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Gutierrez, Prat Núria. "Molecular basis of p38a MAPK signaling." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/663438.
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Cells often need to respond to damaging internal and external stimuli. One of the pathways that is frequently activated by stress stimuli involves activation of the kinase p38alpha, which can phosphorylate different substrates, including MK2.
Experiments using purified proteins have shown that non-phosphorylated p38alpha and MK2 can form a tight complex, in which structural constraints impede the interaction of both kinases with effectors and regulators.
It is therefore critical to understand how the interaction between p38alpha and MK2 is regulated to ensure that they can release from each other and phosphorylate the required substrates that mediate their functions. Here, we show that in cells under homeostatic conditions, endogenous p38alpha and MK2 form a stable complex that is disrupted upon phosphorylation of both proteins.
The separation of the two kinases causes MK2 destabilization and degradation by the proteasome in a MDM2-dependent manner. Depending on the intensity of the stimuli, p38alpha and MK2 undergo different fates. Transient stimulation leads to complex separation and MK2 degradation followed by increased MK2 expression, and the eventual reassembly of the p38alpha:MK2 complex.
On the contrary, in cells exposed to strong stimuli that lead to sustained p38alpha activation, as it is often the case with stress, both kinases remain phosphorylated, cannot bind to each other and eventually become destabilized, being unable to recover the steady state.
Taken together, our results illustrate a new mechanism of p38alpha signaling regulation based on the p38alpha:MK2 complex dynamics, which may have implications for different processes regulated by p38alpha and MK2 signaling.
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Renaud, Emilie. "Inhibition isoforme spécifique des fonctions de la MAPK p38α par des fragments d’anticorps." Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTT088.
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La MAPK p38α est une protéine clé de l’inflammation, également impliquée dans de nombreux processus liés au cancer. Les petites molécules chimiques inhibitrices de p38α bloquent son activité kinase par un mécanisme de compétition à l’ATP. En raison de la grande conservation du domaine kinase, la spécificité de la majorité de ces inhibiteurs n’est pas restreinte à la p38α et des effets « off-targets » ont été rapportés. Dans ce contexte, le projet de ma thèse a porté sur l’utilisation de fragments d’anticorps au format scFv comme nouvel outil de ciblage pharmacologique afin de définir une/des voie(s) alternative(s) d’inhibition de la p38α. Les fragments d’anticorps lient un motif antigénique avec une affinité et une spécificité élevées, tout comme les immunoglobulines classiques. Leur expression intracellulaire permet également le ciblage de protéines cytoplasmiques et l’étude de leurs fonctions dans des processus physiologiques et pathologiques. Nous avons sélectionné par phage display, à partir d’une banque de fragments d’anticorps, 5 scFv spécifiques de la MAPK p38α. Alors que tous ces scFv empêchent l’activation par phosphorylation de la p38α par MKK6, l’un d’entre eux agit directement sur l’enzyme pour inhiber totalement son activité kinase in vitro. Ce scFv possède un site de liaison et un mécanisme d’inhibition distincts des inhibiteurs pharmacologiques déjà décrits : bien qu’il ne cible pas le domaine kinase et n’empêche pas la fixation de l’ATP, le scFv se comporte comme un inhibiteur compétitif de l’hydrolyse de l’ATP. Ces résultats suggèrent un effet allostérique du scFv sur l’activité de la p38α et permettent de le caractériser comme un inhibiteur compétitif non conventionnel. La détermination de son épitope d‘interaction ainsi que la confirmation de sa fonctionnalité une fois exprimé dans le cytosol des cellules nous permettra de définir une voie alternative d'inhibition de la p38α et de valider notre approche de ciblage par l’utilisation de fragments d’anticorps.Ces données ouvrent de nouvelles perspectives de design d’inhibiteurs chimiques de la p38α de meilleure spécificité que ceux actuellement disponiblesMAPK p38α is a key protein in inflammation, but is also involved in many cancer-related processes. All the currently described chemical inhibitors of p38α inhibit its kinase activity by an ATP-competitive mechanism. Because of the high conservation of the ATP-binding pocket, the majority of these inhibitors are not specific to p38α and off-target effects have been reported. To identify alternative approaches to inhibit p38α MAPK, my thesis project focused on the use of scFv antibody fragments as a new highly specific pharmacological tool.Antibody fragments bind to an antigen with high affinity and specificity like conventional immunoglobulins. Their intracellular expression also allows to target cytoplasmic proteins and study the target functions in physiological and pathological processes. Using a naïve library of antibody fragments, we have selected by phage display five scFv specific of MAPK p38α isoform. While all these scFv inhibit the activation of p38α by MMK6, one of them also completely inhibits its kinase activity in vitro. This scFv has a binding site and a mechanism of inhibition distinct from the pharmacological inhibitors currently described: although it does not target the ATP-binding pocket and does not prevent ATP binding, it behaves like a competitive inhibitor of ATP hydrolysis. These results suggest an allosteric effect of this scFv on p38α activity and allow to characterize it as an unconventional competitive inhibitor. The determination of its epitope as well as the confirmation of its inhibitory activity once expressed in the cell cytosol will allow us to propose an alternative approach to target p38α function using antibody fragments.These data open up new perspectives for the design of more specific p38α chemical inhibitors than those currently available
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Visseq, Alexia. "Conception et synthèse d’inhibiteurs sélectifs de protéines kinases pour le traitement de l’allodynie mécanique." Thesis, Université Clermont Auvergne (2017-2020), 2019. http://www.theses.fr/2019CLFAC048.
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La douleur chronique constitue aujourd’hui un problème majeur de santé publique qui touche près de 20% de la population. L’allodynie mécanique, une douleur provoquée par une stimulation normalement non douloureuse, est le symptôme le plus fréquent chez les patients atteints de douleur chronique. Malheureusement, les traitements actuellement disponibles ne sont pas réellement efficaces ou bien présentent d’importants effets secondaires ou contre-indications. L’objectif de ce projet est de concevoir, synthétiser et évaluer biologiquement des inhibiteurs sélectifs de protéines kinases pour le traitement de l’allodynie mécanique. Au cours de ce travail de thèse, nous avons découvert de nouveaux inhibiteurs sélectifs de p38α, une protéine kinase bien connue pour son implication dans la douleur chronique et l’allodynie mécanique. Une étude des relations structure-activités a été réalisée pour identifier les éléments structuraux importants permettant d’améliorer l’activité des molécules in vitro et in vivo sur un modèle animal. Les meilleures molécules ont présenté des IC50 submicromolaires sur p38α et une forte inhibition de l’allodynie mécanique in vivoChronic pain is a global public health priority which affects more than 20% of Europeans. Mechanical allodynia, a pain in response to normally innocuous stimuli, is one of the most prevalent pain symptoms. Despite intensive research toward the study of pain mechanisms, currently available treatments of pain are not always effective, and can produce side-effects. In this context, the aim of the project is to design, synthesize and evaluate selective inhibitors of protein kinases for the treatment of mechanical allodynia. During this PhD work, new selective inhibitors of the protein kinase p38α has been discovered. This protein kinase is known for its implication in chronic pain and mechanical allodynia. A structure-activity relationship study was performed to identify the important structural features allowing a gain of activity of molecules in vitro and in vivo using an animal model. The best compounds showed submicromolar IC50 values toward p38α and a strong inhibition of mechanical allodynia in vivo
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Vitos, Faleato Jessica. "Role of p38α in lung tumor progression." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/462107.
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Tumors evolve by sequentially acquiring genetic abnormalities, like K-Ras activation and Tp53 loss of function, which enable transformed cells to survive, proliferate, invade, and reprogram their microenvironment. Simultaneously, transformed cells need to cope with a stressful scenario, including an accelerated metabolism, genome instability, or immune surveillance. Therefore, cancer cells must rely on some non-oncogenic signaling pathways to tolerate homeostatic control deficiencies, adapt to the new demands, and monitor continuous changes in the microenvironment to respond accordingly.
The p38 MAPK signaling pathway is a stress-related pathway that cells use to transduce extracellular cues and orchestrate appropriate responses. p38α, the most widely expressed p38 MAPK family member, has been classically attributed tumor suppressor functions due to its ability to arrest the cell cycle, induce cell differentiation, and trigger apoptosis. Nevertheless, in several human tumor types, p38 MAPK activity levels have been found increased and sometimes correlated to poor survival, suggesting a pro-tumorigenic role.
In this study, we observed a negative correlation between p38α mRNA expression levels and the overall survival of lung adenocarcinoma patients. Using a K-RasG12V driven mouse model of lung cancer, we show that indeed p38α signaling plays a dual role during lung tumorigenesis. On one hand, p38α avoids malignant transformation in lung epithelial cells by promoting their differentiation. However, in the transformed lung epithelial cells, p38α enhances proliferation as well as the secretion of inflammatory cytokines to form a favorable niche for cancer progression. p38α also plays a pro-tumorigenic role by promoting tumor vascularization and immunotolerance of tumor-infiltrated myeloid cells. Altogether, our data suggest that targeting this pathway might be therapeutically useful for lung adenocarcinoma.Los tumores evolucionan al adquirir anormalidades genéticas de manera secuencial, como la activación de K-Ras y la pérdida de funcionalidad de Tp53, que permiten a las células transformadas sobrevivir, proliferar, e invadir, así como acondicionar su microambiente. Simultáneamente, las células transformadas también han de lidiar con situaciones de estrés, incluyendo un metabolismo acelerado, un genoma altamente inestable, o el sistema de vigilancia de las células inmunes. Por lo tanto, las células cancerosas han de apoyarse en vías de señalización no-oncogénicas que les permiten tolerar las deficiencias en los sistemas de control de homeostasis, adaptarse a los nuevos requerimientos funcionales, y monitorizar los cambios en el microambiente para responder de manera apropiada. La vía de las p38 MAPK está íntimamente relacionada con la respuesta al estrés y es utilizada por las células para transducir señales extracelulares y orquestrar las respuestas correspondientes. p38α es el miembro de la familia de p38 MAPK más ampliamente expresado, y se le han atribuido clásicamente funciones supresoras tumorales gracias a su habilidad para detener el ciclo celular, inducir diferenciación, y desencadenar procesos apoptóticos. No obstante, hay evidencia de que el nivel de actividad de p38 MAPK podría estar incrementado en varios tipos de tumor humanos y, en algunos casos, se ha correlacionado con una baja supervivencia, lo que sugiere un papel pro-tumoral. En este estudio, hemos observado una correlación negativa entre los niveles de expresión de p38α y la supervivencia en pacientes de adenocarcinoma pulmonar. Hemos usado un modelo murino de cáncer de pulmón inducido por la expresión del oncogén K-Ras para demostrar que, efectivamente, p38α juega un papel dual durante el desarrollo de la carcinogénesis de pulmón. Por una parte, p38α evita la transformación maligna de las células pulmonares epiteliales sanas mediante la inducción de diferenciación celular. Sin embargo, en las células epiteliales pulmonares transformadas, p38α estimula la proliferación y la secreción de citocinas inflamatorias que preparan un nicho favorable para la progresión tumoral. p38α también juega un rol pro-tumorigénico al promover la vascularización del tumor y la immunotolerancia por parte de las células mieloides infiltradas. En conjunto, nuestros datos sugieren que la inhibición de esta vía de señalización podría ser útil en términos terapéuticos para los casos de adenocarcinoma de pulmón.
