Serum netrin-1 levels are high in Rheumatoid arthritis associated interstitial lung disease.

BACKGROUND: Recent data show that netrin-1 has a role in development of pulmonary fibrosis. This study was aimed to investigate serum netrin-1 level and its relation to interstitial lung disease(ILD) in patients with rheumatoid arthritis (RA). METHOD: 42 RA patients with RA-ILD, 58 RA patients without RA-ILD (RA non-ILD group), and 61 healthy volunteers were included in this study. The modified DAS28-ESR score was used to calculate disease activity in RA patients. Using the quantitative immunoassay method, Serum netrin-1 levels were measured with an ELISA kit (Catalog number: E-EL-H2328; lab science, lot number: GZWTKZ5SWK, Texas, USA). RESULTS: The median value of netrin-1 was found to be significantly higher in the RA-ILD group (82.9 [59.9-124]) compared to both the RA non-ILD group(52.9 [49.5-73.1])(B = -0.006, OR = 0.994, CI 95 %=0.989-0.999, P = 0.018) and the control group(53.5 [49.5-87.5]) (B: -0.005, OR: 0.994, CI 95 %: 0.990-0.999, p: 0.022). A cut-off value of 61.78 for netrin-1 was found to have a sensitivity of 73.8 % and a specificity of 69 % for the diagnosis of RA-ILD (AUC [95 %Cl] = 0.771 [0.679-0.862], p < 0.0001).It was found that high serum netrin-1 level was strongly associated with the RA-usual interstitial pneumonia(UIP) pattern and poorly related to the RA-nonspecific interstitial pneumonia(NSIP) pattern compared to the RA non-ILD group. CONCLUSIONS: Netrin-1 is elevated in the serum of patients with RA-ILD, especially in the UIP pattern. Netrin-1 may be a potential candidate for predicting the development of RA-ILD that should be investigated in the pathophysiological and therapeutic fields..

Serum Netrin-1 and Urinary KIM-1 levels as potential biomarkers for the diagnosis of early preeclampsia.

The aim of this study was to evaluate whether the Serum Netrin-1 and Urinary KIM-1 (Kidney Injury Molecule-1) levels are associated with the detection of preeclampsia. A total of 90 patients, including 36 normal pregnant women, 29 patients with nonsevere preeclampsia and 25 patients with severe preeclampsia, were included in this study. Maternal serum Netrin-1 and Urinary KIM-1 levels were measured by using an enzyme-linked immunosorbent assay (ELISA). The results showed that the Levels of Netrin-1 and KIM-1 were statistically higher in women with preeclampsia as compared with normal pregnant women. Furthermore, the Netrin-1 level in women with severe preeclampsia was significantly higher than nonsevere preeclamptic women. inconclusion the current study showed that Maternal serum level of Netrin-1 and Urinary level of KIM-1 can be used as early biomarkers for the detection of preeclampsia.IMPACT STATEMENTWhat is already known on this subject? Preeclampsia is a disorder of widespread vascular endothelial malfunction and vasospasm that occurs after 20 weeks' gestation. Netrin-1 was found to promote angiogenesis. Alteration of placental angiogenesis in early pregnancy is a well-known reason for placental dysfunction such as preeclampsia. Kidney injury with proteinuria is a characteristic feature of preeclampsia. Urine KIM-1 is the most potential biomarker for renal injury in preeclampsia. Due to these facts, we aimed to investigate the role of maternal serum Netrin-1 and Urine KIM-1 levels in preeclampsia presence and severity.What the results of this study add? A significant relationship between Netrin-1 and KIM-1 levels with preeclampsia.What the implications are of these findings for clinical practice and/or further research? Based on these findings, we concluded that increased levels of Netrin-1 and KIM-1 are associated with severe preeclampsia.

A nomogram for bladder pain syndrome/interstitial cystitis based on netrin-1.

PURPOSE: This study aimed to combine plasma netrin-1 and clinical parameters to construct a diagnostic model for bladder pain syndrome/interstitial cystitis (BPS/IC). METHODS: We analyzed the independent diagnostic value of netrin-1 and the correlation with clinical symptom scores of BPS/IC. Clinical parameters were selected using LASSO regression, and a multivariate logistic regression model based on netrin-1 was established, and then a nomogram of BPS/IC prevalence was constructed. The nomogram was evaluated using calibration curves, the C-index, and decision curve analysis (DCA). Finally, the model was validated using an internal validation method. RESULTS: The area under the curve for the ability of netrin-1 to independently predict BPS/IC diagnosis was 0.858 (p < 0.001), with a sensitivity of 85% and specificity of 82%. The predicted nomogram included three variables: age, CD3 + /CD4 + T lymphocyte ratio, and netrin-1. The C-index of this nomogram was 0.882, and the predicted values were highly consistent with the actual results in the calibration curve. In addition, the internally validated C-index of 0.870 confirms the high reliability of the model. DCA results show that the net patient benefit of the netrin-1 combined with other clinical parameters was higher than that of the single netrin-1 model. CONCLUSION: Netrin-1 can be used as a diagnostic marker for BPS/IC and is associated with pain. The nomogram constructed by combining netrin-1 and clinical parameters was able to predict BPS/IC with great accuracy. In addition, Netrin-1 may also serve as a novel therapeutic target for BPS/IC.

