Acknowledgement
This research was funded by the Basic Science Research Program through the National Research Foundation of Korea (NRF), the Ministry of Science and ICT, Republic of Korea (2017R1A6A1A03015642).
References
- Medzhitov R, Janeway CJ. Advances in immunology: innate immunity. N Engl J Med 2000;343:338-44. https://doi.org/10.1056/NEJM200008033430506
- Cerny J, StrizI. Adaptive innate immunity or innate adaptive immunity? Clin Sci 2019;133:1549-65. https://doi.org/10.1042/CS20180548
- Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system. Nat Immunol 2015;16:343-53. https://doi.org/10.1038/ni.3123
- Medzhitov R, Janeway CA. Innate immunity: impact on the adaptive immune response. Curr Opin Immunol 1997;9:4-9. https://doi.org/10.1016/S0952-7915(97)80152-5
- Bonilla FA, Oettgen HC. Adaptive immunity. J Allergy Clin Immunol 2010;125: S33-40. https://doi.org/10.1016/j.jaci.2009.09.017
- Bascones-Martinez A, Mattila R, Gomez-Font R, Meurman JH. Immunomodulatory drugs: oral and systemic adverse effects. Med Oral Patol Oral Cir Bucal 2014;19:e24-31. https://doi.org/10.4317/medoral.19087
- Melero I, Hervas-Stubbs S, Glennie M, Pardoll DM, Chen L. Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer 2007;7:95-106. https://doi.org/10.1038/nrc2051
- Paulsen B. Plant polysaccharides with immunostimulatory activities. Curr Org Chem 2005;5:939-50. https://doi.org/10.2174/1385272013374987
- Shahbazi S, Bolhassani A. Immunostimulants: types and functions. J Med Microbiol Infect Dis 2016;4:45-51.
- Alexander C, Rietschel ET. Bacterial lipopolysaccharides and innate immunity. J Endotoxin Res 2001;7:167-202.
- Erridge C, Bennett-Guerrero E, Poxton IR. Structure and function of lipopolysaccharides. Microb Infect 2002;4:837-51. https://doi.org/10.1016/S1286-4579(02)01604-0
- Silipo A, De Castro C, Lanzetta R, Parrilli M, Molinaro A. Lipopolysaccharides. Prokaryotic cell wall Compd. Springer; 2010. p. 133-53.
- Fireman M, DiMartini AF, Armstrong SC, Cozza KL. Immunosuppressants. Psychosomatics 2004;45:354-60. https://doi.org/10.1176/appi.psy.45.4.354
- Suthanthiran M, Morris RE, Strom TB. Immunosuppressants: cellular and molecular mechanisms of action. Am J Kidney Dis 1996;28:159-72. https://doi.org/10.1016/S0272-6386(96)90297-8
- Krensky MA, Bennett MW, Vincenti F. Immunosuppressants, tolerogens and immunostimulants. Brunt LL 2011;1005-31.
- Thompson EB, Lippman ME. Mechanism of action of glucocorticoids. Metabolism 1974;23:159-202. https://doi.org/10.1016/0026-0495(74)90113-9
- Barnes PJ. Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin Sci 1998;94:557-72. https://doi.org/10.1042/cs0940557
- Saklatvala J. Glucocorticoids: do we know how they work? Arthritis Res Ther 2002;4:146. https://doi.org/10.1186/ar398
- Kurosawa S, Kato M. Anesthetics, immune cells, and immune responses. J Anesth 2008;22:263-77. https://doi.org/10.1007/s00540-008-0626-2
- Gajewski TF, Schreiber H, Fu Y-X. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 2013;14:1014-22. https://doi.org/10.1038/ni.2703
- Malech HL, Gallin JI. Neutrophils in human diseases. N Engl J Med 1987;317: 687-94. https://doi.org/10.1056/NEJM198709103171107
- Witko-Sarsat V, Rieu P, Descamps-Latscha B, Lesavre P, HalbwachsMecarelli L. Neutrophils: molecules, functions and pathophysiological aspects. Lab Invest 2000;80:617-54. https://doi.org/10.1038/labinvest.3780067
- Nathan C. Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol 2006;6:173-82. https://doi.org/10.1038/nri1785
- Kobayashi SD, Voyich JM, Burlak C, DeLeo FR. Neutrophils in the innate immune response. Arch Immunol Ther Exp 2005;53:505-17.
- Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K. Development of monocytes, macrophages, and dendritic cells. Science 2010;327:656-61. https://doi.org/10.1126/science.1178331
- Cline MJ, Lehrer RI, Territo MC, Golde DW. Monocytes and macrophages: functions and diseases. Ann Intern Med 1978;88:78-88. https://doi.org/10.7326/0003-4819-88-1-78
- Franken L, Schiwon M, Kurts C. Macrophages: sentinels and regulators of the immune system. Cell Microbiol 2016;18:475-87. https://doi.org/10.1111/cmi.12580
- LaRosa DF, Orange JS. 1. Lymphocytes. J Allergy Clin Immunol 2008;121: S364-9. https://doi.org/10.1016/j.jaci.2007.06.016
- Hauser AE, Hopken UE. B cell localization and migration in health and disease. In: Alt FW, Honjo T, Radbruch A, editors. Reth MBT-MB of BC (second E. Mol. Biol. B cells. second ed. London: Academic Press; 2015. p. 187-214.
- Zhu J, Paul WE. CD4 T cells: fates, functions, and faults. Blood 2008;112: 1557-69.
- Parnham MJ, Nijkamp FP, Rossi AG. Nijkamp and Parnham's principles of immunopharmacology. Springer Nature; 2019.
- Narsale A, Moya R, Davies JD. Human CD4+CD25+CD127hi cells and the Th1/ Th2 phenotype. Clin Immunol 2018;188:103-12. https://doi.org/10.1016/j.clim.2018.01.003
- Allman D, Pillai S. Peripheral B cell subsets. Curr Opin Immunol 2008;20: 149-57. https://doi.org/10.1016/j.coi.2008.03.014
- Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol 2008;9:503-10. https://doi.org/10.1038/ni1582
- Lv M, Zhao X, Chen F, Yu M, Li C, Sun J. A rapid white blood cell classification system based on multimode imaging technology. J Biophot 2020;13:1-10.
- Swartz MA. The physiology of the lymphatic system. Adv Drug Deliv Rev 2001;50:3-20. https://doi.org/10.1016/S0169-409X(01)00150-8
- Boes KM, Durham AC. Bone marrow, blood cells, and the lymphoid/lymphatic system. Pathol Basis Vet Dis 2017:724-804.
- Yun TK, Choi SY. Non-organ specific cancer prevention of ginseng: a prospective study in Korea. Int J Epidemiol 1998;27:359-64. https://doi.org/10.1093/ije/27.3.359
- Zhao Y. Panax notoginseng (burk.) F.H. Chen sanqi (sanqi, notoginseng). Diet. Chinese herbs. Springer; 2015. p. 185-93.
- Lee SM, Bae BS, Park HW, Ahn NG, Cho BG, Cho YL, et al. Characterization of Korean red ginseng (Panax ginseng Meyer): history, preparation method, and chemical composition. J Ginseng Res 2015;39:384-91. https://doi.org/10.1016/j.jgr.2015.04.009
- You L, Cho JY. The regulatory role of Korean ginseng in skin cells. J Ginseng Res 2021;45:363-70. https://doi.org/10.1016/j.jgr.2020.08.004
- Chang-Xiao L, Pei-Gen X. Recent advances on ginseng research in China. J Ethnopharmacol 1992;36:27-38. https://doi.org/10.1016/0378-8741(92)90057-X
- Kim JH, Yi YS, Kim MY, Cho JY. Role of ginsenosides, the main active components of Panax ginseng, in inflammatory responses and diseases. J Ginseng Res 2017;41:435-43. https://doi.org/10.1016/j.jgr.2016.08.004
- Yu H, Zhang C, Lu M, Sun F, Fu Y, Jin F. Purification and characterization of new special ginsenosidase hydrolyzing multi-glycisides of protopanaxadiol ginsenosides, ginsenosidase type I. Chem Pharm Bull 2007;55:231-5. https://doi.org/10.1248/cpb.55.231
- Fuzzati N. Analysis methods of ginsenosides. J Chromatogr B Anal Technol Biomed Life Sci 2004;812:119-33. https://doi.org/10.1016/S1570-0232(04)00645-2
- Yu J, Niu Y, Li R, Liao J, Zhang F, Yu B. Synthetic access toward the diverse ginsenosides. Chem Sci 2013;4:3899-905. https://doi.org/10.1039/c3sc51479j
- Ma X, Xiao H, Liang X. Identification of ginsenosides in Panax quinquefolium by LC-MS. Chromatographia 2006;64:31-6. https://doi.org/10.1365/s10337-006-0812-z
- Romagnani S. T-cell subsets (Th1 versus Th2). Ann Allergy Asthma Immunol 2000;85:9-18. https://doi.org/10.1016/S1081-1206(10)62426-X
- Berger A. Science commentary: Th1 and Th2 responses: what are they? Br Med J 2000;321:424. https://doi.org/10.1136/bmj.321.7258.424
- Shin MS, Song JH, Choi P, Lee JH, Kim SY, Shin KS, et al. Stimulation of innate immune function by Panax ginseng after heat processing. J Agric Food Chem 2018;66:4652-9. https://doi.org/10.1021/acs.jafc.8b00152
- Xin C, Kim J, Quan H, Yin M, Jeong S, Choi J Il, et al. Ginsenoside Rg3 promotes Fc gamma receptor-mediated phagocytosis of bacteria by macrophages via an extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase-dependent mechanism. Int Immunopharm 2019;77:105945. https://doi.org/10.1016/j.intimp.2019.105945
- Kim JH, Doo EH, Jeong M, Kim S, Lee YY, Yang J, et al. Enhancing immunomodulatory function of red ginseng through fermentation using Bifidobacterium animalis subsp. Lactis LT 19-2. Nutrients 2019:11071481.
