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1.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(5): 622-629, 2019 Oct 30.
Artigo em Chinês | MEDLINE | ID: mdl-31699192

RESUMO

Objective To investigate the clinical value of preoperative lymphocyte-to-monocyte ratio(LMR)in evaluating the prognosis of patients with stage T1 non-muscle invasive bladder cancer(NMIBC).Methods A total of 215 patients with stage T1 NMIBC who underwent transurethral resection of bladder tumor were enrolled.Clinical data were collected.Patients were followed up and their disease-free survival(DFS)and overall survival(OS)were recorded.The receiver operating characteristic(ROC)curve of preoperative LMR in detecting patient prognosis was used to determine the optimal cut-off value for LMR.Patients were divided into low LMR group(LMR <3.86,n=77)and high LMR group(LMR ≥ 3.86,n=138).Kaplan-Meier survival curves were explored to compare cumulative DFS and OS rates in patients with different LMR levels,and COX proportional hazards regression model was used to analyze factors associated with DFS and OS.Results All these 215 patients with T1 stage NMIBC were followed up for 2-92 months,and the DFS rate was 59.07% and OS rate was 65.12%.Kaplan-Meier curves showed that the cumulative DFS rate(χ 2=4.784,P=0.029)and cumulative OS rate(χ 2=7.146, P=0.008)in the low LMR group were significantly lower than those in the high LMR group.Tumor size ≥ 3 cm(HR=1.398,95% CI:1.042-1.875,P=0.025),pathological grade G3(HR=1.266,95% CI:1.026-1.563,P=0.028),and LMR ≥ 3.86(HR=2.347,95% CI:1.080-5.101,P=0.031)were independent factors associated with DFS in patients with stage T1 NMIBC.In addition,tumor size ≥ 3 cm(HR=1.228,95% CI:1.015-1.484,P=0.034),pathological grade G3(HR=1.366,95% CI:1.017-1.834,P=0.038),and LMR<3.86(HR=2.008,95% CI:1.052-3.832,P=0.035)were independent factors associated with OS in patients with T1 stage NMIBC. Conclusion Preoperative LMR is an independent factor associated with patients' prognosis in T1 stage NIMBC.Patients with low LMR tend to have higher risk of NMIBC progression and death.


Assuntos
Linfócitos/citologia , Monócitos/citologia , Neoplasias da Bexiga Urinária/diagnóstico , Intervalo Livre de Doença , Humanos , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias da Bexiga Urinária/patologia
2.
Cytogenet Genome Res ; 159(1): 1-11, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31658463

RESUMO

The switch/sucrose non-fermenting (SWI/SNF) complex is an ATP-dependent chromatin remodeller that regulates the spacing of nucleosomes and thereby controls gene expression. Heterozygous mutations in genes encoding subunits of the SWI/SNF complex have been reported in individuals with Coffin-Siris syndrome (CSS), with the majority of the mutations in ARID1B. CSS is a rare congenital disorder characterized by facial dysmorphisms, digital anomalies, and variable intellectual disability. We hypothesized that mutations in genes encoding subunits of the ubiquitously expressed SWI/SNF complex may lead to alterations of the nucleosome profiles in different cell types. We performed the first study on CSS-patient samples and investigated the nucleosome landscapes of cell-free DNA (cfDNA) isolated from blood plasma by whole-genome sequencing. In addition, we studied the nucleosome landscapes of CD14+ monocytes from CSS-affected individuals by nucleosome occupancy and methylome-sequencing (NOMe-seq) as well as their expression profiles. In cfDNA of CSS-affected individuals with heterozygous ARID1B mutations, we did not observe major changes in the nucleosome profile around transcription start sites. In CD14+ monocytes, we found few genomic regions with different nucleosome occupancy when compared to controls. RNA-seq analysis of CD14+ monocytes of these individuals detected only few differentially expressed genes, which were not in proximity to any of the identified differential nucleosome-depleted regions. In conclusion, we show that heterozygous mutations in the human SWI/SNF subunit ARID1B do not have a major impact on the nucleosome landscape or gene expression in blood cells. This might be due to functional redundancy, cell-type specificity, or alternative functions of ARID1B.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Proteínas Nucleares/genética , Nucleossomos/genética , Fatores de Transcrição/genética , Adolescente , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/genética , Criança , Pré-Escolar , Feminino , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Monócitos/citologia , Adulto Jovem
3.
Medicine (Baltimore) ; 98(38): e17108, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31567947

