Changes in the brain endocannabinoid system in rat models of depression

A growing body of evidence implicates the endocannabinoid (eCB) system in the pathophysiology of depression. The aim of this study was to investigate the influence of changes in the eCB system, such as levels of neuromodulators, eCB synthesizing and degrading enzymes, and cannabinoid (CB) receptors, in different brain structures in animal models of depression using behavioral and biochemical analyses. Both models used, i.e., bulbectomized (OBX) and Wistar Kyoto (WKY) rats, were characterized at the behavioral level by increased immobility time. In the OBX rats, anandamide (AEA) levels were decreased in the prefrontal cortex, hippocampus, and striatum and increased in the nucleus accumbens, while 2-arachidonoylglycerol (2-AG) levels were increased in the prefrontal cortex and decreased in the nucleus accumbens with parallel changes in the expression of eCB metabolizing enzymes in several structures. It was also observed that CB(1) receptor expression decreased in the hippocampus, dorsal striatum, and nucleus accumbens, and CB(2) receptor expression decreased in the prefrontal cortex and hippocampus. In WKY rats, the levels of eCBs were reduced in the prefrontal cortex (2-AG) and dorsal striatum (AEA) and increased in the prefrontal cortex (AEA) with different changes in the expression of eCB metabolizing enzymes, while the CB(1) receptor density was increased in several brain regions. These findings suggest that dysregulation in the eCB system is implicated in the pathogenesis of depression, although neurochemical changes were linked to the particular brain structure and the factor inducing depression (surgical removal of the olfactory bulbs vs. genetic modulation)

A study on the spatial and temporal variability in airborne Betula pollen concentration in five cities in Poland using multivariate analyses

During the spring period, Betula pollen is the main cause of inhalant allergies in Poland and therefore it is impor- tant to monitor and forecast airborne pollen concentrations of this taxon. This study conducted a comparative analysis of the basic characteristics of Betula pollen seasons at the regional scale. The study was carried out from 2001 to 2016 in fi ve cities in Poland: Lublin, Warsaw, Cracow, Sosnowiec, and Szczecin. To fi nd the attri- butes of birch pollen seasons that mostly differentiated the individual cities, a general discriminant analysis (GDA) was performed, while a principal component analysis (PCA) allowed us to reduce the data space and pres- ent a scatterplot of PCA scores in order to compare pollen seasons in the individual cities. The contingency table was also analyzed to check whether there was a signi fi cant relationship between pollen counts in the studied years and cities. At most of the sites, biennial cycles of low and high pollen concentrations can be observed. Due to the high variation in seasons in each of these cities, two data groups were distinguished: Group 1 was composed of seasons with high pollen deposition (2001, 2003, 2006, 2008, 2010, 2012, 2014, 2016), and Group 2 comprising the other seasons. Multivariate analyses were performed on both these groups as well as in the entire dataset. End98, Peak Value, and Annual Total had the highest discriminant power. In Group 1, Warsaw and Sosnowiec differed the most in the investigated parameters, while Cracow and Szczecin differed the least. In both groups, most seasons with the highest pollen birch concentration were observed in Lublin, followed by Warsaw, while in Cracow, the number of such seasons was the smallest

S-nitrosoglutathione spraying improves stomatal conductance, Rubisco activity and antioxidant defense in both leaves and roots of sugarcane plants under water deficit

© 2017 Scandinavian Plant Physiology Society Water deficit is a major environmental constraint on crop productivity and performance and nitric oxide (NO) is an important signaling molecule associated with many biochemical and physiological processes in plants under stressful conditions. This study aims to test the hypothesis that leaf spraying of S-nitrosoglutathione (GSNO), an NO donor, improves the antioxidant defense in both roots and leaves of sugarcane plants under water deficit, with positive consequences for photosynthesis. In addition, the roles of key photosynthetic enzymes ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) and phosphoenolpyruvate carboxylase (PEPC) in maintaining CO2 assimilation of GSNO-sprayed plants under water deficit were evaluated. Sugarcane plants were sprayed with water or GSNO 100 μM and subjected to water deficit, by adding polyethylene glycol (PEG-8000) to the nutrient solution. Sugarcane plants supplied with GSNO presented increases in the activity of antioxidant enzymes such as superoxide dismutase in leaves and catalase in roots, indicating higher antioxidant capacity under water deficit. Such adjustments induced by GSNO were sufficient to prevent oxidative damage in both organs and were associated with better leaf water status. As a consequence, GSNO spraying alleviated the negative impact of water deficit on stomatal conductance and photosynthetic rates, with plants also showing increases in Rubisco activity under water deficit

Mechanisms and targets of the modulatory action of S-nitrosoglutathione (GSNO) on inflammatory cytokines expression.

