Cardioprotective effects of the flavonoid quercetin against doxorubicin-Induced cardiotoxicity in H9c2 cardiomyoblasts
Bibliographic record
Abstract
Abstract Background Doxorubicin (DOX) is an effective chemotherapy drug to treat diverse cancers such as breast, ovarian, small cell lung, and leukaemia. However, its use is limited by dose-dependent cardiotoxicity, leading to conditions such as cardiac arrhythmias, cardiomyopathy, and congestive heart failure. The precise mechanism of DOX-induced cardiotoxicity is still unclear but oxidative stress is a pivotal mechanism in DOX-induced cardiotoxicity. DOX causes senescence in cardiac tissues, a key driver of aging and damage-associated loss of tissue homeostasis mediated by oxidative stress. Therefore, attenuation of DOX-induced oxidative stress could be a key strategy in alleviating DOX-induced cardiotoxicity. Accumulative evidence suggests antioxidants such as quercetin (a naturally occurring flavonoid abundant in fruits and vegetables) have beneficial effect in the protection of oxidative stress-induced cell death. Purpose The aim of this study is to investigate the putative cardioprotective effects of antioxidants against DOX and hydrogen peroxide-induced H9c2 cell death. Methods H9C2 cells were seeded (5000 cells/well) onto 96-well plates and pre-treated with either quercetin (50μM), melatonin (1μM) or in combination for 24 hours. Thereafter, some cells were treated with DOX (10-400 μM), DMSO (10-40%), or hydrogen peroxide (0.25-1 mM) for 2 hours. In some assays, cells were pre-treated with either ferrostatin (50uM) or necrostatin (100μM) for 24 hours before treatment with DOX (200μM) or hydrogen peroxide (500μM) for 2 hours. Cell viability was assayed using the MTT and alamarBlue assays. Statistical analyses were conducted using a one-way ANOVA with Tukey’s post hoc test and data plotted as mean ± SD. Results Doxorubicin, hydrogen peroxide and DMSO dose-dependently reduced H9c2 cell viability (n=5 separate experiments,10 wells per treatment group) when compared to untreated control cells (p<0.0001). Doxorubicin (200uM), DMSO (20%) and hydrogen peroxide (500uM) treatment (2 hours) resulted in 55+/-7%, 65 +/- 6% and 19+/- 5.6% cell viability, respectively. However, pre-treatment with quercetin (50μM) completely blocked DOX-cardiotoxicity and attenuated hydrogen-peroxide induced death by increasing cell viability from 19% to 58 +/- 6% (p<0.05). Ferrostatin (50 μM) pretreatment also provided a similar profile of inhibition for DOX and hydrogen-peroxide induced cell death. Necrostatin had no effect on drug-induced cell death. Cells pre-treated with quercetin (50μM), ferrostatin (50μM and necrostatin (50μM) had no significant effect on cell viability (p>0.05). Conclusions Simulated oxidative stress (DOX and hydrogen peroxide) induced dose-dependent cell death in h9c2 cells which was attenuated by quercetin and ferrostatin. It is conceivable that a key mechanism of quercetin is via the blockade of ferroptosis an provides a platform as novel natural therapeutics against DOX-induced cardiotoxicity.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| 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 | 0.001 |
| 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".