ArticleFrontiers in immunology2025
Bioinformatics-driven insights: rapamycin-mediated CaMK2D inhibition alleviates intestinal ischemia-reperfusion injury.
Article in Frontiers in immunology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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6 citing papers in PubMed.
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- Pharmacogenomics in oncology: mutation-targeted therapy and biomarker integration in non-small cell lung cancer.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Repurposing metformin for choriocarcinoma: targeting the AMPK/mTOR pathway.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
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- Glial fibrillary acidic protein (GFAP) in biofluids: analytical considerations and clinical relevance in neurodegenerative diseases.Journal of neurology · 2026Review
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Abstract
Introduction: Intestinal ischemia-reperfusion (I/R) injury, a common and severe clinical condition with high morbidity and mortality, burdens healthcare systems. Our previous investigations established that a nano-delivery system enabled targeted rapamycin delivery to intestinal I/R injury sites with therapeutic efficacy. While calcium/calmodulin-dependent protein kinase IIδ (CaMK2D) has been implicated in myocardial injury and tumorigenesis, its role in intestinal I/R pathophysiology remains unexplored. This study investigates the therapeutic mechanisms of rapamycin in intestinal I/R injury by modulation of CaMK2D signaling. Methods: An oxygen-glucose deprivation/reperfusion (OGD/R) model in Caco-2 human colorectal cancer cells and a murine intestinal I/R model were established. Small interfering RNA (siRNA) and hesperadin (HES) were used to inhibit CaMK2D expression. Transcriptomic profiling was performed via RNA sequencing (RNA-Seq) with subsequent bioinformatic analysis including differential gene expression, MCODE-based protein interaction network clustering, and RAPA-CaMK2D molecular docking studies. Cellular assays included qRT - PCR, western blotting (WB), Fluo-3 calcium flux analysis, flow cytometry, and Enzyme-linked immunosorbent assay (ELISA). In animal experiments, HE staining, immunohistochemistry, TUNEL assay, WB, and ELISA were employed. Results: Both cellular and murine models demonstrated a significant upregulation of CaMK2D phosphorylation with intestinal epithelial apoptosis, barrier dysfunction, and enhanced inflammatory response during I/R. CaMK2D knockdown using siRNA attenuated these pathological manifestations, vice versa. Bioinformatic analysis revealed a CaMK2D-dominated regulatory module (ranked fifth) enriched in calcium-mediated signaling pathways. Mechanistically, I/R induced CaMK2D activation exacerbated inflammatory cascades, epithelial apoptosis, and tight junction disruption. Rapamycin treatment (1.5 mg/kg, i.p.) ameliorated these effects by decreasing CaMK2D expression and phosphorylation (WB, Discussion: Our findings establish CaMK2D hyperactivation as a key to intestinal I/R injury. The therapeutic potential of rapamycin derived from its ability to suppress CaMK2D signaling axis, providing a novel pharmacological strategy for intestinal I/R management.
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