Compound Kushen Injection Research Articles

Compound Kushen Injection Protects Skin From Radiation Injury via Regulating Bim.

Background: Radiation-induced skin injury is a major side-effect observed in cancer patients who received radiotherapy. Thus identifying new radioprotective drugs for prevention or treatment of post-irradiation skin injury should be prompted. A large number of clinical studies have confirmed that Compound Kushen injection (CKI) can enhance efficacy and reduce toxicity of radiotherapy. The aim of this study is to confirm the effect of CKI in alleviating radiotherapy injury in the skin and explore the exact mechanism. Methods: 60 patients who met the inclusion/exclusion criteria were allocated to treatment group (CKI before radiotherapy) or control group (normal saline before radiotherapy) randomly. MTT assay, flow cytometry, Western Blot, and transient transfection were performed to detect the cell viability, cell apoptosis and Bim expression after treatment with CKI or/and radiotherapy. Results: CKI had the effect of alleviating skin injury in cancer patients who received radiotherapy in clinic. CKI induced cancer cell apoptosis when combined with irradiation (IR), while it reversed the induction of cell apoptosis by IR in human skin fibroblast (HSF) cells. And Bim, as a tumor suppressor, was induced in cancer cells but had no change in HSF cells when treated with CKI. Moreover, the above effect could be attenuated when Bim was silenced by siRNA. Conclusion: We conclude that CKI represents a promising radio-protective agent with a potential differential beneficial effect on both cancer cells (inducing apoptosis) and HSF cells (providing radio-protection via inhibiting IR-induced apoptosis), via regulating Bim. Our study uncovers a novel mechanism by which CKI inhibits human cancer cell while protects skin from radiotherapy, indicating CKI might be a promising radio-protective drug. Clinical Trial Registration: Chinese Clinical Trial Registry (www.chictr.org.cn), identifier ChiCTR2100049164.

A systematic review and meta-analysis on the efficacy of Compound Kushen Injection in 3 kinds of digestive tract tumor.

Chemotherapy has become the main means to prolong the life of patients with advanced digestive tract cancer; however, it is associated with serious toxicity and side effects. Compound Kushen Injection (CKI) is a pure Chinese herbal preparation, which can assist chemotherapy, inhibit tumor cell proliferation, and reduce adverse reactions of chemotherapy. In this study, we systematically evaluated reports of CKI as an adjuvant to chemotherapeutic treatment of digestive tract cancer in recent years and provided evidence for clinical diagnosis and treatment. The databases of PubMed, Chinese Biomedical Literature (CBM), China National Knowledge Infrastructure (CNKI) and Web Of Science were searched for clinical randomized controlled trials (RCTs) related to adjuvant chemotherapy with CKI in the treatment of advanced gastrointestinal tumors published from January 2000 to September 2021. After screening the qualified literatures, RevMan 5.4 software was used to evaluate the bias of the included literatures and perform meta-analysis. A total of 12 articles were included in the selection, incorporating 1080 study participants in all; meta-analysis results showed that application of the CKI in the process of chemotherapy for digestive tract tumors could improve the efficacy [odds ratio (OR) =3.11; 95% confidence interval (CI): 2.26 to 4.47, Z=7.00, P<0.00001], increase the patients' median survival time (months) (OR =3.00; 95% CI: 1.47 to 4.52, Z=3.84, P=0.0001), increase the level of CD3+ [mean difference (MD) =4.11; 95% CI: 3.24 to 4.98], CD4+ level (MD =8.24; 95% CI: 3.72 to 12.76), reduce the CD8+ level (MD =-5.42; 95% CI: -8.09 to -2.76), reduce the tumor markers carcinoembryonic antigen (CEA; MD =-14.26; 95% CI: -14.81 to -13.71), CA199 (MD =-138.87; 95% CI: -143.21 to -132.52), and reduce the adverse reactions of chemotherapy: leukopenia (OR =0.28; 95% CI: 0.19 to 0.43), thrombocytopenia (OR =0.38; 95% CI: 0.24 to 061), decreased hemoglobin (OR =0.55; 95% CI: 0.31 to 0.98), and nausea and vomiting symptoms (OR =0.35; 95% CI: 0.24 to 0.53). Adjuvant chemotherapy with CKI in the treatment of digestive tract tumors can effectively improve the symptoms of patients, improve immunity, reduce the level of serum tumor markers, improve efficacy, and reduce toxic and side effects.

