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Research Article a Network Pharmacology-Based Strategy for Unveiling the Mechanisms of Tripterygium Wilfordii Hook F Against Diabetic Kidney Disease

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Research Article a Network Pharmacology-Based Strategy for Unveiling the Mechanisms of Tripterygium Wilfordii Hook F Against Diabetic Kidney Disease Hindawi Journal of Diabetes Research Volume 2020, Article ID 2421631, 14 pages https://doi.org/10.1155/2020/2421631 Research Article A Network Pharmacology-Based Strategy for Unveiling the Mechanisms of Tripterygium Wilfordii Hook F against Diabetic Kidney Disease Yuyang Wang ,1,2 Tongtong Liu,1 Fang Ma,1 Xiaoguang Lu,1 Huimin Mao,1 Weie Zhou,3 Liping Yang,1 Ping Li ,3 and Yongli Zhan 1 1Department of Nephrology, Guang’anmen Hospital of China Academy of Traditional Chinese Medical Sciences, Beijing 100053, China 2Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China 3Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China- Japan Friendship Hospital, Beijing 100029, China Correspondence should be addressed to Ping Li; [email protected] and Yongli Zhan; [email protected] Received 21 May 2020; Revised 1 October 2020; Accepted 2 November 2020; Published 20 November 2020 Academic Editor: Daniela Foti Copyright © 2020 Yuyang Wang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Diabetic kidney disease (DKD) poses a major public-health burden globally. Tripterygium wilfordii Hook F (TwHF) is a widely employed herbal medicine in decreasing albuminuria among diabetic patients. However, a holistic network pharmacology strategy to investigate the active components and therapeutic mechanism underlying DKD is still unavailable. Methods.We collected TwHF ingredients and their targets by traditional Chinese Medicine databases (TCMSP). Then, we obtained DKD targets from GeneCards and OMIM and collected and analyzed TwHF-DKD common targets using the STRING database. Protein-protein interaction (PPI) network was established by Cytoscape and analyzed by MCODE plugin to get clusters. In addition, the cytoHubba software was used to identify hub genes. Finally, all the targets of clusters were subjected for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses via DAVID. Results.A total of 51 active ingredients in TwHF were identified and hit by 88 potential targets related to DKD. Compounds correspond to more targets include kaempferol, beta-sitosterol, stigmasterol, and Triptoditerpenic acid B, which appeared to be high-potential compounds. Genes with higher degree including VEGFA, PTGS2, JUN, MAPK8, and HSP90AA1 are hub genes of TwHF against DKD, which are involved in inflammation, insulin resistance, and lipid homeostasis. Kaempferol and VEGFA were represented as the uppermost active ingredient and core gene of TwHF in treating DKD, respectively. DAVID results indicated that TwHF may play a role in treating DKD through AGE-RAGE signaling pathway, IL-17 signaling pathway, TNF signaling pathway, insulin resistance, and calcium signaling pathway (P <0:05). Conclusion. Kaempferol and VEGFA were represented as the uppermost active ingredient and core gene of TwHF in treating DKD, respectively. The key mechanisms of TwHF against DKD might be involved in the reduction of renal inflammation by downregulating VEGFA. 1. Introduction and even in the presence of adequate glycemic control, it remains the main cause of morbidity and mortality among Diabetic kidney disease (DKD), a highly prevalent microvas- diabetic patients [2, 3]. Since those living with DKD are at cular complication of diabetes, is characterized by thickening higher risks of progression to cardiovascular comorbidities of the glomerular basement membrane, mesangial expan- and end-stage kidney disease (ESKD), thus DKD is emerging sion, podocyte, and glomerular injury, leading to glomerular as a major healthcare challenge around the globe. The clinical sclerosis and tubulointerstitial fibrosis [1]. It occurs in almost hallmark of DKD is described as the presence of progressive 20-50% patients with type 1 or type 2 diabetes worldwide, decline in renal function and persistent excretion of urinary 2 Journal of Diabetes Research albumin. Several mechanisms contribute to DKD pathogen- ADME (absorption, distribution, metabolism, and excretion) esis through driving an overproduction of advanced glyca- models, and the ingredients with OB (oral bioavailability tion end products, hemodynamic changes, inflammation, (OB)) ≥30% and the DL (drug-likeness (DL)) ≥0.18 were oxidative stress, fibrosis, endothelial, and podocyte injury, screened out as candidate compounds for further analysis ultimately leading to albuminuria and reduced renal function according to a suggested criterion by the TCMSP database. [3]. Current standard therapies to manage DKD recommend Meanwhile, the