Expression of progranulin (Acrogranin/PCDGF/Granulin-Epithelin Precursor) in benign and malignant ovarian tumors and activation of MAPK signaling in ovarian cancer cell line.

It has been recently demonstrated that progranulin is overexpressed in ovarian cancer and that this protein is involved in the stimulation of cell proliferation, malignancy, and chemoresistance in ovarian cancer. The goal of the present study was to establish the differences in progranulin expression among normal, benign, and malignant ovarian tissues and to identify the signal transduction pathways activated by progranulin in an ovarian cancer cell line. Compared with benign tumors and normal ovarian tissue, progranulin mRNA and protein were overexpressed in malignant tumors. Survival analysis by the Kaplan-Meier method showed a correlation between high mRNA expression levels with poor survival outcome. Progranulin activated the MAPK-signaling pathway in NIH-OVCAR-3 cells. Progranulin expression may be potentially involved in the pathogenesis and malignant progression of ovarian cancer, and thus may represent a therapeutic target for this particular malignancy.

Adverse reproductive outcomes in urban women with adeno-associated virus-2 infections in early pregnancy.

BACKGROUND: We demonstrated recently that adeno-associated virus-2 (AAV-2) DNA was detected significantly more frequently in placental trophoblast cells from cases of severe pre-eclampsia than from normal term deliveries. Here, we sought to determine if maternal AAV-2 infection early in pregnancy preceded adverse outcomes resulting from placental dysfunction. METHODS: We collected first trimester maternal serum samples and compared anti-AAV-2 IgM antibody levels (indicating primary infection or reactivation of latent AAV-2) between controls delivered at term (n = 106) and three groups of cases: spontaneous abortions (n = 34), spontaneous preterm deliveries (n = 24) and women with at least one outcome usually attributed to placental dysfunction, including pre-eclampsia, intrauterine growth restriction (IUGR) or stillbirth (n = 20). The seroprevalence of immunoglobulin G (IgG) antibodies against AAV-2 and IgM antibodies against viruses that promote AAV-2 replication [adenovirus and cytomegalovirus (CMV)] were also determined. RESULTS: First trimester maternal IgM seropositivity was 5.6 times more prevalent among pre-eclampsia/IUGR/stillbirth cases (P = 0.0004) and 7.6 times more prevalent among preterm deliveries (P < 0.0001) than among controls. CMV and adenovirus IgM antibodies and chronic AAV-2 infections (IgG seropositivity) were not associated with adverse pregnancy outcomes. CONCLUSIONS: Primary or reactivated AAV-2 infection (maternal IgM seropositivity) early in pregnancy was associated with adverse reproductive outcomes associated with placental dysfunction, including pre-eclampsia, stillbirth and spontaneous preterm delivery.

NF-kappaB translocation and endothelial cell activation is potentiated by macrophage-released signals co-secreted with TNF-alpha and IL-1beta.

OBJECTIVE AND METHODS: Over-expression of the immune response can lead to pathological conditions such as septic shock or chronic inflammation. Endothelial cell activation by pro-inflammatory products of activated macrophages plays a key role in these conditions. Here we examine the response of primary human endothelial cells (HUVEC) to conditioned media (CM) obtained from LPS-activated macrophages. We further characterized the translocation of NF-kappaB in the presence of CM by studying the degradation rate of individual IkappaB isoforms. RESULTS: We show that, as expected, CM induced NF-kappaB translocation, as well as adhesion capacity in HUVEC. We further show that this response is critically dependent on TNF-alpha and IL1beta naturally present in the CM. However, both the amplitude of NF-kappaB translocation and adhesiveness observed with CM were well beyond the saturation levels attained after the sole stimulation with recombinant TNF-alpha and IL-1beta, either separately or together. Our results show that CM induced a faster degradation of the IkappaB-beta and IkappaB-epsilon isoforms than the recombinant cytokines, leading to an enhanced recruitment of NF-kappaB activity. CONCLUSIONS: The above results suggest that the physiological context of factors co-secreted by LPS-activated macrophages enhances TNF-alpha mediated endothelial activation.

In-vitro secretion of proinflammatory cytokines by human amniochorion carrying hyper-responsive gene polymorphisms of tumour necrosis factor-alpha and interleukin-1beta.

