Network Pharmacology Approach Research Articles

From Tea to Functional Foods: Exploring Caryopteris mongolica Bunge for Anti-Rheumatoid Arthritis and Unraveling Its Potential Mechanisms

Background: Caryopteris mongolica Bunge (CM) shows promising potential for managing rheumatoid arthritis (RA) and digestive disorders, attributed to its rich content of bioactive compounds such as polyphenols and flavonoids. Despite its common use in herbal tea, the specific mechanisms underlying CM’s anti-inflammatory and joint-protective effects remain unclear, limiting its development as a functional food. This study investigated the effects of aqueous CM extract on RA in collagen-induced arthritis (CIA) rats and explored the underlying mechanisms. Methods: Forty-eight female Sprague-Dawley rats were randomly assigned to six groups (n = 8): normal control, CIA model, methotrexate (MTX), and CM high-, middle-, and low-dose groups. Anti-inflammatory and joint-protective effects were evaluated using biochemical and histological analyses. To elucidate the mechanisms, we applied metabolomics, network pharmacology, and transcriptomics approaches. Results: The results demonstrated that CM extract effectively suppressed synovial inflammation in CIA rats, reducing joint degradation. CM’s anti-inflammatory effects were mediated through the TNF signaling pathway, modulating glycerophospholipid and amino acid metabolism, including reduced levels of tryptophan, LysoPC, and asparagine. Molecular docking identified scutellarin and apigenin as key bioactive compounds. Additionally, immunofluorescence analysis revealed CM’s therapeutic effects via TNF signaling inhibition and suppression of M1 macrophage polarization. Conclusions: These findings highlight the therapeutic potential of CM for RA and support its development as a functional food or pharmaceutical product.

Piceatannol-3'-O-β-D-glucopyranoside inhibits neuroexcitotoxicity and ferroptosis through NMDAR/NRF2/BACH1/ACSL4 pathway in acute ischemic stroke.

Neuronal protection is a well-established method of acute ischemic stroke (AIS) treatment. The pharmacodynamic effect of Piceatannol-3'-O-β-D-glucopyranoside (Chinese name: Quzhazhigan, QZZG) on AIS has been reported, but the molecular mechanism of this effect remains unknown. The purpose of this study is to elucidate the pharmacodynamic effects and mechanisms of QZZG in the treatment of AIS. A combined network pharmacology and metabolomics approach was used to predict the key targets and pathways of QZZG in the treatment of AIS and to elucidate the mechanism of QZZG through experimental validation. In this study, QZZG improved histopathologic features and reduced infarct volume and neurologic deficit scores. Integrated network pharmacology and metabolomics revealed that QZZG may protect neurons by regulating glutamate and its receptors, and that glutamate is closely related to NMDAR1, NRF2, and Caspase-3. Pathway analysis results suggested that NMDAR-mediated Ca2+ inward flow is one of the critical pathways. In terms of neuroexcitotoxicity QZZG inhibited glutamate content, reduced Ca2+ inward flow, protected mitochondrial function, and reduced ROS, as well as being able to effectively inhibit the expression of NMDAR1, Caspase-3, Bax, and promote the expression of Bcl-2, NMDAR2A. In terms of ferroptosis QZZG promoted NRF2, HO-1, GPX4 and nuclear-NRF2, inhibited the expression of BACH1 and ACSL4, and suppressed Fe2+ accumulation and lipid peroxidation. Silencing of BACH1 resulted in elevated expression of NRF2 and decreased expression of ACSL4, which inhibited the sensitivity of neurons to ferroptosis. QZZG was able to further increase NRF2 expression under conditions of silencing BACH1. QZZG induced NRF2 and inhibited BACH1, ACSL4 was inhibited by ML385, and inhibition of NRF2 induced the expression of BACH1 and ACSL4, QZZG protects neurons in an NRF2-dependent manner. In summary, QZZG inhibited neuroexcitotoxicity and ferroptosis by regulating the NMDAR/NRF2/BACH1/ACSL4 pathway. The study provided a relatively novel perspective on the mechanism of traditional Chinese medicine (TCM) treatment of the disease.

