Publications by authors named "Shahla Danaii"

22 Publications

  • Page 1 of 1

The Impact of New Immunological Therapeutic Strategies on Recurrent Miscarriage and Recurrent Implantation Failure.

Immunol Lett 2021 08 6;236:20-30. Epub 2021 Jun 6.

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

Maternal-fetal immune dysregulation is one of the risk factors that increases the probability of embryo rejection and reproductive failure. The stimulation of immunological tolerance and suppression of immunological rejection are prerequisites for protecting embryos and preventing immunological attacks. Hence, it appears that immunomodulatory and immunosuppressive therapies can manage reproductive failures by controlling immune cells. The current medical literature has shown that immunotherapy approaches and cell therapy have promising results in improving pregnancy outcomes and live birth rates. These outcomes are obtained by regulating maternal immune responses, and exerting positive effects on human reproductive processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.imlet.2021.05.008DOI Listing
August 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jri.2021.103317DOI Listing
June 2021

Intrauterine administration of autologous hCG- activated peripheral blood mononuclear cells improves pregnancy outcomes in patients with recurrent implantation failure; A double-blind, randomized control trial study.

J Reprod Immunol 2020 11 4;142:103182. Epub 2020 Aug 4.

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

We aimed to investigate the effect of intrauterine administration of autologous hCG-activated PBMCs in RIF women with low Th-17/Treg cell ratio. 248 women with a history of implantation failure volunteered to receive PBMC-therapy. After immunologic consultation and doing flow cytometry analysis, 100 women with at least three IVF/ET failure who had low Th-17/Treg ratio in comparison with healthy control were enrolled in this study. These 100 patients were randomly divided into two groups as PBMC receiving (n = 50) and controls (n = 50). Then PBMCs were obtained from patients and treated with hCG for 48 h. Afterward, PBMCs were administered into the uterine cavity of the patient in the study group, two days before ET. The concentration of inflammatory cytokines was examined in the supernatant of cultured PBMCs after 2, 24, and 48 h of incubation using the ELISA method. The frequency of Th-17, Treg, and the Th-17/Treg ratio was significantly lower in RIF women than the healthy controls (P < 0.0001). The secretion of inflammatory cytokines was significantly higher after 48 h compared to 2 and 24 h (P < 0.0001). The pregnancy and live birth rate were significantly increased in women undergoing the PBMC-therapy compared to control (PBS-injecting) group (P = 0.032 and P = 0.047, respectively). The miscarriage rate was considerably lower in PBMC-therapy group (P = 0.029). Our findings suggest that intrauterine administration of autologous in vitro hCG-activated PBMCs improves pregnancy outcomes in patients with at least three IVF/ET failures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jri.2020.103182DOI Listing
November 2020

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

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

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

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

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.intimp.2020.106806DOI Listing
October 2020

New insights into the core Hippo signaling and biological macromolecules interactions in the biology of solid tumors.

Biofactors 2020 Jul 22;46(4):514-530. Epub 2020 May 22.

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

As an evolutionarily conserved pathway, Hippo signaling pathway impacts different pathology and physiology processes such as wound healing, tissue repair/size and regeneration. When some components of Hippo signaling dysregulated, it affects cancer cells proliferation. Moreover, the relation Hippo pathway with other signaling including Wnt, TGFβ, Notch, and EGFR signaling leaves effect on the proliferation of cancer cells. Utilizing a number of therapeutic approaches, such as siRNAs and long noncoding RNA (lncRNA) to prevent cancer cells through the targeting of Hippo pathways, can provide new insights into cancer target therapy. The purpose of present review, first of all, is to demonstrate the importance of Hippo signaling and its relation with other signaling pathways in cancer. It also tries to demonstrate targeting Hippo signaling progress in cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/biof.1634DOI Listing
July 2020

The Association between Inflammatory Cytokines and miRNAs with Slow Coronary Flow Phenomenon.

Iran J Allergy Asthma Immunol 2020 Feb 1;19(1):56-64. Epub 2020 Feb 1.

Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran AND Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.

