[Discrimination of anti-tumor and cardioprotective effect quality markers from Aidi Injection based on "spider web" mode].

Chinese medicinal preparations play an equally important role in reducing toxicity and treating tumors. Few studies discriminate the quality markers(Q-markers) conferring different therapeutic effects of traditional Chinese medicine preparations. Therefore, we take Aidi Injection(AD) as an example to comprehensively identify the Q-markers of anti-tumor and cardioprotective effects based on the "spider web" mode. Firstly, based on the principle of measurability, the chemical components in the prescription were qualitatively analyzed, and then the components with high content and capable to be measured were quantitatively analyzed as measurable evaluation indexes. Based on the principle of stability, the effects of light and temperature on the content of each component of AD were investigated as indicators of stability. Based on the principle of compatibility, the compounds were classified according to the law of compatibility of sovereign, minister, assistant, and guide medicinal materials in the prescription. Based on the principle of efficacy, the anti-tumor and antiangiogenic activities of the Q-markers were evaluated, and their synergistic effects with doxorubicin(DOX) in inhibiting tumorigenesis and angiogenesis and lowering cardiotoxicity were evaluated as the evaluation indexes of effectiveness. The seven-dimensional spider web of "compatibility-content-stability-antitumor activity-synergistic anti-tumor activity with DOX-antiangiogenic activity-synergistic anti-angiogenic activity with DOX" and the four-dimensional spider web of "compatibility-content-stability-protective effects against DOX-induced myocardial toxicity" were established, on the basis of which the Q-markers of anti-tumor and cardioprotective effects of AD were comprehensively analyzed. The results showed that 12 components were selected as the Q-markers of AD, among which cantharidin, ginsenoside Re, ginsenoside Rb_1, astragaloside Ⅱ, cryptochlorogenic acid, and ginsenoside Rg_2 were the anti-tumor Q-markers of AD. Ginsenoside Rd, isofraxidin, syringin, eleutheroside E, calycosin-7-O-ß-D-glucoside, and azelaic acid were the cardioprotective Q-markers of AD. Taking into account both the anti-tumor and cardioprotective effects, these Q-markers could cover the four herbs constituting the prescription. The findings provides a scientific basis for the quality control of AD and an effective method for identifying comprehensive and reasonable Q-markers for the two effects of Chinese medicinal preparations.

Efficacy of Aidi injection combined with chemotherapy, radiotherapy or chemoradiotherapy for unresectable esophageal cancer treatment: A meta-analysis and systematic review of 29 randomized controlled trials based on Asian populations (China).

OBJECTIVES: This study aimed to assess the efficacy of Aidi combined with standard treatment, including radiotherapy (R), chemotherapy (C), or chemoradiotherapy (CR), for unresectable esophageal cancer (EC). METHODS: Eight online databases were queried to collect randomized controlled trials (RCTs) published from database construction to August 2022. Patients in the control group underwent standard treatment with R, C, or CR, whereas those in the experimental group underwent Aidi combined with standard treatment. RESULTS: In this meta-analysis, 29 reports with 2079 patients were included. The results showed that the Aidi-based combination therapy groups had higher objective response rates (ORRs), disease control rates (DCRs), one-year overall survival (OS) and improvement and stability of Karnofsky performance status (KPS) than the control group (risk ratio (RR) = 1.24 (95% CI = 1.17-1.33), 1.09 (95% CI = 1.05-1.14), 1.50 (95% CI = 1.31-1.72), and 1.28 (95% CI = 1.16-1.41)). The Aidi-based combination therapy groups also had lower total incidence rates of bone marrow suppression (BMS), chemotherapy-induced nausea and vomiting (CINV) and radiation esophagitis (RE) than the control group (RR = 0.48 (95% CI = 0.41-0.56), 0.46 (95% CI = 0.36-0.58), and 0.49 (95% CI = 0.38-0.62)). In addition, subgroup analysis suggested that the optimal dose and cycle of Aidi injection combined therapy was 80-100 ml/time and 30 days/2 cycles. The efficacy of Aidi combined with DP (docetaxel + cisplatin) was better than the Aidi combined with PF (cisplatin plus fluorouracil). CONCLUSION: Aidi-based combination therapy showed high efficacy for unresectable EC treatment and reduced the incidence rates of adverse events. However, further studies including higher-quality RCTs are needed to validate these findings. TRIAL REGISTRATION NUMBER: INPLASY 202290020.

Cell metabolomics study on synergistic anti-hepatocellular carcinoma effect of Aidi injection combined with doxorubicin.

