Structural basis for the high all-trans-retinaldehyde reductase activity of the tumor marker AKR1B10

AKR1B10 is a human aldo-keto reductase (AKR) found to be elevated in several cancer types and in precancerous lesions. In vitro, AKR1B10 exhibits a much higher retinaldehyde reductase activity than any other human AKR, including AKR1B1 (aldose reductase). We here demonstrate that AKR1B10 also acts as a retinaldehyde reductase in vivo. This activity may be relevant in controlling the first step of retinoic acid synthesis. Up-regulation of AKR1B10, resulting in retinoic acid depletion, may lead to cellular proliferation. Both in vitro and in vivo activities of AKR1B10 were inhibited by tolrestat, an AKR1B1 inhibitor developed for diabetes treatment. The crystal structure of the ternary complex AKR1B10–NADP⁺–tolrestat was determined at 1.25-Å resolution. Molecular dynamics models of AKR1B10 and AKR1B1 with retinaldehyde isomers and site-directed mutagenesis show that subtle differences at the entrance of the retinoid-binding site, especially at position 125, are determinant for the all-trans-retinaldehyde specificity of AKR1B10. Substitutions in the retinaldehyde cyclohexene ring also influence the specificity. These structural features should facilitate the design of specific inhibitors, with potential use in cancer and diabetes treatments.     

Protection against Fas-induced liver apoptosis in transgenic mice expressing cyclooxygenase 2 in hepatocytes

Cyclooxygenase-2 (COX-2) is upregulated in many cancers, and the prostanoids synthesized increase proliferation, improve angiogenesis, and inhibit apoptosis in several tissues. To explore the function of COX-2 in liver, transgenic (Tg) mice were generated containing a fusion gene (LIVhCOX-2) consisting of human COX-2 cDNA under the control of the human ApoE promoter. Six lines were developed; all of them expressed the LIVhCOX-2 transgene selectively in hepatocytes. The Tg mice exhibited a normal phenotype, and the increased levels of PGE2 found were due to the constitutively expressed COX-2. Histological analysis of different tissues and macroscopic examination of the liver showed no differences between wild-type (Wt) and Tg animals. However, Tg animals were resistant to Fas-mediated liver injury, as demonstrated by low levels of plasmatic aminotransferases, a lesser caspase-3 activation, and Bax levels and an increase in Bcl-2, Mcl-1, and xIAP proteins, when compared with the Wt animals. Moreover, the resistance to Fas-mediated apoptosis is suppressed in the presence of COX-2-selective inhibitors, which prevented prostaglandin accumulation in the liver of Tg mice. CONCLUSION: These results demonstrate that expression of COX-2-dependent prostaglandins exerted a protection against liver apoptosis.     

Antiapoptotic drugs: a therapautic strategy for the prevention of neurodegenerative diseases

The purpose of this review is to discuss potential pathways involved in the pathogenesis of neurodegenerative diseases, highlighting current pharmacological drug targets in neuronal apoptosis prevention. The incidence of these disorders is expected to rise in the coming years and so finding effective treatments represents a significant challenge for medicine. Alzheimer's disease and Parkinson's disease were both described almost a century ago and are the most important neurodegenerative disorders in the developed world. However, the molecular mechanisms that lead to the development of the neuronal pathology in both diseases are unclear. For this reason, despite substantial research in the area, an effective treatment for these diseases does not yet exist. In the present study we discuss in depth the pathways involved in apoptosis and neuronal death in neurodegenerative diseases. We also examine drugs that may have a neuroprotective effect. Inhibition of apoptosis mediated by oxidative stress generation and mitochondrial alteration or by the blockade of NMDA receptors could constitute a suitable therapeutic strategy for Alzheimer's disease. A multiple therapy with antioxidants, cell cycle inhibitors, GSK3β inhibitors, and STATINS could, in the future, represent a suitable strategy for delaying the progression of neurodegenerative diseases. This research contributes to the development of new methods in the field of apoptosis inhibitors that could provide the future tools for the treatment of Alzheimer's and Parkinson's disease, as well as other neurodegenerative diseases.     

Human Health Risk Assessment of Environmental Exposure to Organochlorine Compounds in the Catalan Stretch of the Ebro River,Spain

In this study, the environmental impact and human health risks associated with exposure to organochlorine compounds (OCs) through soils and tap water in the Catalan stretch of the Ebro River, Spain, were investigated. The concentrations of polychlorinated biphenyls, hexachlorocyclohexanes, as well as DDT and derivates, were determined. Relatively low levels of these pollutants were observed, with mean concentrations ranging between 0.51–315.8 μg/kg and 0.05–74.6 ng/L in soil and tap water, respectively. These values are similar to those found in a number of recent surveys over the world. In spite of the presence of a chlor-alkali plant located upstream the Ebro River, which could mean a potential source of pollution, the current levels of OCs should not mean significant additional health risks for the local population.     

