Publications by authors named "Majid Ahmadi"

84 Publications

A Deep Insight Into CAR-T Cell Therapy in Non-Hodgkin Lymphoma: Application, Opportunities, and Future Directions.

Front Immunol 2021 23;12:681984. Epub 2021 Jun 23.

German Cancer Research Center, Toxicology and Chemotherapy Unit (G401), Heidelberg, Germany.

Non-Hodgkin's lymphoma (NHL) is a cancer that starts in the lymphatic system. In NHL, the important part of the immune system, a type of white blood cells called lymphocytes become cancerous. NHL subtypes include marginal zone lymphoma, small lymphocytic lymphoma, follicular lymphoma (FL), and lymphoplasmacytic lymphoma. The disease can emerge in either aggressive or indolent form. 5-year survival duration after diagnosis is poor among patients with aggressive/relapsing form of NHL. Therefore, it is necessary to understand the molecular mechanisms of pathogenesis involved in NHL establishment and progression. In the next step, we can develop innovative therapies for NHL based on our knowledge in signaling pathways, surface antigens, and tumor milieu of NHL. In the recent few decades, several treatment solutions of NHL mainly based on targeted/directed therapies have been evaluated. These approaches include B-cell receptor (BCR) signaling inhibitors, immunomodulatory agents, monoclonal antibodies (mAbs), epigenetic modulators, Bcl-2 inhibitors, checkpoint inhibitors, and T-cell therapy. In recent years, methods based on T cell immunotherapy have been considered as a novel promising anti-cancer strategy in the treatment of various types of cancers, and particularly in blood cancers. These methods could significantly increase the capacity of the immune system to induce durable anti-cancer responses in patients with chemotherapy-resistant lymphoma. One of the promising therapy methods involved in the triumph of immunotherapy is the chimeric antigen receptor (CAR) T cells with dramatically improved killing activity against tumor cells. The CAR-T cell-based anti-cancer therapy targeting a pan-B-cell marker, CD19 is recently approved by the US Food and Drug Administration (FDA) for the treatment of chemotherapy-resistant B-cell NHL. In this review, we will discuss the structure, molecular mechanisms, results of clinical trials, and the toxicity of CAR-T cell-based therapies. Also, we will criticize the clinical aspects, the treatment considerations, and the challenges and possible drawbacks of the application of CAR-T cells in the treatment of NHL.
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http://dx.doi.org/10.3389/fimmu.2021.681984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261235PMC
June 2021

Humoral immune mechanisms involved in protective and pathological immunity during COVID-19.

Hum Immunol 2021 Jul 1. Epub 2021 Jul 1.

Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19 is associated with excessive inflammation, as a main reason for severe condition and death. Increased inflammatory cytokines and humoral response to SARS-CoV-2 correlate with COVID-19 immunity and pathogenesis. Importantly, the levels of pro-inflammatory cytokines that increase profoundly in systemic circulation appear as part of the clinical pictures of two overlapping conditions, sepsis and the hemophagocytic syndromes. Both conditions can develop lethal inflammatory responses that lead to tissue damage, however, in many patients hemophagocytic lymphohistiocytosis (HLH) can be differentiated from sepsis. This is a key issue because the life-saving aggressive immunosuppressive treatment, required in the HLH therapy, is absent in sepsis guidelines. This paper aims to describe the pathophysiology and clinical relevance of these distinct entities in the course of COVID-19 that resemble sepsis and further highlights two effector arms of the humoral immune response (inflammatory cytokine and immunoglobulin production) during COVID-19 infection.
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http://dx.doi.org/10.1016/j.humimm.2021.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245343PMC
July 2021

The Potential Use of Mesenchymal Stem Cells and Their Derived Exosomes for Orthopedic Diseases Treatment.

Stem Cell Rev Rep 2021 Jun 24. Epub 2021 Jun 24.

Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Musculoskeletal disorders (MSDs) are conditions that can affect muscles, bones, and joints. These disorders are very painful and severely limit patients' mobility and are more common in the elderly. MSCs are multipotent stem cells isolated from embryonic (such as the umbilical cord) and mature sources (such as adipose tissue and bone marrow). These cells can differentiate into various cells such as osteoblasts, adipocytes, chondrocytes, NP-like cells, Etc. Due to MSC characteristics such as immunomodulatory properties, ability to migrate to the site of injury, recruitment of cells involved in repair, production of growth factors, and large amount production of extracellular vesicles, these cells have been used in many regenerative-related medicine studies. Also, MSCs produce different types of EVs, such as exosomes, to the extracellular environment. Exosomes reflect MSCs' characteristics and do not have cell therapy-associated problems because they are cell-free. These vesicles carry proteins, nucleic acids, and lipids to the host cell and change their function. This review focuses on MSCs and MSCs exosomes' role in repairing dense connective tissues such as tendons, cartilage, invertebrate disc, bone fracture, and osteoporosis treatment.
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http://dx.doi.org/10.1007/s12015-021-10185-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224994PMC
June 2021

Recent advances in antibody-based immunotherapy strategies for COVID-19.

J Cell Biochem 2021 Jun 23. Epub 2021 Jun 23.

Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

The emergence of a new acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), the cause of the 2019-nCOV disease (COVID-19), has caused a pandemic and a global health crisis. Rapid human-to-human transmission, even from asymptomatic individuals, has led to the quick spread of the virus worldwide, causing a wide range of clinical manifestations from cold-like symptoms to severe pneumonia, acute respiratory distress syndrome (ARDS), multiorgan injury, and even death. Therefore, using rapid and accurate diagnostic methods to identify the virus and subsequently select appropriate and effective treatments can help improvement of patients and control the pandemic. So far, various treatment regimens along with prophylactic vaccines have been developed to manage COVID-19-infected patients. Among these, antibody-based therapies, including neutralizing antibodies (against different parts of the virus), polyclonal and monoclonal antibodies, plasma therapy, and high-dose intravenous immunoglobulin (IVIG) have shown promising outcomes in accelerating and improving the treatment process of patients, avoiding the viral spreading widely, and managing the pandemic. In the current review paper, different types and applications of therapeutic antibodies in the COVID-19 treatment are comprehensively discussed.
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http://dx.doi.org/10.1002/jcb.30017DOI Listing
June 2021

Interleukin-25: New perspective and state-of-the-art in cancer prognosis and treatment approaches.

