Publications by authors named "Abbas Mirshafiey"

177 Publications

Anti-tumor effect of M2000 (β-d-mannuronic acid) on the expression of inflammatory molecules in the prostate cancer cell.

Immunopharmacol Immunotoxicol 2021 May 31:1-12. Epub 2021 May 31.

Department of Medical Biotechnology, Faculty of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran.

The importance of chronic inflammation during the progression of prostate cancer (PCa) is well-known. M2000 (β-d-mannuronic acid) is a novel anti-inflammatory drug. According to its potential capacity for the inhibition of molecules involved in creating conditions of inflammation, it is reasonable to assess the anti-inflammatory role of M2000 in PCa cells. MTT assay was performed to determine the cytotoxicity of M2000 in PC3 cells. Correspondingly, these cells were cultured and then treated with low (25 µg/ml) and high (50 µg/ml) doses of M2000 as optimal doses. Thereafter, real-time RT-PCR, flow cytometry analysis, and zymography were performed to evaluate the expressions of MYD-88, NF-kB, IL-8, COX-2, MMP-2, and MMP-9 molecules. Of note, the M2000 at the concentration of ≤200 μg/ml had no cytotoxicity effect on the cells. gene expression was significantly down-regulated at both low and high doses in the M2000-treated cells compared to the control ( = .017 and  = .001, respectively). The expression of the NF-kB was also reduced at both the gene and protein levels (all values were <.001). The expression of and genes was also down-regulated in the high dose of M2000 (<.001,  = .001, respectively). The decreased expression of the gene was observed at both doses (both values were <.001). Inhibitory effects of M2000 on the activity of MMPs in the LPS/M2000-treated cells were evident, but not in the M2000-treated cells. M2000 as a new anti-inflammatory drug appears to constitute a potential agent for down-regulation of inflammatory molecules in the PCa cells.
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http://dx.doi.org/10.1080/08923973.2021.1931301DOI Listing
May 2021

Evaluation of the Effect of Mannuronic Acid as a Novel NSAID with Immunosuppressive Properties on Expression of SOCS1, SOCS3, SHIP1 and TRAF6 Genes and Serum Level of IL-6 and TNF-α in Patients with Multiple Sclerosis.

J Clin Pharmacol 2021 Apr 28. Epub 2021 Apr 28.

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

Multiple sclerosis (MS) is described as a chronic inflammatory, demyelinating disease of the central nervous system of an autoimmune basis which is the most frequent reason of non-traumatic disability in youths. The efficacy and safety of β-D-Mannuronic acid (M2000) as a novel immunosuppressive drug, patented (PCT/EP2017/067920), has been shown in experimental model of MS and also in a phase II clinical trial. The effects of M2000 on SOCS1, SOCS3, TRAF6 and SHIP1 gene expression and also serum level of IL-6 and TNF-α in secondary progressive multiple sclerosis (SPMS) patients have been assessed in this study. In this study, 14 SPMS patients and 14 healthy subjects (as control group) were recruited from the phase II clinical trial (Clinical Trial identifier, IRCT2016111313739N6). The gene expression of SOCS1, SOCS3, TRAF6 and SHIP1 were measured at the baseline and after 6 months of therapy with M2000, by using quantitative real-time PCR method. Furthermore, the serum level of IL-6 and TNF-α were assessed by ELISA method. Our results showed that the gene expression of SOCS1, SOCS3 and SHIP1 were increased after 6 months of therapy with M2000 in MS patients. Moreover, the serum level of IL-6 and TNF-α of patients declined when compared to baseline but this was not statistically significant. The results of this study demonstrated that M2000, with immunosuppressive properties, could upregulate SOCS1, SOCS3 and SHIP1 genes in patients with SPMS. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/jcph.1879DOI Listing
April 2021

Evaluation of the oral administration of α-l-guluronic acid on COX-1 and COX-2 gene expression profile in ankylosing spondylitis patients.

Drug Dev Res 2021 Apr 2;82(2):296-301. Epub 2020 Nov 2.

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

Ankylosing spondylitis (AS) is a chronic autoimmune arthritis disease with a genetic background, affecting the skeletal axis, sacroiliac, and peripheral joints. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line treatment for AS to alleviate the inflammation and pain. Despite the beneficial effect, their use is accompanied by a wide variety of possible side effects in the gastrointestinal and kidneys. The α-l-guluronic acid (G2013) is a new nonsteroidal anti-inflammatory patented (PCT/EP2017/067920) drug, which has shown its anti-inflammatory properties in the previous investigations. The present study revealed the oral administration effect of G2013 on COX-1 and COX-2 gene expression in AS patients. The blood samples of twelve 18-45 years old patients suffering AS and BASDAI >4, and BASFI >4, before and after 12 weeks of treatment with G2013 and 12 blood samples of healthy volunteers were collected and the effect of G2013 on the gene expression of COX-1 and COX-2 enzymes were assessed by Real-Time PCR. The results indicate that G2013 is able to reduce the gene expression level of COX-1 and COX-2 enzymes in treated AS patients compared to healthy control. Statistically significant differences were not observed between the treatment and the healthy control groups. According to the findings, G2013 might be categorized and introduced as a novel NSAID for the treatment of AS.
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http://dx.doi.org/10.1002/ddr.21756DOI Listing
April 2021

Assessment of biochemical determinants in Multiple Sclerosis patients following the oral administration of β-D-Mannuronic acid [M2000].

Curr Drug Discov Technol 2020 Sep 17. Epub 2020 Sep 17.

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

Background: Multiple sclerosis is an autoimmune chronic inflammatory disease of the central nervous system that can lead to some serious disabilities. Despite using various immunomodulatory and anti-inflammatory drugs that have therapeutic effects, they cannot reduce its progression completely, and have some unwanted side effects too. The immunomodulatory and anti-inflammatory effects of the β-D-Mannuronic acid [M2000] have been proven in several surveys, and the present research was designed to determine its toxicity and therapeutic effects in MS patients.

Methods: This study was performed on 15 MS patients who took 25 mg/kg/day the oral form of the β-D-Mannuronic acid for six months, and 15 healthy people as a control group. Serum levels of Urea, Creatinine, GGT, Vitamin D3, Uric acid, and Anti-Phospholipids were compared to evaluate the therapeutic and possible toxic effects of this drug after this period.

Results: Non- toxic effects through the study of Urea, Creatinine, GGT, and non-significant changes in Uric acid and AntiPhospholipids levels, besides a significant rise in Vitamin, D3 levels in the M2000 treated cases were found.

Conclusions: Our results suggested that β-D-Mannuronic acid is a safe drug and has no toxicity when administered orally and also has some therapeutic effects in MS patients.
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http://dx.doi.org/10.2174/1570163817999200918104333DOI Listing
September 2020

A controlled, randomized phase II clinical trial for efficacy and safety evaluation of mannuronic acid in secondary progressive form of multiple sclerosis.

