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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.
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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 SinaisRESUMO
The mechanisms underlying human natural killer (NK) cell phenotypic and functional heterogeneity are unknown. Here, we describe the emergence of diverse subsets of human NK cells selectively lacking expression of signaling proteins after human cytomegalovirus (HCMV) infection. The absence of B and myeloid cell-related signaling protein expression in these NK cell subsets correlated with promoter DNA hypermethylation. Genome-wide DNA methylation patterns were strikingly similar between HCMV-associated adaptive NK cells and cytotoxic effector T cells but differed from those of canonical NK cells. Functional interrogation demonstrated altered cytokine responsiveness in adaptive NK cells that was linked to reduced expression of the transcription factor PLZF. Furthermore, subsets of adaptive NK cells demonstrated significantly reduced functional responses to activated autologous T cells. The present results uncover a spectrum of epigenetically unique adaptive NK cell subsets that diversify in response to viral infection and have distinct functional capabilities compared to canonical NK cell subsets.
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Anticorpos/imunologia , Infecções por Citomegalovirus/genética , Epigênese Genética/imunologia , Células Matadoras Naturais/imunologia , Fatores de Transcrição Kruppel-Like/imunologia , Linfócitos T Citotóxicos/imunologia , Imunidade Adaptativa , Proliferação de Células , Citomegalovirus/imunologia , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/patologia , Infecções por Citomegalovirus/virologia , Metilação de DNA , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Perfilação da Expressão Gênica , Humanos , Imunofenotipagem , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Células Matadoras Naturais/classificação , Células Matadoras Naturais/patologia , Células Matadoras Naturais/virologia , Fatores de Transcrição Kruppel-Like/deficiência , Fatores de Transcrição Kruppel-Like/genética , Análise em Microsséries , Subfamília C de Receptores Semelhantes a Lectina de Células NK/deficiência , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Regiões Promotoras Genéticas , Proteína com Dedos de Zinco da Leucemia Promielocítica , Proteínas Tirosina Quinases/deficiência , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/imunologia , Receptores de IgG/deficiência , Receptores de IgG/genética , Receptores de IgG/imunologia , Transdução de Sinais , Quinase Syk , Linfócitos T Citotóxicos/patologia , Linfócitos T Citotóxicos/virologia , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Fatores de Transcrição/imunologiaRESUMO
BACKGROUND: The atherogenic index of plasma (AIP) is considered an independent risk factor for coronary artery disease (CAD). The present study investigated whether AIP correlates with the formation of coronary collateral circulation (CCC) in CAD patients with chronic total occlusion (CTO). METHODS: This retrospective study included 1093 CAD patients with CTO confirmed by coronary angiography from January 2020 to December 2020 at Beijing Anzhen Hospital. Based on the Rentrop scoring system, the patients were divided into the good CCC group and the poor CCC group. AIP was calculated by log (triglyceride/high-density lipoprotein cholesterol). Meanwhile, the study population was further divided into four groups according to the quartiles of AIP. RESULTS: Patients in the poor CCC group exhibited significantly higher AIP compared to those in the good CCC group (0.31 ± 0.27 vs. 0.14 ± 0.24, p < 0.001). Multivariate logistic regression analysis revealed an independent association between AIP and poor CCC, regardless of whether AIP was treated as a continuous or categorical variable (p < 0.001), after adjusting for confounding factors. Besides, this association remained consistent across most subgroups. The incorporation of AIP into the baseline model significantly enhanced the accuracy of identifying poor CCC [area under the curve (AUC): baseline model, 0.661 vs. baseline model + AIP, 0.721, p for comparison < 0.001]. CONCLUSIONS: Elevated AIP is independently associated with an increased risk of poor CCC in CAD patients with CTO, and AIP may improve the ability to identify poor CCC in clinical practice.
