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1.
Mol Biol Rep ; 51(1): 522, 2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38627337

ABSTRACT

BACKGROUND: Multiple sclerosis (MS) is a complex autoimmune disease that affects the central nervous system, causing inflammation, demyelination, and neurodegeneration. Understanding the dysregulation of Tregs, dynamic cells involved in autoimmunity, is crucial in comprehending diseases like MS. However, the role of lymphocyte-activation gene 3 (Lag-3) in MS remains unclear. METHODS: In this study, we explore the potential of exosomes derived from human umbilical cord mesenchymal stem cells (hUMSCs-Exs) as an immune modulator in experimental autoimmune encephalomyelitis (EAE), a model for MS. RESULTS: Using flow cytometry, our research findings indicate that groups receiving treatment with hUMSC-Exs revealed a significant increase in Lag-3 expression on Foxp3 + CD4 + T cells. Furthermore, cell proliferation conducted on spleen tissue samples from EAE mice using the CFSE method exposed to hUMSC-Exs yielded relevant results. CONCLUSIONS: These results suggest that hUMSCs-Exs could be a promising anti-inflammatory agent to regulate T-cell responses in EAE and other autoimmune diseases. However, further research is necessary to fully understand the underlying mechanisms and Lag-3's precise role in these conditions.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Exosomes , Mesenchymal Stem Cells , Multiple Sclerosis , Animals , Humans , Mice , Mesenchymal Stem Cells/metabolism , Umbilical Cord
2.
Drug Deliv Transl Res ; 13(10): 2589-2603, 2023 10.
Article in English | MEDLINE | ID: mdl-37133768

ABSTRACT

The magnetic doxorubicin-encapsulated liposome/PEG/Fe3O4 (called as DOX@m-Lip/PEG) was synthesized and studied as a novel nanocarrier for the treatment of breast cancer in BALB/c mice. Nanocarrier was characterized by FT-IR, zeta-potential sizer, EDX elemental analysis, EDX mapping, TEM, and DLS techniques. The results showed that the size of the nanocarrier was determined around 128 nm by TEM. EDX study confirmed PEG-conjugation in the magnetic liposomes and was homogenously distributed in the nanosize range (100-200 nm) with a negative surface charge (-61.7 mV). The kinetic studies indicated that the release of doxorubicin from DOX@m-Lip/PEG follows the Korsmeyer-Peppas model. The n-value of the model was 0.315, indicating that doxorubicin release from the nanocarrier had a slow releasing rate and followed Fick's law. The DOX release from the nanocarrier lasted a long time (more than 300 h). In in vivo part, a mouse 4T1 breast tumor model was used. The in vivo results indicated that DOX@m-Lip/PEG caused much stronger tumor cell necrosis and less cardiotoxic effects than the other groups. In conclusion, we show that m-Lip/PEG is a promising nanocarrier for low dosage and slow release of doxorubicin in treating breast cancer, and treatment with encapsulated DOX (DOX@m-Lip/PEG) demonstrated higher efficacy with low cardiac toxicity. Besides, the magnetic property of m-Lip@PEG nanocarrier allows it to be a potent mater for hyperthermia and MRI studies.


Subject(s)
Liposomes , Neoplasms , Animals , Mice , Mice, Inbred BALB C , Spectroscopy, Fourier Transform Infrared , Kinetics , Doxorubicin , Polyethylene Glycols , Neoplasms/pathology , Cell Line, Tumor
4.
Int Immunopharmacol ; 119: 110160, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37080068