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Thapa, Dibesh. "Targeting the interaction between p38α and TAB1." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/targeting-the-interaction-between-p38-and-tab1(9b1a1609-805a-4698-a673-2a686dabf905).html.
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p38α, a member of the mitogen activated protein kinase family, is a stress activated serine/threonine kinase which plays an important role in signalling pathways mediating fundamental processes such as inflammation, apoptosis, autophagy, and cell division, differentiation and death. Over the last two decades, its prominence in ischaemic heart disease has risen rapidly with several studies providing overwhelming evidence that p38α activation aggravates lethal injury during myocardial ischaemia. Several inhibitors have been tested to prevent p38α activation and although they have performed well in the laboratory; unfortunately the results have not translated to clinical trials in patients. This has mainly been due to toxicity such as liver injury, skin rashes, gastrointestinal disorders, and flares-ups of rheumatoid arthritis. These adverse effects are shared by different inhibitors, the majority of which belong to the ATP-mimetic, type I group, suggesting they result from an on-target effect of inhibiting ubiquitously expressed p38α. As a result, an alternative therapeutic strategy, other than the blanket inhibition of p38, is required. TAB1 mediated p38α activation appears to be the culprit behind the detrimental p38α signalling during myocardial ischaemia and selectively targeting this branch of p38α activation, without affecting prototypical p38α activation, is highly desirable. In this thesis I studied the structural features of p38α and TAB1 which contribute to the TAB1-mediated p38α autoactivation mechanism. Using various biochemical and biophysical tools in in-vitro and ex-vivo systems, I have identified the key residue in p38α, and TAB1, which contribute to the auto-activation of p38α by TAB1. The results from my investigations suggest that targeting these residues impairs the autoactivation process and these structural features may be exploited to elucidate p38α’s role in myocardial ischaemia. Ischaemic heart disease continues to be the biggest killer in the world, and the search for p38α inhibitors still continues without any fruitful outcomes. A new direction and strategy focusing on circumstance selective inhibition is required in p38α therapeutics, and hopefully the results in my thesis will contribute to that search.
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Mäkelä, Kimmo K. "Characterization and performance of electrorheological fluids based on pine oils /." Espoo, Finland : University of Oulu, 1999. http://www.vtt.fi/inf/pdf/publications/1999/P385.pdf.
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Heikkilä, Anna-Mari. "Inherent safety in process plant design : an index-based approach /." Espoo [Finland] : Technical Research Centre of Finland, 1999. http://www.vtt.fi/inf/pdf/publications/1999/P384.pdf.
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Uosukainen, Seppo. "JMC method applied to active control of sound : theoretical extensions and new source configurations /." Espoo [Finland] : Technical Research Centre of Finland, 1999. http://www.vtt.fi/inf/pdf/publications/1999/P386.pdf.
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Patil, Ashok R. "High power shunt regulation of spacecraft solar arrays." Diss., Virginia Tech, 1995. http://hdl.handle.net/10919/40216.
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Patterson, Douglas T. "Tribopolymerization as an approach to two-stroke engine lubrication." Thesis, This resource online, 1995. http://scholar.lib.vt.edu/theses/available/etd-01312009-063142/.
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Plamondon, Philippe. "La MAP kinase p38γ influence la structure des cardiomyocytes." Mémoire, Université de Sherbrooke, 2014. http://savoirs.usherbrooke.ca/handle/11143/5307.
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Le cœur est un organe central au fonctionnement du système cardiovasculaire. Il est physiologiquement compartimenté et est constitué de cellules spécialisées qui régulent les impulsions électriques ainsi que la contraction du myocarde. Le cœur adapte le flux sanguin en fonction des besoins du corps. En condition pathologique, le cœur recourt toutefois à des mécanismes compensatoires. Au niveau physiologique, la compensation s’observe par l’hypertrophie des cardiomyocytes qui, bien que bénéfique à court terme, exacerbe à long terme la fonction cardiaque. L’activation des « mitogen activated protein kinases » (MAPK) contribue autant au maintien de la fonction physiologique qu’à la détérioration pathologique du myocarde et serait également une cause de l’hypertrophie observée. Parmi les 5 groupes de MAPK connues, la MAPK p38 est formée de 4 isoformes dont les sérine/thréonine kinases p38α et p38γ sont exprimées de façon prédominante dans le cœur. Les p38 partagent les mêmes activateurs, mais leurs effecteurs diffèrent. Bien que le rôle de p38α semble impliqué dans l’aggravement des troubles cardiaques, celui de p38γ ne semble pas redondant à p38α et demeure incompris. Cette isoforme possède un motif de liaison aux domaines PDZ, unique chez les MAP kinases. Également, chez les cellules cardiaques, elle transloque au noyau en condition de stress. Le but de l’étude ici est de comprendre le rôle de p38γ et de ses motifs uniques sur la structure et la taille des cardiomyocytes. Afin de répondre au but de l’étude, plusieurs mutants adénoviraux de p38 ont été conçus. Un des mutants ne possède pas le motif de liaison aux domaines PDZ, deux autres contrôlent la localisation cellulaire soit au noyau, soit au cytoplasme, et un autre mutant est muté au site de phosphorylation. Des cardiomyocytes en culture ont été infectés par les différents mutants en présence de leur activateur en amont ou de la β-galactosidase. Les réseaux d’α-actinine, ainsi que la taille des cardiomyocytes, ont été observés par microscopie. Les observations effectuées montrent que p38γ entraîne une désorganisation des réseaux d’α-actinine lorsqu’il est phosphorylé. Également, il facilite l’hypertrophie des cardiomyocytes en présence de son activateur s’il est forcé hors du noyau ou en l’absence de son motif de liaison aux domaines PDZ. En conclusion, les résultats obtenus suggèrent que p38γ exerce bel et bien un rôle dans le maintien structural des cardiomyocytes par l’intermédiaire de l’α-actinine.
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Arabacilar, Pelin. "Investigating the mechanisms of p38 activation." Thesis, King's College London (University of London), 2016. http://kclpure.kcl.ac.uk/portal/en/theses/investigating-the-mechanisms-of-p38-activation(ae0beac3-0bab-4ae6-b91a-ef9f8fb9b9ff).html.
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BACKGROUND: p38 mitogen activated protein kinases (p38 MAPKs) respond to stress stimuli and play a role in cell differentiation and apoptosis. Four isoforms of p38 MAPKs have been found; p38-α/β/γ/δ and this project focuses on the role of p38α. There are three pathways leading to p38α activation, the canonical pathway, the ZAP70-mediated pathway and the TAB1-mediated pathway. The latter has been found to occur during myocardial ischaemia. Therefore, if this direct effect of TAB1 on p38α can be controlled and prevented, there might be a potential way to stop or minimise myocardial ischaemic injury. The aim of this project is to investigate the effect of TAB1 on p38α autophosphorylation, as well as assessing competition between this pathway and the canonical cascade of activation. Another signalling pathway, which involves p38α, with a potential role in heart failure, is the amino acid response pathway (AAR). Halofuginone, a compound which activates the AAR pathway, has been implicated in improved cardiac function. Exploring this system by using halofuginone as a tool would provide further insight into whether the activation of this pathway could lead to improvements in several aspects of heart failure, such as hypertrophy, autophagy and inflammation. RESULTS: Using HEK293 cells, co-expression of TAB1 and p38α results in increased phosphorylation of p38α. This phosphorylation is reduced by the p38 inhibitors SB203580 and BIRB796. Mutations in TAB1, preventing p38 binding, diminish TAB1-mediated p38α phosphorylation. Despite spatial overlap in docking domains on p38α, TAB1 does not compete with MKK3b in a mammalian overexpression model. TAB1 and MKK3b induce phosphorylation of p38 independently and this is probably due to their differential in-cell locations, with p38 predominantly localising with MKK3b. p38 appears to be activated in response to halofuginone, and the simultaneous activation of the AAR pathway leads to increased autophagy, changes in the mRNA levels of inflammatory genes, as well as a potential p38-mediated negative feedback mechanism on the AAR pathway. CONCLUSIONS: There is a TAB1-mediated, SB203580-sensitive p38α phosphorylation mechanism which involves direct binding of TAB1 to p38α and induction of p38α autophosphorylation. p38 is activated in response to halofuginone and the associated AAR pathway leads to changes in autophagy and inflammation.
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Tasker, Alexander John. "Processes of hybrid knowledge creation in pastoralist development." Thesis, University of Sussex, 2018. http://sro.sussex.ac.uk/id/eprint/80671/.
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This thesis addresses an under-researched disjunction surrounding knowledge creation between, and within, development and pastoralist groups. Many academics increasingly recognise pastoralist populations as creative and adaptable, yet these populations often lack the resources to develop innovations beyond the local context. Despite often being better resourced than pastoralist communities, development interventions in the Horn of Africa have achieved limited successes; an observation often linked in academic literature with a failure to rethink inappropriate established practices drawn from settled agriculture. The need to explore new ways of understanding hybrid knowledge creation in pastoralist settings emerged from the international community's limited understanding of informal innovation processes and unique contexts of pastoralist regions, due in part to the unsuitability of current frameworks and research tools for conceptualising informal innovation in marginal settings. This study makes an original research contribution by exploring the factors that shape processes of knowledge creation between development and pastoralist groups to answer the question what factors influence innovation in pastoralist areas? An interconnected, mixed-methods research strategy was developed and applied to study the role of knowledge networks and framings in processes of knowledge creation amongst pastoralist and development actors innovating in North Horr, Kenya. The empirical data gathered throughout the research informed the development of an internally-valid analytical framework with which to explore innovation in this setting. The key findings of this study highlight the importance of the contextual and often asymmetric nature of relationships in processes of emergent knowledge creation within pastoralist development. The observations collected throughout the research process provide an empirical basis from which to discuss networks, framings, and knowledge creation in pastoralist settings; contributing to wider debates surrounding informal innovation processes and narratives of pastoralist development.
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Cánovas, Bilbao Begoña. "Role of p38 MAPK in breast cancer." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/405893.
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In normal epithelial cells, p38α has a well-established role as a tumor suppressor. However, recent reports have illustrated pro-tumorigenic functions for the p38α pathway by promoting tumor cell survival and proliferation. Given that the role of p38 MAPKs have been shown to be cell and context dependent, we focused our study on the function of p38α in breast cancer progression.
To investigate the role of p38α in breast tumor progression in vivo, we combined the polyoma middle T (PyMT) mouse model with floxed conditional alleles of p38α. This way, we analyzed the role of p38α in already developed tumors, where we observed a progressive tumor regression following p38α deletion (p38αΔ). This tumor reduction correlated with decreased cell proliferation, increased cell death and elevated levels of DNA damage.
