Exploring the mechanisms underlying the therapeutic effect of Salvia miltiorrhiza in diabetic nephropathy using network pharmacology and molecular docking.

The mechanisms underlying the therapeutic effect of Salvia miltiorrhiza (SM) on diabetic nephropathy (DN) were examined using a systematic network pharmacology approach and molecular docking. The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to screen active ingredients of SM. Targets were obtained using the SwissTargetPrediction and TCMSP databases. Proteins related to DN were retrieved from the GeneCards and DisGeNET databases. A protein-protein interaction (PPI) network was constructed using common SM/DN targets in the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The Metascape platform was used for Gene Ontology (GO) function analysis, and the Cytoscape plug-in ClueGO was used for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Molecular docking was performed using iGEMDOCK and AutoDock Vina software. Pymol and LigPlos were used for network mapping. Sixty-six active ingredients and 189 targets of SM were found. Sixty-four targets overlapped with DN-related proteins. The PPI network revealed that AKT serine/threonine kinase 1 (AKT1), VEGFA, interleukin 6 (IL6), TNF, mitogen-activated protein kinase 1 (MAPK1), tumor protein p53 (TP53), epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase 14 (MAPK14), and JUN were the ten most relevant targets. GO and KEGG analyses revealed that the common targets of DN and SM were mainly involved in advanced glycation end-products, oxidative stress, inflammatory response, and immune regulation. Molecular docking revealed that potential DN-related targets, including tumor necrosis factor (TNF), NOS2, and AKT1, more stably bound with salvianolic acid B than with tanshinone IIA. In conclusion, the present study revealed the active components and potential molecular therapeutic mechanisms of SM in DN and provides a reference for the wide application of SM in clinically managing DN.

Zhang L ，Han L ，Wang X ，Wei Y ，Zheng J ，Zhao L ，Tong X ... -  《-》

Network pharmacology analysis combined with experimental validation to explore the therapeutic mechanism of Schisandra Chinensis Mixture on diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most common and serious microvascular complications of Diabetes mellitus (DM). The inflammatory response plays a critical role in DN. Schisandra Chinensis Mixture (SM) has shown promising clinical efficacy in the treatment of DN while the pharmacological mechanisms are still unclear. In this study, a network pharmacology approach and bioinformatic analysis were adopted to predict the pharmacological mechanisms of SM in DN therapy. Based on the predicted results, molecular docking and in vivo experiments were used for verification. In this study, the candidate bioactive ingredients of SM were obtained via Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and supplementing according to the literature. SM putative targets and the verified targets were acquired from TCMSP and SiwssTartgetPrediction Database. DN-related target genes were collected from GeneCards, OMIM, DisGeNET databases, and microarray data analysis. Biological function and pathway analysis were performed to further explore the pharmacological mechanisms of SM in DN therapy. The protein-protein interaction (PPI) network was established to screen the hub gene. The Receiver Operating Characteristic (ROC) analysis and the molecular docking simulations were performed to validate the potential target-drug interactions. The fingerprint spectrum of multi-components of the SM was characterized by UPLC-MS/MS. The signaling pathways associated with inflammation and hub genes were partially validated in SD rats. A total of 36 bioactive ingredients were contained, and 666 component-related targets were screened from SM, of which 50 intersected with DN targets and were considered potential therapeutic targets. GO analyses revealed that the 50 intersection targets were mainly enriched in the inflammatory response, positive regulation of angiogenesis, and positive regulation of phosphatidylinositol 3-kinase(PI3K) signaling. KEGG analyses indicated that the PI3K-Akt signaling pathway was considered as the most important pathway for SM antagonism to the occurrence and development of DN, with the highest target count enrichment. PPI network results showed that the top 15 protein targets in degree value, VEGFA, JAK2, CSF1R, NOS3, CCR2, CCR5, TLR7, FYN, BTK, LCK, PLAT, NOS2, TEK, MMP1 and MCL1, were identified as hub genes. The results of ROC analysis showed that VEGFA and NOS3 were valuable in the diagnosis of DN. The molecular docking confirmed that the core bioactive ingredients had well-binding affinity for VEGFA and NOS3. The in vivo experiments confirmed that SM significantly inhibited the over-release of inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor receptor (TNF)-α in DN rats, while regulating the PI3K-AKT and VEGFA-NOS3 signaling pathways. This study revealed the multi-component, multi-target and multi-pathway characteristics of SM therapeutic DN. SM inhibited the inflammatory response and improved renal pathological damage in DN rats, which was related to the regulation of the PI3K-Akt and VEGFA-NOS3 signaling pathways.

Ma Y ，Deng Y ，Li N ，Dong A ，Li H ，Chen S ，Zhang S ，Zhang M ... -  《-》

Identification of the molecular mechanisms of Salvia miltiorrhiza relevant to the treatment of osteoarthritis based on network pharmacology.

