基于网络药理学和分子对接技术探讨雷公藤致急性肾损伤的多重作用机制

doi:10.5246/jcps.2021.07.044

中国药学(英文版) ›› 2021, Vol. 30 ›› Issue (7): 556-569.DOI: 10.5246/jcps.2021.07.044

基于网络药理学和分子对接技术探讨雷公藤致急性肾损伤的多重作用机制

李成¹, 朱玉华¹, 孙晓旻¹, 许静¹, 熊丹¹, 王娟¹, 高新庐¹, 陈绪龙¹^,²^,^*()

1. 九江学院附属医院, 江西九江 332000
2. 江西中医药大学现代中药制剂教育部重点实验室, 江西南昌 330004

收稿日期:2021-02-16 修回日期:2021-04-15 接受日期:2021-04-25 出版日期:2021-07-27 发布日期:2021-07-27
通讯作者: 陈绪龙
作者简介:
+ Tel.: +86-791-87118658, E-mail: cxl_0517@163.com
基金资助:
The Science Foundation of Health and Family Planning Commission of Jiangxi Province (Grant No. 20181140) and the Science and Technology Research Project of Jiangxi Provincial Department of Education (Grant No. 201819, 180919).

The multiple mechanisms of tripterygium wilfordii-induced acute kidney injury based on network pharmacology and molecular docking

Cheng Li¹, Yuhua Zhu¹, Xiaomin Sun¹, Jing Xu¹, Dan Xiong¹, Juan Wang¹, Xinlu Gao¹, Xulong Chen¹^,²^,^*()

1 Affiliated Hospital, Jiujiang University, Jiujiang 332000, China
2 Key Laboratory of Modern traditional Chinese Medicine preparations, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China

Received:2021-02-16 Revised:2021-04-15 Accepted:2021-04-25 Online:2021-07-27 Published:2021-07-27
Contact: Xulong Chen

摘要/Abstract

摘要：

急性肾损伤(Acute kidney injury, AKI)是一个严重的健康问题, 发病率和死亡率都在增加。雷公藤(Tripterygium wilfordii, TW)是一种传统的中药, 已被报道可引起肾脏损伤。然而, TW诱导AKI的相关机制尚不清楚。因此, 本研究旨在利用网络药理学和生物信息学技术揭示TW诱导AKI的相关机制。利用TCMSP和CTD数据库对TW的候选化合物和潜在靶标进行筛选, 通过DisGeNET获取AKI相关靶标基因, 取两靶点交集获取雷公藤致AKI的潜在作用靶点。借助STRING数据库软件绘制蛋白相互作用网络(Protein-protein interaction, PPI), 使用Cytoscape3.8.0软件构建"疾病-靶点-成分-通路" 网络图, 采用DAVID生物信息数据库对交集靶点进行GO (Gene ontology)功能、KEGG (Kyoto encyclopedia of genes and genomes)通路的富集分析。最后利用vina1.1.2进行分子对接, 验证了活性化合物和关键靶点的结合能力。文章确定了TW诱导AKI的关键化合物和关键靶点, 包括雷公藤甲素、山奈酚、β谷甾醇、蜜桔黄素、豆甾醇、TNF等。GO富集分析显示雷公藤诱导AKI主要涉及细胞凋亡、氧化应激及炎症反应等生物过程。此外, 还发现了8条相关的信号通路, 包括HIF-1信号通路、VEGF信号通路、凋亡通路等。分子对接结果表明, 核心化合物与基因靶点相应蛋白的亲和力较好。本文从网络药理学的角度初步预测了TW诱导AKI的核心毒性化合物, 靶点及相关途径, 为TW后续临床合理用药及相关研究工作提供理论依据。

关键词: 雷公藤, 急性肾损伤, 生物学机制, 网络药理学, 分子对接

Abstract:

