Network pharmacology-based mechanism of Sijunzi Decoction in treatment of colorectal cancer / 国际中医中药杂志

Objective:To explore the potential target and signaling pathway of Sijunzi Decoction in treating Colorectal Cancer (CRC) with network pharmacology.Methods:The Traditional Chinese Medicine System Platform (TCMSP) and Swiss Target Prediction database were adopted to establish the database of Sijunzi Decoction effective ingredients and targets. Therapeutic Target Database (TTD), Online Mendelian Inheritance in Man, Drugbank and GeneCards were used to build the CRC target database. The common gene names of target proteins were checked in Uniprot database. The STRING database was applied to analyze the interactions between the targets and the DAVID was used for the enrichment analysis on gene ontology (GO) biological process and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. The network topology results were analyzed by Cytoscape 3.7.1 software.Results:134 active compounds of Sijunzi Decoction were gained, and PPI includes 125 targets protein (TP53,AKT1,IL-6,et al.). The 516 cellular biological processes, 53 cellular component and 98 molecular function were obtained through GO biological process enrichment analysis. The result of KEGG pathway enrichment showed that PI3K-Akt signaling pathway, TNF signaling pathway and FoxO signaling pathway were the main pathways.Conclusion:Sijunzi Decoction is mainly used to treat CRC by regulating key proteins such as TP53,AKT1, IL-6 and interfering with signal pathways such as PI3K-Akt, TNF and FoxO, reflecting the characteristics of Sijunzi Decoction in the treatment of CRC with multi-component,multi-target and multi-pathway characters.

Efficacy and safety of Si-Jun-Zi-Tang-based therapies for functional (non-ulcer) dyspepsia: a meta-analysis of randomized controlled trials.

BACKGROUND: The traditional Chinese medicine formula Si-Jun-Zi-Tang (SJZT) has a long history of application in the treatment of functional dyspepsia (non-ulcer dyspepsia, FD)-like symptoms. SJZT-based therapies have been claimed to be beneficial in managing FD. This study aimed to assess the efficacy and safety of SJZT-based therapies in treating FD by meta-analysis. METHODS: Systematic searches for RCTs were conducted in seven databases (up to February 2019) without language restrictions. Data were analyzed using Cochrane RevMan software version 5.3.0 and Stata software version 13.1, and reported as relative risk (RR) or odds ratio (OR) with 95% confidence intervals (CIs). The primary outcome was response rate and the secondary outcomes were gastric emptying, quality of life, adverse effects and relapse rate. The quality of evidence was evaluated according to criteria from the Cochrane risk of bias. RESULTS: A total of 341 potentially relevant publications were identified, and 12 RCTs were eligible for inclusion. For the response rate, there was a statically significant benefit in favor of SJZT-based therapies (RR = 1.23; 95% CI 1.17 to 1.30). However, the benefit was limited to modified SJZT (MSJZT). The relapse rate of FD patients received SJZT-based therapies was lower than that of patients who received conventional medicines (OR = 0.23; 95% CI 0.10 to 0.51). No SJZT-based therapies-related adverse effect was reported. CONCLUSION: SJZT-based prescriptions may be effective in treating FD and no serious side-effects were identified, but the effect on response rate appeared to be limited to MSJZT. The results should be interpreted with caution as all the included studies were considered at a high risk of bias. Standardized, large-scale and strictly designed RCTs are needed to further validate the benefits of SJZT-based therapies for FD management. TRIAL REGISTRATION: Systematic review registration: [PROSPERO registration: CRD42019139136 ].

Mechanism study of Sijunzi Decoction intervening colorectal cancer based on network pharmacology / 国际中医中药杂志

Objective:Based on the network pharmacology, this study preliminarily aims to explore the mechanism of Sijunzi Decoction in the intervention of colorectal cancer. Methods:The active components and targets of Sijunzi Decoction were gained by Traditional Chinese Medicine Pharmacology Database Systems (TCMSP); and the targets were standardized with the help of Uniprot database. The related targets of colorectal cancer were obtained by GeneCards database and Disgenet database, and the intersection targets of berbal medicine and diseases were screened by R language. The visual regulation network of "active ingredient-disease target" of Sijunzi Decoction was constructed by Cytoscape software, and the protein interaction network was constructed by STRING database. The functional enrichment analysis of gene ontology (GO) and the pathway enrichment analysis of Kyoto Encyclopedia of Gene and Genome (KEGG) were carried out by Bioconductor platform. Results:A total of 135 active components and 68 intersection targets of Sijunzi Decoction were obtained. The core target proteins included IL6, VEGFA, CASP3, EGFR and so on. GO functional enrichment analysis involved 91 items, which mainly affected transcription factor activity, enzyme activity, receptor activity and biochemical process regulation. KEGG pathway enrichment analysis contained 126 items, concerning infection, cancer, apoptosis, inflammation and other pathways. Conclusion:The active components of Sijunzi Decoction mainly regulate biological processes such as transcription factor activity and enzyme activity of colorectal cancer cells through cancer signal pathway and inflammatory signal pathway, so as to play a role of interventing of colorectal cancer.

