Effects of calcitriol upon TGF-βs and their receptors in trophoblast cells.

Calcitriol levels increase during pregnancy, contributing to the hormonal and immunological balance, but its deficiency has been associated with problems during this period. Meanwhile, transforming growth factors-β (TGF-βs) play an important role in the maintenance of fetal-maternal immune tolerance; however, exacerbated concentrations of this growth factor are associated with complicated pregnancies. Therefore, we studied the effects of calcitriol on TGF-βs and their receptors in trophoblast cells.

Transcriptional landscape of human trophoblast cells treated with calcitriol and TGF-β1.

Calcitriol and transforming growth factor beta 1 (TGF-β1) are unrelated molecules that regulate biological processes according to the genetic target, cell type, and context. Several studies have shown independent effects of calcitriol and TGF-βs on the placenta, but there is no information regarding the impact of their combination on these cells. Therefore, this study analyzed the effects of calcitriol, TGF-β1, and their combination in primary cultures of human trophoblast cells using a whole genome expression microarray.

Cord Serum Calcitriol Inversely Correlates with Maternal Blood Pressure in Urinary Tract Infection-Affected Pregnancies: Sex-Dependent Immune Implications.

Urinary tract infections (UTI) during pregnancy are frequently associated with hypertensive disorders, increasing the risk of perinatal morbidity. Calcitriol, vitamin D's most active metabolite, has been involved in blood pressure regulation and prevention of UTIs, partially through modulating vasoactive peptides and antimicrobial peptides, like cathelicidin. However, nothing is known regarding the interplay between placental calcitriol, cathelicidin, and maternal blood pressure in UTI-complicated pregnancies.

Placentas associated with female neonates from pregnancies complicated by urinary tract infections have higher cAMP content and cytokines expression than males.

Problem: The cAMP pathway is involved in important biological processes including immune regulation and hormone signaling. At the feto-maternal unit, cAMP participates in placental function/physiology and the establishment of immunoendocrine networks. Low cAMP in male fetuses cord blood has been linked to poorer perinatal outcomes; however, cAMP placental content and its relationship with immune factors and fetal sex in an infectious condition have not been investigated.

Regulation of anti-tumorigenic pathways by the combinatory treatment of calcitriol and TGF-β in PC-3 and DU145 cells.

Calcitriol and transforming growth factors beta (TGF-β) are involved in several biological pathways such as cell proliferation, differentiation, migration and invasion. Their cellular effects could be similar or opposite depending on the genetic target, cell type and context. Despite the reported association of calcitriol deficiency and disruption of the TGF-β pathway in prostate cancer and the well-known independent effects of calcitriol and TGF-βs on cancer cells, there is limited information regarding the cellular effects of calcitriol and TGF-β in combination.

Steroid hormones and pregnancy.

Pregnancy is associated with physiological adjustments in order to allow adequate growth and fetal development. In particular, steroids are necessary to maintain in balance numerous functions during gestation. Steroidogenesis in the maternal, placental and fetal compartments and the biological effects of progestins and estrogens that play a pivotal role before and during pregnancy are described.

Negative correlation between testosterone and TNF-α in umbilical cord serum favors a weakened immune milieu in the human male fetoplacental unit.

Clinical and epidemiological evidence supports that pregnancies carrying a male fetus are more vulnerable to infections and preterm birth, probably due to testosterone immunosuppressive properties. In human placentas, testosterone lowers the expression of CYP27B1, the vitamin D (VD)-activating enzyme, diminishing cathelicidin synthesis, a potent VD-dependent antimicrobial peptide (AMP). VD also stimulates other AMPs, including defensins.

Lipopolysaccharide and cAMP modify placental calcitriol biosynthesis reducing antimicrobial peptides gene expression.

Problem: Calcitriol, the hormonal form of vitamin D (VD), stimulates placental antimicrobial peptides expression; nonetheless, the regulation of calcitriol biosynthesis in the presence of bacterial products and its consequence on placental innate immunity have scarcely been addressed.

Method Of Study: We investigated how some bacterial products modify placental VD metabolism and its ability to induce antimicrobial peptides gene expression.

