地榆通过影响PPARG和SLC7A11/GPX4表达减轻溃疡性结肠炎小鼠损伤
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河北医科大学 药学院

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国家自然科学基金资助项目(82003913);河北省高等学校科学技术研究项目(BJK2024082);河北省自然科学基金资助项目(H2020206010);河北省中医药管理局项目(2021120)


Sanguisorbae Radix alleviates damage in Ulcerative Colitis Mice Based on PPARG and SCL7A11/GPX4
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1.College of Pharmacy,Hebei Medical University,Shijiazhuang,050017;2.Hebei,China;3.College of Pharmacy,Hebei Medical University

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The National Natural Science Foundation of China (General Program, Key Program, Major Research Plan)

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    摘要:

    目的:基于生物信息学探究地榆(Sanguisorbae Radix,SR)改善小鼠溃疡性结肠炎的机制。方法:利用R语言对高通量基因表达数据库(GEO)中GSE92415数据集进行溃疡性结肠炎(UC)差异表达基因筛选和加权基因共表达网络分析(WGCNA),并结合FerrDb数据库,获得UC相关铁死亡特征基因。对特征基因进行蛋白互作分析(PPI)和相关性分析,筛选UC铁死亡核心基因。构建葡聚糖硫酸钠(DSS)诱导的UC小鼠模型,并灌胃给予SR水提物9 d,记录疾病活动指数(DAI)和结肠长度,采用HE染色法观察结肠组织病理变化,酶联免疫吸附测定法(ELISA)检测小鼠结肠组织炎症因子肿瘤坏死因子(TNF)-α、白细胞介素-6(IL-6)和脂质过氧化因子丙二醛(MDA)、谷胱甘肽(GSH)水平,免疫荧光法检测结肠组织闭锁小带蛋白1(ZO-1)表达,蛋白免疫印迹法(Western blotting)检测结肠组织过氧化物酶体增殖物激活受体γ(PPARG)、溶质载体家族7成员11(SLC7A1)和谷胱甘肽过氧化酶4(GPX4)蛋白表达。结果:通过生物信息学筛选得到9个UC相关铁死亡特征基因,其中核心基因为PPARG。相关性分析发现PPARG与铁死亡高度相关。结合生物信息学筛选结果,探讨SR改善小鼠UC的机制,实验结果发现,SR可降低UC小鼠DAI值,缓解结肠缩短,改善肠道粘膜屏障功能,对TNF-α、IL-6、MDA、GSH水平有显著回调作用,并可提高结肠组织PPARG、SLC7A11和GPX4蛋白表达。结论:铁死亡与UC密切相关,SR可通过影响PPARG 和SCL7A11/GPX4蛋白,进而改善UC小鼠结肠上皮损伤和功能障碍,为UC治疗策略提供了思路与方向。

    Abstract:

    Objective: To investigate the mechanism of Sanguisorbae Radix (SR) in the treatment of Ulcerative Colitis (UC). Methods: The study analyzed GSE92415 from the Gene Expression Omnibus (GEO) database using differentially expressed genes analysis, weighted gene correlation network analysis (WGCNA) and FerrDb. Core genes were identified through protein-protein interaction (PPI) network and correlation analysis. The efficacy of SR in UC was evaluated in a dextran sodium sulphate (DSS)-induced colonic inflammatory mouse model by analyzing DAI, histopathology and colon length. ELISA was used to examine levels of inflammatory cytokines and lipid peroxidation. The expression levels of ZO-1 tight junction protein, PPARG, SLC7A11 and GPX4 protein were examined through Western blotting or immunofluorescence labeling. Results:S Nine differentially expressed genes associated with ferroptosis were screened and PPARG was identified as a key gene. The experimental animal results showed that SR significantly prevented colon shortening and ameliorated histological injuries of colons in DSS-treated mice. SR inhibited cytokine levels of IL-6 and TNF-α, improved the reduction of ZO-1 and levels of MDA and GSH in colon tissues of DSS mice. Meanwhile, it enhanced the activation of PPARG, SLC7A11 and GPX4, which reversed the therapeutic effect of DSS in mice with colitis. Conclusion: Iron death is closely related to UC. SR can inhibit iron death by regulating the PPARG and SCL7A11/GPX4 expression, thereby improving colon epithelial injury and dysfunction in UC mice. This provides ideas and direction for UC treatment strategies.

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  • 收稿日期:2024-02-07
  • 最后修改日期:2024-03-14
  • 录用日期:2024-04-16
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