RESUMO

Although some studies found that an increased monocyte count is a predictive, short-term marker of unfavorable outcomes for patients with acute heart failure (HF), others have reported that monocytosis predicts prolonged survival.The current follow-up study aimed to identify different monocyte count patterns and their prognostic association with HF outcomes.Baseline blood samples for complete blood counts, differential counts, renal function tests, and lipid profiles of 303 chronic HF patients (average NYHA classification 2.8) were prospectively obtained to evaluate whether there is an association between monocyte count and clinical outcomes.Mean follow-up was 11.3 years (range 1 month to 16 years) and 111 (36.6%) patients died during follow-up. Mean monocyte count was 10.6 ±â€Š5.5 and mean left ventricular ejection fraction (LVEF) was 36%. Patients with low monocyte counts (≤6%) had significantly lower survival rates than did those with monocyte counts 6.1% to 14%, or >14% (14.3% vs 70.2% vs. 88%, P < .001). Poorest survival was predicted for patients with NYHA class 3 to 4 and monocyte counts ≤6. Regression analysis showed that monocyte levels, NYHA class, and LVEF values were predictors of mortality, in decreasing importance.The total monocyte count was found to be an important prognostic factor that was inversely associated with predicted long-term mortality among patients with chronic HF. A low total monocyte count was strongly correlated with NYHA class and B-type natriuretic peptide levels, but no correlation was found with LVEF and oxidized low-density lipoproteins. It emerged as an independent risk factor for mortality in patients with chronic HF.


Assuntos
Insuficiência Cardíaca/mortalidade , Monócitos/citologia , Idoso , Biomarcadores/sangue , Doença Crônica , Estudos de Coortes , Feminino , Insuficiência Cardíaca/sangue , Humanos , Israel , Contagem de Leucócitos , Masculino , Prognóstico , Estudos Prospectivos , Análise de Sobrevida
4.
Chem Biol Interact ; 314: 108844, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31600484

RESUMO

Using data from Schink et al. (2018), a large number of herbal extracts were assessed for their capacity to induce pro- and anti-inflammatory effects based on TLR4 expression normalized for cell viability in two immune cell models (i.e., HeLa-TLR4 transfected reporter cell line, and THP-1 monocytes) applying seven concentrations (0.01-3.0%). The analysis revealed that 70-80% of the extracts satisfying the a priori entry criteria also satisfied a priori evaluative criteria for hormetic concentration responses. These findings demonstrate that a large proportion of herbal extracts display hormetic dose responses in immune cells, indicating that hormetic mechanisms mediate pro- and anti-inflammatory processes and may provide a means to guide optimal dosing strategies. The identification of doses eliciting only anti-inflammatory therapeutic activity as well as the use of dose-variable herbal extracts in the treatment of inflammatory diseases will be challenging.


Assuntos
Anti-Inflamatórios/farmacologia , Hormese/efeitos dos fármacos , Extratos Vegetais/química , Plantas Medicinais/química , Anti-Inflamatórios/química , Linhagem Celular , Células HeLa , Humanos , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Extratos Vegetais/farmacologia , Plantas Medicinais/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
5.
Medicine (Baltimore) ; 98(41): e17536, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593130

RESUMO

Recently, the monocyte count to high-density lipoprotein cholesterol ratio (MHR) was found to be associated with the SYNTAX score in patients with both stable coronary artery disease (CAD) and acute coronary syndrome (ACS). The MHR was significantly higher in male patients. However, the sex-specific association of MHR with SYNTAX score in stable CAD was not well explored. Thus, the present study aimed to investigate the association of MHR and presence and severity of CAD evaluated by coronary angiography and the SYNTAX score in males and females.In total, 873 patients who received selective coronary angiography between March 2017 and July 2018 were included in the present study. Patients were divided into 3 groups according to MHR tertiles. The MHR was calculated by dividing the monocyte count by the high-density lipoprotein cholesterol level. CAD was defined as at least 50% diameter stenosis of a major coronary artery, including the right coronary, left main coronary, left anterior descending, and left circumflex arteries. The SYNTAX score was calculated by 2 experienced interventional cardiologists. SYNTAX score ≥23 was defined as a high SYNTAX score.Males showed a significantly higher MHR (12.2 [8.9-15.5] vs 9.3 [6.2-12.1], P < .001), accompanied by a higher prevalence of CAD (68.1% vs 53.4%, P < .001). Male sex remained an independent predictor of elevated MHR after correction for confounding factors (adjusted odds ratio [OR] 3.102, P = .001). The association between MHR and SYNTAX score was confirmed only in male stable patients with CAD (r = 0.113, P = .036). Multivariate logistic regression analysis showed that MHR was an independent predictor of SYNTAX score ≥23 only in male patients with CAD. The receiver-operating characteristic curve showed a predictive value of MHR for high SYNTAX score only in males.A higher MHR in males and a positive correlation of MHR with SYNTAX score were observed only in male stable patients with CAD. Such an easily obtained index may help interventional cardiologists detect high-risk patients before coronary catheterization, but its application may be restricted to males.


Assuntos
HDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Contagem de Leucócitos/métodos , Monócitos/citologia , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/epidemiologia , Síndrome Coronariana Aguda/metabolismo , Idoso , Angina Estável/sangue , Angina Estável/epidemiologia , Angina Estável/metabolismo , Angiografia Coronária/métodos , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/metabolismo , Vasos Coronários/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Índice de Gravidade de Doença , Fatores Sexuais
6.
Life Sci ; 235: 116817, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31476309

