Resolution of inflammation-related apoptotic processes by the synthetic tellurium compound, AS101 following liver injury

Miri Brodsky, Shira Hirsh, Michael Albeck, Benjamin Sredni

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Background/Aims: Fulminant hepatic failure is a dangerous condition, which occurs when large parts of the liver become damaged beyond repair, and the liver is no longer able to function. This syndrome is induced by inflammatory processes, resulting in acute liver failure. Recently, the organotellurium compound, trichloro(dioxoethylene-O,O) tellurate (AS101), has been found by our group to be able to directly inhibit caspases, due to its Te(IV)-thiol chemistry. The aim of this study was to examine the potential of AS101 as an anti-inflammatory and anti-apoptotic compound in vitro and in vivo following liver injury. Methods: Propionibacterium acnes-primed LPS-induced liver injury was performed in Balb/c mice. ALT/AST, cytokines, caspase-1,-3 and-8 activities, and liver histology were assessed. Results: AS101 inhibited TNFα or anti-FAS-induced apoptotic processes in hepatocytes in vitro. A P. acnes + LPS in vivo liver injury model revealed lower serum ALT and AST and reduced necrosis and apoptosis in AS101-treated mice. IL-18 and IL-1β reduced levels in AS101-treated mice were associated with caspase-1 activity inhibition. Our findings suggest IL-6, IL-17 and pSTAT3 as additional novel players in the pathogenicity of FHF. Inhibition of caspase-3, and-8 activities by AS101 treatment contributed to decreased hepatocyte death, resulting in increased survival. Conclusions: We suggest that due to its interaction with key-target cysteine residues, AS101 mediates anti-inflammatory and anti-apoptotic effects in this FHF model, which may serve as a potent treatment for mitigation of hepatic damage.

Original languageEnglish
Pages (from-to)491-503
Number of pages13
JournalJournal of Hepatology
Volume51
Issue number3
DOIs
StatePublished - Sep 2009

Bibliographical note

Funding Information:
This work was partly supported by: the Safdiè Institute for AIDS and Immunology Research, The Milton and Lois Shiffman Research Program, and The Dave and Florence Muskovitz Chair in Cancer Research and by grant no.3-2994 from the Chief Scientist Office of the Ministry of Health, Israel. This study was a part of the Ph.D. thesis research of Miri Brodsky.

Funding

This work was partly supported by: the Safdiè Institute for AIDS and Immunology Research, The Milton and Lois Shiffman Research Program, and The Dave and Florence Muskovitz Chair in Cancer Research and by grant no.3-2994 from the Chief Scientist Office of the Ministry of Health, Israel. This study was a part of the Ph.D. thesis research of Miri Brodsky.

FundersFunder number
Milton and Lois Shiffman Research Program
Safdiè Institute for AIDS and Immunology Research
Ministry of Health, State of Israel

    Keywords

    • AS101
    • Caspases
    • FHF

    Fingerprint

    Dive into the research topics of 'Resolution of inflammation-related apoptotic processes by the synthetic tellurium compound, AS101 following liver injury'. Together they form a unique fingerprint.

    Cite this