Oligosaccharides as Potential Therapeutics against Atherosclerosis

Figures

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  Figure 1. The effects of oligosaccharides on cholesterol and lipid metabolism. The low-density lipoprotein receptor (LDL-R), ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1), and liver X receptor (LXR) are the key targets of the COS and GOS, COS, HDO and HPβCD, GOS and HpβCD, respectively. Chitosan oligosaccharide (COS) treatment increased the lipid intake by the liver through the regulation of three transcription factors; forkhead box O3 (FOXO3a), sterol-responsive element-binding protein 2 (SREBPs), and hepatocyte nuclear factor-1α (HNF-1α); which decreased the level of the LDL-R inhibitor proprotein convertase subtilisin/kexin type 9 (PCSK9). Heparin-derived oligosaccharides (HDO) down-regulated the protein kinase B/phosphoinositide 3-kinase (Akt/PI3K); one of the major regulators of cellular metabolism, growth, and proliferation; and up-regulated the ABCA1 transporter. Galacto-oligosaccharides (GOSs) and 2-hydroxypropyl-β-cyclodextrin (HPβCD) acted through LRX and ABCA1 and ABCG1 in an LDL-R-dependent way, decreasing the levels of triglycerides, LDL, and very-low-density lipoprotein (VLDL) cholesterol.

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  Figure 2. The proposed mechanism of β-cyclodextrin action. β-CD binds and forms a β-CD-DAG complex with diacylglycerol (DAG), which prevents the recruitment of PKCε (protein kinase Cε) to the plasma membrane by DAG, and thus inactivates PKCε. Furthermore, the blocked PKCε-catalysed phosphorylation of eNOS (endothelial nitric oxide synthetase) at the active site T-495 activated eNOS, which produced NO (nitric oxide), and inhibited the activation of the nuclear factor kappa B (NFκB) pathway. Therefore, β-CD-mediated NO production blocked the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), thereby inhibiting monocytic adhesion to endothelial cells.

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  Figure 3. Schematic representation of atherosclerosis development and the most important processes contributing to each stage. The coloured dots depict the effects of the corresponding oligosaccharides on the given process.