Zileuton protects against arachidonic acid/5-lipoxygenase/leukotriene axis-mediated neuroinflammation in experimental traumatic brain injury
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1263790 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33599069_1.fastq.gz | Fastqsanger.gz | |||
| SRR33599069_2.fastq.gz | Fastqsanger.gz | |||
| SRR33599070_1.fastq.gz | Fastqsanger.gz | |||
| SRR33599070_2.fastq.gz | Fastqsanger.gz | |||
| SRR33599071_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 24 |
Similar Datasets
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.
2025-05-25 | GSE297412 | GEO
Project description:Demin2013 - PKPD behaviour - 5-Lipoxygenase
inhibitors
This model is described in the article:
Systems pharmacology models
can be used to understand complex
pharmacokinetic-pharmacodynamic behavior: an example using
5-lipoxygenase inhibitors.
Demin O, Karelina T, Svetlichniy D,
Metelkin E, Speshilov G, Demin O Jr, Fairman D, van der Graaf PH,
Agoram BM.
CPT Pharmacometrics Syst Pharmacol
2013; 2: e74
Abstract:
Zileuton, a 5-lipoxygenase (5LO) inhibitor, displays complex
pharmaokinetic (PK)-pharmacodynamic (PD) behavior. Available
clinical data indicate a lack of dose-bronchodilatory response
during initial treatment, with a dose response developing after
~1-2 weeks. We developed a quantitative systems pharmacology
(QSP) model to understand the mechanism behind this phenomenon.
The model described the release, maturation, and trafficking of
eosinophils into the airways, leukotriene synthesis by the 5LO
enzyme, leukotriene signaling and bronchodilation, and the PK
of zileuton. The model provided a plausible explanation for the
two-phase bronchodilatory effect of zileuton-the short-term
bronchodilation was due to leukotriene inhibition and the
long-term bronchodilation was due to inflammatory cell
infiltration blockade. The model also indicated that the
theoretical maximum bronchodilation of both 5LO inhibition and
leukotriene receptor blockade is likely similar. QSP modeling
provided interesting insights into the effects of leukotriene
modulation.CPT: Pharmacometrics & Systems Pharmacology
(2013) 2, e74; doi:10.1038/psp.2013.49; advance online
publication 11 September 2013.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000490.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000490 | BioModels
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: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:Human 5-lipoxygenase (5-LO) is the key enzyme of leukotriene biosynthesis, mostly expressed in leukocytes and thus a crucial component of the innate immune system. In this study, we show that 5-LO, beside its canonical function as a metabolizing enzyme, is also a regulator of gene expression in the monocytic cell line Mono Mac 6 (MM6). Using RNA-Seq, we identified 5-LO regulated genes which could be clustered to several biological functions, e.g. immune/defense response, cell adhesion, transcription and growth/developmental processes. Thereby, the majority of genes were upregulated by 5-LO KO. By conducting a ChIP-Seq analysis, we proved an association of 5-LO to DNA. In summary, we demonstrate an additional noncanonical function of 5-LO as a direct transcriptional regulator in MM6 cells that presumably regulates specific genes in dependence on histone acetylation.
2022-07-25 | GSE200336 | GEO
Project description:Human 5-lipoxygenase (5-LO) is the key enzyme of leukotriene biosynthesis, mostly expressed in leukocytes and thus a crucial component of the innate immune system. In this study, we show that 5-LO, beside its canonical function as a metabolizing enzyme, is also a regulator of gene expression in the monocytic cell line Mono Mac 6 (MM6). Using RNA-Seq, we identified 5-LO regulated genes which could be clustered to several biological functions, e.g. immune/defense response, cell adhesion, transcription and growth/developmental processes. Thereby, the majority of genes were upregulated by 5-LO KO. By conducting a ChIP-Seq analysis, we proved an association of 5-LO to DNA. In summary, we demonstrate an additional noncanonical function of 5-LO as a direct transcriptional regulator in MM6 cells that presumably regulates specific genes in dependence on histone acetylation.
2022-07-25 | GSE200329 | GEO
Project description:Human 5-lipoxygenase (5-LO) is the key enzyme of leukotriene biosynthesis, mostly expressed in leukocytes and thus a crucial component of the innate immune system. In this study, we show that 5-LO, beside its canonical function as a metabolizing enzyme, is also a regulator of gene expression in the monocytic cell line Mono Mac 6 (MM6). Using RNA-Seq, we identified 5-LO regulated genes which could be clustered to several biological functions, e.g. immune/defense response, cell adhesion, transcription and growth/developmental processes. Thereby, the majority of genes were upregulated by 5-LO KO. By conducting a ChIP-Seq analysis, we proved an association of 5-LO to DNA. In summary, we demonstrate an additional noncanonical function of 5-LO as a direct transcriptional regulator in MM6 cells that presumably regulates specific genes in dependence on histone acetylation.
2022-07-25 | GSE200332 | GEO
Project description:Impaired detoxification of Acrolein interrupted ocular vascular integrity and kidney structure in akr7a3-/- zebrafish via enhancing Arachidonic acid/leukotriene metabolism
| PRJNA1216901 | ENA
Project description:Leukotriene (LT) D4 contributes to aberrant cytokine networks of classical Hodgkin lymphonoma, This study has investigated LTD4 induced gene expression and pathway in Hodgkin lymphonma cell line L1236.
2015-01-01 | GSE43855 | GEO
Project description:Breast cancer cells facilitate distant metastasis through the induction of immunosuppressive regulatory B cells, designated tBregs. We report here that, to do this, breast cancer cells produce metabolites of the 5-lipoxygenase (5-LO) pathway such as leukotriene B4 (LTB4) to activate the proliferator-activated receptor alpha (PPARalpha) in B cells. Inactivation of LTB4 signaling or genetic deficiency of PPARalpha in B cells blocks the generation of tBregs and thereby abrogates lung metastasis in mice with established breast cancer. Thus, in addition to eliciting fatty acid oxidation and metabolic signals, PPARalpha initiates programs required for differentiation of tBregs. We propose that PPARalpha in B cells or/and tumor 5-LO pathways represents new targets for pharmacological control of tBreg-mediated cancer escape.
2013-03-13 | GSE43278 | GEO