- Kim MY, Cho JY. 20S-dihydroprotopanaxadiol, a ginsenoside derivative, boosts innate immune responses of monocytes and macrophages. J Ginseng Res 2013;37:293-9. https://doi.org/10.5142/jgr.2013.37.293
- Yang WS, Yi YS, Kim D, Kim MH, Park JG, Kim E, et al. Nuclear factor kappa-Band activator protein-1-mediated immunostimulatory activity of compound K in monocytes and macrophages. J Ginseng Res 2017;41:298-306. https://doi.org/10.1016/j.jgr.2016.06.004
- Wang Y, Liu Y, Zhang XY, Xu LH, Ouyang DY, Liu KP, et al. Ginsenoside Rg1 regulates innate immune responses in macrophages through differentially modulating the NF-kB and PI3K/Akt/mTOR pathways. Int Immunopharm 2014;23:77-84. https://doi.org/10.1016/j.intimp.2014.07.028
- Lee EJ, Ko E, Lee J, Rho S, Ko S, Shin MK, et al. Ginsenoside Rg1 enhances CD4+ T-cell activities and modulates Th1/Th2 differentiation. Int Immunopharm 2004;4:235-44. https://doi.org/10.1016/j.intimp.2003.12.007
- Sun J, Hu S, Song X. Adjuvant effects of protopanaxadiol and protopanaxatriol saponins from ginseng roots on the immune responses to ovalbumin in mice. Vaccine 2007;25:1114-20. https://doi.org/10.1016/j.vaccine.2006.09.054
- Sun J, Song X, Hu S. Ginsenoside Rg1 and aluminum hydroxide synergistically promote immune responses to ovalbumin in BALB/c mice. Clin Vaccine Immunol 2008;15:303-7. https://doi.org/10.1128/CVI.00448-07
- Yuan D, Yuan Q, Cui Q, Liu C, Zhou Z, Zhao H, et al. Vaccine adjuvant ginsenoside Rg1 enhances immune responses against hepatitis B surface antigen in mice. Can J Physiol Pharmacol 2016;94:676-81. https://doi.org/10.1139/cjpp-2015-0528
- Qu DF, Yu HJ, Liu Z, Zhang DF, Zhou QJ, Zhang HL, et al. Ginsenoside Rg1 enhances immune response induced by recombinant Toxoplasma gondii SAG1 antigen. Vet Parasitol 2011;179:28-34. https://doi.org/10.1016/j.vetpar.2011.02.008
- Su F, Wu Y, Li J, Huang Y, Yu B, Xu L, et al. Escherichia coli heat-labile enterotoxin B subunit combined with ginsenoside Rg1 as an intranasal adjuvant triggers type I interferon signaling pathway and enhances adaptive immune responses to an inactivated PRRSV vaccine in ICR mice. Vaccines 2021:9030266.
