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Abstract Severe asthma is a chronic inflammatory airway disease with great therapeutic challenges. Understanding the genetic and molecular mechanisms of severe asthma may help identify therapeutic strategies for this complex condition. RNA expression data were analyzed using a combination of artificial intelligence methods to identify novel genes related to severe asthma. Through the ANOVA feature selection approach, 100 candidate genes were selected among 54,715 mRNAs in blood samples of patients with severe asthmatic and healthy groups. A deep learning model was used to validate the significance of the candidate genes. The accuracy, F1-score, AUC-ROC, and precision of the 100 genes were 83%, 0.86, 0.89, and 0.9, respectively. To discover hidden associations among selected genes, association rule mining was applied. The top 20 genes including the PTBP1, RAB11FIP3, APH1A, and MYD88 were recognized as the most frequent items among severe asthma association rules. The PTBP1 was found to be the most frequent gene associated with severe asthma among those 20 genes. PTBP1 was the gene most frequently associated with severe asthma among candidate genes. Identification of master genes involved in the initiation and development of asthma can offer novel targets for its diagnosis, prognosis, and targeted-signaling therapy.

Background: The economic burden of asthma is a major public health concern. This study estimates the economic burden of asthma in Northwest of Iran.Methods: A longitudinal study was conducted between 2017 and 2018 in Tabriz, Iran using the Persian version of the Work Productivity and Activity Impairment (WPAI) questionnaire. Direct and indirect costs associated with asthma were estimated based on the societal perspective, prevalence-based approach, and bottom-up method. Annual indirect costs were estimated using the human capital (HC) method. The structural equation model was used to evaluate the relationship between costs, sex, and asthma severity. Results: A total of 621 patients with asthma were enrolled in the study. Significant differences were found between female and male patients for the mean cost of radiology (P=0.006), laboratory (P=0.028), and diagnostic (P=0.017) tests at baseline, and for laboratory (P=0.012), and diagnostic (P=0.027) tests at one-year follow-up. The more severe asthma, the more significant the costs for annual physician office visits (P=0.040) and medications (P=0.013). As asthma severity increased, significantly higher expenditures were observed in women for days lost from work at baseline (P=0.009) and one-year follow-up (P=0.001), and in men for productivity loss at work due to impairment at baseline (P=0.045). A significant association between indirect costs and the cost of impairment-related lost productivity at work (β=3.29, P

ABSTRACT Objective: Globally developing metabolic syndrome (MetS) prevalence as a major health problem can be related to multiple factors of genetic and environmental. Dimethylaminohydrolase 2 (DDAH2) is the main enzyme implicated in the cardiovascular system, which regulates the nitric oxide pathway. This study investigated the association of DDAH2 polymorphism −499C/G (rs805305) with the risk of MetS among the Azar-Cohort population. Subjects and methods: The occurrence of SNP rs805305 in the DDAH2 gene was tested using the PCR-RFLP method in 332 MetS cases and 294 healthy controls. Afterward, the association of the allele and genotypes with the risk of MetS and its components were examined. Results: The G allele and GC genotype were significantly associated with a reduced risk of MetS (P ≤ 0.001). Also, the dominant genetic model (GG+GC) significantly decreased the risk of MetS (P = 0.001), however, in sex subtypes MetS risk was significantly reduced in males before and in females after adjustment for age (P ≤ 0.02). Conclusion: The −499C/G polymorphism of DDAH2 may play a protective role and reduce MetS risk among the Azar-Cohort population.

