74 results on '"Ruiz-Ruiz C"'
Search Results
2. Neutron radiobiology studies with a pure cold neutron beam
- Author
-
Pedrosa-Rivera, M., Ruiz-Magaña, M.J., Porras, I., Praena, J., Torres-Sánchez, P., Sabariego, M.P., Köster, U., Forsyth, T., Soldner, T., Haertlein, M., and Ruiz-Ruiz, C.
- Published
- 2020
- Full Text
- View/download PDF
3. Fetal–Placental Hypoxia Does Not Result from Failure of Spiral Arterial Modification in Mice
- Author
-
Leno-Durán, E., Hatta, K., Bianco, J., Yamada, Á.T., Ruiz-Ruiz, C., Olivares, E.G., and Croy, B.A.
- Published
- 2010
- Full Text
- View/download PDF
4. Orphan Receptor Kinase ROR2 is Expressed in the Mouse Uterus
- Author
-
Hatta, K., Chen, Z., Carter, A.L., Leno-Durán, E., Zhang, J., Ruiz-Ruiz, C., Olivares, E.G., MacLeod, R.J., and Croy, B.A.
- Published
- 2010
- Full Text
- View/download PDF
5. Human Decidual Stromal Cells Protect Lymphocytes from Apoptosis
- Author
-
Blanco, O., Leno-Durán, E., Morales, J.C., Olivares, E.G., and Ruiz-Ruiz, C.
- Published
- 2009
- Full Text
- View/download PDF
6. Human decidual stromal cells secrete soluble pro-apoptotic factors during decidualization in a cAMP-dependent manner
- Author
-
Leno-Durán, E., Ruiz-Magaña, M.J, Muñoz-Fernández, R., Requena, F., Olivares, E.G, and Ruiz-Ruiz, C.
- Published
- 2014
- Full Text
- View/download PDF
7. Death on the beach: a rosy forecast for the 21st century.
- Author
-
Munoz-Pinedo, C., Ruiz de Almodovar, C., and Ruiz-Ruiz, C.
- Subjects
CELL death ,TUMOR necrosis factors ,APOPTOSIS - Abstract
Discusses several research presented at the Third European Workshop on Cell Death, which was held on February 23-28, 2002 in Salobrena, Spain. Biology and novel signaling of the tumor necrosis factor ligand family; Regulation of cell death; Sensitization of tumor cells to apoptosis; Apoptosis in the nervous and immune systems; Role of caspase and non-caspase proteases in apoptosis.
- Published
- 2002
- Full Text
- View/download PDF
8. Activation of protein kinase C inhibits TRAIL-induced caspases activation, mitochondrial events and apoptosis in a human leukemic T cell line.
- Author
-
Sarker, M, Ruiz-Ruiz, C, and López-Rivas, A
- Subjects
- *
TUMOR necrosis factors , *APOPTOSIS , *TUMORS , *PROTEIN kinase C , *MITOCHONDRIAL membranes - Abstract
TRAIL causes apoptosis in numerous types of tumor cells. However, the mechanisms regulating TRAIL-induced apoptosis remain to be elucidated. We have investigated the role of PKC in regulating TRAIL-induced mitochondrial events and apoptosis in the Jurkat T cell line. We found a caspasedependent decline in mitochondrial membrane potential and translocation of cytochrome c from mitochondria into the cytosol in response to TRAIL. Both these events were prevented by PKC activation. Moreover, PKC activation considerably reduced the activation of caspases, PARP cleavage and apoptosis when induced upon TRAIL treatment. MAPK activation was involved in the mechanism of PKCmediated inhibition of TRAIL-induced cytochrome c release from mitochondria. Furthermore, inhibition of the MAPK pathway partially reversed the PKC-mediated inhibition of TRAIL-induced apoptosis. Besides, PKC activation may also inhibit the TRAIL-induced apoptosis through a MAPKindependent mechanism. Altogether, these results indicate a negative role of PKC in the regulation of apoptotic signals generated upon TRAIL receptor activation. [ABSTRACT FROM AUTHOR]
- Published
- 2001
- Full Text
- View/download PDF
9. Perinatal derivatives: where do we stand? A roadmap of the human placenta and consensus for tissue and cell nomenclature
- Author
-
Antonietta Rosa Silini, Roberta Di Pietro, Ingrid Lang-Olip, Francesco Alviano, Asmita Banerjee, Mariangela Basile, Veronika Borutinskaite, Günther Eissner, Alexandra Gellhaus, Bernd Giebel, Yong-Can Huang, Aleksandar Janev, Mateja Erdani Kreft, Nadja Kupper, Ana Clara Abadía-Molina, Enrique G. Olivares, Assunta Pandolfi, Andrea Papait, Michela Pozzobon, Carmen Ruiz-Ruiz, Olga Soritau, Sergiu Susman, Dariusz Szukiewicz, Adelheid Weidinger, Susanne Wolbank, Berthold Huppertz, Ornella Parolini, Silini A.R., Di Pietro R., Lang-Olip I., Alviano F., Banerjee A., Basile M., Borutinskaite V., Eissner G., Gellhaus A., Giebel B., Huang Y.-C., Janev A., Kreft M.E., Kupper N., Abadia-Molina A.C., Olivares E.G., Pandolfi A., Papait A., Pozzobon M., Ruiz-Ruiz C., Soritau O., Susman S., Szukiewicz D., Weidinger A., Wolbank S., Huppertz B., and Parolini O.
