The Roles of the Canonical Members of Ribonuclease A Family in Tumorigenesis / 中国生物化学与分子生物学报

In human, the ribonuclease A (RNase A) family contains 8 canonical members (RNase 1-RNase 8). Research evidence indicated that all the canonical members of this family, except RNase 8, are involved in the occurrence and development of a variety of tumors, including pancreatic cancer, colorectal cancer, bladder cancer, breast cancer, and skin cancer, etc. During tumorigenesis, the expression of specific RNase increased and glycosylation modifications changed, which are potential markers for tumor diagnosis; They also participate in tumor initiation, growth, and metastasis with a variety of mechanisms, and are potential targets for tumor therapy; Meanwhile, some members have the function of killing tumor cells and inhibiting tumor development, and it is possible to develop into tumor therapeutic drugs. Concretely, RNase 1 suppresses tumor growth by directly killing tumor cells or reducing local inflammation through its ribonuclease activity-dependent cytotoxicity and extracellular RNA degradation functions; however, its binding and activation of ephrin A4 signaling pathway promotes breast cancer initiation. RNase 2 and RNase 3 are important components of eosinophil granule proteins that play an important role in anti-tumor immune defense, and their function of killing tumor cells depends on both cationic nature and ribonuclease activity. RNase 4 and RNase 5 can promote tumorigenesis by inducing angiogenesis, promoting tumor cell proliferation, and inhibiting tumor cell apoptosis. The molecular mechanisms of RNase 5 action include promoting the transcription of 47 S precursor rRNA, activating signaling pro-tumor growth signaling pathways, and generating tRNA-derived stress-induced RNA (tiRNA). Besides, RNase 6 and RNase 7 are related to the occurrence of tumors thought their specific role and mechanism are still unclear. In this review, we summarized the relevance and mechanism of RNase A family members on promoting or inhibiting tumors and analyzed their clinical application potentials.

Significance of fecal calprotectin and eosinophil-derived neurotoxin in non-IgE-mediated food allergy / 国际儿科学杂志

Non-IgE-mediated food allergy most often presents with gastrointestinal symptoms such as diarrhoea, mucus stools, bloody stools, reflux and vomiting a few hours to days after exposure to the allergenic food.The pathogenesis may be related to the activation of intestinal T lymphocytes to secrete pro-inflammatory cytokines such as TNF-α and IL-4 by food allergens, leading to migration of neutrophils and eosinophils into the intestinal lumen, causing an intestinal inflammatory response and increased intestinal permeability.There is no rapid and specific diagnostic method.The diagnosis is mainly based on clinical manifestations combined with food avoidance and oral food challenge.In recent years, fecal biomarkers have been widely used as specific indicators for determining intestinal inflammation as an aid to diagnosis and condition assessment of intestinal infections and inflammatory bowel diseases, but their application in gastrointestinal allergic diseases is rarely reported.In this paper, we will focus on the significance of fecal calprotectin, fecal eosinophil-derived neurotoxin in non-IgE-mediated food allergy.

Clinical characteristics of children with atopic dermatitis and change in serum levels of Apo A1, 25(OH)D and EDN / 中国医师杂志

Objective:To investigate the clinical characteristics of children with atopic dermatitis (AD) and the changes in serum levels of apolipoprotein A1 (Apo A1), 25-hydroxyvitamin D [25(OH)D] and eosinophil derived neurotoxin (EDN).Methods:200 children with AD treated in Zhuzhou Central Hospital from January 2016 to December 2019 were selected retrospectively as AD group and 100 healthy children as control group. The clinical characteristics of children with AD were analyzed, and the differences in serum Apo A1, 25 (OH)D and EDN levels between two groups were compared. The relationships between serum Apo A1, 25(OH)D, EDN levels and severity of AD were explored.Results:The male to female composition ratio of 200 AD patients was 1.41∶1, and the age of onset <3 months was the highest (64.50%). Inhalation allergens were detected in 118 cases (59.00%) and ingestion allergens in 82 cases (41.00%). The levels of Apo A1 and EDN in AD group were significantly higher than those in control group, while the level of 25(OH)D was significantly lower than that in control group ( P<0.05). With the aggravation of the disease, the serum Apo A1 and EDN levels in AD children increased gradually, while the serum 25(OH)D level decreased significantly (all P<0.05). Severity Scoring of Atopic Dermatitis (SCORAD) was positively correlated with Apo A1 and EDN levels ( P<0.05), and was negatively correlated with 25(OH)D level (all P<0.05). Conclusions:Apo A1, 25 (OH)D and EDN are involved in the pathogenesis of AD in children, and their serum levels are closely related to the severity of AD.

