3,216 research outputs found
Different strategies to target the epigenome
No full textDespite the overriding importance of the role covers by the epigenetic modifications in the control of several cellular processes such as differentiation and development, dysfunctional gene regulation and relative expression is responsible for the onset of many human diseases, first of all cancer. On these bases, the modulation of epigenetic processes is presently and strongly considered an innovative and challenging therapeutic strategy. SIRT4 is one of the three mitochondrial sirtuins and exhibits mainly ADP-ribosyltransferase activity but also deacylase, lipoamidase properties with which affects different targets. Given these recent evidences the emerging role of such human mitochondrial sirtuin generated considerable interest, because could offer new therapeutic opportunities in various disorders such as obesity, diabetes, metabolic syndrome, cardiac hypertrophy and, although the role of SIRT4 is entirely in discussion in this disease, in cancer. No specific and potent SIRT4 inhibitors (SIRT4i) have been reported so far. Starting from a docking screen and a homology model of SIRT4 , the research group of our collaborator prof. Sippl (Martin Luther Universitat of Halle Wittenberg, Germany), identified two inhibitor scaffolds and relative hit candidates: UBCS191 (IC50(SIRT4)= 66.7 μM) and UBCS178 (IC50 (SIRT4)= 45.6 μM). Prof. Steegborn and coworkers (University of Bayreuth, Germany), instead, highlighted the SIRT4 capability to recognize and remove the 3-hydroxy-3-methylglutaric (HMG) residue if linked to the -amino group of a lysine (in addition to the other already accepted enzymatic activities). Since SIRT4 shows little to no detectable deacetylase activity against acetylated histone in vitro, the synthesis of a substrate was needed in order to perform enzymatic assays to evaluate the potential inhibitory capability of the developed SIRT4i. Exploiting the new discovery, we designed an analog of the SIRT1-3 substrate Z-MAL (Z-Lys (Acetyl) AMC) which, instead of being characterized by an acetyl moiety linked to the ε-amino group of lysine, has the HMG residue (Z-Lys (HMG) AMC), toward which, indeed, such mitochondrial sirtuin shows a new catalytic activity. In addition, we were able to develop analogues of both the two main scaffolds identified by Prof. Sippl as well as a series of hybrid compounds between them as a first series of SIRT4i. Beyond the direct inhibition of a specific (epigenetic-)protein of interest ((e-)POI), another approach could be to reduce the levels of the latter by promoting its degradation. This can be reached through Protein-Targeting Chimeras knows as PROTACs. PROTACs molecules are composed of two portions connected with a linker that combine an E3 ligase recognition sequence with a moiety that targets the selected (e-)POI. The key aspect of the mechanism of action of PROTACs provides the selective induction of the degradation of its target protein at sub-stoichiometric concentrations through the recruitment of the ubiquitin-proteasome system (UPS), thus modulating the targeted protein's levels instead of its function To date, about 600 different types of E3 ligases have been identified, which differ in terms of their characteristics and specificity. In this framework, only degraders of bromodomains and BET family members, PCAF and GCN5, SIRT2 and HDAC are reported to literature so far. 34 novel Epi-PROTACs targeting different epigenetic targets in the category of “erasers” (such as LSD1 and JmjC KDMs) and “writers” (such as p300 and EZH2) characterized by different E3 ligase binders, pegylated and non-pegylated linkers and by already known epigenetic modulators to provide the degradation of LSD1, JmJC KDMs, p300 and EZH2 have been developed
Sirtuins
No full textSirtuins are involved in numerous biological processes such as cell survival and metabolism, aging, and DNA repair; thus they modulate crucial metabolic pathways.