Clinical and sociodemographic variables associated with the onset of posttraumatic stress disorder in road traffic accidents

Our objective was to identify variables related to the onset of acute posttraumatic stress disorder (PTSD) after a road traffic accident. We evaluated 60 victims of a motor vehicle accident (MVA) in 2004 at 2 months postaccident. Thirty of them had developed PTSD; the other 30 had not developed PTSD. Clinical data, physical injuries, and sociodemographic characteristics were determined in 60 victims. The Davidson Trauma Scale (DTS) and a Structured Clinical Interview for DSM-IV (SCID) were used to evaluate PTSD occurrence. PTSD scores assessed by DTS and SCID at 2 months were significantly and positively associated with female sex, severe physical injuries, perceived social deprivation, and loss of job activity due to the accident. Female sex, severe physical injury, perceived social deprivation, and sick leave were related to the diagnosis of PTSD 2 months after the accident.     

Novel pharmacological targets based on receptor heteromers

Studies performed in the last 10 years have provided solid evidence indicating that G-protein-coupled receptors are expressed on the plasma membrane as homo and heterodimers. The first consequence of this fact is that homo and heterodimers are the true targets of natural (hormones, neurotransmitters) and synthetic drugs. Furthermore a given receptor in a heteromer may display a different functional and/or pharmacological profile than the same receptor characterized as monomer or as homodimer. Recent evidence indicates that receptor heteromers are sensors that lead to a fine-tuning in neurotransmission or hormone regulation; mainly this is achieved by a modification of the signaling pathways activated via a given receptor when it is forming a given heteromer. Quite often antagonists display variable affinities when a given receptor is expressed with different heteromeric partners. This fact should be taken into account in the development of new drugs. Finally it should be pointed out that radioligand binding data has to be analyzed by a model that considers receptors as dimers and not as monomers. This model provides a novel approach to characterize drugs interacting with the orthosteric center (agonists/antagonists) or with allosteric centers (allosteric regulators).     

Development of a hinge compatible with the kinematics of the knee joint

This study aims to present a new concept of a knee hinge based on a crossed four-bar linkage mechanism which has been designed to optimally follow a motion curve representing the knee kinematics in the position at which the knee hinge should be placed. The methodology used to determine the optimal knee hinge is based on the optimization of certain variables of the crossed four-bar mechanism using genetic algorithms in order to follow a certain motion curve, which was determined using a biomechanical model of the knee motion. Two current, commercially available knee hinges have been used to theoretically determine their motion by means of the path performed by their instantaneous helical axis. Comparison between these two different knee hinges, Optimal Knee Hinge and the theoretical motion performed by a human knee reveals that a common monocentric hinge has a maximum misalignment of up to 27.2 mm; a polycentric hinge has a maximum misalignment of 23.9 mm. In contrast, the maximum misalignment produced by the Optimal Knee Hinge is 1.99 mm. The orthotic joint presented significantly improves the kinematical compatibility and the adjustment between orthotic and human joint motion, and should provide several advantages in terms of comfort and safety. Furthermore, the determination of the instantaneous helical axis for a particular user, by means of human movement measurement techniques, will enable the optimal crossed four-bar mechanisms to be determined in a customized and personalized manner. As a consequence, this new concept of orthotic knee joint design may improve the adaptability of lower limb orthoses for the user, and may lead to significant advantages in the field of orthotics for the lower limb.     

Socioeconomic inequalities in alcohol related cancer mortality among men: To what extent do they differ between Western European populations?

We aim to study socioeconomic inequalities in alcohol related cancers mortality [upper aerodigestive tract (UADT) (oral cavity, pharynx, larynx, oesophagus and liver)] in men and to investigate whether the contribution of these cancers to socioeconomic inequalities in cancer mortality differs within Western Europe. We used longitudinal mortality datasets, including causes of death. Data were collected during the 1990s among men aged 30-74 years in 13 European populations [Madrid, the Basque region, Barcelona, Turin, Switzerland (German and Latin part), France, Belgium (Walloon and Flemish part, Brussels), Norway, Sweden, Finland]. Socioeconomic status was measured using the educational level declared at the census at the beginning of the follow-up period. We conducted Poisson regression analyses and used both relative [Relative index of inequality (RII)] and absolute (mortality rates difference) measures of inequality. For UADT cancers, the RII's were above 3.5 in France, Switzerland (both parts) and Turin whereas for liver cancer they were the highest (around 2.5) in Madrid, France and Turin. The contribution of alcohol related cancer to socioeconomic inequalities in cancer mortality was 29-36% in France and the Spanish populations, 17-23% in Switzerland and Turin, and 5-15% in Belgium and the Nordic countries. We did not observe any correlation between mortality rates differences for lung and UADT cancers, confirming that the pattern found for UADT cancers is not only due to smoking. This study suggests that alcohol use substantially influences socioeconomic inequalities in male cancer mortality in France, Spain and Switzerland but not in the Nordic countries and nor in Belgium.