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1
Asselain, Valentin. "A la recherche de l'épanouissement et de la durabilité au travail. Les dilemmes de la professionnalisation des cueilleurs et cueilleuses de plantes sauvages en France." Electronic Thesis or Diss., université Paris-Saclay, 2025. http://www.theses.fr/2025UPASB018.
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La cueillette commerciale de plantes sauvages a pris progressivement le pas sur les cueillettes que réalisaient les familles paysannes jusqu'aux années 1960 pour compléter leurs revenus. Elle a suivi le cours des mutations du monde agricole et de l'industrie pharmaceutique depuis la moitié du XXème siècle, s'est diversifiée et répond aujourd'hui à de nouvelles attentes sociétales vis-à-vis de la nature et du soin. Les cueilleurs et cueilleuses contemporains, disséminés sur tout le territoire et plus particulièrement dans les zones de moyenne montagne, font appel à un très large éventail de pratiques. Que ce soit en termes de volumes de cueillette, de procédés de transformation, de modes de commercialisation ou encore de rapport à la nature, le groupe professionnel des cueilleurs est marqué par une forte hétérogénéité. Dans leur très grande majorité, les cueilleurs pratiquent aussi la mise en culture de Plantes à Parfum, Aromatique et Médicinales (PPAM), et diversifient leurs sources de revenus.Le rapport au travail des cueilleurs est marqué par l'importance que prennent les dimensions sensibles vis-à-vis des plantes, et plus généralement des milieux naturels qu'ils sont amenés à sillonner de saison en saison. Ils se démarquent ainsi du processus de modernisation agricole ayant dépossédé les paysans de leurs savoirs, au profit d'une relation jugée privilégiée avec la nature et marquée par l'empirisme. Toutefois, diverses menaces planent sur la ressource en plantes sauvages côtoyée par les cueilleurs. Ce métier, jugé attractif et investi par un grand nombre de personnes ces dernières années, est encore mal reconnu par les pouvoirs publics, et peu audible au sein de la profession agricole. L'organisation des cueilleurs en collectifs (associations, syndicats...) œuvre ainsi à la professionnalisation de l'activité. Cette dernière, faite d'une variété de “chemins” sur lesquels s'embarquer ou pas, mène les cueilleurs à redéfinir les contours de leur activité, à se mettre en lien avec de nouvelles “écologies” professionnelles, mais aussi questionner le bien-fondé de telles initiatives. Ces dernières sont en effet ambivalentes, d'autant plus quand les métiers concernés sont en proximité avec le vivant.Après trois années d'entretiens et d'immersion auprès des cueilleurs et des acteurs institutionnels ou économiques proches des cueillettes commerciales, nous tâcherons de répondre à la question suivante : en quoi la professionnalisation de la cueillette pourrait ou non participer à l'émancipation des cueilleurs et la durabilité du métier ? La professionnalisation est souvent le signe d'un bouleversement de l'activité, vers une plus grande normalisation. La voie est donc étroite, entre le souhait de conserver les aspects émancipateurs du métier, et la réponse collective à apporter à différentes menaces, que ce soit la pression sur les milieux naturels, les effets de la mondialisation du marché des plantes, les conséquences du dérèglement climatique ou encore les possibles effets de concurrences entre cueilleurs sur leurs propres sitesThe interest of new actors for professional foraging in continental France has been growing since the 80's. Nowadays, foragers are found everywhere on the territory, especially in semi-montaneous regions. They display a wide range of practices, whether on the amout of gathered plants, their transformation processes, their commercialisation methods or their relation with their environment. Thus, the foragers' professional group is characterised by its heterogeneity. For the most part, they complement their gatherings with the cultivations of Medicinal and Aromatic Plants (MAPs), and look for the diversification of their incomes.The foragers' relationship with work is marked by their sensitivity with plants, and more generally with the natural environments they roam. They differentiate themselves from the agriculture's post-WW2 modernisation process that stripped the agricultors of their traditional knowledge. On the contrary, foragers have maintained a priviledged relation with nature, a direct relation with the living and empirism-driven skills. Nevertheless, the ressource seeked by foragers is under threat. There has been growing interest for their work, and many people started to forage in the past years. But they still lack from recognition, both by the institutions or within the rural world. In response, foragers organised themselves into collectives (syndicates, associations…) and are professionalising their activity. It consists of a series of “paths” on which foragers can decide if they want to engage themselves or not. They are let to redefine the boudaries of their occupation, get in touch with new professional “ecologies”, but can also question the merits and the validity of such processes. In fact, professionalisation is an ambiguous process, even more for activites close from nature.After three years of interviews and immersion in the world of the foragers and the institutions and economic players with whom they are in contact, we will attempt to answer the following question: in what extent the foragers' professionnalisation could participate to their emancipation and the sustainability of their activity ? Professionalising an activity often leads it to its normalisation. Thus, there is only a narrow path between the will to preserve the emancipatory facets of an occupation, and answering collectivly to what threatens it, such as the various pressures on natural habitats, the consequences of climate change, or the possible competition between foragers themselves on their own sites
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Olson, Peter. "PPAR gamma and PPAR delta in glucose and lipid homoeostasis /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2004. http://wwwlib.umi.com/cr/ucsd/fullcit?p3153704.
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Pereira, Viviane Cássia. "Atividade agonista do extrato de Tabebuia heptaphylla sobre os receptores proliferadores peroxissomais Alfa (PPAR a), Beta/Delta (PPAR ß/d) e Gama (PPAR y)." reponame:Repositório Institucional da UnB, 2008. http://repositorio.unb.br/handle/10482/3549.
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Tese (doutorado)—Universidade de Brasília, Faculdade de Ciências da Saúde, 2008.Submitted by Fernanda Weschenfelder (nandaweschenfelder@gmail.com) on 2009-09-29T18:25:17Z No. of bitstreams: 1 Tese_Viviane Cassia.pdf: 1166417 bytes, checksum: 3e62e6213c9494fb3bfe6b2703e4a35d (MD5)
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Nas últimas décadas, a prevalência de distúrbios do metabolismo, tais como obesidade, síndrome metabólica e diabete melito, tem aumentando drasticamente, se tornando uma epidemia global. Dessa forma, novas estratégias terapêuticas para a contenção do avanço dessas patologias terão grande impacto na saúde pública. Os receptores dos proliferadores peroxissomais (PPARs) têm sido utilizados como alvos farmacológicos para o tratamento das alterações fisiológicas supracitadas. PPARs são membros da superfamília de receptores nucleares, os quais são fatores de transcrição que se ligam ao DNA nas regiões regulatórias dos genes alvos. Os três isotipos de receptores dos proliferadores peroxissomais, PPAR?, PPAR?/? e PPAR?, atuam como sensores capazes de adaptar a expressão gênica para integrar os sinais lipídicos com genes envolvidos na regulação do metabolismo energético, adipogênese, sensibilidade à insulina e resposta imune. Plantas com propriedades antidiabéticas vêm sendo rotineiramente utilizadas para realização de screeening de novas substâncias moduladoras da atividade dos PPARs. No Brasil, diversas espécies vegetais são empregadas na medicina tradicional por pacientes diabéticos para reduzir os níveis de glicose sanguínea, dentre elas a Tabebuia heptaphylla (Vell) Toledo (conhecida popularmente como "ipê-roxo"). No presente estudo, nós utilizamos ensaios de gene repórter para investigar se extratos da entrecasca de Tabebuia heptaphylla são capazes de promover a ativação transcricional mediada pelos PPARs. O extrato hexânico, mas não o aquoso e etanólico, ativou significativamente a transcrição mediada pelo PPAR?, PPAR ?/? e PPAR?. Esses resultados sugerem que a entrecasca da Tabebuia heptaphylla possui compostos com alta atividade agonista sobre PPAR?, PPAR?/? e PPAR?, o que pode explicar seu uso popular como hipoglicemiante. _______________________________________________________________________________________ ABSTRACT
Over recent decades, the prevalence of metabolism disorders such as metabolic syndrome, obesity and diabetes have, increased drastically, becoming a global epidemic. Therefore, new effective therapies to avoid the advance these diseases will have a great impact in the public health. Peroxisome proliferators-activated receptors (PPARs) have used as a pharmacological target for the treatment of above physiological changes. PPARs are members of the nuclear receptor superfamily of transcription factors that bind to DNA in the regulatory regions of target genes. The three isotypes, PPARα, PPAR β/δ and PPARγ act like metabolic sensors capable of adapting gene expression to integrate lipid signals with genes involved in regulation of lipid metabolism, adipogenesis, insulin sensitivity and immune response. Plants with anti-diabetic proprieties have been routinely used to screening of news modulators for PPARs activity. In Brazil, many plants have been used in folk medicine by diabetic patients to reduce the glucose levels such as Tabebuia heptaphylla (Vell) Toledo(popular known as “ipê-roxo”). In the current study, using reporter gene assay in U937 cells, we investigated whether extracts from the bark of Tabebuia heptaphylla are capable to activate the transcription mediated by PPAR receptor. Our results showed that the hexanic extract, but not aqueous and ethanolic extracts, significantly activated the transcription mediated by PPARα, PPAR β/δ and PPARγ. These findings suggest that Tabebuia heptaphylla may have some compounds with high agonistic activity on PPARα, PPAR β/δ and PPARγ, which may explain its use traditional as hypoglycemiant.
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Burman, Jonatan, and Fredrik Jonsson. "Framtagning av PPAP dokumentation för fordonsindustrin." Thesis, Linnéuniversitetet, Institutionen för teknik, TEK, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-12039.
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Detta examensarbete är en del i högskoleingenjörsutbildningen vid linneuniversitetet i Växjö. Arbetet är utfört på Ackurat Industriplast AB i Lammhult. Syftet med arbetet är att ta fram samt utveckla fyra av kravelementen i Production Part Approval Process (PPAP) dokumentationen. Kravelementen vilka ingår inom ramen för detta arbete är flödesschema, process FMEA, styrplan samt kontrollinstruktioner. Ackurat har kunder inom fordonsindustrin, dessa kunder ställer höga krav på kvalitén hos produkterna från sina leverantörer. Denna kvalitetssäkring sker dels genom att leverantören skall följa krav ur ISO/ TS 16949 standarden där PPAP är en del av kvalitetssäkringen. Detta innebär att för varje nytt uppdrag så skall PPAP dokumentation bifogas tillsammans med ett utfallsprov. Ackurat upplever att den dokumentation som finns i dagsläget är bristfällig och i behov av uppdatering. Resultatet är utarbetat genom kartläggningsmetoden ” walk through” där en fallstudie av processer har använts . Informationen om processerna har insamlats genom observationer och intervjuer med personal i processerna. Denna empiristiska information om Ackurats processer har sedan analyserats samt sammanställts med litteraturstudien i teoridelen. Examensarbetet resulterade i fem olika flödesscheman för att illustrera det verkliga flödet i Ackurats processer. Process FMEA utarbetades och åskådliggör felmöjligheter i processflödet. Genom kartläggningsarbetet sammanställdes en styrplan där alla kontroller i processerna ingår. Slutligen utarbetades kontrollinstruktioner för de kontroller som sammanställts i styrplanen. Arbetet med kartläggningsarbetet av flödesschemat var en viktig del av genomförandet. Detta berodde på att följande dokument är uppbyggda från det aktuella flödesschemat. Stort fokus har således lagts i utvecklandet samt valideringen av de olika flödesschemana. Vid analys av dessa dokument kom författarna fram till att utformade dokument uppfyller syftet samt målen för arbetet. Denna slutsats framgick genom validering med berörd personal på Ackurat samt handledare. Likaväl som att framtagna dokument kan användas i PPAP dokumentation till Ackurats kunder så kan dokumenten användas till det interna förbättringsarbetet i företagets processer.
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Marques, Elisabete Maria Bras. "Suche nach Mutationen im PPAR-[alpha]-Gen [PPAR-Alpha-Gen] bei Patienten mit Hyperlipidämie und mit Adipositas permagna." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972185526.
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Skogsberg, Josefin. "PPAR delta : its role in cholesterol metabolism /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-604-9.
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Fiatte, Cathy. "Impact des agonistes de PPARy sur l'adhérence et la migration des cellules colorectales humaines HT29." Thesis, Metz, 2008. http://www.theses.fr/2008METZ028S/document.
