Publications by authors named "Maziar Ganji"

17 Publications

  • Page 1 of 1

Utilization of Whole Exome Sequencing in Lethal Form of Multiple Pterygium Syndrome: Identification of Mutations in Embryonal Subunit of Acetylcholine Receptor.

Int J Mol Cell Med 2019 ;8(4):258-269

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

The acetylcholine receptor (AChR) is a member of the superfamily of transmitter-gated ion channels having a critical role in controlling electrical signals between nerves and muscle cells. Disruptive mutations in genes encoding different subunits of AChR result in multiple pterygium syndrome (MPS), which can be associated with a severe prenatally lethal presentation. This study aimed to investigate the etiology of lethal MPS (LMPS) in two consanguineous families with a history of miscarriages. DNA was extracted from a tissue sample of two aborted fetuses (probands) from two different families with a history of spontaneous miscarriages. Parental peripheral blood samples were collected for confirmatory analysis and follow-up testing. Whole-exome sequencing (WES) was performed on DNA from the probands. The results were confirmed and segregated by Sanger sequencing. Moreover, protein structure evaluations were accomplished. We identified a homozygous frameshift mutation of c.753_754delCT (p.V253fs*44) and a homozygous missense mutation of c.715C>T (p.Arg239Cys) in the gene. Both aborted fetuses had pterygium, severe arthrogryposis, and fetal hydrops with cystic hygroma, being compatible with LMPS. The heterozygous state was confirmed in parents for both variants. Likewise, mutation was predicted to display the damaging effects by lowering the number of helixes and modifying the surface electrostatic potential. The present study identified rare sequence variants in the gene in aborted fetuses from consanguineous couples with recurrent miscarriage history. WES is a comprehensive and cost-effective approach to study heterogeneous diseases including MPS. Such findings can improve our knowledge of MPS databases, particularly for genetic counseling of high-risk families and preimplantation genetic diagnosis.
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http://dx.doi.org/10.22088/IJMCM.BUMS.8.4.258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305466PMC
January 2019

Gastric Cancer MicroRNAs Meta-signature.

Int J Mol Cell Med 2019 24;8(2):94-102. Epub 2019 Aug 24.

Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Gastric cancer (GC) is one of the most common types of cancer and the second leading cause of cancer-associated mortalityIdentification of novel biomarkers is critical to prolonging patient survival. MicroRNAs (miRNAs) proved to play diverse roles in the physiological and pathological state in cancers including GC. Herein we aimed at performing a meta-analysis on miRNA profiling studies that used microarray platforms. Relevant studies were retrieved from PubMed and GEO databases. We used the robust rank aggregation to perform the meta-analysis. Moreover, for meta-signature miRNAs target genes, we performed pathway enrichment and GO molecular function enrichment analysis. A total of 19 upregulated miRNAs and seven downregulated miRNAs in GC samples were identified. However, only three upregulated and one downregulated miRNA reached statistical significance after multiple test correction. Here we showed that hsa-miR-21-5p, hsa-miR-93-5p, hsa-miR-25-3p, and hsa-miR-375 are differentially expressed in GC samples.
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http://dx.doi.org/10.22088/IJMCM.BUMS.8.2.94DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081082PMC
August 2019

Effects of tosyl-l-arginine methyl ester (TAME) on the APC/c subunits: An in silico investigation for inhibiting cell cycle.

J Mol Graph Model 2020 06 5;97:107563. Epub 2020 Feb 5.

Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran. Electronic address:

The anaphase-promoting complex/cyclosome (APC/c) is requisite for controlling mitosis, which is activated by Cdh1 and Cdc20 activators. Dysregulation of APC/c is observed in many cancers and is known as a targeted drug particularly in cancer drug resistance. It was shown that tosyl-l-arginine methyl ester (TAME), via mimicking isoleucine-arginine (IR) tail of co-activators, inhibits APC/c functions. However, structure details and interaction of TAME with APC/c are poorly defined. In the current study, a well-established set of computational methods was used to identify the best binding pocket in order to inhibit APC activity. Therefore, the interaction of IR tail and Cbox of co-activators, as well as TAME as an inhibitor, as an inhibitor, with APC3 and APC8 subunits of APC/c were analyzed, regarding structure, molecular docking, molecular dynamics, and free binding energy. The results indicated that TAME bound to APC3 with a higher binding affinity (∼-7.3 kcal/mol) than APC8 (∼-5.7 kcal/mol). Also, the binding free energy value obtained for the APC3-TAME was -22.25 ± 1.12 kcal/mol. According to binding free energies, van der Waals energy was the major favorable contributor to the ligand binding. These results offer that TAME had more affinity to interact with the APC3 subunit, at the IR binding pocket than the APC8 subunit at the Cbox binding pocket. In conclusion, IR binding pocket can serve as an appropriate potential target for TAME as an inhibitor of APC/c.
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http://dx.doi.org/10.1016/j.jmgm.2020.107563DOI Listing
June 2020

