RESUMO
Effective integrated watershed management requires models that can characterize the sources and transport processes of pollutants at the watershed with multiple landscape patterns. However, few studies have investigated the influence of landscape spatial configuration on pollutant transport processes. In this study, the SPARROW_TN and SPARROW_TP models were constructed by combining direct pollution source data and landscape pattern data to investigate the source composition and nutrient transport processes and to reveal the influence of landscape patterns on nutrient transport in the urbanized Beiyun River Watershed. The introduction of landscape metrics significantly improved the simulation results of both models, with R2 increasing from 0.89 to 0.85 to 0.93 and 0.91, respectively. Spatial variations existed in TN and TP loads and yields, as well as the source compositions. Pollution hotspots were effectively identified. Source apportionment showed that for the entire watershed, TN came from atmospheric nitrogen deposition (35.25%), untreated sewage (28.23%), agricultural sources (22.60%), and treated sewage (13.92%). In comparison, TP came from untreated sewage (44.94%), agricultural sources (40.22%), and treated sewage (11.51%). In addition, the largest patch index of grassland correlated positively with both TN and TP, whereas the largest shape index of buildup land and interspersion and juxtaposition index of forest were negatively correlated with TN and TP, respectively. The results of this study will provide insight into effective nutrient control measures that consider spatially varying nutrient sources and associated nutrient transport processes.
Assuntos
Monitoramento Ambiental , Poluentes Químicos da Água , Fósforo/análise , Poluentes Químicos da Água/análise , Esgotos , Rios , Nitrogênio/análise , Nutrientes , ChinaRESUMO
BACKGROUND: Sepsis still remains a major challenge in intensive care medicine with unacceptably high mortality among patients with septic shock. Due to current limitations of human CD19+CD24hiCD38hi Breg cells (Bregs) studies among sepsis, here, we tried to evaluate Bregs in severity and prognostic value in patients with sepsis. METHODS: Peripheral blood from 58 patients with sepsis and 22 healthy controls was analyzed using flow cytometry to evaluate the frequency and number of Bregs. All cases were divided into non-survived or survived group after 28 days followed up. Spearman's correlation analysis was performed on Bregs frequency and clinical indices. The area under the curve was acquired using the receiver operating characteristic analysis to assess the sensitivity and specificity of Bregs for outcome of sepsis. Survival curve analysis and binary logistic regression were applied to estimate the value of Bregs in prognosis among cases with sepsis. RESULTS: Sepsis patients had decreased proportions and number of Bregs. Sepsis patients with low frequency of Bregs were associated with an increased risk of septic shock. Bregs frequency is inversely associated with lactate, SOFA, and APACHE II and positively correlated with Tregs frequency. Low levels of Bregs closely correlated with septic outcomes. Numbers of Bregs were prediction factors for poor prognosis. CONCLUSIONS: Frequency and number of Bregs decreased, and Bregs deficiency revealed poor prognosis in patients with sepsis.
Assuntos
Linfócitos B Reguladores , Sepse , Choque Séptico , Humanos , Sepse/diagnóstico , Citometria de Fluxo , Prognóstico , Proteínas Adaptadoras de Transdução de Sinal , Antígeno CD24RESUMO
BACKGROUND: The role of B cell subsets remained to be elucidated in a variety of immune diseases, though which was used as an effective biomarker for anti-inflammatory or antiviral response. This study aimed to evaluate the early changes of B cell subtypes distribution in elderly patients with community acquired pneumonia (CAP), as well as the association between B cell subtypes and prognosis. METHODS: This prospective study included elderly patients with CAP, severe CAP (sCAP) and healthy elderly subjects between April 2016 and March 2018. Flow cytometry was used to detect CD3, CD20, HLA-DR, CD24, CD27, CD38, IgM, and IgD. CD20+ B cells were further divided into naïve B cells (Bn), IgM/D+ memory B cells (IgM+ Bm), switched B cells (SwB), and transitional B cells (Btr). RESULTS: A total of 22 healthy controls, 87 patients with CAP and 58 patients with sCAP were included in the study. Compared to CAP, sCAP was characterized by significantly lower absolute number of B cells, Bn and Btr, significantly lower Btr and Bn subset percentage, while percentage of IgM+ Bm was significantly higher. Heat map showed Bn and Btr on day 3 and day 7 was negatively correlated with activated partial prothrombin time (APTT), international normalized ratio (INR), sequential organ failure assessment score (SOFA) and Acute Physiology and Chronic Health Evaluation II (APACHE II). After 28-day follow-up, Btr percentage in survival group was significantly higher. Receiver operator characteristic (ROC) curve analysis found that Btr count showed sensitivity of 48.6% and specificity of 87.0% for predicting the 28-day survival, with an area under the ROC curves of 0.689 (p = 0.019). CONCLUSIONS: Severity and prognosis of CAP in elderly people is accompanied by changes in the B cell subsets. Btr subsets could play prognostic role for a short-term mortality of elderly CAP patients.