Synergistic combinations of Angelica sinensis for myocardial infarction treatment: network pharmacology and quadratic optimization approach

Background and aimAngelica sinensis (Oliv.) Diels (Danggui, DG), exhibits potential in myocardial infarction (MI) treatment. However, research on its synergistic combinations for cardioprotective effects has been limited owing to inadequate approaches.Experimental procedureWe identified certain phenolic acids and phthalein compounds in DG. Network pharmacology analysis and experimental validation revealed the components that protected H9c2 cells and reduced lactate dehydrogenase levels. Subsequently, a combination of computational experimental strategies and a secondary phenotypic optimization platform was employed to identify effective component combinations with synergistic interactions. The Chou-Talalay and Zero Interaction Potency (ZIP) models were utilized to quantify the synergistic relationships. The optimal combination identified, Z-Ligustide and Chlorogenic acid (Z-LIG/CGA), was evaluated for its protective effects on cardiac function and cardiomyocytes apoptosis induced by inflammatory in a mouse model of induced by left anterior descending coronary artery ligation. Flow cytometry was further utilized to detect the polarization ratio of M1/M2 macrophages and the expression of inflammatory cytokines in serum was measured, assessing the inhibition of inflammatory responses and pro-inflammatory signaling factors by Z-LIG/CGA.Key resultsQuadratic surface analysis revealed that the Z-LIG/CGA combination displayed synergistic cardioprotective effects (combination index value <1; ZIP value >10). In vivo, Z-LIG/CGA significantly improved cardiac function and reduced the fibrotic area in mice post-MI, surpassing the results in groups treated with Z-LIG or CGA alone. Compared to the MI group, the Z-LIG/CGA group exhibited decreased ratios of the myocardial cell apoptosis-related proteins BAX/Bcl-2 and Cleaved Caspase-3/Caspase-3 in mice. Further research revealed that Z-LIG/CGA treatment significantly increased IL-1R2 levels, significantly decreased IL-17RA levels, and inhibited the activation of p-STAT1, thereby alleviating cell apoptosis after MI. Additionally, the Z-LIG/CGA combination significantly inhibited the ratio of M1/M2 macrophages and suppressed the expression levels of pro-inflammatory cytokines IL-1β, IL-6, IL-17, and TNF-α in the serum.Conclusion and implicationsWe successfully identified a synergistic drug combination, Z-LIG/CGA, which improves MI outcomes by inhibiting cardiomyocyte apoptosis and inflammatory damage through modulating macrophage polarization and regulating the IL-1R2/IL-17RA/STAT1 signaling pathway. This study provides a charming paradigm to explore effective drug combinations in traditional Chinese medicine and a promising treatment for MI.

In Silico and Network Pharmacology Approach for Mechanistic Exploration of Rhododendron arboreum Sm. Leaf in Nonalcoholic Fatty Liver Disease

Rhododendron arboreum Sm. (Burans) (family Ericaceae) has traditionally been used in Indian medicine to treat liver disorders. However, its mechanism against non-alcoholic fatty liver disease (NAFLD) remains elusive. This study utilized in silico methods – network pharmacology, ADMET prediction, molecular docking and molecular dynamics (MD) simulations for mechanistic exploration of Rhododendron arboreum leaves (RAL) in NAFLD. Bioactive compounds were sourced from open databases and assessed for drug-likeness and ADMET profiles. Network pharmacology identified key protein interactions using the STRING platform. GO analysis identified galactose metabolism, pentose and glucuronate interconversions and other processes in treating NAFLD. Molecular docking revealed that amyrin and pectolinarigenin had the highest binding affinities, with dock scores of –12.2 kcal/mol (AKR1C3-amyrin), –10.2 kcal/mol (PI3K-amyrin), –9.3 kcal/mol (AKR1C3-pectolinarigenin) and –9.6 kcal/mol (HSD17B1-pectolinarigenin). MD simulations, focusing on RMSD and RMSF analyses, confirmed the stability of these interactions. The RMSD graphs revealed stable binding pocket regions, highlighted in pink. Notably, the RMSF values for PHE (B:306) in the AKR1C3-amyrin complex and ARG (A:294) in the PI3K-amyrin interaction were 0.623 nm and 0.1586 nm, respectively, indicating stable ligand interactions. Our findings holistically clarify toxicity data, potential bioactives targets and molecular mechanisms of RAL against NAFLD, paving the way for future research.

