RESUMEN

BACKGROUND: Preeclampsia is a unique vascular disease during pregnancy that generally appears after 20 of weeks gestation or until 6 weeks after delivery. Left undiagnosed, preeclampsia can lead rapidly to death of both mother and fetus. OBJECTIVES: To verify the efficacy of peripheral blood inflammatory markers (BIMs)in diagnosing preeclampsia and compare them with results from other studies. METHODS: Our retrospective case-control study comprised two patient groups. Pregnant women with preeclampsia and pregnant women without preeclampsia were compared for BIMs: neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and mean platelet volume (MPV). The primary endpoint of our research was to assess the predictive power of BIMs for preeclampsia diagnosis. RESULTS: The sample size was calculated based on expected differences of BIMs between the control and study groups. Comparison of quantitative variables was conducted with independent sample t-test or alternatively by Wilcoxon rank sum test. The MPV values were slightly higher in the preeclampsia group, but not statistically significant. NLR and PLR did differentiate between study and control groups. CONCLUSIONS: The diagnostic accuracy of BIMs is unsatisfactory for preeclampsia diagnosis. Discrepancies concerning these values need to be clarified. Further large prospective studies are necessary to validate the potential factor accuracy in preeclampsia diagnosis.

Asunto(s)

Biomarcadores , Preeclampsia , Humanos , Femenino , Preeclampsia/sangre , Preeclampsia/diagnóstico , Embarazo , Estudios Retrospectivos , Biomarcadores/sangre , Adulto , Estudios de Casos y Controles , Neutrófilos , Volúmen Plaquetario Medio , Inflamación/sangre , Inflamación/diagnóstico , Valor Predictivo de las Pruebas , Plaquetas , Linfocitos

RESUMEN

The pathogenesis of acute lung injury is complex. Studies have demonstrated the role of neutrophil extracellular traps (NETs) in the process of lipopolysaccharide (LPS)-induced acute lung injury (ALI). However, the underlying mechanism remains unclear. In this study, the regulation of Nrf2 in the formation of NETs, which was pathogenic in LPS-induced ALI, was identified by analyzing the levels of Cit-H3, lung function, lung tissue pathology, lung wet/dry ratio, the inflammatory cells, cytokines and proteins in the bronchoalveolar lavage fluid (BALF) and in addition, the activity of lung myeloperoxidase (MPO) was also measured. Results showed that the levels of Cit-H3 measured by western blot in Nrf2-knockout (KO) mice were higher compared with the WT mice after LPS stimulation. To further investigate the NETs formation was pathogenic during LPS-induced ALI, the Nrf2-KO mice were treated with DNase I. Results showed that DNase I improved lung function and lung tissue pathology and significantly reduced lung wet/dry ratio and proteins in the BALF. Besides, DNase I also attenuated the infiltration of inflammatory cells and the cytokines (TNF-α, IL-1ß) production in the BALF and the activity of lung MPO. Therefore, these results together indicate that Nrf2 may intervene in the release of NETs during LPS-induced ALI in mice.

Asunto(s)

Lesión Pulmonar Aguda , Líquido del Lavado Bronquioalveolar , Trampas Extracelulares , Lipopolisacáridos , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 2 Relacionado con NF-E2 , Animales , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/inducido químicamente , Factor 2 Relacionado con NF-E2/metabolismo , Ratones , Trampas Extracelulares/metabolismo , Líquido del Lavado Bronquioalveolar/química , Masculino , Peroxidasa/metabolismo , Neutrófilos/metabolismo , Pulmón/metabolismo , Pulmón/patología , Interleucina-1beta/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Desoxirribonucleasa I/metabolismo , Citocinas/metabolismo , Western Blotting

RESUMEN

Carbapenem-resistant Klebsiella pneumoniae (CRKP) causes Gram-negative lung infections and fatal pneumonic sepsis for which limited therapeutic options are available. The lungs are densely innervated by nociceptor sensory neurons that mediate breathing, cough, and bronchoconstriction. The role of nociceptors in defense against Gram-negative lung pathogens is unknown. Here, we found that lung-innervating nociceptors promote CRKP pneumonia and pneumonic sepsis. Ablation of nociceptors in mice increased lung CRKP clearance, suppressed trans-alveolar dissemination of CRKP, and protected mice from hypothermia and death. Furthermore, ablation of nociceptors enhanced the recruitment of neutrophils and Ly6Chi monocytes and cytokine induction. Depletion of Ly6Chi monocytes, but not of neutrophils, abrogated lung and extrapulmonary CRKP clearance in ablated mice, suggesting that Ly6Chi monocytes are a critical cellular population to regulate pneumonic sepsis. Further, neuropeptide calcitonin gene-related peptide suppressed the induction of reactive oxygen species in Ly6Chi monocytes and their CRKP-killing abilities. Targeting nociceptor signaling could be a therapeutic approach for treating multidrug-resistant Gram-negative infection and pneumonic sepsis.

