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1.
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
2.
Hematology ; 26(1): 628-636, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34494505

RESUMO

Over the past 20 years, granulocyte colony-stimulating factor (G-CSF) has driven the attention of researchers as a therapeutic agent for curing patients suffering from neutropenia. Despite the successful use of G-CSF, it currently requires daily injections, which are inconvenient, expensive, and distressing for children. Therefore, an alternative strategy for using G-CSF for treatment is needed. Understanding the G-CSF structure, expression, mechanism of action, and how it induces neutrophils mobilization is crucial to producing promising cancer therapy. The ability of G-CSF to mobilize hematopoietic stem cells from the bone marrow into the blood circulation was consequently exploited and altered the practice of hematopoietic stem cell transplantation. This is the motivation for the current review, which sheds light on the history of G-CSF and then focuses on the mechanism of action upon binding to its receptor (G-CSFR) and how that had led to the stimulation of neutrophils mobilization. The findings of this review show new insight into the mechanism of G-CSF that induces neutrophils mobilization. Thus, Understanding the G-CSF will provide a more effective treatment for all neutropenia patients.


Assuntos
Fator Estimulador de Colônias de Granulócitos/metabolismo , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Neutropenia/metabolismo , Neutrófilos/metabolismo , Fator Estimulador de Colônias de Granulócitos/história , Células-Tronco Hematopoéticas/patologia , História do Século XX , História do Século XXI , Humanos , Neutropenia/patologia , Neutropenia/terapia , Neutrófilos/patologia
3.
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
4.
Ecotoxicol Environ Saf ; 223: 112614, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34385063

RESUMO

As the most common heavy metal pollutant, hexavalent chromium [Cr(VI)] has caused serious environmental pollution and health damage. Although the toxic effect of Cr(VI) has been widely studied, and oxidative stress has been confirmed to be the main mechanism of its cytotoxicity, the toxicity of Cr(VI) to human immune system remains to be elucidated. Neutrophil extracellular traps (NETs) participate in the innate immune response, and the release of NETs is considered to be the most important part of the extracellular killing mechanism. We demonstrated in this study that Cr(VI) inhibited the formation of NETs in rat peripheral blood and induced neutrophils apoptosis by inhibiting the AMP-activated protein kinase (AMPK) signaling pathway. Cr(VI)-induced inhibition of NETs was accompanied by down-regulated myeloperoxidase (MPO)/Histones-3 (H3) protein expressions and decreased NETs-associated intracellular and extracellular DNA levels in the neutrophils. Metformin (Met), as an AMPK activator, triggered autophagy and thus alleviated the inhibitory effect of Cr(VI) on NETs. At the same time, Met can reduce the intracellular reactive oxygen species (ROS) level by activating the AMPK/nuclear factor erythroid-2 related factor 2 (Nrf2) signaling pathway, thus alleviating Cr(VI)-induced neutrophils apoptosis. In conclusion, this study elucidated the mechanism of Cr(VI)-induced neutrophils toxicity and the role of AMPK as a key regulatory signal, which could provide valuable experimental basis for the prevention and treatment of related diseases in Cr(VI)-exposed populations.


Assuntos
Armadilhas Extracelulares , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose , Cromo/toxicidade , Armadilhas Extracelulares/metabolismo , Humanos , Neutrófilos/metabolismo , Ratos , Espécies Reativas de Oxigênio , Transdução de Sinais
5.
Medicine (Baltimore) ; 100(34): e27095, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34449514

