Orientador: Fernanda Gonçalves Basso / Resumo: A mucosite é um dos principais efeitos adversos do tratamento oncológico e apresenta influência significativa na morbidade e qualidade de vida dos pacientes submetidos a este tipo de tratamento. A etiopatogenia desta condição vem sendo relacionada não só a toxicidade direta dos quimioterápicos e radiação ionizante, mas também a uma ativação exacerbada da resposta inflamatória dos tecidos. Recentemente, o desenvolvimento e a severidade da mucosite oral também tem sido relacionada a expressão exacerbada de metaloproteinases (MMPs), que resulta na desorganização dos tecidos epitelial e conjuntivo e consequentemente, em atraso do processo de reparo. O manejo da mucosite oral tem sido baseado na utilização de agentes analgésicos tópicos, antibióticos e antifúngicos, bem como na aplicação da laserterapia de baixa intensidade (LBI). A LBI apresenta resultados positivos sobre as lesões de mucosite oral, porém, esta modalidade terapêutica requer a utilização de um equipamento de custo moderado e deve ser feita sob supervisão. Desta forma, novas estratégias preventivas e terapêuticas, que possam atuar na modulação da resposta inflamatória e na expressão de MMPs para diminuir a incidência e a severidade das lesões de mucosite oral e também acelerar o processo de reparo têm sido propostas. Estudos recentes demonstraram a efetividade de compostos naturais, como as antocianinas, na redução da incidência e severidade destas lesões. O objetivo desta pesquisa in vitro foi avaliar comparativam... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Mucositis is the major adverse effect of oncological treatment and presents huge impact on oncological patients' morbidity and quality of life. Etiopathogenesis of oral mucositis has been not only related to a direct toxicity of chemotherapy drugs and radiant therapy, but also to an extended inflammatory reaction. Recently, development and severity of oral mucositis has also been associated to increased expression of metalloproteinases (MMPs), that results in disorganization of epithelial and connective tissues, leading to a delayed tissue healing. Treatment of oral mucositis is based on the application of topic analgesic and antimicrobial compounds, as also low-level lasertherapy (LLLT). LLLT shows positive outcomes on oral mucositis, however, this therapy requires the use of a moderate cost equipament and professional supervision. Therefore, new preventive and therapeutic strategies that can act on the modulation of inflammatory response as well as on MMPs expression could decrease the incidence and severity of oral mucositis, therefore enhancing oral mucosa healing. Recent studies demonstrated the effectiveness of natural compounds, such as antocyanins on the decreased incidence and severity of these lesions. Consequently, the aim of the present in vitro study were to assess the effects of proanthocyanidins (PAs, grape seed extract), naringenin (NA, proanthocyanidins-derived synthetic compound), also denominated flavanones, and LLLT as modulators for synthesis of interleukin-6 and MMPs from gingival fibroblasts. Cells were isolated from the papillary gingival tissue of a young (24 years) and healthy individual by enzymatic digestion, then cultured and submitted to different treatments. The influence of two chemotherapeutic agents (5-fluorouracil - 5-FU and methotrexate - MTX) and inflammatory cytokines (TNF-α, IL-6 and -8) on the induction of MMP-2 and -9 synthesis and gene expression were ... (Complete abstract electronic access below) / Mestre

Les plantes du genre Derris (Fabaceae) sont connues pour contenir des flavonoïdes, en particulier des isoflavonoïdes dont des roténoïdes. Derris ferruginea (Benth.), liane originaire d'Asie, est utilisée traditionnellement comme insecticide, poison de pêche et dans la lutte contre les ectoparasites. L'étude phytochimique d'extraits de tiges et de feuilles de Derris ferruginea a permis d'isoler et de caractériser 14 composés essentiellement de type flavanones et isoflavonoïdes. Ces composés comportent pour la plupart des prénylations. Une évaluation biologique étendue à la fois des extraits et de certains composés a été réalisée. Pour deux composés, des méthodes d'obtention alternatives ont été utilisées. La chromatographie de partage centrifuge a permis d'obtenir en quantité plus importante la cajaflavanone qui s'avère posséder des propriétés intéressantes du point de vue biologique (effet anti-inflammatoire sur cellules microgliales, inhibiteur de la formation des produits terminaux de glycation par un mécanisme non-antioxydatif, effet proangiogénique ex vivo). La synthèse d'un composé original a été entreprise et a permis de valider sa structure. Enfin, le composé majoritaire des feuilles a fait l'objet d'une étude préliminaire sur un modèle d'étude de l'activité insecticide : les DUM neurones de Periplaneta americana. Cette technique électrophysiologique a permis d'appréhender le mécanisme d'action de ce composé.

