Design and synthesis of new antitumor ligands

During last decade, studies on different molecular mechanism involved both in physiological and pathological events, lead researchers to identify new pharmacological targets able to disrupt key steps of oncogenesis and metastasis proliferation. In particular investigation on phosphoinositide-dependent transduction signalling disclosed the key role of PI3K/PDK1/Akt pathway in cancer progression, but also in resistance to chemotherapy, identifying this pathway as promising target for new therapeutic strategies. My PhD thesis focused on the design of OXIDs, a class of potential PI3K/Akt/PDK1 inhibitors, starting from the early stage of synthesis to the biological activity. Effects of OXIDs in different cell line will be discussed and the best OXIDs have been selected for further experiments in Human Glioblastoma Multiforme (GBM) and in GBM-derived stem cells. Moreover, since MP7 is the most potent PDK1 allosteric inhibitor reported in literature, new OXID-pyridon-1-yl hybrids, in which pharmacophoric groups of MP7 are linked with OXIDs scaffold, were designed and synthesised

Oxidative stress, mitochondrial abnormalities and proteins deposition: multitarget approaches in Alzheimer's disease

Alzheimer 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

New Multitarget Approaches in the War Against Glioblastoma: A Mini-Perspective

Glioblastoma multiforme (GBM) is the most common tumor of the CNS, and the deadliest form of brain cancer. The rapid progression, the anatomic location in the brain and a deficient knowledge of the pathophysiology, often limit the effectiveness of therapeutic interventions. Current pillars of GBM therapies include surgical resection, radiotherapy and chemotherapy, but the low survival rate and the short life expectation following these treatments strongly underline the urgency to identify innovative and more effective therapeutic tools. Frequently, patients subjected to a mono-target therapy, such as Temozolomide (TMZ), develop drug resistance and undergo relapse, indicating that targeting a single cellular node is not sufficient for eradication of this disease. In this context, a multi-targeted therapeutic approach aimed at using compounds, alone or in combination, capable of inhibiting more than one specific molecular target, offers a promising alternative. Such strategies have already been well integrated into drug discovery campaigns, including in the field of anticancer drugs. In this miniperspective, we will discuss the recent progress in the treatment of GBM focusing on innovative and effective preclinical strategies, which are based on a multi-targeted approach

Rappresentazione di sé e creatività nella prima adolescenza: uno studio sulle differenze di genere

La ricerca fornisce un contributo agli studi inerenti la relazione tra rappresentazione di sé e creatività nella prima adolescenza. Hanno partecipato alla ricerca 160 soggetti (età media =13 anni) frequentanti l’ultimo anno di scuole medie inferiori della Campania. Sono stati utilizzati due strumenti self-report per la valutazione delle dimensioni della rappresentazione di sé (SPP, Harter 1998) e della creatività (TPC, Williams, 1993). I risultati emersi forniscono un tassello interessante alla comprensione delle relazioni tra le dimensioni considerate. Da un punto di vista generale, sembra che il valore personale globale, cui corrisponde una valutazione positiva della propria persona, oltre che al sentirsi accettati e apprezzati dagli altri, sia legato a caratteristiche personali inerenti le dimensioni della creatività prese in esame

Hydrogen sulfide: A worthwhile tool in the design of new multitarget drugs

H2S 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

Synthesis and functional evaluation of novel aldose reductase inhibitors bearing a spirobenzopyran scaffold

Background: Aldose reductase, the first enzyme of the polyol pathway, is the key determinant for the pathogenesis of long term diabetic complications. Accordingly, its inhibition represents the major therapeutic strategy to treat this kind of pathologies. Objectives: In this work we describe the synthesis and the functional evaluation of a number of spiro-oxazolidinone and spiro-morpholinone acetic acid derivatives, and their benzyloxy analogs, developed as aldose reductase inhibitors. Results: Most of them proved to inhibit the target enzyme, showing IC50 values in the micromolar/low micromolar range. SARs observed among the three different series allowed to highlight their key pharmacophoric elements, thus creating sound basis for the design of novel and more effective inhibitors. Conclusion: Although further substitution patterns are needed, the novel compounds here proposed represent a good starting point for the development of novel and effective ARIs

Нові тенденції розвитку термінознавства : здобутки міжнародної наукової групи Р. Теммерман

Комплексно проаналізовано здобутки міжнародної наукової групи під керівництвом Р. Теммерман: розглянуто основні положення соціокогнітивного термінознавства, питання сутності терміна, фахової мови, фахової комунікації, динаміки терміна, розуміння терміна людиною за різних умов фахового спілкування, оперування великими масивами термінологічних даних, терміноонтографії й терміноонтології, інженерії знань та галузевих онтологій.The paper comprehensively analyses the achievements of the international research group led by R. Temmerman: it examines the main thesis of sociocognitive terminology, questions of the essence of a term, professional language, professional communication, dynamics of a term, understanding of a term by person under various conditions of professional communication, handling large corpora of terminological data, terminoontography and terminoontology, knowledge engineering and specialized ontologies

Contributo alla validazione della versione italiana della scala del Social Support di Susan Harter

