Interferon signal transduction of biphenyl dimethyl dicarboxylate/amantadine and anti-HBV activity in HepG2 2.2.15
Interferon signal transduction of biphenyl dimethyl dicarboxylate/amantadine and anti-HBV activity in HepG2 2.2.15
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联苯二甲酯/金刚烷胺的干扰素信号转导及 HepG2 2.2.15 中的抗 HBV 活性
DOI：
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发表时间：
2006
影响因子：
6.7
通讯作者：
Do Ik Lee
中科院分区：
文献类型：
--
作者：
S. Joo;T. Won;Min Jung Kim;K. Hwang;Do Ik Lee
联苯二甲酸二甲酯(DDB)是一种保肝剂，在慢性肝炎的治疗中用作佐剂。金刚烷胺是一种抗病毒药物，主要用于治疗流感，但偶尔也用于治疗丙型肝炎。在之前的一项研究中，我们报道了DDB与金刚烷胺联用，通过诱导干扰素诱导HepG2 2.2.15细胞株中的基因表达而发挥抗乙肝病毒的作用。本研究的主要目的是确定DDB和/或金刚烷胺是否表现出抗乙肝病毒的特性，以及这些特性可能涉及的作用机制。在我们的研究中，我们能够确定DDB刺激JAK/STAT信号转导，并诱导干扰素-α刺激的基因的表达，最明显的是6-16和ISG12。此外，干扰素-α、PKR、OAS和MXA诱导的抗病毒效应在DDB存在的情况下被调节，其最佳浓度为250μg/mL，其程度与干扰素-α处理组的诱导程度相称。最后，我们发现联苯双酯能抑制前基因组核糖核酸和HBe Ag的复制，当联合使用金刚烷胺(25μg/mL)时，这种抑制作用达到最大。综上所述，本研究结果清楚地表明，双丁胺及其与金刚烷胺的联用能直接抑制干扰素-α信号介导的乙肝病毒在感染肝细胞中的复制，因此可能是一种新的治疗慢性乙型肝炎的方法，其主要特点是安全性高于其他治疗方案。
Biphenyl dimethyl dicarboxylate (DDB) is a hepatoprotectant, which is used as an adjuvant agent in a treatment for chronic hepatitis. Amantadine is an antiviral agent, which is utilized primarily in the treatment of influenza, but also, occasionally in the treatment of hepatitis C. In a previous study, we reported that DDB, coupled with amantadine, would exert an anti-HBV effect,via the induction of interferon-inducible gene expression in the HepG2 2.2.15 cell line. The primary objective of the present study was to determine whether or not DDB and/or amantadine exhibit anti-HBV properties, and what mechanisms of action might be involved in such properties. In our study, we were able to determine that DDB stimulates Jak/Stat signaling, and induces the expression of interferon alpha (IFN-α) stimulated genes, most notably 6–16 and ISG12. In addition, the antiviral effectors induced by IFN-α, PKR, OAS, and MxA, were regulated in the presence of DDB at its optimal concentration (250 μg/mL), to a degree commensurate with the degree of induction associated with the IFN-α treated group. Finally, we determined that the replication of pregenomic RNA and HBeAg was inhibited by DDB treatment, and this inhibition was maximized when coupled with the administration of amantadine (25 μg/mL). In conclusion, the results of this study demonstrated clearly that DDB, as well as the combination of DDB/amantadine, directly inhibited IFN-α signaling-mediated replication of HBV in infected hepatocytes, and thus may represent a novel treatment for chronic hepatitis B, which would be characterized principally by its improved safety over other treatment strategies.
DOI：
10.1073/pnas.84.13.4641
发表时间：
1987-07-01
影响因子：
11.1
作者：
ACS, G;SELLS, MA;POPPER, H
通讯作者：
POPPER, H
DOI：
10.1073/pnas.88.19.8495
发表时间：
1991-10-01
影响因子：
11.1
作者：
DOONG, SL;TSAI, CH;CHENG, YC
通讯作者：
CHENG, YC