Slow coronary flow (SCF) is a coronary artery disorder. Several inflammatory mediators have been reported to be associated with vascular homeostasis and endothelial dysfunction. The aim of this study was to investigate the association between cytokines and miRNAs in patients with SCF compared to the controls. In this regard, blood samples were acquired from 45 SCF patients and 45 age- and sex-matched healthy control subjects. Serum and peripheral blood mononuclear cells (PBMCs) were separated. Expression levels of miRNAs and cytokines in PBMCs were measured by real-time PCR. As a final point, serum levels of cytokines were quantified by ELISA. Expression levels of miR-1, miR-133, miR-208a, miR-206, miR-17, miR-29, miR-223, miR-326, and miR-155 as considerable indicators of inflammatory function significantly increased in SCF patients while the expression levels of miR-15a, miR-21, miR-25, miR-126, miR-17, miR-16 and miR-18a as considerable indicators of anti-inflammatory function significantly decreased in patients with SCF compared to the control group. Additionally, serum IL-1β, IL-8, and TNF-α concentrations were significantly higher in the SCF group than controls. However, no significant differences were observed in IL-10 production in SCF patients compared to the controls. This study provided the potential role of miRNAs as biomarkers for SCF diagnosis as well as suitable markers for monitoring coronary artery disease (CAD) development in these patients. More investigations are still necessary to unravel the detailed essential mechanisms of circulating miRNA levels in patients with heart failure and SCF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18502/ijaai.v19i1.2418DOI Listing
February 2020

Etiology and management of recurrent implantation failure: A focus on intra-uterine PBMC-therapy for RIF.

J Reprod Immunol 2020 06 18;139:103121. Epub 2020 Mar 18.

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

Infertility is one of the most common problems among couples worldwide. Recurrent pregnancy loss, premature ovarian failure, recurrent implantation failure and etc. are common high prevalence disorders in societies. We will review the definition, causes and treatment of recurrent implantation failure disorder in recent studies. Implantation refers to the attachment of the embryo to the endometrial luminal surface and recurrent implantation failure (RIF) is defined as the failure to achieve a pregnancy after transferring high-grade embryos through at least three in vitro fertilization (IVF) cycles to the endometrium. The embryo factors, maternal age, uterine factors, and multifactorial effectors have been considered as the causes of implantation failure. In this review, we aim to focus on immunological factors and cells such as pro-inflammatory cytokines and dendritic cells, macrophages, decidual and uterine NK cells, as well as Th-1 cells. There are different types of treatment according to the cause of RIF including aspirin and low-molecular-weight heparin therapy, immunosuppressive drugs, intravenous immunoglobulins, and hydroxychloroquine. Among immunological recurrent implantation failure therapy, we will discuss the intrauterine PBMC-therapy in detail.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jri.2020.103121DOI Listing
June 2020

Immunological and oxidative stress biomarkers in Ankylosing Spondylitis patients with or without metabolic syndrome.

Cytokine 2020 04 24;128:155002. Epub 2020 Jan 24.

Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Ankylosing Spondylitis (AS) is a chronic inflammatory disorder of the spine and sacroiliac joints with unidentified etiology closely associated with metabolic syndrome (MetS). Recent studies have reported that immunological and oxidative stress factors are implicated in AS pathogenesis. The aim of this study was to investigate the oxidative and immunological factors in AS patients with or without MetS compare to control group. Real-Time PCR measured expression level of cytokines, transcription factors and related miRNAs. In addition, Th17 and Treg frequencies and cytokines secretion were evaluated by flowcytometry and ELISA methods, respectively. The oxidative stress biomarkers were also assessed with biochemical methods. In AS patients with MetS, higher Th17 and lower Treg frequency were observed. Increased levels of NF-kB and AP-1 mRNA expression were seen in AS patients with MetS (p = 0.0263 and p = 0.0104, respectively). MiR-146a and miR-223 were significantly decreased (p = 0.0005, p = 0.0161, respectively) and increase in miR-21 (p = 0.0002) was observed in AS patients with MetS compared to AS patients without MetS. Additionally, the secretion of TNF-α (p = 0.0167), IL-1β (p = 0.303), CCL2 (p = 0.0254), CCL3 (p = 0.0119), CXCL8 (p = 0.0364), adiponectin (p = 0.0183) and the levels of SOD (p = 0.0421), NO (p = 0.0451) and CAT (p = 0.0128) were increased in AS patients with MetS. We were not observed significant differences in TOS and GPX levels between studied groups. The higher levels of oxidative stress and immunological inflammatory markers in AS patients with MetS provide further evidences on the oxidative stress and immunological relationship in these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cyto.2020.155002DOI Listing
April 2020

