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中华肾病研究电子杂志

中华肾病研究电子杂志 ›› 2021, Vol. 10 ›› Issue (04) : 181 -188. doi: 10.3877/cma.j.issn.2095-3216.2021.04.001

论著

基于网络药理学探讨益肾化湿颗粒治疗慢性肾小球肾炎的机制
胡天祥1, 黄贵锐2, 毛炜3, 黎创4,†(), 徐鹏4, 田瑞敏4, 谢晨5   
  1. 1. 510120　省部共建中医湿证国家重点实验室，广州中医药大学第二附属医院；510120　广州，广东省中医院，中医思维研究室
    2. 100029　北京中医药大学第三附属医院呼吸科
    3. 510120　省部共建中医湿证国家重点实验室，广州中医药大学第二附属医院；510120　广东省中医院肾科；510120　广东省中医证候临床研究重点实验室
    4. 510120　省部共建中医湿证国家重点实验室，广州中医药大学第二附属医院；510120　广东省中医院肾科；510120　广东省中医药防治难治性慢病重点实验室
    5. 100039　北京市中西医结合医院肾内科
  • 收稿日期:2021-02-19 出版日期:2021-08-26
  • 通信作者: 黎创
  • 基金资助:
    省部共建中医湿证国家重点实验室课题(SZ2020ZZ05, SZ2020ZZ04, SZ2021ZZ10, SZ2021ZZ11, SZ2021ZZ50); 国家自然科学基金(81173378); 广州中医药大学"双一流"与高水平大学学科协同创新团队项目(2021XK12); 广东省中医药局科研项目(20201140)

Network pharmacology-based study on the mechanism of Yishen-Huashi-Granules in the treatment of chronic glomerulonephritis

Tianxiang Hu1, Guirui Huang2, Wei Mao3, Chuang Li4,†(), Peng Xu4, Ruimin Tian4, Chen Xie5   

  1. 1. State Key Laboratory of Dampness Syndrome of Traditional Chinese Medicine, Second Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510120, Guangdong Province; Chinese Medicine Thinking Research Office, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, Guangdong Province
    2. Department of Respiratory, Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing 100029
    3. State Key Laboratory of Dampness Syndrome of Traditional Chinese Medicine, Second Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510120, Guangdong Province; Department of Nephrology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, Guangdong Province; Guangdong Provincial Key Laboratory of Chinese Medicine Syndrome Clinical Research, Guangzhou 510120, Guangdong Province
    4. State Key Laboratory of Dampness Syndrome of Traditional Chinese Medicine, Second Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510120, Guangdong Province; Department of Nephrology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, Guangdong Province; Guangdong Provincial Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, Guangzhou 510120, Guangdong Province
    5. Department of Nephrology, Beijing Hospital of Integrated Traditional and Western Medicine, Beijing 100039; China
  • Received:2021-02-19 Published:2021-08-26
  • Corresponding author: Chuang Li
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引用本文：

胡天祥, 黄贵锐, 毛炜, 黎创, 徐鹏, 田瑞敏, 谢晨. 基于网络药理学探讨益肾化湿颗粒治疗慢性肾小球肾炎的机制[J]. 中华肾病研究电子杂志, 2021, 10(04): 181-188.

Tianxiang Hu, Guirui Huang, Wei Mao, Chuang Li, Peng Xu, Ruimin Tian, Chen Xie. Network pharmacology-based study on the mechanism of Yishen-Huashi-Granules in the treatment of chronic glomerulonephritis[J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2021, 10(04): 181-188.

目的

基于网络药理学探讨益肾化湿颗粒治疗慢性肾小球肾炎的有效成分、潜在靶点及通路，并阐述其作用机制。

方法

通过传统中药系统药理学数据库和分析平台(TCMSP)，建立益肾化湿颗粒有效成分与靶点数据库。利用人类基因数据库(GeneCards)、人类孟德尔遗传综合数据库(OMIM)、遗传药理学与药物基因组学数据库(Pharm GKB)、治疗靶标数据库(TTD)和药物作用靶点数据库(DrugBank)，筛选慢性肾小球肾炎相关基因及靶点。利用蛋白质相互作用数据库(STRING)进行蛋白质-蛋白质相互作用分析，筛选蛋白互作(PPI)网络得到核心基因。利用Cytoscape软件构建"关键活性成分-核心靶基因"网络。最后，利用基因本体(GO)数据库进行功能富集分析，利用京都基因与基因组百科全书(KEGG)数据库进行信号通路分析。

结果

筛选出258个中药活性成分靶基因，2 143个慢性肾小球肾炎靶基因，132个治疗慢性肾小球肾炎的益肾化湿颗粒活性成分靶基因。其中，核心靶基因分别是原癌基因FOS、丝裂原活化蛋白激酶(MAPK8、MAPK3、MAPK14、MAPK1)、原癌基因JUN等。177个益肾化湿颗粒有效活性成分与治疗慢性肾小球肾炎相关。GO功能富集分析提示，益肾化湿颗粒主要参与11种分子功能、10项生物学过程。KEGG通路富集分析显示，益肾化湿颗粒治疗慢性肾小球肾炎主要涉及糖基化终末产物及其受体(AGE-RAGE)、肿瘤坏死因子(TNF)、白介素17(IL-17)、低氧诱导因子-1(HIF-1)、Toll样受体等信号通路。

结论

益肾化湿颗粒可通过槲皮素、柚皮素、山奈酚、黄芩素等有效成分，调节原癌基因等靶点，介导FOS、MAPK、AGE-RAGE、HIF-1等相关通路，从而影响机体的免疫调节、抗炎、抗氧化等过程，发挥治疗慢性肾小球肾炎作用。益肾化湿颗粒的多成分、多靶点、多通路的整体性调节作用和潜在目标，为今后深入探寻机制与应用提供了研究基础。

关键词: 益肾化湿颗粒, 慢性肾小球肾炎, 网络药理学, 靶点, 机制
Objective

To explore the effective components, potential targets, pathways, and the mechanism of Yishen-Huashi-Granules in the treatment of chronic glomerulonephritis by means of network pharmacology.

