Anterior Pituitary Transcriptomics Following a High-Fat Diet: Impact of Oxidative Stress on Cell Metabolism.

Anterior pituitary cell function requires a high level of protein synthesis and secretion which depend heavily on mitochondrial adenosine triphosphate production and functional endoplasmic reticula. Obesity adds stress to tissues, requiring them to adapt to inflammation and oxidative stress, and adding to their allostatic load. We hypothesized that pituitary function is vulnerable to the stress of obesity. Here, we utilized a 10- to 15-week high-fat diet (HFD, 60%) in a thermoneutral environment to promote obesity, testing both male and female FVB.129P mice. We quantified serum hormones and cytokines, characterized the metabolic phenotype, and defined changes in the pituitary transcriptome using single-cell RNA-sequencing analysis. Weight gain was significant by 3 weeks in HFD mice, and by 10 weeks all HFD groups had gained 20 g. HFD females (15 weeks) had increased energy expenditure and decreased activity. All HFD groups showed increases in serum leptin and decreases in adiponectin. HFD caused increased inflammatory markers: interleukin-6, resistin, monocyte chemoattractant protein-1, and tumor necrosis factorα. HFD males and females also had increased insulin and increased TSH, and HFD females had decreased serum prolactin and growth hormone pulse amplitude. Pituitary single-cell transcriptomics revealed modest or no changes in pituitary cell gene expression from HFD males after 10 or 15 weeks or from HFD females after 10 weeks. However, HFD females (15 weeks) showed significant numbers of differentially expressed genes in lactotropes and pituitary stem cells. Collectively, these studies reveal that pituitary cells from males appear to be more resilient to the oxidative stress of obesity than females and identify the most vulnerable pituitary cell populations in females.

Aerobic Training Associated with Arginine Supplementation Reduces Collagen-Induced Platelet Hyperaggregability in Rats under High Risk to Develop Metabolic Syndrome.

BACKGROUND: Increased platelet response is seen in individuals with metabolic syndrome. Previous reports have shown that arginine supplementation and aerobic exercise training enhance vascular nitric oxide (NO) activity and inhibit platelet hyperaggregability; however, the effects of their association remain unknown. AIM: To investigate whether arginine supplementation and aerobic exercise association may exert beneficial effects, reducing platelet hyperaggregability in rats under high risk to develop metabolic syndrome. METHODS: Wistar rats were divided into two groups: control (C) and fructose (F - water with 10% of fructose). After two weeks, the F group was subdivided into four groups: F, the same as before; fructose + arginine (FA - 880 mg/kg/day of L-arginine by gavage); fructose + training (FT); and fructose + arginine + training (FTA). Treatment lasted for eight weeks. RESULTS: The fructose administration was able to increase the collagen-induced platelet aggregation (27.4 ± 2.7%) when compared to the C group (8.0 ± 3.4%). Although the arginine supplementation (32.2 ± 6.3%) or aerobic training (23.8 ± 6.5%) did not promote any change in platelet collagen-induced hyperaggregability, the association of arginine supplementation and aerobic exercise promoted an inhibition of the platelet hyperaggregability induced by fructose administration (13.9 ± 4.4%) (P < 0.05). These effects were not observed when ADP was employed as an agonist. In addition, arginine supplementation associated with aerobic exercise promoted a decrease in interleukin-6 (IL-6) and interleukin-8 (IL-8) serum levels when compared to the fructose group, demonstrating an anti-inflammatory effect. CONCLUSIONS: Our data indicate an important role of arginine supplementation associated with aerobic exercise, reducing platelet hyperaggregability and inflammatory biomarker levels in rats under high risk to develop metabolic syndrome.

Isolation of chemically well-defined semipreparative liquid chromatography fractions from complex mixtures of proanthocyanidin oligomers and polymers.

