110 research outputs found
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
I corrispondenti di Abramo Massalongo con particolare riguardo ai rapporti con la famiglia di Alberto Parolini
No full textA. Massalongo, grande scienziato e lichenologo, intrattiene rapporti scientifico-amicali con un cultore della botanica e possessore di un giardino botanico conosciuto in Europ
I libri di Abramo Massalongo: note per la conoscenza di una biblioteca scientifica di metà Ottocento
No full textLa biblioteca di Abramo Massalongo, noto naturalista del XIX, parla delle sue conoscenze scientifiche, ma anche dei diversi interessi culturali manifestati dallo scienziato. Si è voluto quindi analizzare il posseduto librario per avvalorare, omologare, ratificare quanto già si conoscesse sullo studioso contestualizzando la sua biblioteca nel panorama dell'editoria scientifica già nota
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
Drive and Agency in the Age of Algorithm-Based Decision Making
No full textThe Freudian drive, which was defined as the “psychical representative of an endosomatic continuously flowing source of stimulation”, has been further explained by Giacomo B. Contri as “the law of motion of bodies [... ] to destination or satisfaction” whose source is the “Thinking of Nature”. The above-mentioned reference to a sort of “psychical agency” would have remained unclear for jurists if the Freudian concept of drive had not been further clarified by Giacomo B. Contri in terms that open the way to further scientific research work also in the field of legal studies.
Legal research on this topic could start by comparing the meaning of the “law of motion of bodies [...] to destination or satisfaction” (i.e., the “drive”) with the legal concept of “agency relationship”. In civil law, agency is the power that the interest holder (principal) confers to another (agent) in order to have its proper interest satisfied through the juridical activity of the latter. The first question here is whether it is possible to consider the juridical relationship between principal and agent as an example of “Subject-Other relationship” described by the psychoanalysis. Legal research concerning parallels between “drive” and “agency” might also utilize Giacomo Contri’s idea of “pact” (“alleanza”), which is as well one the articles of his “Encyclopedia of the Thinking of Nature”, in order to assess whether the “agency partnership” can actually be described as an example of “Subject-Other pact or alliance”.
The starting point of the prospective investigation is the source of voluntary agency, in other words the power of attorney. When power of attorney is granted, the juridical activity of the agent provides benefit to the party who granted the power of attorney (the principal). Acts carried out by the agent in the name of the principal are chiefly to the principal’s benefit, whilst those reducing the principal’s wealth could be annulled if the agent has acted in conflict of interests with the principal. Even though the power of attorney confers on the agent the power to act in the name of the principal, it does not oblige the agent to act: the agency relationship may be described as a “can-do legal relationship” and it differs from the “shall do legal relationships” that arise from contracts. Once entitled by the principal, the agent can still decide whether to act or not, depending on his relationship with the principal. The legal relationship established by “authorization” or “public investiture” of the agent by the principal is not necessarily a contractual one. The granting of power of attorney is perfectly valid and effective even in the absence of an underlying contract of mandate or any other consideration. At the same time, it is necessary but not sufficient for the success of the agency relationship. The concept of “pact” or “alliance”, as it has been developed by psychoanalysis, describes a partnership yet not a contract. This concept might be fruitfully used to study the functioning of the agency partnership in cases where the agency device has been successfully employed. The concept of “pact” or “alliance” has been rarely investigated by private law legal scholars, who would then receive an important research input by the psychoanalysis
La formalizzazione della CSR : obiettivi e strumenti
No full textLAUREA SPECIALISTICAIl mondo imprenditoriale ed il mercato hanno maturato la consapevolezza dell’urgenza di dovere investire in attività socialmente responsabili e giudicate di grande importanza da parte dei loro principali portatori di interesse. Da questa consapevolezza nasce il cambiamento che da anni sta permeando il mondo del business. Non solo, le molteplici iniziative che ricadono nell’ambito tematico della CSR iniziano ad essere percepite come un fattore strategico, un’opportunità ed una leva sulla competitività. Secondo questa visione, le imprese non possono prescindere dalla propria responsabilità sociale, considerata uno strumento strategico in grado di portare benefici alla società ed all’ambiente, e allo stesso tempo rafforzare il vantaggio competitivo aziendale.
Alcuni autori, basandosi sul contesto attuale, ritengono che le imprese utilizzino gli strumenti di formalizzazione della CSR meramente come mezzo per giustificare le proprie azioni al mondo esterno e nascondere i propri reali interessi. In questo senso la CSR rappresenta la risposta delle imprese alla crescente richiesta da parte del pubblico e dei media di rendicontare le attività aziendali, con l’unico scopo di ottenere legittimazione. Queste critiche sono attualmente oggetto di dibattito, inasprito dalla imminente introduzione della certificazione ISO 26000. Il problema discusso fa riferimento al contrasto esistente tra la CSR intesa in senso “cosmetico”, finalizzata ad ottenere legittimazione e incrementare la propria reputazione, e quella che, invece, viene realmente integrata nella strategia aziendale, ritenuta portatrice di una serie di vantaggi ulteriori per l’impresa.
