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Identification of hub genes and small-molecule compounds related to intracerebral hemorrhage with bioinformatics
Zhendong Liu1,2, Ruotian Zhang1,2, Xin Chen1,2
1The First Affiliated Hospital of Harbin Medical University, Department of Neurosurgery, Harbin, Heilongjiang Province, People's Republic of China.
Insights
This study identified ten hub genes and three small-molecule compounds for treating intracerebral hemorrhage (ICH). These findings offer potential new therapeutic targets for ICH, a condition with complex injury mechanisms and limited treatment options.
Area of Science:
- Genomics and Bioinformatics
- Neuroscience
- Translational Medicine
Background:
- Intracerebral hemorrhage (ICH) presents complex injury mechanisms, with conventional treatments showing limited efficacy in reducing mortality.
- Identifying novel therapeutic targets is crucial for improving patient outcomes in ICH.
Purpose of the Study:
- To identify key hub genes associated with intracerebral hemorrhage (ICH) for potential therapeutic targeting.
- To discover small-molecule compounds with therapeutic potential for treating ICH.
Main Methods:
- Differential gene expression analysis of ICH patient data (GSE24265 dataset).
- Functional annotation (GO) and pathway analysis (KEGG) of differentially expressed genes (DEGs).
- Protein-protein interaction (PPI) network construction to identify hub genes, followed by validation in a rat ICH model and drug screening using CMap.
Main Results:
- Identified 59 upregulated and 8 downregulated DEGs in ICH, primarily involved in inflammatory and immune responses.
- Constructed a PPI network revealing 10 significant hub genes crucial for secondary brain injury in ICH.
- Validated increased expression of these hub genes in a rat ICH model and identified three potential therapeutic small-molecule compounds (Hecogenin, Lidocaine, NU-1025).
Conclusions:
- Ten hub genes, including IL6, TLR2, and CXCL1, are implicated in ICH pathology and validated in a rat model.
- Three small-molecule compounds (Hecogenin, Lidocaine, NU-1025) show therapeutic potential for ICH.
- These findings provide novel targets and therapeutic strategies for managing intracerebral hemorrhage.
Background:
Because of the complex mechanisms of injury, conventional surgical treatment and early blood pressure control does not significantly reduce mortality or improve patient prognosis in cases of intracerebral hemorrhage (ICH). We aimed to identify the hub genes associated with intracerebral hemorrhage, to act as therapeutic targets, and to identify potential small-molecule compounds for treating ICH.
Methods:
The GSE24265 dataset, consisting of data from four perihematomal brain tissues and seven contralateral brain tissues, was downloaded from the Gene Expression Omnibus (GEO) database and screened for differentially expressed genes (DEGs) in ICH, with a fold change (FC) value of (|log2FC|) > 2 and a P-value of <0.05 set as cut-offs. The functional annotation of DEGs was performed using Gene Ontology (GO) resources, and the cell signaling pathway analysis of DEGs was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG), with a P-value of <0.05 set as the cut-off. We constructed a protein-protein interaction (PPI) network to clarify the interrelationships between the different DEGs and to select the hub genes with significant interactions. Next, the DEGs were analyzed using the CMap tool to identify small-molecule compounds with potential therapeutic effects. Finally, we verified the expression levels of the hub genes by RT-qPCR on the rat ICH model.
Result:
A total of 59 up-regulated genes and eight down-regulated genes associated with ICH were identified. The biological functions of DEGs associated with ICH are mainly involved in the inflammatory response, chemokine activity, and immune response. The KEGG analysis identified several pathways significantly associated with ICH, including but not limited to HIF-1, TNF, toll-like receptor, cytokine-cytokine receptor interaction, and chemokine molecules. A PPI network consisting of 57 nodes and 373 edges was constructed using STRING, and 10 hub genes were identified with Cytoscape software. These hub genes are closely related to secondary brain injury induced by ICH. RT-qPCR results showed that the expression of ten hub genes was significantly increased in the rat model of ICH. In addition, a CMap analysis of three small-molecule compounds revealed their therapeutic potential.
Conclusion:
In this study we obtained ten hub genes, such as IL6, TLR2, CXCL1, TIMP1, PLAUR, SERPINE1, SELE, CCL4, CCL20, and CD163, which play an important role in the pathology of ICH. At the same time, the ten hub genes obtained through PPI network analysis were verified in the rat model of ICH. In addition, we obtained three small molecule compounds that will have therapeutic effects on ICH, including Hecogenin, Lidocaine, and NU-1025.
