Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

Department

Biomedical and Pharmaceutical Sciences

First Advisor

Navindra P. Seeram

Abstract

Our laboratory initiated a comprehensive research program to investigate the phytochemical composition and biological effects of several botanical based natural products including pomegranate (Punica granatum), red maple (Acer rubrum), polyphenol-enriched maple (Acer saccharum) syrup extract, and various phytocannabinoids (Cannabis sp.). We hypothesize that these bioactive natural products can exert beneficial biological effects via their antioxidant and anti-inflammatory effects.

In Manuscript 1-4, we identified a series of phytochemicals from botanical extracts including pomegranate, red maple, phenolic-enriched maple syrup extract (MSX) and evaluated their biological activities for potential cosmeceutical and/or dermatological applications. In Manuscript 1 (published in Journal of Functional Foods; 2019, 54, 559-567), we evaluated the skin protective and antioxidative effects of pomegranate phenolics [(i.e. punicalagin (PA) and ellagic acid (EA)] and their gut microbial metabolite (i.e. urolithin A; UA) against oxidative stress induced by hydrogen peroxide (H2O2) in human keratinocytes. In this study, we reported that a chemically standardized and commercial available pomegranate extract (PE; Pomella®) and its phenolics including PA, EA, and UA exerted protective effects against oxidative stress and cytotoxicity in human keratinocytes. In Manuscript 2 (Published in Food and Function; 2020, 11, 5105-5114), we investigated the antioxidative and cytoprotective effects of a proprietary red maple leaves extract (commercially available as MaplifaTM) and its major phenolic compound, ginnalin A (GA), in human skin cells exposed to oxidative stress inducers including H2O2 and methylglyoxal (MGO). In this study, we reported that MaplifaTM and GA exerted skin protective effects by down-regulation of reactive oxygen species and apoptosis associated caspase family proteins. In Manuscript 3 (Published in Dermatologic Therapy; 2020, e13426), we reported that phenolic-enriched maple syrup extract (MSX) showed protective effects on human keratinocytes against H2O2 and MGO induced cytotoxicity and DNA damage. In Manuscript 4 (Published in Journal of Functional Foods; 2020, 75, 104208), we assessed the anti-elastase activity, skin permeability, and cytoprotective effects of glucitol-core containing gallotannins (GCGs) from red maple using biochemical-, computational-, and cell culture-based assays. This study reported that GCGs from red maple are skin permeable elastase inhibitors with antioxidant and cytoprotective activities, which supported potential cosmeceutical applications of MaplifaTM.

In Manuscript 5-7, we investigated the anti-inflammatory effects of two inflammasome inhibitors, namely, cannabidiol (CBD) and punicalagin (PA), and explored their mechanisms of action. In Manuscript 5 (Published in Journal of Natural Products, 2020, 83, 2025-2029), we reported that CBD's suppressive effect on the activation of NLRP3 inflammasome is associated with its modulation of P2X7 receptor. In Manuscript 6 (Published in Cannabis and Cannabinoid Research, 2020, Online ahead of print), we used network-based pharmacology analysis and computational docking approach to study CBD’s molecular targets and signaling pathways that involved in the anti-inflammatory activity. We reported that CBD’s anti-inflammatory effect can be associated with a series of molecular targets including proteins and signaling pathways, which supported the utilization of CBD as a promising anti-inflammatory natural product. In Manuscript 7 (To be submitted to Journal of Natural Products), we evaluated the inhibitory effects of PA on NLRP3 inflammasome activation and its effects on inflammasome activation related receptor (i.e. P2X7) with a cellular based model using human monocytes. In addition, we evaluated the anti-inflammatory effects of PA in two different mouse models of peritonitis. Our findings supported that PA's overall anti-inflammatory effects may be attributed to its inhibitory effects on the activation of NLRP3 inflammasome.

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