Glaucoma: role of neuroprotective agents

Glaucoma is an optic neuropathy, considered as the second leading cause of blindness worldwide. Glaucoma is characterized by selective death of retinal ganglion cells (RGC) and a progressive loss of vision. Elevated intraocular pressure (IOP) is one of the most important risk factors for developing glaucoma and hence we mainly focus on lowering IOP to arrest the progression of glaucoma. However, many patients continue to demonstrate a clinically downhill course despite the control of initially raised IOP. In fact, some patients develop what is called normal tension glaucoma, not associated to an increased IOP. This emphasizes that several pressure-independent mechanisms are responsible for the development and progression of glaucomatous neuropathy and that high IOP and vascular insufficiency in the optic nerve head are only risk factors for the development of glaucoma, and are not the only target for the treatment of glaucoma. The reason is that the process of RGC death is thought to be biphasic, and the primary injury is followed by a slower secondary degeneration related to a noxious environment surrounding the apoptotic cells. This environment is characterized by changes in the extra-cellular ionic concentrations, increased amounts of free radicals, neurotrophins (NT) depletion and increased glutamate-induced excitotoxicity due to high extra-cellular glutamate levels, which binds to N-methyl-D-aspartate (NMDA) receptors leading to an abnormally high intracellular Ca2+ concentration. Neuroprotection is a process that attempts to preserve the remaining cells that are still vulnerable to damage, and the main aim of neuroprotective therapy is to employ pharmacologic or other means to attenuate the hostility of the environment surrounding the degenerating cells, or to supply the cells with the tools to deal with this aggression, providing resilience to the insult. Several agents have been reported neuroprotective in glaucoma, both in clinical assays, such as Ca2+ channel blockers, and in experimental studies, such as betaxolol, brimonidine, NMDA antagonists, nitric oxide synthase inhibitors, NT and Ginkgo biloba extract. Most neuroprotective agents for glaucoma have proved beneficial effects over RGC, not showing effects over IOP. However, when analyzing classically used medications for glaucoma, it becomes difficult to understand if its effect over the progression of glaucoma is due to neuroprotective pathways or by means of lowering IOP. The ideal anti-glaucoma drug would be one that when applied topically, reduces IOP, but also probes to reach the retina in appropriate amounts, and activates specific receptors in the retina to attenuate RGC death. In this review, we will examine currently advocated neuroprotective drug-based strategies in the potential management of glaucoma

Evolutionary Action Score of TP53 Identifies High-Risk Mutations Associated with Decreased Survival and Increased Distant Metastases in Head and Neck Cancer

TP53 is the most frequently altered gene in head and neck squamous cell carcinoma, with mutations occurring in over two-thirds of cases, but the prognostic significance of these mutations remains elusive. In the current study, we evaluated a novel computational approach termed evolutionary action (EAp53) to stratify patients with tumors harboring TP53 mutations as high or low risk, and validated this system in both in vivo and in vitro models. Patients with high-risk TP53 mutations had the poorest survival outcomes and the shortest time to the development of distant metastases. Tumor cells expressing high-risk TP53 mutations were more invasive and tumorigenic and they exhibited a higher incidence of lung metastases. We also documented an association between the presence of high-risk mutations and decreased expression of TP53 target genes, highlighting key cellular pathways that are likely to be dysregulated by this subset of p53 mutations that confer particularly aggressive tumor behavior. Overall, our work validated EAp53 as a novel computational tool that may be useful in clinical prognosis of tumors harboring p53 mutations

Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria

(Cell Chemical Biology 24, 1259–1275; October 19, 2017) During the cropping of Figure 2H, the image of the p62 row was deleted in error and then remaining labels were shifted down by one row and were therefore out of registration with the images. Figure 2H has now been corrected in the article online and in print; the corrected Figure 2H is also shown below. The authors apologize for this labeling error

Distinct Effector Memory CD4+ T Cell Signatures in Latent Mycobacterium tuberculosis Infection, BCG Vaccination and Clinically Resolved Tuberculosis

Two billion people worldwide are estimated to be latently infected with Mycobacterium tuberculosis (Mtb) and are at risk for developing active tuberculosis since Mtb can reactivate to cause TB disease in immune-compromised hosts. Individuals with latent Mtb infection (LTBI) and BCG-vaccinated individuals who are uninfected with Mtb, harbor antigen-specific memory CD4+ T cells. However, the differences between long-lived memory CD4+ T cells induced by latent Mtb infection (LTBI) versus BCG vaccination are unclear. In this study, we characterized the immune phenotype and functionality of antigen-specific memory CD4+ T cells in healthy BCG-vaccinated individuals who were either infected (LTBI) or uninfected (BCG) with Mtb. Individuals were classified into LTBI and BCG groups based on IFN-γ ELISPOT using cell wall antigens and ESAT-6/CFP-10 peptides. We show that LTBI individuals harbored high frequencies of late-stage differentiated (CD45RA−CD27−) antigen-specific effector memory CD4+ T cells that expressed PD-1. In contrast, BCG individuals had primarily early-stage (CD45RA−CD27+) cells with low PD-1 expression. CD27+ and CD27− as well as PD-1+ and PD-1− antigen-specific subsets were polyfunctional, suggesting that loss of CD27 expression and up-regulation of PD-1 did not compromise their capacity to produce IFN-γ, TNF-α and IL-2. PD-1 was preferentially expressed on CD27− antigen-specific CD4+ T cells, indicating that PD-1 is associated with the stage of differentiation. Using statistical models, we determined that CD27 and PD-1 predicted LTBI versus BCG status in healthy individuals and distinguished LTBI individuals from those who had clinically resolved Mtb infection after anti-tuberculosis treatment. This study shows that CD4+ memory responses induced by latent Mtb infection, BCG vaccination and clinically resolved Mtb infection are immunologically distinct. Our data suggest that differentiation into CD27−PD-1+ subsets in LTBI is driven by Mtb antigenic stimulation in vivo and that CD27 and PD-1 have the potential to improve our ability to evaluate true LTBI status