RESUMO

ABSTRACT: Neutrophil-to-lymphocyte ratio (NLR) was reported as an independent prognostic factor in many studies, but its cutoff point was not yet concluded. We set forth to prove and validate cutoff point of NLR as a poor prognostic factor for overall survival (OS) in nonmetastatic nasopharyngeal carcinoma (NPC) patients.Retrospective cohort of nonmetastatic NPC adult patients treated with intensity-modulated radiotherapy with curative aim at Siriraj hospital during 2007 to 2014 was enrolled. NLR was defined as absolute neutrophil count divided by absolute lymphocyte count. OS was the primary outcome. We explored our cutoff value by maximum concordance index (C-index) method, and we validated our cutoff and previously reported cutoff values by categorizing patients as NLR ≤ 3 or >3. Internal validation was done by bootstrapping method.Four hundred sixty-three patients were included. The median follow-up time was 70.8 months. By the end of June 2019, 211 patients had died. In univariable analysis of OS by Cox model, an NLR value of 3 showed the highest C-index (0.548) with an HR of 1.43 (95% CI: 1.08-1.89). After adjustment for body mass index, overall staging, age, gender, and histology in multivariable analysis, an NLR >3 was still an independent prognostic factor of poor OS (HR = 1.34, 95% CI = 1.01-1.79). After internal validation, the resampling method shows no overfitting condition and corrected C-index was 0.547 for univariable analysis.A cutoff point of NLR of 3 from routine blood test was found to be an independent poor prognostic factor among patients with nonmetastatic NPC. This prognostic factor could be included in clinical prediction model of NPC and this further prediction model would select high risk patients for intensive treatment.


Assuntos
Contagem de Linfócitos/estatística & dados numéricos , Carcinoma Nasofaríngeo/sangue , Neoplasias Nasofaríngeas/sangue , Neutrófilos/metabolismo , Adulto , Idoso , Biomarcadores Tumorais , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/radioterapia , Prognóstico , Modelos de Riscos Proporcionais , Radioterapia de Intensidade Modulada , Valores de Referência , Estudos Retrospectivos
6.
Int J Mol Sci ; 22(15)2021 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-34360700

RESUMO

Maternal infection-induced early pregnancy complications arise from perturbation of the immune environment at the uterine early blastocyst implantation site (EBIS), yet the underlying mechanisms remain unclear. Here, we demonstrated in a mouse model that the progression of normal pregnancy from days 4 to 6 induced steady migration of leukocytes away from the uterine decidual stromal zone (DSZ) that surrounds the implanted blastocyst. Uterine macrophages were found to be CD206+ M2-polarized. While monocytes were nearly absent in the DSZ, DSZ cells were found to express monocyte marker protein Ly6C. Systemic endotoxic lipopolysaccharide (LPS) exposure on day 5 of pregnancy led to: (1) rapid (at 2 h) induction of neutrophil chemoattractants that promoted huge neutrophil infiltrations at the EBISs by 24 h; (2) rapid (at 2 h) elevation of mRNA levels of MyD88, but not Trif, modulated cytokines at the EBISs; and (3) dose-dependent EBIS defects by day 7 of pregnancy. Yet, elimination of maternal neutrophils using anti-Ly6G antibody prior to LPS exposure failed to avert LPS-induced EBIS defects allowing us to suggest that activation of Tlr4-MyD88 dependent inflammatory pathway is involved in LPS-induced defects at EBISs. Thus, blocking the activation of the Tlr4-MyD88 signaling pathway may be an interesting approach to prevent infection-induced pathology at EBISs.


Assuntos
Lipopolissacarídeos/toxicidade , Fator 88 de Diferenciação Mieloide/metabolismo , Neutrófilos/imunologia , Complicações Infecciosas na Gravidez/imunologia , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Implantação do Embrião , Feminino , Inflamação , Macrófagos , Camundongos , Neutrófilos/metabolismo , Gravidez , Complicações Infecciosas na Gravidez/metabolismo
7.
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
8.
Dis Markers ; 2021: 5566826, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34367376

