Publications by authors named "Farhad Jadidi-Niaragh"

178 Publications

Simultaneous silencing of the A2aR and PD-1 immune checkpoints by siRNA-loaded nanoparticles enhances the immunotherapeutic potential of dendritic cell vaccine in tumor experimental models.

Life Sci 2021 Nov 20;288:120166. Epub 2021 Nov 20.

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:

Following various immunotherapies, lack of proper anti-tumor immune responses is considered a significant problem in novel cancer therapeutic approaches. The expression of inhibitory checkpoint molecules on tumor-infiltrating T cells is one of the main reasons for the ineffectiveness of various immunotherapies. Therefore, we decided to inhibit two of the most important immune checkpoints expressed on tumor-associated T cells, PD-1 and A2aR. Ligation of PD-1 with PD-L1 and A2aR with adenosine significantly suppress T cell responses against tumor cells. Whitin tumors, specific inhibition of these molecules on T cells is of particular importance for successful immunotherapy as well as the elimination of treatment-associated side-effects. Thus, in this study, superparamagnetic iron oxide (SPION) nanoparticles (NPs) were covered by chitosan lactate (CL), functionalized with TAT peptide, and loaded with siRNA molecules against PD-1 and A2aR. Appropriate physicochemical properties of the prepared NPs resulted in efficient delivery of siRNA to tumor-derived T cells and suppressed the expression of A2aR and PD-1, ex vivo. T cell functions such as cytokine secretion and proliferation were considerably enhanced by the downregulation of these molecules which led to an increase in their survival time. Interestingly, treatment of CT26 and 4T1 mouse tumors with siRNA-loaded NPs not only inhibited tumor growth but also markedly increased anti-tumor immune responses and survival time. The results strongly support the efficacy of SPION-CL-TAT NPs loaded with anti-PD-1/A2aR siRNAs in cancer therapy and their further development for cancer patients in the near future.
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http://dx.doi.org/10.1016/j.lfs.2021.120166DOI Listing
November 2021

Simultaneous blockade of TIGIT and HIF-1α induces synergistic anti-tumor effect and decreases the growth and development of cancer cells.

Int Immunopharmacol 2021 Oct 29;101(Pt A):108288. Epub 2021 Oct 29.

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

Purpose: T-cell immunoglobulin and ITIM domain (TIGIT) is an immune checkpoint that is overexpressed on both immune cells and some cancer cells. TIGIT can alter the anti-tumor responses inside the tumor microenvironment. Hypoxia-inducible factor 1-alpha (HIF-1α) plays a significant role in the TME and involves suppressing the anti-tumor responses. Under hypoxic conditions, HIF-1α can enhance the expression of different immune checkpoints. Accordingly, hypoxic TME and TIGIT overexpression cause cancer development. Thus, we decided to inhibit tumor cell expansion by inhibiting TIGIT and HIF-1α molecules and discovering the relationship between TIGIT and HIF-1α.

Methods: In this research, we utilized superparamagnetic iron oxide-based NPs (SPIONs) combined with chitosan lactate (CL) and folic acid (FA) nanoparticles (NPs) loaded with TIGIT-siRNA and HIF-1α- siRNA for suppressing TIGIT and HIF-1α in tumor cells and evaluated the consequences of this treatment strategy on tumor growth, apoptosis, and metastasis.

Results: The results showed that cancer cells treated with TIGIT and HIF-1α siRNA-loaded SPIONs-CL-FA NPs, strongly suppressed the TIGIT and HIF-1α expression, colony formation ability, angiogenesis, and the growth rate of cancer cells.

Conclusions: Present data suggest the combination treatment of TIGIT and HIF-1α as a novel treatment strategy against colorectal and breast cancer, but more researches are required to realize the complete role of TIGIT and HIF-1α inside the TME.
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http://dx.doi.org/10.1016/j.intimp.2021.108288DOI Listing
October 2021

The molecular mechanisms and therapeutic potential of EZH2 in breast cancer.

Life Sci 2021 Dec 13;286:120047. Epub 2021 Oct 13.

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

Due to its high occurrence and mortality rate, breast cancer has been studied from various aspects as one of the cancer field's hot topics in the last decade. Epigenetic alterations are spoused to be highly effective in breast cancer development. Enhancer of zeste homolog 2 (EZH2) is an enzymatic epi-protein that takes part in most vital cell functions by its different action modes. EZH2 is suggested to be dysregulated in specific breast cancer types, particularly in advanced stages. Mounting evidence revealed that EZH2 overexpression or dysfunction affects the pathophysiology of breast cancer. In this review, we discuss biological aspects of the EZH2 molecule with a focus on its newly identified action mechanisms. We also highlight how EZH2 plays an essential role in breast cancer initiation, progression, metastasis, and invasion, which emerged as a worthy target for treating breast cancer in different approaches.
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http://dx.doi.org/10.1016/j.lfs.2021.120047DOI Listing
December 2021

PD-1/PD-L1 blockade: Prospectives for immunotherapy in cancer and autoimmunity.

