University of Surrey

Test tubes in the lab Research in the ATI Dance Research

Short chain fatty acids : the potential therapeutic target to treat high glucose-induced oxidative stress and endothelial dysfunction in type-2 diabetes mellitus.

Maziah Mohd Ghazaly, Maziah (2016) Short chain fatty acids : the potential therapeutic target to treat high glucose-induced oxidative stress and endothelial dysfunction in type-2 diabetes mellitus. Doctoral thesis, University of Surrey.

[img] Image
restriction form 1 revised.jpg
Restricted to Repository staff only
Available under License Creative Commons Attribution Non-commercial Share Alike.

Download (2MB)
[img] Image
restriction form 2 revised.jpg
Restricted to Repository staff only
Available under License Creative Commons Attribution Non-commercial Share Alike.

Download (2MB)
[img] Text
Author_Deposit_Agreement.pdf
Restricted to Repository staff only until 29 January 2017.
Available under License Creative Commons Attribution Non-commercial Share Alike.

Download (165kB)
[img] Text
PhD_Thesis_2015_Maziah_Ghazaly_body amended.pdf
Restricted to Repository staff only until 16 December 2016.
Available under License Creative Commons Attribution Non-commercial Share Alike.

Download (4MB)

Abstract

Dietary obesity, insulin resistance (IR) and type-2 diabetes mellitus (T2DM) are the major risk factors for the development of cardiovascular diseases (CVDs). Recent studies have shown that reactive oxygen species (ROS)-generating enzyme, NADPH oxidase (Nox), causes endothelial oxidative stress and is a prominent feature underlying vascular abnormalities of patients with IR and T2DM. The Nox2 has been found to be constitutively expressed in endothelial cells (ECs) and can be activated in diabetic condition. It is known that short chain fatty acids (SCFAs) i.e. acetate (NaA), propionate (NaP) and butyrate (NaB) are byproducts of bacterial fermentation of resistant starch in the colon and exert beneficial effects in improving insulin sensitivity, colonic cancer and reducing CVDs development. However, the effects of SCFAs in reducing endothelial oxidative stress and dysfunction are still unknown. In this project, I have investigated high glucose (0-30 mM for 24 h)-induced ROS production, Nox2 activation levels, endothelial function (in terms of cell cycle regulation and capillary formation on matrigels), G protein-coupled receptor 43 levels (GPCR43, a SCFAs receptor) and the potential therapeutic effect of SCFAs in diabetes using cultured human pulmonary microvascular ECs (HPMEC). My results have shown that high glucose (30 mM) induced endothelial Nox2 activation and ROS production, which causes ECs cycle deregulation, cell apoptosis and capillaries broken down on matrigels. High glucose increases the levels of cyclin D, E, A and B, p53 and p16 protein expression which lead to abnormal ECs cell cycle regulation, apoptosis and cell death. Adding NaA (5 mM, GPCR43 agonist) into the culture medium can increase the GPCR43 expression on ECs under high glucose conditions, inhibits Nox2-induced ROS production and activation as well as improves ECs function. In short, high glucose causes endothelial oxidative stress and dysfunction via Nox2-induced ROS production. NaA activated GPCR43 inhibits Nox2 activation which reversed high glucose-induced damage on the ECs. SCFAs such as NaA may have the therapeutic potential for treating oxidative stress-related vascular complications in patients with IR, obesity and diabetes.

Item Type: Thesis (Doctoral)
Divisions : Theses
Authors :
AuthorsEmailORCID
Maziah Mohd Ghazaly, Maziahizabaiduri@gmail.comUNSPECIFIED
Date : 29 January 2016
Funders : Malaysian Government (MARA)
Projects : Short Chain Fatty Acids: The Potential Therapeutic Target to Treat High Glucose-Induced Oxidative Stress and Endothelial Dysfunction in Type-2 Diabetes Mellitus
Contributors :
ContributionNameEmailORCID
Thesis supervisorLi, Jian-Meijian-mei.li@reading.ac.ukUNSPECIFIED
Thesis supervisorHowlin, Brendanb.howlin@surrey.ac.ukUNSPECIFIED
Thesis supervisorMulholland, DAd.mulholland@surrey.ac.ukUNSPECIFIED
Additional Information : Research data is unpublished so it is restricted. Please restrict the thesis from public view.
Depositing User : Maziah Mohd Ghazaly
Date Deposited : 09 Feb 2016 10:49
Last Modified : 09 Feb 2016 10:49
URI: http://epubs.surrey.ac.uk/id/eprint/809543

Actions (login required)

View Item View Item

Downloads

Downloads per month over past year


Information about this web site

© The University of Surrey, Guildford, Surrey, GU2 7XH, United Kingdom.
+44 (0)1483 300800