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Dive into the research topics where Jorge Marrero-Alonso is active.

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Featured researches published by Jorge Marrero-Alonso.


European Journal of Pharmacology | 2004

Acute relaxation of mouse duodenun by estrogens: Evidence for an estrogen receptor-independent modulation of muscle excitability

Mario Díaz; Cristina M. Ramírez; Raquel Marin; Jorge Marrero-Alonso; Tomás Gómez; Rafael Alonso

17-beta-Estradiol, the stereoisomer 17-alpha-estradiol and the synthetic estrogen diethylstilbestrol (DES), all caused a rapid (<3 min) dose-dependent reversible relaxation of mouse duodenal spontaneous activity, reduced basal tone and depressed the responses to CaCl(2) and KCl. The steroidal antiestrogen 7alpha-[9-[(4,4,5,5,5,-pentafluoropenty)sulphinyl]nonyl]-estra-1,3,5(19)-triene-3,17beta-diol (ICI182,780) failed to either mimic or prevent the effect of 17-beta-estradiol. The effect of estrogens was unrelated to activation of nitric oxide (NO), mitogen-activated protein kinase (MAPK), protein kinase A (PKA), protein kinase G (PKG) or protein kinase C (PKC). Estrogen-induced relaxation was partially reversed by 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-pyridine-3-carboxilic acid methyl ester (BAY-K8644), depolarization, or by application of tetraethylammonium or 4-aminopyridine, but not by glibenclamide, apamin, charybdotoxin, paxilline or verruculogen. The effects of BAY-K8644 and K(+) channel blockers were synergistic, and allowed relaxed tissues to recover spontaneous activity and basal tone. We hypothesize that the rapid non-genomic spasmolytic effect of estrogens on mouse duodenal muscle might be triggered by an estrogen-receptor-independent mechanism likely involving activation of tetraethylamonium- and 4-aminopyridine-sensitive K(+) channels and inhibition of L-type Ca2(+) channels on the smooth muscle cells.


Molecular Endocrinology | 2010

Androgens Induce Nongenomic Stimulation of Colonic Contractile Activity through Induction of Calcium Sensitization and Phosphorylation of LC20 and CPI-17

María del Carmen González-Montelongo; Raquel Marin; Tomás Gómez; Jorge Marrero-Alonso; Mario Díaz

We show that androgens, testosterone and 5alpha-dihydrotestosterone (DHT), acutely (approximately 40 min) provoke the mechanical potentiation of spontaneous and agonist-induced contractile activity in mouse colonic longitudinal smooth muscle. The results using flutamide, finasteride, cycloheximide, and actinomycin D indicate that androgen-induced potentiation is dependent on androgen receptors, requires reduction of testosterone to DHT, and occurs independently of transcriptional and translational events. Using permeabilized colonic smooth muscle preparations, we could demonstrate that mechanical potentiation is entirely due to calcium sensitization of contractile machinery. In addition, DHT (10 nm) increased phosphorylation of both 20-kDa myosin light chain (LC(20)) [regulatory myosin light chain, (MLC)] and CPI-17 (an endogenous inhibitor of MLC phosphatase). Paralleling these findings, inhibition of Rho-associated Rho kinase (ROK) and/or protein kinase C (PKC) with, respectively, Y27632 and chelerythrine, prevented LC(20) phosphorylation and abolished calcium sensitization. In addition, inhibition of ROK prevents CPI-17 phosphorylation, indicating that ROK is located upstream PKC-mediated CPI-17 modulation in the signalling cascade. Additionally, androgens induce a rapid activation of RhoA and its translocation to the plasma membrane to activate ROK. The results demonstrate that androgens induce sensitization of colonic smooth muscle to calcium through activation of ROK, which in turn, activates PKC to induce CPI-17 phosphorylation. Activation of this pathway induces a potent steady stimulation of LC(20) by inhibiting MLC phosphatase and displacing the equilibrium of the regulatory subunit towards its phosphorylated state. This is the first demonstration that colonic smooth muscle is a physiological target for androgen hormones, and that androgens modulate force generation of smooth muscle contractile machinery through nongenomic calcium sensitization pathways.


Laser Physics Letters | 2015

Random laser in biological tissues impregnated with a fluorescent anticancer drug

F. Lahoz; I.R. Martín; M Urgellés; Jorge Marrero-Alonso; Raquel Marin; C J Saavedra; Alicia Boto; Mario Díaz

We have demonstrated that chemically modified anticancer drugs can provide random laser (RL) when infiltrated in a biological tissue. A fluorescent biomarker has been covalently bound to tamoxifen, which is one of the most frequently used drugs for breast cancer therapy. The light emitted by the drug-dye composite is scattered in tissue, which acts as a gain medium. Both non-coherent and coherent RL regimes have been observed. Moreover, the analysis of power Fourier transforms of coherent RL spectra indicates that the tissues show a dominant random laser cavity length of about 18 µm, similar to the average size of single cells. These results show that RL could be obtained from other drugs, if properly marked with a fluorescent tag, which could be appealing for new forms of combined opto-chemical therapies.