Objective(s): We investigated whether NOS3-c.894G>T transversion (rs1799983), which causes the substitution of glutamate with aspartate (E298D) in the oxygenase domain of endothelial nitric oxide synthase (eNOS), is associated with susceptibility to metabolic syndrome (MetS) risk in Iranian-Azerbaijanis. Materials and Methods: The frequencies of the alleles and genotypes were compared in the 300 cases and 300 controls using PCR-RFLP assay. Also, higher-order MetS interaction with the genotypes, gender, age, and body mass index (BMI) was evaluated by classification and regression tree (CART) analysis. In silico analysis was done to introduce a hypothesis describing the molecular effects of NOS3-c.894G>T. Results: The T allele (OR:1.46; CI:1.054-2.04; P=0.02), GT genotype (OR:1.44; CI:1.02-2.03; P=0.03), and dominant model (TT+GT vs GG, OR:1.48; CI:1.06-2.06; P=0.01) were found to be associated with increased risk of MetS. In the male subpopulation TT genotype (OR:7.19; CI:1.53-33.70; P=0.01) was discovered to be associated with increased odds of MetS. CART analysis showed that NOS3-c.894G>T genotypes and BMI significantly contribute to modulating MetS risk. Furthermore, in silico investigation revealed that c.894G>T may alter eNOS function through affecting interactions of its oxygenase domain with proteins such as B2R, b-actin, CALM1, CAV1, GIT1, HSP90AA1, NOSIP, and NOSTRIN. Conclusion: We showed that NOS3-c.894G>T was associated with an increased risk of MetS in Iranian-Azerbaijanis, and BMI modulates the effects of NOS3-c.894G>T genotypes on MetS risk. Also, in silico analysis found that NOS3-c.894G>T may affect the interaction of the eNOS oxygenase domain with its several functional partners.

Background: Recent evidence underscores to the important regulatory roles of microRNAs as a biomarker for diagnosis of non-small cell lung cancer (NSCLC); this disease often has poor prognosis, and it is the most prevalent cause of cancer-related mortality worldwide. This study investigated the levels of miR-146a-5p and miR-196a-2 in peripheral blood mononuclear cells (PBMC). Methods: In the present case-control research, we collected the PBMCs through isolating blood from 22 NSCLC patients and 22 healthy individuals. Following the extraction of total RNA and cDNA synthesis, we studied the expression levels of miR-146a and miR-196a-2 by using qPCR. Results: Both the miR-146a-5p and miR-196a-2 were significantly down-regulated in the PBMCs of NSCLC patients in comparison with normal healthy ones (P=0.002 and p

Background: Understanding the contributing of influence inflammatory biomarkers in asthmatic patients with metabolic syndrome is more important. Whereby, the present study considering the important association of NADPH oxidase4 (NOX4) and Toll- like receptor4 (TLR4) in the respiratory inflammatory responses in asthmatic patients with metabolic syndrome (AS-MetS) and asthmatic (AS) patients. Materials and Methods: In this case-control study, 30 AS and 34 AS-MetS patients were enrolled. The Peripheral blood mononuclear cells (PBMCs) mRNA and protein levels of TLR4 and NOX4 were measured by qRT-PCR and western blot, respectively. Then their correlation was evaluated. Results: The significant down-regulation of mRNA and protein PBMCs expression levels of TLR4 were observed in the AS-MetS group in comparison to AS one (P=0.03), but the NOX4 expression was non-significant. Additionally, the significant correlation was exhibited between mRNA expression levels of NOX4 and TLR4 in both AS-MetS (r= 0.440, P=0.009) and AS groups (r=0.909, P=0.0001). The association between TLR4 mRNA level and triglyceride in AS-MetS group (r=0.454, P=0.008,) and also white blood cells (WBC) in AS group (r= -0.507, P=0.006,) were significant. Conclusion: The metabolic syndrome can significantly influence the expressions of TLR4 in AS-MetS. This study indicated that TLR4 and NOX4 altogether may provide valuable molecular knowledge of their relation with metabolic syndrome criteria for finding major pathways in different phenotype of asthma.

