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1.
J Clin Lab Anal ; 36(2): e24232, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34995016

RESUMO

BACKGROUND: Combined biomarkers can improve the sensitivity and specificity of ovarian cancer (OC) diagnosis and effectively predict patient prognosis. This study explored the diagnostic and prognostic values of serum CCL18 and CXCL1 antigens combined with C1D, FXR1, ZNF573, and TM4SF1 autoantibodies in OC. METHODS: CCL18 and CXCL1 monoclonal antibodies and C1D, FXR1, ZNF573, and TM4SF1 antigens were coated with microspheres. Logistic regression was used to construct a serum antigen-antibody combined detection model; receiver-operating characteristic curve (ROC) was used to evaluate the diagnostic efficacy of the model; and the Kaplan-Meier method and Cox regression models were used for survival analysis to evaluate the prognosis of OC. Data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) projects and online survival analysis tools were used to evaluate prognostic genes for OC. The CIBERSORT immune score was used to explore the factors influencing prognosis and their relationship with tumor-infiltrating immune cells. RESULTS: The levels of each index in the blood samples of patients with OC were higher than those of the other groups. The combined detection model has higher specificity and sensitivity in the diagnosis of OC, and its diagnostic efficiency is better than that of CA125 alone and diagnosing other malignant tumors. CCL18 and TM4SF1 may be factors affecting the prognosis of OC, and CCL18 may be related to immune-infiltrating cells. CONCLUSIONS: The serum antigen-antibody combined detection model established in this study has high sensitivity and specificity for the diagnosis of OC.


Assuntos
Autoanticorpos/sangue , Biomarcadores Tumorais/sangue , Quimiocina CXCL1/sangue , Quimiocinas CC/sangue , Neoplasias Ovarianas/diagnóstico , Antígenos de Superfície/imunologia , Proteínas Correpressoras/imunologia , Feminino , Humanos , Imunoglobulina G/sangue , Proteínas de Neoplasias/imunologia , Prognóstico , Proteínas de Ligação a RNA/imunologia , Valores de Referência , Sensibilidade e Especificidade
2.
Mol Cell ; 81(5): 953-968.e9, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33503407

RESUMO

While the role of transcription factors and coactivators in controlling enhancer activity and chromatin structure linked to gene expression is well established, the involvement of corepressors is not. Using inflammatory macrophage activation as a model, we investigate here a corepressor complex containing GPS2 and SMRT both genome-wide and at the Ccl2 locus, encoding the chemokine CCL2 (MCP-1). We report that corepressors co-occupy candidate enhancers along with the coactivators CBP (H3K27 acetylase) and MED1 (mediator) but act antagonistically by repressing eRNA transcription-coupled H3K27 acetylation. Genome editing, transcriptional interference, and cistrome analysis reveals that apparently related enhancer and silencer elements control Ccl2 transcription in opposite ways. 4C-seq indicates that corepressor depletion or inflammatory signaling functions mechanistically similarly to trigger enhancer activation. In ob/ob mice, adipose tissue macrophage-selective depletion of the Ccl2 enhancer-transcribed eRNA reduces metaflammation. Thus, the identified corepressor-eRNA-chemokine pathway operates in vivo and suggests therapeutic opportunities by targeting eRNAs in immuno-metabolic diseases.


Assuntos
Quimiocina CCL2/genética , Proteínas Correpressoras/genética , Elementos Facilitadores Genéticos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Correpressor 2 de Receptor Nuclear/genética , Obesidade/genética , Elementos Silenciadores Transcricionais , Tecido Adiposo/imunologia , Tecido Adiposo/patologia , Animais , Sistemas CRISPR-Cas , Quimiocina CCL2/imunologia , Proteínas Correpressoras/imunologia , Edição de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Histona Acetiltransferases/genética , Histona Acetiltransferases/imunologia , Histonas/genética , Histonas/imunologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Subunidade 1 do Complexo Mediador/genética , Subunidade 1 do Complexo Mediador/imunologia , Camundongos , Camundongos Obesos , Correpressor 2 de Receptor Nuclear/imunologia , Obesidade/imunologia , Obesidade/patologia , Células RAW 264.7 , RNA não Traduzido/genética , RNA não Traduzido/imunologia , Transdução de Sinais
3.
J Clin Invest ; 130(4): 1830-1842, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31917688

RESUMO

Foxp3+ Tregs are key to immune homeostasis, but the contributions of various large, multiprotein complexes that regulate gene expression remain unexplored. We analyzed the role in Tregs of the evolutionarily conserved CoREST complex, consisting of a scaffolding protein, Rcor1 or Rcor2, plus Hdac1 or Hdac2 and Lsd1 enzymes. Rcor1, Rcor2, and Lsd1 were physically associated with Foxp3, and mice with conditional deletion of Rcor1 in Foxp3+ Tregs had decreased proportions of Tregs in peripheral lymphoid tissues and increased Treg expression of IL-2 and IFN-γ compared with what was found in WT cells. Mice with conditional deletion of the gene encoding Rcor1 in their Tregs had reduced suppression of homeostatic proliferation, inability to maintain long-term allograft survival despite costimulation blockade, and enhanced antitumor immunity in syngeneic models. Comparable findings were seen in WT mice treated with CoREST complex bivalent inhibitors, which also altered the phenotype of human Tregs and impaired their suppressive function. Our data point to the potential for therapeutic modulation of Treg functions by pharmacologic targeting of enzymatic components of the CoREST complex and contribute to an understanding of the biochemical and molecular mechanisms by which Foxp3 represses large gene sets and maintains the unique properties of this key immune cell.


