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BACKGROUND: There is an urgent need for health care systems to be more efficient and efficacious. An approach to integrate public and private provider organizations such as community pharmacies and public primary health care (PHC) merits consideration. The objective of this review was to identify the types of integration in health care settings and discuss their applicability to the potential integration of community pharmacy and PHC. METHODS: A narrative review using Medline, Scopus and SciELO databases was performed in which terms related to health were combined with terms related to integration. Levels and Types of integration: 14 types of integration were identified (two in breadth, seven as enablers and five in system levels). A model was created which classifies and assigns the types of integration to the different levels of the health system and to the breadth, intensity, and enablers of the integration process. Due to the nature of community pharmacy and PHC system, a horizontal integration at the micro level, supported by meso and macro levels policy, is suggested. The different elements of intensity and enablers can significantly influence the process. CONCLUSION: The application of principles, concepts and types of integration suggest that it might be feasible and practical to integrate community pharmacies and PHC. However, the conflictive historical context would need to be overcome with appropriate policy and incentives.

Calcium phosphate cements (CPCs) offer a promising solution for treating bone defects due to their osteoconductive, injectable, biocompatible, and bone replacement properties. However, their brittle nature restricts their utilization to non-load-bearing applications. In this study, the impact of hybrid silk fibroin (SF) and kappa-carrageenan (k-CG) nanofibers as reinforcements in CPC was investigated. The CPC composite was fabricated by incorporating electrospun nanofibers in 1, 3, and 5% volume fractions. The morphology, mineralization, mechanical properties, setting time, injectability, cell adhesion, and mineralization of the CPC composites were analyzed. The results demonstrated that the addition of the nanofibers improved the CPC mixture, leading to an increase in compressive strength (14.8 ± 0.3 MPa compared to 8.1 ± 0.4 MPa of the unreinforced CPC). Similar improvements were seen in the bending strength and work fracture (WOF). The MC3T3-E1 cell culture experiments indicated that cells attached well to the surfaces of all cement samples and tended to join their adjacent cells. Additionally, the CPC composites showed higher cell mineralization after a culture period of 14 days, indicating that the SF/k-CG combination has potential for applications as a CPC reinforcement and bone cell regeneration promoter.

Vascular stents (VS) have revolutionized the treatment of cardiovascular diseases, as evidenced by the fact that the implantation of VS in coronary artery disease (CAD) patients has become a routine, easily approachable surgical intervention for the treatment of stenosed blood vessels. Despite the evolution of VS throughout the years, more efficient approaches are still required to address the medical and scientific challenges, especially when it comes to peripheral artery disease (PAD). In this regard, three-dimensional (3D) printing is envisaged as a promising alternative to upgrade VS by optimizing the shape, dimensions and stent backbone (crucial for optimal mechanical properties), making them customizable for each patient and each stenosed lesion. Moreover, the combination of 3D printing with other methods could also upgrade the final device. This review focuses on the most recent studies using 3D printing techniques to produce VS, both by itself and in combination with other techniques. The final aim is to provide an overview of the possibilities and limitations of 3D printing in the manufacturing of VS. Furthermore, the current situation of CAD and PAD pathologies is also addressed, thus highlighting the main weaknesses of the already existing VS and identifying research gaps, possible market niches and future directions.

Although a general healthy gut microbiota cannot be defined due to numerous internal and external individual factors, such as sex, age, ethnicity, genetics, environment, diet and drugs affect its composition, certain microbial species and gut microbiota compositions seem to be related to the progression of insulin resistance to type 2 diabetes, as well as the development of microvascular and macrovascular complications of diabetes. The present review aimed at gathering the reported information describing how resveratrol induced changes in microbiota composition can mediate the positive effects of this polyphenol on glucose homeostasis under type 2 diabetic conditions, both in animals and humans. Based on the fact that some changes observed in the gut microbiota of type 2 diabetic animals and patients are reversed by resveratrol treatment, and taking into account that some resveratrol mediated changes in gut microbiota composition are similar to those induced by anti-diabetic drugs such as metformin, it can be proposed that four genera, Alistipes, Allobaculum, Desulfovibrio and Blautia could be involved in the benefits of resveratrol on glycameic control. Nevertheless some limitations are observed in this research field: (a) the number of studies analyzing both the effects of resveratrol on glucose homeostasis and microbiota composition in the same cohort of animals, in order to know the potential involvement of microbiota in the anti-diabetic effects of this phenolic compound, are very scarce and practically inexistent in the case of humans., (b) the studies present inconsistencies concerning the effects of resveratrol on gut microbiota changes, (c) the experimental design used do not allow the researchers to establish a causal relationship between the changes in microbiota and the anti-diabetic effect, in the vast majority of the studies, (d) the knowledge about the role of each type of bacteria on glycaemic control is not sufficient so far.

Modified atmosphere packaging (MAP) has become a good potential strategy to retain quality throughout the shelf life of perishable foods. The aim of this work was to evaluate different packaging atmospheres on semi-hard protected designation of origin Idiazabal cheese wedges. Six different packaging treatments (air, vacuum, and CO2/N2 gas mixtures in the ratio of 20/80, 50/50, 80/20, and 100/0% v/v, respectively) were studied. Changes in gas headspace composition, cheese gross composition, weight loss, pH, acidity, colour, and textural and sensory properties were investigated during 56 days of refrigerated storage at 5 ± 1 °C. MAP was the most effective preserving technique compared to air- and vacuum-packaging treatments. The cheese characteristics with the greatest discriminating weight in the preservation techniques were paste appearance, holes, flavour, a* (redness) and b* (yellowness) colour parameters, and slope to hardness. Air-packaged cheeses, on 35 day, presented a mouldy flavour. Vacuum packaging affected paste appearance (greasy, plastic marks, and non-homogeneous colour) and holes (occluded and unnatural appearance) starting after 14 packaging days. MAP mixtures with CO2 concentration between 50/50 and 80/20% CO2/N2 (v/v) are recommended to ensure sensory quality and stability in the distribution of these raw sheep-milk cheese wedges.

In recent years, progress in nanotechnology provided new tools to treat cancer more effectively. Advances in biomaterials tailored for drug delivery have the potential to overcome the limited selectivity and side effects frequently associated with traditional therapeutic agents. While autophagy is pivotal in determining cell fate and adaptation to different challenges, and despite the fact that it is frequently dysregulated in cancer, antitumor therapeutic strategies leveraging on or targeting this process are scarce. This is due to many reasons, including the very contextual effects of autophagy in cancer, low bioavailability and non-targeted delivery of existing autophagy modulatory compounds. Conjugating the versatile characteristics of nanoparticles with autophagy modulators may render these drugs safer and more effective for cancer treatment. Here, we review current standing questions on the biology of autophagy in tumor progression, and precursory studies and the state-of-the-art in harnessing nanomaterials science to enhance the specificity and therapeutic potential of autophagy modulators.

