Pro-efferocytic nanotherapies reduce vascular inflammation without inducing anemia in a large animal model of atherosclerosis.

Atherosclerosis is an inflammatory disorder responsible for cardiovascular disease. Reactivation of efferocytosis, the phagocytic removal of cells by macrophages, has emerged as a translational target for atherosclerosis. Systemic blockade of the key 'don't-eat-me' molecule, CD47, triggers the engulfment of apoptotic vascular tissue and potently reduces plaque burden. However, it also induces red blood cell clearance, leading to anemia. To overcome this, we previously developed a macrophage-specific nanotherapy loaded with a chemical inhibitor that promotes efferocytosis. Because it was found to be safe and effective in murine studies, we aimed to advance our nanoparticle into a porcine model of atherosclerosis. Here, we demonstrate that production can be scaled without impairing nanoparticle function. At an early stage of disease, we find our nanotherapy reduces apoptotic cell accumulation and inflammation in the atherosclerotic lesion. Notably, this therapy does not induce anemia, highlighting the translational potential of targeted macrophage checkpoint inhibitors.

BST2 induces vascular smooth muscle cell plasticity and phenotype switching during cancer progression.

Background: Smooth muscle cell (SMC) plasticity and phenotypic switching play prominent roles in the pathogenesis of multiple diseases, but their role in tumorigenesis is unknown. We investigated whether and how SMC diversity and plasticity plays a role in tumor angiogenesis and the tumor microenvironment. Methods and Results: We use SMC-specific lineage-tracing mouse models and single cell RNA sequencing to observe the phenotypic diversity of SMCs participating in tumor vascularization. We find that a significant proportion of SMCs adopt a phenotype traditionally associated with macrophage-like cells. These cells are transcriptionally similar to 'resolution phase' M2b macrophages, which have been described to have a role in inflammation resolution. Computationally predicted by the ligand-receptor algorithm CellChat, signaling from BST2 on the surface of tumor cells to PIRA2 on SMCs promote this phenotypic transition; in vitro SMC assays demonstrate upregulation of macrophage transcriptional programs, and increased proliferation, migration, and phagocytic ability when exposed to BST2. Knockdown of BST2 in the tumor significantly decreases the transition towards a macrophage-like phenotype, and cells that do transition have a comparatively higher inflammatory signal typically associated with anti-tumor effect. Conclusion: As BST2 is known to be a poor prognostic marker in multiple cancers where it is associated with an M2 macrophage-skewed TME, these studies suggest that phenotypically switched SMCs may have a previously unidentified role in this immunosuppressive milieu. Further translational work is needed to understand how this phenotypic switch could influence the response to anti-cancer agents and if targeted inhibition of SMC plasticity would be therapeutically beneficial.

Outcomes of Descemet Stripping Only Without Postoperative Use of Topical Rho-associated Protein Kinase Inhibitors.

PURPOSE: Descemet Stripping Only (DSO) is a promising surgical option for select patients with Fuchs endothelial dystrophy (FED). There is growing support for the use of topical Rho-associated protein kinase inhibitors (ROCKi) to optimize DSO outcomes. However, in many settings, ROCKi are either unavailable or not approved to treat corneal diseases. This study sought to characterize patient outcomes after DSO in the absence of ROCKi and potentially broaden the settings where DSO can be offered to patients. METHODS: Single-center retrospective case series of 15 eyes/11 patients (66 years; 52-74) that underwent DSO, alone or combined with cataract surgery, by one surgeon between August 2020 and January 2023. Patients included in analyses had FED with central guttae, no clinical evidence of corneal edema, and a clinically healthy peripheral corneal endothelium. RESULTS: Mean follow-up time was 14 months (2-34). Fourteen of 15 eyes achieved corneal clearance (93.3%). Mean time to clearance was 8.5 weeks (3-23). Eleven eyes (73%) achieved corrected distance visual acuity of ≤0.2 with a significant postoperative improvement at 4 to 8 months (P < 0.05) and sustained improvements at >12 months. No significant astigmatism was introduced by the procedure. Two eyes developed cystoid macular edema postoperatively. A trend toward earlier clearance was observed in the <65 years old group. CONCLUSIONS: Despite a longer time to corneal clearance in this cohort compared with the few studies using ROCKi, the overall success rate and visual outcomes for the patients in our cohort supports the use of DSO in settings where ROCKi are not readily available.

