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Orientador: Carlos Rossa Júnior / Resumo: Curcumin é o principal composto biologicamente ativo extraído do rizoma da espécie Curcuma longa. Diversos estudos relatam efeitos biológicos do curcumin que são de interesse em diferentes condições clínicas, como doenças inflamatórias intestinais, artrite reumatóide, câncer, diabetes, obesidade, depressāo, líquen plano e periodontite. Estudos pré-clínicos em modelos de periodontite experimental consistentemente demonstram efeito anti-inflamatório com a redução da reabsorção óssea. No entanto, existem poucas informações sobre o efeito biológico do curcumin no reparo dos tecidos periodontais, uma vez que na maioria dos estudos pré-clínicos a administração do curcumin é feita como único tratamento e de forma concomitante à indução da doença. Estudos clínicos do uso do curcumin como adjuvante do tratamento periodontal mecânico relatam, em geral, efeitos benéficos; porém há necessidade de avaliação sistemática dos resultados e da validade interna e externa dos trabalhos clínicos. Este trabalho tem o objetivo geral de investigar o potencial do curcumin aplicado localmente como adjuvante do tratamento periodontal mecânico no reparo dos tecidos periodontais. A hipótese é que a aplicação local de curcumin potencializa seus efeitos biológicos favorecendo o reparo tecidual ao evitar as dificuldades associadas às pobres propriedades farmacocinéticas da administração oral. O trabalho está organizado em três estudos: (i) estudo pré-clínico em modelo de periodontite experimental com aplica... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Curcumin is the main biologically active compound extracted from the rhizome of the Curcuma longa. Several studies report biological effects of curcumin that are of interest in different clinical conditions, such as inflammatory bowel diseases, rheumatoid arthritis, cancer, diabetes, obesity, depression, lichen planus and periodontitis. Pre-clinical studies in experimental periodontitis models consistently demonstrate an anti-inflammatory effect by reducing bone resorption. However, there is limited information on the biological effect of curcumin in repairing periodontal tissues, since in most preclinical studies curcumin is administered as the sole treatment and concurrently with the induction of the disease. Clinical studies using curcumin as an adjunct to mechanical periodontal treatment report, in general, beneficial effects; however, there is a need for systematic evaluation of the results and the internal and external validity of clinical studies. This work aims to investigate the potential of locally-delivered curcumin as an adjunct to mechanical periodontal treatment in the repair of periodontal tissues. The hypothesis is that local application of curcumin enhances its biological effects, favoring tissue repair by avoiding issues associated with the poor pharmacokinetic properties of oral administration. The work is organized in three studies: (i) pre-clinical study in an experimental periodontitis model with local application of curcumin as an adjunct to mechanical ... (Complete abstract click electronic access below) / Doutor

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Stress-related psychological ill health has increased dramatically in Europe. A diagnosis equivalent to occupational burnout can be found in the Swedish version of the tenth edition of the “International Statistical Classification of Diseases and Related Health Problems" by the World Health Organization. The Swedish National Board of Health and Welfare lists treatment suggestions including a section of self-care that recommended something that could be translated to “a sensible diet” (“vettig kost”) without providing evidence for what could constitute a sensible diet. By using the hypothesis of burnout being a stress-mediated decrease in neurogenesis which in turn decrease the ability to cope with stress, this article systematically reviews the efficacy of dietary polyphenols on neurogenesis in rodents to evaluate if dietary polyphenols could constitute a part of a sensible diet for burnout patients. Dietary polyphenols significantly increased various parts of neurogenesis, in rodents subjected to stressors, in some cases demonstrating effect sizes comparable to antidepressants. Adverse effects have been observed in extremely high doses and young rodents not exposed to induced stressors with a putative high level of neurogenesis.

