Abstract
Perinatal hypoxia is a common risk factor for CNS development. Using bioinformatics databases, a list of 129 genes involved in perinatal hypoxia was selected from the literature and analyzed with respect to proteins important for biological processes influencing the brain development. Functional enrichment analysis using the DAVID database was performed to identify relevant Gene Ontology (GO) biological processes like response to hypoxia, inflammatory response, positive and negative regulation of apoptosis, and positive and negative regulation of cell proliferation. The selected GO processes contain 17–30 proteins and show an enrichment of 6.3–14.3-fold. The STRING protein-protein interaction network and the Cytoscape data analyzer were used to identify interacting proteins playing a significant role in these processes. The two top protein pairs referring to the proteins with highest degrees and the corresponding proteins connected by high score edges exert opposite or regulatory functions and are essential for the balance between damaging, repairing, protective, or epigenetic processes. The GO response to hypoxia is characterized by the high score protein–protein interaction pairs CASP3/FAS promoting apoptosis and by the protective acting BDNF/MECP2 protein pair. Core components of the GO processes positive and negative regulation of apoptosis are the proteins CASP3/FAS/AKT/eNOS/RPS6KB1 involved in several signal pathways. The GO processes cell proliferation are characterized by the high-score protein–protein interaction pairs MYC/ MAPK1, JUN/MAPK1, IL6/IL1B, and JUN/HDAC1. The study provides new insights into the pathophysiology of perinatal hypoxia and is of importance for future investigations, diagnostics, and therapy of perinatal hypoxia.
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Data Availability
The source for the data used is given in the Reference section.
Abbreviations
- ADHD:
-
Attention deficit hyperactivity disorder
- AKT:
-
Serine/threonine-protein kinase
- AP-1:
-
Activator protein-1
- ATG7:
-
Ubiquitin-like modifier-activating enzyme
- BAD :
-
Bcl2-associated agonist of cell death
- BAX :
-
Apoptosis regulator BAX
- CASP1:
-
Caspase-1
- BCL2:
-
B-cell lymphoma 2, an apoptosis regulator
- BDNF :
-
Brain-derived nerve factor
- bFGF-2:
-
Basic fibroblast growth factor
- BNIP31:
-
BCL2/adenovirus E1B interacting protein 3-like
- BNIP3:
-
BCL2-interacting protein 3
- CASP3:
-
Caspase 3
- CNS:
-
Central nervous system
- DNMT:
-
DNA methyltransferase
- DIM:
-
3,3′-Diindolylmethane
- ERBB4:
-
Receptor tyrosine-protein kinase erbB-4
- ERK:
-
Extracellular signal-regulated kinase
- FAS:
-
Tumor necrosis factor receptor superfamily member 6
- GO:
-
Gene Ontology
- GPCR:
-
G protein-coupled receptor
- GPX1:
-
Glutathione peroxidase 1
- GRIN1:
-
Glutamate receptor ionotropic, NMDA 1
- GRIN2A:
-
Glutamate receptor ionotropic, NMDA 2A
- HIF-1:
-
Hypoxia-inducible factor-1
- HDAC1:
-
Histone deacetylase 1
- HMOX1:
-
Heme oxygenase 1
- HRK:
-
Activator of apoptosis harakiri
- IL1B:
-
Interleukin 1beta
- IL6:
-
Interleukin-6
- IL18:
-
Interleukin-18
- JNK:
-
c-Jun N-terminal kinase
- JIP1:
-
JNK interacting protein 1
- JUN:
-
c-JUN, proto-oncogene
- LEPR:
-
Leptin receptor
- MAPK1 Mitogen:
-
Activated protein kinase 1 (alias ERK2)
- MECP2:
-
Methyl CpG binding protein 2
- MYC:
-
c-MYC, proto-oncogene protein
- mTORC1:
-
Mammalian target of rapamycin complex1
- NFKB1:
-
Nuclear factor NF-kappa-B p105 subunit
- NQO1:
-
NAD(P)H dehydrogenase [quinone] 1
- NGFR:
-
Tumor necrosis factor receptor superfamily member 16
- NO:
-
Nitric oxide
- NOS3:
-
Nitric oxide synthase 3
- PARP-1:
-
Poly (ADP-ribose) polymerase 1
- PI3K:
-
Phosphatidylinositol ‑ 3 kinase
- PMAIP1:
-
Phorbol-12-myristate-13-acetate-induced protein 1
- PPI:
-
Protein-protein interaction network
- PRKDC:
-
DNA-dependent protein kinase catalytic subunit
- PRDX3:
-
Thioredoxin-dependent peroxide reductase, mitochondrial
- PSEN1:
-
Presenilin-1
- PSEN2:
-
Presenilin-2
- RELA:
-
Nuclear factor kappaB subunit p65
- ROS:
-
Reactive oxygen species
- RPS6KB1:
-
Ribosomal protein S6 kinase beta-1 (alias S6K1)
- RPS6:
-
Ribosomal protein S6
- RTK:
-
Receptor tyrosine kinase
- SLC2A4:
-
Glucose transporter (GLUT4)
- SOX4:
-
Transcription factor SOX-4
- TNF:
-
Tumor necrosis factor
- TNFSF6:
-
Tumor necrosis factor ligand superfamily member 6
- VEGFA:
-
Vascular endothelial growth factor A
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Gross, J., Herrera-Marschitz, M. Potential Key Proteins, Molecular Networks, and Pathways in Perinatal Hypoxia. Neurotox Res 41, 571–588 (2023). https://doi.org/10.1007/s12640-023-00663-2
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DOI: https://doi.org/10.1007/s12640-023-00663-2