Peptidome analysis of cerebrospinal fluid in neonates with hypoxic-ischemic brain damage
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RESEARCH
Peptidome analysis of cerebrospinal fluid in neonates with hypoxic‑ischemic brain damage Xuewen Hou†, Zijun Yuan†, Xuan Wang, Rui Cheng, Xiaoguang Zhou* and Jie Qiu*
Abstract Hypoxic-ischemic brain injury (HIBD) causes neonatal death and serious neurological disability; however, there are currently no promising therapies for it excepting cooling. Therefore, in this study, we used peptidome analysis to identify differentially expressed peptides in cerebrospinal fluid (CSF) of neonates with HIBD or controls, which may give a foundation for finding new promising drugs of neonatal HIBD. CSF samples were collected from neonates with HIBD (n = 4) or controls (n = 4). ITRAQ LC–MS/MS was used to identify differentially expressed peptides between two groups. A total of 35 differentially expressed peptides from 25 precursor proteins were identified. The 2671.5 Da peptide (HSQFIGYPITLFVEKER), one of the down-regulated peptides in neonatal HIBD, is a fragment of heat shock protein 90-alpha (HSP90α/HSP90AA1). Results of bioinformatics analysis showed that HSP90α/HSP90AA1 was located in the protein–protein interaction (PPI) network hub and was involved in the NOD-LIKE receptor (NLR) signaling pathway. This peptide, we named it Hypoxic-Ischemic Brain Damage Associated Peptide (HIBDAP), is a hydrophilic peptide with high stability and has a long half-life of 3.5 h in mammalian reticulocytes. It was demonstrated that TAT-HIBDAP could successfully enter PC12 cells and further into the nucleus. After HIBDAP pretreatment and 6 h of OGD treatment, low concentrations of HIBDAP increased the survival rate of cells, except 40 μM had a toxic effect. Safe concentrations of HIBDAP reduced pyroptosis of PC12 cells under OGD, except 20 μM had no effect, by suppressing expressions of NLRP3, ASC and Caspase-1 except NLRP1. The results of our study identified the characterization and expression profiles of peptides in CSF of neonatal HIBD. Several meaningful peptides such as HIBDAP may play significant roles in neonatal HIBD and provide new therapeutic targets for neonatal HIBD. Keywords: Peptidomics, Cerebrospinal fluid, Neonates, Hypoxic-ischemic brain damage, Pyroptosis Introduction Hypoxic ischemic brain injury (HIBD) which could cause neuronal and white matter injury [1] is one of the most common causes of neonatal death. HIBD accounts for 23% of global infant mortality [2] and up to 25% survivors have permanent neuropsychological deficits, including cerebral palsy, learning and behavioral disabilities,
*Correspondence: [email protected]; [email protected] † Xuewen Hou and Zijun Yuan contributed equally to this work Department of Newborn Infants, Children’s Hospital of Nanjing Medical University, Nanjing 210008, Jiangsu, China
epilepsy, and so on [3–5]. However, until now, there are few effective treatments for HIBD except the hypothermia therapy [6–8]. Therefore, looking for new HIBD therapeutic methods is urgently needed. Peptides, low molecular weight fractions of proteins, play significant roles in physiologica
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