Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Ginsenoside Rg2, a principal effective ingredient of Panax ginseng, attenuates DSS-induced ulcerative colitis through NF-κB/NLRP3 pathway

  • Ji Zhang (School of Life Sciences, Huaiyin Normal University) ;
  • Jing Xie (School of Life Sciences, Huaiyin Normal University) ;
  • Zhiqiang Niu (Institute of Translational Medicine, School of Medicine, Yangzhou University) ;
  • Long You (School of Life Sciences, Huaiyin Normal University) ;
  • Yanan Liu (Institute of Translational Medicine, School of Medicine, Yangzhou University) ;
  • Rui Guo (Institute of Translational Medicine, School of Medicine, Yangzhou University) ;
  • Guigui Yang (School of Life Sciences, Huaiyin Normal University) ;
  • Ziliang He (School of Life Sciences, Huaiyin Normal University) ;
  • Ting Shen (Institute of Translational Medicine, School of Medicine, Yangzhou University) ;
  • Honggang Wang (Department of Gastroenterology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University) ;
  • Qi Yan (Department of Otolaryngology, Head and Neck Surgery,Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou University) ;
  • Weicheng Hu (Institute of Translational Medicine, School of Medicine, Yangzhou University)
  • Received : 2024.06.07
  • Accepted : 2025.02.06
  • Published : 2025.05.01
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Abstract

Background: Ginsenoside Rg2 (G-Rg2), a major active compound of Panax ginseng, exhibits a wide range of pharmacological properties, including anticancer, antioxidant and neuroprotective effects. However, the mechanisms by which G-Rg2 mitigates ulcerative colitis (UC) have not been clearly elucidated. Aims: In the present study, we aimed to elucidate the underlying mechanisms by which G-Rg2 mitigated UC. Methods: In this study, we investigated the efficacy of G-Rg2 in ameliorating dextran sulfate sodium (DSS)-induced UC and its potential mechanisms using a DSS-induced UC mouse model and Lipopolysaccharides (LPS)/nigericin (Nig)-induced NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation on immortalized bone marrow-derived macrophages (iBMDMs). Results: Oral administration of G-Rg2 at doses of 10 and 20 mg/kg significantly mitigated weight loss, normalized food and water intake, and improved colon histopathology in DSS-induced UC mice. G-Rg2 also restored mRNA expression levels of occludin, claudin-3, zona occluden (ZO)-1 and mucin 2, thereby enhancing intestinal barrier integrity. G-Rg2 significantly suppressed the nuclear translocation of p65, the subunit of nuclear factor kappa-B (NF-κB), as well as downregulated NLRP3, cleaved IL-1β and caspase1 p20 expression induced by LPS/Nig in iBMDMs. Conclusion: G-Rg2 effectively reduced colon inflammation in DSS-induced UC mice and diminishes inflammatory responses under LPS/Nig conditions by regulating NF-κB/NLRP3 pathway, thereby inhibiting NLRP3 inflammasome activation, which may serve as a potent therapeutic agent for UC.

Keywords

Acknowledgement

This work was financially supported by the National Natural Science Foundation of China (31600281) and the Natural Science Foundation of Jiangsu Higher Education Institutions of China (23KJA550001).