Assuntos
Subpopulações de Linfócitos B , Infecções Comunitárias Adquiridas , Pneumonia , Idoso , Humanos , Imunoglobulina M , Prognóstico , Estudos Prospectivos , Curva ROC , Estudos RetrospectivosRESUMO
BACKGROUND: We recently reported histone methyltransferase enhancer of zeste homolog 2 (EZH2) as a key epigenetic regulator that contributes to the dysfunction of innate immune responses to sepsis and subsequent lung injury by mediating the imbalance of macrophage polarization. However, the role of EZH2 in acute respiratory distress syndrome (ARDS)-associated fibrosis remains poorly understood. METHODS: In this study, we investigated the role and mechanisms of EZH2 in pulmonary fibrosis in a murine model of LPS-induced ARDS and in ex-vivo cultured alveolar macrophages (MH-S) and mouse lung epithelial cell line (MLE-12) by using 3-deazaneplanocin A (3-DZNeP) and EZH2 the small interfering (si) RNA. RESULTS: We found that treatment with 3-DZNeP significantly ameliorated the LPS-induced direct lung injury and fibroproliferation by blocking EMT through TGF-ß1/Smad signaling pathway and regulating shift of macrophage phenotypes. In the ex-vivo polarized alveolar macrophages cells, treatment with EZH2 siRNA or 3-DZNeP suppressed the M1 while promoted the M2 macrophage differentiation through modulating the STAT/SOCS signaling pathway and activating PPAR-γ. Moreover, we identified that blockade of EZH2 with 3-DZNeP suppressed the epithelial to mesenchymal transition (EMT) in co-cultured bronchoalveolar lavage fluid (BALF) and mouse lung epithelial cell line through down-regulation of TGF-ß1, TGF-ßR1, Smad2 while up-regulation of Smad7 expression. CONCLUSIONS: These results indicate that EZH2 is involved in the pathological process of ARDS-associated pulmonary fibrosis. Targeting EZH2 may be a potential therapeutic strategy to prevent and treat pulmonary fibrosis post ARDS.
Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Macrófagos/metabolismo , Fenótipo , Fibrose Pulmonar/metabolismo , Síndrome do Desconforto Respiratório/metabolismo , Animais , Polaridade Celular/efeitos dos fármacos , Polaridade Celular/fisiologia , Técnicas de Cocultura , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/prevenção & controle , RNA Interferente Pequeno/administração & dosagem , Síndrome do Desconforto Respiratório/induzido quimicamente , Síndrome do Desconforto Respiratório/prevenção & controleRESUMO
This study sets out to establish the comparative contribution of PD-L1 expression by pulmonary endothelial cells (ECs) and/or epithelial cells (EpiCs) to the development of indirect acute lung injury (iALI) by taking advantage of the observation that treatment with naked siRNA by intratracheal delivery in mice primarily affects lung EpiCs, but not lung ECs, while intravenous delivery of liposomal-encapsulated siRNA largely targets vascular ECs including the lung, but not pulmonary EpiCs. We showed that using a mouse model of iALI [induced by hemorrhagic shock followed by septic challenge (Hem-CLP)], PD-L1 expression on pulmonary ECs or EpiCs was significantly upregulated in the iALI mice at 24 h post-septic insult. After documenting the selective ability of intratracheal versus intravenous delivery of PD-L1 siRNA to inhibit PD-L1 expression on EpiCs versus ECs, respectively, we observed that the iALI-induced elevation of cytokine/chemokine levels (in the bronchoalveolar lavage fluid, lung lysates, or plasma), lung myeloperoxidase and caspase-3 activities could largely only be inhibited by intravenous, but not intratracheal, delivery of PD-L1 siRNA. Moreover, intravenous, but not intratracheal, delivery led to a preservation of normal tissue architecture, lessened pulmonary edema, and reduced neutrophils influx induced by iALI. In addition, in vitro mouse endothelial cell line studies showed that PD-L1 gene knockdown by siRNA or knockout by CRISPR/Cas9-mediated gene manipulation, reduced monolayer permeability, and maintained tight junction protein levels upon recombinant IFN-γ stimulation. Together, these data imply a critical role for pulmonary vascular ECs in mediating PD-1:PD-L1-driven pathological changes resulting from systemic stimuli such as Hem-CLP.
