Inflammatory responses during trichomoniasis: The role of Toll-like receptors and inflammasomes.

Toll-like receptors (TLRs) and inflammasomes belong to the pattern recognition receptors (PRRs) of innate immunity identifying conserved compounds produced by pathogens or discharged by injured cells. Different cell subsets in the human urogenital system, such as epithelial cells and infiltrating leukocytes, express different kinds of TLRs (such as TLR2, TLR3, TLR4, TLR5 and TLR9) as well as inflammasomes (such as NLRP3, NLRC4 and AIM2). Various types of the Trichomonas vaginalis-derived components such as glycosyl-phosphatidylinositol (GPI), T. vaginalis virus (TVV), Lipophosphoglycan (LPG) and flagellin can be recognized by TLR2, TLR3, TLR4 and TLR5, respectively, leading to the production of proinflammatory cytokines and chemokines in the cervicovaginal mucosa. The T. vaginalis-induced inflammasomes can lead to pyroptosis as well as the release of IL-1ß and IL-18 promoting innate and adaptive immune responses. The PRR-mediated responses to T. vaginalis may contribute to the induction of protective immune responses, local inflammation, promotion of co-infections, or even the development of malignancies, for example, prostate cancer. The protective or pathogenic roles of the TLRs and inflammasomes during trichomoniasis are highlighted in this review. A better understanding of PRR-mediated responses provides invaluable insights to develop effective immunotherapeutic strategies against T. vaginalis infection.

Bidirectional cytokine-microRNA control: A novel immunoregulatory framework in leishmaniasis.

As effector innate immune cells and as a host to the protozoan parasite Leishmania, macrophages play a dual role in antileishmanial immunoregulation. The 2 key players in this immunoregulation are the macrophage-expressed microRNAs (miRNAs) and the macrophage-secreted cytokines. miRNAs, as small noncoding RNAs, play vital roles in macrophage functions including cytokines and chemokines production. In the reverse direction, Leishmania-regulated cytokines alter miRNAs expression to regulate the antileishmanial functions of macrophages. The miRNA patterns vary with the time and stage of infection. The cytokine-regulated macrophage miRNAs not only help parasite elimination or persistence but also regulate cytokine production from macrophages. Based on these observations, we propose a novel immunoregulatory framework as a scientific rationale for antileishmanial therapy.

Interplays between non-coding RNAs and chemokines in digestive system cancers.

Within tumors, chemokines and their cognate receptors are expressed by infiltrated leukocytes, cancerous cells, and related cells of stroma, like tumor-associated fibroblasts and tumor-associated macrophages. In malignancies, the altered expression of chemokines/chemokine receptors governs leukocyte infiltration and activation, epithelial-mesenchymal transition (EMT), cancer cell proliferation, angiogenesis, and metastasis. Non-coding RNAs (ncRNAs) contribute to multiple physiological and pathophysiological processes. Some miRNAs can exert anti-tumorigenic activity in digestive system malignancies by repressing the expression of tumor-promoting chemokines/chemokine receptors or by upregulating tumor-suppressing chemokines/chemokine receptors. However, many miRNAs exert pro-tumorigenic activity by suppressing the expression of chemokines/chemokine receptors or by upregulating tumor-promoting chemokines/chemokine receptors. LncRNA and circRNAs also exert pro- and anti-tumorigenic effects by targeting downstream miRNAs influencing the expression of tumor-promoting and tumor-suppressor chemokines/chemokine receptors. On the other side, some chemokines influence the expression of ncRNAs affecting tumor formation. The current review explains the communications between ncRNAs and chemokines/chemokine receptors in certain digestive system malignancies, such as gastric, colorectal, and pancreatic cancers and hepatocellular carcinoma to gain better insights into their basic crosstalk as well as possible therapeutic modalities.

Reduced Expression of Natural Killer Cell-Related Activating Receptors by Peripheral Blood Mononuclear Cells from Patients with Breast Cancer and Their Improvement by Zoledronic Acid.

BACKGROUND/AIM: Natural killer (NK) cell receptors affect the NK cell-mediated elimination of malignant cells. In this experimental study the effect of Zoledronic acid (ZOL) was investigated on the expression of NK activating- (NKP46 and NKG2D) and inhibitory (KIR2DL1) receptors by Phytohaemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) from breast cancer (BC) patients. MATERIALS AND METHODS: Peripheral blood mononuclear cell-extracted RNA from thirty breast cancer women and twenty-five healthy subjects was analyzed for gene expression of NKP46, NKG2D and KIR2DL1 using real time-PCR. Then, the PBMCs from BC patients were cultured in the presence of PHA with 5 µg/ml, 10 or 20 µg/ml of ZOL for 32 hours and expression of the aforementioned receptors was determined. RESULTS: Expression of NKP46, NKG2D and NKP46/KIR2DL1 ratio in BC women were lower than healthy group (P<0.01, P<0.04 and P<0.05, respectively). NKP46 expression was up-regulated by PHA-stimulated PBMCs treated with 10 µg/ml and 20 µg/ml of ZOL compared with PHA-stimulated cultures (P<0.01 and P<0.05, respectively). NKG2D expression remarkably increased by PHA-stimulated cultures treated with 5 µg/ml, 10 µg/ml and 20 µg/ml of ZOL compared with PHA-stimulated cultures (P<0.05 and P<0.02 and P<0.04, respectively). CONCLUSION: Expression of NK cell-related activating receptors decreased in BC patients. ZOL can improve the expression of NK activating receptors.