The role of IL-10-producing B cells in repeated implantation failure patients with cellular immune abnormalities.

Immunol Lett 2019 10 20;214:16-22. Epub 2019 Aug 20.

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

There are a few data of the role of B cells in RIF pathogenesis. Accordingly, the objective of the current study was to determine the role of IL-10-producing B cells in RIF. Twenty-three RIF women with cellular immune abnormalities and 25 normal controls were enrolled in this experiment. Isolated naïve B cells from peripheral blood of the subjects were cultured in vitro, divided into two parts and activated by CpG ODN and imiquimod as TLR agonists. Afterwards, the number of CD19 IL-10 B cells was evaluated by flow cytometry and their related IL-10 cytokine level was assessed by ELISA. The mRNA expression levels of related genes in just CPG stimulated B cell population were also analyzed using real-time PCR. RIF patients exhibited a decreased level of the cells (P = 0.014, P = 0.023, respectively) and IL-10 cytokine (P = 0.009, P = 0.045, respectively) in both CPG and imiquimod stimulated B cell groups. IL-10 serum level was also lower in these patients (P = 0.0014). Additionally, we found a negative relationship between the frequency of these cells with the number of failed ET and total IgG titers in RIF patients. The mRNA levels of IL-10-producing B cells related genes (IL-10 and PD-L1) was also significantly lower in RIF women, whereas the expression of plasma cells-associated transcriptional factors (BLIMP1, IRF4, and XBP1) was higher. Summing up the obtained results, we concluded that peripheral blood IL-10-producing B cells down-regulation might result in RIF pathogenesis. It is further suggested that these cells can suppress autoantibody generation and contribute to a successful implantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.imlet.2019.08.002DOI Listing
October 2019

Oxidative stress, inflammatory settings, and microRNA regulation in the recurrent implantation failure patients with metabolic syndrome.

Am J Reprod Immunol 2019 10 11;82(4):e13170. Epub 2019 Aug 11.

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

Problem: Increased oxidative stress (OS) and inflammatory factors in metabolic syndrome (MS) patients are considered as risk factors for recurrent implantation failure (RIF). The aim of this study was to investigate OS markers, inflammatory factors, related microRNAs (miRNA) expression, and cytokine and transcription factors RNA expression.

Method Of Study: We evaluated the frequency of helper T (Th) 17 and regulatory T (Treg) cells in recurrent implantation failure (RIF) women with or without MS. miRNA expression, an inflammatory cytokine, and transcription factors were measured by real-time PCR. The level of interleukin (IL)-1β, IL-6, IL-17, tumour necrosis factor-alpha (TNF-alpha) and chemokine (C-C motif) ligand 2 (CCL-2), and C-X-C motif chemokine ligand 8 (CXCL-8) were measured by enzyme-linked immunosorbent assay (ELISA). OS markers were evaluated by spectrophotometric assay. Th17 and Treg cell frequencies were determined by flow cytometry.

Results: The expression of AP1, NF-κB, FOXP3, miRNA-21; serum or plasma level of OS markers (ie, nitric oxide, total oxidant status, and myeloperoxidase); serum level of inflammatory factors (ie, IL1-β, IL-6, IL-17, TNF-alpha, CXCL-8, and CCL-2); and frequency of Th17 cells were increased in RIF-MS patients in comparison with RIF women without MS (RIF-NMS) and control group. The expression of miRNA-223 and 146a, antioxidant enzymes, namely superoxide dismutase (SOD) and catalase (CAT), and frequency of Treg also declined in RIF-MS patients.

