Publications by authors named "Maryam Izad"

42 Publications

Increased Level of Caspase-1 in the Serum of Relapsing-remitting Multiple Sclerosis (RRMS) Patients.

Iran J Allergy Asthma Immunol 2020 Oct 18;19(5):534-538. Epub 2020 Oct 18.

Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran AND MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system, in which proinflammatory cytokines play a critical role in the pathogenic formation of lesions. Caspase-1 is a cysteine protease that proteolytically cleaves precursors of interleukin (IL)-18 and IL-1β and turns them into their active forms. These inflammatory cytokines play an important role in the development of MS. The aim of the present study was the investigation of caspase-1 and its downstream products, IL-18 and IL-1β, in relapsing-remitting MS (RRMS) patients. In this study, we used an ELISA assay to measure serum and cellular caspase-1 and serum levels of IL-18 and IL-1β in RRMS patients in the relapse phase (n=23) and healthy age-and gender-matched controls (n=19). We observed that the caspase-1 level was significantly increased in the serum of MS patients compared to the healthy controls (p=0.03). Although caspase-1 concentration in the lysate of peripheral blood mononuclear cells (PBMCs) was higher than serum among patients and controls (p<0.001), no significant difference was found in cellular levels of caspase-1 between the two groups. There was no significant difference in serum levels of IL-18 and IL-1β between patients and controls. In this study, we found an elevation of extracellular caspase-1, as a reflection of its intracellular level, in the serum of RRMS patients during the relapse phase. Therefore, it suggests being a suitable peripheral biomarker of disease activity in multiple sclerosis.
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http://dx.doi.org/10.18502/ijaai.v19i5.4470DOI Listing
October 2020

Redox Imbalance in CD4+ T Cells of Relapsing-Remitting Multiple Sclerosis Patients.

Oxid Med Cell Longev 2020 2;2020:8860813. Epub 2020 Dec 2.

Immunology Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

As a prevalent autoimmune disease of the central nervous system in young adults, multiple sclerosis (MS) is mediated by T cells, particularly CD4+ subsets. Given the evidence that the perturbation in reactive oxygen species (ROS) production has a pivotal role in the onset and progression of MS, its regulation through the antioxidant molecules is too important. Here, we investigated the level of the redox system components in lymphocytes and CD4+ T cells of MS patients. The study was performed on relapsing-remitting MS (RRMS) patients ( = 29) and age- and sex-matched healthy controls ( = 15). Peripheral blood mononuclear cells (PBMCs) were cultured and stimulated by anti-CD3/CD28. The level of ROS, anion superoxide (O), and L-𝛾-glutamyl-Lcysteinylglycine (GSH) was measured by flow cytometry in lymphocytes/CD4+ T cells. The gene expression level of gp91phox, catalase, superoxide dismutase 1/2 (SOD), and nuclear factor-E2-related factor (Nrf2) was also measured by real-time PCR. We found that lymphocytes/CD4+ T cells of RRMS patients at the relapse phase significantly produced higher levels of ROS and O compared to patients at the remission phase ( value < 0.001) and healthy controls ( value < 0.001 and value < 0.05, respectively). Interestingly, the gene expression level of gp91phox, known as the catalytic subunit of the NADPH oxidase, significantly increased in MS patients at the relapse phase ( value < 0.05). Furthermore, the catalase expression augmented in patients at the acute phase ( value < 0.05), while an increased expression of SOD1 and Nrf2 was found in RRMS patients at relapse and remission phases ( value < 0.05). The increased production of ROS in CD4+ T cells of RRMS patients highlights the importance of amplifying antioxidant components as an efficient approach to ameliorate disease activity in MS patients.
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http://dx.doi.org/10.1155/2020/8860813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735833PMC
December 2020

The inhibitory effect of melatonin on the proliferation of irradiated A549 cell line.

J Cancer Res Ther 2020 Oct-Dec;16(6):1500-1505

Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Background: Lung cancer is the leading cause of cancer-related deaths worldwide. The high resistance of this type of cancer to radiotherapy and chemotherapy is the greatest challenge for the complete eradication of cancer cells. Although the combination of chemotherapeutic agents has some promising results, severe side effects may limit the received tumor dose. The current study aimed at evaluating the possible synergic effect of melatonin on radiation-induced apoptosis and cell proliferation inhibition.

Materials And Methods: A549 cells were incubated with melatonin or vehicle and then irradiated with a single dose of 0, 0.5, 2, or 8 Gy X-rays. The cells were incubated with 1 nM of melatonin or vehicle for 1 week and then treated with 1 mM of melatonin or vehicle 1 h before irradiation. Cell proliferation was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and apoptosis was assessed using flowcytometry detection of annexin V.

Results: Irradiation of the cells with different X-ray doses had no significant impact on MTT results. However, the administration of 1 mM of melatonin 1 h before irradiation significantly reduced the cell proliferation. Nonetheless, there was no significant difference between this treatment group and 1 mM melatonin group. Moreover, the administration of melatonin in combination with irradiation did not show any significant effects on radiation-induced apoptosis.

Conclusion: The current study results indicated that the treatment of A549 cells with melatonin could suppress cell proliferation, whereas it did not mediate the induction of apoptosis.
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http://dx.doi.org/10.4103/jcrt.JCRT_682_19DOI Listing
December 2020

Umbilical cord mesenchymal stem cells as well as their released exosomes suppress proliferation of activated PBMCs in multiple sclerosis.

Scand J Immunol 2020 Dec 18:e13013. Epub 2020 Dec 18.

Department of Immunology, School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran.

Multiple sclerosis (MS) is a central nervous system (CNS) degenerative disorder which is caused by a targeted autoimmune-mediated attack on myelin proteins. Previously, mesenchymal stem cells were considered as a novel and successful treatment of MS. One of the underlying mechanisms behind their immunomodulatory function is the release of extracellular vesicles, particularly exosomes. In this study, we aimed to evaluate the suppressive efficacy of MSCs and their exosomes on the proliferation of peripheral mononuclear blood cells (PBMC) in relapsing-remitting MS (RRMS) patients and healthy subjects. To do, mesenchymal stem cells were derived from human umbilical cord tissues and used for exosome isolation through ultracentrifugation. Suppressive function of MSCs and MSC-derived exosomes was examined in a coculture with CFSE-labelled PBMCs in vitro. PBMC proliferation of the patients and healthy individuals was measured using flow cytometry. We first demonstrated that proliferation of PBMCs decreased in the presence of MSCs and suppression was more efficient by MSC-derived exosomes, with a minimum alloreaction rate. However, suppression capacity of MSCs and their exosomes significantly decreased during extensive sub-culturing. The present study showed that MSC-derived exosomes as an effective cell-free therapy could prevent proliferation of PBMCs. However, further evaluations are need to move towards a functional approach that can be translated to the clinic.
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http://dx.doi.org/10.1111/sji.13013DOI Listing
December 2020

Exogenous Ghrelin Could Not Ameliorate 3,4-methylenedioxymethamphetamine-induced Acute Liver Injury in The Rat: Involved Mechanisms.

