Male-biased association of endothelial nitric oxide synthase Asp298Glu substitution (NOS3-c.894G/T) with asthma risk and severity.

OBJECTIVE: The nitric-oxide pathway plays a crucial role in the pathogeneses of asthma and NOS3-encoded endothelial nitric oxide synthase is one of the main components of the pathway. Variants of NOS3 are known to contribute to asthma development and pathophysiology. METHODS: We investigated the association of NOS3-c.894G/T (rs1799983) with asthma risk and severity by studying frequencies of its genotypes and alleles in 555 asthmatics (93 intermittent, 240 mild, 158 moderate, and 64 severe asthma cases) and 351 control participants using the PCR-FRLP method, logistic regression analysis and generalized ordered logit estimates. RESULTS: GT genotype (ORadj: 1.39; CI: 1.04-1.85; p = 0.026), dominant model GT + TT (ORadj: 1.41; CI: 1.07-1.87; p = 0.015), and T allele (ORadj: 1.32; CI: 1.05-1.67; p = 0.018) was associated with increased ORs in asthmatics. Also, the frequency of GT + TT (ORadj: 1.55; CI: 1.01-2.38; p = 0.044) was significantly higher in males. Furthermore, GT genotype (ORadj: 1.39; CI: 1.04-1.85; p = 0.024), GT + TT (ORadj: 1.42; CI: 1.07-1.87; p = 0.014), and T allele (ORadj: 1.32; CI: 1.05-1.66; p = 0.018) in total population and GT + TT (ORadj: 1.56; CI: 1.02-2.37; p = 0.04) in males were significantly associated with increased risk of severe, moderate, mild, intermittent asthma vs. controls. Also, GT genotype (ORadj: 1.39; CI: 1.02-1.91; p = 0.039) was significantly more frequent in severe, moderate grades vs. lower severity grades in the total population. Frequencies of GT genotype (ORadj: 1.77; CI: 1.05-3.00; p = 0.032) and GT + TT (ORadj: 1.74; CI: 1.04-2.90; p = 0.036) in total population and GT genotype (ORadj: 2.40; CI: 1.16-4.97; p = 0.018) and GT + TT (ORadj: 2.30; CI: 1.12-4.74; p = 0.023) in male subpopulation were significantly higher in severe cases compared to lower grades. CONCLUSIONS: NOS3-c.894G/T may be associated with asthma risk and its severer grades, with greater effects in men.

Female-biased association of NOS2-c.1823C>T (rs2297518) with co-susceptibility to metabolic syndrome and asthma.

The nitric oxide (NO) pathway contributes to the pathogeneses of metabolic syndrome (MetS) and asthma. NOS2 encodes inducible-NO synthase, which is an important enzyme of the pathway, and its variations could affect the risk of asthma and MetS and thereby co-susceptibility to them. This study aims to estimate the association of NOS2-c.1823C>T with risk of asthma, MetS, and asthma with MetS condition (ASMetS), and with asthma stages: intermittent, mild, moderate, and severe asthma. The study included asthmatics (n = 555), MetS (n = 334), and ASMetS cases (n = 232) and 351 controls, which were genotyped by the PCR-RFLP method. The T allele was significantly associated with an increased risk of asthma and MetS in the sample population and females. CT genotype and CT+TT model were significantly associated with increased risk of ASMetS in females. A significant association between CT genotype and increased risk of ASMetS in the sample population and females was found in ASMetS versus MetS. In the sample population and among females, the T allele was significantly associated with severe asthma. The rs2297518 single nucleotide polymorphism of NOS2 contributes to the risk of MetS, asthma, and co-susceptibility to them, and this contribution may be stronger in females compared to males.

Long non-coding RNAs as potential biomarkers in the prognosis and diagnosis of lung cancer: A review and target analysis.

