Rozprawy doktorskie: „Apoptosis”

1

Heiligtag, Sven. "Induction of apoptosis in neuroblastoma analysis of apoptotic pathways and putative apoptosis-mediating receptors /". [S.l.] : [s.n.], 2001. http://www.sub.uni-hamburg.de/disse/464/Disse.pdf.

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Devore, Casey Leigh. "DNR1 Regulates apoptosis: new insights into mosquito apoptosis". Thesis, Kansas State University, 2009. http://hdl.handle.net/2097/11972.

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Master of Science
Department of Biology
Rollie Clem
Apoptosis, or programmed cell death, is a crucial conserved process among organisms for deleting damaged unwanted cells, as well as for development and viral defense, and plays an important role in multiple diseases. Too much apoptosis may lead to Alzheimer’s disease, and too little may result in cancer. Therefore, the ability to understand this process is essential for improved medical knowledge today. Apoptosis has been explored in a number of species and pathways seem relatively conserved among most, with unique aspects contained in each, but little is known about apoptosis in mosquitoes. Improved knowledge and growing interest concerning apoptosis in mosquitoes is necessary considering the vast health effects seen across the globe as a result of diseases transferred by the mosquito vector. The Dengue virus mosquito vector Aedes aegypti was the focus here. A new player named defense repressor 1 was discovered in Drosophila melanogaster (DmDnr1), shown to play a role in apoptosis, and the homolog discovered in A. aegypti (AeDnr1). Silencing Dmdnr1 resulted in cells sensitized to apoptosis but was not enough to induce spontaneous apoptosis. In contrast, silencing Aednr1 in the A. aegypti cell line, Aag2, led to spontaneously induced apoptosis. This showed the importance of AeDnr1 as a member of the apoptotic pathway in this species. Epistasis experiments showed that apoptosis induced by silencing Aednr1 requires the initiator caspase Dronc and the effector caspase CASPS8, whereas apoptosis induced by silencing the inhibitor of apoptosis, Aeiap1, also requires Dronc but acts through the effector caspase CASPS7. Further epistasis experiments showed that apoptosis induced by silencing Aednr1 requires the IAP antagonist Mx, but not IMP. This showed for the first time a gene regulating upstream of an IAP antagonist. Biochemical studies showed that AeDnr1 regulates active CASPS8 but not CASPS7, and interacts with Mx and CASPS8 but not AeDronc, CASPS7 nor AeIAP1. Studies also showed Mx competes effectively with CASPS8 but not CASPS7 for AeIAP1 binding, and IMP competes effectively with CASPS7 but not CASPS8 for AeIAP1 binding. An improved apoptosis pathway for the mosquito A. aegypti emerged involving a potential feedback loop with explanations for the upstream IAP antagonist preference as well as the downstream effector caspase preference resulting from apoptosis induced by Aednr1 silencing. Through the discussed research, multiple unique findings resulted. Studying the mosquito model will allow us to find certain gene relations that are more difficult to uncover in the Drosophila model. Because Dnr1 is found in most systems, this improved pathway may shed light not only on a potential role of Dnr1 in apoptosis in insects but higher organisms as well.

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3

Seton, Kristina. "Eosinophil Apoptosis". Doctoral thesis, Uppsala University, Department of Medical Sciences, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3427.

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Apoptosis or programmed cell death is crucial for the resolution of inflammation, and phagocytosis of apoptotic cells initiates the release of actively anti-inflammatory responses from the phagocytes. Eosinophils are one of the most potent inflammatory cells in the body and is involved in a number of diseases, most commonly associated with parasitic infections and allergic diseases. Apoptosis in eosinophils is therefore one of the most important systems to avoid inflammation. This aim of the present investigation was to examine the mechanisms behind, and the consequences of this process in eosinophils. Apoptotic eosinophils have a unique surface receptor expression that indicates abilities to communicate with T-, B- and antigen presenting cells. They have a novel expression of CD49f, indicating an importance for binding to laminin or unknown functions of the VLA-6 receptor, possibly in the concept of phagocytosis of the apoptotic cell.

In apoptotic eosinophils the granules are translocated to the periphery of the cell, probably through a disruption of the cytoskeleton. This translocation makes the granules easily accessible and the apoptotic eosinophil can release considerable amounts of granule proteins in response to specific stimuli. The spontaneous release however, is decreased as compared with living cells.

Furthermore, the survival of eosinophils in response to an allergen challenge is increased in healthy subjects, but not in allergic patients. Mechanistically, this needs further investigation, but one theory is that it is due to the presence of specific IgE in patients in combination with differences in the response from the epithelial cells.

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4

Quarrie, Lynda H. "Mammary apoptosis". Thesis, University of Glasgow, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318886.

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5

Joza, Nicholas. "Differential requirement for the mitochondrial apoptosis-inducing factor in apoptotic pathways". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/MQ63071.pdf.

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6

Sani, Marc-Antoine. "Apoptosis Regulation via the Mitochondrial Pathway : Membrane Response upon Apoptotic Stimuli". Doctoral thesis, Umeå universitet, Kemiska institutionen, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1883.

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The aim of this thesis was the investigation of the mitochondrial response mechanisms upon apoptotic stimuli. The specific objectives were the biophysical characterization of membrane dynamics and the specific roles of lipids in the context of apoptotic regulation occurring at the mitochondrion and its complex membrane systems. The BH4 domain is an anti-apoptotic specific domain of the Bcl-2 protein. Solid phase peptide synthesis was used to produce large amount of the peptide for biophysical studies. A protocol has been established and optimized, guarantying the required purity for biophysical studies. In detail the purification by high performance liquid chromatography and the characterisation via mass spectroscopy are described. The secondary structure of BH4 changes significantly in the presence of lipid vesicles as observed by infrared spectroscopy and circular dichroism. The BH4 peptide aggregates at the membrane surface and inserts slightly into the hydrophobic part of the membrane. Using nuclear magnetic resonance (NMR) and calorimetry techniques, it could even be shown that the BH4 domain modifies the dynamic and organization of the liposomes which mimic a mitochondrial surface. The second study was on the first helix of the pro-apoptotic protein Bax. This sequence called Bax-α1 has the function to address the cytosolic Bax protein to the mitochondrial membrane upon activation. Once again a protocol has been established for the synthesis and purification of this peptide. The aim was to elucidate the key role of cardiolipin, a mitochondria-specific phospholipid, in the interaction of Bax-α1 with the mitochondrial membrane system. The NMR and circular dichroism studies showed that Bax-α1 interacts with the membrane models only if they contain the cardiolipin, producing a strong electrostatic lock effect which is located at the membrane surface. Finally, a new NMR approach was developed which allows the investigation of the lipid response of isolated active mitochondria upon the presence of apoptotic stimuli. The goal was there to directly monitor lipid specific the occurring changes during these physiological activities.

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7

Sani, Marc Antoine. "Apoptosis regulation via the mitochondrial pathway : membrane response upon apoptotic stimuli". Thesis, Bordeaux 1, 2008. http://www.theses.fr/2008BOR13651/document.

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Le but de cette thèse est de montrer la réponse de la membrane mitochondriale au cours la régulation de l’apoptose en étudiant l’effet de domaines clés sur la dynamique membranaire et l’importance de la composition phospholipidiques des modèles utilisés. Le domaine BH4 est la partie spécifique anti-apoptotique de la famille Bcl-2. La première étape a été de synthétiser le peptide par voie chimique en utilisant la synthèse peptidique en phase solide. Un protocole décrivant les étapes de purification par chromatographie liquide et de caractérisation par spectroscopie de masse, garantissant une pureté indispensable pour des études biophysiques, a été établi. La modification de la structure secondaire du peptide interagissant avec des vésicules a été étudiée par spectroscopie infrarouge ainsi que par dichroïsme circulaire. Le peptide s’agrège à la surface et s’insère peu profondément dans la partie hydrophobe de la membrane. En utilisant la résonance magnétique nucléaire (RMN) et la calorimétrie, il a été montré que le peptide BH4 modifie l’organisation et la dynamique des liposomes mimant la surface mitochondriale. La deuxième étude a porté sur la première hélice de la protéine pro-apoptotique Bax (Bax-a1) qui a la propriété de diriger la protéine cytosolique vers la mitochondrie. Un protocole de synthèse et purification a été à nouveau établi. Le but de cette étude est de démontrer le rôle de l’interaction spécifique entre la cardiolipine, un phospholipide uniquement présent dans la mitochondrie et le peptide Bax-a1. Les études RMN ont montré que Bax-a1 n’interagissait uniquement que si la cardiolipine était présente, produisant un fort effet électrostatique piégeant le peptide à la surface de la membrane. Enfin, un nouveau protocole permettant d’étudier la réponse des lipides de mitochondries isolées toujours actives par RMN est présenté. Le but est de pouvoir directement observer les modifications subies par chaque phospholipide de la mitochondrie.
The aim of this thesis was the investigation of the mitochondrial response mechanisms upon apoptotic stimuli. The specific objectives were the biophysical characterization of membrane dynamics and the specific roles of lipids in the context of apoptotic regulation occurring at the mitochondrion and its complex membrane systems. The BH4 domain is an anti-apoptotic specific domain of the Bcl-2 protein. Solid phase peptide synthesis was used to produce large amount of the peptide for biophysical studies. A protocol has been established and optimized, guarantying the required purity for biophysical studies. In detail the purification by high performance liquid chromatography and the characterisation via mass spectroscopy are described. The secondary structure of BH4 changes significantly in the presence of lipid vesicles as observed by infrared spectroscopy and circular dichroism. The BH4 peptide aggregates at the membrane surface and inserts slightly into the hydrophobic part of the membrane. Using nuclear magnetic resonance (NMR) and calorimetry techniques, it could even be shown that the BH4 domain modifies the dynamic and organization of the liposomes which mimic a mitochondrial surface. The second study was on the first helix of the pro-apoptotic protein Bax. This sequence called Bax-a1 has the function to address the cytosolic Bax protein to the mitochondrial membrane upon activation. Once again a protocol has been established for the synthesis and purification of this peptide. The aim was to elucidate the key role of cardiolipin, a mitochondria-specific phospholipid, in the interaction of Bax-a1 with the mitochondrial membrane system. The NMR and circular dichroism studies showed that Bax-a1 interacts with the membrane models only if they contain the cardiolipin, producing a strong electrostatic lock effect which is located at the membrane surface. Finally, a new NMR approach was developed which allows the investigation of the lipid response of isolated active mitochondria upon the presence of apoptotic stimuli. The goal was there to directly monitor lipid specific the occurring changes during these physiological activities

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8

Schmeiser, Katja. "Expression of apoptosis specific proteins (ASPs) during apoptosis and autophagy". Thesis, University of Birmingham, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394165.

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ASPs (apoptosis specific proteins) are a protein family with a molecular weight betwccn 20K and 140K. Expression has been found mainly in apoptotic cells. However, some family members have also been detected in viable cells. It has been confirmed by confocal microscopy that these proteins are predominately located along the actin cytoskeleton vvith particular high concentrations corresponding to a-actinin. A gene encoding the 32K ASP component has been cloned from a human foetal liver expression library. This 32K ASP protein (termed Apg5L; ApgS [autophagy 5. S. cerevisiae]-like, human [h]Apg5; Apg5) is homologues to the product of the yeast Apg5 gene. In yeast. Apg5 is essential for a novel protein conjugation system during autophagy. It is believed that members of the ASP family (i.e. 32K ASP/Apg5L) are involved in a similar conjugation system in mammals. This assumption is based on the observation that polyclonal antibodies raised against ApgSL recognise a set of proteins with co-localise with members of the ASP family detected by immunofluorescence.

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9

Cabezas, Somalo Maria. "Polimorfismes genètics i tractament antitumoral: evolució dels pacients amb leucèmia limfoblàstica aguda i inducció de leucèmies secundàries". Doctoral thesis, Universitat Autònoma de Barcelona, 2017. http://hdl.handle.net/10803/458541.

