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DOI QR Code

Ginseng and ginsenosides on cardiovascular and pulmonary diseases; Pharmacological potentials for the coronavirus (COVID-19)

  • Ajay Vijayakumar (College of Veterinary Medicine, Biosafety Research Institute, Chonbuk National University) ;
  • Jong-Hoon Kim (College of Veterinary Medicine, Biosafety Research Institute, Chonbuk National University)
  • 투고 : 2023.07.24
  • 심사 : 2023.10.26
  • 발행 : 2024.03.01

초록

Since its outbreak in late 2019, the Coronavirus disease 2019 (COVID-19) pandemic has profoundly caused global morbidity and deaths. The COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has major complications in cardiovascular and pulmonary system. The increased rate of mortality is due to delayed detection of certain biomarkers that are crucial in the development of disease. Furthermore, certain proteins and enzymes in cellular signaling pathways play an important role in replication of SARS-CoV-2. Most cases are mild to moderate symptoms, however severe cases of COVID-19 leads to death. Detecting the level of biomarkers such as C-reactive protein, cardiac troponin, creatine kinase, creatine kinaseMB, procalcitonin and Matrix metalloproteinases helps in early detection of the severity of disease. Similarly, through downregulating Renin-angiotensin system, interleukin, Mitogen-activated protein kinases and Phosphoinositide 3-kinases pathways, COVID-19 can be effectively controlled and mortality could be prevented. Ginseng and ginsenosides possess therapeutic potential in cardiac and pulmonary complications, there are several studies performed in which they have suppressed these biomarkers and downregulated the pathways, thereby inhibiting the further spread of disease. Supplementation with ginseng or ginsenoside could act on multiple pathways to reduce the level of biomarkers significantly and alleviate cardiac and pulmonary damage. Therefore, this review summarizes the potential of ginseng extract and ginsenosides in controlling the cardiovascular and pulmonary diseases by COVID-19.

키워드

과제정보

This research was supported by Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education(2020R1l1A3072212). This research was supported by Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education(2019R1A6A1A03033084).

참고문헌

  1. Su WL, Lu KC, Chan CY, Chao YC. COVID-19 and the lungs: a review. J Infect Public Health 2021;14(11):1708-14.
  2. Calabrese F, Pezzuto F, Fortarezza F, Hofman P, Kern I, Panizo A, von der Thusen J, Timofeev S, Gorkiewicz G, Lunardi F. Pulmonary pathology and COVID-19: lessons from autopsy. The experience of European Pulmonary Pathologists. Virchows Arch 2020;477(3):359-72. https://doi.org/10.1007/s00428-020-02886-6
  3. Kevadiya BD, Machhi J, Herskovitz J, Oleynikov MD, Blomberg WR, Bajwa N, Soni D, Das S, Hasan M, Patel M, et al. Diagnostics for SARS-CoV-2 infections. Nat Mater 2021;20(5):593-605. https://doi.org/10.1038/s41563-020-00906-z
  4. Li J, Zhang Y, Wang F, Liu B, Li H, Tang G, Chang Z, Liu A, Fu C, Lv Y, et al. Cardiac damage in patients with the severe type of coronavirus disease 2019 (COVID-19). BMC Cardiovasc Disor 2020;20(1):1-7. https://doi.org/10.1186/s12872-019-01312-3
  5. Bansal M. Cardiovascular disease and COVID-19. Diabetes Metab Syndr 2020;14 (3):247-50. https://doi.org/10.1016/j.dsx.2020.03.013
  6. Raman B, Bluemke DA, Luscher TF, Neubauer S. Long COVID: post-acute sequelae of COVID-19 with a cardiovascular focus. Eur Heart J 2022;43(11):1157-72. https://doi.org/10.1093/eurheartj/ehac031
  7. Luo J, Zhu X, Jian J, Chen X, Yin K. Cardiovascular disease in patients with COVID19: evidence from cardiovascular pathology to treatment. Acta Biochim Biophys Sin(Shangai). 2021;53(3):273-82.