- Subjects
0301 basic medicine ,Histology ,placenta ,lcsh:Biotechnology ,Cell ,Biomedical Engineering ,Medizin ,Consensus criteria ,Bioengineering ,Review ,cells ,consensus nomenclature ,derivatives ,fetal annexes ,perinatal ,tissues ,Biology ,Bioinformatics ,Cell morphology ,03 medical and health sciences ,0302 clinical medicine ,lcsh:TP248.13-248.65 ,Placenta ,medicine ,derivative ,Settore BIO/13 - BIOLOGIA APPLICATA ,fetal annexe ,Bioengineering and Biotechnology ,Human placenta ,cell ,3. Good health ,Clinical trial ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Identification (biology) ,Biotechnology - Abstract
Progress in the understanding of the biology of perinatal tissues has contributed to the breakthrough revelation of the therapeutic effects of perinatal derivatives (PnD), namely birth-associated tissues, cells, and secreted factors. The significant knowledge acquired in the past two decades, along with the increasing interest in perinatal derivatives, fuels an urgent need for the precise identification of PnD and the establishment of updated consensus criteria policies for their characterization. The aim of this review is not to go into detail on preclinical or clinical trials, but rather we address specific issues that are relevant for the definition/characterization of perinatal cells, starting from an understanding of the development of the human placenta, its structure, and the different cell populations that can be isolated from the different perinatal tissues. We describe where the cells are located within the placenta and their cell morphology and phenotype. We also propose nomenclature for the cell populations and derivatives discussed herein. This review is a joint effort from the COST SPRINT Action (CA17116), which broadly aims at approaching consensus for different aspects of PnD research, such as providing inputs for future standards for the processing and in vitro characterization and clinical application of PnD., Austrian Science Fund (FWF) DOC 31-B26, Medical University Graz, Universita Cattolica del Sacro Cuore, PRIN 2017 program of Italian Ministry of Research and University (MIUR) 2017RSAFK7, Ministry of Health, Italy GR-2018-12366992, Slovenian Research Agency - Slovenia P3-0108, MRIC UL IP-0510, Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion, ISCIII Subdireccion General de Evaluacion y Fomento de la Investigacion, Ministerio de Economia y Competitividad, Spain PI16/01642, European Union (EU), European Community (EC), German Research Foundation (DFG) GE-2223/2-1
- Published
- 2020
10. HDAC inhibitors with different gene regulation activities depend on the mitochondrial pathway for the sensitization of leukemic T cells to TRAIL-induced apoptosis
- Author
-
Morales, J.C., Ruiz-Magaña, M.J., Carranza, D., Ortiz-Ferrón, G., and Ruiz-Ruiz, C.
- Subjects
- *
HISTONE deacetylase , *ENZYME inhibitors , *APOPTOSIS , *GENETIC regulation , *MITOCHONDRIAL membranes , *LYMPHOMAS , *TUMOR necrosis factors , *LYMPHOCYTES , *LEUKEMIA treatment - Abstract
Abstract: Epigenetic modifications commonly associated with tumor development, such as histone deacetylation, may influence the resistance of some tumor cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) by regulating gene transcription of components of the TRAIL signalling pathway. In the present study we have analyzed the effect of six different histone deacetylase inhibitors (HDACi), belonging to the four classic structural families, on TRAIL-induced apoptosis in leukemic T cell lines. Non-toxic and functional doses of all HDACi but apicidin, similarly sensitized different leukemic T cell lines to TRAIL-induced apoptosis, while they showed no effect on the resistance of normal T lymphocytes. Sensitizing doses of vorinostat, valproic acid, sodium butyrate and MS-275 regulated the expression of TRAIL-R2, c-FLIP and Apaf-1 in leukemic cells while TSA modulated only the expression of Apaf-1. The synergistic effect of all HDACi and TRAIL was inhibited in Bcl-2-overexpressing leukemic T cells. Thus, different HDACi may affect the expression of different TRAIL-related genes, but regulation of the mitochondrial pathway seems to be essential for the TRAIL sensitizing effect of HDACi in leukemic T cells. Overall, HDACi represent a promising and safe strategy in combination with TRAIL for treatment of T-cell leukaemia. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
11. BNCT research activities at the Granada group and the project NeMeSis: Neutrons for medicine and sciences, towards an accelerator-based facility for new BNCT therapies, medical isotope production and other scientific neutron applications.
- Author
-
Porras, I., Praena, J., Arias de Saavedra, F., Pedrosa-Rivera, M., Torres-Sánchez, P., Sabariego, M.P., Expósito-Hernández, J., Llamas-Elvira, J.M., Ramírez-Navarro, A., Rodríguez-Fernández, A., Osorio-Ceballos, J.M., Ruiz-Ruiz, C., and Ruiz-Magaña, M.J.
- Subjects
- *
RADIOISOTOPES , *NEUTRONS , *ISOTOPES , *NEUTRON sources , *NUCLEAR cross sections , *BORON compounds - Abstract
The Granada group in BNCT research is currently performing studies on: nuclear and radiobiological data for BNCT, new boron compounds and a new design for a neutron source for BNCT and other applications, including the production of medical radioisotopes. All these activities are described in this report. • Basic research activities at two international facilities: CERN and ILL are shown. • Obtention of accurate nuclear and radiobiological data for reducing uncertainties in treatment planning is pursued. • The conceptual design of a facility for BNCT and isotope production is described. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
12. Decidualized human decidual stromal cells inhibit chemotaxis of activated T cells: a potential mechanism of maternal-fetal immune tolerance.
