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A comercialização de fitoterápicos obtidos a partir de extratos de H. perforatum para o tratamento de depressão em diversas partes do mundo despertou o interesse de investigadores no estudo de plantas do gênero Hypericum, tanto acerca da composição química quanto das propriedades biológicas destas espécies. Objetivos: Investigar a constituição química de espécies nativas do gênero Hypericum (H. caprifoliatum, H. polyanthemum, entre outras); realizar um estudo quimiotaxonômico de derivados de floroglucinol em espécies de Hypericum. Avaliar a atividade antiproliferativa de benzopiranos isolados de H. polyanthemum frente a células endoteliais. Métodos: Para o isolamento e análise dos compostos foram utilizadas técnicas cromatográficas (CC, CCD e CLAE). A elucidação estrutural foi realizada a partir de métodos espectrofotométrico (UV), espectroscópico (RMN1H e 13C) e espectrométrico. A relevância taxonômica de derivados de floroglucinol foi verificada a partir de revisão da literatura. A avaliação da atividade antiangiogênica foi efetuada pelas técnicas de sulfo-rodamina B e citometria de fluxo. Resultados e Conclusões: De H. caprifoliatum e H. polyanthemum foram isolados três derivados de floroglucinol diméricos. Estes produtos podem ser considerados marcadores quimiotaxonômicos das seções Brathys e Trigynobrathys do gênero Hypericum, as quais incluem todas as espécies nativas do sul do Brasil. Os flavonóides, quercetina e hiperosídeo foram isolados de H. caprifoliatum. Os três benzopiranos testados (Hp1, Hp2 e Hp3) demonstraram capacidade de inibir o crescimento de células endoteliais de forma dose-dependente. Os compostos Hp2 e Hp3 foram capazes de bloquear fases do ciclo celular. / The use of St. John’s Wort extracts as a phytomedicine to treat depression in several countries around the world has stimulated investigators in order to study the chemical and biological properties of Hypericum species. Purpose: to investigate the chemical composition of native representants of Hypericum genus (H. caprifoliatum, H. polyanthemum, among others), to carry out a chemotaxonomic study about the significance of phloroglucinol derivatives in Hypericum species and to evaluate the antiproliferative activity of three benzopyrans isolated from H. polyanthemum against endothelial cells. Methods: for the isolation and identification of the compounds chromatographic techniques such as TLC, CC and HPLC were employed. The structures were determined through NMR spectroscopy, spectrometry and ultraviolet analyses. In order to study the significance of the phloroglucinol derivatives, data on the occurrence of these compounds was surveyed in the literature. The antiangiogenic activity was performed in both Sulforhodamine B and Flow Cytometry assays. Results and Conclusions: From H. caprifoliatum and H. polyanthemum three phloroglucinol derivatives with a dimeric structure were identified. These group of products could be considered as chemotaxonomic markers from species of the Hypericum genus belonging to the Brathys and Trigynobrathys sections, which include all the native representants. This work also presents the isolation and structural determination of two well known flavonoids, quercetin and hyperoside, from H. caprifoliatum. The three benzopyrans, Hp1, Hp2 and Hp3, showed a dose-dependant cytotoxic activity against endothelial cells. The isomers Hp2 and Hp3 were able to cause modifications on the normal cell cycle.