IUBMB Life 2021 11;73(11):1293-1306

Department of Immunology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.

Immune checkpoint blockade therapy (ICBT) has become a successful cancer treatment approach in the field of cancer immunotherapy. Blockade of programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) with monoclonal antibodies have been known as successful examples of cancer immunotherapy in recent years. Although ICBT has been shown to be beneficial in cancers, such benefits have only been seen in a portion of cancer patients. In this regard, enhancing the therapeutic effects of inhibiting PD-1 and PD-L1 and reducing the side effects of this approach can be considered as a potential approach in a successful ICBT. In this review, we have highlighted new viewpoints regarding improving the therapeutic effect of PD-1 and PD-L1 blockades in cancer therapy. Besides, their expression levels as a biomarker with prognostic value, their role in intestinal microbiota modulation, combination therapy, and immune-related side effects (irAEs) have been discussed.
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http://dx.doi.org/10.1002/iub.2558DOI Listing
November 2021

Matrix metalloproteinases are involved in the development of neurological complications in patients with Coronavirus disease 2019.

Int Immunopharmacol 2021 Nov 17;100:108076. Epub 2021 Aug 17.

Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran; Department of Immunology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran. Electronic address:

Background: Evidence show that Matrix metalloproteinases (MMPs) have been associated with neurological complications in the viral infections. Here in the current investigation, we intended to reveal if MMPs are potentially involved in the development of neurological symptoms in the patients with Coronavirus disease 2019 (COVID-19).

Methods: The levels of MMPs, inflammatory cytokines, chemokines, and adhesion molecules were evaluated in the serum and cerebrospinal fluid (CSF) samples from 10 COVID-19 patients with neurological syndrome (NS) and 10 COVID-19 patients lacking NS. Monocytes from the CSF samples were treated with TNF-α and the secreted levels of MMPs were determined.

Results: The frequency of monocytes were increased in the CSF samples of COVID-19 patients with NS compared to patients without NS. Levels of inflammatory cytokines IL-1β, IL-6, and TNF-α, chemokines CCL2, CCL3, CCL4, CCL7, CCL12, CXCL8, and CX3CL1, MMPs MMP-2, MMP-3, MMP-9, and MMP-12, and adhesion molecules ICAM-1, VCAM-1, and E-selectin were significantly increased in the CSF samples of COVID-19 patients with NS compared with patients without NS. Treatment of CSF-derived monocytes obtained from COVID-19 patients with NS caused increased production of MMP-2, MMP-3, MMP-9, and MMP-12.

Conclusions: Higher levels of inflammatory cytokines might promote the expression of adhesion molecules on blood-CSF barrier (BCSFB), resulting in facilitation of monocyte recruitment. Increased levels of CSF chemokines might also help to the trafficking of monocytes to CSF. Inflammatory cytokines might enhance production of MMPs from monocytes, leading to disruption of BCSFB (and therefore further infiltration of inflammatory cells to CSF) in COVID-19 patients with NS.
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http://dx.doi.org/10.1016/j.intimp.2021.108076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367754PMC
November 2021

Arctigenin, an anti-tumor agent; a cutting-edge topic and up-to-the-minute approach in cancer treatment.

Eur J Pharmacol 2021 Oct 12;909:174419. Epub 2021 Aug 12.

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

Today, herbal-derived compounds are being increasingly studied in cancer treatment. Over the past decade, Arctigenin has been introduced as a bioactive dibenzylbutyrolactone lignan which is found in Chinese herbal medicines. In addition to anti-microbial, anti-inflammatory, immune-modulatory functions, Arctigenin has attracted growing attention due to its anti-tumor capabilities. It has been shown that Arctigenin can induce apoptosis and necrosis and abolish drug resistance in tumor cells by inducing apoptotic signaling pathways, caspases, cell cycle arrest, and the modulating proteasome. Moreover, Arctigenin mediates other anti-tumor functions through several mechanisms. It has been demonstrated that Arctigenin can act as an anti-inflammatory compound to inhibit inflammation in the tumor microenvironment. It also downregulates factors involved in tumor metastasis and angiogenesis, such as matrix metalloproteinases, N-cadherin, TGF-β, and VEGF. Additionally, Arctigenin, through modulation of MAPK signaling pathways and stress-related proteins, is able to abolish tumor cell growth in nutrient-deprived conditions. Due to the limited solubility of Arctigenin in water, it is suggested that modification of this compound through amino acid esterification can improve its pharmacogenetic properties. Collectively, it is hoped that using Arctigenin or its derivates might introduce new chemotherapeutic approaches in future treatment.
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http://dx.doi.org/10.1016/j.ejphar.2021.174419DOI Listing
October 2021

