Sudachinoid- and Ichangensin-Type Limonoids from Citrus junos Downregulate Pro-Inflammatory Cytokines

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.

The potential mechanism of Bletilla striata in the treatment of ulcerative colitis determined through network pharmacology, molecular docking, and in vivo experimental verification

“…The expression levels of inflammatory factors such as TNF-α, IL-1β, and IL-6 in UC were increased by abnormal activation of the PI3K/AKT signalling pathway (Li et al 2019a , b ; Li et al 2019a , b ). Furthermore, TNF-α is an important proinflammatory cytokine involved in the pathogenesis of UC, inducing the pathological opening of the intestinal tight junction barrier, increasing intestinal epithelial permeability, and disrupting intestinal barrier function (Xiang et al 2021 ; Shin et al 2020 ). Therefore, anti-TNF-α therapy has been widely used in clinical practice as a suitable method of UC treatment.…”

Antiinflammatory activity of natural triterpenes—An overview from 2006 to 2021

“…About 13 limonoids were isolated from Citrus junos (Shin et al, 2020) Gendunin-A (284) and nimbolide (287), both isolated from Azadirachta indica, displayed antiinflammatory activity (Braga et al, 2020). In the case of compound 287, a clinical therapeutic value in rheumatoid arthritis by inhibiting the STAT-3/NF-κB/Notch-1 axis and reducing the levels of proinflammatory cytokines was also observed (Anchi et al, 2021).…”

“…About 13 limonoids were isolated from Citrus junos (Shin et al, 2020) being 10 of them ( 274–283 ) acting as suppressors of the expression of IL‐8 stimulated by LPS at concentrations of 1 and 10 μM. Sudachinoid‐type limonoids methyl sudachinoid A ( 274 ) and sudachinoid B ( 275 ) reduced the pro‐inflammatory cytokines in LPS‐stimulated macrophages at both tested concentrations.…”

Limonin Inhibits IL‐1β‐Induced Inflammation and Catabolism in Chondrocytes and Ameliorates Osteoarthritis by Activating Nrf2

“…Limonin exhibits several significant biological and pharmaceutical activities, including antioxidant, antibacterial, antitumor, analgesic, and anti-inflammatory effects [ 21 , 22 ]. Limonin has been reported to suppress the NF- κ B pathway in RAW 264.7 macrophages stimulated by LPS [ 23 ]. Meanwhile, it has also been shown that limonin may activate Nrf2 in HepG2 cells [ 24 ].…”