Dysfunctional antioxidant capacity of high-density lipoprotein in rheumatoid arthritis.

BACKGROUND: High-density lipoprotein (HDL) presents atheroprotective functions not readily reflected by plasma HDL-cholesterol levels. The aim of this study was to investigate HDL antioxidant function in patients with rheumatoid arthritis (RA). METHODS: This pilot and cross-sectional study included 50 RA patients and 50 controls matched by age, gender, cardiovascular risk factors and drug therapy. The antioxidant capacity of HDL was assessed by the total radical-trapping antioxidative potential test (TRAP-assay) and the susceptibility of low-density lipoprotein (LDL) to oxidation by the Conjugated Dienes Assay (Dmax ). A carotid ultrasound was performed in all participants to detect subclinical atherosclerosis. RESULTS: High-density lipoprotein from RA patients showed lower antioxidant capacity than those from controls [oxidized-LDL%: 35.8 (27-42) vs. 24.4 (20-32), p < .001] when analysed with the TRAP-assay. In addition, the time to achieve 50% of maximal LDL oxidation (Lag-time) was shorter in RA-patients than in matched controls [57.2 (42-71) vs. 69.5 (55-75) minutes, (p = .003)]. RA patients showed a higher atherosclerotic burden than controls. The pro-oxidant pattern in RA was irrespective of the presence of carotid atherosclerosis. On the contrary, there was a positive correlation between inflammatory parameters (erythrocyte sedimentation rate, ultrasensitive C-reactive protein and fibrinogen) and the loss of HDL-anti-oxidant capacity measured by the TRAP-assay (rho = .211, p = .035; rho = .231, p = .021 and rho = .206, p = .041, respectively). Furthermore, the glucocorticoid dose at recruitment was negatively associated with the Lag-time in RA patients (rho = -.387, p = .026). CONCLUSION: Rheumatoid arthritis patients present reduced HDL antioxidant capacity and a lower resistance of LDL particles to oxidation, mainly related to the degree of inflammation.

Safe and Efficient Gene Therapy for Pyruvate Kinase Deficiency.

Pyruvate kinase deficiency (PKD) is a monogenic metabolic disease caused by mutations in the PKLR gene that leads to hemolytic anemia of variable symptomatology and that can be fatal during the neonatal period. PKD recessive inheritance trait and its curative treatment by allogeneic bone marrow transplantation provide an ideal scenario for developing gene therapy approaches. Here, we provide a preclinical gene therapy for PKD based on a lentiviral vector harboring the hPGK eukaryotic promoter that drives the expression of the PKLR cDNA. This therapeutic vector was used to transduce mouse PKD hematopoietic stem cells (HSCs) that were subsequently transplanted into myeloablated PKD mice. Ectopic RPK expression normalized the erythroid compartment correcting the hematological phenotype and reverting organ pathology. Metabolomic studies demonstrated functional correction of the glycolytic pathway in RBCs derived from genetically corrected PKD HSCs, with no metabolic disturbances in leukocytes. The analysis of the lentiviral insertion sites in the genome of transplanted hematopoietic cells demonstrated no evidence of genotoxicity in any of the transplanted animals. Overall, our results underscore the therapeutic potential of the hPGK-coRPK lentiviral vector and provide high expectations toward the gene therapy of PKD and other erythroid metabolic genetic disorders.

Autochthonous Wheat Grown in Organic and Conventional Systems: Nutritional Quality of Flour and Bread.

A growing interest in the recovery and enhancement of crops, particularly local varieties such as 'Caaveiro' wheat, has been observed. This study aims to investigate the impact of cultivation systems (organic versus conventional) on the nutritional quality of 'Caaveiro' flour and breads protected by the PGI "Pan Galego," employing two fermentation methods (sourdough versus sourdough and biological yeast). Organic flour exhibited significantly higher levels of moisture, fat, sucrose, phosphorus (P), sodium (Na), and copper (Cu) while also exhibiting a lower total starch and zinc (Zn) content. Organic bread, produced using both fermentation methods, demonstrated significantly higher protein, carbohydrate, total, resistant, and rapidly digestible starch, ash, Na, P, iron (Fe), and Cu content. Additionally, they contained less moisture compared to conventional bread. Despite variations in nutritional characteristics based on the cultivation system, the organic approach proved effective at producing high-quality products with a positive environmental impact, which is highly appreciated by consumers.

