Bisphenol A and cardiometabolic risk in adolescents: Data from the Generation XXI cohort.

BACKGROUND AND AIMS: Bisphenol A (BPA), an endocrine disruptor widely used in food contact materials, has been linked to a worse health profile. This study intends to estimate the association between BPA exposure and cardiometabolic patterns at adolescence. METHODS AND RESULTS: Data from the Portuguese population-based birth cohort Generation XXI at the age of 13 were used (n = 2386 providing 3-day food diaries and fasting blood samples). BPA exposure was measured in 24-h urine from a subsample (n = 206) and then predicted in all participants using a random forest method and considering dietary intake from diaries. Three cardiometabolic patterns were identified (normal, modified lipid profile and higher cardiometabolic risk) using a probabilistic Gaussian mixture model. Multinomial regression models were applied to associate BPA exposure (lower, medium, higher) and cardiometabolic patterns, adjusting for confounders. The median BPA exposure was 1532 ng/d, corresponding to 29.4 ng/kg/d. Adolescents higher exposed to BPA (compared to medium and lower levels) had higher BMI z-score (kg/m2) (0.68 vs. 0.39 and 0.52, respectively; p = 0.008), higher levels of body fat (kg) (16.3 vs. 13.8 and 14.6, respectively; p = 0.002), waist circumference (76.2 vs. 73.7 and 74.9, respectively; p = 0.026), insulinemia (ug/mL) (14.1 vs. 12.7 and 13.1, respectively; p = 0.039) and triglyceridemia (mg/dL) (72.7 vs. 66.1 and 66.5, respectively; p = 0.030). After adjustment, a significant association between higher BPA and a higher cardiometabolic risk pattern was observed (OR: 2.55; 95%CI: 1.41, 4.63). CONCLUSION: Higher BPA exposure was associated with a higher cardiometabolic risk pattern in adolescents, evidencing the role of food contaminants in health.

Behavior of diclofenac from contaminated fish after cooking and in vitro digestion.

BACKGROUND: Seafood consumers are widely exposed to diclofenac due to the high contamination levels often present in aquatic organisms. It is a potential risk to public health due its endocrine disruptor properties. Limited information is available about diclofenac behavior after food digestion to enable a more realistic scenario of consumer exposure. This study aimed to evaluate cooking effects on diclofenac levels, and determine diclofenac bioaccessibility by an in vitro digestion assay, using commercial fish species (seabass and white mullet) as models. The production of the main metabolite 4'-hydroxydiclofenac was also investigated. Fish hamburgers were spiked at two levels (150 and 1000 ng g-1) and submitted to three culinary treatments (roasting, steaming and grilling). RESULTS: The loss of water seems to increase the diclofenac levels after cooking, except in seabass with higher levels. The high bioaccessibility of diclofenac (59.1-98.3%) observed in both fish species indicates that consumers' intestines are more susceptible to absorption, which can be worrisome depending on the level of contamination. Contamination levels did not affect the diclofenac bioaccessibility in both species. Seabass, the fattest species, exhibited a higher bioaccessibility of diclofenac compared to white mullet. Overall, cooking decreased diclofenac bioaccessibility by up to 40% in seabass and 25% in white mullet. The main metabolite 4'-hydroxydiclofenac was not detected after cooking or digestion. CONCLUSION: Thus, consumption of cooked fish, preferentially grilled seabass and steamed or baked white mullet are more advisable. This study highlights the importance to consider bioaccessibility and cooking in hazard characterization studies. © 2024 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Astaxanthin impact on brain: health potential and market perspective.

