Yes / The ligands L1 and L2 both form separable dinuclear double‐stranded helicate and mesocate complexes with RuII. In contrast to clinically approved platinates, the helicate isomer of [Ru2(L1)2]4+ was preferentially cytotoxic to isogenic cells (HCT116 p53−/−), which lack the critical tumour suppressor gene. The mesocate isomer shows the reverse selectivity, with the achiral isomer being preferentially cytotoxic towards HCT116 p53+/+. Other structurally similar RuII‐containing dinuclear complexes showed very little cytotoxic activity. This study demonstrates that alterations in ligand or isomer can have profound effects on cytotoxicity towards cancer cells of different p53 status and suggests that selectivity can be “tuned” to either genotype. In the search for compounds that can target difficult‐to‐treat tumours that lack the p53 tumour suppressor gene, [Ru2(L1)2]4+ is a promising compound for further development.

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Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Botany and Ecology Author: Radka Kvapilová Supervisor: RNDr. Jitka Vytlačilová, Ph.D. Title of diploma thesis: Antiprotozoal activity of alkaloids II. The development of new antiprotozoal agents for the treatment of infections is very important. Natural substances can be the source of effective drugs. The aim of this study was to evaluate the antiprotozoal activity of these alkaloids - canadine, scoulerine, tetrahydropalmatine and stylopine. The experiment was conducted on typical model organism Tetrahymena thermophila. Percentage inhibition of the organism was determined using the MTT assay. Subsequently median inhibitory concentration IC50 of the test substances was calculated. From our alkaloids stylopine had the greatest antiprotozoal activity. Antiprotozoal activity decreased in the following order stylopine > canadine > scoulerine > tetrahydropalmatine. Key words: Tetrahymena thermophila, antiprotozoal activity, canadine, scoulerine, tetrahydropalmatine, stylopine

Quantum dots (QDs), especially colloidal semiconductor QDs, possess properties including high quantum yields, narrow fluorescence spectra, broad absorption and excellent photostability, making them extremely powerful in bioimaging. In this thesis, we studied the fluorescence properties of QDs and attempted multiple ways to boost applications of QDs in bioimaging field. By time-correlated single photon counting (TCSPC) measurement, we quantitatively interpreted the fluorescence mechanism of colloidal semiconductor QDs. To enhance QD fluorescence, we used a porous alumina membrane as a photonic crystal structure to modulate QD fluorescence. We studied the acid dissociation of 3-mercaptopropionic acid (MPA) coated QDs mainly through electrophoretic mobility of 3-MPA coated CdSe QDs and successfully demonstrated the impact of pH change and Ca2+ ions. Blinking phenomena of both CdSe-CdS/ZnS core-shell QDs and 3C-SiC nanocrystals (NCs) were studied. A general model on blinking characteristics relates the on-state distribution to CdSe QD surface conditions. The energy relaxation pathway of fluorescence of 3C-SiC NCs was found independent of surface states. To examine QD effect on ciliated cells, we conducted a 70-day long experiment on the bioelectric and morphological response of human airway epithelial Calu-3 cells with periodic deposition of 3-MPA coated QDs and found the cytotoxicity of QDs was found very low. In a brief summary, our study of QD could benefit in bioimaging and biosensing. Especially, super-resolution fluorescent bioimaging, such as, stochastic optical reconstruction microscopy (STORM) and photo-activated localization microscopy (PALM), may benefit from the modulation of the QD blinking in this study. And fluorescence lifetime imaging (FLIM) microscopy could take advantage of lifetime modulation based on our QD lifetime study. / <p>QC 20160905</p>

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements of the degree of Masters of Science. February 2017. / Cancer has become a problematic fatal disease in developing and industrialised countries with pancreatic cancer as the seventh leading cause of cancer-related deaths, with an average survival rate of less than 5%. Environmental risk factors associated with pancreatic cancer include smoking, obesity, diet, alcohol etc. Furthermore, pancreatic cancer is commonly diagnosed at a late stage where its response to current anti-cancer agents is poor. Consequently, with South Africa being a 3rd world country and the cost of chemotherapy being so high, this has led to us trying to identify new, cheaper therapeutics for cancer cells. A majority (80%) of the South African population relies on traditional medicines, hence in this study we aimed to assess Lobostemon fruticosus for anti-proliferative effects on pancreatic cancer cell line (AsPC-1). This was achieved by the use of methanol and butanol extracts of L. fruticosus to screen for induction of apoptosis and inhibition of cell proliferation. The plant was collected, dried, crushed and dissolved in butanol and methanol to obtain experimental extracts. Cytotoxicity of the plant on Aspc-1 was determined using MTT Assay, xCELLigence