Structure–activity relationships in hydroxy-2,3-diarylxanthone antioxidants. Fast kinetics spectroscopy as a tool to evaluate the potential for antioxidant activity in biological systems

A structure–activity relationship has been established for eight hydroxy-2,3-diarylxanthones (XH) bearing hydroxy groups on the two aryl rings. One-electron oxidation by superoxide radical-anions (ΣO2 -) and ΣTrp radicals as well as reaction with ΣCCl3O2 and ΣCHCl2O2 radicals demonstrates that two OH groups are required for efficient antioxidant reactivity in cetyltrimethylammonium bromide micelles. Hydroxy groups at the meta and para positions on either of the two phenyl rings confer enhanced reactivity, but XH bearing an OH at the para position of either phenyl ring is unreactive. While oxidation is favoured by OH in both meta and para positions of 2-aryl xanthone substituents, addition of a third and/or fourth OH enhances electron-donating capacity. In Cu2+-induced lipid peroxidation of human LDL, the lag period preceding the commencement of lipid peroxidation in the presence of XH bearing OH at meta and para positions on the 3-phenyl ring is extended to twice that observed with a comparable concentration of quercetin, a reference antioxidant. These antioxidants are also superior to quercetin in protecting human skin keratinocytes against tert-butylhydroperoxideinduced oxidative stress. While XH antioxidant activity in model biological systems is consistent with the structure–activity relationship, their response is also modulated by the localization of XH and by structural factors.This is Document No. NDLR-4864 from the Notre Dame Radiation Laboratory which is supported by the Office of Basic Energy Sciences at the United States Department of Energy. This work was supported by the Franco-Portuguese exchange programs GRICES-INSERM 2005-2006 and Pessoa 07958NF. P. Filipe thanks the “Sociedade Portugesa de Dermatologia e Venerologia” for a travel grant. Thanks are due to the University of Aveiro, “Fundação para a Ciência e a Tecnologia” and FEDER for funding the Organic Chemistry Research Unit. Clementina M. M. Santos thanks the Calouste Gulbenkian Foundation for the award of a short period research grant (proc 87872)

Polyhydroxy-2,3-diarylxanthones as antioxidants

Xanthones are a class of oxygenated heterocyclic compounds widely occurring in nature.[1] The biological properties of these compounds have been extensively reported in the literature and one of the most promising is their potential application as antioxidant agents.[2] This fact led us to start a programme on the synthesis of 2,3-diarylxanthones bearing hydroxyl groups in certain positions of their skeleton for further structure- antioxidant activity studies. In this communication we will describe the synthesis of 2,3-diarylxanthones starting with 2’-hydroxyacetophenone and cinnamic acid derivatives (Scheme 1). The Heck reaction of 3-bromo-2-styrylchromones 3 with styrenes give the methoxyxanthones 4 which, after cleavage of the protecting groups, give the desired polyhydroxy-2,3-diarylxanthones 5.[3] We will also report the inhibitory effect of the synthesized xanthones 5 on Cu2+-induced oxidation of isolated human serum low-density lipoproteins (LDLs). The formation of conjugated dienes and the consumption of carotenoids were chosen as markers of LDL lipid peroxidation.[4] The induction of oxidative stress studies in NCTC 2544 cells will also be presented

RFMirTarget: A Random Forest Classifier for Human miRNA Target Gene Prediction

Abstract. MicroRNAs (miRNAs) are key regulators of eukaryotic gene expression whose fundamental role has been already identified in many cell pathways. The correct identification of miRNAs targets is a major challenge in bioinformatics. So far, machine learning-based methods for miRNA-target prediction have shown the best results in terms of specificity and sensitivity. However, despite its well-known efficiency in other classifying tasks, the random forest algorithm has not been employed in this problem. Therefore, in this work we present RFMirTarget, an efficient random forest miRNA-target prediction system. Our tool analyzes the alignment between a candidate miRNA-target pair and extracts a set of structural, thermodynamics, alignment and position-based features. Experiments have shown that RFMirTarget achieves a Matthew’s correlation coefficient nearly 48 % greater than the performance reported for the MultiMiTar, which was trained upon the same data set. In addition, tests performed with RFMirTarget reinforce the importance of the seed region for target prediction accuracy

Regulation of epidermal growth factor receptor signaling in human cancer cells by microRNA-7

The epidermal growth factor receptor (EGFR) is frequently overexpressed in cancer and is an important therapeutic target. Aberrant expression and function of microRNAs (miRNAs) have been associated with tumorigenesis

Heterogeneous distribution of dopamine D2-like receptors in the rat entorhinal cortex.

