Effects of selected food phytochemicals in reducing the toxic actions of TCDD and p,p'-DDT in U937 macrophages.

To assess the effectiveness of selected food phytochemicals in reducing the toxic effects of the environmental toxicants, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and p,p'-DDT (DDT), we tested the potencies of auraptene, nobiletin, zerumbone, and (±)-13-hydroxy-10-oxo-trans-11-octadecenoic acid (13-HOA) in reversing the inflammatory action of these toxicants in U937 human macrophages. Using quantitative RT-PCR as the initial screening assay, we identified antagonistic actions of zerumbone and auraptene against the action of TCDD and DDT in up-regulating the mRNA expressions of COX-2 and VEGF. The functional significance of the inhibitory action of zerumbone on COX-2 expression was confirmed by demonstrating its suppression of TCDD-induced activation of COX-2 gene expression in mouse MMDD1 cells.

Characterization of the pattern of the nongenomic signaling pathway through which TCDD-induces early inflammatory responses in U937 human macrophages.

2,3,7,8-Tetrachlorodibenzo(p)dioxin (TCDD) has been known to induce inflammatory signaling in a number of cell types and tissues. We found that in U937 macrophages TCDD causes rapid activation of cytosolic phospholipase A2 (cPLA2) within 30min as judged by the increase in the serine 505 phosphorylated form of cPLA2 protein and the increased cellular release of free arachidonic acid. This initial action of TCDD is accompanied with the up-regulation of an important inflammation marker, COX-2 mRNA expression within 1h, and by 3h, several other markers become up-regulated.

Initial and extended inflammatory messages of the nongenomic signaling pathway of the TCDD-activated Ah receptor in U937 macrophages.

Using 2,3,7,8-tetrachlorodibenzo(p)dioxin (TCDD) we have investigated the mechanisms through which the AhR elicits inflammation through the nongenomic pathway. This AhR signaling depends on the initial action of TCDD to rapidly increase the intracellular concentration of free Ca(2+), which subsequently activates cPLA2 and additional inflammatory markers (e.g.

Involvement of RelB in aryl hydrocarbon receptor-mediated induction of chemokines.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a well-known immunotoxic compound affecting the expression of inflammatory genes. We found that TCDD induces the expression of the B-cell activating factor of the tumor necrosis factor family (BAFF), B-lymphocyte chemoattractant (BLC), CC-chemokine ligand 1 (CCL1), and the transcription factor interferon gamma responsive factor (IFR3) in U937 macrophages in an aryl hydrocarbon receptor- (AhR) and RelB-dependent manner. The induction was associated with increased binding activity of an AhR/RelB complex without participation of ARNT to a NF-kappaB element that is recognized by the NF-kappaB subunit RelB and localized on promoters of the cytokine and chemokine genes BAFF, BLC, CCL1, and the transcription factor IRF3.

RelB, a new partner of aryl hydrocarbon receptor-mediated transcription.

The nuclear factor-kappaB (NF-kappaB) transcription factor family has a crucial role in rapid responses to stress and pathogens. We show that the NF-kappaB subunit RelB is functionally associated with the aryl hydrocarbon receptor (AhR) and mediates transcription of chemokines such as IL-8 via activation of AhR and protein kinase A. RelB physically interacts with AhR and binds to an unrecognized RelB/AhR responsive element of the IL-8 promoter linking two signaling pathways to activate gene transcription.

Pathogenesis of aryl hydrocarbon receptor-mediated development of lymphoma is associated with increased cyclooxygenase-2 expression.

Epidemiological studies indicate that exposure to environmental pollutants such as pesticides and dioxins leads to the pathogenesis of lymphoma and leukemia. Here, we show that activation of the aryl hydrocarbon receptor (AhR) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in loss of the programmed cell death (apoptosis) response in three different lymphoma cell lines, which plays a key role in the development of cancer, especially lymphoma and leukemia. The AhR-mediated inhibition of apoptosis in vitro was associated with a clear increase of cyclooxygenase-2 (COX-2) and deregulation of genes of the B-cell lymphoma-2 (Bcl-2) family involved in apoptosis including Bcl-xl and Mcl-1 in several lymphoma cell lines.