A network pharmacology approach to reveal the pharmacological targets and biological mechanism of compound kushen injection for treating pancreatic cancer based on WGCNA and in vitro experiment validation

BackgroundCompound kushen injection (CKI), a Chinese patent drug, is widely used in the treatment of various cancers, especially neoplasms of the digestive system. However, the underlying mechanism of CKI in pancreatic cancer (PC) treatment has not been totally elucidated.MethodsHere, to overcome the limitation of conventional network pharmacology methods with a weak combination with clinical information, this study proposes a network pharmacology approach of integrated bioinformatics that applies a weighted gene co-expression network analysis (WGCNA) to conventional network pharmacology, and then integrates molecular docking technology and biological experiments to verify the results of this network pharmacology analysis.ResultsThe WGCNA analysis revealed 2 gene modules closely associated with classification, staging and survival status of PC. Further CytoHubba analysis revealed 10 hub genes (NCAPG, BUB1, CDK1, TPX2, DLGAP5, INAVA, MST1R, TMPRSS4, TMEM92 and SFN) associated with the development of PC, and survival analysis found 5 genes (TSPOAP1, ADGRG6, GPR87, FAM111B and MMP28) associated with the prognosis and survival of PC. By integrating these results into the conventional network pharmacology study of CKI treating PC, we found that the mechanism of CKI for PC treatment was related to cell cycle, JAK-STAT, ErbB, PI3K-Akt and mTOR signalling pathways. Finally, we found that CDK1, JAK1, EGFR, MAPK1 and MAPK3 served as core genes regulated by CKI in PC treatment, and were further verified by molecular docking, cell proliferation assay, RT-qPCR and western blot analysis.ConclusionsOverall, this study suggests that the optimized network pharmacology approach is suitable to explore the molecular mechanism of CKI in the treatment of PC, which provides a reference for further investigating biomarkers for diagnosis and prognosis of PC and even the clinical rational application of CKI.

A System Pharmacology Model for Decoding the Synergistic Mechanisms of Compound Kushen Injection in Treating Breast Cancer.

Breast cancer (BC) is one of the most common malignant tumors among women worldwide and can be treated using various methods; however, side effects of these treatments cannot be ignored. Increasing evidence indicates that compound kushen injection (CKI) can be used to treat BC. However, traditional Chinese medicine (TCM) is characterized by “multi-components” and “multi-targets”, which make it challenging to clarify the potential therapeutic mechanisms of CKI on BC. Herein, we designed a novel system pharmacology strategy using differentially expressed gene analysis, pharmacokinetics synthesis screening, target identification, network analysis, and docking validation to construct the synergy contribution degree (SCD) and therapeutic response index (TRI) model to capture the critical components responding to synergistic mechanisms of CKI in BC. Through our designed mathematical models, we defined 24 components as a high contribution group of synergistic components (HCGSC) from 113 potentially active components of CKI based on ADME parameters. Pathway enrichment analysis of HCGSC targets indicated that Rhizoma Heterosmilacis and Radix Sophorae Flavescentis could synergistically target the PI3K-Akt signaling pathway and the cAMP signaling pathway to treat BC. Additionally, TRI analysis showed that the average affinity of HCGSC and targets involved in the key pathways reached -6.47 kcal/mmol, while in vitro experiments proved that two of the three high TRI-scored components in the HCGSC showed significant inhibitory effects on breast cancer cell proliferation and migration. These results demonstrate the accuracy and reliability of the proposed strategy.

Compound Kushen Injection Induces Immediate Hypersensitivity Reaction Through Promoting the Production of Platelet-Activating Factor via de Novo Pathway.

Compound Kushen Injection (CKI) is a bis-herbal formulation extracted from Kushen (Radix Sophorae Flavescentis) and Baituling (Rhizoma Heterosmilacis Yunnanensis). Clinically, it is used as the adjuvant treatment of cancer. However, with the increased application, the cases of immediate hypersensitivity reactions (IHRs) also gradually rise. In this study, we investigated the underlying mechanism(s) and active constituent(s) for CKI-induced IHRs in experimental models. The obtained results showed that CKI did not elevate serum total IgE (tIgE) and mouse mast cell protease 1 (MMCP1) after consecutive immunization for 5 weeks, but could induce Evans blue extravasation (local) and cause obvious hypothermia (systemic) after a single injection. Further study showed that alkaloids in Kushen, especially matrine, were responsible for CKI-induced IHRs. Mechanism study showed that various platelet-activating factor (PAF) receptor antagonists could significantly counter CKI-induced IHRs locally or systemically. In cell system, CKI was able to promote PAF production in a non-cell-selective manner. In cell lysate, the effect of CKI on PAF production became stronger and could be abolished by blocking de novo pathway. In conclusion, our study identifies, for the first time, that CKI is a PAF inducer. It causes non-immunologic IHRs, rather than IgE-dependent IHRs, by promoting PAF production through de novo pathway. Alkaloids in Kushen, especially matrine, are the prime culprits for IHRs. Our findings may provide a potential approach for preventing and treating CKI-induced IHRs.

