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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
21

Estudo dos efeitos da terapia fotodinâmica na progressão tumoral e em modelos celulares  tridimensionais / Study of the effects of photodynamic therapy on tumor progression and in three-dimensional cellular models.

Barbugli, Paula Aboud 05 May 2010 (has links)
O melanoma maligno é o tipo de câncer de pele com pior prognóstico, devido à sua elevada probabilidade de causar metástases. Atualmente existem poucos tratamentos efetivos para o tratamento do melanoma, sendo que a sobrevida de pacientes que apresentam metástases é muito baixa, em torno de 8 meses, sendo que as taxas de cura nestas condições não ultrapassam 1%. A terapia fotodinâmica (TFD) é uma modalidade terapêutica seletiva e não invasiva, que vem demonstrando excelentes resultados clínicos no tratamento de tumores de pele do tipo não melanoma, como carcinoma espino e basocelular. O trabalho em questão aborda a efetividade da TFD, em linhagens humana de melanoma em diferentes fases de progressão da neoplasia, desde os estágios iniciais da doença (células de crescimento radial - RGP), até a fase metastática, não só em cultura de células em monocamada (2D), como também através do desenvolvimento de modelos celulares tridimensionais (3D), mistos ou não com fibroblastos humano, cuja proposta é mimetizar in vitro as reais condições de tumorigênese existentes in vivo, tais como o contato célula-célula entre as linhagens neoplásicas e os fibroblastos da derme, o contato célula-matriz extracelular (matriz de colágeno), além de propiciar o crescimento tumoral de forma livre de adesão ao substrato, o que é característico dos processos malignos. Em uma primeira etapa, o fármaco fotossensível Ftalocianina de Cloroalumínio (AlClPc) foi escolhido como agente fotossensibilizante utilizado nos estudos, sendo este encapsulado em vesículas lipossomais, propiciando a solubilidade do composto em meio aquoso, otimizando sua entrada nas células. As propriedades fotoquímicas e fotofísicas da formulação lipossomal foram avaliadas, garantindo que a encapsulação não interfere na capacidade fotodinâmica do agente. Como segunda etapa, a formulação foi testada nos modelos celulares 2D e 3D acima descritos, realizando-se não só estudos de toxicidade, mas também ensaios de morte celular (apoptose versus necrose), incorporação intracelular do fármaco (uptake), de forma quantitativa e também qualitativa, demonstrando a localização intracelular preferencial do fármaco. Tanto em culturas 2D como em culturas 3D, a formulação AlClPc lipossomal apresentou atividade farmacológica superior aos sistemas aplicáveis em TFD, já descritos na literatura, o que abre caminhos para a realização de estudos in vivo em animais com boas perspectivas de resposta ao tratamento do melanoma humano, com possibilidades de futuras aplicações clínicas. / Melanoma is the type of skin cancer with poor prognosis due to its high probability of suffering metastases. Currently there are few effective treatments for the this, and the survival of patients with metastases is very low, around 8 months, with cure rates of these conditions do not exceed 1%. Photodynamic therapy (PDT) is a therapeutic modality selective and non-invasive, it has shown excellent clinical results in the treatment of non-melanoma skin cancers such as squamous and basal cell carcinoma. This work discusses the effectiveness of PDT in human melanoma cell lines in different stages of tumor progression, from the early stages of the disease (radial growth phase cells - RGP), to the metastatic stage, not only in cell culture in monolayer (2D), but also through the development of three-dimensional cellular models (3D), mixed or not with human fibroblasts, which aims to mimic in vitro, the real conditions existing in in vivo tumorigenesis, such as cell-cell contact between cancer cell lines and fibroblasts of the dermis, the contact cell-extracellular matrix (collagen matrix), as well as futher the growth of the tumor cells free from the substrate adhesion, which is characteristic of malignant processes. In a first step, the photosensitizer Cloroaluminum Phthalocyanine (AlClPc) was chosen to be used in the studies, which is encapsulated in liposomal vesicles, allowing the solubility of the drug in water, optimizing its intracellular incorporation. Furthermore, the photochemical and photophysical properties of the liposomal formulation were evaluated, ensuring that the encapsulation does not interfere with its photodynamic activity. As a second step, the formulation was tested in cellular models 2D and 3D above described, performing not only toxicity, but assays of cell death (apoptosis versus necrosis), intracellular drug incorporation (uptake), both quantitative and also qualitative, showing the main intracellular localization of the photosensitizer. Both in 2D cultures and 3D cultures, the liposomal AlClPc showed better pharmacological activity than the current applied PDT protocols, already described in the literature, and this is an open field for in vivo studies with animals with good prospects for responses to the treatment of human melanoma with possibilities for future clinical applications.
22