Protective effects of the knockdown of lncRNA AK139328 against oxygen glucose deprivation/reoxygenation-induced injury in PC12 cells.

Cerebral ischemic stroke is a major cause of adult morbidity and mortality worldwide. Several long non-coding RNAs (lncRNAs) have been reported to participate in cerebral ischemia/reperfusion injury (IRI). However, to the best of our knowledge, the role of lncRNA AK139328 in cerebral ischemic stroke remains poorly understood. The present study aimed to determine the expression and function of lncRNA AK139328 in the progression of IRI. PC12 cells were injured by oxygen glucose deprivation/reoxygenation (OGD/R) to establish an in vitro ischemic stroke model. An MTT assay was performed to determine cell viability. Reverse transcription-quantitative PCR was used to analyze the expression levels of AK139328 and Netrin-1 in blood samples from patients who had suffered a cerebral ischemic stroke and healthy individuals or OGD/R PC12 cells. ELISAs were used to determine the levels of inflammatory cytokines. In addition, oxidative stress levels and the levels of cell apoptosis were evaluated by reactive oxygen species (ROS) kits, flow cytometry and western blotting. Immunofluorescence staining was used for the detection of cell neurite outgrowth. The results of the present study revealed that AK139328 expression levels were upregulated in patients who had suffered a cerebral ischemic stroke and in PC12 cells following stimulation with OGD/R. The knockdown of AK139328 alleviated OGD/R-induced decreases in cell viability, downregulation in Netrin-1 expression and increases in inflammatory cytokines levels, including TNF-α, IL-1ß and IL-6. Moreover, AK139328 silencing suppressed oxidative stress and cell apoptosis in OGD/R-treated PC12 cells. Furthermore, the expression levels of microtubule associated protein 2 and growth associated protein 43 in OGD/R-injured PC12 cells were upregulated following the knockdown of AK139328 expression. In conclusion, these findings suggested that the knockdown of AK139328 expression may protect PC12 cells against OGD/R injury by regulating inflammatory responses, oxidative stress and cell apoptosis. The data suggested a potential therapeutic target for the diagnosis and treatment of cerebral ischemic stroke.

Diagnostic efficacy of serum and urinary netrin-1 in the early detection of diabetic nephropathy.

This study aimed to assess the diagnostic value of serum and urinary netrin-1 in patients with type 2 diabetes mellitus (T2DM) at different stages of diabetic nephropathy (DN) and to compare its efficacy of estimation in serum with that in the urine. This study was carried out on 135 patients with T2DM and 45 healthy subjects. The patients with diabetes were divided according to urinary albumin creatinine ratio (UACR) into: T2DM with normoalbuminuria, incipient DN with microalbuminuria, and overt DN with macroalbuminuria groups. Serum and urinary levels of netrin-1 were measured by ELISA. The mean levels of serum and urinary netrin-1 were significantly higher in the microalbuminuric and macroalbuminuric patients with DN than those in the normoalbuminuric patients with T2DM, with the highest values detected in macroalbuminuric patients with DN. Urinary netrin-1 level was significantly higher in the normoalbuminuric T2DM group than control group, whereas no significant difference existed regarding serum netrin-1 level. In T2DM groups, the urinary and serum netrin-1 correlated with each other and were independently related to fasting blood glucose, UACR, and estimated glomerular filtration rate. Receiver operating characteristic curve analysis showed that the area under the curve of urinary netrin-1 was 0.916 which is significantly higher than that of serum netrin-1 (0.812) for the detection of incipient DN and reached 0.938 on coestimation of both urinary and serum netrin-1. In conclusion, netrin-1 is a potential diagnostic marker for early detection of DN with its estimation in urine has higher accuracy than that of serum.

Serum netrin-1 as a potential biomarker for functional outcome of traumatic brain injury.

