Yes / The extraction of bioactive compounds, produced by plant cell cultures, directly from their culture medium, which contains other by-products, is a great challenge. Resveratrol extraction from its grapevine cell cultures is considered here as an example to improve the extraction processes from plant cell cultures using solubility parameters. Successive liquid-liquid extraction (LLE) processes were exploited to extract resveratrol from the culture medium with an extraction ratio approaching 100%, high selectivity and minimum amounts of solvents. The calculations of partition coefficients as a function of solubility parameters demonstrated that benzyl benzoate is the most suitable intermediate solvent to extract resveratrol from its aqueous medium. The calculations also illustrated the high ability of methanol and ethanol to extract resveratrol from benzyl benzoate. The physicochemical properties of benzyl benzoate and processing conditions were exploited to separate it from aqueous media and organic solvents. The agitation method, component ratios and extraction time were studied to maximize the extraction yield. Under the best studied conditions, the recovery of resveratrol from different culture media approached ∼100% with a selectivity of ∼92%. Ultimately, the improved extraction processes of resveratrol are markedly efficient, selective, rapid and economical. / Mohammad Amin Mohammad gratefully acknowledges CARA (The Council for At-Risk Academics, Stephen Wordsworth and Ryan Mundy) for providing the financial support for an academic fellowship.

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Made available in DSpace on 2016-06-02T19:22:09Z (GMT). No. of bitstreams: 1 5384.pdf: 3646799 bytes, checksum: cae5edc100d549896cd5997951a21e99 (MD5) Previous issue date: 2013-06-21 / Universidade Federal de Sao Carlos / Lead (Pb) is an ubiquitous pollutant in the environmental ecosystem. Its distribution is mainly anthropogenic, coming from the burning of fossil fuels, mining and production of various industrial products. There is little knowledge of the effect of the Pb and its compounds on bone metabolism as well as potential therapies for frames contamination related to the lead. The aim of this study was to determine possible changes in the bones of adult rats contaminated with lead acetate correlated them to the effects of hydroxyapatite and the resveratrol in adult rats contaminated with lead acetate. The biomechanical, biometric, biophysical, microtomographic bone parameters, the radiographic density, the concentration of Pb and metalloproteinase activity in bone tissue were analyzed. The animals were distributed into 6 groups of 8 rats each: control, treated with saline 0.9% (0.1 ml/100g BM), hydroxyapatite, treat with hydroxyapatite (100 mg/kg BM), contaminated, treated with lead acetate (250 mg/kg BM), contaminated + hydroxyapatite, treated with lead acetate (250mg/kg BM) and hydroxyapatite (100mg/kg BM); the treatments were carry out once per week for 8 weeks by gastric gavage. The groups contaminated + resveratrol, treated with lead acetate (250 mg/kg BM) and resveratrol (0.7 mg/kg BM ) and DMSO, treated with dimethylsulfoxide (0.1 ml/100g BM), 5 times a week for 8 weeks by intraperitoneal injections. The contamination with lead acetate promoted incorporation of it in bone tissue leading to a reduction in bone strength of femurs and vertebrae, reduction of vertebral trabecular contingent, and increased activity of metalloproteins type 2. The treatment with hydroxyapatite (100 mg/kg MC) as well with resveratrol (0.7 mg/kg MC) prevented the deleterious effects of lead contamination at the proposed dose, including reducing the activity values of metalloproteins type 2 to levels similar to that of control group. Therefore, the results point to hydroxyapatite and resveratrol as potential treatment agents in lead contamination, preventing damage to the quality of bone tissue caused by this element. / Chumbo (Pb) é um poluente ubíquo no ecossistema cuja distribuição ambiental é principalmente antropogênica, oriunda da queima de combustíveis fósseis, mineração e fabricações industriais diversas. Há pouco conhecimento do envolvimento do Pb e seus compostos sobre o metabolismo ósseo bem como das potenciais terapias para quadros de contaminação relacionadas ao chumbo. O objetivo deste estudo foi avaliar as alterações ósseas causadas pelo acetato de chumbo correlacionado-as aos efeitos da hidroxiapatita e do resveratrol em ratos adultos contaminados com acetato de chumbo. Foram analisados os parâmetros biomecânicos, biométricos, biofísicos, microtomográficos ósseos, a densidade radiográfica, a concentração de Pb e a atividade de metaloproteinases no tecido ósseo. Os animais foram distribuidos em 6 grupos com 8 ratos cada: controle, tratados com salina 0,9% (0,1 ml/100g MC), hidroxiapatita, tratados com hidroxiapatita (100 mg/kg MC), contaminado, tratados com acetato de chumbo (250 mg/kg MC) e contaminado + hidroxiapatita, tratados com acetato da chumbo (250 mg/kg MC) e hidroxiapatita (100 mg/kg MC), 1 vez por semana, por 8 semanas pelo método de gavagem gástrica. Grupo contaminado + resveratrol, tratados com acetato da chumbo (250 mg/kg MC) e resveratrol (0,7 mg/kg MC) e DMSO, tratado com dimetilsulfóxido (0,1 ml/100g MC), 5 vezes por semana, por 8 semanas por meio de injeções intraperitoneais. A contaminação com acetato de chumbo promoveu incorporação de chumbo no tecido ósseo provocando redução da resistência óssea de fêmures e vértebras e do contingente trabecular das vértebras analisadas, promovendo aumento da atividade de metaloproteinases tipo 2. Tanto o tratamento com 100 mg/kg MC de hidroxiapatita quanto o de 0,7 mg/kg MC de resveratrol preveniram os efeitos deletérios da contaminação com chumbo na dose proposta, inclusive reduzindo os valores de atividade de metaloproteinases tipo 2 para níveis semelhantes ao do grupo controle. Portanto, os resultados apontam a hidroxiapatita e o resveratrol como potenciais agentes de tratamento preventivo na contaminação com chumbo, evitando os prejuízos à qualidade do tecido ósseo provocadas por este elemento.

