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Transcriptomic changes upon doxorubicin treatment in hCMEC/D3

ABSTRACT: Current chemotherapy regimens have significantly improved overall survival for children with cancer. However, these curative treatments are associated with detrimental side effects such as chemotherapy-induced cognitive impairment (CICI), or “chemobrain.” Measurable deficits in cognitive function may persist years after chemotherapy treatments, significantly reducing quality of life. Specifically, doxorubicin (DOXO), a commonly used chemotherapeutic agent in curative regimens for children with cancer, plays a pivotal role in the development of CICI, even though it does not cross the blood brain barrier (BBB). We propose to address the poorly understood mechanism of DOXO-related CICI by studying changes induced by DOXO in BBB integrity in vitro, using human cerebral microvascular endothelial cells (hCMEC/D3). Our findings provide critical insights on how DOXO impacts the BBB and builds a foundation for developing preventative measures and therapeutic interventions that may improve the quality of life for patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305805 | GEO | 2025/11/21

REPOSITORIES: GEO

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Project description:Background: Emerging evidence suggests that chronic stress compromises blood‒brain barrier (BBB) integrity by disrupting brain microvascular endothelial cells (BMECs), contributing to the development of cognitive impairments. Thus, targeting the BBB is expected to be a promising treatment strategy. The biological function of rutin has been investigated in neurological disorders; however, its regulatory role in stress-induced BBB damage and cognitive decline and the underlying mechanisms remain elusive. Methods: In a chronic unpredictable mild stress (CUMS) mouse model, a fluorescent dye assay and behavioral tests, including a novel object recognition test and Morris water maze, were performed to evaluate the protective effects of rutin on BBB integrity and cognition. The effects of rutin on BMEC function were also investigated in hCMEC/D3 cells (a human brain microvascular endothelial cell line) in vitro. Furthermore, the molecular mechanisms by which rutin restores BBB endothelium dysfunction were explored via RNA-seq, quantitative real-time PCR, western blotting, immunofluorescence and chromatin immunoprecipitation. Finally, biotinylated tumor necrosis factor-α (TNF-α) was employed to test the influence of rutin on the ability of circulating TNF-α to cross the BBB. Results: We identified that rutin attenuated BBB hyperpermeability and cognitive impairment caused by the 8-week CUMS procedure. Moreover, rutin promoted the proliferation, migration and angiogenesis ability of BMECs through positively regulating the expression of genes involved. Furthermore, rutin impeded histone deacetylase 1 (HDAC1) recruitment and stabilized H3K27ac to increase Claudin-5 protein levels. Ultimately, normalization of the hippocampal HDAC1‒Claudin-5 axis by rutin blocked the infiltration of circulating TNF-α into the brain parenchyma and alleviated neuroinflammation. Conclusions: This work establishes a protective role of rutin in regulating BMEC function and BBB integrity and reveals that rutin is a potential drug candidate for curing chronic stress-induced cognitive deficits.

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Transcriptomic changes upon doxorubicin treatment in hCMEC/D3

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