GABAA receptors as novel drug targets for treatment of mental disorders

A balance between excitatory and inhibitory neurotransmissions in brain is an essential factor for the proper function of the brain. The amino acid gamma-aminobutyric-acid (GABA) is considered as the major inhibitory neurotransmitter in brain. Thus, GABAergic neurons play a key role in regulating behavior. Previous data have revealed the complex subunit structural design for GABAA receptor channel, in which a pentameric assembly resulting from 5 of at least 21 subunits, grouped in the eight classes alpha (α1-6), beta (β1-4), gamma (γ1-4), delta, pi (π), epsilon (ε), theta (θ) and rho (ρ1-3) permits an immense number of putative receptor isoforms. GABAARs are highly diversed in the central nervous system in which this diversity may be related to some mental disorders. Any alteration in expression of the GABAA receptor genes causes neurophysiological and functional consequences that might be associated with neurological disorders. Some neuropsychiatric disorders, such as anxiety, epilepsy and sleep disorders, are effectively treated with therapeutic agents that act on the GABAA receptor. In this article, the contribution of GABAA receptor deficits to central nervous system disorders, in particular anxiety disorders, epilepsy, schizophrenia and insomnia, will be reviewed. The better understanding of GABA and its receptors may help us to find novel therapeutic agents for treatment of mental disorder in future research

The comparison of the expression of miR-126 in breast and normal tissue and the association between these data and age of Iranian population

Background and aims: Breast cancer is the most common cancer among women. miRNAs are a class of non-coding RNAs which play an important role in control of gene expression at post-transcriptional level. miR-126, an intronic miRNA derived from EGFL7 gene. miR-126 has been revealed to down-regulate and play a tumor suppressive role in breast tumors. The aim of this study was to assess the expression of miR-126 in breast and normal tissue and an association between these data and age of Iranian population. Methods: In this study, expression of miR-126 was assessed in cancer specimen and normal breast tissues by Real Time RT-PCR. Then, the association between expression of miR-126 and age were calculated. U6 gene was selected as the control. Data were analyzed statstically by ANOVA and t- test. Results: Data indicated that the expression of miR-126 was significantly down-regulated in tumor status. Also, the expression of miR-126 had a significantly difference between normal and malignant and benign tumor. (P<0.05). In addition, there was a relationship between age and the expression of miR-126, and the age of the patients who had a low expression of miR-126 was less than the age of the patients that had the high expression of miR-126. Conclusion: The results shows that miR-126 expression decreases in tumor status. In addition, a significant correlation between expression of miR-126 and age of patients was observe

The Genetic Role of Retinoic Acid Receptors in Embryonic Development: Study of Genetic Mutations in Retinoic Acid Receptors, Resulting in Tissue Abnormalities

Retinoic acid (RA) is a vitamin A derivative that exerts profound influences in vertebrate development and physiology. All-trans RA and 9-cis RA, are important regulators of embryonic development, cellular activity and tissue homeostasis. Their biological effects are mediated by two families of nuclear hormone receptors, retinoic acid (RAR) and retinoid X (RXR) receptors, which are ligand-dependent transcription factor. In the form of RAR-RXR or RXR-RXR dimers, the receptors act through binding to retinoic acid response elements (RAREs) present in the transcription regulatory region (promoter) of target genes. The identification of the pattern of expression of each isoform is crucial to our complete understanding of retinoid physiology. Compound null mutations of retinoic acid receptor (RAR) genes lead to lethality in uterus or shortly after birth and to numerous developmental abnormalities. The role of RXRs in the mediation of the developmental retinoid signal is less clear, because RXRβ and RXRγ null mutant mice are viable and do not display any abnormality obviously related to a known function of vitamin A. Effects of retinoids in normal as well as abnormal development may be mediated by two members of retinoid receptors together, RARs and RXRs

Comparison of the HER2/neu gene amplification assesment by differential PCR and immunohistochemistry in breast cancer patients in Isfahan