In silico mutagenesis in recombinant human keratinocyte growth factor: Improvement of stability and activity in addition to decrement immunogenicity.

J Mol Graph Model 2020 06 28;97:107551. Epub 2020 Jan 28.

Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran. Electronic address:

The recombinant human keratinocyte growth factor (rhKGF) is clinically applied to decrease the incidence and duration of cancer therapeutic agents. Particularly, it is extensively used for oral mucositis after chemotherapy-induced damage of different human cancers. However, the usage of rhKGF in treatment is limited owing to its short half-life, poor stability, immunogenicity, tendency to aggregate, and side effects. Therefore, there is a need to enhance the stability and to reduce immunogenicity of rhKGF for therapeutic applications. In this study, the stability, activity, and immunogenicity of rhKGF were improved using computational methods. The several mutations were generated based on sequence alignment, amino acids physic-chemical properties, and the structure simulation. The 3D structure of rhKGF and proposed mutants were predicted by Modeller v9.15 program, and then were evaluated using PROSESS, PROCHECK, and ProSA web tools. Afterwards, the effect of these mutants on rhKGF structure, stability, activity, and its interaction with fibroblast growth factor receptor2-IIb (FGFR2-IIb) was analyzed through utilizing GROMACS molecular dynamics simulations and docking tools, respectively. Also, binding free energies were calculated by the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. We found that F63Y, R121K, and combine1 (K38R, F63Y, K72E, N105S) mutants lead to reduction of the number of T-cell epitopes. However, all of the selected mutants, except for R121K, could considerably increase stability and affinity of the rhKGF to FGFR2-IIb, in silico. In conclusion, this study, for the first time, offered that the combine1 and F63Y mutants could highly improve the stability and activity of rhKGF and even reduce immunogenicity without having any significant effect on the biological functions of rhKGF.
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http://dx.doi.org/10.1016/j.jmgm.2020.107551DOI Listing
June 2020

Effects of vitamin D in an animal model of Alzheimer's disease: behavioral assessment with biochemical investigation of Hippocampus and serum.

Metab Brain Dis 2020 02 18;35(2):263-274. Epub 2019 Dec 18.

Department of Toxicology and Pharmacology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran.

Regulatory role of vitamin D (VitD) in cognitive memory and learning has been proposed. Here, we examine the behavioral and biochemical effects of VitD in Alzheimer's disease (AD), as the most common form of dementia, in male Wistar rats. Animals (n = 48) were randomly divided into six groups: control, sham solvent, sham surgery, VitD (by intraperitoneal injection), AD (receiving intrahippocampal injection of amyloid-beta peptide, Aβ), and combination of VitD and Aβ. Learning and memory functions were investigated through the passive avoidance and the Morris water maze (MWM) tasks. Moreover, oxidative stress biomarkers including total antioxidant capacity (TAC), total thiol groups (TTG), lipid peroxidation (LPO), and DNA damage were assessed in hippocampus and serum. In passive avoidance task, Aβ significantly impaired the step-through latency and time in dark compartment. It also increased escape latency and time spent in the target quadrant in the MWM. VitD administration attenuated the Aβ-induced memory impairment in passive avoidance and MWM tests. Furthermore, VitD reduced deleterious biochemical effect of Aβ by enhancing the levels of TAC and TTG in addition to decreasing LPO and DNA damage levels in both hippocampus and serum. We showed, for the first time, that VitD administration improves the impaired Aβ-induced memory and that, by acting as a strong antioxidant, it can attenuate the stress oxidative biomarkers in hippocampus and serum of rats with AD. Altogether, our results provide evidence for further application of VitD in neurodegenerative disorders such as AD to enlighten the involved mechanisms.
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http://dx.doi.org/10.1007/s11011-019-00529-7DOI Listing
February 2020

Association Study of Sequence Variants in Voltage-gated Ca2+ Channel Subunit Alpha-1C and Autism Spectrum Disorders.

