Exploring Ganweikang Tablet as a Candidate Drug for NAFLD Through Network Pharmacology Analysis and Experimental Validation.
Ontology highlight
ABSTRACT:
SUBMITTER: Ma C
PROVIDER: S-EPMC9239345 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Purpose This study aimed to explore the underlying mechanisms of Shenyankangfu tablet (SYKFT) in the treatment of glomerulonephritis (GN) based on network pharmacology, machine learning, molecular docking, and experimental validation. Methods The active ingredients and potential targets of SYKFT were obtained through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, the targets of GN were obtained through GeneCards, etc. Perl and Cytoscape were used to construct an herb-active ingredient–target network. Then, the clusterProfiler package of R was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. We also used the STRING platform and Cytoscape to construct a protein–protein interaction (PPI) network, as well as the SwissTargetPrediction server to predict the target protein of the core active ingredient based on machine-learning model. Molecular-docking analysis was further performed using AutoDock Vina and Pymol. Finally, we verified the effect of SYKFT on GN in vivo. Results A total of 154 active ingredients and 255 targets in SYKFT were screened, and 135 targets were identified to be related to GN. GO enrichment analysis indicated that biological processes were primarily associated with oxidative stress and cell proliferation. KEGG pathway analysis showed that these targets were involved mostly in infection-related and GN-related pathways. PPI network analysis identified 13 core targets of SYKFT. Results of machine-learning model suggested that STAT3 and AKT1 may be the key target. Results of molecular docking suggested that the main active components of SYKFT can be combined with various target proteins. In vivo experiments confirmed that SYKFT may alleviate renal pathological injury by regulating core genes, thereby reducing urinary protein. Conclusion This study demonstrated for the first time the multicomponent, multitarget, and multipathway characteristics of SYKFT for GN treatment.
| S-EPMC8590514 | biostudies-literature
Project description:Background: Non-alcoholic fatty liver disease (NAFLD) is a burgeoning health problem but no drug has been approved for its treatment. Animal experiments and clinical trials have demonstrated the beneficial of saffron on NAFLD. However, the bioactive ingredients and therapeutic targets of saffron on NAFLD are unclear. Purpose: This study aimed to identify the bioactive ingredients of saffron responsible for its effects on NAFLD and explore its therapy targets through network pharmacology combined with experimental tests. Methods: Various network databases were searched to identify bioactive ingredients of saffron and identify NAFLD-related targets. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were conducted to enrich functions and molecular pathways of common targets and the STRING database was used to establish a protein-protein interaction network (PPI). The effect of crocetin (CCT) on NAFLD was evaluated in a mouse model of NAFLD by measuring the biomarkers of lipid, liver and renal function, oxidative stress, and inflammation. Liver histopathology was performed to evaluate liver injury. Nuclear factor erythroid-related factor (Nrf2) and hemeoxygenase-1 (HO-1) were examined to elucidate underlying mechanism for the protective effect of saffron against NAFLD. Results: A total of nine bioactive ingredients of saffron, including CCT, with 206 common targets showed therapeutic effects on NAFLD. Oxidative stress and diabetes related signaling pathways were identified as the critical signaling pathways mediating the therapeutic effects of the active bioactive ingredients on NAFLD. Treatment with CCT significantly reduced the activities of aspartate aminotransferase (AST), alanine transaminase (ALT), and the levels of total cholesterol (TC), triglyceride (TG), malondialdehyde (MDA), blood urea nitrogen (BUN), creatinine (CR), and uric acid (UA). CCT significantly increased the activities of superoxide dismutase (SOD), and catalase (CAT). Histological analysis showed that CCT suppressed high-fat diet (HFD) induced fat accumulation, steatohepatitis, and renal dysfunctions. Results of ELISA assay showed that CCT decreased the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and increased the expression of HO-1 and Nrf2. Conclusion: This study shows that CCT is a potential bioactive ingredient of saffron that treats NAFLD. Its mechanism of action involves suppressing of oxidative stress, mitigating inflammation, and upregulating Nrf2 and HO-1 expression.
