ROS production by PPARbeta-deficient fibroblasts reduces tumor load by triggering an epithelial antioxidant response
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ABSTRACT:
PROVIDER: PRJNA381963 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-08-05 | GSE97473 | GEO
Project description:Nutrient deprivation triggers the release of signal-sequence-lacking antioxidant superoxide dismutase 1 (SOD1). We now report that secreted SOD1 is functionally active and accompanied by export of other antioxidant enzymes such as thioredoxins, (Trx1 and Trx2) and peroxiredoxin Ahp1. Our data reveal that starvation increases mitochondrial activity, which generates higher, but non-toxic, levels of reactive oxygen species (ROS). Inhibiting mitochondrial activity or ROS prevents antioxidants secretion. We suggest that in response to ROS production that can permeate the plasma membrane, the cells respond by secreting antioxidants to prevent ROS-mediated damage in the extracellular space. These findings provide an understanding of why cells secrete signal sequence lacking antioxidant enzymes in response to starvation.
2020-03-26 | PXD016815 | Pride
Project description:Signal-sequence-lacking superoxide dismutase 1 (SOD1) is secreted upon nutrient starvation, but the physiological relevance of this secretion is unclear. We now report that secreted SOD1 is functionally active. In addition, a secretome analysis has revealed number of other secreted cytoplasmic antioxidant enzymes, including both thioredoxins, (Trx1 and Trx2), and the peroxiredoxin Ahp1. Our data reveal that starvation triggers increased mitochondrial activity, leading to increased production of reactive oxygen species (ROS). Inhibiting mitochondrial activity or ROS, inhibited secretion of the antioxidants. We suggest elevated ROS that evade cytoplasmic antioxidants, can permeate across the plasma membrane to the extracellular space. Cells secrete antioxidants to prevent ROS-mediated damage to the extracellular space. These findings thus provide an understanding of why cells secrete signal sequence lacking proteins like SOD1 and the larger family of antioxidants.
2019-05-14 | PXD010849 | Pride
Project description:Tumor stroma has an active role in the initiation, growth, and propagation of many tumor types by secreting growth factors and modulating redox status of the microenvironment. Although PPAR?/? in fibroblasts was shown to modulate oxidative stress in the wound microenvironment, there has been no evidence of a similar effect in the tumor stroma. Here, we present evidence of oxidative stress modulation by intestinal stromal PPAR?/?, using a FSPCre-Pparb/d-/- mouse model and validated it with immortalized cell lines. The FSPCre-Pparb/d-/- mice developed fewer intestinal polyps and survived longer when compared with Pparb/dfl/fl mice. The pre-treatment of FSPCre-Pparb/d-/- and Pparb/dfl/fl with antioxidant N-acetyl-cysteine prior DSS-induced tumorigenesis resulted in lower tumor load. Gene expression analyses implicated an altered oxidative stress processes. Indeed, the FSPCre-Pparb/d-/- intestinal tumors have reduced oxidative stress than Pparb/dfl/fl tumors. Similarly, the colorectal cancer cells and human colon epithelial cells also experienced lower oxidative stress when co-cultured with fibroblasts depleted of PPAR?/? expression. Therefore, our results establish a role for fibroblast PPAR?/? in epithelial-mesenchymal communication for ROS homeostasis.
| S-EPMC5895604 | biostudies-literature
Project description:During their life cycle, trypanosomatids are exposed to stress conditions and adapt their energy and antioxidant metabolism to colonize their hosts. Strigomonas culicis is a monoxenous protist found in invertebrates with an endosymbiotic bacterium that completes essential biosynthetic pathways for the trypanosomatid. Our research group previously generated a wild-type H2O2-resistant (WTR) strain that showed improved mitochondrial metabolism and antioxidant defenses, which led to higher rates of Aedes aegypti infection. Here, we assess the biological contribution of the S. culicis endosymbiont and reactive oxygen species (ROS) resistance to oxidative and energy metabolism processes. Using high-throughput proteomics, several proteins involved in glycolysis and gluconeogenesis, the pentose phosphate pathway and glutathione metabolism were identified. The results suggest that ROS resistance decreases glucose consumption and indicate that the metabolic products from gluconeogenesis are key to supplying the protist with high-energy and reducing intermediates. Our hypothesis was confirmed by biochemical assays showing opposite profiles for glucose uptake and hexokinase and pyruvate kinase activity levels in the WTR and aposymbiotic strains, while the enzyme glucose-6P 1-dehydrogenase was more active in both strains. Regarding the antioxidant system, ascorbate peroxidase has an important role in H2O2 resistance and may be responsible for the high infection rates previously described for A. aegypti. In conclusion, our data indicate that the energy-related and antioxidant metabolic processes of S. culicis are modulated in response to oxidative stress conditions, providing new perspectives on the biology of the trypanosomatid-insect interaction as well as on the possible impact of resistant parasites in accidental human infection.
