The Inhibitory Effect of Artesunate on Excessive Endoplasmic Reticulum Stress Alleviates Experimental Colitis in Mice

Abstract

Endoplasmic reticulum (ER) stress may contribute to the pathogenesis and perpetuation of ulcerative colitis (UC). Previous studies have shown artesuante (ARS) has the protective effect on experimental UC. Therefore, it can be assumed that ARS can regulate ER stress and its related reactions. Dextran sulfate sodium (DSS) induced UC model in mice was used to testify this hypothesis. The results clearly showed that DSS exposure caused excessive ER stress evidenced by a markedly increase of GRP78 and CHOP expression, and then activated the ER stress sensors PERK, IRE1, ATF6 and their respective signaling pathways, followed by upregulated caspases12 and lowered Bcl-2/Bax ratio. However, ARS treatment significantly inhibited the occurrence of ER stress via preventing the activation of PERK-eIF2α-ATF4-CHOP and IRE1α-XBP1 signaling pathways, concurrently ER-stress-associated apoptosis in colon tissues. Moreover, ARS treatment remarkably inhibited the activation of NF-κB and the expression levels of pro-inflammatory cytokines, improved the clinical and histopathological alterations as well as maintained the expression of claudin-1 and Muc2 in mucosal layer of colon. Notably, the classic ER stress inhibitor 4-phenyhlbutyric acid enhanced the beneficial effects of ARS; in contrast, the ER stress inducer 2-deoxy-d-glucose substantially abrogated the above-mentioned effects, uncovering the involvement of ER stress in the response. These findings indicated the protection of ARS on UC is associated with its suppressing excessive ER stress mediated intestinal barrier damage and inflammatory response. This study provides a novel aspect to understand the mechanism of ARS against UC.

Immunoregulation by Artemisinin and Its Derivatives: A New Role for Old Antimalarial Drugs

“…Dihydroartemisinin also regulated the expression of proinflammatory genes and cell junction-associated genes and normalized the abundance of the gut bacteria that was altered in colitis mice ( 39 ). Furthermore, artesunate reportedly reduced expression of IFN-γ, IL-17, and TNF-α in experimental colitis ( 40 ), inhibited TLR4-NF-κB signaling pathway ( 41 ), promoted apoptosis of macrophages and DCs, and reduced TNF-α and IL-12 production in vivo and in vitro ( 42 ) while suppressing excessive ER stress ( 43 ), cell apoptosis and inflammatory responses via the NF-κB pathway ( 44 , 45 ). Thus, ARTs exert immunoregulatory effects on various immune cells, including T helper cells, Tregs, macrophages, neutrophils and DCs, by modulating NF-κB and PI3K/AKT signaling pathways, resulting in an improvement of colitis symptoms.…”

Collagen XV Promotes ER Stress-Induced Inflammation through Activating Integrin β1/FAK Signaling Pathway and M1 Macrophage Polarization in Adipose Tissue

“…Furthermore, the production process of the inflammatory factor was coupled to an increase in IRE1α, which was also accompanied by slight TNFα activation of the NF-κB cascade ( Figure 5 H). IRE1α has been identified to be capable of recruiting TRAF2 into ER under stress, and further coupling with IKKβ to form a complex that activates the NF-κB pathway during ERS [ 34 , 35 , 36 ]. These results indicate that the IRE1α/XBP1 branch of ERS is related to Col XV-induced adipose tissue inflammation.…”

Natural Products Modulate Cell Apoptosis: A Promising Way for the Treatment of Ulcerative Colitis

“…ARS has been demonstrated to alleviate UC by multiple pathways. Besides regulating mitochondria-dependent apoptosis, it also suppressed the activation of PERK-eIF2α-ATF4-CHOP and IRE1α-XBP1 signaling pathways to prevent ERSmediated apoptosis in colon tissues (Yin et al, 2021).…”