2,211 research outputs found
I correttori del CFTR come nuovo approccio farmacologico per le sarcoglicanopatie
No full textSarcoglycanopathies or LGMDR3-6 are rare autosomal recessive disease, affecting mainly the limb proximal musculature that are still without a cure. The onset occurs in childhood, the disease is progressive, very often forcing affected subjects to the wheelchair, even though mild forms may present with late onset and slow progression. Sarcoglycanopathies are caused by mutations in genes coding for sarcoglycans (SG). SG are four glycoproteins forming a tetramer in skeletal and cardiac muscle, located at the sarcolemma that plays a crucial role in protecting the membrane from damages due to muscle contraction. It has been observed that missense mutations, the majority of the reported cases, result in a folding defective, even though potentially functional protein, that is recognized and prematurely discarded by the cell quality control (QC). Lacking one subunit, the SG-complex is disrupted, and the consequent loss of function leads to progressive muscle degeneration. To counteract this harmful process, we proposed to help SGs folding using small molecules, called CFTR correctors, developed to correct mutated cystic fibrosis transmembrane regulator (CFTR) channel, defective in folding and trafficking.
The effective rescue of different SG mutants has been proved for some of such molecules by using cell models and, importantly, myogenic cells from LGMDR3 patients. In these pathological cells we evidenced the possibility to combine correctors to gain an additive or even synergic effect in LGMDR3 myotubes. Furthermore, thanks to the availability of myogenic cells from a LGMDR4 subject, we had the possibility to verify the efficacy of CFTR correctors in the other forms of sarcoglycanopathy. Lastly, once correctors have been successfully tested in vitro, there was the need for animal models in which proving efficacy and safety of this pharmacological approach. To this intent and to overcome the unsuitability of the already existing sarcoglycanopathy murine models, we generated a novel mouse model of LGMDR3. This model is characterized by humanized hind limbs, resulting from the injection of the human α-SG sequence, either wild-type or carrying a missense mutation, via adeno associated virus 1 (AAV1). The transduction was performed in the background of sgca-null newborn mice to assure muscle development in the presence of either the wild-type or mutated human protein and to induce tolerance toward the transgene. Mice expressing R98H α-SG in hind limbs, well mimicking the human pathologic phenotype, were used to test the efficacy of the most promising, according to in vitro data, CFTR corrector, C17. The systemic and chronic administration of the C17 molecule successfully rerouted the SG-complex containing the human α-SG R98H mutant to the sarcolemma, with a clear amelioration of the dystrophic phenotype. Notably, the force of the C17 treated muscle was fully recovered, reaching levels almost identical to the WT, healthy muscles. In addition, the preliminary C17 pharmacokinetic characterization evidenced a large blood stability, in in vitro experiments, and the resistance to metabolization from both cytochromes P450 (CYPs) and UDP glucuronosyltransferases (UGTs), enzymes present in extracted liver microsomes.