Biomarkers for Recurrent Wheezing and Asthma in Preschool Children

Wheezing is one of the characteristic symptoms of asthma, but all preschool children with wheezing are not diagnosed with asthma. Preschool children are not cooperative enough to participate in spirometry and invasive tests. Thus, there is no conventional method to diagnose asthma in preschool children. We reviewed studies on non-invasive biomarkers for assessing asthma in preschool children. Specimens that can be easily obtained by non-invasive methods are blood, exhaled breath and urine. Eosinophils, eosinophil cationic protein and eosinophil-derived neurotoxin (EDN) in blood are helpful in evaluating eosinophilic inflammation of the airways. Exhaled breath contains nitric oxide, volatile organic compounds, various cytokines and mediators as analytical components. Fraction of exhaled nitric oxide has been used to assess the degree of eosinophil inflammation and has been standardized in school-age children and adults, but not yet in preschool children. Exhaled breath condensate (EBC) pH and various cytokines/mediators that are detected in EBC seem to be promising biomarkers for assessing asthma, but need more standardization and validation. There are several biomarkers useful for assessing asthma, but none are ideal. Some biomarkers need standardized methods of obtaining samples from uncooperative preschool children for clinical use and require sufficient validation. Recently, another activated eosinophil marker, serum EDN, has shown promising results as a biomarker for recurrent wheezing and asthma in preschool children.

Serum Levels of Eosinophil-Derived Neurotoxin: A Biomarker for Asthma Severity in Adult Asthmatics

PURPOSE: Eosinophilic inflammation is a key component of severe asthma (SA). However, there has been no reliable serum biomarker for the eosinophilic inflammation of SA. We hypothesized that serum eosinophil-derived neurotoxin (EDN) could predict the eosinophilic inflammation of SA in adult asthmatics. METHODS: Severe asthmatics (n = 235), nonsevere asthmatics (n = 898), and healthy controls (n = 125) were enrolled from Ajou University Hospital, South Korea. The serum levels of EDN and periostin were measured by enzyme-linked immunosorbent assay and compared between severe and nonsevere asthmatics. Their associations with total eosinophil count (TEC) and clinical parameters were evaluated; clinical validation of the K-EDN kit for the measurement of serum EDN was evaluated. RESULTS: Severe asthmatics were older and had longer disease duration with significantly lower levels of forced expiratory volume in 1 second and methacholine PC20 than nonsevere asthmatics. Significant differences were found in TEC or sputum eosinophil count (%) between the groups. The serum levels of EDN and periostin were significantly higher in severe asthmatics than in nonsevere asthmatics and in healthy controls (all P < 0.05). Although significant correlations were found between serum EDN levels measured by the 2 kits (ρ = 0.545, P < 0.0001), higher correlation coefficients between serum EDN levels measured by the K-EDN kit and TEC were higher (ρ = 0.358, P < 0.0001) than those between serum EDN levels measured by the MBL kit and TEC (ρ = 0.319, P < 0.0001) or serum periostin level (ρ = 0.222, P < 0.0001). Multivariate regression analysis demonstrated that serum EDN levels measured by the K-EDN kit predicted the phenotype of SA (P = 0.003), while 2 other biomarkers did not. CONCLUSIONS: The serum EDN level may be a useful biomarker for assessing asthma severity in adult asthmatics.

Montelukast Reduces Serum Levels of Eosinophil-Derived Neurotoxin in Preschool Asthma

