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ADAM8 promotes alcoholic liver fibrosis through the MAPK signaling pathway
Mengli Yang1,2, Sanqiang Li3,4, Renli Luo1,2
1The Molecular Medicine Key Laboratory of Liver Injury and Repair, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 KaiYuan Road, Luoyang, 471000, Henan, China.
Abstract:
The effect and molecular regulatory mechanism of A Disintegrin and Metalloproteinase 8 (ADAM8) were explored in alcoholic liver fibrosis (ALF). C57BL/6N male mice were randomly divided into control, alcohol, and ADAM8-sgRNA3 plasmid groups. The control group received control liquid diet, while the alcohol and ADAM8-sgRNA3 plasmid groups were given alcohol liquid feed diet combined with ethanol gavage treatment for 8 weeks to induce ALF modeling. In addition, the ADAM8-sgRNA3 plasmid group was injected with the effective ADAM8-sgRNA3 plasmid, while the alcohol and control group mice were injected with an equivalent amount of physiological saline. LX-2 human hepatic stellate cells were divided into control, alcohol, si-ADAM8-2, and si-ADAM8-NC groups and induced for 48 h for model establishment in vitro. Serological detection, pathological staining, Western blotting, qRT-PCR and CCK8 assay were performed for experiments. Compared with the alcohol group, ADAM8 mRNA, protein and, positive area rate, serological indicators, pathological changes, and the expression of liver fibrosis marker and MAPK signaling pathway-related factors in the ADAM8-sgRNA3 plasmid group significantly decreased in vivo. Compared with the alcohol group, ADAM8 mRNA and protein expression, cell viability, and the expression of liver fibrosis markers and MAPK signaling pathway-related factors (p-ERK1/2, PCNA, Bcl-2, p-c-Jun, TGFβ1, p-p38 MAPK and HSP27) reduced significantly in the si-ADAM8-2 group. Therefore, ADAM8 promotes ALF through the MAPK signaling pathway, a promising target for treating ALF.
Insights
A Disintegrin and Metalloproteinase 8 (ADAM8) promotes alcoholic liver fibrosis (ALF) by activating the MAPK signaling pathway. Inhibiting ADAM8 shows promise for treating ALF.
Area of Science:
- Hepatology
- Molecular Biology
- Biochemistry
Background:
- Alcoholic liver fibrosis (ALF) is a significant health concern with complex molecular mechanisms.
- A Disintegrin and Metalloproteinase 8 (ADAM8) has been implicated in fibrotic diseases, but its role in ALF requires further elucidation.
Purpose of the Study:
- To investigate the effect and molecular regulatory mechanism of ADAM8 in ALF.
- To explore ADAM8 as a potential therapeutic target for ALF.
Main Methods:
- Establishment of ALF models in C57BL/6N mice and LX-2 human hepatic stellate cells.
- In vivo and in vitro experiments utilizing ADAM8-sgRNA3 plasmid and si-ADAM8 transfection.
- Analysis of ADAM8 expression, liver fibrosis markers, and MAPK signaling pathway activation via serological detection, pathological staining, Western blotting, qRT-PCR, and CCK8 assays.
Main Results:
- Inhibition of ADAM8 (using ADAM8-sgRNA3 plasmid in vivo and si-ADAM8 in vitro) significantly reduced liver fibrosis indicators, pathological changes, and ADAM8 expression.
- ADAM8 inhibition led to decreased expression of key liver fibrosis markers and suppressed MAPK signaling pathway activation (including p-ERK1/2, p-p38 MAPK).
- Cell viability was reduced in the si-ADAM8 group, indicating a pro-fibrotic role for ADAM8.
Conclusions:
- ADAM8 plays a crucial role in promoting ALF, primarily through the activation of the MAPK signaling pathway.
- Targeting ADAM8 presents a promising therapeutic strategy for the treatment of alcoholic liver fibrosis.
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