RESUMO

An excess formation of neutrophil extracellular traps (NETs), previously shown to be strongly associated with cytokine storm and acute respiratory distress syndrome (ARDS) with prevalent endothelial dysfunction and thrombosis, has been postulated to be a central factor influencing the pathophysiology and clinical presentation of severe COVID-19. A growing number of serological and morphological evidence has added to this assumption, also in regard to potential treatment options. In this study, we used immunohistochemistry and histochemistry to trace NETs and their molecular markers in autopsy lung tissue from seven COVID-19 patients. Quantification of key immunomorphological features enabled comparison with non-COVID-19 diffuse alveolar damage. Our results strengthen and extend recent findings, confirming that NETs are abundantly present in seriously damaged COVID-19 lung tissue, especially in association with microthrombi of the alveolar capillaries. In addition, we provide evidence that low-density neutrophils (LDNs), which are especially prone to NETosis, contribute substantially to COVID-19-associated lung damage in general and vascular blockages in particular.


Assuntos
COVID-19/patologia , Armadilhas Extracelulares , Lesão Pulmonar/patologia , Neutrófilos/patologia , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Autopsia , Moléculas de Adesão Celular/metabolismo , Armadilhas Extracelulares/virologia , Feminino , Proteínas Ligadas por GPI/metabolismo , Humanos , Imuno-Histoquímica , Pulmão/patologia , Pulmão/virologia , Lesão Pulmonar/virologia , Masculino , Neutrófilos/metabolismo , Neutrófilos/virologia , Peroxidase/metabolismo
9.
Theranostics ; 11(16): 7797-7812, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335965

RESUMO

Rationale: Corticosteroid resistance (CR) is a serious drawback to steroid therapy in patients with ulcerative colitis (UC); the underlying mechanism is incompletely understood. Twist1 protein (TW1) is an apoptosis inhibitor and has immune regulatory functions. This study aims to elucidate the roles of TW1 in inducing and sustaining the CR status in UC. Methods: Surgically removed colon tissues of patients with ulcerative colitis (UC) were collected, from which neutrophils were isolated by flow cytometry. The inflammation-related gene activities in neutrophils were analyzed by RNA sequencing. A CR colitis mouse model was developed with the dextran sulfate sodium approach in a hypoxia environment. Results: Higher TW1 gene expression was detected in neutrophils isolated from the colon tissues of UC patients with CR and the CR mouse colon tissues. TW1 physically interacted with glucocorticoid receptor (GR)α in CR neutrophils that prevented GRα from interacting with steroids; which consequently abrogated the effects of steroids on regulating the cellular activities of neutrophils. STAT3 (Signal Transducer and Activator of Transcription-3) interacted with Ras protein activator like 1 to sustain the high TW1 expression in colon mucosal neutrophils of CR patients and CR mice. Inhibition of TW1 restored the sensitivity to corticosteroid of neutrophils in the colon tissues of a CR murine model. Conclusions: UC patients at CR status showed high TW1 expression in neutrophils. TW1 prevented steroids from regulating neutrophil activities. Inhibition of TW1 restored the sensitivity to corticosteroids in the colon tissues at the CR status.


Assuntos
Colite Ulcerativa/metabolismo , Resistência a Medicamentos/genética , Proteínas Nucleares/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Corticosteroides/farmacologia , Adulto , Animais , China , Colite , Colite Ulcerativa/genética , Colo/metabolismo , Dexametasona/farmacologia , Modelos Animais de Doenças , Feminino , Humanos , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Proteínas Nucleares/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína 1 Relacionada a Twist/genética
10.
Front Immunol ; 12: 663303, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34194429