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the second most common cause of cancer deaths. This study aimed to explore the inhibitory effect and mechanism of Aidi injection (ADI) combined with doxorubicin (DOX) in HCC treatment. The drug concentrations in the combined therapy was determined by investigating the effect of various concentrations of ADI and DOX on the viability of H22 cells. The combination index was also calculated. A metabolomic strategy based on a ultrahigh-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) platform was established to analyze the metabolites. As a result, the combination index values were less than 1, indicating that the combination of ADI and DOX exerted a synergistic effect on HCC treatment. The combination of 40‰ ADI and 1 µmol/l DOX had the strongest inhibitory effect and was used for subsequent metabolomic analysis. A total of 19 metabolic markers were obtained in metabolomic analysis, including amino acids (l-glutamic acid, l-arginine and l-tyrosine), organic acids (succinic acid and citric acid), adenosine and hypoxanthine. Compared with the treatment using DOX or ADI alone, the combined therapy further regulated the levels of metabolic markers in HCC, which may be the reason for the synergistic effect. Seven metabolic pathways were significantly enriched, including phenylalanine, tyrosine and tryptophan biosynthesis, d-glutamine and d-glutamate metabolism, alanine, aspartate and glutamate metabolism, phenylalanine metabolism, arginine biosynthesis, the tricarboxylic acid cycle and purine metabolism. These findings demonstrated that ADI combined with DOX can effectively inhibit the viability of H22 cells, which may exert a synergistic antitumor effect by balancing the metabolism of amino acids and energy-related substances.

[Overview of systematic reviews and Meta-analysis of Aidi Injection combined with chemotherapy in treatment of non-small cell lung cancer].

At present, many systematic reviews(SRs)/Meta-analysis of Aidi Injection combined with chemotherapy in the treatment of non-small cell lung cancer(NSCLC) have been published, and the effectiveness has been proved.However, the methodological quality and evidence quality of these SRs/Meta-analysis have not been evaluated, and their guiding role in the clinical practice needs to be further verified.In this study, SRs/Meta-analysis of Aidi Injection combined with chemotherapy in the treatment of NSCLC were assessed to provide evidence overview and basis for the application and decision-making of this drug in clinical practice.PubMed, Cochrane Library, EMbase, CNKI, VIP, Wanfang, and SinoMed databases were searched for research articles on SRs/Meta-analysis of Aidi Injection combined with chemotherapy in the treatment of NSCLC.The methodological quality and evidence quality of included 15 articles on SRs/Meta-analysis were evaluated by using the AMSTAR-2 and GRADE system.The results of SRs/Meta-analysis suggested that Aidi Injection combined with chemotherapy had certain advantages over chemotherapy alone in improving short-term efficacy, improving quality of life, and reducing leukopenia, thrombocytopenia, and the incidence of gastrointestinal adverse events.The results of the AMSTAR-2 checklist showed low quality for 11 SRs/Meta-analysis and extremely low quality for another four SRs/Meta-analysis.The top problems included failure to provide the preliminary protocol or guide, unreported funding sources, and non-assessed risk of bias in the included articles on the results.According to the results of the GRADE assessment, 32 of the 148 outcome indicators were of intermediate quality, 40 were of low quality, and 76 were of extremely low quality.The critical factor leading to the downgrade was the risk of bias, followed by imprecision and publication bias.Aidi Injection combined with chemotherapy in the treatment of NSCLC can enhance efficacy and reduce toxicity.However, due to the low methodological quality and evidence quality of the included research articles, the efficacy and safety of Aidi Injection combined with chemotherapy in the treatment of NSCLC still need to be further confirmed by high-quality studies.In the follow-up original research and SRs/Meta-analysis, the corresponding quality evaluation standards should be strictly followed to improve the quality of evidence.

Clinical efficacy and safety of aidi injection combination with vinorelbine and cisplatin for advanced non-small-cell lung carcinoma: A systematic review and meta-analysis of 54 randomized controlled trials.

The Aidi injection contains multiple active ingredients, including astragaloside (Re, Rb1, and Rg1), ginsenoside, cantharidin, elentheroside E, and syringin, and it is administered with vinorelbine and cisplatin (NP) to treat non-small-cell lung carcinoma (NSCLC). In this study, we performed a systematic review and meta-analysis to determine the clinical efficacy and safety of the Aidi injection with NP, and the optimal threshold and treatment regimen to produce the desired responses. We collected all studies regarding the Aidi injection with NP for NSCLC from Chinese and English databases (up to April 2019). Risk of methodological bias was evaluated for each study. Data for analysis were extracted using a standard data extraction form. Evidence quality was assessed following the Grading of Recommendations Assessment, Development and Evaluation approach. We included 54 trials containing 4,053 patients for analysis. Combining the Aidi injection with NP significantly increased the objective response rate (odds ratio [OR], 1.32; confidence interval [CI], 1.23, 1.42), disease control rate (OR, 1.14; CI, 1.11, 1.18), and quality of life (OR, 1.80; CI, 1.61, 1.98), with decreased risks of myelosuppression, neutropenia, thrombocytopenia, anemia, gastrointestinal reaction, and liver dysfunction. For patients with a Karnofsky Performance Status score of ≥60, the Aidi injection (50 mL/day, two weeks/cycle, with two to three cycles) treatment with vinorelbine (25 mg/m2) and cisplatin (30-35 mg/m2 or 40-50 mg/m2) might be the optimal regimen for producing the desired tumor response and achieving a good safety level. Most results were robust, and their quality was moderate. The results suggest that administration of the Aidi injection and concomitant NP is beneficial to NSCLC, and provide evidence for the optimal threshold and treatment regimen that may improve tumor response with a good safety level.

