Cross-domain binding of anti-fibrillation peptide TNGQ to islet amyloid polypeptide provides cytoprotective effects in giant unilamellar vesicles and pancreatic β-cells
Bibliographic record
Abstract
Islet amyloid polypeptide (IAPP) fibrillation induces β-cell dysfunction and toxicity in patients with type 2 diabetes. Cytotoxicity is caused by the ability of IAPP fibrils and fibrillar intermediates to permeate the cellular membrane of pancreatic β-cells, trigger endoplasmic reticular stress, induce reactive oxygen species production, and upregulate apoptosis-related genes. Thus, inhibition of IAPP fibrillation is of great interest for preventing associated cytotoxicity. In this study, the cellular protective effects of three anti-fibrillation tetrapeptides, YMSV, MANT, and TNGQ, against IAPP fibrillation-induced membrane leakage in giant unilamellar vesicles (GUVs) and toxicity in RIN-m cells were evaluated. The anti-fibrillation activity of TNGQ translated to cytoprotective effects as it resulted in a 69.0 ± 7.9% decrease in calcein release in GUVs and a significant increase in cell viability from 6.4 ± 6.4% with IAPP to 47.5 ± 3.8% with the addition of TNGQ. MANT slightly inhibited IAPP-induced GUV leakage and increased cell viability. In contrast, the protective effect of YMSV against IAPP fibrillation-induced membrane damage in GUVs was completely diminished in β-cells. Molecular docking of pentameric IAPP showed that Asn21 and Asn22 of IAPP are important for inhibitor binding, which, coupled with the cross-domain binding interactions of TNGQ, explains its stronger anti-fibrillation and cytoprotective effects than MANT and YMSV. These findings provide insights into the functional significance of peptide-IAPP binding interactions in mitigating fibrillation and IAPP fibrillation-induced cytotoxicity.
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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 | 0.000 | 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) | 0.000 | 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".