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Els pacients amb la leucèmia limfoblàstica aguda (LLA) infantil responen diferentment a la quimioteràpia. Els polimorfismes genètics, juntament amb les alteracions genètiques en les cèl·lules leucèmiques, podrien ser responsables de la variabilitat en aquesta resposta. En la present tesi es va estudiar l’associació de copy number variants i/o single nucleotide polymorphisms (SNPs) en gens que codifiquen enzims metabolitzadors de fàrmacs i proteïnes apoptòtiques (CYP2D6, GSTT1, GSTM1, SULT1A1, UGT2B17 i TP53) amb l’evolució dels pacients amb LLA infantil. Es va observar que els pacients amb el genotip GSTM1 non-null mostraven una supervivència inferior i que els pacients portadors d’almenys un al·lel amb la variant Pro del polimorfisme Arg72Pro de TP53 també mostraven una tendència a una supervivència inferior. A més, la combinació d’ambdós genotips va resultar en una major reducció de la supervivència, comparat amb GSTM1 per si sol. Per avaluar la base biològica d’aquests resultats, es va dissenyar un model in vitro amb cèl·lules leucèmiques Jurkat transfectades amb l’al·lel Arg o Pro de TP53 i amb un siRNA de GSTM1. Els resultats van mostrar que les cèl·lules Jurkat p53Arg GSTM1 null tenien una sensibilitat més gran a un fàrmac antitumoral glucocorticoide, la dexametasona, confirmant els resultats observats en els pacients. S’ha descrit que GSTM1 inhibeix la mort cel·lular induïda per glucocorticoides, i p53Arg indueix l’apoptosi més eficientment que p53Pro, la qual és més eficient en activar l’aturada del cicle cel·lular i la reparació del DNA. Per tant, tenir almenys una còpia del gen GSTM1 i p53Pro, suficient en heterozigosi, podria conduir a una apoptosi menys eficaç en les cèl·lules leucèmiques després del tractament antitumoral i per tant, podria relacionar-se amb una menor supervivència dels pacients amb LLA. Per altra banda, una de les complicacions més greus després de la teràpia antitumoral és el desenvolupament d’un càncer secundari, generalment una neoplàsia mieloide (t-NM). Fins un 20% dels pacients tractats per un càncer primari poden desenvolupar una t-NM. És probable que les variacions genètiques constitucionals estiguin implicades en el risc individual de desenvolupar un càncer secundari. En la present tesi es va analitzar l’impacte de dos polimorfismes en gens de la via de p53 en el desenvolupament de t-NM i es va observar que la variant p53Pro de l’SNP Arg72Pro de TP53 i l’al·lel G de l’SNP309 de MDM2 estaven sobrerepresentats en pacients amb t-NM comparat amb els controls. Per analitzar el possible efecte biològic del polimorfisme de TP53, es va desenvolupar un model amb línies cel·lulars Jurkat isogèniques, que expressaven p53Arg o p53Pro. Després del tractament amb un agent alquilant o un inhibidor de la topoisomerasa II es van avaluar els següents paràmetres: dany en el DNA, nombre de cèl·lules apoptòtiques i formació d’alteracions cromosòmiques característiques de t-NM després d’un cultiu cel·lular a llarg termini. Les cèl·lules Jurkat p53Arg van presentar més foci de γ-H2AX per cèl·lula, un nivell més elevat de dany en el DNA i un potencial apoptòtic més elevat, respecte a les p53Pro. A més a més, es va detectar la translocació t(15;17) i la deleció en 5q33 en les cèl·lules p53Pro, però no en les p53 Arg. Per això, s’ha proposat que les diferències en el risc de desenvolupar t-NM en pacients tractats amb les mateixes dosis de quimioteràpia i/o radioteràpia serien degudes a la capacitat de cada individu de dur a terme més o menys eficientment l’apoptosi o la reparació de les lesions al DNA, segons el polimorfisme que tingui a TP53.
Children with acute lymphoblastic leukemia (ALL) respond differently to chemotherapy. Genetic polymorphisms together with genetic abnormalities in leukemic cells are probably behind variability in response to chemotherapy in childhood ALL. In the present thesis, we investigated whether copy number variants and/or single nucleotide polymorphism (SNPs) in genes coding for proteins involved in drug metabolism or apoptosis (CYP2D6, GSTT1, GSTM1, SULT1A1, UGT2B17 and TP53) have an impact on the therapeutic outcome of childhood ALL. We observed that patients with GSTM1 non-null genotype showed poor survival and patients carrying at least one allele of the Pro variant of the TP53 Arg72Pro SNP also showed a tendency to poor survival. When combining GSTM1 and TP53 genotypes, our data indicated that they can predict survival with higher significance than GSTM1 alone. To validate these results, an in vitro model was created with leukemic Jurkat cell line by transfection of the two TP53 variants at codon 72, either Pro or Arg and a GSTM1 siRNA into Jurkat cells. Results revealed that Jurkat p53Arg GSTM1 null cells exhibited higher sensitivity to dexamethasone, confirming the results observed in patients. It has been reported that GSTM1 inhibits glucocorticoids-induced cell death and that p53Arg induces apoptosis more efficiently than p53Pro, which is a more efficient activator of cell cycle arrest and DNA damage repair. Therefore, at least one copy of the gene GSTM1 and p53Pro, enough in heterozygosis, would lead to less efficient apoptosis in leukemic cells after the antileukemic treatment and could therefore be related to lower survival. On the other hand, one of the most severe complications after successful cancer therapy is the development of a secondary cancer, mostly a myeloid neoplasm (t-MN). Up to 20% of patients treated for a primary cancer develop t-MN. Constitutional genetic variation is likely to impact on an individual’s risk of developing t-MN. In the present thesis, we analyzed the impact of two polymorphisms in the p53 pathway on the development of t-MN. Results revealed that the TP53 Arg72Pro polymorphism and the MDM2 SNP309 were associated with t-MN risk. The p53Pro and the G allele of MDM2 were overrepresented in t-MN patients. To assess the biological effect of the TP53 polymorphism, we established Jurkat isogenic cell lines expressing p53Arg or p53Pro and assessed the number of γ-H2AX foci, chromosome alterations, sister chromatid exchanges, and apoptotic cells, as well as development of chromosomal alterations typical of t-MN, after treatment with an alkylating agent, or a topoisomerase II poison. Jurkat p53Arg cells presented more γ-H2AX foci per cell, higher level of DNA damage and higher apoptotic potential than p53Pro cells. Moreover, Jurkat p53Pro cells presented the t(15;17) translocation and 5q33 deletion whereas Jurkat p53Arg cells did not present the alterations. Therefore, it could be possible that differences in t-MN risk in patients treated with the same doses of chemotherapy and/or radiation are due to the ability of individuals to undergo apoptosis or to repair DNA lesions more or less efficiently related to the TP53 polymorphism.

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10

Deng, Diana Xi. "Metallothionein and apoptosis". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/mq21105.pdf.

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11

Churchman, Adrian Thomas. "Endothelial cell apoptosis". Thesis, University of Hertfordshire, 2005. http://hdl.handle.net/2299/14269.

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Endothelial cell apoptosis is an important process during vasculature remodelling, angiogenesis and inflammation. Medical interest in endothelial cell apoptosis as a target for arthritis and solid tumour treatment has prompted biochemical and pharmacological investigation into the mechanisms controlling endothelial cell survival and angiogenesis. In recent years it has been hypothesised that control of endothelial cell apoptosis and the induction of angiogenesis may in part be due to the enzyme cyclooxygenase (COX)-2. COX-2 is involved in the metabolism of arachidonic acid to prostaglandins in mammals. This pathway has been implicated in controlling inflammation and angiogenesis through prostaglandin (PG) production and more recently has been shown to inhibit endothelial cell death. It was the aim of this study to investigate endothelial cell apoptosis and angiogenesis focussing on the role of COX-2, prostaglandins and endogenous apoptotic inhibitors in these pathways. Endothelial cell apoptosis was assessed by chromatin condensation, DNA fragmentation and caspase activation. Angiogenesis was investigated by examining capillary-like tubule formation. Endothelial cell apoptosis induction and angiogenesis inhibition was observed using the selective COX-2 inhibitor 5-bromo-2-(4-fluorophenyl)-3- (methylsulfonyl) thiophene (DuP-697) at a concentration 100 times lower than has previously been reported. Apoptosis was confirmed by induction of caspases 8, 9 and 3 over 8 hr and DNA fragmentation and condensation over 24 hr. The effects observed may be due to a selective inhibition of COX-2 as apoptosis induction and angiogenic inhibition only occurred when COX-2 was inhibited by selective and non-selective COX inhibitors. Induction of endothelial cell death was induced by treatment with two natural products that inhibit COX-2, namely curcumin and 6-shogaol (from turmeric and ginger respectively) although only at concentrations higher than were required to inhibit COX- 2. Both compounds induced chromatin condensation in endothelial cells and lurkat E6.1 cells with no DNA laddering or caspase induction. Further examination of the mechanisms of endothelial cell survival were investigated by assessing the endogenous expression of the apoptosis repressor with a caspase recognition domain (ARC) protein through examining reverse transcriptase CRT) - peR, native protein expression and transgenic over-expression in the endothelial cells. Endogenous expression of ARC was found in endothelial cells. However this expression declined during in vitro culture. Transgenic expression of ARC was found to increase levels of ARC in vitro. However it had no effect on apoptosis inhibition after 24 hr. The underlying mechanisms of cell death induction may be compound dependent in endothelial cells. Pharmacological inhibition of COX-2 and possibly PGE2 generation has detrimental effects on angiogenesis and endothelial cell survival. However inhibition of COX-2 by natural products at low concentrations may be advantageous in preventing tumour angiogenesis with no apoptosis induction.

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12

Nijhuis, Erwin. "Hyperthermia-induced apoptosis". Enschede : University of Twente [Host], 2008. http://doc.utwente.nl/59801.

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Cornélio, Ana Lívia Gomes [UNESP]. "Citotoxicidade e ação antimicrobiana do cimento Portland associado a diferentes agentes radiopacificadores". Universidade Estadual Paulista (UNESP), 2011. http://hdl.handle.net/11449/90397.

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A proposta deste estudo foi investigar a citotoxicidade, ação antimicrobiana e pH do cimento Portland puro (CP) e associações com agentes radiopacificadores: óxido de bismuto (CPBi), óxido de zircônio (CPZir), tungstato de cálcio (CPCa). Para avaliar o potencial citotóxico, foram empregadas linhagens celulares de fibroblastos do ligamento periodontal de camundongos (mPDL) e osteosarcoma de ratos (ROS 17/2.8). Ambas foram expostas por 24 horas a diferentes concentrações do CP fresco, CP associado com radiopacificadores e cimento de óxido de zinco eugenol. Peróxido de hidrogênio foi aplicado como controle positivo para apoptose. A viabilidade após incubação com os cimentos foi avaliada pela atividade da enzima desidrogenase mitocondrial. A morfologia celular foi analisada microscopicamente pelo corante violeta de cresilo, e o mecanismo de morte celular foi determinado pela metodologia de laranja de acridina/brometo de etídio. Os dados foram analisados estatisticamente por ANOVA e Tukey post-test (p<0.01). A correlação entre os dois tipos de morte celular e valores de pH foi estabelecido pela correlação linear de Pearson. O ensaio da enzima desidrogenase mitocondrial revelou um padrão significante de morte celular apenas nas altas concentrações dos eluídos de cimento. CP puro não foi citotóxico, mesmo na alta concentração de 100mg/ml. As imagens microscópicas mostraram que nenhuma das formulações de CP causaram danos as linhagens celulares. Análises estatísticas dos dados de apoptose/necrose demonstram que CP e CP mais agentes radiopacificadores promoveram morte por necrose estatisticamente significativa apenas em 100mg/ml. Os resultados mostraram que CP associado com óxido de bismuto, óxido de zircônio ou tungstato de cálcio não foram citotóxicos para mPDL ou ROS 17/2.8, e podem ser boas...
The purpose of this study was to investigate the cytotoxicity, antimicrobial and pH of pure Portland cement (PC), and associations with radiopacifier agents: bismuth oxide (CPBi), zirconium oxide (CPZir), calcium tungstate (CPCA). To assess the potential cytotoxicity, fibroblast cell lines from the periodontal ligament of mice (mPDL) and rat osteosarcoma (ROS 17/2.8) were used. Both were exposed for 24 hours with different concentrations of fresh PC, PC associated with radiopacifiers and eugenol zinc oxide cement. Hydrogen peroxide was used as a positive control for apoptosis. The viability after incubation with the cements was evaluated by mitochondrial dehydrogenase enzyme activity. Cell morphology was examined microscopically by cresyl violet stain, and the mechanism of cell death was determined by the method of acridine orange / ethidium bromide. The data were statistically analyzed by ANOVA and Tukey post-test (p <0.01). The correlation between the two types of cell death and pH values was established by Pearson linear correlation. The mitochondrial dehydrogenase enzyme assay revealed a significant pattern of cell death only at high concentrations of the eluted cement. Pure PC was not cytotoxic, even at high concentration of 100mg/ml. Microscopic images showed that none of the formulations of PC caused damage cell lines. Statistical analysis of apoptosis/necrosis data showed that PC and PC plus radiopacifiers agents promoted death by necrosis statistically significant only at 100mg/ml. The results showed that PC associated with bismuth oxide, zirconium oxide or calcium tungstate were not toxic to ROS 17/2.8 or mPDL, and may be good alternatives as radiopacifier agents. The antimicrobial and pH of Portland cement and radiopacifier agents were evaluated. For antimicrobial activity agar diffusion was... (Complete abstract click electronic access below)

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14

Nieuwenhuijsen, Hendrik. "Untersuchungen zum Einfluss des extrinsischen Apoptoseweges bei dehnungsinduzierter Zellschädigung von alveolären Epithelzellen (Typ II-Zellen) aus der Rattenlunge". Doctoral thesis, Universitätsbibliothek Leipzig, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-146677.

