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2.
Zhongguo Zhong Yao Za Zhi ; 46(16): 4201-4207, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34467733

RESUMO

The present study aims to investigate the effects of the main components(aesculin, berberine hydrochloride, and anemoside B4) in the butyl alcohol extract of Baitouweng Decoction(BAEB) on the chemotaxis of neutrophils induced by dimethyl sulfoxide(DMSO). HL60 cells were cultivated in RPMI-1640 complete medium, and transferred into a 6-well plate(2 × 10~5 per mL) with 4 mL in each well, followed by incubation with DMSO at 1.3% for five days. The morphologic changes of cells were observed under an inverted microscope. The CD11 b expression after DMSO induction was analyzed by flow cytometry. The effects of aesculin, berberine hydrochloride, and anemoside B4 on the cell proliferation and migration were detected by CCK8 assay and Transwell assay, respectively. The effects of the main components on the production and polarization of F-actin protein were also examined by flow cytometry and laser confocal microscopy. PI3 K/Akt signaling pathway was checked by Western blot. As revealed by the results, neutrophil-like HL60 cells were observed after DMSO induction. The CD11 b expression in these cells increased significantly as indicated by the flow cytometry. Additionally, 100 µg·mL~(-1) aesculin, 8 µg·mL~(-1) berberine hydrochloride, and 80 µg·mL~(-1) anemoside B4 were potent in inhibiting the migration of neutrophils and reducing F-actin expression. Berberine hydrochloride was verified to be capable of diminishing phosphorylated PI3 K/Akt protein expression. The findings indicate that aesculin, anemoside B4, and especially berberine hydrochloride in the BAEB can inhibit the chemotaxis of neutrophils, which is possibly achieved by the inhibition of F-actin and PI3 K/Akt signaling pathway.


Assuntos
Berberina , Medicamentos de Ervas Chinesas , 1-Butanol , Berberina/farmacologia , Quimiotaxia , Medicamentos de Ervas Chinesas/farmacologia , Neutrófilos
3.
Rev Assoc Med Bras (1992) ; 67(3): 431-436, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34468610

RESUMO

OBJECTIVE: This retrospective study aimed to determine the predictive values of the C-reactive protein (CRP)/albumin ratio (CAR), fibrinogen/albumin ratio (FAR), and neutrophil/lymphocyte ratio (NLR) parameters, which reflect the systemic inflammatory status, for the severity of COVID-19. METHODS: A total of 188 patients diagnosed with COVID-19 were enrolled in this study. Among them, 118 were in the severe group, and 70 were in the non-severe group. Levels of albumin, CRP, D-dimer, procalcitonin, fibrinogen, and hemoglobin; leukocyte, neutrophil, lymphocyte, and monocyte counts; and the FAR, CAR, and NLR were compared between the two groups. RESULTS: The CAR, FAR, and NLR values were significantly higher in the severe group compared to the non-severe group. CAR, FAR, and NLR were positively correlated with leukocyte and neutrophil counts and CRP, procalcitonin, and fibrinogen levels. On the other hand, they were inversely correlated with monocyte (except for NLR) and lymphocyte counts. Receiver operator characteristic analysis showed that the area under the curve (AUC) for CAR, FAR, and NLR was 0.841, 0.737, and 0.802, respectively. CONCLUSIONS: Our investigation revealed that the CAR, FAR, and NLR indices can be used to predict the severity of COVID-19, among which CAR was the best predictor of severe COVID-19.


Assuntos
Proteína C-Reativa , COVID-19 , Albuminas , Proteína C-Reativa/análise , Fibrinogênio , Humanos , Linfócitos/química , Neutrófilos , Estudos Retrospectivos , SARS-CoV-2
4.
J Nutr Sci Vitaminol (Tokyo) ; 67(4): 249-252, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34471000

RESUMO

Elevated neutrophil/lymphocyte ratio (NLR) has been reported as a sensitive marker for predicting poor prognosis in chronic inflammation-based diseases such as stroke, heart failure, cancers, and diabetes, as well as acute inflammatory diseases such as bacterial and viral infections, including COVID-19. NLR is also known to increase with age and is considered to be an aging marker. We conducted a double-blind, placebo-controlled trial in elderly volunteers to examine the effect of a newly developed, highly bioavailable curcumin formulation (curcuRougeTM) on NLR. Both the white blood cell count and the neutrophil rate decreased significantly, and the lymphocyte rate increased significantly from baseline to after curcuRougeTM administration for 4 wk. curcuRougeTM significantly reduced the NLR (p=0.020). On the other hand, in the placebo group, there were no changes in white blood cell count, neutrophil ratio, lymphocyte ratio, or NLR. The present study demonstrates for the first time, in elderly volunteers, that administration of curcuRougeTM significantly reduces NLR, an indicator of prognosis in cardiovascular diseases, cancer, infectious diseases, and aging. Thus, curcuRougeTM might be expected to improve the prognosis of these diseases as well as exhibit anti-aging effects.


