Viral hepatic diseases, especially those induced by the hepatitis B virus, can progress into more serious pathological outcomes and eventually to hepatocellular carcinoma. A growing body of evidence indicates that many trace elements play important roles in a number of carcinogenic processes that proceed through various mechanisms. To examine the status of trace elements during the development of hepatic carcinoma, we determined the selenium, iron, copper, and zinc levels and copper-to-zinc ratios in the serum of patients at different stages of viral hepatic disease. We observed significant changes in the selenium, iron, copper, and zinc levels in the serum of patients having hepatocellular carcinoma, relative to those of healthy controls (p < 0.05). The mean serum copper level in patients with hepatocellular carcinoma was significantly higher than that of the control group. In contrast, the mean selenium, iron, and zinc levels in patients having hepatocellular carcinoma were significantly lower than those of the control group. In addition, the mean zinc level in the serum of patients with hepatic cirrhosis was significantly lower than that of the control group (p < 0.05). Moreover, we found markedly elevated Cu: Zn ratios (p < 0.05) in patients having hepatic cirrhosis or hepatocellular carcinoma. Our findings imply that the levels of some trace elements, such as selenium, iron, copper, and zinc, and Cu: Zn ratios, might serve as biomarkers for the increased severity of viral hepatic damage.

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Several compounds from Cinnamomum kotoense show anticancer activities. However, the detailed mechanisms of most compounds from C. kotoense remain unknown. In this study, we investigated the anticancer activity of obtusilactone A (OA) and ())-sesamin in lung cancer. Our results show that human Lon is upregulated in non-small-cell lung cancer (NSCLC) cell lines, and downregulation of Lon triggers caspase-3 mediated apoptosis. Through enzymebased screening, we identified two small-molecule compounds, obtusilactone A (OA) and ())-sesamin from C. kotoense, as potent Lon protease inhibitors. Obtusilactone A and ())-sesamin interact with Ser855 and Lys898 residues in the active site of the Lon protease according to molecular docking analysis. Thus, we suggest that cancer cytotoxicity of the compounds is partly due to the inhibitory effects on Lon protease. In addition, the compounds are able to cause DNA double-strand breaks and activate checkpoints. Treatment with OA and ())-sesamin induced p53-independent DNA damage responses in NSCLC cells, including G 1 ⁄ S checkpoint activation and apoptosis, as evidenced by phosphorylation of checkpoint proteins (H2AX, Nbs1, and Chk2), caspase-3 cleavage, and sub-G 1 accumulation. In conclusion, OA and ())-sesamin act as both inhibitors of human mitochondrial Lon protease and DNA damage agents to activate the DNA damage checkpoints as well induce apoptosis in NSCLC cells. These dual functions open a bright avenue to develop more selective chemotherapy agents to overcome chemoresistance and sensitize cancer cells to other chemotherapeutics. (Cancer Sci 2010; 101: 2612-2620 L ung cancer is a leading cause of cancer-related death in both men and women in the USA (1) and Taiwan. The survival rate after chemotherapy regimens and the drug development of molecular-targeted agents for lung cancer therapy is still challenging. (2,3) Lon is a highly conserved ATP-dependent serine protease that has been identified from prokaryotes and to mitochondria of eukaryotes.(4) In vivo studies show that Lon plays an important role in mitochondrial DNA maintenance and expression (5)(6)(7) and regulation of mitochondria function.(8) Mitochondrial function is a crucial determinant of cellular sensitivity to cancer therapeutic drugs because of its roles in mediating apoptosis.(9) Enhanced mitochondrial biogenesis as well as tumorigenesis are linked to overexpression and increased proteolytic activity of Lon. (8,10) Downregulation of Lon leads to loss of mitochondrial function, reduced cell proliferation capacity, and apoptosis. (11,12) Deregulation of Lon leading to tumorigenesis has raised its potential as a target in the development of a novel drug in cancer therapy.To date, very few small-molecule inhibitors of Lon protease have been found, although several peptide-based proteasome inhibitors have been reported. (13,14) Cell cycle checkpoints are sophisticated surveillance mechanisms that are used to monitor the integrity of DNA.(15,16) After DNA lesions are sensed by sensor proteins, the kinase activ...

IL-10-(-592) promoter polymorphisms may influence IL-10 and MCP-1 production, which may be an indicator of nephropathy risk in Taiwanese T2DM patients.