Background and aim: Amplification of the oncogene HER-2/neu influences the breast cancer progression, prognosis and therapy. Accurate assessment of HER-2/neu status of the tumor is important for management of the disease and correct selection of patients who are able to respond to trastuzumab neu treatment. This study designed to evaluate the HER-2/neu gene status in breast cancer specimens by differential PCR and to show the concordance between these evaluations and IHC test in some specimens. Methods: In this case-control study the quantitative accuracy of differential PCR was evaluated and then 67 fresh and 16 formalin fixed paraffin embedded breast cancer tissues were analysed using this method. IHC reports were available only for 27 of these samples. Data were analysed using McNemar and kappa test. Results: HER-2/neu gene amplification was estimated (35%) in 29 cases out of 83 specimens (35%), as shown by differential PCR. IHC reports showed that 12 out of the 27 specimens contain overexpressed HER-2/neu. So, there was 70% agreement between these two methods (19 out off 27). Among the 8 discordant samples, 6 cases were negative by IHC but positive by differential PCR and 2 cases with HER-2/neu amplification had normal HER-2/neu expression by IHC. Conclusion: Differential PCR is a simple, rapid and cheap method to determine the gene dosage in samples with small amount of tumor tissue but it does not seem to be so accurate, as it compares the end point products of the PCR. Thus, this method has low accuracy and the observation of 6 cases with HER-2/neu amplification in the absence of HER-2/neu over expression may have come from this reality

Long Non-coding RNAs Including IRF1-AS1, LINC01871, TRG-AS1, and USP30-AS as Tumor Suppressors in Colorectal Cancer: In Silico Analysis

Introduction: Colorectal cancer (CRC) is one of the most frequently diagnosed malignancies in the world with a high mortality rate, making screening and early detection of the condition essential. Long non-coding RNAs (lncRNAs) have a significant role in the initiation and advancement of numerous malignancies, including CRC, by taking part in the control of gene and protein expression that affects apoptosis, cell proliferation, and immunological responses. In this study, through bioinformatics methods, we investigated this non-coding group in CRC and the normal group in both early and advanced stages of the disease. Materials and Methods: In order to identify the lncRNAs that could have a tumor-suppressing role in CRC, RNA sequencing data from the cancer genome atlas (TCGA) were analyzed. Then, the Pearson correlation test was applied between the expression level of candidate lncRNAs and all genes expressed for identifying potential pathway. Genes with the highest correlation were selected and subjected to gene enrichment analysis. Also, the roles of identified lncRNAs were evaluated in terms of biomarkers. Results: The results of the expression analysis for the TCGA data showed that the expression of the IRF1-AS1, LINC01871, TRG-AS1, and USP30-AS decreased during the progression (stages III and IV compared with stages I and II) of CRC. The enrichment results of all the genes in the co-expression network related to IRF1-AS1, LINC01871, TRG-AS1, and USP30-AS showed that these lncRNAs could play a role in immune response, inflammation, and IL-6/JAK/STAT3 signaling and apoptosis pathways. Additionally, our findings demonstrated that the aforesaid lncRNAs were significantly lower in CRC samples compared with normal samples based on TCGA data, Also, the expression of some of them may serve as an appropriate biomarker. Conclusion: The results of this study showed that IRF1-AS1, LINC01871, TRG-AS1, and USP30-AS decreased during the progression of CRC and could play a tumor-suppressing role

Analyzing alternative splicing in Alzheimer’s disease postmortem brain: a cell-level perspective

