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Naturally available antioxidants offer remarkable medicinal applications in wound healing. However, the encapsulation of these phytoactive moieties into suitable nano-scale drug delivery systems has always been challenging due to their inherent characteristics, such as low molecular weight, poor aqueous solubility, and inadequate skin permeability. Here, we provide a systematic review focusing on the major obstacles hindering the development of various lipid and polymer-based drug transporters to carry these cargos to the targeted site. Additionally, this review covers the possibility of combining the effects of a polymer and a lipid within one system, which could increase the skin permeability threshold. Moreover, the lack of suitable physical characterization techniques and the challenges associated with scaling up the progression of these nano-carriers limit their utility in biomedical applications. In this context, consistent progressive approaches for addressing these shortcomings are introduced, and their prospects are discussed in detail.

Liposomes are lipid bilayer vesicles that are highly biocompatible, able to interact with the cell membrane, and able to release their cargo easily. The improvement of the physicochemical properties of liposomes, such as surface charge, lipid composition, and functionalization, makes these vesicles eligible delivery nanosystems for the gene therapy of many pathological conditions. In the present study, pre-formulation analysis was conducted to develop liposomes that facilitate the delivery of nucleic acids to neuronal cells, with the aim of future delivery of a CRISPR/Cas9 system designed to silence genes responsible for autosomal dominant neurodegenerative disorders. To this aim, different nucleic acid cargo models, including λ phage DNA, plasmid DNA, and mRNA encoding GFP, were considered. Liposomes with varying lipid compositions were produced using the ethanol injection method and analyzed for their dimensional stability and ability to interact with DNA. The selected formulations were tested in vitro using a neuroblastoma cell line (SH-SY5Y) to evaluate their potential toxicity and the ability to transfect cells with a DNA encoding the green fluorescent protein (pCMV-GFP). Among all formulations, the one containing phosphatidylcholine, phosphatidylethanolamine, pegylated 1,2-distearoyl-sn-glycero-3-phosphethanolamine, cholesterol, and dioctadecyl-dimethyl ammonium chloride (in the molar ratio 1:2:4:2:2) demonstrated the highest efficiency in mRNA delivery. Although this study was designed with the goal of ultimately enabling the delivery of a CRISPR/Cas9 system for treating autosomal dominant neurodegenerative disorders such as polyglutamine spinocerebellar ataxias (SCAs), CRISPR/Cas9 components were not delivered in the present work, and their application remains the objective of future investigations.

In order to limit global warming to around 1.5–2.0 °C by the end of the 21st century, there is the need to drastically limit the emissions of CO2. This goal can be pursued by promoting the diffusion of advanced technologies for power generation from renewable energy sources. In this field, biomass can play a very important role since, differently from solar and wind, it can be considered a programmable source. This paper reports a techno-economic analysis on the possible commercial application of gasification technologies for small-scale (2 MWe) power generation from biomass. The analysis is based on the preliminary experimental performance of a 500 kWth pilot-scale air-blown bubbling fluidized-bed (BFB) gasification plant, recently installed at the Sotacarbo Research Centre (Italy) and commissioned in December 2017. The analysis confirms that air-blown BFB biomass gasification can be profitable for the applications with low-cost biomass, such as agricultural waste, with a net present value up to about 6 M€ as long as the biomass is provided for free; on the contrary, the technology is not competitive for high-quality biomass (wood chips, as those used for the preliminary experimental tests). In parallel, an analysis of the financial risk was carried out, in order to estimate the probability of a profitable investment if a variation of the key financial parameters occurs. In particular, the analysis shows a probability of 90% of a NPV at 15 years between 1.4 and 5.1 M€ and an IRR between 11.6% and 23.7%.

The present study is aimed to design ethosomes and transethosomes for topical administration of quercetin. To overcome quercetin low bioavailability, scarce solubility and poor permeability that hamper its pharmaceutical use, the drug was loaded in ethosomes and transethosomes based on different concentrations of phosphatidylcholine. Vesicle morphology was studied by cryogenic transmission electron microscopy, while size distribution and quercetin entrapment capacity were evaluated up to 3 months, respectively, by photon correlation spectroscopy and high-performance liquid chromatography. The antioxidant property was studied by photochemiluminescence test. Quercetin release and permeation was investigated in vitro, using Franz cells associated to different membranes. In vitro assays were conducted on human keratinocytes and melanoma cells to study the behavior of quercetin-loaded nano-vesicular forms with respect to cell migration and proliferation. The results evidenced that both phosphatidylcholine concentration and quercetin affected the vesicle size. Quercetin entrapment capacity, antioxidant activity and size stability were controlled using transethosomes produced by the highest amount of phosphatidylcholine. In vitro permeation studies revealed an enhancement of quercetin permeation in the case of transethosomes with respect to ethosomes. Notably, scratch wound and migration assays suggested the potential of quercetin loaded-transethosomes as adjuvant strategy for skin conditions.

