Many studies highlighted the biological potential of vitamin E, especially tocotrienols (T3), a vitamin E subfamily, particularly in the field of cardiovascular diseases and chronic inflammation. A pharmacophore based virtual screening of these substances against various antiinflammatory targets showed that this class could be considered as potential inhibitors of 5- lipoxygenase, a key enzyme in the biosynthesis of chemoattractant and vasoactive leukotrienes. Consequently, this screening was confirmed by in vitro assays. However, usual natural sources of T3 provide complex mixtures involving particularly challenging purification processes. Thus, this work aims at designing and optimizing efficient semisynthesis towards pharmacologically relevant T3 derivatives were developed from δ- tocotrienol, the main T3 isolated from Bixa orellana seeds, a renewable and easily available vegetal source from tropical regions, analyzed mainly by HPLC chromatography. Verification of the most effective reaction conditions of semisynthesis and synthesis another potential inhibitors of 5-LOX based on tocotrienols' structure are the following aims of the work. During this study, the semisynthesis based on δ-tocotrienol was completely optimized and 3 new T3 derivatives were synthesized and fully characterized....

Tocotrienols are members of the vitamin E family but, unlike tocopherols, possess an unsaturated isoprenoid side chain that confers superior anti-cancer properties. The ability of tocotrienols to selectively inhibit the HMG-CoA reductase pathway through posttranslational degradation and to suppress the activity of transcription factor NF-κB could be the basis for some of these properties. Our studies indicate that γ- and δ-tocotrienols have potent antiproliferative activity in pancreatic cancer cells (Panc-28, MIA PaCa-2, Panc-1, and BxPC-3). Indeed both tocotrienols induced cell death (> 50%) by the MTT cell viability assay in all four pancreatic cancer cell lines. We also examined the effects of the tocotrienols on the AKT and the Ras/Raf/MEK/ERK signaling pathways by Western blotting analysis. γ- and δ-tocotrienol treatment of cells reduced the activation of ERK MAP kinase and that of its downstream mediator RSK (ribosomal protein S6 kinase) in addition to suppressing the activation of protein kinase AKT. Suppression of activation of AKT by γ-tocotrienol led to downregulation of p-GSK-3β and upregulation accompanied by nuclear translocation of Foxo3. These effects were mediated by the downregulation of Her2/ErbB2 at the messenger level. Tocotrienols but not tocopherols were able to induce the observed effects. Our results suggest that the tocotrienol isoforms of vitamin E can induce apoptosis in pancreatic cancer cells through the suppression of vital cell survival and proliferative signaling pathways such as those mediated by the PI3-kinase/AKT and ERK/MAP kinases via downregulation of Her2/ErbB2 expression. The molecular components for this mechanism are not completely elucidated and need further investigation.

Oxidative stress is a documented factor in the pathogenesis of inflammation and cancer. Vitamin E with its antioxidant properties holds promise for use in clinical practice. There are two main forms of vitamin E, tocopherols and tocotrienols. Palm oil contains almost 70% of tocotrienols. Tocotrienols exerts its antiproliferative activity against malignant cells but not on normal cells. Tocotrienols play an important role in counteracting cellular inflammatory response secondary to oxidative stress, thus exerting an anticancer property. Tocotrienols mediate function of NF-kappa B, STAT3 (signal transduction and activators), and COX-2. In addition to its role as an antioxidant and anti-inflammatory agent, tocotrienols also mediate multiple cell cycle pathways. More work needs to be done on animal models and in genetic models of pancreatic cancer to gather more data to eventually consider phase III clinical trial in human subjects.