BACKGROUND: Decreased serum netrin-1 concentrations have been found after acute brain injury. We investigated the role of serum netrin in prognosis of traumatic brain injury (TBI). METHODS: In this prospective and observational study, enzyme-linked immunosorbent assay was used to detect serum netrin-1 concentrations in 50 mild TBI patients (Glasgow coma scale (GCS) score, 13-15), 83 moderate TBI patients (GCS score, 9-12), 69 severe TBI patients (GCS score, 3-8) and 50 healthy controls. Glasgow outcome scale score of 1-3 at 6 months after trauma was defined as poor outcome. RESULTS: Serum netrin-1 concentrations were significantly lower in moderate or severe TBI patients than in controls and in severe TBI patients than in moderate TBI patients, while not in mild TBI patients than in controls. GCS score and Rotterdam computed tomography classification were closely correlated with serum netrin-1 concentrations among TBI patients. Forty-two (20.8%) patients had poor outcome. Receiver operating characteristic curve analysis revealed that serum netrin-1 concentrations could distinguish patients with poor outcome from the other remainders significantly. In addition, serum netrin-1 concentrations were independently associated with poor outcome. CONCLUSIONS: Serum netrin-1 might serve as a potential biomarker for prognosis of TBI.

Association between serum netrin-1 and prognosis of ischemic stroke: The role of lipid component levels.

BACKGROUND AND AIMS: High serum netrin-1 levels decrease the risk of ischemic stroke and are negatively associated with outcomes after ischemic stroke. However, it remains unclear whether the association between netrin-1 and ischemic stroke prognosis is modified by lipid component levels. METHODS AND RESULTS: We measured baseline serum netrin-1 levels in 3065 ischemic stroke patients from China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The primary outcome was a combination of death and major disability (modified Rankin Scale score≥3) at 3 months after ischemic stroke. Total cholesterol (TC) levels could modify the association between netrin-1 and prognosis of ischemic stroke (Pinteraction = 0.040). After multivariate adjustment, the odds ratios of the primary outcome associated with the highest quartile of netrin-1 were 0.39 (95%CI, 0.17-0.90; Ptrend = 0.004) for the patients with high TC levels and 0.82 (95%CI, 0.61-1.11; Ptrend = 0.149) for those with normal TC levels. Adding netrin-1 to conventional risk factors improved risk prediction for the primary outcome in the patients with high TC levels (net reclassification improvement: 26.8%, P = 0.015; integrated discrimination index: 1.6%, P = 0.028) but not in those with normal TC levels. CONCLUSIONS: Elevated netrin-1 is associated with improved prognosis at 3 months after ischemic stroke in the patients with high TC levels but not in those with normal TC levels. Further prospective studies from other populations and randomized clinical trials are needed to verify our findings and clarify the potential mechanisms.

Decreased serum netrin-1 is associated with ischemic stroke: A case-control study.

BACKGROUND AND AIMS: Netrin-1 was a laminin-related protein involved in neurovascular protection, and we previously discovered that decreased serum netrin-1 was associated with poor prognosis of ischemic stroke. However, the relationship between serum netrin-1 level and the risk of ischemic stroke remains unclear. The aim of this study was to investigate the association between netrin-1 level and risk of ischemic stroke. METHODS AND RESULTS: A case-control study including 591 ischemic stroke patients and 591 age- and sex-matched healthy individuals was conducted, and serum netrin-1 concentrations were quantitatively determined via enzyme-linked immunosorbent assay for all participants. The serum netrin-1 levels were significantly lower in the ischemic stroke patients than those in matched controls (median, 496.4 vs 652.1 pg/mL; P < 0.001). After adjustment for potential confounders, the odds ratio of ischemic stroke associated with the highest quartile of netrin-1 was 0.07 (95% CI: 0.01-0.65; Ptrend = 0.018) compared with the lowest quartile of netrin-1. Each 1-standard deviation increase of log-transformed netrin-1 was associated with a lower odds of ischemic stroke (odds ratio: 0.45, 95% CI: 0.22-0.94; P = 0.032), and a dose-response relationship between serum netrin-1 and ischemic stroke was observed (Plinearity = 0.003). Incorporating netrin-1 to conventional risk factors improved the discriminatory power for ischemic stroke (net reclassification index = 98.0%, P < 0.001; integrated discrimination improvement = 0.28%, P = 0.027). CONCLUSIONS: Serum netrin-1 was decreased in patients with ischemic stroke compared with healthy controls, suggesting that there was a potential role of netrin-1 in the pathogenesis of ischemic stroke.

Decreased Serum Netrin-1 as a Predictor for Post-Stroke Depression in Chinese Patients with Acute Ischemic Stroke.

