Influence of temperature on the liver circadian clock in the ruin lizard Podarcis sicula

Reptiles represent an interesting animal model to investigate the influence of temperature on molecular circadian clocks. The ruin lizard Podarcis sicula lives in a continental climate and it is subjected to wide range of environmental temperatures during the course of the year. As consequence, ruin lizard daily activity pattern includes either the hibernation or periods of inactivity determined by hypothermia. Here we showed the rhythmic expression of two clock genes, lPer2 and lClock, in the liver of active lizards exposed to summer photo-thermoperiodic conditions. Interestingly, the exposition of lizards to hypothermic conditions, typical of winter season, induced a strong dampening of clock genes mRNA rhythmicity with a coincident decrease of levels. We also examined the qualitative and quantitative distribution of lPER2 and lCLOCK protein in different cellular compartments during the 24-h cycle. In the liver of active lizards both proteins showed a rhythmic expression profile in all cellular compartments. After 3 days at 6 degrees C, some temporal fluctuations of the lCLOCK and lPER2 are still detectable, although, with some marked modifications in respect to the values detected in the liver of active lizards. Besides demonstrating the influence of low temperature on the lizard liver circadian oscillators, present results could provide new essential information for comparative studies on the influence of temperature on the circadian system across vertebrate classes.     

Combined Treatment with Dif1stat<Superscript>®</Superscript> and Diet Reduce Plasma Lipid Indicators of Moderate Hypercholesterolemia More Effectively than Diet Alone: A Randomized Trial in Parallel Groups

An open-labeled randomized trial with parallel groups was carried out to study the effects of Dif1stat^® (Monascus purpureus–Linear aliphatic alcohols–Niacin) in the treatment of primary moderate hypercholesterolemia. The trial lasted 8 months. The patients, males and females, were assigned to two groups: A (#130), treated with diet, and B (#110) submitted to diet + Dif1stat^®. After 4 months, group A did not show significant changes in Total cholesterol (TC), LDL-cholesterol (LDLC), HDL-cholesterol (HDLC) or non-HDL-cholesterol (non-HDLC). The same group, showed a reduction in TC (–22%), LDLC (–30%) and non-HDLC (–27%) after 8 months (P ≤ 0.001). After 4 months, TC (–21.3%), LDLC (–29%), and non-HDLC (–26%) were significantly lowered in group B (P ≤ 0.001). In group B, TC, LDLC and non-HDLC showed a further reduction after 8 months: –29.4, –38 and –37%, respectively (P ≤ 0.001). Even triglycerides (TG) decreased significantly (–33%) (P ≤ 0.001). After 8 months, group B showed a significant reduction of TG (–33%) (P ≤ 0.001), when compared to group A. Some safety parameters were significantly reduced in both groups: AST and γ-GT in group A after 4 and 8 months, as well as ALT, AST and γ-GT in group B after 8 months (P ≤ 0.001). Dif1stat^®, given with a suitable diet, was well tolerated in the long-term and induced an anti-atherogenic plasma lipid and lipoprotein profile, in patients with moderate hypercholesterolemia.     

Oxidative Stress and Respiratory Diseases in Preterm Newborns

Premature infants are exposed to increased generation of reactive oxygen species, and on the other hand, they have a deficient antioxidant defense system. Oxidative insult is a salient part of lung injury that begins as acute inflammatory injury in respiratory distress disease and then evolves into chronic and structural scarring leading to bronchopulmonary dysplasia. Oxidative stress is also involved in the pathogenesis of pulmonary hypertension in newborns through the modulation of the vascular tone and the response to pulmonary vasodilators, with consequent decrease in the density of the pulmonary vessels and thickening of the pulmonary arteriolar walls. Oxidative stress has been recognized as both a trigger and an endpoint for several events, including inflammation, hypoxia, hyperoxia, drugs, transfusions, and mechanical ventilation, with impairment of pulmonary function and prolonged lung damage. Redoxomics is the most fascinating new measure to address lung damage due to oxidative stress. The new challenge is to use omics data to discover a set of biomarkers useful in diagnosis, prognosis, and formulating optimal and individualized neonatal care. The aim of this review was to examine the most recent evidence on the relationship between oxidative stress and lung diseases in preterm newborns. What is currently known regarding oxidative stress-related lung injury pathogenesis and the available preventive and therapeutic strategies are also discussed.     

Structural and Hemodynamic Changes of the Right Ventricle in PH-HFpEF

One of the most important diagnostic challenges in clinical practice is the distinction between pulmonary hypertension (PH) due to primitive pulmonary arterial hypertension (PAH) and PH due to left heart diseases. Both conditions share some common characteristics and pathophysiological pathways, making the two processes similar in several aspects. Their diagnostic differentiation is based on hemodynamic data on right heart catheterization, cardiac structural modifications, and therapeutic response. More specifically, PH secondary to heart failure with preserved ejection fraction (HFpEF) shares features with type 1 PH (PAH), especially when the combined pre- and post-capillary form (CpcPH) takes place in advanced stages of the disease. Right ventricular (RV) dysfunction is a common consequence related to worse prognosis and lower survival. This condition has recently been identified with a new classification based on clinical signs and progression markers. The role and prevalence of PH and RV dysfunction in HFpEF remain poorly identified, with wide variability in the literature reported from the largest clinical trials. Different parenchymal and vascular alterations affect the two diseases. Capillaries and arteriole vasoconstriction, vascular obliteration, and pulmonary blood fluid redistribution from the basal to the apical district are typical manifestations of type 1 PH. Conversely, PH related to HFpEF is primarily due to an increase of venules/capillaries parietal fibrosis, extracellular matrix deposition, and myocyte hypertrophy with a secondary “arteriolarization” of the vessels. Since the development of structural changes and the therapeutic target substantially differ, a better understanding of pathobiological processes underneath PH-HFpEF, and the identification of potential maladaptive RV mechanisms with an appropriate diagnostic tool, become mandatory in order to distinguish and manage these two similar forms of pulmonary hypertension.     

