Association between arachidonate lipoxygenase 15,c.-292 C > T gene polymorphism and non-cystic fibrosis bronchiectasis in children: a pilot study on the effects on airway lipoxin A4 and disease phenotype.

BACKGROUND: Persistent airway inflammation is a central feature of bronchiectasis. Arachidonate 15-lipoxygenase (ALOX-15) controls production of endogenous lipid mediators, including lipoxins that regulate airway inflammation. Mutations at various positions in ALOX-15 gene can influence airway disease development. We investigated association between ALOX-15,c.-292 C > T gene polymorphism and bronchiectasis unrelated to cystic fibrosis in Egyptian children. Also, lipoxin A4 (LXA4) level in bronchoalveolar lavage (BAL) was studied in relation to polymorphism genotypes and disease phenotypes determined by clinical, pulmonary functions, and radiological severity parameters. METHODS: This was an exploratory study that included 60 participants. Thirty children with non-cystic fibrosis bronchiectasis (NCFB) were compared with 30 age and sex-matched controls. ALOX-15,c.-292 C > T polymorphism was genotyped using TaqMan-based Real-time PCR. LXA4 was measured in BAL using ELISA method. RESULTS: There was no significant difference between patients and controls regarding ALOX-15,c.-292 C > T polymorphism genotypes and alleles (OR = 1.75; 95% CI (0.53-5.7), P = 0.35) (OR = 1; 95% CI (0.48-2), p = 1). BAL LXA4 level was significantly lower in patients, median (IQR) of 576.9 (147.6-1510) ng/ml compared to controls, median (IQR) of 1675 (536.8-2542) (p = 0.002). Patients with severe bronchiectasis had a significantly lower LXA4 level (p < 0.001). There were significant correlations with exacerbations frequency (r=-0.54, p = 0.002) and FEV1% predicted (r = 0.64, p = 0.001). Heterozygous CT genotype carriers showed higher LXA4 levels compared to other genotypes(p = 0.005). CONCLUSIONS: Low airway LXA4 in children with NCFB is associated with severe disease phenotype and lung function deterioration. CT genotype of ALOX-15,c.-292 C > T polymorphism might be a protective genetic factor against bronchiectasis development and/or progression due to enhanced LXA4 production.

The potential regulatory role of miR16 to the interplay between interferon and transforming growth factor beta pathways through IRF3 and SMAD7 in hepatitis C virus infected patients.

BACKGROUND: The defensive strategy against hepatitis C virus (HCV) infection depends on two antiviral pathways; interferon (IFN) and transforming growth factor ß (TGFß). We aimed at verifying the relation between TGFß and IFN antiviral pathways in HCV infection through SMAD7 and IRF3, and whether a possible regulatory role for microRNA-16 (miR16) on the interplay between IFN and TGFß signaling pathways exists or not. METHODS: We evaluated miR16, IRF3 and SMAD7 expression by real-time polymerase chain reaction in HCV infected patients and age and gender matched healthy controls. RESULTS: miR16 expression was significantly higher while IRF3 and SMAD7 expression was significantly lower in HCV patients compared with healthy controls. Meanwhile, miR16 was negatively correlated to SMAD7 in HCV patients while IRF3 and SMAD7 were positively correlated. CONCLUSIONS: The interplay between IFN and TGFß pathways through IRF3 and SMAD7 in the context of immunity against HCV infection could be under the control of miR16.

Wild-Type Isocitrate Dehydrogenase 1 Over-Expression is Related to Cancer Stem Cells Survival in Lung Adenocarcinoma.

Altered metabolism is one of the characteristics of cancer cells. We evaluated the expression of wild-type Isocitrate Dehydrogenase 1 (IDH1) and the cancer stem cells (CSCs) marker CD44 by real-time PCR and levels of reduced form of glutathione in lung biopsies of 32 adenocarcinoma patients and 18 control subjects. We found that IDH1 and CD44 expression and the levels of reduced form of glutathione were significantly higher in lung adenocarcinoma patients. IDH1 was positively correlated with CD44 and reduced form of glutathione. In conclusion, wild-type IDH1 is over-expressed in lung adenocarcinoma which probably promoted tumor progression via increasing CSCs survival.