Nowadays, there is an emergent interest in new trend-driven biomolecules to improve health and wellbeing, which has become an interesting and promising field, considering their high value and biological potential. Astaxanthin is one of these promising biomolecules, with impressive high market growth, especially in the pharmaceutical and food industries. This biomolecule, obtained from natural sources (i.e., microalgae), has been reported in the literature to have several beneficial health effects due to its biological properties. These benefits seem to be mainly associated with Astaxanthin's high antioxidant and anti-inflammatory properties, which may act on several brain issues, thus attenuating symptoms. In this sense, several studies have demonstrated the impact of astaxanthin on a wide range of diseases, namely on brain disorders (such as Alzheimer's disease, Parkinson, depression, brain stroke and autism). Therefore, this review highlights its application in mental health and illness. Furthermore, a S.W.O.T. analysis was performed to display an approach from the market/commercial perspective. However, to bring the molecule to the market, there is still a need for more studies to increase deep knowledge regarding the real impact and mechanisms in the human brain.HIGHLIGHTSAstaxanthin has been mainly extracted from the algae Haematococcus pluvialisAstaxanthin, bioactive molecule with high antioxidant and anti-inflammatory propertiesAstaxanthin has an important protective effect on brain disordersAstaxanthin is highly marketable, mainly for food and pharmaceutical industries.

Emerging mycotoxins in infant and children foods: A review.

A proper nutrition is crucial for children's healthy development. Regardless of the usual recommendations to follow a varied diet, some foods can be a source of toxic natural contaminants such as mycotoxins, potent secondary metabolites produced by filamentous fungi. In addition to the most well-known mycotoxins, many of which are subject to tight regulation regarding the maximum levels allowed in different types of food, there is a large group of mycotoxins, the so-called emerging mycotoxins, about which less knowledge has already been acquired, which have gradually been the target of interest from the scientific community due to their prevalence in most foodstuffs, particularly in cereals and cereal-based products. Alternariol and his metabolite alternariol mono-methyl ether, beauvericin, citrinin, culmorin, enniatins, ergot alkaloids, fusaproliferin, kojic acid, moniliformin, sterigmatocystin, tentoxin and tenuazonic acid are the most representative of them. The current review gathered the information of the last ten years that have been published on the levels of emerging mycotoxins in food products dedicated for infants and children. European Union countries are responsible for most of the reported studies, which showed levels that can reach hundreds of mg/kg.

Pesticide residues in herbs and their transfer for infusions.

In this work, a cost-effective gas chromatography-mass spectrometry method was validated for the analysis of twenty-five pesticide residues in herbs and infusions using a quick, easy, cheap, effective, rugged, and safe procedure or a dispersive liquid-liquid microextraction method, respectively. Figures of merit of the method showed good accordance with current guidelines. From the 58 herb samples studied (pertaining to 20 different species), 80% presented at least one detectable pesticide, with 62% of them above the maximum residual level. Results showed that pesticide residues from naturally contaminated herbs were not transferred at a significant rate to the herbal infusions. When a control assay was conducted by spiking a blank herb sample with a large amount of each pesticide (7 mg/L) 15 analytes were detected below the limit of quantification in the infusion.

Potential Biological Properties of Lycopene in a Self-Emulsifying Drug Delivery System.

In recent years, lycopene has been highlighted due to its antioxidant and anti-inflammatory properties, associated with a beneficial effect on human health. The aim of this study was to advance the studies of antioxidant and anti-inflammatory mechanisms on human keratinocytes cells (HaCaT) of a self-emulsifying drug delivery system (SEDDS) loaded with lycopene purified from red guava (nanoLPG). The characteristics of nanoLPG were a hydrodynamic diameter of 205 nm, a polydispersity index of 0.21 and a zeta potential of -20.57, providing physical stability for the nanosystem. NanoLPG demonstrated antioxidant capacity, as shown using the ORAC methodology, and prevented DNA degradation (DNA agarose). Proinflammatory activity was evaluated by quantifying the cytokines TNF-α, IL-6 and IL-8, with only IL-8 showing a significant increase (p < 0.0001). NanoLPG showed greater inhibition of the tyrosinase and elastase enzymes, involved in the skin aging process, compared to purified lycopene (LPG). In vitro treatment for 24 h with 5.0 µg/mL of nanoLPG did not affect the viability of HaCaT cells. The ultrastructure of HaCaT cells demonstrated the maintenance of morphology. This contrasts with endoplasmic reticulum stresses and autophagic vacuoles when treated with LPG after stimulation or not with LPS. Therefore, the use of lycopene in a nanoemulsion may be beneficial in strategies and products associated with skin health.

