Can Panax ginseng help control cytokine storm in COVID-19? |
Choi, Jong Hee
(Department of Convergence Medical Science, College of Korean Medicine, Kyung Hee University)
Lee, Young Hyun (Department of Convergence Medical Science, College of Korean Medicine, Kyung Hee University) Kwon, Tae Woo (Department of Convergence Medical Science, College of Korean Medicine, Kyung Hee University) Ko, Seong-Gyu (Korean Medicine-based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University) Nah, Seung-Yeol (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University) Cho, Ik-Hyun (Department of Convergence Medical Science, College of Korean Medicine, Kyung Hee University) |
1 | Jung JH, Kang TK, Oh JH, Jeong JU, Ko KP, Kim ST. The effect of Korean red ginseng on symptoms and inflammation in patients with allergic rhinitis. Ear Nose Throat J 2020. 145561320907172. |
2 | 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 interleukin-10 and microRNA-146a. Sci Rep 2019;9:4342. DOI |
3 | Huynh DTN, Baek N, Sim S, Myung CS, Heo KS. Minor ginsenoside Rg2 and Rh1 attenuates LPS-induced acute liver and kidney damages via down-regulating activation of TLR4-STAT1 and inflammatory cytokine production in macrophages. Int J Mol Sci 2020:21. |
4 | Yu Q, Zeng KW, Ma XL, Jiang Y, Tu PF, Wang XM. Ginsenoside Rk1 suppresses pro-inflammatory responses in lipopolysaccharide-stimulated RAW264.7 cells by inhibiting the Jak2/Stat3 pathway. Chin J Nat Med 2017;15:751-7. |
5 | Bai X, Fu R, Duan Z, Wang P, Zhu C, Fan D. Ginsenoside Rk3 alleviates gut microbiota dysbiosis and colonic inflammation in antibiotic-treated mice. Food Res Int 2021;146:110465. DOI |
6 | Ju C, Jeon SM, Jun HS, Moon CK. Diol-ginsenosides from Korean Red Ginseng delay the development of type 1 diabetes in diabetes-prone biobreeding rats. J Ginseng Res 2020;44:619-26. DOI |
7 | Hyun SH, Kim SW, Seo HW, Youn SH, Kyung JS, Lee YY, et al. Physiological and pharmacological features of the non-saponin components in Korean Red Ginseng. J Ginseng Res 2020;44:527-37. DOI |
8 | Yoo DG, Kim MC, Park MK, Park KM, Quan FS, Song JM, et al. Protective effect of ginseng polysaccharides on influenza viral infection. PLoS One 2012;7:e33678. DOI |
9 | Lee DY, Park CW, Lee SJ, Park HR, Seo DB, Park JY, et al. Immunostimulating and antimetastatic effects of polysaccharides purified from ginseng berry. Am J Chin Med 2019;47:823-39. DOI |
10 | Nagata K, Nishiyama C. IL-10 in mast cell-mediated immune responses: anti-inflammatory and proinflammatory roles. Int J Mol Sci 2021:22. |
11 | Han H, Ma Q, Li C, Liu R, Zhao L, Wang W, et al. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg Microb Infect 2020;9:1123-30. DOI |
12 | Hamza T, Barnett JB, Li B. Interleukin 12 a key immunoregulatory cytokine in infection applications. Int J Mol Sci 2010;11:789-806. DOI |
13 | Mendoza VMM. Interleukin-17: a potential therapeutic target in COVID-19. J Infect 2020;81:e136-8. DOI |
14 | Cho IH. Effects of Panax ginseng in neurodegenerative diseases. J Ginseng Res 2012;36:342-53. DOI |
15 | Li Q, Gu Y, Tu Q, Wang K, Gu X, Ren T. Blockade of interleukin-17 restrains the development of acute lung injury. Scand J Immunol 2016;83:203-11. DOI |