To investigate the molecular mechanisms underlying mammary tumor regression, we established epithelial cell cultures from PyMT-induced tumors. As increased levels of γ-H2AX were observed in tumors with reduced p38α, we examined DNA damage signaling and genome integrity in the PyMT-expressing epithelial cells. These cultures reproduced the increased levels of γ-H2AX observed in vivo and interestingly, the localization of γ-H2AX in these cells was not restricted to the nuclei, but also appeared in DNA bridges and micronuclei, potentially reflecting DNA double strand breaks resulting from chromosome segregation errors during cytokinesis.
Increased levels of DNA damage are known to impact on DNA replication and hamper its progression. We directly assessed the effect of p38α deletion on DNA replication by analyzing stretched DNA fibers. We found a lower replication rate in p38αΔ cells and the analysis of fibers with bidirectional tracks revealed an increased rate of asymmetric forks, indicative of a high frequency of fork stalling.
The defects in replication fork progression and the increased DNA damage led us to investigate the status of the DNA damage response, an essential network that monitors DNA replication and coordinates cellular responses. We observed defects in ssDNA generation, RPA accumulation, RPA and CHK1 phosphorylation and RAD51 recruitment after treatment with campothecin, a topoisomerase I inhibitor that induces DNA damage specifically in S-phase, indicating that ATR signaling, DNA-end resection and homologous recombination DNA repair were defective in p38α deficient cells.
Moreover, we identified CtIP, a key factor that promotes DNA-end resection in mammalian cells, as a p38α substrate. De-regulation of CtIP due to lack of p38α could impact on the DNA damage response and explain many of the described phenotypes.
Replication stress and DNA damage have been proposed to be the major cause of chromosome instability (CIN) in cancer, leading to both numerical and structural chromosome alterations. Using time- lapse analysis, we observed that some cells showed cytokinesis failure, reflected by the presence of DNA bridges between the daughter cells, and gave rise to multinucleated cells. However, even in the presence of DNA bridges, most of the p38αΔ cells were able to eventually divide, but exhibited micronuclei after mitosis. This indicated that p38α deletion induced missegregation, ultimately leading to aneuploidy.
Our results suggested that targeting p38α would increase tumor cell sensitivity to CIN-inducing agents. We tested this hypothesis both in vitro and in vivo, and found that pharmacological inhibition of p38α increased the effect of both paclitaxel and docetaxel in the PyMT model. These results were further confirmed in patient-derived xenografts, where p38α inhibition enhanced, accelerated or prolonged the anti-tumoral response observed with the taxanes alone.
These results were consistent with the idea that p38α contributes to the DNA damage response and facilitates the survival of cancer cells with high levels of CIN. Moreover, they confirmed the hypothesis that targeting p38α sensitizes cancer cells to CIN-inducing agents such as taxanes, raising the possibility of translating p38α inhibitors into the clinic.La proteína quinasa p38α está considerada como un supresor tumoral. Sin embargo, estudios recientes sugieren que puede promover el crecimiento y la supervivencia en algunos tipos de células tumorales, así como que su inhibición coopera con determinados agentes quimioterapéuticos. Así pues, la función de p38α parece depender tanto del tipo de célula como del contexto. Por ello, este trabajo abordó el papel de p38α en el contexto concreto de la progresión del cáncer de mama. Usando el modelo “Polyoma middle T” (PyMT), hemos observado que la expresión de p38α en las células epiteliales que conforman el tumor es esencial para el crecimiento del mismo. Para analizar los mecanismos moleculares implicados establecimos un sistema ex vivo consistente en líneas celulares derivadas de tumores inducidos por PyMT. Observamos que en ausencia de p38α estas células mostraban estrés replicativo, un mayor daño en el ADN y un incremento en los errores de segregación que correlacionaban con una menor viabilidad celular. Los defectos durante la replicación y el aumento en el daño en el ADN nos llevaron a investigar el estado de la ruta de respuesta al daño en el ADN. Así pues, encontramos que las células deficientes en p38α mostraban defectos en la generación de ADN monocatenario, en la activación de ATR y en el reclutamiento de RAD51 a los focos de daño, lo que sugería que la reparación de ADN por recombinación homóloga estaba afectada. Además identificamos CtIP, un factor esencial para la resección del ADN, como sustrato directo de p38α. La desregulación de CtIP influiría negativamente en la respuesta al daño en el ADN y explicaría en gran medida los fenotipos descritos anteriormente. En conjunto, nuestros datos sugieren que p38α es necesaria para una eficiente reparación y replicación del ADN y por tanto para el mantenimiento de la estabilidad cromosómica en las células epiteliales de cáncer de mama. Los resultados anteriores sugerían que la intervención farmacológica de p38α podría incrementar la sensibilidad a agentes inductores de inestabilidad cromosómica como los taxanos. Confirmamos esta teoría usando el modelo PyMT y xenografías derivadas de pacientes, comprobando que en ambos casos la inhibición de p38α potenció, aceleró o prolongó el efecto anti-tumoral de los taxanos paclitaxel y docetaxel.
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Davies, Gareth. "Folding of p38 mitogen-activated protein kinase." Thesis, University of Warwick, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.412847.
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Jones-Phillips, Dominic. "A role for p38δ MAPK in the pathogenesis of rheumatoid arthritis." Thesis, University of Leeds, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.634754.
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Rheumatoid Arthritis (RA) is a chronic systemic auto immune disease characterised by progressive joint destruction and severe morbidity. Therapeutic treatment of RA has made several important advancements in recent years, with the advent of anti-TNF biologics, and yet non-response and heterogeneity of response to treatment is a constant hurdle to the development of new therapies. Anti-IL-6 receptor A antibody, tocilizumab, has had considerable success in patients refractory to anti-TNF therapies This report investigates the IL-6 pathway in RA and a potential role for p38δ MAPK in driving IL-6 expression via hypoxia-induced mechanisms.
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Dan, Yuzhen 1992. "Signaling networks regulated by the kinase p38α in cancer cell homeostasis." Doctoral thesis, TDX (Tesis Doctorals en Xarxa), 2022. http://hdl.handle.net/10803/673710.
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p38α (encoded by MAPK14) is a major regulator of cellular responses to almost all types of environmental and intracellular stresses. Upon activation, p38α phosphorylates various substrates both in the cytoplasm and nucleus, allowing this pathway to regulate a wide variety of cellular processes, including cell proliferation, differentiation, or survival. Given the plethora of functions that can be controlled by p38α, we performed proteomic and phosphoproteomic analysis to study the signaling networks regulated by p38α during cancer cell homeostasis. Our study identifies 35 proteins and 114 phosphosites that are modulated by p38α, and highlights the importance of other kinase pathways, such as MK2 and mTOR, for p38α-regulated functions. Moreover, the functional analysis of the (phospho)proteome revealed the implication of p38α in the regulation of cell adhesion, DNA replication and RNA processing. We further show that p38α negatively regulates cell-cell adhesion, which is likely mediated by the transcriptional modulation of ArgBP2. Collectively, our results illustrate the complexity of the p38α regulated signaling networks, provide valuable information on p38α-dependent phosphorylation events in cancer cells, and document a mechanism by which p38α regulates cell-cell adhesion during cancer cell homeostasis.p38α (codificada por el gen MAPK14) es una proteína reguladora crucial en las respuestas celulares a casi todos los tipos de estrés tanto provenientes del ambiente extracelular como del interior de la célula. Una vez activada, p38α fosforila varios sustratos en el citoplasma y en el núcleo, lo que permite que esta vía regule una amplia variedad de procesos celulares, que incluyen la proliferación, la diferenciación o la supervivencia celular. Dado la gran cantidad de funciones que pueden ser controladas por p38α, en este trabajo realizamos análisis proteómicos y fosfoproteómicos para estudiar las redes de señalización reguladas por p38α en las células tumorales en homeostasis. Nuestro estudio ha identificado 35 proteínas y 114 sitios de fosforilación que son modulados por p38α, así como la importancia de otras vías de señalización por quinasas, como MK2 y mTOR, en las funciones reguladas por p38α. Además, el análisis funcional del (fosfo)proteoma ha revelado que p38α participa en la regulación de la adhesión celular, la replicación del ADN y el procesamiento del ARN. También mostramos que p38α regula negativamente la adhesión célula-célula, lo que probablemente está mediado por la modulación transcripcional de ArgBP2. En conjunto, nuestros resultados ilustran la complejidad de las redes de señalización reguladas por p38α, proporcionan información valiosa sobre las fosforilaciones dependientes de p38α en células tumorales y documentan un mecanismo por el que p38α regula la adhesión célula-célula durante la homeostasis de las células tumorales.
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Delplanque, Sylvain. "Information émotionnelle et composantes évoquées P3a et P3b." Paris 6, 2004. http://www.theses.fr/2004PA066085.
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Pethel, Michele Lee. "Plasmid-influenced changes in Mycobacterium avium catalase activity." Thesis, Virginia Tech, 1988. http://hdl.handle.net/10919/43266.
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A virulent Mycobacterium avium strain, LR25, which carries 3 plasmids (18, 28, and 165 kb) and grows at 43°C was compared to its plasmid-free, avirulent segregant, strain LR163, to investigate the basis for the latter's inability to grow at 43°C. The failure of mid-log phase cultures of strain LR163 to grow at 43°C was dependent upon the presence of high levels of culture aeration. In addition, highly aerated mid-log phase cultures of strain LR163 failed to grow at 379C, By contrast, late-log phase cultures of strain LR163 were capable of growth when shifted to 43°9C under highly aerobie conditions. Mid-log phase cells of strain LR163 had 30% of the catalase activity of mid-log phase cells of strain LR25 and were more susceptible to hydrogen peroxide (0.08% w/v). Catalase activities of late-log, early-stationary, and stationary phase cells of strain LR163 were Significantly higher than mid-log phase cells. Catalase activity of strain LR25 was highest in cells of mid-log phase cultures, whereas the catalase activity of strain LR163 was highest in cells of stationary phase cultures. These data support the idea that plasmid-encoded genes influence M. avium catalase activity.Master of Science
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Pelletier, Carole. "Une approche philosophique, hétéropolitique et féministe de la vieillesse." Doctoral thesis, Université Laval, 2005. http://hdl.handle.net/20.500.11794/43815.
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La philosophie peut-elle collaborer à la redéfinition d'une conception de l'être humain accordant pleine humanité à l'individu tout au long de sa vie, vieillesse incluse ? Au plan méthodologique, elle peut d'abord contribuer à clarifier les concepts en cause dans l'étude de celle-ci puis, grâce à la méthode du champ définitionnel, à en proposer une définition raisonnée. Mais la philosophie peut aussi aider à déployer la dimension " autre " de la pensée, ce qui, en philosophie politique, mène à l'hétéropolitique, préoccupation pour une société idéalisée incarnée dans une fiction (utopie) ou dans un texte théorique (para-utopie). Comme, toutefois, l'hétéropolitique a trop souvent cédé à la tentation de la pseudo-universalité, il faut la compléter par une démarche féministe axée sur le concept d'oppression. En intégrant systématiquement la variable sexuelle, cette démarche permet de mettre en lumière les préjugés concernant la vieillesse féminine qui, issus de la tradition aristotélicienne et transmis au cours des siècles, cautionnent encore aujourd'hui la loi du double standard. Appliquée aux personnes âgées, la notion d'oppression, jointe à la perspective hétéropolitique, permet d'une part de critiquer la façon dont la société actuelle traite les personnes âgées, d'autre part de déterminer quel nouveau modèle social permettrait le mieux d'améliorer leur sort.
