Ubiquitously specific protease 4 inhibitor-Vialinin A attenuates inflammation and fibrosis in S100-induced hepatitis mice through Rheb/mTOR signalling.
Ubiquitously specific protease 4 inhibitor-Vialinin A attenuates inflammation and fibrosis in S100-induced hepatitis mice through Rheb/mTOR signalling.
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DOI：
10.1111/jcmm.16180
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发表时间：
2021-01
影响因子：
5.3
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Xu J;Chen D;Jin L;Chen Z;Tu Y;Huang X;Xue F;Xu J;Chen M;Wang X;Chen Y
炎症和纤维化是自身免疫性肝炎的主要后果，但其治疗机制仍有待研究。USP 4是一种去泛素化酶，在组织纤维化和免疫性疾病中起重要作用。Vialinin A是蘑菇的提取物，是一种特异性USP 4抑制剂。然而，缺乏证据表明Vialinin A在自身免疫性肝炎中发挥作用。通过在小鼠和AML 12细胞系中使用S100诱导的自身免疫性肝炎，检查Vialinin A的治疗机制。通过肝脏组织学染色和炎性细胞因子记录炎症。通过Masson、天狼星红染色和蛋白质印迹和真实的实时RT-PCR的纤维化细胞因子证实纤维化。在实验动物中，炎症和纤维化以及USP 4增加，并且在Vialinin A治疗后减少。Vialinin A也减少Rheb和磷酸化mTOR。此外，在LPS处理的AML 12细胞中，LPS诱导的USP 4、炎症和纤维化细胞因子、磷酸化mTOR和Rheb。特异性抑制USP 4的siRNA降低USP 4水平和上述参数。总之，USP 4在自身免疫性肝炎小鼠中显著升高，Vialinin A降低USP 4水平并减轻肝脏中的炎症和纤维化。其机制可能与调节Rheb/mTOR信号通路有关。
Inflammation and fibrosis are major consequences of autoimmune hepatitis, however, the therapeutic mechanism remains to be investigated. USP4 is a deubiquitinating enzyme and plays an important role in tissue fibrosis and immune disease. Vialinin A is an extract from mushroom and is a specific USP4 inhibitor. However, there is lack of evidences that Vialinin A plays a role in autoimmune hepatitis. By employing S100‐induced autoimmune hepatitis in mice and AML12 cell line, therapeutic mechanism of Vialinin A was examined. Inflammation was documented by liver histological staining and inflammatory cytokines. Fibrosis was demonstrated by Masson, Sirius red staining and fibrotic cytokines with western blot and real‐time RT‐PCR. In experimental animal, there were increases in inflammation and fibrosis as well as USP4, and which were reduced after treatment of Vialinin A. Vialinin A also reduced Rheb and phosphorylated mTOR. Moreover, in LPS‐treated AML12 cells, LPS‐induced USP4, inflammatory and fibrotic cytokines, phosphorylated mTOR and Rheb. Specific inhibitory siRNA of USP4 reduced USP4 level and the parameters mentioned above. In conclusion, USP4 was significantly elevated in autoimmune hepatitis mice and Vialinin A reduced USP4 level and attenuate inflammation and fibrosis in the liver. The mechanism may be related to regulation of Rheb/mTOR signalling.
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发表时间：
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期刊：
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