Dihydroartemisinin Protects against Dextran Sulfate Sodium-Induced Colitis in Mice through Inhibiting the PI3K/AKT and NF-κB Signaling Pathways

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.

Efficacy and Safety of Sophora flavescens (Kushen) Based Traditional Chinese Medicine in the Treatment of Ulcerative Colitis: Clinical Evidence and Potential Mechanisms

“…By the Network Analyzer on C-T-P network, PI3K-Akt signaling was identified as the top core node of the pathways in Kushen against UC with DHAS with the greatest degrees. As an important signal transduction pathway, PI3K-Akt signaling is involved in the release of multiple pro-inflammatory cytokines, such as NF-κB, IL-6, and IL-17, which could control key cellular processes involved in the immune inflammatory response in UC once activated by Akt, indicating that Kushen may have an anti-inflammatory effect on UC with DHAS through PI3K-Akt signaling and its downstream pathways by acting on these target genes ( Li et al, 2019 ).…”

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

“…Besides, dihydroartemisinin and artesunate have been reported to effectively alleviate colitis symptoms in mice via different cellular and molecular mechanisms. For example, treatment with dihydroartemisinin suppressed activation of PI3K/AKT and NF- κ B signaling pathways ( 37 ), promoted CD4+ T cell apoptosis and restored Th1/Treg cell balance through enhancing heme oxygenase-1 (HO-1) production ( 38 ). 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 ).…”

“…Dihydroartemisinin and artesunate also inhibited NF- κ B signaling, leading to alleviation of colitis. Dihydroartemisinin significantly inhibited phosphorylation of IKK α , I κ B α , and NF- κ B (p65) in DSS-induced murine colitis and IEC-6 cells treated with LPS ( 37 ) while artesunate remarkably suppressed the NF-κB activation with a reduction in mRNA expression of IL-1β, IL-6 and TNF-α and an increase in IL-10 gene expression ( 41 , 44 , 45 ). Taken together, ARTs can hinder activation of NF-κB pathway and therefore suppress inflammatory responses in vivo and in vitro ( Figure 2 ).…”

PDE9 Inhibitor PF-04447943 Attenuates DSS-Induced Colitis by Suppressing Oxidative Stress, Inflammation, and Regulating T-Cell Polarization

“…In the oxidative stress condition, the upregulation of ERK and AKT show the protective role to induce the expression of cytoprotective gene, such as Nrf2 and HO-1 (Wang et al, 2019). Nevertheless, ERK and AKT are profound for their inflammatory role in UC (Gao et al, 2019;Li et al, 2019). But there are growing evidences to support ERK phosphorylation promote Nrf2 expression in colitis.…”