The potential mechanism of Aidi injection against neuroblastoma-an investigation based on network pharmacology analysis.

Background: Aidi injection, a classic traditional Chinese medicine (TCM) formula, has been used on a broader scale in treating a variety of cancers. In this study, we aimed to explore the potential anti-tumor effects of Aidi injection in the treatment of neuroblastoma (NB) using network pharmacology (NP). Methods: To elucidate the anti-NB mechanism of Aidi injection, an NP-based approach and molecular docking validation were employed. The compounds and target genes were collected from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine (BATMAN-TCM) database. The protein-protein interaction network was constructed using the STRING database. clusterProfiler (R package) was utilized to annotate the bioinformatics of hub target genes. The gene survival analysis was performed on R2, a web-based genomic analysis application. iGEMDOCK was used for molecular docking validation, and GROMACS was utilized to validate molecular docking results. Furthermore, we investigated the anticancer effects of gomisin B and ginsenoside Rh2 on human NB cells using a cell viability assay. The Western blot assay was used to validate the protein levels of target genes in gomisin B- and ginsenoside Rh2-treated NB cells. Results: A total of 2 critical compounds with 16 hub target genes were identified for treating NB. All 16 hub genes could potentially influence the survival of NB patients. The top three genes (EGFR, ESR1, and MAPK1) were considered the central hub genes from the drug-compound-hub target gene-pathway network. The endocrine resistance and estrogen signaling pathways were identified as the therapeutic pathways using the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Gomisin B and ginsenoside Rh2 showed a good binding ability to the target protein in molecular docking. The results of cell experiments showed the anti-NB effect of gomisin B and ginsenoside Rh2. In addition, the administration of gomisin B over-regulated the expression of ESR1 protein in MYCN-amplified NB cells. Conclusion: In the present study, we investigated the potential pharmacological mechanisms of Aidi against NB and revealed the anti-NB effect of gomisin B, providing clinical evidence of Aidi in treating NB and establishing baselines for further research.

Combination of Brucea javanica oil emulsion and Aidi injection associated with the long­term survival of a patient with colon cancer and lung metastases post­chemotherapy: A case report.

Colorectal cancer (CRC) ranks as the third most frequently diagnosed cancer and the fourth leading cause of cancer-related mortality worldwide. Treatment options for patients with advanced CRC recurrence and metastases remain limited, particularly for those unable to withstand chemotherapy. Bruscea javanica oil emulsion (BJOE) and Aidi injection (ADI) are two plant-derived products that have antitumor effects. The current report presents the case of a patient with colon cancer and resectable lung metastases. Despite the surgical removal of the metastatic lesions, tumor recurrence was not prevented. The patient underwent three chemotherapy regimens following lung metastasis surgery, namely XELOX, single-agent irinotecan and single-agent tegafur-gimeracil-oteracil potassium capsule, but experienced intolerable adverse reactions with each, and disease progression was observed during subsequent follow-up. Nonetheless, the patient achieved a progression-free survival of >5 years under BJOE + ADI treatment and continues to receive BJOE + ADI treatment to date. Although further research is required to understand the effectiveness of this treatment combination, the present case may instill hope in the treatment of future patients.

A network pharmacology-based approach to explore the molecular mechanism of Aidi injection against prostate cancer.

Objective: To explore the molecular mechanism of Aidi injection in the treatment of prostate cancer (PCa). Materials and methods: CCK-8 and colony formation assays were used to detect the effects of Aidi on PC3 and DU145 cells; effects on the cell cycle and apoptosis of DU145 cells were detected by flow cytometry; effects on migration and invasion of PC3 and DU145 cells were detected by wound healing and transwell assay, respectively. The main active components of Aidi, their corresponding targets, and PCa associated pathways were predicted and analyzed by network pharmacology. Then predicted key targets and related signaling pathways were further verified by western blotting. The potential active components of Aidi were predicted by molecular docking technology. Results: Aidi significantly inhibited the proliferation, colony formation, migration, and invasion of PC3 and DU145 cells; Aidi induced apoptosis and cell cycle G2/M phase arrest of DU145 cells. Network pharmacology analysis yielded 36 potential core targets of Aidi against PCa, and the top 10 signaling pathways including MAPK, PI3K-Akt, and HIF-1α and so on were enriched. Western blotting confirmed that Aidi upregulated the expression levels of p-JNK, p-p38, p-ERK, and ERK in DU145 cells. Molecular docking study showed that kaempferol, (Z)-1-(2,4-dihydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one, 7-O-methylisomucronulatol, calycosin, and N-salicylidene-salicylamine can be well binding with JNK and p38. Conclusion: Aidi could inhibit PCa cell proliferation and metastasis through induction of apoptosis and cell cycle arrest, which may be related to activating JNK and p38 signaling pathway.