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Les récepteurs activables par les proliférateurs de peroxysomes appartiennent à la superfamille des récepteurs nucléaires aux hormones. Trois isotypes de PPAR ont été identifiés¡: PPAR, PPAR et PPAR. Les PPAR sont impliqués dans la régulation du métabolisme lipidique, dans l homéostasie du glucose, la prolifération cellulaire et dans la réponse inflammatoire. Ils interviennent également dans la carcinogenèse colique et/ou la progression tumorale. Nous avons étudié l effet de l activation de PPAR et par les thiazolidinediones et les fibrates, respectivement, sur l adhérence et la migration de la lignée HT29 dérivant d adénocarcinome colique humain. Nos résultats montrent que les thiazolidinediones et le fénofibrate modifient l expression de gènes impliqués dans l adhérence et la migration des cellules HT29, en particulier lorsqu elles sont exposées de façon chronique. Un traitement long, quel que soit l agoniste, induit l expression de l intégrine 5. La modification de l expression des molécules d adhérence par les thiazolidinediones est, au moins en partie, due à un mécanisme PPAR -dépendant, et l ensemble des effets observés diffèrent selon le temps de traitement, la dose et la nature du ligand. In vivo, les thiazolidinediones inhibent la formation de métastases à distance et diminuent le volume tumoral. Administrée en prévention, la pioglitazone abolit la formation des tumeurs et métastases. Avec la même approche expérimentale, des résultats comparables sont obtenus en utilisant le fénofibrate, ligand de PPAR . En conclusion, un traitement par les agonistes de PPARg et pourrait être intéressant pour l amélioration des traitements actuels du cancer du colonPeroxisome proliferator-activated receptors (PPAR) belong to the nuclear hormone receptor family. Three isotypes, encoded by separate genes, have been identified: PPAR, PPAR and PPAR. They are involved in lipid metabolism, glucose homeostasis, cell proliferation and differentiation, and inflammatory response. They have also been implicated in colon carcinogenesis and/or tumour progression. We studied the effect of PPARg and activation by thiazolidinediones and fibrates, respectively, on adhesion and migration of colon adenocarcinoma HT29 cell line. Exposure to thiazolidinedione modifies expression of several genes involved in HT29 cell adhesion and migration, especially when cells are chronically treated with each drug. Of interest, long cell treatment either with pioglitazone, rosiglitazone or fenofibrate induced expression of integrin 5-chain. Our results suggest that the modulation of adhesion molecule expression by thiazolidinediones is partly through PPARg-dependent activation and that effects are different according to the dose and nature of ligand. In vivo, thiazolidinediones especially inhibit distant metastasis formation and diminish tumoral growth. In prevention, pioglitazone abolish tumoral and metastasis development. Using the same experimental approach, we demonstrated that fenofibrate as a ligand of PPAR raised similar results. Collectively, we conclude that treatment with PPARg or agonists may be interesting in the improvement of colon cancer treatment
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Beuzelin, Diane. "Rôle des récepteurs nucléaires PPAR gamma et PPAR alpha dans la conversion d'adipocytes blancs humains en adipocytes bruns/brites." Thesis, Toulouse 3, 2015. http://www.theses.fr/2015TOU30346/document.
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Chez les mammifères, deux types de tissu adipeux (TA) sont présents: le TA blanc, qui est l'organe de stockage et de libération des lipides, et le TA brun, qui est un organe spécialisé dans la production de chaleur grâce à l'expression de la protéine découplante mitochondriale UCP1.Chez l'homme, la présence d'un TA brun métaboliquement actif est inversement corrélée à l'obésité et au diabète de type 2. Ce TA brun est composé de deux types distincts de cellules thermogéniques, les adipocytes bruns classiques présents dans des dépôts spécifiques et les adipocytes "brite " (brown-in-white). Chez la souris, les adipocytes " brite " apparaissent dans le TA blanc lors d'une exposition au froid et sont protecteurs contre l'insulinorésistance induite par l'obésité. Ainsi le "brunissement " du TA blanc ouvre la voie à de nouvelles approches thérapeutiques pour lutter contre les pathologies associées à l'obésité. Toutefois, la capacité des adipocytes blancs humains à acquérir un métabolisme brun/brite reste méconnue. Notre étude cherche donc à identifier les changements moléculaires et métaboliques associés à la conversion d'adipocytes blancs humains différenciés en adipocytes " brite ", après un traitement par des agonistes des récepteurs nucléaires PPARgamma ou PPARalpha. Dans un premier temps, nous avons montré in vitro que les cellules hMADS(adipocytes humains dérivés des cellules souches mésenchymateuses), différenciées en adipocytes blancs sont convertis en adipocytes " brites " par les agonistes PPARgamma et PPARalpha. Ces adipocytes brites ont une activité mitochondriale élevée et expriment la protéine découplante UCP1. Dans un deuxième temps, nous avons mis en évidence que le brunissement s'accompagne d'un profond changement métabolique. La mise en place d'un cycle futile lipolyse/ré-estérification couplé à une augmentation de l'oxydation des acides gras permet de fournir les substrats nécessaires à la thermogenèse mitochondriale. A l'inverse, le transport et l'oxydation du glucose sont diminués notamment suite à l'inhibition de la pyruvate déshydrogénase par la protéine PDK4. A la place le glucose va être dirigé vers la voie de la glycéronéogenèse pour fournir le glycérol-3-phosphate nécessaire à la synthèse des triglycérides. Ainsi, l'ensemble du métabolisme des adipocytes " brite " est réorganisé vers l'utilisation des acides gras comme source principale d'énergie. Enfin, nous avons validé l'implication de PPARalpha dans les mécanismes de brunissement in vivo grâce à l'utilisation de souris dont le gène codant pour PPARalpha a été invalidé. L'induction du brunissement par un agoniste betea3-adrénergique nous a permis de confirmer que PPARalpha est nécessaire à l'expression optimale des gènes thermogéniques et au brunissement du tissu adipeux blanc. L'ensemble de ces données permet d'affirmer que chez l'homme, les adipocytes blancs sont capables de se convertir en adipocytes " brite ". Cette conversion s'accompagne de changements métaboliques qui favorisent l'utilisation intracellulaire des acides gras, ce qui pourrait diminuer leur niveau plasmatique limitant ainsi leur stockage ectopique dans les tissus insulinosensiblesTwo types of adipose tissue are present in mammals, white and brown adipose tissue. White adipose tissue (WAT) is specialized in storage and release of lipids, and brown adipose tissue (BAT) is specialized in energy dissipation as heat through the mitochondrial uncoupling protein 1 (UCP1).In humans,thermogenically-competent brown adipose tissue is negatively associated with body mass index and diabetes. BAT is composed of two distinct types of thermogenic cells, classical brown adipocytes located in specific depots and brite adipocytes (brown-in white). In mice, these cells appear in WAT upon cold exposure and are protective against obesity-induced insulin resistance. Therefore, fighting obesity through "browning" of white adipose tissue emerges as a promising strategy. However, the ability of human white adipocytes to acquire a brown/brite phenotype is not yet understood. Here, we aimed at identifying the molecular and metabolic changes associated with the white-to-brown conversion of human mesenchymal adipose-derived stem (hMADS) cells following treatment by agonists of the nuclear receptor PPARgamma or PPARalpha. First, we demonstrated in vitro that PPARgamma or PPARalpha agonists similarly induce white-to-brown conversion of hMADS cells into brite adipocytes that possess high mitochondrial content and express UCP1. Second, we showed that browning is associated with profound metabolic changes. The lipolytic machinery and fatty acid re-esterification was stimulated by the two treatments, resulting in a futile cycle. These adaptations combined with an increase of fatty acid betaoxidation provide substrates to sustain the high level of mitochondrial thermogenesis. In contrast, glucose uptake and oxidation are decreased through inactivation of the pyruvate dehydrogenase by PDK4. Consequently, glucose-carbons are redirected towards glyceroneogenesis to provide the glycerol-3-phosphate backbone necessary for triglyceride esterification. Thus, brite adipocyte metabolism is modified to promote fatty acid utilization as the main energy source. In order to confirm the involvement of PPARalpha in inducing browning in vivo, we treated mice with inactivation of the PPARalpha gene with a beta3-adrenergic agonist. In subcutaneous WAT, expression of BAT- and brite-specific markers was lower in PPARalpha knock out than in wild type mice, confirming that PPARa is required for WAT browning. Altogether, this study shows that PPARgamma and PPARalpha activation in human white adipocytes promotes browning associated with an increase in fatty acid utilization without enhancement of glucose metabolism. These metabolic changes favor intra-adipose fatty acid utilization and thus could diminish plasma fatty flux for ectopic storage into insulin-sensitive tissues
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Karlevall, Jimmie. "Hur ska du investera dina PPM-pengar? : En studie om PPM-fondernas historiska avkastning." Thesis, Södertörn University College, School of Business Studies, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:sh:diva-3569.
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Purpose: The main purpose of this study is to study the 45 funds, divided into three differentdivisions, then the result will provide a greater understanding of how returns change with ahigher risk.
Methodology: The study is based on a quantitative approach. The survey was conducted bygathering raw data from databases and secondary data from literature, printed and electronicsources.
Theoretical perspectives: The study is based on the theory: the efficient markethypothesis, which argues that future returns can not be calculated as the market is fullyinformed. The study is therefore studying historical yields.
Empirical foundation: Empirical data are acquired from www.morningstar.se, andtherefore also treated on this page. The material is then divided into documents and time axes.
Conclusions: The study has shown that high-risk funds give a higher percentage returns thanmedium-and low-risk funds. However, does not imply a higher risk automatically earn ahigher return when the low-risk funds have shown a higher yield than medium-risk funds. Animportant factor to study when you are looking for the fund which generated the highest ROIis the Sharpe ratio. Although this study demonstrates that high-risk funds have a higherSharpe ratio than competing risk groups.
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Marr, Isabella [Verfasser]. "Materialien für dosimeterartige Gassensoren zur Detektion im ppm- und Sub-ppm-Bereich / Isabella Marr." Aachen : Shaker, 2017. http://d-nb.info/1124366628/34.
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Michel, Ursula. "Assoziation der Variante Pro115Gln im PPAR[gamma]2-Gen [PPAR-gamma-2-Gen] mit Adipositas und Diabetes mellitus Typ II." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=969118597.
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Batista, Fernanda Aparecida Heleno. "Estudos estruturais do receptor ativado por ativadores de peroxissomos humano, hPPAR&delta." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/76/76132/tde-01062012-175615/.
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Os PPARs são fatores de transcrição ativados por ligantes, pertencentes à superfamília dos receptores nucleares, que são considerados sensores de lipídeos capazes de transformar alterações nos padrões de lipídeos/ácidos graxos dos organismos em atividade metabólica. Com isto, os 3 isotipos (α, δ e γ) estão associados a diferentes desordens metabólicas como doenças vasculares, diabetes, obesidade, câncer e certas doenças mentais que constituem um grave problema de saúde pública mundial, o que torna esta classe de proteínas, um valioso alvo para a indústria farmacêutica. Embora a importância do hPPARδ na regulação da transcrição de genes relacionados a uma série de processos metabólicos seja conhecida, não há ainda nenhum fármaco no mercado cujo alvo seja este receptor. O maior conhecimento a respeito da estrutura deste receptor pode trazer esclarecimentos capazes de auxiliar o desenvolvimento racional de fármacos. Desta forma, no presente trabalho, buscou-se encontrar características estruturais importantes para a seletividade e especificidade dos ligantes pelo isotipo δ. Para tal, determinou-se as condições de expressão e purificação da proteína hPPARδ LBD, bem como as condições apropriadas de manutenção da mesma por meio da técnica de dicroísmo circular. O estado oligomérico deste receptor foi determinado em solução através das técnicas de cromatografia por exclusão de tamanho e por espalhamento dinâmico de luz, onde se concluiu que a proteína é monomérica nas condições testadas. Além disto, através de uma estrutura de alta resolução da proteína hPPARδ LBD com o ligante GW 0742, propôs-se a construção de dois mutantes, V312M e I328M, através dos quais concluiu-se que estes dois resíduos são potencialmente importantes para interação de ligantes estruturalmente relacionados com GW 0742, ao isotipo δ, indicando dois determinantes relacionados à seletividade de ligantes por este isotipo. Como existem poucos relatos sobre a estrutura completa deste receptor, e consequentemente da influência que os domínios N-terminal e DBD apresentam sobre o domínio LBD, um breve estudo da interação diferencial entre o receptor nuclear hPPARδ Full e três diferentes cofatores, em presença de ligante agonista e antagonista foi realizado. Para isto, determinou-se as condições de expressão e purificação da proteína hPPARδ Full, e prosseguiu-se com ensaios de anisotropia de fluorescência, através dos quais ficou claro que cada cofator apresenta um padrão diferente de interação com a proteína que pode ser dependente de outras regiões da proteína além daquelas já classicamente descritas. Isto é um forte indicativo de que diferentes regiões do hPPARδ podem ser chave no processo de regulação por intermédio de cofatores.PPARs are transcription factors activated by ligands, belonging to the superfamily of nuclear receptors, which are considered to be lipid sensors capable of making changes in patterns of lipid/fatty acid metabolic activity of organisms. The three isotypes (α, δ and γ) are associated with different metabolic disorders and vascular diseases as diabetes, obesity, cancer and certain mental illnesses which comprise a serious worldwide public health problem, making this class of proteins a valuable target for the pharmaceutical industry. Although it is known the importance of hPPARδ in regulating transcription of genes related to a series of metabolic processes, there is still no drug on the market directed to this receptor. Knowledge about the structure of this receptor can bring clarification able to assist the rational development of drugs. Therefore, in the present study, we sought to find structural features important for selectivity and specificity of ligand binding by the isotype δ. To this end, we determined the conditions of expression and purification of the protein hPPARδ LBD, as well as the appropriate conditions for maintaining it through the technique of circular dichroism. The oligomeric state of this receptor in solution was determined through the techniques of size exclusion chromatography and dynamic light scattering, which concluded that the protein is monomeric under the conditions tested. In addition, through a high-resolution structure of the protein hPPARδ LBD with the ligand GW 0742, we proposed the construction of two mutants, V312M and I328M, through which it was concluded that these two residues are potentially important for interaction of ligands structurally related to GW 0742 with the δ isotype. As there are few reports based on the complete structure of this receptor, and consequently about the influence of the N-terminal and DBD domains with the LBD domain, a brief study of the interaction between the nuclear receptor differential hPPARδ Full and three different cofactors in the presence of agonist and antagonist ligands were performed. For this, we determined the conditions of expression and purification of the protein hPPARδ Full, and using fluorescence anisotropy, it became clear that each cofactor has a different pattern of interaction with the protein which may be dependent on other regions of the protein in addition to those already described classically. This is a strong indication that different regions of hPPARδ can be key points in the regulatory process through cofactors.