Orientador: Livia Nordi Dovigo / Resumo: Na saliva humana é possível identificar a presença de diversas espécies constituintes do microbioma oral. De forma geral, as bactérias presentes na saliva em estado planctônico podem ou não ser agentes causais diretos das doenças, sendo o desequilíbrio microbiano apontado como principal fator a permitir que bactérias mais virulentas se tornem dominantes e desencadeiem patologias. Com o intuito preventivo ou de tratamento diversas formas de tentar conter ou eliminar os microrganismos têm surgido. Uma nova técnica que vem sendo investigada é a Inativação Fotodinâmica (do inglês Photodynamic Inactivation, PDI), cujo mecanismo de ação envolve a utilização de um fotossensibilizador (FS), sua iluminação com uma fonte de luz de comprimento de onda compatível com o espectro de absorção do FS e a presença de oxigênio. A Curcumina (CUR) vem sendo apontada como potencial FS e diversos estudos vêm propondo alternativas farmacológicas para sua veiculação. O objetivo geral desse estudo foi investigar o efeito antimicrobiano da PDI utilizando a CUR em um sistema precursor de cristal líquido (CL) sobre amostras de saliva humana. Tratou-se de estudo experimental laboratorial no qual diferentes indivíduos forneceram amostras de saliva não estimulada, sendo então as amostras de saliva distribuídas aleatoriamente em diferentes grupos. Como variáveis de desfecho tem-se o número de unidades formadoras de colônia por mililitro (UFC/mL), avaliadas em quatro diferentes meios de cultura para identific... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: It is possible to identify the presence of several constituent species of the oral microbiome in human saliva. Generally, bacteria present in saliva in planktonic state could be responsible agents of the diseases, and the microbial imbalance is indicated as the main factor to allow more virulent bacteria to become dominant and to trigger pathologies. In order to prevent or treat, many ways of trying to contain or eliminate microorganisms have arisen. A new technique that has been investigated is the Photodynamic Inactivation (PDI), whose mechanism of action involves the use of a photosensitizer (FS), its illumination with a light source of wavelength compatible with the spectrum of absorption of FS and the presence of oxygen. Curcumin (CUR) has been identified as a potential FS and several studies have proposed pharmacological alternatives for its use. The general objective of this study was to investigate the antimicrobial effect of PDI using CUR in a liquid crystal precursor (CL) system on samples of human saliva. This was an experimental laboratory study in which different individuals provided samples of nonstimulated saliva, and the saliva samples were randomly distributed in different groups. As outcome variables, the number of colony forming units per milliliter (CFU/mL) evaluated in four different culture media for presumptive identification of selected species was used. As independent variables are the treatment (i PDI: Photodynamic Inactivation; ii CUR: curcumin only; iii Control: only the vehicle of the formulations) and formulation (i.CL: liquid crystal precursor system; ii DMSO: 10% DMSO). The crossing of these variables gave rise to six experimental groups. After the treatments, quantification of viable cells in each sample by sowing in four culture media: Mitis Salivarius for presumptive identification of mutans...(Complete abstract electronic access below) / Mestre

>Magister Scientiae - MSc / During the course of this study iron oxide nanoparticles, which have been researched for drug-targeted delivery, were synthesised via the co-precipitation method and characterised using various methods. This study focused on the role of relevant capping agents for the inhibition of agglomeration of the particles; chitosan, polyvinyl alcohol (PVA) and poly lactic glycolic acid (PLGA) were the capping agents of interest. The study is an assessment of the effects brought about the different capping agents used for this work. The prepared particles were then capped with the different capping agents followed by the loading of the drug curcumin. Various analytical methods were used to analyse the particles such as High resolution transmission electron microscopy (HR-TEM), Superconducting quantum interference device (SQUID), Fourier Transform Infrared spectroscopy (FT-IR), X-ray diffraction (XRD), Thermogravimetric analysis (TGA) and zeta potential. PVA, chitosan and PLGA capped SPIONS were successfully prepared and verified by FT-IR spectrometry, various sizes were prepared almost ranging the same for the successfully prepared particles verified by XRD. The resultant particles were found to be spherical with an average particles size between 13- 22 nm. From the study it was concluded that the addition of the different capping agents resulted in the reduction of the intensity of the peaks in XRD, it was also found out the presence of the capping agents did not alter the crystalline phase of the particles. From the study it was also observed that higher saturation magnetization was experienced where PVA was used as the capping agents.

