基于网络药理学的方法研究扶肾颗粒对慢性肾功能衰竭肠屏障损伤的作用机制,Evidence-based Complementary and Alternative Medicine

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基于网络药理学的方法研究扶肾颗粒对慢性肾功能衰竭肠屏障损伤的作用机制
Evidence-based Complementary and Alternative Medicine ( IF 2.650 ) Pub Date : 2021-03-05 , DOI: 10.1155/2021/2097569
Miaoru Han ₁ , Hangxing Yu ₁ , Kang Yang ₁ , Panying Liu ₁ , Haifeng Yan ₁ , Zhihua Yang ₁ , Hongtao Yang ₁

Affiliation

目的。扶肾颗粒（FSG）是一种由医生配制的中药，用于治疗慢性肾功能衰竭患者，通常伴有胃肠功能障碍。在此，我们通过生物信息学分析和实验验证，探讨FSG对慢性肾功能衰竭肠屏障损伤的保护作用。方法. 在这项研究中，收集了与 CRF 相关的 FSG 成分和靶点的信息，以使用网络药理学方法构建和可视化蛋白质-蛋白质相互作用网络和药物-化合物-靶点网络。DAVID用于进行基因本体（GO）富集分析和京都基因和基因组百科全书（KEGG）通路富集分析。然后，通过体外实验对其进行验证。本研究使用人肠上皮（T84）细胞，分为四组：对照组、模型组、FSG低剂量组、FSG高剂量组。实验结束后，MTT法检测T84细胞的活性，紧密连接蛋白ZO-1、claudin-1、核因子红细胞2相关因子（Nrf2）、血红素加氧酶-通过免疫荧光和/或蛋白质印迹检查1 (HO-1)、丙二醛 (MDA) 和环氧合酶- 2 (COX-2)。结果. FSG 确定了 86 个潜在的慢性肾功能衰竭相关靶点；其中筛选出9个核心基因。此外，GO富集分析表明，癌症相关信号通路、PI3K-Akt信号通路、HIF1信号通路和TNF信号通路可能在FSG治疗CRF中起关键作用。MTT方法表明FSG对尿毒症毒素诱导的损伤T84细胞没有细胞毒性。免疫荧光和WB结果表明，与对照组相比，T84细胞中ZO-1、claudin-1、Nrf2蛋白表达水平降低，HO-1、MDA、COX-2蛋白表达水平升高。尿毒治疗后。相反，与模型组相比，ZO-1、claudin-1、结论。FSG对慢性肾功能衰竭尿毒引起的肠上皮屏障损伤具有保护作用，其机制可能与上调Nrf2/HO-1信号转导、抑制组织氧化应激和炎症反应有关。通过网络药理学方法筛选CRF靶点并识别相应的FSG成分是解释FSG改善CRF胃肠功能障碍机制的实用策略。

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A Network Pharmacology-Based Approach to Investigating the Mechanisms of Fushen Granule Effects on Intestinal Barrier Injury in Chronic Renal Failure

Purpose. Fushen Granule (FSG) is a Chinese medicine prepared by doctors for treating patients with chronic renal failure, which is usually accompanied by gastrointestinal dysfunction. Here, we explore the protective effect of FSG on intestinal barrier injury in chronic renal failure through bioinformatic analysis and experimental verification. Methods. In this study, information on the components and targets of FSG related to CRF is collected to construct and visualize protein-protein interaction networks and drug-compound-target networks using network pharmacological methods. DAVID is used to conduct gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Then, it is validated by in vitro experiments. In this study, the human intestinal epithelial (T84) cells are used and divided into four groups: control group, model group, FSG low-dose group, and FSG high-dose group. After the experiment, the activity of T84 cells is detected by a MTT assay, and the expressions of tight junction protein ZO-1, claudin-1, nuclear factor erythroid 2-related factor (Nrf2), heme oxygenase-1 (HO-1), malondialdehyde (MDA), and cyclooxygenase-2 (COX-2) are examined by immunofluorescence and/or western blotting. Results. Eighty-six potential chronic renal failure-related targets are identified by FSG; among them, nine core genes are screened. Furthermore, GO enrichment analysis shows that the cancer-related signaling pathway, the PI3K-Akt signaling pathway, the HIF1 signaling pathway, and the TNF signaling pathway may play key roles in the treatment of CRF by FSG. The MTT method showed that FSG is not cytotoxic to uremic toxin-induced injured T84 cells. The results of immunofluorescence and WB indicate that compared with the control group, protein expressions level of ZO-1, claudin-1, and Nrf2 in T84 cells is decreased and protein expressions level of HO-1, MDA, and COX-2 is increased after urinary toxin treatment. Instead, compared with the model group, protein expressions level of ZO-1, claudin-1, and Nrf2 in T84 cells is increased and protein expressions level of HO-1, MDA, and COX-2 is decreased after FSG treatment. Conclusion. FSG had a protective effect on urinary toxin-induced intestinal epithelial barrier injury in chronic renal failure, and its mechanism may be related to the upregulation of Nrf2/HO-1 signal transduction and the inhibition of tissue oxidative stress and inflammatory responses. Screening CRF targets and identifying the corresponding FSG components by network pharmacological methods is a practical strategy to explain the mechanism of FSG in improving gastrointestinal dysfunction in CRF.

更新日期：2021-03-05

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