Acute kidney injury (AKI) is a common and serious health issue with a growing incidence and mortality rate. Tripterygium wilfordii (TW) is a traditional Chinese medicine that has been reported to cause kidney damage. However, the associated mechanism of TW-induced AKI remains unclear. Therefore, we aimed to uncover the associated mechanisms of AKI induced by TW using network pharmacology and bioinformatics. The candidate compounds of TW and the potential targets were screened using TCMSP and CTD database, and the AKI-related targets were identified from the DisGeNET database. The disease targets were intersected with the drug targets, and the Wayne diagram was drawn by Venny2.1.0 software. We developed protein-protein interactions (PPI) network and the "disease-compound-target-pathway" network through the Cytoscape software. By using the DAVID database, GO and KEGG enrichment analysis was carried out to reveal the potential signaling pathways of the compound-TW-induced AKI. Meanwhile, the Auto dock vina 1.1.2 was used for molecular docking to verify the active compound and key targets’ binding ability. Critical compounds and key targets of TW-induced AKI were identified, including triptolide, kaempferol, β-sitosterol, nobiletin, stigmasterol, TNF, and so on. The GO analysis showed that potential genes’ biological function was mainly involved in apoptosis, oxidative stress, and inflammation. Moreover, eight signaling pathways were found, including the HIF-1 signaling pathway, VEGF signaling pathway, apoptosis, and so on. The molecular docking results proved that the core compound’s affinity with the corresponding protein of the gene targets was good. This study preliminarily predicted the core toxic compounds, targets, and related pathways of TW-induced AKI, providing a theoretical basis for the follow-up clinical rational drug use and related research work of TW.

Key words: Tripterygium wilfordii, Acute renal injury, Biological mechanism, Network pharmacology, Molecular docking

Supporting:

李成, 朱玉华, 孙晓旻, 许静, 熊丹, 王娟, 高新庐, 陈绪龙. 基于网络药理学和分子对接技术探讨雷公藤致急性肾损伤的多重作用机制[J]. 中国药学(英文版), 2021, 30(7): 556-569.

Cheng Li, Yuhua Zhu, Xiaomin Sun, Jing Xu, Dan Xiong, Juan Wang, Xinlu Gao, Xulong Chen. The multiple mechanisms of tripterygium wilfordii-induced acute kidney injury based on network pharmacology and molecular docking[J]. Journal of Chinese Pharmaceutical Sciences, 2021, 30(7): 556-569.

图/表 12

Figure 1. Flowchart of the current study. GO, Gene Ontology; PPI, protein-protein interaction; D-T-C-P, Drug-Target-Components-Pathway.

Table 1. The 29 compounds from TW and corresponding OB and DL.

Figure 2. Venn diagram of targets of TW and AKI.

Figure 3. Network diagram of drug-disease target interactions.

Table 2. Basic information on the key targets of TW.

Figure 4. TW inducing AKI "disease-component-target-pathway" network diagram. The red square is the disease, the green circle is the target genes, the blue arrow is the chemical component, the pink triangle is the pathway, and the line represents each side, indicating the interaction between each other.

Table 3. The BP of compound-TW-induced AKI.

Figure 5. Histogram of GO function enrichment analysis.

Figure 6. Bubble diagram of KEGG pathway enrichment analysis.

Table 4. Target enrichment pathway of compound-TW-induced AKI.

Table 5. Molecular docking results of the core compounds in TW.

Figure 7. (A) Intersection of compound-TW-induced-AKI-target network; (B) Molecular docking between targets of TW-induced AKI and core compounds.