References

  1. Ford AC, Moayyedi P, Hanauer SB, Kirsner JB. Ulcerative colitis. BMJ 2013;346:f432. https://doi.org/10.1136/bmj.f432.
  2. Foerster EG, Mukherjee T, Cabral-Fernandes L, Rocha JDB, Girardin SE, Philpott DJ. How autophagy controls the intestinal epithelial barrier. Autophagy 2022;18:86–103. https://doi.org/10.1080/15548627.2021.1909406.
  3. Dinallo V, Marafini I, Fusco D Di, Laudisi F, Franzè E, Grazia A Di, et al. Neutrophil extracellular traps sustain inflammatory signals in ulcerative colitis. J Crohn's Colitis 2019;13:772–84. https://doi.org/10.1093/ecco-jcc/jjy215.
  4. Frank DN, Amand AL St, Feldman RA, Boedeker EC, Harpaz N, Pace NR. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci USA 2007;104(34):13780–5. https://doi.org/10.1073/pnas.0706625104.
  5. Dubois-Camacho K, Ottum PA, Franco-Muñoz D, De La Fuente M, Torres-Riquelme A, Díaz-Jiménez D, et al. Glucocorticosteroid therapy in inflammatory bowel diseases: from clinical practice to molecular biology. World J Gastroenterol 2017;23:6628–38. https://doi.org/10.3748/wjg.v23.i36.6628.
  6. Seyedian SS, Nokhostin F, Malamir MD. A review of the diagnosis, prevention, and treatment methods of inflammatory bowel disease. J Med Life 2019;12:113–22. https://doi.org/10.25122/jml-2018-0075.
  7. Fu J, Wu H. Structural mechanisms of NLRP3 inflammasome assembly and activation. Annu Rev Immunol 2023;41:301–16. https://doi.org/10.1146/annurev-immunol-081022-021207.
  8. Paik S, Kim JK, Silwal P, Sasakawa C, Jo EK. An update on the regulatory mechanisms of NLRP3 inflammasome activation. Cell Mol Immunol 2021;18:1141–60. https://doi.org/10.1038/s41423-021-00670-3.
  9. Al-Hawary SIS, Jasim SA, Romero-Parra RM, Bustani GS, Hjazi A, Alghamdi MI, et al. NLRP3 inflammasome pathway in atherosclerosis: focusing on the therapeutic potential of non-coding RNAs. Pathol Res Pract 2023;246:154490. https://doi.org/10.1016/j.prp.2023.154490.
  10. Sharma BR, Kanneganti TD. NLRP3 inflammasome in cancer and metabolic diseases. Nat Immunol 2021;22:550–9. https://doi.org/10.1038/s41590-021-00886-5.
  11. He R, Li Y, Han C, Lin R, Qian W, Hou X. L-Fucose ameliorates DSS-induced acute colitis via inhibiting macrophage M1 polarization and inhibiting NLRP3 inflammasome and NF-kB activation. Int Immunopharmacol 2019;73:379–88. https://doi.org/10.1016/j.intimp.2019.05.013.
  12. Wei YY, Fan YM, Ga Y, Zhang YN, Han JC, Hao ZH. Shaoyao decoction attenuates DSS-induced ulcerative colitis, macrophage and NLRP3 inflammasome activation through the MKP1/NF-κB pathway. Phytomedicine 2021;92:153743. https://doi.org/10.1016/j.phymed.2021.153743.
  13. Coll RC, Hill JR, Day CJ, Zamoshnikova A, Boucher D, Massey NL, et al. MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition. Nat Chem Biol 2019;15:556–9. https://doi.org/10.1038/s41589-019-0277-7.
  14. He H, Jiang H, Chen Y, Ye J, Wang A, Wang C, et al. Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity. Nat Commun 2018;9:2550. https://doi.org/10.1038/s41467-018-04947-6.
  15. Liu D, Tian Q, Liu K, Ren F, Liu G, Zhou J, et al. Ginsenoside Rg3 ameliorates DSS-induced colitis by inhibiting NLRP3 inflammasome activation and regulating microbial homeostasis. J Agric Food Chem 2022;71:3472–83. https://doi.org/10.1021/acs.jafc.2c07766.