PURPOSE: Several markers for eosinophilic inflammation have been proposed to predict response to asthma treatment. However, definitive criteria for treatment decisions have not yet been established. We investigate a potentially useful relatively non-invasive biomarker, eosinophil-derived neurotoxin (EDN), to predict favorable responses to budesonide or montelukast, common treatment for children with asthma. METHODS: Young children (1 to 6 years old) were enrolled in this randomized, parallel, 2-group, open-label trial. Criteria for eligibility included: 1) being symptomatic during the run-in period; and 2) having a serum EDN (sEDN) level ≥ 53 ng/mL, with positive specific immunoglobulin E to house dust mite. Eligible patients were randomly placed into 2 groups: the BIS group received budesonide inhalation suspension (BIS) 0.5 mg once daily; the MONT group received montelukast 4 mg once daily. Ineligible patients were invited to receive montelukast 4 mg once daily (OBS group). Treatment period was 12 weeks. RESULTS: Asthma control days increased significantly in the BIS and MONT groups (P < 0.000) over the 12-week study period. There was no significant change in sEDN in the BIS group but there was a significant decrease in the MONT group (P < 0.000). Patients in the OBS group with high EDN levels (< 53 ng/mL) showed a significant decrease due to MONT treatment (P = 0.023). Rescue medication usage significantly decreased in the BIS and MONT groups (P < 0.000). CONCLUSIONS: EDN is a useful relatively non-invasive biomarker for predicting responses to montelukast and budesonide treatment of preschool children with beta2-agonist responsive recurrent wheeze and multiple-trigger wheeze (Trial registry at UMIN Clinical Trials Registry, UMIN000008335).

Progresses in the serum eosinophil-derived neurotoxin in pediatric asthma / 国际儿科学杂志

Asthma is the most common chronic airway disease in children.The main manifestations are recurrent cough,wheezing,and dyspnea.In recent years,the morbidity and mortality rate of childhood asthma shows a clear rising trend.However,the exact mechanism of this disease still remains uncertain.There is still no specific laboratory test to diagnose pediatric asthma,especially for children under five years who cannot finish pulmonary function test.Serum eosinophil-derived neurotoxin (EDN),as a degranulation of eosinophil,the most important participants in childhood asthma,is drawing an increasing attention of investigators in the assistance of diagnosis,classification and prognosis of childhood asthma.This review concentrates on the relationship between EDN and pediatric asthma.

Eosinophil-derived neurotoxin: a novel biomarker for diagnosis and monitoring of asthma / 소아과

Asthma is associated with increased levels of eosinophils in tissues, body fluids, and bone marrow. Elevated levels of eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP) have been noted in asthma patients. Higher levels of EDN and ECP are also associated with exacerbated asthmatic conditions. Thus, EDN, along with ECP, may aid the diagnosis and monitoring of asthma. Several groups have suggested that EDN is more useful than ECP in evaluating disease severity. This may partially be because of the recoverability of EDN (not sticky, 100% recovery rate), as ECP is a sticky and more highly charged protein. In terms of clinical utility, EDN level is a more accurate biomarker than ECP when analyzing the underlying pathophysiology of asthma. As a monitoring tool, EDN has shown good results in children with asthma as well as other allergic diseases. In children too young to fully participate in lung function tests, EDN levels may be useful as an alter native measurement of eosinophilic inflammation. EDN can also be used in adult patients and in multiple specimen types (e.g., serum, sputum, bronchoalveolar lavage fluid, and nasal lavage fluid). These results are repeatable and reproducible. In conclusion, EDN may be a novel biomarker for the diagnosis, treatment, and monitoring of asthma/allergic disease.

Infection, eosinophilia and childhood asthma

There is a growing list of viruses and bacteria associated with wheezing illness and asthma. It is well known that a few of these pathogens are strongly associated with wheezing illness and asthma exacerbations. What is not known is if early childhood infections with these pathogens cause asthma, and, if so, exactly what are the pathophysiologic mechanisms behind its development. The current consensus is respiratory infection works together with allergy to produce the immune and physiologic conditions necessary for asthma diasthesis. One link between respiratory infection and asthma may be the eosinophil, a cell that plays prominently in asthma and allergy, but can also be found in the body in response to infection. In turn, the eosinophil and its associated products may be novel therapeutic targets, or at the very least used to elucidate the complex pathophysiologic pathways of asthma and other respiratory illnesses. Together or separately, they can also be used for diagnosis, treatment and monitoring. The optimal care of a patient must take into consideration not only symptoms, but also the underlying disease mechanisms.