参考文献 41

[1]	Jiang, L.; Zhu, Y.; Luo, X.; Wen, Y.; Du, B.; Wang, M.; Zhao, Z.; Yin, Y.; Zhu, B.; Xi, X.; Beijing Acute Kidney Injury Trial (BAKIT) workgroup Epidemiology of acute kidney injury in intensive care units in Beijing: the multi-center BAKIT study. BMC Nephrol. 2019, 20, 468.
[2]	Ikizler, T.A.; Parikh, C.R.; Himmelfarb, J.; Chinchilli, V.M.; Liu, K.D.; Coca, S.G.; Garg, A.X.; Hsu, C.Y.; Siew, E.D.; Wurfel, M.M.; Ware, L.B.; Faulkner, G.B.; Tan, T.C.; Kaufman, J.S.; Kimmel, P.L.; Go, A.S. A prospective cohort study of acute kidney injury and kidney outcomes, cardiovascular events, and death. Kidney Int. 2021, 99, 456–465.
[3]	Garwood, S. Cardiac surgery-associated acute renal injury: new paradigms and innovative therapies. J. Cardiothorac. Vasc. Anesth. 2010, 24, 990–1001.
[4]	Han, Y.F.; Guo, Q.; Mai, S.Z.; Wang, L.C.; Xu, M.; Tan, G.Z. Acute renal injury induced by oral valacyclovir. Eur. J. Dermatol. 2018, 28, 122–123.
[5]	Almutairy, R.; Aljrarri, W.; Noor, A.; Elsamadisi, P.; Shamas, N.; Qureshi, M.; Ismail, S. Impact of colistin dosing on the incidence of nephrotoxicity in a tertiary care hospital in Saudi Arabia. Antibiotics. 2020, 9, 485.
[6]	Feng, X.; Fang, S.N.; Gao, Y.X.; Liu, J.P.; Chen, W. Current research situation of nephrotoxicity of Chinese herbal medicine. China J. Chin. Mater. Med. 2018, 43, 417–424.
[7]	He, T.M.; Zhang, J.Y.; Li, X.F. Application progress on metabolomics in nephrotoxicity of Chinese materiamedica. Chin. Tradit. Herbal. Drugs. 2019, 50, 3962–3970.
[8]	Chen, J.Y.; Yang, Y.F.; Wei, X.P.; Chu, J.Z.; Jin, L. Analysis and countermeasures on safety factors of clinic use for Chinese patent medicine containing nephrotoxic ingredients. Chin. J. Tradit. Chin. Med. Pharm. 2017, 32, 1449–1451.
[9]	Jiang, M.; Zhang H.B.; Ding Y. Research progress on pharmacological activities and clinical applications of tripterygium glycosides. Chin. Archi. Tradit. Chin. Med. 2020. This article can be found online at http://fffg208e51c2dd88406685526280e50de659hnfkck5vvwox56q0w.fgfy.jxjjxy.cwkeji.cn/kcms/detail/21.1546.R. 20200817.1322.196.html.
[10]	Perazella, M.A. Drug-induced acute kidney injury: diverse mechanisms of tubular injury. Curr. Opin. Crit. Care. 2019, 25, 550–557.
[11]	Feng, X.; Fang, S.N.; Gao, Y.X.; Liu, J.P.; Chen, W. Application of evidence-based rapid review in studying nephrotoxicity of TW preparation. China J. Chin. Mater. Med. 2018, 43, 440–445.
[12]	Hao, J.X.; Gao, Z.S.; Gao,H.; Bi, K.S.; Wang, J.; Li, Z. Study on Mechanism of Nephrotoxicity of Tripterygii Radix Based on Network Pharmacology. Chin. J. ETMF. 2019, 25, 142–151.
[13]	Xing, X.R.; Lu, D.Y.; Chai, Y.F.; Zhu, Z.Y. Advances in the mechanism of Traditional Chinese Medicine by network pharmacology method. J. Pharm. Practice. 2018, 36, 97–102.
[14]	Huang, X.F.; Cheng, W.B.; Jiang, Y.; Liu, Q.; Liu, X.H.; Xu, W.F.; Huang, H.T. A network pharmacology-based strategy for predicting anti-inflammatory targets of ephedra in treating asthma. Int. Immunopharmacol. 2020, 83, 106423.