  8. Yi Y-S. Potential benefits of ginseng against COVID-19 by targeting inflammasomes. J Ginseng Res 2022;46(6):722-30. https://doi.org/10.1016/j.jgr.2022.03.008
  9. Lee YY, Quah Y, Shin JH, Kwon HW, Lee DH, Han JE, Park JK, Kim SD, Kwak D, Park SC, et al. COVID-19 and Panax ginseng: targeting platelet aggregation, thrombosis and the coagulation pathway. J Ginseng Res 2022;46(2):175-82. https://doi.org/10.1016/j.jgr.2022.01.002
  10. Lin H, Wang C, Yu H, Liu Y, Tan L, He S, Li Z, Wang C, Wang F, Li P, et al. Protective effect of total Saponins from American ginseng against cigarette smokeinduced COPD in mice based on integrated metabolomics and network pharmacology. Biomed Pharmacother 2022;149:112823.
  11. Li J, Lu K, Sun F, Tan S, Zhang X, Sheng W, Hao W, Liu M, Lv W, Han W. Panaxydol attenuates ferroptosis against LPS-induced acute lung injury in mice by Keap1- Nrf2/HO-1 pathway. J Transl Med 2021;19(1):1-14. https://doi.org/10.1186/s12967-020-02683-4
  12. Guan S, Xin Y, Ding Y, Zhang Q, Han W. Ginsenoside Rg1 protects against cardiac remodeling in heart failure via SIRT1/PINK1/parkin-mediated mitophagy. Chem Biodivers 2023;20(2):e202200730.
  13. Yu T, Xu X, Wei J, Xu J, Luo W, Li A, Liang G, Wang M. Ginsenoside Rg5 alleviates Ang II-induced cardiac inflammation and remodeling by inhibiting the JNK/AP-1 pathway. Int Immunopharmacol 2023;120:110408.
  14. Hama Amin BJ, Kakamad FH, Ahmed GS, Ahmed SF, Abdulla BA, Mohammed SH, Mikael TM, Salih RQ, Ali RK, Salh AM, et al. Post COVID-19 pulmonary fibrosis; a meta-analysis study. Ann Med Surg (Lond). 2022;77:103590.
  15. An W, Kang JS, Wang Q, Kim TE. Cardiac biomarkers and COVID-19: a systematic review and meta-analysis. J Infect Public Health 2021;14(9):1191-7. https://doi.org/10.1016/j.jiph.2021.07.016
  16. Lim KH, Kang CW, Choi JY, Kim JH. Korea red ginseng induced cardioprotection against myocardial ischemia in Guinea pig. Korean J Physiol Pharmacol 2013;17(4):283.
  17. Lin CH, Lin YA, Chen SL, Hsu MC, Hsu CC. American ginseng attenuates eccentric exercise-induced muscle damage via the modulation of lipid peroxidation and inflammatory adaptation in males. Nutrients 2021;14(1):78.
  18. Lim KH, Cho JY, Kim B, Bae BS, Kim JH. Red ginseng (panax ginseng) decreases isoproterenol-induced cardiac injury via antioxidant properties in porcine. J Med Food 2014;17(1):111-8. https://doi.org/10.1089/jmf.2013.2768
  19. Jang YJ, Lee D, Hossain MA, Aravinthan A, Kang CW, Kim NS, Kim JH. Korean Red Ginseng enhances cardiac hemodynamics on doxorubicin-induced toxicity in rats. J Ginseng Res 2020;44(3):483-9. https://doi.org/10.1016/j.jgr.2019.03.002
  20. Tong-Minh K, van der Does Y, Engelen S, de Jong E, Ramakers C, Gommers D, van Gorp E, Endeman H. High procalcitonin levels associated with increased intensive care unit admission and mortality in patients with a COVID-19 infection in the emergency department. BMC Infect Dis 2022;22(1):1-9. https://doi.org/10.1186/s12879-021-07004-8
  21. Ali N. Elevated level of C-reactive protein may be an early marker to predict risk for severity of COVID-19. J Med Virol 2020;92(11):2409-11. https://doi.org/10.1002/jmv.26097
  22. Fazal M. C-reactive protein a promising biomarker of COVID-19 severity. The Korean J Clin Lab Sci 2021;53(3):201-7. https://doi.org/10.15324/kjcls.2021.53.3.201
  23. Saboori S, Falahi E, Yousefi Rad E, Asbaghi O, Khosroshahi MZ. Effects of ginseng on C-reactive protein level: a systematic review and meta-analysis of clinical trials. Complement Ther Med 2019;45:98-103. https://doi.org/10.1016/j.ctim.2019.05.021
  24. Jung S-J, Hwang J-H, Park S-H, Choi E-K, Ha K-C, Baek H-I, Shin D-G, Seo J-H, Chae S-W. A 12-week, randomized, double-blind study to evaluate the efficacy and safety of liver function after using fermented ginseng powder (GBCK25). Food Nutr Res 2020;64(0).