- Author
-
Llorca T, Ruiz-Magaña MJ, Martinez-Aguilar R, García-Valdeavero OM, Rodríguez-Doña L, Abadia-Molina AC, Ruiz-Ruiz C, and Olivares EG
- Subjects
- Female, Pregnancy, Humans, Animals, Mice, Culture Media, Conditioned, Fetus, CD8-Positive T-Lymphocytes, Chemotaxis, Progesterone
- Abstract
Background: Numerous lines of evidence confirm that decidual stromal cells (DSCs) play a key role in maternal-fetal immune tolerance. Under the influence of progesterone and other hormones, the DSCs go through a process of differentiation (decidualization) during normal pregnancy. In mice, DSCs inhibit the expression of chemokines that attract abortigenic Th1 and Tc cells to the decidua. We have studied this phenomenon in humans., Methods: We established human DSC lines and decidualized these cells in vitro with progesterone and cAMP. We determined the expression of the chemokines CXCL9 , CXCL10 and CXCL11 , whose receptor CXCR3 is expressed by Th1 and Tc cells, in undifferentiated DSCs and decidualized DSCs by qRT-PCR. Activated CD3+CXCR3+ cells, including CD4+ Th1 cells and CD8+ Tc cells, were induced in vitro . The migration capacity of these activated lymphocytes was investigated in Transwell chambers with conditioned media from undifferentiated and decidualized DSCs., Results: We demonstrated that CXCL9 was not expressed by DSCs, whereas the expression of CXCL10 and CXCL11 was inhibited in decidualized cells. Conditioned media from decidualized cells significantly inhibited the migration of Th1 and Tc cells. We found that decidualized cells secrete factors of MW less than 6000-8000 Da, which actively inhibit the chemotaxis of these lymphocytes., Discussion: These results confirm in humans that decidualization of DSCs inhibits the expression by these cells of chemokines that attract Th1 and Tc cells and induces the secretion by DSCs of factors that inhibit the chemotaxis of these lymphocytes, thus preventing the arrival of abortigenic T cells in the decidua., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Llorca, Ruiz-Magaña, Martinez-Aguilar, García-Valdeavero, Rodríguez-Doña, Abadia-Molina, Ruiz-Ruiz and Olivares.)
- Published
- 2023
- Full Text
- View/download PDF
13. Relevance of TMPRSS2 , CD163/CD206, and CD33 in clinical severity stratification of COVID-19.
- Author
-
Martínez-Diz S, Marín-Benesiu F, López-Torres G, Santiago O, Díaz-Cuéllar JF, Martín-Esteban S, Cortés-Valverde AI, Arenas-Rodríguez V, Cuenca-López S, Porras-Quesada P, Ruiz-Ruiz C, Abadía-Molina AC, Entrala-Bernal C, Martínez-González LJ, and Álvarez-Cubero MJ
- Subjects
- Humans, Female, Middle Aged, Antigens, CD metabolism, Receptors, Cell Surface metabolism, Biomarkers, Serine Endopeptidases genetics, Sialic Acid Binding Ig-like Lectin 3, Quality of Life, COVID-19
- Abstract
Background: Approximately 13.8% and 6.1% of coronavirus disease 2019 (COVID-19) patients require hospitalization and sometimes intensive care unit (ICU) admission, respectively. There is no biomarker to predict which of these patients will develop an aggressive stage that we could improve their quality of life and healthcare management. Our main goal is to include new markers for the classification of COVID-19 patients., Methods: Two tubes of peripheral blood were collected from a total of 66 (n = 34 mild and n = 32 severe) samples (mean age 52 years). Cytometry analysis was performed using a 15-parameter panel included in the Maxpar
® Human Monocyte/Macrophage Phenotyping Panel Kit. Cytometry by time-of-flight mass spectrometry (CyTOF) panel was performed in combination with genetic analysis using TaqMan® probes for ACE2 (rs2285666), MX1 (rs469390), and TMPRSS2 (rs2070788) variants. GemStone™ and OMIQ software were used for cytometry analysis., Results: The frequency of CD163+ /CD206- population of transitional monocytes (T-Mo) was decreased in the mild group compared to that of the severe one, while T-Mo CD163- /CD206- were increased in the mild group compared to that of the severe one. In addition, we also found differences in CD11b expression in CD14dim monocytes in the severe group, with decreased levels in the female group (p = 0.0412). When comparing mild and severe disease, we also found that CD45- [p = 0.014; odds ratio (OR) = 0.286, 95% CI 0.104-0.787] and CD14dim /CD33+ (p = 0.014; OR = 0.286, 95% CI 0.104-0.787) monocytes were the best options as biomarkers to discriminate between these patient groups. CD33 was also indicated as a good biomarker for patient stratification by the analysis of GemStone™ software. Among genetic markers, we found that G carriers of TMPRSS2 (rs2070788) have an increased risk (p = 0.02; OR = 3.37, 95% CI 1.18-9.60) of severe COVID-19 compared to those with A/A genotype. This strength is further increased when combined with CD45- , T-Mo CD163+ /CD206- , and C14dim /CD33+ ., Conclusions: Here, we report the interesting role of TMPRSS2 , CD45- , CD163/CD206, and CD33 in COVID-19 aggressiveness. This strength is reinforced for aggressiveness biomarkers when TMPRSS2 and CD45- , TMPRSS2 and CD163/CD206, and TMPRSS2 and CD14dim /CD33+ are combined., Competing Interests: Author CE-B is employed by LORGEN G.P. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Martínez-Diz, Marín-Benesiu, López-Torres, Santiago, Díaz-Cuéllar, Martín-Esteban, Cortés-Valverde, Arenas-Rodríguez, Cuenca-López, Porras-Quesada, Ruiz-Ruiz, Abadía-Molina, Entrala-Bernal, Martínez-González and Álvarez-Cubero.)- Published
- 2023
- Full Text
- View/download PDF
14. Influence of the ectopic location on the antigen expression and functional characteristics of endometrioma stromal cells.
