Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
권호 표지
DOI QR코드

DOI QR Code

Potential benefits of ginseng against COVID-19 by targeting inflammasomes

  • Yi, Young-Su (Department of Life Sciences, Kyonggi University)
  • Received : 2022.02.27
  • Accepted : 2022.03.31
  • Published : 2022.11.01
Download PDF
⟨ Previous Next ⟩

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogenic virus that causes coronavirus disease 2019 (COVID-19), with major symptoms including hyper-inflammation and cytokine storm, which consequently impairs the respiratory system and multiple organs, or even cause death. SARS-CoV-2 activates inflammasomes and inflammasome-mediated inflammatory signaling pathways, which are key determinants of hyperinflammation and cytokine storm in COVID-19 patients. Additionally, SARS-CoV-2 inhibits inflammasome activation to evade the host's antiviral immunity. Therefore, regulating inflammasome initiation has received increasing attention as a preventive measure in COVID-19 patients. Ginseng and its major active constituents, ginsenosides and saponins, improve the immune system and exert anti-inflammatory effects by targeting inflammasome stimulation. Therefore, this review discussed the potential preventive and therapeutic roles of ginseng in COVID-19 based on its regulatory role in inflammasome initiation and the host's antiviral immunity.

Keywords

Acknowledgement

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2020R1F1A1074415).

References

  1. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W, China Novel Coronavirus I, Research T. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020;382:727-33. https://doi.org/10.1056/NEJMoa2001017
  2. Coronaviridae Study Group of the International Committee on Taxonomy of V. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol 2020;5:536-44. https://doi.org/10.1038/s41564-020-0695-z
  3. Tan YJ, Lim SG, Hong W. Characterization of viral proteins encoded by the SARS-coronavirus genome. Antivir Res 2005;65:69-78. https://doi.org/10.1016/j.antiviral.2004.10.001
  4. Dixon BE, Wools-Kaloustian KK, Fadel WF, Duszynski TJ, Yiannoutsos C, Halverson PK, Menachemi N. Symptoms and symptom clusters associated with SARS-CoV-2 infection in community-based populations: results from a statewide epidemiological study. PLoS One 2021;16:e0241875. https://doi.org/10.1371/journal.pone.0241875
  5. Ejaz H, Alsrhani A, Zafar A, Javed H, Junaid K, Abdalla AE, Abosalif KOA, Ahmed Z, Younas S. COVID-19 and comorbidities: deleterious impact on infected patients. J Infect Publ Health 2020;13:1833-9. https://doi.org/10.1016/j.jiph.2020.07.014
  6. Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol 2020;20:355-62. https://doi.org/10.1038/s41577-020-0331-4
  7. Lu JM, Yao Q, Chen C. Ginseng compounds: an update on their molecular mechanisms and medical applications. Curr Vasc Pharmacol 2009;7:293-302. https://doi.org/10.2174/157016109788340767
  8. Zhao B, Lv C, Lu J. Natural occurring polysaccharides from Panax ginseng C. A. Meyer: a review of isolation, structures, and bioactivities. Int J Biol Macromol 2019;133:324-36. https://doi.org/10.1016/j.ijbiomac.2019.03.229
  9. Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999;58:1685-93. https://doi.org/10.1016/S0006-2952(99)00212-9
  10. Sun YJ, Chen H, Hao ZY, Wang JM, Zhang YL, Zhao X, Zheng YN. [Chemical constituents from fruit of Panax ginseng]. Zhong Yao Cai 2014;37:1387-90.
