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Abstract: In this work we calculate the four-point correlation function of vector quark currents of QCD via holographic QCD model. Computing the correlator we take into account the exchange of vector and axial vector bosons and dilaton in the bulk. The result is used for calculation of the two-point correlator of electromagnetic currents in external magnetic field at zero momentum, related to RHIC experiments, chiral magnetic effect and lattice study. At zero temperature we find this quantity to be loosely connected with chiral symmetry breaking and strongly dependent on the confinement properties. Some features of the AdS/QCD models are also discussed. [ABSTRACT FROM AUTHOR]

Abstract: Tissue factor (TF), is a transmembrane protein whose role was first identified as that of the initiator of hemostasis via a series of complicated protein cascades. It is now known however, that TF participates in angiogenesis as well as several processes that contribute to disease progression. Over the last 20 years, our laboratory has studied the expression and function of this molecule in both the pregnant and non-pregnant human endometrium. We demonstrated that TF is particularly upregulated at the time of implantation making it a critical factor to protect against excessive bleeding during trophoblast invasion. We have subsequently demonstrated the altered expression of this factor after long term contraception as well as in endometriosis. We proposed that any changes in this well regulated process can result in various pathologies of the endometrium including, infertility, bleeding, endometriosis, preeclampsia, preterm labor or thrombosis. Below we describe the latest findings of the expression and function of TF as well as its specific role in physiologic or pathologic conditions of the human endometrium. [Copyright &y& Elsevier]

Abstract: Placental infection is associated with adverse fetal outcomes. Toll-like receptors (TLRs) are critical regulators of the innate immune response based on their ability to recognize and respond to pathogen-associated molecular patterns expressed by microbes. To date, cell-type specific expression and regulation of TLR function in human term placenta remains largely unelucidated. The goal of the current study was to examine the in vivo and in vitro patterns of TLR expression and function in major cell types of term placenta. Immunohistochemical analysis of terminal and stem villi localized TLR-2, which recognizes peptidoglycan (PG) from Gram-positive bacteria, to endothelial cells and macrophages, and to a lesser extent to syncytiotrophoblast (SCTs) and fibroblasts (FIBs). Staining for TLR-4, the receptor for Gram-negative bacterial lipopolysaccharide (LPS), was most prominent in SCTs and endothelial cells. Results from Western blotting, conventional, and quantitative PCR (qRTPCR) analyses using protein and mRNA isolated from cultures of SCTs and myofibroblasts (mFIBs) revealed that SCTs expressed TLR-2 and TLR-4, whereas mFIBs expressed only TLR-4. In addition, qRTPCR showed that LPS treatment increased TLR-2 expression in SCTs, indicating that infection with Gram-negative bacteria may enhance innate immune responses in placenta toward a broad range of microorganisms. In addition, treatment with LPS increased IL-8 levels in both SCTs and mFIBs, whereas PG treatment only stimulated IL-8 levels in SCTs. Our results indicate that there exist cell type-specific patterns of TLR function in placenta which likely regulate innate immune response at the maternal-fetal interface. [Copyright &y& Elsevier]

Expression of tissue factor (TF), the primary initiator of hemostasis via thrombin formation, is induced during progesterone (P4)-stimulated decidualization of human endometrial stromal cells (HESCs), and remains elevated in decidualized HESCs of luteal and gestational endometrium. In HESC monolayers, progestins elevate TF mRNA and protein levels and estradiol (E2) plus progestin further enhance TF levels for weeks despite no response to E2 alone. This in vitro model mimics the chronic differential ovarian steroid upregulation of TF levels associated with in vivo decidualization. After incubation of HESCs with E2 plus progestin to elevate TF expression, the antiprogestin RU486 completely reversed this upregulation. Thus, progesterone withdrawal transformed decidualization-associated hemostasis of the luteal phase endometrium to the hemorrhagic milieu of menstruation. Transient transfections with TF promoter constructs containing SP and EGR-1 binding sites before and after inactivation by site-directed mutagenesis revealed that Sp1 mediates basal and progestin-enhanced TF transcriptional activity. Progesterone receptor involvement in TF expression was further confirmed since RU486 was a pure antagonist of progestin-enhanced TF mRNA and protein expression, and progestin-enhanced, but not basal, Sp1-mediated transcriptional activity. Enhanced TF mRNA and protein levels in HESCs require co-incubation with progestin and epidermal growth factor receptor (EGFR) agonist indicating that the EGFR mediates progestin-enhanced TF expression. A peak in the primary angiogenic agent, vascular endothelial growth factor (VEGF) in luteal phase endometrium may be indirectly regulated by P4. Neither E2, nor progestin, nor E2 plus progestin affected VEGF expression in glandular epithelial and stromal cells, whereas thrombin enhanced VEGF mRNA and protein levels in decidualized HESCs, but not in the epithelial cells. Transudation of clotting factors to perivascular decidual cell TF in the luteal phase would generate thrombin, enabling it to act as an autocrine enhancer of VEGF in decidualized HESCs. Abnormal uterine bleeding complicates long-term progestin only contraceptive use. After Norplant administration, endometrial VEGF levels are elevated and TF levels are selectively enhanced in decidualized HESCs at bleeding sites. Over-expressed VEGF causes blood vessels to become leaky, increasing clotting factor access to decidualized HESC-expressed TF to promote feed-forward thrombin and VEGF formation. Since thrombin and VEGF induce angiogenesis via separate endothelial cell receptors, they may synergize to elicit aberrant angiogenesis, and ultimately lead to focal bleeding. [Copyright &y& Elsevier]