Tobacco Taxation in Spain: A tax laggard with a brighter possible future.

INTRODUCTION: In recent years tobacco taxation in Spain has regressed, with its Tobacconomics tax scorecard falling from 3.9 points (out of 5) in 2014, to only 2.625 in 2020. The objective of this research is to provide a detailed analysis of the causes behind this deterioration and identify possible ways forward for reversing this trend. METHODS: A retrospective 2014-2022 analysis of manufactured cigarettes (FM) and roll-your-own tobacco (RYO) markets including tax structure/rates, affordability, retail price gaps across products, and price differentials with bordering countries. A market level simulation model to 2028 studied the impact of various tax policy scenarios on smoking prevalence, premature deaths averted, smoking intensity, product substitution, government revenue, sales, and industry profit. RESULTS: A lack of tax increases in a context of inflation and income growth during the past 8 years means FM and RYO have become 13% more affordable, with a constant differential of €2 between 20 FM and RYO sticks, and the price gap between Spain and neighbouring France increased. Modelling of two realistic reform scenarios that reduce/eliminate the price gap between FM and RYO suggest substantial increases in government revenues and up to 700,000 fewer smokers and 210,000 fewer premature deaths. CONCLUSIONS: Current European Union legislation on tobacco taxes leaves ample room for much needed tobacco tax reform. For the sake of both public health and the economy, Spain should increase its Minimum Excise Tax. This would not only save lives, but also bring much needed revenue for the government. IMPLICATIONS: The stance of Spain on tobacco taxes has deteriorated recently. This study argues that the failure of successive governments to raise minimum taxes in an inflationary context has made tobacco products more affordable, and quantifies the improvements in smoking prevalence and excise revenue that would accrue if the authorities act urgently increasing rates within realistic limits.Spain is representative of European countries where government inaction has rendered minimum tobacco taxes obsolete. Given the postponement of the revision of the European Union Tobacco Tax Directive, this study highlights the need to act unilaterally within the existing legal framework.

Small intestinal bacterial overgrowth in obese patients with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease: a cross-sectional study.

Background/aims: The metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity are frequent comorbidities with a high prevalence worldwide. Their pathogenesis are multifactorial, including intestinal dysbiosis. The role of small intestinal bacterial overgrowth (SIBO) in MASLD progression in obese patients remains unknown. We aimed to determine the association between SIBO and the severity of MASLD in obese patients. Methods: An observational and cross-sectional study was conducted in obese patients, diagnosed with or without MASLD by liver biopsy. Metabolic dysfunction-associated steatotic liver (MASL), metabolic dysfunction-associated steatohepatitis without fibrosis (MASH-NF), MASH with fibrosis (MASH-F), or without MASLD (control subjects, CS) were identified by presence of steatosis, portal and lobular inflammation, and fibrosis. SIBO was determined by standardized lactulose breath tests. Results: A total of 59 patients with MASLD, 16 with MASL, 20 with MASH-NF, 23 with MASH-F, and 14 CS were recruited. Higher percentages of SIBO were observed in MASLD patients (44.2%) compared to CS (14.2%; p = 0.0363). Interestingly, MASH-F showed higher percentages of SIBO (65.2%) in comparison to non-fibrotic MASLD (33.3%; p = 0.0165). The presence of SIBO was not correlated with the level of hepatic steatosis in MASLD patients. Conclusions: A positive correlation between MASLD and SIBO in obese patients was principally explained by the presence of liver fibrosis. Our findings suggest a pathogenic role of intestinal dysbiosis in the progression of MASLD. Future research will elucidate the underlying mechanisms of SIBO in MASLD advancement.