Optics Letters | 2012

Whispering gallery mode laser based on antitumor drug–dye complex gain medium

F. Lahoz; Claudio J. Oton; David López; Jorge Marrero-Alonso; Alicia Boto; Mario Díaz

Optofluidic lasers have emerged as a new research field over the past few years. Most frequently they use conventional dye molecules as the gain medium. In this Letter, we demonstrate a laser emission produced by the coupling of the evanescent whispering gallery modes that resonate in a cylindrical microresonator to a newly developed gain medium. This medium is formed by attachment of a 7-nitrobenzo [c] [1,2,5]-oxadiazol-4-yl fluorescent tag to tamoxifen, the most widely used drug in the treatment of breast cancer. The antitumor character of the gain medium paves the way to novel biophotonic applications.


European Journal of Pharmaceutics and Biopharmaceutics | 2013

Unique SERM-like properties of the novel fluorescent tamoxifen derivative FLTX1.

Jorge Marrero-Alonso; Araceli Morales; Benito García Marrero; Alicia Boto; Raquel Marin; Débora Cury; Tomás Gómez; Leandro Fernández-Pérez; F. Lahoz; Mario Díaz

Tamoxifen is a selective estrogen receptor modulator extensively used on estrogen receptor-positive breast cancer treatment. However, clinical evidences demonstrate the increased incidence of undesirable side effects during chronic therapies, the most life threatening being uterine cancers. Some of these effects are related to tissue-dependent estrogenic actions of tamoxifen, but the exact mechanisms remain poorly understood. We have designed and synthesized a novel fluorescent tamoxifen derivative, FLTX1, and characterized its biological and pharmacological activities. Using confocal microscopy, we demonstrate that FLTX1 colocalizes with estrogen receptor α (ERα). Competition studies showed that FLTX1 binding was totally displaced by unlabeled tamoxifen and partially by estradiol, indicating the existence of non-ER-related triphenylethylene-binding sites. Ligand binding assays showed that FLTX1 exhibits similar affinity for ER than tamoxifen. FLTX1 exhibited antiestrogenic activity comparable to tamoxifen in MCF7 and T47D cells transfected with 3xERE-luciferase reporter. Interestingly, FLTX1 lacked the strong agonistic effect of tamoxifen on ERα-dependent transcriptional activity. Additionally, in vivo assays in mice revealed that unlike tamoxifen, FLTX1 was devoid of estrogenic uterotrophic effects, lacked of hyperplasic and hypertrophic effects, and failed to alter basal proliferating cell nuclear antigen immunoreactivity. In the rat uterine model of estrogenicity/antiestrogenicity, FLTX1 displayed antagonistic activity comparable to tamoxifen at lower doses, and only estrogenic uterotrophy at the highest dose. We conclude that the fluorescent derivative FLTX1 is not only a suitable probe for studies on the molecular pharmacology of tamoxifen, but also a potential therapeutic substitute to tamoxifen, endowed with potent antiestrogenic properties but devoid of uterine estrogenicity.


Archive | 2006

Cellular and Molecular Basis for Acute Nongenomically Mediated Actions of SERMs

Mario Díaz; Jorge Marrero-Alonso; Benito García Marrero; Raquel Marin; Tomás Gómez; Rafael Alonso

Compelling evidence accumulated over the past three decades have demonstrated that, besides their ability to antagonize estrogen binding to their intracellular specific estrogen receptors (ER), selective estrogen receptor modulators (SERMs) can affect a number of biochemical processes in eukaryotic cells. Experimental data from in vivo and in vitro studies have revealed that SERMs and estrogens are surprisingly pleiotropic molecules affecting molecular targets in both estrogen receptor positive (ER+) and negative (ER–) cells. Such “alternative” actions of SERMs and estrogens are typically independent of canonical ERs and do not involve transcriptional or translational events, thereby mediated nongenomically, and usually initiated (and accomplished) within seconds to minutes after presentation of the molecule (Falkestein et al. 2000; Nadal el al. 2001). The spectrumof SERM-induced acute actions includes a wide set of molecular targets, frommodulation of ion channels and signaling molecules to alteration of membrane fluidity. In the following sections we review data from different laboratories, including ours, in the context of cellular and molecular evidences for acute nongenomic effects of SERMs observed at pharmacological circulating concentrations. Special emphasis will be placed on actions that might underlie clinically relevant beneficial effects as well as undesirable side effects.


European Journal of Pharmacology | 2004

Acute relaxation of mouse duodenum [correction of duodenun] by estrogens. Evidence for an estrogen receptor-independent modulation of muscle excitability.

