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Activation of Piezo1-mediated mechanotransduction by LOX promotes neuronal ferroptosis leading to HIBD and discovery of LOX inhibitor TA

ABSTRACT: Neonatal hypoxic-ischemic brain damage (HIBD) is initiated by perinatal asphyxia, leading to brain injury triggered by reduced blood and oxygen flow, resulting in neurological impairments such as cerebral palsy, epilepsy, cognitive deficits, and behavioral disorders.Recent insights collectively suggest the important roles of lysyl oxidase (LOX) in the pathological processes of several acute and chronic neurological diseases, but the molecular regulatory mechanisms in HIBD remain elusive.In this study, we found through the study of HIBD rat models and the oxygen-glucose deprivation/re-oxygenation (OGD/R) cell models that LOX significantly increased after HIBD or OGD/R. RNA seq results showed a significant increase in piezo1 after primary neuron OGD/R, and iron death data was also enriched. Moreover, inhibiting LOX or piezo1 can rescue neuronal ferroptosis and further improve cognitive function in rats. In addition, we also found that traumatic acid can inhibit the enzyme activity of LOX and improve a series of pathological features of neuronal damage caused by increased LOX.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE270560 | GEO | 2024/09/25

REPOSITORIES: GEO

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Project description:Abstract Background: Cerebral ischemia-reperfusion (I/R) frequently caused the late-onset neuronal damage. Breviscapine has a promote in autophagy of microvascular endothelial cells in I/R and it can inhibit the oxidative damage and apoptosis. However, the mediation mechanism of breviscapine on neuronal cell death is unclear. Methods: Firstly, transcriptome sequencing was performed on three groups of mice neuronal normal group (Control group), oxygen-glucose deprivation/reoxygenation group (OGD/R group) and breviscapine administration group (Therapy group). Differentially expressed genes (DEGs) between OGD/R and Control groups, and between Therapy and OGD/R groups were obtained by limma package. The N6-methyladenosine (m6A) methylation related DEGs were selected out by the Pearson correlation analysis. Then, prediction and confirmation of drug targets were performed by Swiss Target Prediction and UniProt Knowledgebase (UniProtKB) datebase, and key genes were obtained by Pearson correlation analysis between m6A-related DEGs and drug target genes. Next, gene set enrichment (GSEA) analysis and Ingenuity pathway analysis (IPA) were used to obtain the pathways of key genes. Finally, a circRNA-miRNA-mRNA network was constructed based on the mRNAs, circRNAs and miRNAs. Results: 2250 DEGs between OGD/R and Control groups and 757 DEGs between Therapy and OGD/R groups were selected out by differential analysis. A total of 7 m6A related DEGs including Arl4d, Gm10653, Gm1113, Kcns3, Olfml2a, Stk26 and Tfcp2l1 were obtained by Pearson correlation analysis. Four key genes (Tfcp2l1, Kcns3, Olfml2a and Arl4d) were acquired, and GSEA showed that these key genes were significantly participated in DNA repair, e2f targets and g2m checkpoint. IPA revealed that Tfcp2l1 played a significant role in human embryonic stem cell pluripotency. The circRNA-miRNA-mRNA network showed that the mmu_circ_0001258 regulated the Tfcp2l1 by mmu-miR-301b-3p. Conclusions: In conclusion, four key genes including Tfcp2l1, Kcns3, Olfml2a and Arl4d significantly associated with the treatment of OGD/R by breviscapine were acquired, which would provide a theoretical basis for clinical trials.

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Activation of Piezo1-mediated mechanotransduction by LOX promotes neuronal ferroptosis leading to HIBD and discovery of LOX inhibitor TA

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