178 p., La descontaminación digestiva selectiva (DDS) es una estrategia profiláctica basada en la administración de antibióticos tópicos no absorbibles en la mucosa oral y en el tracto gastrointestinal y de un antibiótico de amplio espectro, habitualmente una cefalosporina, por vía parenteral. El objetivo es prevenir o minimizar las infecciones endógenas y exógenas producidas por microorganismos potencialmente patógenos, como Enterobacterales, Staphylococcus aureus, Pseudomonas y levaduras presentes en la orofaringe o intestino, sin dañar la microbiota anaerobia, y así reducir la mortalidad de los pacientes críticos. A pesar de los beneficios de la DDS, su utilización no se ha generalizado en los Servicios de Medicina Intensiva, debido principalmente a la percepción por parte de algunos clínicos de que promueve la selección de bacterias resistentes a los antimicrobianos. El objetivo principal de esta Tesis Doctoral ha sido evaluar en el Hospital Universitario Araba (HUA), un hospital terciario de 800 camas y que tiene dos Unidades de Cuidados Intensivos (UCI), una con protocolo de DDS y otra sin protocolo DDS, si el uso de esta técnica se asocia o no con la selección de cepas resistentes. En primer lugar, se analizaron las tasas de sensibilidad de los aislados de la UCI con DDS antes y después de su implantación en 2002. Se analizaron un total de 48 combinaciones antibiótico/microorganismo durante el periodo 1998-2013. Se desarrolló un modelo dinámico lineal de series interrumpidas, introduciendo la DDS como intervención. El modelo incluyó además el número de aislados y el consumo de antibióticos. De todas las combinaciones estudiadas, tras la implantación de la DDS únicamente se detectó disminución de la sensibilidad de Escherichia coli y Proteus mirabilis a amoxicilina/clavulánico, y de Enterococcus faecalis a concentraciones elevadas de gentamicina. La disminución de la sensibilidad de E. coli y P. mirabilis a amoxicilina/clavulánico puede ser explicada por el aumento de

208 p., This PhD thesis has developed a new functional ingredient characterised by the novelty of combining anew L. plantarum K16 strain, isolated from the fermented food Kimchi, with the postbiotic metaboliteGABA produced by a fermentation process using agri-food by-products as substrate media. According tothe scientific literature, this functional ingredient intends to exert a beneficial effect on human health byacting in the intestine, guaranteeing a synergistic effect of the probiotic and GABA. The first step in thedeveloping process was focused on isolating and characterising a GABA-producer lactic acid strain fromfermented food kimchi. Then, am evaluation of the ability to produce GABA by this strain wasconducted, firstly, using commercial MRS broth where the effect of different parameters was assessed.Next, several agri-food by-products have been selected to be used as fermentation media due, on onehand, to their high environmental impact and, on the other hand, to their nutritional value for developinglow-cost culture media. Finally, one of this agri-food by-products was chosen to grow the isolatedbacteria and to produce GABA with it, for finally develop a microencapsulated functional ingredient.

Considering the high relevance of meat tenderness for consumer acceptability, the aim of this study was to investigate post-mortem changes in myofibrillar sub-proteome in steaks from longissimus thoracis et lumborum muscle of six Hispano-Bret ' on horses. Indeed, the ageing process that leads to meat tenderization has been scarcely studied in this species. Steaks (n = 24) were aged (4 degrees C) in the dark under vacuum for 0, 7, 14 and 21 days and the myofibrillar sub-proteome was extracted. Using 2-D DIGE minimal labelling, 35 spots that were differentially abundant between 0 and 21 days aged meat were detected. Of them, 24 were analysed by LC-MS/ MS, identifying a total of 29 equine proteins. These were structural and metabolic proteins, and among them, four (Actin, Troponin T and Myosin binding proteins 1 and 2) were selected for Western blot analysis, reporting changes in their abundance after 0, 7, 14 and 21 days of ageing. Results revealed that they should be further studied as potential protein biomarkers of horse meat tenderization. Additionally, several protein fragments increased after ageing, as was the case of glyceraldehyde-3-phosphate dehydrogenase. Fragments of this protein were present in four protein spots, and their study could be useful for monitoring horse meat tenderization. Significance: Tenderization during ageing has been widely studied in meat from several farm animal species; however, both research and standardized ageing practices are lacking for the particular case of horse meat. In this regard, this study presents novel proteomic findings related to post-mortem evolution of horse muscle pro-teins. Acquired knowledge would support the development and optimization of efficient ageing practices by horse meat industry.

Different encapsulation materials might not only affect lipid hydrolysis but also lipid oxidation during in vitro digestion. Thus, this study aimed to investigate the effect of two commonly used shell materials, starch and gelatin, on the extent of lipolysis and bioaccessibility of the main and some minor lipid compounds, as well as on the oxidative status in encapsulated black seed oil (Nigella sativa) during in vitro digestion. The study was carried out using 1H nuclear magnetic resonance spectroscopy, liquid chromatography-mass spectrometry and high-performance liquid chromatography-UV. It was shown that starch increased the level of lipid hydrolysis in black seed oil during gastric in vitro digestion, while no differences were observed in the intestinal digestates between starch-encapsulated oil and gelatin-encapsulated oil. Similarly, the bioaccessibility of minor compounds (tocopherols, sterols and thymoquinone) was not influenced by the shell materials. However, regarding lipid oxidation, a 20- and 10-fold rise of free oxylipins was obtained in oils encapsulated by starch and gelatin, respectively, after intestinal in vitro digestion. This study evidenced that gelatin rather than starch should be used for the encapsulation of oils to minimize the digestion-induced formation of bioactive oxylipins.

Background The increasing incidence of syphilis and the limitations of first-line treatment with penicillin, particularly in neurosyphilis, neonatal syphilis, and pregnancy, highlight the need to expand the therapeutic repertoire for effective management of this disease. We assessed the in-vitro efficacy of 18 antibiotics from several classes on Treponema pallidum subspecies pallidum (T pallidum), the syphilis bacteria. Methods Using the in-vitro culture system for T pallidum, we exposed the pathogen to a concentration range of each tested antibiotic. After a 7-day incubation, the treponemal burden was evaluated by quantitative PCR targeting the T pallidum tp0574 gene. The primary outcome was the minimum inhibitory concentration (MIC) at which the quantitative PCR values were not significantly higher than the inoculum wells. We also investigated the susceptibility of macrolide-resistant strains to high concentrations of azithromycin, and the possibility of developing resistance to linezolid, a proposed candidate for syphilis treatment. Findings Amoxicillin, ceftriaxone, several oral cephalosporins, tedizolid, and dalbavancin exhibited anti-treponemal activity at concentrations achievable in human plasma following regular dosing regimens. The experiments revealed a MIC for amoxicillin at 0·02 mg/L, ceftriaxone at 0·0025 mg/L, cephalexin at 0·25 mg/L, cefetamet and cefixime at 0·0313 mg/L, cefuroxime at 0·0156 mg/L, tedizolid at 0·0625 mg/L, spectinomycin at 0·1 mg/L, and dalbavancin at 0·125 mg/L. The MIC for zoliflodacin and balofloxacin was 2 mg/L. Ertapenem, isoniazid, pyrazinamide, and metronidazole had either a poor or no effect. Azithromycin concentrations up to 2 mg/L (64 times the MIC) were ineffective against strains carrying mutations associated to macrolide resistance. Exposure to subtherapeutic doses of linezolid for 10 weeks did not induce phenotypic or genotypic resistance. Interpretation Cephalosporins and oxazolidinones are potential candidates for ex

Additive manufacturing, widely known as 3D printing, has revolutionized the production of biomaterials. While conventional 3D-printed structures are perceived as static, 4D printing introduces the ability to fabricate materials capable of self-transforming their configuration or function over time in response to external stimuli such as temperature, light, or electric field. This transformative technology has garnered significant attention in the field of biomedical engineering due to its potential to address limitations associated with traditional therapies. Here, we delve into an in-depth review of 4D-printing systems, exploring their diverse biomedical applications and meticulously evaluating their advantages and disadvantages. We emphasize the novelty of this review paper by highlighting the latest advancements and emerging trends in 4D-printing technology, particularly in the context of biomedical applications.

Purpose Epidemiologic evidence for the association between methyl-donor nutrient intake and colorectal cancer (CRC) risk remains inconclusive. We aimed to examine the relationship between intake of vitamins of the B group, methionine, total choline and betaine and CRC risk, in a population from the CRC screening programme in the Basque Country. Design This observational study included 308 patients with CRC and 308 age- and sex-matched subjects as controls. During recruitment, dietary, anthropometric, lifestyle, socioeconomic, demographic, and health status information was collected. Conditional logistic regression was used to estimate the odds ratios (ORs) for CRC risk. Results The adjusted ORs for CRC risk decreased with higher intakes of choline and betaine (p < 0.05). After further adjustment for folate, high intake of choline and betaine remained associated with a reduced CRC risk (adjusted model for choline, OR third tertile vs first tertile = 0.45, 95% CI 0.26–0.80, p = 0.006; for betaine, OR third tertile vs first tertile = 0.27, 95% CI 0.16–0.47, p < 0.001). Regarding the other nutrients, our findings indicated a non-significant decrease in CRC risk with the high level of intake. Conclusions Our data suggest that choline and betaine intake influence CRC risk in the studied population.