  25. Sutanto YS, Reviono R, Aphridasari J, Ramlie A, Kurniawan H. The effect of ginsenoside 4% on inflammation, bacteremia and clinical improvement in community acquired pneumonia patients. SRP 2021;12(1):686-91.
  26. Estaki M, Noble EG. North American ginseng protects against muscle damage and reduces neutrophil infiltration after an acute bout of downhill running in rats. Appl Physiol Nutr Metab 2015;40(2):116-21. https://doi.org/10.1139/apnm-2014-0331
  27. Lin HF, Tung K, Chou CC, Lin CC, Lin JG, Tanaka H. Panax ginseng and salvia miltiorrhiza supplementation abolishes eccentric exercise-induced vascular stiffening: a double-blind randomized control trial. BMC Complement Altern Med 2016;16(1):1-10. https://doi.org/10.1186/s12906-016-1139-4
  28. Shi L, Fu W, Xu H, Li S, Yang X, Yang W, Sui D, Wang Q. Ginsenoside Rc attenuates myocardial ischaemic injury through antioxidative and anti-inflammatory effects. Pharm Biol 2022;60(1):1038-46. https://doi.org/10.1080/13880209.2022.2072518
  29. Zhang Y, Ma J, Liu S, Chen C, Li Q, Qin M, Ren L. Ginsenoside F1 attenuates pirarubicin-induced cardiotoxicity by modulating Nrf2 and AKT/Bcl-2 signaling pathways. J Ginseng Res 2023;47(1):106-16. https://doi.org/10.1016/j.jgr.2022.06.002
  30. Xing JJ, Hou JG, Liu Y, Zhang RB, Jiang S, Ren S, Wang YP, Shen Q, Li W, Li XD, et al. Supplementation of saponins from leaves of panax quinquefolius mitigates cisplatin-evoked cardiotoxicity via inhibiting oxidative stress-associated inflammation and apoptosis in mice. Antioxidants (Basel) 2019;8(9):347.
  31. Wang QW, Yu XF, Xu HL, Jiang YC, Zhao XZ, Sui DY. Ginsenoside Re attenuates isoproterenol-induced myocardial injury in rats. Evid Based Complement Alternat Med 2018;2018:8637134.
  32. Xue Y, Fu W, Yu P, Li Y, Yu X, Xu H, Sui D. Ginsenoside Rc alleviates myocardial ischemia-reperfusion injury by reducing mitochondrial oxidative stress and apoptosis: role of SIRT1 activation. J Agric Food Chem 2023;71(3):1547-61. https://doi.org/10.1021/acs.jafc.2c06926
  33. Han X, Li M, Zhao Z, Zhang Y, Zhang J, Zhang X, Zhang Y, Guan S, Chu L. Mechanisms underlying the cardio-protection of total ginsenosides against myocardial ischemia in rats in vivo and in vitro: possible involvement of L-type Ca (2+) channels, contractility and Ca(2+) homeostasis. J Pharmacol Sci 2019;139(3):240-8. https://doi.org/10.1016/j.jphs.2019.02.001
  34. Xue Y, Yu X, Zhang X, Yu P, Li Y, Fu W, Yu J, Sui D. Protective effects of ginsenoside Rc against acute cold exposure-induced myocardial injury in rats. J Food Sci 2021;86(7):3252-64. https://doi.org/10.1111/1750-3841.15757
  35. Liu X, Jiang Y, Fu W, Yu X, Sui D. Combination of the ginsenosides Rb3 and Rb2 exerts protective effects against myocardial ischemia reperfusion injury in rats. Int J Mol Med 2020;45(2):519-31.
