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Pharmacological characterization of new modulators of the endocannabinoid system: from single target to multi-target compounds
No full textIl sistema endocannabinoide (SEC), una rete neuronale diffusa, contribuisce attivamente allo sviluppo del sistema nervoso centrale (SNC), regolando diversi processi cognitivi e fisiologici. È composto da endocannabinoidi (eCB), recettori cannabinoidi (CB1R, CB2R) e proteine correlate. La manipolazione del SEC mostra promesse nel trattamento di malattie neurodegenerative, disturbi dell'umore, dolore, infiammazione, cancro e disturbi metabolici.
La ricerca intende caratterizzare dal punto di vista farmacologico nuovi composti modulatori del SEC e valutare il possibile potenziale terapeutico. Il Capitolo 1 riguarda l'indagine di ligandi selettivi per CB2R, in grado di attivare il SEC senza gli effetti collaterali associati a CB1R. I composti in esame sono stati sottoposti a esperimenti di binding recettoriale, rivelando elevata selettività per CB2R. Alcuni composti si comportano come agonisti parziali per il recettore CB2R, mentre altri sono stati identificati come agonisti inversi per tale recettore. Questi composti potrebbero avere un potenziale terapeutico nei disturbi neurodegenerativi del SNC e nelle patologie croniche infiammatorie.
Le connessioni tra neuroinfiammazione e neurodegenerazione sono comuni in numerose patologie che coinvolgono il SNC. Infatti, è noto che il SEC svolge un ruolo cruciale nel controllo della neuroinfiammazione, e di conseguenza l'uso degli inibitori di FAAH potrebbe rappresentare una innovativa strategia terapeutica. Il Capitolo 2 riguarda nuovi composti inibitori degli enzimi di catabolismo degli eCB, coinvolti nell’amplificazione del signalling cellulare riducendo gli effetti collaterali degli agonisti sintetici. Lo studio rivela inibitori selettivi di FAAH altamente potenti, con proprietà anti-neuroinfiammatorie in astrociti e tessuti ippocampali.
Numerosi studi presenti in letteratura mostrano che il sistema melatoninergico è collegato a malattie neurodegenerative con effetti protettivi e di neurogenesi. Il Capitolo 3 ha valutato gli effetti multi-target di nuovi composti sul sistema melatoninergico e SEC, testati per la loro affinità con i recettori della melatonina e per la potenza inibitoria di FAAH. I composti sono stati valutati per le loro capacità antinfiammatorie. I composti hanno mostrato un'affinità significativa per MT1R e MT2R, e FM15 è un potente composto con duplice azione, funzionando come agonista melatoninergico e inibitore di FAAH, capace di ridurre la produzione di TNFα.
Inoltre, lo studio condotto si propone di valutare nuovi composti neuroprotettivi combinando gli effetti degli inibitori di FAAH con quelli degli inibitori di HDAC nei disturbi del SNC legati allo stress ossidativo. Il Capitolo 4 valuta nuovi potenziali inibitori per gli enzimi FAAH e HDAC6 al fine di testare la riduzione dei danni indotti dallo stress ossidativo. Tra i composti analizzati è emerso che FH09 e FH11 sono i composti più efficaci, mostrando significativi effetti neuroprotettivi in modelli cellulari. In particolare, FH11 ha un'attività inibitoria potente su FAAH e HDAC6 senza effetti citotossici negli astrociti.
In sintesi, la diffusa presenza dei recettori cannabinoidi suggerisce che il SEC è coinvolto in vari processi fisiologici e nell'omeostasi. La ricerca si propone di identificare nuovi ligandi farmacologici per modulare il SEC, con potenziale terapeutico per disturbi neurodegenerativi e infiammatori del SNC. Gli inibitori selettivi di FAAH sono considerati promettenti per trattare disturbi infiammatori del SNC, aumentando gli endocannabinoidi e riducendo gli effetti collaterali degli agonisti dei CBR. Inoltre, l'approccio multi-target con composti mirati a diverse condizioni, come lo stress ossidativo e l'infiammazione, potrebbe rappresentare un'innovazione nelle strategie farmacologiche. In definitiva, lo sviluppo di nuovi ligandi multi-target per il SEC potrebbe rivoluzionare le terapie per patologie neurodegenerative e infiammatorie croniche del SNC.The endocannabinoid system (ECS), a widespread neuronal network, actively contributes to the development of the central nervous system (CNS), regulating various cognitive and physiological processes. It consists of endocannabinoids (eCB), cannabinoid receptors (CB1R, CB2R), and related proteins. Manipulating the ECS shows promise in treating neurodegenerative diseases, mood disorders, pain, inflammation, cancer, and metabolic disorders.
