Tesis sobre el tema "MitoTALEN"
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Kubilinskas, Rokas. "MitoTALENs to explore mitochondrial DNA repair and segregation". Electronic Thesis or Diss., Strasbourg, 2024. http://www.theses.fr/2024STRAJ014.
Texto completoFor long, the plant mitochondrial genome (mtDNA) was not amenable to manipulation, until recent advancements in genome engineering using Transcription Activator-Like Effector Nucleases (TALEN). In this work I used TALENs specifically targeted to mitochondria (mitoTALENs) to study plant mtDNA repair and segregation. MitoTALEN constructs were transformed into the background of 10 different Arabidopsis thaliana mutant lines, deficient in various factors involved in plant mitochondrial repair by homologous recombination. The resulting lines were analysed by Illumina sequencing and qPCR approaches. In wild type plants, the mtDNA double-strand-break (DSB) induced by MitoTALENs was repaired by homologous recombination, resulting in the replacement of the region containing the DSB by a distal unaffected sequence of the mtDNA, flanked by the same set of repeated sequences. In mutants deficient in repair factors, repair could shift to alternative pathways, such as Single-Strand Annealing (SSA) and Microhomology-mediated recombination (MHMR). Furthermore, in some mutants, the data revealed no evidence of DSB repair, but rather suggested that plants deficient in key repair factors could survive by reconstituting an alternative viable mitochondrial genome, from pre-existing autonomously replicating sub-genomes
Hescot, Ségolène. "Cibles moléculaires du Mitotane : Implications pour le traitement du corticosurrénalome". Thesis, Paris 11, 2015. http://www.theses.fr/2015PA11T040.
Texto completoMitotane is o,p’DDD, an historic drug derived from an insecticide and represents the treatment of choice for adrenocortical carcinoma (ACC), a rare adrenal tumor associated with bad prognosis. Mitotane is responsible for an inhibition of steroidogenesis associated with an antitumoral effect but its exact molecular mechanisms of action remain unclear and its molecular target remains unknown. However, mitochondria could be an organite targeted by mitotane. In this study we evaluated mitochondrial impact of mitotane using complementary approaches on several experimental models. We showed a mitotane-induced selective inhibition of respiratory chain complexes I and IV, an increased fission of the mitochondrial network and an activation of the mitochondrial biogenesis. These data helped us to identify mitochondrial-associated membranes (MAM) and so-called transduceosome as targeted organites of mitotane. We also reevaluated the potential role of the acid metabolite o,p’DDA and excluded its implication in the cytotoxic action of mitotane. Finally, we demonstrated that free mitotane which is not linked to lipoproteins is more efficient in vitro and could be therefore responsible for pharmacological action in vivo. Altogether, these results allow to better understand mitotane mechanisms of action and should help to identify predictive markers of response to mitotane for a better care of patients with ACC
GENTILIN, Erica. "Studio dell’azione del Mitotane, farmaco adrenolitico, sulla funzionalità ipofisaria". Doctoral thesis, Università degli studi di Ferrara, 2011. http://hdl.handle.net/11392/2388826.
Texto completoAttivi, David. "Mise en forme et amélioration de la biodisponibilité d'un anticancéreux destiné à la voie orale : exemple du mitotane". Thesis, Nancy 1, 2010. http://www.theses.fr/2010NAN10022/document.