Int J Neurosci 2020 Sep 7:1-10. Epub 2020 Sep 7.

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

Background: The β-D-Mannuronic acid (M2000) as a novel immunosuppressive drug, patented (PCT/EP2017/067920), has shown positive effects in experimental model of multiple sclerosis (MS). In this study, our aim was to assess efficacy and safety outcomes in MS treated patients with mannuronic acid compared to the conventional drug.

Methods: In a 6-month, randomized controlled, phase II trial, we enrolled patients who had secondary progressive multiple sclerosis (SPMS), were 21-54 years of age, with a score of 1-7 on the Expanded Disability Status Scale (EDSS), and who had at least one relapse in the previous 6 months. Patients were administered orally 1000 mg/day (two 500 mg/capsule daily) of M2000. Endpoints included changes in brain magnetic resonance imaging (MRI) measures and the EDSS score, as compared to the conventional drug (interferon beta-1a, interferon beta-1b).

Results: A total of 25 (92.5%) of the M2000 treated patients and 25 conventionally treated patients completed the study. M2000 had better performance compared to the conventional drug regarding to MRI-related measurements, however, the differences between groups were not statistically significant. M2000 decreased the disability progression over the 6-month period. The EDSS score was decreased in the M2000 treated group in the sixth month versus the conventional drug ( < 0.009). Furthermore, we did not observe any short-term side effects.

Conclusions: As compared with the conventional drug, mannuronic acid (M2000) improved the rate of disability progression. This clinical trial demonstrated the efficacy and safety of mannuronic acid in patients with SPMS. (Registered Clinical Trials number, IRCT2016111313739N6).
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http://dx.doi.org/10.1080/00207454.2020.1818741DOI Listing
September 2020

A comprehensive review on miR-146a molecular mechanisms in a wide spectrum of immune and non-immune inflammatory diseases.

Immunol Lett 2020 11 15;227:8-27. Epub 2020 Aug 15.

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

MicroRNAs (miRNAs) are single-strand endogenous and non-coding RNA molecules with a length of about 22 nucleotides, which regulate genes expression, through modulating the translation and stability of their target mRNAs. miR-146a is one of the most studied miRNAs, due to its central role in immune system homeostasis and control of the innate and acquired immune responses. Accordingly, abnormal expression or function of miR-146a results in the incidence and progression of immune and non-immune inflammatory diseases. Its deregulated expression pattern and inefficient function have been reported in a wide spectrum of these illnesses. Based on the existing evidence, this miRNA qualifies as an ideal biomarker for diagnosis, prognosis, and activity evaluation of immune and non-immune inflammatory disorders. Moreover, much attention has recently been paid to therapeutic potential of miR-146a and several researchers have assessed the effects of different drugs on expression and function of this miRNA at diverse experimental, animal, besides human levels, reporting motivating results in the treatment of the diseases. Here, in this comprehensive review, we provide an overview of miR-146a role in the pathogenesis and progression of several immune and non-immune inflammatory diseases such as Rheumatoid arthritis, Systemic lupus erythematosus, Inflammatory bowel disease, Multiple sclerosis, Psoriasis, Graves' disease, Atherosclerosis, Hepatitis, Chronic obstructive pulmonary disease, etc., discuss about its eligibility for being a desirable biomarker for these disorders, and also highlight its therapeutic potential. Understanding these mechanisms underlies the selecting and designing the proper therapeutic targets and medications, which eventually facilitate the treatment process.
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http://dx.doi.org/10.1016/j.imlet.2020.07.008DOI Listing
November 2020

The Effects of G2013 (α-L-guluronic Acid) in a Pentylenetetrazole-induced Kindling Animal Model of Epilepsy.

Innov Clin Neurosci 2020 Apr;17(4-6):9-12

Dr. Tahmasebi is with the Research Center for Applied Plant Sciences, Arak Branch, Islamic Azad University, Arak, Iran.

Recent studies have reported observing antioxidant, anti-inflammatory, and anti-aging properties of α-L-Guluronic acid (G2013) in animal and human studies. It has been theorized that the antioxidant and anti-inflammatory properties of G2013 might be beneficial in epilepsy treatment. We sought to determine G2013's effects on epileptic activity in a kindling-induced animal model. Thirty rats were randomly divided evenly into three groups (10 rats in each group): 1) the G2013 group, which was treated with daily injections of G2013 for five days prior to the start of the study; during the 14-day study period, the G2013 rats were given single, daily injections of G2013 that preceded single daily injections of pentylenetetrazole (PTZ), a compound used to induce seizures; 2) the Normal group, which only received injections of saline during the 14-day study, with no seizure induction; and 3) the Control group, which received PTZ injections alone (for seizure induction) for the 14-day study period. The latency between seizure stages and duration of seizures in the G2013 and Control groups were measured using a 5-stage seizure severity scale. Brain samples were taken from all three groups and analyzed histopathologically for parenchymal and meningeal inflammatory cell infiltration. Additionally, the brain samples were analyzed to determine gene expression levels of interleukin-1-beta (IL-1β), IL-6, IL-10), tumor necrosis factor (TNF), chemokine (C-C motif) ligand-2 (CCL2), cyclooxygenase-2 (COX-2), and interferon-gamma (IFN-γ). The G2013 group demonstrated lower latency between Stages 2 and 5 seizures, with significantly longer mean duration of Stage 5 seizures, compared to the Control group. No significant differences were observed between the three groups histopathologically nor were there any observed differences in gene expression levels. Our results demonstrated a greater predisposition to PTZ-induced seizures in the rats who received G2013 and PTZ compared to rats who received PTZ alone, suggesting that G2013's epileptogenic property overshadows its anti-inflammatory effects when applied to a kindled animal model of study.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413338PMC
April 2020

Effect of Guluronic Acid (G2013), As a New Anti-inflammatory Drug on Gene Expression of Pro-inflammatory and Anti-inflammatory Cytokines and Their Transcription Factors in Rheumatoid Arthritis Patients.

Iran J Allergy Asthma Immunol 2019 Nov 11;18(6):639-648. Epub 2019 Nov 11.

Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran AND Research Center for Immunodeficiencies, Children's Medical Centre, Tehran University of Medical Sciences, Tehran, Iran.