Assuntos
COVID-19 , Curcumina , Idoso , Humanos , Contagem de Leucócitos , Contagem de Linfócitos , Linfócitos , Neutrófilos , Estudos Retrospectivos , SARS-CoV-2
5.
Anticancer Res ; 41(9): 4471-4478, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475071

RESUMO

AIM: This study aimed to evaluate the prognostic value of neutrophil-to-lymphocyte ratio (NLR) in elderly patients with Stage I-III colon cancer for long-term oncologic outcomes. PATIENTS AND METHODS: We retrospectively reviewed 175 patients aged >75 years who underwent radical surgery for Stage I-III colon cancer between 2000 and 2015 at our institute. Overall survival (OS), cancer-specific survival (CSS), and relapse-free survival (RFS) were evaluated according to NLR values using propensity score analysis. Patients were allocated to the higher NLR (H-NLR) or the lower NLR (L-NLR) group with a cut-off value of 2.3, based on receiver operating characteristic curve. RESULTS: Before case matching, there were significant differences between the two groups for CSS (p=0.023) and RFS (p<0.001), but not for OS (p=0.069). Similar results were obtained after case matching, with significant differences observed for CSS (p=0.003) and RFS (p=0.027), but not for OS (p=0.145). CONCLUSION: NLR may be a prognostic factor in elderly patients with colon cancer.


Assuntos
Neoplasias do Colo/sangue , Neoplasias do Colo/cirurgia , Neutrófilos/metabolismo , Pontuação de Propensão , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/patologia , Procedimentos Cirúrgicos do Sistema Digestório , Intervalo Livre de Doença , Feminino , Humanos , Contagem de Linfócitos , Masculino , Estadiamento de Neoplasias , Prognóstico , Curva ROC , Estudos Retrospectivos , Resultado do Tratamento
6.
Andes Pediatr ; 92(3): 382-388, 2021 Jun.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-34479244

RESUMO

INTRODUCTION: The multisystem inflammatory syndrome in children associated with SARS-CoV-2 (MIS-C) is cha racterized by a hyperinflammatory state resulting from a cytokine storm, evidenced by alterations in laboratory blood testing and acute-phase proteins. OBJECTIVE: to describe the clinical and labora tory characteristics of patients hospitalized due to MIS-C and identify predictive markers of severity. PATIENTS AND METHOD: Retrospective study of 32 patients. The group was divided into critical and non-critical according to clinical presentation and therapy used. Clinical and laboratory aspects were studied, including complete blood count, coagulation tests, and biomarkers. RESULTS: 18/32 were males, with a median age of 6.8 years. The most frequent manifestations were cardiovascular (84.3%), digestive (84%), and mucocutaneous (59%). The group of critical patients included 15 patients, 12 were males with a median age of 8.9 years, and the non-critical group included 17 patients, 6 were males with a median age of 5.4 years. The laboratory parameters at the admission in the global group showed increased C-reactive protein, D-dimer, leukocytes, neutrophils, ferritin, and fibrinogen. In contrast, albumin and blood sodium levels were decreased. At admission, the critical group was cha racterized by presenting thrombocytopenia, hypoalbuminemia, prolonged prothrombin time, and elevated ferritin. At the time of deterioration, there was an intensification of thrombocytopenia, in creased C-reactive protein together with increased neutrophils level. CONCLUSION: The blood count, C-reactive protein, and albuminemia at admission proved to be significantly important in the identi fication of patients at risk of clinical deterioration.