ABSTRACT

BACKGROUND: Numerous studies have demonstrated the role of T helper (Th) 17 and T regulatory (reg) cells and pro-inflammatory and anti-inflammatory cytokines related to these cells in the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). STAT3 is one of the downstream signaling proteins of IL-23, IL-6, and IL-21 that are required for Th17 cells differentiation. STA-21 is a STAT3 inhibitor that functions by inhibiting STAT3 dimerization and binding to DNA impairing the expression of STAT3 target genes including, RORγt, IL-21 and IL-23R that are also required for Th17 cell differentiation. AIM: In this study, we evaluated the effect of STA-21 on EAE Model and investigated how this small molecule can change Th17/Treg balance leading to amelioration of disease. METHODS: After EAE induction and treatment with STA-21, its effects were assessed. Major assays were H&E and LFB staining, Flow cytometric analysis, Reverse transcription-PCR (RT-PCR), and ELISA. RESULTS: STA-21 ameliorated the EAE severity and decreased the EAE inflammation and demyelination. It also decreased STAT3 phosphorylation, the proportion of Th17 cells and the protein level of IL-17. In contrast, the balance of Tregs and the level of anti-inflammatory cytokine, IL-10 increased in STA-21-treated mice. Moreover, STA-21 significantly decreased the expression of Th17 related transcription factors, RORɣt and IL-23R while FOXP3 expression associated with Treg differentiation was increased. CONCLUSION: This study showed that STA-21 has therapeutic effects in EAE by reducing inflammation and shifting inflammatory immune responses to anti-inflammatory and can be used as a suitable treatment strategy for the treatment of EAE. The effectiveness of inhibiting or strengthening the functional cells of the immune system by these small molecules in terms of easy to access, simple construction and inexpensive expansion make them as a suitable tool for the treatment of inflammatory and autoimmune diseases.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Animals , Mice , Nuclear Receptor Subfamily 1, Group F, Member 3/genetics , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , T-Lymphocytes, Regulatory , Cytokines/metabolism , Inflammation/drug therapy , Anti-Inflammatory Agents/therapeutic use , Th17 Cells , Mice, Inbred C57BL
5.
Colloids Surf B Biointerfaces ; 208: 112091, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34507070

ABSTRACT

The purpose of this study was designing and synthesizing a PLGA formulation targeted with anti-CD40 monoclonal antibody, which has suitable physicochemical properties as a dimethyl fumarate (DMF) drug delivery system having minimal cytotoxicity. Therefore, this research was performed to determine the effect of anti-CD40mAb-DMF-NPs on the expression of IL-1ß, IL-6 and TNF-α cytokine genes in mouse splenocytes. The toxicity of different groups, namely free PLGA, free DMF, DMF-containing PLGA, anti-CD40mAb-DMF-NPs, was evaluated by MTT assay. PLGA formulations conjugated with mAbCD40 were loaded with DMF drug that showed little cytotoxic effect against mouse splenocytes. QRT-PCR method was subsequently used to assess the effect of the mentioned groups on the expression of IL-1ß, TNF-α and IL-6 genes. After treatment of the cells with DMF alone or with polymer carriers, the expression of IL-1ß, IL-6 and TNF-α cytokine genes was significantly reduced. The decrease in expression was markedly higher in the antibody-targeted nanoparticles group relative to other treatment groups. Our results in this area are promising and provide a good basis for further future studies in this regard.


Subject(s)
Dimethyl Fumarate , Nanoparticles , Animals , Dimethyl Fumarate/pharmacology , Drug Carriers , Drug Delivery Systems , Inflammation , Mice , Spleen
6.
Life Sci ; 276: 119395, 2021 Jul 01.
Article in English | MEDLINE | ID: mdl-33781828

ABSTRACT

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, RORÉ£t, whereas FOXP3 expression associated with Treg differentiation was increased. SIGNIFICANCE: Our results show that ruxolitinib may be a promising therapeutic strategy for multiple sclerosis.


