Alzheimer' disease (AD) is the most common form of dementia affecting up to 6% of the population over the age of 65. In order to discover differentially expressed proteins that might serve as potential biomarkers, the serums from AD patients and healthy controls were compared and analyzed using the proteomics approach of isobaric tagging for relative and absolute quantitation (iTRAQ). For the first time, AD biomarkers in serums are investigated in the Han Chinese population using iTRAQ labeled proteomics strategy. Twenty-two differentially expressed proteins were identified and out of which nine proteins were further validated with more sample test. Another three proteins that have been reported in the literature to be potentially associated with AD were also investigated for alteration in expression level. Functions of those proteins were mainly related to the following processes: amyloid-β (Aβ) metabolism, cholesterol transport, complement and coagulation cascades, immune response, inflammation, hemostasis, hyaluronan metabolism, and oxidative stress. These results support current views on the molecular mechanism of AD. For the first time, differential expression of zinc-alpha-2-glycoprotein (AZGP1), fibulin-1 (FBLN1), platelet basic protein (PPBP), thrombospondin-1 (THBS1), S100 calcium-binding protein A8 (S100A8), and S100 calcium-binding protein A9 (S100A9) were detected in the serums of AD patients compared with healthy controls. These proteins might play a role in AD pathophysiology and serve as potential biomarkers for AD diagnosis. Specifically, our results strengthened the crucial role of Aβ metabolism and blood coagulation in AD pathogenesis and proteins related to these two processes may be used as peripheral blood biomarkers for AD.
Autism is one of the most common neurological developmental disorder associated with social isolation and restricted interests in children. The etiology of this disorder is still unknown. There is neither any confirmed laboratory test nor any effective therapeutic strategy to diagnose or cure it. To search for biomarkers for early detection and exploration of the disease mechanisms, here, we investigated the protein expression signatures of peripheral blood mononuclear cells (PBMCs) in autistic children compared with healthy controls by using isobaric tags for relative and absolute quantitation (iTRAQ) proteomics approach. The results showed a total of 41 proteins as differentially expressed in autistic group as compared to control. These proteins are found associated with metabolic pathways, endoplasmic reticulum (ER) stress and protein folding, endocytosis, immune and inflammatory response, plasma lipoprotein particle organization, and cell adhesion. Among these, 17 proteins (13 up-regulated and four down-regulated) are found to be linked with mitochondria. Eight proteins including three already reported proteins in our previous studies were selected to be verified. Five already reported autism associated pro-inflammatory cytokines [interferon-γ (IFN-γ), interleukin-1β (IL-1β), IL-6, IL-12, and tumor necrosis factor-α (TNF-α)] were detected in plasma by enzyme-linked immunosorbent assay (ELISA) analysis. The results were consistent with proteomic results and reports from previous literature. These results proposed that PBMCs from autistic children might be activated, and ER stress, unfolded protein response (UPR), acute-phase response (APR), inflammatory response, and endocytosis may be involved in autism occurrence. These reported proteins may serve as potential biomarkers for early diagnosis of autism. More specifically, simultaneous detection of three proteins [complement C3 (C3), calreticulin (CALR), and SERPINA1] in the plasma and PBMCs could increase the authenticity of detection.
These above described proteins are found involved in different pathways that have previously been linked to the pathophysiology of autism spectrum disorders (ASDs). The results strongly support that focal adhesions, acting cytoskeleton, cell adhesion, motility and migration, synaptogenesis, and complement system are involved in the pathogenesis of autism, and highlight the important role of platelet function in the pathophysiology of autism.
Selenium (Se), an antioxidant trace element, is an important nutrient for maintaining brain functions and is reported to be involved in Alzheimer's disease (AD) pathologies. The present study has been designed to elucidate the protein changes in hippocampus of 3×Tg-AD mice after supplementing sodium selenate as an inorganic source of selenium. By using iTRAQ proteomics technology, 113 differentially expressed proteins (DEPs) are found in AD/WT mice with 37 upregulated and 76 downregulated proteins. Similarly, in selenate-treated 3×Tg-AD (ADSe/AD) mice, 115 DEPs are found with 98 upregulated and 17 downregulated proteins. The third group of mice (ADSe/WT) showed 75 DEPs with 46 upregulated and 29 downregulated proteins. Among these results, 42 proteins (40 downregulated and 2 upregulated) in the diseased group showed reverse expression when treated with selenate. These DEPs are analyzed with different bioinformatics tools and are found associated with various AD pathologies and pathways. Based on their functions, selenate-reversed proteins are classified as structural proteins, metabolic proteins, calcium regulating proteins, synaptic proteins, signaling proteins, stress related proteins, and transport proteins. Six altered AD associated proteins are successfully validated by Western blot analysis. This study shows that sodium selenate has a profound effect on the hippocampus of the triple transgenic AD mice. This might be established as an effective therapeutic agent after further investigation.
