Therapeutic potential of quercetin on human breast cancer in different dimensions

Background: There has been an extensive range of incidence and mortality of breast cancer (BC), and the comprehensively available treatments for BC have not been completely successful in achieving satisfactory outcomes up to date. Hypothesis: Recently, we are watching intense attention paid to the utilization of natural compounds as a novel therapeutic strategy for cancer treatment. Quercetin, a dietary flavonol in a large group of commonly consumed foods, is widely illustrated to apply inhibitory effects on cancer progression through several mechanisms including apoptosis enhancement, cell cycle arrest, metastasis and angiogenesis inhibition, antioxidant replication and estrogen receptor modulation. Methods: We reviewed the most relevant papers published from 2009 to 2018 (except 15 articles), using �pub med� and �web of science� and the search terms �Quercetin�; �Breast cancer�; �Flavonoid�; �Apoptosis�; �Cell cycle�; �chemotherapy�; �Drug resistance�; �Metastasis; �Oxidative stress�, �Breast cancer receptors� and �Quercetin derivatives�. We selected studies on the association of quercetin with breast cancer in different dimensions. Results: Despite the remarkable number of studies on quercetin�s efficacy, multiple aspects of this herbal compound have not been clarified well and this review provides a summarized update of the recent evidence on biologically available efficacies of quercetin which would establish a further biological basis for the potential therapeutic acquisition of quercetin as an anticancer drug. Conclusion: Basic, epidemiological and genetic studies point to the potential role of quercetin in the treatment of breast cancer, but randomized and controlled trials are of great importance to establish the clinical efficacy of quercetin in ill or at-risk subjects. © 2019, Springer Nature Switzerland AG

Immunomodulatory effects of human amniotic epithelial cells on naive CD4+ T cells from women with unexplained recurrent spontaneous abortion

Abstract Introduction Immune imbalance at the maternal-fetal interface plays a fundamental role in the pathogenesis of unexplained recurrent spontaneous abortion (URSA). Human amniotic epithelial cells (hAECs) possess pregnancy-friendly immunomodulatory effects. Here, we investigated how function of naive CD4+ T cells from URSA patients is affected by hAECs. Methods Phenotypic characteristics of hAECs were determined by flow cytometry and their effect on proliferation of allogeneic peripheral blood mononuclear cells (PBMCs) was evaluated by a BrdU cell proliferation assay. Naive CD4+ T cells were isolated from 25 URSA patients and 5 healthy women and co-cultured with hAECs. Immunomodulatory effects of hAECs on cytokines profile, proliferation of stimulated CD4+ T cells and induction of regulatory T cells (Tregs) were assessed by ELISA and flow cytometry, respectively. Functional competency of Tregs was evaluated in an allogeneic mixed lymphocyte reaction (MLR) system. Results hAECs did not elicit allogeneic proliferative responses of PBMCs, inhibited proliferation of naive CD4+ T cells, induced production of Th2 and suppressed production of Th1 and Th17 cytokines. hAECs showed the ability to induce differentiation of Tregs and production of transforming growth factor-beta1 (TGF-β1) and interleukin-10 (IL-10). This ability was found to be superior in control subjects compared to URSA patients. Indeed, Tregs generated in the presence of hAECs expressed higher levels of CTLA-4 compared to Tregs generated in their absence and restrained the proliferation of autologus PBMCs in MLR system. Conclusion Based on these findings, hAECs can be considered as one potential candidate in immunotherapy of patients with URSA. Keywords Immunomodulatory effects Amniotic epithelial cells Naive T cells Unexplained recurrent spontaneous abortio

The Effects of Silymarin and Cyclosporine A on the Proliferation and Cytokine Production of Regulatory T Cells