and cell cycle analysis. MRC-5 cell line was used as a positive control cell line. L. fruticosus extracts induced cell death at IC50 of 60µg/ml (methanol extract) and 50µg/ml (butanol extract) at 48hour treatments on AsPC-1 cell line. Western Blots showed that the methanol and butanol extracts of L. fruticosus led to slight upregulation of the apoptotic gene p53 in AsPC-1 cell line, which was further confirmed by FACS apoptosis detection. Cell cycle analysis further showed the plant extracts do promote cell cycle arrest. LC/MS of the extracts gave spectra of active compounds presumed to play a role in induction of apoptosis on the pancreatic cancer cell line. The data obtained implies that the methanol and butanol extracts of L. fruticosus does have, to a certain extent, growth inhibiting and apoptosis inducing potential on the pancreatic cancer cell line. KEYWORDS: Lobostemon fruticosus, Pancreatic Cancer, methanol extract, butanol extract, AsPC-1 / LG2017

Resveratrol (3, 4, 5-trihidroxiestilbeno) é um polifenol produzido por uma grande variedade de plantas em resposta ao estresse e encontrado predominantemente em cascas de uvas. Este princípio ativo apresenta vários benefícios à saúde, como a capacidade antioxidante, relacionada à prevenção de diversos tipos de câncer e do envelhecimento precoce da pele. No entanto, apresenta baixa biodisponibilidade quando administrado por via oral, o que torna interessante sua aplicação tópica. O principal objetivo deste trabalho foi a incorporação de resveratrol em hidrogéis poliméricos para obtenção de um sistema de liberação utilizado topicamente contra o desenvolvimento de desordens cutâneas, como o envelhecimento cutâneo e o câncer de pele. As matrizes poliméricas compostas por poli(N-vinil-2-pirrolidona) (PVP), poli(etileno glicol) (PEG) e ágar ou PVP e propano-1,2,3-triol (glicerina) e irradiadas a 20 kGy foram caracterizadas pelos ensaios de fração gel e intumescimento; sua biocompatibilidade preliminar foi avaliada in vitro por meio do ensaio de citotoxicidade utilizando o método de incorporação do vermelho neutro. Devido à baixa solubilidade do resveratrol em água, verificou-se o efeito da adição de 2% de etanol às matrizes. Todas as matrizes estudadas, contendo ou não álcool, apresentaram alto grau de reticulação, capacidade de intumescimento e não apresentaram toxicidade em ensaio preliminar de biocompatibilidade. Os dispositivos foram obtidos pela incorporação de resveratrol nas matrizes poliméricas, realizada de forma direta e indireta, ou seja, antes e após irradiação, respectivamente. Os dispositivos obtidos pelo método direto foram submetidos aos ensaios de fração gel, intumescimento e citotoxicidade e apresentaram-se semelhantes às respectivas matrizes. Os dispositivos contendo 0,05% de resveratrol obtidos pelo método direto e os dispositivos contendo 0,1% de resveratrol obtidos pelo método indireto foram submetidos ao ensaio de cinética de liberação durante 24 h. A quantificação do resveratrol liberado foi realizada por cromatografia líquida de alta eficiência (HPLC). Apenas os dispositivos obtidos pelo método indireto apresentaram capacidade de liberar o resveratrol incorporado, que apresentou capacidade antioxidante após liberação. / Resveratrol (3, 4, 5-trihydroxystilbene) is a polyphenolic produced by a wide variety of plants in response to injury and found predominantly in grape skins. This active ingredient has been shown to possess benefits for the health, such as the antioxidant capacity which is related to the prevention of several types of cancer and skin aging. However, the oral bioavailability of resveratrol is poor and makes its topical application interesting. The purpose of this study was to immobilize resveratrol in polymeric hydrogels to obtain a release device for topical use. The polymeric matrices composed of poli(N-vinyl-2-pyrrolidone) (PVP), poly(ethyleneglycol) (PEG) and agar or PVP and glycerol irradiated at 20 kGy dose were physical-chemically characterized by gel fraction and swelling tests and its preliminary biocompatibility by in vitro test of cytotoxicity using the technique of neutral red uptake. Due to low solubility of resveratrol in water, the addition of 2% ethanol to the matrices was verified. All matrices showed a high crosslinking degree, capacity of swelling and the preliminary cytotoxicity test showed nontoxicity effect. The devices were obtained by resveratrol immobilizaton in polymeric matrices, carried out in a one-or-two-steps process, that is, before or after irradiation, respectively. The one step resveratrol devices were characterized by gel fraction, swelling tests and preliminary biocompatibility, and their properties were maintained even after the resveratrol incorporation. The devices containing 0,05% of resveratrol obtained by one-step process and 0,1% of resveratrol obtained by two-steps process were submitted to the release test during 24 h. Resveratrol quantification was done by high performance liquid chromatography (HPLC). The results obtained in the kinetics of release showed that only the devices obtained by two-step process release the resveratrol, which demonstrate antioxidant capacity after the release.

Orientador: Reinaldo Marchetto / Banca: Marlus Chorilli / Banca: Luis Geraldo Vaz / Resumo: A celulose bacteriana (CB) é sintetizada por vários tipos de bactérias, com maior eficiência pela Gluconacetobacter xylinus. A CB é um biomaterial que têm uma estrutura de rede de nano fibras tridimensional com propriedades como biocompatibilidade, não toxicidade, estabilidade mecânica e alto teor de umidade, que a torna promissora para diversas aplicações, sendo que na engenharia de tecidos sua multifuncionalidade abrange a substituição temporária de tecido epitelial em casos de queimaduras, úlceras, lesões, carreador de fármacos, dentre outros propósitos. Apesar da CB apresentar potencial para ser utilizado como curativo, faz-se necessário a realização de modificações de sua superfície, com a incorporação de moléculas de adesão celular, para ajustar as deficiências da CB nativa, a fim de melhorar a adesão, migração, proliferação e diferenciação celular, tornando-se promissora para aplicações biomédicas. Deste modo, este trabalho objetivou desenvolver um curativo à base de CB contendo peptídeo promotor de adesão celular RGD (Arginina-Glicina-Ácido aspártico), sequência encontrada em várias proteínas da matriz extracelular (MEC), e avaliar in vitro sua viabilidade e proliferação de fibroblastos, com a finalidade de aplicação em regeneração tecidual de pele. O peptídeo RGD utilizado (JGB2) foi escolhido por meio de estudos computacionais, sendo sintetizado pelo método da fase sólida (estratégia Fmoc), purificado por CLAE e caracterizado por espectrometria de massas. Membranas ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Bacterial celulose (BC) is synthesizedby some bacteria, with greater efficiency by Gluconacetobacter xylinus.BC is a biomaterial that has a network 3-D structure of nanofibers with properties like biocompatibility, non-toxicity, mechanical stability, and high moisture content, whichmakes it promising fora wide range of applications, being that in the engineering of tissue its multifunctionality includes the temporary substitution of epithelial tissue in cases of burns, ulcers, injuries, drug carriers, among other purposes. Although CB present potential to be used as a dressing, it is necessary to perform modifications of its surface with the incorporation of cell adhesion moleculesto adjust the deficiencies of the native CB, in order to improve cell adhesion, migration, proliferation and differentiation, making it a promising material for biomedical applications.In this way, this work aimed to develop a dressing based on BC containing peptide promoter of cell adhesion RGD (Arginine-Glycine-Aspartic acid), sequence found in several extracellular matrix proteins (ECM) and to evaluate in vitroits viability and proliferation of fibroblasts, with the purpose of application in skin tissue regeneration. The RGD peptide used (JGB2) was chosen by means of computational studies, synthesized by the solid phase method (Fmoc strategy), purified by HPLC and characterized by mass spectrometry. CB membranes were produced by G. xylinuns, purified and functionalized by the esterification of tw... (Complete abstract click electronic access below) / Mestre

by Koo Sze Tak. / Thesis (M.Ph.)--Chinese University of Hong Kong, 1988. / Bibliography: leaves 148-165.