171 p., Obesity is defined as a pathological condition characterized by an abnormal or excessive accumulation of fat, to the extent that it is considered a risk factor or marker for several chronic diseases.In this sense, molecular analysis tools such as metabolomics, genomics or the study of the intestinal microbiome allow us to advance in our knowledge of human metabolic behavior and favors the development of new diagnostic methods for obesity and its associated diseases.Lipids play a decisive role in obesity due to their structural and molecular signaling functions. Although the fatty acid (FA) composition of each tissue is specific, the mature red blood cell (RBC) is considered a good reporter of the metabolic state of different organs, tissues and cells, as it is a circulating cell and its membrane reflects an overall picture of the metabolism of each individual.For this reason, defining the mature RBC membrane FA profile will allow us to know the metabolic and nutritional status of the individuals studied, which is very useful in the molecular characterization of obesity.Taking these considerations into account, the aim of this thesis is to define the RBC membrane FAprofile that characterizes obese children, and to establish its relationship with metabolism and dietaryhabits, in order to be able to design precise nutritional strategies. To this end, a study was carried out in apopulation of normal-weight, overweight and obese children.In turn, a study was carried out to establish the respective differences in RBC membrane FA profilebetween adults and children with obesity, in order to be able to establish specific and personalizednutritional recommendations according to the differences observed by age, and derived from themetabolism of obesity itself.Statistical clustering techniques were also used to isolate a subgroup of obese children with a similar lipidprofile to normal-weight children. Analyzing the RBC membrane FA profile as a biomarker ofinflammation allows us

Pendiente de patente por lo solo se pueden publicar los capítulos 1, 2 y 3 que corresponden a artículos científicos ya difundidos. -- Tesis completa 202 p. -- Tesis censurada 104 p., Esta tesis doctoral nace del interés de BIOSASUN en el desarrollo de formulaciones novedosas como solución a las limitaciones que presentan los polifenoles del olivo. Ello, unido a la especialidad del Grupo Nanobiocel en el diseño de nanoformulaciones ha dado lugar al desarrollo de varios trabajos centrados en la aplicación de los principios de la nanociencia verde para el desarrollo de nanopartículas lipídicas que permitan encapsular y controlar la liberación de polifenoles del olivo de forma eficaz en el lugar de acción deseado. El enfoque del trabajo ha sido desde una perspectiva de Ciencia Verde, hacia un fomento de la economía circular en la industria oleica. Por ello se han diseñado nanopartículas lipídicas con acidos grasos y triglicéridos que pueden obtenerse del propio olivo, y el principio activo a encapsular (oleuropeína) se ha extraído de una forma sostenible a partir de hojas de olivos ecológicos que consituyen, de hecho, un sub-producto importante en la industria del aceite de oliva. Bajo este prisma, se ha desarrollado y validado una técnica anatíca de cromatografía para la caracterización de las materias primas y la nanoformualción, todo ello siguiendo los principios establecidos de la Química Verde. A continuación, se ha desarrollado y caracterizado la nanoformulación que sirve para encapsular el polifenol de olivo seleccionado. El proceso de nanoformulación ha sido diseñado para evitar el uso de solventes orgánicos y se ha caracterizado tanto la eficiencia del proceso como la no-toxicidad de la formulación en células epiteliales. Por último, se ha evaluado la eficacia de la formulación desarrollada in vitro en modelos de inflamación y de estrés oxidativo, así como en un modelo in vivo de colitis ulcerosa que cursa tanto como con procesos inflamatorios como de estrés oxidativo.

722 p. Contiene versión en inglés y en euskera en el mismo tomo, [EN]Although an energy imbalance over a long period seems to be the main cause of overweight/obesity, this factor is included in a complex biological system that is set within a complex societal framework in which no single influence dominates. In this context, the EHU12/24 (code of a survey from the University of theBasque Country/Euskal Herriko Unibertsitatea UPV/EHU) study addresses these research needs using a university community based approach. This observational cohort study was designed to investigate the risk factors of overweight/obesity related to lifestyles, particularly those associated with diet, their psychosocial influences and the interactions among these factors, in a representative sample of the UPV/EHU student population. Anthropometric measurements, direct behavioural determinants, such as physical activity and diet, and indirect determinants, such as social/psychological factors, were considered. The results provide valuable data for analysing the complexity and multidimensionality of obesity in university students., [EU] Nahiz eta, denboraldi luze bateko energia desoreka gainpisua/obesitatearen arrazoi nagusia dela iruditu, faktore hau sistema biologiko konplexu baten parte da eta sistema honetan ez dago menderatzen duen influentzia bakarra. Testuinguru honetan, EHU12/24 ikerketak (Euskal Herriko Unibertsitateko UPV/EHU ikerketa baten kodea) unibertsitate komunitatean oinarritutako ikuspegia erabiltzen du behar hauek aztertzeko. Behaketako kohorte ikerketa hau bizi-ohiturekin lotutako gainpisua/obesitatearen arrisku faktoreak, dietarekin erlazionaturikoak bereziki, bere eragin psikosozialak eta faktore hauen arteko interakzioa, UPV/EHU ikasle lagin adierazgarri batean aztertzeko diseinatu zen. Ikerketa honetan, neurri antropometrikoak, determinatzaileak diren jarrerak, adibidez, ariketa fisikoa eta dieta (osasun eta ingurumenaren ikuspuntuetatik), eta zeharkako jarrerak, esaterako, faktore sozio/psikologikoak kontuan hartu ziren. Emaitzek baliodun datuak ematen dituzte obesitatearen konplexutasuna eta gaixotasunaren determinatzaileen interakzioak analizatzeko unibertsitate ikasleetan.

665 p., En la presente tesis doctoral, por un lado, se abordó el estudio de la caracterización de aceites vegetales de diferente origen botánico, prestando atención a su composición en componentes minoritarios mediante el empleo de una técnica analítica desarrolla en nuestro laboratorio, Inmersión Directa-Microextracción en Fase Sólida seguida de Cromatografía de Gases / Espectrometría de Masas (ID MEFS-CG/EM).Asimismo, se estudiaron los cambios que sufren los componentes lipídicos del aceite de maíz cuando éste es sometido a condiciones oxidativas y/o tratamiento tecnológico, nixtamalización y la elaboración de tortillas, mediante Resonancia Magnética Nuclear de Protón (RMN de 1H) y Inmersión Directa-Microextracción en Fase Sólida seguida de Cromatografía de Gases / Espectrometría de Masas (ID MEFS-CG/EM). Los aspectos composicionales abordados fueron la evolución de la concentración delos componentes mayoritarios y minoritarios, así como la evolución de la concentración de los nuevoscompuestos formados derivados de la degradación de los anteriores. Cabe señalar que algunos de loscompuestos detectados derivados de la degradación de los compuestos tanto mayoritarios comominoritarios del aceite, no habían sido descritos previamente durante el proceso de oxidación de aceites yestán relacionados con diversas enfermedades.Por último, se abordó el estudio de la digestión in vitro en diferentes aceites vegetales, oliva,maíz y lino virgen, prestando especial atención a las reacciones de lipólisis y de oxidación, e intentandorelacionar la bioaccesibilidad de los componentes mayoritarios de los aceites con su composición, si lahubiera. Además, estos mismos aceites fueron enriquecidos con diferentes compuestos fenólicos, alphaygamma-tocoferol, hidroxitirosol acetato y galato de dodecilo, a diferentes concentraciones y sometidosa las mismas condiciones de digestión in vitro, con el objeto de estudiar el efecto que el enriquecimientocon ciertos compuestos fenólicos ejerce sobre el grad

