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Modulation of signal transduction pathways relevant tp atherosclerosis by dietary chemopreventive agents

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thesis
posted on 15.12.2014, 10:32 by Paul Alan Atherfold
The dietary constituents curcumin, resveratrol, epigallocatechin-3-gallate (EGCG), but not indole-3-carbinol (I3C) inhibited the activation of NF-kB in B lymphoblasts and HUVEC. EGCG inhibited NF-kB activation in human umbilical vein endothelial cells (HUVECs) by blocking the activity of IKKa, thus preventing subsequent phosphorylation and degradation of IkBa. In B lymphoblasts inhibition of NF-kB activation by EGCG, appeared to be independent of the effect on IkBa. EGCG also prevented the formation of inducible extracellular and intracellular ROS in B lymphoblasts. EGCG inhibited the growth of B lymphoblasts and HUVEC, which was mediated through a cell cycle arrest and induction of apoptosis. Further analysis of this growth inhibitory effect, identified a number of important cell growth regulators that were a target of EGCG. In HUVEC, EGCG growth inhibition appeared to involve p53, CDK1, cyclin D1, and HMOX-1, but was independent of Pin1 and XIAP. In B lymphoblasts, EGCG growth inhibition appeared to be independent of any significant affect on p53, CDK1, cyclin D1, pin1 and XIAP, but may involve the loss of NF-kB activity or increases in HMOX-1 protein. Treatment with EGCG produced changes in the expression of a number of disease relevant genes including HMOX-1, as detected by microarray analysis. This increase in HMOX-1 mRNA corresponded to an increase in HMOX-1 protein. In B lymphoblasts, further analysis revealed that the increase in HMOX-1 was dependent on the PI3K and p38 pathways. The data obtained facilitate the design of preventive dietary intervention studies in healthy volunteers or groups of at risk patients..

History

Date of award

01/01/2003

Author affiliation

Biochemistry

Awarding institution

University of Leicester

Qualification level

Doctoral

Qualification name

PhD

Language

en

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