引子: 共晶技術和納米沉澱技術於近年被廣泛討論能改進藥物性質和提高體內性能。本論文研究旨在將該兩種技術嘗試應用於五種模型藥物中，分別是薑黃素(CUR)，氟比洛芬(FLU)，布洛芬(IBU)，酮洛芬(KET) 和環氧洛芬(LOX)。這些藥物均難溶於水，擁有較差機械性質，相對高的親油性和潛在治療腦退化症的功用。在共晶技術中，藥物將會與煙酰胺(NCT)先溶於在溶劑中，透過蒸發以誘發共晶產生。另一方面，瞬時納米沉澱(FNP)技術會將藥物溶液(包含穩定劑)與反溶劑在封閉衝擊射流混合器(CIJM)或多入口渦旋混合器(MIVM)快速混合，生成納米藥物。 / 方法: 將藥物和NCT溶於乙醇中，應用旋轉蒸發或簡單蒸發生成共晶。透過不同的檢測方法，包括X射線衍射，差示掃描量熱法，熱重分析，吸濕分析，傅立葉變化紅外線光譜，特性溶出速率量度法和壓實分析將共晶檢定。另一方面，利用CIJM或MIVM，藥物在不同的混合速率，溶劑性質，聚乙二醇-聚乳酸(穩定劑)分子重量或藥物對聚合物比的工藝環境下載入於納米粒子中。生產出來的納米藥物會利用動態光散射測定粒徑; 電泳光散射法測定zeta電位; 掃描電子顯微鏡和原子力顯微鏡測定粒子形貌和其表面性質; X-射線光電子能譜測定表面成分; 高效液相色層分析測定載藥量和包封率。 / 結果: 利用旋轉蒸發，高純度的1:1 IBU-NCT 和FLU-NCT 的共晶能成功生成，但KET-NCT和LOX-NCT 共晶則不能獲得。低純度的CUR-NCT 共晶可根據相同技術取得。相比原來藥物而言，IBU-NCT 和FLU-NCT 共晶均有較好的機械性質，抗吸水性和溶解速度。而在FNP研究中，証實了混合速率，溶劑性質，聚乙二醇-聚乳酸(穩定劑)分子重量或藥物對聚合物比均對生產出來的納米粒子的粒徑有重要影響。另外，納米粒子的穩定性可籍添加輔助穩定劑(如PVA)大幅提高。XPS分析証實輔助穩定劑能與在粒子表面的聚乙二醇起相互作用，更佳地保護粒子。而在一系列對四種不同的洛芬藥物的實驗中，多次線性回歸分析指出三種有關藥物的溶液性質(即溶解度，分配係數和酸度系數)會對生成的納米粒子的粒徑和包封率有顯著影響。 / 結論: 將IBU和FLU與NCT結成共晶能同時提高其機械性質，抗吸水性和溶解速度。而在FNP中，優化不同工藝參數能有效控制納米藥物的粒徑，形態，表面性質和穩定性。 / Introduction: In recent years, cocrystallization and nanoprecipitation have gained increasing popularity as viable strategies for improving the pharmaceutical properties and in vivo performance of drugs. The present thesis was aimed at assessing these two approaches for potential applications in pharmaceutical formulation and manufacture with five model drugs, viz. curcumin (CUR), flurbiprofen (FLU), ibuprofen (IBU), ketoprofen (KET) and loxoprofen (LOX). Selection of these drugs for the study was guided mainly by their poor water solubility, poor compactibility, typical drug‘s lipophilicity (log P =3-5), and potential for treatment of Alzheimer‘s disease. Cocrystallization was induced by the attainment of a sufficient supersaturation level through rapid solvent removal from a solution containing the drug and the coformer, nicotinamide (NCT), while flash nanoprecipitation (FNP) was achieved by rapid and homogenous mixing of drug solution (with stabilizer and co-stabilizer if required) with antisolvent in the mixing chamber of a specially designed confined impinging jet mixer (CIJM) or multi-inlet vortex mixer (MIVM). / Methods: Cocrystals were prepared by rotary solvent evaporation or slow evaporation of a solution of drug and NCT in ethanol, and characterized by powder X-ray diffraction, differential scanning calorimetry, thermogravimetry, moisture sorption analysis, Fourier transform infrared spectroscopy, intrinsic dissolution rate (IDR) measurement and compaction analysis. Polymer-stabilized drug nanoparticles were prepared by FNP using a two-stream CIJM or four-stream MIVM under defined conditions of varying flowrate, solvent type, molecular weight of amphiphilic diblock (PEG-PLA) copolymer (stabilizer), or drug-to-copolymer ratio. The resulting nanoparticles were characterized for particle size by dynamic light scattering; zeta potential by electrophoretic light scattering; particle morphology and surface properties by scanning electron microscopy and atomic force microscopy; surface composition by X-ray photoelectron spectroscopy (XPS); and drug loading and encapsulation efficiency (EE) by high performance liquid chromatography. / Results: Phase-pure 1:1 cocrystals of IBU and FLU with NCT were obtainable by rotary solvent evaporation, but not slow evaporation. Similar solvent removal failed to cause any cocrystal formation for KET and LOX while inducing partial cocrystal conversion for CUR. Both IBU-NCT and FLU-NCT cocrystals displayed enhanced IDR, reduced moisture sorption and improved tabletability compared with the individual profen crystals. FNP studies using the MIVM confirmed the flowrate, solvent type, molecular weight of PEG-PLA copolymer, and drug-to-copolymer mass ratio being important process variables for controlling particle size and particle stability. Particle stability could be enhanced with a hydrophilic co-stabilizer (e.g., PVA). Such co-stabilizers possibly