Identification of key pharmacological components and targets for Aidi injection in the treatment of pancreatic cancer by UPLC-MS, network pharmacology, and in vivo experiments.

BACKGROUND: Pancreatic cancer is one of the most lethal cancers worldwide. Aidi injection (ADI) is a representative antitumor medication based on Chinese herbal injection, but its antitumor mechanisms are still poorly understood. MATERIALS AND METHODS: In this work, the subcutaneous xenograft model of human pancreatic cancer cell line Panc-1 was established in nude mice to investigate the anticancer effect of ADI in vivo. We then determined the components of ADI using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) and explored the possible molecular mechanisms against pancreatic cancer using network pharmacology. RESULTS: In vivo experiments, the volume, weight, and degree of histological abnormalities of implanted tumors were significantly lower in the medium and high concentration ADI injection groups than in the control group. Network pharmacology analysis identified four active components of ADI and seven key targets, TNF, VEGFA, HSP90AA1, MAPK14, CASP3, P53 and JUN. Molecular docking also revealed high affinity between the active components and the target proteins, including Astragaloside IV to P53 and VEGFA, Ginsenoside Rb1 to CASP3 and Formononetin to JUN. CONCLUSION: ADI could reduce the growth rate of tumor tissue and alleviate the structural abnormalities in tumor tissue. ADI is predicted to act on VEGFA, P53, CASP3, and JUN in ADI-mediated treatment of pancreatic cancer.

Aidi injection enhances the anti-tumor impact of doxorubicin in H22 tumor-containing mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Aidi injection (AD) is a traditional medical preparation that has a Chinese origin. It is extensively used particularly in combination with doxorubicin (DOX) for the management of hepatocellular carcinoma (HCC). However, the combination's synergistic mechanism has not yet been clarified. AIM OF THE STUDY: To investigate the anti-tumor impact of AD in combination with DOX and their synergistic mechanism in HCC. MATERIALS AND METHODS: An H22 mouse xenograft model was utilized to study the impact of AD, DOX, and their combination on HCC in vivo. Their effects on cell vitality, apoptosis, mitochondrial membrane potential, reactive oxygen species (ROS) production, caspase-3, and cleaved caspase-3 protein expression were also investigated in H22 cells in vitro. Subsequently, human umbilical vein endothelial cells (HUVECs) were utilized to investigate the impacts of AD, DOX, and their combination on cell viability, migration, invasion, tube formation, and vascular endothelial growth factor (VEGF) protein expression. RESULTS: The study established that the tumor inhibition rate of AD combined with DOX reached 79.51%, which was significantly higher than that of AD (25.14%) or DOX (49.48%) alone. Additionally, the Q-value characterizing the synergy between AD and DOX was 1.72, demonstrating a strong synergistic effect. Furthermore, compared to AD or DOX administration alone, the combined administration group significantly decreased the alpha-fetoprotein (AFP) level in the serum, increased the tumor necrosis area, increased the Bax/Bcl-2, Cyt-c, caspase-9, Fas, Fasl, caspase-8, and caspase-3 protein expression, and significantly increased the CD31 and Ki67 protein expression in tumor tissue. Compared to AD or DOX alone, AD combined with DOX treatment had a synergistic effect on H22 cells (combination index values < 0.9), which inhibited cell viability, reduced mitochondrial membrane potential (MMP), induced apoptosis, promoted MMP loss, and increased ROS generation, cleaved caspase-3/caspase-3 levels, and caspase-3 activity. Moreover, combined administration showed a more pronounced inhibition of cell viability, migration, invasion, tube formation, and VEGF protein expression in HUVECs. CONCLUSIONS: AD enhances the anti-tumor effect of DOX by promoting apoptosis and inhibiting angiogenesis and cell proliferation. The findings of this study lay experimental foundations for the clinical combination of AD and DOX.

Effects of Aidi injection on life quality and incidence of adverse reactions in patients with non-small cell lung cancer compared with traditional chemotherapy: a systematic review and meta-analysis.