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Paillas, Salomé. "Étude des mécanismes de résistance à l’Irinotécan dans le cancer colorectal : implication de la MAPK p38." Thesis, Montpellier 2, 2011. http://www.theses.fr/2011MON20058/document.
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Malgré les récentes avancées réalisées dans le traitement du cancer du côlon, la résistance des tumeurs est une cause fréquente de l'échec des chimiothérapies. Cette thèse a pour objectif d'identifier les mécanismes moléculaires impliqués dans la résistance à l'Irinotécan, un agent couramment utilisé dans le traitement des cancers colorectaux. Nous avons montré l'implication de la MAPK p38 dans la résistance à l'Irinotécan et en particulier avons démontré que les isoformes α et β étaient impliquées dans cette résistance. De plus, nous avons corrélé la faible phosphorylation de p38 dans des tumeurs coliques primaires de patient sensibles au traitement à l'Irinotécan par rapport aux patients non répondeurs. Dans la suite du projet nous avons étudié le rôle de p38 dans les processus autophagiques et leur impact dans la réponse à l'Irinotécan. Nous avons démontré que p38 induisait une autophagie qui mène à la survie des cellules cancéreuses déficientes pour p53, et que l'inhibition de l'autophagie sensibilisait ces cellules au traitement au SN38, métabolite actif de l'Irinotécan. Enfin de manière préliminaire, nous avons étudié le rôle de p38 dans l'augmentation du métabolisme lipidique dans des cellules déficiente pour p53. Ces travaux ouvrent de nouvelles voies de recherche pour l'identification des mécanismes impliqués dans la résistance aux traitements anticancéreux et pour le développement d'approches pharmacologiques pour contourner la résistanceDespite the recent advances achieved in the treatment of colon cancer, tumor resistance is a frequent cause of chemotherapy failure. This work was aimed to determine the molecular mechanisms involved in the resistance to Irinotecan, an anticancer agent widely used in colorectal cancer treatment. We have demonstrated that the α and β forms of p38 MAPK were involved in this resistance. Moreover, we have correlated less phospho-p38 in colon cancer primary tumor of patients sensitive to Irinotecan-based treatment, compared to non responder patients. During the project, we aimed to determine the role of p38 MAPK in the processes of autophagy in colorectal cancer cells, and their impact in Irinotecan cytotoxicity. We have shown that p38 induced survival autophagy in p53 deficient cells. Then, we have shown that autophagy inhibition increased the SN38 cytotoxicity (active metabolite of Irinotecan) in p53 deficient cell lines. Finally, we have studied the role of p38 MAPK in lipid metabolism in p53 deficient cells. All these findings highlight new ways of research to identify the molecular mechanisms involved in chemoresistance as well as new pharmacological approaches to overcome the resistance
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Rahal, Pamela. "Role of GSK3β - MLK3 - p38γ MAPK Signalling in Satellite Cell Proliferation Regulation." Thesis, Lyon, École normale supérieure, 2015. http://www.theses.fr/2015ENSL1000.
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MLK3 est une ser/thr MAP3K qui active la voie de signalisation des MAPKs dans différents types cellulaires. GSK3β interagit et active MLK3 en la phosphorylant sur le residue ser 792. Cependant, le rôle de MLK3 ainsi que l’interaction entre MLK3 et GSK3β n’ont pas été précédemment étudiés dans le muscle squelettique. La croissance post-natale du muscle et la régénération musculaire chez l’adulte sont dépendantes de l’accrétion de myonoyaux, un processus médié par les cellules satellites qui prolifèrent, se différencient puis fusionnent aux fibres préexistantes. Durant ma thèse, j’ai démontré que GSK3β agit en amont de MLK3 pour induire la prolifération des cellules satellites, et cela par l’activation de la voie de signalisation MLK3-p38γ MAPK. In vivo, les muscles de souris déficientes injectés par la CTX montrent une diminution du nombre de cellules satellites prolifératrices Pax7+/ki67+, ainsi qu’une accélération du processus de régénération. En conclusion, mes résultats évoquent un nouveau rôle de MLK3 dans le muscle squelettique pouvant servir pour vaincre les dystrophies musculaireMLK3 is a Ser/Thr MAP3K, which activates MAPKs signalling pathways in different cell types. The Ser/Thr kinase GSK3-β directly phosphorylate Ser 792 residue and activate MLK3. Since neither the role of MLK3, nor GSK3-β -MLK3 interaction have been previously investigated in muscle, the aim of my thesis was to elucidate their contribution in the regulation of muscle mass and physiology.Skeletal muscle post-natal growth and adult regeneration relies on satellite cell-mediated myonuclear accretion, during which, activated satellite cells, proliferate, differentiate and fuse with preexisting myotubes.I have demonstrated that in skeletal muscle, GSK3-β acts upstream of MLK3 to induce satellite cells proliferation through the induction of MLK3-p38γ MAPK signalling. Similarly, in vivo CTX-induced TA damage in MLK3 KO mice resulted in decreased number of proliferating Pax7+/ki67+ satellite cells, with a rapid muscle regeneration ability.These data suggest provide a yet unknown role of MLK3 in skeletal muscle tissue that could help in curing age-related muscle dystrophies
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Sundaresan, Pavithra. "Platelet collagen receptors and regulation of p38 MAP kinase." Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619577.
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Gaffey, Kate. "Glucocorticoid resistance in COPD : the role of p38 MAPK." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/glucocorticoid-resistance-in-copd-the-role-of-p38-mapk(9c60954b-f891-4f8b-8004-825e6d173503).html.
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Chronic Obstructive Pulmonary Disease (COPD) is a chronic, inflammatory condition, characterised by airflow limitation. The use of glucocorticoids (GC) as an anti-inflammatory treatment in COPD has limited clinical benefits, and as such, new treatments are needed. Identifying key pathways involved in the inflammatory response in COPD may enable the development of novel treatments. The aims of this thesis were to examine the steroid sensitivity of an in vitro mixed sputum culture cell model, comparing COPD cells to smoking and non-smoking controls, examine expression of the intracellular signalling molecule p38 Mitogen Activated Protein Kinase (MAPK) in COPD lungs compared with controls, examine the GC and p38 MAPK inhibitor and dual therapy sensitivity of a bronchial epithelial cell line and finally, to understand the mechanisms by which a p38 MAPK inhibitor in combination with a GC synergistically inhibit pro-inflammatory mediator production in a bronchial epithelial cell line. Dexamethasone inhibits mixed sputum cell pro-inflammatory mediator release, with no differences in sensitivity observed between COPD and control cells. Isolated sputum neutrophils demonstrate modest sensitivity to dexamethasone, which is in contrast to blood neutrophils. There are increased numbers of cells positive for activated p38 MAPK in COPD lungs compared with controls, specifically localised to follicular B and CD8+ T cells, bronchial epithelial cells and alveolar and sputum macrophages. Lung and sputum neutrophils are devoid of activated p38 MAPK, and a pharmacological p38 MAPK inhibitor has no effect on pro-inflammatory mediator production from these cells. This is in contrast to blood neutrophils, whereby p38 MAPK activation can be induced following LPS stimulation and in vitro cell culture, and pro-inflammatory mediator release is inhibited by a p38 MAPK inhibitor. Dexamethasone and birb 796 inhibit stimulated pro-inflammatory mediator release from a bronchial epithelial cell line in a dose-dependent manner. Sensitivity to either drug is dependent on stimuli and the pro-inflammatory mediator analysed. There is additive and synergistic inhibition of pro-inflammatory mediator production when combination therapy comprising dexamethasone and birb 796 is used compared with either drug alone. This may be due to Birb 796 enhancing dexamethasone-mediated nuclear translocation of the glucocorticoid receptor, which may enhance the GC-mediated anti-inflammatory effects. Combination therapy may therefore be a useful therapeutic in the treatment of COPD.
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Fortier, Manon. "Rôle de la MAP kinase p38α au cours d'une agression aiguë du foie Hepatospecific ablation of p38α governs the inflammatory response to promote efficient tissue repair during acute liver injury." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB100.