Altogether, the in vitro and in vivo data, are the proof of concept of C17 efficacy in LGMDR3 cases, opening a new way of therapeutic intervention for the forms of sarcoglycanopathy characterized by missense mutation.Le sarcoglicanopatie o LGMDR3-6 sono rare malattie autosomiche recessive incurabili che colpiscono principalmente i muscoli prossimali degli arti. L'esordio avviene in età infantile, la malattia è progressiva, costringendo molto spesso i soggetti alla sedia a rotelle. Sono note anche forme più lievi con esordio tardivo e lenta progressione. Le sarcoglicanopatie sono causate da mutazioni nei geni codificanti i sarcoglicani (SG). I SG sono quattro glicoproteine che formano un tetramero nel muscolo scheletrico e cardiaco, localizzato nel sarcolemma, cruciale nella protezione della membrana dallo stress meccanico dovuto alla contrazione muscolare. È stato osservato che le mutazioni missenso, che rappresentano la maggior parte dei casi riportati, producono una proteina con un “folding” difettoso che, anche se potenzialmente funzionale, viene riconosciuta e degradata dal sistema di controllo qualità della cellula. A causa della mancanza di una subunità, il complesso del SG viene distrutto e la conseguente perdita di funzione determina danni al sarcolemma con progressiva degenerazione muscolare. Per contrastare questo processo, il nostro approccio intende aiutare il corretto ripiegamento dei SG utilizzando piccole molecole sviluppate per correggere la proteina CFTR (cystic fibrosis transmembrane regulator) che quando mutato può presentare difetti nel ripiegamento e nella corretta localizzazione. L’efficacia di alcuni correttori del CFTR nel recupero di diversi mutanti del SG è stata provata utilizzando modelli cellulari e cellule miogeniche provenienti da pazienti LGMDR3. Usando queste cellule abbiamo qui verificato l’uso combinato dei correttori ottenendo un effetto additivo o addirittura sinergico. Inoltre, grazie alla disponibilità di cellule miogeniche di un soggetto LGMDR4, abbiamo provato l’efficacia dei correttori del CFTR nelle altre forme di sarcoglicanopatia. Infine, una volta valutato l’effetto dei correttori in vitro, era necessario validare l'efficacia in vivo. A questo scopo e per superare l'inadeguatezza dei modelli murini di sarcoglicanopatia esistenti abbiamo generato un nuovo modello di LGMDR3, caratterizzato da arti posteriori umanizzati, esprimenti la sequenza umana di α-SG. La sequenza umana, wild-type o mutata, è stata trasdotta con il virus adeno-associato di sierotipo 1 (AAV1). La trasduzione è stata effettuata nel background dei topi sgca-null neonati che non presentano il gene dell’α-SG murino che viene così rimpiazzato dalla proteina umana veicolata dal virus. La precoce trasduzione assicura che il muscolo si sviluppi in presenza del sarcoglicano umano, wild-type o mutato, e che insorga tolleranza immunologica verso il transgene. I topi con arti posteriori umanizzati esprimenti l’α-SG con la mutazione R98H hanno sviluppato e riprodotto con alta fedeltà la patologia umana. Di conseguenza, sono stati utilizzati per testare l'efficacia del correttore del CFTR più promettente, il C17, secondo i dati raccolti in vitro. La somministrazione sistemica in cronico della molecola C17 ha reindirizzato con successo il complesso del SG al sarcolemma, inducendo un forte miglioramento del fenotipo distrofico. È importante sottolineare che la forza dei muscoli dei topi trattati ha raggiunto livelli quasi identici a quelli di muscoli WT. Inoltre, la preliminare caratterizzazione farmacocinetica in vitro della molecola C17 ha evidenziato un’ampia stabilità nel sangue e la resistenza alla metabolizzazione da parte dei citocromi P450 (CYP) e dagli UDP glucuronosiltransferasi (UGT), enzimi presenti nei microsomi estratti da fegato murino.