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Savory, Richard. "PPAR#alpha# : inducibility and species differences in expression." Thesis, University of Nottingham, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337248.
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Fidelak, Jérémy. "Etude théorique de l'équilibre conformationnel du PPAR-γ." Université Louis Pasteur (Strasbourg) (1971-2008), 2006. http://www.theses.fr/2006STR13233.
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Ce travail de thèse a porté sur l'étude des mécanismes moléculaires de la reconnaissance et des changements de conformations induits par la liaison du ligand dans le LBD du récepteur nucléaire PPAR-gamma à l'aide de simulations numériques. L'organisation structurale et le fonctionnement de la super-famille des récepteurs nucléaires sont présentés en introduction. Nous décrivons ensuite les méthodes employées pour nos calculs. Nous avons effectué des calculs de mécanique moléculaire, des calculs de pKa ainsi que des calculs d'énergie libre d'interaction. Puis nous décrivons l'étude de la dynamique du PPAR-gamma ainsi que l'effet de ligands par le biais de calcul de modes normaux de vibration et de dynamique moléculaire. Une étude thermodynamique a également été effectuée par un protocole appelé MM-PBSA (Molecular Mechanics, Poisson-Boltzmann, Surface Area) pour identifier les résidus ayant une contribution importante à l'énergie libre de liaison. L'énergie libre calculée est décomposée en contributions physiques (van der Waals, électrostatiques et non polaires). Le calcul de ces contributions pour chaque résidu dans les complexes ligand-récepteur et coactivateur-récepteur nous apporte des informations supplémentaires sur ces interactions et peuvent aider par exemple à la conception de nouveaux ligands. La dernière partie présente les premiers résultats concernant l'étude du dimère PPAR/RXR. Ce travail permet dans sa globalité une meilleure compréhension du mécanisme moléculaire de la signalisation par le PPARThe work done during the thesis focused on the study of molecular mechanisms of recognition and conformational changes induced by the ligand binding in the ligand binding pocket of nuclear receptor PPAR-gamma by numerical simulations. Structural organization and operation of nuclear receptors super-family are presented in the introduction part. We thus describe the methods that have been used for our calculations. We did molecular mechanics calculations, pKa calculations and interaction free energy calculations. Then we decribe the study of PPAR-gamma dynamic and ligand binding effect by normal modes and molecular dynamic simulations. A thermodynamical study has been carried out by a protocol called MM-PBSA (Molecular Mechanics, Poisson-Boltzmann, Surface Area) to identify residues with large contributions to free energy of binding. The calculated free energy of binding is decomposed into physical contributions (van der Waals, electrostatic and non polar). Calculations of these contributions for each residue in the ligand-receptor complex and coactivator-receptor complex bring us informations on these interactions and could help for example to new ligands design. The last part presents the first results concerning the study of PPAR/RXR dimer. This work permits as a whole a better comprehension of molecular mechanism of signalling by PPAR
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Holmberg, Mattias, and Anna Kulikowski. "Premiepensionssparande : Fondförvaltningsstrategier applicerade på PPM." Thesis, Uppsala universitet, Företagsekonomiska institutionen, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-176656.
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Chan, Hsun-Hung. "Indoor infrared wireless PPM systems." Thesis, Northumbria University, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246144.
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Clarke, Paul Noel. "An Investigation into the mechanisms whereby omega-3 polyunsaturated fatty acids affect plasma lipids." Thesis, University of Nottingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.269713.
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Petit, Valérie. "La teneur en lipides du régime affecte les capacités d'absorption intestinale et la triglycéridémie post-prandiale : contribution du récepteur nucléaire PPARβ ?" Dijon, 2007. http://www.theses.fr/2007DIJOS004.
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L’absorption intestinale des acides gras à longue chaines (AGLC) est très efficace. En revanche, on ignore si ce phénomène est inné ou adaptatif. C’est pourquoi, des souris ont été soumises à un régime hyperlipidique (40% m/m) pendant 21 jours. Nous avons constaté une induction du captage des AGLC, de l’activité proliférative et de la masse relative de la muqueuse, de l’expression des gènes impliqués dans les différentes étapes du processus d’absorption intestinale des AGLC. Ce phénomène est adaptatif puisque ces régulations retournent aux valeurs des témoins lorsque les souris sont renourries avec un régime normolipidique. Ces modifications s’accompagnent d’une augmentation de la clairance plasmatique des lipoprotéines riches en triglycérides. Le Peroxisome Proliferator-Activated ReceptorB (PPARB) pourrait être à l’origine de cette adaptation intestinale. Les données obtenues ont montré que la sur-expression intestinale de PPARB engendre une adaptation moins efficace des capacités d’absorptionIt is well known that intestinal fat absorption is efficient. However, we don’t if the high triglycerides bioavailability of gut is attributable to inborn properties or to acquired properties. To answer this question, mice were subjected to a high-fat diet (40%, w/w) during 21 days. We have shown that high-fat induces intestinal LCFA uptake, intestinal mitotic index which leads to an increase of intestinal relative mass, expression of genes involved in fatty uptake, trafficking and lipoprotein synthesis. These changes were lipid-mediated, in that they were fully abolished in mice refed the control diet. Moreover, these changes induces a higher efficiency of triglycerides clearance in blood. The molecular mechanism at the origin of this intestinal adaptation could be the nuclear receptor, Peroxisome Proliferator-Activated Receptor BPPARB). Our data have shown that the intestinal overexpression of PPARB led to a low fat-mediated adaptation
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Teixeira, Bruno. "Desenvolvimento de um processo PPAP para a manutenção aeronáutica." Master's thesis, Instituto Politécnico de Setúbal. Escola Superior de Tecnologia de Setúbal, 2019. http://hdl.handle.net/10400.26/31421.
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Projeto submetido para obtenção do grau de Mestre em Engenharia de ProduçãoNesta tese de mestrado é apresentada uma revisão bibliográfica no âmbito da regulamentação da manutenção aeronáutica, das ferramentas do planeamento avançado da qualidade do produto (APQP) e por fim os princípios e documentação utilizada no processo de aprovação para fabricação de peças (PPAP) no setor automóvel e no setor de fabricação aeronáutica, sendo assim possível de desenvolver o processo de aprovação para manutenção de peças (MPAP), de forma a garantir um processo de integração e gestão robusto. Nesta tese de mestrado também é demonstrado que o setor de manutenção aeronáutica é diferente e muito específico, sendo evidenciada a enorme importância e o impacto que o processo de gestão da lista de capacidades (LC) tem numa Organização de Manutenção bem como na implementação de um processo PPAP no setor de manutenção aeronáutica. Sem o processo de gestão da lista de capacidades implementado e a funcionar de forma robusta o processo de aprovação para manutenção de peças não poderá ser implementado. Assim, ainda nesta tese de mestrado são demonstradas as implementações de melhorias e os seus ganhos de forma a que o processo de gestão da lista de capacidades seja mais fácil de garantir e manter, tornando-o num processo de aprovação de componentes ágil e robusto, que diferencia as situações que carecem de aprovação/reaprovação, os diferentes níveis de detalhe e os conteúdos de cada nível de aprovação.
This master thesis presents a bibliographic revision in the scope of the aeronautical maintenance regulation, considering the advanced product quality planning tools (APQP) and finally the principles and documentation used in the Production Part Approval Process (PPAP) in the automotive sector and in the aeronautical manufacturing sector. This master thesis gives visibility of a Maintenance Part Approval Process (MPAP) possible to develop, in order to ensure a robust integration and management process in place at aeronautical industry. In this master thesis it is also demonstrated that the aeronautical maintenance sector is very specific, highlighting the huge importance and the high impact that the Capacity List management (LC) process has in a Maintenance Organization as well as the implementation of a MPAP process. Without having a capability list management process in place, a robust functional MPAP approval process for parts maintenance cannot be implemented. In this master thesis it is also demonstrated improvements implementations and their gains, having the possibility to verify that the capacity list management process becomes easier to guarantee and maintain. As a conclusion, a robust component approval process makes a very positive difference in situations that is required the approval / disapproval on different levels of detail and several contents of each approval level.
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Zariwala, Mohammed Gulrez. "Programming of PPAR Action and Triacylglycerol/Fatty Acid Recycling." Thesis, Queen Mary, University of London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.515249.
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Owens, Joanna. "Regulation of peroxisome proliferator-activated receptor-alpha (PPAR#alpha#)." Thesis, University of Surrey, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341337.
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Kraus, Frank [Verfasser], and Bernd [Akademischer Betreuer] Plietker. "Entwicklung PPAP-basierender Antiinfektiva / Frank Kraus ; Betreuer: Bernd Plietker." Stuttgart : Universitätsbibliothek der Universität Stuttgart, 2021. http://d-nb.info/123964874X/34.
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Brückner-Kalb, Jochen Robert. "Sub-ppm-NOx-Verbrennungsverfahren für Gasturbinen." München Verl. Dr. Hut, 2008. http://d-nb.info/990774945/04.
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Takahama, Carina Harumi. "Controle da Anexina 1 sobre a expressão do receptor nuclear proliferador de peroxissomos em diferentes tipos celulares." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/9/9141/tde-26092016-125014/.
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A proteína Anexina A1 (ANXA1), sintetizada e liberada por fagócitos pela ação de glicocorticóides, é uma proteína anti-inflamatória, pois inibe o influxo de neutrófilos para o foco da inflamação, e induz os mecanismos de eferocitose em neutrófilos e macrófagos. Nosso grupo mostrou que a ANXA1 regula a expressão do receptor ativado por proliferadores de peroxissomos (PPAR) em macrófagos. Em continuidade, o presente trabalho investigou o mecanismo da ANXA1 sobre a expressão de PPARγ em macrófagos, e se este controle ocorre em demais leucócitos e tecido adiposo. Para tanto, macrófagos, neutrófilos peritoneais, linfócitos do baço, tecido adiposo epididimal foram obtidos de camundongos machos Balb/c selvagens (wild type, WT) ou geneticamente deficientes para ANXA1 (ANXA1-/-). Os resultados obtidos mostraram que a ANXA1 controla a expressão proteica e gênica de PPARγ em macrófagos, já que os níveis proteico (Western Blot, WB) e de RNAm (Real-time PCR) para PPARγ constitutivo, bem como induzidos pelos tratamentos in vitro com bezafibrato ou pioglitazona estavam reduzidos em macrófagos de animais ANXA1-/- em comparação com os níveis de macrófagos de animais WT, e o efeito parece ser dependente de CREB (WB), já que os níveis constitutivos deste fator de transcrição estavam maiores em macrófagos de animais ANXA1-/-. O tratamento in vitro com cicloheximida (CHX), um inibidor da síntese proteica, reduziu a expressão de PPARγ estimulada por bezafibrato ou LYSO-7 em macrófagos de animais WT, reforçando o papel da ANXA1 na expressão gênica de PPARγ. O FPR2 parece não estar envolvido no efeito, uma vez que o pré-tratamento de macrófagos com o antagonista de FPR2 (WRW4) não modificou a expressão de PPARγ em macrófagos de animais WT. O efeito modulador da ANXA1 ocorre em neutrófilos, mas não em tecido adiposo e linfócitos de animais ANXA1-/-. Ademais, a deficiência de ANXA1 não alterou a apoptose espontânea de neutrófilos. Em conjunto, os resultados obtidos mostram uma possível via adicional da ANXA1 sobre a resolução da inflamação, controlando a expressão de PPARγ em fagócitos.Annexin A1 (ANXA1), is a protein synthetized and released by phagocytes due to the action of glucocorticoids, and an anti-inflammatory protein that inhibits neutrophil influx to site of inflammation and induces the mechanisms of efferocytosis in neutrophils and macrophages. Our group has already demonstrated that ANXA1 regulates the expression of peroxisome proliferator-activated receptor (PPAR) in macrophages. The present work aimed to investigate the role of ANXA1-dependent mechanisms on the expression of PPARγ in macrophages, and if said role also extends to other leukocytes and adipose tissue. For such, macrophages, peritoneal neutrophils, spleen lymphocytes, epididymal adipose tissue were obtained from male Balb/c wild type mice or from mice lacking ANXA1 genetically (ANXA-/-). Obtained results have demonstrated that ANXA1 regulates both proteic and genic expression of PPARγ in macrophages, as protein (Western Blotting, WB) and mRNA (Real-Time PCR) levels of constitutive PPARγ were reduced in macrophages from ANXA1-/- mice in comparison with the observed levels of macrophages from WT mice; the same is true for increased protein and mRNA levels as induced by in vitro treatments with bezafibrate or pioglitazone. This effect appears to be CREB-dependent (WB), as the constitutive levels of this transcription factor were found to be increased in macrophages from ANXA1-/- mice. In vitro treatment with cycloheximide (CHX), an inhibitor of proteic synthesis, reduced the bezafibrate or LYSO-7 (PPAR pan agonist, 10 µM / 2h) induced expression of PPARγ in WT mice, which further suggests a role for ANXA1 in PPARγ genic expression. FPR2 does not seem to be involved with these effects of ANXA1, as pre-treatment of macrophages from WT mice with an FPR2-antagonist (WRW4) did not alter expression of PPARγ. The modulating effect of ANXA1 can be verified in neutrophils of ANXA-/- mice, but not in adipocytes and lymphocytes from the same animals. Moreover, deficiency of ANXA1 did not affect spontaneous apoptosis of neutrophils. Altogether, the obtained results show the existence of a probable additional pathway with which ANXA1 promotes inflammation resolution, also controlling the expression of PPARγ in phagocytes.
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Guimarães, Francielle Rodrigues. "Papel do receptor PPAR alfa na cicatrização de feridas cutâneas induzidas experimentalmente." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/60/60135/tde-05092013-162650/.
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Peroxissome proliferator-activated receptor-alfa (PPAR-?) é um fator de transcrição nuclear envolvido na regulação do metabolismo de lipídeos e da inflamação. PPAR? pode estar relacionado com a modulação da cicatrização de feridas cutâneas, que é um processo multifatorial, dependente de mecanismos de sinalização celular e de inflamação. Deste modo, o objetivo deste trabalho foi analisar o papel do receptor PPAR? na cicatrização de feridas cutâneas induzidas experimentalmente e a sua relação com o metabolismo sistêmico após tratamento com agonista do PPAR?. Para tanto, foram realizadas feridas na pele da região dorsal de camundongos 129/SvEv, que foram tratados diariamente com o agonista de PPAR?, Gemfibrozil, por via oral ou tópica. Os animais foram acompanhados durante 240h pós-cirúrgico (p.c.) para a análise do reparo cutâneo e alterações metabólicas que poderiam ser induzidas pela ativação de PPAR?. Os camundongos tratados apresentaram melhor cicatrização após ativação de PPAR? com 100 ou 50 mg/kg/dia de agonista por via oral ou tópica, respectivamente. O tratamento oral induziu cicatrização mais rápida somente após 24h, 48h e 72h p.c., enquanto que os animais tratados com Gemfibrozil tópico apresentaram cicatrização mais precoce em todos os tempos avaliados. A indução de feridas alterou o metabolismo sistêmico dos camundongos que demonstraram significativa perda de peso e redução de triglicérides, independentemente do tratamento. Porém, a ativação de PPAR? não alterou a glicemia ou a função hepática. Na análise histopatológica das feridas foi verificado infiltrado inflamatório, composto principalmente por neutrófilos e outras células polimorfonucleares. Entretanto, o tratamento com Gemfibrozil tópico levou a um menor infiltrado inflamatório e diferenciada deposição de colágeno após 10 dias p.c. Além disso, houve diminuição do acúmulo de neutrófilos, macrófagos e eosinófilos quando comparados aos animais que receberam apenas o veículo. O tratamento tópico promoveu menor acúmulo de linfócitos TCD4+, TCD8+ e T??, e ainda diferenciado influxo de células dendríticas para a lesão. No entanto, não houve diferença em relação a células T reguladoras nos linfonodos drenantes, mas os animais tratados apresentaram diminuição de Foxp3 nas células CD4+CD25-. Em conclusão, PPAR? atua no reparo cutâneo, e sua ativação local acelera a cicatrização por meio da modulação da inflamação na pele. Finalmente, os resultados sugerem que PPAR? pode ser alvo importante para novas terapias que visam melhorar a cicatrização de feridas, especialmente quando ativado no local da lesão.Peroxissome proliferator-activated receptor alpha (PPAR?) is a nuclear transcription factor involved in the regulation of lipid metabolism and inflammation. PPAR? may be associated to the modulation of wound healing, which is a multifactorial process dependent on mechanisms of cell signaling and inflammation. Then this work aimed to analyze the role of PPAR? receptor in experimental cutaneous wound healing and its relationship to the systemic metabolism of mice treated with a PPAR? agonist. For this, skin wounds were performed in the dorsal region of 129/SvEv mice, treated daily with the PPAR? agonist, Gemfibrozil, by oral or topical route. Mice were followed for 240h post-surgery (p.s.) for skin repair and metabolic changes that could be induced by PPAR? activation. There was improved wound healing in mice treated with 100 or 50 mg/Kg of PPAR? agonist by oral or topical route respectively. The oral treatment induced a better repair in the early 24h, 48h and 72h p.s. while mice treated by topical application of Gemfibrozil presented faster healing in all times evaluated. Wound\'s induction affected the systemic metabolism of mice leading to significant weight loss. PPAR? agonist did not alter glucose, triglycerides or liver function, although all injured animals had a significant decrease on triglycerides levels in the early times p.s., independent on the treatment. In histopathological examination of the wounds it was observed inflammatory infiltrate, composed mainly of neutrophils and other polymorphonuclear cells. However, topical treatment with PPAR? agonist led to lower inflammatory infiltrate and differentiated collagen deposition 10 days p.s. Furthermore, there was decrease of neutrophil, macrophages and eosinophils influx when compared to untreated mice. Topical treatment led to decrease in the TCD4+, TCD8+ e T?? lymphocytes accumulation in the lesions, and differentiated dendritic cell influx to the wounds. However there was no difference regarding CD4+CD25+ T cells in lymph nodes, but treated mice showed decrease Foxp3 expression. In conclusion, the triglycerides serum level was altered in the course of wound healing and may be associated to skin lesion, while PPAR? agonist acts in wound repair by accelerating healing and modulating neutrophil influx to the skin. Finally, our results suggested that PPAR? may be an important target for novel therapies aimed at improved wound healing, especially when administered topically.
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Burke, Rita Velikina. "The associations between diet, flavonoids, polymorphisms of the PPAR-gamma, PPAR-delta, and CRP genes and lung and upper aerodigestive tract (UADT) cancers." Diss., Restricted to subscribing institutions, 2008. http://proquest.umi.com/pqdweb?did=1779690481&sid=3&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Whittall, Christine Biotechnology & Biomolecular Sciences Faculty of Science UNSW. "Interaction between N-(3-oxododecanoyl)-L-homoserine lactone and peroxisome proliferator-activated receptor gamma." Awarded By:University of New South Wales. Biotechnology & Biomolecular Sciences, 2009. http://handle.unsw.edu.au/1959.4/44957.
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Pseudomonas aeruginosa is a significant pathogen of immunocompromised individuals, and the main mechanism by which it mediates virulence is through the coordination of gene expression by an intricate quorum sensing system. One of the signalling molecules of this system, N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL) has been shown to have immunomodulatory capabilities, discrete to its quorum sensing role. While the general focus of research in this area is on the physiological outcomes of this interaction on cell function, there is currently little concrete evidence identifying the receptor(s) for OdDHL in mammalian cells, and hence the biochemical mechanism behind the immunomodulation caused by OdDHL remains largely unknown. This study identifies peroxisome proliferator-activated receptor γ (PPARγ) as a mammalian target for OdDHL. PPARγ is a mammalian transcription factor involved in fatty acid metabolism and is heavily involved in the inflammatory response, being a negative regulator of inflammation. It is shown here that OdDHL is able to instigate signalling through PPARγ by activation of the ligand binding domain (LBD), suggesting that OdDHL may act as a PPARγ agonist. OdDHL is able to compete with the PPARγ agonist, rosiglitazone, causing a relative antagonism of PPARγ activity when given in tandem with the agonist. The bacterial signalling molecule is unable to displace the irreversible PPARγ antagonist GW9662. This effect on PPARγ is specific to OdDHL, as the smaller P. aeruginosa signalling molecule, N-butyryl-L-homoserine lactone had no significant effect on PPARγ activation. In order to confirm PPARγ as a putative receptor for OdDHL in mammalian cells, initial experiments were undertaken to optimise conditions to produce PPARγ LBD protein for binding interaction studies. The fidelity of the protein sequence was established and expression of the protein in an appropriate vector was confirmed. The protein produced was insoluble and hence not functional for binding studies, suggesting that additional optimisation of expression conditions, or manipulation and refolding of the protein is necessary before further experimentation can take place. The identification of PPARγ as a receptor for OdDHL in mammalian cells is an important step in understanding the nature and scope of the interaction between OdDHL and host cell physiology, especially the significance of this interaction during P. aeruginosa infection. Continuation of this research, in particular completion of protein-ligand binding studies between OdDHL and PPARγ has the potential to clarify the significance of the immunomodulation caused by OdDHL, while providing us with a platform from which we may exploit it.
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Lewis, Stephanie N. "Refinement of the Docking Component of Virtual Screening for PPAR." Diss., Virginia Tech, 2013. http://hdl.handle.net/10919/23675.
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Exploration of peroxisome proliferator-activated receptor-gamma (PPAR") as a drug target holds applications for treating a wide variety of chronic inflammation-related diseases. Type 2 diabetes (T2D), which is a metabolic disease influenced by chronic inflammation, is quickly reaching epidemic proportions. Although some treatments are available to control T2D, more efficacious compounds with fewer side effects are in great demand. Drugs targeting PPAR" typically are compounds that function as agonists toward this receptor, which means they bind to and activate the protein. Identifying compounds that bind to PPAR" (i.e. binders) using computational docking methods has proven difficult given the large binding cavity of the protein, which yields a large target area and variations in ligand positions within the binding site. We applied a combined computational and experimental concept for characterizing PPAR" and identifying binders. The goal was to establish a time- and cost-effective way to screen a large, diverse compound database potentially containing natural and synthetic compounds for PPAR" agonists that are more efficacious and safer than currently available T2D treatments. The computational molecular modeling methods used include molecular docking, molecular dynamics, steered molecular dynamics, and structure- and ligand-based pharmacophore modeling. Potential binders identified in the computational component funnel into wet-lab experiments to confirm binding, assess activation, and test preclinical efficacy in a mouse model for T2D and other chronic inflammation diseases. The initial process used provided "-eleostearic acid as a compound that ameliorates inflammatory bowel disease in a pre-clinical trial. Incorporating pharmacophore analyses and binding interaction information improved the method for use with a diverse ligand database of thousands of compounds. The adjusted methods showed enrichment for full agonist binder identification. Identifying lead compounds using our method would be an efficient means of addressing the need for alternative T2D treatments.Ph. D.
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Oxer, Daniella Stefani. "Interação entre as vias de sinalização CD40/CD40L e os PPARs." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/5/5159/tde-17062009-122735/.
