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Purpose: Recent studies indicate that shift work may affect workers' eating habits and overall well-being. This study aimed to assess differences in eating patterns, sleep quality, and mental health between Italian shift and non-shift workers, with a focus on individual chronotype and the type of shift work (day vs. night shift). Methods: The cross-sectional study involved 322 subjects (166 shift and 156 non-shift workers). Eating habits were evaluated using a 7-day diary and the Medi-Lite questionnaire. Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI), and mental health with the Depression Anxiety Stress Scales (DASS). Individual chronotype was defined using the Morningness-Eveningness Questionnaire. Results: No significant differences in daily energy, macronutrient, and micronutrient intake between the two groups, nor in the temporal pattern of eating. However, shift workers had significantly (p < 0.05) lower adherence to the Mediterranean diet (MD) (7.6 ± 2.3 vs 8.1 ± 2.2) compared to non-shift workers. Shift workers also reported significantly poorer sleep quality (mean PSQI score 7.6 ± 3.7 vs. 5.8 ± 3.0) and higher levels of anxiety and stress symptoms. Among shift workers, those with an evening chronotype had significantly lower MD adherence than those with a morning chronotypes. Additionally, night shift workers experienced more sleep disturbances compared to day ones. Conclusion: Shift workers reported lower MD adherence, poorer sleep quality, and a higher prevalence of anxiety and stress symptoms compared to a similar group of non-shift workers. Evening chronotypes and night shift work were associated with worse eating habits and sleep quality. [ABSTRACT FROM AUTHOR]

While cellular metabolism impacts the DNA damage response, a systematic understanding of the metabolic requirements that are crucial for DNA damage repair has yet to be achieved. Here, we investigate the metabolic enzymes and processes that are essential for the resolution of DNA damage. By integrating functional genomics with chromatin proteomics and metabolomics, we provide a detailed description of the interplay between cellular metabolism and the DNA damage response. Further analysis identified that Peroxiredoxin 1, PRDX1, contributes to the DNA damage repair. During the DNA damage response, PRDX1 translocates to the nucleus where it reduces DNA damage‐induced nuclear reactive oxygen species. Moreover, PRDX1 loss lowers aspartate availability, which is required for the DNA damage‐induced upregulation of de novo nucleotide synthesis. In the absence of PRDX1, cells accumulate replication stress and DNA damage, leading to proliferation defects that are exacerbated in the presence of etoposide, thus revealing a role for PRDX1 as a DNA damage surveillance factor. Synopsis: Genetic screens, proteomics, and metabolomics are performed to investigate the crosstalk between metabolism and the DNA damage response. Integrative analyses identify Peroxiredoxin‐1 (PRDX1) as a DNA damage surveillance factor. Systematic approaches following DNA damage induction by etoposide reveal the aspects of metabolism that are crucial for maintaining genome integrity.Loss of electron transport chain enzymes is synthetically viable with etoposide, and some of these enzymes are partially located on chromatin 24 h after etoposide release.The metabolic enzyme PRDX1 contributes to DNA repair and translocates to the nucleus where it reduces DNA damage‐induced nuclear ROS.Loss of PRDX1 lowers aspartate availability and perturbs de novo nucleotide synthesis, which induces replication stress and limits the DNA repair capacities of the cells. [ABSTRACT FROM AUTHOR]

We have previously demonstrated significant in vitro natriuretic effects of anandamide (AEA) nanoformulation in polymeric nanoparticles, whose size prevents their accumulation in organs, such as the kidneys. Therefore, it is of particular interest to design and test nanostructures that can pharmacologically accumulate in these organs. In this regard, we prepared and characterized polymeric nanomicelles (~14 and 40 nm). Likewise, their biodistribution was determined. Spontaneously hypertensive rats (SHR) and normotensive rats (WKY), n = 3 per group, were divided into five treatment conditions: control, sham, free AEA freshly dispersed in aqueous solution or 24 h after its dispersion, and AEA encapsulated in nanomicelles. The kidneys were the main site of accumulation of the nanoformulation after 24 h. Freshly dispersed free AEA showed its classical triphasic response in SHR, which was absent from all other treatments. Nanoformulated AEA produced a sustained antihypertensive effect over 2 h, accompanied by a significant increase in fractional sodium excretion (FSE %). These effects were not observed in WKY, sham, or free AEA-treated rats after 24 h of its aqueous dispersion. Without precedent, we demonstrate in vivo natriuretic, diuretic, and hypotensive effects of AEA nanoformulation in polymeric nanomicelles, suggesting its possible use as a new antihypertensive agent with intravenous administration and passive renal accumulation. [ABSTRACT FROM AUTHOR]

This work aimed to design high-pressure homogenization process able to improve pea protein functionalities. To this purpose, pea protein concentrate suspensions (5% w/w) were homogenised at increasing pressures (up to 150 MPa) and number of passes (up to 3). Samples were analysed for protein structural and conformational modifications, technological functionalities, and in vitro digestibility. As HPH intensity increased, protein unfolding was favoured, leading to solubility and oil holding capacity increase and generating emulsions with rheological properties shifting from liquid-like pseudo-plastic behaviours to gel-like plastic characteristics. The best performing HPH treatment included 3 passes at 70 MPa and leaded to a novel plant-protein based ingredient with improved techno-functionalities and digestibility comparable to original pea proteins. A further increase in HPH intensity at 150 MPa for 3 passes caused protein aggregation with detrimental effects on technological functionalities and digestibility. Results demonstrate the remarkable effect of HPH in tailoring protein functionalities, highlighting the need of a process design step to define HPH process parameters allowing to generate novel high-added value. [ABSTRACT FROM AUTHOR]

High pressure homogenization (HPH) at increasing intensity (50, 100, 150 MPa and 150 MPa for 5 passes) was combined with an alkaline-acid recovery method to prepare protein-enriched okara powders intended as ingredients with improved techno-functional properties. The treatment allowed obtaining from 4 to 8 g powder per 100 g fresh okara. The intensity of HPH treatment significantly affected amount, composition, particle size, protein structure and techno-functional properties. Treatments at intermediate pressures in the range 50−100 MPa resulted the most feasible from an industrial perspective allowing to obtain a good balance between protein content and the techno-functionalities (e.g. solubility, foaming, gelling and emulsifying properties) of the okara ingredient. Thus, HPH combined with simple pH-driven precipitation can be considered an efficacious and industrially feasible pre-treatment for okara valorisation into innovative ingredients. [ABSTRACT FROM AUTHOR]

Thin and porous SnO2 films (70 nm thick with grain size between 10 and 30 nm) have been prepared by e-beam evaporation onto alumina substrate provided with platinum electrodes. The Ohmic character of the contacts was preserved in all measurement conditions utilized for investigations. The dependence of electrical conduction on the composition of the ambient atmosphere has been studied by means of Hall and four point conductance measurements. The experiments were performed in different gas atmospheres containing N2, O2, and CO and at different operation temperatures (between room temperature and 420 °C). A relatively low effective mobility (5–30 cm2 V-1 s-1) and a high charge carrier effective concentration (1018–1019 cm-3) were deduced when using the single crystals recipe, as required by the established models for granular materials. The analysis of these experimental data showed the inadequacy of the geometrical models and effective medium theories to correctly extract the electrokinetic parameters from conductance and Hall measurements in the case of gas sensitive layers and to predict their temperature and gas composition dependences. The conventional approach fails because it considers the samples at different temperatures as one physical system while, in fact, the surface chemistry in oxygen atmosphere leads to new trap generation, which is equivalent to the doping level modification. The use of a nonconventional approach, taking into account the film interaction with the ambient through quasichemical equations, and associated mass action laws together with the surface scattering influence on the carrier mobility allowed for the understanding of the involved mechanisms and good fits for the experimental data. [ABSTRACT FROM AUTHOR]

Abstract Nanotechnology has recently emerged as a promising tool in biomedicine research. An important branch of nanotechnology is drug delivery and drug targeting using a wide range of biomaterials with promising potential applications in cancer research. The aim of this review is to provide an overview of the evolution of nanotechnology in cancer therapy, exemplified by a myriad of applications in drug delivery, tumor targeting and reversal of ATP-binding cassette drug transporter-mediated multidrug resistance (MDR) in cancer cells by the biomaterials used in nanoformulations. Special attention will be focused on liver cancer, especially, on hepatocellular carcinoma, which is among the malignancies with the poorest prognosis due to its extremely "difficult-to-treat" nature related to its high recurrence rate and MDR phenotype. Graphical abstract Unlabelled Image Highlights • HCC is among the malignancies with the poorest prognosis. • The treatment of patients with advanced HCC and overcoming MDR still remains an important challenge. • Nanotechnology emerged as a promising tool in biomedicine research in cancer. • Nanomedicines have all the potential to become an innovative class of therapeutics for HCC. [ABSTRACT FROM AUTHOR]