Rheumatoid arthritis (RA) as a long-term autoimmune disease is characterized by pain, swelling and joints destruction. The therapeutic efficacy of Guluronic acid (G2013) (patented, DEU: 102016113017.6) was reported in phase I/II clinical trial in RA patients. In this study, we aimed to evaluate the effect of G2013 as a novel non-steroidal anti-inflammatory drug (NSAID) with immunosuppressive property on genes expression of anti-inflammatory and pro-inflammatory cytokines and their transcription factors in the blood sample of RA patients. This study was performed on 12 patients with RA who had an inadequate response to conventional treatments which were disease-modifying anti-rheumatic drugs (DMARDs), NSAID, and biologics. G2013 was administered orally at a dose of 500 mg twice daily for 12 weeks. Before and after the treatment of patients with drug G2013, the peripheral blood mononuclear cells (PBMCs) were isolated for evaluating the gene expression level of interleukin 10 (IL10), interleukin 22 (IL22), interferon γ (IFNγ), and transcription factors specific to the T helper cell lineages, forkhead box P3 (Fox-P3), Aryl hydrocarbon receptor (AHR) and T-box-containing protein expressed in T cells (T-bet) using the real-time PCR method. Since these cytokines have a key role in the progression of RA and disease condition expected induction of IFNγ, AHR, IL22, T-bet, and reduction of IL10, Fox-P3. Results indicated a significant reduction in the level of IFNγ, AHR and a significant induction in IL10, Fox-P3 gene expression in comparison with the control group. In conclusion; the results of this investigation showed a part of the immunological mechanism of G2013 as a novel anti-inflammatory that could reduce pro-inflammatory cytokine and their transcription factors. Furthermore, it increased the anti-inflammatory cytokine and its transcription factor (clinical trial identifier: IRCT2016092813739N5).
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http://dx.doi.org/10.18502/ijaai.v18i6.2176DOI Listing
November 2019

The role of β-d-mannuronic acid, as a new non-steroidal anti-inflammatory drug on expression of miR-146a, IRAK1, TRAF6, NF-κB and pro-inflammatory cytokines following a clinical trial in rheumatoid arthritis patients.

Immunopharmacol Immunotoxicol 2020 Jun 29;42(3):228-236. Epub 2020 Mar 29.

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

miR-146a, its targets (IRAK1, TRAF6) and NF-κB transcription factor play a fundamental role in rheumatoid arthritis (RA). Positive effects of drug β-d-mannuronic acid (M2000) were proven on their expression in the HEK-Blue hTLR2 cell line, and results of its phase III clinical trial on RA patients were encouraging. This research aimed to investigate the effects of M2000 on expression of these genes and serum levels of IL-6 and TNF-α as pro-inflammatory cytokines in RA patients. In this study (Trial Registration Number: IRCT2017100213739N10), 12 RA patients (according to the American College of Rheumatology criteria) and 12 healthy subjects (as control group) were selected. The gene expression of miR-146a, IRAK1, TRAF6, and NF-κB were measured at the baseline and after 12 weeks M2000 therapy, using quantitative real-time PCR method. Moreover, the serum levels of IL-6 and TNF-α were evaluated at the similar times by ELISA method. Our findings showed that the gene expression of miR-146a, IRAK1, TRAF6, and NF-κB significantly decreased after 12 weeks M2000 therapy in RA patients (0.81-, 0.68-, 0.79-, 0.82-fold, with  < .05,  < .01,  < .01,  < .05, respectively). Furthermore, the serum levels of IL-6 and TNF-α significantly reduced in these patients after 12 weeks M2000 therapy (both with  < .05). The present research results determined the part of molecular mechanisms of drug M2000 in RA treatment, based on the expression and function modification of miR-146a, IRAK1, TRAF6, NF-κB, IL-6 and TNF-α.
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http://dx.doi.org/10.1080/08923973.2020.1742734DOI Listing
June 2020

Interleukin-1β and interleukin-6 in Common Variable Immunodeficiency and their association with subtypes of B cells and response to the Pneumovax-23 vaccine.

Eur Cytokine Netw 2019 Dec;30(4):123-129

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran, Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.

Introduction: Common Variable Immunodeficiency (CVID) is the most common symptomatic form of primary immunodeficiencies. Current research data show altered B cells, TLRs, and cytokine profile in CVID patients. The aim of this study was to determine levels of IL-1β and IL-6 in CVID patients in response to TLRs stimulation and the association of these cytokines with subtypes of B cells and response to Pneumovax-23 vaccination.

Method: Peripheral blood mononuclear cells of CIVD patients were stimulated with and without TLR2 and TLR4 agonist and specific inhibitors including lipopolysaccharide (LPS), lipoteichoic (LTA), and OxPAPC. The levels of IL-1β and IL-6 were assessed by ELISA in different treatment groups. Finally, association of cytokines levels was assessed among different subtypes of B cells and types of response to Pneumovax-23 vaccine.

Results: Secretion of IL-6 and IL-1β was significantly diminished in CVID patients (p = 0.015 and p = 0.019), but ligand engagement of TLR2 and TLR4 leads to significant increase in IL-6 and IL-1β production. IL-6 was significantly lower in Pneumovax-23 hypo responder patients (p = 0.05) and significant correlations between the concentration of IL-6 and the number of switched memory and CD21 expressing B cells were found.

Conclusion: Secretion of IL-6 and IL-1β is abolished in CVID patients. However, TLR2 and TLR4 are hyper responsive to stimulation with their cognate ligands resulting in the secretion of higher levels of proinflammatory cytokines. This characteristic of CVID TLRs leads to an improvement of cytokine secretion compared to baseline levels. Also, our novel findings about the association concentrations of serum IL-6 and the frequency of with switched memory and CD21 expressing B cells as well as the poor response to Pneumovax-23 should be substantiated by the use of a higher sample size in future studies.
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http://dx.doi.org/10.1684/ecn.2019.0435DOI Listing
December 2019

Mannuronic Acid in Low-Risk and Intermediate-1-Risk Myelodysplastic Syndromes.

J Clin Pharmacol 2020 07 16;60(7):879-888. Epub 2020 Feb 16.

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

The discovery of hematologic improvement and bone marrow modification by the drug β-D mannuronic acid (M2000) during treatment of rheumatoid arthritis in phase 1/2/3 clinical trials prompted us to design a new trial to target hematologic deficits in myelodysplastic syndromes (MDS). In this open-label, randomized phase 2 clinical trial, the potential effect and tolerability of drug M2000 was assessed in patients with low- and intermediate-1-risk MDS. The primary efficacy end point was hematologic improvement after 12 weeks of β-D-mannuronic acid therapy. Among 34 enrolled patients, half received their conventional therapy plus β-D-mannuronic acid, and the other half received only conventional drugs. In the conventional + β-D mannuronic acid treatment group, hematologic improvement and development of transfusion independence and/or reduction in transfusion requirements were seen in 12 patients (92.3%) and 1 patient (7.7%), respectively. Moreover, 5 patients (38.5%), 2 patients (15.4%), and 1 patient (7.7%) in the β-D-mannuronic acid-treated group showed hematologic improvement of the major parameters of erythroid, neutrophil, and platelet responses, respectively, based on the International Working Group criteria), whereas in the conventional treatment group as control, no hematologic improvements including erythroid, neutrophil, and platelet response was seen. In this trial, the addition of β-D mannuronic acid to conventional treatment showed promising results in MDS patients with low and intermediate-1 risk with effects on hematologic improvements without significant adverse effect.
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http://dx.doi.org/10.1002/jcph.1587DOI Listing
July 2020

β-D-Mannuronic Acid (M2000) as a Landmark in Pharmacology.