Gastrointestinal bioaccessibility and fiber mitigation of tropane alkaloids assessed on tea and cookies by in vitro digestion.

BACKGROUND: Tropane alkaloids (TAs) are toxic compounds with a high anticholinergic effect. They have been widely analyzed in food samples, but their fate in the gastrointestinal tract has not been evaluated yet. RESULTS: In this study, static in vitro digestion was performed to assess gastrointestinal bioaccessibility of the most common TAs on tea and home-made cookies. Cookies enriched with dietary fiber (pectin, arabinogalactan, and κ-carrageenan) were also tested to evaluate their influence on TA bioaccessibility. Two extraction methods and a liquid chromatography-mass spectrometry method were optimized and validated. Bioaccessibility for tea (60-105%) was higher than for cookies (39-93%) (P = 0.001-0.002), which indicates TAs could be more easily absorbed when they are contaminating tea. Digestion of cookies enriched with 50 g kg-1 of different fibers showed that, although no significant changes were observed in the gastric phase (P = 0.084-0.920), duodenal bioaccessibility was significantly reduced (P = 0.008-0.039). Pectin was the fiber with a better mitigation effect for all the compounds. CONCLUSION: TAs bioaccessibility was determined after in vitro digestion of contaminated tea and cookies. Dietary fiber seems to be a promising mitigation strategy, significantly reducing TA bioaccessibility percentages. © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Occurrence and risk assessment of endocrine-disrupting compounds in fish muscle: The case study of the Douro River estuary (North East Atlantic Ocean).

This work was focused on evaluating the occurrence of endocrine-disrupting compounds (EDCs) in fish muscles, such as bisphenol analogues, personal care products, including some UV-filters and musk fragrances, and selected pesticides. A total of 238 muscle samples of three fish species (Platichthys flesus, Mugil cephalus, and Dicentrarchus labrax) of an important estuary ending in the North East Atlantic Ocean (Douro River estuary, Portugal), in different seasons of the year, was analysed. M. cephalus was the species with a greater occurrence of contaminants, mainly in fishes collected during the spring. Bisphenol A was the main bisphenol analogue detected with an average content of 23.1 µg/kg wet weight (w.w.). Among chemicals used in personal care products, galaxolide, tonalide, and 2-ethylhexyl salicylate, were the most often found, being present in 15.9% (2.2-538.4 µg/kg w. w.), 4.6% (1.1-57.8 µg/kg w. w.) and 3.4% (3.9-56.1 µg/kg w. w.) of the samples, respectively. About 14% of the samples contained residues of at least one pesticide, being alachlor, aldrin, p,p'-DDT, permethrin, and prochloraz the main chemicals observed, varying from 0.1 µg/kg w. w. (p,p'-DDT) to 37.8 µg/kg w. w. (prochloraz). The daily intake estimates of the most frequent EDCs found in the fish muscles suggested that there are no health concerns, based on the recommended weekly consumption of fish for adults.

Survey on endocrine-disrupting chemicals in seafood: Occurrence and distribution.

Currently, the presence of endocrine disrupting chemicals (EDCs) in the marine environment pose а potential risk to both wildlife and human health. The occurrence of EDCs in seafood depends of several factors such as source and amounts of EDCs that reach the aquatic environment, physicochemical features of EDCs, and its accumulation in trophic chain. This review highlights the occurrence and distribution of EDCs along the seafood in the last 6 years. The following EDCs were included in this review: brominated flame retardants (PBDEs, PBBs, HBCDDs, TBBPA, and novel flame retardants); pharmaceuticals (paracetamol, ibuprofen, diclofenac, carbamazepine), bisphenols, hormones, personal care products (Musk and UV Filters), and pesticides (organochlorides, organophosphates, and pyrethroids). Some of them were found above the threshold that may cause negative effects on human, animal, and environmental health. More control in some countries, as well as new legislation and inspection over the purchase, sale, use, and production of these compounds, are urgently needed. This review provides data to support risk assessment and raises critical gaps to stimulate and improve future research.

