Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Erdao District, 126 Sendai Street, Changchun, Jilin Province 130033, China.
Department of Obstetrics, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, China.
Int Immunopharmacol. 2024 Nov 15;141:113020. doi: 10.1016/j.intimp.2024.113020. Epub 2024 Aug 28.
Ulcerative colitis (UC) is a chronic and recurrent inflammatory bowel disease (IBD). There is a growing prevalence of UC, but current conventional drugs lack efficacy. Carthamin yellow (CY) is a flavonoid compound extracted from safflower that is widely used and has various pharmacological effects. In the present study, we established colitis models in mice via DSS and in Caco-2 cells via lipopolysaccharide (LPS). Our results showed that CY treatment attenuated the symptoms of colitis by decreasing colonic pathological damage and improving disease activity index (DAI) scores. Notably, we observed that CY treatment decreased the levels of proinflammatory cytokines (TNF-α, IL-6, and IL-1β) by inhibiting the NLRP3/Caspase-1/IL-1β and MAPK/NF-κB signaling pathways. Moreover, we verified that treatment with CY obviously improved intestinal barrier function in both DSS-induced mice and LPS-stimulated Caco-2 cells. Ferroptosis-related markers were assessed. CY attenuated DSS-induced colitis by inhibiting ferroptosis, as assessed by Fe accumulation, total antioxidant capacity (T-AOC), and reactive oxygen species (ROS), 4-hydroxynonenal (4-HNE), and glutathione (GSH) levels. Additionally, there was an increase in superoxide dismutase (SOD) and catalase (CAT) activity, as well as alterations in ferroptosis-related protein and gene expression (ACSL4, GPX4, SLC7A11, TfR1, and FTH1). Further analyses revealed that CY could inhibit ferroptosis via the Nrf2/GPX4 axis in both in vivo and RSL3-induced Caco-2 cell models. Importantly, the antiferroptotic and protective effects of CY were nullified by Nrf2 knockout in vivo and by the use of ML385 in vitro. In conclusion, the effects of CY on UC are strongly associated with the Nrf2 pathway. CY might be a potential candidate for the treatment of UC. Therefore, our results provide an important reference for investigating the mechanisms of flavonoid compounds involved in preventing inflammatory diseases.
溃疡性结肠炎（UC）是一种慢性和复发性炎症性肠病（IBD）。UC 的发病率不断上升，但目前的常规药物疗效有限。红花黄色素（CY）是从红花中提取的一种类黄酮化合物，广泛应用于临床，具有多种药理作用。本研究通过 DSS 诱导建立小鼠结肠炎模型和 LPS 诱导 Caco-2 细胞模型，探讨 CY 对 UC 的作用及机制。结果表明，CY 治疗可减轻结肠组织病理学损伤，改善疾病活动指数（DAI）评分，从而缓解结肠炎症状。此外，我们观察到 CY 治疗可通过抑制 NLRP3/Caspase-1/IL-1β和 MAPK/NF-κB 信号通路降低促炎细胞因子（TNF-α、IL-6 和 IL-1β）水平。此外，我们发现 CY 治疗可明显改善 DSS 诱导的小鼠和 LPS 刺激的 Caco-2 细胞的肠道屏障功能。检测铁死亡相关标志物。结果表明，CY 通过抑制铁死亡缓解 DSS 诱导的结肠炎，铁死亡的抑制作用可通过铁积累、总抗氧化能力（T-AOC）和活性氧（ROS）、4-羟基壬烯醛（4-HNE）和谷胱甘肽（GSH）水平来评估。此外，超氧化物歧化酶（SOD）和过氧化氢酶（CAT）活性增加，铁死亡相关蛋白和基因表达（ACSL4、GPX4、SLC7A11、TfR1 和 FTH1）也发生改变。进一步分析表明，CY 可通过体内和 RSL3 诱导的 Caco-2 细胞模型中的 Nrf2/GPX4 轴抑制铁死亡。重要的是，体内 Nrf2 敲除和体外使用 ML385 可消除 CY 的抗铁死亡和保护作用。综上所述，CY 对 UC 的作用与 Nrf2 通路密切相关。CY 可能是治疗 UC 的潜在候选药物。因此，我们的研究结果为研究黄酮类化合物在预防炎症性疾病中的作用机制提供了重要参考。