  36. Ramlie A, Reviono R, Aphridasari J. Effect of ginseng extract supplementation on procalcitonin level, neutrophil, and length of stay in patients with community acquired pneumonia. Respiratory Science 2022;3(1):25-37. https://doi.org/10.36497/respirsci.v3i1.49
  37. Oh J, Lee H, Park D, Ahn J, Shin SS, Yoon M. Ginseng and its active components ginsenosides inhibit adipogenesis in 3T3-L1 cells by regulating MMP-2 and MMP-9. Evid Based Complement Alternat Med 2012;2012:1-14. https://doi.org/10.1155/2012/265023
  38. Oh SJ, Kim K, Lim CJ. Suppressive properties of ginsenoside Rb2, a protopanaxadiol-type ginseng saponin, on reactive oxygen species and matrix metalloproteinase-2 in UV-B-irradiated human dermal keratinocytes. Biosci Biotechnol Biochem 2015;79(7):1075-81. https://doi.org/10.1080/09168451.2015.1020752
  39. Liu Z, Pan H, Zhang Y, Zheng Z, Xiao W, Hong X, Chen F, Peng X, Pei Y, Rong J, et al. Ginsenoside-Rg1 attenuates sepsis-induced cardiac dysfunction by modulating mitochondrial damage via the P2X7 receptor-mediated Akt/GSK-3beta signaling pathway. J Biochem Mol Toxicol 2022;36(1):e22885.
  40. Yang L, Chen PP, Luo M, Shi WL, Hou DS, Gao Y, Xu SF, Deng J. Inhibitory effects of total ginsenoside on bleomycin-induced pulmonary fibrosis in mice. Biomed Pharmacother 2019;114:108851.
  41. Chen Y, Zhang Y, Song W, Zhang Y, Dong X, Tan M. Ginsenoside Rh2 inhibits migration of lung cancer cells under hypoxia via mir-491. Anticancer Agents Med Chem 2019;19(13):1633-41. https://doi.org/10.2174/1871520619666190704165205
  42. Wang D, Wu C, Liu D, Zhang L, Long G, Hu G, Sun W. Ginsenoside Rg3 inhibits migration and invasion of nasopharyngeal carcinoma cells and suppresses epithelial mesenchymal transition. Biomed Res Int 2019;2019:8407683.
  43. Ramezani S, Ezzatifar F, Hojjatipour T, Hemmatzadeh M, Shabgah AG, Navashenaq JG, Aslani S, Shomali N, Arabi M, Babaie F, et al. Association of the matrix metalloproteinases (MMPs) family gene polymorphisms and the risk of coronavirus disease 2019 (COVID-19); implications of contribution for development of neurological symptoms in the COVID-19 patients. Mol Biol Rep 2022;50(1):173-83. https://doi.org/10.1007/s11033-022-07907-y
  44. Shi S, Su M, Shen G, Hu Y, Yi F, Zeng Z, Zhu P, Yang G, Zhou H, Li Q, et al. Matrix metalloproteinase 3 as a valuable marker for patients with COVID-19. J Med Virol 2021;93(1):528-32. https://doi.org/10.1002/jmv.26235
  45. Mohammadhosayni M, Sadat Mohammadi F, Ezzatifar F, Mahdavi Gorabi A, Khosrojerdi A, Aslani S, Hemmatzadeh M, Yazdani S, Arabi M, Marofi F, et al. Matrix metalloproteinases are involved in the development of neurological complications in patients with Coronavirus disease 2019. Int Immunopharmacol 2021;100:108076.
  46. Cho WH, Kim YH, Heo HJ, Kim D, Kwak TW, Kim KH, Yeo HJ. Ginsenoside ameliorated ventilator-induced lung injury in rats. J Intensive Care 2020;8(1):1-9. https://doi.org/10.1186/s40560-019-0415-z
  47. Mitra A, Rahmawati L, Lee HP, Kim SA, Han C-K, Hyun SH, Cho JY. Korean Red Ginseng water extract inhibits cadmium-induced lung injury via suppressing MAPK/ERK1/2/AP-1 pathway. J Ginseng Res 2022;46(5):690-9. https://doi.org/10.1016/j.jgr.2022.04.003
  48. Han Y, Yang DU, Huo Y, Pu J, Lee SJ, Yang DC, Kang SC. In vitro evaluation of antilung cancer and anti-COVID-19 effects using fermented black color ginseng extract. Nat Prod Commun 2021;16(9):1934578X211034387.
