Network Pharmacology Analysis Research Articles

Mechanisms of Tripterygium wilfordii Hook F on treating rheumatoid arthritis explored by network pharmacology analysis and molecular docking.

Rheumatoid arthritis (RA) is a chronic inflammatory and disabling disease that imposes significant economic and social costs. Tripterygium wilfordii Hook F (TwHF) has a long history of use in traditional Chinese medicine for treating joint disorders, and it has been shown to be cost-effective in treating RA, but its exact mechanism is unknown. The goal of the network pharmacology analysis and molecular docking was to investigate the potential active compounds and associated anti-RA mechanisms of TwHF. TCMSP and UniProt databases were searched for active compounds and related targets of TwHF. PharmGKB, DrugBank, OMIM, TTD, and the Human Gene Databases were used to identify RA-related targets. The intersected RA and TwHF targets were entered into the STRING database to create a protein-protein interaction network. R software was used for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking technology was used to analyze the optimal effective components from TwHF for docking with the selected target gene. Following screening and duplicate removal, a total of 51 active compounds and 96 potential targets were chosen. The PPI network revealed that the target proteins are CXCL8, CXCL6, STAT3, STAT1, JUN, PPARG, TP53, IL14, MMP9, VEGFA, RELA, CASP3, PTGS2, IFNG, AKT1, FOS, ICAM1, and MAPK14. The results of the GO enrichment analysis focused primarily on the response to lipopolysaccharide, the response to molecules of bacterial origin, and the response to drugs. The KEGG results indicated that the mechanisms were closely related to lipid and atherosclerosis, chemical carcinogenesis-receptor activation, Kaposi sarcoma-associated, herpesvirus infection, hepatitis B, fluid shear stress and atherosclerosis, IL-17 signaling pathways, Th17-cell differentiation, and so on, all of which are involved in angiogenesis, immune cell chemotaxis, and inflammatory responses. Molecular docking results suggested that triptolide was the appropriate PTGS1, PTGS2, and TNF inhibitors. Our findings provide an essential role and basis for further immune inflammatory studies into the molecular mechanisms of TwHF and PTGS1, PTGS2, and TNF inhibitor development in RA.

The Bioactive Compounds of Epimedium and Their Potential Mechanism of Action in Treating Osteoporosis: A Network Pharmacology and Experimental Validation Study.

Osteoporosis is a global health challenge characterized by bone loss and microstructure deterioration, which urgently requires the development of safer and more effective treatments due to the significant adverse effects and limitations of existing drugs for long-term treatment. Traditional Chinese medicine, like Epimedium, offers fewer side effects and has been used to treat osteoporosis, yet its active compounds and pharmacological mechanisms remain unclear. In this study, 65 potential active compounds, 258 potential target proteins, and 488 pathways of Epimedium were identified through network pharmacology analysis. Further network analysis and review of the literature identified six potential active compounds and HIF-1α for subsequent experimental validation. In vitro experiments confirmed that 2″-O-RhamnosylIcariside II is the most effective compound among the six potential active compounds. It can promote osteoblast differentiation, bind with HIF-1α, and inhibit both HIF-1α gene and protein expression, as well as enhance COL1A1 protein expression under hypoxic conditions. In vivo experiments demonstrated its ability to improve bone microstructures and reduce bone loss by decreasing bone marrow adipose tissue, enhancing bone formation, and suppressing HIF-1α protein expression. This study is the first to describe the therapeutic effects of 2-O-RhamnosylIcariside II on osteoporosis, which was done, specifically, through a mechanism that targets and inhibits HIF-1α. This study provides a scientific basis for the clinical application of Epimedium and offers a new candidate drug for the treatment of osteoporosis. Additionally, it provides new evidence supporting HIF-1α as a therapeutic target for osteoporosis.

Integrated network pharmacology analysis and experimental validation to investigate the mechanism of Flavan-3-ols and aromatic resins in depression.