| S-EPMC8219931 | biostudies-literature
Project description:BackgroundMultiple studies have assessed the role of Cassiae semen (CS) in regulating lipid metabolism. However, the mechanism of action of CS on non-alcoholic fatty liver disease (NAFLD) has seen rare scrutiny.ObjectiveThe objective of this study was to explore the regulatory mechanism of CS on lipid metabolism in NAFLD.MethodsComponents of CS ethanol extract (CSEE) were analyzed and identified using UPLC-Q-Orbirap HRMS. The candidate compounds of CS and its relative targets were extracted from the Traditional Chinese Medicine Systems Pharmacology, Swiss-Target-Prediction, and TargetNet web server. The Therapeutic Target Database, Genecards, Online Mendelian Inheritance in Man, and DisGeNET were searched for NAFLD targets. Binding affinity between potential core components and key targets was established employing molecular docking simulations. After that, free fatty acid (FFA)-induced HepG2 cells were used to further validate part of the network pharmacology results.ResultsSix genes, including Caspase 3 (CASP3), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α (PIK3CA), epidermal growth factor receptor (EGFR), and amyloid β (A4) precursor protein (APP) were identified as key targets. The mitogen-activated protein kinase (MAPK) signaling pathway was found to associate closely with CS's effect on NAFLD. Per molecular docking findings, toralactone and quinizarin formed the most stable combinations with hub genes. About 0.1 (vs. FFA, P<0.01) and 0.2 (vs. FFA, P<0.05) mg/ml CSEE decreased lipid accumulation in vitro by reversing the up-regulation of CASP3, EGFR, and APP and the down-regulation of PIK3CA.ConclusionCSEE can significantly reduce intracellular lipid accumulation by modulating the MAPK signaling pathway to decrease CASP3 and EGFR expression.
| S-EPMC9905789 | biostudies-literature
Project description:Dangguiliuhuang decoction (DGLHD) has been demonstrated to be effective in treating inflammatory, hepatic steatosis, and insulin resistance. In the study, we tried to elucidate the pharmacological efficacy and mechanism of DGLHD against liver fibrosis and predicate potential active ingredients and targets via network analysis and experimental validation. In the formula, we totally discovered 76 potential active ingredients like baicalein, berberine, and wogonin, and 286 corresponding targets including PTGS (prostaglandin-endoperoxide synthase) 2, PPAR (peroxisome proliferator-activated receptors) -γ, and NF-κB (nuclear factor-κB). Pathway and functional enrichment analysis of these putative targets indicated that DGLHD obviously influenced NF-κB and PPAR signaling pathway. Consistently, DGLHD downregulated levels of ALT (alanine transaminase) and AST (aspartate transaminase), reduced production of proinflammatory cytokines-TNF (tumor necrosis factor) -α and IL (Interleukin) -1β in serum and liver from mice with hepatic fibrosis, and inhibited hepatic stellate cell (HSC)-T6 cells proliferation. DGLHD decreased TGF (transforming growth factor) -β1 and α-SMA (smooth muscle actin) expression as well, maintained MMP (matrix metalloprotein) 13-TIMP (tissue inhibitor of metalloproteinases) 1 balance, leading to mitigated ECM (extracellular matrix) deposition in vivo and in vitro. Moreover, our experimental data confirmed that the alleviated inflammation and ECM accumulation were pertinent to NF-κB inhibition and PPAR-γ activation. Overall, our results suggest that DGLHD aims at multiply targets and impedes the progression of hepatic fibrosis by ameliorating abnormal inflammation and ECM deposition, thereby serving as a novel regimen for treating hepatic fibrosis in clinic.
| S-EPMC5844928 | biostudies-literature
Project description:Breast cancer is the most common carcinoma in women, and natural products would be effective preventing some side effects of cancer treatment. In the present study, cytotoxic activities of different Iranian Chrysanthemum morifolium cultivars were evaluated in human breast cancer cell lines (MCF-7) and human lymphocytes. A systems pharmacology approach was employed between major compounds of these cultivars (chlorogenic acid, luteolin, quercetin, rutin, ferulic acid, and apigenin) and known breast cancer drugs (tucatinib, methotrexate, tamoxifen, and mitomycin) with 22 breast cancer-related targets to analyze the mechanism through which Chrysanthemum cultivars act on breast cancer. Target validation was performed by the molecular docking method. The results indicated that Chrysanthemum extracts inhibited the proliferation of MCF7 cells in a dose- and cultivar-dependent manner. In all studied cultivars, the most effective extract concentration with the lowest viability of MCF-7 cells, was as much as 312 µg ml-1. Also, higher concentrations of the extracts (> 1000 µg ml-1) reduced the lymphocyte cell viability, demonstrating that these doses were toxic. The gene ontology analysis revealed the therapeutic effects of Chrysanthemum's active compounds on breast cancer by regulating the biological processes of their protein targets. Moreover, it has been documented that rutin, owing to its anticancer effects and several other health benefits, is a promising multi-targeted herbal ingredient. Finally, the present study compared different Iranian Chrysanthemum cultivars to provide new insights into useful pharmaceutical applications.