Prenatal Exposure to Endocrine Disruptors and Reprogramming of Adipogenesis: An Early-Life Risk Factor for Childhood Obesity.

Obesity is a global health problem. It is characterized by excess adipose tissue that results from either increase in the number of adipocytes or increase in adipocytes size. Adipocyte differentiation is a highly regulated process that involves the activation of several transcription factors culminating in the removal of adipocytes from the cell cycle and induction of highly specific proteins. Several other factors, including hormones, genes, and epigenetics, are among the most important triggers of the differentiation process. Although the main contributing factors to obesity are high caloric intake, a sedentary lifestyle, and genetic predisposition, strong evidence supports a role for life exposure to environmental pollutants. Endocrine-disrupting chemicals are exogenous, both natural and man-made, chemicals that disrupt the body signaling processes, thus interfering with the endocrine system. Several studies have shown that prenatal exposure to endocrine disruptors modulates the mechanisms, by which multipotent mesenchymal stem cells differentiate into adipocytes. This review discusses adipocytes differentiation and highlights the possible mechanisms of prenatal exposure to endocrine disruptors in reprogramming of adipogenesis and induction of obesity later in life. Therefore, this review provides knowledge that reduction of early life exposure to these chemicals could open the door for new strategies in the prevention of obesity, especially during childhood.

Up-regulation of circulating miRNA146a correlates with viral load via IRAK1 and TRAF6 in hepatitis C virus-infected patients.

BACKGROUND: Hepatitis C virus (HCV) is a life threatening human pathogen. It has been found that miRNA146a regulates innate immunity, inflammatory response and antiviral pathway. We evaluated miRNA146a expression by real-time PCR and IL-1 receptor associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6) levels by ELISA in serum of 36 HCV viremia patients and 42 age and gender matched healthy controls. RESULTS: miRNA146a expression was significantly higher in HCV patients with a best cut off value 1.63 to discriminate between HCV patients and healthy controls. Meanwhile, it was negatively correlated to IRAK1 and TRAF6 levels and positively correlated to viral load in HCV patients. CONCLUSIONS: miRNA146a has a potential role in HCV infection and viral replication through IRAK1 and TRAF6. It can also serve as a new screening method for HCV.

The Association Between Circulating Levels of miRNA-181a and Pancreatic Beta Cells Dysfunction via SMAD7 in Type 1 Diabetic Children and Adolescents.

BACKGROUND: miRNA-181a has been implicated in autoimmunity and apoptosis. Therefore, this study was conducted to explore its possible role in pancreatic beta-cells dysfunction. METHODS: miRNA-181a expression was evaluated by real-time PCR in serum of 40 type 1 diabetic children and adolescents and 40 age- and gender-matched healthy controls. RESULTS: miRNA-181a expression was significantly higher in diabetic children and adolescents and it was negatively correlated to fasting C-peptide and SMAD7 levels. CONCLUSION: miRNA-181a appears to play a potential role in pancreatic beta-cells dysfunction via SMAD7.

Association Between CD14 Polymorphism (-1145G/A) and Childhood Bronchial Asthma.

Polymorphisms in the promoter region of CD14 gene have been associated with asthma and atopy although the findings between cohorts have not been uniform. We aimed at investigating the association between CD14 gene (-1145G/A) polymorphism and bronchial asthma in Egyptian children. Genotyping of CD14 gene (-1145G/A) polymorphism was done by real-time PCR in 192 asthmatic children (atopic, n = 100 and non-atopic, n = 92) and 181 age- and gender-matched healthy children. Serum levels of total IgE were measured by ELISA. Skin prick test was performed on all patients. We found that the frequency of AA genotype was significantly higher in asthmatic children compared to healthy controls. Asthmatic children carrying GG genotype had a significantly lower prevalence of atopic asthma. Meanwhile, the "A" allele was significantly higher in atopic asthmatic children compared to healthy and non-atopic children. Moreover, atopic children carrying the "G" allele showed better asthma control. In conclusion, our findings represent an evidence for the role of CD14 gene (-1145G/A) polymorphism in childhood asthma and asthma control.

