Date of Award
2024
Degree Type
Dissertation
Degree Name
Doctor of Philosophy in Interdisciplinary Neuroscience
Department
Biomedical and Pharmaceutical Sciences
First Advisor
Navindra P. Seeram
Abstract
Our laboratory has established a comprehensive program researching the nutraceutical and bioactive properties of various plant-derived phytochemicals, including berries, pomegranate (Punica granatum), maple syrup derivatives such as maple water and maple syrup extract (Acer saccharum), and most recently, Cannabis constituents (Cannabis sativa L.). Our research supports the overarching hypothesis where naturally derived phytochemicals possess neuroprotective and/or immunological properties of promise for future nutraceutical development.
Section 1, (Manuscripts 1-3) investigated the effects of plant derived phytochemicals on nervous system and neuroimmune protein targets. Manuscript 1 (published in Medical Cannabis and Cannabinoids; 2022, 5(1):85-94) evaluated the inhibitory activities of a panel of eight Cannabis derivatives on the cholinergic enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which are vital to nervous system functioning. This study reported moderate inhibitory effects of cannabinoids on the AChE and BChE enzymes via an enzymatic inhibition assay, a competitive inhibition mode by CBD, and interactions via amino acid residues by molecular docking. Manuscript 2 (published in Biology, 2022, 11(10):1416) investigated the inhibitory effects of a panel of cannabinoid and non-cannabinoid (namely, cannflavin A-CFA) Cannabis derivatives, on the tryptophan catabolism enzyme kynurenine-3-monooxygenase (KMO) in the neurotoxic kynurenine pathway. CFA demonstrated the most active inhibitory effect on KMO in an enzymatic assay as compared to the known inhibitor, Ro 61-8048 and ligand-protein interactions were verified via surface plasmon resonance and molecular docking. Manuscript 3 (published in Heliyon; 2023, 9(11):e21265) explored the binding properties of a panel of cannabinoids on the P2X purinoreceptor 4, a protein implicated in neurophysiological dysfunction when aberrantly expressed. Our findings supported the binding of several cannabinoids to P2X4 via an SPR platform screening method with a primarily non-competitive binding manner as compared to a known binder, 5-BDBD shown through a competitive SPR assay and in silico molecular docking.
Section 2, (Manuscripts 4-7) focused on uncovering the anti-inflammatory effects of plant derived phytochemicals through proteomic based approaches. Manuscript 4 (published in Food & Function; 2023, 14(14):6690-6706) elucidated the anti-inflammatory mechanisms of the phenolic-enriched maple syrup extract (MSX) in a mouse model of LPS-induced peritonitis. Specifically, MSX exerted anti-inflammatory activities in several major organs against pro-inflammatory cytokines, and a proteomic analysis indicated modulation of liver and kidney protein targets. Manuscript 5 (published in Food & Function; 2024, 15, 172-182) identified the immunoregulatory properties of MSX in the spleen via a mouse model of LPS-induced peritonitis through proteomic analysis and in vitro immune and T-cell activation models. Results supported immune regulation by MSX through both innate and adaptive immunity supporting its potential as a functional food. Manuscript 6 (in preparation as a Note) evaluated the effects of MSX on the brain through analysis of pro-inflammatory cytokines and proteomics evaluations. Minor immune activation by LPS was counteracted by MSX on protein targets, canonical pathways and upstream regulators as identified by proteomics and bioinformatics analyses of differentially expressed proteins. Manuscript 7 (published in Bio-protocol; 2024, 14(16): e5055) developed a chloroform/methanol protein extraction protocol for bottom-up proteomics analysis, which was utilized throughout our MSX proteomic studies, and may be applied to future studies to delineate the mechanism of action of naturally based phytochemicals. Our findings largely support the extensive findings of the neuroprotective and immunomodulatory therapeutic promise of naturally derived phytochemicals, specifically from the sugar maple and Cannabis plants.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Recommended Citation
Puopolo, Tess, "INVESTIGATING THE NEUROPROTECTIVE & ANTI-INFLAMMATORY BIOACTIVITIES OF PLANT DERIVED PHYTOCHEMICALS" (2024). Open Access Dissertations. Paper 1727.
https://digitalcommons.uri.edu/oa_diss/1727
