Astragaloside IV suppresses the proliferation and inflammatory response of human epidermal keratinocytes and ameliorates imiquimod-induced psoriasis-like skin damage in mice
Main Article Content
Keywords
Astragaloside Iv, Inflammation, Normal Human -Epidermal -Keratinocytes, Proliferation, Psoriasis
Abstract
The primary pathological features of psoriasis include excessive epidermal keratinocytes and infiltration of inflammatory cells, which are pivotal targets for psoriasis therapy. Astragaloside IV (AS-IV), the principal active compound of astragalus, exhibits anti-inflammatory, antioxidant, and immune-modulatory properties. This study aims to investigate AS-IV’s anti--psoriatic effects and underlying mechanisms. Normal human epidermal keratinocytes (NHEKs) were stimulated with a combination of TNF-α, IL-17A, IL-1α, IL-22, and oncostatin M (M5) to replicate psoriatic keratinocyte pathology in vitro. Cell proliferation was assessed using CCK8 and EDU staining. Pro-inflammatory cytokine levels were measured via qRT-PCR. In addition, an imiquimod (IMQ)-induced psoriasis mouse model was utilized. Skin histology changes were evaluated with HE staining, while IL-6 and TNF-α levels in mouse serum were quantified using ELISA. NF-κB pathway protein expression was analyzed by western blotting. The results demonstrated that AS-IV inhibited M5-induced proliferation of NHEKs. AS-IV reduced M5-stimulated IL-1β, IL-6, IL-8, TNF-α, IL-23, and MCP-1 expression in NHEKs. Moreover, M5-induced phosphorylation of IκBα and p65 was significantly attenuated by AS-IV. Furthermore, AS-IV application ameliorated erythema, scale formation, and epidermal thickening in IMQ-induced psoriasis-like mouse models. AS-IV also decreased IL-6 and TNF-α levels in mouse serum and inhibited IκBα and p65 phosphorylation in skin tissues. However, prostratin treatment reversed these effects. These findings underscore AS-IV’s capacity to mitigate M5-induced NHEK proliferation and inflammation. AS-IV shows promise in alleviating IMQ-induced psoriasis-like skin lesions and inflammation by suppressing the NF-κB pathway.
References
1. Raharja A, Mahil SK, Barker JN. Psoriasis: A brief overview. Clin Med (Lond). 2021;21(3):170–3. 10.7861/clinmed.2021-0257
2. Petit RG, Cano A, Ortiz A, Espina M, Prat J, Muñoz M, et al. Psoriasis: From pathogenesis to pharmacological and nano-technological-based therapeutics. Int J Mol Sci. 2021;22(9):4983. 10.3390/ijms22094983
3. Kanda N. Psoriasis: Pathogenesis, comorbidities, and therapy updated. Int J Mol Sci. 2021;22(6):2979. 10.3390/ijms22062979
4. Kaczmarska A, Kwiatkowska D, Skrzypek KK, Kowalewski ZT, Jaworecka K, Reich A. Pathomechanism of pruritus in psoriasis and atopic dermatitis: Novel approaches, similarities and differences. Int J Mol Sci. 2023;24(19). 10.3390/ijms241914734
5. Yao M, Zhang L, Wang L. Astragaloside IV: A promising natural neuroprotective agent for neurological disorders. Biomed Pharmacother. 2023;159:114229. 10.1016/j.biopha.2023.114229
6. Gao Y, Su X, Xue T, Zhang N. The beneficial effects of astragaloside IV on ameliorating diabetic kidney disease. Biomed Pharmacother. 2023;163:114598. 10.1016/j.biopha.2023.114598
7. Tan YQ, Chen HW, Li J. Astragaloside IV: An effective drug for the treatment of cardiovascular diseases. Drug Des Devel Ther. 2020;14:3731–46. 10.2147/DDDT.S272355