Grains, leaves, sheaths, glumes and stalks of sorghum varieties were analyzed for total phenols, condensed tannins, flavan-4-ols, anthocyanins and in vitro antioxidant activity. Black sorghum bran was used to evaluate the effectiveness of organic acids and enzymes on extractability of phenols. Flavonoid profiles of grains and non-grain tissues were determined and characterized using HPLC-PDA and HPLC-ESI-MSn. The presence of a pigmented testa and spreader genes (B1B2S) is a predictor for polymeric flavonoids (tannins) but not for simple phenols such as flavan-4-ols, 3-deoxyanthocyanins, flavones and flavanones. Simple flavonoids increased antioxidant capacity of sorghum, and were present in all sorghum except for the white pericarp sorghums that did not have flavanones. The "red turning into black" gene increased phenols in Type I sorghum. The leaves, sheath and glumes of sorghum had higher levels of phenols (78-600 times more), with in vitro antioxidant properties than commonly seen in grains. Pigmentation of plant components increased levels of 3- deoxyanthocyanins but not flavones nor flavanones. The leaves of biomass sorghum, Collier variety, had 3.4 times more 3-deoxyanthocyanins than the leaves of Tx430 Black x Sumac which had the highest levels (1810 ?g/g) of 3- deoxyanthocyanins among the leaves. The use of 1% HCl/ethanol provides a possible food grade substitute solvent for 1%HCl/methanol in the extraction of phenolic compounds from sorghum. All enzymes evaluated broke down bran particles forming a gel-like material which had increased phenols and antioxidant activities but not 3- deoxyanthocyanins as revealed by HPLC analysis. Microscopy examination showed the gel matrix rich in fiber and can possibly be used for nutraceutical applications. Careful understanding of enzyme activities is necessary for effective extraction of 3-deoxyanthocyanins from sorghum. Sorghum leaves, sheaths and glumes are excellent sources of bioactive compounds, up to 600 times more than the grains of some varieties. Sorghum with the "red turning to black genes" is a potential source of 3- deoxyanthocyanins and flavan-4-ols. With the trend towards sorghum as biomass for ethanol production, plant breeders must select special traits aimed at developing enhanced desired functionality such as antioxidant potential and other healthy attributes with application in food, pharmaceutical/nutraceutical and cosmetic industries.