| S-EPMC8175602 | biostudies-literature
Project description:PurposeThe present study aimed to explore the potential components and mechanisms of Rhodiola rosea-Euonymus alatus drug pair (TY) that ameliorate rheumatoid arthritis (RA).MethodsThe main active components, core targets, and important pathways of TY against RA were predicted by network pharmacology analysis. The binding activity between the main active components and the core targets was verified by the molecular docking technique. Collagen-induced arthritis (CIA) rat model and tumor necrosis factor (TNF)-α-induced fibroblast-like synovial cells in human RA (HFLS-RA) model were established, respectively. The core targets were verified by cell counting kit-8 assay, hematoxylin eosin, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and Western blot analysis, and the therapeutic effect of TY was evaluated.ResultsA total of 18 possible components and 34 core targets were obtained by network pharmacology, among which inflammatory response, phosphatidylinositide 3-kinases (PI3K)-AKT and MAPK pathways were involved in the therapeutic effect of TY on RA. The results of molecular docking showed that kaempferol and quercetin had high binding affinity to interleukin (IL)-1β, IL-6, matrix metalloproteinase (MMP)9, and TNF-α. In vivo and in vitro experiments showed that TY dose-dependently inhibited the proliferation of HFLS-RA cells induced by TNF-α, and significantly reduced the paw swelling and arthritis scores in CIA rats. At the same time, TY inhibited the production of inflammatory factors in CIA rat serum and TNF-α-induced HFLS-RA cells. It also decreased the expression of PI3K, phospho-protein kinase B, MMP1, MMP3, MMP9, and increased the protein and mRNA levels of tissue inhibitors of MMPs (TIMP)1 in synovial tissue.ConclusionTY can inhibit the PI3K/AKT signaling pathway and regulate the balance between MMPs and TIMP, thus playing a therapeutic role in RA.
| S-EPMC10750436 | biostudies-literature
Project description:Luteolin, a natural flavone compound, exists in a variety of fruits and vegetables, and its anticancer effect has been shown in many studies. However, its use in glioma treatment is hampered due to the fact that the underlying mechanism of action has not been fully explored. Therefore, we elucidated the potential antiglioma targets and pathways of luteolin systematically with the help of network pharmacology and molecular docking technology. The druggability of luteolin, including absorption, excretion, distribution, and metabolism, was assessed via the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The potential targets of luteolin and glioma were extracted from public databases, and the intersecting targets between luteolin and glioma were integrated and visualized by a Venn diagram. In addition, GO and KEGG pathway analysis was engaged in Metascape. The network of the luteolin-target-pathway was visualized by Cytoscape. Ultimately, the interactions between luteolin and predicted key targets were confirmed by Discovery studio software. According to the ADME results, luteolin shows great potential for development into a drug. 4860 glioma-associated targets and 280 targets of luteolin were identified, of which 205 were intersection targets. 6 core targets of luteolin against glioma, including AKT1, JUN, ALB, MAPK3, MAPK1, and TNF, were identified via PPI network analysis of which AKT1, JUN, ALB, MAPK1, and TNF harbor diagnostic value. The biological processes of luteolin are mainly involved in the response to inorganic substances, response to oxidative stress, and apoptotic signaling pathway. The essential pathways of luteolin against glioma involve pathways in cancer, the PI3K-Akt signaling pathway, the TNF signaling pathway, and more. Meanwhile, luteolin's interaction with six core targets was verified by molecular docking simulation and its antiglioma effect was verified by in vitro experiments. This study suggests that luteolin has a promising potential for development into a drug and, moreover, it displays preventive effects against glioma by targeting various genes and pathways.
