Gypenosides alleviates HaCaT keratinocyte hyperproliferation and ameliorates imiquimod-induced psoriasis in mice
Main Article Content
Keywords
gypenosides, hyperproliferation, inflammation, NF-κB, Nrf2 activation, psoriasis, STAT3
Abstract
Background: Psoriasis is an autoimmune skin condition characterized by hyperproliferation of keratinocytes and chronic immune responses. Gypenosides (Gyp) exhibits anti-proliferative and anti-inflammatory effects on different diseases. However, its functioning and mechanism of Gyp on psoriasis remains unknown.
Objective: To explore the effect and mechanism of Gyp on psoriasis.
Material and Methods: The impact and mechanism of Gyp on psoriasis in vitro and in vivo were probed through cell counting kit-8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EdU) incorporation assay, reverse transcription quantitative polymerase chain reaction, hematoxylin and eosin staining, enzyme-linked immunosorbent serologic assay, immunofluorescence, and Western Blotting assays.
Results: Gyp inhibited cell proliferation and the release of inflammatory cytokinesin interleukin (IL-22)-induced spontaneously transformed human aneuploid immortal keratinocyte cell line (HaCaT). In addition, Gyp demonstrated enhancement in erythema and scaling as well as reductions in the thickness of epidermal layers, release of inflammatory factors, and Ki-67 (a nuclear protein) level in imiquimod (IMQ)-induced mice. Mechanistically, Gyp upregulated nuclear factor erythroid 2-related factor 2 (Nrf-2) expression and diminished the level of p-p65/p65 and p-STAT3/STAT3 in skin tissues from IMQ-induced mice and IL-22-induced HaCaT cells, which were reversed with the application of ML385, an inhibitor of Nrf2. In addition, the administration of ML385 reversed decrease in cell viability and reduced the expressions of IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) in IL-22-induced HaCaT cells caused by Gyp.
Conclusion: In summary, Gyp reduced excessive cell growth and inflammation in psoriasis by suppressing nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) through activation of Nrf2.
References
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3 Schett G, Rahman P, Ritchlin C, McInnes IB, Elewaut D, Scher JU. Psoriatic arthritis from a mechanistic perspective. Nat Rev Rheumatol. 2022;18(6):311–25. 10.1038/s41584-022-00776-6
4 Dalgard FJ, Gieler U, Tomas-Aragones L, Lien L, Poot F, Jemec GBE, et al. The psychological burden of skin diseases: A cross-sectional multicenter study among dermatological out-patients in 13 European countries. J Invest Dermatol. 2015;135(4):984–91. 10.1038/jid.2014.530
5 Pérez-Chada LM, Hopkins ZH, Balak DMW, Rashid S, Creadore A, Chu B, et al. Patient-reported outcome measures for health-related quality of life in patients with psoriasis: A systematic review. JAMA Dermatol. 2024;160(5):550–63. 10.1001/jamadermatol.2023.5439
6 Amirnia M, Khodaeiani E, Fouladi RF, Hashemi A. Topical steroids versus PUVA therapy in moderate plaque psoriasis: A clinical trial along with cost analysis. J Dermatolog Treat. 2012;23(2):109–11. 10.3109/09546634.2010.519017
7 Boehncke WH, Brembilla NC. Pathogenesis-oriented therapy of psoriasis using biologics. Expert Opin Biol Ther. 2022;22(12):1463–73. 10.1080/14712598.2022.2100219
8 Zhang L, Song J, Kong L, Yuan T, Li W, Zhang W, et al. The strategies and techniques of drug discovery from natural products. Pharmacol Ther. 2020;216:107686. 10.1016/j.pharmthera.2020.107686
9 Kim JH, Han YN. Dammarane-type saponins from Gynostemma pentaphyllum.Phytochemistry.2011;72(11–12):1453–9. 10.1016/j.phytochem.2011.04.003