Influenza hemagglutinin (HA) is the primary target of the humoral response during infection/vaccination. Current influenza vaccines typically fail to elicit/boost broadly neutralizing antibodies (bnAbs), thereby limiting their efficacy. Although several bnAbs bind to the conserved stem domain of HA, focusing the immune response to this conserved stem in the presence of the immunodominant, variable head domain of HA is challenging. We report the design of a thermotolerant, disulfide-free, and trimeric HA stem-fragment immunogen which mimics the native, prefusion conformation of HA and binds conformation specific bnAbs with high affinity. The immunogen elicited bnAbs that neutralized highly divergent group 1 (H1 and H5 subtypes) and 2 (H3 subtype) influenza virus strains in vitro. Stem immunogens designed from unmatched, highly drifted influenza strains conferred robust protection against a lethal heterologous A/Puerto Rico/8/34 virus challenge in vivo. Soluble, bacterial expression of such designed immunogens allows for rapid scale-up during pandemic outbreaks.

Despite significant advancements in the management of thalassemia, cardiac complications still represent a leading cause of disability and death. Heart dysfunction, although mainly related to myocardial iron overload (IO), might already manifest when the homeostasis of circulating iron species is altered. This study aimed to investigate the presence of heart function changes in relation to scheduled blood transfusions (BT) in transfusion-dependent thalassemic patients, to identify alterations in cardiac function early after BT or within a 7-10 days interval. Twenty patients (8 females; average age 41.65 years), followed at the Center for Hereditary Anemias, University Hospital of Modena, were enrolled to perform an echocardiographic evaluation (ECE) before scheduled BT (T0), a targeted ECE immediately after the transfusion (Tearly), and a targeted ECE 7-10 days thereafter (Tlate). Medical history, biochemical data, and parameters related to iron status including serum levels of labile plasma iron (LPI), non-transferrin-bound iron (NTBI), and 3 year-average serum ferritin, were collected to assess predictors of transfusion-related cardiac changes. Global longitudinal strain (GLS) at baseline was worse, on average, in patients with higher ferritin or lower serum calcium; early post-transfusion GLS improved significantly in patients with ferritin>1500 ng/mL or albumin-corrected calcium <8.4 mg/dL, whereas it remained stable in control groups. Notably, several early post-transfusion changes could be consistently predicted by variables related to iron homeostasis or transfusion status. Cardiac MRI T2* showed moderate IO in only one patient. In conclusion, β -thalassemic patients with hyperferritinemia or hypocalcemia are likely those who benefit most from BT in terms of systolic function. Even in the absence of overt myocardial IO, alterations in circulating iron status predict early dysfunctions in cardiac response after scheduled blood transfusion.

The present study investigates the possible use of manganese (Mn)-based liposomal formulations for diagnostic applications in imaging techniques such as magnetic resonance imaging (MRI), with the aim of overcoming the toxicity limitations associated with the use of free Mn2+. Specifically, anionic liposomes carrying two model Mn(II)-based compounds, MnCl2 (MC) and Mn(HMTA) (MH), were prepared and characterised in terms of morphology, size, loading capacity, and in vitro activity. Homogeneous dispersions characterised mainly by unilamellar vesicles were obtained; furthermore, no differences in size and morphology were detected between unloaded and Mn-loaded vesicles. The encapsulation efficiency of MC and MH was evaluated on extruded liposomes by means of ICP-OES analysis. The obtained results showed that both MC and MH are almost completely retained by the lipid portion of liposomes (LPs), with encapsulation efficiencies of 99.7% for MC and 98.8% for MH. The magnetic imaging properties of the produced liposomal formulations were investigated for application in a potential preclinical scenario by collecting magnetic resonance images of a phantom designed to compare the paramagnetic contrast properties of free MC and MH compounds and the corresponding manganese-containing liposome dispersions. It was found that both LP-MC and LP-MH at low concentrations (0.5 mM) show better contrast (contrast-to-noise ratios of 194 and 209, respectively) than solutions containing free Mn at the same concentrations (117 and 134, respectively) and are safe to use on human cells at the selected dose. Taken together, the results of this comparative analysis suggest that these liposome-containing Mn compounds might be suitable for diagnostic purposes.