  16. Kiefer DMD, Pantuso TBS. Panax ginseng - american family physician. Am Fam Physician 2003;68:1539–42.
  17. Xue Q, Yu T, Wang Z, Fu X, Li X, Zou L, et al. Protective effect and mechanism of ginsenoside Rg2 on atherosclerosis. J Ginseng Res 2023;47:237–45. https://doi.org/10.1016/j.jgr.2022.08.001.
  18. Jeon H, Jin Y, Myung CS, Heo KS. Ginsenoside-Rg2 exerts anti-cancer effects through ROS-mediated AMPK activation associated mitochondrial damage and oxidation in MCF-7 cells. Arch Pharm Res (Seoul) 2021;44:702–12. https://doi.org/10.1007/s12272-021-01345-3.
  19. Hnasko TS, Hnasko RM. The western blot. In: Hnasko R, editor. Methods mol. Biol., vol. 1318. New York, NY: Springer New York; 2015. p. 87–96. https://doi.org/10.1007/978-1-4939-2742-5_9.
  20. Le KDR, Choy KT, Roth S, Heriot AG, Kong JCH. Immune mediated colitis: a surgical perspective. ANZ J Surg 2023;93:1495–502. https://doi.org/10.1111/ans.18485.
  21. He Z, Chen S, Pan T, Li A, Wang K, Lin Z, et al. Ginsenoside Rg2 ameliorating CDAHFD-induced hepatic fibrosis by regulating AKT/mTOR-mediated autophagy. J Agric Food Chem 2022;70:1911–22. https://doi.org/10.1021/acs.jafc.1c07578.
  22. Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y, Nakaya R. A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 1990;98:694–702. https://doi.org/10.1016/0016-5085(90)90290-H.
  23. Fu W, Xu H, Yu X, Lyu C, Tian Y, Guo M, et al. 20(: S)-Ginsenoside Rg2 attenuates myocardial ischemia/reperfusion injury by reducing oxidative stress and inflammation: role of SIRT1. RSC Adv 2018;8:23947–62. https://doi.org/10.1039/c8ra02316f.
  24. Tatiya-Aphiradee N, Chatuphonprasert W, Jarukamjorn K. Immune response and inflammatory pathway of ulcerative colitis. J Basic Clin Physiol Pharmacol 2019;30:1-10. https://doi.org/10.1515/jbcpp-2018-0036.
  25. Minton K. Intestinal barrier protection. Nat Rev Immunol 2022;22:144–5. https://doi.org/10.1038/s41577-022-00685-5.
  26. Stevens BR, Goel R, Seungbum K, Richards EM, Holbert RC, Pepine CJ, et al. Increased human intestinal barrier permeability plasma biomarkers zonulin and FABP2 correlated with plasma LPS and altered gut microbiome in anxiety or depression. Gut 2018;67:1555–7. https://doi.org/10.1136/gutjnl-2017-314759.
  27. Tulkens J, Vergauwen G, Van Deun J, Geeurickx E, Dhondt B, Lippens L, et al. Increased levels of systemic LPS-positive bacterial extracellular vesicles in patients with intestinal barrier dysfunction. Gut 2020;69:191–3. https://doi.org/10.1136/gutjnl-2018-317726.
  28. Wu XX, Huang XL, Chen RR, Li T, Ye HJ, Xie W, et al. Paeoniflorin prevents intestinal barrier disruption and inhibits lipopolysaccharide (LPS)-induced inflammation in Caco-2 cell monolayers. Inflammation 2019;42:2215–25. https://doi.org/10.1007/s10753-019-01085-z.
  29. Patel MN, Carroll RG, Galván-Peña S, Mills EL, Olden R, Triantafilou M, et al. Inflammasome priming in sterile inflammatory disease. Trends Mol Med 2017;23:165–80. https://doi.org/10.1016/j.molmed.2016.12.007.
  30. Al-Sadi RM, Ma TY. IL-1β causes an increase in intestinal epithelial tight junction permeability. J Immunol 2007;178:4641–9. https://doi.org/10.4049/jimmunol.178.7.4641.