The present investigation delved into the pharmacological mechanisms underlying the management of depression through Flavan-3-ols and Aromatic Resins, employing in silico and in vivo methodologies. Network pharmacology was utilized to identify targets associated with the antidepressant activity of Flavan-3-ols and Aromatic Resins. Protein-protein interaction and KEGG analyses were conducted to enrich and explore key pathways. Molecular docking and simulation studies were executed to assess the targets. The antidepressant effects were studied using the Forced Swim Test and Tail Suspension Test on both unstressed mice and those subjected to the chronic unpredictable mild stress (CUMS) paradigm. The Compound-Target network analysis revealed a substantial impact of the components on numerous targets, with 332 nodes and 491 edges. Protein-protein interaction analysis indicated significant interactions with targets implicated in depression. KEGG analysis highlighted major pathways, including neuroactive ligand-receptor interaction, dopaminergic synapse, and long-term depression. Docking studies on EGCG demonstrated binding energies of -7.2kcal/mol for serotonin 1A (5-HT1A), -7.9kcal/mol for D2, and - 9.6kcal/mol for MOA-A. Molecular dynamics simulation indicated minute fluctuation, hence suggesting stable complexes formed between small molecules and proteins. The combination of Flavan-3-ols and Aromatic Resins significantly increased mobility time (p < 0.05) in the Forced Swim Test and Tail Suspension Test, while significantly decreasing immobility time and time freezing (p < 0.05) in both unstressed and CUMS mice. This study demonstrated the antidepressant characteristics of Flavan-3-ols and Aromatic Resins, underscoring the need for further research to develop a novel antidepressant medication.

A comprehensive study on the regulation of Compound Zaoren Granules on cAMP/CREB signaling pathway and metabolic disorder in CUMS-PCPA induced insomnia rats

Ethnopharmacological relevanceCompound Zaoren Granules (CZG), an optimized herbal formulation based on the traditional Chinese medicine prescription Suanzaoren decoction, are designed specifically for insomnia treatment. However, the mechanisms underlying its efficacy in treating insomnia are not yet fully understood. Aim of the studyThe research investigated the mechanisms of CZG's improvement in insomnia by regulating cAMP/CREB signaling pathway and metabolic profiles. MethodsThe main components of CZG were characterized by liquid chromatography-mass spectrometry (LC-MS). Subsequently, these validated components were applied to network pharmacological analysis to predict signaling pathways associated with insomnia. We evaluated the effect of CZG on BV-2 cells in vitro. We also evaluated the behavioral indexes of CUMS combined with PCPA induced insomnia in rats. HE staining and Nissl staining were used to observe the pathological damage of hippocampus. ELISA was used to detect the levels of various neurotransmitters, orexins, HPA axis, and inflammatory factors in insomnia rats. Then we detected the expression of cAMP/CREB signaling pathway through ELISA, WB, and IHC. Finally, the metabolomics was further analyzed by using UHPLC-QTOF-MS/MS to investigate the changes in the hippocampus of insomnia rats and the possible metabolic pathways were also speculated. ResultsThe results of CZG in vitro experiments showed that CZG has protective and anti-inflammatory effects on LPS induced BV-2 cells. A total of 161 chemical components were identified in CZG. After conducting network pharmacology analysis through these confirmed components, we select the cAMP/CREB signaling pathway for further investigate. The behavioral research results on insomnia rats showed that CZG significantly prolonged sleep time, mitigated brain tissue pathological damage, and exhibited liver protective properties. CZG treats insomnia by regulating the content of various neurotransmitters, reducing levels of orexin, HPA axis, and inflammatory factors. It can also treat insomnia by upregulating the expression of the cAMP/CREB signaling pathway. Hippocampus metabolomics analysis identified 69 differential metabolites associated with insomnia. The metabolic pathways related to these differential metabolites have also been predicted. ConclusionThese results indicate that CZG can significantly prolong sleep time. CZG is used to treat insomnia by regulating various neurotransmitters, HPA axis, inflammatory factors, cAMP/CREB signaling pathways, and metabolic disorders.

Mechanism of Cnidii Fructus in the Treatment of Infertility Based on Network Pharmacology and Molecular Docking Analysis Technology.

