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Este trabalho teve por objetivos: levantar conceitos alternativos sobre radicais livres na mídia impressa e em livros de Bioquímica; examinar os conceitos alternativos prevalentes em pós-graduandos e em professores de Química e Biologia do Ensino Médio; e, planejar e aplicar intervenção para reduzir a influência destes conceitos. Para o levantamento na mídia impressa, foi selecionada a revista Veja, período de 01/01/2000 a 31/07/2014, e foram criadas as seguintes categorias para classificar o material encontrado: Conceito Alternativo (CA), Informação Indutiva (II), Conceito Indutivo (CI) e Generalização Indevida (GI), formando o grupo dos Conceitos Não Científicos (CNC); Conceito Correto (CC); Conceito Errado (CE); e, não preenche os critérios de inclusão (NPCI). Foram encontrados 294 trechos dos quais: 55,4% CA; 21,1% II; 9,2% CI; 5,4% GI; 4,1% CC; 2,7% CE; 2,0% NPCI; e, 91,2% CNC. Para o levantamento em livros de Bioquímica foram selecionados: Campbell - Bioquímica; Lehninger - Princípios de Bioquímica; Marzzoco e Torres Bioquímica Básica; Stryer - Bioquímica; e, Voet e Voet - Bioquímica. A maior parte dos conceitos encontrados nos livros foram conceitos corretos, contudo 77,5% dos conceitos encontrados destacavam aspectos negativos sobre radicais livres. Para o levantamento de conceitos alternativos em pós-graduandos e professores foi desenvolvido o Questionário de Radicais Livres (QRL), versões piloto e final, aplicadas, respectivamente, a 14 pós-graduandos matriculados na disciplina de pós-graduação Planejamento e Aplicação de Sequências Didáticas Envolvendo o Conteúdo Radicais Livres e 31 professores matriculados no curso de extensão Radicais Livres e suas Interfaces com a Vida, planejado com o auxílio dos pós-graduandos da disciplina. O QRL é um questionário de múltipla-escolha em etapas, composto por uma etapa de avaliação do conteúdo e outra sobre a percepção do participante sobre seu nível de certeza. Os pós-graduandos revelaram baixo domínio sobre o tema e baixo nível de certeza. Os professores, testados pré- e pós-intervenção, também apresentaram alta frequência de erros, bastante semelhante no pré- e no pós-teste, e baixo nível de certeza no pré-teste e aumento do nível de certeza no pós-teste. Acredita-se que estes resultados, tanto entre os pós-graduandos e como entre os professores, sejam reflexo da falta de contato acadêmico com o tema. Aos professores, também foram aplicados dois questionários complementares denominados Perfil Profissional e Conhecimentos Sobre Radicais Livres. Entre outras informações, os dados coletados a partir destes questionários, indicaram que os professores lecionam juntos para aproximadamente 12000 estudantes e que o curso de extensão contribuiu para aumentar seus conhecimentos sobre radicais livres. Estes dados oferecem suporte para a escolha do público-alvo e justificam a execução de cursos de extensão, tanto pelo o potencial de alcançar indiretamente um grande número de pessoas, como pela possibilidade de difusão do tema. Tanto o curso de extensão como a disciplina de pós-graduação foram muito bem avaliados pelos professores e pós-graduandos. Os altos percentuais de conceitos não científicos, principalmente conceitos alternativos, encontrados na mídia impressa, bem como os conceitos alternativos apresentados por pós-graduandos e professores, devem preocupar especialistas e cientistas, pois este tema é objeto de muitos anúncios publicitários que frequentemente incentivam o consumo de suplementos de antioxidantes. Em livros de Bioquímica, o aumento de conteúdo destacando o papel fisiológico dos radicais livres deve contribuir para desfazer o conceito disseminado de que radicais livres seriam prejudiciais à saúde. / This work aimed to survey the misconceptions regarding free radicals published in printed media and in biochemistry textbooks; to examine the misconceptions regarding free radicals prevalent among graduate students and chemistry and biology high school teachers; and to design and implement instructional intervention to reduce the influence of these misconceptions. For surveying printed media, publications from Veja magazine, dating from 01/01/2000 to 07/31/2014, were selected. The published material was categorized as follows: Misconception (MC), Inductive Information (II), Inductive Concept (IC), and Inadequate Generalization (IG) - collectively called Non-Scientific Concepts (NSC) - and Right Concept (RC), Wrong Concept (WC), and not fit for the inclusion criteria (NFIC). A total of 294 text excerpts were obtained, comprising 55.4% MC, 21.1% II, 9.2% IC, 5.4% IG, 4.1% RC, 2.7% WC, 2.0% NFIC, and 91.2% NSC. In order to examine the content in biochemistry textbooks, the following were selected: Campbell - Biochemistry; Lehninger - Principles of Biochemistry; Marzzoco & Torres - Basic Biochemistry; Stryer - Biochemistry; and Voet & Voet - Biochemistry. Most of the excerpts selected from the biochemistry textbooks were right concepts. However, 77.5% of the concepts highlighted negative aspects of free radicals. To investigate misconceptions among graduate students and high school teachers, a Free Radicals Questionnaire (FRQ) was developed. Pilot and final versions were given to 14 students enrolled in the graduate course Planning and Application of Didactical Sequences Encompassing Free Radicals Content and to 31 high school teachers enrolled in the extension course Free Radicals and its Interfaces with Life, respectively. The extension course was planned with the assistance of graduate students enrolled in the graduate course. FRQ is a multiple choice tier test with tiers for content evaluation and the participants perception of their level of certainty. Graduate students exhibited low levels of subject expertise and certainty. Teachers were tested pre- and post-intervention, and exhibited a high frequency of mistakes, comparable to graduate students, with similar pre- and post-test outcomes. However, their certainty level increased post-test. It is believed that these results may have occurred due to an academic lack of contact with the subject of free radicals. Additionally, two complementary questionnaires were given to the teachers: Professional Profile and Free Radicals Knowledge. Data collected from these questionnaires indicated that teachers collectively taught approximately 12,000 students and that the extension course contributed to increasing the teachers knowledge on free radicals. These results support the choice of the target audience and justify the implementation of the extension courses, because these courses have the potential to indirectly reach a large audience and can be used for thematic dissemination of knowledge in the subject area. The extension and graduate courses were highly rated by the teachers and graduate students, respectively. The high percentage of non-scientific concepts, especially misconceptions, found in printed media, as well as the misconceptions regarding free radicals prevalent among graduate students and teachers must concern specialists and scientists, as this topic is the subject of many advertisements encouraging consumption of antioxidant supplements. In biochemistry textbooks, increasing the content highlighting the physiological role of free radicals would contribute considerably in dispelling the widespread notion that free radicals are harmful to health.