Assuntos
Biomarcadores , Circulação Colateral , Angiografia Coronária , Circulação Coronária , Oclusão Coronária , Humanos , Masculino , Oclusão Coronária/fisiopatologia , Oclusão Coronária/diagnóstico por imagem , Oclusão Coronária/sangue , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Doença Crônica , Biomarcadores/sangue , Medição de Risco , Doença da Artéria Coronariana/fisiopatologia , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Valor Preditivo dos Testes , Triglicerídeos/sangue , HDL-Colesterol/sangue , Fatores de Risco , PrognósticoRESUMO
Objective: Investigate the Correlation Between the Severity of Coronary Artery Disease and Retinal Artery Disease, and assess the Efficacy of Angiotensin-Converting Enzyme Inhibitors (ACEIs) Application. Methods: One hundred patients diagnosed with primary hypertension at our hospital were chosen for the study. All patients underwent dual-source 64-layer spiral CT coronary angiography and fundus photography examination. Based on the extent of coronary artery stenosis, the patients were divided into Group A, Group B, Group C, and Group D. Results: In comparison with patients in Group A, individuals in Groups B, C, and D exhibited a notable increase in the severity of retinal artery stenosis and arteriovenous crossing signs (P < .05). Furthermore, the severity of retinal artery stenosis and arteriovenous crossing signs demonstrated an incremental trend with the severity of coronary artery stenosis (P < .05). The arteriovenous crossing sign exhibited a sensitivity of 47.87%, the specificity of 89.21%, positive predictive value of 89.76%, and the negative predictive value of 46.53% for predicting coronary artery stenosis. After treatment, the blood pressure levels of the patients, both systolic (SBP) and diastolic blood pressure (DBP) levels significantly decreased compared to before treatment. Conclusion: A significant positive correlation was observed between the severity of coronary artery lesions and retinal artery lesions. Assessing alterations in retinal blood vessels in hypertensive patients can effectively indicate the extent of coronary artery stenosis indirectly. Concerning medication, the antihypertensive drug captopril demonstrated the potential to alleviate the severity of coronary artery and retinal artery lesions in hypertensive patients. However, specific treatment methods should be tailored to individual patient circumstances.
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BACKGROUND: The triglyceride-glucose (TyG) index, which is a reliable substitute indicator for insulin resistance, has been considered an independent risk factor for long-term outcomes in patients with cardiovascular disease. However, it remains unknown whether the TyG index is associated with poor prognosis in acute coronary syndrome (ACS) patients with prior coronary artery bypass grafting (CABG) undergoing percutaneous coronary intervention (PCI). METHODS: A total of 1158 ACS patients with prior CABG undergoing PCI were retrospectively studied. The TyG index was calculated by ln[fasting triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2]. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), a composite of all-cause death, nonfatal myocardial infarction, nonfatal stroke, and unplanned repeat revascularization. RESULTS: During a median of 42-month follow-up, 350 patients (30.2%) experienced at least one endpoint event. Based on the optimal cut-off value of the TyG index, patients were divided into the high TyG index group and the low TyG index group. Patients in the high TyG index group had higher risks of MACCE (35.3% vs. 25.3%, p < 0.001), major adverse cardiovascular events (MACE) (31.1% vs. 23.4%, p = 0.003), nonfatal stroke (4.2% vs. 1.9%, p = 0.022) and unplanned repeat revascularization (19.4% vs. 11.3%, p < 0.001) than those in the low TyG index group. Cox regression analysis demonstrated that there was an independent association between the TyG index and MACCE regardless of whether the TyG index was a continuous or categorical variable (HR 1.42, 95% CI 1.09-1.86, p = 0.009; HR 1.53, 95% CI 1.16-2.01, p = 0.003, respectively). Restricted cubic spline curve exhibited that the relationship between the TyG index and MACCE was linear (p for non-linear = 0.595, p for overall = 0.005). By incorporating the TyG index groups into baseline risk model, the accuracy of predicting MACCE was improved [AUC: baseline risk model, 0.618 vs. baseline risk model + TyG index groups, 0.636, p for comparison = 0.042]. CONCLUSIONS: The TyG index is independently associated with MACCE, suggesting that the TyG index may serve as a valid indicator for predicting poor prognosis in ACS patients with prior CABG undergoing PCI.
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Síndrome Coronariana Aguda , Doença da Artéria Coronariana , Intervenção Coronária Percutânea , Acidente Vascular Cerebral , Humanos , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/cirurgia , Glucose , Intervenção Coronária Percutânea/efeitos adversos , Triglicerídeos , Estudos Retrospectivos , Ponte de Artéria Coronária/efeitos adversos , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etiologia , Prognóstico , Doença da Artéria Coronariana/etiologiaRESUMO
The memory CD8 T-cell pool must select for clones that bind immunodominant epitopes with high affinity to efficiently counter reinfection. At the same time, it must retain a level of clonal diversity to allow recognition of pathogens with mutated epitopes. How the level of diversity within the memory pool is controlled is unclear, especially in the context of a selective drive for antigen affinity. We find that preservation of clones that bind the activating antigen with low affinity depends on expression of the transcription factor Eomes in the first days after antigen encounter. Eomes is induced at low activating signal strength and directly drives transcription of the prosurvival protein Bcl-2. At higher signal intensity, T-bet is induced which suppresses Bcl-2 and causes a relative survival advantage for cells of low affinity. Clones activated with high-affinity antigen form memory largely independent of Eomes and have a proliferative advantage over clones that bind the same antigen with low affinity. This causes high-affinity clones to prevail in the memory pool, despite their relative survival deficit. Genetic or therapeutic targeting of the Eomes/Bcl-2 axis reduces the clonal diversity of the memory pool, which diminishes its ability to respond to pathogens carrying mutations in immunodominant epitopes. Thus, we demonstrate on a molecular level how sufficient diversity of the memory pool is established in an environment of affinity-based selection.