Avaliação antitumoral da fosfoetanolamina sintética e da formulação lipossomal DODAC/fosfoetanolamina sintética em células tumorais de mama humana / Antitumor evaluation of synthetic phosphoethanolamine and liposomal formulation DODAC/synthetic phosphoethanolamine in human breast tumor cells

Silva, Manuela Garcia Laveli da 20 February 2017 (has links)
A Fosfoetanolamina sintética (Pho-s) é uma molécula análoga aos fosfolipídios de membrana celular com propriedades antitumorais, antiinflamatórias e antiproliferativas. Nosso grupo de pesquisa desenvolveu diversos estudos in vitro e in vivo com a Pho-s mostrando resultados satisfatórios quanto à sua eficácia antitumoral. Neste estudo foram avaliados os efeitos antitumorais in vitro da Pho-s e da formulação lipossomal DODAC/Pho-s em linhagem de adenocarcinoma de mama humana (MCF7). Os efeitos da citotoxicidade da Pho-s na linhagem tumoral MCF7 foi avaliado pela determinação da viabilidade celular pelo teste colorimétrico MTT e os valores obtidos da IC50% foram de 37,2; 25,8; 1,8 mM nos períodos de 24, 48 e 72 horas, respectivamente. Com o tratamento de DODAC vazio nas células MCF7 a IC50% foi de 0,3 mM e com o tratamento de DODAC/Pho-s a IC50% de 1,8 mM, após 24 horas de tratamento. A produção de radicais livres lipoperoxidados foi avaliada pela formação do TBARS em células MCF7, tratadas por 24, 48 e 72 horas com Pho-s, não mostrando diferença significativa nos valores de lipoperoxidação. As alterações nas distribuições das populações celulares nas fases do ciclo celular avaliadas por citometria de fluxo mostraram um aumento do DNA fragmentado após 48 horas e parada na fase G2/M após 24 horas. As alterações nos arranjos celulares foram avaliadas por meio da marcação com os fluorocromos acridine-orange e rodamina 123 por microscopia confocal a laser, no qual foi observada a mudança na morfologia, fragmentação de membranas e perdas da projeção de prolongamentos citoplasmáticos. A indução de células em senescência foi avaliada pela atividade enzimática com a enzima beta-galactosidase, mostrando uma diminuição das células senescentes nas maiores concentrações de tratamento com a Pho-s e com o DODAC/Pho-s. Diversos marcadores de controle e progressão do ciclo celular, stress, angiogênese e receptores hormonais e o potencial mitocondrial foram avaliados por citometria de fluxo. A atividade apoptótica das células tumorais de mama foi avaliada pela Anexina V/PI, mostrando um aumento, principalmente, da apoptose tardia e seus ensaios de proliferação celular pelo teste com o CFSE-DA resultou na diminuição significativa da capacidade de proliferação celular. O tratamento das células de adenocarcinoma de mama humana MCF7 com a Pho-s mostrou ser um composto de natureza fosfolipídica com potencial promissor antitumoral / Synthetic Phosphoethanolamine (Pho-s) is a molecule analogous to cell membrane phospholipids with antitumor, anti-inflammatory and antiproliferative effects. Our research group has developed several in vitro and in vivo studies with Pho-s showing satisfactory results regarding its antitumor efficacy. In this project we evaluated the in vitro antitumor effects of Pho-s and the liposomal formulation DODAC/Pho-s in human breast adenocarcinoma line (MCF7). The effects of the Pho-s cytotoxicity on the MCF7 tumor cell line were evaluated by determining the cell viability by the MTT colorimetric test and the concentration of IC50% were 37.2; 25.8; 1.8 mM in the 24, 48 and 72 hour periods, respectively. With DODAC treatment in MCF7 cells the IC50% was 0.3 mM and the treatment of DODAC/Pho-s at IC50% of 1.8 mM after 24 hours of treatment. The production of lipoperoxides radicals was evaluated by the formation of TBARS in MCF7 cells, treated for 24, 48 and 72 hours with Pho-s, showing no significant difference in lipoperoxidation values. Changes in the cell population distributions in the cell cycle phases evaluated by flow cytometry showed an increase of the fragmented DNA after 48 hours and stop at the G2/M phase after 24 hours. Alterations in the cellular arrangements were evaluated by means of the labeling with the fluorochromes acridine-orange and rhodamine 123 using laser confocal microscopy, in which the change in morphology, membrane fragmentation and loss of the projection of cytoplasmic prolongations were observed. Senescent cell induction was evaluated by enzymatic activity with the ?-galactosidase enzyme, showing a decrease in senescent cells at the highest concentrations of treatment with Pho-s and DODAC/Pho-s. Several control markers and cell cycle progression, stress, angiogenesis and hormone receptors and mitochondrial potential were evaluated by flow cytometry. The apoptotic activity of breast tumor cells was evaluated by Annexin V/PI, showing an increase mainly of late apoptosis and cell proliferation assays by the CFSE-DA with the Pho-s by flow cytometry, resulting in significant decrease of cell proliferation. Treatment of MCF 7 human breast adenocarcinoma cells with Pho-s has been shown to be a phospholipid-type compound with promising antitumor potential
23

