Promoter of lncRNA MORT is aberrantly methylated in colorectal cancer.

Aberrant DNA methylation plays essential roles in the colorectal cancer (CRC) carcinogenesis and has been demonstrated as a promising marker for cancer early detection. In this project, methylation status of the MORT promoter was studied in CRC and their marginal tissues using qMSP assay. Furthermore, we investigated the molecular function of MORT in CRC progression using computational analysis. The results showed a high methylation level of MORT promoter in CRC tissues. By in silico analysis, we found that MORT downregulation could promote the proliferation of CRC cells via sponging of has-miR-574-5p and has-miR-31-5p, and alteration of their targets expression pattern such as MYOCD and FOXP2. In conclusion, based on our results, promoter hypermethylation of MORT might be considered as a potential biomarker for CRC detection.

Aerobic Training with Naringin Supplementation Improved Spatial Cognition via H2S Signaling Pathway in Alzheimer's Disease Model Rats.

OBJECTIVES: This study examined the effects of one-month naringin administration and exercise training on cognitive impairment and H2S signaling pathway in an Amyloid ß (Aß)-injected rat. METHODS: Rats were divided into four groups: control group; rats underwent Aß microinjection surgery, exercise group; rats underwent Aß microinjection surgery and trained by treadmill for four weeks, naringin group; rats underwent Aß microinjection surgery, and rats orally administrated 80 mg.kg-1 naringin for four weeks, naringin+exercise group; rats underwent Aß microinjection surgery and were trained by treadmill for four weeks, and also, rats orally administrated 80 mg.kg-1 naringin for four weeks. After one month of treatment, spatial learning and memory were measured, and then hippocampi were sampled. S-adenosylmethionine (SAM), cystathionine-ß-synthase (CBS), hydrogen sulfide (H2S) levels, and neuronal death were detected in the hippocampi of rats. RESULTS: Naringin and exercise improved spatial learning (latency time, P < .001) and memory (P < .001) in the Morris Water Maze test in Aß-injected rats compared with the control group. SAM (P < .01), CBS (P < .001), and H2S (P < .01) levels are increased in the naringin+exercise group compared with the control group. CONCLUSION: The result of this study supports the effect of exercise and/or naringin to improve cognitive dysfunction and cell death through the production of H2S.

Potential of hsa-miR200a-3p and hsa-miR502-3p as blood-based biomarker for Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is one of the most important known dementia which affects thousands of people every year. Many factors are involved in this process, such as aberrant expression of miRNAs. METHODS AND RESULTS: Firstly, we analyzed two microarray datasets related to AD (GSE48552, GSE129053) to identify the differentially expressed miRNAs, and two miRNAs were selected for further validation. Dataset analysis showed that the expression of hsa-miR200a-3p and hsa-miR502-3p were up-regulated in AD. These findings were validated in plasma samples by qRT-PCR. ROC curve analysis showed that plasma levels of both miRNAs might discriminate the AD and healthy controls. In addition, in silico analysis revealed that the upregulation of these miRNAs could promote AD progression via affecting the expression of target molecules mainly ATF6 and dynactin. CONCLUSION: Totally, hsa-miR200a-3p and hsa-miR502-3p are upregulated in AD and their plasma levels can discriminate AD and healthy people, highlighting their potential as blood-based biomarker for AD.

Aberrant expression of lncRNAs SNHG6, TRPM2-AS1, MIR4435-2HG, and hypomethylation of TRPM2-AS1 promoter in colorectal cancer.

Accumulating evidence has indicated that deregulation of lncRNAs plays essential roles in colorectal cancer (CRC) carcinogenesis. The goal of this study was to analyze the expression of lncRNAs in colorectal cancer and their association with clinicopathological variables. Bioinformatics analysis of published CRC microarray data was performed to identify the important lncRNAs. The expression levels of candidate genes were assessed in the human colon cancer/normal cell lines, CRC, adenomatous colorectal polyps, and their marginal tissues by qRT-PCR. Moreover, the methylation status of the TRPM2-AS1 promoter was studied using qMSP assay. Furthermore, we investigated the molecular mechanisms of these lncRNAs in CRC progression using in silico analysis. Microarray analysis revealed that lncRNAs SNHG6, MIR4435-2HG, and TRPM2-AS1 were upregulated in CRC. These results were validated in colon cell lines. Moreover, qRT-PCR showed that the expression levels of SNHG6 and TRPM2-AS1 were upregulated in the colorectal tumor tissues compared with their paired tissues. Nonetheless, there was no significant increase in MIR4435-2HG expression in CRC samples. Furthermore, we observed a significant hypomethylation of TRPM2-AS1 promoter and its activation in CRC tissues. By in silico analysis, we found that the lncRNAs upregulation could promote proliferation and drug resistance of colorectal cancer cells via miRNAs sponging and modulation of their targets expression. In conclusion, based on our results upregulation of SNHG6 and TRPM2-AS1, and hypomethylation of TRPM2-AS1 promoter might be considered as potential diagnostic biomarkers for CRC initiation and development.

