Nanoparticle-guided brain drug delivery: Expanding the therapeutic approach to neurodegenerative diseases

Neurodegenerative diseases (NDs) represent a heterogeneous group of aging-related disorders featured by progressive impairment of motor and/or cognitive functions, often accompanied by psychiatric disorders. NDs are denoted as ‘protein misfolding’ diseases or proteinopathies, and are classified according to their known genetic mechanisms and/or the main protein involved in disease onset and progression. Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD) are included under this nosographic umbrella, sharing histopathologically salient features, including deposition of insoluble proteins, activation of glial cells, loss of neuronal cells and synaptic connectivity. To date, there are no effective cures or disease-modifying therapies for these NDs. Several compounds have not shown efficacy in clinical trials, since they generally fail to cross the blood-brain barrier (BBB), a tightly packed layer of endothelial cells that greatly limits the brain internalization of endogenous substances. By engineering materials of a size usually within 1–100 nm, nanotechnology offers an alternative approach for promising and innovative therapeutic solutions in NDs. Nanoparticles can cross the BBB and release active molecules at target sites in the brain, minimizing side effects. This review focuses on the state-of-the-art of nanoengineered delivery systems for brain targeting in the treatment of AD, PD and HD. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

A Multiphysics Co-Simulation Framework of a Gas Engine and Three-Way Catalyst toward a Complete Vehicle Design Model

In view of the increasingly stringent emission regulations, the automotive sector needs considerable support from the development of robust and reliable engine and aftertreatment models. Accurate reproduction of engine-out and tailpipe pollutants plays a crucial role in complying with these legislations. Given the difficulty in characterizing some critical phenomena, frequently caused by strong dynamics and related to experimental uncertainties, communication between several calibrated and reliable models is mandatory. This is certainly valid for powertrains that will be powered with alternative gas fuels such as natural gas, bio-methane and hydrogen in the future. This paper describes a methodology to co-simulate a 1D CNG HD 6-cyl engine model and a 1D quasi-steady three-way catalyst model in a global framework for high-fidelity virtual prototyping of the vehicle system. Through the implementation of a dedicated control logic in MATLAB/Simulink, the modeling architecture allows for the reproduction of the engine performance parameters together with the evaluation of the TWC pollutants’ conversion efficiency. An extensive database of experimental tests was used to assess the model response. The latter was validated in multiple steady-state operating conditions of the engine workplan. Using a semi-predictive combustion model, the validation was carried out over a wide range of different air-to-fuel ratios and during fast rich/lean transitions to evaluate the formation and conversion phenomena of the main chemical species, both engine-out and tailpipe. Subsequently, the complete model was validated in dynamic conditions throughout a WHTC, accurately reproducing the cut-off phases and their sudden accelerations. The numerical–experimental agreement on pollutant reproduction is generally good and globally below 3%. Larger deviations occur in extremely rich conditions and in CH4 emission evaluation due to the lack of information related to the combustion process and chemical mechanisms involving the Pd surface

Brg1 chromatin remodeling factor is involved in cell growth arrest, apoptosis and senescence of rat mesenchymal stem cells.

Self-renewal, proliferation and differentiation properties of stem cells are controlled by key transcription factors. However, their activity is modulated by chromatin remodeling factors that operate at the highest hierarchical level. Studies on these factors can be especially important to dissect molecular pathways governing the biology of stem cells. SWI/SNF complexes are adenosine triphosphate (ATP)-dependent chromatin remodeling enzymes that have been shown to be required for cell cycle control, apoptosis and cell differentiation in several biological systems. The aim of our research was to investigate the role of these complexes in the biology of mesenchymal stem cells (MSCs). To this end, in MSCs we caused a forced expression of the ATPase subunit of SWI/SNF (Brg1 – also known as Smarca4) by adenoviral transduction. Forced Brg1 expression induced a significant cell cycle arrest of MSCs in culture. This was associated with a huge increase in apoptosis that reached a peak 3 days after transduction. In addition, we observed signs of senescence in cells having ectopic Brg1 expression. At the molecular level these phenomena were associated with activation of Rb- and p53-related pathways. Inhibition of either p53 or Rb with E1A mutated proteins allowed us to hypothesize that both Rb and p53 are indispensable for Brg1-induced senescence, whereas only p53 seems to play a role in triggering programmed cell death. We also looked at the effects of forced Brg1 expression on canonical MSC differentiation in adipocytes, chondrocytes and osteocytes. Brg1 did not induce cell differentiation per se; however, this protein could contribute, at least in part, to the adipocyte differentiation process. In conclusion, our results suggest that whereas some ATP-dependent chromatin remodeling factors, such as ISWI complexes, promote stem cell self-renewal and conservation of an uncommitted state, others cause an escape from ‘stemness’ and induction of differentiation along with senescence and cell death phenomena

Minimal disease activity in patients with psoriatic arthritis treated with ustekinumab: results from a 24-week real-world study

Psoriatic arthritis (PsA) is a chronic inflammatory joint disease affecting around 40% of psoriasis patients. Minimal disease activity (MDA) criteria have been proposed to identify a state of low disease activity, one of the principal goals of treatment for psoriatic disease. This study investigated treatment with ustekinumab (UST) in the context of a real-world setting. Thirty-four PsA patients who had failure or inadequate response to conventional synthetic disease-modifying antirheumatic drugs or to anti-tumour necrosis factor alpha were enrolled. Demographic and clinical features, MDA criteria, and the impact of psoriatic skin manifestations on patients' quality of life (QoL) using the dermatology life quality index (DLQI) questionnaire were evaluated at baseline and after 24-week treatment. Adverse events were recorded. At week 24, 70.5% of patients (n = 24) achieved MDA. A sub-analysis of dermatological indices of the MDA criteria showed that the psoriasis area severity index score was significantly improved and body surface area was significantly decreased at 24 weeks compared with that at baseline (both p < 0.001). For the rheumatologic indexes, tender joint count, swollen joint count, and tender entheseal points were all significantly improved at 24 weeks of therapy (all p < 0.01 vs. baseline). Mean DLQI value decreased approximately fourfold, and there were no safety concerns. The achievement of MDA as well as the significant improvement in DLQI and lack of adverse events in the context of a real-life setting shown here confirms the efficacy and safety of UST in PsA