Thesis (Ph.D.)--Memorial University of Newfoundland, 1997. / Restricted until December 2000. Bibliography: leaves [252]-282.

Thesis (Ph. D.)--West Virginia University, 2009. / Title from document title page. Document formatted into pages; contains viii, 141 p. : ill. (some col.). Includes abstract. Includes bibliographical references.

Thesis (Ph. D.)--West Virginia University, 2001. / Title from document title page. Document formatted into pages; contains vii, 106 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 83-102).

Cyclopropanation of the unsaturated fatty acid moieties of membrane phospholipids is a commonly observed phenomenon in a number of bacterial systems. The cyclopropane fatty acids are usually synthesized during and after the transition from exponential growth to stationary phase, or under such environmental conditions as acidic culture pH, low oxygen tension or high salt concentrations. S-Adenosylmethionine, the ubiquitous methyl group donor, provides the methylene bridge carbon in the reaction catalyzed by cyclopropane fatty acid synthase. Also formed in the reaction is S-adenosylhomocysteine, a potent inhibitor of cyclopropane fatty acid synthase, which is degraded by S-adenosylhomocysteine nucleosidase. This work provides evidence for at least two modes of regulation of lactobacillic acid synthesis, the cyclopropane fatty acid formed from cis-vaccenic acid (cis-11,12-octadecenoic acid), in Lactobacillus piantarum.

Os ácidos graxos trans competem com os ácidos graxos essenciais inibindo as enzimas envolvidas na síntese dos ácidos graxos polinsaturados de cadeia longa. Quantidades adequadas de ácidos graxos essenciais na dieta minimizam este efeito. No entanto, pouco se conhece da ação dos isômeros trans, sob condições de restrição ou deficiência dietética dos ácidos graxos essenciais, sobre o percentual de deposição tanto dos próprios isômeros trans, como dos ácidos graxos polinsaturados nos lipídios dos tecidos. Foram avaliadas dietas ricas em ácidos graxos trans e com diferentes concentrações de ácidos graxos essenciais em ratos. A incorporação de ambos foi proporcional à concentração na dieta, mas variou entre os tecidos estudados. Verificou-se que as quantidades de ácidos graxos trans incorporadas pelo tecido adiposo foi a maior, enquanto que o cérebro incorporou a menor quantidade. A despeito da incorporação dos ácidos graxos trans, o perfil de ácidos graxos do cérebro manteve-se estável em relação às variações dietéticas. Não se observou acúmulo dos ácidos graxos trans em função do prolongamento do consumo da dieta. Os ácidos graxos essenciais incorporados aos tecidos também foram modulados pela dieta, e em concentrações adequadas influenciaram na menor deposição dos isômeros trans no tecido adiposo, plasma e tecido cardíaco. Avaliando-se a composição dos ácidos graxos nos fosfolipídios do tecido cardíaco, observou-se que a fosfatidiletanolamina incorporou a maior porcentagem dos isômeros trans seguida da fosfatidilcolina e da cardiolipina, respectivamente. Embora tenha incorporado quantidades intermediárias dos ácidos graxos trans a fosfatidilcolina teve uma maior alteração no perfil de ácidos graxos em comparação aos demais. A reduzida concentração de ácidos graxos trans incorporados na cardiolipina das mitocôndrias e no cérebro sugere a existência de um mecanismo protetor para a manutenção da composição lipídica necessária às atividades funcionais. / Trans fatty acids compete with essential fatty acids inhibiting the enzymes of the long chain polyunsaturated fatty acids synthesis. Appropriate amounts of dietary essential fatty acids minimize this effect. However, little is known about the action of trans isomers on the deposition percentage of these own trans isomers itself or as polyunsaturated fatty acids in tissue lipids, when under dietary restriction or deficiency conditions of essential fatty acids. Diets high in trans fatty acids and with different concentrations of essential fatty acids were assessed. The incorporation of trans isomers and of essential fatty acids was proportional to their dietary concentration, but varied among the tissues studied. It was verified that the adipose tissue incorporated the largest amount of trans fatty acids while the brain incorporated the smallest. In spite of the trans fatty acids incorporation, the profile of brain fatty acids was maintained stable in relation to dietary variations. No accumulative deposition of trans fatty acids was observed in relation to extended length of time of dietary consumption Essential fatty acids incorporated in tissues were also modulated by diet and in moderate concentrations influenced the lower deposition of trans isomers in adipose tissue, blood plasma and heart. By assessing fatty acids composition in phospholipids of heart, it was verified that phosphatidylethanolamine incorporated the largest percentage of trans isomers followed by phosphatidylcholine and cardiolipin, respectively. Phosphatidylcholine presented the greatest change in fatty acids profile when compared to the others phospholipids, although incorporating intermediate amounts of trans isomers. The reduced concentration of trans fatty acids incorporated in cardiolipin and brain suggests that there is a protector mechanism for maintenance of the lipids composition required for functional activities.

