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The safety, immunological benefits, and efficacy of ginseng in organ transplantation

  • Lim, Sun Woo (Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The College of Medicine, The Catholic University of Korea) ;
  • Luo, Kang (Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The College of Medicine, The Catholic University of Korea) ;
  • Quan, Yi (Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The College of Medicine, The Catholic University of Korea) ;
  • Cui, Sheng (Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The College of Medicine, The Catholic University of Korea) ;
  • Shin, Yoo Jin (Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The College of Medicine, The Catholic University of Korea) ;
  • Ko, Eun Jeong (Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The College of Medicine, The Catholic University of Korea) ;
  • Chung, Byung Ha (Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The College of Medicine, The Catholic University of Korea) ;
  • Yang, Chul Woo (Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The College of Medicine, The Catholic University of Korea)
  • 투고 : 2019.08.19
  • 심사 : 2020.02.03
  • 발행 : 2020.05.15

초록

Korean ginseng (Panax ginseng) is associated with a variety of therapeutic effects, including antioxidative, anti-inflammatory, vasorelaxative, antiallergic, antidiabetic, and anticancer effects. Accordingly, the use of ginseng has reached an all-time high among members of the general public. However, the safety and efficacy of ginseng in transplant recipients receiving immunosuppressant drugs have still not been elucidated. Transplantation is the most challenging and complex of surgical procedures and may require causation for the use of ginseng. In this regard, we have previously examined the safety, immunological benefits, and protective mechanisms of ginseng with respect to calcineurin inhibitor-based immunosuppression, which is the most widely used regimen in organ transplantation. Using an experimental model of calcineurin inhibitor-induced organ injury, we found that ginseng does not affect drug levels in the peripheral blood and tissue, favorably regulates immune response, and protects against calcineurin inhibitor-induced nephrotoxicity and pancreatic islet injury. On the basis of our experimental studies and a review of the related literature, we propose that ginseng may provide benefits in organ transplant recipients administered calcineurin inhibitors. Through the present review, we aimed to briefly discuss our current understanding of the therapeutic benefits of ginseng related to transplant patient survival.

키워드

참고문헌

  1. Colzani M, Altomare A, Caliendo M, Aldini G, Righetti PG, Fasoli E. The secrets of Oriental panacea: panax ginseng. J Proteomics 2016;130:150-9. https://doi.org/10.1016/j.jprot.2015.09.023
  2. Rastogi V, Santiago-Moreno J, Dore S. Ginseng: a promising neuroprotective strategy in stroke. Front Cell Neurosci 2014;8:457. https://doi.org/10.3389/fncel.2014.00457
  3. Karmazyn M, Moey M, Gan XT. Therapeutic potential of ginseng in the management of cardiovascular disorders. Drugs 2011;71:1989-2008. https://doi.org/10.2165/11594300-000000000-00000
  4. Sun Y, Guo M, Feng Y, Zheng H, Lei P, Ma X, Han X, Guan H, Hou D. Effect of ginseng polysaccharides on NK cell cytotoxicity in immunosuppressed mice. Exp Ther Med 2016;12:3773-7. https://doi.org/10.3892/etm.2016.3840
  5. Kim YR, Yang CS. Protective roles of ginseng against bacterial infection. Microb Cell 2018;5:472-81. https://doi.org/10.15698/mic2018.11.654
  6. Jie YH, Cammisuli S, Baggiolini M. Immunomodulatory effects of panax Ginseng C.A. Meyer in the mouse. Agents Actions 1984;15:386-91. https://doi.org/10.1007/bf01972376
  7. Scaglione F, Ferrara F, Dugnani S, Falchi M, Santoro G, Fraschini F. Immunomodulatory effects of two extracts of Panax ginseng C.A. Meyer. Drugs Exp Clin Res 1990;16:537-42.
  8. Choi KT. Botanical characteristics, pharmacological effects and medicinal components of Korean Panax ginseng C A Meyer. Acta Pharmacol Sin 2008;29:1109-18. https://doi.org/10.1111/j.1745-7254.2008.00869.x
  9. Kitts D, Hu C. Efficacy and safety of ginseng. Public Health Nutr 2000;3:473-85. https://doi.org/10.1017/S1368980000000550
  10. Su Q, Weber L, Le Hir M, Zenke G, Ryffel B. Nephrotoxicity of cyclosporin A and FK506: inhibition of calcineurin phosphatase. Ren Physiol Biochem 1995;18:128-39.
  11. Halloran PF, Helms LM, Kung L, Noujaim J. The temporal profile of calcineurin inhibition by cyclosporine in vivo. Transplantation 1999;68:1356-61. https://doi.org/10.1097/00007890-199911150-00023
  12. Kung L, Batiuk TD, Palomo-Pinon S, Noujaim J, Helms LM, Halloran PF. Tissue distribution of calcineurin and its sensitivity to inhibition by cyclosporine. Am J Transplant 2001;1:325-33. https://doi.org/10.1034/j.1600-6143.2001.10407.x
  13. Liu EH, Siegel RM, Harlan DM, O'Shea JJ. T cell-directed therapies: lessons learned and future prospects. Nat Immunol 2007;8:25-30. https://doi.org/10.1038/ni1429
  14. Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 2004;4:378-83. https://doi.org/10.1111/j.1600-6143.2004.00332.x
  15. Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, Arndorfer J, Christensen L, Merion RM. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003;349:931-40. https://doi.org/10.1056/NEJMoa021744
  16. Olyaei AJ, de Mattos AM, Bennett WM. Nephrotoxicity of immunosuppressive drugs: new insight and preventive strategies. Curr Opin Crit Care 2001;7:384-9. https://doi.org/10.1097/00075198-200112000-00003
  17. Palestine AG, Austin 3rd HA, Nussenblatt RB. Renal tubular function in cyclosporine-treated patients. Am J Med 1986;81:419-24. https://doi.org/10.1016/0002-9343(86)90292-5
  18. Myers BD, Ross J, Newton L, Luetscher J, Perlroth M. Cyclosporine-associated chronic nephropathy. N Engl J Med 1984;311:699-705. https://doi.org/10.1056/NEJM198409133111103
  19. Doh KC, Lim SW, Piao SG, Jin L, Heo SB, Zheng YF, Bae SK, Hwang GH, Min KI, Chung BH, et al. Ginseng treatment attenuates chronic cyclosporine nephropathy via reducing oxidative stress in an experimental mouse model. Am J Nephrol 2013;37:421-33. https://doi.org/10.1159/000349921
  20. Lim SW, Doh KC, Jin L, Piao SG, Heo SB, Zheng YF, Bae SK, Chung BH, Yang CW. Oral administration of ginseng ameliorates cyclosporine-induced pancreatic injury in an experimental mouse model. PLoS One 2013;8:e72685. https://doi.org/10.1371/journal.pone.0072685
  21. Heo SB, Lim SW, Jhun JY, Cho ML, Chung BH, Yang CW. Immunological benefits by ginseng through reciprocal regulation of Th17 and Treg cells during cyclosporine-induced immunosuppression. J Ginseng Res 2016;40:18-27. https://doi.org/10.1016/j.jgr.2015.04.005
  22. Lim SW, Doh KC, Jin L, Jin J, Piao SG, Heo SB, Chung BH, Yang CW. Ginseng treatment attenuates autophagic cell death in chronic cyclosporine nephropathy. Nephrology (Carlton) 2014;19:490-9. https://doi.org/10.1111/nep.12273
  23. Seifeldin R. Drug interactions in transplantation. Clin Ther 1995;17:1043-61. https://doi.org/10.1016/0149-2918(95)80084-0
  24. Saeki T, Ueda K, Tanigawara Y, Hori R, Komano T. Human P-glycoprotein transports cyclosporin A and FK506. J Biol Chem 1993;268:6077-80. https://doi.org/10.1016/S0021-9258(18)53221-X
  25. Ramanathan MR, Penzak SR. Pharmacokinetic drug interactions with panax ginseng. Eur J Drug Metab Pharmacokinet 2017;42:545-57. https://doi.org/10.1007/s13318-016-0387-5
  26. He N, Edeki T. The inhibitory effects of herbal components on CYP2C9 and CYP3A4 catalytic activities in human liver microsomes. Am J Ther 2004;11:206-12. https://doi.org/10.1097/00045391-200405000-00009
  27. Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Cui Y, Ang CY. Clinical assessment of effects of botanical supplementation on cytochrome P450 phenotypes in the elderly: St John's wort, garlic oil, Panax ginseng and Ginkgo biloba. Drugs Aging 2005;22:525-39. https://doi.org/10.2165/00002512-200522060-00006
  28. Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Cui Y, Ang CY. Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans. Clin Pharmacol Ther 2002;72:276-87. https://doi.org/10.1067/mcp.2002.126913
  29. Calvo-Turrubiartes M, Romano-Moreno S, Garcia-Hernandez M, Chevaile-Ramos JA, Layseca-Espinosa E, Gonzalez-Amaro R, Portales-Perez D. Quantitative analysis of regulatory T cells in kidney graft recipients: a relationship with calcineurin inhibitor level. Transpl Immunol 2009;21:43-9. https://doi.org/10.1016/j.trim.2009.02.002
  30. Warrens AN. Pharmacological control of the immune response in renal transplantation. BJU Int 2002;90:784-91. https://doi.org/10.1046/j.1464-410X.2002.03006.x
  31. Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004;351:2715-29. https://doi.org/10.1056/NEJMra033540
  32. Chang JY, Yu J, Chung BH, Yang J, Kim SJ, Kim CD, Lee SH, Lee JS, Kim JK, Jung CW, et al. Immunosuppressant prescription pattern and trend in kidney transplantation: a multicenter study in Korea. PLoS One 2017;12:e0183826. https://doi.org/10.1371/journal.pone.0183826
  33. Hariharan S, Alexander JW, Schroeder TJ, First MR. Outcome of cadaveric renal transplantation by induction treatment in the cyclosporine era. Clin Transplant 1996;10:186-90.
  34. Hariharan S, McBride MA, Cherikh WS, Tolleris CB, Bresnahan BA, Johnson CP. Post-transplant renal function in the first year predicts long-term kidney transplant survival. Kidney Int 2002;62:311-8. https://doi.org/10.1046/j.1523-1755.2002.00424.x
  35. Pascual M, Theruvath T, Kawai T, Tolkoff-Rubin N, Cosimi AB. Strategies to improve long-term outcomes after renal transplantation. N Engl J Med 2002;346:580-90. https://doi.org/10.1056/NEJMra011295
  36. 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. https://doi.org/10.1016/j.imlet.2011.04.005
  37. Hwang I, Ha D, Ahn G, Park E, Joo H, Jee Y. Experimental autoimmune encephalomyelitis: association with mutual regulation of RelA (p65)/NFkappaB and phospho-IkappaB in the CNS. Biochem Biophys Res Commun 2011;411:464-70. https://doi.org/10.1016/j.bbrc.2011.06.195
  38. Oh GN, Son SW. Efficacy of Korean red ginseng in the treatment of alopecia areata. J Ginseng Res 2012;36:391-5. https://doi.org/10.5142/jgr.2012.36.4.391
  39. Zhu D, Liu M, Yang Y, Ma L, Jiang Y, Zhou L, Huang Q, Pi R, Chen X. Ginsenoside Rd ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice. J Neurosci Res 2014;92:1217-26. https://doi.org/10.1002/jnr.23397
  40. Jhun J, Lee J, Byun JK, Kim EK, Woo JW, Lee JH, Kwok SK, Ju JH, Park KS, Kim HY, et al. Red ginseng extract ameliorates autoimmune arthritis via regulation of STAT3 pathway, Th17/Treg balance, and osteoclastogenesis in mice and human. Mediators Inflamm 2014;2014:351856. https://doi.org/10.1155/2014/351856
  41. Yang XP, Ghoreschi K, Steward-Tharp SM, Rodriguez-Canales J, Zhu J, Grainger JR, Hirahara K, Sun HW, Wei L, Vahedi G, et al. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat Immunol 2011;12:247-54. https://doi.org/10.1038/ni.1995
  42. Womer KL, Vella JP, Sayegh MH. Chronic allograft dysfunction: mechanisms and new approaches to therapy. Semin Nephrol 2000;20:126-47.
  43. Nankivell BJ, Borrows RJ, Fung CL, O'Connell PJ, Allen RD, Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med 2003;349:2326-33. https://doi.org/10.1056/NEJMoa020009
  44. de Mattos AM, Olyaei AJ, Bennett WM. Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future. Am J Kidney Dis 2000;35:333-46. https://doi.org/10.1016/S0272-6386(00)70348-9
  45. Yoon HE, Yang CW. Established and newly proposed mechanisms of chronic cyclosporine nephropathy. Korean J Intern Med 2009;24:81-92. https://doi.org/10.3904/kjim.2009.24.2.81
  46. Li C, Lim SW, Sun BK, Yang CW. Chronic cyclosporine nephrotoxicity: new insights and preventive strategies. Yonsei Med J 2004;45:1004-16. https://doi.org/10.3349/ymj.2004.45.6.1004
  47. Li C, Yang CW. The pathogenesis and treatment of chronic allograft nephropathy. Nat Rev Nephrol 2009;5:513-9. https://doi.org/10.1038/nrneph.2009.113
  48. Ghee JY, Han DH, Song HK, Kim WY, Kim SH, Yoon HE, Choi BS, Kim YS, Kim J, Yang CW. The role of macrophage in the pathogenesis of chronic cyclosporineinduced nephropathy. Nephrol Dial Transplant 2008;23:4061-9. https://doi.org/10.1093/ndt/gfn388
  49. Lim SW, Hyoung BJ, Piao SG, Doh KC, Chung BH, Yang CW. Chronic cyclosporine nephropathy is characterized by excessive autophagosome formation and decreased autophagic clearance. Transplantation 2012;94:218-25. https://doi.org/10.1097/TP.0b013e31825ace5c
  50. Yang CW, Faulkner GR, Wahba IM, Christianson TA, Bagby GC, Jin DC, Abboud HE, Andoh TF, Bennett WM. Expression of apoptosis-related genes in chronic cyclosporine nephrotoxicity in mice. Am J Transplant 2002;2:391-9. https://doi.org/10.1034/j.1600-6143.2002.20501.x
  51. Lim SW, Jin L, Luo K, Jin J, Yang CW. Ginseng extract reduces tacrolimusinduced oxidative stress by modulating autophagy in pancreatic beta cells. Lab Invest 2017;97:1271-81. https://doi.org/10.1038/labinvest.2017.75
  52. Lim SW, Jin L, Jin J, Yang CW. Effect of Exendin-4 on autophagy clearance in beta cell of rats with tacrolimus-induced diabetes mellitus. Sci Rep 2016;6:29921. https://doi.org/10.1038/srep29921
  53. Muller FL, Lustgarten MS, Jang Y, Richardson A, Van Remmen H. Trends in oxidative aging theories. Free Radic Biol Med 2007;43:477-503. https://doi.org/10.1016/j.freeradbiomed.2007.03.034
  54. Wang Y, Sun Z. Current understanding of klotho. Ageing Res Rev 2009;8:43-51. https://doi.org/10.1016/j.arr.2008.10.002
  55. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997;390:45-51. https://doi.org/10.1038/36285
  56. Masuda H, Chikuda H, Suga T, Kawaguchi H, Kuro-o M. Regulation of multiple ageing-like phenotypes by inducible klotho gene expression in klotho mutant mice. Mech Ageing Dev 2005;126:1274-83. https://doi.org/10.1016/j.mad.2005.07.007
  57. Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, et al. Suppression of aging in mice by the hormone Klotho. Science 2005;309:1829-33. https://doi.org/10.1126/science.1112766
  58. Lim SW, Shin YJ, Luo K, Quan Y, Cui S, Ko EJ, Chung BH, Yang CW. Ginseng increases Klotho expression by FoxO3-mediated manganese superoxide dismutase in a mouse model of tacrolimus-induced renal injury. Aging 2019;11. Albany NY.
  59. Sharif A. Preventing and managing hyperglycemia in kidney transplant patients. Curr Opin Nephrol Hypertens 2012;21:574-9. https://doi.org/10.1097/MNH.0b013e328358d5d0
  60. Valderhaug TG, Hjelmesaeth J, Hartmann A, Roislien J, Bergrem HA, Leivestad T, Line PD, Jenssen T. The association of early post-transplant glucose levels with long-term mortality. Diabetologia 2011;54:1341-9. https://doi.org/10.1007/s00125-011-2105-9
  61. Tufton N, Ahmad S, Rolfe C, Rajkariar R, Byrne C, Chowdhury TA. New-onset diabetes after renal transplantation. Diabet Med 2014;31:1284-92. https://doi.org/10.1111/dme.12534
  62. Piao SG, Lim SW, Doh KC, Jin L, Heo SB, Zheng YF, Bae SK, Chung BH, Li C, Yang CW. Combined treatment of tacrolimus and everolimus increases oxidative stress by pharmacological interactions. Transplantation 2014;98:22-8.
  63. Jin J, Lim SW, Jin L, Yu JH, Kim HS, Chung BH, Yang CW. Effects of metformin on hyperglycemia in an experimental model of tacrolimus- and sirolimusinduced diabetic rats. Korean J Intern Med 2017;32:314-22. https://doi.org/10.3904/kjim.2015.394
  64. Jin J, Jin L, Luo K, Lim SW, Chung BH, Yang CW. Effect of empagliflozin on tacrolimus-induced pancreas islet dysfunction and renal injury. Am J Transplant 2017;17:2601-16. https://doi.org/10.1111/ajt.14316