Results: Cultured human trophoblasts biosynthesized calcitriol only in the presence of its precursor calcidiol, a process that was inhibited by cyclic-AMP but stimulated by lipopolysaccharide (LPS).

A time-course regulatory and kinetic expression study of steroid metabolizing enzymes by calcitriol in primary cultured human placental cells.

1,25-dihydroxivitamin D (calcitriol), is a secoesteroid involved in several placental functions. In particular, we and others showed that calcitriol regulates peptides, proteins, cytokines and hormones production in human trophoblastic cells. On the other hand, calcitriol modifies the activity and expression of some steroidogenic enzymes, a process that is considered tissue-specific.

Evidence of sexual dimorphism in placental vitamin D metabolism: Testosterone inhibits calcitriol-dependent cathelicidin expression.

Male fetus and neonates show increased immune vulnerability compared to females, which results in a higher risk of perinatal infections. These differences could partially be due to sex steroids differential modulation of vitamin D metabolism; since calcitriol, the most active vitamin D metabolite, regulates immune responses and transcriptionally induces the antimicrobial peptide cathelicidin in the human placenta. Calcitriol availability depends on CYP27B1 and CYP24A1 expression, the cytochromes involved in its synthesis and degradation, respectively.

Vitamin D and Inflammatory Cytokines in Healthy and Preeclamptic Pregnancies.

Preeclampsia is a pregnancy disease characterized by hypertension and proteinuria. Among several disorders, the imbalance of inflammatory cytokines and the alteration of vitamin D metabolism have been reported in preeclampsia. The effects of calcitriol upon inflammatory cytokines has been demonstrated.

In vivo dual targeting of the oncogenic Ether-à-go-go-1 potassium channel by calcitriol and astemizole results in enhanced antineoplastic effects in breast tumors.

Background: The oncogenic ether-à-go-go-1 potassium channel (EAG1) activity and expression are necessary for cell cycle progression and tumorigenesis. The active vitamin D metabolite, calcitriol, and astemizole, a promising antineoplastic drug, target EAG1 by inhibiting its expression and blocking ion currents, respectively. We have previously shown a synergistic antiproliferative effect of calcitriol and astemizole in breast cancer cells in vitro, but the effect of this dual therapy in vivo has not been studied.

IL-10 inhibits while calcitriol reestablishes placental antimicrobial peptides gene expression.

IL-10 and calcitriol help to achieve a successful pregnancy by suppressing active maternal immunity; however, these factors exert opposite effects upon microbial infections. In the skin and immune cells, IL-10 downregulates β-defensins while calcitriol induces cathelicidin gene expression in various tissues including placenta. Though, the regulation of human placental β-defensins by IL-10 and calcitriol has not been studied.

Calcitriol restores antiestrogen responsiveness in estrogen receptor negative breast cancer cells: a potential new therapeutic approach.

Background: Approximately 30% of breast tumors do not express the estrogen receptor (ER) α, which is necessary for endocrine therapy approaches. Studies are ongoing in order to restore ERα expression in ERα-negative breast cancer. The aim of the present study was to determine if calcitriol induces ERα expression in ER-negative breast cancer cells, thus restoring antiestrogen responses.

Placental calcitriol synthesis and IGF-I levels in normal and preeclamptic pregnancies.

Placenta is an extrarenal source of calcitriol and pregnancy is associated with increased maternal serum levels of this hormone. It has been reported that insulin-like growth factor I (IGF-I) stimulates placental calcitriol synthesis and that circulating levels of both hormones are low in preeclampsia. Since calcitriol production has not been determined in placental homogenates in preeclampsia, the aim of the present study was to establish if placental calcitriol synthesis and IGF-I concentration are altered in this tissue obtained from preeclamptic pregnancies.

Regulation of CYP27B1 and CYP24A1 gene expression by recombinant pro-inflammatory cytokines in cultured human trophoblasts.

Placenta is an important source of endocrine and immunological factors. During pregnancy, calcitriol, the active metabolite of vitamin D, is also metabolized by decidua and placental tissue by means of CYP27B1 and CYP24A1 for synthesis and inactivation of calcitriol respectively. Calcitriol production is regulated by several factors in a tissue-specific manner.

Calcitriol reduces thrombospondin-1 and increases vascular endothelial growth factor in breast cancer cells: implications for tumor angiogenesis.