Assuntos
COVID-19/complicações , SARS-CoV-2 , Índice de Gravidade de Doença , Síndrome de Resposta Inflamatória Sistêmica/complicações , Biomarcadores/sangue , Proteína C-Reativa/análise , COVID-19/classificação , Criança , Deterioração Clínica , Estado Terminal , Feminino , Ferritinas/sangue , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Fibrinogênio/análise , Humanos , Leucócitos , Masculino , Neutrófilos , Estudos Retrospectivos , Síndrome de Resposta Inflamatória Sistêmica/classificação , Trombocitopenia/sangue
7.
Dan Med J ; 68(9)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34477095

RESUMO

INTRODUCTION Major emergency abdominal surgery results in a high risk of morbidity and mortality. Preoperative neutrophil-to-lymphocyte ratio (NLR) has been proposed as a predictor of post-operative outcomes in elective surgery. The aim of the present study was to examine whether preoperative NLR was associated with post-operative morbidity and mortality after major emergency abdominal surgery. METHODS We conducted a retrospective cohort study of patients undergoing major emergency abdominal surgery in two university hospitals in Denmark between 2010 and 2016. Associations between preoperative NLR and 30-day post-operative complications and mortality were established through multivariate logistic regression and receiver-operating characteristics (ROC) analysis. RESULTS A total of 570 patients were included in the study. The overall 30-day mortality was 9.3% and 59.3% had post-operative complications. The median preoperative NLR was 8.6 (interquartile range: 4.8-14.7). Although NLR was higher in the group of patients who had complications or died after surgery, a multivariate analysis showed that the NLR was not associated with 30-day post-operative complications (odds ratio (OR) = 1.01 (95% confidence interval (CI): 0.99-1.02); p = 0.424) or mortality (OR = 0.99 (95% CI: 0.97-1.02); p = 0.57). The ROC analysis showed an area under the curve of 0.55 and 0.60 for 30-day post-operative complications and mortality, respectively. CONCLUSIONS Preoperative NLR was not associated with 30-day post-operative complications and mortality in patients undergoing major emergency abdominal surgery. FUNDING none. TRIAL REGISTRATION not relevant.


Assuntos
Linfócitos , Neutrófilos , Humanos , Período Pós-Operatório , Prognóstico , Curva ROC , Estudos Retrospectivos
8.
Molecules ; 26(17)2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34500777

RESUMO

Human neutrophil elastase (HNE) is a uniquely destructive serine protease with the ability to unleash a wave of proteolytic activity by destroying the inhibitors of other proteases. Although this phenomenon forms an important part of the innate immune response to invading pathogens, it is responsible for the collateral host tissue damage observed in chronic conditions such as chronic obstructive pulmonary disease (COPD), and in more acute disorders such as the lung injuries associated with COVID-19 infection. Previously, a combinatorially selected activity-based probe revealed an unexpected substrate preference for oxidised methionine, which suggests a link to oxidative pathogen clearance by neutrophils. Here we use oxidised model substrates and inhibitors to confirm this observation and to show that neutrophil elastase is specifically selective for the di-oxygenated methionine sulfone rather than the mono-oxygenated methionine sulfoxide. We also posit a critical role for ordered solvent in the mechanism of HNE discrimination between the two oxidised forms methionine residue. Preference for the sulfone form of oxidised methionine is especially significant. While both host and pathogens have the ability to reduce methionine sulfoxide back to methionine, a biological pathway to reduce methionine sulfone is not known. Taken together, these data suggest that the oxidative activity of neutrophils may create rapidly cleaved elastase "super substrates" that directly damage tissue, while initiating a cycle of neutrophil oxidation that increases elastase tissue damage and further neutrophil recruitment.


Assuntos
Imunidade Inata , Elastase de Leucócito/metabolismo , Metionina/análogos & derivados , Neutrófilos/imunologia , Biocatálise , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Domínio Catalítico/genética , Ensaios Enzimáticos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Elastase de Leucócito/antagonistas & inibidores , Elastase de Leucócito/genética , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Metionina/metabolismo , Simulação de Dinâmica Molecular , Infiltração de Neutrófilos , Neutrófilos/enzimologia , Oxirredução/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/patologia , SARS-CoV-2/imunologia , Especificidade por Substrato/imunologia
9.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445548

RESUMO

S100A9, a Ca2+-binding protein, is tightly associated to neutrophil pro-inflammatory functions when forming a heterodimer with its S100A8 partner. Upon secretion into the extracellular environment, these proteins behave like damage-associated molecular pattern molecules, which actively participate in the amplification of the inflammation process by recruitment and activation of pro-inflammatory cells. Intracellular functions have also been attributed to the S100A8/A9 complex, notably its ability to regulate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. However, the complete functional spectrum of S100A8/A9 at the intracellular level is far from being understood. In this context, we here investigated the possibility that the absence of intracellular S100A8/A9 is involved in cytokine secretion. To overcome the difficulty of genetically modifying neutrophils, we used murine neutrophils derived from wild-type and S100A9-/- Hoxb8 immortalized myeloid progenitors. After confirming that differentiated Hoxb8 neutrophil-like cells are a suitable model to study neutrophil functions, our data show that absence of S100A8/A9 led to a dysregulation of cytokine secretion after lipopolysaccharide (LPS) stimulation. Furthermore, we demonstrate that S100A8/A9-induced cytokine secretion was regulated by the nuclear factor kappa B (NF-κB) pathway. These results were confirmed in human differentiated HL-60 cells, in which S100A9 was inhibited by shRNAs. Finally, our results indicate that the degranulation process could be involved in the regulation of cytokine secretion by S100A8/A9.