16 | Steen EH, Wang X, Balaji S, Butte MJ, Bollyky PL, Keswani SG. The role of the anti-inflammatory cytokine interleukin-10 in tissue fibrosis. Adv Wound Care 2020;9:184-98. DOI |
17 | McGinley AM, Sutton CE, Edwards SC, Leane CM, DeCourcey J, Teijeiro A, et al. Interleukin-17A serves a priming role in autoimmunity by recruiting IL-1beta-producing myeloid cells that promote pathogenic T cells. Immunity 2020;52:342-356 e6. DOI |
18 | Iwakura Y, Nakae S, Saijo S, Ishigame H. The roles of IL-17A in inflammatory immune responses and host defense against pathogens. Immunol Rev 2008;226:57-79. DOI |
19 | Asrani P, Hassan MI. SARS-CoV-2 mediated lung inflammatory responses in host: targeting the cytokine storm for therapeutic interventions. Mol Cell Biochem 2021;476:675-87. DOI |
20 | Avdeev SN, Trushenko NV, Tsareva NA, Yaroshetskiy AI, Merzhoeva ZM, Nuralieva GS, et al. Anti-IL-17 monoclonal antibodies in hospitalized patients with severe COVID-19: a pilot study. Cytokine 2021;146:155627. DOI |
21 | Sng KS, Li G, Zhou LY, Song YJ, Chen XQ, Wang YJ, et al. Ginseng extract and ginsenosides improve neurological function and promote antioxidant effects in rats with spinal cord injury: a meta-analysis and systematic review. J Ginseng Res 2022;46:11-22. DOI |
22 | 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. DOI |
23 | Shin KK, Yi YS, Kim JK, Kim H, Hossain MA, Kim JH, et al. Korean red ginseng plays an anti-aging role by modulating expression of aging-related genes and immune cell subsets. Molecules 2020;25. |
24 | Hwang I, Ahn G, Park E, Ha D, Song JY, Jee Y. An acidic polysaccharide of Panax ginseng ameliorates experimental autoimmune encephalomyelitis and induces regulatory T cells. Immunol Lett 2011;138:169-78. DOI |
25 | Yang Y, Ju Z, Yang Y, Zhang Y, Yang L, Wang Z. Phytochemical analysis of Panax species: a review. J Ginseng Res 2021;45:1-21. DOI |
26 | Yang J, Li S, Wang L, Du F, Zhou X, Song Q, et al. Ginsenoside Rg3 attenuates lipopolysaccharide-induced acute lung injury via MerTK-dependent activation of the PI3K/AKT/mTOR pathway. Front Pharmacol 2018;9:850. DOI |
27 | Jiang Y, Zhou Z, Meng QT, Sun Q, Su W, Lei S, et al. Ginsenoside Rb1 treatment attenuates pulmonary inflammatory cytokine release and tissue injury following intestinal ischemia reperfusion injury in mice. Oxid Med Cell Longev 2015;2015:843721. |
28 | Huang W-C, Huang T-H, Yeh K-W, Chen Y-L, Shen S-C, Liou C-J. Ginsenoside Rg3 ameliorates allergic airway inflammation and oxidative stress in mice. J Ginseng Res 2021;46:654-64. |
29 | Im K, Kim J, Min H. Ginseng, the natural effectual antiviral: protective effects of Korean Red Ginseng against viral infection. J Ginseng Res 2016;40:309-14. DOI |
30 | Hwang SH, Shin MS, Yoon TJ, Shin KS. Immunoadjuvant activity in mice of polysaccharides isolated from the leaves of Panax ginseng C.A. Meyer. Int J Biol Macromol 2018;107:2695-700. DOI |
31 | Kim KH, Lee YS, Jung IS, Park SY, Chung HY, Lee IR, et al. Acidic polysaccharide from Panax ginseng, ginsan, induces Th1 cell and macrophage cytokines and generates LAK cells in synergy with rIL-2. Planta Med 1998;64:110-5. DOI |