A "source of protein" and a "high protein" bread intended for the elderly were obtained by replacing wheat flour in bread dough with 50 and 165 g/kg pea protein concentrate. Carbohydrate and protein digestibility was evaluated in vitro by mimicking adult and elderly digestive conditions. Protein digestibility was measured by the OPA assay. Carbohydrate digestibility was assessed by determining the incremental area under the glucose curve during the intestinal phase to estimate the glycaemic index (GI e). Pea proteins negatively affected some key features accounting for elderly acceptability of bread, mainly the textural ones, with firmness increasing from 1.2 to 3.3 N. Proteolysis was not affected by physiological conditions but by reformulation, with "high protein" bread presenting the highest proteolysis, followed by "source of protein" and soft wheat bread (around 110, 80 and 70 mmol free NH 2 /g dw , respectively). Conversely, carbohydrate digestibility was restrained in elderly settings compared to adult ones, with glucose concentration during digestion reaching maximum values of 0.5 and 0.8 respectively, with no differences between enriched bread. Results may contribute to a better understanding of food digestibility under different gastrointestinal conditions and of its dependence on technological factors and would help to design age-tailored foods. [Display omitted] • Wheat flour was replaced in bread with 5.0 or 16.5% pea protein concentrate. • Reformulated breads were in vitro digested under adult and elderly setting. • Pea protein addition negatively affected the textural properties of bread. • Proteolysis increased with pea proteins, regardless the physiological setting. • Carbohydrate digestibility decreased from adult to elderly, regardless reformulation. [ABSTRACT FROM AUTHOR]

Breast cancer represents the top cancer among women, accounting 521.000 deaths per year. Development of targeted nanomedicines to breast cancer tissues represents a milestone to reduce chemotherapy side effects. Taking advantage of the over-expression of glucose (Glu) membrane transporters in breast cancer cells, we aim to expand the potential of a paclitaxel (PTX)-loaded mixed micellar formulation based on polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer (Soluplus®) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) by its surface decoration with Glu moieties. The glycopolymer (Soluplus(Glu)) was obtained by microwave-assisted ring opening reaction of δ-gluconolactone initiated by Soluplus®. The glycosylation was confirmed by ¹H NMR and by agglutination assays employing Concanavalin A. The hydrodynamic diameter of Soluplus(Glu) micelles was characterized by dynamic light scattering (100.3 ± 3.8 nm) as well as the critical micellar concentration value (0.0151% w/v). Then, a mixed micelle formulation employing Soluplus®, Soluplus(Glu) and TPGS (3:1:1 wt ratio) loaded with PTX (4 mg/mL) was developed as a multifunctional nanocarrier. Its in vitro anticancer performance in MCF-7 (1.6-fold) and MDA-MB-231 (14.1-fold) was significantly enhanced (p < 0.05) versus the unique commercially available micellar-based PTX-nanoformulation (Genexol®). Furthermore, the in vitro PTX cellular uptake assays revealed that the drug intracellular/cell content was significantly (p < 0.05) higher for the Glu-containing mixed micelles versus Genexol® after 6 h of incubation with MCF-7 (30.5-fold) and MDA-MB-231 (5-fold). Overall, results confirmed the potential of our Glu-decorated mixed colloidal formulation as an intelligent nanocarrier for PTX-targeted breast cancer chemotherapy. [ABSTRACT FROM AUTHOR]

Mitochondrial DNA (mtDNA) can undergo double-strand breaks (DSBs), caused by defective replication, or by various endogenous or exogenous sources, such as reactive oxygen species, chemotherapeutic agents or ionizing radiations. MtDNA encodes for proteins involved in ATP production, and maintenance of genome integrity following DSBs is thus of crucial importance. However, the mechanisms involved in mtDNA maintenance after DSBs remain unknown. In this study, we investigated the consequences of the production of mtDNA DSBs using a human inducible cell system expressing the restriction enzyme PstI targeted to mitochondria. Using this system, we could not find any support for DSB repair of mtDNA. Instead we observed a loss of the damaged mtDNA molecules and a severe decrease in mtDNA content. We demonstrate that none of the known mitochondrial nucleases are involved in the mtDNA degradation and that the DNA loss is not due to autophagy, mitophagy or apoptosis. Our study suggests that a still uncharacterized pathway for the targeted degradation of damaged mtDNA in a mitophagy/autophagy-independent manner is present in mitochondria, and might provide the main mechanism used by the cells to deal with DSBs. [ABSTRACT FROM AUTHOR]

[Display omitted] • Soft, durum, and whole wheat breads were in vitro digested in adult or elderly physiological setting. • Protein digestibility (PD) and the estimated glycaemic index (GI e) were assessed. • PD and GI e decreased in the order soft > durum > whole and durum > soft > whole, respectively. • PD and GI e were lower in the elderly setting compared to the adult one. • PD and GI e were correlated and relied on matrix integrity and physiological setting. Carbohydrate and protein digestibility were assessed in different commercial bread types, i.e. , soft, durum, and whole wheat, by applying in vitro digestion protocols mimicking adult or elderly physiological conditions. Protein digestibility was measured after the gastric and intestinal phases by the o-phthalaldehyde spectrophotometric assay (OPA). Carbohydrate digestibility was assessed by determining the incremental area under glucose curve during the intestinal phase of digestion to estimate the glycaemic index (GI e). Finally, the correlation between protein and carbohydrate digestibility was computed. Bread proteins presented a high gastric resistance, with a digestibility < 10% in all cases while after the intestinal phase, protein digestibility increased, ranging from 40 to 70%. Protein digestibility was affected both by formulation, with whole wheat bread presenting the lowest values, and by physiological conditions, with restrained digestibility under elderly conditions compared to adult ones. The GI e decreased in the order durum > soft > whole, under both adult (119, 101, and 82, respectively) and elderly (107, 93, and 65, respectively) conditions. The extent of differences under different physiological settings varied depending on the bread type, without significant changes for soft wheat bread (ΔGI e = 8), whereas elderly conditions significantly reduced GI e both for durum (ΔGI e = 12) and whole (ΔGI e = 17) wheat bread. An almost strong positive correlation between protein digestibility and GI e was observed (p = 0.69), indicating that concomitantly addressing sarcopenia and type 2 diabetes can only be pursued by a compromise solution or more desirably requires identifying technological strategies to maximize protein digestibility while restraining the glycaemic response. [ABSTRACT FROM AUTHOR]

Background Poly-ADP ribosylation (PARylation) is a post translational modification, catalyzed by Poly(ADP-ribose)polymerase (PARP) family. In Drosophila , PARP-I (human PARP-1 ortholog) is considered to be the only enzymatically active isoform. PARylation is involved in various cellular processes such as DNA repair in case of base excision and strand-breaks. Observations Strand-breaks (SSB and DSB) are detrimental to cell viability and, in Drosophila, that has a unique PARP family organization, little is known on PARP involvement in the control of strand-breaks repair process. In our study, strands-breaks (SSB and DSB) are chemically induced in S2 Drosophila cells using bleomycin. These breaks are efficiently repaired in S2 cells. During the bleomycin treatment, changes in PARylation levels are only detectable in a few cells, and an increase in PARP-I and PARP-II mRNAs is only observed during the recovery period. These results differ strongly from those obtained with Human cells, where PARylation is strongly activating when DNA breaks are generated. Finally, in PARP knock-down cells, DNA stability is altered but no change in strand-breaks repair can be observed. Conclusions PARP responses in DNA strands-breaks context are functional in Drosophila model as demonstrated by PARP-I and PARP-II mRNA increases. However, no modification of the global PARylation profile is observed during strand-breaks generation, only changes at cellular levels are detectable. Taking together, these results demonstrate that PARylation process in Drosophila is tightly regulated in the context of strands-breaks repair and that PARP is essential during the maintenance of DNA integrity but dispensable in the DNA repair process. [ABSTRACT FROM AUTHOR]