[15]	Chung, W.T.; Choe, J.Y.; Jang, W.C.; Park, S.M.; Ahn, Y.C.; Yoon, I.K.; Kim, T.H.; Nam, Y.H.; Park, S.H.; Lee, S.W.; Kim, S.K. Polymorphisms of tumor necrosis factor-α promoter region for susceptibility to HLA-B27-positive ankylosing spondylitis in Korean population. Rheumatol. Int. 2011, 31, 1167–1175.
[16]	Bayley, J.P.; Ottenhoff, T.H.; Verweij, C.L. Is there a future for TNF promoter polymorphisms? Genes. Immun. 2004, 5, 315–329.
[17]	Hashad, D.I.; Elsayed, E.T.; Helmy, T.A.; Elawady, S.M. Study of the role of tumor necrosis factor-α (-308 G/A) and interleukin-10 (-1082 G/A) polymorphisms as potential risk factors to acute kidney injury in patients with severe sepsis using high-resolution melting curve analysis. Ren. Fail. 2017, 39, 77–82.
[18]	Wang, Y.; Zhang, H.Y.; Chen, Q.; Jiao, F.Z.; Shi, C.X.; Pei, M.H.; Lv, J.; Zhang, H.; Wang, L.W.; Gong, Z.J. TNF-α/HMGB1 inflammation signalling pathway regulates pyroptosis during liver failure and acute kidney injury. Cell Prolif. 2020, DOI:10.1111/cpr.12829.
[19]	Zelová, H.; Hošek, J. TNF-α signalling and inflammation: interactions between old acquaintances. Inflamm. Res. 2013, 62, 641–651.
[20]	Zhang, Y.P.; Chen, Y.E.; Li, B.X.; Ding, P.; Jin, D.X.; Hou, S.Z.; Cai, X.C.; Sheng, X.J. The effect of monotropein on alleviating cisplatin-induced acute kidney injury by inhibiting oxidative damage, inflammation and apoptosis. Biomed. Pharmacother. 2020, 129, 110408.
[21]	Brandenburger, T.; Salgado Somoza, A.; Devaux, Y.; Lorenzen, J.M. Noncoding RNAs in acute kidney injury. Kidney Int. 2018, 94, 870–881.
[22]	Lee, S.H.; Lee, H.S.; Park, G.; Oh, S.M.; Oh, D.S. Dual actions on gout flare and acute kidney injury along with enhanced renal transporter activities by Yokuininto, a Kampo medicine. BMC Complementary Altern. Med. 2019, 19, 1–9.
[23]	Liu, L.L.; Li, D.H.; He, Y.L.; Zhou, Y.Z.; Gong, S.H.; Wu, L.Y.; Zhao, Y.Q.; Huang, X.; Zhao, T.; Xu, L.; Wu, K.W.; Li, M.G.; Zhu, L.L.; Fan, M. miR-210 protects renal cell against hypoxia-induced apoptosis by targeting HIF-1 alpha. Mol. Med. 2017, 23, 258–271.
[24]	Li, D.; An, N. Mechaism of R-214-mediated HIF1α and KIMI signaling pathway in rat with ischemic acute kidney injury. J. Hainan. Med. Univ. 2019, 25, 1847–1851.
[25]	Han, X.; Sun, S.; Zhao, M.; Cheng, X.; Chen, G.; Lin, S.; Guan, Y.; Yu, X. Celastrol stimulates hypoxia-inducible factor-1 activity in tumor cells by initiating the ROS/Akt/p70S6K signaling pathway and enhancing hypoxia-inducible factor-1α protein synthesis. PLoS One. 2014, 9, e112470.
[26]	Turner, R.J.; Eikmans, M.; Bajema, I.M.; Bruijn, J.A.; Baelde, H.J. Stability and species specificity of renal VEGF-A splicing patterns in kidney disease. PLoS One. 2016, 11, e0162166.
[27]	Yang, L.L.; Zhan, Y.L. VEGF-A signaling pathway and glomerular filtration barrier. Chin. J. Integrated Tradit. West. Nephrology. 2011, 12, 931–933.