The effects of hesperetin plus naringenin, orange juice and grapefruit juice on mRNA expression of TNF-α, TGF-β1 and TTF-1 in a house dust mite (HDM)-induced asthma animal model were investigated. Interventional mice exposed to HDM for 6 weeks received hesperetin plus naringenin, orange plus grapefruit juice, orange juice, grapefruit juice or water during the last 4 weeks, whereas non-asthmatic control mice consumed water. Lung tissue TNF-α and TGF-β1 expressions in supplemented groups were significantly reduced (p

Severe asthma is a chronic inflammatory airway disease with great therapeutic challenges. Understanding the genetic and molecular mechanisms of severe asthma may help identify therapeutic strategies for this complex condition. RNA expression data were analyzed using a combination of artificial intelligence methods to identify novel genes related to severe asthma. Through the ANOVA feature selection approach, 100 candidate genes were selected among 54,715 mRNAs in blood samples of patients with severe asthmatic and healthy groups. A deep learning model was used to validate the significance of the candidate genes. The accuracy, F1-score, AUC-ROC, and precision of the 100 genes were 83%, 0.86, 0.89, and 0.9, respectively. To discover hidden associations among selected genes, association rule mining was applied. The top 20 genes including the PTBP1, RAB11FIP3, APH1A, and MYD88 were recognized as the most frequent items among severe asthma association rules. The PTBP1 was found to be the most frequent gene associated with severe asthma among those 20 genes. PTBP1 was the gene most frequently associated with severe asthma among candidate genes. Identification of master genes involved in the initiation and development of asthma can offer novel targets for its diagnosis, prognosis, and targeted-signaling therapy. [ABSTRACT FROM AUTHOR]

Background: Epithelial malignancy in lung cancer, which is initiated with myofibroblast differentiation and remodeling, promotes hypoxia and intracellular ROS generation most affected by the prototypical enzyme, NADPH oxidase 4 (NOX4). In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) acts as a critical transcription factor by stimulating antioxidant proteins as redox homeostasis regulators. The aim of this study was to investigate a possible correlation between lung tissue NOX4 and Nrf2 genes (NOX4 and Nrf2) mRNA expression and bronchoalveolar lavage fluid (BALF) protein expression in non-small-cell lung carcinoma (NSCLC) patients. Methods: Samples from 25 patients with various NSCLC types and stages and 20 healthy controls were collected. NOX4 and Nrf2 mRNA were measured by qRT-PCR, and protein by western blot analysis. Results: NOX4 mRNA and protein expression was significantly up-regulated in NSCLC patients' lung tissues and BALFs (p= 0.03 and 0.01, respectively). In addition, by adjusting for age, sex, and NSCLC types and stages, a significant and positive correlation was observed between NOX4 and Nrf2 mRNA expression (r= 0.927, p= 0.001). This was also true when not adjusted as above (r= 0.944, p< 0.001). Conclusions: NOX4 mRNA and protein expression is significantly up-regulated in NSCLC patients' lung tissues and BALFs, and NOX4 and Nrf2 mRNA expression is positively correlated in NSCLC tissues. [ABSTRACT FROM AUTHOR]

However, the eNOS-298D variant had slightly changed RMSD when it submitted as a ligand in eNOS-298E/ eNOS-298D (RMSD=0.29) or eNOS-298D/eNOS-298D dimer (RMSD=0.31). STRING identified 11 eNOS-interacting proteins, among which literature search showed, four proteins CAV1 (37), HSP90AA1 (38), CALM1 (39), and NOSTRIN (40) bound to eNOS through its oxygenase domain. Also, RMSD (Root mean square deviation) of eNOS-298E variant in both eNOS-298E/eNOS-298E and eNOS-298D/eNOS-298E dimers was the same (0.32). However, by reviewing the literature it is concluded that among STRING-reported functional partners of eNOS, CAV1 (37), HSP90AA1 (38), CALM1 (39), and NOSTRIN (40) interact directly with the eNOS oxygenase domain Docking Docking energy score Ligand RMSD (Å) Receptor Ligand eNOS-298E eNOS-298E-1036.83 0.32 eNOS-298E eNOS-298D-968.28 0.29 eNOS-298D eNOS-298E-1012.05 0.32 eNOS-298D eNOS-298D-1037.89 0.31 Figure 8. [Extracted from the article]