In this study, a semipreparative liquid chromatography method was developed for the isolation of chemically well-defined proanthocyanidin (PA) oligomer and polymer fractions. The aim was to achieve better separation than traditionally achieved for the PAs with other chromatographic methods. The method was tested with eleven PA rich Sephadex LH-20 fractions, which originated from eleven different plant species. The resulting semipreparative fractions were analyzed by both triple quadrupole and high-resolution mass spectrometry assisted by ultrahigh-performance liquid chromatography (UPLC) separation. The results showed remarkable differences in the procyanidin to prodelphinidin ratio, mean degree of polymerization, and specific oligomeric and polymeric content. However, some of these features indicated consistent patterns between species as the function of UPLC retention time. The developed method enables the production of tens of well-defined fractions of PA oligomers and polymers from the unresolved chromatographic PA hump. Accordingly, this allows researchers to explore the most bioactive parts of the complex PA humps of any plant species, which have not been possible earlier.

Surface-enhanced infrared absorption with Si-doped InAsSb/GaSb nano-antennas.

We demonstrate surface enhanced infrared absorption spectroscopy using 1-dimensional highly doped semiconductors based on Si-doped InAsSb plasmonic nano-antennas. Engineering the plasmonic array to support the localized surface plasmon resonance aligned with the molecular vibrational absorption mode of interest involves finely setting the doping level and nano-antenna width. Heavily doped nano-antennas require a wider size compared to lightly doped resonators. Increasing the doping level, and consequently the width of the nano-antenna, enhances the vibrational absorption of a ~15 nm thick organic layer up to 2 orders of magnitude compared to the unstructured sample and therefore improves sensing. These results pave the way towards molecule fingerprint sensor manufacturing by tailoring the plasmonic resonators to get a maximum surface enhanced infrared absorption at the target vibrational mode.

Localized surface plasmon resonance frequency tuning in highly doped InAsSb/GaSb one-dimensional nanostructures.

We report a detailed analysis of the influence of the doping level and nanoribbon width on the localized surface plasmon resonance (LSPR) by means of reflectance measurements. The plasmonic system, based on one-dimensional periodic gratings of highly Si-doped InAsSb/GaSb semiconductor nanostructures, is fabricated by a simple, accurate and large-area technique fabrication. Increasing the doping level blueshifts the resonance peak while increasing the ribbon width results in a redshift, as confirmed by numerical simulations. This provides an efficient means of fine-tuning the LSPR properties to a target purpose of between 8-20 µm (1250-500 cm(-1)). Finally, we show surface plasmon resonance sensing to absorbing polymer layers. We address values of the quality factor, sensitivity and figure of merit of 16 700 nm RIU(-1) and 2.5, respectively. These results demonstrate Si-doped InAsSb/GaSb to be a low-loss/high sensitive material making it very promising for the development of biosensing devices in the mid-infrared.

Circulating T cells to infliximab are detectable mainly in treated patients developing anti-drug antibodies and hypersensitivity reactions.

Antibodies recognizing infliximab (IFX) may develop in a proportion of treated patients, leading to loss of response or hypersensitivity reactions (HRs). T cell response to IFX has been poorly investigated. This paper was addressed to detect IFX-specific T cells in treated patients with inflammatory diseases developing, or not, anti-drug antibodies (ADA) and to correlate the presence of specific T cells with the clinical outcomes of the treatment. A co-culture system of IFX-loaded dendritic cells and purified autologous CD4+ T cells was used to detect memory T cells in 32 ADA+ and 39 ADA- IFX-treated patients and control groups. The cytokine profile of IFX-specific T cells was also studied in culture supernatants. IFX-specific cell proliferation was detected mainly in cells from ADA+ patients, irrespective of their different diseases. HR patients displayed higher T cell proliferation than non-responder and tolerant patients. A mixed [interferon (IFN)-γ, interleukin (IL)-13, IL-10] cytokine profile was shown in cells from ADA+ patients, while IL-10 was the most frequently detected cytokine in the supernatants of cultures from ADA- patients. Immunoglobulin (Ig)E+ ADA+ patients with previous HRs exhibited a more pronounced type 2 profile than IgE- ADA+ patients. This work provides evidence that IFX-specific circulating T cells are detectable mainly in ADA+ patients with HRs, regardless of their disease. The IFX-induced cytokine pattern partially correlates with the ADA isotype.

