Shedding light on the methylerythritol phosphate (MEP)-pathway:long hypocotyl 5 (HY5)/phytochrome-interacting factors (PIFs) transcription factors modulating key limiting steps

The plastidial methylerythritol phosphate (MEP) pathway is an essential route for plants as the source of precursors for all plastidial isoprenoids, many of which are of medical and biotechnological importance. The MEP pathway is highly sensitive to environmental cues as many of these compounds are linked to photosynthesis and growth and light is one of the main regulatory factors. However, the mechanisms coordinating the MEP pathway with light cues are not fully understood. Here we demonstrate that by a differential direct transcriptional modulation, via the key-master integrators of light signal transduction HY5 and PIFs which target the genes that encode the rate-controlling DXS1, DXR and HDR enzymes, light imposes a direct, rapid and potentially multi-faceted response that leads to unique protein dynamics of this pathway, resulting in a significant difference in the protein levels. For DXS1, PIF1/HY5 act as a direct activation/suppression module. In contrast, DXR accumulation in response to light results from HY5 induction with minor contribution of de-repression by PIF1. Finally, HDR transcription increases in the light exclusively by suppression of the PIFs repression. This is an example of how light signaling components can differentially multi-target the initial steps of a pathway whose products branch downstream to all chloroplastic isoprenoids. These findings demonstrate the diversity and flexibility of light signaling components that optimize key biochemical pathways essential for plant growth. © 2018 The Authors The Plant Journal © 2018 John Wiley & Sons Lt

Comparative Cytotoxic Activity of Hydroxytyrosol and Its Semisynthetic Lipophilic Derivatives in Prostate Cancer Cells

A high adherence to a Mediterranean diet has been related to numerous beneficial effects in human health, including a lower incidence and mortality of prostate cancer (PCa). Olive oil is an important source of phenolic bioactive compounds, mainly hydroxytyrosol (HT), of this diet. Because of the growing interest of this compound and its derivatives as a cancer chemopreventive agent, we aimed to compare the in vitro effect of HT isolated from olive mill wastewaters and five semisynthetic alkyl ether, ester, and nitro-derivatives against prostate cancer (PCa) cell lines. The effect in cell proliferation was determined in RWPE-1, LNCaP, 22Rv1, and PC-3 cells by resazurin assay, the effect in cell migration by wound healing assay, and tumorsphere and colony formation were evaluated. The changes in key signaling pathways involved in carcinogenesis were assessed by using a phosphorylation pathway profiling array and by Western blotting. Antiproliferative effects of HT and two lipophilic derivatives [hydroxytyrosyl acetate (HT-Ac)/ethyl hydroxytyrosyl ether (HT-Et)] were significantly higher in cancerous PC-3 and 22Rv1 cells than in non-malignant RWPE-1 cells. HT/HT-Ac/HT-Et significantly reduced migration capacity in RWPE-1 and PC-3 and prostatosphere size and colony formation in 22Rv1, whereas only HT-Ac and HT-Et reduced these functional parameters in PC-3. The cytotoxic effect in 22Rv1 cells was correlated with modifications in the phosphorylation pattern of key proteins, including ERK1/2 and AKT. Consistently, HT-Ac and HT-Et decreased p-AKT levels in PC-3. In sum, our results suggest that HT and its lipophilic derivatives could be considered as potential therapeutic tools in PCa

Unleashing the Diagnostic, Prognostic and Therapeutic Potential of the Neuronostatin/GPR107 System in Prostate Cancer

