No description available.

No description available.

<p>During oncogenesis, cancer cells go through metabolic reprogramming to maintain their high growth rates and adapt to changes in the microenvironment and the lack of essential nutrients. Several types of cancer are dependent on de novo fatty acid synthesis to sustain their growth rates by providing precursors to construct membranes and produce vital signaling lipids. Fatty acid synthase (FASN) catalyze the terminal step of de novo fatty acid synthesis and it is highly expressed in many types of cancers where it’s up-regulation is correlated with cancer aggressiveness and low therapeutic outcome. Many FASN inhibitors were developed and showed potent anticancer activity however, only one inhibitor advanced to early stage clinical trials with some dose limiting toxicities. Using a modified fluorescence-linked enzyme chemoproteomic strategy (FLECS) screen, we identified HS-106, a thiophenopyrimiden FASN inhibitor that has anti-neoplastic activity against breast cancer in vitro and in vivo. HS-106 was able to inhibit both; purified human FASN activity and cellular fatty acid synthesis activity as evaluated by radioactive tracers incorporation into lipids experiments. In proliferation and apoptosis assays, HS-106 was able to block proliferation and induce apoptosis in several breast cancer cell lines. Several rescue experiment and global lipidome analysis were performed to probe the mechanism by which HS-106 induces apoptosis. HS-106 was found to induce several changes in lipids metabolism: (i) inhibit fatty acids synthesis. (ii) Inhibit fatty acids oxidation as indicated by the ability of inhibiting Malonyl CoA accumulation to block HS-106 induced apoptosis and the increase in the abundance of ceramides. (iii) Increase fatty acids uptake and neutral lipids formation as confirmed 14C Palmitate uptake assay and neutral lipids staining. (iv)Inhibit the formation of phospholipids by inhibiting de novo fatty acid synthesis and diverting exogenous fatty acids to neutral lipids. All of these events would lead to disruption in membranes structure and function. HS-106 was also tested in Lapatinib resistant cell lines and it was able to induce apoptosis and synergizes Lapatinib activity in these cell lines. This may be due the disruption of lipid rafts based on the observation that HS-106 reduces the expression of both HER2 and HER3. HS-106 was found to be well tolerated and bioavailable in mice with high elimination rate. HS-106 efficacy was tested in MMTV neu mouse model. Although did not significantly reduced tumor size (alone), HS-106 was able to double the median survival of the mice and showed potent antitumor activity when combined with Carboplatin. Similar results were obtained when same combinations and dosing schedule was used in C3Tag mouse model except for the inability of HS-106 affect mice survival.</p><p>From the above, HS-106 represent a novel FASN inhibitor that has anticancer activity both in vivo and in vitro. Being a chemically tractable molecule, the synthetic route to HS-106 is readily adaptable for the preparation of analogs that are similar in structure, suggesting that, the pharmacological properties of HS-106 can be improved.</p> / Dissertation

Understanding the movement and feeding habits of marine animals is crucial when managing their populations. The molecular, and stable carbon isotope composition of fatty acids from an organism provides time-integrated information on its dietary intake. Hence, when spatial differences in the quality of seston exist it should be able to trace these differences up into higher trophic level organisms. The presented study evaluates the applicability of 13C/12C ratios of individual fatty acids, as natural tags and dietary markers in marine pelagic organisms. In addition, the use of 13C/12C ratios of bulk sample, as well as fatty acid composition data in examining the movement, and diet of animals are further explored. Samples of particulate organic matter, zooplankton, larval fish and juvenile salmon collected during three cruises off the west coast of Vancouver Island were analyzed. The fatty acid composition, stable carbon isotope ratio of either bulk sample, or individual fatty acids could typically distinguish samples collected in continental shelf waters from off-shelf samples. The differences in fatty acid composition between the adjoining food webs seem to be mainly caused by the different contribution of diatom-derived material to the base of the food web. The higher 13C/12C ratios found in the diatom-richer seston in shelf waters were not simply caused by the higher contribution of diatoms. Instead, stable carbon isotope data on individual fatty acids indicate that growth conditions favouring diatom growth caused 13C-enrichment in algae other than diatoms as well. The relative abundance of polyunsaturated fatty acids, such as docosahexaenoic acid (22:6n-3), were found to increase with trophic level. Whereas the abundance of saturated, and monounsaturated fatty acids was higher in organisms from lower trophic levels. This suggests that the fatty acid composition may be a useful trophic level indicator. However, literature data indicate that these trends observed in seston. zooplankton, larval fish and juvenile salmon, do not hold for larger organisms and adult life stages. / Graduate

No description available.