RESUMO

AIMS: In the tumor microenvironment, dysregulated immune cells could promote tumor progression, invasion and metastasis, by establishing a symbiotic relationship with cancer cells. A pivotal role is played by monocyte recruitment and induction of tumor-associated macrophages (TAMs), which provide immunosuppression and tumorigenesis. The effect of nemorosone, an antiproliferative phytocomponent present in Cuban Propolis, on TAM-induced tumor progression remains to be elucidated. Here we investigated the symbiotic relationship between monocytic leukemia THP-1 and hepatocellular carcinoma HepG2 cells, and the role of nemorosone in preventing TAM-induced tumor growth. MAIN METHODS: Macrophage differentiation induced by HepG2-conditioned medium was assessed by flow cytometry, analysis of secreted molecules and cytokine expression. The effect of nemorosone and/or conditioned THP-1-medium on HepG2 proliferation was evaluated by MTT assay, colony formation, cells cycle and migration assays. KEY FINDINGS: HepG2 cells induced THP-1 recruitment and differentiation to macrophages. When compared with control THP-1 cells, differentiated THP-1 showed a significant increase of the matrix metalloproteinases MMP-2 and MMP-9 expression (P < 0.01), and slightly induced HepG2 cells growth. This effect was counteracted by nemorosone, which also significantly inhibited colony formation (P < 0.01) and migratory capacity of HepG2 cells, driving a high percentage of cells (80%) to the G0/G1 phase. SIGNIFICANCE: HepG2-conditioned medium is a suitable model for THP-1 modulation and differentiation. Moreover, nemorosone significantly inhibits the proliferation of HepG2 cells, both in presence and absence of the soluble factors secreted by TAMs. Further studies are needed to elucidate the role of this natural compound in the HCC-TAM relationship.


Assuntos
Benzofenonas/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Monócitos/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Diferenciação Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Monócitos/citologia , Monócitos/metabolismo , Células THP-1
7.
Nat Immunol ; 20(9): 1161-1173, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31406378

RESUMO

Induction of the transcription factor Irf8 in the common dendritic cell progenitor (CDP) is required for classical type 1 dendritic cell (cDC1) fate specification, but the mechanisms controlling this induction are unclear. In the present study Irf8 enhancers were identified via chromatin profiling of dendritic cells and CRISPR/Cas9 genome editing was used to assess their roles in Irf8 regulation. An enhancer 32 kilobases (kb) downstream of the Irf8 transcriptional start site (+32-kb Irf8) that was active in mature cDC1s was required for the development of this lineage, but not for its specification. Instead, a +41-kb Irf8 enhancer, previously thought to be active only in plasmacytoid dendritic cells, was found to also be transiently accessible in cDC1 progenitors, and deleting this enhancer prevented the induction of Irf8 in CDPs and abolished cDC1 specification. Thus, cryptic activation of the +41-kb Irf8 enhancer in dendritic cell progenitors is responsible for cDC1 fate specification.


Assuntos
Células Dendríticas/citologia , Elementos Facilitadores Genéticos/genética , Fatores Reguladores de Interferon/metabolismo , Macrófagos/citologia , Monócitos/citologia , Animais , Sistemas CRISPR-Cas/genética , Diferenciação Celular , Linhagem da Célula , Células Dendríticas/imunologia , Regulação da Expressão Gênica , Fatores Reguladores de Interferon/genética , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Células-Tronco/citologia , Células Tumorais Cultivadas
8.
Nord J Psychiatry ; 73(6): 372-379, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31304832

RESUMO

Background: Currently, increasing evidence supports the hypothesis that alterations in the immune-inflammatory system are critical for the pathophysiology of bipolar disorder (BD). Neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), monocyte/lymphocyte ratio (MLR), and mean platelet volume (MPV) have recently been investigated as inexpensive and simple inflammatory markers. Aims: The aim of this study is to compare NLR, PLR, MLR, and MPV in depressive, manic, and euthymic patients with BD and healthy controls, and to evaluate whether values of NLR, PLR, MLR, and MPV are possible state or trait biomarkers in BD. Methods: This retrospective study was conducted with 341 patients with BD (100 patients in a depressive state, 141 patients in a manic state, and 100 patients in a euthymic state) and 114 healthy controls. Results: We found that patients with BD in manic states had higher levels of MPV, NLR, and MLR, and patients with BD in depressive states had higher levels of MPV than the controls. Moreover, MPV predicted all states of BD, while NLR and MLR predicted the manic state of BD. Conclusions: NLR, MLR, and MPV obtained from simple and inexpensive blood tests were significantly higher in patients with BD than in healthy controls, which each imply low-grade inflammation. MPV may serve as a possible trait biomarker of BD, while NLR and MLR may both serve as possible state biomarkers of the manic state.


