Dissertationen zum Thema „Anticholesteremic agents“

Includes bibliographical references (21 leaves). Previous studies have found that green tea and its antitoxidant constituents, the catechins, are hypocholesterolaemic in both epidemiological and animal intervetion studies. The main objectives of the present study were to investigate the mechanism by which green tea and its most abundant catechin constituent epigallocatechin gallate increase the low-density lipoprotein (LDL) receptor of HepG2 cells. In addition, it was hoped to determine if a crude catechin extract from green tea could lower plasma cholesterol levels in the hypercholesterolaemic rabbit and ascertain if this effect was due to an increase in the LDL receptor. The study provides evidence that green tea and its catechins exhibit hypocholesterolaemic properties and may therefore provide protection against heart disease.

The cholesterol-lowering efficacy of the original sugarcane-derived Cuban policosanol (OPC) supplement has been attributed to an exclusive policosanol purity and composition. The first objective of the following study was to compare the purity and composition of the OPC and alternative sugarcane derived policosanol (APC) products. Second, to measure blood lipids and policosanol levels in tissues, plasma and feces in hamsters receiving diet fortified with no policosanols, OPC, or an APC (APC1) product. Results indicated that the policosanol purity and composition of the OPC and APC formulations are similar. Lipid levels were not significantly different between groups. Policosanols were undetectable in the plasma and tissues of any animals following policosanol supplementation. Policosanols were excreted at a higher rate in animals consuming APC1. Sugarcane-derived policosanols are not an efficacious cholesterol-lowering therapy. The purity and relative percent composition of the OPC supplement cannot account for its efficacy as a lipid lowering agent.

Dietary phytochemicals such as saponins have been suggested to have therapeutic uses in the prevention and alleviation of hypercholesterolemia. Thus, twelve Tanzanian plant additives hypothesized to contain saponins and used in soup by the Batemi, were investigated for in vitro hypocholesterolemic potential by: (1) screening for likelihood of detectable saponins using TLC, hemolysis, frothing ability and molluscicidal activity. (2) using changes in hemolytic activity to indirectly examine interactions of plant extracts with cholesterol, cholesterol-analogues, conjugated bile salts and non-conjugated bile salts. (3) using radiolabelled cholesterol to examine direct binding capacity of extracts with cholesterol. Albizia anthelmintica, Myrsine africana and Acacia goetzii were most likely to contain saponins and had significant (p $<$ 0.05) hemolytic activity that was effected by the presence of cholesterol, cholesterol analogues, conjugated and non-conjugated bile salts (p $<$ 0.05). Methanol, ethyl acetate, aqueous and n-butanol extracts of A. anthelmintica and methanol, ethyl acetate and aqueous extracts of A. goetzii bound significant amounts of cholesterol solubilized in ethanol (p $<$ 0.05). Thus, saponins are a detectable component of the Batemi diet and extracts likely containing saponins do interact with chemicals that have been proposed to be involved in in vivo mechanisms of saponin induced hypocholesterolemia. A. anthelmintica and A. goetzii seem likely to have hypocholesterolemic potential as dietary additives.

Background. A high ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol, in addition to increased levels of small low-density lipoprotein (LDL) particles, are important indicators of cardiovascular disease risk. Therefore, interventions that combine the lowering of total cholesterol and raising of HDL cholesterol concentrations that also increase LDL particle size, may be preventive against cardiovascular disease. Plant sterols decrease total cholesterol and LDL cholesterol levels by 10-15%, while exercise increases HDL cholesterol levels by 4-22%. In view of their complementary effects, combining plant sterols with exercise would appear to be an effective lifestyle therapy to decrease the risk of future cardiovascular disease.
Objective. The aim of this study was to examine the independent and combined effects of plant sterols and exercise on blood lipid levels, and LDL particle size in previously sedentary, hypercholesterolemic adults. An additional objective of this trial was to assess the underlying mechanism by which this combination therapy modulates whole body cholesterol metabolism, to in turn improve lipid profiles.
Methods. In an 8-week, parallel-arm trial, 84 subjects were randomized to 1 of 4 interventions: (1) plant sterols and exercise,(2) plant sterols alone, (3) exercise alone, or (4) control. Blood lipid concentrations were measured using enzymatic kits, and LDL particle size was assessed using polyacrylamide gel electrophoresis. Cholesterol absorption and synthesis were determined using the single isotope single tracer technique and the deuterium incorporation approach, respectively.
Results. Plant sterol supplementation decreased (P < 0.01) total cholesterol concentrations by 8.2% when compared to baseline. Exercise increased (P < 0.01) HDL cholesterol levels by 7.5% while decreasing (P < 0.01) triglyceride concentrations by 13.3% when compared to baseline. Exercise reduced (P < 0.05) post-treatment LDL peak particle size from 255 to 253 A, and decreased (P < 0.05) the proportion of large LDL particles by 13.1%. Plant sterols had no effect on particle size distribution. Plant sterol supplementation decreased (P < 0.01) intestinal cholesterol absorption by 18%, while exercise had no effect on cholesterol absorption. Non-significant increases in cholesterol synthesis rates of 63%, 59%, and 57%, were observed in the combination, exercise, and plant sterol groups, respectively, relative to control.
Conclusion. These findings suggest that this combination therapy yields the most favourable alterations in lipid profiles when compared to each intervention alone. This combined intervention exerts its beneficial effects on lipid profiles by suppressing intestinal cholesterol absorption. Therefore, this lifestyle therapy may be an effective means of decreasing the risk of cardiovascular disease in hypercholesterolemic adults.

Plant sterols (PS) are effective in reducing plasma lipid concentrations, however, few studies have examined their cholesterol lowering effects in type 2 diabetics. The objective was to assess whether PS consumption alters blood lipid profile in hypercholesterolemic subjects with and without type 2 diabetes. Fifteen control subjects (age = 55.1 +/- 8.5 yr and BMI = 26.9 +/- 3.0kg/m2) and fourteen diabetic subjects (age = 54.5 +/- 6.7 yr and BMI = 30.2 +/- 3.0kg/m2) participated in a double-blinded, randomized, crossover, placebo-controlled feeding trial. The Western diet included either 1.8g/d of PS or cornstarch placebo each provided over 21 d separated by a 28 d washout period. Subjects consumed only foods prepared in Mary Emily Clinical Nutrition Research Unit of McGill University. Total cholesterol (TC) decreased (p < 0.05) from baseline with PS for control and diabetic subjects by 9.7% and 13.6%, respectively. TC decreased (P < 0.05) from baseline with placebo for control and diabetic subjects by 10.9% and 11.6%, respectively. Non high density lipoprotein cholesterol (non-HDL-C) decreased (p < 0.05) from baseline with PS for diabetic subjects by 18.5%. Low density lipoprotein cholesterol (LDL-C) levels were reduced (p < 0.05) from baseline with PS for control and diabetic subjects by 14.9% and 29.8%, respectively. The reduction of LDL-C due to PS alone is greater with type 2 diabetics. There were no significant changes in HDL-C and TG across diets or treatments. It is thus concluded that PS consumption with diet enhances non-HDL-C and LDL-C reduction compared with diet alone in hypercholesterolemic individuals with and without type 2 diabetes. Demonstration for the first time that PS alone are more efficacious in lowering LDL-C and non-HDL-C in diabetic individuals compared to non-diabetics confirm the beneficial effects of PS to help prevent cardiovascular disease (CVD) for this high risk population.

