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TAK1 inhibition mitigates intracerebral hemorrhage-induced brain injury through reduction of oxidative stress and neuronal pyroptosis via the NRF2 signaling pathway.
- Source :
-
Frontiers in immunology [Front Immunol] 2024 May 02; Vol. 15, pp. 1386780. Date of Electronic Publication: 2024 May 02 (Print Publication: 2024). - Publication Year :
- 2024
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Abstract
- Introduction: Intracerebral hemorrhage (ICH) often triggers oxidative stress through reactive oxygen species (ROS). Transforming growth factor-β-activated kinase 1 (TAK1) plays a pivotal role in regulating oxidative stress and inflammation across various diseases. 5Z-7-Oxozeaenol (OZ), a specific inhibitor of TAK1, has exhibited therapeutic effects in various conditions. However, the impact of OZ following ICH and its underlying molecular mechanisms remain elusive. This study aimed to explore the possible role of OZ in ICH and its underlying mechanisms by inhibiting oxidative stress-mediated pyroptosis.<br />Methods: Adult male Sprague-Dawley rats were subjected to an ICH model, followed by treatment with OZ. Neurobehavioral function, blood-brain barrier integrity, neuronal pyroptosis, and oxidative stress markers were assessed using various techniques including behavioral tests, immunofluorescence staining, western blotting, transmission electron microscopy, and biochemical assays.<br />Results: Our study revealed that OZ administration significantly inhibited phosphorylated TAK1 expression post-ICH. Furthermore, TAK1 blockade by OZ attenuated blood-brain barrier (BBB) disruption, neuroinflammation, and oxidative damage while enhancing neurobehavioral function. Mechanistically, OZ administration markedly reduced ROS production and oxidative stress by facilitating nuclear factor-erythroid 2-related factor 2 (NRF2) nuclear translocation. This was accompanied by a subsequent suppression of the NOD-like receptor protein 3 (NLRP3) activation-mediated inflammatory cascade and neuronal pyroptosis.<br />Discussion: Our findings highlight that OZ alleviates brain injury and oxidative stress-mediated pyroptosis via the NRF2 pathway. Inhibition of TAK1 emerges as a promising approach for managing ICH.<br />Competing Interests: The authors declare the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.<br /> (Copyright © 2024 Zhao, Chen, Ge, Jiang, Hu and Yin.)
- Subjects :
- Animals
Male
Rats
Blood-Brain Barrier metabolism
Blood-Brain Barrier drug effects
Brain Injuries etiology
Brain Injuries metabolism
Brain Injuries drug therapy
Disease Models, Animal
Lactones
Rats, Sprague-Dawley
Reactive Oxygen Species metabolism
Resorcinols
Zearalenone administration & dosage
Cerebral Hemorrhage metabolism
Cerebral Hemorrhage drug therapy
MAP Kinase Kinase Kinases metabolism
MAP Kinase Kinase Kinases antagonists & inhibitors
Neurons drug effects
Neurons metabolism
NF-E2-Related Factor 2 metabolism
Oxidative Stress drug effects
Pyroptosis drug effects
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1664-3224
- Volume :
- 15
- Database :
- MEDLINE
- Journal :
- Frontiers in immunology
- Publication Type :
- Academic Journal
- Accession number :
- 38756773
- Full Text :
- https://doi.org/10.3389/fimmu.2024.1386780