Generalized low levels of serum N-glycans associates with young biological age and good physical condition
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE219147 | GEO | 2023/08/08
REPOSITORIES: GEO
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Project description:Human serum IgM antibodies are composed of heavily glycosylated polymers with five glycosylation sites on the μ (heavy) chain and one glycosylation site on the J chain. In contrast to IgG glycans, which are vital for a number of biological functions, virtually nothing is known about structure-function relationships of IgM glycans. Natural IgM is the earliest immunoglobulin produced and recognizes multiple antigens with low affinity, whilst immune IgM is induced by antigen exposure and is characterized by a higher antigen specificity. Natural anti-lymphocyte IgM is present in the serum of healthy individuals and increases in inflammatory conditions. It is able to inhibit T cell activation, but the underlying molecular mechanism is not understood. Here we show, for the first time, that sialylated N-linked glycans induce the internalization of IgM by T cells, which in turn causes severe inhibition of T cell responses. The absence of sialic acid residues abolishes these inhibitory activities, showing a key role of sialylated N-glycans in inducing the IgM-mediated immune suppression.
2014-11-11 | E-MTAB-3030 | biostudies-arrayexpress
Project description:<h4><strong>BACKGROUND:</strong> Multiple myeloma is characterized by clonal proliferation of malignant plasma cells in the bone marrow that produce monoclonal immunoglobulins. N-glycosylation changes of these monoclonal immunoglobulins have been reported in multiple myeloma, but previous studies only detected limited serum N-glycan features.</h4><h4><strong>METHODS:</strong> Here, a more detailed study of the human serum N-glycome of 91 multiple myeloma patients and 51 controls was performed. We additionally analyzed sequential samples from patients (n = 7) which were obtained at different time points during disease development as well as 16 paired blood serum and bone marrow plasma samples. N-glycans were enzymatically released and measured by mass spectrometry after linkage specific derivatization of sialic acids.</h4><h4><strong>RESULTS:</strong> A decrease in both α2,3- and α2,6-sialylation, galactosylation and an increase in fucosylation within complex-type N-glycans were found in multiple myeloma patients compared to controls, as well as a decrease in difucosylation of diantennary glycans. The observed glycosylation changes were present in all ISS stages, including the 'low-risk' ISS I. In individual patients, difucosylation of diantennary glycans decreased with development of the disease. Protein N-glycosylation features from blood and bone marrow showed strong correlation. Moreover, associations of monoclonal immunoglobulin (M-protein) and albumin levels with glycan traits were discovered in multiple myeloma patients.</h4><h4><strong>CONCLUSIONS & GENERAL SIGNIFICANCE: </strong>In conclusion, serum protein N-glycosylation analysis could successfully distinguish multiple myeloma from healthy controls. Further studies are needed to assess the potential roles of glycan trait changes and the associations of glycans with clinical parameters in multiple myeloma early detection and prognosis.</h4>
2022-04-27 | MTBLS676 | MetaboLights
Project description:Caloric restriction (CR) without malnutrition is one of the most consistent strategies for increasing mean and maximal lifespan and delaying the onset of age-associated diseases. Stress resistance is a common trait of many long-lived mutants and life-extending interventions, including CR. Indeed, better protection against heat shock and other genotoxic insults have helped explain the pro-survival properties of CR. In this study, both in vitro and in vivo responses to heat shock were investigated using two different models of CR. Murine B16F10 melanoma cells treated with serum from CR-fed rats showed lower proliferation, increased tolerance to heat shock and enhanced HSP-70 expression, compared to serum from ad libitum-fed animals. Similar effects were observed in B16F10 cells implanted subcutaneously in male C57BL/6 mice subjected to CR. Microarray analysis identified a number of genes and pathways whose expression profile were similar in both models. These results suggest that the use of an in vitro model could be a good alternative to study the mechanisms by which CR exerts its anti-tumorigenic effects. KEY WORDS: caloric restriction, heat shock, stress response, tumorigenesis, aging
