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Placenta-specific protein 1 (PLAC-1) is a gene primarily expressed in the placenta and the testis. Interestingly, it is also found to be expressed in many solid tumors, and it is involved in malignant cell features. However, no evidence has been reported regarding the relationship between PLAC-1 and cancer stem cells (CSCs). In the current research, we explored the expression of the PLAC-1 molecule in prostate cancer stem cells (PCSCs) derived from the human PC-3 cell line. The enrichment of PCSCs was achieved using a three-dimensional cell culture technique known as the sphere-formation assay. To confirm the identity of PCSCs, we examined the expression of genes associated with stemness and pluripotency, such as SOX2, OCT4, Nanog, C-Myc, and KLF-4, as well as stem cell differentiation molecules like CD44 and CD133. These evaluations were conducted in both the PCSCs and the original tumor cells (parental cells) using real-time PCR and flow cytometry. Subsequently, we assessed the expression of the PLAC-1 molecule in both enriched cells and parental tumor cells at the gene and protein levels using the same techniques. The tumor cells from the PC-3 cell line formed spheroids with CSC characteristics in a non-adherent medium. The expression of SOX2, OCT4, Nanog, and C-Myc genes (p < 0.01), and the molecules CD44 and CD133 (p < 0.05) were significantly elevated in PCSCs compared to the parental cells. The expression of the PLAC-1 molecule in PCSCs showed a significant increase compared to the parental cells at both gene (p < 0.01) and protein (p < 0.001) levels. In conclusion, it was indicated for the first time that PLAC-1 is up-regulated in PCSCs derived from human PC-3 cell line. This study may propose PLAC-1 as a potential target in targeted therapies, which should be confirmed through further studies., (© 2024. The Author(s).)

Background: Fibroblast-like synoviocytes (FLSs) are involved in osteoarthritis (OA) pathogenesis through pro-inflammatory cytokine production. TAK-242, a TLR4 blocker, has been found to have a significant impact on the gene expression profile of pro-inflammatory cytokines such as IL1-β, IL-6, TNF-α, and TLR4, as well as the phosphorylation of Ikβα, a regulator of the NF-κB signaling pathway, in OA-FLSs. This study aims to investigate this effect because TLR4 plays a crucial role in inflammatory responses., Materials and Methods: Ten OA patients' synovial tissues were acquired, and isolated FLSs were cultured in DMEM in order to assess the effectiveness of TAK-242. The treated FLSs with TAK-242 and Lipopolysaccharides (LPS) were analyzed for the mRNA expression level of IL1-β, IL-6, TNF-α, and TLR4 levels by Real-Time PCR. Besides, we used western blot to assess the protein levels of Ikβα and pIkβα., Results: The results represented that TAK-242 effectively suppressed the gene expression of inflammatory cytokines IL1-β, IL-6, TNF-α, and TLR4 which were overexpressed upon LPS treatment. Additionally, TAK-242 inhibited the phosphorylation of Ikβα which was increased by LPS treatment., Conclusion: According to our results, TAK-242 shows promising inhibitory effects on TLR4-mediated inflammatory responses in OA-FLSs by targeting the NF-κB pathway. TLR4 inhibitors, such as TAK-242, may be useful therapeutic agents to reduce inflammation and its associated complications in OA patients, since traditional and biological treatments may not be adequate for all of them., (© 2024. The Author(s).)

Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type of tumor have remained grim for a long time. Currently, it is extremely challenging to prevent or detect it early enough for effective treatment because patients rarely exhibit symptoms and there are no reliable indicators for detection. Most patients have advanced or spreading cancer that is difficult to treat, and treatments like chemotherapy and radiotherapy can only slightly prolong their life by a few months. Immunotherapy has revolutionized the treatment of pancreatic cancer, yet its effectiveness is limited by the tumor's immunosuppressive and hard-to-reach microenvironment. First, this article explains the immunosuppressive microenvironment of pancreatic cancer and highlights a wide range of immunotherapy options, including therapies involving oncolytic viruses, modified T cells (T-cell receptor [TCR]-engineered and chimeric antigen receptor [CAR] T-cell therapy), CAR natural killer cell therapy, cytokine-induced killer cells, immune checkpoint inhibitors, immunomodulators, cancer vaccines, and strategies targeting myeloid cells in the context of contemporary knowledge and future trends. Lastly, it discusses the main challenges ahead of pancreatic cancer immunotherapy., (© 2024. The Author(s).)

Vitamin D is a fat-soluble steroid hormone that was initially known only for regulating calcium and phosphorus levels and maintaining bone health. However, it was later discovered that many organs express vitamin D metabolizing enzymes and have a ligand for vitamin D, which regulates the expression of an extensive assortment of genes. As a result, vitamin D is indispensable for the proper function of organs, and its deficiency is believed to be a critical factor in symptoms and disorders such as cardiovascular diseases, autoimmune diseases, and cancers. The significance of vitamin D in reproductive tissues was recognized later, and studies have revealed its crucial role in male and female fertility, as well as proper reproductive function during pregnancy. Vitamin D deficiency has been identified as a risk factor for infertility, gonadal cancers, pregnancy complications, polycystic ovary syndrome, and endometriosis. However, data investigating the association between vitamin D levels and reproductive disorders, including endometriosis, have encountered inconsistencies. Therefore, the present study aims to review existing research on the effect of vitamin D on proper reproductive function, and the role of deficiency in reproductive diseases and specifically focuses on endometriosis., (© 2024. The Author(s).)

