Investigation of the actions of punicalagin and its metabolites on atherosclerosis and non-alcoholic fatty liver disease

Al Alawi, Sulaiman Amur Said 2024. Investigation of the actions of punicalagin and its metabolites on atherosclerosis and non-alcoholic fatty liver disease. PhD Thesis, Cardiff University. Item availability restricted.

	PDF (PhD thesis) - Accepted Post-Print Version Restricted to Repository staff only until 24 September 2025 due to copyright restrictions. Download (10MB)
	PDF (Publication form) - Supplemental Material Restricted to Repository staff only Download (202kB)

Abstract

Background: Atherosclerosis remains a major factor contributing to cardiovascular disease (CVD), which leads to significant morbidity and mortality worldwide. Existing pharmacological approaches targeting hyperlipidaemia, such as statins, demonstrate limited efficacy in reducing cardiovascular risk and present various drawbacks. Given the limitations associated with statins and other medications, there is a need to explore alternative therapies. Nutraceuticals, specifically punicalagin (PC) and its metabolites (Ellagic Acid [EA]), urolithins A, B, C, D) i.e. urolithin A (UA) are nutraceuticals being used for their potential in affecting multiple atherogenic risks factors and with a favourable safety profile for the prevention and treatment of atherosclerosis. However, their impacts on the entirety of atherosclerotic processes and the precise molecular mechanisms involved are not fully understood. Therefore, the main goals of this study were to investigate the effects of PC and its metabolites on key cellular processes associated with the initiation of atherosclerosis in vitro and to clarify the effects of UA on the progression of atherosclerosis in vivo using a mouse model. Methods: Several in vitro assays were conducted utilising various cell lines and primary cell cultures to investigate the impact of PC and its metabolites on several key cellular processes associated with the development of atherosclerosis. Additionally, to study the impact of UA on the progression of atherosclerotic plaque and non-alcoholic fatty liver diseases (NAFLD) in vivo, 8-week-old male low-density lipoprotein receptor-deficient (LDLr-/-) mice were fed with a high-fat diet (HFD) or HFD-supplemented with UA for 12 weeks. Subsequently, a comprehensive examination of risk factors associated with atherosclerosis initiation and progression, including analyses of plasma lipid profile, staining of resident cells (e.g. macrophages, T-cells and smooth muscle cells (SMCs)) in plaque and RNA sequencing for thoracic aorta and liver of LDLr-/- mice. Results: PC and its metabolites attenuated several key atherosclerosis-associated processes in vitro, such as reactive oxygen species (ROS) production, monocyte migration towards monocyte chemoattractant protein-1(MCP-1) and foam cell formation. Moreover, PC and its metabolites reduced human aortic smooth muscle cells’ (HAoSMCs) invasion and inhibited dill-oxidised low-density lipoprotein (Dill-oxLDL) uptake. In vivo study, mice that were fed with HFD+UA for 12 weeks showed an attenuation of plaque inflammation and improvement in plaque stability. Moreover, analysis of HepG2 cells and liver samples showed that UA has the ability to reduce steatosis. Conclusion: The results of this research offer an important understanding into the antiatherogenic effects of PC and its metabolites in vitro and UA in vivo, identifying them as potential candidates for inclusion in existing strategies for the prevention and management of atherosclerotic CVD. This is attributed to their lack of adverse side effects and their relatively low cost compared to standard pharmacological treatments. However, the potential of UA should be further explored in larger clinical trials.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	24 September 2024
Last Modified:	25 Sep 2024 08:57
URI:	https://orca.cardiff.ac.uk/id/eprint/172356

Actions (repository staff only)

Edit Item