Background: Immunosuppressive agents are necessary to enhance allograft tolerance after transplantation and the treatment of autoimmune disorders. Regulatory T cells (Tregs) play a pivotal role in improving allograft tolerance and determining the fate of transplanted organs. Therefore, the aim of this study was to investigate the immunomodulatory effects of cyclosporine A (CsA) and silymarin on the proliferation and cytokine production of Tregs. Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from healthy voluntaries and Tregs were isolated using an immunomagnetic separation method. The phenotypic characteristics of Tregs were determined by flow cytometry. Tregs were expanded and then cultured with different concentrations of CsA and silymarin. The effects of CsA and silymarin on the viability, proliferation, and transforming growth factor-beta 1 (TGF-β1) production of Tregs were determined after 3 and 5 days of culture. Results: CsA significantly decreased Treg proliferation in a dose-dependent manner (p < 0.01�0.05). CsA failed to change TGF-β1 production of Tregs. On the contrary, silymarin significantly increased the proliferation of Tregs (p < 0.01�0.05). A statistically significant increase was also observed in the TGF-β1 production of Tregs (p < 0.01�0.05). Our data showed that Treg viability was not compromised by CsA and silymarin. Conclusion: Overall, the results of this study for the first time indicate that silymarin, unlike CsA, has the ability to increase the proliferation and TGF-β1 production of Tregs and may be beneficial in the treatment of autoimmune disorders and improvement of Treg-dependent allograft tolerance after transplantation. © 2019, © 2019 Taylor & Francis

Comparison of the Percentage of Regulatory T cells and their p-STAT5 Expression in Allergic and Non-Allergic Common Variable Immunodeficiency Patients

Background: Common Variable Immunodeficiency (CVID) is a primary immunodeficiency characterized by an immunologic deficiency in immunoglobulin production. Regulatory T cells (Tregs) play a key role in preventing the development allergic disorders. p-STAT5 is a known factor for the function and survival of Tregs. This study aimed to investigate the number of Tregs and their p-STAT5 expression in allergic and non-allergic CVID patients. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from 10 healthy volunteers, 10 allergic patients, and 16 CVID patients (allergic and non-allergic) using Ficoll density centrifugation. The percentage of Tregs in PBMCs was analyzed by flow cytometry. Tregs were also isolated from participants using an immunomagnetic separation method and p-STAT5 expression was evaluated in Tregs using flow cytometry. Results: The results revealed that Treg percentage was significantly lower in the CVID patients than the control groups (healthy and allergic individuals) (p<0.001). There was a significant reduction in Treg percentage in allergic patients compared to healthy subjects (p<0.05). No significant difference in Treg percentage between allergic and non-allergic CVID patients was observed. The expression of p-STAT5 in Tregs was significantly lower in CVID patients than the control groups (p<0.001). In addition, the expression of p-STAT5 in Tregs of allergic patients was significantly decreased compared to healthy subjects (p<0.001). However, the deference of p-STAT5 level was not statistically significant between allergic and non-allergic CVID patients. Conclusion: These findings suggest that p-STAT5 signaling defect and decreased Treg number may not participate in the development of allergy in CVID patients. © 2018, © 2018 Taylor & Francis

Immunomodulatory effects of human amniotic epithelial cells on naive CD4 + T cells from women with unexplained recurrent spontaneous abortion

Introduction: Immune imbalance at the maternal-fetal interface plays a fundamental role in the pathogenesis of unexplained recurrent spontaneous abortion (URSA). Human amniotic epithelial cells (hAECs) possess pregnancy-friendly immunomodulatory effects. Here, we investigated how function of naive CD4 + T cells from URSA patients is affected by hAECs. Methods: Phenotypic characteristics of hAECs were determined by flow cytometry and their effect on proliferation of allogeneic peripheral blood mononuclear cells (PBMCs) was evaluated by a BrdU cell proliferation assay. Naive CD4 + T cells were isolated from 25 URSA patients and 5 healthy women and co-cultured with hAECs. Immunomodulatory effects of hAECs on cytokines profile, proliferation of stimulated CD4 + T cells and induction of regulatory T cells (Tregs) were assessed by ELISA and flow cytometry, respectively. Functional competency of Tregs was evaluated in an allogeneic mixed lymphocyte reaction (MLR) system. Results: hAECs did not elicit allogeneic proliferative responses of PBMCs, inhibited proliferation of naive CD4 + T cells, induced production of Th2 and suppressed production of Th1 and Th17 cytokines. hAECs showed the ability to induce differentiation of Tregs and production of transforming growth factor-beta1 (TGF-β1) and interleukin-10 (IL-10). This ability was found to be superior in control subjects compared to URSA patients. Indeed, Tregs generated in the presence of hAECs expressed higher levels of CTLA-4 compared to Tregs generated in their absence and restrained the proliferation of autologus PBMCs in MLR system. Conclusion: Based on these findings, hAECs can be considered as one potential candidate in immunotherapy of patients with URSA. © 201