Satisfacción con la enfermera en atención primaria: herramientas de medida y factores explicativos / Satisfaction with primary care nursing: Use of measurement tools and explanatory factors

Objetivos: Analizar las propiedades psicométricas de 2 herramientas de medida de la satisfacción con la atención recibida de la enfermera en atención primaria y estimar los valores de esta satisfacción y las características del paciente y el servicio asociadas con su variabilidad. Métodos: Los sujetos fueron elegidos aleatoriamente en 23 centros de salud de la Comunidad de Madrid. Se midió la satisfacción con los cuestionarios AMABLE y de Baker, cuyas propiedades psicométricas fueron evaluadas. Se recogieron variables sociodemográficas y otras relativas al estado de salud, o al proceso de atención. Se construyó un modelo explicativo mediante Generalized Estimating Equations. Resultados: Los 662 sujetos expresaron una satisfacción media de 4,95/5 (DE 0,25) con AMABLE y 4,83/5 (DE 0,42) con el cuestionario Baker. AMABLE se explicaba en una única dimensión (alfa Cronbach 0,85), y Baker en 3: cuidados profesionales (media 4,76 [DE 0,48], alfa Cronbach 0,74), profundidad de la relación (media 3,76 [DE 1,18], alfa Cronbach 0,73) y tiempo dedicado (media 4,42 [DE 0,86], alfa Cronbach 0,47). La edad, una mejor percepción del estado de salud y la consulta concertada por la enfermera se asociaban con una mayor satisfacción expresada. La atención en el domicilio, los ingresos hospitalarios, el retraso en la consulta, la familia más extensa o la renta familiar elevada se asociaban con una menor satisfacción. Conclusiones: La satisfacción con la consulta de la enfermera en atención primaria era muy alta y se asociaba con características personales y de la propia consulta. Las herramientas evaluadas eran adecuadas para medir este resultado (AU)

Objectives: This study aims to assess the psychometric properties of two measurement tools for patient satisfaction with nursing care in Primary Care, the satisfaction level, and the personal and consultation characteristics associated with its variability. Methods: Subjects randomly selected in 23 Health Care centres in the Community of Madrid were included. Satisfaction was measured by means of the AMABLE and Baker questionnaires, in which the psychometric properties were evaluated. Sociodemographic characteristics of the consultations, variables related to health status, and other related to the consultation process were collected. An explanatory model using Generalized Estimating Equations was constructed. Results: The 662 subjects expressed a mean satisfaction of 4.95/5 (SD .25) with AMABLE, and 4.83/5 (SD .42) with the Baker questionnaire. AMABLE had a single dimension (Cronbach's alpha .85), and Baker three: professional care (mean 4.76, SD .48 Cronbach's alpha .74), depth of relationship (mean 3.76, SD 1.18, Cronbach's alpha .73), and perceived time (mean 4.42, SD .86, Cronbach's alpha .47). Ageing, a better perception of health status, and appointments arranged by nurses were associated with higher expressed satisfaction. Home care, hospital admissions, delayed consultation, extended family, or high family income were associated with lower satisfaction. Conclusions: Satisfaction with nurse consultations in Primary Care was very high, and varied depending on personal characteristics and on the type of consultation. The assessed tools allowed this outcome to be measured properly (AU)

[Satisfaction with primary care nursing: use of measurement tools and explanatory factors]. / Satisfacción con la enfermera en atención primaria: herramientas de medida y factores explicativos.