The seven members of the Sirtuin family are more and more seen as potential targets for the treatment of cancer, metabolic, neurodegenerative, and cardiovascular diseases
Variations on the Author
No full text“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Imparare le lingue per abbracciare il mondo
No full textL’autrice che si colloca, come Daniela Zorzi, tra i fautori di una linguistica “impegnata”, propone in ricordo della studiosa amica, una riflessione sul ruolo cruciale del multilinguismo e delle lingue- culture, per il successo professionale e il benessere sociale, nella società contemporanea. Il multilinguismo appare come un’urgenza educativa che interpella studiosi e formatori a tutti i livelli al fine di promuovere nei giovani un apprendimento consapevole efficace ed autonomo.Multilingualism constitutes an urgent objective for education, which needs to involve teachers and researchers at all levels if we are to promote effective and autonomous learning in the young. Like Daniela Zorzi, the author considers herself a socially engaged linguist, and in memory of her friend’s work, offers a reflection on the key roles of languages and cultures and of multilingualism for professional success and social welfare today
Recent Advances in Epigenetic Proteolysis Targeting Chimeras (Epi-PROTACs)
No full text: PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules that trigger the poly-ubiquitination of the protein of interest (POI) inducing its degradation via the recruitment of the ubiquitin-proteasome system, thus suppressing the POI's intracellular levels and indirectly all its functions. Recently, one of the fields where the protein knockdown induced by PROTACs has demonstrated to serve as a promising biochemical tool and to provide new opportunities for drug discovery is the epigenetics (epi-PROTACs). A full inhibition of the functions of all domains of a specific epigenetic POI (e-POI), rather than just the block of its catalytic/single domain activity, is in fact a new more effective modality to hit an e-POI and, in principle, the complex it belongs to, and potentially to treat the related diseases, first cancer. In this review, we will present the most relevant progresses made, especially in the last two years, in the application of PROTACs technology to the three main classes of e-POIs: "writers", "erasers" and "readers". Emphasis will be devoted to the medicinal chemistry aspects of the epi-PROTACs design, preparation, and optimization and to the comparison with small molecule epi-drugs for both epi-targets functional annotation and potential anticancer therapy purposes
Epigenetic polypharmacology: a new frontier for epi-drug discovery
No full textRecently, despite the great success achieved by the so-called "magic bullets" in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of "molecular network active compounds," embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi-epi-target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi-targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC-101 and CUDC-907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high-quality reviews on combination therapy and hybrid molecules. Hence, to update the state-of-the-art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi-epi-target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included
Sirt4: A Multifaceted Enzyme at the Crossroads of Mitochondrial Metabolism and Cancer
No full textSirtuins are NAD(+)-dependent deacylases that play crucial roles in the regulation of cellular metabolism, and as a result, are implicated in several diseases. The mitochondrial sirtuin Sirt4, for a long time considered as mainly a mono-ADP-ribosyltransferase, recently has shown a robust deacylase activity in addition to the already accepted substrate-dependent lipoamidase and deacetylase properties. Through these and likely other enzymatic and non-enzymatic activities, Sirt4 closely controls various metabolic events, and its dysregulation is linked to various aging-related disorders, including type 2 diabetes, cardiac hypertrophy, non-alcoholic fatty liver disease, obesity, and cancer. For its capability to inhibit glutamine catabolism and for the modulation of genome stability in cancer cells in response to different DNA-damaging conditions, Sirt4 is proposed as either a mitochondrial tumor suppressor or a tumor-promoting protein in a context-dependent manner. In addition to what is already known about the roles of Sirt4 in different biological settings, further studies are certainly still needed in order to validate this enzyme as a new potential target for various aging diseases
Reclamações ambientais em Aveiro, Portugal: atores, preocupações, padrão territorial e resoluções
No full textThis paper presents an environmental diagnosis based on public complaints on environmental
issues submitted to the Environmental Department of the Aveiro City Council, Portugal, between
2000 and 2005. It discusses the potential influences of these in local environmental planning
and governance. The paper has been organised into five sections. The first of these introduces
the study. The second section focuses on the conceptual approaches relating to environmental
grassroots movements, the main actors involved in these movements and the role played by
local government. It also contains a brief review of the most recent urban environmental
quality challenges in the European context together with a description of the main features of
the associated political and legal framework in Portugal. The third section describes the case
study and the methodology used. The results of the empirical study are detailed in the fourth
section. The final section critically analyses these results with emphases on the temporal
evolution of the submission of complaints, the actors involved, the local environmental problems
and their associated spatial pattern as well as the responses given by the City Council. This
information may then be used to provide a useful indicator for the perception of environmental
quality as well as a credible instrument for the visualisation and evaluation of local performance
in terms of environmental planning and management.AlBan Programme - n. E05M053040B
Jak rozumieć „historyczność” biblijnego Daniela? Różne kierunki wyjaśniania orędzia Księgi Daniela
No full textThe subject of this article is the issue of the historicity of the figure of Daniel, who is the main character of the biblical book bearing his name. The question of whether Daniel is a historical or just a literary figure is important because it influences the exegesis of the text of the Book of Daniel. First, the author will indicate the reasons for questioning the historicity of Daniel, and then he will present different approaches to interpreting the content of the Book of Daniel.Przedmiotem artykułu jest kwestia historyczności postaci Daniela, który jest głównym bohaterem księgi biblijnej noszącej jego imię. Pytanie o to, czy Daniel jest postacią historyczną, czy tylko literacką, jest ważne z tego powodu, że ma wpływ na egzegezę tekstu Księgi Daniela. Najpierw autor wskaże powody, na podstawie których podważa się historyczność Daniela, a następnie przedstawi różne podejścia w interpretacji treści Księgi Daniela
DNA Methylation: Biological Implications and Modulation of Its Aberrant Dysregulation
No full textThe alteration of the DNA methylation pattern is often related to the onset of diseases based on epigenetic dysregulation, primarily cancer. In this scenery the development of DNA methyltransferase inhibitors is one of the most attractive challenges for anticancer therapy. The present chapter proposes a comprehensive classification of the DNA methyltransferase inhibitors known in literature, on the basis of their natural or synthetic nature and their mechanism of action
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