ORCID Profile
0000-0003-3500-4346
Current Organisations
Westmead Institute for Medical Research
,
UNSW Graduate Research School
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Publisher: Springer Science and Business Media LLC
Date: 13-01-2015
DOI: 10.1007/S11064-014-1509-6
Abstract: Glutamate is an excitatory neurotransmitter that is released by the majority of central nervous system synapses and is involved in developmental processes, cognitive functions, learning and memory. Excessive elevated concentrations of Glu in synaptic cleft results in neural cell apoptosis which is called excitotoxicity causing neurodegenerative diseases. Hence, we investigated the possibility of extremely low frequency electromagnetic fields (ELF-EMF) as a risk factor which is able to change Glu concentration in synaptic clef. Synaptosomes as a model of nervous terminal were exposed to ELF-EMF for 15-55 min in flux intensity range from 0.1 to 2 mT and frequency range from 50 to 230 Hz. Finally, all raw data by INForm v4.02 software as an artificial neural network program was analyzed to predict the effect of whole mentioned range spectra. The results showed the tolerance of all effects between the ranges from -35 to +40 % compared to normal state when glutamatergic systems exposed to ELF-EMF. It indicates that glutamatergic system attempts to compensate environmental changes though release or reuptake in order to keep the system safe. Regarding to the wide range of ELF-EMF acquired in this study, the obtained outcomes have potential for developing treatments based on ELF-EMF for some neurological diseases however, in vivo experiments on the cross linking responses between glutamatergic and cholinergic systems in the presence of ELF-EMF would be needed.
Publisher: Springer Science and Business Media LLC
Date: 13-01-2020
DOI: 10.1038/S41598-019-55850-Z
Abstract: Translating the findings of genome wide association studies (GWAS) to new therapies requires identification of the relevant immunological contexts to interrogate for genetic effects. In one of the largest GWAS, more than 200 risk loci have been identified for Multiple Sclerosis (MS) susceptibility. Infection with Epstein-Barr virus (EBV) appears to be necessary for the development of Multiple Sclerosis (MS). Many MS risk loci are associated with altered gene expression in EBV infected B cells (LCLs). We have interrogated this immunological context to identify interaction between MS risk loci and EBV DNA copy number, intrinsic growth rate and EBV encoded miRNA expression. The EBV DNA copy number was associated with significantly more risk alleles for MS than for other diseases or traits. EBV miRNAs BART4-3p and BART3-5p were highly associated with EBV DNA copy number and MS risk loci. The poliovirus receptor (PVR) risk SNP was associated with EBV DNA copy number, PVR and miRNA expression. Targeting EBV miRNAs BART4-3p and BART3-5p, and the gene PVR, may provide therapeutic benefit in MS. This study also indicates how immunological context and risk loci interactions can be exploited to validate and develop novel therapeutic approaches.
Publisher: Elsevier BV
Date: 02-2022
DOI: 10.1016/J.JAUT.2021.102781
Abstract: To investigate the molecular mechanisms through which Epstein-Barr virus (EBV) may contribute to Systemic Lupus Erythematosus (SLE) pathogenesis, we interrogated SLE genetic risk loci for signatures of EBV infection. We first compared the gene expression profile of SLE risk genes across 459 different cell/tissue types. EBV-infected B cells (LCLs) had the strongest representation of highly expressed SLE risk genes. By determining an SLE risk allele effect on gene expression (expression quantitative trait loci, eQTL) in LCLs and 16 other immune cell types, we identified 79 SLE risk locus:gene pairs putatively interacting with EBV infection. A total of 10 SLE risk genes from this list (CD40, LYST, JAZF1, IRF5, BLK, IKZF2, IL12RB2, FAM167A, PTPRC and SLC15A) were targeted by the EBV transcription factor, EBNA2, differentially expressed between LCLs and B cells, and the majority were also associated with EBV DNA copy number, and expression level of EBV encoded genes. Our final gene network model based on these genes is suggestive of a nexus involving SLE risk loci and EBV latency III and B cell proliferation signalling pathways. Collectively, our findings provide further evidence to support the interaction between SLE risk loci and EBV infection that is in part mediated by EBNA2. This interplay may increase the tendency towards EBV lytic switching dependent on the presence of SLE risk alleles. These results support further investigation into targeting EBV as a therapeutic strategy for SLE.