CO2 Levels Modulate Carbon Utilization, Energy Levels and Inositol Polyphosphate Profile in Chlorella.

Microalgae have a growing recognition of generating biomass and capturing carbon in the form of CO2. The genus Chlorella has especially attracted scientists' attention due to its versatility in algal mass cultivation systems and its potential in mitigating CO2. However, some aspects of how these green microorganisms respond to increasing concentrations of CO2 remain unclear. In this work, we analyzed Chlorella sorokiniana and Chlorella vulgaris cells under low and high CO2 levels. We monitored different processes related to carbon flux from photosynthetic capacity to carbon sinks. Our data indicate that high concentration of CO2 favors growth and photosynthetic capacity of the two Chlorella strains. Different metabolites related to the tricarboxylic acid cycle and ATP levels also increased under high CO2 concentrations in Chlorella sorokiniana, reaching up to two-fold compared to low CO2 conditions. The signaling molecules, inositol polyphosphates, that regulate photosynthetic capacity in green microalgae were also affected by the CO2 levels, showing a deep profile modification of the inositol polyphosphates that over-accumulated by up to 50% in high CO2 versus low CO2 conditions. InsP4 and InsP6 increased 3- and 0.8-fold, respectively, in Chlorella sorokiniana after being subjected to 5% CO2 condition. These data indicate that the availability of CO2 could control carbon flux from photosynthesis to carbon storage and impact cell signaling integration and energy levels in these green cells. The presented results support the importance of further investigating the connections between carbon assimilation and cell signaling by polyphosphate inositols in microalgae to optimize their biotechnological applications.

Element Content in Different Wheat Flours and Bread Varieties.

The most consumed cereal-based product worldwide is bread. "Caaveiro", an autochthonous variety with a recent growing interest, is one of the wheat varieties that fulfill the 25% local flour requirement in the PGI "Pan Galego" bread baking industry. The element content of the refined wheat flours used to make "Pan Galego" (''Caaveiro'', FCv; Castilla, FC; and a mixture of both, FM) was evaluated in ICP-MS. In addition, wholegrain flour (FWM) was included in the analysis. Loaves of bread were made with these flours (a, 100% FC; b, 100% FCv); and c, FM: 75% FC + 25% FCv) and their element content was analyzed. Wholegrain flour ranked the highest in almost all elements, highlighting the P (494.80 mg/100 g), while the FM and the FC presented the opposite behavior, with the highest Se values (14.4 and 15.8 mg/100 g, respectively). FCv was situated in an intermediate position regarding P, K, Mg, Mn, Zn, Fe and Na content, standing closer to FWM, although it presents the highest values for Cu (1076.3 µg/100 g). The differences observed in flour were maintained in bread. Hence, the local cultivar ''Caaveiro'' has an interesting nutritional profile from the point of view of the element content.

Invariance of the Trait Emotional Intelligence Construct Across Clinical Populations and Sociodemographic Variables.

Recent research has shown that cultural, linguistic, and sociodemographic peculiarities influence the measurement of trait emotional intelligence (trait EI). Assessing trait EI in different populations fosters cross-cultural research and expands the construct's nomological network. In mental health, the trait EI of clinical populations has been scarcely researched. Accordingly, the present study examined the relationship between trait EI and key sociodemographic variables on Trait Emotional Intelligence Questionnaire (TEIQue-SF) datasets with mental healthcare patients from three different Spanish-speaking countries. Collectively, these datasets comprised 528 participants, 23% from Chile (120), 28% from Peru (150), and 49% from Spain (258). The sociodemographic variables we used for trait EI comparisons were gender, age, educational level, civil status, and occupational status. Analyses involved Multigroup Exploratory Structural Equation Modelling (to test measurement invariance) and analysis of covariance (ANCOVA). Our results revealed significant between-country differences in trait EI across the studied sociodemographic variables and interactions between these variables. Measurement invariance across the datasets was attained up to the scalar level regarding gender and education (i.e., strong invariance), although analyses on age, civil status, and occupation displayed non-invariance. The resultant psychometric evidence supports the suitability of the TEIQue-SF for the accurate cross-cultural assessment of trait EI in mental health settings. It also highlights the importance of incorporating trait EI into extant psychotherapeutic frameworks to enhance non-pharmacological treatment efficacy.