Iran J Pharm Res 2020 ;19(1):343-354

Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

MDMA (3,4-methylenedioxymethamphetamine, ecstasy) is often abused by youth as a recreational drug. MDMA abuse is a growing problem in different parts of the world. An important adverse consequence of the drug consumption is hepatotoxicity of different intensities. However, the underlying mechanism of this toxicity has not been completely understood. Ghrelin is a gut hormone with growth hormone stimulatory effect. It expresses in liver, albeit at a much lower level than in stomach, and exerts a hepatoprotective effect. In this study, we investigated hepatotoxicity effect of MDMA alone and its combination with ghrelin as a hepatoprotective agent. MDMA and MDMA+ ghrelin could transiently increase serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) followed by tissue necrosis. However, they could significantly decrease liver tumor necrosis factor-a (TNF-±) in both treatment groups. Unexpectedly, in MDMA treated rats, Bax, Bcl-xl, Bcl-2, Fas, Fas ligand (Fas-L), caspase 8, cytochrome c, caspase 3 gene expression, and DNA fragmentation were nearly unchanged. In addition, apoptosis in MDMA+ ghrelin group was significantly reduced when compared with MDMA treated animals. In all, MDMA could transiently increase serum transaminases and induce tissue necrosis and liver toxicity. Ghrelin, however, could not stop liver enzyme rise and MDMA hepatotoxicity. MDMA hepatotoxicity seems to be mediated via tissue necrosis than apoptotic and inflammatory pathways. Conceivably, ghrelin as an anti-inflammatory and anti-apoptotic agent may not protect hepatocytes against MDMA liver toxicity.
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http://dx.doi.org/10.22037/ijpr.2020.1100940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462488PMC
January 2020

The Influence of Reactive Oxygen Species in the Immune System and Pathogenesis of Multiple Sclerosis.

Autoimmune Dis 2020 25;2020:5793817. Epub 2020 Jun 25.

Immunology Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Multiple roles have been indicated for reactive oxygen species (ROS) in the immune system in recent years. ROS have been extensively studied due to their ability to damage DNA and other subcellular structures. Noticeably, they have been identified as a pivotal second messenger for T-cell receptor signaling and T-cell activation and participate in antigen cross-presentation and chemotaxis. As an agent with direct toxic effects on cells, ROS lead to the initiation of the autoimmune response. Moreover, ROS levels are regulated by antioxidant systems, which include enzymatic and nonenzymatic antioxidants. Enzymatic antioxidants include superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. Nonenzymatic antioxidants contain vitamins C, A, and E, glutathione, and thioredoxin. Particularly, cellular antioxidant systems have important functions in maintaining the redox system homeostasis. This review will discuss the significant roles of ROS generation and antioxidant systems under normal conditions, in the immune system, and pathogenesis of multiple sclerosis.
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http://dx.doi.org/10.1155/2020/5793817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334772PMC
June 2020

Decreased serum levels of interleukin-17, interleukin-23, TGF-β in pemphigus vulgaris patients, and their association with disease phase.

Dermatol Ther 2020 11 6;33(6):e14071. Epub 2020 Sep 6.

Autoimmune Bullous Disease Research Center, Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran.

The exact pathogenesis of Pemphigus Vulgaris (PV) has remained unclear, but it seems that cytokines play critical roles in this disease. This study aims to assess the serum levels of interleukin (IL)-6, IL-17, IL-23, and TGF-β in PV patients and compare the results to the healthy controls. Serum levels of IL6, IL-17, IL-23, and TGF-β were successfully determined by enzyme-linked immunosorbent assay (ELISA) in 27 newly diagnosed PV, 32 patients in remission, and 29 healthy controls. It was shown that the mean serum levels of IL-17, IL-23, and TGF-β serum are significantly different among the PV patients and healthy controls (P values: <.001, .001, and .003, respectively). It was found that new PV patients have lower serum levels of IL-17, IL-23, and TGF-β as compared to healthy controls (P values: <.001, <.001, and .003, respectively). Regarding IL-6, no significant difference was observed between the healthy controls and the other two groups of patients. IL-17, IL-23, and TGF-β are involved in the pathogenesis of PV. However, more studies are required to clarify their exact roles in the immunopathogenesis of PV.
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http://dx.doi.org/10.1111/dth.14071DOI Listing
November 2020

Adipose-Derived Mesenchymal Stem Cells and Conditioned Medium Attenuate the Memory Retrieval Impairment During Sepsis in Rats.

Mol Neurobiol 2020 Sep 19;57(9):3633-3645. Epub 2020 Jun 19.

Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, 1417613151, Iran.

In this study, we hypothesized that sepsis induction impairs memory retrieval in rats while transplanted mesenchymal stem cells (MSCs) and MSC-conditioned medium (MSC-CM) application are capable of attenuating those complications. MSCs were obtained from adipose tissue of rats and at the second culture passage; MSCs and MSC-CM were collected. Rats were randomly divided into four experimental groups: sham, CLP, MSC, and MSC-CM. Sepsis was induced by cecal ligation and puncture (CLP) model in the CLP, MSC, and MSC-CM groups. The MSC group received 1 × 10 MSCs/rat (i.p., 2 h after CLP surgery); the MSC-CM rats received the conditioned medium (CM) from 1 × 10 MSCs intraperitoneally 2 h after sepsis induction. Novel object recognition test, sepsis score, and blood pressure measurement were performed 24 h after the treatments. The right hippocampus was taken for western blot analysis. CLP rats showed a significantly higher sepsis score and systolic blood pressure. They also had a significant increase in the phosphorylated form of CAMKII-α, cleaved caspase 3 and Bax/Bcl2 ratio, and a reduction in c-fos protein in the hippocampus tissue samples compared with the sham group. MSC transplantation and MSC-CM administration significantly decreased the mean sepsis score and prevented sepsis-induced attenuation of blood pressure compared with the CLP rats. Animals in the MSC and MSC-CM groups showed a better memory retrieval, attenuation in phosphorylated form of CAMKII-α, cleaved caspase 3 and Bax/Bcl ratio, and an increase in c-fos protein expression compared with the CLP group. It seems that CAMKII and c-fos are inversely involved in regulating memory processes in hippocampus. Phosphorylated form of CaMKII-α overexpression may impair the ability of object recognition. Our findings confirmed that MSC-CM application has more advantages compared with transplanted MSCs and may be offered as a promising therapy for inflammatory diseases such as severe sepsis.
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http://dx.doi.org/10.1007/s12035-020-01991-6DOI Listing
September 2020

Mesenchymal Stem Cell-Derived Exosomes: A Promising Therapeutic Ace Card to Address Autoimmune Diseases.