Texto completoMitotane or o, p'-DDD is a organochlorine drug, very slightly soluble in water. It is used in the treatment of non resectable and metastasized adrenocortical carcinoma (Lysodren®). In therapy, to achieve therapeutic plasma level, high cumulative doses of mitotane were usually used during 3-5 months. This regimen causes gastrointestinal and neuromuscular side effects and make patients to be less compliants.The main objective of this work is to developp differents formulations of mitotane in order to improve the relative bioavailability when compared with conventional form Lysodren®. To shorten this equilibration time and reduce side effects, it's necessary to develop a new formulation. In order to increase mitotane solubility and make it more bioavailable, we encapsulated mitotane in polymeric particles and microemulsions.We prepared nanocapsules with biodegradable polymers (poly-epsilon-caprolactone) (PCL) and an association of PCL and non-biodegradable polymers (Eudragit®RL). We have also prepared PCL microparticles and a Self Microemulsifying Drug Delivery System or SMEDDS.Nanocapsules and microparticles diameters were respectively 300 nm and 40 to 76 µm. The zeta potential is negative for PCL particles wheras particles combining PCL and Eudragit®RL polymers exhibited positive zêta potential. For microemulsions, we investigated by constructing ternary phase diagrams and choosing the optimal formulation consisted of a mixture of Capryol®, Tween® 20 and Cremophor® EL (33, 33, 33%) with an emulsion diameter of 40 nm. The release of mitotane from SMEDDS and particles was higher and faster than from the conventional form Lysodren®.Pharmacokinetics after single-dose of oral mitotane formulations (100 mg/kg) in rabbits showed a 339% increase of relative bioavailability with microemulsions, 195% with the nanocapsules and 187% with the microparticles. Caco-2 cell culture showed a complete absorption of mitotane after 4h with microemulsions. For microparticles and nanocapsules, 50 and 45% of the initial dose, were respectively absorbed by Caco-2 cells. Caco-2 cells evaluation confirmed the low absorption of the mitotane powder (10%). Finally, Ussing chamber showed that microemulsions pass through the intestinal barrier 5 times higher than a solution of mitotane. In conclusion, microemulsions showed improvement of bioavailability of mitotane by a factor 3 in rabbits and could allow cost effective production. Microemulsions are a real alternative to Lysodren® which is currently available on the European market
Jacobi, Janin Melanie Katharina [Verfasser] y Florian [Akademischer Betreuer] Lang. "Zelltod humaner Erythrozyten durch Mitotan und Miltefosin / Janin Melanie Katharina Jacobi ; Betreuer: Florian Lang". Tübingen : Universitätsbibliothek Tübingen, 2018. http://d-nb.info/1196704031/34.
Texto completoBENSAID, JEAN-JACQUES. "Insuffisance surrenale definitive induite par op'ddd dans le syndrome de cushing : a propos de 4 observations". Lille 2, 1992. http://www.theses.fr/1992LIL2M256.
Texto completoWiemer, Laura Elisa [Verfasser], Martin [Gutachter] Fassnacht y Andreas [Gutachter] Rosenwald. "In-vitro-Untersuchungen zur molekularen Wirkung von Mitotane beim Nebennierenrindenkarzinom / Laura Elisa Wiemer. Gutachter: Martin Fassnacht ; Andreas Rosenwald". Würzburg : Universität Würzburg, 2013. http://d-nb.info/1102823414/34.
Texto completoSantos, Inês Carreira dos. "Clínica e cirurgia de animais de companhia". Master's thesis, Universidade de Évora, 2018. http://hdl.handle.net/10174/23096.
Texto completoDias, Raquel Macedo. "Separação cromatografica quiral do o,p'-diclorodifenildicloroetano (mitotano) em fase estacionaria quiral O,O'bis[4-terc-butilbenzoil]-N,N'dialil-L-tartadiamida". [s.n.], 2007. http://repositorio.unicamp.br/jspui/handle/REPOSIP/266169.