  11. Yi YS. New mechanisms of ginseng saponin-mediated anti-inflammatory action via targeting canonical inflammasome signaling pathways. J Ethnopharmacol 2021;278:114292. https://doi.org/10.1016/j.jep.2021.114292
  12. Yi YS. Roles of ginsenosides in inflammasome activation. J Ginseng Res 2019;43:172-8. https://doi.org/10.1016/j.jgr.2017.11.005
  13. Zheng D, Liwinski T, Elinav E. Inflammasome activation and regulation: toward a better understanding of complex mechanisms. Cell Discov 2020;6:36. https://doi.org/10.1038/s41421-020-0167-x
  14. Xue Y, Enosi Tuipulotu D, Tan WH, Kay C, Man SM. Emerging activators and regulators of inflammasomes and pyroptosis. Trends Immunol 2019;40: 1035-52. https://doi.org/10.1016/j.it.2019.09.005
  15. Kayagaki N, Warming S, Lamkanfi M, Vande Walle L, Louie S, Dong J, Newton K, Qu Y, Liu J, Heldens S, Zhang J, Lee WP, Roose-Girma M, Dixit VM. Non-canonical inflammasome activation targets caspase-11. Nature 2011;479:117-21. https://doi.org/10.1038/nature10558
  16. Hagar JA, Powell DA, Aachoui Y, Ernst RK, Miao EA. Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science 2013;341:1250-3. https://doi.org/10.1126/science.1240988
  17. Kayagaki N, Wong MT, Stowe IB, Ramani SR, Gonzalez LC, Akashi-Takamura S, Miyake K, Zhang J, Lee WP, Muszynski A, Forsberg LS, Carlson RW, Dixit VM. Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 2013;341:1246-9. https://doi.org/10.1126/science.1240248
  18. Shi J, Zhao Y, Wang Y, Gao W, Ding J, Li P, Hu L, Shao F. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 2014;514:187-92. https://doi.org/10.1038/nature13683
  19. Yi YS. Caspase-11 non-canonical inflammasome: a critical sensor of intracellular lipopolysaccharide in macrophage-mediated inflammatory responses. Immunology 2017;152:207-17. https://doi.org/10.1111/imm.12787
  20. Yi YS. Regulatory roles of the caspase-11 non-canonical inflammasome in inflammatory diseases. Immune Netw 2018;18:e41. https://doi.org/10.4110/in.2018.18.e41
  21. Matikainen S, Nyman TA, Cypryk W. Function and regulation of noncanonical caspase-4/5/11 inflammasome. J Immunol 2020;204:3063-9. https://doi.org/10.4049/jimmunol.2000373
  22. Ruhl S, Broz P. Caspase-11 activates a canonical NLRP3 inflammasome by promoting K(+) efflux. Eur J Immunol 2015;45:2927-36. https://doi.org/10.1002/eji.201545772
  23. Yi YS. Functional crosstalk between non-canonical caspase-11 and canonical NLRP3 inflammasomes during infection-mediated inflammation. Immunology 2020;159:142-55. https://doi.org/10.1111/imm.13134
  24. Corpetti C, Del Re A, Seguella L, Palenca I, Rurgo S, De Conno B, Pesce M, Sarnelli G, Esposito G. Cannabidiol inhibits SARS-Cov-2 spike (S) proteininduced cytotoxicity and inflammation through a PPARgamma-dependent TLR4/NLRP3/Caspase-1 signaling suppression in Caco-2 cell line. Phytother Res 2021;35:6893-903. https://doi.org/10.1002/ptr.7302
  25. Xu H, Akinyemi IA, Chitre SA, Loeb JC, Lednicky JA, McIntosh MT, BhaduriMcIntosh S. SARS-CoV-2 viroporin encoded by ORF3a triggers the NLRP3 inflammatory pathway. Virology 2022;568:13-22. https://doi.org/10.1016/j.virol.2022.01.003
  26. Campbell GR, To RK, Hanna J, Spector SA. SARS-CoV-2, SARS-CoV-1, and HIV-1 derived ssRNA sequences activate the NLRP3 inflammasome in human macrophages through a non-classical pathway. iScience 2021;24:102295. https://doi.org/10.1016/j.isci.2021.102295
  27. Yalcinkaya M, Liu W, Islam MN, Kotini AG, Gusarova GA, Fidler TP, Papapetrou EP, Bhattacharya J, Wang N, Tall AR. Modulation of the NLRP3 inflammasome by sars-CoV-2 envelope protein. Sci Rep 2021;11:24432. https://doi.org/10.1038/s41598-021-04133-7
  28. Pan P, Shen M, Yu Z, Ge W, Chen K, Tian M, Xiao F, Wang Z, Wang J, Jia Y, Wang W, Wan P, Zhang J, Chen W, Lei Z, Chen X, Luo Z, Zhang Q, Xu M, Li G, Li Y, Wu J. SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. Nat Commun 2021;12:4664. https://doi.org/10.1038/s41467-021-25015-6
  29. Kim NE, Kim DK, Song YJ. SARS-CoV-2 nonstructural proteins 1 and 13 suppress caspase-1 and the NLRP3 inflammasome activation. Microorganisms 2021;9.
