In Search of Differential Inhibitors of Aldose Reductase

Aldose reductase, classified within the aldo-keto reductase family as AKR1B1, is an NADPH dependent enzyme that catalyzes the reduction of hydrophilic as well as hydrophobic aldehydes. AKR1B1 is the first enzyme of the so-called polyol pathway that allows the conversion of glucose into sorbitol, which in turn is oxidized to fructose by sorbitol dehydrogenase. The activation of the polyol pathway in hyperglycemic conditions is generally accepted as the event that is responsible for a series of long-term complications of diabetes such as retinopathy, cataract, nephropathy and neuropathy. The role of AKR1B1 in the onset of diabetic complications has made this enzyme the target for the development of molecules capable of inhibiting its activity. Virtually all synthesized compounds have so far failed as drugs for the treatment of diabetic complications. This failure may be partly due to the ability of AKR1B1 to reduce alkenals and alkanals, produced in oxidative stress conditions, thus acting as a detoxifying agent. In recent years we have proposed an alternative approach to the inhibition of AKR1B1, suggesting the possibility of a differential inhibition of the enzyme through molecules able to preferentially inhibit the reduction of either hydrophilic or hydrophobic substrates. The rationale and examples of this new generation of aldose reductase differential inhibitors (ARDIs) are presented

Detection of meteorological inconsistencies by GPS

GPS observations, distances from satellites to receivers and meteorological conditions in neutral atmosphere are known to obey a constraint, which provides a residual or in other words a quality index. A method is discussed which provides a residual epoch by epoch in near real time. In general, distribution of residuals during several consecutive epochs belonging to the same satellites, allows estimates of a mean and a standard deviation of mean. Under normal meteorological conditions distribution of residuals appears to be consistent with zero mean as expected. However, consecutive residuals sometimes appear to have a mean different from zero by more than three standard deviations of mean. Such signifi cant consecutive epochs provide a warning of existing inconsistencies among GPS observations, distances from satellites to receivers as obtained by orbital information, meteorological conditions above receivers (as obtained by ground measurements or by extrapolation of meteorological analysis). A procedure has been set up which warns about these inconsistencies in near real time

Efficacy and safety of felbamate in children under 4 years of age: a retrospective chart review.

Background and purpose: To review our experience of the efficacy and tolerability of felbamate in children younger than 4 years. Methods: We used a retrospective chart review to identify 53 children with seizures who were younger than 4 years. Efficacy was evaluated based on the occurrence of responsiveness, defined as seizure frequency reduction of more than 50% for a minimum period of 4 months. Tolerability was based on parent-reported side effects. Results: Twenty-two (41%) patients resulted to be responders and 31 (59%) did not. By univariate analysis, those achieving seizure remission were probably much older, to have a shorter history of epilepsy and a lower frequency of seizures before felbamate therapy. The number of antiepileptic drugs (AEDs) used before felbamate therapy was the only significant predictor of the duration of response to felbamate, with a longer responsiveness to the drug seen in those who were placed under fewer than three AEDs before felbamate compared with those who had taken more than three (median, 16 months vs. 7 months; P < 0.0084). Side effects occurred in 30% of the subjects, but these did not require discontinuation of the drug. Discussion: Felbamate is an effective medication for a wide range of epilepsy syndromes in children younger than 4 years. Although caution is necessary when the drug is used in children, felbamate might represent a possible option for the treatment of epilepsy in this age group. Introduction The incidence of epilepsy is high during the first year of life and it declines steadily during childhood and adolescence. Few of the new antiepileptic drugs (AEDs) are indicated officially for children younger than 4 years [1–3]. None of them is approved for children younger than 2 years [1,3,4]. There is a striking discrepancy between the high incidence of epilepsy in infancy and the relatively few approved AEDs available for this age group [5]. Felbamate (2-phenyl-1,3-propanediol dicarbamate) is a derivative of the anti-anxiety drug meprobamate, exerting additional anticonvulsant and neuroprotective properties [6–8]. The drug has been approved since 1993 for the treatment of several types of epilepsy. Experimental studies suggested that felbamate might inhibit voltage-dependen

Levulinic acid production from the green macroalgae chaetomorpha linum and valonia aegagropila harvested in the orbetello lagoon