Alteration of Gut Microbiota Composition in the Progression of Liver Damage in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex disorder whose prevalence is rapidly growing in South America. The disturbances in the microbiota-gut-liver axis impact the liver damaging processes toward fibrosis. Gut microbiota status is shaped by dietary and lifestyle factors, depending on geographic location. We aimed to identify microbial signatures in a group of Chilean MASLD patients. Forty subjects were recruited, including healthy controls (HCs), overweight/obese subjects (Ow/Ob), patients with MASLD without fibrosis (MASLD/F-), and MASLD with fibrosis (MASLD/F+). Both MASLD and fibrosis were detected through elastography and/or biopsy, and fecal microbiota were analyzed through deep sequencing. Despite no differences in α- and ß-diversity among all groups, a higher abundance of Bilophila and a lower presence of Defluviitaleaceae, Lachnospiraceae ND3007, and Coprobacter was found in MASLD/F- and MASLD/F+, compared to HC. Ruminococcaceae UCG-013 and Sellimonas were more abundant in MASLD/F+ than in Ow/Ob; both significantly differed between MASLD/F- and MASLD/F+, compared to HC. Significant positive correlations were observed between liver stiffness and Bifidobacterium, Prevotella, Sarcina, and Acidaminococcus abundance. Our results show that MASLD is associated with changes in bacterial taxa that are known to be involved in bile acid metabolism and SCFA production, with some of them being more specifically linked to fibrosis.

Antiproliferative Effects in Colorectal Cancer and Stabilisation in Cyclodextrins of the Phytoalexin Isorhapontigenin.

Isorhapontigenin has been proposed as a better alternative for oral administration than the famous resveratrol, as it shares many biological activities, but with a structure that could make its delivery easier. Although this hydrophobic structure could enhance bioavailability, it could also be a disadvantage in the development of products. In this research, we study the antiproliferative activity of this stilbene against colorectal cancer and overcome its limitations through molecular encapsulation in cyclodextrins. The cytotoxic activity against human colorectal cancer cells of isorhapontigenin was similar to that of resveratrol or piceatannol, supporting its use as a bioactive alternative. The study of the encapsulation through fluorescence spectroscopy and molecular docking revealed that the complexation satisfies a 1:1 stoichiometry and that HP-ß-CD is the most suitable CD to encapsulate this stilbene. Through a spectrophotometric assay, it was observed that this CD could double the basal water solubility, exceeding the solubility of other hydroxylated stilbenes. The stability of these inclusion complexes was higher at a pH below 9 and refrigeration temperatures. Moreover, the use of CDs retained more than 78% of isorhapontigenin after storage for 12 weeks, compared to 15% in free form. Overall, these findings could help design novel formulations to better deliver isorhapontigenin.

In-house standards derived from doping peptides: Enzymatic and serum stability and degradation profile of GHRP and GHRH-related peptides.

Matrix effect and sample pretreatment significantly affect the percentage recovery of peptides in biological matrices, affecting the method robustness and accuracy. To counteract this effect, an internal standard (IS) is used; however, in most cases this is not available, which limits the analytical method. It is important to identify short peptides that can be used as ISs in the quantification of peptides in biological matrices. In this study, doping peptides GHRP-4, GHRP-5, GHRP-6, Sermorelin (1-11), Sermorelin (13-20) and Sermorelin (22-29) were synthesized using solid-phase peptide synthesis. Treatment with human blood, trypsin and chymotrypsin was used to determine the stability of the peptides. Products were evaluated using the high-performance liquid chromatography-diode array detector (HPLC-DAD) method. The analytical methodology and sample pretreatment were effective for the analysis of these molecules. A unique profile related to protein binding and enzymatic stability of each peptide was established. GHRP-4, GHRP-6 and Sermorelin (22-29) can be considered as in-house ISs as they were stable to enzyme and blood treatment and can be used for the quantification of peptides in biological samples. Peptides GHRP-6 and Sermorelin (22-29) were used to analyse a dimeric peptide (26 [F] LfcinB (20-30)2 ) in four different matrices to test these peptides as in-house IS.

Comparison of mini-simple limbal epithelial transplantation and conjunctival-limbal autograft for the treatment of primary pterygium: a randomised controlled trial.

