p300/CBP inhibitor A-485 alleviates acute liver injury by regulating macrophage activation and polarization
文献类型：期刊论文
| 作者 | Peng, Jinjin5,6; Li, Jiacheng3,6; Huang, Jing3,6; Xu, Pan3,6; Huang, Heming5,6; Liu, Yanjun5,6; Yu, Liang3,6 ; Yang, Yaxi6; Zhou, Bing6; Jiang, Hualiang6
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| 刊名 | THERANOSTICS
 |
| 出版日期 | 2019 |
| 卷号 | 9期号:26页码:8344-8361 |
| 关键词 | liver injury inflammation macrophages epigenetics acetyltransferase inhibitor |
| ISSN号 | 1838-7640 |
| DOI | 10.7150/thno.30707 |
| 通讯作者 | Zhang, Yuanyuan(Zhangyy@simm.ac.cn) ; Luo, Cheng(cluo@simm.ac.cn) ; Li, Guangming(ligm68@126.com) |
| 英文摘要 | High morbidity and mortality are associated with acute liver injury (ALI) for which no effective targeted drugs or pharmacotherapies are available. Discovery of potential therapeutic targets as well as inhibitors that can alleviate ALI is imperative. As excessive inflammatory cytokines released by macrophages are a critical cause of liver injury, we aimed to find novel compounds that could inhibit macrophage expression of inflammatory cytokines and alleviate liver injury. Methods: A high throughput assay was established to screen a small molecule inhibitor library of epigenetic targets. A highly selective catalytic p300/CBP inhibitor A-485 was identified as a potent hit in vitro and administrated to the lipopolysaccharide (LPS)/D-galactosamine (GalN)-induced mice in vivo. For in vitro analysis, RAW264.7 cells and primary BMDM cells exposed to LPS were co-incubated with A-485. A model of acute liver injury induced by LPS and GalN was used for evaluation of in vivo treatment efficacy. Results: A-485 inhibited LPS-induced inflammatory cytokine expression in a concentration-dependent manner in vitro. Significantly, A-485 administration alleviated histopathological abnormalities, lowered plasma aminotransferases, and improved the survival rate in the LPS/GalN-stimulated mice. Integrative ChIP-Seq and transcriptome analysis in the ALI animal model and macrophages revealed that A-485 preferentially blocked transcriptional activation of a broad set of pathologic genes enriched in inflammation-related signaling networks. Significant inhibition of H3K27ac/H3K18ac at promoter regions of these pivotal inflammatory genes was observed, in line with their suppressed transcription after A-485 treatment. Reduced expression of these pathological pro-inflammatory genes resulted in a decrease in inflammatory pathway activation, M1 polarization as well as reduced leukocyte infiltration in ALI mouse model, which accounted for the protective effects of A-485 on liver injury. Conclusion: Using a novel strategy targeting macrophage inflammatory activation and cytokine expression, we established a high-throughput screening assay to discover potential candidates for ALI treatment. We demonstrated that A-485, which targeted pathological inflammatory signaling networks at the level of chromatin, was pharmacologically effective in vivo and in vitro. Our study thus provided a novel target as well as a potential drug candidate for the treatment of liver injury and possibly for other acute inflammatory diseases. |
| WOS关键词 | DIFFERENTIAL EXPRESSION ANALYSIS ; EPIGENETIC REGULATION ; TRANSCRIPTION ; INFLAMMATION ; ACETYLATION ; HOMEOSTASIS ; PLASTICITY ; DISCOVERY ; EFFICIENT ; PROGRAM |
| 资助项目 | National Natural Science Foundation of China[81803554] ; National Natural Science Foundation of China[81070344] ; National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[21820102008] ; National Natural Science Foundation of China[81430084] ; Chinese Academy of Science[XDA12020353] ; Ministry of Science and Technology of China[2015CB910304] ; K. C. Wong Education Foundation ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Science and Technology Commission of Shanghai Municipality[19XD1404700] |
| WOS研究方向 | Research & Experimental Medicine |
| 语种 | 英语 |
| WOS记录号 | WOS:000492831200026 |
| 出版者 | IVYSPRING INT PUBL |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/281838]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhang, Yuanyuan; Luo, Cheng; Li, Guangming |
| 作者单位 | 1.Fudan Univ, Key Lab Metab & Mol Med, Dept Biochem & Mol Biol, Sch Basic Med Sci,Minist Educ,Huashan Hosp, Shanghai 200032, Peoples R China 2.Guiyang Univ Tradit Chinese Med, Sch Pharm, South Dong Qing Rd, Guiyang 550025, Guizhou, Peoples R China 3.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China 4.Fujian Med Univ, Sch Pharm, Fuzhou, Fujian, Peoples R China 5.Shanghai Jiao Tong Univ, Xinhua Hosp, Sch Med, Dept Gastroenterol, 1665 Kongjiang Rd, Shanghai 200092, Peoples R China 6.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Peng, Jinjin,Li, Jiacheng,Huang, Jing,et al. p300/CBP inhibitor A-485 alleviates acute liver injury by regulating macrophage activation and polarization[J]. THERANOSTICS,2019,9(26):8344-8361. |
| APA | Peng, Jinjin.,Li, Jiacheng.,Huang, Jing.,Xu, Pan.,Huang, Heming.,...&Li, Guangming.(2019).p300/CBP inhibitor A-485 alleviates acute liver injury by regulating macrophage activation and polarization.THERANOSTICS,9(26),8344-8361. |
| MLA | Peng, Jinjin,et al."p300/CBP inhibitor A-485 alleviates acute liver injury by regulating macrophage activation and polarization".THERANOSTICS 9.26(2019):8344-8361. |
入库方式： OAI收割
来源：上海药物研究所
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