Asunto(s)

Péptido Relacionado con Gen de Calcitonina , Carbapenémicos , Infecciones por Klebsiella , Klebsiella pneumoniae , Pulmón , Nociceptores , Sepsis , Animales , Klebsiella pneumoniae/fisiología , Ratones , Infecciones por Klebsiella/microbiología , Sepsis/metabolismo , Sepsis/microbiología , Pulmón/microbiología , Pulmón/metabolismo , Carbapenémicos/farmacología , Péptido Relacionado con Gen de Calcitonina/metabolismo , Nociceptores/metabolismo , Monocitos/metabolismo , Células Receptoras Sensoriales/metabolismo , Neutrófilos/metabolismo , Modelos Animales de Enfermedad , Antígenos Ly/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/metabolismo , Neumonía Bacteriana/patología , Ratones Endogámicos C57BL

RESUMEN

OBJECTIVE: We conducted this study to summarize the results of studies reporting the role of NLR (neutrophil to lymphocyte ratio) in PSCC (penile squamous cell carcinoma). METHODS: This meta-analysis was conducted using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria. A systematic search was conducted on PubMed, Scopus, and web of science up to March 10, 2023. Fourteen studies were included in the review. The NOS (Newcastle-Ottawa Scale) was used to determine the quality of the included studies. This meta-analysis was conducted on the studies reporting the relationship between NLR and survival using HR (hazard ratio) and 95% CI (confidence interval). RESULTS: There was a significant association between NLR levels and the prognosis, nodal stage, and anatomical tumor stage of PSCC patients. In the meta-analysis of the association of NLR with survival, NLR level was significantly associated with lower cancer-specific survival (HR = 3.51, 95% CI = 2.07-5.98, p < 0.001) and lower disease-free survival (HR = 2.88, 95% CI = 1.60-5.20, p < 0.001). However, NLR was found to have no association with the stage, grade, location, and size of the tumor. CONCLUSION: NLR has a significant diagnostic and prognostic value in PSCC.

Asunto(s)

Carcinoma de Células Escamosas , Neoplasias del Pene , Humanos , Neoplasias del Pene/sangre , Neoplasias del Pene/patología , Neoplasias del Pene/mortalidad , Carcinoma de Células Escamosas/sangre , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Masculino , Pronóstico , Neutrófilos , Linfocitos/patología , Recuento de Linfocitos , Recuento de Leucocitos , Tasa de Supervivencia

RESUMEN

Acute respiratory distress syndrome is a severe lung condition resulting from various causes, with life-threatening consequences that necessitate intensive care. The phenomenon can be modeled in preclinical models, notably through the use of lipopolysaccharide (LPS) instillation in mice. The phenotype induced closely recapitulates the human syndrome, including pulmonary edema, leukocyte infiltration, acute inflammation, impaired pulmonary function, and histological damage. However, the experimental designs using LPS instillations are extremely diverse in the literature. This highly complicates the interpretation of the induced phenotype chronology for future study design and hinders the proper identification of the optimal time frame to assess different readouts. Therefore, the definition of the treatment window in relation to the beginning of the disease onset also presents a significant challenge to address questions or test compound efficacy. In this context, the temporality of the different readouts usually measured in the model was evaluated in both normal and neutrophil-depleted male C57bl/6 mice using LPS-induction to assess the best window for proper readout evaluation with an optimal dynamic response range. Ventilation parameters were evaluated by whole-body plethysmography and neutrophil recruitment were evaluated in bronchoalveolar lavage fluids and in lung tissues directly. Imaging evaluation of myeloperoxidase along with activity in lung lysates and fluids were compared, along with inflammatory cytokines and lung extravasation by enzyme-linked immunoassays. Moreover, dexamethasone, the gold standard positive control in this model, was also administered at different times before and after phenotype induction to assess how kinetics affected each parameter. Overall, our data demonstrate that each readout evaluated in this study has a singular kinetic and highlights the key importance of the timing between ARDS phenotype and treatment administration and/or analysis. These findings also strongly suggest that analyzes, both in-life and post-mortem should be conducted at multiple time points to properly capture the dynamic phenotype of the LPS-ARDS model and response to treatment.

Asunto(s)

Modelos Animales de Enfermedad , Lipopolisacáridos , Ratones Endogámicos C57BL , Fenotipo , Síndrome de Dificultad Respiratoria , Animales , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/patología , Ratones , Masculino , Pulmón/patología , Pulmón/metabolismo , Pulmón/efectos de los fármacos , Líquido del Lavado Bronquioalveolar/química , Factores de Tiempo , Citocinas/metabolismo , Neutrófilos/metabolismo

RESUMEN

BACKGROUND: This study aims to investigate preoperative prognostic factors available for intrahepatic cholangiocarcinoma (ICC) patients and propose a new preoperative prognostic scoring system for ICC that combines CA19-9 and neutrophil/lymphocyte ratio (NLR). METHODS: In this retrospective analysis, 1728 patients diagnosed with ICC and undergoing curative liver resections were studied. This study employed univariate and multivariate Cox regression to find factors affecting recurrence and overall survival (OS), and furthermore assessed how preoperative models influenced tumor traits and postoperative recurrence. RESULTS: The results of the multivariate Cox regression analysis indicated that two preoperative variables, NLR and Ca19-9, were independent risk factors affecting postoperative recurrence and OS in ICC patients. Based on this data, assigning a score of 0 (NLR ≤ 2.4 and Ca19-9 ≤ 37U/ml) or 1 (NLR > 2.4 and Ca19-9 > 37U/ml) to these two factors, a preoperative prognostic score was derived. According to the scoring model, patients were divided into three groups: 0 points (low-risk group), 1 point (intermediate-risk group), and 2 points (high-risk group). The 5-year recurrence and OS rates for the three groups were 56.6%, 68.2%, 77.8%, and 56.8%, 40.6%, 27.6%, respectively, with all P values < 0.001. Furthermore, high-risk group patients were more prone to early recurrence (early recurrence rates for high-, intermediate-, and low-risk groups were 56.8%, 51.5%, and 37.1%, respectively, P < 0.001) and extrahepatic metastasis (extrahepatic metastasis rates for high-, intermediate-, and low-risk groups were 31.7%, 26.4%, and 15.4%, respectively, P < 0.001). In terms of tumor characteristics, high-risk group patients had larger tumor diameters and were more likely to experience microvascular invasion, lymph node metastasis, and perineural invasion. CONCLUSIONS: The predictive capacity of postoperative recurrence and OS rates in ICC patients is effectively captured by the preoperative scoring system incorporating NLR and CA19-9 levels.