Curr Drug Discov Technol 2021 ;18(1):47-57

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

Objectives: The goal of this article is to retrace the studies of β-D-Mannuronic Acid (M2000) as a new immunosuppressive drug with non-steroidal anti-inflammatory drugs (NSAIDs) property in miscellaneous aspects including in vitro, in vivo examinations, clinical trials and related to clinical trials studies. Our goal is to compare the effect of this drug with other similar drugs through varied researches and to follow tolerability, biocompatibility, potency, safety, and efficacy of this medication in different studies, as well as to evaluate its therapeutic effectiveness in various diseases.

Materials And Methods: Different methods were applied in the studies of β-D-Mannuronic Acid under in vitro, in vivo examinations, and clinical trials phase I, II and III and related investigations to these clinical trials using different techniques showing the efficacy of this medication in the treatment of various diseases.

Results: The administration of β -D-Mannuronic Acid showed the greatest tolerability and biocompatibility compared to diclofenac, piroxicam, and dexamethasone without or very low side effects. The drug has shown a punchy effect on many molecules which participate either in physiologic or in pathogenic activities in animal models and human. This new drug not only revealed the anti-inflammatory and immunosuppressive properties but also based on the results of various investigations, β-D-Mannuronic Acid showed the antidiabetic, cardioprotective and anti-tumoral effects.

Conclusion: β-D-Mannuronic Acid (M2000) as a novel immunosuppressive drug with NSAID properties along with antidiabetic, cardioprotective and anti-tumoral efficacy showed great tolerability and safety profile. In addition, it has no or mild adverse events compared with many other medicines, therefore this medicament could be considered as a landmark in pharmacology and represent turn point in the treatment of different diseases based on the experimental and in vitro studies explained and clinical and related studies proved.
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http://dx.doi.org/10.2174/1570163817666191227160300DOI Listing
January 2021

Effects of guluronic acid, as a new NSAID with immunomodulatory properties on IL-17, RORγt, IL-4 and GATA-3 gene expression in rheumatoid arthritis patients.

Immunopharmacol Immunotoxicol 2020 Feb 19;42(1):22-27. Epub 2019 Dec 19.

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

Rheumatoid arthritis (RA) is a prevalent inflammatory, autoimmune diseases characterized by inflammation and destruction of joints. Disease-modifying anti-rheumatic drugs (DMARDs) and biological drugs can have modulatory interference in disease process. In this study, the effect of Guluronic Acid (G2013) as a novel non-steroidal anti-inflammatory drug (NSAID) with immunomodulatory effects was evaluated on , , and gene expression in RA patients. Fourteen patients with RA who had an inadequate response to conventional treatments were included in this clinical trial. During this trial, patients were permitted to continue the conventional therapy excluding NSAIDs. G2013 was administered orally at dose of 500 mg twice daily for 12 weeks. The peripheral blood mononuclear cells (PBMCs) were collected before and after treatment to evaluate the gene expression levels of , , and . Primary and secondary efficacy endpoints and Disease Activity Score (DAS) 28 showed an improvement after 12 weeks of treatment. G2013 has a potent efficacy on gene expression of these molecules, so that it could decrease IL-17 and levels and increase IL-4 and levels after 12 weeks of treatment. Reduction of IL-17 was statistically non-significant whereas for its transcription factor (RORγt was statistically significant. Moreover, the gene expression results were in accordance with the clinical and preclinical assessments. G2013 as a natural novel drug showed a significant increase on and and a significant decrease on gene expression after 12 weeks oral administration of this drug in RA patients. (Clinical trial identifier: IRCT2016092813739N5).
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http://dx.doi.org/10.1080/08923973.2019.1702053DOI Listing
February 2020

The Situation of Chemokine Ligands and Receptors Gene Expression, Following the Oral Administration of Drug Mannuronic Acid in Rheumatoid Arthritis Patients.

Recent Pat Inflamm Allergy Drug Discov 2020 ;14(1):69-77

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

Background: Regarding the leukocytes infiltration into the synovium of Rheumatoid Arthritis (RA) patients is mostly mediated by chemokine ligands and receptors, and following the efficient and motivating results of international Phase III clinical trial of β-D-Mannuronic acid (M2000) patented EP067919 (2017), as a novel anti-inflammatory drug, in patients with RA, the present research was designed.

Objectives: This study aimed to assess the oral administration effects of this new drug on gene expression of some chemokine receptors and ligands, including CXCR4, CXCR3, CCR2, CCR5 and CCL2/MCP-1 in PBMCs of patients with active form of RA.

Methods: Twelve patients suffering from RA, with inadequate response to conventional drugs were selected (Clinical trial identifier IRCT2017100213739N10) and 1000mg/day of M2000 was orally administrated to them for 12 weeks. The mRNA expression of target molecules was then evaluated in PBMCs of the patients before and after treatment with M2000 using real-time PCR and was compared to healthy controls. Patents related to this study were also reviewed.

Results: The results showed that M2000 was able to significantly down-regulate the mRNA expression of CXCR4, CCR2 and CCL2/MCP-1 in the PBMCs of the RA patients. It should be noted that the gene expression situation of the target molecules was in coordinate with the clinical and paraclinical assessments in the patients.

Conclusion: Taken together, the results of this investigation revealed the part of molecular and immunological mechanisms of drug Mannuronic acid (M2000) in the treatment of RA, based on chemokine ligands and receptors mediated processes.
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http://dx.doi.org/10.2174/1872213X13666191114111822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509734PMC
December 2020

Immunopharmacological effect of β-d-mannuronic acid (M2000), as a new immunosuppressive drug, on gene expression of miR-155 and its target molecules (SOCS1, SHIP1) in a clinical trial on rheumatoid arthritis patients.

Drug Dev Res 2020 05 1;81(3):295-304. Epub 2019 Nov 1.