Long non-coding RNAs (lncRNA) have been emerged as a novel class of molecular regulators in cancer. They are dysregulated in many types of cancer; however, there is not enough knowledge available on their expression and functional profiles. Lung cancer is the leading cause of the cancer deaths worldwide. Generally, lncRNAs may be associated with lung tumor pathogenesis and they may act as biomarkers for the cancer prognosis and diagnosis. Compared to other invasive prognostic and diagnostic methods, detection of lncRNAs might be a user-friendly and noninvasive method. In this review article, we selected 27 tumor-associated lncRNAs by literature reviewing to further discussing in detail for using as diagnostic and prognostic biomarkers in lung cancer. Also, in an in silico target analysis, the "Experimentally supported functional regulation" approach of the LncTarD web tool was used to identifying the target genes and regulatory mechanisms of the selected lncRNAs. The reports on diagnostic and prognostic potential of all selected lncRNAs were discussed. However, the target genes and regulatory mechanisms of the 22 lncRNAs were identified by in silico analysis and we found the pathways that are controlled by each target group of lncRNAs. They use epigenetic mechanisms, ceRNA mechanisms, protein interaction and sponge mechanism. Also, 10, 23, 5, and 28 target genes for each of these mechanisms were identified, respectively. Finally, each group of target genes controls 50, 12, 7, and 2 molecular pathways, respectively. In conclusion, LncRNAs could be used as biomarkers in lung cancer due to their roles in control of several signaling pathways related to lung tumors. Also, it seems that lncRNAs, which use epigenetic mechanisms for modulating a large number of pathways, could be considered as important subjects for lung cancer-related diagnostic and prognostic biomarkers.

Role of Steroid Therapy after Ischemic Stroke by n-Methyl-d-Aspartate Receptor Gene Regulation.

BACKGROUND: Stroke is the main cause of cerebrovascular disease mortality. Prolonged stimulation of n-methyl-d-aspartate (NMDA) receptor subtypes by the accumulation of glutamate neurotransmitter in the extracellular space after a stroke could activate cell death pathways. It is reported that progesterone provides different mechanisms of neuroprotection and could be considered as a candidate for stroke treatment. This study aimed to investigate progesterone impact on the expression of NMDA receptor subunits NR1, NR2 (A and B), NR3 (A and B) after an experimental model of ischemic stroke which is followed by an in silico analysis. METHODS: Progesterone was introduced subcutaneously after transient middle cerebral artery occlusion in male rats. After a period of reperfusion, a set of behavioral tests was performed to evaluate the postischemic neurological deficits. The 2,3,5-triphenyltetrazolium chloride staining method was done for quantification of infarct volume and gene expression analysis was performed in the penumbra region using reverse transcription polymerase chain reaction for NMDA receptor subunits. An AutoDock tool was employed to perform molecular docking analyses for evaluation of progesterone interaction with NMDA receptor. RESULTS: Cerebral ischemia caused a significant downregulation in NR1, NR2A, NR2B and a profound upregulation of NR3B in cortical penumbra region. Treatment with progesterone resulted in upregulation of NR1, NR2A, and NR3B which could explain a possible the neuroprotection of steroids via binding to NMDA glutamate receptor. In addition, in silico analysis revealed that progesterone could strongly interact with NR1/NR2B and NR2A. CONCLUSION: The findings elucidate a new aspect of the neuroprotective mechanism of progesterone via NMDA receptors gene regulation.

An in silico approach to investigate the source of the controversial interpretations about the phenotypic results of the human AhR-gene G1661A polymorphism.