Assuntos
Apoptose/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Proteínas com Domínio T/imunologia , Animais , Variação Antigênica/imunologia , Sobrevivência Celular/imunologia , Células Cultivadas , Seleção Clonal Mediada por Antígeno/genética , Seleção Clonal Mediada por Antígeno/imunologia , Regulação da Expressão Gênica/imunologia , Ativação Linfocitária , Camundongos , Células Precursoras de Linfócitos T/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais , Proteínas com Domínio T/genéticaRESUMO
Background and Aims: Epicardial adipose tissue, exosomes, and miRNAs have important activities in atherosclerosis. The purpose of this study was to establish miRNA expression profiles of epicardial adipose tissue-derived exosomes in patients with coronary atherosclerosis. Methods: Biopsies of epicardial adipose tissue were obtained from patients with and without coronary artery disease (CAD, n = 12 and NCAD, n = 12) during elective open-heart surgeries. Tissue was incubated with DMEM-F12 for 24 hours. Exosomes were isolated, then nanoparticle tracking analysis, transmission electron microscopy, and immunoblotting were performed to confirm the existence of exosomes. Total RNA in exosomes was subjected to high-throughput sequencing to identify differentially expressed miRNAs. MicroRNA target gene prediction was performed, and target genes were analyzed by Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and mirPath to identify function. Reverse transcription quantitative PCR was performed to confirm the differentially expressed miRNAs. Results: Fifty-three unique miRNAs were identified (adjusted p < 0.05, fold of change > 2), among which 32 miRNAs were upregulated and 21 miRNAs were downregulated in coronary artery disease patients. Reverse transcription quantitative PCR validated the results for seven miRNAs including miR-141-3p, miR-183-5p, miR-200a-5p, miR-205-5p, miR-429, miR-382-5p and miR-485-3p, with the last two downregulated. GO and KEGG analysis by mirPath indicated that these differentially expressed miRNAs were enriched in cell survival, apoptosis, proliferation, and differentiation. Conclusions: Coronary artery disease patients showed differential epicardial adipose tissue exosomal miRNA expression compared with patients without coronary artery disease. The results provide clues for further studies of mechanisms of atherosclerosis.
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BACKGROUND: The triglyceride-glucose (TyG) index is an alternative marker of insulin resistance (IR) and is closely associated with the prevalence and prognosis of atherosclerotic cardiovascular disease (ASCVD). However, the association between the TyG index and in-stent restenosis (ISR) after drug-eluting stent (DES) implantation in patients with acute coronary syndrome (ACS) remains unknown. METHODS: The present study retrospectively recruited patients who were admitted for ACS and underwent coronary angiography at 6 to 24 months after successful DES-based percutaneous coronary intervention (PCI). In addition, we calculated the TyG index with the following formula: Ln(fasting triglyceride [mg/dL] × fasting blood glucose [mg/dL]/2) and divided patients into 3 groups according to the tertile of the TyG index. Most importantly, multivariate logistic regression analysis models were also constructed to assess the association between the TyG index and DES-ISR in patients with ACS. RESULTS: A total of 1574 patients with ACS (58.4 ± 9.4 years, 77.4% male) were included in this study. At the median follow-up time of 12 (9-14) months, the prevalence of DES-ISR increased stepwise with the increasing tertile of the TyG index (11.6% vs 17.3% vs 19.4%, p = 0.002), and the TyG index was also higher in the ISR group than in the non-ISR group (9.00 ± 0.58 vs 8.84 ± 0.61, p < 0.001). In addition, the positive association between the TyG index and the prevalence of DES-ISR was also determined in the fully adjusted model (TyG, per 1-unit increase: OR 1.424, 95% CI 1.116 to 1.818, p = 0.005; tertile of TyG, the OR (95% CI) values for tertile 2 and tertile 3 were 1.454 (1.013 to 2.087) and 1.634 (1.125 to 2.374), respectively, with tertile 1 as a reference). The association was also reflected in most subgroups. Moreover, adding the TyG index to the predictive model for DES-ISR in patients with ACS could contribute to an increase in C-statistics (0.675 vs 0.659, p = 0.010), categorical net reclassification improvement (0.090, p < 0.001), and integrated discrimination improvement (0.004, p = 0.040). CONCLUSION: An elevated TyG index was independently and positively associated with DES-ISR in patients with ACS who underwent PCI. However, the incremental predictive value of the TyG index for DES-ISR was slight. To further confirm our findings, future studies are needed.