RESUMO

The release of neutrophil extracellular traps (NETs), a process termed NETosis, avoids pathogen spread but may cause tissue injury. NETs have been found in severe COVID-19 patients, but their role in disease development is still unknown. The aim of this study is to assess the capacity of NETs to drive epithelial-mesenchymal transition (EMT) of lung epithelial cells and to analyze the involvement of NETs in COVID-19. Bronchoalveolar lavage fluid of severe COVID-19 patients showed high concentration of NETs that correlates with neutrophils count; moreover, the analysis of lung tissues of COVID-19 deceased patients showed a subset of alveolar reactive pneumocytes with a co-expression of epithelial marker and a mesenchymal marker, confirming the induction of EMT mechanism after severe SARS-CoV2 infection. By airway in vitro models, cultivating A549 or 16HBE at air-liquid interface, adding alveolar macrophages (AM), neutrophils and SARS-CoV2, we demonstrated that to trigger a complete EMT expression pattern are necessary the induction of NETosis by SARS-CoV2 and the secretion of AM factors (TGF-ß, IL8 and IL1ß). All our results highlight the possible mechanism that can induce lung fibrosis after SARS-CoV2 infection.


Assuntos
COVID-19/fisiopatologia , Transição Epitelial-Mesenquimal , Armadilhas Extracelulares/metabolismo , Neutrófilos/metabolismo , Adulto , Biópsia , Líquido da Lavagem Broncoalveolar/citologia , COVID-19/complicações , COVID-19/imunologia , Linhagem Celular , Células Epiteliais/patologia , Humanos , Pulmão/patologia , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/metabolismo
11.
Crit Care ; 25(1): 234, 2021 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-34217339

RESUMO

BACKGROUND: The coronavirus disease 2019 (COVID-19) has induced a worldwide epidemiological event with a high infectivity and mortality. However, the predicting biomarkers and their potential mechanism in the progression of COVID-19 are not well known. OBJECTIVE: The aim of this study is to identify the candidate predictors of COVID-19 and investigate their underlying mechanism. METHODS: The retrospective study was conducted to identify the potential laboratory indicators with prognostic values of COVID-19 disease. Then, the prognostic nomogram was constructed to predict the overall survival of COVID-19 patients. Additionally, the scRNA-seq data of BALF and PBMCs from COVID-19 patients were downloaded to investigate the underlying mechanism of the most important prognostic indicators in lungs and peripherals, respectively. RESULTS: In total, 304 hospitalized adult COVID-19 patients in Wuhan Jinyintan Hospital were included in the retrospective study. CEA was the only laboratory indicator with significant difference in the univariate (P < 0.001) and multivariate analysis (P = 0.020). The scRNA-seq data of BALF and PBMCs from COVID-19 patients were downloaded to investigate the underlying mechanism of CEA in lungs and peripherals, respectively. The results revealed the potential roles of CEA were significantly distributed in type II pneumocytes of BALF and developing neutrophils of PBMCs, participating in the progression of COVID-19 by regulating the cell-cell communication. CONCLUSION: This study identifies the prognostic roles of CEA in COVID-19 patients and implies the potential roles of CEACAM8-CEACAM6 in the progression of COVID-19 by regulating the cell-cell communication of developing neutrophils and type II pneumocyte.


Assuntos
COVID-19/metabolismo , Antígeno Carcinoembrionário/metabolismo , Pneumonia Viral/metabolismo , Adulto , Idoso , Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar/química , COVID-19/mortalidade , Comunicação Celular , China/epidemiologia , Progressão da Doença , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Nomogramas , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , SARS-CoV-2 , Análise de Sobrevida
12.
Int J Mol Sci ; 22(14)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34299030

RESUMO

Neutrophil-derived microvesicles (NDMVs) have the potential to exert anti-inflammatory effects. Our study aimed to explore the effects of NDMVs on proinflammatory cytokines expressed by tumor necrosis factor α (TNFα)-stimulated fibroblast-like synoviocytes (FLS). FLS were isolated from the synovium of knee osteoarthritis (OA) patients undergoing surgery. NDMVs, isolated from TNFα-stimulated healthy neutrophils, were characterized by electron microscopy and nanoparticle tracking analysis. MTT and scratch wound healing assays were used to measure FLS viability and migration after treatment with NDMVs, while internalization of fluorescently labeled NDMVs was appraised by flow cytometry and confocal microscopy. Levels of proinflammatory cytokines in supernatants were quantified by the Bio-Plex system. Incubation of FLS with NDMVs at a vesicle/cell ratio of 100 resulted in a time-dependent uptake, with 35% of synoviocytes containing microvesicles over a 6-24 h time period, with no significant change in cell viability. TNFα stimulated the cytokine expression in FLS, and NDMVs down-regulated TNFα-induced expression of IL-5, IL-6, IL-8, MCP-1, IFNγ and MIP-1ß. However, this down-regulation was selective, as NDMVs had no significant effects on TNFα-stimulated expression of IL-2 or IL-4. NDMVs were internalized by FLS to inhibit TNFα-stimulated broad-spectrum proinflammatory cytokine secretion. NDMVs, therefore, may exhibit an anti-inflammatory role in the regulation of the FLS function.


