1,720,975 research outputs found
Sex and sex steroids as determinants of cardiovascular risk
No full textThere are considerable sex differences regarding the risk of cardiovascular disease (CVD), including arterial hypertension, coronary artery disease (CAD) and stroke, as well as chronic renal disease. Women are largely protected from these conditions prior to menopause, and the risk increases following cessation of endogenous estrogen production or after surgical menopause. Cardiovascular diseases in women generally begin to occur at a later age than in men (on average with a delay of 10 years). Cessation of estrogen production also impacts metabolism, increasing the risk of developing obesity and diabetes. In middle-aged individuals, hypertension develops earlier and faster in women than in men, and smoking increases cardiovascular risk to a greater degree in women than it does in men. It is not only estrogen that affects female cardiovascular health and plays a protective role until menopause: other sex hormones such as progesterone and androgen hormones generate a complex balance that differentiates heart and blood vessel function in women compared to men. Estrogens improve vasodilation of epicardial coronary arteries and the coronary microvasculature by augmenting the release of vasodilating factors such as nitric oxide and prostacyclin, which are mechanisms of coronary vasodilatation that are more pronounced in women compared to men. Estrogens are also powerful inhibitors of inflammation, which in part explains their protective effects on CVD and chronic renal disease. Emerging evidence suggests that sex chromosomes also play a significant role in shaping cardiovascular risk. The cardiovascular protection conferred by endogenous estrogens may be extended by hormone therapy, especially using bioidentical hormones and starting treatment early after menopause
Regulation of human endothelial cell migration by oral contraceptive estrogen receptor ligands
Full text link: Ethinylestradiol (EE) and estetrol (E4) are the two main estrogenic agents used in combined oral contraceptives. These compounds have different binding affinity to and efficacy on estrogen receptors (ER) subtypes. We previously reported that treatment with estrogenic agents enhances angiogenesis via nongenomic, G protein-coupled estrogen receptor (GPER)-dependent mechanisms. However, the impact of EE and E4 on human endothelial function has been little investigated. EE and E4 (10-9- 10-7 M) significantly enhanced migration of human umbilical vein endothelial cells (HUVECs) using scratch and Boyden chamber assays. Mechanistically, both agents increased accumulation of phosphorylated protein tyrosine kinase 2 on tyrosine 397 (FAK Y397), a key player in endothelial cell motility, after 30-min treatment. Treatment with increasing concentrations of EE, but not E4, enhanced accumulation of the glycolysis activator PFKFB3. Of note, effects of EE and E4 on endothelial migration and signalling proteins were abolished by addition of the GPER antagonist G36 (10-6 M). Thus, EE and E4 induced comparable endothelial responses in vitro, suggesting no apparent alterations of vascular remodelling and regeneration capacity by oral contraceptives containing these agents
Post-transcriptional and epigenetic regulation of estrogen signaling
Full text linkPost-translational and epigenetic regulation are important mechanisms controlling functions of genes and proteins. Although the "classic" estrogen receptors (ERs) have been acknowledged to function in mediating estrogen effects via transcriptional mechanisms, estrogenic agents modulate the turnover of several proteins via post-transcriptional and post-translational pathways including epigenetics. For instance, the metabolic and angiogenic action of G-protein coupled estrogen receptor (GPER) in vascular endothelial cells has been recently elucidated. By interacting with GPER, 17β-estradiol (E2) and the GPER agonist G1 enhance endothelial stability of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and capillary tube formation by increasing ubiquitin specific peptidase 19 (USP19) levels, thereby reducing PFKFB3 ubiquitination and proteasomal degradation. In addition to ligands, the functional expression and trafficking of ERs can be modulated by post-translational modification, including palmitoylation. MicroRNAs (miRNAs), the most abundant form of endogenous small RNAs in humans, regulate multiple target genes and are at the center of the multi-target regulatory network. This review discusses also the emerging evidence how miRNAs affect glycolytic metabolism in cancer, as well as their regulation by estrogens. Restoring dysregulated miRNA expression represents a promising strategy to counteract the progression of cancer and other disease conditions. Accordingly, estrogen posttranscriptional regulatory and epigenetic mechanisms represent novel targets for pharmacological and non-pharmacological intervention for the treatment and prevention of hormone-sensentive non-communicable diseases, including estrogen-sensitive cancers of the reproductive system in women
Innate immunity in inflammation
No full textA fine balance between prompt response to pathogens and avoidance of unregulated inflammation, as well as that between protection and self-damage drives the complexity of the immune system, at the same time pointing out the challenge for effective and safe immunopharmacological intervention. A wide variety of clinically relevant drugs are currently used in the treatment of human inflammatory and immune-system associated disorders. Classical therapeutic approaches are now integrated with emerging strategies that largely derive from advances in signalling and regulatory networks and the pathological consequences of their dysregulation in the field of innate immunity. This chapter provides an account of: (i) the interplay between innate immunity and inflammation; (ii) main immune signalling molecules in inflammation including cytokines, prostanoids and cancer-related immune response, and the main aspects of pharmacological control thereof; and (iii) emerging options for therapeutic interventions on cells of innate immunity
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Cyclic AMP in rat ileum: evidence for the presence of an extracellular cyclic AMP-adenosine pathway
No full textSex Differences in the Pro-Angiogenic Response of Human Endothelial Cells: Focus on PFKFB3 and FAK Activation
Full text linkFemale hormones and sex-specific factors are established determinants of endothelial function, yet their relative contribution to human endothelium phenotypes has not been defined. Using human umbilical vein endothelial cells (HUVECs) genotyped by donor's sex, we investigated the influence of sex and estrogenic agents on the main steps of the angiogenic process and on key proteins governing HUVEC metabolism and migratory properties. HUVECs from female donors (fHUVECs) showed increased viability (p < 0.01) and growth rate (p < 0.01) compared with those from males (mHUVECs). Despite higher levels of G-protein coupled estrogen receptor (GPER) in fHUVECs (p < 0.001), treatment with 17β-estradiol (E2) and the selective GPER agonist G1 (both 1–100 nM) did not affect HUVEC viability. Migration and tubularization in vitro under physiological conditions were higher in fHUVECs than in mHUVECs (p < 0.05). E2 treatment (1–100 nM) upregulated the glycolytic activator PFKFB3 with higher potency in fHUVECs than in mHUVECs, despite comparable baseline levels. Moreover, Y576/577 phosphorylation of focal adhesion kinase (FAK) was markedly enhanced in fHUVECs (p < 0.001), despite comparable Src activation levels. While the PI3K inhibitor LY294002 (25 μM) inhibited HUVEC migration (p < 0.05), Akt phosphorylation levels in fHUVECs and mHUVECs were comparable. Finally, digitoxin treatment, which inhibits Y576/577 FAK phosphorylation, abolished sexual dimorphism in HUVEC migration. These findings unravel complementary modulation of HUVEC functional phenotypes and signaling molecules involved in angiogenesis by hormone microenvironment and sex-specific factors, and highlight the need for sex-oriented pharmacological targeting of endothelial function
- …