Aryl hydrocarbon receptor (AhR) acts as an enhancer binding ligand-activated intracellular receptor. Chromatin remodeling components and general transcription factors such as TATA-binding protein (TBP) are evoked on AhR-target genes by interaction with its flexible transactivation domain (TAD). AhR-G1661A single nucleotide polymorphism (SNP: rs2066853) causes an arginine to lysine substitution in the acidic sub-domain of TAD at position 554 (R554K). Although, numerous studies associate the SNP with some abnormalities such as cancer, other reliable investigations refuse the associations. Consequently, the interpretation of the phenotypic results of G1661A-transition has been controversial. In this study, an in silico analysis were performed to investigate the possible effects of the transition on AhR-mRNA, protein structure, interaction properties and modifications. The analysis revealed that the R554K substitution affects secondary structure and solvent accessibility of adjacent residues. Also, it causes to decreasing of the AhR stability; altering the hydropathy features of the local sequence and changing the pattern of the residues at the binding site of the TAD-acidic sub-domain. Generating of new sites for ubiquitination and acetylation for AhR-K554 variant respectively at positions 544 and 560 was predicted. Our findings intensify the idea that the AhR-G1661A transition may affects AhR-TAD interactions, especially with the TBP, which influence AhR-target genes expression. However, the previously reported flexibility of the modular TAD could act as an intervening factor, moderate the SNP effects and causes distinct outcomes in different individuals and tissues.

The c.-190 C>A transversion in promoter region of protamine1 gene as a genetic risk factor for idiopathic oligozoospermia.

The genome condensation in the sperm head is resulted with replacing of histones by protamines during spermatogenesis. It is reported that defects in the protamine 1 (PRM1) and/or 2 (PRM2) genes cause male infertility. Located on chromosome 16 (16p13.2) these genes contain numerous unstudied single nucleotide polymorphisms. This study aimed to investigate the association of c.-190 C>A and g.298 G>C transversions that respectively occur in PRM1 and PRM2 genes with idiopathic oligozoospermia. In a case-control study, we collected blood samples from 130 idiopathic oligozoospermia and 130 fertile men. Detection of c.-190 C>A and g.298 G>C polymorphisms performed by direct sequencing and PCR-RFLP methods respectively. An in silico analysis was performed by ASSP, NetGene 2, and PNImodeler online web servers. Our data revealed that g.298 G>C transversion in PRM2 was not associated with oligozoospermia (P > 0.05). Whereas, -190CA and -190AA genotypes in PRM1 gene were associated significantly with increased risk of oligozoospermia (P = 0.0017 and 0.0103, respectively). Also carriers of A allele (CA+AA) for PRM1 c.-190 C>A were at a high risk for oligozoospermia (OR 3.2440, 95 % CI 1.8060-5.8270, P = 0.0001). Further, in silico analysis revealed that c.-190 C>A transversion may alter transcription factor interactions with the promoter region of PRM1. The results revealed that the c.-190 C>A transversion may involve in the susceptibility for oligozoospermia and could be represented as a noninvasive molecular marker for genetic diagnosis of idiopathic oligozoospermia.

Changes of miR-139-5p, TGFB1, and COL1A1 in the placental tissue of cases with gestational diabetes mellitus.

There are structural changes in the placenta of cases with Gestational Diabetes Mellitus (GDM). TGF-ß and collagen pathways have crucial roles in tissue remodeling and TGF-ß1 and COL1A1 are important genes in these signalling respectively. Also, lncRNA NEAT1, and miRNA hsa-miR-139-5p and hsa-miR-129-5p have regulatory effects on TGF-ß1 and COL1A1. Here we aimed to assess their expressions in the placenta tissue of GDM cases. 30 patients with GDM and 30 healthy pregnant women participated in the study. Placental tissues taken during normal or cesarean delivery were used and total RNA was isolated from the tissues. mRNA levels were determined by qPCR and protein levels were determined by ELISA methods. An in silico analysis was done to elucidate the possible relation of TGF-ß1 and COL1A1 gene networks with GDM. We determined that NEAT1 and miR-129-5p expression levels did not differ between GDM and healthy control groups (p = 0.697 and 0.412, respectively). But, miR-139-5p mRNA level, TGFB1 and COL1A1 protein levels significantly differ between the GDM and control groups (p = 0.000, p = 0.000 and p = 0.001, respectively). The in silico analysis revealed that TGFB1 and COL1A1 genes network may have important role in the GDM with their variety of members and regulatory molecules NEAT1, hsa-miR-139-5p, and hsa-miR-129-5p can control their functions. The expression of TGFB1, COL1A1 and miR-139-5p is changed in placenta tissue of GDM cases and many genes in the interacting networks of TGFB1 and COL1A1 could contribute to the pathogenicity of GDM.