Modulation of the chemokines KC and MCP-1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice.

Activation of the aryl hydrocarbon receptor (AhR) by TCDD may lead to the induction of proinflammatory cytokines in various cell types and organs such as liver leading to active chronic inflammation. Here we studied the expression of the chemokines keratinocyte chemoattractant (KC) and monocyte chemoattractant protein 1 (MCP-1) in different organs of mice after exposure to TCDD. TCDD exposure led to an early and clear induction of KC in liver and spleen on day 1 which was sustained over a period of 10 days.

Polymorphisms of insulin receptor substrate 1 and beta3-adrenergic receptor genes in gestational diabetes and normal pregnancy.

Gestational diabetes mellitus (GDM) is considered an important risk factor for the development of type 2 diabetes mellitus. We studied possible relations between GDM and both insulin receptor substrate 1 (IRS-1) (Gly972Arg) and beta3-adrenergic receptor (ADRB3 Trp64Arg, beta3-AR) gene mutations, considered potential modifying factors in the etiology of type 2 diabetes mellitus. We evaluated the 2 gene mutations in late gestation in 627 pregnant women, all studied using the glucose challenge test, followed (in positive tests) by the oral glucose tolerance test (100 g, Carpenter and Coustan [J Obstet Gynecol.

Induction of proinflammatory cytokines and C-reactive protein in human macrophage cell line U937 exposed to air pollution particulates.

Exposure to particulate matter air pollution causes inflammatory responses and is associated with the progression of atherosclerosis and increased cardiovascular mortality. Macrophages play a key role in atherogenesis by releasing proinflammatory cytokines and forming foam cells in subendothelial lesions. The present study quantified the inflammatory response in a human macrophage cell line (U937) after exposure to an ambient particulate sample from urban dust (UDP) and a diesel exhaust particulate (DEP).

Activation of inflammatory mediators and potential role of ah-receptor ligands in foam cell formation.

Epidemiological data and in vivo animal experiments have indicated that exposure to the Ah-receptor (AhR) ligand dioxin and other dioxin-like compounds can lead to cardiovascular toxicity and atherosclerosis. Here, we investigated the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent AhR ligand, on the differentiation of U937 cells into foam cells, which are considered to be early lesions of atherosclerosis. Our findings show that, like oxidized low-density lipoprotein (oxLDL), TCDD promotes the differentiation of U937 macrophages to atherogenic foam cells, verified by lipid accumulation and extensive formation of blebs on the cell surface, which are characteristics of foam cells.

Dioxin increases C/EBPbeta transcription by activating cAMP/protein kinase A.

The environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD = dioxin) has been shown to increase the expression of C/EBPbeta. The modulated expression of C/EBPbeta has been suggested to be associated with toxic responses of TCDD such as wasting syndrome, diabetes, and inhibition of adipocyte differentiation. This study focused on the regulatory mechanism of TCDD-mediated transcriptional activation of C/EBPbeta.

Fetal pancreatic function in infants of diabetic and rhesus-isoimmunized women.

Objective: To measure insulin and glucagon concentrations in amniotic fluid (AF) collected near term in basal conditions and after an arginine test in diabetic, rhesus-isoimmunized, and control pregnant women.

Methods: At baseline, AF was collected from 44 diabetic, 32 rhesus-isoimmunized, and 27 control pregnant women in late pregnancy. Fifty-two diabetic, six rhesus-isoimmunized, and nine control pregnant women had amniocentesis 2 hours after arginine infusion (30 g intravenous/30 minutes) at 33-36 weeks.

Glucose transporter (Glut1, Glut3) mRNA in human placenta of diabetic and non-diabetic pregnancies.

Transport of glucose into the cell is catalyzed by glucose transporters (Glut). Glut1 and Glut3 are expressed at various levels in many human tissues, including the placenta. It has been reported that ambient glucose can affect both glucose transport activity and expression of the Glut genes, and protein.

Autoimmune markers of diabetes in diabetic pregnancy.

