Impaired detoxification of Acrolein interrupted ocular vascular integrity and kidney structure in akr7a3-/- zebrafish via enhancing Arachidonic acid/leukotriene metabolism
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ABSTRACT:
PROVIDER: PRJNA1216901 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32162987_1.fastq.gz | Fastqsanger.gz | |||
| SRR32162987_2.fastq.gz | Fastqsanger.gz | |||
| SRR32162988_1.fastq.gz | Fastqsanger.gz | |||
| SRR32162988_2.fastq.gz | Fastqsanger.gz | |||
| SRR32162989_1.fastq.gz | Fastqsanger.gz |
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Project description:Acrolein (ACR) is an endogenous reactive unsaturated aldehyde that can be detoxified by the aldo-keto reductase (AKR) enzyme system. The accumulation of ACR is associated with several health issues, including inflammation, oxidative stress, and cardiovascular diseases. In this study, an akr7a3 mutant zebrafish with the Tg(fli1: EGFP) signature was generated to investigate the effect of ACR on vascular integrity. Elevated ACR levels were observed in akr7a3-/- zebrafish larvae and adults. Subsequent experiments demonstrated that increased ACR induced an enlargement of the hyaloid and retinal vasculature, as well as alterations in the larvae pronephron and adult kidney. Transcriptome and metabolomics analyses, followed by validation experiments, revealed that the upregulation of arachidonic acid metabolism and leukotriene production are responsible for the observed vascular and organ changes. In conclusion, our data suggests that the loss of akr7a3 in zebrafish impairs the detoxification of ACR, which subsequently disrupts vascular integrity and normal kidney structure by promoting an inflammatory response.
2025-05-14 | GSE288313 | GEO
Project description:Our previous experiments showed the function of Akr1a1a was related to insulin resistance. The knockout of Akr1a1a led to poor acrolein detoxification and accumulated acrolein inhibits insulin receptors (insra/insrb) expression. To understand how the loss of Akr1a1a and acrolein reflects at the transcriptome level, we performed full genome RNA-Seq between akr1a1a+/+, akr1a1a-/- and akr1a1a+/+ with acrolein treatment zebrafish larvae at 120 hpf. An overview of RNA-Seq, including quality control, principal component analysis (PCA), and volcano plots of regulated genes showed comparable properties between akr1a1a mutants, wild type and acrolein treated wild type zebrafish larvae. We found the insulin receptor signaling pathway was down-regulated significantly in akr1a1a mutants and acrolein treated wild type larvae as compared to wild type larvae via gene set enrichment analysis (normalized enrichment score, -1.888, p=0.028; -1.93, p=0.019). Intriguingly, downstream signaling pathways including MAPK, signal transduction by protein phosphorylation and transmembrane receptor protein tyrosine kinase signaling pathway were also significantly down-regulated in akr1a1a mutants and acrolein treated wild type larvae. Taken together, these results further suggest akr1a1a and acrolein as an important regulator in insulin receptor signaling transduction. Furthermore, we offer a comprehensive and more detailed evaluation of mRNA content within zebrafish larvae. We conclude that RNA-seq based transcriptome would clearly illustrate genetic network and clarify complex biological functions.
2021-09-05 | GSE168786 | GEO
Project description:Acrolein is a major reactive component of vehicle exhaust, cigarette and wood smoke. It is also present in several food substances and is generated endogenously during inflammation and lipid peroxidation. Although previous studies have shown that dietary or inhalation exposure to acrolein results in endothelial activation, platelet activation and accelerated atherogenesis, the basis for these effects is unknown. Moreover, the effects of acrolein on microRNA (miRNA) have not been studied. Using AGILENT miRNA microarray high throughput technology, we have thus characterized the effects of acrolein exposure on miRNA expression in human umbilical vein endothelial cells (HUVEC).
2014-06-03 | GSE56782 | GEO
Project description:Acrolein is a major reactive component of vehicle exhaust, cigarette and wood smoke. It is also present in several food substances and is generated endogenously during inflammation and lipid peroxidation. Although previous studies have shown that dietary or inhalation exposure to acrolein results in endothelial activation, platelet activation and accelerated atherogenesis, the basis for these effects is unknown. Moreover, the effects of acrolein on microRNA (miRNA) have not been studied. Using AGILENT miRNA microarray high throughput technology, we have thus characterized the effects of acrolein exposure on miRNA expression in human umbilical vein endothelial cells (HUVEC). 2 condition, acrolein-exposed and vehicle exposed; 4 replicates of each
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Project description:Zileuton protects against arachidonic acid/5-lipoxygenase/leukotriene axis-mediated neuroinflammation in experimental traumatic brain injury
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Project description:Acute acrolein inhalation in male rats resulted in multi-tissue transcriptomic alterations that were observed through Illumina mRNA sequencing. Specifically, site-specific respiratory expression profile differences were noted between air- and acrolein-exposed groups. Nasal epithelial tissue demonstrated 452 differentially expressed genes (DEGs) (310 up-regulated and 142 down-regulated)and lung tissue demonstrated 95 DEGs (80 up-regulated and 15 down-regulated). Notable transcriptomic alterations were also observed in liver tissue of acrolein-exposed rats, with 1699 identified DEGs (788 up-regulated and 911 down-regulated). A variety of mRNA expression profile differences resulting from acute acrolein inhalation was observed in other peripheral tissues, including adipose, muscle, adrenals, hippocamus, and hypothalamus. Gene changes were largely representative of oxidative and inflammatory response in the nose, as well as xenobiotic metabolism changes in the lung. Liver changes, which were most numerous, included alterated metabolic signaling (Sirtuin and FXR signaling), as well as alterated oxidoreductive, GPCR, and glucocorticoid pathways. Together, these data demonstrate acrolein, a well-characterized respiratory irritant, induces systemic neuroendocrine immunological and metabolic stress.