Exploring the Therapeutic Potential and Mechanisms of Zizyphus jujuba Miller in Chronic Pancreatitis: A Network Pharmacology and Molecular Docking Approach

Objectives: This study employed a network pharmacology approach to explore the potential therapeutic effects and underlying molecular mechanisms of Zizyphus jujuba Miller var. inermis Rehder (Jujube) in the treatment of chronic pancreatitis (CP).Methods: The bioactive compounds of Jujube and their target genes were identified from the HERB, OASIS databases. These putative target genes were then cross-referenced with CP-associated genes to identify potential correlations. A network was subsequently constructed using Cytoscape 3.10.2. To further investigate, functional enrichment analyses were conducted using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway databases. Additionally, binding affinities between active compounds and key genes were assessed by CB-DOCK2.Results: 55 active compounds and 344 associated target genes were identified from Jujube. Among these, 156 genes overlapped with the CP gene set. After screening, 9 key genes were identified from this subset, further emphasizing the significant relationship between the Jujube and CP. GO and KEGG analyses revealed that the 'PI3K-Akt Signaling Pathway' is a significant pathway mediated by 9 key genes in the context of CP. Furthermore, molecular docking analysis confirmed the strong binding affinities between the active compounds and key genes.Conclusions: Through the application of a network pharmacology approach, complemented by molecular docking studies, this research highlights a strong pharmacological relevance of Jujube in CP. These findings provide a valuable foundation for future investigations into the therapeutic potential of Jujube in mitigating CP, possibly through the modulation of the PI3K/Akt signaling pathway.

Pharmacological Effects and Mechanisms of Danlong Oral Liquid in Asthma Airway Remodeling: Insights from Serum Medicinal Chemistry, Network Pharmacology, and Experimental Validation.

Danlong oral liquid (DLOL) is a traditional Chinese proprietary medicine commonly used to treat chronic respiratory diseases, including bronchial asthma and chronic obstructive pulmonary disease. However, the therapeutic effects and pharmacological mechanisms of DLOL in improving airway remodeling remain unclear. This study utilizes in vivo and in vitro experiments, serum pharmacological analysis, and network-based pharmacology approaches to investigate the effects and mechanisms of DLOL on airway remodeling and epithelial-mesenchymal transition (EMT) in asthma. An asthma model was established through ovalbumins (OVA) sensitization and challenge in BALB/c mice to observe the effects of DLOL on airway hyperresponsiveness (AHR), inflammation, remodeling, and molecular markers of EMT. The absorbed chemical prototype constituents of DLOL were analyzed using Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS), and targets for asthma and airway remodeling were predicted using a network pharmacology approach. Key biological processes and signaling pathways were analyzed. Additionally, TGF-β1 was used to induce EMT in BEAS-2B cells. TGF-β1 and DLOL-containing serum were screened to determine the optimal time and concentration in BEAS-2B cells using CCK8 assays. The cell scratch assay was used to assess cell migration, while immunofluorescence and immunohistochemistry were employed to evaluate protein expression levels. DLOL improved AHR in asthmatic mice, reduced inflammatory cell infiltration in lung tissue, decreased airway wall and smooth muscle thickness, and reduced collagen deposition. It also down-regulated mesenchymal markers (N-cadherin, vimentin, α-SMA) and key remodeling factors (TGF-β1, MMP9), while up-regulating the epithelial marker E-cadherin. A total of 17 absorbed chemical prototype constituents were identified, predicting 54 core targets involved in airway remodeling. Following Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, the key targets were found to be associated with the regulation of cell migration, cell-cell adhesion, and cell adhesion molecular processes, with the PI3K-Akt signaling pathway likely playing a critical role. Cellular experiments confirmed that DLOL-containing serum inhibited TGF-β1-induced EMT in BEAS-2B cells and suppressed the phosphorylation of Akt and GSK-3β. This study identifies, for the first time, the serum medicinal chemistry of DLOL using UPLC-MS. Combining network pharmacology, in vivo and in vitro experiments, it elucidates the effects and potential mechanisms of the drug on airway remodeling and EMT. DLOL may offer a novel therapeutic approach for asthma-related airway remodeling.

