State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China.
Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250000, China.
Nutrients. 2024 Jul 19;16(14):2343. doi: 10.3390/nu16142343.
Hesperetin (HT) is a type of citrus flavonoid with various pharmacological activities, including anti-tumor, anti-inflammation, antioxidant, and neuroprotective properties. However, the role and mechanism of HT in ulcerative colitis (UC) have been rarely studied. Our study aimed to uncover the beneficial effects of HT and its detailed mechanism in UC. Experimental colitis was induced by 2.5% dextran sodium sulfate (DSS) for seven days. HT ameliorated DSS-induced colitis in mice, showing marked improvement in weight loss, colon length, colonic pathological severity, and the levels of TNFα and IL6 in serum. A combination of informatics, network pharmacology, and molecular docking identified eight key targets and multi-pathways influenced by HT in UC. As a highlight, the experimental validation demonstrated that PTGS2, a marker of ferroptosis, along with other indicators of ferroptosis (such as ACSL4, Gpx4, and lipid peroxidation), were regulated by HT in vivo and in vitro. Additionally, the supplement of HT increased the diversity of gut microbiota, decreased the relative abundance of Proteobacteria and Gammaproteobacteria, and restored beneficial bacteria (Lachnospiraceae_NK4A136_group and Prevotellaceae_UCG-001). In conclusion, HT is an effective nutritional supplement against experimental colitis by suppressing ferroptosis and modulating gut microbiota.
橙皮素（HT）是一种柑橘类黄酮，具有多种药理活性，包括抗肿瘤、抗炎、抗氧化和神经保护作用。然而，HT 在溃疡性结肠炎（UC）中的作用和机制很少被研究。我们的研究旨在揭示 HT 在 UC 中的有益作用及其详细机制。通过 2.5%葡聚糖硫酸钠（DSS）诱导实验性结肠炎 7 天。HT 改善了 DSS 诱导的小鼠结肠炎，体重减轻、结肠长度、结肠病理严重程度以及 TNFα 和 IL6 在血清中的水平均有明显改善。通过信息学、网络药理学和分子对接的组合，确定了 HT 在 UC 中影响的 8 个关键靶标和多途径。值得一提的是，实验验证表明，PTGS2（铁死亡的标志物）以及其他铁死亡指标（如 ACSL4、Gpx4 和脂质过氧化）在体内和体外均受 HT 调节。此外，HT 的补充增加了肠道微生物群的多样性，降低了变形菌门和γ变形菌门的相对丰度，并恢复了有益细菌（Lachnospiraceae_NK4A136_group 和 Prevotellaceae_UCG-001）。总之，HT 通过抑制铁死亡和调节肠道微生物群，是一种有效的营养补充剂，可用于治疗实验性结肠炎。