Targeting Wee1 kinase as a therapeutic approach in Hematological Malignancies.

DNA Repair (Amst) 2021 11 8;107:103203. Epub 2021 Aug 8.

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:

Hematologic malignancies include various diseases that develop from hematopoietic stem cells of bone marrow or lymphatic organs. Currently, conventional DNA-damage-based chemotherapy drugs are approved as standard therapeutic regimens for these malignancies. Although many improvements have been made, patients with relapsed or refractory hematological malignancies have a poor prognosis. Therefore, novel and practical therapeutic approaches are required for the treatment of these diseases. Interestingly several studies have shown that targeting Wee1 kinase in the Hematological malignancies, including AML, ALL, CML, CLL, DLBCL, BL, MCL, etc., can be an effective therapeutic strategy. It plays an essential role in regulating the cell cycle process by abrogating the G2-M cell-cycle checkpoint, which provides time for DNA damage repair before mitotic entry. Consistently, Wee1 overexpression is observed in various Hematological malignancies. Also, in healthy normal cells, repairing DNA damages occurs due to G1-S checkpoint function; however, in the cancer cells, which have an impaired G1-S checkpoint, the damaged DNA repair process depends on the G2-M checkpoint function. Thus, Wee1 inhibition could be a promising target in the presence of DNA damage in order to potentiate multiple therapeutic drugs. This review summarized the potentials and challenges of Wee1 inhibition combined with other therapies as a novel effective therapeutic strategy in Hematological malignancies.
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http://dx.doi.org/10.1016/j.dnarep.2021.103203DOI Listing
November 2021

Adenosine: The common target between cancer immunotherapy and glaucoma in the eye.

Life Sci 2021 Oct 8;282:119796. Epub 2021 Jul 8.

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

Adenosine, an endogenous purine nucleoside, is a well-known actor of the immune system and the inflammatory response both in physiologic and pathologic conditions. By acting upon particular, G-protein coupled adenosine receptors, i.e., A1, A2- a & b, and A3 receptors mediate a variety of intracellular and immunomodulatory actions. Several studies have elucidated Adenosine's effect and its up-and downstream molecules and enzymes on the anti-tumor response against several types of cancers. We have also targeted a couple of molecules to manipulate this pathway and get the immune system's desired response in our previous experiences. Besides, the outgrowth of the studies on ocular Adenosine in recent years has significantly enhanced the knowledge about Adenosine and its role in ocular immunology and the inflammatory response of the eye. Glaucoma is the second leading cause of blindness globally, and the recent application of Adenosine and its derivatives has shown the critical role of the adenosine pathway in its pathophysiology. However, despite a very promising background, the phase III clinical trial of Trabodenoson failed to achieve the non-inferiority goals of the study. In this review, we discuss different aspects of the abovementioned pathway in ophthalmology and ocular immunology; following a brief evaluation of the current immunotherapeutic strategies, we try to elucidate the links between cancer immunotherapy and glaucoma in order to introduce novel therapeutic targets for glaucoma.
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http://dx.doi.org/10.1016/j.lfs.2021.119796DOI Listing
October 2021

Blockade of CD73 using siRNA loaded chitosan lactate nanoparticles functionalized with TAT-hyaluronate enhances doxorubicin mediated cytotoxicity in cancer cells both in vitro and in vivo.

Int J Biol Macromol 2021 Sep 7;186:849-863. Epub 2021 Jul 7.

