Differential Signal Transduction of Progesterone and Medroxyprogesterone Acetate in Human Endothelial Cells

AbstractThe conjugated equine estrogens-only arm of the Women's Health Initiative trial, showing a trend toward protection from heart disease as opposed to women receiving also medroxyprogesterone acetate (MPA), strengthens the debate on the cardiovascular effects of progestins. We compared the effects of progesterone (P) or MPA on the synthesis of nitric oxide and on the expression of leukocyte adhesion molecules, characterizing the signaling events recruited by these compounds. Although P significantly increases nitric oxide synthesis via transcriptional and nontranscriptional mechanisms, MPA is devoid of such effects. Moreover, when used together with physiological estradiol (E2) concentrations, P potentiates E2 effects, whereas MPA impairs E2 signaling. These findings are observed both in isolated human endothelial cells as well as in vivo, in ovariectomized rat aortas. A marked difference in the recruitment of MAPK and phosphatidylinositol-3 kinase explains the divergent effects of the two gestagens. In addition, both P and MPA decrease the adhesiveness of endothelial cells for leukocytes when given alone or with estrogen. MPA is more potent than P in inhibiting the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1. However, when administered together with physiological amounts of glucocorticoids, MPA (which also binds glucocorticoid receptor) markedly interferes with the hydrocortisone-dependent stabilization of the transcription factor nuclear factor κB and with the expression of adhesion molecules, acting as a partial glucocorticoid receptor antagonist. Our findings show significant differences in the signal transduction pathways recruited by P and MPA in endothelial cells, which may have relevant clinical implications

Investigating the features of PDO green hams during salting: Insights for new markers and genomic regions in commercial hybrid pigs

Protected Designation of Origin (PDO) dry-cured hams production is greatly dependent on raw meat quality. This study was performed to identify genetic markers associated with the quality of dry-cured ham. Carcass traits of 229 heavy pigs belonging to three commercial genetic lines were registered (weight, EUROP classification). Phenotypic traits (Semimembranosus muscle ultimate pH, ham weight and lean meat content, adsorbed salt) of the corresponding thighs, undergone PDO ham process in three different plants, were measured, using a fast and non-invasive technology. Green ham weight and lean meat percentage influenced the estimated salt content and the weight loss during salting, even if the processing plant greatly affected the variability of the measured ham traits. The genomic data were obtained with the GeneSeek Genomic Profiler (GGP) 70k HD Porcine Array, using the slaughter day and the sex of the animals in the statistical analyses. The phenotypic traits were associated with the genotypes through GenAbel software. The results showed that 18 SNPs located on nine porcine chromosomes were found to be associated with nine phenotypic traits, mainly related to ham weight loss during salting. New associations were found between markers in the genes Neural Precursor Cell Expressed Developmentally Down-Regulated 9 (NEDD9, SSC7), T-Cell Lymphoma Invasion and Metastasis 2 (TIAM2, SSC1), and the ham quality traits. After validation, these SNPs may be useful to improve the quality of thighs for the production of PDO dry-cured hams

Compensatory Feto-Placental Upregulation of the Nitric Oxide System during Fetal Growth Restriction

