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Alpha-synuclein (αS) is an extensively studied protein due to its involvement in a group of neurodegenerative disorders, including Parkinson′s disease, and its documented ability to undergo aberrant self-aggregation resulting in the formation of amyloid-like fibrils. In dilute solution, the protein is intrinsically disordered but can adopt multiple alternative conformations under given conditions, such as upon adsorption to nanoscale surfaces. The study of αS-nanoparticle interactions allows us to better understand the behavior of the protein and provides the basis for developing systems capable of mitigating the formation of toxic aggregates as well as for designing hybrid nanomaterials with novel functionalities for applications in various research areas. In this review, we summarize current progress on αS-nanoparticle interactions with an emphasis on the conformational plasticity of the biomolecule.

Sirtuin genes have been associated with aging and are known to affect multiple cellular pathways. Sirtuin 2 was previously shown to modulate proteotoxicity associated with age-associated neurodegenerative disorders such as Alzheimer and Parkinson disease (PD). However, the precise molecular mechanisms involved remain unclear. Here, we provide mechanistic insight into the interplay between sirtuin 2 and α-synuclein, the major component of the pathognomonic protein inclusions in PD and other synucleinopathies. We found that α-synuclein is acetylated on lysines 6 and 10 and that these residues are deacetylated by sirtuin 2. Genetic manipulation of sirtuin 2 levels in vitro and in vivo modulates the levels of α-synuclein acetylation, its aggregation, and autophagy. Strikingly, mutants blocking acetylation exacerbate α-synuclein toxicity in vivo, in the substantia nigra of rats. Our study identifies α-synuclein acetylation as a key regulatory mechanism governing α-synuclein aggregation and toxicity, demonstrating the potential therapeutic value of sirtuin 2 inhibition in synucleinopathies.

Background: The intrinsically disordered, amyloidogenic protein Tau associates with diverse classes of molecules, including proteins, nucleic acids, and lipids. Mounting evidence suggests that fatty acid molecules could play a role in the dysfunction of this protein, however, their interaction with Tau remains poorly characterized. Methods: In a bid to elucidate the association of Tau with unsaturated fatty acids at the sub-molecular level, we carried out a variety of solution NMR experiments in combination with circular dichroism and fluorescence measurements. Our study shows that Tau4RD, the highly basic four-repeat domain of Tau, associates strongly with arachidonic and oleic acid assemblies in a high lipid/protein ratio, perturbing their supramolecular states and itself undergoing time-dependent structural adaptation. The structural signatures of Tau4RD/fatty acid aggregates appear similar for arachidonic acid and oleic acid, however, they are distinct from those of another prototypical intrinsically disordered protein, α-synuclein, when bound to these lipids, revealing protein-specific conformational adaptations. Both fatty acid molecules are found to invariably promote the self-aggregation of Tau4RD and of α-synuclein. Conclusions: This study describes the reciprocal influence that Tau4RD and fatty acids exert on their conformational states, contributing to our understanding of fundamental aspects of Tau/lipid co-assembly.

Fruits of the sweet cherry (Prunus avium L.) accumulate a range of antioxidants that can help to prevent cardiovascular disease, inflammation and cancer. We tested the in vitro antioxidant activity of 18 sweet cherry cultivars collected from 12 farms in the protected geographical indication region of Marostica (Vicenza, Italy) during two growing seasons. Multiple targeted and untargeted metabolomics approaches (NMR, LC-MS, HPLC-DAD, HPLC-UV) as well as artificial simplified phytocomplexes representing the cultivars Sandra Tardiva, Sandra and Grace Star were then used to determine whether the total antioxidant activity reflected the additive effects of each compound or resulted from synergistic interactions. We found that the composition of each cultivar depended more on genetic variability than environmental factors. Furthermore, phenolic compounds were the principal source of antioxidant activity and experiments with artificial simplified phytocomplexes indicated strong synergy between the anthocyanins and quercetins/ascorbic acid specifically in the cultivar Sandra Tardiva. Our data therefore indicate that the total antioxidant activity of sweet cherry fruits may originate from cultivar-dependent interactions among different classes of metabolite.