Cancer Med 2021 Aug 15;10(15):5191-5202. Epub 2021 Jun 15.

Noncommunicable Diseases Research Center, Bam University of Medical Sciences, Bam, Iran.

Cancer is a leading cause of death which imposes a substantial financial burden. Among the several mechanisms involved in cancer progression, imbalance of immune cell-derived factors such as cytokines and chemokines plays a central role. IL-25, as a member of the IL-17 cytokine subfamily, exerts a paradoxical role in cancer, including tumor supportive and tumor suppressive. Hence, we have tried to clarify the role of IL-25 and its receptor in tumor progression and cancer prognosis. It has been confirmed that IL-25 exerts a tumor-suppressive role through inducing infiltration of eosinophils and B cells into the tumor microenvironment and activating the apoptotic pathways. In contrast, the tumor-supportive function has been implemented by activating inflammatory cascades, promoting cell cycle, and inducing type-2 immune responses. Since IL-25 has been dysregulated in tumor tissues and this dysregulation is involved in cancer development, its examination can be used as a tumor diagnostic and prognostic biomarker. Moreover, IL-25-based therapeutic approaches have shown promising results in cancer inhibition. In cancers in which IL-25 has a tumor-suppressive function, employing IL-25-enhancing approaches, such as Virulizin and dihydrobenzofuran administration, has potentially inhibited tumor cell growth. On the other hand, in the case of IL-25-dependent tumor progression, using IL-25 blocking methods, including anti-IL-25 antibodies, might be a complementary approach to the other anticancer agent. Collectively, it is hoped, IL-25 might be a promising target in cancer treatment.
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http://dx.doi.org/10.1002/cam4.4060DOI Listing
August 2021

Different T cell related immunological profiles in COVID-19 patients compared to healthy controls.

Int Immunopharmacol 2021 Aug 28;97:107828. Epub 2021 May 28.

Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

In various pathological conditions, cellular immunity plays an important role in immune responses. Amongimmunecells, T lymphocytes pdomotecellular and humoralresponses as well as innate immunity. Therefore, careful investigation of these cells has a significant impact on accurate knowledge in COVID-19diseasepathogenesis. In current research, the frequency and function of various T lymphocytes involved in immune responses examined in SARS-CoV-2 patients with various disease severity compared to normal subjects. In order to make an accurate comparison among patients with various disease severity, this study was performed on asymptomatic recovered cases (n = 20), ICU hospitalized patients (n = 30), non-ICU hospitalized patients (n = 30), and normal subjects (n = 20). To precisely evaluate T cells activity following purification, their cytokine secretion activity was examined. Similarly, immediately after purification of Treg cells, their inhibitory activity on T cells was investigated. The results showed that COVID-19 patients with severe disease (ICU hospitalized patients) not only had a remarkable increase in Th1 and Th17 but also a considerable decrease in Th2 and Treg cells. More importantly, as the IL-17 and IFN-γ secretion was sharply increased in severe disease, the secretion of IL-10 and IL-4 was decreased. Furthermore, the inhibitory activity of Treg cells was reduced in severe disease patients in comparison to other groups. In severe COVID-19 disease, current findings indicate when the inflammatory arm of cellular immunity is significantly increased, a considerable reduction in anti-inflammatory and regulatory arm occurred.
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http://dx.doi.org/10.1016/j.intimp.2021.107828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162824PMC
August 2021

CAR-NK cell in cancer immunotherapy; A promising frontier.

Cancer Sci 2021 May 29. Epub 2021 May 29.

German Cancer Research Center, Toxicology and Chemotherapy Unit (G401), Heidelberg, Germany.

Chimeric antigen receptors (CARs) have a unique facet of synthetic biology and offer a paradigm shift in personalized medicine as they can use and redirect the patient's immune cells to attack cancer cells. CAR-natural killer (NK) cells combine the targeted specificity of antigens with the subsequent intracellular signaling ability of the receptors to increase their anti-cancer functions. Importantly, CAR-NK cells can be utilized as universal cell-based therapy without requiring human leukocyte antigen (HLA) matching or earlier contact with tumor-associated antigens (TAAs). Indeed, CAR-NK cells can be adapted to recognize various antigens, hold higher proliferation capacity, and in vivo persistence, show improved infiltration into the tumors, and the ability to overcome the resistant tumor microenvironment leading to sustained cytotoxicity against tumors. Accumulating evidence from recent in vivo studies rendering CAR-NK cell anti-cancer competencies renewed the attention in the context of cancer immunotherapy, as these redirected effector cells can be used in the development of the "off-the-shelf" anti-cancer immunotherapeutic products. In the current review, we focus on the therapeutic efficacy of CAR-NK cell therapies for treating various human malignancies, including hematological malignancies and solid tumors, and will discuss the recent findings in this regard, with a special focus on animal studies.
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http://dx.doi.org/10.1111/cas.14993DOI Listing
May 2021

The emerging role of microRNA in regulating the mTOR signaling pathway in immune and inflammatory responses.

Immunol Cell Biol 2021 May 14. Epub 2021 May 14.