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Beatmungsinduzierte Lungenschädigung stellt eine häufige Komplikation bei der Behandlung von ALI / ARDS dar. Selbst kleinere, bereits als protektiv bezeichnete Tidalvolumina können so auf dem Boden einer bereits stark beeinträchtigten Lunge zur einem starken lokalen Entzündungsgeschehen im alveolären Gewebe führen, in dessen weiteren Verlauf es zu einer mechanisch induzierten Apoptose und Nekrose kommen kann. Die Apoptose, auch als programmierter Zelltod bezeichnet, kann auf ihrem extrinsischen Weg über eine Ligand / Rezeptor Interaktion ausgelöst oder gehemmt werden. Dies macht das Zellsterben auf molekularer Ebene in gewisser Weise steuerbar, was sich präventiv und therapeutisch-medikamentös zu Nutze machen ließe. Daher soll in dieser Arbeit untersucht werden, ob bei der mechanisch induzierten Apoptose von Typ II-Pneumozyten durch unphysiologische Beatmung ebenfalls klassische Marker einer extrinsischen Apoptose zu finden sind und welche Rolle sie im Prozess der dehnungsinduzierten Apoptose spielen. Diese Untersuchungen wurden an frisch isolierte Typ II-Pneumozyten aus der Sprague-Dawley-Ratte durchgeführt. Die Zellen wurden auf elastischen 6-Well Platten jeweils 24h bei unphysiologischen (Frequenz 40 / Amplitude 30) auf der Flexercell FX-3000 Dehnmaschine gedehnt und im Anschluss mittels ELISA und Western-Blot auf Marker der extrinsischen Apoptose hin untersucht. Dabei konnte eine mäßige Erhöhung der für den extrinsischen Apoptoseweg typischen, jedoch mit ihm nicht zwangsläufig assoziierten Caspase-8 und TNF-α ermittelt werden. Für die Marker FAS, FAS-L und FADD, die eindeutig für den extrinsischen Apoptoseweg stehen, konnte keine Konzentrationserhöhung nach mechanischer Dehnung nachgewiesen werden. Diese Ergebnisse, frühere Forschungsergebnisse aus unserer Forschungsgruppe und die weltweite Studienlagen lassen somit den Schluss zu, dass die extrinsische Apoptose bei mechanischer Dehnung von Typ II-Pneumozyten keine entscheidende Rolle spielt.

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15

Li, MingLi. "Regulation of apoptosis-induced proliferation and non-apoptotic cell death in Drosophila". Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7491/.

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Apoptosis-induced Proliferation (AiP) refers to an evolutionary conserved process that stress-induced apoptotic cells stimulate neighbouring cells to undergo extra proliferation to compensate for the loss of apoptotic cells. It is therefore involved in tissue regeneration in multi-cellular organisms. I found that dAtg1 (Drosophila autophagy-related gene 1), a gene best known in activating autophagy, is required for AiP. dAtg1 is transcriptionally induced by the JNK pathway, a stress response signalling pathway, during AiP and it regulates AiP by acting upstream of growth signals e.g. Wg/Wnt. Surprisingly, other Atg genes involved in autophagy are not required for AiP. Therefore, dAtg1 regulates AiP independent of its canonical roles in mediating autophagy. In parallel, I investigated the non-apoptotic cell death induced by Eiger (Egr), the Drosophila tumour necrosis factors (TNFs). In mammals, TNF induces apoptosis and, when apoptosis is blocked, necrosis. In Drosophila, the type of cell death induced by Egr remains elusive. I found that expression of egr in the developing Drosophila eye primarily induces apoptosis through the canonical apoptosis pathway. Intriguingly, when apoptosis is blocked by inactivation of effector caspases DrICE and Dcp-1, Egr induces necrosis instead. Therefore, mechanisms underlying TNF-induced cell death are more conserved in Drosophila than previously thought.

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16

Cossu, F. "STRUCTURAL INSIGHTS INTO INHIBITOR OF APOPTOSIS PROTEINS RECOGNITION BY PRO-APOPTOTIC COMPOUNDS". Doctoral thesis, Università degli Studi di Milano, 2012. http://hdl.handle.net/2434/168360.

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Inhibitor of Apoptosis Proteins (IAPs) are negative regulators of apoptosis and their overexpression is observed in many cancer cells, correlating with the inhibition of caspases. IAPs inhibitory function is exploited by the BIR domains, which were firstly identified in baculovirus. Among the IAP family, XIAP (X chromosome-linked IAP) directly inhibits caspases preventing proteolytic cleavage through its BIR2 and BIR3 domains; furthermore, XIAP-BIR1 in a dimeric form recognizes TAB1, a kinase activator, regulating pro-survival pathways. In the last years, cIAPs have become crucial players of the extrinsic pathway; in fact, through the recognition of TRAFs (TNF Receptor Associated Factors) by the cIAP2-BIR1 domain, they are recruited to the TNF- Receptor Signaling Complex and act as E3 ubiquitin ligases. One of the most promising approaches that have been proposed to inhibit these proteins is represented by the structure-based design of small molecules, named Smac-mimetics, that mimic Smac/DIABLO (Second mitochondria-derived activator of caspases/Direct IAp Binding protein with Low pI), an endogenous antagonist of IAPs. Initially designed in 2001 against the BIR3 domain of XIAP, Smac-mimetics have shown to prevent the inhibitory action of XIAP on initiator and executioner caspases, but also to bind to the BIR3 of cIAPs, inducing their autoubiquitylation and degradation. This work focuses on the cloning, expression and purification of the IAPs constructs of interest and their biochemical and biophysical characterization alone and in the presence of some of the Smac-mimetics from our library. The X-ray technique on crystals and protein solutions allowed a structural study of the protein-ligand complexes at atomic level, favoring the process of drug lead optimization. Furthermore, the screening of libraries of pharmacologically active compounds through in silico docking searches on new targets, such as XIAP- and cIAP2-BIR1, resulted in the discovery of potential new pro-apoptotic leads, whose clinical properties are known. Since in the last months new macromolecular protein complexes have been identified as involved in apoptosis and pro-survival pathways, novel protocols for the expression and purification of cIAP1 and TRAFs full length constructs have been optimized to obtain pure and homogeneous samples ready for the structural characterization.

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Mansur, Eli. "A participação da leptina no controle da apoptose em timo de ratos wistar". [s.n.], 2007. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310366.

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Orientador: Licio Augusto Velloso
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas.
Made available in DSpace on 2018-08-17T07:03:20Z (GMT). No. of bitstreams: 1 Mansur_Eli_D.pdf: 1693041 bytes, checksum: a5b3d9f350100a50b16d835341ff4bc9 (MD5) Previous issue date: 2007
Resumo: A leptina, hormônio com semelhança funcional e estrutural às citocinas, é conhecida por exercer, além das ações clássicas de controle da ingestão alimentar e termogênese, importantes funções na modulação das respostas do sistema imune. Alguns destes efeitos são dependentes da propriedade da leptina em modular a apoptose das células tímicas. Neste trabalho, utilizamos ratos Wistar para investigar os mecanismos moleculares envolvidos no controle, dependente da leptina, da apoptose no timo. A apoptose foi avaliada por citometria de fluxo e ELISA para determinação de nucleossomos, enquanto que a transdução do sinal foi avaliada por imunoprecipitação, imunoblot e microscopia confocal. O ObR estava expresso na maioria das células tímicas e a sua quantidade relativa reduziu-se progressivamente durante a maturação dos timócitos. A expressão do ObR estava co-localizada com JAK-2 e STAT-3, e a injeção aguda, in vivo , de leptina promoveu a fosforilação em tirosina de JAK-2 e o engajamento de STAT-3. O tratamento com leptina, também, levou à fosforilação em tirosina de IRS1 e fosforilação em serina de Akt. O tratamento crônico com leptina reduziu a apoptose tímica, e este efeito não foi inibido pelo AG490, um inibidor de JAK, mas foi significativamente inibido por LY294002, um inibidor de PI3-Quinase, e por um oligonucleotídeo antisense para IRS1. Portanto, a leptina inibe a apoptose em células tímicas via um mecanismo independente da ativação de JAK-2 mas dependente do engajamento da via IRS1/PI3-Quinase
Abstract: The cytokine-like hormone leptin is known to exert important functions on the modulation of immune responses. Some of these effects are dependent on the property of leptin to modulate the apoptosis of thymic cells. In the present study, we employed Wistar rats to investigate the molecular mechanisms involved in leptin-dependent control of apoptosis in thymus. Apoptosis was evaluated by flow cytometry and ELISA for nucleosome determination, while signal transduction was evaluated by immunoprecipitation, immunoblot and confocal microscopy. The ObR was expressed in most thymic cells and its relative amount reduced progressively during thymocyte maturation. ObR expression was co-localized with JAK-2 and STAT-3, and an acute, in vivo , injection of leptin promoted the tyrosine phosphorylation of JAK-2 and the engagement of STAT-3. The treatment with leptin also led to the tyrosine phosphorylation of IRS1 and serine phosphorylation of Akt. Chronic treatment with leptin reduced thymic apoptosis, an effect that was not inhibited by the JAK inhibitor AG490 but was significantly inhibited by the PI3-kinase inhibitor LY294002 and by an antisense oligonucleotide to IRS1. Thus, leptin inhibits the apoptosis of thymic cells through a mechanism that is independent of the activation of JAK-2 but depends on the engagement of the IRS1/PI3-kinase pathway
Doutorado
Medicina Experimental

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Vakkala, née Mustonen M. (Merja). "Apoptosis in breast lesions". Doctoral thesis, University of Oulu, 2000. http://urn.fi/urn:isbn:9514256506.

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Abstract In this work the extent of apoptosis was studied in a set of 504 benign and malignant breast lesions to elucidate its role in breast tumor development and progression. Also the correlation of apoptosis with estrogen and progesterone receptor positivity, cell proliferation and patients' prognosis was studied. The breast lesions were also analyzed immunohistochemically with antibodies to apoptosis regulating proteins bcl-2 and bax, and caspases 3, 6 and 8. In addition, the immunohistochemical expression of NO• synthesizing enzyme iNOS in relation to apoptosis and angiogenesis was studied. Furthermore, the expression of the antioxidative enzyme MnSOD was studied in relation to apoptosis and cell proliferation. According to the results, the apoptotic index was lowest in benign breast lesions. It was higher in in situ carcinomas, where a gradual increase in the extent of apoptosis from grade I to III in situ carcinoma was seen. The apoptotic index in invasive carcinomas was higher than in in situ carcinomas, and also in invasive carcinomas there was a gradual increase in apoptosis from grade I to III carcinomas. The apoptotic index was highest in recurrent carcinomas. Strong bcl-2 expression was usually found in benign breast lesions but the immunoreactivity decreased in in situ and invasive carcinomas. There was a significant inverse association between bcl-2 immunoreactivity and the extent of apoptosis. Low bcl-2 immunoreactivity also associated with estrogen- or progesterone receptor negativity. In contrast, bax expression did not show any significant association with apoptosis, hormone receptors or the histologic types of tumors. Strong cytoplasmic caspase 3, 6 and 8 immunoreactivity was found in most carcinomas. It was weaker in in situ carcinomas and only weak immunoreactivity could be seen in benign breast lesions. There was a significant association between the extent of apoptosis and caspase immunoreactivity. iNOS expression was found in both tumor and stromal cells. iNOS expression in tumor cells was more frequently found in invasive than in in situ carcinomas. Its expression correlated significantly with a high apoptotic index and high vascularization of the lesion. There was significantly less MnSOD immunoreactivity in invasive breast carcinomas compared to in situ carcinomas or benign hyperplasias. MnSOD immunoreactivity did not associate with the extent of apoptosis, but there was a marginal inverse association between cell proliferation and MnSOD expression. Increased apoptosis was significantly associated with a high cell proliferation, and inversely associated with a positive estrogen status. A high apoptotic index (< 0.50%) was associated with a decreased survival of the patients. The results of this study show that apoptosis plays a decisive role in the development and progression of breast carcinoma. It is influenced not only by apoptosis regulating proteins, such as bcl-2 and caspases, but also by the estrogen receptor status. Apoptosis was also associated with iNOS positivity, the effect of which is mediated through increased NO• production. In line with the suggested role of MnSOD as a tumor suppressor gene, its expression was downregulated in invasive breast carcinoma. In conclusion, the association of apoptosis with patient survival in breast carcinoma may be secondary to its association with tumor cell proliferation and high tumor grade, not necessarily suggesting any causal association between apoptosis and survival.

