Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Effects of G-Rh2 on mast cell-mediated anaphylaxis via AKT-Nrf2/NF-κB and MAPK-Nrf2/NF-κB pathways

  • Xu, Chang (Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University) ;
  • Li, Liangchang (Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University) ;
  • Wang, Chongyang (Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University) ;
  • Jiang, Jingzhi (Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University) ;
  • Li, Li (Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University) ;
  • Zhu, Lianhua (Department of Anatomy, Histology and Embryology, Medical College, Yanbian University) ;
  • Jin, Shan (Department of Anatomy, Histology and Embryology, Medical College, Yanbian University) ;
  • Jin, Zhehu (Department of Anatomy, Histology and Embryology, Medical College, Yanbian University) ;
  • Lee, Jung Joon (College of Pharmacy, Yanbian University) ;
  • Li, Guanhao (Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University) ;
  • Yan, Guanghai (Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University)
  • Received : 2020.05.11
  • Accepted : 2021.10.04
  • Published : 2022.07.01
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Abstract

Background: The effect of ginsenoside Rh2 (G-Rh2) on mast cell-mediated anaphylaxis remains unclear. Herein, we investigated the effects of G-Rh2 on OVA-induced asthmatic mice and on mast cell-mediated anaphylaxis. Methods: Asthma model was established for evaluating airway changes and ear allergy. RPMCs and RBL-2H3 were used for in vitro experiments. Calcium uptake, histamine release and degranulation were detected. ELISA and Western blot measured cytokine and protein levels, respectively. Results: G-Rh2 inhibited OVA-induced airway remodeling, the production of TNF-α, IL-4, IL-8, IL-1β and the degranulation of mast cells of asthmatic mice. G-Rh2 inhibited the activation of Syk and Lyn in lung tissue of OVA-induced asthmatic mice. G-Rh2 inhibited serum IgE production in OVA induced asthmatic mice. Furthermore, G-Rh2 reduced the ear allergy in IgE-sensitized mice. G-Rh2 decreased the ear thickness. In vitro experiments G-Rh2 significantly reduced calcium uptake and inhibited histamine release and degranulation in RPMCs. In addition, G-Rh2 reduced the production of IL-1β, TNF-α, IL-8, and IL-4 in IgE-sensitized RBL-2H3 cells. Interestingly, G-Rh2 was involved in the FcεRI pathway activation of mast cells and the transduction of the Lyn/Syk signaling pathway. G-Rh2 inhibited PI3K activity in a dose-dependent manner. By blocking the antigen-induced phosphorylation of Lyn, Syk, LAT, PLCγ2, PI3K ERK1/2 and Raf-1 expression, G-Rh2 inhibited the NF-κB, AKT-Nrf2, and p38MAPK-Nrf2 pathways. However, G-Rh2 up-regulated Keap-1 expression. Meanwhile, G-Rh2 reduced the levels of p-AKT, p38MAPK and Nrf2 in RBL-2H3 sensitized IgE cells and inhibited NF-κB signaling pathway activation by activating the AKT-Nrf2 and p38MAPK-Nrf2 pathways. Conclusion: G-Rh2 inhibits mast cell-induced allergic inflammation, which might be mediated by the AKT-Nrf2/NF-kB and p38MAPK-Nrf2/NF-κB signaling pathways.

Keywords

Acknowledgement

This work was supported by National Natural Science Foundation of China (No: 81970018, 81860729, and 82060008), and Jilin Provincial Basic Research Project of Central Guided Local Science and Technology Development Fund (No.: 202002020JC). This work was financially supported by the Higher Education Discipline Innovation Project (111 Project, D18012).

