Geranylgeranylacetone decreases the production of hepatitis B virus‐related antigen by comprehensive downregulation of mRNA transcription activity
Geranylgeranylacetone decreases the production of hepatitis B virus‐related antigen by comprehensive downregulation of mRNA transcription activity
复制标题
香叶基香叶基丙酮通过全面下调 mRNA 转录活性来减少乙型肝炎病毒相关抗原的产生
DOI：
10.1111/jgh.15394
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发表时间：
2021
影响因子：
4.1
通讯作者：
Nakao Kazuhiko
中科院分区：
文献类型：
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作者：
Haraguchi Masafumi;Miuma Satoshi;Yamamoto Kazuo;Nakao Yasuhiko;Ichikawa Tatsuki;Kanda Yasuko;Sasaki Ryu;Fukushima Masanori;Akazawa Yuko;Miyaaki Hisamitsu;Nakao Kazuhiko
背景和目的：目前的治疗很少能达到消除B型肝炎病毒（HBV）的目的.因此，需要更有效的抗HBV治疗。我们先前报道了香叶基香叶基丙酮（GGA）在人肝癌细胞中显示出抗丙型肝炎病毒活性。在这项研究中，我们检查了GGA的抗HBV活性。方法我们使用HepG2.2.15.7细胞，HBV感染的PXB细胞，线性HBV转染的Huh 7细胞，PLC/PRF/5细胞作为HBV感染的肝细胞模型。GGA治疗后，通过荧光免疫法测定HBV相关抗原。通过北方印迹检测HBV相关mRNA。通过真实的实时聚合酶链反应测量cccDNA和内质网应激标志物。HBV启动子和增强子区域的活动进行了检查，使用荧光素酶vectors.ResultsAfter GGA治疗，B型肝炎表面抗原和B型肝炎e抗原分泌减少在所有HBV感染的肝细胞模型。GGA处理也降低了HBV相关mRNA，但cccDNA水平未受影响。此外，GGA处理降低了HBV S1和S2启动子区以及增强子1/增强子2/核心启动子区的活性。主要转录因子肝细胞核因子3和4以及CCAAT/增强子结合蛋白的mRNA表达也降低。此外，内质网应激标志物的表达水平增加GGA治疗，这反映了HBV相关抗原分泌的变化。结论香叶基香叶基丙酮治疗通过抑制HBV启动子和增强子活性的全面下调来降低HBV相关蛋白水平，这可能是由肝脏转录因子表达降低引起的。GGA治疗可以增强抗HBV效果与其他疗法相结合。
Background and AimElimination of hepatitis B virus (HBV) is infrequently achieved with current therapies. Therefore, more effective anti‐HBV therapy is needed. We previously reported that geranylgeranylacetone (GGA) showed anti‐hepatitis C virus activity in human hepatoma cells. In this study, we examined the anti‐HBV activity of GGA.MethodsWe used HepG2.2.15.7 cells, PXB cells infected with HBV, Huh7 cells transfected with linear HBV, and PLC/PRF/5 cells as HBV‐infected hepatocyte models. After GGA treatment, HBV‐related antigen was measured by chemiluminescent immunoassay. HBV‐related mRNA was examined by Northern blot. cccDNA and endoplasmic reticulum stress markers were measured by real‐time polymerase chain reaction. The activities of HBV promoters and enhancer regions were examined using luciferase vectors.ResultsAfter GGA treatment, hepatitis B surface antigen and hepatitis B e antigen secretion was decreased in all HBV‐infected hepatocyte models. HBV‐related mRNA was also decreased by GGA treatment, although cccDNA levels were not affected. Additionally, the activity of HBV S1 and S2 promoter region and Enhancer 1/Enhancer 2/core promoter region was reduced by GGA treatment. The mRNA expression of the main transcription factors, hepatocyte nuclear factor 3 and 4 and CCAAT/enhancer binding protein, was also decreased. Further, the expression levels of endoplasmic reticulum stress markers were increased by GGA treatment, which reflected the change in HBV‐related antigen secretion.ConclusionsGeranylgeranylacetone treatment reduces HBV‐related protein levels by suppressing comprehensive downregulation of HBV promoter and enhancer activity, which might be caused by decreased hepatic transcription factor expression. GGA treatment may enhance anti‐HBV effects in combination with other therapies.