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:

Chemotherapy drugs are still one of the first treatment options used in many cancers; however, problems such as cytotoxic side effects on normal cells after systemic administration and resistance to treatment have reduced the use of chemotherapeutics day by day. Targeted delivery of these drugs to the tumor site and sensitization of cancer cells to death induced by chemotherapy drugs are ways that can overcome the limitations of the use of these drugs. In this study, we designed and generated a novel nanocarrier composed of chitosan lactate nanoparticles (NPs) functionalized by HIV-1 derived TAT peptide (Transactivating transcriptional activator) and hyaluronate (HA) to deliver CD73 siRNA and doxorubicin to 4T1 and CT26 cancer cells, both in vivo and in vitro, as a novel combinatorial treatment strategy. The CD73 molecule plays a key role in many cancer cell behaviors such as proliferation, angiogenesis, metastasis, imunosuppression, and resistance to chemotherapy. Therefore, we decided to reduce the side effects of DOX by simultaneously transmitting CD73 siRNA and DOX by CL-TAT-HA NPs, increase the susceptibility of cancer cells to DOX-induced cell death, and stimulate anti-tumor immune responses, for the first time. These results indicated that simultaneous transfer of CD73 siRNA and DOX to cancer cells (4 T1 and CT26) increased cell death and inhibited the prolifration and spread of cancer cells. Also, the preferential aggregation of NPs in the tumor microenvironment reduced tumor growh, promoted the survival of tumor-bearing mice, and induced anti-tumor immune responses. These findings indicate that CL-TAT-HA NPs are a good candidate for targeted siRNA/drug delivery to cancer cells and the simultaneous transfer of CD73 siRNA and DOX to cancer cells using this nanocarrier can be used to treat cancer.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.07.034DOI Listing
September 2021

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

Hum Immunol 2021 Oct 1;82(10):733-745. Epub 2021 Jul 1.

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

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

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

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

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

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

Application of newly developed SARS-CoV2 serology test along with real-time PCR for early detection in health care workers and on-time plasma donation.

Gene Rep 2021 Jun 13;23:101140. Epub 2021 Apr 13.

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

Background: As the daily number of coronavirus infection disease 19 (COVID19) patients increases, the necessity of early diagnosis becomes more obvious. In this respect, we aimed to develop a serological test for specifically detecting anti-SARS-CoV2 antibodies.

Methods: We collected serum and saliva samples from 609 individuals who work at TBZMED affiliated hospitals in Tabriz, Iran, from April to June of 2020. Real-time PCR technique was used to detect SARS-CoV-2 genome using specific primers. An enzyme linked immunosorbent assay (ELISA) test was designed based on virus nucleocapsid (N), spike (S) and its receptor binding domain (RBD) protein, and the collected sera were subjected to IgM and/or IgG analysis.

Result: Real-time PCR results showed that 66 people were infected with the SARS-CoV-2. Our designed ELISA kit showed 93.75% and 98% of sensitivity and specificity, respectively. In this study, 5.74% of participants had specific IgG against RBD, whereas the percentage for IgM positive individuals was 5.58%. Approximately the same results were observed for S protein. The number of positive participants for NP increased further, and the results of this antigen showed 7.38% for IgG and 7.06% for IgM.

Conclusion: The ELISA test beside real-time PCR could provide a reliable serologic profile for the status of the disease progress and early detection of individuals. More importantly, it possesses the potential to identify the best candidates for plasma donation according to the antibody titers.
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http://dx.doi.org/10.1016/j.genrep.2021.101140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041740PMC
June 2021

TIGIT and CD155 as Immune-Modulator Receptor and Ligand on CD4 T cells in Preeclampsia Patients.

Immunol Invest 2021 Apr 15:1-16. Epub 2021 Apr 15.

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

One of the main characteristics of preeclampsia (PE) is systemic inflammation. CD4 FoxP3 cells play a critical role in both fetomaternal tolerance and successful pregnancy. T-cell immunoglobulin, as well as immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT)/CD155 pathway, possesses critical parts in the development of normal pregnancy by promoting regulatory T (Treg) cells. However, in PE, the relationship between TIGIT/CD155 and Treg differentiation has not been entirely clarified. In the current report, we aimed to assess the frequency of TIGIT and CD155 expressing TCD4 cells in both PE and healthy pregnant women, as well as evaluating the amount of inflammatory and inhibitory cytokines at both mRNA and protein levels before and after blocking TIGIT and CD155. In the present report, 59 healthy, and 52 PE patients were designated to obtain their venous blood. The isolation of peripheral blood mononuclear cells (PBMCs) was performed from the blood samples, and PBMCs were then cultured in the RPMI1640 medium. The percentage of CD155 and TIGIT CD4 cells was assessed by flow cytometry in PBMCs. Cell culture supernatants were utilized to evaluate the secretory levels of transforming growth factor beta (TGF-β), interleukin (IL)-10, IL-17, tumor necrosis factor alpha (TNF-α), and IL-1 β, using enzyme-linked immunosorbent assay technique in pregnant women with or without PE both before and after blocking TIGIT and CD155. The mRNA expression of Foxp3, TIGIT, CD155, SHP-1, TGF-β, IL-10, IL-17, TNF-α, and IL-1β was also assessed by qRT-PCR in PBMCs before and after blocking TIGIT and CD155 in both populations. The data showed a significant decrease in the frequency of TIGIT CD4 and CD155 CD4 T cells in PE women, compared to the control group. Our results showed decreased protein and mRNA levels of TIGIT, CD155, IL-10, FOXP3, and SHP-1 in PE patients. In addition, significant improvements in the levels of IL-17, TNF-α, and IL-1β were observed in PE patients, as compared with the controls. However, blocking TIGIT and CD155 could increase these inflammatory cytokines and decrease anti-inflammatory cytokines. The data obtained in this report illustrated that there existed an imbalance between inflammatory and anti-inflammatory profiles, with an inflammatory status polarization, in PE patients. Additionally, TIGIT/CD155 showed a positive effect on immune regulation by activating ITIM, demonstrating the potential therapeutic value of the TIGIT/CD155 pathway in PE treatment. Also, using some proteins or materials that increased TIGIT/CD155 pathways activity and can be a therapeutic approach in PE.
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http://dx.doi.org/10.1080/08820139.2021.1904976DOI Listing
April 2021