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

The mechanistic/mammalian target of rapamycin (mTOR) is considered to be an atypical protein kinase that plays a critical role in integrating different cellular and environmental inputs in the form of growth factors, nutrients and energy and, subsequently, in regulating different cellular events, including cell metabolism, survival, homeostasis, growth and cellular differentiation. Immunologically, mTOR is a critical regulator of immune function through integrating numerous signals from the immune microenvironment, which coordinates the functions of immune cells and T cell fate decisions. The crucial role of mTOR in immune responses has been lately even more appreciated. MicroRNAs (miRNAs) are endogenous, small, noncoding single-stranded RNAs that act as molecular regulators involved in multiple processes during immune cells development, homeostasis, activation and effector polarization. Several studies have recently indicated that a range of miRNAs are involved in regulating the phosphoinositide 3-kinase/protein kinase B/mTOR (PI3K/AKT/mTOR) signaling pathway by targeting multiple components of this signaling pathway and modulating the expression and function of these targets. Current evidence has revealed the interplay between miRNAs and the mTOR pathway circuits in various immune cell types. The expression of individual miRNA can affect the function of mTOR signaling to determine the cell fate decisions in immune responses through coordinating immune signaling and cell metabolism. Dysregulation of the mTOR pathway/miRNAs crosstalk has been reported in cancers and various immune-related diseases. Thus, expression profiles of dysregulated miRNAs could influence the mTOR pathway, resulting in the promotion of aberrant immunity. This review summarizes the latest information regarding the reciprocal role of the mTOR signaling pathway and miRNAs in orchestrating immune responses.
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http://dx.doi.org/10.1111/imcb.12477DOI Listing
May 2021

Chemokine CXCL14; a double-edged sword in cancer development.

Int Immunopharmacol 2021 Aug 28;97:107681. Epub 2021 Apr 28.

Noncommunicable Diseases Research Center, Bam University of Medical Sciences, Bam, Iran. Electronic address:

Cancer is a leading cause of death worldwide and imposes a substantial financial burden. Therefore, it is essential to develop cost-effective approaches to inhibit tumor growth and development. The imbalance of cytokines and chemokines play an important role among different mechanisms involved in cancer development. One of the strongly conserved chemokines that is constitutively expressed in skin epithelia is the chemokine CXCL14. As a member of the CXC subfamily of chemokines, CXCL14 is responsible for the infiltration of immune cells, maturation of dendritic cells, upregulation of major histocompatibility complex (MHC)-I expression, and cell mobilization. Moreover, dysregulation of CXCL14 in several cancers has been identified by several studies. Depending on the type or origin of the tumor and components of the tumor microenvironment, CXCL14 plays a conflicting role in cancer. Although fibroblast-derived CXCL14 has a tumor-supportive role, epithelial-derived CXCL14 mainly inhibits tumor progression. Hence, this review will elucidate what is known on the mechanisms of CXCL14 and its therapeutic approaches in tumor treatment. CXCL14 is a promising approach for cancer immunotherapy.
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http://dx.doi.org/10.1016/j.intimp.2021.107681DOI Listing
August 2021

CXC chemokine ligand 16: a Swiss army knife chemokine in cancer.

Expert Rev Mol Med 2021 Apr 21;23:e4. Epub 2021 Apr 21.

Noncommunicable Diseases Research Center, Bam University of Medical Sciences, Bam, Iran.

Today, cancer is one of the leading causes of death worldwide. Lately, cytokine and chemokine imbalances have gained attention amongst different involved pathways in cancer development and attracted much consideration in cancer research. CXCL16, as a member of the CXC subgroup of chemokines, has been attributed to be responsible for immune cell infiltration into the tumour microenvironment. The aberrant expression of CXCL16 has been observed in various cancers. This chemokine has been shown to play a conflicting role in tumour development through inducing pro-inflammatory conditions. The infiltration of various immune and non-immune cells such as lymphocytes, cancer-associated fibroblasts and myeloid-derived suppressor cells by CXCL16 into the tumour microenvironment has complicated the tumour fate. Given this diverse role of CXCL16 in cancer, a better understanding of its function might build-up our knowledge about tumour biology. Hence, this study aimed to review the impact of CXCL16 in cancer and explored its therapeutic application. Consideration of these findings might provide opportunities to achieve novel approaches in cancer treatment and its prognosis.
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http://dx.doi.org/10.1017/erm.2021.7DOI Listing
April 2021

Reversible oxygen migration and phase transitions in hafnia-based ferroelectric devices.

Science 2021 05 15;372(6542):630-635. Epub 2021 Apr 15.

Zernike Institute of Advanced Materials, University of Groningen, 9747 AG Groningen, Netherlands.

Unconventional ferroelectricity exhibited by hafnia-based thin films-robust at nanoscale sizes-presents tremendous opportunities in nanoelectronics. However, the exact nature of polarization switching remains controversial. We investigated a LaSrMnO/HfZrO capacitor interfaced with various top electrodes while performing in situ electrical biasing using atomic-resolution microscopy with direct oxygen imaging as well as with synchrotron nanobeam diffraction. When the top electrode is oxygen reactive, we observe reversible oxygen vacancy migration with electrodes as the source and sink of oxygen and the dielectric layer acting as a fast conduit at millisecond time scales. With nonreactive top electrodes and at longer time scales (seconds), the dielectric layer also acts as an oxygen source and sink. Our results show that ferroelectricity in hafnia-based thin films is unmistakably intertwined with oxygen voltammetry.
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http://dx.doi.org/10.1126/science.abf3789DOI Listing
May 2021

A new approach to the preeclampsia puzzle; MicroRNA-326 in CD4 lymphocytes might be as a potential suspect.

J Reprod Immunol 2021 06 30;145:103317. Epub 2021 Mar 30.

Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Background: Alongside many complications in understanding the etiology of Preeclampsia (PE), several determinants, such as the imbalanced proportion of anti-angiogenic/proangiogenic T-cell subsets, especially CD4 (Th17/Treg), as well as alterations in the expression profile of related cytokines, miRNAs, and transcription factors might have been implicated in PE pathogenesis.

