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      Network Pharmacology-Based Prediction and Verification of the Active Ingredients and Potential Targets of Zuojinwan for Treating Colorectal Cancer

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          Abstract

          Background

          Zuojinwan (ZJW), a famous Chinese medicine formula, has been widely used to treat colorectal cancer (CRC). However, its bioactive compounds, potential targets, and molecular mechanism remain largely elusive.

          Aim

          A network pharmacology-based strategy combined with molecular docking studies and in vitro validation were employed to investigate bioactive compounds, potential targets, and molecular mechanism of ZJW against CRC.

          Materials and Methods

          Bioactive compounds and potential targets of ZJW, as well as related genes of CRC, were acquired from public databases. Important ingredients, potential targets, and signaling pathways were determined through bioinformatics analysis, including protein–protein interaction (PPI), the Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, molecular docking and cell experiments were performed to further verify the findings.

          Results

          A total of 36 bioactive ingredients of ZJW and 163 gene targets of ZJW were identified. The network analysis revealed that quercetin, baicalein, wogonin, beta-sitosterol, and isorhamnetin may be candidate agents. The AKT1, JUN, CDKN1A, BCL2L1, and NCOA1 could become potential drug targets. The KEGG indicated that PI3K-AKT signaling pathway may play an important role in the effect of ZJW against CRC. Molecular docking suggested that quercetin, baicalein, and wogonin combined well with AKT1 and JUN. The in vitro experiment showed that quercetin, the most important ingredient of ZJW, could induce apoptosis of HCT116 cells through PI3K-Akt signaling pathway. This finding was congruent with the prediction obtained through the network pharmacology approach.

          Conclusion

          This study comprehensively illuminated the active ingredients, potential targets, and molecular mechanism of ZJW against CRC. It also provided a promising approach to uncover the scientific basis and therapeutic mechanism of traditional Chinese medicine (TCM) formula treating for disease.

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          Most cited references 47

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          Exploring the pharmacological mechanism of Yanghe Decoction on HER2-positive breast cancer by a network pharmacology approach.

          Certain Chinese medicine formulae from traditional Chinese Medicine (TCM) are effective for treating and preventing diseases in clinical practice. Yanghe Decoction (YHD) is a Chinese medicine formula that is used to treat breast cancer, especially HER-positive breast cancer; however, the active compounds, potential targets, and pharmacological and molecular mechanism of its action against cancer remain unclear. Therefore, further investigation is required.
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            CXCR2 promotes breast cancer metastasis and chemoresistance via suppression of AKT1 and activation of COX2.

            Metastasis and chemoresistance are two major causes of breast cancer death. We show here that the chemokine receptor CXCR2 was overexpressed in breast cancer cell lines and tissues. CXCR2 promoted anti-apoptosis, anti-senescence, and epithelial-to-mesenchymal transition (EMT) of breast cancer cells, leading to the enhanced metastasis and chemoresistance. Further study suggested that AKT1 and cyclooxygenase-2 (COX2; PTGS2) might mediate the CXCR2 signaling to inversely control the breast cancer metastasis and chemoresistance through the regulation of EMT, apoptosis, and senescence. Analyses of clinical data indicate that the high expression of CXCR2 was correlated with the high expression of COX2 and the low expression of AKT1, P85α, E-cadherin, and β-catenin in cancer tissues. Poor outcomes were associated with the high expression of CXCR2 or COX2 while favorable survivals were associated with the high expression of P85α, AKT1, or E-cadherin in all cancer patients. Cox multivariate analysis demonstrated that CXCR2, COX2, and AKT1 could be independent predictors for disease free survivals. All these data suggest that CXCR2 promotes breast cancer metastasis and chemoresistance via suppressing AKT1 and activating COX2. Thus, antagonists of the CXCR2 signaling molecules may be used to treat breast cancer patients particularly with high metastasis and chemoresistance.
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              Is Open Access

              Ginsenoside Rg3 targets cancer stem cells and tumor angiogenesis to inhibit colorectal cancer progression in vivo

              Anti-angiogenic therapy has been successfully applied to treat colorectal cancer (CRC). Ginsenoside Rg3, derived from the Chinese herb ginseng, has anti-vascularization effects and can inhibit tumor growth and metastasis, and can sensitize cancer cells to chemotherapy. Therefore, in the present study, we investigated whether Rg3 could be appropriate for CRC treatment. Growth of CRC cells was assessed by an MTT (methyl thiazolyl tetrazolium) assay in vitro and using orthotopic xenograft models in vivo. mRNA expression was evaluated using real-time PCR. Protein levels were tested by western blotting, flow cytometry and immunohistochemistry. Migration was determined using a wound-healing assay. Stemness was further confirmed using a plate clone formation assay. We found that Rg3 repressed the growth and stemness of CRC cells both in vitro and in vivo. Rg3 also impaired the migration of CRC cells in vitro. Rg3 downregulated the expressions of angiogenesis-related genes, and repressed the vascularization of CRC xenografts. In addition, Rg3 strengthened the cytotoxicity of 5-Fluorouracil and oxaliplatin against orthotopic xenografts in vivo. Moreover, Rg3 downregulated the expressions of B7-H1 and B7-H3, high expressions of which were associated with reduced overall survival (OS) of CRC patients. Hence, Rg3 not only repressed the growth and stemness of CRC cells, but could also remodel the tumor microenvironment through repressing angiogenesis and promoting antitumor immunity. Therefore, Rg3 could be a novel therapeutic for the CRC treatment.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                14 July 2020
                2020
                : 14
                : 2725-2740
                Affiliations
                [1 ]Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University , Changsha, Hunan 410011, People’s Republic of China
                [2 ]Department of Pharmacy, The Second Xiangya Hospital, Central South University , Changsha, Hunan 410011, People’s Republic of China
                [3 ]Department of General Surgery, The Second Xiangya Hospital, Central South University , Changsha, Hunan 410011, People’s Republic of China
                [4 ]Hunan Academy of Chinese Medicine, Hunan University of Chinese Medicine , Changsha, Hunan 410013, People’s Republic of China
                Author notes
                Correspondence: Sifang Zhang; Weijun Peng Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University , Changsha, Hunan410011, People’s Republic of ChinaTel +86-73185292111 Email sifangzhang2005@csu.edu.cn; pengweijun87@csu.edu.cn
                Article
                250991
                10.2147/DDDT.S250991
                7369379
                © 2020 Huang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 12, Tables: 2, References: 58, Pages: 16
                Categories
                Original Research

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