Assuntos
Transtorno Bipolar/sangue , Inflamação/sangue , Linfócitos/citologia , Volume Plaquetário Médio , Monócitos/citologia , Neutrófilos/citologia , Adulto , Biomarcadores/sangue , Plaquetas/citologia , Plaquetas/fisiologia , Feminino , Humanos , Masculino , Estudos Retrospectivos
9.
Zhonghua Gan Zang Bing Za Zhi ; 27(7): 527-532, 2019 Jul 20.
Artigo em Chinês | MEDLINE | ID: mdl-31357779

RESUMO

Objective: To observe the expressional changes in Notch signaling pathway and toll-like receptor 4 (TLR4) and their interactions on the functions of CD14(+) monocytes in chronic hepatitis C patients. Methods: A total of 24 treatment-naïve chronic hepatitis C cases and 10 healthy individuals, who visited Shaanxi Provincial People's Hospital from August to October 2017, were enrolled. Selected CD14(+) monocytes were stimulated by the Notch signaling pathway inhibitor DAPT or transfected with TLR4 siRNA, and the levels of Notch1, Notch2, Hes1 and Hes5 mRNA were detected by real-time quantitative PCR. TLR4 protein levels and phosphorylation of NF-κB was detected by Western blot. ELISA was used to detect the level of cytokines secreted from CD14(+) monocytes. A t-test or paired t-test was used for comparison between groups. Results: The relative expression of Notch1 mRNA (3.97 ± 2.03 vs. 0.91 ± 0.76, P < 0.01) and downstream of Notch signaling pathway (5.96 ± 2.31 vs. 0.99 ± 0.45, P < 0.01), Hes1 mRNA and Hes5 mRNA (4.31 ± 1.05 vs. 0.84 ± 0.20, P < 0.01) in CD14+ monocytes of chronic hepatitis C patients was significantly higher than that of healthy individuals. The relative expression of TLR4 mRNA (5.14 ± 1.09 vs. 1.27 ± 0.39) and protein level in CD14(+) monocytes of chronic hepatitis C patients were significantly higher than those of healthy individuals (P < 0.01). An inhibition of Notch signaling pathway with DAPT had reduced the relative expression level of TLR4 mRNA (2.58 ± 1.36 vs. 4.34 ± 1.88, P < 0.05), protein expression and phosphorylation of NF-B in CD14(+) monocytes of chronic hepatitis C patients. Furthermore, the secretion level of MCP-1 [(94.32 ± 23.59) pg/ml vs. (64.07 ± 9.39) pg/ml, P < 0.01] and IL-8 [(12.54 ± 4.89) pg/ml vs. (7.92 ± 3.01) pg/ml, P < 0.05] was significantly reduced. TLR4 siRNA transfection reduced the expressions of Notch1 mRNA (2.09 ± 1.72 vs. 3.73 ± 1.75, P < 0.05), Hes1 (2.87 ± 0.84 vs. 5.54 ± 0.97, P < 0.01), and Hes5 (2.89 ± 0.93 vs. 4.51 ± 1.54, P < 0.01) in CD14(+) monocytes of chronic hepatitis C patients. Conclusion: Interaction of Notch signaling pathway with TLR4 can promote the function of CD14(+) monocytes in chronic hepatitis C patients.


Assuntos
Hepatite C Crônica , Monócitos/citologia , Receptores Notch/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Humanos , Receptores de Lipopolissacarídeos , NF-kappa B/metabolismo
10.
Medicine (Baltimore) ; 98(24): e15876, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31192919

RESUMO

BACKGROUND: Lymphocyte-to-monocyte ratio (LMR) was recently proposed as a prognostic factor of ovarian cancer. However, prognostic value of the LMR in ovarian cancer remains inconclusive. The study aimed to assess prognostic value of the LMR in ovarian cancer. METHODS: Seven common databases were comprehensively searched for relevant studies. The analyses were performed for overall survival (OS), progression-free survival (PFS) and clinical parameters. The hazard ratio (HR) and 95% confidence interval (CI) were used to analyze OS and PFS. RESULTS: A total of 2343 patients with ovarian cancer were included in this meta-analysis. The results showed that a low LMR predicted shorter OS (HR = 1.81, 95% CI = 1.38-2.37, P < .01) and PFS (HR = 1.65 95% CI = 1.46-1.85, P < .01) when compared to a high LMR in ovarian cancer. Besides, a low LMR was significantly associated with advanced clinical stage (P < .01), earlier lymph node metastasis (P = .01), higher carbohydrate antigen-125 levels (P < .01), larger residual tumor (P < .01) and worse chemosensitivity (P < .01) when compared to a high LMR in ovarian cancer. CONCLUSION: Low LMR was associated with unfavorable survival in patients with ovarian cancer. LMR could serve as a prognostic biomarker of ovarian cancer.


Assuntos
Carcinoma Epitelial do Ovário/imunologia , Monócitos/citologia , Neoplasias Ovarianas/imunologia , Carcinoma Epitelial do Ovário/patologia , Feminino , Humanos , Contagem de Leucócitos , Metástase Linfática , Contagem de Linfócitos , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Prognóstico , Análise de Sobrevida
11.
Nat Commun ; 10(1): 2711, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221993

RESUMO

Sepsis is characterized by a systemic inflammatory response followed by immunosuppression of the host. Metabolic defects and mitochondrial failure are common in immunocompromised patients with sepsis. The NLRP3 inflammasome is important for establishing an inflammatory response after activation by the purinergic P2X7 receptor. Here, we study a cohort of individuals with intra-abdominal origin sepsis and show that patient monocytes have impaired NLRP3 activation by the P2X7 receptor. Furthermore, most sepsis-related deaths are among patients whose NLRP3 activation is profoundly altered. In monocytes from sepsis patients, the P2X7 receptor is associated with mitochondrial dysfunction. Furthermore, activation of the P2X7 receptor results in mitochondrial damage, which in turn inhibits NLRP3 activation by HIF-1α. We show that mortality increases in a mouse model of sepsis when the P2X7 receptor is activated in vivo. These data reveal a molecular mechanism initiated by the P2X7 receptor that contributes to NLRP3 impairment during infection.