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Síndrome Coronariana Aguda/terapia , Glicemia/metabolismo , Reestenose Coronária/epidemiologia , Resistência à Insulina , Intervenção Coronária Percutânea , Triglicerídeos/sangue , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/diagnóstico por imagem , Síndrome Coronariana Aguda/epidemiologia , Idoso , Pequim/epidemiologia , Biomarcadores/sangue , Angiografia Coronária , Reestenose Coronária/sangue , Reestenose Coronária/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Valor Preditivo dos Testes , Prevalência , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Recent studies have substantiated the role of the triglyceride glucose (TyG) index in predicting the prognosis of coronary artery disease (CAD) patients, while no relevant studies have revealed the association between the TyG index and coronary collateralization in the event of coronary chronic total occlusion (CTO). The current study intends to explore whether, or to what extent, the TyG index is associated with impaired collateralization in CAD patients with CTO lesions. METHODS: The study enrolled 1093 CAD patients undergoing cardiac catheterization for at least one CTO lesion. Data were collected from the Beijing Anzhen Hospital record system. The degree of collaterals was determined according to the Rentrop classification system. The correlation between the TyG index and coronary collateralization was assessed. RESULTS: Overall, 318 patients were included in a less developed collateralization (Rentrop classification 0-1) group. The TyG index was significantly higher in patients with impaired collateralization (9.3±0.65 vs. 8.8±0.53, P<0.001). After adjusting for various confounding factors, the TyG index remained correlated with the occurrence of impaired collateralization, with odds ratios (ORs) of 1.59 and 5.72 in the T2 and T3 group compared with the first tertile group (P<0.001). In addition, subgroup analysis showed that higher TyG index values remained strongly associated with increased risk of less developed collateralization. To compare the risk assessment efficacy for the formation of collateralization between the TyG index and other metabolic abnormality indicators, an area under the receiver-operating characteristic (ROC) curve (AUC) was obtained. A significant improvement in the risk assessment performance for impaired collateralization emerged when adding the TyG index into a baseline model. CONCLUSIONS: The increased TyG index is strongly associated with less developed collateralization in CAD patients with CTO lesions and its risk assessment performance is better than single metabolic abnormality indicators.
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Glicemia/análise , Circulação Colateral , Doença da Artéria Coronariana/sangue , Oclusão Coronária/sangue , Triglicerídeos/sangue , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/fisiopatologia , Oclusão Coronária/diagnóstico , Oclusão Coronária/etiologia , Oclusão Coronária/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de RiscoRESUMO
AIM: To present the first case series of patients with Langerhans cell histiocytosis (LCH) also affected by Crohn's disease (CD), both of which are granulomatous diseases, and in LCH investigate the role of interleukin (IL)-23, which is a well-described disease mediator in CD. METHODS: A case series of three patients with LCH and CD were described; a cohort of LCH patients (n = 55) as well as controls (n = 55) were analysed for circulating IL-23 levels; and the relation between the percentage of LCH cells in lesions and circulating IL-23 levels was analysed in seven LCH patients. RESULTS: Differential diagnostic challenges for these two granulomatous diseases were highlighted in the case series, and it took up to 3 years to diagnose CD. Elevated IL-23 levels were found in LCH patients. The amount of lesional LCH cells correlated with the levels of circulating IL-23. CONCLUSION: Both CD and LCH should be considered in patients with inflammatory gastrointestinal involvement. The IL-23 pathway is a common immunological trait between these two granulomatous diseases.
