Orientadores: Alba Regina Monteiro Souza Brito, Anderson Luiz Ferreira / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-21T05:05:04Z (GMT). No. of bitstreams: 1 Araujo_DeborahdeAranteseOliveiraValim_M.pdf: 3249893 bytes, checksum: e34705fa3411146e5fa5af997f4991ef (MD5) Previous issue date: 2012 / Resumo: Protium heptaphyllum March (Burseraceae), conhecido como almécega ou breu branco, é uma planta medicinal abundante na região Amazônica. Seu exudato resinoso in natura é um conceituado remédio popular com ação anti-inflamatória, antiulcerogênica, analgésica e cicatrizante. O gênero Protium compreende cerca de 135 espécies, estima-se que a maioria das espécies da família Burseraceae pertençam a este gênero, tendo como principal característica sua capacidade em exsudar resinas aromáticas voláteis, usadas como curativo de feridas, tratamento de dor de dente, antisséptico, analgésico e distúrbios gastrointestinais. O objetivo deste trabalho, foi avaliar o potencial gastroprotetor do óleo essencial comercial do Protium heptaphyllum March (Burseraceae) (BB), bem como os possíveis mecanismos de ação envolvidos, através de modelos de úlcera gástrica em ratos Unib:WH. A análise de cromatografia gasosa-espectrometria de massa (CG-EM) do BB indicou a presença de três monoterpenos majoritários: ?-pineno (40%), p-mentha-1.4(8)-dieno (12%) e ?-phellandreno (10%). Foram realizados diferentes modelos experimentais de úlcera gástrica que, com base em suas respectivas especificações, foram incluídos dois grupos controles, sendo um positivo (Lansoprazol 30 mg/kg, Carbenoxolona 200 mg/kg ou Cimetidina 100 mg/kg) e um negativo (Veículo - Tween 80® 12%, 10 mL/Kg). Após cada experimento, foi realizada eutanásia por deslocamento cervical, os estômagos removidos, abertos na região da maior curvatura e fotografados para quantificação da área de lesão ulcerativa (ALU) por meio do programa AVSoft®. O BB, na dose de 100 mg/Kg (dose mais efetiva), apresentou atividade antiulcerogênica contra lesões gástricas induzidas por etanol absoluto (96%) e por Drogas ant-inflamatórias não esteroidais (DAINEs) (97%). Para avaliar os mecanismos de ação envolvidos a atividade antissecretória, muco, prostaglandina, atividade antioxidante e envolvimento dos Grupamentos Sulfidrila (G-SH), foram analisados. Além disto, o modelo de úlcera gástrica induzida por ácido acético e análise por Western blotting da expressão de COX-2 e EGF foram utilizadas para avaliar a capacidade cicatrizante do BB. Foi verificado que este óleo essencial não interfere na secreção ácida na mucosa gástrica; porém, sua gastroproteção depende de compostos com G-SH. A atividade gastroprotetora do BB não ocorre devido ao aumento na produção de muco induzido pelos níveis gástricos de PGE2. Como o BB não atuou nos mecanismos citoprotetor e antissecretório, objetivou-se verificar o envolvimento do mecanismo antioxidante na atividade gastroprotetora. Existem evidências de que espécies reativas de oxigênio participem na etiologia da úlcera gástrica e muitos óleos essenciais foram recentemente qualificados como antioxidantes naturais. A capacidade do BB de reduzir ou prevenir estresse oxidativo foi avaliada in vivo, a partir de modelos de úlcera induzida por etanol absoluto. O BB apresentou atividade antioxidante modulando enzimas antioxidantes como Superóxido Dismutase (SOD), Glutationa Peroxidase (GSH-Px) e Glutationa Redutase (GSH-Rd), desta forma, diminuindo a peroxidação lipídica (LPO) e atividade da Mieloperoxidase (MPO). BB demonstrou também potente capacidade de cicatrização, com 95% de redução da ALU, aumentando a expressão de COX-2 (55%) e EGF (100%) na mucosa gástrica. Em adição, nenhum sinal de toxicidade foi observado durante os 14 dias de tratamento, considerando os parâmetros analisados. Portanto o BB é composto essencialmente por terpenos, não apresenta atividade antissecretora nem citoprotetora, apresenta atividade antioxidante e cicatrizante / Abstract: Protium heptaphyllum March (Burseraceae), known as "Almécega" or "Breu Branco", a medicinal plant is abundant in the Amazon region, its resinous exudates in nature, is a renowned folk remedy with anti-inflammatory, antiulcer, analgesic and healing. Protium genus comprises about 135 species, it is estimated that most species of Burseraceae, belong to this genus, the main feature, its ability to exude volatile aromatic resins, used for various purposes such as dressing for wounds, pain tooth, antiseptic, analgesic, treatment of stomach, among others. Based on the popular indications of this plant for the treatment of gastrointestinal disturbances, the present work aimed on evaluating the gastroprotective potential of the commercial essential oil of Protium heptaphyllum March (Burseraceae) (BB), as well as its possible mechanisms of action involved, through models of gastric ulcer in rats Unib: WH. Gas chromatography-mass spectrometry (GC-MS) analysis of BB indicated the presence of three majority monoterpenes as major compounds: ?-pinene (40%), p-mentha-1.4(8)-diene (12%) and, ?