Mesenchymal stromal cells (MSCs) have unique immunomodulatory capacities. We investigated hair follicle-derived MSCs (HF-MSCs) from the dermal sheath, which are advantageous as an alternative source because of their relatively painless and minimally risky extraction procedure. These cells expressed neural markers upon isolation and maintained stemness for a minimum of 10 passages. Furthermore, HF-MSCs showed responsiveness to pro-inflammatory environments by expressing type-II major histocompatibility complex antigens (MHC)-II to a lesser extent than adipose tissue-derived MSCs (AT-MSCs). HF-MSCs effectively inhibited the proliferation of peripheral blood mononuclear cells equivalently to AT-MSCs. Additionally, HF-MSCs promoted the induction of CD4+CD25+FOXP3+ regulatory T cells to the same extent as AT-MSCs. Finally, HF-MSCs, more so than AT-MSCs, skewed M0 and M1 macrophages towards M2 phenotypes, with upregulation of typical M2 markers CD163 and CD206 and downregulation of M1 markers such as CD64, CD86, and MHC-II. Thus, we conclude that HF-MSCs are a promising source for immunomodulation.

The present work aimed to analyze, through the GlutenFreeDiet digital platform, the evolution over one year of the nutritional status, dietary profile and symptoms present among celiac people on a gluten-free diet (GFD) while receiving individualized dietary advice. Twenty-seven adults and thirty-one celiac children/adolescents participated in the study. This was then followed up by three visits, at diagnosis, and after 3 and 12 months (vt0, vt3 and vt12). Participants filled out dietary and gastrointestinal symptoms questionnaires. All patients received written personalized dietary advice from dietitians who interpreted data from the platform. Results obtained indicated that participants consumed proteins and lipids in excess and carbohydrates in defect. Low intakes of cereals, fruit and vegetables and high meat intakes were observed. However, gluten-free product (GFP) consumption and that of ultra-processed foods was reduced after 1 year in adults. Symptoms decreased after vt3 but recurred in vt12. Changes in ultra-processed foods and GFP intake, but lack of changes in the rest of the parameters suggested that the platform support was not effective enough. Even though the platform represents a useful tool for monitoring celiac patients and giving dietary advice, modules that require more continuous attention and nutritional education of patients should be provided for interventions to be more effective.

Skin tissue engineering and regeneration aim at repairing defective skin injuries and progress in wound healing. Until now, even though several developments are made in this field, it is still challenging to face the complexity of the tissue with current methods of fabrication. In this review, short, state-of-the-art on developments made in skin tissue engineering using 3D bioprinting as a new tool are described. The current bioprinting methods and a summary of bioink formulations, parameters, and properties are discussed. Finally, a representative number of examples and advances made in the field together with limitations and future needs are provided.

[EN] Interdisciplinary collaboration between health professionals is essential to improve health outcomes. The competences of pharmacists make them professionals capable of contributing to the comprehensive management of pharmacotherapy in collaboration with other healthcare professionals. The Council of Europe adopted resolution CM/Res(2020)3 on implementation of pharmaceutical care for the benefit of patients and health services in order to promote the appropriate and safe use of medicines. One of the activities to be carried out through the pharmaceutical care process is the detection of drug related problems, such as contraindications, duplications, prescription errors, interactions, etc. In many cases, it involves regular patient follow-up and needs an evaluation of the interventions performed, requiring the establishment of an appropriate interprofessional collaboration framework. This article discusses the issues to be addressed to face the change of model towards a care-based pharmacy.

Volatile compounds from cooked and aged (0, 7, 14, 21 days) Hispano-Bret ' on horse meat (loin) were analyzed by solid-phase microextraction coupled to gas chromatography-mass spectrometry. A total of 77 volatile com-pounds were found, from which aldehydes were the predominant family. Most of the identified compounds had their origin in the degradation of lipids, with a negligible contribution of Maillard derived products. Odour impact ratios were calculated and used as indicators of the contribution of each compound to the total aroma and aldehydes were, in general, the major contributors to cooked horse meat aroma. Results revealed that ageing affected 15 of the volatile compounds detected. From them, hexadecanal and 2-and 3-methylbutanal signifi-cantly increased during ageing, presumably affecting the cooked meat odour as these have considerable odorant impact. Under the present study conditions, periods longer than 14 days would be necessary for significant changes in the volatile profile of cooked horse meat.

[EN] Bipolar disorder (BD) might be associated with higher infection rates of coronavirus disease (COVID-19) which in turn could result in worsening the clinical course and outcome. This may be due to a high prevalence of somatic comorbidities and an increased risk of delays in and poorer treatment of somatic disease in patients with severe mental illness in general. Vaccination is the most important public health intervention to tackle the ongoing pandemic. We undertook a systematic review regarding the data on vaccinations in individuals with BD. Proportion of prevalence rates, efficacy and specific side effects of vaccinations and in individuals with BD were searched. Results show that only five studies have investigated vaccinations in individuals with BD, which substantially limits the interpretation of overall findings. Studies on antibody production after vaccinations in BD are very limited and results are inconsistent. Also, the evidence-based science on side effects of vaccinations in individuals with BD so far is poor.

P-glycoprotein (P-gp) is a drug efflux transporter that triggers doxorubicin (DOX) resistance. In this review, we highlight the molecular avenues regulating P-gp, such as Nrf2, HIF-1alpha, miRNAs, and long noncoding (lnc)RNAs, to reveal their participation in DOX resistance. These antitumor compounds and genetic tools synergistically reduce P-gp expression. Furthermore, ATP depletion impairs P-gp activity to enhance the antitumor activity of DOX. Nanoarchitectures, including liposomes, micelles, polymeric nanoparticles (NPs), and solid lipid nanocarriers, have been developed for the co-delivery of DOX with anticancer compounds and genes enhancing DOX cytotoxicity. Surface modification of nanocarriers, for instance with hyaluronic acid (HA), can promote selectivity toward cancer cells. We discuss these aspects with a focus on P-gp expression and activity.

Objective: To evaluate diets in terms of nutritional characteristics and quality from the perspectives of health, greenhouse gas emissions (GHGE) and possible associations with each other in a representative sample of students at a public university. Design: Cross-sectional. Dietary intake was evaluated with a validated FFQ, and diet quality was assessed through the Healthy Eating Index (HEI-2010) and MedDietScore (MDS). GHGE data were obtained from the literature. In addition, sex, socio-economic status (SES) and body fat (BF) status were analysed as covariates. Setting: Basque Autonomous Community, Spain. Participants: Totally, 26 165 healthy adults aged 18-28 years. Results: Student diets were characterised by low consumption of carbohydrates (38 center dot 72 % of total energy intake (TEI)) and a high intake of lipids (39 center dot 08 % of TEI). Over half of the participants had low dietary quality. The low-emitting diets were more likely to be consumed by subjects with low HEI-2010 scores (beta: 0 center dot 039 kg eCO(2)/1000 kcal/d) and high MDS scores (beta: -0 center dot 023 kg eCO(2)/1000 kcal/d), after controlling for sex, SES and BF status. Both the low-emitting and healthy diets were more likely to be consumed by women and by those with normal BF percentage. Conclusions: UPV/EHU university students' diets were characterised by moderate quality from a nutritional perspective and moderate variation in the size of carbon footprints. In this population, diets of the highest quality were not always those with the lowest diet-related GHGE; this relationship depended in part on the constructs and scoring criteria of diet quality indices used.