act by binding to the PEG corona at the particle surface to reinforce the protective steric barrier, as substantiated by XPS data. Comparative studies on nanoparticle production by FNP for the four profens indicated that three structure-related intrinsic solution properties of the profens, namely, water solubility, log P and pKa, were important determinants of the particle size and EE of nanoparticles, as determined by multiple linear regression analysis. / Conclusion: Cocrystallization with NCT can simultaneously improve the tableting behavior, hygroscopicity, and dissolution performance of IBU and FLU. Proper optimization of the process variables in FNP is critical to the controlled production of polymer-stabilized drug nanoparticles with consistent properties and storage stability. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Chow, Shing Fung. / Thesis (Ph.D.) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 224-247). / Abstracts also in Chinese.

O câncer é uma doença que causa grande número de mortes a cada ano e os tratamentos convencionais normalmente ocasionam efeitos colaterais indesejados além do que nem sempre são eficazes. A terapia fotodinâmica (TFD) é uma modalidade alternativa de tratamento, que se baseia na combinação de um fotossensibilizador (FS), luz e oxigênio, e tem mostrado resultados promissores em vários tipos de câncer. No entanto, existem alguns desafios para o desenvolvimento de fotossensibilizadores que cumprem os requisitos para uso clínico. Os compostos, hipericina (HY) e curcumina (CUR), estão presentes em plantas medicinais, possuem altos rendimentos quânticos e podem ser usados como FS em TFD. O objetivo deste trabalho foi comparar a eficiência fotodinâmica da HY e CUR através de suas propriedades físico-químicas e biológicas, tais como coeficiente de absortividade molar (&#949), coeficiente de partição (Log P), fotodegradação, atividade fotodinâmica de geração de oxigênio singlete e a resposta biológica usando ensaios citotóxicos e microscopia de fluorescência para avaliar o tipo de morte celular. A HY apresenta propriedade anfifílica, enquanto a CUR, hidrofóbica. A HY é mais fotoestável, enquanto a CUR fotodegrada facilmente sob irradiação em 455 nm levando à formação de fotoprodutos que possuem menor citotoxicidade que a CUR íntegra, o que sugere que a eficiência da TFD diminui conforme este corante é irradiado. Além disso, a alta eficiência de geração de oxigênio singlete de HY corrobora com a sua fototoxicidade mais elevada em comparação com a CUR. A concentração inibitória média (IC50) da HY em células de carcinoma epidermóide de laringe humana (HEp-2) é 256 vezes menor para CUR sob a mesma dose de luz. A investigação do tipo de morte celular foi realizada por microscopia de fluorescência após TFD utilizando os FSs em concentração equivalente a duas vezes o valor de IC50. HY-TFD promoveu cerca de 1,5 vezes mais apoptose nas células HEp-2 do que a CUR. Além disso, a acumulação intracelular dos FSs analisada por Microscopia Confocal de fluorescência mostrou que a CUR apresenta uma velocidade de acumulação menor que a HY. Em conclusão, os resultados obtidos sugerem que a HY é um FS mais eficiente que a CUR para TFD, porém como a CUR e a HY apresentam baixa toxicidade na ausência de luz, são compostos seguros para serem utilizados clinicamente. / Cancer is a disease that causes several deaths each year and the treatment modalities are not quite selective and usually bring about intensive side effect besides not very effective sometimes. Photodynamic therapy (PDT) is an alternative treatment, which is based on the combination of a photosensitive molecule, light activation and oxygen. Many studies have shown promising results with PDT in diverse types of cancer. However, there are some challenges for the development of photosensitizers to comply the requisites for clinical use. The compounds hypericin (HY) and curcumin (CUR), are present in medicinal plants, have high fluorescence quantum yields and can be used as PS in PDT. In this study, we compare HY and CUR through the study of theirs physic-chemical and biological properties, as well as photo degradation, determination of the partition coefficient (Log P) and the molar absorptivity coefficient (&#949), the photodynamic activity as an indirect estimation of singlet oxygen generation potential and the biological response using cytotoxicity assays as well as fluorescence microscopy. The results suggested that HY presents amphiphilic property while CUR is hydrophobic. HY is more photostable than CUR, which is easily photodegradated at 455 nm leading to the formation of photoproducts. The cytotoxicity of these photoproducts was investigated being lower than that of CUR, which suggests that the efficiency of CUR-PDT decreases while this dye is irradiated. Furthermore, the elevated oxygen singlet generation of HY corroborates with its higher phototoxicity compared to CUR. The median inhibitory concentration (IC50) of HY in human epidermoid cancer cells (HEp-2) is 256 times lower than the IC50 for CUR at equal light irradiance. The investigation on the type of cell death was carried out by fluorescence microscopy after PDT using the photosensitizers at concentration equivalent to 2x IC50 values. HY-PDT induced around more 1.5 times apoptosis cell death than CUR-PDT. Besides, the intracellular accumulation of PS analyzed by fluorescence Confocal Microscopy has demonstrated that the accumulation of CUR is slower than HY. In conclusion, our findings suggest that HY is a more efficient PS than CUR for PDT, however, as CUR and HY present low toxicity in the absence of light, they are safe compounds to be clinically used.

In the United States, more than 130,000 people will be diagnosed with colorectal cancer (CRC) each year and an estimated 50,000 people will die from the disease. Standard of care (SOC) therapies for CRC combine multiple cytotoxic chemotherapeutic drugs. These combinations have varying degrees of effectiveness and can often result in significant patient morbidity. For second recurrence patients, the multi-kinase inhibitor, regorafenib, is an approved agent, but is often poorly tolerated at current doses. In the current study, we propose to develop therapeutic regime of combining agents with modest toxicity profiles: curcumin and sildenafil with regorafenib. Using clinically achievable enterohepatic drug concentrations (~2.0 μM), our laboratory has shown that both sildenafil and curcumin interact to synergistically down regulate the expression of multiple cyto-protective molecular chaperones and kill CRC cells in a greater than additive manner in vitro and suppress the growth of colon cancer tumors in vivo. In this study, the expression of PDGFRb and PDGF in the plasma was increased in colon tumor bearing mice previously exposed to curcumin and sildenafil. Further, the in vitro killing potential of curcumin and sildenafil was shown to be reduced in evolved tumor cells from these mice. The purpose of this study was to determine whether down regulation of PDGFRb using regorafenib would increase the lethality of curcumin and sildenafil in colorectal cancer cell lines in vitro and in vivo. In the current study, we have shown that with the [2μM curcumin + 2μM sildenafil + 2μM regorafenib] drug combination reduces of cyto-protective proteins, enhances cytotoxicity and creates a carnage of CRC cells in a greater than additive in vitro. The combination also suppressed growth of colon cancer tumors in vivo, when compared to curcumin and sildenafil alone. In addition we have shown that the [2μM curcumin + 2μM sildenafil + 2μM regorafenib] drug combination can modulate immune checkpoint proteins in vitro. These results suggest that this drug combination may enhanced the anti-tumor efficacy of anti-PD-1 and anti-CTLA4 antibodies.