Mario Díaz; Cristina M. Ramírez; Raquel Marin; Jorge Marrero-Alonso; Tomás Gómez; Rafael Alonso

17-beta-Estradiol, the stereoisomer 17-alpha-estradiol and the synthetic estrogen diethylstilbestrol (DES), all caused a rapid (<3 min) dose-dependent reversible relaxation of mouse duodenal spontaneous activity, reduced basal tone and depressed the responses to CaCl(2) and KCl. The steroidal antiestrogen 7alpha-[9-[(4,4,5,5,5,-pentafluoropenty)sulphinyl]nonyl]-estra-1,3,5(19)-triene-3,17beta-diol (ICI182,780) failed to either mimic or prevent the effect of 17-beta-estradiol. The effect of estrogens was unrelated to activation of nitric oxide (NO), mitogen-activated protein kinase (MAPK), protein kinase A (PKA), protein kinase G (PKG) or protein kinase C (PKC). Estrogen-induced relaxation was partially reversed by 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-pyridine-3-carboxilic acid methyl ester (BAY-K8644), depolarization, or by application of tetraethylammonium or 4-aminopyridine, but not by glibenclamide, apamin, charybdotoxin, paxilline or verruculogen. The effects of BAY-K8644 and K(+) channel blockers were synergistic, and allowed relaxed tissues to recover spontaneous activity and basal tone. We hypothesize that the rapid non-genomic spasmolytic effect of estrogens on mouse duodenal muscle might be triggered by an estrogen-receptor-independent mechanism likely involving activation of tetraethylamonium- and 4-aminopyridine-sensitive K(+) channels and inhibition of L-type Ca2(+) channels on the smooth muscle cells.


Methods of Molecular Biology | 2016

Colocalization of Estrogen Receptors with the Fluorescent Tamoxifen Derivative, FLTX1, Analyzed by Confocal Microscopy.

Araceli Morales; Raquel Marin; Jorge Marrero-Alonso; Alicia Boto; Mario Díaz

Tamoxifen is a selective estrogen receptor modulator that competitively binds the ligand-binding domain of estrogen receptors. Binding of tamoxifen displaces its cognate ligand, 17β-estradiol, thereby hampering the activation of estrogen receptors. Cellular labeling of ER is typically carried out using specific antibodies which require permeabilization of cells, incubation with secondary antibodies, and are expensive and time consuming. In this article, we describe the usefulness of FLTX1, a novel fluorescent tamoxifen derivative, which allows the labeling of estrogen receptors in immunocytochemistry and immunohistochemistry studies, both under permeabilized and non-permeabilized conditions. Further, besides labeling canonical estrogen receptors, this novel fluorescent probe is also suitable for the identification of unconventional targets such membrane estrogen receptors as well as other noncanonical targets, some of which are likely responsible for the number of undesired side effects reported during long-term tamoxifen treatments.


ChemMedChem | 2015

Synthesis of 4,4'-Diaminotriphenylmethanes with Potential Selective Estrogen Receptor Modulator (SERM)-like Activity.

Gema Guedes; Ángel Amesty; Roberto Jiménez‐Monzón; Jorge Marrero-Alonso; Mario Díaz; Leandro Fernández-Pérez; Ana Estévez-Braun

In this study, a series of new 4,4′‐diaminotriphenylmethanes was efficiently synthesized from aromatic aldehydes and 2,5‐dimethoxybenzenamine under microwave irradiation in the presence of Sc(OTf)3 as a catalyst. Antiproliferative activity was assessed by using the MCF‐7 estrogen receptor (ER)‐positive breast cancer cell line, and antagonist/agonist transcriptional activities were determined. Docking studies and competition studies of triphenylmethanes and radiolabeled estradiol determined that these compounds do not bind the ER, indicating that triphenylmethane‐induced changes in proliferative and transcriptional activities differ from conventional mechanisms of action triggered by other selective ER modulators.


Hormone Molecular Biology and Clinical Investigation | 2011

Membrane-initiated signaling of estrogen related to neuroprotection. “Social networks” are required

Raquel Marin; Jorge Marrero-Alonso; Cecilia Fernández; Débora Cury; Mario Díaz

Abstract Numerous studies indicate that estrogens are crucial in normal brain functioning and preservation against different injuries. At the neuronal membrane, estrogens, binding to estrogen receptors (ERs) or other surface targets, exert rapid actions involving a plethora of signaling pathways that may converge in neuronal survival. Emerging work reveals that at least part of these actions may require the compartmentalization of ERs in signaling platforms, composed of macromolecular signaling proteins and particular lipid composition integrated in lipid rafts. These particular microstructures may provide the optimal microenvironment to trigger multiple ER interactions that may be crucial for neuroprotection against different brain impairments, such as Alzheimers disease (AD). In this order of ideas, recent evidence has demonstrated that a membrane ER (mER) physically interacts with a voltage-dependent anion channel (VDAC) in lipid rafts from septal, hippocampal and cortical neurons, and these interactions may have important consequences in the alternative mechanisms developed by estrogens to achieve neuroprotection against amyloid beta (Aβ)-induced toxicity. This review includes a survey of some of the rapid mechanisms developed by estrogen to prevent neuronal death, and the ER interactions that are involved in the structural maintenance and signal transduction mechanisms important for neuronal survival against AD neuro-pathology. A special emphasis is put on the biological relevance of neuronal membrane VDAC in Aβ-related neurotoxicity, and the potential modulation of this channel as a part of a signaling complex with mER, which may be modified in AD brains.

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Mario Díaz

University of La Laguna

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Raquel Marin

University of La Laguna

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Alicia Boto

Spanish National Research Council

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F. Lahoz

University of La Laguna

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Benito García Marrero

Spanish National Research Council

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