Dissertations / Theses: 'Thiazolidinediones'

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Shiau, Chung-Wai. "Thiazolidinediones: from peroxisome-proliferator-activated receptor γ(PPARγ) to anticancer agents." The Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1128111032.

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Wei, Shuo. "Peroxisome Proliferator-Activated Receptor γ (PPARγ)-Independent Antitumor Effect of Thiazolidinediones." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1259167390.

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Shiau, Chung-Wai. "Thiazolidinediones: from peroxisome-proliferator-activated receptor [gamma] (PPAR[gamma]) to anticancer agents." Columbus, Ohio : Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1128111032.

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Leblond, Julie. "Utilisation des thiazolidinediones chez les patients atteints de diabète de type 2." Mémoire, Université de Sherbrooke, 2003. http://savoirs.usherbrooke.ca/handle/11143/3351.

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Le diabète est une maladie importante, tant en raison du nombre de personnes atteintes qu'en raison des diverses répercussions cliniques et économiques. En 2000, une nouvelle classe d'agents antidiabétiques, les thiazolidinediones, a été ajoutée à l'arsenal thérapeutique du diabète au Canada. Actuellement, la plupart des informations disponibles sur ces molécules proviennent d'études cliniques et très peu d'études de population ont été réalisées sur le sujet. Toutefois, nous savons que l'utilisation des médicaments dans la réalité est typiquement différente de celle des études cliniques randomisées. Si l'utilisation de ces médicaments s'avérait inadéquate, des coûts élevés pourraient y être associés. Les objectifs de cette étude étaient de décrire l'adhérence, ainsi que la persistance au traitement avec les thiazolidinediones et d'identifier ses déterminants. Des données démographiques, médicales et pharmaceutiques ont été obtenues à partir des banques de données de la Régie de l'assurance maladie du Québec. Les patients inclus dans cette étude ont été identifiés, entre octobre 2000 et juillet 2002, par une première prescription dispensée (nommée date index) de thiazolidinediones, pour un suivi variant de 1 à 22 mois. Les patients qui n'étaient pas inscrits à l'assurance médicament au moins un an avant la date index étaient exclus de la cohorte, tout comme les patients ayant été hospitalisés 30 jours et plus durant la période de suivi. Le renouvellement des thiazolidinediones sans interruption durant la période de suivi définissait la persistance au traitement et l'adhérence était déterminée comme étant la prise de 80% à 120% de la médication antidiabétique prescrite. Le taux de persistance a été estimé à l'aide d'une analyse de Kaplan-Meier et les déterminants de la persistance ont été identifiés avec un modèle de Cox."--Résumé abrégé par UMI.

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Botton, Thomas. "Étude des effets anti-mélanome des thiazolidinediones : implication de la chimiokine CXCL1." Nice, 2010. http://www.theses.fr/2010NICE4028.

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Les thiazolidinediones (TZD) sont utilisés dans le traitement du diabète de type 2. Cependant, des études ont montré que les TZD inhibent la croissance de nombreuses cellules tumorales. Nous avons donc testé les effets des TZD dans la lutte contre le mélanome, un cancer très agressif contre lequel on ne dispose d’aucun traitement efficace au stade métastatique. Nous avons montré qu’un TZD, la ciglitazone, inhibe la prolifération des cellules de mélanome mais pas celle des mélanocytes. A de faibles doses, la ciglitazone induit un arrêt du cycle alors qu’à de fortes doses elle entraine une apoptose. Les effets antinéoplasiques de la ciglitazone ont été confirmés dans un modèle murin de xénogreffe de mélanome. Nous avons alors montré que les effets biologiques de la ciglitazone sont précédés par une forte diminution de CXCL1, une chimiokine oncogénique surexprimée durant la mélanomagenèse. Cette diminution de CXCL1 est associée à une diminution de MITF, un facteur de transcription contrôlant à la fois la différenciation mélanocytaire et la progression tumorale des cellules de mélanome. Des expériences de xénogreffe ont confirmé que la diminution du potentiel tumoral des cellules de mélanome est associée à une inhibition de l’expression de MITF et du taux sérique de CXCL1 dans les souris traitées à la ciglitazone. Nos travaux suggèrent donc que la ciglitazone pourrait être un candidat intéressant pour la mise en place d’un test clinique. Ils démontrent également l’existence d’un axe MITF/CXCL1 qui semble jouer un rôle clé dans la tumorogénicité des cellules de mélanome. Cet axe pourrait constituer une cible thérapeutique intéressante dans la lutte contre le mélanome
Thiazolidinediones (TZD) are commonly used in the treatment of type 2 diabetes. However, studies on various cancer types have shown that TZD inhibit tumor growth. Thus, we have tested the effects of TZD in the struggle against melanoma, a very aggressive cancer for which there is no hitherto efficient therapeutics when it is metastatic. We have shown in vitro that ciglitazone, a member of the TZD family, is able to inhibit proliferation of melanoma cells but not of melanocytes. At low concentrations, ciglitazone effects on melanoma cells are mediated by a cell cycle arrest while higher concentrations induce cell death by apoptosis. Then, antineoplastic effects of ciglitazone have been confirmed in a xenograft model. Next, we have shown that the biological effects of ciglitazone are preceded by a dramatic decrease in CXCL1. This chemokine overexpressed in melanoma contributes to tumorigenicity. Interestingly, ciglitazone-induced CXCL1 decrease is mediated by the downregulation of microphthalmia-associated transcription factor, MITF, the master gene in melanocyte differentiation and involved in melanoma development. Additional xenograft experiments have emphasized that dramatic decrease in melanoma tumor potential was associated with an inhibition of MITF and a decrease in serum CXCL1 levels of ciglitazone-treated mice. Thus, our results suggest that ciglitazone might be an interesting candidate for clinical trial in melanoma treatment. They also demonstrate existence of a MITF/CXCL1 axis and highlight the key role of this specific pathway in melanoma malignancy. This axis could be a potential interesting therapeutic target in the future of the struggle against melanoma

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Leblond, Julie. "Utilisations des thiazolidinediones chez les patients atteints de diabète de type 2." Sherbrooke : Université de Sherbrooke, 2003.

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7

Lima, José Gildo de. "Thiazolidinediones et imidazolidinediones substituées : synthèse, stucture, étude pharmacologique et relations quantitatives structure-activité." Université Joseph Fourier (Grenoble), 1992. http://www.theses.fr/1992GRE18009.

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Fadnavis, Rucha. "Effect of hyperglycemia and thiazolidinediones on cardiac angiotensin converting enzyme 2 (ACE2) and neprilysin (NEP) in db/db diabetic mice." Wright State University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=wright1503958100026796.

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Colin-Cassin, Christelle. "Activité PPARgamma-indépendante des ligands de PPAR gamma : une piste pour le traitement des cancers du sein ?" Thesis, Université de Lorraine, 2013. http://www.theses.fr/2013LORR0232/document.

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L'un des enjeux majeurs de la recherche anti-cancéreuse est de développer de nouvelles thérapies en direction des tumeurs réfractaires aux traitements conventionnels. Dans ce contexte, l'identification récente de l'activité anti-tumorale PPARgamma-indépendante des thiazolidinediones ouvre de nouvelles perspectives thérapeutiques. Au sein du laboratoire, il a été montré qu'un analogue inactif de la TGZ, la delta2-TGZ, induit une dégradation protéasome-dépendante du récepteur alpha aux oestrogènes de manière PPARgamma-indépendante. A partir de ces données, les objectifs de ma thèse ont été 1) de participer à la caractérisation de nouveaux composés à activité anti-cancéreuse 2) de mieux comprendre les mécanismes PPARgamma-indépendants mis en jeu dans l'effet anti-cancéreux des TZD. Lors de ce travail de thèse, nous avons caractérisé de nouveaux composés plus efficaces que la delta2-TGZ pour l'inhibition de la prolifération des cellules cancéreuses mammaires MCF-7 et MDA-MB-231 et faiblement toxiques sur des cultures primaires d'hépatocytes humains. De plus, nous avons montré que la delta2-TGZ est capable d'induire un stress du réticulum endoplasmique à des temps précoces dès 3 heures et une apoptose à des temps plus tardifs 48 heures. Cependant, nous n'avons pas pu conclure à l'existence d'un lien entre les deux mécanismes. Enfin, nous avons montré que la biotinylation d'un ligand naturel de PPARgamma, la 15d-PGJ2, accroît son effet anti-prolifératif sur les cellules cancéreuses mammaires MCF-7 et MDA-MB-231 et conduit à un stress du réticulum endoplasmique et à une mort par apoptose. Ces effets sont partiellement dépendants de PPARgamma pour le stress du réticulum endoplasmique mais strictement PPARgamma-indépendants pour l'apoptose. Ce travail pourrait permettre de constituer de nouveaux outils thérapeutiques dans le traitement du cancer du sein
One of the main goals of the anti-cancer research is to develop new therapeutic option for resistant tumor. In this context, the recent discovery of thiazolidinedione devoid of PPARgamma activity with a strong anti-cancer effect opens new perspectives. In a previous study, the laboratory showed that an inactive derivative of PPARgamma, the delta2-TGZ, induce a proteasome-dependent degradation of estrogen receptor alpha in PPARgamma-independent way. Thus, during my thesis we aimed 1) to participate in the study of new compounds less toxic and more effective to inhibit the proliferation of mammary cancer cells, 2) to better understand PPARgamma-independent mechanisms involved in the anti-cancer effect of the TZD. In the present work, we characterise new compounds more effective than delta2-TGZ to inhibit the proliferation of the breast cancer cells MCF-7 and MDA-MB-231 and are less toxic on primary culture of human hepatocytes. We pursued the study on mechanisms involved in PPARgamma-independent anti-proliferative activity of delta2-TGZ. We showed that delta2-TGZ is able to induce endoplasmic reticulum stress as soon as 3 hours and apoptosis in later times 48 hours of treatment. Nevertheless we could not conclude of the existence of a link between these two pathways. Finally, we studied the effect of the biotinylation of a natural ligand of PPAR?: the 15d-PGJ2. This modification drive to an increased effect of the 15d-PGJ2 on the anti-proliferative effect of breast cancer cells, reticulum endoplasmic stress and death by apoptosis. These effects are partially PPARgamma-dependent for reticulum endoplasmic stress and only PPARgamma-independent for apoptosis. This work highlighted new promising tools of breast cancers treatment

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Geoffroy, Marine. "Rôle de la claudine 1 dans les cellules cancéreuses mammaires triple-négatives et son implication dans les effets anticancéreux de dérivés de la troglitazone." Thesis, Université de Lorraine, 2018. http://www.theses.fr/2018LORR0056/document.

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Un défi majeur en cancérologie est le traitement des tumeurs mammaires dites triple-négatives (ER-, PR-, HER2-). Elles sont le plus souvent résistantes aux traitements conventionnels et présentent un haut risque de récidive. De plus, l’absence de cibles thérapeutiques ne permet pas le développement de thérapie spécifique. 78% de ces tumeurs expriment faiblement la claudine 1 et sont de très mauvais pronostic. Cette protéine est impliquée dans l'adhérence des cellules entre elles et pourrait jouer un rôle suppresseur de tumeur dans les cancers mammaires. Dans ce contexte, nous étudions si sa réexpression pourrait être une piste de traitement. Au laboratoire, nous avons développé des dérivés de la famille des thiazolidinediones (TZD) qui stimulent l’expression de la claudine 1 et induisent l’apoptose des cellules cancéreuses mammaires. Les objectifs de ma thèse ont consisté 1) à déterminer l’implication de la claudine 1 dans l’effet pro-apoptotique de ces composés 2) à l’étude de leurs mécanismes d’action 3) évaluer si l’expression de la claudine 1 pourrait sensibiliser les cellules cancéreuses triple-négatives aux agents de chimiothérapie. Au cours de cette thèse, nous avons montré que la surexpression de la claudine 1 et le composé Δ2-TGZ induisent l’apoptose des cellules triple-négatives « claudin 1-low » MDA-MB-231 et Hs578T. De plus, la claudine 1 est impliquée dans l’effet pro-apoptotique de la Δ2-TGZ dans les cellules MDA-MB-231. Par ailleurs, nous avons démontré que les dérivés TGZ, la Δ2-TGZ et l’AB186, agissent de manière précoce en modifiant la morphologie des cellules suivie d’une réexpression de la claudine 1 membranaire et d’une inhibition de la migration cellulaire avant même d’induire la mort cellulaire par apoptose. De plus, la surexpression de la claudine 1 inhibe la migration cellulaire associée à la perte des fibres de stress et la formation des jonctions intercellulaires. Nous avons également montré que la réexpression de la claudine 1 sensibilise les cellules MDA-MB-231 à l’agent de chimiothérapie, le 5-FU. L’ensemble des résultats de thèse a permis de mieux comprendre le mécanisme d’action de la Δ2-TGZ et de l’AB186 sur les cellules cancéreuses mammaires mais aussi d’identifier la claudine 1 comme cible potentielle prometteuse dans les cellules triple-négatives « claudin 1-low »
A major challenge in oncology is the treatment of triple-negative breast cancer (ER-, PR-, HER2-) as no targeted therapy are available. These tumors present often a chemotherapy resistance and a higher relapse incidence. 78% of them do not express claudin 1 and display a poor prognosis. Claudin 1 is involved in cell-cell adhesion and may be a tumor suppressor gene in breast cancer. In this context, we study if claudin 1 re-expression could be a possible approach. In the laboratory, we developed derivatives thaziolidinediones (TZD) compounds, which increase claudin 1 expression and lead to apoptosis of breast cancer cells. The goals of my thesis is 1) to characterize the involvement of claudin 1 in their pro-apoptotic effect 2) to study their mechanism of action 3) to determine if claudin 1 could sensitize the TNBC cells to the chemotherapy agents. During my thesis, we showed that claudin 1 overexpression and the compound Δ2-TGZ induce apoptosis of TNBC « claudin 1-low » MDA-MB-231 and Hs578T cells. Claudin 1 is involved in the pro-apoptotic effect of Δ2-TGZ in MDA-MB-231 cells. Then, we demonstrated that Δ2-TGZ and AB186 lead to early action through a modification of cell morphology followed an expression of claudin 1 at the membrane and an inhibition of cell migration before the apoptosis process. In addition, claudin 1 overexpression decreases the cell migration through the loss of stress fibers and the formation of cell junctions. We showed that claudin 1 overexpression potentialize the pro-apoptotic effect of Δ2-TGZ in MDA-MB-231 cells. Finally, we observed that claudin 1 sensitize the MDA-MB-231 cells to 5-FU. In fine, our data allowed a better understanding of Δ2-TGZ and AB186 mechanism of action and identification of claudin 1 as a promising target in TNBC « claudin 1-low »

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Dewar, Brian J. Graves Lee M. "PPAR[gamma]-independent mechanisms of Src kinase activation and EGFR transactivation in response to thiazolidinediones." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,1222.

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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.
Title from electronic title page (viewed Mar. 26, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum in Toxicology." Discipline: Toxicology; Department/School: Medicine. On title page, [gamma] appears as Greek character.

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Cortelazzo-Polisini, Elodie. "Les Benzylidène-thiazolidinediones et -pyrrolidinediones, des synthons à fort potentiel : synthèse, activité biologique et photoisomérisation." Electronic Thesis or Diss., Université de Lorraine, 2022. http://www.theses.fr/2022LORR0042.