Jiang R ，Zhang X ，Li Y ，Zhou H ，Wang H ，Wang F ，Ma H ，Cao L ... -  《-》

Exploring the pharmacological components and effective mechanism of Mori Folium against periodontitis using network pharmacology and molecular docking.

To investigate the main active components, potential targets of action and analyze the potential molecular mechanisms of Mori Folium in preventing and treating periodontitis using network pharmacology and molecular docking methods. The main components and action targets of Mori Folium were obtained in TCMSP and ETCM databases, and then the action targets of Mori Folium components were inversing screening using Swiss Target Prediction and BATMAN-TCM databases. Targets associated with periodontitis were retrieved from OMIM, Genecard, DrugBank, NCBI Gene and DisGeNET databases. Intersectional targets of Mori Folium and periodontitis were obtained by Venn analysis. Construction of an "active components-targets" network to prevent and treat periodontitis in Mori Folium using Cytoscape 3.8.0. The STRING database was used to construct the protein-protein interaction (PPI) network of intersecting targets, and the core network was screened using CytoNCA and MCODE plug-ins. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were performed using the ClusterProfile package of R software, and then the "Mori Folium active components-targets-signaling pathway" network was constructed using Cytoscape software. Molecular docking was performed using AutoDock Vina software, and Pymol and LigPlus visualized the results. Sixteen active components and 1048 targets were screened from Mori Folium, of which 164 were intersectional with periodontitis targets and were considered potential therapeutic targets. The "Mori Folium active components-action targets" network identified Quercetin, Moracin D, Moracin E, Moracin G, Moracin H and Moracin B as the main active ingredients of Mori Folium for the prevention and treatment of periodontitis. PPI network analysis revealed interleukin 6 (IL6), albumin (ALB), tumor necrosis factor (TNF), vascular endothelial growth factor A (VEGFA), RAC-alpha serine/threonine-protein kinase (AKT1), cellular tumor antigen p53 (TP53), prostaglandin G/H synthase 2 (PTGS2), pro-epidermal growth factor (EGF), matrix metalloproteinase 9 (MMP9) and interleukin 6 (IL10) as the top 10 core potential targets. GO and KEGG enrichment analyses showed that the action targets of Mori Folium against periodontitis were mainly related to the response to bacterium and their lipopolysaccharide, angiogenesis and reactive oxygen species metabolic process, as well as through signaling pathways that regulate processes related to the accumulation of advanced glycation end products (AGEs), response to oxidative stress, response to inflammatory, and osteoclast differentiation during the development of the disease. Molecular docking revealed that Quercetin, Moracin D, Moracin E, Moracin G, Moracin H and Moracin B were able to bind stably to AKT1, PTGS2 and ESR1 targets, with Moracin E showing the most stable structure after binding to AKT1. In conclusion, this study revealed the active components, potential targets of action and the potential molecular mechanisms and pharmacological activities involved in the prevention and treatment of periodontitis in Mori Folium, providing a reference for the development of drugs from Mori Folium for the prevention and treatment of periodontitis.

Wu Z ，Ji X ，Shan C ，Song J ，Zhao J ... -  《-》

Network Pharmacology and Molecular Docking Study on the Potential Mechanism of Yi-Qi-Huo-Xue-Tong-Luo Formula in Treating Diabetic Peripheral Neuropathy.

To investigate the potential mechanism of action of Yi-Qi-Huo-Xue-Tong-Luo formula (YQHXTLF) in the treatment of diabetic peripheral neuropathy (DPN). Network pharmacology and molecular docking techniques were used in this study. Firstly, the active ingredients and the corresponding targets of YQHXTLF were retrieved using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) platform; subsequently, the targets related to DPN were retrieved using GeneCards, Online Mendelian Inheritance in Man (OMIM), Pharmgkb, Therapeutic Target Database (TTD) and Drugbank databases; the common targets of YQHXTLF and DPN were obtained by Venn diagram; afterwards, the "YQHXTLF Pharmacodynamic Component-DPN Target" regulatory network was visualized using Cytoscape 3.6.1 software, and Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on the potential targets using R 3.6.3 software. Finally, molecular docking of the main chemical components in the PPI network with the core targets was verified by Autodock Vina software. A total of 86 active ingredients and 229 targets in YQHXTLF were screened, and 81 active ingredients and 110 targets were identified to be closely related to diabetic peripheral neuropathy disease. PPI network mapping identified TP53, MAPK1, JUN, and STAT3 as possible core targets. KEGG pathway analysis showed that these targets are mostly involved in AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, and MAPK signaling pathway. The molecular docking results showed that the main chemical components of YQHXTLF have a stable binding activity to the core pivotal targets. YQHXTLF may act on TP53, MAPK1, JUN, and STAT3 to regulate inflammatory response, apoptosis, or proliferation as a molecular mechanism for the treatment of diabetic peripheral neuropathy, reflecting its multitarget and multipathway action, and providing new ideas to further uncover its pharmacological basis and mechanism of action.

Lin Y ，Shen C ，Wang F ，Fang Z ，Shen G ... -  《-》