Treatment of retinoblastoma, the most common primary ocular malignancy in children, has greatly improved over the last decade. Still, new devices for chemotherapy are needed to achieve better tumor control. The aim of this project was to develop an ocular drug delivery system for topotecan (TPT) loaded in biocompatible hydrogels of poly(ε-caprolactone)-poly(ethyleneglycol)-poly(ε-caprolactone) block copolymers (PCL-PEG-PCL) for sustained TPT release in the vitreous humor. Hydrogels were prepared from TPT and synthesized PCL-PEG-PCL copolymers. Rheological properties and in vitro and in vivo TPT release were studied. Hydrogel cytotoxicity was evaluated in retinoblastoma cells as a surrogate for efficacy and TPT vitreous pharmacokinetics and systemic as well as ocular toxicity were evaluated in rabbits. The pseudoplastic behavior of the hydrogels makes them suitable for intraocular administration. In vitro release profiles showed a sustained release of TPT from PCL-PEG-PCL up to 7 days and drug loading did not affect the release pattern. Blank hydrogels did not affect retinoblastoma cell viability but 0.4% (w/w) TPT-loaded hydrogel was highly cytotoxic for at least 7 days. After intravitreal injection, TPT vitreous concentrations were sustained above the pharmacologically active concentration. One month after injection, animals with blank or TPT-loaded hydrogels showed no systemic toxicity or retinal impairment on fundus examination, electroretinographic, and histopathological assessments. These novel TPT-hydrogels can deliver sustained concentrations of active drug into the vitreous with excellent biocompatibility in vivo and pronounced cytotoxic activity in retinoblastoma cells and may become an additional strategy for intraocular retinoblastoma treatment. [ABSTRACT FROM AUTHOR]

• Italian commercial breads were evaluated by an instrumental and sensory approach. • Desirable sensory and mechanical properties of bread for the elderly were studied. • Elderly's acceptance was mainly correlated to homemade appearance and texture. • Chewiness and tasteless descriptors corresponded to poor consumers' satisfaction. The aim of this study was to define the desirable sensory and mechanical properties that a bread targeting elderly consumers should have and to understand whether the products currently present in the Italian market meet the desired requirements. Ten types of commercial bread having different formulations and manufacturing processes were characterized for moisture content, texture and parameters. A rapid sensory method was used to describe and identify the key sensory attributes driving the consumers overall liking. The results showed that the instrumental and sensory evaluations showed a good agreement. Overall, the elderly consumers reported a low acceptance for the Italian commercial breads. The sensory evaluation revealed that the ideal bread should have a heterogeneous and homemade appearance, the odor and flavor of bread, a crumbly and soft texture and be easy to swallow, since these attributes were found to drive consumers' satisfaction. In conclusion, this study will provide to bakery industry important information to re-design foods adapted to preferences of vulnerable consumers (e.g., the elderly). [ABSTRACT FROM AUTHOR]

[Display omitted] • An in vitro static digestion method to mimic the elderly conditions was designed. • Different proteins were in vitro digested under adult and elderly conditions. • Elderly conditions reduced protein digestibility in comparison to adult ones. • Proteolysis kinetics was affected by protein characteristics, especially solubility. In this study an in vitro static digestion method mimicking the elderly gastrointestinal conditions was designed by adapting the physiological parameters described in the INFOGEST standardized static in vitro digestion protocol, i.e., pH, digestive phase duration, concentrations of enzymes and bile salts, to the aged GI transit. The digestibility of proteins from different sources (pea, rice, wheat, and milk whey) was then assessed. Protein digestive behaviour was monitored after gastric and intestinal phases by BCA assay and SDS-PAGE to assess protein hydrolysis both from a quantitative and a qualitative point of view. Digested samples were also analysed for physical characteristics in terms of particle size and zeta potential. Data acquired under elderly gastrointestinal conditions were compared to those obtained by using the INFOGEST protocol designed to study adult digestion. Results clearly showed that the elderly gastrointestinal conditions deeply affected proteolysis leading to a general reduction of protein digestibility in comparison to the adult model. The proteolysis extent depended on the protein source with whey and rice proteins showing about 20% reduction using the model mimicking the elderly gut, followed by pea (about 10% reduction) and wheat (about 4% reduction) proteins. The knowledge of protein digestibility under elderly gastrointestinal conditions generated in this study could be useful in the attempt to develop age-tailored products. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) has been stated as “the greatest killer worldwide due to a single infectious agent” behind the human immunodeficiency virus. Standard short-term treatment includes the oral administration of a combination of “first-line” drugs. However, poor-patient compliance and adherence to the long-term treatments represent one of the mayor drawbacks of the TB therapy. An alternative to the oral route is the pulmonary delivery of anti-TB drugs for local or systemic administration. Nanotechnology offers an attractive platform to develop novel inhalable/respirable nanocarriers. The present investigation was focused on the encapsulation of rifampicin (RIF) (a “first-line” anti-TB drug) within nanopolymersomes (nanoPS) employing di- and tri-block poly(ethylene glycol) (PEG)-poly(ɛ-caprolactone) (PCL) based copolymers as biomaterials. The derivatives presented a number-average molecular weight between 12.2 KDa and 30.1 KDa and a hydrophobic/hydrophilic balance between 0.56 and 0.99. The nanoPS were able to enhance the apparent RIF aqueous solubility (up to 4.62 mg/mL) where the hydrodynamic diameters of the drug-loaded systems (1% w/v) were ranged between 65.8 nm and 94 nm at day 0 as determined by dynamic light scattering (DLS). Then, RIF-loaded systems demonstrated as excellent colloidal stability in aqueous media over 14 days with a spherical morphology as determined by transmission electron microscopy (TEM). Furthermore, RIF-loaded nano-sized PS promoted drug accumulation in macrophages (RAW 264.7) versus a drug solution representing promising results for a potential TB inhaled therapy. [ABSTRACT FROM AUTHOR]

Nanotechnology has emerged as a possible solution to improve phytochemicals' limitations. The objective of the present study was to encapsulate beetroot extract (BR Ext) within a chitosan (CS)-based nanogel (NG) designed via ionic crosslinking with tripolyphosphate (TPP) for betanin (Bet) delivery, mainly in the ophthalmic environment. BR Ext is rich in betanin (Bet) according to thin layer chromatography (TLC), UV-visible spectroscopy, and HPLC analysis. NG presented a monodisperse profile with a size of 166 ± 6 nm and low polydispersity (0.30 ± 0.03). ζ potential (ζ-Pot) of +28 ± 1 is indicative of a colloidally stable system. BR Ext encapsulation efficiency (EE) was 45 ± 3%. TEM, with the respective 3D-surface plots and AFM, showed spherical–elliptical-shaped NG. The BR Ext release profile was biphasic with a burst release followed by slow and sustained phase over 12 h. Mucoadhesion assay demonstrated interactions between NG with mucin. Moreover, NG provided photoprotection and pH stability to BR Ext. FRAP and ABTS assays confirmed that BR Ext maintained antioxidant activity into NG. Furthermore, in vitro assays using human retinal cells displayed absence of cytotoxicity as well as an efficient protection against injury agents (LPS and H2O2). NGs are a promising platform for BR Ext encapsulation, exerting controlled release for ophthalmological use. [ABSTRACT FROM AUTHOR]

Worldwide more than 35 million people are living with Human Immunodeficiency Virus (HIV) where 3.3 million are children. This translates in approximately 700 new daily infections in children only in 2012. Prolonged High Activity Antiretroviral Therapy (HAART) regimes could present low-patient compliance, especially in children, affecting therapeutic success. Nelfinavir mesylate (NFV) is a non-peptidic HIV-1 protease inhibitor (IP) which was the first IP recommended for pediatric use (>2 years-old). It exhibits pH-dependant aqueous solubility which results highly restricted at physiological pH values. The former represents a main clinical limitation due to the reduction on drug absorption along the small intestine after an oral administration, leading to unpredictable drug bioavailability. Moreover a liquid formulation of NFV is not available worldwide, preventing appropriate dose adjustment and more convenient administration. In this framework, the present investigation reports the development of a NFV highly concentrated aqueous formulation for a more appropriate management of pediatric anti-HIV therapy. The aim was to encapsulate NFV within d -α-tocopheryl polyethylene glycol 1000 succinate micelles to improve its aqueous solubility and its oral pharmacokinetic parameters. Results show that NFV aqueous solubility was increased up to 80.3 mg/mL. NFV-loaded micelles exhibited a hydrodynamic diameter of 5.6 nm and a spherical morphology as determined by dynamic light scattering and transmission electronic microscopy, respectively. In vitro NFV release profile demonstrated a cumulative drug release of 56% at 6 h. Finally, in vivo data showed a significant ( p < 0.01) increase of Area-Under-the-Curve between 0 and 24 h for NFV encapsulated in micelles in comparison with a NFV suspension prepared with glycerin 20% v/v and carboxymethylcellulose sodium 0.5% w/v, representing an increment on drug oral relative bioavailability of 1.71-fold. Thereby, this formulation represents an innovative nanotechnological platform to improve pediatric HIV pharmacotherapy. [ABSTRACT FROM AUTHOR]