Rep Biochem Mol Biol 2019 Apr;8(1):56-62

Department of Medical Genetics, Shahid Beheshti University of Medical sciences, Tehran, Iran.

Background: Autism spectrum disorders (ASDs) (MIM 209850) are a group of distinct neurodevelopmental disorders characterized by impaired social interactions and communication abilities and abnormal repetitive activities. Many genetic variants have been shown to be associated with ASD. Channelopathies are among putative culprits in the pathogenesis of many neurodevelopmental disorders, including autism. The calcium channel, voltage-dependent, L type, alpha 1C subunit gene () encodes an alpha-1 subunit of a voltage-dependent calcium channel. Genetic variants within this gene have been associated with psychiatric disorders including Autism Spectrum Disorders (ASD). Our aim was to determine whether the SNPs rs1006737, rs4765905, and rs4765913 were associated with ASD in an Iranian population.

Methods: In the present case-control study we investigated the associations of rs1006737, rs4765905, and rs4765913 polymorphisms within and the risk of ASD in a population of 529 Iranian ASD patients and 480 age, gender, and ethnicity-matched healthy subjects.

Results: None of these SNPs were associated with ASD risk in the assessed population. Although previous studies have shown an association between these polymorphisms and psychiatric disorders and an association between rs4765905 and ASD, we did not replicate those results in our study.

Conclusion: Our data indicate that these variants are not involved in the pathogenesis of ASD in the Iranian population.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590947PMC
April 2019

Potential Prognostic Role for SPOP, DAXX, RARRES1, and LAMP2 as an Autophagy Related Genes in Prostate Cancer.

Urol J 2020 03 16;17(2):156-163. Epub 2020 Mar 16.

Urology resident, Shohada-e-Tajrish hospital, Shahid Beheshti Medical University, Tehran, Iran.

Purpose: Autophagy plays a critical role in PCa development. DAXX has a potent pro-survival effect by enhancing cell growth in PCa via suppression of autophagy. Here, we depicted a network governed by DAXX and SPOP by which the autophagy pathway is suppressed through the ubiquitination and modulation of key cellular signaling pathways mediators including LAMP2 and RARRES1.

Materials And Methods: Through network-based bioinformatics approaches, the expression levels of DAXX, RARRES1, LAMP2, and SPOP genes was assessed in 50 PCa tissues and 50 normal adjacent from the same sample as well as 50 benign prostatic hyperplasia (BPH) tissues by quantitative RT-PCR. The normal adjacent tissues were taken from regions more than 5mm away from the bulk of those tumor tissues with clearly distinct margins. RNA extraction, cDNA synthesis and Real-time Quantitative RT-PCR were done for assessment of gene expression. To evaluate the primary gene network centered on autophagy pathway, according to the Query-dependent weighting algorithm, these two networks were integrated with Cytoscape 3.4 software.

Results: We found that in PCa tissues the DAXX expression level was significantly increased (P < 0.001) and the expressions of SPOP, RARRES1, and LAMP2 were significantly down-regulated, when compared to both control groups including normal adjacent and BPH tissues. Moreover, significant correlations were observed between expression levels of all four genes. Additionally, ROC curve analysis revealed that LAMP2 had the most sensitivity and specificity.

Conclusion: These findings suggest that the contribution of SPOP, DAXX, RARRES1, and LAMP2 together could be a putative regulatory element acting as a prognostic signature and therapeutic target in PCa.
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http://dx.doi.org/10.22037/uj.v0i0.4935DOI Listing
March 2020

Expression analysis of long non-coding RNAs and their target genes in multiple sclerosis patients.

Neurol Sci 2019 Apr 24;40(4):801-811. Epub 2019 Jan 24.

Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, PO Box 1985717443, Tehran, Iran.