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

The positive impacts of β-d-mannuronic acid (M2000) on the gene expression of miR-155, its target molecules (SOCS1 and SHIP1), and NF-κB transcription factor were demonstrated in a study using the HEK293-TLR2 cell line. This new drug has been approved as a safe and effective medication by a randomized, multinational, phase III clinical trial on RA patients. The present study aimed to evaluate the oral administration effect of M2000 on the expression levels of the mentioned genes in RA patients. This research was conducted on 12 RA patients and 12 healthy individuals. After extraction of total RNA from PBMCs of patients and synthesis of cDNA, the expression levels of miR-155, SOCS1, SHIP1, and NF-κB genes were measured through quantitative Real-time PCR at baseline and after 12 weeks of M2000 therapy. Our findings showed that the miR-155 gene expression level significantly decreased in the M2000-treated patients compared with the baseline (0.76-fold, with p < .05). The expression levels of SOCS1 and SHIP1 genes significantly increased in the patients treated with M2000 compared with the before treatment (1.46-, 1.54-fold, with p < .01, p < .05, respectively). In addition, it was found that the gene expression level of the NF-κB transcription factor significantly reduced in M2000-treated patients compared with the baseline (0.81-fold, with p < .05). This study showed that the oral administration of M2000 was able to reduce the expression of the miR-155, increase the expression of SOCS1 and SHIP1, and decrease the NF-κB gene expression (Trial Registration Number: IRCT2017100213739N10).
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http://dx.doi.org/10.1002/ddr.21619DOI Listing
May 2020

Influence of β-D-mannuronic Acid, as a New Member of Non-steroidal Anti- Inflammatory Drugs Family, on the Expression Pattern of Chemokines and their Receptors in Rheumatoid Arthritis.

Curr Drug Discov Technol 2021 ;18(1):65-74

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

Background: Based on the encouraging results of phase III clinical trial of β-Dmannuronic acid (M2000) (as a new anti-inflammatory drug) in patients with RA, in this study, we aimed to evaluate the effects of this drug on the expression of chemokines and their receptors in PBMCs of RA patients.

Methods: PBMCs of RA patients and healthy controls were separated and the patients' cells were treated with low, moderate and high doses (5, 25 and 50 μg/mL) of M2000 and optimum dose (1 μg/mL) of diclofenac, as a control in RPMI-1640 medium. Real-time PCR was used for evaluating the mRNA expression of CXCR3, CXCR4, CCR2, CCR5 and CCL2/MCP-1. Cell surface expression of CCR2 was investigated using flow cytometry.

Results: CCR5 mRNA expression reduced significantly, after treatment of the patients' cells with all three doses of M2000 and optimum dose of diclofenac. CXCR3 mRNA expression was downregulated significantly followed by the treatment of these cells with moderate and high doses of M2000 and optimum dose of diclofenac. CXCR4 mRNA expression declined significantly after the treatment of these cells with moderate and high doses of M2000. CCL2 mRNA expression significantly reduced only followed by the treatment of these cells with a high dose of M2000, whereas, mRNA and cell surface expressions of CCR2 diminished significantly followed by the treatment of these cells with a high dose of M2000 and optimum dose of diclofenac.

Conclusion: According to our results, M2000 through the down-regulation of chemokines and their receptors may restrict the infiltration of immune cells into the synovium.
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http://dx.doi.org/10.2174/1570163816666191023103118DOI Listing
January 2021

Anti-Diabetic and Angio-Protective Effect of Guluronic Acid (G2013) as a New Nonsteroidal Anti-Inflammatory Drug in the Experimental Model of Diabetes.

Endocr Metab Immune Disord Drug Targets 2020 ;20(3):446-452

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

Background: This study aimed to investigate the effects of guluronic acid (G2013) on blood sugar, insulin, and gene expression profile of oxLDL receptors (SR-A, CD36, LOX-1, and CD68) in the experimental model of diabetes.

Methods: 18 Sprague Dawley rats were randomly assigned to three groups of healthy control, diabetic control, and G2013 group. Diabetes was induced through intraperitoneal (IP) injection of 60 mg/kg streptozotocin. The subjects were IP treated with 25 mg/kg of G2013 per day for 28 days. The body weight, food intake, fasting blood glucose and insulin were measured. In addition, the expression of mentioned genes was investigated through quantitative real-time PCR.

Results: The data showed that the final weight increased significantly in the G2013-treated subjects compared to the diabetic control (p < 0.05). The results indicated that final food intake significantly reduced in the G2013-treated subjects compared to the diabetic control (p < 0.05). The study findings also suggested that the final fasting blood glucose significantly reduced in the G2013-treated group, whereas the final fasting serum insulin level significantly increased in this group compared to the diabetic control (p < 0.05). Moreover, the gene expression levels of SR-A, CD36, LOX-1, and CD68 in the G2013 group significantly reduced compared to the diabetic control (p < 0.05).

Conclusion: This study showed that G2013, could reduce blood glucose and increase insulin levels and reduce the gene expression level of oxLDL receptors. In addition, it may probably play an important role in reducing the severity of diabetes-induced inflammatory symptoms.
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http://dx.doi.org/10.2174/1871530319666191016103918DOI Listing
January 2021

Effects of guluronic acid (G2013) on gene expression of TLR2, TLR4, MyD88, TNF-α and CD52 in multiple sclerosis under in vitro conditions.

Immunopharmacol Immunotoxicol 2019 Dec 8;41(6):586-590. Epub 2019 Oct 8.

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

Multiple sclerosis (MS) is an autoimmune and chronic inflammatory disease of CNS. The α-L-guluronic acid (G2013) as novel NSAID with immunomodulatory effects has shown its positive effects in various investigations. Present research aimed to study the potency of G2013 on gene expression of TLR2, TLR4, MyD88, TNF-α and CD52 in PBMCs of MS patients under conditions. 24 blood samples from MS patients and healthy controls were considered for RT-PCR and flow cytometry techniques under two different doses of G2013. Our research indicated that this drug could significantly decrease the gene expression of TLR2, TLR4 and TNF-α compared to untreated group. Data demonstrated that the guluronic acid is able to modify the expression levels of TLR2, TLR4 and TNF-α genes to less than the pathogenic boarder line level, which it might be recommended for reducing the pathological process in multiple sclerosis.
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http://dx.doi.org/10.1080/08923973.2019.1672179DOI Listing
December 2019

Evaluation of the acute and 28-day sub-acute intravenous toxicity of α-l-guluronic acid (ALG; G2013) in mice.

Drug Chem Toxicol 2019 Sep 19:1-10. Epub 2019 Sep 19.

