Apelin‐13 Attenuates Blood–Brain Barrier Dysfunction Following Intracerebral Hemorrhage via Targeting the Keap1/Nrf2 Signaling
Bibliographic record
Abstract
BACKGROUND: Blood-brain barrier (BBB) dysfunction serves as a critical driver of the secondary brain injury following intracerebral hemorrhage (ICH). Previous research has indicated that Apelin-13 demonstrates the potential to alleviate BBB dysfunction in various cerebrovascular disorders. However, the precise mechanisms through which Apelin-13 preserves BBB integrity remain elusive. This study investigated whether Apelin-13 exerted neuroprotective effects by targeting the Keap1/Nrf2 signaling. METHODS: An in vivo ICH model was established using collagenase. Neurological function, brain edema, tight junction protein levels, and Evans blue leakage were assessed. In vitro, bEnd.3 monolayers were induced by hemin to simulate ICH conditions. To assess the role of Apelin-13 in the Keap1/Nrf2 signaling, we employed specific shRNAs targeting Nrf2 and apelin receptor (APJ). The neuroprotective effects of Apelin-13 in hemin-stimulated bEnd.3 cells were assessed through transendothelial electrical resistance assay, western blotting, and immunofluorescence analysis. RESULTS: Apelin-13 treatment significantly mitigated brain damage, reduced cerebral edema, and promoted neurological recovery in ICH mice. These effects were accompanied by a significant decrease in matrix metalloproteinase-9 expression and an increase in tight junction protein levels. Similar protective effects were observed in hemin-induced bEnd.3 cells, where Apelin-13 additionally promoted Nrf2 expression and suppressed Keap1 expression, suggesting the involvement of the Keap1/Nrf2 signaling. Critically, APJ silencing blocked the effects of Apelin-13 on the Keap1/Nrf2 pathway. Furthermore, Nrf2 knockdown eliminated the protective effects of Apelin-13, reversing its attenuation of apoptosis, preservation of tight junction integrity, and reduction of oxidative stress in hemin-stimulated bEnd.3 cells. CONCLUSIONS: In conclusion, these findings demonstrate that through its engagement with APJ, Apelin-13 activates the endothelial Keap1/Nrf2 pathway to protect against ICH-induced BBB disruption and facilitate neurological recovery, highlighting its therapeutic promise for ICH.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.002 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".