Multiple sclerosis (MS) is a progressive chronic autoimmune-mediated disease. Recently, long non-coding RNAs (lncRNAs) are characterized to participate in the adjustment of immune responses. Here, we evaluated the expression levels of GSTT1-AS1 and IFNG-AS1 lncRNAs and their targets (TNF and IFNG, respectively) in Iranian MS patients.In this case-control study, 50 relapsing-remitting MS patients and 50 healthy subjects were recruited. Expressions of GSTT1-AS1 and IFNG-AS1 lncRNAs, as well as TNF and IFNG genes, were assessed in their peripheral blood samples by SYBR Green-based Real-time quantitative PCR.Expression levels of GSTT1-AS1 and IFNG-AS1 lncRNAs were both significantly downregulated (p values 0.032 and 0.013, respectively). On the other hand, the expression of TNF and IFNG showed increased levels, however, did not reach statistical significance after our analysis (p > 0.05). Spearman correlation analysis showed that GSTT1-AS1 had a significant positive moderate correlation with IFNG-AS1 (r = 0.541, p < 0.0001), IFNG (r = 0.329, p = 0.001), and TNF (r = 0.204, p = 0.041). Also, IFNG-AS1 revealed the same correlation with IFNG (r = 0.475, p < 0.0001) as well as TNF (r = 0.399, p < 0.0001). Furthermore, GSTT1-AS1 (r = 0.313, p = 0.027) and (IFNG r = 0.478, p < 0.0001) demonstrated a significant positive correlation with age at onset.Briefly, the current study provided for the first time dysregulation of GSTT1-AS1 and IFNG-AS lncRNAs network in MS, which highlights the significant role of epigenetic pathways in this autoimmune disorder. Larger sample size and further investigation assays could shed light on the underlying mechanisms in this area of science.
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http://dx.doi.org/10.1007/s10072-019-3720-3DOI Listing
April 2019

Effect of Extremely Low Frequency Electromagnetic Fields on Expression of T-bet and GATA-3 Genes and Serum Interferon-γ and Interleukin-4.

J Interferon Cytokine Res 2019 02 18;39(2):125-131. Epub 2018 Dec 18.

1 Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran .

This study investigated the effect of various magnetic flux densities of extremely low frequency electromagnetic fields (ELF-EMF) on expression of T-box transcription factor (T-bet) and GATA binding protein-3 (GATA-3) genes in the spleen and thymus of rats injected with human serum albumin (HSA). Moreover, serum levels of interferon (IFN)-γ and interleukin (IL)-4 were evaluated at two phases, that is, prestimulation and poststimulation with HSA. Eighty rats were separated into five groups, and four groups were exposed daily to 50 Hz EMF of 1, 100, 500, and 2000 μT magnetic flux densities for 60 days. To activate the immune system, 100 μg HSA was intraperitoneally injected into each rat on days 31, 44, and 58 of the regimen. Splenic and thymic T-bet and GATA-3 messenger RNA (mRNA) expression on day 61 was evaluated by reverse transcription quantitative PCR. Serum IFN-γ and IL-4 (in blood on day 31 before HSA and again on day 61) levels were evaluated by enzyme-linked immunosorbent assay. Expression of T-bet and GATA-3 mRNA was decreased in the spleen in hosts exposed to densities of 1 and 100 μT. Serum IFN-γ and IL-4 levels were also significantly decreased in 100 μT-exposed rats, but only at the prestimulation phase. From these findings, it appears that (30 and 60 days) ELF-EMF exposure could suppress the expression of some key genes associated with T helper (Th) cells and on some of their associated functions, that is, the ability to generate (in some cases, spontaneously) select cytokines. Whether this is attributable to effects on Th1/Th2 levels in the hosts and/or due to potential effects of the EMF on cellular functions remains to be determined.
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http://dx.doi.org/10.1089/jir.2018.0105DOI Listing
February 2019

microRNA-193a-5p inhibits migration of human HT-29 colon cancer cells via suppression of metastasis pathway.

J Cell Biochem 2018 Dec 2. Epub 2018 Dec 2.

Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Purpose: Altered expression of microRNAs (miRNAs) is indicated strongly in colorectal cancer (CRC). This study aims to evaluate the inhibitory role of miR-193a-5p on epithelial-mesenchymal transition markers in CRC lines. The cellular effects and potential mechanisms of miR-193a-5p were also examined.

