Inhibitory Effects of 4-Hydroxyderricin and Xanthoangelol on Lipopolysaccharide-Induced Inflammatory Responses in RAW264 Macrophages

Abstract

The Japanese herb, Ashitaba (Angelica keiskei Koidzumi), contains two prenylated chalcones, 4-hydroxyderricin and xanthoangelol, which are considered to be the major active compounds of Ashitaba. However, their effects on inflammatory responses are poorly understood. In the present study, we investigated the effects and underlying molecular mechanisms of 4-hydroxyderricin and xanthoangelol on lipopolysaccharide (LPS)-induced inflammatory responses in RAW264 mouse macrophages. LPS-mediated production of nitric oxide (NO) was markedly reduced by 4-hydroxyderricin (10 μM) and xanthoangelol (5 μM) compared with their parent compound, chalcone (25 μM). They also inhibited LPS-induced secretion of tumor necrosis factor-alpha (TNF-α) and expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2). Although chalcone decreased the DNA-binding activity of both activator protein-1 (AP-1) and nuclear factor-kappa B (NF-κB), 4-hydroxyderricin and xanthoangelol suppressed only AP-1 and had no effect on NF-κB. On the other hand, all of the tested chalcones reduced the phosphorylation (at serine 536) level of the p65 subunit of NF-κB. 4-Hydroxyderricin and xanthoangelol may be promising for the prevention of inflammatory diseases.

A Review of the Medicinal Uses and Pharmacology of Ashitaba

“…When tested against Chang liver cells, compounds 7, 10, 11, 14, 24, 26, 28-31, 33, 34, and 38 showed inhibitory effects on NO almost equal to the reference compound glyzyrrhizin [3,17]. In another study, compounds 1 and 2 were also shown to suppress the production of NO in RAW264 macrophages, with negligible effects on cellular function [32]. The authors noted that prenylated chalcones were more effective in suppressing NO formation, with 2 being more potent than 1.…”

“…Ashitaba extract and compound 2 were shown to inhibit inflammation induced by TNF-α in male kwl ICR mice [35]. Another study determined that isolated compounds 1 and 2 had similar TNF-α suppressing effects in RAW264 macrophages [32], and compound 5 induced suppression in porcine aortic endothelial cells [33]. In RAW246.7 macrophages, the n-hexane ashitaba extract had anti-inflammatory activity resulting from the downregulation of NF-κB-dependent gene products [34].…”

“…Modes of action include xanthine oxidase (XO) inhibition [4], free-radical scavenging activity [22,24,31], and reduction in expression of proinflammatory transcription factors [32][33][34]. XOreduces molecular oxygen, leading to anionic O 2 − and hydrogen peroxide.…”

“…Since 2 contains a geranyl group and 1 contains a dimethylallyl group, it is possible that the increased hydrophobicity of additional isoprene units facilitates compound accumulation into the cell, promoting antioxidative activity [32]. Tumor necrosis factor alpha (TNF-α) has been implicated as an important participant in the induction of inflammation [32] and is regulated by transcription factors activator protein 1 (AP-1) and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Ashitaba extract and compound 2 were shown to inhibit inflammation induced by TNF-α in male kwl ICR mice [35].…”

Angelica keiskeiKoidzumi Extracts Improve Some Markers of Liver Function in Habitual Alcohol Drinkers: A Randomized Double-Blind Clinical Trial

“…Xanthoangelol, a major constituent of AKE, exhibits antioxidative and anti-inflammatory properties. 16,17 AKE was suggested to improve the pathological abnormalities associated with ALD and proposed as a possible new therapeutic agent for the treatment of ALD. However, the hepatoprotective effects of AKE have not been well established.…”