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

α-l-Guluronic acid (ALG; G2013) has been previously introduced as a new anti-inflammatory agent with promising therapeutic effects. Thus, in the present study, we aimed to evaluate the acute and sub-acute toxicity of ALG through intravenous (i.v.) administration in Balb/C mice. ALG was administrated i.v. to the mice with doses of 300, 600, and 1000 mg/kg of body weight to investigate acute toxicity (single dose) and with doses of 25, 50, and 100 mg/kg of body weight to sub-acute toxicity study (daily injections for a period of 28 days). The mortality rate, food and water intake, behavior, body weight, gross necropsy, hematological and biochemical parameters as well as histopathological presentations of the vital organs (kidneys, liver, lungs, spleen, and heart) were examined in treated groups and compared to the healthy controls. The results of both acute and sub-acute studies showed that i.v. administrations of ALG did not affect the investigated parameters in both sexes, indicating that the LD of ALG was higher than 1000 mg/kg of body weight. As no difference was observed in toxicity profiles of investigated doses, no-observed-adverse-effect-level for i.v. administration of ALG in the sub-acute study was greater than 100 mg/kg body weight in both female and male mice. According to the finding, i.v. administration of ALG did not lead to any clinical sign in abovementioned doses, suggesting that ALG was well tolerated up to 1000 mg/kg. These pre-clinical findings support the application of ALG in the future clinical trials.
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http://dx.doi.org/10.1080/01480545.2019.1665679DOI Listing
September 2019

The Toll-like Receptor 2 (TLR2)-related Immunopathological Responses in the Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis.

Iran J Allergy Asthma Immunol 2019 Jun 8;18(3):230-250. Epub 2019 Jun 8.

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

Toll-like receptors (TLRs) play principle roles in recognition of autologous components which have been pointed as the danger-associated molecular patterns (DAMP) and microbial components which are identified as pathogen associated molecular patterns (PAMP).The infiltration of various inflammatory cells such as dendritic cells, lymphocytes (CD4+ T, CD8+ T as well as B cells), monocytes and macrophages occur into the central nervous sys-tem (CNS) during multiple sclerosis (MS) and its animal model named experimental autoimmune encephalomyelitis (EAE). The infiltrated leukocytes and residential cells of the CNS express several TLRs (especially TLR2) and their expression are elevated in MS and EAE. TLR2 recognizes a large variety DAMP and PAMP molecules due to its ability to create heterodimers with TLR1, TLR6 and probably TLR10. A wide spectrum of  DAMP molecules, including heat shock protein 60 (HSP60), HSP70, high mobility group box 1 (HMGB1), β-defensin 3, surfactant protein A and D, eosinophil-derived neurotoxin, gangliosides, serum amyloid A, hyaluronic acid and biglycan are identified by TLR2, whose their expression is increased in MS patients. TLR2 may contribute in the development of MS and EAE diseases through the reinforcement of Th1/Th17 cell-related responses, downregulation of regulatory T cells, induction of IL-17+ γδ T cells, inhibition of oligodendrocyte maturation, induction of poly ADP-ribose polymerase-1 (PARP-1)-dependent pathway in microglia, macrophages and astrocytes and inhibition of type I interferons expression. The contribution of TLR2-related immunopathological responses in the MS and EAE pathogenesis and its possible targeting as promising therapeutic potentials are considered in this review.
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http://dx.doi.org/10.18502/ijaai.v18i3.1117DOI Listing
June 2019

The Oral Administration Effect of Drug Mannuronic Acid (M2000) on Gene Expression of Matrix and Tissue Inhibitor of Metalloproteinases in Rheumatoid Arthritis Patients.

Curr Drug Discov Technol 2020 ;17(5):704-710

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

Background: Rheumatoid Arthritis (RA) is a complex disease involving an unknown number of genes, and affecting a large number of organs, tissues, and sites across the body. It is affecting approximately 1% of the population worldwide. The safety and therapeutic efficacy of β-D-mannuronic acid (M2000) as a novel NSAID with immunosuppressive property has been demonstrated under in vitro, in vivo examinations and clinical trials phase 1/11 in Ankylosing Spondylitis (AS) patients in addition to phase I/11 and 111 in Rheumatoid Arthritis (RA) patients.

Objective: In this study, our goal is to evaluate the therapeutic efficacy of oral administration of M2000 on gene expression of the matrix metalloproteinase (MMP2, MMP9) and tissue inhibitor of metalloproteinase (TIMP1, TIMP2) as inflammatory molecules in the progression of rheumatoid arthritis.

Methods: The study has included 15 RA patients who had an insufficient response to the conventional drug. Therefore, mannuronic acid was used as an additive to the conventional regime. The research was a single-blinded study. The dose of M2000 was 500mg orally twice per day for 12 weeks. There were 15 healthy participants considered as control. Blood samples have been collected from both groups once from the healthy control and twice from RA patients before and after treatment with M2000. The Peripheral Blood Mononuclear Cells (PBMCs) were isolated for assessment of the gene expression level of MMP2, MMP9, TIMP1, and TIMP2 using the real-time PCR method.

Results: The gene expression level of MMP2 and MMP9 reported a significant reduction in RA patients after treatment with M2000 compared to before treatment. On the other hand, the gene expression level of TIMP2 demonstrated a significant increase in RA patients after treatment with mannuronic acid compared to before treatment, but there was no significant difference between the group of RA patients before treatment and the control group. Vice versa to other molecules, there was no significant difference in the level of TIMP1 in compression with RA patients before and after treatment.

Conclusion: our findings proved that the β -D- mannuronic acid) as a novel NSAID with immunosuppressive property has a significant effect on the gene expression level of MMP2, MMP9 and TIMP2 molecules in RA patients.
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http://dx.doi.org/10.2174/1570163816666190620113320DOI Listing
January 2020

Vitamin D suppresses cellular pathways of diabetes complication in liver.

Iran J Basic Med Sci 2019 Jun;22(6):690-694

Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran.

Objectives: The aim of this study was to investigate the effect of vitamin D on glucose metabolism, as well as the expression of five key genes involved in the development of diabetes complications in liver tissue of diabetic rats.

Materials And Methods: Twenty-four male Sprague-Dawley rats were randomly divided into three groups (8 rats in each group). The first group served as control and the other two groups received an intraperitoneal injection of 45 mg/kg streptozotocin to develop diabetes. Groups were treated for four weeks either with placebo or vitamin D (two injections of 20000 IU/kg). Thereafter, serum levels of glucose, insulin and HbA1c were assessed. Liver tissue was examined for the level of advanced glycation end products (AGEs) and the gene expression of AGE cellular receptor (AGER), glyoxalase-1 (GLO-1), aldose reductase (AR), O-linked N-acetylglucosamine transferase (OGT) and glutamine/ fructose-6-phosphate aminotransferase (GFAT).

Results: Vitamin D injection resulted in a significant increase in plasma level of 25-hydroxycholecalciferol, which could improve hyperglycemia about 11% compared to placebo-receiving diabetic rats (=0.005). Insulin level increased as a result of vitamin D treatment compared to control (3.31±0.65 vs. 2.15±0.79; = 0.01). Serum HbA1c and liver AGE concentrations had a slight but insignificant reduction following vitamin D intake. Moreover, a significant decline was observed in gene expression of AGER and OGT in liver tissue (=0.04 and <0.001 respectively).