Conclusion: Overall, our findings suggest that MS in RIF patients causes increased inflammatory factors and OS, which in turn leads to implantation failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/aji.13170DOI Listing
October 2019

Sirolimus as a new drug to treat RIF patients with elevated Th17/Treg ratio: A double-blind, phase II randomized clinical trial.

Int Immunopharmacol 2019 Sep 9;74:105730. Epub 2019 Jul 9.

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

Background: RIF is clinically defined as the failure of good quality embryos to implant into the uterus following at least three cycles of In Vitro Fertilization/Embryo Transfer (IVF/ET). During human pregnancy, a genetically different fetus is allowed to survive within the uterus despite the maternal recognition of fetal alloantigens. Compared with normal pregnant women, early loss of embryo is associated with systemic lower levels of Treg cells in IVF. Moreover, several lines of evidence have indicated that differentiation of naive T cells into Th17 is deleterious for normal pregnancy and may cause implantation failure. Sirolimus as the most common mTOR (mammalian target of Rapamycin) inhibitor is able to effectively prevent allograft rejection. Here we aimed to evaluate Sirolimus effects on Th17/Treg axis and subsequently on pregnancy outcome.

Methods And Materials: 121 patients with a history of at least 3 implatation failures were selected and enrolled in this clinical trial. Blood was drawn between days 5 and 10 of the cycle prior to the index IVF/ET cycle to assess baseline value of Th17 cells and regulatory T cells ratios using flowcytometry. A Th17/Treg cell ratio equal or >0.74 was considered to be the elevated Th17/Treg cell ratio. In 76 patients with elevated Th17/Treg ratios, 43 individuals were treated with Sirolimus and 33 remained untreated.

Results: Our results demonstrated that Sirolimus treatment led to an increase in Treg cells number and function in treated group and reduced the frequency and function of Th17 cells. Moreover Th17/Treg cell ratio, significantly reduced from 1.18 ± 0.46% to 0.9 ± 0.45% following Sirolimus intervention (P = 0.024). In contrast, no significant difference in Th17 and Treg cell frequencies and Th17/Treg cell ratio was observed in untreated control subjects before and after ET. Finally our data showed a significantly higher clinical pregnancy rate (55.81%) in Sirolimus-treated patients compared with control group (24.24%) (P < 0.0005). We also found a significantly increased live birth rate (48.83%) in RIF women who received Sirolimus compared with control group (21.21%) (P < 0.0001).

Conclusion: The findings of the current study revealed the fact that Sirolimus exhibit potent immunosuppressive effects by blocking intracellular immune responses downstream of co-stimulatory signals, also is able to improve reproductive outcome in RIF women with imbalanced Th17/Treg ratio by modulate of Th17 /Treg axis, thus representing a new approach for the potential treatment of patients with embryo implantation failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.intimp.2019.105730DOI Listing
September 2019

Metabolic syndrome mediates inflammatory and oxidative stress responses in patients with recurrent pregnancy loss.

J Reprod Immunol 2019 06 9;133:18-26. Epub 2019 May 9.