Orientador: Célia Maria de Sylos / Banca: Thaïs Borges César / Banca: Neura Bragagnolo / Banca: Nancy Preising Aptekmann / Banca: Veridiana Vera de Rosso / Resumo: As frutas cítricas são muito consumidas e apreciadas por todo o mundo, não só devido ao seu paladar agradável como também ao seu valor nutricional. São fontes de constituintes bioativos que podem atuar como antioxidantes em defesa ao nosso organismo. Existem relatos principalmente sobre os fitoquímicos e o potencial antioxidante das laranjas, no entanto as tangerinas, que também apresentam estes constituintes e atividade antioxidante, ainda são pouco estudadas. O Brasil se destaca na produção e exportação do suco das laranjas, sendo o maior exportador mundial do suco da fruta, já a produção das tangerinas e limão tahiti vem crescendo a cada ano que passa. O ácido ascórbico, os compostos fenólicos totais e carotenóides são alguns dos componentes bioativos presentes nas frutas cítricas. Considerando a importância das frutas cítricas com relação aos seus benefícios para a saúde, os objetivos deste estudo foram analisar sete variedades de frutas cítricas quanto aos principais constituintes bioativos, a atividade antioxidante via radical livre DPPH• de dois diferentes extratos (sobrenadante e precipitado) do suco das frutas em três diferentes solventes (água, metanol e acetona) e a atividade antioxidante dos extratos de carotenóides totais e flavanonas isolados das frutas. A variedade limão tahiti apresentou o maior teor de ácido ascórbico e menor de fenólicos totais, já a variedade tangerina poncã conteve o maior teor de flavonóides totais e carotenóides totais. A atividade antioxidante foi maior no extrato aquoso do que nos extratos metanólico e cetônico. Das diferentes flavanonas analisadas (eriocitrina, naringina, neohesperidina, hesperidina e poncirina), somente a hesperidina esteve presente em todas as variedades, sendo que a variedade tangerina cravo foi a que apresentou o maior teor deste flavonóide... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The citrus fruits are consumed and enjoyed by the whole world, not only because of its pleasant taste but also by its nutritional value. They are sources of bioactive constituents that can act as antioxidants to defend our body. There are reports mainly on the phytochemical and antioxidant potential of oranges; however the tangerines, which also have these constituents and antioxidant activity, are still little studied. Brazil stands out in the production and exportation of the juice of oranges, the world's largest exporter of fruit juice, since the production of tangerine and Tahiti lemon is growing each year that passes. Some bioactive components present in citrus fruits are ascorbic acid, the total phenolic compounds, and carotenoids. Taking into account the benefits of citrus fruits to the human health, the objectives of this study were to analyze the main bioactive constituents, the antioxidant activity by DPPH• free radical of two different extracts (supernatant and precipitate) of fruit juice in three different solvents (water, methanol and acetone), and the antioxidant activity of extracts of total carotenoids and flavanones isolated from seven varieties of citrus fruits (pera orange, lima orange, valencia orange, ponkan tangerine, cravo tangerine, murcote tangor, and tahiti lemon). The tahiti lemon presented the highest content of ascorbic acid and the lowest content of total phenolic, since the variety ponkan tangerine contained the highest content of total flavonoids and total carotenoids. The antioxidant activity was higher in the aqueous extract than in the methanolic and cetones extracts. Analyzed the different flavanones (eriocitrin, naringin, neohesperidin, hesperidin, and poncirin), the only one presented in all varieties was the hesperidin, so that the cravo tangerine presented the highest content of this flavonoid. The antioxidant activity... (Complete abstract click electronic access below) / Doutor

Orientador: Luis Carlos Spolidorio / Resumo: O objetivo do estudo foi avaliar o efeito dos flavonoides cítricos eriocitrina e eriodictiol sobre a periodontite experimental induzida por injeção de LPS de E. coli em camundongos. Setenta camundongos BALB/c foram submetidos a diferentes tratamentos: dieta convencional, dieta enriquecida com eriocitrina, dieta enriquecida com eriodictiol, ambas nas concentrações de 25 e 50 mg/kg de peso corporal/dia e dieta enriquecida com naproxeno 10mg/kg de peso corporal/dia. Após 30 dias de suplementação os animais foram submetidos a indução de periodontite experimental por injeção bilateral de LPS de Escherichia coli 3x/semana por 4 semanas. Avaliou-se o peso corporal, consumo alimentar e energético ao longo de todo período experimental. No fim do período experimental os animais foram eutanasiados e coletados fígado e maxila para, realização de análise microscópica, quantificação de perda óssea por micro-Ct, análise microscópica e estereométrica dos maxilares, perfil de citocinas pró e anti-inflamatórias do tecido gengival por imunoensaio multiplex e avaliação da atividade de mieloperoxidase. In vitro foi avaliada a viabilidade celular por MTT em um período de 48 horas e avaliação da proliferação celular de cultura de fibroblastos L929 através do método de AlamarBlue® por 1, 3 e 7 dias. Ao longo do experimento os animais que consumiram ração enriquecida com flavonoides ou naproxeno apresentaram ganho de peso e consumo alimentar/energético semelhante aos grupos controles. Na análise micr... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

Yes / Active packaging consisting of polyethylene terephthalate (PET) trays coated with a Citrus extract, without and with plasma pre-treatment, can reduce lipid oxidation in cooked meat. The mechanism of action of the packaging was investigated by quantifying the extent of transfer of antioxidant components from the active packaging into cooked turkey meat. Kinetic studies revealed the affinity for water of phenolic compounds and carboxylic acids in the Citrus extract, suggesting their diffusion into the water phase of the meat facilitated their antioxidant effect. Analysis by high-performance liquid chromatography permitted the identification of carboxylic acids and flavanones as major components of the extract. Their quantification in meat after contact with the trays revealed a release of 100% of the total coated amount for citric acid, 30% for salicylic acid, 75% for naringin and 58% for neohesperidin, supporting the release of these components into cooked meat as a mechanism of action of the antioxidant active packaging.