[EN] The ageing process after animal slaughter enhances tenderness and influences the value of meat. Horse meat is becoming more popular but lacks standardized ageing practices that should be supported by a better understanding of post-mortem muscle biochemistry. Steaks from Longissimus Thoracis et Lumborum (LTL) of eight Hispano-Breton horses were aged for 0, 7, 14 and 21days and myofibrillar proteins were resolved by one dimensional gel electrophoresis (1-DE). Ten protein bands were found to change (p≤0.05) among ageing periods. Most changes were observed between days 0 and 14, suggesting that tenderization occurred primary during the first two weeks. Liquid isoelectric focusing (OFFGEL) technology was applied to better resolve myofibrillar sub-proteome and evidenced fourteen protein bands that changed (p≤0.05) between 0 and 21days. Three of them were protein fragments coming from troponins T and I and from creatine kinase. Identified molecules could be further studied as potential markers for horse meat tenderness.

Fluoroquinolones (FQs) are a critical group of antimicrobials prescribed in urological infections as they have a broad antimicrobial spectrum of activity and a favorable tissue penetration at the site of infection. However, their clinical practice is not problem-free of treatment failure, risk of emergence of resistance, and rare but important adverse effects. Due to their critical role in clinical improvement, understanding the dose-response relation is necessary to optimize the effectiveness of FQs therapy, as it is essential to select the right antibiotic at the right dose for the right duration in urological infections. The aim of this study was to review the published literature about inter-individual variability in pharmacological processes that can be responsible for the clinical response after empiric dose for the most commonly prescribed urological FQs: ciprofloxacin, levofloxacin, and moxifloxacin. Interindividual pharmacokinetic (PK) variability, particularly in elimination, may contribute to treatment failure. Clearance related to creatinine clearance should be specifically considered for ciprofloxacin and levofloxacin. Likewise, today, undesired interregional variability in FQs antimicrobial activity against certain microorganisms exists. FQs pharmacology, patient-specific characteristics, and the identity of the local infecting organism are key factors in determining clinical outcomes in FQs use.

Sunflower oil samples, both unenriched and enriched with four different concentrations of hydroxytyrosol acetate, were subjected to accelerated storage at 70 °C until a very advanced oxidation stage and the process was monitored by 1H NMR spectroscopy. The aim of the study is to know the effect that the presence of this antioxidant has on the oxidation process of sunflower oil under the aforementioned conditions, as well as on the formation and evolution of the concentration of a significant number of oxylipins. The oxidation process was studied globally by monitoring, during storage time, the degradation of both the linoleic acyl group of sunflower oil, which is the main component of sunflower oil, and the added hydroxytyrosol acetate. Simultaneously, the identification of up to twenty-six different types of oxylipins formed in the oxidation process and the monitoring of the evolution of their concentration over the storage time were carried out. In this way, essential information about the effect that hydroxytyrosol acetate provokes on the oxidation of this oil rich in omega-6 polyunsaturated acyl groups, has been obtained. It has also been shown that the enrichment of sunflower oil with this antioxidant under the conditions tested does not prevent the oxidation process but slows it down, affecting the entire oxidation process.

The present review aims at analyzing the current evidence regarding probiotic administration for non-alcoholic fatty liver disease (NAFLD) management. Additionally, the involved mechanisms of action modulated by probiotic administration, as well as the eventual limitations of this therapeutic approach and potential alternatives, are discussed. Preclinical studies have demonstrated that the administration of single-strain probiotics and probiotic mixtures effectively prevents diet-induced NAFLD. In both cases, the magnitude of the described effects, as well as the involved mechanisms of action, are comparable, including reduced liver lipid accumulation (due to lipogenesis downregulation and fatty acid oxidation upregulation), recovery of gut microbiota composition and enhanced intestinal integrity. Similar results have also been reported in clinical trials, where the administration of probiotics proved to be effective in the treatment of NAFLD in patients featuring this liver condition. In this case, information regarding the mechanisms of action underlying probiotics-mediated hepatoprotective effects is scarcer (mainly due to the difficulty of liver sample collection). Since probiotics administration represents an increased risk of infection in vulnerable subjects, much attention has been paid to parabiotics and postbiotics, which seem to be effective in the management of several metabolic diseases, and thus represent a suitable alternative to probiotic usage.

Coronavirus 2 (SARS-CoV2) (COVID-19) causes severe acute respiratory syndrome. Severe illness of COVID-19 largely occurs in older people and recent evidence indicates that demented patients have higher risk for COVID-19. Additionally, COVID-19 further enhances the vulnerability of older adults with cognitive damage. A balance between the immune and inflammatory response is necessary to control the infection. Thus, antimicrobial and anti-inflammatory drugs are hopeful therapeutic agents for the treatment of COVID-19. Accumulating evidence suggests that lactoferrin (Lf) is active against SARS-CoV-2, likely due to its potent antiviral and anti-inflammatory actions that ultimately improves immune system responses. Remarkably, salivary Lf levels are significantly reduced in different Alzheimer's disease (AD) stages, which may reflect AD-related immunological disturbances, leading to reduced defense mechanisms against viral pathogens and an increase of the COVID-19 susceptibility. Overall, there is an urgent necessity to protect AD patients against COVID-19, decreasing the risk of viral infections. In this context, we propose bovine Lf (bLf) as a promising preventive therapeutic tool to minimize COVID-19 risk in patients with dementia or AD.

Epistaxis is one of the most common otorhinolaryngology emergencies worldwide. Although there are currently several treatments available, they present several disadvantages. This, in addition to the increasing social need of being environmentally respectful, led us to investigate whether a sponge-like scaffold (SP-CH) produced from natural by-products of the food industry - soy protein and beta-chitin - can be employed as a nasal pack for the treatment of epistaxis. To evaluate the potential of our material as a nasal pack, it was compared with two of the most commonly used nasal packs in the clinic: a basic gauze and the gold standard Merocel. Our SP-CH presented great physicochemical and mechanical properties, lost weight in aqueous medium, and could even partially degrade when incubated in blood. It was shown to be both biocompatible and hemocompatible in vitro, clearing up any doubt about its safety. It showed increased blood clotting capacity in vitro, as well as increased capacity to bind both red blood cells and platelets, compared to the standard gauze and Merocel. Finally, a rat-tail amputation model revealed that our SP-CH could even reduce bleeding time in vivo. This work, carried out from a circular economy approach, demonstrates that a green strategy can be followed to manufacture nasal packs using valorized by-products of the food industry, with equal or even better hemostatic properties than the gold standard in the clinic.

307 p., La presente Tesis Doctoral tiene como objetivo analizar el papel que juegan tanto los microRNAs como las adipocitokinas en el mecanismo de acción de diferentes patologías, además de su uso potencial como biomarcadores del desrrollo de esas enfermedades o de respuesta a sus tratamientos. Con el fin de alcanzar ese objetivo, se llevaron a cabo 3 proyectos de investigación:En el primero, se analizó cómo los microRNAs pueden estar involucrados en los efectos positivos del pteroestilbeno sobre la esteatosis hepática. Para ello, se midió la expresión de una serie de microRNAs en tejido hepático de ratas con esteatosis tratadas con pteroestilbeno y, mediante transfección de los mismos en hepatocitos, se estudió su mecanismo de acción a nivel celular.En el segundo, se analizó cómo los microRNAs pueden estar involucrados en los efectos sobre el metabolismo de la glucosa de un extracto de orujo de uva en personas con síndrome metabólico, y, al mismo tiempo, determinar su posible uso como marcadores de respuesta al tratamiento. Para ello, se analizó la expresión de varios microRNAs en muestras de sangre de personas con síndrome metabólico antes y después de ser tratadas con un extracto de orujo de uva, y también se compararon los valores entre los sujetos que respondieron al tratamiento y los que no.En el tercero, se investigó si las adipocitokinas podrían estar involucradas en la velocidad de crecimientode niños pequeños para la edad gestacional (PEG) y si podrían considerarse marcadores de futuras alteraciones metabólicas. Para esto, se analizó la concentración de varias adipokinas en sangre de niños PEG que tenían distintas velocidades de crecimiento durante los primeros 2 años de vida.Se pudo concluir que los microRNAs y las adipokinas pueden mediar en los mecanismos de acción y ser marcadores de respuesta terapéutica y de evolución de diferentes patologías.

