than ES mussels, suggesting an environmental stress. The lipid extracts of JL and OL mussels administered to rats induce a disruption of plasmatic parameters (glucose, creatinine, transaminases and triglycerides) with an increase of HDL-cholesterol. In vitro, only JL and OL lipid extracts induce MIN-6 cell death by a non-apoptotic process. This process is associated with mitochondrial depolarization, lysosomal destabilization and an increase of the cytoplasmic membrane permeability, parameters measured by flow cytométrie in a cytomic context. They also induce an overproduction of H2O2, an increase of catalase activity, a decrease of reduced glutathion, lipid peroxidation and a strong stimulation of insulin secretion with a more marked effect in presence of JL lipid extracts.Overall, JL mussel lipids induce various side effects in vivo and in vitro, which are more pronounced that those observed with OL and ES. A large-scale epidemiological study could be of interest to confirm the potential side effects of these mussels to favor metabolic disorders
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Ristow, Gerhard. "Immunophänotypisierung des entzündlichen Infiltrates der Arthrose assoziierten Synovialitis." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2003. http://dx.doi.org/10.18452/14856.
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Die Entzündungsreaktion der Arthrose wird als eine sekundäre Reaktion auf einen degenerativen Prozeß des Gelenkknorpels angesehen. Die Ursache für die Degeneration kann im Mißverhältnis zwischen Belastbarkeit und Beanspruchung liegen, es können metabolische Störungen (Urämie, Diabetes mellitus) verantwortlich gemacht werden, weswegen von sekundärer Arthrose gesprochen wird. Die Ursache der primären Arthrose bleibt unbekannt. Es kann als bewiesen angesehen werden der Zusammenhang mit Alter und Geschlecht der Patienten, denn Arthrose ist in der Regel eine Erkrankung jenseits des fünfzigsten Lebensjahres und betrifft vornehmlich Frauen. In der vorliegenden Arbeit wurde die Synovialis von 20 Patienten aufgearbeitet und hinsichtlich des enthaltenen entzündlichen Infiltrates untersucht. Unter Anwendung der indirekten Immunperoxidase Technik und der indirekten Immunfluoreszenz Technik wurde die Expression der Antigene CD 20, CD 23, CD 40, CD 27, IgG, IgA, IgM, Kappa, Lambda, CD 3, CD 4, CD 8, Ki M4, CD 68, Ki 67 sowie die Expression der Cytokine IL 2 und IL 10 analysiert. Die Synovialmembran zeigte histologisch eine Verbreiterung der Deckzellschicht, Knorpelfragmente innerhalb der Synovialmembran und ein insgesamt schwach ausgeprägtes entzündliches Infiltrat. In lediglich drei von 20 Fällen fand sich eine stärkere entzündliche Infiltration. Diese entzündlichen Infiltrate wiesen eine perivaskuläre Verteilung auf. Am häufigsten wurden in gefäßnahen Regionen B Lymphozyten identifiziert, Plasmazellen wiesen in der Regel einen deutlich größeren Abstand zum Gefäß auf. Unter den nachgewiesenen Plasmazellen fand sich eine prädominante Expression an IgG bei ausgewogener Anwesenheit sowohl der Kappa- als auch der Lambda- Leichtketten. T Lymphozyten waren ebenfalls zirkulär um die Gefäße anzutreffen und zeigten eine prädominante Interleukin 10 Expression. Lymphozytäre Aggregate, mit follikelähnlicher Struktur ließen sich in lediglich in 4 von 20 Fällen nachweisen. Makrophagen waren sowohl perivaskulär als auch in der Deckzellschicht nachweisbar. Ki M4 positive Retikulumzellen (FDC) waren dagegen nur in einem von 20 Fällen nachweisbar. Alle Zellpopulationen der Membrana synovialis wiesen nur eine schwache Proliferationsaktivität auf. Das Fehlen von dem Keimzentrum des Lymphfollikels vergleichbaren Strukturen, die deutliche Abwesenheit von Ki M4 positiver FDC's sowie die schwache Expression von Ki 67, sprechen trotz Anwesenheit der ebenfalls zur Antigenpräsentation befähigten Makrophagen gegen eine Einwanderung und Maturation nativer B Lymphozyten in die Membrana Synovialis. Wandern dagegen Gedächtniszellen in die Membrana synovialis ein, so ist eine Maturation mit Follikelbildung nicht mehr notwendig. Unter der Mithilfe von T Lymphozyten und Makrophagen können die B Lymphozyten zu Plasmazellen differenzieren. T