Chinese Hepatolgy ›› 2019, Vol. 24 ›› Issue (10): 1125-1128.

• Original Articles • Previous Articles     Next Articles

Protective effect and mechanism of histone acetyltransferase inhibitor DCH36_06 on mice with acute liver injury

PENG Jin-jin1, HUANG He-ming1, LIU Yan-jun1, SHI Cui-cui1, FAN Jian-gao1, ZHANG Yuan-yuan2, LUO Cheng2, LI Guang-ming1   

  1. 1. Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China;
    2. Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
  • Received:2019-07-08 Published:2020-03-27
  • Contact: LI Guang-ming, Email: liguangming@xinhuamed.com.cn

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Abstract: Objective To investigate the protective effect of histone acetyltransferase inhibitor DCH36_06 on mice with lipopolysaccharide (LPS)/D-galactose (D-Gal)-induced acute liver injury (ALI) and its mechanism. Methods A total of 75 C57BL/6 mice were randomly divided into 4 groups, 20 in normal control group, 20 in LPS/D-Gal-induced ALI group, 20 in DCH36_06 treatment group and 15 in DCH36_06 control group, injected intraperitoneally with normal saline, LPS/D-Gal, LPS/D-Gal + DCH36_06 and DCH36_06, respectively. After 4 hours of LPS/D-Gal injection, 5 mice in each of the first 3 groups were sacrificed. The peripheral serum and liver tissues of the mice were harvest to detect biochemical indexes, to evaluate liver tissue pathological changes and hepatocyte apoptosis by hematine-eosin and terminal deoxynucleotidyl transferase mediated biotinylated deoxyuridine triphosphate nick end labelling staining, and to detect the expression of pro-inflammatory cytokines in liver tissues by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. The remaining mice were kept for 24 hours to test the 24-hour survival rate of each group. Results The 24-hour survival rate in the ALI group was only 40% (6/15), which reached 86.6% (13/15) in DCH36_06 treatment group (P<0.05). The necroinflammation and hepatocyte apoptosis of liver tissue were ameliorated in DCH36_06 treatment group compared with those in the ALI group. The serum levels of aspartate aminotransferase, alanine aminotransferase and total bilirubin in the treatment group were significantly lower than those in the ALI group (281.4±48.1 U/L vs 1151.0±111.1 U/L, 175.2±32.5 U/L vs 921.5±47.9 U/L, and 9.8±0.7 μmol/L vs 21.0±0.4 μmol/L, P<0.05). Additionally, the mRNA and protein levels in liver tissues of tumor necrosis factor alpha, interleukin 1β and interleukin 6 in the treatment group (72.0±9.3, 91.4±4.6, 175.5±19.6, 25.9±2.3 pg/mL, 816.5±60.8 pg/mL and 305.6±20.1 pg/mL) were significantly lower than those in the ALI group (15.4±0.2, 6.0±1.6, 21.5±0.9, 7.9±1.2 pg/mL, 211.4±22.4 pg/mL and 53.2±7.3 pg/mL) (P<0.05). Conclusion DCH36_06 can protect mice from LPS/D-Gal-induced ALI, and the mechanism might be related to the inhibition of crucial pro-inflammatory cytokines expression and liver inflammatory injury, indicating the epigenetic regulation could be a promising target for the treatment of ALI.

Key words: Acute liver injury, DCH36_06, Cytokine, Apoptosis