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Afin de lutter contre des agressions aiguës pouvant être induites par une hépatite virale, des toxines ou bien une surcharge médicamenteuse, le foie active différents processus interconnectés tels que la prolifération hépatocytaire, l'inflammation ou la mort cellulaire. Une protéine clé se trouve au carrefour de ces différents processus cellulaires : la protéine p38 alpha MAP (Mitogen Activated Protein) Kinase. Dans le foie, de nombreux travaux décrivent un double rôle de cette protéine. En effet, elle est considérée comme un suppresseur de tumeur en régulant négativement la prolifération des hépatocytes, cellules majoritaires du foie, mais peut aussi agir comme un oncogène en favorisant certains processus liés au cancer et notamment l'inflammation. Cependant, son action lors d'une agression aiguë du foie adulte reste peu caractérisée. L'objectif de mon travail de thèse était donc de caractériser le rôle de la protéine p38 alpha lors d"une agression hépatique aiguë, grâce à un modèle murin pour lequel l'expression de cette protéine est invalidée spécifiquement dans les hépatocytes (modèle murin KO). Pour répondre à cette question, nous avons utilisé le modèle expérimental d'hépatopathie classiquement utilisé pour reproduire la division hépatocytaire en contexte inflammatoire : le modèle du tétrachlorure de carbone (CCl4). L'injection de cet hépatotoxique à des souris entraîne une cytolyse hépatocytaire dans les zones centro-lobulaires rapidement suivie par une infiltration de cellules immunitaires et une prolifération compensatoire des hépatocytes sains, pour réparer le tissu lésé. Des souris contrôles et KO ont été sacrifiées à différents temps après injection permettant d'établir une cinétique post-CCl4, au cours de laquelle du sang et du tissu hépatique ont été collectés. Les lésions hépatiques, l'inflammation, l'apoptose et la prolifération ont ensuite été étudiées. Tout d'abord, nous avons observé que le nombre d'hépatocytes en phase S (marquage BrdU, taux de CyclinA2) est diminué en l'absence de p38a au cours de la phase de régénération post-CCl4. Par ailleurs, nous montrons que la perte d'expression de la protéine p38a confère un effet protecteur contre les lésions hépatiques induites par le CCl4. En effet, les zones de cytolyse et les taux d'alanine transaminase (reflet de la mort hépatocytaire) sont significativement diminués (de 40H à 60H post-CCl4) chez les souris KO. Pour expliquer ce phénotype, nous avons analysé l'apoptose au cours de la cinétique de régénération, mais nos résultats ne montrent pas de différences significatives dans la mise en place de ce processus entre les animaux contrôles et KO. En revanche, nous montrons que la réponse anti-oxydante dans le foie des animaux KO est amplifiée et pourrait donc participer à la protection du tissu hépatique. Enfin, nos observations immunohistochimiques montrent un recrutement massif de cellules inflammatoires dans les zones de cytolyse corrélé à une augmentation importante des niveaux de cytokines (comme le TNFa) et chimiokines pro-inflammatoires (CCL2 et CCL5). Laensemble de ces données suggèrent fortement que la déficience en p38a induit une réponse immunitaire spécifique favorisant le nettoyage et la réparation du tissu hépatique. En conclusion, mes travaux de thèse montrent que lors d'une lésion aiguë l'absence de la MAP Kinase p38a protège le foie en ajustant la balance « prolifération - réponse inflammatoire », favorisant ainsi une réparation précoce du tissu et le maintien de l'homéostasie hépatiqueTo prevent acute liver injuries induced by viral hepatitis, toxins or drug overload, liver activates different interconnected processes such as proliferation, inflammation or cell death. Interestingly, one protein is at the crossroad of these pathways: the MAP (Mitogen Activated Protein) kinase p38 alpha. Several studies showed a dual role for the p38a mitogen-activated protein kinase pathway in liver. Even if its role as a negative regulator of hepatocyte proliferation has been largely described, p38a may also harbor an oncogenic role involving cancer related-processes and notably inflammation. However, its function during an acute injury, in adult liver, remains uncharacterized. My thesis aim was to characterize p38 alpha MAP Kinase role during an acute liver injury thanks to a mouse model with a conditional hepatocyte specific deletion of p38a (KO model). To that end, we used an experimental hepatopathy system classically used to reproduce hepatocyte division in inflammatory context: the carbon tetrachloride model (CCl4). An injection of this hepatotoxic in mice induces hepatocyte cytolysis in centrilobular zone rapidly followed by immune cell infiltration and compensatory healthy hepatocyte proliferation to repair hepatic tissue. Control (CT) and KO mice were sacrificed at different timings after injection to establish a post-CCl4 kinetic, during which blood and liver tissue were collected. Liver injuries, inflammation, apoptosis and proliferation processes were then assayed. First, absence of p38a decreases hepatocyte number into cell cycle S phase (BrdU labelling, CyclinA2 levels) during regenerative process post-CCl4. Interestingly, we showed that p38a deficiency confers a protective effect against hepatic injuries induced by CCl4. Indeed, cytolysis areas and alanine transaminase levels (hepatocyte death reflection) were significantly decreased (40H to 60H post-CCl4) in KO mice. To explain this phenotype, we investigated apoptosis pathway during regenerative kinetic, but our results did not show any significant differences between CT and KO mice. On the other hand, antioxidant response is increased in KO livers and could therefore be involved in the hepatic tissue protection. Finally, immunohistochemistry analysis showed a massive inflammatory cell recruitment to cytolysis areas correlated with a significant increase of cytokines (as TNFa) and pro-inflammatory chemokines (as CCL2 and CCL5). These data strongly suggest that p38a deficiencies mediate a specific immune response to favor hepatic tissue clearance and repair. In conclusion, my thesis work shows that the absence of p38a MAP Kinase is hepatoprotective during an acute liver injury enhancing "proliferation - inflammatory response" balance, therefore promoting early tissue repair and maintaining liver homeostasis
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Marais, Erna. "Role of cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP) and p38 mitogen activated protein kinase (p38 MAPK) in preconditioning of the ischaemic myocardium." Thesis, Stellenbosch : Stellenbosch University, 2002. http://hdl.handle.net/10019.1/53039.
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Thesis (PhD)--University of Stellenbosch, 2002.ENGLISH ABSTRACT: Ischaemic preconditioning (PC) is the phenomenon whereby a short episode of coronary occlusion followed by reperfusion protects the myocardium against a subsequent period of prolonged (also called index or sustained) ischaemia. Even though the exact mechanism of PC remains to be established, it implies that the heart has an endogenous protective mechanism against ischaemia which, if identified, may have important clinical implications. The importance of establishing the mechanism of PC lies in the potential to convert this biological phenomenon into a therapeutic modality to be used clinically. If mediated by certain components of a signal transduction pathway, such a goal will be achievable. Several triggers and signal transduction pathways have been implicated in the mechanism of protection induced by PC: for example, receptor-dependent endogenous triggers (such as adenosine and opioids) and receptor-independent endogenous triggers (such as free radicals and calcium). However, the involvement of both the ~-adrenergic signalling pathway as well as nitric oxide (NO) in PC has not been defined. It has been suggested that all triggers are linked to a common final pathway, for example, activation of protein kinase C (PKC) and/or the mitogen-activated kinases (MAPKs), in particular p38 MAPK. However, the role of the latter is still controversial. The aim of this study was to: (A) characterize changes in the cyclic nucleotides, cAMP and cGMP, and p38 MAPK occurring during the entire experimental procedure in an attempt to gain insights into the possible mechanisms involved in ischaemie PC (Chapter 3); (8) establish the significance of the changes observed in cAMP and cGMP by pharmacological manipulation of their respective pathways (Chapters 4 and 5); (C) establish the role of p38 MAPK in ischaemie PC: trigger or mediator involvement (Chapter 6). Isolated perfused working rat hearts were preconditioned by 3 x 5 min global ischaemia, interspersed by 5 min reperfusion, followed by 25 min global ischaemia and 30 min reperfusion. Functional recovery during reperfusion was used as end-point. Hearts were freeze-clamped at different times during the PC protocol, sustained ischaemia, as well as during reperfusion. Tissue cyclic nucleotides (cAMP and cGMP), cyclic nucleotide phosphodiesterase (cAMP- and cGMP-PDE) activities, adenylyl cyclase and protein kinase A activities and p-adrenergic receptor characteristics were determined. p38 MAPK activation was also assessed by Western blotting, using dual phospho-p38 MAPK (Thr180ITyr182) antibody as well as activating transcription factor 2 (ATF2) activation. In addition, to evaluate the role of p38 MAPK in PC protection, the effect of inhibition of p38 MAPK activation, by 8B203580, was determined in adult isolated rat cardiomyocytes as well as in isolated perfused rat hearts. Based on the results obtained, it is proposed that during a multi-cycle ischaemie PC protocol triggers (presumably endogenous catecholamines and NO) are released which induce cyclic changes in cyclic nucleotides, cAMP and cGMP. Both these cyclic nucleotides transiently activate the downstream stress kinase, p38 MAPK, which may trigger further downstream adaptive processes. Furthermore, the sustained ischaemic period of PC hearts was characterized by attenuated cAMP and elevated cGMP levels, as well as attenuated activation of p38 MAPK, which was associated with cardioprotection. In addition, pharmacological attenuation of p38 MAPK activation during sustained ischaemia led to functional recovery. It is concluded that the cardioprotection of PC is due to attenuation of ischaemia-induced p38 MAPK activation. Pharmacological manipulation of this kinase should be considered as a therapeutic modality in the future.
AFRIKAANSE OPSOMMING: Isgemiese prekondisionering (PK) verwys na die verskynsel waardeur 'n kort, verbygaande episode van isgemie gevolg deur herperfusie, die miokardium teen 'n daaropvolgende langdurige periode van isgemie beskerm. Die presiese meganisme van beskerming van PK moet nog opgeklaar word, maar dit impliseer dat die hart oor 'n endogene beskermingsmeganisme beskik wat, indien geïdentifiseer, belangrike kliniese implikasies mag hê. Die belang van opklaring van die meganisme van PK lê daarin dat 'n biologiese verskynsel in 'n terapeutiese modaliteit vir kliniese gebruik, omgeskakel kan word. Sou dit deur bepaalde komponente van 'n seintransduksiepad gemedieër word, is so 'n doel bereikbaar. Verskeie stimuli en seintransduksiepaaie is in PK betrokke: byvoorbeeld, reseptorafhanklike endogene stimuli (soos adenosien en opioïde), asook reseptor-onafhanklike endogene stimuli (soos vrye radikale en kalsium). Die betrokkenheid van die padrenerge seintransduksiepad asook stikstofoksied (NO) in PK egter nog nie behoorlik evalueer nie. Dit is voorgestel dat alle stimuli op 'n finale algemene pad uitloop, soos byvoorbeeld die aktivering van protein kinase C (PKC) en/of die mitogeen-geaktiveerde kinases (MAPKs), spesifiek die p38 MAPKs. Laasgenoemde se rol in PK is steeds kontroversieël. Die doel van die studie was dus: (A) karakterisering van die veranderinge in die sikliese nukleotiede, cAMP en cGMP, en p38 MAPK wat tydens die hele eksperimentele prosedure plaasvind, in 'n poging om meer insig te verkry aangaande moontlike meganismes betrokke in isgemiese PK (Hoofstuk 3); (8) bepaling van die belang van die waargenome veranderinge in cAMP en cGMP deur hulonderskeie paaie farmakologies te manipuleer (Hoofstukke 4 en 5); (C) bepaling van die rol van p38 MAPK in PK: betrokkenheid as stimulus of mediator (Hoofstuk 6). Geïsoleerde, geperfuseerde werkende rotharte is geprekondisioneer deur blootstelling aan 3 x 5 min globale isgemie, afgewissel met 5 min herperfusie, gevolg deur 25 min globale isgemie en 30 min herperfusie. Funksionele herstel tydens herperfusie is as eindpunt gebruik. Harte is op verskillende tye tydens die PK protokol, volgehoue isgemie, asook herperfusie gevriesklamp. Weefsel sikliese nukleotiede (cAMP en cGMP), die aktiwiteit van sikliese nukleotied fosfodiesterases (cAMP- en cGMP-PDE), adeniel siklase en protein kinase A (PKA) asook die eienskappe van die p-adrenerge reseptor is gemeet. p38 MAPK aktivering is met Westerse oordragtegnieke bepaal, deur van dubbel gefosforileerde p38 MAPK (Thr180fTyr182) antiliggame asook geaktiveerde transkripsie faktor 2 (ATF2) gebruik te maak. Die rol van p38 MAPK in PK beskerming is evalueer deur die effek van inhibisie van p38 MAPK aktivering met SB 203580, in volwasse geïsoleerde rot kardiomiosiete asook in geïsoleerde geperfuseerde rotharte, te bepaal. Na aanleiding van die resultate, is voorgestel dat, tydens 'n multi-siklus isgemie PK protokol, stimuli (moontlik endogene katekolamiene en NO) vrygestel word wat die sikliese veranderinge in sikliese nukleotiede, cAMP en cGMP, veroorsaak. Beide hierdie sikliese nukleotiede aktiveer die distale stres kinase, p38 MAPK, op 'n betekenisvolle, maar verbygaande manier. Hierdie kinase mag verdere distale aanpassingsprosesse stimuleer. Die volgehoue isgemiese periode van PK harte is gekenmerk deur verminderde cAMP en verhoogde cGMP vlakke, asook verminderde aktivering van p38 MAPK. Hierdie veranderinge is met beskerming van die hart teen isgemie geassosieer. Daarbenewens, farmakologiese vermindering van p38 MAPK aktivering tydens volgehoue isgemie het tot verbeterde funksionele herstel gelei. Die gevolgtrekking is gemaak dat die beskermende effek van PK die gevolg is van verminderde aktivering van isgemies-geïnduseerde p38 MAPK. Farmakologiese manipulasie van hierdie kinase moet in die toekoms as terapeutiese modaliteit oorweeg word.