Yohimbine treatment improves pulmonary fibrosis by attenuating the inflammation and oxidative stress via modulating the MAPK pathway

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disorder characterized by the accumulation of extracellular matrix and collagen, resulting in significant parenchymal scarring and respiratory failure that leads to mortality. Yohimbine (YBH) is an α-2 adrenergic receptor antagonist with anti-oxidant and anti-inflammatory properties. In the current study, we aimed to investigate the anti-inflammatory, anti-oxidant and anti-fibrotic activity of YBH against LPS/TGF-β-induced differentiation in BEAS-2B/LL29 cells and bleomycin (BLMN) induced pulmonary fibrosis model in rats. Network pharmacology, gene expression, Western-blot analysis, immune-cytochemistry/immunohistochemistry, lung function and histology techniques were used to assess the fibrotic marker expression/levels in cells or rat lung tissues. YBH treatment significantly attenuated the LPS-induced pro-inflammatory (identified through a network-pharmacology approach) and oxidative stress markers expression in lung epithelial cells. TGF-β stimulation significantly elevated the fibrotic cascade of markers and treatment with YBH attenuated these markers’ expression/levels. Intra-tracheal administration of BLMN caused a significant elevation of various inflammatory/oxidative stress and fibrotic markers expression in lung tissues and treatment with YBH significantly mitigated the same. Ashcroft score analysis revealed that BLMN exhibited severe distortion of the lungs, elevation of thickness of the alveolar walls and accumulation of collagen in tissues, further treatment with YBH significantly suppressed these events and improved the lung architecture. Lung functional parameters demonstrated that BLMN-induced stiffness and resistance were reduced considerably upon YBH treatment and restored lung function dose-dependently. Overall, this study reveals that YBH treatment significantly attenuated the BLMN-induced fibrosis by regulating the MAPK pathway and provided insightful information for progressing towards translational outcomes.

Integrated network pharmacology, bioinformatics, and experimental approach to explore the mechanism of honokiol liposomes against glioblastoma

Integrated network pharmacology, bioinformatics, and experimental approach to explore the mechanism of honokiol liposomes against glioblastoma

Unveiling the therapeutic potential of quercetin and its metabolite (Q3OG) for targeting inflammatory pathways in Crohn's disease: A network pharmacology and molecular dynamics approach

Unveiling the therapeutic potential of quercetin and its metabolite (Q3OG) for targeting inflammatory pathways in Crohn's disease: A network pharmacology and molecular dynamics approach

The inhibition of rutin on Src kinase blocks high glucose-induced EGFR/ERK transactivation in diabetic nephropathy by integrative approach of network pharmacology and experimental verification

BackgroundAlthough clinical strategies for diabetic nephropathy (DN) therapy include stringent blood pressure control through blockade of the renin-angiotensin system and management of hyperglycemia, the condition is still observed to progress relentlessly. PurposeTo elucidate the protective effects of rutin on podocytes in db/db mice with integrative approach of network pharmacology and experimental verification. MethodsThe study employs network pharmacology to identify common targets between rutin and DN, constructs a potential protein-protein interaction (PPI) network, and conducts Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Molecular docking is utilized to evaluate the interaction between rutin and protein targets. Additionally, experimental validation is performed using db/db mice and human podocyte cell models. ResultsRutin has been found to have a significant renoprotective effect, reducing blood glucose, proteinuria, and improving renal function in db/db mice. Rutin's inhibition of Src kinase reduces the phosphorylation levels of EGFR and ERK, which may mitigate podocyte injury. Additionally, rutin exhibits antioxidant properties, capable of lowering the levels of reactive oxygen species (ROS) in kidney tissue and increasing the activity of antioxidant enzymes like superoxide dismutase (SOD). These effects help protect podocytes from oxidative stress, further supporting the potential application of rutin in the treatment of DN. ConclusionsThe inhibition of rutin on Src kinase blocks high glucose-induced EGFR/ERK transactivation and protects podocyte injury in DN, indicating it might serve as a promising therapeutic agent for podocyte-targeted therapies.