Background: Depression is one of the most common psychological disorders among multiple sclerosis (MS) patients that characterized as the first symptoms. Ellagic acid is a natural polyphenol that may have neuroprotective properties through antioxidant, anti-inflammatory, and immunomodulatory effects., Purpose: The aim of the present study was to investigate the effects of Ellagic acid on circulating levels of brain derived neurotrophic factor (BDNF), interferon-γ (IFN-ƴ), nitric oxide (NO), nuclear factor erythroid-2-related factor 2 (Nrf2), cortisol, serotonergic system, and indoleamine 2, 3-dioxygenase (IDO) gene expression in MS patients with mild to moderate depressive symptoms., Study Design: A randomized triple-blind clinical trial., Methods: The eligible patients according to the inclusion criteria were randomly divided into two groups: either 180 mg Ellagic acid (Axenic company) (n = 25) or 180 mg maltodextrin (n = 25) group for 12 weeks. The Ellagic acid supplement were identical to placebo in shape, color and odor. Serum BDNF, NO, Nrf2, cortisol, serotonin, and IFN-ƴ were measured by ELISA kit in the baseline and end of the study. Also, demographic characteristics, anthropometric measurements, physical activity, food intake, Beck Depression Inventory-II (BDI-II) and expanding disability status scale (EDSS) questionnaires, as well as IDO gene expression were assessed. SPSS software version 24 was used for statistical analysis., Results: Fifty patients were evaluated, and a significant decrease in BDI-II (p = 0.001), IFN-ƴ (p = 0.001), NO (p = 0.004), cortisol (p = 0.015), IDO gene expression (p = 0.001) and as well as increased the level of BDNF (p = 0.006) and serotonin (p = 0.019) was observed among those who received 90 mg Ellagic acid twice a day for 12 weeks versus control group. However, there were no significant differences between groups for Nrf2 levels (p>0.05) at the end of study., Conclusion: The current study indicates that Ellagic acid intervention has a favorable effect on depression in MS patients. This is achieved by reducing BDI-II scores, as well as levels of NO, cortisol, IFN-ƴ, and IDO gene expression. Furthermore, we found a significant elevation in circulating levels of BDNF and serotonin., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Background: Multiple sclerosis (MS) is a chronic autoimmune disease. Ellagic acid is a natural polyphenol and affects the fate of neurons through its anti-inflammatory and antioxidant properties. The present study aimed to investigate ellagic acid effects on disease severity, the expression of involved genes in the pathogenesis of MS, and the levels of related cytokines., Methods: The present study was a triple-blind clinical trial. Eligible patients were randomly assigned to two groups: Ellagic acid (25 subjects) for 12 weeks, receiving 180 mg of Ellagic acid (Axenic, Australia) and the control group (25 subjects) receiving a placebo, before the main meals. Before and after the study, the data including general information, foods intake, physical activity, anthropometric data, expanded disability status scale (EDSS), general health questionnaire (GHQ) and pain rating index (PRI), fatigue severity scale (FSS) were assessed, as well as serum levels of interferon-gamma (IFNγ), interleukin-17 (IL-17), interleukin-4 (IL-4) and transforming growth factor-beta (TGF-β), nitric-oxide (NO) using enzyme-linked immunoassay (ELISA) method and expression of T-box transcription factor (Tbet), GATA Binding Protein 3 (GATA3), retinoic acid-related orphan receptor-γt (RORγt) and Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) genes were determined using Real-Time Quantitative Reverse Transcription PCR (RT-qPCR) method., Findings: Ellagic acid supplementation led to a reduction in IFNγ, IL-17, NO and increased IL-4 in the ellagic acid group, however in the placebo group no such changes were observed (-24.52 ± 3.79 vs. -0.05 ± 0.02, p < 0.01; -5.37 ± 0.92 vs. 2.03 ± 1.03, p < 0.01; -18.03 ± 1.02 vs. -0.06 ± 0.05, p < 0.01, 14.69 ± 0.47 vs. -0.09 ± 0.14, p < 0.01, respectively). Ellagic acid supplementation had no effect on TGF-β in any of the study groups ( p > 0.05). Also, the Tbet and RORγt genes expression decreased, and the GATA3 gene expression in the group receiving ellagic acid compared to control group significantly increased (0.52 ± 0.29 vs. 1.51 ± 0.18, p < 0.01, 0.49 ± 0.18 vs. 1.38 ± 0.14, p < 0.01, 1.71 ± 0.39 vs. 0.27 ± 0.10, p < 0.01). Also, ellagic acid supplementation led to significant decrease in EDSS, FSS and GHQ scores ( p < 0.05), and no significant changes observed in PRI score ( p > 0.05)., Conclusion: Ellagic acid supplementation can improve the health status of MS patients by reduction of the inflammatory cytokines and Tbet and RORγt gene expression, and increment of anti-inflammatory cytokines and GATA3 gene expression. Clinical trial registration : (https://en.irct.ir/trial/53020), IRCT20120415009472N22., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jafari Karegar, Aryaeian, Hajiluian, Suzuki, Shidfar, Salehi, Ashtiani, Farhangnia and Delbandi.)

Background: The reconstitution of different T-cell subsets following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is critical for efficient pathogen protection and the prevention of graft-versus-host disease (GvHD). In particular, studies have highlighted the importance of balanced ratios of regulatory T-cells (Tregs) and distinct functionally T-cells in preventing acute and chronic GvHD., Methods: We evaluated the regeneration of CD4 and CD8 T-cell subpopulations in nine pediatric patients with non-malignant disorders following allo-HSCT from a fully HLA-identical donor., Results: CD4 and CD8 T-cells were higher 12 months after the transplant but still lower than in healthy controls and pre-transplant. However, we found after allo-HSCT, central memory and effector memory cell subsets were the predominant phenotypes in the CD4 and CD8 T-cell populations, respectively. In patients who had developed acute GvHD, there was an increase in the frequency of TEMRA (effector memory T cells that re-express CD45RA) cells within the CD4 T-cell population. Meanwhile, in patients with chronic GvHD, we observed a decrease in Th1 cells in CD4 T-cells and effector memory cells within the CD8 T-cell population. In addition, we found decreased TEMRA cell subsets in CD4 and CD8 T-cell populations in chronic GvHD., Conclusion: Our findings suggest a possible relationship between the influence of acute GvHD and its prevention on delayed CD4 T-cell reconstitution and, reciprocally, unbalanced regeneration of CD4 and CD8 T-cell subsets in the development of chronic GvHD., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Background: Seminal plasma exosomes are now recognized to play a complex role in the regulation of the female reproductive system infertility. The objective of this study was to assess the effect of exosomes derived from the sperm of men with oligoasthenoteratozoospermia on endometrial implantation-related genes., Methods: To isolate the exosomes, we employed an ultracentrifugation method on samples derived from 10 fertile men with normal sperm parameters and 10 men with oligoasthenoteratozoospermia. The size distribution and ultrastructure of the exosomes were then characterized using transmission electron microscopy and dynamic light scattering. We detected an exosome marker using western blot analysis and confirmed the cytoplasmic localization of the exosomes by incubating them with DiI dye and visualizing them using fluorescence microscopy. After 6 hours of in vitro treatment of endometrial epithelial cells with 100 µg/ml seminal exosome, the endometrial receptivity genes were examined using qRT-PCR. To perform data analysis and quantification, we utilized Image J and Prism software. P< 0.05 were considered statistically significant., Results: After 6 hours of treatment, the mRNA levels of MUC1, LIF, G-CSF, CX3CL1, and VEGF were significantly downregulated in the endometrial epithelial cells treated with oligoasthenoteratozoospermia exosomes compared to the normal group. Although changes were observed in the mean mRNA levels of IL8 and TGF-β genes in the oligoasthenoteratozoospermia group compared to the normal group, these differences did not reach statistical significance (p > 0.05)., Conclusions: Oligoasthenoteratozoospermia exosomes have a distinct effect on endometrial receptivity compared to normal exosomes, leading to reduced expression of implantation-related genes., Competing Interests: The authors declare no conflicts of interest.

Antibody-based cancer immunotherapy has become a powerful asset in the arsenal against malignancies. In this regard, bispecific antibodies (BsAbs) are a ground-breaking novel approach in the therapy of cancers. Recently, BsAbs have represented a significant advancement in improving clinical outcomes. BsAbs are designed to target two different antigens specifically. Over a hundred various BsAb forms currently exist, and more are constantly being manufactured. An antagonistic regulator of T cell activation is cytotoxic T lymphocyte-associated protein 4 (CTLA-4) or CD152, a second counter-receptor for the B7 family of co-stimulatory molecules was introduced in 1996 by Professor James P. Allison and colleagues. Contrary to the explosive success of dual immune checkpoint blockade for treating cancers, a major hurdle still yet persist is that immune-related adverse events (irAEs) observed by combining immune checkpoint inhibitors (ICIs) or monoclonal antibodies such as ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). A promising strategy to overcome this hurdle is using BsAbs. This article will summarize BsAbs targeting CTLA-4, their applications in cancer immunotherapy, and relevant clinical trial advances. We will also discuss the pre-clinical rationale for using these BsAbs, and provide the current landscape of the field., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Farhangnia, Ghomi, Akbarpour and Delbandi.)