Certain components of the somatostatin-system play relevant roles in Prostate Cancer (PCa), whose most aggressive phenotype (Castration-Resistant-PCa (CRPC)) remains lethal nowadays. However, neuronostatin and the G protein-coupled receptor 107 (GPR107), two novel members of the somatostatin-system, have not been explored yet in PCa. Consequently, we investigated the pathophysiological role of NST/GPR107-system in PCa. GPR107 expression was analyzed in well-characterized PCa patient′s cohorts, and functional/mechanistic assays were performed in response to GPR107-silencing and NST-treatment in PCa cells (androgen-dependent (AD: LNCaP) and androgen-independent (AI: 22Rv1/PC-3), which are cell models of hormone-sensitive and CRPC, respectively), and normal prostate cells (RWPE-1 cell-line). GPR107 was overexpressed in PCa and associated with key clinical parameters (e.g., advance stage of PCa, presence of vascular invasion and metastasis). Furthermore, GPR107-silencing inhibited proliferation/migration rates in AI-PCa-cells and altered key genes and oncogenic signaling-pathways involved in PCa aggressiveness (i.e., KI67/CDKN2D/MMP9/PRPF40A, SST5TMD4/AR-v7/In1-ghrelin/EZH2 splicing-variants and AKT-signaling). Interestingly, NST treatment inhibited proliferation/migration only in AI-PCa cells and evoked an identical molecular response than GPR107-silencing. Finally, NST decreased GPR107 expression exclusively in AI-PCa-cells, suggesting that part of the specific antitumor effects of NST could be mediated through a GPR107-downregulation. Altogether, NST/GPR107-system could represent a valuable diagnostic and prognostic tool and a promising novel therapeutic target for PCa and CRPC

Spatial distribution and incidence of dengue cases: an analysis of the situation in Medellín, Colombia

ABSTRACT: To analyze the spatial distribution of dengue cases and the incidence of this disease. Methodology: 17.400 dengue cases were spatially located by means of the addresses of patients which were reported by Data Generating Primary Units to the Medellin Office of the Health Secretary from 2007 to 2011. Dengue incidences were calculated and geospatially ranked with the ArcGIS 9.3 software, and they were categorized by risk level according to the Pan American Health Organization. Results and Discussion: the disease was distributed heterogeneously throughout the various neighborhoods of the city. The years 2007 and 2010 had the highest number of cases, thus being epidemic years; the other years showing an endemic behavior. In 2007 none of the neighborhoods was in very high risk category; however, in 2010, 49 neighborhoods were placed inside this category. As for endemic years according to dengue incidence, of the 249 neighborhoods of the city, just two of them were found in high risk in 2008 and 2009, but none in 2011. Moreover, a large percentage of neighborhoods in these years were considered to be in the low risk category."RESUMEN:Analizar la distribución espacial de los casos y la incidencia de dengue. Metodología: se ubicaron espacialmente 17.400 casos de dengue notificados por las Unidades Primarias Generadoras de Datos a la Secretaría de Salud de Medellín en el período 2007 a 2011 a través de las direcciones de las viviendas de los pacientes. Se calcularon las incidencias y se ubicaron geoespacialmente utilizando el software ArcGis 9,3, categorizándolas por niveles de riesgo según la Organización Panamericana de la Salud. Resultados y discusión: la enfermedad se distribuyó heterogéneamente en los diferentes barrios de la ciudad. Los años 2007 y 2010 presentaron el mayor número de casos, correspondiendo a años epidémicos, mientras que los demás años mostraron un comportamiento endémico. En el 2007 ningún barrio se ubicó en la categoría riesgo muy alto, pero sí 49 localidades para el año 2010. Para los años endémicos según la incidencia de dengue, de los 249 barrios de la ciudad, en los años 2008 y 2009, solo dos se encontraron en riesgo alto y ninguno para 2011, y un gran porcentaje de barrios en estos años se ubicaron en riesgo bajo."RESUMEN:Analizar la distribución espacial de los casos y la incidencia de dengue. Metodología: se ubicaron espacialmente 17.400 casos de dengue notificados por las Unidades Primarias Generadoras de Datos a la Secretaría de Salud de Medellín en el período 2007 a 2011 a través de las direcciones de las viviendas de los pacientes. Se calcularon las incidencias y se ubicaron geoespacialmente utilizando el software ArcGis 9,3, categorizándolas por niveles de riesgo según la Organización Panamericana de la Salud. Resultados y discusión: la enfermedad se distribuyó heterogéneamente en los diferentes barrios de la ciudad. Los años 2007 y 2010 presentaron el mayor número de casos, correspondiendo a años epidémicos, mientras que los demás años mostraron un comportamiento endémico. En el 2007 ningún barrio se ubicó en la categoría riesgo muy alto, pero sí 49 localidades para el año 2010. Para los años endémicos según la incidencia de dengue, de los 249 barrios de la ciudad, en los años 2008 y 2009, solo dos se encontraron en riesgo alto y ninguno para 2011, y un gran porcentaje de barrios en estos años se ubicaron en riesgo bajo