Deciphering the Multifaceted Mechanism of Shuang Huang Lian in Treating Upper Respiratory Tract Infections: A Metabolomics-Based Network Pharmacology Approach

Deciphering the Multifaceted Mechanism of Shuang Huang Lian in Treating Upper Respiratory Tract Infections: A Metabolomics-Based Network Pharmacology Approach

Sanguinarine identified as a natural dual inhibitor of AURKA and CDK2 through network pharmacology and bioinformatics approaches

Cervical cancer (CA) continues to be a female malignant tumor with limited therapeutic options, resulting in a high mortality rate. Sanguinarine (SANG), a naturally occurring alkaloid, has demonstrated notable efficacy in preclinical treatment of CA. However, the mechanism through which SANG acts against CA is not fully understood. To address this, utilizing nine drug target prediction databases, we have successfully identified 379 potential targets for SANG. Venn diagram analysis compared 2367 CA-related targets from the GeneCards disease database, 2618 CA-closely related targets derived from multiple datasets in GEO through WGCNA analysis, and the 379 potential targets of SANG, resulting in 35 shared targets. Subsequently, by employing PPI network analysis, the Cytohubba plugin, the Human Protein Atlas, TCGA database data, and ROC curve analysis, we have identified AURKA and CDK2 as key targets of SANG in combating CA. Single-gene GSEA results suggest that the overexpression of AURKA and CDK2 is closely correlated with DNA replication, cell cycle progression, and various DNA repair pathways in CA. Molecular docking and molecular simulation dynamics analyses have confirmed the stable binding of both AURKA and CDK2 to SANG. In summary, by integrating diverse methodological approaches, this study discovered that SANG potentially inhibits the malignant features of CA by targeting AURKA and CDK2, thereby regulating DNA replication, cell cycle progression, and multiple DNA repair pathways. This lays a solid foundation for further exploring the pharmacological role of SANG in CA therapy. However, further in-depth in vitro and in vivo experiments are required to corroborate our findings.

Interaction of molecular mechanisms of plant-derived metabolites in Type 2 diabetes mellitus: A network pharmacology, docking and molecular dynamics approach on AKT1 kinase

BackgroundT2DM is a common metabolic disease with enormous effects on health worldwide; moreover, the use of phytochemicals as therapeutic compounds has drawn increasing attention. Therefore, the objective of this study was to assess the effectiveness of these phytochemicals in combating diabetes through a comprehensive evaluation of their interactions with biological networks through network pharmacology, molecular docking, and molecular dynamics simulations. ObjectivesThe first goal of this study was to search and screen potential phytochemicals for binding with key proteins involved in T2DM, with special emphasis on AKT1 kinase, an integral component of the insulin signaling pathway. MethodsNetwork pharmacology analysis was carried out, and the interaction network of targets associated with T2DM was generated using KEGG, STRING and Cytoscape 3.9.1 software's. To determine the specific metabolic processes, cellular compartments, and molecular functions involved in T2DM, we performed Gene Ontology and KEGG analyses. An initial and short molecular docking study was conducted to analyze the binding modes, while the molecular dynamics simulations provided insights into the binding energy and stability of phytochemicals at target sites, with emphasis on rutin engaged with AKT1. ResultsIn total, 10 hub genes were proposed to be involved in T2DM and can be considered candidate therapeutic targets, namely MTOR, CASP3, CCND1, TNF, MMP9, ALB, MDM2, AKT1, and HSP90AA1. Rutin was found to have the highest binding score for AKT1 in docking studies, while MD simulations identified the structural stability and persistence of the compound's activity at the target enzyme loci. ConclusionsThis study identified rutin and flavonoids as potential anti-diabetes phytochemicals. Based on these observations, an opportunity for other in vitro experiments and additional in vivo studies to confirm these buildings as multi-target drugs in T2DM patients is provided.

