Abstract
Ulcerative colitis is a common inflammatory bowel disease, and the activation of thePI3K/AKT and NF-κB signaling pathways plays a pivotal role in its pathogenesis. Dihydroartemisinin (DHA) is a widely used antimalarial drug and has shown anticancer effect partially through inhibiting the activation of PI3K/AKT and NF-κB. This study aimed to investigate the effect of dihydroartemisinin on ulcerative colitis and its mechanism. Adult male C57 mice were subjected to 3.0% dextran sulfate sodium (DSS) for seven days; simultaneously, dihydroartemisinin or control saline was administered by oral gavage once a day. In vitro, the intestinal epithelial cell-6 was treated with LPS for 24 hours with or without dihydroartemisinin combined with PI3K/Akt activator 740 Y-P or NF-κB activator phorbol myristate acetate. Western blotting was used to test the activation of PI3K/AKT and NF-κB. Dihydroartemisinin significantly ameliorated body weight loss, shortened colon length, and increased DAI in DSS-induced colitis. Meanwhile, histological damage was improved and was accompanied by decreased expression and secretion of proinflammatory cytokines. Moreover, DSS-induced elevation of phosphorylation of PI3K, AKT, IKKα, IκBα, and NF-κB (p65) was remarkably blunted by dihydroartemisinin both in vivo and in vitro, indicating an inhibitive property on the PI3K/AKT and NF-κB signaling pathways. Furthermore, administration of 740 Y-P or PMA significantly blocked protective activity of dihydroartemisinin against colitis in vitro. In conclusion, dihydroartemisinin can attenuate DSS-induced colitis, and its anticolitis effect might be mediated via the PI3K/AKT and NF-κB signaling pathways. DHA might serve as a promising drug for patients with ulcerative colitis.
Highlights
Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) caused by a combination of environmental and genetic factors and is characterized by inflammation, homeostasis disruption, and epithelial barrier damage in the intestinal tract [1, 2]
To explore whether dihydroartemisinin exerts therapeutic effects on colitis, we established a mouse model of dextran sulfate sodium (DSS)-induced colitis and dihydroartemisinin was administered daily at various doses by oral gavage for 7 days. e results showed that DSS induced drastic body weight loss, and dihydroartemisinin administration significantly blunted the body weight loss in a dose-dependent manner (Figure 1(a))
DSS induced a significant shortening of the colon length (Figures 1(b) and 1(c)), which is a marker of sufficient induction of colitis and is inversely associated with the severity of colitis
Summary
Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) caused by a combination of environmental and genetic factors and is characterized by inflammation, homeostasis disruption, and epithelial barrier damage in the intestinal tract [1, 2]. E clinical manifestations of UC include development of bloody diarrhea with or without mucus, weight loss, abdominal pain, rectal urgency, tenesmus, and even systemic symptoms in severe cases [3]. The main therapy for UC is anti-inflammatory treatment using nonsteroid drugs such as mesalamine and corticosteroids. The nonsteroid drugs lack a universal response and have potential adverse side effects, such as infection and neoplasia. Erefore, it is urgent to develop new drugs for safer and more effective treatment of UC. The pathophysiology of UC is not fully understood, promising advances have been achieved in the knowledge of inflammatory and immune mechanisms [4]. Many cellular signaling pathways, such as MAPK/AP-1, Nrf, PPAR-α, PI3K/AKT, and NF-κB, are generally believed to be involved in inflammatory and immune disorders in UC.
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