In this work, Nevirapine (NVP) was encapsulated within three derivatives of poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) (PEO–PPO–PEO) block copolymers (Tetronic ® 904, 1107 and Pluronic ® F127) with and without the addition of three pharmaceutical cosolvents (glycerin, propylene glycol and polyethylene glycol 400) over a wider range of concentrations (0–40% v/v). Also, we evaluated the effect of addition of the cosolvents on the micellar size as determined by dynamic light scattering (DLS) measurements and transmission electron microscopy (TEM). The solubilization capacity of the systems was investigated by UV-spectrophotometry (282 nm) and the systems stability was evaluated for 1 month at 25 °C. Finally, oral bioavailability of the NVP-loaded micellar systems (2 mg/mL) was assessed in male Wistar rats (8 mg/kg) and compared with a pediatric commercially available formulation (Viramune ® ). The present study demonstrates that PEO–PPO–PEO polymeric micelles were able to enhance apparent aqueous solubility of NVP with the addition of cosolvents. Moreover, micellar nanocarriers significantly ( p < 0.05) improved the oral bioavailability of the drug versus Viramune ® . Overall results support the suitability of the strategy toward the development of an optimized NVP aqueous formulation to prevent HIV/AIDS mother-to-child transmission. [ABSTRACT FROM AUTHOR]

Abstract: More than 65 new Nd isotope analyses are presented for the vicinity of the Central Metasedimentary Belt Boundary Zone (CMBBZ) near Haliburton in the Grenville Province of Ontario, Canada. They fall into two well-defined groups, with distinct ranges of TDM model ages. These two groups comprise the CMBBZ with an average TDM age=1.46Ga, and rocks of the Central Metasedimentary Belt (CMB) with an average TDM age of 1.28Ga. However, a distinct block of crust within the CMB comprising the Dysart gneiss complex has an older model age signature (TDM age=1.40Ga) resembling the CMBBZ rather than the rift zone. The Dysart complex is surrounded by marble tectonites interspersed with elongate bodies of orthogneiss that yield young Nd model ages typical of the CMB. However, it is argued that the development of the Dysart complex as a distinct crustal block predates ductile deformation during the Grenville orogeny. Instead, the Dysart Block is thought to have rifted away from the Central Gneiss Belt to the northwest during the formation of the CMB as an ensimatic back-arc rift zone. Isotopic mapping of the Dysart block, along with the previously discovered Elzevir block, provides evidence for the geometry of the rifting process, and also has important implications for the structure of Grenville basement in eastern North America. [Copyright &y& Elsevier]

• The NUDIX proteins NUDT6 and NUDT9 localize to mitochondria. • NUDT6- and/or NUDT9-deficiency impacts mitochondrial functions. • In vitro , NUDT6 is mainly active towards NADH while NUDT9 displays a higher activity towards ADPR. The 22 members of the NUDIX (NUcleoside DIphosphate linked to another moiety, X) hydrolase superfamily can hydrolyze a variety of phosphorylated molecules including (d)NTPs and their oxidized forms, nucleotide sugars, capped mRNAs and dinucleotide coenzymes such as NADH and FADH. Beside this broad range of enzymatic substrates, the NUDIX proteins can also be found in different cellular compartments, mainly in the nucleus and in the cytosol, but also in the peroxisome and in the mitochondria. Here we studied two members of the family, NUDT6 and NUDT9. We showed that NUDT6 is expressed in human cells and localizes exclusively to mitochondria and we confirmed that NUDT9 has a mitochondrial localization. To elucidate their potential role within this organelle, we investigated the functional consequences at the mitochondrial level of NUDT6- and NUDT9-deficiency and found that the depletion of either of the two proteins results in an increased activity of the respiratory chain and an alteration of the mitochondrial respiratory chain complexes expression. We demonstrated that NUDT6 and NUDT9 have distinct substrate specificity in vitro , which is dependent on the cofactor used. They can both hydrolyze a large range of low molecular weight compounds such as NAD+(H), FAD and ADPR, but NUDT6 is mainly active towards NADH, while NUDT9 displays a higher activity towards ADPR. [ABSTRACT FROM AUTHOR]

Abstract: Tuberculosis (TB) is the second most deadly infectious disease behind the Human Immunodeficiency Virus (HIV). An effective pharmacotherapy has been available for more than 5 decades. However, the length of the treatment and the pill burden result in low patient compliance and adherence to the regimens. Nanotechnologies can overcome these basic technological drawbacks. The present work explored the molecular implications governing the encapsulation and water solubilization of RIF within flower-like micelles of poly(epsilon-caprolactone)-b-poly(ethylene glycol)-poly(epsilon-caprolactone) (PCL-PEG-PCL) block copolymers. Ten derivatives of different molecular weight and hydrophobic/hydrophilic caprolactone/ethylene oxide ratio (CL/EO) were synthesized by a fast and high-yield Microwave-Assisted Polymer Synthesis (MAPS) technique; CL/EO values are determined by taking the ratios of the number of repeating units in the PCL and the PEG segments. The aggregation behavior of the copolymers was thoroughly investigated by means of surface tension (critical micellar concentration), dynamic light scattering (size, size distribution and zeta potential) and transmission electron microscopy (morphology). In general, the greater the central PEG segment, the larger the micelles formed. The physical stability was intimately associated with the molecular weight and the composition. Then, the encapsulation of RIF in the different copolymer families was evaluated, and the physical stability of the drug-loaded aggregates characterized. The micellar size appears as the most crucial property, this phenomenon being primarily controlled by the molecular weight of the PEG central block. Having expressed this, sufficiently high CL/EO ratios (and long PCL segments) are also demanded to attain stable micellar systems with cores that are large enough to host the bulky RIF molecule. [Copyright &y& Elsevier]

Abstract: Nd isotope analyses of orthogneissic rocks were conducted in the vicinity of the Allochthon Boundary Thrust (ABT) in the Central Gneiss Belt of Ontario, Canada. Gneisses from the parautochthonous belt have relatively homogeneous Nd isotope signatures with an average TDM model age of 1.91Ga, consistent with an origin as an accreted Paleoproterozoic arc terrane (Barilia). Orthogneissic rocks from the overlying allochthonous belt have a wider range of model ages from 1.46 to 1.79Ga, consistent with a more complex geological history that may involve reworking of sedimentary material in a long-lived ensialic arc (Algonquia). The isotopic boundary between these terranes, represented by the ABT, is consistent with the distribution of distinct types of metabasic rock, previously used as a criterion for recognising rocks of the allochthonous and parautochthonous belts of the Grenville Province. However, the location of the ABT proposed on the basis of isotopic analysis has been modified from that of other workers, because Nd isotopes provide a much more detailed tool for mapping the original zone of convergence (thrusting) between allochthonous and parautochthonous terranes with distinct crustal formation ages. The isotopic boundary is also supported by field-based mapping of high-strain zones in critical areas. Other mapped shear zones may represent later extensional structures with lesser geological significance. [Copyright &y& Elsevier]

Abstract: Heart-cutting two-dimensional liquid chromatography/UV detection methods were developed to determine 2-acetyl-4-(1,2,3,4-tetrahydroxybutyl)imidazole (noted as THI) in Class III caramel colours. In the first dimension, the caramel sample diluted in water was fractionated either by reversed-phase chromatography on C18 silica packing or by ion-exchange chromatography using strong cationic exchanger (SCX) stationary phase. In each case, THI elution domain was recovered in a loop and transferred to a second column packed with porous graphitic carbon (PGC) for the selective separation of THI. From the accuracy profiles with acceptance limit fixed at 20% and β-expectation tolerance interval fixed at 90%, the two methods, C18–PGC and SCX–PGC, were validated for THI/caramel ratios included between 5–50 and 10–50ppm, respectively. Finally, the two methods were compared for the analysis of numerous caramel samples. [Copyright &y& Elsevier]

