Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

Specialization

Pharmacology and Toxicology

Department

Biomedical and Pharmaceutical Sciences

First Advisor

Navindra P. Seeram

Abstract

Background: Chronic inflammation is linked to a number of diseases and disorders such as diabetes, heart disease, liver disease, neurological diseases and even certain cancers. In the brain, inflammation activates and promotes recruitment of microglia leading to reactive microgliosis and implicated in the pathogenesis of a number of neurodegenerative diseases. Systemically, inflammatory stimuli can cause glucose/insulin intolerance, disrupt liver lipid transport, metabolism and catabolism leading to pre-mature liver failure and cancer. Pomella (POM), a standardized pomegranate extract and Maple Syrup Extract (MSX) could be a source of beneficial phytonutrients capable of mitigating these inflammatory processes.

Methods: A pilot scale diet induced obesity study with Male C57BL/6 mice with or without POM or MSX at for 12 weeks were used to probe if POM or MSX could prevent inflammation within the hippocampus. A larger C57BL/6 mouse modeling a typical western diet was used to further evaluate MSX for its ability to modulate inflammation and metabolic syndrome progression. Finally, a human macrophage study modeling systemic inflammation and a co-culture system of murine microglia and human neurons modeling the microenvironment within the brain were used to explore anti-inflammatory effects of POM metabolites (Urolithins) and MSX.

Results and Conclusions: Mice fed a HFD for 12 weeks showed elevated expression of both pro and anti-inflammatory cytokine/growth factors and neurodegenerative associated genes in hippocampal tissues. POM supplementation in HFD mice allowed for a significant reduction in the gene expression of IL-1α, IL-1β, IL-7, IL-11, TNFα, MAPT, APP, GSK3β, and LEPR. MSX supplementation in HFD feed allowed for a significant reduction in the gene expression of IL-7, IL-11, IL-19, TNFα, IFNα, CD40L, CD70, NFEL2, SOD1, ITGAM, and LEPR. In a western diet model, MSX exacerbated liver lipid accumulation but decreased white adipose tissue weight and attenuating serum levels of IL-6. In human macrophages, MSX significantly reduced pro-inflammatory cytokine release. In a co-culture neuroinflammation model, urolithins and MSX significantly abrogated cytokine and reactive species release while also preventing neuronal cell death.

Available for download on Monday, April 19, 2021

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