[28]	Wu, B.N.; Chen, H.Y.; Liu, C.P.; Hsu, L.Y.; Chen, I.J. Kmup-1 inhibits H441 lung epithelial cell growth, migration and proinflammation VIA increased NO/CGMP and inhibited RHO KINASE/VEGF signaling pathways. Int. J. Immunopathol. Pharmacol. 2011, 24, 925–939.
[29]	Sun, L.X.; Li, H.; Huang, X.; Wang, T.; Zhang, S.; Yang, J.; Huang, S.; Mei, H.F.; Jiang, Z.Z.; Zhang, L.Y. Triptolide alters barrier function in renal proximal tubular cells in rats. Toxicol. Lett. 2013, 223, 96–102.
[30]	Shen, Q.Q.; Wang, J.J.; Roy, D.; Sun, L.X.; Jiang, Z.Z.; Zhang, L.Y.; Huang, X. Organic anion transporter 1 and 3 contribute to traditional Chinese medicine-induced nephrotoxicity. Chin. J. Nat. Med. 2020, 18, 196–205.
[31]	Yang, F.; Ren, L.; Zhuo, L.; Liu, L. Role of apoptosis in triptolide-induced acute nephrotoxicity and possible mechanisms in rats. Chin. Tradit. Herbal. Drugs. 2011, 42, 923–928.
[32]	Zhang, W.; Zhang, J.Q.; Meng, F.M.; Xue, F.S. Dexmedetomidine protects against lung ischemia-reperfusion injury by the PI3K/Akt/HIF-1α signaling pathway. J. Anesth. 2016, 30, 826–833.
[33]	Chi,Y.; Ma, Q.; Ding, X.Q.; Qin,X.; Wang,C.; Zhang,J. Research on protective mechanism of ibuprofen in myocardial ischemia-reperfusion injury in rats through the PI3K/Akt/mTOR signaling pathway. Eur. Rev. Med. Pharmacol. Sci. 2019, 23, 4465–4473.
[34]	Deng, X.B.; Rui, W.; Zhang, F.; Ding, W.J. PM2.5 induces Nrf2-mediated defense mechanisms against oxidative stress by activating PIK₃/AKT signaling pathway in human lung alveolar epithelial A549 cells. Cell Biol. Toxicol. 2013, 29, 143–157.
[35]	Bai, J.; Wu, Y.K.; Wu, K.M.; Zhu, H.L.; Li, N.; Chen, M.; Liu, L.X. Triptolide induces autophagy of ovarian granulosa cells via PI3K/AKT/m TOR pathway. Chin. J. Chin. Mater. Med. 2019, 44, 3429–3434.
[36]	Li, H.L.; Wang, Y.Y.; Zhou, Z.Q.; Tian, F.; Yang, H.H.; Yan, J.Z. Combination of leflunomide and benazepril reduces renal injury of diabetic nephropathy rats and inhibits high-glucose induced cell apoptosis through regulation of NF-κB, TGF-β and TRPC₆. Ren. Fail. 2019, 41, 899–906.
[37]	Ren, Q.; Cen, G. D.; Gao, Y. X. Mechanism of TWP Inducing Apoptosis of Rat Kidney Cells Through NF-κB Signaling Pathway. J. Chengdu Univ. Tradit. Chin. Med. 2011, 34, 39–44.
[38]	Zhu, H.; Sun, B.; Shen, Q. TNF-α induces apoptosis of human nucleus pulposus cells via activating the TRIM14/NF-κB signalling pathway. Artif. Cells Nanomed. Biotechnol. 2019, 47, 3004–3012.
[39]	Chen, X.; Yang, Y.L.; Li, W.H.; Liu, M.; Zhang, S.S.; Wang, Y.H.; Du, G.H. Esculin alleviates acute kidney injury and inflammation induced by LPS in mice and its possible mechanism. J. Chin. Pharm. Sci. 2020, 29, 322–332.
[40]	Chang, L.J.; Li, Z.J.; Li, Q.; Sui, Z.Y.; Li, X.; Bi, K.S. Metabonomic analysis on serum in nephrotoxic rats induced by radix et rhizoma Tripterygii. Chin. J. Exp. Tradit. Med. Formulae. 2016, 22, 89–94.
[41]	Meng, F.C.; Tang, L.D. Challenges and prospect in research of Chinese materiamedica network pharmacology. Chin. Tradit. Herbal. Drugs. 2020, 51, 2232–2237.

