1,720,985 research outputs found
Estrogen receptor activation protects against TNFa-induced endothelial dysfunction
No full textLack of estrogen is a cause of cardiovascular disease in men and postmenopausal women. We examined the effects of estrogen receptors (ERs) activation/inactivation on endothelial cells subjected to tumor necrosis factor (TNF)α, which is involved in vascular disease pathogenesis. Endothelial nitric oxide synthase (eNOS) and matrix metalloproteinases (MMP)-9 expression, as well as protein kinase B (PKB) activation were evaluated as markers of endothelial dysfunction. TNFα induces eNOS and MMP-9 expression and PKB activation. ER activation by apigenin, a non-steroidal compound with estrogen-like activity mediated through ER binding-dependent pathways, counteracts these effects. These effects are reversed by classic (ERα and ERβ) and non-classic (GPR30) ER inhibitors (ICI182, 780 and PTX, respectively). Our data suggest that ER activation counteracts endothelial dysfunction induced by TNFα. The use of ER activators, such as apigenin, may represent a strategy to prevent vascular disease associated with endothelial dysfunction, while avoiding the feminizing effects of estrogens
Apigenin inhibits the TNFα-induced expression of eNOS and MMP-9 via modulating Akt signalling through oestrogen receptor engagement.
No full textApigenin is a naturally occurring plant flavone with strong antioxidant and anti-inflammatory activity. While the anticancer properties of Apigenin have been extensively studied, little is known about its effects on endothelial dysfunction. We investigated the effects of Apigenin in EAhy926 endothelial cells exposed to TNFa by evaluating the expression of eNOS and MMP-9, two key molecules in endothelial dysfunction. MMP-9 activity was measured by gel zymography. Western Blot analysis was performed to analyze eNOS expression and signal transduction. Treatment with Apigenin (50 microM) counteracted the TNFa-induced expression of eNOS and MMP-9 and the TNFa- triggered activation of Akt, p38MAPK and JNK signalling suggesting that multiple signalling pathways are involved in mediating the protective effects of Apigenin on endothelial function.To better understand the molecular mechanisms underlying the protective effects of Apigenin, we used a pharmacological approach with specific inhibitors. The use of an Akt inhibitor mimicked the inhibitory effects of Apigenin on eNOS and MMP-9 expression, suggesting that eNOS and MMP-9 induction by TNFa depends on Akt activation. The TNFa-induced expression of MMP-9 was also affected by the JNK inhibitor SP600125. No effect on eNOS and MMP-9 expression was observed in the presence of the p38MAPK inhibitor SB203580 or the ERK 1/2 inhibitor PD98059. Pretreatment with ‘classic’ (ERa and ERb) or ‘non classic’ (GPR30) estrogen receptor (ER) inhibitors (ICI182,780 and PTX, respectively) counteracted the ability of Apigenin to decrease the TNFa-triggered activation of the Akt pathway. Consistently, the use of both ER inhibitors reversed the inhibitory effects of Apigenin on the TNFa-induced expression of eNOS and, to a lesser extent, MMP-9. We can conclude that Apigenin exerts its inhibitory effect on the TNFa-induced expression of eNOS and MMP-9 through the Akt signalling inhibition generated by ER activation. Estrogen signalling has been implicated in protection from cardiovascular disease. Therefore, having regard to its ability to bind to ERs, Apigenin may be considered an estrogen-like molecule to potentially be used against the onset and progression of vascular diseases associated with endothelial dysfunction
Hind limb unloading of mice modulates gene expression at the protein and mRNA level in mesenchymal bone cells
No full textAbstract Background We investigated the extent, modalities and reversibility of changes at cellular level in the expression of genes and proteins occurring upon Hind limb unloading (HU) in the tibiae of young C57BL/6J male mice. We focused on the effects of HU in chondrogenic, osteogenic, and marrow mesenchymal cells. Methods We analyzed for expression of genes and proteins at two time points after HU (7 and 14 days), and at 14 days after recovery from HU. Levels of mRNAs were tested by in situ hybridization. Protein levels were tested by immunohistochemistry. We studied genes involved in osteogenesis (alkaline phosphatase (AP), osteocalcin (OC), bonesialoprotein (BSP), membrane type1 matrix metalloproteinase (MT1-MMP)), in extracellular matrix (ECM) formation (procollagenases (BMP1), procollagenase enhancer proteins (PCOLCE)) and remodeling (metalloproteinase-9 (MMP9), RECK), and in bone homeostasis (Stro-1, CXCL12, CXCR4, CD146). Results We report the following patterns and timing of changes in gene expression induced by HU: 1) transient or stable down modulations of differentiation-associated genes (AP, OC), genes of matrix formation, maturation and remodelling, (BMP1, PCOLCEs MMP9) in osteogenic, chondrogenic and bone marrow cells; 2) up modulation of MT1-MMP in these same cells, and uncoupling of its expression from that of AP; 3) transient down modulation of the osteoblast specific expression of BSP; 4) for genes involved in bone homeostasis, up modulation in bone marrow cells at distal epiphysis for CXCR4, down modulation of CXCL12, and transient increases in osteoblasts and marrow cells for Stro1. 14 days after limb reloading expression returned to control levels for most genes and proteins in most cell types, except AP in all cells, and CXCL12, only in bone marrow. Conclusions HU induces the coordinated modulation of gene expression in different mesenchymal cell types and microenvironments of tibia. HU also induces specific patterns of expression for homeostasis related genes and modulation of mRNAs and proteins for ECM deposition, maturation and remodeling which may be key factors for bone maintenance.</p
Effects of Pleiotrophin on endothelial and inflammatory cells: Pro-angiogenic and anti-inflammatory properties and potential role for vascular bio-prosthesis endothelialization
No full textPurpose: One of the limitations emerged with both synthetic and degradable vascular grafts is the lack of endothelialization after implantation that is known to be the main reason leading to unfavourable outcomes. It emerges the need to find new strategies to promote a rapid endothelialization of the scaffold. Pleiotrophin is a growth/differentiation cytokine for various cell type. We here evaluated the effect of Pleiotrophin on endothelial cells (EC), monocytes and macrophages that have been shown as key cells promoting neovascularization.
Material/Methods: Eahy926 endothelial cells, THP-1 monocytes and PMA-differentiated macrophages were treated with Pleiotrophin (10 and 100 ng/ml).VEGF, Flk-1, Nrp-1, COX-2, ICAM-1 and TGFβ expression were detected by Western Blot, IL-10, MCP-1 and TNF levels by ELISA. Chemotaxis was performed in Boyden chambers. Wound healing was performed by scratch wound assay.
Results: Pleiotrophin induces in EC the expression of VEGF and its receptors Flk-1 and Nrp-1 and improves the migratory capacity. In THP-1 monocytes, Pleiotrophin induces the expression of VEGF and its receptor Nrp-1 and decreases the levels of COX-2 and TNFα. In PMA-differentiated macrophages COX-2 expression was significantly reduced by Pleiotrophin, while IL-10 and TGFβ were increased.
Conclusions: Pleiotrophin acts as an angiogenesis ‘driver’ by promoting the creation of a pro-angiogenic environment, a migratory behaviour in EC and a pro-regenerative alternative phenotype in macrophages. Our results suggest that Pleiotrophin might be considered for vascular prosthesis engineering
Pro-collagen I COOH-terminal trimer induces directional migration and metalloproteinases in breast cancer cells.
No full textTrimer carboxyl propeptide of collagen I produced by mature osteoblasts is chemotactic for endothelial cells.
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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
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