Identification of hub genes and small-molecule compounds related to intracerebral hemorrhage with bioinformatics analysis

Zhendong Liu; Ruotian Zhang; Xin Chen; Penglei Yao; Tao Yan; Wenwu Liu; Jiawei Yao; Andrei Sokhatskii; Ilgiz Gareev; Shiguang Zhao

doi:10.7717/peerj.7782

Identification of hub genes and small-molecule compounds related to intracerebral hemorrhage with bioinformatics analysis

PeerJ. 2019 Oct 25:7:e7782. doi: 10.7717/peerj.7782. eCollection 2019.

Authors

Zhendong Liu^#^{1

2}, Ruotian Zhang^#^{1

2}, Xin Chen^{1

2}, Penglei Yao^{1

2}, Tao Yan^{1

2}, Wenwu Liu^{1

2}, Jiawei Yao^{1

2}, Andrei Sokhatskii³, Ilgiz Gareev³, Shiguang Zhao^{1

2}

Affiliations

¹ The First Affiliated Hospital of Harbin Medical University, Department of Neurosurgery, Harbin, Heilongjiang Province, People's Republic of China.
² Harbin Medical University, Institute of Brain Science, Harbin, Heilongjiang Province, People's Republic of China.
³ Bashkir State Medical University, Ufa, Russia.

^# Contributed equally.

Abstract

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.

Keywords: Compounds; Differentially expressed genes; Gene expression profile; Hub gene; Intracerebral hemorrhage; Stroke.

Grants and funding

This work was supported by the China Postdoctoral Science Foundation (2017M620119); Heilongjiang Postdoctoral Fund (LBH-Z17108) and the Scientific Research Project of Heilongjiang Provincial Department of Health (Nos. 2013030). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.