- Author
-
Ruiz-Magaña MJ, Puerta JM, Llorca T, Méndez-Malagón C, Martínez-Aguilar R, Abadía-Molina AC, Olivares EG, and Ruiz-Ruiz C
- Subjects
- Humans, Female, Endometrium metabolism, Progesterone metabolism, Stromal Cells metabolism, Endometriosis metabolism, Uterine Diseases
- Abstract
Research Question: Are the alterations observed in the endometriotic cells, such as progesterone resistance, already present in the eutopic endometrium or acquired in the ectopic location?, Design: The response to decidualization with progesterone and cyclic AMP for up to 28 days was compared in different endometrial stromal cell (EnSC) lines established from samples of endometriomas (eEnSC), eutopic endometrium from women with endometriosis (eBEnSC), endometrial tissue from healthy women (BEnSC) and menstrual blood from healthy donors (mEnSC)., Results: Usual features of decidualized cells, such as changes in cell morphology and expression of prolactin, were similarly observed in the three types of eutopic EnSC studied, but not in the ectopic cells upon decidualization. Among the phenotypic markers analysed, CD105 was down-regulated under decidualization in all cell types (mEnSC, P = 0.005; BEnSC, P = 0.029; eBEnSC, P = 0.022) except eEnSC. mEnSC and BEnSC underwent apoptosis during decidualization, whereas eBEnSC and eEnSC were resistant to the induction of cell death. Lastly, migration studies revealed that mEnSC secreted undetermined factors during decidualization that inhibited cell motility, whereas eEnSC showed a significantly lower ability to produce those migration-regulating factors (P < 0.0001, P < 0.001 and P = 0.0013 for the migration of mEnSC at 24, 48 and 72 h, respectively; P < 0.0001 for the migration of eEnSC at all times studied)., Conclusions: This study provides novel insights into the differences between endometriotic and eutopic endometrial cells and reinforces the idea that the microenvironment in the ectopic location plays additional roles in the acquisition of the alterations that characterize the cells of the endometriotic foci., (Copyright © 2022 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
15. Stromal cells of the endometrium and decidua: in search of a name and an identity†.
- Author
-
Ruiz-Magaña MJ, Llorca T, Martinez-Aguilar R, Abadia-Molina AC, Ruiz-Ruiz C, and Olivares EG
- Subjects
- Pregnancy, Female, Humans, Stromal Cells, Cell Differentiation, Cells, Cultured, Decidua physiology, Endometrium
- Abstract
Human endometrial and decidual stromal cells are the same cells in different environments (nonpregnancy and pregnancy, respectively). Although some authors consider decidual stromal cells to arise solely from the differentiation of endometrial stromal cells, this is a debatable issue given that decidualization processes do not end with the formation of the decidua, as shown by the presence of stromal cells from both the endometrium and decidua in both undifferentiated (nondecidualized) and decidualized states. Furthermore, recent functional and transcriptomic results have shown that there are differences in the decidualization process of endometrial and decidual stromal cells, with the latter having a greater decidualization capacity than the former. These differences suggest that in the terminology and study of their characteristics, endometrial and decidual stromal cells should be clearly distinguished, as should their undifferentiated or decidualized status. There is, however, considerable confusion in the designation and identification of uterine stromal cells. This confusion may impede a judicious understanding of the functional processes in normal and pathological situations. In this article, we analyze the different terms used in the literature for different types of uterine stromal cells, and propose that a combination of differentiation status (undifferentiated, decidualized) and localization (endometrium, decidua) criteria should be used to arrive at a set of accurate, unambiguous terms. The cell identity of uterine stromal cells is also a debatable issue: phenotypic, functional, and transcriptomic studies in recent decades have related these cells to different established cells. We discuss the relevance of these associations in normal and pathological situations., (© The Author(s) 2022. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2022
- Full Text
- View/download PDF
16. Estrogen- and Progesterone (P4)-Mediated Epigenetic Modifications of Endometrial Stromal Cells (EnSCs) and/or Mesenchymal Stem/Stromal Cells (MSCs) in the Etiopathogenesis of Endometriosis.
- Author
-
Szukiewicz D, Stangret A, Ruiz-Ruiz C, Olivares EG, Soriţău O, Suşman S, and Szewczyk G
- Subjects
- Adult, Female, Humans, Endometriosis genetics, Endometriosis pathology, Epigenesis, Genetic, Estrogens, Mesenchymal Stem Cells cytology, Progesterone, Stromal Cells cytology
- Abstract
Endometriosis is a common chronic inflammatory condition in which endometrial tissue appears outside the uterine cavity. Because ectopic endometriosis cells express both estrogen and progesterone (P4) receptors, they grow and undergo cyclic proliferation and breakdown similar to the endometrium. This debilitating gynecological disease affects up to 15% of reproductive aged women. Despite many years of research, the etiopathogenesis of endometrial lesions remains unclear. Retrograde transport of the viable menstrual endometrial cells with retained ability for attachment within the pelvic cavity, proliferation, differentiation and subsequent invasion into the surrounding tissue constitutes the rationale for widely accepted implantation theory. Accordingly, the most abundant cells in the endometrium are endometrial stromal cells (EnSCs). These cells constitute a particular population with clonogenic activity that resembles properties of mesenchymal stem/stromal cells (MSCs). Thus, a significant role of stem cell-based dysfunction in formation of the initial endometrial lesions is suspected. There is increasing evidence that the role of epigenetic mechanisms and processes in endometriosis have been underestimated. The importance of excess estrogen exposure and P4 resistance in epigenetic homeostasis failure in the endometrial/endometriotic tissue are crucial. Epigenetic alterations regarding transcription factors of estrogen and P4 signaling pathways in MSCs are robust in endometriotic tissue. Thus, perspectives for the future may include MSCs and EnSCs as the targets of epigenetic therapies in the prevention and treatment of endometriosis. Here, we reviewed the current known changes in the epigenetic background of EnSCs and MSCs due to estrogen/P4 imbalances in the context of etiopathogenesis of endometriosis. Graphical Abstract., (© 2021. The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
17. Decidualization modulates the mesenchymal stromal/stem cell and pericyte characteristics of human decidual stromal cells. Effects on antigen expression, chemotactic activity on monocytes and antitumoral activity.