Assuntos
Calgranulina A/metabolismo , Calgranulina B/metabolismo , Citocinas/metabolismo , Proteínas de Homeodomínio/metabolismo , Neutrófilos/imunologia , Células-Tronco/imunologia , Animais , Calgranulina A/genética , Calgranulina B/genética , Estrogênios/farmacologia , Células HL-60 , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Neoplasias , Neutrófilos/citologia , Neutrófilos/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo
10.
Nat Commun ; 12(1): 5024, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408137

RESUMO

There is an unmet clinical need for stratification of breast lesions as indolent or aggressive to tailor treatment. Here, single-cell transcriptomics and multiparametric imaging applied to a mouse model of breast cancer reveals that the aggressive tumor niche is characterized by an expanded basal-like population, specialization of tumor subpopulations, and mixed-lineage tumor cells potentially serving as a transition state between luminal and basal phenotypes. Despite vast tumor cell-intrinsic differences, aggressive and indolent tumor cells are functionally indistinguishable once isolated from their local niche, suggesting a role for non-tumor collaborators in determining aggressiveness. Aggressive lesions harbor fewer total but more suppressed-like T cells, and elevated tumor-promoting neutrophils and IL-17 signaling, disruption of which increase tumor latency and reduce the number of aggressive lesions. Our study provides insight into tumor-immune features distinguishing indolent from aggressive lesions, identifies heterogeneous populations comprising these lesions, and supports a role for IL-17 signaling in aggressive progression.


Assuntos
Neoplasias da Mama/imunologia , Mama/patologia , Evasão Tumoral , Animais , Mama/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Progressão da Doença , Feminino , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Camundongos , Neutrófilos/imunologia , Análise de Célula Única
12.
Cells ; 10(7)2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34359987

RESUMO

Since the end of 2019, a new, dangerous virus has caused the deaths of more than 3 million people. Efforts to fight the disease remain multifaceted and include prophylactic strategies (vaccines), the development of antiviral drugs targeting replication, and the mitigation of the damage associated with exacerbated immune responses (e.g., interleukin-6-receptor inhibitors). However, numerous uncertainties remain, making it difficult to lower the mortality rate, especially among critically ill patients. While looking for a new means of understanding the pathomechanisms of the disease, we asked a question-is our immunity key to resolving these uncertainties? In this review, we attempt to answer this question, and summarize, interpret, and discuss the available knowledge concerning the interplay between neutrophils, neutrophil extracellular traps (NETs), and T-cells in COVID-19. These are considered to be the first line of defense against pathogens and, thus, we chose to emphasize their role in SARS-CoV-2 infection. Although immunologic alterations are the subject of constant research, they are poorly understood and often underestimated. This review provides background information for the expansion of research on the novel, immunity-oriented approach to diagnostic and treatment possibilities.


Assuntos
COVID-19/imunologia , Armadilhas Extracelulares/imunologia , Neutrófilos/imunologia , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Animais , COVID-19/diagnóstico , COVID-19/patologia , COVID-19/terapia , Humanos , Imunidade Inata , Neutrófilos/patologia , Linfócitos T/patologia
13.
Acta Derm Venereol ; 101(8): adv00527, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34405247

RESUMO

Systemic inflammatory response markers, including neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and monocyte-to-lymphocyte ratio, are useful prognostic factors for various malignant tumours. The aim of this study was to investigate the clinical relevance of these markers in primary cutaneous angiosarcoma. Twenty-six patients were retrospectively divided into 2 groups according to pretreatment peri-pheral blood cell counts or systemic inflammatory response marker levels; overall survival and progression-free survival were compared. Univariate analysis found that high neutrophil count (> 3.1×109/l), high neutrophil-to-lymphocyte ratio (> 2.4), high platelet-to-lymphocyte ratio (> 175) and low lymphocyte count (≤ 1.3×109/l) were related to shorter overall survival, while high neutrophil and low lymphocyte groups had shorter progression-free survival. In multivariate analysis, high neutrophil count and high neutrophil-to- lymphocyte ratio (hazard ratio 7.44 and 5.04, 95% confidence interval 1.48-37.2 and 1.26-20.1, respectiv-ely) were identified as independent prognostic factors for poor overall survival. These results indicate that systemic inflammatory response markers serve as prognostic predictors in primary cutaneous angiosarcoma, as well as in other types of soft-tissue sarcoma.