Material And Method: After sample collection and preparation, CD4 cells were isolated from PE and non-PE pregnant woman and were cultured. Furthermore, analysis such as flow cytometry, real-time PCR, western blotting, and ELISA were performed to assess determinants related to PE manifestation, including sFlt-1, sEng, STAT-3, RORγt, SMAD-7, Foxp3, IL-17, IL-22, Ets-1, and miRNA-326.

Results: Our results showed that the miRNA-326 expression level increased in CD4 Cells and Th17 in PE patients which downregulated Ets-1 expression that acts as a negative control for Th17 development. Furthermore, we showed that the number and expression level of Th17 s and transcription factor RORγt escalated, respectively. While Treg and its related transcription factor (Foxp3) demonstrated a decrease. Flow cytometry analysis illustrated that the Th17/Treg ratio increased in PE. Additionally, we demonstrated that expression and concentration levels of cytokines (IL-17 and IL22) and anti-angiogenic molecules (sEng and sFlt-1) soared in isolated CD4 cells from PE patients, which could be correlated with PE pathogenicity.

Conclusion: In conclusion, we comprehensively evaluated immunological factors and molecules involved in PE manifestation. Interestingly, the CD4 T-cell subset could be an extra source of antiangiogenic factors for the maintenance of this hypertension disorder.
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http://dx.doi.org/10.1016/j.jri.2021.103317DOI Listing
June 2021

Nanocurcumin improves Treg cell responses in patients with mild and severe SARS-CoV2.

Life Sci 2021 Jul 28;276:119437. Epub 2021 Mar 28.

Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

In Coronavirus disease 2019 (COVID-19), a decreased number of regulatory T (Treg) cells and their mediated factors lead to a hyperinflammatory state due to overactivation of the inflammatory cells and factors during the infection. In the current study, we evaluated the Nanocurcumin effects on the Treg cell population and corresponding factors in mild and severe COVID-19 patients. To investigate the Nanocurcumin effects, 80 COVID-19 patients (40 at the severe stage and 40 at the mild stage) were selected and classified into Nanocurcumin and placebo arms. In both the Nanocurcumin and placebo groups, the Treg cell frequency, the gene expression of Treg transcription factor forkhead box P3 (FoxP3), and cytokines (IL-10, IL-35, and TGF-β), as well as the serum levels of cytokines were measured before and after treatment. In both mild and severe COVID-19 patients, Nanocurcumin could considerably upregulate the frequency of Treg cells, the expression levels of FoxP3, IL-10, IL-35, and TGF-β, as well as the serum secretion levels of cytokines in the Nanocurcumin-treated group compared to the placebo group. The abovementioned factors were remarkably increased in the post-treatment with Nanocurcumin before pre-treatment conditions. By contrast, it has been observed no notable alteration in the placebo group. Our findings revealed the SinaCurcumin® effective function in a significant increase in the number of Treg cells and their mediated factors in the Nanocurcumin group than in the placebo group in both mild and severe patients. Hence, it would be an efficient therapeutic agent in rehabilitating COVID-19 infected patients.
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http://dx.doi.org/10.1016/j.lfs.2021.119437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005319PMC
July 2021

Simultaneous inhibition of CD73 and IL-6 molecules by siRNA-loaded nanoparticles prevents the growth and spread of cancer.

Nanomedicine 2021 Jun 24;34:102384. Epub 2021 Mar 24.

Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

High concentrations of adenosine and interleukin (IL)-6 in the tumor microenvironment have been identified as one of the leading causes of cancer growth. Thus, we decided to inhibit the growth of cancer cells by inhibiting the production of adenosine and IL-6 in the tumor environment at the same time. For this purpose, we used chitosan-lactate-PEG-TAT (CLP-TAT) nanoparticles (NPs) loaded with siRNA molecules against CD73, an adenosine-producing enzyme, and IL-6. Proper physicochemical properties of the produced NPs led to high cell uptake and suppression of target molecules. Administration of these NPs to tumor-bearing mice (4T1 and CT26 models) greatly reduced the size of the tumor and increased the survival of the mice, which was accompanied by an increase in anti-tumor T lymphocyte responses. These findings suggest that combination therapy using siRNA-loaded CLP-TAT NPs against CD73 and IL-6 molecules could be an effective treatment strategy against cancer that needs further study.
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http://dx.doi.org/10.1016/j.nano.2021.102384DOI Listing
June 2021

P53 long noncoding RNA regulatory network in cancer development.

Cell Biol Int 2021 Aug 8;45(8):1583-1598. Epub 2021 Apr 8.

Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

The protein p53 as a transcription factor with strong tumor-suppressive activities is known to trigger apoptosis via multiple pathways and is directly involved in the recognition of DNA damage and DNA repair processes. P53 alteration is now recognized as a common event in the pathogenesis of many types of human malignancies. Deregulation of tumor suppressor p53 pathways plays an important role in the activation of cell proliferation or inactivation of apoptotic cell death during carcinogenesis and tumor progression. Mounting evidence indicates that the p53 status of tumors and also the regulatory functions of p53 may be relevant to the long noncoding RNAs (lncRNA)-dependent gene regulation programs. Besides coding genes, lncRNAs that do not encode for proteins are induced or suppressed by p53 transcriptional response and thus control cancer progression. LncRNAs also have emerged as key regulators that impinge on the p53 signaling network orchestrating global gene-expression profile. Studies have suggested that aberrant expression of lncRNAs as a molecular-genomic signature may play important roles in cancer biology. Accordingly, it is important to elucidate the mechanisms by which the crosstalk between lncRNAs and p53 occurs in the development of numerous cancers. Here, we review how several classes of lncRNAs and p53 pathways are linked together in controlling the cell cycle and apoptosis in various cancer cells in both human and mouse model systems.
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http://dx.doi.org/10.1002/cbin.11600DOI Listing
August 2021

The effects of oxygen-ozone therapy on regulatory T-cell responses in multiple sclerosis patients.