Subject(s)
Cytokines/metabolism , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Multiple Sclerosis/drug therapy , Pyrazoles/pharmacology , T-Lymphocytes, Regulatory/drug effects , Th17 Cells/drug effects , Animals , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Mice , Mice, Inbred C57BL , Multiple Sclerosis/immunology , Multiple Sclerosis/metabolism , Multiple Sclerosis/pathology , Nitriles , Pyrimidines , Signal Transduction , T-Lymphocytes, Regulatory/immunology , Th17 Cells/immunology
7.
Immunol Invest ; 50(2-3): 304-321, 2021 Feb.
Article in English | MEDLINE | ID: mdl-32507051

ABSTRACT

Background: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. The present study intends to specify rs1059703, rs4810485, and rs1883832 gene polymorphisms of interleukin-1 receptor-associated kinase (IRAK1) and cluster of differentiation 40 (CD40) in RA. IRAK1 is a serine/threonine kinase and CD40 is a tumor necrosis factor receptor, both of which are involved in RA. There are conflicting results on functional effects of these polymorphisms, so we performed this research for a more accurate estimation on rheumatoid arthritis risk. Methods: Two-hundred RA patients diagnosed according to ACR criteria and 200 normal controls participated in this case-control study. DNA Purification kit (Gene Transfer Pioneers, GTP) was used for genomic DNA extraction and three SNPs, including IRAK1 rs1059703 (C/T), CD40 rs1883832 (C/T) and rs4810485 (G/T), were genotyped by PCR-RFLP. The genotypes and allele frequencies of SNPs were analyzed by chi-square test to detect their contribution to RA. Results: A significant correlation was found between rs1059703 T allele (OR = 2.36, 95% CI = 1.7-3.1, p = .0001) and TT and CT genotypes (TT genotype, OR = 2.54, 95%CI = 1.2-3.3, P = .0078, CT genotype; OR = 2.18 95%CI = 1.4-3.2P = .0002) of rs1059703 C/T polymorphism in terms of susceptibility to RA in recessive and over-dominant models. Alleles and genotypes of CD40 SNPs were not significantly different between RA cases and controls. The findings showed significant differences in rs1059703 IRAK1 genotypes with medical and laboratory features of patients. Conclusion: Our results showed that the rs1059703 T allele (risk allele) of IRAK1 gene increases the risk of RA and the severity of disease, affecting the onset age of RA in Iranian patients.


Subject(s)
Arthritis, Rheumatoid/genetics , Genotype , Interleukin-1 Receptor-Associated Kinases/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Female , Gene Frequency , Genetic Association Studies , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Young Adult
8.
Int Immunopharmacol ; 84: 106572, 2020 Jul.
Article in English | MEDLINE | ID: mdl-32416452

ABSTRACT

Maintaining immune tolerance is a dynamic biological process which is provided by various types of tolerance mechanisms. In the light of the remarkable role of co-inhibitory receptors for switching-off the immune system, the potential impact of these receptors in controlling auto-reactivity is needed to be interrogated. Recent investigations suggested that sustained expression of co-inhibitory receptors in chronic immune responses including cancer and chronic infections can result in immunological consequences called exhaustion. Because of the co-inhibitory receptors, exhaustion confers a potent "switch-off" mechanism for immune response. Using both co-inhibitory receptors and transcription factors in controlling T cells behavior, this review provide an overview of the potential effects of co-inhibitory receptors in maintaining tolerance and discuss how impaired co-inhibitory receptors might results in autoimmunity.


Subject(s)
Immune Tolerance , Receptors, Cell Surface/immunology , T-Lymphocytes/immunology , Transcription Factors/immunology , Animals , Humans
9.
Chem Biol Drug Des ; 95(2): 215-223, 2020 02.
Article in English | MEDLINE | ID: mdl-31512406

ABSTRACT

Ovarian cancer is considered as one of the most lethal gynecological cancers, and cisplatin-based therapy has an important role as the first-line option for chemotherapy. Resistance to chemotherapy is the main obstacle against successful cancer chemotherapy with cisplatin. Therefore, identifying potent compositions and molecules with fewer side-effects is a big challenge to overcome cisplatin resistance. In this study, we investigated the possible mechanism and potency of sanguinarine, a plant-derived alkaloid, in human cisplatin-resistant ovarian cancer (A2780/R) cells. The effect of sanguinarine on cytotoxicity of cisplatin was determined by MTT assay. Apoptosis-inducing effect of sanguinarine alone and in combination with cisplatin was evaluated by annexin V/PI assay and DAPI staining. Intracellular glutathione (GSH) content was quantitated using GSH assay kit after treatment with sanguinarine. Results indicated that sanguinarine enhances the sensitivity of A2780/R cells to cisplatin. Apoptosis-inducing effect of cisplatin was also enhanced when combined with sanguinarine. Furthermore, sanguinarine reduced intracellular GSH content in a dose-dependent but not time-dependent manner. These findings suggest that sanguinarine could reverse cisplatin resistance in A2780/R cells through GSH reduction. Therefore, sanguinarine can be used as one of the potent adjuvants for ovarian cancer chemotherapy.


Subject(s)
Antineoplastic Agents/pharmacology , Benzophenanthridines/pharmacology , Cisplatin/pharmacology , Drug Resistance, Neoplasm/drug effects , Glutathione/metabolism , Isoquinolines/pharmacology , Ovarian Neoplasms/pathology , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Synergism , Female , Humans , Ovarian Neoplasms/metabolism
10.
Res Pharm Sci ; 14(2): 146-154, 2019 Apr.
Article in English | MEDLINE | ID: mdl-31620191

ABSTRACT

T helper (Th)-17 mediate inflammation in both peripheral tissues and the central nervous system. Signal transducer and activator of transcription factor3 (STAT3) is required for Th-cell pathogenicity and its activation in the brain has been demonstrated during the acute phase of experimental autoimmune encephalomyelitis (EAE) through the mammalian target of rapamycin (mTOR) signaling. Rapamycin (RAPA), an inhibitor of mTOR, can drive Forkhead box P3 (FOXP3+) induction as a regulatory factor. The aim of this study was to determine the effects of hemp seed/evening primrose oils (HSO/EPO) supplement on the expression of FOXP3+, STAT3, and interleukin (IL)-17 genes in EAE lymph nodes. EAE was induced by myelin oligodendrocyte glycoprotein peptide in mice, and then the mice were assigned to three treatment groups compared to two control groups (EAE and naive). The histological findings of the spinal cord were evaluated. To determine the expression of FOXP3+, STAT3, and IL-17 genes in the lymphocytes, qRT-PCR was used. Our results showed that EAE severity was reduced in HSO/EPO mice by reducing the expression of STAT3 and IL-17 genes and increasing the expression of FOXP3+ gene, which was confirmed by slight inflammation in the spinal cord. Histological findings showed a significant improvement in the HSO/EPO group. Our findings suggest that the HSO/EPO treatment can be used to ameliorate the demyelination of spinal cord, which was confirmed by immunological and histological findings.

11.
Res Pharm Sci ; 14(4): 308-319, 2019 Aug.
Article in English | MEDLINE | ID: mdl-31516507

ABSTRACT

An increasing trend in the incidence of allergic diseases including asthma and related morbidity and mortality is observed worldwide during the last decades. Allergen-specific immunotherapy is suggested for the treatment of some allergic diseases; nevertheless, there is always a menace of uncommon, but life-treating reactions due to increasing the administration of allergen extract doses. Hence, improving its efficacy may reduce the required doses as well as the risk of such reactions. The current study aimed at examining the effects of nicotine (NIC), as a tolerogenic adjuvant, on the improvement of immunotherapy efficacy in a mouse model of allergic asthma. BALB/c mice were sensitized using alum and ovalbumin (OVA) on the days 0 and 7. Mice received OVA either alone or together with NIC (1 or 10 mg/kg) on the days 21, 23, and 25. Then, the mice were challenged with OVA 5% using a nebulizer on the days 35, 38, and 41 and sacrificed the next day. Co-administration of OVA and NIC decreased the inflammation of the lung tissue, eosinophils count in the bronchoalveolar lavage (BAL) fluid, the serum level of OVA-specific immunoglobulin E, as well as interleukin (IL)-4 production, while increasing the population of antigen-specific regulatory T-cells (Treg cells) and transforming growth factor-ß/IL-4 (TGF-ß/IL-4) ratio compared to the OVA and control groups in a dose-dependent manner. Collectively, the findings suggest that administration of NIC plus the allergen increased immunotherapy efficacy through decreasing allergic inflammation and allergic responses intensity, and increasing Treg cells population.