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

Recurrent pregnancy loss (RPL) is defined as three or more consecutive pregnancy losses prior to the 20th week of gestation. Exaggerated maternal immune response and oxidative stress status have been proposed as one of the main underlying mechanisms for RPL. The aim of this study was to evaluate the role of inflammatory pathway and oxidative stress imbalance in RPL patients with or without metabolic syndrome (MetS). 21 and 28 RPL patients with (RPL-MS) and without (RPL-NMS) metabolic syndrome were enrolled in this clinical study. 42 healthy women also were considered as the control group. The levels of IL1β, IL6, IL17, TNFα, CCL2, CXCL8 were evaluated by ELISA method. Additionally, the oxidative stress biomarkers including TAS, TOS, NO, CAT, SOD, AOPP, MPO were analyzed by spectrophotometry. The expression levels of IL1β, IL6, IL17, TNFα, CCL2, CXCL8, NFĸB, AP1, miR-21, miR-146-a, miR-223 were also assessed by real time PCR. The frequency of Th17 and T-reg cells was also measured by flow cytometry. Significant increase in the expression levels of IL1β, IL6, IL17, TNFα, CCL2, CXCL8, NFĸB, AP1 and miR-21 was observed in RPL-MS patients. Furthermore, significant decreased expression levels of FoxP3, miR-146-a and miR-223 was also observed in RPL-MS group. The levels of IL1β, IL6, IL17, TNFα, CCL2, CXCL8, NO, MPO and TOS were found to be higher in RPL-MS group compared to the RPL-NMS and healthy controls. In contrast, the level of CAT and SOD in RPL-MS patients was decreased. The frequency of Th17 and Treg cells was also higher and lower in RPL-MS patients compared to the other groups, respectively. Our results support the concept that subclinical inflammatory state, oxidative stress and metabolic syndrome play a crucial role in the etiopathogenesis of RPL assisting clinicians for pregnancy consequences prediction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jri.2019.05.001DOI Listing
June 2019

Cyclosporine A improves pregnancy outcomes in women with recurrent pregnancy loss and elevated Th1/Th2 ratio.

J Cell Physiol 2019 08 28;234(10):19039-19047. Epub 2019 Mar 28.

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

Recurrent pregnancy loss (RPL) is a one of the most common obstetrical complications. Since, the successful pregnancy occurs in T helper 2 (Th2)-dominant situation and since, Th1 type immunity is related to pregnancy failure, we investigated the effects of cyclosporine on Th1 and Th2 cells in RPL women. Totally, 76 RPL patients (38 women as treated group and 38 as control group) were included in this study. Flow cytometry was utilized to analyze the frequency of Th1 and Th2 in blood samples. Also, real-time polymerase chain reaction was carried out to assess the messenger RNA (mRNA) expression of transcription factors and enzyme-linked immunosorbent assay was used to evaluate Th1 and Th2 related cytokines. Significant decrease in Th1 frequency (p = 0.0004), Th1/Th2 ratio (p < 0.0001), T-bet mRNA expression (p < 0.0001), interferon-γ (p = 0.0007), and tumor necrosis factor α (p = 0.0002) secretion level were observed in cyclosporine group. Moreover, significant increase in Th2 frequency (p < 0.0001), mRNA expression of GATA binding protein 3 (p = 0.0001), and interleukin 10 secretion level (p = 0.0027) was also evident in treated group. At the end of the investigation, 31 (81.5%) patients in cyclosporine-treated group had successful childbirth when compared with 16 (42.1%) women in control group (p = 0.0001). Given this, cyclosporine treatment for RPL patients with elevated Th1/Th2 ratio can result in improved pregnancy outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcp.28543DOI Listing
August 2019

Evaluation of ovarian cancer risk in granulosa cells treated with steroid-depleted endometriosis serum: Role of NF-κB/RelA and AKT.

J Cell Physiol 2019 07 4;234(7):12011-12018. Epub 2018 Dec 4.

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

Background: Despite at the beginning known as a benign disease, endometriosis is defined as a risk factor for developing ovarian carcinoma. The effect of endometriosis on ovarian malignancy is known but its role in granulosa cell tumor is still unclear.

Methods And Materials: In this study, serum samples were collected from patients with endometriosis and divided into whole and steroid-depleted groups. Desertification was performed according to the charcoal-dextran protocol and sera were added to the culture media of granulosa cells retrieved from tubal or male factor infertile women. Quantitative real-time polymerase chain reaction and flow cytometry were performed to determine the expression level of inflammatory and apoptotic genes and apoptosis level of granulosa cells. The total concentration of lipid was measured using gas chromatography method in the granulosa cells.