Abstract  Functional micro- and nanosized metal oxide thin film structures are very promising candidate for future gas-sensors. Their reduced size offers an increased surface to volume ratio thus improving sensitivity and sensor performance. Whilst most experimental nanostructures are produced using a bottom-up approach, a top-down sputtering technique for structuring nano-sized gas sensitive metal oxide areas is presented in this letter. Oxidised silicon wafers were used as substrates. The silicon dioxide film of 1 μm thickness was prepared by thermal oxidation in order to insulate the gas sensing elements from the substrate. The sensor chips had an overall size of (1.5 × 1.5) mm2 onto which a Ta/Pt film (20/200 nm thickness) was deposited and patterned to act as electrodes, heater and temperature sensor. In a second step micro-scaled tin dioxide layers (60 nm thick, 5 μm width) were deposited by sputtering techniques and photolithographical patterning between the platinum micro-electrodes (4 μm gap). Finally, the width of the stripes was reduced using focused ion beam technology to obtain the desired size and structure. This enables the control of the dimensions of the structures down to the resolution limit of the FIB-system which is about 10 nm. The structural and electrical characterisation of the sensors and their responses during exposure to several test gases including O2, CO, NO2 and H2O are presented as well. [ABSTRACT FROM AUTHOR]

Abstract: A solid-phase extraction coupled to liquid chromatography/tandem mass spectrometry for the determination of estrogens in sewage influent and effluent has been performed. The possibility of preparing estrogen derivatives directly on a solid-phase extraction bed in which the targeted analytes have been previously isolated and pre-concentrated was explored. This method uses an Oasis HLB column (2.1mm×20mm i.d.) for on-line sample cleanup and derivatization support, and a Sunfire C18 column (150mm×2.1mm i.d.) with a mobile phase consisting of acetonitrile–water–formic acid for separation. After sample introduction, some matrix interferences are removed by washing up SPE column with methanol–water. Phenolic hydroxyl group of estrogens is subsequently derivatized with dansyl chloride. Reaction takes place in the on-line solid-phase extraction column. The excess of reagent and other matrix interferences are then removed by a second washing. Dansylated estrogens are further back eluted and analyzed with HPLC–MS–MS. The optimized on-line protocol is emphasized owing to a low limit of quantification (1ngL−1) is achieved with only around 1mL of sample and a low sensitive MS instrument. Developed strategy has been demonstrated to be an improvement over existing methods due to its greater sensitivity and the low volume of matrix used and the total analysis time (extraction, derivatization, analysis) is less than 17min. [Copyright &y& Elsevier]

• GF and GC breads differed in eating duration and texture perception. • GF breads were crumbly, dry and sandy and were kept longer in the mouth. • Softness characterized the GC bread. • Spreads in breads increased softness perception but did not alter chewing behavior. Little is known about the oral processing behavior of gluten-free (GF) products. This study investigated the oral processing behavior of one commercial GF bread and one gluten-containing (GC) equivalent with and without spreads. Oral processing parameters were determined through video recording and the predominant texture attributes were accessed using a check-all-that-apply test. The GF bread was perceived crumbly, dry and sandy and had a longer eating duration than the GC bread, which was perceived soft, spongy, pasty and sticky. Results suggest that the structure of the GF bread was easily fragmented during mastication and a longer period in the mouth was required to prepare a cohesive bolus for swallowing. The addition of spreads increased softness perception but did not affect chewing behavior. Oral processing behavior of GF products should be further investigated to understand how eating rate, satiation responses and food intake can be modulated in GF products. [ABSTRACT FROM AUTHOR]

Background/Objective: World Health Organization latest statistics state that 17% of infectious diseases are transmitted by vectors, causing more than 700,000 deaths each year. Particularly, dengue (DENV), Zika (ZIKV) and yellow fever (YFV) viral infections have generated international awareness due to their epidemic proportion and risks of international spread. In this framework, the repositioning strategy of Efavirenz (EFV) represents a key clinical feature to improve different antiviral therapies. Therefore, the development of Soluplus®-based nanomicelles (NMs) loaded with EFV (10 mg/mL) for optimized oral pharmacotherapy against ZIKV, DENV and YFV infections was investigated. Methods: EFV-NMs were obtained by an acetone diffusion technique. Micellar size and in vitro micellar interaction with mucin were assessed by dynamic light scattering. In vitro cytocompatibility was investigated in A549 and Vero cells and micellar in vitro antiviral activity against ZIKV, DENV and YFV was evaluated. In vivo oral bioavailability and histological studies were assessed in Wistar rats. Results: EFV encapsulation within Soluplus® NMs increased the drug's apparent aqueous solubility up to 4803-fold with a unimodal micellar size distribution and a micellar size of ~90 nm at 25 and 37 °C. Micellar in vitro interaction with mucin was also assessed in a pH range of 1.2–7.5 and its storage micellar physicochemical stability at 4 °C was confirmed over 2 years. In vitro cytocompatibility assays in A549 and Vero cells confirmed that EFV micellar dispersions resulted in safe nanoformulations. Interestingly, EFV-loaded NMs exhibited significantly higher in vitro antiviral activity compared with EFV solution for all the tested flaviviruses. In addition, the selectivity index (SI) values reveal that EFV-loaded NMs exhibited considerably more biological efficacy compared to EFV solution in A549 and Vero cell lines and for each viral infection (SI > 10). Further, the drug pharmacokinetics parameters were enhanced after the oral administration of EFV-loaded NMs, being biocompatible by not causing damage in the gastrointestinal segments. Conclusions: Overall, our EFV nanoformulation highlighted its potential as a novel drug delivery platform for optimized ZIKV, DENV and YFV antiviral therapy. [ABSTRACT FROM AUTHOR]

Metabolism is a fundamental cellular process that can become harmful for cells by leading to DNA damage, for instance by an increase in oxidative stress or through the generation of toxic byproducts. To deal with such insults, cells have evolved sophisticated DNA damage response (DDR) pathways that allow for the maintenance of genome integrity. Recent years have seen remarkable progress in our understanding of the diverse DDR mechanisms, and, through such work, it has emerged that cellular metabolic regulation not only generates DNA damage but also impacts on DNA repair. Cancer cells show an alteration of the DDR coupled with modifications in cellular metabolism, further emphasizing links between these two fundamental processes. Taken together, these compelling findings indicate that metabolic enzymes and metabolites represent a key group of factors within the DDR. Here, we will compile the current knowledge on the dynamic interplay between metabolic factors and the DDR, with a specific focus on cancer. We will also discuss how recently developed high-throughput technologies allow for the identification of novel crosstalk between the DDR and metabolism, which is of crucial importance to better design efficient cancer treatments. [ABSTRACT FROM AUTHOR]

Background: Previous studies employing polymeric micelles and molecular imaging for in vivo nanosystem characterization have led to the development of radionanoprobes (RNPs) designed for diagnosing and monitoring therapeutic interventions in preclinical oncology research, specifically within breast and colon cancer models. These models exhibit high GLUT1 expression on tumor cells and VEGFR expression on the tumor vasculature. We aimed to enhance the tumor-targeting specificity of these RNPs by functionalizing micelles with glucose and bevacizumab. The choice of 99mTc to label the nanoprobes is based on its availability and that direct labeling method is a widespread strategy to prepare radiopharmaceuticals using cold reagents and a 99Mo/99mTc generator. Soluplus® is an attractive polymer for synthesizing micelles that also allows their functionalization. With all the above, the objective of this work was to design, develop and characterize nanoprobes based on polymeric micelles and radiolabeled with 99mTc for the characterization of biological processes associated to the diagnosis, prognosis and monitoring of animal models of breast and colon cancer in preclinical research using molecular images. Results: Four RNPs ([99mTc]Tc-Soluplus®, [99mTc]Tc-Soluplus®+TPGS, [99mTc]Tc-Soluplus®+glucose and [99mTc]Tc-Soluplus®+bevacizumab) were produced with high radiochemical purity (> 95% in all cases) and stability in murine serum for up to 3 h. The RNPs maintained the 100 nm size of the Soluplus® polymeric micelles even when they were functionalized and labeled with 99mTc. The image acquisition protocol enabled the visualization of tumor uptake in two cancer experimental models using the assigned RNPs. In vivo biological characterization showed signal-to-background ratios of 1.7 ± 0.03 for [99mTc]Tc-Soluplus®+TPGS, 1.8 ± 0.02 for [99mTc]Tc-Soluplus®, and 2.3 ± 0.02 for [99mTc]Tc-Soluplus®+glucose in the breast cancer model, and 1.8 ± 0.04 for [99mTc]Tc-Soluplus® and 3.7 ± 0.07 for [99mTc]Tc-Soluplus®+bevacizumab in the colon cancer model. Ex vivo biodistribution, showed that the uptake of the tumors, regardless of the model, is < 2% IA/g while the blood activity concentration is higher, suggesting that the enhanced permeability and retention effect (EPR) would be one of the mechanisms involved in imaging tumors in addition to the active targeting of RNPs. Conclusions: Soluplus®-based polymeric micelles provide a promising nanotechnological platform for the development of RNPs. The functionalization with glucose and bevacizumab enhances tumor specificity enabling effective imaging and monitoring of cancer in animal models. [ABSTRACT FROM AUTHOR]