As naftoquinonas são quinonas relacionadas com o sistema naftalênico. Essas substâncias constituem também uma classe de intermediários toxicológicos gerados através da biotransformação de hidrocarbonetos aromáticos policíclicos, estrógenos, catecolaminas e de vários outros fármacos.. Micro-organismos têm sido utilizados como ferramentas para prever o metabolismo dos fármacos, servindo como uma plataforma de estudos muito eficiente. Nesse sentido, os fungos filamentosos são utilizados por promover transformações mimetizando as reações hepáticas in vivo dos fármacos. As bactérias intestinais também têm sido empregadas, pois quando as substâncias entram em contato com a microbiota intestinal, também podem ser modificadas por essas bactérias. Juntos, esses micro-organismos podem contribuir para a elucidação de rotas metabólicas dos compostos, fornecendo informações sobre a geração de substâncias mais ativas, inativas ou tóxicas. Além disso, estudos de biotransformação podem ser ferramentas muito úteis para obtenção de novos derivados. Dessa forma, o presente trabalho relata os estudos de metabolismo microbiano de oito naftoquinonas com diferentes substituições (1,2-naftoquinona, 1,4-naftoquinona, lausona, menadiona, lausona metoxilada, plumbagina, 5-hidroxi-naftoquinona e vitamina K1) por diferentes espécies de fungos filamentosos (C.elegans, A.niger, A.brasiliensis, A.alliaceus, C.echinulata, M.rouxii, A.phoenicis, A.ochraceus e R.stolonifer) e bactérias intestinais (Bifidobacterium sp, L.acidophillus e E.coli) bem como pela levedura probiótica S.boulardii. Para isso, inicialmente, foram estabelecidas as condições de cultivo adequadas para cada micro-organismo. Foram feitos estudos sobre a estabilidade dos substratos nas condições experimentais padronizadas, bem como para o estabelecimento das condições de extração dos mesmos. As reações de biotransformação foram monitoradas por 10 dias para os fungos filamentosos e por 36 horas para as bactérias intestinais e para a levedura probiótica e os processos mais promissores foram selecionados para serem realizados em escala ampliada visando o isolamento dos derivados produzidos. A biotransformação da lausona metoxilada possibilitou a produção do derivado codificado como BLM1, identificado como lausona. As reações com a menadiona possibilitaram o isolamento e identificação de cinco metabólitos codificados como BM1, BM2, BM4, BM5 e BM6. Todas as naftoquinonas utilizadas como substratos nos processos de biotransformação e os derivados obtidos foram submetidos a ensaios de citotoxicidade frente a linhagens celulares normais e tumorais. De uma forma geral, as naftoquinonas não apresentaram citotoxicidade elevada quando comparadas com o controle positivo do experimento (doxorrubicina). No entanto, pode-se correlacionar o efeito das pequenas modificações nas estruturas químicas das naftoquinonas com diferentes respostas biológicas. Pôde-se estabelecer também que a manutenção dos grupos cetônicos do núcleo quinonóide são indispensáveis para o aparecimento da atividade citotóxica / Quinones are important organic compounds widely distributed in nature and used as colorants in cosmetics and food. These compounds are also used in medicine as anti-tumor, anti-inflammatory, antimicrobial, among other applications. Naphthoquinones are quinones related to the naphthalene system. These molecules belong to a class of toxic intermediates generated by the biotransformation of polycyclic aromatic hydrocarbons, estrogens, catecholamines and other drugs. The determination of safety and efficacy of drugs is closely related to the study of derivatives formation by in vivo metabolism reactions. Microorganisms have been used as tools to predict drug metabolism and are considered a very efficient platform of studies. Hereof, filamentous fungi are used due to their ability to promote chemical modifications that mimics in vivo liver reactions. Intestinal bacteria have also been used since they are known to modify drugs and other substances that may come into contact with the gut microbiota. Both fungi and bacteria can contribute to the elucidation of metabolic pathways of compounds, providing information about the generation of more active, inactive or toxic substances. Furthermore, biotransformation studies can be useful tools to obtain new derivatives. Hence, the goal of this work was to study the microbial metabolism of eight naphthoquinones with different substitutions (1,2-naphthoquinone, 1,4-naphthoquinone, lawsone, menadione, methoxy lawsone, plumbagin, 5-hydroxy-naphthoquinone and vitamin K1) by several species of filamentous fungi (C.elegans, A.niger, A.brasiliensis, A.alliaceus, C.echinulata, M.rouxii, A.phoenicis, A.ochraceus e R.stolonifer), intestinal bacteria (Bifidobacterium sp, L.acidophillus e E.coli) and the probiotic yeast S.boulardii. Additionally, all naphthoquinones used as substrates in biotransformation processes and the obtained derivatives were evaluated in cytotoxicity assays using normal and tumor cell lines. Initially, appropriate growth conditions were established for each microorganism. Stability studies with the substrates and the determination of appropriate