Infertility is a condition characterized by a low fertility rate, which significantly affects the physical and mental health of women of reproductive age. Typically, the treatment duration is prolonged, and the therapeutic outcomes are often unsatisfactory. Professor Cheng-yao He, a renowned expert in traditional Chinese medicine, commonly uses the herb Cnidii Fructus (SCZ) for the treatment of infertility. However, the exact mechanism remains unclear, and there is limited research available on this topic. The active ingredients of SCZ were obtained from the traditional chinese medicine system pharmacology (TCMSP) database and screened for pharmacokinetics (PK), involving absorption, distribution, metabolism, and excretion (ADME). Target prediction was performed by SwissTargetPrediction database, and infertility-related disease targets were searched in GeneCards, TTD, DrugBank, and OMIM database. The protein-protein interaction (PPI) network was constructed using the STRING database (Version 11.5) and analyzed by Cytoscape software (Version 3.9.1). Additionally, the target genes were subjected to biological enrichment analysis in the Metascape database, including gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis, and the "Disease-Ingredient-pathway-target" network was constructed using Cytoscape software. With the assistance of AutoDockVina, Ligplot, and PyMOL software, a validation of Molecular docking results and a visualization of the results were performed. This study identified 11 retained active ingredients of SCZ, 447 drug targets, 233 of which were related to infertility, and 5393 disease targets. GO enrichment analysis mainly involved 221 biological processes such as cellular response to chemical stress and gland development. KEGG enrichment analysis mainly involved 68 pathways such as thyroid hormone signaling pathway, estrogen signaling pathway, FOXO signaling pathway, and PI3K/Akt signaling pathway. Molecular docking showed that the core active ingredients of SCZ, including Ammidin, Diosmetin, Xanthoxylin N, and Prangenidin, had strong binding abilities with core targets such as MDM2, MTOR, CCND1, EGFR, and AKT1. This study preliminarily demonstrated that SCZ may act on the PI3K/Akt signaling pathway, exerting its therapeutic effects on infertility by improving energy metabolism disorders and endometrial receptivity, inducing primordial follicle activation, regulating oocyte proliferation, differentiation, and apoptosis, and promoting the release of dominant follicles.

The Mechanism of Scopolamine’s Effect on Migration Function of Lung Cancer Cells: A Network Pharmacology and Bioinformatics Perspective

Background. This study utilized network pharmacology and bioinformatics analysis to identify the hub genes influenced by scopolamine in lung cancer. Methods. The effect of scopolamine on lung cancer was investigated by cell invasion assay and cell scratch assay. The analysis involved protein-protein interaction (PPI) networks topology analysis to identify these genes, and subsequent differential analysis and survival analysis were conducted using gene expression profile interaction analysis (GEPIA). Furthermore, the findings were supported by molecular docking experiments for verification. Results. Results from cell invasion and scratch assays suggest that scopolamine inhibits the migration of lung cancer cells. JAK2, JAK3, CCR5, and ACE were identified as the top four hub genes that have an impact on lung cancer. KEGG enrichment analysis revealed that the scopolamine response in lung cancer is significantly associated with ten pathways, including “neuroactive ligand-receptor interaction in cancer,” “PD-1 checkpoint pathway in cancer,” “chemokine signaling pathway,” “PD-L1 expression,” and others. Additionally, the expression levels of JAK2, JAK3, CCR5, and ACE were found to be correlated with survival in patients with lung cancer. Furthermore, molecular docking experiments demonstrated that scopolamine binds and forms stable complexes with the protein products of all four aforementioned genes. The main targets of scopolamine in the treatment of lung cancer are JAK2, JAK3, CCR5, and ACE. Conclusion. Scopolamine has a significant effect on various cellular functions in lung cancer cells, potentially reducing the likelihood of metastasis. Based on these findings, it is recommended to consider administering scopolamine as part of the preoperative phase for patients with lung cancer.

Study on the Mechanism of Action of the Traditional Chinese Medical Prescription Gushukang in Treating Osteoporosis Based on Network Pharmacology and Experimental Verification.

Gushukang (GSK), a traditional Chinese medical prescription, has made a great and extensive contribution to the treatment of different forms of osteoporosis, but polypharmacology studies of its mechanism of action are lacking. This study investigates the pharmacological mechanism of osteoporosis using network pharmacology and molecular docking. Experimental verification was carried out to confirm the efficacy of GSK on RANKLinduced osteoclast differentiation in RAW264.7 cells to verify the network pharmacology studies. The effective chemical components and corresponding targets of osteoporosis with oral bioavailability of more than 30% and drug-like properties greater than 0.18 were searched in the TCMSP and TCM-ID databases. DrugBank, GeneCards, OMIM, TTD, and other databases were examined for targets related to osteoporosis. Using Cytoscape software, a network of possible TCM-active ingredient-osteoporosis targets was created. STRING software was used to create the networks of protein-protein interactions. The DAVID program was carried out to conduct GO and KEGG pathway enrichment analyses of the targets. Molecular docking and pattern of action analysis were carried out using software like AutoDock Vina and Discovery Studio Visualizer. The growth media for RAW264.7 cells contained varying doses of GSK serum and 50 ng/mL RANKL. The activity of TRAP was altered. Additionally, genes related to osteoclasts were examined using an RT-PCR assay. Network pharmacological analysis revealed that the primary efficacy targets of osteoporosis were PTGS2, PTGS1, HSP90AA1, NCOA2, ADRB2, ESR1, NCOA1, and AR. The pharmacological targets of osteoporosis may be mediated by substances including quercetin, kaempferol, luteolin, naringenin, icariin, anthocyanin, tanshinone IIA, and cryptotanshinone. GSK markedly inhibited RANKL-induced TRAP activity. qRT-PCR results revealed decreased expression of the PTGS2 and ADRB2 genes upon GSK treatment. The findings of network pharmacology, molecular docking, as well as experimental verification provide a new further study for elucidating the pharmacodynamic substance basis and polypharmacology mechanism of GSK in treating osteoporosis.

