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A Network Pharmacology-Based Strategy for Unveiling the Mechanisms of Tripterygium Wilfordii Hook F against Diabetic Kidney Disease.

ABSTRACT: 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.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7695487 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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A Network Pharmacology-Based Strategy for Unveiling the Mechanisms of Tripterygium Wilfordii Hook F against Diabetic Kidney Disease.

Wang Yuyang Y Liu Tongtong T Ma Fang F Lu Xiaoguang X Mao Huimin H Zhou Weie W Yang Liping L Li Ping P Zhan Yongli Y

Journal of diabetes research 20201120

<h4>Background</h4>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.<h4>Methods</h4>We collected TwHF ingredients and their targets by traditional Chinese Medicine databases (TCMSP). Then, we obtained ...[more]

PMID: 33274236

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Project description:BackgroundTripterygium wilfordii (TW), when formulated in traditional Chinese medicine (TCM), can effectively treat diabetic kidney disease (DKD). However, the pharmacological mechanism associated with its success has not yet been elucidated. The current work adopted network pharmacology and molecular docking for exploring TW-related mechanisms in treating DKD. Methods: In the present work, the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was employed to obtain the effective components and candidate targets of TW. Additionally, this work utilized the UniProt protein database for screening and standardizing human-derived targets for effective components. The Cytoscape software was utilized to construct an effective component-target network for TW. Targets for DKD were acquired in the GEO, DisGeNET, GeneCards, and OMIM databases. Additionally, a Venn diagram was also plotted to select the possible targets of TW for treating DKD. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were conducted to explore the TW-related mechanism underlying DKD treatment. This work also built a protein-protein interaction (PPI) network based on the Cytoscape and String platform. Then, molecular docking was conducted in order to assess the affinity of key proteins for related compounds. Results: In total, 29 active components and 134 targets of TW were acquired, including 63 shared targets, which were identified as candidate therapeutic targets. Some key targets and important pathways were included in the effect of TW in treating DKD. Genes with higher degrees, including TNF and AKT1, were identified as hub genes of TW against DKD. Molecular docking showed that TNF and AKT1 bind well to the main components in TW (kaempferol, beta-sitosterol, triptolide, nobiletin, and stigmasterol).ConclusionsTW primarily treats DKD by acting on two targets (AKT1 and TNF) via the five active ingredients kaempferol, beta-sitosterol, triptolide, nobiletin, and stigmasterol.

Project description:BackgroundDiabetic nephropathy (DN) is the most common cause of end-stage renal failure. Although angiotensin II receptor blockers (ARBs) can be used to attenuate proteinuria in DN patients, their efficacy remains limited. This clinical trial aimed to evaluate the efficacy of Tripterygium wilfordii Hook F (TwHF) extract in the treatment of type 2 diabetes mellitus (DM)-induced nephropathy.MethodsA total of 65 DN patients with proteinuria levels ≥ 2.5 g/24 h and serum creatinine levels<3 mg/dl were enrolled in this six-month, prospective, randomized, controlled study. The patients were randomized into treatment groups that received either 120 mg of TwHF extract per day for three months, followed by 60 mg per day for three more months, or 160 mg of valsartan daily for six months. The urinary protein and estimated glomerular filtration (eGFR) level were measured at one, three, and six months after the commencement of treatment. The primary measure of treatment efficacy was a reduction in the 24-h urine protein level between baseline and the end of the study, and the secondary measure of treatment efficacy was a reduction in the eGFR value.ResultsAt the end of the treatment period, the mean urine protein level in the TwHF group was dramatically decreased (4.99 ± 2.25 g/24 h vs 2.99 ± 1.81 g/24 h, p< 0.01), with decreases at one, three, and six months of 32.9%, 38.8%, and 34.3%, respectively. In contrast, the proteinuria in the valsartan group was not significantly attenuated, and the decreases in urine protein levels at treatment months one, three, and six were 1.05%, 10.1%, and -11.7%, respectively. The mean decrease in eGFR in the valsartan group was greater than that in the TwHF group (26.4% vs. 13.7%, respectively; p =0.067).ConclusionsTwHF extract can reduce the urine protein level of DN patients and represents a novel, potentially effective, and safe drug for the treatment of DN patients with proteinuria.Trial registrationClinicalTrials.gov: NCT00518362.