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 objective of this research was to examine the effects of plant sterols and glucomannan on lipid profiles, plasma plant sterol levels and glycemic control in mildly hypercholesterolemic subjects. Thirteen type 2 diabetic and sixteen non-diabetic individuals participated in a randomized crossover trial consisting of 4 phases, of 21 days each. During the study period, subjects were supplemented with plant sterols and/or glucomannan. Overall reductions of total cholesterol and low-density lipoprotein (LDL) cholesterol concentrations were greater after consumption of plant sterols and glucomannan compared to plant sterol or glucomannan supplementation alone. Plasma lathosterol levels, indicators of cholesterol biosynthesis, were decreased after combination treatment. The results suggest that a combination of glucomannan and plant sterols substantially improve plasma lipids by reducing cholesterol absorption and synthesis simultaneously. Supplementation of plant sterols and glucomannan can thus be used as an effective treatment for management of circulating cholesterol levels and prevention of cardiovascular disease.

The effect of diets with various dietary fiber sources on the plasma lipids, liver cholesterol, the histology of the gastrointestinal tract, heart, liver and kidney and the fecal neutral steroid excretion was investigated in hamsters. 155, 9-11 wk old, male Golden-syrian hamsters were fed a purified basal hypercholesterolemic diet (0.1% cholesterol, 10% fat, 4% dietary fiber) for 5 wk to elevate plasma lipid levels. Based on wk 4 plasma total cholesterol (TC) levels hamsters with elevated levels were randomly assigned, 16 animals/group, into six groups for another 4 wk: control, oat bran, guar gum, cellulose, xylan and sacrifice. After 4 wk of the fiber diets (10% dietary fiber), the plasma TC levels were significantly lowered in the oat bran, guar gum and xylan groups (16%, 12% and 15%, respectively) (p<.05). They were also significantly lower than the control and cellulose groups. Plasma HDL-C concentrations tended to be lower in all the treatment groups, but was significantly decreased only in the guar gum group (12%) (p<.05). The combined plasma VLDL-C + LDL-C was significantly lowered by the oat bran, cellulose and xylan diets (38%, 40% and 34%, respectively) (p<.05). The liver cholesterol concentration increased significantly from 1 mg cholesterol/g liver to 4.1 mg cholesterol/g liver (p<.05) after 4 wk of the control diet; this was further increased significantly only in the cellulose group (5.6 mg cholesterol/g liver), while the other treatment groups showed no significant changes or differences compared to the control diet group (wk 4). The total fecal neutral steroid excretion was significantly (p<.05) higher in the oat bran group compared to the other treatment groups. No major differences were observed in the tissue histology of the animals in the different treatment groups. In the present study, it appeared that oat bran, guar gum and xylan were effective hypocholesterolemic agents; however, their mechanism of action is still not clear.
Ph. D.

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.

This thesis shows the research carried out on two specific diseases: familial hypercholesterolemia, which is included within the cardiovascular diseases group, and cancer. These diseases are the major cause of deaths in Spain and worldwide. The study of familial hypercholesterolemia is of great interest, as it is mainly caused by a protein called PCSK9 whose atypical functioning leads to an increase of LDL-C in blood. Thus, the study of new diseases results in the study of new therapeutic targets. Therefore, a thorough investigation on the PCSK9 protein has been conducted by means of molecular modelling analysis. Also, the synthesis of potentially PCSK9 inhibitors new compounds has been performed. The modelling studies have been based on the research of new binding sites and in de novo synthesis of new inhibitors. On the other side, the experimental synthesis of new compounds has been conducted by the preparation of pyrrolo[2,3-d]pyrimidines and finally, by the preparation of a series of compounds analogues of Combretastatin A4 through modification in the two aromatic rings and the fixation of its configuration with the introduction of a cycle. In the case of cancer, the study is based mainly on the research of a key protein in cell proliferation, growth and cell signalling. KRAS protein is either active or mutated in most common cancers, being the main cause of pancreas and colorectal cancer. Research on this target is of high chemical and biological relevance since no drugs have been found to act directly on said target. Molecular modelling studies are performed in order to find the binding site of a reference product whose inhibiting capacity over the protein is known. Furthermore, the synthesis of a series of symmetric pyrazoles with different structural modifications has also been carried out. Additionally, biological WST-8 / CCK8 assay have been performed on some of the synthetized compounds, specifically on two Combretastatin A4 analogues, in an endothelial cell line that allows studying both endothelial dysfunction and cardiovascular diseases. Research on the MAPK signalling pathway has been performed with pyrazoles structure derivatives.

Thesis (Ph.D. in Clinical Science) -- University of Colorado Denver, 2007.
Typescript. Includes bibliographical references (leaves 86-91). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

Cheung, Chi Yun.
"September 2011."
Thesis (M.Phil.)--Chinese University of Hong Kong, 2011.
Includes bibliographical references (leaves 57-59).
Abstracts in English and Chinese.
Acknowledgment --- p.i
Table of Contents --- p.ii
Abstract --- p.iii
Abstract (Chinese Version) --- p.iv
Abbreviation --- p.v
Chapter 1. --- Introduction --- p.1
Chapter 1.1 --- General Background --- p.1
Chapter 1.2 --- Mechanism of action --- p.3
Chapter 1.2.1 --- Biosynthetic pathway of cholesterol --- p.3
Chapter 1.2.2 --- Inhibition of HMG-CoA reductase by statins --- p.4
Chapter 1.2.3 --- Plasma cholesterol reduction effect --- p.5
Chapter 1.3 --- Previous syntheses of statin analogs --- p.5
Chapter 1.3.1 --- Synthesis from (S)-malic acid --- p.6
Chapter 1.3.2 --- Synthesis via enantioselective deprotonation --- p.7
Chapter 1.3.3 --- Synthesis via asymmetric Diels-Alder reaction --- p.9
Chapter 2. --- Results and Discussion --- p.11
Chapter 2.1 --- Approaches towards construction of statin analogs --- p.11
Chapter 2.2 --- Attempt to synthesize alkene 49 from D-arabinose --- p.12
Chapter 2.3 --- Construction of alkene 49 from D-mannitol --- p.14
Chapter 2.4 --- Olefin metathesis and conversion to statin analogs --- p.28
Chapter 3. --- Conclusion --- p.32
Chapter 4. --- Experimental Section --- p.33
Chapter 5. --- References --- p.57
Chapter 6. --- Appendix ii --- p.60