Assessment of microRNA-146a in generalized aggressive periodontitis and its association with disease severity

Background and Objective: MicroRNA-146a (miR-146a) is a small noncoding RNA that plays a critical role in the negative regulation of the innate immune response, and the dysregulation of miR-146a has been associated with several inflammatory disorders. In generalized aggressive periodontitis (GAgP) the degree of clinical inflammation appears to be similar to that of chronic periodontitis, and, in this situation, age of onset and family history are important additional criteria for diagnosis. This study was performed to evaluate the level of miR-146a expressed in gingival tissues of patients with GAgP and its association with disease severity. Material and Methods: Gingival samples from 18 patients with GAgP and 10 healthy subjects were collected and the level of miR-146a and its targets, including necrosis factor-alpha, interleukin-1beta, and interleukin-6, were assessed using real-time PCR. Clinical parameters, including probing depth and clinical attachment loss, were measured and their correlations with the level of miR-146a were determined. Results: Our results demonstrated an elevation in the level of miR-146a expressed in patients with GAgP compared with healthy controls (P <.001), which was directly associated with disease severity (P <.05). Overexpression of miR-146a was accompanied by a reduction in the levels of pro-inflammatory cytokines. Conclusions: Our findings suggest that there is an association between miR-146a and GAgP and imply that miR-146a may serve as an indicator of periodontal disease severity. However, further studies and additional information are required to confirm this relationship and the precise role of miR-146a in the development and/or progression of periodontitis. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Lt

Regulatory t-cells and their impacts on cytokine profile of end-stage renal disease patients suffering from systemic lupus erythematosus

Autoimmunity is an identified factor for development of end-stage renal disease (ESRD). Regulatory T-cells (Tregs) play a fundamental role in preventing autoimmunity. This study aimed to determine Treg frequency and its effects on cytokine profile of ESRD patients with and without systemic lupus erythematosus (SLE). Moreover, this study also determines how Treg number is affected by blood transfusion and gender. Peripheral blood mononuclear cells were isolated from 26 ESRD and 10 healthy subjects and stained with anti-CD4, anti-CD25, and anti-FoxP3 antibodies. Treg frequencies in ESRD patients with and without blood transfusion were determined by flow cytometry. Antibodies against human leukocyte antigens (HLAs) were investigated by panel-reactive antibodies screening. Tumor growth factor (TGF)-β1, interleukin (IL)-4, IL-10, TNF-α, IL-17A, and interferon (IFN)-γ serum levels in participants were measured by enzyme-linked immunoasorbent assay (ELISA). ESRD patients with SLE, unlike the patients without SLE, showed a significant reduction in Treg percentage compared to healthy subjects (P < 0.01). All women had a reduced number of Tregs compared to men. Treg number was significantly decreased in ESRD patients with HLA antibodies (P < 0.05). Blood transfusion enhanced Treg development in ESRD patients without SLE, unlike the patients with SLE (P < 0.05). ESRD patients with low Treg showed a reduction in TGF-β1 and IL-4 and an increase in TNF-α and IL-17A levels compared to control groups (P < 0.05�0.0001). However, no change was observed in IL-10 and IFN-γ levels. Treg frequency was negatively associated with the age of patients (P < 0.01), while this association was not observed in healthy subjects. Based on these findings, it can be observed that reduction in Treg number may contribute to ESRD development in patients with SLE. © The Author(s) 2019

The effect of lipopolysaccharide on the expression level of immunomodulatory and immunostimulatory factors of human amniotic epithelial cells