BackgroundAutism is a severe childhood neurological disorder with poorly understood etiology and pathology. Currently, there is no authentic laboratory test to confirm the diagnosis of autism. Oxidative damage may play a central role in the pathogenesis of autism. Present study is an effort to search for possible biomarkers of autism and further clarify the molecular changes associated with oxidative stress that occurs in the plasma of autistic children.MethodsWe performed redox proteomics analysis to compare carbonylated proteins in the plasma of autistic subjects and healthy controls. Immunoprecipitation and Western blot analysis were used to validate carbonylated proteins identified by the redox proteomics.ResultsProtein carbonylation levels in two proteins, complement component C8 alpha chain and Ig kappa chain C were found to be significantly increased in autistic patients compared with controls. These two proteins were successfully validated via immunoprecipitation and Western blot analysis.ConclusionsThe results further highlight the role of oxidative stress in the pathogenesis of autism and provide some information for the diagnosis and/or monitoring of autism.
Purpose This study is designed to screen serum proteins that may serve as biomarkers for gestational diabetes mellitus (GDM), and clarify the mechanisms of disease. Experimental Design By using isobaric tags for relative and absolute quantitation proteomics analysis, serum proteins levels were quantified in pregnant women who subsequently developed GDM (12–16 weeks), GDM patients (24–28 weeks), and their corresponding controls. The strategy of mixing samples is used in proteomic analysis. Results Thirty‐one and 27 differentially expressed proteins are identified in the serum of pregnant women with developed GDM at 12–16 weeks and GDM patients during 24–28 weeks, respectively. Thirty eight and 28 proteins are identified in 24–28 weeks versus 12–16 weeks controls (24/12 CTR group), and 24–28 weeks GDM patients versus 12–16 weeks women with subsequently developed GDM (24/12 GDM group), respectively. Most of these proteins in the case and control subjects are associated with diabetes and maternal and perinatal short‐ and long‐term complications. Conclusions and Clinical Relevance The results highlight the roles of complement system and the blood clotting cascade in the pathogenesis of GDM. Differentially expressed proteins may serve as potential biomarkers for GDM prediction and diagnosis in the future.
Background: Alzheimer's disease (AD) is the major cause of dementia in population aged over 65 years, accounting up to 70% dementia cases. However, validated peripheral biomarkers for AD diagnosis are not available up to present. In this study, we adopted a new strategy of combination of computational prediction and experimental validation to identify blood protein biomarkers for AD.Methods: First, we collected tissue-based gene expression data of AD patients and healthy controls from GEO database. Second, we analyzed these data and identified differentially expressed genes for AD. Third, we applied a blood-secretory protein prediction program on these genes and predicted AD-related proteins in blood. Finally, we collected blood samples of AD patients and healthy controls to validate the potential AD biomarkers by using ELISA experiments and Western blot analyses.Results: A total of 2754 genes were identified to express differentially in brain tissues of AD, among which 296 genes were predicted to encode AD-related blood-secretory proteins. After careful analysis and literature survey on these predicted blood-secretory proteins, ten proteins were considered as potential AD biomarkers, five of which were experimentally verified with significant change in blood samples of AD vs. controls by ELISA, including GSN, BDNF, TIMP1, VLDLR, and APLP2. ROC analyses showed that VLDLR and TIMP1 had excellent performance in distinguishing AD patients from controls (area under the curve, AUC = 0.932 and 0.903, respectively). Further validation of VLDLR and TIMP1 by Western blot analyses has confirmed the results obtained in ELISA experiments.Conclusion: VLDLR and TIMP1 had better discriminative abilities between ADs and controls, and might serve as potential blood biomarkers for AD. To our knowledge, this is the first time to identify blood protein biomarkers for AD through combination of computational prediction and experimental validation. In addition, VLDLR was first reported here as potential blood protein biomarker for AD. Thus, our findings might provide important information for AD diagnosis and therapies.
Selenium (Se) deficiency is believed to be involved in pathogenesis of Alzheimer's disease (AD) due to failure of antioxidant system. Its supplementation may restore the antioxidant system and compensate the impairments caused by AD. Present study reveals the effect of Se on the proteomic changes in cortex within triple transgenic male AD mice (3 × Tg-AD) after 4 months sodium selenate supplementation. Using iTRAQ comparative proteomics approach, 142 proteins found significant alterations with 96 down-regulated and 46 up-regulated proteins in the cortices of AD mice in comparison with the wild non-transgenic type mice. On treatment with sodium selenate, 41 proteins showed reverse expression, that is, thirty three proteins were down-regulated in AD mice but up-regulated in selenate treated AD mice while eight up-regulated proteins in AD mice showed lower expression in selenate treated mice. OmicsBean bioinformatics analysis revealed that Se positively affected the proteins vital in biological process, structural cores, and molecular functions, which include metabolic proteins, structural proteins, signaling molecules, oxidative stress balancers, and proteosomal degradation proteins. Results of mass spectrometry (MS) were further confirmed by Western blot analysis of five important proteins, prompting the authenticity of the MS results. This paper fills the protein-based molecular gap between AD and Se-treatment, and it provides a full view of Se in reversing the change of cortical protein levels during AD formation.
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