Jingfang granules protects against intracerebral hemorrhage by inhibiting neuroinflammation and protecting blood-brain barrier damage.

Intracerebral hemorrhage (ICH) can induce intensive oxidative stress, neuroinflammation, and brain cell apoptosis. However, conventional methods for ICH treatment have many disadvantages. There is an urgent need for alternative, effective therapies with minimal side effects. Pharmacodynamics experiment, molecular docking, network pharmacology, and metabolomics were adopted to investigate the treatment and its mechanism of Jingfang Granules (JFG) in ICH. In this study, we investigated the therapeutic effects of JFG on ICH using behavioral, brain water content and Magnetic resonance imaging experiments. However, the key active component and targets of JFG remain unknown. Here we verified that JFG was beneficial to improve brain injury after ICH. A network pharmacology analysis revealed that the anti-inflammatory effect of JFG is predominantly mediated by its activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway through Luteolin, (+)-Anomalin and Phaseol and their targeting of AKT1, tumor necrosis factorα (TNF-α), and interleukin-1β (IL-1β). Molecular docking analyses revealed an average affinity of -8.633 kcal/mol, indicating a binding strength of less than -5 kcal/mol. Metabolomic analysis showed that JFG exerted its therapeutic effect on ICH by regulating metabolic pathways, such as the metabolism of taurine and hypotaurine, biosynthesis of valine, leucine, and isoleucine. In conclusion, we demonstrated that JFG attenuated neuroinflammation and BBB injury subsequent to ICH by activating the PI3K/Akt signaling pathway.

Insights into the potential dual-antibacterial mechanism of Kelisha capsule on Escherichia coli

Traditional Chinese medicine (TCM), AYURVEDA and Indian medicine are essential in disease prevention and treatment. Kelisha capsule (KLSC), a TCM formula listed in the Chinese Pharmacopoeia, has been clinically proven to possess potent antibacterial properties. However, the precise antimicrobial mechanism of KLSC remained unknown. This study aimed to elucidate the dual antibacterial mechanism of KLSC using network pharmacology, molecular docking, and experimental validation. By analyzing the growth curve of Escherichia coli (E. coli), it was observed that KLSC significantly inhibited its growth, showcasing a remarkable antibacterial effect. Furthermore, SEM and TEM analysis revealed that KLSC damaged the cell wall and membrane of E. coli, resulting in cytoplasmic leakage, bacterial death, and the exertion of antibacterial effects. The network pharmacology analysis revealed that KLSC exhibited an effect on E. coli ATP synthase, thereby influencing the energy metabolism process. The molecular docking outcomes provided evidence that the active compounds of KLSC could effectively bind to the ATP synthase subunit. Subsequently, experimental findings substantiated that KLSC effectively suppressed the activity of ATP synthase in E. coli and consequently decreased the ATP content. This study highlighted the dual antibacterial mechanism of KLSC, emphasizing its effects on cell structure and energy metabolism, suggesting its potential as a natural antibacterial agent for E. coli-related infections. These findings offered new insights into exploring the antibacterial mechanisms of TCM by focusing on the energy metabolism process.

Network pharmacology, molecular docking, and dynamics analyses to predict the antiviral activity of ginger constituents against coronavirus infection.

