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Punicalagin alleviates the hyperproliferation of keratinocytes in psoriasis through inhibiting SKP2 expression

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Abstract

Psoriasis is a chronic inflammatory skin disorder characterized by abnormal keratinocytes proliferation and multiple immune cells infiltration in the dermis and epidermis. Although most psoriasis-related researches have been concentrated on the interleukin-23 (IL-23)/interleukin-17 (IL-17) axis, new data suggest that keratinocytes also play a pivotal role in psoriasis. Previously, we found that punicalagin (PUN), a bioactive ellagitannin extracted from Pericarpium Granati (the pericarpium of Punica granatum L.), exerts a therapeutic effect on psoriasis. However, the underlying mechanism, especially its potential modulatory effect on keratinocytes, remains obscure. Our study aims to reveal the potential regulatory effect and its underlying cellular mechanism of PUN on the hyperproliferation of keratinocytes. We used tumor necrosis factor α (TNF-α), IL-17A and interleukin-6 (IL-6) to induce abnormal proliferation of HaCaT cells (Human Keratinocytes Cells) in vitro. Then, we evaluated the effects of PUN through MTT assay, EdU staining and cell cycle detection. Finally, we explored the underlying cellular mechanisms of PUN via RNA-sequencing, WB in vitro and in vivo. Here, we found that PUN can directly and dose-dependently decrease TNF-α, IL-17A and IL-6-induced abnormal proliferation of HaCaT cells in vitro. Mechanically, PUN suppresses the hyperproliferation of keratinocytes through repressing S-phase kinase-associated protein 2 (SKP2) expression in vitro and in vivo. Moreover, overexpression of SKP2 can partly abolish PUN-mediated inhibition of aberrantly proliferative keratinocytes. These results illustrate that PUN can reduce the severity of psoriasis through directly repressing SKP2-mediated abnormal proliferation of keratinocytes, which gives new insight into the therapeutic mechanism of PUN on psoriasis. Moreover, these findings imply that PUN might be a promising drug candidate for the treatment of psoriasis.

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Abbreviations

DEGs:

Differentially expressed genes

DEX:

Dexamethasone cream

GSEA:

Gene set enrichment analysis

IL-6:

Interleukin-6

IL-17A:

Interleukin-17A

IL-23:

Interleukin-23

IMQ:

Imiquimod

KEGG:

Kyoto encyclopedia of genes and genomes

PUN:

Punicalagin

SCF:

SKP1/Cullin1/F-box protein complex

SKP2:

S-phase kinase-associated protein 2

TNF-α:

Tumor necrosis factor-α

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Acknowledgements

This study was supported by the Joint Funding Project of Municipal Schools (Colleges) of Science and Technology Program of Guangzhou (No. 202102010192); The Specific Fund of State Key Laboratory of Dampness Syndrome of Chinese Medicine (SZ2021ZZ23); The Specific Fund of “Young Talents Program” of Guangdong College of Traditional Chinese Medicine (SZ2022QN10); The 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund (Guangdong-Hong Kong-Macau Joint Lab) (2020B1212030006); The Specific Research Fund for TCM Science and Technology of Guangdong Provincial Hospital of Chinese Medicine (YN2018QJ03); The Specific Fund for the Administration of Traditional Chinese Medicine of Guangdong Province (20222066); Science and Technology Planning Project of Guangzhou (202102021001); The China-Dutch special projects of Guangdong Provincial Hospital of Chinese Medicine (YN2019HL01, YN2019HL02).

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Author notes

  1. Lipeng Tang and Bowen Zhang contributed equally to this study.

Authors and Affiliations

  1. State Key Laboratory of Dampness, Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, 111 Dade Road, Guangzhou, 510000, China

    Lipeng Tang, Bowen Zhang, Guanzhuo Li & Guangjuan Zheng

  2. Guangdong-Hong Kong-Macau Joint Lab On Chinese Medicine and Immune Disease Research, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, 510000, China

    Lipeng Tang, Bowen Zhang, Guanzhuo Li, Ying Zhu, Bing Feng, Zuqing Su & Guangjuan Zheng

  3. Department of Pharmacology of Traditional Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, 510000, China

    Lipeng Tang, Bowen Zhang, Guanzhuo Li, Ying Zhu, Bing Feng, Zuqing Su, Hongxia Li, Laijun Yang, Yanjing Lu, Zeting Ye & Guangjuan Zheng

  4. School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China

    Wenhui Han

  5. School of Clinical Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510000, China

    Huilin Huang & Qiuping Li

  6. Department of Rheumatology Clinical and Basic Research, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, 510000, China

    Maojie Wang

  7. Department of Immunology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, 510000, China

    Yuchao Chen, Huazhen Liu & Zhenhua Dai

  8. Department of Material Basis of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, 510000, China

    Dinghong Wu

  9. Department of Pathology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, 510000, China

    Guangjuan Zheng

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  1. Lipeng Tang
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Correspondence to Guangjuan Zheng.

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Tang, L., Zhang, B., Li, G. et al. Punicalagin alleviates the hyperproliferation of keratinocytes in psoriasis through inhibiting SKP2 expression. J Nat Med 77, 712–720 (2023). https://doi.org/10.1007/s11418-023-01711-z

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