Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and bear dismal prognoses compared to group B ependymomas (PFBs). PFAs overexpress the oncohistone-like protein ...EZHIP (enhancer of Zeste homologs inhibitory protein), causing global reduction of repressive histone H3 lysine 27 trimethylation (H3K27me3), similar to the oncohistone H3K27M. Integrated metabolic analyses in patient-derived cells and tumors, single-cell RNA sequencing of tumors, and noninvasive metabolic imaging in patients demonstrated enhanced glycolysis and tricarboxylic acid (TCA) cycle metabolism in PFAs. Furthermore, high glycolytic gene expression in PFAs was associated with a poor outcome. PFAs demonstrated high EZHIP expression associated with poor prognosis and elevated activating mark histone H3 lysine 27 acetylation (H3K27ac). Genomic H3K27ac was enriched in PFAs at key glycolytic and TCA cycle–related genes including
and
. Similarly, mouse neuronal stem cells (NSCs) expressing wild-type EZHIP (EZHIP-WT) versus catalytically attenuated EZHIP-M406K demonstrated H3K27ac enrichment at
and
, accompanied by enhanced glycolysis and TCA cycle metabolism.
α
, a key component of the metabolic regulator AMP-activated protein kinase (AMPK), also showed H3K27ac enrichment in PFAs and EZHIP-WT NSCs. The AMPK activator metformin lowered EZHIP protein concentrations, increased H3K27me3, suppressed TCA cycle metabolism, and showed therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Our data indicate that PFAs and EZHIP-WT–expressing NSCs are characterized by enhanced glycolysis and TCA cycle metabolism. Repurposing the antidiabetic drug metformin lowered pathogenic EZHIP, increased H3K27me3, and suppressed tumor growth, suggesting that targeting integrated metabolic/epigenetic pathways is a potential therapeutic strategy for treating childhood ependymomas.
Objective
To explore the association of both plasma vitamin D and K concentrations with all-cause mortality, cardiovascular mortality, and cardiovascular events in the general population.
Methods
We ...studied 4742 participants of the Prevention of REnal and Vascular ENd-Stage Disease (PREVEND) Study. At baseline, vitamin D and K status was determined by measurement of 25-hydroxyvitamin D 25(OH)D and dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP), respectively. Patients were categorized into: 25(OH)D < 50 or ≥ 50 nmol/L and dp-ucMGP < 361 or ≥ 361 pmol/L with 25(OH)D > 75 nmol/L and dp-ucMGP < 361 pmol/L as reference. Cause of death was coded according to International Classification of Diseases 9&10 codes from the 2001-2003 examination until date of death/event or censoring date (January 1st, 2017).
Results
Mean age was 52.6 ± 11.9 years and 2513 (53%) were female. During a median of 14.2 year follow-up, 620 participants died of which 142 were due to cardiovascular causes. Combined low vitamin D and K status was present in 970 participants (20%) and was associated with a greater risk of all-cause mortality compared to high vitamin D and high vitamin K status group (
n
= 1424) after adjusting for potential confounders: hazard ratio 1.46 (95% confidence intervals 1.12–1.90). We observed similar trends, albeit non-significant for cardiovascular mortality, and cardiovascular events: 1.42 (0.79–2.55), 1.28 (0.93–1.77), respectively.
Conclusions
Combined low vitamin D and K status are associated with increased all-cause mortality risk and possibly with cardiovascular mortality and cardiovascular events compared with adequate vitamin D and K status. Future studies should investigate the effect of combined vitamin D and K supplementation on clinical outcomes.
Oxidative stress is known to be involved in the development of hypertension, but accurate redox biomarkers predicting the risk of developing hypertension are scarce. Serum free sulfhydryl groups ...(R–SH, free thiols) have been shown to accurately reflect systemic oxidative stress in various conditions. In this study, we aimed to investigate associations between serum free thiols and the risk of developing new-onset hypertension in a population-based cohort study.
Subjects (n = 3,575) who participated in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, a prospective, population-based cohort study in the Netherlands, were included. Baseline protein-adjusted serum free thiols were studied for their associations with the development of hypertension, defined as a systolic blood pressure (SBP) of at least 140 mmHg, a diastolic blood pressure (DBP) of at least 90 mmHg, or the first usage of antihypertensive medication. Subjects with hypertension at baseline were excluded from the study.
Mean protein-adjusted serum free thiols at baseline was 5.16 μmol/g of protein (range: 1.62–8.41 μmol/g). Protein-adjusted serum free thiols were significantly associated with the risk of incident hypertension (hazard ratio HR per doubling 0.60 95% confidence interval CI: 0.49–0.72, P < 0.001), also after adjustment for age and sex (HR 0.81 95% CI: 0.66–0.91, P < 0.05), but not after additional adjustment for relevant confounding factors (HR 0.90 95% CI: 0.70–1.15, P = 0.382).
Higher levels of serum free thiols, i.e. less oxidative stress, are associated with a decreased risk of developing incident hypertension in subjects from the general population.
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•Oxidative stress is implicated in the pathophysiology of hypertension.•Serum sulfhydryl groups (R–SH) reflect whole-body redox status in health and disease.•Serum R–SH associate with new-onset cardiovascular and renal morbidity in many patient cohorts.•High serum R–SH are associated with a decreased risk of hypertension in the general population.•Serum R–SH may potentially serve as a monitoring tool for future development of cardiovascular diseases.
