[关键词]
[摘要]
目的 考察龙血竭(CDB)对葡聚糖硫酸钠(DSS)诱导的小鼠溃疡性结肠炎(UC)的作用,以及通过网络药理学预测CDB潜在的主要活性成分、作用靶点、信号通路。方法 利用DSS诱导小鼠UC模型。Balb/c小鼠随机分为对照组,模型组,CDB组高、中、低剂量组及美沙拉嗪对照组,每组10只。除对照组外,各组小鼠自由饮用3.0% DSS溶液,连续7 d,CDB组、美沙拉嗪组在造模期间ig给予对应的药物,每天称量小鼠体质量,进行隐血实验,观察动物粪便性状,进行DAI评分,实验末处死小鼠,取结肠进行HE染色并评分。通过TCMSP、String、Cytoscape等在线数据库构建"化合物-化合物靶点-疾病靶点"网络,提取核心化合物靶点、化合物作用的疾病靶点,对相关靶点进行GO、KEGG富集分析,分析CDB治疗UC可能调控的生物过程及作用机制。结果 与对照组比较,模型组小鼠炎症细胞浸润明显,大量杯细胞消失,病变程度波及肌层甚至全层;CDB组大鼠杯细胞重新长出,病变程度仅限于黏膜层,炎症减轻。通过网络药理学筛选出CDB的作用靶点112个,其中ABL1、F2、JAK2等14个核心化合物靶点可作用于ICAM1、IL-6、PTGS2、MTOR等11个疾病靶点。GO分析中包含415条富集通路,其中生物过程389条,分子功能9条,细胞组成17条。利用KEGG数据库对入选靶点进行相关通路富集,筛选出84条通路与UC有关。结论 CDB可以缓解DSS诱导的UC小鼠结肠黏膜损伤,可能通过剑叶龙血素C等黄酮类成分调控ABL1、F2、JAK2等靶点表达,然后间接调控IL-6、PTGS2等疾病蛋白表达,进而干预JAK2/STAT3、PI3K-Akt-mTOR通路,调节炎症因子的水平,抑制炎症反应,最终缓解UC小鼠结肠黏膜损伤。
[Key word]
[Abstract]
Objective To investigate the effects of Chinese Dragon's Blood (CDB) on DSS-induced ulcerative colitis (UC) in mice, and predict the potential main active ingredients, targets and signaling pathways of CDB by network pharmacology. Methods Mouse UC model was induced by DSS. Balb/c mice were randomly divided into control group, UC group, CDB high, medium, and low dose group, mesalazine control group, 10 mice in each group. Except the control group, each group drank 3.0% DSS solution freely for seven consecutive days. The CDB group and mesalazine group were given corresponding medicines for gastric perfusion during the modeling period. The mice were weighed regularly every day to conduct occult blood test and observe the animals. The fecal traits were evaluated by DAI. At the end of the experiment, the mice were sacrificed and HE stained and scored. The "compound-compound target-disease target" network was constructed by online databases such as TCMSP, String, Cytoscape, etc, and the target targets of core compound targets and compounds were extracted, GO and KEGG enrichment analysis was performed on related targets. Treatment of biological processes and mechanisms of action that UC may regulate were analyzed. Results Compared with the control group, the infiltration of inflammatory cells in the model group was obvious, and a large number of cup cells disappeared, and the degree of lesions spread to the muscle layer or even the whole layer; The cup cells in the CDB group re-grew, the extent of the lesion was limited to the mucosa, and the inflammation was alleviated. Through the network pharmacology, 112 target targets of CDB were screened, and 14 core compound targets such as ABL1, F2, and JAK2 could be applied to 11 disease targets such as ICAM1, IL-6, PTGS2, and MTOR. The GO analysis contained 415 enrichment pathways, including 389 biological processes, nine molecular functions, and 17 cell components. The KEGG database was used to enrich the relevant pathways, and 84 pathways such as PI3K-Akt were screened for UC. Conclusion CDB can alleviate colonic mucosal injury induced by DSS in UC mice. It may regulate the expression of ABL1, F2, JAK2 and other target proteins through flavonoids, and then indirectly regulate the expression of IL-6, PTGS2 and other disease proteins. The JAK2/STAT3 and PI3K-Akt-mTOR pathways regulate the levels of inflammatory factors, inhibit the inflammatory response, and ultimately alleviate UC colonic mucosal damage.
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[基金项目]
广西自然科学基金资助项目(2017GXNSFAA198078);国家自然科学基金资助项目(81560674);国家自然科学基金资助项目(81960872);2019年广西高校中青年教师科研基础能力提升项目(2019KY0319)