Biomarker and Drug Target Discovery Using Quantitative Proteomics Post-Intracerebral Hemorrhage Stroke in the Rat Brain

Abstract

The pathological mechanisms of acute intracerebral hemorrhage (ICH) remain unknown and unverified. In the present study, we used quantitative proteomics to elucidate the pathological mechanisms and to identify novel biomarker and therapeutic target candidates via tissue proteome in a rat model of acute ICH. Rats were experimentally induced with ICH (n = 6) or Sham (n = 6), and their brain tissue was obtained by 24 h. The TMT-LC–MS/MS-based proteomics approach was used to quantify the differential proteomes across brain tissue, and the results were further analyzed by ingenuity pathway analysis to explore canonical pathways and the relationship involved in the uploaded data. Upon quantification, we found that 96 secreted proteins that were identified in the ICH 24-h group were significantly different those in the control group (P < 0.05); among these proteins, 57 increased and 39 decreased in abundance. Bioinformatic analyses of differentially expressed proteins demonstrated that the protein localization and ERK1 and ERK2 cascade were the top two biological processes with the highest concentrations of differentially proteins. The top protein-protein action network with high confidence levels of protein was the albumin and ERK signaling pathways. Albumin, ERK, and p-ERK were assessed in brain tissue by western blot analysis, and higher expression levels of albumin and p-ERK were observed in the ICH group. Our proteomic results highlight important change in the biological processes of ERK1 and ERK2 cascade, which are possible targets for future interventions of ICH. To our knowledge, this study provides in-depth analysis of ICH in brain tissue, and we propose 96 new biomarker candidates for ICH, including albumin and ERK.Electronic supplementary materialThe online version of this article (10.1007/s12031-018-1206-z) contains supplementary material, which is available to authorized users.

Albumin Reduces Oxidative Stress and Neuronal Apoptosis via the ERK/Nrf2/HO‐1 Pathway after Intracerebral Hemorrhage in Rats

“…Although albumin has a variety of neuroprotective effects on ICH-induced injury, however, the potential molecular mechanisms involved with the activation of ERK by albumin have not been fully investigated. Our previous quantitative proteomics study [ 23 ] showed that the ERK1 and ERK2 cascades were the top two biological processes after ICH and that the albumin and ERK1/2 signaling pathways were the top protein-protein interaction networks. Recently, some studies showed that there was an important link between albumin and the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase, ERK1/ERK2 in kidney disease, and ERK1/2 signaling pathway was the downstream signal activated by albumin therapy [ 24 , 51 ].…”

“…Previous studies demonstrated that human serum albumin treatment had neuroprotective effects on focal and global cerebral ischemia [ 18 , 19 ], subarachnoid hemorrhage [ 20 , 21 ], and ICH [ 22 ]. Our previous quantitative proteomics study showed that albumin increased after ICH [ 23 ], but the specific mechanism remains unclear.…”

“…Extracellular signal-regulated kinase (ERK) 1/2, a prototypic subfamily of MAPKs, is considered the top biological factor that participates in oxidative and ER stress [ 23 ]. Albumin therapy activates the downstream protein ERK1/2 signaling [ 24 , 25 ].…”

Proteomics and metabolomics of raw rhubarb and wine-processed rhubarb in the treatment of rats with intracerebral hemorrhage

“…Proteomics is the large-scale analysis of proteins, including post-translational modifications and protein interactions, so as to reveal the function of proteins. Proteomics has been used in the screening of vaccines, clinical drug development, the prediction of prognosis, and to guide treatment approaches (7). Metabolomics is the qualitative and quantitative analysis of all low molecular weight metabolites in the biological system at a specific time and under specific conditions, and describes the responses of endogenous metabolites to internal and external changes.…”

Polymeric nanoparticles improved Curcumin brain delivery and its therapeutic efficacy against intracerebral hemorrhage

“…Unfortunately, effective pharmaceutical approaches for ICH are lacking at present [11]. One of the challenges in drug development is the poor oral bioavailability and brain accumulation [12,13].To resolve these puzzles, extensive research efforts have been pursued in the quest for novel compounds from herbal medicines [14].…”