Development of novel galactosylated PLGA nanoparticles for hepatocyte targeting using molecular modelling

FCT/MEC (UID/QUI/50006/2019). ERDF under the PT2020 Partnership Agreement (POCI-01-0145-FEDER-007265).Doxorubicin-loaded PLGA nanoparticles conjugated with a new galactose-based ligand for the specific recognition by human hepatoma cellular carcinoma cells (Hep G2) were successfully produced. The new targeting compound was selected using molecular docking combined with quantum chemical calculations for modelling and comparing molecular interactions among the H1 subunit of the asialoglycoprotein receptor containing the carbohydrate recognition domain and the ligand. The ligand, bis(1-O-ethyl-β-D-galactopyranosyl)amine, was synthetized, characterized, and subsequently linked to PLGA. Unloaded (PLGA-di-GAL NP) and doxorubicin-loaded (DOX-PLGA-di-GAL NP) nanoparticles were prepared using an emulsion method and characterized. The produced DOX-PLGA-di-GAL NP are spherical in shape with a size of 258 ± 47 nm, a zeta potential of-62.3 mV, and a drug encapsulation efficiency of 83%. The in vitro drug release results obtained show a three-phase release profile. In vitro cell studies confirmed the interaction between Hep G2 cells and PLGA-di-GAL NP. Cell cytotoxicity tests showed that unloaded NP are nontoxic and that DOX-PLGA-di-GAL NP caused a decrease of around 80% in cellular viability. The strategy used in this work to design new targeting compounds represents a promising tool to develop eective hepatocyte targeting drug delivery systems and can be applied to other tissues/organs.publishersversionpublishe

Self-organizing maps and VolSurf approach to predict aldose reductase inhibition by flavonoid compounds

Aldose Reductase (AR) is the polyol pathway key enzyme which converts glucose to sorbitol. High glucose availability in insulin resistant tissues in diabetes leads into an accumulation of sorbitol, which has been associated with typical chronic complications of this disease, such as neuropathy, nephropathy and retinopathy. In this study, 71 flavonoids AR inhibitors were subjected to two methods of SAR to verify crucial substituents. The first method used the PCA (Principal Component Analysis) to elucidate physical and chemical characteristics in the molecules that would be essential for the activity, employing VolSurf descriptors. The rate obtained explained 53% of the system total variance and revealed that a hydrophobic-hydrophilic balance in the molecules is required, since very polar or nonpolar substituents decrease the activity. Artificial Neural Networks (ANNs) was also employed to determine key substituents by evaluating substitution patterns, using NMR data. This study had a high success rate (85% accuracy in the training set and 88% accuracy in the test set) and showed polihydroxilations are essential for high activity and methoxylations and glicosilations primarily at positions C7, C3' and C4' decrease the activity.CNPqFAPES

Characterization of Volatile Organic Compounds (VOC) in wet-white and metal-free leathers

Content: As it is known in the tanning sector, in recent times, the so-called wet-white and/or metal-free concepts have had a certain increase. For example, in the automotive sector, the wet-white tanning system, carried out with glutaraldehyde and tannins, has been widely diffused. In fact, car manufacturers offer, for interior furnishings, leather not only for high-end cars but increasingly also in the lower segments. The components on which the leather upholstery is applied are mainly steering wheel, seats, dashboard and panels. Therefore, the use of leather also in this context must be able to meet both the aesthetic/performance criteria and the environmental ones; environmental criteria should also consider the air quality of the interior of a motor vehicle. In practice, the interior furniture consisting of finished leather must be able to release a few volatile substances and, at the same time, provide a typical smell of leather. Considering, therefore, the diffusion of alternative chrome tanning systems for the different uses, in this work, wet-white (glutaraldehyde and tannins) will be investigated, both from the point of view of the performance characteristics and from the ecotoxicological ones. and leathers deriving from the latest generation of metal-free tanning. For the characterization of Volatile Organic Compounds (VOC) the GC-MS will be used coupled with the 'Purge and Trap' technique with the aim of obtaining information on the new substances used in the wetwhite / metal free production process and then avoiding undesired effects during use (eg bad smell, SVHC substances, etc.) Take-Away: metal-free automotive VO

