Rapamycin and FK506 derivative TH2849 could ameliorate neurodegenerative diseases through autophagy with low immunosuppressive effect
Bibliographic record
Abstract
Summary Autophagy is an essential cellular process concern with cellular homeostasis down‐regulated by mTOR, whose activity can be modulated by rapamycin, a kind of lipophilic macrolide antibiotic, through forming a complex with immunophilin FKBP12 essential for mTOR regulation to induce autophagy. Therefore, rapamycin is normally used as a neuron protective agent. The immunophilin FKBP12 binding ligand FK506 is well known as an immunosuppressive agent by inhibiting the calcineurin expression. In this study, we synthesized a series of modified compounds based on the FKBP12 binding moiety to as same as the binding structure of rapamycin and FK506 particularly. We removed the other binding regions of the complex that has the property of immunosuppression. We found that a novel small molecule named TH2849 from these derivative compounds has a significant binding connection with mTOR by comparing to calcineurin. The effects of TH2849 on calcineurin/NFAT were not as significant as FK506, and weak effects on IL2/p34 cdc2 /cyclin signaling pathway were also found. Moreover, TH2849 also shows mitochondrial protective effect through stabilizing the mitochondrial structure and transmembrane potential (ΔΨm) and could rescue dopaminergic neurons in MPTP‐treated zebrafishes as well as mice models with less immunosuppressive effect. Our present study shows that TH2849 works as a neuroprotective agent possibly by inducing autophagy and low immunosuppressive effect.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 |
| 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".