Caracterização das propriedades antitumorais da fosfoetanolamina sintética e da formulação lipossomal DODAC/fosfoetanolamina em células de leucemia humana K-562 / Characterization of the antitumor properties of synthetic phosphoethanolamine and the liposomal formulation DODAC/phosphoethanolamine in human K-562 leukemia cells

Thais de Oliveira Conceição 06 October 2017 (has links)
Fosfoetanolamina sintética (Pho-s) é um monoéster análogo à fosfoetanolamina da membrana celular fosforilada artificialmente, com propriedades antiinflamatórias e apoptóticas para vários tipos de células tumorais humanas e murinas. Neste projeto foram avaliados os efeitos antitumorais in vitro da Pho-s e da formulação lipossomal DODAC/Pho-s na linhagem tumoral de leucemia mielóide crônica humana (K-562), em comparação ao modelo resistente a múltiplas drogas K-562 Lucena (MDR+). Os efeitos de citotoxicidade da Pho-s na linhagem tumoral K-562 e K-562 Lucena (MDR+) foram avaliados pela viabilidade celular utilizando o teste da Sulforodamina B, e os valores da IC50% obtidos foram de 43.1 mM e 145.9 mM, respectivamente após 24 horas de tratamento. O tratamento com o carreador DODAC vazio nas células K-562 e K-562 Lucena (MDR+) a IC50% foi de 0,0003mM e 0,008mM respectivamente, e com o tratamento com a formulação lipossomal DODAC/Pho-s a IC50% obtida respectivamente de, 0,56 mM e 0,31 mM. A viabilidade celular foi determinada a exclusão pelo azul de tripan 0,2%, em sistema automatizado Vi-Cell e foram significativas as diminuições da viabilidade celular em comparação ao grupo controle não tratado nas diversas concentrações e em diferentes períodos de tempo de tratamento. As alterações nas distribuições nas populações celulares nas fases do ciclo celular determinadas por citometria de fluxo mostraram aumento do DNA fragmentado (Sub/G1) em 12 e 24 horas de tratamento. Atividade apoptótica das células tumorais pela expressão da Anexina V/PI, no estágio de apoptose inicial, apoptose tardia e necrose foram quantificadas em citometria de fluxo, o tratamento com Pho-s, quando comparado ao grupo controle K-562 (40 e 80 mM) e K-562 Lucena (MDR+) (146 e 292 mM) ocorreu aumento significativo do número de células apoptóticas e em menor percentual o número de células necróticas. O tratamento com a Pho-s em célula leucêmica K-562 e K-562 Lucena (MDR+) tratadas, respectivamente com 40 e 80 mM e 146 e 292 mM mostraram que independente da expressão do fenótipo de resistência há uma redução significativa no potencial elétrico mitocondrial, analisado pelo o ensaio da rodamina-123. Os marcadores de controle e progressão do ciclo celular e da apoptose, mostraram efeitos moduladores da Pho-s dependentes da p53 na expressão da moléculas pró-apoptóticas. Esse conjunto de informações demonstrou os efeitos