extraction conditions were also carried out. The biotransformation reactions were monitored during 10 days for the filamentous fungi and during 36 h for intestinal bacteria and probiotic yeast. The most promising processes were selected to be carried out in enlarged scale for the isolation of the produced derivatives. The biotransformation of the methoxy-lawsone produced a compound encoded as BLM1 and identified as lawsone. Five metabolites encoded as BM1, BM2, BM4, BM5 e BM7 were identified and isolated from the menadione biotransformations. Regarding the cytotoxicity experiments, the naphthoquinones in general did not display high cytotoxicity when compared with the positive control doxorubicin. However, slight modifications in the naphthoquinones chemical structures were correlated to different biological responses. Additionally, the maintenance of ketone groups of the quinonoid nucleus were considered essential for the cytotoxic activity

Resveratrol (3, 4, 5-trihidroxiestilbeno) é um polifenol produzido por uma grande variedade de plantas em resposta ao estresse e encontrado predominantemente em cascas de uvas. Este princípio ativo apresenta vários benefícios à saúde, como a capacidade antioxidante, relacionada à prevenção de diversos tipos de câncer e do envelhecimento precoce da pele. No entanto, apresenta baixa biodisponibilidade quando administrado por via oral, o que torna interessante sua aplicação tópica. O principal objetivo deste trabalho foi a incorporação de resveratrol em hidrogéis poliméricos para obtenção de um sistema de liberação utilizado topicamente contra o desenvolvimento de desordens cutâneas, como o envelhecimento cutâneo e o câncer de pele. As matrizes poliméricas compostas por poli(N-vinil-2-pirrolidona) (PVP), poli(etileno glicol) (PEG) e ágar ou PVP e propano-1,2,3-triol (glicerina) e irradiadas a 20 kGy foram caracterizadas pelos ensaios de fração gel e intumescimento; sua biocompatibilidade preliminar foi avaliada in vitro por meio do ensaio de citotoxicidade utilizando o método de incorporação do vermelho neutro. Devido à baixa solubilidade do resveratrol em água, verificou-se o efeito da adição de 2% de etanol às matrizes. Todas as matrizes estudadas, contendo ou não álcool, apresentaram alto grau de reticulação, capacidade de intumescimento e não apresentaram toxicidade em ensaio preliminar de biocompatibilidade. Os dispositivos foram obtidos pela incorporação de resveratrol nas matrizes poliméricas, realizada de forma direta e indireta, ou seja, antes e após irradiação, respectivamente. Os dispositivos obtidos pelo método direto foram submetidos aos ensaios de fração gel, intumescimento e citotoxicidade e apresentaram-se semelhantes às respectivas matrizes. Os dispositivos contendo 0,05% de resveratrol obtidos pelo método direto e os dispositivos contendo 0,1% de resveratrol obtidos pelo método indireto foram submetidos ao ensaio de cinética de liberação durante 24 h. A quantificação do resveratrol liberado foi realizada por cromatografia líquida de alta eficiência (HPLC). Apenas os dispositivos obtidos pelo método indireto apresentaram capacidade de liberar o resveratrol incorporado, que apresentou capacidade antioxidante após liberação. / Resveratrol (3, 4, 5-trihydroxystilbene) is a polyphenolic produced by a wide variety of plants in response to injury and found predominantly in grape skins. This active ingredient has been shown to possess benefits for the health, such as the antioxidant capacity which is related to the prevention of several types of cancer and skin aging. However, the oral bioavailability of resveratrol is poor and makes its topical application interesting. The purpose of this study was to immobilize resveratrol in polymeric hydrogels to obtain a release device for topical use. The polymeric matrices composed of poli(N-vinyl-2-pyrrolidone) (PVP), poly(ethyleneglycol) (PEG) and agar or PVP and glycerol irradiated at 20 kGy dose were physical-chemically characterized by gel fraction and swelling tests and its preliminary biocompatibility by in vitro test of cytotoxicity using the technique of neutral red uptake. Due to low solubility of resveratrol in water, the addition of 2% ethanol to the matrices was verified. All matrices showed a high crosslinking degree, capacity of swelling and the preliminary cytotoxicity test showed nontoxicity effect. The devices were obtained by resveratrol immobilizaton in polymeric matrices, carried out in a one-or-two-steps process, that is, before or after irradiation, respectively. The one step resveratrol devices were characterized by gel fraction, swelling tests and preliminary biocompatibility, and their properties were maintained even after the resveratrol incorporation. The devices containing 0,05% of resveratrol obtained by one-step process and 0,1% of resveratrol obtained by two-steps process were submitted to the release test during 24 h. Resveratrol quantification was done by high performance liquid chromatography (HPLC). The results obtained in the kinetics of release showed that only the devices obtained by two-step process release the resveratrol, which demonstrate antioxidant capacity after the release.