Design, synthesis and characterization of novel thiazolidinone derivatives: Insights from a network pharmacology approach for breast cancer therapy

Among various types, breast cancer remains the most prevalent reason of cancer-related fatalities, underscoring its profound effect on women's health globally. In this study, we reported the synthesis and characterization of a new sequence of thiazolidinone derivatives linked to 2,4-dichlorobenzaldehyde. The compound's structures were confirmed through HRMS, while their detailed structural features were determined via IR, ¹H- and ¹³CNMR spectroscopic analysis. To identify potential biological targets, network pharmacology techniques were applied to the synthesized 2,4-dichlorobenzaldehyde derivatives, which pointed to STAT3 as a primary target of interest. Additionally, the ADMET properties and molecular docking of these compounds were evaluated against the STAT3 protein. Virtual docking analyses acknowledged compound 11 as having the competent binding affinity, with a docking score of -7.87 kcal/mol, suggesting robust interactions with the key amino acid residues, Trp243 and His457. Furthermore, molecular dynamics simulation recognised the stability of compound 11, as it maintained its structural integrity within the protein binding pocket throughout the 100 ns simulation.

Potential of gut microbiota metabolites in treating COPD: network pharmacology and Mendelian randomization approaches.

The gut microbiota and its metabolites exert a significant influence on COPD, yet the underlying mechanisms remain elusive. We aim to holistically evaluate the role and mechanisms of the gut microbiota and its metabolites in COPD through network pharmacology and Mendelian randomization approaches. Employing network pharmacology, we identified the gut microbiota and its metabolites' impact on COPD-related targets, elucidating the complex network mechanisms involving the gut microbiota, its metabolites, targets, and signaling pathways in relation to COPD. Further, promising gut microbiota metabolites and microbiota were pinpointed, with their causal relationships inferred through Mendelian randomization. A complex biological network was constructed, comprising 39 gut microbiota, 20 signaling pathways, 19 targets, and 23 metabolites associated with COPD. Phenylacetylglutamine emerged as a potentially promising metabolite for COPD treatment, with Mendelian randomization analysis revealing a causal relationship with COPD. This study illuminates the intricate associations between the gut microbiota, its metabolites, and COPD. Phenylacetylglutamine may represent a novel avenue for COPD treatment. These findings could aid in identifying individuals at high risk for COPD, offering insights into early prevention and treatment strategies.

Abstract B072: Molecular targets of caffeine in breast cancer treatment: A network pharmacology approach

Abstract In Ghana, breast cancer leads in female cases (31.8%), demanding advanced treatments. Rising caffeine-filled energy drinks raise concerns. Yet, caffeine's role in breast cancer lacks understanding, urging more research. Our study uses network pharmacology and molecular docking to unravel the intricate molecular targets of caffeine in breast cancer, offering new therapies for this widespread disease We identified breast cancer-related targets from GEO datasets and TCGA databases, while caffeine targets were obtained from the SwissTarget Prediction database and literature. Common targets of both caffeine and breast cancer were considered using Venny software. PPI networks were generated using STRING and Cytoscape, identifying hub genes. Target proteins were annotated using the GO database, and pathway enrichment analysis was performed using KEGG. To investigate the binding affinity target proteins were retrieved from the Protein DataBank and docking studies were conducted using AutoDock Vina to explore the binding interactions between caffeine and potential target proteins identified. We identified 108 targets, and 6 common targets, including Cyclin-Dependent Kinase 1, Cyclin B1, Epidermal Growth Factor Receptor, Cyclin B2, Monoamine Oxidase A, and Carbonic Anhydrase 12 in relation to breast cancer. Gene Ontology (GO) and KEGG pathway enrichment analysis revealed their interactions in key pathways such as the P53 signaling pathway and Foxo signaling pathway, suggesting their critical roles in anti-breast cancer processes. Notably, caffeine exhibited the best overall binding affinity when interacting with CDK1, CCNB1, EGFR, and CCNB2 These findings provide valuable insights into the potential molecular targets and pathways associated with caffeine's anti-breast cancer effects, offering new strategies for therapeutic strategies. Citation Format: Kingsley A Osei, Justina S Owusu. Molecular targets of caffeine in breast cancer treatment: A network pharmacology approach [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B072.