Orientador: Eliane Chaves Jorge / Abstract: Background: The standard treatment of retinopathy of prematurity (ROP) is the ablation of the avascular retina with laser or cryotherapy. However, this therapy may leave permanent structural and visual sequelae and may not be effective in cases of posterior and aggressive ROP. Vascular endothelial growth factor (VEGF) is involved in the pathogenesis of ROP, and antiangiogenic therapy is an option in cases of failure of standard treatment. The potential adverse effects of the use of antiangiogenic drugs in preterm neonates and the lack of concrete evidence on the efficacy of these drugs justify a systematic review of the literature. Objective: To evaluate the efficacy and safety of antiangiogenic therapy, when compared with laser photocoagulation, cryotherapy or combination therapy, in the treatment of ROP. Method: A systematic review of the literature was conducted using the Cochrane collaboration methodology and electronic search platforms to identify studies using antiangiogenic drugs in the treatment of ROP. The quality of the evidence was evaluated by the GRADE system (Grading of Recommendations Assessment, Development, and Evaluation). Results: Twelve studies were included in this review (six randomized controlled trials - RCTs and six non-randomized observational studies), including 677 preterm infants. Through the meta-analyzes, there was a statistical difference benefiting anti-VEGF therapy in the occurrence of progression to retinal detachment (RR 0.14 [95% CI 0.05, ... (Complete abstract click electronic access below) / Resumo: Introdução: O tratamento padrão da retinopatia da prematuridade (ROP) é a ablação da retina avascular com laser ou crioterapia. No entanto, esta terapia pode deixar sequelas estruturais e visuais permanentes e não ser efetiva em casos de ROP posterior e agressiva. O fator de crescimento do endotélio vascular (VEGF) está envolvido na patogênese da ROP e a terapia antiangiogênica é opção nos casos de falha do tratamento padrão. Os potenciais efeitos adversos com o uso de antiangiogênicos em neonatos prematuros e a falta de evidências concretas sobre a eficácia destas drogas justifica uma revisão sistemática da literatura. Objetivo: Avaliar a eficácia e a segurança da terapia antiangiogênica, quando comparada com fotocoagulação a laser, crioterapia ou terapia combinada, no tratamento da ROP. Método: Uma revisão sistemática da literatura foi realizada, utilizando a metodologia da colaboração Cochrane e plataformas eletrônicas de busca para identificar estudos utilizando drogas antiangiogênicas no tratamento da ROP. A qualidade da evidência foi avaliada pelo sistema GRADE (Grading of Recommendations Assessment, Development and Evaluation). Resultados: Doze estudos foram incluídos nesta revisão (seis ensaios clínicos randomizados e seis estudos observacionais não randomizados), incluindo 677 recém-nascidos pré-termo (1288 olhos). Pelas metanálises, houve diferença estatística beneficiando a terapia anti-VEGF na ocorrência de progressão para descolamento de retina (RR 0.14 [IC 95% 0... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

A comercialização de fitoterápicos obtidos a partir de extratos de H. perforatum para o tratamento de depressão em diversas partes do mundo despertou o interesse de investigadores no estudo de plantas do gênero Hypericum, tanto acerca da composição química quanto das propriedades biológicas destas espécies. Objetivos: Investigar a constituição química de espécies nativas do gênero Hypericum (H. caprifoliatum, H. polyanthemum, entre outras); realizar um estudo quimiotaxonômico de derivados de floroglucinol em espécies de Hypericum. Avaliar a atividade antiproliferativa de benzopiranos isolados de H. polyanthemum frente a células endoteliais. Métodos: Para o isolamento e análise dos compostos foram utilizadas técnicas cromatográficas (CC, CCD e CLAE). A elucidação estrutural foi realizada a partir de métodos espectrofotométrico (UV), espectroscópico (RMN1H e 13C) e espectrométrico. A relevância taxonômica de derivados de floroglucinol foi verificada a partir de revisão da literatura. A avaliação da atividade antiangiogênica foi efetuada pelas técnicas de sulfo-rodamina B e citometria de fluxo. Resultados e Conclusões: De H. caprifoliatum e H. polyanthemum foram isolados três derivados de floroglucinol diméricos. Estes produtos podem ser considerados marcadores quimiotaxonômicos das seções Brathys e Trigynobrathys do gênero Hypericum, as quais incluem todas as espécies nativas do sul do Brasil. Os flavonóides, quercetina e hiperosídeo foram isolados de H. caprifoliatum. Os três benzopiranos testados (Hp1, Hp2 e Hp3) demonstraram capacidade de inibir o crescimento de células endoteliais de forma dose-dependente. Os compostos Hp2 e Hp3 foram capazes de bloquear fases do ciclo celular. / The use of St. John’s Wort extracts as a phytomedicine to treat depression in several countries around the world has stimulated investigators in order to study the chemical and biological properties of Hypericum species. Purpose: to investigate the chemical composition of native representants of Hypericum genus (H. caprifoliatum, H. polyanthemum, among others), to carry out a chemotaxonomic study about the significance of phloroglucinol derivatives in Hypericum species and to evaluate the antiproliferative activity of three benzopyrans isolated from H. polyanthemum against endothelial cells. Methods: for the isolation and identification of the compounds chromatographic techniques such as TLC, CC and HPLC were employed. The structures were determined through NMR spectroscopy, spectrometry and ultraviolet analyses. In order to study the significance of the phloroglucinol derivatives, data on the occurrence of these compounds was surveyed in the literature. The antiangiogenic activity was performed in both Sulforhodamine B and Flow Cytometry assays. Results and Conclusions: From H. caprifoliatum and H. polyanthemum three phloroglucinol derivatives with a dimeric structure were identified. These group of products could be considered as chemotaxonomic markers from species of the Hypericum genus belonging to the Brathys and Trigynobrathys sections, which include all the native representants. This work also presents the isolation and structural determination of two well known flavonoids, quercetin and hyperoside, from H. caprifoliatum. The three benzopyrans, Hp1, Hp2 and Hp3, showed a dose-dependant cytotoxic activity against endothelial cells. The isomers Hp2 and Hp3 were able to cause modifications on the normal cell cycle.