Chlorella vulgaris Extracts as Modulators of the Health Status and the Inflammatory Response of Gilthead Seabream Juveniles (Sparus aurata).

This study aimed to evaluate the effects of short-term supplementation, with 2% Chlorella vulgaris (C. vulgaris) biomass and two 0.1% C. vulgaris extracts, on the health status (experiment one) and on the inflammatory response (experiment two) of gilthead seabream (Sparus aurata). The trial comprised four isoproteic (50% crude protein) and isolipidic (17% crude fat) diets. A fishmeal-based (FM), practical diet was used as a control (CTR), whereas three experimental diets based on CTR were further supplemented with a 2% inclusion of C. vulgaris biomass (Diet D1); 0.1% inclusion of C. vulgaris peptide-enriched extract (Diet D2) and finally a 0.1% inclusion of C. vulgaris insoluble fraction (Diet D3). Diets were randomly assigned to quadruplicate groups of 97 fish/tank (IBW: 33.4 ± 4.1 g), fed to satiation three times a day in a recirculation seawater system. In experiment one, seabream juveniles were fed for 2 weeks and sampled for tissues at 1 week and at the end of the feeding period. Afterwards, randomly selected fish from each group were subjected to an inflammatory insult (experiment two) by intraperitoneal injection of inactivated gram-negative bacteria, following 24 and 48 h fish were sampled for tissues. Blood was withdrawn for haematological procedures, whereas plasma and gut tissue were sampled for immune and oxidative stress parameters. The anterior gut was also collected for gene expression measurements. After 1 and 2 weeks of feeding, fish fed D2 showed higher circulating neutrophils than seabream fed CTR. In contrast, dietary treatments induced mild effects on the innate immune and antioxidant functions of gilthead seabream juveniles fed for 2 weeks. In the inflammatory response following the inflammatory insult, mild effects could be attributed to C. vulgaris supplementation either in biomass form or extract. However, the C. vulgaris soluble peptide-enriched extract seems to confer a protective, anti-stress effect in the gut at the molecular level, which should be further explored in future studies.

Bioactive Hydrolysates from Chlorella vulgaris: Optimal Process and Bioactive Properties.

Microalgae have been described as a source of bioactive compounds, such as peptides. Microalgae are easy to produce, making them a sustainable resource for extracting active ingredients for industrial applications. Several microalgae species have interesting protein content, such as Chlorella vulgaris with around 52.2% of protein, making it promising for peptide hydrolysate production. Therefore, this work focused on the production of water-soluble hydrolysates rich in proteins/peptides from the microalgae C. vulgaris and studied bioactive properties. For that, a design of experiments (DOE) was performed to establish the optimal conditions to produce hydrolysates with higher levels of protein, as well as antioxidant and antihypertensive properties. Four experimental factors were considered (cellulase percentage, protease percentage, hydrolysis temperature, and hydrolysis duration) for three responses (protein content, antioxidant activity, and antihypertensive activity). The optimal conditions determined by the DOE allowed producing a scaled-up hydrolysate with 45% protein, with antioxidant activity, measured by oxygen radical absorbance capacity assay, of 1035 µmol TE/g protein, IC50 for angiotensin-converting enzyme inhibition activity of 286 µg protein/mL, and α-glucosidase inhibition of 31% (30 mg hydrolysate/mL). The obtained hydrolysates can be used as functional ingredients for food and nutraceuticals due to their antioxidant, antihypertensive, and antidiabetic potential. Moreover, the antioxidant potential of the extracts may be relevant for the cosmetic industry, especially in antiaging formulations.

Effects of Green Tea Marinade in the Bioaccessibility of Tonalide and Benzophenone 3 in Cooked European Seabass.

