Mechanism of Aidi injection on hepatocellular carcinoma based on network pharmacology

Objective:To explore the active ingredients and potential mechanism of Aidi injection in the treatment of hepatocellular carcinoma by network pharmacology.Methods:Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)and Traditional Chinese Medicines Integrated Database(TCMID)were used to screen the active ingredients of four traditional Chinese medicines of Renshen,Huangqi,Ciwujia,and Banmao and corresponding potential targets.Screening of hepatocellular carcinoma-related targets through the Online Mendelian Inheritance in Man(OMIM)and GeneCards Suite(The Human Gene Database)database platforms.The drug and disease targets are merged to obtain the intersection,and the information is imported into Cytoscape 3.7.2 to construct a network diagram of the active ingredients of Aidi injection and related targets of hepatocellular carcinoma,and the topology analysis is performed.A protein-protein interaction(PPI)network was constructed and analyzed using the STRING online analysis platform.Uses the Database for Annotation,Visualization and Integrated Discovery(DAVID)to perform GO function enrichment analysis of targets and enrichment of KEGG pathways analysis.Results:A total of 33 potential active ingredients were screened from Aidi injection for treating hepatocellular carcinoma,including quercetin,kaempferol,beta-sitosterol,isorhamnetin and other important active ingredients.There are 106 potential targets for active ingredient action,6,677 disease-related targets,and 89 drug-disease common targets.Through the network diagram,it was found that the highest degree of target is PTGS1.In the PPI graph,a total of 87 nodes.Among them,the higher degree values include IL6,CASP3,VEGFA,MAPK8,JUN,EGFR,MYC,PTGS2 and FOS.A total of 60 related signal pathways were obtained by GO enrichment analysis.It mainly involves biological processes such as inhibiting abnormal proliferation and differentiation of hepatocellular carcinoma cells,inhibiting angiogenesis of hepatocellular carcinoma,regulating cell cycle and promoting apoptosis.KEGG pathway enrichment analysis screened a total of eight significantly different signal pathways.Among them,P53,VEGF,MAPK,Toll-like receptor,ErbB signaling pathways play an important role in treatment.Conclusion:This study initially revealed the potential mechanism of multi-component,multi-target and multi-pathway treatment of Aidi injection for hepatocellular carcinoma,and provided ideas for the subsequent verification of the molecular mechanism of Aidi injection for hepatocellular carcinoma.

Effects of Aidi injection on vinorelbine plus cisplatin chemotherapy for advanced non-small cell lung cancer

Objective： To evaluate the effects of Aidi injection on vinorelbine plus cisplatin （NP） chemotherapy for advanced non-small cell lung cancer （NSCLC）. Methods： Ninety eight patients with advanced NSCLC were randomized to receive either NP alone or NP plus Aidi injection every 3 weeks. The primary endpoint was overall survival; secondary endpoints included overall response rate, time to progression, and safety. Results： The median overall survival time was 11.6 months in NP plus Aidi-treated patients and 10.1 months in NP alone-treated ones, and 1- and 2-year survival rates were higher in the former （47% and 22%） than the latter （42% and 15%）. The overall response rates in Aidi injection plus NP-treated patients tended to be higher but not statistically significant compared with NP alone-treated ones. The occurrence rates of grades 3 or 4 toxicities, e.g. fatigue, nausea, vomiting, appetite loss, leucopenia, thrombocytopenia and anemia, were lower in Aidi injec- tion plus NP-treated patients than NP alone-treated ones, although not significantly different between them. Con^lusion：Aidi injection promotes NP chemotherapeutic effects, reduces the toxicities, and improves the patients＇ tolerance to chemotherapy as well. It may be an effective adjunct to chemotherapy in patients with NSCLC.

Assessment on the Efficacy and Safety of Aidi Injection Combined with Vinorelbine and Cisplatin for Treatment of Advanced Nonsmall Cell Lung Cancer

