Guo Ning-Ke, Si Li-Ning, Li Pei-Qing, Gan Gui-Fen
Graduate School, Qinghai University, Xining, Qinghai, People's Republic of China.
Affiliated Hospital, Qinghai University, Xining, Qinghai, People's Republic of China.
Int J Nanomedicine. 2024 Dec 31;19:14125-14141. doi: 10.2147/IJN.S497081. eCollection 2024.
Acacetin (AC) is a flavonoid compound with antiperoxidant, anti-inflammatory, and antiplasmodial activity. However, the solubility of AC is poor and nano acacetin (Nano AC) was synthesized. The intestinal mucosal barrier is impaired in sepsis rats, and the protective effects and mechanism of AC and Nano AC on the intestinal mucosal barrier are unclear.
Cecal ligation and perforation (CLP) was used to induce sepsis in rats, and lipopolysaccharide (LPS)-stimulated intestinal epithelial cells were used to observe the effects of AC and our synthesized Nano AC on the amelioration of intestinal mucosal damage. The molecular docking technique was used to predict the binding energy of AC to thioredoxin reductase 1 (TRX1) signaling pathway proteins. TRX1 inhibitor (PX-12) was employed to elucidate the protective signaling pathway of Nano AC in LPS-stimulated intestinal epithelial cells.
Our synthesized Nano AC, with an average particle size of 17.18 ± 0.48 nm and an uptake rate of 95% in intestinal epithelial cells. The maximum binding capacity of AC to TRX1 was -6.82 kcal/mol, supporting the hypothesis that TRX1 is a potential target of AC. AC and Nano AC ameliorated the survival rate, intestinal mucosal damage score, pathological morphology, hepatic and renal function, and myocardial troponin levels, decreased serum levels of pyroptosis-related factors, upregulated TRX1, down-regulated NOD-like receptor protein 3 inflammasome (NLRP3), cysteinyl aspartate specific proteinase-11 (Caspase-11), Gasdermin D (GSDMD) in sepsis rats. They improved mitochondrial morphology and mitochondrial reactive oxygen species (ROS) levels, reduced pyroptosis levels, and upregulated TRX1, which adjusted NLRP3/ Caspase-11/ GSDMD signaling pathway in LPS-stimulated intestinal epithelial cells. Moreover, Nano AC was more effective.
AC and Nano-AC can inhibit the NLRP3/Caspase-11/GSDMD signaling pathway by upregulating TRX1 to ameliorate intestinal mucosal injury in sepsis rats, and the effect of Nano AC is more prominent.
刺槐素（AC）是一种具有抗氧化、抗炎和抗疟活性的黄酮类化合物。然而，AC的溶解度较差，因此合成了纳米刺槐素（纳米AC）。脓毒症大鼠的肠黏膜屏障受损，AC和纳米AC对肠黏膜屏障的保护作用及其机制尚不清楚。
采用盲肠结扎穿孔术（CLP）诱导大鼠脓毒症，并使用脂多糖（LPS）刺激的肠上皮细胞来观察AC和我们合成的纳米AC对改善肠黏膜损伤的作用。分子对接技术用于预测AC与硫氧还蛋白还原酶1（TRX1）信号通路蛋白的结合能。使用TRX1抑制剂（PX-12）来阐明纳米AC在LPS刺激的肠上皮细胞中的保护性信号通路。
我们合成的纳米AC平均粒径为17.18±0.48nm，在肠上皮细胞中的摄取率为95%。AC与TRX1的最大结合能力为-6.82kcal/mol，支持TRX1是AC潜在靶点的假设。AC和纳米AC改善了脓毒症大鼠的存活率、肠黏膜损伤评分、病理形态、肝肾功能和心肌肌钙蛋白水平，降低了血清中焦亡相关因子的水平，上调了TRX1，下调了NOD样受体蛋白3炎性小体（NLRP3）、半胱天冬酶-11（Caspase-11）、gasdermin D（GSDMD）。它们改善了线粒体形态和线粒体活性氧（ROS）水平，降低了焦亡水平，并上调了TRX1，从而调节了LPS刺激的肠上皮细胞中的NLRP3/Caspase-11/GSDMD信号通路。此外，纳米AC的效果更显著。
AC和纳米AC可通过上调TRX1抑制NLRP3/Caspase-11/GSDMD信号通路，改善脓毒症大鼠的肠黏膜损伤，且纳米AC的效果更突出。