Objective Human amniotic epithelial cells (hAECs) are a novel source of stem cells and have immunomodulatory effects on both the innate and adoptive immune system. hAECs can differentiate into multiple cell lineages that make them a suitable cell source for regenerative medicine. These cells express multiple toll-like receptors (TLRs) and respond to various TLR ligands. This study aimed to evaluate the effect of lipopolysaccharide (LPS), a TLR4 ligand, on the level of immunomodulatory and immunostimulatory factors of hAECs. Results Our results indicated that LPS had the ability to up-regulate the expression of prostaglandin E2 synthase and transforming growth factor-beta1 in hAECs. However, there was no change in the level of interleukin-1beta, interleukin-6 and interleukin-10 in hAECs when were stimulated with LPS. In addition, we observed tumor necrosis factor-alpha was only expressed at very low level in some of hAECs samples which its expression was independent of the effects of LPS. Keywords: Human amniotic epithelial cells Toll-like receptors Lipopolysaccharide Immunomodulatory effects Regenerative medicin

Human amniotic epithelial cells inhibit activation and pro-inflammatory cytokines production of naive CD4+ T cells from women with unexplained recurrent spontaneous abortion

Unexplained recurrent spontaneous abortion (URSA) has been assumed to be caused by a defect in maternal immunological tolerance to the fetus. Human amniotic epithelial cells (hAECs) have stem cell-like features and the ability to modulate the innate and adoptive immune responses. This study aimed to investigate whether hAECs have immunomodulatory effects on naive CD4+ T cells from URSA patients. hAECs were obtained from 15 healthy pregnant women and phenotypic profile of hAECs was determined by flow cytometry. Naive CD4+ T cells were isolated from 25 URSA patients using an immunomagnetic separation method. Naive T cells were stimulated with anti-CD3/anti-CD28 antibodies and co-cultured with different numbers of hAECs for 3 and 6 days. Immunomodulatory effect of hAECs on activation of stimulated T cell was assessed by flow cytometry and Enzyme-linked immunoasorbent assay (ELISA). The hAECs effect on pro-inflammatory cytokines production of activated T cells was also measured by ELISA. Our results indicated that hAECs significantly inhibited the activation of naive T cells in a dose-dependent manner (p < 0.0001–0.05). They significantly reduced the production of transforming growth factor-beta1 (TGF-β1) of stimulated CD4+T cells (p < 0.0001–0.05). Moreover, hAECs had potent immunomodulatory effects on the production of interferon-gamma (IFN-γ) and interleukin-17A (IL-17A) of activated T cells (p < 0.0001–0.01). These findings suggest that hAECs may be a suitable cell source to modulate abnormal immune responses in women with URSA

Association of programmed death-1 gene polymorphisms with the risk of basal cell carcinoma

Environmental and genetic factors play a fundamental role in the pathogenesis of basal cell carcinoma (BCC) defined as the most common cancer of skin. Programmed death-1 (PD-1), encoded by programmed cell death-1 (PDCD1) gene, serves as an inhibitory molecule in the suppression of immune responses and a risk factor in the development of different cancers. In this study, we investigated the role of two single nucleotide polymorphisms (SNPs) within PDCD1 gene, and haplotypes defined by these SNPs, in the development of BCC in an Iranian population. Whole blood samples were obtained from 210 BCC and 320 healthy subjects. Genomic DNA was extracted from whole blood samples, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to genotype determinations of PD1.3 (rs11568821) and PD1.5 (rs2227981) SNPs, and 4 haplotypes were constructed by PDCD1 SNPs. The frequency of G allele of PD1.3 was significantly higher in BCC patients than healthy subjects (p < 0.02), while these significant differences were not observed in the frequencies of PD1.5 alleles between BCC and healthy subjects. Moreover, we found that there were no statistically significant differences in PD1.3 and PD1.5 genotypes between BCC and control groups. Of all estimated haplotypes for PDCD1, only AC haplotype was associated with BCC (OR = 0.22, 95 CI = 0.06�0.79, p < 0.01). These findings suggest that PD1.3G allele and AC haplotype of PDCD1 contribute to BCC in the Iranian population. However, further studies in different populations with larger sample size are required to confirm this study. © 2019 John Wiley & Sons Lt