Publications by authors named "Kamran Ghaedi"

159 Publications

Bee Venom-Derived BBB Shuttle and its Correlation with Oligodendrocyte Proliferation Markers in Mice Model of Multiple Sclerosis.

Neurotox Res 2021 Apr 19. Epub 2021 Apr 19.

Department of Toxicology and Pharmacology, Faculty of Pharmacy, Isfahan Pharmaceutical Science Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.

Multiple sclerosis is a chronic demyelinating disease with a functional disturbance in the immune system and axonal damages. It was shown that Apamin as a blood-brain barrier shuttle acts as a Ca2+ activated K+ channels (SK channels) blocker. In this study, the effects of Apamin on oligodendrocyte differentiation markers were evaluated on an induced model of MS. Briefly, C57BL/6 male mice (22 ± 5 g) except the control group were fed with 0.2% (w/w) cuprizone pellets for 6 weeks. After cuprizone withdrawal, mice were divided randomly into six groups. Apamin (100 µg/kg/BW) was administered intraperitoneally as a co-treatment during phase I (demyelination) or post-treatment phase II (remyelination) twice a week. Mice were anesthetized, perfused with phosphate-buffered saline, then fixed brains were coronally sectioned and the changes in oligodendrocytes markers such as Olig2, PDGFR-α, and BrdU incorporation were assessed by immunohistochemistry assay. Apamin administration increased Olig2+ cells in phase I as compared to the control group (p < 0.0001). Also, a decreasing trend in PDGFRa+ cells observed after cuprizone withdrawal (p < 0.001). 5-Bromo-2'-deoxyuridine (BrdU) incorporation test was confirmed stimulation of oligodendrocyte progenitor cell proliferation in phase I in the Apamin exposed group (p < 0.0001), especially at the subventricular zone. This study highlights the potential therapeutic effects of Apamin as a bee venom-derived peptide on oligodendrocyte precursor proliferation and elevation in myelin content in an oxidative induced multiple sclerosis model due to cuprizone exposure.
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http://dx.doi.org/10.1007/s12640-021-00361-xDOI Listing
April 2021

A new hypothetical model for pancreatic development based on change in the cell division orientation.

Gene 2021 Mar 26;785:145607. Epub 2021 Mar 26.

Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science & Technology, University of Isfahan, Hezar Jerib Ave., Azadi Sq., Isfahan, Iran. Electronic address:

Although lifelong renewal and additional compensatory growth in response to demand are undeniable facts, so far, no specific stem cells have been found for pancreatic cells. According to the consensus model, the development of pancreas results from the hierarchical differentiation of pluripotent stem cells towards the appearance of the first endocrine and exocrine cells at approximately 7.5 to 8th gestation week (GW) of human embryo. However, the primitive endocrine cells arising from the embryonic phase of development do not appear to be mature or fully functional. Asymmetric localization of cellular components, such as Numb, partition protein complexes (PAR), planar cell polarity components, and certain mRNAs on the apical and basal sides of epithelial cells, causes cellular polarization. According to our model, the equal distribution of cellular components during symmetric cell division yields similar daughter cells that are associated with duct expansion. In contrast, asymmetric cell division is associated with uneven distribution of cellular components among daughter cells, resulting in different fates. Asymmetric cell division leads to duct branching and the development of acinar and stellate cells by a daughter cell, as well as the development of islet progenitor cells through partial epithelial-to-mesenchymal transition (EMT) and delamination of another daughter cell. Recently, we have developed an efficient method to obtain insulin-secreting cells from the transdifferentiation of hESC-derived ductal cells inducing a partial EMT by treatment with Wnt3A and activin A in a hypoxic environment. Similar models can be offered for other tissues and organs such as mammary glands, lungs, prostate, liver, etc. This model may open a new horizon in the field of regenerative medicine and be useful in explaining the cause of certain abnormalities, such as the occurrence of certain cysts and tumors.
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http://dx.doi.org/10.1016/j.gene.2021.145607DOI Listing
March 2021

Fndc5 knockdown significantly decreased the expression of neurotrophins and their respective receptors during neural differentiation of mouse embryonic stem cells.

Hum Cell 2021 Mar 8. Epub 2021 Mar 8.

Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Hezar Jerib Ave, Azadi Square, 81746, Isfahan, Iran.

Fibronectin type III domain-containing-5 (Fndc5) is a trans-membrane protein which is involved in a variety of cellular events including neural differentiation of mouse embryonic stem cells (mESCs) as its knockdown and overexpression diminishes and facilitates this process, respectively. However, downstream targets of Fndc5 in neurogenesis are still unclear. Neurotrophins including NGF, BDNF, NT-3, and NT-4 are the primary regulators of neuronal survival, growth, differentiation, and repair. These biomolecules exert their actions through binding to two different receptor families, Trk and p75NTR. In this study, considering the fact that neurotrophins and their receptors play crucial roles in neural differentiation of ESCs, we sought to evaluate whether knockdown of Fndc5 decreased neural differentiation of mESCs by affecting the neurotrophins and their receptors expression. Results showed that at neural progenitor stage, the mRNA and protein levels of BDNF, Trk, and p75NTR receptors decreased following the Fndc5 knockdown. In mature neural cells, still, the expression of Trk and p75NTR receptors at mRNA and protein levels and BDNF and NGF expression only at protein levels showed a significant decrease in Fndc5 knockdown cells compared to control groups. Taken together, our results suggest that decreased efficiency of neural differentiation following the reduction of Fndc5 expression could be attributed to decreased levels of NGF and BDNF proteins in addition to their cognate receptors.
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http://dx.doi.org/10.1007/s13577-021-00517-zDOI Listing
March 2021

Increased expression of MUSASHI1 in epithelial breast cancer cells is due to down regulation of miR-125b.

BMC Mol Cell Biol 2021 Feb 4;22(1):10. Epub 2021 Feb 4.

Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Hezar Jerib Ave., Azadi Square, Isfahan, P.O. Code 81746, Iran.

Background: Musashi1 (MSI1) is an oncogenic protein with a crucial role in the proliferation and characteristics of the epithelial cells in breast cancer. The change in expression of MSI1 has a role in solid tumor progression. There are different factors that regulate MSI1 expression in various cancer tissues including microRNAs which are considered as one of the most important of these factors. The aim of our study is identification of the molecular cause of maximal expression of MSI1 in epithelial breast cancer cell lines.

Results: Among predicted microRNAs, miR-125b, miR-637 and miR-802 were able to significantly reduce the luciferase activity. In addition, the relative expression of these three miRNAs were measured in the cancerous cell lines that results showed a significant reduction in expression of all microRNAs. On the other hand, only the overexpression of miR-125b caused a change in the expression pattern of MSI1 in breast epithelial cancer cell lines. Accordingly, our results demonstrated that the exogenous expression of miR-125b decreased not only the MSI1 protein but also expression of epithelial markers in breast cancer cells.

Conclusions: The results of luciferase reporter assay showed that MSI1 is a direct target for miR-125b in epithelial breast cancer cells. Moreover, higher amount of MSI1 in those cell lines seems due to the reduced amount of miR-125b, which is responsible for epithelial features of those kinds of cancer cells. Therefore, the modulation of miR-125b may be a potential approach to help to combat against epithelial breast tumors.
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http://dx.doi.org/10.1186/s12860-021-00348-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863248PMC
February 2021

A combination of herbal compound (SPTC) along with exercise or metformin more efficiently alleviated diabetic complications through down-regulation of stress oxidative pathway upon activating Nrf2-Keap1 axis in AGE rich diet-induced type 2 diabetic mice.

Nutr Metab (Lond) 2021 Jan 19;18(1):14. Epub 2021 Jan 19.

Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Hezar Jerib Avenue, Azadi Sq., Isfahan, 81746-73441, Iran.

Background: SPTC is a mix of four herbal components (Salvia officinalis, Panax ginseng, Trigonella foenum-graeceum, and Cinnamomum zeylanicum) which might be prevented the development of AGE rich diet-induced diabetic complication and liver injury through activated the nuclear factor erythroid-2-related-factor-2 (Nrf2) pathway. Nrf2, as a master regulator of antioxidant response elements by activating cytoprotective genes expression, is decreased oxidative stress that associated with hyperglycemia and increases insulin sensitivity. the aim of this study was to assess whether the combination therapy of SPTC along with exercise or metformin moderate oxidative stress related liver injurie with more favorable effects in the treatment of AGE rich diet-induced type 2 diabetic mice.

Methods: We induced diabetes in C57BL/6 mice by AGE using a diet supplementation and limitation of physical activity. After 16 weeks of intervention, AGE fed mice were compared to control mice. Diabetic mice were assigned into seven experimental groups (each group; n = 5): diabetic mice, diabetic mice treated with SPTC (130 mg/kg), diabetic mice treated with Salvia Officinalis (65 mg/kg), diabetic mice treated with metformin (300 mg/kg), diabetic mice with endurance exercise training, diabetic mice treated with SPTC + metformin (130/300 mg/kg), diabetic mice treated with SPTC + exercise training.

Results: SPTC + exercise and SPTC + metformin reduced diabetic complications like gain weight, water and calorie intake, blood glucose, insulin, and GLUT4 content more efficiently than each treatment. These combinations improved oxidative stress hemostasis by activating the Nrf2 signaling pathway and attenuating keap1 protein more significantly.

Conclusion: Eventually, combined treatment of SPTC with exercise or metformin as a novel approach had more beneficial effects to prevent the development of diabetes and oxidative stress associated with hyperglycemia.
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http://dx.doi.org/10.1186/s12986-021-00543-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816367PMC
January 2021

Full small molecule conversion of human fibroblasts to neuroectodermal cells via a cocktail of Dorsomorphin and Trichostatin A.

Regen Ther 2020 Dec 15;15:44-52. Epub 2020 Jun 15.

Department of Cellular Biotechnology at Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.

A revolutionary new approach to produce efficient cells is to induce transdifferentiation to make it conventional in therapeutic strategies. In this paper, we describe a brief cocktail of small molecules including Dorsomorphin (DSM) and Trichostatin A (TSA) to produce safe neuroectodermal cells as a resource to produce various types of nervous system cells for a safe cytotherapy. Furthermore, in order to optimize this strategy, we implemented a cocktail of neurotrophic factors to enhance the viability of the cell. This modification was accompanied by pretreatment of the culture dishes with a combination of poly-l-ornithine and laminin and fibronectin. In order to decrease the length of protocol and transdifferentiation variation concomitantly, TSA was utilized as an epigenetic modulator. Finally, this improved protocol mediated neuroectodermal conversion of human fibroblasts within 12 days with an average efficiency of 24%, promising a fast strategy to produce neuroectodermal cells applicable for therapeutic purposes in neural damages. Here we induce neural cells by a cocktail consists of two small molecules of DSM and TSA. Our protocol is a 12 day protocol with the efficiency of 24% which is a more efficient one in comparison to previous protocols inducing neural cells. Consequently, our protocol shortens the path of in vitro and preclinical studies in the field of neural conversion and neuroregeneration.
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http://dx.doi.org/10.1016/j.reth.2020.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770348PMC
December 2020

Integrative in silico and in vitro transcriptomics analysis revealed new lncRNAs related to intrinsic apoptotic genes in colorectal cancer.

Cancer Cell Int 2020 Nov 10;20(1):546. Epub 2020 Nov 10.

Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.

Background: Pathogenesis of colorectal cancer (CRC) is connected to deregulation of apoptosis while the effect of lncRNAs, as critical regulatory molecules, on this pathway is not clear well. The present study aimed to identify differential expression of genes and their related lncRNAs which are significantly associated with intrinsic apoptotic pathway in CRC.

Methods: The connection between CRC and apoptosis was investigated by literature reviews and the genes were enriched by using Enrichr. At the next step, differential expression of enriched genes were evaluated between normal and tumor populations in data sets and were downloaded from GEO. Then, meta-analysis and probe re-annotation were performed. For lncRNAs selection through the highest expression correlation with each of candidate genes, mRNA-lncRNA interaction of screened genes and all of lncRNAs were visualized using Cytoscape. Identified differential expression genes and lncRNAs were validated using TCGA-COAD and the obtained data were confirmed by in vitro studies in the presence of Ag@Glu-TSC nanoparticle as an apoptotic inducer. Cytotoxicity and apoptosis induction effect of Ag@Glu-TSC on Caco-2 cells was determined via MTT and Annexin V/PI, respectively. The expression of genes and lncRNAs were assayed in presence of mentioned nanoparticle. Finally, the expression level of desired genes and lncRNAs were proven in CRC tissues compared to adjacent normal tissues.

Results: After detection of 48 genes associated with intrinsic apoptosis in CRC according to literature, Enrichr screened 12 common genes involved in this pathway. Among them, 6 genes including BCL2, BCL2L11, BAD, CASP7, CASP9, and CYCS expression reduced in tumor tissue compared to normal according to meta-analysis studies and RNA-seq TCGA data. Afterwards, association of 8 lncRNAs comprising CDKN2B-AS1, LOC102724156, HAGLR, ABCC13, LOC101929340, LINC00675, FAM120AOS, PDCD4-AS1 with more than 5 candidate genes were identified. In vitro studies revealed that four selected lncRNAs including, CDKN2B-AS1, LOC102724156, HAGLR and FAM120AOS were significantly increased in the presence of in optimum concentration of Ag@Glu/TSC and decreased in tumor tissues versus adjacent normal tissues.

Conclusion: This study developed a new data mining method to screen differentially expressed lncRNAs which are involved in regulation of intrinsic apoptosis pathway in CRC quickly using published gene expression profiling microarrays. Moreover, we could validate a number of these regulators in the cellular and laboratory disease models.
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http://dx.doi.org/10.1186/s12935-020-01633-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653898PMC
November 2020

A compound downregulation of SRRM2 and miR-27a-3p with upregulation of miR-27b-3p in PBMCs of Parkinson's patients is associated with the early stage onset of disease.

PLoS One 2020 10;15(11):e0240855. Epub 2020 Nov 10.

Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.

Parkinson's disease (PD) is diagnosed when motor symptoms emerges, which almost 70% of dopamine neurons are lost. Therefore, early diagnosis of PD is crucial to prevent the progress of disease. Blood-based biomarkers, which are minimally invasive, potentially used for diagnosis of PD, including miRNAs. The aim of this study was to assess whether SRRM2 and miR-27a/b-3p could act as early diagnostic biomarkers for PD. Total RNAs from PBMCs of 30 PD's patients and 14 healthy age and gender matched subjects was extracted. The expression levels of respective genes were assessed. Data were presented applying a two-tailed unpaired t-test and one-way ANOVA. We observed significant down-regulation of SRRM2 (p = 0.0002) and miR-27a-3p (p = 0.0001), and up-regulation of miR-27b-3p (p = 0.02) in PBMCs of Parkinson's patients. Down-regulation of miR-27a-3p is associated with increasing disease severity, whereas the up-regulation of miR-27b-3p was observed mostly at HY-1 and disease duration between 3-5 years. There was a negative correlation between SRRM2 and miR-27b-3p expressions, and miR-27a-3p positively was correlated with miR-27b-3p. Based on functional enrichment analysis, SRRM2 and miR-27a/b-3p acted on common functional pathways. miR-27a/b-3p could potentially predict the progression and severity of PD. Although both miRs had no similarity on expression, a positive correlation between both miRs was identified, supporting their potential role as biomarkers in clinical PD stages. Of note that SRRM2 and miR-27a-3p were able to distinguish PD patients from healthy individuals. Functional analysis of the similarity between genes associated with SRRM2 and miR-27a/b-3p indicates common functional pathways and their dysfunction correlates with molecular etiopathology mechanisms of PD onset.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240855PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654768PMC
December 2020

Upregulation of miR-9 and miR-193b over human Th17 cell differentiation.

Mol Genet Genomic Med 2020 12 31;8(12):e1538. Epub 2020 Oct 31.

Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.

Background: Th17 cells are a newly discovered subset of CD4 T cells known as key participants in various immune responses and inflammatory conditions including autoimmune diseases. Mi(cro)RNAs are a family of non-coding RNAs that regulate numerous critical immune functions. Immuno-miRNAs modulate cell biological processes in T cells, such as differentiation and function of Th17 cells. The aim of the present study is to investigate the expression of miR-9-5p, miR-193b-3p, and autoimmunity-related genes during human Th17 cells differentiation.

Methods: Human naïve CD4 T cells were purified from peripheral blood mononuclear cells (PBMCs) by magnetic cell sorting system (MACS) and their purity was checked by flow-cytometric analysis. Naïve CD4 T cells were cultured under Th17-polarizing condition for 6 days. IL- 17 secretion was determined by means of enzyme-linked immunosorbent assay (ELISA). Next, the expression levels of miRNAs and putative targets genes were assessed by qRT-PCR at different time points of differentiation.

Results: Our result showed dramatic downregulation of TCF7, MAP3K1, ENTPD1, and NT5E genes during human Th17 differentiation. Polarization also had a significant inducible effect on the expression of miR-9 and miR-193b over differentiation of human Th17 cells. According to our results, miR-9-5p and miR-193b-3p may contribute to Th17 differentiation probably by inhibiting the expression of negative regulators of Th17 differentiation.

Conclusion: This study confirmed deregulation of TCF7, MAP3K1, ENTPD1, and NT5E genes in Th17 differentiation process and introduced miR-9 and miR-193b as Th17 cell-associated miRNAs, making them good candidates for further investigations.
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http://dx.doi.org/10.1002/mgg3.1538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767567PMC
December 2020

Receptor for Advanced Glycation End Products Acts as a Fuel to Colorectal Cancer Development.

Front Oncol 2020 29;10:552283. Epub 2020 Sep 29.

Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, Academic Center for Education, Culture and Reasearch (ACECR), Isfahan, Iran.

Receptor for advanced glycation end-products (RAGE) is a multiligand binding and single-pass transmembrane protein taken in diverse chronic inflammatory conditions. RAGE behaves as a pattern recognition receptor, which binds and is engaged in the cellular response to a variety of damage-associated molecular pattern molecules, as well as HMGB1, S100 proteins, and AGEs (advanced glycation end-products). The RAGE activation turns out to a formation of numerous intracellular signaling mechanisms, resulting in the progression and prolongation of colorectal carcinoma (CRC). The RAGE expression correlates well with the survival of colon cancer cells. RAGE is involved in the tumorigenesis, which increases and develops well in the stressed tumor microenvironment. In this review, we summarized downstream signaling cascade activated by the multiligand activation of RAGE, as well as RAGE ligands and their sources, clinical studies, and tumor markers related to RAGE particularly in the inflammatory tumor microenvironment in CRC. Furthermore, the role of RAGE signaling pathway in CRC patients with diabetic mellitus is investigated. RAGE has been reported to drive assorted signaling pathways, including activator protein 1, nuclear factor-κB, signal transducer and activator of transcription 3, SMAD family member 4 (Smad4), mitogen-activated protein kinases, mammalian target of rapamycin, phosphoinositide 3-kinases, reticular activating system, Wnt/β-catenin pathway, and Glycogen synthase kinase 3β, and even microRNAs.
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http://dx.doi.org/10.3389/fonc.2020.552283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551201PMC
September 2020

Selective dysregulation of ABC transporters in methotrexate-resistant leukemia T-cells can confer cross-resistance to cytarabine, vincristine and dexamethasone, but not doxorubicin.

Curr Res Transl Med 2021 Jan 16;69(1):103269. Epub 2020 Oct 16.

Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Iran.

Pediatric acute lymphoblastic leukemia (pALL) includes 75 % of childhood leukemias, and methotrexate (MTX) is one of the most effective chemotherapy agents prescribed for pALL treatment. The aim of this study was to establish and characterize an MTX-resistant tumor cell model in order to study the mechanism contributing to drug sensitivity loss in pALL. Parental CCRF-CEM cells were treated with a gradual increasing concentration of MTX from 5 nM to 1.28 μM. The resistant subline was then characterized according to the cellular morphology, cellular growth curves and specific mRNA expression changes associated with drug resistance in ALL. Moreover, in vitro cytotoxicity assays were used to analyze cells relative responsiveness to a set of clinically used anti-ALL chemotherapy drugs. The morphological changes observed in the new R-CCRF-CEM/MVCD subline were associated with dysregulation of the EMT-related genes, Twist1 and CDH1. Cells demonstrated downregulation of ABCC1 and the overexpression of ABCA2, ABCA3, and ABCB1 membrane transporters. However, short treatment of the sensitive and parental cell line with MTX did not affect the expression profiles of the former ABC pumps. Moreover, R-CCRF-CEM/MVCD cells demonstrated cross-resistance to cytarabine (cytosine arabinoside, ara-C), vincristine, and dexamethasone, but not doxorubicin. The induced cross-resistance to specific chemotherapy drugs may possibly be attributed to selective dysregulation of the ABC transporters and EMT-related genes. These data may pave the way for the development of new cancer therapeutic strategies.
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http://dx.doi.org/10.1016/j.retram.2020.09.003DOI Listing
January 2021

The interaction between MALAT1 target, miR-143-3p, and RALGAPA2 is affected by functional SNP rs3827693 in breast cancer.

Hum Cell 2020 Oct 3;33(4):1229-1239. Epub 2020 Sep 3.

Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.

A higher expression of MALAT1 has been reported in breast cancer. However, more studies are needed to decipher the mechanisms by which this lncRNA imposes its oncogenic effects. In this study, blood and tissue samples were taken from healthy normal and breast cancer subjects. qPCR was used to analyze the gene expression. HRM-PCR method was carried out to genotype the selected samples. Computational analysis was recruited to find novel targets of MALAT1 and miR-143-3p. The data analyses revealed that MALAT1 was up-regulated in breast cancer and could be a distinctive factor to diagnose cancer. The expression of MALAT1 was inversely correlated with miR-143-3p expression in the studied clinical samples. The down-regulation of miR-143-3p was proven in the clinical tumor samples as compared to the healthy controls. A negative correlation of miR-143-3p with its putative target, RALGAPA2 was observed. A functional SNP rs3827693 located within the 3'UTR region of RALGAPA2 mRNA was validated in this study to associate with breast cancer risk. The rs3827693 allele G significantly decreased the breast cancer incidence and augmented the negative correlation between RALGAPA2 and miR-143-3p, presumably through strengthening the interaction between these two transcripts. This study proposed MALAT1 miR-143-3p and miR-143-3p RALGAPA2 axis in breast cancer, whereby the latter can be altered by the clinically functional SNP rs3827693.
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http://dx.doi.org/10.1007/s13577-020-00422-xDOI Listing
October 2020

Fluctuating expression of miR-584 in primary and high-grade gastric cancer.

BMC Cancer 2020 Jul 2;20(1):621. Epub 2020 Jul 2.

Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.

Background: Gastric cancer is the fifth most common cancer worldwide. Along with environmental factors, such as Helicobacter pylori (H. pylori) infection, genetic changes play important roles in gastric tumor formations. miR-584 is a less well-characterized microRNA (miRNA), with apparent activity in human cancers. However, miR-584 expression pattern in gastric cancer development has remained unclear. This study aims to analyze the expression of miR-584 in gastric cancer samples and investigates the associations between this miRNA and H. pylori infection and clinical characteristics.

Methods: The expression level of miR-584 was studied in primary gastric cancers versus healthy control gastric mucosa samples using the RT-qPCR method. The clinical data were analyzed statistically in terms of miR-584 expression. In silico studies were employed to study miR-584 more broadly in order to assess its expression and find new potential target genes.

Results: Both experimental and in silico studies showed up-regulation of miR-584 in patients with gastric cancer. This up-regulation seems to be induced by H. pylori infection since the infected samples showed increased levels of miR-584 expression. Deeper analyses revealed that miR-584 undergoes a dramatic down-regulation in late stages, invasive and lymph node-metastatic gastric tumors. Bioinformatics studies demonstrated that miR-584 has a substantial role in cancer pathways and has the potential to target STAT1 transcripts. Consistent with the inverse correlation between TCGA RNA-seq data of miR-584 and STAT1 transcripts, the qPCR analysis showed a significant negative correlation between these two RNAs in a set of clinical samples.

Conclusion: miR-584 undergoes up-regulation in the stage of primary tumor formation; however, becomes down-regulated upon the progression of gastric cancer. These findings suggest the potential of miR-584 as a diagnostic or prognostic biomarker in gastric cancer.
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http://dx.doi.org/10.1186/s12885-020-07116-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345521PMC
July 2020

Circular RNAs and Glioma: Small Molecule with Big Actions.

Curr Mol Med 2021 ;21(1):25-44

Department of Medical Genetics, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

Glioma is known as one of very important tumors that is associated with high rate of mortality worldwide. The mean rate of survival of these patients has not changed (approximately 14 months) even with improvements in comprehensive therapeutic approaches, such as chemotherapy, radiation, and surgery. Therefore, it seems that new therapeutic or developed platforms are needed. In this regard, more understanding about genetic and epigenetic modifications in the glioma, could contribute to finding and developing these platforms. Among epigenetic mechanisms, circular RNAs have crucial roles in the glioma pathogenesis. Reported by several studies, some of the abilities of circRNAs include the exhibition of tissue specificity in humans and regulation of genes. Research has also confirmed the participation of circRNAs in different pathological or biological procedures, including migration, invasion, and apoptosis of glioma. Herein, we summarized circular RNAs involved in glioma.
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http://dx.doi.org/10.2174/1566524020666200610171139DOI Listing
January 2021

Role of non-coding RNAs as novel biomarkers for detection of colorectal cancer progression through interaction with the cell signaling pathways.

Gene 2020 Aug 22;753:144796. Epub 2020 May 22.

Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran; Department of Cellular Biotechnology, Cell Science Research Centre, Royan Institute for Biotechnology, ACECR, Isfahan, Iran. Electronic address:

Colorectal cancer (CRC) is one of the most common types of cancer which affects the colon and the rectum. Approximately one third of annual CRC mortality occurs due to the late detection of this type of cancer. Therefore, there is an urgent need for more powerful diagnostic and prognostic tools for identification and treatment of colorectal tumorigenesis. Non-coding RNAs (ncRNAs) have been implicated in the pathology of CRC and also linked to metastasis, proliferation, differentiation, migration, angiogenesis and apoptosis in numerous cancers. Recently, attention has turned towards ncRNAs as specific targets for diagnosis, prognosis and treatment of various types of cancers, including CRC. In this review, we have tried to outline the roles of ncRNAs, and their involvement in signaling pathways responsible for the progression of CRC.
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http://dx.doi.org/10.1016/j.gene.2020.144796DOI Listing
August 2020

Intracellular functions of RNA-binding protein, Musashi1, in stem and cancer cells.

Stem Cell Res Ther 2020 05 24;11(1):193. Epub 2020 May 24.

Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Hezar Jerib Ave., Azadi Square, Isfahan, P.O. Code 81746, Iran.

RNA-binding protein, musashi1 (MSI1), is a main protein in asymmetric cell division of the sensory organ precursor cells, whereas its expression is reported to be upregulated in cancers. This protein is a critical element in proliferation of stem and cancer stem cells, which acts through Wnt and Notch signaling pathways. Moreover, MSI1 modulates malignancy and chemoresistance of lung cancer cells via activating the Akt signaling. Due to the main role of MSI1 in metastasis and cancer development, MSI1 would be an appropriate candidate for cancer therapy. Downregulation of MSI1 inhibits proliferation of cancer stem cells and reduces the growth of solid tumors in several cancers. On the other hand, MSI1 expression is regulated by microRNAs in such a way that several different tumor suppressor miRNAs negatively regulate oncogenic MSI1 and inhibit migration and tumor metastasis. The aim of this review is summarizing the role of MSI1 in stem cell proliferation and cancer promotion.
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http://dx.doi.org/10.1186/s13287-020-01703-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245930PMC
May 2020

Mechanistic Pathways of Malignancy in Breast Cancer Stem Cells.

Front Oncol 2020 30;10:452. Epub 2020 Apr 30.

Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.

Breast cancer stem cells (BCSCs) are the minor population of breast cancer (BC) cells that exhibit several phenotypes such as migration, invasion, self-renewal, and chemotherapy as well as radiotherapy resistance. Recently, BCSCs have been more considerable due to their capacity for recurrence of tumors after treatment. Recognition of signaling pathways and molecular mechanisms involved in stemness phenotypes of BCSCs could be effective for discovering novel treatment strategies to target BCSCs. This review introduces BCSC markers, their roles in stemness phenotypes, and the dysregulated signaling pathways involved in BCSCs such as mitogen-activated protein (MAP) kinase, PI3K/Akt/nuclear factor kappa B (NFκB), TGF-β, hedgehog (Hh), Notch, Wnt/β-catenin, and Hippo pathway. In addition, this review presents recently discovered molecular mechanisms implicated in chemotherapy and radiotherapy resistance, migration, metastasis, and angiogenesis of BCSCs. Finally, we reviewed the role of microRNAs (miRNAs) in BCSCs as well as several other therapeutic strategies such as herbal medicine, biological agents, anti-inflammatory drugs, monoclonal antibodies, nanoparticles, and microRNAs, which have been more considerable in the last decades.
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http://dx.doi.org/10.3389/fonc.2020.00452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212408PMC
April 2020

New insights into the cellular activities of Fndc5/Irisin and its signaling pathways.

Cell Biosci 2020 30;10:51. Epub 2020 Mar 30.

1Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.

Fndc5, a well-defined myokine and also identified as an adipokine, has a critical role in modulation of metabolism and protection against obesity. These important functions are mediated by irisin, a secretory peptide produced from proteolytic processing of Fndc5. The other beneficial physiological effects of irisin are alleviation of oxidative stress, neuroprotective effects, and anti-inflammatory properties and associated anti-metastatic effects. Fndc5/irisin exerts its biological effects through several intracellular signaling pathways. The major signaling pathway is thought to be MAPK signaling pathways which are involved in neural differentiation, browning of white adipocytes, as well as osteoblast proliferation and differentiation. Other essential functions of Fndc5/irisin are mediated through additional pathways including AMPK pathway, PI3K/AKT, and STAT3/Snail. Thorough understanding of the mechanisms of irisin actions are essential in order to develop Fndc5/irisin for therapeutic purposes. In the present review, we focus on the current knowledge of the signaling pathways that elicit irisin actions.
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http://dx.doi.org/10.1186/s13578-020-00413-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106581PMC
March 2020

The Efficacy of Electrospun PAN/Kefiran Nanofiber and Kefir in Mammalian Cell Culture: Promotion of PC12 Cell Growth, Anti-MCF7 Breast Cancer Cells Activities, and Cytokine Production of PBMC.

Int J Nanomedicine 2020 31;15:717-728. Epub 2020 Jan 31.

Department of Biology, Faculty of Science, University of Isfahan, Hezar Jerib, Isfahan, Iran.

Background: Kefiran is a useful polysaccharide made of branched glucogalactose which is produced by microorganisms. Here the anti-MCF-7 breast cancer cells activity of kefiran and cytokine productions (IL-6) of peripheral blood mononuclear cells (PBMC) treated by kefiran was studied. Also, the effect of using kefiran as a useful and cost-effective scaffold in neural stem cell culture (PC12 cell culture) was investigated.

Material And Methods: Kefiran was produced from raw milk with 0.5% fat and 10 g of kefir grains. After incubation for 48 hrs at room temperature, the solvent collected (crude kefiran). These samples were kept at 100°C for 1 hr (boiled kefiran) and the supernatant was precipitated by ethanol (pure kefiran). Then, the electrospun nanofibers, pure polyacrylonitrile (PAN), PAN/kefiran 5%, and PAN/kefiran 10% were fabricated and used as scaffolds in the cell culture. The structure of fabricated was studied by SEM and the cytokine production (IL-6) in vitro in the cell culture supernatant of PBMC line after treatment with kefiran (1mg/mL, 5 mg/mL) and kefiran-PAN 5% and 10% were carried out by enzyme-linked immunosorbent assay (ELISA). The attachment of PC12 cells was examined by inverted microscope. Also, cytotoxicity of kefiran for PC12 and MCF7 cells and morphological changes of PC12 cells were evaluated by MTT and Cresyl violet staining (Nissl staining) respectively.

Results: The mean diameter of fabricated PAN/kefiran 5% and 10% nanofibers were 310.2±43.97 nm. The contact angle measurement results (26.9± 1.9 for the pure PAN scaffold vs 12.3± 1.13 for the PAN/kefiran) revealed enhanced hydrophilicity of scaffolds upon the incorporation of kefiran and PAN. Seeding of PC12 cells on the scaffolds showed that fabrication of kefiran into PAN led to the enhancement of cell attachment, proliferation, and morphological changes. Also, the promotion of PBMC growth and decreasing of MCF7 cell lines viability were shown through MTT assay. No significant changes were measured for the level of IL-6 in PAN/kefiran 5% treated cells compared to the control (p ≥ 0.05).

Conclusion: These results suggest superior properties of kefiran/PAN nanofibrous scaffolds for the neural stem cell culture especially for repairing injured spinal cord. Also, the pure kefiran could be used for the enhancement of PBMC growth and reducing the MCF7 cancerous cells growth. So, using biocompatible, anti-bacterial, and anti-tumor kefiran/PAN nanofibers for regenerative medicine seems promising.
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http://dx.doi.org/10.2147/IJN.S232264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002384PMC
April 2020

rs1016860 of BCL2 3'UTR associates with hsa-miR-629-5p binding potential in breast cancer and gastric cancer in Isfahan population.

Gene 2020 May 17;738:144457. Epub 2020 Feb 17.

Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran.

Introduction: Breast cancer is caused by the interaction of inherited and environmental risk factors. Also, gastric cancer is the second fatal carcinoma. B-cell leukemia/lymphoma 2 gene family plays a crucial role in carcinogenesis by inhibiting the apoptosis process.

Materials And Methods: In this study, 129 patients with breast cancer and 132 controls as well as 136 patients with gastric cancer and 50 controls were enrolled. We used Real time PCR to determine the genotype of the samples. Finally, we analyzed the diagram based on high temperature melting curve diagram using the MICPCR software, followed by bioinformatics prediction of rs1016860 functions.

Results: rs1016860 of BCL2 gene with CC, CT, and TT genotypes were observed in this region. The association of Estrogen receptor and Progesterone receptor, cancer stage and grade of cancer in the patients with genotypes was significant in breast cancer. The association of the status of primary tumor in the patients with genotypes is significant in gastric cancer (Chi-Square p < 0.05 and p = 0.000 did not follow the Hardy-Weinberg equilibrium).

Discussion: It was predicted that the TT genotype could be dangerous in breast cancer and gastric cancer; it is expected via bioinformatics that this SNP could lead to signaling pathways of cancer progression, by altering the binding potential of miR-629-5p to BCL2 3'UTR.
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http://dx.doi.org/10.1016/j.gene.2020.144457DOI Listing
May 2020

ErbB4 3'-UTR Variant (c.*3622A>G) is Associated with ER/PR Negativity and Advanced Breast Cancer.

Indian J Clin Biochem 2020 Jan 28;35(1):115-120. Epub 2018 Sep 28.

Department of Biology, Faculty of Basic Science, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.

A genetic variant may alter a gene expression level and as a result be associated with pathological characteristics in breast cancer. In this research, the frequency and association of the ErbB4 3'-untranslated region (3'-UTR) variant, rs12471583 (c.*3622A>G) was studied in an Iranian breast cancer patients. assessment was performed to predict the function of the rs12471583 variant located on the 3'-UTR of ErbB4. Furthermore, as a case-control study, this polymorphism was genotyped in 243 breast cancer patients and non-cancerous controls using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The Armitage's trend test and regular association tests were performed to analyze a possible association between the rs12471583 and risk of breast cancer and its relevant pathological traits. The bioinformatics analysis predicted that the rs12471583 SNP is located on the four miRNA binding sites, including miR-511-5p, miR-4659a-5p, miR-4659b-5p, and miR-6830-3p. According to logistic regression tests, the G allele is negatively associated with ER- (OR = 0.20, 95% C.I. = 0.04-0.93,  = 0.026), PR- (OR = 0.31, 95% C.I. = 0.10-0.98,  = 0.039), ER-/PR- (OR = 0.20, 95% C.I. = 0.04-0.93,  = 0.026), and advanced breast cancer (OR = 0.40, 95% C.I. = 0.18-0.85,  = 0.016). It has been found that ErbB4 expression may be linked to unfavorable outcomes in breast cancer. Likewise, our results suggest that the G allele may strengthen miRNA-ErbB4 binding efficiency and as a result reduce expression of ErbB4. This is a possible explanation for the observed association.
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http://dx.doi.org/10.1007/s12291-018-0793-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995472PMC
January 2020

Drug Resistance Biomarkers and Their Clinical Applications in Childhood Acute Lymphoblastic Leukemia.

Front Oncol 2019 17;9:1496. Epub 2020 Jan 17.

Division of Cellular and Molecular Biology, Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Sciences and Technologies, University of Isfahan, Isfahan, Iran.

Biomarkers are biological molecules found in body fluids or tissues, which can be considered as indications of a normal or abnormal process, or of a condition or disease. There are various types of biomarkers based on their application and molecular alterations. Treatment-sensitivity or drug resistance biomarkers include prognostic and predictive molecules with utmost importance in selecting appropriate treatment protocols and improving survival rates. Acute lymphoblastic leukemia (ALL) is the most prevalent hematological malignancy diagnosed in children with nearly 80% cure rate. Despite the favorable survival rates of childhood ALL (chALL), resistance to chemotherapeutic agents and, as a consequence, a dismal prognosis develops in a significant number of patients. Therefore, there are urgent needs to have robust, sensitive, and disease-specific molecular prognostic and predictive biomarkers, which could allow better risk classification and then better clinical results. In this article, we review the currently known drug resistance biomarkers, including somatic or germ line nucleic acids, epigenetic alterations, protein expressions and metabolic variations. Moreover, biomarkers with potential clinical applications are discussed.
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http://dx.doi.org/10.3389/fonc.2019.01496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978753PMC
January 2020

Positive effects of conjugated linoleic acid (CLA) on the PGC1-α expression under the inflammatory conditions induced by TNF-α in the C2C12 cell line.

Gene 2020 Apr 24;735:144394. Epub 2020 Jan 24.

Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan (UI), Isfahan 81746-73441, Iran; Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology (RIB), ACECR, Khorasgan, Isfahan 81651-31378, Iran. Electronic address:

The aim of the current study was to evaluate the effects of conjugated linoleic acid (CLA) on the expression of the genes involved in the reduction of inflammatory conditions induced by tumor necrosis factor alpha (TNF-α). To fulfill this, the C2C12 murine myoblast cell line was used. The experimental treatments consisted of 50 and 100 µM of CLA with 10, 15 and 20 ng/mL of TNF-α. Our results indicated that the concentrations of 50, 100 and 150 µM of CLA at 24 and 48 h increased the cell survival rate (p < 0.05), as compared with the control group. The effect of pre-treating CLA before the inflammation induced by TNF-α showed that the amount of cell death caused by TNF-α was inhibited in both 50 and 100 µM concentrations of CLA (p < 0.05). Modulatory effects of CLA on PGC1-α and Fndc5 transcript levels showed that the PGC1-α and Fndc5 expression levels were significantly increased 48 h after treating with 50 and 100 µM of CLA (p < 0.05). Overall, these findings indicate that using CLA could considerably improve the inflammatory condition induced by TNF-α.
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http://dx.doi.org/10.1016/j.gene.2020.144394DOI Listing
April 2020

Modified level of miR-376a is associated with Parkinson's disease.

J Cell Mol Med 2020 02 12;24(4):2622-2634. Epub 2020 Jan 12.

Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.

Parkinson's disease (PD) is a frequent progressive neurodegenerative disorder. Impaired mitochondrial function is a major feature of sporadic PD. Some susceptibility or causative genes detected in PD are strongly associated with mitochondrial dysfunction including PGC1α, TFAM and GSK3β. microRNAs (miRNAs) are non-coding RNAs whose altered levels are proven in disparate PD models and human brains. Therefore, the aim of this study was to detect modulations of miRs upstream of PGC1α, TFAM and GSK3β in association with PD onset and progress. In this study, a total of 33 PD subjects and 25 healthy volunteers were recruited. Candidate miRNA (miR-376a) was selected through target prediction tools and literature survey. Chronic and acute in vitro PD models were created by MPP -intoxicated SHSY5Y cells. The levels of miR-376a and aforementioned genes were assessed by RT-qPCR. The expression of target genes was decreased in chronic model while there were dramatically up-regulated levels of those genes in acute model of PD. miR-376a was strongly altered in both acute and chronic PD models as well as PBMCs of PD patients. Our results also showed overexpression of PGC1α, and TFAM in PBMCs is inversely correlated with down-regulation of miR-376a, suggesting that miR-376a possibly has an impact on PD pathogenesis through regulation of these genes which are involved in mitochondrial function. miR-376a expression in PD-derived PBMCs was also correlated with disease severity and may serve as a potential biomarker for PD diagnosis. This is the first study showing altered levels of miR-376a in PD models and PBMCs, suggesting the probable role of this miRNA in PD pathogenesis. The present study also proposed TFAM and PGC1α as target genes of miR-376a for the first time, through which it possibly can exert its impact on PD pathogenesis.
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http://dx.doi.org/10.1111/jcmm.14979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028860PMC
February 2020

Signaling pathways involved in colorectal cancer progression.

Cell Biosci 2019 2;9:97. Epub 2019 Dec 2.

3Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.

Colorectal cancer (CRC) is the fourth leading cause of the worldwide cancer mortality. Different molecular mechanisms have been attributed to the development and progress of CRC. In this review, we will focus on the mitogen-activated protein kinase (MAPK) cascades downstream of the epidermal growth factor receptor (EGFR), Notch, PI3K/AKT pathway, transforming growth factor-β (TGF-β), and Wnt signaling pathways. Various mutations in the components of these signaling pathways have been linked to the development of CRC. Accordingly, numerous efforts have been carried out to target the signaling pathways to develop novel therapeutic approaches. Herein, we review the signaling pathways involved in the incidence and progression of CRC, and the strategies for the therapy targeting components of signaling pathways in CRC.
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http://dx.doi.org/10.1186/s13578-019-0361-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889432PMC
December 2019

Could analysis of testis-specific genes, as biomarkers in seminal plasma, predict presence of focal spermatogenesis in non-obstructive azoospermia?

Andrologia 2020 Mar 3;52(2):e13483. Epub 2019 Dec 3.

Department of Reproductive Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.

Cell-free seminal mRNA (cfs-mRNA) exists in the human ejaculate that is proposed as a potential noninvasive procedure to prognosis pathophysiological conditions. This study applied cfs-mRNA of ESX1, ZMYND15 and its target haploid genes (TNP1 and PRM1) to identify the presence of spermatozoa in men with azoospermia. This study included 35 semen samples from 16 normozoospermic and 19 nonobstructive azoospermic individuals. Expression levels of target genes were determined by real-time reverse transcription-polymerase chain reaction using ΔΔCt method. The expression level of these genes (ZMYND15, TNP1 and PRM1) was significantly decreased in semen samples of nonobstructive azoospermia compared to normozoospermia. Similarly, the expression level of TNP1 and PRM1 was significantly decreased in the sample with negative sperm (SR-) versus positive sperm retrieval (SR+). The expression level of these genes may have the potential for prediction of successful sperm retrieval with high sensitivity and specificity according to the receiver operating characteristics (ROC) curve analysis.
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http://dx.doi.org/10.1111/and.13483DOI Listing
March 2020

Evaluation of The Expression Levels of Three Long Non-Coding RNAs in Multiple Sclerosis.

Cell J 2020 Jul 14;22(2):165-170. Epub 2019 Oct 14.

Department of Biology, School of Sciences, University of Isfahan, Isfahan, Iran.

Objective: Multiple sclerosis (MS) is a chronic disorder involving both inflammatory and neurodegenerative responses. Long non-coding RNAs (lncRNAs) have been had an emerging role as the biomarkers of different disorders, including autoimmune diseases. Previous studies have shown that NR_003531.3 (MEG3a), AC000061.1_201, and AC007182.6 play a role in the pathogenesis of human autoimmune diseases. However, the potential significance of these lncRNAs, as the diagnostic biomarkers of MS, has not been studied yet. We aimed to quantitatively evaluate the expression levels of NR_003531.3, AC000061.1_201, and AC007182.6 in peripheral blood samples of MS patients in comparison with healthy controls.

Materials And Methods: In this case-control study, the blood samples from 20 MS patients and 10 healthy controls were collected. Total RNA was extracted, and the expression levels of three selected lncRNAs were quantitatively measured using the quantitative real time-polymerase chain reaction (qRT-PCR) method.

Results: We detected a significant down-regulation in the expression of NR_003531.3 in MS patients, while no marked changes were observed in the expression of AC000061.1_201 and AC007182.6 in patients compared with controls. Based on the receiver operating characteristic (ROC) curve analysis, NR_003531.3 could discriminate MS patients from healthy subjects effectively. Regarding the prognosis of MS patients, NR_003531.3 is significantly and inversely correlated with the expanded disability status scale (EDSS).

Conclusion: The potential role of NR_003531.3 lncRNA as a diagnostic biomarker to distinguish MS patients is proposed. Prognostically, NR_003531.3 correlates with lower disability rates in MS patients.
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http://dx.doi.org/10.22074/cellj.2020.6555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874792PMC
July 2020

The antitoxic effects of quercetin and quercetin-conjugated iron oxide nanoparticles (QNPs) against HO-induced toxicity in PC12 cells.

Int J Nanomedicine 2019 26;14:6813-6830. Epub 2019 Aug 26.

Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan, Iran.

Background: We recently showed that quercetin-conjugated iron oxide nanoparticles (QNPs) promoted the bioavailability of quercetin (Qu) in the brain of rats and improved the learning and memory of diabetic rats. In this study, we characterized the modifications in the antitoxic effects of Qu after conjugation.

Materials And Methods: We conjugated Qu to dextran-coated iron oxide nanoparticles (DNPs) and characterized DNPs and QNPs using FTIR, XRD, DLS, Fe-SEM, and EDX analyzes. The antiradical properties of Qu, DNPs, and QNPs were compared by 2, 2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity assay. Catalase-like activities of DNPs and QNPs were estimated using catalase activity assay kit, and the antitoxic effects of Qu and QNPs were evaluated with spectrophotometry, MTT assay, flow cytometry, and real-time q-PCR.

Results: Qu had a stronger anti-radical activity than DNPs and its activity decreased after being conjugated to DNPs. The catalase-like activity of DNPs remained intact after conjugation. DNPs had less toxicity on PC12 cells viabilities as compared to free Qu, and the conjugation of Qu with DNPs attenuated its cytotoxicity. Furthermore, MTT assay results indicated 24 h pretreatment with Qu had more protective effects than QNPs against HO-induced cytotoxicity, while Qu and QNPs had the same effects for 48 and 72 h incubation. Although the total antioxidant capacity of Qu was attenuated after conjugation, the results of flow cytometry and real-time q-PCR confirmed that 24 h pretreatment with the low concentrations of Qu and QNPs had the similar antioxidant, anti-inflammatory, and anti-apoptotic effects against the cytotoxicity of HO.

Conclusion: Qu and QNPs showed the similar protective activities against HO-induced toxicity in PC12 cells. Given the fact that QNPs have magnetic properties, they may serve as suitable carriers to be used in neural research and treatment.
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http://dx.doi.org/10.2147/IJN.S212582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716587PMC
February 2020