Coumarin-Chalcone Hybrids as Inhibitors of MAO-B: Biological Activity and In Silico Studies.

Fourteen coumarin-derived compounds modified at the C3 carbon of coumarin with an α,ß-unsaturated ketone were synthesized. These compounds may be designated as chalcocoumarins (3-cinnamoyl-2H-chromen-2-ones). Both chalcones and coumarins are recognized scaffolds in medicinal chemistry, showing diverse biological and pharmacological properties among which neuroprotective activities and multiple enzyme inhibition, including mitochondrial enzyme systems, stand out. The evaluation of monoamine oxidase B (MAO-B) inhibitors has aroused considerable interest as therapeutic agents for neurodegenerative diseases such as Parkinson's. Of the fourteen chalcocumarins evaluated here against MAO-B, ChC4 showed the strongest activity in vitro, with IC50 = 0.76 ± 0.08 µM. Computational docking, molecular dynamics and MM/GBSA studies, confirm that ChC4 binds very stably to the active rMAO-B site, explaining the experimental inhibition data.

Live endothelial cells on plasma-nitrided and oxidized titanium: An approach for evaluating biocompatibility.

We evaluated the effects of titanium plasma nitriding and oxidation on live endothelial cell viscoelasticity. For this, mechanically polished titanium surfaces and two surfaces treated by planar cathode discharge in nitriding (36N2 and 24H2) and oxidant (36O2 and 24H2). Surfaces were characterized regarding wettability, roughness and chemical composition. Rabbit aortic endothelial cells (RAECs) were cultured on the titanium surfaces. Cell morphology, viability and viscoelasticity were evaluated by scanning electron microscopy (SEM), methyl thiazolyl tetrazolium (MTT) assay and atomic force microscopy (AFM), respectively. Grazing Incidence X-ray Diffraction confirmed the presence of TiN0,26 on the surface (grazing angle theta 1°) of the nitrided samples, decreasing with depth. On the oxidized surface had the formation of TiO3 on the material surface (Theta 1°) and in the deeper layers was noted, with a marked presence of Ti (Theta 3°). Both plasma treatments increased surface roughness and they are hydrophilic (angle <90°). However, oxidation led to a more hydrophilic titanium surface (66.59° ± 3.65 vs. 76.88° ± 2.68; p = 0.001) due to titanium oxide films in their stoichiometric varieties (Ti3O, TiO2, Ti6O), especially Ti3O. Despite focal adhesion on the surfaces, viability was different after 24 h, as cell viability on the oxidized surface was higher than on the nitrided surface (9.1 × 103 vs. 4.5 × 103cells; p < 0.05). This can be explained by analyzing the viscoelastic property of the cellular cytoskeleton (nuclear and peripheral) by AFM. Surface oxidation significantly increased RAECs viscoelasticity at cell periphery, in comparison to the nucleus (2.36 ± 0.3 vs. 1.5 ± 0.4; p < 0.05), and to the RAECs periphery in contact with nitrided surfaces (1.36 ± 0.7; p < 0.05) and polished surfaces (1.55 ± 0.6; p < 0.05). Taken together, our results have shown that titanium plasma treatment directly increased cell viscoelasticity via surface oxidation, and this mechanobiological property subsequently increased biocompatibility.

Experiencia de diagnóstico comunitario bajo el modelo de enfermería de Elizabeth Anderson / Community diagnosis experience on the model of nursing

RESUMEN Introducción: Trabajar con y para la comunidad permite integrar la perspectiva de las personas respecto a su estado de salud, los beneficios que otorga su entorno, el gobierno y los sistemas de salud, identificar problemas que afectan el bienestar integral de las personas que la forman. Objetivo: Describir la experiencia de aplicar un diagnóstico comunitario bajo el modelo de enfermería de Elizabeth Anderson. Métodos: Estudio descriptivo de corte transversal, con una muestra de 285 personas de 63 familias en la comunidad "Los Microbuseros" de Peñalolén, Santiago de Chile. Para obtener la información se aplicó una encuesta que se procesó en el programa SPSS. Las variables estudiadas fueron los 8 subsistemas del modelo Elizabeth Anderson. Resultados: De la muestra, padecían diabetes mellitus II el 34,92 por ciento, hipertensión arterial el 42,85 por ciento, sedentarismo el 67,36 por ciento y tabaquismo el 31,22 por ciento; el 55,55 por ciento no participaba en organizaciones comunitarias; el 96,82 por ciento no usaba programas municipales, el 80,95 por ciento de las familias no recibía información sobre programas gubernamentales de salud, el 95,23 por ciento aumentó el consumo de alcohol y drogas en la vía pública en el último año, el 74,60 por ciento desconocía el número de seguridad policial del sector. El 80,85 por ciento no conocía el programa de salud cardiovascular, el 96,82 por ciento no acudía al Centro de salud. Conclusión: El modelo de Anderson permite valorar la comunidad de manera holística, evidenciar que la salud puede ser influenciada por otros sistemas como la economía, la seguridad, la educación, entre otros. Por ello surge la necesidad de fortalecer los factores protectores e intervenir sobre los riesgos para mejorar la calidad de vida de la comunidad(AU)

