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Title: Experimental modelling of flavonoid membrane interactions
Author: Sanver, Didem
ISNI:       0000 0004 6347 7041
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2017
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Flavonoids, a class of polyphenols, are commonly found in fruits, vegetables, nuts, and grains. Increasing evidence from epidemiological and clinical studies show a relationship between high flavonoid consumption in diet and reduced risk of several chronic diseases. Several mechanisms, including specific binding of flavonoids to proteins, have been proposed for flavonoids to exert their biological activities. However, it has also been reported that nonspecific interactions of flavonoids with phospholipids can induce structural changes in the membrane’s features (e.g., thickness and fluctuations) and indirectly modulate membrane proteins, as well as influence their pharmacological potentials. This thesis investigates the interactions between flavonoids and model biomembranes through three distinctively different but complementary approaches, with a special emphasis on employing monolayer membrane model in proof of concept experiments using one lipid type; 1,2 dioleoyl-sn-glycero-3-phosphocholine (DOPC). Hence, a well characterised electrochemical sensor system; phospholipid monolayer coated mercury (Hg) film electrode was established by rapid cyclic voltammetry (RCV) to screen structure-dependent interactions of a variety of flavonoids. The data revealed that flavonoids adopting a planar configuration altered the membrane properties more significantly than nonplanar flavonoids. The extent of interactions can be ranked in the order of quercetin > kaempferol > naringenin > hesperetin > catechin for flavonoid aglycones and tiliroside > rutin > naringin for flavonoid glycosides. Quercetin, rutin, and tiliroside were selected for follow-up experiments with Langmuir monolayers, Brewster angle microscopy (BAM), and small-angle X-ray scattering (SAXS). Relaxation phenomena in DOPC monolayers and visualisation of the surface with BAM revealed a pronounced monolayer stabilisation effect with both quercetin and tiliroside, whereas rutin disrupted the monolayer structure rendering the surface entirely smooth. The following ranking of the interactions: quercetin>tiliroside>rutin, yielded comparable results to those obtained from the previous technique. SAXS showed a monotonous membrane thinning for all flavonoids studied associated with an increase in the mean fluctuations of the membrane. The extent of interactions was concentration and temperature dependent with an order of quercetin>tiliroside>rutin except for tiliroside where a high concentration of tiliroside (>2 mol%) revealed the most pronounced response. In addition to the novelty of employing phospholipid monolayers for the systematic characterisation of a variety of flavonoids, this is the first report investigating the effect of tiliroside with biomimetic membrane models. All the flavonoids studied are believed to be localised in the lipid/water interface region. Both this location and the membrane perturbations might have implications for the therapeutic features of flavonoids.
Supervisor: Murray, Brent S. ; Nelson, Andrew L. Sponsor: Turkish Ministry of National Education
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available