Polycystic ovarian syndrome (PCOS) is a highly variable syndrome and one of the most common female endocrine disorders. Although the association inositols-glucomannan may represent a good therapeutic strategy in the treatment of PCOS women with insulin resistance, the effect of inositols on the metabolomic profile of these women has not been described yet. Fifteen PCOS-patients and 15 controls were enrolled. Patients were treated with myo-inositol (1.75 g/day), D-chiro-inositol (0.25 g/day) and glucomannan (4 g/day) for 3 months. Blood concentrations of glucose, insulin, triglycerides and cholesterol, and ovary volumes and antral follicles count, as well as metabolomic profiles, were evaluated for control subjects and for cases before and after treatment. PCOS-patients had higher BMI compared with Controls, BMI decreased significantly after 3 months of treatment although it remained significantly higher compared to controls. 3-methyl-1-hydroxybutyl-thiamine-diphosphate, valine, phenylalanine, ketoisocapric, linoleic, lactic, glyceric, citric and palmitic acid, glucose, glutamine, creatinine, arginine, choline and tocopherol emerged as the most relevant metabolites for distinguishing cases from controls. Our pilot study has identified a complex network of serum molecules that appear to be correlated with PCOS, and with a combined treatment with inositols and glucomannan. ClinicalTial.gov, NCT03608813 . Registered 1st August 2018 - Retrospectively registered, .

Fetal growth restriction is an obstetrical pathological condition that causes high neonatal mortality and morbidity. The mechanisms of its onset are not completely understood. Metabolites were extracted from 493 placentas from non-complicated pregnancies in Hamilton Country, TN (USA), and analyzed by gas chromatography–mass spectrometry (GC–MS). Newborns were classified according to raw fetal weight (low birth weight (LBW; 2500 g)), and according to the calculated birth weight centile as it relates to gestational age (small for gestational age (SGA), large for gestational age (LGA), and adequate for gestational age (AGA)). Mothers of LBW infants had a lower pre-pregnancy weight (66.2 ± 17.9 kg vs. 73.4 ± 21.3 kg, p < 0.0001), a lower body mass index (BMI) (25.27 ± 6.58 vs. 27.73 ± 7.83, p < 0.001), and a shorter gestation age (246.4 ± 24.0 days vs. 267.2 ± 19.4 days p < 0.001) compared with non-LBW. Marital status, tobacco use, and fetus sex affected birth weight centile classification according to gestational age. Multivariate statistical comparisons of the extracted metabolomes revealed that asparagine, aspartic acid, deoxyribose, erythritol, glycerophosphocholine, tyrosine, isoleucine, serine, and lactic acid were higher in both SGA and LBW placentas, while taurine, ethanolamine, β-hydroxybutyrate, and glycine were lower in both SGA and LBW. Several metabolic pathways are implicated in fetal growth restriction, including those related to the hypoxia response and amino-acid uptake and metabolism. Inflammatory pathways are also involved, suggesting that fetal growth restriction might share some mechanisms with preeclampsia.

