Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA395254 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5855380_1.fastq.gz | Fastqsanger.gz | |||
| SRR5855380_2.fastq.gz | Fastqsanger.gz | |||
| SRR5855381_1.fastq.gz | Fastqsanger.gz | |||
| SRR5855381_2.fastq.gz | Fastqsanger.gz | |||
| SRR5855372_1.fastq.gz | Fastqsanger.gz |
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Project description:Islet β-cell dysfunction and aggressive macrophage activity are early features in the pathogenesis of type 1 diabetes (T1D). 12/15-lipoxygenase (12/15-LOX) is induced in β cells and macrophages during T1D and produces pro-inflammatory lipids and lipid peroxides that exacerbate β-cell dysfunction and macrophage activity. Inhibition of 12/15-LOX provides a potential therapeutic approach to prevent glycemic deterioration in T1D. Two inhibitors recently identified by our groups through screening efforts, ML127 and ML351, have been shown to selectively target 12/15-LOX with high potency. Only ML351 exhibited no apparent toxicity across a range of concentrations in mouse islets, and molecular modeling suggested reduced promiscuity of ML351 compared to ML127. In mouse islets, incubation with ML351 improved glucose-stimulated insulin secretion in the presence of pro-inflammatory cytokines and triggered gene expression pathways responsive to oxidative stress and cell death. Consistent with a role for 12/15-LOX in promoting oxidative stress, its chemical inhibition reduced production of reactive oxygen species in both mouse and human islets in vitro. In a streptozotocin-induced model of T1D in mice, ML351 prevented the development of diabetes, with coincident enhancement of nuclear Nrf2 in islet cells, reduced β-cell oxidative stress, and preservation of β-cell mass. In the non-obese diabetic mouse model of T1D, administration of ML351 during the prediabetic phase prevented dysglycemia, reduced β-cell oxidative stress, and increased the proportion of anti-inflammatory macrophages in the insulitis. Our data provide the first evidence to date that small molecules that target 12/15-LOX can prevent progression of β-cell dysfunction and glycemic deterioration in models of T1D.
2017-10-29 | GSE101722 | GEO
Project description:The goal of this study is to determine the effect of the 12/15-lipoxygenase deficiency on transcriptomic profile of alveolar macrophages.
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Project description:The goal of this study is to determine the role of the 12/15-lipoxygenase pathway in the development and maintenance of alveolar macrophages.
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Project description:Cardiac 12/15-lipoxygenase-induced inflammation is involved in heart failure
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Project description:To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, 12/15 lipoxygenase (12/15-LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that 12/15-LOX transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in 12/15-LOX transgenic mice with advancing age, and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein-1 (Mcp-1) was up-regulated in 12/15-LOX transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenotic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells, but not in cardiomyocytes. Inhibition of Mcp-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in 12/15-LOX transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac Mcp-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition.
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Project description:Gliotoxin (GT), a major secondary metabolite and virulence factor of Aspergillus fumigatus, suppresses innate immunity and supports the evasion of host immune responses. Recently, we revealed that GT blocks leukotriene (LT)B4 formation by directly inhibiting LTA4 hydrolase (LTA4H) in activated human neutrophils and monocytes. Here, we elucidated the impact of GT on LTB4 biosynthesis and the complex lipid mediator network in human M1- and M2-like monocyte-derived macrophage (MDM) subtypes and studied the respective consequences for innate immune cell functions. Notably, in resting MDMs, GT elicited prostaglandin and 12/15-lipoxygenase product formation, although less efficient than bacterial exotoxins. In activated MDM, LTB4 formation was effectively suppressed by GT, connected to impaired macrophage phagocytic activity, and detrimental consequences for neutrophil movement and migration. Conclusively, GT impairs functions of activated innate immune cells through suppression of LTB4 formation, while GT may prime the immune system by provoking prostaglandin formation and 12/15-lipoxygenase-derived LM.
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Project description:ZMYND8 Protects Breast Cancer Stem Cells against Oxidative Stress and Ferroptosis through Activation of NRF2
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Project description:To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, 12/15 lipoxygenase (12/15-LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that 12/15-LOX transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in 12/15-LOX transgenic mice with advancing age, and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein-1 (Mcp-1) was up-regulated in 12/15-LOX transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenotic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells, but not in cardiomyocytes. Inhibition of Mcp-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in 12/15-LOX transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac Mcp-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition. Heart failure is still one of the leading causes of death worldwide. Therefore, it is important to elucidate the underlying mechanisms of heart failure and develop more effective treatments for this condition. To clarify the molecular mechanisms of heart failure, we performed microarray analysis using cardiac tissue samples obtained from a hypertensive heart failure model (Dahl salt-sensitive rats). ~300 genes showed significant changes of expression in the failing hearts compared with control hearts. Among the genes analyzed, 12/15-lipoxygenase (12/15-LOX) was most markedly up-regulated in failing hearts compared with control hearts .
2009-06-06 | E-GEOD-16199 | biostudies-arrayexpress
Project description:Diabetic hyperglycemia promotes reactive oxygen species (ROS) production to lead to oxidative stress and apoptosis responsible for progressive deterioration of the structure and function of organs. It has been indicated that factors and pathways regulating ROS production and the cellular redox state play a key role in the progression of diabetes and diabetes complications including cardiomyopathy. Recent studies had demonstrated that long non-coding RNAs (lncRNAs) played crucial roles on modulation of oxidative stress and apoptosis activity. In this study, we first established a high glucose induced oxidative stress and apoptosis model on primary rat cardiomyocytes. ROS formation and apoptosis activity were significantly increased at 24h/48h after high glucose stimulation. RNA sequencing analysis was applied to detect differentially expressed lncRNAs during cardiomyocytes oxidative stress and apoptosis.
2019-01-19 | GSE109441 | GEO