Asunto(s)

Neoplasias de los Conductos Biliares , Antígeno CA-19-9 , Colangiocarcinoma , Hepatectomía , Linfocitos , Recurrencia Local de Neoplasia , Neutrófilos , Humanos , Colangiocarcinoma/cirugía , Colangiocarcinoma/sangre , Colangiocarcinoma/patología , Colangiocarcinoma/mortalidad , Masculino , Femenino , Neutrófilos/patología , Persona de Mediana Edad , Pronóstico , Neoplasias de los Conductos Biliares/cirugía , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/sangre , Neoplasias de los Conductos Biliares/mortalidad , Estudios Retrospectivos , Linfocitos/patología , Antígeno CA-19-9/sangre , Anciano , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/patología , Adulto , Periodo Preoperatorio , Recuento de Linfocitos , Factores de Riesgo

RESUMEN

BACKGROUND: The neutrophil-to-high-density lipoprotein cholesterol ratio (NHR) has emerged as a promising biomarker for assessing inflammation and lipid dysregulation. Increasing evidence indicates that these metabolic disturbances play a crucial role in the development of metabolic dysfunction-associated steatotic liver disease(MASLD). This study aims to investigate the association between NHR, MASLD, and liver fibrosis. METHODS: This cross-sectional study analyzed data from the 2017-2020 National Health and Nutrition Examination Survey (NHANES). Weighted multivariate logistic regression models were used to investigate the association between NHR and both MASLD and liver fibrosis. Smoothed curve fitting and threshold effect analysis were performed to detect potential nonlinear relationships. Subgroup analyses were conducted to assess the consistency of these associations across different groups. RESULTS: The study involved 4,761 participants. We observed a significant positive association between NHR and MASLD (OR = 1.20, 95% CI: 1.09-1.31). However, there was no significant association between NHR and liver fibrosis (OR = 1.01; 95% CI: 0.94-1.09). The analysis of smoothed curve fitting and threshold effect revealed an inverted U-shaped relationship between NHR and MASLD, with a turning point at 5.63. CONCLUSION: Our findings indicate a positive correlation between elevated NHR levels and MASLD prevalence. However, we did not observe a significant association between NHR and liver fibrosis prevalence. Further prospective research is needed to validate these findings in a longitudinal setting.

Asunto(s)

HDL-Colesterol , Cirrosis Hepática , Neutrófilos , Encuestas Nutricionales , Humanos , Estudios Transversales , Masculino , Femenino , Cirrosis Hepática/sangre , Cirrosis Hepática/epidemiología , Cirrosis Hepática/patología , Persona de Mediana Edad , HDL-Colesterol/sangre , Estados Unidos/epidemiología , Adulto , Biomarcadores/sangre , Anciano , Hígado Graso/sangre , Hígado Graso/epidemiología , Hígado Graso/patología

RESUMEN

PROBLEM: Cesarean scar pregnancy (CSP) is characterized by a gestational sac fully or partially implanted in the scar from a previous cesarean section. Systemic immune-inflammation indices (SIIs) have recently been discussed as additional diagnostic markers in placenta accreta and preeclampsia. CSP shares a similar pathogenesis with these diseases, suggesting that assessing the SIIs and neutrophil-to-lymphocyte ratio (NLR) could enhance additional predictability in diagnosing CSP. METHOD OF STUDY: In this study, we analyzed the complete blood counts between 264 women who were confirmed with CSP by ultrasound and 295 women who underwent elective termination. RESULTS: The mean counts of total white cells and neutrophils were significantly higher, whereas the counts of monocytes, lymphocytes, and platelets were significantly lower in the CSP group compared to the control group (p < 0.001). Additionally, the SII, systemic inflammation response index (SIRI), or NLR was significantly higher in the CSP group compared to the control group (p < 0.0001). Given the limited effect of SII and SIRI on the increased risk of developing CSP, the optimal cut-off value for NLR in predicting CSP was 2.87 (area under the curve [AUC] 0.656, 68% sensitivity). The optimal cut-off value for NLR in predicting type 2 CSP was 2.91 (AUC 0.690, 71% sensitivity). CONCLUSIONS: Although ultrasound or magnetic resonance imaging images are a gold standard for visualizing the gestational sac's location in the diagnosis of CSP, assessing peripheral blood tests is cost-effective, and NLR may provide additional diagnosis value for CSP.