Long non-coding RNA AGAP2-AS1 is up regulated in colorectal cancer.

Accumulating evidence has indicated that, aberrant lncRNA expression plays essential roles in the colorectal cancer (CRC) tumorigenesis. AGAP2-AS1 is upregulated in some cancers, however, its involvement in the CRC tumorigenesis in the population of North-West of Iran has remained unknown. In this study, we evaluated its deregulation in CRC microarray datasets, colon cell lines, CRC tumor, adenomatous colorectal polyps and their paired normal tissues. The results showed that AGAP2-AS1 is upregulated in CRC and might be considered as a potential biomarker for CRC development. Moreover, our results suggest AGAP2-AS1 promoted CRC progression by sponging the hsa-miR-15/16 family and upregulation of their targets.

Correlation between expression levels of lncRNA FER1L4 and RB1 in patients with colorectal cancer.

Colorectal cancer (CRC) is a major life-threatening malignancy. Studies demonstrated the lncRNA fer-1 like family member 4 (FER1L4) was downregulated in different cancers and its expression was positively correlated with the retinoblastoma 1 (RB1) mRNA in a competing endogenous RNAs network. We investigated expression levels of FER1L4 and RB1 in patients with colorectal cancer. 50 paired colorectal tumors and non-tumor marginal tissues, 30 paired adenomatous colorectal polyps (ACPs) and matched adjacent normal tissues were obtained from the patients. Total RNA was extracted from the samples and cDNAs were synthesized. Their expression was quantified by qRT-PCR. Correlation between FER1L4 and RB1 expression levels was analyzed by Pearson correlation test. Finally, ROC curve analysis was used to evaluate their biomarker potency. We observed significant downregulation of FER1L4, but upregulation of RB1 in the colorectal tumors compared with non-tumor and the polyp tissues. However, RB1 expression was positively correlated with FER1L4 expression both in the tumor and polyp samples. ROC curve analysis showed both FER1L4 and RB1 expression levels could discriminate tumor from non-tumor and tumor from polyp samples. None of the clinicopathological characteristics of patients were associated with FER1L4 or RB1 expression levels. Despite the downregulation of FER1L4 and upregulation of RB1 in tumors compared with non-tumor tissues, the expression of RB1 was positively correlated with the expression of FER1L4 in the colorectal tumor as well as in the polyp tissues. FER1L4 expression level might be considered as a potential biomarker for colorectal cancer development.

Long Noncoding RNAs in Gastrointestinal Cancer: Tumor Suppression Versus Tumor Promotion.

Approximately 80% of the human genome harbors biochemical marks of active transcription that its majority transcribes to noncoding RNAs, namely long noncoding RNAs (lncRNAs). LncRNAs are heterogeneous RNA transcripts that regulate critical biological processes such as cell survival and death. They involve in the progression of different cancers by affecting transcriptional and post-transcriptional modifications as well as epigenetic control of numerous tumor suppressors and oncogenes. Recent findings show that aberrant expression of lncRNAs is associated with tumor initiation, progression, invasion, and overall survival of patients with gastrointestinal (GI) cancers. Some lncRNAs play as tumor suppressors in all GI cancers, but others play as tumor promoters. However, some other lncRNAs might function as a tumor suppressor in one GI cancer, but as a tumor promoter in another GI cancer type. This fact highlights possible context dependency of the expression patterns and roles of at least some lncRNAs in GI cancer development and progression. Here, we review the functional relation of lncRNAs involved in the development and progression of GI cancer by focusing on their roles as tumor suppressor and tumor promoter genes.

lncRNA-miRNA-mRNA interaction network for colorectal cancer; An in silico analysis.