The signaling lymphocytic activation molecule (SLAM) family receptors were discovered in immune cells for the first time. The SLAM-family receptors are a significant player in cytotoxicity, humoral immune responses, autoimmune diseases, lymphocyte development, cell survival, and cell adhesion. There is growing evidence that SLAM-family receptors have been involved in cancer progression and heralded as a novel immune checkpoint on T cells. Previous studies have reported the role of SLAMs in tumor immunity in various cancers, including chronic lymphocytic leukemia, lymphoma, multiple myeloma, acute myeloid leukemia, hepatocellular carcinoma, head and neck squamous cell carcinoma, pancreas, lung, and melanoma. Evidence has deciphered that the SLAM-family receptors may be targeted for cancer immunotherapy. However, our understanding in this regard is not complete. This review will discuss the role of SLAM-family receptors in cancer immunotherapy. It will also provide an update on recent advances in SLAM-based targeted immunotherapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Farhangnia, Ghomi, Mollazadehghomi, Nickho, Akbarpour and Delbandi.)

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment option for hereditary hemoglobin disorders, such as beta-thalassemia; However, this procedure is not without constraints, mainly engendering complications such as acute graft-versus-host disease (aGvHD), chronic GvHD (cGvHD), and susceptibility to infections. The clinical outcomes of allo-HSCT are highly dependant on the quality and quantity of T-cell subsets reconstitution. Following the allo-HSCT of six pediatric patients afflicted with beta-thalassemia, their mononuclear cells were isolated, and then cultured with a combination of phorbol myristate acetate (PMA)/ionomycin and Brefeldin A. The content of CD4 T-cell subsets, including T helper 17 (Th17) cells and regulatory T cells (Tregs), were determined by specific conjugated-monoclonal antibodies three and six months post-HSCT. An increased frequency of total CD4 T-cells, Tregs and Th17 cells was observed at day 90 and 180 after allo-HSCT, albeit the numbers were still lower than that of our healthy controls. In patients who developed cGvHD, a lower Th17/Treg ratio was observed, owing it to a decreased proportion of Th17 cells. In conclusion, creating balance between Th17 and Treg subsets may prevent acute and chronic GvHD in patients after allo-HSCT., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Research Question: What is the effect of vitamin D3 (1,25(OH) 2 D 3 ) on proliferation, cell cycle and apoptosis of endometrial stromal cells (ESC) in endometriotic patients?, Design: ESC isolated from 10 women with endometriosis and 10 healthy controls were treated with 1,25(OH) 2 D 3 . The proliferation of control endometrial stromal cells (CESC), eutopic endometrial stromal cells (EuESC) and ectopic endometrial stromal cells (EESC) was analysed 72 h after the treatment using methyl thiazolyl tetrazolium assay. Propidium iodide staining and flow cytometry were used to determine the cell cycle distribution in ESC. Annexin V/propidium iodide double staining was used to evaluate apoptosis in ESC., Results: In the presence of oestrogen, 1,25(OH) 2 D 3 treatment inhibited the proliferation of ESC from all three origins (P = 0.009 for CESC, P = 0.005 for EuESC and P < 0.001 for EESC). The percentage of S phase cells in EESC was higher than in EuESC and CESC (P = 0.002 and P = 0.001, respectively). The percentage of S phase cells in EuESC was higher than in CESC (P = 0.005). The percentage of G1 phase cells in EESC was lower than that of EuESC and CESC (P = 0.003 and P = 0.002, respectively) and the percentage of G1 phase cells in EuESC was lower than that of CESC (P = 0.007). Moreover, 1,25(OH) 2 D 3 inhibited cell cycle regardless of cell type (P = 0.002 in EESC, P = 0.001 in EuESC and P = 0.014 in CESC), but in the absence of oestrogen, inhibited cell cycle only in EuESC (P = 0.012)., Conclusions: Although 1,25(OH) 2 D 3 increased apoptotic and necrotic cells and decreased live cells in the EuESC and EESC, it did not affect apoptosis in CESC and only increased necrotic cells. These findings indicate that 1,25(OH) 2 D 3 potentially has a growth-inhibiting and pro-apoptotic effect on ESC from endometriotic patients., (Copyright © 2022 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: Beta-thalassemia major is an autosomal recessive disorder in hemoglobin synthesis. Ineffective erythropoiesis is the main characteristic of the disease, which results in anemia following the extensive destruction of red blood cells. Chronic antigenic stimulation following frequent blood transfusions lead to immune abnormalities, especially regarding T cells, which is one of the reasons for the high susceptibility to infection in beta-thalassemia., Methods: Six pediatric patients and six age- and sex-matched healthy children were selected. Immunophenotyping of functional T-cells was performed using flow cytometry with staining for surface and intracellular markers. The proliferative response of T lymphocytes was also investigated after labeling with CFSE and following stimulation with anti-CD3 and anti-CD28., Results: Examination of T lymphocyte subpopulations showed a significant increase in regulatory T cells (Tregs) in beta-thalassemia patients. Hence, the Treg:Tcons (conventional T cells) and Treg:CD8 ratios were significantly increased. In addition, a significant increase in CD8 T cell proliferation activity was observed. Multivariate analysis showed a significant association of central memory cells with serum ferritin levels and the duration of transfusion. In particular, patients with cytomegalovirus (CMV) infection exhibited a significant increase in CD4 central memory cells., Conclusion: Patients with beta-thalassemia have functionally distinct CD4 and CD8 T cell subsets imbalances, and this may contribute to their high susceptibility to infections and immune dysregulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Introduction: The development of therapeutic antibodies targeting immune checkpoint molecules (ICMs) that induce long-term remissions in cancer patients has revolutionized cancer immunotherapy. However, a major drawback is that relapse after an initial response may be attributed to innate and acquired resistance. Additionally, these treatments are not beneficial to all patients. Therefore, the discovery and targeting of novel ICMs and their combination with other immunotherapeutics are urgently needed., Areas Covered: There has been increasing evidence of the CD96-TIGIT axis as ICMs in cancer immunotherapy in the last five years. This review will highlight and discuss the current knowledge about the role of CD96 and TIGIT in hematological and solid tumor immunotherapy in the context of empirical studies and clinical trials, and provide a comprehensive list of ongoing cancer clinical trials on the blockade of these ICMs, as well as the rationale behind combinational therapies with anti-PD-1/PD-L1 agents, chemotherapy drugs, and radiotherapy. Moreover, we share our perspectives on anti-CD96/TIGIT-related combination therapies., Expert Opinion: CD96-TIGIT axis regulates anti-tumor immune responses. Thus, the receptors within this axis are the potential candidates for cancer immunotherapy. Combining the inhibition of CD96-TIGIT with anti-PD-1/PD-L1 mAbs and chemotherapy drugs has shown relatively effective results in the context of preclinical studies and tumor models.

1,25(OH)2D3 has anti-inflammatory and growth inhibitory effects. Our study explored the effect of 1,25(OH)2D3 treatment on the expression of monocyte chemotactic protein-1 (MCP-1), hepatocyte growth factor (HGF), and insulin-like growth factor-1 (IGF-1) by peripheral blood mononuclear cells (PBMCs), peritoneal fluid mononuclear cells (PFMCs), endometrial stromal cells (ESCs), and its effect on the proliferation of PBMCs and PFMCs of patients with endometriosis compared with controls. PBMCs, PFMCs, and ESCs were obtained from 10 endometriosis patients and 10 non-endometriotic individuals. After treating cells with 0.1 μM of 1,25(OH)2D3 for 6, 24, and 48 h, the gene and protein expression of mentioned factors were evaluated by real-time PCR and ELISA methods, respectively. 1,25(OH)2D3 treatment significantly reduced the protein expression of MCP-1, HGF, and IGF-1 in PBMCs and PFMCs of endometriotic patients at 48 h (p &lt; 0.05-&lt;0.01). Also, this treatment significantly reduced MCP-1, HGF, and IGF-1 gene and/or protein expression in EESCs and EuESCs at 24 and 48 h (p &lt; 0.05-&lt;0.01). 1,25(OH)2D3 treatment also reduced the proliferation of PBMCs and PFMCs of endometriotic patients compared with controls (p &lt; 0.01). 1,25(OH)2D3 can be considered as a potentially effective agent in the prevention and treatment of endometriosis along with other therapies., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Hypoxia is a common characteristic of the tumor microenvironment. In response to hypoxia, expression of the hypoxia-inducible factor (HIF) can lead to activation of downstream molecular events such as epithelial-mesenchymal transition (EMT), invasion, and angiogenesis. In this study, CoCl2 was used to simulate hypoxia in SKBR3 and HEK293T cell lines to investigate whether this treatment can induce hypoxia-associated EMT and invasion in the studied cells. SKBR3 and HEK293T cells were treated with different concentrations of CoCl2 at different exposure times and their viability was analyzed. To confirm successful hypoxia induction, the expression levels of HIF1α and vascular endothelial growth factor A (VEGFA) mRNA were assessed. Additionally, the expression of EMT-associated markers including snail, E-cadherin, N-cadherin, and vimentin, as well as invasion-related genes including matrix metalloproteinase-2 (MMP2) and MMP9 was measured. We found that cell viability in CoCl2-treated cells was concentration-dependent and was not affected at low doses. While the expression of HIF and VEGFA genes was upregulated following hypoxia induction. E-cadherin expression was significantly downregulated in HEK293T cells; while, N-cadherin and snail were upregulated in both cell lines. Moreover, an increment of MMP expression was only observed in SKBR3 cells. Taken together, the findings indicated that CoCl2 can mimic hypoxia in both cell lines, but EMT was triggered in SKBR3 cells more effectively than in HEK293T cells, and invasion was only stimulated in SKBR3 cells. In conclusion, SKBR3 cancer cells can be used as an EMT model to better understand its control and manipulation mechanisms and to investigate new therapeutic targets for the suppression of tumor metastasis.

In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged, causing a global pandemic called COVID-19. Currently, there is no definitive treatment for this emerging disease. Global efforts resulted in developing multiple platforms of COVID-19 vaccines, but their efficacy in humans should be wholly investigated in the long-term clinical and epidemiological follow-ups. Despite the international efforts, COVID-19 vaccination accompanies challenges, including financial and political obstacles, serious adverse effects (AEs), the impossibility of using vaccines in certain groups of people in the community, and viral evasion due to emerging novel variants of SARS-CoV-2 in many countries. For these reasons, passive immunotherapy has been considered a complementary remedy and a promising way to manage COVID-19. These approaches arebased on reduced inflammation due to inhibiting cytokine storm phenomena, immunomodulation,preventing acute respiratory distress syndrome (ARDS), viral neutralization, anddecreased viral load. This article highlights passive immunotherapy and immunomodulation approaches in managing and treating COVID-19 patients and discusses relevant clinical trials (CTs)., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: A few studies investigated the relationship between allergy and Meniere disease considering complete allergen panel. We aimed to evaluate the serum immunoreactivity in patients with Meniere's disease (MD) compared with healthy people according to common indigenous Iranian inhalation and food allergens., Methods: Thirty-nine patients with MD referred to Rasoul Akram Hospital (Tehran, Iran) were evaluated and compared with a 41 membered control group. A panel of common inhalation and food allergens (using an immunoblotting method), as well as total immunoglobulin E (IgE) level (using the sandwich enzyme-linked immunosorbent assay method), were checked on the patients' serum., Results: The mean total IgE level was 193.85 ± 175.43 IU/ml in the patients with MD and 117.61 ± 138.05 IU/ml in the control group, which was significantly higher than the other subjects in the control group ( P = .016). There was a significant difference between the two groups regarding inhalation allergens such as; sweet vernal grass, cultivated rye, cultivated oat, Russian thistle, goosefoot, and rough pigweed ( P = .01-0.038). Patients with MD reported more reactive to food allergens such as; rye flour, hazelnut, pepper, citrus mix 2, potato, strawberry, and celery allergens. There was a significant relationship between Meniere and serum immunoreactivity to inhalation and food allergens (both P = .001). Conclusion : Serum total IgE level in patients with MD (in both inhalation and food allergens groups) was higher than the control group, and there was a relationship between MD and immunoreactivity to common indigenous inhalation and food allergens of Iran.

Evidence has demonstrated that a new class of anti-diabetic drugs, sodium-glucose co-transporter 2 (SGLT2) inhibitors, could exert beneficial effects on atherosclerotic complications of diabetes. Atherosclerosis is widely accepted as an inflammatory disease. Therefore, we aimed to assess the direct anti-inflammatory effects of SGLT2 inhibitors dapagliflozin (DAPA) on two cell types involved in the process of atherogenesis. Human umbilical vein endothelial cells (HUVECs) and macrophages were exposed to DAPA and lipopolysaccharide (LPS 20 ng/mL) for 24 h under normal (5.5 mmol/L, NG) or high glucose (25 mmol/L, HG) conditions. Then, levels of TLR-4/p-NF-κB, inflammatory cytokines, inflammation-related miR-146a and miR-155 as well as alteration in the ratio of M1/M2 macrophage polarization was assessed. DAPA (0.5 μM) could significantly attenuate LPS-induced TLR-4 overexpression (23.9% and 33.1% under NG and HG conditions in HUVECs and 53.3% and 52.4% under NG and HG states in macrophages, respectively). NF-κB p65 phosphorylation was also significantly decreased to 30.1% under NG condition in HUVECs and 51.9% and 34.5% under NG and HG states in macrophages by 0.5 μM DAPA. Moreover, DAPA elevated expression levels of anti-inflammatory miR-146a, while values of miR-155 decreased in those cells. DAPA also caused a shift from inflammatory M1 macrophages toward M2-dominant macrophages. These data suggest that regardless of glucose concentrations, DAPA could exert direct anti-inflammatory effects, at least partly, by inhibiting the expression of TLR-4 and activation of NF-κB along with the secretion of pro-inflammatory mediators., (Copyright © 2021. Published by Elsevier B.V.)