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Ferreiro, Neira Isabel. "Transcriptional regulation by the mammalian stress-activated protein kinase p38." Doctoral thesis, Universitat Pompeu Fabra, 2011. http://hdl.handle.net/10803/80661.
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Regulation of transcription by Stress Activated Protein Kinases (SAPKs) is an essential aspect for adaptation to extracellular stimuli. In mammals, the activation of the p38 SAPK results in the regulation of gene expression through the direct phosphorylation of several transcription factors. However, how p38 SAPK regulates the proper gene expression program of adaptation to stress as well as the basic mechanisms used by the SAPK remains uncharacterized. The results displayed in this manuscript show that the p38 SAPK plays a central role in the regulation of gene expression upon stress, as up to 80% of the upregulated genes are p38 SAPK dependent. Moreover, we also observed that a specific set of genes were upregulated in response to each specific stimuli, and just a small set of genes were commonly up-regulated by several stresses, which involves mainly transcription factors. In addition, we observed that, to proper regulate gene transcription, the p38 SAPK is recruited to stress-induced promoters via its interaction with transcription factors. Additionally, p38 activity allows the recruitment of RNA polymerase II and the MAPKK MKK6 to stress-responsive promoters. The presence of active p38 SAPK at open reading frames also suggests the involvement of the SAPK in elongation. Altogether, the results showed in this manuscript establish the p38 SAPK as an essential regulator in the transcriptional response to stress, as well as define new roles for p38 in the regulation of transcription in response to stress.La regulación de la transcripción por las Proteínas Quinasas activadas por Estrés (SAPKs) es un aspecto esencial para la adaptación a los estímulos extracelulares. En mamíferos, la activación de la SAPK p38 da lugar a la regulación de la expresión génica a través de la fosforilación de varios factores de transcripción. Sin embargo, cómo p38 SAPK regula el programa de expresión génica de adaptación al estrés así como los mecanismos utilizados por la SAPK permanece sin caracterizar. Los resultados presentados en este manuscrito muestran que p38 SAPK juega un rol central en la regulación de la expresión génica en respuesta a estrés, ya que hasta el 80% de los genes inducidos son dependientes de p38 SAPK. También observamos que en respuesta a cada tipo de estrés se induce un grupo de genes específicos, y sólo hay una pequeña respuesta de genes comunes a los diferentes tipos de estrés la cual engloba principalmente factores de transcripción. Además, hemos observado que para regular la transcripción, p38 se recluta a los promotores de respuesta a estrés a través de su interacción con factores de transcripción. Asimismo, la actividad de p38 permite el reclutamiento de la RNA Polimerasa II y de la MAPKK MKK6 a los promotores inducidos por estrés. La presencia de p38 activa en las regiones codificantes sugiere su participación durante la elongación. En conjunto, los resultados mostrados en este manuscrito establecen a p38 como un regulador esencial de la transcripción en respuesta a estrés, así como definen nuevas funciones de p38 en la regulación de la transcripción en respuesta a estrés.
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Wieland, Andreas [Verfasser]. "Funktion der p38 mitogenaktivierten Proteinkinase in kultivierten Pankreaskarzinomzellen / Andreas Wieland." Ulm : Universität Ulm. Medizinische Fakultät, 2014. http://d-nb.info/1049561392/34.
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Niswander, Julie M. "Molecular Correlates of Adaptation and Apoptosis: p38 Signaling in Hippocampus." University of Toledo Health Science Campus / OhioLINK, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=mco1085678685.
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Roger, Séverine. "Implication des MAP Kinases ERK2 et p38 dans l'activation plaquettaire." Paris 7, 2005. http://www.theses.fr/2005PA077165.
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Sakurai, Kenji. "Cutaneous p38 mitogen-activated protein kinase activation triggers psoriatic dermatitis." Doctoral thesis, Kyoto University, 2020. http://hdl.handle.net/2433/245835.
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京都大学0048
新制・課程博士
博士(医学)
甲第22150号
医博第4541号
新制||医||1039(附属図書館)
京都大学大学院医学研究科医学専攻
(主査)教授 竹内 理, 教授 稲垣 暢也, 教授 杉田 昌彦
学位規則第4条第1項該当
Doctor of Medical Science
Kyoto University
DFAM
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Loonat, Aminah Ahmed. "The involvement of p38 gamma MAPK in pathological cardiac hypertrophy." Thesis, King's College London (University of London), 2016. http://kclpure.kcl.ac.uk/portal/en/theses/the-involvement-of-p38gamma-mapk-in-pathological-cardiac-hypertrophy(f00e26a7-dab2-474d-9d3e-a52dfe9e873e).html.
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p38-mitogen activated protein kinases (p38-MAPKs) are stress activated serine/threonine kinases that are activated during several different cardiac pathologies. Classically, studies have focused solely on p38α signaling in the heart. However, there is also high cardiac expression of the p38γ isoform but little is known about its cardiac function. The aim of this study was to elucidate the signaling pathway of p38γ, with a particular focus on its role in the progression of pathological cardiac hypertrophy. Comparisons of cardiac function and structure of wild type (WT) and p38γ knock out (KO) mice, in response to abdominal aortic banding, found that KO mice developed less ventricular hypertrophy than their corresponding WT controls, and have preserved cardiac function. Basal p38γ myocardial staining was primarily localised at the membranes and throughout the cytoplasm. Following aortic constriction, nuclear staining of p38γ increased, but no accumulation of p38α was observed. This suggests that the two isoforms play distinct roles in the heart. To elucidate its signaling pathway, we generated an analogue sensitive p38γ, which is mutated at a gatekeeper residue, to specifically track and identify its endogenous substrates in the myocardium. The mutation allows only the mutant kinase, but not WT kinases, to utilise analogues of ATP that are expanded at the N6 position and contain a detectable tag on the γ-phosphate. Transfer of this tag to substrates allows subsequent isolation and identification. Furthermore, unlike other p38-MAPKs, p38γ contains a C-terminal PDZ domain interacting motif. We have utilised this motif in co pull-down assays to identify interacting proteins of p38γ in the heart. Using these techniques we have identified, amongst other substrates, LDB3 and calpastatin as novel substrates of p38γ and we have determined the residues that are targeted for phosphorylation. Lastly we have shown that phosphorylation of calpastatin reduces its efficiency as a calpain inhibitor in vitro, hence proposing a mechanism by which p38γ may mediate its pro-hypertrophic role.
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Domeyer, David. "Docking-basiertes virtuelles Wirkstoff-Design von p38 MAP Kinase-Inhibitoren /." [S.l. : s.n.], 2005. http://www.gbv.de/dms/bs/toc/52427083X.pdf.
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Niswander, Julie Marie. "Molecular correlates of adaptation and apoptosis : p38 signaling in hippocampus." Connect to full-text via OhioLINK ETD Center, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=mco1085678685.
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Thesis (Ph.D.)--Medical College of Ohio, 2004."In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Medical Sciences." Major advisor: Linda A. Dokas. Document formatted into pages: iv, 150 p. Title from title page of PDF document. Bibliography: pages 44-52.
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Bruns, Svenja Anne [Verfasser]. "Autophagy regulation by the p38 MAP kinase / Svenja Anne Bruns." Magdeburg : Universitätsbibliothek, 2017. http://d-nb.info/1128726491/34.
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Wissing, Erin R. "Uncovering the complexity of muscular dystrophy pathology through disease signaling." University of Cincinnati / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1393236115.
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Dietrich, Justin David. "The Design, Synthesis, and Evaluation of Novel DFG-out Allosteric Kinase Inhibitors." Diss., The University of Arizona, 2008. http://hdl.handle.net/10150/195661.
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Today, current drug discovery and lead generation efforts focus on high throughput screening of large chemical libraries as the primary source of lead candidates. A lack of investment in novel chemotype development by pharmaceutical companies over the last 15 years coupled with the concurrent merger of screening collections and the availability of generic compound libraries commercially have resulted in many discovery efforts that lack uniqueness and do not offer a strong patent position to operate. The need for better, more diverse, and more drug-like libraries is essential in order to feed high throughput screening efforts with molecules that probe new dimensions of chemical space and allow for the discovery of untapped intellectual property.This dissertation details a complete structure based study to design novel inhibitors of B-Raf and p38a MAP Kinase. A structural evaluation of the important and similar interactions necessary for DFG-out allosteric inhibitors to bind their respective targets was accomplished through the synthesis and evaluation of three known allosteric kinase inhibitors, Gleevec®, Nexavar®, and BIRB-796, and 8 additional DFG-out allosteric inhibitors that were developed directly from fragments of these successful scaffolds. The structural insight that was gained from the evaluation of known DFG-out allosteric inhibitors was then utilized to design novel inhibitors that incorporated two unique scaffolds based on two new [3+2] cycloaddition reactions.A pyrrolo-3,4-dicarboximide scaffold has been developed through the utilization of a novel tandem [3+2] cycloaddition then elimination reaction scheme. This scaffold, which contains three sites for variation, was then rationally incorporated into lead molecules using structure-based methods and in silico feedback for the production of dual DFG-out allosteric kinase inhibitors of p38a and B-Raf kinase. These inhibitors display micromolar to submicromolar enzymatic IC50's for both p38a and B-Raf kinase and low micromolar inhibition of cell growth in 4 separate cancer cell lines.We also explored new chemistry that utilizes a key one pot, [3+2] cycloaddition reaction to obtain highly substituted imidazoles and their application in the design of specific allosteric B-Raf inhibitors. Inhibitors based on this scaffold display subnanomolar potency and a favorable kinase profile.
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Youssif, Catrin. "Myeloid p38 MAPK signaling in intestinal homeostasis, inflammation and tumorigenesis = Señalización por la MAPK p38 de células mieloides en la homeostasis, inflamación y tumorogénesis intestinal." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/462108.
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Chronic inflammation is a hallmark of colon cancer, and patients with inflammatory bowel disease are prone to developing colon tumors. In recent years, many efforts have been devoted to characterize the interplay between inflammation, the tumor microenvironment and tumorigenesis. However, the molecular and cellular events involved in the pathogenesis of colitis-associated carcinogenesis are not fully understood.
Myeloid cells play a key role in the tumor microenvironment, regulating tumor growth and therapeutic responses. One of the pathways that is often implicated in inflammatory diseases and cancer relies on the protein kinase p38. Specifically, p38 is a key regulator of epithelial cell homeostasis protecting against inflammation-associated colon tumorigenesis in mice. However, the contribution of myeloid p38 to colitis-associated tumorigenesis has been largely neglected. Therefore, the objective of this thesis is to investigate the role of myeloid p38 in intestinal mucosal repair and its implications in colorectal cancer by performing in vivo assays in mice. We further complemented the in vivo experiments using cellular models.