Assuntos
Inflamassomos/imunologia , Monócitos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Sepse/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Modelos Animais de Doenças , Feminino , Seguimentos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamassomos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/imunologia , Monócitos/citologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Receptores Purinérgicos P2X7/imunologia , Sepse/sangue , Sepse/microbiologia , Sepse/mortalidade , Regulação para Cima/imunologia
12.
J Ovarian Res ; 12(1): 51, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31151469

RESUMO

INTRODUCTION: Prognostic biomarkers are highly needed to properly manage patients with cancer and improve their clinical courses. The relationship between lymphocyte-to-monocyte ratio (LMR) at diagnosis and ovarian cancer prognosis has been extensively studied, but little consensus has been reached regarding its utility as a biomarker of poor outcome. Thus, this study aimed to investigate the potential prognostic value of pretreatment LMR in such patients to shed light on this issue. METHODS: We searched the scientific databases of MEDLINE, Embase, Cochrane Library, and WangFang for relevant studies about the inflammatory prognostic factor LMR in ovarian cancer, based on specific inclusion and exclusion criteria. The following parameters were analyzed among others: LMR values and respective cut-offs, patient's overall survival (OS) and progression-free survival (PFS), and clinicopathological features. RESULTS: Eight studies, including 2259 patients, were eligible for inclusion in this meta-analysis. We found that low LMR was associated with both poor OS [Hazard ratio (HR): 1.92; 95% confidence interval (CI): 1.58-2.34; p < 0.001] and PFS (HR: 1.70; 95% CI: 1.54-1.88; p < 0.001). Moreover, our findings revealed that low LMR was correlated with high G2/G3 histological grade (OR: 1.67; 95% CI: 1.26-2.20; p < 0.001) and late III-IV FIGO stage tumors (OR: 3.55; 95% CI: 2.68-4.70; p < 0.001), high serum CA-125 level (OR: 2.18; 95% CI: 1.71-2.77; p < 0.001), and presence of malignant ascites (OR: 1.87; 95% CI: 1.11-3.14; p = 0.02) and lymph node metastases (OR: 1.70; 95% CI: 1.13-2.54; p = 0.01). CONCLUSION: Pretreatment LMR is a potential prognostic marker of poor outcome in ovarian cancer patients and may thus be important in clinical care and disease control.


Assuntos
Linfócitos/citologia , Monócitos/citologia , Neoplasias Ovarianas/sangue , Biomarcadores Tumorais/sangue , Feminino , Humanos , Contagem de Leucócitos , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico , Intervalo Livre de Progressão , Taxa de Sobrevida
13.
Radiat Res ; 192(2): 121-134, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31161966

RESUMO

Radiation-induced fibrosis (RIF) is a common delayed effect of acute ionizing radiation exposure (DEARE) affecting diverse tissues including the heart, lungs, liver and skin, leading to reduced tissue function and increased morbidity. Monocytes, which may be classified into classical (CD14++, CD16-), intermediate (CD14++, CD16+) and non-classical (CD14+/low, CD16++) subtypes in humans and non-human primates (NHPs), and monocyte-derived macrophages may play an integral role in the pathogenesis of RIF. We tested the hypothesis that moderate to high levels of total-body exposure to radiation would alter monocyte polarization and produce phenotypes that could promote multi-organ fibrosis in a wellestablished NHP model of DEARE. Subjects were 16 young adult male rhesus macaques, ten of which were exposed to high-energy, 4 Gy X-ray total-body irradiation (TBI) and six that received sham irradiation (control). Total monocytes assessed by complete blood counts were 89% depleted in TBI animals by day 9 postirradiation (P < 0.05), but recovered by day 30 postirradiation and did not differ from control levels thereafter. Monocytes were isolated from peripheral blood mononuclear cells (PBMCs) and sorted into classical, intermediate and non-classical subsets using fluorescence-activated cell sorting (FACS) prior to and at 6 months post-TBI. At 6 months postirradiation, monocyte polarization shifted towards lower classical (92% → 86%) and higher intermediate (7% → 12%) and non-classical monocyte subsets (0.6% → 2%) (all P < 0.05) in TBI animals compared to baseline. No change in monocyte subsets was observed in control animals. Transcriptional profiles in classical and intermediate monocyte subsets were assessed using RNAseq. Classical monocyte gene expression did not change significantly over time or differ cross-sectionally between TBI and control groups. In contrast, significant numbers of differentially expressed genes (DEGs) were detected in intermediate monocyte comparisons between the TBI animals and all animals at baseline (304 DEGs), and in the TBI versus control animals at 6 months postirradiation (67 DEGs). Intermediate monocytes also differed between baseline and 6 months in control animals (147 DEGs). Pathway analysis was used to identify genes within significant canonical pathways, yielding 52 DEGs that were specific to irradiated intermediate monocytes. These DEGs and significant canonical pathways were associated with pro-fibrotic and anti-inflammatory signaling pathways that have been noted to induce M2 macrophage polarization. These findings support the hypothesis that TBI may alter monocyte programming and polarization towards a profibrotic phenotype, providing a novel target opportunity for therapies to inhibit or prevent RIF.


