Biomarkers of apoptosis.
Ontology highlight
ABSTRACT:
SUBMITTER: Ward TH
PROVIDER: S-EPMC2538762 | biostudies-other | 2008 Sep
REPOSITORIES: biostudies-other
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Project description:This study tests biopsy and tissue from patients who have been treated for primary rectal cancer at the Royal Marsden Hospital between 2011 and 2013, who have an mrTRG score at post-chemoradiotherapy MRI. It is a retrospective pilot study to determine the apoptotic and proliferative index count pre and post chemoradiotherapy.
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Project description:Cells undergoing apoptosis show a plethora of time-dependent changes. The available tools for imaging apoptosis in live cells rely either on the detection of the activity of caspases, or on the visualization of exposure of phosphatidyl serine in the outer leaflet of the cell membrane. We report here a novel method for the detection of mitochondrial events during apoptosis, namely translocation of Bax to mitochondria and release of cytochrome c (Cyt c) using bimolecular fluorescence complementation. Expression of split yellow fluorescent protein (YFP) fragments fused to Bax and Cyt c, resulted in robust induction of YFP fluorescence at the mitochondria of apoptotic cells with very low background. In vivo expression of split YFP protein fragments in liver hepatocytes and intra-vital imaging of subcutaneous tumor showed elevated YFP fluorescence upon apoptosis induction. Thus, YFP complementation could be applied for high-throughput screening and in vivo molecular imaging of mitochondrial events during apoptosis.
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Project description:Despite the importance of the immune system in many diseases, there are currently no objective benchmarks of immunological health. In an effort to identifying such markers, we used influenza vaccination in 30 young (20-30 years) and 59 older subjects (60 to >89 years) as models for strong and weak immune responses, respectively, and assayed their serological responses to influenza strains as well as a wide variety of other parameters, including gene expression, antibodies to hemagglutinin peptides, serum cytokines, cell subset phenotypes and in vitro cytokine stimulation. Using machine learning, we identified nine variables that predict the antibody response with 84% accuracy. Two of these variables are involved in apoptosis, which positively associated with the response to vaccination and was confirmed to be a contributor to vaccine responsiveness in mice. The identification of these biomarkers provides new insights into what immune features may be most important for immune health.
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Project description:BackgroundApoptosis-associated biomarkers are rarely studied, especially their role in predicting the development of tuberculosis (TB) from latent TB infection and in prognostication.MethodsPatients with TB and interferon-gamma release assay (IGRA)-positive and IGRA-negative family contacts were evaluated to analyze changes in apoptosis-associated serum biomarkers, which included decoy receptor 3 (DcR3), prostaglandin 2 (PGE2), and lipoxin. The prognostic implications of these serum biomarkers were also analyzed.ResultsOne hundred TB patients and 92 IGRA-negative and 91 IGRA-positive family contacts were recruited. The DcR3 and PGE2 levels decreased from the IGRA-negative group to the IGRA-positive group, and peaked in the TB group. Lipoxin decreased to trough in the TB group. The three apoptosis serum markers and age were independent factors discriminating active TB from latent TB infection. In active TB, older age, co-morbidity, and higher serum DcR3 and monocyte chemotactic protein (MCP)-1 were independently associated with poorer six-month survival.ConclusionApoptosis-associated serum biomarkers change along with the status of Mycobacterium tuberculosis infection. In close contacts with positive IGRA, high DcR3 and PGE2 and low lipoxin may increase the probability of active TB. Older age, co-morbidity, and high DcR3 and MCP-1 levels might be important prognostic factors that warrant further investigation.
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Project description:The intriguing cell biology of apoptotic cell death results in the externalization of numerous autoantigens on the apoptotic cell surface, including protein determinants for specific recognition, linked to immune responses. Apoptotic cells are recognized by phagocytes and trigger an active immunosuppressive response ("innate apoptotic immunity" (IAI)) even in the absence of engulfment. IAI is responsible for the lack of inflammation associated normally with the clearance of apoptotic cells; its failure also has been linked to inflammatory and autoimmune pathology, including systemic lupus erythematosus and rheumatic diseases. Apoptotic recognition determinants underlying IAI have yet to be identified definitively; we argue that these molecules are surface-exposed (during apoptotic cell death), ubiquitously expressed, protease-sensitive, evolutionarily conserved, and resident normally in viable cells (SUPER). Using independent and unbiased quantitative proteomic approaches to characterize apoptotic cell surface proteins and identify candidate SUPER determinants, we made the surprising discovery that components of the glycolytic pathway are enriched on the apoptotic cell surface. Our data demonstrate that glycolytic enzyme externalization is a common and early aspect of cell death in different cell types triggered to die with distinct suicidal stimuli. Exposed glycolytic enzyme molecules meet the criteria for IAI-associated SUPER determinants. In addition, our characterization of the apoptosis-specific externalization of glycolytic enzyme molecules may provide insight into the significance of previously reported cases of plasminogen binding to α-enolase on mammalian cells, as well as mechanisms by which commensal bacteria and pathogens maintain immune privilege.
