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Research ArticleInflammation, Immunopharmacology, and Asthma

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′-bibenzo[d][1,3]dioxole-5,5′-dicarboxylate (7k), Alleviates the Development of d-Galactosamine/Lipopolysaccharide-Induced Acute Liver Failure by Inhibiting Macrophage Infiltration and Regulating Cytokine Expression

Chongyang Deng, Juan Liu, Guangcheng Wang, Liang Ma, Caifeng Xie, Xuewei Wang, Xiuxia Li and Lijuan Chen
Journal of Pharmacology and Experimental Therapeutics April 2012, 341 (1) 146-155; DOI: https://doi.org/10.1124/jpet.111.189498
Chongyang Deng
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Juan Liu
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Guangcheng Wang
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Liang Ma
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Caifeng Xie
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Xuewei Wang
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Xiuxia Li
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Lijuan Chen
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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.

    http://dx.doi.org/10.1124/jpet.111.189498.

  • ↵Embedded Image 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
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Journal of Pharmacology and Experimental Therapeutics: 341 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 341, Issue 1
1 Apr 2012
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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′-bibenzo[d][1,3]dioxole-5,5′-dicarboxylate (7k), Alleviates the Development of d-Galactosamine/Lipopolysaccharide-Induced Acut…
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Research ArticleInflammation, Immunopharmacology, and Asthma

7k Alleviates the Development of Acute Liver Failure

Chongyang Deng, Juan Liu, Guangcheng Wang, Liang Ma, Caifeng Xie, Xuewei Wang, Xiuxia Li and Lijuan Chen
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 146-155; DOI: https://doi.org/10.1124/jpet.111.189498

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Research ArticleInflammation, Immunopharmacology, and Asthma

7k Alleviates the Development of Acute Liver Failure

Chongyang Deng, Juan Liu, Guangcheng Wang, Liang Ma, Caifeng Xie, Xuewei Wang, Xiuxia Li and Lijuan Chen
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 146-155; DOI: https://doi.org/10.1124/jpet.111.189498
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