BACKGROUND AND AIMS: Experimental studies demonstrated that netrin-1 (NT-1) is an important factor influencing the recovery after ischemic stroke. However, whether NT-1 levels were associated with the post-stroke depression (PSD) remains unclear. We aimed to evaluate the relationship between NT-1 levels and PSD at 3 months in patients with ischemic stroke. METHODS: From January 2018 to December 2019, consecutive Chinese patients with first-ever ischemic stroke were prospectively recruited. Serum NT-1 levels were measured at admission. Patients with a 17-item Hamilton Depression Scale score of ≥7 were given the Structured Clinical Interview of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, for diagnosis of PSD. RESULTS: A total of 238 patients (mean age, 62.5 years; 45.4% female) were enrolled. The median NT-1 concentrations were 467.8 pg/mL (interquartile range, 351.8-581.0 pg/mL). During the 3-month follow-up period, 64 patients (26.9%) experienced PSD. Serum NT-1 levels were significantly lower in PSD patients than in patients without PSD (median, 380.3 pg/mL versus 478.5 pg/mL; P = 0.001). After adjusting for demographic characteristic, National Institutes of Health stroke score, and other potential confounders by multiple logistic regression analysis, patients with NT-1 levels in the first quartile were more likely to have 3-month PSD (as compared with the fourth quartile, odds ratio 3.83, 95% confidence intervals, 1.53-9.63, P = 0.004). Similar significant findings were observed when the NT-1 levels were added as a continuous variable. CONCLUSIONS: Our data demonstrated that decreased serum NT-1 levels, in a Chinese population, were significantly associated with PSD at 3 months.

Prediction Power on Cardiovascular Disease of Neuroimmune Guidance Cues Expression by Peripheral Blood Monocytes Determined by Machine-Learning Methods.

Atherosclerosis is the underlying pathology in a major part of cardiovascular disease, the leading cause of mortality in developed countries. The infiltration of monocytes into the vessel walls of large arteries is a key denominator of atherogenesis, making monocytes accountable for the development of atherosclerosis. With the development of high-throughput transcriptome profiling platforms and cytometric methods for circulating cells, it is now feasible to study in-depth the predicted functional change of circulating monocytes reflected by changes of gene expression in certain pathways and correlate the changes to disease outcome. Neuroimmune guidance cues comprise a group of circulating- and cell membrane-associated signaling proteins that are progressively involved in monocyte functions. Here, we employed the CIRCULATING CELLS study cohort to classify cardiovascular disease patients and healthy individuals in relation to their expression of neuroimmune guidance cues in circulating monocytes. To cope with the complexity of human datasets featured by noisy data, nonlinearity and multidimensionality, we assessed various machine-learning methods. Of these, the linear discriminant analysis, Naïve Bayesian model and stochastic gradient boost model yielded perfect or near-perfect sensibility and specificity and revealed that expression levels of the neuroimmune guidance cues SEMA6B, SEMA6D and EPHA2 in circulating monocytes were of predictive values for cardiovascular disease outcome.

Is Netrin-1 Deficiency Responsible for Inflammation and Systemic Diseases Related to Pseudoexfoliation?

PRECIS: Serum netrin-1 levels are significantly lower in patients with pseudoexfoliation syndrome (PES) and pseudoexfoliative glaucoma (PEG) compared with the control group. PURPOSE: To investigate serum netrin-1 levels in PES and PEG patients and to determine the relevance of this molecule in the etiopathogenesis of PES-related and PEG-related diseases. MATERIALS AND METHODS: This prospective study included 29 PES and 17 PEG patients in the study groups and age-sex matched 47 cataract patients without pseudoexfoliative accumulation as a control group. Serum netrin-1 levels were measured by enzyme-linked immunosorbent assay. RESULTS: Serum netrin-1 level was significantly lower in the PES and PEG groups compared with the control group (P=0.007). Multinominal logistic regression analysis was performed in terms of netrin-1 levels ≤712.9 pg/mL, >712.9 pg/mL and sex which may affect PES and PEG. It were found that netrin-1 was a significant negative predictor for PES (odds ratio, 3.45; 95% confidence interval, 1.230-9.716; P=0.019) and PEG (odds ratio, 3.57; 95% confidence interval, 1.008-12.669; P=0.049), respectively. CONCLUSIONS: Decreased serum netrin-1 levels were detected in PES and PEG patients, similar to atherosclerosis and Alzheimer disease. Inflammation lays behind in the common pathogenesis of these diseases. Therefore, netrin-1 promises a potential anti-inflammatory role.

Serum netrin-1 as a biomarker for colorectal cancer detection.

BACKGROUND: Recent evidence support that netrin-1 involves in colorectal carcinogenesis. OBJECTIVE: This study was to evaluate the performance of serum netrin-1 for detection of colorectal cancer (CRC) in both clinical/screening sets. METHODS: A total of 115 consecutive patients with CRC and matched healthy controls were included in Clinical Set. Fifty subjects with CRC, 50 subjects with advanced adenoma (AA), and 150 matched control participants free of neoplasia were included in Screening Set. RESULTS: In Clinical set, subjects with CRC presented higher levels of serum netrin-1 (513.9 ± 22.6 pg/mL) than controls (347.8 ± 20.3 pg/mL, p< 0.0001). Similar in Screening set, serum netrin-1 was higher in CRC (644.5 ± 37.0 pg/mL, both p< 0.0001), compared with controls (407.7 ± 14.8 pg/mL) and AA (416.5 ± 18.5 pg/mL). However, there was no difference between controls and AA (p= 0.752). Compared with the low netrin-1 group, the high group presented increased risk of CRC (Clinical set: OR = 4.300, p< 0.001; Screening set: OR = 7.731, p< 0.001). ROC curve of netrin-1 was developed to detect CRC (Clinical set: AUC 0.703; Screening set: AUC 0.759). CONCLUSIONS: It suggests netrin-1 as a potential biomarker for CRC detection.