Results: Results revealed that the expression of AKT and NF-κB/RelA gene was significantly higher in the granulosa cells treated with steroid-depleted serum obtained from patients with distrificated endometriosis (DE) compared with the control group (9.39- and 7.9-folds, respectively; p < 0.0001). In the DE group, the declined pattern of expression was observed for the genes related to apoptosis. The synthesis of saturated fatty acids was significantly decreased; however, unsaturated fatty acids showed increased levels in the DE group.

Conclusion: The effect of steroids on endometriosis is contradictory. The level of cortisol and sex hormones could be affected by endometriosis, causing alterations of the disease progression. Reduced level of steroid hormones in patients with endometriosis may be considered as a critical risk factor for granulosa cell tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcp.27862DOI Listing
July 2019

NK cell frequency and cytotoxicity in correlation to pregnancy outcome and response to IVIG therapy among women with recurrent pregnancy loss.

J Cell Physiol 2019 06 14;234(6):9428-9437. Epub 2018 Oct 14.

Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Background: Recurrent miscarriage (RM) has a multifactorial etiology mainly due to chromosomal abnormalities and immunological factors. Treating RM has remained to be a challenging issue and the role of intravenous immunoglobulin (IVIG) in treating RM is still controversial.

Materials And Methods: This study aimed to evaluate the changes in natural killer (NK) cells' frequency and cytotoxicity in patients with RM who received the IVIG therapy. A total of 78 women with a history of three or more recurrent miscarriages were included and their peripheral blood was drawn in case of positive pregnancy test. On the same date, 400 mg/kg of IVIG was administrated intravenously in 38 women and it continued every four weeks through weeks 30-32 of gestation. The remaining 40 patients with RM were included to be the untreated control group. Then, the effects of IVIG on NK cell frequency, cytotoxic activity, and the expression of inhibitory and activating receptors in the patients with RM, pre and posttreatment were assessed.

Results: NK cells percentage and cytotoxicity were significantly reduced in the IVIG-treated patients after 32 weeks of gestation (p < 0.0001). Expression levels of inhibitory receptors was increased, however, the expression levels of activating receptors were significantly decreased after the IVIG therapy. Pregnancy outcome after the treatment was significantly higher (86.8%) in the IVIG-treated patients than controls (45%; p = 0.0006).

Conclusion: Our results suggested that women with RM may benefit from IVIG as a therapeutic approach and the frequency and functional status of peripheral NK cells may serve as a valuable predictive factor of therapy response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcp.27627DOI Listing
June 2019

Natural killer T cells in Preeclampsia: An updated review.

Biomed Pharmacother 2017 Nov 12;95:412-418. Epub 2017 Sep 12.

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

Preeclampsia (PE), as a pregnancy-specific syndrome, has become one of the main causes of maternal and fetal mortality worldwide and is known as a major risk factor for preterm birth. PE is typically characterized by hypertension, significant proteinuria, and an excessive maternal systemic inflammatory response. Recent evidences provide support for the notion that Natural killer T (NKT) cells (a small, but significant immunoregulatory T cell subset of human peripheral blood lymphocytes) play pivotal roles in pregnancy. NKT cells with unique transcriptional and cytokine profiles exist in different peripheral tissues acting as mediators between the innate and adaptive immune systems. NKT cells secrete Interleukin-4 (IL-4) and Interferon-γ (IFN-γ) which might regulate the balance between Type 1T helper (Th1) and Type 2T helper (Th2) responses. During pregnancy, maternal immunity is biased towards type II cytokine production to inhibit the function of type I cytokines that could be harmful for the developing fetus. This shift to type II cytokines does not occur in preeclamptic patients. In this review, we discuss the numbers, phenotype, changes, and the functional activity of Natural killer T (NKT) cells during normal pregnancy and preeclampsia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopha.2017.08.077DOI Listing
November 2017

Effect of Intravenous immunoglobulin on Th1 and Th2 lymphocytes and improvement of pregnancy outcome in recurrent pregnancy loss (RPL).

Biomed Pharmacother 2017 Aug 12;92:1095-1102. Epub 2017 Jun 12.

