Fumonisin B1 induced intestinal epithelial barrier damage through endoplasmic reticulum stress triggered by the ceramide synthase 2 depletion.

Fumonisin B1 (FB1) contamination in feed is of great concern nowadays. The intestine would be the first line when FB1-contaminated food or feed was ingested. However, the intestinal toxicity and mechanism of FB1 have rarely been studied. In this study, we found that FB1 inhibited cell viability, and promoted the severe release of lactate dehydrogenase. Meantime, FB1 destroyed the intestinal physical barrier by reducing the expressions of tight junctions. And FB1 induced excessive production of cytokines like tumor necrosis factor-α, resulting in damage to the intestinal immunological barrier. Furthermore, we observed that FB1 preferentially inhibited the expressions of ceramide synthase 2 (CerS2) and upregulated the expression of endoplasmic reticulum (ER) stress markers. The siRNA-mediated knockdown of CerS2 and CerS2 overexpression proved that CerS2 depletion induced by FB1 triggered ER stress, which then destructed the intestinal barrier. FB1-induced intestinal impairment could be restored by CerS2 over-expression or 4-Phenylbutyric acid (ER stress inhibitor). Overall, our findings demonstrated intestinal toxicity and potential mechanism of FB1, and the intestinal impairment risk posed by FB1 must be taken seriously.

Soy isoflavones ameliorate experimental colitis by targeting ERα/NLRP3 inflammasome pathways.

Soy isoflavones (SIFs) are selective estrogen receptor modulators (SERMs) that have anti-inflammatory activities. Our previous study found that estrogen receptor α (ERα) directly regulates the NLRP3 transcription and NLRP3 inflammasome assembly. Therefore, we hypothesized that SIFs alleviate colitis via an ERα-dependent mechanism by targeting the NLRP3 inflammasome. The influence of SIFs on colitis and the potential mechanisms were thoroughly determined in this study. The results suggested that SIFs ameliorated dextran sodium sulfate (DSS)-induced body weight loss, reduced disease activity index and promoted the recovery of colon pathological damage in mice. Moreover, expression of the NLRP3 inflammasome was significantly inhibited, and the release of IL-1ß and IL-18 was suppressed by SIFs. Furthermore, ERα blockade ameliorated DSS-induced inflammatory responses in the intestine, and SIFs markedly suppressed the expression of ERα in a dose-dependent manner. Our study demonstrated that the protective therapeutic action of SIFs on DSS-induced colitis depended on inhibition of ERα and subsequent NLRP3 inflammasome activation, and SIFs are promising therapeutic agents for the treatment of colitis.