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Doença de Crohn , Histiocitose de Células de Langerhans , Doença de Crohn/diagnóstico , Histiocitose de Células de Langerhans/diagnóstico , Humanos , Interleucina-23RESUMO
Heterozygous GATA2 mutation is associated with immunodeficiency, lymphedema, and myelodysplastic syndrome. Disease presentation is variable, often coinciding with loss of circulating dendritic cells, monocytes, B cells, and natural killer (NK) cells. Nonetheless, in a proportion of patients carrying GATA2 mutation, NK cells persist. We found that peripheral blood NK cells in symptomatic patients uniformly lacked expression of the transcription factor promyelocytic leukemia zinc finger (PLZF), as well as expression of intracellular signaling proteins FcεRγ, spleen tyrosine kinase (SYK), and EWS/FLI1-Activated Transcript 2 (EAT-2) in a variegated manner. Moreover, consistent with an adaptive identity, NK cells from patients with GATA2 mutation displayed altered expression of cytotoxic granule constituents and produced interferon-γ upon Fc-receptor engagement but not following combined interleukin-12 (IL-12) and IL-18 stimulation. Canonical, PLZF-expressing NK cells were retained in asymptomatic carriers of GATA2 mutation. Developmentally, GATA-binding protein-2 (GATA-2) was expressed in hematopoietic stem cells, but not in NK-cell progenitors, CD3-CD56bright, canonical, or adaptive CD3-CD56dim NK cells. Peripheral blood NK cells from individuals with GATA2 mutation proliferated normally in vitro, whereas lineage-negative progenitors displayed impaired NK-cell differentiation. In summary, adaptive NK cells can persist in patients with GATA2 mutation, even after NK-cell progenitors expire. Moreover, our data suggest that adaptive NK cells are more long-lived than canonical, immunoregulatory NK cells.
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Proliferação de Células , Fator de Transcrição GATA2 , Células-Tronco Hematopoéticas/imunologia , Células Matadoras Naturais/imunologia , Mutação , Adolescente , Adulto , Proteínas de Ligação a Calmodulina/genética , Proteínas de Ligação a Calmodulina/imunologia , Criança , Feminino , Fator de Transcrição GATA2/genética , Fator de Transcrição GATA2/imunologia , Humanos , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-18/genética , Interleucina-18/imunologia , Masculino , Pessoa de Meia-Idade , Proteína EWS de Ligação a RNA , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/imunologia , Receptores de IgE/genética , Receptores de IgE/imunologia , Quinase Syk/genética , Quinase Syk/imunologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologiaRESUMO
BACKGROUND: Recent studies have indicated that monocyte chemoattractant protein-1 (MCP-1) plays an important role in the initiation and progression of ischaemic heart disease. However, no previous research has investigated the correlation between serum MCP-1 levels and early changes in myocardial function in patients with ST-segmental elevation myocardial infarction (STEMI) after primary percutaneous coronary intervention (PCI). METHODS: A total of 87 STEMI patients who had undergone a successful primary PCI were consecutively recruited. All the patients included in this study were grouped into two subgroups according to the median value of MCP-1 upon admission. An early change in left ventricular ejection fraction (LVEF) was defined as (LVEF at 3 months post-STEMI)-(LVEF at 2 days post-STEMI). RESULTS: Serum MCP-1 levels increased gradually over time during the first 72 h after the onset of STEMI. The concentration of hypersensitive cardiac troponin I (hs-cTnI) upon admission as well as at 24 h and 72 h after primary PCI, especially the peak hs-cTnI concentration, declined significantly in the low admission MCP-1 group. As continuous variable, admission MCP-1 also correlated positively with admission hs-cTnI, hs-cTnI at 24 h after primary PCI, and peak hs-cTnI. Additionally, the absolute early change in LVEF improved markedly in the low admission MCP-1 group (3.77% ± 6.05% vs - 0.18% ± 7.69%, p = 0.009) compared to that in the high admission MCP-1 group. Most importantly, the global LVEF in the low admission MCP-1 group also improved significantly at 3 months compared to baseline LVEF (55.79% ± 7.05% vs 59.60% ± 6.51%, p = 0.011), while an improvement in global LVEF was not observed in the high admission MCP-1 group. Furthermore, as a continuous variable, the MCP-1 level up admission also correlated negatively with early changes in LVEF (r = - 0.391, p = 0.001). After assessment by multiple linear regression analysis, the MCP-1 level upon admission remained correlated with early changes in LVEF [beta = - 0.089, 95% CI (- 0.163 to - 0.015), p = 0.020]. CONCLUSION: MCP-1 upon admission not only correlated positively with hs-cTnI at different time points and peak hs-cTnI, but also associated inversely with early improvements in myocardial function in patients with first STEMI. So we speculated that suppression the expression of MCP-1 via various ways may be a promising therapeutic target in myocardial I/R injury in the future.
