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UBC Theses and Dissertations

Role of phenolic acids on intestinal epithelial cell signaling and functionality Mu, Kaiwen


Phenolic compounds derived from the diet are typically sourced from cereals, fruits and vegetables and also beverages. They are documented to have biological functions that include antioxidant and anti-inflammatory activities, and can mitigate gastrointestinal disorders. This thesis focused on looking at mechanism(s) of phenolic acid induced intracellular hydrogen peroxide (H₂O₂) level and effects on intestinal epithelial cell signaling that are related to intestinal epithelial functionality. The first experiment showed that different phenolic acids varied specifically in relative stability and capacity to produce H₂O₂ when incubated in cell culture media for 24 hr. Phenolic acids varied in affinity to induce apoptosis and inhibit proliferation in non-differentiated Caco-2 cells. Subsequent studies demonstrated the effect of selective phenolic acids on extracellular/intracellular redox by controlling H₂O₂ influx activity and to relate this event to cell signaling and control of oxidative stress in differentiated Caco-2 cells. HyPer-3, a genetically encoded fluorescent H₂O₂ sensitive indicator was constructed to monitor intracellular H₂O₂ in differentiated Caco-2 cells. Results showed that extracellular generation of H₂O₂ occurred from autoxidation of phenolic acids in culture and subsequent disappearance corresponded to intracellular uptake in differentiated Caco-2 cells. Phenolic acid specific pro-oxidant activity was sufficient to activate intracellular nuclear factor-erythroid factor 2-related factor 2 (Nrf2) cell signaling; the degree of which was dependent on both the source of the phenolic acid and concentration used in culture. A Caco-2/RAW 264.7 co-culture model enabled intercellular cell signaling measurements in response to an inflammatory response by inflamed macrophage. The capacity of specific phenolic acids to regulate the inflammatory status of activated RAW 264.7 cells was dependent on the type of phenolic acid which influenced Nrf2 cell signaling, monolayer integrity, and cytokine production in Caco-2 cells. It is concluded from these experiments that phenolic acids regulate extracellular/intracellular redox due to a susceptibility for pro-oxidant activity that is specific for individual phenolic acids. The pro-oxidant activity was related to capacity to produce H₂O₂, or its cellular influx, which in turn had a role in cell signaling, cytokine production and intestinal epithelial cell functionality.

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