Conclusion: Vitamin D might contribute in ameliorating diabetes complications not only by improving blood glucose and insulin levels, but also by suppressing AGER and OGT gene expression in the liver.
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http://dx.doi.org/10.22038/ijbms.2019.36054.8584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570757PMC
June 2019

Vitamin D downregulates key genes of diabetes complications in cardiomyocyte.

J Cell Physiol 2019 11 7;234(11):21352-21358. Epub 2019 Jun 7.

Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran.

Objective: Vitamin D deficiency has been reported to be associated with the incidence of type 1 and type 2 diabetes and worsening of diabetes complications. This study was designed to investigate the effect of vitamin D treatment on the expression of five key genes involved in the development of diabetic cardiomyopathy.

Methods: Twenty-four male Sprague-Dawley rats were randomly divided into three groups. The first group served as control and the other two groups received an intraperitoneal injection of 45 mg/kg streptozotocin (STZ) to develop diabetes. Then groups were treated for 4 weeks either with placebo or vitamin D (two injections of 20,000 IU/kg). Serum levels of glucose, insulin, HbA1c, and advanced glycation end products (AGEs), as well as the gene expression of AGE cellular receptor (RAGE), glyoxalase, aldose reductase, O-GlcNAc transferase (OGT), and glutamine-fructose-6-phosphate aminotransferase (GFAT) and nuclear factor-kB (NF-kB) activity of nuclear extracts were assessed at the end of experiment.

Results: Increment in serum cholecalciferol could improve hyperglycaemia and hypoinsulinemia in diabetic rats. In addition, a significant reduction was observed in RAGE, OGT, and GFAT gene expression and NF-kB activity in cardiac myocytes.

Conclusions: Vitamin D might contribute in reducing diabetic cardiomyopathy not only by improving blood glucose and insulin levels but also via downregulating AGE and hexosamine pathways and decreasing NF-kB activity in heart tissue.
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http://dx.doi.org/10.1002/jcp.28743DOI Listing
November 2019

The safety and efficacy of Guluronic acid (G2013) in ankylosing spondylitis: A randomized controlled parallel clinical trial.

Pharmacol Rep 2019 Jun 10;71(3):393-398. Epub 2019 Feb 10.

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

Background: To assess the therapeutic efficacy, safety and tolerability of Guluronic acid (G2013) in patients with ankylosing spondylitis (AS) patients.

Methods: This investigation was a 12-week randomized, placebo-controlled, phase I/II clinical trial involving 75 AS patients that were randomly divided into 3 groups: 25 as placebo, 25 Guluronic acid and 25 naproxen groups. Patients who had AS with active disease at baseline according to the modified New York criteria were considered for this trial. The primary consequence measure was the Appraisement of Spondyloarthritis International Society (ASAS) 20 response-rate at week 12.

Results: There were no statistically significant differences between groups at the entry. ASAS20 response at week 12 was achieved (60.8%) in patients receiving Guluronic acid compared with - (68.4% of) - patients in the naproxen group (p > 0.05) and (21.0%) of patients in the placebo group. In comparison with the placebo group from the baseline to week 12, patients who received Guluronic acid and naproxen showed significantly greater improvement in all secondary endpoints. Moreover, Guluronic acid decreased some inflammatory parameters more dramatically than naproxen and placebo group. Patients in the naproxen group had more incidence of gastrointestinal and others adverse events in comparison with Guluronic acid and placebo groups.

Conclusion: The present research indicated that Guluronic acid and naproxen are similar in terms of efficacy. However, Guluronic acid had more notable safety characteristics identifying information than naproxen. Accordingly, it is proposed that Guluronic acid could be appropriate for management of AS. Clinical trial identifier; IRCT2016091813739N4.
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http://dx.doi.org/10.1016/j.pharep.2019.02.002DOI Listing
June 2019

Vaccine potential of LenA and LcpA proteins of in combination with heat-labile enterotoxin, B subunit (LTB).

Iran J Microbiol 2019 Feb;11(1):39-47

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

Background And Objectives: Leptospirosis is a zooanthroponosis caused by the genus of . It is an emerging public health problem due to its increasing incidence. The achievement to a vaccine that prevent from entrance of to the deeper tissues of the host is needed. This study aimed to investigate the immunogenicity of LcpA (rLcpA) and LenA (rLenA) recombinant proteins in combination with LTB (rLTB) recombinant protein as an adjuvant against leptospiral infection in hamsters.

Materials And Methods: The genes encoding these proteins were cloned into pGH cloning vector and then and genes subcloned into pET-15b and pET-28a expression vectors, respectively. The hamsters were immunized with the purified recombinant proteins and challenged with for evaluation of their survival. The antibody responses to the recombinant proteins were determined by ELISA. Then, data entered into SPSS software. Statistical Kruskal-Wallis test was used to compare the significant differences among different groups. The groups with significant differences were further analyzed by post hoc tests. The value < 0.05 statistically was considered significant.

Results: Immunized hamsters with rLenA-plus-rLTB, rLcpA-plus-rLTB and rLenA-plus-rLcpA-plus-rLTB proteins showed 60%, 74%, and 80% survival rates, respectively. A significant amount of interleukin-17 (IL-17), interleukin-4 (IL-4) and gamma interferon (IFNγ) cytokines were produced in immunized hamsters.

Conclusion: Based on our findings, rLcpA and rLenA proteins in combination with rLTB can protect the hamsters against and effectively induce a protective antibody response. Thus, these proteins can be used as an additional prophylactic tool against leptospira.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462271PMC
February 2019

Downregulation of A2AR by siRNA loaded PEG-chitosan-lactate nanoparticles restores the T cell mediated anti-tumor responses through blockage of PKA/CREB signaling pathway.

Int J Biol Macromol 2019 Jul 30;133:436-445. Epub 2019 Mar 30.

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:

Adenosine and its receptors are novel promising targets for cancer immunotherapy. In here, we aimed to evaluate the efficacy of Polyethylene glycol (PEG)-chitosan-lactate (PCL) nanoparticles (NPs) loaded with A2AR-specific siRNA for interfering with differentiation and function of T cells derived from the 4T1 breast tumor-bearing Balb/C mice, ex vivo. The size of synthesized NPs was about 100 nm in association with low polydispersive index (pdi < 0.3) and a zeta potential of 11 mV. In association with good physicochemical characteristics, NPs exhibited high transfection efficiency in T cells and low toxicity on the various cell lines. T cells were treated with A2AR siRNA-loaded NPs demonstrated suppressed expression of A2AR which was associated with increased proliferation, reduced apoptosis, increased production of inflammatory and reduced secretion of inhibitory cytokines compared to untreated T cells. Moreover, differentiation of conventional T cells purified from tumor-bearing mice to regulatory T cells (Treg) was blocked using A2AR-specific siRNA-loaded NPs. These immune-stimulatory effects were in part through downregulation of protein kinase A/cAMP-response element binding protein (PKA/CREB) axis and upregulation of nuclear factor-κB (NF-κB).
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http://dx.doi.org/10.1016/j.ijbiomac.2019.03.223DOI Listing
July 2019

A randomized, controlled, phase II clinical trial of β-D-mannuronic acid (M2000) in pre-surgical breast cancer patients at early stage (T1-T2).