2015-08-06 | GSE67430 | GEO
Project description:Sustained caloric restriction (CR) extends lifespan in animal models but the mechanism and primary tissue target(s) have not been identified. Gene expression changes with aging and CR were examined in both heart and subcutaneous white adipose tissue (WAT) of F344 male rats using Affymetrix® RAE 230 arrays and validated by qRT-PCR on 18 genes. In heart, age- associated changes but not CR-associated changes in old. In WAT, genes were identified where the aging change is suppressed by CR (candidate markers of healthy aging) and those affected by CR but not normal aging (candidate longevity assurance genes). 10-21% of age-associated genes were regulated in common between tissues. Gene set enrichment analysis (GSEA) revealed coordinate small magnitude changes in ribosomal, proteasomal, and mitochondrial genes with similarities between heart and WAT. Further analysis revealed PPARgamma as a potential upstream regulator of altered gene expression in old CR WAT. These results demonstrate a reduced mRNA response to CR with age in heart relative to WAT. In WAT, we identified candidate CR mimetic targets and candidate markers of healthy aging. These data suggest a role for subcutaneous WAT in the effects of CR and strengthen the role for PPAR signaling in aging and CR while indicating that the effects of CR in heart can occur independent of global changes in mRNA level. Experiment Overall Design: Tissues (n=5-7 animals per group) were obtained from the NIH-NIA aging rodent tissue bank. According to supplier records, animals were housed in a specific pathogen free barrier facility under contract with BioReliance. AL animals were housed 3 per cage and CR animals were housed singly. CR (60% of AL) was initiated at 4 months of age with a switch from the NIH 31 to NIH fortified diet. F344 male rats were sacrificed at 4 months (4AL) or 28 months of age (28AL, 28CR). Animals with gross tumor pathologies were excluded from the study. All animals were euthanized by CO2 asphixiation and tissues were frozen in liquid nitrogen then stored at â80°C. Subcutaneous WAT was collected from the abdominal region. Recorded body weights differed dramatically between the 3 groups (4AL = 253±8 g, 28AL = 382±20 g, 28CR = 288±7 g) and heart weight as a fraction of body weight was not significantly different between the groups (data not shown). The apical ~1/3 of the heart was homogenized for the expression studies. Sections from the cut face were stained with haematoxylin and eosin to confirm expected aging-associated pathology changes.
2008-06-15 | E-GEOD-6718 | biostudies-arrayexpress
Project description:Unnatural monosaccharides such as azidosugars that can be metabolically incorporated into cellular glycans are currently used as a major tool for glycan imaging and glycoproteomic profiling. As a common practice to enhance membrane permeability and cellular uptake, the unnatural sugars are per O-acetylated, which, however, can induce a long-overlooked side reaction, non enzymatic S-glycosylation. Herein, we develop 1,3-di-esterified N azidoacetylgalactosamine (GalNAz) as the next generation chemical reporters for metabolic glycan labeling. Both 1,3-di-O-acetylated GalNAz (1,3-Ac2GalNAz) and 1,3-di-O propionylated GalNAz (1,3-Pr2GalNAz) exhibited high efficiency for labeling protein O-GlcNAcylation with no artificial S-glycosylation. Applying 1,3-Pr2GalNAz in mouse embryonic stem cells (mESCs), we identified ESRRB, a critical transcription factor for pluripotency, as an O-GlcNAcylated protein. We showed that ESRRB O-GlcNAcylation is important for mESC self-renewal and pluripotency. Mechanistically, ESRRB is O-GlcNAcylated by O-GlcNAc transferase (OGT) at serine 25 (Ser 25), which stabilizes ESRRB, promotes its transcription activity and facilitates its interactions with two master pluripotency regulators, OCT4 and NANOG.
