Abstract
Limonoids, a dominant group of phytochemicals in the Rutaceae family, are known to exhibit several pharmacological activities. To identify natural products having efficacy against inflammatory bowel disease (IBD), we isolated 13 limonoids including a new compound, methyl sudachinoid A, from the seeds of Citrus junos and investigated their anti-inflammatory effects by assessing the expression of pro-inflammatory cytokines in lipopolysaccharide-stimulated RAW 264.7 mouse macrophages and HT-29 human colon epithelial cells. Our findings revealed that limonoids significantly downregulated the pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α, and nuclear transcription factor κB. In particular, sudachinoid-type compounds, methyl sudachinoid A and sudachinoid B, and ichangensin-type compound, 1-O-methyichangensin downregulated the expression of pro-inflammatory cytokines more potently than other limonoids, nomilin and limonin, which have been previously reported to exhibit anti-inflammatory activities in other cells; nomilin and limonin were therefore employed as positive controls in this study. Herein, we reveal that the anti-inflammatory activities of limonoids including a new compound methyl sudachinoid A from C. junos were mediated via the downregulation of pro-inflammatory cytokines and these limonoids can be employed as potential therapeutic phytochemicals for IBD.
Highlights
Inflammation is a biological response to stimuli, such as pathogen infection, which serves as a major obstacle in the maintenance of a high quality of life [1]
The 13C-NMR spectrum of compound 1 contained resonances corresponding to three carbonyl carbon groups [δc 208.4 (C-7), 169.0 (C-21) and 166.9 (C-16)], one double bond that might be the conjugated enone [δc 148.7 (C-22) and 135.5 (C-20)], two acetal carbon signals [δc 108.1 (C-1) and 103.5 (C-23)], three oxygenated methane carbon signals [δc 103.5 (C-23), 75.1 (C-17), and 55.6 (C-15)], two methoxy groups [δc 56.0 (C-OCH3) and 48.2(C-OCH3)], and six methyl carbon signals [δc 31.6 (C-25), 23.6 (C-26), 18.9 (C-24), 18.4 (C-18), 17.6 (C-2), and 14.5 (C-19)]
Further validation of the structure was achieved with the 1H-1H correlation spectroscopy (COSY) correlations of δH 7.61 (H-22) with δH 6.08 (H-23) and δH 2.87 (H-9) with δH 1.71 (H-11) (Figure 2)
Summary
Inflammation is a biological response to stimuli, such as pathogen infection, which serves as a major obstacle in the maintenance of a high quality of life [1]. The chronic immune reaction in IBD may be regulated via increased secretion of pro-inflammatory cytokines caused by an improper response to the initial stimulating effect or impaired downregulation of cytokine secretion [4]. The aberrant production of pro-inflammatory factors, such as chemokines (e.g., IL-8), often results in chronic inflammation [8] The release of these cytokines results in the development of many inflammatory diseases, such as rheumatoid arthritis and IBD. We sought to isolate limonoids and investigate their potential anti-inflammatory response by measuring the levels of inflammatory mediators, such as IL-1β and IL-6, and the activation of TNF-α, in RAW 264.7 mouse macrophage cells, and the level of IL-8 in HT-29 human colon carcinoma cells
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