Project description:Background: Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease. The effective treatment of DKD would rely on the incorporation of a multi-disciplinary. Studies have shown that Tripterygium wilfordii Hook.F. and Trichosanthes kirilowii Maxim have remarkable curative effects in treating DKD, but their combination mechanism has not been fully elucidated. Methods: We explored the mechanism of Tripterygium wilfordii Hook.F.-Trichosanthes kirilowii Maxim decoction (Leigongteng-Tianhuafen Decoction,LTD) in the treatment of DKD by network pharmacology and molecular docking. The main active components and action targets of LTD were collected from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database. The speculative targets of DKD were obtained from GeneCards, DisGeNET, and Online Mendelian Inheritance in Man (OMIM) databases. Then, an herb-component-target network was constructed based on the above analyses. The biological function of targets was subsequently investigated, and a protein-protein interaction (PPI) network was constructed to identify hub targets of DKD. The gene ontology (GO) function enrichment analysis and kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were performed by RStudio. Finally, molecular docking was performed by AutoDock Vina and PyMOL software to explore the interaction between compounds and targets. Furthermore, the DKD model of human renal tubular cells (HK-2) induced by high glucose (HG) was selected, and the predicted results were verified by western blot analysis and immunofluorescence. Results: A total of 31 active components of LTD were screened out, and 196 targets were identified based on the TCMSP database. A total of 3,481 DKD related targets were obtained based on GeneCards, DisGeNET, and OMIM databases. GO function enrichment analysis included 2,143, 50, and 167 GO terms for biological processes (BPs), cellular composition (CCs), and molecular functions (MFs), respectively. The top 10 enrichment items of BP annotations included response to lipopolysaccharide, response to molecule of bacterial origin, response to extracellular stimulus, etc. CC was mainly enriched in membrane raft, membrane microdomain, plasma membrane raft, etc. The MF of LTD analysis on DKD was predominately involved in nuclear receptor activity, ligand-activated transcription factor activity, RNA polymerase II-specific DNA-binding transcription factor binding, etc. The involvement signaling pathway of LTD in the treatment of DKD included AGE-RAGE signaling pathway in diabetic complications, IL-17 signaling pathway, insulin resistance, TNF signaling pathway, etc. Molecular docking results showed that kaempferol, triptolide, nobiletin, and schottenol had a strong binding ability to PTGS2 and RELA. Furthermore, the in vitro experiments confirmed that LTD effectively decreased the expression of PTGS2, NF-κB, JNK, and AKT in the HG-induced DKD model. Conclusion: The findings of this study revealed that the therapeutic efficacy of LTD on DKD might be achieved by decreasing the expression of PTGS2, NF-κB, JNK, and AKT, which might improve insulin resistance, inflammation, and oxidative stress. These findings can provide ideas and supply potential therapeutic targets for DKD.

Project description:Background:Tripterygium wilfordii Hook. f. (T. wilfordii) is an important medicinal plant with anti-inflammatory, immunosuppressive and anti-tumor activities. The main bioactive ingredients are diterpenoids and triterpenoids, such as triptolide, triptophenolide and celastrol. However, the production of terpenoids from original plants, hairy roots and dedifferentiated cells (DDCs) are not satisfactory for clinical applications. To find a new way to further improve the production of terpenoids, we established a new culture system of cambial meristematic cells (CMCs) with stem cell-like properties, which had strong vigor and high efficiency to produce large amounts of terpenoids of T. wilfordii. Results:CMCs of T. wilfordii were isolated and cultured for the first time. CMCs were characterized consistent with stem cell identities based on their physiological and molecular analysis, including morphology of CMCs, hypersensitivity to zeocin, thin cell wall and orthogonal partial least square-discriminant analysis, combination of transcriptional data analysis. After induction with methyl jasmonate (MJ), the maximal production of triptolide, celastrol and triptophenolide in CMCs was 312%, 400% and 327% higher than that of control group, respectively. As for medium, MJ-induced CMCs secreted 231% triptolide and 130% triptophenolide at the maximum level into medium higher than that of control group. Maximal celastrol production of induced CMCs medium was 48% lower than that of control group. Long-term induction significantly enhanced the production of terpenoids both in cells and medium. The reason for increasing the yield of terpenoids was that expression levels of 1-deoxy-d-xylulose-5-phosphate synthase (DXS), 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR) and hydroxymethylglutaryl-CoA synthase (HMGS) were upregulated in CMCs after induction. Conclusions:For the first time, CMCs of T. wilfordii were isolated, cultured, characterized and applied. Considering the significant enrichment of terpenoids in CMCs of T. wilfordii, CMCs could provide an efficient and controllable platform for sustainable production of terpenoids, which can be a better choice than DDCs.

Project description:AbstractTo explore the possible molecular mechanism of reproductive toxicity of Tripterygium wilfordii from the perspective of network pharmacology and bioinformatics.The compounds of T wilfordii were obtained by querying the relevant Chinese medicine database, the effective compounds were screened and the corresponding targets were obtained, and then compared with the reproductive toxicities related to disease targets obtained from the disease gene database to infer the potential toxic targets of reproductive toxicity of T wilfordii. Then, the key targets of reproductive toxicity of T wilfordii were screened using Search Tool for the Retrieval of Interacting Genes/Protein and Cytoscape. The gene ontology function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, as well as module analysis, were performed on the key targets using Database for Annotation, Visualization, and Integrated Discovery and Cytoscape, respectively. Finally, the network between effective compounds-toxic targets was conducted to see how the compounds interacted.A total of 48 effective compounds and 482 potential toxic targets related to the reproductive toxicity of T wilfordii were screened. The enrichment analysis results showed that the key targets were mainly enriched in biological processes such as response to drug, ionotropic glutamate receptor signaling pathway, and KEGG pathways such as neuroactive ligand-receptor interaction, cAMP signaling pathway. In the protein-protein interaction network of potential toxic targets, there were 78 key targets such as TP53, INS, IL6, AGT, ADCY3, and so on. Enrichment analysis of the top module with 19 genes from module analysis indicated that T wilfordii might cause reproductive toxicity by gene ontology terms and KEGG pathways such as regulation of vasoconstriction, G-protein coupled receptor signaling pathway, inflammatory response, cAMP signaling pathway, and so on. In the network between effective compounds of T wilfordii and key targets, there were 5 compounds with high degree including Tingenone, Wilfordic Acid, Abruslactone A, Nobilin, and Wilforlide B.The complex molecular mechanism of reproductive toxicity of T wilfordii can be preliminarily elucidated with the help of the network pharmacology method, and the analysis results can provide some reference for the further mechanism research of reproductive toxicity of T wilfordii.

Dataset Information

A Network Pharmacology-Based Strategy for Unveiling the Mechanisms of Tripterygium Wilfordii Hook F against Diabetic Kidney Disease.

Publications

A Network Pharmacology-Based Strategy for Unveiling the Mechanisms of Tripterygium Wilfordii Hook F against Diabetic Kidney Disease.

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