Class of 2015 Abstract / Objectives: To determine the effects of the dietary supplement, “Omega Q Plus ® Resveratrol” on cardiovascular health. More specifically, to review randomized controlled trials to determine the effects of resveratrol, coenzyme Q10, and omega-3-fatty acids on lipid levels and blood pressure. Methods: Randomized, double-blinded, placebo-controlled trials were searched using PubMed and Embase. Studies that assessed the effects of either resveratrol, coenzyme Q10, or omega-3 fatty acids on lipid levels and/or blood pressure in humans were included. Studies that did not use less than 1 gram of EPA and DHA were excluded. Data extraction and validity assessment was conducted by one reviewer; validity for trials were assessed using the Potential for Methodological Bias Assessment Tool (PBMAT). Results: A total of 24 studies were included; 11 for resveratrol, seven for coenzyme Q10, and six for omega-3 fatty acids, totaling to 1633 participants combined. Doses ranged from 8 mg to 3,000 mg of resveratrol per day, 100 mg to 200 mg of coenzyme Q10 per day, and 67 mg EPA + 33 mg DHA to 1944 mg EPA + 1686 mg DHA. Results across trials were inconsistent in regards to efficacy on lipid levels and blood pressure. Subjects with metabolic syndrome or hypertriglyceridemia seemed to benefit from omega-3 fatty acids through improvement in triglyceride levels, however effects with healthy patients were less clear. Conclusions: Overall, the interventions demonstrated mixed results in affecting lipid levels and blood pressure. No conclusions can be made at this point about the efficacy of Omega Q Plus® Resveratrol on cardiovascular health. Further research into these dietary supplements need to be conducted in order to assess their efficacy

Global cerebral ischemia is an established animal model mimicking the effects of cardiac arrest in humans. It is characterized by selective neuronal damage in the hippocampus and significant behavioural and cognitive impairments. In this light, novel therapeutic compounds with numerous physiological targets as well as neuroprotective capabilities and the capacity to lessen residual cognitive deficits pose as great candidates in the treatment of ischemic pathology. The current thesis investigates the possible therapeutic properties of resveratrol (3, 4, 5´trihydroxystilbene), a naturally occurring phytoalexin present in the skin of grapes, against cerebral ischemia-induced neuronal degeneration and cognitive impairments, as well as elaborate on possible mechanisms of action of the compound in male Wistar rats. In Article 1, neuronal density assessment and behavioural testing following chronic pretreatment with resveratrol at two doses (1 and 10 mg/kg) revealed that the compound has important neuroprotective properties at short and long post-ischemic intervals. Despite comparable neuronal protection, the two resveratrol doses showed distinct behavioural effects, highlighting independent actions of the polyphenol on discrete physiological systems mediating cellular survival and behavioural recovery. Articles 2 and 3 investigated possible mechanisms of action of the polyphenol that have not yet been explored with regards to cerebral ischemia. Specifically, Article 2 demonstrated that resveratrol influences markers of plasticity in both ischemic and control animals as well as promotes angiogenesis in the hippocampal region postischemia. Further elaborating on documented effects attributing non-neuronal mechanisms of action of resveratrol in reducing glial activation postischemia, Article 3 highlighted important regulatory effects of resveratrol on mediating glial type-1 glutamate transporter expression at a short reperfusion interval. These findings support the notion of multiple biological targets by resveratrol and highlight its potential role in attenuating forebrain ischemia-induced neuronal degeneration through multiple physiological targets, while cautioning against possible dose-related effects on behaviour and in healthy controls.

The tumor suppressor protein p53 is one of the major regulators of the cell cycle after DNA damage. In addition to stopping the cycle and repairing DNA, it can, in extreme cases, induce programmed cell death - apoptosis. Mutations in the gene encoding p53 are present in more than 50% of cancer cases. This thesis examines alternative natural polyphenolic substances that could increase the level and expression of p53 protein in tumor cells. These substances could be an alternative to non-specific cytostatics, which bring many undesirable additional effects during treatment. In the theoretical part of the thesis the structure and properties of the p53 protein and describes alternative therapeutic approaches with a focus on polyphenolic substances is explained. The aim of the experimental part was to determine the effect of curcumin and resveratrol in comparison with often used cytostatic drug, doxorubicin, on cell viability of tumor cells and on p53 protein levels. The effect of these substances on the binding of p53 to DNA in yeast systems was also examined. It was found that doxorubin efficiency is many times higher than the examined polyphenolic agents, but resveratrol was showing some potential as a suitable alternative in the treatment of tumors, thanks to the ability to activate apotosis. It was clearly demonstrated that there is an association between induced programmed death and increased p53 protein expression after resveratrol treatment.