Cell Biol Int 2021 Jul 26;45(7):1498-1509. Epub 2021 Mar 26.

Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Multiple sclerosis (MS) is a common degenerative disorder of the central nervous system. The decreased frequency and dysfunction of Treg cells cause inflammation and disease progression. Ozone autohemotherapy can be used as a potential therapeutic approach to regulate the immune system responses and inflammation in MS. For this purpose, 20 relapsing-remitting multiple sclerosis patients were under treatment with ozone twice weekly for 6 months. The frequency of Treg cell, the expression levels of the Treg cell-related factors (FoxP3, IL-10, TGF-β, miR-17, miR-27, and miR-146A), and the secretion levels of IL-10 and TGF-β were assessed. We found a significant increase in the number of Treg cells, expression levels of FoxP3, miRNAs (miR-17 and miR-27), IL-10, and TGF-β factors in patients after oxygen-ozone (O -O ) therapy compared to before treatment. In contrast, oxygen-ozone therapy notably decreased the expression level of miR-146a in treated patients. Interestingly, the secretion levels of both IL-10 and TGF-β cytokines were considerably increased in both serum and supernatant of cultured peripheral blood mononuclear cells in posttreatment condition compared to pretreatment condition. According to results, oxygen-ozone therapy raised the frequency of Treg cell and its relevant factors in treated MS patients. Oxygen-ozone therapy would contribute to improving the MS patients by elevating the Treg cell responses.
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http://dx.doi.org/10.1002/cbin.11589DOI Listing
July 2021

Mesenchymal stem cells and cancer therapy: insights into targeting the tumour vasculature.

Cancer Cell Int 2021 Mar 8;21(1):158. Epub 2021 Mar 8.

Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

A crosstalk established between tumor microenvironment and tumor cells leads to contribution or inhibition of tumor progression. Mesenchymal stem cells (MSCs) are critical cells that fundamentally participate in modulation of the tumor microenvironment, and have been reported to be able to regulate and determine the final destination of tumor cell. Conflicting functions have been attributed to the activity of MSCs in the tumor microenvironment; they can confer a tumorigenic or anti-tumor potential to the tumor cells. Nonetheless, MSCs have been associated with a potential to modulate the tumor microenvironment in favouring the suppression of cancer cells, and promising results have been reported from the preclinical as well as clinical studies. Among the favourable behaviours of MSCs, are releasing mediators (like exosomes) and their natural migrative potential to tumor sites, allowing efficient drug delivering and, thereby, efficient targeting of migrating tumor cells. Additionally, angiogenesis of tumor tissue has been characterized as a key feature of tumors for growth and metastasis. Upon introduction of first anti-angiogenic therapy by a monoclonal antibody, attentions have been drawn toward manipulation of angiogenesis as an attractive strategy for cancer therapy. After that, a wide effort has been put on improving the approaches for cancer therapy through interfering with tumor angiogenesis. In this article, we attempted to have an overview on recent findings with respect to promising potential of MSCs in cancer therapy and had emphasis on the implementing MSCs to improve them against the suppression of angiogenesis in tumor tissue, hence, impeding the tumor progression.
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http://dx.doi.org/10.1186/s12935-021-01836-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938588PMC
March 2021

Mesenchymal stem cell alongside exosomes as a novel cell-based therapy for COVID-19: A review study.

Clin Immunol 2021 05 6;226:108712. Epub 2021 Mar 6.

Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

In the past year, an emerging disease called Coronavirus disease 2019 (COVID-19), caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been discovered in Wuhan, China, which has become a worrying pandemic and has challenged the world health system and economy. SARS-CoV-2 enters the host cell through a specific receptor (Angiotensin-converting enzyme 2) expressed on epithelial cells of various tissues. The virus, by inducing cell apoptosis and production of pro-inflammatory cytokines, generates as cytokine storm, which is the major cause of mortality in the patients. This type of response, along with responses by other immune cell, such as alveolar macrophages and neutrophils causes extensive damage to infected tissue. Newly, a novel cell-based therapy by Mesenchymal stem cell (MSC) as well as by their exosomes has been developed for treatment of COVID-19 that yielded promising outcomes. In this review study, we discuss the characteristics and benefits of MSCs therapy as well as MSC-secreted exosome therapy in treatment of COVID-19 patients.
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http://dx.doi.org/10.1016/j.clim.2021.108712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935675PMC
May 2021

Blockade of HIF-1α and STAT3 by hyaluronate-conjugated TAT-chitosan-SPION nanoparticles loaded with siRNA molecules prevents tumor growth.

Nanomedicine 2021 Jun 3;34:102373. Epub 2021 Mar 3.

Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

HIF-1α and STAT3 are two of the critical factors in the growth, proliferation, and metastasis of cancer cells and play a crucial role in inhibiting anti-cancer immune responses. Therefore, we used superparamagnetic iron oxide (SPION) nanoparticles (NPs) coated with thiolated chitosan (ChT) and trimethyl chitosan (TMC) and functionalized with hyaluronate (H) and TAT peptide for delivery of siRNA molecules against STAT3 and HIF-1α to cancer cells both in vivo and in vitro. The results indicated that tumor cell transfection with siRNA-encapsulated NPs robustly inhibited proliferation and migration and induced apoptosis in tumor cells. Furthermore, simultaneous silencing of HIF-1α and STAT3 significantly repressed cancer development in two different tumor types (4T1 breast cancer and CT26 colon cancer) which were associated with upregulation of cytotoxic T lymphocytes and IFN-γ secretion. The findings suggest inhibiting the HIF-1α/STAT3 axis by SPION-TMC-ChT-TAT-H NPs as an effective way to treat cancer.
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http://dx.doi.org/10.1016/j.nano.2021.102373DOI Listing
June 2021

Shedding more light on the role of Midkine in hepatocellular carcinoma: New perspectives on diagnosis and therapy.

