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 penumbraregion. Treatment with progesterone resu lted 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. Keywords: Stroke NMDA receptor Progesterone Gene expressio

Survivin polymorphisms and susceptibility to prostate cancer: A genetic association study and an in Silico analysis

Survivin is a member of the apoptosis inhibitor protein family and its polymorphisms may lead to susceptibility to cancer. The aim of this study was to investigate the possible association of c.-31G>C (rs9904341), c.454G>A (rs2071214), c.*148T>C (rs2239680) and c.*571T>C (rs1042489) polymorphisms of survivin gene with prostate cancer risk and provide some justification using in silico analysis. The 157 men with prostate cancer and 145 healthy controls were included in a case-control study. The studied polymorphisms were genotyped using PCRRFLP method. An in silico approach was employed to show the possible effects of the polymorphisms on the survivin gene function. The study revealed that there are significant associations between c.-31CC genotype (OR= 2.29, 95 CI= 1.20-4.37, p= 0.012), c.-31C allele (OR= 1.62, 95 CI= 1.17-2.26, p= 0.004), c.454AG genotype (OR= 2.03, 95 CI= 1.02-4.04, p= 0.043), and c.*148C allele (OR= 1.49, 95 CI= 1.04-2.15, p= 0.031) with prostate cancer. Using stratified analysis, we found also significant effects of age distribution on the association of c.-31G>C with prostate cancer risk (OR= 2.10, 95 CI= 1.08-4.10, p= 0.030). Also as a preliminary study, it was shown that smoking status has significant effects on the association of c.-31G>C (OR= 1.94, 95 CI= 1.08- 3.49, p= 0.027) and c.*148T>C (OR= 2.60, 95 CI= 1.47-4.60, p= 0.001) polymorphisms with prostate cancer risk. Finally, in silico analysis revealed that c.-31G>C, which is located in a CpG island of the promoter may change transcriptional regulation of survivin gene and c.454G>A and *148T>C could affect protein structure and possible miRNA interaction with 3'-UTR of survivin transcript respectively. According to the results, c.-31G>C, c.454G>A, and c.*148T>C polymorphisms could be genetic risk factors for prostate cancer in an Iranian population. However, further studies with larger sample size and different ethnicities are required to obtain more comprehensive results. © 2018, Leibniz Research Centre for Working Environment and Human Factors. All rights reserved

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. © 2016, Springer Science+Business Media Dordrecht

Association of CCND1 Gene c.870G>A Polymorphism with Breast Cancer Risk: A Case-ControlStudy and a Meta-Analysis

Cyclin D1 (CCND1) plays an essential role in regulating the progress of the cell cycle from G1 to S phase. There is a common c.870G>A polymorphism in the CCND1 gene. The aim of this study was to investigate the association of CCND1 gene c.870G>A polymorphism with breast cancer risk in a case-control study, which followed by a meta-analysis and an in silico analysis. Three hundred and thirty-five subjects composed of 174 women with breast cancer and 161 healthy controls were included in the case-control study. CCND1 gene c.870G>A genotyping was performed by PCR-RFLP. Meta-analysis was done for 14 studies composed of 7281 cases and 6820 controls. Some bioinformatics tools were applied to investigate the effects of c.870G>A on the mRNA splicing and structure. Our data obtained from case-control study revealed that GA genotype (OR: 1.89, 95CI: 1.12�3.17, p = 0.017), AA genotype (OR: 1.95, 95CI: 1.08�3.53, p = 0.027), and A allele (OR: 1.44, 95CI: 1.06�1.95, p = 0.019) were significantly associated with breast cancer risk. The results of meta-analysis showed a significant association between CCND1 c.870G>A polymorphism and breast cancer risk, especially in Caucasian population. In silico analysis revealed that c.870G>A transition affect CCND1 mRNA splicing and secondary structure. © 2016 Arányi Lajos Foundatio