- Author
-
Ruiz-Magaña MJ, Martinez-Aguilar R, Llorca T, Abadia-Molina AC, Ruiz-Ruiz C, and Olivares EG
- Subjects
- Adult, Antigens metabolism, Cell Differentiation immunology, Chemotactic Factors metabolism, Chemotaxis immunology, Coculture Techniques, Culture Media, Conditioned metabolism, Decidua cytology, Decidua immunology, Female, Healthy Volunteers, Humans, Mesenchymal Stem Cells metabolism, Neoplasms immunology, Pericytes immunology, Pericytes metabolism, Pregnancy, THP-1 Cells, Young Adult, Decidua growth & development, Histocompatibility, Maternal-Fetal, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells immunology, Neoplasms therapy
- Abstract
Decidual stromal cells (DSCs) are the most abundant cellular component of human decidua and play a central role in maternal-fetal immune tolerance. Antigen phenotyping and functional studies recently confirmed the relationship of DSCs with mesenchymal stem/stromal cells (MSCs) and pericytes, the latter two cell types being closely related or identical. The present study investigated the effect of decidualization, a process of cell differentiation driven by progesterone (P4) and other pregnancy hormones, on the MSC/pericyte characteristics of DSCs. To this end we isolated undifferentiated DSC (preDSC) lines that were decidualized in vitro (dDSC) by the effect of P4 and cAMP. Using flow cytometry, we found significant downmodulation of the expression of the MSC/pericyte markers α-smooth muscle actin, nestin, CD140b, CD146 and SUSD2 in dDSCs. The dDSCs did not differ, compared to preDSCs, in the expression of angiogenic factors (characteristic of pericytes) HGF, FGF2, ANGPT1 or VEGF according to RT-PCR results, but had significantly increased PGF expression. In migration assays, preDSC-conditioned media had a chemotactic effect on the THP-1 monocytic line (characteristic of pericytes), and this effect was significantly greater in dDSC-conditioned media. Media conditioned with dDSC, but not with preDSC, induced apoptosis in 4 out of 6 different tumor cell lines (characteristic of MSCs) according to propidium iodide staining and flow cytometry results. Our findings show that decidualization induces phenotypic and functional changes in the MSC/pericyte properties of DSCs that may have a role in the normal development of pregnancy., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
18. Perinatal Derivatives: Where Do We Stand? A Roadmap of the Human Placenta and Consensus for Tissue and Cell Nomenclature.
- Author
-
Silini AR, Di Pietro R, Lang-Olip I, Alviano F, Banerjee A, Basile M, Borutinskaite V, Eissner G, Gellhaus A, Giebel B, Huang YC, Janev A, Kreft ME, Kupper N, Abadía-Molina AC, Olivares EG, Pandolfi A, Papait A, Pozzobon M, Ruiz-Ruiz C, Soritau O, Susman S, Szukiewicz D, Weidinger A, Wolbank S, Huppertz B, and Parolini O
- Abstract
Progress in the understanding of the biology of perinatal tissues has contributed to the breakthrough revelation of the therapeutic effects of perinatal derivatives (PnD), namely birth-associated tissues, cells, and secreted factors. The significant knowledge acquired in the past two decades, along with the increasing interest in perinatal derivatives, fuels an urgent need for the precise identification of PnD and the establishment of updated consensus criteria policies for their characterization. The aim of this review is not to go into detail on preclinical or clinical trials, but rather we address specific issues that are relevant for the definition/characterization of perinatal cells, starting from an understanding of the development of the human placenta, its structure, and the different cell populations that can be isolated from the different perinatal tissues. We describe where the cells are located within the placenta and their cell morphology and phenotype. We also propose nomenclature for the cell populations and derivatives discussed herein. This review is a joint effort from the COST SPRINT Action (CA17116), which broadly aims at approaching consensus for different aspects of PnD research, such as providing inputs for future standards for the processing and in vitro characterization and clinical application of PnD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Silini, Di Pietro, Lang-Olip, Alviano, Banerjee, Basile, Borutinskaite, Eissner, Gellhaus, Giebel, Huang, Janev, Kreft, Kupper, Abadía-Molina, Olivares, Pandolfi, Papait, Pozzobon, Ruiz-Ruiz, Soritau, Susman, Szukiewicz, Weidinger, Wolbank, Huppertz and Parolini.)
- Published
- 2020
- Full Text
- View/download PDF
19. Menstrual blood-derived stromal cells modulate functional properties of mouse and human macrophages.
- Author
-
Martínez-Aguilar R, Romero-Pinedo S, Ruiz-Magaña MJ, Olivares EG, Ruiz-Ruiz C, and Abadía-Molina AC
- Subjects
- Animals, Female, Humans, Macrophages metabolism, Mice, Neutrophils metabolism, Peritonitis chemically induced, Peritonitis metabolism, Sepsis chemically induced, Sepsis metabolism, Stromal Cells metabolism, Thioglycolates toxicity, Macrophages cytology, Menstruation blood, Stromal Cells cytology
- Abstract
Menstrual blood-derived stromal cells (MenSCs) are emerging as a strong candidate for cell-based therapies due to their immunomodulatory properties. However, their direct impact on innate immune populations remains elusive. Since macrophages play a key role in the onset and development of inflammation, understanding MenSCs implication in the functional properties of these cells is required to refine their clinical effects during the treatment of inflammatory disorders. In this study, we assessed the effects that MenSCs had on the recruitment of macrophages and other innate immune cells in two mouse models of acute inflammation, a thioglycollate (TGC)-elicited peritonitis model and a monobacterial sepsis model. We found that, in the TGC model, MenSCs injection reduced the percentage of macrophages recruited to the peritoneum and promoted the generation of peritoneal immune cell aggregates. In the sepsis model, MenSCs exacerbated infection by diminishing the recruitment of macrophages and neutrophils to the site of infection and inducing defective bacterial clearance. Additional in vitro studies confirmed that co-culture with MenSCs impaired macrophage bactericidal properties, affecting bacterial killing and the production of reactive oxygen intermediates. Our findings suggest that MenSCs modulate the macrophage population and that this modulation must be taken into consideration when it comes to future clinical applications.
