Research on the mechanisms of taraxerol for the treatment of gastric cancer effect based on network pharmacology

Background: Modern pharmacological studies have shown that traditional Chinese medicine (TCM) Taraxacum mongolicum possesses anti-cancer activity. Taraxerol (TRX) is a pentacyclic triterpene isolated from T. mongolicum, which is widely used in clinical treatment, and its anti-cancer effects have been extensively studied. However, the effects and molecular mechanism of TRX in gastric cancer (GC) have not been fully explicated. Methods: We used public databases to derive information on potential targets of TRX and proteins related to GC. Also, STRING and R3.6.2 software were used to analyze the protein–protein interaction (PPI). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were done to explain the potential mechanism underlying the regulatory role of TRX in GC. The role of TRX in GC was verified by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide (MTT) assay, apoptosis analysis, Transwell assay, and wound healing assay, and the key signaling pathways were verified. Results: We identified 135 potential targets for the treatment of GC via network pharmacological analysis. GO and KEGG enrichment analysis showed that steroid hormone receptor activity and the PI3K/AKT signaling pathway were the biological processes and pathways with the highest degree of enrichment. Additionally, cellular experiments revealed that TRX inhibited the proliferation, migration, and invasion of GC cells as well as induced G1 phase arrest and apoptosis in GC cells. Conclusion: Here, we used multi-target and multi-pathway network pharmacological analysis to verify the anti-cancer activity of TRX in GC. Also, in vitro experimental data were used to derive the potential molecular mechanism.

Preventive Effect of Anemarrhenae rhizome and Phellodendri cortex on Danazol-Induced in Precocious Puberty in Female Rats and Network Pharmacological Analysis of Active Compounds

Anemarrhenae rhizome and Phellodendri cortex have historically been used for the treatment of precocious puberty (PP) in oriental medicine. Our study aimed to evaluate the effect of APE, a mixture of the extracts from these herbs, against danazol-induced PP in female rats. The offspring were injected danazol to establish the PP model, and then treated with APE daily, and observed for vaginal opening. At the end of the study, the levels of gonadotropic hormones, such as estradiol, follicle-stimulating hormone, and luteinizing hormone, were determined by ELISA. Moreover, the mRNA expression of GnRH, netrin-1, and UNC5C in hypothalamic tissues was determined by real-time PCR. Network pharmacological analysis was performed to predict the active compounds of APE and their potential actions. APE treatment delayed vaginal opening in rats with PP. In addition, APE treatment reduced LH levels and suppressed UNC5C expression. Gene set enrichment analysis revealed that the targets of APE were significantly associated with GnRH signaling and ovarian steroidogenesis pathways. In conclusion, APE may be used as a therapeutic remedy to inhibit the activation of the hypothalamic–pituitary–gonadal axis.

Anticancer Action of Xiaoxianxiong Tang in Non-Small Cell Lung Cancer by Pharmacological Analysis and Experimental Validation

Xiaoxianxiong Tang (XXXT) is a well-known traditional Chinese medicine formula. Evidence is emerging supporting the benefits of XXXT in ameliorating therapy for non-small cell lung cancer (NSCLC). The purpose of this study aimed to explore the effects and mechanisms of XXXT through network pharmacological analysis and biological validation. TCMSP database was used to identify potentially active compounds in XXXT with absorption, distribution, metabolism, excretion screening, and their potential targets. The disease targets related to NSCLC were predicted by searching for Therapeutic Target database, GeneCards database, DrugBank database, and DisGeNET database. Of the 4385 NSCLC-related targets, 156 targets were also the targets of compounds present in XXXT. Subsequently, GO function and KEGG pathway enrichment and PPI network analyses revealed that, of the 95 targets and 20 pathways influenced by 20 ingredients in XXXT, 20 targets were associated with patient survival, and XXXT could exert an inhibitory action on the PI3K-AKT signaling pathway. Moreover, XXXT restrained the proliferation of A549 and H460 cells in a concentration-dependent manner and suppressed the mRNA and protein levels of key targets CCNA2, FOSL2, and BIRC5 closely linked to the PI3K-AKT pathway. Hence, XXXT has the potential to improve therapy for NSCLC by targeting the PI3K-AKT signaling pathway.