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O receptor CD40 e seu ligante CD40L possuem um papel importante na interface entre a resposta imune inata e a adaptativa. Disfunções desta via de sinalização são descritas em doenças de origem inflamatória e autoimunes. Em Lúpus eritematoso sistêmico (LES) foi descrito um aumento nos níveis séricos de CD40L solúvel, que participa na produção de autoanticorpos. Receptores ativados por proliferadores de peroxisomos (PPARs) são fatores de transcrição que inicialmente foram descritos como envolvidos apenas no metabolismo lipídico, mas que atualmente são também descritos como atuantes no controle da resposta imune. Com isso, nosso objetivo é determinar se a ativação dos PPARs modula o processo inflamatório através da interação com CD40/CD40L in vitro ou in vivo. Células de linhagem monocítica humana THP-1 foram tratadas por 24 horas com forbol-éster (PMA, 40 nM) e posteriormente estimuladas com CD40L recombinante (rhCD40L, 1 g/ml) por diferentes períodos. Transcritos de mRNA foram analisados por real time PCR e os resultados expressos como razão da expressão do gene housekeeping GAPDH. As células THP-1 apresentam um aumento na expressão de PPAR e após 16 e 2 horas de estímulo com rhCD40L, respectivamente. Estas células também foram estimuladas com LPS (10 g/ml) e LPS+rhCD40L para sabermos se a resposta obtida anteriormente era específica ao estímulo com rhCD40L. O resultado mostra que há uma diminuição na expressão de PPAR e após o estimulo com LPS ou LPS+rhCD40L, indicando que nessas condições a modulação da expressão de PPARs é especifica para a via de sinalização CD40/CD40L. Foi medida também a expressão de CD36, que é descrito na literatura como um indicador da atividade de PPARs. O resultado mostra que o estímulo com CD40L promove um aumento de CD36, o que indica indiretamente que o PPAR estava ativo neste modelo experimental. Para mostrar a interação direta destas duas vias de sinalização, silenciamos o gene de PPAR por siRNA e posteriormente anlisamos a expressão de CD80, cuja expressão encontra-se aumentada logo após a ativação do CD40 de acordo com a literatura. O resultado mostra que, com o silenciamento de PPAR , há um aumento de CD80 logo após a ativação do CD40, evidenciando assim a interação entre essas duas vias de sinalização. A fim de verificar se os achados encontrados in vitro poderiam ser observados in vivo, foi isolada a fração mononuclear de sangue periférico de pacientes com LES com a doença em atividade (n=17), a doença inativa (n=21) ou doadores saudáveis (n=12) e foi medida a expressão de PPAR e por real time PCR. PPAR apresenta um aumento em pacientes com a doença ativa ou inativa em comparação aos doadores saudáveis. Já a expressão de PPAR apresenta aumento apenas em lúpicos em atividade quando comparados com lúpicos inativos ou doadores saudáveis. Quando considerado nesta análise o efeito do tratamento dos pacientes com corticosteróides nos níveis de PPAR, obsevou-se que a expressão de PPAR apresenta o mesmo padrão anterior. Estes resultados sugerem a hipótese de que PPAR seja um possível marcador de atividade de LES. Para confirmar esta especificidade, foram adicionadas à analise células mononucleares retiradas de pacientes com tuberculose e com infecções agudas. Os dados mostram que os níveis elevados de PPAR se mantém apenas em pacientes com lúpus ativo, o que confirma nossa hipótese. Nossos achados sugerem que PPAR e são regulados especificamente em reposta a ativação da via do CD40/CD40L, em monócitos em cultura e em células obtidas de pacientes com LES. Podemos também sugerir que PPAR possa ser um marcador para a atividade de LES. Estes resultados podem representar um novo mecanismo de controle da via de sinalização do CD40/CD40L, participando no controle da resposta inflamatória em cultura e em células de pacientes lúpicosThe membrane receptor CD40 and its ligand CD40L play an important role in the interface between innate and acquired immunity. Dysfunction of this signaling pathway was described in inflammatory and autoimmune diseases. In systemic lupus erythematosus (SLE), increased serum levels of soluble CD40L have been detected, where it plays a significant role in the generation of auto-antibodies. Peroxisome proliferator activator receptors (PPARs) are transcription factors originally described in lipid metabolism. More recently, they were also characterized as inflammatory modulators. Therefore, our objective was to determine whether the activation of PPARs may modulate the inflammatory process through interaction with the CD40/CD40L signaling pathway in vitro and in vivo. Macrophages derived from the human monocytic cell line THP-1 by 24h-treatment with PMA (40 nM) were stimulated with human recombinant CD40L (rhCD40L, 1 g/ml) for different periods. Messenger RNA (mRNA) transcripts for PPAR , and were determined by real time PCR and expressed as a ratio of the housekeeping gene GAPDH transcripts. THP-1 cells express a basal level of PPAR and gene transcription, which is increased 16 and 2 hours after exposure to rhCD40L, respectively. We also stimulated the THP-1 cells with LPS (10 g/ml) and LPS+rhCD40L to see if the increase of PPAR was a response specific to the rhCD40L stimuli. The data show that there is a decrease in PPAR and genes expression upon LPS or LPS+rhCD40L stimulation, indicating that in these times (2 and 16 hours) the response is specific for the CD40/CD40L signaling pathway. Increased expression of CD36 is known as an indicator of PPARs activity. We measured CD36 and saw an increase of this receptor after rhCD40L stimulus, indicating indirectly that PPARs were active in this experimental model. To prove the direct interaction between CD40/CD40L and PPAR , we silenced the PPAR gene by siRNA and analyzed the expression of CD80, which is known to increase after CD40 activation. The results show an increase in CD40L-stimulated CD80 expression upon silencing of PPAR , showing that there is an interaction between these signaling pathways. To confirm whether these findings also occur in vivo, mononuclear cells were isolated from whole blood samples from SLE patients with active (n=17) and inactive disease (n=21), and healthy donors (n=12). The mRNA transcripts for PPARs were detected by real time PCR. In both active and inactive SLE patients, monocytes show an increase in PPAR mRNA expression, as compared to healthy donors. PPAR mRNA is increased only in active patients when compared to healthy donors and inactive lupus patients. Further in this analysis, when we separated the patients with and without the administration of corticosteroids, PPAR displayed the same pattern as above. These results suggested that PPAR may be a marker for lupus activity. To validate this hypothesis, we compared the results obtained from patients with tuberculosis and acute infections. Results showed that only active-lupus patients have an increase in PPAR , confirming the specificity of this phenomenon and hence our hypothesis Our findings suggest that PPAR and are up-regulated specifically in response to CD40/CD40L activation, in both cultured macrophages and in monocytes obtained from SLE patients. We could also suggest that PPAR may be marker for lupus activity. Our results may represent a new control mechanism of the CD40/CD40L signaling pathway and seem to be implicated in the control of the inflammatory response in both human macrophages in vitro and SLE patients
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Batatinha, Helena Angelica Pereira. "Exercício aeróbio crônico reduz o acúmulo de gordura hepático, mas promove inflamação no fígado de camundongos PPAR-alpha knockout, via inibição do PPAR-gama." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/42/42134/tde-08122015-185802/.
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A NAFLD é uma das principais patologias de fígado. Estudos reportam o exercício físico como um dos principais alvos terapêuticos para esta doença. Verificamos se o treinamento melhora a resistência à insulina, inflamação e esteatose hepática causados pela dieta hiperlipídica (HF) e se o PPAR-alpha está envolvido neste processo. Animais selvagens C57BL6 (WT) e knockout para PPARα (KO) foram alimentados com dieta padrão ou HF durante 12 semanas e treinados por 8 semana. Metade dos animais KO treinados receberam rosiglitazona. A dieta HF aumentou TAG hepático, e resistência periférica à insulina levando a NALFD. O treinamento foi eficiente em reduzir esses parâmetros em ambos genótipos. O desenvolvimento da NAFLD não foi associado à inflamação hepática, entretanto animais KO treinados apresentaram uma resposta inflamatória exacerbada, causada pela redução de PPARγ. Quando eles receberam rosi apresentaram melhora no quadro inflamatório hepático e na resistência à insulina. O exercício diminuiu os danos causados pela dieta HF independente do PPARα; a ausência do PPARα junto com exercício leva a queda na expressão de PPARγ, e a uma resposta inflamatória exacerbada, que é revertida pela administração da rosiglitazona.NAFLD is one of the main liver diseases. Studies have shown the beneficial effects of exercise on reverse NAFLD. We verify whether exercise improve insulin resistance, liver inflammation and steatohepatitis caused by a high fat diet (HF) and whether PPARα is involved in these actions. C57BL6 wild type (WT) and PPAR-α knockout (KO) mice were fed with a standard (SD) or HF during 12 weeks and trained on a treadmill during 8 weeks, half of KO trained animals received 15mg/kg/day of rosiglitazone. HF diet increased TAG in the liver and peripheral insulin resistance leading to NAFLD. Exercise reduced all this parameters in both animals genotype. NAFLD was not associated with inflammation, however KO mice when trained presented an inflammatory response that was caused by a decrease on PPARγ. When these mice were treated with rosiglitazone, they presented decrease on inflammatory cytokines as well as improvement on insulin sensitivity. Exercise improved the damage caused by a HF independently of PPARα and the absence of PPARα together with exercise leads to decrease on PPARγ expression and an inflammatory response, which was attenuated by rosiglitazone administration.
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Anderson, John Ross. "The role of PPAR-γ receptor agonists in mild asthma." Thesis, University of Nottingham, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.665481.
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Asthma is complex and heterogeneous condition characterised by airway inflammation, airway hyperresponsiveness, variable airflow obstruction and symptoms including cough, wheeze and breathlessness. Many of those with asthma fail to achieve optimal control and there is a need to identify novel therapeutic targets and improve the way we detect airway inflammation if the burden of asthma is to be reduced. Chapters 1-4 explore whether agonists for the transcription factor, Peroxisome proliferator-activated receptor gamma (PPAR-y) have a role in asthma. We performed a single centre randomised two parallel group, double blind placebo controlled trial over a 12 week period using pioglitazone to activate PPAR-y. This was followed by a series of mechanistic in vitro experiments investigating whether there was evidence of PPAR-y translocation in sputum cells and airway smooth muscle cells.
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Liberato, Marcelo Vizoná. "Ácidos graxos de cadeia média como ligantes da proteína PPAR." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/76/76132/tde-19032009-111236/.
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Receptores ativados da proliferação de peroxissomos (PPAR) são receptores nucleares que regulam o metabolismo de gordura e glicose, adipogênese e polarização de macrófagos, e são os mediadores da ação de uma grande classe de fármacos usada no tratamento de diabetes tipo 2, as tiazolidinadionas (TZD). Enquanto as TZDs reduzem a glicose do sangue e aumentam efetivamente a sensibilidade à insulina, elas podem também apresentar efeitos colaterais como aumento do risco de complicações cardiovasculares, ganho de peso, retenção de fluido e toxicidade hepática. Por causa disso, novos fármacos que possuem respostas mais favoráveis devem ser desenvolvidos, e o mecanismo de ativação do PPAR por ligantes vem sendo intensamente examinado. Para entender a relação entre a ligação de agonistas ao PPAR e a ativação transcricional, pretendíamos primeiramente obter cristais de PPAR-LBD (domínio de ligação ao ligante) humano na forma apo. Porém, surpreendentemente, a análise do sítio de ligação ao ligante revelou a presença de três pequenas moléculas, identificadas como ácidos nonanoicos e octanoicos. Este trabalho reporta a análise da estrutura cristalográfica do PPAR LBD complexado simultaneamente com três ácidos graxos de cadeia média (AGCM), provindos de bactérias (organismo de expressão), localizados no sítio de ligação ao ligante. A análise estrutural e funcional sugere que os AGCM são agonistas parciais que estabilizam a conformação do LBD do PPAR por mecanismo independente da hélice 12.PPARs (peroxisome proliferator activated receptors) are nuclear receptors that regulate glucose and fat metabolism, adipogenesis and macrophage polarization and mediate actions of a major class of drugs that are used to treat type 2 diabetes, the thiazolidinediones. While TZDs reduce blood glucose and improve insulin sensitivity effectively, they can also exhibit deleterious side effects such as increased cardiovascular risk, weight gain, fluid retention and liver toxicity. Because it is desirable to develop new PPAR drugs with more favorable spectrums of response, mechanisms of PPAR ligand activation have come under intense scrutiny. To understand relationships between PPAR ligand binding and transcriptional activation, we sought to obtain apo human PPAR-LBD (ligand binding domain) crystals that diffract to high resolution. More surprisingly, close analysis of the ligand binding pocket revealed the presence of three small molecules, identified as nonanoic acid and octanoic acid. Here, we report the X-ray structural analysis of the PPAR LBD complexed with three bacterial (expression organism) medium chain fatty acids (MCFAs) that simultaneously occupy the buried ligand binding pocket (LBP). Structural and functional analysis suggests that MCFAs are partial agonists that stabilize PPAR LBD conformation, through a helix 12 independent mechanism.
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Prokeš, Tomáš. "Výroba přírub s využitím postupu PPAP a normy ISO 9001." Master's thesis, Vysoké učení technické v Brně. Fakulta strojního inženýrství, 2016. http://www.nusl.cz/ntk/nusl-241034.
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In the first part of this thesis is described implementation of quality management system in a small company according to ISO 9001. Next part is about production process by method PPAP. In this section is solved primarily ISO 9001 standard, statistical control of production and certification company according to requirements of ISO 9001. Second part is focused on mass production of flange by using the company facilities Kovobrábění Sobotka. In the end of thesis are reflected weaknesses of production. In the conclusion is described technical and economic evaluation of implementation QMS and machining sample parts.
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Régnier, Marion. "Homéostasie des céramides et hépatopathies métaboliques." Thesis, Toulouse 3, 2018. http://www.theses.fr/2018TOU30222/document.