Methods

Through use of the analysis platform of the Traditional Chinese Medicine Systems Pharmacology (TCMSP), a database was established for the active ingredients and targets of the Yishen-Huashi-Granules. Screening of the chronic glomerulonephritis-related genes and targets was performed with the human gene database (GeneCards), the database of Online Mendelian Inheritance in Man (OMIM), the Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB), the Therapeutic Target Database (TTD), and drug action target database (DrugBank). The protein-protein association database (STRING) was used to analyze the protein-protein interaction, and the core genes were obtained from screening of the Protein-Protein Interaction(PPI) network. By use of the Cytoscape software, a "key active ingredient-core target gene" network was constructed. Finally, the gene ontology (GO) database was applied to perform the function enrichment analysis, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used for signal pathway analysis.

Results

The screening found out 258 target genes for active ingredients of traditional Chinese medicine, 2143 target genes for chronic glomerulonephritis, and 132 target genes for active ingredients of Yishen-Huashi-Granules in the treatment of chronic glomerulonephritis. Among these, the core target genes were the proto-oncogene FOS, mitogen-activated protein kinases (MAPK8, MAPK3, MAPK14, MAPK1), and the proto-oncogene JUN, etc. 177 active ingredients of Yishen-Huashi-Granules were related to the treatment of chronic glomerulonephritis. The GO function enrichment analysis indicated that the Yishen-Huashi-Granules were mainly involved in 11 molecular functions and 10 biological processes. The KEGG pathway enrichment analysis showed that the treatment of chronic glomerulonephritis by Yishen-Huashi-Granules mainly involved signal molecules including the advanced glycation end products (AGEs) and the receptor for AGE (RAGE), tumor necrosis factor (TNF), interleukin-17 (IL-17), hypoxia inducible factor-1 (HIF-1), and Toll-like receptors, etc.

Conclusion

Through quercetin, naringenin, kaempferol, baicalein, and other active ingredients, the Yishen-Huashi-Granules could regulate targets as proto-oncogenes, mediate the FOS, MAPK, AGE-RAGE, HIF-1, and other related pathways, and affect the body′s immune regulation, anti-inflammatory, antioxidant, and other processes, playing a role in the treatment of chronic glomerulonephritis. The Yishen-Huashi-Granules′ integral regulation of multi-ingredient, multi-target, and multi-pathway as well as the potential goals may provide a research foundation for the in-depth exploration of the mechanisms and applications in the future.

Key words: Yishen-Huashi-Granules, Chronic glomerulonephritis, Network pharmacology, Targets, Mechanism
表1 益肾化湿颗粒活性成分及其对应的靶基因数目
药物 活性成分(个) 成分对应靶基因(个)
人参 22 748
黄芪 20 953
白术 7 774
茯苓 15 121
泽泻 10 165
半夏 13 1 302
羌活 15 1 243
独活 9 650
防风 18 1 931
柴胡 17 2 737
黄连 14 596
白芍 13 990
陈皮 5 479
甘草 92 2 506
生姜 5 2 225
大枣 29 1 329
图1 疾病数据库获取慢性肾小球肾炎相关基因韦恩分析图
图2 益肾化湿颗粒治疗慢性肾小球肾炎靶基因韦恩分析图
图3 蛋白互作(PPI)网络的关键蛋白筛选过程
表2 益肾化湿颗粒治疗慢性肾小球肾炎相关的核心活性成分
名称 有效成分ID 药物成分(英文名称) 药物成分(中文名称) 口服利用吸收度(%) 类药性
甘草 MOL004891 shinpterocarpin   80.30 0.73
  MOL004328 naringenin 柚皮素 59.29 0.21
  MOL000098 quercetin 槲皮素 46.43 0.28
  MOL003896 7-methoxy-2-methyl isoflavone 7-甲氧基-2-甲基异黄酮 42.56 0.20
  MOL000422 kaempferol 山柰酚 41.88 0.24
  MOL000497 licochalcone-A 甘草查耳酮甲 40.79 0.29
黄芪 MOL000378 7-O-methylisomucronulatol   74.69 0.30
  MOL000098 quercetin 槲皮素 46.43 0.28
  MOL000422 kaempferol 山柰酚 41.88 0.24
柴胡 MOL000098 quercetin 槲皮素 46.43 0.28
  MOL000422 kaempferol 山柰酚 41.88 0.24
陈皮 MOL004328 naringenin 柚皮素 59.29 0.21
  MOL005828 nobiletin 川陈皮素 61.67 0.52
白芍 MOL000422 kaempferol 山柰酚 41.88 0.24
半夏 MOL002714 baicalein 黄芩素 33.52 0.21
大枣 MOL000098 quercetin 槲皮素 46.43 0.28
防风 MOL000173 wogonin 汉黄芩素 30.68 0.23
黄连 MOL000098 quercetin 槲皮素 46.43 0.28
人参 MOL000422 kaempferol 山柰酚 41.88 0.24
图4 "核心成分-关键靶基因"网络
图5 GO功能富集分析益肾化湿颗粒治疗慢性肾小球肾炎的关键靶点
图6 KEGG功能富集分析益肾化湿颗粒治疗慢性肾小球肾炎的关键靶点
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