| A Novel Small Molecule, (E)-5-(2,4-di-tert-butyl-6- ((2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)-5'-methyl-7,7'-dimethoxy-4,4'-biben-zo[d][1,3]dioxole-5,5'-dicarboxylate (7k) Alleviates the Development of D-GalN/LPS-induced Acute Liver Failure by Inhibiting Macrophage Infiltration and Regulating cytokines expression. | |
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MedLine Citation:
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PMID: 22238210 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Acute liver failure (ALF) is a relatively rare liver disorder that leads to the massive death of hepatocytes. Our previous study has reported that a novel small-molecule agent, (E)-5-(2,4-di-tert-butyl-6-((2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)-5'-methyl-7,7'-dimethoxy-4,4'-biben-zo[d][1,3]dioxole-5,5'-dicarboxylate (7k), possessed potent anti-inflammatory activity. In the present study, we further evaluated the therapeutic effects of 7k on lipopolysaccharide (LPS)-induced ALF, and investigated the mechanisms of action. Our results demonstrated that 7k inhibited the migration of RAW264.7 macrophages, blocked the activity of nuclear factor (NF)-κB protein, and dose-dependently down-regulated the production of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) as well as their corresponding mRNAs in RAW264.7 cells. Oral administration of 7k at a dose of 50mg/kg significantly suppressed the serum level of enzyme activity and prevented inflammatory the damage of liver tissue in GalN/LPS-induced ALF. Treatment with 7k also remarkably blocked the increase in the number of CD11b(+) and CD68(+) positive cells in the liver and the in vivo NF-κB activity, known to regulate inflammatory responses in many cell types, was effectively inhibited. The serum concentrations and hepatic mRNA expressions of proinflammatory cytokines TNF-α, IL-1β, and IL-6 were markedly down-regulated in mice by the treatment of 7k. In summary, 7k alleviated the development and progression of GalN/LPS-induced ALF by inhibiting macrophage infiltration and regulating the expression of cytokines. |
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Authors:
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Chongyang Deng; Juan Liu; Guangcheng Wang; Liang Ma; Caifeng Xie; Xuewei Wang; Xiuxia Li; Lijuan Chen |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-11 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: - ISSN: 1521-0103 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-12 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan Universi. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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