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Ce travail de thèse concerne la synthèse de nouveaux dérivés de benzylidène-thiazolidinedione et benzylidène-pyrrolidinedione à visée anticancéreuse. Afin d’améliorer la sélectivité de ces composés vis-à-vis des cellules cancéreuses, nous nous sommes attachés à préparer de nouveaux analogues de notre précédente molécule tête de série impliquant la modulation de la position du fragment benzylidène, la modulation de l’hétéroatome central ainsi que la nature du cycle central. Une stratégie de synthèse multi-étapes a été développée et malgré les difficultés rencontrées dues à la complexité des structures envisagées, plus de vingt molécules ont été obtenues. Les propriétés antiprolifératives de ces molécules cibles ont été évaluées sur plusieurs lignées cellulaires, permettant une étude des relations structure-activité. Les propriétés de fluorescence intrinsèques de certains de nos composés ont permis leur suivi dans le milieu cellulaire, et des études ont été menées pour comprendre leur mécanisme d’action. Dans une seconde partie nous nous sommes intéressés à l’isomérisation de la double liaison du fragment benzylidène-thiazolidinedione par photoinduction. Une étude poussée combinant la synthèse organique et les spectroscopies UV-visible et RMN nous a permis de comprendre cette réaction de photoisomérisation. En particulier, grâce à un protocole d’irradiation in-situ couplé à un suivi par UV-visible et RMN, les éléments cinétiques de la réaction ainsi que les facteurs à moduler pour orienter cette isomérisation ont été déterminés. Enfin, l’application de cette séquence de photoisomérisation aux dérivés o-aminobenzylidène-hétérocycliques a conduit au développement d’une voie d’accès rapide et originale à de nouveaux quinolo-hétérocycles fusionnés
High valuable Benzylidene-thiazolidinedione and -pyrrolidinedione moieties : synthesis, biological activity and photoisomerization.Abstract : This PhD work deals with the preparation of new benzylidene-heterocycles derivatives for anti-cancer therapy. In order to improve their selectivity towards cancer cell lines, we synthesized new analogs of our previous lead compound by modulating the relative position of the benzylidene-heterocycle moiety, changing the central heteroatom and the nature of the central cycle. A multistep synthesis was developed, and in spite of the encountered difficulties, due to the high complexity of the structures of the target compounds, more than 20 molecules were obtained. Antiproliferative properties of these compounds were evaluated on several cell lines leading to a structure-activity relationship study. Intrinsic fluorescent properties of our molecules allowed us to follow them inside the cells and further studies were achieved in order to understand their mechanism of action. In a second, part we explored the photoisomerization of the double bond of the benzylidene-thiazolidinedione moiety. An important in-depth study combining organic synthesis and UV-visible and NMR spectroscopies allowed us to understand this reaction. Thanks to an in-situ irradiation procedure monitored by NMR and UV-visible spectroscopy, we could determine kinetic parameters of this reaction as well as determinant factors to control the isomerization. Eventually, the extension of this sequence to o-aminobenzylidene-heterocycles led to the development of a fast and original synthesis pathway to new fused heterocyclic quinoline

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Tanaka, Tokuji. "Down regulation of peroxisome proliferator-activated receptorγ expression by inflammatory cytokines and its reversal by thiazolidinediones." Kyoto University, 2001. http://hdl.handle.net/2433/151454.

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Chbicheb, Sarra. "Etude du facteur de transcription précoce EGR1 dans l'effet antiprolifératif des ligands de PPAR[gamma] sur les cellules cancéreuses mammaires." Thesis, Nancy 1, 2011. http://www.theses.fr/2011NAN10039.

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Les ligands des récepteurs nucléaires PPAR[gamma] (15-deoxy-[delta]12,14-Prostaglandine J2 (15d-PGJ2) et les thiazolidinediones (TZDs) : troglitazone (TGZ), ciglitazone (CGZ)) exercent un effet antiprolifératif sur les lignées cancéreuses mammaires. Plusieurs études suggèrent que les effets anticancéreux sont liés à des effets PPAR[gamma]-indépendants. Notre travail s?inscrit dans la compréhension de tels mécanismes d?action. Notre étude a montré une induction du facteur de transcription EGR1 (Early Growth Response gene 1) par certains ligands de PPAR[gamma] (TGZ, CGZ, 15d-PGJ2 et [delta]2-TGZ (agoniste inactif de PPAR[gamma])) dans les cellules cancéreuses mammaires hormono-dépendantes MCF7. Cet effet est précoce et PPAR[gamma]-indépendant. Il est lié à une libération quasi immédiate de calcium intracellulaire suivie de l?activation des ERK1/2. L?induction d?EGR1 a aussi lieu dans les cellules hormono-indépendantes MDA-MB-231 exposées à la [delta]2-TGZ. Cependant, l?induction d?EGR1 ne joue qu?un rôle partiel dans l?effet antiprolifératif. Les données d?une analyse par puce à ADN ont suggéré l?induction d?un stress du réticulum endoplasmique (RE) dans les cellules MCF7 exposées à la [delta]2-TGZ. Des analyses complémentaires ont confirmé que la [delta]2-TGZ induit un tel stress dans les cellules MCF7 et MDA-MB-231. Cependant, le rôle du stress du RE dans l?effet antiprolifératif de la [delta]2-TGZ reste à déterminer. Nous avons enfin testé l?hypothèse d?un lien entre EGR1 et stress du RE. En effet, EGR1 est aussi induit précocement par d?autres inducteurs de stress du RE. Les diverses situations où l?induction d?EGR1 est inhibée suggèrent une régulation possible de l?expression du facteur de transcription ATF3 par EGR1
The ligands of PPAR[gamma] nuclear receptors (15-deoxy-[delta]12,14-Prostaglandin J2 (15d-PGJ2) and thiazolidinediones (TZDs) : troglitazone (TGZ), ciglitazone (CGZ)) show antiproliferative effects on breast cancer cell lines. Several studies suggest that the anti-cancer effects are PPAR[gamma]-independent. Our work is focused on the comprehension of such mechanisms of action. Our study has shown the induction of the transcription factor EGR1 (Early Growth Response gene 1) by some PPAR[gamma] ligands (TGZ, CGZ, 15d-PGJ2, and [delta]2-TGZ (PPAR[gamma] inactive agonist)) in the hormone-dependent breast cancer cells MCF7. This early effect is PPAR[gamma]-independent. It is associated with the almost immediate release of intracellular calcium followed by the activation of ERK1/2. EGR1 induction also occurs in the hormone-independent breast cancer cells MDA-MB-231 treated with [delta]2-TGZ. However, EGR1 induction plays only a partial role in the antiproliferative effect. Data analysis of DNA array has suggested the induction of an endoplasmic reticulum stress (ER) in MCF7 cells treated with [delta]2-TGZ. Complementary data have confirmed this result in MCF7 cells and in MDA-MB-231 cells. However, the role of ER stress in the antiproliferative effect is still to be determined. Finally, we have tested the hypothesis of a link between EGR1 and ER stress. Indeed, EGR1 is also early induced by other ER stress inductors. Diverse conditions where EGR1 is inhibited suggest a possible regulation of ATF3 expression by EGR1

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Berthe, Audrey. "Métabolisme énergétique et traitements anticancéreux : caractérisation des effets de la Δ2-troglitazone et du 2-désoxyglucose sur les cellules d’adénocarcinomes mammaires." Thesis, Université de Lorraine, 2017. http://www.theses.fr/2017LORR0082/document.

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L’absence de réponse et la résistance des cellules cancéreuses mammaires aux thérapies actuelles justifient de développer de nouveaux traitements. Une stratégie prometteuse consiste à cibler le métabolisme énergétique des cellules cancéreuses. Dans ce contexte, des thiazolidinediones (TZD) présentent des effets antiprolifératifs qui pourraient résulter d’une atteinte du métabolisme énergétique. Notre laboratoire étudie des TZD dérivées de la troglitazone (TGZ). Durant cette thèse, nous avons cherché à déterminer si la Δ2-Troglitazone (Δ2-TGZ) modifie le métabolisme énergétique des cellules cancéreuses mammaires. Jusqu’à présent, les expériences menées au laboratoire étaient réalisées dans un milieu de culture contenant 1% de sérum de veau fœtal (SVF) qui crée un stress peu propice à l’étude du métabolisme. Nous avons donc d’abord caractérisé les effets de la Δ2-TGZ dans un milieu de culture contenant 10% SVF. Dans ces conditions, la Δ2-TGZ diminue toujours la prolifération des cellules cancéreuses mammaires, mais les doses requises sont plus élevées. En outre, la Δ2-TGZ induit des effets cytostatiques plutôt que l’apoptose. Nous avons ensuite montré que la Δ2-TGZ induit une perturbation du métabolisme énergétique, consistant en un blocage de la respiration mitochondriale que les cellules semblent compenser en stimulant la glycolyse. En parallèle, nous avons caractérisé le mode d’action du 2-désoxyglucose dont l’action antiproliférative dans les cellules cancéreuses mammaires est due à l’inhibition de la glycolyse et à la perturbation de la N-glycosylation des protéines. Il reste à déterminer la part des altérations métaboliques dans l’action anti-cancéreuse de la Δ2-TGZ
The absence of response and the resistance of cancer cells to therapies are strong arguments for the development of new therapeutic strategies. Data from the literature suggest that it could be interesting to target energy metabolism of cancer cells. In this context, thiazolidinediones (TZDs) display antiproliferative effects that could be the result of energy metabolism alteration. During this PhD, we aimed at determining if Δ2-Troglitazone (Δ2-TGZ) could modify energy metabolism of breast cancer cells. The experiments performed previously used a culture medium containing 1% of fetal calf serum (FCS) that is rather a stress inducing condition that can disturb cell metabolism. Thus, we first characterized the effects of Δ2-TGZ in a 10% FCS containing medium. In this case, Δ2-TGZ still decreases cell proliferation of breast cancer cells, but it requires high doses. Besides, Δ2-TGZ induces cell cycle arrest instead of apoptosis. Then, we have shown that Δ2-TGZ induced modifications of energy metabolism, which are due to a decrease in oxidative phosphorylation. We also observed an increase in glycolytic activity that is probably a compensatory mechanism. During this part of our work, we have also characterized the mechanisms involved in the anticancer activity of 2-deoxyglucose. We have shown that in breast cancer cells, this compound acts not only by glycolysis inhibition but also by protein N-glycosylation alteration. We have now to determine the part of metabolic alterations that are involved in the anti-cancer effects of Δ2-TGZ

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CARDOSO, Pablo Ramon Gualberto. "Avaliação da atividade imunomoduladora de novos derivados tiazolidínicos em células do sangue periférico de pacientes portadores de Psoríase." Universidade Federal de Pernambuco, 2014. https://repositorio.ufpe.br/handle/123456789/17185.

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Introdução: A psoríase afeta cerca de 2-3% da população. Esta doença é uma dermatite crônica, recorrente e tem envolvimento inflamatório mediado por células T. A apresentação mais comum da psoríase é o envolvimento da pele com placas eritematosas bem definidas, escamosas, de posição e tamanhos variados. Na placa psoriásica há uma disfunção imunológica que envolve vários tipos celulares e mediadores inflamatórios, como citocinas, tal qual IL -17A. Estuda-se uma atividade imunomoduladora dos derivados tiazolidinadionas (TZD). Esta classe de medicamentos tem uma possível ação anti-inflamatória, e pode ser capaz de reduzir as lesões de psoriásicas. Materiais e Métodos: Portanto, decidiu-se estudar três novos derivados TZD em células mononucleadas do sangue periférico (PBMC) de pacientes com psoríase. Depois da confirmação da estrutura química, os compostos LPSF-SF-33, LPSF-SF-34 e LPSF-SF-35 foram adicionados em cultura de PBMC estimuladas ou não com PMA/Iono. Após 48h os sobrenadantes destas culturas foram utilizados para a avaliação da IL-17A, IL-22 e IL-6. Resultados: O LPSF-SF-33 mostrou uma boa atividade imunomoduladora, reduzindo os níveis de IL - 17A e IL - 22 no sobrenadante de cultura em comparação com a estimulação por PMA/Iono. O LPSF-SF-34 mostrou bons resultados de inibição de IL-17A e IL-22 e ainda em todas as doses foi mais eficaz do que a metilprednisolona, droga padrão, na redução da IL-22. O composto do LPSF-SF-35 diminuiu a produção de IL-17A e IL-22 e também foi capaz de diminuir a produção de IL-6 quando comparado com PMA/Iono. Conclusão: Estes novos derivados tiazolidínicos LPSF-SF-33, LPSF-SF-34 and LPSF-SF-3 são capazes de inibir a produção de IL-17A, IL-22 e IL-6 em doses diferentes e o efeito pode indicar melhoria da inflamação.
Introduction: Psoriasis affects about 2-3% of the population. This is a chronic dermatitis, recurrent and inflammatory disease mediated by T cells. The most common presentation of psoriasis is skin involvement with well-defined and demarcated erythematous plaque, scaly, and random position in the patient's body. In psoriatic plaque, there is an immune dysfunction involving many cell types and inflammatory mediators such as cytokines like IL-17A. There is an immunomodulatory activity of thiazolidinedione derivatives. This class of drugs has a possible anti-inflammatory action, may be able to mitigate the psoriatic lesions. Objectives and Methods: Therefore, we decided to study three new TZD derivatives in PBMC of patients with Pso. After chemical structure confirmation, the thiazolidinedione derivatives LPSF-33, LPSF-34 and LPSF-35 were prepared in culture of PBMC, stimulated or not with PMA / Iono. After that, the supernatant of these cultures were used for IL-17A, IL-22 and IL-6 evaluation. Discussion: The three new TZDs tested were able to reduce the expression of IL-17A and IL-22 at different doses compared to PMA/Iono, but only LPSF-SF-35 was able to reduce a significant IL-6 levels. The compounds differ in their molecular structure that is added by the radical and perhaps the LPSF-SF-35 has been better because in its final structure it features a pyridine. Conclusion: The new thiazolidinedione derivatives LPSF-SF-33, LPSF-SF-34 and LPSF-SF-35 are capable of inhibiting the production of IL-17A, IL-22 and IL-6 at different doses and the effect may indicate improvement in inflammation.

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Chew, Angela Christine. "The anti-proliferative effects of thiazolidinediones and non-steriodal anti-inflammatory drugs on androgen-independent prostate cancer." University of Western Australia. School of Medicine and Pharmacology, 2009. http://theses.library.uwa.edu.au/adt-WU2009.0200.