  49. Seo SH. Ginseng protects ACE2-transgenic mice from SARS-CoV-2 infection. Frontiers in Biosci(Landmark Ed) 2022;27(6):180.
  50. Lee CS, Lee JH, Oh M, Choi KM, Jeong MR, Park JD, Kwon DY, Ha KC, Park EO, Lee N, et al. Preventive effect of KRG for acute respiratory illness: a randomized and double-blind clinical trial. J Korean Med Sci 2012;27(12):1472-8. https://doi.org/10.3346/jkms.2012.27.12.1472
  51. Lee JH, Min DS, Lee CW, Song KH, Kim YS, Kim HP. Ginsenosides from KRG ameliorate lung inflammatory responses: inhibition of the MAPKs/NF-κB/c-Fos pathways. J Ginseng Res 2018;42(4):476-84. https://doi.org/10.1016/j.jgr.2017.05.005
  52. Lev-ari S, Starr AN, Vexler A, Kalich-Philosoph L, Yoo HS, Kwon KR, Yadgar M, Bondar E, Bar-shai A, Volovitz I, et al. Rh2-enriched Korean ginseng (Ginseng Rh2 +) inhibits tumor growth and development of metastasis of non-small cell lung cancer. Food Funct 2021;12(17):8068-77. https://doi.org/10.1039/D1FO00643F
  53. Kim H, Choi P, Kim T, Kim Y, Song BG, Park YT, Choi SJ, Yoon CH, Lim WC, Ko H, et al. Ginsenosides Rk1 and Rg5 inhibit transforming growth factor-β1-induced epithelial-mesenchymal transition and suppress migration, invasion, anoikis resistance, and development of stem-like features in lung cancer. J Ginseng Res 2021;45(1):134-48. https://doi.org/10.1016/j.jgr.2020.02.005
  54. Wang D, Lv L, Xu Y, Jiang K, Chen F, Qian J, Chen M, Liu G, Xiang Y. Cardioprotection of Panax Notoginseng saponins against acute MI and heart failure through inducing autophagy. Biomed Pharmacother 2021;136:111287.
  55. Wan S, Cui Z, Wu L, Zhang F, Liu T, Hu J, Tian J, Yu B, Liu F, Kou J, et al. Ginsenoside Rd promotes omentin secretion in adipose through TBK1-AMPK to improve mitochondrial biogenesis via WNT5A/Ca(2+) pathways in heart failure. Redox Biol 2023;60:102610.
  56. Cao Y, Li Q, Yang Y, Ke Z, Chen S, Li M, Fan W, Wu H, Yuan J, Wang Z, et al. Cardioprotective effect of stem-leaf saponins from panax notoginseng on mice with sleep deprivation by inhibiting abnormal autophagy through PI3K/Akt/mTOR pathway. Front Cardiovasc Med 2021;8:694219.
  57. Li CY, Yang P, Jiang YL, Lin Z, Pu YW, Xie LQ, Sun L, Lu D. Ginsenoside Rb1 attenuates cardiomyocyte apoptosis induced by myocardial ischemia reperfusion injury through mTOR signal pathway. Biomed Pharmacother 2020;125:109913.
  58. Wu Q, Wang R, Shi Y, Li W, Li M, Chen P, Pan B, Wang Q, Li C, Wang J, et al. Synthesis and biological evaluation of panaxatriol derivatives against myocardial ischemia/reperfusion injury in the rat. Eur J Med Chem 2020;185:111729.
  59. Sato K, White N, Fanning JP, Obonyo N, Yamashita MH, Appadurai V, Ciullo A, May M, Worku ET, Helms L, et al. Impact of renin-angiotensin-aldosterone system inhibition on mortality in critically ill COVID-19 patients with pre-existing hypertension: a prospective cohort study. BMC Cardiovasc Disord 2022;22(1):1-12. https://doi.org/10.1186/s12872-021-02434-3
  60. Rysz S, Al-Saadi J, Sjostrom A, Farm M, Campoccia Jalde F, Platten M, Eriksson H, Klein M, Vargas-Paris R, Nyren S, et al. COVID-19 pathophysiology may be driven by an imbalance in the renin-angiotensin-aldosterone system. Nat Commun 2021;12(1):2417.
