Abstract
Acute liver failure (ALF) is a relatively rare liver disorder that leads to the massive death of hepatocytes. Our previous study 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′-bibenzo[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-κB protein, and dose-dependently down-regulated the production of interleukin (IL)-1β, tumor necrosis factor-α, and IL-6 as well as their corresponding mRNAs in RAW264.7 cells. Oral administration of 7k at a dose of 50 mg/kg significantly suppressed the serum level of enzyme activity and prevented the damage of liver tissue in d-galactosamine/LPS-induced ALF. Treatment with 7k also remarkably blocked the increase in the number of CD11b+- and CD68+-positive cells in the liver, and in vivo nuclear factor-κB activity, known to regulate inflammatory responses in many cell types, was effectively inhibited. The serum concentrations and hepatic mRNA expression of proinflammatory cytokines tumor necrosis factor-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 d-galactosamine/LPS-induced ALF by inhibiting macrophage infiltration and regulating the expression of cytokines.
Footnotes
This work was supported by the National Key Technologies R&D Program of China [Grant 2009ZX09501-015].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
↵
The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
-
ABBREVIATIONS:
- ALF
- acute liver failure
- GalN
- d-galactosamine
- LPS
- lipopolysaccharide
- ALT
- alanine aminotransferase
- AST
- aspartate transaminase
- IL
- interleukin
- TNF
- tumor necrosis factor
- NF-κB
- nuclear factor-κB
- ELISA
- enzyme-linked immunosorbent assay
- EMSA
- electrophoretic mobility-shift assay
- RT-PCR
- reverse transcription-polymerase chain reaction
- TUNEL
- terminal deoxynucleotidyl transferase dUTP nick-end labeling
- DTT
- dithiothreitol
- PMSF
- phenylmethylsulfonyl fluoride
- bp
- base pairs
- NO
- nitric oxide
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- 7k
- (E)-5-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)-5′-methyl-7,7′-dimethoxy-4,4′-bibenzo[d][1,3]dioxole-5,5′-dicarboxylate.
- Received October 22, 2011.
- Accepted January 9, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|