apoptóticos da Pho-s e da formulação lipossomal nas células tumorais independentemente do perfil molecular de resistência (MDR+), o que possibilita dizer que esse composto possui significativo potencial terapêutico nesse grupo de leucemias / Synthetic phosphoethanolamine (Pho-s) is a monoester analogous to the phosphoethanolamine which composes the membrane of an artificially phosphorylated cell, with anti-inflammatory and apoptotic properties for various types of human and murine tumor cells. In this project, we evaluated in vitro antitumor effects of Pho-s and the DODAC/Pho-s liposomal formulation in the human chronic myeloid leukemia (K-562) tumor line in comparison with the K-562 Lucena (MDR+). The effects of cytotoxicity of Pho-s on K-562 and K-562 Lucena (MDR +) tumor cells lines were evaluated by cell viability using the Sulforhodamine B test, and the IC50% values obtained were 43.1 mM and 145.9 mM after 24 hours of treatment, respectively. Treatment with the empty DODAC carrier on the K-562 and K-562 Lucena (MDR+) at IC50% cells was 0.0003 mM and 0.008 mM, and the treatment with the DODAC/Pho-s liposomal formulation obtained results of 0.56 mM and 0.31 mM, respectively. Cell viability was determined by 0.2% trypan blue exclusion in automated Vi-Cell system and the decreases in cell viability were significant in comparison to the untreated control group at various concentrations and different treatment time periods. Alterations in the distributions of cell populations in the cell cycle phases determined by flow cytometry showed increment of fragmented DNA (Sub/G1) in 12 and 24 hours of treatment. Apoptotic activity of tumor cells by the expression of Annexin V/PI, in the early apoptosis, late apoptosis phase and necrosis stage were quantified in flow cytometry, the treatment with Pho-s, when compared to the control group K-562 (40 and 80 mM) and K-562 Lucena (MDR +) (146 and 292 mM) demonstrated that there was a significant increase in the number of apoptotic cells and, in a lower percentage, the number of necrotic cells. Treatments with Pho-s in leukemic cell K-56 with 40 and 80 mM and in K-562 Lucena (MDR+) with 146 and 292 mM showed that independent of the expression of the resistance phenotype there is a significant reduction in the electrical potential of the mitochondrial membrane, analyzed with the rhodamine-123 assay. Control and progression markers of cell cycle and apoptosis showed p53-dependent modulating effects on the expression of pro-apoptotic molecules. This set of information demonstrated the apoptotic effects of Pho-s and liposomal formulation on tumor cells independently of the molecular resistance profile (MDR+), which makes it possible to say that this compound has significant therapeutic potential in this group of leukemias
24

