As an important protective mechanism against cerebral ischemia, angiogenesis has become a topic of interest in the treatment of ischemic stroke with the challenge that few drugs promote angiogenesis. Previous studies of the identification of drug–target interactions mainly focused on the overall structures of drugs and proteins, which limited the discovery of novel structure drugs. In this article, we proposed a new strategy for discovering proangiogenic drugs based on the assumption that drug–protein interaction is mediated by substructure and domain. First, we identified substructure–domain relationships according to the known drug–protein interactions and established the drug–substructure–domain–protein relationships of genes that are proangiogenic in brain tissue and expressed significantly during ischemic stroke. Then we quantified the intensity of interaction between each drug and each protein. Finally, we obtained 540 interactive relationships between 238 drugs and 54 genes, establishing a drug–gene network with two patterns of independent and complex drug–gene interactions. Both of the patterns facilitated finding not only drugs with the same overall structure but also drugs with a different overall structure based on the same or a similar protein spectrum. In addition, we analyzed the mechanism of action of each predicted drug and extracted drugs with similar mechanisms. In vitro, our results showed that azelnidipine, azilsartan, lercanidipine, nafcillin, and vortioxetine enhanced bEnd.3 cell proliferation, migration, tube formation, and the expression of angiogenic marker PCNA. Azelnidipine, azilsartan, lercanidipine, and nafcillin increased the level of expression of proangiogenic factor VEGF. Unlike previous studies focusing on the overall structures of drugs, our research highlighted local structural similarity, which has great potential in the search for more proangiogenic drugs with novel structures.
Huanqi Zhang,Ziyan Liu,Jing Cheng,Yiming Jiang,Xiaoli Zheng,Chong Zhang,Yangling Li
Glioblastoma (GBM), the most aggressive primary brain tumor, presents significant therapeutic challenges owing to limited treatment options beyond the cornerstone chemotherapy temozolomide (TMZ) and its intrinsic chemoresistance. This study elucidates additional mechanisms of the multimodal antidepressant vortioxetine in GBM, extending beyond the reported PI3K/Akt pathway modulation. RNA-sequencing analysis identified five potential vortioxetine-responsive targets in GBM cells: SCN5A , HTR1D , SLC6A9 , KIF11 , and ADRB2 . Notably, only HTR1D overexpression correlated with poor disease-free survival in GBM patients. Vortioxetine-mediated HTR1D suppression suggests its potential role as an HTR1D inhibitor in GBM progression. HTR1D-overexpressing GBM cells exhibited enhanced proliferative and migratory capacities. LinkedOmics database analysis revealed the HTR1D regulation on PI3K/Akt axis, a dominant signaling pathway showing significant positive correlation with TMZ resistance. Crucially, HTR1D knockdown enhanced TMZ sensitivity in GBM cells. Moreover, the TMZ-vortioxetine combination demonstrated marked synergistic anti-tumor effects concomitant with HTR1D suppression. In vivo , the TMZ-vortioxetine combination more effectively suppressed GBM proliferation than either agent alone. Collectively, these findings identify HTR1D as a novel vortioxetine target in GBM that modulates proliferation, metastasis, and TMZ resistance via PI3K/Akt signaling. This study provides convincing preclinical evidence for TMZ-vortioxetine combination therapy, proposing both a new therapeutic target and a viable strategy to circumvent TMZ resistance in GBM.
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