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[Truncated abstract] In recent years a better understanding of the biology of PPAR , a nuclear transcription factor, has emerged, leading to a resurgence in targeting PPAR for chemotherapy. The family of synthetic PPAR agonists, the thiazolidinediones (TZDs), and non-steroidal anti-inflammatory drugs (NSAIDs) have been implicated in the inhibition of cell proliferation, apoptosis and cell cycle arrest of androgen-sensitive (LNCaP) and androgen-independent (PC-3 and DU145) prostate cancer cells generating much interest in their use for potential curative cancer therapies. In light of the potential use of TZDs and NSAIDs in prostate cancer prevention and their ability to induce inhibitory effects in vitro and in vivo, the first aim of this project was to undertake a comprehensive study of the effects of ciglitazone (TZD) and indomethacin (NSAID) on the androgen-independent prostate cancer cell line DU145, using standardised concentrations and time-points to compare the effects of TZDs and NSAIDs on cell proliferation, cell cycle and apoptosis. Treating the cells with either 10 µM ciglitazone or 10 µM indomethacin resulted in a time-dependent decrease in DU145 cell proliferation. The anti-proliferative effects were found to be in-part attributed to the slowing of cell progression through the G1/S-phase checkpoint of the cell cycle, and in the case of ciglitazone, apoptosis also played a role in its anti-proliferative effects in this cell line. Interestingly, although indomethacin failed to induce apoptosis, its antiproliferative effects were more potent than ciglitazone. The second aim of this project was to further investigate the underlying mechanisms responsible for the anti-proliferative effects of ciglitazone and indomethacin by evaluating their ability to modulate PPAR mRNA and protein expression, and to induce PPAR transcriptional activity. ... In addition, ligandinduced regulation of secreted frizzled related protein 4 (sFRP4) expression, a Wnt/ - catenin antagonists, was investigated. It was demonstrated that both ciglitazone and indomethacin attenuated Wnt/ -catenin signalling via the down-regulation of total - catenin levels within the cells, inhibition or slowing of the translocation of cytoplasmic -catenin into the nucleus and inhibition of cyclinD1 expression An inverse relationship between PPAR and -catenin protein levels was also detected, suggesting that PPAR may directly bind to -catenin itself. sFRP4 expression was transiently upregulated by ciglitazone and indomethacin-treatment, suggesting that the antiproliferative effects of the ligands may be mediated in part through regulation of sFRP4 mRNA and protein levels. In summary, the anti-proliferative effects of ciglitazone and indomethacin on the androgen-independent prostate cancer cell line, DU145, described in this thesis are progressive steps in characterising the role of PPAR in prostate cancer cell proliferation. The identification of indomethacin as a more potent PPAR agonist than ciglitazone represents a novel target for the development of preventative strategies for advanced disease, and the relationship between PPAR and the Wnt/ -catenin signalling pathway provide an insight into the mechanisms involved in the anti-proliferative effects of ciglitazone and indomethacin. Further studies into this relationship would advance help identify novel preventative and curative therapeutic strategies for advanced prostate cancer.

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Tordjman, Joan. "L'aspartate aminotransferase cytosolique et son implication dans la glycéronéogenèse adipocytaire : nouvelles cibles de l'action antidiabétique des thiazolidinediones." Paris 7, 2003. http://www.theses.fr/2003PA077233.

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Muller, Claire. "Métabolisme énergétique et thérapie anticancéreuse : caractérisation des effets de dérivés désoufrés de la troglitazone sur les cellules d’adénocarcinomes mammaires." Thesis, Université de Lorraine, 2019. http://www.theses.fr/2019LORR0305.

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De nombreuses options thérapeutiques existent pour les cancers du sein luminaux, HER2 et normal like. En revanche, seule la chimiothérapie est utilisée pour les cancers du sein triple-négatifs. Par ailleurs, quels que soient les sous-types de cancer du sein, il existe des cas d’absence de réponse et des phénomènes de résistance aux traitements. Ces derniers peuvent être associés à la présence de cellules souches cancéreuses (CSC) au sein des tumeurs. Une des pistes thérapeutiques est de cibler le métabolisme énergétique souvent modifié dans les cellules cancéreuses et les CSC. Les thiazolidinediones (TZD) sont étudiées dans ce contexte car elles présentent une action anticancéreuse pouvant résulter d’une altération du métabolisme énergétique. Notre laboratoire s’intéresse à la troglitazone (TGZ) dont plusieurs dérivés présentent une efficacité accrue et une toxicité réduite envers les hépatocytes. Des dérivés désoufrés de la TGZ ont récemment été synthétisés. Nous avons d’abord réalisé une étude des relations structure activité afin d’évaluer l’importance du soufre dans l’action anticancéreuse. Nous avons montré que la suppression du soufre au niveau du cycle TZD améliore l’efficacité anticancéreuse des composés sur des lignées de cellules cancéreuses mammaires. Le dérivé le plus actif est EP13, composé qui combine différentes modifications chimiques potentialisatrices et l’absence de soufre. Il induit l’apoptose des cellules MDA-MB-231. Puis, nous avons étudié l’effet d’EP13 sur le métabolisme énergétique des cellules MDA-MB-231. Il induit une altération du fonctionnement de la chaîne respiratoire associée à la production d’espèces réactives de l’oxygène (ERO) dans les cellules MDA-MB-231. Une stimulation de la glycolyse permet de compenser l’altération de la respiration mitochondriale. De faibles concentrations d’EP13 potentialisent l’action de la doxorubicine et du 5-fluorouracile dans les cellules MDA-MB-231. Enfin nous avons établi un modèle de culture cellulaire 3D (mammosphères), qui permettrait un enrichissement en CSC. EP13 est capable d’affecter les mammosphères constituées à partir de cellules MDA-MB-231 et MCF-7. EP13 se présente comme un candidat potentiel pour des stratégies thérapeutiques visant à cibler le métabolisme énergétique. Il reste à déterminer s’il existe un lien entre la modification du métabolisme énergétique et l’effet anti-cancéreux et à exploiter le modèle des mammosphères pour déterminer si EP13 affecte aussi les CSC
Numerous therapeutic options are available for Luminal, HER2-enriched and Normal-like breast cancers. However, only chemotherapy can be used for triple-negative breast cancers. Moreover, regardless of breast cancer subtypes, there are many cases of absence of responsiveness and treatment resistances. In some cases, resistance comes from the presence of cancer stem cells (CSC) within the tumor. A possible therapeutic approach consists of targeting the energy metabolism often modified in cancer cells and CSC. Thiazolidinediones (TZD) are studied in this context since they display an anticancer activity and can induce alterations of the energy metabolism. Our laboratory studies troglitazone (TGZ) from which we could obtain several derivatives displaying a higher efficiency and a lower toxicity towards human hepatocytes. Desulfurylated derivatives of TGZ have been synthetized recently. First we performed a structure-activity relationship study in order to determine the impact of the sulfur atom on the anticancer activity. We observed that desulfurylated derivatives of TGZ displayed a higher efficiency towards breast cancer cells. and the most active compound was EP13, one of the desulfurylated TDZ derivatives, on breast cancer cells. The most active compound, EP13, combined different potentiating chemical modifications and the removal of the sulfur moiety from the TZD cycle. Unlike TGZ, EP13 induces apoptosis of MDA-MB-231 cells. Then we showed that EP13 disrupted energy metabolism of MDA-MB-231 cells by inducing alteration of mitochondrial respiratory chain function, associated with reactive oxygen species (ROS) production in MDA-MB-231 cells. A glycolysis stimulation seems to compensate secondarily the mitochondrial respiration alteration. EP13 at low doses was able to potentiate doxorubicin and 5-fluorouracil actions on MDA-MB-231 cells. Finally, we established a 3D cell culture model, which could allow enrichment in CSC. EP13 could alter the establishment of mammospheres from MDA-MB-231 and MCF-7 cells. This work suggests a potential interest of EP13 for the development of therapeutic strategies targeting energy metabolism. It remains to establish if there is a link between modifications of energy metabolism and EP13-induced apoptosis and to use the mammosphere experimental model to determine if EP13 can affect breast CSC

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Fletcher, Glory, and Darcy Tincombe. "Appropriateness of the use of Thiazolidinediones for the treatment of Type 2 Diabetes Mellitus at the Southern Arizona Veterans Affairs Hospital." The University of Arizona, 2005. http://hdl.handle.net/10150/624726.

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Class of 2005 Abstract
Objectives: The purpose of the study was to evaluate if rosiglitazone was being used in full compliance with the SAVA consensus criteria for appropriate use of thiazolinediones. Methods: A retrospective chart review was performed on 50 SAVA patients selected at random from a list of patients that were on rosiglitazone treatment as of March 15, 2005. Results: The percent of patients who met all of the criteria set forth by the SAVA when initiating therapy was 44%. Rosiglitazone treatment should not have been started in 28 out of the 50 patients. Once initiated on rosiglitazone, patients’ follow-up ALT was only obtained in 16% of patients. Once rosiglitazone has been prescribed for 3 months, HbA1c should decrease. Twenty percent of the patients showed an increase in HbA1c from baseline and were continued on the medication despite the criteria. Implications: Once therapy was initiated, the majority of patients studied failed to meet the SAVA guidelines for the appropriate use of rosiglitazone. In addition, a majority failed to follow the aspects of the guideline regarding initiation of rosiglitazone therapy.

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HALLAKOU, SOPHIE. "Thiazolidinediones et sensibilite a l'insuline : actions au niveau adipocytaire et musculaire chez le rat zucker obese fa/fa." Paris 7, 1998. http://www.theses.fr/1998PA077075.

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Le diabete noninsulinodependant se caracterise par une alteration de la secretion d'insuline et par une insulinoresistance. Une famille d'antidiabetiques oraux, les thiazolidinediones (tzd), dont l'action passe par une amelioration de la sensibilite a l'insuline est commercialisee. Le mecanisme d'action des tzd est aujourd'hui tres mal connu. Les tzd sont des ligands d'un recepteur nucleaire adipocytaire : le ppar. Celui-ci est implique dans le processus de differenciation adipocytaire. Il a ete etabli une relation directe entre l'activite antidiabetique des tzd et leur affinite pour le ppar. Le but de notre travail a ete d'etudier chez le rat obese zucker fa/fa quelle etait l'action des tzd au niveau musculaire et adipocytaire. Nous avons pu verifier sur ce modele, que le traitement par la pioglitazone (pio) entraine une amelioration de la tolerance au glucose et de la sensibilite a l'insuline. Cette amelioration de la sensibilite a l'insuline affecte le tissu adipeux et les muscles. Dans le tissu adipeux blanc, la pio entraine une augmentation de l'expression de proteines controlant les etapes clefs de l'utilisation de glucose : le transporteur de glucose glut4, la synthase des acides gras et enfin la phosphoenolpyruvate carboxykinase (pepck). L'augmentation de l'expression de ces genes pouvait s'expliquer soit par une action genique directe de la pio soit par une augmentation de la differenciation adipocytaire. Un traitement court par la pio entraine une augmentation de l'expression de genes identifies comme etant des marqueurs precoces du processus de differenciation adipocytaire : c/ebp et a2co16. Le denombrement des adipocytes revele que la pio entraine une augmentation du nombre de petits adipocytes. Ces deux observations demontrent que la pio in vivo active la differenciation adipocytaire. Les petits adipocytes sont capables de se charger en triglycerides a la suite d'un regime riche en lipides. La pio exerce egalement un effet direct sur l'expression de la pepck dans des adipocytes matures primaires en culture. Enfin, nous avons montre que l'augmentation de la sensibilite a l'insuline musculaire par la pio, in vivo, n'est pas due a une augmentation de la differenciation adipocytaire intramusculaire ni a une dedifferenciation des myoblastes en adipoblastes comme ceci a ete suggere in vitro.

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Cadoudal, Thomas. "Régulation de la glycéronéogenèse du tissu adipeux par les thiazolidinediones et les acides rétinoïques : implications dans le diabète de type 2." Paris 5, 2007. http://www.theses.fr/2007PA05D035.

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L'obésité est le principal facteur de risque de l'insulino-résistance et du diabète de type 2. Le lien entre l'hypertrophie du tissu adipeux et ces pathologies serait les acides gras non-estérifiés (AGNE) provenant de la lipolyse adipocytaire. Une élévation chronique des AGNE sanguins induirait une résistance à l'insuline. Dans l'adipocyte, une fraction des AGNE issus de la lipolyse est ré-estérifiée en triglycérides. Cette ré-estérification requiert la synthèse de glycérol-3-phosphate qui provient, à jeun, du pyruvate et lactate circulants grâce à une voie métabolique appelée glycéronéogenèse et dont l'enzyme clé est la phosphoénolpyruvate carboxykinase cytosolique (PEPCK-C). Au cours de ce travail, nous avons monté que les thiazolidinediones et les rexinoïdes exercent leurs effets hypolipidémiants et antidiabétiques grâce à une induction rapide et sélective de la transcription du gène PEPCK-C qui conduit à une augmentation de l'activité PEPCK-C et de la glycéronéogenèse
Obesity is a major risk factor for insulin resistance and type 2 diabetes. The link between hypertrophied adipose tissue and this pathology is thought to be non-esterified fatty acids (NEFA) arising from adipocyte lipolysis. Sustained increase in plasma NEFA induces insulin resistance. In adipocytes, a significant part of lipolytic NEFA is re-esterified to triacylglycerol. Re-esterification requires glycerol-3-phosphate which, during fasting, is synthesized from lactate or pyruvate in metabolic pathway named glyceroneogenesis, whose key enzyme is the cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C). In this study, we give evidence that thiazolidinediones and rexinoids exert their hypolipidemic and antidiabetic effects in adipose tissue at least in part through a rapid and selective induction of PECK-C gene transcription leading to increased PECK-C and glyceroneogenesis. Subsequent fatty acid re-esterification participates in the reduction in blood NEFA and insulin resistance

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23

Lagane, Céline. "Rôle de l'IL-13 et des ligands de PPAR-gamma dans la réponse anti-infectieuse des macrophages murins et des monocytes humains vis-à-vis de Candida Albicans : implication de PPAR-gamma." Toulouse 3, 2007. http://thesesups.ups-tlse.fr/57/.

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Candida albicans est le champignon pathogène le plus commun chez l'homme. Il est la cause de candidoses gastro-intestinales, infections opportunistes qui touchent essentiellement les patients immunodéprimés. L'induction d'une immunité à médiation cellulaire contre C. Albicans plus particulièrement par les cellules du système immunitaire inné joue un rôle critique dans la défense de l'hôte. Nous avons démontré précédemment in vitro sur des macrophages péritonéaux de souris que les cytokines Th2, et notamment l'IL-13, peuvent activer les fonctions effectrices de ces cellules qui sont impliquées dans la reconnaissance de C. Albicans, sa phagocytose et son élimination. Dans ce cas, le mécanisme impliqué est l'induction du récepteur mannose (RM) via l'activation du récepteur nucléaire PPAR-gamma. Aussi, nous montrons que l'inhibition de la prolifération de C. Albicans par les macrophages peut être également entraînée par des ligands synthétiques de PPAR-gamma. Dans une première étude, nous avons montré in vivo que le traitement de souris immunocompétentes ou immunodéficientes par les ligands PPAR-gamma ou par l'IL-13 favorisent l'élimination d'une candidose digestive induite par administration orale de C. Albicans. L'utilisation de souris immunodéficientes RAG-2-/- nous a permis de mimer les candidoses gravissimes rencontrées chez des patients immunodéprimés. Cette élimination s'accompagne d'un recrutement de macrophages exprimant le RM au site d'infection. Nous avons aussi pu mettre en évidence ex vivo que ces traitements entraînaient, via l'activation de PPAR-gamma, une augmentation de l'expression du RM à la surface des macrophages et des fonctions effectrices qui lui sont associées telles que la phagocytose et la synthèse d'agents oxydants. Dans une seconde étude, nous nous sommes intéressés à la réponse anti-infectieuse de monocytes humains traités par l'IL-13 ou la rosiglitazone vis-à-vis de Candida albicans. Nous avons montré que, comme chez le macrophage murin, ces traitements potentialisent les fonctions anti-infectieuses des monocytes à savoir la phagocytose et la sécrétion d'espèces réactives de l'oxygène via l'activation de PPAR-gamma. .
Candida albicans is the most frequent opportunistic pathogen identified in immunocompromised patients, where it causes serious gastro-intestinal infections. Induction of cellular immunity against C. Albicans, and more particularly of cells of innate immunity, plays a critical role in host defence. We previously demonstrated in vitro on murine peritoneal macrophages that Th2 cytokines such as IL-13 can activate effective functions of these cells implicated in binding, phagocytosis and elimination of C. Albicans. Mechanism involved is induction of mannose receptor (MR) expression via the activation of the nuclear receptor PPAR-gamma. We showed too that PPAR-gamma synthetic ligands can also promote C. Albicans elimination by macrophages. In a first study, we showed in vivo, on immunocompetent or immunodeficient mice infected by oral route with Candida albicans, that IL-13 or PPAR-gamma ligands promote elimination of gastro-intestinal candidiasis. The use of RAG-2-/- immunodeficient mice allowed us to mimic serious candidiasis developed by immunocompromised patients. This elimination is correlated with a recruitment on the site of infection of macrophages expressing MR. We also showed ex vivo that IL-13 and PPAR-gamma ligands increase MR expression on macrophages and increase associated effective functions such as phagocytosis and reactive oxygen species production. In a second part, we studied anti-candistatic functions of human monocytes treated with IL-13 or rosiglitazone. We showed that, as in murine macrophages, these treatments potentate monocytes effective functions such as phagocytosis and reactive oxygen species production via PPAR-gamma activation. .