Colon cancer is a leading cause of cancer related deaths worldwide. Lifestyle factors such as diet and exercise have been implicated as important agents in colon cancer development and progression. Epidemiological, in vivo and in vitro studies have found that n-3 polyunsaturated fatty acids (PUFAs) reduce colon carcinoma. The role of n-6 PUFAs remains a controversial topic, with studies indicating both promoting and preventing capabilities published. In order to better understand the effects of PUFAs on colon carcinoma, it is important to have an understanding of how they will be broken down in the body. During this study, in silico metabolism of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and arachidonic acid (AA) predicted the formation of hydroxy-, di-hydroxy- and epoxy-FAs. A gas chromatography-mass spectrometry method was developed and validated for the detection of these PUFAs and their cytochrome P450 (CYP) metabolites. A human liver microsomal system for the in vitro metabolism of EPA, DHA and AA was optimised in terms of microsomal and PUFA concentration. The system resulted in the metabolism of the positive control, lauric acid, to 12-hydroxy-lauric acid but was unable to metabolise the PUFAs of interest. EPA, DHA and AA reduced cell viability in the colon carcinoma cell lines SW480 and SW620 in the micromolar concentration range (25 – 200 μM). The CYP epoxidation metabolite of EPA, 17, 18-epoxyeicosatetraenoic acid (17, 18-EpETE) resulted in a significant reduction in SW480 cell viability relative to the parent compound at lower concentrations (25 and 50 μM). Annexin V apoptosis analysis revealed that EPA and 17, 18- EpETE did not result in apoptosis in SW480 cells at a concentration of 25 μM and over an incubation period of 24 hours. A significant reduction in reactive oxygen species production was seen in SW480 cells after incubation with 25 μM 17, 18-EpETE for 24 hours. EPA and 17, 18-EpETE were implicated in the reduction of colon cancer metastasis since they were able to reduce SW480 migration and anchorage independent cell growth. These results indicate that the dietary intake of EPA, DHA and AA may be beneficial to one’s health due to the negative effects that these PUFAs had on colon carcinoma. Future studies are needed to confirm these benefits and compare the effects of the PUFAs to their CYP-metabolites.

Fatty acids (FAs) are used as trophic markers in aquatic food web studies, but few studies have quantified individual variability in FAs profiles over several sites in a range of conditions. I investigated whether FAs profiles of yellow perch (YP), Perca flavescens, vary with body size and between lakes with and without largemouth (Micropterus salmoides), and smallmouth bass (Micropterus dolomieu), the most common and abundant piscivores in lakes of the region. I analyzed the FAs of YP as well as zooplankton, benthic invertebrates, and prey fish collected from eight lakes where bass were either present or absent in the Outaouais region over the summer of 2016. I compared the growth rate of YP between the lakes and the YP in lakes without bass exhibited a slower growth rate. I also compared the FA signatures of YP using redundancy analysis (RDA). 23 FAs could be identified and quantified. FAs profiles were dominated by palmitic- (16:0), oleic- (18:1), stearic- (18:0), and palmitoleic acid (16:1). The RDA analysis based on FAs profiles of YP revealed variation along two main gradients (the presence of bass and the date of capture). The first two eigenvectors accounted for 42.1% of the variation (RDA1=27.6% and 2=14.6%). Arachidonic (20:4) and docosatrienoic (22:3) were the most correlated FAs with RDA1. Due to the sampling period, it was impossible to determine if the observed effects were due to the date of capture, the presence of bass, or a change in metabolism, but the last two were deemed as the most plausible explanations. It was concluded that the utility of FA signatures to quantify diet in natural environments is limited and that FAs might be more successful as markers in primary consumers and other lower trophic levels. It is recommended that a combination of FAs, stable isotopes, and modelling should be used in the future.

