Stabilization of hypoxia-inducible factor 1α in neural stem cells with prolyl hydroxylase inhibition induces delayed tolerance against focal cerebral ischemia
Bibliographic record
Abstract
Cytoprotective strategies using pharmacological agents have yielded limited success in the prevention of cerebral ischemic injury. Tolerance to cerebral ischemia can be induced experimentally by a number of physical or pharmacologic strategies. Recent data indicate that Hypoxia-inducible factor 1 (HIF-1) plays major roles in the prevention of myocardial and cerebral ischemia. Inhibitors of HIF-1 prolyl hydroxylases (e.g. Deferroxamine, DFX) stabilize the transcriptional activator HIF-1 and activate target genes involved in compensation for ischemia, such as erythropoietin and VEGF. In this study, we are to investigate whether HIF-1a may be stabilized in human neural stem cells (NSCs) by inhibition of prolyl hydroxylase, and stabilization of HIF-1 in NSCs may induce prolonged ischemic tolerance. DFX (0.4 mM) was added to the cultures of human NSCs (F3), and mRNA or protein levels of HIF-1 were analyzed. In DFX-treated NSCs, protein level of HIF-1 was increased about 100 folds time-dependently, up to 24 hours (0–72 hrs), while mRNA expression was unchanged. Unlike the DFX-treated NSCs, no changes in protein expression were observed in the hypoxia (1% O2)-treated NSCs. Subsequent transcriptional activation (VEGF, Glut-1, CXCR4) of HIF-1a was also observed. To test an ability to induce ischemic tolerance in vivo, DFX-treated NSCs (100,000 cells) and naive NSCs (100,000 cells) were transplanted in the left striatum of adult rats (n=12 respectively). 7 days following the transplantation, 90 minutes-focal cerebral ischemia with reperfusion (MCAO) was performed and rats were sacrificed at 24 hours. Infarct volumes were reduced in both NSCs groups, compared with MCAO-only with PBS injection group (Corrected lesion volume%: DFX-treated NSCs group: 8–12%; naive NSCs group: 18–23%; MCAO-only group: 38–45%; p<0.01) by examining TTC staining, and NeuN- or Map-2ab immunohistochemistry. Striatal infarcts were further reduced in DFX-treated NSCs group. Histologic examination showed less TUNEL-positive cells and less GFAP-positive astrogliosis were found in both NSCs groups, and further decrease in DFX-treated NSCs group (p<0.001). These findings provide evidence that HIF-1 stabilization in human NSCs can be achieved effectively by inhibition of prolyl hydroxylase, and HIF-1-stabilized NSCs may induce delayed ischemic tolerance.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".