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Sun, Mei Guo. "Mitochondrial structure during apoptosis". Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3273480.

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Thesis (Ph. D.)--University of California, San Diego, 2007.
Title from first page of PDF file (viewed August 31, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 129-140).

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20

Barnett, Anna L. "Baculovirus inhibitors of apoptosis". Thesis, Oxford Brookes University, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388865.

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21

Cook, Stuart Alexander. "Regulation of cardiac apoptosis". Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393164.

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22

Rossouw, Sophia Catherine. "Apoptosis in Haematopoietic progenitors". Master's thesis, University of Cape Town, 2009. http://hdl.handle.net/11427/3179.

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Introduction: Intracranial pressure (ICP) monitoring is a cornerstone of care for patients with severe traumatic brain injury (TBI). The primary goal of ICP treatment is to preserve brain oxygenation, and since brain oxygenation is usually not measured, the control of ICP is used as a surrogate marker. However studies indicating that cerebral hypoxia/ischemia may occur in the face of adequate ICP and cerebral perfusion pressure (CPP) suggest that the interaction between ICP and brain oxygenation is poorly understood and warrants further investigation. This is of particular importance in the context of children in whom the interpretation of relationships between intracranial factors is even more complex due to changing physiological norms with age. To date little scientific data exists in children and treatment threshold values are often extrapolated from adult guidelines. This study aims to better understand the relationship between ICP and brain oxygenation measured as brain tissue oxygen tension (PbtO2) in a large paediatric cohort suffering from severe TBI. Specifically analysis 1) investigated ICP and PbtO2 profiles over time following TBI, 2) examined the relationship between ICP and PbtO2 from time-linked paired observations, 3) explored various critical thresholds for ICP and PbtO2, and 4) interrogated digital data trends depicting the relationship between ICP and PbtO2. The level of agreement between hourly recorded and high frequency electronic data for ICP and PbtO2 was also evaluated. Method: Paired ICP and PbtO2 data from 75 children with severe TBI were tested with correlation and regression. Additional analyses controlled for mean arterial pressure (MAP), arterial partial pressure of oxygen (PaO2), CPP, arterial partial pressure of carbon dioxide (PaCO2) and haemoglobin (Hb) using multivariate logistic regression analysis and general estimating equations. Various thresholds for ICP were examined; these included age-related thresholds to account for the potential influence of age. Receiver-operating curves (ROCs) were used to graphically demonstrate the relationships between various thresholds of ICP and various definitions of low PbtO2. These were constructed for pooled and individual patient data. Interrogation of electronically recorded data allowed for case illustrations examining the relationship between ICP and PbtO2 at selected time points. Hourly and electronic data were compared using Bland and Altman plots and by contrasting the frequency of ICP and PbtO2 perturbations recorded with each system. 5 Result: Analyses using over 8300 hours of paired observations revealed a weak relationship between ICP and PbtO2, with an initially positive but weak slope (r = 0.05) that trended downwards only at higher values of ICP. Controlling for inter-individual differences, as well as MAP, CPP, PaO2, PaCO2 and Hb did not strengthen this association. This poor relationship was further reflected in the examination of threshold ICP values with ROCs, no singular critical ICP threshold for compromised brain oxygenation was discernible. Using age-based thresholds did not improve this relationship and individual patient ROCs demonstrated inter-individual heterogeneity in the relationship between ICP and PbtO2. However, it was clear that in individual patients ICP did exhibit a strong negative relationship with PbtO2 at particular time points, but various different relationships between the 2 variables were also demonstrated. A high level of agreement was found between hourly and electronic data. Conclusion: These results suggest that the relationship between ICP and PbtO2 is highly complex. Although the relationship in individual children at specific time points may be strong, pooled data for the entire cohort of patients, and even for individual patients, suggest only a weak relationship. This is likely because several other factors affect PbtO2 outside of ICP, and some factors affect both independently of each other. These results suggest that more study should be directed at optimising ICP thresholds for treatment in children. The use of complimentary monitoring modalities may assist in this task. Depending on the adequacy of measures of brain perfusion, metabolism or oxygenation, it is possible that targeting a range of ICP values in individual patients may be appropriate; however this would require detailed investigation.

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Ward, Carol. "Mechanisms regulating granulocyte apoptosis". Thesis, University of Edinburgh, 1999. http://hdl.handle.net/1842/22722.

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Few factors present at inflammatory foci have not been demonstrated to accelerate granulocyte apoptosis; most inhibit the process, adding to the longevity of these cells. The purpose of these studies was to examine the role of different classes of inflammatory mediators in the induction of granulocyte apoptosis and investigate the possible mechanisms involved. We have shown that the majority of pro-inflammatory cytokines inhibit the process of apoptosis in granulocytes. The anti-inflammatory cytokine IL-10 had no effect on granulocyte apoptosis, but in neutrophils, it inhibited the survival effects of LPS. TGF-β, inhibited granulocyte apoptosis but potentiated the pro-apoptotic effects of TNF-α, at early timepoints in neutrophils. Eicosanoids also exert differential effects on granulocyte apoptosis, however prostaglandins of the J series proved to be potent inducers of apoptosis in both cell types. The use of receptor agonists demonstrated that these pro-apoptosis effects may be mediated via a class of intracellular peroxisome proliferator activated receptors (PPARs), for which these prostanoids are ligands. Both TGF-β and PPARs can inhibit the transcription factor nuclear factor-kappa B (NF-κB). Further examination of the role of this transcription factor in granulocyte apoptosis illustrated that it exerts potent survival effects in both neutrophils and eosinophils, and that inhibition of its activation synergistically enhanced the pro-apoptotic response of TNF-α in neutrophils, and induced eosinophils to respond to the pro-apoptotic effects of this cytokine. The data presented strongly support the hypothesis that NF-κB activation is necessary for the survival of granulocytes, and that certain physiological mediators, such as TNF-α, prostaglandins of the J series and the cytokine TGF-β may be involved in the physiological resolution of inflammation, by inhibiting the activity of this transcription factor.

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Toft, Neil John. "MSH2, apoptosis, and carcinogenesis". Thesis, University of Edinburgh, 1998. http://hdl.handle.net/1842/22693.

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Tumour cells which lack DNA mismatch repair are resistant to the cytotoxic effects of DNA methylating agents and Cisplatin. To address whether this resistance is mediated through loss of an MSH2-dependent apoptotic pathway, the apoptotic response of the murine small intestine to DNA methylating agents and Cisplatin was studied. MSH2 was found to play a significant role in the initiation of apoptosis in vivo. The immediate apoptotic response to these agents was p53-dependent in the first 24 hours, however a smaller p53-independent apoptotic response was observed beyond this point. Mice doubly null for both MSH2 and p53 revealed that this delayed p53-indepdnent response was entirely MSH2-dependent. These results demonstrate the existence of a pathway to apoptosis following DNA methylation which is dependent upon both MSH2 and p53. The DNA repair enzyme O⁶-Alkylguanine-DNA-alkyltransferase (AGT), which removes potentially mutagenic methyl groups from guanine residues, was found to play no role in modulating the MSH2-dependeent apoptotic response of intestinal cells to methylating agents or Cisplatin, indicating that the rate of removal of methylated bases is not a major factor in the decision to enter this pathway. O⁶-Benzylguanine, a competitive inhibitor of AGT, prevented the metabolic activation of Dacarbazine probably through the inhibition of cytochrome P450 enzymes. This novel finding has adverse implications towards the potential clinical use of O⁶-Benzylguanine. The data presented in this thesis demonstrate that MSH2 plays a pivotal role in determining both the apoptotic response and mutation frequency of the murine intestine to methylating DNA damage and suggests that the consequences of MSH2-deficiency may be more significant to the initial stages of carcinogenesis that loss of p53.

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Turunen, née Virkajärvi N. (Nina). "Apoptosis and expression of apoptosis-regulating proteins in hepatocellular, gallbladder and pancreatic carcinomas". Doctoral thesis, Oulun yliopisto, 2000. http://urn.fi/urn:isbn:9514255828.

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Abstract Apoptosis is a biochemically regulated mechanism leading to the destruction of an individual cell. An inadequate apoptosis is partly responsible for uncontrolled survival of malignantly transformed cells and formation of cancer. The growth of a tumor depends on the proliferative capacity and destruction of tumor cells either through apoptosis or necrosis. In this work, the extent of apoptosis and the expression of apoptosis-regulating proteins were studied by 3'-end labeling of fragmented DNA (TUNEL) and immunohistochemistry in a set of 166 tissue samples consisting of 33 HCCs, 39 gallbladder carcinomas, 7 gallbladder dysplasias and 87 pancreatic carcinomas. In addition, p53 protein and P-glycoprotein expression was studied immunohistochemically. The extent of apoptosis was estimated by using apoptotic index, defined as a percentage of apoptotic cells in the entire tumor cell population. The present results show an average apoptotic index of 0.73% in HCC, 0.68% in gallbladder and 0.69% in pancreatic carcinoma. Bcl-2 positivity was found in only 3% of the HCCs, 10% of gallbladder and 13% of pancreatic carcinomas. Bax positivity was seen in all of the gallbladder and pancreatic carcinoma cases. Mcl-1 positivity was found in 87% of gallbladder and 86% of pancreatic tumors. The apoptotic index in bcl-2 positive cases was lower (0.35%) than in cases showing no immunoreactivity (0.64%) in pancreatic tumors (P = 0.013). Apoptotic index was higher in pancreatic tumors with strong bax immunoreactivity (0.70%) than in other cases (0.34%) (P = 0.002). Caspase 3, 6 and 8 expression was found in 92%, 92% and 73% of HCC, 95%, 77% and 77% of gallbladder carcinoma and 80%, 80% and 74% of pancreatic carcinoma cases, respectively. p53 positivity was found in 23% of hepatocellular, 57% of gallbladder and 41% of pancreatic carcinomas. P-glycoprotein was observed in 65% of the HCCs. Patients with Pgp positive tumors had a significantly shorter disease-free interval than those with Pgp negative tumors (P < 0.05). To evaluate the growth potential of HCC and pancreatic carcinoma, a growth index from the scores obtained for apoptosis, necrosis and cell proliferation was designed. Patients with a high degree of proliferation relative to the degree of necrosis and apoptosis (i.e. had a positive growth index) in HCC lesions had a significantly shorter survival (P = 0.004) and disease-free interval after operation (P = 0.019) than those with a tumor predominated by apoptosis and necrosis. Results were in line with HCC in pancreatic carcinoma, but the association did not reach statistical significance (P = 0.09). According to the results the extent of apoptosis was similar in HCCs, gallbladder and pancreatic carcinomas. These tumors also showed here a similar expression pattern of the bcl-2 family of proteins and caspases. None of the individual parameters associated significantly with apoptosis except for bcl-2 and bax in pancreatic carcinoma, neither was there any association between p53 and P-glycoprotein expression and apoptosis. Calculation of a growth index might be helpful in assessing the prognosis of patients with tumors with a scant stroma, such as HCC.

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Zhuang, Jianguo. "Biochemical mechanisms of apoptosis : ordering of the biochemical events in chemical-induced apoptosis". Thesis, Open University, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.284375.

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Ruby, Vincent. "Étude des évènements mitochondriaux impliqués dans le contrôle de l'apoptose par rbf1, l'homologue de drosophile du gène suppresseur de tumeur rb". Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLV039/document.