Conclusion. The present results indicate that, baicalein with optimal dosage of 30 muM suppressed collagen deposition in AngII stimulated SHR CF cultures. In animal model of hypertension, high dose of baicalein feeding for 12 week showed optimal antifibrotic effect in hypertensive hearts. (Abstract shortened by UMI.) / For in-vivo study, comparing to control group, HW/BW (x1000) of SHR was significantly reduced in 12 weeks-high dose baicalein and (-0.78+/-0.23, p=0.014) 12 weeks-Valsartan group (-0.71+/-0.22, p=0.021), however, no significant change was observed in the LW/BW ratio. / In Blood pressure control, no effects on attenuation of SBP were observed after 4 weeks and 12 weeks daily administration of baicalein, only 12 weeks feeding of Valsartan significantly down-regulated the systolic blood pressure by -19.25+/-10.09 mmHg, p=0.049. / In the in-vivo study, SHR was used as a model of genetic hypertension. The objectives were: firstly, to determine the efficacy of baicalein in the prevention of myocardial fibrosis (interstitial fibrosis) in SHR, & compared with WKY rats as normal controls. Secondly, to determine if over-expression of pro-collagen I (and III, if any) gene in the ventricles could be normalized by baicalein. Thirdly, to determine if left ventricular hypertrophy in SHR is improved by baicalein. Furthermore, to determine if blood pressure and blood biochemistry parameters (plasma level of brain natriuretic peptides (BNP), and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) level could be alternated by baicalein. Besides, to determine the body weight (BW), heart weight to body ratio (HW/BW), liver weight to body weight ratio (LW/BW), serum AST and ALT level could be alternated by baicalein. Finally to evaluate by echocardiography if there are changes of ivss and ivsd in SHR after administration of baicalein. / Keywords. baicalein, wogonin, collagen, cardiac fibrosis, hypertension / Objectives. In the in-vitro study, cardiac fibroblast culture was prepared from neonatal SHR and WKY rats. The objectives were multi-fold: firstly, to determine over-expression of pro-collagen I mRNA (and III, if any) in cardiac fibroblasts cultures could be normalized by baicalein and wogonin after AngII activation. Secondly, to evaluate the efficacy of baicalein and wogonin on the suppression of total collagen protein production in cardiac fibroblasts cultures after AngII activation. Thirdly, to evaluate the mechanism (in protein level) of baicalein and wogonin on regulating collagen deposition in cardiac fibroblasts after AngII activation. Furthermore, to determine if there were any effects on cytotoxicity and membrane integrity of baicalein and wogonin towards cardiac fibroblasts cultures. Finally, to determine the optimal concentration of baicalein and wogonin for the above actions in-vitro. / Results. For in-vitro study, incubation of AngII resulted in significant up-regulation of COL-I and COL-III mRNA and total collagen protein production. Addition of either baicalein or wogonin significantly suppressed the mRNA synthesis and total collagen protein in CF with an optimal dosage of 30 muM. No effects on viability and membrane integrity were observed on baicalein and wogonin towards cardiac fibroblasts cultures. / Kong, Kam Chuen Ebenezer. / Advisers: Cheuk-Man Yu; Gabriel W. K. Yip. / Source: Dissertation Abstracts International, Volume: 71-01, Section: B, page: 0242. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 176-204). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese.