COVID-19 is a global pandemic that caused a dramatic loss of human life worldwide, leading to accelerated research for antiviral drug discovery. Herbal medicine is one of the most commonly used alternative medicine for the prevention and treatment of many conditions including respiratory system diseases. In this study, a computational pipeline was employed, including network pharmacology, molecular docking simulations, and molecular dynamics simulations, to analyze the common phytochemicals of ginger rhizomes and identify candidate constituents as viral inhibitors. Furthermore, experimental assays were performed to analyze the volatile and non-volatile compounds of ginger and to assess the antiviral activity of ginger oil and hydroalcoholic extract. Network pharmacology analysis showed that ginger compounds target human genes that are involved in related cellular processes to the viral infection. Docking analysis highlighted five pungent compounds and zingiberenol as potential inhibitors for the main protease (Mpro), spike receptor-binding domain (RBD), and human angiotensin-converting enzyme 2 (ACE2). Then, (6)-gingerdiacetate was selected for molecular dynamics (MD) simulations as it exhibited the best binding interactions and free energies over the three target proteins. Trajectories analysis of the three complexes showed that RBD and ACE2 complexes with the ligand preserved similar patterns of root mean square deviation (RMSD) and radius of gyration (Rg) values to their respective native structures. Finally, experimental validation of the ginger hydroalcoholic extract confirmed the existence of (6)-gingerdiacetate and revealed the strong antiviral activity of the hydroalcoholic extract with IC of 2.727 . Our study provides insights into the potential antiviral activity of (6)-gingerdiacetate that may enhance the host immune response and block RBD binding to ACE2, thereby, inhibiting SARS-CoV-2 infection.

Network pharmacology and transcriptomics analysis reveal the mechanism of BushenHuoxue formula attenuates premature ovarian failure via modulation PI3K/AKT pathway.

This study aims to analyze the active components and mechanism of Bushen Huoxue (BSHX) formula on the autoimmune premature ovarian insufficiency (POI) by combining network pharmacology and Transcriptomics. The active components and targets of BSHXF were screened through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). POI-related targets were identified through Therapeutic Targets Database (TTD), DisGeNET and drugbank database. The Veen diagram was performed to obtain the action targets. The active compound-target network and Protein-Protein Interaction (PPI) network were built by using STRING database and Cytoscape software. Key targets and active compounds were further identified by topological analysis. Molecular docking shows that Kaempferol, Isorhamnetin and Anhydroicaritin have strong binding to AKT. Finally, a zp3-induced autoimmune ovarian function deficiency mouse model was used to explore the potential mechanism of POI. The potential pathways of BSHXF for the treatment of POI were identified by Transcriptomic analysis. PI3K-AKT and NF-kb pathways were the common pathways between network pharmacology and transcriptomics. Our results revealed that BSHXF could reduce the FSH expression levels and raise the E2, and AMH levels in the serum. Western bloting demonstrates that BSHXF could upregulate the expression of p-PI3K and p-AKT.

Network Pharmacology Analysis of the Potential Pharmacological Mechanism of a Sleep Cocktail.

Insomnia, also known as sleeplessness, is a sleep disorder due to which people have trouble sleeping, followed by daytime sleepiness, low energy, irritability, and a depressed mood. It may result in an increased risk of accidents of all kinds as well as problems focusing and learning. Dietary supplements have become popular products for alleviating insomnia, while the lenient requirements for pre-market research result in unintelligible mechanisms of different combinations of dietary supplements. In this study, we aim to systematically identify the molecular mechanisms of a sleep cocktail's pharmacological effects based on findings from network pharmacology and molecular docking. A total of 249 targets of the sleep cocktail for the treatment of insomnia were identified and enrichment analysis revealed multiple pathways involved in the nervous system and inflammation. Protein-protein interaction (PPI) network analysis and molecular complex detection (MCODE) analysis yielded 10 hub genes, including AKT1, ADORA1, BCL2, CREB1, IL6, JUN, RELA, STAT3, TNF, and TP53. Results from weighted correlation network analysis (WGCNA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of insomnia-related transcriptome data from peripheral blood mononuclear cells (PBMCs) showed that a sleep cocktail may also ease insomnia via regulating the inflammatory response. Molecular docking results reveal good affinity of Sleep Cocktail to 9 selected key targets. It is noteworthy that the crucial target HSP90AA1 binds to melatonin most stably, which was further validated by MD simulation.

Health Benefits of Antioxidant Bioactive Compounds in Ginger (Zingiber officinale) Leaves by Network Pharmacology Analysis Combined with Experimental Validation.

