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Published on: August 10, 2017
Histone deacetylase 6 inhibitor ACY-1215 protects against experimental acute liver failure by regulating the
Wen-Bin Zhang1, Hai-Yue Zhang1, Fang-Zhou Jiao1
1Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
Abstract:
Histone deacetylase 6 (HDAC6) is considered a new target for anticancer, anti-inflammatory, and neurodegenerative treatment. ACY-1215 is a selective histone deacetylase 6 inhibitor, and it has been recognized as a potential anticancer and anti-inflammation drug. The aim of our study was to investigate whether ACY-1215 has protective effects on acute liver failure (ALF) in mice and explore its potential mechanism. Male C57/BL6 mice were divided into normal, model, and ACY-1215 groups. ACY-1215 (25mg/kg) and same amounts of saline were given to mice. After 2h, the ALF models were induced by lipopolysaccharide (LPS, 100μg/kg) combined with D-galactosamine (D-gal, 400mg/kg). All animals were killed after 24h. The expressions of HDAC6 were determined by western blotting and RT-PCR assay. The expression levels of inflammatory cytokines were detected by ELISA and RT-PCR. The protein expression of Toll-like receptor 4 (TLR4), mitogen-activated protein kinase (MAPK), and nuclear factor κB (NF-κB) species were determined by western blot. The mortality of mice with ALF induced by LPS and D-gal was significantly decreased by ACY-1215 pretreatment. Procedures to manage ALF caused adversely affected liver histology and function; this damage was repaired by pretreatment of ACY-1215. ACY-1215 treatment also attenuated the serum and messenger RNA levels of the proinflammatory cytokines. Pretreatment of ACY-1215 significantly decreased the protein expression of TLR4 and the activation of MAPK and NF-κB signalling pathways. ACY-1215 has potential therapeutic value in mice with ALF by directly inhibiting inflammatory response via regulation of the TLR4-MAPK/NF-kB pathway.
Insights
ACY-1215, a selective histone deacetylase 6 (HDAC6) inhibitor, significantly reduced mortality and liver damage in mice with acute liver failure (ALF). It works by inhibiting inflammatory responses through the TLR4-MAPK/NF-κB pathway.
Area of Science:
- Pharmacology
- Immunology
- Hepatology
Background:
- Histone deacetylase 6 (HDAC6) is a therapeutic target for various diseases.
- ACY-1215 is a selective HDAC6 inhibitor with potential anti-inflammatory and anti-cancer properties.
- Acute liver failure (ALF) is a critical condition with high mortality and limited treatment options.
Purpose of the Study:
- To investigate the protective effects of ACY-1215 against ALF in a mouse model.
- To explore the underlying mechanisms of ACY-1215's action in ALF.
- To evaluate ACY-1215's impact on inflammatory pathways in ALF.
Main Methods:
- Male C57/BL6 mice were used to establish an ALF model induced by lipopolysaccharide (LPS) and D-galactosamine (D-gal).
- Mice were pretreated with ACY-1215 (25mg/kg) or saline.
- Liver damage, mortality, inflammatory cytokine levels, and key signaling pathway proteins (HDAC6, TLR4, MAPK, NF-κB) were assessed.
Main Results:
- ACY-1215 pretreatment significantly decreased mortality in ALF mice.
- Liver histology and function were improved by ACY-1215 treatment.
- ACY-1215 attenuated pro-inflammatory cytokine levels and inhibited the TLR4-MAPK/NF-κB signaling pathways.
Conclusions:
- ACY-1215 demonstrates significant therapeutic potential for treating acute liver failure in mice.
- The protective effects are mediated by the direct inhibition of inflammatory responses.
- ACY-1215 regulates the TLR4-MAPK/NF-κB pathway, offering a novel therapeutic strategy for ALF.