10 Ju X, Liu Y, Wang Y, Sui G, Ma Y, Cao H, et al. The potential molecular mechanism underlying gypenoside amelioration of atherosclerosis in ApoE-/-mice: A multi-omics investigation. Heliyon. 2024;10(8):e29164. 10.1016/j.-heliyon.2024.e29164
11 Xie J, Luo M, Chen Q, Zhang Q, Qin L, Wang Y, et al. Hypolipidemic effect and gut microbiota regulation of Gypenoside aglycones in rats fed a high-fat diet. J Ethnopharmacol. 2024 Jun 28;328:118066. 10.1016/j.jep.2024.118066
12 Wang H, Li Z, Wang Q, Lin W, Zhou Z, Mu X, et al. Gypenosides ameliorate morphine-induced immunosuppression with an increased proportion of thymic T lymphocyte subsets and are involved in the regulation of the cAMP-CREM/CREB-IL-2 pathway. Genes Dis. 2024;11(3):101049. 10.1016/j.gendis.2023.05.026
13 Ma C, Li H, Liu W, Lu S, Li X, Chen J, et al. Therapeutic effect of gypenosides on antioxidant stress injury in orbital fibroblasts of graves' orbitopathy. J Immunol Res. 2022;2022:4432584. 10.1155/2022/4432584
14 Zhou T, Cao L, Du Y, Qin L, Lu Y, Zhang Q, et al. Gypenosides ameliorate high-fat diet-induced nonalcoholic fatty liver disease in mice by regulating lipid metabolism. Peer J. 2023;11:e15225. 10.7717/peerj.15225
15 Xiao MY, Li FF, Xie P, Qi YS, Xie JB, Pei WJ, et al. Gypenosides suppress hepatocellular carcinoma cells by blocking cholesterol biosynthesis through inhibition of MVA pathway enzyme HMGCS1. Chem Biol Interact. 2023;383:110674. 10.1016/j.cbi.2023.110674
16 Mu RH, Fang XY, Wang SS, Li CF, Chen SM, Chen XM, et al. Antidepressant-like effects of standardized gypenosides: Involvement of brain-derived neurotrophic factor signaling in hippocampus. Psychopharmacology (Berl). 2016;233(17):3211–21. 10.1007/s00213-016-4357-z
17 Li X, Liu H, Lv C, Du J, Lian F, Zhang S, et al. Gypenoside-induced apoptosis via the PI3K/AKT/mTOR signaling pathway in bladder cancer. Biomed Res Int. 2022;2022:9304552. 10.1155/2022/9304552
18 Qi YS, Xie JB, Xie P, Duan Y, Ling YQ, Gu YL, et al. Uncovering the anti-NSCLC effects and mechanisms of gypenosides by metabolomics and network pharmacology analysis. J Ethnopharmacol. 2021;281:114506. 10.1016/j.jep.2021.114506
19 Yan H, Wang X, Wang Y, Wang P, Xiao Y. Antiproliferation and anti-migration induced by gypenosides in human colon cancer SW620 and esophageal cancer Eca-109 cells. Hum Exp Toxicol. 2014;33(5):522–33. 10.1177/0960327113497771
20 Xia X, Chen J, Ren H, Zhou C, Zhang Q, Cheng H, et al. Gypenoside pretreatment alleviates the cerebral ischemia injury via inhibiting the microglia-mediated neuroinflammation. Mol Neurobiol. 2024 Feb;61(2):1140–56. 10.1007/s12035-023-03624-0
21 Ke JY, Liu ZY, Wang YH, Chen SM, Lin J, Hu F, et al. Gypenosides regulate autophagy through Sirt1 pathway and the anti-inflammatory mechanism of mitochondrial autophagy in systemic lupus erythematosus. Bioengineered. 2022;13(5):13384–97. 10.1080/21655979.2022.2066749
22 Zhu KN, Tian SS, Wang H, Tian YS, Gu GZ, Qiu YY, et al. Study on effect of gypenosides on insulin sensitivity of rats with diabetes mellitus via regulating NF-κB signaling pathway. Zhongguo Zhong Yao Za Zhi. 2021;46(17):4488–96. 10.19540/j.cnki.cjcmm.20210527.401
23 Li X, Alhasani RH, Cao Y, Zhou X, He Z, Zeng Z, et al. Gypenosides alleviate cone cell death in a zebrafish model of retinitis pigmentosa. Antioxidants (Basel). 2021;10(7):1050. 10.3390/antiox10071050
24 Tu Q, Zhu Y, Yuan Y, Guo L, Liu L, Yao L, et al. Gypenosides inhibit inflammatory response and apoptosis of endothelial and epithelial cells in LPS-induced ALI: A study based on bioinformatic analysis and in vivo/vitro experiments. Drug Des Devel Ther. 2021;15:289–303. 10.2147/DDDT.S28629
