Role of enhancer of zeste homolog 2 polycomb protein and its significance in tumor progression and cell differentiation

Epigenetics is a branch of genetics that focuses on the heritable changes of DNA or associated proteins, other than DNA sequence variations, which carry information content during cell division [1,2]. These heritable changes are ascribed to chromatin, which constitutes the ultrastructure of DNA and whose modifications affect the genetic material functionality. Differences in chromatin structure have been associated to transcription regulation [3-5] and chromosome stability [6,7], affecting both gene’s information, expression and heritability. Noteworthy, these epigenetic modifications are involved in both transcriptional activation and repression, indicating their widespread role as modulators of gene expression in numerous biological processes [8,9]. Chromatin is subjected to numerous modifications roughly classified in two groups: DNA and histone post-translational modifications (histone-PTMs). DNA methylation is the most studied epigenetic modification of DNA and corresponds to the covalent addition of a methyl (CH3) group to the nucleotide cytosine within CG dinucleotides or CNG trinucleotides where N can be C, A, G or T. Usually, DNA methylation induces decreased protein-DNA binding of transcription factors and leads to the repression of gene expression [10]. DNA “methylable” sequences are not uniform across the human genome but restricted in CpG rich DNA regions termed CpG islands (CGI). CGI are localized at repetitive sequences, heavy methylated, to prevent the reactivation of endoparasitic sequences such as transposons, and at gene promoter sequences, which are normally refractory to methylation in normal somatic cells [8,11].</br

Histone Deacetylase Inhibitors in the Treatment of Hematological Malignancies and Solid Tumors

The human genome is epigenetically organized through a series of modifications to the histone proteins that interact with the DNA. In cancer, many of the proteins that regulate these modifications can be altered in both function and expression. One example of this is the family of histone deacetylases (HDACs), which as their name implies remove acetyl groups from the histone proteins, allowing for more condensed nucleosomal structure. HDACs have increased expression in cancer and are also believed to promote carcinogenesis through the acetylation and interaction with key transcriptional regulators. Given this, small molecule histone deacetylases inhibitors have been identified and developed, which not only inhibit HDACs, but can also lead to growth arrest, differentiation, and/or apoptosis in tumors both in vitro and in vivo. Here, we will discuss some of the recent developments in clinical trials utilizing HDACs inhibitors for the treatment of both hematological malignancies as well as solid tumors

Su alcune formazioni a <i>Olea europaea</i> L. var. <i>sylvestris</i> Brot. della Sardegna

On the Olea europaea L. var. sylvestris Brot. woodlands in Sardinia.The phytosociological analysis of Olea europaea. var. sylvestris woodlands occurring in Sardinia are here presented. The following sintaxa are described for the first time: Cyclamino repandi-Oleetum sylvestris and Myrto communis-Oleetum sylvestris are referred to the Quercion ilicis alliance while Asparago acutifolii-Oleetum sylvestris and Asparago albi-Oleetum sylvestris are referred to the Oleo-Ceratonion alliance

Su alcune formazioni a Olea europaea L. var. sylvestris Brot. della Sardegna

On the Olea europaea L. var. sylvestris Brot. woodlands in Sardinia.The phytosociological analysis of Olea europaea. var. sylvestris woodlands occurring in Sardinia are here presented. The following sintaxa are described for the first time: Cyclamino repandi-Oleetum sylvestris and Myrto communis-Oleetum sylvestris are referred to the Quercion ilicis alliance while Asparago acutifolii-Oleetum sylvestris and Asparago albi-Oleetum sylvestris are referred to the Oleo-Ceratonion alliance

R-Roscovitine (Seliciclib) prevents DNA damage-induced cyclin A1 upregulation and hinders non-homologous end-joining (NHEJ) DNA repair

<p>Abstract</p> <p>Background</p> <p>CDK-inhibitors can diminish transcriptional levels of cell cycle-related cyclins through the inhibition of E2F family members and CDK7 and 9. Cyclin A1, an E2F-independent cyclin, is strongly upregulated under genotoxic conditions and functionally was shown to increase NHEJ activity. Cyclin A1 outcompetes with cyclin A2 for CDK2 binding, possibly redirecting its activity towards DNA repair. To see if we could therapeutically block this switch, we analyzed the effects of the CDK-inhibitor <it>R</it>-Roscovitine on the expression levels of cyclin A1 under genotoxic stress and observed subsequent DNA damage and repair mechanisms.</p> <p>Results</p> <p>We found that <it>R</it>-Roscovitine alone was unable to alter cyclin A1 transcriptional levels, however it was able to reduce protein expression through a proteosome-dependent mechanism. When combined with DNA damaging agents, <it>R</it>-Roscovitine was able to prevent the DNA damage-induced upregulation of cyclin A1 on a transcriptional and post-transcriptional level. This, moreover resulted in a significant decrease in non-homologous end-joining (NHEJ) paired with an increase in DNA DSBs and overall DNA damage over time. Furthermore, microarray analysis demonstrated that <it>R</it>-Roscovitine affected DNA repair mechanisms in a more global fashion.</p> <p>Conclusions</p> <p>Our data reveal a new mechanism of action for <it>R</it>-Roscovitine on DNA repair through the inhibition of the molecular switch between cyclin A family members under genotoxic conditions resulting in reduced NHEJ capability.</p