The importance of T cell-derived cytokines in post-kala-azar dermal leishmaniasis.

Infection with the same species of Leishmania (L)donovani causes different manifestations including visceral leishmaniasis (VL) and post kala-azar dermal leishmaniasis (PKDL), indicating that the host-related immunological parameters perform a decisive role in the pathogenesis of diseases. As PKDL is a reservoir of the parasite, a better understanding of the host immune responses is necessary to restrict the L. donovani transmission. The proper local production of Th1 cell-related cytokines (including IFN-γ, TNF-α and IL-12), Th17 cell-derived cytokines (such as IL-17A, IL-17F and IL-22), and CD8+ cytotoxic T lymphocyte (CTL)-derived IFN-γ are protective against PKDL. However, dominant production of regulatory CD4+ T cell-derived cytokines (such as IL-10 and TGF-ß), Th2 cell-derived cytokines (such as IL-4/IL-13), M2 macrophage-derived cytokines (such as IL-4 and IL-10), keratinocyte-derived IL-10, regulatory CD8+ T cell-derived IL-10, and dendritic cell-derived IL-10, IL-27 and IL-21 can contribute to the parasite persistence and PKDL development. Understanding of the T cell-related cytokine network within PKDL lesions gives rise to novel insights concerning the role of each cytokine in the protection or susceptibility to disease. Manipulation of the cytokine network can be considered as an interesting immunotherapeutic strategy for the treatment of L. donovani-mediated PKDL.

Decreased circulating interleukin-33 concentration in Helicobacter pylori-infected patients with peptic ulcer: Evaluation of its association with a cytokine gene polymorphism, gender of patients and bacterial virulence factor CagA.

IL-33 has powerful immunoregulatory activities such as reinforcement of Th2 cell responses. The aim was to assess the circulating IL-33 levels and IL-33 rs1929992 polymorphism in H. pylori-infected peptic ulcer (PU) patients and asymptomatic (AS) subjects. Blood samples were obtained from 100 PU patients, 100 AS subjects and 100 uninfected individuals. Circulating IL-33 levels were detected by ELISA. After DNA extraction, the IL-33 rs1929992 polymorphism was determined using PCR-RFLP method. Serum IL-33 quantities were significantly lower in PU patients compared with AS and uninfected groups. IL-33 levels were higher in AS subjects compared with uninfected group. In PU, AS and uninfected groups, IL-33 levels were significantly higher in women than men. In PU and AS groups, the CagA+H. pylori-infected subjects exhibit higher IL-33 levels compared with carriers of CagA-H. pylori strains. In PU patients, the frequency of genotype GG and allele G at IL-33 rs1929992 was significantly higher compared with all healthy subjects (AS + uninfected groups). The presence of genotypes GG and AG, and allele G in rs1929992 conferred greater risk for PU. In whole H. pylori-infected population (PU + AS groups), IL-33 levels in individuals with genotype AA or allele A at rs1929992 were higher than subjects with GG genotype or allele G. The reduced IL-33 production could contribute to the PU development during H. pylori infection. The IL-33 levels may be affected by individual gender, rs1929992 polymorphism, and the CagA status of bacteria. The rs1929992-related GG genotype and G allele may be associated with PU development.

Association of elevated interleukin-33 serum levels with tumorstages in patients with prostate cancer.

BACKGROUND: Inflammation has a prominent role in cancer development and interleukin (IL)-33 has both inflammatory and anti-inflammatory properties. The aim of this study was to measure IL-33 quantities and genetic alterations in the rs1929992 SNP within IL-33 gene in patients with prostate cancer (PC). METHODS: This investigation was conducted on blood specimens from 150 newly diagnosed PC patients and 150 healthy age-matched controls. Serum IL-33 measurements and genotyping were performed by ELISA and PCR-RFLP, respectively. RESULTS: Elevated IL-33 quantities were detected in PC patients compared with controls (P < 0.001). The PC patients with Gleason scores 7-10 displayed greater IL-33 quantities than those who had Gleason scores 1-6 (P < 0.001). Significant differences were found between PC stages regarding the IL-33 serum levels (P < 0.001). The frequencies of the genotype GG and allele G in rs1929992 SNP were higher, whereas the frequencies of the genotype AA and allele A were lower in PC patients, as compared with controls (P < 0.05, 0.01, P < 0.002 and P < 0.01, respectively). The genotype GG and allele G of rs1929992 SNP were associated with a greater risk of cancer development (OR: 4.533; P < 0.001, and OR: 1.516; P < 0.01, respectively). The IL-33 levels were not significantly different between the subjects carrier genotypes AA, AG and GG, or alleles A and G in rs1929992 SNP, neither in patients nor in controls. CONCLUSION: Higher IL-33 quantities were found in patients with PC, especially in those with greater stages which raises the possiblity that IL-33 may contribute to PC progression. The rs1929992 SNP-related genotype GG and allele G were associated with an increased risk of cancer development.

A Comparative Study of the Effects of Sodium Selenite and Glutathione Mono Ethyl Ester on Aged Adipose-Derived Stem Cells: The Telomerase and Cellular Responses.

The proliferation and differentiation potential of adipose-derived stem cells (ADSCs) decline with aging. Moreover, Alzheimer's disease is associated with progressive decline in cholinergic neurons. The purpose of this study is to enhance the proliferation potential of aged rat ADSCs and their differentiation into cholinergic neurons. The ADSCs were collected from aged male rats cultured and treated with different concentrations of sodium selenite for 3 days or glutathione mono ethyl ester (GSH-MEE) for 1 day. Incubating the ADSCs with 27 nM sodium selenite for 3 days significantly increased the relative cell proliferation, compared with the control, without any change in the telomerase activity, the related telomerase gene expression, and the telomere length, but it does improve differentiation of the aged ADSCs to cholinergic neuron-like cells. GSH-MEE at a concentration of 2 mM for 1 day resulted in increased relative cell proliferation, but it did not change the telomerase activity, the related telomerase gene expression, the telomere length, and differentiation potential. Sodium selenite is more effective than GSH-MEE in improving the aged ADSCs' properties. However, both did not have any effect on telomerase activity.

Stimulation of cell proliferation by glutathione monoethyl ester in aged bone marrow stromal cells is associated with the assistance of TERT gene expression and telomerase activity.

The proliferation and differentiation potential of aged bone marrow stromal cells (BMSCs) are significantly reduced. In order to improve the performance of the aged BMSCs, these cells were treated with 2 mM glutathione monoethyl ester (GSH-MEE) for 24 h. Proliferation rate, telomerase activity, telomere length, and differentiation to cholinergic neuron-like cells (CNLCs) were observed to increase. Though, the expression level of telomerase reverse transcriptase gene increased, but CTC1 and TEN1 genes from Ctc1-Stn1-Ten1 complex encoding proteins with regulatory function significantly decreased. Trypan blue exclusion assay was used to analyze the proliferation and, while telomere length, its several related gene expressions, and telomerase activity were measured using the real time reverse transcription-polymerase chain reaction and polymerase chain reaction enzyme-linked immunosorbent assay techniques, respectively. CNLCs differentiation potential was evaluated by estimating the percentage of choline acetyltransferase immunereactive cells.The results suggested that GSH-MEE could improve aged rat BMSC properties and would be of potential benefit for enhancing the performance of aged people's BMSCs.

Lectin reactivity of expanded mouse blastocysts after exposure to sera from women with unexplained recurrent spontaneous abortion.

Embryotoxic factors existing in maternal sera may influence their effects via specific binding to, or alteration of cell surface molecules in the conceptus. This study was undertaken to determine the effects of sera from women with unexplained recurrent spontaneous abortion (URSA) on cell surface glycoconjugates of the early conceptus. Four cell stage embryos were cultured in medium supplemented with sera from women with URSA, from normal women, or in medium without serum. Developmental competence was assessed as the stage distribution of embryos advancing to during 96h in culture. Hatched (expanded) blastocysts were stained with wheat germ agglutinin (WGA), peanut agglutinin (PNA) and dolichos biflorus agglutinin (DBA) to detect surface glucoconjugates. We observed that patient sera could be divided into high- and low-risk groups on the basis of the ability to decrease the number of four-cell embryos reaching the expanded blastocyst stage. Furthermore, the intensity of reactivity to PNA changed after exposure to high-risk sera. Morula formation was reduced and blastocyst formation was delayed. Although the sera from women with URSA had embryotoxic effects, no influence on the glycoconjugate patterns were evident in hatched blastocysts, aside from PNA reactivivity. We suggest altered developmental display of PNA-reactive proteins was a biomarker for poor developmental quality due to emrbyotoxic factors in serum from URSA patients.