Orientador: Valéria Cristina Sandrim / Resumo: A pré-eclâmpsia é uma das principais causas de mortalidade e morbidade entre as gestantes no Brasil e em vários países. A fisiopatologia desta doença é complexa e envolve vários processos. Um desses relaciona-se a um status oxidativo, onde há prevalência de produção de radicais livres e/ou redução da atividade antioxidante. Recentemente, vem sendo explorado como terapia em várias doenças o antioxidante resveratrol, presente em grandes quantidades principalmente nas uvas vermelhas. O resveratrol, além de sequestrar espécies reativas de oxigênio e possuir outros mecanismos de ação, atua ativando o fator de transcrição Nrf2 (nuclear factor, erythroid 2-like 2), responsável pela transcrição de diversos genes que promovem a proteção celular através da codificação de enzimas antioxidantes, como a hemeoxigenase (HO-1). Logo, o objetivo desse estudo foi verificar os efeitos do resveratrol sob a via de ativação do Nrf2 e seus genes alvos em modelo in vitro de pré-eclâmpsia. Esse modelo consiste na incubação de plasma/soro de pacientes pré-eclâmpticas em células endoteliais a fim de se mimetizar a disfunção endotelial característica dessa síndrome. Além disso, foi feito um estudo clínico piloto em que gestantes pré-eclâmpticas beberam suco de uva de forma aguda e tiveram o soro coletado após 1 hora da ingestão para incubação nas células endoteliais. Concluímos que há um potencial de uso do resveratrol na prevenção e tratamento da pré-eclâmpsia. Considerando ainda o uso do suco de uva a... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Preeclampsia is one of the main causes of mortality and morbidity among pregnant women in Brazil and in several countries. The pathophysiology of this disease is complex and involves several processes. One of these is related to an oxidative status, where there is a prevalence of free radical production and /or reduced antioxidant activity. Recently, the antioxidant resveratrol present in large quantities mainly in red grapes, has been explored as potential therapy in several diseases. Resveratrol, in addition of reactive oxygen species scavenging and acting on other mechanisms of action, acts by activating the transcription factor Nrf2 (nuclear factor, erythroid 2-like 2), responsible for the transcription of several genes that promote cell protection through the coding of antioxidant enzymes, such as heme oxygenase-1 (HO-1). Therefore, the aim of this study was to verify the effects of resveratrol on Nrf2 activation and its target genes in an in vitro model of preeclampsia. This model consists of the incubation of plasma/serum from pre-eclamptic patients in endothelial cells in order to mimic the endothelial dysfunction characteristic of this syndrome. In addition, a pilot clinical study was carried out in which pre-eclamptic pregnant women drank grape juice acutely and had the serum collected after 1 hour of ingestion for incubation in endothelial cells. We conclude that there is a potential use of resveratrol in the prevention and management of preeclampsia. Especially th... (Complete abstract click electronic access below) / Doutor

Resveratrol, a naturally-occurring phytoestrogenic stilbene derivative, has been shown to elicit shifts in physiology of obese animals consuming a high calorie or ad libitum diet toward that of lean counterparts. This study was designed to evaluate effects of oral resveratrol supplementation on parameters of metabolic health and reproductive cyclicity in obese mares on pasture. Seventeen healthy, mares were matched by age and assigned to obese control (OBC; n=5, mean BCS=7.4±0.3), obese supplemented with 5g/d resveratrol (OBR; n=6, mean BCS=7.4±0.2) or non-obese control (NOC; n=6, mean BCS=5.4±0.1) treatments. Control horses received the resveratrol carrier paste. Across three consecutive estrous cycles, morphometric measurements were collected biweekly and follicular dynamics were evaluated via transrectal ultrasonography every other day. Frequently-sampled intravenous glucose tolerance tests were conducted pre- and post- treatment. Insulin and glucose kinetics were analyzed via minimal model. Resveratrol supplementation had no discernible effect on reproductive parameters (P>0.05), however obese mares had more (6 vs. 0) hemorrhagic anovulatory follicles. Neither resveratrol treatment nor time on study influenced morphometric measurements or minimal model parameters (raw data or data adjusted for animal size). As a whole, horses became more insulin resistant over time (Si value < 0.78 (1/[mU/L"min]). NOC horses had lower (P=0.01) acute insulin response to glucose relative to OBC or OBR. Although resveratrol supplementation did not elicit detectable responses in this study, promising results in other species warrant further investigation of the compound in horses, including exploration of bioavailability and possible effects at the tissue or cellular levels. / Master of Science

Skin cancer is a major health problem worldwide. It is the most common cancer in the United States and poses a significant healthcare burden. Excessive UVR exposure is the most common cause of skin cancer. Despite various precautionary measures to avoid direct UVR exposure, the incidence of skin cancer and mortality related to it remains high. Furthermore, the current treatment options are expensive and have side effects including toxicity to normal cells. Thus, a safe and effective approach is needed to prevent and treat skin cancer. Chemopreventive strategy using naturally occurring compounds, such as resveratrol, is a promising approach to reduce the incidence of UVR-induced skin cancer and delay its progression. This review highlights the current body of evidence related to chemopreventive role of resveratrol and its molecular mechanisms in UVR-induced skin carcinogenesis.