References

  1. Del Giacco SR, Bakirtas A, Bel E, Custovic A, Diamant Z, Hamelmann E, Heffler E, Kalayci O, Saglani S, Sergejeva S, et al. Allergy in severe asthma. Allergy 2017;72:207-20. https://doi.org/10.1111/all.13072
  2. Kuo CH, Collins AM, Boettner DR, Yang Y, Ono SJ. Role of CCL7 in type I hypersensitivity reactions in murine experimental allergic conjunctivitis. J Immunol 2017;198:645-56. https://doi.org/10.4049/jimmunol.1502416
  3. Liu H, Tan J, Liu J, Feng H, Pan D. Altered mast cell activity in response to rhinovirus infection provides novel insight into asthma. J Asthma 2020;57:459-67. https://doi.org/10.1080/02770903.2019.1585870
  4. Babina M, Wang Z, Franke K, Guhl S, Artuc M, Zuberbier T. Yin-yang of IL-33 in human skin mast cells: reduced degranulation, but augmented histamine synthesis through p38 activation. J Invest Dermatol 2019;139:1516-25. https://doi.org/10.1016/j.jid.2019.01.013
  5. Zhou J, Zhang C, Shang J. IL-33 promotes degranulation of mouse bone marrow-derived mast cells and release of cytokines IL-1β, IL-6 and TNF-α, vol. 32; 2016. p. 462-75. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi.
  6. Buckley MG, Williams CM, Thompson J, Pryor P, Ray K, Butterfield JH, Coleman JW. IL-4 enhances IL-3 and IL-8 gene expression in a human leukemic mast cell line. Immunology 1995;84:410-5.
  7. Furuno T, Shinkai N, Inoh Y, Nakanishi M. Impaired expression of the mitochondrial calcium uniporter suppresses mast cell degranulation. Mol Cell Biochem 2015;410:215-21. https://doi.org/10.1007/s11010-015-2554-4
  8. Mazurek N, Berger G, Pecht I. A binding site on mast cells and basophils for the anti-allergic drug cromolyn. Nature 1980;286:722-3. https://doi.org/10.1038/286722a0
  9. Mendez-Enriquez E, Hallgren J. Mast cells and their progenitors in allergic asthma. Front Immunol 2019;10:821. https://doi.org/10.3389/fimmu.2019.00821
  10. Gast M, Preisinger C, Nimmerjahn F, Huber M. IgG-independent Coaggregation of FcεRI and FcγRIIB results in LYN- and SHIP1-dependent tyrosine phosphorylation of FcγRIIB in murine bone marrow-derived mast cells. Front Immunol 2018;9:1937. https://doi.org/10.3389/fimmu.2018.01937
  11. Suurmond J, Habets KLL, Tatum Z, Schonkeren JJ, Hoen PAC, Huizinga TWJ, Laros JFJ, Toes REM, Kurreeman F. Repeated FcεRI triggering reveals modified mast cell function related to chronic allergic responses in tissue. J Allergy Clin Immunol 2016;138:869-80. https://doi.org/10.1016/j.jaci.2016.01.017
  12. Chen YC, Chang YC, Chang HA, Lin YS, Tsao CW, Shen MR, Chiu WT. Differential Ca(2+) mobilization and mast cell degranulation by FcεRI- and GPCR-mediated signaling. Cell Calcium 2017;67:31-49. https://doi.org/10.1016/j.ceca.2017.08.002
  13. Kempuraj D, Thangavel R, Selvakumar GP, Ahmed ME, Zaheer S, Raikwar SP, Zahoor H, Saeed D, Dubova I, Giler G, et al. Mast cell proteases activate astrocytes and glia-neurons and release Interleukin-33 by activating p38 and ERK1/2 MAPKs and NF-κB. Mol Neurobiol 2019;56:1681-93. https://doi.org/10.1007/s12035-018-1177-7
  14. Miao Y, Jiang M, Qi L, Yang D, Xiao W, Fang F. BCAP regulates dendritic cell maturation through the dual-regulation of NF-κB and PI3K/AKT signaling during infection. Front Immunol 2020;11:250. https://doi.org/10.3389/fimmu.2020.00250
  15. Ye J, Piao H, Jiang J, Jin G, Zheng M, Yang J, Jin X, Sun T, Choi YH, Li L, et al. Polydatin inhibits mast cell-mediated allergic inflammation by targeting PI3K/Akt, MAPK, NF-κB and Nrf2/HO-1 pathways. Sci Rep 2017;7:11895. https://doi.org/10.1038/s41598-017-12252-3
  16. Cui CH, Jeon BM, Fu Y, Im WT, Kim SC. High-density immobilization of a ginsenoside-transforming b-glucosidase for enhanced food-grade production of minor ginsenosides. Appl Microbiol Biotechnol 2019;103:7003-15. https://doi.org/10.1007/s00253-019-09951-4
  17. Gao Y, Wang T, Wang G, Li G, Sun C, Jiang Z, Yang J, Li Y, You Y, Wu X, et al. Preclinical safety of ginsenoside compound K: acute, and 26-week oral toxicity studies in mice and rats. Food Chem Toxicol 2019;131:110578. https://doi.org/10.1016/j.fct.2019.110578
