Protect effect of bicyclol on cisplatin-induced nephrotoxicity in mice.

This study investigated the protective effects of bicyclol against cisplatin-induced nephrotoxicity and the possible mechanisms in mice. Bicyclol (250 mg/kg, p.o., 5 days) showed significant protection as evidenced by the decrease of elevated serum creatine and blood urea nitrogen, and improvement of histopathological injury induced by cisplatin. The formation of kidney malondialdehyde with a concomitant reduction of reduced glutathione were also inhibited by bicyclol, while the activities of kidney superoxide dismutase, catalase and glutathione peroxidase were all increased, respectively. Bicyclol also inhibited the increase of kidney and serum nitric oxide induced by cisplatin. In addition, induction of induced nitric oxide synthase and nitrotyrosine were suppressed by bicyclol. Bicyclol suppressed cisplatin-induced extracelluar signal regulated kinases 1/2 and p38 mitogen-activated protein kinase activation in the kidney of mice. Results obtained demonstrate that bicyclol pre-administration can prevent the nephrotoxicity induced by cisplatin.

[Effect of bicyclol on gene expression profiles in mice with liver injury induced by concanavalin A].

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.

Silencing the YB-1 gene inhibits cell migration in gastric cancer in vitro.

The Y-Box-Binding Protein-1 (YB-1) is known to regulate the processes of transcription, translation, cellular response to drug treatment and viral infection as well as DNA repair among others. As gastric cancer is a common cancer with a high incidence in countries in Asia, we evaluated the association of YB-1 with the malignant potential of gastric cancer cells in vitro. YB-1 mRNA expression levels were first determined by real-time RT-PCR in two adherent gastric cancer cell lines (viz., MKN7 and NUGC3 gastric cancer cells) and a normal GES-1 gastric epithelial cell line. Poorly differentiated NUGC3 gastric cancer cells were found to have the highest YB-1 gene expression among the adherent cells. YB-1 gene expression was also observed to be higher in non-adherent SNU5 gastric cancer cells compared to more aggressive SNU16 cells. Silencing of the YB-1 gene by siRNA in NUGC3 cells was associated with a significant reduction of the YB-1 protein by more than 55% as verified by Western blot analysis. Down-regulation of YB-1 protein expression was further demonstrated qualitatively by immunocytochemistry and immunofluorescence staining. Silencing of the YB-1 gene induced significant inhibition of cell migration in NUGC3 cells by 60% but did not influence cell invasion. Although epithelial-mesenchymal-transition (EMT) is known to be associated with the migratory phenotype in cancer cells, there was no change in the expression of EMT genes when YB-1 expression was modulated. YB-1 appears to have an integral role in cancer cell migration, a process which is important for gastric cancer metastasis.

Y-box binding protein 1 is up-regulated in proliferative breast cancer and its inhibition deregulates the cell cycle.

The Y-box-binding protein 1 (YB-1), a member of the cold-shock domain RNA-and DNA-binding protein family, has pleiotropic functions such as regulation of the cell cycle. The aim of this study was to evaluate if YB-1 is a proliferative marker in breast cancer and elucidate potential downstream targets involved in YB-1-mediated cell cycle regulation using RNA interference technology. YB-1 protein expression was evaluated in tissue microarrays of 131 breast invasive ductal carcinomas by immunohistochemistry, while the YB-1 gene expression profile was evaluated in the T-47D, MDA-MB-231, ZR-75-1 and MCF7 breast cancer cell lines. Silencing of the YB-1 gene in T-47D breast cancer cells was performed using siRNA and the effects of down-regulation of YB-1 on cell growth and regulation of the cell cycle were ascertained. A focused panel of 84 genes involved in cell cycle progression was also examined. In tissue microarrays, YB-1 expression was shown to be associated with proliferating cell nuclear antigen (PCNA) immunostaining. siRNA-mediated silencing of the YB-1 gene inhibited cell proliferation and induced G1 phase cell cycle arrest in T-47D breast cancer cells. Knockdown of the YB-1 gene induced up-regulation of two genes which contribute to G1-arrest (RAD9A and CDKN3 genes) and down-regulation of ten genes associated with positive regulation of the cell cycle (SKP2, SUMO1, ANAPC4, CCNB1, CKS2, MNAT1, CDC20, RBBP8, KPNA2 and CCNC genes). The data obtained from the tissue microarrays and cell lines provide evidence that YB-1 is a reliable marker of cell proliferation and possibly a potential molecular target in breast cancer therapy.

Effect of bicyclol on cisplatin-induced hepatotoxicity in the hepatocarcinoma 22 tumour-bearing mice.

The aim of this study was to determine the effect of bicyclol against cisplatin-induced hepatotoxicity and the influence on the antitumour capacity of cisplatin in hepatocarcinoma 22 (H22) tumour-bearing mice. ICR mice were treated with bicyclol (250 mg/kg, orally) 2 hr before the injection of cisplatin (5 mg/kg, intraperitoneally) for 5 days (once daily) after H22 tumour cells were implanted. All animals were killed on the fifth day after cisplatin treatment and tumour weight of each animal was measured. Liver pathological changes were examined by light microscopy and biochemical assay. The expressions of liver inducible nitric oxide synthase (iNOS and nitric oxide synthase 2) and 3-nitrotyrosine were assessed by Western blotting. Bicyclol showed a significant protection as evidenced by the decrease of elevated serum aminotransferases and lactate dehydrogenase, and improvement of histopathological injury induced by cisplatin. The formation of liver malondialdehyde with a concomitant reduction of reduced glutathione was also inhibited by bicyclol, while the activities of liver superoxide dismutase, catalase and glutathione peroxidase were all increased, respectively. In addition, the over expressions of liver iNOS and 3-nitrotyrosine were suppressed by bicyclol. The administration of bicyclol had no affect on the anti-tumour capacity of cisplatin in mice bearing H22 tumour. The hepatoprotective action of bicyclol provides a new approach for preventing the hepatotoxicity induced by cisplatin in the clinic.