8. Zhang J, Wu C, Gao L, Du G, Qin X. Astragaloside IV derived from astragalus membranaceus: A research review on the pharmacological effects. Adv Pharmacol (San Diego, Calif). 2020;87:89–112. 10.1016/bs.apha.2019.08.002
9. Liang Y, Chen B, Liang D, Quan X, Gu R, Meng Z, et al. Pharmacological effects of astragaloside IV: A review. Molecules (Basel, Switzerland). 2023;28(16). 10.3390/molecules28166118
10. Xiao L, Dai Z, Tang W, Liu C, Tang B. Astragaloside IV alleviates cerebral ischemia-reperfusion injury through NLRP3 inflammasome-mediated pyroptosis inhibition via activating Nrf2. Oxid Med Cell Longev. 2021;2021:9925561. 10.1155/2021/9925561
11. Hu Y, Tang W, Liu W, Hu Z, Pan C. Astragaloside IV alleviates renal tubular epithelial-mesenchymal transition via CX3CL1-RAF/MEK/ERK signaling pathway in diabetic kidney disease. Drug Des Devel Ther. 2022;16:1605–20. 10.2147/DDDT.S360346
12. Wang J, Ke J, Wu X, Yan Y. Astragaloside prevents UV-induced keratinocyte injury by regulating TLR4/NF-κB pathway. J Cosmet Dermatol. 2022;21(3):1163–70. 10.1111/jocd.14174
13. Xiuping Y, Xiaotong Z, Rongjia Z, Ping S. Effect of astragaloside IV on the immunoregulatory function of adipose-derived mesenchymal stem cells from patients with psoriasis vulgaris. J Trad Chin Med. 2022;42(4):513–9.
14. Talagas M, Lebonvallet N, Berthod F, Misery L. Cutaneous nociception: Role of keratinocytes. Expl Dermatol. 2019;28(12):1466–9. 10.1111/exd.13975
15. Cibrian D, de la Fuente H, Sánchez-Madrid F. Metabolic pathways that control skin homeostasis and inflammation. Trends Molecular Med. 2020;26(11):975–86. 10.1016/j.molmed.2020.04.004
16. Rucsandra Cristina D, Andreea Lili B, Loredana Elena S, Ștefan Cristian D, Cristina Elena B, Horațiu Valeriu P, et al. Review: A contemporary, multifaced insight into psoriasis pathogenesis. J Pers Med. 2024;14(5):535. 10.3390/jpm14050535
17. Xinxin W, Jiankun S, Ying Z, Le K, Changya L, Xin M, et al. Exploring the role of autophagy in psoriasis pathogenesis: Insights into sustained inflammation and dysfunctional keratinocyte differentiation. Int Immunopharmacol. 2024;135(0):112244. 10.1016/j.intimp.2024.112244
18. Katarzyna B, Marta M, Magdalena G-C. Use of cytokine mix-, imiquimod-, and serum-induced monoculture and lipopolysaccharide-and interferon gamma-treated co-culture to establish in vitro psoriasis-like inflammation models. Cells. 2021;10(11):2985. 10.3390/cells10112985
19. Zhou X, Chen Y, Cui L, Shi Y, Guo C. Advances in the pathogenesis of psoriasis: From keratinocyte perspective. Cell Death Dis. 2022;13(1):81. 10.1038/s41419-022-04523-3
20. Yingyi Z, Ruoqi L, Yuan Z, Shanshan Z, Xiang F. Investigation on the potential targets of astragaloside IV against intracerebral hemorrhage based on network pharmacology and experimental validation. Bioorg Chem. 2022;127(0). 10.1016/j.bioorg.2022.105975
21. Ding Z, Liu J, Qian H, Wu L, Lv M. Cinnamaldehyde inhibits psoriasis-like inflammation by suppressing proliferation and inflammatory response of keratinocytes via inhibition of NF-κB and JNK signaling pathways. Mol Med Rep. 2021;24(3):638. 10.3892/mmr.2021.12277
22. Chen C, Wu N, Duan Q, Yang H, Wang X, Yang P, et al. C10orf99 contributes to the development of psoriasis by promoting the proliferation of keratinocytes. Sci Rep. 2018;8(1):8590. 10.1038/s41598-018-26996-z
