Biologically Informed Polygenic Scores for Brain Insulin Receptor Network Are Associated with Cardiometabolic Risk Markers and Diabetes in Women.

Backgruound: To investigate associations between variations in the co-expression-based brain insulin receptor polygenic score and cardiometabolic risk factors and diabetes mellitus.

Methods: This cross-sectional study included 1,573 participants from the Helsinki Birth Cohort Study. Biologically informed expression-based polygenic risk scores for the insulin receptor gene network were calculated for the hippocampal (hePRS-IR) and the mesocorticolimbic (mePRS-IR) regions.

Decidual glycodelin-A polarizes human monocytes into a decidual macrophage-like phenotype through Siglec-7.

Decidual macrophages constitute 20-30% of the total leukocytes in the uterus of pregnant women, regulating the maternal immune tolerance and placenta development. Abnormal number or activities of decidual macrophages (dMs) are associated with fetal loss and pregnancy complications, such as preeclampsia. Monocytes differentiate into dMs in a decidua-specific microenvironment.

Glycodelin-A stimulates the conversion of human peripheral blood CD16-CD56bright NK cell to a decidual NK cell-like phenotype.

Study Question: Does glycodelin-A (GdA) induce conversion of human peripheral blood CD16-CD56bright natural killer (NK) cells to decidual NK (dNK) cells to facilitate placentation?

Summary Answer: GdA binds to blood CD16-CD56bright NK cells via its sialylated glycans and converts them to a dNK-like cells, which in turn regulate endothelial cell angiogenesis and trophoblast invasion via vascular endothelial growth factor (VEGF) and insulin-like growth factor-binding protein 1 (IGFBP-1) secretion, respectively.

What Is Known Already: dNK cells are the most abundant leucocyte population in the decidua. These cells express CD16-CD56bright phenotype.

The Pleiotropic Effect of Glycodelin-A in Early Pregnancy.

Successful pregnancy depends largely on adequate placentation and maternal tolerance of the fetus. Glycodelin-A is a glycoprotein abundant in the decidua during early pregnancy. It plays an important role in placental development and fetomaternal defense.

Glycodelin-A stimulates interleukin-6 secretion by human monocytes and macrophages through L-selectin and the extracellular signal-regulated kinase pathway.

Macrophages represent the second major type of decidual leukocytes at the fetomaternal interface. Changes in macrophage number and activity are associated with fetal loss and pregnancy complications. Glycodelin-A (GdA) is an abundant glycoprotein in the first-trimester decidua.

Glycodelin-A protein interacts with Siglec-6 protein to suppress trophoblast invasiveness by down-regulating extracellular signal-regulated kinase (ERK)/c-Jun signaling pathway.

During placentation, the cytotrophoblast differentiates into the villous cytotrophoblast and the extravillous cytotrophoblast. The latter invades the decidualized endometrium. Glycodelin-A (GdA) is abundantly synthesized by the decidua but not the trophoblast.

Glycodelin-A as a paracrine regulator in early pregnancy.

Glycodelin-A (GdA) is a glycoprotein secreted from the endometrial glands and decidual glandular epithelium. Given its abundance and ubiquitous distribution in the first trimester uterus, GdA may be involved in early placental development via its modulatory effect on immune and trophoblast cells. GdA inhibits activation and proliferation, and induces apoptosis of T cells.

Glycosylation failure extends to glycoproteins in gestational diabetes mellitus: evidence from reduced α2-6 sialylation and impaired immunomodulatory activities of pregnancy-related glycodelin-A.

Objective: Gestational diabetes mellitus (GDM) is a common metabolic disorder of pregnancy. Patients with GDM are at risk for high fetal mortality and gestational complications associated with reduced immune tolerance and abnormal carbohydrate metabolism. Glycodelin-A (GdA) is an abundant decidual glycoprotein with glycosylation-dependent immunomodulatory activities.

Differential actions of glycodelin-A on Th-1 and Th-2 cells: a paracrine mechanism that could produce the Th-2 dominant environment during pregnancy.

Background: The maternal-fetal interface has a unique immunological response towards the implanting placenta. It is generally accepted that a T-helper type-2 (Th-2) cytokine prevailing environment is important in pregnancy. The proportion of Th-2 cells in the peripheral blood and decidua is significantly higher in pregnant women in the first trimester than in non-pregnant women.

Hormonal evaluation and midcycle detection of intrauterine glycodelin in women treated with levonorgestrel as in emergency contraception.

Background: The study was conducted to assess the effects of levonorgestrel (LNG) on hormonal behavior and on the secretory pattern of intrauterine glycodelin at the midcycle of ovulatory women.