Abstract: Vascular injury increases access and binding of plasma-derived factor VII to perivascular cell membrane-bound tissue factor (TF). The resulting TF/VIIa complex promotes hemostasis by cleaving pro-thrombin to thrombin leading to the fibrin clot. In human pregnancy, decidual cell-expressed TF prevents decidual hemorrhage (abruption). During placentation, trophoblasts remodel decidual spiral arteries into high conductance vessels. Shallow trophoblast invasion impedes decidual vascular conversion, producing an inadequate uteroplacental blood flow that elicits abruption-related placental ischemia. Thrombin induces several biological effects via cell surface protease activated receptors. In first trimester human DCs thrombin increases synthesis of sFlt-1, which elicits placental ischemia by impeding angiogenesis-related decidual vascular remodeling. During pregnacy, the fibrillar collagen-rich amnion and choriodecidua extracellular matrix (ECM) provides greater than additive tensile strength and structural integrity. Thrombin acts as an autocrine/paracrine mediator that degrades these ECMs by augmenting decidual cell expression of: 1) matrix metalloproteinases and 2) interleukin-8, a key mediator of abruption-associated decidual infiltration of neutrophils, which express several ECM degrading proteases. Among the cell types at the maternal fetal interface at term, TF expression is highest in decidual cells indicating that this TF meets the hemostatic demands of labor and delivery. TF expression in cultured term decidual cells is enhanced by progestin and thrombin suggesting that the maintenance of elevated circulating progesterone provides hemostatic protection and that abruption-generated thrombin acts in an autocrine/paracrine fashion on decidual cells to promote hemostasis via enhanced TF expression. [Copyright &y& Elsevier]

Abstract: Objective: Chemokines initiate the immune response by controlling leukocyte migration and lymphocyte development. Macrophage infiltration of the decidua has been implicated in the genesis of recurrent miscarriage and preeclampsia. Therefore, we determined whether cultured human decidual cells produce monocyte/macrophage-recruiting chemokines in response to a potent pro-inflammatory cytokine, interleukin-1β (IL-1β), and whether decidual cell-conditioned medium contains monocyte- and macrophage-chemoattractant activity. Methods: Leukocyte-free first trimester decidual cells were treated for 6h with estradiol (E2) and medroxyprogesterone acetate (MPA) to mimic the steroidal milieu of pregnancy, or E2 and MPA and IL-1β (1ng/ml) to mimic inflamed decidua. Total RNA was used for cDNA synthesis. Biotinylated cRNAs were generated and chemically fragmented for hybridization on Affymetrix HG_U133 Plus 2.0 chips followed by fluorescence labeling and optical scanning. Raw data generated from Affymetrix GCOS 1.2 (GeneChip Operating Software) were analyzed by GeneSpring 7.2 software. Subsequently microarray results were validated by real time RT-PCR and Western blotting. A functional study of monocyte migration was carried out also using conditioned media from culture. Results: Five chemokines responsible for monocyte/macrophage chemoattraction and activation, including C-C motif ligand 2 (CCL2), CCL5, C-X-C motif ligand 2 (CXCL2), CXCL3 and CXCL8, were markedly elevated from 29- to 975-fold after exposure to IL-1β in cultured first trimester decidual cells. The results of real-time RT-PCR (up-regulation from 43- to 3069-fold) and Western blotting (up-regulation from 15- to 300-fold) confirmed the microarray findings. Monocyte migration was significantly induced by the conditioned medium from IL-1β-treated decidual cells. Conclusions: Treatment of first trimester decidual cells with IL-1β induces secretion of monocyte/macrophage recruiting-chemokines and promotes monocyte migration. Extrapolation of these in vitro results to the milieu of implantation site suggests a mechanism whereby IL-1β could mediate excessive macrophage infiltration of the decidua. [Copyright &y& Elsevier]