Assuntos
Monócitos/citologia , Monócitos/efeitos da radiação , Irradiação Corporal Total/efeitos adversos , Animais , Polaridade Celular/efeitos da radiação , Regulação da Expressão Gênica/efeitos da radiação , Macaca mulatta , Masculino , Monócitos/metabolismo , Fatores de Tempo , Transcrição Genética/efeitos da radiação
14.
Cell Physiol Biochem ; 52(6): 1398-1411, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31075190

RESUMO

BACKGROUND/AIMS: Visfatin is known to act as a mediator in several metabolic disorders, such as obesity, diabetes, and cardiovascular diseases. This study aimed to investigate the effect of visfatin on the adhesion of THP-1 monocytes to human vascular endothelial cells and the underlying mechanism. METHODS: Monocytes adhesion to endothelial cells was determined by using fluorescence-labeled monocytes. ICAM-1 and VCAM-1 expression in endothelial cells were measured by western blotting. Production of reactive oxygen species (ROS) was measured by using a fluorescent dye. The amounts of nuclear factor-kappa B (NF-κB) and phosphorylation of inhibitory factor of NF-κB (IκB) were determined by using western blot analysis. The translocation of NF-κB from the cytoplasm to the nucleus was determined by using immunofluorescence. RESULTS: Here we showed that visfatin significantly caused the upregulation of intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in endothelial cells, as well as enhanced monocyte adhesion to endothelial cells. Moreover, we found that inhibition of PI3K, Akt, and p38 MAPK activation significantly prevented visfatin-enhanced expression of ICAM-1 and VCAM-1 and monocyte adhesion to endothelial cells. Visfatin enhanced ROS production and IKK/NF-кB activation and then led to upregulation of ICAM-1 and VCAM-1 and enhanced monocyte adhesion to endothelial cells. These effects were also p38/PI3K/Akt-dependent. CONCLUSION: These results demonstrated that visfatin promoted monocyte-endothelial cell adhesion by increasing ICAM-1 and VCAM-1 expression via the activation of p38/PI3K/Akt signaling and downstream ROS production and IKK/NF-кB activation.


Assuntos
Adesão Celular/efeitos dos fármacos , Nicotinamida Fosforribosiltransferase/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Humanos , Proteínas I-kappa B/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Monócitos/citologia , NADPH Oxidases/metabolismo , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
J Nanobiotechnology ; 17(1): 69, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31113488

RESUMO

BACKGROUND: The major obstacle impeding human immunodeficiency virus-1 (HIV-1) eradication in antiretroviral treatment (ART) treated HIV-1 subjects is the establishment of long-lived latently infected resting CD4+ T cells. Due to the fact that no drug has been effective, the search for new drugs and combinations are a priority in the HIV cure. Treatments based on nanotechnology have emerged as an innovative and promising alternative to current and conventional therapies. In this respect, nanotechnology opens up a new door for eliminating latent HIV infection. We studied the role of G1-S4, G2-S16 and G3-S16 polyanionic carbosilane dendrimers in the context of latent HIV-1 persistence. Moreover, we study the efficiency of these dendrimers in combination with latency reversal agents (LRAs) against HIV-1 infection. METHODS: J89GFP lymphocyte and THP89GFP monocyte derived cell lines latently infected with HIV-1 p89GFP were used as an in vitro model of latency for our study. Viability assays by 3-(4-5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) were performed to determine the working concentrations of dendrimers and LRAs. Both cell lines were treated with G1-S4, G2-S16 and G3-S16 either alone or in combination with bryostatin (BRY), romidepsin (RMD) or panobinostat (PNB) for 24 and 48 h. The expression pattern of GFP was measured by flow cytometry and referred as measure of viral reactivation. RESULTS AND DISCUSSION: The combination treatment of the dendrimers with the protein kinase C (PKC) agonist did not modify the antilatency activity in J89GFP lymphocyte cell line. Interestingly enough, G3-S16 dendrimer alone and its combination with BRY, RMD or PNB showed a significant increased expression of GFP in the THP89GFP monocyte cell line. CONCLUSION: We showed for the first time that nanoparticles, in this case, G3-S16 anionic carbosilan dendrimer may play an important role in new treatments against HIV-1 infection.


