Nuclear factor erythroid 2 related Factor-1 is stimulated by the nutraceutical celastrol at proteasome inhibiting doses
Bibliographic record
Abstract
The mechanism by which many nutraceuticals promote health is incompletely understood. Some act by inhibiting the proteasome. Nuclear Factor Erythroid 2 Related Factor 1 (NRF1) is a stress-protective transcription factor that is stimulated by suppressed proteasome activity, such as upon exposure to proteasome inhibitor. Here, we investigated whether nutraceutical compounds with proteasome inhibitory properties stimulate NRF1 to regulate stress-protective genes. Using a luciferase-based promoter reporting the activity of NRF1 and its homolog NRF2 in Hepa 1-6 cells, we performed a small nutraceutical screen and identified that 2 and 4 μM treatment with celastrol exhibited robust stimulatory effect. Using the same reporter in wild type and gene deleted murine embryonic fibroblasts, we found that Nrf1 deficiency reduced celastrol-stimulated luciferase activity. In Hep3B cells, we found that 2 μM celastrol, but not lower concentrations, increased NRF1 processing and nuclear accumulation while also suppressing trypsin-like, chymotrypsin-like, and caspase-like activities of the proteasome, similar to proteasome inhibiting drugs. However, using control and NRF1 deficient Hep3B cells treated with 2 μM celastrol, MG132, bortezomib, or vehicle, we found distinct effects by celastrol versus MG132 and bortezomib on NRF1-dependent regulation of stress-protective genes. Our results show that celastrol can stimulate NRF1 at concentrations that suppress proteasome activity, but its effect on gene regulation is distinct compared to proteasome inhibitor. Overall, our findings reveal that NRF1 may play a role in the health promoting effects of celastrol and possibly other nutraceuticals with proteasome inhibitory properties.
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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 | 0.001 | 0.002 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| 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".