We observed that mice with myeloid cell-specific downregulation of p38α generate less colon tumors in response to AOM/DSS treatment compared to wild-type mice. Our results extend previous findings indicating that myeloid p38 is a key mediator of inflammatory responses, and identify insulin-like growth factor-1 (IGF-1) as a novel effector downstream of p38 signaling in macrophages. To our knowledge, the regulation of IGF-1 by p38 in macrophages has not been described previously. IGF-1 is a natural growth hormone that is known to have also anti-inflammatory and pro-repair functions. We found that myeloid cells are a major source of IGF-1 in the large intestine, and genetic or pharmacological inhibition of IGF-1 suppresses inflammatory cell recruitment and reduces colitis-associated colon tumor burden.
Ly6ChiCCR2+ monocytes are continuously generated in the bone marrow from hematopoietic stem cells and recruited to healthy and injured tissues, where they give rise to intestinal effector cells. Our studies demonstrate that Ly6ChiCCR2+ monocytes are reduced in p38-ΔMC mice and IGF-1-ΔMC mice compared to WT mice, even without any treatment. We believe this is important for the observed phenotype, given the key role of inflammatory monocytes in triggering the recruitment of other immune cells as well as in the initiation of the adaptive immune response. Our results indicate that suppression of p38 in myeloid cells ameliorates intestinal inflammation mainly through repression of inflammatory cell recruitment, which in turn results in reduced tumor burden. Several human and mouse studies have demonstrated that the regulation of inflammatory cytokines by p38 plays important roles in the pathogenesis of inflammatory diseases. In accordance, we observed that p38 in myeloid cells positively regulates key inflammatory mediators during intestinal inflammation. However, our results indicate that the decreased levels of inflammatory mediators and IGF-1 observed in DSS-treated p38-ΔMC mice correlates with a reduced number of infiltrated immune cells.
Currently, the IGF-1 pathway is gaining tremendous interest due to its important role in cancer as well as inflammatory bowel disease, not only by modulating the innate and acquired immune system, but also through its multi-functional involvement in the tumor microenvironment. Our results suggest that targeted inhibition of the p38 pathway in myeloid cells could be therapeutically useful especially in tumors associated with chronic inflammation. Of note, IGF-1 is known to have mitogenic and anti-apoptotic functions, in addition to its role in inflammatory cell recruitment. Therefore, the targeting of extracellular effectors produced by myeloid cells that are implicated in disease pathogenesis such as IGF-1 might overcome the difficulty of targeting specific cell types.
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Lazarus, Philip. "Mechanism of decrease of protein synthesis by sodium cyanate in murine P388 leukemia cells." Thesis, McGill University, 1987. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=75367.
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The objective of this study was to examine the inhibition of protein synthesis in murine P388 cells by sodium cyanate (NaOCN). The characterization of amino acid transport systems present in P388 cells provided a basis for some of these studies. NaOCN had no effect on the kinetics of amino acid transport systems L, A, ASC, N, or y$ sp+.$ The decrease in protein synthesis seen after NaOCN treatment was not secondary to alterations in amino acid metabolism or changes in nucleotide pools. Significant reductions in DNA and RNA synthesis were observed in P388 cells from NaOCN pretreated mice. No effect with NaOCN was observed on total cellular RNA. NaOCN does not appear to affect the P388 cell ribosomal machinery, tRNA or protein synthesis elongation processes. The formation of the 48 S initiation complex was significantly inhibited by NaOCN. These results suggest that the decrease in protein synthesis observed with NaOCN in P388 cells is due to alterations in mRNA synthesis and/or the inhibition of the early stages of protein synthesis initiation.
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Patel, Niranjan M. "Multicomponent network and linear polymer systems : thermal and morphological characterization /." Diss., This resource online, 1990. http://scholar.lib.vt.edu/theses/available/etd-07122007-103930/.
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Pascual, Vincent D. "The conceptual design and evaluation of an accuracy control system to support the hull construction of aircraft carriers." Master's thesis, This resource online, 1991. http://scholar.lib.vt.edu/theses/available/etd-01122010-020056/.
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Leipelt, Juliano. "Avaliação in vitro do potencial biológico de Myrciaria plinioides (D. Legrand) em células tumorais." reponame:Repositório Institucional da UNIVATES, 2016. http://hdl.handle.net/10737/1110.
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O câncer é apontado como a segunda maior causa de morte em todo o mundo, com previsão de em breve ser tornar a primeira. O câncer de próstata está entre os 5 tipos de câncer mais diagnosticados em homens, sendo que o câncer hepático está em segundo lugar em taxa de mortalidade entre homens e mulheres. Indícios apontam para uma ativação das vias da inflamação associados a uma inibição das vias de morte celular no processo de carcinogênese. A regulação destas vias torna-se alvo importante e complementar no controle do câncer, sendo estimulada a busca de biomoléculas com este potencial. As plantas são importante fonte de descoberta de novas biomoléculas com ampla utilização para o tratamento de diversas patologias. A família Myrtaceae possui diversas espécies que são apontadas como fortes candidatos em potencial nesta busca, incluindo as do gênero Myrciaria. A espécie Myrciaria plinioides não possui estudos referentes suas propriedades terapêuticas ou a atuação em vias de sinalização envolvidas na inflamação ou na carcinogênese. Neste contexto, este estudo teve por objetivo avaliar a atividade do extrato etanólico de M. plinioides em células de carcinoma hepatocelular (HepG2) e próstata (LNCaP) , através da análise de expressão dos marcadores p38-α, pp38-α, NF-κB e caspase-3, envolvidos na carcinogênese, e o efeito sobre a viabilidade celular através do método de MTT. A viabilidade das células foi alterada significativamente, em ambas as linhagens celulares quando tratadas com o extrato etanólico. A análise da expressão proteica demonstra significativa inibição da expressão de p38-α e caspase-3 nas células LNCaP, quando tratadas com extrato etanólico de M. plinioides seguido de LPS. Em células HepG2, somente houve alteração na expressão da caspase-3 na concentração de 200 μg/mL, com ou sem adição de LPS após tratamento com extrato. Os resultados deste estudo demonstraram redução da viabilidade celular nas duas linhagens tumorais, expressão diferenciada de proteínas envolvidas em apoptose, o que leva a indícios da ativação de mecanismos distintos pelo extrato em cada tipo celular. Estudos futuros para averiguar o mecanismo celular e a indução de morte em células tumorais de câncer de próstata e de fígado podem contribuir para a identificação e elucidação de novas biomoléculas com potencial antitumoral.
Cancer is touted as the second leading cause of death worldwide, forecast to soon be making the first. Prostate cancer is among the five most cancers diagnosed in men, and liver cancer is second in mortality between men and women. Evidence points to the activation of pathways of inflammation associated with an inhibition of cell death pathways in carcinogenesis. The regulation of these pathways becomes important and complementary target in cancer control, and stimulated the search for biomolecules with this potential. The plants are important source of discovery of new biomolecules with wide use for the treatment of various diseases. The Myrtaceae family has many species that are identified as potential candidates strong in this search, including the Myrciaria genre. The species Myrciaria plinioides not have studies on its therapeutic properties or performance in signaling pathways involved in inflammation or carcinogenesis. In this context, this study aimed to evaluate the activity of the ethanol extract of M. plinioides in hepatocellular carcinoma cells (HepG2) and prostate (LNCaP) by expression analysis of p38-α markers, PP38-α, NF-kB and caspase-3, involved in carcinogenesis, and the effect on cell viability by the MTT method. The viability of cells was significantly altered in both cell lines when treated with ethanolic extract. Protein expression analysis demonstrates significant inhibition of p38-α expression and caspase-3 in LNCaP cells, when treated with ethanolic extract of M. plinioides followed by LPS. In HepG2 cells there was only a change in the expression of caspase-3 at a concentration of 200 / ml, with or without addition of LPS after treatment with extract. The results showed reduction of cell viability in both tumor lines, differential expression of proteins involved in apoptosis, leading to evidence of activation by distinct mechanisms in each extract cell type. Further studies to investigate the cellular mechanism, and induction of death in tumor cells of prostate and liver cancer may contribute to the identification and elucidation of new biomolecules with antitumor potential.
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Paul, Anton Dilojaan. "Electrocatalytically induced liberation of mineral matter from coal." Diss., Virginia Polytechnic Institute and State University, 1988. http://hdl.handle.net/10919/82636.
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A new method for demineralizing coal has been developed which is based on the osmotic pressures that occur when electrical double layers overlap. In this technique, coal is exposed to ferric ions in an acidic medium which causes the coal to lose electrons and become positively charged, thereby establishing ionic double layers in the vicinity of its surface. Inside the pores and crevices in which mineral matter is entrapped, the ionic double layers overlap and reduce the chemical potential of water, creating an osmotic pressure. The build-up of such pressure pushes the mineral matter out of the crevices, resulting in mineral liberation. Since the process, which is termed electro catalytically induced liberation (EIL), relies on surface-chemical reactions, the energy consumption is substantially lower than in conventional liberation processes based on comminution.
Tests on several different seams of coal from varying geological locations have indicated that the process may be used to remove over 70% of the mineral matter present in coal. Mass balance studies conducted on a Wyodak coal indicate that approximately 90% of the ash removed is by the EIL mechanism, while the balance may be attributed to acid dissolution and the loss of material during handling. Scanning electron micrographs of the coal samples taken before and after treatment show morphological changes consistent with the proposed EIL mechanism. The technique has been used successfully to clean bituminous coals, low-rank coals and preparation plant refuse, and to further reduce the ash content of coals pre-cleaned by other means.
A theoretical model has been developed to calculate the osmotic pressure that occurs inside a typical coal crevice during the EIL treatment. The changes in the aqueous chemical potential are calculated using semi-empirical equations derived from solution theory, while partial molar volume changes are accounted for in the final calculation of the osmotic pressure. The model indicates that pressures on the order of 4-7 atmospheres can develop inside crevices with walls 100-1000Å apart. These values are numerically consistent with those predicted by other models developed using different approaches.Ph. D.
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Barbosa, Bruna Zelante. "Comprometimento funcional de células dendríticas derivadas de monócitos de pacientes com câncer: envolvimento das vias de sinalização p38 e ERK1/2 (p44/p42) MAPK." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/42/42133/tde-10052017-150608/.
