Multi-dimensional data-driven computational drug repurposing strategy for screening novel neuroprotective agents in ischemic stroke.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:40756350", "kind": "science-record", "revision": 4, "content_hash": "sha256:2688f9b2c1647e36f69a6c3259e1411b572d89ed12146d15e797f748bb5aaa7c", "created_at": "2026-11-01T20:30:51Z", "updated_at": "2026-11-01T22:56:56Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Multi-dimensional data-driven computational drug repurposing strategy for screening novel neuroprotective agents in ischemic stroke.", "doi": "10.7150/thno.112608", "pmid": "40756350", "authors": ["Qingqi Meng", "Qing Liu", "Yan Mi", "Libin Xu", "Feng Wang", "Danyang Mu", "Yueyang Liu", "Yuxin Yang", "Yongye Huang", "Dakuo He", "Yue Hou"], "journal": "Theranostics", "year": 2025, "abstract": "Background: The complexity of biological systems and misconceptions about neuroprotection have hindered the development of neuroprotective drugs for ischemic stroke. This study aims to identify new neuroprotective agents by integrating ischemic stroke transcriptomics with neuronal protection data using a Multidimensional Data-Driven Computational Drug Repositioning strategy (MDCDR). Methods: Three microarray datasets related to ischemic stroke (GSE16561, GSE58294, and GSE22255) were obtained from the GEO dataset and pre - processed to analyze differentially expressed genes (DEGs). The Connectivity Map (CMap) database was used to predict potential drugs. A neuroprotection activity prediction model was constructed by combining six molecular fingerprints with three machine learning algorithms (Random Forest RF, Support Vector Machine SVM, Gradient Boosting Decision Tree GBDT) to screen for potential neuroprotective agents. The efficacy of the screened compounds was evaluated through in vitro experiments on SH-SY5Y cells treated with oxygen-glucose deprivation/reperfusion (OGD/R) and in vivo experiments on middle cerebral artery occlusion/reperfusion (MCAO/R) rat models. Multiple experimental techniques (such as RNA sequencing, DARTS, CETSA, etc.) were used to explore their potential mechanisms of action. Results: The MDCDR strategy screened out 19 potential neuroprotective agents, among which sulbutiamine (SUL) stood out. SUL significantly increased the survival rate, reduced neurological deficit scores, and decreased neuronal loss in MCAO/R rat models, and inhibited cell death in OGD/R - induced cell models. Mechanistic studies revealed that SUL inhibited pyruvate dehydrogenase kinase 2 (PDK2), enhanced mitochondrial function, reduced reactive oxygen species (ROS) levels, thereby suppressing the MAPK signaling pathway and reducing neuronal apoptosis. Silencing PDK2 abolished the protective effect of SUL on OGD/R - treated SH - SY5Y cells. Conclusion: This study successfully developed the MDCDR strategy for screening neuroprotective agents for ischemic stroke. SUL was identified as a promising neuroprotective agent, and PDK2 was a crucial target. This research provides new directions and a theoretical basis for the development of neuroprotective agents against ischemic stroke.", "claims": [{"id": "claim-method", "statement": "The data variance among multiple experimental groups was assessed using one-way analysis of variance (ANOVA) for independent samples or repeated-measures ANOVA for data with repeated measures, depending on the experimental design. For post-hoc testing, Tukey's test was conducted when the data met the assumptions of normality and homogeneity of variances, while Dunnett's T3 test was used if the data violated these assumptions.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40756350", "locator": "sections[31] \"Statistical analysis\" paragraph 2", "quote": "The data variance among multiple experimental groups was assessed using one-way analysis of variance (ANOVA) for independent samples or repeated-measures ANOVA for data with repeated measures, depending on the experimental design. For post-hoc testing, Tukey's test was conducted when the data met the assumptions of normality and homogeneity of variances, while Dunnett's T3 test was used if the data violated these assumptions."}], "state": "complete"}, {"id": "claim-data-access", "statement": "This study obtained three microarray datasets related to IS from the GEO database (https://www.ncbi.nlm.nih.gov/geo/), and loaded these datasets using the GEOquery package in R (version 4.2.0). Specifically, the GSE16561 dataset contains 39 IS samples and 24 normal samples; the GSE58294 dataset contains 69 IS samples and 23 normal samples; the GSE22255 dataset contains 20 IS samples and 20 normal samples 19-21.