Int J Stem Cells 2020 Mar;13(1):13-23

Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

With the development of novel treatments for autoimmune disorders, it has become a popular research focus which mesenchymal stem cells (MSCs) have the capacity to counteract with autoimmune diseases progression. One of the underlying mechanisms behind their activities is the release of extracellular vesicles especially exosomes. MSC-derived exosomes are hypoimmunogenic nanocarriers which contain numerous immunoregulatory factors and similar to other exosomes, are able to pass through boundaries like the blood-brain barrier (BBB). Accumulating evidence provided by animal studies has demonstrated that MSC-derived exosomes, as a novel therapy, can re-induce self-tolerance, without subsequent complications reported for other treatments. Therefore, therapeutic applications of MSC-derived exosomes are contributing to core advances in the field of autoimmune diseases. Here, we briefly describe the biological characteristics of MSC-derived exosomes and review the experimentally verified outcomes for autoimmune disease therapy purposes.
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http://dx.doi.org/10.15283/ijsc19108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7119210PMC
March 2020

Circulating mesenchymal stem cells, stromal derived factor (SDF)-1 and IP-10 levels increased in clinically active multiple sclerosis patients but not in clinically stable patients treated with beta interferon.

Mult Scler Relat Disord 2019 Oct 12;35:233-238. Epub 2019 Aug 12.

MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Background: Mesenchymal stem cells (MSCs) have the capacity to migrate into the inflammatory regions in response to chemokines such as, IP-10 and SDF-1α and function as anti-inflammatory and immunomodulatory cells.

Methods: In this study we investigated the MSCs frequency in peripheral blood of Relapsing-Remitting Multiple Sclerosis (RRMS) patients in clinically active and not on disease-modifying therapy (DMT) (n = 22) and clinically stable on DMT (Interferon-β (IFN-β) therapy) for at least 6 months (n = 22) in comparison to sex and age-matched healthy controls (n = 25) using flow cytometry. The serum and gene expression levels of IP-10 and SDF-1a were also measured in studied groups by ELISA and Real time- PCR.

Results: We obtained significant high levels of circulating CD45CD34 CD90 and CD45CD34 CD105 cells in clinically active patients, not on DMT and patients under IFNβ therapy compared with control group. Furthermore, a significant increase in the percentage of circulating CD45CD34 CD105 CD90 cells was found in clinically active patients and not on DMT compared with control group. Serum analysis of IP-10 and SDF-1α showed a significant increase in IP10 concentration in both clinically active not on DMT (P = 0.02) and on DMT (P = 0.005) RRMS patients in comparison with controls. The expression level of SDF-1α mRNA significantly increased in clinically active not on DMT (P = 0.03), while decreased in patients under IFNβ therapy (P = 0.04). The mRNA expression of IP-10 only increased in patients on DMT compared with controls (P = 0.05).

Conclusion: Circulating MSCs, IP-10 and SDF-1α levels, increased in RRMS patients with clinically active not on DMT and IFN-β therapy reduced circulating MSCs and SDF-1α levels.
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http://dx.doi.org/10.1016/j.msard.2019.08.013DOI Listing
October 2019

The Effects of Synbiotic Supplementation on Antioxidant Capacity and Arm Volumes in Survivors of Breast Cancer-Related Lymphedema.

Nutr Cancer 2020 28;72(1):62-73. Epub 2019 May 28.

Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran Iran.

Synbiotics found to be beneficial in breast cancer survivors (BCSs) through its antioxidant properties. The aim of this study was to assess the effects of synbiotic supplementation on edema volume and some oxidative markers among obese and overweight patients with BCRL. This randomized double-blind, placebo-controlled trial was conducted on 88 overweight and obese BCSs aged 18-65 years. All the subjects were given a specified low-calorie diet (LCD) and were randomly assigned into two groups to intake 10 CFU/day synbiotic supplement ( = 44) or placebo ( = 44) for 10 wk. Edema volume and serum total antioxidant capacity (TAC), malondialdehyde (MDA), glutathione peroxidase (GPx), and superoxide dismutase (SOD) concentration were measured at baseline and after the 10-wk intervention. Ten-wk supplementation with synbiotics leads to a significant reduction in serum MDA levels ( = 0.001) and an increase in serum SOD concentration ( = 0.007) compared to placebo. No significant changes were observed in serum GPx, TAC, and edema volume between groups. Our findings reveal that 10-wk synbiotic supplementation along with a LCD program-reduced serum MDA levels and elevate the activity of SOD in overweight and obese patients with BCRL. However, its effect on serum GPx, TAC, and edema volume was not significant.
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http://dx.doi.org/10.1080/01635581.2019.1616781DOI Listing
September 2020

Altered Expression of miR-326 in T Cell-derived Exosomes of Patients with Relapsing-remitting Multiple Sclerosis.

Iran J Allergy Asthma Immunol 2019 Feb;18(1):108-113

Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran AND Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.

 Invasion of auto-reactive CD4+ T cells especially Th17 into central nervous system (CNS) is an underlying pathogenic mechanism in multiple sclerosis (MS). CD4+ T cells release exosomes which are enriched in microRNAs, reflective of cell's physiological or pathological condition. Thus exosomes could be potent agents to provide quantitative and qualitative information about involved cells in MS. We investigated the expression of pathogenic microRNAs in T cells-derived exosomes of MS patients or healthy controls. Conventional T cells (Tconv) derived from relapsing-remitting (RR) MS patients (n=10) and healthy controls (n=10) were purified and cultured for 3 days by soluble anti-CD3/CD28. Exosomes were purified from cultured-T cells supernatants. The expression levels of exosomal miR-146a, miR-29a, miR-155, and miR-326 were quantified by real-time PCR. A statistically significant increased expression of miR-326 in Tconv-derived exosomes was observed in RRMS patients as compared with controls (7.5±1.88vs 2.51±0.9 p=0.03), On the contrary, no differences were found in the expression levels of miR-155, miR-146a, and miR-29a, in Tconv-derived exosomes of  patients as compared with controls (p>0.05). Our results point to altered expression in exosome-derived microRNAs. MiR-326 was previously shown to play a role in the immunopathogenesis of MS by inducing TH17 differentiation and maturation. Therefore, miR-326 containing exosomes might also be a potential clinical target in course of MS. Moreover, the deregulation of this miRNA in exosomes may serve as a diagnostic and prognostic biomarker.
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February 2019

Effects of vitamin D supplements on frequency of CD4 T-cell subsets in women with Hashimoto's thyroiditis: a double-blind placebo-controlled study.

