A mechanistic study on the phototoxicity of atorvastatin: singlet oxygen generation by a phenanthrene-like photoproduct

Atorvastatin calcium (ATV) is one of the most frequently prescribed drugs worldwide. Among the adverse effects observed for this lipid-lowering agent, clinical cases of cutaneous adverse reactions have been reported and associated with photosensitivity disorders. Previous work dealing with ATV photochemistry has shown that exposure to natural sunlight in aqueous solution leads to photoproducts resulting from oxidation of the pyrrole ring and from cyclization to a phenanthrene derivative. Laser flash photolysis of ATV, at both 266 and 308 nm, led to a transient spectrum with two maxima at λ ) 360 and λ ) 580 nm (τ ) 41 μs), which was assigned to the primary intermediate of the stilbene-like photocyclization. On the basis of the absence of a triplet-triplet absorption, the role of the parent drug as singlet oxygen photosensitizer can be discarded. By contrast, a stable phenanthrene-like photoproduct would be a good candidate to play this role. Laser flash photolysis of this compound showed a triplet-triplet transient absorption at λmax ) 460 nm with a lifetime of 26 μs, which was efficiently quenched by oxygen (kq ) 3 ((0.2) × 109 M-1 s-1). Its potential to photosensitize formation of singlet oxygen was confirmed by spin trapping experiments, through conversion of TEMP to the stable free radical TEMPO. The photoreactivity of the phenanthrene-like photoproduct was investigated using Trp as a marker. The disappearance of the amino acid fluorescence (λmax ) 340 nm) after increasing irradiation times at 355 nm was taken as a measurement of photodynamic oxidation. To confirm the involvement of a type II mechanism, the same experiment was also performed in D2O; this resulted in a significant enhancement of the reaction rate. On the basis of the obtained photophysical and photochemical results, the phototoxicity of atorvastatin can be attributed to singlet oxygen formation with the phenanthrene-like photoproduct as a photosensitizer

Neuroserpin: a serpin to think about

Proteinases and their inhibitors play important roles in neural development, homeostasis and disease. Neuroserpin is a member of the serine proteinase inhibitor (serpin) superfamily that is secreted from the growth cones of neurons and inhibits the enzyme tissue-type plasminogen activator (tPA). The temporal and spatial pattern of neuroserpin expression suggests a role in synaptogenesis and is most prominent in areas of the brain that participate in learning, memory and behaviour. Neuroserpin also provides neuronal protection in pathologies such as cerebral ischaemia and epilepsy by preventing excessive activity of tPA. Point mutations in neuroserpin cause aberrant conformational transitions and the formation of loop-sheet polymers that are retained within the endoplasmic reticulum of neurons, forming inclusion bodies that underlie an autosomal dominant dementia that we have called familial encephalopathy with neuroserpin inclusion bodies or FENIB. We review here the role of neuroserpin and other proteinase inhibitors in brain development, function and disease

An antibody raised against a pathogenic serpin variant induces mutant-like behaviour in the wild-type protein

A monoclonal antibody (mAb) that binds to a transient intermediate may act as a catalyst for the corresponding reaction; here we show this principle can extend on a macro molecular scale to the induction of mutant-like oligomerization in a wild-type protein. Using the common pathogenic E342K (Z) variant of α1-antitrypsin as antigen-whose native state is susceptible to the formation of a proto-oligomeric intermediate-we have produced a mAb (5E3) that increases the rate of oligomerization of the wild-type (M) variant. Employing ELISA, gel shift, thermal stability and FRET time-course experiments, we show that mAb5E3 does not bind to the native state of α1-antitrypsin, but recognizes a cryptic epitope in the vicinity of the post-helix A loop and strand 4C that is revealed upon transition to the polymerization intermediate, and which persists in the ensuing oligomer. This epitope is not shared by loop-inserted monomeric conformations. We show the increased amenity to polymerization by either the pathogenic E342K mutation or the binding of mAb5E3 occurs without affecting the energetic barrier to polymerization. As mAb5E3 also does not alter the relative stability of the monomer to intermediate, it acts in a manner similar to the E342K mutant, by facilitating the conformational interchange between these two states

Novel Microscopic Mechanism of Intermixing during Growth on Soft Metallic Substrates

Generic computer simulations using empiric interatomic potentials suggest a new, collective mechanism that could be responsible for mixing at heteroepitaxial interfaces. Even if single adsorbate atoms diffuse by hopping on the substrate surface and do not mix at the terraces, two-dimensional islands formed by nucleation may become unstable above a certain critical size and explode upwards forming clusters of several atomic layers. This process is accompanied by strong distortions of the underlying atomic layers, and on soft materials it can result in surface etching and incorporation of substrate atoms into the islands.Fil: Gomez, Liliana Maria. Universidad Nacional de Rosario. Facultad de Ciencias Exactas, Ingeniería y Agrimensura; ArgentinaFil: Slutzky, Claudia Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Ferron, Julio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: de la Figuera, J.. Sandia National Laboratories; Estados UnidosFil: Camarero, J.. Universidad Autónoma de Madrid; EspañaFil: Vazquez de Parga, A.. Universidad Autónoma de Madrid; EspañaFil: de Miguel, J.J.. Universidad Autónoma de Madrid; EspañaFil: Miranda, R.. Universidad Autónoma de Madrid; Españ

Occurrence of mite Ophionyssus natricis (Acari: Macronyssidae) on captive snakes from Panama