2019-11-27 | PXD015717 | Pride
Project description:The molecular mechanisms of exercise-induced cardiovascular protection are poorly understood. There is growing evidence that reactive oxygen species (ROS) are necessary for some of these adaptations and antioxidants may be used to investigate this effect. This study aimed to determine the effects of exercise and/or antioxidant supplementation on myocardial and vascular endothelium gene expression. Male Wistar rats were divided into four groups: i) endurance exercise (90min of treadmill running 4d/week, 14 weeks); ii) antioxidant-treated; iii) antioxidant and endurance exercise and iv) control. The supplemented animals received Vitamin E (1000 IU/kg diet) and ï¡-lipoic acid (1.6 g/kg diet) mixed with rat chow. cDNA microarray analysis was performed using purified endothelial RNA from myocardial and coronary artery endothelial cells and showed that the expression levels of 35, 40 and 40 genes were altered for groups i, ii, and iii respectively compared to control. Differentially expressed genes were analysed using the KEGG pathway database, hierarchical cluster and DAVID analysis. These analyses revealed that a gene involved in cardiovascular disease progression, Ras homolog gene family member A (RhoA) was down-regulated by exercise, upregulated by antioxidant supplementation and the combination of exercise and antioxidant blunted both effects. These findings were confirmed by real-time PCR. In summary, exercise and antioxidant supplementation affect endothelial cell gene expression and ROS appear necessary for some of these adaptations. 48 Male Wistar rats were divided into four groups: i) endurance exercise (90min of treadmill running 4d/week, 14 weeks); ii) antioxidant-treated; iii) antioxidant and endurance exercise and iv) control. The supplemented animals received Vitamin E (1000 IU/kg diet) and ï¡-lipoic acid (1.6 g/kg diet) mixed with rat chow. cDNA microarray analysis was performed using purified endothelial RNA from myocardial and coronary artery endothelial cells. Based on the limited material available, it was necessary to combine the RNA into three pools per treatment group for CAEC (approx 400 ng of total RNA), and four pools for LVEC (approx 1 μg of total RNA) with an additional reference pool from each control group.
2010-06-25 | E-GEOD-14044 | biostudies-arrayexpress
Project description:The molecular mechanisms of exercise-induced cardiovascular protection are poorly understood. There is growing evidence that reactive oxygen species (ROS) are necessary for some of these adaptations and antioxidants may be used to investigate this effect. This study aimed to determine the effects of exercise and/or antioxidant supplementation on myocardial and vascular endothelium gene expression. Male Wistar rats were divided into four groups: i) endurance exercise (90min of treadmill running 4d/week, 14 weeks); ii) antioxidant-treated; iii) antioxidant and endurance exercise and iv) control. The supplemented animals received Vitamin E (1000 IU/kg diet) and alpha-lipoic acid (1.6 g/kg diet) mixed with rat chow. cDNA microarray analysis was performed using purified endothelial RNA from myocardial and coronary artery endothelial cells and showed that the expression levels of 35, 40 and 40 genes were altered for groups i, ii, and iii respectively compared to control. Differentially expressed genes were analysed using the KEGG pathway database, hierarchical cluster and DAVID analysis. These analyses revealed that a gene involved in cardiovascular disease progression, Ras homolog gene family member A (RhoA) was down-regulated by exercise, upregulated by antioxidant supplementation and the combination of exercise and antioxidant blunted both effects. These findings were confirmed by real-time PCR. In summary, exercise and antioxidant supplementation affect endothelial cell gene expression and ROS appear necessary for some of these adaptations.