Combination of Compound Kushen Injection and cisplatin shows synergistic antitumor activity in p53-R273H/P309S mutant colorectal cancer cells through inducing apoptosis

Ethnopharmacological relevanceColorectal cancer (CRC) is one type of worldwide popular and refractory tumors. Compound Kushen Injection (CKI) is a frequently applied traditional Chinese medicine formula as an adjuvant drug for the chemotherapy of CRC. P53 is the most commonly mutated gene in CRC, accounting for the development, malignant and prognosis progression of CRC. However, effect of CKI on the therapeutic efficacy of p53-mutant CRC remains understood. Besides, the combined efficacy of different chemotherapeutics drugs in combination with CKI for CRC treatment is rarely concerned. Aim of studyTo investigate the combined efficacy of the CKI-derived combination strategies in the p53-mutant CRC. Materials and methodsTwo CRC cell lines HCT116 and SW480 cells, which respectively harbor wild-type p53 and p53-R273H/P309S mutant, were applied. Cisplatin (Cis) and 5-fluorouracil (5FU) were combined chemotherapeutics drugs of CKI-derived combination strategies in this article. In vitro antitumor activity was detected by sulforhodamine B (SRB) assay and colony formation assay. Combenefit soft was applied to evaluate the synergetic/antagonistic effect of drug combination. Lentivirus-mediated overexpression method was used to generate a set of p53-mutant and wild-type CRC cell lines harboring identical genomes. Transcriptomics and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were applied to predicate the underlying mechanism of synergetic interaction between drug combination. Western blot was performed to verify predicated pathways contributing to the synergy of drug combination. ResultsCKI preferentially combined with Cis but not 5FU, to produce a synergistical antitumor efficiency for p53-R273H/P309S mutant, rather than wild-type p53 harboring CRC cells. The combination of CKI and Cis strongly reprogrammed the transcriptional profiles of SW480 cells. Cytokine-cytokine receptor interaction pathway was a key pathway involved in cooperativity between CKI and Cis in SW480 cells. Mechanistically, compared to that Cis individually triggered necroptosis, the co-treatment of CKI and Cis reinforced the cell death of SW480 cells in a possible synergistic manner by inducing extrinsic apoptosis pathway. ConclusionThis article provides a novel perspective into the precision clinical application of CKI-derived combination therapy programs of CRC based on genetic variation and the classes of chemotherapeutics drugs.

Compound Kushen Injection intervenes metabolic reprogramming and epithelial-mesenchymal transition of HCC via regulating β-catenin/c-Myc signaling

BackgroundHepatocellular carcinoma (HCC) is one of the most extensive and most deadly cancers worldwide. The invasion and metastasis characteristics of HCC dramatically affect the prognosis and survival of HCC patients. Compound Kushen Injection (CKI) is a GMP produced, proverbially applied traditional Chinese medicine formula in China to treat cancer-associated pains, and used as an adjunctive therapy for HCC. Until so far, whether CKI could suppress the metastasis of HCC through regulation of epithelial-mesenchymal transition or metabolic reprogramming is still ambiguous. PurposeIn this study, the anti-metastasis effects of CKI were clarified and its pharmacological mechanisms were systematically explored. MethodsCell invasion and cell adhesion assay were performed in SMMC-7721 cells to assess the anti-metastasis role of CKI, and the histopathological evaluation and biochemical detection were utilized in DEN-induced HCC rats to verify the anti-HCC effect of CKI. Serum and liver samples were analyzed with 1H NMR metabolomics approach to screen the differential metabolites and further target quantification the content of key metabolites. Finally, western blotting and immunofluorescence assay were applied to verify the crucial signaling pathway involved in metabolites. ResultsCKI markedly repressed the invasion and adhesion in SMMC-7721 cells and significantly improved the liver function of DEN-induced HCC rats. CKI significantly regulated the expression of epithelial-mesenchymal transition (EMT) markers (Vimentin and E-cadherin). Metabolomics results showed that CKI regulated the metabolic reprogramming of HCC by inhibiting the key metabolites (citrate and lactate) and enzymes (HK and PK) in glycolysis process. Importantly, we found that c-Myc mediates the inhibitory effect of CKI on glycolysis. We further demonstrated that CKI inhibits c-Myc expression through modulating Wnt/β-catenin pathway in SMMC-7721 cells and DEN-induced HCC rats. Furthermore, through activating Wnt/β-catenin pathway with LiCl, the inhibitory effects of CKI on HCC were diminished. ConclusionTogether, this study reveals that CKI intervenes metabolic reprogramming and epithelial-mesenchymal transition of HCC via regulating β-catenin/c-Myc signaling pathway. Our research provides a new understanding of the mechanism of CKI against invasion and metastasis of HCC from the perspective of metabolic reprogramming.