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

Background: Women with elevated natural killer (NK) cell frequency and function during pregnancy, suffer from recurrent pregnancy loss (RPL). In the present study, the possible effect of intravenous immunoglobulin (IVIG) administration on Th1 and Th2 cell frequency, cytokine secretion, and expression of transcription factors is compared between RPL patients and control group.

Materials And Methods: Totally, 44 women with a history of RPL (32 women as treated group and 12 as control group) were enrolled in the study. The frequency of Th1 and Th2 lymphocytes, the expression of transcription factors related to these cells and the serum levels of associated cytokines were assessed by flowcytometry, real-time PCR and ELISA, respectively. All, assessments were performed both before and after treatment with IVIG.

Results: A significant reduction in Th1 lymphocyte frequency, transcription factor expression and cytokine levels were observed in IVIG-treated group, while all the above parameters indicated a significant increase for Th2 lymphocytes. Th1/Th2 ratio decreased significantly (p value<0.0001) at the end of treatment and 28 out of 32 (87.5%) women in IVIG-treated group had live birth in comparison with 5 out of 12 (41.6%) in untreated group.

Conclusion: IVIG administration proves to be an efficient therapeutic strategy which is able to enhance the success rate of pregnancy through a shift in Th2 responses. Furthermore, IVIG presents efficacy for the treatment of reproduction failures especially in subjects with immune cell abnormalities and increased NK cell level and function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopha.2017.06.001DOI Listing
August 2017

Association of endothelial nitric oxide synthase gene variants (-786 T>C, intron 4 b/a VNTR and 894 G>T) with idiopathic recurrent pregnancy loss: A case-control study with haplotype and in silico analysis.

Eur J Obstet Gynecol Reprod Biol 2017 Aug 30;215:93-100. Epub 2017 May 30.

Human Genetic Research Center, Baqiyatallah university of Medical Science, Tehran, Iran. Electronic address:

Objective(s): Many lines of evidence suggest that reduced production of nitric oxide (NO) due to single nucleotide polymorphisms in endothelial nitric oxide synthase (eNOS) gene may affect the implantation and maintenance of pregnancy. Accordingly, our objective was to investigate whether the eNOS polymorphisms (-786 T>C, intron 4 b/a VNTR and 894 G>T) and haplotypes may be associated with increased susceptibility to recurrent pregnancy loss (RPL).

Study Design: A total of 130 women with a history of two or more unexplained consecutive first trimester miscarriages and 110 ethnically matched women with at least two normal pregnancies and no history of pregnancy loss were included in the study as cases and controls, respectively. To identify the genotypes, we used polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP) methods In addition, an in silico analysis was conducted to predict the possible effects of the eNOS 894 G>T polymorphism on the structure and function of eNOS mRNA and protein using prediction servers.

Results: Our findings revealed that the prevalence of eNOS -786 T>C polymorphism, eNOS -786C allele and TC+CC genotype in cases were significantly higher than those in healthy controls (p<0.05). Also, the combination genotypes -786TT/4b4a and -786TT/894GG were significantly associated with reduced risk of RPL. We also found that the C-4a-G haplotype of the eNOS gene studied polymorphisms was significantly associated with a predisposition to RPL (odds ratio, 3.219; 95% confidence interval, 1.649-6.282; p=0.0003). The in silico analysis showed that the eNOS 894 G>T polymorphism couldn't affects eNOS mRNA and protein significantly.

Conclusion: Our findings provide evidence to support the hypothesis that eNOS -786 T>C polymorphism and the -786C-4a-894G haplotype are associated with the high risk of RPL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejogrb.2017.05.024DOI Listing
August 2017

Novel immunotherapeutic approaches for treatment of infertility.

Biomed Pharmacother 2016 Dec 31;84:1449-1459. Epub 2016 Oct 31.