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La prévalence de l'obésité et du diabète de type II est en constante augmentation dans les pays industrialisés. La manifestation hépatique de ces pathologies est la NAFLD (" Non-Alcoholic Fatty Liver Disease "). Celle-ci représente aujourd'hui un réel problème de santé publique et résulte d'atteintes métaboliques et hépatiques. La NAFLD démarre par l'accumulation excessive de lipides dans les hépatocytes nommée " stéatose hépatique ". Ces lipides s'accumulent sous différentes formes comme les triglycérides, les esters de cholestérol, les diglycérides et les céramides. La lipotoxicité induite par l'accumulation de ces espèces lipidiques est à l'origine d'un dysfonctionnement au niveau cellulaire et d'une insulino-résistance. Dans ce contexte, les objectifs de ce travail de thèse ont été d'étudier in vivo le rôle des céramides dans l'apparition et les complications de la NAFLD. Pour cela, nous avons utilisé différentes approches : pharmacologiques, génétiques et nutritionnelles. Par une approche pharmacologique, nous avons montré que la fumonisine B1, un contaminant alimentaire ciblant la synthèse des céramides, est à l'origine d'une toxicité hépatique dépendante d'un facteur de transcription essentiel du métabolisme lipidique, LXR (" Liver X Receptor "). Puis, nous avons combiné différentes approches nutritionnelles et génétiques permettant d'induire ou de protéger de la stéatose hépatique. Pour cela, nous avons utilisé des souris invalidées de façon totale ou hépatocyte-spécifique pour PPARa (" Peroxisome Proliferator-Activated Receptor alpha "), un facteur de transcription essentiel au catabolisme des lipides. Cela nous a permis de confirmer le rôle essentiel de PPARa hépatocytaire dans la réponse au jeûne et l'implication systémique de PPARa dans la régulation du métabolisme des céramides au cours de l'obésité induite par un régime HFD (" High Fat Diet "). Enfin, nous avons utilisé des souris invalidées au niveau hépatocytaire pour la sous-unité catalytique de la PI3 Kinase alpha, p110a. Cela nous a permis de confirmer le rôle majeur de la voie de signalisation à l'insuline dépendante de p110a dans l'apparition de l'insulino-résistance dissociée de la stéatose hépatique induite par un régime HFD. De façon intéressante, grâce à ce modèle, nous avons démontré que la lipolyse adipocytaire (et non l'inhibition de la voie insulinémique) représente le signal dominant de l'activité hépatique de PPARa durant le jeûne. L'ensemble de ces travaux mettent en avant le rôle des céramides dans la lipotoxicité associée à la stéatose hépatiquePrevalence of obesity and type II diabetes is constantly increasing in industrialized countries. NAFLD (" Non-Alcoholic Fatty Liver Disease ") is the hepatic manifestation of these pathologies. NAFLD represents a significant public health problem and is defined as a nexus of metabolic and hepatic diseases. NAFLD begins with fatty accumulation in the liver named "hepatic steatosis". Lipids can accumulate in different forms like triglycerides, cholesterol esters, diglycerides and ceramides. Lipotoxicity induced by the accumulation of these lipid species leads to cellular dysfunction and insulin resistance. In this context, we studied the role of ceramides in apparition and evolution of NAFLD in vivo. For this purpose, we used pharmacological, genetic and nutritional approaches. By pharmacological approach, we showed that fumonisin b1, a mycotoxin targeting ceramide synthesis, leads to hepatic toxicity, which is dependent from LXR ("Liver X Receptor"), a major transcriptional regulator of lipid metabolism. Then, we combined genetic and nutritional approaches in order to induce or protect from hepatic steatosis. For this, we used mice with hepatic or total deletion for PPARa (" Peroxisome Proliferator-Activated Receptor alpha "), a transcriptional factor essential in fatty acid catabolism. First, this model allow us to confirm the role of hepatocyte PPARa in response to fasting and second, to demonstrate the systemic involvement of PPARa in regulating ceramide metabolism during obesity induced by an HFD ("High Fat Diet"). Last, we used p110a liver-specific knockout mice, the catalytic subunit of PI3Kinase alpha. With this model, we confirmed the critical role of p110a-dependent insulin signaling in insulin resistance dissociated from hepatic steatosis induced by a HFD. Interestingly, we demonstrated with this model that free fatty acid released from adipocyte lipolysis (rather than inhibition by p110a-dependent insulin signaling) determines PPARa activity in the liver. Finally, this work highlights the key role of ceramides in lipotoxicity associated with hepatic steatosis
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Šťastný, Petr. "Implementace systému na podporu řízení projektů v IT společnosti." Master's thesis, Vysoká škola ekonomická v Praze, 2008. http://www.nusl.cz/ntk/nusl-5397.
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Práce je zaměřena na problematiku zavádění softwarových nástrojů pro podporu projektového řízení. Na konkrétním projektu implementace ukazuje možnosti dnešních PM nástrojů a navrhuje postup projektu, který umožní co nejlépe využít vlastností zaváděného systému ve vztahu k požadavkům a možnostem organizace. Cílem práce je ukázat, že vhodnout konfigurací lze dosáhnout mnohem širšího využití tohoto typu nástrojů pro řízení celé společnosti
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Gomes, Emerson Rodrigo Machi 1977. "Caracterização bioquímica e celular da glutaminase isoforma Kidney-type com seus parceiros de interação." [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311950.
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Orientador: Sandra Martha Gomes DiasDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Células tumorais apresentam uma autonomia metabólica aumentada em comparação a células não-transformadas, incorporando nutrientes e metabolizando-os através de vias que suportam o seu crescimento e proliferação. O foco deste trabalho foi a enzima glutaminase, a qual processa glutamina em glutamato para posterior produção de alfa-cetoglutarato pela enzima glutamato desidrogenase, reabastecendo o ciclo do TCA e suportando seu funcionamento e geração de metabólitos essenciais para a síntese de macromoléculas. O gene GLS1 codifica para as isoformas glutaminase kidney-type (KGA) e glutaminase C (GAC). Estas proteínas apresentam outros domínios além do catalítico, e, no caso da KGA, repetições do tipo ankirin, sabidamente envolvidas em contatos proteínas-proteínas. Os objetivos deste projeto foram de encontrar parceiros de interação para a glutaminase kidney-type (KGA) e avaliar o impacto desta interação para o metabolismo tumoral. Um candidato inicialmente avaliado, a Aldolase A, não foi confirmado como parceiro de interação. Outro candidato, a BNIP-H, apesar de ter sido mostrado interagir com a KGA em células nervosas, não mostrou indícios de interação com a KGA em linhagem de células de câncer de mama. Por fim, estudos de duplo-híbrido em levedura revelaram o receptor nuclear PPAR? (Peroxisome proliferator-activated receptor gamma) como forte candidato a parceiro de interação. Realizou-se um mapeamento dos domínios responsáveis pela interação entre estas duas proteínas, também por duplo híbrido, tendo sido identificado o domínio LBD da proteína PPAR? como envolvido na interação. Mesmo estudos realizados com fragmento da KGA, apesar de incompletos, mostraram que a interação não ocorre pelo domínio carboxi-terminal da enzima. Ensaios de anisotropia de fluorescência com as proteínas KGA e PPAR? purificadas indicaram que a interação é favorecida pela presença do produto da reação glutaminolítica, glutamato, e apresenta um Kd de 4,6 ± 0,5 ?M. Microscopia confocal de imunofluorescência mostrou que ambas as proteínas se co-localizam no citoplasma, mas não no núcleo. Mais se verificou que em células HEK 293T a presença de KGA diminui a capacidade de transativação de PPAR? induzida pelo ativador roziglitazona, enquanto que celular PC3 com superexpressão de KGA apresentam níveis diminuídos de expressão da proteína ACADL, alvo do PPAR?. Da mesma maneira, ensaios in vitro de atividade da KGA mostraram que a presença de PPAR? inibe a atividade da glutaminase. Nossos resultados mostram a interação in vitro entre as proteínas KGA-PPAR? e a potencial influência funcional que uma proteína exerce sobre a outra. Dado a participação de ambas as proteínas no processo tumoral, especula-se que esta interação possa ter impacto no desenvolvimento do câncer
Abstract: Tumor cells have an increased metabolic autonomy compared to non-transformed cells, metabolizing nutrients and incorporating them through pathways that support cell growth and proliferation. The focus of this study was the glutaminase enzyme, which processes glutamine to glutamate for subsequent production of alpha-ketoglutarate, by the glutamate dehydrogenase enzyme, replenishing TCA cycle and bearing its function and the generation of metabolites essential for the synthesis of macromolecules. The gene GLS1 codes for the isoforms kidney-type glutaminase (KGA) and glutaminase C (GAC). These proteins exhibit other domains besides the catalytic, and in the case of KGA, ankirin repeats, known to be involved in protein-protein contacts. The goal of this project was to investigate potential interacting partners of KGA and contextualize the interaction within the metabolic demands of tumor cells. A candidate initially evaluated, the Aldolase A, was not confirmed as a partner of interaction. Another candidate, the BNIP-H, despite having been shown to interact with the KGA in nervous cells, showed no evidence of interaction with KGA in one tested breast cancer cell lines. Finally, yeast two-hybrid studies revealed the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR?) as a strong interaction partner candidate. We mapped the domains responsible for the interaction between these two proteins, also by two-hybrid and identified the LBD domain of PPAR? as involved in the interaction. The same studies with KGA fragments, although incomplete, showed that the interaction did not involve the carboxy-terminal domain of the enzyme. KGA and PPAR? proteins were expressed in E. coli, purified and their interaction was analyzed by pull-down, fluorescence anisotropy, electrophoresis under native conditions, gel filtration chromatography and crosslinking. The assays indicated that the interaction is favored by the presence of the reaction product glutamate and has a Kd of 4,6 ± 0,5 ?M and disfavored by phosphate. Immunogold labeling followed by transmission electron microscopy of SKBR3 cells revealed a curious nuclear staining pattern probably heterochromatic of KGA. Immunofluorescence confocal microscopy showed that both proteins co-localize in the cytoplasm but not in the nucleus. Moreover, it was found that in HEK 293T cells, the presence of KGA decreases PPAR? ability of inducing transactivation of a reporter gene, while PC3 cell overexpressing KGA have low levels of protein expression ACADL target this receptor. Likewise, activity in vitro assays in the presence of KGA showed that PPAR? receptor inhibits the glutaminase activity. Our results demonstrate the in vitro interaction between proteins KGA-PPAR? and the potential functional influence that these proteins exerts on each other. Given the involvement of both proteins in the tumor growth, it is speculated that this interaction may have impact on the development of cancer
Mestrado
Clinica Medica
Mestre em Ciências
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Espíndola-Antunes, Daniela [UNIFESP]. "A expressão da 11beta-hidroxisteroide desidrogenase tipo 1 e reguladores chave da adipogênese humana não estão aumentados na síndrome de Cushing." Universidade Federal de São Paulo (UNIFESP), 2008. http://repositorio.unifesp.br/handle/11600/23884.
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Serrano, Marco Lucía. "PPAR β/δ, inflamació i resistència a la insulina en adipòcits." Doctoral thesis, Universitat de Barcelona, 2011. http://hdl.handle.net/10803/96332.
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Des de fa un parell de dècades s’ha establert una relació causa efecte entre l’estat inflamatori crònic de baixa intensitat que es presenta en obesitat i l’aparició de resistència a insulina i Diabetis Mellitus tipus 2 associades a aquesta patologia. Aquest estat inflamatori es caracteritza per la sobreproducció de citocines proinflamatòries com el TNF-α(factor de necrosi tumoral-α) o la interleucina 6 (IL-6), que són produïdes en gran mesura pel teixit adipós.
Els Receptors Activats per proliferadors Peroxisòmics (PPAR) s'han proposat com a possibles dianes terapèutiques per al tractament i la prevenció del procés inflamatori i de la resistència a la insulina. D’aquests receptors nuclears el subtipus PPARβ/δ juga un paper important en la prevenció del procés inflamatori, ja que diversos estudis han demostrat que pot evitar la producció de IL-6 induïda per lipopolisacárid en el teixit adipós, i a més pot inhibir l’activació del factor de transcripció proinflamatori NF-κB.
Per això, els objectiu d’aquesta tesi doctoral han estat, d'una banda, avaluar els efectes de l’obesitat i la inflamació sobre PPARβ/δ, i d’altra banda, conèixer si l’activació d’aquest receptor nuclear per GW501516 és capaç de prevenir la resistència a la insulina induïda per la via IL-6/STAT3/SOCS3 i els mecanismes implicats en adipòcits.
Els resultats que es van obtenir a partir de mostres de teixit adipós humà indiquen que en presència d’obesitat hi ha un increment de citocines proinflamatòries (IL-6 i TNF-α) i de NF-κB, ambdós factors afavoreixen el procés inflamatori. Aquesta situació s’acompanyà d'una disminució de l’activitat de PPARβ/δ, la qual es va veure reflectida en la disminució dels gens diana d'aquest. Però l'activació de PPARβ/δ i la inhibició de NF-κB en estudis in vitro amb cèl•lules adiposes SGBS van ser capaços de revertir aquest efecte (Serrano-Marc L, BBA of Lipids, 2012). D'altra banda, estudis en ratolins i en cèl•lules 3T3-L1 van demostrar que l’activació de PPARβ/δ per GW501516 podria evitar l’aparició de resistència a la insulina inhibint l’activació de la via IL-6/STAT3/SOCS3 mitjançant dos mecanismes. L’activació del receptor nuclear va impedir la fosforilació en el residu de Tyr705 de STAT3 (Signal Transductor and Activator of transcription 3, un factor de transcripció) i d’aquesta manera va inhibir la unió de Hsp90 amb aquest (necessària per a queSTAT3 s’activi). D’altra banda, l’activació per GW501516 va impedir la fosforilació de la ERK1 / 2 (Extracellular Receptor Kinase 1/2) i d’aquesta manera es va evitar la fosforilació en el residu de Ser727 de STAT3, necessària per a la seva activació transcripcional. La inhibició del factor de transcripció STAT3 va implicar una disminució en els seus gens diana, entre ells SOCS3 (Supressor of Citokine Signaling 3), que és el responsable de la degradació d'IRS-1 (Insulin Receptro Substrate-1), proteïna essencial per donar resposta a la insulina (Serrano-Marco, L, Diabetis, 2011).It has been established a causal link between the chronic inflammatory state of low intensity that occurs in obesity and the onset of insulin resistance and type 2 diabetes. This inflammatory condition is characterized by the overproduction of proinflammatory citokines such TNF-α (Tumor Necrosis Factor-α) or interleukin 6 (IL-6), which are largely produced by the adipose tissue. The Peroxisomic Proliferator Activated Receptors (PPAR) have been proposed as potential therapeutic targets for the treatment and prevention of inflammation and insulin resistance. Of these nuclear receptors the subtype PPARβ/δ plays an important role in preventing the inflammatory process. Therefore, the objective of this work is, one hand, to evaluate the effects of inflammation in obesity and in PPARβ/δ; and secondly, to determine whether the activation of PPARβ/δ with GW501516 in adipocytes is capable of preventing insulin resistance induced through the IL-6/STAT3/SOCS3 pathway, and also the mechanisms involved. The results obtained from human adipose tissue samples show that in the presence of obesity there is an increase of proinflammatory cytokines (IL-6 and TNF-α) and of NF-κB. This was accompanied by a decrease in the PPARβ/δ activity. But the activation of PPARβ/δ and the inhibition of NF-κB in in vitro studies with SGBS adipose cells were able to reverse these effects (Serrano-Marco L, BBA of Lipids, 2012). Furthermore, studies in mice and in 3T3-L1 cells demonstrated that activation of PPARβ/δ by GW501516 could prevent the development of insulin resistance by inhibiting the activation of the IL-6/STAT3/SOCS3 pathway (Serrano-Marco L, Diabetes, 2011). Taking all these data together the final conclusion of this work is: PPARβ/δ is involved in the regulation of the chronic inflammatory state that links obesity and insulin resistance. Therefore, the activation of this nuclear receptor could prevent IL6 induced insulin resistance.