Asunto(s)

Biomarcadores , Cesárea , Cicatriz , Inflamación , Embarazo Ectópico , Humanos , Femenino , Embarazo , Cicatriz/inmunología , Adulto , Inflamación/inmunología , Biomarcadores/sangre , Embarazo Ectópico/diagnóstico , Embarazo Ectópico/inmunología , Embarazo Ectópico/sangre , Neutrófilos/inmunología , Linfocitos/inmunología

RESUMEN

BACKGROUND: Aortic dissection (AD) is a serious cardiovascular condition associated with high mortality rates. The systemic inflammatory response can influence the prognosis of AD, and in this context, the neutrophil-to-lymphocyte ratio (NLR) emerges as a simple and rapid inflammatory biomarker. METHODS: This retrospective cohort study included 103 patients diagnosed with AD and treated in the emergency department between 2018 and 2023. Patient demographics, clinical features, and laboratory results were evaluated. Multivariate logistic regression analysis was performed to adjust for potential confounders such as age, mean systolic blood pressure, oxygen saturation, hemoglobin, lactate values, and the presence of coronary artery disease. The ability of NLR to predict mortality was analyzed using receiver operating characteristic (ROC) analysis. RESULTS: The study population was divided into two groups: non-survivors (68% mortality rate) and survivors (32% survival rate). The non-survivor group had significantly higher NLR values compared to the survivor group (median NLR 7.66 vs. 2.5, p<0.001). Multivariate logistic regression analysis identified NLR as an independent predictor of in-hospital mortality (adjusted odds ratio [OR] 2.33, 95% confidence interval [CI] 1.42-3.82, p<0.001). ROC analysis for NLR demonstrated high discriminative power with an area under the ROC curve (AUROC) of 0.851 (95% CI 0.768-0.914). The determined cut-off point was >5.08 with a sensitivity of 77.14% and specificity of 81.82%. CONCLUSION: The findings indicate that high NLR is strongly associated with increased mortality risk in patients with AD and can be used in emergency clinical settings to predict mortality.

Asunto(s)

Disección Aórtica , Servicio de Urgencia en Hospital , Mortalidad Hospitalaria , Linfocitos , Neutrófilos , Humanos , Disección Aórtica/mortalidad , Disección Aórtica/sangre , Masculino , Femenino , Estudios Retrospectivos , Servicio de Urgencia en Hospital/estadística & datos numéricos , Persona de Mediana Edad , Anciano , Pronóstico , Recuento de Linfocitos , Valor Predictivo de las Pruebas , Biomarcadores/sangre , Curva ROC , Recuento de Leucocitos

RESUMEN

OBJECTIVE: To explore the predictive value of leukocyte derived markers for postoperative delirium (POD) in patients undergoing cardiac valve surgery. METHODS: A prospective cohort study was conducted. The patients who underwent cardiac valve surgery admitted to Beijing Anzhen Hospital of Capital Medical University from October 2021 to March 2023 were enrolled. The demographic, baseline and perioperative data were collected, and the neutrophil to lymphocyte ratio (NLR) and platelet to white blood cell ratio (PWR) were calculated before operation and within 24 hours after operation. Delirium assessment was conducted twice a day for patients within 1-5 days after surgery or discharged within 5 days. According to the evaluation results, the patients were divided into delirium group and non-delirium group. The clinical indexes between the two groups were compared. Multivariate Logistic regression analysis was used to screen the independent risk factors of POD, and the POD predictive model was constructed. The predictive value of POD predictive model was evaluated by receiver operator characteristic curve (ROC curve). RESULTS: A total of 235 patients were enrolled in the analysis, of which 83 patients had POD (35.32%) and 152 patients did not have POD (64.68%). Compared with the non-delirious group, the patients in the delirious group had higher Charlson comorbidity index (CCI) score and lower mini-mental state examination (MMSE) score. In terms of perioperative data, compared with the non-delirium group, the patients in the delirium group had longer operative time, duration of cardiopulmonary bypass, length of intensive care unit (ICU) stay, duration of mechanical ventilation, and postoperative hospital stay, higher incidence of perioperative atrial fibrillation, and lower discharge life score. In terms of leukocyte derived markers, NLR within 24 hours after surgery in both groups were significantly higher than those before surgery, and PWR were significantly lower than those before surgery. The NLR within 24 hours after surgery, PWR difference and NLR difference in the delirium group were significantly higher than those in the non-delirium group. Multivariate Logistic regression analysis showed that CCI score [odds ratio (OR) = 1.394, 95% confidence interval (95%CI) was 1.038-1.872, P = 0.027], perioperative atrial fibrillation (OR = 3.697, 95%CI was 1.711-7.990, P < 0.001), duration of cardiopulmonary bypass (OR = 1.008, 95%CI was 1.002-1.015, P = 0.016), length of ICU stay (OR = 1.006, 95%CI was 1.002-1.010, P = 0.002), NLR difference (OR = 1.029, 95%CI was 1.009-1.050, P = 0.005) and PWR difference (OR = 1.044, 95%CI was 1.009-1.080, P = 0.013) were independently correlated with POD. POD predictive model was constructed by multivariate Logistic regression analysis result: POD predictive model index = -4.970+0.336×CCI score+1.317×perioperative atrial fibrillation+0.009×duration of cardiopulmonary bypass+0.006×length of ICU stay+0.030×NLR difference+0.044×PWR difference. ROC curve analysis showed that the area under the ROC curve (AUC) of NLR difference for predicting POD was 0.659 (95%CI was 0.583-0.735), the optimal critical value was 16.62, the sensitivity was 60.2%, and the specificity was 70.4% (P < 0.05). The AUC of PWR difference for predicting POD was 0.608 (95%CI was 0.528-0.688), the optimal critical value was 25.68, the sensitivity was 51.8%, and the specificity was 75.7% (P < 0.05). The AUC of POD predictive model for predicting POD was 0.805 (95%CI was 0.745-0.865), the optimal critical value was 0.39, the sensitivity was 74.7%, and the specificity was 79.6% (P < 0.05). CONCLUSIONS: The differences of NLR and PWR are independently related to POD, which has potential value in predicting POD after cardiac valve surgery.