- Published
- 2020
- Full Text
- View/download PDF
20. The purinergic P2X7 receptor as a potential drug target to combat neuroinflammation in neurodegenerative diseases.
- Author
-
Calzaferri F, Ruiz-Ruiz C, de Diego AMG, de Pascual R, Méndez-López I, Cano-Abad MF, Maneu V, de Los Ríos C, Gandía L, and García AG
- Subjects
- Animals, Humans, Mice, Purinergic P2X Receptor Antagonists pharmacology, Receptors, Purinergic P2X7, Alzheimer Disease, Neurodegenerative Diseases drug therapy, Pharmaceutical Preparations
- Abstract
Neurodegenerative diseases (NDDs) represent a huge social burden, particularly in Alzheimer's disease (AD) in which all proposed treatments investigated in murine models have failed during clinical trials (CTs). Thus, novel therapeutic strategies remain crucial. Neuroinflammation is a common pathogenic feature of NDDs. As purinergic P2X7 receptors (P2X7Rs) are gatekeepers of inflammation, they could be developed as drug targets for NDDs. Herein, we review this challenging hypothesis and comment on the numerous studies that have investigated P2X7Rs, emphasizing their molecular structure and functions, as well as their role in inflammation. Then, we elaborate on research undertaken in the field of medicinal chemistry to determine potential P2X7R antagonists. Subsequently, we review the state of neuroinflammation and P2X7R expression in the brain, in animal models and patients suffering from AD, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and retinal degeneration. Next, we summarize the in vivo studies testing the hypothesis that by mitigating neuroinflammation, P2X7R blockers afford neuroprotection, increasing neuroplasticity and neuronal repair in animal models of NDDs. Finally, we reviewed previous and ongoing CTs investigating compounds directed toward targets associated with NDDs; we propose that CTs with P2X7R antagonists should be initiated. Despite the high expectations for putative P2X7Rs antagonists in various central nervous system diseases, the field is moving forward at a relatively slow pace, presumably due to the complexity of P2X7Rs. A better pharmacological approach to combat NDDs would be a dual strategy, combining P2X7R antagonism with drugs targeting a selective pathway in a given NDD., (© 2020 Wiley Periodicals LLC.)
- Published
- 2020
- Full Text
- View/download PDF
21. Chronic administration of P2X7 receptor antagonist JNJ-47965567 delays disease onset and progression, and improves motor performance in ALS SOD1 G93A female mice.
- Author
-
Ruiz-Ruiz C, García-Magro N, Negredo P, Avendaño C, Bhattacharya A, Ceusters M, and García AG
- Subjects
- Animals, Cell Survival drug effects, Endpoint Determination, Female, Humans, Mice, Inbred C57BL, Mice, Transgenic, Motor Neurons drug effects, Motor Neurons pathology, Niacinamide administration & dosage, Niacinamide chemistry, Niacinamide pharmacology, Niacinamide therapeutic use, Piperazines chemistry, Piperazines pharmacology, Purinergic P2X Receptor Antagonists chemistry, Purinergic P2X Receptor Antagonists pharmacology, Rotarod Performance Test, Survival Analysis, Weight Loss drug effects, Amyotrophic Lateral Sclerosis drug therapy, Amyotrophic Lateral Sclerosis physiopathology, Disease Progression, Motor Activity drug effects, Niacinamide analogs & derivatives, Piperazines administration & dosage, Piperazines therapeutic use, Purinergic P2X Receptor Antagonists administration & dosage, Purinergic P2X Receptor Antagonists therapeutic use, Receptors, Purinergic P2X7 metabolism
- Abstract
Neuroinflammation is one of the main physiopathological mechanisms of amyotrophic lateral sclerosis (ALS), produced by the chronic activation of microglia in the CNS. This process is triggered by the persistent activation of the ATP-gated P2X7 receptor (P2RX7, hereafter referred to as P2X7R). The present study aimed to evaluate the effects of the chronic treatment with the P2X7R antagonist JNJ-47965567 in the development and progression of ALS in the SOD1
G93A murine model. SOD1G93A mice were intraperitoneally (i.p.) injected with either 30 mg/kg of JNJ-47965567 or vehicle 4 times per week, from pre-onset age (here, postnatal day 60; P60) until study endpoint. Body weight, motor coordination, phenotypic score, disease onset and survival were measured throughout the study, and compared between vehicle- and drug-injected groups. Treatment with the P2X7R antagonist JNJ-47965567 delayed disease onset, reduced body weight loss and improved motor coordination and phenotypic score in female SOD1G93A mice, although it did not increase lifespan. Interestingly, neither beneficial nor detrimental effects were observed in males in any of the analyzed parameters. Treatment did not affect motor neuron survival or ChAT, Iba-1 and P2X7R protein expression in endpoint individuals of mixed sexes. Overall, chronic administration of JNJ-47965567 for 4 times per week to SOD1G93A mice from pre-onset stage altered disease progression in female individuals while it did not have any effect in males. Our results suggest a partial, yet important, effect of P2X7R in the development and progression of ALS., Competing Interests: Competing interestsThe authors of this article have no competing interests to declare. A.B. and M.C. are full-time employees of Janssen Research and Development., (© 2020. Published by The Company of Biologists Ltd.)- Published
- 2020
- Full Text
- View/download PDF
22. Thermal Neutron Relative Biological Effectiveness Factors for Boron Neutron Capture Therapy from In Vitro Irradiations.
- Author
-
Pedrosa-Rivera M, Praena J, Porras I, Sabariego MP, Köster U, Haertlein M, Forsyth VT, Ramírez JC, Jover C, Jimena D, Osorio JL, Álvarez P, Ruiz-Ruiz C, and Ruiz-Magaña MJ
- Subjects
- Gamma Rays, Humans, Boron Neutron Capture Therapy methods, Neoplasms drug therapy, Neutrons therapeutic use, Relative Biological Effectiveness
- Abstract
The experimental determination of the relative biological effectiveness of thermal neutron factors is fundamental in Boron Neutron Capture Therapy. The present values have been obtained while using mixed beams that consist of both neutrons and photons of various energies. A common weighting factor has been used for both thermal and fast neutron doses, although such an approach has been questioned. At the nuclear reactor of the Institut Laue-Langevin a pure low-energy neutron beam has been used to determine thermal neutron relative biological effectiveness factors. Different cancer cell lines, which correspond to glioblastoma, melanoma, and head and neck squamous cell carcinoma, and non-tumor cell lines (lung fibroblast and embryonic kidney), have been irradiated while using an experimental arrangement designed to minimize neutron-induced secondary gamma radiation. Additionally, the cells were irradiated with photons at a medical linear accelerator, providing reference data for comparison with that from neutron irradiation. The survival and proliferation were studied after irradiation, yielding the Relative Biological Effectiveness that corresponds to the damage of thermal neutrons for the different tissue types.