ABSTRACT Introduction: Working with and for the community allows integrating the perspective of people regarding their health status, the benefits of their environment, government and health systems, identify problems that affect the well-being of the people who form it . Objective: To describe the experience of applying a community diagnosis under the nursing model of Elizabeth Anderson in community "Los Microbuseros" of Peñalolén, Santiago de Chile. Methods: Descriptive cross-sectional study with a sample of 285 people from 63 families. To obtain the information a survey was applied and processed in the SPSS program. The variables studied were the 8 subsystems of the Elizabeth Anderson model. Results: Diabetes Mellitus II presents 34.92 percent, arterial hypertension 42.85 percent, sedentarism 67.36 percent, smoking 31.22 percent, does not participate in community organizations 55.55 percent, does not use municipal programs 96.82 percent Does not receive information on government health programs, 80,95 percent of families increased alcohol and drug consumption on public roads in the last year 95.23 percent, did not know the number of police security in the sector 74,60 percent. 80.85 percent did not know the cardiovascular health program, 96.82 percent did not go to the Health Center. Conclusion: The Anderson model allows valuing the community in a holistic way, showing that health can be influenced by other systems such as economy, safety, education, among others. Therefore, the need to strengthen the protective factors and intervene on the risks to improve the quality of life of the community arises(AU)

In vivo and in vitro oncogenic effects of HIF2A mutations in pheochromocytomas and paragangliomas.

Pheochromocytomas and paragangliomas are highly vascular tumors of the autonomic nervous system. Germline mutations, including those in hypoxia-related genes, occur in one third of the cases, but somatic mutations are infrequent in these tumors. Using exome sequencing of six paired constitutive and tumor DNA from sporadic pheochromocytomas and paragangliomas, we identified a somatic mutation in the HIF2A (EPAS1) gene. Screening of an additional 239 pheochromocytomas/paragangliomas uncovered three other HIF2A variants in sporadic (4/167, 2.3%) but not in hereditary tumors or controls. Three of the mutations involved proline 531, one of the two residues that controls HIF2α stability by hydroxylation. The fourth mutation, on Ser71, was adjacent to the DNA binding domain. No mutations were detected in the homologous regions of the HIF1A gene in 132 tumors. Mutant HIF2A tumors had increased expression of HIF2α target genes, suggesting an activating effect of the mutations. Ectopically expressed HIF2α mutants in HEK293, renal cell carcinoma 786-0, or rat pheochromocytoma PC12 cell lines showed increased stability, resistance to VHL-mediated degradation, target induction, and reduced chromaffin cell differentiation. Furthermore, mice injected with cells expressing mutant HIF2A developed tumors, and those with Pro531Thr and Pro531Ser mutations had shorter latency than tumors from mice with wild-type HIF2A. Our results support a direct oncogenic role for HIF2A in human neoplasia and strengthen the link between hypoxic pathways and pheochromocytomas and paragangliomas.

MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma.

PURPOSE: Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest-derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations contribute to PCC/PGL and associated phenotypes remain unclear. This study aimed to examine the prevalence and associated phenotypic features of germline and somatic MAX mutations in PCC/PGL. DESIGN: We sequenced MAX in 1,694 patients with PCC or PGL (without mutations in other major susceptibility genes) from 17 independent referral centers. We screened for large deletions/duplications in 1,535 patients using a multiplex PCR-based method. Somatic mutations were searched for in tumors from an additional 245 patients. The frequency and type of MAX mutation was assessed overall and by clinical characteristics. RESULTS: Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P = 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine. CONCLUSIONS: Germline mutations in MAX are responsible for 1.12% of PCC/PGL in patients without evidence of other known mutations and should be considered in the genetic work-up of these patients.