Complessivamente, i dati in vitro ed in vivo sono il “proof of concept” dell’efficacia del C17 nei casi di LGMDR3, e aprono nuove possibilità di intervento terapeutico per tutte le forme di sarcoglicanopatia caratterizzate da mutazione missenso
Photodynamic therapy for the successful management of cyclosporine-related gum hypertrophy: A novel therapeutic option
No full textBACKGROUND: Drug-induced gingival overgrowth is associated with the intake of three classes of drugs: anticonvulsants, immunosuppressants, and calcium channel blockers. It is clinically characterized by hyperplasia of the gingival connective tissue which appears edematous, bloody, and purplish-red in color. In more severe cases, drug-induced gingival hyperplasia negatively affects the patient’s quality of life, making it difficult to eat and practice good oral hygiene. Drug-induced gingival overgrowth therapy is controversial and, in fact, no studies in the literature highlight a well-defined therapeutic protocol. The therapies that are described provide primarily for non-surgical periodontal treatment and second-line surgical treatment. The aim of this work is to highlight a case of drug-induced gingival hyperplasia which was completely resolved thanks to photodynamic therapy which is completely free from side effects. DESIGN AND METHODS: Photodynamic therapy was performed on an 18 year-old female patient with LEDs at a power of 450–470 nm and 5500 mW/cm(2) + 7500 mW/cm(2), combined with a Curcuma longa-based photosensitizer. A single session was performed, with applications of approximately 30 s for each interdental papilla. RESULTS: The patient improved markedly after only one cycle of PDT. There was an absence of clinically detectable inflammation, edema, and rubor of the involved dental papillae. At the 4, 6, and 12 week follow-ups there were no recurrences. CONCLUSIONS: This case report highlights the first case of drug-induced gingival hypertrophy entirely treated with photodynamic therapy to be described in the literature. Therefore, although it is only a case report, this therapy which is free from side effects should be investigated as an alternative to current therapies
Tailoring MOFs to Biomedical Applications: A Chimera or a Concrete Reality? The Case Study of Fe-BTC by bio-friendly Mechanosynthesis
No full textWe point-out an exceptional tailorability of iron(III) trimesate metal-organic framework to bio-friendly conditions. This is particularly attractive in sight of one-pot immobilization of biomolecules for biomedical applications. Synthesis is carried out via mechanochemical approach under green, biocompatible conditions without additional solvents, in just 1 hour, at room temperature. Solvents are proven to be unnecessary to build the framework, in contrast to solution-based methods. Microstructure and thermal stability of the material are not affected by pH. Conversely, textural properties can be tuned by simply varying the amount of base
Metabolite profiles of formula milk compared to breast milk
No full textBreast milk (BM) feeding is the gold standard in neonate nutrition. When BM is not available it can be substituted or integrated with commercial formula milk (FM) usually sold under different brands and formulations. In this work, the low-molecular-weight hydrophilic compounds in milk were studied by gas chromatography electronic impact mass spectrometry (GC–MS), comparing eight different FM brands with BM samples. With the aid of multivariate statistical data analysis, a marked variability among FM brands, especially driven by the presence of prebiotics in their formulation, was highlighted. Quali-quantitative differences were found between FM and BM. Orotic acid and isomaltulose were found exclusively in FM, while phenylalanine and tyrosine levels were high in two FM brands. Moreover, higher levels of malic acid, sugars (glucose, fructose and galactose), and mannitol were detected in FM. On the other hand, BM showed a higher amino acid content. In conclusion, GC–MS proved to be a very sensitive analytical technique for the study of FM, highlighting metabolite differences among FM brands, and between FM and BM, that may have a possible strong impact on neonatal nutrition
Cagliari città di giardini. La villa Congiu-Pattarozzi. Note di storia e conservazione
No full textIl tema dei giardini storici è nuovamente al centro degli interessi internazionali, a seguito dei profondi cambiamenti ambientali e sociali degli ultimi decenni. Il rinnovato interesse per essi pone in luce la carenza di competenze specialistiche e l’inadeguatezza delle normative, per cui sembra opportuno affrontare un percorso di ricerca innovativo, capace di leggerli come sintesi di aspetti riferibili a discipline diverse. In tale filone di investigazione rientra lo studio qui presentato, condotto sul verde urbano della città di Cagliari nel contesto otto-novecentesco, con approfondimenti sulla villa Congiu-Pattarozzi, opera di Dionigi Scano. L’obiettivo è quello di ampliare la conoscenza di tale patrimonio, rimarcando il significato e l’importanza della sua memoria, al fine di salvaguardarne la sua trasmissione alle generazioni future. Nello specifico, l’analisi condotta si pone come obiettivo il recupero dell’architettura del giardino e dei suoi manufatti, ricucendo le relazioni, ora recise, tra gli elementi costruiti, scultorei e vegetali. Infine, aspetto centrale dello studio rimane quello di garantire la qualità del progetto di conservazione e valorizzazione, attraverso un approccio transcalare e multidisciplinare