Calcitriol, a potent antineoplastic vitamin D metabolite, inhibits proliferation, induces apoptosis and slows the growth of tumors. Calcitriol also may exert either antiangiogenic or proangiogenic effects depending on the tissue. Vascular endothelial growth factor (VEGF) and thrombospondin-1 (Tsp-1) are key factors involved in promoting and inhibiting angiogenesis, respectively.

Associations between insulin-like growth factor I, vascular endothelial growth factor and its soluble receptor 1 in umbilical serum and endothelial cells obtained from normotensive and preeclamptic pregnancies.

The aim of this study was to investigate the associations between insulin-like growth factor I (IGF-I) with vascular endothelial growth factor (VEGF) and its soluble receptor 1 (sFlt-1) in umbilical serum and to study the effects of IGF-I upon sFlt-1 synthesis in human umbilical vein endothelial cells (HUVEC) in normotensive (NT) and preeclamptic (PE) pregnancies. As compared with the NT group, umbilical serum IGF-I and VEGF levels were lower in the PE group, while sFlt-1 concentrations were higher. Levels of sFlt-1 correlated with IGF-I in the NT group and with VEGF in the PE group.

Calcitriol downregulates TNF-α and IL-6 expression in cultured placental cells from preeclamptic women.

Placenta is an important source and target of hormones that contribute to immunological tolerance and maintenance of pregnancy. In preeclampsia (PE), placental calcitriol synthesis is low; whereas pro-inflammatory cytokines levels are increased, threatening pregnancy outcome. Previously, we showed that calcitriol inhibits Th-1 cytokines under experimental inflammatory conditions in normal trophoblasts.

Astemizole synergizes calcitriol antiproliferative activity by inhibiting CYP24A1 and upregulating VDR: a novel approach for breast cancer therapy.

Background: Calcitriol antiproliferative effects include inhibition of the oncogenic ether-à-go-go-1 potassium channel (Eag1) expression, which is necessary for cell cycle progression and tumorigenesis. Astemizole, a new promising antineoplastic drug, targets Eag1 by blocking ion currents. Herein, we characterized the interaction between calcitriol and astemizole as well as their conjoint antiproliferative action in SUM-229PE, T-47D and primary tumor-derived breast cancer cells.

Calcitriol inhibits interleukin-10 expression in cultured human trophoblasts under normal and inflammatory conditions.

Preeclampsia is associated with systemic inflammation and increased expression of placental Th1-cytokines. IL-10 and calcitriol inhibit proinflammatory cytokines expression in human placenta helping to fetal allograft toleration. Regulation of placental IL-10 by calcitriol and Th-1 cytokines has not yet been fully elucidated.

Calcitriol down-regulates human ether a go-go 1 potassium channel expression in cervical cancer cells.

Background/aim: Human ether à-go-go-1 (EAG1) potassium channels are promising anticancer targets. Calcitriol has antitumoural properties. This study investigated EAG1 regulation by calcitriol in normal and cancer cells.

Effects of calcitriol on calbindins gene expression and lipid peroxidation in human placenta.

Pregnancy is associated with increased maternal calcitriol levels and placenta is an extrarenal source of this hormone. Calbindin-D9k and calbindin-D28k are vitamin D-dependent. Since calbindin-D28k has been considered as an antioxidant factor, the aim of the present work was to investigate the effects of calcitriol on calbindins gene expression and lipid peroxidation in cultured syncytiotrophoblast cells obtained from healthy human placentas.

Calcitriol inhibits Ether-à go-go potassium channel expression and cell proliferation in human breast cancer cells.

Antiproliferative actions of calcitriol have been shown to occur in many cell types; however, little is known regarding the molecular basis of this process in breast carcinoma. Ether-à-go-go (Eag1) potassium channels promote oncogenesis and are implicated in breast cancer cell proliferation. Since calcitriol displays antineoplastic effects while Eag1 promotes tumorigenesis, and both factors antagonically regulate cell cycle progression, we investigated a possible regulatory effect of calcitriol upon Eag1 as a mean to uncover new molecular events involved in the antiproliferative activity of this hormone in human breast tumor-derived cells.