- Published
- 2020
- Full Text
- View/download PDF
23. Radiobiology data of melanoma cells after low-energy neutron irradiation and boron compound administration.
- Author
-
Pedrosa-Rivera M, Ruiz-Magaña MJ, Álvarez P, Porras I, Praena J, Sabariego MP, Köster U, Haertlein M, Forsyth VT, Soldner T, Ramírez JC, Jover C, Jimena D, Osorio JL, Postuma I, and Ruiz-Ruiz C
- Subjects
- Boron Neutron Capture Therapy methods, Cell Line, Tumor, Humans, Neutrons, Boron Compounds administration & dosage, Melanoma pathology
- Abstract
The cold neutron beam at the PF1b line at the Institut Laue-Langevin (ILL), without fast neutrons and a low contribution of gamma rays, is a very suitable facility to measure cell damage following low-energy neutron irradiation. The biological damage associated with the thermal and the boron doses can be obtained in order to evaluate the relative biological effectiveness (RBE) for Boron Neutron Capture Therapy. Three different experiments were carried out on the A375 melanoma cell line: the first one in a hospital LINAC, to obtain the reference radiation data, and the other two at the ILL, in which the damage to cells with and without boron compounds added was measured., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020. Published by Elsevier Ltd.)
- Published
- 2020
- Full Text
- View/download PDF
24. Endometrial and decidual stromal precursors show a different decidualization capacity.
- Author
-
Ruiz Magaña MJ, Puerta JM, Martínez-Aguilar R, Llorca T, Blanco O, Muñoz-Fernández R, Olivares EG, and Ruiz-Ruiz C
- Subjects
- Adult, Cells, Cultured, Decidua metabolism, Endometrium metabolism, Female, Humans, Mesenchymal Stem Cells metabolism, Pregnancy, Stromal Cells metabolism, Young Adult, Cell Differentiation, Decidua cytology, Endometrium cytology, Mesenchymal Stem Cells cytology, Progesterone metabolism, Receptors, Progesterone metabolism, Stromal Cells cytology
- Abstract
Endometrial stromal cells (EnSCs) and decidual stromal cells (DSCs) originate from fibroblastic precursors located around the vessels of the human nonpregnant endometrium and the pregnant endometrium (decidua), respectively. Under the effect of ovarian or pregnancy hormones, these precursors differentiate (decidualize), changing their morphology and secreting factors that appear to be essential for the normal development of pregnancy. However, the different physiological context - that is, non-pregnancy vs pregnancy - of those precursors (preEnSCs, preDSCs) might affect their phenotype and functions. In the present study, we established preEnSC and preDSC lines and compared the antigen phenotype and responses to decidualization factors in these two types of stromal cell line. Analyses with flow cytometry showed that preEnSCs and preDSCs exhibited a similar antigen phenotype compatible with that of bone marrow mesenchymal stem/stromal cells. The response to decidualization in cultures with progesterone and cAMP was evaluated by analyzing changes in cell morphology by microscopy, prolactin and IL-15 secretion by enzyme immunoassay and the induction of apoptosis by flow cytometry. In all four analyses, preDSCs showed a significantly higher response than preEnSCs. The expression of progesterone receptor (PR), protein kinase A (PKA) and FOXO1 was studied with Western blotting. Both types of cells showed similar levels of PR and PKA, but the increase in PKA RI subunit expression in response to decidualization was again significantly greater in preDSCs. We conclude that preEnSCs and preDSCs are equivalent cells but differ in their ability to decidualize. Functional differences between them probably derive from factors in their different milieus.
- Published
- 2020
- Full Text
- View/download PDF
25. P2X7 Receptor Antagonism as a Potential Therapy in Amyotrophic Lateral Sclerosis.
- Author
-
Ruiz-Ruiz C, Calzaferri F, and García AG
- Abstract
This review focuses on the purinergic ionotropic receptor P2X7 (P2X7R) as a potential target for developing drugs that delay the onset and/or disease progression in patients with amyotrophic lateral sclerosis (ALS). Description of clinical and genetic ALS features is followed by an analysis of advantages and drawbacks of transgenic mouse models of disease based on mutations in a bunch of proteins, particularly Cu/Zn superoxide dismutase (SOD1), TAR-DNA binding protein-43 (TDP-43), Fused in Sarcoma/Translocated in Sarcoma (FUS), and Chromosome 9 open reading frame 72 (C9orf72). Though of limited value, these models are however critical to study the proof of concept of new compounds, before reaching clinical trials. The authors also provide a description of ALS pathogenesis including protein aggregation, calcium-dependent excitotoxicity, dysfunction of calcium-binding proteins, ultrastructural mitochondrial alterations, disruption of mitochondrial calcium handling, and overproduction of reactive oxygen species (ROS). Understanding disease pathogenic pathways may ease the identification of new drug targets. Subsequently, neuroinflammation linked with P2X7Rs in ALS pathogenesis is described in order to understand the rationale of placing the use of P2X7R antagonists as a new therapeutic pharmacological approach to ALS. This is the basis for the hypothesis that a P2X7R blocker could mitigate the neuroinflammatory state, indirectly leading to neuroprotection and higher motoneuron survival in ALS patients., (Copyright © 2020 Ruiz-Ruiz, Calzaferri and García.)
- Published
- 2020
- Full Text
- View/download PDF
26. A simple approximation for the evaluation of the photon iso-effective dose in Boron Neutron Capture Therapy based on dose-independent weighting factors.
