Preclinical data indicate a direct anti-tumor effect of zoledronic acid (ZA) outside the skeleton, but its molecular mechanism is still not completely clarified. The aim of this study was to investigate the anti-cancer effects of ZA in human breast cancer cell lines, suggesting that they may in part be mediated via the miR-21/PTEN/Akt signaling pathway. The effect of ZA on cell viability was measured by MTT assay, and cell death induction was analyzed using either a double AO/EtBr staining and M30 ELISA assay. A Proteome Profiler Human Apoptosis Array was executed to evaluate the molecular basis of ZA-induced apoptosis. Cell cycle analysis was executed by flow cytometry. The effect of ZA on miR-21 expression was quantified by qRT-PCR, and the amount of PTEN protein and its targets were analyzed by Western blot. ZA inhibited cell growth in a concentration- and time-dependent manner, through the activation of cell death pathways and arrest of cell cycle progression. ZA downregulated the expression of miR-21, resulting in dephosphorilation of Akt and Bad and in a significant increase of p21 and p27 proteins expression. These results were observed also in MDA-MB-231 cells, commonly used as an experimental model of bone metastasis of breast cancer. This study revealed, for the first time, an involvement of the miR-21/PTEN/Akt signaling pathway in the mechanism of ZA anti-cancer actions in breast cancer cells. We would like to underline that this pathway is present both in the hormone responsive BC cell line (MCF-7) as well as in a triple negative cell line (MDA-MB-231). Taken together these results reinforce the use of ZA in clinical practice, suggesting the role of miR-21 as a possible mediator of its therapeutic efficacy.

A dysregulation of the Nerve Growth Factor (NGF)-mediated control of prostate cell growth is associated with the malignant progression of prostate epithelial cells.Exogenous NGF induced in prostate cancer (PCa) cell lines DU145 and PC3 the expression of p75 NGFR , accompanied by a reduction of the cell malignancy.The aim of this study was to analyze the profile of NGF-regulated genes the PCa cell line DU145 by using the cDNA microarray technique.NGF treatment of DU145 cells decreased the expression of 52 known genes, while the expression of 40 known genes was increased.NGF treatment of the DU145 cell line modified the expression profile of clusters of genes involved in invasion and metastasis, in cell proliferation and apoptosis, inflammation, cell metabolism and transcriptional activity.Interestingly, NGF induced the same pattern of gene modifications in both PCa cell lines.Data presented here may help to identify gene/proteins that dispose to PCa progression and to assess future markers that could allow the development of new clinic diagnostic and therapeutical approaches.

Metalliferous deposits are described from the eastern flank of the East Pacific Rise (EPR) offshore Costa Rica, close to a basaltic seamount called "Dorado high". Based on heat-flow data and porewater profiles, the site is an area of active low-temperature hydrothermal discharge. We focus on the mineralogical and chemical analysis from a 124 cm long gravity core (GC50), located on the northwestern slope of the 100 in high Dorado. In this core, the sediments consist of detrital clay minerals as well as authigenic minerals such as zeolites, apatites, and Fe/Mn-rich oxyhydroxides. In contrast, the reference sediments from adjacent areas without hydrothermal activity are olive gay hemipelagic muds composed of volcanic glass particles, clay minerals, siliceous microfossils, and some detrital quartz and feldspar.Bulk sediment chemistry and chemical enrichment factors calculated with respect to the reference sediment indicate that the most important chemical changes occurred at the base of the core from 100 to 124 cm bsf, with strong enrichments in MnO, CaO, P2O5, and Fe2O3. These enrichments are correlated with the occurrence of authigenic Fe-oxyhydroxide (goethite) and Mn oxide (todorokite and vernadite, at 100 cm bsf), and hydrothermal apatite (110-124 cm bsf). In the upper section of the core from 12 to 70 cm, the sediment is composed of abundant smectite and authigenic phillipsite, and only minor chemical changes can be observed with respect to the reference sediments.The ubiquitous presence of phillipsite suggests that the entire sedimentary column of core GC50 was first affected by diagenesis. However, below 70 cm bsf, these phillipsites are partially dissolved and Fe oxides occur from 110 to 124 cm, followed upward by Mn oxides at 100 cm. This transition from Fe to Mn-rich sediments can be interpreted in terms of an upward increasing redox potential. PAAS-normalized REY patterns of GC50 sediments present clearly negative Ce and positive Y anomalies inherited from seawater at the base of core GC50. These anomalies decrease upward, which we interpret together with the transition from Fe to Mn-rich sediments by an upward migrating low-temperature hydrothermal fluid. Thus, after a first stage of diagenesis, the discharge of a low-temperature hydrothermal fluid occurred through the sedimentary column, leading to the precipitation of hydrothermal compounds that are lacking towards the surface. (c) 2008 Elsevier B.V. All rights reserved.

