1,720,994 research outputs found
Oxidative stress, mitochondrial abnormalities and proteins deposition: multitarget approaches in Alzheimer's disease
Full text linkAlzheimer diseases (AD) is a multifactorial pathology characterized by a complex etiology. The hallmarks of AD, such as Aβ deposits in senile plaque and neurofibrillary tangles (NFT), are strongly intertwined with reactive oxygen species (ROS)production and oxidative stress (OS),which are considered the common effectors of the cascade of degenerative events. An increasing body of evidence reveals that both mitochondrial abnormalities and metal accumulations synergistically act as major producers of ROS, thus contributing to neuronal toxicity. Consequently, the detrimental role of ROS production together with the neurodegenerative events involved in AD has been widely investigated as new potential therapeutic strategies. This review will concisely summarize the link between OS and the hallmarks of AD, emphasizing on their strong correlation with neurodegenerative events and elucidating the pivotal role of ROS in AD pathology. Furthermore, through this review, we will provide a short account of some of the efforts, challenges and opportunities in developing multitarget drugs by addressing ROS production, metal accumulation and protein depositions
Hydrogen sulfide: A worthwhile tool in the design of new multitarget drugs
Full text linkH2S is a gaseous molecule able to trigger a plethora of central physiological and pharmacological effects as antioxidant, pro- and anti-inflammatory, pro- and anti-nociceptive, neuromodulator, and cytoprotective. The polypharmacology of H2S depends on the wide variety of targets implicated, but, despite the efforts, the mechanisms of action that should clarify its activity are still not completely unrevealed. Nevertheless, many attempts to exploit the multifaceted profile of this molecule have already been accomplished and many chemical entities containing an H2S-releasing pharmacophore have been synthetized. Here we discuss recent investigations on multitarget molecules able to release H2S, with a particular focus on the combinations of "native drug" with moieties structurally able to release H2S and their applications as therapeutic tools in bone disease, gastrointestinal system and neurodegenerative disorders
Targeting the upregulated PI3K-PDK1-Akt pathway: a drug discovery approach of treating cancer.
No full textThe phosphoinositide 3-kinase/3-phosphoinositide-dependent kinase 1 (PDK1)/Akt signaling pathway plays a key role in cancer cell growth, invasion, and survival. Moreover, its pivotal role in carcinogenesis and tumor progression has been definitely established (1). Aberrant activation of this pathway has been implicated in many cancers such as ovarian, lung, breast, colon cancer and glioblastoma (2), therefore it could be considered as an attractive target for cancer therapy.
Starting from an analysis of recent patented Akt pathway inhibitors chosen as lead structures, we designed and synthesised a new collection of oxyindolone derivatives (OXIDs). Although the 2-oxyindole nucleus has been widely investigated, and in particular as regards the effects induced by different type of substitutions in 3- position, only few cases regarded the insertion of electron reach groups in 5-position.The absence of a detailed study of this kind of modification prompted us to explore it. Then, we synthesised new OXIDs in which the C5 carbon was substituted by aromatic moieties anchored to the 2-oxyindole nucleus through different amidoalkyl chains.
A preliminary evaluation on human NSCLC showed a significant antiproliferative effects, and a marked suppression of Akt phosphorylation at P-Thr308. Finally a flow cytometry analysis showed that OXIDs lead to a G1 phase arrest associated to a reduction of G2/M phase and a relative loss of S-phase population.
OXID
Symbiotic approach applied to the synthesis of new agents for the treatment of Alzheimer’s disease
No full textAlzheimer disease (AD) is a progressive age-dependent neurodegenerative pathology. The number of people with AD is steadily increasing and has a severe impact on individuals, families, and society. Although the etiology of AD is not yet completely explored, it is now commonly established that it is a multifactorial neurodegenerative pathology.
Nowadays, many agents have been synthesized for the treatment of memory and cognition impairments able to interact with different targets. Unfortunately, AD therapy still lack in effectiveness therefore, the search for new potential drugs is heavily pursued. Consistently, the search for new multitarget agents has led us to design and
synthesize a series of tacrine–hydroxycinnamic acid (caffeic or ferulic acid) hybrids that showed acetylcholinesterase (AChE) inhibitory activity and antioxidants properties1
. Recently, with the aim of increasing the affinity for the butyrylcholinesterase (BuChE) we reported the synthesis and in vitro activities of novel rivastigmine-hydroxycinnamic
acid hybrids as inhibitors of AChE and BuChE, ROS scavengers and inhibitors of Aβ aggregation 2.. In order to expand the SAR study for this new class of compounds, herein we describe the design and synthesis of analogs 1-6 obtained by the symbiotic combination of rivastigmine skeleton with natural antioxidant agents such as gallic acid and 2-chromonecarboxylic acid. The new ligands were evaluated in different systems for neuroprotective, antioxidant, ChE inhibitory and inhibitory of Aβ aggregation properties
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
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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