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Based on Network Pharmacology Tools to Investigate the Mechanism of Tripterygium wilfordii Against IgA Nephropathy.

ABSTRACT: Background: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease and poses a global major public health burden. The preparation of Tripterygium wilfordii Hook F (TwHF) is widely applied for treating patients with Immunoglobulin A nephropathy in China, while the molecular mechanisms remain unclear. This study aimed to verify the therapeutic mechanism of TwHF on IgAN by undertaking a holistic network pharmacology strategy in combination with in vitro and in vivo experiments. Methods: TwHF active ingredients and their targets were obtained via the Traditional Chinese Medicine Systems Pharmacology Database. The collection of IgAN-related target genes was collected from GeneCards and OMIM. TwHF-IgAN common targets were integrated and visualized by Cytoscape. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to determine the predominant molecular mechanisms and pathways of TwHF on the treatment of IgAN. The protein-protein interaction network was constructed by the STRING online search tool, and hub genes were identified using R software. The expression of hub gene and related signaling were evaluated in TwHF-treated mice through immunohistochemistry and western blot and further validated in human mesangial cells (HMCs). In addition, Cell counting kit 8 (CCK8) and flow cytometry were used to detect the effects of TwHF on cell proliferation and cell cycle of mesangial cells. Results: A total of 51 active ingredients were screened from TwHF and 61 overlapping targets related to IgAN were considered potential therapeutic targets, GO functions and KEGG analyses demonstrated that these genes were primarily associated with DNA-binding transcription factor binding, lipid and atherosclerosis pathway. Genes with higher degrees including AKT1, CXCL8, MMP9, PTGS2, CASP3, JUN are hub genes of TwHF against IgAN. Verification of hub gene JUN both in vitro and in vivo showed that TwHF significantly attenuated JUN phosphorylation in the kidneys of IgAN mice and aIgA1-activated HMCs, meanwhile suppressing HMCs proliferation and arresting G1-S cell cycle progression. Conclusion: Our research strengthened the mechanisms of TwHF in treating IgAN, inhibition of JUN activation may play a pivotal role in TwHF in alleviating IgAN renal injury.

SUBMITTER: Xia M

PROVIDER: S-EPMC8715946 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

Project description:BackgroundDiabetic 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.MethodsWe 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.ResultsA 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).ConclusionKaempferol 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.

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: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.

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Based on Network Pharmacology Tools to Investigate the Mechanism of Tripterygium wilfordii Against IgA Nephropathy.

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