246 p., Gene therapy is based on the delivery of exogenous genetic material into target cells to modulate theexpression of an altered genome in order to treat a specific disease. Lipid nanocarriers, such as niosomesbased on cationic lipids, non-ionic surfactants and ¿helper¿ components, are considered attractivecandidate for non-viral vectors due to their suitable biocompatibility and high versatility. The niosomechemical composition and their elaboration method influence the biophysical properties which have animpact on transfection efficiency and cytotoxicity. Indeed, compounds with specific properties have beenincluded to overcome some disadvantages of niosome formulations, such as chloroquine, which promotesendosomal escape. Gene therapy can be an excellent treatment for many disorders, in particular cysticfibrosis that is an autosomal monogenic recessive disease caused by different mutations in the cysticfibrosis conductance regulator (CFTR) gene. In this doctoral thesis, we focused on the development andin-depth biophysical and biological characterization of non-viral vectors based on cationic niosomes toface cystic fibrosis by gene therapy approach. The data obtained support that the inclusion of thechloroquine molecule in niosome formulations improves the biophysical properties of niosomes withenhanced transfection efficiencies and lower cytotoxicity. In addition, these niosomes are able to increasethe production of functional CFTR protein in cystic fibrosis cells. Furthermore, the development of athree-dimensional scaffold that better mimics the in vivo environment showed utility for evaluating newtreatments and different schedules of administration for cystic fibrosis.

172 p., La resistencia a los antibióticos (AMR) es un problema grave que debe abordarse lo antes posible. La colistina y la amikacina representan unos de los pocos antibióticos eficaces contra las infecciones de las bacterias gran-negativas multirresistentes, pero son altamente neuro y nefrotóxicos. De hecho, los médicos se ven obligados a elegir entre una dosis efectiva o segura, lo cual conduce mayoritariamente al fracaso del tratamiento. Teniendo eso en cuenta, los transportadores lipídicos nanoestructurados (NLCs) representan una estrategia cautivadora para reducir la toxicidad del fármaco, capaz de liberar antibióticos de manera sostenida y permitir la reducción de la dosis. En esta tesis doctoral, se han desarrollado, caracterizado y analizado las NLCs cargadas con colistina en modelos de neumonía en ratones con resultados prometedores, logrando una reducción significativa de la dosis, una mayor eficacia y una posible reducción de la toxicidad. Además, se probó la seguridad de la NLCs vacías aplicada tópicamente en piel intacta y dañada. Las NLCs resultaron ser seguras y podrían ejercer un efecto local sobre las heridas infectadas, lo cual representa una gran oportunidad a explotar en un futuro cercano. En esencia, los NLC podrían ser la más segura estrategia para el suministro de antibióticos en infecciones multiresistentes del tracto respiratorios y de heridas.

[EN] Background Levetiracetam pharmacokinetics is extensively altered in critically ill patients with augmented renal clearance (ARC). Consequently, the dosage regimens commonly used in clinical practice may not be sufficient to achieve target plasma concentrations. The aim of this study is to propose alternative dosage regimens able to achieve target concentrations in this population. Furthermore, the feasibility of the proposed dosing regimens will be discussed from a clinical point of view. Methods Different dosage regimens for levetiracetam were evaluated in critically ill patients with ARC. Monte Carlo simulations were conducted with extended or continuous infusions and/or high drug doses using a previously developed population pharmacokinetic model. To assess the clinical feasibility of the proposed dosages, we carried out a literature search to evaluate the information on toxicity and efficacy of continuous administration or high doses, as well as the post-dilution stability of levetiracetam. Results According to the simulations, target concentrations in patients with CrCl of 160 or 200 mL/min can be achieved with the 3000 mg daily dose by prolonging the infusion time of levetiracetam. For patients with CrCl of 240 mL/min, it would be necessary to administer doses higher than the maximum recommended. Available evidence suggests that levetiracetam administration in continuous infusion or at higher doses than those approved seems to be safe. It would be desirable to re-examinate the current recommendations about drug stability and to achieve a consensus in this issue. Conclusions Conventional dosage regimens of levetiracetam (500-1500 mg twice daily in a short infusion) do not allow obtaining drug plasma concentrations among the defined target in critically ill patients with ARC. Therefore, new dosing guidelines with specific recommendations for patients in this subpopulation are needed. This study proposes new dosages for levetiracetam, including extended (4 o

[EN] Background Mesenchymal stromal cells (MSCs) and their extracellular vesicles (MSC-EVs) have demonstrated to elicit immunomodulatory and pro-regenerative properties that are beneficial for the treatment of chronic wounds. Thanks to different mediators, MSC-EVs have shown to play an important role in the proliferation, migration and cell survival of different skin cell populations. However, there is still a big bid to achieve the most effective, suitable and available source of MSC-EVs. Methods We isolated, characterized and compared medium-large EVs (m-lEVs) and small EVs (sEVs) obtained from hair follicle-derived MSCs (HF-MSCs) against the gold standard in regenerative medicine, EVs isolated from adipose tissue-derived MSCs (AT-MSCs). Results We demonstrated that HF-EVs, as well as AT-EVs, expressed typical MSC-EVs markers (CD9, CD44, CD63, CD81 and CD105) among other different functional markers. We showed that both cell types were able to increase human dermal fibroblasts (HDFs) proliferation and migration. Moreover, both MSC-EVs were able to increase angiogenesis in human umbilical vein endothelial cells (HUVECs) and protect HDFs exposed to a hyperglycemic environment from oxidative stress and cytotoxicity. Conclusions Taken together, HF-EVs demonstrated to exhibit comparable potential to that of AT-EVs as promising candidates in the treatment of chronic wounds.

[EN] Microalgae and microalgae-derived ingredients are one of the top trends in the food industry. However, consumers' acceptance and purchase intention of a product will be largely affected by odour and flavour. Surprisingly, the scientific literature present a very limited number of studies on the volatile composition of microalgae and cyanobacteria. In order to fill the gap, the main objective of the present study was to elucidate the volatile composition of seven microalgal and cyanobacterial strains from marine and freshwaters, with interest for the food industry while establishing its potential impact in odour. Among the seven selected strains, Arthrospira platensis showed the highest abundance and chemical diversity of volatile organic compounds (VOCs). Aldehydes, ketones, and alcohols were the families with the highest diversity of individual compounds, except in Arthrospira platensis and Scenedesmus almeriensis that showed a profile dominated by branched hydrocarbons. Marine strains presented a higher abundance of sulfur compounds than freshwater strains, while the ketones individual profile seemed to be more related to the taxonomical domain. The results of this study indicate that the VOCs composition is mainly driven by the individual strain although some volatile profile characteristics could be influenced by both environmental and taxonomical factors.

When analysing the beneficial effects of phenolic compounds, several factors that exert a clear influence should be taken into account. The content of phenolic compounds in foods is highly variable, directly affecting individual dietary intake. Once ingested, these compounds have a greater or lesser bioaccessibility, defined as the amount available for absorption in the intestine after digestion, and a certain bioavailability, defined as the proportion of the molecule that is available after digestion, absorption and metabolism. Among the external factors that modify the content of phenolic compounds in food are the variety, the cultivation technique and the climate. Regarding functional foods, it is important to take into account the role of the selected food matrix, such as dairy matrices, liquid or solid matrices. It is also essential to consider the interactions between phenolic compounds as well as the interplay that occurs between these and several other components of the diet (macro- and micronutrients) at absorption, metabolism and mechanism of action levels. Furthermore, there is a great inter-individual variability in terms of phase II metabolism of these compounds, composition of the microbiota, and metabolic state or metabotype to which the subject belongs. All these factors introduce variability in the responses observed after ingestion of foods or nutraceuticals containing phenolic compounds.