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Saito, Cristiane Akemi Iamamoto. "Atividade de novos derivados de tiazolidinodionas sobre a diferenciação de pré-osteoblastos e pré-adipócitos." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-27052015-103052/.

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As tiazolidinodionas (TZDs) são sensibilizadores de insulina utilizados no tratamento do diabetes mellitus tipo 2. Contudo, apesar dos efeitos benéficos sobre a glicemia, importantes efeitos adversos incluindo perda óssea e aumento de adiposidade são relatados com o uso clínico das TZDs. Assim, é necessário o desenvolvimento de novos derivados de TZDs com potenciais efeitos benéficos sobre a hiperglicemia e menos efeitos adversos. Neste estudo, investigamos os efeitos de 5 novos derivados de TZDs (LYSO-7, GQ-89, GQ-150, GQ-177 e SF-3) sobre a diferenciação celular de pré-osteoblastos murinos MC3T3-E1, pré-adipócitos murinos 3T3-L1 e pré-adipócitos SGBS de linhagem humana. Seus potenciais efeitos sobre a utilização de glicose, a produção de adipocinas e mediadores pró-inflamatórios também foram avaliados, utilizando linhagens murinas e humanas de adipócitos, e macrófagos THP-1 de linhagem humana. O principal achado de nosso estudo foi que os novos derivados de TZDs estimulam a utilização celular de glicose, porém não alteram o processo de diferenciação celular de pré-osteoblastos e pré-adipócitos, quando comparados com a TZD clássica Rosiglitazona. Conforme esperado, o tratamento com Rosiglitazona na concentração de 5 μM inibiu a osteogênese de pré-osteoblastos murinos MC3T3-E1. No entanto, o tratamento com 2 novos derivados de TZDs (GQ-89 e GQ-177) na mesma concentração não afetou a diferenciação celular, sendo possível observar níveis de mineralização de matriz extracelular similares aos do grupo controle. Além disso, enquanto a GQ-89 estimulou a atividade da fosfatase alcalina, a GQ-177 não modulou sua atividade enzimática e induziu a expressão gênica de osteocalcina. Contudo, ambos inibiram a expressão de Runx2 e colágeno. Por sua vez, quando os efeitos foram avaliados sobre a diferenciação de adipócitos, foi possível observar que ao contrário do efeito pró-adipogênico constatado com a Rosiglitazona na concentração de 1 μM, as TZDs GQ-150, GQ-177, LYSO-7 e SF-3 foram incapazes de induzir o acúmulo lipídico em pré-adipócitos murinos e humanos. Além disso, a GQ-150 inibiu a expressão gênica de C/EBPα, assim como a expressão gênica e os níveis protéicos de CD36, enquanto que a SF-3 estimulou a expressão gênica de C/EBPα e de FABP4 e diminuiu a expressão gênica e os níveis protéicos de CD36, os quais não foram modificados pela LYSO-7 em pré-adipócitos murinos 3T3-L1. No entanto, em pré-adipócitos SGBS de linhagem humana, nenhum efeito sobre os marcadores de fenótipo adipogênico C/EBPα e FABP4 foi observado com os novos derivados de TZDs. Ademais, os novos derivados de TZDs não interferiram na via de sinalização de Wnt, não apresentaram qualquer efeito sobre a expressão de adipocinas (adiponectina, resistina e leptina) e mediadores pró-inflamatórios (IL-6, CCL2/MCP-1, TNF-α e JNK), bem como não ativaram o fator de transcrição PPARγ no ensaio de gene repórter. Por sua vez, a LYSO-7, GQ-150 e SF-3 aumentaram o consumo de glicose em presença de insulina em adipócitos 3T3-L1 e modificaram a atividade de enzimas mitocondriais em adipócitos SGBS e macrófagos THP-1. Entretanto, o efeito sensibilizador de insulina foi confirmado somente com a GQ-177 pelo aumento da captação de glicose e somente a LYSO-7 e a SF-3 foram capazes de inibir o consumo de oxigênio e modificar a taxa de glicólise em macrófagos, sugerindo que também poderiam alterar os níveis de ATP/ADP. Considerando que baixos níveis de ATP estimulam a via de sinalização de AMPK, essa via também foi investigada em nosso estudo. Entretanto, os resultados sobre a ativação de AMPK foram inconclusivos. Desse modo, nossos resultados apontam que os novos derivados de TZDs não atuam como ligantes de PPARγ, apresentam atividade sensibilizadora de insulina in vitro, e que exercem menores efeitos antiosteoblásticos e adipogênicos quando comparados com a Rosiglitazona. Mais estudos são necessários para elucidar os mecanismos responsáveis por esses efeitos, bem como para estabelecer se os novos derivados de TZDs são mais seguros in vivo, com relação ao risco de fraturas ósseas e ganho de massa adiposa.
Thiazolidinediones (TZDs) are insulin sensitizers used in the treatment of type 2 diabetes mellitus. However, despite the beneficial effects on blood glucose, significant adverse effects including bone loss and increased adiposity are reported with the clinical use of TZDs. Thus, it is necessary to develop new derivatives of TZDs with potential beneficial effects on hyperglycemia and fewer adverse effects. In this study, we investigated the effects of 5 new derivatives of TZDs (LYSO-7, GQ-89, GQ-150, GQ-177 e SF-3) on cellular differentiation in murine MC3T3-E1 preosteoblasts, murine 3T3-L1 preadipocytes, and SGBS preadipocytes from human lineage. Potential effects on glucose consumption, adipokines, and pro-inflammatory mediators were also assessed using murine and human strains of adipocytes, and macrophages from human THP-1 lineage. The main finding of this study was that new derivatives of TZDs stimulate glucose consumption, but do not change the cell differentiation process of preosteoblasts and preadipocytes compared to classical TZD Rosiglitazone. As expected, the treatmet with Rosiglitazone, at 5μM, inhibited the osteogenesis in murine MC3T3-E1 preosteoblasts. However, the treatment with 2 new derivatives of TZDs (GQ-89 and GQ-177) at the same concentration did not affect cell differentiation, and levels of mineralization of the extracellular matrix similar to the control group were observed. In addition, whereas the GQ-89 stimulated the activity of alkaline phosphatase, GQ-177 does not modulate its enzymatic activity and induced gene expression of osteocalcin. However, both of them inhibit the expression of Runx2 and collagen. In turn, when the effects were assessed on the adipocyte differentiation, unlike the proadipogenic effect observed with Rosiglitazone at a concentration of 1 μM, the new TZDs GQ-150, GQ-177, LYSO-7 and SF-3 were unable to induce lipid accumulation in human and murine preadipocytes. In addition, GQ-150 inhibited the gene expression of C/EBPα , as well as the gene expression and protein levels of CD36, whereas SF-3 stimulated the gene expression of C/EBPα and FABP4 and decreased gene expression and protein levels of CD36, which was not modified by LYSO-7 on murine 3T3- L1 preadipocytes. However, no effect on markers of adipogenic phenotype C/EBPα and FABP4 has been observed with the novel derivatives of TZDs in human SGBS preadipocytes. Furthermore, the new derivatives of TZDs do not interfere with the Wnt signaling pathway, showed no effect on the adipokines expression (adiponectin, resistin and leptin) and proinflammatory mediators (IL-6, CCL2 / MCP-1, TNF α and JNK) and did not activate the transcription factor PPARγ in the gene reporter assay. In turn, LYSO-7, GQ-150, and SF-3 increased glucose consumption in the presence of insulin in 3T3-L1 adipocytes and modified the activity of mitochondrial enzymes in SGBS adipocytes and THP-1 macrophages. However, the effect on insulin sensitization was confirmed only to GQ-177 that increased glucose uptake and just LYSO-7 and SF-3 were able to inhibit oxygen consumption and modify the rate of glycolysis in macrophages, suggesting that they could also alter the levels of ATP/ADP. Since low levels of ATP could stimulate AMPK pathway, this signaling pathway was also investigated in our study. However, the results on the AMPK activation were inconclusive. Thus, our results demonstrate that the new derivatives of TZDs do not act as PPARγ ligands, present insulin sensitizing activity in vitro, and display minor antiosteoblastic and adipogenic effects when compared to Rosiglitazone. More studies are needed to elucidate the exact mechanisms responsible for these effects, as well as to establish whether the safety of the new TZDs with respect to the risk of bone fractures and body mass gain using in vivo models.

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25

Rogue, Alexandra. "Recherche de gènes cibles de ligands de PPARs et étude de leurs mécanismes d'action." Rennes 1, 2011. http://www.theses.fr/2011REN1B082.

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Goenka, Nirupam. "The use of head-out water immersion in the investigation of the renal and hormonal effects of thiazolidinediones and sulphonylureas." Thesis, University of Warwick, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426753.

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27

Filion, Kristian. "The effects of glycemic control and thiazolidinediones on the risk of congestive heart failure among patients with type 2 diabetes." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=66720.

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The objectives of this thesis are to describe prescription patterns of anti-diabetic therapy among patients with type 2 diabetes and to examine the effects of glycemic control and the oral anti-diabetic thiazolidinedione medications on the risk of incident congestive heart failure in a population-based study. Pertinent data were extracted from the United Kingdom's General Practice Research Database, a clinical database that records information from over 400 practices and contains over 39 million person-years of observation. The first study describes prescription patterns of anti-diabetic medical therapy. There was a substantial increase in the prescription of anti-diabetic medications during the study period from 2000 to 2006. This increase was particularly evident for thiazolidinediones and metformin. The second study examines the effect of glycemic control, measured by hemoglobin A1c, on the risk of heart failure in a nested case-control study. As part of this study, the effects of misclassification of hemoglobin A1c on this relationship were assessed. Increasing hemoglobin A1c was associated with an increased rate of heart failure. Although patients with hemoglobin A1c values ≥ 8% had an increase in heart failure, those with an hemoglobin A1c between 7% and 8% had a similar rate as those with hemoglobin A1c < 7%. Measurement error adjustment did not appreciably alter this relationship. The third study uses a nested case-control design to estimate the effect of thiazolidinediones on the risk of incident heart failure. This study found no definitive evidence that thiazolidinediones are associated with an increased rate of incident heart failure, although a potentially clinically important effect could not be excluded. In conclusion, this thesis found that prescription of anti-diabetic medications increased dramatically during the study period. In addition, this thesis failed to find a benefit with intensive glycemic con
Les objectifs de cette thèse étaient de décrire les modes de prescription de traitement anti-diabétique chez les patients atteints du diabète de type 2 et d'examiner les effets du contrôle glycémique ainsi que des médicaments anti-diabétiques thiazolidinediones sur l'incidence d'insuffisance cardiaque congestive (ICC) dans cette population. Les données pertinentes furent extraites de la General Practice Research Database, une banque de données cliniques qui compile l'information de plus de 400 pratiques et qui contient plus de 39 millions personnes-années d'observation. La première étude décrit les modes de prescription de traitements anti-diabétique oraux. Elle démontre une augmentation substantielle des prescriptions de médications anti-diabétiques pendant la période étudiée (2000-2006). Cette augmentation fut particulièrement évidente pour les thiazolidinediones et la metformine. La deuxième étude examine l'effet du contrôle glycémique, mesuré par l'hémoglobine glyquée, sur l'incidence d'ICC dans une étude cas-témoin nichée. Les effets des erreurs de classification de l'hémoglobine glyquée furent évalués. Une augmentation de l'hémoglobine glyquée était associée à une augmentation du taux d'ICC. Bien que les patients ayant une hémoglobine glyquée ≥ 8% avaient une augmentation d'ICC, ceux ayant une hémoglobine glyquée entre 7% et 8% avaient un taux d'ICC similaire à ceux ayant une hémoglobine glyquée < 7%. L'ajustement pour les erreurs de mesure n'a pas sensiblement changé cette observation. Enfin, la troisième étude, une étude de cas-témoin nichée, examine les effets des thiazolidinediones sur l'incidence d'ICC. Cette étude n'a pu identifier de façon définitive une association entre les thiazolidinediones et une augmentation du taux d'incidence d'ICC, bien qu'un effet potentiellement cliniquement important n'a pu être exclu. En conclusion, cette thèse démont

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SILVA, Ricardo Martins. "Determinação Quantitativa de um Derivado Tiazolidínico (3-(2-bromo-benzil)-5-(5-bromo-2-metoxi-benzilideno)-tiazolidina-2,4-diona) em Plasma de Ratos Wistar: Desenvolvimento e Validação de um Método Analítico Recife." Universidade Federal de Pernambuco, 2011. https://repositorio.ufpe.br/handle/123456789/18484.