Clin Exp Pharmacol Physiol 2019 06;46(6):527-532

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

Following the potent efficacy of β-D-Mannuronic acid in a breast cancer murine model, we evaluated the efficacy of this novel non-steroidal anti-inflammatory drug in breast cancer patients in the present clinical trial. The study was an 8-week randomized, controlled, phase II clinical trial (IRCT: 2017012213739N7 (in 48 pre-surgical breast cancer patients. Patients who had breast cancer at early stage, with invasive ductal carcinoma, were placed on a waiting-list for surgery and were allocated to the study. β-D-Mannuronic was administrated at a dose of two capsules (1000 mg/d) orally during a period of 8 weeks. The end point of this study was when the patients were admitted for surgery. Moreover, the patients' well-being status was followed up on for safety. There were no statistically significant differences between treatment and non-treatment groups at baseline. β-D-Mannuronic acid therapy, from 20 patients, showed that in one patient (5%) tumour size was decreased; in five patients (25%) tumour growth was stopped; and in 14 patients (70%) the growth rate in the treatment group did not show significant change, compared to the non-treatment group. Evaluation of two tumour markers (carcinoembryonic antigen and cancer antigen 15-3) showed that there was no significant difference between before and after treatment. Although the use of some non-steroidal anti-inflammatory drugs in a long time period has shown a prophylactic effect in breast cancer, their therapeutic efficacy in a short time period is unknown, whereas treatment with β-D-Mannuronic acid during 8 weeks could show 30% therapeutic effects in pre-surgical breast cancer patients.
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http://dx.doi.org/10.1111/1440-1681.13086DOI Listing
June 2019

The Anti-tumoral Effect of β-D-Mannuronic Acid (M2000) as a Novel NSAID on Treg Cells Frequency and MMP-2, MMP-9, CCL22 and TGFβ1 Gene Expression in Pre-surgical Breast Cancer Patients.

Iran J Allergy Asthma Immunol 2019 Feb;18(1):80-90

Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran AND Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

With respect to the role of chronic inflammation in the induction and progression of breast cancer (BC). The relationship between tumor and tumor microenvironment may be a hopeful strategy for BC therapy. According to the effect of β-D-Mannuronic acid (M2000) as a novel non-steroidal anti-inflammatory drug (NSAID) on BC murine model and 4T1 cell line, we started to study that was a phase II, randomized, controlled clinical trial. 24 women with BC were included in this study and were followed by fixed oral doses of M2000, 500 mg two times a day (6-8 weeks). Blood samples were collected at baseline and weeks 6-8. To compare the patterns of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), C-C motif chemokine ligand 22 (CCL22) and The transforming growth factor-beta 1 (TGFβ1) gene expression and T regulatory cells (Tregs) frequency of healthy women normal controls with BC patients, a set of 10 blood samples of  women healthy volunteers was collected. The gene expression was evaluated by quantitative Real-time PCR (qRT-PCR) and the frequency of Tregs was assessed by flow cytometry. Our results showed, reduction in MMP-2 (p=0.08), MMP-9 (p=0.03), CCL22 (p=0.003) and TGFβ1 (p=0.1) gene expression and Tregs frequency (p=0.01) which play a main role in the development of chronic inflammation, angiogenesis, tumorigenesis and metastasis. Our findings demonstrated that M2000 therapy as a novel designed NSAID had valuable therapeutic effects on BC. No adverse effects were observed following the use of M2000 after 6-8 weeks.
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February 2019

The Effect of Vitamin D on Cellular Pathways of Diabetic Nephropathy.

Rep Biochem Mol Biol 2019 Jan;7(2):217-222

Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran.

Background: Diabetic nephropathy is one of the most important microvascular complications and a major cause of morbidity and mortality in diabetic patients. This study was designed to investigate the effect of vitamin D on the expression of three key genes involved in the development of diabetic nephropathy.

Methods: Twenty-four male Sprague-Dawley rats were randomly divided into three groups. The first group served as control and the other two groups received intraperitoneal injections of 45 mg/kg STZ to develop diabetes. The groups were treated for four weeks either with placebo or two vitamin D injections of 20,000 IU/kg. Serum glucose, insulin, and HbA1c levels, and AGE cellular receptor (), aldose reductase () and glutamine: fructose-6-phosphate aminotransferase () gene expression were assessed in kidney tissue at the end of the experiment.

Results: Vitamin D treatment resulted in a significant increase in insulin concentration, which could improve hyperglycaemia in diabetic rats. Serum HbA1c decreased slightly but insignificantly following the vitamin D injections. In addition, expression of , a key regulatory enzyme in the hexosamine pathway, was significantly reduced following vitamin D administration.

Conclusion: Vitamin D may reduce diabetic nephropathy not only by improving blood glucose and insulin levels, but also by modulating hexosamine pathways in kidney.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374056PMC
January 2019

Antagonistic Property of G2013 (α-L-Guluronic Acid) on Gene Expression of MyD88, Tollip, and NF-κB in HEK293 TLR2 and HEK293 TLR4.

Endocr Metab Immune Disord Drug Targets 2019 ;19(2):144-149

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Introduction: Inhibition of Toll-like receptors (TLRs) signaling plays a crucial role in suppressing the inflammation and available data presenting G2013 as an immunomodulatory agent, therefore, we designed this study to answer whether G2013 can affect the signaling pathway of TLR2 and TLR4.

Methods: Cytotoxicity study of G2013 was performed by MTT assay. HEK293 TLR2 and HEK293 TLR4 cell lines were cultured and treated with low dose (5µg/ml) and high dose (25µg/ml) of G2013 for 24 hours. Gene expressions of MyD88, Tollip, and NF-κB were defined by quantitative real-time PCR.

Results: The cytotoxicity assay showed that the concentrations lesser than 125μg/ml of G3012 had no apparent cytotoxicity, however, the concentrations of 5µg/ml and 25µg/ml could suppress the mRNA expression of MyD88, Tollip and NF-κB in HEK293 TLR2 and HEK293 TLR4 cell lines.

Conclusion: in our study, we verified the linkage between the immunosuppressive property of G2013 and TLR2, TLR4 signaling cascade; but so far, the specific target of G2013 and its molecular mechanism has not been detected yet. We recommend further studies on other Patten Recognition Receptors (PRRs)and other mechanisms of inflammation like oxidative stress to be conducted in the future.
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http://dx.doi.org/10.2174/1871530319666181126153752DOI Listing
June 2019