Objective: Although the clinical application value of Aidi injection when treating non-small cell lung cancer (NSCLC) patients is explained only by the effectiveness of a certain literature or the improvement of a certain evaluation index, and the result is not convincing. To evaluate the effect of Aidi injection on life quality and incidence of adverse reactions in patients with NSCLCcompared with traditional chemotherapy. Methods: PubMed, EMBASE, ScienceDirect, Cochrane Library, China Journal full-text Database (CNKI), VIP full-text Database, Wanfang Database and Chinese Biomedical Literature data (CBM), search relevant Chinese and foreign periodicals, conference papers, degree papers, etc. were searched Database and China Biomedical Literature Database (CBM) to search case-control trials of Aidi injection when treating NSCLC patients. The retrieval period begins with the establishment of the database and ends when the database is closed. Cochrane Handbook 5.3 was adopted to assess the bias risk of each contained literature based on independently extracted data by two researchers. A meta-analysis of the collected data was carried out using RevMan5.3 statistical software. Results: 2306 articles were retrieved by computer database, 1422 articles were harvested by excluding repeated studies, 865 articles were harvested by preliminary reading of article titles and abstracts, and 533 articles were initially contained by excluding unrelated studies, reviews, case reports and uncontrolled articles, and then the full text of the literature was carefully read. Eight clinical controlled studies were finally included, with a total of 784 samples, after excluding 525 literatures with incomplete data and no primary outcome indicators. Data from the contained studies were not noticeably heterogeneous in the meta-analysis of treatment effectiveness. The fixed effect model analysis indicated that the treatment effective rate of the study group was noticeably better, and the difference was statistically significant(P<0.05). The findings of the heterogeneity test were clearly heterogeneous among the contained research data, according to the meta-analysis of the levels of T lymphocyte subsets following treatment. The random effect model analysis indicated that the improvement of the cellular immune function of the research group was obvious, and the difference was statistically significant (P<0.05). According to the meta-analysis of the life quality scores after treatment, data from the contained research were evidently heterogeneous, according to results of the heterogeneity test. The random effect model analysis indicated that the life quality of the study group was noticeably higher, and the difference was statistically significant (P<0.05). The levels of serum vascular endothelial growth factor (VEGF) after treatment were measured by meta. Data from the contained research were evidently heterogeneous, according to results of the heterogeneity test. Random effect model analysis indicated that the level of serum VEGF in the study group was noticeably lower, and the difference was not statistically significant (P>0.05). A meta-analysis was conducted on the incidence of adverse reactions after treatment. The results of the heterogeneity test indicated that data from the contained research were evidently heterogeneous. The incidence was noticeably lower, and the difference was statistically significant (P<0.05). The funnel chart was drawn based on the effective rate of treatment, the level of T lymphocyte subsets, the score of life quality, the level of serum VEGF and the incidence of adverse reactions, and the publication bias analysis was carried out. The results indicated that most of the funnel maps were symmetrical and a small part of them were asymmetrical, suggesting that despite the heterogeneity of the study and the small number of included literatures, a publication bias was apparent in the included literature. Conclusion: Based on routine chemotherapy associated with Aidi injection, the therapeutic effect of NSCLC patients can be noticeably enhanced, the effective rate of treatment can be noticeably promoted, the immune function and life quality can be improved, and the incidence of adverse reactions is low, which is worth popularizing in clinical practice, but several studies and follow-ups are needed to improve methodological quality and to verify the results over a longer period of time.

The evidence framework of traditional Chinese medicine injection (Aidi injection) in controlling malignant pleural effusion: A clustered systematic review and meta-analysis.

INTRODUCTION: Aidi injection (Aidi), a traditional Chinese medicine injection, is often practiced to control malignant pleural effusion (MPE). OBJECTIVES: We performed a registered systematic review and meta-analysis (PROSPERO: CRD42022337611) to clarify the clinical role of Aidi in MPE, reveal optimal combinations of Aidi and chemical agents, their indications, therapeutic route and usage, and demonstrate their clinical effectiveness and safety. METHODOLOGY: All randomized controlled trials (RCTs) about Aidi in controlling MPE were collected from Chinese and English databases (up to October 2022). We clustered them into multiple homogenous regimens, evaluated the risk-of-bias at outcome level using a RoB 2, extracted and pooled the data using meta-analysis or descriptive analysis, and finally summarized their evidence quality. RESULTS: All 56 studies were clustered into intrapleural administration with Aidi alone or plus chemical agents, and intravenous administration with Aidi for MPE. Intrapleural administration with Aidi alone displayed similar clinical responses on Cisplatin (DDP) alone. Only administration with Aidi plus DDP significantly improved complete response and quality of life, and displayed a low pleurodesis failure, disease progression, hematotoxicity, gastrointestinal and hepatorenal toxicity. For patients with moderate to massive effusion, Karnofsky Performance Status score ≥ 50 or anticipated survival time ≥3 months, Aidi (50 ml to 80 ml each time, one time each week and three to eight times) plus DDP (20 to 30 mg, 40 to 50 mg, or 60 to 80 mg each time) significantly improved clinical responses. Most results had moderate to low quality. CONCLUSIONS: Current evidences indicate that Aidi, a pleurodesis agent, plays an interesting clinical role in controlling MPE. Aidi plus DDP perfusion is a most commonly used regimen, which shows a significant improvement in clinical responses. These findings also provide an indication and possible optimal usage for rational drug use.