OBJECTIVES: This study aims to assess the psychometric properties of two measurement tools for patient satisfaction with nursing care in Primary Care, the satisfaction level, and the personal and consultation characteristics associated with its variability. METHODS: Subjects randomly selected in 23 Health Care centres in the Community of Madrid were included. Satisfaction was measured by means of the AMABLE and Baker questionnaires, in which the psychometric properties were evaluated. Sociodemographic characteristics of the consultations, variables related to health status, and other related to the consultation process were collected. An explanatory model using Generalized Estimating Equations was constructed. RESULTS: The 662 subjects expressed a mean satisfaction of 4.95/5 (SD .25) with AMABLE, and 4.83/5 (SD .42) with the Baker questionnaire. AMABLE had a single dimension (Cronbach's alpha .85), and Baker three: professional care (mean 4.76, SD .48 Cronbach's alpha .74), depth of relationship (mean 3.76, SD 1.18, Cronbach's alpha .73), and perceived time (mean 4.42, SD .86, Cronbach's alpha .47). Ageing, a better perception of health status, and appointments arranged by nurses were associated with higher expressed satisfaction. Home care, hospital admissions, delayed consultation, extended family, or high family income were associated with lower satisfaction. CONCLUSIONS: Satisfaction with nurse consultations in Primary Care was very high, and varied depending on personal characteristics and on the type of consultation. The assessed tools allowed this outcome to be measured properly.

Photoexcited-induced sensitivity of InGaAs surface QDs to environment.

A detailed analysis of the impact of illumination on the electrical response of In0.5Ga0.5As surface nanostructures is carried out as a function of different relative humidity conditions. The importance of the surface-to-volume ratio for sensing applications is once more highlighted. From dark-to-photo conditions, the sheet resistance (SR) of a three-dimensional In0.5Ga0.5As nanostructure decays two orders of magnitude compared with that of a two-dimensional nanostructure. The electrical response is found to be vulnerable to the energy of the incident light and the external conditions. Illuminating with high energy light translates into an SR reduction of one order of magnitude under humid atmospheres, whereas it remains nearly unchanged under dry environments. Conversely, lighting with energy below the bulk energy bandgap, shows a negligible effect on the electrical properties regardless the local moisture. Both illumination and humidity are therefore needed for sensing. Photoexcited carriers can only contribute to conductivity if surface states are inactive due to water physisorption. The strong dependence of the electrical response on the environment makes these nanostructures very suitable for the development of highly sensitive and efficient sensing devices.

Mesenchymal stem cells regulate airway contractile tissue remodeling in murine experimental asthma.

BACKGROUND: Mesenchymal stem cells may offer therapeutic potential for asthma due to their immunomodulatory properties and host tolerability, yet prior evidence suggests that bloodborne progenitor cells may participate in airway remodeling. Here, we tested whether mesenchymal stem cells administered as anti-inflammatory therapy may favor airway remodeling and therefore be detrimental. METHODS: Adipose tissue-derived mesenchymal stem cells were retrovirally transduced to express green fluorescent protein and intravenously injected into mice with established experimental asthma induced by repeat intranasal house dust mite extract. Controls were house dust mite-instilled animals receiving intravenous vehicle or phosphate-buffered saline-instilled animals receiving mesenchymal stem cells. Data on lung function, airway inflammation, and remodeling were collected at 72 h after injection or after 2 weeks of additional intranasal challenge. RESULTS: The mesenchymal stem cells homed to the lungs and rapidly downregulated airway inflammation in association with raised T-helper-1 lung cytokines, but such effect declined under sustained allergen challenge despite a persistent presence of mesenchymal stem cells. Conversely, airway hyperresponsiveness and contractile tissue underwent a late reduction regardless of continuous pathogenic stimuli and inflammatory rebound. Tracking of green fluorescent protein did not show mesenchymal stem cell integration or differentiation in airway wall tissues. CONCLUSIONS: Therapeutic mesenchymal stem cell infusion in murine experimental asthma is free of unwanted pro-remodeling effects and ameliorates airway hyper-responsiveness and contractile tissue remodeling. These outcomes support furthering the development of mesenchymal stem cell-based asthma therapies, although caution and solid preclinical data building are warranted.

Strong influence of the humidity on the electrical properties of InGaAs surface quantum dots.