Publisher: Springer Science and Business Media LLC
Date: 29-12-2013
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.CBI.2015.06.023
Abstract: Safranal, a component of saffron, indicates anti-tumor activities however, the precise mechanism of this effect has remained elusive. In this study we investigated tubulin assembly and structure in the presence of safranal to open the new horizons about the potential of safranal as an anti-tumor agent via microtubule disfunction. Anti-microtubule activity of safranal was evaluated by turbidimetric method and transmission electron microscopy (TEM). Safranal (0.1-70μM) was incubated with tubulin (5μM) and tubulin structural changes was surveyed using fluorometry. Tubulin binding site with safranal was estimated by molecular docking. Microtubule polymerization decreased significantly in the presence of safranal, regardless of its concentration and the IC50 value was obtained 72.19μM. Safranal was situated between α and β tubulin closer to α-tubulin and hydrogen bond with Gly 142 and hydrophobic interactions played critical roles for safranal molecule stabilization in binding site. It seems that decline of tubulin assembly could result from tubulin structural changes through safranal bindings between alpha and beta tubulin with ΔG(0) of -5.63kcal/mol. Safranal can be taken into account as an anticancer agent however, in vivo experiments are required to confirm this conclusion.
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.IJBIOMAC.2014.01.006
Abstract: Acetylcholinesterase (AChE) is the enzyme that controls the acetylcholine (ACh) concentrations in cholinergic synaptic clefts by hydrolyzing ACh to choline and acetate. Cholinergic synapses are involved in important functions such as learning, memory and cognition. In this study, we investigated the effects of a wide range of extremely low frequency electromagnetic fields (ELF-EMFs) on synaptic ACh concentrations through AChE enzyme activity assay. Synaptosome suspensions were prepared as a neural terminus from cerebral cortex of sheep brain. Prepared synaptosomes were exposed to ELF-EMFs with frequency ranging from 50 Hz to 230 Hz for duration between 15 and 120 min and flux intensity between 0.1 mT and 1.7 mT. Consequently, AChE activity was measured by Ellman method. Raw data were analyzed by neural network based software, Inform 4.02, to predict AChE activity pattern through nine 3D curves. These curves showed that AChE activity decreases when exposed to ELF-EMFs of 1.2 mT to 1.7 mT intensity and 50 Hz to 90 Hz frequency. Thus, it is proposed that exposure to fields of in this range of frequency-intensity would be effective in clinical treatments of cholinergic disorders to increase synaptic ACh concentration. However, more in vivo experiments are needed to develop this suggested treatment.
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.PEP.2015.10.007
Abstract: Tau protein consists of six different isoforms and each one has particular physiological roles. In order to analyze the specific function of each single isoforms, large quantity of highly purified tau isoforms is essential. Many studies have been done to purify tau isoforms by heat treatment, followed by perchloric acid and glycerol precipitation. We found out that 1N/4R tau is soluble in glycerol, that is why mentioned methods do not work for purifying this isoform. In this study, large amounts of active and highly purified (97%) 1N/4R tau protein has been prepared by utilization of trichloroacetic acid as precipitating agent.
