Beauvericin Ameliorates Experimental Colitis by Inhibiting Activated T Cells via Downregulation of the PI3K/Akt Signaling Pathway

Abstract

Crohn's disease is a common, chronic inflammatory bowel condition characterized by remission and relapse. Accumulating evidence indicates that activated T cells play an important role in this disease. In the present study, we aimed to examine the effect of beauvericin, a natural cyclic peptide, on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice, which mimics Crohn's disease. Beauvericin significantly reduced weight loss, diarrhea and mortality, accompanied with notable alleviation of macroscopic and microscopic signs. In addition, this compound decreased serum levels of tumor necrosis factor (TNF)-α and interferon (IFN)- γ in a concentration-dependent manner in mice with experimental colitis. These effects of beauvericin are attributed to its inhibition on activated T cells. Flow cytometry and immunoblot assay data showed that beauvericin suppressed T-cell proliferation, activation and IFN-γ-STAT1-T-bet signaling and subsequently led to apoptosis of activated T cells by suppressing Bcl-2 and phosphorylated Bad as well as increasing cleavage of caspase-3, -9, -12 and PARP. Furthermore, inhibition of PI3K/Akt signaling, which was an upstream regulator of cell activation and survival in activated T cells, contributed to the effect of beauvericin. Overall, these results supported beauvericin as a novel drug candidate for the treatment of colonic inflammation mainly by targeting PI3K/Akt in activated T cells.

Human skin permeation of emerging mycotoxins (beauvericin and enniatins)

“…So have Gammelsrud et al 88 shown that ENN B en BEA influenced the expression of various co-stimulatory molecules, indicating that ENN B as well as BEA, could disturb dendritic cell migration and interfere with the macrophage differentiation process, inhibit the initiation of a specific immune response, modulate cytokine secretion and change the orientation of an immune response. 84,89 Moreover, Wu et al 90 have demonstrated that BEA decreased serum levels of TNF-α and IFN-γ in mice with experimental colitis and suppressed T-cell proliferation and activation, leading to apoptosis of activated T cells and making BEA a novel drug candidate for the treatment of colonic inflammation, such as Crohn's disease. 90 Immunological skin cells can thus be considered as possible targets for these cyclic depsipeptides.…”

“…84,89 Moreover, Wu et al 90 have demonstrated that BEA decreased serum levels of TNF-α and IFN-γ in mice with experimental colitis and suppressed T-cell proliferation and activation, leading to apoptosis of activated T cells and making BEA a novel drug candidate for the treatment of colonic inflammation, such as Crohn's disease. 90 Immunological skin cells can thus be considered as possible targets for these cyclic depsipeptides. Our results showed that application of 1 mg/ml after 24 h resulted in dermis concentrations up to 12.53 μM for intact and 32.70 μM for damaged skin, whereas for the epidermis this was 577.70 μM and 659.96 μM, respectively (ENN A).…”

Vacuolar protein sorting 4B regulates apoptosis of intestinal epithelial cells via p38 MAPK in Crohn's disease

“…Crohn's disease is one of the chronic intestinal inflammation, characterized by remission and frequently relapsing, affecting the gastrointestinal tract mainly in mucosal and submucosal inflammation, with clinical symptoms such as diarrhea with passage of blood or mucus, abdominal pain and the loss of weight (Hollenbach et al, 2005). In Western countries, CD has a highly incidence of 27-48 cases in about 100,000 persons every year (Bernstein et al, 2006;Wu et al, 2013). Meanwhile, in recent years, CD has a continually increasing incidence in China (Zheng et al, 2011).…”

Deoxyschizandrin suppresses dss-induced ulcerative colitis in mice

“…The number of mucosal activated CD4 T cells is closely related to the structural integrity of intestinal mucosa because activated T cells can interact with the intestinal epithelial cells and damage the structure of intestinal mucosa. [36] High levels of CD4 T cell aggregation and T cell infiltration have been observed in the intestinal tract of UC mice. [37] Deoxyschizandrin significantly reduced the level of DSS-induced mucosal T cell infiltration in the colon [Figure 3d], suggesting an inhibitory role of deoxyschizandrin in T lymphocyte aggregation and mucosal infiltration in UC.…”