The impact of the environment on the electrical properties of uncapped In0.5Ga0.5As nanostructures is studied as a function of different atmospheres for sensing applications. Electrical response from surface quantum dots (QD) shows a strong dependence on the atmosphere, in contrast to the response of 2D nanostructures. The sheet resistance drops by 99% from vacuum to air, and decreases more than one order of magnitude when relative humidity changes from 0 to 70%. The adsorption of water molecules onto the QD surface improves the conductivity likely by reducing the density of surface states acting as carrier traps, which enhances electron transport.

East-West gradient in the incidence of inflammatory bowel disease in Europe: the ECCO-EpiCom inception cohort.

OBJECTIVE: The incidence of inflammatory bowel disease (IBD) is increasing in Eastern Europe. The reasons for these changes remain unknown. The aim of this study was to investigate whether an East-West gradient in the incidence of IBD in Europe exists. DESIGN: A prospective, uniformly diagnosed, population based inception cohort of IBD patients in 31 centres from 14 Western and eight Eastern European countries covering a total background population of approximately 10.1 million people was created. One-third of the centres had previous experience with inception cohorts. Patients were entered into a low cost, web based epidemiological database, making participation possible regardless of socioeconomic status and prior experience. RESULTS: 1515 patients aged 15 years or older were included, of whom 535 (35%) were diagnosed with Crohn's disease (CD), 813 (54%) with ulcerative colitis (UC) and 167 (11%) with IBD unclassified (IBDU). The overall incidence rate ratios in all Western European centres were 1.9 (95% CI 1.5 to 2.4) for CD and 2.1 (95% CI 1.8 to 2.6) for UC compared with Eastern European centres. The median crude annual incidence rates per 100,000 in 2010 for CD were 6.5 (range 0-10.7) in Western European centres and 3.1 (range 0.4-11.5) in Eastern European centres, for UC 10.8 (range 2.9-31.5) and 4.1 (range 2.4-10.3), respectively, and for IBDU 1.9 (range 0-39.4) and 0 (range 0-1.2), respectively. In Western Europe, 92% of CD, 78% of UC and 74% of IBDU patients had a colonoscopy performed as the diagnostic procedure compared with 90%, 100% and 96%, respectively, in Eastern Europe. 8% of CD and 1% of UC patients in both regions underwent surgery within the first 3 months of the onset of disease. 7% of CD patients and 3% of UC patients from Western Europe received biological treatment as rescue therapy. Of all European CD patients, 20% received only 5-aminosalicylates as induction therapy. CONCLUSIONS: An East-West gradient in IBD incidence exists in Europe. Among this inception cohort--including indolent and aggressive cases--international guidelines for diagnosis and initial treatment are not being followed uniformly by physicians.

Allergological in vitro and in vivo evaluation of patients with hypersensitivity reactions to infliximab.

BACKGROUND: The administration of biological agents is potentially affected by IgE-mediated infusion reactions. OBJECTIVE: The aim of the study was to evaluate the utility of skin testing in patients who have experienced infliximab (IFX)-related reactions. METHODS: Thirty patients with previous immediate hypersensitivity reaction to IFX, 20 disease-matched non exposed subjects, 15 IFX-treated disease-matched tolerant patients and 15 IFX non-responder patients were enrolled. Non-isotype-specific and IgE anti-drug antibodies (ADAs) were measured by a double-capture ELISA kit and ImmunoCAP assay, respectively. Prick and intra-dermal tests were carried out with the commercial IFX preparation serially diluted. RESULTS: Skin testing, performed in 23 of 30 reactive patients, resulted positive in 7 of them (30.4%), whereas no positivity was found in other groups of patients. The majority of reactive patients displayed non-isotype-specific ADAs (23/30, 76.6%) and the presence of anti-IFX IgE antibodies was detected in 6 of them (26%). All 6 IgE-positive reactive patients showed skin testing positivity. One reactive ADAs-positive patient who resulted skin test positive, with no detectable serum IFX-specific IgE ADAs, was also found. Skin testing positivity was associated with severe and early reactions (within the 3rd dose). No unexpected adverse reactions to skin testing were recorded. CONCLUSIONS AND CLINICAL RELEVANCE: This study shows that about 30% of reactive patients display skin testing positivity. They usually develop severe reactions, mainly during the first administrations of IFX. The specificity and the safety of skin testing procedure for this biological agent are also confirmed.