IUBMB Life 2021 Apr 3;73(4):659-669. Epub 2021 Mar 3.

Student Research Committee, Bam University of Medical Sciences, Bam, Iran.

One of the most common malignant tumors is hepatocellular carcinoma (HCC). Progression of HCC mainly results from highly complex molecular and pathological pathways. Midkine (MDK) is a growth factor that impacts viability, migration, and other cell activities. Since MDK has been involved in the inflammatory responses, it has been claimed that MDK has a crucial role in HCC. MDK acts as an anti-apoptotic factor, which mediates tumor cell viability. In addition, MDK blocks anoikis to promote metastasis. There is also evidence that MDK is involved in angiogenesis. It has been shown that the application of anti-MDK approaches might be promising in the treatment of HCC. Besides, due to the elevated expression in HCC, MDK has been proposed as a biomarker in the prognosis and diagnosis of HCC. In this review, we will discuss the role of MDK in HCC. It is hoped that the development of new strategies concerning MDK-based therapies will be promising in HCC management.
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http://dx.doi.org/10.1002/iub.2458DOI Listing
April 2021

Immunomodulatory effects of nanocurcumin on Th17 cell responses in mild and severe COVID-19 patients.

J Cell Physiol 2021 07 28;236(7):5325-5338. Epub 2020 Dec 28.

Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

In novel coronavirus disease 2019 (COVID-19), the increased frequency and overactivation of T helper (Th) 17 cells and subsequent production of large amounts of proinflammatory cytokines result in hyperinflammation and disease progression. The current study aimed to investigate the therapeutic effects of nanocurcumin on the frequency and responses of Th17 cells in mild and severe COVID-19 patients. In this study, 40 severe COVID-19 intensive care unit-admitted patients and 40 patients in mild condition were included. The frequency of Th17 cells, the messenger RNA expression of Th17 cell-related factors (RAR-related orphan receptor γt, interleukin [IL]-17, IL-21, IL-23, and granulocyte-macrophage colony-stimulating factor), and the serum levels of cytokines were measured in both nanocurcumin and placebo-treated groups before and after treatment. A significant decrease in the number of Th17 cells, downregulation of Th17 cell-related factors, and decreased levels of Th17 cell-related cytokines were found in mild and severe COVID-19 patients treated by nanocurcumin compared to the placebo group. Moreover, the abovementioned parameters were significantly decreased in the nanocurcumin-treated group after treatment versus before treatment. Curcumin could reduce the frequency of Th17 cells and their related inflammatory factors in both mild and severe COVID-19 patients. Hence, it could be considered as a potential modulatory compound in improving the patient's inflammatory condition.
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http://dx.doi.org/10.1002/jcp.30233DOI Listing
July 2021

Codelivery of STAT3 and PD-L1 siRNA by hyaluronate-TAT trimethyl/thiolated chitosan nanoparticles suppresses cancer progression in tumor-bearing mice.

Life Sci 2021 Feb 9;266:118847. Epub 2020 Dec 9.

Immunology research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Immunotherapy methods using potential tumor microenvironment modulators have elicited durable therapeutic responses in cancer treatment. Immune checkpoint molecule programmed cell death-ligand 1 (PD-L1) and oncogenic transcription factor STAT3 (signal transducer and activator of transcription-3) assigned as inhibitory targets of our study and particular delivery system designed to deliver small interfering RNAs (siRNAs) to silence the targeted genes. Generated trimethyl chitosan (TMC) and thiolated chitosan (TC) nanoparticles (NPs) conjugated with HIV-1-derived TAT peptide and HA (hyaluronic acid) exhibited eligible physicochemical characteristics, notable siRNA encapsulation, serum stability, non-toxicity, controlled siRNA release, and extensive cellular uptake by cancer cells. Dual inhibition with STAT3/PD-L1 siRNA-loaded HA-TAT-TMC-TC NPs led to promising results, including significant downregulation of PD-L1 and STAT3 genes, striking suppressive effects on proliferation, migration, and angiogenesis of breast and melanoma cancer cell lines, and restrained tumor growth in vivo. These findings infer the capability of HA-TAT-TMC-TC NPs containing STAT3/PD-L1 siRNAs as a novel tumor-suppressive candidate in cancer treatment.
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http://dx.doi.org/10.1016/j.lfs.2020.118847DOI Listing
February 2021

The role of non-coding genome in the behavior of infiltrated myeloid-derived suppressor cells in tumor microenvironment; a perspective and state-of-the-art in cancer targeted therapy.

Prog Biophys Mol Biol 2021 May 28;161:17-26. Epub 2020 Nov 28.

Student Research Committee, Bam University of Medical Sciences, Bam, Iran; Noncommunicable Diseases Research Center, Bam University of Medical Sciences, Bam, Iran. Electronic address:

Cancer is one of the healthcare problems that affect many communities around the world. Many factors contribute to cancer development. Besides, these factors are counted as the main impediment in cancer immunotherapy. Myeloid-derived suppressor cells (MDSCs) are one of these impediments. MDSCs inhibit the immune responses through various mechanisms such as inhibitory cytokine release and nitric oxide metabolite production. Several factors are involved in forming these cells, including tumor secreted cytokine and chemokines, transcription factors, and non-coding RNA. In the meantime, micro-RNAs (miRNAs) and long non-coding RNAs (lncRNAs) are the vital gene regulatory elements that affect gene expression. In this study, we are going to discuss the role of miRNAs and lncRNAs in MDSCs development in a cancer situation. It is hoped that miRNA and lncRNAs targeting may prevent the growth and development of these inhibitory cells in the cancer environment.
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http://dx.doi.org/10.1016/j.pbiomolbio.2020.11.006DOI Listing
May 2021

Nano-curcumin therapy, a promising method in modulating inflammatory cytokines in COVID-19 patients.

Int Immunopharmacol 2020 Dec 20;89(Pt B):107088. Epub 2020 Oct 20.

Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Background: As an ongoing worldwide health issue, Coronavirus disease 2019 (COVID-19) has been causing serious complications, including pneumonia, acute respiratory distress syndrome (ARDS), and multi-organ failure. However, there is no decisive treatment approach available for this disorder, which is primarily attributed to the large amount of inflammatory cytokine production. We aimed to identify the effects of Nano-curcumin on the modulation of inflammatory cytokines in COVID-19 patients.

Method: Forty COVID-19 patients and 40 healthy controls were recruited and evaluated for inflammatory cytokine expression and secretion. Subsequently, COVID-19 patients were divided into two groups: 20 patients receiving Nano-curcumin and 20 patients as the placebo group. The mRNA expression and cytokine secretion levels of IL-1β, IL-6, TNF-α and IL-18 were assessed by Real-time PCR and ELISA, respectively.

Result: Our primary results indicated that the mRNA expression and cytokine secretion of IL-1β, IL-6, TNF-α, and IL-18 were increased significantly in COVID-19 patients compared with healthy control group. After treatment with Nano-curcumin, a significant decrease in IL-6 expression and secretion in serum and in supernatant (P = 0.0003, 0.0038, and 0.0001, respectively) and IL-1β gene expression and secretion level in serum and supernatant (P = 0.0017, 0.0082, and 0.0041, respectively) was observed. However, IL-18 mRNA expression and TNF-α concentration were not influenced by Nano-curcumin.

Conclusion: Nano-curcumin, as an anti-inflammatory herbal based agent, may be able to modulate the increased rate of inflammatory cytokines especially IL-1β and IL-6 mRNA expression and cytokine secretion in COVID-19 patients, which may cause an improvement in clinical manifestation and overall recovery.
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http://dx.doi.org/10.1016/j.intimp.2020.107088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574843PMC
December 2020

Th17 and Treg cells function in SARS-CoV2 patients compared with healthy controls.

J Cell Physiol 2021 04 14;236(4):2829-2839. Epub 2020 Sep 14.

Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

In the course of the coronavirus disease 2019 (COVID-19), raising and reducing the function of Th17 and Treg cells, respectively, elicit hyperinflammation and disease progression. The current study aimed to evaluate the responses of Th17 and Treg cells in COVID-19 patients compared with the control group. Forty COVID-19 intensive care unit (ICU) patients were compared with 40 healthy controls. The frequency of cells, gene expression of related factors, as well as the secretion levels of cytokines, were measured by flow cytometry, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay techniques, respectively. The findings revealed a significant increase in the number of Th17 cells, the expression levels of related factors (RAR-related orphan receptor gamma [RORγt], IL-17, and IL-23), and the secretion levels of IL-17 and IL-23 cytokines in COVID-19 patients compared with controls. In contrast, patients had a remarkable reduction in the frequency of Treg cells, the expression levels of correlated factors (Forkhead box protein P3 [FoxP3], transforming growth factor-β [TGF-β], and IL-10), and cytokine secretion levels (TGF-β and IL-10). The ratio of Th17/Treg cells, RORγt/FoxP3, and IL-17/IL-10 had a considerable enhancement in patients compared with the controls and also in dead patients compared with the improved cases. The findings showed that enhanced responses of Th17 cells and decreased responses of Treg cells in 2019-n-CoV patients compared with controls had a strong relationship with hyperinflammation, lung damage, and disease pathogenesis. Also, the high ratio of Th17/Treg cells and their associated factors in COVID-19-dead patients compared with improved cases indicates the critical role of inflammation in the mortality of patients.
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http://dx.doi.org/10.1002/jcp.30047DOI Listing
April 2021

Synthesis of 2D Germanane (GeH): a New, Fast, and Facile Approach.

Angew Chem Int Ed Engl 2021 Jan 3;60(1):360-365. Epub 2020 Nov 3.

Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 4, 9747, AG, Groningen, The Netherlands.

Germanane (GeH), a germanium analogue of graphane, has recently attracted considerable interest because its remarkable combination of properties makes it an extremely suitable candidate to be used as 2D material for field effect devices, photovoltaics, and photocatalysis. Up to now, the synthesis of GeH has been conducted by substituting Ca by H in a β-CaGe layered Zintl phase through topochemical deintercalation in aqueous HCl. This reaction is generally slow and takes place over 6 to 14 days. The new and facile protocol presented here allows to synthesize GeH at room temperature in a significantly shorter time (a few minutes), which renders this method highly attractive for technological applications. The GeH produced with this method is highly pure and has a band gap (E ) close to 1.4 eV, a lower value than that reported for germanane synthesized using HCl, which is promising for incorporation of GeH in solar cells.
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http://dx.doi.org/10.1002/anie.202010404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821264PMC
January 2021

Changes in Th17 cells frequency and function after ozone therapy used to treat multiple sclerosis patients.

Mult Scler Relat Disord 2020 Nov 24;46:102466. Epub 2020 Aug 24.

Health Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran; Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Background: Multiple sclerosis (MS) is a neurodegenerative autoimmune disease with chronic inflammation. In the course of the disease, the increased levels of Th17 cell, and its relevant inflammatory factors, may cause disease inflammation and progression. Ozone therapy with anti-oxidant and anti-inflammatory functions is known as a beneficial therapeutic approach. The current non-controlled study aimed to evaluate the therapeutic implications of ozone autohemotherapy on Th17 responses in MS patients.

Methods: 20 MS patients as the experimental group received ozone therapy (100 ml of O2/O3 compound (25 ugs/ml concentration) with 100 ml of autologous blood) twice per week for 6 months. The frequency of Th17 cells, gene expression of the relevant factors (RORɣt, IL-17, IL-23, miR-141, miR-155, and miR-200), as well as the secretion levels of IL-17 and IL-23 cytokines, were compared between the patient and control groups, as well as the group of patients before and after ozone therapy using the flow cytometry, Real-time PCR, and ELISA techniques, respectively.