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

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

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

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

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

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

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

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

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

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

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

Ruxolitinib attenuates experimental autoimmune encephalomyelitis (EAE) development as animal models of multiple sclerosis (MS).

Life Sci 2021 Jul 27;276:119395. Epub 2021 Mar 27.

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

Aims: STAT3 signaling is critical for Th17 development that plays an important role in multiple sclerosis pathogenesis. To evaluate the anti-inflammatory and regulatory T cells effects of JAK1/2 and STAT3 inhibition, we assessed the JAK 1/2 inhibitor ruxolitinib effects on Th17 cell/Tregs balance.

Main Methods: Ruxolitinib was administered to experimental autoimmune encephalomyelitis (EAE) mice via oral gavage, and its effects were assessed. The expression of pro-inflammatory and anti-inflammatory cytokines, including IL-17A and IL-10, were analyzed by real-time PCR. The frequency of Th17 cells and Tregs were evaluated by flow cytometry.

Key Finding: Ruxolitinib ameliorated the EAE severity and decreased the proportion of Th17 cells and inflammatory markers levels. In contrast, the balance of Tregs and the level of anti-inflammatory cytokine were increased in ruxolitinib-treated mice. Furthermore, ruxolitinib markedly decreased the expression of Th17 related transcription factor, RORɣt, whereas FOXP3 expression associated with Treg differentiation was increased.

Significance: Our results show that ruxolitinib may be a promising therapeutic strategy for multiple sclerosis.
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http://dx.doi.org/10.1016/j.lfs.2021.119395DOI Listing
July 2021

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

Nanomedicine 2021 06 24;34:102384. Epub 2021 Mar 24.

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

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

Silencing STAT3 enhances sensitivity of cancer cells to doxorubicin and inhibits tumor progression.

Life Sci 2021 Jun 19;275:119369. Epub 2021 Mar 19.

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:

Aims: Despite extensive efforts to find new treatments, chemotherapy is still one of the first and foremost choices for cancer treatment. The main problems of using these drugs are the resistance of cancer cells and reducing their sensitivity to chemotherapy as well as the side effects of their systemic administration. Because STAT3 plays a very important role in the survival and susceptibility of cancer cells to apoptosis, we hypothesized that suppression of STAT3 expression could induce greater susceptibility to DOX-induced cancer cell death.

Materials And Methods: We used pegylated chitosan lactate nanoparticles (NPs) functionalized by TAT peptide and folate to deliver STAT3 siRNA and DOX to cancer cells simultaneously, both in vitro and in vivo.

Key Findings: The results showed that NPs could effectively deliver siRNA and DOX to cancer cells, which was associated with suppression of STAT3 expression and increased induction of DOX-mediated cell death. Concomitant delivery of DOX and STAT3 siRNA also suppressed tumor growth in 4T1 and CT26 cancer models, which was associated with induction of anti-tumor immune responses.

Significance: These findings suggest that the use of NPs can be an effective strategy for the targeted delivery of STAT3-specific siRNA/DOX to cancer cells.
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http://dx.doi.org/10.1016/j.lfs.2021.119369DOI Listing
June 2021

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

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

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

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

T-cell immunoglobulin and ITIM domain, as a potential immune checkpoint target for immunotherapy of colorectal cancer.

