Synthesis and Evaluation of Voltage-Gated Sodium Channel Blocking Pyrroline Derivatives Endowed with Both Antiarrhythmic and Antioxidant Activities

Under the hypothesis that cardioprotective agents might benefit from synergism between antiarrhythmic activity and antioxidant properties, a small series of mexiletine analogues were coupled with the 2,2,5,5-tetramethylpyrroline moiety, known for its antioxidant effect, in order to obtain dual-acting drugs potentially useful in the protection of the heart against post-ischemic reperfusion injury. The pyrroline derivatives reported herein were found to be more potent as antiarrhythmic agents than mexiletine and displayed antioxidant activity. The most interesting tetramethylpyrroline congener, a tert-butyl-substituted analogue, was at least 100 times more active as an antiarrhythmic than mexiletine.     

Connexin 43 and Connexin 26 Involvement in the Ponatinib-Induced Cardiomyopathy: Sex-Related Differences in a Murine Model

Cardiac connexins (Cxs) are proteins responsible for proper heart function. They form gap junctions that mediate electrical and chemical signalling throughout the cardiac system, and thus enable a synchronized contraction. Connexins can also individually participate in many signal transduction pathways, interacting with intracellular proteins at various cellular compartments. Altered connexin expression and localization have been described in diseased myocardium and the aim of this study is to assess the involvement of Cx43, Cx26, and some related molecules in ponatinib-induced cardiac toxicity. Ponatinib is a new multi-tyrosine kinase inhibitor that has been successfully used against human malignancies, but its cardiotoxicity remains worrisome. Therefore, understanding its signaling mechanism is important to adopt potential anti cardiac damage strategies. Our experiments were performed on hearts from male and female mice treated with ponatinib and with ponatinib plus siRNA-Notch1 by using immunofluorescence, Western blotting, and proteomic analyses. The altered cardiac function and the change in Cxs expression observed in mice after ponatinib treatment, were results dependent on the Notch1 pathway and sex. Females showed a lower susceptibility to ponatinib than males. The downmodulation of cardiac Cx43, Cx26 and miR-122, high pS368-Cx43 phosphorylation, cell viability and survival activation could represent some of the female adaptative/compensatory reactions to ponatinib cardiotoxicity.     

Toxicity assessment of common xenobiotic compounds on municipal activated sludge: comparison between respirometry and Microtox

The toxicity of four xenobiotic compounds 3,5-dichlorophenol, formaldehyde, 4-nitrophenol and dichloromethane, representative of industrial wastewater contaminants was evaluated by a simple respirometric procedure set up on the basis of OECD Method 209 and by the Microtox bioassay. Very good reproducibility was observed for both methods, the variation coefficients being in the range of 2-10% for the respirometric procedure and 6-15% for Microtox, values that can be considered very good for a biological method. Comparison of EC(50) data obtained with the two methods shows that in both cases 3,5-dichlorophenol is more toxic than other compounds investigated and dichloromethane has a very low toxicity value. Intermediate EC(50) values were found for the two other chemicals, formaldehyde and 4-nitrophenol. Moreover, the Microtox EC(50) values are generally lower (except for dichloromethane) than the respirometric ones: these differences could be explained by the fact that the Microtox method uses a pure culture of marine species and, therefore, should not necessarily be expected to behave like a community of activated sludge bacteria. In conclusion, both methods can be usefully applied for toxicity detection in wastewater treatment plants but it is advisable to take into account that Microtox is more sensitive than respirometry in estimating the acute toxicity effect on the biomass operating in the plant.     

Assessing regulatory emotional self-efficacy in three countries.

The Regulatory Emotional Self-Efficacy (RESE) scale was developed to assess perceived self-efficacy in managing negative (NEG) and in expressing positive (POS) affect (G. V. Caprara & M. Gerbino, 2001). In this study of young adults, the factorial structure of the RESE scale was found to be similar in Italy, the United States, and Bolivia. In addition to a factor for POS, NEG was represented by a second-order factor of 2 different negative affects: despondency-distress (DES) and anger-irritation (ANG). Overall, there was partial invariance at both metric and scalar levels across gender and countries. Discriminant and convergent validity of the RESE scale was further examined in the Italian sample. Stronger patterns of association of POS with prosocial behavior, of ANG with low aggressive behavior problems and irritability, and of DES with low anxiety/depressive problems and shyness and high self-esteem were found. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Verification of distributed systems with local�Cglobal predicates

This paper describes a methodology for developing and verifying a class of distributed systems in which the state space may be discrete or continuous. Our focus is on systems where changes are local in that a small number of components change state while the remainder of the system is unchanged. A proof methodology is developed that ensures global properties, such as invariants and convergence, by guaranteeing local properties within subsystems. This methodology is used to prove the correctness of concrete examples. We present a PVS library of theorems and proofs that can be used to reduce the work required to develop and verify programs in this class. A transformation of these libraries to Java is also outlined.     

Applications of Isothermal Titration Calorimetry in Biophysical Studies of G-quadruplexes

G-quadruplexes are higher-order nucleic acids structures formed by G-rich sequences that are stabilized by tetrads of hydrogen-bonded guanine bases. Recently, there has been growing interest in the study of G-quadruplexes because of their possible involvement in many biological processes. Isothermal titration calorimetry (ITC) has been proven to be a useful tool to study the energetic aspects of G-quadruplex interactions. Particularly, ITC has been applied many times to determine the thermodynamic properties of drug-quadruplex interactions to screening among various drugs and to address drug design. In the present review, we will focus on the ITC studies of G-quadruplex structures and their interaction with proteins and drugs and the most significant results will be discussed.     

Determination of metals in wine with atomic spectroscopy (flame-AAS, GF-AAS and ICP-AES); a review

Metals in wine occur at the mg l 1 level or less and, though not directly related to the taste of the final product, their content should be determined because excess is undesirable, and in some cases prohibited, due to potential toxicity. Lead content in wine, for example, is restricted in several states by legislation to guarantee consumer health protection. Of several methods for metal determination, techniques of atomic spectroscopy are the most sensitive and rapid. Most of the elements present in wine can be determined with these techniques, at concentrations ranging from the mg l -1 to the μg l -1 level. Here, inductively coupled plasma-atomic emission spectrometry (ICP-AES), flame atomic absorption spectrometry (flame-AAS) and graphite furnace-atomic absorption spectrometry (GF-AAS) are compared for their characteristics as employed in metal determination in wine.     

Content of phytoestrogens in soy-based dietary supplements

The isoflavone content of 14 soy-based dietary supplements intended to help alleviate perimenopausal and menopausal symptoms on sale in Italy were analysed using HPLC with UV detection. The aim was to quantify soy isoflavones after hydrolysis as aglycones, which are the bioactive part of isoflavone molecules. In the examined products, the amounts of isoflavones were frequently expressed ambiguously, and none of the products stated whether the isoflavone content of the product was expressed as aglycones or as conjugates. Each product revealed a different aglycone concentration profile. These supplements have different “fingerprints”, probably due to different sources of raw materials and to methods used in processing and preparation of extracts. In more than half the supplements tested, the actual values contained were below those stated and below those expected to help alleviate perimenopausal and menopausal symptoms.