Background: Recent evidence underscores to the important regulatory roles of microRNAs as a biomarker for diagnosis of non-small cell lung cancer (NSCLC); this disease often has poor prognosis, and it is the most prevalent cause of cancerrelated mortality worldwide. This study investigated the levels of miR-146a-5p and miR-196a-2 in peripheral blood mononuclear cells (PBMC). Methods: In the present case-control research, we collected the PBMCs through isolating blood from 22 NSCLC patients and 22 healthy individuals. Following the extraction of total RNA and cDNA synthesis, we studied the expression levels of miR-146a and miR-196a-2 by using qPCR. Results: Both the miR-146a-5p and miR-196a-2 were significantly down-regulated in the PBMCs of NSCLC patients in comparison with normal healthy ones (P=0.002 and P<0.001, respectively). There was an association between the expression levels of microRNAs and the types of tumors, which was significant for miR-146a-5p (P=0.02). Furthermore, in NSCLC cases, a significant positive correlation existed between miR-196a-2 and miR-146a-5p expression levels (r=0.71, P=0.002). Conclusion: According to the study results, miR-146a-5p and miR-196a-2 that were down-regulated in the PBMCs of NSCLC patients might serve as potential biomarkers for diagnosis if confirmed in future studies. [ABSTRACT FROM AUTHOR]

Background: The relationship between dietary pattern and the risk of chronic obstructive pulmonary disease (COPD) has been described; however, the exclusive role of dietary factors remains controversial. Hence, we conducted this systematic meta-analysis to clarify the role of some nutrients and antioxidant vitamins in the risk of COPD. Materials and Methods: PubMed, Embase, and Scopus databases were searched for studies evaluating the associations between COPD outcome measures, symptoms, and mortality, and intake of fruits and vegetables, fiber, fish, n-3 or n-6 fatty acids, and antioxidant vitamins in adults. The randomeffect model meta-analyses were used to pool the results. Results: Ten cohort, six case-control, and 20 cross-sectional studies were identified. The pooled relative risks (RRs) of the COPD and confidence intervals (CIs) for the highest intake group compared with the lowest intake group were 0.74 (95% CI: 0.65-0.85) for fruit, 0.65 (95% CI: 0.55-0.78) for dietary fiber, 0.71 (95% CI: 0.58-0.85) for fish, and 0.89 (95% CI: 0.76-0.99) for vitamin C. No association was observed between the risk of COPD and the intake of vegetables, n-3 f atty a cids, v itamin E, a nd ß -carotene; however, it was associated with n-6 fatty acids 1.06 (95% CI: 0.87-1.30). Conclusion: The results suggested that a higher intake of fruits, probably dietary fiber, and fish reduce the risk of COPD. [ABSTRACT FROM AUTHOR]

Background: Understanding the contributing of influence inflammatory biomarkers in asthmatic patients with metabolic syndrome is more important. Whereby, the present study considering the important association of NADPH oxidase4 (NOX4) and Toll- like receptor4 (TLR4) in the respiratory inflammatory responses in asthmatic patients with metabolic syndrome (AS-MetS) and asthmatic (AS) patients. Materials and Methods: In this case-control study, 30 AS and 34 AS-MetS patients were enrolled. The Peripheral blood mononuclear cells (PBMCs) mRNA and protein levels of TLR4 and NOX4 were measured by qRT-PCR and western blot, respectively. Then their correlation was evaluated. Results: The significant down-regulation of mRNA and protein PBMCs expression levels of TLR4 were observed in the AS-MetS group in comparison to AS one (P=0.03), but the NOX4 expression was non-significant. Additionally, the significant correlation was exhibited between mRNA expression levels of NOX4 and TLR4 in both AS-MetS (r= 0.440, P=0.009) and AS groups (r=0.909, P=0.0001). The association between TLR4 mRNA level and triglyceride in AS-MetS group (r=0.454, P=0.008,) and also white blood cells (WBC) in AS group (r= -0.507, P=0.006,) were significant. Conclusion: The metabolic syndrome can significantly influence the expressions of TLR4 in AS-MetS. This study indicated that TLR4 and NOX4 altogether may provide valuable molecular knowledge of their relation with metabolic syndrome criteria for finding major pathways in different phenotype of asthma. [ABSTRACT FROM AUTHOR]