Les agrumes très consommés au niveau mondial, représente des sources de caroténoïdes tels que la β-cryptoxanthine, qui contribuent avec les flavonoïdes (hespéridine) aux effets santé de ces fruits et en particulier dans la prévention du diabète de type 2 (DT2). Le DT2 est une pathologie mondiale en croissance exponentielle. L’objectif général de ce travail est par conséquent d’étudier les propriétés nutrition-santé de concentrés de jus de clémentine, obtenus par une technologie membranaire innovante et spécifiquement enrichis en β-cryptoxanthine (βCX) et hespéridine (HES) mais également en pectines. Le devenir digestif de ces phytomicronutriments, garants de la qualité nutritionnelle des concentrés a évalué dans un premier temps en couplant le modèle de digestion in vitro aux cellules intestinales de type Caco-2. Pour une meilleure vision physiologique des mécanismes associés aux premières étapes de la digestion, des modèles de digestion, statique et dynamique, sont comparés. La bioaccessibilité et l’absorption intestinale des caroténoïdes sont fortement influencées par la teneur et structure des pectines. Dans un second temps, les activités biologiques (disglycémie, dislipidémie, inflammation) impliquées dans la prévention du DT2 sont évaluées in vivo chez le rat après administration du concentré d’agrume. L’étude a démontré qu'un aliment à base d'agrume spécifiquement enrichi en βCX et HES est efficace dans la prévention du syndrome métabolique/DT2, soulignant le rôle possible de la βCX et de sa bioconversion en rétinoïdes. Une étude in vitro complémentaire sur macrophages murins révèle des effets anti-inflammatoires synergiques des 2 phytomicronutriments. / Citrus fruits, which are widely consumed worldwide, represent sources of carotenoids such as βCX, which contribute with flavonoids (HES) to the health effects of these fruits, particularly in the prevention of type 2 diabetes (T2D). T2D is a worldwide pathology that is growing exponentially. The general objective of this work is therefore to study the nutritional and health properties of clementine juice concentrates obtained by innovative membrane technology and specifically enriched in both βCX and HES but also in pectins. The digestive behaviour of these phytomicronutrients, guarantors of the nutritional quality of the concentrates, was first assessed by coupling the in vitro digestion model with the Caco-2 intestinal cells. For a better physiological vision of the mechanisms associated with the first stages of digestion, models of static and dynamic digestion are compared. The bioavailability and intestinal absorption of carotenoids are strongly influenced by the content and structure of pectins. In a second step, the biological activities (disglycemia, dislipidemia, inflammation) involved in the prevention of T2D are evaluated in vivo in rat after administration of the citrus concentrate. The study demonstrated that a citrus food specifically enriched in βCX and HES is effective in preventing metabolic syndrome/T2D, highlighting the possible role of βCX and its retinoid bioconversion. A complementary in vitro study on murine macrophages reveals synergistic anti-inflammatory effects of the two phytomicronutrients.