- Bi S, Chi X, Zhang Y, Ma X, Liang S, Wang Y, et al. Ginsenoside Rg1 enhanced immune responses to infectious bursal disease vaccine in chickens with oxidative stress induced by cyclophosphamide. Poultry Sci 2018;97:2698-706. https://doi.org/10.3382/ps/pey132
- Sun HX, Chen Y, Ye Y. Ginsenoside Re and notoginsenoside R1: immunologic adjuvants with low haemolytic effect. Chem Biodivers 2006;3:718-26. https://doi.org/10.1002/cbdv.200690074
- Yang ZG, Ye YP, Sun HX. Immunological adjuvant effect of ginsenoside Rh4 from the roots of Panax notoginseng on specific antibody and cellular response to ovalbumin in mice. Chem Biodivers 2007;4:232-40. https://doi.org/10.1002/cbdv.200790028
- Song X, Chen J, Sakwiwatkul K, Li R, Hu S. Enhancement of immune responses to influenza vaccine (H3N2) by ginsenoside Re. Int Immunopharm 2010;10: 351-6. https://doi.org/10.1016/j.intimp.2009.12.009
- Qu D, Han J, Du A. Enhancement of protective immune response to recombinant Toxoplasma gondii ROP18 antigen by ginsenoside Re. Exp Parasitol 2013;135:234-9. https://doi.org/10.1016/j.exppara.2013.07.013
- Su X, Pei Z, Hu S. Ginsenoside Re as an adjuvant to enhance the immune response to the inactivated rabies virus vaccine in mice. Int Immunopharm 2014;20:283-9. https://doi.org/10.1016/j.intimp.2014.03.008
- Wu R, Ru Q, Chen L, Ma B, Li C. Stereospecificity of ginsenoside Rg3 in the promotion of cellular immunity in hepatoma H22-bearing mice. J Food Sci 2014;79:H1430-5. https://doi.org/10.1111/1750-3841.12518
- Liu X, Zhang Z, Liu J, Wang Y, Zhou Q, Wang S, et al. Ginsenoside Rg3 improves cyclophosphamide-induced immunocompetence in Balb/c mice. Int Immunopharm 2019;72:98-111. https://doi.org/10.1016/j.intimp.2019.04.003
- Qian Y, Huang R, Li S, Xie R, Qian B, Zhang Z, et al. Ginsenoside Rh2 reverses cyclophosphamide-induced immune deficiency by regulating fatty acid metabolism. J Leukoc Biol 2019;106:1089-100. https://doi.org/10.1002/JLB.2A0419-117R
- Wang M, Yan SJ, Zhang HT, Li N, Liu T, Zhang YL, et al. Ginsenoside Rh2 enhances the antitumor immunological response of a melanoma mice model. Oncol Lett 2017;13:681-5. https://doi.org/10.3892/ol.2016.5490
- Wei X, Chen J, Su F, Su X, Hu T, Hu S. Stereospecificity of ginsenoside Rg3 in promotion of the immune response to ovalbumin in mice. Int Immunol 2012;24:465-71. https://doi.org/10.1093/intimm/dxs043
- Song X, Zang L, Hu S. Amplified immune response by ginsenoside-based nanoparticles (ginsomes). Vaccine 2009;27:2306-11. https://doi.org/10.1016/j.vaccine.2009.02.040
- Yang Z, Chen A, Sun H, Ye Y, Fang W. Ginsenoside Rd elicits Th1 and Th2 immune responses to ovalbumin in mice. Vaccine 2007;25:161-9. https://doi.org/10.1016/j.vaccine.2006.05.075
- Han Y, Rhew KY. Ginsenoside Rd induces protective anti-Candida albicans antibody through immunological adjuvant activity. Int Immunopharm 2013;17:651-7. https://doi.org/10.1016/j.intimp.2013.08.003
- Rivera E, Pettersson FE, Ingan as M, Paulie S, Gronvik KO. The Rb1 fraction of ginseng elicits a balanced Th1 and Th2 immune response. Vaccine 2005;23: 5411-9. https://doi.org/10.1016/j.vaccine.2005.04.007
- Kang N, Gao H, He L, Liu Y, Fan H, Xu Q, et al. Ginsenoside Rb1 is an immunestimulatory agent with antiviral activity against enterovirus 71. J Ethnopharmacol 2021;266:113401. https://doi.org/10.1016/j.jep.2020.113401
- Zou Y, Tao T, Tian Y, Zhu J, Cao L, Deng X, et al. Ginsenoside Rg1 improves survival in a murine model of polymicrobial sepsis by suppressing the inflammatory response and apoptosis of lymphocytes. J Surg Res 2013;183: 760-6. https://doi.org/10.1016/j.jss.2013.01.068
- Zhang L, Zhu M, Li M, Du Y, Duan S, Huang Y, et al. Ginsenoside Rg1 attenuates adjuvant-induced arthritis in rats via modulation of PPAR-g/NF-kB signal pathway. Oncotarget 2017;8:55384-93. https://doi.org/10.18632/oncotarget.19526
- Yu ZQ, Yi HY, Ma J, Wei YF, Cai Meng-Kai, Li Q, et al. Ginsenoside Rg1 suppresses type 2 prrsv infection via NF-kB signaling pathway in vitro, and provides partial protection against HP-PRRSV in piglet. Viruses 2019:1045.