Assuntos
Micropartículas Derivadas de Células/metabolismo , Fibroblastos/metabolismo , Mediadores da Inflamação/metabolismo , Neutrófilos/metabolismo , Osteoartrite do Joelho/metabolismo , Sinoviócitos/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Micropartículas Derivadas de Células/patologia , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Fibroblastos/patologia , Humanos , Neutrófilos/patologia , Osteoartrite do Joelho/tratamento farmacológico , Osteoartrite do Joelho/imunologia , Osteoartrite do Joelho/patologia , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/imunologia , Sinoviócitos/patologia
13.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299338

RESUMO

Obesity manifests itself with low-grade chronic inflammation that shapes immune responses during infection. Albeit obese individuals are at risk of higher mortality due to comorbidities, they are better protected from systemic inflammation. Recently, we showed that in the vasculature of obese mice kept on high-fat diet (HFD), neutrophils produce less neutrophil extracellular traps (NETs) than in lean controls (normal diet, ND). NETs are used by neutrophils to counteract severe infection, but they also cause collateral damage. Hardly anything is known about metabolic requirements for their formation, especially in the context of obesity and/or sepsis. Thus, we aimed to study the immunometabolism of NET formation by application of ex vivo neutrophil analyses (Seahorse analyzer, selective inhibitors, confocal imaging) and intravital microscopy. The obtained data show that glycolysis and/or pentose phosphate pathway are involved in NETs release by ND neutrophils in both physiological and inflammatory conditions. In contrast, such cells of septic HFD mice utilize these routes only to spontaneously cast NETs, while after secondary ex vivo activation they exhibit so called "exhausted phenotype", which manifests itself in diminished NET release despite high glycolytic potential and flexibility to oxidize fatty acids. Moreover, impact of ATP synthase inhibition on NET formation is revealed. Overall, the study shows that the neutrophil potential to cast NETs depends on both the metabolic and inflammatory state of the individual.


Assuntos
Armadilhas Extracelulares/metabolismo , Obesidade/metabolismo , Animais , Dieta Hiperlipídica , Armadilhas Extracelulares/imunologia , Glicólise , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Neutrófilos/metabolismo , Obesidade/imunologia , Obesidade/patologia , Via de Pentose Fosfato , Sepse/metabolismo
14.
Arterioscler Thromb Vasc Biol ; 41(9): 2509-2511, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34261329
15.
Am J Physiol Cell Physiol ; 321(3): C415-C428, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34260299

