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Current Pharmaceutical Design

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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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Research Article

Qingxiong Ointment and its Active Ingredient, Shikonin Treat Psoriasis through HIF-1 Signaling Pathway

Author(s): Bin Zhang, Ge Yan, Fei Li, Ye Tang, Guangyao Xu, Yanan Zhang and Kan Ze*

Volume 30, Issue 24, 2024

Published on: 03 June, 2024

Page: [1927 - 1938] Pages: 12

DOI: 10.2174/0113816128287142240529120346

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Abstract

Background: Psoriasis is a common chronic inflammatory skin disorder. Qingxiong ointment (QX) is a natural medicinal combination frequently employed in clinical treatment of psoriasis. However, the active ingredients of QX and its precise mechanisms of improving psoriasis remain unclear. This study elucidated the effects of QX on an Imiquimod (IMQ)-induced mouse model of psoriasis while also exploring the regulation of the active ingredient of QX, shikonin, on the HIF-1 signaling pathway in HaCaT cells.

Methods: A mouse model of psoriasis was established through topical application of IMQ, and the local therapeutic effect of QX was evaluated using dorsal skin tissue with mouse psoriatic lesion and Psoriasis Area Severity Index (PASI) scores, hematoxylin-eosin (HE) staining, and immunohistochemical staining. Elisa and qPCR were employed to identify changes in the expression of inflammation-related factors in the mouse dorsal skin. Immunofluorescence was used to assess changes in the expression of T cell subsets before and after treatment with various doses of QX. HPLC was used to analyze the content of shikonin, and network pharmacology was employed to analyze the main targets of shikonin. Immunofluorescence was used to identify the effects of shikonin on the HIF-1 signaling pathway in IL6-induced psoriasis HaCaT cells. Finally, qPCR was used to identify the differential expression of the HIF-1 signaling pathway in skin tissues.

Results: QX significantly reduces PASI scores on the backs of IMQ-induced psoriasis mice. HE staining reveals alleviated epidermal thickness in the QX group. Immunohistochemical analysis shows a significant reduction in ICAM, KI67, and IL17 expression levels in the QX group. Immunofluorescence results indicate that QX can notably decrease the proportions of CD4+ T cells, γδ T cells, and CD8+ T cells while increasing the proportion of Treg cells. Network pharmacology analysis demonstrates that the main targets of shikonin are concentrated in the HIF-1 signaling pathway. Molecular docking results show favorable binding affinity between shikonin and key genes of the HIF-1 signaling pathway. Immunofluorescence results reveal that shikonin significantly reduces p-STAT3, SLC2A1, HIF1α, and NOS2 expression levels. qPCR results show significant downregulation of the HIF-1 signaling pathway at cellular and tissue levels.

Conclusion: Our study revealed that QX can significantly reduce the dorsal inflammatory response in the IMQ-induced psoriasis mouse model. Furthermore, we discovered that its main component, shikonin, exerts its therapeutic effect by diminishing the HIF-1 signaling pathway in HaCaT cells.

Keywords: Qingxiong ointment, shikonin, psoriasis, network pharmacology, HIF-1 signaling pathway, skin disorder.