AZITHROMYCIN THERAPY REDUCES CARDIAC INFLAMMATION AND MITIGATES ADVERSE CARDIAC REMODELING AFTER MYOCARDIAL INFARCTION

Al-Darraji, Ahmed Hamish Neamah 01 January 2019 (has links)
Introduction: Myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide. Induced by cardiomyocyte death, MI initiates a prolonged and uncontrolled inflammatory response which impairs the healing process. Immune cells, such as macrophages, play a central role in organizing the early post-MI inflammatory response and the subsequent repair phase. Two activation states of macrophages have been identified with distinct and complementary functions (inflammatory vs. reparatory). This bimodal pattern of macrophage activation is an attractive therapeutic target to favorably resolve post-MI inflammation and enhance recovery. It has been demonstrated that azithromycin (AZM), a commonly used antibiotic with immunomodulatory effects, polarizes macrophages towards the reparatory phenotype. AZM has an excellent safety profile and has been approved for human use. We hypothesize that AZM reduces inflammation and improves heart function in MI. Methods and results: In our initial studies, we demonstrated that oral free AZM (160 mg/kg daily for 7 days), initiated 3 days prior to MI, enhances post-MI cardiac recovery as a result of shifting macrophages to the reparatory state. We observed a significant reduction in mortality with AZM therapy. AZM-treated mice showed a significant decrease in pro-inflammatory and an increase in reparative macrophages, decreasing the pro-inflammatory/reparative macrophage ratio. Macrophage changes were associated with a significant decline in pro- and an increase in anti-inflammatory cytokines. Additionally, AZM treatment was correlated with a distinct decrease in neutrophil count due to apoptosis, a known signal for shifting macrophages towards the reparative phenotype. Finally, AZM treatment improved cardiac recovery, scar size, and angiogenesis. We designed this proof of concept study using pre-MI AZM therapy to achieve steady state levels prior to injury. Therefore, in our follow-up studies we targeted inflammatory macrophages using a non-Pegylated liposomal formulation of AZM (Lazm) which has been shown in multiple studies to promote drug efficacy and minimize off-target effects. To test the hypothesis that Lazm is more effective and safer than free AZM, low doses of free/liposomal AZM (10 or 40 mg/kg, administered intravenously) were initiated immediately after MI. We observed that Lazm induces early resolution of the post-MI inflammatory response as evidenced by switching of the activation state of monocytes/macrophages towards the reparatory phenotype. Neutrophils were substantially decreased, particularly pro-inflammatory neutrophils. Cytokine profiles were also shifted to the anti-inflammatory status with Lazm therapy. Taken together, AZM treatment resulted in a significant shift in macrophage activation towards the reparatory state. The shift in inflammatory state was accompanied by a decrease in apoptosis and infarct size in the injured heart, as well as enhanced angiogenesis and LV functional recovery in our long-term studies. In addition, Lazm was protective against off-target effects of AZM on the heart. Conclusion: This is the first evidence of a novel and clinically-relevant therapeutic strategy to modulate post-MI inflammation. We found that AZM reduces cardiac inflammation and improves adverse cardiac remodeling after infarction via promoting a shift of macrophage activation state. The overarching significance of this work is the modulation of sterile inflammation, which can be a viable therapeutic target in many conditions including stroke and heart attack. Additionally, this is the first study to demonstrate the immune modulation properties of liposomal AZM, which has wide potential therapeutic applications beyond the cardiovascular field. Importantly, liposomal formulation of AZM is protective from its cardiac off-target effects. Our findings strongly support clinical trials using AZM as a novel and clinically relevant therapeutic target to improve cardiac recovery and reduce heart failure post-MI in humans.
25

Die Magnetresonanztomographie im Therapiemonitoring liposomaler Glukokortikosteroide in zwei Tiermodellen der Multiplen Sklerose unter Berücksichtigung von Läsions- und Seitenventrikelgröße sowie Liquorsignalintensität / Magnetic resonance imaging in therapy monitoring of liposomal glucocorticosteroids in two animal models of multiple sclerosis in consideration of the size of lesion and lateral ventricle as well as cerebrospinal fluid signal intensity