Fine particles (especially PM 2.5 particles) in ambient air can cause irreversible effects on human health. In the present study, seasonal variations in toxicity PM 2.5 (cell viability and release of pro-inflammatory cytokines) were exposed human lung cells (A549) to concentrations of PM 2.5 samples in summer (sPM 2.5 ) and winter (wPM 2.5 ) seasons. Cells were separately exposed to three concentrations of PM 2.5 (25, 50, and 100 μg/mL) and three times (12 h, 1 and 2 days). We evaluated cell viability by MTT assay [3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide] and liberation of pro-inflammatory cytokines (interleukin-6 and interleukin-8) by the ELISA method. The toxicological results of this study showed that increasing the concentration of PM 2.5 particulates and contact time with it reduces cell viability and increases inflammatory responses. Seasonal cytotoxicity of PM 2.5 particles in high-traffic areas at summer season compared to winter season was lower. The lowest percent of viability at 2 days of exposure and 100 μg/mL exposure in the winter sample was observed. Also, PM 2.5 particles were influential in the amount of interleukins 8 and 6. The average release level of IL-6 and IL-8 in the cold season (winter) and the enormous exposure time and concentrations (2 days-100 μg/mL) was much higher than in the hot season (summer). These values were twice as high for winter PM 2.5 samples as for summer samples. The compounds in PM 2.5 at different seasons can cause some biological effects. The samples' chemical characteristics in two seasons displayed that the PMs were diverse in chemical properties. In general, heavy metals and polycyclic aromatic hydrocarbons were more in the winter samples. However, the samples of wPM 2.5 had a lower mass quota of metals such as aluminum, iron, copper, zinc, and magnesium. Concentrations of chromium, cadmium, arsenic, mercury, nickel, and lead were more significant in the sample of wPM 2.5 ., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: To study the concentrations of monocyte chemoattractant protein-1 (MCP-1), hepatocyte growth factor (HGF), and insulin-like growth factor-1 (IGF-1) in peritoneal fluid (PF) and serum, and to evaluate their expressions by PF and peripheral blood mononuclear cells (PFMCs and PBMCs, respectively), and ectopic and eutopic endometrial stromal cells of patients with endometriosis (EESCs and EuESCs, respectively) compared with controls., Methods: The concentrations of mentioned cytokines in serum and PF, as well as their expression in PBMCs, PFMCs, EuESCs and EESCs from endometriosis patients and controls were assessed., Results: The levels of MCP-1, HGF, and IGF-1 in serum and PF in women with endometriosis were significantly higher than the controls (P < 0.05-P < 0.001). Gene expression of MCP-1 and IGF-1 in the PFMCs, PBMCs and EESCs also showed an increased level compared to controls (P < 0.05-P < 0.01). The protein expression of MCP-1 and IGF-1 by PFMCs was statistically higher in endometriotic women (P < 0.05 and P < 0.01, respectively). The gene and protein expression of HGF in PFMCs and its gene expression by EESCs were significantly higher in endometriotic women compared to controls (P < 0.05-P < 0.01)., Conclusions: The higher concentrations of mentioned cytokines in serum and PF and their higher expression by PFMCs and EESCs in endometriosis patients may contribute to the development of endometriosis., (© 2021. The Author(s).)

Endometriosis is a chronic inflammatory disease that has been reported to be associated with immune system dysfunction. On the other hand, the effect of Vitamin D as an immune modulator and its relation with several autoimmune and inflammatory diseases has been previously investigated. Moreover, several studies have reported the polymorphisms of VDR and VDBP genes can change the functions of these molecules. Therefore, these polymorphisms may be influential on endometriosis pathogenesis. In this study, we aimed at evaluating the association between VDR gene (FokI (F/f), BsmI (B/b), ApaI (A/a), TaqI (T/t)), and VDBP gene (GC*1S, GC*1F, and GC*2) polymorphisms with endometriosis in Iranian women population. This case-control study was performed on 120 women with endometriosis and 110 healthy women. ARMS-PCR and PCR-RFLP methods were used to inspect polymorphisms in VDR and VDBP genes, respectively. Based on the results, there was no statistically significant difference between the cases with endometriosis and control subjects in terms of genotypes and allele frequencies of VDR and VDBP gene polymorphisms. These data suggest that VDR and VDBP gene polymorphisms may have no role in endometriosis susceptibility in Iranian women., (© 2021. Society for Reproductive Investigation.)

Fibroblast-like synoviocytes (FLSs) produce lots of inflammatory molecules that trigger immune responses and intensification the inflammation and thereby play important roles in Rheumatoid Arthritis )RA( pathogenesis. Due to the important roles of toll-like receptor 4 (TLR4) in cytokine production and inflammation, we aimed to evaluate the effects of TAK-242 (Resatorvid) on interleukin (IL)1-β, IL-6, TNF-α, and TLR4 expression and two important proteins of nuclear factor-κB (NF-κB) signaling pathway (Ikβα and pIkβα) in RA and trauma FLSs. FLSs were isolated from synovial tissues of trauma (n=10) and RA (n=10) patients and cultured in Dulbecco's Modified Eagle Medium (DMEM). 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) was performed to evaluate the cytotoxicity effects of TAK-242 on the RA FLSs. Real-time PCR was performed to measure the expression level of IL1-β, IL-6, TNF-α, and TLR4 genes in Lipopolysaccharide (LPS) and TAK-242 treated FLSs. Furthermore, the treated FLSs were evaluated for protein levels of Ikβα and pIkβα by western blot. The baseline expression of IL1-β, IL-6, TNF-α, and TLR4 showed no significant differences between healthy and RA FLSs. LPS stimulated FLSs significantly increased mRNA levels of IL-1β, IL-6, TNF-α, and TLR4 genes in both the healthy and RA FLSs compared with that of their control groups, and pretreatment with TAK-242 reversed the effect. Furthermore, LPS-stimulated FLSs significantly increased the level of pIkβα in both the healthy and RA FLSs compared with that of their control groups, and pretreatment with TAK-242 reversed the effect. We provide the data that TAK-242 through inhibiting the NF-κB signaling pathway may modulate TLR4-mediated inflammatory responses and could be considered as a potential therapeutic agent for RA patients.

Resveratrol is a phytochemical with anti-angiogenic, anti-inflammatory, and antioxidant properties. The present study has evaluated the effect of resveratrol on the expression of vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β) and matrix metalloproteinase-9 (MMP-9) as factors related to endometriosis progression. Thirteen eutopic (EuESCs) and 8 ectopic (EESCs) endometrial stromal cells from women with endometriosis and 11 control endometrial stromal cells (CESCs) were treated with resveratrol (100 µM) for 6, 24 and 48 h. The gene and protein expression levels of VEGF, TGF-β, and MMP-9 were measured using real-time PCR and ELISA methods, respectively. Results showed that the basal gene and protein expression of VEGF and MMP-9 were higher in EESCs compared to EuESCs and CESCs (P < 0.01 to  < 0.001 and P < 0.05 to  < 0.01 respectively). Also, resveratrol treatment decreased the gene and protein expression of VEGF and MMP-9 in EuESCs, EESCs and CESCs (P < 0.05 to  < 0.01 and P < 0.05 to  < 0.01 respectively) and gene and protein expression of TGF-β in EESCs and EuESCs (P < 0.05 to  < 0.01). The effect of resveratrol in reduction of VEGF gene expression was statistically more noticeable in EESCs compared to EuESCs and CESCs (P < 0.05). According to the findings, resveratrol may ameliorate endometriosis progression through reducing the expression of VEGF, TGF-β, and MMP-9 in endometrial stromal cells (ESCs).