Multiple Sclerosis and Its Relationship with Oxidative Stress, Glutathione Redox System, ATPase System, and Membrane Fluidity

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) with a focus on inflammation, demyelination, and damage to axons leading to neurological deficits. MS pathology is associated with excessive reactive oxygen species (ROS) and generation of reactive nitrogen species (RNS), causing oxidative/nitrosative stress. Deregulation of glutathione homeostasis and alterations in glutathione‐dependent enzymes are implicated in MS. Reactive oxygen species enhance both monocyte adhesion and migration across brain endothelial cells. In addition, ROS can activate the expression of the nuclear transcription factor‐kappa, which upregulates the expression of many genes involved in MS, such as tumor necrosis factor‐α and nitric oxide synthase, among others, leading to mitochondrial dysfunction and energy deficits that result in mitochondrial and cellular calcium overload. Loss of mitochondrial membrane potential can increase the release of cytochrome c, one pathway that leads to neuronal apoptosis. Clinical studies suggest that omega‐3 long‐chain polyunsaturated fatty acids (PUFAs) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have anti‐inflammatory, antioxidant, and neuroprotective effects in MS and animal models of MS. Here, we review the relationship of oxidative stress, the glutathione redox system, the ATPase system, and membrane fluidity with the development of MS. In addition, we describe the main findings of a clinical trial conducted with relapsing‐remitting MS patients who received a diet supplemented with 4 g/day of fish oil or olive oil. The effects of PUFAs supplementation on the parameters indicated above are analyzed in this work

Oncogenic Role of Secreted Engrailed Homeobox 2 (EN2) in Prostate Cancer

Engrailed variant-2 (EN2) has been suggested as a potential diagnostic biomarker; however, its presence and functional role in prostate cancer (PCa) cells is still controversial or unknown. Here, we analyzed 1) the expression/secretion profile of EN2 in five independent samples cohorts from PCa patients and controls (prostate tissues and/or urine) to determine its utility as a PCa biomarker; and 2) the functional role of EN2 in normal (RWPE1) and tumor (LNCaP/22Rv1/PC3) prostate cells to explore its potential value as therapeutic target. EN2 was overexpressed in our two cohorts of PCa tissues compared to control and in tumor cell lines compared with normal-like prostate cells. This profile was corroborated in silico in three independent data sets [The Cancer Genome Atlas(TCGA)/Memorial Sloan Kettering Cancer Center (MSKCC)/Grasso]. Consistently, urine EN2 levels were elevated and enabled discrimination between PCa and control patients. EN2 treatment increased cell proliferation in LNCaP/22Rv1/PC3 cells, migration in RWPE1/PC3 cells, and PSA secretion in LNCaP cells. These effects were associated, at least in the androgen-sensitive LNCaP cells, with increased AKT and androgen-receptor phosphorylation levels and with modulation of key cancer-associated genes. Consistently, EN2 treatment also regulated androgen-receptor activity (full-length and splicing variants) in androgen-sensitive 22Rv1 cells. Altogether, this study demonstrates the potential utility of EN2 as a non-invasive diagnostic biomarker for PCa and provides novel and valuable information to further investigate its putative utility to develop new therapeutic tools in PCa

Charge separation relative to the reaction plane in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}}= 2.76 TeV

Measurements of charge dependent azimuthal correlations with the ALICE detector at the LHC are reported for Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV. Two- and three-particle charge-dependent azimuthal correlations in the pseudo-rapidity range $|\eta| < 0.8$ are presented as a function of the collision centrality, particle separation in pseudo-rapidity, and transverse momentum. A clear signal compatible with a charge-dependent separation relative to the reaction plane is observed, which shows little or no collision energy dependence when compared to measurements at RHIC energies. This provides a new insight for understanding the nature of the charge dependent azimuthal correlations observed at RHIC and LHC energies.Comment: 12 pages, 3 captioned figures, authors from page 2 to 6, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/286