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Submitted by Caroline Falcao (caroline.rfalcao@ufpe.br) on 2017-04-04T19:21:33Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) 2011-Dissertação-RicardoSilva.pdf: 2010474 bytes, checksum: fa5ce1fda4e849fa7743b5d5b4e55481 (MD5)
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Dentre vários compostos sintetizados pelo Laboratório de Planejamento e Síntese de Fármacos (LPSF) da Universidade Federal de Pernambuco, o derivado tiazolidínico (3-(2-Bromo-benzil)-5-(5-bromo-2-metoxi-benzilideno)-tiazolidina-2,4-diona) (LPSF/GQ-113B) apresentou importante atividade antiinflamatória em ratos Wistar. Tal resultado despertou nosso interesse no desenvolvimento e validação de um método bioanalítco para determinação do LPSF/GQ-113B em fluídos biológicos. Nesse contexto, um método bioanalítico sensível e seletivo foi desenvolvido e validado utilizando a técnica de Cromatografia Líquida de Alta Eficiência acoplada a um detector ultravioleta (CLAE-UV) para quantificação do LPSF/GQ-113B em plasma de ratos Wistar. O método envolveu precipitação das proteínas plasmática com acetonitrila e, o LPSF/GQ-113B foi separado utilizando uma fase móvel composta por uma mistura de acetonitrila/água e ácido acético (85:14:1 v/v/v) eluida de forma isocrática através de uma coluna analítica Phenomenex® C18 5μ (150mm x 4.6mm) a uma temperatura de 40 ºC. O comprimento de onda para a detecção foi de 254 nm. A curva de calibração foi linear na faixa de 500-16000 ng/ml/L, com coeficientes de determinação (r²) próximos da unidade (0.997-0.999). Os rendimentos de extração para as concentrações de 1500, 7500 e 13.000 ng/ml/L foram 94.2%, 92.2% e 97.3%, respectivamente. O limite de quantificação para o LPSF/GQ-113B foi de 500 ng/mL. A validação do método incluiu a análise dos parâmetros analíticos de exatidão e precisão intra-dia e inter-dia que se apresentaram dentro dos limites exigidos pela legislação pertinente. Dessa forma, o método proposto pode ser aplicado para determinação quantitativa do LPSF/GQ-113B em plasma de ratos Wistar em estudos farmacológicos, toxicológicos, farmacocinéticos e de biodisponibilidade.
Among several compounds synthesized by the Laboratory of Planning and Synthesis of Drugs, from Federal University of Pernambuco, the thiazolidine derivative (3 - (2-bromo-benzyl) -5 - (5-bromo-2-methoxy-benzylidene)-thiazolidine -2,4-dione) (LPSF/GQ-113B) showed significant antiinflammatory activity in rats. This result has stimulated our interest in the development and validation of a method for determining LPSF/GQ-113B in biological fluids. In this context a fast, sensitive, and selective detection has been developed and validated for quantifying LPSF/GQ-113B in rat plasma by high-performance liquid chromatography coupled UV detector method . A plasma protein precipitation method was used with acetonitrile and, LPSF/GQ-113B was separated using a mobile phase (acetonitrile/water/acetic acid (85:14:1 v/v/v)) on the analytical column Phenomenex ® C18 5μm ( 150mm x 4.6mm) stored into the oven at 40 ºC temperature. The wavelength selected for detection was 254 nm. Over the range 500-16000 ng/mL, the calibration curve was linear with coefficient of determination (r²) were close to unit (0.997564- 0.999765). The recoveries at concentrations of 500, 7500 and 13000 ng/mL were 94.2%, 92.2% and 97.3%. The lower limit of quantification obtained was 500 ng/mL. Validation of the method included analysis of the analytical parameters of accuracy and within-batch and between-batch were inside the limits required by the competent authorities. Thus, the proposed method can be applied for quantitative determination of LPSF/GQ-113B in plasma of Wistar rats in pharmacological studies, toxicological, pharmacokinetic and bioavailability.

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Vella, Sandro. "Pharmacological modulation of insulin resistance : benefits and harms." Thesis, University of Dundee, 2013. https://discovery.dundee.ac.uk/en/studentTheses/4428eca5-5018-4816-95d0-30c0a3043409.

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Aims: Thiazolidinediones have been advocated as second or third line insulin sensitizing agents in the management of type 2 diabetes (T2DM). Their widespread use has been hampered by concerns about their cardiovascular safety, including fluid retention. Metformin is established as first-line glucose-lowering pharmacotherapy in T2DM. It has also been suggested that it may have benefits in alleviating insulin resistance in type 1 diabetes (T1DM). This thesis examined: (i) cardiovascular, renal and metabolic differences between individuals with T2DM ‘tolerant’ or ‘intolerant’ of TZDs; (ii) risk factors for TZD-associated oedema in T2DM; and (iii) the potential for metformin as adjunct therapy in T1DM. Methods: (i) A small clinical study characterising TZD tolerant and intolerant individuals with T2DM; (ii) A population-based epidemiological study of TZD induced oedema in individuals with T2DM in Tayside, Scotland (using incident loop diuretic prescription as a surrogate); (iii) A systematic review and meta-analysis of published studies of adjunct metformin in T1DM. Results (i) During a five-day high sodium diet, two known TZD-intolerant individuals with T2DM had reductions in haematocrit, aldosterone, and diastolic BP and increases in ANP and central and peripheral augmentation indices which were outwith reference ranges derived from nine TZD-tolerant individuals; (ii) Predictors of time to loop diuretic prescription included age, body mass index, systolic BP, haematocrit, ALT and macrovascular disease but rates of this outcome did not differ by therapy: 4.3% (TZDs) vs 4.7% (other agents) [unadjusted OR 0.909 (95% CI 0.690, 1.196); p = 0.493]; (iii) In meta-analysis of nine small studies in T1DM (192.8 patient-years of follow-up), metformin was associated with a reduction in total daily insulin dose (6.6 units/day; p < 0.001) but no studies examined cardiovascular surrogates or outcomes. Conclusions: Hypotheses were generated for several potential biomarkers predictive of TZD-induced oedema but the clinical importance of TZDs as a risk factor for oedema in individuals with T2DM was questioned. As there is some evidence for the safety of metformin as an adjunct therapy in T1DM but little evidence of efficacy, larger studies are warranted.

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TEBOUL, LYDIA. "Modulation de l'expression des genes par les acides gras et les thiazolidinediones. Consequences cellulaires et implications dans le traitement du diabete de type ii." Nice, 1997. http://www.theses.fr/1997NICE5122.

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Les acides gras (ags) ont un role pivot a la fois dans le phenomene de differenciation adipocytaire et dans l'etablissement de l'obesite et du diabete de type ii. Nous presentons une etude des mecanismes d'action des ags, aux niveaux moleculaire et cellulaire, dans le preadipocyte. Des caracteristiques communes du mode d'action des ags et des thiazolidinediones (thzs), une famille de composes antidiabetiques, sur la transcription des genes de la differenciation dans le preadipocyte ont ete mises en evidences. Ces molecules exercent leurs effets via l'activation d'un recepteur nucleaire, le fatty acid-activated receptor (faar). Les regions regulatrices d'un de leurs genes cibles, le fatty acid transporter, impliquees dans cette regulation et dans l'expression specifique de la differenciation adipocytaire, ont ete definies. Enfin, l'implication des niveaux de regulation post-transcriptionnel et post-traductionnel par les ags a ete egalement etudiee dans le cas d'un autre gene cible : la lipoproteine lipase. Faar etant egalement exprime dans le myoblaste, les effets des ags et des thzs, activateurs de ce recepteur, sur l'expression des genes ont ete etudies chez ce type cellulaire, issu d'une lignee etablie et en culture primaire. L'evenement original de trans-differenciation du myoblaste en adipocyte, en presence d'un ag ou d'une thz, a ainsi ete montre. Le phenotype des cellules trans-differenciees a ete precise. Cette etude a permis de mettre en evidence l'existence de mecanismes differentiels entre les ags et les thzs sur l'expression des genes de la differenciation adipocytaire dans le myoblaste. La pharmacologie de cet evenement de trans-differenciation a ete etudiee. Ces resultats amenent de nombreuses hypotheses nouvelles tant pour la comprehension du phenomene de la determination myocytaire de la cellule d'origine mesodermale, que pour l'explication d'evenements physiologiques lies au diabete de type ii et aussi du mode d'action therapeutique des thiazolidinediones.

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Gras, Delphine. "Inflammation et réparation bronchique dans l'asthme sévère : mécanismes de régulation par des médiateurs pro et anti-inflammatoires." Montpellier 1, 2007. http://www.theses.fr/2007MON1T032.

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Les anomalies morphologiques et physiologiques de l'épithélium bronchique contribuent à l'initiation et/ou à la prolongation du processus inflammatoire et donc à la physiopathologie de l'asthme. Le but de ce travail était de mieux caractériser l'état d'activation de l'épithélium dans l'asthme sévère en analysant i) les effets d'un médiateur pro-inflammatoire : l'IL-8, ii) les effets de médiateurs endogènes (la lipoxine A4 (LXA4)) ou pharmacologiques (les thiazolidinédiones (TZDs) dans la résolution de l'inflammation et dans les remaniements structuraux. Dans les cellules épithéliales des petites voies aériennes (SAEC), nous avons montré que l'IL-8 est capable d'induire spécifiquement la sécrétion d'un peptide de 4820 m/z en utilisant une approche protéomique, une sécrétion d'IL-6 de façon dose dépendante mais qu'elle n'a pas d'effet sur l'expression d'une molécule d'adhésion pro-inflammatoire, l'ICAM-1. Nous avons ensuite montré que les cellules épithéliales bronchiques sont capables de synthétiser in vitro de la LXA4 en présence de son substrat et que la LXA4 exogène inhibe la sécrétion d'IL-8 induite par le TNF-α dans ces cellules. Enfin, nous avons montré que les TZDs induisent la prolifération des cellules épithéliales bronchiques normales indépendamment de PPARγ, via l'activation d'un nouveau récepteur, le GPR40. Une attention spécifique aux mécanismes cellulaires et moléculaires gouvernant l'état d'activation de l'épithélium et ses remaniements structuraux pourrait donc avoir des conséquences thérapeutiques majeures, plus particulièrement dans l'asthme sévère.

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César, Fernanda Andrade de. "Propriedades antiaterogênicas de novas tiazolidino-2,4-dionas." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-07052013-154220/.

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Tiazolidinadionas (TZDs) são agentes sensibilizadores de insulina que agem por ligação ao receptor gama ativado por proliferador de peroxissomos (PPARγ). Elas têm apresentado efeitos cardioprotetores em humanos e propriedades anti-aterogênicas em modelos animais. Estudos in vitro têm sugerido que esses efeitos anti-aterogênicos da ativação de PPARγ ocorrem por inibição da expressão de genes pro-inflamatórios e por aumentar o efluxo de colesterol via ativação dos receptores LXR-ABCA1. Entretanto, vários efeitos colaterais são associados ao tratamento com as TZDs, tornando necessária a pesquisa por novos compostos desta classe. Neste estudo, 14 novas tiazolidina-2,4- dionas, que são TZDs modificadas por bioisosterismo, foram avaliadas quanto à expressão de fatores aterogênicos e inflamatórios em linhagens de macrófagos J774 e RAW 264.7 e em camundongos com deleção genética para o receptor de LDL (LDLr-/-). Após a avaliação da citotoxicidade em macrófagos, foram eleitas cinco TZDs, denominadas de GQ-11, GQ-97, GQ-177, GQ-145 e LYSO-7. Três destas TZDs (GQ- 145, GQ-177 e LYSO-7) aumentaram significativamente a expressão de RNAm dos fatores de transcrição PPARγ1, PPARγ2 e do receptor CD36, assim como também aumentaram a expressão gênica de ABCA1 em 2.9, 3.5 e 6.7 vezes, respectivamente. Em adição, estas TZDs diminuíram a expressão gênica de iNOS, COX2, VCAM e IL-6 associado a redução na produção de nitritos, mas apenas a LYSO-7 reduziu significativamente a expressão desses genes quando comparada à rosiglitazona (RSG), além de diminuir a expressão da proteína-1 quimiotática para monócitos (MCP-1). No estudo experimental, os camundongos LDLr-/- machos foram alimentados com dieta hipercolesterolêmica por 16 semanas e quatro semanas antes da eutanásia receberam os derivados tiazolidínicos (20 mg/kg/dia) por gavagem. GQ-177 inibiu a progressão da placa aterosclerótica associada à aumento nas concentrações plasmáticas de HDL-C, com elevação na expressão de ABCA1, e redução da via inflamatória CD40-CD40L. LYSO-7 também mostrou inibição da aterogênese associada à redução das concentrações plasmáticas de colesterol total e triacilgliceróis, com diminuição na interação entre CD40-CD40L e expressão de citocinas inflamatórias. A GQ-145 não alterou os níveis plasmáticos dos lipídeos, mas aumentou a expressão de todos os genes pró-aterogênicos e pró-inflamatórios. Adicionalmente, as vias de ativação destas novas TZDs também foram estudadas por ensaio de luciferase, como gene repórter. A GQ-177 induziu ativação de PPARγ e ligação ao seu domínio, enquanto a LYSO-7 estimulou ativação de PPARα e PPARδ. Portanto, conclui-se que as novas TZDs, especialmente a GQ-177 e a LYSO-7, podem apresentar propriedades ateroprotetoras associadas ao transporte reverso de colesterol e aos efeitos antiinflamatórios, e poderiam ser uma alternativa promissora para o tratamento da aterosclerose. Porém, estudos complementares são requeridos para caracterizar as vias de sinalização intracelular, visto que as duas demonstraram ativar diferentes isotipos do fator de transcrição PPAR.
Thiazolidinediones (TZDs) are insulin-sensitizing agents that act by binding to peroxisome proliferator-activated receptor-γ (PPARγ). They have been demonstrated to possess cardioprotective effects in humans and antiatherogenic properties in animal models. In vitro studies have also suggested that these antiatherogenic effects of PPARγ activation occur by inhibiting the inflammatory gene expression and by increasing cholesterol efflux via LXR-ABCA1 activation. However, several side effects are associated with TZDs treatment making necessary the search for new compounds. In this study, 14 new thiazolidine-2,4-diones, modified TZDs by bioisosterism, were tested for aterogenic and inflammtary factors in RAW 264.7 macrophages and in low-density lipoprotein receptor-deficient mice. After the citotoxicity evaluation in RAW 264.7 macrophages the TZDs named GQ-11, GQ-97, GQ-177, GQ-145 e LYSO-7 were selected for this study. Three of these TZDs (GQ-177, GQ-145 and LYSO-7) significantly increased the expression of PPARγ1, PPARγ2 and CD36 mRNA, and enhanced the expression of ABCA1 mRNA in 2.9, 3.5 and 6.7 fold, respectively. Moreover, they also significantly decreased the expression of iNOS, COX2, VCAM and IL-6 mRNA in relation to control, and these results are associated to reduction on nitrits concentration. In addition, LYSO-7 significantly reduced the expression of these genes when compared to rosiglitazone, and decreased expression of MCP1 mRNA. In the experimental study, male LDLr-/- mice were fed an atherogenic diet containing 0.5% cholesterol for 16 weeks, and 4 weeks before euthanasia they received TZDs (20mg/kg/ per day) by gavage. GQ-177 treatment inhibited progression of atherosclerotic plaque associated to increased plasma concentrations of HDL-C, with enhance of ABCA1 expression and reduction on CD40-CD40L interaction. LYSO-7 treatment also showed inhibition of the atherogenesis associated to decreased plasma concentrations of total cholesterol and TAG, with reduction on CD40-CD40L pathway and inflammatory cytokines expression.GQ-145 did not alter the lipid plasma levels and increased the expression of all pro-atherogenic and pro-inflammatory genes. Furthermore, the activation of PPARs has also been studied, by luciferase assay as reporter gene. GQ-177 induced activation of PPARγ, whereas LYSO-7 stimulated activation of PPARα and PPARβ/δ. Altogether, our data suggest that the new TZDs derivatives, specially GQ- 177 and LYSO-7, may have atheroprotective properties associated with the reverse cholesterol transport and anti-inflammatory effects, and could be a promising alternative for the treatment of atherosclerosis. However, further studies are warranted in order to characterize the pathways of intracellular signaling since both have demonstrated to activate different isotypes of PPAR.

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Coimbra, Cassio Negro. "Efeito da pioglitazona sobre a viabilidade funcional e o índice de apoptose de ilhotas pancreáticas murídeas em cultura." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-13102008-115420/.

