Protect neurons from ischemia-induced death by targeting BNIP3 gene family
Bibliographic record
Abstract
The BNIP3 family, a group of death-inducing mitochondrial proteins, includes BNIP3, NIX and BNIP3h. These proteins share structural and functional similarities. BNIP3 causes neuronal cell death in a necrosis-like, caspase-independent manner with mitochondrial dysfunction. We reported that BNIP3 plays a role in delayed neuronal death in stroke models. Over-expression of BNIP3 causes up to 70% neuronal death, while knockdown of BNIP3 only protects 23% neurons from hypoxia. Thus, we hypothesize that other members of the BNIP3 subfamily compensate for the loss of BNIP3. BNIP3 and NIX were highly upregulated in the oxygen and glucose deprivation (OGD)/reoxygenation model, and knockdown of BNIP3 or NIX protected about 20% - 44% of neurons. Knockdown of BNIP3 family reduced neuronal death by 48%. Mitochondrial membrane potential loss, mitochondrial permeability transition pore (MPTP) opening and reactive oxygen species (ROS) production were all significantly attenuated by BNIP3 and/or NIX inhibition. AIF and EndoG were reported involving in caspase-independent cell death in ischemic stroke. We found that AIF was released from mitochondria and translocated into nuclei in neurons after OGD/reoxygenation, while inhibition of BNIP3 blocked AIF and EndoG translocation and prevented neuronal death. Over-expression of BNIP3 and NIX caused AIF translocation and subsequent neuronal death. These data reveal the effects of the BNIP3 family in neuronal death and indicate that AIF and EndoG are two downstream factors in the BNIP3-mediated cell death pathway. Meanwhile, necrostatin-1 (Nec-1), an inhibitor for a caspase-independent necrotic cell death, is able to protect neurons from death in stroke, mechanism of which is unclear. Here, we confirmed that Nec-1 significantly increased survival of neurons in models of stroke in vivo and in vitro. It also attenuated hypoxia or BNIP3-induced mitochondrial dysfunction and prevented mitochondrial release of AIF. Nec-1 did not affect the expression levels of BNIP3 but prevented its integration into mitochondria. These results suggest that Nec-1 protects neurons against ischemia by targeting BNIP3. In summary, this research indicates that the BNIP3 family is one of the regulators of caspase-independent neuronal death in stroke and that Nec-1 is an inhibitor for BNIP3 and a potential therapeutic agent for stroke.
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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 | 0.001 |
| 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".