Biomimetic nanoparticles and resveratrol as therapeutic interventions in ischemic stroke
Bibliographic record
Abstract
Ischemic stroke is a leading killer worldwide and the primary cause of disability in Canada caused by vessel occlusion from clots. Recombinant tissue plasminogen activator (rtPA) thrombolysis remains the only available effective treatment option and is limited by a short half-life of 4.5 minutes. With a therapeutic time window post-stroke of only 3 hours and its several contraindications, rtPA is limited to a select subpopulation of stroke patients. We investigated a novel nanocarrier fabricated from platelet membranes which were reassembled into monodisperse biomimetic nanoparticles (called cellsomes) loaded with rtPA as a potential treatment alternative. Leveraging the inherent interaction between platelet membrane proteins with clots causing ischemic stroke, we expect to increase rtPA localisation to the occlusion site. The inclusion of rtPA as cargo within the cellsome may protect rtPA from being degraded by plasminogen activator inhibitor 1, improving the therapeutic time window and increasing the ratio of patients achieving reperfusion and improved functional outcomes. Pursuant to stroke, a multiplicity of molecular pathways and cellular reactions are engaged to help protect the brain from damage but can lead to further damage themselves through a vicious pro-inflammatory cycle. In response to stress, cells release damage-associated molecular patterns including High-Mobility Group Box 1 (HMGB1) and Heat Shock protein 70 kDa family (HSP72). HMGB1 can activate pro-inflammatory cytokine production when it is acetylated (AcHMGB1). AcHMGB1 is mainly localised in the cytosol. This study shows HMGB1 and HSP72 modulation following treatment with rtPA-cellsomes and an anti-inflammatory agent (resveratrol) in a stroke model in vitro. We demonstrate that rtPA-cellsomes are not cytotoxic within clinically relevant concentrations and that they retain the thrombolytic activity of free-rtPA, without exerting a hemolytic effect. Under an oxygen-glucose deprivation (OGD) in vitro model of stroke, nuclear abundance of HMGB1 and AcHMGB1 in human microglia and macrophages decreased, whereas treatment with rtPA-cellsomes did not alter nuclear nor cytosolic abundance. Treatment with resveratrol increased HSP72 cytosolic abundance in microglia. Using a proximity ligation assay, HSP72 interacted with HMGB1 and with AcHMGB1, but to different extents. Treatment with resveratrol under OGD conditions further decreased HSP72-HMGB1 interactions. In contrast, resveratrol increased HSP72-AcHMGB1 interactions in microglia, normalising their state similar to controls. This study lends credence to the use of a novel platelet membrane-derived biomimetic nanocarrier as a platform for the effective delivery of rtPA. These findings also point out a salient molecular interaction suited for a two-pronged nanotherapeutic intervention in stroke by enhancing rtPA delivery and by normalising interactions between HMGB1 and HSP72 with resveratrol. Collectively, results from this study suggest that combination therapy using cellsomes and neuroprotective agents merits further investigations in vivo
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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 | 0.001 | 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".