Seroprevalence and associated risk factors of Toxoplasma gondii infection in psychiatric patients: a case-control study in eastern China.

In recent years, the effect of Toxoplasma gondii infection on the cerebrum and neuropsychiatric patients has been increasingly highlighted. However, there is limited information about the epidemiology of T. gondii infection in psychiatric patients in Shandong province, eastern China. Therefore, through a case-control study, 445 patients hospitalized for diacrisis or treatment in Weihai, eastern China, and 445 control subjects from the general population of the same region matched by gender, age, and residence were examined with enzyme-linked immunoassays for the presence of IgG and IgM antibodies to T. gondii and associated sociodemographic and behavioural characteristics in a population of psychiatric patients. Seroprevalence of IgG antibodies to T. gondii in psychiatric patients (77/445, 17·30%) was significantly higher than in control subjects (55/445, 12·36%) (P = 0·038). Fourteen (3·15%) psychiatric patients and 10 (2·25%) control subjects had IgM antibodies to T. gondii (P = 0·408). Multivariate analysis using logic regression showed that T. gondii infection was associated with cats at home and consumption of raw/undercooked meat in psychiatric patients. Considering that most psychiatric patients usually have lower cognitive functioning and additional transmission routes related to their inappropriate behaviours that could enhance the risk of infection, psychiatric patients should be considered as a specific group of T. gondii infection.

Cross talk between cAMP and p38 MAPK pathways in the induction of leptin by hCG in human placental syncytiotrophoblasts.

Leptin produced by the placental syncytiotrophoblasts participates in a number of processes in pregnancy including implantation, proliferation of the cytotrophoblasts, and nutrient transfer across the placenta. Despite the functional significance of leptin in pregnancy, the regulation of leptin synthesis is poorly understood in human placental syncytiotrophoblasts. In this study, we investigated the role of endogenous human chorionic gonadotropin (hCG) in the regulation of leptin production as well as the underlying mechanism involving the cross talk between cAMP and p38 mitogen-activated protein kinase (MAPK) pathways. We found that neutralization of endogenous hCG with its antibody dose dependently decreased leptin mRNA level and secretion, whereas exogenous hCG increased leptin mRNA level and secretion. Activation of the cAMP pathway with dibutyryl cAMP (db cAMP) or forskolin recapitulated the stimulatory effect of hCG on leptin expression. Inhibition of protein kinase A with H89 not only reduced the basal leptin expression but also attenuated the induced leptin expression by hCG. Treatment of the syncytiotrophoblasts with db cAMP and hCG phosphorylated p38 MAPK. Inhibition of p38 MAPK with SB203580 not only reduced the basal leptin production but also attenuated the leptin-induced production by both hCG and db cAMP. These data suggest that endogenous hCG plays a significant role in maintaining leptin production in human placental syncytiotrophoblasts, and this effect involves a cross talk between cAMP and p38 MAPK pathways.

Role of human chorionic gonadotropin in maintaining 11beta-hydroxysteroid dehydrogenase type 2 expression in human placental syncytiotrophoblasts.

Proper glucocorticoid exposure in utero is vital for normal fetal organ maturation, but excess glucocorticoids are detrimental to fetal growth and can even predispose the individuals to the high risk of having certain diseases in adulthood. The fetus is protected from 10 times higher maternal glucocorticoid levels by the placental enzyme 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2), which converts biologically active cortisol to inactive cortisone. Thus it is of primary importance to understand how this enzyme is regulated. Activation of cAMP/PKA pathway is known to upregulate 11beta-HSD2 expression in placental syncytiotrophoblasts, however the endogenous hormones utilizing this pathway remain largely unknown. By using cultured human placental syncytiotrophoblasts, we demonstrated that inhibition of protein kinase A with H89 attenuated 11beta-HSD2 expression in the syncytiotrophoblasts, suggesting endogenous factors from the syncytiotrophoblasts using this pathway to maintain 11beta-HSD2 expression in the syncytiotrophoblasts. Neutralization of human chorionic gonadotropin (hCG) secreted by the syncytiotrophoblasts with hCG antibody decreased 11beta-HSD2 promoter activity, mRNA and protein expression as well as intracellular cAMP level, while treatment of the syncytiotrophoblasts with exogenous hCG increased 11beta-HSD2 expression, which was attenuated by H89. Furthermore, we found that cortisol increased both hCG expression and secretion. The up-regulation of 11beta-HSD2 expression by cortisol was significantly attenuated by co-treatment with hCG antibody or H89 in the syncytiotrophoblasts. In conclusion, hCG is an important paracrine or autocrine hormone maintaining 11beta-HSD2 expression and the up-regulation of 11beta-HSD2 expression by cortisol may be mediated in part by hCG in the syncytiotrophoblasts.

