AI Article Synopsis
- PCSK9 is a protein linked to high cholesterol and cardiovascular disease, making it a key target for drug development, but existing medications are expensive and not effective enough.* -
- This study investigates the potential of alkaloids from the plant Nauclea latifolia to inhibit PCSK9, aiming to uncover new, cost-effective treatments for managing high cholesterol.* -
- The research found that a specific compound, 3R-3,14-dihydroangustoline, enhances LDL uptake while increasing LDL receptor levels and decreasing PCSK9 levels, suggesting its promise as a new therapeutic option.*
Article Abstract
Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been found to play a major role in atherosclerotic cardiovascular disease (ASCVD) by promoting hyperlipidemia. Its inhibition has therefore emerged as a viable drug target for improving the outcome of ASCVD. However, current monoclonal antibody PCSK9 inhibitors are considered cost ineffective and there is the need to discover new effective and cheaper small molecule alternatives.
Purpose: The methanolic and ethanolic crude extracts of Nauclea latifolia have been shown to possess anti-hyperlipidemic activity, but the chemical component(s) responsible for this activity and the mechanism of action have remained unknown. The objective of this study was therefore to identify N. latifolia constituents with anti-hyperlipidemic activity and to investigate the inhibition of PCSK9 as a probable mechanism of action.
Method: In the present study, compounds were isolated from the ethanolic extract of the stem of N. latifolia. The alkaloids were evaluated for their DiI-LDL uptake promoting activity in HepG2 cell. The most active compound was further assessed for its effect on low density lipoprotein receptor (LDLR) and PCSK9 protein expressions by western blot.
Results: 3R-3,14-dihydroangustoline (5), showed a relatively good activity in promoting LDL uptake (1.26-fold). It further increased LDLR protein expression and decreased the protein expression of PCSK9 in a dose dependent manner (1-50 µM).
Conclusion: Alkaloids from N. latifolia may serve as a source of new PCSK9 inhibitors.
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| http://dx.doi.org/10.1016/j.phymed.2018.06.041 | DOI Listing |
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