Study Design: Thirty healthy sterilized women with normal ovarian function were studied during one control untreated cycle and one LNG-treated cycle. In the treated cycle, each woman received two doses of 0.

Zona pellucida-induced acrosome reaction in human spermatozoa is potentiated by glycodelin-A via down-regulation of extracellular signal-regulated kinases and up-regulation of zona pellucida-induced calcium influx.

Background: Glycodelin-A interacts with spermatozoa before fertilization, but its role in modulating sperm functions is not known. Zona pellucida-induced acrosome reaction is crucial to fertilization and its dysfunction is a cause of male infertility. We hypothesized that glycodelin-A, a glycoprotein found in the female reproductive tract, potentiates human spermatozoa for zona pellucida-induced acrosome reaction.

Glycodelin-A modulates cytokine production of peripheral blood natural killer cells.

Glycodelin-A increased the secretion of interleukin-6, interleukin-13, and granulocyte-macrophage colony-stimulating factor from natural killer cells in the peripheral blood but does not affect their viability, cell death, and cytotoxicity. These data suggest that glycodelin-A contributes to the cytokine shift in early pregnancy.

Effects of glycodelins on functional competence of spermatozoa.

Glycodelin is a glycoprotein with 4 known glycoforms, namely glycodelin-S, glycodelin-A, glycodelin-F and glycodelin-C. The glycoforms are present in the female reproductive tract which the spermatozoa must pass through before fertilizing the oocyte. Thus the spermatozoa interact with each of these glycoforms in succession.

Cumulus-associated alpha2-macroglobulin derivative retains proconceptive glycodelin-C in the human cumulus matrix.

Background: Glycodelin-C is a glycodelin isoform isolated from the cumulus matrix. It stimulates spermatozoa-zona pellucida binding. Here, we report the isolation and characterization of a novel glycodelin interacting protein (GIP) from human cumulus matrix.

The role of glycodelin in cell differentiation and tumor growth.

Glycodelin is a lipocalin family glycoprotein expressed mainly in reproductive tissues. It is involved in cell recognition, and its relationship with epithelial differentiation is well established. Glycodelin actually appears to drive epithelial differentiation.

Effects of differential glycosylation of glycodelins on lymphocyte survival.

Glycodelin is a human glycoprotein with four reported glycoforms, namely glycodelin-A (GdA), glycodelin-F (GdF), glycodelin-C (GdC), and glycodelin-S (GdS). These glycoforms have the same protein core and appear to differ in their N-glycosylation. The glycosylation of GdA is completely different from that of GdS.

Glycodelin reduces breast cancer xenograft growth in vivo.

Malignant growth is characterized by loss of cell differentiation, uncontrolled proliferation and resistance to apoptosis. Many tumor suppressor genes that protect cells against malignant transformation regulate cell differentiation. Here, we show for the first time that glycodelin, a differentiation-related protein, reduces breast cancer tumor growth in vivo.

Glycodelin: a molecule with multi-functions on spermatozoa.

Glycodelin is a glycoprotein with three isoforms, namely glycodelin-S, glycodelin-A and glycodelin-F. They have similar protein core but different glycan side chains. Spermatozoa are exposed to these isoforms during their passage to the fertilization site.

In vivo assessment of the human sperm acrosome reaction and the expression of glycodelin-A in human endometrium after levonorgestrel-emergency contraceptive pill administration.

Background: The objectives were firstly to assess acrosome reaction (AR) status of spermatozoa following uterine flushing, secondly to measure levonorgestrel (LNG) levels in serum and in uterine flushing fluid and finally to measure endometrial glycodelin-A expression after administration of LNG as a form of emergency contraception (EC).

Methods: Forty-eight experiments were conducted on 15 regularly menstruating women. Four groups were formed based on different intercourse to treatment interval and treatment to recovery of spermatozoa and the biopsies.

Cumulus oophorus-associated glycodelin-C displaces sperm-bound glycodelin-A and -F and stimulates spermatozoa-zona pellucida binding.

Spermatozoa have to swim through the oviduct and the cumulus oophorus before fertilization in vivo. In the oviduct, spermatozoa are exposed to glycodelin-A and -F that inhibit spermatozoa-zona pellucida binding. In this study, we determined whether these glycodelins would inhibit fertilization.

Glycodelin-A interacts with fucosyltransferase on human sperm plasma membrane to inhibit spermatozoa-zona pellucida binding.

Fertilization depends on successful binding of the spermatozoa to the zona pellucida of the oocyte. Glycodelin-A inhibits spermatozoa-zona pellucida binding. Previous data showed that glycodelin-A receptor(s) and zona pellucida protein receptor(s) on human spermatozoa are closely related.