Publisher: Springer Science and Business Media LLC
Date: 16-10-2019
DOI: 10.1038/S41435-019-0089-5
Abstract: Epstein–Barr Virus (EBV) infection appears to be necessary for the development of Multiple Sclerosis (MS), although the specific mechanisms are unknown. More than 200 single-nucleotide polymorphisms (SNPs) are known to be associated with the risk of developing MS. About a quarter of these are also highly associated with proximal gene expression in B cells infected with EBV (lymphoblastoid cell lines—LCLs). The DNA of LCLs is hypomethylated compared with both uninfected and activated B cells. Since methylation can affect gene expression, and so cell differentiation and immune evasion, we hypothesised that EBV-driven hypomethylation may affect the interaction between EBV infection and MS. We interrogated an existing dataset comprising three in iduals with whole-genome bisulfite sequencing data from EBV transformed B cells and CD40L-activated B cells. DNA methylation surrounding MS risk SNPs associated with gene expression in LCLs (LCLeQTL) was less likely to be hypomethylated than randomly selected chromosomal regions. Differential methylation was independent of genomic features such as promoter regions, but genes preferentially expressed in EBV-infected B cells, including the LCLeQTL genes, were underrepresented in the hypomethylated regions. Our data does not indicate MS genetic risk is affected by EBV hypomethylation.
Publisher: Bentham Science Publishers Ltd.
Date: 04-2014
DOI: 10.2174/0929866521666131223120713
Abstract: Cellular protein degradation systems are necessary to avoid the accumulation of misfolded or damaged proteins. Deficiency in these systems might cause to partial degradation of misfolded proteins and generation of amyloidogenic fragments. Protein misfolding is believed to be the primary cause of neurodegenerative disorders such as Alzheimer's disease (AD). In this study, we investigate effect of two anionic peptide fragments including, an acidic fragment of human Aβ (Aβ1-11) and a phosphorylated fragment of β-Casein (Tetraphosphopeptide), on tau protein aggregation. According to our results, these peptide fragments, induced tau fibrillization in vitro. In sum, we suggest that structural and conformational characters of inducer are as important as charge distribution on anionic inducer molecules however more experiments would be need to exactly confirm this suggestion.
Publisher: Oxford University Press (OUP)
Date: 04-10-2018
DOI: 10.1093/HMG/DDY324
Abstract: Epidemiological, molecular and genetic studies have indicated that high serum vitamin D levels are associated with lower risk of several autoimmune diseases. The vitamin D receptor (VDR) binding sites in monocytes and dendritic cells (DCs) are more common in risk genes for diseases with latitude dependence than in risk genes for other diseases. The transcription factor genes Zinc finger MIZ domain-containing protein 1 (ZMIZ1) and interferon regulatory factor 8 (IRF8)-risk genes for many of these diseases-have VDR binding peaks co-incident with the risk single nucleotide polymorphisms (SNPs). We show these genes are responsive to vitamin D: ZMIZ1 expression increased and IRF8 expression decreased, and this response was affected by genotype in different cell subsets. The IL10/IL12 ratio in tolerogenic DCs increased with vitamin D. These data indicate that vitamin D regulation of ZMIZ1 and IRF8 in DCs and monocytes contribute to latitude-dependent autoimmune disease risk.
Publisher: Springer Science and Business Media LLC
Date: 11-05-2014
Publisher: Springer Science and Business Media LLC
Date: 20-03-2014
Publisher: Springer Science and Business Media LLC
Date: 30-04-2019
Publisher: Cold Spring Harbor Laboratory
Date: 24-10-2020
DOI: 10.1101/2020.10.23.351353
Abstract: SARS-CoV-2, the causative agent of COVID-19, has an RNA genome, which is, overall, closely related to the bat coronavirus sequence RaTG13. However, the ACE2-binding domain of this virus is more similar to a coronavirus isolated from a Guangdong pangolin. In addition to this unique feature, the genome of SARS-CoV-2 (and its closely related coronaviruses) has a low CpG content. This has been postulated to be the signature of an evolutionary pressure exerted by the host antiviral protein ZAP. Here, we analyzed the sequences of a wide range of viruses using both alignment-based and alignment free approaches to investigate the origin of SARS-CoV-2 genome. Our analyses revealed a high level of similarity between the 5’UTR of SARS-CoV-2 and that of the Guangdong pangolin coronavirus. This suggests bat and pangolin coronaviruses might have recombined at least twice (in the 5’UTR and ACE2 binding regions) to seed the formation of SARS-CoV-2. An alternative hypothesis is that the lineage preceding SARS-CoV-2 is a yet to be s led bat coronavirus whose ACE2 binding domain and 5’UTR are distinct from other known bat coronaviruses. Additionally, we performed a detailed analysis of viral genome compositions as well as expression and RNA binding data of ZAP to show that the low CpG abundance in SARS-CoV-2 is not related to an evolutionary pressure from ZAP.
