An Algal Metabolite-Based PPAR-γ Agonist Displayed Anti-Inflammatory Effect via Inhibition of the NF-κB Pathway

Abstract

In our previous study, a synthetic compound, (+)-(R,E)-6a1, that incorporated the key structures of anti-inflammatory algal metabolites and the endogenous peroxisome proliferator-activated receptor γ (PPAR-γ) ligand 15-deoxy-∆12,14-prostaglandin J2 (15d-PGJ2), exerted significant PPAR-γ transcriptional activity. Because PPAR-γ expressed in macrophages has been postulated as a negative regulator of inflammation, this study was designed to investigate the anti-inflammatory effect of the PPAR-γ agonist, (+)-(R,E)-6a1. Compound (+)-(R,E)-6a1 displayed in vitro anti-inflammatory activity in lipopolysaccharides (LPS)-stimulated murine RAW264.7 macrophages. Compound (+)-(R,E)-6a1 suppressed the expression of proinflammatory factors, such as nitric oxide (NO), inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), possibly by the inhibition of the nuclear factor-κB (NF-κB) pathway. In macrophages, (+)-(R,E)-6a1 suppressed LPS-induced phosphorylation of NF-κB, inhibitor of NF-κB α (IκBα), and IκB kinase (IKK). These results indicated that PPAR-γ agonist, (+)-(R,E)-6a1, exerts anti-inflammatory activity via inhibition of the NF-κB pathway.

Peroxisome Proliferator-Activated Receptors as a Therapeutic Target in Asthma

“…PPARs inhibit many transcription factors possessing a proinflammatory action: NF-κB, AP-1, protein C/EBP (CCAAT/enhancer-binding protein), and signal transducers and activators of transcription (STAT). The relationships between PPARs and NF-κB are of special interest [5,6,37,45,46].…”

Purple Napiergrass (Pennisetum purpureum Schumach) Hot Water Extracts Ameliorate High-Fat Diet-Induced Obesity and Metabolic Disorders in Mice

“…PPAR-γ, a key regulator, can be activated by both synthetic agonists like thiazolidinediones (glitazones) used in diabetes treatment 45,46 and bioactive compounds found in food (terpenoids, anthocyanins, polyunsaturated fatty acids, flavonoids, and capsaicin), which induce an oxidative stress response to reduce inflammation. 47,48 In a human trial targeting metabolic syndrome, a daily anthocyanin intake of 320 mg for 4 weeks increased PPAR-γ expression, leading to reduced inflammatory markers (IL-1, IL-6, TNF-α), and a negative correlation with lipid-related markers. 49 Anthocyanins not only activate PPAR-γ expression but also boost ADIPOQ expression, mitigating the inflammatory response caused by an HFD, reducing liver fat…”

Chronic exposure to low-level lipopolysaccharide dampens influenza-mediated inflammatory response via A20 and PPAR network

“…Both PPAR-a and PPAR-g inhibit NF-kB activation like A20 and PPAR-a has been reported to be positively regulated by A20 (10)(11)(12). In addition, PPAR-a/g also exerts anti-inflammatory effects during influenza infection (13,14).…”