Eur J Clin Nutr 2019 09 29;73(9):1236-1243. Epub 2019 Jan 29.

Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.

Background: Vitamin D is a modulator of immune functions. Investigations on the mechanisms of vitamin D action and pathogenesis of Hashimoto's thyroiditis (HT) have revealed that vitamin D can reduce damages to thyroid cells caused by autoreactive immune cells.

Methods: Totally, 48 female patients with HT disease were introduced to the study by endocrinologists. Patients were divided into two major groups of 24 individuals and treated weekly with 50,000 IU of cholecalciferol (vitamin D group) or placebo (placebo group) using oral administration for 3 months. Eventually, 17 of the 24 patients in each group finished the study. Before and after supplementation, frequencies of Th1, Th17, Th2 and Tr1 cells and mean fluorescent intensity (MFI) of the associated cytokines, including IFN-γ, IL-17, IL-4 and IL-10, were assessed using flow cytometry. Furthermore, gene expression of IL-10 was assessed using real-time PCR.

Results: Results of this study showed that cholecalciferol supplementation caused a significant decrease in Th17/Tr1 ratio. The proportion and MFI of Th1, Th2, Tr1 and Th17 cells included no significant changes in vitamin D group, compared to those in placebo group. Expression rate and MFI of IL-10 increased in both groups. This increase was higher in vitamin D group than placebo group with no significance.

Conclusions: In this novel preliminary clinical trial study, supplementation with cholecalciferol in HT patients for 3 months changed the balance of CD4 T-cell subsets to improve the disease control. However, further studies are necessary to investigate effects of vitamin D on immune functions in HT patients.
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http://dx.doi.org/10.1038/s41430-019-0395-zDOI Listing
September 2019

Post-infarct morphine treatment mitigates left ventricular remodeling and dysfunction in a rat model of ischemia-reperfusion.

Eur J Pharmacol 2019 Mar 23;847:61-71. Epub 2019 Jan 23.

Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Following myocardial infarction, the heart undergoes a series of dramatic compensations which may later form a maladaptive picture characterized by ventricular dilation and pump failure. Among several opioid agents, morphine has been shown to confer protection against reperfusion injury and infarct size. Here, we sought to study the cardioprotective effect of post-infarct morphine treatment against left ventricular adverse remodeling. We induced myocardial infarction in male Sprague - Dawley rats by ligating left anterior descending artery and then, treated these animals with three different doses of morphine -0.3, 3 and 10 mg/kg (i.p.). The echocardiographic evaluation depicted improved cardiac performance and lesser chamber dilation in the animals that had received 3 mg/kg of morphine. Next, we studied the effect of 3 mg/kg morphine administration on left ventricular hemodynamics, infarct size, tissue architecture, changes in lung and heart weight, circulating TNF-α level and post-MI mRNA expression of collagen-1, collagen-3, TGF-β, TNF-α, MMP-2 and MMP-9. Five-day morphine administration markedly improved LV function, and also reduced infarct size, myocyte hypertrophy, fibrosis, index of infarct expansion, heart weight and serum TNF-α level. Moreover, morphine alleviated MI-induced increase in wet and dry lung weight. Morphine also altered the mRNA expression of fibrosis-related genes, TNF-α, MMP-2 and MMP-9. In conclusion, post-infarct morphine treatment can mitigate adverse remodeling and cardiac dysfunction after MI. Beside analgesic effect, we may be able to harvest benefits from the antifibrotic and anti-remodeling action of morphine in patients with the acute coronary syndrome.
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http://dx.doi.org/10.1016/j.ejphar.2019.01.023DOI Listing
March 2019

Increased Circulating T Follicular Helper Cells in Iranian Children with Type I Diabetes.

Iran J Allergy Asthma Immunol 2018 Dec 3;17(6):557-563. Epub 2018 Dec 3.

Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

 Type 1 diabetes (T1D) is an autoimmune disease resulting from the damage of pancreatic B-cells mediated by autoreactive CD4+ and CD8+ T cells. In recent years, follicular T helper (Tfh) cells have been recognized as a subpopulation of CD4+ T cells providing help for B cells differentiation and antibody production. In this study, we examined the frequency of circulating CD4+CXCR5+ and CD4+CXCR5+ICOS+ (representing Tfh) cells as well as serum levels of anti-glutamic acid decarboxylase 65 (GAD65) and islet cell autoantibodies (ICA) in children with type I diabetes. We analyzed the percentage of Tfh cells within peripheral blood mononuclear cells in 20 children with T1D (≤300 days from disease onset; Mean age 6.8±4.6 years) and 18 healthy individuals (Mean age 8.8±2.2 years) using flow cytometry. Anti-glutamic acid decarboxylase (GAD) and islet-cell cytoplasmic autoantibodies (ICA) levels were determined by ELISA and indirect immunofluorescence respectively. We found that the frequency of CD4+CXCR5+ and CD4+CXCR5+ICOS+ (Tfh) cells were significantly increased in the peripheral blood of patients compared with healthy controls (p<0.001). Furthermore, elevated levels of anti-GAD and ICA antibodies were detected in children with T1D (p=0.001 and p=0.02 respectively). There was no correlation between Tfh cells frequency and the autoantibody levels. The results of our study indicate an increased frequency of Tfh cells in children With T1D that could suggest a possible role of these cells in the disease pathogenesis.
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December 2018

Thymol as a reciprocal regulator of T cell differentiation: Promotion of regulatory T cells and suppression of Th1/Th17 cells.

Int Immunopharmacol 2019 Feb 31;67:417-426. Epub 2018 Dec 31.

Department of Immunology, Medical School, Shiraz University of Medical Sciences, Shiraz, Iran; Autoimmune Diseases Research Center, Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address:

Regulatory T cells (Tregs) are critical for maintaining immune response and enhancing their differentiation has therapeutic implications for autoimmune diseases. In this study, we investigated the effects of thymol a well-known monoterpene from Thyme on differentiation and function of Tregs. In vitro generation of Tregs from purified naïve CD4CD25 T cells in the presence of thymol was carried out. Suppressor activity of generated Tregs was examined by changes in the proliferation of CFSE-labeled conventional T cells. Thymol promotes differentiation of naïve CD4CD25 T cells to CD4CD25Foxp3 Tregs [66.9-71.8% vs. control (47%)] and increased intensity of Foxp3 expression on Tregs (p < 0.01). In functional assay, an increased immune suppression by thymol-induced Tregs (≈2.5 times of untreated Tregs) was detected. For in vivo study, thymol was intraperitoneally administered to ovalbumin (Ova)-immunized mice. Flow cytometry assessment of spleens from thymol-treated Ova-immunized mice showed increased number of CD4 Foxp3 Tregs (>8%, p < 0.01(and decreased levels of CD4T-bet Th1 and CD4RORγt Th17 cells resulted in significant decreased Th1/Treg and Th17/Treg ratios. In ex vivo Ova challenge of splenocytes from thymol-treated Ova-immunized mice, similarly higher levels of CD4 Foxp3 Tregs, and also elevated TGF-β expression in CD4Foxp3 population (48.1% vs. 18.9% in untreated Ova-immunized group) and reduced IFN-γ-producing CD4T-bet T cells and IL-17-producing CD4RORγt T cells were detected. This led to marked decreased ratios of IFNγ/TGF-β and IL-17/TGF-β expressions. In conclusion, this study revealed thymol as a compound with enhancing effects on Treg differentiation and function, which may have potential benefits in treatment of immune-mediated diseases with Th1/Th17 over-activation.
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http://dx.doi.org/10.1016/j.intimp.2018.12.021DOI Listing
February 2019

Characterization of CD4+ and CD8+ T Cell Subsets and Interferon Regulatory Factor 4 (IRF4) in MS Patients Treated with Fingolimod (FTY-720): A Follow-up Study.

Iran J Allergy Asthma Immunol 2018 Aug 12;17(4):346-360. Epub 2018 Aug 12.

Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran AND MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.

Fingolimod is a novel immunomodulatory drug used in patients with relapsing multiple sclerosis (MS) which reversibly inhibits egress of lymphocytes from lymph nodes. In this longitudinal study, the frequency of Interferon- gamma (IFN-γ)+, IL4+, IL17+ and IL10+ CD4+ and CD8+ T cell subsets were measured in Fingolimod treated patients before and after 12 months'(12M) therapy using flow cytometry and compared to those of naive, Betaferon treated MS patients and healthy individuals. Additionally, the level of transcription factor IRF4 and IL-6, IL-23, TGF-β1 cytokines, required for differentiation of IL-17+ T cells, were assessed by RT-PCR and ELISA, respectively. In Fingolimod treated MS patients, we observed a significant decrease in the percentage of IFN-γ+/IL17+ CD4+ and CD8+ T cell subsets. In contrast, Fingolimod increased IL10+ CD4+ T cells. We also showed that IFN-γ+IL17+ co-producing CD8+ T cells were reduced in patients under fingolimod therapy. furthermore, Fingolimod could reduce the expression level of IRF4 in patients while IL6 was increased in the supernatant of cultured peripheral blood mononuclear cells. Our data showed that Fingolimod treatment alters CD4+ and CD8+ T cell subsets and reduces expression of IRF-4, which affects the proportion of pathogenic memory T cells in peripheral blood.
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http://dx.doi.org/10.18502/ijaai.v17i4.94DOI Listing
August 2018

Evaluation of IL-17 Producing Memory Regulatory and Effector T Cells Expressing CD26 Molecule in Patients with Psoriasis.

Iran J Allergy Asthma Immunol 2018 Oct 14;17(5):453-463. Epub 2018 Oct 14.

Immunology Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran AND Immunology, Asthma and Allergy Research Institute (IAARI), Tehran University of Medical Sciences, Tehran, Iran.

Memory regulatory T cells (Tregs) has been demonstrated to produce IL-17 in Psoriasis. Forkhead box P3 (Foxp3) has been demonstrated not to be reliable marker to evaluate Treg cells. Effector CD4+T cells also express Foxp3 after activation. Human T helper-17 cells (Th-17) express high level of surface CD26, while regulatory T cells are CD26 negative or low and this phenotype is stable even after activation of Treg cells. In this study, we aimed to analyze IL-17 producing Treg cells using CD26. Memory T cells were isolated from 10 patients with psoriasis and 10 controls. Ex vivo stimulated IL-17 producing regulatory (Forkhead Box P3 (Foxp3)+CD25+CD26-/low) and effector (Foxp3+CD25+CD26hi) memory T cells were analyzed by flow cytometry. IL-23, IL-6, TNFα, TGFβ and IL-17 cytokine levels were also evaluated. No significant difference in IL-17+memory regulatory T cells was seen between patients and controls (p=0.19). A significant decrease in the percentage of IL-17 producing CD26hi effector memory T cells was observed in patients (p=0.04). However, the percentage of these cells was not different between patients with mild or severe form of psoriasis compared to controls (p=0.13). We could not find any significant difference regarding IL-23, IL-6, TNFα, TGFβ and IL-17 cytokine levels in plasma and cell culture supernatant samples between patients and controls. Taken together, our results showed a reduced IL-17 producing effector memory CD26hi T cells in patients with psoriasis compared to controls. However, IL-17 producing memory regulatory CD4+T cells of patients showed no significant difference from that of controls.
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October 2018

Differential regulation of CD4 T cell subsets by Silymarin in vitro and in ovalbumin immunized mice.

Daru 2018 Dec 26;26(2):215-227. Epub 2018 Nov 26.

Department of Immunology, Medical School, Shiraz University of Medical Sciences, Shiraz, 71348-45794, Iran.

CD4 T cell subsets including regulatory T cells (Tregs), Th1 and Th17 are critical for control and development of inflammation and autoimmunity. We investigated the in vitro and in vivo effects of silymarin, a well-known herbal medicine on differentiation and function of Tregs and Th1 and Th17 responses. For in vitro study, mice splenocytes treated with 20-30 μg/ml silymarin were evaluated for gene expressions of specific transcription factors and cytokines of CD4 T cell subsets using real-time PCR. Induction of Treg cell development in the presence of silymarin was performed on isolated naïve CD4 T cells. Effect of silymarin-induced Tregs on T cell suppression was determined by CFSE labeling method. Results of this part showed that silymarin significantly decreased IFNγ, RORγt and IL-17 gene expressions and upregulated Foxp3, TGF-β and IL-10 mRNA. More silymarin-enhanced naïve CD4 T cells differentiated to Tregs (67%) than the control (47%). Silymarin-induced Tregs reduced proliferation of naïve activated T cells (<50%). For in vivo study, mice were immunized with ovalbumin (Ova) on days 1 and 14. Silymarin (100 mg/Kg) was intraperitoneally administered two days before the first Ova challenge followed by on every day for two weeks. Splenocytes were then isolated for assessment of CD4 T cell subsets and ex vivo analysis using flow cytometry. Treatment of Ova-immunized mice with silymarin increased Tregs (11.24 ± 1.2%, p < 0.01(but decreased Th1 (1.72 ± 0.4%, p < 0.001) and Th17 (1.07 ± 0.04%, p < 0.001) cells. Ex vivo Ova challenge of splenocytes from Ova-immunized mice treated with silymarin decreased proliferation of splenocytes, IFNγ (2.76% of control) and IL-17 (<8%) along with increased TGF-β (59.7%) expressions in CD4T-bet, CD4RORγt and CD4Foxp3 T cells, respectively. In conclusion, silymarin promoted Treg differentiation and function and decreased Th1 and Th17 cells. Silymarin may differentially regulate CD4 T cell responses which can provide potential benefits for its use as treatment of immune-related diseases. Graphical abstract ᅟ.
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http://dx.doi.org/10.1007/s40199-018-0229-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279658PMC
December 2018

Redox imbalance and IL-17 responses in memory CD4 T cells from patients with psoriasis.