Cagliari città di giardini. La villa Congiu-Pattarozzi. Note di storia e conservazione = Cagliari City of Gardens. The Congiu-Pattarozzi Villa. History and Conservation Notes
No full textIl tema dei giardini storici è nuovamente al centro degli interessi internazionali, a seguito dei profondi cambiamenti ambientali e sociali degli ultimi decenni. Il rinnovato interesse per essi pone in luce la carenza di competenze specialistiche e l’inadeguatezza delle normative, per cui sembra opportuno affrontare un percorso di ricerca innovativo, capace di leggerli come sintesi di aspetti riferibili a discipline diverse. In tale filone di investigazione rientra lo studio qui presentato, condotto sul verde urbano della città di Cagliari nel contesto otto-novecentesco, con approfondimenti sulla villa Congiu-Pattarozzi, opera di Dionigi Scano. L’obiettivo è quello di ampliare la conoscenza di tale patrimonio, rimarcando il significato e l’importanza della sua memoria, al fine di salvaguardarne la sua trasmissione alle generazioni future. Nello specifico, l’analisi condotta si pone come obiettivo il recupero dell’architettura del giardino e dei suoi manufatti, ricucendo le relazioni, ora recise, tra gli elementi costruiti, scultorei e vegetali. Infine, aspetto centrale dello studio rimane quello di garantire la qualità del progetto di conservazione e valorizzazione, attraverso un approccio transcalare e multidisciplinare.The theme of historic gardens is once again at the centre of international interest, following the profound environmental and social changes of recent decades. The renewed interest in them highlights the lack of specialised skills and the inadequacy of regulations, so it seems appropriate to tackle an innovative research path, capable of reading them as a synthesis of aspects referring to different disciplines. This line of investigation includes the study conducted on urban greenery in the city of Cagliari in the nineteenth-twentieth-century context, with in-depth studies on the villa Congiu-Pattarozzi, the work of Dionigi Scano. The objective is to expand knowledge of this heritage, emphasizing the significance and importance of its memory, in order to safeguard its transmission to future generations. More specifically, the analysis conducted aims to recover the garden architecture and its artefacts, mending the
relationships, now severed, between the built, sculptural and plant elements. Finally, the central aspect of the study remains that of guaranteeing the quality of the conservation and valorisation project, through a transcalar and multidisciplinary approach
Martina Drijverová and her literary works for children (author´s portrait)
No full textThis thesis Martina Drijverova and her literatur for children (the author´s portrait) is engaged in work of writer and screenwriter Martina Drijeverová. She is an excellent writer of literature for children. In the first part of this work her story writing is mentioned and the second part deals with her fairy-tale writing. The other author´s work written for children is in the third part. The conclusion of this thesis appreciates the author´s credit in literature for chidlren. Analysis of some books are available. The supplementary part is composed of autor´s biography and her photograph, some book covers, list of the autor´s work {--} televiews, radio plays and serials, audio tapes and CDs, stage plays, books written in Braille
HERStory Makers 2022: Martina Čagalj
No full textMartina Čagalj is a PhD candidate at the University of Split studying seaweeds as a potential source of bioactive compounds. She took part in HERStory Makers 2022.What is HERStory Makers?HERStory Makers is a social media competition for female-identifying early career researchers to share their research, their career journeys, and to inspire the next generation. Winners are selected by public vote. HERStory Makers is also part of EXPLORATHON, Scotland's contribution to European Researchers' Night.In 2022-23, EXPLORATHON was supported by the Engineering & Physical Sciences Research Council [grant number EP/X020894/1].Author contributions to contentMartina Čagalj conceived, planned, and recorded the video content. Kirsty Ross edited the video content to insert HERStory Maker credits, add subtitles, and maintain video length below Twitter/X limit of 2 mins and 20 secs, prior to scheduling the social media posts.</p
- …