Lymphozyten zeichnen sich ebenfalls durch eine starke perivaskuläre Verteilung aus. Dabei ist die Expression von IL 10 prädominant, was sich als eine Immunantwort von TH2-Typus interpretieren läßt. Diese ermöglicht eine Differenzierung der B Lymphozyten zu Plasmazellen. Reife B Lymphozyten, die unter dem Einfluß einer TH2 Subpopulation von CD 4 positiven T Lymphozyten ohne Keimzentrum zu Plasmazellen differenzieren, könnten ein Grund dafür sein, daß follikuläre Strukturen fehlen. Vorgereifte B Lymphozyten benötigen auch keine inflammatorisch hochpotenten Zytokine um eine schnelle Reifung und eine Immunantwort zu ermöglichen. Dies könnte ein Grund sein, warum die entzündliche Reaktion bei Arthrose so schwach ausgeprägt ist.Inflammation in osteoarthritis is a secondary reaction to a degenerating process of the articular cartilage. Cause of Degeneration can be a disproportion of mechanical stress and resistance or metabolic diseases like diabetes mellitus. This kind of osteoarthritis is called "secondary osteoarthritis". Primary osteoarthritis has an unknown cause. Age and sex of the patient are a predictor for osteoarthritis, hense it is a disease of people above the age of 50 and more often it is found in women than in men. This paper investigated the synovial membranes of twenty patients to characterize the inflammatory Infiltrate. It characterized the cell surface antigen CD 20, CD 23, CD 40, CD 27, CD 3, CD 4, CD 8, Ki M4, CD 68, the antibodies IgG, IgA, IgM, Kappa, Lambda, the proliferating antigen Ki 67 and the expression profile of the cytokines IL 2 and IL 10 by using immunohistochemical staining (indirect immunoperoxidase technique and indirect immunofluorescence technique) with monoclonal antibodies. The synovial membrane shows in histology a dissemination of cover cells, fragments of cartilage and a slight expression of inflammatory infiltrate with a perivascular allocation. In only three of twenty cases we detected stronger inflammatory infiltrates. Most of the perivascular cells express CD 20. They are B lymphocytes. Plasma cells have more distance to the blood vessels and showed a predominant expression of IgG. T-lymphocytes were also detected perivascular. The expression of IL 10 was predominant. Lymphocytes aggregates like lymph follicle were detected in four of twenty cases. Macrophages were proved perivascular as well as in the cover cells. Ki M4 positive reticulum cells were found in only one of twenty cases. All kind of cells in the synovial membrane showed a low proliferation activity. The absence of germinal centers or comparable structures, the low expression of Ki M4 and Ki 67 speak against the immigration and maturation of native B lymphocytes in the synovial membrane. Memory B-lymphocytes don't need germinal centers or compatible structures for maturation, they can mature to plasma cells by help of T-lymphocytes, macrophages or other B-lymphocytes. It is more probably that the detected B lymphocytes are memory cells. The perivascular T lymphocytes in combination with the predominant expression of IL 10 may be interpreted as a TH2 immune reaction. This supports the maturation of B-lymphocytes to plasma cells. The maturation of memory B-lymphocytes under influence of TH2 immune reaction can be the reason for the missing of germinal centers or comparable structures. Matured B-lymphocytes don't need high-grade inflammatory cytokines for quick immune response. This is the possible reason for the low-grade inflammatory reaction of osteoarthritis.
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Hulíková, Jana. "Vliv bakteriálních komponent na produkci cytokinů leukocyty mléčné žlázy skotu." Master's thesis, 2013. http://www.nusl.cz/ntk/nusl-169478.
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O'Connor, David Hayden. "Simian immunodeficiency virus escape from cytoxic T-lymphocyte responses." 2001. http://www.library.wisc.edu/databases/connect/dissertations.html.
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Mikulecký, Pavel. "Zvýšení afinity receptoru 1 pro interferon gama k interferonu gama kombinací molekulárního modelování a experimentálních metod." Doctoral thesis, 2015. http://www.nusl.cz/ntk/nusl-350092.
