Lonicerin targets EZH2 to alleviate ulcerative colitis by autophagy-mediated NLRP3 inflammasome inactivation
| Autor: | Jian Liu, Qi Lv, Yinan Zhang, Yao Xing, Dong Dong, Yue Liu, Lihong Hu, Hongzhi Qiao |
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| Rok vydání: | 2021 |
| Předmět: |
PMSF
phenylmethanesulfonyl fluoride MPO myeloperoxidase ATG7 autophagy-related protein 7 DMSO dimethyl sulfoxide CETSA cellular thermal shift assay 0302 clinical medicine EZH2 enhancer of zeste homolog 2 General Pharmacology Toxicology and Pharmaceutics M-CSF macrophage colony stimulating factor 0303 health sciences Chemistry BMDMs bone marrow-derived macrophages EZH2 Inflammasome ELISA enzyme-linked immunosorbent assay Colitis PMA phorbol myristate acetate Ulcerative colitis ChIP chromatin immunoprecipitation 030220 oncology & carcinogenesis Histone methyltransferase LPS lipopolysaccharide Original Article DAI disease activity index medicine.drug AIM2 absent in melanoma 2 ATP adenosine triphosphate ECL enhanced chemiluminescent 3-MC 3-methylcholanthrene ATG5 RM1-950 macromolecular substances SIP solvent-induced protein precipitation Lonicerin 03 medical and health sciences CHX cycloheximide FBS fetal bovine serum PAMPs pathogen-associated molecular patterns DSS dextran sulfate sodium Autophagy medicine Epigenetics TEM transmission electron microscopy 030304 developmental biology EDTA ethylenediaminetetraacetic acid RMSF root mean-square fluctuation RMSD root mean-square deviation MDP muramyldipeptide medicine.disease NLRP3 inflammasome ATG5 autophagy-related protein 5 MSU monosodium urate crystals UC ulcerative colitis 5-ASA 5-aminosalicylic acid DTT dithiothreitol DAMPs damage-associated molecular patterns H&E hematoxylin and eosin Cancer research Therapeutics. Pharmacology NLRP3 nucleotide-binding domain-like receptors family pyrin domain containing 3 PRC2 polycomb repressive complex 2 |
| Zdroj: | Acta Pharmaceutica Sinica. B Acta Pharmaceutica Sinica B, Vol 11, Iss 9, Pp 2880-2899 (2021) |
| ISSN: | 2211-3835 |
| DOI: | 10.1016/j.apsb.2021.03.011 |
| Popis: | Aberrant activation of NLRP3 inflammasome in colonic macrophages strongly associates with the occurrence and progression of ulcerative colitis. Although targeting NLRP3 inflammasome has been considered to be a potential therapy, the underlying mechanism through which pathway the intestinal inflammation is modulated remains controversial. By focusing on the flavonoid lonicerin, one of the most abundant constituents existed in a long historical anti-inflammatory and anti-infectious herb Lonicera japonica Thunb., here we report its therapeutic effect on intestinal inflammation by binding directly to enhancer of zeste homolog 2 (EZH2) histone methyltransferase. EZH2-mediated modification of H3K27me3 promotes the expression of autophagy-related protein 5, which in turn leads to enhanced autophagy and accelerates autolysosome-mediated NLRP3 degradation. Mutations of EZH2 residues (His129 and Arg685) indicated by the dynamic simulation study have found to greatly diminish the protective effect of lonicerin. More importantly, in vivo studies verify that lonicerin dose-dependently disrupts the NLRP3–ASC–pro-caspase-1 complex assembly and alleviates colitis, which is compromised by administration of EZH2 overexpression plasmid. Thus, these findings together put forth the stage for further considering lonicerin as an anti-inflammatory epigenetic agent and suggesting EZH2/ATG5/NLRP3 axis may serve as a novel strategy to prevent ulcerative colitis as well as other inflammatory diseases. Graphical abstract Lonicerin can be considered as an anti-inflammatory epigenetic agent and EZH2/ATG5/NLRP3 axis may serve as a novel strategy to prevent ulcerative colitis as well as other inflammatory diseases.Image 1 |
| Databáze: | OpenAIRE |
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