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Le gène rb est le premier suppresseur de tumeur découvert chez l’homme. Il prévient l’apparition de tumeurs notamment en régulant négativement le cycle cellulaire. Le rôle de pRb dans le contrôle de l’apoptose est plus complexe et les mécanismes moléculaires contrôlés par ce facteur de transcription ne sont pas complétement élucidés. Il existe un homologue de rb chez la drosophile : rbf1. J’ai contribué à caractériser les évènements mitochondriaux induits au cours de l’activation de l’apoptose par Rbf1 dans le disque imaginal d'aile, un tissu en prolifération de la larve de drosophile. Dans cette voie d’apoptose, la protéine Debcl, seule membre pro-apoptotique de la famille Bcl-2 chez la drosophile, est activée et induit le recrutement et l’oligomérisation de Drp1, protéine effectrice principale de la fission mitochondriale. C’est ainsi qu’est déclenchée la fragmentation mitochondriale et l’accumulation d’espèces activées de l’oxygène (EAOs) mitochondriales. Ces deux évènements participent à la transmission du signal apoptotique. J’ai par ailleurs pu mettre en évidence l’implication de facteurs participant au maintien du contrôle qualité mitochondriale. Celui-ci s’assure de l’intégrité des mitochondries et, le cas échéant, déclenche la digestion des éléments défaillants par mitophagie. Enfin, j’ai contribué à l’étude des liens entre la traduction et l’apoptose induite par Rbf1. Dans cette étude, nous montrons que la poly-A binding protein (PABP) peut supprimer le phénotype d’encoche induit par Rbf1 chez l’adulte alors que la mort cellulaire induite au cours du stade larvaire n’est pas inhibée mais augmentée. Ces résultats nous ont poussé à étudier les mécanismes de compensation induits par l’appareil traductionnel, ce qui nous a permis de montrer qu'une modulation de la traduction pourrait permettre de compenser la perte de tissu consécutive à l'apoptose induite par Rbf1 sans impliquer une inhibition de l'apoptose
The gene rb is the first tumor suppressor discovered in humans. Its prevents the appearance of tumors by regulating negatively the cell cycle. The role of pRb in apoptosis is more complex and the molecular mechanisms triggered by this transcription factor are not completely elucidated. There is a rb homologue in drosophila: rbf1. I participated in the characterization of mitochondrial events induced during activation of apoptosis by Rbf1 in a proliferating tissue of this model organism, the wing disc. In this apoptosis pathway, the Debcl protein, the only drosophila pro-apoptotic member of the Bcl-2 family, is activated and induces recruitment and oligomerization of Drp1, the main effector of mitochondrial fission. This triggers the mitochondrial fragmentation and the accumulation of mitochondrial reactive oxygen species (ROS). Both events participate to the transmission of the apoptotic signal. I have also been able to highlight the implication of factors involved in maintaining mitochondrial quality control which ensures the integrity of the mitochondria and, if necessary, triggers the degradation of damaged elements by mitophagy. Finally, I have contributed to the study of the links between translation and apoptosis induced by Rbf1. In this study, we show that the Poly-A Binding Protein (PABP) can suppress the Rbf1-induced notch phenotype in adults while cell death induced during larval stage was not inhibited but increased. These results prompted us to study the compensation mechanisms induced by the translational apparatus, which allowed us to show that a mRNA translation-related mechanism could counteract the loss of tissue resulting from Rbf1-induced apoptosis independently of apoptosis inhibition

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Joselin, Alvin Paul. "The role of the apoptosis and splicing associated protein Acinus during apoptotic nuclear changes". [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=982187599.

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Gama, Vivian. "Regulation of the Anti-apoptotic Protein Ku70 and the Implications for Bax-Mediated Apoptosis". Case Western Reserve University School of Graduate Studies / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1221831227.

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30

Rovere, Querini Patrizia. "Clearance of dying cells by antigen presenting and scavenger phagocytes : implications for autoimmunity and tolerance". Thesis, Open University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323272.

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31

Eerola, A. K. (Anna-Kaisa). "Apoptosis and apoptosis regulating proteins and factors in small and large cell lung carcinoma". Doctoral thesis, University of Oulu, 1999. http://urn.fi/urn:isbn:9514254066.

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Abstract Aptosis denotes a biochemically and morphologically distinct chain of events leading to self-destruction of cell. It is pivotal in the maintenance of tissue homeostasis and also plays a role in neoplasm. In this work, the extent of apoptosis and apoptosis regulating proteins and factors was studied in a total of 94 patients operated for lung carcinoma, including 56 small cell lung carcinomas (SCLC) and 38 large cell lung carcinomas (LCLC). The extent of apoptosis was determined by detecting and counting the relative and absolute numbers of apoptotic cells and bodies using 3'- end labelling of the apoptotic DNA. The extent of apoptosis in SCLC was compared with the cell proliferation activity as determined by Ki-67 immunohistochemistry, with the volume density of necrosis and with the occurrence of immunohistochemically detectable p53 and bcl-2 proteins. In order to test the hypothesis that increased apoptotic activity is connected with neuroendocrine differentiation and with low differentiation degree in LCLC and that it is regulated by bcl-2 family proteins, the extent of apoptosis and tumour necrosis was analysed in relation to the expression of bcl-2 family proteins bcl-2, mcl-1, bax and bak. Apoptosis, tumour infiltrating lymphocytes (TILs), and angiogenesis are important factors that contribute to tumour growth. In the present study immunohistochemical methods were used to investigate the relationships of these factors and their role in the prognosis of the patients with LCLC and SCLC. A remarkably high apoptotic activity was detected in both SCLC and LCLC. The mean apoptotic index in SCLC was 2.70 % and in LCLC 2.49 %. Exceptionally high proliferation activity and high percentage of tumour necrosis was seen in SCLC. 58 % of SCLC showed more than 40 % of Ki-67 positive nuclei, and tumour necrosis was seen in 83 % of the cases. P53 protein accumulation was detected in 38 % and bcl-2 expression in 50 % of SCLC. The extent of apoptosis in SCLC was inversely related to tumour necrosis and p53 protein accumulation. In LCLC, bcl-2 expression was detected in 40 % of the cases. It was associated with neuroendocrine differentiation and predicted favourable prognosis of the patients. A high number of T cells and macrophages with a small number of B cells was detected in both SCLC and LCLC. The occurrence of intratumoural cytotoxic CD8 cells was associated with the occurrence of apoptotic bodies in SCLC. The increased number of intratumoural T cells, CD8-positive cells and macrophages predicted favourable prognosis of the patients with SCLC. In LCLC, an increased number of B cells and macrophages, but not T cells, was associated with better survival. Iaddition to tumour cells, numerous apoptotic bodies could also be found within alveolar macrophages within and close to tumour tissue. In order to test whether such cells could be found in sputum smears and if their presence could be utilised as a marker of malignancy in tumour diagnosis, the occurrence of alveolar macrophages with apoptotic bodies (AMWABs) was analysed in 84 sputum samples and 13 broncho-alveolar lavage (BAL) specimens from patients with and without lung carcinoma. AMWABs could be found in cytological samples of the patients with lung carcinoma. In sputum and BAL specimens, enhanced apoptosis, as measured by an increased number of AMWABs reflected and was indicative of malignancy. This was also true for cytological specimens of the patients even when the actual malignant cells were not found. Therefore the AMWABs served as a marker of pulmonary malignancy.

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Gibson, Hilary D. F. "Proteolytic processing of the X-linked inhibitor of apoptosis protein during Fas-mediated apoptosis". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/MQ58456.pdf.

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Garcia, Andréa Fontes [UNESP]. "Mediadores da via intrínseca da morte celular programada relacionados à infecção in vitro pelo herpesvirus bovino tipo 5". Universidade Estadual Paulista (UNESP), 2013. http://hdl.handle.net/11449/121912.

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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
O herpesvirus bovino tipo 5 (BoHV-5) é um α-herpesvirus responsável por uma doença neurológica em bovinos jovens e também, ocasionalmente incriminado em alterações reprodutivas. Apesar de vários estudos descreverem as vias do processo de apoptose induzidos por infecções virais, pertencendo à família Herpesviridae, poucas informações estão disponíveis sobre as vias intrínsecas da morte celular programada em interações entre BoHV-5 e seus hospedeiros. O BoHV-5 foi capaz, no presente estudo, de replicar e de produzir efeitos citopátcos, caracterizados por um aumento e fusão celular, tanto em células mesenquimais como nas epiteliais. Os antígenos virais foram detectados em células infectadas pela reação de imunofluorescência nos períodos pós-infecção (p.i) compreendido 48 à 96 h. De acordo com a observação dos períodos p.i., entre 48 e 72 h sinais intensos de fluorescência foram observados para a proteína anti-apoptótica BCL-2 e comparação à proteína apoptótica Bax. As células infectadas revelaram um aumento do fenótipo BCL-2 entre 48 e 96 h p.i por citometria de fluxo. Entre 48 a 96 h p.i a expressão de RNA mensageiro relacionado a proteína Bax não foi verificada em nenhuma célula infectada. Ao contrário, a expressão do RNA mensageiro relacionado a proteína BCL-2 foi quantificada em Log 10 1,6 x 10 2 cópias de fita complementar de DNA (cDNA) em todos os p.i. O BoHV-5 quando está em fase de replicação nas células mesenquimais parece modular a expressão e respectiva transcrição gênica da proteína BCL-2, no sentido de aumentar a produção de partículas virais
Bovine herpesvirus 5 (BoHV-5) is α-herpesvirus responsible for neurological disease in young cattle and also occasionally incriminated in reproductive disorders.In spite of many studies describing the apoptotic pathways induced by viruses belonging to the family Herpesviridae, scare information about intrinsic programmed cell death pathway in host-BoHV-5 interactions is currently available. BoHV-5 was able to replicate and to produce cytopathology characterized by cellular swelling and cell fusion on both mesenchymal and epithelial cell lines. Viral antigens were detected in infected cells by immunofluorescence assay at 48 to 96 h post-infection (p.i.). According to sequential p.i observation, at 48 to 72 h p.i. higher fluorescent signals were visible for anti-apoptotic BCl-2 antigens in comparison to Bax, considered a proapoptotic protein. Infected cells revealed an increase of BCl-2 phenotype population from 48 to 96 h p.i. by flow cytometric analysis. At 48 to 96 h p.i. Bax mRNA was not expressed among of any infected cell monolayers. In contrast, BCl-2 mRNA was quantified Log10 1,6 x 102 cDNA copies at all p.i. for both cells. BoHV-5 replication seems to modulate BCl-2 expression and respective gene transcription in order to enhance production of progeny virus
FAPESP: 22010/52465-9

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Smith, Mickaela Cardoso Martinez. "Alterações lisossomais e indução de morte celular programada em celulas leucemicas tratadas com paladaciclo". [s.n.], 2006. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308722.

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Orientador: Claudia Bincoletto Trindade
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: Estudos experimentais envolvendo a caracterização fármaco-toxicológica de novos fármacos são de grande importância na pesquisa inicial sobre drogas (ERDAL et al., 2005). Sendo assim, neste projeto um dos nossos objetivos iniciais foi avaliar os possíveis efeitos antineoplásicos de uma nova classe de drogas organometálicas contendo paládio como metal de transição, denominada paladaciclo ferroceno 1:2, utilizando para isto, a linhagem de células leucêmica K562 (leucemia mielóide crônica) e Jurkat (leucemia linfóide aguda). Os valores de IC50% obtidos na linhagem K562 após 72 horas de tratamento com o composto paladaciclo foram 4,1 e 2,9 µM, nos testes de redução do MTT e exclusão por azul de trypan, respectivamente. Através da fragmentação de DNA observamos que o composto foi capaz de induzir apoptose nas células K562 e Jurkat. Aspectos morfológicos de apoptose nestas células também foram confirmados através da coloração de acredine orange visualizadas em microscopia de fluorescência nas células K562. Utilizando acredine orange, um corante que tem a característica de se acumular principalmente em lisossomas secundários de células tumorais, nós também analisamos o mecanismo bioquímico envolvido no processo de morte celular das células K562 induzidas pelo composto paladaciclo. Nossos resultados demonstraram que a expressão dos genes envolvidos no controle da apoptose (Bcl-2 e Bax) em ambas as linhagens celulares tratadas com o paladaciclo é similar ao controle sem tratamento. Por outro lado, o composto em estudo (6,0 µM) induziu a permeabilização da membrana lisossomal de células K562 após 5 horas de tratamento com ativação das caspases efetoras da apoptose 3 e 6. Este processo de ativação das caspases também foi observado após 72 horas de incubação com o paladaciclo. Como a catepsina B está abundantemente presente nos lisossomoas e sua liberação para o citosol é esperada após alterações da permeabilidade da membrana lisossomal, investigamos também a ativação de ambas as caspases, descritas acima, após a incubação das células K562 com um inibidor de catepsina B (CA074) por 2 horas antes da exposição ao paladaciclo (6,0 µM). Este estudo forneceu um resultado bastante interessante, pois demonstrou que a ativação das caspases efetoras da morte celular programada foi prevenida, sugerindo assim que a catepsina B está fortemente associada ao processo apoptótico em células K562. Sendo assim, podemos sugerir que o composto paladaciclo apresenta potencial antileucêmico, merecendo estudos adicionais que comprovem sua eficácia terapêutica
Abstract: Experimental studies involving the pharmaco-toxicogical properties of new drugs are of very importance in its initial development (ERDAL et al., 2005). In this study it was evaluated the possible antileukemic effects of a new organometallic class of drugs called palladacycle ferrocene 1:2, using the K562 and Jurkat leukaemia cell lines. The cell death mechanism of cytotoxicity induced by the Biphosphinic Palladacycle Complex (BPC) was studied using a K562 leukaemia cell line. The IC50% values obtained for K562 cells post 72 h of BPC were less than 5.0 µM by using MTT and trypan blue assays. Complex triggers apoptosis in K562 and Jurkat cells, inducing DNA fragmentation, as analysed through electrophoresis. Using the Acridine Orange (AO) vital staining combining fluorescence microscopy it was confirmed the presence these process in K562 cells. Lysosomal membrane permeabilization was also observed in K562 cells post 5 h of BPC, which suggests intralysossomal accumulation by proton-trapping, previous study, revealed that its pKa value ranged from 5.1 to 6.5. Caspase-3, and -6 activity induced by BPC in K562 cells was prevented by the cathepsin B inhibitor (CA-074). These events occurred in the presence of endogenous Bcl-2 and Bax expression. Taken together, these data suggest a novel lysosomal pathway for BPCinduced apoptosis, in which lysosomes are the primary target and cathepsin B acts as death mediator
Mestrado
Farmacologia
Mestre em Farmacologia

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Marostica, Marta Contieri. "Efeito do tratamento com inibidores de secreção acida na infecção por Helicobacter Pylori em camundongos". [s.n.], 2007. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311373.