Rivers and streams of rural areas of the Buenos Aires Province contain variable concentrations of heavy metals and glyphosate. In this study, the toxicity of the metals Cu, Pb and Zn, the herbicide glyphosate (active product and ATANOR® formulation) and their binary combinations, was assessed on two green algae species (the standard species Raphidocelis subcapitata and a native strain of Scenedesmus acutus isolated from Burgos Stream [Buenos Aires]). The bioassays were carried out applying a concentration range of 0.5 mg/L - 20 mg/L, in incubations lasting 7 days after which the algal density was estimated. To obtain the effective concentrations inhibiting 10, 20 and 50% of the growth (EC10, EC20 and EC50) of individual substances and their combinations, the percentage of growth inhibition (%I) was modeled as a function of each concentration by a nonlinear fit. According to the EC50 obtained for each species, the toxicity of Cu and Zn was higher in R. subcapitata (7.47±2.14 and 6.51±2.26 mg/L, respectively) than in S. acutus (10.90±3.75 and> 20 mg/L), while Pb and glyphosate active compound were not toxic for neither of the two strains. ATANOR® glyphosate was toxic only to R. subcapitata (EC50=12.00±3.10 mg/L). According to the EC10 and EC20 values of the individual substances and the binary combinations, S. acutus showed higher sensitivity than R. subcapitata. From the analysis of toxic units (TU), the combinations Cu+Zn, Cu+glyphosate ATANOR® and Zn+glyphosate ATANOR® showed antagonistic effects on R. subcapitata (according to the TU values obtained from EC20 and EC50), while the Cu+Pb and Cu+Zn combinations showed synergistic and antagonistic effects, respectively, on S. acutus (according to the TU values obtained from the EC20). These results highlight the importance of conducting bioassays of toxic substances using native algal strains which allow inferring potential effects in native communities and food webs. [ABSTRACT FROM AUTHOR]

The individual and combined toxicities of chlortetracycline (CTC), oxytetracycline (OTC) and enrofloxacin (ENF) have been examined in two green algae representative of the freshwater environment, the international standard strain Pseudokichneriella subcapitata and the native strain Ankistrodesmus fusiformis . The toxicities of the three antibiotics and their mixtures were similar in both strains, although low concentrations of ENF and CTC + ENF were more toxic in A. fusiformis than in the standard strain. The toxicological interactions of binary mixtures were predicted using the two classical models of additivity: Concentration Addition (CA) and Independent Action (IA), and compared to the experimentally determined toxicities over a range of concentrations between 0.1 and 10 mg L −1 . The CA model predicted the inhibition of algal growth in the three mixtures in P. subcapitata , and in the CTC + OTC and CTC + ENF mixtures in A. fusiformis . However, this model underestimated the experimental results obtained in the OTC + ENF mixture in A. fusiformis . The IA model did not predict the experimental toxicological effects of the three mixtures in either strain. The sum of the toxic units (TU) for the mixtures was calculated. According to these values, the binary mixtures CTC + ENF and OTC + ENF showed an additive effect, and the CTC + OTC mixture showed antagonism in P. subcapitata , whereas the three mixtures showed synergistic effects in A. fusiformis . Although A. fusiformis was isolated from a polluted river, it showed a similar sensitivity with respect to P. subcapitata when it was exposed to binary mixtures of antibiotics. [ABSTRACT FROM AUTHOR]

Background: Ursodeoxycholic acid (UDCA) is a therapeutic agent used for the treatment of cholestatic hepatobiliary diseases in pediatric patients. It is a bile acid that presents high lipophilicity, and it belongs to Class II of the Biopharmaceutical Classification System (BCS), which exhibits low water solubility and high intestinal permeability, which leads to poor oral absorption. The objective of this work was to design and optimize UDCA nanosuspensions by means of the precipitation-ultrasonication method to improve the solubility, dissolution, and oral bioavailability of UDCA. Methods: A three-level, three-factor Box–Behnken design was used to optimize formulation variables and obtain uniform, small-particle-size UDCA nanosuspensions. The independent variables were: stabilizer percentage (X1), amplitude (X2), and sonication time (X3), and the dependent variable was the particle size (Y1). In the precipitation–ultrasonication method, UDCA was dissolved in acetone:PEG 400 (1:1 v/v) and quickly incorporated into the antisolvent (pre-cooled aqueous dispersion of HPMC E-15 0.3%), by means of intense sonication at 50 W for 5 min, controlling temperature through an ice water bath. The lyophilization efficacy was evaluated by means of a cryoprotective efficacy test, working with 10% maltose at −80 °C. The nanosuspensions were characterized by dynamic light scattering (DLS), X-ray diffraction, and scanning electron microscopy (SEM). The physicochemical stability was determined at 25 °C and 4 °C at 7, 14, 30, and 60 days, and the UDCA content was analyzed via HPLC-UV. An in vitro dissolution assay and an oral bioavailability study were performed in male Wistar rats. Results: A significant impact was achieved in the optimized nanosuspension with 0.3% (stabilizer), 50 W (amplitude), and 5 min (sonication time), with a particle size of 352.4 nm, PDI of 0.11, and zeta potential of −4.30 mV. It presented adequate physicochemical stability throughout the study and the UDCA content was between 90% and 110%. In total, 86% of UDCA was dissolved in the in vitro dissolution test. The relative oral bioavailability was similar without significant statistical differences when comparing the lyophilized nanosuspension and the commercial tablet, the latter presenting a more erratic behavior. The pharmacokinetic parameters of the nanosuspension and the commercial tablet were Tmax (1.0 ± 0.9 h vs. 2.0 ± 0.8 h, respectively), Cmax (0.558 ± 0.118 vs. 0.366 ± 0.113 µM, respectively), ΔCmax (0.309 ± 0.099 vs. 0.232 ± 0.056, respectively), AUC (4.326 ± 0.471 vs. 2.188 ± 0.353 µg/mL.h, respectively, p < 0.02), and IAUC0–24h (2.261 ± 0.187 µg/mL.h vs. 1.924 ± 0.440 µg/mL.h, respectively). Conclusions: The developed nanosuspension presents an appropriate dosage and administration for pediatric patients. On the other hand, it exhibits an adequate absorption and UDCA oral bioavailability. [ABSTRACT FROM AUTHOR]

Introduction In recent years, nanomedicines have raised as a powerful tool to improve prevention, diagnosis and treatment of different pathologies. Among the most well investigated biomaterials, D-α-tocopheryl polyethylene glycol succinate (also known as TPGS) has been on the spot for the last decade. We therefore designed a method to biologically characterize TPGS-based nanomicelles by labeling them with 99m Tc. Methods Labeling process was performed by a direct method. The average hydrodynamic diameter of TPGS nanomicelles was measured by dynamic light scattering and radiochemical purity was assessed by thin layer chromatography. Imaging: a dynamic study was performed during the first hour post radioactive micelles administration in a gamma camera (TcO 4 − was also administered for comparative purposes). Then two static images were acquired in ventral position: 1 h and 12 h post injection. Blood pharmacokinetics of 99m Tc-TPGS during 24 h was performed. Results Images revealed whole body biodistribution at an early and delayed time and semiquantification was performed in organs of interest (%Total counts: soft tissue 6.1 ± 0.5; 3.9 ± 0.1, Bone 1.2 ± 0.2; 1 ± 0.1, Heart 1.5 ± 0.6; 0.7 ± 0.3, Kidneys 16.6 ± 1.3; 26.5 ± 1.7, Liver 8.6 ± 1.1; 11.1 ± 0.1 for 1 and 12 h post injection respectively). Conclusion This work demonstrated that TPGS based nanomicelles are susceptible to be radiolabeled with 99m Tc thus they can be used to perform imaging studies in animal models. Moreover radiolabeling of these delivery nano systems reveals their possibility to be used as diagnostic agents in the near future. [ABSTRACT FROM AUTHOR]

