Introduction Post-traumatic stress disorder (PTSD), is associated with an elevated risk of neurodegenerative disorders, but the molecular mechanism was not wholly identified. Aberrant methylation status and miRNA expression pattern have been identified to be associated with PTSD, but their complex regulatory networks remain largely unexplored. Methods The purpose of this study was to identify the key genes/pathways related to neurodegenerative disorder development in PTSD by evaluating epigenetic regulatory signature (DNA methylation and miRNA) using an integrative bioinformatic analysis. We integrated DNA expression array data with miRNA and DNA methylation array data - obtained from the GEO database- to evaluate the epigenetic regulatory mechanisms. Results Our results indicated that target genes of dysregulated miRNAs were significantly related to several neurodegenerative diseases. Several dysregulated genes in the neurodegeneration pathways interacted with some members of the miR-17 and miR-15/107 families. Our analysis indicated that APP/CaN/NFATs signaling pathway was dysregulated in the peripheral blood samples of PTSD. Besides, the DNMT3a and KMT2D genes, as the encoding DNA and histone methyltransferase enzymes, were upregulated, and DNA methylation and miRNA regulators were proposed as critical molecular mechanisms. Our study found dysregulation of circadian rhythm as the CLOCK gene was upregulated and hypomethylated at TSS1500 CpGs S_shores and was also a target of several dysregulated miRNAs. Conclusion In conclusion, we found evidence of a negative feedback loop between stress oxidative, circadian rhythm dysregulation, miR-17 and miR-15/107 families, some essential genes involved in neuronal and brain cell health, and KMT2D/DNMT3a in the peripheral blood samples of PTSD.

Background:Previous studies have demonstrated the strong association of inflammatory cytokines and vitamin D (VitD) deficiency and ischemic stroke (IS) pathogenesis. Due to the negative correlation between long non-coding RNA (lncRNA) Malat1 and pro-inflammatory factors we decided to investigate the associations between Malat1 expression with serum interleukin-1β (IL-1β), and VitD levels in IS patients. Materials and Methods:In this cross-sectional study, 63 IS patients were included. We used enzyme-linked immunosorbent assays to evaluate the serum levels of VitD and IL-1β. Malat1 expression was evaluated by the real-time polymerase chain reaction test. The associations between Malat1expression with VitD and IL-1β were analysed with linear regression (Stepwise model) and Pearson’s correlation analysis. Results: The Malat1 expression was inversely correlated with stroke severity (r=-0.25, P=0.043). Stepwise regression analysis showed a significant positive relationship between VitD level and Malat1 expression (Beta=0.28, P=0.02), and also showed a non-significant negative relationship between IL-1β and stroke severity. VitD level showed a positive Pearson correlation with Malat1 (r=0.28, P=0.023) and a negative correlation with IL-1β (r=-0.29, P=0.018) while it could not detect a significantly negative correlation with stroke severity. Conclusion: For the first time the associations between Malat1 expression with IL-1β and VitD in IS patients was analyzed. We found a significant positive relationship between VitD and Malat1. This correlation needs to be investigated with a larger sample size to achieve a strong and reliable association between VitD and Malat1.[GMJ.2023;12:e2457]

Background Long non-coding RNA (lncRNA) has the main role in gene regulation and it might serve as a potential biomarker in clinical practice. Malat1 and THRIL LncRNAs have been demonstrated to play key roles in inflammation and atherosclerosis. It was hypothesized that the Malat1 and THRIL expression increase in patients with atherosclerotic ischemic stroke (IS) with significant diagnostic value for discriminating IS from controls. Methods We evaluated Malat1 and THRIL expression on days 1,3, and 5 after stroke in 59 IS cases with small-vessel disease (SVD) and large artery atherosclerosis (LAA), and 63 controls. A real-time polymerase chain reaction was used for the evaluation of lncRNA expression. Results In patients with SVD or LAA, Malat1 and THRIL expression significantly were higher than the controls and mix model analysis showed significantly higher expression of lncRNAs on days 5 relative to days 1 and 3 after stroke while the positive correlation was also detected between Malat1 expression and time after stroke (r = 0.27, p = 0.03). After logistic regression analysis, elevated Malat1 and THRIL showed a significant positive association with the risk of SVD and LAA. We found Malat1 could be used as a diagnostic marker with an area under the curve of 0.78 (p < 0.001). Conclusion This was the first study that demonstrated the significant upregulation of THRIL from 24 hours after IS until 5 days. This upregulation may serve as a biomarker for the diagnosis of IS. To reach a reliable conclusion we need a larger sample size.

Background: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system characterized by infiltration of inflammatory leukocytes to the CNS followed by oligodendrocyte cell death, myelin sheath destruction, and axonal injury. A logical incidence occurring after demyelination is remyelination. G-protein coupled receptors (GPCRs) activate internal signal transduction cascades through binding to different ligands. This family of receptors are targeted by more than 40% of currently marketed drugs. GPCRs can be successfully targeted for induction of remyelination. GPCRs highly enriched in oligodendrocyte progenitor cells compared to oligodendrocytes are proposed to hamper oligodendrocyte differentiation and therefore their inhibition might induce remyelination. This study aimed to investigate the expression of GPCRs in silico and in vitro. Methods: We performed gene expression analysis using DAVID and Panther websites on a RNA-seq dataset (GSE52564 accession number). Primary embryonic neural stem/progenitor cell isolation and culture were performed and subsequently NSPCs were characterized by Immunocytochemistry with Anti-Nestin antibody. Expression of GPR37L1, EDNRB, PDGFRα, CNPase and GFAP were assessed using real-time PCR. All the experiments were conducted at Shiraz University of Medical Sciences (SUMS), Shiraz, Iran, in the year 2018. Results: The 14 most highly expressed GPCRs in oligodendrocyte progenitor cells (OPCs) compared to Oligodendrocytes were presented in our study. Conclusion: The investigation of the most highly expressed GPCRs in OPCs compared to oligodendrocyte in silico and in vitro presents the significant role of GPCRs in remyelination induction. Among the 14 GPCRs mentioned in this study, GPR37L1 is a potential remyelinating drug target and is suggested for further studies.

The orexin 2 receptor plays a central role in maintaining sleep and wakefulness. Recently, it has been shown that sleep and wakefulness orchestrate the proliferation and differentiation of oligodendrocytes. Here, we explored the role of a selective orexin 2 receptor antagonist (JNJ-10397049) in proliferation and differentiation of neural progenitor cells (NPCs). We evaluated the proliferation potential of NPCs after exposure to different concentrations of JNJ-10397049 by using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide and neurosphere assays. Moreover, the expression of differentiation markers was assessed by immunocytochemistry and real-time polymerase chain reaction. JNJ-10397049 significantly increased the proliferation of NPCs at lower concentrations. In addition, orexin 2 receptor antagonist facilitated progression of differentiation of NPCs towards oligodendroglial lineage by considerable expression of Olig2 and 2’,3’-cyclic-nucleotide 3’-phosphodiesterase as well as decreased expression of nestin marker. The results open a new avenue for future investigations in which the production of more oligodendrocytes from NPCs is needed.