Assuntos
Hemangiossarcoma , Neutrófilos , Humanos , Linfócitos , Prognóstico , Estudos Retrospectivos
14.
Braz J Med Biol Res ; 54(10): e11409, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34406210

RESUMO

Obesity has been associated with an increased risk of breast cancer recurrence and death. Some readily available biomarkers associated with systemic inflammation have been receiving attention as potential prognostic indicators in cancer, including neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). This study aimed to explore the correlation between body mass index (BMI) and invasive breast cancer and the association of NLR, PLR, and BMI with breast cancer outcomes. We undertook a retrospective study to evaluate patients treated for breast cancer over 14 years. Clinicopathological data was obtained before receiving any treatment. Of the 1664 patients included with stage I-III, 567 (34%) were obese (BMI≥30 kg/m2). Obese patients had larger tumors compared to non-obese patients. Higher BMI was associated with recurrence and worse survival only in patients with stage I disease. NLR and PLR were classified into high and low level groups. The NLRhigh (NLR>4) was found to be an independent prognostic factor for recurrence and mortality, while the PLRhigh (PLR>150) group had no impact on survival. A subgroup of patients with NLRhigh and BMIhigh had the worst disease-free survival (P=0.046), breast cancer-specific survival (P<0.001), and overall survival (P=0.006), compared to the other groups. Patients with early-stage breast cancer bearing NLRhigh and BMIhigh had worse outcomes, and this might be explained by the dysfunctional milieu of obesity in adipose tissue and its effects on the immune system. This study highlights the importance of lifestyle measures and the immune system interference with clinical outcomes in the early breast cancer setting.


Assuntos
Neoplasias da Mama , Neutrófilos , Feminino , Humanos , Linfócitos , Recidiva Local de Neoplasia , Obesidade/complicações , Prognóstico , Estudos Retrospectivos
15.
Biomed Res Int ; 2021: 9987931, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34423043

RESUMO

Objective: Respiratory failure is the leading cause of mortality in COVID-19 patients, characterized by a generalized disbalance of inflammation. The aim of this study was to investigate the relationship between immune-inflammatory index and mortality in PSI IV-V patients with COVID-19. Methods: We retrospectively reviewed the medical records of COVID-19 patients from Feb. to Apr. 2020 in the Zhongfa Xincheng Branch of Tongji Hospital, Wuhan, China. Patients who presented high severity of COVID-19-related pneumonia were enrolled for further analysis according to the Pneumonia Severity Index (PSI) tool. Results: A total of 101 patients diagnosed with COVID-19 were identified at initial research. The survival analysis revealed that mortality of the PSI IV-V cohort was significantly higher than the PSI I-III group (p = 0.0003). The overall mortality in PSI IV-V patients was 32.1% (9/28). The fatal cases of the PSI IV-V group had a higher level of procalcitonin (p = 0.022) and neutrophil-to-lymphocyte ratio (p = 0.033) compared with the survivors. Procalcitonin was the most sensitive predictor of mortality for the severe COVID-19 population with area under receiver operating characteristic curve of 0.78, higher than the neutrophil-to-lymphocyte ratio (0.75) and total lymphocyte (0.68) and neutrophil (0.67) counts. Conclusion: Procalcitonin and neutrophil-to-lymphocyte ratio may potentially be effective predictors for mortality in PSI IV-V patients with COVID-19. Increased procalcitonin and neutrophil-to-lymphocyte ratio were associated with greater risk of mortality.


