Site-specific alterations of N-glycans define the glycoproteomic landscape of thymic aging in rats
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ABSTRACT:
ORGANISM(S): Rattus Rattus
SUBMITTER: 
Shisheng Sun
PROVIDER: PXD066435 | iProX | Wed Jul 23 00:00:00 BST 2025
REPOSITORIES: iProX
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Project description:Although glucocorticoids (GCs) are known to exert numerous effects in the hippocampus, their chronic regulatory functions remain poorly understood. Moreover, evidence is inconsistent regarding the longstanding hypothesis that chronic GC exposure promotes brain aging/Alzheimer's disease. Here, we adrenalectomized male F344 rats at 15-months-of-age, maintained them for 3 months with implanted corticosterone (CORT) pellets producing low or intermediate (glucocorticoid-receptor (GR)-activating) blood levels of CORT, and performed microarray/pathway analyses in hippocampal CA1. We defined the chronic GC-dependent transcriptome as 393 genes that exhibited differential expression between Intermediate- and Low-CORT groups. Short-term CORT (4 days) did not recapitulate this transcriptome. Functional processes/pathways overrepresented by chronic CORT-upregulated genes included learning/plasticity, differentiation, glucose metabolism and cholesterol biosynthesis, whereas processes overrepresented by CORT-downregulated genes included inflammatory/immune/glial responses and extracellular structure. These profiles indicate that GCs chronically activate neuronal/metabolic processes while coordinately repressing a glial axis of reactivity/inflammation. We then compared the GC-transcriptome with a previously-defined hippocampal aging transcriptome, revealing a high proportion of common genes. Although CORT and aging moved expression of some common genes in the same-direction, the majority were shifted in opposite directions by CORT and aging (e.g., glial inflammatory genes downregulated by CORT are upregulated with aging). These results contradict the hypothesis that GCs simply promote brain aging, and also suggest that the opposite-direction shifts during aging reflect resistance to CORT regulation. Therefore, we propose a new model in which aging-related GC resistance develops in some target pathways while GC overstimulation develops in others, together generating much of the brain aging phenotype. Forty male Fischer 344 rats aged 14-15 months (late mid-age) were either sham operated (n=10) or adrenalectomized (n=30) at Harlan, Inc. (Indianapolis) and shipped to University of Kentucky 7-10 d after surgery. Animals were allowed to acclimate for 2 weeks after receipt prior to pellet-implant and were provided with food and water ad lib. Adrenalectomized (ADX) animals were maintained on drinking water containing isotonic saline with 1% sucrose, and also given supplemental feed mash (standard chow mixed with water and warmed) and apple chunks, as well as subcutaneous injections of 1.25 mg corticosterone sulfate (Solu-DeltaCort, Pfizer). During pellet-implant surgery, subjects were anesthetized with isoflurane, placed on a warming pad, and a 3 cm2 area on the animal's flank was shaved and sterilized. A 1-cm incision was made through the skin to form a subcutaneous pocket. Each sham animal received an inert pellet. ADX animals were divided into two groups, low-dose animals (n = 20) received one 25 mg CORT pellet and intermediate-dose animals (n = 10) received one 200 mg CORT pellet (slow release pellets, Innovative Research of America, Sarasota, FL). Incisions were closed with wound clips (removed after 7-10 days). Following implant surgery, subjects were housed singly for 3 months prior to euthanasia at age 18 months. Low-dose animals continued to receive saline/ sucrose drinking water, but other supplementation (food mash, Solu-Delta CORT, apple chunks) was discontinued. One ADX animal was removed from the study for declining health. During the twelfth week, just prior to study termination, half of the ADX low-dose CORT subjects were given a short-term, high-dose regimen consisting of 4 daily IP injections of 5mg/d CORT (considered a relatively high dose- Makino et al., 1995). All animals were killed between 8 and 10 AM on the last two days of the study. After deep CO2 anesthesia and decapitation, trunk blood was collected for CORT radioimmunoassay and hippocampal CA1 brain tissue was dissected as described previously (Blalock et al., 2003) for microarray analysis (see below). Final treatment groups consisted of: 1) Sham (intact) control, 2) Low-CORT (ADX), 3) Intermediate-CORT (ADX), and 4) Low-CORT (ADX) + short-term high-dose injected (n=9-10/group).
2013-07-22 | E-GEOD-37618 | biostudies-arrayexpress
Project description:Although glucocorticoids (GCs) are known to exert numerous effects in the hippocampus, their chronic regulatory functions remain poorly understood. Moreover, evidence is inconsistent regarding the longstanding hypothesis that chronic GC exposure promotes brain aging/Alzheimer's disease. Here, we adrenalectomized male F344 rats at 15-months-of-age, maintained them for 3 months with implanted corticosterone (CORT) pellets producing low or intermediate (glucocorticoid-receptor (GR)-activating) blood levels of CORT, and performed microarray/pathway analyses in hippocampal CA1. We defined the chronic GC-dependent transcriptome as 393 genes that exhibited differential expression between Intermediate- and Low-CORT groups. Short-term CORT (4 days) did not recapitulate this transcriptome. Functional processes/pathways overrepresented by chronic CORT-upregulated genes included learning/plasticity, differentiation, glucose metabolism and cholesterol biosynthesis, whereas processes overrepresented by CORT-downregulated genes included inflammatory/immune/glial responses and extracellular structure. These profiles indicate that GCs chronically activate neuronal/metabolic processes while coordinately repressing a glial axis of reactivity/inflammation. We then compared the GC-transcriptome with a previously-defined hippocampal aging transcriptome, revealing a high proportion of common genes. Although CORT and aging moved expression of some common genes in the same-direction, the majority were shifted in opposite directions by CORT and aging (e.g., glial inflammatory genes downregulated by CORT are upregulated with aging). These results contradict the hypothesis that GCs simply promote brain aging, and also suggest that the opposite-direction shifts during aging reflect resistance to CORT regulation. Therefore, we propose a new model in which aging-related GC resistance develops in some target pathways while GC overstimulation develops in others, together generating much of the brain aging phenotype.