Submitted by MATHEUS SENNA PEREIRA OGATA (mspogata@gmail.com) on 2018-09-18T00:16:15Z No. of bitstreams: 1 Dissertação (REFERENCIAS CORRGIIDAS) - Matheus Senna Pereira Ogata.pdf: 3338159 bytes, checksum: a4719346512d617a2a7beeb12f2c4a85 (MD5) / Approved for entry into archive by ROSANGELA APARECIDA LOBO null (rosangelalobo@btu.unesp.br) on 2018-09-18T17:16:07Z (GMT) No. of bitstreams: 1 ogata_msp_me_bot.pdf: 3338159 bytes, checksum: a4719346512d617a2a7beeb12f2c4a85 (MD5) / Made available in DSpace on 2018-09-18T17:16:07Z (GMT). No. of bitstreams: 1 ogata_msp_me_bot.pdf: 3338159 bytes, checksum: a4719346512d617a2a7beeb12f2c4a85 (MD5) Previous issue date: 2018-07-25 / Introdução: O tratamento padrão da retinopatia da prematuridade (ROP) é a ablação da retina avascular com laser ou crioterapia. No entanto, esta terapia pode deixar sequelas estruturais e visuais permanentes e não ser efetiva em casos de ROP posterior e agressiva. O fator de crescimento do endotélio vascular (VEGF) está envolvido na patogênese da ROP e a terapia antiangiogênica é opção nos casos de falha do tratamento padrão. Os potenciais efeitos adversos com o uso de antiangiogênicos em neonatos prematuros e a falta de evidências concretas sobre a eficácia destas drogas justifica uma revisão sistemática da literatura. Objetivo: Avaliar a eficácia e a segurança da terapia antiangiogênica, quando comparada com fotocoagulação a laser, crioterapia ou terapia combinada, no tratamento da ROP. Método: Uma revisão sistemática da literatura foi realizada, utilizando a metodologia da colaboração Cochrane e plataformas eletrônicas de busca para identificar estudos utilizando drogas antiangiogênicas no tratamento da ROP. A qualidade da evidência foi avaliada pelo sistema GRADE (Grading of Recommendations Assessment, Development and Evaluation). Resultados: Doze estudos foram incluídos nesta revisão (seis ensaios clínicos randomizados e seis estudos observacionais não randomizados), incluindo 677 recém-nascidos pré-termo (1288 olhos). Pelas metanálises, houve diferença estatística beneficiando a terapia anti-VEGF na ocorrência de progressão para descolamento de retina (RR 0.14 [IC 95% 0.05, 0.38] p=0.0001, I2 = 0%) e ocorrência de miopia ( Diferença de média ponderada 0.25 [IC 95% 0.14, 0.37] p<0.0001, I2 = 76%). No desfecho recorrência de ROP houve diferença estatística beneficiando o laser (RR 1.88 [IC 95% 1.34, 2.63] p=0.0003, I2 = 82%). Não houve porém, diferença entre a terapia anti-VEGF e o laser quanto à ocorrência de complicações oculares (RR 0.84 [IC 95% 0.34, 2.08] p=0.71, I2 = 0%). Na análise de sub grupo, na comparação entre as zonas de acometimento da ROP, o anti-VEGF apresentou menor risco de recorrência exigindo retratamento que o laser, em prematuros com ROP em zona I (RR 0.23 [IC 95% 0.11, 0.49] p=0.0001, I2 = 61%). A qualidade da evidência pelo GRADE variou de muito baixa a baixa. Conclusões: Há evidências de que a terapia anti-VEGF, usada como monoterapia, quando comparada ao laser, reduz o risco de progressão para descolamento de retina, a ocorrência de miopia e o risco de recorrência de ROP em prematuros com doença na zona I. No entanto, ainda faltam evidências de qualidade que permitam atestar a segurança da terapia, especialmente quanto aos potenciais efeitos sistêmicos em prematuros. Palavras-chave: Retinopatia da Prematuridade, antiangiogênicos, metanálise. / Background: The standard treatment of retinopathy of prematurity (ROP) is the ablation of the avascular retina with laser or cryotherapy. However, this therapy may leave permanent structural and visual sequelae and may not be effective in cases of posterior and aggressive ROP. Vascular endothelial growth factor (VEGF) is involved in the pathogenesis of ROP, and antiangiogenic therapy is an option in cases of failure of standard treatment. The potential adverse effects of the use of antiangiogenic drugs in preterm neonates and the lack of concrete evidence on the efficacy of these drugs justify a systematic review of the literature. Objective: To evaluate the efficacy and safety of antiangiogenic therapy, when compared with laser photocoagulation, cryotherapy or combination therapy, in the treatment of ROP. Method: A systematic review of the literature was conducted using the Cochrane collaboration methodology and electronic search platforms to identify studies using antiangiogenic drugs in the treatment of ROP. The quality of the evidence was evaluated by the GRADE system (Grading of Recommendations Assessment, Development, and Evaluation). Results: Twelve studies were included in this review (six randomized controlled trials - RCTs and six non-randomized observational studies), including 677 preterm infants. Through the meta-analyzes, there