Free radicals have been implicated in various pathological conditions such as, stroke, aging and ischemic heart disease (IHD), as well as neurodegenerative diseases like Alzheimer’s, Parkinson’s, and Huntington’s disease. The role of antioxidants in protection from the harmful effects of free radicals has long been recognized. Trapping extremely reactive free radicals and eliminating them from circulation has been shown to be effective in animal models. Nitrone-based free radical traps have been extensively explored in biological systems. Examples include nitrones such as PBN, NXY-059, MDL-101,002, DMPO and EMPO. However, these nitrones have extremely high oxidation potentials as compared to natural antioxidants such as Vitamin E (á-tocopherol), and glutathione. Becker et al. (1995) synthesized novel azulenyl nitrones, which were shown to have oxidation potentials much lower than that of any of the previously reported nitrone based spin traps. Another azulenyl nitrone derivative, stilbazulenyl nitrone (STAZN), was shown to have an even lower oxidation potential within the range of natural antioxidants. STAZN, a second generation free radical trap, was found to be markedly superior than the two most studied nitrones, PBN and NXY-059, in animal models of cerebral ischemia and in an in vitro assay of lipid peroxidation. In this study, a third generation azulenyl nitrone was synthesized with an electron donating group on the previously synthesized STAZN derivative with the aim to lower the oxidation potential even more. Pseudoazulenes, because of the presence of an annular heteroatom, have been reported to possess even lower oxidation potential than that of the azulenyl counterpart. Therefore, pseudoazulenyl nitrones were synthesized for the first time by extracting and elaborating valtrate from the roots of Centranthus ruber (Red valerian or Jupiter’s beard). Several pseudoazulenyl nitrones were synthesized by using a facile experimental protocol. The physical and biological properties of these pseudoazulenyl nitrones can be easily modified by simply changing the substituent on the heteroatom. Cyclic voltammetry experiments have shown that these pseudoazulenyl nitrones do indeed have low oxidation potentials. The oxidation potential of these nitrones was lowered even more by preparing derivatives bearing an electron donating group at the 3-position of the five membered ring of the pseudoazulenyl nitrone.