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

One of the most important reasons of infertility and human reproductive failure is related to uncontrolled immunological response of maternal immune system to early embryo or fetus, that cause rejection of this semi-allograft. Therefore, a tolerance in the immune system is essential to modulate the reactions against the fetus to avoid rejection. The immune system imbalance during implantation or pregnancy may lead to implantation failure or miscarriage. So, use of immunosuppressive or immunomodulator agents can be helpful to prevent immunological attack. Initially, there was a focus on steroids like prednisolone or intralipids in treatment of miscarriage that suppressed the activity of most immune cells, Intravenous Immunoglobulin (IVIG) was then introduced with various mechanisms. Nowadays, novel and specific strategies are established such as monoclonal antibodies and cytokines. More recently, Tacrolimus and Cyclosporine, which were utilized in prevention of transplantation reject, are used as immunosuppressive factors in modulation of immune responses against the fetus. This review is focused on the main immunotherapeutic methods of infertility treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopha.2016.10.062DOI Listing
December 2016

The Role of Heparin in Embryo Implantation in Women with Recurrent Implantation Failure in the Cycles of Assisted Reproductive Techniques (Without History of Thrombophilia).

J Family Reprod Health 2015 Jun;9(2):59-64

Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Objective: Several studies have shown the improving effect of heparin on the outcomes of ART. Moreover, it has been reported that adding heparin in non-thrombophilia patients with RIF is useful.The aim of this study was to evaluate the beneficial effects of heparin on ART outcomes in women with history of recurrent implantation failure (RIF) and without history of congenital or acquired thrombophilia in a randomized, controlled clinical trial (RCT).

Materials And Methods: In this study, 100 patients with a history of two or more failures in implantation in cycles of ART were randomly subdivided into two groups of study and control. Patients of the control group just received the luteal phase support. In the patients of study group, in addition to the routine support of luteal phase following in vitro fertilization (IVF) or intra cytoplasmic sperm injection (ICSI), 5000 units of subcutaneous heparin was administered for 15 days from the day of oocyte pick up. Pregnancy test (β-HCG) was done for patient of two groups 15 days after IVF.

Results: In the study group, pregnancy test was positive in 16 (32%) patients and negative in 34 (68%) patients. In the control group, pregnancy test was positive in 15 (30%) patients and negative in 35 (70%) patients. There was no significant difference between two groups for the role of heparin in the pregnancy rate (p = 0.5).

Conclusion: Although the effect of heparin on pregnancy was not statistically significant in this study, with regard to the numerous benefits of this agent, it is recommended to study its effects in further studies with lager sample size.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500816PMC
June 2015

A comparison of 4- and 24-hour urine samples for the diagnosis of proteinuria in pregnancy.

Iran J Med Sci 2011 Sep;36(3):167-71

Department of Gynecology and Obstetrics, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.

Background: Preeclampsia is a serious complication of pregnancy, and it is vital to diagnosis the condition as early as possible. Proteinuria is an important symptom of preeclampsia, and repeated urine analysis to screen for the condition is part of the standard antenatal care. The purpose of this study was to determine the correlation between 4- and 24-hour urine total protein values to examine whether the 4-hour urine samples could be used for the diagnosis of proteinuria in hypertensive disorders of pregnancy.

Methods: A cross-sectional study was performed on 110 pregnant (after gestational week 20 of pregnancy) patients who were hypertensive (blood pressure ≥140/90 mmHg) and had proteinuria as defined by positive urinary protein of at least 1+ in dipstick. Patients' urine samples were collected over 24 hours; the first 4 hours were collected separately from the next 20-hours. Patients, who did not collect the 24-hour urine, were excluded from the study. One hundred patients met the criteria, and were included in the study. The urine volume, total protein and creatinine levels of 4- and 24-hours samples were measured. The correlation between 4-hour and 24-hour samples was examined using Pearson correlation test.

Results: Of the 100 patients, 42 had no proteinuria, 44 had mild proteinuria, and 14 had severe proteinuria. The urine protein values of 4-hour samples correlated with those of the 24-hours samples for patients with mild and severe forms of the disease (P<0.001, r=0.86).

Conclusion: This study showed there was a correlation between 4-hour and 24-hour urine proteins. The finding indicates that a random 4-hour sample might be used for the initial assessment of proteinuria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3556766PMC
September 2011
-->