Rescue of pyruvate kinase deficiency in mice by gene therapy using the human isoenzyme.

Human erythrocyte R-type pyruvate kinase deficiency (PKD) is a disorder caused by mutations in the PKLR gene that produces chronic nonspherocytic hemolytic anemia. Besides periodic blood transfusion and splenectomy, severe cases require bone marrow (BM) transplant, which makes this disease a good candidate for gene therapy. Here, the normal human R-type pyruvate kinase (hRPK) complementary (cDNA) was expressed in hematopoietic stem cells (HSCs) derived from pklr deficient mice, using a retroviral vector system. These mice show a similar red blood cell phenotype to that observed in human PKD. Transduced HSCs were transplanted into myeloablated adult PKD mice or in utero injected into nonconditioned PKD fetuses. In the myeloablated recipients, the hematological manifestations of PKD were completely resolved and normal percentages of late erythroid progenitors, reticulocyte and erythrocyte counts, hemoglobin levels and erythrocyte biochemistry were restored. Corrected cells preserved their rescuing capacity after secondary and tertiary transplant. When corrected cells were in utero transplanted, partial correction of the erythrocyte disease was obtained, although a very low number of corrected cells became engrafted, suggesting a different efficiency of cell therapy applied in utero. Our data suggest that transduction of human RPK cDNA in PKLR mutated HSCs could be an effective strategy in severe cases of PKD.

Osteoporosis and vascular calcification: A shared scenario. / Osteoporosis y calcificación vascular: un escenario compartido.

Osteoporosis is a systemic skeletal disease, characterised by low bone mass and deterioration in the micro-architecture of bone tissue, which causes increased bone fragility and consequently greater susceptibility to fractures. It is the most frequent metabolic bone disease in our population, and fractures resulting from osteoporosis are becoming more common. Furthermore, vascular calcification is a recognised risk factor of cardiovascular morbidity and mortality that historically has been considered a passive and degenerative process. However, it is currently recognised as an active process, which has histopathological characteristics, mineral composition and initiation and development mechanisms characteristic of bone formation. Paradoxically, patients with osteoporosis frequently show vascular calcifications. Traditionally, they have been considered as independent processes related to age, although more recent epidemiological studies have shown that there is a close relationship between the loss of bone mass and vascular calcification, regardless of age. In fact, both conditions share risk factors and pathophysiological mechanisms. These include the relationship between proteins of bone origin, such as osteopontin and osteoprotegerin (OPG), with vascular pathology, and the intercellular protein system RANK/RANKL/OPG and the Wnt signalling pathway. The mechanisms linked in both pathologies should be considered in clinical decisions, given that treatments for osteoporosis could have unforeseen effects on vascular calcification, and vice versa. In short, a better understanding of the relationship between both entities can help in proposing strategies to reduce the increasing prevalence of vascular calcification and osteoporosis in the aging population.

Rhabdomyolysis and drug abuse in a patient with bulimia nervosa.

OBJECTIVE: Eating disorders, particularly bulimia nervosa, have long been associated with alcohol and illicit drug abuse. Impulsivity has been linked to substance abuse, but there are other explanations for this association. This comorbidity could be very harmful, even deadly, because of the medical consequences of drug abuse. METHOD: This article reports on the case of a 23-year-old woman with bulimia nervosa, severe alcohol and illicit drug abuse, and impulsive behavior who developed rhabdomyolysis. One of the reasons for her drug addiction was the effect of these substances in appetite suppression. RESULTS: The patient successfully recovered after medical and psychological treatment. CONCLUSION: This article presents the case of a patient with bulimia nervosa and a serious medical complication of illicit drug abuse. It is important to be aware of the increased risk of morbidity and mortality for this patient group.

Cognitive Fusion Mediates the Relationship between Dispositional Mindfulness and Negative Affects: A Study in a Sample of Spanish Children and Adolescent School Students.