Numerous studies have found certain unmethylated phytochemicals to possess anti-carcinogenic activity; however, they have been associated with poor oral bioavailability which is a major limiting factor in their usage in chemopreventative treatment. The purpose of this study was to investigate if methylation of a compound would affect bioavailability, in terms of transport and permeability, in a Caco-2 cell model as well as the effect of cell viability and cellular uptake in human colon cancer cell lines. Furthermore, a new analytic method using reversed-phase high performance liquid chromatography coupled with electrochemical detector (HPLC-EC) for the detection and quantification of resveratrol and pterostilbene was developed. This new method was simple, rapid, and more sensitive compared to other detection methods used to analyze resveratrol and pterostilbene. Linear range, limit of detection (LOD), precision and recovery were used to validate this new analytical method. There was a significant increase in intracellular uptake and stronger growth inhibitory of pterostilbene in human cancer cells lines in comparison to resveratrol. Resveratrol exhibited a higher and more rapid rate of transport than pterostilbene across the Caco-2 monolayer regardless of the concentration tested and direction. Pterostiblene exhibited little difference in the rate of transport from either direction. The HCT-116 colon cells had intracellular uptake of each of the polymethoxyflavones (PMFs) tested. Transport was observed by all the PMFs and each had different rates of transport. Overall, location and amount of methyl groups had an effect on bioavailablity of a compound and these compounds show promise as chemopreventative agents.

No description available.

La tétraploïdie – cellule contenant le double du génome d’une cellule diploïde – est considérée comme un état métastable, à l’origine de l’aneuploïdie des cancers. Présentes dans les lésions précancéreuses, les cellules tétraploïdes sont associées à la progression tumorale. Etant donné le rôle clé de la tétraploïdie au cours de l’oncogenèse, le développement d’agents pharmacologiques éliminant spécifiquement les cellules tétraploïdes pourrait permettre de prévenir et limiter l’évolution vers un état cancéreux. Afin d'identifier des composés délétères pour les cellules tétraploïdes, nous avons développé une méthode de criblage basée sur la vidéomicroscopie à fluorescence automatisée. La chimiothèque de l'Institute of Chemistry and Cell Biology (ICCB) a été criblée, et nous avons mis en évidence plusieurs hits aux effets cytostatiques et/ou cytotoxiques préférentiels pour les cellules tétraploïdes. En raison de ses propriétés chimiopréventives, le resvératrol est le premier composé dont nous avons choisi de poursuivre la caractérisation. Sa sélectivité pour les cellules tétraploïdes a été confirmée sur différents types cellulaires, stables ou en cours de polyploïdisation. L’étude du mécanisme d’action anti-tétraploïde du resvératrol a permis d’identifier le senseur de la charge énergétique 5’-adenosine monophosphate-activated kinase (AMPK), comme une cible moléculaire responsable de la mort sélective des cellules tétraploïdes. Une série d’agents pharmacologiques activant directement ou indirectement AMPK – parmi lesquels l’aspirine et son métabolite le salicylate, dont l’action chimiopréventive a été établie par plusieurs études épidémiologiques et essais cliniques – a montré une toxicité préférentielle pour les cellules tétraploïdes. De la même manière que le resvératrol, ces agents éliminent les cellules tétraploïdes stables et limitent la polyploïdisation. Finalement, l’effet anti-tétraploïde du resvératrol et de l’aspirine a été évalué in vivo. L’administration orale de ces deux composés aux doses décrites comme chimiopréventives, réduit le développement des cellules épithéliales tétraploïdes et aneuploïdes des cryptes intestinales des souris ApcMin/+, le modèle murin de la polypose adénomateuse familiale. Collectivement les résultats de cette étude suggèrent que l’action chimiopréventive du resvératrol et de l’aspirine est associée à l’élimination des cellules tétraploïdes précurseur de tumeurs. / Tetraploidy – cells that contain twice the normal amount of chromosomes – is a metastable state leading to aneuploidy in cancer. Tetraploid cells have been observed in precancerous lesions and constitute a step toward tumor progression. Given the importance of tetraploidization for oncogenesis, developing drugs that selectively target tetraploid cells should prevent cancer.To discover compounds toxic to tetraploid cells, we developed an assay-system based on automatic fluorescence videomicroscopy. We screened the Institute of Chemistry and Cell Biology (ICCB) chemical library and identified several hits exerting a selective cytostatic and/or cytotoxic effect on tetraploid cells. Due to its well known chemopreventive properties, resveratrol was the first compound we further characterized. Its selectivity for tetraploid cells was confirmed on various stable or polyploidizing cancer cell lines, as well as primary epithelial cells. The mechanism accounting for the preferential killing of tetraploid cells involves the 5’-adenosine monophosphate-activated kinase (AMPK) signaling pathway. A series of additional agents that stimulate AMPK – including aspirin and salicylate whose chemopreventive action have been established by several epidemiological studies and clinical trials – display a selective toxicity toward tetraploid cells. Similar to resveratrol, these drugs eliminate stable tetraploid cells and reduce polyploidization. Finally, we validated the anti-tetraploid effect of resveratrol and aspirin in vivo. Oral treatment with either of these two compounds at chemopreventive doses, repressed the accumulation of tetraploid and subsequently aneuploid intestinal epithelial cells from the crypts of the ApcMin/+ mouse model of familial adenomatous polyposis.Collectively, our results suggest that the chemopreventive action of resveratrol and aspirin involves the elimination of tetraploid cancer cell precursors.

