The mechanism of dioscin preventing lung cancer based on network pharmacology and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Dioscorea nipponica Makino as a Chinese folk medicine has been used for the treatment of chronic bronchitis, cough, and asthma. Several studies have established the antimetastatic potential of Dioscorea nipponica Makino extract. Dioscin is a major bioactive compound in Dioscorea nipponica Makino and has anti-tumor property in lung cancer cell lines. However, the preventive effect of dioscin against lung cancer and its key mechanism haven't been identified yet. AIM OF STUDY: To identify the prevention effect of dioscin on lung cancer and explore its key mechanism based on network pharmacology and experimental validation. METHODS: The potential targets of dioscin were obtained from the HERB database. The therapeutic targets of lung cancer were acquired from the GeneCards database. Protein-protein interaction network (PPI) was constructed in the STRING 11.0 database. The David database was used for enrichment analysis. Molecular Docking was finished by the AutoDock Vina. NSCLC cell lines and mouse lung cancer model were used to confirm the prevention effect of dioscin on lung cancer and its key mechanism. RESULTS: 76 potential targets of dioscin were identified to be involved in lung cancer treatment, which refer to 512 biological processes, 47 molecular functions, 77 cellular components and 107 signal pathways. The molecular docking suggested that dioscin might bind to AKT1, Caspase3, TP53, C-JUN and IL-6. The DARTS indicated that dioscin could bind to AKT1. In vitro, dioscin could decrease proliferation, invasion and migration in A549 and PC-9 cells with the significant reduction in the expression of p-AKT, MMP2, and PCNA. In vivo, dioscin could reduce lung nodules, lung injury, and mortality in mouse lung cancer model with reducing the expression of p-AKT, MMP2, PCNA and increasing the expression of active-caspase3. CONCLUSION: Dioscin could prevent lung cancer and its key target is AKT1 kinase, a center protein of PI3K/AKT signaling pathway.

The mechanism and active compounds of semen armeniacae amarum treating coronavirus disease 2019 based on network pharmacology and molecular docking.

BACKGROUND: Coronavirus disease 2019 (COVID-19) outbreak is progressing rapidly, and poses significant threats to public health. A number of clinical practice results showed that traditional Chinese medicine (TCM) plays a significant role for COVID-19 treatment. OBJECTIVE: To explore the active components and molecular mechanism of semen armeniacae amarum treating COVID-19 by network pharmacology and molecular docking technology. METHODS: The active components and potential targets of semen armeniacae amarum were retrieved from traditional Chinese medicine systems pharmacology (TCMSP) database. Coronavirus disease 2019-associated targets were collected in the GeneCards, TTD, OMIM and PubChem database. Compound target, compound-target pathway and medicine-ingredient-target disease networks were constructed by Cytoscape 3.8.0. Protein-protein interaction (PPI) networks were drawn using the STRING database and Cytoscape 3.8.0 software. David database was used for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The main active components were verified by AutoDock Vina 1.1.2 software. A lipopolysaccharide (LPS)-induced lung inflammation model in Institute of Cancer Research (ICR) mice was constructed and treated with amygdalin to confirm effects of amygdalin on lung inflammation and its underlying mechanisms by western blot analyses and immunofluorescence. RESULTS: The network analysis revealed that nine key, active components regulated eight targets (Proto-oncogene tyrosine-protein kinase SRC (SRC), interleukin 6 (IL6), mitogen-activated protein kinase 1 (MAPK1), mitogen-activated protein kinase 3 (MAPK3), vascular endothelial growth factor A (VEGFA), epidermal growth factor receptor (EGFR), HRAS proto-oncogene (HRAS), caspase-3 (CASP3)). Gene ontology and KEGG enrichment analysis suggested that semen armeniacae amarum plays a role in COVID-19 by modulating 94 biological processes, 13 molecular functions, 15 cellular components and 80 potential pathways. Molecular docking indicated that amygdalin had better binding activity to key targets such as IL6, SRC, MAPK3, SARS coronavirus-2 3C-like protease (SARS-CoV-2 3CLpro) and SARS-CoV-2 angiotensin converting enzyme II (ACE2). Experimental validation revealed that the lung pathological injury and inflammatory injury were significantly increased in the model group and were improved in the amygdalin group. CONCLUSION: Amygdalin is a candidate compound for COVID-19 treatment by regulating IL6, SRC, MAPK1 EGFR and VEGFA to involve in PI3K-Akt signalling pathway, VEGF signalling pathway and MAPK signalling pathway. Meanwhile, amygdalin has a strong affinity for SARS-CoV-2 3CLpro and SARS-CoV-2 ACE2 and therefore prevents the virus transcription and dissemination.

