期刊
PANCREATOLOGY
卷 17, 期 5, 页码 689-697出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.pan.2017.06.005
关键词
Acute pancreatitis; Epigenetics; BET inhibition; Drug discovery
资金
- GlaxoSmithKline plc
- UK/China Postgraduate Research Scholarship for Excellence
- Liverpool China Scholarship Council Award
- CORE, UK
- UK Medical Research Council
- UK National Institute for Health Research Biomedical Research Unit Funding Scheme
- Academy of Medical Sciences (AMS) [AMS-SGCL10-Mukherjee] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0515-10084, CL-2012-07-001] Funding Source: researchfish
Objectives: To evaluate the therapeutic potential of I-BET-762, an inhibitor of the bromodomain and extra-terminal (BET) protein family, in experimental acute pancreatitis (AP). Methods: AP was induced by retrograde infusion of taurolithocholic acid sulphate into the biliopancreatic duct (TLCS-AP) or 2 intraperitoneal (i.p.) injections of ethanol and palmitoleic acid 1 h apart (FAEEAP) or 12 hourly i.p. injections of caerulein (CER-AP). In all treatment groups, I-BET-762 (30 mg/kg, i.p.) was administered at the time of disease induction and again 12 h later. AP severity was assessed at 24 h by serum biochemistry, multiple cytokines and histopathology. Results: TLCS-AP, FAEE-AP and CER-AP resulted in characteristic elevations in serum amylase and cytokine levels, increased pancreatic trypsin and myeloperoxidase activity, typical pancreatic histopathological changes and lung injury. Treatment with I-BET-762 significantly reduced biochemical, cytokine and histopathological responses in TLCS-AP and FAEE-AP, but not CER-AP. Conclusions: These results suggest that in different forms of AP there are significant differences in the epigenetic control of gene transcription contributing to the severity of disease responses. There is therapeutic potential in targeting bromodomains for the treatment of gallstone- and alcohol-related pancreatitis. (C) 2017 Published by Elsevier B.V. on behalf of IAP and EPC.
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