12.
Res Pharm Sci ; 14(1): 36-45, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30936931

ABSTRACT

The mammalian target of rapamycin (mTOR) signaling plays a critical role in lipid synthesis and immune responses. The T regulatory cells (Treg) as suppressor of T cells, are a subset of T cells that modulate the immune system, maintain tolerance, and prevent autoimmune diseases.. The interleukin (IL) -10 derived from the Treg and T helper (Th) 2 is an anti-inflammatory cytokine in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Due to the exclusive roles of rapamycin (RAPA) in mTOR inhibition, we evaluated the regulatory effect of the hemp seed oil/evening primrose oil (HSO/EPO) supplement in comparison with RAPA in EAE. EAE was induced by using myelin oligodendrocyte glycoprotein peptide and complete freund's adjuvant (CFA) in C57BL/6 mice, total mRNA was extracted from local lymph nodes and real-time polymerase chain reaction was used to evaluate the expression level of the rapamycin-insensitive companion of mTOR complex 2 (RICTOR) and IL-10 genes. The expression of IL-10 and RICTOR genes were significantly increased in HSO/EPO group. In contrast with RAPA groups, histological findings have shown that the HSO/EPO treated group remarkably reduced cell infiltration and promoted remyelination. The EPO/HSO has beneficial effects on the repair of myelin, which was confirmed by immunological and histological findings.

13.
J Neuroimmunol ; 323: 105-108, 2018 10 15.
Article in English | MEDLINE | ID: mdl-30196822

ABSTRACT

Multiple sclerosis (MS), is an autoimmune disorder of central nervous system (CNS) characterized by inflammation and demyelination. Self-tolerance impairment is considered to be induced by a combination of inherited susceptibility and environmental agents. In this work, we demonstrate that a reduction in the comparative expression of well-known inhibitory receptors (i.e., CTLA-4, PD-1, and TIM-3) is importantly linked with MS patients compared to healthy controls. The relative expression of interested genes was performed on peripheral blood mononuclear cells (PBMCs), by using quantitative real time-PCR (qRT-PCR). Our data highlighted the role of inhibitory receptors in the maintenance of immune homeostasis in autoimmune disease.


Subject(s)
CTLA-4 Antigen/blood , Down-Regulation/physiology , Hepatitis A Virus Cellular Receptor 2/blood , Multiple Sclerosis/blood , Programmed Cell Death 1 Receptor/blood , Adult , CTLA-4 Antigen/biosynthesis , CTLA-4 Antigen/genetics , Female , Gene Expression , Hepatitis A Virus Cellular Receptor 2/biosynthesis , Hepatitis A Virus Cellular Receptor 2/genetics , Humans , Leukocytes, Mononuclear/metabolism , Male , Middle Aged , Multiple Sclerosis/genetics , Multiple Sclerosis/metabolism , Programmed Cell Death 1 Receptor/biosynthesis , Programmed Cell Death 1 Receptor/genetics
14.
Int Immunopharmacol ; 63: 239-245, 2018 Oct.
Article in English | MEDLINE | ID: mdl-30114604

ABSTRACT

Nicotine, an nAChR agonist, shows prominent anti-inflammatory properties, and some studies have illustrated its suppressive effects on inflammation. Here, we have examined whether nicotine as a medicine may have beneficial effects on the treatment of asthma in a mouse model of allergic asthma. BALB/c mice were sensitized with OVA and alum. Two weeks later, the mice received nicotine with concentrations of 1 and 10 mg/kg three times every other day. After 10 days, the mice were challenged with OVA (5%) using an ultrasonic nebulizer and died the next day. Our results showed that the administration of nicotine reduced lung-tissue inflammation, the number of eosinophils in bronchoalveolar fluid, allergen-specific IgE and IL-4 production, while it increased the TGF-ß/IL-4 ratio and the number of Treg cells. Our results showed that nicotine applies its suppressive effects in a dose-dependent manner: administration of 10 mg/kg of nicotine showed more suppressive effects than 1 mg/kg. Such data suggested that nicotine might be a good candidate to be used as a medicine in the treatment of allergic asthma by decreasing allergic inflammation severity and potentiating Treg cells proliferation against the allergen.


Subject(s)
Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Nicotine/therapeutic use , Allergens/immunology , Animals , Anti-Asthmatic Agents/pharmacology , Asthma/immunology , Asthma/pathology , Bronchoalveolar Lavage Fluid/cytology , Eosinophils/immunology , Immunoglobulin E/blood , Interleukin-4/immunology , Male , Mice, Inbred BALB C , Nicotine/pharmacology , Ovalbumin/immunology , T-Lymphocytes, Regulatory/immunology , Transforming Growth Factor beta/immunology
15.
Res Pharm Sci ; 13(6): 523-532, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30607150

ABSTRACT

The mammalian target of rapamycin (mTOR) has a fundamental role in the metabolism, growth, and regulation of the immune system. The interferon gamma (IFN-γ)derived from T helper 1 (Th1) cells is a prominent pro-inflammatory cytokine in multiple sclerosis (MS) and its animal model, the experimental autoimmune encephalomyelitis (EAE). Due to the exclusive role of rapamycin (RAPA) in mTOR complex 1 (mTORC1) inhibition, essentially Th1 differentiation and IFN-γ production, we evaluated the potential therapeutic effects of hemp seed/evening primrose oils (HSO/EPO) in comparison with RAPA administration in EAE. To evaluate the therapeutic effects of EPO/HSO supplement in comparison with RAPA, EAE was induced using myelin oligodendrocyte glycoprotein (MOG) peptide and complete Freund's adjuvant in C57BL/6 mice. The weight, clinical score, and histological findings were evaluated. Total mRNA was extracted from local lymph nodes and qRT-PCR was used for the purpose of the genes expression level of regulatory associated protein of TORC1 (RAPTOR) and IFN-γ. Our results indicated that the relative expression of RAPTOR and IFN-γ genes were significantly reduced in HSO/EPO, RAPA, and RAPA + HSO/EPO treated groups in comparison with the untreated group. Interestingly, histological findings have shown that the HSO/EPO treated group remarkably regenerated the myelin sheath, but this did not occur in the case of RAPA or combined RAPA and HSO/EPO treated groups. Our findings suggeste that HSO/HPO can be used as a potent immunomodulator and as a good candidate for re-myelination and downregulation of immune response for treatment of MS.

16.
Clin Immunol ; 169: 98-106, 2016 08.
Article in English | MEDLINE | ID: mdl-27373971

ABSTRACT

Interferon-ß (IFN-ß) is commonly used as a disease modifying drug for the treatment of relapse-remitting multiple sclerosis (RR-MS). However, the underlying mechanism by which IFN-ß mediate this immunosuppressive effect is still unknown. In this study, we analyzed the effects of genetically modified adipose-derived mesenchymal stem cells (AD-MSCs) expressing murine interferon beta (MSCs-VP/IFN-ß) on the animal model of MS, experimental autoimmune encephalomyelitis (EAE). Lymph node mononuclear cells and serum were examined by using RT-PCR and ELISA methods to measure the production of IL-10 and IL-17 gene and protein expression, respectively. Our results indicated that in the MSCs-VP/IFN-ß treated group induction of Tregs and IL-10 and reduction of IL-17 were significant. Taken together, we showed that using AD-MSCs expressing IFN-ß as an anti-inflammatory agent, offer evidence supporting that the stem cell therapies in EAE conceivably will improve the valuable effects of IFN-ß in this autoimmune disease.


Subject(s)
Adipose Tissue/cytology , Encephalomyelitis, Autoimmune, Experimental/therapy , Interferon-beta/metabolism , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/metabolism , Animals , Blotting, Western , Cells, Cultured , Cytokines/genetics , Cytokines/immunology , Cytokines/metabolism , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/metabolism , Enzyme-Linked Immunosorbent Assay , Female , Humans , Interferon-beta/genetics , Interleukin-10/genetics , Interleukin-10/immunology , Interleukin-10/metabolism , Interleukin-17/genetics , Interleukin-17/immunology , Interleukin-17/metabolism , Mesenchymal Stem Cells/cytology , Mice , Mice, Inbred C57BL , Multiple Sclerosis/genetics , Multiple Sclerosis/metabolism , Multiple Sclerosis/therapy , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism
17.
Tumour Biol ; 37(3): 3371-8, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26446460

ABSTRACT

Recent studies have shown that Helicobacter pylori has a special role in tropism of mesenchymal stem cells (MSCs) towards gastric tissues. This study aimed to find the effects of H. pylori on human adipose-derived mesenchymal stem cells (hA-MSCs) transforming toward cancer cells and also metastasis of tumor cells by synergic effects of H. pylori and gastric epithelial cells (AGS) on MSCs. The expressions of p53, bcl-2, MMP-2, and MMP-9 were examined in hA-MSCs by qRT-PCR technique. Our results demonstrated that H. pylori tries to improve the hA-MSCs carcinogenic activities by overexpression of bcl2 gene as an anti-apoptosis agent against the p53 gene expression as main apoptosis agent. In addition, it showed that H. pylori effects in metastatic activities of hA-MSCs by upregulation of related genes in this process. Perhaps, when hA-MSCs are attracted toward H. pylori chronic or ulcer infected tissues for their tissue healing function, they will be trapped under special gastric microenvironment. We demonstrated the direct and synergic effects of H. pylori in hA-MSCs through alteration of related genes involved in carcinogenesis processes. Hence, understanding of H. pylori-induced molecular pathogenesis could be a powerful strategy not only in identifying the origin and initiation of gastric cancer but also in the treatment of related disease and modification of stem cell therapy methods in the future.


Subject(s)
Adipose Tissue/cytology , Helicobacter pylori/pathogenicity , Mesenchymal Stem Cells/pathology , Stomach Neoplasms/etiology , Apoptosis , Cells, Cultured , Humans , Matrix Metalloproteinase 2/physiology , Matrix Metalloproteinase 9/physiology , Neoplasm Metastasis , Stem Cell Transplantation , Stomach Neoplasms/pathology
18.
Int Immunopharmacol ; 24(2): 474-480, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25445955

ABSTRACT

Plasmacytoid dendritic cell (pDC), plays central role in antiviral immunity. The aim of this study was to assess the effect of Flt3 ligand (FL) alone or with L929 fibroblast feeder or L929 conditioned media on differentiation of mouse bone marrow (BM) cells into pDC in vitro. Murine BM cells were cultured with FL or with L929 or conditioned media for 9days. The differentiated cells were analyzed using flow cytometry for PDCA-1, B220 and CXCR4. The relative expression of Stat3, CXCR4, CXCR7, IFN-ß, TGF-ß and Runx2 in differentiated cells determined by real time PCR. The development of pDC showed up to 19% increase after co-culture of BM cells with fibroblast feeder. Upregulation of Stat3, Runx2 and CXCR4 due to the presence of fibroblast feeder with FL in culture results in improved pDC development. Furthermore, 30% L929 supernatant along with Flt3 ligand was able to derive pDC up to 8.9% in comparison with FL alone, which was 6.6% in vitro. Thus, for the first time we introduced L929 fibroblast feeder as a niche producer of M-CSF and probably other growth factors and chemokines, which promotes the development of pDC in vitro along with FL, similar to in vivo niche.