A number of experimental studies has documented that S-nitrosoglutathione (GSNO), the main endogenous low-molecular weight S-nitrosothiol, can exert modulatory effects on inflammatory processes, thus supporting its potential employment in medicine for the treatment of important disease conditions. At molecular level, GSNO effects have been shown to modulate the activity of a series of transcription factors (notably NF-jB, AP-1, CREB and others) as well as other components of signal transduction chains (e.g. IKK-b, caspase 1, calpain and others), resulting in the modulation of several cytokines and chemokines expression (TNFa, IL-1b, IFN-c, IL-4, IL-8, RANTES, MCP-1 and others). Results reported to date are however not univocal, and a single main mechanism of action for the observed anti-inflammatory effects of GSNO has not been identified. Conflicting observations can be explained by differences among the various cell types studies as to the relative abundance of enzymes in charge of GSNO metabolism (GSNO reductase, c-glutamyltransferase, protein disulfide isomerase and others), as well as by variables associated with the individual experimental models employed. Altogether anti-inflammatory properties of GSNO seem however to prevail, and exploration of the therapeutic potential of GSNO and analogues appears therefore warranted

Mass spectrometry imaging of endogenous metabolites in response to doxorubicin in a novel 3D osteosarcoma cell culture model

Three‐dimensional (3D) cell culture is a rapidly emerging field which mimics some of the physiological conditions of human tissues. In cancer biology, it is considered a useful tool in predicting in vivo chemotherapy responses compared with conventional two‐dimensional cell culture. We have developed a novel 3D cell culture model of osteosarcoma comprised of aggregated proliferative tumour spheroids, which shows regions of tumour heterogeneity formed by aggregated spheroids of polyclonal tumour cells. Aggregated spheroids show local necrotic and apoptotic regions, and have sizes suitable for the study of spatial distribution of metabolites by mass spectrometry imaging (MSI). We have used this model to perform a proof‐of‐principle study showing a heterogeneous distribution of endogenous metabolites that co‐localise with the necrotic core and apoptotic regions in this model. Cytotoxic chemotherapy (Doxorubicin) responses were significantly attenuated in our 3D cell culture model compared with standard cell culture, as determined by Resazurin assay, despite sufficient doxorubicin diffusion demonstrated by localisation throughout the 3D constructs. Finally, changes to the distribution of endogenous metabolites in response to Doxorubicin were readily detected by MSI. Principle component analysis identified 50 metabolites which differed most in their abundance between treatment groups, and of these, 10 were identified by both in‐software t test and mixed effects ANOVA. Subsequent independent MSI of identified species were consistent with principle component analysis findings. This proof‐of‐principle study shows for the first time that chemotherapy‐induced changes in metabolite abundance and distribution may be determined in 3D cell culture by MSI, highlighting this method as a potentially useful tool in elucidation of chemotherapy responses as an alternative to in vivo testing

Enhanced triacylglycerol catabolism by carboxylesterase 1 promotes aggressive colorectal carcinoma

The ability to adapt to low-nutrient microenvironments is essential for tumor cell survival and progression in solid cancers, such as colorectal carcinoma (CRC). Signaling by the NF-κB transcription factor pathway associates with advanced disease stages and shorter survival in patients with CRC. NF-κB has been shown to drive tumor-promoting inflammation, cancer cell survival, and intestinal epithelial cell (IEC) dedifferentiation in mouse models of CRC. However, whether NF-κB affects the metabolic adaptations that fuel aggressive disease in patients with CRC is unknown. Here, we identified carboxylesterase 1 (CES1) as an essential NF-κB–regulated lipase linking obesity-associated inflammation with fat metabolism and adaptation to energy stress in aggressive CRC. CES1 promoted CRC cell survival via cell-autonomous mechanisms that fuel fatty acid oxidation (FAO) and prevent the toxic build-up of triacylglycerols. We found that elevated CES1 expression correlated with worse outcomes in overweight patients with CRC. Accordingly, NF-κB drove CES1 expression in CRC consensus molecular subtype 4 (CMS4), which is associated with obesity, stemness, and inflammation. CES1 was also upregulated by gene amplifications of its transcriptional regulator HNF4A in CMS2 tumors, reinforcing its clinical relevance as a driver of CRC. This subtype-based distribution and unfavorable prognostic correlation distinguished CES1 from other intracellular triacylglycerol lipases and suggest CES1 could provide a route to treat aggressive CRC