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Acredita-se que a diminuição progressiva da massa de células observada durante a evolução do diabetes mellitus tipo 2 (DM 2) ocorra por apoptose deste tipo celular. As tiazolidinedionas (TZDs), uma classe de medicamentos utilizada no tratamento do DM 2, atuam como ligantes dos receptores ativados por proliferadores de peroxissomos (PPAR) e e promovem diminuição da resistência periférica à insulina. Embora existam estudos controversos, tem se especulado que as TZDs possam exercer efeitos diretos sobre as células pancreáticas, prevenindo a perda por apoptose e melhorando a sua viabilidade. O objetivo deste estudo foi avaliar os efeitos diretos da Pioglitazona (PIO) na concentração de 10 M sobre a viabilidade funcional e o índice de apoptose de ilhotas pancreáticas isoladas de ratos Wistar expostas a concentrações fisiológica (5,6 mM) e suprafisiológica (23 mM) de glicose durante 24, 48 e 72 horas. A viabilidade funcional foi avaliada pela análise da secreção de insulina estimulada por glicose e do conteúdo total de insulina nas ilhotas. O índice de apoptose foi avaliado pela medida da fragmentação do DNA, da expressão do RNAm dos genes Bcl2 (anti-apoptótico) e Bax (pró-apoptótico) e da atividade proteolítica da caspase-3 em ilhotas tratadas e não tratadas com a PIO. Em 5,6 mM de glicose, não se observou efeito significativo sobre a secreção de insulina, mas a avaliação do conteúdo total de insulina evidenciou uma diminuição transitória nas ilhotas tratadas com PIO por 24 horas, seguida por um aumento no conteúdo de insulina quando as ilhotas foram cultivadas por 48 e 72 horas em presença da droga. Em relação à avaliação da apoptose, observou-se uma diminuição na expressão do RNAm do gene Bax nas ilhotas tratadas com PIO por 24 horas, entretanto, após 48 e 72 horas, houve um aumento da expressão do RNAm deste gene nas ilhotas tratadas com a droga. Não foram observadas diferenças estatisticamente significativas na expressão do RNAm do gene Bcl2 em nenhum dos tempos estudados e a avaliação da apoptose determinada pela medida da fragmentação do DNA somente demonstrou uma diminuição do índice de apoptose após 48 horas de tratamento com a PIO. Em 23 mM de glicose, a PIO promoveu um aumento transitório na secreção de insulina estimulada por glicose e no conteúdo total de insulina (após 48 horas), no entanto, após 72 horas, observou-se diminuição significativa no conteúdo total de insulina. Em relação à apoptose, o tratamento com PIO determinou um aumento do índice de apoptose medido pela fragmentação do DNA e da atividade proteolítica da caspase-3 após 48 e 72 horas e uma diminuição da expressão do RNAm do gene Bcl2 nos tempos 24 e 48 horas. Os resultados do presente estudo sugerem que os efeitos diretos da PIO sobre as ilhotas pancreáticas murídeas em cultura variam de acordo com a concentração de glicose a qual as ilhotas estão expostas: em concentração fisiológica de glicose, a PIO parece exercer efeitos diretos benéficos, enquanto em concentração suprafisiológica de glicose, ela exerce efeitos diretos deletérios sobre a viabilidade funcional e o índice de apoptose de ilhotas pancreáticas murídeas em cultura.
The progressive decrease in -cell mass observed during the evolution of type 2 diabetes (T2DM) is believed to occur due to cell apoptosis. Thiazolidinediones (TZDs), a class of agents used for the treatment T2DM, act as ligands of the peroxisome proliferator-activated receptor (PPAR) and and decrease peripheral insulin resistance. Although still controversial, some studies have shown a direct effect of TZDs on pancreatic -cell, preventing cell loss due to apoptosis and improving their viability. The objective of this study was to evaluate the direct effects of 10 M Pioglitazone (PIO) on functional viability and apoptosis rate of islets isolated from Wistar rats exposed to physiological (5.6 mM) and supraphysiological (23 mM) glucose concentrations during 24, 48 and 72 hours. The functional viability was evaluated by the analysis of insulin secretion after glucose challenge and of islet total insulin content. Apoptosis rate was evaluated by measurement of DNA fragmentation, of Bcl2 (antiapoptotic) and Bax (proapoptotic) mRNA expression and of proteolytic activity of caspase-3 in pancreatic islets treated or not with PIO. At 5.6 mM glucose concentration, no significant effects in insulin secretion were observed, while a transitory decrease (after 24 hours) followed by an increase in total insulin content was observed in islets treated with PIO for 48 and 72 hours. Regarding apoptosis, a lower expression of Bax mRNA was detected in islets treated with PIO for 24 hours, followed, however, by an increase in the expression of this gene after 48 and 72 hours of drug exposition. PIO treatment did not promote significant changes in Bcl2 mRNA expression, while decreased the apoptosis rate measured by DNA fragmentation only after 48 hours of exposition. At 23 mM glucose concentration, PIO treatment elicited a transitory increase in insulin secretion after glucose challenge and in islet total insulin content after 48 hours followed by a decrease in the islet total insulin content after 72 hours. Concerning apoptosis, PIO treatment determined an increase in the apoptose rate measured by DNA fragmentation and by proteolytic activity of caspase-3 after 48 and 72 hours and a decrease in Bcl2 mRNA expression after 24 and 48 hours. These findings suggest that the direct effects of PIO on pancreatic islets depend on glucose concentration to which they are exposed: while under physiological glucose concentration the direct effects seem to be beneficial, under supraphysiological glucose concentration, PIO exerts direct deleterious effects on the functional viability and on the apoptosis rate of murine pancreatic islets.

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Logan, Suzanna J. "Optimization of Stem Cell Therapies for Coronary Collateral Growth in Cardiovascular Disease." NEOMED Integrated Pharmaceutical Medicine / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ne2mh1401096082.

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Fulgencio, Jean-Pierre. "Effets d'un biguanide et de deux thiazolidinediones sur le métabolisme du glucose et des acides gras dans des hepatocytes de rat : des flux métaboliques à l'expression de gènes." Paris 7, 2003. http://www.theses.fr/2003PA077047.

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Leroyer, Stephanie. "Voies de recyclage des acides gras au sein du tissu adipeux en situation de lipolyse : mécanismes impliqués, altérations dans l'obésité et en réponse aux antirétroviraux, amélioration par les thiazolidinediones." Paris 6, 2007. http://www.theses.fr/2007PA066689.

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Dias, Cristiano. "Rosiglitazone pode causar lesão tubular renal em ratos normais mas não em ratos hipercolesterolêmicos." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/5/5148/tde-25022010-160938/.

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Introdução: Rosiglitazone (RGL) é um ligante dos receptores PPAR e vem sendo usada no tratamento do Diabetes Mellitus tipo 2 e nas doenças inflamatórias. Mas, RGL pode reduzir a filtração glomerular (FG), a carga excretada de sódio na urina (UVNa) e aumentar a expressão da Na+,K+- ATPase na medula renal. Então, RGL pode causar edema e insuficiência cardíaca congestiva. Entretanto, não tem sido reportado se RGL pode induzir insuficiência renal aguda (IRA). Objetivo: Verificar se a redução da FG causada pelo tratamento com RGL predispõe à IRA em ratos. Avaliar em condições basais e de vasoconstrição renal e se há diferenças entre ratos normocolesterolêmicos (NC) e hipercolesterolêmicos (HC). Métodos: A FG foi medida pelo clearance de inulina no 8º dia em ratos (~200g) NC e HC tratados ou não com RGL (48 mg/kg/dieta) na situação basal e durante a infusão endovenosa de Ang II (40 ng/kg/min). Além disso, a atividade da Na+,K+-ATPase foi avaliada em homogenato renal em outra série de animais. Resultados: Na situação basal, NC e HC apresentaram FG semelhante e o tratamento com RGL reduziu a FG apenas em NC de 0,78±0,03 para 0,50±0,05* ml/min/100g, *p<0,001. Apesar da redução da FG, a UVNa em NC+RGL não se modificou. Durante a infusão de Ang II, a FG de NC, HC e HC+RGL reduziu-se para o mesmo patamar de NC+RGL e um significante aumento da UVNa foi observada apenas em NC+RGL (NC= 3,32±0,88; NC+RGL=5,86±1,04*; HC= 2,63±0,43 e HC+RGL= 2,23±0,39 uEq/min, *p<0,01). Além disso, RGL induziu aumento na atividade da Na+,K+-ATPase em HC+RGL e não modificou em NC+RGL. Os valores expressos em M Pi/mg proteína.h-1 foram de 45±7 em NC, 43±5 em NC+RGL, 48±7 em HC e 64±4* em HC+RGL, *p<0,05. Analisando todos os resultados em conjunto, a redução da FG associada com a alta natriurese e ausência da modulação da atividade da Na+,K+-ATPase em NC+RGL sugerem lesão renal neste grupo. Conclusão: Os mecanismos de ação da RGL diferem de acordo com a condição metabólica. Então, RGL deve ser prescrita com cautela na ausência de hipercolesterolemia e requer a monitoração da função renal principalmente nas situações de vasoconstrição
Introduction: Rosiglitazone (RGL) is a ligand for PPAR used to treat type 2 Diabetes Mellitus and inflammatory diseases. However, RGL can reduce the glomerular filtration rate (GFR), urinary sodium excretion (UVNa) and increase the expression of Na+, K+-ATPase in renal medulla. Thus, RGL may induce edema and congestive heart failure. However, acute renal failure (ARF) provoked by RGL treatment has not been reported. Aim: To test whether reduced GFR by RGL may predispose to ARF at baseline and during a renal vasoconstriction state, and if the findings differ between normocholesterolemic (NC) and hypercholesterolemic (HC) rats. Methods: GFR was measured by inulin clearance on the 8th day in NC and HC rats (~200g) treated or not with RGL (48 mg/kg diet) at baseline and during intravenous infusion of Ang II (40 ng/kg/min). Furthermore, the Na+,K+- ATPase activity was determined in renal homogenates in other series of animals. Results: At baseline, NC and HC had similar GFR and the treatment with RGL reduced GFR only in NC from 0.78±0.03 to 0.50±0.05* ml/min/100g, *p<0.001. Although GFR was reduced, UVNa was unchanged in NC+RGL. During Ang II infusion, GFR was significantly reduced in NC, HC and HC+RGL and it remained at the same reduced level in NC+RGL. At this time, when GFR was reduced the same range in all groups, a significant increment in UVNa was only observed in NC+RGL (NC = 3.32±0.88; NC+RGL = 5.86±1.04*; HC = 2.63±0.43 and HC+RGL = 2.23±0.39 Eq/min, *p<0.01). Moreover, RGL induced an increase in the activity of Na+, K+-ATPase in HC+RGL, but it did not modify the activity of this enzyme in NC+RGL. The values expressed in M Pi/mg.protein.h-1 were 45±7 in NC, 43±5 in NC+RGL, 48±7 in HC and 64±4* in HC+RGL, *p<0.05. Taken together, reduction in GFR associated with high natriuresis and without changes in the Na+, K+-ATPase activity in renal medulla of NC+RGL may suggest renal injury in this group. Conclusion: RGL may act distinctly in normocholesterolemia and in hypercholesterolemia. Thus, RGL may be prescribed with caution in absence of hypercholesterolemia and requires monitoring of renal function specially if a renal vasoconstriction state is associated.

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Gama, Ricardo Ribeiro. "Efeitos de quimioprevenção dos ligantes do PPAR- e dos ácidos graxos poliinsaturados ômega-3 no processo de carcinogênese da via aerodigestiva superior induzida pelo uso de 4-nitroquinolina-1-óxido em camundongos Swiss." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/5/5155/tde-27092010-152430/.

