concanavalin-a and bicyclol

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 kappaB degradation and nuclear factor kappaB (NF-kappaB) 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-kappaB-mediated apoptosis and necrosis in liver tissue.

Topics: Animals; Biphenyl Compounds; Concanavalin A; DNA-Binding Proteins; Dose-Response Relationship, Drug; Heat Shock Transcription Factors; HSP27 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; I-kappa B Proteins; Liver; Male; Mice; NF-kappa B; NF-KappaB Inhibitor alpha; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors

The aim of this study was to investigate the effect of the novel antihepatitis drug bicyclol on the gene expression profiles in concanavalin A (Con A) intoxicated mice by using cDNA microarray analysis. Bicyclol (250 mg x kg(-1)) was given orally to mice three doses before Con A intravenous injection (26.5 mg x kg(-1)). Serum levels of aminotransferases were examined by biochemical methods. Liver mRNA was extracted and reversely transcribed to cDNA with the incorporation of labeled Cy3-dUTP and Cy5-dUTP, separately. The probes were hybridized to the cDNA microarray. The acquired image was scanned and analyzed by Cenepix Pro 3.0 software. Microarray analysis showed that 287 genes exhibited differential expression in bicyclol group, in which 121 genes were up-regulated and 166 genes were down-regulated comparing with that of untreated Con A intoxicated mice. The differential gene expression after bicyclol treatment was involved in the biotransformation, protein synthesis, degradation and circadian rhythm, proliferation and signal transduction. Bicyclol might regulate a series of genes expressions in Con A intoxicated mice.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Biphenyl Compounds; Chemical and Drug Induced Liver Injury; Concanavalin A; Gene Expression Profiling; Male; Mice; Mice, Inbred ICR; Oligonucleotide Array Sequence Analysis; Random Allocation

Bicyclol, 4, 4'-dimethoxy-5, 6, 5', 6'-dimethylene-dioxy-2-hydroxymethyl -2'-carbonyl biphenyl, is a new anti-hepatitis drug. The aim of the present study was to investigate the protective effect of bicyclol on concanavalin A (Con A)-induced immunological liver injury in mice and its mechanism.. Liver injury was induced by injection of Con A via tail vein of mice and assessed biochemically and histologically. Serum transaminase and tumor necrosis factor alpha (TNF-alpha) were determined. Liver lesions were observed by light microscope. Expressions of TNF-alpha, interferon gamma (IFN-gamma), Fas and Fas ligand (FasL) mRNA in the livers were measured by RT-PCR.. Serum transaminase level and liver lesions in Con A-induced mice were markedly reduced by oral administration of 100, 200 mg/kg of bicyclol. TNF-alpha level in serum was also reduced by bicyclol. Con A injection induced up-regulation of TNF-alpha, IFN-gamma, Fas and FasL mRNA expression in liver tissues. Bicyclol significantly down-regulated the expression of IFN-gamma, Fas and FasL mRNA, but only slightly affected TNF-alpha mRNA expression in liver tissues.. Bicyclol protects against Con A-induced liver injury mainly through inhibition of Fas/FasL mRNA expression in liver tissues and TNF-alpha release in mice.

Topics: Animals; Apoptosis; Biphenyl Compounds; Chemical and Drug Induced Liver Injury; Concanavalin A; Fas Ligand Protein; fas Receptor; Gene Expression; Interferon-gamma; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; RNA, Messenger; Transaminases; Tumor Necrosis Factor-alpha