An Advanced Systems Pharmacology Strategy Reveals AKR1B1, MMP2, PTGER3 as Key Genes in the Competing Endogenous RNA Network of Compound Kushen Injection Treating Gastric Carcinoma by Integrated Bioinformatics and Experimental Verification.

Gastric carcinoma (GC) is a severe tumor of the digestive tract with high morbidity and mortality and poor prognosis, for which novel treatment options are urgently needed. Compound Kushen injection (CKI), a classical injection of Chinese medicine, has been widely used to treat various tumors in clinical practice for decades. In recent years, a growing number of studies have confirmed that CKI has a beneficial therapeutic effect on GC, However, there are few reports on the potential molecular mechanism of action. Here, using systems pharmacology combined with proteomics analysis as a core concept, we identified the ceRNA network, key targets and signaling pathways regulated by CKI in the treatment of GC. To further explore the role of these key targets in the development of GC, we performed a meta-analysis to compare the expression differences between GC and normal gastric mucosa tissues. Functional enrichment analysis was further used to understand the biological pathways significantly regulated by the key genes. In addition, we determined the significance of the key genes in the prognosis of GC by survival analysis and immune infiltration analysis. Finally, molecular docking simulation was performed to verify the combination of CKI components and key targets. The anti-gastric cancer effect of CKI and its key targets was verified by in vivo and in vitro experiments. The analysis of ceRNA network of CKI on GC revealed that the potential molecular mechanism of CKI can regulate PI3K/AKT and Toll-like receptor signaling pathways by interfering with hub genes such as AKR1B1, MMP2 and PTGERR3. In conclusion, this study not only partially highlighted the molecular mechanism of CKI in GC therapy but also provided a novel and advanced systems pharmacology strategy to explore the mechanisms of traditional Chinese medicine formulations.

Research Progress on the Antitumor Mechanism of Compound Kushen Injection

Compound Kushen Injection (CKI), as a clinical traditional Chinese medicine preparation, has prominent antitumor effect but with several side effects. A large number of studies have shown that CKI plays an antitumor role by regulating tumor cell proliferation, inducing tumor cell differentiation and apoptosis, inhibiting tumor cell invasion and metastasis, reducing tumor angiogenesis, regulating the immunity, and so on. Clinically, CKI is widely used to treat various tumors, where it is often combined with surgery, chemotherapy, radiotherapy, targeted therapy, and other antitumor treatments. This article reviews the antitumor mechanism of CKI and the progress of its clinical application in order to provide a theoretical basis for further clinical application.

High Throughput Transcriptome Data Analysis and Computational Verification Reveal Immunotherapy Biomarkers of Compound Kushen Injection for Treating Triple-Negative Breast Cancer.

BackgroundAlthough notable therapeutic and prognostic benefits of compound kushen injection (CKI) have been found when it was used alone or in combination with chemotherapy or radiotherapy for triple-negative breast cancer (TNBC) treatment, the effects of CKI on TNBC microenvironment remain largely unclear. This study aims to construct and validate a predictive immunotherapy signature of CKI on TNBC.MethodsThe UPLC-Q-TOF-MS technology was firstly used to investigate major constituents of CKI. RNA sequencing data of CKI-perturbed TNBC cells were analyzed to detect differential expression genes (DEGs), and the GSVA algorithm was applied to explore significantly changed pathways regulated by CKI. Additionally, the ssGSEA algorithm was used to quantify immune cell abundance in TNBC patients, and these patients were classified into distinct immune infiltration subgroups by unsupervised clustering. Then, prognosis-related genes were screened from DEGs among these subgroups and were further overlapped with the DEGs regulated by CKI. Finally, a predictive immunotherapy signature of CKI on TNBC was constructed based on the LASSO regression algorithm to predict mortality risks of TNBC patients, and the signature was also validated in another TNBC cohort.ResultsTwenty-three chemical components in CKI were identified by UPLC-Q-TOF-MS analysis. A total of 3692 DEGs were detected in CKI-treated versus control groups, and CKI significantly activated biological processes associated with activation of T, natural killer and natural killer T cells. Three immune cell infiltration subgroups with 1593 DEGs were identified in TNBC patients. Then, two genes that can be down-regulated by CKI with hazard ratio (HR) > 1 and 26 genes that can be up-regulated by CKI with HR < 1 were selected as key immune- and prognosis-related genes regulated by CKI. Lastly, a five-gene prognostic signature comprising two risky genes (MARVELD2 and DYNC2I2) that can be down-regulated by CKI and three protective genes (RASSF2, FERMT3 and RASSF5) that can be up-regulated by CKI was developed, and it showed a good performance in both training and test sets.ConclusionsThis study proposes a predictive immunotherapy signature of CKI on TNBC, which would provide more evidence for survival prediction and treatment guidance in TNBC as well as a paradigm for exploring immunotherapy biomarkers in compound medicines.

