1,720,974 research outputs found
SINTESI DI NUOVE MOLECOLE PER IL TRATTAMENTO DI PATOLOGIE INFIAMMATORIE
Full text linkRecently, the role of hydrogen sulphide (H2S) a well known toxic gas with reducing properties has received a great interest. It has been found that H2S is produced in consistent quantity in the mammalian tissues and it exerts several physiological effects that suggest its role as a regulating mediator. H2S is involved in the regulation of the muscular tone, of the myocardial contractility, in the inflammatory processes, in the neurotransmission and in insulin secretion. Reduced levels of H2S were observed in several animal models of artery and pulmonary hypertension, damages of gastric mucosa and hepatic cirrhosis. Exogenous H2S inhibits inflammation, improves cardiac dysfunctions associated to ischemia/reperfusion and reduces the gastric damage induced by anti-inflammatory drugs. On the other hand, if not properly controlled and in excessive doses, endogenous H2S may contribute to tissue inflammation through stimulation of related converting enzymes (CBA and CBS).
H2S has also an active role in the redox imbalance processes. In particular this gas mediator influences the activation of cellular inflammatory processes interacting with signalling mechanisms, transcription factors and neutralizing ROS. Moreover it has been reported that it has cytoprotective properties due to GSH production in several tissues.
On this basis, it is clear the utility of molecules capable to modulate the plasma and tissue concentration of H2S especially in pathologies characterised by disorders of GSH homeostasis and increase of oxidative stress as it happens in neurodegenerative diseases, cystic fibrosis and other severe lung pathologies, but also in cardiovascular diseases (such as metabolic syndrome) etc.
An interesting and innovative approach is the synthesis of hybrid molecules that combine the structure of a known drug with a sulfurated moiety able to in vivo slowly release H2S. Therefore, the purpose of this thesis was the synthesis of hybrid compounds active in neurodegenerative diseases (PD), such as sulfurated derivatives of L-DOPA and H2S-releasing drugs active on the peripheral circulatory system, such as sulfurated derivatives of phosphodiesterase 5 (PDE-5) inhibitors, in order to improve the efficacy and tolerability of the parent compound. Cysteine hybrid compounds coupled to dithiolethiones, addressed to treatment of specific metabolic conditions such as hyperhomocysteinemia, were also synthesized.
The pharmacological studies conducted until now show that the H2S-releasing drugs, described in this thesis, by in vivo H2S releasing and modulating, have important antioxidant, anti-inflammatory and cytoprotective properties, while maintaining the pharmacological profile of the original drug. These data confirm the potential usefulness of new compounds in the treatment of many different diseases in which there is an inflammatory and / or a redox imbalance component
Modulation of thiol homeostasis induced by a novel H2S-releasing compound
No full textRecently, the physiological function of hydrogen sulfide (H2S) has been discovered and a potential therapeutic use of this gas for the treatment of diseases characterized by its altered concentrations has been suggested. A possible approach for a therapeutic administration of H2S is represented by molecules able to release H2S in a controlled manner, mimicking what happens physiologically. Dithiolethiones have been found to behave as H2S donors in physiological conditions.
N-Acetylcysteine (NAC) is under investigation as potential therapeutic agent against several different pathologies characterized by the occurrence of oxidative stress and a decrease in GSH although results deriving from large, multi-center, prospective clinical trials are on most case contradictory and inconclusive. It is possible that the scarce efficacy of NAC is due to its low oral bioavailability (about 8%).
We have recently observed that both dithiolethione containing molecules and the derivative of NAC, N-acetylcysteine ethylester (NACET) are able to significantly reduce circulating and tissue levels of hyperomocysteinemia (hCys), probably via an increase of the thiol to disulfide ratio in extracellular fluids. Mild hCys is considered an independent risk factor for cardiovascular and cerebrovascular disease.
Starting from these observations, we synthesized new dithiolethione–cysteine hybrids (ACS94, ACS96, ACS97) with the assumption that they could have synergic effect in reducing plasma hCys, as well (by tissue glutathione increase) correcting the redox imbalance process present in several diseases.