A novel strategy to reveal clinical advantages and molecular mechanism of aidi injection in the treatment of pancreatic cancer based on network meta-analysis and network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Pancreatic cancer is a common malignancy worldwide due to its poor prognosis and high mortality rate. It is clinically proven that the combination of chemotherapeutic drugs and Traditional Chinese Medicine injections (TCMIs) significantly improves the therapeutic effect. AIM OF THE STUDY: To evaluate the efficacy and clinical benefits of TCMIs in combination with chemotherapy in the treatment of pancreatic cancer and to explore the mechanism of clinical advantage of Aidi injection. METHODS: Randomized controlled trials (RCTs) were searched in databases by NMA before December 29, 2020. WinBUGS 1.4, Stata 14.0, and R 4.0.4 software were used for calculations. All results were expressed as odds ratios and 95% credible intervals. Through the network pharmacology method, the chemical components and their targets, as well as the disease targets were further analyzed. And then, biological experiments were integrated to verify the results of network pharmacology analysis. (PROSPERO ID: CRD42021283559). RESULTS: A total of 33 RCTs with 8 TCMIs and 2011 patients were included. The results of NMA showed that Aidi injection can significantly improve the clinical efficacy (OR = 0.34, 95%CI: 0.16-0.74), and the clinical advantage was that it can significantly alleviate the leukopenia and thrombocytopenia caused by chemotherapy (OR = 5.65, 95%CI: 1.18-28.13). A total of 23 chemical compounds and 280 potential targets for Aidi injection were obtained from the online databases. Among them, there were 22 compounds, 50 targets and 211 signaling pathways closely related to leukopenia. Five genes were predicted to be core targets of ADI in alleviating leukopenia, and 2 of them (TP53 and VEGFA) were confirmed by biological experiments as regulatory targets of ADI in the treatment of PC. CONCLUSIONS: In conclusion, TCMIs in combination with chemotherapy, can improve clinical efficacy and safety in the treatment of pancreatic cancer. However, the overall evidence base is low, and large samples with multi-center RCTs are still needed to support further research findings. Aidi injection can alleviate leukopenia mainly by intervening in oxidative stress, regulating cell proliferation and apoptosis, and regulating the inflammatory response. The combined application of NMA, network pharmacology, and biological experiments provides a reference for clinical evaluation and mechanism of action exploration of other drugs.

Aidi injection altered the activity of CYP2D4, CYP1A2, CYP2C19, CYP3A2, CYP2E1 and CYP2C11 in normal and diethylnitrosamine-induced hepatocellular carcinoma in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Aidi injection (ADI), a traditional chinese medicine preparation, is widely used in combination with chemotherapy for the treatment of various malignant tumors, such as hepatocellular carcinoma (HCC). Studies have shown that changes in cytochrome P450 (CYP450) activity in disease states would affect the metabolism of drugs in vivo, especially liver diseases. However, the changes of Aidi injection on the activities of CYP2D4, CYP1A2, CYP2C19, CYP3A2, CYP2E1 and CYP2C11 in normal and HCC states are still unknown. AIM OF THE STUDY: The cocktail probe drugs method was used to investigate the effects of ADI on the activity of CYP2D4, CYP1A2, CYP2C19, CYP3A2, CYP2E1 and CYP2C11 in normal and HCC rats. MATERIALS AND METHODS: The HCC rats was induced by diethylnitrosamine (DEN). Then, both normal and HCC rats were randomly divided into 2 groups (n = 6). They were given saline or ADI (10 mL/kg/d, i.p) for 2 weeks, respectively. On the fifteenth day, cocktail probe mixing solution, including metoprolol (10 mg/kg), caffeine (1.0 mg/kg), omeprazole (2.0 mg/kg), midazolam (2.0 mg/kg), chlorzoxazone (4.0 mg/kg) and tolbutamide (0.5 mg/kg), was injected into tail vein of all rats in each group. The blood sample was obtained at specified time. After the protein is precipitated, six probe drugs are analyzed by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). RESULTS: Compared with control group, the activity of CYP3A2 and CYP2E1 was significantly lower in the ADI group. Compared with the model group, the activities of CYP1A2, CYP3A2, CYP2E1, and CYP2C11 enzymes in the ADI model group were significantly reduced. Additionally, the activity of CYP2D4, CYP1A2, CYP2C19, CYP3A2, CYP2E1 and CYP2C11 enzymes in model group was significantly lower than control group. CONCLUSIONS: ADI can inhibit a lot of CYP450 enzyme, so it may reduce the dosage of chemotherapeutic drugs to reach the required plasma concentration of chemotherapeutic drugs, which is of great significance for the combination of anti-tumor chemotherapeutic drugs and is worthy of further in-depth study and clinical attention.

Chinese patent medicine Aidi injection for cancer care: An overview of systematic reviews and meta-analyses.