  18. Kim YJ, Perumalsamy H, Castro-Aceituno V, Kim D, Markus J, Lee S, Kim S, Liu Y, Yang DC. Photoluminescent and self-assembled hyaluronic acid-zinc oxide-ginsenoside Rh2 nanoparticles and their potential caspase-9 apoptotic mechanism towards cancer cell lines. Int J Nanomed 2019;14:8195-208. https://doi.org/10.2147/IJN.S221328
  19. Li LC, Piao HM, Zheng MY, Lin ZH, Choi YH, Yan GH. Ginsenoside Rh2 attenuates allergic airway inflammation by modulating nuclear factor-κB activation in a murine model of asthma. Mol Med Rep 2015;12:6946-54. https://doi.org/10.3892/mmr.2015.4272
  20. Ko E, Park S, Lee JH, Cui CH, Hou J, Kim MH, Kim SC. Ginsenoside Rh2 ameliorates atopic dermatitis in NC/nga mice by suppressing NF-kappaB-Mediated thymic stromal lymphopoietin expression and T helper type 2 differentiation. Int J Mol Sci 2019;20:6111. https://doi.org/10.3390/ijms20246111
  21. Zhu C, Liu F, Qian W, Zhang T, Li F. Combined effect of sodium selenite and ginsenoside Rh2 on HCT116 human colorectal carcinoma cells. Arch Iran Med 2016;19:23-39.
  22. Ma J, Gao G, Lu H, Fang D, Li L, Wei G, Chen A, Yang Y, Zhang H, Huo J. Reversal effect of ginsenoside Rh2 on oxaliplatin-resistant colon cancer cells and its mechanism. Exp Ther Med 2019;18:630-46.
  23. Lv DL, Chen L, Ding W, Zhang W, Wang HL, Wang S, Liu WB. Ginsenoside G-Rh2 synergizes with SMI-4a in anti-melanoma activity through autophagic cell death. Chin Med 2018;13:11. https://doi.org/10.1186/s13020-018-0168-y
  24. Wang YS, Lin Y, Li H, Li Y, Song Z, Jin YH. The identification of molecular target of (20S) ginsenoside Rh2 for its anti-cancer activity. Sci Rep 2017;7:12408. https://doi.org/10.1038/s41598-017-12572-4
  25. Li L, Jin G, Jiang J, Zheng M, Jin Y, Lin Z, Li G, Choi Y, Yan G. Cornuside inhibits mast cell-mediated allergic response by down-regulating MAPK and NF-κB signaling pathways. Biochem Biophys Res Commun 2016;473:408-14. https://doi.org/10.1016/j.bbrc.2016.03.007
  26. 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
  27. 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
  28. Li Q, Li Y, Wang X, Fang X, He K, Guo X, Zhan Z, Sun C, Jin YH. Co-treatment with ginsenoside Rh2 and betulinic acid synergistically induces apoptosis in human cancer cells in association with enhanced capsase-8 activation, bax translocation, and cytochrome c release. Mol Carcinog 2011;50:760-9. https://doi.org/10.1002/mc.20673
  29. Lodhi RS, Nakabayashi K, Suzuki K, Yamada AY, Hazama R, Ebina Y, Yamada H. Relaxin has anti-apoptotic effects on human trophoblast-derived HTR-8/SV neo cells. Gynecol Endocrinol 2013;29:1051-64. https://doi.org/10.3109/09513590.2013.829444
  30. Khassawneh B, Tsai SC, Meltzer LJ. Polysomnographic characteristics of adolescents with asthma and low risk for sleep-disordered breathing. Sleep Breath 2019;23:943-51. https://doi.org/10.1007/s11325-018-01774-3
  31. Shou Q, Lang J, Jin L, Fang M, Cao B, Cai Y, Ni Z, Qiu F, Li C, Cao G, et al. Total glucosides of peony improve ovalbumin-induced allergic asthma by inhibiting mast cell degranulation. J Ethnopharmacol 2019;244:112136. https://doi.org/10.1016/j.jep.2019.112136
  32. She NN, Hou Y, Wang YH, Gui Y, Xi GH, Chen XW, Chen KB, Ma CX, Liu XH, Zhang XB. [Effects of 18β-sodium glycyrrhetinic acid on TNF-α expression in rats with allergic rhinitis]. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2019;33:262-76.
  33. Li Y, Mu Z, Wang H, Liu J, Jiang F. The role of particulate matters on methylation of IFN-γ and IL-4 promoter genes in pediatric allergic rhinitis. Oncotarget 2018;9:17406-19. https://doi.org/10.18632/oncotarget.24227
  34. Xiao P, Long X, Zhang L, Ye Y, Guo J, Liu P, Zhang R, Ning J, Yu W, Wei F, et al. Neurotensin/IL-8 pathway orchestrates local inflammatory response and tumor invasion by inducing M2 polarization of Tumor-Associated macrophages and epithelial-mesenchymal transition of hepatocellular carcinoma cells. OncoImmunology 2018;7:1440166.