Comparison of moderate-intensity continuous training and high-intensity interval training effects on the Ido1-KYN-Ahr axis in the heart tissue of rats with occlusion of the left anterior descending artery.

Myocardial infarction (MI) affects many molecular pathways in heart cells, including the Ido1-KYN-Ahr axis. This pathway has recently been introduced as a valuable therapeutic target in infarction. We examined the effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on the axis in the heart tissue of male Wistar rats with occluded left anterior descending (OLAD). Thirty rats (age 10-12 weeks, mean weight 275 ± 25 g) were divided into five groups with 6 animals: Control (Ct) group, MICT group, rats with OLAD as MI group, rats with OLAD treated with MICT (MIMCT group) and rats with OLAD treated with HIIT (MIHIIT group). Rats performed the training protocols for 8 weeks, 5 days a week. HIIT included 7 sets of 4 min running with an intensity of 85-90% VO2max and 3 min of recovery activation between sets. MICT included continuous running at the same distance as HIIT with an intensity of 50-60% VO2max for 50 min. The expressions of Ahr, Cyp1a1, and Ido1 were assayed by real-time PCR. Malondialdehyde (MDA) and Kynurenine levels, and AHR, CYP1A1, and IDO1 proteins were detected using ELISA. Data were analyzed using the ANOVA and MANOVA tests. Compared to the CT group, MI caused an increase in all studied factors, but only statistically significant (P < 0.05) for MDA and IDO1. With a greater effect of HIIT, both protocols significantly lowered the proteins expressions in the MIHIIT and MIMCT groups, compared with the MI group (P < 0.001). In healthy rats, only AHR protein significantly decreased in the MICT group compared to the Ct group (P < 0.05). HIIT and MICT protocols significantly reduced the gene and protein expression of Cyp1a1 (P < 0.05) and Ido1 (P < 0.01), and HIIT had a greater effect. In conclusion, both protocols were effective at reducing the levels of Ido1-Kyn-Ahr axis components and oxidative stress in the infarcted heart tissue and HIIT had a higher significant effect.

Synergistic effect of endurance training and nettle leaf extract on the IDO1-KYN-AHR pathway homeostasis and inhibiting of liver toxicity in rats with STZ-induced diabetes.

Introduction: Diabetes adversely affects a number of hepatic molecular pathways, including the kynurenine (KYN) pathway. KYN is produced by indoleamine 2,3-dioxygenase (IDO) and activates the aryl hydrocarbon receptor (AHR). This study evaluated the effect of endurance training (EndTr) and nettle leaf extract (NLE) on the IDO1-KYN-AHR pathway in the livers of rats with streptozotocin-induced diabetes. Methods: We divided 48 rats into six groups: controls (Ct), treated with EndTr (EndTr), diabetes-induced (D), D treated with NLE (D + NLE), D treated with EndTr (D + EnTr), and D treated with EndTr and NLE (D + EndTr + NLE). EndTr, D + EnTr, and D + EndTr + NLE groups were subjected to training with running on treadmill for 8 weeks, 5 days per week, 25 min in first session to 59 min at last session with intensity of 55% to 65% VO2max. Using real-time PCR gene (Ahr, Cyp1a1, and Ido1) expressions and ELISA, malondialdehyde (MDA) and protein (IDO1, AHR, and CYP1A1) levels were determined in the liver samples. Results: A significant three-way interaction of exercise, nettle, and diabetes was observed on the all variables (P< 0.001). In particular, significant increases in blood glucose level (BGL), in gene and protein expression, and in MDA and KYN levels were observed in the liver samples of the D group versus the Ct group (P< 0.05). BGL and liver MDA levels were significantly lower in the D + EndTr and D + NLE groups than that in the D group. However, the D + EndTr + NLE group showed a more significant decrease in these factors (P< 0.05). In addition, liver KYN levels were significantly lower in the EndTr group compared with that in the Ct group as well as in the D + EndTr + NLE and D + EndTr groups compared with that in the D groups (P< 0.05). Whereas both the EndTr and D + NLE groups showed lower Ahr expression and AHR level compared with the Ct and D groups, respectively (P< 0.05), the D + EndTr + NLE group showed a higher significant reduction in the AHR level than the D group (P< 0.05). The Cyp1a1 expression and IDO1 level significantly decreased only in the D + EndTr + NLE group compared to that in the D group (P< 0.05). Conclusion: Overall, this study showed that the combination of EndTr and NLE may synergistically restore the imbalanced IDO1-KYN-AHR pathway in diabetic liver.