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Protein-protein interactions play an important role in nearly all processes of the living cells and the function of many proteins is dependent on their specific interactions with other biomolecules. A reliable tool to modulate these interactions would be invaluable for the development of molecules suitable for diagnostics, medicine, and biotechnology. In this work, we aimed to study the specificity of interactions in the model system of Interferon gamma receptor 1 (IFNgR1) and its natural ligand Interferon gamma (IFNg), important in innate immunity. We searched for mutations within the interferon receptor molecule IFNgR1 to modulate (increase as well as decrease) its affinity to IFNg by in silico analysis of the existing crystal structures of the complex between IFNgR1 and IFNg. We modeled amino acid substitutions and gauged how they influenced the interaction using empirical force field implemented in software FoldX. All selected promising IFNgR1 variants were expressed in Escherichia coli, purified to homogeneity, characterized, and kinetics of their interactions with IFNg was measured by Surface Plasmon Resonance (SPR). The first set of IFNgR1 variants included mutations on the interface of the IFNg/IFNgR1 complex. According to our SPR measurements, the affinity of most of these receptor...
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Malicki, Stanisław. "Różnicowe zmiany niektórych cytokin i enzymów odczynu zapalnego w nowotworze jelita grubego." Praca doktorska, 2010. http://ruj.uj.edu.pl/xmlui/handle/item/41452.
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Thomas, Philip. "Changes in buccal cytome biomarkers in relation to ageing and Alzheimer’s Disease." 2008. http://hdl.handle.net/2440/56186.
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The aim of this thesis was to investigate the possibility of using buccal cells derived from a multi layered epithelial tissue from the oral mucosa as a model to identify potential biomarkers of genomic instability in relation to normal ageing and premature ageing syndromes such as AD and DS. A buccal micronucleus cytome assay was developed and used to investigate biomarkers for DNA damage, cell proliferation and cell death in healthy young, healthy old and young Down’s syndrome cohorts. Cells with micronuclei, karyorrhectic cells, condensed chromatin cells and basal cells increased significantly with normal ageing (P<0.0001). Cells with micronuclei and binucleated cells increased (P<0.0001) and condensed chromatin, karyorrhectic, karyolytic and pyknotic cells decreased (P<0.002) significantly in Down’s syndrome relative to young controls. The buccal micronucleus cytome assay was used to measure ratios of buccal cell populations and micronuclei in clinically diagnosed Alzheimer’s patients compared to age and gender matched controls. Frequencies of basal cells (P<0.0001), condensed chromatin cells (P<0.0001) and karyorrhectic cells (P<0.0001) were found to be significantly lower in Alzheimer’s patients, possibly reflecting changes in the cellular kinetics or structural profile of the buccal mucosa. Changes in telomere length were investigated using a quantitative RTm-PCR method to measure absolute telomere length (in Kb per diploid genome) and show agerelated changes in white blood cells and buccal cell telomere length (in kb per diploid genome) in normal healthy individuals and Alzheimer’s patients. We observed a significantly lower telomere length in white blood cells (P<0.0001) and buccal cells (P<0.01) in Alzheimer’s patients relative to healthy age-matched controls (31.4% and 32.3% respectively). However, there was a significantly greater telomere length in hippocampus cells of Alzheimer’s brains (P=0.01) compared to control samples (49.0). Buccal cells were also used to investigate chromosome 17 and 21 aneuploidy. A 1.5 fold increase in trisomy 21 (P<0.001) and a 1.2 fold increase in trisomy 17 (P<0.001) was observed in buccal cells of Alzheimer’s patients compared to age and gender matched controls. Chromosome 17 and chromosome 21 monosomy and trisomy increase significantly with age (P<0.001). Down’s syndrome, which exhibits similar neuropathological features to those observed in Alzheimer’s disease also showed a strong increase in chromosome 17 monosomy and trisomy compared to matched controls (P<0.001). However, aneuploidy rate for chromosome 17 and 21 in the nuclei of hippocampus cells of brains from Alzheimer’s patients and controls were not significantly different. Observations that AD individuals have altered plasma folate, B12 and Hcy levels compared to age-matched controls who have not been clinically diagnosed with AD were investigated. Genotyping studies were undertaken to determine whether polymorphisms within particular genes of the folate methionine pathway contributed to AD pathogenesis. Correlations between folate, B12 and Hcy status with previously determined buccal micronucleus assay cytome biomarkers for DNA damage, cell proliferation and cell death markers was investigated. Lastly, the potential protective effects of phytonutrient polyphenols on genomic instability events in a transgenic mouse model for AD were investigated. We determined the effects of curcumin and GSE polyphenols on DNA damage by testing the mice over a 9 month period utilizing a buccal micronucleus cytome assay, an erythrocyte micronucleus assay and measuring telomere length in both buccal cells and olfactory lobe brain tissue.http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1313395
Thesis (Ph.D.) -- The University of Adelaide, School of Molecular and Biomedical Science, 2008
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Thomas, Philip. "Changes in buccal cytome biomarkers in relation to ageing and Alzheimer’s Disease." Thesis, 2008. http://hdl.handle.net/2440/56186.