Network pharmacology is an ideal tool to explore the effects of therapeutic components derived from plants on human metabolic diseases that are linked to inflammation. This study investigated the antioxidant effects of ginger leaves (GLs) and predicted targets for antioxidant activity. Quantitative and free radical scavenging analyses were performed to detect the main bioactive compounds of GLs and evaluate their antioxidant activities. Chemical diversity and network pharmacology approaches were used to predict key antioxidant components of GLs and their molecular targets. Nine major bioactive compounds of GLs were quantified using an internal standard method, and the antioxidant activity was evaluated using the DPPH and ABTS free radical scavenging methods. We first built the compound-gene-pathways and protein-protein interaction networks of GLs-related antioxidant targets and then conducted gene ontology and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analyses. Molecular docking results show that astragalin, a compound isolated from GLs, had the highest level of connectivity in the compound-target network and was involved in inflammation-related biosynthesis by directly impacting cytokine gene expression and PTGS2 inhibition markers. These findings not only suggest that the compounds isolated from GLs can be developed as potential antioxidants, but also demonstrate the applicability of network pharmacology to assess the potential of foods for disease treatment.

Matrine inhibits invasion and migration of gallbladder cancer via regulating the PI3K/AKT signaling pathway.

Gallbladder cancer (GBC) is a common malignant cancer in the biliary system, which poses a serious threat to human health. It is urgent to explore ideal drugs for the treatment of GBC. Matrine is the main active ingredient of Sophora flavescentis, with a wide range of biological activities encompassing anti-inflammatory, antiviral, immunomodulatory, and anti-tumor. However, the underlying mechanism by which Matrine treats GBC is still unclear. The purpose of this study is to investigate the anti-tumor effects of Matrine on GBC in vivo and in vitro and to clarify the potential regulatory mechanisms. Here, we found that Matrine had a significant killing effect on GBC through CCK8 and flow cytometry, including arrest of cell cycle, inhibition of GBC cell, and induction of apoptosis. Further in vivo studiesconfirmed the inhibitory effect of Matrine on tumor growth in NOZ xenografted nude mouse. At the same time, Matrine also significantly suppressed the migration and invasion of GBC cells through scratch and Transwell experiments. In addition, by detecting the mRNA and protein levels of epithelial-mesenchymal transition (EMT) and matrix metalloproteinases, Matrine furtherly substantiated the inhibitory role on invasion and migration of GBC. From a mechanistic perspective, network pharmacology analysis suggests that the potential targets of Matrine in the treatment of GBC are enriched in the PI3K/AKT signaling pathway. Subsequently, Matrine effectively decreased the abundance of p-PI3K and p-AKT protein in vivo and in vitro. More importantly, PI3K activator (740 Y-P) antagonized the anti-tumor effect of Matrine, while PI3K inhibitor (LY294002) increased the sensitivity of Matrine for GBC. Based on the above findings, we conclude that Matrine inhibits the invasion and migration of GBC by regulating PI3K/AKT signaling pathway. Our results indicate the crucial role and regulatory mechanism of Matrine in suppressing the growth of GBC, which provides a theoretical basis for Matrine to be a candidate drug for the treatment and research of GBC.

Paeoniae Radix Alba effectively attenuates Polygonum multiflorum Thunb. -induced idiosyncratic liver injury by modulating M2 macrophage polarization

Objective: Polygonum multiflorum Thunb. (PM) is a commonly used tonic herb known to cause idiosyncratic drug-induced liver injury (IDILI). This study explored the detoxification effects and potential mechanisms of action of Paeoniae Radix Alba (PRA) on PM-induced IDILI. Methods: Network pharmacology analysis was utilized to predict the related targets of "PRA-PM-innate immunity.” A non-hepatotoxic lipopolysaccharide (LPS) and PM-induced IDILI model was used to evaluate the detoxification effects of PRA by measuring liver function indicators, pathological examinations, and macrophage-related factors. Bone marrow-derived macrophages (BMDMs) were stimulated with IL-4 to differentiate into M2 macrophages, and the effects of PM and PRA on M2 macrophage polarization were explored. Results: Target screening of "PRA-PM-innate immunity" identified 21 intersecting targets, most of which were closely associated with macrophage polarization. In rat models of IDILI induced by PM, the combined use of PRA significantly reduced the extent of liver damage and the levels of inflammatory factors, while promoting the expression of M2 macrophage-related factors such as IL-4, IL-10, Arg1, and CD206. In vitro, PM dose-dependently inhibited the expression of the Arg1 protein and M2 macrophage-related genes, whereas PRA exhibited the opposite effect. When used in combination, PRA ameliorated the inhibitory effect of PM on M2 macrophage polarization. Conclusions: Our results demonstrate that PRA has a therapeutic effect on PM-induced IDILI; its mechanism may involve alleviating liver injury by promoting M2 macrophage polarization, thus reducing the expression of inflammatory factors.