Methods: Quantitative reverse-transcription polymerase chain reaction (RT-PCR) was performed to determine the expression of miR-193a-5p in three CRC cell lines (HCT-116, SW-480, and HT-29) and its impact on metastasis-related genes ( vimentin and CXCR4) before and after mimic transfection. Of those, the cell line with the highest changes was selected for the next upcoming experiments such as wound-healing assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and annexin-V staining tests.

Results: Our results revealed that miR-193a-5p was significantly downregulated in three CRC cell lines and that HT-29 displayed the most decrease ( P < 0.0001). The restoration of miR-193a-5p in human HT-29 cell line inhibited cell migration. But, miR-193a-5p transfection did not affect cell viability and had no significant effect on apoptosis induction. Also, the quantitative RT-PCR analysis of miR-193a-5p mimic transfected cells revealed a significant increase in miR-193a-5p messenger RNA (mRNA) expression level ( P < 0.0001) with reduction of vimentin and CXCR4 mRNA expression levels in HT-29 cell line ( P < 0.01 and < 0.05, respectively).

Conclusion: Our results indicated that miR-193a-5p acts as a tumor suppressor miRNA and its downregulation plays an important role in metastasis via upregulation of metastasis-related genes in CRC. Therefore, it can be considered as a potential therapeutic target for applying in CRC management in the future.
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http://dx.doi.org/10.1002/jcb.28164DOI Listing
December 2018

Role of Cerium Oxide Nanoparticles in a Paraquat-Induced Model of Oxidative Stress: Emergence of Neuroprotective Results in the Brain.

J Mol Neurosci 2018 Nov 3;66(3):420-427. Epub 2018 Oct 3.

Department of Toxicology and Pharmacology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran.

Paraquat (PQ), as a widely used herbicide, enhances the formation of free radicals and oxidative stress. Cerium oxide nanoparticles (CeNPs) are one of the most utilized and effective nanoparticles having strong antioxidative properties and inhibiting free radicals. Here, we aimed to investigate the effects of CeNPs on brain oxidative toxic stress injury induced with PQ. The male rats were treated intraperitoneally daily with PQ (50 mg/kg/day) and CeNPs (15, 30, and 60 mg/kg/day) alone or in combination for 2 weeks. After treatments, the brain tissue samples were collected. Oxidative toxic stress biomarkers including lipid peroxidation (LPO), total antioxidant capacity (TAC), and total thiol molecules (TTM) as well as DNA damage and caspase-3 levels were measured. Moreover, the mRNA expression levels of Nestin and Neurod1 were assayed. Our results showed that PQ has significantly increased brain LPO, DNA damage, and caspase-3 levels and further reduced TAC and TTM contents, as well as expression levels of Nestin and Neurod1, compared with the control group (injection of saline). CeNPs (15- and 30-mg/kg doses) in groups co-administered with PQ significantly ameliorated the LPO, DNA damage, and caspase-3 levels while increasing TAC and TTM contents as well as enhancing Nestin and Neurod1 mRNA expression levels in the brain samples (P < 0.05). These findings suggest a neuroprotective and antioxidant role for CeNPs in PQ-induced brain injury. However, further studies are required to clarify its clinical/pharmacological significance.
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http://dx.doi.org/10.1007/s12031-018-1191-2DOI Listing
November 2018

Down-regulation of RORA gene expression in the blood of multiple sclerosis patients.

Hum Antibodies 2018 ;26(4):219-224

Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Multiple sclerosis (MS) is an autoimmune disease characterized by recurrent episodes of demyelination and loss of oligodendrocytes. The demyelination process is caused by various subsets of CD4+ T cells with a Th1 and Th17 phenotype. The retinoid acid-related orphan receptor A (RORA) is expressed in Th17 cells and promote Th17 differentiation. In this study, we compared the expression level of RORA gene in the blood of 50 relapsing-remitting MS (RRMS) patients who were treated with IFN-β and 50 healthy controls by TaqMan Quantitative Real-Time PCR.We found that RORA expression was significantly down-regulated in MS patients compared with controls (P= 0.006). However, there was no significant correlation between RORA gene expression and Kurtzke Expanded Disability Status Scale (EDSS). Our findings suggest a possible contribution of IFN-β in the downregulation of RORA. In addition, RORA downregulation may be a potential indicator of positive response to interferon beta treatment of multiple sclerosis patients.
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http://dx.doi.org/10.3233/HAB-180341DOI Listing
December 2018

Soluble Receptor for Advanced Glycation End Products (sRAGE) is Up-Regulated in Multiple Sclerosis Patients Treated with Interferon β-1a.

