Yin Shaojie, Li Liuhui, Tao Ya, Yu Jie, Wei Simin, Liu Mingjiang, Li Jingui
College of Veterinary Medicine, Yangzhou University, Yangzhou, China.
Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China.
Front Pharmacol. 2021 Mar 9;12:629798. doi: 10.3389/fphar.2021.629798. eCollection 2021.
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.
内质网（ER）应激可能在溃疡性结肠炎（UC）的发病机制及病情持续发展中起作用。既往研究表明青蒿琥酯（ARS）对实验性UC具有保护作用。因此，可以推测ARS能够调节内质网应激及其相关反应。本研究采用葡聚糖硫酸钠（DSS）诱导的小鼠UC模型来验证这一假说。结果清楚地表明，DSS暴露导致内质网应激过度，表现为GRP78和CHOP表达显著增加，进而激活内质网应激传感器PERK、IRE1、ATF6及其各自的信号通路，随后caspases12上调，Bcl-2/Bax比值降低。然而，ARS治疗通过阻止PERK-eIF2α-ATF4-CHOP和IRE1α-XBP1信号通路的激活，显著抑制了内质网应激的发生，同时也抑制了结肠组织中与内质网应激相关的细胞凋亡。此外，ARS治疗显著抑制了NF-κB的激活和促炎细胞因子的表达水平，改善了临床和组织病理学改变，并维持了结肠黏膜层中claudin-1和Muc2的表达。值得注意的是，经典的内质网应激抑制剂4-苯基丁酸增强了ARS的有益作用；相反，内质网应激诱导剂2-脱氧-D-葡萄糖则基本消除了上述作用，揭示了内质网应激参与了这一反应。这些发现表明ARS对UC的保护作用与其抑制内质网应激介导的肠道屏障损伤和炎症反应有关。本研究为理解ARS抗UC的机制提供了一个新的视角。
