Samareh salavatipour, M.,
Tavakoli, S.,
Tavoosi, S.,
Nodehi, M.,
Baghsheikhi, A.H.,
Vaezi, M.,
Verdi, J.,
Rahgozar, S.,
Barkhordar, M.,
Ahmadvand, M. International Journal Of Cancer Management (25384422)17(1)
Context: Adoptive T-cell therapy with chimeric antigen receptor (CAR) has shown tremendous progress in hematological cancers. However, some obstacles, such as high price tag, cytokine release syndrome, inability to penetrate solid tumors, and manufacturing complexity limit the wide application of this therapy. Natural killer (NK) cells can kill target cells via mechanisms similar to those of CD8+ cytotoxic T cells; therefore, CAR-NK cell therapy is a promising strategy for cancer treatment. Evidence Acquisition: In this manuscript, all articles published in English regarding CAR-NKs and their application for the treatment of different types of cancers were collected from several databases, including PubMed, Scopus, and Google Scholar, using related keywords such as "Cancer, CAR construction, NK cells, and CAR-NK cells". Results: Compared with CAR-T cells, CAR-NK cells have several advantages, including less toxicity, a high potential opportunity for universal off-the-shelf manufacturing, increased infiltration into solid tumors, overcoming resistant tumor microenvironment, and absence of graft-versus-host disease (GVHD). Conclusions: In this review, we discuss NK cell biology, the source of CAR-NK cells, CAR structure, advances, challenges, and ways to overcome these challenges in CAR-NK cell therapy. Furthermore, we have summarized and highlighted some preclinical and clinical studies in this field. © 2024, Samareh Salavati et al.
Zangooie, A.,
Tavoosi, S.,
Arabhosseini, M.,
Halimi, A.,
Zangooie, H.,
Baghsheikhi, A.H.,
Rahgozar, S.,
Ahmadvand, M.,
Jarrahi, A.M.,
Salehi, Z. Bmc Cancer (14712407)24(1)
Following publication of the original article [1], the authors identified an error in the affiliations of Shima Tavoosi, Hossein Baghsheikhi, Soheila Rahgozar and Zahra Salehi. Shima Tavoosi is affiliated to institution 3, Hossein Baghsheikhi to institution 8, Soheila Rahgozar to institution 3, and Zahra Salehi is affiliated to institution 11. The original article [1] has been corrected. © The Author(s) 2024.
Nanomedicine Research Journal (24767123)9(2)pp. 172-179
Objective(s): Pediatric acute lymphoblastic leukemia (pALL) is the most prevalent neoplasm in children. pALL diagnostic process is invasive, and children need to be anesthetized for bone marrow aspiration. Exosomes are nanoparticles that reflect the status of parental cells. Given the elevated levels of exosomes in the peripheral blood of pALL patients, they can be readily extracted from blood plasma. The aim of this study was to compare the reliability of two different techniques of exosome purification in order to select the best method for clinical use in pALL. Methods: Exosomes were isolated from plasma samples using two methods: ultracentrifugation and the ExoQuick exosome isolation (EQ) kit. The performances of these methods were compared based on the nanoparticle tracking analysis (NTA), field emission electron microscopy (FESEM), and immunoblotting assays. Results: NTA results showed that exosome fractions extracted by the EQ kit were more concentrated and homogeneous compared with the ultracentrifugation method. Electron microscopy depicted spherical morphology for the isolated exosomes in both methods; however, the appearance of exosomes enriched by the commercial kit was more intact. Following the immunoblotting assays investigating the exosomal biomarkers, densitometry analysis showed that the exosome populations related to the EQ kit had higher concentrations and extreme purity. Conclusions: The data demonstrated that the commercial kit exhibited superior efficacy in isolating concentrated, intact, and pure exosomes from small quantities of patients' plasma samples when compared to the standard ultracentrifugation method. According to those findings, the ExoQuick exosome segregation kit was preferred to be used in pALL diagnostic investigations. © 2024 Tehran University of Medical Sciences. All rights reserved.
Scientific Reports (20452322)14(1)
Acute lymphoblastic leukemia (ALL) is a cancer with high incidence rate in pediatrics and drug resistance is a major clinical concern for ALL treatment. The current study was designed to evaluate the role of exosomal miR-326 in diagnosis and treatment of children with B-ALL. Exosomes were isolated from plasma samples of 30 patients and B-ALL cell lines followed by characterization, using nanoparticle tracking analysis, immunoblotting assay and electron microscopy. qPCR showed significantly increased levels of miR-326 in patients exosomes compared with non-cancer controls (P < 0.05, AUC = 0.7500). Moreover, a comparison between the sensitive and drug resistant patients revealed a prognostic value for the exosomal miR326 (P < 0.05, AUC = 0.7755). Co-culture studies on drug resistant patient primary cells and B-ALL cell lines suggested that exosomes with high miR-326 level act as vehicles for reducing cells viability. B-ALL cell line transfection with naked miR-326 mimic confirmed the results, and fluorescence microscopy validated uptake and internalization of exosomes by target cells. The novel introduced features of the exosomal miR-326 address a non-invasive way of diagnosing primary drug resistance in pediatric ALL and advocates a novel therapeutic strategy for this cancer. © 2024, The Author(s).
Samareh salavatipour, M.,
Tavakoli, S.,
Halimi, A.,
Tavoosi, S.,
Baghsheikhi, A.H.,
Talebi-taheri, A.,
Niloufari, M.,
Salehi, Z.,
Verdi, J.,
Rahgozar, S. Frontiers in Pharmacology (16639812)15
Background: Ubiquitin-specific peptidases (USPs), also known as deubiquitinating enzymes (DUBs), play a crucial role in maintaining cellular homeostasis by selectively removing ubiquitin molecules from targeted proteins. This process affects protein stability, subcellular localization, and activity, thereby influencing processes such as DNA repair, cell cycle regulation, and apoptosis. Abnormal USP activities have been linked to various diseases, including cancer. Emerging evidence in lymphoma studies highlights the significance of USPs in controlling signaling pathways related to cancer initiation and progression and presents them as potential therapeutic targets. Aim: This study aimed to elucidate the multifaceted roles of USPs in lymphoma. Methods: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles published in English up to May 2023 were retrieved from PubMed, Web of Science, and Scopus. The inclusion criteria focused on studies investigating the role of USPs in lymphoma cancer, involving human subjects or relevant lymphoma cell lines, exploring molecular mechanisms and signaling pathways, and assessing diagnostic or prognostic value. Results: After the selection process, 23 studies were selected for analysis. USPs were found to affect various aspects of lymphoma development and progression. Specific USPs were identified with roles in cell-cycle regulation, apoptosis modulation, drug resistance, DNA repair, and influence of key oncogenic pathways, such as B cell receptor (BCR) signaling. Conclusion: This systematic review underscores the emerging role of USPs in lymphoma and their potential as therapeutic targets. Inhibitors of USPs, such as USP14 inhibitors, show promise in overcoming drug resistance. The dynamic interplay between USPs and lymphoma biology presents an exciting opportunity for future research and the development of more effective treatments for patients with lymphoma. Understanding the intricate functions of USPs in lymphoma offers new insights into potential therapeutic strategies, emphasizing the significance of these enzymes in the context of cancer biology. Copyright © 2024 Samareh Salavatipour, Tavakoli, Halimi, Tavoosi, Baghsheikhi, Talebi-Taheri, Niloufari, Salehi, Verdi, Rahgozar, Mosavi-Jarrahi and Ahmadvand.
Zangooie, A.,
Tavoosi, S.,
Arabhosseini, M.,
Halimi, A.,
Zangooie, H.,
Baghsheikhi, A.H.,
Rahgozar, S.,
Ahmadvand, M.,
Jarrahi, A.M.,
Salehi, Z. Bmc Cancer (14712407)24(1)
Background: Leukemia, a type of blood cell cancer, is categorized by the type of white blood cells affected (lymphocytes or myeloid cells) and disease progression (acute or chronic). In 2020, it ranked 15th among the most diagnosed cancers and 11th in cancer-related deaths globally, with 474,519 new cases and 311,594 deaths (GLOBOCAN2020). Research into leukemia’s development mechanisms may lead to new treatments. Ubiquitin-specific proteases (USPs), a family of deubiquitinating enzymes, play critical roles in various biological processes, with both tumor-suppressive and oncogenic functions, though a comprehensive understanding is still needed. Aim: This systematic review aimed to provide a comprehensive review of how Ubiquitin-specific proteases are involved in pathogenesis of different types of leukemia. Methods: We systematically searched the MEDLINE (via PubMed), Scopus, and Web of Science databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA) to identify relevant studies focusing on the role of USPs in leukemia. Data from selected articles were extracted, synthesized, and organized to present a coherent overview of the subject matter. Results: The review highlights the crucial roles of USPs in chromosomal aberrations, cell proliferation, differentiation, apoptosis, cell cycle regulation, DNA repair, and drug resistance. USP activity significantly impacts leukemia progression, inhibition, and chemotherapy sensitivity, suggesting personalized diagnostic and therapeutic approaches. Ubiquitin-specific proteases also regulate gene expression, protein stability, complex formation, histone deubiquitination, and protein repositioning in specific leukemia cell types. Conclusion: The diagnostic, prognostic, and therapeutic implications associated with ubiquitin-specific proteases (USPs) hold significant promise and the potential to transform leukemia management, ultimately improving patient outcomes. © The Author(s) 2024.
Katebi, M.,
Rahgozar, S.,
Kazemi, F.,
Rahmani, S.,
Najafi dorcheh, S. Cancer Science (13497006)114(10)pp. 3984-3995
Plant-based combination strategies have been widely considered in cancer therapy to attenuate chemotherapeutics side effects. The anti-leukemic effect of the whole ginger extract was previously portrayed by our team, and the current study is centered around the cytotoxicity and mechanism of action of a phenolic subsidiary of ginger, GingerenoneA, on pediatric acute lymphoblastic leukemia. GingernoneA imposed, dose-dependently, inhibitory effects on the viability of T and B leukemia cell lines confirmed by MTT assays. Resistance to Dexamethasone, a mostly used chemotherapeutic in acute lymphoblastic leukemia treatments, was overcome by GingernoneA. A synergistic effect of Dexamethasone and GingrenoneA on T leukemia cell lines and patient primary cells was confirmed. Annexin-V/PI and acridine orange/ethidium bromide staining illustrated dose-dependent apoptosis in CCRF-CEM cells developed by GingerenoneA. The intrinsic and extrinsic apoptosis induction and antiproliferative attribution of GingerenoneA were validated by western blot and qPCR. Despite the supposed loss of function in CCRF-CEM cells, TP53 showed increased expression levels and functional activity upon treatment with GingernoneA. Bioinformatic studies revealed the conceivable impact of GingerenoneA on the reactivity of mutant P53 through its binding to Cys124. Our findings may provide novel strategies for therapeutic intervention to ameliorate pALL outcomes. © 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
Cancer Drug Resistance (2578532X)6(2)pp. 242-256
Aim: Given the encouraging results of the p53-Mdm2 inhibitor RG7388 in clinical trials and the vital function of miR-16-5p in suppressing cell proliferation, the aim of the present study was to investigate the combined impact of RG7388 and miR-16-5p overexpression on the childhood acute lymphoblastic leukemia (chALL). Methods: miRTarBase and miRDB, along with KEGG and STRING databases, were used to predict miR-16-5p target genes and explore protein-protein interaction networks, respectively. B- and T-lymphoblastic cell lines, in addition to patient primary cells, were treated with RG7388. Ectopic overexpression of miR-16-5p in Nalm6 cell line was induced through cell electroporation and transfection of microRNA mimics was confirmed by qRT-PCR. Cell viability was evaluated using the MTT assay. Western blot analyses were performed to evaluate the effects of RG7388 and miR-16-5p upregulation on the protein levels of p53 and its downstream target genes in chALL cells. Paired sample t-test was employed for statistical analyses. Results: MTT assay showed RG7388-induced cytotoxicity in wild-type p53 Nalm6 cell line and p53 functional patient primary cells. However, CCRF-CEM and p53 non-functional leukemic cells indicated drug resistance. Western blot analyses validated the bioinformatics results, confirming the downregulation of WIP1, p53 stabilization, as well as overexpression of p21WAF1 and Mdm2 proteins in Nalm6 cells transfected with miR-16-5p. Moreover, enhanced sensitivity to RG7388 was observed in the transfected cells. Conclusion: This is the first study indicating the mechanistic importance of miR-16-5p overexpression in chALL and its inhibitory role in leukemia treatment when combined with the p53-Mdm2 antagonist, RG7388. These findings might be useful for researchers and clinicians to pave the way for better management of chALL. © The Author(s) 2023.
Amini, E.,
Rahgozar, S.,
Golpich, M.,
Kefayat, A.,
Fesharaki, M. International Journal of Biological Macromolecules (01418130)238
Melanoma is the major type of skin cancer, which its treatment is still a challenge in the world. In recent years, interest in hibernation-based therapeutic approaches for various biomedical applications has been increased. Many studies indicated that some factors in the blood plasma of hibernating animals such as alpha-2-macroglobulin (A2M) cause anti-proliferative effects. Considering that, the present study was conducted to investigate the anti-cancer effects of hibernating common carp plasma (HCCP) on murine melanoma (B16-F10) in vitro and in vivo. The effect of HCCP on cell viability, migration, apoptosis rate, and cell cycle distribution of B16-F10 cells, tumor growth, and rate of survival were evaluated. To investigate the role of A2M in the anti-cancer effects of HCCP, the gene of interest and proteins in HCCP and non-hibernating common carp plasma (NHCCP) were evaluated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay as well as sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and mass spectrometry analysis. Based on our findings, HCCP significantly decreased B16-F10 cell viability. Moreover, HCCP caused morphological alternations, inhibition of migration, induction of apoptosis, and significantly induced the cell cycle arrest at the G2/M phase. In addition, A2M level was significantly increased in HCCP compared with NHCCP. Taken together, our findings suggested that HCCP had the potential to be a promising novel therapeutic target for cancer treatment because of its anti-cancer properties. © 2023 Elsevier B.V.
Samii, B.,
Jafarian, A.,
Rabbani, M.,
Zolfaghari, B.,
Rahgozar, S.,
Pouraboutaleb, E. Research In Pharmaceutical Sciences (17355362)18(4)pp. 381-391
Background and purpose: One strategy to overcome methotrexate (MTX) resistance in acute lymphoblastic leukemia is suppressing MDR1 expression. It has been proved Astragalus polysaccharides (APS) exert their anticancer effect by reversing drug resistance. Due to the structural similarity of tragacanthin and bassorin with APS, we aimed to investigate the effects of the aforementioned polysaccharides on the expression of the MDR1 gene in the MTX-treated CCRF-CEM cells. Experimental approach: Cytotoxicity of APS, bassorin, and tragacanthin on CCRF-CEM, CCRF-CEM/MTX (cells treated with MTX at IC50), and CCRF-CEM/R cells (CCRF-CEM cells resistant to MTX) was evaluated by MTT assay. The effect of all three compounds on MDR1 expression was evaluated using RT-PCR. Findings/Results: All the concentrations of tragacanthin, bassorin, and APS (except at 0.8-100 μg/mL in CCRF-CEM) decreased the viability of all the cells compared to the negative control group; and against the positive control (MTX-treated cells), only bassorin at 20-100 μg/mL in CCRF-CEM/R and tragacanthin at 50 and 100 μg/mL in CCRF-CEM/MTX and at 2-100 μg/mL in CCRF-CEM/R decreased cell viability. Tragacanthin diminished MDR1 expression in CCRF-CEM/MTX and CCRF-CEM/R cells, which MTX had already induced. Conclusion and implication: According to the results of this study, tragacanthin was a potent cytotoxic agent against CCRF-CEM cells and enhanced the chemosensitivity of CCRF-CEM/MTX and CCRF-CEM/R cells to MTX by down-regulation of MDR1 gene expression. Therefore, it could be a promising compound against cancer. Other possible mechanisms of action of tragacanthin should be evaluated and further in vitro and in vivo investigations are required. © 2023 Wolters Kluwer Medknow Publications. All rights reserved.
Critical Reviews in Oncology/Hematology (10408428)178
Iron metabolism are frequently disrupted in cancer. Patients with cancer are prone to anemia and receive transfusions frequently; the condition which results in iron overload, contributing to serious therapeutic complications. Iron is introduced as a carcinogen that may increase tumor growth. However, investigations regarding its impact on response to chemotherapy, particularly the induction of drug resistance are still limited. Here, iron contribution to cell signaling and various molecular mechanisms underlying iron-mediated drug resistance are described. A dual role of this vital element in cancer treatment is also addressed. On one hand, the need to administer iron chelators to surmount iron overload and improve the sensitivity of tumor cells to chemotherapy is discussed. On the other hand, the necessary application of iron as a therapeutic option by iron-oxide nanoparticles or ferroptosis inducers is explained. Authors hope that this paper can help unravel the clinical complications related to iron in cancer therapy. © 2022
Journal Of Cellular And Molecular Medicine (15821838)25(13)pp. 6148-6160
Combination therapies, using medicinal herbs, are broadly recommended to attenuate the chemotherapy adverse effects. Based on our previous findings considering the anti-leukaemic effects of ginger extract on acute lymphoblastic leukaemia (ALL) cells, the present study was aimed to investigate the anti-cancer role of this pharmaceutical plant on ALL mice models. Moreover, we worked towards identifying the most anti-leukaemic derivative of ginger and the mechanism through which it may exert its cytotoxic impact. In vivo experiments were performed using five groups of six C57BL/6 nude mice, and the anti-leukaemic activity of ginger extract alone or in combination with methotrexate (MTX) was examined. Results showed increased survival rate and reduced damages in mice brain and liver tissues. Subsequently, MTT assay demonstrated synergistic growth inhibitory effect of 6-shogaol (6Sh) and MTX on ALL cell lines and patients primary cells. Eventually, the molecular anti-neoplastic mechanism of 6Sh was evaluated using Bioinformatics. Flow cytometry illustrated 6Sh-mediated apoptosis in Nalm-6 cells confirmed by Western blotting and RT-PCR assays. Further analyses exhibited the generation of reactive oxygen species (ROS) through 6Sh. The current study revealed the in vivo novel anti-leukaemic role of ginger extract, promoted by MTX. Moreover, 6-shogaol was introduced as the major player of ginger cytotoxicity through inducing p53 activity and ROS generation. © 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
Molecular Biology Reports (03014851)48(2)pp. 1531-1538
Long non-coding RNAs (lncRNAs) and their role in competitive endogenous RNA (ceRNA) networks have emerged as fundamental debates in the biological processes of initiation and progression of cancer. This study aimed to identify and measure the expression levels of relevant ceRNA regulatory genes contributing to acute lymphoblastic leukemia (ALL). lncRNA H19 and BCL-2 mRNA were chosen based on in silico studies and their interactions with miR-326. Subsequently, the aforementioned coding/non-coding gene expression profiles were measured using qRT-PCR in 50 bone marrow samples, including 33 cases with pediatric ALL and 17 controls with no evidence of malignancy. lncRNA H19 was identified as an oncogenic factor which was noticeably increased in the newly diagnosed patients (P = 0.0019, AUC = 0.84) and negatively associated with miR-326 (r = −0.6, P = 0.02). Furthermore, a negative correlation was introduced between the transcriptional levels of miR-326 and the anti-apoptotic BCL-2 gene (r = −0.6, P = 0.028). The novel experimental and bioinformatic results achieved in this study may provide new insights into the molecular leukemogenesis of pediatric ALL. © 2021, The Author(s), under exclusive licence to Springer Nature B.V. part of Springer Nature.
Current Research in Translational Medicine (24523186)69(1)
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. © 2020 Elsevier Masson SAS
Iranian Journal of Medicinal and Aromatic Plants Research (17350905)37(1)pp. 1-12
Chemotherapy, as the most common way of cancer treatment, has many side effects that make it difficult to continue the treatment process. The studies show that the use of medicinal plants alone or in combination with the chemotherapy drugs can reduce the harmful effects of chemotherapy. This study aimed at investigating the effect of 10-gingerol, as one of the major derivatives of ginger (Zingiber officinale Roscoe), on the acute lymphoblastic leukemia cell lines. The acute lymphoblastic cell lines (CCRF-CEM, R-CCRF-CEM, Nalm-6, and RN95) were treated with increasing concentrations of 10-gingerol after drawing their growth curves. The survival percentage was evaluated by the MTT assay. In addition, the trypan blue staining method was used to evaluate the rate of cell death and confirm the results of MTT assay. To explore the biological processes, molecular function, and cellular components related to the 10-gingerol target genes, a functional annotation analysis was performed using the gene ontology (GO) and Enrichr (a comprehensive gene set enrichment analysis tool) database. The Graph Pad Prism 6 software was also used for statistical analyses. The results of this study indicated that 10-gingerol had a cytotoxic effect on R-CCRF-CEM, Nalm-6, and RN95 cell lines significantly (P ˂ 0.05). This effect was stronger in R-CCRF-CEM and Nalm-6 than in CCRF-CEM at the higher concentrations. The GO analyses also recognized the apoptosis as the most important biological process associated with 10-gingerol. In the present study, for the first time, the cytotoxic effect of 10-gingerol on the acute lymphoblastic leukemia cell lines was demonstrated. © 2021, Research Institute of Forests and Rangelands of Iran. All rights reserved.
Frontiers in Oncology (2234943X)9
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. © Copyright © 2020 Aberuyi, Rahgozar, Ghodousi and Ghaedi.
Ghaeidamini, M.H.,
Rahgozar, S.,
Rahimi, S.B.,
Safavi, A.,
Ghodousi e.s., E.S. Scientific Reports (20452322)10(1)
Altered metabolism of fatty acid synthesis is considered a hallmark characteristic of several malignancies, including acute lymphoblastic leukemia (ALL). To evaluate the impact of fatty acid synthase (FASN) on drug resistant ALL, bone marrow samples were collected from 65 pediatric ALLs, including 40 de novo and 25 relapsed patients. 22 non-cancer individuals were chosen as controls. Quantitative RT-PCR showed increased expression levels of FASN in drug resistant patients compared with the therapy responders. Single and combined treatment of malignant cells were analyzed using Annexin-V/PI double staining and MTT assays. Incubation of resistant primary cells with ginger showed simultaneous increased apoptosis rates and reduced FASN expression levels. Furthermore, docking studies demonstrated high affinity bindings between ginger derivatives and FASN thioesterase and ketosynthase domains, compared with their known inhibitors, fenofibrate and morin, respectively. Finally, combined treatment of in-house multidrug resistant T-ALL subline with ginger and dexamethasone induced drug sensitivity and down regulation of FASN expression, accordingly. To the best of our knowledge, this is the first study that introduces FASN upregulation as a poor prognostic factor for drug resistant childhood ALL. Moreover, it was revealed that FASN inhibition may be applied by ginger phytochemicals and overcome dexamethasone resistance, subsequently. © 2020, The Author(s).
Cancer Medicine (20457634)9(10)pp. 3537-3550
Drug resistance is a fundamental clinical concern in pediatric acute lymphoblastic leukemia (pALL), and methotrexate (MTX) is an essential chemotherapy drug administered for the treatment. In the current study, the effect of iron in response to methotrexate and its underlying mechanisms were investigated in pALL cells. CCRF-CEM and Nalm6 cell lines were selected as T and B-ALL subtypes. Cells were pretreated with ferric ammonium citrate, exposed to the IC50 concentration of MTX and cell viability was assessed using MTT, colony formation, and flow cytometry assays. Iron-loaded cells were strongly resistant to MTX cytotoxicity. The inhibitory effect of N-acetyl cysteine to reverse the acquired MTX resistance was greater than that of the iron chelator, deferasirox, highlighting the importance of iron-mediated ROS in MTX resistance. Subsequently, the upregulation of BCL2, SOD2, NRF2, and MRP1 was confirmed using quantitative RT-PCR. Moreover, a positive correlation was demonstrated between the MRP1 expression levels and bone marrow iron storage in pALL patients. Further supporting our findings were the hematoxylin and eosin-stained histological sections showing that iron-treated nude mice xenografts demonstrated significantly more liver damage than those unexposed to iron. Overall, iron is introduced as a player with a novel role contributing to methotrexate resistance in pALL. Our findings suggest that the patients' bone marrow iron stores are necessary to be assessed during the chemotherapy, and transfusions should be carefully administrated. © 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
Ghaeidamini harouni, M.,
Rahgozar, S.,
Rahimi babasheikhali, S.,
Safavi, A.,
Ghodousi e.s., E.S. Scientific Reports (20452322)10(1)
The original version of the Article contained errors in the author names Maryam Ghaeidamini Harouni and Somayeh Rahimi Babasheikhali which were incorrectly given as Maryam Harouni Ghaeidamini and Somayeh Babasheikhali Rahimi. The Author Contributions section now reads: “M.G.H. and S.R.B conceived the ideas and performed the experiments. M.G.H. and E.S.G. wrote the article. A.S. and E.S.G. did and wrote in silico studies. S.R. conceived the ideas, designed the study, wrote and reviewed the article.” These errors have now been corrected in the PDF and HTML versions of the Article. © 2020, The Author(s).
Frontiers in Neuroscience (1662453X)14
Alzheimer’s disease (AD) is a neurodegenerative disease with cognitive impairment. Oxidative stress in neurons is considered as a reason for development of AD. Antioxidant agents such as quercetin slow down AD progression, but the usage of this flavonoid has limitations because of its low bioavailability. We hypothesized that quercetin-conjugated superparamagnetic iron oxide nanoparticles (QT-SPIONs) have a better neuroprotective effect on AD than free quercetin and regulates the antioxidant, apoptotic, and APP gene, and miRNA-101. In this study, male Wistar rats were subjected to AlCl3, AlCl3 + QT, AlCl3 + SPION, and AlCl3 + QT-SPION for 42 consecutive days. Behavioral tests and qPCR were used to evaluate the efficiency of treatments. Results of behavioral tests revealed that the intensity of cognitive impairment was decelerated at both the middle and end of the treatment period. The effect of QT-SPIONs on learning and memory deficits were closely similar to the control group. The increase in expression levels of APP gene and the decrease in mir101 led to the development of AD symptoms in rats treated with AlCl3 while these results were reversed in the AlCl3 + QT-SPIONs group. This group showed similar results with the control group. QT-SPION also decreased the expression levels of antioxidant enzymes along with increases in expression levels of anti-apoptotic genes. Accordingly, the antioxidant effect of QT-SPION inhibited progression of cognitive impairment via sustaining the balance of antioxidant enzymes in the hippocampus of AD model rats. © Copyright © 2021 Amanzadeh Jajin, Esmaeili, Rahgozar and Noorbakhshnia.
Cancer Management and Research (11791322)12pp. 1611-1619
Purpose: Sal-like protein 4 transcription factor (SALL4) is a stem cell transcription factor that plays an essential role in the maintenance and self-renewal of embryonic and hematopoietic stem cells, functioning as an oncogene in several cancers. However, the role of SALL4 in the biological behavior of childhood acute lymphoblastic leukemia and its relationship with multidrug resistance and relapse has remained largely unknown. Patients and Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to characterize the expression pattern of SALL4 in the bone marrow samples of 43 patients with Philadelphia negative ALL and 18 children in the non-cancer control group. The presence of minimal residual disease was measured a year after the initial therapy using SSCP (single-strand conformation polymorphism). In addition, the correlation between the expression of SALL4 and ABCA3 in relapsed patients was analyzed statistically. Results: Results showed an overexpression of SALL4 in de novo patients compared with the control group (P=0.0001, AUC= 0.93), indicating the importance of this gene in the induction of leukemia. A significant increase in the ABCA3 expression levels was revealed in the relapsed patients, in comparison with the drug-sensitive group (P = 0.0005). The leukemo-genetic effect of SALL4 can be related to the effect of this gene on the maintenance of pluripotency in cancer stem cells. Results also suggest that the expression of SALL4 can be considered as a diagnostic marker for pediatric ALL. Moreover, SALL4 expression levels in the minimal residual disease positive (mrd+) ALL group was significantly higher than those in the mrd− group (p=0.0001, AUC= 0.92). Conclusion: These data demonstrate the prognostic impact of SALL4 in childhood ALL. Our findings also indicated a direct correlation between the mRNA expression levels of SALL4 and ABCA3 transporter in the relapsed group of ALL patients (r=0.7). These results describe a possible mechanism by which SALL4 may lead to the development of multidrug resistance. © 2020 Ohadi et al.
Japanese Journal of Clinical Oncology (03682811)50(6)pp. 671-678
Objective: Multidrug resistance and consequent relapse are two major obstacles for treating children with acute lymphoblastic leukemia, the most frequent childhood malignancy. MicroRNAs have potential regulatory roles in response to chemotherapy. The goal of this study was to determine the microRNA that may have effects on the expression level of brain and acute lymphoblastic leukemia (BAALC) and to investigate the in vitro and ex vivo association between their expression levels. Methods: In silico tools were utilized to determine a putative miRNA targeting BALLC. Quantitative real-time polymerase chain reaction was used to investigate expression levels of BAALC and its predicted microRNA, miR-326, in bone marrow samples of 30 children with acute lymphoblastic leukemia and 13 controls, in addition to the resistant and parental CCRF-CEM cell lines. To assess the status of response to therapy, minimal residual disease was measured using single-strand conformation polymorphism. Results: MiR-326 was selected due to the strong possibility of its interaction with BAALC according to the obtained in silico results. Statistical analysis showed a significant downregulation of miR-326 and overexpression of BALLC in drug-resistant acute lymphoblastic leukemia cell line and patients compared with the parental cell line and drug-sensitive patients, respectively (P = 0.015, 0.005, 0.0484 and 0.0005, respectively). The expression profiles of miR-326 and BAALC were inversely correlated (P = 0.028). Conclusions: The results introduced the inversely combined expression levels of miR-326 and BAALC as a novel, independent prognostic biomarker for pediatric acute lymphoblastic leukemia (P = 0.007). Moreover, bioinformatics data showed a possible regulatory role for miR-326 on BAALC mRNA, which may possibly contribute to the development of drug resistance in patients with childhood acute lymphoblastic leukemia. © 2020 The Author(s).
Reviews in the Neurosciences (21910200)30(5)pp. 555-572
Quercetin is a polyphenolic flavonoid, which is frequently found in fruits and vegetables. The antioxidant potential of quercetin has been studied from subcellular compartments, that is, mitochondria to tissue levels in the brain. The neurodegeneration process initiates alongside aging of the neurons. It appears in different parts of the brain as Aβ plaques, neurofibrillary tangles, Lewy bodies, Pick bodies, and others, which leads to Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and other diseases. So far, no specific treatment has been identified for these diseases. Despite common treatments that help to prevent the development of disease, the condition of patients with progressive neurodegenerative diseases usually do not completely improve. Currently, the use of flavonoids, especially quercetin for the treatment of neurodegenerative diseases, has been expanded in animal models. It has also been used to treat animal models of neurodegenerative diseases. In addition, improvements in behavioral levels, as well as in cellular and molecular levels, decreased activity of antioxidant and apoptotic proteins, and increased levels of antiapoptotic proteins have been observed. Low bioavailability of quercetin has also led researchers to construct various quercetin-involved nanoparticles. The treatment of animal models of neurodegeneration using quercetin-involved nanoparticles has shown that improvements are observed in shorter periods and with use of lower concentrations. Indeed, intranasal administration of quercetin-involved nanoparticles, constructing superparamagnetic nanoparticles, and combinational treatment using nanoparticles such as quercetin and other drugs are suggested for future studies. © 2019 Walter de Gruyter GmbH, Berlin/Boston 2019.
Gene (18790038)692pp. 35-43
Acute lymphoblastic leukemia (ALL) is the most prevalent cancer among children, and multidrug efflux mediated by overexpression of ABC transporters is the major impediment to successful chemotherapy in this malignancy. The goal of this study is to identify the non-coding RNAs (ncRNAs) which may affect the expression levels of ABCA3; the previously identified prognostic biomarker for multidrug resistance (MDR) in childhood ALL (cALL). Bone marrow samples from 64 cALLs, including 46 de novo and 18 relapsed patients, in addition to 30 non-cancer controls were collected, and ncRNAs were nominated using in silico studies. Quantitative RT-PCR showed low expression profiles of miR-335-3p in cALLs compared with the control group (P = 0.018). Inverse correlation was determined between the miR-335-3p and ABCA3 mRNA expression profiles in cALL patients (r = 0.5019, P = 0.002). Moreover, it was shown that the expression levels of miR-335-3p was downregulated in the drug-resistant samples (MDR group) compared with the drug-sensitive patients (mrd− group), (P = 0.0005, AUC = 0.801). On the other hand, negative correlations were identified between the expression levels of miR-335-3p and the selected LncRNAs, NEAT1 and MALAT1, in the MDR group compared with the mrd− patients (P = 0.009), suggesting a sponge effect for these LncRNAs. The current study showed a potential regulatory role for miR-335-3p in ABCA3 expression targeted by NEAT1 and MALAT1 long non-coding RNAs. This negative impact may possibly contribute to the development of chemoresistance in childhood ALL, and provide an exceptional insight to new therapeutic approaches. © 2019 Elsevier B.V.
Journal Of Cancer Research And Clinical Oncology (01715216)145(8)pp. 1987-1998
Purpose: Based on the poor prognosis of drug resistance in pediatric acute lymphoblastic leukemia (ALL) and adverse effects of chemotherapy, this study was aimed to evaluate the effect of several herbal extracts on leukemic cells. Methods: Two subtypes of T- and B-ALL cell lines, followed by ALL primary cells were treated with cinnamon, ginger, and green tea extracts, alone or in combination with methotrexate (MTX). Possible apoptosis was investigated using Annexin-V/PI double staining. Real-time PCR was applied to evaluate the expression levels of related ABC transporters upon combination therapy. Results: The IC50s for cinnamon, ginger and green tea extracts on ALL cell lines were 300 μg/ml, 167 μg/ml and 70 μg/ml, respectively. Surprisingly, the methotrexate (MTX)-resistant sub-line showed more sensitivity to ginger. Combined treatment with ginger and MTX showed synergistic effects on CCRF-CEM, Nalm-6 and ALL primary cells. It was shown that ginger does not impair the high expression levels of ABCA2 or ABCA3 transporter genes in the ALL malignant cells, suggesting other molecular pathways involved in its anticancer potential. Conclusion: To the best of our knowledge, this is the first study that reveals the antileukemic effect of ginger extract on both, pediatric ALL cell lines and primary cells. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.
Qi m., M.,
Weaver, J.C.,
Rahgozar, S.,
Giannakopoulos b., B.,
Krilis s.a., S.A. Methods in Molecular Biology (19406029)1967pp. 285-293
Angiotensinogen mediates an important role in the pathophysiology of preeclampsia, a disorder of pregnancy characterized by hypertension and proteinuria usually after 20 weeks of gestation. Angiotensinogen is found in two distinct posttranslational forms in the plasma, an oxidized and a reduced (free thiol) form. Higher levels of the oxidized form are associated with an increased risk of preeclampsia. We have developed novel ELISA assays to quantitate the levels of total and free thiol angiotensinogen allowing for calculation of the amount of oxidized angiotensinogen species. We describe the methodology for performing these assays. © Springer Science+Business Media, LLC, part of Springer Nature 2019.
Avicenna Journal Of Medical Biotechnology (20084625)11(1)pp. 24-27
Background: Archived bone marrow aspirate slides are almost infinite, readily available resource of biospecimens that enable retrospective molecular investigations of diseases. RNAs obtained from slides has limitations in utility because of their low quality and highly fragmented nature. MicroRNAs are small (<22 nt) noncoding RNAs with various cellular regulatory roles. Due to their small size, microRNAs are less prone to degradation and modification, therefore, can be preserved well in archived tissues. Methods: The current study investigated the efficacy of archived bone marrow aspirate slides for miRNA expression analysis in pediatric leukemia. Total RNA was isolated from air-dried unstained archived slides using High pure miRNA isolation Kit with some modifications and from fresh samples using TRizol. After cDNA synthesis, RTqPCR was then carried out using specific hsa-miR-326 LNA primers. Finally, statistical analyses were conducted using GraphPad Prism 6 software. Results: The difference observed in miRNA expression due to disease state was far greater than the differences between archived slides and their matching fresh bone marrow specimens. In fact, the expression of archival slide smears for the miR-326 closely mimicked that of fresh-frozen tissues (0.035±0.04 vs. 0.03±0.04) (Mean±SD, p>0.05). Differential expression of hsa-miR-326 was detected between leukemic and non-leukemic samples from archived slides or fresh frozen bone marrows. Conclusion: The demonstration that archived bone marrow aspirate slides can be utilized for miRNA expression studies offers tremendous potential for future investigations into the role that miRNAs play in the development and long term outcome of hematologic, as well as non-hematologic diseases. © 2019, Avicenna Journal of Medical Biotechnology. All rights reserved.
Current Drug Targets (18735592)20(11)pp. 1091-1111
MDM2 protein is the core negative regulator of p53 that maintains the cellular levels of p53 at a low level in normal cells. Mutation of the TP53 gene accounts for 50% of all human cancers. In the remaining malignancies with wild-type TP53, p53 function is inhibited through other mechanisms. Recently, synthetic small molecule inhibitors have been developed which target a small hydrophobic pocket on MDM2 to which p53 normally binds. Given that MDM2-p53 antagonists have been undergoing clinical trials for different types of cancer, this review illustrates different aspects of these new cancer targeted therapeutic agents with the focus on the major advances in the field. It emphasizes on the p53 function, regulation of p53, targeting of the p53-MDM2 interaction for cancer therapy, and p53-dependent and-independent effects of inhibition of p53-MDM2 interaction. Then, representatives of small molecule MDM2-p53 binding antagonists are introduced with a focus on those entered into clinical trials. Furthermore, the review discusses the gene signatures in order to predict sensitivity to MDM2 antagonists, potential side effects and the reasons for the observed hematotoxicity, mechanisms of resistance to these drugs, their evaluation as monotherapy or in combination with conventional chemotherapy or with other targeted therapeutic agents. Finally, it highlights the certainly intriguing questions and challenges which would be addressed in future studies. © 2019 Bentham Science Publishers.
International Journal Of Nanomedicine (11782013)14pp. 6813-6830
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 H2O2- 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 antiapoptotic effects against the cytotoxicity of H2O2. Conclusion: Qu and QNPs showed the similar protective activities against H2O2-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. © 2019 Yarjanli et al.
Cancer Management and Research (11791322)11pp. 7621-7630
Purpose: Multidrug resistance (MDR) and the subsequent disease relapse are the major causes of childhood acute lymphoblastic leukemia (ALL) related death. The Hedgehog (Hh) signaling pathway can contribute to cancer MDR. In the current study, Smoothened (Smo) was selected as the experimental target due to its importance in the Hh pathway in order to evaluate its probable role in pediatric B-ALL drug resistance. Patients and methods: The study included 27 pediatric B-ALL and 16 control bone marrow samples. Quantitative RT-PCR was used to investigate the expression levels of Smo and miR-326 as the key players of the Hh pathway. Western blot analysis was performed. The presence of minimal residual disease was studied using PCR-SSCP. The association between Smo expression and drug resistance was analyzed statistically. Results: Results showed a significant increase in the Smo expression levels in drug-resistant patients in comparison with drug-sensitive children with B-ALL (P=0.0128, AUC=0.82). A considerable negative association between miR-326 and Smo expression levels was identified (r=−0.624, P=0.002). A binomial test confirmed the regulatory role of miR-326 on the translational repression of Smo (P=0.031). Statistics showed no association between Smo and ABCA2 expression levels. However, a significant positive correlation was observed between the Smo and ABCA3 transcripts in the resistant ALL children (r=0.607, P=0.016). Conclusion: Data revealed the possible oncogenic impact of Smo on leukemogenesis and drug resistance in pediatric B-ALL. Upregulation of Smo was introduced, for the first time, as a prognostic factor for drug resistance in childhood B-ALL. To the best of our knowledge, this is the first study that shows a positive correlation between Smo and ABCA3 expression levels in pediatric B-ALL, explaining a possible mechanism for the development of drug resistance in this cancer. Moreover, the current project revealed a negative modulatory effect of miR-326 on the expression levels of Smo. © 2019 Sheybani et al.
Fakhimikabir, H.,
Tavakoli, M.B.,
Zarrabi, A.,
Amouheidari, A.,
Rahgozar, S. Journal of Thermal Biology (18790992)78pp. 73-83
The therapeutic effect of polyglycerol coated iron oxide nanoparticles (PG-SPIONs, non-targeted nanoparticles) and folic acid-conjugated polyglycerol coated iron oxide nanoparticles (FA-PG-SPIONs, targeted nanoparticles) in combination with hyperthermia on viability of HeLa cells was investigated. It was observed that coated and uncoated SPIONs have spherical shapes with an average diameter of 17.9 ± 2.85 nm and 5.4 ± 0.75 nm, respectively. The penetration rate for cells treated with targeted nanoparticles was shown to be more than that of non-targeted nanoparticles. Moreover, it was revealed that the treatment of cells with ≥ 50 µg/ml FA-PG-SPIONs in combination with hyperthermia induced cytotoxicity in comparison to control cells. The results also showed that increasing the concentrations of targeted nanoparticles (FA-PG-SPIONs) and heating time would increase the value of thermal enhancement factor (TEF). In contrast, TEF values were not increased with increasing heating time and concentrations of non-targeted nanoparticles (PG-SPIONs). On the other hand, TEF values were increased with increasing concentrations and heating time so that the maximum TEF value was obtained at the highest concentration (FA-PG-SPION, 200 µg/ml) as well as the longest heating duration (60 min). Thus, it is concluded that FA-PG-SPIONs with concentrations ≥ 100 µg/ml could be introduced and used as hyperthermia sensitizing agents leading to enhanced cancer therapy efficiency. © 2018 Elsevier Ltd
Journal of Cellular Biochemistry (07302312)119(7)pp. 6024-6032
Multidrug resistance (MDR) is considered as the major obstacle for treating pediatric acute lymphoblastic leukemia (ALL). MicroRNAs (miRNAs) are small non coding RNAs which may potentially regulate response to chemotherapy. In this study, total RNA was isolated from bone marrow samples of 46 children with de novo ALL and 16 controls. Quantitative reverse transcriptase polymerase chain reaction was used to investigate the expression profile of the predicted miRNAs; miR-326 and miR-200c, and their predicted targets ABCA2, and ABCA3 transporters. The presence of minimal residual disease was studied using PCR-SSCP (single-strand conformation polymorphism) 1 year after treatment. The association between the miRNA expression and drug resistance was analyzed statistically. Results showed a significant down-regulation of both miR-326 and miR-200c expressions in ALL patients compared with non-cancer controls (P = 0.0002, AUC = 0.813 and P = 0.035, AUC = 0.79, respectively). A considerable negative association between miR-326 expression and MDR was identified which could raise the risk of chemoresistance by 4.8- fold. The expression profiles of miR-326 and ABCA2 transporter were inversely correlated. Data revealed, a novel diagnostic role for miR-326 and miR-200c as potential biomarkers of pediatric ALL. Down-regulation of miR-326 was introduced, for the first time, as a prognostic factor for drug resistance in childhood ALL. To the best of our knowledge, this is the first time that ABCA2 transporter is proposed as a target gene for miR-326, through which it can exert its impact on drug resistance. These data may provide novel approaches to new therapeutics and diagnostics. © 2018 Wiley Periodicals, Inc.
Fakhimikabir, H.,
Tavakoli, M.B.,
Zarrabi, A.,
Amouheidari, A.,
Rahgozar, S. Journal of Photochemistry and Photobiology B: Biology (18732682)182pp. 71-76
Background and Purpose: The objective of this study was to investigate the therapeutic effect of Folic Acid-Conjugated polyglycerol coated iron oxide nanoparticles on the radiosensitivity of HeLa cells when irradiated with 6 MeV electron beams. Materials and Methods: Different concentrations of iron oxide nanoparticles (PG-SPIONs and FA-PG-SPIONs (25, 50, 100, 200 μg ml−1)) were synthesized by the thermal decomposition technique. The effect of PG-SPIONs and FA-PG-SPIONs in combination with radiation (2, 4, 6 Gy) on the viability of cells and cell survival were estimated using the trypan blue dye exclusion test and MTT assay immediately and 48 h after irradiations, respectively. Results: It was observed that the penetration rate of uptake for cells treated with >50 μg ml−1 FA-PG-SPIONs was more than that of non-targeted nanoparticles. The data obtained by trypan blue dye exclusion test showed no significant reduction in cell viability for all groups in comparison with control group. The results revealed that increasing the radiation doses in the presence of the concentrations of the nanoparticles increased the value of radiosensitivity. The most radiosensitivity was obtained at the highest concentration of FA-PG-SPIONs (200 μg ml−1) as well as the longest radiation doses. Conclusion: It was revealed that higher concentrations of the FA-PG-SPIONs in combination with 6 MeV electron beams could enhance radiosensitization of HeLa cells. © 2018
Cancer Chemotherapy and Pharmacology (14320843)80(1)pp. 109-117
Objectives: ATP-binding cassette subfamily C member 4 (ABCC4) encoding MRP4 protein is involved in pediatric acute lymphoblastic leukemia (ALL) drug resistance. The nonsynonymous single nucleotide polymorphism (SNP) rs2274407 (G912T; K304N) is located in the 3′ splice acceptor site of exon 8 of ABCC4 pre-mRNA. The aim of this study was to investigate the prognostic value of rs2274407 in childhood ALL and its possible functional effect on MRP4. Methods: ABCC4 G912T SNP was genotyped in 145 Iranian Philadelphia-negative (Ph−) children with ALL using modified tetra-primer ARMS PCR and evaluated for possible association with 3-year disease-free survival (3DFS). In addition, functional impact of rs2274407 on the MRP4 activity and possible post-transcriptional modifications were bioinformatically and experimentally studied. Results: ABCC4 912T allele carriers (G/T and T/T genotypes) are associated with worse 3DFS in Pre-B cell ALL [P = 0.00019, OR (95% CI) = 13.17 (2.55–68.11)]. In addition, computational studies showed that K304N alteration has no impact on the MRP4 activity. However, it may disrupt the normal splicing process of ABCC4 pre-mRNA. Conclusions: To date, this is the first study that shows the potential functional impact of rs2274407 SNP on the aberrant splicing of ABCC4 mRNA. We also demonstrated a robust association between G912T and pediatric ALL negative outcome, which may be explained by the novel computational studies performed in this study. © 2017, Springer-Verlag Berlin Heidelberg.
BMC Neuroscience (14712202)18(1)
Background: In the recent decade, iron oxide nanoparticles (IONPs) have been proposed for several applications in the central nervous system (CNS), including targeting amyloid beta (Aβ) in the arteries, inhibiting the microglial cells, delivering drugs, and increasing contrast in magnetic resonance imaging. Conversely, a notable number of studies have reported the role of iron in neurodegenerative diseases. Therefore, this study has reviewed the recent studies to determine whether IONPs iron can threaten the cellular viability same as iron. Results: Iron contributes in Fenton's reaction and produces reactive oxygen species (ROS). ROS cause to damage the macromolecules and organelles of the cell via oxidative stress. Iron accumulation and oxidative stress are able to aggregate some proteins, including Aβ and α-synuclein, which play a critical role in Alzheimer's and Parkinson's diseases, respectively. Iron accumulation, oxidative stress, and protein aggregation make a positive feedback loop, which can be toxic for the cell. The release of iron ions from IONPs may result in iron accumulation in the targeted tissue, and thus, activate the positive feedback loop. However, the levels of IONPs induced toxicity depend on the size, concentration, surface charge, and the type of coating and functional groups of IONPs. Conclusion: IONPs depending on their properties can lead to iron accumulation, oxidative stress and protein aggregation in the neural cells. Therefore, in order to apply IONPs in the CNS, the consideration of IONPs properties is crucial. © 2017 The Author(s).
Journal of Mazandaran University of Medical Sciences (17359260)27(154)pp. 212-231
Mice are the preferred model organisms in tumor and cancer research, concerning tumor biology (initiation, progression, and metastasis) or developing and screening the potential therapeutics. Different murine models including genetically engineered mice (GEM), xenografts, and chemical models may be used for this purpose. By reviewing the most recent scientific reports and publications, in the current paper, these models and their applications in different aspects of cancer research are introduced and their advantages and pitfalls are discussed. This article summarizes the opportunities provided by each model and their limitations and the fundamental differences between mouse and human such as species-specific and pharmacological differences. This article shed light on some key points for selection of the best murine model depending on the purpose of the research. © 2017, Mazandaran University of Medical Sciences. All rights reserved.
Safavi, A.,
Emamzadeh, R.,
Nazari, M.,
Ehsani m., ,
Zarkesh-esfahani, H.,
Rahgozar, S. Molecular BioSystems (1742206X)13(3)pp. 470-475
The human immunodeficiency virus (HIV) destroys CD4+ lymphocytes and monitoring these cells is one of the best techniques for studying HIV infection. In the present study a novel bioluminescent probe, super RLuc8-sFv, is developed in order to detect human CD4+ cells by fusion of an anti-human CD4 sFv to the C-terminus of super RLuc8. The results indicate that the probe can bind to CD4+ cells via its sFv domain; also it emits visible light through its signalling domain. Super RLuc8-sFv provides a new gateway for detection of human CD4+ cells using luminometric-based assays and may reduce the difficulties involved in, and the cost of, HIV-related diagnostic tests. © The Royal Society of Chemistry.
Moafi, A.,
Vallian, R.,
Vallian borujeni, S.,
Rahgozar, S.,
Torfenajad, M.,
Moafi, H. Journal of Medical Screening (09691413)24(1)pp. 1-5
Objective: To evaluate the repercussions of recent changes to the cut-offs used in the first screening step of the pre-marital screening programme for thalassaemia prevention in Iran. Methods: The profiles of 984 subjects referred to a genetic laboratory, and the tests of 242 parents of children with thalassaemia major were assessed for red blood cell (RBC) indices, haemoglobin (Hb) A2 levels and results of Hb electrophoresis. Results: Of 407 suspected thalassaemia minor (STM) cases, 18 proved positive for thalassaemia minor on molecular analysis (18/407, confidence interval 2.6–6.9%). If the revised screening cut-offs had been used to determine who would undergo molecular analysis, two of these cases would not have been identified. Only 4.4% of suspected cases with lower than normal RBC indices (mean corpuscular volume <80 fl and mean corpuscular Hb <27 pg) and HbA2 (<3.5%) were diagnosed with thalassaemia minor. Conclusion: The thalassaemia major prevention programme is performed in two separate steps. One step involves the screening of subjects and identification of b-thalassaemia minor, suspected cases for thalassaemia minor (STM), and normal subject groups. The other step concerns the identification of thalassaemia minor in the STM group. Changing the cut-offs at the first screening step does not result in significant improvement from an economic view, and is associated with significant risk at the second screening step. © The Author(s) 2016.
Moafi, A.,
Ziaie, M.,
Abedi, M.,
Rahgozar, S.,
Reisi, N.,
Nematollahi, P.,
Moafi, H. Medicine (United States) (00257974)96(44)
Iron is an intracellular element whose accumulation in the body is associated with tissue damage. This study examines the effect of iron on pediatric acute lymphoblastic leukemia (ALL) and its "response to treatment." At the end of the first year of treatment, bone marrow iron store (BMIS) was evaluated in children with ALL and the relationship between iron store and minimal residual disease was investigated. Moreover, the 3-year disease-free survival (3-DFS) of patients was determined. Patients' BMIS were compared with that of subjects with normal bone marrow. The study examined 93 children, including 78 Pre-B and 15 T-cell ALL patients. BMIS did not differ between the children with ALL and those with no evidence of cancer. BMIS was increased in 26.6% of patients at the end of the first year of treatment. Drug resistance and BM relapses were more prevalent in cases with high BMIS in both Pre-B and T-cell groups. Bone marrow iron store is not considered a risk factor for childhood ALL. However, high levels of BMIS are associated with poor response to treatment and the risk of relapse. Bone marrow iron store control during treatment can therefore help achieve better outcomes and improve the chances of recovery. Copyright © 2017 the Author(s).
Aberuyi, Arges,
Aberuyi, N.,
Dehaghi, Zohreh Khosravi,
Moafi, Alireza,
Aberuyi, N.,
Rahgozar, S.,
Dehaghi, Z.K.,
Moafi, A.,
Masotti A.,
Paolini A. ONCOTARGETS AND THERAPY (11786930)10pp. 3373-3380
Purpose: The aim of this work was to study the correlation between the expressions of the ABCA2 and ABCA3 genes at the mRNA and protein levels in children with acute lymphoblastic leukemia (ALL) and the effects of this association on multidrug resistance (MDR). Materials and methods: Sixty-nine children with de novo ALL and 25 controls were enrolled in the study. Mononuclear cells were isolated from the bone marrow. The mRNA levels of ABCA2 and ABCA3 were measured by real-time polymerase chain reaction (PCR). Samples with high mRNA levels were assessed for respective protein levels by Western blotting. Following the first year of treatment, persistent monoclonality of T-cell gamma receptors or immunoglobulin H (IgH) gene rearrangement was assessed and considered as the MDR. The tertiary structure of ABCA2 was predicted using Phyre2 and I-TASSER web systems and compared to that of ABCA3, which has been previously reported. Molecular docking was performed using DOCK 6.7. Results: Real-time quantitative PCR (qRT-PCR) showed high levels of ABCA2 and ABCA3 mRNAs in 13 and 17 samples, respectively. Among them, five and eight individuals demonstrated high levels of ABCA2 and ABCA3, respectively. Response to chemotherapy was significantly decreased (P=0.001) when the mRNA and protein of both genes were overexpressed compared to individuals with high transcriptional levels of either ABCA2 or ABCA3 alone. Close similarity between ABCA2 and ABCA3 structures was revealed by protein tertiary structure prediction, whereas molecular docking analysis suggested similar binding of chemotherapy drugs and therefore a potentially similar role in determining the MDR. Conclusion: Our findings suggested, for the first time, that quantification of the protein level of ABCA2 and ABCA3 transporters had a prognostic impact on pediatric ALL MDR. Furthermore, the tertiary structure of ABCA2 was predicted for the first time, and docking analysis revealed a possible compensatory effect between ABCA2 and ABCA3 transporters, which may contribute to the efflux of cytotoxic drugs and, ultimately, to chemoresistance.
Nadimi, M.,
Rahgozar, S.,
Moafi, A.,
Tavassoli, M.,
Mesrian tanha, H. Cancer Genetics (22107762)209(7-8)pp. 348-353
Acute leukemia is the most common cancer in children and involves several factors that contribute to the development of multidrug resistance and treatment failure. According to our recent studies, the BAALC gene is identified to have high mRNA expression levels in childhood acute lymphoblastic leukemia (ALL) and those with multidrug resistance. Several polymorphisms are associated with the expression of this gene. To date, there has been no study on the rs62527607 [GT] single nucleotide polymorphism (SNP) of BAALC gene and its link with childhood acute lymphoblastic and myeloid leukemia (AML). The purpose of this study is to evaluate the prevalence of this polymorphism in pediatric acute leukemia, as well as its relationship with prognosis. DNA samples were extracted from bone marrow slides of 129 children with ALL and 16 children with AML. The rs62527607 [GT] SNP was evaluated using mismatch polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)-based analysis. The association between the SNP alleles and patient disease-free survival was then assessed. The prevalence of the T-allele of rs62527607 [GT] SNP in childhood T-ALL and pre-B-ALL was 28.3% and 11.2%, respectively. In the pre-B-ALL patients, 3 year disease free survival was associated with the GG genotype. Results showed a robust association between the rs62527607 SNP and the risk of relapse in ALL, but not AML, patients. T-ALL patients with the GT genotype had an 8.75 fold higher risk of relapse. The current study demonstrates a significant association between the genotype GT and the polymorphic allele G424T, and introduces this SNP as a negative prognostic factor in children with ALL. © 2016 Elsevier Inc.
Mesrian tanha, H.,
Mojtabavi naeini, M.,
Rahgozar, S.,
Moafi, A.,
Honardoost, M.A. Tumor Biology (14230380)37(6)pp. 7861-7872
Acute lymphoblastic leukemia (ALL) is the major neoplasia type among children. Despite the tremendous success of current treatment strategies, drug resistance still remains a major cause of chemotherapy failure and relapse in pediatric patients. Overwhelming evidence illustrates that microRNAs (miRNAs) act as post-transcriptional regulators of drug-resistance-related genes. The current study was aimed at how dysregulated miRNA-mRNA-signaling pathway interaction networks mediate resistance to four commonly used chemotherapy agents in pediatric ALL, including asparaginase, daunorubicin, prednisolone, and vincristine. Using public expression microarray datasets, a holistic in silico approach was utilized to investigate candidate drug resistance miRNA-mRNA-signaling pathway interaction networks in pediatric ALL. Our systems biology approach nominated significant drug resistance and cross-resistance miRNAs, mRNAs, and cell signaling pathways based on anti-correlative relationship between miRNA and mRNA expression pattern. To sum up, our systemic analysis disclosed either a new potential role of miRNAs, or a possible mechanism of cellular drug resistance, in chemotherapy resistance of pediatric ALL. The current study may shed light on predicting drug response and overcoming drug resistance in childhood ALL for subsequent generations of chemotherapies. © 2015, International Society of Oncology and BioMarkers (ISOBM).
Jodeiri farshbaf, M.,
Forouzanfar, M.,
Ghaedi, K.,
Kiani-esfahani, A.,
Peymani, M.,
Shoaraye nejati, A.,
Izadi, T.,
Karbalaie, K.,
Noorbakhshnia, M.,
Rahgozar, S. Molecular And Cellular Biochemistry (15734919)420(1-2)pp. 29-42
Parkinson’s disease (PD) can degenerate dopaminergic (DA) neurons in midbrain, substantia-nigra pars compacta. Alleviation of its symptoms and protection of normal neurons against degeneration are the main aspects of researches to establish novel therapeutic strategies. PPARγ as a member of PPARs have shown neuroprotection in a number of neurodegenerative disorders such as Alzheimer’s disease and PD. Nuclear receptor related 1 protein (Nurr1) is, respectively, member of NR4A family and has received great attentions as potential target for development, maintenance, and survival of DA neurons. Based on neuroprotective effects of PPARγ and dual role of Nurr1 in anti-inflammatory pathways and development of DA neurons, we hypothesize that PPARγ and Nurr1 agonists alone and in combined form can be targets for neuroprotective therapeutic development for PD in vitro model. 1-Methyl-4-phenylpyridinium (MPP+) induced neurotoxicity in PC12 cells as an in vitro model for PD studies. Treatment/cotreatment with PPARγ and Nurr1 agonists 24 h prior to MPP+ induction enhanced the viability of PC12 cell. The viability of PC12 cells was determined by MTS test. Mitochondrial membrane potential (MMP) and intracellular reactive oxygen species (ROS) were detected by flow cytometry. In addition, the relative expression of four genes including TH (the marker of DA neurons), Ephrin A1, Nurr1, and Ferritin light chain were assessed by RT-qPCR. In the MPP+-pretreated PC12 cells, PPARγ and Nurr1 agonists and their combined form resulted in a decrease in the cell death rate. Moreover, production of intracellular ROS and MMP modulated by MPP+ was decreased by PPARγ and Nurr1 agonists’ treatment alone and in the combined form. © 2016, Springer Science+Business Media New York.
Dabaghi, M.,
Rahgozar, S.,
Moshtaghian, J.,
Moafi, A.,
Abedi, M.,
Pourabutaleb, E. Genetic Testing and Molecular Biomarkers (19450265)20(9)pp. 516-521
Background: Multidrug resistance is one of the major causes of treatment failure in pediatric acute lymphoblastic leukemia (ALL), and SORCIN is an intracellular calcium modulator protein. The current study was designed to investigate the in vitro and in vivo relationships between the expression levels of SORCIN: in tumor cell lines and children with ALL; its possible correlation with MDR1/P-glycoprotein (P-gp), a multidrug resistance-related gene; and response to therapy. Materials and Methods: Childhood T-lymphoblastic leukemia (CCRF-CEM) cell lines resistant to methotrexate (MTX) were developed. Patient studies were performed by including 30 children with ALL at diagnosis, 3 children with bone marrow relapse, and 15 children with no symptoms of cancer. The mRNA expression profiles of SORCIN and MDR1/P-gp was assessed using quantitative polymerase chain reaction (qPCR). Minimal residual disease (MRD) was measured in the patient population, a year following the initial therapy using qPCR. Results: Cell line data analyses showed a positive correlation between SORCIN mRNA levels and resistance to MTX. The difference between patient and control groups for SORCIN expression levels was not significant. However, patients with a negative response to therapy showed an increase in SORCIN mRNA levels (up to 6.8-fold) compared with those with negative MRD. In addition, the results demonstrated a significant positive correlation between SORCIN and MDR1/P-gp gene expression levels. Conclusion: The current study introduces, for the first time, a possible prognostic value of SORCIN in childhood ALL, which may be correlated with MDR1/P-gp gene expression in these patients. © 2016, Mary Ann Liebert, Inc.
Rahgozar, S.,
Amirian, T.,
Qi m., M.,
Shahshahan, Z.,
Entezar-e-ghaem, M.,
Tehrani, H.G.,
Miroliaei, M.,
Krilis s.a., S.A.,
Giannakopoulos b., B. PLoS ONE (19326203)10(8)
Objective: Angiotensinogen exists in two distinct redox forms in plasma, the oxidized sulfhydryl-bridge form and the reduced, unbridged, free thiol form. The oxidized form of angiotensinogen compared to the free thiol form preferentially interacts with renin resulting in increased generation of angiotensin. The predictive potential of the ratio of free-thiol to oxidized angiotensinogen in the plasma for pre-eclampsia was first suggested by the Read group in ref 10. We propose an improved method for determining the ratio and validate the method in a larger cohort of pregnant women. Methods: Plasma samples from 115 individuals with pre-eclampsia and from 55 healthy pregnant control subjects were collected sequentially over a 2 year period. Using two distinct enzyme-linked immunosorbent assays (ELISAs) the plasma levels of total and free thiol angiotensinogen were quantified. The oxidized angiotensinogen plasma level is derived by subtracting the level of free thiol, reduced angiotensinogen from the total angiotensinogen levels in the plasma. Results: The relative proportion of free thiol angiotensinogen, expressed as a percentage of that observed with an in-house standard, is significantly decreased in pre-eclamptic patients (70.85% ± 29.49%) (mean ± SD) as compared to healthy pregnant controls (92.98 ± 24.93%) (mean ± SD) p ≤ 0.0001. The levels of total angiotensinogen did not differ between the two groups. © 2015 Rahgozar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Genetic Testing and Molecular Biomarkers (19450265)19(3)pp. 156-161
Objectives: Genotyping of single-nucleotide polymorphisms (SNPs) has been applied in various genetic contexts. Tetra-primer amplification refractory mutation system (ARMS) polymerase chain reaction (PCR) is reported as a prominent assay for SNP genotyping. However, there were published data that may question the reliability of this method on some occasions, in addition to a laborious and time-consuming procedure of the optimization step. In the current study, a new SNP genotyping method named modified tetra-primer ARMS (MTPA) PCR was developed based on tetra-primer ARMS PCR. Design and Methods: The modified method has two improvements in its instruction, including equalization of outer primer and inner primer strength by additional mismatch in outer primers, and consideration of equal annealing temperature of specific fragments more than melting temperature of primers. Advantageously, a new computer software was provided for designing primers based on novel concepts. Results: The usual tetra-primer ARMS PCR has a laborious process for optimization. In nonoptimal PCR programs, identification of the accurate genotype was found to be very difficult. However, in MTPA PCR, equalization of the amplicons and primer strength leads to increasing specificity and convenience of genotyping, which was validated by sequencing. Conclusions: In the MTPA PCR technique, a new mismatch at -2 positions of outer primers and equal annealing temperature improve the genotyping procedure. Together, the introduced method could be suggested as a powerful tool for genotyping single-nucleotide mutations and polymorphisms. © Mary Ann Liebert, Inc. 2015.
Biomedical Reports (20499434)3(3)pp. 371-374
BAALC is a novel molecular marker in leukemia that is highly expressed in patients with acute leukemia. Increased expression levels of BAALC are known as poor prognostic factors in adult acute myeloid and lymphoid leukemia. The purpose of the present study was to evaluate the prognostic significance of the BAALC gene expression levels in pediatric acute lymphoblastic leukemia (ALL) and its association with MDR1. Using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR), the mRNA expression levels of BAALC and MRD1 were measured in bone marrow samples of 28 new diagnosed childhood ALL patients and 13 children without cancer. Minimal residual disease (MRD) was measured one year after the initiation of the chemotherapy using the RT‑qPCR method. The high level expression of BAALC had a significant association with the pre‑B‑ALL subtype, leukocytosis and positive MRD after one year of treatment in leukemic patients. In addition, a positive correlation between BAALC and MDR1 mRNA expression was shown in this group. In conclusion, to the best of our knowledge, the increase of BAALC expression as a poor prognostic factor for childhood ALL is shown for the first time. Additionally, the correlation between BAALC and MDR1 in mRNA expression levels can aid for an improved understanding of the mechanism through which BAALC may function in ALL and multidrug resistance. © 2015, Spandidos Publications. All rights reserved.
Rahgozar, S.,
Moafi, A.,
Abedi, M.,
Entezar-e-ghaem, M.,
Moshtaghian, J.,
Ghaedi, K.,
Esmaeili, A.,
Montazeri, F. Cancer Biology and Therapy (15384047)15(1)pp. 35-41
Multidrug resistance (MDR) is an important cause of treatment failure in acute lymphoblastic leukemia (ALL). The ABC family of membrane transporters is proposed, albeit with controversy, to be involved in this process. The present study aims to investigate the mRNA expression profile of several genes of this family, including ABCA 2, ABCA 3, ABCB1/MDR1, MRP1/ABCC 1, MRP3/ABCC 3, ABCG2/BCRP, and the intracellular transporter MVP/LRP, in childhood ALL, and to evaluate their association with response to therapy. Some genes in the present research are being studied for the first time in Iran. Using quantitative real time PCR, we evaluated 27 children with ALL at diagnosis and 15 children with normal bone marrow. The status of response to therapy was assessed one year after the onset of therapy through investigating the IgH/TCRγ gene rearrangements. Our findings indicate a considerable and direct relationship between mRNA expression levels of ABCA 2, ABCA 3, MDR1, and MRP1 genes and positive minimal residual disease (MRD) measured after one-year treatment. Statistical analysis revealed that expression of these genes higher than the cutoff point will raise the risk of MRD by 15-, 6.25-, 12-, and 9-fold, respectively. No relationship was found between of MVP/LRP, MRP3 and ABCG2 genes expression and ALL prognoses. Considering the direct and significant relationship between the increased expression of ABCA 2, ABCA 3, MDR1, and MRP1 genes and positive risk of MRD in children with ALL, evaluating the expression profile of these genes on diagnosis may identify high risk individuals and help plan a more efficient treatment strategy. © 2014 Landes Bioscience.
Journal of Mazandaran University of Medical Sciences (17359260)24(113)pp. 11-26
Background and purpose: MDR1 is nowadays considered as a known transporter involved in drug resistance of different cancers. However, the importance of this protein in different systems of the body and its functional role in other diseases is less studied. This article aimed at investigating the role of MDR1 in the immune system and neurological disorders, and also exploring the possible therapeutic use of this protein. Material and Methods: In this review we studied 68 reputable articles published between 1998 and 2014 (both in Persian and English). The search engines included PubMed, Google Scholar, Science Direct and Elsevier databases. Results: The expression of MDR1 increases during the maturation of dendritic cells and their migration to lymph nodes to activate T lymphocytes. The function of this protein has been reported in naive B cells and it is expressed during the activation of CD4+ and CD8+ T lymphocytes. Compared with other leukocyte populations, MDR1 expression levels are the highest in NK cells. MDR1activity in brain capillary endothelial cells, involved in blood-brain barrier, prevents the entry of small drugs and inflammatory molecules into the CNS. The protein expression is reduced in a variety of immune destructive diseases. Conclusion: This article identifies the importance and function of MDR1in brain capillary endothelial cells and those involved in the immune system. Considering the confirmed role of MDR1 in immunological and degenerative disorders, this article may help in resolving the disorders caused by the lack of MDR1expression.
Honardoost, M.A.,
Tanha, H.M.,
Etemadifar, M.,
Rahgozar, S.,
Salehi, M.,
Ghaedi, K. Genetics in the Third Millennium (24237159)12(1)
Multiple sclerosis is a chronic inflammatory and myelin destructive disease which involves the central nervous system (the brain and spinal cord). miRNAs are a new group of non-coding and small RNA molecules which control posttranscriptional gene expression. By now, the role of miRNAs in several important biological processes has been emerged including growth, cell cycle, development, differentiation, metabolism, and apoptosis. miRNA Expression profiling studies show that the expression of some miRNAs (such as miR-155 and miR-326) changes in the blood cells or brain lesions of multiple sclerosis patients in comparison with healthy subjects. Furthermore, it has been reported that deficiency of these miRNAs in animal models of multiple sclerosis can change the clinical symptoms of the disease. In this review article, we first explained the mechanism of biogenesis and function of miRNAs briefly and then review the most recent studies on miRNA expression profiling in multiple sclerosis patients, the possible targets of disregulated miRNAs and the possible ways through which they could participate in the pathogenesis of multiple sclerosis. © 2014, Iranian Neurogenetics Society. All rights reserved.
Journal of Spinal Cord Medicine (20457723)36(1)pp. 66-71
Background: Study of molecular responses to central nervous system injury would be helpful for controlling the harmful pathways post-injury and triggering the useful pathways required for the treatment of injury. Objective: To investigate the expression level of liver X receptor α (LXRα) which has anti-inflammatory effects and pro-apoptotic Bcl-2-associated X protein (Bax) upon spinal cord injury (SCI). Design: To induce SCI, transection was carried out at T9 level of male Wister rats. Approximately 8 mm of rostral, caudal, and epicenter tissues of injured sites in treated rats were chosen for quantitative real-time polymerase chain reaction at the 6, 24, and 72 hours, and 7 and 10 days post-surgery. Results: Our results showed a complicated temporal and spatial pattern of alteration in LXRα and Bax mRNA expression levels after SCI. LXRα expression level followed a homologues pattern (additive and subtractive wave) with a difference in time at three areas of studied. Rostral, caudal, and epicenter expression patterns of Bax were dissimilar in these areas. Gradual increase in the expression of Bax without any decrease at the rostral area was observed, presumably indicating the active transcription process of this gene, regardless of its protein situation. Conclusion: A time lapse significant change in Bax expression level was observed only in the epicenter of injury, emphasizing that apoptotic responses are limited to this area. Furthermore, an increase in LXRα transcription level was observed first in rostral area and then extended to epicentral and caudal areas, implying that inflammation responses extended from rostral to caudal areas. © The Academy of Spinal Cord Injury Professionals, Inc. 2013.
Journal of Isfahan Medical School (10277595)31(228)pp. 274-293
Background: P-glycoprotein 170 is encoded by MDR1 gene and belongs to the ATP-binding cassette transporters (ABC) superfamily. This protein has important roles in cell physiology and its function in cancerous cells may contribute to failure treatment. The molecular structure of P-glycoprotein and its corresponding gene is introduced in this research. Moreover, the pathophysiological role of this protein and its effects on pharmacokinetics are discussed. Methods: EBSCO, Elsevier, PubMed and OVID databases were reviewed to introduce the most recent studies regarding p-glycoprotein, MDR1 and their clinical importance in health and disease. Authors' novel findings regarding MDR1 and leukemia were also discussed. Findings: P-glycoprotein is naturally expressed in many tissues such as liver, intestine and brain. This protein is involved in many cellular processes such as inflammation, immune cell differentiation, detoxification and hormone secretion. Reduction of the treatment efficiency and the consecutive relapse due to drug resistance are the most important consequences of this protein function, and addressed as the most challenging obstacles in cancer treatment. Conclusion: P-glycoprotein is an important transporter with a protecting function in normal cell life. On the other hand, it may provide drug resistance in some cancerous cells. Comprehensive studies about MDR1 and P-glycoprotein 170 may provide novel approaches to new diagnostics and therapeutics.
Journal of Isfahan Medical School (10277595)31(234)
Background: Preeclampsia is a multisystem disorder of pregnancy, which complicates 3-5% of pregnancies. It is a major cause of maternal and neonatal mortality worldwide. Despite decades of research, the etiology of preeclampsia has remained unknown and undetectable prior to the onset of symptoms. The current review article discusses different aspects of preeclampsia in order to delineate the pathophysiology of the disease. Methods: This study has reviewed 96 publications explaining the various characteristics of preeclampsia including etiology, genetics, proteomics and metabolomics, using EBSCO, OVID, PubMed, Elsevier and NCBI databases. Findings: Based on the published studies, endothelial dysfunction and oxidative stress are the major problems in preeclampsia. Related genes and biomarkers are reported which may improve the diagnosis of preeclampsia. Proteomics and metabolomics have provided new insights into better understanding of the etiology and management of the disease. Conclusion: Preeclampsia is a complicated and multifactorial disease which needs to be evaluated in different aspects. This review article introduces novel approaches to the diagnosis and treatment of this disorder.
Journal of Isfahan Medical School (10277595)30(213)pp. 1919-1934
Background: Multi-drug resistance (MDR) is a prevalent phenomenon occurred in tumor cells in response to chemotherapy. The main cause of MDR is the efflux of drugs by ATP-binding Cassette (ABC) transporters. Since identifying the role of these proteins in resistance to chemotherapeutic agents, extensive researches have been started to find out methods to selectively overcome their effects. The purpose of this study was to review the methods used to conquer ABC transportersmediated MDR. Methods: Reviewing more than 70 basic and recently published articles, this paper is discussing the methods of defeating MDR. Findings: The first step to counteract the ABC transporters effects is using chemical inhibitors. Unpredictable cytotoxicity and side effects of these modulators may require more attentiveness in their clinical application. Another technique in this regard is the use of drug delivery systems such as nanoparticles and liposomes. This method can be employed along with sonication to improve the specificity. Down-regulation of ABC transporters expression by means of RNA interference system is another method to overcome MDR. siRNA and shRNA are utilized in this system and are introduced into the cells by various carriers such as viral vectors, lipid carriers and chemical polymers. Destruction of mRNA is the aim of this method. Conclusion: Despite great advances in overcoming ABC transporters-mediated MDR, most of the techniques are in preclinical and early stages of clinical trials and await more delineation for becoming clinically applicable. Two main reasons for this slow progress are wide range of substrate specificity as well as the tissue distribution of ABC transporters.
Iranian Journal Of Immunology (17351383)9(2)pp. 73-85
Beta 2 glycoprotein I (β2GPI) is a single chain 50 kDa highly glycosylated glycoprotein at an approximate concentration of 4 μM in cells. The abundance of this protein in plasma and its high state of preservation indicate the important role of this protein in mammalian. In addition, β2GPI has a particular structure in the fifth domain, and is categorized as the major antigen recognized by autoantibodies present in antiphospholipid syndrome. Beta 2 glycoprotein I has been usually studied in the context of antiphospholipid antibody production. Complexes of β2GPI/anti-β2GPI antibodies have been examined in different coagulation and cell activation pathways. However, the function of β2GPI, independent from the antibodies, has not been clearly determined. In this paper different features of β2GPI including its structure, plasma concentration and its proposed in vitro and in vivo functions in clot formation and fibrinolysis along with anti-β2GPI antibodies (Abs) are discussed. Their inhibitory or promotive effects are delineated in each facet.
Moafi, A.,
Rahgozar, S.,
Hajian, M.,
Ghyas, M.,
Ghorbani, N.,
Hassanzadeh, A. HealthMED (18402291)6(6)pp. 2047-2051
Background: Iron deficiency without anemia is highly prevalent among female university students. Objective: Considering the intense competition for future educational opportunities and the possible impacts of iron deficiency on brain activities, we tried to investigate the effects of supplemental iron on educational achievements of students with iron deficiency without anemia entering universities. Methods: The iron status was evaluated in 209 female students at Faculty of Science, University of Isfahan. Iron deficiency without anemia was detected in 40.46% of the cases of which 72 individuals entered the clinical trial. The subjects were divided into two groups of 36 and treated with iron supplements or placebo. Afterwards, their educational progress was assessed. Results: Students who received supplemental iron showed more improved educational rankings (p = 0.05) and average scores (p = 0.009) compared to the control group. Conclusion: The findings of this study indicated the positive effects of iron supplementation on the educational achievements of female students suffering iron deficiency without anemia.
Moafi, A.,
Rahgozar, S.,
Ghias, M.,
Ahar, E.V.,
Borumand, A.,
Sabbaghi, A.,
Sameti, A.,
Hashemi, S.M. International Journal Of Preventive Medicine (20088213)2(4)pp. 280-285
Objectives: Obesity and increased blood pressure are identified as risk factors for cardiac and pulmonary disorders. On the other hand, iron deficiency (another preventable disease) is common in adolescence and considered as associated with health impairment. The present study evaluates body mass index (BMI) and its association with blood pressure and hematological indices in freshman students entering the University of Isfahan in 2009. Methods: All the 1675 students who entered the University of Isfahan in September 2009 were examined. Height, weight, BMI, blood pressure, hemoglobin (Hb) and red blood cell (RBC) indices of these students were measured. The prevalence of high blood pressure, its association with BMI and the relation between BMI and anemia, iron deficiency and educational achievement were assessed. Results: All participants, including 514 males and 1161 females, went under clinical observations. The average age was 20.7 ± 3.8. year Among the students, 18.2% of males and 20% of females were underweight. High systolic blood pressure was more common in the students with BMI > 25 kg/m2 (p < 0.001). Anemia was seen in 8.7% of females. In males, however, a relation between anemia frequency and BMI < 18.5 kg/m2 was more distinct (p = 0.002). There was no association between anemia and students' average test scores. Conclusions: High incidence of abnormal BMI in the study population, and its association with systolic blood pressure indicate the importance of nutritional guidelines and counseling programs for freshman students. On the other hand, high incidence of anemia in this population ascertains the necessity of anemia screening programs before academic studies.
Passam, F.H.,
Rahgozar, S.,
Qi m., M.,
Raftery, M.J.,
Wong, J.W.H.,
Tanaka, K.,
Ioannou, Y.,
Zhang, J.,
Gemmell, R.,
Qi, J.C. Blood (15280020)116(11)pp. 1995-1997
Ioannou, Y.,
Zhang, J.,
Passam, F.H.,
Rahgozar, S.,
Qi, J.C.,
Giannakopoulos b., B.,
Qi m., M.,
Yu, P.,
Yu, D.M.,
Hogg, P.J. Blood (15280020)116(11)pp. 1961-1970
β2-Glycoprotein I (β2GPI) is an evolutionary conserved, abundant circulating protein. Although its function remains uncertain, accumulated evidence points toward interactions with endothelial cells and components of the coagulation system, suggesting a regulatory role in vascular biology. Our group has shown that thioredoxin 1 (TRX-1) generates free thiols in β2GPI, a process that may have a regulatory role in platelet adhesion. This report extends these studies and shows for the first time evidence of β2GPI with free thiols in vivo in both multiple human and murine serum samples. To explore how the vascular surface may modulate the redox status of β2GPI, unstimulated human endothelial cells and EAhy926 cells are shown to be capable of amplifying the effect of free thiol generation within β2GPI. Multiple oxidoreductase enzymes, such as endoplasmic reticulum protein 46 (ERp 46) and TRX-1 reductase, in addition to protein disulfide isomerase are secreted on the surface of endothelial cells. Furthermore, one or more of these generated free thiols within β2GPI are also shown to be nitrosylated. Finally, the functional significance of these findings is explored, by showing that free thiol-containing β2GPI has a powerful effect in protecting endothelial cells and EAhy926 cells from oxidative stress-induced cell death. © 2010 by The American Society of Hematology.
Moafi, A.,
Valian, S.,
Nikyar, Z.,
Zeinalian, M.,
Momenzadeh, M.,
Rahgozar, S. International Journal Of Hematology-Oncology And Stem Cell Research (17351243)4(1)pp. 23-27
Introduction: The current study evaluated the value of red blood cell (RBC) indices and the corresponding cutoffpoints for β-thalassemia control programs in Iran. Materials and Methods: 1,150 individuals (575 couples) with low RBC indices and normal hemoglobin A2 who had been referred to the Genetic Centre of Isfahan, were tested during pre-marital screening analyses, in the 2 year period, 2006-2008. β-thalassemia mutations were evaluated. Results: β-thalassemia was identified in 67.8% of the cases with both mean corpuscular volume (MCV) less than 78fl and mean corpuscular hemoglobin (MCH) less than 26 pg. However, 4.1% of the individuals with 78≤ MCV≤ 80 tested positive for thalassemia. MCV showed a higher diagnostic reliability than MCH. However, the accompaniment of MCH<26 with MCV<78 increased the risk of thalassemia 35 times. A significant association was found between the prevalence of minor β-thalassemia and educational levels, raceand familial relationships. Conclusion: According to the results of this study, it seems that MCV=80fl can be used as a proper cut-off point for the screening of minor β-thalassemia. Although in the present study MCV was found to have a higher diagnostic reliability than MCH, MCH <26 along with MCV are very helpful indices for the counselor physician to estimate the risk of minor β-thalassemia more accurately.
Passam, F.H.,
Rahgozar, S.,
Qi m., M.,
Raftery, M.J.,
Wong, J.W.H.,
Tanaka, K.,
Ioannou, Y.,
Zhang, J.,
Gemmell, R.,
Qi, J.C. Journal of Thrombosis and Haemostasis (15387836)8(8)pp. 1754-1762
Background: β2-Glycoprotein I (β2GPI) is an abundant plasma protein that is closely linked to blood clotting, as it interacts with various protein and cellular components of the coagulation system. However, the role of β2GPI in thrombus formation is unknown. We have recently shown that β2GPI is susceptible to reduction by the thiol oxidoreductases thioredoxin-1 and protein disulfide isomerase, and that reduction of β2GPI can take place on the platelet surface. Methods: β2GPI, reduced by thioredoxin-1, was labeled with the selective sulfhydryl probe Na-(3-maleimidylpropionyl)biocytin and subjected to mass spectrometry to identify the specific cysteines involved in the thiol exchange reaction. Binding assays were used to examine the affinity of reduced β2GPI for von Willebrand factor (VWF) and the effect of reduced β2GPI on glycoprotein (GP)Ibα binding to VWF. Platelet adhesion to ristocetin-activated VWF was studied in the presence of reduced β2GPI. Results: We demonstrate that the Cys288-Cys326 disulfide in domain V of β2GPI is the predominant disulfide reduced by thioredoxin-1. Reduced β2GPI in vitro displays increased binding to VWF that is dependent on disulfide bond formation. β2GPI reduced by thioredoxin-1, in comparison with non-reduced β2GPI, leads to increased binding of GPIbα to VWF and increased platelet adhesion to activated VWF. Conclusions: Given the importance of thiol oxidoreductases in thrombus formation, we provide preliminary evidence that the thiol-dependent interaction of β2GPI with VWF may contribute to the redox regulation of platelet adhesion. © 2010 International Society on Thrombosis and Haemostasis.
Rahgozar, S.,
Giannakopoulos b., B.,
Yan, X.,
Wei, J.,
Jian, C.Q.,
Gemmell, R.,
Krilis s.a., S.A. Arthritis and Rheumatism (00043591)58(4)pp. 1146-1155
Objective. Beta2-glycoprotein I (β2GPI) is an important autoantigen in the antiphospholipid syndrome (APS). In vitro studies suggest that it may have multifaceted physiologic functions, since it displays both anticoagulant and procoagulant properties. We have previously reported that β2GPI can directly bind thrombin, a key serine protease in the coagulation pathway. The present study was undertaken to examine the influence of β2GPI on thrombin inactivation by the serpin heparin cofactor II (HCII). The effect of anti-β2GPI antibodies was also examined. Methods. HCII inactivation of thrombin was assessed using chromogenic and various platelet functional assays. The influence of intact and proteolytically cleaved β2GPI and anti-β2GPI antibodies was deter-mined in these systems. Results. β2GPI protected thrombin against inactivation by HCII/heparin. Cleavage of β2GPI at Lys317-Thr318 abrogated its protective effect. Patient polyclonal IgG and murine monoclonal anti-β2GPI antibodies potentiated the procoagulant influence of β2GPI in this system. Conclusion. These novel findings suggest that β2GPI may regulate thrombin inactivation by HCII/ heparin. The observation that anti-β2GPI antibodies potentiate the protective effect of β2GPI on thrombin in this system, thereby promoting a procoagulant response, may potentially delineate one of the pathophysiologic mechanisms contributing to the prothrombotic tendency in patients with APS. © 2008, American College of Rheumatology.
Rahgozar, S.,
Yang, Q.,
Giannakopoulos b., B.,
Yan, X.,
Miyakis, S.,
Krilis s.a., S.A. Arthritis and Rheumatism (00043591)56(2)pp. 605-613
Objective. Beta2-glycoprotein I (β2GPI) is a dominant antigenic target in antiphospholipid syndrome (APS). Beta 2-glycoprotein I may bind to factor XI and serve a physiologic function as a regulator of factor XI activation by thrombin. We undertook this study to investigate the possible interactions of β2GPI with thrombin in β2GPI-regulated factor XI activation by thrombin and to evaluate the effect of anti-β2GPI antibodies on this system. Methods. The β2GPI interaction with thrombin was investigated in direct and competitive assays using β2GPI domain mutants and thrombin-binding exosite oligonucleotides. Beta2-glycoprotein I inhibition of thrombin-mediated factor XI activation was assessed in the presence of 8 anti-β2GPI monoclonal antibodies (mAb) directed against domain I. Results. Domain V of β2GPI was involved in direct binding to thrombin, and exosite I and exosite II on thrombin took part in this interaction. Anti-β2GPI mAb produced a >70% inhibition of thrombin-mediated factor XI activation in the presence of β2GPI. Conclusion. We demonstrate that β2GPI interacts with thrombin exosites I and II. This novel finding necessitates a reinterpretation of previous studies from which the detection of anti-human thrombin antibodies in APS has been reported. We also show that anti-β2GPI antibodies potentiate the inhibitory effect of β2GPI on thrombin-mediated factor XIa generation. © 2007, American College of Rheumatology.
Giannakopoulos b., B.,
Passam, F.H.,
Rahgozar, S.,
Krilis s.a., S.A. Blood (15280020)109(2)pp. 422-430
The antiphospholipid syndrome (APS) is an important cause of acquired thrombophilia. It is characterized by the core clinical manifestations of thrombosis, either venous or arterial, and in women it can also be associated with recurrent fetal loss. The detection of persistently elevated levels of antiphospholipid antibodies (aPL Abs) is a requisite laboratory feature for the diagnosis to be made. The dominant antigenic targets in APS are beta 2-glycoprotein I (β2-GPI) and prothrombin. There is an accumulating body of experimental evidence that suggests that specific subgroups of aPL Abs may directly contribute to disease pathogenesis. This review critically examines the experimental evidence underlying the various propositions made to explain how these antibodies may predispose to disease in humans. Furthermore, it also examines the evidence relating to the immunologic mechanisms that may contribute to the breakage of peripheral tolerance in this disorder. Delineating the strengths and limitations of the experimental evidence accumulated thus far will hopefully stimulate further experimentation toward achieving the ultimate goal of precisely defining the dominant pathogenic mechanisms operational in APS. This may pave the way for the development of improved therapies. © 2007 by The American Society of Hematology.
Enattah, N.S.,
Trudeau, A.,
Pimenoff, V.,
Maiuri, L.,
Auricchio, S.,
Greco, L.,
Rossi, M.,
Lentze, M.,
Seo j.k., ,
Rahgozar, S. American Journal of Human Genetics (15376605)81(3)pp. 615-625
A single-nucleotide variant, C/T-13910, located 14 kb upstream of the lactase gene (LCT), has been shown to be completely correlated with lactase persistence (LP) in northern Europeans. Here, we analyzed the background of the alleles carrying the critical variant in 1,611 DNA samples from 37 populations. Our data show that the T-13910 variant is found on two different, highly divergent haplotype backgrounds in the global populations. The first is the most common LP haplotype (LP H98) present in all populations analyzed, whereas the others (LP H8-H12), which originate from the same ancestral allelic haplotype, are found in geographically restricted populations living west of the Urals and north of the Caucasus. The global distribution pattern of LP T-13910 H98 supports the Caucasian origin of this allele. Age estimates based on different mathematical models show that the common LP T-13910 H98 allele (∼5,000-12,000 years old) is relatively older than the other geographically restricted LP alleles (∼1,400-3,000 years old). Our data about global allelic haplotypes of the lactose-tolerance variant imply that the T-13910 allele has been independently introduced more than once and that there is a still-ongoing process of convergent evolution of the LP alleles in humans. © 2007 by The American Society of Human Genetics. All rights reserved.
American Journal of Hematology (03618609)65(3)pp. 192-195
Sickle cell anemia is not considered to be a significant disease in Iran, although the sickle cell trait is estimated to have a high incidence in the Southern provinces. Since 1977, when the presence of a mild sickle cell anemia was reported in this country, there have been no further investigations published giving precise data on the incidence and origins of the sickle cell mutation in Iran. We report here the finding of patients with the sickle cell trait, sickle cell anemia, and sickle-β thalassemia in Central Iran. A survey of 300 individuals from a village in Southeast Esfahan revealed an incidence of the sickle cell trait of 8.33%. 'Cascade screening' enabled 96 relatives in four surrounding villages to be tested, and the at-risk couples were offered counseling as a 'sickle cell control program.' The hematological indices and HbF levels of the affected patients were determined. The HbF levels were unusually high, ranging from 18% to 41.4%, and SS patients with the highest levels were asymptomatic. Linkage analysis revealed the β(s) gene haplotype in this population to be the Indian-Arab haplotype. (C) 2000 Wiley-Liss, Inc.