ETHNOPHARMACOLOGICAL RELEVANCE: Aidi injection is one of the China Food and Drug Administration approved Chinese herbal injections and the most competitive product in cancer care in China. It is composed of the extracts from Mylabris Phalerata, Astragalus Membranaceus, Panax Ginseng, and Acanthopanax Senticosus. AIM OF THE STUDY: This overview aims to map systematic reviews (SRs) of Aidi injection for cancer and provide a summarized evidence for clinical practice and decision making. MATERIALS AND METHODS: Seven databases were searched for SRs and/or meta-analyses of randomized controlled trials on Aidi injection for cancer care until December 2020. Six authors worked in pairs independently identified studies, collected data, and assessed the quality of included studies according to the revised Assessment of Multiple Systematic Reviews (AMSTAR 2) and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A narrative synthesis was used for the evidence mapping. RESULTS: Fifty-two SRs on Aidi injection as adjuvant therapy were included, involving lung cancer (20 SRs), liver cancer (10), colorectal cancer (7), gastric cancer (6), lymphoma (2), breast cancer (2), esophageal cancer (1), ovary cancer (1), and a mix of different cancers (4). Except for one SR focusing on Aidi injection used alone, other SRs evaluated Aidi injection in combination with chemotherapy (43), radiotherapy (4), or chemo/radiology/targeting therapy (4). Aidi injection showed additional beneficial effects on survival (9), objective response rate (44), quality of life (42), and the reduction of side-effects from chemo/radiotherapy (48). Using AMSTAR 2 tool, two reviews were assessed as low and the rest as critically low methodological quality mainly due to the lack of prospective registration. The reporting quality was insufficient assessed with PRISMA in the reporting of search strategy (26, 50.0%), additional analysis (19, 36.5%), and the summary of evidence (2, 3.8%). CONCLUSION: Aidi injection has been evaluated for its adjuvant beneficial effects on cancer survival, tumor responses, quality of life, and reducing the side effects of chemo/radiotherapy, mainly focusing on lung, liver and colorectal cancer. The methodological and reporting quality are weak and need to be improved in the future.

Exploring the mechanism of aidi injection for lung cancer by network pharmacology approach and molecular docking validation.

BACKGROUND: Aidi injection (ADI) is an effective Traditional Chinese medicine preparation widely used for lung cancer. However, the pharmacological mechanisms of ADI on lung cancer remain to be elucidated. METHODS: A network pharmacology (NP)-based approach and the molecular docking validation were conducted to explore underlying mechanisms of ADI on lung cancer. The compounds and target genes were screened by Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine (Batman-TCM) database. The STRING database was utilized for protein interaction network construction. The R package clusterProfiler was used for bioinformatics annotation of hub target genes. The gene expression analysis and survival analysis were performed based on The Cancer Genome Atlas (TCGA) database. The Autodock Vina was used for molecular docking validation. RESULTS: A total of five key compounds with 324 putative target genes were screened out, and 14 hub target genes were identified for treating lung cancer. Six hub genes could influence the survival of non-small cell lung cancer (NSCLC) patients. Of these hub genes, the expression pattern of EGFR, MYC, PIK3CA, and SMAD3 were significantly higher in the LUSC, while PIK3CA and RELA expressed lower in the LUAD group and LUSC group, respectively. These six hub genes had good docking affinity with the key compounds of ADI. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that ADI may exert therapeutic effects on lung cancer by regulating critical pathways including the thyroid hormone signaling pathway, MAPK signaling pathway, and PI3K-Akt signaling pathway. CONCLUSIONS: The present study explored the potential pharmacological mechanisms of ADI on lung cancer, promoting the clinical application of ADI in treating lung cancer, and providing references for advanced researches.

Meta-Analysis of Aidi Injection and First-Generation Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Therapy in Treating Advanced Non-Small Cell Lung Cancer.

The combination of Aidi injection (ADI) and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in treating non-small cell lung cancer (NSCLC) has been reported, but the effects of this therapy have not been systematically assessed. Randomized controlled trials (RCTs) published before June 2020 were searched from 6 databases. Two reviewers independently assessed the methodological quality of 8 RCTs involving 667 patients diagnosed with stage III-IV NSCLC. We found that ADI combined with EGFR-TKI increased the objective response rate (ORR) significantly (relative risk [RR]: 1.60; 95% confidence interval [CI]: 1.28-1.99, P < 0.0001). There was also improvement in the disease control rate (DCR) (RR: 1.25; 95% CI: 1.11-1.40, P = 0.0002) as compared with EGFR-TKI alone. This therapy also increased the percentage of CD3+ cells (weighted mean difference [WMD]: 9.86; 95% CI: 4.62-15.10), CD4+ cells (WMD: 6.10; 95% CI: 1.67-10.53), and the CD4+/CD8+ (WMD: 0.35; 95% CI: 0.28-0.43). With regard to drug toxicity, the occurrence of rash was significantly reduced by ADI combined with EGFR-TKI (RR: 0.78, 95% CI: 0.63-0.97, P = 0.03); however, we did not find a significant reduction in the occurrence of dry skin, nausea and vomiting, as well as diarrhea between the 2 therapies. ADI combined with first-generation EGFR-TKIs may be more effective in improving tumor response, reducing the occurrence of rash, and enhancing immune function in NSCLC than EGFR-TKI alone.

Pharmacokinetic herb-drug interactions between Aidi injection and doxorubicin in rats with diethylnitrosamine-induced hepatocellular carcinoma.