  31. Lu P, Chen J, Chen Y, Quan X, Liu J, Han Y, et al. 20(S)-Protopanaxadiol saponins isolated from Panax notoginseng target caveolin-1 against intestinal barrier dysfunction by alleviating inflammatory injury and oxidative stress in experimental murine colitis. Food Front 2023;4:2081–96. https://doi.org/10.1002/fft2.285.
  32. Luo D, Huang Z, Jia G, Zhao H, Liu G, Chen X. Naringin mitigates LPS-induced intestinal barrier injury in mice. Food Funct 2023;14:1617–26. https://doi.org/10.1039/d2fo03586c.
  33. Wang H, Huang X, Xia S, Chen X, Chen C, Zhang Y, et al. Antagonistic effect of kale soluble dietary fiber and kale flavonoids, fails to alleviate colitis. Food Front 2023;4:459–73. https://doi.org/10.1002/fft2.191.
  34. Wu X, Huang H, Li M, Wang Y, Wu X, Wang Q, et al. Excessive consumption of the sugar rich longan fruit promoted the development of nonalcoholic fatty liver disease via mediating gut dysbiosis. Food Front 2023;4:491–510. https://doi.org/10.1002/fft2.185.
  35. Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 2008;9:847–56. https://doi.org/10.1038/ni.1631.
  36. Swanson KV, Deng M, Ting JPY. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol 2019;19:477–89. https://doi.org/10.1038/s41577-019-0165-0.
  37. Dorrington MG, Fraser IDC. NF-κB signaling in macrophages: dynamics, crosstalk, and signal integration. Front Immunol 2019;10. https://doi.org/10.3389/fimmu.2019.00705.
  38. El-Sherbiny M, Eisa NH, Abo El-Magd NF, Elsherbiny NM, Said E, Khodir AE. Anti-inflammatory/anti-apoptotic impact of betulin attenuates experimentally induced ulcerative colitis: an insight into TLR4/NF-κB/caspase signalling modulation. Environ Toxicol Pharmacol 2021;88:103750. https://doi.org/10.1016/j.etap.2021.103750.
  39. McKee CM, Coll RC. NLRP3 inflammasome priming: a riddle wrapped in a mystery inside an enigma. J Leukoc Biol 2020;108:937–52. https://doi.org/10.1002/JLB.3MR0720-513R.
  40. Huang Y, Xu W, Zhou R. NLRP3 inflammasome activation and cell death. Cell Mol Immunol 2021;18:2114–27. https://doi.org/10.1038/s41423-021-00740-6.
  41. Li X, Wan A, Liu Y, Li M, Zhu Z, Luo C, et al. P2X7R mediates the synergistic effect of ATP and MSU crystals to induce acute gouty arthritis. Oxid Med Cell Longev 2023;2023:3317307. https://doi.org/10.1155/2023/3317307.
  42. Jurisic V, Radenkovic S, Konjevic G. The actual role of LDH as tumor marker, biochemical and clinical aspects. In: Scatena R, editor. Adv. Exp. Med. Biol., vol. 867. Dordrecht: Springer Netherlands; 2015. p. 115–224. https://doi.org/10.1007/978-94-017-7215-0_8.
  43. Baeuerle PA, Henkel T. Function and activation of NF-κB in the immune system. Annu Rev Immunol 1994;12:141–79. https://doi.org/10.1146/annurev.iy.12.040194.001041.
  44. Zhang X, Zhou Y, Cheong MS, Khan H, Ruan CC, Fu M, et al. Citri Reticulatae Pericarpium extract and flavonoids reduce inflammation in RAW 264.7 macrophages by inactivation of MAPK and NF-κB pathways. Food Front 2022;3:785–95. https://doi.org/10.1002/fft2.169.
  45. Cullen SP, Kearney CJ, Clancy DM, Martin SJ. Diverse Activators of the NLRP3 inflammasome promote IL-1β secretion by triggering necrosis. Cell Rep 2015;11:1535–48. https://doi.org/10.1016/j.celrep.2015.05.003.