The identification of polymorphisms in genes encoding proinflammatory cytokines that affect transcription or the secretion rate has opened new ways to understand the variation in responses to infection during pregnancy. In this study, human amniochorion carrying hyper-responsive alleles of tumour necrosis factor-alpha (TNF-alpha: TNF*2 at -308) and interleukin-1beta (IL-1beta: IL-1*2 at +3953) were stimulated in vitro with bacterial lipopolysaccharide (LPS) and compared with tissues carrying the common alleles (TNF*1 and IL-1*1). Fetal membranes carrying the TNF*1 allele displayed an identical dose-response pattern to tissues carrying a TNF*2 allele, except at the highest dose of LPS tested (50 ng/ml) there was a significantly greater production of TNF-alpha in the presence of a TNF*2 allele. Membranes carrying the IL-1*2 polymorphism secreted IL-1beta in a dose-response curve that was different from IL-1* tissues when challenged with 5, 10 and 50 ng/ml LPS. These observations support the hypothesis that reproductive tissues carrying hyper-responsive proinflammatory cytokine genes may over-respond to intrauterine infection secreting higher amounts of cytokines, which in turn, may lead to adverse pregnancy outcomes.

[Tumor necrosis factor-alpha and interleukin-1 beta in maternal, fetal and retroplacental intravascular compartments at term and preterm labor]. / Factor de necrosis tumoral-alpha e interleucina-1 beta en los compartimentos intravascular materno, fetal y retroplacentario en parto a término y pretérmino.

Neonato preterm birth (before 37 pregnancy weeks) account more than 80% perinatal deaths not attributable to congenital malformations. Preterm and term labor full mechanisms are unknown at present. Proinflammatory cytokinesis direct participation have been involved in the phenomena by several experimental evidence. The study's aim was to determine TNF-alpha and IL-1 beta concentration at maternal, fetal and fetal-maternal vascular compartments in women with term and preterm delivery and in women at term childbirth without labor. TNF-alpha and IL-1 beta concentration were determinated by commercial immunoassay. TNF-alpha concentration showed a tendency to be in more proportion at fetal and fetal-maternal compartments in preterm and term childbirth groups versus TNF-alpha concentration in term group without labor at same places. IL-1 beta concentration showed same tendency of increase than TNF-alpha in preterm and term childbirth groups, but alone at fetal-maternal compartment. Statistical difference were not documented at any compartment or group compared. Data allow to identify fetal-maternal compartments as target places where TNF-alpha and IL-1 beta were synthesized. Gradient concentration synthesis of cytokinesis allows to intend fetus as TNF-alpha initial producer.

[Apoptosis in trophoblast of patients with recurrent spontaneous abortion of unidentified cause]. / Apoptosis en trofoblasto de pacientes con aborto espontáneo recurrente de causa no identificada.

Recurrent spontaneous abortion of unidentified cause or idiopatic is an important problem of reproduction health. In this study, the study has been started of one of the mechanisms that could act in the pathology of human pregnancy. The general hypothesis proposed, is that in the case of patients with recurrent spontaneous abortion of non identified cause (RSA) there are phenomenons in the materno/fetal/placentary means that manifest themselves in harm to the functionality and/or vitality of placentary tissue. The hypothesis was consistent with the finding of massive activation of cellular death in all the cases with RSA studied in this work.

Evidence of endothelial cytotoxic compounds in placental extracts from preeclamptic women.

OBJECTIVE: To determine whether placenta and plasma of preeclamptic women contain factors that cause endothelial cell damage. METHODS: Placental extracts and plasma from preeclamptic and normotensive women were added to cultures of normal human umbilical vein endothelial cells and their effect on their viability, was determined by MTT reduction and 51chromium release. RESULTS: Placental extracts from normotensive and preeclamptic women were cytotoxic to endothelial cells, but not the plasma from both groups. Mean +/- standard deviation values of cytotoxicity index in preeclamptic and normotensive placental extracts using the MTT reduction were 70.3 +/- 6.76% and 51.4 +/- 8.81%, respectively, showing a significant difference (P < .0001). Using the 51chromium-release assay, preeclamptic placental extracts showed cytotoxic effects of 87.6 +/- 13.47% compared with 17 +/- 20.60% in control patients. The cytotoxic activity decreased after trypsin digestion and heat treatment in both groups. CONCLUSIONS: A cytotoxic factor to endothelial cells in placental extracts of preeclamptic women was identified. This compound is thermolabile and sensitive to trypsin digestion.