Uncovering the therapeutic efficacy and mechanisms of Quercetin on traumatic brain injury animals: a meta-analysis and network pharmacology analysis.

Quercetin, a flavonoid and natural antioxidant derived from fruits and vegetables, has shown promising results in the improvement of traumatic brain injury (TBI). This study aims to elucidate the therapeutic role and potential mechanisms of quercetin in TBI through systematic evaluations and network pharmacology approaches. First, the meta-analysis was conducted via Review Manager 5.4 software. The meta-analysis results confirmed that quercetin could improve TBI, primarily by inhibiting inflammation, oxidative stress, and apoptosis. Subsequently, targets related to quercetin and those related to TBI were extracted from drug-related databases and disease-related databases, respectively. We found that the potential mechanism by which quercetin treats TBI is largely associated with ferroptosis, as indicated by functional analysis. Based on this, we identified 29 ferroptosis-related genes (FRGs) associated with quercetin and TBI, and then performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis using the DAVID database. The functional enrichment results revealed that these FRGs mainly involve the HIF-1 signaling pathway, IL-17 signaling pathway, and PI3K-Akt signaling pathway. Subsequently, we constructed a PPI network and identified the top 10 targets-HIF1A, IL6, JUN, TP53, IL1B, PTGS2, PPARG, EGFR, IFNG, and GSK3B-as hub targets. Meanwhile, molecular docking results further demonstrated that quercetin could stably bind to the top 10 hub targets. In conclusion, the above results elucidated that quercetin could effectively attenuates TBI by inhibiting inflammation, oxidative stress, and apoptosis. Notably, quercetin may also target these hub targets to regulate ferroptosis and improve TBI.

Integrating Metabolomic Analysis, Network Pharmacology, and Molecular Docking to Underlying Pharmacological Mechanism and Ethnobotanical Rationalization for Diabetes Mellitus: Study on Medicinal Plant Fibraurea tinctoria Lour.

Fibraurea tinctoria Lour. has long been used in traditional medicine to treat diabetes mellitus (DM). However, a comprehensive scientific understanding of its potential active compounds and underlying pharmacological mechanisms still needs to be unveiled. This study, therefore, presents a novel approach by integrating metabolomic profiling, pharmacological network, and molecular docking analysis to investigate the potential of F. tinctoria as antidiabetes mellitus. Active compounds were obtained through analysis using ultrahigh-performance liquid chromatography-quadrupole-orbital ion trap-high resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS) and screening of active compounds using Lipinski rule of five and ADMET parameters. Potential targets of F. tinctoria compounds and DM-related targets were retrieved from public databases, such as DisGeNET, GeneCards, OMIM, PharmaGKB, and TTD. The targets' gene ontology (GO) was created using DAVID and protein-protein interactions using STRING. The plant-organ-compound-target-disease network was constructed using Cytoscape. Then, molecular docking analysis predicted and verified the interactions of essential bioactive compounds of F. tinctoria and DM core targets. The network pharmacology approach identified 35 active compounds, 565 compound-related targets, and 17,289 DM-related targets. EGFR, HSP90AA1, ESR1, HSP90AB1, and GSK3B were the core targets, whereas isolariciresinol, cubebin, corypalmine, (-)-8-oxocanadine, and (+)-N-methylcoclaurine were the most active compounds of F. tinctoria with DM potential. GO functional enrichment analysis revealed 483 biological processes, 485 cellular components, and 463 molecular functions. REACTOME pathway enrichment analysis yielded 463 significantly enriched signaling pathways. Of these pathways, the cytokine signaling in the immune system pathway may play a key role in treating DM. The results of molecular docking analysis showed that the core targets of DM, such as 5gnk, 3o0i, 6psj, 5ucj, and 1q5k, bind stably to the analyzed bioactive compounds of F. tinctoria. This study provides significant insights into the potential mechanism of F. tinctoria in treating DM. The main active compounds of F. tinctoria were found to interact with the core targets (EGFR, HSP90AA1, ESR1, HSP90AB1, and GSK3B) through the cytokine signaling pathway in the immune system, suggesting a potential therapeutic pathway for DM. However, it is essential to note that these findings are preliminary, and further research is necessary to validate them. Those research studies could involve invitro and invivo studies to confirm the bioactivity of the identified compounds and their interactions with the core targets. When the findings are confirmed, they could have significant clinical implications, potentially leading to developing new therapeutic strategies for DM.