Background: Fetal Growth Restriction is often associated with a feto-placental vascular dysfunction conceivably involving endothelial cells. Our study aimed to verify this pathogenic role for feto-placental endothelial cells and, coincidentally, demonstrate any abnormality in the nitric oxide system. Methods: Prenatal assessment of feto-placental vascular function was combined with measurement of nitric oxide (in the form of S-nitrosohemoglobin) and its nitrite byproduct, and of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine. Umbilical vein endothelial cells were also harvested to determine their gene profile. The study comprised term pregnancies with normal (n = 40) or small-for-gestational-age (n = 20) newborns, small-for-gestational-age preterm pregnancies (n = 15), and bi-chorial, bi-amniotic twin pregnancies with discordant fetal growth (n = 12). Results: Umbilical blood nitrite (p<0.001) and S-nitrosohemoglobin (p = 0.02) rose with fetal growth restriction while asymmetric dimethylarginine decreased (p = 0.003). Nitrite rise coincided with an abnormal Doppler profile from umbilical arteries. Fetal growth restriction umbilical vein endothelial cells produced more nitrite and also exhibited reciprocal changes in vasodilator (upwards) and vasoconstrictor (downwards) transcripts. Elevation in blood nitrite and S-nitrosohemoglobin persisted postnatally in the fetal growth restriction offspring. Conclusion: Fetal growth restriction is typified by increased nitric oxide production during pregnancy and after birth. This response is viewed as an adaptative event to sustain placental blood flow. However, its occurrence may modify the endothelial phenotype and may ultimately represent an element of risk for cardiovascular disease in adult life.Fil: Pisaneschi, Silvia. Università degli Studi di Pisa; Italia. Scuola Superiore Sant’Anna; ItaliaFil: Strigini, Francesca A. L.. Università degli Studi di Pisa; ItaliaFil: Sanchez, Angel Matias. Università degli Studi di Pisa; Italia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Begliuomini, Silvia. Università degli Studi di Pisa; ItaliaFil: Casarosa, Elena. Università degli Studi di Pisa; ItaliaFil: Ripoli, Andrea. National Research Council. Institute of Clinical Physiology, ; ItaliaFil: Ghirri, Paolo. Università degli Studi di Pisa; ItaliaFil: Boldrini, Antonio. Università degli Studi di Pisa; ItaliaFil: Fink, Bruno. Noxygen Science Transfer and Diagnostics; AlemaniaFil: Genazzani, Andrea R.. Università degli Studi di Pisa; ItaliaFil: Coceani, Flavio. Scuola Superiore Sant’Anna; ItaliaFil: Simoncini, Tommaso. Università degli Studi di Pisa; Itali

Out-of-equilibrium systems and planetary habitability

The VI workshop of the “Thermodynamics, disequilibrium and evolution” Focus Group was held in the beautiful setting of Villa il Gioiello. This meeting focused on out-of- equilibrium systems, which could provide the conditions for the emergence of life, and on the use of thermodynamic instruments for the study of planetary habitability

Dehydroepiandrosterone modulates endothelial nitric oxide synthesis via direct genomic and nongenomic mechanisms.

Abstract Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) are the major circulating steroid hormones in humans, and their levels progressively decline with age. Epidemiological studies suggest that DHEA/DHEAS concentrations may be inversely related to cardiovascular risk, but disagreement exists on this issue. Preliminary studies show that DHEA regulates vascular function, but few data have been published on the mechanisms. We show that DHEA administration to human endothelial cells triggers nitric oxide synthesis, due to enhanced expression and stabilization of endothelial nitric oxide synthase (eNOS). Additionally, DHEA rapidly activates eNOS, through a nontranscriptional mechanism that depends on ERK1/2 MAPK, but not on phosphatidylinositol 3-kinase/Akt. DHEA is not converted to estrogens or androgens by endothelial cells, and its genomic and nongenomic effects are not blocked by antagonists of the estrogen, progesterone, glucocorticoid, or androgen receptors, suggesting that DHEA acts through a specific receptor. Oral DHEA administration to ovariectomized Wistar rats dose-dependently restores aortic eNOS levels and eNOS activity, confirming the effects of DHEA in vivo. Our present data suggest that DHEA may have direct genomic and nongenomic effects on the vascular wall that are not mediated by other steroid hormone receptors, leading to eNOS activation and induction

Spectral estimates for saddle point matrices arising in weak constraint four-dimensional variational data assimilation

We consider the large-sparse symmetric linear systems of equations that arise in the solution of weak constraint four-dimensional variational data assimilation, a method of high interest for numerical weather prediction. These systems can be written as saddle point systems with a $3 \times 3$ block structure but block eliminations can be performed to reduce them to saddle point systems with a $2 \times 2$ block structure, or further to symmetric positive definite systems. In this paper, we analyse how sensitive the spectra of these matrices are to the number of observations of the underlying dynamical system. We also obtain bounds on the eigenvalues of the matrices. Numerical experiments are used to confirm the theoretical analysis and bounds