Oxidative stress indices induced by industrial and urban PM2.5-bound metals in A549 cells.

The detrimental effects of atmospheric fine particulate matter (PM2.5) on human health are of major global concern. PM2.5-bound metals are toxic compounds that contribute to cellular damage. To investigate the toxic effects of water-soluble metals on human lung epithelial cells and their bioaccessibility to lung fluid, PM2.5 samples were collected from both urban and industrial areas in the metropolitan city of Tabriz, Iran. Oxidative stress indices, including proline content, total antioxidant capacity (TAC), cytotoxicity, and DNA damage levels of water-soluble components of PM2.5, were evaluated. Furthermore, an in vitro test was conducted to assess the bioaccessibility of various PM2.5-bound metals to the respiratory system using simulated lung fluid. PM2.5 average concentrations in urban and industrial areas were 83.11 and 97.71 µg/m3, respectively. The cytotoxicity effects of PM2.5 water-soluble constituents from urban areas were significantly higher than in industrial areas and the IC50 was found to be 96.76 ± 3.34 and 201.31 ± 5.96 µg/mL for urban and industrial PM2.5 samples, respectively. In addition, higher PM2.5 concentrations increased the proline content in a concentration-dependent manner in A549 cells, which plays a protective role against oxidative stress and prevents PM2.5-induced DNA damage. Also, the partial least squares regression revealed that Be, Cd, Co, Ni, and Cr, were significantly correlated with DNA damage and proline accumulation, which caused cell damage through oxidative stress. The results of this study showed that PM2.5-bound metals in highly polluted metropolitan city caused substantial changes in the cellular proline content, DNA damage levels and cytotoxicity in human lung A549 cells.

Economic Burden of Asthma in Northwest Iran.

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 (ß=3.29, P<0.001), and between severe asthma and indirect costs (ß=32.36, P<0.001) was observed. Conclusion: High costs are incurred by Iranian asthma patients, especially because of impairment-related productivity loss at work associated with asthma exacerbation.

Efficacy of Analytical Technologies in Metabolomics Studies of the Gastrointestinal Cancers.

According to the reports of the World Health Organization and the International Agency for Research on Cancer, cancer is the second leading cause of human death worldwide. However, early-stage detection of cancers can efficiently enhance the chance of therapy and saving lives. Metabolomics strategies apply a variety of approaches to discover new potential diagnoses, prognoses, and/or therapeutic biomarkers of various diseases. Metabolomics aims to identify and measure different low-molecular-weight biomolecules in physiological environments. In these studies, special metabolites are extracted from biological samples and identified using analytical techniques. Afterward, using data processing programs discovering significantly associated biomarkers is pursued. In the present review, we aimed to discuss recently reported analytical approaches on the metabolomics studies of gastrointestinal cancers including gastric, colorectal, and esophageal cancers. The gas- and liquid-chromatography with different detectors have been shown that are the main analytical techniques and for metabolites quantification, nuclear magnetic resonance has been utilized as a master method.