The reduced lifespan of cryopreserved spermatozoa in the mare reproductive tract has been attributed to both capacitative and apoptotic changes. However, there is a lack of studies investigating both ...phenomena simultaneously. In order to improve our knowledge in this particular point, we studied in raw and frozen-thawed samples apoptotic and capacitative markers using a wide battery of test based in flow cytometry. Apoptotic markers evaluated were caspase 3 activity, externalization of phosphatidylserine (PS), and mitochondrial membrane potential. Markers of changes resembling capacitation were membrane fluidity, tyrosine phosphorylation, and intracellular sodium. Conventional and computational flow cytometry using nonlinear dimensionally reduction techniques (t-distributed stochastic neighbor embedding (t-SNE)) and automatic classification of cellular expression by nonlinear stochastic embedding (ACCENSE) were used. Most of the changes induced by cryopreservation were apoptotic, with increase in caspase 3 activation (P < 0.01), PS translocation to the outer membrane (P < 0.001), loss of mitochondrial membrane potential (P < 0.05), and increase in intracellular Na+ (P < 0.01). Average values of markers of capacitative changes were not affected by cryopreservation; however, the analysis of the phenotype of individual spermatozoa using computational flow cytometry revealed the presence of subpopulations of spermatozoa experiencing capacitative changes. For the first time advanced computational techniques were applied to the analysis of spermatozoa, and these techniques were able to disclose relevant information of the ejaculate that remained hidden using conventional flow cytometry.
Hormones play essential roles during development and maintaining homeostasis in adult organisms, regulating a plethora of biological processes. Generally, hormones are secreted by glands and perform ...a systemic action. Here we show that Juvenile Hormones (JHs), insect sesquiterpenoids synthesized by the corpora allata, are also synthesized by the adult Drosophila gut. This local, gut specific JH activity, is synthesized by and acts on the intestinal stem cell and enteroblast populations, regulating their survival and cellular growth through the JH receptors Gce/Met and the coactivator Tai. Furthermore, we show that this local JH activity is important for damage response and is necessary for intestinal tumor growth driven by activating mutations in Wnt and EGFR/Ras pathways. Together, our results identify JHs as key hormonal regulators of gut homeostasis and open the possibility that analogous hormones may play a similar role in maintaining vertebrate adult intestinal stem cell population and sustaining tumor growth.
The development of strategies to monitor the applications of pesticides is of primary importance. In the present report, two aspects of the surface‐enhanced Raman scattering (SERS) effect of the ...fungicide thiram were investigated: quantitative analysis using the standard addition method and the thiram adsorption mechanism onto Ag nanostructures using theoretical approach. Experimentally, SERS intensity varies linearly from 1.0 × 10−8 to 4.0 × 10−7 mol/L with thiram concentration leading to a limit of detection of 1.2 × 10−8 mol/L for the band at 560 cm−1 and 1.7 × 10−9 mol/L for 1386 cm−1. The loss of linearity (above 10−6 mol/L) was associated with changes in the Ag colloid aggregation, also indicated by complementary analyses via UV‐Vis extinction spectroscopy, dynamic light scattering, and zeta potential. The differences in the spectral profiles observed for thiram Raman powder and SERS are ascribed to S–S cleavage, leading the degraded thiram adsorbing to Ag surface not only through S atoms but also through methyl groups.
The analytical detection of distinct analytes at low concentration using surface‐enhanced Raman scattering (SERS) technique has shown to be possible. SERS was successfully applied in the detection and quantification of thiram pesticide in silver colloid.
Nanoparticulate-based drug carriers have been developed to overcome the problems of conventional anticancer pharmacotherapy, i.e., the little specificity and low accumulation of the drug into the ...tumor interstitium, and the extensive biodistribution leading to severe toxicity. Unfortunately, conventional nanoparticles have been demonstrated to merely accumulate the loaded drug into organs associated to the reticuloendothelial system, e.g., the liver. Recently, drug delivery strategies involving the use of nanoplatforms surface decorated with unique biomolecules have demonstrated their potential in concentrating the chemotherapy agent specifically into the malignant cells. This review will be focused on the analysis of the current state of the art and future perspectives of such passive and active targeting strategies based on the enhanced permeability and retention effect and on a ligand-mediated transport, respectively. Special attention will be given to the use of these surface functionalized nanocarriers to overcome multi-drug resistances in cancer cells.
The mechanisms for neurodegeneration in amyotrophic lateral sclerosis (ALS) are not understood. We found that motor neuron degeneration in ALS structurally resembles apoptosis. The progression of ...neuronal death is divisible into 3 sequential stageschromatolysis, somatodendritic attrition, and apoptosis. In ALS spinal cord anterior horn and motor cortex, DNA fragmentation is detectable in situ and in gels and is intermucleosomal, occurring in the presence of DNA fragmentation factor-45/40 activation and increased caspase-3 activity. By immunoblotting, changes occur in the subcellular distribution of cell death proteins that would promote apoptosis. In selectivity vulnerable CNS regions in ALS compared with controls, the proapoptotic proteins Bax and Bak are elevated in the mitochondrial-enriched membrane compartment, but are reduced or unchanged in the cytosol. In contrast, the antiapoptotic protein Bcl-2 is decreased in the mitochondrial-enriched membrane compartment of vulnerable regions in ALS, but is increased in the cytosol, whereas Bcl-x, levels are unchanged in both subcelluar compartments. Coimmunoprecipitation experiments showed that Bax-Bax interactions are greater in the mitochondrial-enriched membrane compartment of ALS motor cortex compared with controls, whereas Bax-Bcl-2 interactions are lower in the membrane compartment of ALS motor cortex compared with controls. We conclude that a PCD mechanism, involving cytosol-to-membrane and membrane-to-cytosol redistribution of cell death proteins and caspase-3 activation, participates in the pathogenesis of ALS.
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