201. Compound 9a, a novel synthetic histone deacetylase inhibitor, protects against septic injury in mice by suppressing MAPK signalling
- Author
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Young Hoon Jung, So-Jin Kim, Ki Seon Baek, Sun-Mee Lee, and Hyun-Ju Park
- Subjects
0301 basic medicine ,Pharmacology ,MAPK/ERK pathway ,medicine.drug_class ,Histone deacetylase inhibitor ,Biology ,HDAC1 ,Nitric oxide ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,chemistry ,Intensive care ,Immunology ,medicine ,MAPK phosphatase ,Tumor necrosis factor alpha ,Histone deacetylase - Abstract
Background and Purpose Sepsis is a life-threatening clinical condition characterized by uncontrolled inflammatory responses and is a major cause of death in intensive care units. Histone deacetylase (HDAC) inhibitors have recently exhibited anti-inflammatory properties. MAPK phosphatase (MKP) suppresses MAPK signalling, which plays an important role in inflammatory responses. The purpose of this study was to investigate the protective mechanisms of Compound 9a, a newly synthetized HDAC inhibitor, against septic injury. Experimental Approach The anti-inflammatory properties of Compound 9a were assayed in LPS-stimulated RAW264.7 cells. In vivo, polymicrobial sepsis was induced in C57BL/6 mice by caecal ligation and puncture (CLP). The mice were treated with Compound 9a (i.p., 10 mg∙kg−1) 2 h before and immediately after CLP. Key Results Compound 9a inhibited the increased production of TNF-α, IL-6 and NO in LPS-stimulated RAW264.7 cells. In mice with CLP, Compound 9a improved survival rate, attenuated organ injuries and decreased serum TNF-α and IL-6 levels. CLP increased expression of toll-like receptor 4, phosphorylated (p)-p38, p-JNK and p-ERK proteins, which was attenuated by Compound 9a. Compound 9a decreased MKP-1 association with HDAC1 and enhanced MKP-1 acetylation and enhanced MKP-1 association with p-p38 and p-ERK. Moreover, the inhibitory effects of Compound 9a on serum cytokine levels and phosphorylation of MAPK were abolished by MKP-1 siRNA. Conclusions and Implications Our findings suggest that Compound 9a protected against septic injury by suppressing MAPK-mediated inflammatory signalling.
- Published
- 2016
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