[Study on the professional procedures, experiences and needs of parents when they are told their child has a disability or developmental disorder. Breaking the news]. / Estudio sobre los procedimientos profesionales, las vivencias y las necesidades de los padres cuando se les informa de que su hijo tiene una discapacidad o un trastorno del desarrollo. La primera noticia.

INTRODUCTION: Both the moment and the way chosen to break the news that a child aged 0-6 years is suffering, or may suffer, from a developmental disorder or disability have an effect on the parents and on the familial system that goes beyond the actual fact of knowing about the circumstance in itself. It is a very significant social act that represents the first encounter in which the parents explore and anticipate the social attitudes of inclusion or exclusion towards the child. AIMS: To gather information about the practices usually employed by professionals when it comes to breaking the news to the families, to evaluate what aspects of the process could be improved, to determine the families' needs in these circumstances and to gain a deeper understanding of the affective-emotional processes experienced by the parents. SUBJECTS AND METHODS: The research was conducted using a questionnaire with 43 items, which was specifically designed for the population under examination in the study. Altogether, 418 parents from 15 different autonomous regions of Spain took part in the study. At the same time, the existing literature on diagnostic information in Spanish was reviewed. RESULTS AND CONCLUSIONS: It can be concluded that, to 'break the bad news', professionals must know the family; they must take the utmost care in choosing when, where and how to give that news; the parents must be together when they are told; and they must take into account the type of disability the child suffers from as well as its intensity. These guidelines of conduct become manifest in strategies and keys to be applied to each situation, in the contents of the messages to be communicated and in the attitudes of professionals.

The development of activating and inhibiting camelid VHH domains against human protein kinase C epsilon.

The 10 isozymes of the protein kinase C (PKC) family can have different roles on the same biological process, making isozyme specific analysis of function crucial. Currently, only few pharmacological compounds with moderate isozyme specific effects exist thus hampering research into individual PKC isozymes. The antigen binding regions of camelid single chain antibodies (VHHs) could provide a solution for obtaining PKC isozyme specific modulators. In the present study, we have successfully selected and characterized PKCɛ specific VHH antibodies from two immune VHH libraries using phage display. The VHHs were shown to exclusively bind to PKCɛ in ELISA and immunoprecipitation studies. Strikingly, five of the VHHs had an effect on PKCɛ kinase activity in vitro. VHHs A10, C1 and D1 increased PKCɛ kinase activity in a concentration-dependent manner (EC(50) values: 212-310nM), whereas E6 and G8 inhibited PKCɛ activity (IC(50) values: 103-233nM). None of these VHHs had an effect on the activity of the other novel PKC isozymes PKCδ and PKCθ. To our knowledge, these antibodies are the first described VHH activators and inhibitors for a protein kinase. Furthermore, the development of PKCɛ specific modulators is an important contribution to PKC research.

Effect of ATP binding and hydrolysis on dynamics of canine parvovirus NS1.

The replication protein NS1 is essential for genome replication and protein production in parvoviral infection. Many of its functions, including recognition and site-specific nicking of the viral genome, helicase activity, and transactivation of the viral capsid promoter, are dependent on ATP. An ATP-binding pocket resides in the middle of the modular NS1 protein in a superfamily 3 helicase domain. Here we have identified key ATP-binding amino acid residues in canine parvovirus (CPV) NS1 protein and mutated amino acids from the conserved A motif (K406), B motif (E444 and E445), and positively charged region (R508 and R510). All mutations prevented the formation of infectious viruses. When provided in trans, all except the R508A mutation reduced infectivity in a dominant-negative manner, possibly by hindering genome replication. These results suggest that the conserved R510 residue, but not R508, is the arginine finger sensory element of CPV NS1. Moreover, fluorescence recovery after photobleaching (FRAP), complemented by computer simulations, was used to assess the binding properties of mutated fluorescent fusion proteins. These experiments identified ATP-dependent and -independent binding modes for NS1 in living cells. Only the K406M mutant had a single binding site, which was concluded to indicate ATP-independent binding. Furthermore, our data suggest that DNA binding of NS1 is dependent on its ability to both bind and hydrolyze ATP.