7-hydroxycoumarin ameliorates ulcerative colitis in mice by inhibiting the MAPK pathway and alleviating gut microbiota dysbiosis

ObjectiveThis research aimed to delineate the pharmacological mechanisms of 7-Hydroxycoumarin (7-HC) on ulcerative colitis (UC) employing network pharmacology and experimental validation.MethodsTo investigate the therapeutic effects of 7-HC on UC, a UC mouse model was established through the unrestricted intake of 3.0% dextran sulfate sodium (DSS) in their drinking water. Subsequently, we predicted the core targets and signaling pathways of 7-HC for the treatment of UC using the network pharmacology approach. Finally, the insights gained from network pharmacology were further validated by molecular docking, molecular dynamics simulation as well as in vivo experiments.ResultsAdministering 7-HC orally to mice with UC led to a marked improvement in colitis indicators. Furthermore, 7-HC significantly lowered the levels of inflammatory cytokines (TNF-α, IL-1β) in the colon and modulated oxidative stress markers (MPO, SOD). Subsequent studies identified 2 core targets (AKT1 and EGFR) in the colon of UC mice that were inhibited by 7-HC. Network pharmacology and experimental validation showed that 7-HC can reduce the expression of MAPK pathway markers P38, JNK, ERK, and their phosphorylation; 7-HC can also ameliorate UC by regulating the gut microbiome.Conclusion7-HC demonstrates considerable efficacy in alleviating UC in mice, primarily through substantial diminution of tissue inflammation and oxidative stress. This is the first time that 7-HC has been found to treat UC by inhibiting the MAPK pathway and modulating the gut microbiota, providing a fresh perspective on the pharmacological mechanisms through which 7-HC operates in the management of UC.

Corynoxine suppresses lung adenocarcinoma proliferation and metastasis via inhibiting PI3K/AKT pathway and suppressing Cyclooxygenase-2 expression

BackgroundLung adenocarcinoma (LUAD) is the most common lung cancer subtype, and the prognosis of affected patients is generally poor. The traditional Chinese medicine Uncaria rhychophaylla has been reported to exhibit anti-lung cancer properties. Accordingly, the main bioactive ingredient in Uncaria rhychophaylla, Corynoxine, may hold great value as a treatment for lung cancer.MethodsThe impact of Corynoxine on the viability of LUAD cells was assessed using the Cell Counting Kit-8 (CCK-8) assay. Apoptosis in A549 cells was evaluated via flow cytometry. Migration and invasion capabilities were determined through wound healing and Transwell assays, respectively. The key pathways targeted by Corynoxine in LUAD were identified using a network pharmacology approach. Additionally, Western immunoblotting, quantitative real-time PCR (qRT-PCR), and ELISA assays were conducted to validate the underlying mechanisms. The in vivo anti-tumor efficacy of Corynoxine was assessed in xenograft nude mice.ResultsIn this study, Corynoxine treatment was found to markedly suppress in vitro LUAD cell proliferative, migratory, and invasive activity. It additionally downregulated Vimentin and promoted E-cadherin upregulation consistent with the disruption of epithelial-mesenchymal transition (EMT) induction while also accelerating apoptotic death. Furthermore, network pharmacology analysis revealed that the PI3K/AKT pathway is a potential target of Corynoxine in LUAD. In vitro assays demonstrated that treatment with Corynoxine resulted in the suppression of PI3K/AKT signaling and a consequent drop in cyclooxygenase-2 (COX-2) expression. These findings were further confirmed in vivo in mice harboring A549 tumor xenografts in which Corynoxine was able to interfere with the PI3K/AKT/COX-2 signaling axis.ConclusionThis study elucidated the potential effects of Corynoxine in suppressing proliferation and metastasis in LUAD, along with investigating the underlying mechanisms. These data highlight the promise of Corynoxine as a novel therapeutic tool for the treatment of individuals diagnosed with LUAD.