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Center for Internal Medicine
Center for Internal Medicine
5,194
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10
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Institute of Biochemistry
Institute of Biochemistry
1,931
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Institute of Organic Chemistry and Chemical Biology
Institute of Organic Chemistry and Chemical Biology
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Member activityView all

  • Source
    Article: In vitro epigenetic reprogramming of human cardiac mesenchymal stromal cells into functionally competent cardiovascular precursors.
    Matteo Vecellio, Viviana Meraviglia, Simona Nanni, Andrea Barbuti, Angela Scavone, Dario Difrancesco, Antonella Farsetti, Giulio Pompilio, Gualtiero I Colombo, Maurizio C Capogrossi, Carlo Gaetano, Alessandra Rossini
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    ABSTRACT: Adult human cardiac mesenchymal-like stromal cells (CStC) represent a relatively accessible cell type useful for therapy. In this light, their conversion into cardiovascular precursors represents a potential successful strategy for cardiac repair. The aim of the present work was to reprogram CStC into functionally competent cardiovascular precursors using epigenetically active small molecules. CStC were exposed to low serum (5% FBS) in the presence of 5 µM all-trans Retinoic Acid (ATRA), 5 µM Phenyl Butyrate (PB), and 200 µM diethylenetriamine/nitric oxide (DETA/NO), to create a novel epigenetically active cocktail (EpiC). Upon treatment the expression of markers typical of cardiac resident stem cells such as c-Kit and MDR-1 were up-regulated, together with the expression of a number of cardiovascular-associated genes including KDR, GATA6, Nkx2.5, GATA4, HCN4, NaV1.5, and α-MHC. In addition, profiling analysis revealed that a significant number of microRNA involved in cardiomyocyte biology and cell differentiation/proliferation, including miR 133a, 210 and 34a, were up-regulated. Remarkably, almost 45% of EpiC-treated cells exhibited a TTX-sensitive sodium current and, to a lower extent in a few cells, also the pacemaker I(f) current. Mechanistically, the exposure to EpiC treatment introduced global histone modifications, characterized by increased levels of H3K4Me3 and H4K16Ac, as well as reduced H4K20Me3 and H3s10P, a pattern compatible with reduced proliferation and chromatin relaxation. Consistently, ChIP experiments performed with H3K4me3 or H3s10P histone modifications revealed the presence of a specific EpiC-dependent pattern in c-Kit, MDR-1, and Nkx2.5 promoter regions, possibly contributing to their modified expression. Taken together, these data indicate that CStC may be epigenetically reprogrammed to acquire molecular and biological properties associated with competent cardiovascular precursors.
    PLoS ONE 01/2012; 7(12):e51694.
  • Source
    Article: Chemical synthesis of 2'-O-alkylated siRNAs.
    Joachim W Engels, Dalibor Odadzic, Romualdas Smicius, Jens Haas
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    ABSTRACT: Chemical synthesis has been a major endeavor to create active siRNAs. The downregulation of mRNA by 21-mer double-stranded siRNAs can be improved by using modified nucleotides, especially 2'-O-alkylated ones. Besides the commercially available 2 cent-O-methyl ribosides, 2'-alkyl groups bearing positive charges are especially promising candidates. We have shown that in a proper formulation they are superior to unmodified siRNAs. This may be due to enhanced stability and most probably to a better uptake into the cells.
    Methods in molecular biology (Clifton, N.J.) 01/2010; 623:155-70.
  • Source
    Article: 2-C-methyluridine modified hammerhead ribozyme against the estrogen receptor.
    Rodrigo Pontiggia, Osvaldo Pontiggia, Marina Simian, Javier M Montserrat, Joachim W Engels, Adolfo M Iribarren
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    ABSTRACT: A new synthesis of 2'-C-methyluridine phosphoramidite is presented. Special emphasis is dedicated to the improvement of the protection of the tertiary 2'-hydroxyl group. Comparison to previous protecting strategies and analysis of stability under 5'-DMTr removing conditions are discussed. The synthetic incorporation of this modified nucleoside into the catalytic core of a hammerhead ribozyme against the estrogen receptor alpha protein (ER-alpha), and transfection experiments in MCF-7 cell line are also presented.
    Bioorganic & medicinal chemistry letters 03/2010; 20(9):2806-8.

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