Adrenergic receptors (ARs) are a class of proteins belonging to the G protein-coupled receptor family. Pharmacological and molecular studies allowed dividing ARs into three different categories: α1, α2 and β. In this review, we focused on α1 ARs and α1 AR antagonists, since α 1 ARs play an important role in the pathophysiology of a number of urinary tract (UT) dysfunctions. α1 ARs are widely expressed in human UT; in particular, the three ureter areas (distal, medial and proximal) show different patterns of receptor expression (i.e. distal > medial = proximal), giving the molecular basis for the use of α1 ARs antagonist in the expulsive therapy of distal ureter calculi. Bladder areas are characterized by important differences among trigone, detrusor and neck, the first showing a different pattern of expression compared to the other parts. Further, there are evidences of both density and subtype gender-dependent expressions. α1 ARs expression in prostate and detrusor is a widely investigated area of research, mainly due to the clinical impact of benign prostatic hyperplasia (BPH). Urethra has not been well studied in human, although it plays a role in the control of continence. Studies carried out on α1 AR subtype expression in the UT indicate that, although the presence of each subtype is observed, α1A firstly and then α1D ARs seem to be more expressed than α1B ARs. Thus, drugs that demonstrate high α1A/D AR selectivity have drawn the researchers’ attention. As it relates specifically to the α1 AR antagonists used in the treatment of lower UT symptoms, the concept of uroselectivity has been operationally defined; indeed, in a number of recent publications uroselectivity has been defined as the degree to which a given compound inhibits norepinephrine-induced increase in urinary muscle contractions and/or its propensity to generate unwanted cardiovascular effects, such as decreases in blood pressure.

Les echantillons etudies proviennent de carottages effectues lors de la campagne en mer Ticoflux 2 au large de la cote ouest du Costa Rica, en 2002. Ils ont ete preleves sur les pentes nord-ouest du « Mont Dorado » : une zone ou des decharges diffuses de fluides de faible temperature ont ete localisees. Nos donnees ont ete focalisees sur la carotte GC50, composee de boues hemipelagiques alterees presentant des argiles, des zeolites, localement des oxydes Fe/Mn, ainsi que des phosphates. La caracterisation mineralogique (DRX, MEB, MET-EDX) et chimique (majeurs, traces, terres rares) des nouvelles phases minerales formees in situ dans le sediment GC50 a permis de mettre en evidence deux phases d'alteration. La premiere phase consiste en un processus de diagenese precoce. La deuxieme phase d'alteration engendre la precipitation d'apatites et d'oxydes Mn/Fe essentiellement localises pres de l'interface sediment-basalte. Les donnees de la geochimie isotopique du strontium et du neodyme, ainsi que la distribution des spectres des Terres Rares, ont permis de preciser la nature du fluide a l'origine de la seconde phase d'alteration. Ces marqueurs geochimiques suggerent la decharge d'un fluide hydrothermal de basse temperature ayant tres peu interagit avec le basalte lors de sa circulation dans la croute. Une etude plus poussee (EXAFS, METHR) sur les echantillons riches en oxydes Mn/Fe a permis de proposer un modele de formation et d'evolution des oxydes Mn, dans ce contexte hydrothermal hors axe. Ce modele demontre que la formation de todorokite (tectomanganate), mineral ubiquiste en milieu marin, necessite la presence d'un precurseur, ici la vernadite (phyllomanganate).

Metalliferous deposits are ubiquitous in marine sediments and play a major role in the elemental cycles of iron, manganese, and other trace elements. The metalliferous sediments studied here were sampled near a basaltic seamount named "Dorado", on the eastern flank of the East Pacific Rise, west of Nicoya Peninsula (Costa Rica). Based on heat flow data and porewater profiles, this site is an area of active low-temperature hydrothermal discharge. Most samples are from gravity core GC50, which is characterized by the presence of abundant authigenic minerals (mainly Fe-Mn-oxyhydroxides and apatites).Our data suggest that these minerals have initially precipitated during the Miocene from a high-temperature hydrothermal plume when the Dorado site was located near the East Pacific Rise. With increasing distance from the ridge axis, the plume precipitates were buried under hemipelagic sediments. After the onset of the present-day low temperature hydrothermal activity these precipitates were dissolved and re-precipitated higher up in the sediment pile to form the observed assemblage of authigenic minerals.The study thus shows that the metalliferous deposits of the Dorado seamount have a very complex origin, which could be unraveled by a combined approach based on Nd-Sr isotopes, REV data (rare earth elements and yttrium), and mineralogical observations. (C) 2012 Elsevier B.V. All rights reserved.

Adrenergic receptors (ARs) are a class of proteins belonging to the G protein- coupled receptor family. Pharmacological and molecular studies allowed dividing ARs into three different categories: α1, α2 and β. In this review, we focused on α1 ARs and α1 AR antagonists, since α1 ARs play an important role in the pathophysiology of a number of uri- nary tract (UT) dysfunctions. α1 ARs are widely expressed in human UT; in particular, the three ureter areas (distal, medial and proximal) show different patterns of receptor expres- sion (i.e. distal > medial = proximal), giving the molecular basis for the use of α1 ARs an- tagonist in the expulsive therapy of distal ureter calculi. Bladder areas are characterized by important differences among trigone, detrusor and neck, the first showing a different pat- tern of expression compared to the other parts. Further, there are evidences of both den- sity and subtype gender-dependent expressions. α1 ARs expression in prostate and de- trusor is a widely investigated area of research, mainly due to the clinical impact of benign prostatic hyperplasia (BPH). Urethra has not been well studied in human, although it plays a role in the control of continence. Studies carried out on α1 AR subtype expression in the UT indicate that, although the pres- ence of each subtype is observed, α1A firstly and then α1D ARs seem to be more expressed than α1B ARs. Thus, drugs that demonstrate high α1A/D AR selectivity have drawn the re- searchers' attention. As it relates specifically to the α1 AR antagonists used in the treat- ment of lower UT symptoms, the concept of uroselectivity has been operationally defined; indeed, in a number of recent publications uroselectivity has been defined as the degree to which a given compound inhibits norepinephrine-induced increase in urinary muscle con- tractions and/or its propensity to generate unwanted cardiovascular effects, such as de- creases in blood pressure. (Urologia 2007; 74: 53-60)