Identification of molecular pathways affected by pterostilbene, a natural dimethylether analog of resveratrol

<p>Abstract</p> <p>Background</p> <p>Pterostilbene, a naturally occurring phenolic compound produced by agronomically important plant genera such as <it>Vitis </it>and <it>Vacciunium</it>, is a phytoalexin exhibiting potent antifungal activity. Additionally, recent studies have demonstrated several important pharmacological properties associated with pterostilbene. Despite this, a systematic study of the effects of pterostilbene on eukaryotic cells at the molecular level has not been previously reported. Thus, the aim of the present study was to identify the cellular pathways affected by pterostilbene by performing transcript profiling studies, employing the model yeast <it>Saccharomyces cerevisiae</it>.</p> <p>Methods</p> <p><it>S. cerevisiae </it>strain S288C was exposed to pterostilbene at the IC₅₀concentration (70 μM) for one generation (3 h). Transcript profiling experiments were performed on three biological replicate samples using the Affymetrix GeneChip Yeast Genome S98 Array. The data were analyzed using the statistical methods available in the GeneSifter microarray data analysis system. To validate the results, eleven differentially expressed genes were further examined by quantitative real-time RT-PCR, and <it>S. cerevisiae </it>mutant strains with deletions in these genes were analyzed for altered sensitivity to pterostilbene.</p> <p>Results</p> <p>Transcript profiling studies revealed that pterostilbene exposure significantly down-regulated the expression of genes involved in methionine metabolism, while the expression of genes involved in mitochondrial functions, drug detoxification, and transcription factor activity were significantly up-regulated. Additional analyses revealed that a large number of genes involved in lipid metabolism were also affected by pterostilbene treatment.</p> <p>Conclusion</p> <p>Using transcript profiling, we have identified the cellular pathways targeted by pterostilbene, an analog of resveratrol. The observed response in lipid metabolism genes is consistent with its known hypolipidemic properties, and the induction of mitochondrial genes is consistent with its demonstrated role in apoptosis in human cancer cell lines. Furthermore, our data show that pterostilbene has a significant effect on methionine metabolism, a previously unreported effect for this compound.</p

Boundary management preferences from a gender and cross-cultural perspective

Although work is increasingly globalized and mediated by technology, little research has accu- mulated on the role of culture in shaping individuals' preferences regarding the segmentation or integration of their work and family roles. This study examines the relationships between gender egalitarianism (the extent a culture has a fluid understanding of gender roles and promotes gender equality), gender, and boundary management preferences across 27 countries/territories. Based on a sample of 9362 employees, we found that the pattern of the relationship between gender egalitarianism and boundary management depends on the direction of segmentation preferences. Individuals from more gender egalitarian societies reported lower preferences to segment family-from-work (i.e., protect the work role from the family role); however, gender egalitarianism was not directly associated with preferences to segment work-from-family. Moreover, gender was associated with both boundary management directions such that women preferred to segment family-from-work and work-from-family more so than did men. As theo- rized, we found gender egalitarianism moderated the relationship between gender and segmen- tation preferences such that women's desire to protect family from work was stronger in lower (vs. higher) gender egalitarianism cultures. Contrary to expectations, women reported a greater preference to protect work from family than men regardless of gender egalitarianism. Implica- tions for boundary management theory and the cross-national work-family literature are discussed

Humane Orientation, Work–Family Conflict, and Positive Spillover Across Cultures

Although cross-national work–family research has made great strides in recent decades, knowledge accumulation on the impact of culture on the work–family interface has been hampered by a limited geographical and cultural scope that has excluded countries where cultural expectations regarding work, family, and support may differ. We advance this literature by investigating work–family relationships in a broad range of cultures, including understudied regions of the world (i.e., Sub-Saharan Africa, Southern Asia). We focus on humane orientation (HO), an overlooked cultural dimension that is however central to the study of social support and higher in those regions. We explore its moderating effect on relationships between work and family social support, work–family conflict, and work–family positive spillover. Building on the congruence and compensation perspectives of fit theory, we test alternative hypotheses on a sample of 10,307 participants from 30 countries/territories. We find HO has mostly a compensatory role in the relationships between workplace support and work-to-family conflict. Specifically, supervisor and coworker supports were most strongly and negatively related to conflict in cultures in which support is most needed (i.e., lower HO cultures). Regarding positive spillover, HO has mostly an amplifying role. Coworker (but not supervisor) support was most strongly and positively related to work-to-family positive spillover in higher HO cultures, where providing social support at work is consistent with the societal practice of providing support to one another. Likewise, instrumental (but not emotional) family support was most strongly and positively related to family-to-work positive spillover in higher HO cultures