Synthesis of GAP and PAMMO Homopolymers from Mesylate Polymeric Precursors

In azidic binders for solid propellants, the N3 functionality is introduced by substitution of a halogen or tosyl group, but recently the mesyl group has been suggested as an alternative. The mesylate group has two advantages, mainly related to its small dimensions and low cost. Poly(glycidyl azide) and poly 3-azidomethyl-3-methyl oxetane were prepared by using both tosylate and mesylate precursors. The azidation kinetics were studied at three different temperatures while keeping all other operating parameters the same. The results confirmed the good potential of the mesylate precursors for the production of azidic binders

The Role of Metformin in the Management of NAFLD

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide. Its prevalence ranges 10–24% in the general population, reaching 60–95% and 28–55% in obese and diabetic patients, respectively. Although the etiology of NAFLD is still unclear, several lines of evidences have indicated a pathogenetic role of insulin resistance in this disorder. This concept has stimulated several clinical studies where antidiabetic drugs, such as insulin sensitizers including metformin, have been evaluated in insulin-resistant, NAFLD patients. These studies indicate that metformin might be of benefit in the treatment of NAFLD, also in nondiabetic patients, when associated to hypocaloric diet and weight control. However, the heterogeneity of these studies still prevents us from reaching firm conclusions about treatment guidelines. Moreover, metformin could have beneficial tissue-specific effects in NAFLD patients irrespective of its effects as insulin sensitizer

Sintesi e polimerizzazione di precursori mesilati per la produzione di leganti azidici

Negli ultimi anni la ricerca nel settore della propulsione aerospaziale si è focalizzata sullo sviluppo di nuovi materiali polimerici, i cosiddetti "polimeri energetici", che, oltre a fungere da leganti, migliorano le prestazioni del propellente solido in termini di impulso specifico e velocità di combustione. Tutto ciò è reso possibile dalla presenza, lungo le catene polimeriche, di gruppi funzionali, come per esempio quelli azidici o nitrici, capaci di sviluppare molta energia durante la decomposizione esotermica alle alte temperature. Nei leganti azidici il gruppo funzionale N3 viene generalmente introdotto attraverso una sostituzione nucleofila bimolecolare (SN2) di un alogeno o di un gruppo tosile. Recentemente si è pensato di utilizzare il mesile in alternativa ai suddetti gruppi uscenti. Tale scelta è giustificata principalmente dal basso costo di questo gruppo rispetto agli alogeni e dal fatto che, sebbene il tosile sia migliore come gruppo uscente rispetto al mesile, quest'ultimo ha dimensioni più piccole e pertanto è ragionevole supporre che la presenza di una molecola meno ingombrante possa favorire, dopo la polimerizzazione, la fase di azidazione. Il presente lavoro di tesi è consistito nella sintesi del poli-glicidil-azide (GAP) e del poli-3-azidometil-3-metilossetano (PAMMO) a partire da precursori polimerici sia tosilati che mesilati al fine di confrontare i vantaggi e/o gli svantaggi derivanti dalla presenza di questi due gruppi funzionali. I risultati ottenuti hanno confermato l'elevato potenziale dei precursori mesilati per la produzione di leganti azidici. L'elaborato è suddiviso in sei capitoli. Nel primo capitolo vengono descritte le caratteristiche generali dei leganti polimerici e le strategie di sintesi dei polimeri energetici azidici impiegate negli ultimi anni. Il secondo, il terzo e il quarto capitolo sono dedicati alla preparazione, rispettivamente, dei monomeri (tosilati e mesilati), dei polimeri precursori e dei polimeri azidici, attraverso l'ottimizzazione delle varie fasi di sintesi messe a punto in lavori di ricerca precedenti. Il quinto capitolo è dedicato alla caratterizzazione di tutti i prodotti sintetizzati e allo studio della cinetica di azidazione dei precursori polimerici tosilati e mesilati. Infine, nell'ultimo capitolo vengono riportate le conclusioni generali

Nonalcoholic Fatty Liver: A Possible New Target for Type 2 Diabetes Prevention and Treatment

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide. Several lines of evidence have indicated a pathogenic role of insulin resistance, and a strong association with type 2 diabetes (T2MD) and metabolic syndrome. Importantly, NAFLD appears to enhance the risk for T2MD, as well as worsen glycemic control and cardiovascular disease in diabetic patients. In turn, T2MD may promote NAFLD progression. The opportunity to take into account NAFLD in T2MD prevention and care has stimulated several clinical studies in which antidiabetic drugs, such as metformin, thiazolidinediones, GLP-1 analogues and DPP-4 inhibitors have been evaluated in NAFLD patients. In this review, we provide an overview of preclinical and clinical evidences on the possible efficacy of antidiabetic drugs in NAFLD treatment. Overall, available data suggest that metformin has beneficial effects on body weight reduction and metabolic parameters, with uncertain effects on liver histology, while pioglitazone may improve liver histology. Few data, mostly preclinical, are available on DPP4 inhibitors and GLP-1 analogues. The heterogeneity of these studies and the small number of patients do not allow for firm conclusions about treatment guidelines, and further randomized, controlled studies are needed

ERAP1 and ERAP2 Enzymes: A Protective Shield for RAS against COVID-19?

Patients with coronavirus disease 2019 (COVID-19) have a wide variety of clinical outcomes ranging from asymptomatic to severe respiratory syndrome that can progress to life-threatening lung lesions. The identification of prognostic factors can help to improve the risk stratification of patients by promptly defining for each the most effective therapy to resolve the disease. The etiological agent causing COVID-19 is a new coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that enters cells via the ACE2 receptor. SARS-CoV-2 infection causes a reduction in ACE2 levels, leading to an imbalance in the renin-angiotensin system (RAS), and consequently, in blood pressure and systemic vascular resistance. ERAP1 and ERAP2 are two RAS regulators and key components of MHC class I antigen processing. Their polymorphisms have been associated with autoimmune and inflammatory conditions, hypertension, and cancer. Based on their involvement in the RAS, we believe that the dysfunctional status of ERAP1 and ERAP2 enzymes may exacerbate the effect of SARS-CoV-2 infection, aggravating the symptomatology and clinical outcome of the disease. In this review, we discuss this hypothesis

ERAP1 regulates natural killer cell function by controlling the engagement of inhibitory receptors

The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by MHC class I (MHC-I) molecules. Herein, we demonstrate that genetic or pharmacological inhibition of ERAP1 on human tumor cell lines perturbs their ability to engage several classes of inhibitory receptors by their specific ligands, including killer cell Ig-like receptors (KIR) by classical MHC-I-peptide (pMHC-I) complexes and the lectin-like receptor CD94-NKG2A by nonclassical pMHC-I complexes, in each case leading to natural killer (NK) cell killing. The protective effect of pMHC-I complexes could be restored in ERAP1-deficient settings by the addition of known high-affinity peptides, suggesting that ERAP1 was needed to positively modify the affinity of natural ligands. Notably, ERAP1 inhibition enhanced the ability of NK cells to kill freshly established human lymphoblastoid cell lines from autologous or allogeneic sources, thereby promoting NK cytotoxic activity against target cells that would not be expected because of KIR-KIR ligand matching. Overall, our results identify ERAP1 as a modifier to leverage immune functions that may improve the efficacy of NK cell-based approaches for cancer immunotherapy