Results: Findings indicated the significant decrease in the frequency of Th17 cells (P = 0.0002), the expression levels of RORɣt and IL-17 (P = 0.0001 and P = 0.0004, respectively), as well as miR-141 and miR-155 (P<0.0001 and P<0.0001, respectively) in post-treatment condition with Ozone compared to pre-treatment condition. Also, the significant reduction in the secretion level of IL-17 (P = 0.043) was detected in treated patients.

Discussion: Since increased levels and responses of Th17 cells may have critical roles in MS pathogenesis and inflammation, our findings revealed that ozone autohemotherapy could lower the Th17 responses in peripheral blood of MS patients and can be a beneficial approach in MS treatment.
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http://dx.doi.org/10.1016/j.msard.2020.102466DOI Listing
November 2020

IL-10-producing B cells play important role in the pathogenesis of recurrent pregnancy loss.

Int Immunopharmacol 2020 Oct 18;87:106806. Epub 2020 Jul 18.

Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Interleukin (IL)-10-producing B cells are recently known for their regulatory function in several disorders. However, the possible role of these cells remains unclear in recurrent pregnancy loss (RPL) pathogenesis. Total B cells from 24 RPL patients with cellular immune abnormalities, as well as that of 25 normal pregnant women were cultured and stimulated by Toll Like Receptor (TLR) agonists (CpG oligodeoxynucleotides (ODN) and imiquimod). Then, the frequency of IL-10 CD19 B cells was found out using flow cytometry. Enzyme-linked immunosorbent assay (ELISA) was used to assess the levels of IL-10 in supernatant medium and serum of stimulated B cells, as well as those of several serum autoantibodies. Real-Time PCR method was carried out for determining the IL-10 expression level and specific genes transcripts. RPL patients indicated a lower proportion of IL-10 CD19 B cells, and reduced levels of IL-10 in both serum and supernatant of the culture medium of the stimulated B cells. According to the results, total IgG levels was greater in serum of RPL patients in comparison with healthy pregnant women. Similarly, the percentage of these cells was negatively correlated with serum total IgG levels and the number of miscarriages. The expression levels of the mRNA of programmed death-ligand 1 (PD-L1) and IL-10 were lower in RPL patients, while those of x binding protein 1 (XBP-1), interferon regulatory factor 4 (IRF4), and B lymphocyte-induced maturation protein 1 (BLIMP1) were significantly increased. These observations indicated that the reduction in the population of peripheral blood IL-10-synthesizing B cells may prompt RPL pathogenesis, suggesting suppressive effects of these cells on autoantibody production and successful pregnancy outcomes.
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http://dx.doi.org/10.1016/j.intimp.2020.106806DOI Listing
October 2020

Dysregulation of microRNAs regulating survivin in CD4+ T cells in multiple sclerosis.

Mult Scler Relat Disord 2020 Sep 20;44:102303. Epub 2020 Jun 20.

Stem Cell Research Center, Tabriz University of Medical Sciences, Daneshghah St., Imam Reza Hospital, Tabriz, Iran; Student's Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Background: Impaired elimination mechanisms of the autoreactive lymphocytes, like T lymphocytes, via apoptosis may be the cause of continues inflammatory state in multiple sclerosis (MS). BIRC5 gene codify for the survivin, which participates in the modulation of apoptosis and cell survival. The objective of this study was investigation of the role of important confirmed miRNAs, including miR-335, miR-485, miR-542, and miR-708, in the regulation of survivin mRNA in the CD4+ T cells of MS cases.

Methods: In this study, 50 RRMS patients as well as 50 healthy matched controls were recruited. The peripheral blood mononuclear cells (PBMCs) were isolated from whole blood samples and CD4+ T cells were prepared. After that, RNA was extracted, cDNA was synthesized, and the expression levels of miR-335, miR-485, miR-542, and miR-708 were measured using Real-time PCR. Moreover, the mRNA expression of survivin was detected. Serum level of survivin was detected using ELISA.

Results: The mRNA of survivin was 2-folds upregulated in the CD4+ T cells from MS patients in comparison to the healthy controls (P = 0.0053). Serum level of survivin was higher in patients than controls. There was statistically significant downregulation of miR-485 (P = 0.001) and miR-708 (P = 0.011) in CD4+ T cells of patients compared with controls. The miR-485 downregulation had statistically significant correlation with the mRNA expression and serum level of survivin.

Conclusion: miRNAs play a role in the regulation of survivin, and therefore apoptosis of CD4+ T cells, and hence are probably participating in a persistent inflammatory condition in MS patients.
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http://dx.doi.org/10.1016/j.msard.2020.102303DOI Listing
September 2020

Epigenetic Modifications and Therapy in Chronic Obstructive Pulmonary Disease (COPD): An Update Review.

COPD 2020 06 19;17(3):333-342. Epub 2020 Jun 19.

Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Chronic obstructive pulmonary disease (COPD) that is one of the most prevalent chronic adult diseases and the third leading cause of fatality until 2020. Elastase/anti-elastase hypothesis, chronic inflammation, apoptosis, oxidant-antioxidant balance and infective repair cause pathogenesis of COPD are among the factors at play. Epigenetic changes are post-translational modifications in histone proteins and DNA such as methylation and acetylation as well as dysregulation of miRNAs expression. In this update review, we have examined recent studies on the upregulation or downregulation of methylation in different genes associated with COPD. Dysregulation of HDAC activity which is caused by some factors and miRNAs plays a key role in the suppression and reduction of COPD development. Also, some therapeutic approaches are proposed against COPD by targeting HDAC2 and miRNAs, which have therapeutic effects.
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http://dx.doi.org/10.1080/15412555.2020.1780576DOI Listing
June 2020
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