2009-12-18 | GSE14044 | GEO
Project description:Excessive reactive oxygen species (ROS) can cause oxidative stress and consequently cell injury contributing to a wide range of diseases. Addressing the critical gaps in our understanding of the adaptive molecular events downstream ROS provocation holds promise for the identification of druggable metabolic vulnerabilities. Herein, we unveil a direct molecular link between the activity of two estrogen-related receptor (ERR) isoforms and the control of glutamine utilization and glutathione antioxidant production. ERRα downregulation restricts glutamine entry into the TCA cycle while ERRγ upregulation promotes glutamine-driven glutathione production. Notably, we identify increased ERRγ expression/activation as a hallmark of oxidative stress triggered by mitochondrial disruption or chemotherapy. Enhanced tumor antioxidant capacity is an underlying feature of human breast cancer (BCa) patients that respond poorly to treatment. We demonstrate that pharmacological inhibition of ERRγ with the selective inverse agonist GSK5182 increases antitumor efficacy of the chemotherapeutic paclitaxel on poor outcome BCa tumor organoids. Our findings thus underscore the ERRs as novel redox sensors and effectors of a ROS defense program and highlight the potential therapeutic advantage of exploiting ERRγ inhibitors for the treatment of BCa and other diseases where oxidative stress plays a central role. In this study, ERRγ ChIP-seq analysis was performed under normal conditions in the breast cancer cell line BT-474.
2020-02-07 | GSE144224 | GEO
Project description:Hypercholesterolemic APOE-deficient mice are a widely used experimental model of atherosclerosis and increased generation of reactive oxygen species (ROS) is a prominent feature of atherosclerosis development. To study the impact of ROS on atherogenesis, we treated APOE-deficient mice for 7 months with the antioxidant vitamin E (2000 IU/kg diet) and performed whole genome microarray gene expression profiling of aortic genes. Microarray gene expression profiling was performed of whole aortas isolated from vitamin E-treated APOE-deficient relative to untreated APOE-deficient mice with overt atherosclerosis, and nontransgenic B6 control mice. Microarray gene expression profiling revealed that vitamin E treatment prevented atherosclerosis-related gene expression changes of the aortic intima and media. Microarray gene expression profiling was performed of whole aortas isolated from APOE-deficient mice with atherosclerosis relative to vitamin E-treated APOE-deficient mice, and nontransgenic B6 control mice. Three study groups were analyzed, i.e. 8 months-old untreated APOE-deficient mice with overt atherosclerosis, age-matched APOE-deficient mice treated for 7 months with the antioxidant vitamin E (2000 IU/kd diet), and nontransgenic B6 control (C57BL/6J) mice. Two biological replicates were made of each group, and total RNA of three aortas was pooled for one gene chip. The study complements microarray study GSE19286.
2012-12-11 | E-GEOD-42813 | biostudies-arrayexpress
Project description:Amyloid-beta (Aβ)-induced neurotoxicity is a major contributor to the pathologies associated with Alzheimer’s disease (AD). The formation of reactive oxygen species (ROS), and early response induced by the Aβ peptide, plays a significant role in effecting cellular pathogenesis. Here we apply a particularly effective form of exogenous Aβ, i.e., amyloid beta-derived diffusible ligands (ADDLs), to cultured primary cortical/hippocampal neurons to elicit ROS and drive cellular dysfunction. To prevent and even reverse such effects, we employed a cell-penetrating, peroxisome-targeted, protein biologic - called CAT-SKL. We show the recombinant enzyme enters neurons, reverses Aβ-induced oxidative stress, and increases cell viability. Dramatic restorative effects on damaged neuronal processes were also observed. CAT-SKL, a targeted antioxidant, may represent a new therapeutic approach for treatment disorders, like Alzheimer’s disease, where oxidative stress is manifest. Preclinical testing is warranted and ongoing Primary Rat E18 coritical/hippocampal neurons (derived from Sprague Dawley E18 cortical/hippocampus tissue obtained from BrainBits®, Springfield, IL) were treated with ADDLs in the presence or absence of the targeted antioxidant CAT-SKL to investigate genes that displayed altered expression in response to treatmetns total RNA was isolated and analyzed in an Agilent two-color experiment. Two biological replicates of each condition were directly compared, ratios are treated relative to control (untreated)
2014-04-11 | E-GEOD-55369 | biostudies-arrayexpress