A posteriori dietary patterns and rheumatoid arthritis disease activity: A beneficial role of vegetable and animal unsaturated fatty acids

To our knowledge, no studies have investigated the relationship between a posteriori dietary patterns (DPs)\u2014representing current dietary behavior\u2014and disease activity in patients with rheumatoid arthritis (RA). We analyzed data from a recent Italian cross-sectional study including 365 RA patients (median age: 58.46 years, 78.63% females). Prevalent DPs were identified through principal component factor analysis on 33 nutrients. RA activity was measured according to the Disease Activity Score on 28 joints (DAS28) and the Simplified Disease Activity Index (SDAI). Single DPs were related to disease activity through linear and logistic regression models, adjusted for the remaining DPs and confounders. We identified five DPs (~80% variance explained). Among them, Vegetable unsaturated fatty acids (VUFA) and Animal unsaturated fatty acids (AUFA) DPs were inversely related to DAS28 in the overall analysis, and in the more severe or long-standing RA subgroups; the highest score reductions (VUFA: 0.81, AUFA: 0.71) were reached for the long-standing RA. The SDAI was inversely related with these DPs in subgroups only. This Italian study shows that scoring high on DPs based on unsaturated fats from either source provides independent beneficial effects of clinical relevance on RA disease activity, thus strengthening evidence on the topic

Robust avoidance of edge-localized modes alongside gradient formation in the negative triangularity tokamak edge

In a series of high performance diverted discharges on DIII-D, we demonstrate that strong negative triangularity (NT) shaping robustly suppresses all edge-localized mode (ELM) activity over a wide range of plasma conditions: $\langle n\rangle=0.1-1.5\times10^{20}$m$^{-3}$, $P_\mathrm{aux}=0-15$MW and $|B_\mathrm{t}|=1-2.2$T, corresponding to $P_\mathrm{loss}/P_\mathrm{LH08}\sim8$. The full dataset is consistent with the theoretical prediction that magnetic shear in the NT edge inhibits access to ELMing H-mode regimes; all experimental pressure profiles are found to be at or below the infinite-$n$ ballooning stability limit. Importantly, we also report enhanced edge pressure gradients at strong NT that are significantly steeper than in traditional ELM-free L-mode plasmas and provide significant promise for NT reactor integration.Comment: 5 pages, 5 figure

Assessment of the mycorrhizal community in the rhizosphere of maize (Zea mays L.) genotypes contrasting for phosphorus efficiency in the acid savannas of Brazil using denaturing gradient gel electrophoresis (DGGE).

Community structure of indigenous arbuscular mycorrhizal fungi (AMF) in the rhizosphere of tropical maize genotypes contrasting for phosphorus efficiency was evaluated using denaturing gradient gel electrophoresis (DGGE). Fragments of AMF ribosomal DNA (rDNA) were amplified using nested PCR with fungal universal primers and ITS (internal transcribed spacer) specific primers for Acaulosporaceae, Glomaceae and Gigasporaceae. ITS-Acaulosporaceae and Glomaceae-specific primers and DGGE were efficient in differentiating the composition of mycorrhizal communities. Maize genotypes had a greater influence on the rhizosphere mycorrhizal community than the level of P in the soil. DGGE profiles of maize roots revealed bands that were present only in P efficient genotypes (L3 and HT3060), suggesting that some mycorrhizal groups were stimulated by P efficient maize genotypes. Acaulospora longula, A. rugosa, A. scrobiculata, A. morrowiae and Glomus caledonium were found only in the rhizosphere of P efficient maize genotypes cultivated in low P soils. A greater number of mycorrhizal DGGE bands were found in soil samples from no-till maize than conventional tillage. Effective mycorrhizal colonization of crops may influence the maize yield under Brazilian savanna acid soils by modulating the capacity of different cultivars to tolerate P deficiency

