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      Danggui Buxue Decoction in the Treatment of Metastatic Colon Cancer: Network Pharmacology Analysis and Experimental Validation

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          Abstract

          Purpose

          This study aimed to reveal Danggui Buxue Decoction (DBD) candidate targets and mechanisms in the treatment of metastatic colon cancer (MCC), using network pharmacology-based analyses and experimental validation.

          Methods

          Traditional Chinese Medicine Systems Pharmacology (TCMSP) database query and text mining were used to screen active compounds in DBD, and the Swiss target prediction platform was applied to predict compound-related target proteins. Targets likely associated with MCC were determined using GeneCards and OMIM databases. Targets common to DBD and MCC were obtained from the Venn platform; subsequently, Cytoscape was used to construct drug-compound-target-disease and protein-protein interaction networks. The hub gene was determined by R, while GO and KEGG enrichment analyses were performed on common targets to elucidate biological processes and signaling pathways involved in DBD against MCC. Finally, the metastatic colon cancer mouse model was used to detect the levels of expression of protein Bax, Bcl2, Caspase3, and Cleaved caspase3 by Western blot.

          Results

          A total of 28 active compounds and 61 common targets were predicted. The main compounds were quercetin, hederagenin, jaranol, methylnissolin, formononetin, calycosin, kaempferol, 3.9-di-O-methylnissolin, 24-propylcholesterol, and 7-O-methylisomucronulatol, present in Astragalus membranaceus (Huangqi, HQ). In addition, beta-sitosterol, ferulic acid, and stigmasterol, present in Angelica sinensis (Danggui, DG), were detected. JUN, PTSG2, EGFR, ESR1and, CASP3 genes were the top 5 hub genes in the PPI network. GO and KEGG enrichment analyses indicated that apoptosis played a major role in the biological processes and signaling pathways involved. Moreover, the in vivo experiment revealed that DBD inhibited MCC by up-regulating the expression of Bax, Caspase3, and Cleaved caspase3, and by down-regulating the expression of Bcl2.

          Conclusion

          This study revealed candidate DBD targets and mechanisms in the treatment of MCC, using network pharmacology-based analyses and experimental validation. The present findings provide a reference for tumor treatment during the perioperative period.

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          Most cited references 41

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          Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

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            Hallmarks of Cancer: The Next Generation

            The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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              The effects of surgery on tumor growth: a century of investigations.

              A few clinical investigations suggest that while primary breast cancer surgical removal favorably modifies the natural history for some patients, it may also hasten the metastatic development for others. The concepts underlying this disease paradigm, i.e. tumor homeostasis, tumor dormancy and surgery-driven enhancement of metastasis development, have a long history that is reviewed. The review reveals the context in which these concepts were conceived and structured to explain experimental data and shows that they are not so new and far fetched. The idea that surgical cancer resection has both beneficial and adverse effects upon cancer spread and growth that result from the modulation of tumor dormancy by the resection should be considered a potentially fruitful working hypothesis.
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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
                24 February 2021
                2021
                : 15
                : 705-720
                Affiliations
                [1 ]Yong Chuan Hospital of Chongqing Medical University, College of Traditional Chinese Medicine, Chongqing Medical University , Chongqing, People’s Republic of China
                [2 ]College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases , Chongqing, People’s Republic of China
                [3 ]Yong Chuan Hospital of Chongqing Medical University , Chongqing, People’s Republic of China
                Author notes
                Correspondence: Shu-Mei Wang College of Traditional Chinese Medicine, Chongqing Medical University , No. 1 Medical College Road, Chongqing, 400016, People’s Republic of ChinaTel +86-18716369329 Email wangshumei@cqmu.edu.cn
                Ao Li Yong Chuan Hospital of Chongqing Medical University , NO. 439 Xuan Hua Road, Yongchuan District, Chongqing, 402160, People’s Republic of ChinaTel +86-18580779649 Email wo_shi_li_ao_2@163.com
                [*]

                These authors contributed equally to this work

                Article
                293046
                10.2147/DDDT.S293046
                7917330
                © 2021 Feng 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: 8, Tables: 4, References: 41, Pages: 16
                Funding
                Funded by: the National Natural Science Foundation of China (NSFC);
                This work was supported by the National Natural Science Foundation of China (NSFC) (grant No. 81704033).
                Categories
                Original Research

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