RESUMO

Leucine-rich α-2-glycoprotein-1 (LRG1) is a novel profibrotic factor that modulates transforming growth factor-ß (TGF-ß) signaling. However, its role in the corneal fibrotic response remains unknown. In the present study, we found that the LRG1 level increased in alkali-burned mouse corneas. In the LRG1-treated alkali-burned corneas, there were higher fibrogenic protein expression and neutrophil infiltration. LRG1 promoted neutrophil chemotaxis and CXCL-1 secretion. Conversely, LRG1-specific siRNA reduced fibrogenic protein expression and neutrophil infiltration in the alkali-burned corneas. The clearance of neutrophils effectively attenuated the LRG1-enhanced corneal fibrotic response, whereas the presence of neutrophils enhanced the effect of LRG1 on the fibrotic response in cultured TKE2 cells. In addition, the topical application of LRG1 elevated interleukin-6 (IL-6) and p-Stat3 levels in the corneal epithelium and in isolated neutrophils. The clearance of neutrophils inhibited the expression of p-Stat3 and IL-6 promoted by LRG1 in alkali-burned corneas. Moreover, neutrophils significantly increased the production of IL-6 and p-Stat3 promoted by LRG1 in TKE2 cells. Furthermore, the inhibition of Stat3 signaling by S3I-201 decreased neutrophil infiltration and alleviated the LRG1-enhanced corneal fibrotic response in the alkali-burned corneas. S3I-201 also reduced LRG1 or neutrophil-induced fibrotic response in TKE2 cells. In conclusion, LRG1 promotes the corneal fibrotic response by stimulating neutrophil infiltration via the modulation of the IL-6/Stat3 signaling pathway. Therefore, LRG1 could be targeted as a promising therapeutic strategy for patients with corneal fibrosis.


Assuntos
Queimaduras Químicas/genética , Quimiotaxia/efeitos dos fármacos , Queimaduras Oculares/genética , Glicoproteínas/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética , Álcalis , Ácidos Aminossalicílicos/farmacologia , Animais , Benzenossulfonatos/farmacologia , Queimaduras Químicas/tratamento farmacológico , Queimaduras Químicas/metabolismo , Queimaduras Químicas/patologia , Linhagem Celular , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Epitélio Corneano/efeitos dos fármacos , Epitélio Corneano/metabolismo , Epitélio Corneano/patologia , Queimaduras Oculares/induzido quimicamente , Queimaduras Oculares/tratamento farmacológico , Queimaduras Oculares/patologia , Fibrose/prevenção & controle , Regulação da Expressão Gênica , Glicoproteínas/antagonistas & inibidores , Glicoproteínas/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/patologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
16.
Cell Death Dis ; 12(7): 675, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226527

RESUMO

Mutations in the transcription factor C/EBPα are found in ~10% of all acute myeloid leukaemia (AML) cases but the contribution of these mutations to leukemogenesis is incompletely understood. We here use a mouse model of granulocyte progenitors expressing conditionally active HoxB8 to assess the cell biological and molecular activity of C/EBPα-mutations associated with human AML. Both N-terminal truncation and C-terminal AML-associated mutations of C/EBPα substantially altered differentiation of progenitors into mature neutrophils in cell culture. Closer analysis of the C/EBPα-K313-duplication showed expansion and prolonged survival of mutant C/EBPα-expressing granulocytes following adoptive transfer into mice. C/EBPα-protein containing the K313-mutation further showed strongly enhanced transcriptional activity compared with the wild-type protein at certain promoters. Analysis of differentially regulated genes in cells overexpressing C/EBPα-K313 indicates a strong correlation with genes regulated by C/EBPα. Analysis of transcription factor enrichment in the differentially regulated genes indicated a strong reliance of SPI1/PU.1, suggesting that despite reduced DNA binding, C/EBPα-K313 is active in regulating target gene expression and acts largely through a network of other transcription factors. Strikingly, the K313 mutation caused strongly elevated expression of C/EBPα-protein, which could also be seen in primary K313 mutated AML blasts, explaining the enhanced C/EBPα activity in K313-expressing cells.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Diferenciação Celular , Células Precursoras de Granulócitos/metabolismo , Leucemia Monocítica Aguda/metabolismo , Mutação , Neutrófilos/metabolismo , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Células Cultivadas , Feminino , Regulação Leucêmica da Expressão Gênica , Células Precursoras de Granulócitos/transplante , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Leucemia Monocítica Aguda/genética , Camundongos Endogâmicos C57BL , Neutrófilos/transplante , Regulação para Cima
17.
Biochim Biophys Acta Rev Cancer ; 1876(1): 188587, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34237352

