First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
College of Integrative Medicine, Dalian Medical University, Dalian, 116011, China.
Food Funct. 2024 May 7;15(9):4970-4982. doi: 10.1039/d3fo04500e.
Inhibition of ferroptosis in intestinal epithelial cells serves as an attractive target for the development of therapeutic strategies for colitis. Pinobanksin, one of the main flavonoids derived from propolis, possesses significant anti-inflammatory effects and inhibits the cell death of several cell lines. Here, we evaluated whether pinobanksin influenced colitis by modulation of epithelial ferroptosis. Mice treated with 2.5% DSS dissolved in sterile distilled water were established for an acute colitis model. The mitochondrial morphology, colonic iron level, lipid peroxidation products MDA/4-HNE, and lipid reactive oxygen species levels were measured to assess ferroptosis in epithelial cells. RNA-seq and functional analyses were performed to reveal key genes mediating pinobanksin-exerted modulation of ferroptosis. We found that pinobanksin, at different doses, induced significant anti-colitis effects and inhibited the elevated ferroptosis in colonic epithelial cells isolated from DSS-treated mice largely by activating GPX4 (negative regulator of ferroptosis). Furthermore, RNA-seq assays indicated that pinobanksin significantly increased the cystine transporter SLC7A11 in colonic tissues from mice with colitis. Depletion of SLC7A11 largely blocked pinobanksin-induced promotion of cystine uptake/glutathione biosynthesis and suppression of ferroptosis in epithelial cells from mice with colitis or IEC-6 cells pretreated with RSL3. Altogether, pinobanksin alleviated DSS-induced colitis largely by inhibition of ferroptosis in epithelial cells. Activation of SLC7A11 by pinobanksin resulted in the promotion of cystine uptake and enhancement of glutathione biosynthesis. This work will provide novel guidance for the clinical use of pinobanksin to treat colitis through inhibition of epithelial ferroptosis.
抑制肠上皮细胞中的铁死亡可作为开发结肠炎治疗策略的一个有吸引力的靶点。Pinobanksin 是从蜂胶中提取的主要类黄酮之一，具有显著的抗炎作用，并抑制几种细胞系的细胞死亡。在这里，我们评估了 Pinobanksin 是否通过调节上皮细胞铁死亡来影响结肠炎。用无菌蒸馏水溶解的 2.5% DSS 处理小鼠以建立急性结肠炎模型。测量线粒体形态、结肠铁水平、脂质过氧化产物 MDA/4-HNE 和脂质活性氧水平，以评估上皮细胞中的铁死亡。进行 RNA-seq 和功能分析以揭示介导 Pinobanksin 调节铁死亡的关键基因。我们发现，Pinobanksin 在不同剂量下可显著诱导抗结肠炎作用，并通过激活 GPX4（铁死亡的负调节剂）抑制 DSS 处理的小鼠结肠上皮细胞中升高的铁死亡。此外，RNA-seq 分析表明，Pinobanksin 可显著增加结肠炎小鼠结肠组织中的胱氨酸转运体 SLC7A11。SLC7A11 的耗竭在很大程度上阻断了 Pinobanksin 诱导的结肠炎小鼠或用 RSL3 预处理的 IEC-6 细胞中胱氨酸摄取/谷胱甘肽合成的促进和铁死亡的抑制。总之，Pinobanksin 通过抑制上皮细胞中的铁死亡来缓解 DSS 诱导的结肠炎。Pinobanksin 通过激活 SLC7A11 促进胱氨酸摄取并增强谷胱甘肽合成。这项工作将为通过抑制上皮细胞铁死亡来临床使用 Pinobanksin 治疗结肠炎提供新的指导。