Basic and clinical research documents the benefits of dietary milled flaxseed (MFX), a rich source of alpha-linolenic acid (ALA) and lignans, in the attenuation of risk factors key to regulating cardiovascular disease (CVD) progression. ALA has antihypertensive properties and the lignan metabolites, enterodiol (END) and enterolactone (ENL), have antioxidative potential. The effectiveness of these bioactives to reduce risk factors of CVD may be dependent upon their plasma concentrations. To study this, we first designed and validated a method using supported liquid extraction and gas chromatography/mass spectrometry to isolate and quantify enterolignans in plasma. Applying this technique, we examined MFX doses of 10-40 g/d administered to healthy, younger adults (18-49 years of age) for 4 weeks. Ten g/d was sufficient to significantly increase circulating ALA (1.5 fold) and enterolignans (5-31 fold). There was no significant dose-dependent response. In another investigation, younger (18-29 years of age) and older (45-69 years of age) healthy adults were studied to determine if age influenced enterolignan metabolism. CVD is associated with advanced age but older people may not be able to obtain lignan metabolites from dietary MFX. Following 4 weeks of MFX consumption, both age groups increased plasma total enterolignans (END + ENL) with no between-group differences. This suggested that older and younger adults metabolize MFX lignans equally. A final study assessed MFX bioactives in plasma of peripheral artery disease patients >40 years of age. Plasma enterolignans increased 10-50 fold and ALA 1-2 fold after only one month of MFX ingestion. Dietary MFX also attenuated total (11%) and LDL (15%) cholesterol in these patients after 1-6 months of administered MFX compared to placebo. The attenuation in cholesterol was due to the high fiber content of flaxseed, and not to ALA and enterolignans, despite their marked increase in circulation. MFX did not interfere with cholesterol-lowering medications but instead decreased cholesterol levels beyond the effects of medications alone. To conclude, dietary supplementation with MFX resulted in an increase in plasma enterolignan and ALA concentrations in healthy younger and older adults and in patients with pre-existing CVD. The cholesterol-lowering benefits of MFX were additional to cholesterol-lowering drugs and likely attributed to MFX fiber. / May 2016

A thesis submitted to the Faculty of Medicine, University o-f the Witwatersrand, Johannesburg, ■for the degree o-f Master o-f Science. Johannesburg, 1990. / In this thesis the role of essential fatty acids (EFAs) in thermoregulation and the polyunsaturates (PUFA) in the genesis of fever is investigated. Although recognised, that metabolites of arachidonic acid are involved in the biochemical sequences leading to fever, it is also acknowledged that fever response depends on lipid mobilisation. However, the exact biochemical mechanisms involved in this event remain unknown to date. In order to investigate a relation between serum lipids and fever, rabbits were subjected to dietary manipulation (deficient, or excessive EFA diet) and their hyperthermic responses to intravenous injections of (a) human leucocyte pyrogen (HLP); (b) endotoxin (Salmonella Thyphosa); and (c) cerebroventricular injections of prostaglandin E2» were compared with rabbits fed on a normal diet / IT2018

IT2018

David Chi-cheong Wan. / Bibliography: leaves 75-85 / Thesis (M.Ph.)--Chinese University of Hong Kong, 1984