Exploring the Therapeutic Mechanism of Tingli Dazao Xiefei Decoction on Heart Failure Based on Network Pharmacology and Experimental Study

Background. Tingli Dazao Xiefei decoction (TDXD) has been shown to have a therapeutic effect on heart failure (HF). Nevertheless, its molecular mechanism for treating HF is still unclear. Materials and Methods. TDXD and HF targets were collected from the databases, and protein-protein interaction (PPI) analysis and enrichment analysis were performed on the overlapping targets. Then, AutoDock was employed for molecular docking. Finally, we used the left anterior descending coronary artery (LAD) ligation to induce HF model rats for in vivo experiments and verified the effect and mechanism of TDXD on HF. Results. Network pharmacological analysis showed that the main active components of TDXD in treating HF were quercetin, kaempferol, beta-carotene, isorhamnetin, and beta-sitosterol, and the core targets were IL-6, VEGFA, TNF, AKT1, and MAPK1. Multiple gene functions and signaling pathways were obtained by enrichment analysis, among which inflammation-related, PI3K/Akt, and MAPK signaling pathways were closely related to HF. Furthermore, the molecular docking results showed that the core targets had good binding ability with the main active components. Animal experiments showed that TDXD could effectively improve left ventricular ejection fraction (EF) and left ventricular fractional shortening (FS), decrease left ventricular internal diastolic diameter (LVIDd) and left ventricular internal systolic diameter (LVIDs), reduce the area of myocardial fibrosis, and decrease serum BNP, LDH, CK-MB, IL-6, IL-1β, and TNF-α levels in HF rats. Meanwhile, TDXD could upregulate the expression of Bcl-2, downregulate the expression of Bax, and reduce cardiomyocyte apoptosis. At the same time, it was verified that TDXD could significantly decrease the expression of PI3K, P-Akt, and P-MAPK. Captopril showed similar effects. Conclusions. Combining network pharmacological analysis and experimental validation, this study verified that TDXD could improve cardiac function and protect against cardiac injury by inhibiting the activation of PI3K/Akt and MAPK signaling pathways.

Scutellarin ameliorates neonatal hypoxic-ischemic encephalopathy associated with GAP43-dependent signaling pathway

Background Neonatal hypoxic-ischemic encephalopathy (HIE) refers to the perinatal asphyxia caused by the cerebral hypoxic-ischemic injury. The current study was aimed at investigating the therapeutic efficacy of Scutellarin (Scu) administration on neurological impairments induced by hypoxic-ischemic injury and exploring the underlying mechanisms. Methods Primary cortical neurons were cultured and subjected to oxygen–glucose deprivation (OGD), and then treated with Scu administration. The growth status of neurons was observed by immunofluorescence staining of TUJ1 and TUNEL. Besides, the mRNA level of growth-associated protein 43 (GAP43) in OGD neurons with Scu treatment was detected by quantitative real-time polymerase chain reaction (qRT-PCR). To further verify the role of GAP43 in Scu treatment, GAP43 siRNA and knockout were applied in vitro and in vivo. Moreover, behavioral evaluations were performed to elucidate the function of GAP43 in the Scu-ameliorated long-term neurological impairments caused by HI insult. The underlying biological mechanism of Scu treatment was further elucidated via network pharmacological analysis. Finally, the interactive genes with GAP43 were identified by Gene MANIA and further validated by qRT-PCR. Results Our data demonstrated that Scu treatment increased the number of neurons and axon growth, and suppressed cell apoptosis in vitro. And the expression of GAP43 was downregulated after OGD, but reversed by Scu administration. Besides, GAP43 silencing aggravated the Scu-ameliorated neuronal death and axonal damage. Meanwhile, GAP43 knockout enlarged brain infarct area and deteriorated the cognitive and motor dysfunctions of HI rats. Further, network pharmacological analysis revealed the drug targets of Scu participated in such biological processes as neuronal death and regulation of neuronal death, and apoptosis-related pathways. GAP43 exhibited close relationship with PTN, JAK2 and STAT3, and GAP43 silencing upregulated the levels of PTN, JAK2 and STAT3. Conclusions Collectively, our findings revealed Scu treatment attenuated long-term neurological impairments after HI by suppressing neuronal death and enhancing neurite elongation through GAP43-dependent pathway. The crucial role of Scutellarin in neuroprotection provided a novel possible therapeutic agent for the treatment of neonatal HIE. Graphic abstract