Hydroxytyrosol is one of the most powerful known antioxidants. It is a naturally occurring polyphenol, most commonly produced in Olive tree, (Olea europaea). The remarkable antioxidant and pharmacological properties of hydroxytyrosol has made it an outstanding compound in the polyphenol family and of great interest to many researchers. Hydroxytyrosol has the ability to scavenge free radicals produced during cellular oxidative stress and helps to protect the integrity of cells in living systems. Despite its numerous biological and pharmacological uses, it is found in very low concentration in olive oil, this limits its biomedical applications. A novel method for synthesizing pure hydroxytyrosol from commercially less expensive precursor catechol was successfully developed in our lab. However, it is believed that the cellular uptake of hydroxytyrosol is slow because of its high hydrophilicity. Therefore, we plan in this ongoing research to synthesize less hydrophilic derivatives of hydroxytyrosol by introducing some hydrophobic groups (such as alkyl, acyl, …) to its molecular skeleton.

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.

Polymeric carbohydrates have been reported to modulate inflammatory responses in vitro and in vivo. Previous reports suggest that certain carbohydrate polymers, such as (1→3)-β-D-glucans, may possess free radical scavenging activity. If glucans are free radical scavengers then it might explain, in part, the ability of these ligands to modulate inflammatory responses. The present study examined the free radical scavenging activity of a variety of carbohydrate polymers and the effect of the polymers on free radical levels in a murine macrophage cell line. All of the carbohydrates exhibited concentration dependent antioxidant effects (EC50 range = 807 to 43 μg/ml). However, the antioxidant activity for the carbohydrates was modest in comparison with PDTC (EC50 = 0.13 μg/ml) and the carbohydrate concentration required for antioxidant activity was high (×̄ EC50 = 283 μg/ml). The antioxidant ability of the polymers was greater (p < .05) than their monosaccharide constituents, i.e., dextrose EC50 = 807 vs. glucan sulfate EC50 = 43 μg/ml. Coincubation of glucans with murine J774a.1 cells increased free radical levels when compared to controls. Therefore, the weak free radical scavenging activity of glucan polymers cannot explain their modulatory effect on inflammatory responses in tissue culture and/or disease models of inflammation.

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The effect of steric strain on the esr hyperfine coupling constants of several free-radical adducts of perfluoropropene and perfluoro-2-butene were investigated. Silyl, hydroxyalkyl, thiyl and alkoxy free radicals, which were generated by photo-irradiation, reacted with these olefins to form free-radical adducts. Trends in the esr hfs were then looked for in each class of adducts. The thiyl and alkoxy radicals were found to be unsuitable for this type of study due to the low degree of steric strain produced by these species in the adducts. Trends toward higher a-Fβ/CF₃ hfs and lower a^Fα hfs were observed for the silyl and hydroxyalkyl radical adducts as the steric strain in the adduct was increased. The ratio of the ^Fα to a-Fβ/CF₃ hfs was shown to be a good measure of the degree of steric strain in these radical adducts. The possibility that the (Me₃Si)₂CHC(SiMe₃)₂ free radical, which has been reported to contain an "esr invisible" β-H, might be misidentified was investigated. Our conclusion was that the β-H is present and has not been replaced by a t-butoxy group. / Ph. D.

The results of our studies demonstrate a link between selectivity in free radical brominations and the internal pressure of solvent. The study encompassed l8 solvents and/or mixtures over which the rate constant ratio for SH2 ring opening of cyclopropylbenzene (kC) vs hydrogen abstraction from toluene (kH) by bromine atom was found to vary by nearly a factor of twenty as a function of solvent. The observed rate constant ratios correlate with the cohesive energy density of the solvent, which is approximately equal to the internal pressure (kC/kH is found to increase with increasing solvent pressure) for the solvents used in this study. A similar competition pitting cyclopropylbenzene against p-chlorotoluene shows the same solvent effect. It is suggested that the observed variation in selectivity "with solvent pressure occurs because the volume of activation with kC is more negative than for kH by about 20 cm3/mol. / Master of Science