Purpose: Vitamin D (Vit D), as an immunomodulator, has been hypothesized to play a critical role in the pathogenesis of endometriosis. Thus, in this study, we evaluated whether there is an association between 25-hydroxyvitamin D [25(OH)D] and susceptibility to endometriosis in Iranian women., Methods: Women at reproductive age, including 56 healthy women and 54 patients with endometriosis, were enrolled in the study. Serum levels of 25(OH)D, calcium, parathyroid hormone (PTH), and peritoneal fluid (PF) levels of 25(OH)D were assessed., Results: The serum and PF levels of 25(OH)D in the patients with endometriosis were significantly lower than the control group (P = 0.001 and P = 0.03, respectively). Subjects with serum levels of 25(OH)D lower than 20 ng/mL had a 2.7 times higher risk of endometriosis than people with 25(OH)D serum levels higher than 20 ng/mL (non-deficient) (OR = 2.7, 95 % confidence interval: 1.24-5.80, P = 0.01). The serum levels of calcium and PTH were significantly lower and higher in patients with endometriosis compared with controls, respectively (P < 0.001, P = 0.02, respectively). Also, the serum levels of 25(OH)D were lower in stages I-II endometriosis than stage III-IV; however, no significant difference was observed., Conclusion: Our findings showed that people with Vit D deficiency are at higher risk of endometriosis., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Endometriosis is an inflammatory disease affecting reproductive-aged women. Immunologic disturbance, as well as inflammation, have crucial roles in the pathogenesis of endometriosis. In this study, we evaluated the effects of resveratrol treatment on expression of monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), IL-8, and regulated upon activation, normal T cell expressed and secreted (RANTES) in endometrial stromal cells from patients with endometriosis compared with non-endometriotic controls. Thirteen eutopic (EuESCs) and nine ectopic (EESCs) endometrial stromal cells from endometriotic patients as well as eleven endometrial stromal cells from non-endometriotic controls (CESCs) were treated with resveratrol (100 μmol/L) or ethanol, and gene and/or protein expression of MCP-1, IL-6, IL-8 and RANTES was examined at 6, 24 and 48 hours following treatment in the cells from all origins. Resveratrol treatment significantly reduced gene and protein expression of MCP-1, IL-6, and IL-8 in EuESCs and EESCs compared with CESCs (P < .05-.001, P < .05-.001 and P < .05-<.01, respectively), and this reduction was more noticeable in EESCs than EuESCs (P < .05-<.001). Besides, resveratrol treatment significantly reduced RANTES protein expression in EESCs in all time intervals (P < .05). Resveratrol treatment significantly reduced the expression of MCP-1, IL-6, IL-8 and RANTES in EESCs., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Research Question: Endometriosis, an inflammatory disease, is assumed to be associated with an increased production of growth-related cytokines. Based on the emerging immunomodulatory role of vitamin D3 in different inflammatory conditions, this study aimed to examine its modulatory effect on the expression levels of the genes for platelet-derived growth factor-B (PDGFB), monocyte/macrophage-derived growth factor (MDGF, also known as PPBP) and epidermal growth factor (EGF) in peritoneal fluid mononuclear cells (PFMC) in women with and without endometriosis., Design: PFMC from 10 women with endometriosis and 10 control participants were treated with vitamin D3.The gene expression levels of PDGFB, MDGF and EGF were measured 6, 24 and 48 h following vitamin D3 administration using real-time PCR., Results: Gene expression levels of EGF and PDGFB were higher in the PFMC of women with endometriosis than the control group (P = 0.006, P < 0.001, respectively). Although MDGF expression showed an increase in the endometriosis group compared with non-endometriotic controls, no significant difference was found. Vitamin D3 significantly decreased EGF expression at 6, 24 and 48 h (P < 0.001, P < 0.001 and P = 0.007, respectively), MDGF at 24 and 48 h (P < 0.001 and P = 0.009, respectively) and PDGFB at 6 h (P = 0.047) in the endometriosis group. Vitamin D3 treatment had no significant effect on expression of the genes in the PFMC of non-endometriotic women., Conclusions: The study concluded that PDGFB and EGF gene expression increases in endometriosis, and vitamin D3 could markedly decrease this expression, suggesting its therapeutic potential in endometriosis., (Copyright © 2020 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Tuberculosis has been declared as a global emergency. Latent tuberculosis infection (LTBI) is a state in which host immunity cannot completely eradicate Mycobacterium tuberculosis . Cigarette smoke increases the risk of respiratory infections, such a TB, as it has adverse effects on respiratory immune function. In this cross-sectional study, which was performed from 2016 to 2017, 31 patients with newly diagnosed lung cancer, 63 Chronic obstructive pulmonary disease (COPD), 46 with problems in respiratory system, and 40 healthy subjects were studied. Demographic data of all subjects were recorded via a questionnaire. IGRAs (Interferon-γ release assays) were used to determine LTBI. We showed that smoking has significant odds ratio for COPD patients (OR: 4.58, 95% CI: 1.93-10.87). Also, the concordance of smoking with COPD (OR: 22, 95% CI: 2.7-179.2), lung cancer (OR: 10, 95% CI: 1.03-97), and other respiratory diseases (OR: 4.54, 95% CI: 1.93-10.87) is a significant risk factor for the presence of LTBI whereas the existence of LTBI in the study groups did not show any significant odds ratio. This study is the first to analyze the relationship between smoking in patients with respiratory diseases and LTBI susceptibility in Iran by IGRAs, which proposes cigarette smoking as a powerful risk factor for LTBI.

Background: The present study was designed to verify the accuracy of the noninvasive biomarkers enolase/Cr, CA125, and CA19-9 as a clinical diagnostic tool for the detection of endometriosis., Methods: A cross-sectional study was performed at Rasool-e-Akram Hospital affiliated to Iran University of Medical Sciences, Tehran, Iran, from April 2015 to April 2018. Eighty-six women were scheduled to undergo laparoscopy due to chronic pelvic pain, infertility, pelvic mass, and abnormal uterine bleeding. Serum and urine samples of all patients were collected preoperatively. Serum levels of CA125 and CA19-9, and urine levels of enolase-1 were measured. Serum levels of CA125 and CA19-9 were determined by the electrochemiluminescence method (ECL). Urinary enolase-1 was measured by the ELISA method., Result: Serum levels of CA125 and CA19-9 were significantly higher in the endometriosis group than in controls ( p < 0.001, p = 0.004, respectively). Levels of enolase I and enolase/Cr were higher in patients with endometriosis, but the differences were not statistically significant. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of combined enolase/Cr, CA125, and CA19-9 were 65%, 66.6%, 71%, and 60.1%, respectively. The positive likelihood ratio (PLR) and negative likelihood ratio (NLR) of combined enolase/Cr, CA125, and CA19-9 was 1.94 and 0.52, respectively. The area under the ROC curve for enolase/Cr + CA125 + CA19 - 9 was 0.675 (95% confidence interval 0.573-0.710)., Conclusion: The present study revealed that concurrent measurement of enolase-1, CA125, and CA19-9 might be a valuable noninvasive test for the identification of endometriosis., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2020 Samaneh Rokhgireh et al.)

Background: We aimed to examine resveratrol effects on gene expression of Bcl-2, Bax and Bcl-2/Bax ratio in endometrial stromal cells derived from women with and without endometriosis., Methods: Endometrial tissues were obtained from 40 endometriotic patients and 15 non-endometriotic controls undergoing laparoscopic surgery or hysterectomy in the gynecology ward of Rassoul Akram Hospital, Tehran, Iran from 2015 to 2017. After the enzymatic digestion, eutopic (EuESCs) and ectopic (EESCs) endometrial stromal cells from patients with endometriosis as well as endometrial stromal cells from non-endometriotic controls (CESCs) were treated with or without resveratrol (100 μM) and the levels of Bcl-2, Bax and Bcl-2/Bax gene expression ratio in the cells from all origins were examined at 6, 24 and 48 h post-treatment by real-time PCR., Results: Resveratrol treatment increased Bcl-2 expression in CESCs at 24 and 48 h and in EuESCs at 48 h ( P <0.05), but had no significant effects on the expression of this gene in EESCs. On the other hand, resveratrol treatment increased Bax expression in EuESCs at 6 h and decreased its expression in EESCs at 48 h ( P <0.05). Regarding the Bcl-2/Bax gene expression ratio, resveratrol treatment increased Bcl-2/Bax gene expression ratio in CESCs and EuESCs at 48 h ( P <0.01). However, this treatment had no significant differential effect on Bcl-2 and Bcl-2/Bax gene expression ratio between CESCs and EuESCs at 48 h., Conclusion: Resveratrol treatment significantly increased Bcl-2/Bax gene expression ratio in EuESCs and CESCs but had no significant effect in EESCs., Competing Interests: Conflict of interest Authors declare that there is no conflict of interest., (Copyright© Iranian Public Health Association & Tehran University of Medical Sciences.)