Paradoxical stimulation of cyclooxygenase-2 expression by glucocorticoids via a cyclic AMP response element in human amnion fibroblasts.

Human amnion fibroblasts produce abundant prostaglandins toward the end of gestation, which is one of the major events leading to parturition. In marked contrast to its well-described antiinflammatory effect, glucocorticoids have been shown to up-regulate cyclooxygenase-2 (COX-2) expression in human amnion fibroblasts. The mechanisms underlying this paradoxical induction of COX-2 by glucocorticoids have not been resolved. Using cultured human amnion fibroblasts, we found that the induction of COX-2 mRNA expression by cortisol was a glucocorticoid receptor (GR)-dependent process requiring ongoing transcription. Upon transfection of a COX-2 promoter-driven reporter gene into the amnion fibroblasts, cortisol stimulated the COX-2 promoter activity. This was abolished by mutagenesis of a cAMP response element (CRE) at -53 to approximately -59bp as well as by cotransfection of a plasmid expressing dominant-negative CRE-binding protein (CREB). The phosphorylation level of CREB-1 was significantly increased by cortisol treatment of the amnion fibroblasts, whereas the effect was attenuated either by the protein kinase A inhibitor H89 or the p38 -MAPK inhibitor SB203580. The induction of the COX-2 promoter activity and the phosphorylation of CREB-1 were also blocked by the GR antagonist RU486. Chromatin immunoprecipitation (ChIP) assay revealed that the binding of CREB-1 to the CRE of the COX-2 promoter was increased by cortisol treatment of the amnion fibroblasts. In conclusion, cortisol, via binding to GR, stimulated COX-2 expression by increasing phosphorylated CREB-1 binding to the CRE of the COX-2 gene. Cortisol may phosphorylate CREB-1 by activating either protein kinase A or p38-MAPK in the amnion fibroblasts.

Expression of progesterone receptor A form and its role in the interaction of progesterone with cortisol on cyclooxygenase-2 expression in amnionic fibroblasts.

CONTEXT: Human amnion fibroblasts produce abundant prostaglandins toward the end of gestation, which is believed to be one of the major events leading to parturition. Glucocorticoids have been shown to up-regulate cyclooxygenase-2 (COX-2) expression, the crucial enzyme catalyzing prostaglandin synthesis, in human amnion fibroblasts. Although a major propregnancy hormone, the effect of progesterone and the associated progesterone receptor subtypes in the regulation of both basal and glucocorticoid-induced COX-2 expression in human amnion fibroblasts have not been resolved. METHODS AND RESULTS: Cultured human amnion fibroblasts prepared from the fetal membranes at term pregnancy without labor mainly expressed the progesterone receptor A form (PRA). Inhibition of endogenous progesterone production with trilostane or knockdown of PRA expression with small interfering RNA significantly enhanced the glucocorticoid receptor (GR)-mediated COX-2 induction by cortisol, whereas overexpression of PRA attenuated the induction by cortisol. Co-immunoprecipitation assay revealed PRA in the GR protein complex. Although exogenous progesterone did not alter COX-2 expression under basal conditions, it attenuated cortisol-induced COX-2 expression at concentrations about 10- to 50-fold higher, which might be achieved by competition with cortisol for GR. CONCLUSIONS: We demonstrated in this study that endogenous progesterone might counteract the induction of prostaglandin synthesis by cortisol via PRA transdominant repression of GR function, whereas high levels of progesterone might further inhibit the induction by cortisol via competitive binding to GR in human amnion fibroblasts. These inhibitory actions of progesterone and PRA on glucocorticoids and GR may partly explain the inconsistent effects of glucocorticoids on parturition in humans.