We report for the first time the presence of the snake mite, Ophionyssus natricis (Gervais) (Mesostigmata: Macronyssidae) on captive snakes kept at Panama City, Panama. This occurrence adds a new record to the geographical distribution of O. natricis as well as confirms its high prevalence on captive reptiles. Several Boidae species, Boa constrictor, Epicrates maurus, Corallus ruschenbergerii, Corallus caninus and a Pythonidae, Python regius were found infested with intensities varying from 10 to 2200 mites each. These findings represent the second record of O. natricis for Central America

Concept mapping as a tool to break disciplinary boundaries: isomerism in biological systems

O mapeamento conceitual foi utilizado como uma ferramenta para verificar as mudanças conceituais de estudantes de Ensino Médio após a realização de atividades didáticas desenvolvidas durante as aulas de Química. O objetivo pedagógico a ser atingido foi romper as fronteiras que segregam o conhecimento científico em disciplinas isoladas. Os estudantes foram intencionalmente provocados a relacionar conceitos de Química e de Biologia, a fim de compreender melhor e explicar as conseqüências biológicas da isomeria. Os mapas conceituais elaborados pelos estudantes, antes e após as atividades propostas, evidenciaram o aparecimento de relações entre conceitos químicos e biológicos, que foram avaliadas qualitativamente. Este trabalho mostra que os mapas conceituais podem ser utilizados como ferramentas para auxiliar o professor na realização de práticas didáticas interdisciplinares na escola, bem como para acompanhar o progresso dos estudantes em direção à interdisciplinaridade.Concept mapping was used as a tool for checking the conceptual changes caused by didactic activities implemented during chemistry classes in high school. Its pedagogical aim was to break down the boundaries, which segregate scientific knowledge into isolated disciplines. The students were intentionally provoked to merge concepts from chemistry and biology, in order to better understand and explain the biological consequences of isomerism. The concept maps produced by the students before and after the activities confirmed the appearance of relationships among chemical and biological concepts, which were qualitatively evaluated. This work shows that concept maps can be used to follow the students' progress towards interdisciplinarity, and to help the teacher to devise future classroom activities to reinforce and to expand interdisciplinary relationships.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) - PIBI

Functional status following pulmonary rehabilitation: responders and non-responders

The 6 min walking test (6MWT) has been largely studied. Less is, however, known about responders and non-responders to pulmonary rehabilitation (PR) in other meaningful activities. We explored responders and non-responders and the predictors of response to PR in the 1 min sit-to-stand test (1 min STS) and the 6MWT and compared both measures in classifying responders. An observational study was conducted with 121 people with chronic obstructive pulmonary disease (COPD). The functional status was assessed before and after PR. Baseline differences between responders and non-responders were tested with Mann–Whitney U, chi-square, or Fisher exact tests. Predictors were explored with binary logistic regressions. Agreement between both measures was assessed with chi-square, Cohen’s kappa, and McNemar tests. There were 54.5% and 57.0% of responders in the 1 min STS and the 6MWT, respectively. The proportion of responders was significantly different (p = 0.048), with a small agreement between the measures (kappa = 0.180; p = 0.048). The baseline 6MWT was the only significant predictor of response in the 6MWT (OR = 0.995; pseudo-r2 = 0.117; p < 0.001). No significant predictors were found for the 1 min STS. A large number of non-responders in terms of functional status exist. The 1 min STS and the 6MWT should not be used interchangeably. Future studies should explore the added benefit of personalizing PR to this outcome and investigate other potential predictors.publishe

Role of STAT3 in In Vitro Transformation Triggered by TRK Oncogenes

TRK oncoproteins are chimeric versions of the NTRK1/NGF receptor and display constitutive tyrosine kinase activity leading to transformation of NIH3T3 cells and neuronal differentiation of PC12 cells. Signal Transducer and Activator of Transcription (STAT) 3 is activated in response to cytokines and growth factors and it has been recently identified as a novel signal transducer for TrkA, mediating the functions of NGF in nervous system. In this paper we have investigated STAT3 involvement in signalling induced by TRK oncogenes. We showed that TRK oncogenes trigger STAT3 phosphorylation both on Y705 and S727 residues and STAT3 transcriptional activity. MAPK pathway was involved in the induction of STAT3 phosphorylation. Interestingly, we have shown reduced STAT3 protein level in NIH3T3 transformed foci expressing TRK oncogenes. Overall, we have unveiled a dual role for STAT3 in TRK oncogenes-induced NIH3T3 transformation: i) decreased STAT3 protein levels, driven by TRK oncoproteins activity, are associated to morphological transformation; ii) residual STAT3 transcriptional activity is required for cell growth

X-Ray Fluorescence Analysis of Ground Coffee

Coffee is becoming one of the most popular beverages in Mexico. In the present work, X-ray Fluorescence (XRF) was used to determine the contents of several elements (with atomic numbers between 11 and 38) in 11 samples of commercial ground coffee, comparing with another one of soluble coffee and two of used ground coffee. Samples were dried at room temperature and pelletized. XRF analyses were carried out using a spectrometer based on an Rh X-ray tube, registering the characteristic x-rays with a Silicon Drift Detector. The system detection calibration and accuracy check was performed through the analysis of NIST certified reference materials 1547 (peach leaves), 1570a (spinach leaves), 1573a (tomato leaves), and 1571 (orchid leaves). As a general rule, the elemental concentrations measured are similar in all samples of coffee, in values not exceeding toxic levels. However, the differences among the elemental concentrations are shown