Scand J Immunol 2019 Jan 19;89(1):e12730. Epub 2018 Dec 19.

Immunology Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

All stages of the inflammatory process involved in T cell-mediated chronic skin disorders like psoriasis are affected by redox imbalance. On the other hand, Th17 cells have a critical role in the pathogenesis of psoriasis. In this study, we evaluated redox status in memory CD4 + T cells and plasma of patients with psoriasis and its correlation with IL-17 response. To this end, memory T cells were isolated from 10 patients with psoriasis and 10 controls. Intracellular Glutathione (GSH), reactive oxygen species (ROS) and superoxide as well as IL-17 were measured using flow cytometry. Plasma total anti-oxidant capacity (TAC) was quantified by ferric reducing ability of plasma (FRAP) assay. The expression of catalase (CAT), superoxide dismutase 1(SOD1), superoxide dismutase 2 (SOD2), nuclear factor, erythroid 2 like 2 (NFE2L2) and cytochrome b-245 beta chain (CYBB) genes were analysed using real-time PCR. Our results showed an increased intracellular ROS production in memory CD4 + T cells of patients compared to controls, (P = 0.04). Furthermore, a significant decrease in expression of catalase gene was found in patients, (P = 0.02). However, no significant differences were observed for intracellular GSH, IL-17 and TAC levels between patients and controls. Also, no correlation was seen between the intracellular IL-17 level and intracellular ROS, GSH and catalase gene expression levels. Collectively, we found an increased ROS production in stimulated memory T cells of patients that could be due to reduced expression of catalase gene. However, it seems that these redox abnormalities have no relationship with IL-17 response in memory T cells.
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http://dx.doi.org/10.1111/sji.12730DOI Listing
January 2019

Association of nod-like receptor protein-3 single nucleotide gene polymorphisms and expression with the susceptibility to relapsing-remitting multiple sclerosis.

Int J Immunogenet 2018 Dec 28;45(6):329-336. Epub 2018 Sep 28.

Immunology Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Nod-like receptor protein 3 (NLRP3) inflammasome is a multi-protein complex that controls the production of pro-inflammatory cytokines, IL-18 and IL-1β, through caspase-1 activation. These inflammatory cytokines play an important role in the development of multiple sclerosis (MS). The inflammasome NLRP3 gene variations and expression level have been suggested to affect the immune system activity. This case-control study was performed to determine the association of NLRP3 genetic variants and differential expression with MS. We analysed four common single nucleotide polymorphisms (SNPs) of NLRP3 (rs-10754558, rs-35829419, rs-3806265, rs-4612666) in a group of 150 Iranian patients with relapsing-remitting MS (RRMS) in comparison with 100 healthy controls. The genotyping was performed using the TaqMan method. For the analysis of NLRP3 gene expression level, we studied a group of 37 RRMS patients (18 patients at relapse phase and 19 at remission phase, treated with IFN-β) in comparison with 22 healthy controls using real-time PCR. In this study, we found that NLRP3 rs3806265 C allele and CC genotype were significantly more frequent in the RRMS patients (p value = 0.03 OR = 1.66, 95% CI = 1.14-2.43) and p value = 0.04, OR = 3.26, 95% CI = 1.19-8.93, respectively), while the frequency of T allele significantly decreased in controls (p value = 0.03, OR = 0.6, 95% CI = 0.41-0.87). The frequency of CG genotype at position rs10754558 was also significantly higher in the controls compared with patients (p value = 0.03, OR = 0.5, 95% CI = 0.30-0.80). Moreover, expression level of the NLRP3 in patients at remission phase was significantly reduced in comparison with patients at relapse phase and also healthy controls (p = 0.01 and p = 0.04, respectively). The association of NLRP3 polymorphisms with the susceptibility of MS and its reduced expression after IFN-β therapy, support the idea that NLRP3 inflammasome could have a critical role in inflammatory responses in MS.
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http://dx.doi.org/10.1111/iji.12401DOI Listing
December 2018

Immunomodulatory function of Treg-derived exosomes is impaired in patients with relapsing-remitting multiple sclerosis.

Immunol Res 2018 08;66(4):513-520

Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Poorsina St., 16 Azar St., Enghelab Ave., Tehran, Iran.

Multiple sclerosis (MS) is an autoimmune disease which is characterized by neuroaxonal degeneration in the central nervous system. Impaired function of regulatory T cells (Tregs) is believed to be an underlying pathogenic mechanism in MS. Tregs is able to release exosomes, which contain a considerable amount of protein and RNA. Exosomes are capable of transporting their content to other cells where the released content exerts biological functions. Here, we investigated whether Tregs exosomes of RRMS patients or healthy controls might regulate the proliferation or survival of T lymphocytes. Regulatory T cells derived from MS patients or healthy controls were cultured for 3 days and exosomes were purified from supernatants. Treg-derived exosomes were co-cultured with conventional T cells (Tconv). The percentages of Tconv proliferation and apoptosis were measured. Our findings showed that the percentage of proliferation suppression induced by exosomes in patients compared to healthy controls was 8.04 ± 1.17 and 12.5 ± 1.22, respectively, p value = 0.035. Moreover, the rate of Tconv apoptosis induced by exosome of MS patient was less than healthy controls (0.68 ± 0.12 vs. 1.29 ± 0.13; p value = 0.015). Overall, Treg-derived exosomes from MS patients and healthy controls suppressed the proliferation and induced apoptosis in Tconv. However, the effect of MS-derived exosomes was significantly less than healthy controls. Our results point to an alternative Treg inhibitory mechanism which might be important in immunopathogenesis of MS. Although, the cause of the exosomal defect in MS patients is unclear, manipulation of patients' Treg-derived exosomes to restore their suppressive activity might be considered as a potential therapeutic approach. Graphical abstract ᅟ.
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http://dx.doi.org/10.1007/s12026-018-9008-5DOI Listing
August 2018

Alteration in CD8 T cell subsets in enterovirus-infected patients: An alarming factor for type 1 diabetes mellitus.

