Equine estrogens differentially inhibit DNA fragmentation induced by glutamate in neuronal cells by modulation of regulatory proteins involved in programmed cell death
Why this work is in the frame
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Bibliographic record
Abstract
BACKGROUND: Recent data indicate that excitotoxicity of high levels of neurotransmitter glutamate may be mediated via programmed cell death (apoptosis) and that it can be prevented in HT22 mouse hippocampal cells by various equine estrogens with Delta8,17beta-estradiol (Delta8,17beta-E2) being the most potent. In order to delineate the mechanism(s), glutamate-induced cell death of HT22 cells was assessed by measuring (a) DNA fragmentation in the presence or absence of 11 equine estrogens (components of the drug CEE); (b) cell death and (c) levels of anti-apoptotic (Bcl-2) and proapoptotic (Bax) proteins in the presence or absence of two equine estrogens, Delta8,17beta-E2 and 17beta-estradiol (17beta-E2) by LDH release assay and Western blot analysis respectively. RESULTS: Glutamate treatment induced cell death was time and dose-dependent. After 18 to 24 h, glutamate induced DNA fragmentation and morphological characteristics of apoptotic cell death. DNA fragmentation and morphological changes induced by 10 mM glutamate were completely inhibited by some equine estrogens. Exposure of cells to various concentrations of glutamate, resulted in a significant increase in cell death associated LDH release that was time-dependent. Both Delta8,17beta-E2 and 17beta-E2 inhibited the glutamate-induced LDH release and cell death in a dose-dependent manner with Delta8,17beta-E2 being 10 times more potent than 17beta-E2. Western blot analysis indicated that glutamate also significantly decreased the levels of Bcl-2 and increased Bax levels. This glutamate-induced change in the ratio of Bcl-2 to Bax was reversed by estrogens with Delta8,17beta-E2 being more potent. CONCLUSIONS: In HT22 mouse hippocampal cells, glutamate induced apoptosis that was associated with DNA fragmentation, morphological changes and up-regulation of the pro-apoptotic protein Bax and down-regulation of the anti-apoptotic protein Bcl-2. This apoptotic process was differentially prevented by some equine estrogens with Delta8,17beta-E2 being more potent than 17beta-E2. Since HT22 cells lacked both glutamate and estrogen receptors, the neuroprotective effects of estrogens most likely involve both genomic and non-genomic mechanisms. Since Delta8-estrogens are less feminizing estrogens than 17beta-E2, further chemical modifications of these Delta8-estrogens may provide more selective estrogens that will be useful in the prevention of neurodegenerative diseases such as Alzheimer's and Parkinson's in both aging men and women.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| 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 | 0.000 |
| 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 it