[Models of intervention in children with autism]. / Modelos de intervención en niños con autismo.

INTRODUCTION: Autism spectrum disorders make up a group of neurodevelopmental disorders that globally affect different higher brain functions in the individual, such as intelligence, the capacity to use language and social interaction. Today, although there is still no curative treatment for autism, there are a number of non pharmacological interventions that can modify the poor prognosis that is generally associated to this type of disorders. AIM: To briefly review the different approaches to the neuro rehabilitation of patients suffering from autism spectrum disorders, which are usually known as methods of intervention. DEVELOPMENT: From the categorical point of view, three types of methods of intervention can be distinguished, depending on whether the orientation is psychodynamic, biomedical or psycho educational. It is difficult to compare the results of the different methods of intervention, but researchers have identified several common elements that they should have if they are to be effective. At present, the psycho educational methods are preferred, since they are the only ones that, to date, have proved to be effective in research studies. CONCLUSIONS: Early intervention by diagnostic and early care centres, with the use of mixed models of psycho educational intervention that nevertheless also include an important percentage of behavioural elements, has proved to be capable of modifying the course of patients with autism spectrum disorders and is currently the most suitable approach.

Synthesis and analgesic profile of conformationally constrained N-acylhydrazone analogues: discovery of novel N-arylideneamino quinazolin-4(3H)-one compounds derived from natural safrole.

In this work we reported the synthesis and evaluation of the analgesic, anti-inflammatory, and platelet anti-aggregating properties of new 3-(arylideneamino)-2-methyl-6,7-methylenedioxy-quinazolin-4(3H)-one derivatives (3a-j), designed as conformationally constrained analogues of analgesic 1,3-benzodioxolyl-N-acylhydrazones (1) previously developed at LASSBio. Target compounds were synthesized in very good yields exploiting abundant Brazilian natural product safrole (2) as starting material. The pharmacological assays lead us to identify compounds LASSBio-1240 (3b) and LASSBio-1272 (3d) as new analgesic prototypes, presenting an antinociceptive profile more potent and effective than dipyrone and indomethacin used, respectively, as standards in AcOH-induced abdominal constrictions assay and in the formalin test. These results confirmed the success in the exploitation of conformation restriction strategy for identification of novel cyclic N-acylhydrazone analogues with optimized analgesic profile.

Expression of iron-related genes in human brain and brain tumors.

BACKGROUND: Defective iron homeostasis may be involved in the development of some diseases within the central nervous system. Although the expression of genes involved in normal iron balance has been intensively studied in other tissues, little is known about their expression in the brain. We investigated the mRNA levels of hepcidin (HAMP), HFE, neogenin (NEO1), transferrin receptor 1 (TFRC), transferrin receptor 2 (TFR2), and hemojuvelin (HFE2) in normal human brain, brain tumors, and astrocytoma cell lines. The specimens included 5 normal brain tissue samples, 4 meningiomas, one medulloblastoma, 3 oligodendrocytic gliomas, 2 oligoastrocytic gliomas, 8 astrocytic gliomas, and 3 astrocytoma cell lines. RESULTS: Except for hemojuvelin, all genes studied had detectable levels of mRNA. In most tumor types, the pattern of gene expression was diverse. Notable findings include high expression of transferrin receptor 1 in the hippocampus and medulla oblongata compared to other brain regions, low expression of HFE in normal brain with elevated HFE expression in meningiomas, and absence of hepcidin mRNA in astrocytoma cell lines despite expression in normal brain and tumor specimens. CONCLUSION: These results indicate that several iron-related genes are expressed in normal brain, and that their expression may be dysregulated in brain tumors.