Assuntos
Lesão Pulmonar Aguda/metabolismo , Antígeno B7-H1/metabolismo , Células Endoteliais/metabolismo , Células Epiteliais/metabolismo , Animais , Líquido da Lavagem Broncoalveolar , Células Cultivadas , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Peroxidase/metabolismo , RNA Interferente Pequeno/metabolismo , Sepse/metabolismo , Choque Hemorrágico/metabolismoRESUMO
Circular RNAs (circRNAs) make up a large class of non-coding RNAs and play important roles in the pathology of a variety of diseases. However, their roles in pulmonary macrophage polarization after sepsisinduced lung injury is unknown. In this study, mice were divided into two groups: Sham control group and cecal ligation and puncture (CLP)-induced ALI group. Macrophages were isolated from lung homogenates 24 hours after SCLP/CLP. We started with RNA-seq of circRNA changes in macrophages and validated by RT-PCR in the following experiments. A total of 4318 circRNAs were detected in the two groups. Of these, 11 and 126 circRNAs were found to be significantly upregulated and downregulated, respectively, compared to the control (p≤0.05, Fold Change ≥2). Differentially expressed circRNAs with a high foldchange (fold-change >4, P<0.05) were selected for validation by qRT-PCR, 10 of which were verified. Furthermore, the most differentially expressed circRNAs within all the comparisons were annotated in detail with circRNA/miRNA interaction information using miRNA target prediction software. The network of circRNA-miRNA-mRNA was illustrated by cytoscape software. Gene ontology analyses indicated the upregulated circRNAs were involved in the multiple biological functions such as regulation of mitochondrion distribution and Notch binding, while the down-regulated circRNAs mainly involved in the biological process as histone H3K27 methylation. KEGG pathway analysis revealed TGF-beta signaling pathway was related to the upregulated circRNAs. The present study provides a novel insight into the roles of circRNAs in pulmonary macrophage differentiation and polarization post septic lung injury.
Assuntos
Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/genética , Regulação da Expressão Gênica , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , RNA Circular/genética , Sepse/complicações , Animais , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Pulmão/patologia , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais/genéticaRESUMO
Inflammatory responses play a critical role in left ventricular remodeling after acute myocardial infarction (AMI). NR4A3, a member of the NR4A orphan nucleus receptor family, has recently emerged as a therapeutic target for treatment of inflammation. This aim of this study is to explore the therapeutic effect of NR4A3 in cardiac remodeling post AMI. Male C57BL/6 mice were administered with lentiviral over-expression of NR4A3 (lenti-NR4A3) or empty vector (lenti-con) 7 days before coronary artery ligation. H9c2 cardiomyocytes deprived of serum were used to mimic ischemic conditions in vivo. Lenti-NR4A3 treatment significantly repressed neutrophil infiltration in the myocardium, reduced infarct size, and attenuated the reduction of left ventricular function after AMI. Furthermore, NR4A3 over-expression inhibited the NF-κB (IκB) signaling by decreasing IκBα phosphorylation and by inhibiting the translocation of p65 to the nucleus. Meanwhile, NR4A3 over-expression also increases the activity of JAK2-STAT3 signaling in mouse hearts after AMI. The inhibitory effect of NR4A3 on NF-κB activation was almost completely abolished by the JAK2 inhibitor AG490, indicating that NR4A3 prevented serum deprivation induced NF-κB activation in a STAT3 dependent manner. These findings provide novel evidence that NR4A3 could inhibit post-AMI inflammation responses via JAK2-STAT3/NF-κB signaling and may well be a therapeutic target for cardiac remodeling after AMI.