Background and aims: Treatment of acute fulminant liver damage arising as a result of various origins (ischemia-reperfusion injury, toxic shock, an infectious cause or cholestasis) still remains a major clinical problem. We currently do not have available clinically proven, pharmacologically effective and universal compound for the treatment of acute liver injury. The main aim of my research work was, therefore, to test the potential hepatoprotective effect of selected cytoprotective drugs and try to find out or suggest their mechanism of action, which we have examined in the systems for the intracellular gaseous signaling molecules NO and CO, where the key enzymes for their formation are NOS / HO respectively. My PhD study had two main directions: 1) Experimental study of the relationship between HO / CO and NOS / NO systems in the environment of hepatotoxic substances on isolated primary rat hepatocytes and in rat model, 2) Evaluation of ameliorative effect of selected substances in the hepatotoxicity models and to test the relationship of this effect on changes in some parameters of cytotoxicity / cytoprotection, antioxidant parameters, gene expression of mRNA for selected genes and histological changes in the state of cells / tissues / organs. Methods: We measured urea, bilirubin and liver...

<p>Doktorsku disertaciju čine tri celine kojima je zajednički element ispitivanje fenola, u pogledu njihovog sadržaja i dostupnosti u dijetetskim suplementima na bazi grožđa i japanskog troskota, ispitivanja uticaja suplementacije kod eksperimentalnih životinja, odnosno mogućnosti ekstrakcije fenolnih jedinjenja iz komine grožđa. Osnovni ciljevi prvog dela bili su ispitivanje bezbednosti i kvaliteta 14 suplemenata na bazi grožđa i japanskog troskota u pogledu ujednačenosti mase, sadržaja i brzine rastvorljivosti. U drugom delu je radi provere terapijske delotvornosti suplementa koji sadrži čist resveratrol ispitan njegov uticaj na glikemiju i lipidni status eksperimentalnih životinja. Treći deo je obuhvatio analizu pet različitih komina grožđa i razvoj metode ekstrakcije fenola iz odabrane komine kako bi se dobili ekstrakti sa &scaron;to je moguće većim prinosom, koristeći rastvarače koji su bezbedni po ljudsko zdravlje. Rezultati su pokazali da dva od četrnaest suplemenata nisu ispunila zahteve farmakopeje za lekove u pogledu ujednačenosti mase i sadržaja aktivne komponente, dok ni jedan suplement nije ispunio zahteve u pogledu brzine rastvorljivosti aktivne supstance, zbog čega se postavlja pitanje delotvornosti ispitanih suplemenata. Ni kod jednog suplementa nisu kvantifikovani ostaci pesticida ni toksični metali, čime je potvrđena njihova bezbednost. Farmakodinamska ispitivanja na pacovima pokazala su antioksidantna, anti-dijabetska i hipolipidemijska svojstva dijetetskog suplementa na bazi resveratrola, čime je potvrđena njegova delotvornost. Za potvrdu delotvornosti suplementa na ljudima neophodno je sprovesti dobro dizajnirano kliničko ispitivanje na dovoljnom broju ispitanika. Analiza pet različitih komina grožđa pokazala je da ovaj nusprodukt proizvodnje vina sadrži različite fenole, od kojih je samo katehin bio prisutan u značajnoj količini. Kvalitativan i kvantitativan sastav komine značajno varira zavisno od sorte i berbe grožđa, kao i od primenjenog tehnolo&scaron;kog procesa proizvodnje vina. Imajući u vidu sveobuhvatne kriterijume u pogledu efikasnosti ekstrakcije, zaključeno je da su 55% etanol, odnos uzorak / rastvarač 1:40, pH 4,5, T 55&deg;C i vreme od 30 min optimalni eksperimentalni uslovi za ekstrakciju fenola iz komine grožđa. U zavisnosti od osnovnog cilja procesa ekstrakcije ovi parametri se mogu lako modifikovati. Vi&scaron;estruke su mogućnosti za iskori&scaron;ćenje komine grožđa, a jedan od njih bi mogla biti i da se koristi kao sirovina za izradu dijetetskih suplemenata.</p> / <p>The dissertation consists of three parts with a common element &ndash; testing phenols in terms of content and availability in grape and Polygonum cuspidatum-based dietary supplements, testing the supplement&rsquo;s impact on experimental animals and the possibility to extract phenolic compounds from grape pomace. The primary objectives of the first part were testing safety and quality of fourteen grape and Polygonum cuspidatum-based supplements in terms of uniformity of mass, content and dissolution profile. In the second part, to test the therapeutic efficacy of a supplement containing pure resveratrol, its effect on the glycemia and lipid profile of experimental animals was examined. The third part covers the analysis of five different grape pomaces and the development of a phenol extraction method from the selected grape pomace to obtain extracts with the highest possible yield, using solvents that are safe for human health. The results showed that two out of fourteen supplements have not met the Pharmacopoeia requirements in terms of uniformity of mass and active substance content, while no supplement has met requirements in terms of dissolution test of the active substance, which raises the question of the effectiveness of the tested supplements. No pesticide or heavy metal residues were quantified in any of the supplements which confirms their safety. Pharmacodynamic testing on rats has shown antioxidant, antidiabetic and hypolipidemic properties of the resveratrol-based dietary supplement which confirms its efficacy. In order to confirm the supplement efficacy on people, it is necessary to conduct a well-designed clinical trial on a sufficient number of human participants. The analysis of five different grape pomaces revealed that this byproduct of vine production contains different phenols, and only catechin was present in significant amounts. The qualitative and quantitative composition of grape pomace varies significantly depending on grape variety and harvesting as well as on the technological process that was applied in vine production. Considering the comprehensive criteria in terms of extraction efficacy, it was concluded that optimal experimental conditions for the extraction of phenol from grape pomace include 55% ethanol, sample/solvent ratio 1:40, pH 4.5, T 55&deg;C for 30 minutes. Depending on the primary objective in the extraction process, these parameters can be easily modified. There are multiple possibilities for utilizing grape pomace and one of them could be as raw material in production of dietary supplements.</p>