Abstract: Tibolone and its metabolites were evaluated on matrix metalloproteinase (MMP) expression in human endometrial stromal cells (HESCs) under the hypothesis that these steroids would act as progestins on MMP-1, -2, and -3 expression. After 7 days of priming and 24h experimental incubation of confluent cultured HESCs, 10−7 M medroxyprogesterone acetate (P) reduced MMP-1 to 49±34% (p <0.05) and MMP-3 to 33±22% of basal levels (mean±S.E.M., p <0.05, n =5). Although HESCs were unaffected by 10−8 M estradiol (E), E+P reduced MMP-1 and MMP-3 levels an additional 2.5-fold from P alone. Tibolone and Δ-4 tibolone were equivalent to E+P in inhibiting MMP-1 and MMP-3 output, whereas 10−6 M of 3α-OH or 3β-OH tibolone was required to elicit significant inhibition of both MMPs (p <0.05). By contrast, none of the treatments affected HESC-secreted MMP-2 output. The ELISA results were confirmed by Western blotting and by substrate gel zymography. Quantitative RT-PCR demonstrated corresponding changes in MMP-1 and MMP-3 mRNA levels. Inhibition of MMP-1 and MMP-3 expression by tibolone and Δ-4 tibolone is consistent with the metabolism of tibolone to Δ-4 tibolone, and subsequent binding of Δ-4 tibolone to the progesterone receptor. Since 3α-OH and 3β-OH tibolone bind exclusively to the estrogen receptor, their inhibition of MMP-1 and MMP-3 suggests metabolism by HESCs to Δ-4 tibolone. These observations help to explain the paradox that the endometrium becomes atrophic after tibolone administration despite the persistence in the circulation of 3α-OH and 3β-OH tibolone, but not tibolone or Δ-4 tibolone. [Copyright &y& Elsevier]

Abstract: Tibolone is a highly effective postmenopausal hormone treatment that has its biological activity dependent on metabolism to 3α- and 3β-OH tibolone, which bind solely to the estrogen receptor. Despite the high levels of estrogen receptor-binding metabolites in the circulation, the endometrium becomes atrophic, suggesting inactivation of the estrogen response in this tissue which may be due to the progestogenic activity of tibolone and the Δ-4 tibolone metabolite. We evaluated the effects of tibolone and its metabolites on tissue factor (TF) and plasminogen activator inhibitor type 1 (PAI-1) expression in human endometrial stromal cells (HESCs). Since TF and PAI-1 exhibit long-term in vivo and in vitro up-regulation by progestin they serve as endpoints for assessing chronic effects of progestin exposure. Confluent HESCs were primed in serum-containing medium with vehicle control, 10−8 mol/L estradiol, 10−7 mol/L medroxyprogesterone acetate, or 10−8 to 10−6 mol/L tibolone or its metabolites, then switched to a defined medium with corresponding vehicle or steroids. After 24h, ELISAs indicated that the progestin elevated TF (6.2-fold ±3.0; p &#60;0.05) and PAI-1 (eight-fold ±2.1; p &#60;0.05) levels, whereas the cells were refractory to estradiol exposure. Tibolone and Δ-4 tibolone (10−8 to 10−6 mol/L) were as effective as 10−7 mol/L medroxyprogesterone acetate in enhancing TF and PAI-1 output (p &#60;0.05). Unexpectedly, at the higher concentrations 3α- and 3β-OH tibolone also elevated TF and PAI-1 expression (p &#60;0.05). Western blotting confirmed the ELISA results. Our findings suggest that HESCs metabolize 3α- and 3β-OH tibolone to tibolone and subsequently to Δ-4 tibolone, which can both stimulate the progesterone receptor. Since TF and PAI-1 promote hemostasis by complementary mechanisms, our findings account for the reduced occurrence of abnormal uterine bleeding associated with tibolone therapy. [Copyright &y& Elsevier]