Identification of a novel anti-inflammatory compound that acts via the Nrf2 pathway
Bibliographic record
Abstract
Excessive inflammation contributes to tissue injury in numerous acute illnesses including acute respiratory distress syndrome (ARDS) and ischemia-reperfusion after trauma. Although ARDS is commonly initiated by infection with a viral or bacterial pathogen, treatment with antiviral drugs or antibiotics is often insufficient to improve mortality. This has been attributed to excessive endothelial and innate immune cell activation during infection, resulting in excessive recruitment of leukocytes, overproduction of pro-inflammatory cytokines and the development of lung and systemic endothelial leakage and multi-organ dysfunction. This suggests that treating these patients with compounds that moderate the aberrant host response could improve outcomes. It has previously been shown that the human influenza virus can productively infect larval zebrafish, resulting in edema and death. We performed a phenotypic screen of chemical libraries using flu-infected zebrafish and identified a promising compound, Aeroplysinin-1 (Ap). Ap was able to reduce edema and improve survival of influenza-infected zebrafish; it also improved oxygen saturation in mice infected with a lethal dose of influenza. Ap had no antiviral activity, suggesting it acts to improve the host response. Ap was also evaluated in mouse models of bacterial pneumonia and endotoxin-induced lung injury, where it improved oxygen saturation. It also reduced liver damage in a model of ischemia-reperfusion-induced liver injury. In vitro work indicated that Ap reduces endothelial and leukocyte activation. Pathway analysis revealed induction of the Nrf2 antioxidant pathway by Ap. We confirmed that Ap rapidly induced the loss of Keap1, the natural repressor of Nrf2, which increases Nrf2 levels and Nrf2 antioxidant and anti-inflammatory target genes such as HO-1. Knockdown of Keap1 and Nrf2 by siRNA greatly reduced the effects of the drug. Ap was unable to improve oxygen saturation in Nrf2 KO mice and had no effect in leukocytes isolated from Nrf2 KO mice. We created and screened novel derivates of Ap and identified Aeroplysinin-9 (Ap9) a functional derivative of Ap, able to induce the Nrf2 pathway, improve oxygen saturation during bacterial pneumonia, and reduce injury during ischemia reperfusion injury. This compound or its derivatives may be useful for the treatment of a broad range of inflammatory conditions.
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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) | 0.002 | 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".