A Multidimensional Bayesian Network Meta-Analysis of Chinese Herbal Injections for Treating Non-small Cell Lung Cancer With Gemcitabine and Cisplatin.

Introduction: As non-small cell lung cancer (NSCLC) seriously threatens human health, several clinical studies have reported that Chinese herbal injections (CHIs) in combination with and gemcitabine plus cisplatin (GP) are beneficial. This multidimensional network meta-analysis aimed to compare the clinical efficacy and safety of different CHIs in combination with GP against NSCLC.Methods: Randomized controlled trials (RCTs) for the treatment of NSCLC were retrieved from seven electronic databases from inception to April 30, 2020. Study selection and data extraction were based on a priori criteria. Data analysis was performed using Stata 13.0, WinBUGS 14.0 software. Multidimensional cluster analysis was performed using the “scatterplot3d” package in R 3.6.1 software.Results: This network meta-analysis included 71 eligible RCTs and 10 Chinese herbal injections. Delisheng injection and Kangai injection had the highest probability in terms of clinical effectiveness rate (94.60%) and gastrointestinal reactions (82.62%) when combined with GP compared with the other interventions. Compound Kushen injection combined with GP ranked ahead of the other interventions in terms of performance status (73.36%) and abnormal liver function (87.17%). Shenmai injection combined with GP had the highest probability in terms of leukopenia (94.59%) and thrombocytopenia (99.18%).Conclusion: The current evidence revealed that CHIs combined with GP have a better impact on patients with NSCLC than GP alone. Aidi injection, Compound kushen injection, and Kanglaite injection deserve more attention of clinicians when combined with GP in patients with NSCLC. Additionally, due to the limitations of this network meta-analysis, further well-designed, large-sample, multicenter RCTs are required to support our findings adequately.

Effect of Psychological Intervention Combined with Family Cooperation on the Perioperative Quality of Life and Psychological States of Elderly Patients with Prostate Cancer Treated with Compound Kushen Injection.

Objective The purpose of the study was to investigate the nursing effect of psychological intervention combined with family cooperation on elderly patients with prostate cancer treated with compound kushen injection and put forward effective suggestions. Methods 122 elderly patients with prostate cancer admitted to our hospital from June 2018 to June 2019 were selected and randomly divided into a control group (n = 61) and experimental group (n = 61). The patients in the control group received routine nursing intervention during the perioperative period, while the patients in the experimental group were treated with psychological intervention combined with family cooperation on the basis of routine nursing. The quality of life and psychological states of patients in the two groups were statistically analyzed. Results The evaluation of psychological states at 24 hours before surgery and 24 hours before discharge in the experimental group was significantly better than that in the control group (P < 0.05), with statistical significance. On comparing the basic conditions between the two groups in the perioperative period, the length of hospitalization, length of catheter retention after surgery, and incidence of complications in the experimental group were all significantly better than those in the control group (P < 0.05), with statistical significance. The satisfaction of patients with the nursing process in both groups was recorded and statistically analyzed through questionnaires. The satisfaction with nursing process in the experimental group was significantly higher than that in the control group (P < 0.05), with statistical significance. The quality of life of the patients was followed up at three months after discharge. The quality of life of the experimental group was significantly better than that of the control group (P < 0.05), with statistical significance. Conclusion Psychological intervention combined with family cooperation for the elderly patients with prostate cancer treated with compound kushen injection is beneficial to improve their psychological states, encourage them to face the disease in a more positive manner, effectively improve the quality of life after intervention, ensure the therapeutic effect during perioperative period, increase happiness index, and enhance their satisfaction with the nursing process, which is worthy of clinical application and popularization.

