A DNA methylation atlas of normal human cell types.

DNA methylation is a fundamental epigenetic mark that governs gene expression and chromatin organization, thus providing a window into cellular identity and developmental processes1. Current datasets typically include only a fraction of methylation sites and are often based either on cell lines that underwent massive changes in culture or on tissues containing unspecified mixtures of cells2-5. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing, allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell type are more than 99.5% identical, demonstrating the robustness of cell identity programmes to environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny and identifies methylation patterns retained since embryonic development. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hypermethylated loci are rare and are enriched for CpG islands, Polycomb targets and CTCF binding sites, suggesting a new role in shaping cell-type-specific chromatin looping. The atlas provides an essential resource for study of gene regulation and disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.

A synergistic effect of Ambroxol and Beta-Glucosylceramide in alleviating immune-mediated hepatitis: A novel immunomodulatory non-immunosuppressive formulation for treatment of immune-mediated disorders.

BACKGROUND: Ambroxol hydrochloride is being used in respiratory diseases as a broncholytic therapy. Beta-Glucosylceramide (GC) is a naturally occurring glycosphingolipid that exerts an immune protective effect. The aim of the present study was to determine the synergistic immunomodulatory effect between these two compounds. METHODS: Immune-mediated hepatitis was induced in the mice by administration of Con A. Mice were treated with either Ambroxol or GC alone or with the combination of both. Mice were followed for their effect on the liver injury, cytokine profile, and the immune system. RESULTS: Coadministration of Ambroxol and GC significantly alleviated the liver injury induced by ConA, as demonstrated by the decreased liver enzymes. The combined treatment had a statistically significant synergistic effect on the suppression of intrahepatic CD8+CD25+, an increase in the CD4/CD8 lymphocyte ratio and in the CD8+ intrahepatic lymphocyte trapping, as well as on change of serum in the IL4 levels. The beneficial effect was associated with the promotion of regulatory T lymphocytes subsets, and with a trend for a pro-inflammatory to an anti-inflammatory cytokine shift. CONCLUSIONS: Coadministration of Ambroxol with GC exerted a synergistic immunoprotective effect in a model of immune-mediated acute liver damage. Considering the high safety profile of both agents, the combination may become a novel immunomodulatory non-immunosuppressive therapeutic agent. SIGNIFICANCE STATEMENT: Coadministration of Ambroxol with glucocerebroside exerted a synergistic immunoprotective effect in a model of immune-mediated acute liver damage.

Oral Co-administration of Soy-derived Extracts with Alcohol or with Sugar-sweetened Beverages Exerts Liver and Sugar Protective Effects.

Background and Aims: Both alcoholic drinks and high sugar-containing soft drinks cause major health problems worldwide. Oral administration of OS and M1 soy-derived extracts has been shown to alleviate liver injury in animal models. The aim of the present study was to determine the liver- and sugar-protective effect of OS and M1 soy-derived extracts when added to alcohol and sugar-enriched drinks. Methods: Mice were treated with alcohol or high sugar-containing drinks, with and without administration of a combination of OS and M1 soy extracts. Mice were observed for the effects on liver injury, glucose metabolism, and the immune system. Results: Co-administration of the soy extracts OS and M1 significantly alleviated the liver injury induced by acute alcohol, as evidenced by decreased liver enzymes. These beneficial effects were associated with promotion of subsets of regulatory T lymphocytes and with a trend towards a pro-inflammatory to an anti-inflammatory cytokine shift. Co-administration of OS M1 soy extracts with sugar-sweetened beverages significantly alleviated the increases in serum sugar levels. Conclusions: OS and M1 extracts exert a synergistic hepato- and glucose-protective effect in models of alcohol-induced liver damage and soft drinks-associated increases in serum glucose. These extracts may provide a solution to the two pressing health problems.