Yeung Ming.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2003.
Includes bibliographical references (leaves 136-162).
Abstracts in English and Chinese.
THESIS COMMITTEE --- p.i
ACKNOWLEDGEMENTS --- p.ii
ABSTRACT (ENGLISH) --- p.iii~v
ABSTRACT (CHINESE) --- p.vi~vii
TABLE OF CONTENTS --- p.viii~xiii
LIST OF TABLES --- p.xiv~xv
LIST OF FIGURES --- p.xvi~xviii
LIST OF ABBREVIATIONS --- p.xix~xx
Chapter CHAPTER ONE: --- INTRODUCTION --- p.1
Chapter 1.1 --- Different lipoproteins and their functions --- p.1
Chapter 1.1.1 --- Chylomicrons --- p.4
Chapter 1.1.2 --- VLDL --- p.4
Chapter 1.1.3 --- LDL --- p.4
Chapter 1.1.4 --- HDL --- p.5
Chapter 1.2 --- Risk factors of coronary heart disease (CHD) --- p.5
Chapter 1.2.1 --- Background information of CHD --- p.6
Chapter 1.2.2 --- "Relationship between serum total cholesterol (TC), Low-density lipoprotein (LDL) cholesterol and CHD" --- p.7
Chapter 1.2.3 --- High-density lipoprotein (HDL) cholesterol and CHD --- p.8
Chapter 1.2.4 --- Triglyceride and CHD --- p.9
Chapter 1.3 --- Cholesterol homeostasis --- p.10
Chapter 1.3.1 --- Roles of HMG-CoA reductase in cholesterol biosynthesis --- p.13
Chapter 1.3.2 --- Roles of cholesterol 7α-hydroxylase (CYP7A) in cholesterol catabolism…… --- p.15
Chapter 1.3.3 --- Effects of Short-Chain Fatty Acid (SCFA) --- p.17
Chapter 1.3.4 --- Related hormone --- p.18
Chapter 1.4 --- Possible mechanisms of hypolipidemic agents --- p.19
Chapter 1.4.1 --- Hypolipidemic functional foods --- p.20
Chapter 1.4.2 --- Pharmacological drugs --- p.26
Chapter 1.5 --- Edible and medicinal mushrooms --- p.28
Chapter 1.5.1 --- General introduction --- p.28
Chapter 1.5.2 --- Hypolipidemic agents from Fungi --- p.31
Chapter 1.6 --- Animal model --- p.35
Chapter 1.7 --- Objectives --- p.36
Chapter CHAPTER TWO: --- MATERIALS AND METHODS --- p.37
Chapter 2.1 --- Materials --- p.37
Chapter 2.1.1 --- Mushroom samples and control --- p.37
Chapter 2.1.1.1 --- Sample introduction --- p.37
Chapter 2.1.1.2 --- Sample collection --- p.40
Chapter 2.1.1.3 --- Sample preparation --- p.41
Chapter 2.1.1.4 --- Moisture content --- p.45
Chapter 2.1.2 --- Animal diets for different experiments --- p.45
Chapter 2.1.2.1 --- Basal diet --- p.45
Chapter 2.1.2.2 --- Diet for preliminary screening --- p.46
Chapter 2.1.2.3 --- Diet for dosage experiment --- p.46
Chapter 2.1.2.4 --- Diet for active ingredient experiments --- p.47
Chapter 2.1.2.5 --- Diet for long-term feeding experiment --- p.47
Chapter 2.1.3 --- Animal model --- p.49
Chapter 2.2 --- Methods --- p.49
Chapter 2.2.1 --- Nutritional components of mushroom samples --- p.49
Chapter 2.2.1.1 --- Crude protein content (Kjeldahl method) --- p.49
Chapter 2.2.1.2 --- Total dietary fiber content --- p.50
Chapter 2.2.1.3 --- Crude lipid content --- p.52
Chapter 2.2.1.4 --- Ash content --- p.53
Chapter 2.2.1.5 --- Moisture content --- p.53
Chapter 2.2.2 --- Animal handling experiments --- p.54
Chapter 2.2.2.1 --- Feeding experiment standards --- p.54
Chapter 2.2.2.1.1 --- Feeding experiments of preliminary screening test --- p.54
Chapter 2.2.2.1.2 --- Feeding experiments of dosage test --- p.55
Chapter 2.2.2.1.3 --- Feeding experiments of solvent extracts from Agrocybe aegerita (Brig) Sing (AA) --- p.56
Chapter 2.2.2.1.3.1 --- Fractionation of ethanol & water soluble components of AA --- p.56
Chapter 2.2.2.1.3.2 --- Feeding experiments of ethanol & water soluble components of AA --- p.57
Chapter 2.2.2.1.4 --- Feeding experiment of long-term test --- p.58
Chapter 2.2.2.2 --- Blood sample collection --- p.58
Chapter 2.2.2.3 --- Serum preparation --- p.58
Chapter 2.2.2.4 --- Liver sample preparation --- p.58
Chapter 2.2.2.5 --- Fecal sample preparation --- p.59
Chapter 2.2.3 --- Determination of serum lipid profiles --- p.59
Chapter 2.2.3.1 --- Serum total cholesterol (TC) assay --- p.59
Chapter 2.2.3.2 --- Serum triglyceride (TG) assay --- p.60
Chapter 2.2.3.3 --- Serum high-density lipoprotein (HDL) cholesterol assay --- p.61
Chapter 2.2.3.3.1 --- Separation of HDL fraction --- p.61
Chapter 2.2.3.3.2 --- HDL cholesterol (HDL-c) determination --- p.61
Chapter 2.2.4 --- Determination of liver lipid profiles --- p.62
Chapter 2.2.4.1 --- Liver total cholesterol (TC) level determination --- p.62
Chapter 2.2.4.2 --- Determination of liver total lipid (TL) level --- p.64
Chapter 2.2.5 --- Quantitative determination of fecal neutral & acidic sterols --- p.64
Chapter 2.2.5.1 --- Separation of fecal neutral & acidic sterols --- p.64
Chapter 2.2.5.2 --- Derivatisation of fecal neutral sterols --- p.65
Chapter 2.2.5.3 --- Derivatisation of fecal acidic sterols --- p.65
Chapter 2.2.5.4 --- Gas chromatographic analysis of fecal neutral & acidic sterols --- p.66