  35. Shiratori T, Kyumoto-Nakamura Y, Kukita A, Uehara N, Zhang J, Koda K, Kamiya M, Badawy T, Tomoda E, Xu X, et al. IL-1β induces pathologically activated osteoclasts bearing extremely high levels of resorbing activity: a possible pathological subpopulation of osteoclasts, accompanied by suppressed expression of Kindlin-3 and talin-1. J Immunol 2018;200:218-28. https://doi.org/10.4049/jimmunol.1602035
  36. Kim JH, Kim AR, Kim HS, Kim HW, Park YH, You JS, Park YM, Her E, Kim HS, Kim YM, et al. Rhamnus davurica leaf extract inhibits Fyn activation by antigen in mast cells for anti-allergic activity. BMC Compl Alternative Med 2015;15:80. https://doi.org/10.1186/s12906-015-0607-6
  37. Jin Y, Zhu M, Guo Y, Foreman D, Feng F, Duan G, Wu W, Zhang W. Fine particulate matter (PM(2.5)) enhances FcεRI-mediated signaling and mast cell function. Cell Signal 2019;57:102-19. https://doi.org/10.1016/j.cellsig.2019.01.010
  38. Amin K. The role of mast cells in allergic inflammation. Respir Med 2012;106:204-7. https://doi.org/10.1016/j.rmed.2011.09.007
  39. Im YS, Lee B, Kim EY, Min JH, Song DU, Lim JM, Eom JW, Cho HJ, Sohn Y, Jung HS. Antiallergic effect of gami-hyunggyeyeongyotang on ovalbumin-induced allergic rhinitis in mouse and human mast cells. J Chin Med Assoc 2016;79:185-94. https://doi.org/10.1016/j.jcma.2015.08.012
  40. Jiang W, Hu S, Che D, An H, Liu R. A mast-cell-specific receptor mediates Iopamidol induced immediate IgE-independent anaphylactoid reactions. Int Immunopharm 2019;75:105800. https://doi.org/10.1016/j.intimp.2019.105800
  41. Che D, Hou Y, Zeng Y, Li C, Zhang Y, Wei D, Hu S, Liu R, An H, Wang Y, et al. Dehydroandrographolide inhibits IgE-mediated anaphylactic reactions via calcium signaling pathway. Toxicol Appl Pharmacol 2019;366:46-53. https://doi.org/10.1016/j.taap.2019.01.019
  42. Shi P, Zhang L, Wang J, Lu D, Li Y, Ren J, Shen M, Zhang L, Huang J. Porcine FcεRI mediates porcine reproductive and respiratory syndrome virus multiplication and regulates the inflammatory reaction. Virol Sin 2018;33:249-60. https://doi.org/10.1007/s12250-018-0032-3
  43. Nunes de Miranda SM, Wilhelm T, Huber M, Zorn CN. Differential Lyn-dependence of the SHIP1-deficient mast cell phenotype. Cell Commun Signal 2016;14:12. https://doi.org/10.1186/s12964-016-0135-0
  44. Conti P, Shaik-Dasthagirisaheb YB. Mast cell serotonin immunoregulatory effects impacting on neuronal function: implications for neurodegenerative and psychiatric disorders. Neurotox Res 2015;28:147-53. https://doi.org/10.1007/s12640-015-9533-0
  45. Rivera J, Olivera A. A current understanding of Fc epsilon RI-dependent mast cell activation. Curr Allergy Asthma Rep 2008;8:14-20. https://doi.org/10.1007/s11882-008-0004-z
  46. Shamji MH, Durham SR. Mechanisms of allergen immunotherapy for inhaled allergens and predictive biomarkers. J Allergy Clin Immunol 2017;140:1485-98. https://doi.org/10.1016/j.jaci.2017.10.010
  47. Tamura S, Yoshihira K, Kawano T, Murakami N. Inhibitor for FcεRI expression on mast cell from Verbasucum thapsus L. Bioorg Med Chem Lett 2018;28:3342-65. https://doi.org/10.1016/j.bmcl.2018.09.007
  48. Zhang YZ, Yao JN, Zhang LF, Wang CF, Zhang XX, Gao B. Effect of NLRC5 on activation and reversion of hepatic stellate cells by regulating the nuclear factor-κB signaling pathway. World J Gastroenterol 2019;25:3044-55. https://doi.org/10.3748/wjg.v25.i24.3044
  49. Xiao Q, Piao R, Wang H, Li C, Song L. Orientin-mediated Nrf2/HO-1 signal alleviates H(2)O(2)-induced oxidative damage via induction of JNK and PI3K/AKT activation. Int J Biol Macromol 2018;118:747-55. https://doi.org/10.1016/j.ijbiomac.2018.06.130
  50. Wang Z, Xiong L, Wang G, Wan W, Zhong C, Zu H. Insulin-like growth factor-1 protects SH-SY5Y cells against β-amyloid-induced apoptosis via the PI3K/Akt-Nrf2 pathway. Exp Gerontol 2017;87:23-32. https://doi.org/10.1016/j.exger.2016.11.009
  51. Stahli A, Maheen CU, Strauss FJ, Eick S, Sculean A, Gruber R. Caffeic acid phenethyl ester protects against oxidative stress and dampens inflammation via heme oxygenase 1. Int J Oral Sci 2019;11:1418-26.