32 | Choi SH, Lee R, Nam SM, Kim DG, Cho IH, Kim HC, et al. Ginseng gintonin, aging societies, and geriatric brain diseases. Integr Med Res 2021;10:100450. DOI |
33 | Choi JH, Jang M, Oh S, Nah SY, Cho IH. Multi-target protective effects of gintonin in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Mediated model of Parkinson's disease via lysophosphatidic acid receptors. Front Pharmacol 2018;9:515. DOI |
34 | Singh TU, Parida S, Lingaraju MC, Kesavan M, Kumar D, Singh RK. Drug repurposing approach to fight COVID-19. Pharmacol Rep 2020;72:1479-508. DOI |
35 | Lee JS, Lee YN, Lee YT, Hwang HS, Kim KH, Ko EJ, et al. Ginseng protects against respiratory syncytial virus by modulating multiple immune cells and inhibiting viral replication. Nutrients 2015;7:1021-36. DOI |
36 | Lee JS, Ko EJ, Hwang HS, Lee YN, Kwon YM, Kim MC, et al. Antiviral activity of ginseng extract against respiratory syncytial virus infection. Int J Mol Med 2014;34:183-90. DOI |
37 | Wang C, Liu J, Deng J, Wang J, Weng W, Chu H, et al. Advances in the chemistry, pharmacological diversity, and metabolism of 20(R)-ginseng saponins. J Ginseng Res 2020;44:14-23. DOI |
38 | Park SJ, Lee D, Kim D, Lee M, In G, Han ST, et al. The non-saponin fraction of Korean Red Ginseng (KGC05P0) decreases glucose uptake and transport in vitro and modulates glucose production via down-regulation of the PI3K/AKT pathway in vivo. J Ginseng Res 2020;44:362-72. DOI |
39 | Yin SY, Kim HJ, Kim HJ. A comparative study of the effects of whole red ginseng extract and polysaccharide and saponin fractions on influenza A (H1N1) virus infection. Biol Pharm Bull 2013;36:1002-7. DOI |
40 | Jang M, Choi JH, Chang Y, Lee SJ, Nah SY, Cho IH. Gintonin, a ginseng-derived ingredient, as a novel therapeutic strategy for Huntington's disease: activation of the Nrf2 pathway through lysophosphatidic acid receptors. Brain Behav Immun 2019;80:146-62. DOI |
41 | Katouzian I, MahdiJafari S. Nano-encapsulation as a promising approach for targeted delivery and controlled release of vitamins. Trends Food Sci Technol 2016;53:34-48. DOI |
42 | Bae CH, Kim J, Nam W, Kim H, Kim J, Nam B, et al. Fermented red ginseng alleviates ovalbumin-induced inflammation in mice by suppressing interleukin-4 and immunoglobulin E expression. J Med Food 2021;24:569-76. DOI |
43 | Fan J, Liu S, Ai Z, Chen Y, Wang Y, Li Y, et al. Fermented ginseng attenuates lipopolysaccharide-induced inflammatory responses by activating the TLR4/MAPK signaling pathway and remediating gut barrier. Food Funct 2021;12:852-61. DOI |
44 | Iqbal H, Rhee DK. Ginseng alleviates microbial infections of the respiratory tract: a review. J Ginseng Res 2020;44:194-204. DOI |
45 | Gadotti AC, de Castro Deus M, Telles JP, Wind R, Goes M, Garcia Charello Ossoski R, et al. IFN-gamma is an independent risk factor associated with mortality in patients with moderate and severe COVID-19 infection. Virus Res 2020;289:198171. DOI |
46 | Kim Y, Cho SH. The effect of ginsenosides on depression in preclinical studies: a systematic review and meta-analysis. J Ginseng Res 2021;45:420-32. DOI |
