Dihydromyricetin (DHM), also ampelopsin, is a flavonoid compound which exhibits a broad spectrum of positive effects on the human body. Herbal extracts containing this compound have been widely used in traditional Chinese medicine mainly for their hepatoprotective properties. DHM also helps with alcohol intoxication and reduces the signs of hangover or abstinence. Given the fact that the mechanism of DHM effects on the ethanol metabolism has not been clarified yet, the effect of dihydromyricetin on the expression and activity of alcohol dehydrogenase (ADH), one of the most important enzymes involved in ethanol metabolism, was therefore studied in this thesis. The cultivation conditions of primary hepatocytes which were isolated from unpretreated and ethanol-pretreated rats and subsequently exposed to EtOH and DHM were optimized. While determining the degree of cell damage caused by EtOH in the presence of DHM, no significant trend in the protective effect of DHM was found. On the other hand, the protective effect of ethanol in hepatocytes cultivated in EtOH and DHM was detected by technique of ELISA (the determination of alanine transaminase). The Western blot technique followed by immunodetection did not detect the induction of ADH expression in hepatocytes. Furthemore, the modulation effect of...

The primary aim of this project was to synthesize new heterocyclic dimers of isoflavones and flavones, and investigate various methodologies for their synthesis. The secondary aim of the project was to synthesize some flavonoid natural products. Dimeric systems were synthesized using various methodologies including acid catalyzed arylation of isoflavanols and flavanols, acid catalyzed dimerization of flavenes, oxidative dimerization, Sonogashira coupling, Ullmann coupling and Suzuki-Miyaura coupling reactions. The acid catalyzed arylation of isoflavanols was found to proceed in a very stereoselective fashion to give trans-4-arylisoflavans in good yield in a single step. However, related flavanols under similar conditions gave mixtures of cis and trans isomers of 4-arylflavans. Interestingly, it was found that appropriately substituted flavenes, upon treatment with acid undergo stereoselective rearrangement and dimerization to give benzopyranobenzopyrans in high yields. A rationale for the rearrangement is proposed and this dimerization was used for the stereoselective synthesis of the natural product dependensin. As part of the project, some polycyclic natural products such as octandrenolone, flemiculosin, 3-deoxy-MS-II and laxichalcone were also synthesized. Oxidative dimerization of activated isoflavones was found to be very regioselective, and novel isoflavone dimeric systems were synthesized. Related flavones however, failed to undergo dimerization under similar conditions. A probable explanation for high regioselectivity in the case of isoflavones and unreactivity of flavones has been presented. Phenol oxidative coupling was used for the one-step synthesis of another natural product kudzuisoflavone-A from daidzein. Sonogashira coupling was utilized for the synthesis of dimeric systems linked via an acetylic linker. A variety of soflavone isoflavone, flavone-flavone and isoflavone-flavone dimers were synthesized in "one-pot" by this methodology and in excellent yields. Although Ullmann coupling was found not to be suitable for the synthesis of isoflavone or flavone dimers, one-pot Suzuki-Miyaura methodology gave flavone dimers and various other heterocyclic dimers in good yields.

Bibliography: p. 227-253. / xvii, 254 p. : ill. (chiefly col.), photos (col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / This project sought to examine the spatial and temporal distribution, as well as the composition, of the flavan-3-ols, proanthocyanidins and flavonols in winegrapes throughout berry development. In addition, the author sought to explore how modifying bunch exposure to light would impact upon flavonoid biosynthesis in the grape berry by comparing the flavonoid composition of shaded and exposed grapes. The expression of key genes in the flavonoid biosynthetic pathway was also investigated to understand how the pathway is regulated during berry development. / Thesis (Ph.D.)--University of Adelaide, School of Agriculture and Wine, Discipline of Wine and Horticulture, 2004

The goal of this dissertation is to investigate the interaction between cimetidine and dietary flavonoids using the Caco-2 cell transport model. It has been shown that flavonoids can change the bioavailability of pharmaceuticals, either by inhibiting metabolizing enzymes or inhibiting the drug efflux transporters. However, the effect of dietary flavonoids in the absorption of cimetidine has not been investigated. Therefore, the hypothesis of this study is that the absorption of cimetidine is mediated by a drug efflux pump, P-glycoprotein, of which dietary flavonoids can enhance the permeability of cimetidine by reducing P-glycoprotein function. The increase in permeability of cimetidine can increase the bioavailability of cimetidine. To test the hypothesis, three objectives were proposed. The first objective was to validate the Caco-2 transport model in our laboratory. The validation was performed by measuring the electrical resistance ofthe monolayer and determining the transport of paracellular marker. Also P-glycoprotein function was determined using rhodamine 123. The second objective was to describe the transport characteristics of cimetidine in the Caco-2 cell monolayers. The permeability of cimetidine was determined at different pH environments. When the permeability of cimetidine from apical to basolateral and basolateral to apical was compared, there appeared to be an effiux mechanism involved transport of cimetidine. The permeability of cimetidine in the presence of verapamil, a P-glycoprotein competitive inhibitor, suggested that P-glycoprotein was involved in the effiux. The third objective was to study the effect of dietary flavonoids on the permeability of cimetidine in the Caco-2 cell model. In the present study, four different flavonoids, quercetin, genistein, naringenin, and xanthohumol were selected. When co-treated with flavonoid aglycones, the permeability ofcimetidine was significantly reduced in the basolateral to apical direction. However, only genistin, a glycoside of genistein, significantly reduced the efflux of cimetidine. The present studies demonstrate that some dietary flavonoids, especially aglycones, can significantly reduce the effiux of cimetidine in the Caco-2 cell monolayers. Therefore, the fiavonoids consumed in a normal diet have the potential to enhance the bioavailability of cimetidine and possibly other P-glycoprotein substrates by altering their permeability. / Graduation date: 2004

The neuroprotective effects of AF4, a flavonoid-enriched extract derived from the peel of Northern Spy apples (containing quercetin-3-O-glucoside, quercetin-3-O-galactoside, quercetin-3-O-rhamnoside, quercetin-3-O-rutinoside, epicatechin, and cyanidin-3-O-galactoside) were examined by assessing neuronal loss and motor impairment resulting from hypoxic-ischemic (HI) brain injury in adult C57BL/6 mice. Relative to vehicle treatment (water, 10mL/kg/day), oral administration of AF4 (50 mg/kg/day) for 3 days reduces HI-induced neuronal loss in the striatum and hippocampus, motor impairments, and reduces the ability of LPS to stimulate the production of TNF-alpha in whole blood. Pretreatment with AF4 (1 ug/mL) decreased the death of mouse primary cortical neurons subjected to oxygen glucose deprivation (12 hours) in comparison to vehicle (DMSO) or the same concentration of quercetin or its metabolites. Taken together these findings indicate that AF4 reduces HI-induced brain injury and motor deficits by increasing the resistance of vulnerable neurons to ischemic cell death and decreasing the production of inflammatory cytokines.

Dissertation (Ph.D.)--University of South Florida, 2008. / Includes vita. Includes bibliographical references.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences