Publications by authors named "Mahmoud Reza Hadjighassem"

8 Publications

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Effects of multiple injections on the efficacy and cytotoxicity of folate-targeted magnetite nanoparticles as theranostic agents for MRI detection and magnetic hyperthermia therapy of tumor cells.

Sci Rep 2020 02 3;10(1):1695. Epub 2020 Feb 3.

Brain and Spinal Cord Injury research center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.

Folate-targeted iron oxide nanoparticles (FA@FeO NPs) were prepared by a one-pot hydrothermal method and then used as cancer theranostic agents by combining magnetic resonance imaging (MRI) and magnetic hyperthermia therapy (MHT). Crystal structure, morphology, magnetic properties, surface functional group, and heating efficacy of the synthesized nanoparticles were characterized by XRD, TEM, VSM, FTIR, and hyperthermia analyses. The results indicated that the crystal structure, magnetic properties, and heating efficacy of the magnetite nanoparticles were improved by hydrothermal treatment. Toxicity of the prepared NPs was assessed in vitro and in vivo on the mammary cells and BALB/c mice, respectively. The results of the in vitro toxicity analysis showed that the FA@FeO NPs are relatively safe even at high concentrations of the NPs up to 1000 µg mL. Also, the targetability of the FA@FeO NPs for the detection of folate over-expressed cancer cells was evaluated in an animal model of breast tumor using MRI analysis. It was observed that T-weighted magnetic resonance signal intensity was decreased with the three-time injection of the FA@FeO NPs with 24 h interval at a safe dose (50 mg kg), indicating the accumulation and retention of the NPs within the tumor tissues. Moreover, the therapeutic efficacy of the MHT using the FA@FeO NPs was evaluated in vivo in breast tumor-bearing mice. Hyperthermia treatment was carried out under a safe alternating magnetic field permissible for magnetic hyperthermia treatment (f = 150 kHz, H = 12.5 mT). The therapeutic effects of the MHT were evaluated by monitoring the tumor volume during the treatment period. The results showed that the mice in the control group experienced an almost 3.5-fold increase in the tumor volume during 15 days, while, the mice in the MHT group had a mild increase in the tumor volume (1.8-fold) within the same period (P < 0.05). These outcomes give promise that FA@FeO NPs can be used as theranostic agents for the MRI and MHT applications.
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http://dx.doi.org/10.1038/s41598-020-58605-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997166PMC
February 2020

Brain Derived Neurotrophic Factor Modification of Epileptiform Burst Discharges in a Temporal Lobe Epilepsy Model.

Basic Clin Neurosci 2016 Apr;7(2):115-20

Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.; Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.

Introduction: Transforming Growth Factor-Beta 1 (TGF-β1) is a pleiotropic cytokine with potent anti-inflammatory property, which has been considered as an essential risk factor in the inflammatory process of Ischemic Stroke (IS), by involving in the pathophysiological progression of hypertension, atherosclerosis, and lipid metabolisms. -509C/T TGF-β1 gene polymorphism has been found to be associated with the risk of IS. The aim of this meta-analysis was to provide a relatively comprehensive account of the relation between -509C/T gene polymorphisms of TGF-β1 and susceptibility to IS.

Methods: Male Wistar rats were divided into sham (receiving phosphate buffered saline within dorsal hippocampus), pilocarpine (epileptic model of TLE), single injection BDNF (epileptic rats which received single high dose of BDBF within dorsal hippocampus), and multiple injections BDNF (epileptic rats which received BDNF in days 10, 11, 12, and 13 after induction of TLE) groups. Their electrocorticogram was recorded and amplitude, frequency, and duration of spikes were evaluated.

Results: Amplitude and frequency of epileptiform burst discharges were significantly decreased in animals treated with BDNF compared to pilocarpine group.

Conclusion: Our findings suggested that BDNF may modulate the epileptic activity in the animal model of TLE. In addition, it may have therapeutic effect for epilepsy. More studies are necessary to clarify the exact mechanisms of BDNF effects.
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http://dx.doi.org/10.15412/J.BCN.03070205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892316PMC
April 2016

cAMP-Epac Pathway Stimulation Modulate Connexin-43 and MicroRNA-21 Expression in Glioma Cells.

Basic Clin Neurosci 2015 Jan;6(1):52-7

Neuroscience Institute, Brain and Spinal Cord Injury Research Center, Tehran University of Medical Sciences, Tehran, Iran.; Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Introduction: Malignant astrocytic gliomas are the most common and lethal brain malignancies due to their refractory to the current therapies. Nowadays, molecular targeted therapy has attracted great attention in treatment of glioma. Connexin 43 (Cx43) and micro ribonucleic acid-21(miR-21) are among molecules that are involved in glioma development and progression. These molecules showed potential to be as target molecules with regard to glioma. Some studies have reported that cyclic adenosine monophosphate (cAMP) signaling could be effective on Cx43 and miR-21 in tissues other than in brain. We investigate possible relationship between β-adrenergic receptor and its newly described downstream, exchange protein directly activated by cAMP (Epac) signaling pathway and expression of Cx43 and miR-21 in low (1321N1) and high grade (U87MG) glioma cell lines.

Methods: We treated cells with β-adrenergic agonist and Epac activator with and without adenyl cyclase inhibitor. Cx43 and miR-21 expression were measured with real-time PCR.

Results: Our data showed that in 1321N1 cells, β-adrenergic-Epac pathway stimulation up and down-regulated Cx43 and miR-21 expression respectively. Whereas, in U87MG cells these interventions had no effect on Cx43 and miR-21 expression.

Discussion: These findings demonstrate that low grade astrocytoma cells have better response to our pharmacological interventions.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741269PMC
January 2015

Fluoxetin upregulates connexin 43 expression in astrocyte.

Basic Clin Neurosci 2014 ;5(1):74-9

Department of Neuroscience, School of Advanced Medical Technologies, Tehran University of Medical Sciences, Tehran, Iran ; Division of Neuroscience, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran ; Neuroscience Institute, Brain and Spinal cord Injury Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Introduction: Recent studies have shown that astrocytes play major roles in normal and disease condition of the central nervous system including multiple sclerosis (MS). Molecular target therapy studies in MS have revealed that connexin-43 (Cx43) and Aquaporin-4 (AQP4) contents of astrocytes undergo expression alteration. Fluoxetine had some effects in MS patients unrelated to its known antidepressant effects. Some of fluoxetine effects were attributed to its capability of cAMP signaling pathway stimulation. This study aimed to investigate possible acute effects of fluoxetine on Cx43 and AQP4 expression in astrocyte.

Methods: Astrocytoma cells were treated for 24 hours with fluoxetine (10 and 20 µg/ml) with or without adenyl cyclase (AC) and protein kinase A (PKA) inhibition. Cx43 expression at both mRNA and protein levels and AQP4 expression at mRNA level were evaluated.

Results: Acquired results showed that fluoxetine with and without AC and PKA inhibition resulted in Cx43 up-regulation both in mRNA and protein levels, whereas AQP4 expression have not changed.

Discussion: In conclusion, data showed that fluoxetine alone and in the absence of serotonin acutely up-regulated Cx43 expression in astrocytes that can be assumed in molecular target therapy of MS patients. It seems that cAMP involvement in fluoxetine effects need more researches.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4202606PMC
December 2014

BDNF modifies hippocampal KCC2 and NKCC1 expression in a temporal lobe epilepsy model.

Acta Neurobiol Exp (Wars) 2014 ;74(3):276-87

Department of Neuroscience, School of Advanced Technologies in Medicine,

Excitatory GABA actions, induced by altered expression of chloride transporters (KCC2/NKCC1), can contribute to seizure generation in temporal lobe epilepsy. In the present study, we evaluated whether BDNF administration can affect KCC2/NKCC1 expression, ictogenesis and behavioral alterations in this paradigm. Status epilepticus was induced in male rats with pilocarpine, followed by a treatment of either a single high dose or multiple injections of BDNF during the latent phase of temporal lobe epilepsy. Chloride transporters expression, spontaneous recurrent seizures, and hyperexcitability post-seizural behaviors were evaluated after treatment. NKCC1 protein expression was markedly upregulated, whereas that of KCC2 was significantly downregulated in epileptic hippocampi compared to intact controls. Application of BDNF (both single high dose and multiple injections) increased KCC2 expression in epileptic hippocampi, while NKCC1 expression was downregulated exclusively by the single high dose injection of BDNF. Development of spontaneous recurrent seizures was delayed but not prevented by the treatment, and hyperexcitability behaviors were ameliorated for a short period of time. To prevent GABA-A mediated depolarization and design appropriate treatment strategies for temporal lobe epilepsy, chloride transporters can be considered as a target. Future studies are warranted to investigate any possible therapeutic effects of BDNF via altering chloride transporters expression.
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May 2015

Selective β2 adrenergic agonist increases Cx43 and miR-451 expression via cAMP-Epac.

Mol Med Rep 2014 Jun 8;9(6):2405-10. Epub 2014 Apr 8.

Department of Neuroscience, School of Advanced Medical Technologies, Tehran University of Medical Sciences, Tehran 1417755469, Iran.

It has been demonstrated that connexin 43 (Cx43) and microRNAs have significant roles in glioma. Cyclic adenosine monophosphate (cAMP) is suggested to be a regulator of connexins and microRNAs. However, it remains elusive whether cAMP and exchange protein directly activated by cAMP (Epac2), have a regulatory effect on Cx43 and microRNA-451 (miR-451) in astrocytoma cells. We treated 1321N1 astrocytoma cells with a selective β2 adrenergic agonist and a selective Epac activator with and without adenyl cyclase and protein kinase A inhibition. Cx43 and miR-451 expression were measured. Next, we evaluated the effect of miR-451 overexpression on Cx43 expression. Cell proliferation was measured using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The results demonstrated that cAMP-Epac2 increased Cx43 and miR-451 expression. However, the alteration of miR-451 expression required a higher dose of drugs. Overexpression of miR-451 had no significant effect on Cx43 expression. The MTT assay showed that cAMP-Epac stimulation and miR-451 overexpression had a synergic inhibitory effect on cell proliferation. These findings may expand our understanding of the molecular biology of glioma and provide new potential therapeutic targets.
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http://dx.doi.org/10.3892/mmr.2014.2120DOI Listing
June 2014

The effects of poly L-lactic acid nanofiber scaffold on mouse spermatogonial stem cell culture.

Int J Nanomedicine 2013 27;8:4563-76. Epub 2013 Nov 27.

Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran ; Department of Anatomical Sciences, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.

Introduction: A 3D-nanofiber scaffold acts in a similar way to the extracellular matrix (ECM)/basement membrane that enhances the proliferation and self-renewal of stem cells. The goal of the present study was to investigate the effects of a poly L-lactic acid (PLLA) nanofiber scaffold on frozen-thawed neonate mouse spermatogonial stem cells (SSCs) and testis tissues.

Methods: The isolated spermatogonial cells were divided into six culture groups: (1) fresh spermatogonial cells, (2) fresh spermatogonial cells seeded onto PLLA, (3) frozen-thawed spermatogonial cells, (4) frozen-thawed spermatogonial cells seeded onto PLLA, (5) spermatogonial cells obtained from frozen-thawed testis tissue, and (6) spermatogonial cells obtained from frozen-thawed testis tissue seeded onto PLLA. Spermatogonial cells and testis fragments were cryopreserved and cultured for 3 weeks. Cluster assay was performed during the culture. The presence of spermatogonial cells in the culture was determined by a reverse transcriptase polymerase chain reaction for spermatogonial markers (Oct4, GFRα-1, PLZF, Mvh(VASA), Itgα6, and Itgβ1), as well as the ultrastructural study of cell clusters and SSCs transplantation to a recipient azoospermic mouse. The significance of the data was analyzed using the repeated measures and analysis of variance.

Results: The findings indicated that the spermatogonial cells seeded on PLLA significantly increased in vitro spermatogonial cell cluster formations in comparison with the control groups (culture of SSCs not seeded on PLLA) (P≤0.001). The viability rate for the frozen cells after thawing was 63.00% ± 3.56%. This number decreased significantly (40.00% ± 0.82%) in spermatogonial cells obtained from the frozen-thawed testis tissue. Both groups, however, showed in vitro cluster formation. Although the expression of spermatogonial markers was maintained after 3 weeks of culture, there was a significant downregulation for some spermatogonial genes in the experimental groups compared with those of the control groups. Furthermore, transplantation assay and transmission electron microscopy studies suggested the presence of SSCs among the cultured cells.

Conclusion: Although PLLA can increase the in vitro cluster formation of neonate fresh and frozen-thawed spermatogonial cells, it may also cause them to differentiate during cultivation. The study therefore has implications for SSCs proliferation and germ cell differentiation in vitro.
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http://dx.doi.org/10.2147/IJN.S45535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848747PMC
June 2014

Bumetanide reduces seizure frequency in patients with temporal lobe epilepsy.

Epilepsia 2013 Jan 12;54(1):e9-12. Epub 2012 Oct 12.

Cellular and Molecular Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Alterations in the balance of K-Na-2Cl cotransporter (NKCC1) and Na-Cl cotransporter (KCC2) activity may cause depolarizing effect of γ-aminobutyric Acid (GABA), and contribute to epileptogenesis in human temporal lobe epilepsy. NKCC1 facilitates accumulation of chloride inside neurons and favors depolarizing responses to GABA. In the current pilot study we provide the first documented look at efficacy of bumetanide, a specific NKCC1 antagonist, on reduction of seizure frequency in adult patients with temporal lobe epilepsy. According to our results, seizure frequency was reduced considerably in these patients. Furthermore, epileptiform discharges decreased in two of our patients. If the efficacy of bumetanide is proven in large scale studies, it can be used as a supplemental therapy in temporal lobe epilepsy.
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http://dx.doi.org/10.1111/j.1528-1167.2012.03654.xDOI Listing
January 2013