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Orientadores: Nelci Fenalti Hoehr, Alessandra Gambero
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: O mecanismo pelo qual o H. pylori provoca a inflamação gástrica inclui a secreção de substâncias pró-inflamatórias pela bactéria e a estimulação da liberação de citocinas induzida pelo contato direto entre a bactéria e as células epiteliais gástricas. A resposta inicial à infecção por H. pylori é predominantemente neutrofílica e estes, liberam mediadores inflamatórios e enzimas proteolíticas que induzem o dano gástrico. Estresse oxidativo ocorre em pacientes infectados com H. pylori onde a expressão de enzimas como a óxido nítrico sintase induzida (iNOS), superóxido dismutase e catalase encontram-se aumentadas. A iNOS participa da resposta inflamatória e promove a apoptose de células na mucosa gástrica. Durante a infecção por H. pylori, observa-se níveis reduzidos da expressão de Bcl-2 e o aumento da expressão de Bax na mucosa gástrica, sugerindo que uma tendência pró-apoptótica na infecção. A erradicação pode ser alcançada pela combinação de antibióticos associada a uma droga anti-ácida. As duas maiores classes de inibidores de secreção ácida são: os inibidores de bomba protônica, como o omeprazol, e os antagonistas de receptor de histamina H2, como a ranitidina. Várias evidências experimentais têm mostrado que o omeprazol apresenta efeitos anti-ulcerogênicos adicionais. Deste modo, o objetivo deste trabalho foi avaliar o efeito do tratamento com omeprazol e ranitidina em um modelo animal de infecção por H. pylori, enfocando possíveis propriedades adicionais destes fármacos Para este estudo foram utilizados camundongos machos C57BL/6 com 4 semanas de idade. Os camundongos receberam por via oro-gástrica suspensão de H. pylori. Na 11ª semana de inóculo, os animais foram tratados (i.p.) com omeprazol (100 mg/kg), ranitidina (100 mg/kg) ou veículo (PBS) durante 7 dias sempre no mesmo horário. As duas drogas inibiram a produção de ácido gástrico no tratamento agudo, porém no tratamento por uma semana, apenas o omeprazol inibiu a secreção ácida. Os animais tratados com omeprazol apresentaram um aumento significativo nos níveis de colonização gástrica e elevado nível de MPO. Ambas as drogas diminuíram as lesões da mucosa provocada pela infecção. O tratamento com omeprazol restaurou a produção de Bcl-2 na mucosa gástrica e não alterou a produção de Bax. O omeprazol não protegeu a mucosa gástrica contra o dano ao DNA gerado pela infecção e o tratamento com ranitidina aumentou os níveis de dano oxidativo ao DNA. Não observamos a presença de propriedades anti-neutrofílicas, atribuídas ao omeprazol, após uma semana de tratamento, sugerindo que essas propriedades são restrita a ensaios in vitro. Entretanto, o omeprazol restaurou a produção de Bcl-2 na mucosa gástrica, sugerindo uma atividade anti-apoptótica dessa droga
Abstract: H. pylori induces gastric inflammation characterized by secretion of pro-inflammatory substances by bacteria and the stimulation of cytokine release by the gastric epithelial cells. The initial response to the H. pylori infection is predominantly by neutrophils and these cells liberate inflammatory mediators and enzymes that induce the gastric damage. Oxidative stress also occurs in infected patients where induced nitric oxide sintase (iNOS), superoxide dismutase and catalase expression were increased. Nitric oxide participates in the inflammatory response and promotes apoptosis of gastric mucosa cells. Eradication therapy can be achieved with antibacterial agents in association with anti-acid drugs. There are two major classes of gastric acid inhibitors: the proton pump inhibitors, such as omeprazole, and the histamine H2 receptor antagonists, such as ranitidine. Some experimental evidence demonstrates that omeprazole has additional pharmacological properties. Thus, the aim of this study was to evaluate the effect of omeprazole and ranitidine treatment on H. pylori-infected mice, focusing on possible additional pharmacological properties. For this study, male C57BL/6 mice that received H. pylori suspension were used. After the 11th week, the mice were treated intraperitoneally (i.p.) with omeprazole (100 mg/kg), ranitidine (100 mg/kg) or vehicle (PBS) for 7 days. Both drugs inhibited the gastric acid production after acute administration; however after one week of treatment just omeprazole inhibited gastric acid secretion. Omeprazole-treated mice presented an increase in H. pylori and MPO levels in gastric mucosa. Both drugs reduced the mucosa damage provoked by H. pylori infection. Omeprazole treatment restored the Bcl-2 production in the gastric mucosa and did not modify Bax production. Omeprazole did not reduce the DNA damage in the gastric mucosa while ranitidine treatment increased it. We conclude that some additional omeprazole-related properties, such as antineutrophil properties, were not observed in H. pylori-infected mice after one week of treatment. However, the antiapoptotic activity of omeprazole could be attributed to an ability to modify the protein expression of Bcl-2, decreased by H. pylori infection
Mestrado
Patologia Clinica
Mestre em Ciências Médicas

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Moraes, Juliana Contin. "Apoptose de neuronios hipotalamicos em ratos alimentados com dieta hiperlipidica". [s.n.], 2009. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310358.

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Orientador: Licio Augusto Velloso
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: Durante as últimas décadas tem se observado um aumento surpreendente na prevalência de obesidade e diabetes mellitus em populações de várias regiões do mundo, inclusive no Brasil. Medidas terapêuticas baseadas em mudanças de hábito alimentar e estilo de vida têm se mostrado ineficazes para conter o avanço destas epidemias. Somente a completa caracterização dos mecanismos fisiopatológicos envolvidos no desenvolvimento de ambas as condições deverão apontar potenciais alvos para o desenvolvimento de fármacos mais efetivos e de medidas profiláticas mais eficientes. Diversos estudos epidemiológicos apontam o consumo de dietas ricas em lípides como um dos mais importantes fatores de risco para o desenvolvimento de obesidade e diabetes. Em estudo recente realizado por nosso grupo, verificamos por macroarray de cDNA que em hipotálamo de ratos alimentados com dieta hiperlipídica há um aumento na expressão de genes de codificam proteínas participantes de respostas pró-inflamatórias como TNF-?, IL-2, IL-6 e IL-1?. Além disso, ao realizarmos avaliação histológica da expressão de citocinas como TNF-?, no hipotálamo, observamos que o número de neurônios hipotalâmicos estava aparentemente reduzido nos animais tratados com dieta hiperlípidica. Como muitas destas citocinas pró-inflamatórias podem ativar vias apoptóticas decidimos investigar a ocorrência de apoptose de neurônios em ratos alimentados com dieta hiperlípidica, sendo este o objetivo principal do presente trabalho. Utilizando real-time PCR, TUNEL, imunohistoquímica, imunoblot, e microscopia eletrônica de transmissão, observamos que neurônios do hipotálamo são alvos de apoptose. As sub-populações de neurônios preferencialmente afetadas dependem do background genético do animal, de tal forma que em animais com baixa predisposição para obesidade, tanto neurônios orexigênicos como anorexigênicos são igualmente afetados, enquanto que em cepas com maior predisposição para obesidade, neurônios anorexigênicos são alvos principais da apoptose. Por fim, revelamos que a presença de receptores TLR4 íntegros protegem neurônios da apoptose, sugerindo que essa via de sinalização do sistema imune inato tem papel duplo, participando da indução de inflamação, mas ao mesmo tempo protegendo neurônios de danos irreversíveis. Acreditamos que tais estudos possam contribuir para que se obtenham avanços na caracterização da fisiopatologia da obesidade e da participação de fenômenos nutricionais e inflamatórios na regulação funcional do centro regulador da fome e da termogênese
Abstract: Obesity and diabetes have reached epidemic proportions in several regions of the world. General changes in life-style, including consumption of fat-rich diets, are amongst the most important factors leading to an unprecedented increase in the prevalence of these diseases. The complete characterization of the pathophysiological mechanisms leading to obesity and diabetes may disclose potential targets for the development of specific drugs and development of better prophylactic approaches. Recent work has shown that the consumption of a fat-rich diet for 16 weeks leads to the increased expression of pro-inflammatory cytokines in the hypothalamus, which is accompanied by an apparent reduction in the numbers of neurons in this region. Because many of these cytokines can activate apoptotic pathways we decided to investigate the presence of apoptosis in neurons from rats fed on high-fat diet. Using real-time PCR, TUNEL, immunoblot, immunohistochemistry and transmission electron microscopy we observed increased apoptosis of neurons of the hypothalamus. The subpopulations preferentially affected depend on genetic background. Thus, in a strain genetically protected from obesity, apoptosis affects both, orexigenic and anorexigenic neurons, while in an obesity-prone strain, the anorexigenic neurons are preferentially affected. In addition, we observed that the presence of an intact TLR4 expression protects against apoptosis, suggesting that this receptor of the innate immune system plays a dual role, participating in the activation of an inflammatory response and protecting against further neuronal damage. We believe the present data will contribute to unveil some the pathophysiological mechanisms involved in the development of obesity and the roles played by nutritional and immunological factors in this context
Doutorado
Ciencias Basicas
Doutor em Clínica Médica

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Cândido, Larissa Ananias. "Investigação dos mecanismos de resistência ao tratamento com halofuginona em leucemia mieloide aguda". Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/17/17147/tde-06012017-164157/.