47 | Ratan ZA, Haidere MF, Hong YH, Park SH, Lee JO, Lee J, et al. Pharmacological potential of ginseng and its major component ginsenosides. J Ginseng Res 2021;45:199-210. DOI |
48 | Lorz LR, Kim MY, Cho JY. Medicinal potential of Panax ginseng and its ginsenosides in atopic dermatitis treatment. J Ginseng Res 2020;44:8-13. DOI |
49 | Park SK, Hyun SH, In G, Park CK, Kwak YS, Jang YJ, et al. The antioxidant activities of Korean Red Ginseng (Panax ginseng) and ginsenosides: a systemic review through in vivo and clinical trials. J Ginseng Res 2021;45:41-7. DOI |
50 | Aravinthan A, Hossain MA, Kim B, Kang CW, Kim NS, Hwang KC, et al. Ginsenoside Rb1 inhibits monoiodoacetate-induced osteoarthritis in postmenopausal rats through prevention of cartilage degradation. J Ginseng Res 2021;45:287-94. DOI |
51 | Lu S, Zhang Y, Li H, Zhang J, Ci Y, Han M. Ginsenoside Rb1 can ameliorate the key inflammatory cytokines TNF-alpha and IL-6 in a cancer cachexia mouse model. BMC Compl Med Ther 2020;20:11. DOI |
52 | Ahn H, Han BC, Kim J, Kang SG, Kim PH, Jang KH, et al. Nonsaponin fraction of Korean Red Ginseng attenuates cytokine production via inhibition of TLR4 expression. J Ginseng Res 2019;43:291-9. DOI |
53 | Li Q, Zhai C, Wang G, Zhou J, Li W, Xie L, et al. Ginsenoside Rh1 attenuates ovalbumin-induced asthma by regulating Th1/Th2 cytokines balance. Biosci Biotechnol Biochem 2021;85:1809-17. DOI |
54 | Tang Y, Liu J, Zhang D, Xu Z, Ji J, Wen C. Cytokine storm in COVID-19: the current evidence and treatment strategies. Front Immunol 2020;11:1708. DOI |
55 | Desjarlais M, Wirth M, Lahaie I, Ruknudin P, Hardy P, Rivard A, et al. Nutraceutical targeting of inflammation-modulating microRNAs in severe forms of COVID-19: a novel approach to prevent the cytokine storm. Front Pharmacol 2020;11:602999. DOI |
56 | Tang L, Yin Z, Hu Y, Mei H. Controlling cytokine storm is vital in COVID-19. Front Immunol 2020;11:570993. DOI |
57 | Cho M, Choi G, Shim I, Chung Y. Enhanced Rg3 negatively regulates Th1 cell responses. J Ginseng Res 2019;43:49-57. DOI |
58 | Kim M, Sur B, Villa T, Yun J, Nah SY, Oh S. Gintonin regulates inflammation in human IL-1b-stimulated fibroblast-like synoviocytes and carrageenan/kaolin-induced arthritis in rats through LPAR2. J Ginseng Res 2021;45:575-82. DOI |
59 | Liu Y, Zhu H, Zhou W, Ye Q. Anti-inflammatory and anti-gouty-arthritic effect of free Ginsenoside Rb1 and nano Ginsenoside Rb1 against MSU induced gouty arthritis in experimental animals. Chem Biol Interact 2020;332:109285. DOI |
60 | Huang K, Zhang P, Zhang Z, Youn JY, Wang C, Zhang H, et al. Traditional Chinese Medicine (TCM) in the treatment of COVID-19 and other viral infections: efficacies and mechanisms. Pharmacol Ther 2021;225:107843. DOI |
61 | Moon PD, Han NR, Lee JS, Kim HM, Jeong HJ. p-coumaric acid, an active ingredient of Panax ginseng, ameliolates atopic dermatitis-like skin lesions through inhibition of thymic stromal lymphopoietin in mice. J Ginseng Res 2021;45:176-82. DOI |
62 | Yin Y, Wunderink RG. MERS, SARS and other coronaviruses as causes of pneumonia. Respirology 2018;23:130-7. |