基于网络药理学和分子对接技术探讨雷公藤致急性肾损伤的多重作用机制

The multiple mechanisms of tripterygium wilfordii-induced acute kidney injury based on network pharmacology and molecular docking

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表 12

参考文献 41

相关文章 15

编辑推荐

Metrics

本文评价

[1]	吴梦瑶, 刘璐, 张鹏, 张乐乐, 龚云, 杨秀伟. 基于网络药理学和实验验证研究补血益母丸治疗产后腹痛的作用机制[J]. 中国药学(英文版), 2023, 32(9): 691-703.
[2]	尚平, 刘琳, 方毅. 基于网络药理学和分子对接探讨桂枝茯苓丸治疗子宫内膜异位症的作用机制[J]. 中国药学(英文版), 2023, 32(9): 704-719.
[3]	张格第, 刘庚鑫, 晏子友. 基于meta分析和网络药理学理冲汤(丸)治疗癌症的疗效评价及作用机制研究[J]. 中国药学(英文版), 2023, 32(9): 720-735.
[4]	武东燕, 王小丹, 柴金苗, 李钦青, 李悦, 毕梅, 桂婉威, 曹慧敏. 基于网络药理学及实验验证探究当归补血汤治疗糖尿病性视网膜病变的作用机制[J]. 中国药学(英文版), 2023, 32(7): 527-538.
[5]	王番, 李锐莉, 王文军, 周晓燕, 刘美佑, 赵瑾怡, 文爱东, 王婧雯, 贾艳艳. α-乳香酸通过抑制TLR4介导的炎症通路改善急性肾损伤[J]. 中国药学(英文版), 2023, 32(7): 539-550.
[6]	闫焕, 王健, 付浩, 杨敏, 曲苗, 方志娥. 基于网络药理学探讨大柴胡汤治疗高脂血症的潜在作用靶点和机制[J]. 中国药学(英文版), 2023, 32(6): 446-459.
[7]	王孟亚, 张宽友, 陈馨, 付浩, 彭守春. 基于网络药理学方法探讨犀角地黄汤治疗系统性红斑狼疮的作用机制[J]. 中国药学(英文版), 2023, 32(5): 351-359.
[8]	沈广志, 崔新刚, 那志敏, 邹玉龙, 邹桂华. 利用网络药理学探究淫羊藿治疗性功能障碍的药理作用机制[J]. 中国药学(英文版), 2023, 32(5): 379-391.
[9]	敖民, 包明兰, 侯亚星, 月英, 李慧芳, 吴国华, 苏日嘎拉图. 基于网络药理学的蒙药肋柱花抗急性肝损伤作用机制研究[J]. 中国药学(英文版), 2023, 32(4): 268-282.
[10]	李雅静, 白雅雯, 杜宇, 严长宏, 麻春杰, 孙丽宁, 卜凤跃, 严昊阳. 玉屏风散治疗慢性肾小球肾炎的临床疗效评价及作用机制研究[J]. 中国药学(英文版), 2023, 32(12): 1006-1026.
[11]	孙志勇, 高淑丽, 张阳, 薛刚强, 苑子林, 王少男. 基于网络药理学和分子对接技术研究蒲公英治疗乳腺增生的潜在机制[J]. 中国药学(英文版), 2023, 32(11): 893-910.
[12]	张玉倩, 牛海英, 靳怡然. 基于网络药理学技术探讨长春花治疗癌症的作用机制[J]. 中国药学(英文版), 2023, 32(11): 911-922.
[13]	周代英, 陈靓, 吕志刚. 基于网络药理学和分子对接探讨灯盏细辛治疗年龄相关性黄斑变性的机制[J]. 中国药学(英文版), 2023, 32(11): 923-934.
[14]	魏东升, 刘孝生, 李路珍, 齐佳杰, 王雨轩, 张哲. 基于综合生物信息学和单细胞测序方法揭示红花-丹参治疗冠心病的生物学和免疫学机制[J]. 中国药学(英文版), 2023, 32(10): 796-812.
[15]	丁宁, 张涛, 罗吉, 刘皓辰, 邓宇, 何永恒. 基于网络药理学和分子对接探究白芍七物汤治疗结直肠癌的作用机制[J]. 中国药学(英文版), 2023, 32(1): 17-31.