Investigation on the clinical efficacy and mechanism of compound kushen injection in treating esophageal cancer based on multi-dimensional network meta-analysis and in vitro experiment

Ethnopharmacological relevanceEsophageal cancer, as a high incidence of gastrointestinal cancer, has an indelible impact on human life and health. The combination of Chinese herbal injections and chemotherapy is commonly applied in the treatment of Esophageal cancer. Aim of the studyThis study aimed to confirm the clinical advantage of Compound Kushen Injection to treat esophageal cancer and explore its molecular mechanism. MethodsThe network meta-analysis method was used for the clinical evaluation of anti-tumor Chinese herbal injections. Initially, several electronic databases were searched to identify randomized controlled trials regarding Chinese herbal injections to treat esophageal cancer from their inception to September 5, 2020. Then, WinBugs and Stata software was used to calculate and analyze the outcome indicators, including total clinical efficiency, improvement of quality of life and adverse reactions. Furthermore, the surface under the cumulative ranking curve and three-dimensional cluster analysis were used to rank the efficacy and safety of Chinese herbal injections about each outcome. Cell Counting Kit-8 assay was used to observe the effect of Compound Kushen Injection on the proliferation of esophageal cancer cells. Real-Time Quantitative PCR and Western Blot analysis were used to detect the mRNA and protein expression of EGFR and AURKA in ESCA cells. ResultsThe surface under the cumulative ranking curve of Compound Kushen Injection combined with chemotherapy in total clinical efficiency, quality of life, reduction of nausea and vomiting were ranking at 89.1%, 81.8% and 92.4%, respectively. Compound Kushen Injection was determined as the dominant variety in the treatment of esophageal cancer which can inhibit the proliferation of esophageal cancer cells and downregulate the overexpression of EGFR and AURKA mRNA and protein. ConclusionIn this study, network meta-analysis was applied to confirm that Compound Kushen Injection has a curative effect on esophageal cancer and is superior to other anti-tumor Chinese herbal injections. Combined with the network pharmacology and in vitro experiment, the mechanism of Compound Kushen Injection inhibiting the proliferation of esophageal cancer cells by regulating the abnormal expression of EGFR and AURKA was revealed.

Rebalancing TGF-β/Smad7 signaling via Compound kushen injection in hepatic stellate cells protects against liver fibrosis and hepatocarcinogenesis.

BackgroundLiver fibrosis and fibrosis‐related hepatocarcinogenesis are a rising cause for morbidity and death worldwide. Although transforming growth factor‐β (TGF‐β) is a critical mediator of chronic liver fibrosis, targeting TGF‐β isoforms and receptors lead to unacceptable side effect. This study was designed to explore the antifibrotic effect of Compound kushen injection (CKI), an approved traditional Chinese medicine formula, via a therapeutic strategy of rebalancing TGF‐β/Smad7 signaling.MethodsA meta‐analysis was performed to evaluate CKI intervention on viral hepatitis‐induced fibrosis or cirrhosis in clinical randomized controlled trials (RCTs). Mice were given carbon tetrachloride (CCl4) injection or methionine‐choline deficient (MCD) diet to induce liver fibrosis, followed by CKI treatment. We examined the expression of TGF‐β/Smad signaling and typical fibrosis‐related genes in hepatic stellate cells (HSCs) and fibrotic liver tissues by qRT‐PCR, Western blotting, RNA‐seq, immunofluorescence, and immunohistochemistry.ResultsBased on meta‐analysis results, CKI improved the liver function and relieved liver fibrosis among patients. In our preclinical studies by using two mouse models, CKI treatment demonstrated promising antifibrotic effects and postponed hepatocarcinogenesis with improved liver function and histopathologic features. Mechanistically, we found that CKI inhibited HSCs activation by stabilizing the interaction of Smad7/TGF‐βR1 to rebalance Smad2/Smad3 signaling, and subsequently decreased the extracellular matrix formation. Importantly, Smad7 depletion abolished the antifibrotic effect of CKI in vivo and in vitro. Moreover, matrine, oxymatrine, sophocarpine, and oxysophocarpine were identified as material basis responsible for the antifibrosis effect of CKI.ConclusionsOur results unveil the approach of CKI in rebalancing TGF‐β/Smad7 signaling in HSCs to protect against hepatic fibrosis and hepatocarcinogenesis in both preclinical and clinical studies. Our study suggests that CKI can be a candidate for treatment of hepatic fibrosis and related oncogenesis.

Investigation on the Efficiency of Chinese Herbal Injections combined with Concurrent Chemoradiotherapy for Treating Nasopharyngeal Carcinoma based on Multidimensional Bayesian Network Meta-analysis.