-phellandreno (10%). We performed different experimental models of gastric ulcer, based on your specifications included two control groups, a positive (Lansoprazole 30 mg/kg, Cimetidine 100 mg/kg or Carbenoxolone 200 mg/kg) and a negative (Vehicle - Tween 80, 12%, 10 mL/Kg). After each experiment, rats were killed by cervical dislocation, their stomachs removed and opened in the region of greater curvature and photographed for quantification of lesion area ulcerative through the AVSoft program. BB at a dose of 100 mg / kg (effective dose) showed antiulcer activity against gastric lesions induced by absolute ethanol (96%) and nonsteroidal ant-inflammatory drugs (NSAIDs) (97%). To evaluate the mechanisms involved in the BB aniulcerogenic activity, the antisecretory action, mucus, prostaglandins, antioxidant activity and involvement of sulfhydryl group (G-SH) were analyzed. The acetic acid-induced gastric ulcer model and western blotting assay COX-2 and EGF were also used to evaluate the BB healing capacity. This essential oil does not interfere with acid secretion in the gastric mucosa, but their gastroproteção depends on G-SH compounds. The gastroprotective activity of the BB is not due to increased production of gastric mucus induced by PGE2 levels. As the BB did not act in cytoprotective mechanisms and antissecretório, aimed to verify the involvement of the antioxidant mechanism in gastroprotective activity. There is evidence that reactive oxygen species involved in the etiology of gastric ulcer and many essential oils have recently been classified as natural antioxidants. The role of the essential oil in reducing or preventing the oxidative stress was evaluated in vivo, from absolute ethanol-induced gastric ulcer model. The BB showed antioxidant activity by modulating antioxidant enzymes like Superoxide Dismutase (SOD), glutathione peroxidase (GSH-Px) and glutathione reductase (GSH-Rd), thereby decreasing lipid peroxidation (LPO) and activity Myeloperoxidase (MPO). The BB has demonstraded potent healing capacity, with 95% reduction of the ulcerative lesion area due to increased expression of COX-2 (55%) and EGF (100%) in the gastric mucosa. In addition, no signs of toxicity were observed during the 14 days of treatment, considering the analyzed parameters. So BB is composed mainly of terpenes, shows no activity antissecretora or cytoprotective, exhibits antioxidant activity and healing / Mestrado / Farmacologia / Mestre em Farmacologia

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The products from a gaseous r.f. electric discharge in ammonia have been studied using electron spin resonance spectroscopy. A paramagnetic species from the discharge was detected and the results were consistent with it being the imine (NH) free radical. The E.S.R. Spectrum fitted the theoretical treatment and was similar to that observed for NH in a frozen matrix. No other radicals could be detected in the discharge except for the atomic species. The low pressure gas phase E.S.R. spectrum of (formula omitted) was also studied. The results showed that at low pressures the spectrum becomes exceedingly complex. A partial assignment of lines was made from the results of a simplified treatment of the theory. The work served a further purpose in developing experimental techniques for the study of unstable free radical species in the gas phase. / Science, Faculty of / Chemistry, Department of / Graduate

The Arrhenius parameters have been measured for the addition of the ethyl radical to methyl acrylate and its mono-methyl derivatives, methyl methacrylate, methyl cis-crotonate and methyl trans-crotonate. The energy of activation for each of these derivatives is significantly greater than for methyl acrylate, probably because of the adverse polar effect introduced by the methyl group. The activation energy for the addition to methyl methacrylate appears to be lower than for either the cis- or trans- methyl crotonate. This can probably be attributed to the fact that the ∝-methyl group can more effectively stabilise the adduct radical resulting from the addition of the ethyl radical to the methyl methacrylate, than the β-methyl group can in the case of crotonates. The pre-exponential factor is significantly smaller for each of the methyl crotonate isomers than for methyl methacrylate; partial shielding of the β-carbon atom of methyl crotonate is thus expressed by a steric factor rather than by an energy term. In terms of the rate constant for the addition reaction over the range 70°C to 160°C, methyl trans-crotonate is significantly more reactive than methyl cis-crotonate, and each isomer is only about one tenth as reactive as the vinyl compounds, methyl acrylate and methyl methacrylate, in which the site of radical attack is comparatively unobstructed. The cis-trans isomerisation of methyl crotonate is photo-sensitised by diethyl ketone illuminated by 3130 Å radiation in the gaseous phase; a mechanism of triplet state energy transfer is proposed for the process below 200°C; above 200°C an alternative mechanism involving the reversible addition of the ethyl radical to the double bond becomes the predominant process of isomerisation. / Science, Faculty of / Chemistry, Department of / Graduate

