Potential mechanism underlying the effect of matrine on COVID-19 patients revealed through network pharmacological approaches and molecular docking analysis.

BACKGROUND: The clinical efficacy of matrine in treating coronavirus disease (COVID-19) has been confirmed; however, its underlying mechanism of action remains unknown. METHODS: TCMSP, SwissTargetPrediction, SEA, GeneCards, CTD, and TTD were used to identify potential targets for matrine in SARS-CoV-2. Cytoscape software was used to determine the target-pathway network for topographical analysis. The online STRING analysis platform and Cytoscape were together used to generate a PPI network and for GO and KEGG pathway enrichment analysis. Finally, molecular docking simulations were performed to study matrine-Mpro, matrine-ACE2, and matrine-RdRp interactions. RESULTS: Ten common matrine targets were obtained, particularly including TNF-α, IL-6, and CASP3. GO and KEGG pathway enrichment analysis revealed five significantly enriched signalling pathways involved in cell proliferation, apoptosis, programmed cell death, and immune responses. CONCLUSIONS: During COVID-19 treatment, matrine regulates viral replication, host cell apoptosis, and inflammation by targeting the TNF-α, IL-6, and CASP3 in the TNF signalling pathway.

Network Pharmacology and Molecular Docking Analysis on Molecular Targets and Mechanisms of Aidi Injection Treating of Nonsmall Cell Lung Cancer.

Background: Aidi injection (ADI) is a compound preparation injection of Chinese herbs used to treat patients of nonsmall cell lung cancer (NSCLC) in China. This study aimed to reveal the mechanism of ADI in the treatment of NSCLC by using network pharmacology and molecular docking. Methods: The related targets of ADI and NSCLC were obtained from multiple databases. The network diagram of disease-drug-components-targets (DDCT) and protein-protein interaction (PPI) was constructed to screen key targets. Then, the key targets and main signaling pathways were screened by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Next, in order to validate the results of network pharmacology, expression analysis and survival analysis of key genes were performed. Finally, we carried out the technology of molecular docking to further validate the accuracy of the above results. Results: A total of 207 targets of ADI and 5282 targets of NSCLC were obtained finally. Through the construction of DDCT and PPI network diagrams, 28 key targets were finally obtained. The results of the KEGG enrichment analysis indicated that multiple signaling pathways were associated with NSCLC, which included the MAPK signaling pathway, the IL-17 signaling pathway, and the PI3K/AKT signaling pathway. The key genes in the signaling pathway mainly include TP53, CASP3, MMP9, AKT1, PTGS2, and MAPK1. The results of differently expressed analysis of key genes showed that TP53, CASP3, MMP9, AKT1, PTGS2, and MAPK1 had statistical differences in lung squamous cell carcinoma (LUSC) compared with normal tissue (p < 0.001). In lung adenocarcinoma (LUAD), the expression of TP53, CASP3, MMP9, AKT1, and PTGS2 had statistical differences compared with normal tissue (p < 0.001), while the expression of MAPK1 had no statistical difference (p > 0.05). The results of survival analysis of key genes showed that AKT1, MAPK1, CASP3, MMP9, TP53, and PTGS2 had statistical differences in the OS or RFS of NSCLC patients (p < 0.05). In addition, the results of molecular docking indicated that the key genes and the main components have good docking activity. Conclusions: This study revealed the potential mechanism of ADI in the treatment of NSCLC with multipathways and multitargets and provided a scientific basis for the in-depth study of ADI in the treatment of NSCLC.

Clinical efficacy and safety of NSCLC ancillary treatment with compound Kushen injection through immunocompetence regulation: A systematic review and meta-analysis.

