MAGL deficiency in liver macrophages
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA781292 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16970291_1.fastq.gz | Fastqsanger.gz | |||
| SRR16970291_2.fastq.gz | Fastqsanger.gz | |||
| SRR16970292_1.fastq.gz | Fastqsanger.gz | |||
| SRR16970292_2.fastq.gz | Fastqsanger.gz | |||
| SRR16970293_1.fastq.gz | Fastqsanger.gz |
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Project description:Comparative expression profile of liver macrophages from mice invalidated (MAGL Mye-/-) or not (MAGL fl/fl) for MAGL
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Project description:The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E2 (PGE2), which stimulates β-catenin activation of GSC and M2-like TAM polarization. Specific knockdown of ARS2 or MAGL significantly suppressed self-renewal and tumor growth, and increased survival in a mouse intracranial xenograft model of GSCs. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE2 production. The M2-like signature is enriched in mesenchymal subtype and predicted poor survival in GBM patients. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients.
2020-05-16 | GSE150630 | GEO
Project description:The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E2 (PGE2), which stimulates β-catenin activation of GSC and M2-like TAM polarization. Specific knockdown of ARS2 or MAGL significantly suppressed self-renewal and tumor growth, and increased survival in a mouse intracranial xenograft model of GSCs. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE2 production. The M2-like signature is enriched in mesenchymal subtype and predicted poor survival in GBM patients. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients. Methods: X01 subcutatneous model treated vehicle or JZL184 Results: abstract copy and paste Conclusion: abstract copy and paste
2020-05-16 | GSE150631 | GEO
Project description:Background Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy and is characterized by a pathological cascade of excitotoxicity that leads to neuroinflammation, progressive neuronal loss, and subsequent cognitive decline. Despite its prevalence, effective disease-modifying therapies remain lacking. Previous studies have demonstrated that the endocannabinoid system contributes to epileptic activity. In particular, inactivation of monoacylglycerol lipase (MAGL), the key rate-limiting enzyme responsible for the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG), an endogenous lipid mediator with anti-inflammatory and neuroprotective properties, suppresses seizures and reduces neuroinflammation. However, the cellular and molecular mechanisms underlying these protective effects remain unclear. Methods To dissect the cellular mechanisms underlying MAGL-mediated neuroprotection, we employed a kainic acid (KA)-induced status epilepticus model in mice with global, astrocyte-specific (aKO), and neuron-specific (nKO) deletion of mgll. We combined single-nucleus RNA sequencing (snRNA-seq) to map the transcriptomic landscape of glial responses with pharmacological interventions to validate key signaling pathways, as well as behavioral assays to assess functional recovery. Results We demonstrated that astrocyte-specific, but not neuron-specific, mgll deletion was sufficient to attenuate seizure susceptibility and hippocampal neurodegeneration, thereby recapitulating the protective phenotype observed in global knockouts. Transcriptomic profiling revealed that astrocytic MAGL deficiency fundamentally reshaped the glial response to injury by preventing the transition to pro-inflammatory reactive astrocyte states and suppressing the activation of disease-associated microglia (DAM). Mechanistically, we identified a signaling pathway in which the neuroprotective effects of MAGL inhibition depend on cannabinoid receptor 1 (CB1) activation and are mediated by downstream peroxisome proliferator-activated receptor γ (PPAR-γ) signaling. Either genetic deletion of CB1 or pharmacological blockade of PPAR-γ abolished the protective effects. Furthermore, aKO mice exhibited reduced neuronal loss, preserved synaptic structural integrity and protection against post-seizure cognitive deficits. Conclusion These findings reveal astrocytic MAGL as a crucial regulatory node in the epileptic brain and demonstrated that enhancing 2-AG signaling in astrocytes orchestrates neuroprotection via CB1-PPAR-γ signaling pathways, thereby reducing neuroinflammation, preserving synaptic function, and preventing the cognitive comorbidities associated with epilepsy.
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Project description:In the brain, 2-Arachidonoylglycerol (2-AG) is the most abundant endogenous cannabinoid. Enhancing 2-AG signaling by inhibiting monoacylglycerol lipase (MAGL) in astrocytes, the primary enzyme that degrades 2-AG in the brain, produces anti-inflammatory and neuroprotective effects in neurodegenerative diseases. However, the effects of astrocytic MAGL inhibition in 5xFAD mice were still unclear. To address this question, behavioral tests were performed and hippocampal nuclei were isolated from WT, TG, TG-aKO, TG-nKO, and TG-tKO mice. Our behavioral and electrophysiological results showed that cognitive and synaptic functions were rescued in TG-aKO mice. Using single-nucleus RNA sequencing analysis, we show here that neuronal MAGL KO mice display distinct gene expression profiles of synaptic DEGs in neurons and glial cells
2026-02-20 | GSE311467 | GEO
Project description:Vitamin D, a fat-soluble vitamin, plays a critical role in calcium homeostasis, the immune system, and normal development. Many epidemiological cohort studies globally have found high prevalence rates of vitamin D deficiency and insufficiency, recognized as an important health issue that needs to be solved. In particular, reproductive age and pregnant women low in vitamin D status may confer risks of diseases like obesity on their offspring. While observational studies have suggested associations between prenatal vitamin D deficiency and metabolic phenotypes in offspring, not yet determined is whether prenatal vitamin D deficiency permanently alters the development of the liver, a major metabolic organ. We tested the histopathology and the transcriptomic profiles of livers from male C57BL/6J mice exposed to prenatal vitamin D deficiency through a maternal dietary intervention model. We found that prenatal vitamin D deficiency increases the prevalence of histopathological changes in the liver, and alters its gene expression profile. Cell subtype proportion analysis showed that the liver of prenatal vitamin D deficiency alters non-parenchymal cells of the liver, specifically macrophages, a subset of endothelial cells, and dendritic cells. Our results indicate the long-term memory of prenatal vitamin D deficiency exposure in the adult liver, a potential contributor to offspring health risks.
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Project description:This study focuses on the protein degradation effects of the MAGL inhibitor JZL184 and the newly synthesized MAGL-PROTAC on MAGL.
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