Ontology highlight
ABSTRACT:
PROVIDER: PRJNA922223 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23030813_1.fastq.gz | Fastqsanger.gz | |||
| SRR23030813_2.fastq.gz | Fastqsanger.gz | |||
| SRR23030814_1.fastq.gz | Fastqsanger.gz | |||
| SRR23030814_2.fastq.gz | Fastqsanger.gz | |||
| SRR23030815_1.fastq.gz | Fastqsanger.gz |
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Project description:Comparison between wild-type and cardiomyocyte-restricted knock-out of IL6 cytokines receptor component gp130 after surgical intervention for pressure-overload induced cardiomyopathy.
2004-06-30 | E-MEXP-104 | biostudies-arrayexpress
Project description:BMP6 is an iron-sensing cytokine produced by liver sinusoidal endothelial cells (LSECs). The transcription factor NRF2 was proposed to induce Bmp6 expression in response to iron-triggered oxidative stress, and NRF2 knock-out mice were shown not capable of regulating Bmp6 in response to massive diet-imposed iron overload. However, LSEC Bmp6 expression levels in the hemochromatosis mouse model reflect hepatocytic, not endothelial iron content. Hence, it is not fully resolved how iron signals translate into alterations of Bmp6 mRNA levels. To further explore the mechanisms of Bmp6 regulation, we employed female mice aged 10-11 months that are hallmarked by hepatocytic, but not LSEC iron accumulation and decreased transferrin saturation, hinting at the absence of systemic iron overload. We found that LSECs of aged mice exhibit increased Bmp6 levels as compared to young controls, but do not show oxidative stress or a transcriptional signature characteristic of activated NFR2-mediated signaling in FACS-sorted LSECs. We further observed that primary murine LSECs derived from both wild-type and NRF2 knock-out mice induce Bmp6 in response to acute iron exposure. By analyzing RNA sequencing data of FACS-sorted LSECs from aged versus young mice, as well as upon acute injections of iron citrate in young mice, we identified ETS1 as a candidate transcription factor involved in Bmp6 regulation. By conducting siRNA-mediated knock-down and small-molecule treatments in primary LSECs, we show that Bmp6 transcription is regulated in an NRF2-independent manner via ETS1, which is activated downstream of p38 MAP kinase-mediated signaling. This knowledge expands the understanding of Bmp6 transcriptional control in both iron-triggered oxidative stress and under the conditions uncoupled to LSECs reactive oxygen species levels.
2024-01-25 | GSE235975 | GEO
Project description:BMP6 is an iron-sensing cytokine produced by liver sinusoidal endothelial cells (LSECs). The transcription factor NRF2 was proposed to induce Bmp6 expression in response to iron-triggered oxidative stress, and NRF2 knock-out mice were shown not capable of regulating Bmp6 in response to massive diet-imposed iron overload. However, LSEC Bmp6 expression levels in the hemochromatosis mouse model reflect hepatocytic, not endothelial iron content. Hence, it is not fully resolved how iron signals translate into alterations of Bmp6 mRNA levels. To further explore the mechanisms of Bmp6 regulation, we employed female mice aged 10-11 months that are hallmarked by hepatocytic, but not LSEC iron accumulation and decreased transferrin saturation, hinting at the absence of systemic iron overload. We found that LSECs of aged mice exhibit increased Bmp6 levels as compared to young controls, but do not show oxidative stress or a transcriptional signature characteristic of activated NFR2-mediated signaling in FACS-sorted LSECs. We further observed that primary murine LSECs derived from both wild-type and NRF2 knock-out mice induce Bmp6 in response to acute iron exposure. By analyzing RNA sequencing data of FACS-sorted LSECs from aged versus young mice, as well as upon acute injections of iron citrate in young mice, we identified ETS1 as a candidate transcription factor involved in Bmp6 regulation. By conducting siRNA-mediated knock-down and small-molecule treatments in primary LSECs, we show that Bmp6 transcription is regulated in an NRF2-independent manner via ETS1, which is activated downstream of p38 MAP kinase-mediated signaling. This knowledge expands the understanding of Bmp6 transcriptional control in both iron-triggered oxidative stress and under the conditions uncoupled to LSECs reactive oxygen species levels.