Nowadays, mindfulness-based interventions (MBI) have experienced a remarkable development of studies among childhood and adolescent interventions. For this reason, dispositional mindfulness (DM) measures for children and adolescents have been developed to determine the effectiveness of MBI at this age stage. However, little is known about how key elements of DM (for example, cognitive de/fusion or experiential avoidance that both confirm psychological inflexibility) are involved in the mechanisms of the children and adolescents' mental health outcomes. This research examined the mediating effect of cognitive fusion between DM and anxiety and other negative emotional states in a sample of 318 Spanish primary-school students (aged between 8 and 16 years, M = 11.24, SD = 2.19, 50.8% males). Participants completed the AFQ-Y (Avoidance and Fusion Questionnaire for youth), which is a measure of psychological inflexibility that encompasses cognitive defusion and experiential avoidance; CAMM (DM for children and adolescents), PANAS-N (positive and negative affect measure for children, Spanish version of PANASC), and STAIC (an anxiety measure for children). The study accomplished ethical standards. As MBI relevant literature has suggested, cognitive defusion was a significant mediator between DM and symptoms of both negative emotions and anxiety in children and adolescents. However, experiential avoidance did not show any significant mediating relationship. Probably, an improvement of the assessment of experiential avoidance is needed. MBI programs for children and adolescents may include more activities for reducing effects of the cognitive defusion on their emotional distress.

A Brief Spanish Version of the Child and Adolescent Mindfulness Measure (CAMM). A Dispositional Mindfulness Measure.

Dispositional Mindfulness (DM) is the awareness of the thoughts and feelings in the present moment. DM in children and adolescents has been related to mechanisms of change in mindfulness-based interventions, which have shown significant mediation relationships with mental health outcomes (for instance, lower social anxiety, depression symptoms, or perceived stress). However, the assessment of DM among children and adolescents is being unsatisfactory due cultural biases and/or reliability issues. In this study, we examined the psychometric properties of the Spanish version of the Child and Adolescent Mindfulness Measure (CAMM) in a sample of 687 children and adolescents between 8 and 16 years old. Although the CAMM has been validated in English, Portuguese, Italian, and Catalonian versions, until now no data has been reported in a Spanish context. Results showed that the best CAMM factor structure was constituted by five items from the original version (1, 4, 7, 8, and 9). These items defined dispositional mindfulness. The rest of the items (2, 3, 5, 6, and 10) were eliminated from the Spanish final version. The analyses revealed good reliability and internal consistency for the Spanish version of the CAMM. As we expected, the confirmatory factor analysis showed the unidimensional structure of the CAMM.

High prevalence of gallstone disease in rheumatoid arthritis: A new comorbidity related to dyslipidemia?

OBJECTIVE: To assess the prevalence of gallstone disease and identify associated risk factors in rheumatoid arthritis (RA) patients compared to the general population. METHODS: Eighty-four women with rheumatoid arthritis were included in the study. Each patient was assessed via a structured interview, physical examination, abdominal ultrasound and blood test including lipid profile. The prevalence of gallstone disease in rheumatoid arthritis was compared with data from a study of the Spanish population matched by age groups. RESULTS: Twenty-eight of the 84 women had gallstone disease (33.3%). RA women with and without gallstone disease were similar in most of the variables assessed, except for older age and menopausal status in the former. A greater prevalence of gallstone disease was seen in rheumatoid arthritis patients compared to the general population of the same age; however, the differences were significant only in women aged 60 or older (45.5% versus 23.1% respectively, P-value .008). The age-adjusted OR of developing gallstone disease in RA women compared with general population women was 2,3 (95% CI: 1.3-4.1). A significantly higher HDL3-c subfraction and higher apoA-I/HDL and HDL3-c/TC ratios were observed in patients with gallstone disease. CONCLUSION: Women with rheumatoid arthritis may have a predisposition to gallstones that can manifest in middle or older age compared with women in the general population. This situation could be related to chronic inflammation and HDL metabolism.

Do Trait Emotional Intelligence and Dispositional Mindfulness Have a Complementary Effect on the Children's and Adolescents' Emotional States?

