Bioinformatic Identification of Hub Genes and and TWS-119 As a Potential Agent for the Treatment of Massive Cerebral Infarction

Overview

Journal Front Neurosci

Date 2023 May 26

PMID 37234258

Authors

Ai Guo

Bin Gao

Mengting Zhang

Xiaoyu Shi

Weina Jin

Decai Tian

Affiliations

Soon will be listed here.

Abstract

Background: Massive cerebral infarction (MCI) causes severe neurological deficits, coma and can even result in death. Here, we identified hub genes and pathways after MCI by analyzing microarray data from a murine model of ischemic stroke and identified potential therapeutic agents for the treatment of MCI.

Methods: Microarray expression profiling was performed using the GSE28731 and GSE32529 datasets from the Gene Expression Omnibus (GEO) database. Data from a sham group ( = 6 mice) and a middle cerebral artery occlusion (MCAO) group ( = 7 mice) were extracted to identify common differentially expressed genes (DEGs). After identifying gene interactions, we generated a protein-protein interaction (PPI) network with Cytoscape software. Then, the MCODE plug-in in Cytoscape was used to determine key sub-modules according to MCODE scores. Enrichment analyses were then conducted on DEGs in the key sub-modules to evaluate their biological functions. Furthermore, hub genes were identified by generating the intersections of several algorithms in the cytohubba plug-in; these genes were then verified in other datasets. Finally, we used Connectivity MAP (CMap) to identify potential agents for MCI therapy.

Results: A total of 215 common DEGs were identified and a PPI network was generated with 154 nodes and 947 edges. The most significant key sub-module had 24 nodes and 221 edges. Gene ontology (GO) analysis showed that the DEGs in this sub-module showed enrichment in inflammatory response, extracellular space and cytokine activity in terms of biological process, cellular component and molecular function, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that TNF signaling was the most enriched pathway. and were identified as hub genes and TWS-119 was identified as the most potential therapeutic agent by CMap.

Conclusions: Bioinformatic analysis identified two hub genes ( and ) for ischemic injury. Further analysis identified TWS-119 as the best potential candidate for MCI therapy and that this target may be associated with TLR/MyD88 signaling.

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References

Xu H, Tang Y, Liu D, Ran R, Ander B, Apperson M . Gene expression in peripheral blood differs after cardioembolic compared with large-vessel atherosclerotic stroke: biomarkers for the etiology of ischemic stroke. J Cereb Blood Flow Metab. 2008; 28(7):1320-8. DOI: 10.1038/jcbfm.2008.22. View

Chang E, Weinstock C, Zhang L, Fiero M, Zhao M, Zahalka E . FDA Approval Summary: Tivozanib for Relapsed or Refractory Renal Cell Carcinoma. Clin Cancer Res. 2021; 28(3):441-445. PMC: 8810577. DOI: 10.1158/1078-0432.CCR-21-2334. View

Rahimifard M, Maqbool F, Moeini-Nodeh S, Niaz K, Abdollahi M, Braidy N . Targeting the TLR4 signaling pathway by polyphenols: A novel therapeutic strategy for neuroinflammation. Ageing Res Rev. 2017; 36:11-19. DOI: 10.1016/j.arr.2017.02.004. View

Subramanian A, Narayan R, Corsello S, Peck D, Natoli T, Lu X . A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles. Cell. 2017; 171(6):1437-1452.e17. PMC: 5990023. DOI: 10.1016/j.cell.2017.10.049. View

Szklarczyk D, Morris J, Cook H, Kuhn M, Wyder S, Simonovic M . The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 2016; 45(D1):D362-D368. PMC: 5210637. DOI: 10.1093/nar/gkw937. View

Wang H, Park U, Kim S, Lee J, Kim S, Gwag B . Free radical production in CA1 neurons induces MIP-1alpha expression, microglia recruitment, and delayed neuronal death after transient forebrain ischemia. J Neurosci. 2008; 28(7):1721-7. PMC: 6671544. DOI: 10.1523/JNEUROSCI.4973-07.2008. View

Lamb J, Crawford E, Peck D, Modell J, Blat I, Wrobel M . The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science. 2006; 313(5795):1929-35. DOI: 10.1126/science.1132939. View

Jickling G, Xu H, Stamova B, Ander B, Zhan X, Tian Y . Signatures of cardioembolic and large-vessel ischemic stroke. Ann Neurol. 2010; 68(5):681-92. PMC: 2967466. DOI: 10.1002/ana.22187. View

Deng Y, He W, Cai H, Jiang J, Yang Y, Dan Y . Analysis and Validation of Hub Genes in Blood Monocytes of Postmenopausal Osteoporosis Patients. Front Endocrinol (Lausanne). 2022; 12:815245. PMC: 8792966. DOI: 10.3389/fendo.2021.815245. View

10.