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Project description:Hereditary Hemochromatosis (HH) is an autosomal recessive disorder characterized by an abnormally low expression or functional derangement of the iron regulatory hormone hepcidin. The absorption of dietary iron is disproportionate in these patients, leading to iron deposition in several tissues and consequent damage of organs including liver, heart, and pancreas. Late complications in absence of diagnosis and treatment include cirrhosis, hepatocellular carcinoma, cardiomyopathy and diabetes. Unfortunately, iron overload appears also as an acquired complication. This is the case of a variety of anemias (thalassemias, myelodysplastic syndromes, hemoglobinopathies, etc.) in which compensating mechanisms increase iron absorption. Another cause of iron overload in these patients are the repeated transfusional treatments they receive. It follows that iron overload is a common clinical problem. Therefore, we investigated the effects of iron overload on gene expression in skeletal muscle and heart using microarray technology. Genes with up-regulated expression after iron overload in both skeletal and heart muscle included angiopoietin-like 4, pyruvate dehydrogenase kinase 4 and calgranulin A and B. The expression of transferrin receptor, heat shock protein 1B and DnaJ homolog B1 were down-regulated by iron in both muscle types. Two potential hepcidin regulatory genes, hemojuvelin and neogenin, showed no clear change in expression after iron overload. Concluding, microarray analysis revealed iron-induced changes in the expression of several genes involved in the regulation of glucose and lipid metabolism, transcription and cellular stress responses. These may represent novel connections between iron overload and pathological manifestations of HH such as cardiomyopathy and diabetes. Keywords: iron induced stress response
2007-11-30 | GSE9726 | GEO
Project description:Oxidative stress has been implicated in the pathogenesis of age-related macular degeneration, the leading cause of blindness in older adults, with retinal pigment epithelium (RPE) cells playing a key role. To better understand the cytotoxic mechanisms underlying oxidative stress, we used a mouse model of iron overload, as iron can catalyze reactive oxygen species formation in the RPE. In a liver-specific Hepc (Hamp) knockout murine model of systemic iron overload, RPE cells accumulated lipid peroxidation adducts and lysosomes, developed progressive hypertrophy, and underwent cell death. Proteomic and lipidomic analyses revealed accumulation of lysosomal proteins, ceramide biosynthetic enzymes, and ceramides. The proteolytic enzyme cathepsin D had impaired maturation. A large proportion of lysosomes were galectin-3 positive, suggesting cytotoxic lysosomal membrane permeabilization. RNA sequencing was performed and did not show evidence of upregulation of CLEAR network genes, suggesting that the lysosomal accumulation was due to decreased lysosomal turnover and not increased lysosomal biogenesis. Collectively, these results demonstrate that iron overload induces lysosomal accumulation and impairs lysosomal function, likely owing to iron-induced lipid peroxides that can inhibit lysosomal enzymes.
2023-07-13 | GSE237309 | GEO
Project description:Oxidative stress has been implicated in the pathogenesis of age-related macular degeneration(AMD), the leading cause of blindness in the elderly, with retinal pigment epithelial (RPE) cells playing a key role. To better understand the cytotoxic mechanisms underlying oxidative stress, we used cell culture and mouse models of iron overload, as iron can catalyze reactive oxygen species formation in the RPE. Iron-loading of cultured iPS-RPE cells increased lysosomal abundance, impaired proteolysis, and reduced the activity of a subset of lysosomal enzymes,including lysosomal acid lipase and acid sphingomyelinase. In a murine model of systemiciron overload, RPE cells accumulated lipid peroxidation adducts and lysosomes, developed progressive hypertrophy, and underwent cell death. Proteomic and lipidomic analyses revealed accumulation of lysosomal proteins, ceramide biosynthetic enzymes, and ceramides. The proteolytic enzyme cathepsin D had impaired maturation. A large proportion oflysosomes were galectin-3 positive, suggesting cytotoxic lysosomal membrane permeabilization (LMP). Collectively, these results demonstrate that iron overload induces lysosomal accumulation and impairs lysosomal function, likely due to iron-induced lipid peroxides that can inhibit lysosomal enzymes.