Fish consumption is an indicator of human exposure to personal care products (PCP) such as tonalide (AHTN) and benzophenone 3 (BP3). Although most fish consumed is cooked, the impact of cooking procedures on PCP levels is difficult to evaluate. Hence, the aim of this work was to provide thorough information on the stability and bioaccessibility of AHTN and BP3 upon cooking and in vitro digestion. A green tea (Camellia sinensis) marinade, rich in polyphenol, was used as mitigating strategy to reduce these contaminants. Roasting and frying reduced AHTN and BP3 levels in European seabass (Dicentrarchus labrax) spiked samples. Additionally, the green tea marinade promoted a reduction of up to 47% AHTN and 35% BP3. Bioaccessibility of AHTN was higher (up to 45%), and increased with the use of green tea marinades. BP3 showed a bioaccessibility below 19% in all cooked samples. Overall, a decrease in PCP levels was observed after cooking; this decrease was even more pronounced when marination was previously used. However, this decrease is cancelled out by the fact that the bioaccessible fraction of the contaminants increases in an inverse way; therefore, none of these processes can be considered a mitigating alternative.

Fine-Tuning of Sox17 and Canonical Wnt Coordinates the Permeability Properties of the Blood-Brain Barrier.

RATIONALE: The microvasculature of the central nervous system includes the blood-brain barrier (BBB), which regulates the permeability to nutrients and restricts the passage of toxic agents and inflammatory cells. Canonical Wnt/ß-catenin signaling is responsible for the early phases of brain vascularization and BBB differentiation. However, this signal declines after birth, and other signaling pathways able to maintain barrier integrity at postnatal stage are still unknown. OBJECTIVE: Sox17 (SRY [sex-determining region Y]-box 17) constitutes a major downstream target of Wnt/ß-catenin in endothelial cells and regulates arterial differentiation. In the present article, we asked whether Sox17 may act downstream of Wnt/ß-catenin in inducing BBB differentiation and maintenance. METHODS AND RESULTS: Using reporter mice and nuclear staining of Sox17 and ß-catenin, we report that although ß-catenin signaling declines after birth, Sox17 activation increases and remains high in the adult. Endothelial-specific inactivation of Sox17 leads to increase of permeability of the brain microcirculation. The severity of this effect depends on the degree of BBB maturation: it is strong in the embryo and progressively declines after birth. In search of Sox17 mechanism of action, RNA sequencing analysis of gene expression of brain endothelial cells has identified members of the Wnt/ß-catenin signaling pathway as downstream targets of Sox17. Consistently, we found that Sox17 is a positive inducer of Wnt/ß-catenin signaling, and it acts in concert with this pathway to induce and maintain BBB properties. In vivo, inhibition of the ß-catenin destruction complex or expression of a degradation-resistant ß-catenin mutant, prevent the increase in permeability and retina vascular malformations observed in the absence of Sox17. CONCLUSIONS: Our data highlight a novel role for Sox17 in the induction and maintenance of the BBB, and they underline the strict reciprocal tuning of this transcription factor and Wnt/ß-catenin pathway. Modulation of Sox17 activity may be relevant to control BBB permeability in pathological conditions.

Phthalic acid esters and adipates in herbal-based soft drinks: an eco-friendly method.

Phthalic acid esters (PAEs) and adipates are plasticizers with high applicability in several products and building materials (e.g. cosmetics, packing) very persistent in the environment, features which render them ubiquitous pollutants. These substances can contaminate food through the environment (water, air, and soil) and/or migration from packaging materials, which creates a health concern due to their toxicity. This paper describes an eco-friendly dispersive liquid-liquid microextraction (DLLME) procedure to extract five phthalates and bis(2-ethylhexyl) adipate (DEHA) from bottled herbal-based beverages followed by GC-MS/MS quantification. The method showed low limits of detection (5.0-13 µg L-1) and quantification (20-35 µg L-1), good inter- and intraday precision (RSD < 19%), and recoveries ranging from 82 to 111%. It was applied to 16 real samples, of which 13 showed the presence of at least one of the analytes under study. Additionally, an exposure assessment was performed, and resulted in a hazard quotient less than 1 (HQ < 1) for all analytes. Therefore, PAEs and DEHA found in samples do not pose a health issue.

Urinary bisphenol levels in plastic industry workers.