Asunto(s)

Biomarcadores , Delirio , Complicaciones Posoperatorias , Humanos , Delirio/diagnóstico , Delirio/etiología , Estudios Prospectivos , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/epidemiología , Biomarcadores/sangre , Factores de Riesgo , Masculino , Femenino , Válvulas Cardíacas/cirugía , Valor Predictivo de las Pruebas , Modelos Logísticos , Curva ROC , Neutrófilos , Linfocitos , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Persona de Mediana Edad , Leucocitos

RESUMEN

Streptococcus suis (S. suis) is an important swine bacterial pathogen and causes human infections, leading to a wide range of diseases. However, the role of 5'-nucleotidases in its virulence remains to be fully elucidated. Herein, we identified four cell wall-anchored 5'-nucleotidases (Snts) within S. suis, named SntA, SntB, SntC, and SntD, each displaying similar domains yet exhibiting low sequence homology. The malachite green reagent and HPLC assays demonstrated that these recombinant enzymes are capable of hydrolysing ATP, ADP, and AMP into adenosine (Ado), with the hierarchy of catalytic efficiency being SntC>SntB>SntA>SntD. Moreover, comprehensive enzymatic activity assays illustrated slight variances in substrate specificity, pH tolerance, and metal ion requirements, yet highlighted a conserved substrate-binding pocket, His-Asp catalytic dyad, metal, and phosphate-binding sites across Snts, with the exception of SntA. Through bactericidal assays and murine infection assays involving in site-mutagenesis strains, it was demonstrated that SntB and SntC collaboratively enhance bacterial survivability within whole blood and polymorphonuclear leukocytes (PMNs) via the Ado-A2aR pathway in vitro, and within murine blood and organs in vivo. This suggests a direct correlation between enzymatic activity and enhancement of bacterial survival and virulence. Collectively, S. suis 5'-nucleotidases additively contribute to the generation of adenosine, influencing susceptibility within blood and PMNs, and enhancing survival within blood and organs in vivo. This elucidation of their integral functions in the pathogenic process of S. suis not only enhances our comprehension of bacterial virulence mechanisms, but also illuminates new avenues for therapeutic intervention aimed at curbing S. suis infections.

Asunto(s)

5'-Nucleotidasa , Adenosina , Modelos Animales de Enfermedad , Evasión Inmune , Infecciones Estreptocócicas , Streptococcus suis , Animales , Streptococcus suis/patogenicidad , Streptococcus suis/enzimología , Streptococcus suis/inmunología , Streptococcus suis/genética , 5'-Nucleotidasa/genética , 5'-Nucleotidasa/inmunología , 5'-Nucleotidasa/metabolismo , Ratones , Adenosina/metabolismo , Virulencia , Infecciones Estreptocócicas/microbiología , Infecciones Estreptocócicas/inmunología , Femenino , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/inmunología , Neutrófilos/inmunología , Neutrófilos/microbiología , Ratones Endogámicos BALB C , Especificidad por Sustrato

RESUMEN

Neutrophils utilize a variety of metabolic sources to support their crucial functions as the first responders in innate immunity. Here, through in vivo and ex vivo isotopic tracing, we examined the contributions of different nutrients to neutrophil metabolism under specific conditions. Human peripheral blood neutrophils, in contrast to a neutrophil-like cell line, rely on glycogen storage as a major metabolic source under resting state but rapidly switch to primarily using extracellular glucose upon activation with various stimuli. This shift is driven by a substantial increase in glucose uptake, enabled by rapidly increased GLUT1 on cell membrane, that dominates the simultaneous increase in gross glycogen cycling capacity. Shifts in nutrient utilization impact neutrophil functions in a function-specific manner: oxidative burst depends on glucose utilization, whereas NETosis and phagocytosis can be flexibly supported by either glucose or glycogen, and neutrophil migration and fungal control are enhanced by the shift from glycogen utilization to glucose utilization. This work provides a quantitative and dynamic understanding of fundamental features in neutrophil metabolism and elucidates how metabolic remodeling shapes neutrophil functions, which has broad health relevance.