Assuntos
Cardiotônicos/metabolismo , Proteínas de Ligação a DNA/metabolismo , Janus Quinase 2/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptores de Esteroides/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Animais , Citocinas/metabolismo , Inflamação , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Infiltração de Neutrófilos , Regulação para CimaRESUMO
Platelets are traditionally considered to be essential components of primary hemostasis. Recent investigations have revealed that platelets can be activated in patients with sepsis and are implicated in the development of sepsis and sepsis-induced-acute kidney injury (SAKI). In the present study, ticagrelor was used to induce a mouse model of SAKI by cecal ligation and puncture. It was found that ticagrelor could inhibit platelet activity, decrease the levels of interleukin-1ß and serum creatinine, reduce infiltration of neutrophils in renal tissue, and attenuate cell apoptosis in the kidney. The results suggested that ticagrelor could protect renal function by inhibiting inflammation, recruitment of neutrophils into the kidney, and cell apoptosis in renal tissue. Thus, the findings might provide new strategies for preventing SAKI.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Sepse/complicações , Sepse/tratamento farmacológico , Ticagrelor/uso terapêutico , Animais , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Inibidores da Agregação Plaquetária/farmacologia , Sepse/patologia , Ticagrelor/farmacologiaRESUMO
CD8+ T cells are considered to be critical in tumor surveillance and elimination. Increased CD8+ T cell frequency and function is associated with better prognosis in cancer patients. Interleukin 10 is a cytokine with controversial roles in CD8+ T cell-mediated anti-tumor immunity. We therefore examined the interleukin 10 expression and consumption in CD8+ T cells harvested from the peripheral blood and resected tumors of gastric cancer patients of stages II-IV. We found that the gastric cancer patients presented significantly elevated frequencies of interleukin 10-expressing cells in both CD4+ and CD8+ T cells compared to healthy controls. But distinctive from the interleukin 10-expressing CD4+ T cells, which increased in frequency in advanced cancer, the interleukin 10-expressing CD8+ T cells did not increase with cancer stage in the peripheral blood and actually decreased with cancer stage in resected tumor. Interleukin 10 and interleukin 10 receptor expression was also enriched in interferon gamma-expressing activated CD8+ T cells. Compared to interleukin 10-nonexpressing CD8+ T cells, interleukin 10 receptor-expressing CD8+ T cells secreted significantly elevated interferon gamma levels. Treatment of anti-CD3/CD28-stimulated, purified CD8+ T cells with interleukin 10 alone could significantly enhance CD8+ T cell survival, an effect dependent on interleukin 10 receptor expression. Interleukin 10 also increased CD8+ T cell proliferation synergistically with interferon gamma but not alone. Analysis of downstream signal transducer and activator of transcription molecules showed that interleukin 10 treatment significantly increased the phosphorylation of signal transducer and activator of transcription 3 and signal transducer and activator of transcription 1 to lesser extent. Together, these results demonstrate that interleukin 10 possessed stimulatory roles in activated CD8+ T cells from gastric cancer patients.
Assuntos
Interferon gama/genética , Interleucina-10/biossíntese , Receptores de Interleucina-10/genética , Neoplasias Gástricas/genética , Adulto , Idoso , Antígenos CD28/imunologia , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células/genética , Feminino , Humanos , Interferon gama/imunologia , Interleucina-10/genética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptores de Interleucina-10/biossíntese , Fatores de Transcrição STAT/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologiaRESUMO
Increased Src activity has been associated with the pathogenesis of renal tumors and some glomerular diseases, but its role in renal interstitial fibrosis remains elusive. To evaluate this, cultured renal interstitial fibroblasts (NRK-49F) were treated with PP1, a selective inhibitor of Src. This resulted in decreased expression of α-smooth muscle actin, fibronectin, and collagen I in response to serum, angiotension II, or transforming growth factor-ß1 (TGF-ß1). Silencing Src with siRNA also inhibited expression of those proteins. Furthermore, inhibition of Src activity blocked renal fibroblast proliferation. In a murine model of renal interstitial fibrosis induced by unilateral ureteral obstruction, the active form of Src (phopsho-Src Tyr416) was upregulated in both renal interstitial fibroblasts and renal tubular cells of the fibrotic kidney. Its inactivation reduced renal fibroblast activation and attenuated extracellular matrix protein deposition. Src inhibition also suppressed activation of TGF-ß1 signaling, activation of the epidermal growth factor receptor and STAT3, and reduced the number of renal epithelial cells arrested at the G2/M phase of the cell cycle after ureteral obstruction. Thus, Src is an important mediator of renal interstitial fibroblast activation and renal fibrosis, and we suggest that Src is a potential therapeutic target for treatment of chronic renal fibrosis.