A Review of Substrates for Solid-State Fermentation of Lingzhi or Reishi Medicinal Mushroom, Ganoderma lucidum (Agaricomycetes), for Basidiome Production and Effect on Bioactive Compounds.

Mushrooms in the genus Ganoderma have been collected and used as medicine since ancient times. However, commercial basidiome production has only recently been achieved. The solid substrates for basidiome production usually consist of lignocellulosic materials as the major component and the supplements (e.g., different types of bran and flour) as the minor segment. Research on substrates for solid-state fermentation with the purpose of basidiome production has focused on investigating locally available agrowaste materials, and their suitability is judged by the economic outputs. This review summarizes the formulations of the substrates and discusses their effects on the yield of basidiome or its bioactive compounds. Through a comprehensive look, this review concludes that future research focused on various treatments to modulate extracellular enzyme production may bring more options to the table for innovative solid substrate formulation.

The oxidative and neurotoxic potentials of the ambient PM2.5 extracts: The efficient multi-solvent extraction method.

The health effects of ambient air particulate matter with a diameter of ≤2.5 µm (PM2.5) on the central nervous system are well known and the induced oxidative stress has been shown as their main neuropathologic outcome. Ambient air PM2.5 sampling methods mostly use air sampler systems that collect PM2.5 on filters, which is followed by a PM2.5 extraction approach. Inefficient extraction may lead to compositional bias and unreal interpretation of the results. This study aimed to compare our proposed multi-solvent extraction (MSE) approach for PM2.5 extraction with a conventional aqueous extraction (AqE) method using the analysis of oxidative effects and cytotoxicity in the human neuroblastoma SH-SY5Y cell line. Ambient PM2.5 samples were collected from an urban traffic location in Tehran city, the capital of Iran, using a high-volume sampler. The developed MSE method was proved to have superior advantages over the AqE method including an increased extraction efficiency (as much as 96 against 48% for PMms and PMaq, respectively), and decreased artifacts and compositional biases. Ambient PM2.5, besides PMms and PMaq were analyzed for water-soluble ions, metals, and major elements. Dithiothreitol, ascorbic acid, lipid peroxidation, and cell viability assays on SH-SY5Y cells represented the significantly higher oxidative potential for PMms compared to PMaq. The increased cytotoxicity may occur because of the increased oxidative potential of PMms and possibly is associated with higher efficiency of the MSE over the AqE method for removal of total redox-active PM components.

Polymorphism (-499C/G) in DDAH2 promoter may act as a protective factor for metabolic syndrome: A case-control study in Azar-Cohort population.

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. 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.

Association Between NOX4 And Nrf2 Genes in Non-Small-Cell Lung Carcinoma: A Case-Control Study.

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). CONCLUSION: 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.

Identifying Potential miRNA Biomarkers for Gastric Cancer Diagnosis Using Machine Learning Variable Selection Approach.

Aim: This study aimed to accurately identification of potential miRNAs for gastric cancer (GC) diagnosis at the early stages of the disease. Methods: We used GSE106817 data with 2,566 miRNAs to train the machine learning models. We used the Boruta machine learning variable selection approach to identify the strong miRNAs associated with GC in the training sample. We then validated the prediction models in the independent sample GSE113486 data. Finally, an ontological analysis was done on identified miRNAs to eliciting the relevant relationships. Results: Of those 2,874 patients in the training the model, there were 115 (4%) patients with GC. Boruta identified 30 miRNAs as potential biomarkers for GC diagnosis and hsa-miR-1343-3p was at the highest ranking. All of the machine learning algorithms showed that using hsa-miR-1343-3p as a biomarker, GC can be predicted with very high precision (AUC; 100%, sensitivity; 100%, specificity; 100% ROC; 100%, Kappa; 100) using with the cut-off point of 8.2 for hsa-miR-1343-3p. Also, ontological analysis of 30 identified miRNAs approved their strong relationship with cancer associated genes and molecular events. Conclusion: The hsa-miR-1343-3p could be introduced as a valuable target for studies on the GC diagnosis using reliable biomarkers.