23. Moos S, Mohebiany AN, Waisman A, Kurschus FC. Imiquimod-induced psoriasis in mice depends on the IL-17 signaling of keratinocytes. J Invest Dermatol. 2019;139(5):1110–7. 10.1016/j.jid.2019.01.006
24. 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
25. Wu L, Liu G, Wang W, Liu R, Liao L, Cheng N, et al. Cyclodextrin-modified CeO(2) nanoparticles as a multifunctional nanozyme for combinational therapy of psoriasis. Int J Nanomedicine. 2020;15:2515–27. 10.2147/IJN.S246783
26. Guo Q, Jin Y, Chen X, Ye X, Shen X, Lin M, et al. NF-κB in biology and targeted therapy: New insights and translational implications. Signal Transduct Target Ther. 2024;9(1):53. 10.1038/s41392-024-01757-9
27. Wang W, Qu R, Wang X, Zhang M, Zhang Y, Chen C, et al. GDF11 antagonizes psoriasis-like skin inflammation via suppression of NF-κB signaling pathway. Inflammation. 2019;42(1):319–30. 10.1007/s10753-018-0895-3
28. 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
29. Shi Q, He Q, Chen W, Long J, Zhang B. Ginsenoside Rg1 abolish imiquimod-induced psoriasis-like dermatitis in BALB/c mice via downregulating NF-κB signaling pathway. J Food Biochem. 2019;43(11):e13032. 10.1111/jfbc.13032
30. Liu A, Zhang B, Zhao W, Tu Y, Wang Q, Li J. Catalpol ameliorates psoriasis-like phenotypes via SIRT1 mediated suppression of NF-κB and MAPKs signaling pathways. Bioengineered. 2021;12(1):183–95. 10.1080/21655979.2020.1863015
31. Bai D, Cheng X, Li Q, Zhang B, Zhang Y, Lu F, et al. Eupatilin inhibits keratinocyte proliferation and ameliorates imiquimod-induced psoriasis-like skin lesions in mice via the p38 MAPK/NF-κB signaling pathway. Immunopharm Immunot. 2023;45(2):133–9. 10.1080/08923973.2022.2121928
32. Tian Y, Chu X, Huang Q, Guo X, Xue Y, Deng W. Astragaloside IV attenuates IL-1β-induced intervertebral disc degeneration through inhibition of the NF-κB pathway. J Orthop Surg Res. 2022;17(1):545. 10.1186/s13018-022-03438-1
33. Tian L, Tao S, He C, Dong S, Chen Y, Chen L, et al. Astragaloside IV regulates TL1A and NF-κB signal pathway to affect inflammation in necrotizing enterocolitis. Tissue and Cell. 2023;83:102128. 10.1016/j.tice.2023.102128
34. Hsieh HL, Liu SH, Chen YL, Huang CY, Wu SJ. Astragaloside IV suppresses inflammatory response via suppression of NF-κB, and MAPK signalling in human bronchial epithelial cells. Arch Physiol Biochem. 2022;128(3):757–66. 10.1080/13813455.2020.1727525
2. Petit RG, Cano A, Ortiz A, Espina M, Prat J, Muñoz M, et al. Psoriasis: From pathogenesis to pharmacological and nano-technological-based therapeutics. Int J Mol Sci. 2021;22(9):4983. 10.3390/ijms22094983
3. Kanda N. Psoriasis: Pathogenesis, comorbidities, and therapy updated. Int J Mol Sci. 2021;22(6):2979. 10.3390/ijms22062979
4. Kaczmarska A, Kwiatkowska D, Skrzypek KK, Kowalewski ZT, Jaworecka K, Reich A. Pathomechanism of pruritus in psoriasis and atopic dermatitis: Novel approaches, similarities and differences. Int J Mol Sci. 2023;24(19). 10.3390/ijms241914734
5. Yao M, Zhang L, Wang L. Astragaloside IV: A promising natural neuroprotective agent for neurological disorders. Biomed Pharmacother. 2023;159:114229. 10.1016/j.biopha.2023.114229
6. Gao Y, Su X, Xue T, Zhang N. The beneficial effects of astragaloside IV on ameliorating diabetic kidney disease. Biomed Pharmacother. 2023;163:114598. 10.1016/j.biopha.2023.114598