High Serum Netrin-1 and IL-1ß in Elderly Females with ACS: Worse Prognosis in 2-years Follow-up. / Níveis Elevados de Netrina-1 e IL-1ß em Mulheres Idosas com SCA: Pior Prognóstico no Acompanhamento de Dois Anos.

BACKGROUND: Several markers have been evaluated for a potential impact on clinical decisions or mortality prediction in acute coronary syndrome (ACS), including Netrin-1 and IL-1ß that have been associated with cardiovascular disease. OBJECTIVE: Our study examined the prognostic value of Netrin-1 and IL-1ß in patients with ACS (2-year follow-up). METHODS: We evaluate Netrin-1, IL-1ß and other risk factors in the serum sample of 803 patients. Kaplan-Meier curves and Cox regression were used for the analysis of all-cause mortality, cardiovascular mortality, and a combined outcome of fatal myocardial infarction (MI) or new non-fatal MI, considering p-value < 0.05. RESULTS: There were 115 deaths from all causes, 78 deaths due to cardiovascular causes and 67 events in combined outcomes. Netrin-1 levels above the median (>44.8 pg/mL) were associated with a worse prognosis (all-cause mortality and cardiovascular mortality) in elderly females, even after model adjustment (HR: 2.08, p = 0.038 and HR: 2.68, p = 0.036). IL-1ß levels above the median (>13.4 pg/mL) in elderly females were associated with increased risk of all outcomes after adjustment (all-cause mortality - HR: 2.03, p = 0.031; cardiovascular mortality - HR: 3.01, p = 0.013; fatal MI or new non-fatal MI - HR: 3.05, p = 0.029). For males, no associations were observed between Netrin-1 or IL-1ß and outcomes. CONCLUSION: High serum levels of Netrin-1 and IL-1ß showed significant association with worse prognosis in elderly females. They may be useful as prognostic indicators in ACS. (Arq Bras Cardiol. 2020; 114(3):507-514).

FUNDAMENTO: Vários marcadores têm sido avaliados quanto a um potencial impacto nas decisões clínicas ou na predição de mortalidade na síndrome coronariana aguda (SCA), incluindo Netrina-1 e IL-1ß. OBJETIVO: Examinamos o valor prognóstico de Netrina-1 e IL-1ß em pacientes com SCA (2 anos de acompanhamento). MÉTODOS: Avaliamos Netrina-1, IL-1ß e outros fatores de risco em amostras de soro de 803 pacientes. Curvas de Kaplan-Meier e regressão de Cox foram usadas para análise de óbito por todas as causas, óbito por doenças cardiovasculares (DCV) e desfecho combinado de infarto agudo do miocárdio (IAM) fatal ou novo IAM não fatal, considerando p < 0,05. RESULTADOS: Houve 115 óbitos por todas as causas, 78 óbitos por DCV e 67 eventos no desfecho combinado. Níveis de Netrina-1 acima da mediana (> 44,8 pg/mL) foram associados a pior prognóstico (óbito por todas as causas e por DCV) em mulheres idosas, mesmo após o ajuste do modelo (HR: 2,08, p = 0,038 e HR: 2,68, p = 0,036). Níveis de IL-1ß acima da mediana (> 13,4 pg/mL) em mulheres idosas foram associados a risco aumentado para todos os desfechos após o ajuste (todas as causas - HR: 2,03, p = 0,031; DCV - HR: 3,01, p = 0,013; desfecho combinado - HR: 3,05, p = 0,029). Para homens, não foram observadas associações entre Netrina-1 ou IL-1ß e os desfechos. CONCLUSÃO: Níveis séricos elevados de Netrina-1 e IL-1ß mostraram associação significativa com pior prognóstico em idosas do sexo feminino. Eles podem ser úteis como indicadores prognósticos em SCA. (Arq Bras Cardiol. 2020; 114(3):507-514).

Serum netrin-1 levels at presentation and delayed neurological sequelae in unintentional carbon monoxide poisoning.

