DOI QR코드

DOI QR Code

Korean Red Ginseng water extract inhibits cadmium-induced lung injury via suppressing MAPK/ERK1/2/AP-1 pathway

  • Mitra, Ankita (Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University) ;
  • Rahmawati, Laily (Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University) ;
  • Lee, Hwa Pyoung (Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University) ;
  • Kim, Seung A. (Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University) ;
  • Han, Chang-Kyun (R&D Headquarters, Korea Ginseng Corporation) ;
  • Hyun, Sun Hee (R&D Headquarters, Korea Ginseng Corporation) ;
  • Cho, Jae Youl (Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University)
  • Received : 2022.01.05
  • Accepted : 2022.04.18
  • Published : 2022.09.01

Abstract

Background: Few studies reported the therapeutic effect of Korean Red Ginseng (KRG) in lung inflammatory diseases. However, the anti-inflammatory role and underlying molecular in cadmium-induced lung injury have been poorly understood, directly linked to chronic lung diseases (CLDs): chronic obstructive pulmonary disease (COPD), cancer etc. Therefore, in this study we aim to investigate the therapeutic activities of water extract of KRG (KRG-WE) in mouse cadmium-induced lung injury model. Method: The anti-inflammatory roles and underlying mechanisms of KRG-WE were evaluated in vitro under cadmium-stimulated lung epithelial cells (A549) and HEK293T cell line and in vivo in cadmium-induced lung injury mouse model using semi-quantitative polymerase chain reaction (RT-PCR), quantitative real-time PCR (qPCR), luciferase assay, immunoblotting, and FACS. Results: KRG-WE strongly ameliorated the symptoms of CdSO4-induced lung injury in mice according to total cell number in bronchoalveolar lavage fluid (BALF) and severity scores as well as cytokine levels. KRG-WE significantly suppressed the upregulation of inflammatory signaling comprising mitogen-activated protein kinases (MAPK) and their upstream enzymes. In in vitro study, KRG-WE suppressed expression of interleukin (IL)-6, matrix metalloproteinase (MMP)-2, and IL-8 while promoting recovery in CdSO4-treated A549 cells. Similarly, KRG-WE reduced phosphorylation of MAPK and c-Jun/c-Fos in cadmium-exposed A549 cells. Conclusion: KRG-WE was found to attenuate symptoms of cadmium-induced lung injury and reduce the expression of inflammatory genes by suppression of MAPK/AP-1-mediated pathway.

Keywords

Acknowledgement

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (2017R1A6A1A03015642), by the Korean Socieity of Ginseng (2021), and by Korea Basic Science Institute (National research Facilities and Equipment Center) grant funded by the Ministry of Education. (grant No. 2020R1A6C101A191), Korea.

References

  1. Lee P-H, Park S, Lee Y-G, Choi S-M, An M-H, Jang A-S. The impact of environmental pollutants on barrier dysfunction in respiratory disease. Allergy Asthma Immunol Res 2021;13:850-62. https://doi.org/10.4168/aair.2021.13.6.850
  2. Healy C, Munoz-Wolf N, Strydom J, Faherty L, Williams NC, Kenny S, Donnelly SC, Cloonan SM. Nutritional immunity: the impact of metals on lung immune cells and the airway microbiome during chronic respiratory disease. Respir Res 2021;22:133. https://doi.org/10.1186/s12931-021-01722-y
  3. Kirschvink N, Vincke G, Fievez L, Onclinx C, Wirth D, Belleflamme M, Louis R, Cataldo D, Peck MJ, Gustin P. Repeated cadmium nebulizations induce pulmonary MMP-2 and MMP-9 production and emphysema in rats. Toxicology 2005;211:36-48. https://doi.org/10.1016/j.tox.2005.02.012
  4. Kc R, Shukla SD, Gautam SS, Hansbro PM, O'Toole RF. The role of environmental exposure to non-cigarette smoke in lung disease. Clin Transl Med 2018;7:39. 39.
  5. Vogelmeier CF, Criner GJ, Martinez FJ, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, Chen R, Decramer M, Fabbri LM, Frith P, Halpin DM, Lopez Varela MV, Nishimura M, Roche N, Rodriguez-Roisin R, Sin DD, Singh D, Stockley R, Vestbo J, Wedzicha JA, Agusti A. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. GOLD executive summary. Am J Respir Crit Care Med 2017;195:557-82. https://doi.org/10.1164/rccm.201701-0218PP
  6. Pan J, Plant JA, Voulvoulis N, Oates CJ, Ihlenfeld C. Cadmium levels in Europe: implications for human health. Environ Geochem Health 2010;32:1-12. https://doi.org/10.1007/s10653-009-9273-2
  7. Tang J, Xiao T, Wang S, Lei J, Zhang M, Gong Y, Li H, Ning Z, He L. High cadmium concentrations in areas with endemic fluorosis: a serious hidden toxin? Chemosphere 2009;76:300-5. https://doi.org/10.1016/j.chemosphere.2009.03.064
  8. Cormet-Boyaka E, Jolivette K, Bonnegarde-Bernard A, Rennolds J, Hassan F, Mehta P, Tridandapani S, Webster-Marketon J, Boyaka PN. An NF-kappaBindependent and Erk1/2-dependent mechanism controls CXCL8/IL-8 responses of airway epithelial cells to cadmium. Toxicol Sci 2012;125:418-29. https://doi.org/10.1093/toxsci/kfr310
  9. Jarup L, Berglund M, Elinder CG, Nordberg G, Vahter M. Health effects of cadmium exposure-a review of the literature and a risk estimate. Scand J Work Environ Health 1998;24(Suppl 1):1-51. https://doi.org/10.5271/sjweh.270
  10. Yoo JI, Kim KH, Jang HN, Seo YC, Seok KS, Hong JH, Jang M. The development of PM emission factor for small incinerators and boilers. Environ Technol 2002;23:1425-33. https://doi.org/10.1080/09593332508618447
  11. Ganguly K, Levanen B, Palmberg L, Akesson A, Linden A. Cadmium in tobacco smokers: a neglected link to lung disease? Eur Respir Rev 2018;27.
  12. Larson-Casey JL, Gu L, Fiehn O, Carter AB. Cadmium-mediated lung injury is exacerbated by the persistence of classically activated macrophages. J Biol Chem 2020;295:15754-66. https://doi.org/10.1074/jbc.RA120.013632
  13. Sundblad BM, Ji J, Levanen B, Midander K, Julander A, Larsson K, Palmberg L, Linden A. Extracellular cadmium in the bronchoalveolar space of long-term tobacco smokers with and without COPD and its association with inflammation. Int J Chronic Obstr Pulm Dis 2016;11:1005-13.
  14. Go YM, Orr M, Jones DP. Actin cytoskeleton redox proteome oxidation by cadmium. Am J Physiol Lung Cell Mol Physiol 2013;305:L831-43. https://doi.org/10.1152/ajplung.00203.2013
  15. Go YM, Orr M, Jones DP. Increased nuclear thioredoxin-1 potentiates cadmium-induced cytotoxicity. Toxicol Sci 2013;131:84-94. https://doi.org/10.1093/toxsci/kfs271
  16. Yun TK. Brief introduction of Panax ginseng C.A. Meyer. J Korean Med Sci 2001;16(Suppl). S3-5. https://doi.org/10.3346/jkms.2001.16.S.S3
  17. Lee SM, Bae BS, Park HW, Ahn NG, Cho BG, Cho YL, Kwak YS. 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
  18. Youn SH, Lee SM, Han C-K, In G, Park C-K, Hyun SH. Immune activity of polysaccharide fractions isolated from Korean red ginseng. Molecules 2020;25:3569. https://doi.org/10.3390/molecules25163569
  19. 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 autophagypromoting activities in aged mice. Journal of Ginseng Research 2021;45: 717-25. https://doi.org/10.1016/j.jgr.2021.03.009
  20. Skoner DP. Allergic rhinitis: definition, epidemiology, pathophysiology, detection, and diagnosis. J Allergy Clin Immunol 2001;108:S2-8. https://doi.org/10.1067/mai.2001.115569
  21. Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE. siRNA directed against c-Src enhances pancreatic adenocarcinoma cell gemcitabine chemosensitivity. J Am Coll Surg 2004;198:953-9. https://doi.org/10.1016/j.jamcollsurg.2004.01.037
  22. Shin SJ, Jeon SG, Kim JI, Jeong YO, Kim S, Park YH, Lee SK, Park HH, Hong SB, Oh S, Hwang JY, Kim HS, Park H, Nam Y, Lee YY, Kim JJ, Park SH, Kim JS, Moon M. Red ginseng attenuates ab-induced mitochondrial dysfunction and ab-mediated pathology in an animal model of alzheimer's disease. Int J Mol Sci 2019;20.
  23. Park HW, In G, Han ST, Lee MW, Kim SY, Kim KT, Cho BG, Han GH, Chang IM. Simultaneous determination of 30 ginsenosides in Panax ginseng preparations using ultra performance liquid chromatography. J Ginseng Res 2013;37: 457-67. https://doi.org/10.5142/jgr.2013.37.457
  24. Kim S-J, Choi S, Kim M, Park C, Kim G-L, Lee S-O, Kang W, Rhee D-K. Effect of Korean Red Ginseng extracts on drug-drug interactions. Journal of Ginseng Research 2018;42:370-8. https://doi.org/10.1016/j.jgr.2017.08.008
  25. Lim CY, Moon JM, Kim BY, Lim SH, Lee GS, Yu HS, Cho SI. Comparative study of Korean White Ginseng and Korean Red Ginseng on efficacies of OVA-induced asthma model in mice. J Ginseng Res 2015;39:38-45. https://doi.org/10.1016/j.jgr.2014.07.004
  26. Zhang W, Zhi J, Cui Y, Zhang F, Habyarimana A, Cambier C, Gustin P. Potentiated interaction between ineffective doses of budesonide and formoterol to control the inhaled cadmium-induced up-regulation of metalloproteinases and acute pulmonary inflammation in rats. PLoS One 2014;9:e109136. https://doi.org/10.1371/journal.pone.0109136
  27. Wu ZH, Lin C, Liu MM, Zhang J, Tao ZH, Hu XC. Src inhibition can synergize with gemcitabine and reverse resistance in triple negative breast cancer cells via the AKT/c-Jun pathway. PLoS One 2016;11:e0169230. https://doi.org/10.1371/journal.pone.0169230
  28. Gerlier D, Thomasset N. Use of MTT colorimetric assay to measure cell activation. J Immunol Methods 1986;94:57-63. https://doi.org/10.1016/0022-1759(86)90215-2
  29. Choi E, Kim E, Kim JH, Yoon K, Kim S, Lee J, Cho JY. AKT1-targeted proapoptotic activity of compound K in human breast cancer cells. J Ginseng Res 2019;43:692-8. https://doi.org/10.1016/j.jgr.2019.07.001
  30. Lee YG, Chain BM, Cho JY. Distinct role of spleen tyrosine kinase in the early phosphorylation of inhibitor of kappaB alpha via activation of the phosphoinositide-3-kinase and Akt pathways. Int J Biochem Cell Biol 2009;41:811-21. https://doi.org/10.1016/j.biocel.2008.08.011
  31. Gao Y, Zhu LH, Guo J, Yuan T, Wang LQ, Li H, Chen LX. Farnesyl phenolic enantiomers as natural MTH1 inhibitors from Ganoderma sinense. Oncotarget 2017;8:95865-79. https://doi.org/10.18632/oncotarget.21430
  32. Kimura K, Nakano Y, Sugizaki T, Shimoda M, Kobayashi N, Kawahara M, Tanaka KI. Protective effect of polaprezinc on cadmium-induced injury of lung epithelium. Metallomics 2019;11:1310-20. https://doi.org/10.1039/c9mt00060g
  33. Lag M, Westly S, Lerstad T, Bjornsrud C, Refsnes M, Schwarze PE. Cadmiuminduced apoptosis of primary epithelial lung cells: involvement of Bax and p53, but not of oxidative stress. Cell Biol Toxicol 2002;18:29-42. https://doi.org/10.1023/A:1014467112463
  34. Refsnes M, Skuland T, Lag M, Schwarze PE, Ovrevik J. Differential NF-kB and MAPK activation underlies fluoride- and TPA-mediated CXCL8 (IL-8) induction in lung epithelial cells. J Inflamm Res 2014;7:169-85.
  35. Hossen MJ, Kim MY, Cho JY. MAPK/AP-1-Targeted anti-inflammatory activities of Xanthium strumarium. Am J Chin Med 2016;44:1111-25. https://doi.org/10.1142/S0192415X16500622
  36. Bilia AR, Bergonzi MC. The G115 standardized ginseng extract: an example for safety, efficacy, and quality of an herbal medicine. Journal of Ginseng Research 2020;44:179-93. https://doi.org/10.1016/j.jgr.2019.06.003
  37. Wu L, Zhang AL, Di YM, Shergis JL, Chen Y, Guo X, Wen Z, Thien F, Worsnop C, Lin L, Xue CC. Panax ginseng therapy for chronic obstructive pulmonary disease: a clinical trial protocol and pilot study. Chin Med 2014;9:20. https://doi.org/10.1186/1749-8546-9-20
  38. Lee JH, Min DS, Lee CW, Song KH, Kim YS, Kim HP. Ginsenosides from Korean Red Ginseng ameliorate lung inflammatory responses: inhibition of the MAPKs/NF-kB/c-Fos pathways. J Ginseng Res 2018;42:476-84. https://doi.org/10.1016/j.jgr.2017.05.005
  39. Song H, Lee YY, Park J, Lee Y. Korean Red Ginseng suppresses bisphenol Ainduced expression of cyclooxygenase-2 and cellular migration of A549 human lung cancer cell through inhibition of reactive oxygen species. Journal of Ginseng Research 2021;45:119-25. https://doi.org/10.1016/j.jgr.2020.01.002
  40. Kim SJ, Kwak HJ, Kim DS, Choi HM, Sim JE, Kim SH, Um JY, Hong SH. Protective mechanism of Korean Red Ginseng in cisplatin-induced ototoxicity through attenuation of nuclear factor-kB and caspase-1 activation. Mol Med Rep 2015;12:315-22. https://doi.org/10.3892/mmr.2015.3396
  41. Yang Y, Yang WS, Yu T, Yi YS, Park JG, Jeong D, Kim JH, Oh JS, Yoon K, Kim JH, Cho JY. Novel anti-inflammatory function of NSC95397 by the suppression of multiple kinases. Biochem Pharmacol 2014;88:201-15.
  42. Yang Y, Lee J, Rhee MH, Yu T, Baek KS, Sung NY, Kim Y, Yoon K, Kim JH, Kwak YS, Hong S, Kim JH, Cho JY. Molecular mechanism of protopanaxadiol saponin fraction-mediated anti-inflammatory actions. J Ginseng Res 2015;39: 61-8. https://doi.org/10.1016/j.jgr.2014.06.002
  43. Troutman TD, Bazan JF, Pasare C. Toll-like receptors, signaling adapters and regulation of the pro-inflammatory response by PI3K. Cell Cycle 2012;11: 3559-67. https://doi.org/10.4161/cc.21572
  44. Song SY, Bae CH, Choi YS, Kim YD. Cadmium induces mucin 8 expression via Toll-like receptor 4-mediated extracellular signal related kinase 1/2 and p38 mitogen-activated protein kinase in human airway epithelial cells. Int Forum Allergy Rhinol 2016;6:638-45. https://doi.org/10.1002/alr.21705
  45. Ding Q, Zhu W, Diao Y, Xu G, Wang L, Qu S, Shi Y. Elucidation of the mechanism of action of ginseng against acute lung injury/acute respiratory distress syndrome by a network pharmacology-based strategy. Front Pharmacol 2021:11.