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| Content Provider | Springer Nature : BioMed Central |
|---|---|
| Author | Luo, Lvyin Ma, Xinlong Kong, Debin Dai, Yuxiang Li, Tao Yu, Han Liu, Jingzheng Li, Maogui Xu, Yangyang Xiang, Guo Zhao, Zhimin Zhong, Weiying Wang, Donghai Wang, Yunyan |
| Abstract | Background Intracranial aneurysm (IA) is a severe cerebrovascular disease, and effective gene therapy and drug interventions for its treatment are still lacking. Oxidative stress (OS) is closely associated with the IA, but the key regulatory genes involved are still unclear. Through multiomics analysis and experimental validation, we identified two diagnostic markers for IA associated with OS. Methods In this study, we first analyzed the IA dataset GSE75436 and conducted a joint analysis of oxidative stress-related genes (ORGs). Differential analysis, functional enrichment analysis, immune infiltration, WGCNA, PPI, LASSO, and other methods were used to identify IA diagnostic markers related to OS. Next, the functions of TLR4 and ALOX5 expression in IA and their potential targeted therapeutic drugs were analyzed. We also performed single-cell sequencing of patient IA and control (superficial temporal artery, STA) tissues. 23,342 cells were captured from 2 IA and 3 STA samples obtained from our center. Cell clustering and annotation were conducted using R software to observe the distribution of TLR4 and ALOX5 expression in IAs. Finally, the expression of TLR4 and ALOX5 were validated in IA patients and in an elastase-induced mouse IA model using experiments such as WB and immunofluorescence. Results Through bioinformatics analysis, we identified 16 key ORGs associated with IA pathogenesis. Further screening revealed that ALOX5 and TLR4 were highly expressed to activate a series of inflammatory responses and reduce the production of myocytes. Methotrexate (MTX) may be a potential targeted drug. Single-cell analysis revealed a notable increase in immune cells in the IA group, with ALOX5 and TLR4 primarily localized to monocytes/macrophages. Validation through patient samples and mouse models confirmed high expression of ALOX5 and TLR4 in IAs. Conclusions Bioinformatics analysis indicated that ALOX5 and TLR4 are the most significant ORGs associated with the pathogenesis of IA. Single-cell sequencing and experiments revealed that the high expression of ALOX5 and TLR4 are closely related to IA. These two genes are promising new targets for IA therapy. |
| Related Links | https://jneuroinflammation.biomedcentral.com/counter/pdf/10.1186/s12974-024-03226-0.pdf |
| Ending Page | 14 |
| Page Count | 14 |
| Starting Page | 1 |
| File Format | HTM / HTML |
| ISSN | 17422094 |
| DOI | 10.1186/s12974-024-03226-0 |
| Journal | Journal of Neuroinflammation |
| Issue Number | 1 |
| Volume Number | 21 |
| Language | English |
| Publisher | BioMed Central |
| Publisher Date | 2024-09-15 |
| Access Restriction | Open |
| Subject Keyword | Neurosciences Neurology Neurobiology Immunology Intracranial aneurysm Oxidative stress Bioinformatics analysis Single-cell sequencing Mouse IA model |
| Content Type | Text |
| Resource Type | Article |
| Subject | Neuroscience Immunology Cellular and Molecular Neuroscience Neurology |
| Journal Impact Factor | 9.3/2023 |
| 5-Year Journal Impact Factor | 9.8/2023 |
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