Asunto(s)

Glucosa , Glucógeno , Neutrófilos , Fagocitosis , Humanos , Neutrófilos/metabolismo , Neutrófilos/inmunología , Glucosa/metabolismo , Glucógeno/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Nutrientes/metabolismo , Activación Neutrófila , Estallido Respiratorio , Trampas Extracelulares/metabolismo

RESUMEN

Enterotoxigenic Escherichia coli (ETEC) are a major cause of diarrheal illness in humans and animals, induced by enterotoxins produced by these pathogens. Despite the crucial role of neutrophils in combatting bacterial infections, our understanding of how enterotoxins impact neutrophil function is limited. To address this knowledge gap, we used heat-labile enterotoxin (LT) and heat-stable enterotoxin a (STa) to investigate their impact on the effector functions of neutrophils. Our study reveals that pSTa does not exert any discernible effect on the function of neutrophils. In contrast, LT altered the migration and phagocytosis of neutrophils and induced the production of inflammatory factors via activation of cAMP/PKA and ERK1/2 signaling. LT also attenuated the release of neutrophil extracellular traps by neutrophils via the PKA signaling pathway. Our findings provide novel insights into the impact of LT on neutrophil function, shedding light on the underlying mechanisms that govern its immunoregulatory effects. This might help ETEC in subverting the immune system and establishing infection.

Asunto(s)

Toxinas Bacterianas , Proteínas Quinasas Dependientes de AMP Cíclico , AMP Cíclico , Escherichia coli Enterotoxigénica , Enterotoxinas , Infecciones por Escherichia coli , Proteínas de Escherichia coli , Neutrófilos , Fagocitosis , Enterotoxinas/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , Humanos , AMP Cíclico/metabolismo , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Toxinas Bacterianas/metabolismo , Toxinas Bacterianas/inmunología , Infecciones por Escherichia coli/inmunología , Infecciones por Escherichia coli/microbiología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Trampas Extracelulares/metabolismo , Trampas Extracelulares/inmunología , Transducción de Señal

RESUMEN

BACKGROUND: At present, hepatic ischemia-reperfusion injury (IRI) is an important complication of partial hepatectomy and liver transplantation, and it is an important cause of poor prognosis. Spleen tyrosine kinase(SYK) plays an important role in a variety of signaling pathways in the liver, but its role in hepatic IRI is still unclear. This study aims to investigate the role and mechanism of SYK in hepatic IRI and tumor recurrence. METHODS: We first observed the activation of SYK in the liver of mice in response to hepatic IRI. Subsequently, Pharmacological inhibitions of SYK were used to evaluated the effect of SYK on neutrophil recruitment and NETosis, and further explored the effect of SYK on IRI and tumor recurrence. RESULTS: Our study shows that SYK is activated in response to hepatic IRI and aggravates liver injury. On the one hand, neutrophils SYK during the early stage of liver reperfusion increases neutrophil extracellular traps (NETs) production by promoting Pyruvate kinase M2(PKM2) nuclear translocation leading to upregulation of phosphorylated STAT3, thereby exacerbating liver inflammation and tumor recurrence. On the other hand, macrophages SYK can promote the recruitment of neutrophils and increase the activation of NLRP3 inflammasome and IL1ß, which further promotes the formation of NETs. CONCLUSIONS: Our study demonstrates that neutrophil and macrophage SYK synergistically promote hepatic IRI and tumor recurrence, and SYK may be a potential target to improve postoperative hepatic IRI and tumor recurrence.

Asunto(s)

Trampas Extracelulares , Proteínas de la Membrana , Neutrófilos , Daño por Reperfusión , Factor de Transcripción STAT3 , Quinasa Syk , Quinasa Syk/metabolismo , Animales , Factor de Transcripción STAT3/metabolismo , Trampas Extracelulares/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Fosforilación , Ratones , Proteínas de la Membrana/metabolismo , Masculino , Neutrófilos/metabolismo , Proteínas Portadoras/metabolismo , Piruvato Quinasa/metabolismo , Hígado/metabolismo , Hígado/patología , Proteínas de Unión a Hormona Tiroide , Recurrencia Local de Neoplasia/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Humanos , Transducción de Señal

RESUMEN

BACKGROUND: Tumor-associated neutrophils (TANs) constitute an abundant component among tumor-infiltrating immune cells and have recently emerged as a critical player in pancreatic ductal adenocarcinoma (PDAC) progression. This study aimed to elucidate the pro-tumor mechanisms of TAN and identify a novel target for effective immunotherapy against PDAC. METHODS: Microarray and cytokine array analyses were performed to identify the mechanisms underlying the function of TANs. Human and mouse TANs were obtained from differentiated HL-60 cells and orthotopically transplanted PDAC tumors, respectively. The interactions of TANs with cancer and cytotoxic T-cells were evaluated through in vitro co-culture and in vivo orthotopic or subcutaneous models. Single-cell transcriptomes from patients with PDAC were analyzed to validate the cellular findings. RESULTS: Increased neutrophil infiltration in the tumor microenvironment was associated with poor survival in patients with PDAC. TANs secreted abundant amounts of chemokine ligand 5 (CCL5), subsequently enhancing cancer cell migration and invasion. TANs subpopulations negatively correlated with cytotoxic CD8+ T-cell infiltration in PDAC and promoted T-cell dysfunction. TANs upregulated the membranous expression of Nectin2, which contributed to CD8+ T-cell exhaustion. Blocking Nectin2 improved CD8+ T-cell function and suppressed tumor progression in the mouse model. Single-cell analysis of human PDAC revealed two immunosuppressive TANs phenotypes: Nectin2+ TANs and OLR1+ TANs. Endoplasmic reticulum stress regulated the protumor activities in TANs. CONCLUSIONS: TANs enhance PDAC progression by secreting CCL5 and upregulating Nectin2. Targeting the immune checkpoint Nectin2 could represent a novel strategy to enhance immunotherapy efficacy in PDAC.

