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Celastrol inhibits hepatitis C virus replication by upregulating heme oxygenase-1 via the JNK MAPK/Nrf2 pathway in human hepatoma cells
Antiviral Research ( IF 7.6 ) Pub Date : 2017-09-19 , DOI: 10.1016/j.antiviral.2017.09.010
Chin-Kai Tseng , Sung-Po Hsu , Chun-Kuang Lin , Yu-Hsuan Wu , Jin-Ching Lee , Kung-Chia Young

background and purpose

Celastrol, a quinone methide triterpene isolated from the root extracts of Tripterygium wilfordii, can greatly induce the gene expression activity of heme oxygenase-1 (HO-1) to achieve disease prevention and control. HO-1 induction was recently shown to result in anti-HCV activity by inducing type I interferon and inhibiting hepatitis C virus (HCV) NS3/4A protease activity. The aim of the present study is to evaluate the anti-HCV activity of celastrol and characterize its mechanism of inhibition.

Methods

The anti-HCV activity of celastrol was evaluated using the HCV subgenomic replicon and HCVcc infection systems. The anti-HCV mechanism of celastrol targeting HO-1 expression was clarified using specific inhibitors against several signaling pathways. The transcriptional regulation of celastrol on target gene expression was determined using promoter-based reporter activity assay. The synergistic effect of celastrol and a numbers of clinically used anti-HCV drugs was determined via a drug combination assay.

Results

Celastrol inhibited HCV replication in both the HCV subgenomic and HCVcc infection systems with EC50 values of 0.37 ± 0.022 and 0.43 ± 0.019 μM, respectively. Celastrol-induced heme oxygenase 1 (HO-1) expression promoted antiviral interferon responses and inhibition of NS3/4A protease activity, thereby blocking HCV replication. These antiviral effects were abrogated by treatment with the HO-1-specific inhibitor SnMP or silencing of HO-1 expression by transfection of shRNA, which indicates that HO-1 induction contributes to the anti-HCV activity of celastrol. JNK mitogen-activated protein kinase and nuclear factor erythroid 2-related factor 2 (Nrf2) were confirmed to be involved in the inductive effect of celastrol on HO-1 expression. Celastrol exhibited synergistic effects in combination with interferon-alpha, the NS5A inhibitor daclatasvir, and the NS5B inhibitor sofosbuvir.

Conclusion

Celastrol can serve as a potential supplement for blocking HCV replication. Targeting the JNK/Nrf2/HO-1 axis presents a promising strategy against HCV infection.



中文翻译:

Celastrol通过上调人肝癌细胞中JNK MAPK / Nrf2途径的血红素加氧酶-1来抑制丙型肝炎病毒复制

背景和目的

雷公藤的根提取物中分离出的甲基萘醌三萜烯Celastrol可以极大地诱导血红素加氧酶-1(HO-1)的基因表达活性,从而实现疾病的预防和控制。最近显示,HO-1诱导通过诱导I型干扰素并抑制丙型肝炎病毒(HCV)NS3 / 4A蛋白酶活性而导致抗HCV活性。本研究的目的是评估Celastrol的抗HCV活性并表征其抑制机制。

方法

使用HCV亚基因组复制子和HCVcc感染系统评估了Celastrol的抗HCV活性。使用针对几种信号传导途径的特异性抑制剂阐明了Celastrol靶向HO-1表达的抗HCV机制。使用基于启动子的报道分子活性测定法确定了Celastrol对靶基因表达的转录调控。通过药物组合测定法确定了Celastrol和许多临床使用的抗HCV药物的协同作用。

结果

Celastrol抑制HCV亚基因组和HCVcc感染系统中的HCV复制,其EC50值分别为0.37±0.022和0.43±0.019μM。Celastrol诱导的血红素加氧酶1(HO-1)表达促进抗病毒干扰素应答并抑制NS3 / 4A蛋白酶活性,从而阻止HCV复制。通过使用HO-1特异性抑制剂SnMP处理或通过转染shRNA沉默HO-1表达可消除这些抗病毒作用,这表明HO-1诱导有助于celastrol的抗HCV活性。JNK丝裂原活化蛋白激酶和核因子红系2相关因子2(Nrf2)被证实与Celastrol对HO-1表达的诱导作用有关。Celastrol与NS5A抑制剂daclatasvir干扰素-α组合显示出协同作用,

结论

Celastrol可以作为阻断HCV复制的潜在补充剂。靶向JNK / Nrf2 / HO-1轴提出了针对HCV感染的有前途的策略。

更新日期:2017-09-19
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