Abstract
Heat shock proteins (HSPs) are molecular chaperones critical for cell survival under adverse environmental conditions and for normal cellular homeostasis. Bicyclol, a novel antihepatitis drug, has been shown to protect against liver injury in animals. However, it is unclear how bicyclol protects against liver injury. We recently found that bicyclol is an inducer of HSPs. We wondered whether bicyclol regulated the expression of HSPs to produce a liver protection in vivo. Thus, this study was designed to address these questions using a mouse model with concanavalin A (ConA)-induced liver injury. Oral administration of bicyclol markedly alleviated ConA-caused liver injury in mice as indicated by the reduction of serum aminotransferases, liver necrosis, and the release of cytochrome c and apoptosis-inducing factor from mitochondria and hepatic DNA fragmentation. Correlated with this, bicyclol induced the increase of mRNA and protein levels of hepatic 27- and 70-kDa HSPs (HSP27 and HSP70) in the mice. Correspondingly, the elevated HSP27 and HSP70 suppressed inhibitor κB degradation and nuclear factor κB (NF-κB) activation that were caused by ConA. The protective effects of bicyclol on ConA-induced mouse liver injury were markedly attenuated by quercetin, an inhibitor of HSPs synthesis. Our results suggest that the antihepatitis drug bicyclol may protect against liver injury by inducing the expression of hepatic HSP27 and HSP70 and consequently inhibit the transcription factor NF-κB-mediated apoptosis and necrosis in liver tissue.
Footnotes
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This work was supported by the Chinese Ministry of Science and Technology [Grant 96-901-01-45].
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ABBREVIATIONS: HSPs, heat shock proteins; HSP27, 27-kDa HSP; HSP70, 70-kDa HSP; TNF-α, tumor necrosis factor-α;IL, interleukin; ConA, concanavalin A; RT-PCR, reverse transcription-polymerase chain reaction; HSF1, heat shock factor-1; AIF, apoptosis-inducing factor; HSE, heat shock element; NF-κB, nuclear factor-κB; IκB, inhibitor κB; IKK, inhibitor κB kinase; TBS-T, Tris-buffered saline/Tween 20; MG132, N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal.
- Received November 3, 2008.
- Accepted January 21, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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