University of Hertfordshire Research Archive

        JavaScript is disabled for your browser. Some features of this site may not work without it.

        Browse

        All of UHRABy Issue DateAuthorsTitlesThis CollectionBy Issue DateAuthorsTitles

        Arkivum Files

        My Downloads
        View Item 
        • UHRA Home
        • University of Hertfordshire
        • Research publications
        • View Item
        • UHRA Home
        • University of Hertfordshire
        • Research publications
        • View Item

        Co-Incubation with PPARβ/δ Agonists and Antagonists Modeled Using Computational Chemistry: Effect on LPS Induced Inflammatory Markers in Pulmonary Artery

        View/Open
        ijms_22_03158_v2.pdf (PDF, 2Mb)
        Author
        Perez Diaz, Noelia
        Lione, Lisa
        Hutter, Victoria
        Mackenzie, Louise Susan
        Attention
        2299/24169
        Abstract
        Peroxisome proliferator activated receptor beta/delta (PPARβ/δ) is a nuclear receptor ubiquitously expressed in cells, whose signaling controls inflammation. There are large discrepan-cies in understanding the complex role of PPARβ/δ in disease, having both anti‐ and pro‐effects on inflammation. After ligand activation, PPARβ/δ regulates genes by two different mechanisms; induction and transrepression, the effects of which are difficult to differentiate directly. We studied the PPARβ/δ‐regulation of lipopolysaccharide (LPS) induced inflammation (indicated by release of nitrite and IL‐6) of rat pulmonary artery, using different combinations of agonists (GW0742 or L−165402) and antagonists (GSK3787 or GSK0660). LPS induced release of NO and IL‐6 is not significantly reduced by incubation with PPARβ/δ ligands (either agonist or antagonist), however, co-incubation with an agonist and antagonist significantly reduces LPS‐induced nitrite production and Nos2 mRNA expression. In contrast, incubation with LPS and PPARβ/δ agonists leads to a significant increase in Pdk−4 and Angptl−4 mRNA expression, which is significantly decreased in the presence of PPARβ/δ antagonists. Docking using computational chemistry methods indicates that PPARβ/δ agonists form polar bonds with His287, His413 and Tyr437, while antagonists are more promiscuous about which amino acids they bind to, although they are very prone to bind Thr252 and Asn307. Dual binding in the PPARβ/δ binding pocket indicates the ligands retain similar binding energies, which suggests that co‐incubation with both agonist and antagonist does not prevent the specific binding of each other to the large PPARβ/δ binding pocket. To our knowledge, this is the first time that the possibility of binding two ligands simultaneously into the PPARβ/δ binding pocket has been explored. Agonist binding followed by antagonist simultaneously switches the PPARβ/δ mode of action from induction to transrepression, which is linked with an increase in Nos2 mRNA expression and nitrite production.
        Publication date
        2021-03-19
        Published in
        International Journal of Molecular Sciences
        Published version
        https://doi.org/10.3390/ijms22063158
        Other links
        http://hdl.handle.net/2299/24169
        Metadata
        Show full item record
        Keep in touch

        © 2019 University of Hertfordshire

        I want to...

        • Apply for a course
        • Download a Prospectus
        • Find a job at the University
        • Make a complaint
        • Contact the Press Office

        Go to...

        • Accommodation booking
        • Your student record
        • Bayfordbury
        • KASPAR
        • UH Arts

        The small print

        • Terms of use
        • Privacy and cookies
        • Criminal Finances Act 2017
        • Modern Slavery Act 2015
        • Sitemap

        Find/Contact us

        • T: +44 (0)1707 284000
        • E: ask@herts.ac.uk
        • Where to find us
        • Parking
        • hr
        • qaa
        • stonewall
        • AMBA
        • ECU Race Charter
        • disability confident
        • AthenaSwan