Assuntos
COVID-19/imunologia , COVID-19/fisiopatologia , Pandemias , SARS-CoV-2 , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , COVID-19/mortalidade , China/epidemiologia , Estudos de Coortes , Feminino , Humanos , Inflamação/imunologia , Inflamação/fisiopatologia , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Pneumonia Viral/fisiopatologia , Pró-Calcitonina/sangue , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Análise de Sobrevida
16.
FASEB J ; 35(10): e21843, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34464475

RESUMO

Robust inflammatory responses are critical to survival following respiratory infection, with current attention focused on the clinical consequences of the Coronavirus pandemic. Epigenetic factors are increasingly recognized as important determinants of immune responses, and EZH2 is a prominent target due to the availability of highly specific and efficacious antagonists. However, very little is known about the role of EZH2 in the myeloid lineage. Here, we show EZH2 acts in macrophages to limit inflammatory responses to activation, and in neutrophils for chemotaxis. Selective genetic deletion in macrophages results in a remarkable gain in protection from infection with the prevalent lung pathogen, pneumococcus. In contrast, neutrophils lacking EZH2 showed impaired mobility in response to chemotactic signals, and resulted in increased susceptibility to pneumococcus. In summary, EZH2 shows complex, and divergent roles in different myeloid lineages, likely contributing to the earlier conflicting reports. Compounds targeting EZH2 are likely to impair mucosal immunity; however, they may prove useful for conditions driven by pulmonary neutrophil influx, such as adult respiratory distress syndrome.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/imunologia , Inflamação/imunologia , Macrófagos/imunologia , Neutrófilos/imunologia , Animais , Células Cultivadas , Macrófagos/citologia , Camundongos Endogâmicos C57BL , Neutrófilos/citologia
17.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 33(7): 849-854, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34412756

RESUMO

OBJECTIVE: To investigate the effect of neutrophils on T lymphocyte function in septic mice and the role of CD80/cytotoxic T lymphocyte antigen-4 (CTLA-4) signaling pathway in this modulated effects. METHODS: (1) In vivo experiment: 6-8 weeks old male C57BL/6 mice were divided into sham operation group (Sham group, n = 20), Sham+CTLA-4 antibody treatment group (Sham+aCTLA-4 group, n = 20), cecum ligation and perforation (CLP) induced sepsis model group (CLP group, n = 30) and CLP+CTLA-4 antibody treatment group (CLP+aCTLA-4 group, n = 30) according to the random number table. CLP was used to reproduce mouse sepsis model. The mice in the Sham group were treated identically but their cecums were neither punctured nor ligated. In CTLA-4 antibody treatment groups, 50 µg CTLA-4 antibody was injected intraperitoneally 6 hours and 24 hours after the operation. Forty-eight hours after operation, 6 mice in Sham group and Sham+aCTLA-4 group, 14 mice in CLP group and CLP+aCTLA-4 group were randomly selected to detect the expression of CD69 in spleen. At the same time, spleen, bone marrow and peripheral blood were collected, and the expression of CD80 on neutrophils was detected by flow cytometry. The expression of CTLA-4 on the surface of T lymphocytes in spleen was detected by immunofluorescence and flow cytometry. The remaining mice in each group were used to observe the 96-hour survival after operation. (2) In vitro experiment 1: neutrophils were extracted from bone marrow of healthy mice and stimulated with LPS (1 mg/L) for 4, 8 and 12 hours respectively. The control group was added with the same amount of phosphate buffer saline (PBS) at each time point, and the expression of CD80 was detected at each time point. (3) In vitro experiment 2: splenic T lymphocytes of healthy mice were extracted and divided into PBS control group, LPS group (final concentration of LPS 1 mg/L), neutrophil group and neutrophil+LPS group. In the latter two groups, the co-culture model of neutrophils and T lymphocytes was established, and then the corresponding treatment was given to detect the expression of CTLA-4 on the surface of T lymphocytes. With the above four groups as controls, CTLA-4 antibody treatment groups (final concentration of CTLA-4 antibody 50 mg/L) were set up respectively. After 48 hours, the level of interleukin-2 (IL-2) in the cell supernatant was detected by enzyme linked immunosorbent assay (ELISA). RESULTS: (1) Results of in vivo experiment: compared with Sham group, the expression of CD80 on neutrophils in spleen, bone marrow and peripheral blood was significantly up-regulated, while the expression of CTLA-4 on the surface of T lymphocytes was significantly increased [(9.98±0.84)% vs. (3.48±0.64)%, P < 0.05]. It suggested that neutrophils may affect T lymphocytes function through CD80/CTLA-4 pathway in sepsis. Compared with CLP group, CTLA-4 antibody could significantly improve the 96-hour cumulative survival rate of CLP mice (56.25% vs. 18.75%, P < 0.05), and increase the expression of CD69 on the surface of T lymphocytes. It suggested that CTLA-4 antibodies might increase T lymphocytes activation in sepsis and improve survival. (2) Results of in vitro experiment: with the prolongation of LPS stimulation, the expression of CD80 on neutrophils gradually increased in time-dependent manner as compared with PBS control group [4 hours: (6.35±0.40)% vs. (3.41±0.40)%, 8 hours: (8.57±0.64)% vs. (3.09±0.27)%, 12 hours: (19.83±1.06)% vs. (5.16±0.36)%, all P < 0.05]. Compared with PBS control group, the expression of CTLA-4 on CD4+/CD8+ T lymphocytes was not significantly affected by LPS stimulation alone, but CTLA-4 was increased after co-culture with neutrophils [CD4+: (4.92±0.30)% vs. (3.33±0.25)%, CD8+: (4.26±0.21)% vs. (2.53±0.66)%, both P < 0.05], and the increased trend of CTLA-4 was more obvious after co-culture with LPS-stimulated neutrophils [CD4+: (6.34±0.50)% vs. (3.33±0.25)%, CD8+: (6.21±0.41)% vs. (2.53±0.66)%, both P < 0.05]. In the PBS control group and LPS group, CTLA-4 antibody had no significant effect on IL-2 secretion of T lymphocytes. Compared with PBS control group, co-culture with neutrophils could inhibit the secretion of IL-2 by T lymphocytes (ng/L: 1 938.00±68.45 vs. 2 547.00±218.00, P < 0.05), and the inhibitory effect of neutrophils stimulated by LPS was more obvious (ng/L: 1 073.00±34.39 vs. 2 547.00±218.00, P < 0.05). CTLA-4 antibodies could partially restore IL-2 secretion. In conclusion, after promoting the expression of CTLA-4 on the surface of T lymphocytes, neutrophils might mediate the inhibition of T lymphocytes function by reducing the production of IL-2. CONCLUSIONS: Neutrophils mediate T lymphocytes dysfunction in sepsis, and the CD80/CTLA-4 pathway plays an important role. The CTLA-4 antibody improves survival and T lymphocytes function in sepsis mice, which may be a new method of immunotherapy for sepsis.