2023-07-19 | PXD043613 | Pride
Project description:Hepatic iron overload is a risk factor for progression of hepatocellular carcinoma (HCC), although the molecular mechanisms underlying this association have remained unclear. We now show that the iron-sensing ubiquitin ligase FBXL5 is previously unrecognized oncosuppressor in liver carcinogenesis in mice. Hepatocellular iron overload evoked by FBXL5 ablation gives rise to oxidative stress, tissue damage, inflammation and compensatory proliferation in hepatocytes and to consequent promotion of liver carcinogenesis induced by exposure to a chemical carcinogen. The tumor-promoting effect of FBXL5 deficiency in the liver is also operative in a model of virus-induced HCC. FBXL5-deficient mice thus constitute the first genetically engineered mouse model of liver carcinogenesis induced by iron overload. Dysregulation of FBXL5-mediated cellular iron homeostasis was also found to be associated with poor prognosis in human HCC, implicating FBXL5 plays a significant role in defense against hepatocarcinogenesis.
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Project description:Voltage dependent anion channel 2 (VDAC2) is an outer mitochondrial membrane porin known to play a significant role in apoptosis and calcium signaling. Abnormalities in calcium homeostasis often leads to electrical and contractile dysfunction and can cause dilated cardiomyopathy and heart failure. However, the specific role of VDAC2 in intracellular calcium dynamics and cardiac function is not well understood. To elucidate the role of VDAC2 in calcium homeostasis, we generated a cardiac ventricular myocyte-specific developmental deletion of Vdac2 in mice. Our results indicate that loss of VDAC2 in the myocardium causes severe impairment in excitation-contraction coupling by altering both intracellular and mitochondrial calcium signaling. We also observed adverse cardiac remodeling which progressed to severe cardiomyopathy and death. Reintroduction of VDAC2 in 6-week-old knock-out mice partially rescued the cardiomyopathy phenotype. Activation of VDAC2 by efsevin increased cardiac contractile force in a mouse model of pressure-overload induced heart failure. In conclusion, our findings demonstrate that VDAC2 plays a crucial role in cardiac function by influencing cellular calcium signaling. Through this novel role in cellular calcium dynamics and excitation-contraction coupling VDAC2 emerges as a plausible therapeutic target for heart failure.
2021-03-09 | GSE168487 | GEO
Project description:Hereditary hemochromatosis and transfusional iron overload are frequent clinical conditions associated with progressive iron accumulation in parenchymal tissues leading to eventual organ failure. We have discovered a novel mechanism to reverse iron overload by pharmacological modulation of the divalent metal transporter-1 (DMT-1). DMT-1 mediates intracellular iron transport during the transferrin cycle and apical iron absorption in the duodenum. Additional functions in iron handling in the kidney and liver are less well understood. We show that the L- type calcium-channel blocker nifedipine increases DMT-1 mediated cellular iron transport 10-to 100-fold at concentrations between 1-100 uM. Mechanistically, nifedipine causes this effect by prolongation of the activity of DMT-1 to transport iron. We show that nifedipine mobilizes iron from the liver of mice with primary and secondary iron overload, and enhances urinary iron excretion. Modulation of DMT-1 function by L-type calcium-channel blockers emerges a novel pharmacological concept to treat iron overload disorders.<br> <br> In this experiment mice were subjected to dietary iron overload before being treated with nifedipine at 5 ug/g bodyweight, or mock treated with the same volume of solvent.
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Project description:The purpose of this study is to characterize gene expression changes that occur when conditional knock-out of Srf rescues mutant phenotypes in the cornea of Dstncorn1 mice. This study uses a unique model combining genetic and genomic approaches to identify genes that are regulated by SRF.
2013-08-10 | GSE49688 | GEO