BACKGROUND: Compound Kushen injection (CKI) is a Chinese patented medicine that improves the immunity level of cancer patients and inhibits tumor cell proliferation and metastasis. Clinically, CKI is widely used in combination with platinum-based chemotherapy (PBC) for non-small cell lung cancer (NSCLC) treatment. This study attempted to systemically evaluate the efficacy and safety of a combination of CKI and PBC for NSCLC treatment by modulating the immune function. PURPOSE: To evaluate the clinical efficacy and safety of CKI in combination with PBC for NSCLC. MATERIALS AND METHODS: English and Chinese databases were retrieved for randomized controlled trials (RCTs) of NSCLC treatment using a combination of CKI and PBC, and the changes of peripheral blood T lymphocytes (such as CD3+ T cells, CD4+ T cells, CD8+ T cells), and CD4+/CD8+ T cell ratio among NSCLC patients were detected before and after treatment using CKI with PBC. The search deadline was set as November 2021. The systemic evaluation was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The methodology and quality of each study included in the systemic evaluation were assessed. Review Manager 5.4, Stata12.0, and trial sequential analysis (TSA) were used for data analysis. The outcome indicators were qualified using GRADEprofiler software. RESULTS: A total of 25 RCTs involving 2460 cases of patients were included. The results showed that the combination of CKI with PBC effectively increased the objective response rate (ORR) [relative risk (RR) = 1.31, 95% confidence interval (CI) (1.19, 1.44)] and disease control rate (DCR) [RR = 1.16, 95%CI (1.09,1.23)], regulated the expression of peripheral blood T lymphocytes (such as CD3+T cells, CD4+T cells, CD8+T cells, and CD4+/CD8+T cell ratio), upregulated the level of serum immunoglobulins (such as IgA, IgG, and IgM), and reduced the frequency of gastrointestinal reaction, marrow inhibition, hepatorenal toxicity, reduction of white blood cells and blood platelets, baldness, infection, neutrophilic granulocyte counts, diarrhea, or constipation. According to subgroup analysis results, chemotherapy cycles (1-2) had a more significant effect on DCR. A combination of CKI and GP regimens had better effects on improving CD3+T cell levels, and there were no significant changes among other chemotherapies regiments. CONCLUSION: A combination of CKI and PBC had a marked effect in improving tumor response, priming immune function, and decreasing the frequency of adverse reactions, which was safe for NSCLC treatment.

LC-MS Based Metabolomics Study of the Effects of EGCG on A549 Cells.

(-)-Epigallocatechin-3-gallate (EGCG) is the main bioactive catechin in green tea. The antitumor activity of EGCG has been confirmed in various types of cancer, including lung cancer. However, the precise underlying mechanisms are still largely unclear. In the present study, we investigated the metabolite changes in A549 cells induced by EGCG in vitro utilizing liquid chromatography-mass spectrometry (LC-MS)-based metabolomics. The result revealed 33 differentially expressed metabolites between untreated and 80 µM EGCG-treated A549 cells. The altered metabolites were involved in the metabolism of glucose, amino acid, nucleotide, glutathione, and vitamin. Two markedly altered pathways, including glycine, serine and threonine metabolism and alanine, aspartate and glutamate metabolism, were identified by MetaboAnalyst 5.0 metabolic pathway analysis. These results may provide potential clues for the intramolecular mechanisms of EGCG's effect on A549 cells. Our study may contribute to future molecular mechanistic studies of EGCG and the therapeutic application of EGCG in cancer management.

Meta-Analysis of Therapy of Cinobufacini Capsule Adjunct with First-Line Platinum-Based Chemotherapy for the Treatment of Advanced NSCLC.

BACKGROUND: Cinobufacini capsule, an anticancer traditional Chinese patent medicine, has been widely used as adjunctive treatment to platinum-based chemotherapy in patients with advanced NSCLC. PURPOSE: To evaluate the efficacy and safety of cinobufacini capsule combined with first-line platinum-based chemotherapy for advanced NSCLC. Study Design. A systematic review and meta-analysis of eight outcome measures selected for this study were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. METHODS: A comprehensive literature search was conducted in 7 electronic databases to identify all the relevant randomised controlled trials. Cochrane handbook 5.1.0 was applied to evaluate the quality of included trials, and the RevMan 5.3 and Stata 15.1 software were used to combine the trials for data analysis and assess the publication bias. RESULTS: From the 19 studies reviewed, a total of 1,564 patients were included. Compared with first-line platinum-based chemotherapy alone, cinobufacini capsule combined with chemotherapy showed significant effects in improving ORR (RR = 1.49, 95% CI (1.33, 1.66)), 1-year survival rate (RR = 1.44, 95% CI (1.28, 1.63)), and 2-year survival rate (RR = 1.78, 95% CI (1.42, 2.22)), raising the percentages of CD3+ cells (SMD = 1.25, 95% CI (1.05, 1.45)), CD4+ cells (SMD = 1.52, 95% CI (1.33, 1.71)), and ratio of CD4+/CD8+ (SMD = 1.36, 95% CI (1.17, 1.54)), and reducing chemotherapy toxicity including leukopenia (RR = 0.61, 95% CI (0.51, 0.72)), thrombocytopenia (RR = 0.52, 95% CI (0.41, 0.67)), and vomiting (RR = 0.79, 95% CI (0.70, 0.88)). CONCLUSION: Cinobufacini capsule may increase the therapeutic effectiveness, improve cellular immune function, and reduce the toxicity of first-line platinum-based chemotherapy in patients with NSCLC. These results require confirmation by further rigorously designed randomised controlled trials (RCTs).

Citrus Alkaline Extracts Inhibit Senescence of A549 Cells to Alleviate Pulmonary Fibrosis via the ß-Catenin/P53 Pathway.