- Paik S, Choe JH, Choi GE, Kim JE, Kim JM, Song GY, et al. Rg6, a rare ginsenoside, inhibits systemic inflammation through the induction of interleukin10 and microRNA-146a. Sci Rep 2019;9:4342. https://doi.org/10.1038/s41598-019-40690-8
- Samimi R, Xu WZ, Lui EMK, Charpentier PA. Isolation and immunosuppressive effects of 600- O-acetylginsenoside Rb1 extracted from north american ginseng. Planta Med 2014;80:509-16. https://doi.org/10.1055/s-0034-1368319
- Infante M, Allavena P, Garlanda C, Nebuloni M, Morenghi E, Rahal D, et al. Prognostic and diagnostic potential of local and circulating levels of pentraxin 3 in lung cancer patients. Int J Cancer 2016;138:983-91. https://doi.org/10.1002/ijc.29822
- Ahmmed B, Kampo S, Khan M, Faqeer A, kumar SP, Yulin L, et al. Rg3 inhibits gemcitabine-induced lung cancer cell invasiveness through ROS-dependent, NF-kB- and HIF-1a-mediated downregulation of PTX3. J Cell Physiol 2019;234:10680-97. https://doi.org/10.1002/jcp.27731
- Zhang Y, Wang S, Song S, Yang X, Jin G. Ginsenoside Rg3 alleviates complete Freund's adjuvant-induced rheumatoid arthritis in mce by regulating CD4+CD25+Foxp3+Treg cells. J Agric Food Chem 2020;68:4893-902. https://doi.org/10.1021/acs.jafc.0c01473
- Wang Y, Qin Q, Chen J, Kuang X, Xia J, Xie B, et al. Synergistic effects of Isatis tinctoria L. and tacrolimus in the prevention of acute heart rejection in mice. Transpl Immunol 2009;22:5-11. https://doi.org/10.1016/j.trim.2009.09.004
- Ma PF, Gao C, Cheng PP, Li JL, Huang X, Lin YY, et al. Immunosuppressive effect of compound K on islet transplantation in an STZ-induced diabetic mouse model. Diabetes 2014;63:3458-69. https://doi.org/10.2337/db14-0012
- Wang L, Zhang Y, Chen J, Li S, Wang Y, Hu L, et al. Immunosuppressive effects of ginsenoside-Rd on skin allograft rejection in rats. J Surg Res 2012;176: 267-74. https://doi.org/10.1016/j.jss.2011.06.038
- Yamamura H, Matsuura H, Nakagawa J, Fukuoka H, Domi H, Chujoh S. Effect of favipiravir and an anti-inflammatory strategy for COVID-19. Crit Care 2020;24:413. https://doi.org/10.1186/s13054-020-03137-5
- Xia Q-D, Xun Y, Lu J-L, Lu Y-C, Yang Y-Y, Zhou P, et al. Network pharmacology and molecular docking analyses on Lianhua Qingwen capsule indicate Akt1 is a potential target to treat and prevent COVID-19. Cell Prolif 2020;53: e12949. https://doi.org/10.1111/cpr.12949
- Zhang JL, Li WX, Li Y, Wong MS, Wang YJ, Zhang Y. Therapeutic options of TCM for organ injuries associated with COVID-19 and the underlying mechanism. Phytomedicine 2021;85:153297. https://doi.org/10.1016/j.phymed.2020.153297
- Lee WS, Rhee DK. Corona-Cov-2 (COVID-19) and ginseng: comparison of possible use in COVID-19 and influenza. J Ginseng Res 2021;45:535-7. https://doi.org/10.1016/j.jgr.2020.12.005
- Zhang D, Hamdoun S, Chen R, Yang L, Ip CK, Qu Y, et al. Identification of natural compounds as SARS-CoV-2 entry inhibitors by molecular dockingbased virtual screening with bio-layer interferometry. Pharmacol Res 2021: 105820.
- Xu W, Larbi A. Immunity and inflammation: from jekyll to hyde. Exp Gerontol 2018;107:98-101. https://doi.org/10.1016/j.exger.2017.11.018
- Xiao TS. Innate immunity and inflammation. Cell Mol Immunol 2017;14:1-3. https://doi.org/10.1038/cmi.2016.45
- Akaza H, Kotake T, Machida T. Bropirimine, an orally active anticacner agent for superficial bladder cancer. Eur Urol 1998;34:107-10. https://doi.org/10.1159/000019693
- Trevillian P. Immunosuppressants - clinical applications. Aust Prescr 2006;29: 102-8. https://doi.org/10.18773/austprescr.2006.065
- Baeg IH, So SH. The world ginseng market and the ginseng (Korea). J Ginseng Res 2013;37:1-7. https://doi.org/10.5142/jgr.2013.37.1