Chapter 2.2.6 --- Assays of liver key enzymes in cholesterol metabolism --- p.67
Chapter 2.2.6.1 --- Preparation of hepatic microsome --- p.67
Chapter 2.2.6.2 --- Assay of HMG-CoA reductase activity --- p.68
Chapter 2.2.6.3 --- Assay of CYP7A activity --- p.69
Chapter 2.3 --- Data statistics --- p.71
Chapter CHAPTER THREE: --- RESULTS AND DISCUSSION --- p.72
Chapter 3.1 --- Preliminary screening of eleven mushrooms for their hypolipidemic effect in hyperlipidemic S.D. rats --- p.72
Chapter 3.1.1 --- Body weight and food intake --- p.73
Chapter 3.1.2 --- Effect of mushroom supplementation on serum lipid profiles --- p.75
Chapter 3.1.2.1. --- Effect of mushroom supplementation on serum TC levels --- p.75
Chapter 3.1.2.2. --- Effect of mushroom supplementation on serum TG levels --- p.77
Chapter 3.1.2.3. --- Effect of mushroom supplementation on serum HDL levels --- p.79
Chapter 3.1.2.4 --- Discussion of serum lipid profiles of S.D. rats fed M.S. diets in mushroom screening experiments --- p.83
Chapter 3.1.3 --- Effect and discussion of mushroom supplementation on hepatic lipid profiles --- p.84
Chapter 3.1.4 --- Effect and discussion of mushroom supplementation on fecal neutral sterol excretion --- p.87
Chapter 3.1.5 --- Summary (mushroom screening experiments) --- p.90
Chapter 3.2 --- Hypolipidemic effect of Agrocybe aegerita (Brig.) Sing (AA) in a dose response study in hyperlipidemic S.D. rats --- p.91
Chapter 3.2.1 --- Nutritional composition of AA mushroom --- p.91
Chapter 3.2.2 --- Body weight and food intake --- p.91
Chapter 3.2.3 --- Effect of three different dosages of AA mushroom supplementation on blood lipid profiles of S.D. rats --- p.93
Chapter 3.2.3.1 --- Effect of different dosages of AA mushroom supplementation diets on serum TC level --- p.93
Chapter 3.2.3.2 --- Effect of different dosages of AA mushroom supplementation diets on serum TG level --- p.93
Chapter 3.2.3.3 --- Effect of different dosages of AA mushroom supplementation diets on serum HDL level --- p.95
Chapter 3.2.3.4 --- Discussion of different dosages of AA mushroom supplementation diets on serum lipid profiles --- p.97
Chapter 3.2.4 --- Effect and discussion of three different dosages of AA mushroom supplementation on hepatic lipid profiles --- p.98
Chapter 3.2.5 --- Effect and discussion of three different dosages of AA mushroom supplementation on fecal neutral & acidic sterol excretion --- p.101
Chapter 3.2.6 --- Summary (dose response study) --- p.105
Chapter 3.3 --- Hypolipidemic effect of ethanol extract (E.E.) & water extract (W.E.) from AA in hyperlipidemic S.D. rats --- p.106
Chapter 3.3.1 --- Extraction yield --- p.106
Chapter 3.3.2 --- Body weight & food intake --- p.106
Chapter 3.3.3 --- Effect of AA extract supplementation on serum lipid profiles --- p.107
Chapter 3.3.3.1 --- Effect of AA extract supplementation on serum TC level --- p.107
Chapter 3.3.3.2 --- Effect of AA extract supplementation on serum TG level --- p.108
Chapter 3.3.3.3 --- Effect of AA extract supplementation on serum HDL level --- p.109
Chapter 3.3.4 --- Effect of AA extract supplementation on hepatic lipid profiles --- p.111
Chapter 3.3.5 --- Effect of AA extract supplementation on fecal neutral & acidic sterols excretion --- p.111
Chapter 3.3.6 --- Discussion (active fraction extract study) --- p.113
Chapter 3.4 --- Long-term evaluation of the hypolipidemic effect of AA supplementation in normolipic S.D. rats --- p.116
Chapter 3.4.1 --- Body weight & food intake --- p.116
Chapter 3.4.2 --- Effect of long term AA supplementation on serum lipid profiles --- p.117
Chapter 3.4.2.1 --- Effect of long term AA supplementation on serum TC level --- p.117
Chapter 3.4.2.2 --- Effect of long term AA supplementation on serum TG level --- p.118
Chapter 3.4.2.3 --- Effect of long term AA supplementation on serum HDL level --- p.119
Chapter 3.4.3 --- Effect of long term AA supplementation on hepatic lipid profiles --- p.119
Chapter 3.4.4 --- Effect of long term AA supplementation on fecal neutral & acidic sterols excretion --- p.121
Chapter 3.4.5 --- Effect of long term AA supplementation on hepatic key enzymes of cholesterol metabolism ´ؤ HMG-CoA reductase and CYP7A --- p.123
Chapter 3.4.5.1 --- Quantitation of hepatic microsomal protein --- p.123
Chapter 3.4.5.2 --- Effect of long term AA supplementation on HMG-CoA reductase activity in S.D. rats --- p.124
Chapter 3.4.5.3 --- Effect of long term AA supplementation on CYP7A activity in S.D. rats --- p.124
Chapter 3.4.7 --- Discussion (long-term study) --- p.126
Chapter CHAPTER FOUR: --- CONCLUSION AND FUTURE PERSPECTIVES --- p.130
References --- p.136

