Abstract
ObjectivesNatural products have played a significant role in drug discovery and development. Inflammatory mediators such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) have been suggested to connect with various inflammatory diseases. In this study, we explored the anti-inflammatory potential of aciculatin (8-((2R,4S,5S,6R)-tetrahydro-4,5-dihydroxy-6-methyl-2H-pyran-2-yl)-5-hydroxy-2-(4-hydroxyphenyl)-7-methoxy-4H-chromen-4-one), one of main components of Chrysopogon aciculatis, by examining its effects on the expression and activity of iNOS and COX-2 in lipopolysaccharide (LPS)-activated macrophages.MethodsWe used nitrate and prostaglandin E2 (PGE2) assays to examine inhibitory effect of aciculatin on nitric oxide (NO) and PGE2 levels in LPS-activated mouse RAW264.7 macrophages and further investigated the mechanisms of aciculatin suppressed LPS-mediated iNOS/COX-2 expression by western blot, RT-PCR, reporter gene assay and confocal microscope analysis.ResultsAciculatin remarkably decreased the LPS (1 μg/mL)-induced mRNA and protein expression of iNOS and COX-2 as well as their downstream products, NO and PGE2 respectively, in a concentration-dependent manner (1-10 μM). Such inhibition was found, via immunoblot analyses, reporter gene assays, and confocal microscope observations that aciculatin not only acts through significant suppression of LPS-induced NF-κB activation, an effect highly correlated with its inhibitory effect on LPS-induced IκB kinase (IKK) activation, IκB degradation, NF-κB phosphorylation, nuclear translocation and binding of NF-κB to the κB motif of the iNOS and COX-2 promoters, but also suppressed phosphorylation of JNK/p38 mitogen-activated protein kinases (MAPKs).ConclusionOur results demonstrated that aciculatin exerts potent anti-inflammatory activity through its dual inhibitory effects on iNOS and COX-2 by regulating NF-κB and JNK/p38 MAPK pathways.
Highlights
Natural products have proven to be a valuable source for new therapeutic agents
The present study examines the inhibitory effect of aciculatin on the expression of inducible nitric oxide synthase (iNOS), COX-2 and elucidates the anti-inflammatory mechanisms in LPS-stimulated RAW264.7 macrophages model
Effects of Aciculatin on the LPS-Induced nitric oxide (NO) and prostaglandin E2 (PGE2) Production To investigate whether aciculatin has anti-inflammatory activities, LPS-induced NO and PGE2 production was determined in the presence or absence of aciculatin (1-10 μM) in RAW264.7 mouse macrophage cells
Summary
Natural products have proven to be a valuable source for new therapeutic agents. In a search for anti-inflammatory products, aciculatin (8-((2R,4S,5S,6R)-tetrahydro-4,5-dihydroxy-6-methyl-2H-pyran-2-yl)-5-hydroxy-2-(4-hydroxyphenyl)-7-methoxy-4H-chromen-4-one), was selected. The two proinflammatory enzymes, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), which can be induced by LPS or cytokines, are found to work in concert in a number of similar pathophysiological activities and inflammatory disease [8,9]. The products of iNOS and COX-2, including nitric oxide (NO) and prostaglandins (PGs), are involved in modulation of cellular functions and homeostasis. They are highly regulated by biosynthetic pathways that are responsible for pulsed release of nanomolar concentrations of both mediators [10,11]. A compound with the dual inhibitory effect on iNOS and COX-2 expression would hold tremendous potential in advancing the treatment of inflammatory or chronic immune disorders
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