A preservação do sêmen suíno refrigerado para fins de inseminação artificial é a forma mais utilizada no mundo. Para tal, os espermatozoides são diluídos em meios que forneçam substratos para nutrir e proteger estas células. Porém, a faixa de temperatura de armazenamento do sêmen suíno refrigerado não é capaz de cessar completamente os mecanismos metabólicos dos espermatozoides, que em ambiente aeróbico da dose inseminante, produzem e liberam continuamente produtos do metabolismo do oxigênio. A ação das espécies reativas de oxigênio sobre o espermatozoide é uma das razões do declínio na população de células espermaticas estrutural e funcionalmente aptas à fertilizarem os gametas femininos. Portanto, a adição de um composto antioxidante ao meio diluidor poderia melhorar ou manter constante o número de espermatozoides viáveis ao longo do período de conservação da dose inseminante. Neste contexto, este trabalho objetivou verificar se a adição do antioxidante resveratrol geraria modificações positivas em parâmetros celulares relacionados à qualidade do sêmen suíno refrigerado à 15-17°C avaliados por sistema computadorizado da motilidade espermática e citometria de fluxo (experimento in vitro), e se este antioxidante melhoraria os índices de fertilidade na inseminação artificial intrauterina (IAIU) através da recuperação, contagem e identificação dos embriões (experimento in vivo). As concentrações testadas no experimento in vitro não superaram os resultados do tratamento controle (p&lt;0,05), sendo a concentração de 1,0 mM prejudicial ao espermatozoide suíno (p&lt;0,05). A utilização da concentração de 0,01 mM de resveratrol para inseminação das fêmeas suínas no experimento in vivo não apresentou efeito positivo nos índices de taxa de prenhez e fertilidade ajustada total (p&gt;0,05), além de ter resultado em uma baixa taxa de embriões viáveis (p&lt;0,05), quando comparados ao tratamento controle. Deste modo, pode concluir que não é indicado a adição do antioxidante resveratrol ao meio diluidor para inseminação artificial, uma vez que compromete a qualidade das células espermáticas do reprodutor suíno e impacta negativamente na fertilidade das fêmeas. / The preservation of chilled boar semen for artificial insemination is the most performed worldwide. For this, the sperm are extended in medium that provides substrates to nourish and protect these cells. However, the storage temperature range of chilled semen is not able to completely stop the metabolic mechanisms of sperm, which keeps producting and releasing oxygen reactive products in aerobic environment of insemination doses. The action of reactive oxygen species on the sperm is one of the reasons for decreasing sperm population with structural and functional capacity to fertilize the female gamete. Therefore, the addition of antioxidant compound to the extender medium could improve or maintain the number of viable spermatozoa throughout the conservation time of insemination doses. In this context, this work aimed to determine whether addition of antioxidant resveratrol would generate positive changes in cell parameters related to the quality of boar semen cooled to 15-17 °C assessed by computered analysis of sperm motility and flow citometry (in vitro experiment) and whether this antioxidant would improve fertility rates using intrauterine insemination (IUI) by the recovery, counting and embryos identification (in vivo experiment). The concentrations tested in vitro experiment have not exceed control treatment results (p &lt;0.05), with the concentration of 1.0 mM being detrimental to the boar spermatozoa (p &lt;0.05). The concentration of 0.01 mM of resveratrol used for gilts insemination in experiment in vivo has not shown positive effect on pregnancy rate and the total adjusted fertility (p&gt; 0.05) and have resulted in a low rate viable embryos (p &lt;0.05) compared to control. Thus, we conclued that the addition of resveratrol antioxidant in boar extender medium is not suitable for artificial insemination, once it compromises the quality of boar sperm cells and impairs on female fertility.