DNA hypermethylation is a common epigenetic alteration in human prostate cancer and is considered to contribute to development of this disease. Accumulating data suggest that dietary factors may alter cancer risk by modifications of epigenetic processes in the cell. The present study was designed to investigate whether selenium (Se) would alter epigenetic events to regulate methylation-silenced genes in human prostate cancer cells. DNA methylation, histone modifications and gene expression were studied in LNCaP cells after selenite treatment using polymerase chain reaction, western blot analysis, chromatin immunoprecipitation assay and enzymatic activity assay. Our study shows that selenite treatment caused partial promoter DNA demethylation and reexpression of the pi-class glutathione-S-transferase (GSTP1) in LNCaP cells in a dose- and time-dependent manner. Selenite treatment decreased messenger RNA levels of DNA methyltransferases (DNMTs) 1 and 3A and protein levels of DNMT1. Selenite also decreased histone deacetylase activity and increased levels of acetylated lysine 9 on histone H3 (H3-Lys 9), but decreased levels of methylated H3-Lys 9. Selenite treatment reduced levels of DNMT1 and methylated H3-Lys 9 associated with the GSTP1 promoter, but increased levels of acetylated H3-Lys 9 associated with this promoter. Additionally, selenite treatment decreased general DNA methylation and caused partial promoter demethylation and reexpression of the tumor suppressor adenomatous polyposis coli and cellular stress response 1, a gene involving tumor growth and metastasis. Our study demonstrates that Se can epigenetically modulate DNA and histones to activate methylation-silenced genes. These epigenetic modifications may contribute to cancer prevention by Se.

The worldwide outbreak of severe acute respiratory syndrome (SARS) in 2003 had caused a high rate of mortality. Main protease (M) of SARS-associated coronavirus (SARS-CoV) is an important target to discover pharmaceutical compounds for the therapy of this life-threatening disease. During the course of screening new anti-SARS agents, we have identified that a series of unsymmetrical aromatic disulfides inhibited SARS-CoV M significantly for the first time. Herein, 40 novel unsymmetrical aromatic disulfides were synthesized chemically and their biological activities were evaluated in vitro against SARS-CoV M. These novel compounds displayed excellent IC data in the range of 0.516-5.954 μM. Preliminary studies indicated that these disulfides are reversible and mpetitive inhibitors. A possible binding mode was generated via molecular docking simulation and a comparative field analysis (CoMFA) model was constructed to understand the structure-activity relationships. The present research therefore has provided some meaningful guidance to design and identify anti-SARS drugs with totally new chemical structures.

Spinal cord injury (SCI) leads to induction and/or suppression of several genes, the interplay of which governs the neuronal death and subsequent loss of motor function. Using GeneChip w , the present study analyzed changes in the mRNA abundance at 3 and 24 h after SCI in adult rats. SCI was induced at T9 level by the New York University impactor by dropping a 10-g weight from a height of 25 mm. Several transcription factors, immediate early genes, heat-shock proteins, pro-in¯ammatory genes were up-regulated by 3 h, and persisted at 24 h, after SCI. On the other hand, some neurotransmitter receptors and transporters, ion channels, kinases and structural proteins were down-regulated by 3 h, and persisted at 24 h, after SCI. Several genes that play a role in growth/differentiation, survival and neuroprotection were up-regulated at 24 h after SCI. Using real-time quantitative PCR, the changes observed by GeneChip w were con®rmed for seven up-regulated (interleukin-6, heat-shock protein-70, heme oxygenase-1, suppressor of cytokine signaling 2, suppressor of cytokine signaling 3, interferon regulatory factor-1, neuropeptide Y), two down-regulated (vesicular GABA transporter and cholecystokinin precursor) and two unchanged (Cu/Zn-superoxide dismutase and phosphatidyl inositol-3-kinase) genes. The present study shows that in¯ammation, neurotransmitter dysfunction, increased transcription, ionic imbalance and cytoskeletal damage starts as early as 3 h after SCI. In addition to these effects, 24 h after SCI the repair and regeneration process begins in an attempt to stabilize the injured spinal cord.

Identifying the gene expression changes induced by hepatic encephalopathy (HE) leads to a better understanding of the molecular mechanisms of HE-induced neurological dysfunction. Using GeneChip and real-time PCR, the present study evaluated the gene expression profile of rat cerebral cortex at 4 weeks after portacaval shunting. Among 1,263 transcripts represented on the chip, mRNA levels of 31 transcripts were altered (greater than twofold; 16 increased and 15 decreased) in the portacaval shunted (PCS) rat compared to sham control. Changes observed by GeneChip analysis were confirmed for 20 transcripts (8 increased, 7 decreased, and 5 unchanged in PCS rat brain) by real-time PCR. Neurotransmitter receptors, transporters, and members of the second messenger signal transduction are the major groups of genes altered in PCS rat brain. Of importance was that the increased heme oxygenase-1 and decreased Cu,Zn-superoxide dismutase expression observed raise the possibility of oxidative stress playing a pathogenic role in chronic HE.