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ERK1/2-HNF4α axis is involved in epigallocatechin-3-gallate inhibition of HBV replication.
- Source :
-
Acta pharmacologica Sinica [Acta Pharmacol Sin] 2020 Feb; Vol. 41 (2), pp. 278-285. Date of Electronic Publication: 2019 Sep 25. - Publication Year :
- 2020
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Abstract
- Epigallocatechin gallate (EGCG), a major polyphenol in green tea, exhibits diverse biological activities. Previous studies show that EGCG could effectively suppress HBV gene expression and replication, but the role of EGCG in HBV replication and its underlying mechanisms, especially the signaling pathways involved, remain unclear. In this study we investigated the mechanisms underlying EGCG inhibition on HBV replication with a focus on the signaling pathways. We showed that EGCG (12.5-50 μM) dose-dependently inhibited HBV gene expression and replication in HepG2.2.15 cells. Similar results were observed in HBV mice receiving EGCG (25 mg· kg <superscript>-1</superscript> · d <superscript>-1</superscript> , ip) for 5 days. In HepG2.2.15 cells, we showed that EGCG (12.5-50 μM) significantly activate ERK1/2 MAPK signaling, slightly activate p38 MAPK and JAK2/STAT3 signaling, while had no significant effect on the activation of JNK MAPK, PI3K/AKT/mTOR and NF-κB signaling. By using specific inhibitors of these signaling pathways, we demonstrated that ERK1/2 signaling pathway, but not other signaling pathways, was involved in EGCG-mediated inhibition of HBV transcription and replication. Furthermore, we showed that EGCG treatment dose-dependently decreased the expression of hepatocyte nuclear factor 4α (HNF4α) both at the mRNA and protein levels, which could be reversed by pretreatment with the ERK1/2 inhibitor PD98059 (20 μM). Moreover, we revealed that EGCG treatment dose-dependently inhibited the activity of HBV core promoter and the following HBV replication. In summary, our results demonstrate that EGCG inhibits HBV gene expression and replication, which involves ERK1/2-mediated downregulation of HNF4α.These data reveal a novel mechanism for EGCG to inhibit HBV gene expression and replication.
- Subjects :
- Animals
Antiviral Agents administration & dosage
Antiviral Agents pharmacology
Catechin administration & dosage
Catechin pharmacology
Disease Models, Animal
Dose-Response Relationship, Drug
Gene Expression Regulation, Viral drug effects
Hep G2 Cells
Hepatitis B genetics
Hepatitis B virology
Hepatocyte Nuclear Factor 4 genetics
Hepatocyte Nuclear Factor 4 metabolism
Humans
Mice
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase 1 metabolism
Mitogen-Activated Protein Kinase 3 metabolism
Catechin analogs & derivatives
Hepatitis B drug therapy
Hepatitis B virus drug effects
Virus Replication drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1745-7254
- Volume :
- 41
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Acta pharmacologica Sinica
- Publication Type :
- Academic Journal
- Accession number :
- 31554961
- Full Text :
- https://doi.org/10.1038/s41401-019-0302-0