Abstract 16683: Subcellular Changes in NF-κB p50-Dependent iNOS Regulation in Doxorubicin-Induced Cardiomyopathy (DIC)
Bibliographic record
Abstract
A repeat use of doxorubicin (Dox), an anti-cancer drug, can cause heart failure in cancer patients. Dox-induced cardiac mitochondrial as well as ER damage due to oxidative and nitrosative stress (O/NS) has been widely studied. However, mechanism by which Dox exerts iNOS changes via mitochondrial damage and/or ER stress is yet to be elucidated. We investigated whether iNOS induced inflammatory changes in Dox exposed hearts involve mitochondrial and/or endoplasmic reticulum (ER) damage. A cumulative dose of Dox (15mg/kg B.W., ip) was given to Male Wistar rats. We noted an increase in cytC release in the cytoplasm due to O/NS indicating mitochondrial injury. Dox induced linking of chaperone binding immunoglobulin protein (Bip) to activating transcription factor 6 (ATF6) suggested an increased unfolded protein response (UPR) contributing to ER stress which was independent of upstream transcription factors inositol requiring enzyme 1 (IRE1) and protein kinase RNA-like ER kinase (PERK). ATF6-induced ER stress promoted NFκBp105/p50-induced expression of iNOS and NO production in the myocardium. The latter was associated with increased expression of TLR2 and TRAF2 together with NFκB105/50 expression suggesting that ER-stress promoted the inflammatory response in the myocardium. Co-localization of iNOS or TLR2 together with calnexin/grp78 (ER markers) but not with Tom20 (mitochondria marker) suggested that only ER stress promoted inflammatory response. The study suggests that inhibition of Bip binding to ATF6 may modulate ER-stress-mediated inflammation in DIC and presents a novel avenue for a development of the therapeutics for treatment of DIC.
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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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.002 |
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".