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Oxidative Stress in Hypoxic-Ischemic Encephalopathy: Molecular Mechanisms and Therapeutic Strategies.

ABSTRACT: Hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of morbidity and mortality in neonates. Because of high concentrations of sensitive immature cells, metal-catalyzed free radicals, non-saturated fatty acids, and low concentrations of antioxidant enzymes, the brain requires high levels of oxygen supply and is, thus, extremely sensitive to hypoxia. Strong evidence indicates that oxidative stress plays an important role in pathogenesis and progression. Following hypoxia and ischemia, reactive oxygen species (ROS) production rapidly increases and overwhelms antioxidant defenses. A large excess of ROS will directly modify or degenerate cellular macromolecules, such as membranes, proteins, lipids, and DNA, and lead to a cascading inflammatory response, and protease secretion. These derivatives are involved in a complex interplay of multiple pathways (e.g., inflammation, apoptosis, autophagy, and necrosis) which finally lead to brain injury. In this review, we highlight the molecular mechanism for oxidative stress in HIE, summarize current research on therapeutic strategies utilized in combating oxidative stress, and try to explore novel potential clinical approaches.

SUBMITTER: Zhao M

PROVIDER: S-EPMC5187878 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Oxidative Stress in Hypoxic-Ischemic Encephalopathy: Molecular Mechanisms and Therapeutic Strategies.

Zhao Mingyi M Zhu Ping P Fujino Masayuki M Zhuang Jian J Guo Huiming H Sheikh IdrisAhmed I Zhao Lingling L Li Xiao-Kang XK

International journal of molecular sciences 20161210 12

Hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of morbidity and mortality in neonates. Because of high concentrations of sensitive immature cells, metal-catalyzed free radicals, non-saturated fatty acids, and low concentrations of antioxidant enzymes, the brain requires high levels of oxygen supply and is, thus, extremely sensitive to hypoxia. Strong evidence indicates that oxidative stress plays an important role in pathogenesis and progression. Following hypoxia and ischemi ...[more]

PMID: 27973415

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Project description:BackgroundNeonatal hypoxic-ischemic brain damage (HIBD) is a clinical syndrome causing brain injury in newborns with obscure etiology. Increasing evidence suggests that ferroptosis plays a role in HIBD. This study aimed to clarify the key ferroptosis-related genes (FRGs) of HIBD, construct a long non-coding RNA-microRNA-messenger RNA (lncRNA-miRNA-mRNA) network, and further investigate the pathogenesis of HIBD.MethodsGene expression data were downloaded from the Gene Expression Omnibus and FerrDb databases. The differentially expressed lncRNAs and FRGs were screened, and the related miRNAs and mRNAs were predicted. The obtained mRNA was intersected with the differentially expressed FRGs (DE-FRGs) to identify the key DE-FRGs. Cell-type Identification by Estimating Relative Subsets of RNA Transcripts method was applied to analyze the immune cell infiltration level and the relationship between key genes and immune cells.ResultsGene differential expression analysis revealed that 1,178 lncRNAs, 207 miRNAs, and 647 mRNAs were differentially expressed in the blood of HIBD patients in comparison to healthy controls. The correlations of the lncRNAs, miRNAs, and mRNAs lead to the establishment of a competing endogenous RNA (ceRNA) network associated with ferroptosis in HIBD. Further validation using an external dataset and quantitative real-time polymerase chain reaction (PCR) analysis of brain tissues from hypoxic-ischemic encephalopathy rats confirmed the expression patterns of three key genes, including HMOX1, MYCN, and QSOX1. Meanwhile, the three key genes were closely correlated with the infiltration of multiple immune cells and might affect the function of HIBD regulatory genes such as CPT2 and GCK. In addition, drug prediction suggested that four drugs, including cephaeline, emetine, mestranol, and sulmazole, might alleviate HIBD.ConclusionsOur study established a ceRNA network, identified three key genes, and predicted four drugs that are associated with ferroptosis in HIBD, which provides new ideas for the investigation of the disease mechanisms and might facilitate the diagnosis and treatment of the disease.

Dataset Information

Oxidative Stress in Hypoxic-Ischemic Encephalopathy: Molecular Mechanisms and Therapeutic Strategies.

Publications

Oxidative Stress in Hypoxic-Ischemic Encephalopathy: Molecular Mechanisms and Therapeutic Strategies.

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