7. Tan YQ, Chen HW, Li J. Astragaloside IV: An effective drug for the treatment of cardiovascular diseases. Drug Des Devel Ther. 2020;14:3731–46. 10.2147/DDDT.S272355
8. Zhang J, Wu C, Gao L, Du G, Qin X. Astragaloside IV derived from astragalus membranaceus: A research review on the pharmacological effects. Adv Pharmacol (San Diego, Calif). 2020;87:89–112. 10.1016/bs.apha.2019.08.002
9. Liang Y, Chen B, Liang D, Quan X, Gu R, Meng Z, et al. Pharmacological effects of astragaloside IV: A review. Molecules (Basel, Switzerland). 2023;28(16). 10.3390/molecules28166118
10. Xiao L, Dai Z, Tang W, Liu C, Tang B. Astragaloside IV alleviates cerebral ischemia-reperfusion injury through NLRP3 inflammasome-mediated pyroptosis inhibition via activating Nrf2. Oxid Med Cell Longev. 2021;2021:9925561. 10.1155/2021/9925561
11. Hu Y, Tang W, Liu W, Hu Z, Pan C. Astragaloside IV alleviates renal tubular epithelial-mesenchymal transition via CX3CL1-RAF/MEK/ERK signaling pathway in diabetic kidney disease. Drug Des Devel Ther. 2022;16:1605–20. 10.2147/DDDT.S360346
12. Wang J, Ke J, Wu X, Yan Y. Astragaloside prevents UV-induced keratinocyte injury by regulating TLR4/NF-κB pathway. J Cosmet Dermatol. 2022;21(3):1163–70. 10.1111/jocd.14174
13. Xiuping Y, Xiaotong Z, Rongjia Z, Ping S. Effect of astragaloside IV on the immunoregulatory function of adipose-derived mesenchymal stem cells from patients with psoriasis vulgaris. J Trad Chin Med. 2022;42(4):513–9.
14. Talagas M, Lebonvallet N, Berthod F, Misery L. Cutaneous nociception: Role of keratinocytes. Expl Dermatol. 2019;28(12):1466–9. 10.1111/exd.13975
15. Cibrian D, de la Fuente H, Sánchez-Madrid F. Metabolic pathways that control skin homeostasis and inflammation. Trends Molecular Med. 2020;26(11):975–86. 10.1016/j.molmed.2020.04.004
16. Rucsandra Cristina D, Andreea Lili B, Loredana Elena S, Ștefan Cristian D, Cristina Elena B, Horațiu Valeriu P, et al. Review: A contemporary, multifaced insight into psoriasis pathogenesis. J Pers Med. 2024;14(5):535. 10.3390/jpm14050535
17. Xinxin W, Jiankun S, Ying Z, Le K, Changya L, Xin M, et al. Exploring the role of autophagy in psoriasis pathogenesis: Insights into sustained inflammation and dysfunctional keratinocyte differentiation. Int Immunopharmacol. 2024;135(0):112244. 10.1016/j.intimp.2024.112244
18. Katarzyna B, Marta M, Magdalena G-C. Use of cytokine mix-, imiquimod-, and serum-induced monoculture and lipopolysaccharide-and interferon gamma-treated co-culture to establish in vitro psoriasis-like inflammation models. Cells. 2021;10(11):2985. 10.3390/cells10112985
19. Zhou X, Chen Y, Cui L, Shi Y, Guo C. Advances in the pathogenesis of psoriasis: From keratinocyte perspective. Cell Death Dis. 2022;13(1):81. 10.1038/s41419-022-04523-3
20. Yingyi Z, Ruoqi L, Yuan Z, Shanshan Z, Xiang F. Investigation on the potential targets of astragaloside IV against intracerebral hemorrhage based on network pharmacology and experimental validation. Bioorg Chem. 2022;127(0). 10.1016/j.bioorg.2022.105975
21. Ding Z, Liu J, Qian H, Wu L, Lv M. Cinnamaldehyde inhibits psoriasis-like inflammation by suppressing proliferation and inflammatory response of keratinocytes via inhibition of NF-κB and JNK signaling pathways. Mol Med Rep. 2021;24(3):638. 10.3892/mmr.2021.12277