Background: Endometriosis is one of the most common chronic gynecological disorders affecting women at reproductive age. Dysregulation of immune cells, including regulatory T (Treg) cells has contributed to the growth of ectopic lesion in patients with endometriosis., Objective: The present study investigated the frequency of Tregs in peripheral blood and the expression of Foxp3 in eutopic and ectopic endometriotic tissues in women with and without endometriosis., Materials and Methods: Peripheral blood mononuclear cells (PBMCs) and eutopic and ectopic endometriotic tissues were obtained from 23 endometriotic and 20 non-endometriotic control women. The frequency of Treg cells in PBMCs was measured using flowcytometry and the expression of Foxp3 in eutopic and ectopic endometriotic tissues was determined by real-time PCR, western blotting and immunohistochemistry., Result: The frequency of circulating Tregs was significantly higher in endometriotic patients compared with non-endometriotic controls (P < 0.01). The mRNA and protein expression of Foxp3 in eutopic and ectopic endometriotic tissues had no significant differences between the two study groups., Conclusion: Higher frequency of circulating Tregs in patients with endometriosis compared with controls may be considered as a compensatory mechanism to regulate the inflammatory condition in this disease., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020. Published by Elsevier B.V.)

Human platelet antigens (HPAs) are membranous glycoproteins considered as alloantigens due to their polymorphisms. HPA-incompatibility in multiple pregnancies or blood transfusion can induce the development of alloantibodies leading to thrombocytopenia. The frequency of HPAs varies among populations, so that deep knowledge of HPA frequencies will help us to reduce those incompatibilities. Herein, we studied the allele and genotype frequencies of HPA1-6, HPA9, and HPA15 among the Iranians with intra- and inter-populations analyses on 36 worldwide populations with diverse ethnicities. The analysis shows that the HPA2 and HPA5 have the greatest differences in genotype distribution between the Iranians and other nations, although similar to other populations, the sole allele found in HPA4, 6, and 9 is "a". Despite other HPAs, the most frequent allele in HPA15 is "b", which is also abundant in HPA3. Hierarchical clustering indicates the highest degree of global similarity in HPA genotype frequency among Iranian, Argentinian, Brazilian, and German Turkish populations. Our findings can be applied to decrease the risk of alloimmunizations and platelet disorders, especially in neonates.

Due to the increasing resistance of various Candida species to azole drugs, particularly fluconazole, it would be of significant importance to look for alternative therapies. The aim of this study was to investigate the antifungal activity of capric acid and its in vitro interactions with nystatin and fluconazole against Candida isolates. A total of 40 Candida isolates ( C. albicans , 36; C. kefyr , 2; C. tropicalis , 1; C. glabrata , 1) collected from the oral cavity of neonates with oropharyngeal candidiasis and a reference strain of C. albicans (ATCC 10231) were used in this study. Antifungal activity of capric acid and two comparator antifungal drugs, namely fluconazole and nystatin, was tested according to CLSI M27-A3/M60 method. The in vitro interaction between capric acid with fluconazole and nystatin was determined following a checkerboard method and results were interpreted using fractional inhibitory concentration index. Nystatin had the lowest minimum inhibitory concentrations (range, 0.125-8 μg/mL; geometric mean [GM], 0.6229 μg/mL) followed by fluconazole (range, 0.5-16 μg/mL; GM, 1.9011 μg/mL) and capric acid (range, 128-2,048 μg/mL; GM, 835.9756 μg/mL). When tested in combination, capric acid with fluconazole demonstrated synergistic, indifferent, and antagonistic interactions in 3 (7.317%), 24 (58.536%), and 14 (34.146%) cases, respectively. For combination of capric acid with nystatin, synergistic, indifferent, and antagonistic interactions were observed in 1 (2.439%), 19 (46.341%), and 21 (51.219%) cases, respectively. All cases of synergistic interactions were against resistant or susceptible dose-dependent isolates. Fluconazole, nystatin, and capric acid seem to be more effective when they are used alone compared with their combination. However, their combination might be effective on resistant isolates.

Mesenchymal stromal cells (MSCs) have potent immunomodulatory abilities to regulate most of the immune cells. Not only the tissue origin of MSCs can affect their functions, but also their microenvironment can strongly influence their biology, particularly through toll-like receptors (TLR)/ligands interaction. In the present study, we compared MSCs derived from two different sources, i.e. human olfactory ecto-mesenchymal stem cells (OE-MSCs) and adipose tissue (AT-MSCs), in terms of their immunosuppressive effects before and after TLR3 and TLR4 stimulation through low-level and short-term TLR-priming protocol. After isolation and characterization of OE-MSCs and AT-MSCs, flow cytometry analyses were used to assess the expression of TLR3, TLR4 by MSCs. Secretion and expression levels of immune-related genes were analyzed using ELISA and RT-qPCR techniques. Based on the results, the proliferation potential of OE-MSCs was significantly higher than that of AT-MSCs. The gene expression and also protein levels of both TLR3 and TLR4 were significantly higher in OE-MSCs, compared to AT-MSCs. Among the examined cytokines and chemokines, OE-MSCs exhibited significantly higher levels of CCL5, IL-8, and TGF-β production, in comparison with AT-MSCs. However, IL-6 secretion by AT-MSCs was considerably more than that by OE-MSCs. OE-MSCs were only affected by the TLR4 ligand, and IL-8 and IL-6 production levels increased after LPS treatment. However, only IL-8 significantly increased after adding LPS or Poly (I:C) to the AT-MSC media. According to the obtained data, OE-MSCs exhibited a higher proliferative potential and greater expression levels of TLR3 and TLR4 genes, compared to AT-MSCs. However, unlike AT-MSCs, the expression of TLR3 by OE-MSCs was nonfunctional. Finally, based on our findings, OE-MSCs have a stronger secretion of immunosuppressive cytokines both before and after LPS or PIC treatment, compared to AT-MSCs.

Background: Endometriosis is a chronic, painful, and inflammatory disease characterized by extra-uterine growth of endometrial tissues. Increased angiogenesis and resistance to apoptosis have been suggested to be involved in pathogenesis and development of endometriosis. The objective of this study was to examine apoptosis potential and angiogenesis contribution of eutopic (EuESCs) and ectopic (EESCs) endometrial stromal cells in patients with endometriosis compared to endometrial stromal cells from non-endometriotic controls (CESCs)., Methods: Stromal cells were isolated by enzymatic digestion of ectopic (n = 11) and eutopic (n = 17) endometrial tissues from laparoscopically-confirmed endometriotic patients. Endometrial stromal cells of 15 non-endometriotic patients served as control. Following cell characterization by immunofluorescent staining and flow cytometry using a panel of antibodies, the total RNA was isolated from the cultured cells, and analyzed for the expression of genes involved in apoptosis (Bcl-2, Bcl-xL, Bax, and caspase-3) and angiogenesis [vascular endothelial growth factor-A (VEGF-A) and hepatocyte growth factor (HGF)] by Real-time PCR., Results: Significantly higher gene expression levels of Bcl-2 and Bcl-xL were found in EESCs compared with EuESCs and CESCs (p < 0.01). The gene expression of Bax in EESCs, EuESCs, and CESCs was not statistically significant. Furthermore, EuESCs exhibited a significantly lower caspase-3 gene expression compared with CESCs (p < 0.01) or EESCs (p < 0.05). Regarding angiogenesis, VEGF-A gene expression in EESCs (p < 0.001) and EuESCs (p < 0.05) were significantly higher compared with those of CESCs. EESCs exhibited a significantly higher HGF gene expression compared with EuESCs (p < 0.05)., Conclusions: These findings suggest reduced propensity to apoptosis and increased angiogenesis potential of EESCs, which may be involved in pathogenesis of endometriosis.