  61. Lee KH, Bae IY, Park SI, Park J-D, Lee HG. Antihypertensive effect of KRG by enrichment of ginsenoside Rg3 and arginine-fructose. J Ginseng Res 2016;40(3):237-44. https://doi.org/10.1016/j.jgr.2015.08.002
  62. Huang Q, Su J, Xu J, Yu H, Jin X, Wang Y, Yan M, Yu J, Chen S, Wang Y, et al. Beneficial effects of Panax notoginseng (Burkill) F. H. Chen flower saponins in rats with metabolic hypertension by inhibiting the activation of the renin-angiotensin-aldosterone system through complement 3. BMC Complement Med Ther 2023;23(1):13.
  63. Salama A, Mansour D, Hegazy R. The cardio and renoprotective role of ginseng against epinephrine-induced MI in rats: involvement of angiotensin II type 1 receptor/protein kinase C. Toxicol Reps 2021;8:908-19. https://doi.org/10.1016/j.toxrep.2021.04.008
  64. Liu J, Liu Y, Lin H, Zhou B, Yu H, Li L, Wang C, Li X, Li P, Liu J, et al. The effect of ginsenoside Rg5, isolated from black ginseng, on heart failure in zebrafish based on untargeted metabolomics. J Funct Foods 2021;76:104325.
  65. Cusato J, Manca A, Palermiti A, Mula J, Costanzo M, Antonucci M, Trunfio M, Corcione S, Chiara F, De Vivo ED, et al. COVID-19: a possible contribution of the MAPK pathway. Biomedicines 2023;11(5):1459.
  66. Grimes JM, Grimes KV. p38 MAPK inhibition: a promising therapeutic approach for COVID-19. J Mol Cell Cardiol 2020;144:63-5. https://doi.org/10.1016/j.yjmcc.2020.05.007
  67. Goel S, Saheb Sharif-Askari F, Saheb Sharif Askari N, Madkhana B, Alwaa AM, Mahboub B, Zakeri AM, Ratemi E, Hamoudi R, Hamid Q, et al. SARS-CoV-2 switches 'on' MAPK and NFκB signaling via the reduction of nuclear DUSP1 and DUSP5 expression. Front Pharmacol 2021;12:631879.
  68. Yang S, Li F, Lu S, Ren L, Bian S, Liu M, Zhao D, Wang S, Wang J. Ginseng root extract attenuates inflammation by inhibiting the MAPK/NF-κB signaling pathway and activating autophagy and p62-Nrf2-Keap1 signaling in vitro and in vivo. J Ethnopharmacol 2022;283:114739.
  69. Xin C, Quan H, Kim JM, Hur YH, Shin JY, Bae HB, Choi JI. Ginsenoside Rb1 increases macrophage phagocytosis through p38 mitogen-activated protein kinase/ Akt pathway. J Ginseng Res 2019;43(3):394-401. https://doi.org/10.1016/j.jgr.2018.05.003
  70. Saba E, Jeon BR, Jeong DH, Lee K, Goo YK, Kwak D, Kim S, Roh SS, Kim SD, Nah SY, et al. A novel KRG compound gintonin inhibited inflammation by MAPK and NF-kappaB pathways and recovered the levels of mir-34a and mir-93 in RAW 264.7 cells. Evid Based Complement Alternat Med 2015;2015:624132.
  71. Fattahi S, Khalifehzadeh-Esfahani Z, Mohammad-Rezaei M, Mafi S, Jafarinia M. PI3K/Akt/mTOR pathway: a potential target for anti-SARS-CoV-2 therapy. Immunol Res 2022;70(3):269-75. https://doi.org/10.1007/s12026-022-09268-x
  72. Al-Qahtani AA, Pantazi I, Alhamlan FS, Alothaid H, Matou-Nasri S, Sourvinos G, Vergadi E, Tsatsanis C. SARS-CoV-2 modulates inflammatory responses of alveolar epithelial type II cells via PI3K/AKT pathway. Front Immunol 2022;13:1020624.