Introduction: Given the wide utilization of Chinese herbal injections in the treatment of nasopharyngeal carcinoma (NPC), this network meta-analysis (NMA) was devised to compare the clinical efficacy and safety of different Chinese herbal injections combined with concurrent chemoradiotherapy (CCRT) against NPC. Methods: Randomized controlled trials (RCTs) were retrieved from seven electronic databases from the date of database establishment to October 5, 2020. Study selection and data extraction conformed to a priori criteria. Focusing on clinical effective rate, performance status, grade ≥3 oral mucositis, nausea and vomiting, leukopenia, and thrombopenia, this NMA was performed with Review Manager 5.3.5, Stata 13.1, WinBUGS 1.4.3, and R 4.0.3 software. Results: Ten inventions from 37 RCTs involving 2,581 participants with NPC that evaluated the clinical effective rate, nausea and vomiting, leukopenia, thrombopenia, and grade ≥3 oral mucositis were included. Compared with CCRT alone, Elemene injection and Compound Kushen injection were associated with significantly improved clinical effective rates, and Elemene injection plus CCRT had the highest probability in terms of clinical effective rate (78.07%) compared with the other interventions. Shenqifuzheng injection, Xiaoaiping injection, and Shenmai injection ranked the best in terms of performance status (79.02%), nausea and vomiting (86.35%), and grade ≥3 oral mucositis (78.14%) when combined with CCRT. Kangai injection combined with CCRT ranked ahead of the other injections in terms of leukopenia (90.80%) and thrombopenia (91.04%), and had a better impact on improving performance status and reducing leukopenia, thrombopenia, grade ≥3 oral mucositis, and nausea and vomiting in the multidimensional cluster analysis. Conclusion: Current clinical evidence indicates that Elemene injection combined with CCRT has the best clinical effective rate and that Kangai injection might have a comprehensively better impact on improving performance status and reducing adverse reactions against NPC. Additionally, due to the limitations of this NMA, more multicenter, high-quality, and head-to-head RCTs are needed to properly support our findings.

A metabolic data-driven systems pharmacology strategy for decoding and validating the mechanism of Compound Kushen Injection against HCC

Ethnopharmacological relevanceCompound Kushen Injection (CKI) is a widely used TCM formula for treatment of carcinomatous pain and tumors of digestive system including hepatocellular carcinoma (HCC). However, the potential mechanisms of CKI for treatment of HCC have not been systematically and deeply studied. Aim of studyA metabolic data-driven systems pharmacology approach was utilized to investigate the potential mechanisms of CKI for treatment of HCC. Materials and methodsBased on phenotypic data generated by metabolomics and genotypic data of drug targets, a propagation model based on Dijkstra program was proposed to decode the effective network of key genotype-phenotype of CKI in treating HCC. The pivotal pathway was predicted by target propagation mode of our proposed model, and was validated in SMMC-7721 cells and diethylnitrosamine-induced rats. ResultsMetabolomics results indicated that 12 differential metabolites, and 5 metabolic pathways might be involved in the anti-HCC effect of CKI. A total of 86 metabolic related genes that affected by CKI were obtained. The results calculated by propagation model showed that 6475 shortest distance chains might be involved in the anti-HCC effect of CKI. According to the results of propagation mode, EGFR was identified as the core target of CKI for the anti-HCC effect. Finally, EGFR and its related pathway EGFR-STAT3 signaling pathway were validated in vivo and in vitro. ConclusionThe proposed method provides a methodological reference for explaining the underlying mechanism of TCM in treating HCC.

Comparative Efficacy and Safety of Chinese Herbal Injections Combined With Cyclophosphamide and 5-Fluorouracil Chemotherapies in Treatment of Breast Cancer: A Bayesian Network Meta-Analysis.