Cell Physiol Biochem 2018 28;46(2):561-567. Epub 2018 Mar 28.

Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background/aims: Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system. Considering the role of immune system in its pathogenesis, researchers have focused on evaluation of the expression of immune-related genes or proteins in MS patients. Among proteins whose participation in inflammatory process has been documented is the receptor for advanced glycation end products (RAGE).

Methods: In the present study, we compared RAGE transcript levels by means of quantitative real-time PCR as well as the serum level of soluble RAGE (sRAGE) by means of enzyme- linked immunosorbent assay (ELISA) in 50 IFNβ-1a responsive relapsing-remitting MS patients when compared with age and sex-matched healthy subjects.

Results: Elevated expression of RAGE as well as higher levels of sRAGE were detected in IFN-β responsive MS patients compared with the controls. A significant inverse correlation between sRAGE plasma concentrations and the expanded disability status scale (EDSS) was also detected in which each unit of increase in sRAGE level resulted in a 0.308 unit decrease in EDSS.

Conclusion: Considering the stable clinical state of the MS patients in this study and their response to IFNβ-1a, the elevated levels of sRAGE in patients compared with healthy subjects could be related to the effects of this kind of treatment.
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http://dx.doi.org/10.1159/000488622DOI Listing
July 2018

Cytokine profile in autistic patients.

Cytokine 2018 08 28;108:120-126. Epub 2018 Mar 28.

Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

The etiology of Autism Spectrum Disorders (ASDs) as severe neurodevelopmental ailments is not known. However, several evidences point to dysregulation of immune system as an underlying cause of ASD. In the present study we evaluated the mRNA expression levels of TNF-α, TGF-β, IFN-γ, CXCL8, IL-1β, IL-2, 1L-4, IL-6, IL-17 in whole blood samples of 30 ASD patients and 41 age and sex-matched healthy subjects with means of real-time PCR. TNF-α, IL-6 and IL-17 have been shown to be significantly up-regulated in ASD patients compared with healthy subjects (P < 0.0001, P = 0.001 and P < 0.0001 respectively). IL-2 has been shown to be significantly down-regulated in total ASD patients (P < 0.0001). No significant difference has been found in expression levels of other cytokines between patients and healthy subjects. The present study provides further evidences for dysregulation of immune response in ASD patients.
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http://dx.doi.org/10.1016/j.cyto.2018.03.034DOI Listing
August 2018

Expression Analysis of Vitamin D Signaling Pathway Genes in Epileptic Patients.

J Mol Neurosci 2018 Apr 16;64(4):551-558. Epub 2018 Mar 16.

Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Vitamin D deficiency has been detected in epileptic patients. Vitamin D participates in neuroprotection, brain cell proliferation, and differentiation. Consequently, vitamin D supplementation has been suggested as an alternative treatment in epileptic patients. We aimed at assessment of vitamin D signaling pathway in epileptic patients. In the present study, we evaluated vitamin D serum concentration as well as expression of vitamin D receptor (VDR) gene and genes encoding for vitamin D activating enzyme 1-alpha-hydroxylase (CYP27B1) and deactivating enzyme 24-hyroxylase (CYP24A1) in epileptic patients compared with healthy individuals. We found significant lower levels of vitamin D in epileptic patients compared with healthy subjects. Expression analyses showed significant downregulation of VDR expression in peripheral blood of epileptic patients compared with healthy subjects (relative expression (REx) = 0.16, P < 0.001). However, there was no significant difference in CYP24A1 expression between epileptic patients and normal subjects. CYP27B1 expression analysis showed significant upregulation in male patients aged between 30 and 40 (REx = 5.43, P = 0.013). After using two-way ANCOVA for adjusting the effects of sex and age, there was a statistically significant difference in the VDR expression values between patient and control groups (P < 0.001). Spearman's correlation analysis showed no significant correlation between genes expression levels and patients' age or vitamin D serum concentrations. However, we found significant correlations between VDR expression levels and CYP24A1/ CYP27B1 expression levels in epileptic patients (r = 0.435 and P < 0.001; r = 0.26 and P = 0.02 respectively). There was also a significant correlation between the expression levels of CYP24A1 and CYP27B1 (r = 0.349 and P = 0.001). Our study shows a possible role for VDR in the pathogenesis of epilepsy.
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http://dx.doi.org/10.1007/s12031-018-1059-5DOI Listing
April 2018