| S-EPMC8643232 | biostudies-literature
Project description:Berberine (BBR) is the main component of Coptidis rhizoma, the dried rhizome of Coptis chinensis and is a potential plant alkaloid used for the treatment of cancer due to its high antitumor activity. The present study examined the therapeutic potential and molecular mechanism of action of BBR against HCC, using systematic pharmacology combined with a molecular docking approach and experimental validation in vitro. Through systematic pharmacological analysis, it was found that BBR serves a significant role in inhibiting HCC by affecting multiple pathways, especially the PI3K/AKT signaling pathway. Furthermore, the docking approach indicated that the binding of BBR to AKT could lead to the suppression of AKT activity. The present study examined the inhibitory effect of BBR on the PI3K/AKT pathway in HCC and identified that BBR downregulated the expressions of phosphorylated AKT and PI3K in MHCC97‑H and HepG2 cells, inhibiting their growth, cell migration and invasion in a dose‑dependent manner. In addition, inhibition of the AKT pathway by BBR also contributed to cell apoptosis in MHCC97‑H and HepG2 cells. Taken together, the results of the present study suggested that BBR may be a promising antitumor drug for HCC that acts by inhibiting the PI3K/AKT pathway.
| S-EPMC6797955 | biostudies-literature
Project description:Rheumatoid arthritis is a chronic autoimmune disease characterized by persistent hyperplasia of the synovial membrane and progressive erosion of articular cartilage. Disequilibrium between the proliferation and death of RA fibroblast-like synoviocytes (RA-FLSs) is the critical factor in progression of RA. Naringin has been reported to exert anti-inflammatory and antioxidant effect in acute and chronic animal models of RA. However, the therapeutic effect and underlying mechanisms of naringin in human RA-FLS remain unclear. Based on network pharmacology, the corresponding targets of naringin were identified using SwissTargetPrediction database, STITCH database, and Comparative Toxicogenomics Database. Deferentially expressed genes (DEGs) in RA were obtained from the GEO database. The protein-protein interaction (PPI) networks of intersected targets were constructed using the STRING database and visualized using Cytoscape. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed, and the pathways directly related to pathogenesis of RA were integrated manually. Further, in vitro studies were carried out based on network pharmacology. 99 target genes were intersected between targets of naringin and DEGs. The PPI network and topological analysis indicated that IL-6, MAPK8, MMP-9, TNF, and MAPK1 shared the highest centrality among all. GO analysis and KEGG analysis indicated that target genes were mostly enriched in (hsa05200) pathways in cancer, (hsa05161) hepatitis B, (hsa04380) osteoclast differentiation, (hsa04151) PI3K-Akt signaling pathway, and (hsa05142) Chagas disease (American trypanosomiasis). In vitro studies revealed that naringin exposure was found to promote apoptosis of RA-FLS, increased the activation of caspase-3, and increased the ratio of Bax/Bcl-2 in a dose-dependent manner. Furthermore, treatment of naringin attenuated the production of inflammatory cytokines and matrix metalloproteinases (MMPs) in TNF-ɑ-induced RA-FLS. Moreover, treatment of naringin inhibited the phosphorylation of Akt and ERK in RA-FLS. Network pharmacology provides a predicative strategy to investigate the therapeutic effects and mechanisms of herbs and compounds. Naringin inhibits inflammation and MMPs production and promotes apoptosis in RA-FLS via PI3K/Akt and MAPK/ERK signaling pathways.
| S-EPMC8160516 | biostudies-literature
Project description:BackgroundDiabetic nephropathy (DN) has become one of the leading causes of the end-stage renal disease (ESRD). Tang-Shen-Ning (TSN) decoction, an effective Traditional Chinese formula for DN, can improve the renal function and inhibit renal fibrosis in DN. However, its potential mechanism is still unexplored.MethodsA network pharmacology approach was employed in this study, including screening for differential expressed genes of DN (DN-DEGs), protein-protein interaction (PPI) network analysis, and GO and KEGG enrichment analysis. Besides, a rat model was established to verify the potential effect of TSN in DN.ResultsTwenty-three TSN-related DN-DEGs targets were identified. These genes were associated with decreased glomerular filtration rate (GFR) DN. The enrichment analysis suggested that the inhibition of renal fibrosis and inflammation through growth factors and chemokines is the potential mechanism through which TSN improves DN. TSN reduced renal fibrosis and improved pathological damage in the kidney in vivo through the regulation of GJA1, CTGF, MMP7, and CCL5, which are genes associated with ECM deposition.ConclusionThis study revealed that TSN improves DN through a multicomponent, multitarget, and multipathway synergy. We provide a scientific basis for potential targets for TSN use to treat DN, yet further experimental validation is needed to investigate these targets and mechanisms.
| S-EPMC8445713 | biostudies-literature