  30. Olajide OA, Iwuanyanwu VU, Lepiarz-Raba I, Al-Hindawi AA. Induction of exaggerated cytokine production in human peripheral blood mononuclear cells by a recombinant SARS-CoV-2 spike glycoprotein S1 and its inhibition by dexamethasone. Inflammation 2021;44:1865-77. https://doi.org/10.1007/s10753-021-01464-5
  31. Kucia M, Ratajczak J, Bujko K, Adamiak M, Ciechanowicz A, Chumak V, Brzezniakiewicz-Janus K, Ratajczak MZ. An evidence that SARS-Cov-2/COVID19 spike protein (SP) damages hematopoietic stem/progenitor cells in the mechanism of pyroptosis in Nlrp3 inflammasome-dependent manner. Leukemia 2021;35:3026-9. https://doi.org/10.1038/s41375-021-01332-z
  32. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003;426:450-4. https://doi.org/10.1038/nature02145
  33. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, Bao L, Zhang B, Liu G, Wang Z, Chappell M, Liu Y, Zheng D, Leibbrandt A, Wada T, Slutsky AS, Liu D, Qin C, Jiang C, Penninger JM. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med 2005;11:875-9. https://doi.org/10.1038/nm1267
  34. Ratajczak MZ, Bujko K, Ciechanowicz A, Sielatycka K, Cymer M, Marlicz W, Kucia M. SARS-CoV-2 entry receptor ACE2 is expressed on very small CD45(-) precursors of hematopoietic and endothelial cells and in response to virus spike protein activates the Nlrp3 inflammasome. Stem Cell Rev Rep 2021;17: 266-77. https://doi.org/10.1007/s12015-020-10010-z
  35. Sun X, Liu Y, Huang Z, Xu W, Hu W, Yi L, Liu Z, Chan H, Zeng J, Liu X, Chen H, Yu J, Chan FKL, Ng SC, Wong SH, Wang MH, Gin T, Joynt GM, Hui DSC, Zou X, Shu Y, Cheng CHK, Fang S, Luo H, Lu J, Chan MTV, Zhang L, Wu WKK. SARSCoV-2 non-structural protein 6 triggers NLRP3-dependent pyroptosis by targeting ATP6AP1. Cell Death Differ 2022.