Combination Compositions Composed of l-Glutamine and Si-Jun-Zi-Tang Might Be a Preferable Choice for 5-Fluorouracil-Induced Intestinal Mucositis: An Exploration in a Mouse Model.

Intestinal mucositis is a common toxicity of many anti-neoplastic therapies that negatively influences health, the quality of life, economic outcomes, and even the success of cancer treatment. Unfortunately, there is presently no optimal medicine that is able to effectively manage this condition. l-glutamine is one of the most frequently used agent in practice among the limited treatment choices due to its safety and inexpensiveness despite there being a lack of evidence. Previous studies indicated that l-glutamine may alleviate mucositis and mucosal atrophy but failed to improve patients' macroscopic conditions, such as the occurrence of diarrhea. A compound glutamine capsule (G-SJZ), composed of l-glutamine and the traditional Chinese herbal formula Si-Jun-Zi-Tang, has been used in China for 23 years to treat many types of gastrointestinal diseases, including gastrointestinal reactions induced by radiotherapy and chemotherapy. However, the exact effect of G-SJZ on intestinal mucositis is unclear, and moreover, whether l-glutamine combined with Si-Jun-Zi-Tang is more effective than l-glutamine alone have not been studied. In the current study, we explored the effects of G-SJZ and l-glutamine in a mouse model of intestinal mucositis induced by 5-fluorouracil (5-Fu). The results revealed that pretreatment with G-SJZ ameliorated the physical manifestations of weight loss and the severity of diarrhea following continuous 5-Fu injections in mice. Likewise, the histopathological damage and the destruction of villus and crypt structures in the intestinal mucosa as well as the increase in circulating intestinal injury markers caused by 5-Fu were reversed with G-SJZ pretreatment. Furthermore, the protective effect of G-SJZ was accompanied by modulations in the immunohistochemical expression of tight junction proteins. Interestingly, although treatment with a dose of l-glutamine alone that was equivalent to the dose in G-SJZ also showed a protective effect, it did not appear to be as strong as treatment with G-SJZ. Si-Jun-Zi-Tang in G-SJZ may compensate for the deficiencies of l-glutamine in this model which seems not to be related to the regulation of tight junction proteins. Our study is the first to suggest that the combined use of l-glutamine and Si-Jun-Zi-Tang might be more effective than l-glutamine alone despite exact mechanism still needs further study. Because of the limited number of therapeutic agents, G-SJZ is likely to be a preferable choice for intestinal mucositis.

A traditional Chinese medicine formula inhibits tumor growth in mice and regulates the miR-34b/c-Met/ß-catenin pathway.

ETHNOPHARMACOLOGY RELEVANCE: Si-Jun-Zi-Tang (SJZT) is a traditional Chinese medicine formula used to treat chronic and debilitating diseases including melanoma. SJZT-based therapies have achieved good clinical outcomes in melanoma management. However, the pharmacological basis of SJZT for its clinical use in melanoma treatment is not fully understood. AIM OF THE STUDY: To investigate the anti-melanoma effects and mechanism of action of an ethanolic extract of SJZT. MATERIALS AND METHODS: SJZT was extracted using 50% ethanol. A murine B16 melanoma-bearing mouse model was employed to investigate the anti-melanoma effects of SJZT. microRNA (miRNA) and mRNA levels were examined by RT-qPCR, and protein levels were measured by Western blotting. RESULTS: SJZT significantly inhibited B16 tumor growth in mice. Mechanistic investigations revealed that SJZT elevated miR-34b (a tumor suppressing miRNA), and lowered c-Met (a miR-34b target gene) and ß-catenin (a downstream molecule of c-Met signaling) expression levels in the B16 tumors. CONCLUSIONS: In this study we found, for the first time, that SJZT exerts anti-melanoma effects and regulates the miR-34b/c-Met/ß-catenin pathway in a melanoma mouse model. Our findings provide pharmacological justifications for the clinical use of SJZT in treating melanoma.