Publisher: IEEE
Date: 04-2015
Publisher: Springer Science and Business Media LLC
Date: 27-08-2016
DOI: 10.1007/S12017-016-8437-3
Abstract: Reelin is an extracellular glycoprotein which contributes to synaptic plasticity and function of memory in the adult brain. It has been indicated that the Reelin signaling cascade participates in Alzheimer's disease (AD). Besides the neurons, glial cells such as astrocytes also express Reelin protein. While functional loss of astrocytes has been reported to be associated with AD, dysfunction of astrocytic Reelin signaling pathway has not received much attention. Therefore, we investigated the effects of α-boswellic acid (ABA) as one of the major component of Boswellia serrata resin on primary fetal human astrocytes under a stress paradigm as a possible model for AD through study on Reelin cascade. For this aim, we used streptozotocin (STZ), in which from an outlook generates Alzheimer's hallmarks in astrocytes, and assayed Reelin expression, Tau and Akt phosphorylation as well as reactive oxygen species (ROS) generation and apoptosis in the presences of ABA. Our results indicated that while STZ (100 µM) down-regulated the expression of Reelin, ABA (25 µM) up-regulated its expression (p < 0.01) for 24 h. ABA efficiently reduced hyperphosphorylated Tau (Ser404) in STZ-treated astrocytes (p < 0.01). Furthermore, STZ-induced apoptosis by increasing cleaved caspase three (p < 0.01) and ROS generation (p < 0.01), a further pathological hallmark of Tauopathy. On the other hand, ABA decreased ROS generation and promoted proliferation of astrocytes through elevating Survivin expression (p < 0.01). These results showed that ABA could be considered as a potent therapeutic agent for prevention and decreasing the progression of Alzheimer's hallmarks in astrocytes however, more in vivo studies would be needed.
Publisher: Springer Science and Business Media LLC
Date: 09-02-2013
DOI: 10.1007/S00775-013-0980-X
Abstract: In recent decades, considerable efforts have been made to understand the mechanism of memory, cognition, and relevant neurodegenerative diseases in the human brain. Several studies have shown the importance of microtubule proteins in the memory mechanism and memory dysfunction. Microtubules possess dynamicity, which is essential for functions of neuronal networks. Microtubule-associated proteins, i.e., tau, play vital roles in microtubule stability. On the other hand, the ferromagnetic mineral magnetite (Fe(3)O(4)) has been detected in the normal human brain, and elevated levels of magnetite are also observed in the brains of Alzheimer's disease patients. Therefore, we propose that a relationship between microtubule organization in axons and brain magnetite nanoparticles is possible. In this study we found alterations of microtubule polymerization in the presence of increasing concentrations of magnetite through transmission electron microscopy images and a turbidimetry method. Structural changes of microtubule and tau protein, as an essential microtubule-associated protein for tubulin assembly, were detected via circular dichroism spectroscopy, intrinsic fluorescence, and 8-anilino-1-naphthalenesulfonic acid fluorometry. We predicted three possible binding sites on tau protein and one possible binding site on tubulin dimer for magnetite nanoparticles. Magnetite also causes the morphology of PC12 cells to change abnormally and cell viability to decrease. Finally, we suggest that magnetite changes microtubule dynamics and polymerization through two paths: (1) changing the secondary and tertiary structure of tubulin and (2) binding to either tubulin dimer or tau protein and preventing tau-tubulin interaction.
No related grants have been discovered for Ali Afrasiabi.