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Introdução: O carcinoma de células escamosas da via aerodigestiva superior (VADS) geralmente é unifocal e advém da progressão das lesões pré-neoplásicas. O risco de segundos tumores primários é de 3 a 7% ao ano para pacientes tratados previamente de câncer da VADS, sendo importante avançar em estratégias de quimioprevenção. Nos estudos clínicos realizados, as drogas promissoras mostraramse ineficazes quando aplicadas em doses baixas para minimizar a toxicidade. Neste trabalho, ácidos graxos poliinsaturados ômega-3 (óleo de peixe) e pioglitazone, um agonista PPAR-?, foram utilizados com intenção quimiopreventiva, em modelo animal de carcinogênese da VADS, induzida com o uso de 4- nitroquinolina-1-óxido (4-NQO). Métodos: Camundongos Swiss foram submetidos à indução tumoral com 4-NQO nas doses: 25, 50 ou 100 g/ml diluído em água por 8 semanas. Quimioprevenção foi testada com óleo de peixe nas concentrações de 10% ou 5%. Também foi realizada, em outros grupos, quimioprevenção com pioglitazone nas concentrações de 300 ppm ou 100 ppm. A quimioprevenção foi realizada na iniciação e pós-iniciação tumorais (por 32 semanas) ou apenas na pós- iniciação (por 24 semanas). Resultados: As incidências de neoplasias oral e esofágica foram, respectivamente, similares entre os grupos 4-NQO 100 77,7% e 55,5% e 4-NQO 50 72,9% e 37,8%. O grupo 4-NQO 25, ao ser observado 24 semanas a mais, obteve 78,2% de neoplasia oral e 34,7% de esofágica. A mortalidade por câncer nas 24 semanas após o término do 4-NQO foi de 55,6% no grupo 4-NQO 100, de 11,6% no 4-NQO 50 e de 13,6% no 4-NQO 25; sendo significante na comparação entre os grupos 100 com 50 (p<0,01) e 100 com 25 (p<0,01). Assim, foi observado que 4- NQO 100 g/ml gerou uma mortalidade mais acelerada neste grupo. A maioria dos animais desenvolvia lesões invasoras em mais de um órgão ou a associação destas com pré-neoplásicas. A incidência de neoplasia oral foi similar na comparação entre o grupo 4-NQO 100 (77,7%) com óleo de peixe 10% (80%) p=1,00 e com o grupo pioglitazone 300 ppm (61,1%) p=0,27. Entre os grupos 4-NQO 50 com óleo de peixe 5% (controle - 72,9%, com óleo de peixe na pós- iniciação - 84,2% e com óleo de peixe na iniciação e pós- iniciação - 64,7%) p=0,34 e entre os grupos 4-NQO 50 com pioglitazone 100 ppm (controle - 72,9%, com pioglitazone na pós-iniciação - 76,1% e com pioglitazone na iniciação e pós-iniciação - 62,5%) p=0,63, a incidência de neoplasia oral foi semelhante na comparação entre os grupos. A presença de neoplasia esofágica não diferiu entre o grupo 4-NQO 100 (55,5%) com óleo de peixe 10% (50%) p=0,73 e com o grupo pioglitazone 300 ppm (50%) p=0,73; e foi também similar entre os grupos 4-NQO 50 com pioglitazone 100 ppm (controle - 37,8%, com pioglitazone na pós- iniciação - 57,1% e com pioglitazone na iniciação e pós- iniciação - 31,2%) - p=0,22; porém diferiu nos grupos 4-NQO 50 com óleo de peixe 5% (controle37,8%, com óleo de peixe na pós-iniciação68,4% e com óleo de peixe na iniciação e pós- iniciação29,4%), sendo estatisticamente significante - p=0,02. Interessante foi a observação de que o grupo que realizou quimioprevenção com pioglitazone desenvolveu câncer gástrico na mesma proporção dos demais grupos, porém apresentou uma doença mais agressiva, com disseminação metastática, fato não observado nos outros grupos. Considerando-se a sobrevida, não foi observada diferença estatística significante nas 24 semanas comparando-se os grupos 4-NQO 100 e entre os grupos 4-NQO 50 com ou sem quimioprevenção com óleo de peixe ou com pioglitazone. Conclusão: A indução tumoral com 4-NQO, independente da dose, foi obtida com sucesso em camundongos Swiss. Neste estudo, não foram observados efeitos de quimioprevenção do óleo de peixe e do pioglitazone nas diferentes fases da carcinogênese estudadas. O óleo de peixe na pós-iniciação pode ter potencializado a ação carcinogênica do 4-NQO no esôfago, assim como a associação do 4-NQO com o pioglitazone possa ter criado um novo modelo de carcinogênese gástrica, não vista nos grupos que não receberam esta associação.
Introduction: The squamous cell carcinoma of the upper aerodigestive tract (UADT) is generally unifocal and arises from the progression of premalignant lesions. Between 3% to 7% of patients with head and neck carcinoma will develop subsequent primary tumors of the UADT annually; therefore, the importance of advancing in new chemopreventive strategies is unquestionable. In clinical studies, promising drugs were ineffective when used at low doses to minimize toxicity. In the present study, the potential chemopreventive effects of polyunsaturated fatty acids omega-3 (fish oil) and of a PPAR-? ligand (pioglitazone) were tested in an animal model of UADT carcinogenesis induced by 4-nitroquinoline-1-oxide (4-NQO) in Swiss mice. Methods : The animals underwent tumor induction with 25, 50 or 100 g/ml of 4-NQO diluted in water for eight weeks. Chemoprevention was tested with 10% or 5% fish oil and with 300 ppm or 100 ppm pioglitazone in other groups. Chemoprevention was conducted on tumor initiation and postinitiation for 32 weeks or only on postinitiation for 24 weeks. Results : The incidence rates of oral and esophageal neoplasms were similar between groups 4-NQO 100 (77,7% and 55,5%, respectively) and 4-NQO 50 (72,9% and 37,8%, respectively). Group 4-NQO 25 was followed for 24 weeks longer than the others and showed incidence rates of 78,2% for oral neoplasia and 34,7% for esophageal neoplasia. Cancer-related mortality rates in the 24 weeks following the conclusion of the tumor induction phase were 55,6%, 11,6% and 13,6% in groups 4-NQO 100, 4-NQO 50 and 4-NQO 25, respectively. The differences were statistically significant when comparing groups 100 with 50 (p<0,01) and 100 with 25 (p<0,01). The dose of 100 g/ml 4-NQO led to faster mortality compared with 50 g/ml or 25 g/ml 4-NQO. Most animals developed invasive lesions in more than one site of the UADT or, more frequently, an association of premalignant and malignant lesions. The incidence of oral neoplasia was similar in the comparison of the control group 4-NQO 100 with 10% fish oil (77,7% vs 80%, p=1,00) or with 300 ppm pioglitazone (77,7% vs 61,1%, p=0,27). Results were also similar when comparing 4-NQO 50 groups with 5% fish oil (control72,9%, fish oil on postinitiation84,2%, and fish oil on initiation and postinitiation64,7%, p=0,34), and between 4-NQO 50 groups with 100 ppm pioglitazone (control72,9%, pioglitazone on postinitiation76,1%, and pioglitazone on initiation and postinitiation62,5%, p=0,63). The incidence of esophageal neoplasia reached no statistical difference either when 4-NQO 100 control group was compared with 10% fish oil (55,5% vs 50%, p=0,73) or with 300 ppm pioglitazone (55,5% vs 50%, p=0,73). The same was true between 4-NQO 50 groups with 100 ppm pioglitazone (control37,8%, pioglitazone on postinitiation57,1%, and pioglitazone on initiation and postinitiation31,2%, p=0,22). Statistically significant differences were found between 4-NQO 50 groups with 5% fish oil (control37,8%, fish oil on postinitiation68,4%, and fish oil on initiation and postinitiation29,4%, p=0,02). Interestingly, the group receiving chemoprevention with 300 ppm pioglitazone had a gastric cancer incidence rate comparable to that of other groups, but with more aggressive disease and metastatic dissemination, unlike the others. No statistically significant differences were found in the survival rates for the 24-week period after induction when comparing the control groups 4-NQO 100 and 4-NQO 50 with their respective experimental groups, which received chemoprevention with fish oil or pioglitazone. Conclusions : Tumor induction with 4-NQO was successfully achieved in Swiss mice, regardless of the dose. In this study, no chemopreventive effects of fish oil or pioglitazone were observed either on postinitiation or on initiation and postinitiation. The introduction of fish oil on the postinitiation phase may have potentialized the carcinogenic action of 4-NQO on the esophageal epithelium; the same can be said about the association of 4-NQO and pioglitazone, which may have created a new model of gastric carcinogenesis not seen in the groups that did not receive that combination of drugs.

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Plissonnier, Marie-Laure. "Implication de TRAIL dans l'induction de l'apoptose par les thiazolidinediones, agents antidiabétiques, ligands de PPARy : étude dans deux modèles de carcinogenèse épithéliale : le cancer de vessie (non viro-induit) et le cancer du col de l'utérus (viro-induit)." Besançon, 2009. http://www.theses.fr/2009BESA0011.

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Des altérations des processus de prolifération/différenciation et d'apoptose sont impliquées dans le cancer et sont à l'origine de la résistance des cellules tumorales aux radio- et chimiothérapies et à leur élimination par le système immunitaire. Les pistes actuellement explorées visent à identifier de nouvelles molécules capables de rétablir le programme apoptotique réprimé dans les cellules tumorales tout en préservant les cellules saines. Dans ce contexte, nous avons montré que, dans deux modèles de carcinogenèse épithéliale (le cancer de vessie et le cancer du col de l'utérus dont le facteur étiologique est l'infection par HPV), les thiazolidinediones ou TZD (rosiglitazone, troglitazone et ciglitazone), ligands du récepteur nucléaire PPARy (Peroxisome Proliferator-Actived Receptor gamma), induisent un arrêt du cycle cellulaire ou l'apoptose des cellules tumorales mais indépendamment de l'activation du récepteur. Nos résultats montrent que la rosiglitazone conduit à l'arrêt du cycle cellulaire en phase GO/G1 ou G2/M uniquement dans des cellules dérivées de cancer de vessie, arrêt associé à une régulation du taux d'expression de protéines régulatrices du cycle cellulaire. La ciglitazone et la troglitazone ont des effets apoptotiques qui impliquent la voie extrinsèque de l'apoptose via les récepteurs de mort DR4 et DR5. Pour la première fois dans nos modèles cellulaires, nous montrons que ces TZD augmentent l'expression de la cytokine TRAIL et de ses récepteurs DR4 et DR5 tout en diminuant l'expression des protéines survivine et c-FLIP. L'effet de la ciglitazone sur l'apoptose a été confirmé dans un modèle in vivo de xénogreffes de cellules dérivées de cancer de la vessie et du col de l'utérus. D'autre part, dans les cellules CaSki dérivées de cancer du col de l'utérus où l'apoptose est court-circuitée par les oncoprotéines virales E6 et E7 de HPV16, la ciglitazone conduit à l'apoptose en diminuant l'expression des ARNm de E6. La rosiglitazone et la ciglitazone, en plus de leur effet propre, sont capables, dans des cellules résistantes à TRAIL, de sensibiliser les cellules cancéreuses à TRAIL ou, dans des cellules sensibles à TRAIL, de potentialiser son effet. Ainsi, ces TZD, seules ou en combinaison avec TRAIL, ouvrent de nouvelles perspectives thérapeutiques dans le traitement des cancers de vessie et du col de l'utérus
As known, defects in cell death or in proliferation pathways confer a survival benefit to tumour cells and a resistance to anticancer treatment. Current studies in cancer therapy focused on new targets for eradication of tumour cells while sparing normal cells. In this study, we showed that the thiazolidinediones, rosiglitazone, troglitazone and ciglitazone, which are high-affinity ligands for the Peroxisome Proliferator-Activated Receptor gamma (PPARgamma), triggered a cell cycle arrest or apoptosis in two models of epithelial carcinogenesis such a bladder cancer and cervical cancer (HPV positive cells) through PPARy activation -independent mechanisms. We demonstrated that rosiglitazone induces a cell cycle arrest in GO/G1 or G2/M phase characterized by an overexpression of cell cycle regulatory proteins. Furthermore, ciglitazone and troglitazone induce apoptosis mediaded through activation of the extinsic pathway involving the death receptors DR4 and DR5. Notably, we showed that TZD up-regulate soluble and membrane-bound TRAIL and its receptors in concomitance with a down-regulation of c-FLIP and survivin expression level. Our results with ciglitazone were confirmed in vivo in a xenograpt model using bladder and cervical cancer cells. Morevover, we showed that ciglitazone decreased the expression of E6 at mRNA level in cervical cancer cells where the expression of E6 and E7 viral oncoproteins of HPV short-circuits apoptosis. More interestingly, we demonstrated that rosiglitazone and ciglitazone amplified TRAIL-induced apoptosis in TRAIL-sensitive cells or let TRAIL-refractory cells to respond to TRAIL. These data suggest that PPARy agonist, alone or combined with TRAIL can produce significant antitumour effect and may provide an exciting novel therapeutic approach for the treatment of bladder and cervical cancers

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Khin, Myo Oo Korbtham Sathirakul. "Bioequivalence study of pioglitazone tablets in Thai healthy volunteers /." Abstract, 2007. http://mulinet3.li.mahidol.ac.th/thesis/2550/cd401/4837398.pdf.

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Murro, Ada Leticia Barbosa. "Efeitos da rosiglitazona sobre marcadores de risco cardiovascular e função da celula beta em diabeticos tipo 2 virgens de tratamento." [s.n.], 2007. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310702.

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Orientador: Marcos Antonio Tambascia
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: A principal causa de mortalidade entre os portadores de Diabetes tipo 2 é a doença cardiovascular. Estudos têm cada vez mais procurado alterações inerentes ao diabetes tipo 2 que justifiquem a maior incidência de doença cardiovascular nesse grupo. A presença de resistência à insulina, redução de adiponectina, aumento de PCR, disfunção endotelial e aumento de PAI-1 são candidatos possivelmente relacionados a esse aumento. A redução da resistência à insulina com uso de tiazolidinedionas, entre elas a rosiglitazona, tem potencial de reduzir o risco cardiovascular em diabéticos tipo 2, uma vez que altera citocinas relacionadas a risco cardiovascular de forma positiva. O objetivo desse estudo é avaliar o efeito clínico e laboratorial (sensibilidade à insulina, função de célula ß, lípides, PCR, adiponectina, resistina e PAI-1) e o efeito sobre a espessura da íntima-média carotídea da administração, por 12 semanas, de 8mg de rosiglitazona ao dia, em pacientes diabéticos tipo 2 virgens de tratamento anti-diabético, atendidos no Ambulatório de Diabetes Mellitus tipo 2, do Hospital das Clínicas da Faculdade de Ciências Médicas da UNICAMP. Os pacientes foram submetidos a uma avaliação inicial com dosagem de glicemia, hemoglobina glicada, insulinemia, colesterol total, HDL, LDL, triglicérides, ácidos graxos livres, AST, ALT, adiponectina, resistina, PAI-1, PCR, ácido úrico e fibrinogênio, após jejum de 12 horas. A sensibilidade à insulina e a função de célula ß foram avaliadas pela fórmula matemática do HOMA e a espessura da íntima média carotídea foi avaliada pelo ultrassom doppler. Os pacientes iniciavam o uso de Rosiglitazona na dose de 8 mg/dia dividida em duas tomadas diárias. Após 12 semanas de tratamento todas as avaliações foram novamente realizadas. Para a análise estatística foi realizado o teste de Wilcoxon para estudar as variações pré e pós Rosiglitazona e o coeficiente de correlação de Spearman. O nível de significância adotado foi de 5 % (p<0,05). Dos 15 pacientes inicialmente incluídos, 13 completaram o tratamento. Houve redução estatisticamente significante dos níveis de PCR, ácido úrico e aumento de adiponectina. Houve redução de HOMA IR e resistina, não estatisticamente significante e aumento do HOMA ß A análise das correlações possíveis mostrou relação inversa entre HOMA ß e ácidos graxos livres. Não houve alteração significante da espessura da íntima-média carotídea. O tratamento do Diabetes Mellitus com rosiglitazona tem potencial de reduzir o risco cardiovascular à medida que reduz marcadores de risco, como a PCR, e aumenta a adiponectina. Apesar de não ter sido estatisticamente significante, possivelmente devido ao tamanho da amostra, houve redução de 25% do valor médio da resistina, sugerindo uma relação entre resistina e resistência à insulina, controversa na literatura. Além da melhora da sensibilidade à insulina houve notável aumento do HOMA ß mostrando melhora da função da célula ß. Esse dado sugere que o tratamento com rosiglitazona desacelera a progressão da doença. A relação entre o aumento do HOMA ß e a redução dos ácidos graxos livres fala a favor da melhora da lipotoxicidade como um dos fatores de melhora da função da célula ß. Mais estudos populacionais de longa duração são necessários para comprovar o efeito da rosiglitazona sobre eventos cardiovasculares
Abstract: Cardiovascular disease is the major mortality cause among diabetic patients. Most studies are trying to find disturbances typical of diabetes that could explain the grater incidence of cardiovascular disease in this group. Insulin resistance, adiponectin reduction, CRP elevation, endothelial dysfunction and PAI-1 elevation are candidates possibly related to this prevalence. Reducing insulin resistance with thiazolidinediones, including rosiglitazone, probably reduces cardiovascular risk among type 2 diabetic patients once it alters cytokines related to cardiovascular risk in a positive manner. The aim of this study is to evaluate clinical and laboratorial effects (insulin sensitivity, lipids profile, ß-cell function, CRP, adiponectin, resistin and PAI-1) and the effects on carotid intima media thickness of 12 weeks use of rosiglitazone 4 mg BID for type 2 diabetic drug naïve patients currently assisted at Hospital das Clínicas da Faculdade de Ciências Médicas da UNICAMP Type 2 diabetes out-clinics. At the first visit we evaluated glycemia, glicated hemoglobin, insulin, total cholesterol, LDL, HDL, triglycerides, AST, ALT, free fatty acids, uric acid, PAI-1, fibrinogen, CRP, adiponectin and resistin after a twelve hours fasting. Insulin sensitivity and ß cell function were estimated using the HOMA model and intima media thickness was evaluated by a Doppler ultrasound. Patients started using Rosiglitazone 4 mg BID and after 12 weeks the same parameters were evaluated again. The statistical analyses used Wilcoxon test to study variations before and after rosiglitazone treatment and Spearman correlation coefficient. We considered p<0,05 as statistical significant. From the 15 patients included, 13 completed treatment. We observed a statistically significant reduction on CRP and acid uric levels and an adiponectin levels elevation. Non statistical significant HOMA IR and resistin reductions and HOMA ß improvement occurred. Correlations analyses showed negative correlation between HOMA ß and free fatty acids. It was observed no change in intima media thickness. Treating type 2 diabetes mellitus with rosiglitazone has a potencial to reduce cardiovascular risk once it reduces cardiovascular risk markers as CRP and increases adiponectin. Although is was no statistically significant, possibly due to sample size, there was a 25% reduction in medium resistin levels, suggesting relation between resistin and insulin resistance, still unproved in the literature. Besides the improvement in insulin sensitivity there was a notable increase in HOMA ß showing improvement in ßcell function. This data suggests that rosiglitazone treatment slows disease progression. Correlation between HOMA ß improvement and free fatty acid agrees with improvement in lipotoxicity as one factor that leeds to improvement in ß cell function. We need more long term epidemiological studies to attest rosiglitazone effect in cardiovascular events
Mestrado
Clinica Medica
Mestre em Clinica Medica

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Brackenridge, Anna. "The effect of thiazolidinediones on lipoprotein metabolism : a double blind randomised placebo controlled trial using stable isotopes to investigate the effect of pioglitazone, rosiglitazone and placebo on lipoprotein (apolipoprotein B100, VLDL, IDL and LDL) metabolism." Thesis, University of Surrey, 2005. http://epubs.surrey.ac.uk/843498/.