PURPOSE: The purpose of this double-masked, parallel randomised controlled trial was to compare the recurrence rate and other outcomes between conjunctival-limbal autograft (CLAu) and mini-simple limbal epithelial transplantation (mini-SLET) after excision of pterygium. METHODS: Eligibility criteria for participants was the presence of a primary nasal pterygium extending equally to or greater than two millimetres on the cornea on its horizontal axis from the nasal limbus. The participants were allocated into two groups (CLAu and mini-SLET) using simple randomisation with a table of random numbers. Participants and the outcome assessor were masked to the intervention. The study protocol is listed and available on https://clinicaltrials.gov (Identifier: NCT03363282). RESULTS: A total of 61 eyes were enrolled in the study, 33 underwent CLAu (group 1) and 28 mini-SLET (group 2), all eyes were analysed in each group. At 2, 3, 6 and 12 months the CLAu group exhibited a recurrence of 0%, 6.1%, 8.1% and 8.1%, while the mini-SLET exhibited a recurrence of 0%, 17.9%, 50% and 53.5% (p<0.05). There were no intraoperative or postoperative complications in either of the two groups. CONCLUSION: The findings of this study suggest that mini-SLET has a higher recurrence rate and provides no advantage over CLAu in the treatment of primary pterygium.

The Iron and Calcium Availability and the Satiating Effect of Different Biscuits.

Biscuits are bakery products made with wheat flour. Wheat is a good source of minerals and dietary fibre, although the presence of phytate or other components could modify mineral availability. In addition, cereal-based products are usually characterised by high fibre content that can influence satiety. The objectives of this study were to evaluate both the iron and calcium availability and the satiety effect of different types of biscuits (traditional recipe vs. "Digestive") sold in the Spanish market, identifying whether the biscuit type could have effects on these parameters. Nutritional composition and the use of the generic descriptor "Digestive" of biscuits were collected from labels. Phytate and mineral contents were also measured. All samples were previously digested by a simulated process of the gastrointestinal conditions. The satiating effect of biscuits was evaluated according to VAS questionnaires. Results indicated that the mineral content and availability were different between types of biscuits (the traditional recipe showed the highest calcium concentration, while iron was higher in the "Digestive" type). However, mineral availability showed the highest percentages for both minerals, calcium and iron, in the Maria-type samples. Regardless of the different fibre content of both types of biscuits, and despite being higher in the Digestive type than in the Maria type, the satiety measures indicated that the Maria type had more effect on the food intake control. Thus, the descriptor "Digestive¨ in biscuits does not seem to be a marker of better nutritional quality, including parameters of effects on health such as mineral availability or satiety.

Improvement of the Physicochemical Limitations of Rhapontigenin, a Cytotoxic Analogue of Resveratrol against Colon Cancer.

It has been argued that methoxylated stilbenes are better candidates for oral administration than hydroxylated stilbenes, including resveratrol, as they share many biological activities but have better bioavailability. By contrast, they have a disadvantage to consider, i.e., their lower hydrophilic character that leads to precipitation issues in the final product. In this work, we analysed and compared the growth inhibition of colorectal cancer cells of the methoxylated stilbene rhapontigenin and some analogues and overcame potential problems in the development of fortified products by designing inclusion complexes. Among several cyclodextrins, we found the one that best fit the molecule by physicochemical and bioinformatics assays. The stoichiometry and the encapsulation constants with natural and modified cyclodextrins were determined by fluorescence spectroscopy. The most promising complexes were analysed at different temperature and pH conditions, determining the thermodynamic parameters, to discover the optimal conditions for the preparation and storage of the products. The results showed that rhapontigenin solubility and stability were significantly improved, achieving a sevenfold increase in water solubility and maintaining more than 73% of the stilbene after three months. These findings could be of great interest for industries that aim to deliver novel bioactive compounds with higher solubility and lower degradation.

Particle Exposure Hazards of Visiting Outdoor Smoking Areas for Patients with Asthma or COPD Even in EU Countries with Comprehensive Smokefree Laws.