Assuntos
Rim/enzimologia , Rim/patologia , Miofibroblastos/enzimologia , Obstrução Ureteral/metabolismo , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/metabolismo , Actinas/metabolismo , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Colágeno Tipo I/metabolismo , Células Epiteliais , Receptores ErbB/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Fibrose , Pontos de Checagem da Fase G2 do Ciclo Celular , Inativação Gênica , Túbulos Renais Proximais/enzimologia , Túbulos Renais Proximais/patologia , Pontos de Checagem da Fase M do Ciclo Celular , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/patologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , RNA Interferente Pequeno/farmacologia , Ratos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Quinases da Família src/genéticaRESUMO
BACKGROUND: Acute lung injury (ALI) is characterized by rapid induction of inflammation at the alveolar-capillary membrane, and immunosuppressive mechanisms were shown to contribute to its resolution. Despite the central role of lymphocytes in initiating and mediating an inflammatory response, their influx dynamics in ALI has not been examined. METHODS: We collected mini-BAL samples from the lung of ALI patients over a maximum period of 7 days, and examined the lymphocyte composition. RESULTS: CD3+CD4+IFN-gamma+ Th1 cells were detected early on in all patients examined, while IL-10-producing B cells and CD3+CD4+CD25hiFoxp3+ Treg cells appeared later. Interestingly, IL-10-producing B cells appeared earlier than Tregs in most subjects, which possibly exerted anti-inflammatory function before Tregs. We then found that in patients with earlier recruitment of IL-10-producing B cells, the magnitude of Th1 inflammation decreased significantly over time, which was not observed in patients with later recruitment of IL-10-producing B cells. Furthermore, early IL-10-producing B cell recruiters also had significantly earlier recruitment of Tregs and better survival than late IL-10-producing B cell recruiters. CONCLUSION: This study provided data on the alveolar infiltration of lymphocytes during ALI, which suggested an inhibitory role of IL-10-producing B cells in ALI and emphasized the importance of controlling inflammation during the initial stage of ALI.
Assuntos
Lesão Pulmonar Aguda/patologia , Linfócitos B/imunologia , Interleucina-10/metabolismo , Alvéolos Pulmonares/metabolismo , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/mortalidade , Idoso , Linfócitos B/citologia , Linfócitos B/metabolismo , Feminino , Citometria de Fluxo , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Células Th1/citologia , Células Th1/imunologiaRESUMO
Activation of the purinergic P2X7 receptor (P2X7R) has been associated with the development of experimental nephritis and diabetic and hypertensive nephropathy. However, its role in acute kidney injury (AKI) remains unknown. In this study, we examined the effects of P2X7R inhibition in a murine model of ischemia-reperfusion (I/R)-induced AKI using A438079, a selective inhibitor of P2X7R. At 24 h after I/R, mice developed renal dysfunction and renal tubular damage, which was accompanied by elevated expression of P2X7R. Early administration of A438079 immediately or 6 h after the onset of reperfusion protected against renal dysfunction and attenuated kidney damage whereas delayed administration of A438079 at 24 h after restoration of perfusion had no protective effects. The protective actions of A438079 were associated with inhibition of renal tubule injury and cell death and suppression of renal expression of monocyte chemotactic protein-1 and regulated upon expression normal T cell expressed and secreted (RANTES). Moreover, I/R injury led to an increase in phosphorylation (activation) of extracellular signal-regulated kinases 1/2 in the kidney; treatment with A438079 diminished this response. Collectively, these results indicate that early P2X7R inhibition is effective against renal tubule injury and proinflammatory response after I/R injury and suggest that targeting P2X7R may be a promising therapeutic strategy for treatment of AKI.