Toll-like receptors (TLRs) are inevitable elements for immunity development and antibody production. TLRs are in close interaction with Bruton's tyrosine kinase which has been found mutated and malfunctioned in the prototype antibody deficiency disease named X-linked agammaglobulinemia (XLA). TLRs' ability was evaluated to induce transcription of TLR-negative regulators, including suppressor of cytokine signaling 1 (SOCS1), interleukin-1 receptor-associated kinase 3 (IRAK-M), tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20), and Ring finger protein 216 (RNF216), and Tumor necrosis factor-α (TNF-α) and Interferon-α (IFN-α) production via Lipopolysaccharides (LPS) and CpG-A oligodeoxynucleotides (CpG-A ODN). Measured by TaqMan real-time polymerase chain reaction (PCR), meaningfully increased transcripts of SOCS1 and RNF216 were found in XLA peripheral blood mononuclear cells (PBMCs). Also, TLR inductions of XLA have led to similar downregulations in the regulator's transcription which was different from that in healthy donors. Cytokine measurement by enzyme-linked immunosorbent assay (ELISA) revealed a significant lower TNF-α production both before and after LPS. By selected molecules in this study, TLRs' potential defectiveness range expands TLRs expression, downstream signaling, and cytokine production. The results show new potential elements that could play a part in TLRs defect and pathogenesis of agammaglobulinemia as well.

Resveratrol, a phytoalexin polyphenol, has antiproliferative, antiangiogenic, anti-inflammatory, and antioxidant properties. The present study has assessed the effect of resveratrol treatment on the expression of insulin-like growth factor-1 (IGF-1) and hepatocyte growth factor (HGF) in endometrial stromal cells (ESCs) from women with and without endometriosis. Endometrial tissues were obtained from 40 endometriotic patients and 15 nonendometriotic control women. After the enzymatic digestion, 13 eutopic ESCs (EuESCs), 8 ectopic ESCs (EESCs), and 11 control ESCs (CESCs) were treated with resveratrol (100 μM) for 6, 24, and 48 hr. The gene and protein expressions of IGF-1 and HGF were measured using real-time polymerase chain reaction and enzyme-linked immunosorbent assay methods, respectively. Results showed that resveratrol treatment decreased significantly the gene expression of IGF-1 and HGF in EuESCs, EESCs, and CESCs (p < 0.05). The effect of resveratrol treatment on the reduction of IGF-1 gene expression was statistically more noticeable in EESCs compared with CESCs (p < 0.05). Also, in the case of HGF gene expression, the reducing effect of resveratrol treatment was statistically more considerable in EESCs compared with EuESCs and CESCs (p < 0.05 and p < 0.01, respectively). The IGF-1 and HGF protein production decreased significantly in EuESCs and EESCs (p < 0.05) but not in CESCs. These findings suggest that resveratrol treatment could reduce the expression of IGF-1 and HGF in ESCs especially in EESCs, which play a pivotal role in disease progression., (© 2019 John Wiley & Sons, Ltd.)

Common variable immunodeficiency (CVID), a clinically symptomatic primary immunodeficiency disease (PID), is characterized by hypogammaglobulinemia leading to recurrent infections and various complications. Recently, some defects in the signaling of TLRs have been identified in CVID patients which led us to investigate the expression of TLR4 and 9 negative regulatory molecules and their upregulation status following their activation. Using TaqMan real-time PCR, SOCS1, TNFAIP3, RFN216, and IRAK-M transcripts among peripheral blood mononuclear cells (PBMCs) were measured with/without TLR4 and 9 activations. TLR4 and 9 were activated by lipopolysaccharide (LPS) and unmethylated CpG-oligodeoxynucleotide (CpG-ODN), respectively. Production of IFN-α and TNF-α cytokines, as a part of the functional response of mentioned TLRs, was also measured using ELISA. Deficient transcripts of IRAK-M and TNFAIP3 in unstimulated PBMCs and lower production of TNF-α and IFN-α after treatments were observed. Upregulation of RFN216 and TNFAIP3 after TLR9 activation was abnormal compared to healthy individuals. Significant correlations were found between abnormal IRAK-M and TNFAIP3 transcripts, and lymphadenopathy and inflammatory scenarios in patients, respectively. It seems that the transcriptional status of some negative regulatory molecules is disturbed in CVID patients, and this could be caused by the underlying pathogenesis of CVID and could involve complications like autoimmunity and inflammatory responses.

Problem: We aimed to evaluate modulatory effects of vitamin D3 on endometriosis-related features of endometriotic stromal cells., Method of Study: The effect of vitamin D3 on adhesion, invasion, proliferation, apoptosis, cytokine production, and angiogenesis potential of the eutopic (EuESCs), ectopic (EESCs), and control (CESCs) stromal cells from 25 women with and 20 women without endometriosis was investigated., Results: In all groups, vitamin D3 significantly increased cell adhesion (P = 0.0013-0.042), while decreased invasion (P = 0.026-0.031) and proliferation (P = 0.0013-0.039) of EESCs and EuESCs. Such treatment also resulted in a significant decrease in IL-6 production by EESCs (P = 0.039), but had no significant effect on the IL-8 production. This vitamin also caused significant decrease in Bcl-2 gene expression by EuESCs (P = 0.04) and Bcl-xL by EESCs (P = 0.044-0.009). In addition, vitamin D3 treatment reduced VEGF-A gene expression by EESCs (P = 0.046-0.009)., Conclusion: Based on substantial favourable in vitro effects of vitamin D3 in endometriosis-related features of human endometriotic stromal cells, further investigations on therapeutic potential of this hormone in endometriosis are warranted., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To study immunophenotype, differential proliferation capacity, invasiveness, adhesion, and cytokine production in ectopic and eutopic endometrial stromal cells (EESCs and EuESCs) from patients with endometriosis., Design: In vitro study., Setting: Academic research center., Patient(s): Patients with ovarian endometriosis (endometrioma) and nonendometriotic controls., Intervention(s): None., Main Outcome Measure(s): EESCs and EuESCs from 25 patients with endometrioma and ESCs from 20 nonendometriotic controls (CESCs) were isolated, and their immunophenotype, proliferation, invasion, adhesion, and cytokine production were assessed and compared., Result(s): Isolated ESCs from all three sources expressed markers specific for cells of mesenchymal origin but were negative for hematopoietic markers. EESCs exhibited a significantly lower proliferation rate in fibronectin-coated plates and less invasive capacity compared with CESCs or EuESCs. Among all stromal cell groups studied, EuESCs showed the highest invasive behavior. EESCs adhered more firmly to extracellular matrix than EuESCs or CESCs in all time intervals examined. The levels of interleukin (IL) -6 and IL-8 production by EESCs were significantly higher compared with those of EuESCs or CESCs., Conclusion(s): The results of the present study demonstrated that retrograde menstruation alone does not account for the pathogenesis of endometriosis as eutopic and ectopic counterparts of ESCs from patients with endometriosis exhibit differential invasive, adhesive, and proliferative behavior., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)