  73. Pelzl L, Singh A, Funk J, Witzemann A, Zlamal J, Marini I, Weich K, AbouKhalel W, Hammer S, Uzun G, et al. Platelet activation via PI3K/AKT signaling pathway in COVID-19 [abstract]. Res Pract Thromb Haemost 2021;5.
  74. Han SY, Kim J, Kim E, Kim SH, Seo DB, Kim J-H, Shin SS, Cho JY. AKT-targeted anti-inflammatory activity of Panax ginseng calyx ethanolic extract. J Ginseng Res 2018;42(4):496-503. https://doi.org/10.1016/j.jgr.2017.06.003
  75. Byun BH, Cho TH, Park KM. Inhibition of mTOR signaling pathway by aqueous extract of Siberian ginseng. J Korean Med 2017;38(2):7-14. https://doi.org/10.13048/jkm.17013
  76. Kwon HW, Shin JH, Cho HJ, Rhee MH, Park HJ. Total saponin from Korean Red Ginseng inhibits binding of adhesive proteins to glycoprotein IIb/IIIa via phosphorylation of VASP (Ser(157)) and dephosphorylation of PI3K and Akt. J Ginseng Res 2016;40(1):76-85. https://doi.org/10.1016/j.jgr.2015.05.004
  77. Xing Jj, Hou Jg, Ma Zn, Wang Z, Ren S, Wang Yp, Liu Wc, Chen C, Li W. Ginsenoside Rb3 provides protective effects against cisplatin-induced nephrotoxicity via regulation of AMPK-/mTOR-mediated autophagy and inhibition of apoptosis in vitro and in vivo. Cell Prolif 2019;52(4):e12627.
  78. Zheng X, Wang S, Zou X, Jing Y, Yang R, Li S, Wang F. Ginsenoside Rb1 improves cardiac function and remodeling in heart failure. Exp Anim 2017 Aug 5;66(3):217-28. https://doi.org/10.1538/expanim.16-0121
  79. Jiang Y, Li M, Lu Z, Wang Y, Yu X, Sui D, Fu L. Ginsenoside Rg3 induces ginsenoside Rb1-comparable cardioprotective effects independent of reducing blood pressure in spontaneously hypertensive rats. Exp Ther Med 2017;14(5):4977-85. https://doi.org/10.3892/etm.2017.5198
  80. Li H, Cui L, Liu Q, Dou S, Wang W, Xie M, Xu X, Zheng C, Li T, Huang S, et al. Ginsenoside Rb3 alleviates CSE-induced TROP2 upregulation through p38 MAPK and NF-kappaB pathways in basal cells. Am J Respir Cell Mol Biol 2021;64(6):747-59. https://doi.org/10.1165/rcmb.2020-0208OC
  81. Li H, Zhu J, Xu YW, Mou FF, Shan XL, Wang QL, Liu BN, Ning K, Liu JJ, Wang YC, et al. Notoginsenoside R1-loaded mesoporous silica nanoparticles targeting the site of injury through inflammatory cells improves heart repair after MI. Redox Biol 2022;54:102384.
  82. Wang H, Wu W, Wang G, Xu W, Zhang F, Wu B, Tian Y. Protective effect of ginsenoside Rg3 on lung injury in diabetic rats. J Cell Biochem 2019;120(3):3323-30. https://doi.org/10.1002/jcb.27601
  83. Oh JM, Chun S. Ginsenoside CK inhibits the early stage of adipogenesis via the AMPK, MAPK, and AKT signaling pathways. Antioxidants (Basel) 2022;11(10):1890.
  84. Shaukat A, Guo YF, Jiang K, Zhao G, Wu H, Zhang T, Yang Y, Guo S, Yang C, Zahoor A, et al. Ginsenoside Rb1 ameliorates Staphylococcus aureus-induced Acute Lung Injury through attenuating NF-kappaB and MAPK activation. Microb Pathog 2019;132:302-12. https://doi.org/10.1016/j.micpath.2019.05.003
  85. Jin Y, Tangchang W, Kwon OS, Lee JY, Heo KS, Son HY. Ginsenoside Rh1 ameliorates the asthma and allergic inflammation via inhibiting Akt, MAPK, and NF-kappaB signaling pathways in vitro and in vivo. Life Sci 2023;321:121607.