Smokefree laws are intended to protect against second-hand smoke (SHS) in outdoor areas. We examined if exposure to PM2.5 particles in outdoor smoking areas changed breathing rates in 60 patients with asthma (n = 30) or with COPD (n = 30), in an open, non-randomised, interventional study model in Czechia, Ireland and Spain. The patients wore a PM2.5 particle monitor (AirSpeck) and a breath monitor (RESpeck) for 24 h to determine changes in breathing rates (Br) at rest and during a visit to an outside smoking area. Spirometry and breath CO were measured before and the day after visiting an outdoor smoking area. The PM2.5 levels at the 60 venues were highly variable, ranging from ≥2000 µg/m3 (in 4 premises) to ≤10 µg/m3 (in 3 premises, which had only a single wall in the structure). At 39 venues, the mean PM 2.5 levels were ≥25 µg/m3. The breathing rate changed significantly in 57 of the 60 patients, resulting in an increase in some patients and a decrease in others. Comprehensive smokefree laws were ineffective in protecting asthma and COPD patients from exposure to high levels of SHS in outside areas of pubs and terraces, which should be avoided by these patients. These findings also support the extension of smokefree laws to outside areas.

A multi-centre peptidomics investigation of food digesta: current state of the art in mass spectrometry analysis and data visualisation.

Mass spectrometry has become the technique of choice for the assessment of a high variety of molecules in complex food matrices. It is best suited for monitoring the evolution of digestive processes in vivo and in vitro. However, considering the variety of equipment available in different laboratories and the diversity of sample preparation methods, instrumental settings for data acquisition, statistical evaluations, and interpretations of results, it is difficult to predict a priori the ideal parameters for optimal results. The present work addressed this uncertainty by executing an inter-laboratory study with samples collected during in vitro digestion and presenting an overview of the state-of-the-art mass spectrometry applications and analytical capabilities available for studying food digestion. Three representative high-protein foods - skim milk powder (SMP), cooked chicken breast and tofu - were digested according to the static INFOGEST protocol with sample collection at five different time points during gastric and intestinal digestion. Ten laboratories analysed all digesta with their in-house equipment and applying theirconventional workflow. The compiled results demonstrate in general, that soy proteins had a slower gastric digestion and the presence of longer peptide sequences in the intestinal phase compared to SMP or chicken proteins, suggesting a higher resistance to the digestion of soy proteins. Differences in results among the various laboratories were attributed more to the peptide selection criteria than to the individual analytical platforms. Overall, the combination of mass spectrometry techniques with suitable methodological and statistical approaches is adequate for contributing to the characterisation of the recently defined digestome.

[Anti-inflammatory effect of milk whey from different species after in vitro digestion]. / Efecto antiinflamatorio del suero de leche de diferentes especies tras una digestión in vitro.

Introduction: Introduction: there is a close relationship between obesity, gut health and immune system. A low-grade of inflammation, which could precede obesity, may have implications for the development of metabolic syndrome and insulin resistance. Objective: analyzing the anti-inflammatory capacity of several types of whey (cow, sheep, goat and a mixture of them). Methods: an in vitro model of intestinal inflammation employing a cell co-culture (Caco-2 and RAW 264.7) was performed after an in vitro digestion and fermentation (simulating mouth-to-colon conditions). Inflammatory markers such as IL-8 and TNF-α, as well as the transepithelial electrical resistance (TEER) of Caco-2 monolayer, were determined. Results: digested and fermented whey had a protective effect on cell permeability, being lower in the case of fermented goat whey and mixture. The anti-inflammatory activity of whey was greater the more digestion progressed. Fermented whey showed the greatest anti-inflammatory effect, inhibiting IL-8 and TNF-α secretion, probably due to its composition (protein degradation products such as peptides and amino acids, and SCFA). However, fermented goat whey did not show this degree of inhibition, perhaps due to its low SCFA concentration. Conclusion: milk whey, especially after being fermented in the colon, can be useful nutritional strategy to preserve the intestinal barrier and mitigate the low-grade of inflammation that characterizes metabolic disorders and obesity.

