The objective of this study was to compare the effect of phytosterols (PS) on lipid profiles and cholesterol kinetics of hypercholesterolemic individuals with or without type 2 diabetes. It was hypothesised that the response to PS would differ between both groups due to different lipid metabolism. During this randomised, double blind, crossover trial, participants consumed a controlled diet with placebo or PS for 21 days. / Plasma total cholesterol (TC) decreased with placebo and PS (10.9% and 9.7% in non-diabetic versus 11.6% and 13.6% in diabetic participants, p < 0.05). Plasma low-density lipoprotein cholesterol (LDL) significantly decreased with PS in both groups. The reduction in LDL with PS was greater in diabetic compared to non-diabetic individuals (29.8% versus 14.9%, p < 0.05). Cholesterol absorption decreased on average (p = 0.06) by 26.5% with PS compared with placebo in the diabetic group only. Therefore, a controlled heart healthy diet reduced TC and LDL concentrations in non-diabetic and diabetic individuals. Adding PS as adjuncts to a hypocholesterolemic dietary treatment was associated with lower LDL concentrations and cholesterol absorption in hypercholesterolemic participants with type 2 diabetes.

The current study examined the impact of plant sterols, stanols, sterol esters, and stanol esters on (i) cholesterol-lowering efficiency, (ii) gene expression of ABCG5 and ABCG8 sterol transporters in the liver and small intestine, and (iii) colon mucosal cell proliferation in hamsters. After 5 weeks on experimental diets, plasma total cholesterol levels were reduced ( P<0.05) by stanols, sterol esters and stanol esters compared to cholesterol-control diet. Different PS analogs did not alter ABCG5 and ABCG8 mRNA levels in small intestine and liver as compared to cholesterol control. In addition, colon mucosal cell proliferation was 21.4% lower (P<0.01) in group fed 0.7% stanol esters relative to cholesterol control. Results suggest that hypocholesterolemic effects of PS analogs are not associated with changes of liver and small intestine ABCG5 and ABCG8 sterol transporters. Data also indicated that plant stanol ester may possess anticarcinogenic properties.

The objective of this study was to examine the effects of plant sterols and/or glucomannan on lipid profiles and cholesterol kinetics in hyperlipidemic individuals with or without type 2 diabetes. It was hypothesized that plant sterols and glucomannan reduce circulating cholesterol levels and may have an additive or synergistic effect when combined by reducing cholesterol absorption. Thirteen type 2 diabetics and sixteen non-diabetics all mildly hypercholesterolemic free living subjects participated in a randomized crossover trial consisting of 4 phases, 21 days each. Subjects consumed plant sterols and glucomannan during the trial. Overall reductions in total and LDL-cholesterol levels were greater (P<0.05) after consumption of the combination supplement. Effects of supplements were not different between diabetics and non-diabetics. No significant changes were observed in cholesterol absorption or synthesis in both diabetics and non-diabetics. The intake of plant sterols and glucomannan together may be an alternative approach in reducing blood cholesterol levels.

Statins are widely used to treat hypercholesterolemia. Statins inhibit cholesterol biosynthesis, thereby activating genes involved in cholesterol homeostasis, which are under the control of the Sterol Regulatory Element (SRE). Statins also have cholesterol-independent beneficial cardiovascular effects mediated through the phosphoinositide 3-kinase (PI3-K) / Akt signaling pathway and by inhibition of protein prenylation. Because statins inhibit the synthesis of isoprenoids, they can act by inhibiting the small signaling GTPases Ras and Rho, which require post-translational prenylation to become membrane-anchored and functional. We showed that simvastatin-mediated inhibition of protein prenylation does not appear to play a role in activation of SRE transcriptional activity in HepG2 cells. We also found that when isoprenoids were replenished, basal phospho-Akt decreased, suggesting that inhibition of prenylation by simvastatin mediates Akt phosphorylation. Future studies will be needed to investigate the role that inhibition of protein prenylation plays in the activation of the PI3-K/Akt pathway by simvastatin. / Department of Biology

Tez (Tıpta Uzmanlık) - Süleyman Demirel Üniversitesi, Tıp Fakültesi, Biyokimya Anabilim Dalı, 2006. / Bibliyografya var.