63 | Costela-Ruiz VJ, Illescas-Montes R, Puerta-Puerta JM, Ruiz C, Melguizo-Rodriguez L. SARS-CoV-2 infection: the role of cytokines in COVID-19 disease. Cytokine Growth Factor Rev 2020;54:62-75. DOI |
64 | Choi JH, Oh J, Lee MJ, Ko SG, Nah SY, Cho IH. Gintonin mitigates experimental autoimmune encephalomyelitis by stabilization of Nrf2 signaling via stimulation of lysophosphatidic acid receptors. Brain Behav Immun 2021;93:384-98. DOI |
65 | Chei S, Song JH, Oh HJ, Lee K, Jin H, Choi SH, et al. Gintonin-enriched fraction suppresses heat stress-induced inflammation through LPA receptor. Molecules 2020;25. |
66 | Karmazyn M, Gan XT. Chemical components of ginseng, their biotransformation products and their potential as treatment of hypertension. Mol Cell Biochem 2021;476:333-47. DOI |
67 | Pollard CA, Morran MP, Nestor-Kalinoski AL. The COVID-19 pandemic: a global health crisis. Physiol Genom 2020;52:549-57. DOI |
68 | Zhou P, Yang X-L, Wang X-G, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270-3. DOI |
69 | Yang L, Liu S, Liu J, Zhang Z, Wan X, Huang B, et al. COVID-19: immunopathogenesis and Immunotherapeutics. Signal Transduc Targe Ther 2020;5:1-8. DOI |
70 | McIntosh K. Coronavirus disease 2019 (COVID-19): clinical features. Mass: UpToDate Waltham; 2020. UpToDate. |
71 | Sapra L, Bhardwaj A, Azam Z, Madhry D, Verma B, Rathore S, et al. Phytotherapy for treatment of cytokine storm in COVID-19. Front Biosci (Landmark Ed) 2021;26:51-75. DOI |
72 | Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, et al. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Front Immunol 2020;11:827. DOI |
73 | Lee JI, Park KS, Cho IH. Panax ginseng: a candidate herbal medicine for autoimmune disease. J Ginseng Res 2019;43:342-8. DOI |
74 | Hu H, He Y, Niu Z, Shen T, Zhang J, Wang X, et al. A review of the immunomodulatory activities of polysaccharides isolated from Panax species. J Ginseng Res 2022;46:23-32. DOI |
75 | Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med 2020;383:2255-73. DOI |
76 | Del Valle DM, Kim-Schulze S, Huang HH, Beckmann ND, Nirenberg S, Wang B, et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med 2020;26:1636-43. DOI |
77 | Chen J, Li Z, Hua M, Sun Y. Protection by ginseng saponins against cyclophosphamide-induced liver injuries in rats by induction of cytochrome P450 expression and mediation of the l-arginine/nitric oxide pathway based on metabolomics. Phytother Res 2021;35:3130-44. DOI |
78 | Hayden MS, Ghosh S. Regulation of NF-kappaB by TNF family cytokines. Semin Immunol 2014;26:253-66. DOI |
79 | Kircheis R, Haasbach E, Lueftenegger D, Heyken WT, Ocker M, Planz O. NF-kappaB pathway as a potential target for treatment of critical stage COVID-19 patients. Front Immunol 2020;11:598444. DOI |
80 | Tay MZ, Poh CM, Renia L, MacAry PA, Ng LFP. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol 2020;20:363-74. DOI |
81 | Mortaz E, Tabarsi P, Jamaati H, Dalil Roofchayee N, Dezfuli NK, Hashemian SM, et al. Increased serum levels of soluble TNF-alpha receptor is associated with ICU mortality in COVID-19 patients. Front Immunol 2021;12: 592727. DOI |
82 | Mosser DM, Zhang X. Interleukin-10: new perspectives on an old cytokine. Immunol Rev 2008;226:205-18. DOI |