Cancer is the second leading cause of death in the United States and is expected to become the primary cause of disease-related death within the next decade. There are significant country-to-country variations in cancer incidence, which suggests that nutrition and dietary factors are important to the carcinogenesis process. An increased risk of cancer is associated with obesity and a high body mass index demonstrating that nutrition has a central role in the promotion of cancer. Healthy eating habits protect against cancer, while unhealthy eating habits increase the risk of cancer. Mediterranean societies have a lower risk for many cancers than those of northern Europe and the Americas. Mediterranean diets consist of a high consumption of fruits, vegetables, grains, beans, nuts, and seeds, with olive oil as an important source of monounsaturated fat. These foods are rich in lipid soluble antioxidants such as vitamin E. Vitamin E may prevent cancer by decreasing the formation of mutagens arising from the oxidation of lipids, decreasing oxidative stress in the epithelial cells as well as modulating molecular mechanisms that influence cell death, cell cycle, and transcriptional events. Vitamin E is a major fat-soluble antioxidant and it occurs naturally as eight compounds (alpha-, beta gamma-, and delta-tocopherol or alpha-, beta-, gamma-, and delta-tocotrienol). Since the recognition of vitamin E in 1922 as an essential nutrient for reproduction, alphatocopherol has been considered the major form of vitamin E. It has the highest concentration in the plasma and has been studied more in epidemiological and clinical studies than any other form of vitamin E. Recent data suggests that other isoforms of vitamin E may be important in the control of cancer. These isoforms of vitamin E have varying anti-carcinogenic potencies. Data indicate that gamma-tocopherol may be a more effective anti-cancer agent than alpha-tocopherol. Our laboratories and others have demonstrated that tocotrienols are even more effective than tocopherols at inhibiting cell proliferation in cancer cells. Differences in apoptotic induction among the various vitamin E isoforms are reflective of different avenues of apoptotic signaling and may be tissue specific. Dietary fat has been linked to an increase in a number of cancers including colon, prostate, and breast cancer. Vitamin E modulates a number of molecular mechanisms involved in fat metabolism. These include: the peroxisome proliferator activator receptor (PPAR), arachidonic acid metabolism, de novo sphingolipid metabolism, and cholesterol metabolism. Vitamin E family members have demonstrated the potential to activate pathways involved in cell proliferation, differentiation, apoptosis, and cell cycle. This chapter reviews data that identify the molecular targets of vitamin E action against the development of cancer.

This research, focusing mainly on tocotrienols, includes two parts. The first part concerns the uptake and growth inhibition of tocotrienols in PC-3 cells. The second part is a study of the physiochemical properties of Vitamin E. In the cellular study our results suggested that position 5 of chroman head and side-chain are very important in determining the uptake of tocotrienols and growth inhibition of PC-3 cells. The uptake and growth inhibition are not necessarily related to the antioxidant properties of tocotrienols. Of the physiochemical studies, the results suggested that the antioxidant properties of vitamin E are due to the phenolic O-H group. In ethanol solution, each tocotrienol has a higher oxidation potential than its corresponding tocopherol. The oxidation potentials of vitamin E are in the order ofα-form < γform < δ-form. The theoretical calculations show that the side chains of tocotrienols are less ordered than those of tocopherols.