Ng Yuk Fan.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2005.
Includes bibliographical references (leaves 145-162).
Abstracts in English and Chinese.
Thesis Committee: --- p.i
Acknowledgements --- p.ii
Abstract --- p.iii
摘要 --- p.v
Content --- p.vii
List of Tables --- p.xiii
List of Figures --- p.xvi
Abbreviations --- p.xviii
Chapter Chapter 1: --- Introduction --- p.1
Chapter 1.1 --- Antioxidants --- p.1
Chapter 1.1.1 --- Definition and mode of actions of antioxidants --- p.1
Chapter 1.1.2 --- Synthetic antioxidants --- p.2
Chapter 1.1.3 --- Natural antioxidants --- p.3
Chapter 1.2 --- Changes of antioxidant activity in food processing --- p.4
Chapter 1.2.1 --- Blanching --- p.4
Chapter 1.2.2 --- Drying --- p.5
Chapter 1.2.3 --- Microwave and Infrared energy --- p.7
Chapter 1.2.4 --- Freezing --- p.8
Chapter 1.3 --- Lipid oxidation and antioxidant --- p.8
Chapter 1.3.1 --- Free radicals --- p.8
Chapter 1.3.1.1 --- Superoxide --- p.10
Chapter 1.3.1.2 --- Hydrogen peroxide --- p.11
Chapter 1.3.1.3 --- Hydroxyl radical --- p.13
Chapter 1.3.2 --- Mechanism of lipid oxidation --- p.14
Chapter 1.3.3 --- Oxidation of low-density-liporoproteins (LDLs) and coronary heart disease --- p.15
Chapter 1.3.4 --- Role of antioxidants in inhibiting lipid oxidation --- p.16
Chapter 1.4 --- Hypocholesterolemic and antioxidant activity of phenolics --- p.19
Chapter 1.5 --- Medicinal properties of mushrooms --- p.21
Chapter 1.5.1 --- Background information of mushrooms --- p.21
Chapter 1.5.2 --- Phenolics in mushrooms --- p.22
Chapter 1.5.3 --- Hypocholesterolemic effect in mushroom --- p.23
Chapter 1.5.4 --- Previous studies in Agrocybe aegerita --- p.25
Chapter 1.6 --- Animal model for hypocholesteroliemic study --- p.27
Chapter 1.6.1 --- General requirements --- p.27
Chapter 1.6.2 --- Hamster model --- p.27
Chapter 1.7 --- Principles of assays that involved in antioxidant activity --- p.30
Chapter 1.7.1 --- ABTS + radical cation scavenging activity --- p.30
Chapter 1.7.2 --- Beta carotene bleaching method --- p.31
Chapter 1.7.3 --- Ferric reducing antioxidant power (FRAP) --- p.31
Chapter 1.7.4 --- Scavenging activity of hydroxyl radical --- p.32
Chapter 1.7.5 --- Inhibition of low-density lipoproteins (LDLs) oxidation --- p.33
Chapter 1.7.6 --- Total phenolic content determination --- p.33
Chapter 1.8 --- Principles of assays in hypocholesterolemic study --- p.34
Chapter 1.8.1 --- HDL-Cholesterol determination --- p.34
Chapter 1.8.2 --- Total cholesterol determination --- p.34
Chapter 1.8.3 --- Determination of plasma total triglyceride --- p.35
Chapter 1.9 --- Objectives --- p.36
Chapter Chapter 2: --- Materials and Methods --- p.37
Chapter 2.1 --- Sample preparation --- p.37
Chapter 2.2 --- Proximate Analysis of FAa and DAa --- p.38
Chapter 2.2.1 --- Determination of crude protein --- p.38
Chapter 2.2.2 --- Determination of ash --- p.39
Chapter 2.2.3 --- Total dietary fiber --- p.39
Chapter 2.2.4 --- Determination of fat --- p.41
Chapter 2.2.5 --- Moisture content --- p.42
Chapter 2.3 --- Sample extraction --- p.42
Chapter 2.3.1 --- Small-scale extraction --- p.42
Chapter 2.3.2 --- Large-scale extraction --- p.43
Chapter 2.4 --- Total phenolic content of DAa and FAa extract --- p.44
Chapter 2.5 --- Chemical assays for in vitro antioxidative properties determination --- p.45
Chapter 2.5.1 --- Hydroxyl free radical scavenging activity --- p.45
Chapter 2.5.2 --- Beta-carotene bleaching method --- p.46
Chapter 2.5.3 --- Inhibition of human low-density-lipoproteins (LDLs) oxidation --- p.47
Chapter 2.5.4 --- Scavenging activity of ABTS+radical cation --- p.50
Chapter 2.6 --- In vivo tests for antioxidative and hypocholesterolemic effect of DAa --- p.51
Chapter 2.6.1 --- Feeding experiments --- p.51
Chapter 2.6.2 --- Collection of plasma --- p.52
Chapter 2.6.3 --- Liver sample preparation --- p.52
Chapter 2.6.4 --- Determination of in vivo antioxidative effect --- p.54
Chapter 2.6.4.1 --- FRPA assay --- p.54
Chapter 2.6.4.2 --- ABTS + radical cation scavenging activity --- p.55
Chapter 2.6.5 --- Determination of plasma lipid profiles --- p.55
Chapter 2.6.5.1 --- Plasma total cholesterol (TC) --- p.55
Chapter 2.6.5.2 --- Plasma total triglyceride (TG) --- p.56
Chapter 2.6.5.3 --- Plasma high density lipoprotein cholesterol (HDL-C) determination --- p.57
Chapter 2.6.5.4 --- Hepatic cholesterol determination by gas chromatography analysis --- p.57
Chapter 2.7 --- Statistical analysis --- p.59
Chapter Chapter 3: --- Results and discussion --- p.61
Chapter 3.1 --- Proximate analysis --- p.61
Chapter 3.2 --- Small-scale extraction scheme --- p.63
Chapter 3.2.1 --- Extraction yield --- p.63
Chapter 3.2.2 --- Antioxidant assays --- p.65
Chapter 3.2.2.1 --- Hydroxyl free radical scavenging activity --- p.65
Chapter 3.2.2.2 --- Beta-carotene bleaching method --- p.68
Chapter 3.2.2.3 --- The formation of TBARS in human LDL oxidation --- p.75
Chapter 3.2.2.4 --- Total phenolic content (TPC) in DAa and FAa ethanolic and water extracts --- p.81
Chapter 3.2.2.5 --- Correlation between total phenolic content and antioxidant activity of mushroom extracts --- p.84
Chapter 3.2.2.6 --- Comparison of antioxidant activity and TPC in DAa and FAa ethanolic and water extracts in the small-scale extraction scheme --- p.88
Chapter 3.3 --- Large-scale extraction scheme --- p.91
Chapter 3.3.1 --- Extraction yield --- p.91
Chapter 3.3.2 --- Antioxidant assays --- p.91
Chapter 3.3.2.1 --- Hydroxyl free radical scavenging activity --- p.91
Chapter 3.3.2.2 --- Beta-carotene bleaching method --- p.94
Chapter 3.3.2.3 --- ABTS + radical cation scavenging activity --- p.96
Chapter 3.3.2.4 --- Formation of TBARS in human LDL oxidation in the DAa_E_l and Daa_W_1 --- p.97
Chapter 3.3.2.5 --- Total phenolic content (TPC) of DAa_E_l and DAa_W_l --- p.97
Chapter 3.3.2.6 --- Correlation between total phenolic content and antioxidant activity --- p.101
Chapter 3.3.2.7 --- Summary of large-scale extraction scheme --- p.103
Chapter 3.4 --- In vivo antioxidant activity and hypocholesterolemic effect of DAa studied by animal model --- p.104
Chapter 3.4.1 --- Effect of DAa´ؤE_1 and DAa_W_l on body weight and food intake --- p.105
Chapter 3.4.2 --- Effect of DAa一E´ؤ1 and DAa_W_l on plasma total cholesterol (TC) in hamsters --- p.108
Chapter 3.4.3 --- Effect of DAa´ؤE_1 and DAa W l on plasma total triglycerides (TG) in hamsters --- p.114
Chapter 3.4.4 --- Effect of DAa_E_l and DAa_W_l on plasma high-density-lipoprotein cholesterol (HDL-C) in hamsters --- p.119
Chapter 3.4.5 --- Effect of DAa_E_l and DAa一W_1 on hepatic cholesterol (HC) profile in hamsters --- p.124
Chapter 3.4.6 --- Effect of DAa_E_l and DAa W l on ferric reducing antioxidant power (FRAP) in hamsters (FRAP) --- p.128
Chapter 3.4.7 --- Effect of DAa_E_l and DAa_W_l on ABTS + cation radical scavenging activity --- p.131
Chapter 3.4.8 --- The antioxidant activity and hypocholesterolemic effect of DAa extracts --- p.134
Chapter 3.4.9 --- Summary of in vivo antioxidant activity and hypocholesterolemic effect of DAa studied by animal model --- p.140
Chapter Chapter 4: --- Conclusions --- p.142
References --- p.145

