| 赵昱棋,焦雪菲,胡清林,高波.沙棘提取物治疗肾缺血-再灌注损伤的作用机制:基于网络药理学预测与实验验证[J].济宁医学院学报,2025,48(6):522-529 |
| 沙棘提取物治疗肾缺血-再灌注损伤的作用机制:基于网络药理学预测与实验验证 |
| Effect and mechanism of Hippophae rhamnoides L. on the treatment of renal ischemia-reperfusion injury: network pharmacology prediction and experimental validation |
| 投稿时间：2025-06-20 |
| DOI：10.3969/j.issn.1000-9760.2025.06.008 |
| 中文关键词: 沙棘;肾缺血-再灌注损伤;超高效液相色谱-四极杆-飞行时间质谱法;网络药理学;p53;HIF-1信号通路 |
| 英文关键词: Hippophae rhamnoides L.;Renal ischemia-reperfusion injury;UPLC-Q-TOF-MS/MS;Network pharmacology;p53;HIF-1 signaling pathway |
| 基金项目:济宁医学院大学生创新创业训练计划资助项目(cx2023065z) |
| 作者 | 单位 | E-mail | | 赵昱棋 | 济宁医学院药学院, 日照 276826 | | | 焦雪菲 | 济宁医学院药学院, 日照 276826 | | | 胡清林 | 济宁医学院药学院, 日照 276826 | | | 高波 | 济宁医学院药学院, 日照 276826 | gaobo69@126.com |
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| 中文摘要: |
| 目的 综合运用超高效液相色谱-四极杆-飞行时间质谱法(UPLC-Q-TOF-MS)技术、网络药理学和动物实验探讨沙棘在治疗肾缺血-再灌注损伤(renal ischemia-reperfusion injury, RIRI)的潜在作用机制。方法 运用UPLC-Q-TOF-MS技术,系统性地解析并鉴定沙棘的化学组分。应用网络药理学方法,基于筛选出的交集靶点,构建蛋白-蛋白相互作用网络图(protein-protein interaction networks,PPI)及“活性成分-靶点-通路”网络,并进行基因本体(gene ontology,GO)功能与京都基因与基因组百科全书(kyoto encyclopedia of genes and genomes,KEGG)通路富集分析,旨在发掘沙棘治疗RIRI的关键靶点。选取18只Sprague-Dawley雄性大鼠,随机均分为假手术组(Sham组)、模型组(Model组)与沙棘提取物组(H组),每组6只,构建RIRI大鼠模型,测定血浆中肌酐(Cr)、尿素氮(BUN)、谷胱甘肽(GSH)、丙二醛(MDA)水平,应用苏木素-伊红(hematoxylin-eosin,HE)染色观察肾脏组织病理学改变,免疫荧光染色检测肾脏肿瘤蛋白p53表达。结果 鉴定出沙棘中74种有效化学成分。基于TCMSP等数据库共筛选获得的429个沙棘潜在作用靶点,通过获取RIRI疾病相关靶点并取交集,共得肿瘤蛋白p53、白细胞介素-6(interleukin 6,IL-6)和肿瘤坏死因子(tumor necrosis factor,TNF)等226个交集靶点,GO功能与KEGG通路富集分析,结果显示其显著富集于缺氧诱导因子(hypoxia inducible factor-1,HIF-1)等信号通路中。动物实验结果显示,Model组与Sham组相比,大鼠血清中Cr、BUN和MDA水平明显升高,GSH水平明显下降(均P＜0.05);与Model组相比,H组处理的大鼠血清中,Cr、BUN、MDA浓度明显降低,GSH浓度明显升高,肾小管细胞内p53蛋白表达下降(均P＜0.05)。Model组大鼠肾小球皱缩,可见炎性细胞浸润,H组有少量炎性细胞聚集,肾小球形状较贴合。结论 沙棘可能通过抑制p53蛋白表达,上调HIF-1α信号通路从而减轻体内氧化应激状态,并降低大鼠RIRI中Cr和BUN浓度,改善损伤肾小管的形态和功能,治疗RIRI。 |
| 英文摘要: |
| Objective Employing advanced ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry (UPLC-Q-TOF-MS) technology,in conjunction with comprehensive network pharmacology analysis and rigorous animal experimentation,we conducted an in-depth exploration and validation of the chemical constituents and pharmacological mechanisms underlying the therapeutic efficacy of Hippophae rhamnoides L.in reducing the adverse effects associated with renal ischemia-reperfusion injury. Method UPLC-Q-TOF-MS technology was utilized to analyze the chemical components of Hippophae rhamnoides L.Using network pharmacology methods,based on the screened intersection targets,a protein-protein interaction network (PPI) and an "active component-target-pathway" network were constructed,and Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to identify the key targets of seabuckthorn in the treatment of renal ischemia-reperfusion injury.Eighteen male Sprague-Dawley rats were selected and randomly divided equally into the sham operation group (Sham group),the model group (Model group),and the seabuckthorn extract group (Group H),with 6 rats in each group.A rat model of renal ischemia-reperfusion injury (RIRI) was established.The levels of creatinine (Cr),blood urea nitrogen (BUN),glutathione (GSH),and malondialdehyde (MDA) in plasma were measured.Hematoxylin-eosin (HE) staining was used to observe the histopathological changes of renal tissue,and the expression of tumor protein p53 in the kidney was detected by immunofluorescence staining. Result 74 chemical components were identified in sea buckthorn.Network pharmacology screening based on the TCMSP database yielded 429 potential targets.Intersection with RIRI-related targets identified 226 common targets,including tumor protein p53,IL-6,and TNF.GO function and KEGG pathway enrichment analysis showed that these targets were significantly enriched in signaling pathways such as hypoxia inducible factor-1 (HIF-1).In animal experiments,compared with the Sham group,the Modole group showed that the levels of Cr,BUN and MDA were significantly increased,while the level of GSH was significantly decreased (P＜0.05).In comparison to the model group,the concentrations of Cr,BUN and MDA were significantly decreased, while the level of GSH was significantly increased in the H group.The expression of p53 protein in renal tubular cells decreased (P＜0.05).The glomerular of the model group rats were shrunken,with visible infiltration of inflammatory cells.In the H group,there was a small amount of inflammatory cell aggregation,and the shape of the glomeruli was relatively intact. Conclusion Hippophae rhamnoides L. may alleviate the oxidative stress state in the body by inhibiting the expression of p53 protein and up-regulating the HIF-1α signaling pathway, reduce the concentrations of Cr and BUN in rats with RIRI,improve the morphology and function of injured renal tubules, and thus treat RIRI. |
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