A peptide from yak ameliorates hypoxia-induced kidney injury by inhibiting inflammation and apoptosis via Nrf2 pathway

Chronic kidney disease is a prevalent and severe significant complication of hypoxia. This study found that peptide LVYPFPGPIPN could protect hypoxia-induced renal injury in the animal model. Network pharmacology and molecular docking analysis indicated that cathepsin B (CTSB) and interleukin-1β (IL-1β) represent potential targets for the prevention/treatment of hypoxic-induced renal injury. GO analysis revealed the involvement of these genes in various biological processes, including apoptosis regulation, oxidative stress response, and adaptive immune modulation. Experimental results in vitro and in vivo demonstrated that peptide LVYPFPGPIPN could effectively inhibit apoptosis and stress responses of kidney cells by regulating the NRF2/IL-1β/mitochondrial apoptosis pathway, thereby protecting hypoxic human embryonic kidney cells from damage. The anti-hypoxic effect of the LVYPFPGPIPN offers a novel therapeutic clue for the treatment/prevention of hypoxic-induced kidney injury and inflammation-associated chronic kidney disease.

Study on the bioactive ingredients and mechanism of Huangqi against diabetic retinopathy based on network pharmacology and experimental verification.

Diabetic retinopathy (DR) is one of the most well-known microvascular complications of diabetes mellitus. As a traditional Chinese medicine, Huangqi (HQ), has been used for treating DR for a long time. However, its anti-DR active ingredients and mechanism are still unknown. Therefore, we designed this study to explore the active components and mechanism of HQ against DR via network pharmacology analysis. The ingredients of HQ, and potential targets of HQ and DR were obtained from public databases. We used the protein-protein interaction (PPI) network, Kyoto Encyclopedia of Genes and Genomes (KEGGs) pathway enrichment, and Gene Ontology (GO) analysis to identify core targets and pathways of HQ against DR. Finally, molecular docking and vitro experiments were applied to validate our results. A total of 34 potential targets of HQ against DR were obtained. Based on PPI network, VEGFA, PTGS2, Interleukin-6 (IL-6), and CCL2 were considered as core targets. GO analysis involved 692 biological processes, 21 cellular components, and 35 molecular functions. KEGG enrichment analysis manifested that the anti-DR effect of HQ was mainly mediated via the AGE-RAGE signaling pathway in diabetic complications. The molecular docking results indicated that kaempferol had higher affinity with CCL2, IL-6, VEGFA, and PTGS2. The vitro experiments showed that the mRNA expressions of CCL2, IL-6, VEGFA, and PTGS2 in ARPE-19 cells were differentially decreased after kaempferol treatment. This study preliminarily unveiled that the therapeutic efficacy of HQ against DR might be attributed to the reduced expression of CCL2, IL-6, VEGFA, and PTGS2.

#971 Effects of arsenic trioxide on MMP9/IL-17A expression in lupus nephritis—results from bioinformatics analysis and in vitro studies

Abstract Background and Aims Previous research has indicated that ATO treatment at low doses may decrease the likelihood of flares in active systemic lupus erythematosus (SLE) patients, but the pharmacological mechanisms of such effect have not been studied. Method Machine learning and network pharmacology analysis were employed to explore the potential targets from differentially expressed genes (DEGs) of human SLE and LN peripheral blood mononuclear cells (PBMCs) microarray datasets and pharmacological databases. GO and KEGG analyses were performed, and the protein-protein interaction (PPI) network was constructed. The association of these characteristic genes and immune cells were further examined and validated. Results Three machine learning models (RF, SVM, and XGB) were utilized to identify five immunoregulatory genes in SLE among twelve intersection DEGs. Among these genes, MMP9 exhibited the highest ROC AUC (0.92) in predicting disease development. KEGG analysis revealed significant associations with the IL-17 signaling pathway (p = 1.67E-18). Furthermore, ssGSEA analysis indicated positive correlations between MMP9 and macrophages (correlation coefficient 0.88) as well as neutrophils (correlation coefficient 0.66). In vitro treatment of PBMCs from lupus nephritis (LN) patients with ATO resulted in downregulation of MMP9 and IL-17A, validating our bioinformatics findings. Conclusion ATO has the potential to mitigate the MMP/IL-17A pathways in PBMCs in LN patients, and hence maybe a promising and innovative therapeutic alternative.

Analysis of an Aqueous Extract from Turkish Galls Based on Multicomponent Qualitative and Quantitative Analysis Combined with Network Pharmacology and Chemometric Analysis.