The Clinical Efficiency and the Mechanism of Sanzi Yangqin Decoction for Chronic Obstructive Pulmonary Disease.

This work is carried out to evaluate the clinical efficacy of Sanzi Yangqin decoction (SZYQD) treating chronic obstructive pulmonary disease (COPD) and to analyze its mechanism. The clinical efficacy of SZYQD treating COPD was evaluated by meta-analysis, and its mechanism was analyzed by network pharmacology. Molecular docking validation of the main active compounds and the core targets was performed by AutoDock vina software. A cigarette smoke (CS) and LPS-induced COPD model in ICR mice was constructed to confirm the effects of luteolin on COPD. Results showed that SZYQD has a greater benefit on the total effect (OR = 3.85, 95% CI [3.07, 4.83], P=1) in the trial group compared with the control group. The percentage of forced expiratory volume in one second (FEV1%) (MD = 0.5, 95% CI [0.41, 0.59], P < 0.00001) and first seconds breathing volume percentage of forced vital capacity (FEV1%/FVC) were improved (MD = 5.97, 95% CI [3.23, 8.71], P < 0.00001). There are 27 compounds in SZYQD targeting 104 disease targets related to COPD. PPI network analysis indicated that EGFR, MMP9, PTGS2, MMP2, APP, and ERBB2 may be the core targets for the treatment of COPD. Molecular docking demonstrated that luteolin in SZYQD showed the strongest binding activity to core targets. Experimental results revealed that the expression of COPD-related targets in lung tissue was significantly increased in the COPD group and was improved in the luteolin group. Our data indicated that SZYQD has a curative effect on COPD and luteolin is a candidate compound for COPD treatment by regulating EGFR, MMP9, PTGS2, MMP2, APP, and ERBB2.

The mechanism and candidate compounds of aged citrus peel (chenpi) preventing chronic obstructive pulmonary disease and its progression to lung cancer.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an important risk factor for developing lung cancer. Aged citrus peel (chenpi) has been used as a dietary supplement for respiratory diseases in China. OBJECTIVE: To explore the mechanism and candidate compounds of chenpi preventing COPD and its progression to lung cancer. METHODS: The active components and potential targets of chenpi were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Disease-associated targets of COPD and lung cancer were collected in the Gene Cards and TTD database. The component-target network and PPI network were constructed using the Cytoscape 3.8.0 software. David database was used for GO and KEGG enrichment analysis. The main active components were verified by using the autodock Vina 1.1.2 software. Mouse lung cancer with COPD was induced by cigarette smoking (CS) combined with urethane injection to confirm preventing the effect of hesperetin (the candidate compound of chenpi) on COPD progression to lung cancer and its underlying mechanisms. RESULTS: The network analysis revealed that the key active components of chenpi (nobiletin, naringenin, hesperetin) regulate five core targets (AKT1, TP53, IL6, VEGFA, MMP9). In addition, 103 potential pathways of chenpi were identified. Chenpi can prevent COPD and its progression to lung cancer by getting involved in the PI3K-Akt signaling pathway and MAPK signaling pathway. Molecular docking indicated that hesperetin had better binding activity for core targets. In mouse lung cancer with COPD, treatment with hesperetin dose-dependently improved not only lung tissue injury in COPD but also carcinoma lesions in lung cancer. Meanwhile, hesperetin could suppress the protein expression of AKT1, IL6, VEGFA, MMP9 and up-regulate the protein expression of TP53, and thus reduced the risk of COPD progression to lung cancer. CONCLUSION: Hesperetin is a candidate compound of chenpi that helps in preventing COPD and its progression to lung cancer by regulating AKT1, IL6, VEGFA, MMP9 and TP53.