Scopo del presente lavoro è proporre una versione italiana della Social Support Scale for adolescents di Susan Harter (1985) e di testarne le proprietà psicometriche. La scala permette di valutare il grado di supporto sociale percepito dal soggetto e la considerazione che sente di riceve da parte di altri significativi. La versione italiana è stata somministrata, in fase di pre-test, a 80 soggetti. I rilievi emersi hanno condotto ad alcuni adattamenti; la versione così ottenuta è stata somministrata ad un campione di 1203 soggetti (11-18 anni). Le analisi statistiche hanno consentito di verificare la consistenza interna e la struttura fattoriale della scala. Tali analisi hanno confermato l’attendibilità e la validità della versione italiana rispetto allo strumento originario. È stato inoltre realizzato un modello di Equazioni Strutturali, al fine di verificare la presenza di una struttura fattoriale sovrapponibile a quella originaria proposta dalla Harter. I rilievi emersi sembrano indicare che anche la versione italiana della scala proposta rappresenta un utile strumento per la comprensione e lo studio del supporto che l’adolescente percepisce di ricevere da parte di altri significativi. SUMMARY. In this paper we aim to propose an Italian version of the Social Support Scale for adolescents of Susan Harter (1985) and to explore its psychometric properties. The Social Support Scale allows to estimate the subject degree of perceived social support and the consideration from significant others. The Italian version was administered, in pre-test phase to 80 subjects. The results lead to some adaptations and this version was administered to a sample of 1203 subjects (11-18 years). The statistical analyses verified the internal consistency and the factorial structure of the Italian version with respect to the structure of the original scale. It was performed a Structural Equations modelling, to assess the properties of factorial structure. These results seem to indicate proposed Italian version of Social Support Scale can be a useful instrument to study the support that the adolescent perceives to receive from significant others

Evolution of congenital hypothyroidism in a cohort of preterm born children

Background: Congenital hypothyroidism (CH) is reported to be more common in preterm infants than in term infants, especially in sick preterm infants. Though a frequent possibility of transitory thyroidal alterations in this category of neonates, the evolution of CH to transient or permanent forms is unpredictable. Methods: We retrospectively analyzed medical records of 28 preterm infants (<37 weeks gestation) who had exhibited a positive screening for CH at birth during the period 2000–2015 followed in our Center. Children were divided into three groups: permanent CH (PCH) with thyroid dysgenesis, PCH with eutopic normal-sized thyroid gland, and transient CH (TCH) with eutopic normal-sized thyroid gland. In all groups we described clinical and biochemical characteristics. Secondly, we analyzed the differences between patients with thyroid dysgenesis and patients with eutopic normal-sized gland and we compared PCH and TCH groups with normal-sized thyroid gland in order to identify clinical or biochemical data for early detection of transient forms. Results: Of all patients, 21.4% showed thyroid dysgenesis while 78.6% presented eutopic normal-sized gland. Infants with thyroid dysgenesis had higher median (IQR) baseline s-TSH and levothyroxine (L-T4) dose per weight at 12 months (12 m-dose) than patients with eutopic normal-sized gland. At re-evaluation of the patients with eutopic normal-sized gland, 36% showed PCH and 64% had TCH. The age of the patients at the beginning of L-T4 treatment, gestational age (GA), birth weight, blood thyroid stimulating hormone levels (b-TSH) at first newborn screening (NBS), baseline serum thyroid stimulating hormone (s-TSH), and L-T4 12 m-dose were statistically different between the two groups. Conclusions: Our results demonstrate that factors as GA, birth weight, b-TSH levels at first NBS, baseline s-TSH, L-T4 12 m-dose and age at the start of the treatment may be considered useful predictive elements for the evolution of CH

Combined inhibition of AKT/mTOR and MDM2 enhances Glioblastoma Multiforme cell apoptosis and differentiation of cancer stem cells

The poor prognosis of Glioblastoma Multiforme (GBM) is due to a high resistance to conventional treatments and to the presence of a subpopulation of glioma stem cells (GSCs). Combination therapies targeting survival/self-renewal signals of GBM and GSCs are emerging as useful tools to improve GBM treatment. In this context, the hyperactivated AKT/mammalian target of the rapamycin (AKT/mTOR) and the inhibited wild-type p53 appear to be good candidates. Herein, the interaction between these pathways was investigated, using the novel AKT/mTOR inhibitor FC85 and ISA27, which re-activates p53 functionality by blocking its endogenous inhibitor murine double minute 2 homologue (MDM2). In GBM cells, FC85 efficiently inhibited AKT/mTOR signalling and reactivated p53 functionality, triggering cellular apoptosis. The combined therapy with ISA27 produced a synergic effect on the inhibition of cell viability and on the reactivation of p53 pathway. Most importantly, FC85 and ISA27 blocked proliferation and promoted the differentiation of GSCs. The simultaneous use of these compounds significantly enhanced GSC differentiation/apoptosis. These findings suggest that FC85 actively enhances the downstream p53 signalling and that a combination strategy aimed at inhibiting the AKT/mTOR pathway and re-activating p53 signalling is potentially effective in GBM and in GSCs