Introducción: Introducción: existe una estrecha relación entre obesidad, salud intestinal y sistema inmune. Un bajo grado de inflamación, que precedería a la obesidad, puede tener implicaciones en el desarrollo de síndrome metabólico y resistencia a la insulina. Objetivo: analizar el poder antiinflamatorio de varios tipos de lactosuero (vaca, oveja, cabra y mezcla de los anteriores). Metodología: se utilizó un modelo in vitro de inflamación intestinal, empleando un cocultivo celular (Caco-2 y RAW 264.7). Para ello, se realizó una digestión y fermentación in vitro (simulando las condiciones de boca a colon). Se estudiaron IL-8 y TNF-α como marcadores inflamatorios y la resistencia eléctrica transepitelial celular (RETE) de la monocapa celular Caco-2. Resultados: el suero digerido y fermentado tuvo un efecto protector sobre la permeabilidad celular que fue menor en el caso de lactosuero fermentado de cabra y mezcla. La actividad antiinflamatoria del suero fue mayor cuanto más progresaba la digestión. El lactosuero fermentado mostró el mayor efecto antiinflamatorio, inhibiendo la secreción de IL-8 y TNF-α, probablemente debido a su composición (productos de degradación proteica como péptidos y aminoácidos, y ácidos grasos de cadena corta [AGCC]). Sin embargo, el suero fermentado de cabra no mostró ese grado de inhibición, quizás debido a su baja concentración en AGCC. Conclusión: el lactosuero, sobre todo tras ser fermentado en colon, puede ser una estrategia nutricional útil para preservar la barrera intestinal y mitigar el bajo grado de inflamación que caracteriza a desordenes metabólicos y a la obesidad.

Promoting convergence and closing gaps using affordability-based minimum taxes: an illustration using the European Union Tobacco Tax Directive.

BACKGROUND: The rules governing tobacco taxation in the European Union (EU) are currently under revision. Earlier research has proposed reforms aimed at stimulating price convergence across countries by linking national minimum taxes to a measure of average prices across the EU. This paper proposes that revised tax rules include an affordability criterion whereby minimum taxes are required to be no less than a common prespecified fraction of domestic average disposable income. METHODS: Longitudinal data on prices and taxes on factory-made cigarettes and roll-your-own tobacco in 24 EU member states and the UK between 2011 and 2019 are used to estimate econometric models for their weighted average prices as a function of taxes. Two scenarios are simulated with the models' estimates: a baseline scenario for the actual tax stance pertaining to 2020 and a reform scenario implementing an additional affordability criterion. RESULTS: The affordability criterion would significantly increase the price of both tobacco products, particularly in richer countries with relatively low tobacco prices that are often not affected by the increases in nominal minima mandated by the EU rules. There would also be some price convergence between the two tobacco products, both on average and in the majority of countries. CONCLUSIONS: Such results show an affordability criterion could be a potentially fruitful complement to the tax reforms proposed in earlier research.

Electronic Cigarette Use in 12 European Countries: Results From the TackSHS Survey.

BACKGROUND: Limited data on electronic cigarette prevalence, patterns, and settings of use are available from several European countries. METHODS: Within the TackSHS project, a face-to-face survey was conducted in 2017-2018 in 12 European countries (Bulgaria, England, France, Germany, Greece, Ireland, Italy, Latvia, Poland, Portugal, Romania and Spain). Overall, 11,876 participants, representative of the population aged ⩾15 years in each country, provided information on electronic cigarette. RESULTS: 2.4% (95% confidence interval [CI], 2.2-2.7%) of the subjects (2.5% among men and 2.4% among women; 0.4% among never, 4.4% among current- and 6.5% among ex-smokers) reported current use of electronic cigarette, ranging from 0.6% in Spain to 7.2% in England. Of the 272 electronic cigarette users, 52.6% were dual users (ie, users of both electronic and conventional cigarettes) and 58.8% used liquids with nicotine. In all, 65.1% reported using electronic cigarette in at least one indoor setting where smoking is forbidden; in particular, at workplaces (34.9%) and bars and restaurants (41.5%). Multivariable logistic regression analysis showed that electronic cigarette use was lower among older individuals (P for trend <0.001) and higher among individuals with high level of education (P for trend = 0.040). Participants from countries with higher tobacco cigarette prices more frequently reported electronic cigarette use (odds ratio 3.62; 95% CI, 1.80-7.30). CONCLUSION: Considering the whole adult population of these 12 European countries, more than 8.3 million people use electronic cigarettes. The majority of users also smoked conventional cigarettes, used electronic cigarettes with nicotine, and consumed electronic cigarettes in smoke-free indoor areas.