Objectives: The early identification of patients with a high risk of developing delayed neurological sequelae (DNS) can improve the quality of care in carbon monoxide (CO) poisoning cases. The aim of this study is to investigate whether the serum netrin-1 levels measured at presentation to the emergency department (ED) predicted the development of DNS after acute CO intoxication.Methods: This prospective observational study was conducted between 1 August 2018 and 31 July 2019 in a single tertiary hospital. The patients with acute CO intoxication and serum netrin-1 levels measured at the time of ED presentation were included in the study. All patients were followed up for six weeks regarding the development of DNS. The patients were divided into two groups, including those who developed DNS (DNS group) and those who did not (non-DNS group).Results: A total of 183 patients were included in the study, and 54 (29.5%) developed DNS. The median serum netrin-1 level at ED presentation was significantly lower in the DNS group (391.5 pg/mL [263.0-550.5]) than in the non-DNS group (626.0 pg/mL [505.9-755.6]) (p < .001). Multivariate analysis revealed that a low serum netrin-1 level (adjusted odds ratio [AOR]: 8.02, 95% CI: 2.45-26.20), low Glasgow coma scale (GCS) score at ED presentation (AOR: 0.81, 95% CI: 0.68-0.97), long CO exposure time (AOR: 1.96, 95% CI: 1.49-2.56), and the presence of acute brain lesions (AOR: 8.24, 95% CI: 2.37-28.58) on diffusion-weighted imaging were independent predictors of DNS. Serum netrin-1 levels less than 432 pg/mL predicted the development of DNS with a sensitivity of 68.5% (95% CI: 54.4%-80.5%) and a specificity of 86.0% (95% CI: 78.8%-91.5%).Conclusions: Low serum netrin-1 levels were significantly associated with the development of DNS. Therefore, serum netrin-1 at ED presentation can help identify patients at risk of developing DNS following discharge.

Níveis Elevados de Netrina-1 e IL-1β em Mulheres Idosas com SCA: Pior Prognóstico no Acompanhamento de Dois Anos / High Serum Netrin-1 and IL-1β in Elderly Females with ACS: Worse Prognosis in 2-years Follow-up

Resumo Fundamento Vários marcadores têm sido avaliados quanto a um potencial impacto nas decisões clínicas ou na predição de mortalidade na síndrome coronariana aguda (SCA), incluindo Netrina-1 e IL-1β. Objetivo Examinamos o valor prognóstico de Netrina-1 e IL-1β em pacientes com SCA (2 anos de acompanhamento). Métodos Avaliamos Netrina-1, IL-1β e outros fatores de risco em amostras de soro de 803 pacientes. Curvas de Kaplan-Meier e regressão de Cox foram usadas para análise de óbito por todas as causas, óbito por doenças cardiovasculares (DCV) e desfecho combinado de infarto agudo do miocárdio (IAM) fatal ou novo IAM não fatal, considerando p < 0,05. Resultados Houve 115 óbitos por todas as causas, 78 óbitos por DCV e 67 eventos no desfecho combinado. Níveis de Netrina-1 acima da mediana (> 44,8 pg/mL) foram associados a pior prognóstico (óbito por todas as causas e por DCV) em mulheres idosas, mesmo após o ajuste do modelo (HR: 2,08, p = 0,038 e HR: 2,68, p = 0,036). Níveis de IL-1β acima da mediana (> 13,4 pg/mL) em mulheres idosas foram associados a risco aumentado para todos os desfechos após o ajuste (todas as causas - HR: 2,03, p = 0,031; DCV - HR: 3,01, p = 0,013; desfecho combinado - HR: 3,05, p = 0,029). Para homens, não foram observadas associações entre Netrina-1 ou IL-1β e os desfechos. Conclusão Níveis séricos elevados de Netrina-1 e IL-1β mostraram associação significativa com pior prognóstico em idosas do sexo feminino. Eles podem ser úteis como indicadores prognósticos em SCA. (Arq Bras Cardiol. 2020; 114(3):507-514)

Abstract Background Several markers have been evaluated for a potential impact on clinical decisions or mortality prediction in acute coronary syndrome (ACS), including Netrin-1 and IL-1β that have been associated with cardiovascular disease. Objective Our study examined the prognostic value of Netrin-1 and IL-1β in patients with ACS (2-year follow-up). Methods We evaluate Netrin-1, IL-1β and other risk factors in the serum sample of 803 patients. Kaplan-Meier curves and Cox regression were used for the analysis of all-cause mortality, cardiovascular mortality, and a combined outcome of fatal myocardial infarction (MI) or new non-fatal MI, considering p-value < 0.05. Results There were 115 deaths from all causes, 78 deaths due to cardiovascular causes and 67 events in combined outcomes. Netrin-1 levels above the median (>44.8 pg/mL) were associated with a worse prognosis (all-cause mortality and cardiovascular mortality) in elderly females, even after model adjustment (HR: 2.08, p = 0.038 and HR: 2.68, p = 0.036). IL-1β levels above the median (>13.4 pg/mL) in elderly females were associated with increased risk of all outcomes after adjustment (all-cause mortality - HR: 2.03, p = 0.031; cardiovascular mortality - HR: 3.01, p = 0.013; fatal MI or new non-fatal MI - HR: 3.05, p = 0.029). For males, no associations were observed between Netrin-1 or IL-1β and outcomes. Conclusion High serum levels of Netrin-1 and IL-1β showed significant association with worse prognosis in elderly females. They may be useful as prognostic indicators in ACS. (Arq Bras Cardiol. 2020; 114(3):507-514)

Netrin-1 and the Grade of Atherosclerosis Are Inversely Correlated in Humans.