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Clark, Jordan. "The role of PPAR ligands in collecting duct growth and apoptosis." Thesis, University of Ottawa (Canada), 2008. http://hdl.handle.net/10393/27671.
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The collecting duct (CD) has considerable expression of PPARdelta and PPARgamma. While their roles are unknown in the CD, in other cells they have been shown to regulate both growth and apoptosis. We thus investigated the hypothesis that PPARs reduce apoptotic responses in the mouse collecting duct IMCD-K2 and M-1 cells and that while PPARgamma has an inhibitory effect on cell growth, PPARdelta stimulates growth in these cells. This study characterized the growth and apoptotic responses in the collecting duct cells, M-1 and IMCD-K2, in response to the PPARdelta and PPARgamma ligands, GW501516 and troglitazone. The extent of apoptosis in IMCD-K2 and M-1 cells, induced by anisomycin, was only affected by troglitazone, which reduced the protein levels of cleaved caspase-3 in M-1 cells. GW501516 treatment increased DNA synthesis in IMCD-K2 cells, decreased DNA synthesis in M-1 cells, and decreased protein synthesis in both IMCD-K2 and M-1 cells. Additionally, troglitazone reduced DNA and protein synthesis in M-1 cells, and this effect was unaltered in the presence of the PPARgamma antagonist and ERK inhibitor. However, troglitazone treatment alone increased the levels of pERK. These results show PPAR ligands negatively regulate growth and apoptosis in CD cell lines, but more work is needed to ascertain the therapeutic potential of PPAR ligands in the prevention of CD injury.
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Jamshidi, Yalda. "Role of PPAR#alpha# in coronary heart disease and cardiac hypertrophy." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252393.
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Tremblay, Hugo. "Identification et caractérisation d'agonistes mixtes des récepteurs GPR40 et PPAR[gamma]." Mémoire, Université de Sherbrooke, 2011. http://savoirs.usherbrooke.ca/handle/11143/4930.
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Le diabète de type II est une maladie impliquant deux déficiences majeures : la résistance à l'insuline et la diminution de sécrétion d'insuline. Afin d'identifier de nouvelles pistes de traitement potentiel pour cette maladie nous avons utilisé une approche polypharmacologique ciblant simultanément ces deux déficiences. Pour ce faire nous avons conçu et synthétisé une librairie de 29 composés et caractérisé leur activité biologique sur les récepteurs GPR40 et PPAR[gamma], dans le but d'identifier des agonistes mixtes. Ce travail a mené l'identification de deux composés ayant une activité sur PPAR[gamma] et des EC[indice inférieur 50] au niveau du micromolaire sur GPR40.
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Abboud, Georges. "Rôle de FcεRI, CD16 et PPAR-α dans la dermatite atopique." Lille 2, 2008. http://tel.archives-ouvertes.fr/tel-00285004/fr/.
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Les récepteurs de forte et de faible affinité pour l'IgE, FcεRI et FcεRII/CD23 et le récepteur de faible affinité pour l'IgG, FcγRIII/CD16, jouent un rôle essentiel dans les maladies allergiques. CD23 est une lectine de type C alors que FcεRI et CD16 sont multimériques et s'associent, comme d'autres FcRs, à la chaîne FcRγ essentielle à leur assemblage et signalisation. Dans la peau humaine, ces FcRs sont exprimés par des cellules présentatrices d'antigène et effectrices recrutées au derme durant l'inflammation. Plusieurs publications montrent que des pathologies allergiques et plus particulièrement la dermatite atopique (DA) peuvent être médiées par ces 3 FcRs. La DA est une maladie inflammatoire chronique de la peau caractérisée par un épaississement épidermique et un infiltrat dermique de lymphocytes T mémoire activés, macrophages, mastocytes et éosinophiles avec des phases aiguë et chronique associées à des profils cytokiniques de type Th2 et Th1 respectivement. Chez la majorité des patients atteints de DA, une augmentation de production d'IgE et IgG totales et spécifiques d'allergène et d'antigènes microbiens est observée. Nous avons étudié le rôle de ces FcRs dans un modèle de DA murin qui mime la pathologie humaine en comparant des animaux déficients en ces FcRs aux animaux correspondants de type sauvage (WT). Les symptômes de la DA sont complètement absents dans les souris déficientes en FcRγ et partiellement inhibés dans les souris déficientes en FcεRI ou CD16. Cette inhibition est correlée avec une agmentation de l'expression cutanée de l'IL-10 et Foxp3. Alors que FcεRI régule les réponses Th1 et Th2, le recrutement des mastocytes vers les ganglions drainants et la production d'IgE, le CD16 régule uniquement la réponse Th2, la prolifération des LT et la production d'IgG1. FcεRI et CD16 sembleraient réguler la production spécifique de leurs ligands en régulant différentiellement les réponses IL-4 et IL-21 ganglionnaires. D'une façon importante, l'absence de CD23 aboutit à une inhibition drastique de la pathologie cutanée et comme celle de FcεRI, à une diminution des réponses cutanées Th1 et Th2 ainsi que de la production sérique de l'IgE mais pas celle de l'IgG1. Ensuite nous avons étudié le rôle régulateur potentiel du récepteur nucléaire, PPAR-α, dans ce modèle de DA. En effet, il est exprimé par plusieurs cellules inflammatoires cutanées. Outre son rôle régulateur bien connu dans le métabolisme lipidique et glucidique, PPAR-α possède des propriétés anti-inflammatoires. Suite à la sensibilisation cutanée, nous avons remarqué que les souris déficientes en PPAR-α montrent une exacerbation des réponses cutanée et pulmonaire, et de la production de l'IgE et IgG2a par rapport aux souris WT. Ce phénomène est correlé avec une exacerbation des réponses moléculaires cutanées Th2 et surtout Th1 ainsi qu'à une augmentation d'expression de NF-κB. D'une façon intéressante, l'expression de PPAR-α a été diminuée dans les lésions cutanées de patients atteints de DA suggérant que cette diminution d'expression peut contribuer à la pathologie. Enfin, l'application d'un agoniste spécifique de PPAR-α diminue significativement la maladie chez la souris. Finalement, IgE/FcεRs et IgG/FcγRs ou PPAR-α constituent des cibles thérapeutiques importantes dans plusieurs maladies allergiques
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Almad, Akshata A. "Role Of PPAR Family Of Transcription Factors In Spinal Cord Injury." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1292952253.
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Kim, Dasom. "PPAR-gamma Regulates T Cell Responses in Air Pollutant-associated Inflammation." University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1522414820700163.
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Goswami, Ashwini. "DEVELOPMENT OF PPAR-γ RECEPTOR AGONISTS AS THERAPEUTIC AGENTS FOR DIABETES." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1881.
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The peroxisome proliferator-activated receptors (PPARs) are the transcriptional regulators of glucose, lipids and cholesterol metabolisms. It has been established that PPAR-γ is the receptor for thiazolidinediones (TZDs) class of type II anti-diabetic drugs. These compounds act as agonists of PPAR-γ. They may delay the development of type II diabetes in individuals at high risk of developing the condition, and have been shown to have potentially beneficial effects on cardiovascular risk factors. PPAR-γ receptor activation by TZDs improves insulin sensitivity by promoting fatty acid uptake into adipose tissue, increasing production of adiponectin (responsible for glucose regulation and fatty acid metabolism) and reducing levels of inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha), plasminogen activator inhibitor-1(PAI-1) and interleukin-6 (IL-6). Our goal is to take advantage of the mode of binding of known PPAR-γ agonists, such as Rosiglitazone to PPAR-γ to rationally design novel agonists of PPAR-γ. Our long-term objective is to generate new and potent PPAR-γ agonists that could be used to treat diabetes. To achieve our goal the study was divided into five specific aims, including: Aim 1. Expression and purification of PPAR-γ ligand binding domain (LBD). Aim 2. Molecular modeling to design PPAR-γ receptor modulators. Aim 3. Synthesis of potential PPAR-γ receptor modulators. Aim 4. Functional studies to determine the binding affinity of PPAR-γ receptor modulators. Aim 5. Structural studies of PPAR-γ LBD in complex with PPAR-γ receptor modulators. We expressed the His-tagged PPAR-γ LBD protein in Rosetta DE3 cells, and used a one step affinity chromatography (Ni-NTA column) to obtain a significant yield of pure protein. Using the structural features and the known binding mode of Rosiglitazone to PPAR-γ LBD as a starting point, two classes of compounds (type-I and type-II compounds) were designed as potential PPAR-γ agonists. These novel compounds were rationalized to improve on the binding modes of Rosiglitazone via additional hydrogen-bonding and/or hydrophobic interactions to the protein. Five type-I and II compounds were synthesized and tested against PPAR-γ receptor for binding affinity, using fluorescent polarization assay. The IC-50 value of the most potent compound (compound B) was found to be ~ 7-fold lower than Rosiglitazone, significantly lower than the expected value. It seems that unlike Rosiglitazone which has free rotatable thiazolidinedione ring that can make optimal interactions with His323 and His449 (two critical residues that are important for binding affinity), the thiazolidinedione ring in our compounds are fixed in one position that may not lead to optimal contact with the protein. We are currently synthesizing analogs of our compounds with rotatable thiazolidinedione ring for further studies. X-ray crystallographic study has been initiated to determine the binding modes of our compounds with PPAR-γ LBD which would allow for structural modifications for improving existing interactions and/or formation of new favorable interactions that could lead to higher affinity and potency. We have also initiated testing of these compounds to determine their PPAR-γ agonistic effects.
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Evans, Kyle William. "PPAR gamma AND eNOS CONTRIBUTE TO THE RESOLUTION OF CHRONIC INFLAMMATION." Diss., Temple University Libraries, 2011. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/197871.
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Microbiology and ImmunologyPh.D.
Chronic inflammation follows defined phases of induction, inflammation, and resolution. The resolution phase requires cycloxygenase-2 (COX-2) activity. This study aims to address what other molecules are required for a functional resolution phase. We demonstrated that in murine collagen-induced arthritis the transcription factor, PPARgamma plays a role in the resolution phase. Inhibition of COX-2 activity results in fewer PPARgamma positive cells in the arthritic synovium. Treatment with a PPARgamma antagonist, SR202, alone, also disrupts the process of resolution. PPARgamma antagonist treatment results in a decrease in eNOS phosphorylation within the arthritic synovium. These observations indicate that PPARgamma may function to regulate eNOS activity. The source of pro-resolving nitric oxide is eNOS but not, iNOS. The effect of COX-2 inhibition on the resolution phase is ameliorated by injection of a PGE2 analog. Restoration of PGE2 levels results in an increase in PPARgamma positive cells in the arthritic synovium which correlates with this restoration of resolution. Thus, this study provides in vivo evidence for the pro-resolving role of PPARgamma and its relationship with PGE2 and eNOS.
Temple University--Theses
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Baker, Amelia Rachel Haas. "Environmental PPAR-gamma agonists accelerate aging of bone and impair lymphopoiesis." Thesis, Boston University, 2012. https://hdl.handle.net/2144/12274.
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Thesis (Ph.D.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.A growing number of environmental contaminants, including phthalates and organotins, are being recognized for their ability to activate peroxisome proliferator-activated receptor γ (PPARγ) and promote adipogenesis, and have been termed environmental obesogens. Organotins have been pollutants of concern in the marine environment due to use as antifoulants; however, organotin use in wood preservatives, plastics manufacturing, and agricultural pesticides has caused widespread environmental contamination. Tributyltin (TBT) is a highly potent activator of PPARγ, as well as its dimerization partner RXR. Bone marrow (BM) is a multifunctional organ which supports bone homeostasis, lymphopoiesis and whole body energy homeostasis. BM multipotent mesenchymal stromal cells (BM-MSCs) differentiate into adipocytes and osteoblasts, the balance of which constitutes the BM microenvironment. PPARγ sits at the crossroad, promoting adipogenesis and suppressing osteogenesis. Osteoblasts are necessary for optimal lymphopoiesis and adipocytes negatively regulate lymphopoiesis. With age, increased marrow adiposity is associated with concomitant loss of osteoblasts, and reduced cellular and humoral immunity. We tested the hypothesis that TBT skews the BM microenvironment, increasing marrow adiposity and suppressing osteoblast differentiation, ultimately impacting both bone quality and lymphopoiesis, a process resembling premature bone aging. TBT induced adipogenesis in a BM-MSC cell line in a PPARγ-dependent manner and also activated liver X receptor (LXR)-dependent gene transcription. TBT concomitantly induced adipogenesis and suppressed osteogenesis in an ex vivo BM-MSC model and increased marrow adipogenesis and reduced cortical bone in vivo. These changes in differentiation were accompanied by PPARγ upregulation and Runx2 downregulation. Surprisingly, shRNA-mediated knockdown of PPARγ revealed its potential role in early osteogenesis. Experiments in ex vivo cultures also revealed that TBT modifies BM-MSC differentiation distinctly from either a PPARγ or an RXR agonist; a likely mechanism, activation of LXR also was evident in vivo. At environmentally relevant concentrations, TBT directly induced apoptosis in developing B cells in vitro and suppressed developing and peripheral B cells in vivo, likely in part by altering the microenvironment in which they mature. Collectively, these studies contribute to the understanding of how environmental contaminants alter the adipocyte-osteoblast balance, contributing new mechanism-based information on how exogenous exposures affect the interrelationship between lymphopoiesis and the BM microenvironment.
