A novel sorbicillinoid compound as a potent anti-inflammation agent through inducing NLRP3 protein degradation.
A novel sorbicillinoid compound as a potent anti-inflammation agent through inducing NLRP3 protein degradation.
复制标题
通过诱导NLRP 3蛋白降解作为有效抗炎剂的新型索比西林类化合物。
DOI：
10.1111/bph.16058
复制
发表时间：
2023-08
影响因子：
7.3
通讯作者：
Zhang, Youwei
中科院分区：
文献类型：
--
作者：
Wang, Fangfang;Zhang, Meng;Yuan, Meng;Xia, Zixuan;Yang, Fengge;Zhang, Sihao;Lin, Tengyu;Luo, Lianxiang;Tang, Jinshan;Zhang, Youwei
关键词：
慢性炎症是致病的，也是人类疾病的致病因素，对公众健康造成重大威胁。NLRP3(NLRP3)是目前最典型的炎症调节因子。因此，靶向NLRP3具有治疗炎症性疾病和改善人类健康的潜力。用脂多糖诱导细胞培养产生炎症反应。用脂多糖/D-氨基半乳糖和葡聚糖硫酸钠分别诱导C57BL/6J小鼠急性肝炎和溃疡性结肠炎。采用免疫印迹、免疫荧光、免疫沉淀、定量聚合酶链式反应和酶联免疫吸附试验等方法检测细胞培养和小鼠体内炎症反应的激活情况。JNUTS013是我们最近合成的一种新的山梨素类化合物，在细胞培养和小鼠模型中都有明显的抑制炎症作用。在机制上，JNUTS013诱导NLRP3蛋白酶体依赖的降解。因此，它抑制了NLRP3炎症体的形成以及下游炎性细胞因子和趋化因子的产生。证实JNUTS013对小鼠NLRP3蛋白表达有抑制作用。重要的是，JNUTS013未能改善Nlrp3−/−基因敲除小鼠的肠道炎症，支持NLRP3作为JNUTS013抑制炎症的生物靶点。进一步的研究揭示了JNUTS013诱导NLRP3降解所需的关键化学部分。本研究鉴定了一个新的化合物JNUTS013，它通过在体内外诱导NLRP3蛋白降解来抑制炎症，不仅支持JNUTS013作为抗炎药的发展，而且为通过化学诱导NLRP3降解来治疗炎症开辟了一条新的途径。
Chronic inflammation is pathogenic and contributes to human diseases, causing a significant threat to public health. The NLR family pyrin domain-containing protein 3 (NLRP3) is the best-characterized factor regulating inflammation. Therefore, targeting NLRP3 has the potential to treat inflammatory diseases and improve human health. Lipopolysaccharide was used to induce inflammation in cell cultures. Lipopolysaccharide/d-galactosamine and dextran sulfate sodium salt were used to induce acute liver inflammation and ulcerative colitis respectively in C57BL/6J mice. Western blotting, immunofluorescence, immunoprecipitation, quantitative PCR and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the activation of the inflammatory response in cell cultures and in mice. JNUTS013, a novel sorbicillinoid compound recently synthesized by us, significantly inhibited inflammation both in cell cultures and in mouse models. Mechanistically, JNUTS013 induced proteasome-dependent degradation of NLRP3. Hence, it suppressed the formation of the NLRP3 inflammasome and the production of downstream inflammatory cytokines and chemokines. The inhibitory effect of JNUTS013 on NLRP3 protein expression was confirmed in mice. Importantly, JNUTS013 failed to ameliorate bowel inflammation in Nlrp3−/− knockout mice, supporting NLRP3 as the biological target by which JNUTS013 inhibits inflammation. Further studies revealed critical chemical moieties of JNUTS013 required for inducing NLRP3 degradation. This study identifies a novel compound JNUTS013 that inhibits inflammation through inducing NLRP3 protein degradation in vitro and in vivo, which not only supports the development of JNUTS013 as an anti-inflammation agent but also creates a new way for treatment of inflammation by chemically inducing NLRP3 degradation.
登录
查看更多内容
影响因子：
4.5
作者：
通讯作者：
--
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.8
作者：
Laliberte, RE;Perregaux, DG;Gabel, CA
通讯作者：
Gabel, CA
DOI：
10.1126/science.aas8995
发表时间：
2020-09-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Magupalli VG;Negro R;Tian Y;Hauenstein AV;Di Caprio G;Skillern W;Deng Q;Orning P;Alam HB;Maliga Z;Sharif H;Hu JJ;Evavold CL;Kagan JC;Schmidt FI;Fitzgerald KA;Kirchhausen T;Li Y;Wu H
通讯作者：
Wu H
影响因子：
64.8
作者：
Hochheiser, Inga, V;Pilsl, Michael;Geyer, Matthias
通讯作者：
Geyer, Matthias