Background： The aim of this study was to assess the efficacy and safety of vinorelbine and cisplatin （NP chemotherapy） alone or in combination with Aidi injection for the treatment of advanced nonsmall cell lung cancer （NSCLC）. Methods： Pertinent publications were identified in PubMed, EMBASE, Cochrane Library, CNKI, CQVIR and Wanfang databases, up to December 8, 2015. After quality assessment of all included randomized controlled trials evaluating Aidi injection combined with NP chemotherapy for the treatment of advanced NSCLC, a meta-analysis was performed by Review Manager 5.2 and STATA 12.0 for statistical analyses. Results： Twelve studies including 509 and 503 cases in the experimental and control groups, respectively, were finally analyzed. The meta-analysis revealed that when cisplatin dose ranging from 20 to 40 mg/m2, combination of Aidi injection and NP chemotherapy was statistically different compared with NP chemotherapy alone in enhancing efficiency （relative risk [RR] = 1.24, 95% confidence interval [C/] [ 1.05-1.47], P = 0.010） and reducing the incidence of Grade II or above nausea and vomiting （RR = 0.49, 95% CI [0.30-0.80], P = 0.005）. Meanwhile, with cisplatin ranging from 80 to 120 mg/m2, no significant differences in efficiency （RR = 1.11, 95% CI [0.87- 1.42], P = 0.390） and Grade II or above nausea and vomiting （RR = 0.88, 95% CI [0.71-1.10], P = 0.260） were obtained. In addition, Aidi injection combined with NP chemotherapy was superior to NP chemotherapy alone in improving the quality of life, alleviating Grade II or above leukopenia and thrombocytopenia. Conclusions： Aidi injection combined with NP chemotherapy can enhance efficiency, improve the quality of life, and decrease adverse effects in patients with advanced NSCLC.

Application of Aidi Injection (艾迪注射液) in the Bronchial Artery Infused Neo-Adjuvant Chemotherapy for stage ⅢA Non-small Cell Lung Cancer before surgical Operation

Objective： To study the effect of Aidi Injection （艾迪注射液,ADI） applied in the bronchial artery infused （BAI） neo-adjuvant chemotherapy for stage ⅢA non-small cell lung cancer （NSCLC） before surgical operation.Methods： The 60 patients with NSCLC stage ⅢA underwent two courses BAI chemotherapy before tumor incision were assigned to two groups,the treatment and the control groups,using a random number table,30 in each group.ADI （100 mL） was given to the patients in the treatment group by adding into 500 mL of 5% glucose injection for intravenous dripping once daily,starting from 3 days before each course of chemotherapy,and it lasted for 14 successive days,so a total of 28 days of administration was completed.The therapeutic effectiveness and the adverse reaction that occurred were observed,and the levels of T-lymphocyte subsets,natural killer cell activity,and interleukin-2 in peripheral blood were measured before and after the treatment.Results： The effective rate in the treatment group was higher than that in the control group （70.0% vs.56.7%,P〈0.05）.Moreover,as compared with the control group,the adverse reaction that occurred in the treatment group was less and mild,especially in terms of bone marrow suppression and liver function damage （P〈0.05）.Cellular immune function was suppressed in NSCLC patients,but after treatment,it ameliorated significantly in the treatment group,showing significant difference as compared with that in the control group （P〈0.05）.Conclusion： ADI was an ideal auxiliary drug for the patients in stage ⅢA NSCLC received BAI neo-chemotherapy before surgical operation;it could enhance the effectiveness of chemotherapy,ameliorate the adverse reaction and elevate patients＇ cellular immune function;therefore,it is worthy for spreading in clinical practice.

Aidi Injection (艾迪注射液) Alters the Expression Profiles of MicroRNAs in Human Breast Cancer Cells

Objective: To investigate the effects of Aidi Injection (艾迪注射液 ADI) on the MicroRNAs (miRNA) expression profiles in human breast cancer cells and explore the potential targets of the cancer treatment. Methods: MCF-7 breast cancer cells were grown in RPMI 1640 medium supplemented with different concentrations of ADI. The inhibition of cell proliferation was measured by MTT assay. MCF-7 cells were treated by ADI with above 50% inhibiting concentration (IC50) for 48 h. The expression profiles of miRNA in ADI-treated and ADI-untreated MCF-7 cells were detected with miRNA microarray chips and the array data were verified by quantitative RT-PCR. MCF-7 cells were transiently transfected with miRNA mimics by liposome method. Potential mRNA targets were predicted by informatics analysis with TargetScan and PicTar software. Results: ADI significantly inhibited the proliferation of MCF-7 cells in a dose-dependent manner. The IC50 of ADI was 55.71 mg/mL after treatment for 48 h. The 60 mg/mL ADI was used as the therapeutic drug concentration. Microarray analysis identified 45 miRNAs that were up-regulated and 55 miRNAs that were down-regulated in response to ADI treatment. Many ADI-induced miRNAs were related to breast cancers. The microarray data were validated by qRT-PCR. Ectopic expression of 100 nmol/L mir-126 mimics significantly inhibited the proliferation of MCF-7 cells. The 12 potential target genes of mir-126 were predicted by both TargetScan and PicTar software. Conclusions: The miRNA may serve as therapeutic targets, and the modulation of miRNA expression is an important mechanism of ADI inhibiting breast cancer cell growth.

