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KMID : 1377020230200060965
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Tissue Engineering and Regenerative Medicine
2023 Volume.20 No. 6 p.965 ~ p.979
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Therapeutic Effect of HDAC5 Binding and Cell Penetrating Peptide for the Treatment of Inflammatory Bowel Disease
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Kim Deog-Il
Lee Dong-Woo
Yoon Gook-Jin
Jeong Eui-Kyun
Choi Moon-Sil
Lee Hoo-Cheol
Park Yoon-Shin
Chung Chong-Pyung
Lee Jue-Yeon
Park Yoon-Jeong
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Abstract
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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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KEYWORD
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Cell-penetrating peptide, Anti-inflammatory agent, Inflammatory bowel disease, Macrophage, Histone deacetylase
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