title: 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.
authors: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu Province, China.
authors: Xue-Feng
authors: XF
authors: Wu
authors: Rui
authors: R
authors: Xu
authors: Zi-Jun
authors: ZJ
authors: Ouyang
authors: Cheng
authors: C
authors: Qian
authors: Yan
authors: Y
authors: Shen
authors: Xu-Dong
authors: XD
authors: Wu
authors: Yan-Hong
authors: YH
authors: Gu
authors: Qiang
authors: Q
authors: Xu
authors: Yang
authors: Y
authors: Sun
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy*; D047630:Depsipeptides / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects*; D014302:Trinitrobenzenesulfonic Acid / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D047630:Depsipeptides; D014409:Tumor Necrosis Factor-alpha; C004456:beauvericin; D007371:Interferon-gamma; D014302:Trinitrobenzenesulfonic Acid; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt