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Therapeutic Effect of HDAC5 Binding and Cell Penetrating Peptide for the Treatment of Inflammatory Bowel Disease

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Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

Background:

Inflammatory bowel disease (IBD) is an incurable disease that negatively influences the quality of life of patients. Current and emerging therapies target proinflammatory cytokines and/or receptors to downregulate proinflammatory responses, but insufficient remission requires other therapeutic agents. Herein, we report that the synthetic anti-inflammatory peptide 15 (SAP15) is capable of cell penetration and anti-inflammatory activity in human macrophages.

Methods:

SAP15 was labeled with fluorescence and administered to human leukemia monocytic cells (THP-1) cells for cell penetration analysis. Using biolayer interferometry analysis, the binding affinity of SAP15 with histone deacetylase 5 (HDAC5) was measured. SAP15-treated THP-1 cells were analyzed by protein phosphorylation assay, flow cytometry, and enzyme-linked immunosorbent assay (ELISA). In addition, in vivo analysis of the therapeutic effect on IBD was observed in a dextran sulfate sodium (DSS)-induced model. Samples from SAP15-treated mice were analyzed at both the macroscopic and microscopic levels using ELISA, myeloperoxidase (MPO) assays, and histological evaluations.

Results:

SAP15 was internalized within the cytosol and nucleus of THP-1 cells and bound to the HDAC5 protein. SAP15-treated macrophages were assessed for protein phosphorylation and showed inhibited phosphorylation of HDAC5 and other immune-related proteins, which led to increased M2-like macrophage markers and decreased M1-like macrophage markers and tumor necrosis factor-α and interleukin-6 cytokine levels. The SAP15 treatment on IBD model showed significant recovery of colon length. Further histological analysis of colon demonstrated the therapeutic effect of SAP15 on mucosal layer. Moreover, proinflammatory cytokine levels and MPO activity from the plasma show that SAP15 is effective in reduced proinflammatory responses.

Conclusion:

These findings suggest that SAP15 is a novel peptide with a novel cell-penetrating peptide with anti-inflammatory property that can be used as a therapeutic agent for IBD and other inflammatory diseases.

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Acknowledgement

This study was supported in part by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2021R1A6A1A03039462).

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Authors and Affiliations

  1. Research Institute, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul, 03127, Republic of Korea

    Deogil Kim, Dong Woo Lee, Eui Kyun Jeong, Moon Sil Choi, Hoo Cheol Lee, Chong Pyung Chung, Jue-Yeon Lee & Yoon Jeong Park

  2. Department of Dental Regenerative Biotechnology and Dental Research Institute, School of Dentistry, Seoul National University, #403 Biomaterial Research Building, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea

    Dong Woo Lee, Gookjin Yoon & Yoon Jeong Park

  3. Department of Biological Sciences and Biotechnology, School of Biological Sciences, College of Natural Sciences, Chungbuk National University, Cheongju, 28644, Republic of Korea

    Yoon Shin Park

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  1. Deogil Kim
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Contributions

Conceptualization and draft supervision of project: JYL, YSP, CPC, and YJP. Overall experiments and preparation of the original draft: DK Writing the manuscript: DK, JYL, and YJP. Biological experiments: DWL, and GY. Peptide synthesis: EKJ, MSC, HCL. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Yoon Jeong Park.

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The animal studies were performed after receiving approval of the Institutional Animal Care and Use Committee (IACUC) in Seoul National University (IACUC Approval No. SNU-190121-1).

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Kim, D., Lee, D.W., Yoon, G. et al. Therapeutic Effect of HDAC5 Binding and Cell Penetrating Peptide for the Treatment of Inflammatory Bowel Disease. Tissue Eng Regen Med 20, 965–979 (2023). https://doi.org/10.1007/s13770-023-00572-7

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