Chin, Chi Hou.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2010.
Includes bibliographical references (leaves [165]-178).
Abstracts in English and Chinese.
Abstract --- p.i
Abstract in Chinese (摘要） --- p.iv
Acknowledgements --- p.vi
Abbreviations --- p.vii
List of Figures and Tables --- p.xi
Publications --- p.xv
Chapter Chapter 1 --- General Introduction
Chapter 1.1. --- Hematopoiesis and Leukemia --- p.2
Chapter 1.1.1. --- Hematopoiesis --- p.2
Chapter 1.1.2. --- Leukemia --- p.8
Chapter 1.1.2.1. --- Overview of leukemia --- p.8
Chapter 1.1.2.2. --- Symptoms and diagnosis of leukemia --- p.9
Chapter 1.1.2.3. --- Classification of leukemia --- p.9
Chapter 1.1.2.4. --- Epidemiology of leukemia --- p.13
Chapter 1.1.2.5. --- Conventional treatments for leukemia --- p.15
Chapter 1.1.2.6. --- Novel approaches to leukemia treatment --- p.18
Chapter 1.2. --- Statins --- p.22
Chapter 1.2.1. --- Overview of statins --- p.22
Chapter 1.2.2. --- Chemical structures of statins --- p.24
Chapter 1.2.3. --- Pharmacokinetics of statins --- p.26
Chapter 1.2.4. --- Pleiotropic effects of statins --- p.29
Chapter 1.2.4.1. --- Anti-inflammatory and immunomodulatory effects of statins --- p.29
Chapter 1.2.4.2. --- Anti-angiogenic effects of statins --- p.30
Chapter 1.2.4.3. --- Anti-tumor effects of statins --- p.31
Chapter 1.3. --- Objectives and scope of the present study --- p.33
Chapter Chapter 2 --- Materials and Methods
Chapter 2.1. --- Materials --- p.36
Chapter 2.1.1. --- Animals --- p.36
Chapter 2.1.2. --- Cell lines --- p.36
Chapter 2.1.3. --- "Cell culture media, buffers and other reagents" --- p.37
Chapter 2.1.3.1. --- Cell culture media and reagents --- p.37
Chapter 2.1.3.2. --- Drugs and chemicals --- p.40
Chapter 2.1.3.3. --- Reagents and buffers for primary culture --- p.42
Chapter 2.1.3.4. --- Dye solutions --- p.43
Chapter 2.1.3.5. --- Reagents for cell proliferation assays --- p.44
Chapter 2.1.3.6. --- Reagents and buffers for flow cytometry --- p.44
Chapter 2.1.3.7. --- Reagents for Hoechst staining --- p.45
Chapter 2.1.3.8. --- Reagents and buffers for DNA isolation --- p.46
Chapter 2.1.3.9. --- Reagents and buffers for DNA agarose gel electrophoresis --- p.48
Chapter 2.1.3.10. --- Reagents and buffers for Cell Death ELISA --- p.50
Chapter 2.1.3.11. --- Reagents and buffers for measuring caspase activity --- p.51
Chapter 2.1.3.12. --- Reagents and buffers for Western blotting --- p.55
Chapter 2.1.3.13. --- Reagents for determining nitric oxide production --- p.63
Chapter 2.2. --- Methods --- p.64
Chapter 2.2.1. --- Culture of tumor cell lines --- p.64
Chapter 2.2.2. --- "Isolation, preparation and culture of murine peritoneal macrophages" --- p.64
Chapter 2.2.3. --- Cell proliferation and cytotoxicity studies --- p.66
Chapter 2.2.4. --- In vivo tumorigenicity study --- p.68
Chapter 2.2.5. --- Cell cycle profile and flow cytometric analysis --- p.69
Chapter 2.2.6. --- Hoechst staining --- p.69
Chapter 2.2.7. --- DNA fragmentation analysis --- p.70
Chapter 2.2.8. --- Cell Death ELISA --- p.71
Chapter 2.2.9. --- Mitochondrial membrane potential analysis --- p.73
Chapter 2.2.10. --- Measurement of caspase activity --- p.73
Chapter 2.2.11. --- Protein expression study --- p.75
Chapter 2.2.12. --- Cell morphological staining --- p.80
Chapter 2.2.13. --- Cell size and granularity analysis by flow cytometry --- p.81
Chapter 2.2.14. --- Determination of nitric oxide production by macrophages --- p.81
Chapter 2.2.15. --- Statistical analysis --- p.82
Chapter Chapter 3 --- Anti-Proliferative Effect of Statins on Myeloid Leukemia Cells
Chapter 3.1. --- Introduction --- p.84
Chapter 3.2. --- Results --- p.86
Chapter 3.2.1. --- Anti-proliferative effect of statins on various murine and human myeloid leukemia cells --- p.86
Chapter 3.2.2. --- Cytotoxicity of fluvastatin on murine myelomonocytic leukemia WEHI-3B JCS cells --- p.93
Chapter 3.2.3. --- Cytotoxicity of fluvastatin on primary murine myeloid cells --- p.96
Chapter 3.2.4. --- Kinetic and reversibility studies on the anti-proliferative effect of fluvastatin on WEHI-3B JCS cells --- p.98
Chapter 3.2.5. --- Relationship between the anti-proliferative effect of fluvastatin and the cholesterol biosynthesis pathway in WEHI-3B JCS cells --- p.102
Chapter 3.2.6. --- Effect of fluvastatin on the in vivo tumorigenicity of WEHI-3B JCS cells --- p.106
Chapter 3.2.7. --- Effect of fluvastatin on the cell cycle profile of WEHI-3B JCS cells --- p.108
Chapter 3.2.8. --- Effect of fluvastatin on the expression of cell cycle regulatory proteins inWEHI-3B JCS cells --- p.113
Chapter 3.3. --- Discussion --- p.116
Chapter Chapter 4 --- Apoptosis- and Differentiation-inducing Effects of Fluvastatin on Murine Myelomonocytic Leukemia WEHI-3B JCS Cells
Chapter 4.1. --- Introduction --- p.124
Chapter 4.2. --- Results --- p.128
Chapter 4.2.1. --- Induction of chromatin condensation in WEHI-3B JCS cells by fluvastatin --- p.128
Chapter 4.2.2. --- Induction of DNA fragmentation in WEHI-3B JCS cells by fluvastatin --- p.130
Chapter 4.2.3. --- Effect of fluvastatin on the mitochondrial membrane potential in WEHI-3B JCS cells --- p.134
Chapter 4.2.4. --- Effect of fluvastatin on the caspase activities in WEHI-3B JCS cells --- p.138
Chapter 4.2.5. --- Effect of fluvastatin on the expression of pro-apoptotic protein AIF in WEHI-3B JCS cells --- p.144
Chapter 4.2.6. --- Effect of fluvastatin on the morphology of WEHI-3B JCS cells --- p.147
Chapter 4.2.7. --- Effect of fluvastatin on the cell size and granularity of WEHI-3B JCS cells --- p.149
Chapter 4.2.8. --- Immunomodulation of murine peritoneal macrophages by fluvastatin --- p.151
Chapter 4.3. --- Discussion --- p.153
Chapter Chapter 5 --- Conclusions and Future Perspectives --- p.160
References --- p.165