IUBMB Life 2021 05 30;73(5):726-738. Epub 2021 Mar 30.

Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

The importance of the tumor microenvironment in cancer progression has been well studied for many years. Immune checkpoint inhibitors (ICIs) are regarded as potential strategies in enhancing the immune responses in patients with cancer, particularly colorectal cancer (CRC). Notably, CRCs are extraordinarily heterogeneous and mostly are microsatellite-stable (MSS) or cold tumors, which means that the immune response is not usually as strong as that of foreign cells. T-cell immunoglobulin and ITIM domain (TIGIT) is a new immune checkpoint receptor overexpressed inside the CRC tumor-immune microenvironments. Moreover, several studies have shown that TIGIT in combination with other ICIs and/or conventional treatments, can lead to a robust anti-tumor response in CRC. This review looks deep inside TIGIT expression patterns, their various functions, and possible immunotherapy strategies to increase survival rates and decrease immune-related adverse events.
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http://dx.doi.org/10.1002/iub.2461DOI Listing
May 2021

PD-L1 silencing inhibits triple-negative breast cancer development and upregulates T-cell-induced pro-inflammatory cytokines.

Biomed Pharmacother 2021 Jun 2;138:111436. Epub 2021 Mar 2.

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

Triple-negative breast cancer (TNBC) is an invasive tumor with a high incidence of distant metastasis and poor prognosis. In TNBC cells, high PD-L1 expression can induce an immunosuppressive tumor microenvironment, repressing the anti-tumoral immune responses. Although FDA-approved agents targeting the PD-1/PD-L1 axis are potent to eliminate tumoral cells, their immune-related adverse events have become worrisome. As the regulator of gene expression, siRNAs can directly target PD-L1 in breast cancer cells. The gene modification of tumoral PD-L1 can reduce our reliance on the current method of targeting the PD-L1/PD-1 axis. We initiated the study with bioinformatics analysis; the results indicated that TNBC and the MDA-MB-231 cells significantly overexpressed PD-L1 compared to other breast cancer subtypes and cell lines. Our results demonstrated that PD-L1 silencing substantially reduced PD-L1 expression at mRNA and protein levels in MDA-MB-231 cells. Moreover, our results demonstrated that PD-L1 knockdown reduced cancer cell proliferation and induced apoptosis via intrinsic and extrinsic apoptosis pathways. We observed that PD-L1 silencing effectively inhibited the migration of TNBC cells. Further investigation also displayed that silencing of PD-L1 in breast cancer cells induced T-cell cytotoxic function by upregulating the gene expression of pro-inflammatory cytokines, i.e., IL-2, IFN-γ, and TNF-α, and downregulating the gene expression of anti-inflammatory cytokines, i.e., IL-10, and TGF-β, in a co-culture system.
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http://dx.doi.org/10.1016/j.biopha.2021.111436DOI Listing
June 2021

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

Nanomedicine 2021 06 3;34:102373. Epub 2021 Mar 3.

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

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

The role of exosomal non-coding RNAs in aging-related diseases.

Biofactors 2021 May 23;47(3):292-310. Epub 2021 Feb 23.

Neurosciences Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.

Aging is a biological process caused by the accumulation of senescent cells with a permanent proliferative arrest. To the influence of aging on human life expectancy, there is essential for new biomarkers which possibly will assistance in recognizing age-associated pathologies. Exosomes, which are cell-secreted nanovesicles, make available a new biomarker detection and therapeutic approach for the transfer of different molecules with high capacity. Recently, non-coding RNAs (ncRNA) which are contained in exosomes have developed as important molecules regulating the complexity of aging and relevant human diseases. The discovery of ncRNA provided perceptions into an innovative regulatory platform that could interfere with cellular senescence. The non-coding transcriptome includes a different of RNA species, spanning from short ncRNAs (<200 nucleotides) to long ncRNAs, that are >200 bp long. Upgraded evidence displays that targeting ncRNAs possibly will influence senescence pathways. In this article, we will address ncRNAs that participated in age-related and cellular senescence diseases. Growing conception of ncRNAs in the aging process possibly will be responsible for new understandings into the improvement of age-related diseases and elongated life span.
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http://dx.doi.org/10.1002/biof.1715DOI Listing
May 2021

Association of the genetic variants in the endoplasmic reticulum aminopeptidase 2 gene with ankylosing spondylitis susceptibility.

Int J Rheum Dis 2021 Apr 7;24(4):567-581. Epub 2021 Feb 7.

Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.