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Currently, paclitaxel (PTX) represents the first-line therapy for TNBC; however it presents a hydrophobic behavior and produces severe adverse effects. The aim of this work is to improve the therapeutic index of PTX through the design and characterization of novel nanomicellar polymeric formulations composed of a biocompatible copolymer Soluplus® (S), surface-decorated with glucose (GS), and co-loaded either with histamine (HA, 5 mg/mL) and/or PTX (4 mg/mL). Their micellar size, evaluated by dynamic light scattering, showed a hydrodynamic diameter between 70 and 90 nm for loaded nanoformulations with a unimodal size distribution. Cytotoxicity and apoptosis assays were performed to assess their efficacy in vitro in human MDA-MB-231 and murine 4T1 TNBC cells rendering optimal antitumor efficacy in both cell lines for the nanoformulations with both drugs. In a model of TNBC developed in BALB/c mice with 4T1 cells, we found that all loaded micellar systems reduced tumor volume and that both HA and HA-PTX-loaded SG micelles reduced tumor weight and neovascularization compared with the empty micelles. We conclude that HA-PTX co-loaded micelles in addition to HA-loaded formulations present promising potential as nano-drug delivery systems for cancer chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract: Odor of food constitutes one of the main drivers of the consumers' acceptance. Its characterization thus represents a main challenge for the food industry. Gas chromatography/olfactometry (GC/O) constitutes an intersection between physico-chemical and sensory studies by using the human nose as a detector to evaluate the odor properties of volatile compounds. As GC/O does not make possible the evaluation of mixture of odorants, we propose an original approach to evaluate the impact of compounds on the typicality of caramel aroma by considering their odor qualities in mixtures. Indeed, the present study relies on the main hypothesis that the qualitative properties are as important as quantitative one with regard to the typicality. First, previously identified odorant compounds were distributed into eight odor categories using a classification wheel established from our GC/O descriptors. Each category was reconstituted separately and then a Whole Mixture was obtained by mixing all categories in specific proportions and validated by sensory analyses. Second, the impact of specific odor notes on the caramel typicality was studied individually by omission and addition tests and a 24 factorial design was built to investigate their interactions in complex mixtures. The caramel typicality results from a complex balance between fruity, vegetal, sharp, nutty and caramel notes arising from the presence of carboxylic acids, aldehydes, oxygenated heterocyclic compounds, ketones and carbocyclic compounds. This study brings new clues to understand the contribution of the caramel volatile compounds to its odor while proposing a promising experimental approach to understand the contribution of volatile compounds to the odor of complex products. [Copyright &y& Elsevier]

Among respiratory infections, tuberculosis was the second deadliest infectious disease in 2020 behind COVID-19. Inhalable nanocarriers offer the possibility of actively targeting anti-tuberculosis drugs to the lungs, especially to alveolar macrophages (cellular reservoirs of the Mycobacterium tuberculosis). Our strategy was based on the development of a mannose-decorated micellar nanoformulation based in Soluplus® to co-encapsulate rifampicin and curcumin. The former is one of the most effective anti-tuberculosis first-line drugs, while curcumin has demonstrated potential anti-mycobacterial properties. Mannose-coated rifampicin (10 mg/mL)–curcumin (5 mg/mL)-loaded polymeric micelles (10% w/v) demonstrated excellent colloidal properties with micellar size ~108 ± 1 nm after freeze-drying, and they remain stable under dilution in simulated interstitial lung fluid. Drug-loaded polymeric micelles were suitable for drug delivery to the deep lung with lung accumulation, according to the in vitro nebulization studies and the in vivo biodistribution assays of radiolabeled (99mTc) polymeric micelles, respectively. Hence, the nanoformulation did not exhibit hemolytic potential. Interestingly, the addition of mannose significantly improved (5.2-fold) the microbicidal efficacy against Mycobacterium tuberculosis H37Rv of the drug-co-loaded systems in comparison with their counterpart mannose-free polymeric micelles. Thus, this novel inhaled nanoformulation has demonstrated its potential for active drug delivery in pulmonary tuberculosis therapy. [ABSTRACT FROM AUTHOR]

Along with the AgNP applications development, the concern about their possible toxicity has increasingly gained attention. As the respiratory system is one of the main exposure routes, the aim of this study was to evaluate the harmful effects developed in the lung after an acute AgNP exposure. In vivo studies using Balb/c mice intranasally instilled with 0.1 mg AgNP/kg b.w, were performed. 99mTc-AgNP showed the lung as the main organ of deposition, where, in turn, AgNP may exert barrier injury observed by increased protein content and total cell count in BAL samples. In vivo acute exposure showed altered lung tissue O 2 consumption due to increased mitochondrial active respiration and NOX activity. Both O 2 consumption processes release ROS triggering the antioxidant system as observed by the increased SOD, catalase and GPx activities and a decreased GSH/GSSG ratio. In addition, increased protein oxidation was observed after AgNP exposure. In A549 cells, exposure to 2.5 μg/mL AgNP during 1 h resulted in augment NOX activity, decreased mitochondrial ATP associated respiration and higher H 2 O 2 production rate. Lung 3D tissue model showed AgNP-initiated barrier alterations as TEER values decreased and morphological alterations. Taken together, these results show that AgNP exposure alters O 2 metabolism leading to alterations in oxygen metabolism lung toxicity. AgNP-triggered oxidative damage may be responsible for the impaired lung function observed due to alveolar epithelial injury. [Display omitted] • Exposure to AgNP altered lung tissue O 2 consumption due to increased mitochondrial active respiration and NOX activity. • Increased NOX activity and mitochondrial H 2 O 2 production rate led to oxidative damage. • Lung 3D tissue model showed AgNP-initiated barrier alterations as TEER values decreased. • Oxidative damage may be responsible for the impaired lung function observed due to alveolar epithelial injury. [ABSTRACT FROM AUTHOR]

We present an optical gas sensor based on the classical nondispersive infrared technique using ultracompact photonic crystal gas cells. The ultracompact device is conceptually based on low group velocities inside a photonic crystal gas cell and low-reflectivity antireflection layers coupling light into the device. Experimentally, an enhancement of the CO2 infrared absorption by a factor of 2.6 to 3.5 as compared to an empty cell, due to slow light inside a 2D silicon photonic crystal gas cell, was observed; this is in excellent agreement with numerical simulations. We show that, theoretically, for an optimal design enhancement factors of up to 60 are possible in the region of slow light. However, the overall transmission of bulk photonic crystals, and thus the performance of the device, is limited by fluctuations of the pore diameter. Numerical estimates suggest that the positional variations and pore diameter fluctuations have to be well below 0.5% to allow for a reasonable transmission of a 1 mm device. [ABSTRACT FROM AUTHOR]

[Display omitted] The present investigation was focused on the development of Soluplus®-based nanomicelles (NMs) (10 % w/v) loaded with Efavirenz (EFV) (5 mg/mL) and Curcumin (natural bio-enhancer) (CUR) (5, 10 and 15 mg/mL) to improve the oral bioavalability of EFV. Micellar formulations were obtained employing an acetone-diffusion technique. Apparent aqueous solubility was increased up to ∼1250-fold and 25,000-fold for EFV and CUR, respectively. Drug-loaded nanoformulations showed an excellent colloidal stability with unimodal size distribution and PDI values < 0.30. In vitro drug release was 41.5 % (EFV) and 2.6 % (CUR) from EFV-CUR-NMs over 6 h in simulated gastrointestinal fluids. EFV-CUR-loaded NMs resulted as safe nanoformulations according to the in vitro cytocompatibility assays in Caco-2 cells. Furthermore, CUR bio-enhancer activity was demonstrated for those nanoformulations. A CUR concentration of 15 mg/mL produced a significant (p < 0.05) increment (2.64-fold) of relative EFV oral bioavailability. Finally, the active role of the lymphatic system in the absorption process of EFV, after its oral administration was assessed in a comparative pharmacokinetic study in presence and absence of cycloheximide, a lymphatic transport inhibitor. Overall our EFV-CUR-NMs denoted their potential as a novel nanotechnological platform, representing a step towards an optimized "nano-sized" therapy for AIDS patients. [ABSTRACT FROM AUTHOR]

Abstract Doxorubicin (DOX) hydrochloride is a powerful anthracycline antibiotic used for the treatment of various types of malignancies, particularly ovarian and metastatic breast cancer. However, DOX presents severe side effects, such as hepatotoxicity, nephrotoxicity, dose-limiting myelosuppression, brain damage and cardiotoxicity. A liposomal formulation, Doxil®, was approved by the FDA, which has managed to reduce the number of cardiac events in patients with metastatic breast cancer. However, in comparison to free DOX, Doxil® has not shown significant improvements regarding survival. We have previously designed DOX-loaded mixed micelles (MMDOX) composed of D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and Tetronic® T1107. To assess the potential toxic effects of this novel formulation, in this work the zebrafish (Danio rerio) model was used to evaluate its in vivo toxicity and teratogenicity. This study evaluated and compared the effects of DOX exposure from different formulations (free DOX, MMDOX and Doxil®) on the swimming activity, morphological alterations, cardiac rhythm, lethality rate and DOX biodistribution. MMDOX showed lower lethal effects, morphological alterations and neurotoxic effects than the free drug. This study shows the potential of the MMDOX to be an effective DOX-delivery system because it could reduce the side effects. Graphical abstract Unlabelled Image Highlights • The in vivo toxicity of three DOX formulations was studied on a zebrafish model. • DOX-loaded mixed micelles were less cardiotoxic than free DOX. • DOX-loaded mixed micelles presented less morphological alterations than free DOX. • DOX-loaded mixed micelles exhibited lower neurotoxic effects than free DOX. • The encapsulation of DOX into mixed micelles reduced the toxic effects of free DOX. [ABSTRACT FROM AUTHOR]

Shiga toxin producing Escherichia coli (STEC) are foodborne pathogens that release Shiga toxin (Stx), virulence factor responsible for the development of Hemolytic Uremic Syndrome (HUS). Stx causes endothelial cell damage, which leads to platelets deposition and thrombi formation within the microvasculature. It has been described that Stx activates blood cells and induces the shedding of proinflammatory and prothrombotic microvesicles (MVs) containing the toxin. In this sense, it has been postulated that MVs containing Stx2 (MVs-Stx2+) can contribute to the physiopathology of HUS, allowing Stx2 to reach the target organs while evading the immune system. In this work, we propose that circulating MVs-Stx2+ can be a potential biomarker for the diagnosis and prognosis of STEC infections and HUS progression. We developed a rat HUS model by the intraperitoneal injection of a sublethal dose of Stx2 and observed: decrease in body weight, increase of creatinine and urea levels, decrease of creatinine clearance and histological renal damages. After characterization of renal damages, we investigated circulating total MVs and MVs-Stx2+ by flow cytometry at different times after Stx2 injection. Additionally, we evaluated the correlation of biochemical parameters such as creatinine and urea in plasma with MVs-Stx2+. As a result, we found a significant circulation of MVs-Stx2+ at 72 and 96 h after Stx2 injection, nevertheless no correlation with creatinine and urea plasma levels were detected. Our results suggest that MVs-Stx2+ may be an additional biomarker for the characterization and diagnosis of HUS progression. A further analysis is required in order to validate MVs-Stx2+ as biomarker of the disease. [Display omitted] • A rat model of HUS was established with pure Stx2. • Total circulating microvescicles were increased in Stx2 treated rats. • Circulating MVs containing Stx2 (MVs-Stx2+) were detected in Stx2 treated rats by flow cytometry. • Biochemical parameters of disease do not correlate with MVs-Stx2+ amount. • Detection of circulating MVs-Stx2+ in patients may be useful for diagnosis and predictive for severity of disease. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) is used as a “first-line” antineoplastic drug in ovarian and metastatic breast cancer. However, serious side effects, such as cardiotoxicity have been reported after DOX intravenous administration. Hence, we investigated different micelle-former biomaterials, as Soluplus ® , Pluronic F127, Tetronic T1107 and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) to develop a potential mixed micellar nanocarrier for DOX delivery. Since DOX hydrochloride is a poor candidate to be encapsulated inside the hydrophobic core of the mixed micelles, we assayed a hydrophobic complex between DOX and sodium deoxycholate (NaDC) as an excellent candidate to be encapsulated within polymeric micelles. The combination of T1107:TPGS (1:3, weight ratio) demonstrated the best physicochemical properties together with a high DL capacity (6.43% w/v). Particularly, DOX in vitro release was higher at acidic tumour microenvironment pH value (5.5) than at physiological counterpart (7.4). The hydrodynamic diameter of the DOX/NaDC-loaded mixed micellar system was 10.7 nm (PDI = 0.239). The in vitro cytotoxicity of the mixed micellar formulation resulted significantly (p < 0.05) higher than Doxil ® against ovarian (SKOV-3) and triple-negative breast cancer cells (MDA-MB- 231). Further, the in vitro cellular uptake assays demonstrated a significant increment (p < 0.05) of the DOX intracellular content for the mixed micelles versus Doxil ® for both, SKOV-3 (at 2, 4 and 6 h of incubation) and MDA-MB-231 (at 4 h of incubation) cells. These findings suggest that T1107:TPGS (1:3) mixed micelles could be employed as a potential nanotechnological platform for drug delivery of DOX. [ABSTRACT FROM AUTHOR]

In recent years, the nanotechnology has offered researchers the opportunity to solve the problems caused by the vehicle of the standard and first formulation of paclitaxel (Taxol ® ), while maximizing the proven antineoplastic activity of the drug against many solid tumors. Hence, different types of nanocarriers have been employed to improve the efficacy, safety, physicochemical properties and pharmacokinetic/pharmacodynamic profile of this drug. To date, paclitaxel is the unique drug that is marketed in three different nanoplatforms for its parenteral delivery: polymeric nanoparticles (Abraxane ® ), liposomes (Lipusu ® ), and polymeric micelles (Genexol ® , Nanoxel ® and Paclical ® ). Indeed, a fourth nanocarrier might be available soon, because phase III studies of Opaxio™, a polymeric-conjugated, are near completion. Furthermore, other several nanoformulations are currently in various stages of clinical trials. Therefore, it is only through the critical analysis of clinical evidence from these studies that we can get a more concrete idea of what has been achieved with pharmaceutical nanotechnology so far. This review attempts to summarize current information available regarding the clinical status and the physicochemical characteristic of different nanocarriers for paclitaxel delivery in cancer therapy. We present an overview of the preclinical and clinical data of these systems including their pharmacokinetics, dose and administration, adverse events and clinical efficacy. [ABSTRACT FROM AUTHOR]

Objectives Carvedilol ( CAR) is a poorly water-soluble beta-blocker. Its encapsulation within nanomicelles ( NMs) could improve drug solubility and its oral bioavailability, allowing the development of a paediatric liquid CAR formulation with commercially available copolymers: D-α-tocopheryl polyethylene glycol 1000 succinate ( TPGS) and poly(vinyl caprolactam)-poly(vinyl acetate)-poly(ethylene glycol) (Soluplus®). Methods Drug-loaded NMs were prepared by copolymer and CAR dispersion in distilled water. Micellar size and morphology were characterized by dynamic light scattering and transmission electron microscopy, respectively. In-vitro drug permeation studies were evaluated by conventional gut sac method. In-vivo CAR oral bioavailability from NMs dispersions and drug control solution was evaluated in Wistar rats. Key findings Carvedilol apparent aqueous solubility was increased (up to 60.4-folds) after its encapsulation within NMs. The micellar size was ranged between 10.9 and 81.9 nm with a monomodal size distribution. There was a significant enhancement of CAR relative oral bioavailability for both copolymers vs a micelle-free drug solution ( P < 0.05). This improvement was higher for TPGS-based micelles (4.95-fold) in accordance with the in-vitro CAR permeation results. Conclusions The present investigation demonstrates the development of highly concentrated CAR liquid micellar formulation. The improvement on drug oral bioavailability contributes to the potential of this NMs formulation to enhance CAR paediatric treatment. [ABSTRACT FROM AUTHOR]