Includes bibliographical references (21 leaves).
1 v. (various pagings) : ill. ; 30 cm.
Previous studies have found that green tea and its antitoxidant constituents, the catechins, are hypocholesterolaemic in both epidemiological and animal intervetion studies. The main objectives of the present study were to investigate the mechanism by which green tea and its most abundant catechin constituent epigallocatechin gallate increase the low-density lipoprotein (LDL) receptor of HepG2 cells. In addition, it was hoped to determine if a crude catechin extract from green tea could lower plasma cholesterol levels in the hypercholesterolaemic rabbit and ascertain if this effect was due to an increase in the LDL receptor. The study provides evidence that green tea and its catechins exhibit hypocholesterolaemic properties and may therefore provide protection against heart disease.
Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 2000

Lam Wai Yee.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2006.
Includes bibliographical references (leaves 124-148).
Abstracts in English and Chinese.
Chapter Chapter 1: --- Introduction --- p.1
Chapter 1.1 --- Lipoproteins --- p.1
Chapter 1.1.1 --- General structure --- p.1
Chapter 1.1.2 --- Chylomicrons --- p.2
Chapter 1.1.3 --- Very-low-density lipoprotein (VLDL) --- p.3
Chapter 1.1.4 --- Low-density lipoprotein (LDL) --- p.4
Chapter 1.1.5 --- High-density lipoprotein (HDL) --- p.4
Chapter 1.1.6 --- Lipoprotein metabolism --- p.5
Chapter 1.1.6.1 --- Exogenous pathway --- p.5
Chapter 1.1.6.2 --- LDL receptor pathway --- p.6
Chapter 1.1.6.3 --- Reverse cholesterol transport --- p.6
Chapter 1.2 --- Cholesterol homeostasis --- p.8
Chapter 1.2.1 --- Role of Acyl-CoA: Cholesterol Acyltransferase (ACAT) in intracellular cholesterol regulation --- p.8
Chapter 1.2.2 --- Cholesterol biosynthesis --- p.9
Chapter 1.2.3 --- Bile acid metabolism --- p.10
Chapter 1.3 --- Coronary heart disease (CHD) --- p.14
Chapter 1.3.1 --- Risk factors of CHD --- p.16
Chapter 1.3.2 --- Lipoprotein cholesterol and CHD --- p.18
Chapter 1.4 --- Animal models for hypercholesterolemic study --- p.20
Chapter 1.5 --- Physico-chemical properties of water-soluble dietary fiber (SDF) --- p.22
Chapter 1.5.1 --- Water-holding capacity --- p.23
Chapter 1.5.2 --- Viscosity --- p.24
Chapter 1.5.3 --- Adsorption or entrapment of organic molecules --- p.25
Chapter 1.5.4 --- Fermentability --- p.25
Chapter 1.6 --- Hypocholesterolemic effect of SDF and proposed mechanisms --- p.26
Chapter 1.7 --- Medicinal properties of edible mushrooms --- p.28
Chapter 1.7.1 --- Background information --- p.28
Chapter 1.7.2 --- Hypocholesterolemic effect of edible mushrooms --- p.29
Chapter 1.7.3 --- Previous studies on edible jelly mushrooms --- p.31
Chapter 1.8 --- Objectives
Chapter Chapter 2: --- Materials and Methods --- p.34
Chapter 2.1 --- Materials --- p.34
Chapter 2.1.1 --- Sample preparation --- p.34
Chapter 2.1.2 --- Animal model --- p.35
Chapter 2.2 --- Methods --- p.35
Chapter 2.2.1 --- Extraction scheme of mushroom water-soluble non-starch polysaccharides (SNSPs) --- p.35
Chapter 2.2.2 --- Proximate analyses of samples --- p.36
Chapter 2.2.2.1 --- Crude protein --- p.36
Chapter 2.2.2.2 --- Fat --- p.37
Chapter 2.2.2.3 --- Total dietary fiber --- p.38
Chapter 2.2.2.4 --- Soluble and insoluble dietary fiber --- p.39
Chapter 2.2.2.5 --- Ash --- p.40
Chapter 2.2.2.6 --- Moisture --- p.41
Chapter 2.2.3 --- Chemical characterization of mushroom SNSPs --- p.41
Chapter 2.2.3.1 --- Monosaccharide composition by gas chromatography --- p.41
Chapter 2.2.3.2 --- Total carbohydrate content --- p.44
Chapter 2.2.3.3 --- Uronic acid content --- p.44
Chapter 2.2.3.4 --- Soluble protein content --- p.45
Chapter 2.2.4 --- Rheological study of mushroom SNSPs --- p.46
Chapter 2.2.4.1 --- Determination of intrinsic viscosity [ η] of mushroom SNSPs --- p.46
Chapter 2.2.4.2 --- Determination of apparent viscosity [ηap] of mushroom SNSPs --- p.48
Chapter 2.2.5 --- In vivo study --- p.50
Chapter 2.2.5.1 --- Animal diets --- p.50
Chapter 2.2.5.1.1 --- Study for hypocholesterolemic potential of mushroom SNSPs --- p.50
Chapter 2.2.5.1.2 --- Study for dose-dependent effect on hypocholesteolemic potential of Auricularia polytricha (AP) SNSP --- p.50
Chapter 2.2.5.2 --- Feeding experiments --- p.51
Chapter 2.2.5.2.1 --- Screening for hypocholesterolemic potential of mushroom SNSPs --- p.51
Chapter 2.2.5.2.2 --- Dose-dependent effect on hypocholesterolemic potential of AP SNSP --- p.52
Chapter 2.2.5.3 --- Blood samples collection --- p.52
Chapter 2.2.5.4 --- Plasma preparation --- p.53
Chapter 2.2.5.5 --- Liver samples collection and preparation --- p.53
Chapter 2.2.5.6 --- Fecal samples collection and preparation --- p.53
Chapter 2.2.5.7 --- Determination of plasma lipid profiles --- p.54
Chapter 2.2.5.7.1 --- Plasma total cholesterol (TC) analysis --- p.54
Chapter 2.2.5.7.2 --- Plasma high-density lipoprotein cholesterol (HDL-C) analysis --- p.54
Chapter 2.2.5.7.3 --- Plasma triglycerides (TG) analysis --- p.55
Chapter 2.2.5.8 --- Determination of hepatic cholesterol profile by gas chromatography --- p.56
Chapter 2.2.5.9 --- Determination of hepatic enzymes activity --- p.58
Chapter 2.2.5.9.1 --- Preparation of hepatic microsomes --- p.58
Chapter 2.2.5.9.2 --- Determination of 3-hydroxy-3-methyl- glutaryl-Coenzyme A reductase (HMG-CoA reductase) activity --- p.58
Chapter 2.2.5.10 --- Determination of fecal lipid profiles by gas chromatography --- p.61
Chapter 2.2.5.10.1 --- Separation of fecal neutral and acidic sterols --- p.61
Chapter 2.2.5.10.2 --- Fecal neutral sterol analysis --- p.61
Chapter 2.2.5.10.3 --- Fecal acidic sterol analysis --- p.62
Chapter 2.2.6 --- Statistical analysis --- p.63
Chapter Chapter 3: --- Results and Discussion --- p.65
Chapter 3.1 --- Proximate analysis of edible jelly mushrooms --- p.65
Chapter 3.2 --- Yield of mushroom SNSP crude extracts --- p.67
Chapter 3.3 --- Chemical characterization of mushroom SNSPs --- p.68
Chapter 3.3.1 --- Total carbohydrate content --- p.68
Chapter 3.3.2 --- Uronic acid content --- p.68
Chapter 3.3.3 --- Soluble protein content --- p.68
Chapter 3.3.4 --- Monosaccharide composition --- p.69
Chapter 3.4 --- Rheological behavior of mushroom SNSPs --- p.71
Chapter 3.4.1 --- Intrinsic viscosity [η] --- p.71
Chapter 3.4.2 --- Apparent viscosity [ηap] --- p.75
Chapter 3.5 --- In vivo hypocholesterolemic potential of mushroom SNSPs --- p.78
Chapter 3.5.1 --- Effect on body weight and diet intake --- p.79
Chapter 3.5.2 --- Effect on plasma TC concentration --- p.81
Chapter 3.5.3 --- Effect on plasma HDL-C concentration --- p.84
Chapter 3.5.4 --- Effect on plasma TG concentration --- p.86
Chapter 3.5.5 --- Effect on hepatic cholesterol profile --- p.89
Chapter 3.5.6 --- Effect on HMG-CoA reductase activity by AA and AP SNSPs --- p.92
Chapter 3.5.7 --- Effect on neutral and acidic sterols excretion by AA and AP SNSPs --- p.93
Chapter 3.5.8 --- Correlation between hypocholesterolemic potential and viscosity of mushroom SNSPs --- p.97
Chapter 3.6 --- In vivo dose-dependent effect on hypocholesterolemic potential of AP SNSP --- p.99
Chapter 3.6.1 --- Effect on body weight and diet intake --- p.100
Chapter 3.6.2 --- Effect on plasma TC concentration --- p.102
Chapter 3.6.3 --- Effect on plasma HDL-C concentration --- p.105
Chapter 3.6.4 --- Effect on plasma TG concentration --- p.107
Chapter 3.6.5 --- Effect on hepatic cholesterol profile --- p.110
Chapter 3.6.6 --- Effect on HMG-CoA reductase activity --- p.113
Chapter 3.6.7 --- Effect on neutral and acidic sterols excretion --- p.114
Chapter 3.6.8 --- Correlation between dosage and hypocholesterolemic effect of AP SNSP --- p.119
Chapter Chapter 4: --- Conclusions and Future works --- p.121
List of References --- p.124
Related Publications --- p.149