Efficacy of Aidi Injection(艾迪注射液)on Overexpression of P-Glycoprotein Induced by Vinorelbine and Cisplatin Regimen in Patients with Non-Small Cell Lung Cancer

Objective：To investigate the efficacy of Aidi Injection（艾迪注射液） on overexpression of P-glycoprotein（P-gp） induced by vinorelbine and cisplatin（NP） regimen in patients with non-small cell lung cancer（NSCLC）, and study the difference between intravenous administration and targeting intratumor administration of Aidi Injection with thoracoscope. Methods：Totally 150 patients with NSCLC were randomly assigned to the control group, the intravenous group and the intratumor group by the random envelope method, 50 cases in each group. The patients were treated with NP regimen（2 cycles）, NP regimen（2 cycles） plus Aidi intravenous injection, or NP regimen（2 cycles） plus Aidi intratumor injection with thoracoscope, respectively for 6 weeks. The clinical efficacy was observed based on Response Evaluation Criteria in Solid Tumors（RECIST） rules, the expression of P-gp in the tumor tissue was tested before, 3 and 6 weeks after treatment, the safety was evaluated by monitoring the toxicity in the process of treatment, and the progressionfree survival（PFS） was measured. Results：Fifteen cases dropped out because of the irreconcilable conditions which had no relationship with the treatment, 4 in the control group, 5 in the intravenous group, and 6 in the intratumor group, respectively. Compared with the control group, the response rates（complete remission ＋ partial response） and the disease control rates（complete remission ＋ partial response ＋ stable disease） were significantly higher, the P-gp expressions were significantly decreased after 3 and 6 weeks of treatment, and the Kaplan-Meier survival curves of PFS were significantly longer in the intravenous and intratumor groups（P〈0.05 or P〈0.01）, and the intratumor group showed better effects than the intravenous group（P〈0.05 or P〈0.01）. Compared with the control group, the occurrences of rash, nausea and leukocytopenia were significantly decreased in the intravenous and intratumor groups（P〈0.05）, but without significant difference between the intravenous and intratumor groups（P〉0.05）. Conclusion：Aidi Injection not only improves the efficacy of NP regime, but also has the function of reducing adverse events and preventing against overexpression of P-gp induced by chemotherapy of NP regimen.

Effect of Aidi injection plus chemotherapy on gastric carcinoma:a Meta-analysis of randomized controlled trials

OBJECTIVE: To conduct a Meta-analysis of studies on the effect of Aidi injectioncombined with chemotherapy versus chemotherapy alone in the treatment of gastric cancer(GC).METHODS: Nine electronic databases and six gray literature databases were comprehensively searcheduntil April 20,2013. Two reviewers independently selected and assessed included trialsaccording to the inclusion and exclusion criteria. The risk of bias tool from the Cochrane Handbook version 5.1.0was used to assess trial quality. All calculations were performed using Review Manager 5.0.RESULTS: Thirty-two studies including 1927 participants met the inclusion criteria,most of which were low quality. Compared with chemotherapy alone,Aidi injection plusthe same chemotherapy significantly improved the effective rate [OR = 1.52,95% CI(1.24,1.86),P < 0.0001],clinical beneficial rate [OR = 1.77,95% CI(1.33,2.36),P < 0.0001],and quality of life [OR = 3.02,95% CI(2.39,3.82),P <0.000 01]. There was a significant improvement in nausea and vomiting incidence [OR = 0.34,95%CI(0.24,0.47),P < 0.000 01],diarrhea [OR = 0.47,95%CI(0.33,0.69),P < 0.000 01],leukopenia( 3,0.51),P = 0.05],hemⅢ-ogⅣ)[OR = 0.34,95%CI(0.2lobin decrease(thromⅢ-boⅣ) [OR = 0.42,95%CI(0.18-1.00),P = 0.05],cytopenia(4],and Ⅲ-damⅣ) [OR = 0.46,95%CI(0.22,0.96),P = 0.0age to liver function [OR = 0.36,95%CI(0.24,0.54),P < 0.000 01].CONCLUSION: Aidi injection combined with chemotherapy significantly improved the clinical effect of chemotherapy,reducing the incidence of adverse events. Use of the CONSORT statement for randomized controlled trials is recommended for stricter reporting.