  36. Mick E, Kamm J, Pisco AO, Ratnasiri K, Babik JM, Castaneda G, DeRisi JL, Detweiler AM, Hao SL, Kangelaris KN, Kumar GR, Li LM, Mann SA, Neff N, Prasad PA, Serpa PH, Shah SJ, Spottiswoode N, Tan M, Calfee CS, Christenson SA, Kistler A, Langelier C. Upper airway gene expression reveals suppressed immune responses to SARS-CoV-2 compared with other respiratory viruses. Nat Commun 2020;11:5854. https://doi.org/10.1038/s41467-020-19587-y
  37. Esmaeili Gouvarchin Ghaleh H, Hosseini A, Aghamollaei H, Fasihi-Ramandi M, Alishiri G, Saeedi-Boroujeni A, Hassanpour K, Mahmoudian-Sani MR, Farnoosh G. NLRP3 inflammasome activation and oxidative stress status in the mild and moderate SARS-CoV-2 infected patients: impact of melatonin as a medicinal supplement. Z Naturforsch C J Biosci 2022;77:37-42. https://doi.org/10.1515/znc-2021-0101
  38. Junqueira C, Crespo A, Ranjbar S, Lewandrowski M, Ingber J, de Lacerda LB, Parry B, Ravid S, Clark S, Ho F, Vora SM, Leger V, Beakes C, Margolin J, Russell N, Kays K, Gehrke L, Adhikari UD, Henderson L, Janssen E, Kwon D, Sander C, Abraham J, Filbin M, Goldberg MB, Wu H, Mehta G, Bell S, Goldfeld AE, Lieberman J. SARS-CoV-2 infects blood monocytes to activate NLRP3 and AIM2 inflammasomes, pyroptosis and cytokine release. Res Sq 2021.
  39. Rodrigues TS, de Sa KSG, Ishimoto AY, Becerra A, Oliveira S, Almeida L, Goncalves AV, Perucello DB, Andrade WA, Castro R, Veras FP, TollerKawahisa JE, Nascimento DC, de Lima MHF, Silva CMS, Caetite DB, Martins RB, Castro IA, Pontelli MC, de Barros FC, do Amaral NB, Giannini MC, Bonjorno LP, Lopes MIF, Santana RC, Vilar FC, Auxiliadora-Martins M, Luppino-Assad R, de Almeida SCL, de Oliveira FR, Batah SS, Siyuan L, Benatti MN, Cunha TM, AlvesFilho JC, Cunha FQ, Cunha LD, Frantz FG, Kohlsdorf T, Fabro AT, Arruda E, de Oliveira RDR, Louzada-Junior P, Zamboni DS. Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients. J Exp Med 2021:218.
  40. Iadecola C, Anrather J, Kamel H. Effects of COVID-19 on the nervous system. Cell 2020;183:16-27 e11. https://doi.org/10.1016/j.cell.2020.08.028
  41. Abboud H, Abboud FZ, Kharbouch H, Arkha Y, El Abbadi N, El Ouahabi A. COVID-19 and SARS-cov-2 infection: pathophysiology and clinical effects on the nervous system. World Neurosurg 2020;140:49-53. https://doi.org/10.1016/j.wneu.2020.05.193
  42. Olajide OA, Iwuanyanwu VU, Adegbola OD, Al-Hindawi AA. SARS-CoV-2 spike glycoprotein S1 induces neuroinflammation in BV-2 microglia. Mol Neurobiol 2022;59:445-58. https://doi.org/10.1007/s12035-021-02593-6
  43. Cama VF, Marin-Prida J, Acosta-Rivero N, Acosta EF, Diaz LO, Casadesus AV, Fernandez-Marrero B, Gilva-Rodriguez N, Cremata-Garcia D, CervantesLlanos M, Piniella-Matamoros B, Sanchez D, Del Rosario-Cruz L, Borrajero I, Diaz A, Gonzalez Y, Penton-Arias E, Montero-Gonzalez T, Guillen-Nieto G, Penton-Rol G. The microglial NLRP3 inflammasome is involved in human SARS-CoV-2 cerebral pathogenicity: a report of three post-mortem cases. J Neuroimmunol 2021;361:577728. https://doi.org/10.1016/j.jneuroim.2021.577728
  44. Chen Y, Klein SL, Garibaldi BT, Li H, Wu C, Osevala NM, Li T, Margolick JB, Pawelec G, Leng SX. Aging in COVID-19: vulnerability, immunity and intervention. Ageing Res Rev 2021;65:101205. https://doi.org/10.1016/j.arr.2020.101205
  45. Akbar AN, Gilroy DW. Aging immunity may exacerbate COVID-19. Science 2020;369:256-7. https://doi.org/10.1126/science.abb0762
  46. Lara PC, Macias-Verde D, Burgos-Burgos J. Age-induced NLRP3 inflammasome over-activation increases lethality of SARS-CoV-2 pneumonia in elderly patients. Aging Dis 2020;11:756-62. https://doi.org/10.14336/AD.2020.0601
  47. Lee HC, Wei YH. Mitochondria and aging. Adv Exp Med Biol 2012;942: 311-27. https://doi.org/10.1007/978-94-007-2869-1_14
  48. Oka T, Hikoso S, Yamaguchi O, Taneike M, Takeda T, Tamai T, Oyabu J, Murakawa T, Nakayama H, Nishida K, Akira S, Yamamoto A, Komuro I, Otsu K. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature 2012;485:251-5. https://doi.org/10.1038/nature10992
  49. Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP, Fitzgerald KA, Ryter SW, Choi AM. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 2011;12:222-30.