Investigation of Pluronic© F127–Water solutions phase transitions by DSC and dielectric spectroscopy

The water solutions of the block copolymers PEO_n‐PPO_m‐PEO_n, known as pluronics, show a complex thermal behavior, since they are liquid at low temperature (5°C), and they can give soft gel when heated at body temperature (37°C). These properties are of great interest in biomedical applications. To properly design these applications, a prerequisite is the knowledge of the thermodynamics—how much—and of the kinetics—how fast—with which these transformations take place. In this work, solutions of F127 (the copolymer for which n = 100 and m = 65) were studied by varying the concentration and the temperature and analyzing their behavior when heated under several heating rates. The studies were performed by differential scanning calorimetry (DCS) and dielectric spectroscopy. The investigations carried out under equilibrium conditions allowed us to determine the thermodynamics of the phase transitions, whereas the investigations carried out under varying conditions allowed us to quantify the kinetics of the phase transitions. Empirical models were also proposed to describe both the thermodynamics and the kinetics observed. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Phospholipid film in electrolyte-gated organic field-effect transistors

A totally innovative electrolyte-gated field effect transistor, embedding a phospholipid film at the interface between the organic semiconductor and the gating solution, is described. The electronic properties of OFETs including a phospholipid film are studied in both pure water and in an electrolyte solution and compared to those of an OFET with the organic semiconductor directly in contact with the gating solution. In addition, to investigate the role of the lipid layers in the charge polarization process and quantify the field-effect mobility, impedance spectroscopy was employed. The results indicate that the integration of the biological film minimizes the penetration of ions into the organic semiconductor thus leading to a capacitive operational mode as opposed to an electrochemical one. The OFETs operate at low voltages with a field-effect mobility in the 10⁻³ cm² V⁻¹ s⁻¹ range and an on/off current ratio of 10³. This achievement opens perspectives to the development of FET biosensors potentially capable to operate in direct contact with physiological fluids.     

(R)‐α‐Lipoyl‐Glycyl‐L‐Prolyl‐L‐Glutamyl Dimethyl Ester Codrug as a Multifunctional Agent with Potential Neuroprotective Activities

The (R)‐α‐lipoyl‐glycyl‐L ‐prolyl‐L ‐glutamyl dimethyl ester codrug (LA‐GPE, 1 ) was synthesized as a new multifunctional drug candidate with antioxidant and neuroprotective properties for the treatment of neurodegenerative diseases. Physicochemical properties, chemical and enzymatic stabilities were evaluated, along with the capacity of LA‐GPE to penetrate the blood–brain barrier (BBB) according to an in vitro parallel artificial membrane permeability assay for the BBB. We also investigated the potential effectiveness of LA‐GPE against the cytotoxicity induced by 6‐hydroxydopamine (6‐OHDA) and H₂O₂ on the human neuroblastoma cell line SH‐SY5Y by using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) reduction assay. Our results show that codrug 1 is stable at both pH 1.3 and 7.4, exhibits good lipophilicity (log P=1.51) and a pH‐dependent permeability profile. Furthermore, LA‐GPE was demonstrated to be significantly neuroprotective and to act as an antioxidant against H₂O₂‐ and 6‐OHDA‐induced neurotoxicity in SH‐SY5Y cells.     

Identifying Lysophosphatidic Acid Acyltransferase β (LPAAT-β) as the Target of a Nanomolar Angiogenesis Inhibitor from a Phenotypic Screen Using the Polypharmacology Browser PPB2

By screening a focused library of kinase inhibitor analogues in a phenotypic co-culture assay for angiogenesis inhibition, we identified an aminotriazine that acts as a cytostatic nanomolar inhibitor. However, this aminotriazine was found to be completely inactive in a whole-kinome profiling assay. To decipher its mechanism of action, we used the online target prediction tool PPB2 ( http://ppb2.gdb.tools ), which suggested lysophosphatidic acid acyltransferase β (LPAAT-β) as a possible target for this aminotriazine as well as several analogues identified by structure–activity relationship profiling. LPAAT-β inhibition (IC₅₀ ≈15 nm ) was confirmed in a biochemical assay and by its effects on cell proliferation in comparison with a known LPAAT-β inhibitor. These experiments illustrate the value of target-prediction tools to guide target identification for phenotypic screening hits and significantly expand the rather limited pharmacology of LPAAT-β inhibitors.     

Electrosynthesis and characterization of gold nanoparticles for electronic capacitance sensing of pollutants

In the present study, gold/surfactant core/shell colloidal nanoparticles with a controlled morphology and chemical composition have been obtained via the so-called sacrificial anode technique, carried out in galvanostatic mode. As synthesized Au-NPs had an average core diameter comprised between 4 and 8 nm, as a function of the electrochemical process experimental conditions. The UV–Vis characterization of gold nanocolloids showed clear spectroscopic size effects, affecting both the position and width of the nanoparticle surface plasmon resonance peak.The nanomaterial surface spectroscopic characterization showed the presence of two chemical states, namely nanostructured Au(0) (its abundance being higher than 90%) and Au(I). Au-NPs were then deposited on the top of a capacitive field effect sensor and subjected to a mild thermal annealing aiming at removing the excess of stabilizing surfactant molecules. Au-NP sensors were tested towards some gases found in automotive gas exhausts. The sensing device showed the largest response towards NO_x, and much smaller – if any – responses towards interferent species such as NH₃, H₂, CO, and hydrocarbons.