Effect of Aidi injection plus transarterial chemoembolization on primary hepatic carcinoma： a systematic review and Meta-analysis

OBJECTIVE: To assess the efficacy and safety of Aidi injection plus transarterial chemoembolization(TACE) in patients with primary hepatic carcinoma.METHODS: A comprehensive research of seven electronic databases was performed for comparative studies evaluating Aidi injection combined with TACE for primary hepatic carcinoma until September 2016. Two authors independently extracted data and assessed the methodological quality of the included trials using the Cochrane risk of bias tool from the Cochrane Handbook version 5.1.0. Data was synthesized by using Rev Man 5.3 software.RESULTS: Forty-nine studies involving 3435 patients met the inclusion criteria, most of which were low methodological quality. Compared with TACE alone, Aidi injection plus TACE can significantly improve the efficiency rate [RR = 1.33, 95% CI(1.24, 1.43), P < 0.000 01], clinical beneficial rate[RR = 1.25, 95% CI(1.17, 1.33), P < 0.000 01], survival rate [6 months, RR = 1.19, 95% CI(1.09, 1.29), P <0.0001], 12 months, [RR = 1.37, 95% CI(1.24, 1.52),P < 0.000 01], 18 months, [RR = 2.00, 95% CI(1.26,3.20), P < 0.004], 24 months, [RR = 1.44, 95% CI(1.22, 1.70), P < 0.0001], 36 months, [RR = 1.50, 95%CI(1.07, 2.11), P = 0.02 < 0.05], quality of life [RR =1.84, 95% CI(1.64, 2.05), P < 0.000 01] and immune function [CD3+, MD = 11.12, 95% CI(7.93, 14.30),P < 0.000 01], CD4 +, [MD = 10.37, 95% CI(7.29,13.45), P < 0.000 01], CD4+/CD8+, [MD = 0.30, 95%CI(0.07, 0.53), P = 0.01 < 0.05], NK, [MD = 7.49, 95%CI(6.64, 8.34), P < 0.000 01]. A significant improvement was also found in improvement of symptoms[RR = 1.64, 95%CI(1.38, 1.94), P < 0.000 01], leukopenia [RR = 0.60, 95% CI(0.54, 0.66), P < 0.000 01],thrombocytopenia [RR = 0.46, 95% CI(0.34, 0.61),P < 0.000 01], nausea and vomiting incidence [RR =0.66, 95% CI(0.54, 0.81), P < 0.0001), liver damage rate [RR = 0.57, 95% CI(0.42, 0.77), P = 0.0003 <0.05), and kidney damage rate [RR = 0.18, 95% CI(0.05, 0.68), P = 0.01 < 0.05].CONCLUSION: The results suggested that Aidi injection plus TACE significantly improve the clinical effect of TACE, and reduce the incidence of adverse events. However, rigorous multicenter trials with larger size are warranted to further confirm the findings.

A New Triterpenoid Saponin from Aidi Injection

Objective To investigate the chemical constituents from Aidi Injection.Methods The chemical constituents were isolated by chromatography on Sephadex LH-20 gel columns and reverse phase semi-preparative HPLC repeatedly.Their structures were identified by spectroscopic analysis(NMR and MS).Results Twenty-two compounds were isolated and identified to be 3-O-3′,4′-diacetyl-β-D-xylopyranosyl-6-O-β-D-glucopyranosyl- cycloastragenol(1),astragaloside IV(2),astragaloside II(3),astragaloside I(4),isoastragaloside I(5), acetylastragaloside I(6),ginsenosid Re(7),ginsenoside Rf(8),ginsenoside Rg1(9),ginsenoside Rb3(10), notoginsenoside R4(11),ginsenoside Rb1(12),ginsenoside Rc(13),ginsenoside Rb2(14),ginsenoside Rd(15), lucyoside H(16),3-O-β-D-glucopyranosyl(1→4)-β-D-glucopyranosyl(1→3)-α-L-rhamnopyranosyl(1→2)-α-L- arabinopyranosyl oleanolic acid 28-O-α-L-rhamnopyranosyl(1→4)-β-D-glucopyranosyl(1→6)-β-D-glucopyranoside (17),3-O-β-D-glucopyranosyl(1→3)-α-L-rhamnopyranosyl[β-D-glucopyranosyl-(1→4)]-(1→2)-α-L-arabinopyranosyl oleanolic acid 28-O-α-L-arabinopyranosyl(1→4)-β-D-glucopyranosyl(1→6)-β-D-glucopyranoside(18),syringin (19),elentheroside E(20),4-(1,2,3-trihydroxypropyl)-2,6-dimethoxyphenyl-1-O-β-D-glucopyranoside(21),and coniferin(22).Conclusion Compounds 1-6 are originated from Astragalus membranceus,compounds 7-18 are originated from Panax ginseng,and compounds 19-22 are originated from Acanthopanax senticosus by LC-MS analysis.Compound 1 is a new compound.