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      Ginseng berry polysaccharides on inflammation-associated colon cancer: inhibiting T-cell differentiation, promoting apoptosis, and enhancing the effects of 5-fluorouracil

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          Abstract

          Background

          Ginseng is a commonly used herbal medicine in treating various medical conditions. Chronic gut inflammation is a recognized factor for the development of colorectal cancer (CRC). In this project, Asian ginseng berry polysaccharide preparations were used to assess their effects on CRC and related immune regulation mechanisms.

          Methods

          Ginseng berry polysaccharide extract (GBPE) and purified ginseng berry polysaccharide portion (GBPP) were used to evaluate their activities on human HCT-116 and HT-29 CRC cell proliferation. Interleukin-8 secretion analysis was performed on HT-29 cells. Naive CD4 cell isolation and T-helper cell differentiation were performed and determined using flow cytometry for Th1 and Treg in addition to cell cycle and apoptotic investigation.

          Results

          GBPE and GBPP significantly inhibited interleukin-8 secretion and cancer cell proliferation, inhibited CD4 +IFN-γ + cell (Th1) differentiation, and decreased CD4 +FoxP3 + cell (Treg) differentiation. Compared to the GBPE, GBPP showed more potent antiinflammatory activities on the malignant cells. This is consistent with the observation that GBPP can also inhibit Th1-cell differentiation better, suggesting that it has an important role in antiinflammation, whereas Treg cells hinder the body's immune response against malignancies. Supported by cell cycle and apoptosis data, GBPE and GBPP, at various degrees, remarkably enhanced the anticancer activities of 5-fluorouracil.

          Conclusion

          Data from this project suggested that Asian ginseng berry potentially has clinical utility in managing enteric inflammation and suppressing CRC through immunomodulation mechanisms.

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          Most cited references38

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          TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis

          Most patients with colorectal cancer die as a result of the disease spreading to other organs. However, no prevalent mutations have been associated with metastatic colorectal cancers. Instead, particular features of the tumour microenvironment, such as lack of T-cell infiltration, low type 1 T-helper cell (TH1) activity and reduced immune cytotoxicity or increased TGFβ levels predict adverse outcomes in patients with colorectal cancer. Here we analyse the interplay between genetic alterations and the tumour microenvironment by crossing mice bearing conditional alleles of four main colorectal cancer mutations in intestinal stem cells. Quadruple-mutant mice developed metastatic intestinal tumours that display key hallmarks of human microsatellite-stable colorectal cancers, including low mutational burden, T-cell exclusion and TGFβ-activated stroma. Inhibition of the PD-1-PD-L1 immune checkpoint provoked a limited response in this model system. By contrast, inhibition of TGFβ unleashed a potent and enduring cytotoxic T-cell response against tumour cells that prevented metastasis. In mice with progressive liver metastatic disease, blockade of TGFβ signalling rendered tumours susceptible to anti-PD-1-PD-L1 therapy. Our data show that increased TGFβ in the tumour microenvironment represents a primary mechanism of immune evasion that promotes T-cell exclusion and blocks acquisition of the TH1-effector phenotype. Immunotherapies directed against TGFβ signalling may therefore have broad applications in treating patients with advanced colorectal cancer.
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            Regulatory T cells, tumour immunity and immunotherapy.

            Tumours express a range of antigens, including self-antigens. Regulatory T cells are crucial for maintaining T-cell tolerance to self-antigens. Regulatory T cells are thought to dampen T-cell immunity to tumour-associated antigens and to be the main obstacle tempering successful immunotherapy and active vaccination. In this Review, I consider the nature and characteristics of regulatory T cells in the tumour microenvironment and their potential multiple suppressive mechanisms. Strategies for therapeutic targeting of regulatory T cells and the effect of regulatory T cells on current immunotherapeutic and vaccine regimens are discussed.
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              Ginseng pharmacology: multiple constituents and multiple actions.

              Ginseng is a highly valued herb in the Far East and has gained popularity in the West during the last decade. There is extensive literature on the beneficial effects of ginseng and its constituents. The major active components of ginseng are ginsenosides, a diverse group of steroidal saponins, which demonstrate the ability to target a myriad of tissues, producing an array of pharmacological responses. However, many mechanisms of ginsenoside activity still remain unknown. Since ginsenosides and other constituents of ginseng produce effects that are different from one another, and a single ginsenoside initiates multiple actions in the same tissue, the overall pharmacology of ginseng is complex. The ability of ginsenosides to independently target multireceptor systems at the plasma membrane, as well as to activate intracellular steroid receptors, may explain some pharmacological effects. This commentary aims to review selected effects of ginseng and ginsenosides and describe their possible modes of action. Structural variability of ginsenosides, structural and functional relationship to steroids, and potential targets of action are discussed.
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                Author and article information

                Contributors
                Journal
                J Ginseng Res
                J Ginseng Res
                Journal of Ginseng Research
                Elsevier
                1226-8453
                2093-4947
                02 January 2019
                March 2020
                02 January 2019
                : 44
                : 2
                : 282-290
                Affiliations
                [1 ]Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago, Chicago, USA
                [2 ]Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, USA
                [3 ]Department of Pharmaceutics, School of Pharmacy, Jiangsu University, Zhenjiang, China
                [4 ]Vital Beautie Research Institute, R&D Center, AmorePacific Corporation, Yongin, Republic of Korea
                [5 ]Department of Biotechnology, Yonsei University, Seoul, Republic of Korea
                [6 ]Department of Food Science and Biotechnology, Kyonggi University, Suwon, Republic of Korea
                [7 ]Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, USA
                Author notes
                []Corresponding author. Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago, 5841 South Maryland Avenue, MC 4028, Chicago, Illinois 60637, USA. cyuan@ 123456dacc.uchicago.edu
                [∗∗ ]Corresponding author. School of Pharmacy, Jiangsu University, Zhenjiang 212013, China. wanjinyi1128@ 123456163.com
                Article
                S1226-8453(18)30139-8
                10.1016/j.jgr.2018.12.010
                7031751
                32148410
                1344cfc5-66da-42f0-942a-617e57cbc0ee
                © 2019 The Korean Society of Ginseng, Published by Elsevier Korea LLC.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 3 May 2018
                : 13 November 2018
                : 26 December 2018
                Categories
                Pharmacology and Physiology

                adaptive immune response,colorectal cancer,5-fluorouracil,ginseng berry polysaccharides,inflammation

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