Assuntos
Proteínas Correpressoras/imunologia , Imunidade Celular , Complexos Multiproteicos/imunologia , Neoplasias Experimentais/imunologia , Proteínas do Tecido Nervoso/imunologia , Linfócitos T Reguladores/imunologia , Animais , Linhagem Celular Tumoral , Proteínas Correpressoras/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Complexos Multiproteicos/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Proteínas do Tecido Nervoso/genética , Linfócitos T Reguladores/patologia
4.
Nat Commun ; 8(1): 624, 2017 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-28935892

RESUMO

The innate inflammatory response contributes to secondary injury in brain trauma and other disorders. Metabolic factors such as caloric restriction, ketogenic diet, and hyperglycemia influence the inflammatory response, but how this occurs is unclear. Here, we show that glucose metabolism regulates pro-inflammatory NF-κB transcriptional activity through effects on the cytosolic NADH:NAD+ ratio and the NAD(H) sensitive transcriptional co-repressor CtBP. Reduced glucose availability reduces the NADH:NAD+ ratio, NF-κB transcriptional activity, and pro-inflammatory gene expression in macrophages and microglia. These effects are inhibited by forced elevation of NADH, reduced expression of CtBP, or transfection with an NAD(H) insensitive CtBP, and are replicated by a synthetic peptide that inhibits CtBP dimerization. Changes in the NADH:NAD+ ratio regulate CtBP binding to the acetyltransferase p300, and regulate binding of p300 and the transcription factor NF-κB to pro-inflammatory gene promoters. These findings identify a mechanism by which alterations in cellular glucose metabolism can influence cellular inflammatory responses.Several metabolic factors affect cellular glucose metabolism as well as the innate inflammatory response. Here, the authors show that glucose metabolism regulates pro-inflammatory responses through effects on the cytosolic NADH:NAD+ ratio and the NAD(H)-sensitive transcription co-repressor CtBP.


Assuntos
Oxirredutases do Álcool/imunologia , Proteínas Correpressoras/imunologia , Proteínas de Ligação a DNA/imunologia , Imunidade Inata , Fosfoproteínas/imunologia , Transcrição Gênica , Oxirredutases do Álcool/genética , Oxirredutases do Álcool/metabolismo , Animais , Sítios de Ligação , Proteínas Correpressoras/genética , Proteínas Correpressoras/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Dimerização , Metabolismo Energético , Glucose/imunologia , Glucose/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Microglia/imunologia , Microglia/metabolismo , NAD/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Células RAW 264.7 , Ratos , Transdução de Sinais , Fatores de Transcrição de p300-CBP/genética , Fatores de Transcrição de p300-CBP/imunologia , Fatores de Transcrição de p300-CBP/metabolismo
5.
J Virol ; 91(1)2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27795407

RESUMO

Neuroinvasive herpesviruses have evolved to efficiently infect and establish latency in neurons. The nervous system has limited capability to regenerate, so immune responses therein are carefully regulated to be nondestructive, with dependence on atypical intrinsic and innate defenses. In this article we review studies of some of these noncanonical defense pathways and how herpesvirus gene products counter them, highlighting the contributions that primary neuronal in vitro models have made to our understanding of this field.


Assuntos
Inativação Gênica , Herpesviridae/crescimento & desenvolvimento , Evasão da Resposta Imune , Neurônios/virologia , Latência Viral/imunologia , Autofagia/genética , Autofagia/imunologia , Transporte Axonal , Proteínas Correpressoras/genética , Proteínas Correpressoras/imunologia , Herpesviridae/imunologia , Histona Desacetilases/genética , Histona Desacetilases/imunologia , Histona Desmetilases/genética , Histona Desmetilases/imunologia , Humanos , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/imunologia , Imunidade Inata , Interferons/genética , Interferons/imunologia , MicroRNAs/genética , MicroRNAs/imunologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/imunologia , Neurônios/imunologia , Transdução de Sinais , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia
6.
Cell Immunol ; 275(1-2): 80-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22483981

RESUMO

Physical and psychological stressors reduce natural killer cell function. This reduction in cellular function results from stress-induced release of glucocorticoids. Glucocorticoids act upon natural killer cells to deacetylate and transrepress immune response genes through epigenetic processes. However, other than the glucocorticoid receptor, the proteins that participate in this process are not well described in natural killer cells. The purpose of this study was to identify the proteins associated with the glucocorticoid receptor that are likely epigenetic participants in this process. Treatment of natural killer cells with the synthetic glucocorticoid, dexamethasone, produced a significant time dependent reduction in natural killer cell activity as early as 8h post treatment. This reduction in natural killer cell activity was preceded by nuclear localization of the glucocorticoid receptor with histone deacetylase 1 and the corepressor, SMRT. Other class I histone deacetylases were not associated with the glucocorticoid receptor nor was the corepressor NCoR. These results demonstrate histone deacetylase 1 and SMRT to associate with the ligand activated glucocorticoid receptor within the nuclei of natural killer cells and to be the likely participants in the histone deacetylation and transrepression that accompanies glucocorticoid mediated reductions in natural killer cell function.


Assuntos
Proteínas Correpressoras/imunologia , Histona Desacetilases/imunologia , Células Matadoras Naturais/imunologia , Receptores de Glucocorticoides/imunologia , Linhagem Celular Tumoral , Dexametasona/farmacologia , Humanos , Células Matadoras Naturais/efeitos dos fármacos
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