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Wilson-Fritch, Leanne. "Analysis of Mitochondrial Remodeling in Adipocytes during Adipogenesis and Obesity Development: a Dissertation." eScholarship@UMMS, 2004. http://escholarship.umassmed.edu/gsbs_diss/291.

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The prevalence of type 2 diabetes mellitus is increasing worldwide and is considered one of the top health concerns globally. The occurrence of type 2 diabetes is linked to the rapidly increasing trend of obesity in both adults and children, which is proposed to be a contributing factor in the development of insulin resistance and type 2 diabetes. White adipose tissue, an insulin target tissue, is an important endocrine organ involved in the control of energy homeostasis through its direct influence on metabolism, insulin sensitivity and food intake. To better understand these functions, we studied adipocyte differentiation in 3T3-Ll cells, a white adipose tissue cell line. Many mitochondrial proteins exhibit an increase in expression levels during adipogenesis as identified by mass spectrometry. Moreover, increased mitochondrial mass and altered morphology was observed by light microscopy. Qualitative changes in mitochondrial gene expression were also observed during adipogenesis as revealed by Affymetrix GeneChip analysis. Additionally, striking changes in mitochondrial protein expression and morphology were identified following treatment with the insulin sensitizing agent, rosiglitazone. These results suggest that mitochondrial biogenesis and remodeling is inherent to white adipocyte differentiation. To investigate the physiological relevance of these findings, mRNA and protein expression profiles and mitochondrial morphology were studied during the development of insulin resistance and obesity and following treatment with rosiglitazone in ob/ob mice. These studies reveal a marked decrease in transcript levels for over 50% of mitochondrial genes with the onset of obesity in ob/ob mice. Rosiglitazone treatment stimulates enhanced expression in approximately half of these genes, as well as changes in mitochondrial mass and remodeling. Furthermore, these studies reveal that depressed oxygen consumption and fatty acid oxidation occur with obesity development and these alterations can be reversed with rosiglitazone treatment. This work identifies the previously underscored plasticity of mitochondria in white fat and suggests that mitochondrial biogenesis and remodeling in white adipose tissue may lead to systemic changes in insulin sensitivity and energy homeostasis. Lastly, these studies suggest that mitochondria may be an important therapeutic target for antidiabetic drugs.

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Pickavance, Lucy Cecilia. "Thiazolidinedione treatment in models of insulin resistance." Thesis, University of Liverpool, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367553.

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Blouin, Jean-Marc. "Réversion métabolique et conséquences sur la physiopathologie du tissu adipeux et du côlon: rôle de la phosphoénolpyruvate carboxykinase cytosolique et des pyruvate déshydrogénase kinases." Paris 5, 2009. http://www.theses.fr/2009PA05T034.

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Le diabète de type 2 (DT2) et certains cancers sont caractérisés par des dérégulations métaboliques. Nous avons étudié l'expression d'enzymes du métabolisme glucido-lipidique, la phosphoénolpyruvate carboxykinase cytosolique (PEPCK-C) et les pyruvate déshydrogénase kinases (PDK). Dans le cadre du DT2 nous avons montré que par leurs effets sur la PEPCK-C et les PDK, les thiazolidinediones activent la glycéronéogenèse du tissu adipeux (TA), une voie métabolique qui participe à leur effet hypolipidémiant bénéfique en augmentant la réestérification des acides gras issus de la lipolyse des triglycérides du TA. Dans la seconde partie nous avons montré que le butyrate par ses effets sur les PDK modifie le métabolisme de la glutamine dans des cellules tumorales coliques. La glutamine étant un substrat essentiel des ces cellules, nous présentons ici une des voies potentielles par lesquelles le butyrate induit une réversion du métabolisme anormal des cellules tumorales coliques
Type 2 diabetes (T2D) and certain cancers are characterized by metabolic dysregulations. We studied the expression of enzymes involved in carbohydrate and lipid metabolism, namely cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) and the pyruvate dehydrogenase kinases (PDK). For T2D, we showed that thiazolidinediones (TZD), trough their induction of expression of PEPCK-C and PDK4, activate glyceroneogenesis in adipose tissue (AT). The stimulation of this metabolic pathway contributes to the beneficial lipid-lowering effect of TZD by increasing re-esterification of lipolytic fatty acids in adipocytes. In the second part of our studies we have shown that butyrate, through its inductive action on PDK modifies glutamine metabolism in colonic tumor cells. Glutamine is a major substrate of these cells. We present herein one of the potential pathways by which butyrate induces reversion of the abnormal metabolism of colonic tumor cells

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Dubois, Mathilde. "Dysfonctionnement des cellules β au cours du diabète de type 2 : rôle de la glucotoxicité et de la lipotoxicité et influence du Peroxisome Proliferator-Activated Receptor γ." Lille 2, 2003. http://www.theses.fr/2003LIL2P009.

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Torres, Rogil José de Almeida [UNIFESP]. "Avaliação das anormalidades precoces esclerocoriorretinianas observadas em coelhos hipercolesterolemicos tratados com Rosiglitazona." Universidade Federal de São Paulo (UNIFESP), 2010. http://repositorio.unifesp.br/handle/11600/9053.

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O objetivo deste trabalho é avaliar as anormalidades da esclera, coroide e retina de coelhos induzidas pela dieta hipercolesterolêmica, além da possibilidade de prevenção dessas anormalidades com administração sistêmica de rosiglitazona. Para isto, 54 coelhos new zealand foram distribuídos em quatro grupos: grupo-controle (GC) recebeu dieta normal; grupo 1 recebeu dieta hipercolesterolêmica; grupo 2 recebeu dieta hipercolesterolêmica associada à administração diária de 3 mg de rosiglitazona a partir do 14º dia do início do experimento; e grupo 3 recebeu dieta hipercolesterolêmica associada à administração diária de 3 mg de rosiglitazona desde o início do experimento. Os coelhos foram pesados e submetidos à dosagem sérica de colesterol total, triglicerídeos, high density lipoprotein (HDL) colesterol e glicemia de jejum no início do experimento, no 14º dia e no momento da eutanásia (42º dia). A esclera e coroide foram submetidas à análise histológica e histomorfométrica. A retina foi submetida à análise imuno-histoquímica com o anticorpo monoclonal anticalretinina (CR) e anticorpo anti-glial fibrillary acidic protein (GFAP). Quando positivo para o marcador anticalretinina, duas análises quantitativas foram realizadas. Na primeira, foram contadas todas as células ganglionares imunorreativas. Na segunda, todas as células e elementos celulares imunorreativos foram avaliados pelo exame de morfometria de cores. Os dados foram analisados pelo teste nãoparamétrico de Kruskal-Wallis e teste de Shapiro-Wilks-Testand. Valores abaixo de 0,05 foram considerados estatisticamente significantes. Os resultados referentes ao peso demonstraram significativo aumento nos grupos 1 e 3 em relação ao GC no 14º dia (p<0,009), enquanto no 42º dia os grupos 1, 2 e 3 apresentaram representativamente mais peso que o GC (p<0,023). Quanto às variáveis laboratoriais, destacaram-se o aumento significativo da glicose e colesterol total de G1 em relação ao controle (p<0,001), assim como o acentuado aumento da HDL no G3 em relação aos demais grupos (p<0,001), no 14º dia. A HDL manteve-se expressivamente elevada no G3 em relação aos demais grupos no momento da eutanásia (p<0,001). À análise histomorfométrica da esclera e coroide obteve-se normalidade do GC. Por outro lado, o G1 mostrou marcante aumento da espessura da esclera e coroide em relação ao GC (p=0,008), enquanto que no G3 houve espessamento de esclera e coroide menor que no G1 (p=0,048). Elevado número de histiócitos foi observado na parede escleral do grupo submetido à dieta hipercolesterolêmica (G1), seguido de forma decrescente por G2, G3 e GC. A análise imuno-histoquímica da retina com o anticorpo monoclonal anticalretinina ressaltou número mais alto de células ganglionares imunorreativas no G1 que no G3 (p=0,002). O exame de morfometria de cores revelou significativa imunorreatividade das células e elementos celulares do G1 em relação aos outros grupos (p<0,001). Nesta análise evidenciou-se também acentuada imunorreatividade das células e elementos celulares de G2 e G3 em relação ao GC (p≤0,002). GFAP foi negativo em todos os grupos. Neste modelo, os achados permitem concluir que a hipercolesterolemia provoca anormalidades precoces histomorfométricas e imuno-histoquímicas do complexo esclerocoriorretiniano; e a ativação dos receptores do PPAR gama-ocular, a partir da dieta oral de rosiglitazona, foi efetiva em atenuar tais anormalidades nessas estruturas.
The purpose of this study is to evaluate scleral, choroid and retinal abnormalities in rabbits induced by a hypercholesterolemic diet and the prevention of these abnormalities after oral administration of rosiglitazone in rabbits. Fifty-four new zealand rabbits were divided into four groups: the control group (CG) was fed a normal diet; group 1 G1), a hypercholesterolemic diet; group 2 (G2) a hypercholesterolemic diet associated with daily administration of 3 mg of rosiglitazone from day 14 after the beginning of the diet; and group 3 G3), a hypercholesterolemic diet associated with daily administration of 3 mg of rosiglitazone since the beginning of the experiment. The rabbits were weighed and underwent the following examinations: seric dosages of total cholesterol, triglycerides, cholesterol HDL, and fasting glycemia at the beginning of the experiment, on the 14th day and on the 42nd, the euthanasia day. The sclera and choroid underwent histologic and histomorphometric analyses and the retina underwent immunohistochemical analysis with anti-calretinin (CR) and anti-glial fibrillary acidic protein (GFAP) antibody. When positive for the anti-calretinin marker, two quantitative analyses were performed. In the first analysis, all immunoreactive ganglion cells were counted. In the second analysis, all immunoreactive cells and cell elements were studied with the color morphometry method. The data were evaluated using the nonparametric Kruskal-Wallis and the Shapiro – Wilk tests. Values of p<0.05 were considered statistically significant. The results obtained showed a significant weight increase in Groups 1 and 3 in relation to CG on Day 14 (p<0.009). Additionally, a significant weight increase was observed in G1, G2 and G3 in relation to CG on Day 42 (p<0.023). The lab results showed a significant increase in glucose and total cholesterol in G1 in relation to CG (p<0.001) on Day 14, as well as a significant HDL increase in G3, when compared with the other groups (p<0.001) on Day 14. HDL in G3 was significantly high when compared to the other groups, on the euthanasia day (p<0.001). The results obtained regarding weight showed a significant increase in Groups 1, 2 and 3 in relation to CG on Day 14 (p<0.01) and Day 42 (p<0.02). The lab results showed a significant increase in glucose and total cholesterol in Groups 1, 2 and 3 in relation to CG (p<0.01) on Day 14, as well as a significant increase in HDL in G3 when compared with the other groups, on euthanasia day (p<0.01). The histomorphometric analysis of CG sclera and choroid presented normal results. Conversely, G1 showed a significant increase in sclera and choroid thickness in relation to CG (p= 0,008), whereas G3 showed thickness lower than in G1 (p=0,048). A larger number of histiocytes were observed on the scleral wall of the group that was fed the hypercholesterolemic diet (G1), followed, in a descending order, by groups 2 and 3, and the control group. The immunohistochemical analysis of the retina with the anti-calretinin monoclonal antibody showed that G1 presented a larger number of immunoreactive ganglion cells than G3 (p = 0.002). The color morphometry showed significant immunoreactivity of G1 cells and cell elements when compared with the other groups (p<0.001). A significant immunoreactivity of G2 and G3 cells and cell elements in relation to CG was also observed (p<0.002). GFAP results were negative in all groups. The findings of this proposed study model suggest that hypercholesterolemia induces early histomorphometric and immunohistochemical abnormalities in the sclerochorioretinal complex and that the activation of PPAR gamma in ocular cells attenuated these abnormalities with the administration of the oral rosiglitazone diet.
TEDE
BV UNIFESP: Teses e dissertações

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Coste, Agnès. "Mécanisme de régulation de l'expression du récepteur mannose des macrophages par les cytokines TH1 et TH2 : rôle de PPAR-γ(gamma), conséquences dans la résistance à l'infection candidosique." Toulouse 3, 2003. http://www.theses.fr/2003TOU30158.

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Revelo, Xavier. "Effects of Insulin and 2,4-Thiazolidinedione on Bovine Neutrophil Function In Vitro." ScholarWorks @ UVM, 2009. http://scholarworks.uvm.edu/graddis/191.

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The dairy cow experiences a period of immunosuppression around the time of calving that contributes to the increased incidence and severity of infectious diseases observed during this period. This reduction in immune capacity is due in part to the impairment of neutrophil function, a key component of the innate immune system. In fact, the success of the host defense mechanisms against infection depends on the ability of neutrophils to reach the site of the infection, recognize, engulf and ultimately destroy the pathogen using several mechanisms such as the generation and release of reactive oxygen species (ROS) and the recently described neutrophil extracellular traps or NETs. The alteration in some of these functions and the overall killing ability of neutrophils during the periparturient period has been widely described. However, the physiological mechanisms underlying the period of immunosuppression are not completely elucidated. Interestingly, the impairment of these immune defense mechanisms coincides with the profound metabolic changes associated with parturition and lactogenesis. Changes in several hormones and metabolites have been proposed to be the cause of the reduction in neutrophil function, but the effect of insulin on the functional capacity of these cells has not been investigated. Not only does the concentration of plasma insulin fall as parturition approaches, but also the animal experiences a period of impaired insulin action, termed insulin resistance, during this same time-frame. Therefore, we isolated circulating neutrophils from periparturient and midlactating cows and incubated them with insulin alone or in combination with the insulin-sensitizing agent 2,4- thiazolidinedione (TZD). Subsequently, we measured the total, extracellular, and intracellular generation of ROS, NETs release, phagocytic and killing ability. Insulin did not improve any of the parameters used to assess neutrophil function. In contrast, TZD had a potent inhibitory effect on the total ROS generation, despite an increase in extracellular superoxide anion production. Surprisingly, TZD did not alter the ability of neutrophils to phagocytose and/or kill Staphylococcus aureus during an in vitro coculture. Results suggest that TZD can reduce the oxidative stress that neutrophils experience during their respiratory burst and diminish the damage that ROS cause to the surrounding tissue without compromising the capacity of neutrophils to eliminate the invading pathogen.

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Kim-Sohn, Kyung-Ah. "Etude pharmacologique et mecanistique d'un nouvel agoniste non-thiazolidinedione du PPARgamma chez le rat : aspects cellulaires et moleculaires." Paris 6, 2004. http://www.theses.fr/2004PA066174.

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Dissertations / Theses on the topic 'Thiazolidinediones'

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