Background: Genetic polymorphisms in the endoplasmic reticulum aminopeptidase gene ERAP2 has been attributed with the etiopathogenesis of ankylosing spondylitis (AS). Here we assessed the association of ERAP2 gene single nucleotide polymorphisms (SNPs) with AS predisposition in Iranian patients and determined their effect on the inflammatory state of the patients.

Methods: For genotyping of rs2548538, rs2287988, and rs17408150 SNPs using a real-time allelic discrimination approach, DNA was extracted from the whole blood of 250 AS patients and 250 healthy individuals. RNA of the peripheral blood mononuclear cells was separated, cDNA was synthesized, and transcriptional levels of cytokines, including interleukin (IL)-17A, IL-23, IL-10, and transforming growth factor-β, were measured. Enzyme-linked immunosorbent assay was used to measure the serum concentration on the cytokines.

Results: Three ERAP2 gene SNPs were not associated significantly with AS risk. Nonetheless, rs2287988 and rs17408150 SNPs showed statistically significant association with susceptibility to the disease in those AS patients who were positive for human leukocyte antigen (HLA)-B27. Transcriptional level and serum concentration of IL-17A and IL-23 were higher, but those of IL-10 were lower in both AS patients and the HLA-B27-positive patient group relative to the control group. Nevertheless, ERAP2 gene SNPs in the HLA-B27-positive AS patients did not affect the transcription level and serum concentration of cytokines.

Conclusions: ERAP2 gene rs2287988 and rs17408150 SNPs are associated with susceptibility to AS, but they are probably not determining the levels of IL-17A, IL-23, and IL-10 in this disease.
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http://dx.doi.org/10.1111/1756-185X.14079DOI Listing
April 2021

The Role of the IL-33/ST2 Immune Pathway in Autoimmunity: New Insights and Perspectives.

Immunol Invest 2021 Feb 1:1-27. Epub 2021 Feb 1.

Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.

Interleukin (IL)-33, a member of IL-1 cytokine family, is produced by various immune cells and acts as an alarm to alert the immune system after epithelial or endothelial cell damage during cell necrosis, infection, stress, and trauma. The biological functions of IL-33 largely depend on its ligation to the corresponding receptor, suppression of tumorigenicity 2 (ST2). The pathogenic roles of this cytokine have been implicated in several disorders, including allergic disease, cardiovascular disease, autoimmune disease, infectious disease, and cancers. However, alerted levels of IL-33 may result in either disease amelioration or progression. Genetic variations of gene may confer protective or susceptibility risk in the onset of autoimmune diseases. The purpose of this review is to discuss the involvement of IL-33 and ST2 in the pathogenesis of a variety of autoimmune disorders, such as autoimmune rheumatic, neurodegenerative, and endocrine diseases.
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http://dx.doi.org/10.1080/08820139.2021.1878212DOI Listing
February 2021

The role of regulatory T cells in the pathogenesis and treatment of prostate cancer.

Life Sci 2021 Nov 26;284:119132. Epub 2021 Jan 26.

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:

Despite developments in the treatment of various cancers, prostate cancer is one of the deadliest diseases known to men. Systemic therapies such as androgen deprivation, chemotherapy, and radiation therapy have not been very successful in treating this disease. Numerous studies have shown that there is a direct relationship between cancer progression and inhibition of anti-tumor immune responses that can lead to progression of various malignancies, including prostate cancer. Interestingly, CD4CD25FoxP3 regulatory T cells significantly accumulate and increase in draining lymph nodes and PBMCs of patients with prostate cancer and other solid tumors. In vivo and in vitro studies have shown that Tregs can suppress anti-tumor responses, which is directly related to the increased risk of cancer recurrence. Tregs are essential for preserving self-tolerance and inhibiting extra immune responses harmful to the host. Since the tumor-related antigens are mainly self-antigens, Tregs could play a major role in tumor progression. Accordingly, it has discovered that prostate cancer patients with higher Tregs have poor prognosis and low survival rates. However, anti-tumor responses can be reinforced by suppression of Tregs with using monoclonal antibodies against CD25 and CTLA-4. Therefore, depleting Tregs or suppressing their functions could be one of the effective ways for prostate cancer immunotherapy. The purpose of this review is to investigate the role of Treg cells in the progression of prostate cancer and to evaluate effective strategies for the treatment of prostate cancer by regulating Treg cells.
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http://dx.doi.org/10.1016/j.lfs.2021.119132DOI Listing
November 2021

The importance of co-delivery of nanoparticle-siRNA and anticancer agents in cancer therapy.