Bisphenol A (BPA) is a known endocrine disruptor compound that is widely applied as a monomer base in polycarbonate plastics and as a binding agent in several epoxy resins. Plastic industry workers have usually heavier and prolonged exposures to BPA. Hence, the present work aims to assess the levels of BPA and their analogs (S, F, B, AF, Z, E, and AP) in 170 urine samples from a cross-sectional study of workers from a plastic industry located in north Constantine (Algeria). This work was complemented with a questionnaire about sexual functions and evaluation of sexual hormone levels. The results showed a stable presence of BPA (average of 3.24 µg/L), accounting for more than 90% of the total BPs. Of the remaining BP analogs, only trace amounts of BPB were detected in three samples (average of 2.73 µg/L). Significant associations with BPA urinary levels were noted with age (p = 0.006), occupational level of exposure (p = 0.023), and years of experience (p = 0.001).

Neurodevelopmental Outcomes following Prenatal Diagnosis of Isolated Corpus Callosum Agenesis: A Systematic Review.

Abnormalities of corpus callosum are one of the most common brain anomalies. Fetuses with isolated corpus callosum agenesis (CCA) have a better prognosis than those with additional anomalies. However, unpredictable neurodevelopmental outcomes of truly isolated CCA make prenatal counseling a challenge. The aim of this review is to evaluate neurodevelopmental outcomes in children with prenatal diagnosis of isolated CCA. Controlled clinical trials published between May 23, 2009, and May 23, 2019, using the MeSH term "agenesis of corpus callosum" were reviewed. A total of 942 articles were identified, and 8 studies were included in the systematic review depending on the inclusion criteria. These studies included 217 fetuses with isolated CCA and no other anomalies at prenatal assessment. Neurodevelopmental outcome was reported to be normal in 83 children with a prenatal diagnosis of isolated CCA confirmed at birth within 128 completed assessments. About 45 children presented borderline, moderate, or severe neurodevelopmental outcome. In this review, neurodevelopment was favorable in two-thirds of the cases, but mild disabilities emerged in older children. Despite this, disabilities can occur later beyond school age and a low risk of severe cognitive impairment exists. Our study highlights the essential early diagnosis and proper supportive therapy.

Hydrolysate from Mussel Mytilus galloprovincialis Meat: Enzymatic Hydrolysis, Optimization and Bioactive Properties.

Mussel production generates losses and waste since their commercialisation must be aligned with target market criteria. Since mussels are rich in proteins, their meat can be explored as a source of bioactive hydrolysates. Thus, the main objective of this study was to establish the optimal production conditions through two Box-Behnken designs to produce, by enzymatic hydrolysis (using subtilisin and corolase), hydrolysates rich in proteins and with bioactive properties. The factorial design allowed for the evaluation of the effects of three factors (hydrolysis temperature, enzyme ratio, and hydrolysis time) on protein/peptides release as well as antioxidant and anti-hypertensive properties of the hydrolysates. The hydrolysates produced using the optimised conditions using the subtilisin protease showed 45.0 ± 0.38% of protein, antioxidant activity via ORAC method of 485.63 ± 60.65 µmol TE/g of hydrolysate, and an IC50 for the inhibition of ACE of 1.0 ± 0.56 mg of protein/mL. The hydrolysates produced using corolase showed 46.35 ± 1.12% of protein, antioxidant activity of 389.48 ± 0.21 µmol TE/g of hydrolysate, and an IC50 for the inhibition of ACE of 3.7 ± 0.33 mg of protein/mL. Mussel meat losses and waste can be used as a source of hydrolysates rich in peptides with relevant bioactive properties, and showing potential for use as ingredients in different industries, such as food and cosmetics, contributing to a circular economy and reducing world waste.

VE-Cadherin-Mediated Epigenetic Regulation of Endothelial Gene Expression.