The research aims to pharmacologically characterize new ECS modulatory compounds and assess their potential therapeutic effects. Chapter 1 focuses on investigating selective ligands for CB2R capable of activating the ECS without the side effects associated with CB1R. Various compounds underwent receptor binding experiments, revealing agonists with high selectivity for CB2R. Some compounds exhibited excellent affinity and selectivity for CB2R. Other compounds acted as partial agonists for CB2R, while others were identified as inverse agonists. The study unveils compounds with therapeutic potential in CNS neurodegenerative disorders and chronic inflammatory pathologies.
Currently, it is crucial to evaluate the possible connections between neuroinflammation and neurodegeneration common in numerous CNS-related diseases. The ECS plays a crucial role in controlling neuroinflammation, and the use of FAAH inhibitors could represent an innovative therapeutic strategy. Chapter 2 deals with new inhibitors of eCB catabolism enzymes involved in amplifying cellular signaling, reducing side effects of synthetic agonists. The study reveals highly potent FAAH selective inhibitors with anti-neuroinflammatory properties in astrocytes and hippocampal tissues.
Numerous literature studies show that the melatoninergic system is linked to neurodegenerative diseases with protective and neurogenic effects. Chapter 3 evaluates the multitarget effects of new compounds on the melatoninergic system and ECS, tested for their affinity with melatonin receptors and FAAH inhibitory potency. Synthetic compounds were assessed for their anti-inflammatory capabilities using assays measuring inflammatory and anti-inflammatory factors. Compounds FM07-FM15 showed a significant affinity for MT1R and MT2R, and FM15 is a potent dual-action compound, functioning as a melatoninergic agonist and FAAH inhibitor, capable of reducing TNFα production.
Furthermore, the study aims to evaluate new neuroprotective compounds by combining the effects of FAAH inhibitors with HDAC inhibitors in CNS disorders related to oxidative stress. Chapter 4 assesses new potential inhibitors for FAAH and HDAC6 enzymes to test antioxidant properties and evaluate the reduction of oxidative stress-induced damage. Among the analyzed compounds, FH09 and FH11 emerged as the most effective, showing significant neuroprotective effects in cellular models. Particularly, FH11 has potent inhibitory activity on FAAH and HDAC6 without cytotoxic effects. Additional cell viability assays reveal the effectiveness of these compounds in mitigating glutamate-induced toxicity.
In conclusion, the widespread presence of cannabinoid receptors indicates the involvement of the ECS in various physiological processes and in maintaining homeostasis. One of the research goals was to pharmacologically characterize new ligands for ECS modulation with therapeutic potential in CNS neurodegenerative disorders and chronic inflammatory pathologies. Selective FAAH inhibitors can treat inflammatory CNS disorders by increasing eCB levels, reducing side effects of CBR agonists. Moreover, multi-target compounds offer an innovative approach for multifactorial conditions, especially those related to oxidative stress and inflammatory states. Consequently, developing new multi-target ligands for the ECS could revolutionize pharmacological strategies for neurodegenerative and chronic inflammatory CNS pathologies
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Update on the recent development of allosteric modulators for adenosine receptors and their therapeutic applications
No full textAdenosine receptors (ARs) have been identified as promising therapeutic targets for countless pathological conditions, spanning from inflammatory diseases to central nervous system disorders, from cancer to metabolic diseases, from cardiovascular pathologies to respiratory diseases, and beyond. This extraordinary therapeutic potential is mainly due to the plurality of pathophysiological actions of adenosine and the ubiquitous expression of its receptors. This is, however, a double-edged sword that makes the clinical development of effective ligands with tolerable side effects difficult. Evidence of this is the low number of AR agonists or antagonists that have reached the market. An alternative approach is to target allosteric sites via allosteric modulators, compounds endowed with several advantages over orthosteric ligands. In addition to the typical advantages of allosteric modulators, those acting on ARs could benefit from the fact that adenosine levels are elevated in pathological tissues, thus potentially having negligible effects on normal tissues where adenosine levels are maintained low. Several A(1) and various A(3)AR allosteric modulators have been identified so far, and some of them have been validated in different preclinical settings, achieving promising results. Less fruitful, instead, has been the discovery of A(2A) and A(2B)AR allosteric modulators, although the results obtained up to now are encouraging. Collectively, data in the literature suggests that allosteric modulators of ARs could represent valuable pharmacological tools, potentially able to overcome the limitations of orthosteric ligands
Variations on the Author
Get PDF“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
Get PDFWe 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
Get PDFWe 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
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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