Research on Effect and Mechanism of Xuefu Zhuyu Decoction on CHD Based on Meta-Analysis and Network Pharmacology.

Xuefu Zhuyu Decoction (XFZY) is an ancient compound widely used in the treatment of coronary heart disease. However, its efficacy evaluation is not complete and its mechanism of action is not clear enough. In an attempt to address these problems, the efficacy was evaluated by meta-analysis and the mechanism was elucidated by the network pharmacology method. We systematically searched relevant studies in PubMed, Chinese National Knowledge Infrastructure Database (CNKI), Cochrane Library, Wanfang Data, and other databases from 2007 to 2019. The association between XFZY treatment and CHD was estimated by risk ratio (RR) and corresponding 95% confidence intervals (95% CIs). The compounds and the potential protein targets of XFZY were obtained from TCMSP, and active compounds were selected according to their oral bioavailability and drug similarity. The potential genes of coronary heart disease were obtained from TTD, OMIM, and GeneCards. The potential pathways related to genes were determined by GO and KEGG pathway enrichment analyses. The compound-target and compound-target-pathway networks were constructed. Molecular docking validates the component and the target. A total of 21 studies including 1844 patients were enrolled in the present meta-analysis, indicating that XFZY has a greater beneficial on total effect (fixed effect RR = 1.30; 95% Cl: 1.24-1.36; P=0.82; I 2 = 0.0%) and electrocardiogram efficacy (fixed effect RR = 1.40; 95% Cl: 1.26-1.56; P=0.96; I 2 = 0.0%) compared with the control group. A total of 1342 components in XFZY were obtained, among which, 241 were chosen as bioactive components. GO and KEGG analyses got top 10 significantly enriched terms and 10 enriched pathways. The C-T network included 192 compounds and 3085 targets, whereas the C-T-P network included 10 compounds, 109 targets, and 5 pathways. There was a good binding activity between the components and the targets. XFZY has the curative effect on coronary heart disease, and its mechanism is related to 10 compounds, 10 core targets, and 5 pathways.

Berberine Maintains the Neutrophil N1 Phenotype to Reverse Cancer Cell Resistance to Doxorubicin.

This study explores the contributions of neutrophils to chemotherapeutic resistance and berberine-regulated cancer cell sensitivity to doxorubicin (DOX). In vitro experiments, continuous DOX treatment led to the shift of HL-60 cells to N2 neutrophils and thus induced chemotherapeutic resistance. The combination treatment with DOX and 2 µM berberine resulted in the differentiation of HL-60 cells toward N1 and therefore stimulated HL-60 cell immune clearance. Berberine increased reactive oxygen species (ROS) and decreased autophagy and therefore induced apoptosis in HL-60-N2 cells with morphological changes, but had no effect on cell viability in HL-60-N1 cells. The neutrophil-regulating efficacy of berberine was confirmed in the urethane-induced lung carcinogenic model and H22 liver cancer allograft model. Furthermore, we found that DOX-derived neutrophils had high levels of CD133 and CD309 surface expression, which prevented both chemotherapeutic sensitivity and immune rejection by self-expression of PD-L1 and surface expression of PD-1 receptor on T cells, whereas berberine could downregulate CD133 and CD309 surface expression. Finally, berberine-relevant targets and pathways were evaluated. This study first suggests an important role of berberine in regulating neutrophil phenotypes to maintain cancer cell sensitivity to DOX.