Subject(s)
Bone Marrow Cells/drug effects , Dendritic Cells/cytology , Fibroblasts/drug effects , Membrane Proteins/pharmacology , Animals , Bone Marrow Cells/cytology , Cell Differentiation/drug effects , Cell Line , Coculture Techniques , Core Binding Factor Alpha 1 Subunit/genetics , Dendritic Cells/metabolism , Fibroblasts/cytology , Fibroblasts/metabolism , Gene Expression/drug effects , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Mice , Mice, Inbred C57BL , Receptors, CXCR4/genetics , STAT3 Transcription Factor/genetics
19.
Int Immunopharmacol ; 20(2): 316-21, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24704622

ABSTRACT

It has been proposed that the immunomodulatory properties of mesenchymal stem cells (MSCs) play a crucial role in establishing and leading T lymphocytes, especially Th cell subsets, toward different functional subsets. To determine the effect of the immunomodulatory and regulatory functions of adipose-derived MSCs (AD-MSCs) on C57BL/6 spleen-isolated mononuclear cells (Spleen-MNCs), the gene expression of well-known effector and regulatory Th cell-related transcription factors, i.e., t-bet, GATA-3, Ror-γt and Foxp3, and their related cytokines, i.e., IFN-γ for Th1 cells, IL-4 for Th2 cells, IL-17 for Th17 cells and IL-10 and TGF-ß for regulatory T cells, was studied using a co-culture condition system. The proliferation index of Spleen-MNCs was analyzed using a cell proliferation assay kit that utilized the CFSE staining method. Our findings indicate that AD-MSCs greatly impact the up-regulation of immunomodulatory cytokines, such as TGF-ß (p<0.001), and the down-regulation of inflammatory cytokines, such as IFN-γ (p<0.005), and transcription factors, such as t-bet (p<0.001). Considering the immunomodulatory effects of MSCs in the differentiation of Th cell subsets, understanding and harnessing this property of MSCs could be a powerful strategy in the treatment of inflammatory autoimmune diseases such as multiple sclerosis.


Subject(s)
Adipose Tissue/immunology , Mesenchymal Stem Cells/immunology , Spleen/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Cell Communication , Cell Differentiation , Cells, Cultured , Cytokines/metabolism , Gene Expression Regulation , Immunomodulation , Inflammation Mediators/metabolism , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Transcription Factors/genetics , Transcription Factors/metabolism
20.
Rheumatol Int ; 32(9): 2833-6, 2012 Sep.
Article in English | MEDLINE | ID: mdl-21879377

ABSTRACT

Apoptosis signals are essential for establishing homeostasis and adequate immune response. Dysregulation of apoptosis-related genes in the immune system, which could be due to gene polymorphisms, conduct to autoimmune diseases including rheumatoid arthritis. In the current study, the apoptosis-related gene Fas_-670A>G, FasL_844C>T, and FasLIVS2nt_124A>G polymorphisms were genotyped in 120 Iranian patients with rheumatoid arthritis (RA) and 112 unrelated healthy controls using PCR-RFLP method. Among the 120 RA patients being heterozygous in the promoter region of Fas_-670A/G (OR 1.42,CI 0.92-1.52, P = 0.18) and FasL_-844C/T (OR 1.42, CI 0.92-1.52, P = 0.18) and homozygous in the minor allele for FasLIVS2nt_124G/G (OR 1.43, CI 0.76-1.81, P = 0.7), the frequency of these polymorphisms is higher in the cases than in controls and the elevated risk of RA were observed when the patient compared with controls, although this is not statistically significant.


Subject(s)
Apoptosis/genetics , Arthritis, Rheumatoid/ethnology , Arthritis, Rheumatoid/genetics , Fas Ligand Protein/genetics , Polymorphism, Single Nucleotide/genetics , fas Receptor/genetics , Adult , Case-Control Studies , Female , Gene Frequency/genetics , Genetic Predisposition to Disease/genetics , Heterozygote , Homozygote , Humans , Iran/epidemiology , Male , Middle Aged , Risk Factors
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