25 Li H, Ma C, Liu W, He J, Li K. Gypenosides protect orbital fibroblasts in graves ophthalmopathy via anti-inflammation and anti-fibrosis effects. Invest Ophthalmol Vis Sci. 2020;61(5):64. 10.1167/iovs.61.5.64
26 Ping K, Yang R, Chen H, Xie S, Li M, Xiang Y, et al. Gypenoside XLIX alleviates intestinal injury by inhibiting sepsis--induced inflammation, oxidative stress, apoptosis, and autophagy. Chem Biol Interact. 2024;397:111077. 10.1016/j.cbi.2024.111077
27 He Q, Zhang B, Hu F, Long J, Shi Q, Pi X, et al. Triptolide inhibits the proliferation of HaCaT cells induced by IL22 via upregulating miR-181b-5p. Drug Des Devel Ther. 2020;14:2927–35. 10.2147/DDDT.S254466
28 He Q, Liu N, Hu F, Shi Q, Pi X, Chen H, et al. Circ_0061012 contributes to IL-22-induced proliferation, migration and invasion in keratinocytes through miR-194-5p/GAB1 axis in psoriasis. Biosci Rep. 2021;41(1):BSR20203130. 10.1042/BSR20203130
29 Liu CT, Yen JJ, Brown DA, Song YC, Chu MY, Hung YH, et al. Targeting Nrf2 with 3 H-1,2-dithiole-3-thione to moderate OXPHOS-driven oxidative stress attenuates IL-17A-induced psoriasis. Biomed Pharmacother. 2023;159:114294. 10.1016/j.biopha.2023.114294
30 National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the care and use of laboratory animals. 8th ed. Washington, DC: National Academy of Sciences; 2011. Reports funded by National Institutes of Health. PMid: 21595115.
31 Gao J, Chen F, Fang H, Mi J, Qi Q, Yang M. Daphnetin inhibits proliferation and inflammatory response in human HaCaT keratinocytes and ameliorates imiquimod-induced psoriasis-like skin lesion in mice. Biol Res. 2020;53(1):48. 10.1186/s40659-020-00316-0
32 Tastan B, Arioz BI, Tufekci KU, Tarakcioglu E, Gonul CP, Genc K, et al. Dimethyl fumarate alleviates NLRP3 inflammasome activation in microglia and sickness behavior in LPS-challenged mice. Front Immunol. 2021;12:737065. 10.3389/fimmu.2021.737065
33 Schäfer M, Werner S. Nrf2--A regulator of keratinocyte redox signaling. Free Radic Biol Med. 2015;88(Pt B):243–52. 10.1016/j.freeradbiomed.2015.04.018
34 Greenwald M, Ben-Sasson S, Bianco-Peled H, Kohen R. Skin redox balance maintenance: The NEED FOR AN NRF2-activator delivery system. Cosmetics. 2016;3:1. 10.3390/cosmetics3010001
35 Goldminz AM, Au SC, Kim N, Gottlieb AB, Lizzul PF. NF-κB: An essential transcription factor in psoriasis. J Dermatol Sci. 2013;69(2):89–94. 10.1016/j.jdermsci.2012.11.002
36 Calautti E, Avalle L, Poli V. Psoriasis: A STAT3-centric view. Int J Mol Sci. 2018;19(1):171. 10.3390/ijms19010171
37 Sano S, Chan KS, Carbajal S, Clifford J, Peavey M, Kiguchi K, et al. Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model. Nat Med. 2005;11(1):43–9. 10.1038/nm1162
38 Armstrong AW, Read C. Pathophysiology, clinical presentation, and treatment of psoriasis: A review. JAMA. 2020;323(19):1945–60. 10.1001/jama.2020.4006
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Nov 1, 2024
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Liu, T., He, Y., & Liao, Y. (2024). Gypenosides alleviates HaCaT keratinocyte hyperproliferation and ameliorates imiquimod-induced psoriasis in mice. Allergologia Et Immunopathologia, 52(6), 22-32. https://doi.org/10.15586/aei.v52i6.1157
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How to Cite
Liu, T., He, Y., & Liao, Y. (2024). Gypenosides alleviates HaCaT keratinocyte hyperproliferation and ameliorates imiquimod-induced psoriasis in mice. Allergologia Et Immunopathologia, 52(6), 22-32. https://doi.org/10.15586/aei.v52i6.1157