Kaohsiung J Med Sci 2018 May 20;34(5):274-280. Epub 2018 Jan 20.

Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.

Type 1 diabetes is a multi-factorial disease that can develop due to the combination of genetic and environmental factors. Viruses, particularly enteroviruses, are major environmental candidates in the pathogenesis of type 1 diabetes, even though the mechanisms of pathogenicity of these viruses and their effects on the immune system have not been understood very well yet. Previous studies show that any imbalance in the population of different lymphocyte subsets could develop autoimmune diseases. Our theory is that enteroviral infection causes an impairment in the distribution of lymphocyte subtypes and consequently results in the diabetes onset in some individuals. Therefore, in this project, we evaluated the distribution of T CD8+ lymphocytes and their subsets in type 1 diabetes patients. This study was conducted to investigate the relationship between enteroviral infection and type 1 diabetes mellitus in an Iranian population, and suggestion a predicting approach for susceptible subjects.
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http://dx.doi.org/10.1016/j.kjms.2017.12.010DOI Listing
May 2018

Specific immune responses induced by multi-epitope DNA derived from Mycobacterium tuberculosis DosR antigens.

Acta Microbiol Immunol Hung 2018 Jun 19;65(2):193-209. Epub 2018 Mar 19.

1 Department of Microbiology, School of Medicine, Tehran University of Medical Sciences , Tehran, Iran.

One third of the world population are latently infected with Mycobacterium tuberculosis and are at the risk of reactivation of tuberculosis (TB). The most effective strategy for control of TB worldwide is the development of a vaccine that inhibits progression of latent TB to active infection. In this study, two optimized constructs consisting of multi-epitopes DNA derived from three latency antigens Rv2029c, Rv2031c, and Rv2627c fused with or without light chain 3 (LC3) are synthetized. The immunogenicity effectiveness of two DNA constructs was evaluated in the mouse model. LC3-fused multi-epitope DNA construct induced strong specific Th1 immune responses with high increase in IFN-γ CD4 and IL-2 CD4 T cell populations (both with p < 0.0001) and IFN-γ IL-2 CD4 T cell population (p < 0.0001) compared with empty vector, BCG, and multi-epitope DNA construct groups. The LC3-fused construct induced IFN-γ CD8 T cell population (p < 0.0001) compared with empty vector and BCG groups but could not induce the T cell population compared with construct without LC3. Importantly, LC3-fused DNA construct did not induce epitope-specific IL-4 and IL-10 from CD4 and CD8 T cell populations. The results indicated that LC3-fused multi-epitope DNA construct has a potential to be investigated for future development of a new TB vaccine.
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http://dx.doi.org/10.1556/030.65.2018.019DOI Listing
June 2018

Association Study of HLA-DQB1*0602 Allele in Iranian Patients with Narcolepsy.

Iran J Allergy Asthma Immunol 2017 Oct;16(5):452-456

Department  of  Immunology,  School  of  Medicine,  International  Campus,  Tehran  University  of  Medical  Sciences, Tehran, Iran.

Narcolepsy is a rare, disabling disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations and sleep paralysis. Several studies demonstrated its association with HLA-DQB1*0602 in various ethnic groups. Our study aimed to determine the prevalence of HLA-DQB1*0602 allele in Iranian patients with narcolepsy and assess its predictive parameters for diagnosing narcolepsy. In addition, car accidents and job problems were assessed among narcoleptic patients. We studied 44 narcoleptic patients, 30 patients with other types of excessive daytime sleepiness (EDS)  and 50 healthy age and sex matched individuals in this case-control study. Patients and controls filled out a questionnaire including items about car accidents due to sleepiness and job problems. International classification of sleep disorders-2 criteria was used as the gold standard for diagnosis of narcolepsy. The DNAs isolated from whole blood samples were collected from the patients and controls to assess the presence of HLA-DQB1*0602. The results showed that HLA DQB1*0602 was present in 4 (8%) individual of controls and 20 (45.5%) patients with higher prevalence in patients with cataplexy (78.9%) than patients without cataplexy (p<0.001). The sensitivities of the DQB1*0602 for diagnosing narcolepsy with cataplexy and narcolepsy without cataplexy were 78.9 and 20; specificities were 88 and 72.4, respectively. 18.2% of patients had car accidents due to sleepiness and 68.2% suffered from job problems. Our study shows that evaluation of DQB1*0602 in patients suspected to narcolepsy could be helpful especially in complex cases with atypical cataplexy and indistinguishable multiple sleep latency test MSLT results. Moreover, high rates of car accidents and job problems are found among narcoleptic patients.
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October 2017

Punica granatum L. Fruit Aqueous Extract Suppresses Reactive Oxygen Species-Mediated p53/p65/miR-145 Expressions followed by Elevated Levels of irs-1 in Alloxan-Diabetic Rats.

Cell J 2018 Jan 4;19(4):520-527. Epub 2017 Nov 4.

Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Objectives: Reactive oxygen species (ROS) is an apoptosis inducer in pancreatic β-cells that stimulates p53/p65 mediated microRNA (miR)-145 expression. Punica granatum L. (pomegranate) is an antioxidant fruit that attenuates ROS generation. This study examines the effects of pomegranate fruit aqueous extract (PGE) on the levels of ROS, p53, p65, miR-145, and its target insulin receptor substrate 1 (irs-1) mRNA in Alloxan-diabetic male Wistar rats.

Materials And Methods: In this experimental study, diabetic rats received different doses of PGE. The effects of the PGE polyphenols were examined through a long-term PGE treatment period model, followed by an evaluation of the plasma and tissue contents of free fatty acids (FFAs), triglycerides (TG), and glycogen compared with diabetic controls (DC) and normal controls (NC). We used real-time polymerase chain reaction (PCR) to investigate the modulation of p53, p65, miR-145, and irs-1 expression levels.

Results: There was a noticeable reduction in fasting blood glucose (FBG) and ROS generation compared to DC. We observed marked decreases in p53, p65, miR-145 expression levels followed by an elevated level of irs-1, which contributed to improvement in insulin sensitivity.

Conclusions: PGE administration downregulated miR-145 levels in Alloxan-diabetic Wistar rats by suppression of ROS-mediated p53 and p65 overexpression.
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http://dx.doi.org/10.22074/cellj.2018.4550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5672089PMC
January 2018

Modulation of CD4+ T Cell Subsets by Euphorbia microciadia and Euphorbia osyridea Plant Extracts.

Iran J Immunol 2017 Jun;14(2):134-150

Department of Immunology, Medical School, Shiraz University of Medical Sciences, Shiraz, Iran.

Background: Euphorbia plants are traditionally used in folk medicine for infections, inflammation, and cancer.