Kehrer, Dominique Peter 20 March 2012 (has links)
No description available.
26

Avaliação antitumoral da fosfoetanolamina sintética e da formulação lipossomal DODAC/fosfoetanolamina sintética em células tumorais de mama humana / Antitumor evaluation of synthetic phosphoethanolamine and liposomal formulation DODAC/synthetic phosphoethanolamine in human breast tumor cells

Manuela Garcia Laveli da Silva 20 February 2017 (has links)
A Fosfoetanolamina sintética (Pho-s) é uma molécula análoga aos fosfolipídios de membrana celular com propriedades antitumorais, antiinflamatórias e antiproliferativas. Nosso grupo de pesquisa desenvolveu diversos estudos in vitro e in vivo com a Pho-s mostrando resultados satisfatórios quanto à sua eficácia antitumoral. Neste estudo foram avaliados os efeitos antitumorais in vitro da Pho-s e da formulação lipossomal DODAC/Pho-s em linhagem de adenocarcinoma de mama humana (MCF7). Os efeitos da citotoxicidade da Pho-s na linhagem tumoral MCF7 foi avaliado pela determinação da viabilidade celular pelo teste colorimétrico MTT e os valores obtidos da IC50% foram de 37,2; 25,8; 1,8 mM nos períodos de 24, 48 e 72 horas, respectivamente. Com o tratamento de DODAC vazio nas células MCF7 a IC50% foi de 0,3 mM e com o tratamento de DODAC/Pho-s a IC50% de 1,8 mM, após 24 horas de tratamento. A produção de radicais livres lipoperoxidados foi avaliada pela formação do TBARS em células MCF7, tratadas por 24, 48 e 72 horas com Pho-s, não mostrando diferença significativa nos valores de lipoperoxidação. As alterações nas distribuições das populações celulares nas fases do ciclo celular avaliadas por citometria de fluxo mostraram um aumento do DNA fragmentado após 48 horas e parada na fase G2/M após 24 horas. As alterações nos arranjos celulares foram avaliadas por meio da marcação com os fluorocromos acridine-orange e rodamina 123 por microscopia confocal a laser, no qual foi observada a mudança na morfologia, fragmentação de membranas e perdas da projeção de prolongamentos citoplasmáticos. A indução de células em senescência foi avaliada pela atividade enzimática com a enzima beta-galactosidase, mostrando uma diminuição das células senescentes nas maiores concentrações de tratamento com a Pho-s e com o DODAC/Pho-s. Diversos marcadores de controle e progressão do ciclo celular, stress, angiogênese e receptores hormonais e o potencial mitocondrial foram avaliados por citometria de fluxo. A atividade apoptótica das células tumorais de mama foi avaliada pela Anexina V/PI, mostrando um aumento, principalmente, da apoptose tardia e seus ensaios de proliferação celular pelo teste com o CFSE-DA resultou na diminuição significativa da capacidade de proliferação celular. O tratamento das células de adenocarcinoma de mama humana MCF7 com a Pho-s mostrou ser um composto de natureza fosfolipídica com potencial promissor antitumoral / Synthetic Phosphoethanolamine (Pho-s) is a molecule analogous to cell membrane phospholipids with antitumor, anti-inflammatory and antiproliferative effects. Our research group has developed several in vitro and in vivo studies with Pho-s showing satisfactory results regarding its antitumor efficacy. In this project we evaluated the in vitro antitumor effects of Pho-s and the liposomal formulation DODAC/Pho-s in human breast adenocarcinoma line (MCF7). The effects of the Pho-s cytotoxicity on the MCF7 tumor cell line were evaluated by determining the cell viability by the MTT colorimetric test and the concentration of IC50% were 37.2; 25.8; 1.8 mM in the 24, 48 and 72 hour periods, respectively. With DODAC treatment in MCF7 cells the IC50% was 0.3 mM and the treatment of DODAC/Pho-s at IC50% of 1.8 mM after 24 hours of treatment. The production of lipoperoxides radicals was evaluated by the formation of TBARS in MCF7 cells, treated for 24, 48 and 72 hours with Pho-s, showing no significant difference in lipoperoxidation values. Changes in the cell population distributions in the cell cycle phases evaluated by flow cytometry showed an increase of the fragmented DNA after 48 hours and stop at the G2/M phase after 24 hours. Alterations in the cellular arrangements were evaluated by means of the labeling with the fluorochromes acridine-orange and rhodamine 123 using laser confocal microscopy, in which the change in morphology, membrane fragmentation and loss of the projection of cytoplasmic prolongations were observed. Senescent cell induction was evaluated by enzymatic activity with the ?-galactosidase enzyme, showing a decrease in senescent cells at the highest concentrations of treatment with Pho-s and DODAC/Pho-s. Several control markers and cell cycle progression, stress, angiogenesis and hormone receptors and mitochondrial potential were evaluated by flow cytometry. The apoptotic activity of breast tumor cells was evaluated by Annexin V/PI, showing an increase mainly of late apoptosis and cell proliferation assays by the CFSE-DA with the Pho-s by flow cytometry, resulting in significant decrease of cell proliferation. Treatment of MCF 7 human breast adenocarcinoma cells with Pho-s has been shown to be a phospholipid-type compound with promising antitumor potential
27