Full textAbstract:
The aim of this thesis was to investigate the possibility of using buccal cells derived from a multi layered epithelial tissue from the oral mucosa as a model to identify potential biomarkers of genomic instability in relation to normal ageing and premature ageing syndromes such as AD and DS. A buccal micronucleus cytome assay was developed and used to investigate biomarkers for DNA damage, cell proliferation and cell death in healthy young, healthy old and young Down’s syndrome cohorts. Cells with micronuclei, karyorrhectic cells, condensed chromatin cells and basal cells increased significantly with normal ageing (P<0.0001). Cells with micronuclei and binucleated cells increased (P<0.0001) and condensed chromatin, karyorrhectic, karyolytic and pyknotic cells decreased (P<0.002) significantly in Down’s syndrome relative to young controls.
The buccal micronucleus cytome assay was used to measure ratios of buccal cell populations and micronuclei in clinically diagnosed Alzheimer’s patients compared to age and gender matched controls. Frequencies of basal cells (P<0.0001), condensed chromatin cells (P<0.0001) and karyorrhectic cells (P<0.0001) were found to be significantly lower in Alzheimer’s patients, possibly reflecting changes in the cellular kinetics or structural profile of the buccal mucosa.
Changes in telomere length were investigated using a quantitative RTm-PCR method to measure absolute telomere length (in Kb per diploid genome) and show agerelated changes in white blood cells and buccal cell telomere length (in kb per diploid genome) in normal healthy individuals and Alzheimer’s patients. We observed a significantly lower telomere length in white blood cells (P<0.0001) and buccal cells (P<0.01) in Alzheimer’s patients relative to healthy age-matched controls (31.4% and 32.3% respectively). However, there was a significantly greater telomere length in hippocampus cells of Alzheimer’s brains (P=0.01) compared to control samples (49.0).
Buccal cells were also used to investigate chromosome 17 and 21 aneuploidy. A 1.5 fold increase in trisomy 21 (P<0.001) and a 1.2 fold increase in trisomy 17 (P<0.001) was observed in buccal cells of Alzheimer’s patients compared to age and gender matched controls. Chromosome 17 and chromosome 21 monosomy and trisomy
increase significantly with age (P<0.001). Down’s syndrome, which exhibits similar neuropathological features to those observed in Alzheimer’s disease also showed a strong increase in chromosome 17 monosomy and trisomy compared to matched controls (P<0.001). However, aneuploidy rate for chromosome 17 and 21 in the nuclei of hippocampus cells of brains from Alzheimer’s patients and controls were not significantly different.
Observations that AD individuals have altered plasma folate, B12 and Hcy levels compared to age-matched controls who have not been clinically diagnosed with AD were investigated. Genotyping studies were undertaken to determine whether polymorphisms within particular genes of the folate methionine pathway contributed to AD pathogenesis. Correlations between folate, B12 and Hcy status with previously determined buccal micronucleus assay cytome biomarkers for DNA damage, cell proliferation and cell death markers was investigated.
Lastly, the potential protective effects of phytonutrient polyphenols on genomic instability events in a transgenic mouse model for AD were investigated. We determined the effects of curcumin and GSE polyphenols on DNA damage by testing the mice over a 9 month period utilizing a buccal micronucleus cytome assay, an erythrocyte micronucleus assay and measuring telomere length in both buccal cells and olfactory lobe brain tissue.Thesis (Ph.D.) -- The University of Adelaide, School of Molecular and Biomedical Science, 2008
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Haug, Andrea [Verfasser]. "Oberflächenanalytische Untersuchungen von dünnen Cytosin, Thymin-, Uracil- und Hydrogen-Silsesquioxan-Filmen / vorgelegt von Andrea Haug." 2009. http://d-nb.info/999514555/34.