target genes related to active ingredients of drugs controlling blood pressure and hyperglycemia, mainly TwHF were gathered based on the TCMSP database. UniProt including renin angiotensin aldosterone system (RAAS) database (https://www.uniprot.org) provides access to a vast inhibitors, sodium glucose cotransporter 2 (SGLT2) inhibi- amount of sequence and functional information of proteins tors, and glucagon-like peptide 1 (GLP1) receptor agonist. in a comprehensive, high-quality, and freely accessible way Despite those strategies showing promising results in DKD, for scientists worldwide [21]. All obtained targets were subse- many diabetic patients continue to progress to DKD and quently put into UniProtKB, with the organism selected as ESKD [3, 4]. The multifactorial origin of DKD and the mul- “Homo sapiens,” to search for official target names. There- tiple underlying molecular mechanisms involved make it dif- fore, we collected the active compound and involved target ficult to achieve successful results with one single drug. Novel genes of TwHF, and the details are described in Table S1. therapeutic agents based on multiple targets contribute to Additionally, components correspond to more targets (top DKD progression are therefore urgently required. 10) were imported into PubChem database (https:// Guided by accumulative empirical experience, Chinese pubchem.ncbi.nlm.nih.gov/) for acquiring the compound herbal medicine [5] acts as an effective therapy in the treat- structures. ment of DKD for centuries in China and some Asian coun- tries. Different from chemical medications, it is reported 2.2. Identification of DKD Targets. The keyword “diabetic that Chinese herbal medicine [5] targets on diverse pathways kidney disease” was used in the GeneCards (https://www to restore cellular homeostasis, which may provide a new .genecards.org) and Online Mendelian Inheritance in Man option for the treatment of multifactorial diseases like DKD (OMIM, https://www.omim.org) databases to search for [6]. Tripterygium wilfordii Hook F (TwHF) is the most DKD-related targets. GeneCards is a comprehensive, author- well-known drug for DKD among CHM and exerts a itative human gene compendium that enables scientific com- remarkable effect in decreasing albuminuria excretion. Evi- munity to effectively navigate concise genome, dence obtained from clinical trials suggested treatment of transcriptome, proteome, disease, and function data on all TwHF in combination of ARB/ACEI is more effective than predicted and known human genes [22, 23]. OMIM is con- ARB/ACEI monotherapy in reduction of proteinuria for sidered as the primary repository of comprehensive [24], DKD patients [7, 8]. A wide spectrum of biological activities freely accessible information on genes, genetic phenotypes, about TwHF including anti-inflammatory, immunosuppres- and gene-phenotype relationships. sive, antioxidation, and antifibrosis has been demonstrated in the last decades [9–13], which may attribute to its renopro- 2.3. Construction and Analysis of the Protein-Protein tective effects against DKD [14, 15]. However, a satisfactory Interaction (PPI) Network. The intersection of the compound explanation of its pharmacological mechanisms and material targets and DKD disease targets was determined with the bases related to DKD remains unavailable at the moment. semiprogrammed foot software R project (×64 3.6.1) and Network pharmacology is an interactive network used to taken as the candidate targets for the components of TwHF study “compound-proteins/genes-disease” pathways, which in the treatment of DKD. A protein-protein interaction own the ability of elucidating complexities for biological sys- (PPI) network of overlapped target genes was built based on tems, drugs, and diseases from a systemic perspective [16, the STRING database (http://stringdb.org) with the organism 17]. This concept shares a quite similar holistic philosophy set as “Homo sapiens” [25]. Afterwards, the target interaction as CHM, which supplies a comprehensive method to system- information was drawn and analyzed in the visualization soft- atically reveal the interactions between multicomponents, ware Cytoscape (Version 3.7.2; https://www.cytoscape.org/). multitargets, and multipathways of the active ingredients in The color of the node was displayed in a gradient from red CHM [18, 19]. This study is aimed at exploring the pharma- to yellow according to the descending order of the degree cological mechanisms of TwHF for DKD employing network value, and a higher degree value node was utilized to present pharmacology approach. Our workflow was exhibited in putative crucial targets in the PPI network. Besides, the cyto- Figure 1. Hubba software was used to select hub genes based on mixed character calculation (MCC) score, and the Molecular
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