Atheroma, heart attacks and strokes continue to be a major cause of morbidity and mortality in our community. Atherosclerosis is a chronic inflammatory vascular disease, characterised by thickening of the vascular wall due to lipid accumulation, infiltration by circulating monocytes and T cells and proliferation of smooth muscle cells. Leukocyte adherence to the blood vessel wall is promoted by the up-regulation of cell adhesion molecules (CAM) by atherogenic substances such as tumour necrosis factor (TNF-α) and oxidised low density lipoprotein (oxidised-LDL). Recently our group has synthesised a novel polyunsaturated fatty acid, β-oxa 23:4n-6 which inhibits CAM up-regulation in blood vessel walls. It was therefore the objective of this thesis to determine whether this fatty acid protects against atherosclerosis. Advantage was taken of an experimental model of this disease, the apoE deficient mouse (apoE [superscript -/-]) which spontaneously develop atherosclerosis. To assist our studies on MP3, we established an appropriate classification of different stages of atherosclerotic lesions and defined the kinetics of development of the disease in this model. By examining of the sections at the level of aortic roots the atherosclerotic lesions were classified into six categories. This classification was based on the histological characteristics of the plaque component including the degree of macrophage infiltration and foam cells formation, the presence of cholesterol clefts and confluent lipid cores, calcification and ossification, the composition of the fibrous cap, the media involvement and the incipient/actual aneurysm formation and inflammation, including neutrophils. Kinetics of plaque development under the influence of a high fat and high cholesterol diet followed an exponential relationship of y= -e [ superscript -x ]. The asymptotic characteristic of this lesion development was however a function of compensatory aortic enlargement which accompanied the increase in lesion development and size. Thus it is concluded that the level of atherosclerosis needs to be gauged by the size of the lesion per se. This may be particularly important for the assessment of anti-atherogenic effects of drugs. Therefore attempts to develop a quantitative system to assess plaques revealed that expression of plaque size as % of occupation of blood vessel had limitations. Using this model we were able to demonstrate that injections of the novel polyunsaturated fatty acid, MP3 led to a significant reduction/inhibition (70%) of plaque area and a corresponding 60% inhibition of aortic size. As expected this inhibition was not as evident when results were expressed as % of aortic lumen size. The results also suggested that protection by MP3 was dependent on conditions which promoted increased uptake into tissues by, for example, preloading animals with MP3 prior to commencing the high fat high cholesterol diet. The protective effects of MP3 are consistent with a role for the activation of the transcriptional factor, NFkB and up-regulation of cell adhesion molecules in this disease, and the ability of MP3 to inhibit these targets. Thus the objective of this research has been achieved and the hypothesis proven. / Thesis (M.Med.Sc.)--Univesity of Adelaide, School of Paediatrics & Reproductive Health, 2005.

published_or_final_version / Botany / Doctoral / Doctor of Philosophy

Thesis (Ph. D.)--Faculty of Agriculture, University of Sydney, 1998. / Bibliography: leaves 184-218. Also available in print form.

Thesis--Ph. D., University of Hong Kong. / Typewritten.

Thesis (Ph. D.)--University of Hong Kong, 1999. / Includes bibliographical references (leaves 147-165).

No description available.

Ruminant products, meat and milk, were long ago discovered to contain a high content of saturated fat associated with various chronic diseases in human, including coronary heart disease. Increased consumption of n-3 fatty acids, linolenic (LNA; 18:3n-3), eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) by man has been linked with reduced incidences of these diseases. Therefore, in vitro experiments carried out in this thesis investigated the possibility that the dietary inclusion of essential oil compounds (EOC) might modify ruminal biohydrogenation of polyunsaturated fatty acids (PUFA), and thereby improve the fatty acid profiles of ruminant derived foods. In the first experiment, twenty EOC were screened, of which carvacrol, thymol, cis/trans-citral, geraniol, nerol, (+)-α-pinene, l-menthone, linalyl acetate and (R)-(+)-pulegone were most effective at protecting the PUFA from biohydrogenation. The reduced accumulation of stearic acid with concomitant increases in vaccenic acid following the addition of the EOC confirmed their capacity to inhibit biohydrogenation of both LA and LNA. However, the observed decreases in total volatile fatty acids concentrations suggested that the inclusion of these compounds at 300 mg l-1 also suppressed microbial fermentation. Of these EOC, carvacrol and thymol were the most potent inhibitors of fermentation as they decreased total VFA concentrations by ≥60% from those of the control. In the second experiment, selected EOC, namely linalyl acetate, l-menthone and (+)-α-pinene, were tested at lower doses. It was observed that these EOC when added at 100 and 200 mg l-1 also inhibited biohydrogenation with minimal effect on VFA concentration. In experiment 3, pure culture work was undertaken to assess the effects of EOC on three key Butyrivibrio spp., involved in the biohydrogenation process, namely B. fibrisolvens, B. hungatei and B. proteoclasticus. The EOC inhibited biohydrogenation through their bacteriostatic effects on these bacteria. In conclusion, these studies revealed that EOC have the potential to modify ruminal biohydrogenation to varying extents depending on the type of compound used and the dose applied. Consequently, they might be useful at improving the healthiness of ruminant products, however their effects have to be confirmed in vivo and ensure that they do not cause significant inhibition of fibre digestion.

published_or_final_version / Zoology / Doctoral / Doctor of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

No description available.