The Association of Eosinophilic Airway Inflammation in Mycoplasma pneumonia and Asthma / 소아알레르기및호흡기학회지

PURPOSE:To investigate whether airway eosinophilic degranulation develops in Mycoplasma pneumonia (M. pneumonia), and to elucidate the association between M. pneumonia and asthma. METHODS:Forty patients with M. pneumonia, 20 stable asthma patients (stable asthma) and 20 normal controls were recruited from October 2005 to February 2007. In the M. pneumonia, blood and induced sputum sampling were collected at admission (acute stage) and 6 to 8 weeks later (convalescent stage). Eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP) levels in sputum and serum were measured in all 3 groups. RESULTS:Serum levels of EDN and ECP in the acute stage of M. pneumonia were comparable to those in the stable asthma group. However, in the convalescent stage of M. pneumonia, EDN and ECP levels were significantly lower than in the stable asthma (P<0.01 and P<0.05, respectively). Sputum levels of EDN and ECP levels in the acute stage of M. pneumonia were comparable to those in the stable asthma. Sputum EDN levels in the convalescent stage of M. pneumonia were significantly lower than those in the stable asthma (P<0.05), and sputum ECP levels were lower than those in the stable asthma, which was not statistically significant. CONCLUSION:Eosinophilic degranulation may play an important role in the pathogenesis of M. pneumonia, which suggests the association between M. pneumonia and asthma.

Relationship with Eosinophil Cationic Protein (ECP)/Eosinophil-derived Neurotoxin (EDN) Levels and Growth Status among Asthmatic Children / 대한소아내분비학회지

PURPOSE: Short statue or obesity has been reported in asthmatic children, but the results are inconsistent. Recently eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN) levels has been known as important markers of airway inflammation and reflect asthma severity as well. The aim of this study is to evaluate the growth status and to analyze the possible relation with serum EDN and ECP levels. METHODS: A total of 90 children (57 boys and 33 girls, 4 to 16 years old) who had been admitted for bronchial asthma were included. To standardize the data for age and sex, standard deviation scores (SDS) were calculated for height and weight. Values less than -2 SDS below the mean were considered to be extremely low, -1 SDS to 1 SDS as normal, values higher than 2 SDS considered very high. Serum EDN and ECP levels were measured. RESULTS: The mean height SDS was 0.33+/-0.85 and weight SDS was 0.23+/-1.20. The prevalence of short stature was 2.2%, normal stature 75.5%, and tall stature 22.2%. The prevalence of underweight was 7.8%, normal weight 71.1%, and overweight 21.1%. Height SDS was negatively correlated with serum ECP (r=-0.27, P=0.01) and EDN (r=-0.27, P=0.009) and weight SDS was negatively correlated with serum ECP (r=-0.20, P=0.05). Height SDS were significantly lower in high ECP and EDN groups compared to normal ECP and EDN groups (P<0.01 and P<0.009, respectively). Weight SDS was lower in high ECP group compared to normal ECP group (P<0.05). CONCLUSION: Growth (height and weight) was inversely correlated with serum EDN and ECP levels. These results suggest that high ECP and EDN levels might be related with growth retardation of asthmatic children.

Eosinophil-derived Neurotoxin and Eosinophil Cationic Protein Levels Correlate with Bronchial Wall Thickness in Children with Asthma Exacerbation / 소아알레르기및호흡기학회지

PURPOSE: Eosinophilic inflammation plays a critical role in asthma and high-resolution computed tomography (HRCT) scoring systems have been used to evaluate the extent and severity in long standing adult asthma. We investigated if there is a correlation between eosinophil degranulation markers and HRCT scores in childhood asthma. METHODS: Children with acute asthma exacerbation (n=25) underwent HRCT and were assessed for bronchial wall thickening (BWT), low lung density (LLD), and bronchial dilatation (BD) using semi-quantitative scoring techniques. Serum eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP) levels indicating eosinophil degranulation were determined. Comparisons were made with normal control subjects (n=14). RESULTS: BWT (P<0.001) and LLD (P<0.001) scores were higher in the childhood asthma group than in the control group, but BD scores were not. The EDN (r=0.405, P<0.05) and ECP (r=0.565, P<0.01) levels significantly correlated with BWT scores, but not with LLD and BD in the childhood asthma group. The EDN (r=0.710, P<0.0001) and the ECP (r=0.580, P<0.0001) levels were significantly correlated with serum total eosinophil counts. CONCLUSION: The EDN and ECP levels were correlated with BWT scores on HRCT. These findings suggest that EDN and ECP may be valuable for quantifying airway thickening in children with asthma exacerbation.