was a statistical difference benefiting anti-VEGF therapy in the occurrence of progression to retinal detachment (RR 0.14 [95% CI 0.05, 0.38] p = 0.0001, I2 = 0%) and myopia occurrence (Weighted mean difference 0.25 [95% CI 0.14, 0.37] p <0.0001, I2 = 76%). At the end of ROP recurrence, there was a statistical difference benefiting the laser (RR 1.88 [95% CI 1.34, 2.63], p = 0.0003, I2 = 82%). There was, however, no difference between the anti-VEGF therapy and the laser in the occurrence of ocular complications (RR 0.84 [95% CI 0.34, 2.08] p = 0.71, I2 = 0%). In the subgroup analysis, in the comparison between the ROP involvement zones, the anti-VEGF presented a lower risk of recurrence requiring retreatment than the laser in premature infants with zone I ROP (RR 0.23 [95% CI 0.11, 0.49] p = 0.0001, I2 = 61%).The quality of the GRADE evidence varied from very low to low. Conclusions: There is evidence that anti-VEGF therapy, used as monotherapy, when compared to laser, reduces the risk of progression to retinal detachment, the occurrence of myopia, and the risk of recurrence of ROP in preterm infants with the disease in zone I.However, there is still a lack of quality evidence to attest to the safety of therapy, especially regarding potential systemic effects in preterm infants.

A comercialização de fitoterápicos obtidos a partir de extratos de H. perforatum para o tratamento de depressão em diversas partes do mundo despertou o interesse de investigadores no estudo de plantas do gênero Hypericum, tanto acerca da composição química quanto das propriedades biológicas destas espécies. Objetivos: Investigar a constituição química de espécies nativas do gênero Hypericum (H. caprifoliatum, H. polyanthemum, entre outras); realizar um estudo quimiotaxonômico de derivados de floroglucinol em espécies de Hypericum. Avaliar a atividade antiproliferativa de benzopiranos isolados de H. polyanthemum frente a células endoteliais. Métodos: Para o isolamento e análise dos compostos foram utilizadas técnicas cromatográficas (CC, CCD e CLAE). A elucidação estrutural foi realizada a partir de métodos espectrofotométrico (UV), espectroscópico (RMN1H e 13C) e espectrométrico. A relevância taxonômica de derivados de floroglucinol foi verificada a partir de revisão da literatura. A avaliação da atividade antiangiogênica foi efetuada pelas técnicas de sulfo-rodamina B e citometria de fluxo. Resultados e Conclusões: De H. caprifoliatum e H. polyanthemum foram isolados três derivados de floroglucinol diméricos. Estes produtos podem ser considerados marcadores quimiotaxonômicos das seções Brathys e Trigynobrathys do gênero Hypericum, as quais incluem todas as espécies nativas do sul do Brasil. Os flavonóides, quercetina e hiperosídeo foram isolados de H. caprifoliatum. Os três benzopiranos testados (Hp1, Hp2 e Hp3) demonstraram capacidade de inibir o crescimento de células endoteliais de forma dose-dependente. Os compostos Hp2 e Hp3 foram capazes de bloquear fases do ciclo celular. / The use of St. John’s Wort extracts as a phytomedicine to treat depression in several countries around the world has stimulated investigators in order to study the chemical and biological properties of Hypericum species. Purpose: to investigate the chemical composition of native representants of Hypericum genus (H. caprifoliatum, H. polyanthemum, among others), to carry out a chemotaxonomic study about the significance of phloroglucinol derivatives in Hypericum species and to evaluate the antiproliferative activity of three benzopyrans isolated from H. polyanthemum against endothelial cells. Methods: for the isolation and identification of the compounds chromatographic techniques such as TLC, CC and HPLC were employed. The structures were determined through NMR spectroscopy, spectrometry and ultraviolet analyses. In order to study the significance of the phloroglucinol derivatives, data on the occurrence of these compounds was surveyed in the literature. The antiangiogenic activity was performed in both Sulforhodamine B and Flow Cytometry assays. Results and Conclusions: From H. caprifoliatum and H. polyanthemum three phloroglucinol derivatives with a dimeric structure were identified. These group of products could be considered as chemotaxonomic markers from species of the Hypericum genus belonging to the Brathys and Trigynobrathys sections, which include all the native representants. This work also presents the isolation and structural determination of two well known flavonoids, quercetin and hyperoside, from H. caprifoliatum. The three benzopyrans, Hp1, Hp2 and Hp3, showed a dose-dependant cytotoxic activity against endothelial cells. The isomers Hp2 and Hp3 were able to cause modifications on the normal cell cycle.