Discovery of cheap, nontoxic and readily available antiatherosclerotic drugs is an extraordinary challenge in this modern world. Atherosclerosis and cardiovascular diseases have been predicted to be the leading cause of death by the year 2030. Hence, this thesis was designed to search for plant (s) with anti-atherogenic properties, investigate its possible side effects and extrapolate its likely mechanism(s) of action. An ethnobotanical survey was employed in identification of locally important plants used for the management and treatment of cardiovascular diseases and its predisposing factors in Nkonkobe Municipality, Eastern Cape in South Africa. Information on the names of plants, their parts used and methods of preparation was collected through a questionnaire which was administered to herbalists, traditional healers and rural dwellers. The most frequently used plant (Rhizomes of Tulbaghia violacea Harv.) was investigated for toxicity using brine shrimp lethality (in vitro) and in vivo toxicity test (acute and subchronic) on rats to determine safety dosage. The in vitro antioxidant and free radical scavenging activity of the plant was investigated using models such as 1,1-diphenyl-2- picrylhydrazyl (DPPH), superoxide anions, hydrogen peroxide (H2O2), nitric oxide (NO), 2,2’- azinobis [3-ethylbenzothiazoline-6-sulfonic acid] diammonium salt (ABTS), lipid peroxidation inhibition and the ferric reducing agent. Phytochemical content and the effect of oral administration of fresh methanolic extract rhizomes of Tulbaghia violacea (250, 500 mg/kg. bwt/day) on Lipid peroxidation (TBARS), serum and tissue antioxidant enzymes in normal, hypercholesterolemic and diet induced atherogenic rats were also assessed. More so, the potential of the extract (250 and 500 mg/kg. bwt) to protect against atherogenic diet (4 percentage cholesterol 1 pecentage cholic acid and 0.5 percentage thiouracil) induced fatty streaks formation, dyslipidemia, oxidative stress and endothelial dysfunction was also investigated. Ethnobotanical study revealed that 19 plant species are used for the treatment of heart related diseases in the Municipality. 53 percentage of the plants mentioned were used for the management of chest pain, 47 percentage for high blood pressure, 42 percent for heart disease, 16 percentage for stroke and 11 percentage for the treatment of hypercholesterolemia. Tulbaghia violacea was repeatedly mentioned as the plant species used for the treatment of high blood pressure and predisposing factors in the study area. The brine shrimp cytotoxicity test revealed that fresh, dried methanolic extracts and essential oil of the T. violacea exhibited a high degree of cytotoxic activity with IC50 values of 18.18 (fresh) and 19.24 (dried) μg/ml. An IC50 value of 12. 59 μg/ml was obtained for the essential oil of the plant. The low cytotoxicity values obtained, suggested that rhizome of T. violacea may serve as a potential source of antimicrobial and anticancer agents. In vivo acute study of single oral administration of 5g/kg dose does not produce mortality or significant behavioral changes during 14 days observation. In the sub-chronic study, the extract (250, 500 mg/kg/bwt/ day) administered for a period of 28 days showed no mortality or morbidity. The weekly body and organ weight of the rats showed no significant differences between the control and the rats treated with the extract. The extract at all doses does not show any effect on of biomarkers of liver or renal damage. However, a significant decrease in the activity of ƔGT was observed in the extract treated groups. Hematological evaluation revealed that oral administration of fresh methanolic extracts of rhizomes of T. violacea does not cause anaemia or leucocytosis in the animals. Furthermore, histopathology results of the internal organs revealed no detectable inflammation. These results demonstrated that the rhizome extract of T. violacea was potentially safe for consumption orally even in chronic concentration. In vitro antioxidant evaluation showed that the essential oil, fresh and dried methanolic extracts exhibited potent antioxidant activities in a concentration dependent manner. Phytochemical investigation reveals that the fresh and the dry extract of RTV are rich in flavonoid, flavonol, phenols, tannin and proanthocyanidin, while the essential oil contained dimethy disulfide, dimethyl trisulfide, (methyl methylthio) methyl, 2,4-dithiapentane (11.35 percent) and (methylthio) acetic acid, 2- (methylthio) ethanol, 3-(methylthio) - and propanenitrile (7.20 percent). The fresh extract had higher radicals scavenging activity than the essential oil or dried extract, with 50 percentage inhibition of DPPH, hydrogen peroxide and lipid peroxidation at a concentration of 35.0 ± 0.12, 19.3 ± 0.11 and 17.9 ± 0.15 μg/ml respectively. Oral administration of methanolic extract of RTV in 125, 250 and 500 mg/kg to female Wistar rats significantly inhibited reduction of glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT). The extracts also inhibited (p< 0.05) lipid peroxidation in normal, high cholesterol and diet induced atherosclerosis fed rats in a dose dependant manner. Also the extract (250 and 500 mg/kg/bwt/day) caused a significant (p<0.05) improvement in body weight of treated animals compared with untreated hypercholesterolemia control rats. The extracts also protected significantly (p<0.05) against atherogenic diet induced liver damage or fatty streaks formation in the aorta as revealed by histological examination. The anti-cholesterolemia and anti-atherosclerotic activities of the extract compared favorably well with standard drugs Gemfibrozil and Atorvastatin respectively. Conclusively, rhizomes of T. violacea possess significant anti-atherogenic activity and its mechanism of action(s) may be due to its antioxidant and anti-hypercholesterolemia properties. The results of this study also suggested that rhizome of T. violacea is relatively safe for human consumption and it may be used as an alternative to garlic.

