scholarly journals Knockdown of Mitogen-Activated Protein Kinase Kinase 3 Negatively Regulates Hepatitis A Virus Replication

2021 ◽  
Vol 22 (14) ◽  
pp. 7420
Author(s):  
Tatsuo Kanda ◽  
Reina Sasaki-Tanaka ◽  
Ryota Masuzaki ◽  
Naoki Matsumoto ◽  
Hiroaki Okamoto ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Zinc Chloride ◽  
Hepatitis A ◽  
Hepatitis A Virus ◽  
Hepatoma Cell ◽  
Mitogen Activated Protein Kinase ◽  
Human Hepatoma Cell ◽  
Tlr Signaling ◽  
Hepatoma Cell Lines ◽  
Mitogen Activated Protein

Zinc chloride is known to be effective in combatting hepatitis A virus (HAV) infection, and zinc ions seem to be especially involved in Toll-like receptor (TLR) signaling pathways. In the present study, we examined this involvement in human hepatoma cell lines using a human TLR signaling target RT-PCR array. We also observed that zinc chloride inhibited mitogen-activated protein kinase 3 (MAP2K3) expression, which could downregulate HAV replication in human hepatocytes. It is possible that zinc chloride may inhibit HAV replication in association with its inhibition of MAP2K3. In that regard, this study set out to determine whether MAP2K3 could be considered a modulating factor in the development of the HAV pathogen-associated molecular pattern (PAMP) and its triggering of interferon-β production. Because MAP2K3 seems to play a role in antiviral immunity against HAV infection, it is a promising target for drug development. The inhibition of MAP2K3 may also prevent HAV patients from developing a severe hepatitis A infection.

scholarly journals Melatonin Inhibits the Progression of Hepatocellular Carcinoma through MicroRNA Let7i-3p Mediated RAF1 Reduction

2018 ◽  
Vol 19 (9) ◽  
pp. 2687 ◽  
Author(s):  
Tong-Hong Wang ◽  
Chuen Hsueh ◽  
Chin-Chuan Chen ◽  
Wan-Syuan Li ◽  
Chau-Ting Yeh ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Hepatoma Cell ◽  
Mitogen Activated Protein Kinase ◽  
Migration And Invasion ◽  
Small Rna Sequencing ◽  
Human Hepatoma Cell ◽  
Melatonin Treatment ◽  
Hepatoma Cell Lines ◽  
Mitogen Activated Protein

Melatonin is the main pineal hormone that relays light/dark-cycle information to the circadian system. Recent studies have examined the intrinsic antitumor activity of melatonin in various cancers, including hepatocellular carcinoma (HCC), the primary life-threatening malignancy in both sexes in Taiwan. However, the detailed regulatory mechanisms underlying melatonin’s anti-HCC activity remain incompletely understood. Here, we investigated the mechanisms by which the anti-HCC activity of melatonin is regulated. Human hepatoma cell lines were treated with 1 and 2 mM melatonin, and functional assays were used to dissect melatonin’s antitumor effect in HCC; small-RNA sequencing was performed to identify the microRNAs (miRNAs) involved in the anti-HCC activity of melatonin; and quantitative RT-PCR and Western blotting were used to elucidate how miRNAs regulate melatonin-mediated HCC suppression. Melatonin treatment at both doses strongly inhibited the proliferation, migration and invasion capacities of Huh7 and HepG2 cell lines, and melatonin treatment markedly induced the expression of the miRNA let7i-3p in cells. Notably, transfection of cells with a let7i-3p mimic drastically reduced RAF1 expression and activation of mitogen-activated protein kinase signaling downstream from RAF1, and rescue-assay results demonstrated that melatonin inhibited HCC progression by modulating let7i-3p-mediated RAF1 suppression. Our findings support the view that melatonin treatment holds considerable promise as a therapy for HCC.

scholarly journals Different Mechanisms of Action of Regorafenib and Lenvatinib on Toll-Like Receptor-Signaling Pathways in Human Hepatoma Cell Lines

2020 ◽  
Vol 21 (9) ◽  
pp. 3349 ◽  
Author(s):  
Reina Sasaki ◽  
Tatsuo Kanda ◽  
Mariko Fujisawa ◽  
Naoki Matsumoto ◽  
Ryota Masuzaki ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Cell Lines ◽  
Hepg2 Cells ◽  
Hepatoma Cell ◽  
Human Hepatoma ◽  
Toll Like Receptor ◽  
Human Hepatoma Cell ◽  
Tlr Signaling ◽  
Hepatoma Cell Lines ◽  
Gene Expression Levels

Multiple kinase inhibitors are available for patients with advanced hepatocellular carcinoma (HCC). It is largely unknown whether regorafenib or lenvatinib modulates innate immunity including Toll-like receptor (TLR)-signaling pathways in HCC. We performed real-time RT-PCR to investigate 84 TLR-associated gene expression levels and compared these gene expression levels in each hepatoma cells treated with or without regorafenib or lenvatinib. In response to regorafenib, nine and 10 genes were upregulated in Huh7 and HepG2 cells, respectively, and only C-X-C motif chemokine ligand 10 was upregulated in both cell lines. A total of 14 and 12 genes were downregulated in Huh7 and HepG2 cells, respectively, and two genes (Fos proto-oncogene, AP-1 transcription factor subunit, and ubiquitin conjugating enzyme E2 N) were downregulated in both cell lines. In response to lenvatinib, four and 16 genes were upregulated in Huh7 and HepG2 cells, respectively, and two genes (interleukin 1 alpha and TLR4) were upregulated in both cells. Six and one genes were downregulated in Huh7 and HepG2, respectively, and no genes were downregulated in both cell lines. In summary, regorafenib and lenvatinib affect TLR signaling pathways in human hepatoma cell lines. Modulation of TLR signaling pathway may improve the treatment of HCC patients with refractory disease.

scholarly journals Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling

2008 ◽  
Vol 205 (6) ◽  
pp. 1491-1503 ◽  
Author(s):  
Wangsen Cao ◽  
Clare Bao ◽  
Elizaveta Padalko ◽  
Charles J. Lowenstein
Keyword(s):  
Protein Kinase ◽  
Histone Deacetylase Inhibitors ◽  
Inflammatory Diseases ◽  
Mapk Pathway ◽  
Critical Role ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Toll Like Receptor ◽  
Tlr Signaling ◽  
Mitogen Activated Protein

The mitogen-activated protein kinase (MAPK) pathway plays a critical role in Toll-like receptor (TLR) signaling. MAPK phosphatase-1 (MKP-1) inhibits the MAPK pathway and decreases TLR signaling, but the regulation of MKP-1 is not completely understood. We now show that MKP-1 is acetylated, and that acetylation regulates its ability to interact with its substrates and deactivate inflammatory signaling. We found that LPS activates acetylation of MKP-1. MKP-1 is acetylated by p300 on lysine residue K57 within its substrate-binding domain. Acetylation of MKP-1 enhances its interaction with p38, thereby increasing its phosphatase activity and interrupting MAPK signaling. Inhibition of deacetylases increases MKP-1 acetylation and blocks MAPK signaling in wild-type (WT) cells; however, deacetylase inhibitors have no effect in cells lacking MKP-1. Furthermore, histone deacetylase inhibitors reduce inflammation and mortality in WT mice treated with LPS, but fail to protect MKP-1 knockout mice. Our data suggest that acetylation of MKP-1 inhibits innate immune signaling. This pathway may be an important therapeutic target in the treatment of inflammatory diseases.

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