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Quimiocina CCL2/sangue , Admissão do Paciente , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Volume Sistólico , Função Ventricular Esquerda , Adulto , Idoso , Pequim , Biomarcadores/sangue , Estudos Transversais , Humanos , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Regulação para CimaRESUMO
Dendritic cells (DCs) involved in proinflammatory immune responses derive mainly from peripheral monocytes, and the cells subsequently mature and migrate into the inflammatory micromilieu. Here we report that suppressing of 15-lipoxygenase-1 led to a substantial reduction in DC spreading and podosome formation in vitro. The surface expression of CD83 was significantly lower in both sh-15-lipoxygenase-1 (15-LOX-1)-transduced cells and DCs cultivated in the presence of a novel specific 15-LOX-1 inhibitor. The T-cell response against tetanus-pulsed DCs was only affected to a minor extent on inhibition of 15-LOX-1. In contrast, endocytosis and migration ability of DCs were significantly suppressed on 15-LOX-1 inhibition. The expression of 15-LOX-1 in DCs was also demonstrated in affected human skin in atopic and contact dermatitis, showing that the enzyme is indeed expressed in inflammatory diseases in vivo. This study demonstrated that inhibiting 15-LOX-1 led to an impaired podosome formation in DCs, and consequently suppressed antigen uptake and migration capacity. These results indicated that 15-LOX-1 is a potential target for inhibiting the trafficking of DCs to lymphoid organs and inflamed tissues and decreasing the inflammatory response attenuating symptoms of certain immunologic and inflammatory disorders such as dermatitis.-Han, H., Liang, X., Ekberg, M., Kritikou, J. S., Brunnström, Å., Pelcman, B., Matl, M., Miao, X., Andersson, M., Yuan, X., Schain, F., Parvin, S., Melin, E., Sjöberg, J., Xu, D., Westerberg, L. S., Björkholm, M., Claesson, H.-E. Human 15-lipoxygenase-1 is a regulator of dendritic-cell spreading and podosome formation.
Assuntos
Araquidonato 15-Lipoxigenase/metabolismo , Citocinas/metabolismo , Células Dendríticas/fisiologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Podossomos/fisiologia , Araquidonato 15-Lipoxigenase/genética , Movimento Celular/fisiologia , Citocinas/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Células de Langerhans/metabolismo , Monócitos , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismoRESUMO
Contrast-induced acute kidney injury (CI-AKI) is associated with increasing in-hospital and long-term adverse clinical outcomes in high-risk patients undergoing percutaneous coronary intervention (PCI). Contrast media (CM)-induced renal tubular cell apoptosis is reported to participate in this process by activating endoplasmic reticulum (ER) stress. An angiotensin II type 1 receptor (AT1R) antagonist can alleviate ER stress-induced renal apoptosis in streptozotocin (STZ)-induced diabetic mice and can reduce CM-induced renal apoptosis by reducing oxidative stress and reversing the enhancement of bax mRNA and the reduction of bcl-2 mRNA, but the effect of the AT1R blocker on ER stress in the pathogenesis of CI-AKI is still unknown. In this study, we explored the effect of valsartan on meglumine diatrizoate-induced human renal tubular cell apoptosis by measuring changes in ER stress-related biomarkers. The results showed that meglumine diatrizoate caused significant cell apoptosis by up-regulating the expression of ER stress markers, including glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), CCAAT/enhancer-binding protein-homologous protein (CHOP) and caspase 12, in a time- and dose-dependent manner, which could be alleviated by preincubation with valsartan. In conclusion, valsartan had a potential nephroprotective effect on meglumine diatrizoate-induced renal cell apoptosis by inhibiting ER stress.