A partire dal dibattito sopramenzionato e dall’analisi della letteratura, la presente ricerca avrà lo scopo di identificare quali sono i vantaggi che le imprese hanno conseguito attraverso il processo di formalizzazione della CSR. Si vuole indagare se gli obiettivi delle imprese relativi ai vantaggi dell’adozione degli strumenti siano di tipo reputazionale, oppure se le imprese ricerchino benefici che abbiano un impatto interno. L’analisi dei vantaggi attesi permette di individuare i diversi approcci alla formalizzazione che le imprese possono adottare in tale processo.The business world and the market have developed an awareness of the urgency with which they must invest in socially responsible activities and judge the importance of these initiatives for their stakeholders. From this knowledge is born a change that, for years, has been permeated the world of business. Furthermore, the multitude of initiatives that refer to this set of themes within CSR begin to be seen as a strategic factor, an opportunity and a tool with which to compete. According to this vision, these businesses cannot shy away from their social responsibilities, which are considered a strategic instrument that brings benefits to the society and the environment and at the same time reinforces the company’s competitive advantage.
Several authors, basing their work within an real-world context, think that the companies use the formalisation instruments of CSR only as a way to justify their actions to the external world and hide their real interests. In this sense CSR represents the response of the companies to the rising demand on the part of the public and media to recount the businesses’ activities, with the objective of obtaining legitimacy. These criticisms are, in actuality, subjects of debate, accentuated by the imminent introduction of the certificate ISO 26000. The problem discussed refers to the existing contrast between cosmetic CSR, which aims to achieve legitimacy and an improvement in reputation, and integrated CSR, which aims to achieve other advantages for the business.
Starting from the debate mentioned above and on premises drawn from the literature, the present analysis has the objective to identify those advantages for the company that derive from the formalisation of CSR. This paper aims to understand why companies formalise CSR, if this approach is designed to improve the reputation of the company or if the company aspire to obtain other benefits that have an internal impact on the company. The analysis of these expected advantages allows differentiation between various approaches to formalisation
Binding and unbinding of potent melatonin receptor ligands: Mechanistic simulations and experimental evidence
No full textThe labeled ligand commonly employed in competition binding studies for melatonin receptor ligands, 2-[125I]iodomelatonin, showed slow dissociation with different half-lives at the two receptor subtypes. This may affect the operational measures of affinity constants, which at short incubation times could not be obtained in equilibrium conditions, and structure-activity relationships, as the Ki values of tested ligands could depend on either interaction at the binding site or the dissociation path. To address these issues, the kinetic and saturation binding parameters of 2-[125I]iodomelatonin as well as the competition constants for a series of representative ligands were measured at a short (2 h) and a long (20 h) incubation time. Concurrently, we simulated by molecular modeling the dissociation path of 2-iodomelatonin from MT1 and MT2 receptors and investigated the role of interactions at the binding site on the stereoselectivity observed for the enantiomers of the subtype-selective ligand UCM1014. We found that equilibrium conditions for 2-[125I]iodomelatonin binding can be reached only with long incubation times, particularly for the MT2 receptor subtype, for which a time of 20 h approximates this condition. On the other hand, measured Ki values for a set of ligands including agonists, antagonists, nonselective, and subtype-selective compounds were not significantly affected by the length of incubation, suggesting that structure-activity relationships based on data collected at shorter time reflect different interactions at the binding site. Molecular modeling simulations evidenced that the slower dissociation of 2-iodomelatonin from the MT2 receptor can be related to the restricted mobility of a gatekeeper tyrosine along a lipophilic path from the binding site to the membrane bilayer. The enantiomers of the potent, MT2-selective agonist UCM1014 were separately synthesized and tested. Molecular dynamics simulations of the receptor-ligand complexes provided an explanation for their stereoselectivity as due to the preference shown by the eutomer at the binding site for the most abundant axial conformation adopted by the ligand in solution. These results suggest that, despite the slow-binding kinetics occurring for the labeled ligand, affinity measures at shorter incubation times give robust results consistent with known structure-activity relationships and with interactions taken at the receptor binding site
Caffeine for Prevention of Alzheimer's Disease: Is the A2A Adenosine Receptor Its Target?
No full textAlzheimer's disease (AD) is the most prevalent kind of dementia with roughly 135 million cases expected in the world by 2050. Unfortunately, current medications for the treatment of AD can only relieve symptoms but they do not act as disease-modifying agents that can stop the course of AD. Caffeine is one of the most widely used drugs in the world today, and a number of clinical studies suggest that drinking coffee may be good for health, especially in the fight against neurodegenerative conditions such as AD. Experimental works conducted "in vivo" and "in vitro" provide intriguing evidence that caffeine exerts its neuroprotective effects by antagonistically binding to A2A receptors (A2ARs), a subset of GPCRs that are triggered by the endogenous nucleoside adenosine. This review provides a summary of the scientific data supporting the critical role that A2ARs play in memory loss and cognitive decline, as well as the evidence supporting the protective benefits against neurodegeneration that may be attained by caffeine's antagonistic action on these receptors. They are a novel and fascinating target for regulating and enhancing synaptic activity, achieving symptomatic and potentially disease-modifying effects, and protecting against neurodegeneration
Cytotoxic and Antiproliferative Effects of [64Cu]CuCl2 in Tumor Cells for Radiometabolic Therapy: a Preliminary Study
No full textCytotoxic and Antiproliferative Effects of [64Cu]CuCl2 in Tumor Cells for Radiometabolic Therapy: a Preliminary Study.
No full text- …