Mindfulness is both a non-judgmental and present-centered awareness, which has been applied to reduce negative emotions. On the other hand, Trait Emotional Intelligence (TEI) is the way of how good people perceive their emotional intelligence abilities (perceiving, expressing, understanding, and regulating emotions), which are involved in people's social functioning. This empirical study was designed to analyze whether dispositional mindfulness (DM) and TEI have a potential combined role for children and adolescent's emotional states. In a sample of primary school students (N = 318), age ranged from 8 to 16 years old (M = 11.25, SD = 2.20), participants filled a TEI measure (ESCQ, Emotional skills and competence questionnaire) and two measures of DM (CAMM, Child and Adolescent Mindfulness Measure and AFQ-Y, Avoidance and Fusion Questionnaire for Youth). Measures selected included: PANAS (Positive affect and negative affect schedule), White Bear Suppression Inventory (a thought suppression inventory), and STAIC (State-Trait Anxiety for Children). Findings pointed out that TEI measures (labeling and expression, understanding, and managing emotions) were positively and significantly related to positive emotional states (especially, positive affect and balance) and negatively with a lower association with state anxiety. However, DM measures were both negatively and strongly associated with negative emotional states (thought suppression, negative affect, and anxiety). Conclusions indicate that a combined effect of both TEI skills and DM based interventions would be more complete than each one separately for better social functioning of children and teenagers.

[Nutrition and gastronomy in the community of Cantabria]. / Nutrición y gastronomía en la comunidad de Cantabria.

INTRODUCTION: Introduction: Cantabria is characterized by a large coastal territory and an important livestock tradition, which define its gastronomy. Objectives: population increasingly demands a healthy gastronomy, which promotes a state of health. We will analyze how is the gastronomy, food consumption, and nutritional profile in the community of Cantabria. We will try to relate it to the prevalence of obesity in Cantabria Methods: bibliographic search of scientific articles in PubMed, Google academic databases, and nutrition books. In addition, a search of materials in newspapers of Cantabria and institutions of Cantabria has been developed. Results: in Cantabria a greater amount of fish, oil, dairy products, pastries, pastries, cookies and cereals and fresh fruits is consumed compared to the national average. However, the consumption of soft drinks and soda, fresh vegetables, and bread is lower. With Galicia it occupies the first place in the consumption of fish, food of high nutritional value and high protein content. This consumption profile could contribute to lower energy intake (2038 kcal in 2016) and influence the prevalence of obesity in our community. According to data from 2016, Cantabria with a rate of 17,6% is the fourth community with the lowest prevalence of obesity in Spain. Conclusions: although the prevalence of obesity in our community is in the last places in Spain, the recommendations and nutritional objectives established for the Spanish population have not been reached. Cantabrian gastronomy has to promote a healthy diet, based on a lower contribution of fats and more complex carbohydrates to reach these recommendations.

INTRODUCCIÓN: Introducción: Cantabria se caracteriza por un gran territorio costero y una importante tradición ganadera, que definen su gastronomía. Objetivos: la población demanda cada vez más una gastronomía saludable que promueva un buen estado de salud. Analizaremos cómo es la gastronomía, el consumo alimentario y el perfil nutricional en Cantabria, y trataremos de relacionarlo con la prevalencia de obesidad. Métodos: búsqueda bibliográfica de artículos científicos en las bases de datos PubMed, Google Académico y en tratados de nutrición. Además, se ha realizado una búsqueda de materiales en la prensa local y en las instituciones de Cantabria. Resultados: en Cantabria se consume más pescado, aceite, derivados lácteos, bollería, pastelería, galletas y cereales y frutas frescas que la media nacional. Sin embargo, el consumo de bebidas refrescantes y gaseosas, hortalizas frescas y pan es menor. Junto a Galicia, ocupa el primer puesto en el consumo de pescado, alimento de alto valor nutritivo y elevado contenido proteico. Este perfil de consumo podría contribuir a que la ingesta energética sea menor (2038 kcal en 2016) e influir en la prevalencia de obesidad. Cantabria, en 2016, con una tasa de 17,6%, fue la cuarta comunidad con menor obesidad en España. Conclusiones: aunque la prevalencia de obesidad en nuestra comunidad se encuentra en los últimos puestos de España, no se alcanzan las recomendaciones y objetivos nutricionales establecidos para la población española. La gastronomía cántabra ha de promover una alimentación saludable, basada en un menor aporte de grasas y mayor de hidratos de carbono complejos para cumplir estas recomendaciones.