  50. Jha PK, Vijay A, Halu A, Uchida S, Aikawa M. Gene expression profiling reveals the shared and distinct transcriptional signatures in human lung epithelial cells infected with SARS-CoV-2, MERS-CoV, or SARS-CoV: potential implications in cardiovascular complications of COVID-19. Front Cardiovasc Med 2020;7:623012.
  51. Tuncer S, Fiorillo MT, Sorrentino R. The multifaceted nature of NLRP12. J Leukoc Biol 2014;96:991-1000. https://doi.org/10.1189/jlb.3RU0514-265RR
  52. 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. https://doi.org/10.1038/s41577-020-0311-8
  53. Gurung P, Kanneganti TD. NLRP12 in autoimmune diseases. Oncotarget 2015;6:19950-1. https://doi.org/10.18632/oncotarget.4585
  54. Moustaqil M, Ollivier E, Chiu HP, Van Tol S, Rudolffi-Soto P, Stevens C, Bhumkar A, Hunter DJB, Freiberg AN, Jacques D, Lee B, Sierecki E, Gambin Y. SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species. Emerg Microb Infect 2021;10:178-95. https://doi.org/10.1080/22221751.2020.1870414
  55. Chen W, Wang J, Luo Y, Wang T, Li X, Li A, Li J, Liu K, Liu B. Ginsenoside Rb1 and compound K improve insulin signaling and inhibit ER stress-associated NLRP3 inflammasome activation in adipose tissue. J Ginseng Res 2016;40: 351-8. https://doi.org/10.1016/j.jgr.2015.11.002
  56. 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. https://doi.org/10.1016/j.cbi.2020.109285
  57. Xu Y, Yang C, Zhang S, Li J, Xiao Q, Huang W. Ginsenoside Rg1 protects against non-alcoholic fatty liver disease by ameliorating lipid peroxidation, endoplasmic reticulum stress, and inflammasome activation. Biol Pharm Bull 2018;41:1638-44. https://doi.org/10.1248/bpb.b18-00132
  58. Li Y, Zhang D, Li L, Han Y, Dong X, Yang L, Li X, Li W, Li W. Ginsenoside Rg1 ameliorates aginginduced liver fibrosis by inhibiting the NOX4/NLRP3 inflammasome in SAMP8 mice. Mol Med Rep 2021;24.
  59. Zhao J, He B, Zhang S, Huang W, Li X. Ginsenoside Rg1 alleviates acute liver injury through the induction of autophagy and suppressing NF-kappaB/NLRP3 inflammasome signaling pathway. Int J Med Sci 2021;18:1382-9. https://doi.org/10.7150/ijms.50919
  60. Wang T, Gao Y, Yue R, Wang X, Shi Y, Xu J, Wu B, Li Y. Ginsenoside Rg1 alleviates podocyte injury induced by hyperlipidemia via targeting the mTOR/ NF-kappaB/NLRP3 Axis. Evid Based Complement Alternat Med 2020;2020: 2735714.