There is mounting evidence to support combined therapy with radiation (RT) and antiangiogenic agents (AA) for the treatment of brain tumors. However, the therapeutic benefit of this combined treatment hinges on the specific dose, schedule, and duration of each treatment. Early biomarkers that reflect tumor physiological responses provide key information that could guide these aspects of treatment. Pre-clinical tumor models are invaluable tools for identifying potential biomarkers, their optimal timing for measurement and their ability to guide therapy in clinical translation. This thesis demonstrates the feasibility and potential of serial MRI to guide the design, delivery and measure of early response to combined AA and RT in a murine intracranial glioma model. We identified promising biomarker changes reflecting early treatment response that may ultimately facilitate individualized spatio-temporal delivery of radiotherapy (RT) and anti-angiogenic agents (AA) for brain tumors.

There is mounting evidence to support combined therapy with radiation (RT) and antiangiogenic agents (AA) for the treatment of brain tumors. However, the therapeutic benefit of this combined treatment hinges on the specific dose, schedule, and duration of each treatment. Early biomarkers that reflect tumor physiological responses provide key information that could guide these aspects of treatment. Pre-clinical tumor models are invaluable tools for identifying potential biomarkers, their optimal timing for measurement and their ability to guide therapy in clinical translation. This thesis demonstrates the feasibility and potential of serial MRI to guide the design, delivery and measure of early response to combined AA and RT in a murine intracranial glioma model. We identified promising biomarker changes reflecting early treatment response that may ultimately facilitate individualized spatio-temporal delivery of radiotherapy (RT) and anti-angiogenic agents (AA) for brain tumors.

A brief introduction to cancer biology and treatment is presented with a focus on current clinical advances in the delivery of chemotherapy and antiangiogenic therapies. Mathematical oncology is then surveyed with summaries of various models of tumor growth, tumor angiogenesis and other relevant biological entities such as angiogenic growth factors. Both strictly time-dependent ordinary differential equation (ODE)-based and spatial partial differential equation (PDE)-based models are considered. These biological models are first developed into an ODE model where various treatment options can be compared including different combinations of drugs and dosage schedules. This model gives way to a PDE model that includes the spatially heterogeneous blood vessel distribution found in tumors, as well as angiogenic growth factor imbalances. This model is similarly analyzed and implications are summarized. Finally, including the effects of interstitial fluid pressure into an angiogenic activity model is performed. This model displays the importance of factor convection on the angiogenic behaviour of tumours.

A brief introduction to cancer biology and treatment is presented with a focus on current clinical advances in the delivery of chemotherapy and antiangiogenic therapies. Mathematical oncology is then surveyed with summaries of various models of tumor growth, tumor angiogenesis and other relevant biological entities such as angiogenic growth factors. Both strictly time-dependent ordinary differential equation (ODE)-based and spatial partial differential equation (PDE)-based models are considered. These biological models are first developed into an ODE model where various treatment options can be compared including different combinations of drugs and dosage schedules. This model gives way to a PDE model that includes the spatially heterogeneous blood vessel distribution found in tumors, as well as angiogenic growth factor imbalances. This model is similarly analyzed and implications are summarized. Finally, including the effects of interstitial fluid pressure into an angiogenic activity model is performed. This model displays the importance of factor convection on the angiogenic behaviour of tumours.