The effects on thiols pool in different organs and in plasma, after iv or oral administration of NAC (10mg/kg) or equimolar ACS94 to healthy rats and after ip administration of paracetamol (as a model of hepatic toxicity), have been investigated.
The results clearly indicate that ACS94 protects from paracetamol induced hepatic toxicity better than NAC and that ACS94 prevents paracetamol induced thiol depletion in kidney and liver. In addition a more significant decrease of hCys compared to NAC, was observed in some rat target organs and in plasma
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“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
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
New sulfurated derivatives of valproic acid with enhanced histone deacetylase enhibitory activity
No full textOne dithiolthione and two new methanethiosulfonate derivatives of valproic acid (VPA) were synthesized and tested
in vitro as histone deacetylase (HDAC) inhibitors. The new molecules, as well as their sulfurated moieties, exhibited a much stronger
inhibition of HDAC enzymatic and antiproliferative activities and histone hyperacetylation than VPA. ACS 2 is the most interesting
compound among the new VPA derivatives and its sulfurated moiety, 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione, also known to
be a metabolite of anethole trithione, seems to contribute significantly to its activity. This is the first time that HDAC inhibitory
activity is described for dithiolethiones and thiosulfonates.
New aryldithiolethione derivatives as potent histone deacetylase inhibitors
No full textHistone deacetylases (HDACs) are a family of enzymes that regulate chromatin remodelling
and gene transcription and there is a growing interest in inhibitors of HDAC as a promising class of anticancer agents.
Recently we have found that 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADTOH) and its valproic acid ester ACS 2 potently inhibited in vitro HDAC enzymatic activity as well as A549 cell proliferation with increased levels of hyperacetylated histone H4-acetylation [1].
On this ground and with the aim to explore further the anticancer potentialities of
dithiolethiones, we designed and synthesized novel derivatives taking as a model the
chemical structure of the well known and recently marketed HDAC inhibitor SAHA.
In our new compounds the aryldithiolethione moiety is linked to an alkyl chain by mean of
an ester or an ether linkage.
All compounds exhibited in vitro HDAC inhibitory activity, sometimes comparable or higher than SAHA (IC50<0.1μM). A discussion on structure-activity relationships of the synthesized compounds will be performed. Data on inhibition of cellular proliferation and on histone hyperacetylation by the most active compounds will be also reporte
Pharmacological profile of a novel H2S-releasing aspirin
No full textPrevention of aspirin toxicity represents still an unmet medical need. Already several years ago, nitric oxide was utilized as a tool to reduce gastric toxicity [1], by preparing NOreleasing aspirin (NO-aspirin) and many other NO-donating agents. NO-aspirin appears unequivocally to be better tolerated in animals and humans, although consistently higher doses were needed to obtain comparable prostaglandin suppression to aspirin in humans. It remains to be understood if this could be at least partially dependent on the tachyphylaxis
responses observed for NO-aspirin.
With this general approach in mind, we were intrigued to determine whether a chemically
modified aspirin with the ability to release hydrogen sulfide (H2S) might prove of value as a novel stomach-sparing aspirin. The idea came from the evidence that this gaseous mediator possesses all of the positive effects of NO without the capacity to form peroxynitrite, the toxic metabolite, which has been thought to be involved in tachyphylaxis and related to redox imbalance disorders.
The pharmacological profile of a new safe and effective hydrogen sulfide-releasing aspirin (ACS 14) will be described. We report the synthesis of this compound and of its metabolite(ACS21) and the preliminary pharmacokinetics and in vivo metabolism with the determination of the hydrogen sulphide (H2S) plasma levels after intravenous rat
administration, using an improved validated HPLC analytical method. While it maintains the thromboxane suppressing activity owned by the parent compound, ACS14 appears to spare the gastric mucosa, by affecting redox imbalance processes via H2S/GSH increased
formation and isoprostane suppression.
In conclusion, the new H2S-donating aspirin appears to be an effective and safe compound,
with significant advantages over the native aspiri
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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