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A leucemia mieloide aguda (LMA) compreende um grupo heterogêneo de doenças hematológicas caracterizadas pela expansão clonal de células mieloides imaturas que apresentam diferentes tipos de alterações genéticas e epigenéticas. O diagnóstico requer a identificação de infiltração da medula óssea e/ou sangue por blastos mieloides leucêmicos em frequência igual ou superior a 20% das células nucleadas. Os tratamentos mais frequentemente empregados para a LMA englobam o uso de quimioterapia convencional com uso de citarabina e antraciclinas, bem como agentes imunoterápicos. Embora a pesquisa da biologia da LMA tenha levado ao desenvolvimento de novos agentes direcionados a alvos específicos como as mutações em FLT3, faltam avanços para os pacientes com outras leucemias que não a leucemia promielocítica aguda (LPA). A halofuginona (HF) é um derivado halogenado de febrifugina, que possui propriedades antifibróticas, anticancerígenas, antiinflamatórias e pró-apoptóticas. No presente estudo, avaliamos a indução de apoptose pela HF nas linhagens de LMA Kasumi-1,THP-1, MV4-11, U937 e OCI-AML3, verificando a sensibilidade ao tratamento. Verificamos que a linhagem Kasumi-1 foi sensível à atividade pró-apoptótica da HF exibindo dose efetiva 50 DE50 de 125,58 ng/ml, e que as células THP-1 foram resistentes exibindo DE50 de 786,15 ng/ml. As células Kasumi-1 sofreram diminuição significativa da percentagem de células na fase S do ciclo celular, enquanto que as percentagens de células THP-1 em qualquer das fases analisadas não se alterou em comparação às amostras controles tratadas com veículo. Usando a metodologia de Western Blot, foi detectada a ativação da via das caspases com aumento da clivagem de caspase 3 após 3 horas de incubação com HF nas amostras de células Kasumi-1 e após 12 horas para as células THP-1. Bandas correspondentes a forma clivada de PARP foram identificadas em amostras de células Kasumi-1 após 12 horas de tratamento e nas amostras de células THP-1 após 3 horas de tratamento. Usando a metodologia de Proteome Profiler TM Array - HumanPhospho-Kinase Array para rastreio de proteinas fosforiladas pelo tratamento com HF, detectamos que houve modulação de 3 proteínas diferencialmente para as duas linhagens, 9 proteínas moduladas exclusivamente nas células Kasumi-1 e 6 exclusivamente nas células THP-1 . Entre as alterações mais relevantes, destacamos a diminuição da fosforilação de Stat3 e Stat5 nas células Kasumi-1 e a diminuição das formas fosforiladas de p53 nas células THP-1. Nossos achados confirmam o efeito pró-apoptótico da HF, sobretudo nas células Kasumi-1, e sugerem que este efeito envolva a diminuição das fosforilações de Stat3 e de Stat5.
Acute myeloid leukemia (AML) is a heterogeneous hematological disorder characterized by the clonal expansion of immature myeloid cells exhibiting different types of genetic and epigenetic alterations. A diagnosis is established when a patient presents >= 20% of blast in the bone marrow or in the peripheral blood. The WHO classifies AML in seven subtypes depending on the morphology, immunophenotype, genetics and clinical presentation of the cells. The most common treatment until nowadays is chemotherapy in combination with cytarabine and anthracycline and furthermore also the application of immunotherapeutic agents. Although researchers have attempted to develop new agents targeting directly specific mutations such as FLT3, further studies are necessary to find new therapeutic approaches for other leukemic subtypes aside from acute promyelocytic leukemia (APL). Halofuginone (HF) is a halogenated derivate of Febrifugine, which is a molecule isolated from the plant Dichroa febrifuga. It has been demonstrated that Halofuginone exhibits antifibrotic, anti-cancerogenic, anti-inflammatory and pro-apoptotic properties. We evaluated the induction of apoptosis of HF in the AML cell lines Kasumi-1,THP-1, MV4-11, U937 e OCIAML3, we verified the sensitivity and resistance of these cell lines after treatment, performed a cell cycle analysis, analyzed the activation of proteins associated with apoptosis and the proteins associated with cell proliferation and survival. We established that the Kasumi-1 cell line was sensitive to the treatment of HF displaying a dose IC50 of 125, 58 ng/ml, while the THP-1 cell lines presented resistance displaying a dose IC50 of 786,15 ng/ml . When treated with HF, the Kasumi-1 cell line stopped in the S phase of the cell cycle displaying significant decrease of proliferation, while HF showed no significant on THP-1. Furthermore we performed a western blot and It was demonstrated that the cleavage of caspase 3 appeared after 3 hours of treatment in Kasumi-1 and after 12 hours of treatment in THP-1, while cleavage of caspase 9 appeared after 12 hours in both cell lines. PARP was cleaved in Kasumi-1 after 12 hours of HF treatment, whereas the cleavage of PARP in THP-1 remained the same after 3 hours of treatment. Performing the methodology of Proteome Profiler TM Array - HumanPhospho-Kinase Array we detected 3 proteins modulated in both cell lines, 9 proteins were modulated only in Kasumi-1 cells and 6 in THP-1 cells. Amongst the different tyrosine kinases and signaling pathways that were modulated, we observed that the phosphorylation of Stat3 and Stat5 was diminished in Kasumi-1, while THP-1 presented iii decreased phosphorylation of p53. Our findings confirm that HF exhibits pro-apoptotic effect on Kasumi-1 and is capable of modulating the various proteins important for cell survival.

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Massarotto, Giovana. "Mirtilo, gênero Vaccinium, cv. Misty cultivado no Brasil : caracterização química e atividade citotóxica em células de mamíferos". reponame:Repositório Institucional da UCS, 2014. https://repositorio.ucs.br/handle/11338/945.

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O mirtilo é um fruto originário da região sul dos Estados Unidos, caracterizada pela presença de clima temperado e foi introduzido no Brasil a partir dos anos 1980. Atualmente, Vacaria (RS) é a cidade com maior produção do fruto no Brasil, isso se dá principalmente pela localização geográfica montanhosa numa região de clima bastante frio, nos Campos de Cima da Serra. Os mirtilos são conhecidos por serem ricos em antocianinas, substância localizada na casca do fruto e que está associada à importante atividade antioxidante, com redução do risco cardiovascular, atividade anti-inflamatória e antitumoral. Neste estudo, buscou-se caracterizar quimicamente os extratos hidroalcóolicos obtidos do fruto inteiro e das frações da casca e polpa do fruto e do extrato metanólico do fruto inteiro de mirtilo da cultivar Misty, do grupo Southern Highbush por cromatografia líquida acoplada a espectrômetria de massas (GC-MS) com fonte de electrospray de alta resolução, acoplada a espectrômetro de massas (ESI-QTOF MS/MS) em modo negativo e positivo. A identificação química confirmou a presença de antocianinas nas amostras de casca e fruto inteiro dos extratos hidroalcóolico e metanólico, sendo encontrados derivados da delfinidina, cianidina, peonidina, petunidina e malvidina, além de compostos polifenólicos como ácido clorogênico, quercetinas, proantocianidinas na polpa do extrato hidroalcóolico e no fruto inteiro dos extratos hidroalcóolico e metanólico. Todos os extratos analisados apresentaram menor citotoxicidade na linhagem não tumoral (MRC-5) e seletividade para linhagens tumorais (Hep-2, HeLa, HT-29), sendo que verificou-se menor atividade no extrato obtido da polpa em relação as demais amostras. Observou-se uma redução importante na viabilidade celular em linhagens tumorais com aumento do tempo de exposição (de 24h para 72h) ao extrato metanólico do fruto inteiro. Indução de apoptose foi observada após 24h e 72h de exposição aos extratos hidrolcóolico e metanólico por coloração de laranja de acridina e brometo de etídio, em que a maioria das linhagens tumorais apresentaram-se em estágios finais do processo de apoptose e necrose. A partir desses resultados, sugere-se que o extrato de mirtilo da cultivar Misty possui atividade biológica em células tumorais, porém mais estudos são necessários com a finalidade de entender os mecanismos envolvidos na citotoxidade e comprovar a eficácia dessa espécie como possível agente antitumoral.
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, CAPES.
The blueberry is originally from southern United States which is, characterized by a temperate climate. It was subsequently introduced in Brazil in, 1980. Currently, Vacaria (RS) is the city with the largest fruit production in Brazil, this is mainly because of its geographic region of very cold weather in the mountains, in Campos de Cima da Serra. Blueberries are known to be rich in anthocyanins, a substance found in the skin of the fruit and is associated with significant antioxidant activity with cardiovascular risk reduction, anti-inflammatory activity and antitumor. Hydroalcoholic extracts of whole fruit and skin and pulp fractions of the fruit and the methanol extract of the whole fruit of fruits blueberry of the cultivar Misty were chemically characterized by gas chromatography-mass spectrometry (GC-MS) and high-resolution electrospray ionization mass spectrometry (ESI-HRMS) in negative mode. The chemical identification confirmed the presence of anthocyanins in samples of whole fruit and skin of methanolic and hydroalcoholic extracts, delphinidin, cyanidin, petunidin, malvidin being found, and polyphenolic compounds such as chlorogenic acid, quercetins, proanthocyanidins in the pulp of the hydroalcoholic extract and the whole fruit of the hydroalcoholic and the methanol extract. All the extracts analyzed showed lower cytotoxicity in non-tumor cell line (MRC-5) and selectivity to tumor cell lines (Hep-2, HeLa, HT-29), with less activity in the extract from the pulp in relation to the other samples analyzed. An important decrease in cell viability in tumor cell lines was observed when increasing time of exposure (from 24h to 72h) using methanol extract of the whole fruit. Induction of apoptosis was observed after 24h and 72h exposure to ethanol and methanol extract by ethidium bromide and acridine orange staining, where the majority of tumor lines showed increase in percentage at late apoptosis stages and necrosis. The results here observed suggests that the extract of blueberry, Misty cultivar, presents biological activity in tumor cell lines, but further studies are needed to understand the mechanisms involved in cytotoxicity and evaluate the effectiveness of these species as possible antitumor agent are necessary.

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Garcia, Andréa Fontes. "Mediadores da via intrínseca da morte celular programada relacionados à infecção in vitro pelo herpesvirus bovino tipo 5 /". Araçatuba :, 2013. http://hdl.handle.net/11449/121912.

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Orientador: Tereza Cristina Cardoso Silva
Co-orientador: Fábio Erminio Mingatto
Banca: Vera Cláudia Lorenzetti Magalhaes Curci
Banca: Roberto Gameiro de Carvalho
Banca: Mário Jefferson Quirino Louzada
Resumo: O herpesvirus bovino tipo 5 (BoHV-5) é um α-herpesvirus responsável por uma doença neurológica em bovinos jovens e também, ocasionalmente incriminado em alterações reprodutivas. Apesar de vários estudos descreverem as vias do processo de apoptose induzidos por infecções virais, pertencendo à família Herpesviridae, poucas informações estão disponíveis sobre as vias intrínsecas da morte celular programada em interações entre BoHV-5 e seus hospedeiros. O BoHV-5 foi capaz, no presente estudo, de replicar e de produzir efeitos citopátcos, caracterizados por um aumento e fusão celular, tanto em células mesenquimais como nas epiteliais. Os antígenos virais foram detectados em células infectadas pela reação de imunofluorescência nos períodos pós-infecção (p.i) compreendido 48 à 96 h. De acordo com a observação dos períodos p.i., entre 48 e 72 h sinais intensos de fluorescência foram observados para a proteína anti-apoptótica BCL-2 e comparação à proteína apoptótica Bax. As células infectadas revelaram um aumento do fenótipo BCL-2 entre 48 e 96 h p.i por citometria de fluxo. Entre 48 a 96 h p.i a expressão de RNA mensageiro relacionado a proteína Bax não foi verificada em nenhuma célula infectada. Ao contrário, a expressão do RNA mensageiro relacionado a proteína BCL-2 foi quantificada em Log 10 1,6 x 10 2 cópias de fita complementar de DNA (cDNA) em todos os p.i. O BoHV-5 quando está em fase de replicação nas células mesenquimais parece modular a expressão e respectiva transcrição gênica da proteína BCL-2, no sentido de aumentar a produção de partículas virais
Abstract: Bovine herpesvirus 5 (BoHV-5) is α-herpesvirus responsible for neurological disease in young cattle and also occasionally incriminated in reproductive disorders.In spite of many studies describing the apoptotic pathways induced by viruses belonging to the family Herpesviridae, scare information about intrinsic programmed cell death pathway in host-BoHV-5 interactions is currently available. BoHV-5 was able to replicate and to produce cytopathology characterized by cellular swelling and cell fusion on both mesenchymal and epithelial cell lines. Viral antigens were detected in infected cells by immunofluorescence assay at 48 to 96 h post-infection (p.i.). According to sequential p.i observation, at 48 to 72 h p.i. higher fluorescent signals were visible for anti-apoptotic BCl-2 antigens in comparison to Bax, considered a proapoptotic protein. Infected cells revealed an increase of BCl-2 phenotype population from 48 to 96 h p.i. by flow cytometric analysis. At 48 to 96 h p.i. Bax mRNA was not expressed among of any infected cell monolayers. In contrast, BCl-2 mRNA was quantified Log10 1,6 x 102 cDNA copies at all p.i. for both cells. BoHV-5 replication seems to modulate BCl-2 expression and respective gene transcription in order to enhance production of progeny virus
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Cornélio, Ana Lívia Gomes. "Citotoxicidade e ação antimicrobiana do cimento Portland associado a diferentes agentes radiopacificadores /". Araraquara : [s.n.], 2011. http://hdl.handle.net/11449/90397.