Assuntos
Apoptose/fisiologia , Meios de Contraste/toxicidade , Estresse do Retículo Endoplasmático/fisiologia , Valsartana/farmacologia , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Túbulos Renais/citologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/fisiologia , Camundongos , Substâncias Protetoras/farmacologiaRESUMO
Classical Hodgkin lymphoma (cHL) has a unique pathological feature characterized by a minority of malignant Hodgkin Reed-Sternberg (H-RS) cells surrounded by numerous inflammatory cells. Cysteinyl-leukotrienes (CysLTs) are produced by eosinophils, macrophages and mast cells in the HL tumor microenvironment. In the present study we have explored the signal transduction pathways leading to leukotriene (LT) D4 induced expression of cytokines in the Hodgkin lymphoma cell line L1236 and KM-H2. Stimulation of L1236 and KM-H2 cells with LTD4 led to a concentration- and time-dependent increase at the transcriptional level of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-8, chemokine (C-C motif) ligand 3 (CCL3) and CCL4. The expression of several transcription factors was induced upon stimulation of Hodgkin cell lines with LTD4. Among these, EGR-1 was required for cytokine production. Inhibition of EGR-1 expression using shEGR-1 transduced by lentivirus led to suppression of the expression of TNF-α and IL-6. The effect of LTD4 on the expression of transcription factors and cytokines were also blocked by the specific CysLT1 receptor antagonist zafirlukast. These results demonstrate that EGR-1 plays a critical role in LTD4-induced cytokine transcription in Hodgkin cell lines.
Assuntos
Citocinas/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Doença de Hodgkin/patologia , Leucotrieno D4/farmacologia , Transcrição Gênica/efeitos dos fármacos , Linhagem Celular Tumoral , Proteína 1 de Resposta de Crescimento Precoce/deficiência , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Doença de Hodgkin/genética , Humanos , Receptores de Leucotrienos/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
PURPOSE: We aimed to describe the facilitators and barriers of physical activity for patients with coronary heart disease. METHODS: A qualitative descriptive study using semi-structured interviews was conducted with 15 participants with coronary heart disease. The interview guide was developed based on a multi-theory model. Interviews were audio-recorded, transcribed verbatim, and analyzed using a thematic analysis. RESULTS: Two main themes were identified: facilitators of initiation and maintenance of physical activity (behavioral motivation, perceived benefits, behavioral confidence, supportive physical environment, positive emotional experience, self-regulation, supportive social environment, illness perception, and excellent self-control), barriers of initiation and maintenance of physical activity (perceived barriers, restricted physical environment, psychological distress, insufficient social support, and poor self-control). CONCLUSIONS: This study presents an in-depth theory-based exploration of facilitators and barriers to initiating and maintaining physical activity among people with coronary heart disease. Relevant factors should be taken into account to increase their effectiveness when designing the target interventions to encourage a physically active lifestyle in this population.
Before commencing cardiac rehabilitation, it is imperative to assess patients with coronary heart disease (CHD) to ascertain whether they have limited activity capacity, psychological distress, insufficient social support, and poor self-control.A customized cardiac rehabilitation plan should be meticulously devised for each patient with CHD.For patients in the early stage of initiating physical activity (PA), rehabilitation professionals should assist them in recognizing the severity of their condition and the advantages of engaging in PA.Rehabilitation professionals should also promote active utilization of social networks, stimulate CHD patients' motivation, and enhance their behavioral confidence.When guiding patients during the maintenance stage of PA, it is essential to regularly evaluate their psychological well-being, assist them in self-regulation based on their physical condition, and foster the development of self-control.Rehabilitation professionals should consistently provide social support to reinforce the patients' motivation to maintain their PA behavior.
RESUMO
Elevation in mitral valve pressure gradient (MVPG) after mitral valve transcatheter edge-to-edge repair (M-TEER) is common, however, evidence on its prognosis is scarce and debatable. Thus, this study aims to investigate the impact of increased MVPG after M-TEER on outcomes. Studies reporting the associations between the elevated MVPG after M-TEER and outcomes were identified in a systematic search of published literatures. Associations were pooled by meta-analysis using a random-effects model. The primary outcome was the composite of all-cause mortality and heart failure (HF) hospitalization. Seven observational studies with 2,730 patients (mean age, 77.7 ± 9.3 years; male, 64.4%; functional mitral regurgitation [MR], 65.2%) were eligible for the present analysis. M-TEER was performed entirely using the MitraClip system (Abbott), followed by 29.7% of patients having increased MVPG. Elevated postprocedural MVPG was not associated with a higher risk of the primary outcome, compared to low MVPG [hazard ratio (HR) = 1.22; 95% confidence interval (CI) 0.95-1.58; p = 0.12; I2 = 53.5%). However, the prognosis of elevated MVPG was observed in degenerative MR patients (HR = 1.37; 95% CI 1.03-1.84; p = 0.03; I2 = 0%), whereas not in functional MR patients. Patients with low MVPG + high residual MR had a higher risk of the primary outcome than those with high MVPG + low residual MR after M-TEER (HR = 1.50; 95% CI 1.10-2.03; p = 0.01; I2 = 13%). In conclusion, elevated MVPG seems to predict adverse outcomes mainly in patients with degenerative MR. Future studies are needed to prove these findings.