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Project description:PurposeWe have previously developed the caspase-based radiotracer, 18F-ICMT-11, for PET imaging to monitor treatment response. We further validated 18F-ICMT-11 specificity in a murine melanoma death-switch tumour model with conditional activation of caspase-3 induced by doxycycline.MethodsCaspase-3/7 activity and cellular uptake of 18F-ICMT-11, 18F-ML-10 and 18F-FDG were assessed in B16ova and B16ovaRevC3 cells after death-switch induction. Death-switch induction was confirmed in vivo in xenograft tumours, and 18F-ICMT-11 and 18F-ML-10 biodistribution was assessed by ex vivo gamma counting of select tissues. PET imaging was performed with 18F-ICMT-11, 18F-ML-10 and 18F-FDG. Caspase-3 activation was confirmed by immunohistochemistry.ResultsSignificantly increased caspase-3/7 activity was observed only in B16ovaRevC3 cells after death-switch induction, accompanied by significantly increased 18F-ICMT-11 (p < 0.001) and 18F-ML-10 (p < 0.05) and decreased 18F-FDG (p < 0.001) uptake compared with controls. B16ova and B16ovaRevC3 tumours had similar growth in vivo; however, B16ovaRevC3 growth was significantly reduced with death-switch induction (p < 0.01). Biodistribution studies showed significantly increased 18F-ICMT-11 tumour uptake following death-switch induction (p < 0.01), but not for 18F-ML-10. Tumour uptake of 18F-ICMT-11 was higher than that of 18F-ML-10 after death-switch induction. PET imaging studies showed that 18F-ICMT-11 can be used to detect apoptosis after death-switch induction, which was accompanied by significantly increased expression of cleaved caspase-3. 18F-FDG signal decreased in tumours after death-switch induction.ConclusionsWe demonstrate that 18F-ICMT-11 can be used to detect caspase-3 activation in a death-switch tumour model, independent of the confounding effects of cancer therapeutics, thus confirming its specificity and supporting the development of this radiotracer for clinical use to monitor tumour apoptosis and therapy response.
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Project description:Ferroptosis, a cell death pathway driven by lipid peroxidation, is implicated in several human diseases including cancer. Although ferroptosis is entwined with apoptosis, it currently has no characteristic biomarkers or gene signature. In this project we established a continuous phenotypic gradient between ferroptosis and apoptosis and coupled it to transcriptomic and metabolomic landscapes. Omics and mechanistic studies revealed that ferroptosis was associated with enhanced MITF activity, lysosomal function, glutaminolysis, TCA cycle, and activation of ATF4, while its transition into apoptosis was attributed to enhanced ER-stress, ATF4/CHOP switch and PE/PC metabolic shift. The gradual ferroptosis-to-apoptosis transcriptomic landscape was used to generate a unique, unbiased transcriptomic predictor, the Gradient Gene Set (GGS), which classified ferroptosis and apoptosis with high accuracy. Further GGS optimization and datasets analysis of various ferroptotic and apoptotic responses revealed highly specific ferroptosis biomarkers, which were robustly validated in vitro and in vivo. A subset of the GGS was correlated with poor prognosis in breast cancer patients and in PDX models and was found to consist of different ferroptosis repressors, including PDAP1, whose knockdown suppressed breast tumor growth in a mouse model. Collectively, this study highlights molecular switches between ferroptosis and apoptosis, uncovering a highly prognostic predictive ferroptosis gene signature, pointing to a few ferroptosis repressors for targeted breast cancer therapy.
