Amphotericin B potentiates the activation of inducible nitric oxide synthase and causes nitric oxide‐dependent mitochondrial dysfunction in cytokine‐treated rodent astrocytes
Bibliographic record
Abstract
Because the neurotoxic effects of the antifungal drug amphotericin B (AMB) closely resemble those ascribed to the highly reactive gaseous free radical nitric oxide (NO), we investigated the effect of AMB on NO production in rodent astrocytes. AMB caused a dose-dependent increase of NO generation in interferon-gamma (IFN-gamma)-stimulated rat and mouse astrocytes, as well as in IFN-gamma + tumor necrosis factor-alpha (TNF-alpha)-activated rat astrocytoma cell line C6. Treatment of rat astrocytes with AMB markedly potentiated IFN-gamma-triggered expression of mRNA for iNOS, but not for its transcription factor IRF-1. The activation of transcription factor NF-kappaB was apparently required for AMB-induced iNOS mRNA expression, as the latter was abolished by NF-kappaB inhibitors: pyrrolidine dithiocarbamate and MG132. AMB-mediated enhancement of astrocyte NO production was partly dependent on endogenous IL-1, as shown by partial inhibition of AMB effect with IL-1 receptor antagonist. IFN-gamma + AMB treatment led to reduction of astrocyte mitochondrial respiration (measured by MTT assay) that has been completely reverted by selective iNOS inhibitor aminoguanidine. AMB toxicity toward IFN-gamma-stimulated astrocytes was dependent on both AMB and NO action, since AMB and NO-releasing substance SNP synergized in inducing astrocyte mitochondrial dysfunction. These results suggest that the enhancement of cytokine-induced iNOS activation in astrocytes and the subsequent release of high amounts of NO might be at least partly responsible for AMB neurotoxicity.
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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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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) | 0.000 | 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".