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theses

American cranberry (Vaccinium macrocarpon), a North American native species, possesses various secondary metabolites with important implications for human health. Flavonoid compounds, as major cranberry secondary metabolites, also occur widely across other different plant species, and have important functions for plant growth, reproduction and survival. Major cranberry flavonoids consist of anthocyanins, flavonols and flavan-3-ols (proanthocyanidins, PACs). Varied in their structures, the three flavonoid subgroups have been associated with various human health benefits both in vitro and in vivo. The aim of the dissertation is to characterize and illustrate the natural occurrence of these flavonoid compounds in cranberry, and to discuss their bioactivity against cancer disease as well as bioavailability in human body. The objectives of the dissertation were to: (1) quantify and characterize flavonoids across fruit development in cranberry, (2) better define quantification of PACs using the 4-dimethylaminocinamaldehyde (DMAC) spectrophotometric assay, (3) evaluate cytotoxicity and molecular basis of activity of specific flavonoid compounds toward ovarian cancer cell lines, and (4) evaluate the bioavailability of cranberry flavonoids. The dissertation will first focus on the natural occurrence and analysis of different cranberry flavonoids in cranberry. Both variety and harvest date significantly affect the levels of PACs and anthocyanins in cranberry cultivars. PACs occur as the most abundant flavonoids, with levels of decreasing during fruit development and early ripening, and slightly increasing at late fruit maturation. Anthocyanins increase sharply during fruit maturation, while flavonol concentrations remain consistent over entire season. Quantification of PACs in plant and food materials often utilizes DMAC spectrophotometric assay which has been considered to offer ease, high sensitivity and selectivity. However, in the course of research for this dissertation it was found that individual PAC monomers and oligomers with various structural variations exhibited differential molar absorption coefficients (MACs); the value of MAC is affected by both degree-of-polymerization (DP) and inter-flavan linkage type and position. Individual cranberry PACs and flavonols showed differential cytotoxicity against two ovarian cancer cell lines. The two most active cranberry flavonoids, quercetin aglycone and PAC DP-9 (nonamer), exhibited promising in vitro cytotoxic and anti-proliferative properties. They induced cell apoptosis, cell cycle arrest, cellular caspase-3 activation and PARP deactivation; in addition, they increased cancer cells' sensitivity to cisplatin. Urine clearance of cranberry flavonol glycosides and PACs were determined in female subjects following cranberry juice consumption. While PACs were not detected, five flavonol glycosides common in cranberry were identified. Quercetin-3-galactoside, the most abundant cranberry flavonol, exhibited highest peak urine concentration, followed by quercetin-3-rhamnoside, quercetin-3-arabinoside, myricetin-3-arabinoside and myricetin-3-galactoside. Quercetin-3-arabinoside showed delayed clearance compared to other flavonols. These observations suggest that both aglycone and conjugated sugar moiety structures mediate the flavonol's bioavailability.

ETD_7568

Ph.D.

Includes bibliographical references

by Yifei Wang

doi:10.7282/T36975WF

ETD doctoral

The author owns the copyright to this work.