RATIONALE: The mechanistic foundation of vascular maturation is still largely unknown. Several human pathologies are characterized by deregulated angiogenesis and unstable blood vessels. Solid tumors, for instance, get their nourishment from newly formed structurally abnormal vessels which present wide and irregular interendothelial junctions. Expression and clustering of the main endothelial-specific adherens junction protein, VEC (vascular endothelial cadherin), upregulate genes with key roles in endothelial differentiation and stability. OBJECTIVE: We aim at understanding the molecular mechanisms through which VEC triggers the expression of a set of genes involved in endothelial differentiation and vascular stabilization. METHODS AND RESULTS: We compared a VEC-null cell line with the same line reconstituted with VEC wild-type cDNA. VEC expression and clustering upregulated endothelial-specific genes with key roles in vascular stabilization including claudin-5, vascular endothelial-protein tyrosine phosphatase (VE-PTP), and von Willebrand factor (vWf). Mechanistically, VEC exerts this effect by inhibiting polycomb protein activity on the specific gene promoters. This is achieved by preventing nuclear translocation of FoxO1 (Forkhead box protein O1) and ß-catenin, which contribute to PRC2 (polycomb repressive complex-2) binding to promoter regions of claudin-5, VE-PTP, and vWf. VEC/ß-catenin complex also sequesters a core subunit of PRC2 (Ezh2 [enhancer of zeste homolog 2]) at the cell membrane, preventing its nuclear translocation. Inhibition of Ezh2/VEC association increases Ezh2 recruitment to claudin-5, VE-PTP, and vWf promoters, causing gene downregulation. RNA sequencing comparison of VEC-null and VEC-positive cells suggested a more general role of VEC in activating endothelial genes and triggering a vascular stability-related gene expression program. In pathological angiogenesis of human ovarian carcinomas, reduced VEC expression paralleled decreased levels of claudin-5 and VE-PTP. CONCLUSIONS: These data extend the knowledge of polycomb-mediated regulation of gene expression to endothelial cell differentiation and vessel maturation. The identified mechanism opens novel therapeutic opportunities to modulate endothelial gene expression and induce vascular normalization through pharmacological inhibition of the polycomb-mediated repression system.

Using the quality by design (QbD) approach to optimize formulations of lipid nanoparticles and nanoemulsions: A review.

Quality-by-design (QbD) approach has been applied to optimize lipid-based nanosystems formulations, including solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and nanoemulsions, besides being increasingly requested by regulatory authorities. Different mathematical models and statistical tests have been used, with similar conclusions regarding the parameters that influence the physical features of the resulting nanosystems. These include, variations in composition (e.g. lipid(s) and/or emulsifier(s)) and manufacturing parameters (e.g. emulsification rate and/or time, sonication amplitude and/or time, and homogenization pressure and/or cycles). These are critical parameters that influence nanoparticle/globule mean size, polydispersity index, zeta potential, drug encapsulation efficiency and in vitro drug release. This review addresses the concepts and applications of QbD for the development of lipid-based nanosystems, reporting successful examples published in the last 2 years. Although, some limitations have been identified, it is expected that in the upcoming years the application of QbD in pharmaceutical development will be an established approach.

Deregulated TGF-ß/BMP Signaling in Vascular Malformations.

Correct organization of the vascular tree requires the balanced activities of several signaling pathways that regulate tubulogenesis and vascular branching, elongation, and pruning. When this balance is lost, the vessels can be malformed and fragile, and they can lose arteriovenous differentiation. In this review, we concentrate on the transforming growth factor (TGF)-ß/bone morphogenetic protein (BMP) pathway, which is one of the most important and complex signaling systems in vascular development. Inactivation of these pathways can lead to altered vascular organization in the embryo. In addition, many vascular malformations are related to deregulation of TGF-ß/BMP signaling. Here, we focus on two of the most studied vascular malformations that are induced by deregulation of TGF-ß/BMP signaling: hereditary hemorrhagic telangiectasia (HHT) and cerebral cavernous malformation (CCM). The first of these is related to loss-of-function mutation of the TGF-ß/BMP receptor complex and the second to increased signaling sensitivity to TGF-ß/BMP. In this review, we discuss the potential therapeutic targets against these vascular malformations identified so far, as well as their basis in general mechanisms of vascular development and stability.