The false fruits of apple (Malus domestica) and pear (Pyrus communis) are consumed all over the world, contributing to the dietary intake of health-promoting antioxidant phytochemicals. For example, polyphenols confer many beneficial effects (according to their chemical structure, bioavailability, and absorption efficiency in the gut) and the consumption of polyphenol-rich apple and pear fruits may therefore reduce the risk of some diseases. However, the content of such molecules is highly dependent on the specific fruit cultivar. To examine this metabolic diversity in detail, we used metabolomic analysis (NMR and HPLC-DAD/MS) to profile the metabolome of six apple and five pear cultivars. We also determined the antioxidant capacity of the extracts (FRAP assay) and correlated this with the metabolomic composition and abundance of specific metabolites. We observed the cultivar-specific accumulation of sugars, amino acids, malic acid, and various polyphenols, which was also related to the growing season for some cultivars. We found that the ancient Italian apple Pom Prussian was enriched for chlorogenic acid as well as more characteristic polyphenols (phloretin derivatives), the pear cultivar Abate Fetel was low in sucrose, and both cultivars displayed high in vitro antioxidant activity. These cultivars may, therefore, be particularly attractive to health-conscious consumers.

Background Incidence of ulcerative colitis (UC) in elderly population is increasing because of ageing and because of its minimal impact on life span. Data on natural history, outcomes and therapeutic strategies are limited. Our aim is to characterize UC in elderly-onset patients followed at our Inflammatory Bowel Disease outpatient clinic and compare with adult-onset UC. Methods From January 2000 to June 2019, 94 patients with UC diagnosed after the age of 65 years (elderly group, E-O) were identified and matched 1–1 according to gender and calendar year of diagnosis with patients diagnosed with UC at age between 40 and 64 years (adult age, A-O). Results Comorbidity Index (3.8 vs 1.6, p < 0.0005 ) was higher for elderly UC patients. Symptoms at presentation were similar between the two groups, although abdominal pain was more common in adults, and weight loss was more common in the elderly. At diagnosis, left colitis (61% vs 39%) and proctitis (14% vs 26%) ( p = 0.011 ) were more frequent in the elderly. Therapy and clinical behaviour were similar. Surgery was more frequently performed in the elderly (20% vs 9%, p  = 0.02), while biological therapy was less used (2.1% vs 22%, p < 0.0005 ). Complications were more frequent in the elderly. Extraintestinal manifestations were lower in elderly patients (9.6% vs 19.2%, p = 0.061 ). Time to first relapse was similar between the two groups . Mortality ( p < 0.0005 ) was higher in elderly patients. Conclusions Ulcerative Colitis has similar presentation and behaviour in elderly and adults patients. However, the elderly are more fragile because of comorbidities, increased risk of infections and disease-related complications.

Diets rich in fruits and vegetables are associated with better psychological wellbeing and cognitive functions, although it is unclear which molecules and mechanisms are involved. One potential explanation is the inhibition of monoamine oxidases (MAOs), which have been linked to several neurological disorders. The present study investigated the ability of kiwifruit to inhibit MAO-A and MAO-B, refining an in vitro assay to avoid confounding effects. Ultra-performance liquid chromatography/mass spectrometry (UPLC-QTOF) and nuclear magnetic resonance spectroscopy (NMR) were used to select individual kiwifruit metabolites for further analysis. Moreover, extracts of other common fruits and vegetables were screened to identify promising candidate inhibitors. Multiple extracts and compounds inhibited both enzymes, and the selective inhibition of MAO-B by the major kiwifruit specialized metabolite D-(−)-quinic acid was observed. These results suggest that fruits and vegetables contain metabolites that inhibit the activity of MAO-A and -B, offering a potential natural option for the treatment of neurological disorders, in which MAOs are involved.