2019-07-27 | GSE131246 | GEO
Project description:Caloric restriction (CR) without malnutrition is one of the most consistent strategies for increasing mean and maximal lifespan and delaying the onset of age-associated diseases. Stress resistance is a common trait of many long-lived mutants and life-extending interventions, including CR. Indeed, better protection against heat shock and other genotoxic insults have helped explain the pro-survival properties of CR. In this study, both in vitro and in vivo responses to heat shock were investigated using two different models of CR. Murine B16F10 melanoma cells treated with serum from CR-fed rats showed lower proliferation, increased tolerance to heat shock and enhanced HSP-70 expression, compared to serum from ad libitum-fed animals. Similar effects were observed in B16F10 cells implanted subcutaneously in male C57BL/6 mice subjected to CR. Microarray analysis identified a number of genes and pathways whose expression profile were similar in both models. These results suggest that the use of an in vitro model could be a good alternative to study the mechanisms by which CR exerts its anti-tumorigenic effects. KEY WORDS: caloric restriction, heat shock, stress response, tumorigenesis, aging In Vivo: Male C57BL/6 mice (3 month old) were single-housed in duplex caging in a room maintained at a constant temperature (20-22 °C) and humidity (30-70%) in a light:dark 12:12-h schedule, according to established animal protocols and NIH guidelines. They were fed either a standard purified mouse diet (NIH-31) ad libitum (AL; n=10) or maintained on a 40% calorie restriction regimen (CR; n=10) for the six week study. B16F10 melanoma cells (ATCC® CRL-6475™) were purchased from American Type Culture Collection (Manassas, VA); they were cultured in Dulbecco's Modified Essential Medium (DMEM) supplemented with 10% fetal bovine serum and penicillin/streptomycin (Gibco, Gaithersburg, MD) under standard cell culture conditions. One month into the study, 5 mice from each diet group were injected with 1x106 B16F10 melanoma cells in the periscapular region. Fourteen days later, animals were euthanized and tumors were excised and frozen for RNA isolation. In Vitro: B16F10 melanoma cells were incubated in media with 10% serum from either AL- or CR-fed rats, serum was obtained from overnight fasted, anesthetized 6-month-old male Fisher 344 rats. Cells were grown for 96 hours before being harvested, washed and collected for RNA isolation. The RNA was extracted using the RNeasy Mini Kit from Qiagen using standard protocols and labeled with Biotin using the standard Illumina protocol. Samples were hybed overnight to Illumina's Sentrix MouseRef-8 v1.1 Expression BeadChips. Arrays were washed, stained with Cy-3 and scanned at 0.8 micron resolution in a 500 GX Illumina Bead Array Reader.
2015-08-06 | E-GEOD-67430 | biostudies-arrayexpress
Project description:Calorie restriction (CR) is the most robust non-genetic intervention to universally delay the onset of age-related diseases and extend mean and maximum lifespan. However, species, strain, sex, diet, age of onset, and level of CR are emerging as important variables to consider for a successful CR response. Here, we investigated the role of strain, sex and level of CR on outcomes of health and survival in mice. Response to CR varied from lifespan extension to no effect on survival, while consistently delaying the onset and impact of diseases independently of strain, sex and level of dietary restriction. CR led to transcriptional and metabolomics changes in the liver indicating anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. Additionally, CR prevented the age-associated decline in the proteostasis network. Further, CR increased mitochondrial number and preserved their ultrastructure and function with age. Abrogation of mitochondrial function by deletion of fumarate hydratase or malate dehydrogenase 2 negated the life-prolonging effects of CR in yeast and worms. In F1 hybrid strains of mice, the lifespan response to CR tracked with the dam, indicating that the mitochondrial haplotype is an important regulator of CR. Our data illustrate the complexity of the CR responses within a single animal species in the context of aging, with a clear separation of outcomes related to health and survival, highlighting the complexities of translation of CR into human interventions. The study examines the effects of sex (male/female), mouse strain (DBA2/J versus C57BL/J), and diet (Ad libitum, 20% caloric restriction (20%CR), or 40%CR) using six biological replicate samples per group.