RESUMO

In recent years, the tumor microenvironment (TME) has been a research hotspot, as it is composed of distinct cellular and non-cellular elements that may influence the diagnosis, prognosis, and treatment of breast cancer patients. Cancer cells are able to escape immune control through an immunoediting process which depends on complex communication networks between immune and cancer cells. Thus, a better understanding of the immune cell infiltrate in the breast cancer microenvironment is crucial for the development of more effective therapeutic approaches. In this review article, we overview the different actors that orchestrate the complexity of the TME, including tumor infiltrating lymphocytes (TILs), natural killer cells, tumor infiltrating dendritic cells (TIDCs), tumor associated macrophages (TAMs), tumor associated neutrophils (TANs), cancer associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), distinct pro-angiogenic factors and immune checkpoint biomarkers. Additionally, we summarize the recent advances in the TME of feline mammary carcinoma (FMC). FMC has been proposed as a reliable cancer model for the study of human breast cancer, as they share clinicopathological, histopathological and epidemiological features, as well as the pathways involved in cancer initiation and progression.


Assuntos
Neoplasias da Mama/imunologia , Microambiente Tumoral/imunologia , Proteínas Angiogênicas/metabolismo , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/metabolismo , Gatos , Modelos Animais de Doenças , Feminino , Humanos , Proteínas de Checkpoint Imunológico/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Fenótipo , Transdução de Sinais , Evasão Tumoral , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo
18.
Arterioscler Thromb Vasc Biol ; 41(9): 2417-2430, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34320837

RESUMO

Objective: Systemic lupus erythematosus (SLE) is associated to boosted atherosclerosis development and a higher cardiovascular disease risk. This study aimed to delineate the role of anti-double stranded DNA (anti-dsDNA) antibodies on the molecular profile and the activity of immune and vascular cells, as well as on their enhanced cardiovascular risk. Approach and Results: Eighty SLE patients were included. Extensive clinical/analytical evaluation was performed, including cardiovascular disease parameters (endothelial function, proatherogenic dyslipidemia, and carotid intima-media thickness). Gene and protein expression profiles were evaluated in monocytes from patients diagnosed positive or negative for anti-dsDNA antibodies by using NanoString and cytokine arrays, respectively. NETosis and circulating inflammatory profile was assessed in both neutrophils and plasma. Positivity and persistence of anti-dsDNA antibodies in SLE patients were associated to endothelial dysfunction, proatherogenic dyslipidemia, and accelerated atherosclerosis. In parallel, anti-dsDNA antibodies were linked to the aberrant activation of innate immune cells, so that anti-dsDNA(+) SLE monocytes showed distinctive gene and protein expression/activity profiles, and neutrophils were more prone to suffer NETosis in comparison with anti-dsDNA(−) patients. Anti-dsDNA(+) patients further displayed altered levels of numerous circulating mediators related to inflammation, NETosis, and cardiovascular risk. In vitro, Ig-dsDNA promoted NETosis on neutrophils, apoptosis on monocytes, modulated the expression of inflammation and thrombosis-related molecules, and induced endothelial activation, at least partially, by FcR (Fc receptor)-binding mechanisms. Conclusions: Anti-dsDNA antibodies increase the cardiovascular risk of SLE patients by altering key molecular processes that drive a distinctive and coordinated immune and vascular activation, representing a potential tool in the management of this comorbidity.