Familial hypercholesterolemia (FH) is an autosomal dominant disorder in which the primary defect is a mutation in the LDL receptor. Heterozygous FH is among the most common inborn errors of metabolism and remains as the best example of an inherited defect causing premature coronary artery disease (CAD). This thesis describes the physical and biochemical characteristics of heterozygous FH in a large cohort consisting of 208 women and 156 men. The influence of both genetic and environmental factors on the clinical expression of FH were investigated to better understand the phenotypic variation within FH and thus improve the prediction and treatment of CAD in affected individuals. The general incidence of CAD in this population was lower compared to previous reports but the differences between the sexes were expected. It was shown that men had a much higher frequency of CAD (31%) compared to women (13%) despite having lower concentrations of total and LDL cholesterol. In addition, the average age of onset of coronary symptoms was delayed in females, 55 years compared to 48 years for males. A greater risk of developing CAD for men was associated with low levels of HDL cholesterol and a history of smoking. In women, however, CAD was associated with elevated triglyceride levels and the presence of hypertension. In order to efficiently assess the influence of the co-inheritance of the apolipoprotein E polymorphism in this large FH population, a novel apo E phenotyping procedure was developed. Phenotypes were determined directly from plasma which was neuraminidase treated, delipidated and focused in polyacrylamide minigels. The accuracy of this method was confirmed by making a comparison to the established procedure of phenotyping by isoelectric focusing of delipidated VLDL. The low cost, speed and simplicity of the minigel methodology provided ideal conditions to phenotype a large patient population. The frequencies of the ɛ2, ɛ3 and ɛ4 alleles of apolipoprotein E in 125 unrelated FH subjects did not differ significantly from the normal population. In addition, there was no apparent relationship between apo E4 and the concentration of any of the parameters in the plasma lipid profile. However, the presence of the E2 isoform was associated with significantly elevated triglycerides in both sexes. From this study, it is evident that the mutant FH gene exerts its effect within a system of interacting environmental and polygenic factors that are known to modify atherosclerotic risk. It has been established that the dissimilarity in the frequency of CAD between men and women is related to differences between the impact of known risk factors and the incidence of CAD. Therefore, the importance of the influence of these risk factors and the differences between men and women should be emphasized when treating and predicting the development of CAD in patients with FH. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

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