Assuntos
Injúria Renal Aguda/prevenção & controle , Rim/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2X/farmacologia , Piridinas/farmacologia , Receptores Purinérgicos P2X7/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Tetrazóis/farmacologia , Agentes Urológicos/farmacologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Injúria Renal Aguda/fisiopatologia , Proteínas de Fase Aguda/metabolismo , Animais , Células Cultivadas , Quimiocina CCL2/metabolismo , Quimiocina CCL5/metabolismo , Citoproteção , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Lipocalina-2 , Lipocalinas/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Oncogênicas/metabolismo , Fosforilação , Interferência de RNA , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , TransfecçãoRESUMO
BACKGROUND/AIMS: Over-activation of cellular inflammatory effectors adversely affects myocardial function after acute myocardial infarction (AMI). The CC-chemokine CCL21 is, via its receptor CCR7, one of the key regulators of inflammation and immune cell recruitment, participates in various inflammatory disorders, including cardiovascular ones. This study explored the therapeutic effect of an anti-CCL21 antibody in cardiac remodeling after myocardial infarction. METHODS AND RESULTS: An animal model of AMI generated by left anterior descending coronary artery ligation in C57BL/6 mice resulted in higher levels of circulating CCL21 and cardiac CCR7. Neutralization of CCL21 by intravenous injection of anti-CCL21 monoclonal antibody reduced infarct size after AMI, decreased serum levels of neutrophil and monocyte chemo attractants post AMI, diminished neutrophil and macrophage recruitment in infarcted myocardium, and suppressed MMP-9 and total collagen content in myocardium. Anti-CCL21 treatment also limited cardiac enlargement and improved left ventricular function. CONCLUSIONS: Our study indicated that CCL21 was involved in cardiac remodeling post infarction and anti-CCL21 strategies might be useful in the treatment of AMI.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Neutralizantes/administração & dosagem , Quimiocina CCL21/antagonistas & inibidores , Infarto do Miocárdio/tratamento farmacológico , Remodelação Ventricular/efeitos dos fármacos , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Quimiocina CCL21/sangue , Colágeno/metabolismo , Modelos Animais de Doenças , Injeções Intravenosas , Macrófagos/efeitos dos fármacos , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/sangue , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
Lung cancer is the leading cause of death worldwide. Non-small-cell lung cancer (NSCLC) accounts for most of these cases. T-cell immunoglobulin- and mucin-domain-containing molecule 3 (TIM-3) has been established as a negative regulatory molecule and plays a critical role in immune tolerance. Studies have shown that polymorphisms in TIM-3 gene can be associated with various diseases. The aim of this study was to investigate whether polymorphisms in the TIM-3 gene were associated with susceptibility to NSCLC. Three polymorphisms in TIM-3 gene (-1516G/T, -574G/T, and +4259T/G) were identified by polymerase chain reaction-restriction fragment length polymorphism in 432 NSCLC patients and 466 healthy controls. Results showed that frequencies of TIM-3 +4259TG genotype for cases and controls were 10.9 and 4.1 %, respectively; subjects carrying the +4259TG genotype had a 2.81-fold increased risk of NSCLC compared to the wild-type genotype (P < 0.0001). The TIM-3 -1516G/T and -574G/T polymorphisms did not show any correlation with NSCLC. In addition, when analyzing the survival time of NSCLC patients with TIM-3 +4259T/G polymorphism, cases with +4259TG genotype had significantly shorter survival time compared to the wild-type patients (15.2 months vs. 26.7 months, P = 0.007). These results suggested polymorphism in TIM-3 gene is associated with increased susceptibility to NSCLC and could be used as prognostic factor for this malignancy.
Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Proteínas de Membrana/genética , Polimorfismo Genético/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/terapia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/terapia , Estudos de Casos e Controles , DNA/genética , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Receptor Celular 2 do Vírus da Hepatite A , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prognóstico , Taxa de SobrevidaRESUMO
The C-X-C chemokine receptor type 5 (CXCR5) is one of the principal regulators for targeting T cells, B cells and dendritic cells into secondary lymphoid organs. Polymorphism studies of CXCR5 gene remain extremely scarce. The aim of this study was to examine the effect of polymorphisms in the CXCR5 gene on the development of non-Hodgkin lymphoma (NHL) in the Chinese population. Four polymorphisms in CXCR5 gene, rs148351692C/G, rs6421571C/T, rs80202369G/A and rs78440425G/A, were tested by polymerase chain reaction-restriction fragment length polymorphism in 404 NHL cases and 456 age-matched healthy controls. Data were analyzed using the χ(2) test. Results showed that individuals with the rs6421571 CT, rs6421571 TT and rs80202369 AA genotype had significantly increased susceptibility to NHL [Odd ratio (OR) = 1.41, 95 % confidence interval (CI): 1.04-1.92, p = 0.028; OR = 2.30, 95 % CI: 1.44-3.65, p < 0.001; and OR = 3.24, 95 % CI: 1.26-8.32, p = 0.010, respectively]. When analyzing the haplotypes of these polymorphisms, the prevalence of the TGG (rs6421571, rs80202369, and rs78440425) haplotype was significantly higher in NHL cases than in controls (OR = 1.59, 95 % CI: 1.25-2.03, p < 0.001). In addition, numbers of rs6421571 TT genotype and T allele were significantly increased in NHL patients with high Ann Arbor stages (p < 0.03) or NHL with B cell subtype (p < 0.02). These data indicate that CXCR5 gene polymorphisms may be new risk factors for NHL. The finding that the adjacent SNPs, rs6421571C/T and rs80202369G/A, are both associated with NHL suggests that the 87 bp region carrying these 2 polymorphisms may have important functional significance.
Assuntos
Predisposição Genética para Doença , Linfoma não Hodgkin/genética , Polimorfismo de Nucleotídeo Único , Receptores CXCR5/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fatores de Risco , Adulto JovemRESUMO
High intensity focused ultrasound (HIFU), as one of the most advanced and preferred cancer treatment modes, has shown great promise due to its minimal invasiveness and irradiation-free nature. However, a key limiting factor for its further clinical application is its relatively low therapeutic potency. In this study, CaO2@SiO2 NPs were developed for efficient O2 bubble-assisted HIFU surgery against tumors. After entering the tumor sites, these nanoparticles can release O2 and H2O2, achieving enhancement of US imaging signals and improved potency of HIFU surgery. In addition, local temperature increase during HIFU treatment could trigger O2 generation by the conversion of unstable H2O2 into O2 gas, further augmenting the efficacy of HIFU treatment. This work not only provides a paradigm of CaO2 for cancer management in nanomedicine, but also presents an efficient way for bubble-enhanced HIFU surgery.
Assuntos
Ablação por Ultrassom Focalizado de Alta Intensidade , Nanopartículas , Neoplasias , Ablação por Ultrassom Focalizado de Alta Intensidade/métodos , Humanos , Peróxido de Hidrogênio/farmacologia , Neoplasias/terapia , Peróxidos , Dióxido de SilícioRESUMO
Purpose: Sepsis is a condition that derives from a dysregulated host response to infection. Although B lymphocytes play a pivotal role in immune response, little is known about status of their terminally differentiated cells, antibody-secreting cells (ASCs) during immunosuppressive phase of sepsis, especially in elderly patients. Our aim was to extensively characterize the immune functions of ASCs in elderly septic patients. Patients and Methods: Clinical and laboratory data were collected on days 1, 3, and 7 of hospitalization. Circulating ASCs were evaluated by flow cytometry from fresh whole blood in elderly septic patients at the onset of disease. RNA sequencing analyzed ASCs gene expression profile. Receiver operating characteristic (ROC) curve analysis and logistic regression predicted the survival rate of 28-day mortality. Results: A total of 103 septic patients were enrolled. The number and proportion of ASCs among total lymphocytes dramatically increased in septic patients, and RNA sequencing analysis showed that ASCs from septic patients exhibited a different gene expression profile. Furthermore, we found these ASCs could promote the function of T cells. Logistic regression analysis showed ASCs population was an independent outcome predictor in septic shock patients. Conclusion: Our study revealed the complex nature of immune disorders in sepsis and identified circulating ASCs population as a useful biomarker for predicting mortality in elderly septic patients, which provided a novel clue to combat this severe disease.