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a disease related to aging, which has become increasingly prevalent as the population has aged. However, there remains no effective treatment for the disease. Alveolar epithelial type II cell (AEC II) senescence plays an important role in the occurrence and development of IPF. Therefore, enhancing our understanding of aging AEC IIs might facilitate the development of a new therapeutic strategy for the prevention and treatment of IPF. The aim of this study was to investigate the effect of citrus alkaline extracts (CAE) on senescence in A549 cells and elucidate the mechanism by which CAE function. MATERIAL AND METHODS Adriamycin RD (ARD) induces the senescence of A549 cells. Relevant indicators were identified following administration of 3 concentrations of CAE (50 µg/mL, 100 µg/mL, and 200 µg/mL) to A549 cells. RESULTS CAE inhibited senescence in ARD-induced A549 cells. It inhibited p16, p21, p53, and a senescence-associated secretory phenotype, and reduced expression of the senescence-related positive cells of ß-galactosidase. Further study revealed that activation of the ß-catenin signaling pathway is closely associated with p53. CAE inhibited senescence in A549 cells via the ß-catenin/p53 pathway. Further, inhibition of b-catenin was associated with reduced expression levels of p53 and p21, and the anti-aging effects of CAE were enhanced. When expression of p53 was inhibited, expression levels of ß-catenin also tended to decrease. CONCLUSIONS In summary, our study showed that CAE can inhibit aging in A549 cells to alleviate pulmonary fibrosis, and thus limit the secretion of the extracellular matrix and collagen in lung fibroblasts.

Combined Treatment of Non-Small-Cell Lung Cancer Using Shenyi Capsule and Platinum-Based Chemotherapy: A Meta-Analysis and Systematic Review.

BACKGROUND: The efficacy and safety of combined treatment of non-small-cell lung cancer (NSCLC) using Shenyi capsules and platinum-based chemotherapy were comprehensively evaluated. METHODS: A computer-based search was used to identify reports on clinical randomized controlled trials (RCTs) on this combined treatment for NSCLC from the PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), VIP, China Biomedical (CBM), and Wanfang Data electronic databases. The databases were searched from their start to February 2020. The quality of the included studies was evaluated and then crosschecked by two independent evaluators. A meta-analysis was conducted using RevMan5.3. RESULTS: A total of 27 RCTs involving 2,663 patients were included in the meta-analysis, including 1,380 and 1,283 patients in the treatment and control groups, respectively. The results of the meta-analysis showed that, compared to platinum-based chemotherapy alone, the 1-year survival rate (relative risk (RR) = 1.27, 95% confidence interval (CI) [1.10, 1.47], P < 0.01), 2-year survival rate (RR = 1.35, 95% CI [1.10, 1.65], P < 0.01), objective tumour remission rate (RR = 1.52, 95% CI [1.35, 1.71], P < 0.01), and body CD4+/CD8+ ratio (standardized mean difference (SMD) = 0.12, 95% CI [0.07, 0.17], P < 0.01) were increased for the combined treatment of NSCLC using Shenyi capsules and platinum-based chemotherapy; moreover, quality of life was also improved (RR = 2.09, 95%CI [1.75, 2.50], P < 0.01) and it reduced leukocyte toxicity (RR = 0.49, 95%CI [0.39, 0.63], P < 0.01), haemoglobin toxicity (RR = 0.48, 95% CI [0.28, 0.81], P < 0.01), platelet toxicity (RR = 0.44, 95% CI [0.28, 0.70], P < 0.01), vomiting reaction (RR = 0.60, 95% CI [0.45, 0.78], P < 0.01), and serum vascular endothelial growth factor level (SMD = -63.67, 95% CI [-67.59, -59.75], P < 0.01). CONCLUSIONS: The treatment of NSCLC using Shenyi capsules together with routine platinum-based chemotherapy could enhance short- and long-term efficacy, improve patient quality of life, alleviate toxicity and side-effects of platinum-based chemotherapeutic drugs, boost body immune function, and inhibit tumour neovascularisation. These findings require further validation in large-sample, high-quality RCTs.

[Meta-analysis of Banmao Capsules in adjuvant treatment for non-small cell lung cancer].

