Zheng Peng, Ma Rui, Liu Xiaoya, Song Luda, Ma Bing, Zou Guijun
Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, People's Republic of China.
Department of General Surgery, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, 100048, People's Republic of China.
J Inflamm Res. 2025 Jun 18;18:7973-7988. doi: 10.2147/JIR.S504696. eCollection 2025.
Saikosaponin-d (SSD), a bioactive triterpenoid saponin derived from Bupleurum species (a traditional Chinese medicine), is recognized for its gastrointestinal protective properties. This study investigates the therapeutic potential and mechanisms of SSD against irinotecan (IRI)-induced intestinal mucositis.
Using a CT26 colorectal cancer Syngeneic mouse model (BALB/c mice), we evaluated the synergistic antitumor efficacy of SSD combined with IRI. Concurrently, the protective effects of SSD against IRI-induced intestinal toxicity were assessed in vivo (BALB/c mice) and in vitro (lipopolysaccharide (LPS)-stimulated Caco-2 cells). In vivo evaluations included monitoring body weight changes, diarrhea severity, colon length, and histopathological alterations. Mechanistic insights into the anti-inflammatory and antioxidant effects were elucidated through RT-qPCR, Western blotting, immunohistochemistry, and oxidative stress marker analysis.
SSD significantly mitigated IRI-induced intestinal injury, as demonstrated by attenuated body weight loss, improved diarrhea scores, and preserved colon length. Histopathological examination revealed that SSD protected intestinal epithelial integrity and enhanced barrier function. Mechanistically, SSD reduced oxidative stress by modulating antioxidant enzyme activities (SOD, GSH-Px) and suppressing lipid peroxidation (MDA levels). Furthermore, SSD inhibited proinflammatory cytokine production (IL-6, TNF-α, IL-1β) via downregulation of the TAK1/NF-κB pathway in both IRI-treated mice and LPS-challenged Caco-2 cells.
Our findings demonstrate that SSD alleviates IRI-induced intestinal mucositis through suppression of the TAK1/NF-κB signaling cascade, highlighting its potential as an adjuvant therapy to enhance the safety profile of IRI-based chemotherapy.
柴胡皂苷-d（SSD）是一种源自柴胡属植物（一种传统中药）的生物活性三萜皂苷，以其胃肠道保护特性而闻名。本研究调查了SSD对伊立替康（IRI）诱导的肠道粘膜炎的治疗潜力和机制。
使用CT26结直肠癌同基因小鼠模型（BALB/c小鼠），我们评估了SSD与IRI联合的协同抗肿瘤疗效。同时，在体内（BALB/c小鼠）和体外（脂多糖（LPS）刺激的Caco-2细胞）评估了SSD对IRI诱导的肠道毒性的保护作用。体内评估包括监测体重变化、腹泻严重程度、结肠长度和组织病理学改变。通过RT-qPCR、蛋白质免疫印迹、免疫组织化学和氧化应激标志物分析阐明了抗炎和抗氧化作用的机制。
SSD显著减轻了IRI诱导的肠道损伤，表现为体重减轻减轻、腹泻评分改善和结肠长度保持。组织病理学检查显示，SSD保护肠道上皮完整性并增强屏障功能。机制上，SSD通过调节抗氧化酶活性（超氧化物歧化酶、谷胱甘肽过氧化物酶）和抑制脂质过氧化（丙二醛水平）来降低氧化应激。此外，SSD在IRI处理的小鼠和LPS刺激的Caco-2细胞中均通过下调TAK1/NF-κB途径抑制促炎细胞因子的产生（白细胞介素-6、肿瘤坏死因子-α、白细胞介素-1β）。
我们的研究结果表明，SSD通过抑制TAK1/NF-κB信号级联反应减轻了IRI诱导的肠道粘膜炎，突出了其作为辅助治疗以提高基于IRI的化疗安全性的潜力。