OBJECTIVE: Netrin-1 has been shown to play a role in the initiation of atherosclerosis in mice models. However, little is known about the role of Netrin-1 in humans. We set out to study whether Netrin-1 is associated with different stages of atherosclerosis. Approach and Results: Plasma Netrin-1 levels were measured in different patient cohorts: (1) 22 patients with high cardiovascular risk who underwent arterial wall inflammation assessment using positron-emission tomography / computed tomography, (2) 168 patients with a positive family history of premature atherosclerosis in whom coronary artery calcium scores were obtained, and (3) 104 patients with chest pain who underwent coronary computed tomography angiography imaging to evaluate plaque vulnerability and burden. Netrin-1 plasma levels were negatively correlated with arterial wall inflammation (ß, -0.01 [95% CI, 0.02 to -0.01] R2, 0.61; P<0.0001), and concentrations of Netrin-1 were significantly lower when atherosclerosis was present compared with individuals without atherosclerosis (28.01 versus 10.51 ng/mL, P<0.001). There was no difference in Netrin-1 plasma concentrations between patients with stable versus unstable plaques (11.17 versus 11.74 ng/mL, P=0.511). However, Netrin-1 plasma levels were negatively correlated to total plaque volume (ß, -0.09 [95% CI, -0.11 to -0.08] R2, 0.57, P<0.0001), calcified plaque volumes (ß, -0.10 [95% CI, -0.12 to -0.08] R2, 0.53; P<0.0001), and noncalcified plaque volumes (ß, -0.08 [95% CI, -0.10 to -0.06] R2, 0.41; P<0.0001). Treatment of inflammatory stimulated endothelial cells with plasma with high Netrin-1 level resulted in reduced endothelial inflammation and consequently, less monocyte adhesion. CONCLUSIONS: Netrin-1 plasma levels are lower in patients with subclinical atherosclerosis and in patients with arterial wall inflammation. Netrin-1 is not associated with plaque vulnerability; however, it is negatively correlated to plaque burden, suggesting that Netrin-1 is involved in some, but not all, stages of atherosclerosis.

Association between new circulating proinflammatory and anti-inflammatory adipocytokines with coronary artery disease.

BACKGROUND: The aim of this study was to evaluate the diagnostic and risk predictive value of emerging proinflammatory and anti-inflammatory adipocytokines on coronary artery disease (CAD). PATIENTS AND METHODS: The study involved 259 inpatients suspected acute coronary syndrome who underwent coronary angiography. Demographic, clinical characteristics, and coronary artery stenosis rated by Gensini score were collected by cardiovascular doctors. The levels of serum inflammatory adipocytokines were evaluated by ELISA. The correlations of the cytokines with clinical parameters were assessed. Receiver operating characteristic curves were constructed for the diagnosis of CAD. RESULTS: The 259 inpatients were assigned to the CAD (n = 180) and control groups (n = 79). Compared with the control group, the CAD group displayed significantly higher serum levels of retinol-binding protein-4 (RBP4), pentraxin 3 (PTX3), galectin-3 (GAL-3), and plasminogen activator inhibitor (PAI-1), and significantly lower levels of netrin-1 (NTN1), interleukin-37 (IL-37), and adiponectin (ADP) (all P < 0.05). PAI-1 was significantly upregulated, and IL-37 and ADP were significantly downregulated in the three-vessels CAD subgroup compared to the one- and two-vessels CAD subgroups (P < 0.05). The RBP4, PTX3, GAL-3, PAI-1, and IL-37 inflammatory cytokines were significantly positively correlated with Gensini score, and ADP was negatively correlated (all P < 0.001). IL-37 was a more accurate anti-inflammatory biomarker than NTN1 and ADP. Combining cytokines significantly increased the sensitivity and specificity. CONCLUSION: The inflammatory adipocytokines GAL-3, RBP4, PTX3, NTN1, and IL-37 were more effective than the classical biomarkers PAI-1 and ADP in the diagnosis and risk assessment of CAD patients.

Serum netrin-1 serves as a prognostic biomarker of aneurysmal subarachnoid hemorrhage.