Daño en la pared arterial de las ratas Wistar sometidas a dieta hiperglucídica / Arterial wall damage in Wistar rats subjected to a hyperglycemic diet

RESUMEN Introducción: Los modelos experimentales en animales proporcionan una valiosa información para comprender los procesos fisiopatológicos de las lesiones de los vasos sanguíneos y sus consecuencias. Objetivo: Analizar los cambios histológicos y morfométricos que se observaron en la aorta abdominal de las ratas Wistar sometidas a una dieta hiperglucídica. Métodos: Se formaron aleatoriamente dos grupos experimentales de 10 animales cada uno. El grupo control alimentado con dieta estándar para la especie, y el grupo experimental alimentado con dieta estándar más sacarosa al 35 %, como agua de bebida desde el destete hasta las 20 semanas de vida. El estudio se realizó en muestras de aorta fijadas y procesadas por la técnica clásica de inclusión en parafina y coloreadas con las técnicas de hematoxilina - eosina y Verhoeff. Se realizó la descripción de las capas de la pared arterial y la determinación de variables morfométricas en cada lámina histológica. Resultados: Las ratas Wistar pertenecientes al grupo experimental desarrollaron modificaciones incipientes en la pared arterial de la aorta abdominal, las cuales corresponden con la presencia de tumefacción en la célula endotelial y vacuolización en la célula muscular lisa vascular, así como marcada desorganización de las fibras elásticas y musculares de la capa media. Las variables morfométricas que mostraron diferencias significativas entre los grupos fueron el grosor de la túnica media y el cociente media/ lumen. Conclusiones: La pared media resultó ser la capa más afectada demostrándose el efecto nocivo de la dieta hiperglucídica en la pared arterial.

ABSTRACT Introduction: experimental animal models provide valuable information to understand the physiological and pathological processes of blood vessel injuries and their consequences. Objective: to analyze the histological and morphometric changes observed in the abdominal aorta of Wistar rats subjected to a hyperglycemic diet. Methods: two experimental groups of 10 animals each were randomly formed. The control group was fed with a standard diet for this species, and the experimental group was fed with a standard diet plus 35% sucrose, as drinking water from weaning to 20 weeks of life. The study was performed on aortic samples fixed and processed by the classic paraffin embedding technique and stained with the hematoxylin-eosin and Verhoeff techniques. The description of the layers of the arterial wall and the determination of morphometric variables in each histological slide were made. Results: the Wistar rats belonging to the experimental group developed incipient changes in the arterial wall of the abdominal aorta, which correspond to the presence of endothelial cell swelling and vacuolation in the vascular smooth muscle cell, as well as marked disorganization of the muscle and elastic fibers of the middle layer. The morphometric variables that showed significant differences between the groups were the thickness of the tunica media and the media/lumen ratio. Conclusions: the middle wall turned out to be the most affected layer, demonstrating the harmful effect of the hyperglycemic diet on the arterial wall.

PAC1 receptor: emerging target for septic shock therapy.

Septic shock is a systemic response to severe bacterial infections, generally caused by Gram-negative bacterial endotoxins, with multiple manifestations such as hypotension, tissue injury, disseminated intravascular coagulation, and multi-organ failure. All these effects, are induced by the generation of pro-inflammatory and vasodilator mediators, cell adhesion molecules, coagulation factors, and acute-phase proteins. Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two immunopeptides with anti-inflammatory properties exerted through type 1 and 2 VIP receptors (VPAC1 and VPAC2, respectively), and PACAP receptor (PAC1). The present results recapitulate the protective role of PAC1 in an experimental model of lethal endotoxemia using a knockout for the PAC1 receptor. Our results demonstrate that VIP and PACAP decrease lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) production, neutrophil infiltration and intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and fibrinogen expression through PAC1 receptor, providing an advantage to design more specific drugs complementing standard intensive care therapy in septic shock.

Time-course expression of Toll-like receptors 2 and 4 in inflammatory bowel disease and homeostatic effect of VIP.