Dans le but de rechercher de nouveaux inhibiteurs de l'ARN polymérase NS5 du virus de la dengue (DENV), un criblage a été mené sur 650 plantes néo-calédoniennes. A la suite de ce criblage, deux espèces (Cryptocarya chartacea Kostermans et Trigonostemon cherrieri Veillon) ont été sélectionnées. L'extrait AcOEt des écorces de Cryptocarya chartacea (Lauraceae) a montré une forte inhibition de la NS5 polymérase (99 % à 10 µg/ml). L'étude phytochimique de l'extrait a mis en évidence une série de nouvelles flavanones 6-mono et 6,8-dialkylées, nommées chartacéones. Celles-ci sont présentes sous forme de mélanges racémiques au sein de C. chartacea. La chartacéone A a été purifiée sur colonne chirale conduisant à l'isolement de quatre diastéréoisomères optiquement purs. Une étude configurationnelle basée sur le calcul théorique de spectres de dichroïsme circulaire a permis la détermination de leur configuration absolue. Les chartacéones inhibent de façon sélective la NS5 polymérase du DENV. L'étude des extraits AcOEt des écorces et du bois de Trigonostemon cherrieri (Euphorbiaceae) a mis en évidence une série de métabolites secondaires originaux de type Diterpènes Daphnane Orthoester (DDO) chlorés : les trigocherrines (non-macrocycliques) et les trigocherriolides (macrocycliques). Ces composés ont montré une inhibition de l'activité enzymatique de la NS5 polymérase du DENV et une activité antivirale sur le virus du chikungunya in cellulo.

Baicalein is known to be a potent antifungal agent and induces programmed cell death in Candida albicans. In the present study, we found that baicalein also inhibited the growth of C. krusei isolates. The minimal inhibitory concentrations of baicalein against eight C. krusei isolates were 1.35--2.70 microg/ml. One-hour exposure to baicalein elicited a consistent and moderate post-antifungal effect on the C. krusei isolates. Further flow cytometric study demonstrated a depolarization of mitochondrial membrane potential. However, both the levels of reactive oxygen species and DNA fragmentation were not significantly changed after baicalein treatment in C. krusei. It can be concluded that the antifungal activity of baicalein was mitochondria-dependent in both C. krusei and C. albicans, but the antifungal mechanism was different. Reactive oxygen species may not play a direct role and baicalein does not initiate programmed cell death or apoptosis in C. krusei. The structure-activity relationship study showed that the three hydroxyl groups in baicalein were essential for its antifungal potency. / Candidiasis has become a serious infection with very high mortality and morbidity in the world if not providing effective treatments. However, due to clinical limitation and resistance of the current antifungal agents, there is an urgent need to search for novel antifungals. In this study, after screening a compound library (n=400) for antifungal activity, three members (metergoline, purpurin and baicalein) were chosen for further study. Their antifungal characteristics and the antifungal mechanisms were investigated. / Metergoline, a serotonin receptor antagonist, was found to have potent antifungal activity against the intrinsically fluconazole-resistant human fungal pathogen Candida krusei. The minimal inhibitory concentration and minimal fungicidal concentration of metergoline against C. krusei were 4 microg/ml and 8 microg/ml respectively. Metergoline induced post-antifungal effect. Significant synergism was found in combination of metergoline with amphotericin B by a checkerboard assay, which may be due to the perturbation of cell permeability and increase in the intracellular accumulation of antifungal agents. Metergoline also inhibited extracellular phospholipase production in C. krusei. To gain insights into the mechanisms, intracellular changes that accompany apoptosis were examined by flow cytometry and spectrophotometry. The results showed an increase in the level of reactive oxygen species, depolarization of mitochondrial membrane potential, phosphatidylserine externalization, and positive terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labelling in the metergoline-treated C. krusei . Taken together, we conclude that metergoline may promote apoptosis in C. krusei through reactive oxygen species production and perturbation in mitochondrial homeostasis, implying its antifungal potential to treat candidiasis. / The antifungal activity of purpurin, a natural red anthraquinone pigment in madder root (Rubia tinctorum L.), was evaluated against Candida isolates by a broth microdilution assay. The minimal inhibitory concentrations of purpurin against Candida species isolates were 1.28--5.12 microg/ml. Mechanistic studies indicated that purpurin inhibited energy-dependent efflux pumps of Candida isolates. Furthermore, purpurin demonstrated a depolarization of mitochondrial membrane potential, suggesting a possible linkage of the antifungal mechanism of purpurin to Candida apoptosis. / Kang, Kai. / Adviser: Fong Wing Ping. / Source: Dissertation Abstracts International, Volume: 73-02, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 98-123). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.