To identify bioactive natural products possessing anti-inflammatory activity, the potential of fulgidic acid from the rhizomes of Cyperus rotundus and the underlying mechanisms involved in its anti-inflammatory activity were evaluated in this study. Fulgidic acid reduced the production of nitric oxide (NO), prostaglandin E 2 (PGE 2 ), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. Consistent with these findings, fulgidic acid suppressed the LPS-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the protein level, as well as iNOS, COX-2, TNF-α, and IL-6 at mRNA levels. Fulgidic acid suppressed the LPS-induced transcriptional activity of activator protein-1 (AP-1) as well as the phosphorylation of c-Fos and c-Jun. On the other hand, fulgidic acid did not show any effect on LPS-induced nuclear factor κB (NF-κB) activity. Taken together, these results suggest that the anti-inflammatory effect of fulgidic acid is associated with the suppression of iNOS, COX-2, TNF-α, and IL-6 expression through down-regulating AP-1 activation in LPSinduced RAW264.7 macrophages.
Two chromone C-glucosides, biflorin (1) and isobiflorin (2), were isolated from the flower buds of Syzygium aromaticum L. (Myrtaceae). Here, inhibitory effects of 1 and 2 on lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and prostaglandin E2 (PGE2) in RAW 264.7 macrophages were evaluated, and 1 (IC50 = 51.7 and 37.1 μM, respectively) was more potent than 2 (IC50 > 60 and 46.0 μM). The suppression of NO and PGE2 production by 1 correlated with inhibition of iNOS and COX-2 protein expression. Compound 1 reduced inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA expression via inhibition of their promoter activities. Compound 1 inhibited the LPS-induced production and mRNA expression of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6. Furthermore, 1 reduced p-STAT1 and p-p38 expression but did not affect the activity of nuclear factor κ light-chain enhancer of activated B cells (NF-κB) or activator protein 1 (AP-1). In a mouse model of LPS-induced endotoxemia, 1 reduced the mRNA levels of iNOS, COX-2, and TNF-α, and the phosphorylation-mediated activation of the signal transducer and activator of transcription 1 (STAT1), consequently improving the survival rates of mice. Compound 1 showed a significant anti-inflammatory effect on carrageenan-induced paw edema and croton-oil-induced ear edema in rats. The collective data indicate that the suppression of pro-inflammatory gene expression via p38 mitogen-activated protein kinase and STAT1 inactivation may be a mechanism for the anti-inflammatory activity of 1.
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