Background: Given the limitations of chemotherapy for the treatment of breast cancer (BC) and the wide exploration of Chinese herbal injections (CHIs), this network meta-analysis (NMA) was conducted to analyze the comparative efficacy and safety of nine CHIs combined with CF (Cyclophosphamide and 5-Fluorouracil) chemotherapy regimens in the treatment of BC. Methods: Several electronic databases were searched to identify randomized controlled trials (RCTs) from inception to January 6, 2020. RCTs were screened by pre-established eligibility criteria, and the quality of which was assessed using the Cochrane risk of bias tool. Outcomes such as the clinical effectiveness rate, performance status, peripheral hemogram, and detection of T-lymphocyte subsets were analyzed using the Winbugs 1.4.3 and Stata 13.0 software. Surface under the cumulative ranking curve (SUCRA) probability values were applied to rank the examined treatments. Cluster analysis was performed to compare the effect of CHIs between two or three different outcomes. Results: A total of 84 RCTs involving 7855 patients and nine CHIs were included. The results showed that compared to CF chemotherapy regimens alone, the ones injected along with Aidi, Shenmai, Shenqi Fuzheng, Kangai, Kanglaite, or Shengmai combined with CF can improve the clinical effectiveness rate. Aidi, Shenmai, Shenqi Fuzheng, Compound Kushen, Kangai, and Kanglaite injection combined with CF can improve the performance status. Shenqi Fuzheng injection was considered as a favorable choice for relieving adverse reactions. According to the results of cluster analysis, Aidi injection and Compound Kushen injection plus CF were more favorable for the clinical effectiveness rate and performance status. Conclusion: In conclusion, Shenqi Fuzheng, Compound Kushen, Aidi, and Kangai injection combined with CF chemotherapy regimen have more significant effects for patients with BC. However, more high-quality clinical RCTs, especialy which correctly use blinding and allocation concealment, are required to support the conclusions.

Molecular Evidence of Compound Kushen Injection Against Lung Cancer: A Network Pharmacology-Based Investigation from Western Medicine to Traditional Medicine.

Compound Kushen Injection (CKI) is used clinically for relieving cancer pain and treating various solid tumors, particularly lung cancer. However, the underlying mechanisms of CKI in lung cancer remain to be further elucidated. This study aimed to obtain evidence regarding the potential efficacy of the active compounds and therapeutic targets of CKI at a molecular level by using Network Pharmacology (NP), which is an emerging technique for dealing with complex systems, such as those of herbal medicine. The chemical and predicted target information of CKI was obtained from databases and computational prediction, respectively; lung-cancer drugs and their corresponding targets were retrieved from Drugbank and Drugcentral. The online tool, STRING, was used to gather target-pathway interactions for establishing a target-(pathway)-target network to identify the target group that was most relevant to cancer. Based on this module, a protein-protein interaction network was established for identifying the potential therapeutic targets and the potential active ingredients. CKI might affect lung cancer drug targets or their neighbor nodes to trigger anti-cancer effects. The compounds that were predicted to bind to the potential therapeutic targets were recommended as potential active ingredients of CKI, which included naringenin from Baituling, and kurarinone and isoxanthohumol from Kushen. This NP-based study might provide insights into understanding CKI from the perspective of modern science with reference to approved Western medicine for lung cancer. Moreover, network-based methods could also be further used with distinct advantages in dealing with complex information and systems of medicine.

Iron Increases the Susceptibility of Colorectal Cancer Cells to Compound Kushen Injection Via the Decrease of TOP2A and P53

Iron Increases the Susceptibility of Colorectal Cancer Cells to Compound Kushen Injection Via the Decrease of TOP2A and P53

Therapeutic Effect of a Traditional Chinese Medicine Compound Mixture Compound Kushen Injection in Treating Multiple Myeloma

Abstract Background: Multiple myeloma (MM) is a hematology malignant disease originated from B-cell line and still incurable. Compound Kushen Injection (CKI) as a Traditional Chinese Medicines are promising agents in our previous research for treating cancer. The effect of CKI on multiple myeloma was still unknown. Methods: In vitro experiment, flow cytometry was used to evaluate effect of CKI on multiple myeloma cells. Optofluidic chip was applied to detect effect at single-cell level. And in vivo RPMI-8226 GFP+ B-NSG mouse model was built to assess the role of CKI in multiple myeloma treatment. Results: CKI inhibited MM cells proliferation of and increased its apoptosis rate. And the cell cycle of MM cells was also arrested by CKI treatment. In contrast, CKI has few toxic effects on mesenchymal stem cells (MSCs) and MC3T3 cells. At the single-cell level, MM cells was died in time and dose dependent manner. Transcriptome find that the expression of MYC and TERT in CKI-treated RPMI-8226 cells was significantly down-regulated and confirmed by qRT-PCR and Western blot. Overexpression of TERT can partly reverse the inhibition effect of CKI on RPMI-8226 cells. B-NSG mouse was injected with GFP+ RPMI-8226 cells through caudal vein, and the disease was partially alleviated by decreased tumor burden in the CKI-treated group. Furthermore, it is surprising that in animal models with myeloma bone disease, the bone mass was higher in CKI treatment group than control. Conclusions: CKI inhibits MM cells through the MYC/TERT signaling pathway and improve the quality of life of MM mouse. Our findings provide preclinical evidence to show that CKI could be a promising candidate in human MM therapy. Disclosures No relevant conflicts of interest to declare.