Background: Previous studies implicated cardiotonic steroids, including Na/K-ATPase inhibitor marinobufagenin (MBG), in the pathogenesis of preeclampsia (PE). Immunoneutralization of heightened MBG by Digibind, a digoxin antibody, reduces blood pressure (BP) in patients with PE, and anti-MBG monoclonal antibody lessens BP in a rat model of PE. Recently, we demonstrated that MBG induces fibrosis in cardiovascular tissues via a mechanism involving inhibition of Fli-1, a nuclear transcription factor and a negative regulator of collagen-1 synthesis. Objectives and Methods: We hypothesized that in PE, elevated placental MBG levels are associated with development of fibrosis in umbilical arteries. Eleven patients with PE (mean BP 124 ± 4 mmHg; age 29 ± 2 years; 39 weeks gest. age) and 10 gestational age-matched normal pregnant subjects (mean BP 92 ± 2 mmHg; controls) were enrolled in the clinical study. Results: PE was associated with a higher placental (0.04 ± 0.01 vs. 0.49 ± 0.11 pmol/g; p < 0.01) and plasma MBG (0.5 ± 0.1 vs. 1.6 ± 0.5 nmol/L; p < 0.01), lower Na/K-ATPase activity in erythrocytes (2.7 ± 0.2 vs. 1.5 ± 0.2 µmol Pi/mL/hr; p < 0.01), 9-fold decrease of Fli-1 level and 2.5-fold increase of collagen-1 in placentae (p < 0.01) vs. control. Incubation of umbilical arteries from control patients with 1 nmol/L MBG was associated with four-fold decrease in Fli-1 level and two-fold increase in collagen-1 level vs. those incubated with placebo (p < 0.01), i.e., physiological concentration of MBG mimicked effect of PE in vitro. Collagen-1 abundance in umbilical arteries from PE patients was 4-fold higher than in control arteries, and this PE-associated fibrosis was reversed by monoclonal anti-MBG antibody ex vivo. Conclusion: These results demonstrate that elevated placental MBG level is implicated in the development of fibrosis of the placenta and umbilical arteries in PE.

Despite prophylaxis and attempts to select a therapy, the frequency of preeclampsia does not decrease and it still takes the leading position in the structure of maternal mortality and morbidity worldwide. In this review, we present a new theory of the etiology and pathogenesis of preeclampsia that is based on the interaction of Na/K-ATPase and its endogenous ligands including marinobufagenin. The signaling pathway of marinobufagenin involves an inhibition of transcriptional factor Fli1, a negative regulator of collagen synthesis, followed by the deposition of collagen in the vascular tissues and altered vascular functions. Moreover, in vitro and in vivo neutralization of marinobufagenin is associated with the restoration of Fli1. The inverse relationship between marinobufagenin and Fli1 opens new possibilities in the treatment of cancer; as Fli1 is a proto-oncogene, a hypothesis on the suppression of Fli1 by cardiotonic steroids as a potential anti-tumor therapeutic strategy is discussed as well. We propose a novel therapy of preeclampsia that is based on immunoneutralization of the marinobufagenin by monoclonal antibodies, which is capable of impairing marinobufagenin-Na/K-ATPase interactions.

Previous studies implicated cardiotonic steroids, including Na/K-ATPase inhibitor marinobufagenin (MBG), in the pathogenesis of preeclampsia (PE). Recently, we demonstrated that (i) MBG induces fibrosis in rat tissues via a mechanism involving Fli1, a negative regulator of collagen-1 synthesis, and (ii) MBG sensitive Na/K-ATPase inhibition is reversed by mineralocorticoid antagonists. We hypothesized that in human PE elevated MBG level is associated with the development of fibrosis of the umbilical arteries and that this fibrosis can be attenuated by canrenone. Fifteen patients with PE (mean BP = 118 ± 4 mmHg; 34 ± 2 years; 38 ± 0.3 weeks gest. age) and twelve gestational age-matched normal pregnant subjects (mean BP = 92 ± 2 mmHg; 34 ± 1 years; 39 ± 0.2 weeks gest. age) were enrolled in the study. PE was associated with a higher plasma MBG level, with a four-fold decrease in Fli1 level and a three-fold increase in collagen-1 level in the PE umbilical arteries vs. those from the normal subjects (p < 0.01). Isolated rings of umbilical arteries from the subjects with PE exhibited impaired responses to the relaxant effect of sodium nitroprusside vs. control vessels (EC₅₀ = 141 nmol/L vs. EC₅₀ = 0.9 nmol/L; p < 0.001). The effects of PE on Fli1 and collagen-1 were blocked by the in vitro treatment of umbilical arteries by 10 μmol/L canrenone. Similar results were obtained for umbilical arteries pretreated with MBG. These data demonstrate that elevated MBG level is implicated in the development of the fibrosis of umbilical arteries in PE, and that this could be blocked by mineralocorticoid antagonists.