Texto completoDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Quimica
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Resumo: O mitotano (o,p?-diclorodifenildicloroetano) é um fármaco utilizado no tratamento de carcinoma adrenocortical. Ele é comercializado na forma racêmica, ou seja, na proporção 1:1 dos seus enantiômeros R e S. A influência da quiralidade da molécula sobre seu efeito farmacológico ainda não foi estudada. Portanto, a separação dos enantiômeros é importante para testes biológicos comparativos de efeitos colaterais. Este trabalho foi desenvolvido com o intuito de estudar a separação deste fármaco pela técnica de cromatografia líquida de alta eficiência utilizando coluna recheada com a fase estacionária quiral O,O?-bis[4-tercbutilbenzoil]-N,N?-dialil-L-tartardiamida. Diferentes combinações de fase móvel foram testadas e os melhores resultados foram obtidos com hexano/acetato de etila na proporção 95/5 (v/v). Experimentos de pulsos com soluções diluídas do traçador e dos enantiômeros do mitotano foram realizados variando a vazão de fase móvel e a temperatura do sistema. Foram determinados as porosidades do sistema, os parâmetros cromatográficos, os dados de equilíbrio, coeficientes de dispersão axial e parâmetros de transferência de massa. Os resultados mostraram separação satisfatória, com número de pratos superando 9000 e fatores de separação na ordem de 1,13. Os valores dos coeficientes de Henry foram maiores que a unidade para ambos os enantiômeros, sendo que o enantiômero mais retido R-(+)-mitotano, apresentou maior afinidade pela coluna quiral. Valores de km superiores a 300 min-1 revelaram baixo efeito dos fenômenos de transferência de massa e consequentemente predomínio dos efeitos termodinâmicos (energia entálpica superior -10 kJ/mol para os enantiômeros). Experimentos a altas concentrações foram realizados com a finalidade de se determinar às isotermas pelo método da análise frontal e também os cromatogramas sob estas condições. Para a concentração da mistura até 16 g/L as isotermas mostraram um bom ajuste ao modelo de Langmuir. A partir da separação em batelada determinaram-se as regiões de separação dos enantiômeros para um sistema cromatográfico contínuo do tipo leito móvel simulado para diferentes concentrações de alimentação da mistura racêmica. Avaliaram-se as variáveis desempenho (consumo de solvente e produtividade) no sistema contínuo e compararam-se com as obtidas em separações em batelada. Melhores resultados foram obtidos para um sistema contínuo do tipo leito móvel simulado
Abstract: Mitotane (o, p'-dichlorodiphenyldichloroethane) is a drug used in the treatment of adrenocortical carcinoma. It is marketed in the racemic form, proportion 1:1 of their R and S enantiomers. The influence of the molecule quirality on its pharmacology effect was not studied yet. For this reason, this separation is important for comparative biological tests of collateral effects. This work was developed with intention to study the separation of this drug via liquid chromatography using columns packed with the chiral stationary phase, O,O?-bis[4-terc-butylbenzoyl] - N, N' - diallyl-L-tartardiamide. Different combinations of mobile phase was tested and better results were achieved with hexane/ethyl acetate in ratio 95/5 (v/v). Pulses experiments with diluted solutions of the inert and the enantiomers were accomplished at different flow rates and temperature. The system porosities, chromatographic parameters, equilibrium constants, axial dispersion and mass transference parameters were obtained. The results showed satisfactory separation, with number of plates overcoming 9000 and separation factors in the order of 1,13. The values of Henry coefficients were greater than one for both enantiomers, the most retained was R (+) -mitotane, and it presented greater affinity for the chiral column. The overall mass transfer coefficient achieved values higher than 300 min-1, demonstrating low mass transfer effect rates and consequently a prevalence of the thermodynamic effects (enthalpy energy greater than -10 kJ/mol for the enantiomers). Experiments in overload conditions were realized in order to determining the isotherms using the method of the frontal analysis as well the chromatograms under these conditions. For the concentration of the mixture smaller than 16 g/L the isotherms showed a good adjusted to the Langmuir model. The separation regions for a chromatographic continuous system like simulated moving bed were determined with different feed concentrations. This permits the comparison of the performance parameters using the continuous system and batch ones
Mestrado
Desenvolvimento de Processos Biotecnologicos
Mestre em Engenharia Química
Asp, Vendela. "In Vitro Studies of Adrenocorticolytic DDT Metabolites, with Special Focus on 3-methylsulfonyl-DDE". Doctoral thesis, Uppsala universitet, Ekotoxikologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-122721.
Texto completoFREEMAN, CORINNE JOHNSON. "ADRENAL AND LIVER TRANSFORMATIONS OF MITOTANE". 1985. http://catalog.hathitrust.org/api/volumes/oclc/68296218.html.