2023-11-16 | GSE247698 | GEO
Project description:Human umbilical vein endothelial cells (HUVEC) or the human macrophage cell line, Mono-Mac-6, treated with Leukotriene D4 for 1 hour Keywords = Leukotriene-Transcriptome Keywords = Mono-Mac-6 Keywords = HUVEC Keywords: other
2004-08-20 | GSE1644 | GEO
Project description:Dysregulated cell death leading to uncontrolled cell proliferation is a major hallmark of cancer. Chemotherapy-induced cell death is critical for the success of cancer treatment but this process is impaired by metabolic byproducts. How these metabolic byproducts interfere with the efficacies of anti-cancer therapy is unclear. Here, we show that the metabolic byproduct acrolein derived from polyamine metabolic pathways, tobacco smoke or fuel combustion, induces ferroptosis independently of the immune sensor ZBP1, inflammasomes and type I IFN signaling. In addition, acrolein suppresses necroptosis in cancer cells by inhibiting the oligomerization of the necroptosis effector MLKL. Loss of SAT1, a key enzyme in polyamine metabolism responsible for intracellular acrolein production, sensitizes cells to necroptosis. In tumor xenograft models, administration of an acrolein-trapping agent in mice, to remove acrolein and relieve necroptosis blockade, enhances the therapeutic efficacy of the chemotherapeutic agent cyclophosphamide. In humans, patients with high cell death activity but low expression of polyamine metabolism-related genes exhibit improved survival. These findings highlight that the removal of toxic metabolic byproducts that block necroptosis improves the success of certain chemotherapies.
2025-05-13 | PXD059944 | Pride
Project description:Helicobacter pylori is the primary cause of gastric cancer and there is a need to discover new molecular targets for therapeutic intervention in H. pylori disease progression. We have previously shown that spermine oxidase (SMOX), the enzyme that catabolizes the back-conversion of the polyamine spermine to spermidine, is upregulated during infection and is associated with increased cancer risk in humans. We sought to determine the direct role of SMOX in gastric carcinogenesis during H. pylori infection. In this study, we demonstrate that transgenic FVB/N insulin-gastrin (INS-GAS) mice that develop gastric carcinoma with H. pylori infection were protected from cancer development with Smox deletion. RNA sequencing revealed that genes associated with the immune system and cancer were downregulated in the infected Smox–/– mice. Furthermore, there was a decrease in cell proliferation and DNA damage in infected Smox–/– animals. There was significant generation of adducts of the highly reactive electrophile acrolein, a byproduct of SMOX activity, in tissues from H. pylori-infected WT mice and humans. Genetic deletion of Smox or chemical inhibition of SMOX in murine organoids and human gastric epithelial cells and organoids, respectively, significantly reduced generation of acrolein induced by H. pylori. Furthermore, acrolein induced DNA damage in gastric epithelial cells, which was ablated with the electrophile scavenger 2-hydroxybenzylamine (2-HOBA). Infected 2-HOBA treated INS-GAS WT mice with reduced gastric carcinoma had attenuated gastric acrolein adduct formation. These findings implicate SMOX and acrolein in H. pylori-induced carcinogenesis in gastric epithelial cells, thus indicating potential therapeutic targets.
2025-02-05 | GSE266944 | GEO
Project description:Traumatic brain injury (TBI) is a leading cause of death and disability globally. Several studies have shown that 5-lipoxygenase (5-LOX) inhibition reduces leukotriene (LT) release and the inflammatory response, attenuating the development of respiratory diseases, myocardial infarction, and ischemic cerebral injury. However, its role in the pathophysiology of TBI remains unclear. In this study, controlled cortical impact injury was induced to construct a mouse model of TBI. Pericontusional brain tissue samples from sham and TBI mice at 7 days after injury were used for RNA-seq analysis. Altered gene enrichment following TBI, based on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, was quantified through real-time polymerase chain reaction (RT-PCR). Immunocytochemistry, Western blotting, and single-cell sequencing experiments were also performed to analyze 5-LOX protein expression. Arachidonic acid (AA) was detected through liquid chromatography mass spectrometry/mass spectrometry. Enzyme-linked immunosorbent assay was used to detect LTB4 release after TBI with or without zileuton treatment. Brain damage, blood–brain barrier disruption, and neuronal apoptosis were detected through histological examination. Neurological outcomes were determined through rotarod and fear conditioning tests. TBI induced significant upregulation of genes related to the AA metabolic pathway, particularly the AA/5-LOX/LT axis, as verified by RT-PCR. AA and LTB4 production increased significantly after TBI. The expression levels of Pla2g4a, which hydrolyses phospholipids to release AA, and 5-LOX, which in turn act downstream to convert AA to LT, were dramatically upregulated up to 7 days after TBI. 5-LOX accumulated in the cytoplasm of activated ameboid microglial cells. In vivo, 5-LOX inhibition with zileuton blocked LT release and reduced microglial activation and the production of inflammatory cytokines, including Il-1β, Ccl7, Spp1, Ccr1, Ccl2, and Il-10. Zileuton also reduced TBI-induced lipid ROS and neuronal cell apoptosis, ameliorating brain damage compared to the vehicle group and improving neurological outcomes after TBI. Mechanically, TBI-induced LT upregulation may stimulate BV2 microglial activation through the ERK, NF-κB, and Akt pathways. Our findings demonstrated the role of 5-LOX in TBI and its potential as a therapeutic target in TBI treatment.
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