Asunto(s)

Carcinoma Ductal Pancreático , Nectinas , Neutrófilos , Neoplasias Pancreáticas , Microambiente Tumoral , Humanos , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/genética , Microambiente Tumoral/inmunología , Animales , Ratones , Nectinas/metabolismo , Nectinas/genética , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Regulación hacia Arriba , Femenino , Línea Celular Tumoral , Masculino , Modelos Animales de Enfermedad

RESUMEN

Immune-related adverse events (irAEs) impact outcomes, with most research focusing on early prediction (baseline data), rather than near-term prediction (one cycle before the occurrence of irAEs and the current cycle). We aimed to explore the near-term predictive value of neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), absolute eosinophil count (AEC) for severe irAEs induced by PD-1 inhibitors. Data were collected from tumor patients treated with PD-1 inhibitors. NLR, PLR, and AEC data were obtained from both the previous and the current cycles of irAEs occurrence. A predictive model was developed using elastic net logistic regression Cutoff values were determined using Youden's Index. The predicted results were compared with actual data using Bayesian survival analysis. A total of 138 patients were included, of whom 47 experienced grade 1-2 irAEs and 18 experienced grade 3-5 irAEs. The predictive model identified optimal α and λ through 10-fold cross-validation. The Shapiro-Wilk test, Kruskal-Wallis test and logistic regression showed that only current cycle data were meaningful. The NLR was statistically significant in predicting irAEs in the previous cycle. Both NLR and AEC were significant predictors of irAEs in the current cycle. The model achieved an area under the ROC curve (AUC) of 0.783, with a sensitivity of 77.8% and a specificity of 80.8%. A probability ≥ 0.1345 predicted severe irAEs. The model comprising NLR, AEC, and sex may predict the irAEs classification in the current cycle, offering a near-term predictive advantage over baseline models and potentially extending the duration of immunotherapy for patients.

Asunto(s)

Inhibidores de Puntos de Control Inmunológico , Neoplasias , Neutrófilos , Humanos , Masculino , Femenino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Anciano , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neutrófilos/inmunología , Valor Predictivo de las Pruebas , Adulto , Linfocitos/inmunología , Eosinófilos/inmunología , Anciano de 80 o más Años , Estudios Retrospectivos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Teorema de Bayes , Plaquetas/efectos de los fármacos , Plaquetas/inmunología

RESUMEN

The innate immune response is triggered rapidly after injury and its spatiotemporal dynamics are critical for regeneration; however, many questions remain about its exact role. Here we show that MyD88, a key component of the innate immune response, controls not only the inflammatory but also the fibrotic response during zebrafish cardiac regeneration. We find in cryoinjured myd88-/- ventricles a significant reduction in neutrophil and macrophage numbers and the expansion of a collagen-rich endocardial population. Further analyses reveal compromised PI3K/AKT pathway activation in the myd88-/- endocardium and increased myofibroblasts and scarring. Notably, endothelial-specific overexpression of myd88 reverses these neutrophil, fibrotic and scarring phenotypes. Mechanistically, we identify the endocardial-derived chemokine gene cxcl18b as a target of the MyD88 signaling pathway, and using loss-of-function and gain-of-function tools, we show that it controls neutrophil recruitment. Altogether, these findings shed light on the pivotal role of MyD88 in modulating inflammation and fibrosis during tissue regeneration.

Asunto(s)

Fibrosis , Inmunidad Innata , Factor 88 de Diferenciación Mieloide , Regeneración , Transducción de Señal , Proteínas de Pez Cebra , Pez Cebra , Animales , Animales Modificados Genéticamente , Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Endocardio/metabolismo , Endocardio/patología , Endocardio/inmunología , Corazón/fisiopatología , Inmunidad Innata/genética , Macrófagos/metabolismo , Macrófagos/inmunología , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Miofibroblastos/metabolismo , Miofibroblastos/patología , Infiltración Neutrófila , Neutrófilos/metabolismo , Neutrófilos/inmunología , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Regeneración/genética , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo

RESUMEN

Tumor cells remodel the phenotype and function of tumor microenvironment (TME) cells to favor tumor progression. Previous studies have shown that neutrophils in TME are polarized to N2 tumor-associated neutrophils (TANs) by tumor derived factors, thus promoting tumor growth and metastasis, angiogenesis, therapy resistance, and immunosuppression. Exosomes act as critical intercellular messengers in human health and diseases including cancer. So far, the biological roles of exosomes from N2 TANs in gastric cancer have not been well characterized. Herein, we represented the first report that exosomes from N2 TANs promoted gastric cancer metastasis in vitro and in vivo. We found that exosomes from N2 TANs transferred miR-4745-5p/3911 to gastric cancer cells to downregulate SLIT2 (slit guidance ligand 2) gene expression. Adenovirus-mediated overexpression of SLIT2 reversed the promotion of gastric cancer metastasis by N2 TANs derived exosomes. We further revealed that gastric cancer cells induced glucose metabolic reprogramming in neutrophils through exosomal HMGB1 (high mobility group protein B1)/NF-κB pathway, which mediated neutrophil N2 polarization and miR-4745-5p/3911 upregulation. We further employed ddPCR (droplet digital PCR) to detect the expression of miR-4745-5p/3911 in N2 TANs exosomes from human serum samples and found their increased levels in gastric cancer patients compared to healthy controls and benign gastric disease patients. Conclusively, our results indicate that N2 TANs facilitate cancer metastasis via regulation of SLIT2 in gastric cancer cells by exosomal miR-4745-5p/3911, which provides a new insight into the roles of TME cells derived exosomes in gastric cancer metastasis and offers a potential biomarker for gastric cancer diagnosis.

