Abstract
A polyphenol-enriched fraction (PEF) from Acalypha wilkesiana, whose leaves have been traditionally utilized for the treatment of diverse medical ailments, was investigated for the anti-inflammatory effect and molecular mechanisms by using lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophages and acetaminophen- (APAP-) induced liver injury mouse model. Results showed that PEF significantly attenuated LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production and suppressed the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) in RAW 264.7 macrophages. PEF also reduced the secretion of proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin- (IL-) 1β, and IL-6 in LPS-stimulated RAW 264.7 macrophages. Moreover, PEF potently inhibited LPS-induced phosphorylation of mitogen-activated protein kinases (MAPKs) as well as the activation of nuclear factor-κB (NF-κB) by preventing the degradation of inhibitor κB-α (IκB-α). In vivo, PEF pretreatment ameliorated APAP-induced liver injury and hepatic inflammation, as presented by decreased hepatic damage indicators and proinflammatory factors at both plasma and gene levels. Additionally, PEF pretreatment remarkably diminished Toll-like receptor 3 (TLR3) and TLR4 expression and the subsequent MAPKs and NF-κB activation. HPLC analysis revealed that two predominantly polyphenolic compounds present in PEF were geraniin and corilagin. These results indicated that PEF has an anti-inflammatory effect, and its molecular mechanisms may be involved in the inactivation of the TLR/MAPK/NF-κB signaling pathway, suggesting the therapeutic potential of PEF for inflammatory diseases.
Highlights
Inflammation, which is considered to play a crucial role in the body’s immune defense system, functions to eliminate the initial cause of cell injury and clear out necrotic cells and tissues damaged from the original insult and the inflammatory process [1]
Similar results were observed in the determination of mRNA levels of inducible nitric oxide synthase (iNOS) and COX-2 (Figure 3(b)). These results indicated that polyphenol-enriched fraction (PEF)-mediated inhibition of nitric oxide (NO) and prostaglandin E2 (PGE2) production was probably attributed to the downregulation of iNOS and COX-2 genes
LPS treatment caused prominent inhibitor κB-α (IκB-α) degradation as compared to the untreated control cells; PEF pretreatment notably recovered the protein level of IκB-α (Figure 5(b)). These results suggested that the inhibitory effect of PEF on the production of inflammatory mediators and proinflammatory cytokines was attributed to the inactivation of nuclear factor-κB (NF-κB) in LPS-stimulated RAW 264.7 macrophages
Summary
Inflammation, which is considered to play a crucial role in the body’s immune defense system, functions to eliminate the initial cause of cell injury and clear out necrotic cells and tissues damaged from the original insult and the inflammatory process [1]. Redundant inflammatory mediators (NO and PGE2) and proinflammatory cytokines (TNF-α, IL-1β, and IL-6) produced by activated macrophages have been considered crucial causes for acute inflammatory responses as well as chronic inflammatory diseases including rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease [6, 7]. The activated NF-κB binds to κB sites in the promoter regions of target genes and enhances the expression of inflammatory mediators and proinflammatory cytokines [11]. Synthetic or naturally derived compounds that inhibit the activation of NF-κB and MAPKs can be considered and developed as potential therapeutic medicines for inflammatory diseases [14]
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