Deoxynivalenol (DON), a common food contaminant, induces pyroptosis in intestinal epithelial cells by activating the NLRP3 inflammasome, though the mechanism remains unclear. This study utilized 32 male Kunming mice and rat small intestinal epithelial (IEC-6) cells treated with DON at concentrations of 0-4.8 mg/kg (7 days) and 0-1 μM (24 h), respectively. Results demonstrated that DON induced intestinal epithelial damage and activated the NLRP3 inflammasome, leading to pyroptosis, while also activating the TLR4-NF-κB/p38 MAPK pathway. Pretreatment with PDTC (NF-κB inhibitor) and SB203580 (p38 MAPK inhibitor) suppressed NLRP3 inflammasome priming and activation, respectively, reducing pyroptosis in IEC-6 cells. TLR4 inhibition with TLR4-IN-C34 confirmed that TLR4 acts as an upstream regulator controlling both NF-κB and p38 MAPK signaling, thus inhibiting NLRP3 inflammasome activation and alleviating pyroptosis. Thus, DON activates the TLR4-NF-κB/p38 MAPK pathway, triggering NLRP3 inflammasome priming and activation, which ultimately leads to pyroptosis in intestinal epithelial cells.
Wang-Yong Yu, Ya-Fei Sun, Ming-Yue Wang et al.· Ecotoxicology and Environmen...· 0 citations
1-Ethoxy-2,3-difluoro-4-(trans-4-propylcyclohexyl) benzene (EDPrB), a highly polluting fluorinated liquid-crystal monomers (FLCMs), accumulates in the kidneys over the long term. First, our study demonstrates that exposure to EDPrB can induce inflammatory responses and fibrosis in human renal cortical proximal tubule epithelial cells (HK-2), posing a risk of nephrotoxicity. Next, our study investigates the renal injury induced by EDPrB in male Kunming mice after 70-day exposure at 13, 130, and 1300 μg/kg bw/day, using an adverse outcome pathway (AOP) framework. Histopathological observations demonstrate that EDPrB corresponds to an elevated probability of developing chronic kidney disease (CKD). Proteomics and Western blot analysis revealed that mTOR signaling may be the mechanism by which EDPrB induces CKD in mice and causes damage to HK-2 cells. Finally, by treating EDPrB-exposed mice with RAPA, we demonstrated that activation of the mTOR signaling is the molecular initiating event driving EDPrB-induced CKD in mice. This study proposes an AOP framework focused on EDPrB-induced CKD. The molecular initiating event is identified as mTOR activation, followed by autophagy inhibition leading to inflammation and fibrosis as key events, ultimately resulting in CKD as an adverse outcome. This highlights the renal risks of FLCMs and supports stricter environmental release regulations.
Chenjiao Miao, Binwen Zhang, Wangyong Yu et al.· Environmental Science and Te...· 0 citations
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