Human predecidual stromal cells are mesenchymal stromal/stem cells and have a therapeutic effect in an immune-based mouse model of recurrent spontaneous abortion

Human decidual stromal cells (DSCs) are involved in the maintenance and development of pregnancy, in which they play a key role in the induction of immunological maternal–fetal tolerance. Precursors of DSCs (preDSCs) are located around the vessels, and based on their antigen phenotype, previous studies suggested a relationship between preDSCs and mesenchymal stromal/stem cells (MSCs). This work aimed to further elucidate the MSC characteristics of preDSCs. Under the effect of P4 and cAMP, the preDSC lines and clones decidualized in vitro: the cells became rounder and secreted PRL, a marker of physiological decidualization. PreDSC lines and clones also exhibited MSC characteristics. They differentiated into adipocytes, osteoblasts, and chondrocytes, and preDSC lines expressed stem cell markers OCT- 4, NANOG, and ABCG2; exhibited a cloning efficiency of 4 to 15%; significantly reduced the embryo resorption rate (P < 0.001) in the mouse model of abortion; and survived for prolonged periods in immunocompetent mice. The fact that 3 preDSC clones underwent both decidualization and mesenchymal differentiation shows that the same type of cell exhibited both DSC and MSC characteristics. Together, our results confirm that preDSCs are decidual MSCs and suggest that these cells are involved in the mechanisms of maternal–fetal immune toleranceThis work was supported by the Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–2016, ISCIII-Subdirección General de Evaluación y Fomento de la Investigación, the Ministerio de Economía y Competitividad, Spain (Grant PI16/01642) and European Regional Development Fund (ERDF/ FEDER funding), the European Community, and the Cátedra de Investigación Anto nio Chamorro–Alejandro Otero, Universidad de Granada (CACH2017-1)

Allosteric interactions at adenosine A1 and A3 receptors: new insights into the role of small molecules and receptor dimerization

Keywords:adenosine;allosterism;receptor;GPCR;dimerization;biased signalling The purine nucleoside adenosine is present in all cells in tightly regulated concentrations. It is released under a variety of physiological and pathophysiological conditions to facilitate protection and regeneration of tissues. Adenosine acts via specific GPCRs to either stimulate cyclic AMP formation, as exemplified by Gs-protein-coupled adenosine receptors (A2A and A2B), or inhibit AC activity, in the case of Gi/o-coupled adenosine receptors (A1 and A3). Recent advances in our understanding of GPCR structure have provided insights into the conformational changes that occur during receptor activation following binding of agonists to orthosteric (i.e. at the same binding site as an endogenous modulator) and allosteric regulators to allosteric sites (i.e. at a site that is topographically distinct from the endogenous modulator). Binding of drugs to allosteric sites may lead to changes in affinity or efficacy, and affords considerable potential for increased selectivity in new drug development. Herein, we provide an overview of the properties of selective allosteric regulators of the adenosine A1 and A3 receptors, focusing on the impact of receptor dimerization, mechanistic approaches to single-cell ligand-binding kinetics and the effects of A1- and A3-receptor allosteric modulators on in vivo pharmacology

Caracterización de la célula decidual estromal y su implicación en la interfase materno-fetal

Tesis Univ. Granada. Departamento de Bioquímica y Biología Molecular. Leída el 20 de marzo de 200

ALLOSTERIC MODULATION OF A1-ADENOSINE RECEPTOR. A REVIEW

Allosteric modulators of adenosine receptors represent an alternative to direct-acting adenosine agonists and nucleoside uptake blockers, preferably those can selectively modulate the response to adenosine in only those organs or localized areas of a given organ in which production of adenosine is increased. Allosteric enhancers at the adenosine A1 receptor have received attention as anti-arrhythmic cardiac agents, and, more recently, as anti-lipolytic agents. In addition, this class of compounds has therapeutic potential as analgesics and neuroprotective agents

Anticancer activity of novel hybrid molecules containing 5-benzylidene thiazolidine-2,4-dione

Hybridization of two different bioactive molecules with different mechanism of action is one of the methods that are being adopted to treat cancer. Molecules bearing a thiazolidine-2,4-dione scaffold have been recognized as antineoplastic agents with a broad spectrum of activity against many cancer cell lines. In this manuscript we have described the synthesis and biological evaluation of two series of N-3-substituted-5-arylidene thiazolidine-2,4-diones, bearing the α-bromoacryloylamido moiety at the para- or meta-position on the phenyl of the arylidene portion. We have observed that selected compounds 5a, 5c and 5g suppress proliferation of human myeloid leukaemia HL-60 and U937 cells by triggering morphological changes and internucleosomal DNA fragmentation, which are well-known features of apoptosis. Finally, our results indicated that the investigated compounds induced apoptotic cell death through a mechanism that involved activation of multiple caspases and was also associated with the release of cytochrome c from the mitochondria.This work was partially supported by the Ministry of Science and Innovation of Spain and the European Regional Development Fund (SAF2010-21380) and Instituto Canario de Investigación del Cáncer to F.E. Jan Balzarini is funded by GOA (Krediet no. 10/14) of the KU Leuven.Peer Reviewe

Anticancer and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors

This research was funded by Convocatoria 2019 Proyectos de I + D + i - RTI Tipo B "Ministerio de Innovacion y Ciencia" grant number PID2019-109294RB-I00 and University of Granada, Cei-BioticProject grant number CEI2013-MP-1.Choline kinase inhibitors are an outstanding class of cytotoxic compounds useful for the treatment of different forms of cancer since aberrant choline metabolism is a feature of neoplastic cells. Here, we present the most in-depth structure-activity relationship studies of an interesting series of non-symmetric choline kinase inhibitors previously reported by our group: 3a–h and 4a–h. They are characterized by cationic heads of 3-aminophenol bound to 4-(dimethylamino)- or 4-(pyrrolidin-1-yl)pyridinium through several linkers. These derivatives were evaluated both for their inhibitory activity on the enzyme and their antiproliferative activity in a panel of six human tumor cell lines. The compounds with the N-atom connected to the linker (4a–h) show the best inhibitory results, in the manner of results supported by docking studies. On the contrary, the best antiproliferative compounds were those with the O-atom bounded to the linker (3a–h). On the other hand, as was predictable in both families, the inhibitory effect on the enzyme is better the shorter the length of the linker. However, in tumor cells, lipophilicity and choline uptake inhibition could play a decisive role. Interestingly, compounds 3c and 4f, selected for both their ability to inhibit the enzyme and good antiproliferative activity, are endowed with low toxicity in non-tumoral cells (e.g., human peripheral lymphocytes) concerning cancer cells. These compounds were also able to induce apoptosis in Jurkat leukemic cells without causing significant variations of the cell cycle. It is worth mentioning that these derivatives, besides their inhibitory effect on choline kinase, displayed a modest ability to inhibit choline uptake thus suggesting that this mechanism may also contribute to the observed cytotoxicity.Convocatoria 2019 Proyectos de I + D + i - RTI Tipo B "Ministerio de Innovacion y Ciencia" PID2019-109294RB-I00University of Granada, Cei-BioticProject CEI2013-MP-

Design, Synthesis and Biological Evaluation of Hybrid Molecules Containing Conjugated Styryl Ketone and alpha-Bromoacryloyl Moieties

There was a major interest in the last years in the design of anticancer agents containing the 1,5-diaryl-3-oxo- 1,4-pentadienyl system. The modification of this pharmacophore by the introduction of an additional Michael acceptor represents a strategy to obtain novel potential antiproliferative agents. In a continuing study of hybrid compounds containing the α-bromoacryloyl moiety as potential anticancer drugs, we synthesized two novel series of hybrids 3a-i and 4a-i, in which this moiety was linked to the 1,5-diaryl-1,4-pentadien-3-one system. Many of the conjugates prepared (3b, 3c and 3g) demonstrated pronounced antiproliferative activity against five cancer cell lines, being more active than the reference compound Melphalan. Compounds 3e and 4b were also examined for their effects on the cell cycle progression of K562 cells. The detection of a sub-G1 peak upon incubation with these compounds suggested that 3e and 4b also exert their growth inhibiting effects by induction of apoptosis