Toll-like receptor 2 (TLR2) and -4 mediate signals from a great variety of bacterial gut products, giving the host a panel of microbe-recognizing receptors. Under homeostatic conditions, TLRs act as protective receptors of the intestinal epithelium. When homeostasis is disrupted in diseases such as inflammatory bowel disease, TLR2 and -4 are deregulated. Our study demonstrates, by using a trinitrobenzene sulfonic acid-induced colitis model of Crohn's disease, the constitutive expression and the up-regulation of TLR2 and -4 at messenger and protein levels in colon extracts, as well as in macrophages, dendritic cells, and lymphocytes from mesenteric lymphoid nodes. Vasoactive intestinal peptide (VIP) treatment induced a decrease of TLR2 and -4 expressions approaching ethanol control levels. Our results suggest that VIP modulation of TLR2 and -4 could be explained by two possible mechanisms. The first one would be the secondary reduction of TLR2 and -4 caused by the VIP-mediated decrease of inflammatory mediators such as interleukin-1beta and interferon-gamma, which synergize with bacterial products, contributing to the amplification of TLR presence in the intestine. The other possible mechanism would involve a VIP-mediated decrease of nuclear factor-kappaB, which would cause a direct down-regulation of TLR expression. In summary, the resultant physiological effect is the decrease of TLR2 and -4 expressions to homeostatic levels. Our study describes for the first time the role of a peptide present in the gut microenvironment as an effective modulator of the initial steps of acute inflammation, acting at local and systemic levels and leading to the restoration of the homeostasis lost after an established inflammatory/autoimmune disease.

[New agents for hypercholesterolemia]. / Nuevos tratamientos para la hipercolesterolemia.

An elevated proportion of high cardiovascular risk patients do not achieve the therapeutic c-LDL goals. This owes to physicians' inappropriate or insufficient use of cholesterol lowering medications or to patients' bad tolerance or therapeutic compliance. Another cause is an insufficient efficacy of current cholesterol lowering drugs including statins and ezetimibe. In addition, proprotein convertase subtilisin kexin type 9 inhibitors are a new cholesterol lowering medications showing safety and high efficacy to reduce c-LDL in numerous already performed or underway clinical trials, potentially allowing an optimal control of hypercholesterolemia in most patients. Agents inhibiting apolipoprotein B synthesis and microsomal transfer protein are also providing a new potential to decrease cholesterol in patients with severe hypercholesterolemia and in particular in homozygote familial hypercholesterolemia. Last, cholesteryl ester transfer protein inhibitors have shown powerful effects on c-HDL and c-LDL, although their efficacy in cardiovascular prevention and safety has not been demonstrated yet. We provide in this article an overview of the main characteristics of therapeutic agents for hypercholesterolemia, which have been recently approved or in an advanced research stage.

cDNA array analysis of cytokines, chemokines, and receptors involved in the development of TNBS-induced colitis: homeostatic role of VIP.

Crohn's disease (CD) is a chronic inflammatory pathology of the intestine, characterized by diarrhea and weight loss. A healing effect of vasoactive intestinal peptide (VIP) in the murine model of CD based on 2,4,6-trinitrobencene sulfonic acid (TNBS) administration has been previously shown. The aim of this work was to analyze the expression of several mediators related to the inflammatory cascade in colitic and VIP-treated animals. With this aim, mice received either only TNBS or TNBS and VIP treatment on alternate days. cDNA microarray analysis and real-time polymerase chain reaction were performed on total mRNA from colon to study the expression of a battery of proinflammatory molecules such as the enzyme COX-2, the chemokines CX3CL1, CXCL12, CXCL13, CXCL14, CCR5, and CXCR2, and the cytokines interleukin (IL)-1beta, IL-12, IL-18, IL-10, interferon-gamma, and IL-4. TNBS administration induced the expression of all the proinflammatory mediators studied, whereas VIP treatment reduced their levels, increasing the anti-inflammatory IL-10 and the TH2 cytokine IL-4, explaining its beneficial action through inhibition of the inflammatory/TH1 response. These data describe not only the relation of several proinflammatory mediators to the development of TNBS colitis, reporting their time-course, but also show the beneficial action of VIP in this model through complete blockage of the inflammatory cascade and recovery of the colon homeostasis, providing a potential new alternative for CD therapy.