A total of 146 Chinese patients with various degrees of hyperlipidaemia and high cardiovascular risk, suitable for treatment with rosuvastatin 10 mg daily and in whom it was possible to obtain baseline lipid profiles measured on no lipid lowering drug, were enrolled in to the study. The drug compliance was assessed by personal interview and 9 patients were excluded from the efficacy analysis because they stated their compliance was less than 80%. From the remaining 137 subjects, 62 had a clinical diagnosis of familial hypercholesterolaemia. Data for dietary intake were available in 121 of the 137 subjects. The average reduction in LDL-cholesterol in these subjects was 48.8 +/- 12.8% and as anticipated there was a wide range between individuals. The percentage reductions in LDL-cholesterol were significantly greater in the female than in the male subjects (-51.35 +/-10.89% vs. -46.38 +/-13.96%; p = 0.025), but this was no longer significant after adjustment for body weight. In patients with familial hypercholesterolaemia the absolute reductions in total cholesterol and LDL-cholesterol were significantly greater (p<0.001) than in those without familial hypercholesterolaemia, but the percentage reductions were not significantly different in the two groups. The increases in HDL-cholesterol and the decreases in triglycerides were significantly greater in the subjects with familial hypercholesterolaemia than in those without familial hypercholesterolaemia, both for the absolute changes and for the percentage changes. There were no significant effects on the percentage changes in lipids with rosuvastatin treatment due to age, measurements of body fatness, smoking or alcohol drinking status, or having hypertension or diabetes.
Polymorphisms in the CYP2D6 gene were analyzed and the subjects were divided into 4 groups as wild-type or extensive metabolisers, heterozygotes for CYP2D6*10 and wild-type, homozygotes for CYP2D6*10, and subjects with one allele for poor metaboliser status. The groups in this order would be expected to have decreasing activity of the CYP2D6 enzyme. There was a tendency for greater reduction in LDL-cholesterol in groups with lower CYP2D6 activity, most obvious in male subjects and this was significant in the patients with familial hypercholesterolaemia comparing the first 3 groups. The fourth group had a low number of subjects, which may have biased that result. In the subjects without familial hypercholesterolaemia, the % change in LDL-cholesterol was similar in all genotype groups, but the % reduction in triglycerides was numerically higher in the wild-type group than in groups with CYP2D6*10 alleles and the group with poor metaboliser status showed a lower % reduction. These differences were not significant and may be influenced by the baseline levels of triglycerides, which were not corrected for in this analysis.
The daily calorie intake and percentage of different macronutrient intake was obtained by using seven days food recall records. Dietary intake of most nutrients with higher in male than in female patients and was higher in the patients compared to gender-matched population data. Higher intake of most nutrients was associated with higher baseline triglyceride levels, but not LDL-cholesterol levels in all patients, and in lower HDL-cholesterol levels in the patients without familial hypercholesterolaemia. Higher intake of total calories was associated with less percentage reduction in LDL-cholesterol with rosuvastatin in the patients without familial hypercholesterolaemia and a similar non-significant tendency was seen with higher intake of total fat, saturated fat and cholesterol.
The study described in this thesis examined the role of the CYP2D6*10 polymorphism on the lipid response to rosuvastatin in addition to a number of phenotypic factors such as diet, gender, measures of obesity and other medical conditions.
These findings suggest that the CYP2D6 genotype may have some influence on the lipid response to rosuvastatin, but it appears to interact with other factors including, gender, diet and the presence of familial hypercholesterolaemia. (Abstract shortened by UMI.)
Lui, Siu Hung.
"February 2007."
Adviser: Brian Tomlinson.
Source: Dissertation Abstracts International, Volume: 69-01, Section: B, page: 0248.
Thesis (Ph.D.)--Chinese University of Hong Kong, 2007.
Includes bibliographical references (p. 165-190).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstracts in English and Chinese.
School code: 1307.

Indiana University-Purdue University Indianapolis (IUPUI)
Drug-drug interactions (DDIs) refer to situations where one drug affects the pharmacokinetics or pharmacodynamics of another. DDIs represent a major cause of morbidity and mortality. A common adverse drug reaction (ADR) that can result from, or be exacerbated by DDIs is drug-induced myopathy. Identifying DDIs and understanding their underlying mechanisms is key to the prevention of undesirable effects of DDIs and to efforts to optimize therapeutic outcomes. This dissertation is dedicated to identification of clinically important myopathic DDIs and to elucidation of their underlying mechanisms. Using data mined from the published cytochrome P450 (CYP) drug interaction literature, 13,197 drug pairs were predicted to potentially interact by pairing a substrate and an inhibitor of a major CYP isoform in humans. Prescribing data for these drug pairs and their associations with myopathy were then examined in a large electronic medical record database. The analyses identified fifteen drug pairs as DDIs significantly associated with an increased risk of myopathy. These significant myopathic DDIs involved clinically important drugs including alprazolam, chloroquine, duloxetine, hydroxychloroquine, loratadine, omeprazole, promethazine, quetiapine, risperidone, ropinirole, trazodone and simvastatin. Data from in vitro experiments indicated that the interaction between quetiapine and chloroquine (risk ratio, RR, 2.17, p-value 5.29E-05) may result from the inhibitory effects of quetiapine on chloroquine metabolism by cytochrome P450s (CYPs). The in vitro data also suggested that the interaction between simvastatin and loratadine (RR 1.6, p-value 4.75E-07) may result from synergistic toxicity of simvastatin and desloratadine, the major metabolite of loratadine, to muscle cells, and from the inhibitory effect of simvastatin acid, the active metabolite of simvastatin, on the hepatic uptake of desloratadine via OATP1B1/1B3. Our data not only identified unknown myopathic DDIs of clinical consequence, but also shed light on their underlying pharmacokinetic and pharmacodynamic mechanisms. More importantly, our approach exemplified a new strategy for identification and investigation of DDIs, one that combined literature mining using bioinformatic algorithms, ADR detection using a pharmacoepidemiologic design, and mechanistic studies employing in vitro experimental models.

This thesis presents studies of health trajectories using administrative data. In the first study, we propose a new method for clustering of Medicare Benefit Schedule (MBS) claim trajectories. In the second study, we examine the extent to which the adult Australian population on lipid-lowering medications receives the level of High-Density Lipoprotein-Cholesterol (HDL-C) testing recommended by national guidelines. Finally, we study mental health services and medications usage in the MBS and Pharmaceutical Benefit Scheme (PBS) administrative data for the purpose of finding groups of patients with similar utilisation patterns. For these studies, we analyse records from seven years (2008-2014) of the 10% publicly available sample of de-identified, individual level, linked MBS and PBS administrative data. In the first study, we apply a Hierarchical Deep Belief Networks (HDBN) to cluster individuals’ health trajectories in four types of services: general practitioner attendances, specialist attendances, pathology tests, and diagnostic imaging. In the second study, the PBS data is used to identify individuals on stable lipid-lowering medications. The MBS data is used to estimate the annual frequency of HDL-C testing. We develop a methodology to address the issue of “episode coning” in the MBS data, which causes an undercounting of pathology tests. We use a published figure on the proportion of unreported HDL-C tests to correct for the undercounting and estimate the probability that an HDL-C test is performed. The rate of HDL-C testing is then compared to national guidelines that people at high-risk for cardiovascular disease undergo annual testing, to determine appropriateness. For mental health study, we create individual level utilisation patterns describing the sequence of mental health services and medications, extracted from the MBS and PBS data, respectively. We propose an Extended Inter-Spike Interval (EISI) metric to estimate the pairwise distances between the individuals’ utilisation patterns. Then, we develop a split-and-merge Partitioning Around Medoids (PAM) algorithm to cluster the study population and discover “interesting” utilisation patterns. In order to better understand the extent to which particular personal characteristics impact an individual utilisation pattern, we perform descriptive and multivariate analyses with gender, age, state of residence, and concessional status as covariates. For the health trajectories clustering study, we applied the proposed HDBN algorithm to cluster one million health trajectories of the New South Wales patients with the age of 45-55 years extracted from the MBS data and detected 31 clusters. For the HDL-C testing study, we estimated that approximately 50% of the population on stable lipid-lowering medications did not receive any HDL-C test in each year. We also found that approximately 19% of the same population received two or more HDL-C tests a year. These levels of underutilisation and overutilisation have been changing at an average rate of 2% and -4% a year, respectively, since 2009. The yearly expenditure associated with test overutilisation was approximately A$4.3M during the study period, while the cost averted because of test underutilisation was approximately A$11.3M a year. For the mental health study, after having excluded obvious and common utilisation patterns, we find that mental health patients can be grouped into 10 clusters with distinct and interpretable utilisation patterns. We find that patients differ in the composition of mental health services and medications and the length of use of those services. The largest cluster (27.1% of the study population) is composed of individuals who only visit general practitioners and take psycholeptics medications for a short period of time. The smallest cluster (4.4% of the study population) contains individuals that have occasional visits with general practitioners, and regularly utilise both psycholeptics and psychoanaleptics medications over long periods of time.