Recovery scenario and immunity in COVID-19 disease: A new strategy to predict the potential of reinfection.

Background: The recent ongoing outbreak of coronavirus disease 2019 (COVID-19), still is an unsolved problem with a growing rate of infected cases and mortality worldwide. The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is targeting the angiotensin-converting enzyme 2 (ACE2) receptor and mostly causes a respiratory illness. Although acquired and resistance immunity is one of the most important aspects of alleviating the trend of the current pandemic; however, there is still a big gap of knowledge regarding the infection process, immunopathogenesis, recovery, and reinfection. Aim of Review: To answer the questions regarding "the potential and probability of reinfection in COVID-19 infected cases" or "the efficiency and duration of SARS-CoV-2 infection-induced immunity against reinfection" we critically evaluated the current reports on SARS-CoV-2 immunity and reinfection with special emphasis on comparative studies using animal models that generalize their finding about protection and reinfection. Also, the contribution of humoral immunity in the process of COVID-19 recovery and the role of ACE2 in virus infectivity and pathogenesis has been discussed. Furthermore, innate and cellular immunity and inflammatory responses in the disease and recovery conditions are reviewed and an overall outline of immunologic aspects of COVID-19 progression and recovery in three different stages are presented. Finally, we categorized the infected cases into four different groups based on the acquired immunity and the potential for reinfection. Key Scientific Concepts of Review: In this review paper, we proposed a new strategy to predict the potential of reinfection in each identified category. This classification may help to distribute resources more meticulously to determine: who needs to be serologically tested for SARS-CoV-2 neutralizing antibodies, what percentage of the population is immune to the virus, and who needs to be vaccinated.

Association of NOS3-c.894G>T transversion with susceptibility to metabolic syndrome in Azar-cohort population: A case-control study and in silico analysis of the SNP molecular effects.

OBJECTIVES: 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.

Refinement of coding SNPs in the human aryl hydrocarbon receptor gene using ISNPranker: An integrative-SNP ranking web-tool.

Different bioinformatic methods apply various approaches to predict how much the effect of a SNP could be deleterious and therefore their results may differ significantly. However, variation studies often need to consider an integrated prediction result to analyze the effect of SNPs. To address this problem, we used an algorithm to map ordinal predictions to a numeral space and averaging them, and based on it we developed the ISNPranker web-tool (http://isnpranker.semilab.ir/). It takes heterogonous outputs of different predictors and generates integrated numerical predictions and ranks SNPs based on them. Afterward, we used ISNPranker to identify the most deleterious coding SNPs (cSNPs) of the human aryl hydrocarbon receptor (AHR) gene. AHR is a ligand-activated transcription factor that governs many molecular and cellular mechanisms and cSNPs may affect its structure, interactions, and function. Forty validated cSNPs of AHR were initially analyzed using 16 publicly available SNP analyzers and the results were introduced to the ISNPranker and integrated predictions were obtained. The cSNPs were ranked in 34 levels of danger and rs200257782 in the ARNT dimerization domain (ADD121-289) of AHR was identified as the most deleterious cSNP. The rs148360742, which affect ADD40-79 and Hsp90 binding domain (HBD27-79) was in the second rank and the third and fourth ranks were occupied by ADD121-289-located variations rs571123681 and rs141667112 respectively. In conclusion, we introduced ISNPranker, which is a web-tool for integrative ranking of SNPs, and we showed that AHR structure and function may be highly sensitive to the cSNPs in the ARNT dimerization domain.