Promoting convergence and closing gaps: a blueprint for the revision of the European Union Tobacco Tax Directive.

BACKGROUND AND AIMS: Despite the European Union (EU) Tobacco Tax Directive (TTD), a lack of convergence in EU tobacco prices promotes high levels of cross-border shopping and down-trading from factory-made (FM) to roll-your-own tobacco (RYO) cigarettes. This study presents a blueprint for reform, whereby minimum taxes are related to the overall price level in the EU and where taxation of RYO is related to that of FM. METHODS: Longitudinal data on prices and taxes on FM and RYO in 25 member states over 2011-2019 are used to estimate econometric models for their weighted average prices as a function of taxes. Two scenarios are simulated with the models' estimates: a baseline scenario for the actual tax stance pertaining to 2020 and a reform scenario implementing the blueprint. RESULTS: The baseline results show that, while the prices of both products have experienced a slight increase since 2016 in real terms, the dispersion in the prices of FM across countries has increased and the difference in the prices of RYO within countries has widened. The results for the reform scenario show dispersion would diminish both EU-wide and in hotspots for cross-border sales of FM. The reform would also lead to a substantial reduction in the price gap between FM and RYO. CONCLUSION: To promote price convergence and close the price gap between FM and RYO, the revised TTD should ensure minimum FM taxes track a measure of their average EU price, and RYO taxes are related to FM taxes.

Stilbenes: Characterization, bioactivity, encapsulation and structural modifications. A review of their current limitations and promising approaches.

Stilbenes are phenolic compounds naturally synthesized as secondary metabolites by the shikimate pathway in plants. Research on them has increased in recent years due to their therapeutic potential as antioxidant, antimicrobial, anti-inflammatory, anticancer, cardioprotective and anti-obesity agents. Amongst them, resveratrol has attracted the most attention, although there are other natural and synthesized stilbenes with enhanced properties. However, stilbenes have some physicochemical and pharmacokinetic problems that need to be overcome before considering their applications. Human clinical evidence of their bioactivity is still controversial due to this fact and hence, exhaustive basis science on stilbenes is needed before applied science. This review gathers the main physicochemical and biological properties of natural stilbenes, establishes structure-activity relationships among them, emphasizing the current problems that limit their applications and presenting some promising approaches to overcome these issues: the encapsulation in different agents and the structural modification to obtain novel stilbenes with better features. The bioactivity of stilbenes should move from promising to evident.

Deciphering the Role and Signaling Pathways of PKCα in Luminal A Breast Cancer Cells.

Protein kinase C (PKC) comprises a family of highly related serine/threonine protein kinases involved in multiple signaling pathways, which control cell proliferation, survival, and differentiation. The role of PKCα in cancer has been studied for many years. However, it has been impossible to establish whether PKCα acts as an oncogene or a tumor suppressor. Here, we analyzed the importance of PKCα in cellular processes such as proliferation, migration, or apoptosis by inhibiting its gene expression in a luminal A breast cancer cell line (MCF-7). Differential expression analysis and phospho-kinase arrays of PKCα-KD vs. PKCα-WT MCF-7 cells identified an essential set of proteins and oncogenic kinases of the JAK/STAT and PI3K/AKT pathways that were down-regulated, whereas IGF1R, ERK1/2, and p53 were up-regulated. In addition, unexpected genes related to the interferon pathway appeared down-regulated, while PLC, ERBB4, or PDGFA displayed up-regulated. The integration of this information clearly showed us the usefulness of inhibiting a multifunctional kinase-like PKCα in the first step to control the tumor phenotype. Then allowing us to design a possible selection of specific inhibitors for the unexpected up-regulated pathways to further provide a second step of treatment to inhibit the proliferation and migration of MCF-7 cells. The results of this study suggest that PKCα plays an oncogenic role in this type of breast cancer model. In addition, it reveals the signaling mode of PKCα at both gene expression and kinase activation. In this way, a wide range of proteins can implement a new strategy to fine-tune the control of crucial functions in these cells and pave the way for designing targeted cancer therapies.