Indiana University-Purdue University Indianapolis (IUPUI) / Resveratrol has been shown to inhibit cell growth and induce apoptosis, as well as augment chemotherapeutics and irradiation in multiple cancer types. However, it is unknown if resveratrol is beneficial for treating drug-resistant cancer cells. To study the effects of resveratrol in triple negative breast cancer cells that are resistant to the common cancer drug, paclitaxel, a novel paclitaxel-resistant cell line was generated from the MDA-MB-231 breast cancer cell line. The resulting cell line, MDA-MB-231/PacR, exhibited a 12-fold increased resistance to paclitaxel but remained sensitive to resveratrol treatment. Resveratrol treatment reduced cell proliferation and colony formation and increased senescence and apoptosis in both the parental MDA-MB-231 and MDA-MB-231/PacR cell lines. Importantly, resveratrol treatment augments the effects of paclitaxel in both cell lines. The expression of the drug efflux transporter gene, MDR1, and the main metabolizing enzyme of paclitaxel gene, CYP2C8, was increased in the resistant cells. Moreover, pharmacological inhibition of the protein products of these genes, P-glycoprotein and CYP2C8, decreased paclitaxel resistance in the resistant but not in the parental cells, which suggests that the increase of these proteins are important contributors to the resistance of these cells. In conclusion, these studies imply that resveratrol, both alone and in combination with paclitaxel, may be useful in the treatment of paclitaxel-sensitive and paclitaxel-resistant triple negative breast cancers.