2013-07-22 | GSE37618 | GEO
Project description:We carried out blood transcriptome-wide association studies and replicated results to identify genes whose expression differs across the human aging spectrum. The transcriptional landscape of aging in humans
2014-06-15 | E-GEOD-58137 | biostudies-arrayexpress
Project description:BackgroundAberrant glycosylation has been recognized as a hallmark of cancer and N-glycosylation is one of the main types of glycosylation in eukaryotes. Although N-glycoproteomics has made contributions to the discovery of biomarkers in a variety of cancers, less is known about the abnormal glycosylation signatures in esophageal squamous cell carcinoma (ESCC).MethodsIn this study, we reported the proteomics and N-glycoproteomic site-mapping analysis of eight pairs of ESCC tissues and adjacent normal tissues. With zic-HILIC enrichment, TMT-based isobaric labeling, LC-MS/MS analysis, differentially expressed N-glycosylation was quantitatively characterized. Lectin affinity enrichment combined with western blot was used to validate the potential biomarkers in ESCC.ResultsA series of differentially expressed glycoproteins (e.g., LAMP2, PLOD2) and enriched signaling pathways (e.g., metabolism-related pathway, ECM-receptor interaction, focal adhesion) were identified. Besides that, seven significantly enriched motifs were found from the identified N-glycosylation sites. Three clusters were identified after conducting the dynamic profiling analysis of glycoprotein change during lymph node metastasis progression. Further validation found that the elevated fucosylation level of ITGB1, CD276 contributed to the occurrence and development of ESCC, which might be the potential biomarkers in ESCC.ConclusionIn summary, we characterized the N-glycosylation and N-glycoprotein alterations associated with ESCC. The typical changes in glycoprotein expression and glycosylation occupancy identified in our study will not only be used as ESCC biomarkers but also improve the understanding of ESCC biology.
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Project description:Type 2 diabetes (T2D) is consistently associated with an elevated risk of cognitive decline and dementia. The underlying molecular mechanisms relating T2D to cognitive decline remain unclear, impeding the ability to detect the earliest stages of cognitive decline in older adults with T2D, consequently hindering advancement of preventive interventions. This study compared quantitative alterations in glycoproteoforms, represented by tryptic glycopeptiforms—specific glycan compositions on amino acid sites of proteins—in older T2D adults. We utilized label free, mass spectrometry-based glycoproteomics to analyze protein N-glycosylation and glycation patterns in serum samples, collected at two time points (T1 and T2), an average 52 months apart, from two initially cognitively healthy T2D groups. One group was comprised of individuals who experienced cognitive decline (“decliners”; N=8), and the other, of individuals who maintained normal cognition (“non-decliners”; N=14) over time. Comparison of these two groups revealed distinct patterns for glycosylation and glycation. Glycosylation primarily affected platelet function pathways. Glycation was also involved in immune system and platelet function along with various metabolic pathways. These findings suggest that aberrant glycoproteomic modifications may contribute to the development of cognitive impairment in T2D and may serve as potential early biomarkers. Further research is warranted to elucidate the functional implications of glycopeptiform modifications in T2D-related cognitive decline.
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Project description:We performed a large-scale, site-specific N-glycoproteome profiling study of human Alzheimer’s disease (AD) and control brains using mass spectrometry–based quantitative N-glycoproteomics. The study provided a system-level view of human brain N-glycoproteins and in vivo N-glycosylation sites and identified disease signatures of altered N-glycopeptides, N-glycoproteins, and N-glycosylation site occupancy in AD. Glycoproteomic data-driven network analysis showed 13 modules of co-regulated N-glycopeptides/glycoproteins, 6 of which are associated with AD phenotypes.
2022-11-02 | PXD037229 | Pride
Project description:The precise molecular mechanisms of diabetic retinopathy (DR) pathogenesis are unclear, and treatment options are limited. There is an urgent need to discover and develop novel therapeutic targets for the treatment of this disease. Glycosylation is a post-translational modification that plays a critical role in determining protein structure, function, and stability. Recent studies have found that serum glycoproteomic changes are associated with the presence or progression of several inflammatory diseases. However, very little is known about the glycoproteomic changes associated with DR. In this study, glycoproteomic profiling of the serum of diabetic patients with and without DR was performed. A total of 15 glycopeptides from 11 glycoproteins were found to be significantly altered (5 upregulated and 10 downregulated) within the serum glycoproteome of DR patients. These glycoproteins are known to be involved in the maintenance of the extracellular matrix and complement system through peptidolytic activity or regulation.
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Project description:DNA methylation array data generated from epidermal samples (suction blister roofs) of healthy female subjects between 21 and 76 years. Aim of the project was the investigation of non-linearities in the human aging progression using an integrative multi-omics analysis. DNA was extracted from suction blisters taken from the volar forearms of each subject, bisulfite converted, and profiled using Illumina Infinium MethylationEPIC BeadChip arrrays.
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