The current quality control method for Turkish gall (TG) is limited to assessing total tannin or gallic acid (GA), which offers a basic level of quality control but does not fully capture the true quality of TG. Therefore, it is essential to establish a comprehensive method that utilizes multiple indicators to assess the intrinsic quality of TG. This research utilized UPLC-Q-TOF-MS/MS technology to qualitatively analyze the chemical composition of TG. Subsequently, the potential main active ingredients, targets, and pathways of TG in treating recurrent aphthous ulcers (RAU) were explored and analyzed using network pharmacology technology. Quantitative analysis of multicomponents by single marker (QAMS) was then employed to quantify the primary pharmacodynamic components in TG. Finally, chemometrics analysis was utilized to interpret the measured results and identify the markers of scavenging quality. The study identified 36 chemical components in TG, highlighting ellagic acid (EA), GA, and so on as key components in treating RAU. A method for simultaneously determining GA, EA, 1,2,3,6-tetra-O-galloyl-β-D-glucose (TEGG) and 1,2,3,4,6-penta-O-galloyl-β-D-glucose (PEGG) in TG was established. Statistical analysis revealed significant differences in the content of these 4 components across 14 batches of TG, with GA and PEGG identified as the primary contributors to the variations. This study determined a quality index for TG, providing a reference for quality evaluation and introducing a cost-effective and efficient quality control method. Furthermore, it addressed the challenge of developing new Chinese medicine by overcoming the lack of reference substances.

Exploring the mechanism of 6-Methoxydihydrosanguinarine in the treatment of lung adenocarcinoma based on network pharmacology, molecular docking and experimental investigation

Background6-Methoxydihydrosanguinarine (6-MDS) has shown promising potential in fighting against a variety of malignancies. Yet, its anti‑lung adenocarcinoma (LUAD) effect and the underlying mechanism remain largely unexplored. This study sought to explore the targets and the probable mechanism of 6-MDS in LUAD through network pharmacology and experimental validation.MethodsThe proliferative activity of human LUAD cell line A549 was evaluated by Cell Counting Kit-8 (CCK8) assay. LUAD related targets, potential targets of 6-MDS were obtained from databases. Venn plot analysis were performed on 6-MDS target genes and LUAD related genes to obtain potential target genes for 6-MDS treatment of LUAD. The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database was utilized to perform a protein-protein interaction (PPI) analysis, which was then visualized by Cytoscape. The hub genes in the network were singled out by CytoHubba. Metascape was employed for GO and KEGG enrichment analyses. molecular docking was carried out using AutoDock Vina 4.2 software. Gene expression levels, overall survival of hub genes were validated by the GEPIA database. Protein expression levels, promotor methylation levels of hub genes were confirmed by the UALCAN database. Timer database was used for evaluating the association between the expression of hub genes and the abundance of infiltrating immune cells. Furthermore, correlation analysis of hub genes expression with immune subtypes of LUAD were performed by using the TISIDB database. Finally, the results of network pharmacology analysis were validated by qPCR.ResultsExperiments in vitro revealed that 6-MDS significantly reduced tumor growth. A total of 33 potential targets of 6-MDS in LUAD were obtained by crossing the LUAD related targets with 6-MDS targets. Utilizing CytoHubba, a network analysis tool, the top 10 genes with the highest centrality measures were pinpointed, including MMP9, CDK1, TYMS, CCNA2, ERBB2, CHEK1, KIF11, AURKB, PLK1 and TTK. Analysis of KEGG enrichment hinted that these 10 hub genes were located in the cell cycle signaling pathway, suggesting that 6-MDS may mainly inhibit the occurrence of LUAD by affecting the cell cycle. Molecular docking analysis revealed that the binding energies between 6-MDS and the hub proteins were all higher than − 6 kcal/Mol with the exception of AURKB, indicating that the 9 targets had strong binding ability with 6-MDS.These results were corroborated through assessments of mRNA expression levels, protein expression levels, overall survival analysis, promotor methylation level, immune subtypes andimmune infiltration. Furthermore, qPCR results indicated that 6-MDS can significantly decreased the mRNA levels of CDK1, CHEK1, KIF11, PLK1 and TTK.ConclusionsAccording to our findings, it appears that 6-MDS could possibly serve as a promising option for the treatment of LUAD. Further investigations in live animal models are necessary to confirm its potential in fighting cancer and to delve into the mechanisms at play.