« Previous Next »
[1]
Dey AK, Joshi AA, Chaturvedi A, et al. Association between skin and aortic vascular inflammation in patients with psoriasis. JAMA Cardiol 2017; 2(9): 1013-8.
[http://dx.doi.org/10.1001/jamacardio.2017.1213] [PMID: 28564678]
[2]
Alrefai H, Muhammad K, Rudolf R, et al. NFATc1 supports imiquimod-induced skin inflammation by suppressing IL-10 synthesis in B cells. Nat Commun 2016; 7(1): 11724.
[http://dx.doi.org/10.1038/ncomms11724] [PMID: 27222343]
[3]
Cibrian D, Saiz ML, de la Fuente H, et al. CD69 controls the uptake of L-tryptophan through LAT1-CD98 and AhR-dependent secretion of IL-22 in psoriasis. Nat Immunol 2016; 17(8): 985-96.
[http://dx.doi.org/10.1038/ni.3504] [PMID: 27376471]
[4]
Rendon A, Schäkel K. Psoriasis pathogenesis and treatment. Int J Mol Sci 2019; 20(6): 1475.
[http://dx.doi.org/10.3390/ijms20061475] [PMID: 30909615]
[5]
van de Kerkhof PCM. From empirical to pathogenesis-based treatments for psoriasis. J Invest Dermatol 2022; 142(7): 1778-85.
[http://dx.doi.org/10.1016/j.jid.2022.01.014] [PMID: 35249726]
[6]
Chang HW, Yan D, Singh R, et al. Alteration of the cutaneous microbiome in psoriasis and potential role in Th17 polarization. Microbiome 2018; 6(1): 154.
[http://dx.doi.org/10.1186/s40168-018-0533-1] [PMID: 30185226]
[7]
Armstrong AW, Read C. Pathophysiology, clinical presentation, and treatment of psoriasis. JAMA 2020; 323(19): 1945-60.
[http://dx.doi.org/10.1001/jama.2020.4006] [PMID: 32427307]
[8]
Hoegler KM, John AM, Handler MZ, Schwartz RA. Generalized pustular psoriasis: A review and update on treatment. J Eur Acad Dermatol Venereol 2018; 32(10): 1645-51.
[http://dx.doi.org/10.1111/jdv.14949] [PMID: 29573491]
[9]
Shah KN. Diagnosis and treatment of pediatric psoriasis: Current and future. Am J Clin Dermatol 2013; 14(3): 195-213.
[http://dx.doi.org/10.1007/s40257-013-0026-8] [PMID: 23677694]
[10]
Kamata M, Tada Y. Efficacy and safety of biologics for psoriasis and psoriatic arthritis and their impact on comorbidities: A literature review. Int J Mol Sci 2020; 21(5): 1690.
[http://dx.doi.org/10.3390/ijms21051690] [PMID: 32121574]
[11]
Stein Gold L, Papp K, Pariser D, et al. Efficacy and safety of apremilast in patients with mild-to-moderate plaque psoriasis: Results of a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol 2022; 86(1): 77-85.
[http://dx.doi.org/10.1016/j.jaad.2021.07.040] [PMID: 34343599]
[12]
Topaloğlu Demir F, Özkök Akbulut T, Kıvanç Altunay İ, et al. Evaluation of the adverse effects of biological agents used in the treatment of psoriasis: A multicenter retrospective cohort study. Dermatol Ther 2020; 33(6): e14216.
[http://dx.doi.org/10.1111/dth.14216] [PMID: 32827159]
[13]
Li P, Lin T, Hu J. Clinical observation on the treatment of progressive psoriasis vulgaris with green staghorn cream combined with QingXiong ointment. Chin Trad Pat Med 2017; 39(7): 1542-4.
[14]
Tao T, Chen Y, Lai B, et al. Shikonin combined with methotrexate regulate macrophage polarization to treat psoriasis. Bioengineered 2022; 13(4): 11146-55.
[http://dx.doi.org/10.1080/21655979.2022.2062090] [PMID: 35485255]
[15]
Lan XO, Wang HX, Qi RQ, et al. Shikonin inhibits CEBPD downregulation in IL-17-treated HaCaT cells and in an imiquimod-induced psoriasis model. Mol Med Rep 2020; 22(3): 2263-72.
[http://dx.doi.org/10.3892/mmr.2020.11315] [PMID: 32705251]
[16]
Yu Y, Xu Y, Lan X, et al. Shikonin induces apoptosis and suppresses growth in keratinocytes via CEBP-δ upregulation. Int Immunopharmacol 2019; 72: 511-21.
[http://dx.doi.org/10.1016/j.intimp.2019.04.047] [PMID: 31075711]
[17]
Zhang X, Li J, Yu Y, et al. Shikonin controls the differentiation of CD4+CD25+ regulatory T cells by inhibiting AKT/mTOR pathway. Inflammation 2019; 42(4): 1215-27.
[http://dx.doi.org/10.1007/s10753-019-00982-7] [PMID: 31028576]
[18]
Shishodia SK, Shankar J. Proteomic analysis revealed ROS-mediated growth inhibition of Aspergillus terreus by shikonin. J Proteomics 2020; 224: 103849.
[http://dx.doi.org/10.1016/j.jprot.2020.103849] [PMID: 32485396]
[19]
Srivastava T, Tyagi D, Fatima S, et al. A natural small molecule- mediated inhibition of alpha-synuclein aggregation leads to neuroprotection in Caenorhabditis elegans. J Neurochem 2023; jnc.15907.
[http://dx.doi.org/10.1111/jnc.15907] [PMID: 37429595]
[20]
Lin ZM, Ma M, Li H, et al. Topical administration of reversible SAHH inhibitor ameliorates imiquimod-induced psoriasis-like skin lesions in mice via suppression of TNF-α/IFN-γ-induced inflammatory response in keratinocytes and T cell-derived IL-17. Pharmacol Res 2018; 129: 443-52.