Assuntos
Anticorpos Antinucleares/sangue , Doenças Cardiovasculares/imunologia , DNA/imunologia , Células Endoteliais/imunologia , Imunoglobulina G/sangue , Leucócitos/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Adulto , Apoptose , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/genética , Células Cultivadas , Técnicas de Cocultura , Estudos Transversais , Citocinas/genética , Citocinas/metabolismo , Células Endoteliais/metabolismo , Armadilhas Extracelulares/metabolismo , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Leucócitos/metabolismo , Lipídeos/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/genética , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Estresse Oxidativo , Estudos Retrospectivos , Medição de Risco , Transdução de Sinais
19.
J Coll Physicians Surg Pak ; 31(7): S93-S98, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34271803

RESUMO

OBJECTIVE: To investigate the symptoms and laboratory results of children hospitalised with the diagnosis of COVID-19, aiming to reveal the characteristics of symptomatic cases. STUDY DESIGN: A descriptive cross-sectional study. PLACE AND DURATION OF STUDY: Department of Pediatrics, Kastamonu Training and Research Hospital, Kastamonu, Turkey from March to December 2020. METHODOLOGY: Seventy-nine children, hospitalised with the diagnosis of COVID-19, were included in the study and were divided into two groups as symptomatic and asymptomatic. The demographic data, laboratory results and clinics of the patients of the two groups were compared. RESULTS: The mean age of participants was 10.43 ± 5.91 (0-17) years, and 57% (n=45) of them were girls. Five patients in the symptomatic group had comorbidities (2 allergic asthma,  cerebral palsy, type-1 diabetes mellitus and anorexia nervosa). The most common symptom was fever (36.7%, n=29). It was noteworthy that everyone with an NLR >3.13 (high-NLR) was symptomatic. Significantly more patients in the high-NLR group were symptomatic compared with the low-NLR group (p=0.005). On the other hand, symptomatic children had significantly higher levels of C-reactive protein (2.8 (IQR: 1.2-10.0) mg/L vs. 1.4 (IQR: 0.4-2.0) mg/L, p=0.011); and procalcitonin (0.05 (IQR: 0.02-0.10) ng/mL vs. 0.01 (IQR: 0.00-0.03) ng/mL, p<0.001) than those without symptoms. One of the children with cerebral palsy died from pneumonia during the study. CONCLUSION: C-reactive protein, procalcitonin and NLR levels were found to be significantly higher in symptomatic children. NLR can be suggested as a potential marker associated with disease severity in COVID-19 patients, which needs to be supported by other studies. Key Words: COVID-19, Children, Neutrophil / lymphocyte ratio, C-reactive protein, Procalcitonin.


Assuntos
COVID-19 , Pediatria , Adolescente , COVID-19/sangue , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Linfócitos/metabolismo , Masculino , Neutrófilos/metabolismo , Estudos Retrospectivos , SARS-CoV-2 , Turquia/epidemiologia
20.
Anticancer Res ; 41(7): 3673-3682, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230166

RESUMO

AIM: This study aimed to investigate useful prognostic factors of immunotherapy in patients with lung cancer. PATIENTS AND METHODS: We retrospectively observed 73 patients who underwent immunotherapy (nivolumab, pembrolizumab, and atezolizumab) for lung cancer. The systemic inflammatory score (SIS) was calculated as the sum of the following factors scored one point each: Hemoglobin <12.5 g/dl and serum albumin <3.6 g/dl, resulting in scores of 0-2. We examined the correlation between the SIS and initial tumor response and progression-free and overall survival with other existing markers, namely tumor programmed death-ligand 1 (PD-L1) expression level; neutrophil-to-lymphocyte ratio (NLR); modified Glasgow prognostic score; and prognostic nutritional index, etc. Results: SIS ≤1 was significantly associated with better initial tumor response. In multivariate analysis, PD-L1 expression ≥50% (p=0.010), SIS ≤1 (p=0.028) and NLR <5.6 (p=0.047) were significantly associated with longer progression-free survival, and SIS ≤1 (p=0.030) and NLR <5.6 (p=0.037) were associated with longer overall survival. CONCLUSION: SIS is a useful marker of the efficacy of immunotherapy that can be obtained via routine blood tests.


Assuntos
Inflamação/patologia , Neoplasias Pulmonares/patologia , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Imunoterapia/métodos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Neutrófilos/patologia , Nivolumabe/uso terapêutico , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos
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