Lipid oxidation causes food degradation and the formation of toxic compounds. Therefore, the addition to foods of compounds able to avoid, delay or minimize this degradative process is a commonly used strategy. Nevertheless, neither the identity of most of the formed compounds in this complex process nor the way in which their formation is affected by the strategy used are well known. In this context, the effect the temperature increase and the enrichment level in alpha-tocopherol on the evolution of the walnut oil oxidation, as a model of an oil rich in polyunsaturated omega-6 acyl groups, submitted to storage conditions, are tackled by 1H NMR. The study has allowed knowing the degradation kinetic of both the oil acyl groups and alpha-tocopherol, the identification of a very high number of oxylipins and the kinetic of their formation. The temperature increase accelerates the formation of all oxylipins, favouring the formation of hydroperoxy conjugated E,E-dienes and related derivatives versus that of the Z,E-isomers. The enrichment in alpha-tocopherol accelerates the formation of hydroperoxy conjugated Z,E-dienes and related derivatives, and delays in relation to the formation of the former that of the E,E-isomers and related derivatives, hindering, to a certain extent, the formation of the latter in line with the enrichment level.

[EN] Central nervous system (CNS) diseases, especially acute ischemic events and neurodegenerative disorders, constitute a public health problem with no effective treatments to allow a persistent solution. Failed therapies targeting neuronal recovery have revealed the multifactorial and intricate pathophysiology underlying such CNS disorders as ischemic stroke, Alzheimers disease, amyotrophic lateral sclerosis, vascular Parkisonism, vascular dementia, and aging, in which cerebral microvasculature impairment seems to play a key role. In fact, a reduction in vessel density and cerebral blood flow occurs in these scenarios, contributing to neuronal dysfunction and leading to loss of cognitive function. In this review, we provide an overview of healthy brain microvasculature structure and function in health and the effect of the aforementioned cerebral CNS diseases. We discuss the emerging new therapeutic opportunities, and their delivery approaches, aimed at recovering brain vascularization in this context. SIGNIFICANCE STATEMENT: The lack of effective treatments, mainly focused on neuron recovery, has prompted the search of other therapies to treat cerebral central nervous system diseases. The disruption and degeneration of cerebral microvasculature has been evidenced in neurodegenerative diseases, stroke, and aging, constituting a potential target for restoring vascularization, neuronal functioning, and cognitive capacities by the development of therapeutic pro-angiogenic strategies.

[EN] The ability of mesenchymal stromal cells (MSCs) to release a plethora of immunomodulatory factors makes them valuable candidates to overcome inflammatory bowel diseases (IBD). However, this cell therapy approach is still limited by major issues derived from nude MSC-administration, including a rapid loss of their immunomodulatory phenotype that impairs factor secretion, low persistence and impossibility to retrieve the cells in case of adverse effects. Here, we designed a licensing hydrogel system to address these limitations and thus, obtain a continuous delivery of bioactive factors. IFN gamma-loaded heparin-coated beads were included in injectable in situ crosslinking alginate hydrogels, providing a 3D microenvironment that ensured continuous inflammatory licensing, cell persistence and implant retrievability. Licensing-hydrogel encapsulated human MSCs (hMSCs) were subcutaneously xenotransplanted in an acute mouse model of ulcerative colitis. Results showed that encapsulated hMSCs exerted a delocalized systemic protection, not presenting significant differences to healthy mice in the disease activity index, colon weight/length ratio and histological score. At day 7, cells were easily retrieved and ex vivo assays showed fully viable hMSCs that retained an immunomodulatory phenotype, as they continued secreting factors including PGE2 and Gal-9. Our data demonstrate the capacity of licensing hydrogelencapsulated hMSCs to limit the in vivo progression of IBD.

[EN] BACKGROUND: Neurodegenerative diseases (NDs) are an accelerating global health problem. Nevertheless, the stronghold of the brain- the blood-brain barrier (BBB) prevents drug penetrance and dwindles effective treatments. Therefore, it is crucial to identify Trojan horse-like drug carriers that can effectively cross the blood-brain barrier and reach the brain tissue. We have previously developed polyunsaturated fatty acids (PUFA)-based nanostructured lipid carriers (NLC), namely DHAH-NLC. These carriers are modulated with BBB-permeating compounds such as chitosan (CS) and trans-activating transcriptional activator (TAT) from HIV-1 that can entrap neurotrophic factors (NTF) serving as nanocarriers for NDs treatment. Moreover, microglia are suggested as a key causative factor of the undergoing neuroinflammation of NDs. In this work, we used in vitro models to investigate whether DHAH-NLCs can enter the brain via the BBB and investigate the therapeutic effect of NTF-containing DHAH-NLC and DHAH-NLC itself on lipopolysaccharide-challenged microglia. METHODS: We employed human induced pluripotent stem cell-derived brain microvascular endothelial cells (BMECs) to capitalize on the in vivo-like TEER of this BBB model and quantitatively assessed the permeability of DHAH-NLCs. We also used the HMC3 microglia cell line to assess the therapeutic effect of NTF-containing DHAH-NLC upon LPS challenge. RESULTS: TAT-functionalized DHAH-NLCs successfully crossed the in vitro BBB model, which exhibited high transendothelial electrical resistance (TEER) values (3000 Omega*cm2). Specifically, the TAT-functionalized DHAH-NLCs showed a permeability of up to 0.4% of the dose. Furthermore, using human microglia (HMC3), we demonstrate that DHAH-NLCs successfully counteracted the inflammatory response in our cultures after LPS challenge. Moreover, the encapsulation of glial cell-derived neurotrophic factor (GNDF)-containing DHAH-NLCs (DHAH-NLC-GNDF) activated the Nrf2/HO-1 pathway, sugge

[EN] Nanodiamonds (NDs) are promising materials for gene delivery because of their unique physicochemical and biological features, along with their possibility of combination with other nonviral systems. Our aim was to evaluate the biophysical performance of NDs as helper components of niosomes, named nanodiasomes, to address a potential nonviral gene delivery nanoplatform for therapeutic applications in central nervous system (CNS) diseases. Nanodiasomes, niosomes, and their corresponding complexes, obtained after genetic material addition at different ratios (w/w), were evaluated in terms of physicochemical properties, cellular uptake, intracellular disposition, biocompatibility, and transfection efficiency in HEK-293 cells. Nanodiasomes, niosomes, and complexes fulfilled the physicochemical features for gene therapy applications. Biologically, the incorporation of NDs into niosomes enhanced 75% transfection efficiency (p < 0.001) and biocompatibility (p < 0.05) to values over 90%, accompanied by a higher cellular uptake (p < 0.05). Intracellular trafficking analysis showed higher endocytosis via clathrins (p < 0.05) in nanodiaplexes compared with nioplexes, followed by higher lysosomal colocalization (p < 0.05), that coexisted with endosomal escape properties, whereas endocytosis mediated by caveolae was the most efficient pathway in the case of nanodiaplexes. Moreover, studies in CNS primary cells revealed that nanodiaplexes successfully transfected neuronal and retinal cells. This proof-of-concept study points out that ND integration into niosomes represents an encouraging nonviral nanoplatform strategy for the treatment of CNS diseases by gene therapy.

Pre-slaughter stress can lead to 'dark cutting' defective meat characterized by a high ultimate pH (pHu) in cattle, causing high economical losses in the meat industry. Therefore, the study of biochemical mechanisms related to animal stress response is a fact that needs to be addressed. The aim of this work was to determine caspase 9 and 3/7 activities in high and normal pHu muscle samples at 24 h post mortem as a way to reveal stress situations in different Spanish local breeds (Asturiana de los Valles, Retinta and Rubia Gallega) and crossbred animals (n = 83). Either breed or pHu factors had an effect in both caspase activities, showing the high pHu group the highest caspase activity independently of the studied breed. In contrast, activity levels among breeds were slightly different for each caspase and between the high and normal pHu group in the case of caspase 3/7. Overall, this study demonstrated that caspase activity can be a good indicator to detect stress situations that might lead to defective high pHu meats.