Le but principal de ce travail a été de mettre en évidence le potentiel synthétique de nouvelles bases mixtes fer-lithium dans des réactions de déprotométallation en série aromatique. Dans un premier chapitre, les travaux de la littérature sur les composés fer-métal alcalin et notamment les bases ont d’abord été exposés. Notre étude a permis d’optimiser  une  nouvelle base fer-lithium et a montré la capacité de celle-ci à réaliser des réactions de déprotonation relativement chimiosélectives et efficaces. Les paramètres de la réaction de déprotométallation ont été optimisés en utilisant l’iode comme électrophile. Cette méthode a été étendue à divers hétérocycles et le piégeage subséquent à différents électrophiles. Dans un second chapitre, le comportement de la base fer-lithium développée a été comparé à celui d’autres bases bimétalliques utilisées au laboratoire. La fonctionnalisation des triazoles par ces bases a montré que la base zinc-lithium était la base la plus appropriée pour ce type de substrats. La fonctionnalisation à l’aide de cette base a donc été étendue en série indazole et benzotriazole. Les résultats ont été rationalisés en utilisant les acidités des hydrogènes des substrats (pKₐ). Dans un dernier chapitre, les méthodes développées ont été valorisées par la synthèse de 2,4-diaryl-1,2,3-triazoles analogues du resvératrol. Les propriétés cytotoxiques de ces molécules seront évaluées. Cette application reste à approfondir. / The main purpose of this work was to highlight the synthetic potential of new mixed iron-lithium bases in aromatic deprotometallation reactions. In the first chapter, literature works about iron-alkali metal compounds and notably bases were firstly presented. Our study led to the optimization of a new iron-lithium base and showed its ability to achieve rather chemoselective and efficient deprotonation reactions. The reaction parameters of deprotometallation were optimized by using iodine as the electrophile. This method was extended to various heterocycles and the subsequent trapping to different electrophiles. In a second chapter, the behaviour of the iron-lithium base developed was compared with that of other bimetallic bases used in th laboratory. The functionalization of triazoles using these bases showed that the zinc-lithium was the most suitable base for this kind of substrate. Thus, the functionalization using this base was extended to indazole and benzotriazole series. The results were rationalized by using the hydrogen acidities of the substrates (pKₐ). In the last chapter, the methods developed were made more attractive by the synthesis of 2,4-diaryl-1,2,3-triazoles analogues of resveratrol. The cytotoxic properties of these molecules will be evaluated. This application remains to be explored.

7 ABSTRACT (EN) This dissertation thesis is focused on the study of electrochemical properties of new types of carbon paste electrodes (CPE) and carbon fiber rod electrodes (CFRE), which were used for the development of new highly sensitive and selective voltammetric and amperometric methods for the determination of 5-amino-6-nitroquinoline and trans- and cis- isomers of resveratrol. The carbon paste electrodes were compared in terms of size of the microparticles of glassy carbon contained in the paste (diameters 0.4 - 12 µm; 10 - 20 µm; 20 - 50 µm) in comparison with carbon paste electrode consisting of crystalline graphite and solid glassy carbon electrode. The electrochemical properties were tested using potassium hexacyanoferrate in an aqueous supporting electrolyte and 5-amino-6-nitroquinoline (5A6NQ) in a mixed methanol-water supporting electrolyte. The carbon paste electrode was further used in an amperometric detector of a wall-jet type connected in series with a spectrophotometric detector for the development of a new HPLC method with electrochemical detection and spectrophotometric detection for the determination of trans-resveratrol and cis-resveratrol in samples of grains, hulls and leaves of common and tartary buckwheat. The method was optimized and used for the determination of resveratrol in...

Depuis les cinquante dernières années, l'incidence de la maladie de Crohn,maladie chronique inflammatoire de l'intestin (MICI) a plus que doublée. C'est une pathologie multifactorielle et idiopathique utilisant des traitements comme des anti-inflammatoires, des corticoïdes, des immunosuppresseurs et plus récemment les anti-TNF.Ils présentent des limites avec une intolérance aux principes actifs et une résistance au traitement conduisant à un échec thérapeutique. L’objectif de ce travail sera de développer une forme orale tout en minimisant le risque d’effets secondaires en améliorant la biodisponibilité. Des techniques d'encapsulation protégeant les principes actifs extraits de plantes comme le Resvératrol, le Bêta-carotène, et la Curcumine seront réalisées. Quatre types de synthèse seront respectivement utilisés : la micro-encapsulation , la nanoémulsion, et la synthèse de nanoparticules solides lipidiques (SLN), ainsi que la squalénisation.Une comparaison des effets anti-inflammatoires des traitements conventionnels versus les vecteurs synthétisés au cours de cette étude pourra permettre de conclure sur la contribution originale de ce projet. / For the last fifty years, the incidence of Crohn's disease, a chronic inflammatory bowel disease (IBD) has more than doubled. It is a multifactorial and idiopathic pathology using treatments such as anti-inflammatories, corticosteroids, immunosuppressants and more recently anti-TNFα.They have limits with intolerance to active principles and resistance to treatment leading to therapeutic failure . The goal of this work will be to develop an oral form while minimizing the risk of side effects by improving bioavailability. Encapsulation techniques protecting the active ingredients extracted from plants such as Resveratrol, Beta-carotene, and Curcumin will be performed. Four types of synthesis will be used respectively: micro-encapsulation, nanoemulsion, and the synthesis of lipid solid nanoparticles (SLN), as well as squalenization. A comparison of the anti-inflammatory effects of conventional treatments versus the vectors synthesized during this study. The study may conclude on the original contribution of this project.