Inhibition of Ocular Aldose Reductase by a New Benzofuroxane Derivative Ameliorates Rat Endotoxic Uveitis

The study investigated the effects of the aldose reductase (AR) inhibitor benzofuroxane derivative 5(6)-(benzo[d]thiazol-2-ylmethoxy) benzofuroxane (herein referred to as BF-5m) on the biochemical and tissue alterations induced by endotoxic uveitis in rats. BF-5m has been administered directly into the vitreous, in order to assess the expression and levels of (i) inflammatory markers such as the ocular ubiquitin-proteasome system, NF-κB, TNF-α, and MCP-1; (ii) prooxidant and antioxidant markers such as nitrotyrosine, manganese superoxide dismutase (MnSOD), and glutathione peroxidase (GPX); (iii) apoptotic/antiapoptotic factors caspases and Bcl-xl; (iv) markers of endothelial progenitor cells (EPCs) recruitment such as CD34 and CD117. 5 L of BF-5m (0.01; 0.05; and 0.1 M) into the right eye decreased in a dose-dependent manner the LPS-induced inflammation of the eye, reporting a clinical score 1. It reduced the ocular levels of ubiquitin, 20S and 26S proteasome subunits, NF-κB subunits, TNF-α, MCP-1, and nitrotyrosine. BF-5m ameliorated LPS-induced decrease in levels of MnSOD and GPX. Antiapoptotic effects were seen from BF-5m by monitoring the expression of Bcl-xl, an antiapoptotic protein. Similarly, BF-5m increased recruitment of the EPCs within the eye, as evidenced by CD34 and CD117 antibodies

Impact of hormonal treatment duration in combination with radiotherapy for locally advanced prostate cancer: Meta-analysis of randomized trials

<p>Abstract</p> <p>Background</p> <p>Hormone therapy plus radiotherapy significantly decreases recurrences and mortality of patients affected by locally advanced prostate cancer. In order to determine if difference exists according to the hormonal treatment duration, a literature-based meta-analysis was performed.</p> <p>Methods</p> <p>Relative risks (RR) were derived through a random-effect model. Differences in primary (biochemical failure, BF; cancer-specific survival, CSS), and secondary outcomes (overall survival, OS; local or distant recurrence, LR/DM) were explored. Absolute differences (AD) and the number needed to treat (NNT) were calculated. Heterogeneity, a meta-regression for clinic-pathological predictors and a correlation test for surrogates were conducted.</p> <p>Results</p> <p>Five trials (3,424 patients) were included. Patient population ranged from 267 to 1,521 patients. The longer hormonal treatment significantly improves BF (with significant heterogeneity) with an absolute benefit of 10.1%, and a non significant trend in CSS. With regard to secondary end-points, the longer hormonal treatment significantly decrease both the LR and the DM with an absolute difference of 11.7% and 11.5%. Any significant difference in OS was observed. None of the three identified clinico-pathological predictors (median PSA, range 9.5-20.35, Gleason score 7-10, 27-55% patients/trial, and T3-4, 13-77% patients/trial), did significantly affect outcomes. At the meta-regression analysis a significant correlation between the overall treatment benefit in BF, CSS, OS, LR and DM, and the length of the treatment was found (p≤0.03).</p> <p>Conclusions</p> <p>Although with significant heterogeneity (reflecting different patient' risk stratifications), a longer hormonal treatment duration significantly decreases biochemical, local and distant recurrences, with a trend for longer cancer specific survival.</p

Inflation and Dark Energy from spectroscopy at z > 2

The expansion of the Universe is understood to have accelerated during two epochs: in its very first moments during a period of Inflation and much more recently, at z < 1, when Dark Energy is hypothesized to drive cosmic acceleration. The undiscovered mechanisms behind these two epochs represent some of the most important open problems in fundamental physics. The large cosmological volume at 2 < z < 5, together with the ability to efficiently target high-$z$ galaxies with known techniques, enables large gains in the study of Inflation and Dark Energy. A future spectroscopic survey can test the Gaussianity of the initial conditions up to a factor of ~50 better than our current bounds, crossing the crucial theoretical threshold of $\sigma(f_{NL}^{\rm local})$ of order unity that separates single field and multi-field models. Simultaneously, it can measure the fraction of Dark Energy at the percent level up to $z = 5$, thus serving as an unprecedented test of the standard model and opening up a tremendous discovery space

Effects of PPARs Agonists on Cardiac Metabolism in Littermate and Cardiomyocyte-Specific PPAR-γ –Knockout (CM-PGKO) Mice

Understanding the molecular regulatory mechanisms controlling for myocardial lipid metabolism is of critical importance for the development of new therapeutic strategies for heart diseases. The role of PPARγ and thiazolidinediones in regulation of myocardial lipid metabolism is controversial. The aim of our study was to assess the role of PPARγ on myocardial lipid metabolism and function and differentiate local/from systemic actions of PPARs agonists using cardiomyocyte-specific PPARγ –knockout (CM-PGKO) mice. To this aim, the effect of PPARγ, PPARγ/PPARα and PPARα agonists on cardiac function, intra-myocyte lipid accumulation and myocardial expression profile of genes and proteins, affecting lipid oxidation, uptake, synthesis, and storage (CD36, CPT1MIIA, AOX, FAS, SREBP1-c and ADPR) was evaluated in cardiomyocyte-specific PPARγ –knockout (CM-PGKO) and littermate control mice undergoing standard and high fat diet (HFD). At baseline, protein levels and mRNA expression of genes involved in lipid uptake, oxidation, synthesis, and accumulation of CM-PGKO mice were not significantly different from those of their littermate controls. At baseline, no difference in myocardial lipid content was found between CM-PGKO and littermate controls. In standard condition, pioglitazone and rosiglitazone do not affect myocardial metabolism while, fenofibrate treatment significantly increased CD36 and CPT1MIIA gene expression. In both CM-PGKO and control mice submitted to HFD, six weeks of treatment with rosiglitazone, fenofibrate and pioglitazone lowered myocardial lipid accumulation shifting myocardial substrate utilization towards greater contribution of glucose. In conclusion, at baseline, PPARγ does not play a crucial role in regulating cardiac metabolism in mice, probably due to its low myocardial expression. PPARs agonists, indirectly protect myocardium from lipotoxic damage likely reducing fatty acids delivery to the heart through the actions on adipose tissue. Nevertheless a direct non- PPARγ mediated mechanism of PPARγ agonist could not be ruled out