  61. Gao Y, Li J, Chu S, Zhang Z, Chen N, Li L, Zhang L. Ginsenoside Rg1 protects mice against streptozotocin-induced type 1 diabetic by modulating the NLRP3 and Keap1/Nrf2/HO-1 pathways. Eur J Pharmacol 2020;866:172801. https://doi.org/10.1016/j.ejphar.2019.172801
  62. Luo M, Yan D, Sun Q, Tao J, Xu L, Sun H, Zhao H. Ginsenoside Rg1 attenuates cardiomyocyte apoptosis and inflammation via the TLR4/NF-kB/NLRP3 pathway. J Cell Biochem 2020;121:2994-3004. https://doi.org/10.1002/jcb.29556
  63. Wang F, Park JS, Ma Y, Ma H, Lee YJ, Lee GR, Yoo HS, Hong JT, Roh YS. Ginseng saponin enriched in Rh1 and Rg2 ameliorates nonalcoholic fatty liver disease by inhibiting inflammasome activation. Nutrients 2021;13.
  64. Yoon SJ, Park JY, Choi S, Lee JB, Jung H, Kim TD, Yoon SR, Choi I, Shim S, Park YJ. Ginsenoside Rg3 regulates S-nitrosylation of the NLRP3 inflammasome via suppression of iNOS. Biochem Biophys Res Commun 2015;463:1184-9. https://doi.org/10.1016/j.bbrc.2015.06.080
  65. Kim J, Ahn H, Han BC, Lee SH, Cho YW, Kim CH, Hong EJ, An BS, Jeung EB, Lee GS. Korean red ginseng extracts inhibit NLRP3 and AIM2 inflammasome activation. Immunol Lett 2014;158:143-50. https://doi.org/10.1016/j.imlet.2013.12.017
  66. Zhai J, Gao H, Wang S, Zhang S, Qu X, Zhang Y, Tao L, Sun J, Song Y, Fu L. Ginsenoside Rg3 attenuates cisplatin-induced kidney injury through inhibition of apoptosis and autophagy-inhibited NLRP3. J Biochem Mol Toxicol 2021;35:e22896. https://doi.org/10.1002/jbt.22896
  67. Ren B, Feng J, Yang N, Guo Y, Chen C, Qin Q. Ginsenoside Rg3 attenuates angiotensin II-induced myocardial hypertrophy through repressing NLRP3 inflammasome and oxidative stress via modulating SIRT1/NF-kappaB pathway. Int Immunopharm 2021;98:107841. https://doi.org/10.1016/j.intimp.2021.107841
  68. Zhu Y, Zhu C, Yang H, Deng J, Fan D. Protective effect of ginsenoside Rg5 against kidney injury via inhibition of NLRP3 inflammasome activation and the MAPK signaling pathway in high-fat diet/streptozotocin-induced diabetic mice. Pharmacol Res 2020;155:104746. https://doi.org/10.1016/j.phrs.2020.104746
  69. Liu C, Wang J, Yang Y, Liu X, Zhu Y, Zou J, Peng S, Le TH, Chen Y, Zhao S, He B, Mi Q, Zhang X, Du Q. Ginsenoside Rd ameliorates colitis by inducing p62- driven mitophagy-mediated NLRP3 inflammasome inactivation in mice. Biochem Pharmacol 2018;155:366-79. https://doi.org/10.1016/j.bcp.2018.07.010
  70. Yao Y, Hu S, Zhang C, Zhou Q, Wang H, Yang Y, Liu C, Ding H. Ginsenoside Rd attenuates cerebral ischemia/reperfusion injury by exerting an antipyroptotic effect via the miR-139-5p/FoxO1/Keap1/Nrf2 axis. Int Immunopharm 2022;105:108582. https://doi.org/10.1016/j.intimp.2022.108582
  71. Wang H, Lv J, Jiang N, Huang H, Wang Q, Liu X. Ginsenoside Re protects against chronic restraint stress-induced cognitive deficits through regulation of NLRP3 and Nrf2 pathways in mice. Phytother Res 2021.