Assuntos
Implante de Prótese de Valva Cardíaca , Insuficiência da Valva Mitral , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Cateterismo Cardíaco/efeitos adversos , Implante de Prótese de Valva Cardíaca/efeitos adversos , Valva Mitral/diagnóstico por imagem , Valva Mitral/cirurgia , Insuficiência da Valva Mitral/cirurgia , Prognóstico , Resultado do TratamentoRESUMO
This study aimed to explore the effect of long-term (≥1 year) sleep quality on coronary lesion complexity and cardiovascular prognosis in young acute coronary syndrome (ACS) patients. We consecutively recruited young patients aged from 18 to 44 years old with first-episode ACS and significant epicardial stenosis on coronary angiography from January 2016 to January 2017. Coronary lesion complexity was evaluated based on SYNTAX scores. Long-term sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) (PSQI ≤ 5 and PSQI > 5 groups). The primary endpoints were major adverse cardiovascular events (MACEs). A total of 466 young ACS patients (93.13% male; median age, 41 years) were included. Poor sleepers (PSQI > 5) had higher SYNTAX scores. After adjusting for confounders, PSQI scores (continuous variables, OR: 1.264; 95%CI: 1.166-1.371; p < 0.001) and PSQI grade (binary variable, OR: 3.864; 95%CI: 2.313-6.394; p = 0.001) were significantly associated with an increased risk of complex coronary lesions. During a median follow-up of 74 months, long-term poor sleep quality (PSQI > 5) was significantly associated with an increased risk of MACEs (HR: 4.266; 95%CI: 2.274-8.001; p < 0.001). Long-term poor sleep quality was a risk factor for complex coronary lesions and has adverse effects on cardiovascular prognosis in the young ACS population.
RESUMO
Background: The atherogenic index of plasma (AIP) and hyperuricemia (HUA) have been shown to be closely associated with morbidity and mortality of coronary artery disease. However, studies targeting predictive value of AIP and HUA for chronic total occlusion (CTO) lesions are still lacking. Methods: In total, 5,238 patients meeting the eligibility criteria were recruited in this analysis. CTO was defined as the condition of lesions without forward blood flow and with over three months of occlusion time. AIP was calculated as log10 [triglycerides (mmol/L)/high-density lipoprotein cholesterol (mmol/L)]. HUA was defined based on sex-specific criteria: serum uric acid 420 and 360â µmol/L for males and females, respectively. Results: CTO lesions were presented in 907 (17.3%) patients. Compared with patients showing lower AIP levels and non-HUA, the CTO lesion risks increased by 5.225 and 2.765 times in patients with higher AIP levels and HUA. Patients with AIP >0.15 and HUA exhibited the greatest CTO incidence (odds ratio 11.491; 95% confidence interval 9.019-14.641, P < 0.001). In addition, AIP combined with HUA had significantly increased effects (a 38.5% increase in CTO risk) relative to the sum of respective effects. Conclusion: Patients having higher AIP levels and HUA exhibited the highest CTO incidence, in comparison with patients who have the increased single index. AIP combined with HUA displayed significant synergistic effect on the prediction of CTO lesion.
RESUMO
Patients with well-controlled low-density lipoprotein cholesterol (LDL-C) levels still suffer from the progress of the atherosclerotic cardiovascular disease (ASCVD) and can develop adverse outcomes. We conducted this study to analyze the relationship between elevated lipoprotein(a) [Lp(a)] levels and ASCVD risk. We enrolled 8070 patients in the ASCVD group and 440 participants in the non-ASCVD group [median age of 60 years; 6376 (74.9%) were male]. Multivariate logistic regression models were used to identify the relationships between the lipids and ASCVD. These models showed that the Lp(a) level was a significant independent risk factor for ASCVD [odds ratio (OR) = 1.025, confidence interval (CI) = 1.020-1.029, P < .001]. The different categories analysis showed the OR of the high Lp(a)/low LDL-C group was 9.612 [CI = 6.206-14.887], P < .001. Our study demonstrated that elevated Lp(a) levels were associated with the increased ASCVD risk. Also, the patients with low LDL-C but high Lp(a) levels still had a higher risk of developing ASCVD than the low Lp(a)/high LDL-C group. In addition, elevated Lp(a) levels were associated with a higher ASCVD risk in males, hypertensive, and diabetic patients.