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Células dendríticas são as principais células apresentadoras de antígeno e apresentam alterações em pacientes com câncer. As vias de sinalização ERK 1/2 e p38 MAPK participam da diferenciação de DCs derivadas de monócitos (Mo-DCs). A exposição ao sobrenadante tumoral (ST) da linhagem MCF-7 levou à diminuição de CD1a e aumento de CD14 (frequência), além do aumento de IL-6 e IL-10. A inibição da via ERK1/2 MAPK corrigiu a expressão de CD14 e corrigiu parcialmente a produção das citocinas. A inibição da via p38 MAPK corrigiu a expressão de CD1a e CD14 e diminuiu parcialmente a produção das citocinas. Identificamos a proteína de choque térmico HSP27. A exposição à HSP27 não levou às alterações observados quando as células foram expostas ao ST. Por fim, em Mo-DCs de pacientes com câncer de mama o tratamento com o inibidor da p38 MAPK diminuiu a expressão de CD86 e HLA-DR. Portanto, os resultados deste trabalho sugerem que a inibição da via p38 MAPK não parece ser uma abordagem interessante na manipulação de Mo-DCs de pacientes com carcinoma ductal invasivo de mama.Dendritic cells are the main presenting cells and present alterations in cancer patients. The signaling pathways p38 and ERK1/2 MAPK participate of monocyte-derived dendritic cells (Mo-DCs) differentiation. Exposition to MCF-7s supernatant (TS) decreased CD14 and CD1a expression (frequency) while enhanced IL-6 and IL-10 production. Inhibition of ERK1/2 MAPK reverted CD14 expression and partially reverted cytokines production. Inhibition of p38 MAPK reverted CD1a and CD14 expression and partially reverted cytokines production too. We identified the heat shock protein HSP27. Exposition to HSP27 did not cause the observed alterations seen when the cells were exposed to TS. Lastly, treatment of Mo-DCs from breast cancer patients with the p38 inhibitor decreased CD86 and HLA-DR expression. Therefore, the data presented in this study suggest that p38 MAPK inhibition does not appear to be an interesting approach in the manipulation of Mo-DCs from breast cancer patients.
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Anerillas, Aljama Carlos. "Caracterización de la senescencia celular inducida por Sprouty: papel de p38." Doctoral thesis, Universitat de Lleida, 2019. http://hdl.handle.net/10803/666058.
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Els membres de la família de proteïnes Sprouty han estat clàssicament descrits com a inhibidors de la senyalització iniciada pels receptors tirosina quinasa, sent per això reiteradament proposats com supressors tumorals. D'altra banda, la senescència cel·lular és una resposta a certs nivells d'estrès en la qual les cèl·lules decideixen abandonar la seva capacitat proliferativa i secretar un ampli ventall de factors per influir sobre l'entorn proper. Treballs previs demostren que Spry1 promou la inducció de senescència cel·lular tant en tiroide com en el desenvolupament de la vagina de manera independent a la seva acció clàssica sobre els receptors tirosina quinasa. En la present tesi hem expandit la implicació de Spry1 en senescència a paradigmes en els quals aquesta és rellevant com l'envelliment, la reparació de teixits o la senescència associada a quimioteràpia. A més, hem revelat que Spry1 respon a l'estrès oxidatiu potenciant la via p38. Per tant, els resultats exposats confirmen a les proteïnes Spry com a mediadors generals de la senescència cel·lular.Los miembros de la familia de proteínas Sprouty han sido clásicamente descritos como inhibidores de la señalización iniciada por los receptores tirosina quinasa, siendo por ello reiteradamente propuestos como supresores tumorales. Por otro lado, la senescencia celular es una respuesta a ciertos niveles de estrés en la que las células deciden abandonar su capacidad proliferativa y secretar un amplio abanico de factores para influir sobre el entorno próximo. Trabajos previos demuestran que Spry1 promueve la inducción de senescencia celular tanto en tiroides como en el desarrollo de la vagina de manera independiente a su acción clásica sobre los receptores tirosina quinasa. En la presente tesis hemos expandido la implicación de Spry1 en senescencia a paradigmas en los que ésta es relevante como el envejecimiento, la reparación de tejidos o la senescencia asociada a quimioterapia. Además, hemos desvelado que Spry1 responde al estrés oxidativo potenciando la vía p38. Por tanto, los resultados expuestos confirman a las proteínas Spry como mediadores generales de la senescencia celular.
Members of Sprouty family of genes (Spry1-4) have been classically assumed to be inhibitors of signaling initiated by receptor tyrosine kinases. As such, they have been proposed as tumor suppressor genes. On the other hand, cellular senescence is a response in front of different cellular stresses in which cells decide to cease their proliferation. Moreover, senescent cells implement the secretion of a myriad of factors to influence their proximal environment. Previous data from our group demonstrate that Spry1 promotes cellular senescence in the thyroid gland and in vaginal development, but in an ERK-independent manner. The present work expands the implications of Spry genes to other cellular senescence scenarios such as age-related and regeneration-related senescence. Surprisingly, Spry1 induction in the senescent response is controlled by oxidative stress. Mechanistically, Spry proteins enhance p38 MAPK activation required for the proper induction of most of the traits of cellular senescence. Hence, these results confirm Spry genes as novel, general mediators of cellular senescence.
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Sarafraz, Shekary Negin. "Contribution of p38 mitogen-activated protein kinase isotypes to cardiac physiology." Thesis, King's College London (University of London), 2010. http://kclpure.kcl.ac.uk/portal/en/theses/contribution-of-p38-mitogen-activated-protein-kinase-isotypes-to-cardiac-physiology(9976a51e-2703-4ead-8746-a1bbc3a56326).html.
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The isoform-specific functions of the four isoforms of p38 mitogen-activated protein kinase (p38 α-, β-, γ- and δ- MAPK) in the adult heart are largely unknown, partly due to the lack of isotype-specific tools to manipulate or measure p38 MAPK isoform activity. Improved understanding of p38 MAPK isoform regulation will benefit development of selective pharmacological inhibitors and move towards eliminating the potential drawbacks of chronic systematic inhibition of this important kinase. This Thesis describes our investigation of endogenous expression of p38 MAPK in the murine heart; the functional contributions of endogenously expressed p38 MAPK in response to clinically-relevant stimuli such as such as pharmacological preconditioning, ischaemia and reperfusion, and pro- inflammatory cytokines (central in the progression of heart failure, such as TNF-α, IL-1) and osmotic stress; and the involvement of p38 and MAPK isoforms in left ventricular (LV) remodelling in response to in vivo models of cardiac hypertrophy and following myocardial infarction (MI). Using commercially available isoform-specific antibodies we have demonstrated that all p38 MAPK isoforms are expressed in the murine heart with p38α and being the most abundant. p38β and MAPK expressed at lower levels. The transcripts for all the p38 MAPK isoforms were detected. Immunocytochemistry of isolated cardiac myocytes demonstrated a diverse localization of p38 MAPK isoforms which suggest different functions. In isolated perfused hearts, we showed that mice lacking the β isoform (p38β KO) are refractory to pharmacological preconditioning by the carbon monoxide-releasing molecule, CORM-3. Our data demonstrate that CORM-3 pre-treatment followed by a 5 min washout of hearts prior to an in vitro ischaemia-reperfusion results in decreased infarct size and preserved LV function. With respect to p38 and δ isoforms, we observed a significant reduction in left ventricular developed pressure in response to sorbitol (osmotic stressor) in wild type (WT) hearts which was significantly ameliorated in p38 knockout (p38 KO) hearts. This was accompanied by a reduction in the level of p38 MAPK phosphorylation in transgenic mice compared with the WT. A comparable response was observed between WT and p38 KO mice in response to the other stimuli. The potential roles of p38 and δ MAPK were examined in a model of isoproterenol (ISO)-induced cardiac hypertrophy. Our studies revealed no significant differences between the WT and the transgenic phenotypes in response to hypertrophic stimuli. Infusion of ISO resulted in comparable LV remodelling, as assessed by echocardiography. In addition, no differences were observed in the cardiac function (assessed by pressure volume analysis) between the two genotypes. These finding suggest that p38γ and δ MAPK are unlikely to be involved in geometric remodelling of hypertrophy. Investigating the possible contribution of p38γ and δ MAPK in post-MI remodelling in vivo (using a permanent left anterior descending artery ligation model) revealed no apparent difference between WT and p38 KO mice. Echocardiographic and pressure-volume analysis showed comparable LV dilatation in WT and p38δ KO mice. Our data confirmed that p38α MAPK is the dominant isoform in the murine myocardium and is activated in response to ischaemia, ischaemia reperfusion and a number of pro-inflammatory cytokines. We propose that p38β MAPK is implicated in pharmacological preconditioning whereas p38γ and δ isoforms appear to be important in the myocardial response to osmotic stress. p38γ and δ isoforms also seem to be implicated in LV remodelling and somehow contribute to functional changes during cardiac hypertrophy and following-MI.
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Nishimura, Masaki. "Activation of p38 kinase in the gerbil hippocampus showing ischemic tolerance." Kyoto University, 2005. http://hdl.handle.net/2433/144725.
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Kyoto University (京都大学)0048
新制・課程博士
博士(医学)
甲第11401号
医博第2824号
新制||医||888(附属図書館)
23044
UT51-2005-D151
京都大学大学院医学研究科脳統御医科学系専攻
(主査)教授 下遠野 邦忠, 教授 淀井 淳司, 教授 影山 龍一郎
学位規則第4条第1項該当
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Fritz, Martina Désirée. "p38 MAP Kinase Inhibitoren : Synthese, Analytik und biologische Testung substituierter Isoxazole /." [S.l. : s.n.], 2004. http://www.gbv.de/dms/bs/toc/39191703X.pdf.
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Lepage, Pierre 1962. "Activation of the mouse mdr3 gene in multidrug resistant derivatives of the lymphoid tumor P388." Thesis, McGill University, 1995. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=28822.
Full textAbstract:
In independently derived drug resistant sublines of the mouse lymphoid tumor P388, multidrug resistance (MDR) is associated with the exclusive overexpression of the mdr3 gene, which occurs either from a single copy gene (P388/VGR-10) or after gene amplification (P388/ADM-2). The mechanism underlying mdr3 overexpression in these cells was investigated. Nucleotide sequence analysis revealed the presence of several putative cis-regulatory elements in the genomic region overlapping the transcription start site of mdr3. However, the 5$ sp prime$ end of mdr3 mRNAs was shown to be altered in the MDR derivatives of P388, indicating that the normal start site is not used in these cells. In the two cell lines, these alterations are associated with a genomic rearrangement in the 5$ sp prime$ region of the gene caused by the insertion of retroviral sequences. In P388/ADM-2, the integration of an intracistemal A particle within an L1Md repetitive element immediately upstream of mdr3 results in the activation of the gene. In P388/VCR-10 cells, transcriptional activation of mdr3 is caused by the integration of an intact mouse mammary tumor virus (MMTV) within intron I in the opposite transcriptional (antisense) orientation compared to that of the gene. This integration results in the production of MMTV/mdr3 fusion transcripts from a cryptic promoter in the 5$ sp prime$ long terminal repeat (LTR) of the provirus. In transient transfection experiments, it was shown that the antisense 5$ sp prime$ LTR alone only weakly activates the reporter gene luciferase. However, addition of mdr3-derived sequences from intron I downstream of the 5$ sp prime$ LTR strongly activates the expression of luciferase, suggesting the presence of an activator/enhancer element in this region. These results and subsequent identification of independent genomic rearrangements in the 5$ sp prime$ region of mdr3 in additional MDR P388 derivatives analyzed in this study suggest a mechanism of gene activation i
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Klameth, Nelli [Verfasser], and Martin A. [Akademischer Betreuer] Wahl. "Permeationsmechanismus und intrazelluläre Aufnahme von p38α-MAP-Kinase-Inhibitoren / Nelli Klameth ; Betreuer: Martin A. Wahl." Tübingen : Universitätsbibliothek Tübingen, 2016. http://d-nb.info/1197694722/34.
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