Assuntos
Neutrófilos , Sepse , Animais , Antígeno CTLA-4 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Linfócitos T Citotóxicos
18.
Medicina (Kaunas) ; 57(8)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34441017

RESUMO

Background and Objectives: The aim of this study was to evaluate the diagnostic accuracy and prognostic value of neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte (PLR) ratios and to compare them with other biomarkers and clinical scores of sepsis outside the intensive care unit. Materials and methods: In this retrospective study, 251 patients with sepsis and 126 patients with infection other than sepsis were enrolled. NLR and PLR were calculated as the ratio between absolute values of neutrophils, lymphocytes, and platelets by complete blood counts performed on whole blood by Sysmex XE-9000 (Dasit, Italy) following the manufacturer's instruction. Results: The best NLR value in diagnosis of sepsis was 7.97 with sensibility, specificity, AUC, PPV, and NPV of 64.26%, 80.16%, 0.74 (p < 0.001), 86.49%, and 53.18%, respectively. The diagnostic role of NLR significantly increases when PLR, C-reactive protein (PCR), procalcitonin (PCT), and mid-regional pro-adrenomedullin (MR-proADM) values, as well as systemic inflammatory re-sponse syndrome (SIRS), sequential organ failure assessment (SOFA), and quick-sequential organ failure assessment (qSOFA) scores, were added to the model. The best value of NLR in predicting 90-day mortality was 9.05 with sensibility, specificity, AUC, PPV, and NPV of 69.57%, 61.44%, 0.66 (p < 0.0001), 28.9%, and 89.9%, respectively. Sensibility, specificity, AUC, PPV, and NPV of NLR increase if PLR, PCR, PCT, MR-proADM, SIRS, qSOFA, and SOFA scores are added to NLR. Conclusions: NLR and PLR represent a widely useful and cheap tool in diagnosis and in predict-ing 90-day mortality in patients with sepsis.