[EN] This study tackles the individual and joint effect of alpha-tocopherol and hydroxytyrosol acetate on the oxidation of sunflower oil submitted to accelerated storage conditions at intermediate temperature, in order to deepen the understanding of antioxidant–prooxidant behaviour. This was accomplished by 1H Nuclear Magnetic Resonance. For this purpose, the evolution of the degradation of both the main components of the oil and the aforementioned added compounds was monitored by this technique throughout the storage time. Furthermore, the formation of a very large number of oxylipins and the evolution of their concentration up to a very advanced stage of oil oxidation, as well as the occurrence of lipolysis, were also simultaneously studied. The results obtained show very clearly and thoroughly that in the oxidation process of the oil enriched in binary mixtures, interactions occur between alpha-tocopherol and hydroxytyrosol acetate that notably reduce the antioxidant effect of the latter compound with the corresponding negative consequences that this entails. The methodology used here has proved to be very efficient to evaluate the antioxidant power of mixtures of compounds

145 p., Introduction: Augmented renal clearance (ARC) is a phenomenon recently identified in critically ill patients.ARC has the potential to influence the pharmacokinetic profile of any drug that is renally cleared andknown to have a direct correlation between renal clearance (CL) and creatinine clearance (CrCl), such aslevetiracetam. Objective: The aim of this thesis was initially to evaluate the adequacy of levetiracetamdosing for the achievement of therapeutic levels in patients with normal or high renal clearance admittedto the ICU by the characterization of its pharmacokinetics by population modelling and simulation.Alternative dosage regimens able to achieve target concentrations in this population have been alsoproposed using stochastic simulations and considering biopharmaceutical and pharmacokinetic aspects.Methods: A systematic review on ARC phenomenon was conducted. A multicentre prospective study incritically ill patients treated with levetiracetam was carried out. A population pharmacokinetic model oflevetiracetam in critically ill patients was developed. Alternative dosage regimens were evaluated byMonte Carlo simulation. Results and discussion: The systematic review showed that ARC, defined as a CrCl>130 mL/min/1.73 m2 measured in urine, is present in 20 to 65% of critically ill patients, being youngerage, polytrauma and lower severity illness identified risk factors. Twenty-seven critically ill patients wereincluded in the pharmacokinetic study. A two-compartment model best described levetiracetampharmacokinetics in this population, only CrCl was found to be a significant covariate of its CL. In criticallyill patients with ARC conventional dosage regimens (500-1500 mg twice daily in a short infusion) do notallow to obtain trough plasma concentrations in the defined target, between 12 and 46mg/L. Newdosage regimens to be implemented in critically ill patients with ARC were proposed by using MonteCarlo simulations based on the population pharmacokinetic model

The present narrative review gathers the studies reported so far, addressing sex differences in the effects of cold exposure, feeding pattern and age on brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. In rodents, when exposed to decreasing temperatures, females activate thermogenesis earlier. Results obtained in humans go in the same line, although they do not provide results as solid as those obtained in rodents. Regarding the effects of overfeeding, interesting sex differences on BAT thermogenic capacity have been reported, and the greater or lower sensitivity of each sex to this dietary situation seems to be dependent on the type of feeding. In the case of energy restriction, females are more sensitive than males. In addition, sex differences have also been observed in thermogenesis changes induced by phenolic compound administration. During sexual development, an increase in BAT mass and BAT activity takes place. This phenomenon is greater in boys than in girls, probably due to its relation to muscle-mass growth. The opposite situation takes place during ageing, a lifespan period where thermogenic capacity declines, this being more acute in men than in women. Finally, the vast majority of the studies have reported a higher susceptibility to developing WAT browning amongst females. The scarcity of results highlights the need for further studies devoted to analysing this issue, in order to provide valuable information for a more personalised approach.

An essential step in the infection life cycle of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the proteolytic activation of the viral spike (S) protein, which enables membrane fusion and entry into the host cell. Two distinct classes of host proteases have been implicated in the S protein activation step: cell-surface serine proteases, such as the cell-surface transmembrane protease, serine 2 (TMPRSS2), and endosomal cathepsins, leading to entry through either the cell-surface route or the endosomal route, respectively. In cells expressing TMPRSS2, inhibiting endosomal proteases using nonspecific cathepsin inhibitors such as E64d or lysosomotropic compounds such as hydroxychloroquine fails to prevent viral entry, suggesting that the endosomal route of entry is unimportant; however, mechanism-based toxicities and poor efficacy of these compounds confound our understanding of the importance of the endosomal route of entry. Here, to identify better pharmacological agents to elucidate the role of the endosomal route of entry, we profiled a panel of molecules identified through a high-throughput screen that inhibit endosomal pH and/or maturation through different mechanisms. Among the three distinct classes of inhibitors, we found that inhibiting vacuolar-ATPase using the macrolide bafilomycin A1 was the only agent able to potently block viral entry without associated cellular toxicity. Using both pseudotyped and authentic virus, we showed that bafilomycin A1 inhibits SARS-CoV-2 infection both in the absence and presence of TMPRSS2. Moreover, synergy was observed upon combining bafilomycin A1 with Camostat, a TMPRSS2 inhibitor, in neutralizing SARS-CoV-2 entry into TMPRSS2-expressing cells. Overall, this study highlights the importance of the endosomal route of entry for SARS-CoV-2 and provides a rationale for the generation of successful intervention strategies against this virus that combine inhibitors of both entry pathways.

The serious challenge posed by multidrug-resistant bacterial infections with concomitant treatment failure and high mortality rates presents an urgent threat to the global health. We herein report the discovery of a new class of potent antimicrobial compounds that are highly effective against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The compounds were efficiently synthesized in one-pot employing a cascade of Groebke-Blackburn-Bienayme and aza-Michael addition reactions. Phenotypic screening of the pilot library against various bacterial species including methicillin-sensitive and MRSA strains, has identified potent chemotypes with minimal inhibitory concentrations (MIC) of 3.125-6.25 mu g/ml. The most potent compounds were fast-acting at eradicating exponentially growing MRSA, with killing achieved after 30 min of exposure to the compounds. They were also able to kill MRSA persister cells which are tolerant to most available medications. Microscopic analysis using fluorescence microscope and atomic force microscope indicate that these compounds lead to disruption of bacterial cell envelopes. Most notably, bacterial resistance toward these compounds was not observed after 20 serial passages in stark contrast to the significant resistance developed rapidly upon exposure to a clinically relevant antibiotic. Furthermore, the compounds did not induce significant hemolysis to human red blood cells. In vivo safety studies revealed a high safety profile of these motifs. These small molecules hold a promise for further studies and development as new antibacterial agents against MRSA infections.

[EN] There is limited evidence to support the relationship between the consumption of animal-source foods other than red meat and processed meat and colorectal cancer (CRC) risk. We aimed to examine the recent available evidence from observational studies about the association between these food groups’ intake and CRC risk. For this systematic review, we searched the PubMed database for the last five years. A total of fourteen cohort studies and seven case–control studies comprising a total of >60,000 cases were included. The studies showed a consistent significant decrease in CRC risk, overall and by subsites, associated with a high consumption of total dairy products. Less strong effects associated with the consumption of any subtype of dairy product were observed. Fish consumption, overall and by subtypes (oily or non-oily and fresh or canned), showed a mild inverse association with CRC risk. The association between white meat and egg intake and CRC risk was low and based on a small number of studies; thus, these findings should be interpreted with caution. In conclusion, a high consumption of total dairy products was associated with a lower CRC risk. However, evidence for fish, white meat, and eggs and the CRC risk were not as strong.