BACKGROUND: Colorectal cancer (CRC) is one of the most frequent and diagnosed diseases. Accumulating evidences showed that mRNAs and noncoding RNAs play important regulatory roles in tumorigenesis. Identification and determining the relationship between them can help diagnosis and treatment of cancer. METHODS: Here we analyzed three microarray datasets; GSE110715, GSE32323 and GSE21510, to identify differentially expressed lncRNAs and mRNAs in CRC. The adjusted p-value ≤0.05 was considered statistically significant. Gene set enrichment analysis was carried out using DAVID tool. The miRCancer database was searched to obtain differentially expressed miRNAs in colorectal cancer, and the miRDB database was used to attain the targets of the obtained miRNAs. To predict the lncRNA-miRNA interactions we used DIANA-LncBase v2 and RegRNA 2.0. Finally the lncRNA-miRNA-mRNA-signaling pathway network was constructed using Cytoscape v3.1. RESULTS: By analyzing the three datasets, a total of 21 mRNAs (15 up- and 6 down-regulated) and 24 lncRNAs (18 up- and 6 down-regulated) were identified as common differentially expressed genes between CRC tumor and marginal tissues. Nevertheless, the constructed lncRNA-miRNA-mRNA-signaling pathway network revealed a convergence on 6 lncRNAs (3 up- and 3 downregulated), 7 mRNAs (2 up- and 5 downregulated) and 6 miRNAs (3 up- and 3 downregulated). We found that dysregulation of lncRNAs such as PCBP1-AS1, UCA1 and SNHG16 could sequester several miRNAs such as hsa-miR-582-5p and hsa-miR-198 and promote the proliferation, invasion and drug resistance of colorectal cancer cells. CONCLUSIONS: We introduced a set of lncRNAs, mRNAs and miRNAs differentially expressed in CRC which might be considered for further experimental research as potential biomarkers of CRC development.

Comparison of Glibenclamide and Insulin on Neonatal Outcomes in Pregnant Women with Gestational Diabetes.

BACKGROUND: Untreated or poorly controlled gestational diabetes can cause serious complications for mother and newborn. Glibenclamide is rarely used in treating mothers with this disease. This study aimed at comparing the effect of glibenclamide and insulin on neonatal outcomes in women with gestational diabetes mellitus. METHODS: In this randomized controlled clinical trial, 249 pregnant women aged 18-45 years within the 11(th)-33(rd) weeks of gestation with gestational diabetes, single fetus pregnancy, and in need of hyperglycemia treatment were entered and grouped randomly as either glibenclamide or insulin. In the insulin group (n = 129), insulin was administered with an initial dose of 0.2 IU/kg subcutaneously twice per day, whereas in the glibenclamide group (n = 120), 1.25 mg oral glibenclamide was administered once daily and increased if needed. RESULTS: The results showed no significant difference in means age, gestational age, and body mass index between women in the two groups. In addition, there were no significant differences in the frequency of neonatal hypoglycemia, anomaly, hyperbilirubinemia, admission in Neonatal Intensive Care Unit (NICU), and neonatal respiratory distress between two groups. Macrosomia was lower in the glibenclamide group than the insulin group (3.3% vs. 13.2%, respectively, P = 0.005). Regression logistics model results showed that the type of treatment (odds ratio [OR]: 4.62; confidence interval [CI]: 1.45-14.02; P = 0.01) and gestational age at delivery (OR: 1.41; CI: 1.04-1.74; P = 0.01) were as predictor factors of macrosomia. CONCLUSIONS: The results of this study revealed that glibenclamide is able to reduce the risk of fetal macrosomia without increasing neonatal anomalies, jaundice, hypocalcemia, infant respiratory distress, and NICU admission.

Role of XmnIgG Polymorphism in Hydroxyurea Treatment and Fetal Hemoglobin Level at Isfahanian Intermediate ß-Thalassemia Patients.

BACKGROUND: ß-thalassemia is the most common monogenic disorder in human. The (C-->T) polymorphism at -158 upstream region of the γG-globin gene and pharmacological factors such as hydroxyurea have been reported to influence γ-globin gene expression and the severity of clinical symptoms of ß-thalassemia. METHODS: In the present study, 51 ß-thalassemia intermediate patients were studied. Xmn1γG polymorphism genotype was determined using Tetra-Primer ARMS-PCR technique. Hemoglobin (Hb) and fetal hemoglobin (HbF) levels were determined by gel electrophoresis. RESULTS: Of 51 patients, 35 (68.6%) patients were heterozygous (CT) and 16 (31.4%) patients were homozygous (CC). Of 30 patients under treatment by hydroxyurea, 20 (66.7%) patients were heterozygous (CT) and 10 (33.3%) patients were homozygous (CC). Our results demonstrated that in the heterozygous (CT) genotype, the Hb (9.58 ± 1.25 gm/dl) and HbF (89.30 ± 21.87) levels were significantly higher in comparison with homozygous (CC) genotype (7.94 ± 1.34 gm/dl and 70.32 ± 40.56, respectively). Furthermore, we observed that after drug usage, the Hb and HbF levels in patients with heterozygous (CT) genotype (0.7 ± 1.26 gm/dl and 5.95 ± 14.8, respectively) raised more in comparison with homozygous (CC) genotype (0.26 ± 1.43 gm/dl and 0.8 ± 1.31, respectively). CONCLUSION: Hb and HbF levels in the patients carrying T allele are increased significantly, and they also response to hydroxyurea treatment.