Abstract:
The purpose of this study was to explore the therapeutic effect of the oral administration of pseudo-ginsenoside RT4 (RT4) on ulcerative colitis (UC), and to determine the rate of absorption and distribution of RT4 in mice with UC. Balb/c mice were induced using dextran sulfate sodium salts (DSS) to establish the UC model, and 10, 20, or 40 mg/kg of RT4 was subsequently administered via gavage. The clinical symptoms, inflammatory response, intestinal barrier, content of total short-chain fatty acids (SCFAs), and gut microbiota were investigated. Caco-2 cells were induced to establish the epithelial barrier damage model using LPS, and an intervention was performed using 4, 8, and 16 µg/mL of RT4. The inflammatory factors, transient electrical resistance (TEER), and tight-junction protein expression were determined. Finally, pharmacokinetic and tissue distribution studies following the intragastric administration of RT4 in UC mice were performed. According to the results in mice, RT4 decreased the disease activity index (DAI) score, restored the colon length, reduced the levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), and boosted the levels of immunosuppressive cytokine IL-10, increased the content of SCFAs, improved the colonic histopathology, maintained the ultrastructure of colonic mucosal epithelial cells, and corrected disturbances in the intestinal microbiota. Based on the results in caco-2 cells, RT4 reduced the levels of TNF-α, IL-6, and IL-1β; protected integrity of monolayers; and increased tight-junction protein expression. Additionally, the main pharmacokinetic parameters (Cmax, Tmax, t1/2, Vd, CL, AUC) were obtained, the absolute bioavailability was calculated as 18.90% ± 2.70%, and the main distribution tissues were the small intestine and colon. In conclusion, RT4, with the features of slow elimination and directional distribution, could alleviate UC by inhibiting inflammatory factors, repairing the intestinal mucosal barrier, boosting the dominant intestinal microflora, and modulating the expression of SCFAs.
摘要:
目的探讨口服伪人参皂苷RT4(RT4)对溃疡性结肠炎(UC)的治疗作用,并确定UC小鼠对RT4的吸收和分布速率。用葡聚糖硫酸钠(DSS)诱导Balb/c小鼠建立UC模型,随后通过管饲法施用10、20或40mg/kg的RT4。临床症状,炎症反应,肠屏障,总短链脂肪酸(SCFA)含量,和肠道微生物群进行了调查。采用LPS诱导Caco-2细胞建立上皮屏障损伤模型,使用4,8和16µg/mL的RT4进行干预。炎症因子,瞬态电阻(TEER),并测定紧密连接蛋白的表达。最后,在UC小鼠中胃内施用RT4后进行药代动力学和组织分布研究。根据老鼠的结果,RT4降低了疾病活动指数(DAI)评分,恢复了结肠长度,降低促炎细胞因子(TNF-α,IL-6和IL-1β),并提高免疫抑制细胞因子IL-10的水平,增加SCFAs的含量,改善结肠组织病理学,维持结肠粘膜上皮细胞的超微结构,并纠正了肠道微生物群的紊乱。根据caco-2细胞的结果,RT4降低了TNF-α的水平,IL-6和IL-1β;保护单层的完整性;并增加紧密连接蛋白的表达。此外,主要药代动力学参数(Cmax,Tmax,t1/2,Vd,CL,获得AUC),绝对生物利用度计算为18.90%±2.70%,主要分布组织为小肠和结肠。总之,RT4,具有消除缓慢和定向分布的特点,可以通过抑制炎症因子来缓解UC,修复肠粘膜屏障,促进优势肠道菌群,并调节SCFA的表达。