The squalestatins are a new family of natural products which display potent cholesterol lowering effects. Common to all these natural products is the highly oxidised bicyclic core and the aim of this project was to achieve a concise synthetic route to this core unit. Initial studies were carried out using 2-benzyloxycyclohexanone as a model template. Following conversion to the 2-oxa-3-oxo-spiro<4.5>decan-6-one via addition of the dianion of 3-(para- tolylsulphonyl)propionic acid, coupling of a C(2) fragment was explored. Addition of carboethoxymethylenetriphenylphosphorane, followed by oxidation to the diol and protection as the acetonide led to the formation of 4- Ethoxycarbonyl-(2,2-dimethyl-5"-oxodispiro[perhydro[l,3]dioxolane-4,r- cyclohexane-2',2"-(5"-H-furan)]-5-yl. The alternative order of addition of the C(4) and C(2) units has also been undertaken. Manipulation of the ester group to a silyl ether afforded a less reactive functionality and C(4) was manipulated to allow for the coupling of the next fragment to form the spiro lactone. The addition of the dianion of 3-(parc-tolylsulphonyl)propionic acid to4-((^t)butyldimethylsilyloxymethyl)-2,2-dimethyl-l,3-dioxa-spiro<4.5>decan-6-one failed and another route to the spiro lactone was explored. Formation of 4 - ((^t)butyldimethy Isilyloxymethy l)-2,2-dimethyl-1,3,7-trioxa- dispiro<4.0.4.4>tetradecan-8-one (I) was achieved by allylation at C(4) followed by hydroboration of the double bond and subsequent oxidation. The C(l) side chain could be added to the spiro lactone using allyl magnesium bromide without compromising the other functionality present. Acid treatment of 4-((^t)butyldimethylsilyloxymethyl)-8-methoxy-2,2-dimethyl-8- propyl-l,3,7-trioxa-dispiro<4.0.4.4>tetradecane (II) promoted deprotection of the acetonide followed by concomitant cyclisation to the desired 6-hydroxy-9-propyl- 8,12-dioxatricyclo<7.2.1,0>dodec-7-yl-l-methanol (III). This showed the viability of the retrosynthetic analysis as a route to core analogues of the squalestatins. Studies to the fully substituted core were commenced using cis-cyclohexadiene diol. The diol was protected as its p-anisaldehyde acetal before the formation of the Diels Alder adduct (IV) using 4-phenyl-l,3,5-triazolinone. However a lack of time prevented its manipulation to the a-alkoxy ketone species through Lewis Acid mediated cleavage of the acetal. In a second retrosynthetic plan 2-benzyloxycyclohexanone was coupled with methyl tetronate prepared following the procedure of Pelter. Preliminary studies towards the addition of the C(l) side chain have been undertaken and initial results seem promising

No description available.

Migraine is associated with a number of cardiometabolic risk factors including abnormalities in lipid metabolism. However, little is known about these associations among pregnant migraineurs. We conducted the present study to evaluate the extent to which altered lipid profiles are associated with history of migraine among pregnant women.

Thesis (Ph.D.)--Boston University. The following pages are missing: 110, 136-137, 145, and 157. / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Some aspects of sterol and steroid biosynthesis were investigated to gain an insight into the control and regulatory mechanisms. In some of the initial experiments, LH was found to increase the incorporation of acetate-1-14C into DPS and cholesterol, suggesting that one of the sites of action of LH is before the formation of cholesterol. [TRUNCATED] / 2031-01-01

by Wai-kee Cheung. / Bibliography: leaves 307-332 / Thesis (M.Ph.)--Chinese University of Hong Kong, 1984

by Ying-tat Mak. / Thesis (M.Phil.)--Chinese University of Hong Kong. / Bibliography: leaves 59-62.

Our laboratory has recently reported that lecithin:cholesterol acyltransferase (LCAT) deficient mice are hypersensitive to insulin and resistant to diet-induced obesity, particularly in the LDL receptor (LDLR) knockout background. These phenotypes are linked to hepatic endoplasmic reticulum (ER) stress, which we showed is elevated basally and highly inducible in LDLR deficient mice. While in LCAT/LDLR deficient mice, ER stress is normalized basally and its diet-induction is attenuated. Mechanistically, we show here that excess free cholesterol (FC), in part from the bile, accumulates in the ER membrane of LDLR deficient mice. In contrast, LCAT/LDLR deficient mice have reduced levels of ER membrane FC and are resistant to cholesterol diet-induced elevations, in part from increased INSIG-1 expression and cholesterol esterification by ACAT2. Our analysis has led to the first report of cholesterol-induced hepatic ER stress in vivo and the identification of ER FC levels as a critical indicator of ER stress susceptibility.

The objective was to assess the effect of a high-monounsaturated fat (MUFA) dietary portfolio of cholesterol-lowering foods on oxidative stress and cardiovascular risk. Twenty-four hyperlipidemic subjects followed a very low-saturated-fat therapeutic control diet for 4 weeks after which they were randomized to receive the dietary portfolio, consisting of soy protein (20g/1000kcal), viscous fibre (10.3g/1000kcal), plant sterols (2-3g) and almonds (21.5g/1000kcal), in combination with high- or low-MUFA (25.9% and 12.9% MUFA, respectively) for the next 4 weeks, where MUFA replaced 13.0% of dietary carbohydrate. On high-MUFA, there were significantly greater increases in HDL-C and apoA1 and significantly greater reductions in total:high-density lipoprotein cholesterol (total:HDL-C) ratio and high-sensitivity C-reactive protein (hs-CRP) compared to the low-MUFA dietary portfolio. In all diets there were significant increases in protein thiols and reductions in conjugated dienes and thiobarbituric acid reactive substances (TBARS) measured in the LDL-fraction, however no difference between the high- and low-MUFA diets.

In vivo research following ingesting of commercially available Lactobacillus tablets, which contain about 2X10⁶ cfu/tablet of Lactobacillus acidophilus and Lactobacillus bulgaricus cells in a dose of four tablets daily, showed serum lipoprotein concentrations did not change significantly. In order to increase the number of viable Lactobacillus bacteria after challenging in low pH solution (gastric fluid), enteric coating polymer was applied over dried calcium alginate beads containing Lactobacillus. Survival of Lactobacillus bacteria was generally higher from freeze dried calcium alginate beads compared to vacuum dried products. However, after pretreatment with simulated gastric fluid (pH = 1.5) for 2 hours, only the coated products from vacuum drying showed promising results. Lactobacillus bacteria were fully protected against gastric pH after formulating the bacteria inside mini-tablets which were coated with Eudragit L30D, an enteric coating polymer. Alginic acids are naturally occurring substances found only in the brown seaweeds. Alginic acid salts formed with most di-, and polyvalent metals are insoluble in water. The most common application of alginate precipitation in drug product formulation is based on insolubilization of alginate by addition of calcium salt. By altering the composition of calcium alginate, drug loading, enteric coating thickness, and sustained release coating thickness, the lag time for drug dissolution can be controlled. This formulation research provides oral dosage form design for targeted delivery of drug to any desired site in the gastrointestinal tract. Examples of site specific targeted delivery are given for Lactobacillus bacteria, ibuprofen, sulfasalazine, and 5-aminosalicylic acid. / Graduation date: 1991

Thesis (Ph. D.)--University of Queensland, 2001. / Includes bibliographical references.