J. Neural Trasm., 103/10, XLII, 1996. Rome October 28-30 199

Validation of ACE-FTS N2O measurements

The Atmospheric Chemistry Experiment (ACE), also known as SCISAT, was launched on 12 August 2003,carrying two instruments that measure vertical profiles of atmospheric constituents using the solar occultation technique.One of these instruments, the ACE Fourier Transform Spectrometer (ACE-FTS), is measuring volume mixing ratio profiles of nitrous oxide (N2O) from the upper troposphere to the lower mesosphere. In this study, the quality of the ACE-FTS version 2.2 N2O data is assessed rough comparisons with coincident measurements made by other satellite, balloon-borne, aircraft, and ground-based instruments.These consist of vertical profile comparisons with the SMR, MLS, and MIPAS satellite instruments, multiple aircraft flights of ASUR, and single balloon flights of SPIRALE and FIRS-2, and artial column comparisons with a network of ground-based Fourier Transform InfraRed spectrometers(FTIRs). Overall, the quality of the ACE-FTS version 2.2 N2O VMR profiles appears to be good over the entire altitude range from 5 to 60 km. Between 6 and 30 km, the meanabsolute differences for the satellite comparisons lie between -42 ppbv and +17 ppbv, with most within 20 ppbv, correspondingto relative deviations from the mean that are mostly within 5%. Between 18 and 30 km, the mean absolute differences are generally within 10 ppbv, with relative deviations from the mean within 20%, except for the aircraft and balloon comparisons. From 30 to 60 km, the mean absolute differences are within 4 ppbv, and are mostly between -2 and +1 ppbv. Given the small N2O VMR in this region, therelative deviations from the mean are therefore large at these altitudes, with most suggesting a negative bias in the ACEFTS data between 30 and 50 km. In the comparisons with the FTIRs, the mean relative differences between the ACE-FTS and FTIR partial columns are within 6.6% for eleven of thetwelve contributing stations. This mean relative difference is negative at eight stations, suggesting a small negative bias in the ACE-FTS partial columns over the altitude regions compared.Excellent correlation (R=0.964) is observed between the ACE-FTS and FTIR partial columns, with a slope of 1.01and an intercept -0.20 on the line fitted to the data

Rab14 Is Involved in Membrane Trafficking between the Golgi Complex and Endosomes

Rab GTPases are localized to various intracellular compartments and are known to play important regulatory roles in membrane trafficking. Here, we report the subcellular distribution and function of Rab14. By immunofluorescence and immunoelectron microscopy, both endogenous as well as overexpressed Rab14 were localized to biosynthetic (rough endoplasmic reticulum, Golgi, and trans-Golgi network) and endosomal compartments (early endosomal vacuoles and associated vesicles). Notably overexpression of Rab14Q70L shifted the distribution toward the early endosome associated vesicles, whereas the S25N and N124I mutants induced a shift toward the Golgi region. A similar, although less pronounced, redistribution of the transferrin receptor was also observed in cells overexpressing Rab14 mutants. Impairment of Rab14 function did not however affect transferrin uptake or recycling kinetics. Together, these findings suggest that Rab14 is involved in the biosynthetic/recycling pathway between the Golgi and endosomal compartments

Role of protein kinase C in anterior pituitary hormone release

The effects of intercellular coupling conductance on the activity of two electrically coupled isolated rabbit sinoatrial nodal cells were investigated. A computer-controlled version of the “coupling clamp” technique was used in which isolated sinoatrial nodal cells, not physically in contact with each other, were electrically coupled at various values of ohmic coupling conductance, mimicking the effects of mutual interaction by electrical coupling through gap junctional channels. We demonstrate the existence of four types of electrical behavior of coupled spontaneously active cells. As the coupling conductance is progressively increased, the cells exhibit: (a) independent pacemaking at low coupling conductances, (b) complex dynamics of activity with mutual interactions, (c) entrainment of action potential frequency at a 1:1 ratio with different action potential waveforms, and (d) entrainment of action potentials at the same frequency of activation and virtually identical action potential waveforms. The critical value of coupling conductance required for 1:1 frequency entrainment was <0.5 nS in each of the five cell pairs studied. The common interbeat interval at a relatively high coupling conductance (10 nS), which is sufficient to produce entrainment of frequency and also identical action potential waveforms, is determined most by the intrinsically faster pacemaker cell and it can be predicted from the diastolic depolarization times of both cells. Evidence is provided that, at low coupling conductances, mutual pacemaker synchronization results mainly from the phase-resetting effects of the action potential of one cell on the depolarization phase of the other. At high coupling conductances, the tonic, diastolic interactions become more important