2016-06-27 | E-GEOD-81959 | biostudies-arrayexpress
Project description:Sustained caloric restriction (CR) extends lifespan in animal models but the mechanism and primary tissue target(s) have not been identified. Gene expression changes with aging and CR were examined in both heart and subcutaneous white adipose tissue (WAT) of F344 male rats using Affymetrix® RAE 230 arrays and validated by qRT-PCR on 18 genes. In heart, age- associated changes but not CR-associated changes in old. In WAT, genes were identified where the aging change is suppressed by CR (candidate markers of healthy aging) and those affected by CR but not normal aging (candidate longevity assurance genes). 10-21% of age-associated genes were regulated in common between tissues. Gene set enrichment analysis (GSEA) revealed coordinate small magnitude changes in ribosomal, proteasomal, and mitochondrial genes with similarities between heart and WAT. Further analysis revealed PPARgamma as a potential upstream regulator of altered gene expression in old CR WAT. These results demonstrate a reduced mRNA response to CR with age in heart relative to WAT. In WAT, we identified candidate CR mimetic targets and candidate markers of healthy aging. These data suggest a role for subcutaneous WAT in the effects of CR and strengthen the role for PPAR signaling in aging and CR while indicating that the effects of CR in heart can occur independent of global changes in mRNA level. Keywords: Aging Caloric Restriction
2007-10-23 | GSE6718 | GEO
Project description:Glycoproteomics, TNF-alpha, membrane proteomics, insulin resistance, adipocyte, SILAC Insulin resistance (IR) is a complex process arising from both environmental and genetic perturbations and leads to a variety of diseases including type-2 diabetes (T2D). The expansion of adipose tissue during obesity results in secretion of proinflammatory cytokines which significantly impairs insulin sensitivity throughout the entire body. Inflammation modulates glycosylation in a variety of cell types however, an investigation of changes in glycosylation following inflammation-induced IR in adipocytes has not been performed. In the present study, we performed a quantitative N-glycomic analysis of TNF-alpha induced IR in adipocytes and identified the regulation of specific N-glycans including an increase in terminal di-galactose- and decrease in di-sialic acid-containing glycans with alpha-2,3 linkages. Quantitative analysis of the membrane-associated proteome in TNF-alpha treated adipocytes identified the regulation of specific glycosyltransferases and glycosidases which correlated with the regulated N-glycans. This included the up- and down-regulation of B4GalT5 and ST3Gal6, respectively at both the protein and mRNA level. To identify the protein and glycosylation sites modified with these regulated N-glycans, we performed a site-specific quantitative glycoproteomic analysis of enriched N-glycopeptides from TNF-alpha treated adipocytes with and without deglycosylation. The combined workflow provided a relative quantification of changes in protein abundance verses N-glycosylation occupancy verses site-specific N-glycans on a proteome-wide level. This revealed the modulation of a subset of N-glycan compositions on specific proteins including those previously associated with insulin-stimulated GLUT4 trafficking to the plasma membrane. Finally, knockdown of B4GalT5 with siRNA and analysis of released N-glycans resulted in the down-regulation of di-galactose containing glycans, confirming the involvement of this enzyme in the TNF-alpha regulated N-glycome.
2015-11-09 | PXD002435 | Pride
Project description:Aberrant glycosylation is a crucial strategy employed by cancer cells to evade cellular immunity. However, homologous recombination (HR) status-dependent glycosylation has never been explored therapeutically. Here, we show that the inhibition of branched N-glycans sensitizes HR-proficient, but not HR-deficient, epithelial ovarian cancers (EOCs) to immune checkpoint blockade (ICB). In contrast to fucosylation whose inhibition sensitizes EOCs to anti-PD-L1 immunotherapy regardless of HR-status, we observe a unique enrichment of branched N-glycans on HR-proficient compared to HR-deficient EOCs. Mechanistically, BRCA1/2 transcriptionally promotes the expression of MGAT5, the enzyme responsible for catalyzing branched N-glycans. The branched N-glycans on HR-proficient tumors augment their resistance to anti-PD-L1 by enhancing its binding with PD-1 on CD8_ T cells. In orthotopic syngeneic EOC mouse models, inhibiting branched N-glycans, using 2-Deoxy-D-glucose, sensitizes HR-proficient, but not HR-deficient EOCs, to anti-PD-L1. These findings indicate branched N-glycans as promising therapeutic targets whose inhibition sensitizes HR-proficient EOCs to ICB by overcoming immune evasion
2024-09-29 | GSE244367 | GEO