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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.

The mouse bitter taste receptors Tas2r143, Tas2r135, and Tas2r126 are encoded by genes that cluster on chromosome 6 and have been suggested to be expressed under common regulatory elements. Previous studies indicated that the Tas2r143/Tas2r135/Tas2r126 cluster is expressed in the heart, but other organs had not been systematically analyzed. In order to investigate the expression of this bitter taste receptor gene cluster in non-gustatory tissues, we generated a BAC (bacterial artificial chromosome) based transgenic mouse line, expressing CreERT2 under the control of the Tas2r143 promoter. After crossing this line with a mouse line expressing EGFP after Cre-mediated recombination, we were able to validate the Tas2r143-CreERT2 transgenic mouse line and monitor the expression of Tas2r143. EGFP-positive cells, indicating expression of members of the cluster, were found in about 47% of taste buds, and could also be found in several other organs. A population of EGFP-positive cells was identified in thymic epithelial cells, in the lamina propria of the intestine and in vascular smooth muscle cells of cardiac blood vessels. EGFP-positive cells were also identified in the epithelium of organs readily exposed to pathogens including lower airways, the gastrointestinal tract, urethra, vagina, and cervix. With respect to the function of cells expressing this bitter taste receptor cluster, RNA-seq analysis in EGFP-positive cells isolated from the epithelium of trachea and stomach showed expression of genes related to innate immunity. These data further support the concept that bitter taste receptors serve functions outside the gustatory system.

Phosphatase of regenerating liver 3 (PRL-3) is known to be overexpressed in many tumors, and its transcript level is high in the vasculature and endothelial cells of malignant tumor tissue. However, the mechanism(s) underlying its enhanced expression and its function in endothelial cells remain unknown. Here, we report that vascular endothelial growth factor (VEGF) can induce PRL-3 transcription in human umbilical vein endothelial cells (HUVEC). An analysis of its 5′UTR revealed that PRL-3 transcription is initiated from two distinct sites, which results in the formation of the two transcripts, PRL-3-iso1 and PRL-3-iso2, but only the latter is up-regulated in HUVEC by VEGF. The PRL-3-iso2 promoter region includes two functional MEF2 (myocyte enhancer factor2) binding sites. The over-expression of the constitutively active form of MEF2C promotes the abundance of the PRL-3-iso2 transcript in a number of human cell lines. The siRNA-induced knockdown of MEF2C abolished the stimulative effect of VEGF on PRL-3 transcript in HUVEC, indicating that the VEGF-induced promotion of PRL-3 expression requires the presence of MEF2C. Finally, blocking PRL-3 activity or expression suppresses tube formation by HUVEC. We suggest that PRL-3 functions downstream of the VEGF/MEF2C pathway in endothelial cells and may play an important role in tumor angiogenesis.