Orientador: Julian Martínez / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia de Alimentos / Made available in DSpace on 2018-08-27T11:44:01Z (GMT). No. of bitstreams: 1 Barrales_FranciscoManuel_M.pdf: 2768336 bytes, checksum: 142a36d90affeb4da8cdcb77e0d9bd5e (MD5) Previous issue date: 2015 / Resumo: O presente trabalho teve como principal objetivo avaliar a influência da aplicação de ultrassom na extração de óleo de semente de maracujá com CO2 supercrítico, focando no rendimento da extração, na cinética do processo, conteúdo de tocoferóis e tocotrienóis, perfil de ácidos graxos, e atividade sequestrante do radical DPPH do óleo, usando como matéria-prima sementes de maracujá misturadas com polpa provenientes da indústria de processamento da fruta. Com esse intuito, a metodologia de superfície de resposta foi empregada, partindo como base de um planejamento experimental de tipo composto central para três fatores. Os fatores avaliados foram temperatura (38; 40; 45; 50 e 52°C), pressão (13; 16; 21; 26 e 29 MPa) e potência de ultrassom (0; 160; 400; 640 e 800 W). Os extratos obtidos apresentaram alto porcentagem de ácidos graxos poli-insaturados (aproximadamente 67%) e teor de tocoferóis e tocotrienóis (entre 60 e 90 mg/100g óleo), atividade sequestrante do radical DPPH (entre 1,8 e 2,6 mg TE/g óleo) que demonstrou correlação com o conteúdo total de tocoferóis e tocotrienóis (r = +0,872). A análise de polifenóis totais não conseguiu detectar a presença de polifenóis nos extratos. A aplicação de ultrassom na menor potência (160 W) resultou vantajosa, gerando incrementos de até 29% no rendimento de SFE. Este efeito foi registrado na temperatura de 40 °C e pressão de 16 MPa. O modelo de Sovová (1994) mostrou-se adequado para descrever o comportamento da cinética de extração, permitindo avaliar os parâmetros ajustados. Quando foi evidenciado grande incremento no rendimento da SFE, decorrente da aplicação do ultrassom, os parâmetros cinéticos foram modificados, sendo o tempo da etapa CER maior, junto com o coeficiente de transferência de massa da fase fluida, houve diminuição da proporção de extrato de difícil acesso. As imagens obtidas por microscopia eletrônica de varredura com fonte de emissão de campo (FESEM) demonstraram efeitos de atrito e menor tamanho de partículas quando o ultrassom foi aplicado / Abstract: The present work had as main objective the evaluation of the effect of the application of ultrasound in the extraction of passion fruit seed oil using supercritical CO2, on the global extraction yield, the process kinetics, the tocopherol and tocotrienol content and DPPH radical scavenging activity, using as raw material passion fruit seeds mixed with pulp, a byproduct of the pulp processing industry. To accomplish that, the response surface methodology was used. The evaluated factors were: temperature (38; 40; 45; 50 and 52 °C), pressure (13; 16; 21; 26 and 29 MPa) and ultrasound power (0; 160; 640 and 800 W). Fatty acids composition, total polyphenolic content, identification and quantification of tocopherols and tocotrienols and the antioxidant activity were evaluated on the extracts, which resulted rich in polyunsaturated fatty acids (about 67%) and tocopherols and tocotrienols (between 60 and 90 mg/100g oil), of high antioxidant activity (between 1,8 to 2,6 mgTE/g oil) that shown correlation with the tocopherol and tocotrienol total content (r = +0,872). The total polyphenol analysis was not able to detect the presence of polyphenols in the extracts. The application of low power ultrasound (160 W) resulted advantageous; the SFE global yield improvement achieved 29%. This effect was registered at a temperature of 40 °C and pressure of 16 MPa. The model of Sovová (1994) was adequate to describe the extraction kinetics behavior, and it was possible to evaluate the adjusted parameters. When a great increase of SFE yield was achieved due to the ultrasound application, the kinetic parameters were modified, being the CER time and the fluid phase mass transfer coefficient increased, also showing reduction of solute ratio inside the cells. . The images obtained by field emission scanning electron microscopy (FESEM) demonstrated mechanical damage effects and smaller particle size when ultrasound was applied / Mestrado / Engenharia de Alimentos / Mestre em Engenharia de Alimentos

This review focuses on the roles antioxidants and pro-oxidants in colorectal cancer (CRC). Considerable evidence suggests that environmental factors play key roles in the incidence of sporadic CRC. If pro-oxidant factors play an etiological role in CRC it is reasonable to expect causal interconnections between the well-characterized risk factors for CRC, oxidative stress and genotoxicity. Cigarette smoking, a high dietary consumption of n-6 polyunsaturated fatty acids and alcohol intake are all associated with increased CRC risk. These risk factors are all pro-oxidant stressors and their connections to oxidative stress, the intestinal microbiome, intestinal microfold cells, cyclooxygenase-2 and CRC are detailed in this review. While a strong case can be made for pro-oxidant stressors in causing CRC, the role of food antioxidants in preventing CRC is less certain. It is clear that not every micronutrient with antioxidant activity can prevent CRC. It is plausible, however, that the optimal food antioxidants for preventing CRC have not yet been critically evaluated. Increasing evidence suggests that RRR-gamma-tocopherol (the primary dietary form of vitamin E) or other "non-alpha-tocopherol" forms of vitamin E (e.g., tocotrienols) might be effective. Aspirin is an antioxidant and its consumption is linked to a decreased risk of CRC.

Orientador: Eduardo Augusto Caldas Batista / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia de Alimentos / Made available in DSpace on 2018-08-19T16:41:52Z (GMT). No. of bitstreams: 1 Ansolin_Marina_M.pdf: 2006299 bytes, checksum: 85ab382490105e2f51c9502c620b007a (MD5) Previous issue date: 2012 / Resumo: Os óleos vegetais, em sua grande maioria, quando destinados ao consumo humano necessitam passar pelas etapas de refino, visando à retirada de substâncias indesejáveis. Das etapas do refino, a desacidificação ou retirada de ácidos graxos livres é a mais importante e normalmente é realizada pelo método químico ou físico. Uma alternativa para a desacidificação é a extração líquido-líquido ou refino com solvente. Nesse processo ocorrem reduções significativas de perda de óleo neutro, além de ser conduzida à temperatura ambiente e pressão atmosférica, reduzindo custos energéticos. O óleo vegetal resultante apresenta teores aceitáveis de ácidos graxos livres, sabor e odor brando e redução das perdas de compostos minoritários desejáveis como os tocoferóis e tocotrienóis (tocóis), que são antioxidantes naturais presentes nos óleos vegetais. Com base no exposto, o objetivo desse trabalho é a determinação de dados experimentais de equilíbrio líquido-líquido de sistemas graxos, com ênfase na distribuição de tocoferóis e tocotrienóis. Os sistemas graxos estudados foram óleo de soja degomado + ácido linoléico comercial + etanol anidro, óleo de soja degomado + ácido linoléico comercial + etanol + água, óleo de farelo de arroz + ácido oléico comercial + etanol anidro e óleo de farelo de arroz refinado + ácido oléico comercial + etanol + água. Os experimentos foram realizados nas temperaturas de 298,15 K, 313,15 K e 323,15 K. A partir dos resultados obtidos, verificou-se que a solubilidade mútua do óleo vegetal + solvente (etanol anidro ou etanol + água) e o coeficiente de distribuição dos tocóis foram afetados pela temperatura, concentração de ácidos graxos livres e presença de água. Quanto maior a temperatura e teor de ácidos graxos livres, maior o coeficiente de distribuição dos tocóis devido ao aumento da solubilidade entre os componentes do sistema. Em contrapartida, quando adicionado água ao etanol, o coeficiente de distribuição dos tocóis diminui, fazendo com que eles fiquem mais retidos na fase oleosa / Abstract: Vegetable oils, mostly, when for human consumption, need to be refined, with the objective of removal of undesirable substances. Deacidification or free fatty acid removal is the most important step and it is usually performed by physical or chemical method. An alternative to deacidification is the liquid-liquid extraction or solvent refining. In this process, significant reductions of loss of neutral oil occur, and it is conducted at room temperature and atmospheric pressure, reducing energy cost. The resulting vegetable oil has acceptable levels of free fatty acids, mild taste and odor and reduction in the losses of desirable minor compounds, such as tocopherols and tocotrienols (tocols), which are natural antioxidants present in vegetable oils. Based on the exposed, the objective of this study is the determination of experimental data for liquid-liquid equilibrium of fatty systems, with emphasis on the distribution of tocopherols and tocotrienols. The fatty systems studied were composed by degummed soybean oil + commercial linoleic acid + anhydrous ethanol, degummed soybean oil + commercial linoleic acid + ethanol + water, refined rice bran oil + commercial oleic acid + anhydrous ethanol and refined rice bran oil + commercial oleic acid + ethanol + water. The experiments were performed at temperatures of 298.15 K, 313.15 K and 323.15 K. From the results obtained, it was found that the mutual solubility between vegetable oil and solvent (ethanol or ethanol + water) and the distribution coefficients of the tocols were affected by temperature, concentration of free fatty acids and the water presence. The higher the temperature and free fatty acid content, higher the distribution coefficients of tocols, due to the increase of solubility among the components of the systems. In contrast, the distribution coefficients of tocols decrease when water is added to ethanol, which represents the increase in retention of tocols in the oil phase / Mestrado / Engenharia de Alimentos / Mestre em Engenharia de Alimentos