To systemically evaluate the efficacy and safety of Banmao Capsules in the adjuvant treatment for non-small cell lung cancer(NSCLC). All of randomized controlled trials(RCT) about Banmao Capsules in adjuvant treatment for non-small cell lung cancer were retrieved in PubMed, EMbase, Cochrane Library, CNKI, VIP, CBM, WanFang database from database inception to August 2019. Two researchers extracted data and assessed literature quality separately, and made a Meta-analysis by RevMan 5.3 software. Thirteen trials involving 1 148 patients, including 595 in treatment group and 553 in control group, were enrolled in the review. The Meta-analysis showed that compared with conventional treatment, adjuvant treatment of NSCLC with Banmao Capsules can enhance the objective tumor response rate(RR=1.43,95%CI[1.30,1.58],P<0.01), and the disease control rate(RR=1.16,95%CI[1.11,1.22],P<0.01); improve the quality of life(RR=1.56,95%CI[1.27,1.92],P<0.01); reduce the incidence of myelosuppression(RR=0.41,95%CI[0.26,0.66],P<0.01), gastrointestinal reactions(RR=0.46,95%CI[0.33,0.65],P<0.01), liver and kidney dysfunction(RR=0.44,95%CI[0.29,0.66],P<0.01). The results showed that in the treatment of NSCLC, Banmao Capsules can increase the short-term efficacy, improve the quality of life of patients, and reduce the side effects of platinum-based chemotherapy drugs. More high-quality and large-scale randomized controlled trials are required in the future.

[Meta-analysis of Cinobufacini Injection combined with platinum-contained first-line chemotherapy in treatment of non-small cell lung cancer].

To systemically evaluate the efficacy and safety of Cinobufacini Injection in combination with platinum-contained first-line chemotherapy for treatment of non-small cell lung cancer(NSCLC). The randomized controlled trials(RCT) about the Cinobufacini in combination with platinum-contained first-line chemotherapy(versus chemotherapy alone) were collected through PubMed,Cochrane library,CNKI,VIP,CBM,and Wan Fang Database from database inception to December 2018. Two researchers extracted data and assessed the literature quality separately,and made a Meta-analysis by using Rev Man 5. 3 software. Twenty-seven RCTs were included in the present review,involving 2 125 patients,1 082 in treatment group and 1 043 in control group. The Meta-analysis results showed that as compared with chemotherapy alone,the combination of Cinobufacini and platinum-contained first-line chemotherapy could enhance one year survival rate(RR = 1. 34,95%CI[1. 17,1. 55],P< 0. 01),two year survival rate(RR = 1. 84,95% CI[1. 31,2. 59],P<0. 01),objective tumor response rate(RR = 1. 47,95%CI[1. 33,1. 63],P<0. 01); improve the quality of life for patients(RR =1. 54,95%CI[1. 37,1. 72],P < 0. 01); and reduce the incidences of WBC toxicity(RR = 0. 63,95% CI[0. 49,0. 80],P < 0. 01),platelet toxicity(RR = 0. 54,95%CI[0. 35,0. 84],P<0. 01),gastrointestinal reactions(RR = 0. 60,95%CI[0. 45,0. 80],P<0. 05),pain(RR = 1. 68,95% CI[1. 38,2. 03],P< 0. 01),and hair loss reaction(RR = 0. 76,95% CI[0. 59,0. 98],P < 0. 05). The results showed that for the treatment of NSCLC,the addition of cinofacini to conventional platinum-contained chemotherapy can increase the long-term and short-term efficacy of chemotherapy,improve the quality of life for patients,and reduce the side effects of platinumbased chemotherapy drugs. However,more high quality and large-scale randomized controlled trials are required to verify this conclusion in the future.

Citrus alkaline extracts prevent fibroblast senescence to ameliorate pulmonary fibrosis via activation of COX-2.

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal lung disease with a poor prognosis and limited treatment options. The incidence of IPF increases with age, and the mechanisms related to aging such as cellular senescence have been strongly implicated in disease pathology. Therefore, a better understanding of fibroblasts senescence might provide a new therapeutic strategy to prevent and treat pulmonary fibrosis. In this study, we aimed to explore the effects of citrus alkaline extracts (CAE) on the fibroblasts senescence, and elucidate the underlying mechanism to ameliorate pulmonary fibrosis. We demonstrated that CAE mitigated the collagen deposition by the initial early treatment, suggesting a potential preventive effect of CAE on pulmonary fibrosis. The expression of senescence biomarkers P16INK4a and P21, concomitant with down-regulation of the myofibroblasts marker α-SMA, and the number of senescence-associated ß-galactosidase (SA-ß-Gal) positive cells were decreased by CAE treatment, indicating a significant inhibitory effect of CAE on fibroblast senescence. Additionally, CAE down-regulated the expression of the senescence-associated secretory phenotype (SASP) in etoposide-induced senescent fibroblasts. Further studies indicated that COX-2 activation was required for CAE to inhibit the lung fibroblast senescence through a P53-dependent pathway. Results showed that the anti-senescence effect of CAE was abrogated when COX-2 was knocked down or inhibited by COX-2 inhibitor NS-398 or indomethacin in lung fibroblasts. Meanwhile, the anti-fibrotic and anti-senescence effect of CAE were abolished due to disruption of COX-2 in vivo. Collectively, our results provided a novel insight into the potential mechanism of CAE to inhibit the fibroblasts activation through preventing cellular senescence.