2024-03-07 | GSE235201 | GEO
Project description:BackgroundApoptosis is a key mechanism involved in ischemic acute kidney injury (AKI), but its role in septic AKI is controversial. Biomarkers indicative of apoptosis could potentially detect developing AKI prior to its clinical diagnosis.MethodsAs a part of the multicenter, observational FINNAKI study, we performed a pilot study among critically ill patients who developed AKI (n = 30) matched to critically ill patients without AKI (n = 30). We explored the urine and plasma levels of cytokeratin-18 neoepitope M30 (CK-18 M30), cell-free DNA, and heat shock protein 70 (HSP70) at intensive care unit (ICU) admission and 24h thereafter, before the clinical diagnosis of AKI defined by the Kidney Disease: Improving Global Outcomes -creatinine and urine output criteria. Furthermore, we performed a validation study in 197 consecutive patients in the FINNAKI cohort and analyzed the urine sample at ICU admission for CK-18 M30 levels.ResultsIn the pilot study, the urine or plasma levels of measured biomarkers at ICU admission, at 24h, or their maximum value did not differ significantly between AKI and non-AKI patients. Among 20 AKI patients without severe sepsis, the urine CK-18 M30 levels were significantly higher at 24h (median 116.0, IQR [32.3-233.0] U/L) than among those 20 patients who did not develop AKI (46.0 [0.0-54.0] U/L), P = 0.020. Neither urine cell-free DNA nor HSP70 levels significantly differed between AKI and non-AKI patients regardless of the presence of severe sepsis. In the validation study, urine CK-18 M30 level at ICU admission was not significantly higher among patients developing AKI compared to non-AKI patients regardless of the presence of severe sepsis or CKD.ConclusionsOur findings do not support that apoptosis detected with CK-18 M30 level would be useful in assessing the development of AKI in the critically ill. Urine HSP or cell-free DNA levels did not differ between AKI and non-AKI patients.
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Project description:IntroductionOsteoarthritis (OA) is a chronic disease with high morbidity and disability rates whose molecular mechanism remains unclear. This study sought to identify OA markers associated with synovitis and cartilage apoptosis by bioinformatics analysis.MethodsA total of five gene-expression profiles were selected from the Gene Expression Omnibus database. We combined the GEO with the GeneCards database and performed Gene Ontology and Kyoto Encyclopedia of Genes and Genome analyses; then, the least absolute shrinkage and selection operator (LASSO) algorithm was used to identify the characteristic genes, and a predictive risk score was established. We used the uniform manifold approximation and projection (UMAP) method to identify subtypes of OA patients, while the CytoHubba algorithm and GOSemSim R package were used to screen out hub genes. Next, an immunological assessment was performed using single-sample gene set enrichment analysis and CIBERSORTx.ResultsA total of 56OA-related differential genes were selected, and 10 characteristic genes were identified by the LASSO algorithm. OA samples were classified into cluster 1 and cluster 2 subtypes byUMAP, and the clustering results showed that the characteristic genes were significantly different between these groups. MYOC, CYP4B1, P2RY14, ADIPOQ, PLIN1, MFAP5, and LYVE1 were highly expressed in cluster 2, and ANKHLRC15, CEMIP, GPR88, CSN1S1, TAC1, and SPP1 were highly expressed in cluster 1. Protein-protein interaction network analysis showed that MMP9, COL1A, and IGF1 were high nodes, and the differential genes affected the IL-17 pathway and tumor necrosis factor pathway. The GOSemSim R package showed that ADIPOQ, COL1A, and SPP1 are closely related to the function of 31 hub genes. In addition, it was determined that mmp9 and Fos interact with multiple transcription factors, and the ssGSEA and CIBERSORTx algorithms revealed significant differences in immune infiltration between the two OA subtypes. Finally, a qPCR experiment was performed to explore the important genes in rat cartilage and synovium tissues; the qPCR results showed that COL1A and IL-17A were both highly expressed in synovitis tissues and cartilage tissues of OA rats, which is consistent with the predicted results.DiscussionIn the future, common therapeutic targets might be found forsimultaneous remissions of both phenotypes of OA.
| S-EPMC10401591 | biostudies-literature
Project description:Backgrounds:Macrophages are one of HIV reservoirs. Vpr is essential for infection of macrophages by HIV-1 and has the potential to promote survival of macrophages, which could be a highly significant factor in the development and/or maintenance of macrophage viral reservoirs. However, the impact of vpr on macrophages resistance to apoptosis is yet to be comprehended. Methods:We determined the expression profiles of lncRNAs in THP1-MAC and THP1-MAC treated with Vpr peptides using microarray analysis. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to explore their function. We also constructed competing endogenous RNA (ceRNA) networks with bioinformatics methods. Results：We identified 410 lncRNAs that were differentially expressed between THP1-MAC and THP1-MAC after Vpr peptides treatment. Significantly enriched GO terms and pathways were identified, some of which were linked to apoptosis and inflammatory responses. CeRNA analysis showed that lncRNA LINC02249 was paired with the most differentially expressed gene. qRT-PCR results confirmed the reliability of the microarray data. Conclusions：LINC02249 associated ceRNA network may play a role in macrophages resistant to vpr induced apoptosis. This will provide a new avenue for investigating the pathogenesis of macrophages resistant to vpr-induced apoptosis.
2022-08-16 | GSE211274 | GEO