Alzheimer’s disease (AD) is a neurodegenerative disease with no effective cure that attacks the brain’s cells resulting in memory loss and changes in behavior and language skills. Alternative splicing is a highly regulated process influenced by specific cell types and has been implicated in age-related disorders such as neurodegenerative diseases. A comprehensive detection of alternative splicing events (ASEs) at the cellular level in postmortem brain tissue can provide valuable insights into AD pathology. Here, we provided cell-level ASEs in postmortem brain tissue by employing bioinformatics pipelines on a bulk RNA sequencing study sorted by cell types and two single-cell RNA sequencing studies from the prefrontal cortex. This comprehensive analysis revealed previously overlooked splicing and expression changes in AD patient brains. Among the observed alterations were changed in the splicing and expression of transcripts associated with chaperones, including CLU in astrocytes and excitatory neurons, PTGDS in astrocytes and endothelial cells, and HSP90AA1 in microglia and tauopathy-afflicted neurons, which were associated with differential expression of the splicing factor DDX5. In addition, novel, unknown transcripts were altered, and structural changes were observed in lncRNAs such as MEG3 in neurons. This work provides a novel strategy to identify the notable ASEs at the cell level in neurodegeneration, which revealed cell type-specific splicing changes in AD. This finding may contribute to interpreting associations between splicing and neurodegenerative disease outcomes

Molecular Basis of Proxysomal Disorders in Zellweger Syndrome

Peroxisomes are organelles present in all eukaryotic cells from yeast to human cells. It is now well known that approximately fifty different biochemical reactions occur within the peroxisome, including synthesis of bile acids, cholesterol, ether-phospholipids (plasmalogens), docosahexaenoic acid and catabolism of certain fatty acids, particularly very long chain fatty acids (VLCFAs). Proteins involved in peroxisomal function are known as peroxins. At least 29 peroxins are required for peroxisome membrane biogenesis, fission, and protein import. So far, mutations in 13 genes that encode peroxins are associated with human disease. Peroxisomal disorders currently falling into one of three groups peroxisome biogenesis disorders (PBDs), peroxisomal multi-enzyme disorders, and peroxisomal single-enzyme disorders. Infantile Refsum’s disease (IRD), neonatal adrenoleukodystrophy (NALD) and Zellweger’s syndrome (ZS) are different variants of a group of congenital diseases known as peroxisome biogenesis disorders. These disorders are characterized by the absence of normal peroxisomes in the cells of the body which mostly are fatal. Here we describe molecular events that cause these deficiencies and we introduce current molecular approaches for diagnosis of these disorders like mutation analysis and fibroblasts characterization derived from the patients

The effect of endurance training on the cardiac apelin gene expression in Wistar male rats

زمینه و هدف: اپلین، پروتئین مؤثر بر عملکرد عروق می باشد که به فراوانی در بافت قلبی میوکارد پستانداران دیده می شود. این پپتید و گیرنده&zwnj;ی آن در لایه میانی آئورت و شریان&zwnj;های کرونری به خوبی شناسایی شده&zwnj;اند. اپلین دارای کارکردهای قلبی عروقی گوناگون می &zwnj;باشد و سبب کاهش فشار خون می&zwnj;شود، لذا هدف از تحقیق حاضر بررسی اثر یک دوره تمرین استقامتی بر بیان ژن اپلین در بطن چپ قلب موش&zwnj;های نر نژاد ویستار است. روش بررسی: در تحقیق تجربی حاضر تعداد 12 عدد موش صحرائی به دو گروه کنترل و تجربی تقسیم شدند. موش&zwnj;های گروه تجربی (6n=) مدت 8 هفته، 5 روز در هفته، با سرعت متوسط 28 متر در دقیقه (شیب صفر درجه) و به مدت 60 دقیقه، روی نوار گردان تمرین داده شدند. 24 ساعت پس از آخرین جلسه&zwnj;ی تمرین ورزشی، رت ها بیهوش شدند. پس از شکاف سینه، بافت قلب جدا شد، سپس RNA هر نمونه تبدیل به cDNA شد. پس از پایان واکنش و تعیین خط آستانه، سیکل آستانه ژن مورد نظر با ژن خانه&zwnj; گردان میزان بیان نسبی ژن اپلین نظر از روش 2-∆∆Ct به دست آمد. برای تجزیه تحلیل داده ها از آزمون t مستقل استفاده شد. یافته ها: نتایج به روشنی نشان داد که بیان ژن اپلین پس از 8 هفته تمرین استقامتی نسبت به گروه کنترل افزایش معنی دار (2 برابر) یافته است (05/0&gt;P). نتیجه گیری: تمرینات استقامتی بر افزایش بیان ژن اپلین تاثیر مثبتی داشته و بدین وسیله می تواند در پیشگیری از بیماری قلبی عروقی موثر می باشد