It is well established that a cardiomyopathy independent of atherosclerosis develops in both humans and animals with diabetes mellitus. The etiology of diabetic cardiomyopathy is very complex involving many different processes, one of which may be the increased fatty acid utilization, and/or the concomitant decrease in glucose utilization, by the diabetic heart. We compared control and 6-week streptozotocin(STZ)-induced diabetic isolated working rat hearts and were able to demonstrate cardiac dysfunction in the diabetic as assessed by depressed heart rate (HR), heart rate peak systolic pressure product (HR X PSP), left ventricular developed pressure (LVDP), rate of pressure rise (+dP/dt) and rate of pressure decline (-dP/dt). Paralleling depressed cardiac function in the diabetic were hyperglycemia, hyperlipidemia and decreased body weight gain as compared to age-matched controls. The addition of free fatty acids, in the form of 1.2 mM palmitate, to the isolated working heart perfusate had no effect on either control or diabetic heart function, with the exception of a depressive effect on +dP/dt of diabetic hearts and -dP/dt of control hearts. But, diabetic hearts perfused with palmitate-containing perfusate plus the glucose oxidation stimulator dichloroacetate (DCA) showed a marked improvement in function. Heart rate, HR X PSP, LVDP and +/-dP/dt were all restored to control heart values in diabetic hearts perfused in the presence of DCA. Creatine phosphate and adenosine 5'-triphosphate (ATP) levels were similar under all perfusion conditions, therefore eliminating energy stores as the limiting factor in heart function. Results indicate that DCA-induced stimulation of glucose oxidation acutely reversed diabetic cardiac function depression. Therefore, depression of glucose oxidation in the diabetic heart may be contributing to diabetic cardiomyopathy. / Pharmaceutical Sciences, Faculty of / Graduate

The potential use of four radioiodinated fatty acids as myocardial imaging agents were evaluated. Preliminary distribution studies revealed that the terminal labeled fatty acids demonstrated higher myocardial uptake. Thus, 10-Iodocapric acid (10-iododecanoic) and 12-Iodolauric acid were subjected to further investigation. Comprehensive tissue distribution studies involving both radioiodinated fatty acids in mice indicated that the highest accumulation of the total injected activity occurred in the muscle and the blood. Other organs investigated included the heart, liver, lung, kidneys, spleen, stomach, intestines, bone and adrenals. The heart exhibited the highest concentration of the radioiodinated fatty acids for the relative accumulation of activity per unit weight. Erom the tissue distribution studies, the optimum scanning time was found to be immediately following injection of the radiopharmaceutical. Toxicity studies were performed in mice after intravenous administration of 10-Bromocapric acid and 12-Bromolauric acid. The LD₅₀ of Sodium Bromolaurate in 10% Human Serum Albumin was found to be 210 mg/kg (194 mg/kg - 228 mg/kg). The stability problem encountered with 10-Bromocapric acid necessitated the use of a different solvent system. The LD₅₀ obtained after intravenous injection was found to be 86.1 mg/kg (83.0 mg/kg - 89.3 mg/kg). However, this observed toxicity may not necessarily reflect the toxicity of the Bromocapric acid solely. Whole body excretion studies were performed in mice and revealed a triexponential excretion curve. For 10-Iodocapric acid, the effective half-lives were .90 hours (36.7%), 3.91 hours (61.6%) and 74.9 hours (14.5%). For 12-Iodolauric acid, the effective half-lives were 1.67 hours (46.6%), 7.68 hours (38.4%), and 71.6 hours (17.8%). For both 10-Iodocapric acid and 12-Iodolauric acid, the first as well as the second component of the excretion curve presumably represented a decrease in the whole body activity due mainly to urinary excretion. The third component appeared to represent activity which was tightly bound and slowly released. The third component presumably represented elimination by fecal excretion. The excretion of the injected activity was primarily in the urine, although some activity was recovered in the feces. For 10-Iodocapric acid, 82.4% of the injected activity had been recovered in the urine within the first 24 hours and 8.88% had been recovered in the feces. For 12-Iodolauric acid, 78.9% of the injected dose was recovered in the urine at 24 hours and 9.4% in the feces. From the urine results, the effective half-life of the radio-iodinated fatty acids in the kidneys was found to be 4.8 hours. Myocardial scans were done on rabbits using ¹³¹I-capric acid, ¹³¹I-lauric acid, NaI-131 (6% Human Serum Albumin), and Thallium-201 at specified time intervals after injection. Iodine-123, a radionuclide possessing more favorable imaging properties, was not readily available due to production problems at the time of scanning. The mean absorbed dose to the whole body, the liver, the kidneys, the muscle, and the heart were computed based on the results from the distribution and excretion studies. The dosimetry calculations were done using Iodine-123 as the radionuclide. For ¹³¹I-capric acid, the radiation doses were calculated as 34.76 mrads/2 mCi for the whole body, 136.3 mrads/2 mCi for the kidneys, 86.6 mrads/2 mCi for the liver, 38.5 mrads/2 mCi for the muscle, and 25.89 mrads/2 mCi for the heart. For ¹³¹I-lauric acid, the radiation doses were 41.73 mrads/2 mCi for the whole body, 199.8 mrads/2 mCi for the kidneys, 185.9 mrads/2 mCi for the liver, 52.07 mrads/2 mCi for the muscle, and 46.39 mrads/2 mCi for the heart. / Pharmaceutical Sciences, Faculty of / Unknown

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