Texto completoCai, Wei. "Bioactivation mechanisms for mitotane and its analogs". 1993. http://catalog.hathitrust.org/api/volumes/oclc/68796822.html.
Texto completoDJANEGARA, TANYA K. S. "ADRENAL METABOLISM OF MITOTANE AND RELATED COMPOUNDS". 1989. http://books.google.com/books?id=MzxtAAAAMAAJ.
Texto completoRUANGWISES, NONGLUCK. "ANALYTICAL AND METABOLIC STUDIES OF MITOTANE AND ITS ANALOGUES". 1990. http://books.google.com/books?id=-05tAAAAMAAJ.
Texto completoWiemer, Laura Elisa. "In-vitro-Untersuchungen zur molekularen Wirkung von Mitotane beim Nebennierenrindenkarzinom". Doctoral thesis, 2013. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-94526.
Texto completoIn-vitro studies to elucidate the moclecuar actions of Mitotane in adrenocortical carcinoma
POLI, GIADA. "Ricerca di nuovi target terapeutici nel carcinoma corticosurrenalico e studio dei meccanismi di azione del farmaco mitotane". Doctoral thesis, 2015. http://hdl.handle.net/2158/1004007.
Texto completoLin, Chia-Wen y 林嘉紋. "Mechanisms of Anti-steroidogenesis and Anti-tumorigenesis of Mitotane on Human Adrenocortical NCI-H295 Cells". Thesis, 2012. http://ndltd.ncl.edu.tw/handle/13544168232567294942.
Texto completo國立陽明大學
生理學研究所
100
Adrenocortical carcinoma (ACC) is an extremely rare and aggressive endocrine neoplasm with poor prognosis. Hypercortisolism (Cushing’s syndrome) is the most common complication of functional ACCs. Mitotane not only moderates the signs and symptoms caused by glucocorticoid excess but also improves the metastasis and recurrence of ACC. However, the biological mechanism of anti-steroidogenesis and anti-tumorogenesis of mitotane remains unknown. In this study, adrenocortical carcinoma NCI-H295 cells were used and treated with mitotane (0 - 40 M) for 24 hrs. Mitotane significantly inhibited basal, ACTH (1, 100 nM)-, FK (1, 10 M)- and 8-Br-cAMP (10, 100 M)-induced cortisol secretion in a dose-dependent manner but did not cause cell death. Gene transcription activity of various steroidogenic enzymes including StAR, CYP11A1, CYP11B1, CYP11B2, CYP17 and CYP21 were also diminished by mitotane treatment but not HSD3B2. Interestingly, mitotane expressed biphasic effect on CYP11B1 and CYP11B2 genes. Administration of mitotane potentiated ERK phosphorylation in a dose-dependent manner under both microenvironments. The total protein of SF-1 and DAX-1 were unchanged. These results suggested that mitotane suppressed cortisol production of NCI-H295 cells via interfering basal and cAMP-mediated gene transcription of steroidogenic enzymes. The ERK-mediated signaling might contribute to this effect through altering the protein-protein interaction between SF-1 and DAX-1. VEGF plays a crucial role in angiogenesis and tumor cell growth and previous studies demonstrated that ACC tumor expresses VEGF receptor. Mitotane suppressed basal VEGF production of ACC cells in a dose-dependent manner. Mitotane (40 – 80 M) inhibited VEGF production and cell viability, while 100 M mitotane expressed the more potential inhibitory effect on VEGF production than cell viability. Moreover, the VEGF production induced by CoCl2-induced hypoxia was suppressed by 60-70 M mitotane. These results suggested that mitotane inhibited tumorigenesis might be through blocking VEGF/VEGFR autocrine loop and/or inducing cell death in NCI-H295 cells.
"The Role of Corticosterone in Stress-induced Suppression of Innate Immunity in the Male House Sparrow". Doctoral diss., 2017. http://hdl.handle.net/2286/R.I.44130.
Texto completoDissertation/Thesis
Doctoral Dissertation Biology 2017