Group A Streptococcus Secreted Esterase Hydrolyzes Platelet-Activating Factor to Impede Neutrophil Recruitment and Facilitate Innate Immune Evasion

The innate immune system is the first line of host defense against invading organisms. Thus, pathogens have developed virulence mechanisms to evade the innate immune system. Here, we report a novel means for inhibition of neutrophil recruitment by Group A Streptococcus (GAS). Deletion of the secreted esterase gene (designated sse) in M1T1 GAS strains with (MGAS5005) and without (MGAS2221) a null covS mutation enhances neutrophil ingress to infection sites in the skin of mice. In trans expression of SsE in MGAS2221 reduces neutrophil recruitment and enhances skin invasion. The sse deletion mutant of MGAS5005 (ΔsseMGAS5005) is more efficiently cleared from skin than the parent strain. SsE hydrolyzes the sn-2 ester bond of platelet-activating factor (PAF), converting biologically active PAF into inactive lyso-PAF. KM and kcat of SsE for hydrolysis of 2-thio-PAF were similar to those of the human plasma PAF acetylhydrolase. Treatment of PAF with SsE abolishes the capacity of PAF to induce activation and chemotaxis of human neutrophils. More importantly, PAF receptor-deficient mice significantly reduce neutrophil infiltration to the site of ΔsseMGAS5005 infection. These findings identify the first secreted PAF acetylhydrolase of bacterial pathogens and support a novel GAS evasion mechanism that reduces phagocyte recruitment to sites of infection by inactivating PAF, providing a new paradigm for bacterial evasion of neutrophil responses

Epigenetic modulators as therapeutic targets in prostate cancer

Prostate cancer is one of the most common non-cutaneous malignancies among men worldwide. Epigenetic aberrations, including changes in DNA methylation patterns and/or histone modifications, are key drivers of prostate carcinogenesis. These epigenetic defects might be due to deregulated function and/or expression of the epigenetic machinery, affecting the expression of several important genes. Remarkably, epigenetic modifications are reversible and numerous compounds that target the epigenetic enzymes and regulatory proteins were reported to be effective in cancer growth control. In fact, some of these drugs are already being tested in clinical trials. This review discusses the most important epigenetic alterations in prostate cancer, highlighting the role of epigenetic modulating compounds in pre-clinical and clinical trials as potential therapeutic agents for prostate cancer management.info:eu-repo/semantics/publishedVersio

Effectiveness of dry eye therapy under conditions of environmental stress

Purpose: Dry eye is often characterized by increased tear evaporation due to poor tear film quality, especially of the lipid component of the tear film. Using an environmental chamber to induce environmental stress, this study compared the effect of three lubricant eye drops on various aspects of tear physiology in a crossover design (evaporation was the principal outcome measure). Methods: Three eye drop formulas were tested: 0.5% carmellose sodium (Drop C), 0.5% carmellose sodium with added lipid (Drop C-L) and 1.0% glycerine with added lipid (Drop G-L). Nineteen control and 18 dry eye subjects used each product for 2 weeks, three times per day, in a random order, with a minimum 1-week washout between treatment periods. Tear evaporation, break up time, osmolarity, tear structure (by interferometry) and patient symptoms were assessed with the subjects adapted for 10 min in an environmental chamber controlled at 20% relative humidity and 22 °C. The treatment effects were analyzed using general linear model repeated measures analyses of variance. Results: In dry eye subjects, evaporation, break up time, osmolarity and symptoms improved for all formulas (p < 0.05). Normal subjects showed some improvements: evaporation with C-L, osmolarity with C and symptoms with C-L and G-L. Change in evaporation was greater for both C-L and G-L versus C (p < 0.05), and there was a trend for C-L to reduce evaporation more than G-L (p < 0.11). There were no significant treatment effects on tear film structure. Conclusion: Overall, the eye drop formula containing both carmellose sodium and lipid (C-L) produced a greater treatment effect on tear evaporation than the other formulations containing only one of these ingredients. This study also demonstrates the utility of a controlled environmental chamber in showing the difference in performance between dry eye treatments