Estudo dos efeitos da terapia fotodinâmica na progressão tumoral e em modelos celulares  tridimensionais / Study of the effects of photodynamic therapy on tumor progression and in three-dimensional cellular models.

Paula Aboud Barbugli 05 May 2010 (has links)
O melanoma maligno é o tipo de câncer de pele com pior prognóstico, devido à sua elevada probabilidade de causar metástases. Atualmente existem poucos tratamentos efetivos para o tratamento do melanoma, sendo que a sobrevida de pacientes que apresentam metástases é muito baixa, em torno de 8 meses, sendo que as taxas de cura nestas condições não ultrapassam 1%. A terapia fotodinâmica (TFD) é uma modalidade terapêutica seletiva e não invasiva, que vem demonstrando excelentes resultados clínicos no tratamento de tumores de pele do tipo não melanoma, como carcinoma espino e basocelular. O trabalho em questão aborda a efetividade da TFD, em linhagens humana de melanoma em diferentes fases de progressão da neoplasia, desde os estágios iniciais da doença (células de crescimento radial - RGP), até a fase metastática, não só em cultura de células em monocamada (2D), como também através do desenvolvimento de modelos celulares tridimensionais (3D), mistos ou não com fibroblastos humano, cuja proposta é mimetizar in vitro as reais condições de tumorigênese existentes in vivo, tais como o contato célula-célula entre as linhagens neoplásicas e os fibroblastos da derme, o contato célula-matriz extracelular (matriz de colágeno), além de propiciar o crescimento tumoral de forma livre de adesão ao substrato, o que é característico dos processos malignos. Em uma primeira etapa, o fármaco fotossensível Ftalocianina de Cloroalumínio (AlClPc) foi escolhido como agente fotossensibilizante utilizado nos estudos, sendo este encapsulado em vesículas lipossomais, propiciando a solubilidade do composto em meio aquoso, otimizando sua entrada nas células. As propriedades fotoquímicas e fotofísicas da formulação lipossomal foram avaliadas, garantindo que a encapsulação não interfere na capacidade fotodinâmica do agente. Como segunda etapa, a formulação foi testada nos modelos celulares 2D e 3D acima descritos, realizando-se não só estudos de toxicidade, mas também ensaios de morte celular (apoptose versus necrose), incorporação intracelular do fármaco (uptake), de forma quantitativa e também qualitativa, demonstrando a localização intracelular preferencial do fármaco. Tanto em culturas 2D como em culturas 3D, a formulação AlClPc lipossomal apresentou atividade farmacológica superior aos sistemas aplicáveis em TFD, já descritos na literatura, o que abre caminhos para a realização de estudos in vivo em animais com boas perspectivas de resposta ao tratamento do melanoma humano, com possibilidades de futuras aplicações clínicas. / Melanoma is the type of skin cancer with poor prognosis due to its high probability of suffering metastases. Currently there are few effective treatments for the this, and the survival of patients with metastases is very low, around 8 months, with cure rates of these conditions do not exceed 1%. Photodynamic therapy (PDT) is a therapeutic modality selective and non-invasive, it has shown excellent clinical results in the treatment of non-melanoma skin cancers such as squamous and basal cell carcinoma. This work discusses the effectiveness of PDT in human melanoma cell lines in different stages of tumor progression, from the early stages of the disease (radial growth phase cells - RGP), to the metastatic stage, not only in cell culture in monolayer (2D), but also through the development of three-dimensional cellular models (3D), mixed or not with human fibroblasts, which aims to mimic in vitro, the real conditions existing in in vivo tumorigenesis, such as cell-cell contact between cancer cell lines and fibroblasts of the dermis, the contact cell-extracellular matrix (collagen matrix), as well as futher the growth of the tumor cells free from the substrate adhesion, which is characteristic of malignant processes. In a first step, the photosensitizer Cloroaluminum Phthalocyanine (AlClPc) was chosen to be used in the studies, which is encapsulated in liposomal vesicles, allowing the solubility of the drug in water, optimizing its intracellular incorporation. Furthermore, the photochemical and photophysical properties of the liposomal formulation were evaluated, ensuring that the encapsulation does not interfere with its photodynamic activity. As a second step, the formulation was tested in cellular models 2D and 3D above described, performing not only toxicity, but assays of cell death (apoptosis versus necrosis), intracellular drug incorporation (uptake), both quantitative and also qualitative, showing the main intracellular localization of the photosensitizer. Both in 2D cultures and 3D cultures, the liposomal AlClPc showed better pharmacological activity than the current applied PDT protocols, already described in the literature, and this is an open field for in vivo studies with animals with good prospects for responses to the treatment of human melanoma with possibilities for future clinical applications.
28