Mangiferin is a natural glucosyl xanthone with antioxidant and anti-inflammatory activity, making it suitable for protection against cutaneous diseases. In this study ethosomes and transethosomes were designed as topical delivery systems for mangiferin. A preformulation study was conducted using different surfactants in association with phosphatidylcholine. Vesicle dimensional distribution was monitored by photon correlation spectroscopy, while antioxidant capacity and cytotoxicity were respectively assessed by free radical scavenging analysis and MTT on HaCaT keratinocytes. Selected nanosystems were further investigated by cryogenic transmission electron microscopy, while mangiferin entrapment capacity was evaluated by ultracentrifugation and HPLC. The diffusion kinetics of mangiferin from ethosomes and transethosomes evaluated by Franz cell was faster in the case of transethosomes. The suitability of mangiferin-containing nanovesicles in the treatment of skin disorders related to pollutants was investigated, evaluating, in vitro, the antioxidant and anti-inflammatory effect of ethosomes and transethosomes on human keratinocytes exposed to cigarette smoke as an oxidative and inflammatory challenger. The ability to induce an antioxidant response (HO-1) and anti-inflammatory status (IL-6 and NF-kB) was determined by RT-PCR and immunofluorescence. The data demonstrated the effectiveness of mangiferin loaded in nanosystems to protect cells from damage. Finally, to gain insight into the keratinocytes’ uptake of ethosome and transethosome, transmission electron microscopy analyses were conducted, showing that both nanosystems were able to pass intact within the cells.

In this study an in situ forming gel for curcumin and piperine delivery is investigated as a long-lasting strategy in the local treatment of inflammatory and degenerative joint disease, such as osteoarthritis and rheumatoid arthritis. Particularly glyceryl monooleate, in association with phosphatidylcholine and ethanol, were employed. Different ratios between excipients were tested, with the aim to obtain a liquid form suitable for subcutaneous injection, gaining a semisolid consistency in contact with biological fluids. A formulative study was conducted to assess the composition impact on the structural properties of the formulations, particularly focusing on injectability and phase transition. Curcumin and piperine were loaded, singularly or jointly, in selected in situ forming gels. Structural characterization, performed by X-ray scattering, revealed disordered reverse micellar phases, undergoing transition to hexagonal and cubic Pn3m phase upon hydration. In vitro dialysis release study demonstrated a sustained release of both drugs over 96 h, with a faster release in the case of jointly loaded drugs. Mechanistic analysis and water uptake studies indicated a drug release governed by both diffusion and swelling/erosion of the lipid supramolecular structure. Furthermore, an ex vivo release analysis performed using human skin explants suggested the formulation suitability for subcutaneous injection, indicating that the presence of piperine in the in situ formed gel allowed to double the curcumin release with respect to the simple curcumin loaded gel.

San Nicolas Island (SNI) foxes historically had the highest densities of the six subspecies of Channel Island fox, four of which were listed as endangered in the 1990s. As an island species, SNI foxes are inherently vulnerable because they evolved in isolation from many potential threats, and their small range features relatively simple and degraded habitats, limiting their population size and heightening susceptibility to climate‐driven habitat changes. In the past decade, the SNI fox population has decreased by nearly half, spurring concern. Our analyses of 18 yr of trapping data suggest that both drought and density dependence contributed to this decline. Density dependence in survival acted on older individuals and its strength doubled after recent drought‐induced habitat changes. Annual precipitation was a strong driver of pup production, but density dependence moderated precipitation benefits. Using a stochastic model with island‐specific drivers of demography, we developed a risk isocline tool to predict 50‐yr quasi‐extinction risk based on population size and mortality. Predicted extinction risk for SNI foxes is currently <5% and expected to decrease. Compared to the previously listed subspecies, risk isoclines indicate the SNI subspecies is more resistant to quasi‐extinction at moderate population sizes and mortality rates, but quasi‐extinction risk does not decline as rapidly at higher population sizes or lower mortality rates. Thus, limiting human‐caused mortality and monitoring for novel threats such as exotic disease remain important. The ability of SNI foxes to increase pup production following high‐rainfall low‐density years is a key feature stabilizing their dynamics. Habitat‐ and location‐specific dynamics produce substantial portfolio effects, whereby asynchrony in growth rates stabilizes overall population numbers, and restoration efforts that increase food resources and habitat diversity will further enhance the resilience of this population. Although the SNI fox appears to be rebounding, its recent decline may foreshadow future dynamics and serves as a cautionary tale for stewards of island species facing unprecedented climatic conditions, especially those inhabiting small and less diverse systems. Finally, our analyses highlight limitations in applying risk analyses from one population to related species, or even the same species in different habitat settings.