Assuntos
Neutrófilos , Sepse , Plaquetas , Humanos , Unidades de Terapia Intensiva , Linfócitos , Prognóstico , Curva ROC , Estudos Retrospectivos , Sepse/diagnóstico
19.
Medicina (Kaunas) ; 57(8)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34441020

RESUMO

Background and Objectives: Alpha-1 antitrypsin is a serine protease inhibitor that demonstrates an array of immunomodulatory functions. Individuals with the genetic condition of alpha-1 antitrypsin deficiency (AATD) are at increased risk of early onset emphysematous lung disease. This lung disease is partly driven by neutrophil mediated lung destruction in an environment of low AAT. As peripheral neutrophil hyper-responsiveness in AATD leads to excessive degranulation and increased migration to the airways, we examined the expression of the membrane voltage-gated proton channel-1 (HVCN1), which is integrally linked to neutrophil function. The objectives of this study were to evaluate altered HVCN1 in AATD neutrophils, serine protease-dependent degradation of HVCN1, and to investigate the ability of serum AAT to control HVCN1 expression. Materials and Methods: Circulating neutrophils were purified from AATD patients (n = 20), AATD patients receiving AAT augmentation therapy (n = 3) and healthy controls (n = 20). HVCN1 neutrophil expression was assessed by flow cytometry and Western blot analysis. Neutrophil membrane bound elastase was measured by fluorescence resonance energy transfer. Results: In this study we demonstrated that HVCN1 protein is under-expressed in AATD neutrophils (p = 0.02), suggesting a link between reduced HVCN1 expression and AAT deficiency. We have demonstrated that HVCN1 undergoes significant proteolytic degradation in activated neutrophils (p < 0.0001), primarily due to neutrophil elastase activity (p = 0.0004). In addition, the treatment of AATD individuals with AAT augmentation therapy increased neutrophil plasma membrane HVCN1 expression (p = 0.01). Conclusions: Our results demonstrate reduced levels of HVCN1 in peripheral blood neutrophils that may influence the neutrophil-dominated immune response in the AATD airways and highlights the role of antiprotease treatment and specifically AAT augmentation therapy in protecting neutrophil membrane expression of HVCN1.


Assuntos
Neutrófilos , Deficiência de alfa 1-Antitripsina , Humanos , Pulmão , Proteólise , Prótons , Deficiência de alfa 1-Antitripsina/tratamento farmacológico , Deficiência de alfa 1-Antitripsina/genética
20.
Pestic Biochem Physiol ; 178: 104944, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34446210

RESUMO

Maneb (MB)- and paraquat (PQ)-induced oxidative stress in rat polymorphonuclear leukocytes (PMNs) is regulated in parallel by cytochrome P450 2E1 (CYP2E1) and inducible nitric oxide synthase (iNOS). However, mechanism underlying their regulation is not yet understood. The study investigated the role of nuclear factor- kappa B (NF-κB) and mitogen-activated protein kinase/extracellular signal regulated kinase/protein kinase C (MEK/ERK/PKC) pathway in the regulation of iNOS- and CYP2E1-induced oxidative stress in PMNs. MB + PQ-induced changes in nitrite content, lipid peroxidation (LPO), iNOS expression/activity and inflammatory mediators were alleviated by aminoguanidine (AG), an iNOS inhibitor, without any change in CYP2E1. Alternatively, diallyl sulphide (DAS), a CYP2E1 inhibitor, rescued from MB + PQ-induced changes in CYP2E1 activity/expression, free radical generation, superoxide dismutase (SOD) activity, LPO and pro-inflammatory cytokines without any alterations in nitrite content and iNOS activity/expression. Pyrrolidine dithiocarbamate (PDTC), NF-κB inhibitor, did not alter CYP2E1 but mitigated free radical generation, SOD activity, LPO, nitrite content, iNOS activity/expression and levels of pro-inflammatory cytokines (tumor necrosis factor-α, interleukine-1ß and interleukine-4). Ex-vivo treatment with MEK inhibitor (PD98059), ERK1/2 inhibitor (AG126) or PKC inhibitor (rottlerin) ameliorated MB + PQ-induced increase in free radical generation and CYP2E1 activity/expression in PMNs. While PD98059 and AG126 abated MB + PQ-induced increase in ERK1/2, PKC-α/δ and CYP2E1 levels, rottlerin restored PKC-α/δ and CYP2E1 towards normalcy without affecting ERK1/2 level in MB + PQ-treated group. The results suggest that iNOS and CYP2E1 contributing to MB + PQ-induced oxidative stress in rat PMNs exhibit differential regulatory mechanisms. The inflammatory mediators regulate iNOS expression while CYP2E1 expression is triggered via MEK-ERK1/2-PKC pathway.


Assuntos
Maneb , Animais , Citocromo P-450 CYP2E1/metabolismo , NF-kappa B , Neutrófilos/metabolismo , Óxido Nítrico , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo , Paraquat/toxicidade , Ratos
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