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Bieńkowska, Anna. "Rola sygnałów aktywacyjnych i cytokin w powstawaniu in vitro pochodzących z grasicy limfocytów T regulatorowych." Doctoral thesis, 2019. https://depotuw.ceon.pl/handle/item/3415.
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Pochodzące z grasicy limfocyty T regulatorowe (tTreg, ang. thymus-derived regulatory T cells) o fenotypie CD4+CD25+Foxp3+ odgrywają ważną rolę w utrzymaniu tolerancji immunologicznej. Różnorodne czynniki zaangażowane w ich powstawanie i funkcje biologiczne są ciągle przedmiotem badań, które są szczególnie trudne ze względu na niewielką liczbę tych komórek w organizmie oraz ich dużą wrażliwość na indukcję apoptozy in vitro.
Celem niniejszej pracy było opracowanie optymalnych warunków hodowli in vitro, umożliwiających badanie rozwoju limfocytów tTreg oraz możliwych mechanizmów ich powstawania z niesortowanych tymocytów, ze szczególnym uwzględnieniem roli sygnałów aktywacyjnych i cytokin.
Wykazano, że metody używane standardowo do uzyskiwania limfocytów T regulatorowych w drodze indukcji z aktywowanych naiwnych limfocytów T izolowanych z obwodowych narządów limfoidalnych są nieprzydatne w badaniu rozwoju limfocytów Treg powstających w grasicy. W pracy przedstawiono opracowany nowy model hodowli tymocytów oparty o powszechnie uznawany dwuetapowy szlak rozwoju limfocytów tTreg. W pierwszym etapie powstawanie limfocytów tTreg zależne jest od silnego sygnału aktywacji z udziałem receptora limfocytów T (TCR) i sygnału kostymulacyjnego od cząsteczki CD28, a w drugim etapie - od cytokin. W grasicy, sygnał do TCR dostarczany jest przez kompleks MHC II/ własny peptyd korowych komórek nabłonkowych grasicy, który w opracowanym modelu zastąpiony został przez użycie przeciwciał monoklonalnych anty-CD3. Jako źródło sygnału dostarczanego do CD28 wykorzystano cząsteczki kostymulatorowe ulegające ekspresji na komórkach prezentujących antygen, w roli których użyto niedojrzałe komórki dendrytyczne linii JAWS II. Nowy model hodowli tymocytów in vitro umożliwił skuteczne uzyskiwanie funkcjonalnych limfocytów tTreg w hodowli niesortowanych tymocytów. Wykazano, że efektywne uzyskiwanie limfocytów tTreg z niesortowanych tymocytów występujących fizjologicznie w grasicy wymaga obecności komórek prezentujących antygen oraz silnego sygnału aktywacji z udziałem kompleksu TCR/CD3. Obecność komórek dendrytycznych sprzyja powstawaniu tymocytów SP CD4+ oraz zapewnia dużą żywotność tymocytów w hodowli wskutek endocytozy komórek apoptotycznych. Dostarczenie tymocytom silnego sygnału aktywacji z udziałem kompleksu TCR/CD3 sprzyja ich ukierunkowanemu rozwojowi in vitro w limfocyty tTreg.
Zbadano rolę wybranych cytokin w generowaniu limfocytów Treg in vitro. Wykazano, iż w rozwoju limfocytów tTreg w opracowanym modelu hodowli ważną rolę odgrywają nie pojedyncze cytokiny, lecz ich określony zestaw, którego zastosowanie w hodowli tymocytów wpływa na efektywność uzyskiwania dojrzałych limfocytów tTreg. Dużą skuteczność w powstawaniu limfocytów tTreg in vitro wykazały IL-7 i TGF-β. Stworzone warunki umożliwiły powstawanie limfocytów tTreg zarówno z komórek prekursorowych, jak również w drodze indukcji w mikrośrodowisku cytokinowym. Uzyskane in vitro limfocyty tTreg zachowały aktywność supresyjną, a mechanizm ich działania nie był zależny od wydzielanych cytokin supresorowych: IL-10 i TGF-β.