Small free radicals trapped in solid argon, krypton and carbon tetrachloride at 4.2°K have been studied using electron spin resonance (ESR). An attempt was made to determine whether the methylene radical, produced by the photolysis of diazomethane and ketene trapped in the solid matrix, has a triplet ground state. No signal definitely attributable to the methylene radical was observed. It is postulated that the zero field splitting due to the spin-spin coupling of the unpaired electrons broadened any ESR signal beyond detectability„ The ESR signal of trapped methyl radicals was observed in some experiments, and it is suggested that they were formed by abstraction of hydrogen atoms from another deposited material by methylene radicals. An experiment in which diazomethane was photolysed in the presence of D₂O in an argon matrix at 4.2°K yielded an ESR signal which may possibly have been due to the CH₂D radical. An investigation has been carried out of the populations of the rotational levels of methyl radicals produced by the photolysis of trapped methyl iodide and dimethyl mercury at 4.2°K. For thermal equilibrium freely rotating radicals should populate only the ground state at this temperature, but it was found that the lowest two levels were both populated. It is suggested that either there was not thermal equilibrium, or, more likely, the methyl radicals were undergoing hindered rotation. Room temperature equilibrium mixtures of N₂F₄ - NF₂ were trapped in the three matrices at 4.2°K, and ESR absorption due to the trapped NF₂ radicals was observed. Three lines were observed at this temperature, with the centre one of greater amplitude and smaller line width than the outer two. During warmup the amplitudes and widths of these lines became approximately equal and two further triplets appeared, symmetrically distributed about the centre line. From the warmup spectra the isotropic hyperfine splitting constants for fluorine and nitrogen have been deduced to be 168 and 48 mc./sec. respectively. It is suggested that the radicals underwent slow isotropic rotation at 4.2°K. The degree of s-character of the molecular orbital containing the unpaired electron is discussed in the light of the isotropic hyperfine splitting constants. An unsuccessful attempt to find hyperfine and rotational structure in the ESR signal of the NF₂ radical in the gas phase was carried out. The photolysis of CF₃I in krypton and carbon tetrachloride matrices at 4.2°K yielded a very complicated ESR spectrum. A phase reversal of some of the lines was observed. A broad single line was observed when CF₃I in carbon tetrachloride was irradiated at 77°K. At the time of writing no definite interpretation of the spectra can be suggested. / Science, Faculty of / Chemistry, Department of / Graduate

The technique of electron-nuclear double resonance spectroscopy (ENDOR) has been used to determine the identity and structure of radicals trapped in x-irradiated single crystals of cytosine monohydrate and caffeine hydrochloride dihydrate. The radical studied in cytosine mono-hydrate had previously been observed by several workers using electron paramagnetic resonance (EPR) but its identity was in question. All intramolecular and several intermolecular proton hyperfine couplings were analyzed in detail. The experimentally determined coupling parameters were compared with ones obtained by theoretical means for several possible radical species. The agreement between the observed and calculated parameters fit best for the radical formed by net addition of a hydrogen atom to 0(2) of cytosine, with the hydroxyl proton lying in the nodal plane of the π-system. The appearance of twice the number of certain ENDOR lines than expected from the crystal symmetry was interpreted by postulating that the radical was stabilized in two different conformations at 77°K. The assignment of the hyperfine couplings to specific protons was supported by an ENDOR study of a partially deuterated cytosine monohydrate crystal, grown from heavy water. Three different radical species were identified in caffeine hydrochloride dihydrate x-irradiated at room temperature. The EPR spectrum of this system, which had not previously been reported, was too complex to be analyzed. Furthermore, the EPR spectra of two of the radicals studied by ENDOR could not be distinguished in the overall EPR lineshape. One of these radicals had a lifetime of only a few hours and was tentatively identified as the methyl radical, primarily on the basis of the observed isotropic proton hyerpfine coupling constant of -62.65 MHz. The other radical was indefinitely stable and was identified as that formed by net abstraction of a hydrogen atom from N(9) of the caffeine moiety. This radical is equivalent to that which would be produced by the loss of an electron from a neutral caffeine molecule, the caffeine cation; as such, it is the first reported cation radical in a purine derivative. The radical which dominated the EPR spectrum was identified as that resulting from net addition of a hydrogen atom to C(8) of the protonated caffeine molecule. The identification of this radical was based on the analysis of four different proton hyperfine couplings. Nitrogen (¹⁴N) hyperfine and quadrupole coupling tensors were also obtained from the ENDOR spectra and were attributed to N(7). The observation of ¹⁴N-ENDOR lines, which had not previously been reported in any pyrimidine or purine derivative, provided a second, independent estimate of the unpaired spin density centred on N(7). An indirect second-order effect, giving rise to a non-crossing phenomenon, was observed between the methylene protons, which were also found to be non-equivalent. The structure of this radical was found to agree with those determined previously by EPR and by molecular orbital calculations for the analogous species in other purine derivatives. / Science, Faculty of / Chemistry, Department of / Graduate