Integrative computational mRNA-miRNA interaction analyses of the autoimmune-deregulated miRNAs and well-known Th17 differentiation regulators: An attempt to discover new potential miRNAs involved in Th17 differentiation

Th17 cells are a lineage of CD4(+) T helper cells in immune system which differentiate from naive CD4(+) T cells and have demonstrated to play a critical role in the pathogenesis of different autoimmune disorders. miRNAs are a novel group of non-coding RNAs which participate in post-transcriptional regulation of gene expression mostly by pairing with 3'UTR of their mRNA targets and inhibition of its translation. It has been demonstrated that miRNAs function in various cellular processes such as differentiation, proliferation, and apoptosis. By now, several signaling pathways and their downstream positive and negative regulators involve in Th17 differentiation have been discovered. Several studies have reported the aberrant miRNA expression profile in patients with autoimmune disease called autoimmune-deregulated miRNAs. Here, using integrative miRwalk database which assembles the data gathered from ten different bioinformatics databases designed to predict miRNA-target interaction, we analyzed possible targeting effect of ``autoimmune-deregulated miRNAs'' on prominent positive and negative regulators of Th17 differentiation. Our resulting mRNA-miRNA network simply nominated several miRNAs with strong possibility which probably may have inducing (miR-27b, miR-27a, miR-30c, miR-1, and miR-141) or inhibitory (miR-20b, miR-93, miR-20a, miR-152, miR-21, and miR-106a) role in Th17 differentiation by targeting negative or positive regulators of Th17 differentiation, respectively. (C) 2015 Elsevier B.V. All rights reserved

A Comparison of chromatin structure and PLCζ in sperms of subfertile oligoasthenoteratozoospermic and fertile men

زمینه و هدف: مهم ترین علل عدم فعال شدن تخمک پس از تکنیک های کمک باروری، عدم رهایش فاکتورهای اسپرمی فعال کننده تخمک و آسیب به DNA اسپرم است. PLC&zeta; یکی از فاکتورهای اسپرمی است که در فعال شدن تخمک نقش دارد. هدف از این مطالعه مقایسه PLC&zeta;، کمبود پروتامین (مارکر بلوغ کروماتین اسپرم) و آسیب DNA اسپرم در 2 گروه افراد بارور و نابارور الیگوآستنوتراتوزواسپرمی است. روش بررسی: در این مطالعه شاهد کنترل، نمونه مایع منی از 10 فرد نابارور الیگوآستنوتراتوزواسپرمی و 10 فرد بارور جمع آوری گردید. پارامترهای اسپرمی (غلظت، تحرک و مورفولوژی)، بیان پروتئین PLC&zeta;، آسیب DNA و کمبود پروتامین به ترتیب بر اساس پروتکل سازمان بهداشت جهانی، فلوسایتومتری، رنگ آمیزی TUNEL و کرومایسین A3 مورد بررسی قرار گرفت. یافته ها: درصد اسپرم های PLC&zeta; مثبت، سلامت DNA و محتوی پروتامین در افراد نابارور الیگوآستنوتراتوزواسپرمی نسبت به افراد بارور، به طور معنی داری کمتر بود؛ همچنین ارتباط معنی داری بین درصد اسپرم های PLC&zeta; مثبت با پارامترهای اسپرمی و درصد کمبود پروتامین مشاهده گردید. ارتباط معنی داری نیز بین درصد آسیب DNA اسپرم و کمبود پروتامین مشاهده شد. نتیجه گیری: در این افراد نابارور، سلامت کروماتین اسپرم و درصد اسپرم ها با PLC&zeta; مثبت به شدت کاهش یافته است که می تواند یکی از دلایل عدم لقاح در این افراد باشد؛ لذا روش فعال سازی مصنوعی تخمک برای این نوع ناباروران پیشنهاد می شود