In literature, there are conflicting opinions on the development of cardiovascular disease risk in patients with coeliac disease (CD). The aim of the research was to identify in young subjects without cardiovascular risk factor and newly diagnosed CD, alterations in different instrumental parameters that are associated with an augmented cardiovascular risk. Twenty-one consecutive young adults with a new diagnosis of CD and without cardiovascular risk factors were prospectively enrolled and underwent transthoracic echocardiography to analyse ascending aorta elastic properties [including tissue Doppler imaging strain (TDI-ε)] and left ventricular 2D strains (global longitudinal, radial and circumferential), and applanation tonometry by SphygmoCor. Cases were compared with 21 age- and sex-matched healthy controls. Mean age of the cases was 38 ± 9 years and 15 of them (71%) were female. Brachial and central blood pressure was higher in the CD group. Elastic properties of the ascending aorta were all impaired in the CD group: TDI-ε was altered in 57% of cases (0% of controls, p < 0.001). Concentric remodelling and grade I diastolic dysfunction were present in 38% and 24% of cases, respectively (0% of controls, p < 0.001). Global longitudinal strain was normal in all subjects, while radial and circumferential strain were altered in 67% and 35%, respectively (0% of controls, p < 0.001). In young subjects without cardiovascular risk factor, a newly diagnosed CD is associated with altered aortic elastic properties, left ventricular concentric remodelling and diastolic dysfunction and altered radial and circumferential strain.

Data regarding double switching from originator infliximab (IFX) to IFX biosimilars in inflammatory bowel diseases (IBDs) are lacking. The purpose of this study was to evaluate the safety and efficacy of switching from originator IFX to CT‐P13 and subsequently to SB2 (double switch) in patients with IBD. Patients undergoing IFX‐double switch in eight Centers in Lombardy (Italy) from November 2018 to May 2019 were retrospectively analyzed. The IFX discontinuation rate, incidence and type of adverse events (AEs), and clinical remission rate were recorded. A comparison with a control group of patients with IBD single‐switched from originator IFX to CT‐P13 was performed, before and after an inverse probability of treatment weighting (IPTW)‐based propensity score analysis. Fifty‐two double‐switched patients with IBD were enrolled. The 24‐ and 52‐week proportions of patients continuing on IFX therapy following the second switch (CTP13 → SB2) were 98% (95% confidence interval [CI] 94%–100%) and 90% (95% CI 81%–99%), respectively. Four patients experienced a total of five AEs, all graded 1–3 according to Common Terminology Criteria for Adverse Events (CTCAE). No infusion reactions were observed. The 24‐week and follow‐up end clinical remission rates following the second switch were 94% and 88%, respectively. No differences were observed in the safety and efficacy outcomes by comparing the double‐switch group with a single‐switch group of 66 patients with IBD; all these results were confirmed by IPTW‐adjusted analysis. The study suggests both the safety and efficacy of the double switch from originator IFX to CT‐P13 and SB2 in patients with IBD is maintained. This strategy may be associated with potential cost implications.

As essential components of the molecular machine assembling heterochromatin in eukaryotes, HP1 (Heterochromatin Protein 1) proteins are key regulators of genome function. While several high-resolution structures of the two globular regions of HP1, chromo and chromoshadow domains, in their free form or in complex with recognition-motif peptides are available, less is known about the conformational behavior of the full-length protein. Here, we used NMR spectroscopy in combination with small angle X-ray scattering and dynamic light scattering to characterize the dynamic and structural properties of full-length human HP1β (hHP1β) in solution. We show that the hinge region is highly flexible and enables a largely unrestricted spatial search by the two globular domains for their binding partners. In addition, the binding pockets within the chromo and chromoshadow domains experience internal dynamics that can be useful for the versatile recognition of different binding partners. In particular, we provide evidence for the presence of a distinct structural propensity in free hHP1β that prepares a binding-competent interface for the formation of the intermolecular β-sheet with methylated histone H3. The structural plasticity of hHP1β supports its ability to bind and connect a wide variety of binding partners in epigenetic processes.