Objectives: To investigate the effects of the butanolic extracts of Euphorbia micorociadia and Euphorbia osyridea on specific transcription factors and cytokines expression of T cell subsets.

Methods: Activated mouse splenocytes were cultured in the presence of non-cytotoxic concentrations of the extracts. Cells were evaluated for the gene expressions of T cell transcription factors and cytokines of T helper (Th)1 [T-bet and interferon gamma (IFNγ)], Th17 [retinoic acid receptor related orphan receptor (RORγt) and interleukin (IL)-17], and T regulatory (Treg) cells [forkhead box P3(Foxp3), IL-10, and Transforming growth factor (TGF)-β] using real-time PCR. The cytokine secretions were evaluated by ELISA and Foxp3 protein expression by flow cytometry.

Results: Both E. osyridea and E. microciadia extracts at 0.1 μg/ml increased T-bet expression [>1.73 relative fold change (RFC), p<0.05] and IFNγ production (>1195 pg/ml, p<0.001). Both decreased Foxp3 (<0.41 RFC, p<0.05) expression. At the higher concentration both extracts significantly reduced T-bet mRNA as well as IFNγ, IL-17, IL-10, and TGF-β cytokines and Foxp3 at the mRNA and protein levels.

Conclusion: These data showed the immunomodulatory effects of E. osyridea and E. micorociadia extracts on T cell-mediated responses. The extracts caused upregulation of Th1 and downregulation of Treg cells at a low concentration which suggested their possible therapeutic value in tumor models and infectious diseases. The observed immunosuppressive effects at the higher concentration potentially make these plants candidates for identification of active components and studying their mechanisms of action.
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http://dx.doi.org/IJIv14i2A5DOI Listing
June 2017

Differential Frequency of CD8+ T Cell Subsets in Multiple Sclerosis Patients with Various Clinical Patterns.

PLoS One 2016 28;11(7):e0159565. Epub 2016 Jul 28.

Immunology Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Recent evidence points to a pathogenic role for CD8+ cytotoxic T (Tc) cells in Multiple sclerosis (MS). Based on cytokine profile, Tc cells can be divided into different subsets: IFN-γ (Tc1), IL-4 (Tc2), IL-10 (Tc10), IL-17 (Tc17), IL-21 (Tc21), IL-22 (Tc22) and TNF-α producing cells. In this study we evaluated the frequency of Tc cell subsets and the serum level of Tc17 differentiation cytokines in MS patients with different clinical patterns. We analyzed Tc cell subsets percentage in peripheral blood of relapsing-remitting (RRMS) (n = 28), secondary-progressive (SPMS) (n = 10) and primary-progressive (PPMS) (n = 4) MS patients in comparison to healthy controls (n = 15) using flow cytometry. Serum level of TGF-β, IL-6 and IL-23 were measured by ELISA. We showed elevated levels of Tc1 and Tc17 cells in SPMS and RRMS patients in relapse phase, respectively (P = 0.04). Interestingly, the percentage of TNF-α producing CD8+ T cells in relapse and remission phase of RRMS and SPMS patients were higher than controls (P = 0.01, P = 0.004, P = 0.01, respectively) and Tc21 increased in remission phase of RRMS compared to SPMS (P = 0.03). We also found higher frequency of CD8+ IFN-γ+ TNF-α+ IL-17+ T cells in relapse phase of RRMS compared to remission phase, SPMS patients and controls (P = 0.01, P = 0.004 and P = 0.02, respectively). TGF- β increased in sera of RRMS patients in remission phase (P = 0.03) and SPMS (P = 0.05) compared to healthy subjects. Increased level of Tc17 and CD8+ IFN-γ+ TNF-α+ IL-17+ T cells in relapse phase highlights the critical role of IL-17 in RRMS pathogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0159565PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965085PMC
July 2017

Anti-rubella, Mumps and Measles IgG Antibodies in Medical Students of Tehran University.

Iran J Allergy Asthma Immunol 2016 Jun;15(3):244-50

Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Measles, mumps and rubella are viral infectious diseases that may result in serious complications. Since the production of vaccines, the number of cases of these diseases has been dropped. Nevertheless, these infectious diseases are still one of the major health problems in developing countries. In this study, in order to evaluate the protective responses against measles, mumps and rubella, the level and avidity of virus-specific IgG antibodies were measured in 53 medical students of Tehran University, aged between 20-30 years. Except for mumps vaccine, all the students had been vaccinated against measles and rubella according to Iran's nationwide mass vaccination protocol for all persons aged 5-25 in 2003. Our results showed that 96.2% of the volunteers had a protective level (>15 IU/ml) of IgG against rubella, 79.2% had a protective level (>11 IU/ml) of IgG against measles and 64.16% had a protective level (>11 IU/ml) of IgG against mumps. Over ten years after nationwide measles-rubella vaccination campaign, most young adults aged 20-30 had protective levels of humoral immunity against measles and rubella. However, Iranian young population is still unvaccinated against mumps, and therefore relatively large number of young adults had no protective level of IgG against it. This finding may be due to reduction in circulating of wild strain. We recommend screening of medical students for immunity against infectious agents such as measles, mumps, rubella, because they are at a high risk of these infectious agents.
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June 2016

TIM-3 Rs10515746 (A/C) and Rs10053538 (C/A) Gene Polymorphisms and Risk of Multiple Sclerosis.

Iran J Public Health 2016 May;45(5):644-9

Dept. of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Sina Hospital, Tehran, Iran.

Background: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) caused by auto-reactive T cells against myelin antigens. T-cell immunoglobulin mucin -3 (TIM-3) is a negative regulator glycoprotein expressed by a range of immune cells, including, Th1 cells, activated CD8+ T cells and in a lower level on Th17 cells. A defect in TIM-3 regulation has been shown in multiple sclerosis patients. In humans, several single nucleotide polymorphisms (SNPs) have been identified in the TIM-3 gene and are associated with inflammatory diseases. The aim of this study was to analyze the association between TIM-3 -574A>C and -1516 C>A SNPs in the promoter region, and susceptibility to MS.

Methods: DNA samples from 102 patients and 102 healthy controls were genotyped using RFLP-PCR method.

Results: In this case-control study, analysis of the alleles and genotypes revealed a significant higher frequency of C/C and lower frequency of A/C genotypes for -574 locus of TIM-3 gene in MS patients (P=0.0002). We also found that C/C genotype for locus of -1516 increased in MS patients, while A/C genotype decreased (P=0.012). Allele C of -574C/C and -1516 C>A SNPs were also more frequent in MS patients (P=0.036 and 0.0027 respectively).

Conclusion: -574 A>C and -1516 C>A SNPs in the promoter region of TIM3 gene may affect the disease susceptibility.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935708PMC
May 2016