In recent years, the replacement of fossil resources with renewable ones has received great interest, especially as regards the production of new valuable bio-products and bio-fuels, in order to replace the traditional petroleum-based ones. In this context, the exploitation of waste biomasses into added-value biochemicals is strongly encouraged. Among these ones, the algae ones are attracting considerable attention, in particular macroalgae which cause eutrophication problems in estuaries and lagoons, due to the drastic reduction of dissolved oxygen during their decomposition. This is true for Orbetello lagoon (Italy), where a large amount of algal biomasses is removed every year through an expensive practice, with consequent environmentally serious disposal problems. In this work, for the first time, the acid-catalyzed conversion of two different macroalgae harvested in Orbetello lagoon, Chaetomorpha linum (Muller) Kutzing and Valonia aegagropila C. Agardh, into levulinic acid was studied and optimized, adopting a one-pot hydrothermal treatment, under microwave heating and in the presence of aqueous diluted mineral acids, H2SO4 and HCl. Levulinic acid is a versatile platform chemical, classified by the United States Department of Energy as one of the top-12 promising bio-based building blocks. The effect of the main reaction parameters to give levulinic acid was investigated and discussed, in particular the type and concentration of the acid catalyst, the temperature and the reaction time. The highest levulinic acid yields of 19 wt% for Chaetomorpha linum and 16 wt% for Valonia aegagropila, calculated respect to the weight of the starting dried biomass, were reached. The achieved results are very promising and confirm the significant potential of these green algae as renewable starting feedstocks for levulinic acid production

Pathways of 4-hydroxy-2-nonenal detoxification in a human astrocytoma cell line

One of the consequences of the increased level of oxidative stress that often characterizes the cancer cell environment is the abnormal generation of lipid peroxidation products, above all 4-hydroxynonenal. The contribution of this aldehyde to the pathogenesis of several diseases is well known. In this study, we characterized the ADF astrocytoma cell line both in terms of its pattern of enzymatic activities devoted to 4-hydroxynonenal removal and its resistance to oxidative stress induced by exposure to hydrogen peroxide. A comparison with lens cell lines, which, due to the ocular function, are normally exposed to oxidative conditions is reported. Our results show that, overall, ADF cells counteract oxidative stress conditions better than normal cells, thus confirming the redox adaptation demonstrated for several cancer cells. In addition, the markedly high level of NADP+-dependent dehydrogenase activity acting on the glutahionyl-hydroxynonanal adduct detected in ADF cells may promote, at the same time, the detoxification and recovery of cell-reducing power in these cells

L-Idose: an attractive substrate alternative to d-glucose for measuring aldose reductase activity

Although glucose is one of the most important physio-pathological substrates of aldose reductase, it is not an easy molecule for in vitro investigation into the enzyme. In many cases alternative aldoses have been used for kinetic characterization and inhibition studies. However these molecules do not completely match the structural features of glucose, thus possibly leading to results that are not fully applicable to glucose. We show how aldose reductase is able to act efficiently on L-idose, the C-5 epimer of D-glucose. This is verified using both the bovine lens and the human recombinant enzymes. While the kcat values obtained are essentially identical to those measured for D-glucose, a significant decrease in KM was observed. This can be due to the significantly higher level of the free aldehyde form present in L-idose compared to D-glucose. We believe that L-idose is the best alternative to D-glucose in studies on aldose reductase

Current advances on the regeneration of musculoskeletal interfaces

The regeneration of the musculoskeletal system has been widely investigated. There is now detailed knowledge about the organs composing this system. Research has also investigated the zones between individual tissues where physical, mechanical, and biochemical properties transition. However, the understanding of the regeneration of musculoskeletal interfaces is still lacking behind. Numerous disorders and injuries can degrade or damage tissue interfaces. Their inability to regenerate can delay the tissue repair and regeneration process, leading to graft instability, high morbidity, and pain. Moreover, the knowledge of the mechanism of tissue interface development is not complete. This review presents an overview of the most recent approaches of the regeneration of musculoskeletal interfaces, including the latest in vitro, preclinical, and clinical studies

Elastic Pion Scattering on the Deuteron in a Multiple Scattering Model

Pion elastic scattering on deuterium is studied in the KMT multiple scattering approach developed in momentum space. Using a Paris wave function and the same methods and approximations as commonly used in pion scattering on heavier nuclei excellent agreement with differential cross section data is obtained for a wide range of pion energies. Only for $T_{\pi}>250$ MeV and very backward angles, discrepancies appear that are reminiscent of disagreements in pion scattering on $^3$He, $^3$H, and $^4$He. At low energies the second order corrections have been included. Polarization observables are studied in detail. While tensor analyzing powers are well reproduced, vector analyzing powers exhibit dramatic discrepancies.Comment: 25 pages LATEX and 9 postscript figures in a self-extracting uufile archiv

Avaliação de genótipos de soja de diferentes grupos de maturação e resistência aos percevejos.

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