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Orientador: Juliane Maria Guerreiro Tanomaru
Banca: Fernanda de Freitas Anibal
Banca: Joni Augusto Cirelli
Resumo: A proposta deste estudo foi investigar a citotoxicidade, ação antimicrobiana e pH do cimento Portland puro (CP) e associações com agentes radiopacificadores: óxido de bismuto (CPBi), óxido de zircônio (CPZir), tungstato de cálcio (CPCa). Para avaliar o potencial citotóxico, foram empregadas linhagens celulares de fibroblastos do ligamento periodontal de camundongos (mPDL) e osteosarcoma de ratos (ROS 17/2.8). Ambas foram expostas por 24 horas a diferentes concentrações do CP fresco, CP associado com radiopacificadores e cimento de óxido de zinco eugenol. Peróxido de hidrogênio foi aplicado como controle positivo para apoptose. A viabilidade após incubação com os cimentos foi avaliada pela atividade da enzima desidrogenase mitocondrial. A morfologia celular foi analisada microscopicamente pelo corante violeta de cresilo, e o mecanismo de morte celular foi determinado pela metodologia de laranja de acridina/brometo de etídio. Os dados foram analisados estatisticamente por ANOVA e Tukey post-test (p<0.01). A correlação entre os dois tipos de morte celular e valores de pH foi estabelecido pela correlação linear de Pearson. O ensaio da enzima desidrogenase mitocondrial revelou um padrão significante de morte celular apenas nas altas concentrações dos eluídos de cimento. CP puro não foi citotóxico, mesmo na alta concentração de 100mg/ml. As imagens microscópicas mostraram que nenhuma das formulações de CP causaram danos as linhagens celulares. Análises estatísticas dos dados de apoptose/necrose demonstram que CP e CP mais agentes radiopacificadores promoveram morte por necrose estatisticamente significativa apenas em 100mg/ml. Os resultados mostraram que CP associado com óxido de bismuto, óxido de zircônio ou tungstato de cálcio não foram citotóxicos para mPDL ou ROS 17/2.8, e podem ser boas... (Resumo completo, clicar aesso eletrônico abaixo)
Abstract: The purpose of this study was to investigate the cytotoxicity, antimicrobial and pH of pure Portland cement (PC), and associations with radiopacifier agents: bismuth oxide (CPBi), zirconium oxide (CPZir), calcium tungstate (CPCA). To assess the potential cytotoxicity, fibroblast cell lines from the periodontal ligament of mice (mPDL) and rat osteosarcoma (ROS 17/2.8) were used. Both were exposed for 24 hours with different concentrations of fresh PC, PC associated with radiopacifiers and eugenol zinc oxide cement. Hydrogen peroxide was used as a positive control for apoptosis. The viability after incubation with the cements was evaluated by mitochondrial dehydrogenase enzyme activity. Cell morphology was examined microscopically by cresyl violet stain, and the mechanism of cell death was determined by the method of acridine orange / ethidium bromide. The data were statistically analyzed by ANOVA and Tukey post-test (p <0.01). The correlation between the two types of cell death and pH values was established by Pearson linear correlation. The mitochondrial dehydrogenase enzyme assay revealed a significant pattern of cell death only at high concentrations of the eluted cement. Pure PC was not cytotoxic, even at high concentration of 100mg/ml. Microscopic images showed that none of the formulations of PC caused damage cell lines. Statistical analysis of apoptosis/necrosis data showed that PC and PC plus radiopacifiers agents promoted death by necrosis statistically significant only at 100mg/ml. The results showed that PC associated with bismuth oxide, zirconium oxide or calcium tungstate were not toxic to ROS 17/2.8 or mPDL, and may be good alternatives as radiopacifier agents. The antimicrobial and pH of Portland cement and radiopacifier agents were evaluated. For antimicrobial activity agar diffusion was... (Complete abstract click electronic access below)
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41

Kogianni, Georgia. "Biological significance of osteocyte apoptosis". Thesis, University of Edinburgh, 2004. http://hdl.handle.net/1842/24788.

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Work in this thesis has focused on identifying a biological role for the incidence of osteocyte apoptosis, the identity of osteocyte-derived resorption targeting signals and addresses the design of methods of blockade of the excess apoptosis observed during the use of glucocorticoids. An early event in the bone resorption process is the clearance of osteoblasts; hence I have studied the effects of osteocyte apoptotic bodies on osteoblastic cells. Apoptotic bodies derived from different cell types were also used to determine behavioural responses in osteoblast and other potential target cells. Osteoblasts were shown to undergo apoptosis upon contact with osteocyte apoptotic bodies, while apoptotic products derived from different cell types, did not induce osteoblast death. Furthermore, target cells other than osteoblasts, did not undergo apoptosis in the presence of osteocyte or other cell type apoptotic products. These data indicated a specific role for osteocyte apoptosis in the bone microenvironment that might be directing the behaviour of osteoblasts in the bone remodelling process. In addition, the demonstration of phenotypic specificity in the apoptotic body-derived signals points to a further level of physiological “meaning” to apoptosis. The physical interaction of apoptotic osteocytes with osteoblasts and the resultant osteoblast death were dependent t on membrane changes in the apoptotic body and appeared to involve the phagocytic receptors CD14 and scavenger receptor A as evidenced by using gene knockout animal models. Having identified an important potential role for apoptotic osteocytes in targeting osteoblast removal at sites of remodelling, mechanisms that could interfere with the induction of osteocyte apoptosis in response to Dexamethasone were investigated. Dexamethasone-induced apoptosis was associated with activation of the Fas death receptor and ERK1/2 pathways. Bisphosphonates suppressed the pro-apoptotic stimuli, independently of their detailed structure and their in vivo anti-resorptive potency. These data suggested that bisphosphonates could provide therapeutic approaches against excess osteocytic death observed in glucocorticoids-induced osteoporosis in order to maintain a balance between osteocyte viability and death, which might ultimately lead to stabilised bone turnover activity and better bone quality.

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Dewson, Grant. "Regulation of human eosinophil apoptosis". Thesis, University of Leicester, 2001. http://hdl.handle.net/2381/29380.

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Eosinophils play a pivotal role in the pathogenesis of asthma and allergic disease. The accumulation and persistence of eosinophils at sites of inflammation are mediated at least in part by the extended survival of eosinophils in response to circulating hematopoietins IL-3, IL-5 and GM-CSF. The apoptosis and subsequent clearance of eosinophils without histotoxic mediator release is thought to be crucial in the resolution of airway inflammation in asthma. This study characterised the morphological and biochemical events of human eosinophil apoptosis in vitro and investigated the mechanism by which IL-5 induces eosinophil survival. Peripheral blood eosinophils have a distinct expression profile of Bcl-2 homologues, critical regulators of apoptosis, with detectable expression of pro-apoptotic family homologues Bax, Bcl-xs, Bim, Bak, Bid, and Bad, and anti-apoptotic homologue Bcl-xL, with little or no detectable Bcl-2 expression. Stimulation with IL-5 induced modest upregulation of Bcl-2 mRNA and protein, with no significant modulation of the other Bcl-2 homologues examined. Caspases are the conserved executioners of the apoptosis. Eosinophils endogenously expressed 'initiator' caspase-8 and -9, and 'effector' caspase-3, -6, and -7. Spontaneous eosinophil apoptosis involved caspase-independent translocation of Bax to the mitochondria, resulting in perturbation of the mitochondrial membrane, cytochrome c release, and subsequent activation of caspase-3, -6, -7, -8, and -9. IL-5 inhibited constitutive eosinophil apoptosis at a site upstream of Bax translocation to the mitochondria, thereby preventing cytochrome c release and caspase activation. Eosinophils constitutively expressed the conformationally active form of Bax diffusely in the cytosol, but predominantly in the nucleus. Apoptosis induced by Fas receptor ligation involved detectable activation of caspase-3 and -8, and caspase-dependent Bax translocation to the mitochondria, supporting classification of eosinophils as a Type II cell in terms of apoptotic control. The data implicate Bax and mitochondria as pivotal regulators of eosinophil apoptosis in response to diverse stimuli.

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King, Diane. "Apoptosis in chronic lymphocytic leukaemia". Thesis, University of Leicester, 2000. http://hdl.handle.net/2381/29360.

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B cell chronic lymphocytic leukaemia (B-CLL) is the most common adult leukaemia in the western world. The disease is characterised by the accumulation of a CD5+ B cell clone. Drug resistance is a major problem in B-CLL and complete remissions are uncommon. The lymphoaccumulative nature of B-CLL implies that dysregulation of the apoptotic process may be responsible for the development and progression of the disease. B-CLL cells were freshly isolated from patients, and an in vitro apoptosis sensitivity assay was developed using flow cytometric techniques. Initial studies confirmed the existence of 'spontaneous apoptosis' when B-CLL cells were cultured in vitro, and demonstrated a strong correlation between sensitivity to spontaneous apoptosis and sensitivity to apoptosis induced by the chemotherapeutic drug chlorambucil in vitro. Immunoblotting of chlorambucil and prednisolone treated B-CLL cells demonstrated the expression and activation of caspases -3, -7, and -8 in all samples analysed, whilst activation of caspase-2 was seen in cells from only one patient. Activation of caspases -3 and -7 was accompanied by the proteolysis of the DNA repair enzyme, poly (ADP-ribose) polymerase (PARP). Induction of apoptosis and activation of all the caspases was inhibited by the cell permeable caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone (Z-VAD.fmk). These results demonstrated a key role for the activation and processing of caspases in the execution phase of apoptosis in B-CLL cells. The B cell growth factors interleukin-4 and CD40 were demonstrated to strongly influence survival of B-CLL cells in in vitro culture, and also to modulate the response of the cells to chemotherapeutic drugs. Investigations into Fas induced apoptosis in B-CLL cells demonstrated the expression of the adapter protein, FDD, but no overexpression of the capase-8 inhibitory protein, c-FLIP. Additionally, B-CLL cells did not show rapid assembly of the death inducing signalling complex (DISC) in response to stimulation of Fas receptor, implying that these cells may preferentially utilise the Bcl-2-inhibitable Type II (mitochondrial) pathway of apoptosis induction, underlining the important role that Bcl-2 plays in determining the apoptotic sensitivity of B-CLL cells.

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Dimberg, Lina. "Apoptosis Regulation in Multiple Myeloma". Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7099.

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Wolbers, Floor. "Apoptosis chip for drug screening". Enschede : University of Twente [Host], 2007. http://doc.utwente.nl/57881.

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Marani, Michela. "Targeting apoptosis for cancer therapy". Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404985.

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Johnson, Timothy Scott. "Transglutaminase apoptosis and tumour progression". Thesis, Nottingham Trent University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283035.

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Hegyi, Laszlo. "Macrophage apoptosis and human atherosclerosis". Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627017.

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Chan, Ching Wan. "Apoptosis in breast cancer cells". Thesis, University of Bristol, 2004. http://hdl.handle.net/1983/8971525c-0de9-4e21-9677-ab73d61ae65c.

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Luccarelli, James. "Small Molecule Modulators of Apoptosis". Thesis, Harvard University, 2017. http://nrs.harvard.edu/urn-3:HUL.InstRepos:32676118.

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Control of cell survival relies on a delicate balance between pro-apoptotic and anti-apoptotic signalling. In humans, the key regulatory proteins are those of the BCL-2 family, which include effector proteins such as BAX and BAK, anti-apoptotic proteins including BCL-2 and MCL-1, and pro-apoptotic proteins including BID and BIM. Dysregulation of apoptosis is among the Hallmarks of Cancer, and modulation of apoptosis holds promise as an effective therapeutic strategy for a range of malignancies. This thesis advances new strategies for modulating apoptosis using small molecules. The first section explores the properties of stapled peptides. These molecules incorporate two non-natural amino acids with olefin sidechains that are then covalently linked. The resulting “staple” modifies the biophysical properties of the molecule. This chapter shows how stapling results in greater serum stability of the peptides, improves binding affinity for anti-apoptotic targets, and allows for facile transformation of a native sequence into an improved peptide, as demonstrated by stapling a SOS1 peptide to target KRAS. The second section targets MCL-1, an antiapoptotic BCL-2 family protein that has emerged as a major pathogenic factor in human cancer. MCL-1 bears a surface groove whose function is to sequester the BH3 killer domains of proapoptotic BCL-2 family members, but successful drugging of this groove has not been achieved. This chapter develops an alternative strategy using a small molecule that covalently modifies C286 at a novel interaction site distant from the BH3-binding groove. This allosteric mechanism results in reduced BH3 binding capacity of MCL-1 and impairs the oncogenic anti-apoptotic activity of the protein. The final chapter targets BAX, a critical executioner protein in the apoptotic pathway whose oligomerization causes permeabilization of the mitochondrial outer membrane. Using STD-NMR, a library of nearly 1,000 fragments was screened for binding to full-length BAX. This resulted in the discovery of a compound BIF-44 that sensitizes BAX by engaging a noncanonical hydrophobic pocket formed by the junction of the α3-α4 and α5-α6 hairpins. Biochemical and structural analyses indicate that the molecule sensitizes BAX by allosterically mobilizing the α1-α2 loop, a mechanism implicated in the initiation of BH3-mediated direct BAX activation. The identified compound thus informs the mechanism for initiation of BAX activation, and provides a new opportunity to reduce the apoptotic threshold for potential therapeutic benefit.

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