22. Chen C, Wu N, Duan Q, Yang H, Wang X, Yang P, et al. C10orf99 contributes to the development of psoriasis by promoting the proliferation of keratinocytes. Sci Rep. 2018;8(1):8590. 10.1038/s41598-018-26996-z
23. Moos S, Mohebiany AN, Waisman A, Kurschus FC. Imiquimod-induced psoriasis in mice depends on the IL-17 signaling of keratinocytes. J Invest Dermatol. 2019;139(5):1110–7. 10.1016/j.jid.2019.01.006
24. 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
25. Wu L, Liu G, Wang W, Liu R, Liao L, Cheng N, et al. Cyclodextrin-modified CeO(2) nanoparticles as a multifunctional nanozyme for combinational therapy of psoriasis. Int J Nanomedicine. 2020;15:2515–27. 10.2147/IJN.S246783
26. Guo Q, Jin Y, Chen X, Ye X, Shen X, Lin M, et al. NF-κB in biology and targeted therapy: New insights and translational implications. Signal Transduct Target Ther. 2024;9(1):53. 10.1038/s41392-024-01757-9
27. Wang W, Qu R, Wang X, Zhang M, Zhang Y, Chen C, et al. GDF11 antagonizes psoriasis-like skin inflammation via suppression of NF-κB signaling pathway. Inflammation. 2019;42(1):319–30. 10.1007/s10753-018-0895-3
28. 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
29. Shi Q, He Q, Chen W, Long J, Zhang B. Ginsenoside Rg1 abolish imiquimod-induced psoriasis-like dermatitis in BALB/c mice via downregulating NF-κB signaling pathway. J Food Biochem. 2019;43(11):e13032. 10.1111/jfbc.13032
30. Liu A, Zhang B, Zhao W, Tu Y, Wang Q, Li J. Catalpol ameliorates psoriasis-like phenotypes via SIRT1 mediated suppression of NF-κB and MAPKs signaling pathways. Bioengineered. 2021;12(1):183–95. 10.1080/21655979.2020.1863015
31. Bai D, Cheng X, Li Q, Zhang B, Zhang Y, Lu F, et al. Eupatilin inhibits keratinocyte proliferation and ameliorates imiquimod-induced psoriasis-like skin lesions in mice via the p38 MAPK/NF-κB signaling pathway. Immunopharm Immunot. 2023;45(2):133–9. 10.1080/08923973.2022.2121928
32. Tian Y, Chu X, Huang Q, Guo X, Xue Y, Deng W. Astragaloside IV attenuates IL-1β-induced intervertebral disc degeneration through inhibition of the NF-κB pathway. J Orthop Surg Res. 2022;17(1):545. 10.1186/s13018-022-03438-1
33. Tian L, Tao S, He C, Dong S, Chen Y, Chen L, et al. Astragaloside IV regulates TL1A and NF-κB signal pathway to affect inflammation in necrotizing enterocolitis. Tissue and Cell. 2023;83:102128. 10.1016/j.tice.2023.102128
34. Hsieh HL, Liu SH, Chen YL, Huang CY, Wu SJ. Astragaloside IV suppresses inflammatory response via suppression of NF-κB, and MAPK signalling in human bronchial epithelial cells. Arch Physiol Biochem. 2022;128(3):757–66. 10.1080/13813455.2020.1727525
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Sep 1, 2024
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Liu, T., Ai, L., Jiang, A., Wang, Y., Jiang, R., & Liu, L. (2024). Astragaloside IV suppresses the proliferation and inflammatory response of human epidermal keratinocytes and ameliorates imiquimod-induced psoriasis-like skin damage in mice. Allergologia Et Immunopathologia, 52(5), 44-50. https://doi.org/10.15586/aei.v52i5.1140
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How to Cite
Liu, T., Ai, L., Jiang, A., Wang, Y., Jiang, R., & Liu, L. (2024). Astragaloside IV suppresses the proliferation and inflammatory response of human epidermal keratinocytes and ameliorates imiquimod-induced psoriasis-like skin damage in mice. Allergologia Et Immunopathologia, 52(5), 44-50. https://doi.org/10.15586/aei.v52i5.1140