Opracowany model hodowli wykorzystano w badaniach wpływu glukokortykoidów na rozwój limfocytów tTreg in vitro. Potwierdzono rolę glukokortykoidów jako czynnika selekcyjnego w rozwoju limfocytów tTreg wskutek bezpośredniego działania na tymocyty (zróżnicowana wrażliwość tymocytów na indukcję apoptozy) oraz pośredniego na komórki prezentujące antygen (modulowanie ekspresji cząsteczek kostymulatorowych).
Potwierdzono użyteczność opracowanego modelu hodowli do generowania in vitro limfocytów tTreg myszy starych.
W oparciu o udowodnioną użyteczność opracowanego modelu hodowli zasugerowano jego potencjalną przydatność do badania roli różnych czynników w powstawaniu i funkcji limfocytów tTreg, będących aktualnie obiektem intensywnego zainteresowania w kontekście wdrażanych nowych terapii opartych o limfocyty Treg.Thymus-derived regulatory T cells (tTregs) of CD4+CD25+Foxp3+ phenotype play an important role in maintaining immune tolerance. Distinct factors involved in their generation and biological functions are still the subject of research. Due to the small number of these cells in the body and their high sensitivity to the induction of apoptosis in vitro, research on factors affecting their development is highly difficult. The aim of this study was to develop optimal conditions for in vitro culture, to enable the study on tTreg development from unsorted thymocytes, with particular attention on the role of activation signals and cytokines in the generation of these cells. The methods used as standard for obtaining regulatory T cells by induction from activated naive T cells isolated from peripheral lymphoid organs are not useful in studying the development of thymus-derived Tregs. Within the study the new in vitro culture model has been developed based on the widely recognized two-stage tTreg development pathway. The first step of tTreg development is dependent on a strong signal provided by T cell receptor (TCR) and a co-stimulatory signal by CD28 molecule, the second stage is dependent on cytokines. In the thymus, the signal for TCR is delivered by MHC II/self-peptide complexes of cortical thymic epithelial cells, which has been replaced in presented model by the use of anti-CD3 monoclonal antibodies. As the source for the CD28 signal, costimulatory molecules of JAWS II immature dendritic cells have been used. The new culture model allowed the generation of functional tTregs from unsorted thymocytes. It has been confirmed that efficient generation of tTregs in vitro from unsorted thymocytes occurring physiologically in the thymus requires antigen presenting cell-thymocyte contact and strong signal to the TCR/CD3 complex. Dendritic cells contact promotes generation of SP CD4+ and provides high viability of thymocytes in culture due to endocytosis of apoptotic cells by JAWS II cells. Strong signal to the TCR/CD3 complex provides lineage commitment of precursors cells into tTregs in vitro. The role of selected cytokines in the generation of Tregs in vitro was examined. It has been shown that during tTreg development, not only single cytokines play an important role, but their set, which supplementation in vitro affects the efficiency of tTreg generation. IL-7 and TGF-β have been shown to be highly effective in the development of tTregs in vitro. Created conditions enabled the generation of tTreg cells from both precursor cells as well as by induction under cytokine microenvironment. The suppressive activity of generated in vitro tTregs has been maintained, while the mechanism of their action was not dependent on secreted suppressor cytokines: IL-10 and TGF-β. The new model has been utilized to conduct studies on the effect of glucocorticoids on the development of tTregs. The role of glucocorticoids as selective factor in tTreg development has been confirmed acting directly on thymocytes (by differentiated sensitivity of thymocytes to glucocorticoids-induced apoptosis) and indirectly on antigen presenting cells (by modulating the expression of costimulatory molecules on their surface). The utility of the developed model for in vitro generation of tTregs of old mice was confirmed. Based on the proven utility of the developed culture model, it has been suggested as a potential research tool for the studies on the role of distinct factors in generation and function of tTreg, including pilot studies for new therapies based on Treg to be developed nowadays.
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Wiacek, Claudia [Verfasser]. "Cytomics: Strategien von Cupriavidus necator JMP134 beim Umgang mit dem toxischen Substrat Phenol / von Claudia Wiacek." 2007. http://d-nb.info/990044459/34.
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Zacke, Laura. "Beeinflussung des Verlaufs von Pneumokokken-Meningitis in Mäusen durch Stimulation mit einem Cytosin-Guanin-haltigen Oligonukleotid." Doctoral thesis, 2020. http://hdl.handle.net/21.11130/00-1735-0000-0005-12FD-A.