Gestational diabetes mellitus (GDM) has been described in 1-3% of pregnancies and increases the risk (up to 60-70%) to subsequently developing an overt diabetes (generally of type 2 non insulin-dependent diabetes mellitus (NIDDM)). Several humoral autoimmune phenomena have been described in GDM: islet cell antibodies (ICA) have been found and it was shown that ICA+ patients tend to have a worse glucose tolerance. Recently, autoantibodies against glutamic acid decarboxylase (GAD), were detected in type 1 diabetic sera before or at the onset of the disease; these markers, as well as ICA and insulin antibodies, seem to have a predictive value for the onset of the disease.

Levels of advanced glycosylation end-products (AGE) in sera of pregnant diabetic women: comparison between type 1, type 2 and gestational diabetes mellitus.

The chronic hyperglycemia can lead to an increase of the advanced glycosylation end-products (AGE) levels on proteins and macromolecules. Abnormal levels of AGE in several tissues has been associated with the pathogenesis of late diabetic complications. In diabetic pregnant women, high AGE levels might influence the delicate maternal-fetal balance and therefore alter the pregnancy outcome.

Glucose transporters (GLUT 1, GLUT 3) mRNA in human placenta of diabetic and non-diabetic pregnancies.

Glucose transporters (GLUT) catalyse the transport of glucose in many human tissues, including the placenta. On the other hand glucose concentrations can affect both glucose transport activity and level of GLUT mRNA and protein. Up to now very few studies, concerning GLUT in the placenta appeared and studies in vivo in human diabetic pregnancy are lacking.

Combined therapy with insulin and sulfonylurea for the treatment of new-onset insulin-dependent diabetes mellitus.

The progressive B-cell destruction at the onset of type 1 diabetes and the relevance of residual B-cell function to metabolic control prompted us to try to prevent further B-cell destruction in new-onset type 1 diabetic patients. Having already shown positive effects of sulfonylreas in long-standing IDDM patients, we decided to try the association of gliclazide with insulin in newly diagnosed IDDM patients. Therefore, 22 patients were randomly assigned to either gliclazide, 160 mg/24 h, or placebo (in association with standard insulin treatment) from the third week since the onset of the disease.

Amniotic fluid insulin and C peptide levels in diabetic and nondiabetic women during early pregnancy.

Thanks to the widespread use of amniocentesis, glucose, insulin, and C peptide have often been measured in amniotic fluid (AF) during late gestation, but little is known about their concentrations during early pregnancy. To better understand early fetal beta-cell function under normal conditions and in the presence of maternal diabetes, we measured glucose, insulin, and C peptide in the AF collected during weeks 15-22 in 77 healthy and 9 diabetic women undergoing amniocentesis for clinical indications and compared the results with those obtained during late pregnancy (weeks 34-36). The AF C peptide concentration was higher in diabetic women (102 +/- 53 vs.

Glucagon and insulin secretion in low birthweight preterm infants. The effect of glucose infusion.

The effect of the intravenous glucose on plasma levels of glucagon and insulin were evaluated in thirty-five LBW preterm infants who were appropriate for gestational age. Their mean birthweight and gestational age were 1220 +/- 55 g (range 750-1730 g) and 29 +/- 1 weeks (range 25-35 weeks), respectively. A 30 min glucose infusion in 16 infants (1 g/kg b.

Influence of maternal metabolic control and insulin antibodies on neonatal complications and B cell function in infants of diabetic mothers.

Circulating insulin antibodies at birth and the degree of maternal metabolic control were measured in 68 infants of insulin-treated diabetic mothers. Their correlation with neonatal B cell function and with the clinical features of the infants was evaluated in order to better understand their influence on fetal outcome. Maternal metabolic control was assessed on the basis of blood glucose levels, glycosuria and the occurrence of hypoglycemia and/or ketonuria.

Gastro-entero-pancreatic hormones in amniotic fluid from normal and diabetic pregnant women.

Clinical applications of analyses of hormones in amniotic fluid (AF) have recently been increased. In diabetic pregnancy, determinations of insulin and C-peptide in AF have been suggested as good indicators of the status of the foetus. We have investigated the pancreatic alpha and beta cell function by measuring insulin (IRI), C-peptide (CPR), glucagon (IRG), somatostatin (SLI), and gastric inhibitory polypeptide (GIP) in amniotic fluid collected during basal conditions or 2 h after an arginine test in 92 diabetic and 32 non-diabetic pregnant women.