by Sea Man Mei, Mandy. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 203-214). / Abstract also in Chinese. / ACKNOWLEDGMENTS --- p.i / ABSTRACT --- p.ii / LIST OF ABBREVAIATIONS --- p.vi / TABLE OF CONTENTS --- p.vii / Chapter Chapter1 --- General Introduction / Chapter 1.1 --- DEFINITION --- p.2 / Chapter 1.2 --- MOTIVATION OF THE ONSET OF WEIGHT CYCLING --- p.3 / Chapter 1.3 --- PHYSIOLOGICAL EFFECTS OF WEIGHT CYCLING --- p.6 / Chapter 1.3.1 --- """Dieting-Induced Obesity"" Hypothesis" --- p.6 / Chapter 1.3.1.1 --- Food Efficiency --- p.6 / Chapter 1.3.1.2 --- Proposed Mechanisms for the Increase of Food Efficiency --- p.10 / Chapter 1.3.1.3 --- Change in Body Fat --- p.14 / Chapter 1.3.2 --- Association with Increased Mortality and Coronary Heart Disease (CHD) --- p.15 / Chapter Chapter2 --- Depletion of Linoleic Acid and α-Linolenic Acid Caused by Weight Cycling is Independent of the Extent of Calorie-Restriction / Chapter 2.1 --- INTRODUCTION --- p.18 / Chapter 2.1.1 --- Nomenclature of Fatty Acids --- p.18 / Chapter 2.1.2 --- Metabolism and Physiological Roles of LA and α-LnA --- p.19 / Chapter 2.1.2.1 --- "LA, α-LnA and their Derivatives as Structural Components" --- p.21 / Chapter 2.1.2.2 --- Production of Eicosanoids from LA and α-LnA --- p.22 / Chapter 2.1.2.3 --- Other Physiological Roles --- p.23 / Chapter 2.1.3 --- Dietary LA and α-LnA Relative to CHD --- p.24 / Chapter 2.1.3.1 --- Dietary LA and CHD --- p.24 / Chapter 2.1.3.2 --- Dietary α-LnA and CHD --- p.26 / Chapter 2.1.4 --- WC-Induced Alteration in the Composition of Tissue Lipids --- p.27 / Chapter 2.2 --- OBJECTIVE OF THE PRESENT STUDY --- p.29 / Chapter 2.3 --- MATERIALS AND METHODS --- p.30 / Chapter 2.3.1 --- Animals and Diets --- p.30 / Chapter 2.3.2 --- Lipid Analysis --- p.32 / Chapter 2.3.3 --- Triacylglycerol Species Analysis --- p.34 / Chapter 2.3.4 --- Other Assays --- p.35 / Chapter 2.3.5 --- Statistics --- p.35 / Chapter 2.4 --- RESULTS --- p.36 / Chapter 2.4.1 --- Food Intake --- p.36 / Chapter 2.4.2 --- Change of Body weight --- p.38 / Chapter 2.4.3 --- Weight of Liver and Adipose Tissues --- p.40 / Chapter 2.4.4 --- Serum Cholesterol and Triglycerides --- p.41 / Chapter 2.4.5 --- Carcass Total Fatty Acids --- p.42 / Chapter 2.4.6 --- Adipose Tissue Fatty Acids --- p.44 / Chapter 2.4.7 --- Liver Fatty Acids --- p.47 / Chapter 2.5 --- DISSCUSION --- p.50 / Chapter Chapter3 --- Influence of Dietary Fat Level on Fatty Acid Composition and Adiposity in Weight-Cycled Rats / Chapter 3.1 --- INTRODUCTION --- p.56 / Chapter 3.1.1 --- Fat Preference and Intake in Humans --- p.56 / Chapter 3.1.2 --- Alteration of Lipid Metabolism Induced by Dietary Fat --- p.58 / Chapter 3.1.3 --- Interaction Between Weight Cycling and Fat Intake --- p.60 / Chapter 3.2 --- OBJECTIVE OF THE PRESENT STUDY --- p.62 / Chapter 3.3 --- MATERIALS AND METHODS --- p.63 / Chapter 3.3.1 --- Animals and Diets --- p.63 / Chapter 3.3.2 --- Analysis of Adipocytes --- p.66 / Chapter 3.3.3 --- Fatty Acid Analysis --- p.67 / Chapter 3.3.4 --- "Determination of Serum Cholesterol, Triglycerides and Glucose" --- p.68 / Chapter 3.3.5 --- Statistics --- p.68 / Chapter 3.4 --- RESULTS --- p.69 / Chapter 3.4.1 --- Body Weight --- p.69 / Chapter 3.4.2 --- Food Intake and Food Efficiency --- p.71 / Chapter 3.4.3 --- Weight of Liver --- p.74 / Chapter 3.4.4 --- Weight of Adipose Tissue --- p.74 / Chapter 3.4.5 --- Number and Size of Adipocytes --- p.81 / Chapter 3.4.6 --- "Serum Triglycerides, Cholesterol and Glucose" --- p.85 / Chapter 3.4.7 --- Fatty Acid Composition --- p.92 / Chapter 3.5 --- DISCUSSION --- p.145 / Chapter 3.5.1 --- Weight Cycling-Induced Obesity Only with a High-Fat Diet --- p.145 / Chapter 3.5.1.2 --- Effect of Weight Cycling on the Size of Adipocytes --- p.147 / Chapter 3.5.1.3 --- Food Efficiency during Weight Cycling --- p.148 / Chapter 3.5.2 --- Weight-Cycling Induced Specific Alteration of Fatty Acid Metabolism --- p.149 / Chapter Chapter4 --- Weight Cycling Altered the Activities of Lipoprotein Lipase and Lipogenic Enzymes in Rats / Chapter 4.1 --- INTRODUCTION --- p.152 / Chapter 4.1.1 --- Fatty Acid Metabolism --- p.152 / Chapter 4.1.1.1 --- Fatty Acid Synthesis --- p.152 / Chapter 4.1.1.2 --- Fatty Acid Storage --- p.155 / Chapter 4.1.1.3 --- Fatty Acid Oxidation --- p.156 / Chapter 4.1.2 --- Hormonal Control of Fatty Acid Metabolism During Fasting and Refeeding --- p.158 / Chapter 4.1.2.1 --- Fatty Acid Metabolism During Fasting --- p.158 / Chapter 4.1.2.2 --- Fatty Acid Metabolism During Fed-State --- p.160 / Chapter 4.2 --- OBJECTIVE OF THE PRESENT STUDY --- p.161 / Chapter 4.3 --- MATERIALS AND METHODS --- p.162 / Chapter 4.3.1 --- Samples --- p.162 / Chapter 4.3.2 --- Enzymatic Analysis --- p.162 / Chapter 4.3.2.1 --- Lipoprotein Lipase (LPL; EC 3.1.1.34) --- p.162 / Chapter 4.3.2.2 --- Fatty Acid Synthase (FAS; EC 2.3.1.85) --- p.165 / Chapter 4.3.2.3 --- Malic Enzyme (ME; EC 1.1.1.40) --- p.166 / Chapter 4.3.2.4 --- Pyruvate Kinase (PK; EC 2.7.1.40) --- p.166 / Chapter 4.3.2.5 --- Acetyl-CoA Carboxylase (ACC; EC 6.4.1.2) --- p.167 / Chapter 4.3.2.6 --- "Phosphoenolpyruvate Carboxykinase (PEPCK, EC 4.1.1.32)" --- p.168 / Chapter 4.3.2.7 --- Determination of Protein Content --- p.169 / Chapter 4.3.3 --- Determination of Serum Insulin and Serum Glucagon --- p.169 / Chapter 4.3.4 --- Statistics --- p.169 / Chapter 4.4 --- RESULTS --- p.170 / Chapter 4.4.1 --- Enzymatic Analysis --- p.170 / Chapter 4.4.1.1 --- Lipoprotein Lipase --- p.170 / Chapter 4.4.1.2 --- Fatty Acid Synthase --- p.175 / Chapter 4.4.1.3 --- Malic Enzyme --- p.182 / Chapter 4.4.1.4 --- Pyruvate Kinase --- p.182 / Chapter 4.4.1.5 --- Acetyl-CoA Carboxylase --- p.187 / Chapter 4.4.1.6 --- Phosphoenolpyruvate Carboxykinase --- p.187 / Chapter 4.4.2 --- Level of Serum Insulin and Glucagon --- p.192 / Chapter 4.5 --- DISCUSSION --- p.196 / Chapter 4.5.1 --- Effect of Weight Cycling on Activity of Lipoprotein Lipase and Lipogenic Enzymes Activity --- p.196 / Chapter 4.5.2 --- The Overshoot of Enzymatic Activities in Relation to Tissue Fatty Acid Composition --- p.198 / Chapter 4.5.3 --- No Elevation of Plasma Insulin in Weight Cycled Rats --- p.199 / Chapter Chapter5 --- Conclusion --- p.200 / References --- p.203