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Lödige, Inga [Verfasser]. "Untersuchungen zur Rolle des Kernexportes des Transkriptionsfaktors STAT1 in der Cytokin-abhängigen Geninduktion / vorgelegt von Inga Lödige." 2006. http://d-nb.info/981926789/34.
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Feldhaus, Beatrix [Verfasser]. "Periventrikuläre Leukomalazie : Untersuchung Cytokin-induzierter Schädigungen von Oligodendrocyten-Vorläuferzellen und Protektion durch Corticoide / vorgelegt von Beatrix Feldhaus." 2003. http://d-nb.info/968797806/34.
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Fritsch, Anja. "Analyse der Cytokin-vermittelten Wachstumsregulation in Homöostase und Wundheilung der Haut : Interleukin-18 in der dermal-epidermalen Kommunikation /." 2004. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=013118563&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Ng, Billy Yu-Chung. "Optimization of physical parameters for attachment and growth of Vero cells on Cytodex 1 and Cultispher G microcarriers." 1995. http://hdl.handle.net/1993/18972.
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Sezer, Ömer [Verfasser]. "Der Einfluß von Doxycyclin auf die Cytokin- und Lipidmediatorsynthese sowie die Proliferation humaner Leukozyten / vorgelegt von Ömer Sezer." 2003. http://d-nb.info/971468885/34.
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Janatová, Kateřina. "Význam prolaktinu jako periferního cytokinu u dysbalance imunitního systému." Master's thesis, 2010. http://www.nusl.cz/ntk/nusl-296605.
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Background: Interactions between the neuroendocrine and immune system play an importatnt role in maintaining homeostasis. This communication is mediated by cytokines, neurotransmiters and hormones through endocrine, paracrine and autocrine signaling. Prolactin (PRL), hormone of anterior pituitary, is produced by a number of other tissues and cells of immune system. On periphery, PRL is cytokine. Sepsis is an inflamatory response of the organism to severe infection, Th1 immune response is activated and PRL could participate in it. Toll-like receptors (TLR) play a key role in a recognition of bacteial components and mediate a systemic response (with PRL secretion) during infection. It is supposed that activated immune system leads to increasing of PRL, TLR2 and TLR4 gene expression. We detected PRL, TLR2 a TLR4 mRNA levels in monocytes from patiens with system inflammation. We studied influence of single nucleotide polymorphism (SNP -1149 G/T) in PRL gene promotor, it supposed that G allele increases PRL expression. Materials and Methods: For the pilot study 30 patients diagnose with severe infectious event. Collectoin of patiens blood samples was performed consequently three times. Control group comprised 40 healthy individuals. One blood sample was taken from each healthy subject. For testing of...
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Hillemann, Annett [Verfasser]. "Verstärkung des bystander Effektes von Suizidgentherapeutika : molekularbiologische Charakterisierung von zellpermeablen HBV-TLM-Cytosin Desaminase Fusionsproteinen / Annett Hillemann, geb. Wetterney." 2005. http://d-nb.info/979752841/34.
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Herckelrath, Tanja [Verfasser]. "Genexpressionsmuster nach Behandlung von Hepatomzellen mit dem Cytokin TGF-β [TGF-Beta] bzw. mit Tumorpromotoren / vorgelegt von Tanja Herckelrath." 2004. http://d-nb.info/97251936X/34.
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SLÁMOVÁ, Martina. "Vliv klíštěcích slin na interakce mezi spirochetami \kur{Borrelia affzelii} a myšími dendritickými buňkami." Master's thesis, 2010. http://www.nusl.cz/ntk/nusl-52281.
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Interaction between mouse dendritic cells (DCs) and Borrelia afzelii spichochetes was studied on three different levels: phagocytosis of borrelia by DCs, production of cytokines by borrelia-activated DCs and the ablilty of DCs to activate CD4+ T cells. The effect of Ixodes ricinus saliva on each of these levels was examined. Tick saliva was shown to decrease the number of phagocosing DCs. The ability of borrelia-activated DCs to induce both proliferation and IL-2 production in specific CD4+ T cells was significantly reduced by tick saliva. And surprisingly, we have shown an inhibitory effect of I. ricinus saliva on the production of both Th1 (IL-6 and TNF-{$\alpha$}) and Th2 (IL-10) cytokines. Our data reveal a complex inhibitory effect of tick saliva on DC function.