Assuntos
Adjuvantes Imunológicos/farmacologia , Fármacos Anti-HIV/farmacologia , Dendrímeros/química , Infecções por HIV/tratamento farmacológico , Polímeros/química , Silanos/química , Briostatinas/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Depsipeptídeos/farmacologia , Liberação Controlada de Fármacos , Quimioterapia Combinada/métodos , HIV-1/efeitos dos fármacos , Humanos , Linfócitos/citologia , Monócitos/citologia , Panobinostat/farmacologia , Tamanho da Partícula , Propriedades de Superfície
16.
Immunity ; 50(6): 1453-1466.e4, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31053503

RESUMO

In lymph nodes, subcapsular sinus macrophages (SSMs) form an immunological barrier that monitors lymph drained from peripheral tissues. Upon infection, SSMs activate B and natural killer T (NKT) cells while secreting inflammatory mediators. Here, we investigated the mechanisms regulating development and homeostasis of SSMs. Embryonic SSMs originated from yolk sac hematopoiesis and were replaced by a postnatal wave of bone marrow (BM)-derived monocytes that proliferated to establish the adult SSM network. The SSM network self-maintained by proliferation with minimal BM contribution. Upon pathogen-induced transient deletion, BM-derived cells contributed to restoring the SSM network. Lymphatic endothelial cells (LECs) were the main source of CSF-1 within the lymph node and conditional deletion of Csf1 in adult LECs decreased the network of SSMs and medullary sinus macrophages (MSMs). Thus, SSMs have a dual hematopoietic origin, and LECs are essential to the niche supporting these macrophages.


Assuntos
Células Endoteliais/metabolismo , Macrófagos/metabolismo , Animais , Biomarcadores , Comunicação Celular , Diferenciação Celular , Expressão Gênica , Genes Reporter , Hematopoese/genética , Hematopoese/imunologia , Homeostase , Linfonodos/citologia , Linfonodos/imunologia , Vasos Linfáticos , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/citologia , Macrófagos/imunologia , Camundongos , Monócitos/citologia , Monócitos/metabolismo , Saco Vitelino
17.
Cell Mol Life Sci ; 76(18): 3667-3678, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31062071

RESUMO

Cardiolipins (CLs) are tetra-acylated diphosphatidylglycerols found in bacteria, yeast, plants, and animals. In healthy mammals, CLs are unsaturated, whereas saturated CLs are found in blood cells from Barth syndrome patients and in some Gram-positive bacteria. Here, we show that unsaturated but not saturated CLs block LPS-induced NF-κB activation, TNF-α and IP-10 secretion in human and murine macrophages, as well as LPS-induced TNF-α and IL-1ß release in human blood mononuclear cells. Using HEK293 cells transfected with Toll-like receptor 4 (TLR4) and its co-receptor Myeloid Differentiation 2 (MD2), we demonstrate that unsaturated CLs compete with LPS for binding TLR4/MD2 preventing its activation, whereas saturated CLs are TLR4/MD2 agonists. As a consequence, saturated CLs induce a pro-inflammatory response in macrophages characterized by TNF-α and IP-10 secretion, and activate the alternative NLRP3 inflammasome pathway in human blood-derived monocytes. Thus, we identify that double bonds discriminate between anti- and pro-inflammatory properties of tetra-acylated molecules, providing a rationale for the development of TLR4 activators and inhibitors for use as vaccine adjuvants or in the treatment of TLR4-related diseases.


Assuntos
Cardiolipinas/farmacologia , Macrófagos/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Animais , Anti-Infecciosos/química , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Ligação Competitiva , Cardiolipinas/química , Cardiolipinas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CXCL10/metabolismo , Células HEK293 , Humanos , Receptores de Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Antígeno 96 de Linfócito/genética , Antígeno 96 de Linfócito/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Monócitos/citologia , Monócitos/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ligação Proteica , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/metabolismo
18.
Int J Mol Sci ; 20(10)2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096581

RESUMO

The FLUMIAS (Fluorescence-Microscopic Analyses System for Life-Cell-Imaging in Space) confocal laser spinning disk fluorescence microscope represents a new imaging capability for live cell imaging experiments on suborbital ballistic rocket missions. During the second pioneer mission of this microscope system on the TEXUS-54 suborbital rocket flight, we developed and performed a live imaging experiment with primary human macrophages. We simultaneously imaged four different cellular structures (nucleus, cytoplasm, lysosomes, actin cytoskeleton) by using four different live cell dyes (Nuclear Violet, Calcein, LysoBrite, SiR-actin) and laser wavelengths (405, 488, 561, and 642 nm), and investigated the cellular morphology in microgravity (10-4 to 10-5 g) over a period of about six minutes compared to 1 g controls. For live imaging of the cytoskeleton during spaceflight, we combined confocal laser microscopy with the SiR-actin probe, a fluorogenic silicon-rhodamine (SiR) conjugated jasplakinolide probe that binds to F-actin and displays minimal toxicity. We determined changes in 3D cell volume and surface, nuclear volume and in the actin cytoskeleton, which responded rapidly to the microgravity environment with a significant reduction of SiR-actin fluorescence after 4-19 s microgravity, and adapted subsequently until 126-151 s microgravity. We conclude that microgravity induces geometric cellular changes and rapid response and adaptation of the potential gravity-transducing cytoskeleton in primary human macrophages.