BACKGROUND: Aidi Injection (ADI), a Chinese herbal preparation with anti-cancer activity, is used for the treatment of hepatocellular carcinoma (HCC). Several clinical studies have shown that co-administration of ADI with doxorubicin (DOX) is associated with reduced toxicity of chemotherapy, enhanced clinical efficacy and improved quality of life for patients. However, limited information is available about the herb-drug interactions between ADI and DOX. The study aimed to investigate the pharmacokinetic mechanism of herb-drug interactions between ADI and DOX in a rat model of HCC. METHODS: Experimental HCC was induced in rats by oral administration of diethylnitrosamine. The HCC rats were pretreated with ADI (10 mL/kg, intraperitoneal injection) for 14 consecutive days prior to administration of DOX (7 mg/kg, intravenous injection) to investigate pharmacokinetic interactions. Plasma concentrations of DOX and its major metabolite, doxorubicinol (DOXol), were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). RESULTS: Preadministration of ADI significantly altered the pharmacokinetics of DOX in HCC rats, leading to increased plasma concentrations of both DOX and DOXol. The area under the plasma drug concentration-time curve (AUCs) of DOX and DOXol in rats pretreated with ADI were 3.79-fold and 2.92-fold higher, respectively, than those in control rats that did not receive ADI. CONCLUSIONS: Increased levels of DOX and DOXol were found in the plasma of HCC rats pretreated with ADI.

Aidi injection induces apoptosis of hepatocellular carcinoma cells through the mitochondrial pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The incidence and mortality rates of hepatocellular carcinoma are very high all over the world, which seriously threatens human life and health. Aidi injection as a Chinese medicine preparation has a positive curative effect on hepatocellular carcinoma, but its mechanism remains unclear. AIM OF THE STUDY: The purpose of this study is to evaluate the anti-hepatocellular carcinoma effects of Aidi injection and explore its mechanism of action vitro and vivo. MATERIALS AND METHODS: The main components of Aidi injection were determined by LC-MS/MS. The effects of Aidi injection on the viability of HepG2 and PLC/PRF/5 cells were detected via CCK-8 analysis and Calcein AM/PI staining. DAPI staining and flow cytometry were applied to analyze the apoptosis-induced effects of Aidi injection on hepatocellular carcinoma cells (HCCs). The growth inhibition of Aidi injection on hepatocellular carcinoma was observed in nude mice bearing PLC/PRF/5 cells. The related signal transduction and apoptosis pathways were investigated through assays for JC-1 mitochondrial membrane potential (MMP), RNA-seq, KEGG, PPI and WB. RESULTS: There were 12 main chemical components contained in Aidi injection, viz. cantharidin, syringin, calycosin-7-o-ß-Dglucoside, isozinpidine, ginsenosides Rd, Rc, Rb1, Re, and Rg1, astragalosides II and IV, and eleutheroside E. Aidi injection significantly inhibited the proliferation of HepG2 and PLC/PLF/5 cells with IC50 of 20.66 mg/ml and 27.5 mg/ml at 48h, respectively, increased the proportion of dead cells, induced cell apoptosis, suppressed the tumor growth of nude mice bearing PLC/PLF/5 cells, reduced MMP, activated PI3K/Akt and MAPK signal transduction pathways, down-regulated the expression of p-PI3K and Bcl-xL, and up-regulated the expression of p-JNK, p-p38 and Bim. CONCLUSION: Aidi injection inhibits the growth of liver cancer probably through regulating PI3K/Akt and MAPK signal transduction pathways, inducing MMP collapse to activate the mitochondrial apoptosis pathway, and then eliciting apoptosis of HCCs.

Aidi injection, a traditional Chinese biomedical preparation for gynecologic tumors: a systematic review and PRISMA-compliant meta-analysis.

Aidi injection (ADI), a traditional Chinese biomedical preparation, is a promising adjuvant therapy for gynecologic tumors (GTs), including cervical cancer (CC), endometrial cancer (EC), and ovarian cancer (OC). Although studies have reported positively on ADI therapy, its exact effects and safety in GT patients remain controversial. Therefore, a wide-ranging systematic search of electronic databases was performed for this meta-analysis. Data from 38 trials including 3309 GT patients were analyzed. The results indicated that the combination of conventional treatment and ADI markedly improved the patients' overall response rate (P<0.00001), disease control rate (P<0.00001), and quality of life (P<0.05) compared with conventional treatment alone. Furthermore, patient immunity was enhanced with combined treatment, as indicated by significantly increased percentages of CD3+ (P=0.005) and CD4+ (P<0.00001) and increased CD4+/CD8+ ratio (P=0.001). Most of the adverse events caused by radiochemotherapy such as gastrointestinal issues, leukopenia, thrombocytopenia, and hepatotoxicity, (P<0.05 for all) were significantly alleviated when ADI was used in the GT patients. However, other adverse events such as nephrotoxicity, diarrhea, alopecia, and neurotoxicity did not significantly differ between the two groups. Overall, these results suggest that the combination of conventional and ADI treatment is more effective than conventional treatment alone.