Vegetazione forestale e serie di vegetazione della Sardegna (con rappresentazione cartografica alla scala 1:350.000)

This monograph includes a comprehensive synthesis of the forest vegetation of Sardinia, with a physiographic, bioclimatic and biogeographic characterization of the investigated territories. Our work allowed to resume the knowledge status of the vegetation studies carried out on the Island, identify the actual plant landscape, define the vegetation series and geoseries, as well as draw a map of their potential distribution. In total, 23 principal vegetation series were identified, with 21 of them being exclusive of the Sardinian biogeographic sub province and 2 of the Corsican-Sardinian province. In addition 5 geoseries were described: 2 exclusive of Sardinia, 1 of Sardinia and Corsica and 2 with a Mediterranean distribution. These geoseries are related to hygrophylous, riparian and lowland habitats, to ponds, coastal lagoons and dunal systems. Data on the structure, floristic composition, litomorphology, climate and serial and catenal succession for each series and geoseries, are here presented. All the cenosis are here summarized in a syntaxonomical scheme constitued by 5 classes, 7 orders, 11 alliances, 6 suballiances, 43 associations and 27 subassociations. Regulatory aspects, protection measures as well as in situ and ex situ conservation strategies concerning the forest taxa and syntaxa are also discussed. An annexe map (scale 1:350,000) of the potential forest series and geoseries of the Island is also presented

Hyaluronan Esters Drive Smad Gene Expression and Signaling Enhancing Cardiogenesis in Mouse Embryonic and Human Mesenchymal Stem Cells

BACKGROUND: Development of molecules chemically modifying the expression of crucial orchestrator(s) of stem cell commitment may have significant biomedical impact. We have recently developed hyaluronan mixed esters of butyric and retinoic acids (HBR), turning cardiovascular stem cell fate into a high-yield process. The HBR mechanism(s) remain still largely undefined. METHODOLOGY/PRINCIPAL FINDINGS: We show that in both mouse embryonic stem (ES) cells and human mesenchymal stem cells from fetal membranes of term placenta (FMhMSCs), HBR differentially affected the patterning of Smad proteins, one of the major conductors of stem cell cardiogenesis. Real-time RT-PCR and Western blot analyses revealed that in both cell types HBR enhanced gene and protein expression of Smad1,3, and 4, while down-regulating Smad7. HBR acted at the transcriptional level, as shown by nuclear run-off experiments in isolated nuclei. Immunofluorescence analysis indicated that HBR increased the fluorescent staining for Smad1,3, and 4, confirming that the transcriptional action of HBR encompassed the upregulation of the encoded Smad proteins. Chromatin immune precipitation and transcriptional analyses showed that HBR increased the transcription of the cardiogenic gene Nkx-2.5 through Smad4 binding to its own consensus Smad site. Treatment of mouse ES cells and FMhMSCs with HBR led to the concomitant overexpression of both Smad4 and α-sarcomeric actinin. Smad4 silencing by the aid of lentiviral-mediated Smad4 shRNA confirmed a dominant role of Smad4 in HBR-induced cardiogenesis. CONCLUSIONS/SIGNIFICANCE: The use of HBR may pave the way to novel combinatorial strategies of molecular and stem cell therapy based on fine tuning of targeted Smad transciption and signaling leading to a high-throughput of cardiogenesis without the needs of gene transfer technologies

RNAseq Analysis of Novel 1,3,4-Oxadiazole Chalcogen Analogues Reveals Anti-Tubulin Properties on Cancer Cell Lines

1,3,4-Oxadiazole derivatives are among the most studied anticancer drugs. Previous studies have analyzed the action of different 1,3,4-oxadiazole derivatives and their effects on cancer cells. This study investigated the characterization of two new compounds named 6 and 14 on HeLa and PC-3 cancer cell lines. Based on the previously obtained IC50, cell cycle effects were monitored by flow cytometry. RNA sequencing (RNAseq) was performed to identify differentially expressed genes, followed by functional annotation using gene ontology (GO), KEGG signaling pathway enrichment, and protein–protein interaction (PPI) network analyses. The tubulin polymerization assay was used to analyze the interaction of both compounds with tubulin. The results showed that 6 and 14 strongly inhibited the proliferation of cancer cells by arresting them in the G2/M phase of the cell cycle. Transcriptome analysis showed that exposure of HeLa and PC-3 cells to the compounds caused a marked reprograming of gene expression. Functional enrichment analysis indicated that differentially expressed genes were significantly enriched throughout the cell cycle and cancer-related biological processes. Furthermore, PPI network, hub gene, and CMap analyses revealed that compounds 14 and 6 shared target genes with established microtubule inhibitors, indicating points of similarity between the two molecules and microtubule inhibitors in terms of the mechanism of action. They were also able to influence the polymerization process of tubulin, suggesting the potential of these new compounds to be used as efficient chemotherapeutic agents