[http://dx.doi.org/10.1016/j.phrs.2017.11.012] [PMID: 29155016]
[21]
Guo Y, Mao W, Bai N, et al. Integrated network pharmacological analysis revealed that Smilax glabra Roxb. alleviates IMQ-induced psoriatic skin inflammation through regulating T cell immune response. J Ethnopharmacol 2024; 325: 117836.
[http://dx.doi.org/10.1016/j.jep.2024.117836] [PMID: 38301985]
[22]
Song J, Jiang J, Kuai L, et al. TMT-based proteomics analysis reveals the protective effect of Jueyin granules on imiquimod-induced psoriasis mouse model by causing autophagy. Phytomedicine 2022; 96: 153846.
[http://dx.doi.org/10.1016/j.phymed.2021.153846] [PMID: 34785109]
[23]
Liu L, Chen X, Lu Y, et al. Celastrol gel ameliorates imiquimod- induced psoriasis-like dermatitis in mice by targeting Langerhans cells. Biomed Pharmacother 2022; 147: 112644.
[http://dx.doi.org/10.1016/j.biopha.2022.112644] [PMID: 35051865]
[24]
Cai Y, Xue F, Quan C, et al. A critical role of the IL-1β–IL-1R signaling pathway in skin inflammation and psoriasis pathogenesis. J Invest Dermatol 2019; 139(1): 146-56.
[http://dx.doi.org/10.1016/j.jid.2018.07.025] [PMID: 30120937]
[25]
Li X, Xie X, Zhang L, et al. Hesperidin inhibits keratinocyte proliferation and imiquimod-induced psoriasis-like dermatitis via the IRS-1/ERK1/2 pathway. Life Sci 2019; 219: 311-21.
[http://dx.doi.org/10.1016/j.lfs.2019.01.019] [PMID: 30658103]
[26]
Chen Y, Miao X, Xiang Y, et al. Qinzhu Liangxue inhibits IL-6-induced hyperproliferation and inflammation in HaCaT cells by regulating METTL14/SOCS3/STAT3 axis. J Ethnopharmacol 2023; 317: 116809.
[http://dx.doi.org/10.1016/j.jep.2023.116809] [PMID: 37336334]
[27]
Cheng Y, Liu Y, Tan J, et al. Integrated serum metabolomics and network pharmacology approach to reveal the potential mechanisms of withanolides from the leaves of Datura metel L. on psoriasis. J Pharm Biomed Anal 2020; 186: 113277.
[http://dx.doi.org/10.1016/j.jpba.2020.113277] [PMID: 32302925]
[28]
Wu X, Pan J, Yu JJJ, et al. DiDang decoction improves mitochondrial function and lipid metabolism via the HIF-1 signaling pathway to treat atherosclerosis and hyperlipidemia. J Ethnopharmacol 2023; 308: 116289.
[http://dx.doi.org/10.1016/j.jep.2023.116289] [PMID: 36822344]
[29]
Zhou Y, Zhou B, Pache L, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 2019; 10(1): 1523.
[http://dx.doi.org/10.1038/s41467-019-09234-6] [PMID: 30944313]
[30]
Dong Y, Tao B, Xue X, et al. Molecular mechanism of Epicedium treatment for depression based on network pharmacology and molecular docking technology. BMC Complement Med Ther 2021; 21(1): 222.
[http://dx.doi.org/10.1186/s12906-021-03389-w] [PMID: 34479552]
[31]
Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol 2015; 16(5): 448-57.
[http://dx.doi.org/10.1038/ni.3153] [PMID: 25898198]
[32]
Blauvelt A, Chiricozzi A. The immunologic role of IL-17 in psoriasis and psoriatic arthritis pathogenesis. Clin Rev Allergy Immunol 2018; 55(3): 379-90.
[http://dx.doi.org/10.1007/s12016-018-8702-3] [PMID: 30109481]
[33]
Singh R, Koppu S, Perche PO, Feldman SR. The cytokine mediated molecular pathophysiology of psoriasis and its clinical implications. Int J Mol Sci 2021; 22(23): 12793.
[http://dx.doi.org/10.3390/ijms222312793] [PMID: 34884596]
[34]
Hu P, Wang M, Gao H, et al. The role of helper T cells in psoriasis. Front Immunol 2021; 12: 788940.
[http://dx.doi.org/10.3389/fimmu.2021.788940] [PMID: 34975883]
[35]
Zhong L, Luo N, Zhong X, Xu T, Hao P. The immunoregulatory effects of natural products on psoriasis via its action on Th17 cells versus regulatory T cells balance. Int Immunopharmacol 2022; 110: 109032.
[http://dx.doi.org/10.1016/j.intimp.2022.109032] [PMID: 35810491]
[36]
Pietraforte I, Frasca L. Autoreactive T-Cells in psoriasis: Are they spoiled tregs and can therapies restore their functions? Int J Mol Sci 2023; 24(5): 4348.
[http://dx.doi.org/10.3390/ijms24054348] [PMID: 36901778]
[37]
Zhu WJ, Li P, Wang L, Xu YC. Hypoxia-inducible factor-1: A potential pharmacological target to manage psoriasis. Int Immunopharmacol 2020; 86: 106689.
[http://dx.doi.org/10.1016/j.intimp.2020.106689] [PMID: 32585606]
[38]
Kim JH, Bae HC, Kim J, et al. HIF-1α-mediated BMP6 down-regulation leads to hyperproliferation and abnormal differentiation of keratinocytes in vitro. Exp Dermatol 2018; 27(11): 1287-93.
[http://dx.doi.org/10.1111/exd.13785] [PMID: 30230035]
[39]
Tashiro N, Segawa R, Tobita R, et al. Hypoxia inhibits TNF-α-induced TSLP expression in keratinocytes. PLoS One 2019; 14(11): e0224705.
[http://dx.doi.org/10.1371/journal.pone.0224705] [PMID: 31682627]

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