1,720,972 research outputs found
Chemical elaboration of synthetic and natural bioactive compounds to improve bioavailability and activity
Full text linkThe project aimed to synthesize new prodrugs of bioactive molecules and new self-assembling fully biocompatible macromolecular structures as vehicles for drug delivery. Initially, I worked on the chemical modification of the phenolic group of pterostilbene – a natural bioactive polyphenol used as model in this study – in order to improve its bioavailability after oral administration. I synthesized and tested new pterostilbene derivatives using five different types of protecting groups to functionalize the hydroxyl group and convert the natural phenol, specifically, into a methylthiomethyl ether (MTM), a phosphonic ester, an alkylcarbonyloxymethyl (ACOM) ether, an alkyloxycarbonyloxymethyl (AOCOM) ether and an N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) ether. The derivatives display very different chemical stability profiles. In preliminary screenings, the AOCOM and ACOM derivatives gave the best results in terms of chemical and biological stability. These compounds were thus tested in pharmacokinetic experiments in vivo. The blood concentration vs. time profiles of pterostilbene and its sulfate obtained with the ACOM prodrug were very similar to those determined after administrating pterostilbene as such. Those afforded by the AOCOM derivative showed instead a considerable shift to longer times after administration, indicating that it indeed behaves as a prodrug.
During the second year, I developed two new classes of selective tumor killing agents based on the natural phenol 5-hydroxypsoralen and on the anti-leprosy drug clofazimine. The aim of this part of my project was the design, synthesis and test of novel selective inhibitors of the mitochondrial potassium channel Kv 1.3. This channel is expressed in the inner mitochondrial membrane of many types of cancer cells and its inhibition plays an important role in the induction of apoptosis. In a series of in vitro and in vivo tests three of my psoralen derivatives (patented) proved to be remarkably effective. As for the clofazimine derivatives, only a few in vitro assays have been performed so far and further in depth tests are currently under way.
More recently, during the time I spent at ETH in Zürich, I worked on the design and synthesis of biocompatible polymeric micelles for drug delivery. In particular, I developed and characterized a series of novel resveratrol –OEG-co-adipate and polymethyloxazolines -co-pterostilbene based copolymers that self-assemble in water to form core-shell nanocarriers. In order to test their ability as nanocarriers I loaded them with clofazimine and studied their behavior under various experimental conditions. In the case of polyoxazolines-co-pterostilbene constructs, these preliminary tests gave encouraging results which prove the value of this approach to obtain a highly modular copolymer platform to be used for the safe delivery of its drug load into solid tumors by exploiting the Enhanced Permeability and Retention (EPR) effect
Synthesis of resveratrol sulfates: turning a nightmare into a dream
No full textAbstract The growing interest in the bioactivity of natural polyphenols and of their metabolites requires pure metabolites to be used in bioassays and as standards in analytical protocols. We report here the synthesis of all five resveratrol sulfates achieved using a known approach of selective protection via silyl ether and sulfation but new reaction conditions and isolation procedures, which result in simplified protocols and greatly improved yields. A rationale for the problems so far encountered in handling and isolating resveratrol sulfates is provided as well as a solution based on avoidance of low pressure conditions during purification/isolation. These conclusions are probably of more general scope and might be usefully taken into consideration for obtaining other phenolic sulfates in high yield
Improving the efficacy of plant polyphenols.
No full textPlant polyphenols exhibit potentially useful effects in a wide variety of pathophysiological settings. They interact with proteins such as signalling kinases, transcription factors and ion channels, and modulate redox processes, such as those taking place in mitochondria. Biomedical applications of these natural compounds are however severely hindered by their low bioavailability, rapid metabolism, and often by unfavourable physico-chemical properties, e.g. a generally low water solubility. Derivatives are under development with the aim of improving their bioavailability and/or bioefficacy. Various strategies can be adopted. An increase in circulating blood levels of non-metabolized natural compound may be attainable through prodrugs. In the ideal prodrug, phenolic hydroxyls are protected by capping groups which a) help or at least do not hinder permeation of epithelia; b) prevent conjugative modifications during absorption and first-pass through the liver; c) are eliminated with opportune kinetics to regenerate the parent compound. Moreover, prodrugs may be designed with the goals of modulating physical properties of the parent compound, and/or changing its distribution in the body. A more specific action may be achieved by concentrating the compounds at specific sites of action. An example of the second approach is represented by mitochondria-targeted redox-active polyphenol derivatives, designed to intervene on radical processes in these organelles and as a tool either to protect cells from oxidative insults or to precipitate their death. Mitochondrial targeting can be achieved through conjugation with a triphenylphosphonium lipophilic cation. Quercetin and resveratrol were chosen as model polyphenols for these proof-of-concept studies. Data available at the moment show that both quercetin and resveratrol mitochondria-targeted derivatives are pro-oxidant and cytotoxic in vitro, selectively killing fast-growing and tumoural cells when supplied in the low μM range; the mechanism of ROS generation appears to differ between the two classes of compounds. These approaches are emerging as promising strategies to obtain new efficient chemopreventive and/or chemotherapeutic drugs based on polyphenols derivatives
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
Regulation of Proliferation by a Mitochondrial Potassium Channel in Pancreatic Ductal Adenocarcinoma Cells
Full text linkPrevious results link the mitochondrial potassium channel Kv1.3 (mitoKv1.3) to the regulation of apoptosis. By synthesizing new, mitochondria-targeted derivatives (PAPTP and PCARBTP) of PAP-1, a specific membrane-permeant Kv1.3 inhibitor, we have recently provided evidence that both drugs acting on mitoKv1.3 are able to induce apoptosis and reduce tumor growth in vivo without affecting healthy tissues and cells. In the present article, by exploiting these new drugs, we addressed the question whether mitoKv1.3 contributes to the regulation of cell proliferation as well. When used at low concentrations, which do not compromise cell survival, both drugs slightly increased the percentage of cells in S phase while decreased the population at G0/G1 stage of cells from two different pancreatic ductal adenocarcinoma lines. Our data suggest that the observed modulation is related to ROS levels within the cells, opening the way to link mitochondrial ion channel function to downstream, ROS-related signaling events that might be important for cell cycle progression
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
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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