Blocking S1P4 signaling attenuates brain injury in mice with ischemic stroke
Why this work is in the frame
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Bibliographic record
Abstract
• The FTY720 analog NXC736 is an S1P 4 -selective functional antagonist. • S1P 4 is a novel pathogenic factor of ischemic stroke. • The pathogenic function of S1P 4 is associated with neuroinflammation like microglial activation. • NLRP3 inflammasome activation underlies the S1P 4 -mediated pathogenesis of ischemic stroke. The functions of S1P receptors have been revealed using genetic and pharmacological tools, including the potent non-selective modulator FTY720. However, studies on subtype-specific agonists and antagonists are limited; hence, the role of S1P 4 remains unclear. To identify a novel function of S1P 4 as a pathogenic factor in stroke using a newly developed S1P 4 -selective modulator and S1P 4 knockdown. Heteroaromatic analogs of FTY720 were synthesized, a β-arrestin assay was conducted against S1P receptors, and the developed compound (NXC736) was characterized as a functional S1P 4 antagonist. To clarify the function of S1P 4 , the therapeutic potential of NXC736 in ischemic stroke was determined using a transient middle cerebral artery occlusion (tMCAO) mouse model, which was validated using S1P 4 knockdown. The S1P 4 -dependent pathogenic mechanisms were determined using immunohistochemical and biochemical analyses. Molecular modeling studies provide valuable clues for understanding S1P 4 selectivity of NXC736. NXC736 contains a triazole ring instead of a phenyl ring and exhibits S1P 4 -selective activity as a functional antagonist. Its action on S1P 4 does not require phosphorylation by sphingosine kinase 2. Notably, NXC736 exhibited substantial therapeutic activity against ischemic stroke by attenuating tMCAO-induced acute brain injuries, including brain infarction, neurological deficits, and neuronal apoptosis. This suggested that S1P 4 is a pathogenic factor in ischemic stroke. This function was confirmed using AAV-based S1P 4 knockdown. NXC736 or S1P 4 knockdown attenuated blood–brain barrier disruption, neutrophil infiltration, microglial activation and proliferation, and the upregulation of pro-inflammatory cytokines, thereby demonstrating that S1P 4 influences neuroinflammatory responses in ischemic stroke. The underlying mechanisms were activation of NLRP3 inflammasome, NF-κB, and MAPKs. S1P 4 also contributed to chronic brain injuries caused by ischemic stroke because NXC736 exerted long-term neuroprotective effects against tMCAO challenge. Using a functional S1P 4 antagonist (NXC736) and a genetic tool for S1P 4 knockdown, we identified S1P 4 as a novel pathogenic factor in ischemic stroke.
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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 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 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 it