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40756350", "locator": "sections[4] \"Datasets and pre-processing\" paragraph 2", "quote": "This study obtained three microarray datasets related to IS from the GEO database (https://www.ncbi.nlm.nih.gov/geo/), and loaded these datasets using the GEOquery package in R (version 4.2.0). Specifically, the GSE16561 dataset contains 39 IS samples and 24 normal samples; the GSE58294 dataset contains 69 IS samples and 23 normal samples; the GSE22255 dataset contains 20 IS samples and 20 normal samples 19-21."}], "state": "complete"}, {"id": "claim-target-result", "statement": "The MDCDR strategy screened out 19 potential neuroprotective agents, among which sulbutiamine (SUL) stood out.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:40756350", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "The MDCDR strategy screened out 19 potential neuroprotective agents, among which sulbutiamine (SUL) stood out."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "The MDCDR strategy screened out 19 potential neuroprotective agents, among which sulbutiamine (SUL) stood out.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:40756350"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE16561"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE16561"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:40756350", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.7150/thno.112608", "sha256": "sha256:9e23b3ec2b340322a0b70cd7d48afa0d718957f6d3a5c786dd45f92833b99e12", "bytes": 86135, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.7150/thno.112608", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC12316036", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE16561", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE16561", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE16561", "version": null, "note": "This study obtained three microarray datasets related to IS from the GEO database (https://www.ncbi.nlm.nih.gov/geo/), and loaded these datasets using the GEOquery package in R (version 4.2.0). 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Multiple experimental techniques (such as RNA sequencing, DARTS, CETSA, etc.) were used to explore th", "ective agents by integrating ischemic stroke transcriptomics with neuronal protection data using a Multid", "ted through in vitro and in vivo validation, transcriptome analysis, and mechanistic exploration. Machi"], "order_basis": "paper_text_order:340", "id": "assay:1"}, {"role": "data_generation", "definition_id": "microarray", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["positioning strategy (MDCDR). Methods: Three microarray datasets related to ischemic stroke (GSE1656"], "order_basis": "paper_text_order:489", "id": "assay:2"}, {"role": "data_generation", "definition_id": "cell_culture", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["as evaluated through in vitro experiments on SH-SY5Y cells treated with oxygen-glucose deprivatio", "mic and mechanistic studies in OGD/R exposed SH-SY5Y cells and MCAO/R rats, respectively. The wor", "e literature 23. Cell culture and cell model SH-SY5Y cells were cultivated in DMEM enriched with", "well-established methodology was applied to SH-SY5Y cells. In a nutshell, SH-SY5Y cells were ini"], "order_basis": "paper_text_order:1107", "id": "assay:3"}, {"role": "data_generation", "definition_id": "animal_model", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["-glucose deprivation/reperfusion (OGD/R) and in vivo experiments on middle cerebral artery occlus", "rebral artery occlusion/reperfusion (MCAO/R) rat models. Multiple experimental techniques (su", "cores, and decreased neuronal loss in MCAO/R rat models, and inhibited cell death in OGD/R -", "ompound were elucidated through in vitro and in vivo validation, transcriptome analysis, and mech"], "order_basis": "paper_text_order:1185", "id": "assay:4"}, {"role": "data_generation", "definition_id": "apoptosis_assay", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.69, "evidence": ["MAPK signaling pathway and reducing neuronal apoptosis. Silencing PDK2 abolished the protective eff"], "order_basis": "paper_text_order:1958", "id": "assay:5"}, {"role": "analysis", "definition_id": "group_comparison", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["group_summary", "welch_t", "bootstrap_mean_difference", "group_comparison_anova"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["The data variance among multiple experimental groups was assessed using one-way analysis of variance (ANOVA) for independent samples or repeated-measures ANOVA for data with repeated measures, depending on the experimental design. For post-hoc testing, Tukey's test was conducted when the data met the assumptions of normality and homogeneity of variances, while Dunnett's T3 test was used if the data violated these assumptions."], "order_basis": "consumes_earlier_output", "id": "assay:6"}]}