  72. Kim M, Yi YS, Kim J, Han SY, Kim SH, Seo DB, Cho JY, Shin SS. Effect of polysaccharides from a Korean ginseng berry on the immunosenescence of aged mice. J Ginseng Res 2018;42:447-54. https://doi.org/10.1016/j.jgr.2017.04.014
  73. Zhou L, Zheng Y, Li Z, Bao L, Dou Y, Tang Y, Zhang J, Zhou J, Liu Y, Jia Y, Li X. Compound K attenuates the development of atherosclerosis in ApoE(-/-) mice via LXRalpha activation. Int J Mol Sci 2016;17.
  74. Chei S, Oh HJ, Jang H, Lee K, Jin H, Choi Y, Lee BY. Korean red ginseng suppresses the expression of oxidative stress response and NLRP3 inflammasome genes in aged C57BL/6 mouse ovaries. Foods 2020;9.
  75. Yuan C, Liu C, Wang T, He Y, Zhou Z, Dun Y, Zhao H, Ren D, Wang J, Zhang C, Yuan D. Chikusetsu saponin IVa ameliorates high fat diet-induced inflammation in adipose tissue of mice through inhibition of NLRP3 inflammasome activation and NF-kappaB signaling. Oncotarget 2017;8:31023-40. https://doi.org/10.18632/oncotarget.16052
  76. Shao A, Fei J, Feng S, Weng J. Chikusetsu saponin IVa alleviated sevofluraneinduced neuroinflammation and cognitive impairment by blocking NLRP3/ caspase-1 pathway. Pharmacol Rep 2020;72:833-45. https://doi.org/10.1007/s43440-020-00078-2
  77. Zhang Z, Yang H, Yang J, Xie J, Xu J, Liu C, Wu C. Pseudoginsenoside-F11 attenuates cognitive impairment by ameliorating oxidative stress and neuroinflammation in dgalactose-treated mice. Int Immunopharm 2019;67:78-86. https://doi.org/10.1016/j.intimp.2018.11.026
  78. Zhou Z, He M, Zhao Q, Wang D, Zhang C, Liu C, Zhao H, Dun Y, He Y, Yuan C, Yuan D, Wang T. Panax notoginseng saponins attenuate neuroinflammation through TXNIP-mediated NLRP3 inflammasome activation in aging rats. Curr Pharmaceut Biotechnol 2021;22:1369-79. https://doi.org/10.2174/1389201021999201110204735
  79. Zhang Y, Hu W, Zhang B, Yin Y, Zhang J, Huang D, Huang R, Li W, Li W. Ginsenoside Rg1 protects against neuronal degeneration induced by chronic dexamethasone treatment by inhibiting NLRP-1 inflammasomes in mice. Int J Mol Med 2017;40:1134-42. https://doi.org/10.3892/ijmm.2017.3092
  80. Xu TZ, Shen XY, Sun LL, Chen YL, Zhang BQ, Huang DK, Li WZ. Ginsenoside Rg1 protects against H2O2induced neuronal damage due to inhibition of the NLRP1 inflammasome signalling pathway in hippocampal neurons in vitro. Int J Mol Med 2019;43:717-26.
  81. Ahn H, Han BC, Lee SH, Lee GS. Fructose-arginine, a non-saponin molecule of Korean Red Ginseng, attenuates AIM2 inflammasome activation. J Ginseng Res 2020;44:808-14. https://doi.org/10.1016/j.jgr.2020.06.002
  82. Young-Su Yi. Dual roles of the caspase-11 non-canonical inflammasome in inflammatory bowel disease. Int Immunopharmacol 2022;108:108739. https://doi.org/10.1016/j.intimp.2022.108739.