BACKGROUND: Netrin-1 exhibits anti-inflammatory properties. Netrin-1 could alleviate brain injury of subarachnoid hemorrhage (SAH) rat. This study was designed to discern the utility of serum netrin-1 as a biomarker for assessing the severity and prognosis of patients with aneurysmal SAH. METHODS: Netrin-1 concentrations were gauged in serum from 104 patients and 104 controls. Hemorrhagic clinical and radiological severity was assessed utilizing World Federation of Neurological Surgeons (WFNS) score, modified Fisher score, and Hunt Hess score. Glasgow Outcome Scale (GOS) score was recorded at 6 months after SAH. GOS score of 1-3 was considered as a poor outcome. RESULTS: Patients showed substantially lower serum netrin-1 concentrations than controls (median, 237.9 pg/ml; interquartile range, 189.6-271.2 pg/ml vs. median, 815.4 pg/ml; interquartile range, 581.8-990.4 pg/ml). Netrin-1 concentrations were independently correlated with WNFS score, modified Fisher score, Hunt Hess score and serum C-reactive protein concentrations (t = -4.667, -3.792, -4.304 and - 3.549 respectively). Area under ROC curve was 0.837 (95% CI, 0.752-0.902) for predicting 6-month poor prognosis. Serum netrin-1 concentrations <229.3 pg/ml emerged as an independent prognostic predictor (odds ratio, 14.316; 95% confidence interval, 5.032-40.726). CONCLUSIONS: Serum netrin-1 might represent a potential biomarker for reflecting severity, inflammation and prognosis of human aneurysmal SAH.

Netrin­1 interference potentiates epithelial­to­mesenchymal transition through the PI3K/AKT pathway under the hypoxic microenvironment conditions of non­small cell lung cancer.

Netrin­1 is overexpressed in several types of cancer. However, whether netrin­1 can potentiate hypoxia­induced tumor progression in lung cancer has not been reported to date. Thus, the objective of the present study was to investigate whether netrin­1 regulates cancer cell migration and invasion under hypoxic conditions in lung cancer and explore the underlying mechanism. A three­dimensional microfluidic chip was used to observe real­time changes in cancer cells, and cobalt chloride (CoCl2) was used to simulate a hypoxic microenvironment. Netrin­1 siRNA was employed in the A549 and PC9 cell lines to downregulate the expression of netrin­1. Microfluidic chip, wound healing and Transwell assays were used to examine cell migration and invasion. The expression levels of E­cadherin and vimentin were detected by western blotting. The data demonstrated that netrin­1 mediated epithelial­to­mesenchymal transition (EMT) of A549 and PC9 cells in vitro, which may be associated with the phosphoinositide 3 kinase/AKT pathway. This effect of netrin­1 on the EMT was not observed in the normoxic microenvironment. In this retrospective study, netrin­1 concentrations were evaluated in serum obtained from patients with non­small cell lung cancer (NSCLC) and compared with healthy control samples by quantitative enzyme­linked immunosorbent analysis. The serum concentration of netrin­1 was found to be significantly higher in NSCLC patients compared with that in healthy donors. Taken together, the findings of the present study highlight a novel role for netrin­1 in tumor development under hypoxia in NSCLC and provide further evidence for the use of netrin­1 as a therapeutic target.

Increased Serum Netrin-1 Is Associated With Improved Prognosis of Ischemic Stroke.

Background and Purpose- Previous experimental studies suggested that serum netrin-1 was associated with the progression of ischemic stroke. Knowledge about netrin-1 among ischemic stroke patients may provide new ideas for the prognostic assessment of ischemic stroke. The aim of this study was to investigate the association between serum netrin-1 and prognosis of ischemic stroke. Methods- Serum netrin-1 levels at baseline were measured for 3346 ischemic stroke patients from the CATIS (China Antihypertensive Trial in Acute Ischemic Stroke), and all patients were followed up at 3 months after stroke onset. The primary outcome was a combination of death and major disability (modified Rankin Scale score of ≥3) within 3 months after stroke onset. Results- Up to 3 months after stroke onset, 845 patients (25.25%) experienced death or major disability. After adjustment for baseline National Institutes of Health Stroke Scale score and other potential confounders, elevated serum netrin-1 was associated with a decreased risk of primary outcome (odds ratio, 0.65; 95% CI, 0.47-0.88; Ptrend=0.002) when 2 extreme quartiles were compared. Each SD increase of log-transformed netrin-1 was associated with 17% (95% CI, 7%-26%) decreased risk of primary outcome. Multivariable-adjusted spline regression models showed a negative linear dose-response relationship between serum netrin-1 and the risk of primary outcome ( Plinearity=0.003). Adding netrin-1 quartile to a model containing conventional risk factors improved risk prediction for primary outcome (net reclassification improvement index =14.74%; P=0.002; integrated discrimination improvement =0.40%; P=0.005). Conclusions- Elevated serum netrin-1 levels were associated with improved prognosis at 3 months after ischemic stroke, suggesting that serum netrin-1 may be a potential prognostic biomarker for ischemic stroke. Further studies from other samples of ischemic stroke patients are needed to replicate our findings and to clarify the potential mechanisms. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01840072.