BET选择性抑制剂38号化合物对急性肝损伤小鼠保护作用研究*

doi:10.3969/j.issn.1672-5069.2022.05.004

Abstract

Abstract: Objective The aim of this study was to investigate the protective effect of compound 38, a selective bromodomain and extra-terminal (BET) inhibitor, on CCl₄-induced acute liver injury (ALI) in mice. Methods The Raw264.7 cells was stimulated by LPS with or without compound 38 co-culture, and the Raw264.7 cells with no stimulation served as control. The cell RNA was extracted by Trizol, and the cell inflammation-related genes were detected by RT-qPCR. Twenty-four mice were divided randomly into control, model and compound 38-intervened group, and the model was established by CCl₄administration intraperitoneally. Serum ALT and AST level was measured, and the pathological changes of liver tissues were observed. The intrahepatic neutrophil and macrophage was detected by immunohistochemistry. Results In model cells, the IL-1βmRNA, IL-6 mRNA and TNF-αmRNA levels were (23246.0±1185.0), (7740.0±322.2) and (132.2±2.7), significantly higher than [(1.1±0.1), (1.1±0.4) and (1.0±0), P＜0.05], while in the compound 38-intervened cells were all greatly dose-dependently decreased as compared to those in the model (all P＜0.05); serum ALT and AST levels in mice with ALI were (8281.0±2710.0)U/L and (5330.0±2435.0)U/L, significantly higher than [(51.5±7.0)U/L) and (215.3±12.4)U/L, respectively, P＜0.05] in the control, while in the compound 38-intervended cells were (3634.0±713.9.0) U/L and (2876.0±667.1)U/L, greatly decreased compared to in the model (P＜0.05); the histopathological examination showed that the liver tissue structure was disordered with obvious inflammatory response, such as hepatocyte necrosis, destruction of normal lobule structure and aggregation of a large number of inflammatory cells in the model group, while the above pathological changes were alleviated in the intervention group. Conclusion The copound 38, a selective BET inhibitor, could alleviate CCl₄-induced acute liver injury in mice, and the mechanism might be related to the inhibition of inflammation-related cytokine expression and decreased infiltration of macrophages.

Key words: Acute liver injures, Bromodomain and extra-terminal inhibitor, Compound 38, Raw264.7 macrophages, Mice

Fu Rong, Wu Kanghui, Shi Cuicui, et al.. Protective effect of BET selective inhibitor, compound 38 on acute liver injury in mice[J]. Journal of Practical Hepatology, 2022, 25(5): 620-623.

References

[1]Kim S J, Lee S M. NLRP3 inflammasome activation in D-galactosamine and lipopolysaccharide-induced acute liver failure: role of heme oxygenase-1. Free Radic Biol Med, 2013, 65:997-1004.
[2]Filippakopoulos P, Knapp S. Targeting bromodomains: epigenetic readers of lysine acetylation. Nat Rev Drug Discov, 2014, 13(5): 337-356.
[3]Arrowsmith C H, Bountra C, Fish P V, et al. Epigenetic protein families: a new frontier for drug discovery. Nat Rev Drug Discov, 2012, 11(5): 384-400.
[4]Shi J, Vakoc C R. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol Cell, 2014, 54(5): 728-736.
[5]Filippakopoulos P, Picaud S, Mangos M, et al. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell, 2012, 149(1): 214-231.
[6]Borck P C, Guo L-W, Plutzky J. BET epigenetic reader proteins in cardiovascular transcriptional programs. Circ Res, 2020, 126(9): 1190-1208.
[7]Duan Q, Wu P, Liu Z, et al. BET bromodomain inhibition suppresses adipogenesis in mice. Endocrine, 2020, 67(1): 264-267.
[8]Kulikowski E, Rakai B D, Wong N C W. Inhibitors of bromodomain and extra-terminal proteins for treating multiple human diseases. Med Res Rev, 2021, 41(1): 223-245.
[9]Shu S, Lin C Y, He H H, et al. Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature, 2016, 529(7586): 413-417.
[10] Farzanegi P, Dana A, Ebrahimpoor Z, et al. Mechanisms of beneficial effects of exercise training on non-alcoholic fatty liver disease (NAFLD): Roles of oxidative stress and inflammation. Eur J Sport Sci, 2019, 19(7):994-1003.
[11] Matyas C, Haskó G, Liaudet L, et al. Interplay of cardiovascular mediators, oxidative stress and inflammation in liver disease and its complications. Nat Rev Cardiol, 2021, 18(2): 117-135.
[12] Mansouri A, Gattolliat C H, Asselah T. Mitochondrial dysfunction and signaling in chronic liver diseases. Gastroenterology, 2018, 155(3): 629-647.
[13] Li Z, Xiao S, Yang Y, et al. Discovery of 8-methyl-pyrrolo[1,2-]pyrazin-1(2)-one derivatives as highly potent and selective bromodomain and extra-terminal (BET) bromodomain inhibitors. J Med Chem, 2020, 63(8): 3956-3975.
[14] Dai C, Xiao X, Li D, et al. Chloroquine ameliorates carbon tetrachloride-induced acute liver injury in mice via the concomitant inhibition of inflammation and induction of apoptosis. Cell Death Dis, 2018, 9(12): 1-13.
[15] Peng J, Li J, Huang J, et al. p300/CBP inhibitor A-485 alleviates acute liver injury by regulating macrophage activation and polarization. Theranostics, 2019, 9(26): 8344-8361.
[16] Liu Y, Li J, Liao L, et al. Cyclin-dependent kinase inhibitor roscovitine attenuates liver inflammation and fibrosis by influencing initiating steps of liver injury. Clin Sci (Lond), 2021, 135(7): 925-941.
[17] Mukhopadhyay P, Rajesh M, Cao Z, et al. Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis. Hepatology, 2014, 59(5): 1998-2009.
[18] Doherty D G. Immunity, tolerance and autoimmunity in the liver: A comprehensive review. J Autoimmun, 2016, 66: 60-75.
[19] Heymann F, Tacke F. Immunology in the liver-from homeostasis to disease. Nat Rev Gastroenterol Hepatol, 2016, 13(2):88-110.
[20] Robinson M W, Harmon C, O'farrelly C. Liver immunology and its role in inflammation and homeostasis. Cell Mol Immunol, 2016, 13(3): 267-276.
[21] Macpherson A J, Heikenwalder M, Ganal-Vonarburg S C. The liver at the nexus of host-microbial interactions. Cell Host Microbe, 2016, 20(5): 561-571.
[22] Bai P, Ye H, Xie M, et al. A synthetic biology-based device prevents liver injury in mice. J Hepatol, 2016, 65(1): 84-94.

Protective effect of BET selective inhibitor, compound 38 on acute liver injury in mice

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