83 | Yang L, Xie X, Tu Z, Fu J, Xu D, Zhou Y. The signal pathways and treatment of cytokine storm in COVID-19. Signal Transduct Target Ther 2021;6:255. DOI |
84 | Grasshoff H, Comduhr S, Monne LR, Muller A, Lamprecht P, Riemekasten G, et al. Low-dose IL-2 therapy in autoimmune and rheumatic diseases. Front Immunol 2021;12:648408. DOI |
85 | Billing U, Jetka T, Nortmann L, Wundrack N, Komorowski M, Waldherr S, et al. Robustness and information transfer within IL-6-induced JAK/STAT signalling. Commun Biol 2019;2:27. DOI |
86 | Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:271-280.e8. DOI |
87 | Xi QY, Jiang Y, Zhao S, Zeng B, Wang F, Wang LN, et al. Effect of ginseng polysaccharides on the immunity and growth of piglets by dietary supplementation during late pregnancy and lactating sows. Anim Sci J 2017;88:863-72. DOI |
88 | Hyun SH, Ahn HY, Kim HJ, Kim SW, So SH, In G, et al. Immuno-enhancement effects of Korean Red Ginseng in healthy adults: a randomized, double-blind, placebo-controlled trial. J Ginseng Res 2021;45:191-8. DOI |
89 | Ma J, Liu H, Wang X. Effect of ginseng polysaccharides and dendritic cells on the balance of Th1/Th2 T helper cells in patients with non-small cell lung cancer. J Tradit Chin Med 2014;34:641-5. DOI |
90 | Hoffmann M, Kleine-Weber H, Pohlmann S. A multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells. Mol Cell 2020;78:779-84. e5. DOI |
91 | Yang J-K, Zhao M-M, Yang W-L, Yang F-Y, Zhang L, Huang W, et al. Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development. medRxiv 2020. |
92 | Giang HTN, Banno K, Minh LHN, Trinh LT, Loc LT, Eltobgy A, et al. Dengue hemophagocytic syndrome: a systematic review and meta-analysis on epidemiology, clinical signs, outcomes, and risk factors. Rev Med Virol 2018;28:e2005. DOI |
93 | Yang H, Lyu Y, Hou F. SARS-CoV-2 infection and the antiviral innate immune response. J Mol Cell Biol 2020;12:963-7. DOI |
94 | Sette A, Crotty S. Adaptive immunity to SARS-CoV-2 and COVID-19. Cell 2021;184:861-80. DOI |
95 | Coperchini F, Chiovato L, Croce L, Magri F, Rotondi M. The cytokine storm in COVID-19: an overview of the involvement of the chemokine/chemokine-receptor system. Cytokine Growth Factor Rev 2020;53:25-32. DOI |
96 | Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020;46:846-8. DOI |
97 | Luo W, Li YX, Jiang LJ, Chen Q, Wang T, Ye DW. Targeting JAK-STAT signaling to control cytokine release syndrome in COVID-19. Trends Pharmacol Sci 2020;41:531-43. DOI |
98 | Bianchi M, Meng C, Ivashkiv LB. Inhibition of IL-2-induced Jak-STAT signaling by glucocorticoids. Proc Natl Acad Sci U S A 2000;97:9573-8. DOI |
99 | Hou CW, Lee SD, Kao CL, Cheng IS, Lin YN, Chuang SJ, et al. Improved inflammatory balance of human skeletal muscle during exercise after supplementations of the ginseng-based steroid Rg1. PLoS One 2015;10:e0116387. DOI |
100 | Jung HL, Kwak HE, Kim SS, Kim YC, Lee CD, Byurn HK, et al. Effects of Panax ginseng supplementation on muscle damage and inflammation after uphill treadmill running in humans. Am J Chin Med 2011;39:441-50. DOI |
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