The diagnostic efficacy of nectin 4 expression in ovarian cancer patients.

CONTEXT: Nectin 4 plays a significant role in cancer cell growth and invasion. OBJECTIVE: To explore its diagnostic role in ovarian cancer. MATERIALS AND METHODS: Evaluation of nectin 4 expression in ovarian biopsies by real-time PCR and serum nectin 4 and CA-125 by ELISA in 39 ovarian cancer patients, 21 females with benign ovarian neoplasms and 25 control females. RESULTS: Nectin 4 expression was significantly higher in ovarian cancer patients and it was significantly correlated to serum nectin 4 and CA-125. CONCLUSIONS: Ovarian tissue expression and serum nectin 4 appear to be potential markers in ovarian cancer.

Serum level of soluble receptor for advanced glycation end products in asthmatic children and its correlation to severity and pulmonary functions.

BACKGROUND: Soluble receptor for advanced glycation end products (sRAGE) acts as a decoy receptor for RAGE which has several distinct pro-inflammatory ligands in the extracellular compartment, and is believed to afford protection against inflammation and cell injury. This study was conducted to measure serum sRAGE in asthmatic children and to assess its correlation with clinical and functional severity and to asthma phenotype according to sputum cytology. METHODS: The study was conducted on 60 asthmatic children from the Pediatric Chest Clinic, Children's Hospital, Ain Shams University. The patients were divided according to asthma control and severity. RESULTS: sRAGE showed statistically significant lower levels in asthmatic patients (899.1 +/- 399.8 pg/mL) compared to the control group (1406.7 +/- 474.3 pg/mL, p = 0.000), with a cut off value of asthma diagnosis of 1080.4 pg/mL with a sensitivity and specificity of 77% and 75%, respectively. Uncontrolled and severe asthmatic subgroups showed lower levels of sRAGE, cut off value of sRAGE for the severity of asthma was 829 pg/mL with 89% sensitivity and 81% specificity. Asthmatic patients stratified according to sputum cytology revealed that those with > 2% eosinophils and > or = 40% neutrophils showed lower levels of sRAGE (710 +/- 258 pg/mL) compared to those with > 2% eosinophils and < 40% neutrophils (1064 +/- 431 pg/mL) (p = 0.000). There was a highly significant positive correlation between sRAGE levels and FEV 1% (r = 0.41, p < 0.01), a highly significant negative correlation with eosinophilic count and total IgE (r = -0.49 and -0.39, respectively, p < 0.01). CONCLUSIONS: Serum level of sRAGE may correlate with severity of bronchial asthma clinically and functionally. It may be a target of future therapeutic interventions.

Evaluation of nestin in lung adenocarcinoma: relation to VEGF and Bcl-2.

CONTEXT: Nestin is a marker of multipotent precursor cells that is up regulated in cancer. OBJECTIVE: To explore its diagnostic role and its relationship to vascular endothelial growth factor (VEGF) and Bcl-2 in lung adenocarcinoma. MATERIALS AND METHODS: Evaluation of nestin expression in lung biopsies by real-time PCR and serum VEGF and Bcl-2 by ELISA in 27 adenocarcinoma patients and 15 control subjects. RESULTS: Nestin was significantly higher in lung adenocarcinoma patients especially with advanced grade and stage and it was significantly correlated to VEGF and Bcl-2. CONCLUSION: Nestin can be considered as a potential diagnostic marker in lung adenocarcinoma.