Modified Si-Jun-Zi-Tang Attenuates Airway Inflammation in a Murine Model of Chronic Asthma by Inhibiting Teff Cells via the mTORC1 Pathway.

Background: Modified Si-Jun-Zi-Tang (MSJZT), a multi-herb formulation, is frequently used in traditional Chinese medicine for patients during the remission stage of asthma. However, the pharmacological basis underlying the effects of MSJZT on asthma has yet to be elucidated. This study aims at evaluating the anti-asthmatic effects of MSJZT and investigating its possible mechanism. Methods: A chronic murine model of asthma was established by sensitization and repeated challenge with ovalbumin (OVA) in female BALB/c mice, followed with oral administration of MSJZT during remission, and then mouse were re-challenged by OVA. The chemical profile of MSJZT was analyzed by high-performance liquid chromatography. The characteristic features of allergic asthma, including airway hyperreactivity, histopathology, cytokine levels (IL-4, -5, -13, -17, and INF-γ), T regulatory (Treg) lymphocytes (Foxp3+CD4+CD25+), and T effector (Teff) lymphocytes (Foxp3-CD25+CD4+) in bronchoalveolar lavage fluid (BALF), and downstream proteins of mTORC1/2 signaling pathway were examined. Results: MSJZT markedly suppressed airway hyper-responsiveness to aerosolized methacholine, and reduced levels of IL-4, IL-5, and IL-13 in the BALF. Histological studies showed that MSJZT significantly reduced inflammatory infiltration in lung tissues. The percentage and absolute number of Teff cells were suppressed to a remarkable level by MSJZT without affecting Treg cells. Furthermore, MSJZT effectively inhibited the mTORC1 activity, but exerted limited effects on mTORC2, as assessed by the phosphorylation of the mTORC1 and mTORC2 substrates, S6 ribosomal protein, p70 S6 kinase, mTOR S2481, and Akt, respectively. Conclusion: MSJZT attenuated chronic airway inflammation in a mouse model of asthma by inhibiting Teff cells, which occurred, at least in part, via modulation of the mTORC1 signaling pathway.

The modulatory properties of Si Jun Zi Tang enhancing anticancer of gefitinib by an integrating approach.

Lung cancer remains the leading cause of cancer death worldwide, and the current therapy seems to have reached a plateau due to toxicities and acquired resistance. Therefore, exploration of novel therapeutic avenues may be useful. Si Jun Zi Tang (SJZ), a four-herb Chinese medicine formula first described approximately one thousand years, is often prescribed for cancer patients as a complementary therapy. However, whether SJZ benefits cancer patients as well as the main active constituents and its regulatory mechanism in combination with anticancer drugs remains unknown. Here, we investigated the anti-lung cancer potency and underlying mechanisms of the combination of gefitinib plus SJZ in mice with Lewis lung carcinoma (LLC), using histopathology and an integrated strategy of metabolomics and network pharmacology. The results showed that SJZ significantly enhanced gefitinib suppressing tumor growth and inhibiting LLC metastasis in LLC-bearing mice. Furthermore, 9 potential metabolomics biomarkers that differentially expressed in the SJZ/gefitinib group compared to the SJZ group or gefitinib group were identified by untargeted metabolomics, mainly involved three pathways: tricarboxylic acid cycle, tyrosine and tryptophan biosynthesis metabolism and linoleic acid metabolism. Five active ingredients, kaempferol, ginsenoside Rf, caprylic acid, lauric acid and naringenin, acted directly on 9 targets and regulated 4 out of 9 metabolites. Our results indicated that SJZ enhanced the anti-lung cancer effects of gefitinib via the key targets ABCG2, ABCC1, ABAT, GSR, CYP1A2, ALOX5, CYP3A4, PLA2G1B and PLA2G2A and the key metabolites 2-oxoglutarate, taurocholic acid, oxidized glutathione and linoleic acid. This work illustrated the modulatory properties of SJZ, which enhanced the anticancer effects of gefitinib, using metabolomics and network pharmacology analyses, and provided insights into underlying the mechanism the active ingredients of SJZfor the treatment of lung cancer in combination with gefitinib.