Assuntos
Citoesqueleto/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Ausência de Peso , Citoesqueleto de Actina , Actinas/metabolismo , Linhagem Celular , Núcleo Celular , Citoplasma , Humanos , Lisossomos , Microscopia Confocal/instrumentação , Microscopia Confocal/métodos , Microscopia de Fluorescência/instrumentação , Microscopia de Fluorescência/métodos , Monócitos/citologia , Voo Espacial
19.
Artif Cells Nanomed Biotechnol ; 47(1): 1839-1845, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31066305

RESUMO

Atherosclerosis is the chronic inflammatory disease, and inflammation-elicited endothelial activation is an early event in the development of atherosclerosis. The P2Y11 receptor is a purinergic receptor and a member of the P2 family of G coupled protein which has been shown to modulate vascular function. Progress in the study of purine receptors has been tremendous and these receptors have become pharmacological targets for various diseases. In this study, we show that the P2Y11R antagonist NF157 can mitigate oxidized LDL (ox-LDL)-induced endothelial inflammation. Our study demonstrates that P2Y11R is expressed to a fair degree in human aortic endothelial cells and is induced by treatment with ox-LDL. Blockage of P2Y11R by its selective antagonist NF157 ameliorates ox-LDL-induced adhesion of THP-1 monocytes to endothelial cells. NF157 inhibits ox-LDL-induced expression of adhesion molecules including E-selectin and VCAM-1. NF157 also suppresses ox-LDL-associated ROS production and induction of the NADPH oxidase subunit NOX-4. Moreover, NF157 has an inhibitory effect on the production of major cytokines including IL-6 and TNF-α. Mechanistically, we show that NF157 mitigates ox-LDL-induced phosphorylation of MAPK kinase p38 and NF-κB activation. Our findings indicate that blockage of P2Y11R signalling by its antagonist NF157 may protect endothelial cells from ox-LDL-induced endothelial inflammation. Therefore, NF157 may have therapeutic implications in the modulation of atherosclerosis-associated inflammation.


Assuntos
Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Lipoproteínas LDL/farmacologia , Receptores Purinérgicos P2/metabolismo , Suramina/análogos & derivados , Adesão Celular/efeitos dos fármacos , Selectina E/genética , Ativação Enzimática/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Inflamação/tratamento farmacológico , Interleucina-6/biossíntese , Monócitos/citologia , Monócitos/efeitos dos fármacos , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Suramina/farmacologia , Suramina/uso terapêutico , Fator de Necrose Tumoral alfa/biossíntese , Molécula 1 de Adesão de Célula Vascular/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
J Nanobiotechnology ; 17(1): 72, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31133024

RESUMO

BACKGROUND: Nano-sized vesicles, so called extracellular vesicles (EVs), from regenerative cardiac cells represent a promising new therapeutic approach to treat cardiovascular diseases. However, it is not yet sufficiently understood how cardiac-derived EVs facilitate their protective effects. Therefore, we investigated the immune modulating capabilities of EVs from human cardiac-derived adherent proliferating (CardAP) cells, which are a unique cell type with proven cardioprotective features. RESULTS: Differential centrifugation was used to isolate EVs from conditioned medium of unstimulated or cytokine-stimulated (IFNγ, TNFα, IL-1ß) CardAP cells. The derived EVs exhibited typical EV-enriched proteins, such as tetraspanins, and diameters mostly of exosomes (< 100 nm). The cytokine stimulation caused CardAP cells to release smaller EVs with a lower integrin ß1 surface expression, while the concentration between both CardAP-EV variants was unaffected. An exposure of either CardAP-EV variant to unstimulated human peripheral blood mononuclear cells (PBMCs) did not induce any T cell proliferation, which indicates a general low immunogenicity. In order to evaluate immune modulating properties, PBMC cultures were stimulated with either Phytohemagglutin or anti-CD3. The treatment of those PBMC cultures with either CardAP-EV variant led to a significant reduction of T cell proliferation, pro-inflammatory cytokine release (IFNγ, TNFα) and increased levels of active TGFß. Further investigations identified CD14+ cells as major recipient cell subset of CardAP-EVs. This interaction caused a significant lower surface expression of HLA-DR, CD86, and increased expression levels of CD206 and PD-L1. Additionally, EV-primed CD14+ cells released significantly more IL-1RA. Notably, CardAP-EVs failed to modulate anti-CD3 triggered T cell proliferation and pro-inflammatory cytokine release in monocultures of purified CD3+ T cells. Subsequently, the immunosuppressive feature of CardAP-EVs was restored when anti-CD3 stimulated purified CD3+ T cells were co-cultured with EV-primed CD14+ cells. Beside attenuated T cell proliferation, those cultures also exhibited a significant increased proportion of regulatory T cells. CONCLUSIONS: CardAP-EVs have useful characteristics that could contribute to enhanced regeneration in damaged cardiac tissue by limiting unwanted inflammatory processes. It was shown that the priming of CD14+ immune cells by CardAP-EVs towards a regulatory type is an essential step to attenuate significantly T cell proliferation and pro-inflammatory cytokine release in vitro.


Assuntos
Doenças Cardiovasculares/terapia , Vesículas Extracelulares/imunologia , Monócitos/imunologia , Miócitos Cardíacos/imunologia , Doenças Cardiovasculares/imunologia , Linhagem Celular , Proliferação de Células , Técnicas de Cocultura , Citocinas/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Imunomodulação , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Monócitos/citologia , Miócitos Cardíacos/citologia , Regeneração , Linfócitos T/citologia , Linfócitos T/imunologia
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