Thermotolerance induced by non-lethal heat shock at 40 °C is activated by mitochondrial ROS and is Nrf2-dependent
Bibliographic record
Abstract
Hyperthermia is generally administered as an adjuvant to chemotherapy/radiotherapy and sensitizes tumors to these anticancer treatments. Repeated heat treatments (≥42 °C) cause development of transient thermotolerance, an adaptive survival response. This response can be mediated by upregulation of cellular defense pathways and remains unclear. We aim to clarify the mechanistic explanations behind activation of this response. In vitro, thermotolerance can be induced by mild heat stress at 40 °C and protects cells against subsequent lethal heat shock (≥42 °C). When HeLa cells were heated at 42 °C, cellular and mitochondrial superoxide and peroxide levels increased. Treatment with mitochondrial antioxidant MitoQ, or NADPH oxidase (NOX) inhibitor apocynin, decreased levels of reactive oxygen species (ROS) and apoptotic cell death, indicating that mitochondria and NOX are important sources of ROS at 42 °C. Mild heat stress at 40 °C increased production of ROS, which are thought to activate the adaptive response, and reduce subsequent cell death at 42 °C. Our results show that heat-derived ROS are linked to expression of master antioxidant regulator Nrf2. When Nrf2 was overexpressed or knocked down, Nrf2 expression was directly associated with protective ability of the adaptive response induced by mild heat stress (40 °C). Mitochondrial ROS were found to be essential in mediating Nrf2-dependent thermotolerance, because MitoQ treatment prior to exposure to 40 °C reduced Nrf2 levels and dissipated the subsequent protective effect of thermotolerance against toxicity at 42 °C. Our study demonstrates that specific sources of ROS had biologically different implications in activating Nrf2, underlining potential therapeutic targets that may contribute to thermotolerance in anticancer treatments.
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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 | 0.001 |
| 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) | 0.001 | 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".