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Chemodynamic therapy represents a distinct anti-tumor strategy by activating intratumoral chemical catalytic reactions to produce highly toxic reactive oxygen species (ROS) from non-/limited-toxic nanocatalysts. However, the low efficacy of ROS generation still remains a major challenge for further clinical translation. Herein, a liposomal nanosystem which simultaneously encapsulated copper peroxide nanodots (CPNs) and artemisinin (ART) was constructed for autophagy-enhanced and ferroptosis-involved cancer cell death owing to Cu-based dual catalytic strategy. To be specific, the CPN components, served as a H2O2 self-supplying platform, release H2O2 and Cu2+ under acidic tumor environment and endogenously generate .OH via Fenton-like reaction (catalytic reaction I). In addition, Cu2+ species catalyze ART components to produce ROS radicals (catalytic reaction II), further augmenting the intracellular oxidative damage and lipid peroxide accumulation, leading to cancer cell death. Specifically, ART also acted as a potent autophagy inducer increasing the level of intracellular iron pool through degradation of ferritin, which could promote cancer cell ferroptosis, producing the best antineoplastic effect. After accumulation into the tumor sites, ultrasound irradiation was applied to trigger the release of CPNs and ART from liposomal nanosystems, and amplify the efficacy of catalytic reaction for maximum therapeutic effect. Both in vitro and in vivo therapeutic outcomes suggest the outstanding autophagy-augmented ferroptosis-involved cancer-therapeutic efficacy, which was further corroborated by transcriptome sequencing. In this work, Cu was firstly proven to trigger ART to produce ROS species, but also provide a TME-responsive nanoplatform for potentially suppressing tumor growth by autophagy-augmented ferroptosis-involved cancer nanotherapy.
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OBJECTIVE: To investigate the role of miR-205 and GATA3 in Pulmonary Fibrosis (PF). METHODS: Bleomycin (BLM) was used to induce PF in SD rats and in vitro PF model was established by using TGFß1-induced RLE-6TN cells. miR-205 mimics were used for the overexpression of miR- 205. The expression of miR-205, GATA3, α-SMA, Collagen I, CHOP and GRP78 were measured using RT-qPCR or western blotting. Dual-luciferase reporter assay was used to confirm binding between GATA3 3'-UTR and miR-205. RESULTS: The expression of miR-205 was significantly down-regulated, while the expression of GATA3 was remarkably up-regulated in the model rats. GATA3 levels were remarkably decreased when miR-205 was overexpressed. When miR-205 was overexpressed, the lung injury by BLM-induced fibrosis was improved. The expression of α-SMA, Collagen I, as well as GRP78 and CHOP, was significantly up-regulated in both in vivo and in vitro PF models, and overexpression of miR-205 remarkably reversed the effects. Dual-luciferase reporter assay showed that miR-205 directly targeted and negatively regulated GATA3. CONCLUSION: miR-205 improved pulmonary fibrosis through inhibiting ER-stress by targeting GATA3.
Assuntos
Estresse do Retículo Endoplasmático , Fator de Transcrição GATA3/metabolismo , MicroRNAs/metabolismo , Fibrose Pulmonar/metabolismo , Actinas , Animais , Bleomicina/farmacologia , Linhagem Celular , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Estresse do Retículo Endoplasmático/genética , Fator de Transcrição GATA3/genética , MicroRNAs/genética , Ligação Proteica , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/metabolismo , Regulação para CimaRESUMO
Recent studies have shown that epigenetic factors may affect immune responses. We previously reported that histone methyltransferase enhancer of zeste homolog 2 (EZH2) was involved in the innate inflammatory responses both in animal model of sepsis and in septic patients. In this study, we prospectively evaluated EZH2 expression kinetics in peripheral CD4+ and CD8+ T cells and HLA-DR expression in CD14+ cells from 48 patients with sepsis and 48 healthy controls. Results showed higher level of EZH2 in CD4+ T cells and CD8+ T cells in sepsis patients than in controls. Meanwhile, EZH2 expression was correlated with CD27 status on T cells. Mean fluorescence intensity (MFI) of EZH2 in CD8+ T cells on day 1 independently predicted death in septic patients. Also, the combination of CD8+ T cell EZH2 expression with APACHEII and SOFA score could enhance the prognostic predictive ability. Moreover, multivariate logistic regression analysis showed that increased expression (proportion and MFI) of EZH2 in CD4+ and CD8+ lymphocytes on day 3 were independently associated with nosocomial infection in septic patients. Additionally, spearman correlation analysis indicated that the levels of EZH2 in CD4+ T cells and CD8+ T cells correlated to CD14+ cells-expressing HLA-DR in patients with sepsis at each time point. Overall, these findings suggest that EZH2 in CD4+ T cells or/and CD8+ T cells may be a novel biomarker for predicting adverse outcomes (mortality and secondary infectious complications) in patients with sepsis.