  86. Qin GW, Lu P, Peng L, Jiang W. Ginsenoside Rb1 inhibits cardiomyocyte autophagy via PI3K/Akt/mTOR signaling pathway and reduces myocardial ischemia/ reperfusion injury. Am J Chin Med 2021;49(8):1913-27. https://doi.org/10.1142/S0192415X21500907
  87. Chen P, Li X, Yu X, Yang M. Ginsenoside Rg1 suppresses non-small-cell lung cancer via MicroRNA-126-PI3K-AKT-mTOR pathway. Evid Based Complement Alternat Med 2022;2022:1244836.
  88. Zhao T, Wang X, Liu Q, Yang T, Qu H, Zhou H. Ginsenoside Rd promotes cardiac repair after MI by modulating monocytes/macrophages subsets conversion. Drug Des Devel Ther 2022;16:2767-82. https://doi.org/10.2147/DDDT.S377624
  89. Tian G, Li J, Zhou L. Ginsenoside Rg1 regulates autophagy and endoplasmic reticulum stress via the AMPK/mTOR and PERK/ATF4/CHOP pathways to alleviate alcohol-induced myocardial injury. Int J Mol Med 2023;52(1):1-11. https://doi.org/10.3892/ijmm.2023.5259
  90. Fachrurrodji F, Sidharta BRA, Ariningrum D, Suparyatmo J, Pramudianti MD. The effect of ginseng extract on serum interleukin-6 levels in patients with communityacquired pneumonia [Internet] Indonesian J. Clin. Pathol. Med. Lab. 2022 Sep. 19; 28(3):278-84 [cited 2023 Jul. 4].
  91. 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 Complement Med Ther 2020;20(1):1-9. https://doi.org/10.1186/s12906-019-2780-5
  92. Jung JH, Kang TK, Oh JH, Jeong JU, Ko KP, Kim ST. The effect of KRG on symptoms and inflammation in patients with allergic rhinitis. Ear Nose Throat J 2021;100(5_suppl). 712S-9S. https://doi.org/10.1177/0145561320907172
  93. Kim JK, Shin KK, Kim H, Hong YH, Choi W, Kwak Y-S, Han C-K, Hyun SH, Cho JY. Korean Red Ginseng exerts anti-inflammatory and autophagy-promoting activities in aged mice. J Ginseng Res 2021;45(6):717-25. https://doi.org/10.1016/j.jgr.2021.03.009
  94. Lee JS, Ko EJ, Hwang HS, Lee YN, Kwon YM, Kim MC, Kang SM. Antiviral activity of ginseng extract against respiratory syncytial virus infection. Int J Mol Med 2014; 34(1):183-90. https://doi.org/10.3892/ijmm.2014.1750
  95. Paik S, Choe JH, Choi G-E, Kim J-E, Kim J-M, Song GY, Jo E-K. Rg6, a rare ginsenoside, inhibits systemic inflammation through the induction of interleukin10 and microRNA-146a. Sci Rep 2019;9(1):4342.
  96. Chen T, Xiao L, Zhu L, Ma S, Yan T, Ji H. Anti-asthmatic effects of ginsenoside Rb1 in a mouse model of allergic asthma through relegating Th1/Th2. Inflammation 2015;38(5):1814-22. https://doi.org/10.1007/s10753-015-0159-4
  97. Coomes EA, Haghbayan H. Interleukin-6 in Covid-19: a systematic review and meta-analysis. Rev Med Virol 2020;30(6):1-9. https://doi.org/10.1002/rmv.2141
  98. Yin JX, Agbana YL, Sun ZS, Fei SW, Zhao HQ, Zhou XN, Chen JH, Kassegne K. Increased interleukin-6 is associated with long COVID-19: a systematic review and meta-analysis. Infect Dis Poverty 2023;12(1):43.
  99. Sabaka P, Koscalova A, Straka I, Hodosy J, Liptak R, KmotorkovaB, Kachlikova M, KusnirovaA. Role of interleukin 6 as a predictive factor for a severe course of Covid-19: retrospective data analysis of patients from a long-term care facility during Covid-19 outbreak. BMC Infect Dis 2021;21(1):1-8. https://doi.org/10.1186/s12879-020-05706-z