Effect of benzalkonium chloride on dentin bond strength and endogenous enzymatic activity

Objective: This in vitro study evaluated at baseline (T0) and over time (T12 months), the effect of a multi-mode universal adhesive compared with two experimental formulations blended with different concentrations of benzalkonium chloride (BAC), on bond strength and endogenous enzymatic activity. Methods and materials: Specimens were assigned to the following groups according to the adhesive protocol: G1) All-Bond Universal (ABU) self-etch (SE); G2) ABU + 0.5% BAC SE; G3) ABU + 1% methacrylate BAC SE; G4) ABU etch-and-rinse (E&R); G5) ABU + 0.5% BAC E&R; G6) ABU + 1% methacrylate BAC E&R. Gelatin zymography was performed on dentin powder obtained from eight human third molars. Endogenous enzymatic activity within the hybrid layer was examined using in situ zymography after 24 h (T0) or 1-year storage in artificial saliva (T12). Forty intact molars were prepared for microtensile bond strength test at T0 and T12. Results were statistically analyzed with three-way ANOVA (\u3b1 = 0.05). Results: Gelatin zymography assay and in situ zymography quantification analyses indicated that all the BAC-containing formulations decreased matrix metalloproteinase expression. However, in situ zymography showed a general trend of enzymatic activity increase after aging. Microtensile bond-strength testing showed decrease in bond strength over time in all the tested groups; performances of the 1% methacrylate BAC experimental groups were worse than the control. Conclusions: BAC-containing adhesives reduce endogenous enzymatic activity both immediately and over time. However, independently from the adhesive employed, increase in the gelatinolytic activity over time and decrease in bond strength was found (especially in the BAC + 1% methacrylate groups), probably due to impaired polymerization properties. Clinical significance: Adhesives containing protease inhibitors are practical and efficient tools in clinical practice for enhancement of the longevity of dental restorations. However, extensive investigation of the mechanical and adhesive properties of the material is necessary prior to their clinical use

Noninvasive assessment of airflows by electrical impedance tomography in intubated hypoxemic patients : an exploratory study

Background: Noninvasive monitoring of maximal inspiratory and expiratory flows (MIF and MEF, respectively) by electrical impedance tomography (EIT) might enable early recognition of changes in the mechanical properties of the respiratory system due to new conditions or in response to treatments. We aimed to validate EIT-based measures of MIF and MEF against spirometry in intubated hypoxemic patients during controlled ventilation and spontaneous breathing. Moreover, regional distribution of maximal airflows might interact with lung pathology and increase the risk of additional ventilation injury. Thus, we also aimed to describe the effects of mechanical ventilation settings on regional MIF and MEF. Methods: We performed a new analysis of data from two prospective, randomized, crossover studies. We included intubated patients admitted to the intensive care unit with acute hypoxemic respiratory failure (AHRF) and acute respiratory distress syndrome (ARDS) undergoing pressure support ventilation (PSV, n = 10) and volume-controlled ventilation (VCV, n = 20). We measured MIF and MEF by spirometry and EIT during six different combinations of ventilation settings: higher vs. lower support during PSV and higher vs. lower positive end-expiratory pressure (PEEP) during both PSV and VCV. Regional airflows were assessed by EIT in dependent and non-dependent lung regions, too. Results: MIF and MEF measured by EIT were tightly correlated with those measured by spirometry during all conditions (range of R2 0.629\u20130.776 and R2 0.606\u20130.772, respectively, p < 0.05 for all), with clinically acceptable limits of agreement. Higher PEEP significantly improved homogeneity in the regional distribution of MIF and MEF during volume-controlled ventilation, by increasing airflows in the dependent lung regions and lowering them in the non-dependent ones. Conclusions: EIT provides accurate noninvasive monitoring of MIF and MEF. The present study also generates the hypothesis that EIT could guide PSV and PEEP settings aimed to increase homogeneity of distending and deflating regional airflows