Strategy of Virtual Screening Based Discovery of HSP90 C-terminal Inhibitors and Network Pharmacological Analysis

Background: HSP90 has been considered as an important anticancer target for several decades, but traditional HSP90 N-terminal inhibitors often suffered from organ toxicity and/or drug resistance. Methods: The development of HSP90 C-terminal inhibitors represents a reliable alternative strategy. In the view of rare examples of structure based identification of HSP90 C-terminal inhibitors, we reported a virtual screening based strategy for the discovery of HSP90 C-terminal inhibitors as anticancer agents from natural products. Results & Discussion: 13 chemical ingredients from licorice were identified as possible HSP90 inhibitors and 3 of them have been reported as anticancer agents. The binding modes of them towards HSP90 C-terminus were predicted by molecular docking and refined by molecular dynamics stimulation. Conclusion: Further network pharmacological analysis predicted overall possible targets involved in the pathways in cancer and revealed that 8 molecules possibly interact with HSP90.

Exploring the Potential Molecular Mechanism of Scutellaria baicalensis Georgi in the Treatment of Gastric Cancer Based on Network Pharmacological Analysis and Molecular Docking Technology

Objective: To explore the molecular mechanism of Scutellaria baicalensis Georgi in treating gastric cancer by network pharmacological analysis and molecular docking.Methods: Taking Scutellaria baicalensis Georgi as the object, the active components and corresponding potential drug targets in Scutellaria baicalensis Georgi were obtained from the database of TCM Pharmacological System Analysis Platform (TCMSP). GeneCards/OMIM/DrugBank and other databases were used to collect gastric cancer-related genes, and the obtained genes were intersected with drug targets to obtain the target genes of Scutellaria baicalensis Georgi on gastric cancer. Furthermore, the interaction network of Scutellaria baicalensis Georgi-active ingredients-target-gastric cancer-related genes was constructed. Protein–protein interaction analysis and gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed on target genes. The PubChem website was used to screen the compounds corresponding to the target genes, and the target protein and 3D structure pdb format files were obtained from the PDB database. Finally, the molecular docking calculation was performed by the AutoDock Vina program. The in vivo cell experiments on the effect of Scutellaria baicalensis on proliferation and migration of gastric cancer cells were used to determine the therapeutic effect of Scutellaria baicalensis on gastric cancer, and the two genes ESR1 and FOS are the key targets of Scutellaria baicalensis on gastric cancer.Results: A total of 10 gastric cancer-related target genes were screened out, and Scutellaria baicalensis Georgi contained 10 active compounds targeting 10 gene sites. There are 30 effective compounds in Scutellaria baicalensis Georgi targeted to treat gastric cancer, and there are 91 corresponding targeting gene sites, involving a total of 10 pathways. The results of molecular docking show that ESR1, FOS, and Scutellaria baicalensis Georgi have good binding free energy and docking fraction. The docking fraction of FOS is −4.200 and the binding free energy is −27.893 kcal/mol. The docking fraction of ESR1 is −5.833 and the binding free energy is −30.001 kcal/mol. The effect of Scutellaria baicalensis Georgi on gastric cancer was verified by in vitro cell experiments and Western blotting.Conclusion:Scutellaria baicalensis Georgi can target and regulate multiple signal pathways by acting on ESR1 and FOS gene loci, thus having a potential therapeutic effect on gastric cancer.