  83. Marquez-Flores YK, Villegas I, Cardeno A, Rosillo MA, Alarcon-de-la-Lastra C. Apigenin supplementation protects the development of dextran sulfate sodium-induced murine experimental colitis by inhibiting canonical and noncanonical inflammasome signaling pathways. J Nutr Biochem 2016;30:143-52. https://doi.org/10.1016/j.jnutbio.2015.12.002
  84. Zhong X, Liu M, Yao W, Du K, He M, Jin X, Jiao L, Ma G, Wei B, Wei M. Epigallocatechin-3-Gallate attenuates microglial inflammation and neurotoxicity by suppressing the activation of canonical and noncanonical inflammasome via TLR4/NF-kappaB pathway. Mol Nutr Food Res 2019;63:e1801230.
  85. Ye J, Zeng B, Zhong M, Li H, Xu L, Shu J, Wang Y, Yang F, Zhong C, Ye X, He X, Ouyang D. Scutellarin inhibits caspase-11 activation and pyroptosis in macrophages via regulating PKA signaling. Acta Pharm Sin B 2021;11:112-26. https://doi.org/10.1016/j.apsb.2020.07.014
  86. Zhang ZT, Zhang DY, Xie K, Wang CJ, Xu F. Luteolin activates Tregs to promote IL-10 expression and alleviating caspase-11-dependent pyroptosis in sepsisinduced lung injury. Int Immunopharm 2021;99:107914. https://doi.org/10.1016/j.intimp.2021.107914
  87. Xu J, Li S, Jiang L, Gao X, Liu W, Zhu X, Huang W, Zhao H, Wei Z, Wang K, Yang Z. Baicalin protects against zearalenone-induced chicks liver and kidney injury by inhibiting expression of oxidative stress, inflammatory cytokines and caspase signaling pathway. Int Immunopharm 2021;100:108097. https://doi.org/10.1016/j.intimp.2021.108097
  88. Gao X, Xu J, Jiang L, Liu W, Hong H, Qian Y, Li S, Huang W, Zhao H, Yang Z, Liu Q, Wei Z. Morin alleviates aflatoxin B1-induced liver and kidney injury by inhibiting heterophil extracellular traps release, oxidative stress and inflammatory responses in chicks. Poultry Sci 2021;100:101513. https://doi.org/10.1016/j.psj.2021.101513
  89. Hwang SH, Lorz LR, Yi DK, Noh JK, Yi YS, Cho JY. Viburnum pichinchense methanol extract exerts anti-inflammatory effects via targeting the NFkappaB and caspase-11 non-canonical inflammasome pathways in macrophages. J Ethnopharmacol 2019;245:112161. https://doi.org/10.1016/j.jep.2019.112161
  90. Min Ji-Hyun, Cho Hui-Jin, Young-Su Yi. A novel mechanism of Korean red ginseng-mediated anti-inflammatory action via targeting caspase-11 noncanonical inflammasome in macrophages. J Ginseng Res 2021:In Press. https://doi.org/10.1016/j.jgr.2021.12.009. In press.
  91. Ge G, Yan Y, Cai H. Ginsenoside Rh2 inhibited proliferation by inducing ROS mediated ER stress dependent apoptosis in lung cancer cells. Biol Pharm Bull 2017;40:2117-24. https://doi.org/10.1248/bpb.b17-00463
  92. 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
  93. Lee YY, Kim SD, Park SC, Rhee MH. Panax ginseng: inflammation, platelet aggregation, thrombus formation, and atherosclerosis crosstalk. J Ginseng Res 2022;46:54-61. https://doi.org/10.1016/j.jgr.2021.09.003
  94. Hyun SH, Ahn HY, Kim HJ, Kim SW, So SH, In G, Park CK, Han CK. Immunoenhancement effects of Korean Red Ginseng in healthy adults: a randomized, double-blind, placebo-controlled trial. J Ginseng Res 2021;45:191-8. https://doi.org/10.1016/j.jgr.2020.08.003
  95. Shin MS, Song JH, Choi P, Lee JH, Kim SY, Shin KS, Ham J, Kang KS. 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