Modulation of nociception by medial pre-optic area orexin a receptors and its relation with morphine in male rats.

Brain Res Bull 2016 10 15;127:141-147. Epub 2016 Sep 15.

Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran. Electronic address:

Introduction: Recent studies have shown that medial pre-optic area (MPOA) of hypothalamus are involved in nociception. Orexin A (hypocretin 1) has been found to have numerous applications including pain modulation. However, the role of orexin A receptors in the MPOA on the nociception has not been yet studied. Therefore, the aim of the present study is to investigate the effect of orexin A microinjection on MPOA on the nociception transmission and morphine induced analgesia in adult male rats.

Methods: Using stereotaxic surgery, a cannula was implanted at a site 1mm above the MPOA in the anesthetized rats. After the recovery period, tail-flick (TF) latency was measured as 0, 15, 30, 45 and 60min following the onset of two experimental protocols. Two experiments were carried out. Experiment 1: The male rats received intra-MPOA of 25, 100, 1000, 10000pmol/0.5μl orexin A or 0.5μl of aCSF (control, just 5min before the TF assay. Experiment 2: The aim of this experiment was to examine the effect of orexin microinjection into MPOA on morphine analgesia (3mg/kg,s.c). Morphine was administered 30min before orexin A intra-MPOA microinjection (four doses similar to experiment 1) or aCSF, then TF latency was measured.

Results: The results indicated that microinjection of orexin A into the MPOA showed anti-nociceptive effect in a time-dependent manner. Dose response curve results also revealed that the maximum effective dose of orexin A injection into MPOA for pain inhibition is 1000pmol/0.5μl. Co-administration of systemic morphine and orexin into the MPOA has additive analgesia with different time course compared morphine or orexin alone.

Conclusion: It can be concluded that MPOA OrexinA receptors play an important role in the modulation of pain in normal and morphine treated male rats.
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http://dx.doi.org/10.1016/j.brainresbull.2016.09.009DOI Listing
October 2016

Oxidative stress biomarkers in endometrial secretions: A comparison between successful and unsuccessful in vitro fertilization cycles.

J Reprod Immunol 2016 08 13;116:70-5. Epub 2016 May 13.

Department of Toxicology and Pharmacology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran.

A potential role of oxidative stress has been implicated in the outcome of various steps of assisted reproductive technology (ART). In a prospective cohort study, a total of 100 patients undergoing IVF/ICSI procedure due to male factor infertility were recruited based on the inclusion criteria. In all patients, 1-2ml of endometrial secretions was aspirated prior to embryo transfer. The oxidative stress markers in endometrial secretions, including superoxide dismutase (SOD), catalase (CAT) activities, lipid peroxidation (LPO), total thiol groups (TTG), and total antioxidant power (TAP) were investigated and compared among study groups including term pregnancy, failed IVF cycle, and miscarriage. P<0.05 was considered statistically different. Of the 100 patients, 28 cases (28%) resulted in ongoing pregnancy (biochemical pregnancy followed by clinical pregnancy), 11 cases (11%) resulted in miscarriage, and 61 cases (61%), resulted in failed IVF cycle. SOD, LPO, CAT, and TAP levels in the endometrial secretions of the three groups were statistically different (P-value <0.01, <0.001, <0.001, and <0.001, respectively). TTG levels in endometrial secretion of three groups were not statistically different (P-value=0.837). Our results indicated that higher levels of antioxidants such as SOD, CAT, or TAP, and lower levels of oxidative stress markers such as LPO in the endometrial secretions were associated with successful IVF outcome.
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http://dx.doi.org/10.1016/j.jri.2016.05.003DOI Listing
August 2016