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Helin, Lionel. "Régulation de l'homéostasie du cholestérol par les récepteurs nucléaires PPARα et LXR dans les macrophages primaires humains." Lille 2, 2007. http://www.theses.fr/2007LIL2S001.
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Les maladies cardiovasculaires représentent la cause majeure de mortalité dans les pays industrialisés. L'athérosclérose est à l'origine de nombreux décès par accidents ischémiques aigüs. Les macrophages jouent un rôle essentiel dans le développement de cette maladie. Les récepteurs nucléaires Peroxysome proliferators-activated receptor (PPAR) α et Liver X receptors (LXR) sont des récepteurs nucléaires exprimés dans les macrophages humains et impliqués dans la modulation du métabolisme des lipides. Des études cliniques chez l'homme et sur des modèles animaux ont montré que l'activation de PPARα et des LXR par leurs ligands synthétiques peut inhiber le développement de l'athérosclérose. Ceci, indépendamment de leur effet sur les lipides plasmatiques par leurs actions au niveau de la paroi artérielle. Dans un premier temps, nous avons montré dans les macrophages primaires humains que les agonistes des récepteurs nucléaires PPAR et LXR augmentent l'efflux de cholestérol vers l'apoAI non seulement par l'induction de l'expression du transporteur ABCA1 mais également en mobilisant le cholestérol vers la membrane plasmique par l'induction des protéines NPC-1 et NPC-2. Dans un second temps, nous avons mis en évidence que l'activation de LXR induit également la captation sélective des esters de cholestérol provenant des HDL. Cette régulation fonctionnelle est associée à une augmentation de l'efflux de cholestérol vers ces mêmes HDL et à une augmentation de l'expression de différentes protéines telles que l'apolipoprotéine E, la lipoprotéine lipase et la cavéoline impliquées dans les phénomènes de captation des esters de cholestérol. Ceci suggère que l'effet anti-athérogène de LXR soit assuré, en partie, par l'augmentation des flux du cholestérol dans le macrophage humain. Nos travaux sont donc en étroite adéquation avec l'hypothèse de propriétés anti athéroscléreuses des récepteurs nucléaires par leur action directe sur la régulation du métabolisme du cholestérol dans le macrophageThe cardiovascular diseases represent the major cause of mortality in industrial countries. Atherosclerosis is responsible of many ischemic troubles. Macrophages play a pivotal role in the development of atherosclerosis. Peroxysome proliferators-activated receptor (PPAR) alpha and Liver X receptors (LXR) are nuclear receptors expressed in human macrophages that regulate the expression of genes controlling lipid metabolism. Clinical trials and studies on animal models show that PPAR alpha and LXRs agonists can repress development of atherosclerosis by their actions on arterial wall, especially on cholesterol homeostasis regulation in macrophages. First, we have shown that PPAR and LXR agonists induce NPC-1 and NPC-2 genes and proteins expression and stimulate the postlysosomal mobilization of cholesterol to plasma membrane, associated with inhibition of cellular cholesterol esterification. Cholesterol becomes more available for its efflux to extracellular acceptors via the ABCA1 pathway. Then, we have shown that LXR agonists induce a strong increase in selective cholesteryl ester uptake. This functional regulation is associated with an induction of cholesterol efflux out of the cell and an induction in several protein expressions as apolipoprotein E, lipoprotein lipase ans caveolin. These proteins are associated to cholesteryl ester uptake phenomenae. These results suggest that the LXR athero-protective effect is mediated in part by enhanced fluxes in cholesterol intracellular trafficking in the human macrophage
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Fidaleo, Marco. "Effets des proliférateurs de peroxysomes sur la voie de signalisation contrôlée par PPAR alpha dans trois modèles différents de rongeurs." Dijon, 2008. http://www.theses.fr/2008DIJOS005.
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Cette thèse illustre dans la première partie les effets du ciprofibrate et de l'aspirine (qui sont largement utilisés pour leurs propriétés thérapeutiques et aussi connues pour induire la prolifération de peroxysomes chez les rongeurs) dans rats nourrissons et rats adultes, respectivement. Par ailleurs, la même approche pharmacologique a permis de mettre en évidence, dans la seconde partie de cette thèse, les défauts des souris mutants pour la 3-cétoacyl-CoA Thiolase B (ThB) de peroxysomes. Rats nourrissons nourris par des mères traitées avec ciprofibrate montrent une forte induction de l’activité de beta-oxydation de peroxysome surtout dans le foie, tandis que l'activité de la catalase a été faiblement up-regulated, confirmant ainsi une dilution de cette dernière activité que, à son tour, pourrait conduire à un stress oxydatif. En outre, une perturbation sur la prolifération cellulaire et l'apoptose a été observée uniquement dans le foie. Alors que, ce déséquilibre et le stress oxydatif produit par le ciprofibrate dans les rats nourrissons peut produire la tumeur du foie, comme a été observé dans les rats adultes traités pour une période très long. Le traitement des rats adultes avec de l'aspirine a démontré que ce médicament est capable de produire, comme prévu, une légère induction de certaines enzymes de peroxysomes dans le foie et les reins, tandis que aucune modification sur la prolifération cellulaire ou sur l'apoptose ni pendant ni après traitement a été observée. La corrélation entre la prolifération cellulaire et prolifération de peroxysomes est, actuellement, largement étudiée et on pense que les deux phénomènes sont liés, mais pas strictement liées. Dans la dernière partie de cette thèse, nous avons étudié la caractérisation de la souris déficiente pour la thiolase B. A première vue, la souris déficiente pour la ThB était viable, saine, fertile et sans gros défauts phénotypiques dans les conditions basales. Le traitement pharmacologique avec WY 14,643, ce qui induit l’expression de la thiolase B dans le fois et de la prolifération de peroxysomes, a mis en évidence certaines altérations moléculaires: en particulier, en utilisant des puces à ADN a été montré que le manque de ThB dysrégulation la biosynthèse du cholestérol, tandis que la voie de signalisation contrôlée par PPAR alpha n’est pas affectée. Au niveau physiologique, nous n'avons pas observé de changements dans le cholestérol contenu dans le foie, alors qu'une augmentation significative des concentrations plasmatiques de triglycérides a été observée chez les souris déficiente pour la ThB par rapport au type sauvageThis thesis illustrates the effects of ciprofibrate and aspirin, which are widely used for their therapeutic properties and also known to induce peroxisome proliferation in rodents, on suckling and adult rats, respectively. Moreover, the same pharmacologic approach was used to highlight defects of thiolase B mutation in knock out mouse. Suckling rats fed by lactating-mothers treated with ciprofibrate showed a strong induction of peroxisomal beta-oxidation activity especially in liver, while catalase activity was weakly up-regulated, confirming a dilution of this enzyme activity, which, in turn, could lead to an oxidative stress. Furthermore, a perturbation on cell proliferation and apoptosis was observed exclusively in liver. So that, this imbalance and the oxidative stress produced by ciprofibrate in suckling rats may mediate the hepatocarcinogenesis, as observed in PP long term administration in adults rats. Treatment of adult rats with aspirin has demonstrated that this drug is able to produce, as expected, a slight induction of some peroxisomal enzymes both in liver and kidney, while no modification on cell proliferation or apoptosis neither during drug treatment nor after withdrawal was observed. The correlation between the peroxisome and cell proliferation is, at present, widely investigated and it is thought that the two phenomena are associated but not closely related. In the last part of this thesis, we studied the characterization of the thiolase B knoch out mouse. At first sight, thiolase B-/- mouse was viable, healthy, fertile and devoid of gross phenotypic defects under basal conditions. The pharmacologic treatment with WY14,643, which induces both expression of the thiolase B and peroxisome proliferation, highlighted some molecular alterations: in particular, it was shown by Affymetrix microarrays that the lack of thiolase B dysregulated the cholesterol biosinthesis, while PPAR alpha signaling was not affected. At physiological level, we did not observe any changes in hepatic cholesterol contents, while a significant increase of plasma triglicerides profile was observed in knoch out mice with respect to the wild type
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Staumont-Sallé, Delphine. "Mécanismes immunologiques de la dermatite atopique." Lille 2, 2008. http://www.theses.fr/2008LIL2S003.
Full textAbstract:
La dermatite atopique (DA) est l'une des maladies inflammatoires chroniques les plus courantes. Elle pose un véritable problème de santé publique puisqu'elle affecte 10 à 20 % des enfants et 1 à 3 % des adultes dans les pays développés. Il est donc indispensable de progresser dans la connaissance de la physiopathologie complexe de cette maladie, afin de développer de nouvelles armes thérapeutiques ciblées. Les PPARs (Peroxisome Proliferator-Activated Receptors), facteurs de transcription activés par des ligands, appartenant à la superfamille des récepteurs nucléaires, pourraient représenter une cible de choix pour le traitement de la DA. En effet, outre leur rôle régulateur dans les métabolismes lipidique et glucidique, les PPARs sont capables d'exercer des propriétés anti-inflammatoires. Or, les 3 isoformes des PPARs (alpha, beta et gamma) sont exprimées par de nombreuses cellules recrutées dans la peau lors de la réponse inflammatoire. De plus, PPAR-alpha et -beta sont impliqués dans les processus de prolifération et de différenciation des kératinocytes, et dans les mécanismes de réparation cutanée. Nous avons évalué le potentiel rôle anti-inflammatoire de PPAR-alpha dans un modèle murin où un tableau proche de celui de la DA humaine est obtenue par application cutanée répétée d'un antigène protéique utilisé sans adjuvant, l'ovalbumine (OVA). Nous avons observé une exacerbation de la réponse inflammatoire cutanée et systémique induite par l'OVA chez les animaux déficients pour PPAR-alpha. Cette réponse était associée à une augmentation de la réponse Th2 mais aussi TH1, et à une surexpression cutanée du facteur de transcription pro-inflammatoire NF-kappaB. Nous avons ensuite corrélé ces résultats à la pathologie humaine, en montrant un défaut d'expression de PPAR-alpha dans la peau lésée de malades atteints de DA, en comparaison à des témoins sains appariés. Enfin, nous avons observé une réduction significative de la réponse inflammatoire cutanée induite par l'OVA après traitement topique des souris par le WY-14. 643, un agoniste de PPAR-alpha. Nos résultats ont donc confirmé le rôle anti-inflammatoire de PPAR-alpha dans la DA et le potentiel effet thérapeutique d'un agoniste de cette isoforme. Les récepteurs à l'IgE constituent d'autres cibles pour le traitement de la DA. En effet, la plupart des individus porteurs d'une DA présente des taux circulants élevés d'IgE, dirigées contre des allergènes environnentaux, des agents microbiens, tels que le staphylocoque doré, ou encore des auto-antigènes. En appliquant le même protocole de sensibilisation vis-à-vis de l'OVA chez des souris chez lesquelles le gène codant pour le récepteur de haute affinité pour l'IgE (FcepsilonRI) a été invalidé, nous avons démontré que ce récepteur jouait un rôle important dans la réponse inflammatoire cutanée dans ce modèle de DA, mais qu'il n'était cependant pas indispensable à l'induction de cette réaction. Cette observation sous-tendait donc l'implication d'autres récepteurs, dont le rôle dans la physiopathologie de la DA restait méconnu, en particulier le récepteur de faible affinité pour l'IgE (FcepsilonRII/CD23) et les récepteurs pour l'IgG. Nous avons voulu étayé cette hypothèse en reproduisant ce modèle de DA chez des souris déficientes respectivement pour CD23, FcRgamma (sous-unité partagée par FcepsilonRI et les récepteurs pour l'IgG), et enfin le récepteur de faible affinité pour l'IgG (FcgammaRIII/CD16). Bien que CD23 soit connu comme un récepteur inhibiteur chez la souris, nous avons été surpris de constater une abolition de la réponse inflammatoire cutanée chez les animaux déficients en CD23 dans ce modèle de sensibilisation par l'OVA, ce qui était très différent des résultats ayant fait l'objet jusqu'ici de quelques rares publications. Par ailleurs, nous avons prouvé que FcgammaRIII/CD16 jouait également un rôle dans l'induction de la réponse inflammatoire, mais en exerçant une régulation en partie différente de celle de FcepsilonRI. CD23 et CD16 représentent donc également des cibles thérapeutiques d'intérêt dans cette affection invalidante.