Cao Ruijie, Zhou Jinhui, Liu Jiale, Wang Yaxuan, Dai Yandong, Jiang Yun, Yamauchi Akira, Atlas Daphne, Jin Tiancheng, Zhou Jiedong, Wang Cuixue, Tan Qihuan, Chen Yifei, Yodoi Junji, Tian Hai
Department of Basic Medicine, Medical College, Shaoxing University, Shaoxing, China.
Department of Breast Surgery, Misugi-kai Sato Hospital Breast Center, HIrakata, Osaka, Japan.
Inflammation. 2025 Mar 14. doi: 10.1007/s10753-025-02282-9.
The activation of inflammasomes (NLRP3 and NLRP1) is central to the pathogenesis of inflammatory bowel disease (IBD). Here we examined the protective effects of a thioredoxin-mimetic peptide CB13 (TXM-CB13), known for its antioxidative stress and anti-inflammatory properties. We examined the effects of TXM-CB13 on dextran sulfate sodium (DSS)-induced colitis and lipopolysaccharide (LPS)-induced NLRP3 inflammasome activation in RAW264.7 macrophages. TXM-CB13 appeared to alleviate symptoms of DSS-induced colitis and to significantly suppress the protein and mRNA levels of NLRP3, Mlck, and IL-1β in colonic tissues. Additionally, TXM-CB13 treatment increased the levels of the intestinal barrier proteins Occludin, ZO-1, and NLRP1, as shown through immunohistochemistry and Western blot analysis. In vitro, TXM-CB13 inhibited LPS-induced TLR4 signaling, reducing MyD88 levels and consequently attenuating the activation of the NF-κB pathways, including p-IκB-α/IκB-α and p-NF-κB-p65/NF-κB-p65. This inhibition further reduced the activation of the NLRP3 inflammasome components, NLRP3, ASC, Caspase-1, GSDMD, and IL-1β. In addition, TXM-CB13 prevented the ROS-mediated dissociation of TXNIP from TRX, inhibiting NLRP3 activation. These findings suggest that TXM-CB13 is a potential therapeutic candidate for IBD through its modulation of the TLR4/MyD88/NF-κB/NLRP3 and ROS/TXNIP/TRX/NLRP3 pathways.
炎性小体（NLRP3和NLRP1）的激活是炎症性肠病（IBD）发病机制的核心。在此，我们研究了一种硫氧还蛋白模拟肽CB13（TXM-CB13）的保护作用，该肽以其抗氧化应激和抗炎特性而闻名。我们研究了TXM-CB13对葡聚糖硫酸钠（DSS）诱导的结肠炎以及脂多糖（LPS）诱导的RAW264.7巨噬细胞中NLRP3炎性小体激活的影响。TXM-CB13似乎减轻了DSS诱导的结肠炎症状，并显著抑制了结肠组织中NLRP3、Mlck和IL-1β的蛋白质和mRNA水平。此外，通过免疫组织化学和蛋白质印迹分析表明，TXM-CB13处理增加了肠道屏障蛋白闭合蛋白、紧密连接蛋白1和NLRP1的水平。在体外，TXM-CB13抑制LPS诱导的TLR4信号传导，降低MyD88水平，从而减弱包括p-IκB-α/IκB-α和p-NF-κB-p65/NF-κB-p65在内的NF-κB途径的激活。这种抑制进一步降低了NLRP3炎性小体成分NLRP3、ASC、半胱天冬酶-1、Gasdermin D和IL-1β的激活。此外，TXM-CB13阻止了ROS介导的硫氧还蛋白相互作用蛋白（TXNIP）与硫氧还蛋白（TRX）的解离，抑制了NLRP3的激活。这些发现表明，TXM-CB13通过调节TLR4/MyD88/NF-κB/NLRP3和ROS/TXNIP/TRX/NLRP3途径，是IBD的一种潜在治疗候选药物。