Chem Biol Drug Des 2021 04 18;97(4):997-1015. Epub 2021 Feb 18.

Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

According to global statistics, cancer is the second leading cause of death worldwide. Because of the heterogeneity of cancer, single-drug therapy has many limitations due to low efficacy. Therefore, combination therapy with two or more therapeutic agents is being arisen. One of the most important approaches in cancer therapy is the shot down of key genes involved in apoptotic processes and cell cycle. In this regard, siRNA is a good candidate, a highly attractive method to suppressing tumor growth and invasion. Combination therapy with siRNAs and chemotherapeutic agents can overcome the multidrug resistance and increase apoptosis. The efficient delivery of siRNA to the target cell/tissue/organ has been a challenge. To overcome these challenges, the presence of suitable delivery systems by using nanoparticles is interesting. In this review, we discuss the current challenges for successful RNA interference. Also, we suggested proper a strategy for delivering siRNA that can be useful in targeting therapy. Finally, the combination of a variety of anticancer drugs and siRNA through acceptable delivery systems and their effects on cell cycle and apoptosis will be evaluated.
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http://dx.doi.org/10.1111/cbdd.13824DOI Listing
April 2021

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

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

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

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

MicroRNAs Implications in the Onset, Diagnosis, and Prognosis of Osteosarcoma.

Curr Mol Med 2021 ;21(7):573-588

Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.

Osteosarcoma (OS) is a primary bone malignancy, which has a high incidence in children and adolescents. The affected cells and tissues show the properties of drug-resistance and the prognosis remains poor in OS; therefore, there is an essential need for novel therapeutic approaches. MicroRNAs (miRNAs) expression pattern has been established to be involved in the pathogenesis of OS. miRNAs are small non-coding RNA molecules, which negatively regulate gene expression at the post-transcriptional level. There are copious miRNAs that have a critical role in the onset of the disease, modulation of disease progression, and response to treatment. At the moment, the recently launched version 3.0 of Human MicroRNA Disease Database (HMDD v3.0) reports that 194 miRNAs are dysregulated in OS that might be involved in proliferation, migration, invasion, and epithelial-mesenchymal transition of tumor cells. The balance between oncogene and tumor suppressor miRNAs has vital importance in the final fate of the cell behaviors in OS. Additionally, networks of miRNAs may act in concert to induce oncogenic or tumor-suppressing properties during the initiation or the progression of OS. Up or down-regulation of these miRNAs affect the status of the disease during or after therapy. To date, over 40 miRNAs have been identified in OS disease that possess oncogenic or tumor-suppressing properties, and treatment approaches are trying to establish a proper level of such miRNAs in favor of OS therapy. The role of miRNAs involved in the pathogenesis of OS and their therapeutic potential are the reference points in this review article.
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http://dx.doi.org/10.2174/1566524020999201203212824DOI Listing
January 2021

Inhibition of HIF-1α/EP4 axis by hyaluronate-trimethyl chitosan-SPION nanoparticles markedly suppresses the growth and development of cancer cells.

Int J Biol Macromol 2021 Jan 20;167:1006-1019. Epub 2020 Nov 20.

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:

Increased expression of Hypoxia-inducible factor-1α (HIF-1α) in the tumor microenvironment, mainly due to tumor growth, plays a major role in the growth of cancer. Tumor cells induce the expression of cyclooxygenase 2 (COX2) and its product, prostaglandin E2 (PGE2), through overexpression of HIF-1α. It has been shown that ligation of PGE2 with its receptor, EP4, robustly promotes cancer progression. HIF-1α/COX2/PGE2/EP4 signaling pathways appear to play an important role in tumor growth. Therefore, we decided to block the expansion of cancer cells by blocking the initiator (HIF-1α) and end (EP4) of this pathway. In this study, we used hyaluronate (HA), and trimethyl chitosan (TMC) recoated superparamagnetic iron oxide nanoparticles (SPIONs) loaded with HIF-1α-silencing siRNA and the EP4 antagonist (E7046) to treat cancer cells and assessed the effect of combination therapy on cancer progression. The results showed that optimum physicochemical characteristics of NPs (size 126.9 nm, zeta potential 27 mV, PDI < 0.2) and linkage of HA with CD44 molecules overexpressed on cancer cells could deliver siRNAs to cancer cells and significantly suppress the HIF-1α in them. Combination therapy of cancer cells by using HIF-1α siRNA-loaded SPION-TMC-HA NPs and E7046 also prevent proliferation, migration, invasion, angiogenesis, and colony formation of the cancer cells, remarkably.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.11.056DOI Listing
January 2021
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