Liver glycogen phosphorylase is upregulated in glioblastoma and provides a metabolic vulnerability to high dose radiation

Channelling of glucose via glycogen, known as the glycogen shunt, may play an important role in the metabolism of brain tumours, especially in hypoxic conditions. We aimed to dissect the role of glycogen degradation in glioblastoma (GBM) response to ionising radiation (IR). Knockdown of the glycogen phosphorylase liver isoform (PYGL), but not the brain isoform (PYGB), decreased clonogenic growth and survival of GBM cell lines and sensitised them to IR doses of 10–12 Gy. Two to five days after IR exposure of PYGL knockdown GBM cells, mitotic catastrophy and a giant multinucleated cell morphology with senescence-like phenotype developed. The basal levels of the lysosomal enzyme alpha-acid glucosidase (GAA), essential for autolysosomal glycogen degradation, and the lipidated forms of gamma-aminobutyric acid receptor-associated protein-like (GABARAPL1 and GABARAPL2) increased in shPYGL U87MG cells, suggesting a compensatory mechanism of glycogen degradation. In response to IR, dysregulation of autophagy was shown by accumulation of the p62 and the lipidated form of GABARAPL1 and GABARAPL2 in shPYGL U87MG cells. IR increased the mitochondrial mass and the colocalisation of mitochondria with lysosomes in shPYGL cells, thereby indicating reduced mitophagy. These changes coincided with increased phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase 2, slower ATP generation in response to glucose loading and progressive loss of oxidative phosphorylation. The resulting metabolic deficiencies affected the availability of ATP required for mitosis, resulting in the mitotic catastrophy observed in shPYGL cells following IR. PYGL mRNA and protein levels were higher in human GBM than in normal human brain tissues and high PYGL mRNA expression in GBM correlated with poor patient survival. In conclusion, we show a major new role for glycogen metabolism in GBM cancer. Inhibition of glycogen degradation sensitises GBM cells to high-dose IR indicating that PYGL is a potential novel target for the treatment of GBMs.Subject terms: Cancer metabolism, CNS cancer     

SCRaPL: A Bayesian hierarchical framework for detecting technical associates in single cell multiomics data

Single-cell multi-omics assays offer unprecedented opportunities to explore epigenetic regulation at cellular level. However, high levels of technical noise and data sparsity frequently lead to a lack of statistical power in correlative analyses, identifying very few, if any, significant associations between different molecular layers. Here we propose SCRaPL, a novel computational tool that increases power by carefully modelling noise in the experimental systems. We show on real and simulated multi-omics single-cell data sets that SCRaPL achieves higher sensitivity and better robustness in identifying correlations, while maintaining a similar level of false positives as standard analyses based on Pearson and Spearman correlation.     

Thiol redox state and related enzymes in sclerotium-forming filamentous phytopathogenic fungi

Thiol redox state (TRS) reduced and oxidized components form profiles characteristic of each of the four main types of differentiation in the sclerotiogenic phytopathogenic fungi: loose, terminal, lateral-chained, and lateral-simple, represented by Rhizoctonia solani, Sclerotinia sclerotiorum, Sclerotium rolfsii, and Sclerotinia minor, respectively. A common feature of these fungi is that as their undifferentiated mycelium enters the differentiated state, it is accompanied by a decrease in the low oxidative stress-associated total reduced thiols and/or by an increase of the high oxidative stress-associated total oxidized thiols either in the sclerotial mycelial substrate or in its corresponding sclerotium, indicating a relationship between TRS-related oxidative stress and sclerotial differentiation. Moreover, the four studied sclerotium types exhibit high activities of TRS-related antioxidant enzymes, indicating the existence of antioxidant protection of the hyphae of the sclerotium medulla until conditions become appropriate for sclerotium germination.     

Growth and Physiology of Maize (Zea mays L.) in a Nickel-Contaminated Soil and Phytoremediation Efficiency Using EDTA

Journal of Plant Growth Regulation - Nickel (Ni) element is strongly phytotoxic at high concentrations for several plants, but due to its dual behavior and complicated chemistry, it has received...     

Coumarin derivatives protection against ROS production in cellular models of Aβ toxicities

The role of oxidative stress and free radicals in the development of Alzheimer's disease (AD) has been the focus of many recent studies. The role of hydrogen peroxide (H₂O₂) in AD is thought to be associated with Aβ (amyloid – β) damage in cells. A number of coumarin derivatives were previously found to be potent anti-inflammatory and antioxidant agents. Herein, these coumarin derivatives were tested as H₂O₂ scavengers with the DCF assay using two types of neuronal cells: (a) wild type (N2a) neuroblastoma cells and (b) APP/PS1 transgenic cell line expressing Aβ. Their scavenging activity was varied between the types of cell cultures and it was found to be concentration and time dependent in the mutant cells. Their protective role against cell death further supports this notion. These results suggest that these compounds could be used as a template in the design of new molecules with a possible role in AD.     

Biological Evaluation of Several Coumarin Derivatives Designed as Possible Anti-inflammatory/Antioxidant Agents

Several linear and angular coumarins designed and synthesised as possible anti-inflammatory and antioxidant agents were evaluated for their biological activities, using the carrageenin-induced rat paw oedema model. In general, the compounds were found to be potent anti-inflammatory agents. Compound (4) was found to possess protective properties in adjuvant-induced arthritis in rats. The compounds were found to interact with 1,1-diphenyl-2-picryl-hydrazyl stable free radical (DPPH) whereas most of them were essentially inactive in other tests. The anti-inflammatory activity seemed to be connected with their reducing activity. R M values were determined as an expression of their lipophilicity which was also calculated as clog P. Only a poor relationship existed between lipophilicity and anti-inflammatory activity.