The Vasoactive Peptide Urotensin II Stimulates Spontaneous Release From Frog Motor Nerve Terminals

Brailoiu, E., Brailoiu, G. C., Miyamoto, M. D., Dun, N. J. 01 April 2003 (has links)
1. The effect of urotensin II (U-II) on spontaneous transmitter release was examined in the frog to see if the biological activity of this vasoactive peptide extended to neural tissues. 2. In normal Ringer solution, frog and human U-II (fU-II and hU-II, respectively) caused concentration-dependent, reversible increases in miniature endplate potential (MEPP) frequency, with hU-II about 22 times more potent than fU-II. hU-II caused a dose-dependent increase in MEPP amplitude, whereas fU-II caused an increase, followed by a decrease with higher concentrations. 3. Increasing extracellular Ca 2+ three-fold had no effect on the MEPP frequency increase to 25 μM hU-II. Pretreatment with thapsigargin to deplete endoplasmic reticulum Ca 2+ caused a 61% reduction in the MEPP frequency increase to 25 μM hU-II. 4. Pretreatment with the phospholipase C inhibitor U-73122 caused a 93% reduction in the MEPP frequency increase to 25 μM hU-II and a 15% reduction in the increase in MEPP amplitude. Pretreating with antibodies against the inositol 1,4,5-trisphosphate (IP 3) type 1 receptor using liposomal techniques reduced the MEPP frequency increase by 83% but had no effect on MEPP amplitude. 5. Pretreating with protein kinase C inhibitors (bisindolylmaleimide I and III) had no effect on the response to 25 μM hU-II, but pretreating with protein kinase A inhibitors (H-89 and KT5720) reduced the MEPP frequency increase by 88% and completely abolished the increase in MEPP amplitude. 6. Our results show that hU-II is a potent stimulator of spontaneous transmitter release in the frog and that the effect is mediated by IP 3 and cyclic AMP/protein kinase A.
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A comparison of liposomal bupivacaine and bupivacaine for pain control in untreated symptomatic vital teeth

Bultema, Kristy 14 October 2015 (has links)
No description available.

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