Asunto(s)

Exosomas , Regulación Neoplásica de la Expresión Génica , Péptidos y Proteínas de Señalización Intercelular , MicroARNs , Proteínas del Tejido Nervioso , Neutrófilos , Neoplasias Gástricas , Microambiente Tumoral , Neoplasias Gástricas/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Exosomas/metabolismo , Exosomas/genética , Humanos , Neutrófilos/metabolismo , Neutrófilos/patología , MicroARNs/genética , Animales , Ratones , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Línea Celular Tumoral , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Péptidos y Proteínas de Señalización Intercelular/genética , Microambiente Tumoral/genética , Metástasis de la Neoplasia , Proteína HMGB1/metabolismo , Proteína HMGB1/genética , Masculino

RESUMEN

Metastasis has been one of the primary reasons for the high mortality rates associated with tumours in recent years, rendering the treatment of current malignancies challenging and representing a significant cause of recurrence in patients who have undergone surgical tumour resection. Halting tumour metastasis has become an essential goal for achieving favourable prognoses following cancer treatment. In recent years, increasing clarity in understanding the mechanisms underlying metastasis has been achieved. The concept of premetastatic niches has gained widespread acceptance, which posits that tumour cells establish a unique microenvironment at distant sites prior to their migration, facilitating their settlement and growth at those locations. Neutrophils serve as crucial constituents of the premetastatic niche, actively shaping its microenvironmental characteristics, which include immunosuppression, inflammation, angiogenesis and extracellular matrix remodelling. These characteristics are intimately associated with the successful engraftment and subsequent progression of tumour cells. As our understanding of the role and significance of neutrophils in the premetastatic niche deepens, leveraging the presence of neutrophils within the premetastatic niche has gradually attracted the interest of researchers as a potential therapeutic target. The focal point of this review revolves around elucidating the involvement of neutrophils in the formation and shaping of the premetastatic niche (PMN), alongside the introduction of emerging therapeutic approaches aimed at impeding cancer metastasis.

Asunto(s)

Metástasis de la Neoplasia , Neoplasias , Neutrófilos , Microambiente Tumoral , Humanos , Neutrófilos/metabolismo , Neutrófilos/patología , Neoplasias/patología , Neoplasias/terapia , Neoplasias/metabolismo , Animales

RESUMEN

OBJECTIVE: To investigate the correlation between neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and risk stratification indicators as well as thrombus burden in patients with moderate-to-high risk acute pulmonary embolism (APE), and to assess the changes in these parameters following interventional therapy. METHODS: This study retrospectively included patients with moderate-to-high risk APE who were admitted to the Department of Interventional Vascular Surgery at Putian First Hospital from May 2020 to May 2024. All patients received anticoagulation therapy, pulmonary artery catheter-directed thrombolysis, and/or mechanical thrombectomy. Patients were further divided into subgroup A if they did not present with any of the following conditions at admission: a) acute inflammatory diseases (including lung infections); b) malignant tumors; c) history of trauma or surgery within the past 2 months. Patients with any of the aforementioned conditions were classified as subgroup B. Additionally, 50 healthy individuals were randomly selected as the healthy control group. RESULTS: The NLR and PLR in subgroup A were significantly lower than those in subgroup B (P < .01). Compared with the healthy control group, the NLR in the APE group and subgroup A was significantly higher (P < .001). There were no significant differences in NLR and PLR between the troponin I-negative and troponin I-positive groups (P > .05), or between the N-terminal pro-B-type natriuretic peptide (NT-proBNP)-negative and NT-proBNP-positive groups (P > .05). There were no significant correlations between NLR and PLR with risk stratification indicators and pulmonary artery embolism index (P > .05). Compared with before treatment, NLR, troponin I, NT-proBNP, right ventricular diameter/left ventricular diameter ratio, and pulmonary artery embolism index were significantly reduced after treatment (P < .05), while there was no significant difference in PLR before and after treatment (P > .05). CONCLUSION: Elevated NLR in patients with APE, which decreases after effective treatment, may be used for assessing disease status and treatment efficacy. However, there is no correlation between NLR and risk stratification indicators or thrombus burden. PLR does not demonstrate significant value in assessing APE.

Asunto(s)

Plaquetas , Linfocitos , Neutrófilos , Embolia Pulmonar , Humanos , Embolia Pulmonar/sangre , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Enfermedad Aguda , Anciano , Trombosis/sangre , Trombosis/etiología , Medición de Riesgo/métodos , Adulto