Schaller T, Batich K, Suryadevara C, Desai R, Sampson J . Chemokines as adjuvants for immunotherapy: implications for immune activation with CCL3. Expert Rev Clin Immunol. 2017; 13(11):1049-1060. PMC: 6020048. DOI: 10.1080/1744666X.2017.1384313. View

11.

Kostulas N, Pelidou S, Kivisakk P, Kostulas V, Link H . Increased IL-1beta, IL-8, and IL-17 mRNA expression in blood mononuclear cells observed in a prospective ischemic stroke study. Stroke. 1999; 30(10):2174-9. DOI: 10.1161/01.str.30.10.2174. View

12.

Lee J, Wei Z, Cao W, Won S, Gu X, Winter M . Regulation of therapeutic hypothermia on inflammatory cytokines, microglia polarization, migration and functional recovery after ischemic stroke in mice. Neurobiol Dis. 2016; 96():248-260. PMC: 5161414. DOI: 10.1016/j.nbd.2016.09.013. View

13.

Zong P, Feng J, Yue Z, Li Y, Wu G, Sun B . Functional coupling of TRPM2 and extrasynaptic NMDARs exacerbates excitotoxicity in ischemic brain injury. Neuron. 2022; 110(12):1944-1958.e8. PMC: 9233078. DOI: 10.1016/j.neuron.2022.03.021. View

14.

Pillai D, Dittmar M, Baldaranov D, Heidemann R, Henning E, Schuierer G . Cerebral ischemia-reperfusion injury in rats--a 3 T MRI study on biphasic blood-brain barrier opening and the dynamics of edema formation. J Cereb Blood Flow Metab. 2009; 29(11):1846-55. PMC: 2848453. DOI: 10.1038/jcbfm.2009.106. View

15.

Kolosowska N, Gotkiewicz M, Dhungana H, Giudice L, Giugno R, Box D . Intracerebral overexpression of miR-669c is protective in mouse ischemic stroke model by targeting MyD88 and inducing alternative microglial/macrophage activation. J Neuroinflammation. 2020; 17(1):194. PMC: 7304130. DOI: 10.1186/s12974-020-01870-w. View

16.

Takami S, Minami M, Nagata I, Namura S, Satoh M . Chemokine receptor antagonist peptide, viral MIP-II, protects the brain against focal cerebral ischemia in mice. J Cereb Blood Flow Metab. 2001; 21(12):1430-5. DOI: 10.1097/00004647-200112000-00007. View

17.

Yan H, Zheng G, Qu J, Liu Y, Huang X, Zhang E . Identification of key candidate genes and pathways in multiple myeloma by integrated bioinformatics analysis. J Cell Physiol. 2019; 234(12):23785-23797. PMC: 6771956. DOI: 10.1002/jcp.28947. View

18.

Babcock A, Toft-Hansen H, Owens T . Signaling through MyD88 regulates leukocyte recruitment after brain injury. J Immunol. 2008; 181(9):6481-90. DOI: 10.4049/jimmunol.181.9.6481. View

19.

Zhang Y, Liu G, Wang Y, Su Y, Leak R, Cao G . Procalcitonin as a Biomarker for Malignant Cerebral Edema in Massive Cerebral Infarction. Sci Rep. 2018; 8(1):993. PMC: 5772664. DOI: 10.1038/s41598-018-19267-4. View

20.

Putnam N, Fulbright L, Curry J, Ford C, Petronglo J, Hendrix A . MyD88 and IL-1R signaling drive antibacterial immunity and osteoclast-driven bone loss during Staphylococcus aureus osteomyelitis. PLoS Pathog. 2019; 15(4):e1007744. PMC: 6481883. DOI: 10.1371/journal.ppat.1007744. View