- Author
-
Pedrosa-Rivera M, Praena J, Porras I, Ruiz-Magaña MJ, and Ruiz-Ruiz C
- Subjects
- Animals, Brain Neoplasms radiotherapy, Dose-Response Relationship, Radiation, Gliosarcoma radiotherapy, Humans, Photons therapeutic use, Rats, Boron Neutron Capture Therapy methods, Radiotherapy Dosage
- Abstract
The current methodology for determining the biological effect of Boron Neutron Capture Therapy (BNCT) has recently been questioned, and a more accurate framework based in the photon iso-effective dose has been proposed. In this work we derive a first order approximation to this quantity. The new approach removes the main drawbacks of the current method, being based on new weighting factors which are true constants (dose independent) but which can be evaluated from published data on the existing (dose-dependent) weighting factors. In addition to this, we apply the formalism to allow the comparison to a fractionated conventional radiotherapy treatment, for which there is a lot of knowledge from clinical practice. As an application, the photon iso-effective dose of a BNCT treatment for a brain tumor is estimated. An excel sheet used for these calculations is also provided as supplementary material and can be used also with user-provided input data for the estimation of the photon iso-effective dose for comparison with conventional radiotherapy, both to single and fractionated treatments., Competing Interests: Declaration of competing interest The authors declare no conflict of interest for this work., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
27. Tactical Variables Related to Gaining the Ball in Advanced Zones of the Soccer Pitch: Analysis of Differences Among Elite Teams and the Effect of Contextual Variables.
- Author
-
Fernandez-Navarro J, Ruiz-Ruiz C, Zubillaga A, and Fradua L
- Abstract
Attacking tactical variables have been commonly studied in soccer to analyze teams' performance. However, few studies investigated defensive tactical variables during match-play and the influence of contextual variables on them. The aims of the present study were (1) to examine the defensive behaviors of soccer teams when gaining the ball in advanced zones of the pitch and (2) to evaluate the effect of contextual variables on these defensive behaviors. A sample of 1,095 defensive pieces of play initiated in the opposing half of the pitch obtained from 10 matches of the season 2010/11 of La Liga and involving 13 teams was collected using the semiautomated tracking system Amisco Pro. Five defensive tactical variables, the outcome of defensive pieces of play, and contextual variables (i.e., match status, venue, quality of opposition, and match period) were recorded for every defensive piece initiated in the opposing half of the pitch. Results showed that there were significant differences among teams in the outcome of defensive pieces of play originating from the opposing half (χ
2 = 111.87, p < 0.01, φc = 0.22), and in the outcome of offensive pieces of play following ball gains (χ2 = 49.92, p < 0.001, φc = 0.22). Cluster analysis revealed four groups describing different defensive behaviors from high-pressure to a defense close to their own goal. Match status (χ2 = 25.87, p < 0.05, φc = 0.11) and quality of opposition (χ2 = 21.19, p < 0.05, φc = 0.10) were the contextual variables that showed a significant effect on defensive pieces of play initiated in the opposite half of the pitch. Teams winning gained more balls in the zone close to their own goal, and losing teams gained more balls in advanced zones of the pitch. Moreover, the greater the quality of the opponent the lesser the chance of gaining the ball in advanced zones of the pitch. Neither venue or match period influenced the defensive pieces of play analyzed. Soccer teams could employ a similar analysis to improve their performance and prepare for opposition teams in competition., (Copyright © 2020 Fernandez-Navarro, Ruiz-Ruiz, Zubillaga and Fradua.)- Published
- 2020
- Full Text
- View/download PDF
28. Growth and differentiation factor 15 as a biomarker for mitochondrial myopathy.
- Author
-
Poulsen NS, Madsen KL, Hornsyld TM, Eisum AV, Fornander F, Buch AE, Stemmerik MG, Ruiz-Ruiz C, Krag TO, and Vissing J
- Subjects
- Adolescent, Adult, Aged, Biomarkers blood, Biomarkers metabolism, Exercise Test, Female, Gene Expression Regulation physiology, Humans, Male, Middle Aged, Mitochondrial Myopathies genetics, Oxidative Stress, Pilot Projects, Young Adult, Growth Differentiation Factor 15 blood, Mitochondrial Myopathies metabolism
- Abstract
Objective: We investigated if Growth and Differentiation Factor 15 (GDF-15) can be used as a biomarker to distinguish patients with mitochondrial myopathy from patients with other myopathies., Methods: Serum GDF-15 was measured in 28 patients with mitochondrial disease, 24 with metabolic myopathies, 27 with muscular dystrophy and 21 healthy controls., Results and Conclusions: Our findings indicate that elevated GDF-15 can distinguish patients with mitochondrial myopathy from other myopathies, including metabolic myopathies. This suggests that increases in GDF-15 is specific to respiratory chain dysfunction rather than general metabolic dysfunction or muscle defect., (Copyright © 2019 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
29. Human predecidual stromal cells are mesenchymal stromal/stem cells and have a therapeutic effect in an immune-based mouse model of recurrent spontaneous abortion.
- Author
-
Muñoz-Fernández R, De La Mata C, Requena F, Martín F, Fernandez-Rubio P, Llorca T, Ruiz-Magaña MJ, Ruiz-Ruiz C, and Olivares EG
- Subjects
- Abortion, Habitual pathology, Abortion, Spontaneous pathology, Animals, Cell Differentiation, Cells, Cultured transplantation, Decidua cytology, Disease Models, Animal, Endometrium cytology, Endometrium transplantation, Female, Humans, Mesenchymal Stem Cells cytology, Mice, Pregnancy, Abortion, Habitual therapy, Abortion, Spontaneous therapy, Decidua transplantation, Mesenchymal Stem Cell Transplantation
- Abstract
Background: 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., Methods: We established 15 human preDSC lines and 3 preDSC clones. Physiological differentiation (decidualization) of these cell lines and clones was carried out by in vitro culture with progesterone (P4) and cAMP. Decidualization was confirmed by the change in cellular morphology and prolactin (PRL) secretion, which was determined by enzyme immunoassay of the culture supernatants. We also studied MSC characteristics: (1) In mesenchymal differentiation, under appropriate culture conditions, these preDSC lines and clones differentiated into adipocytes, osteoblasts, and chondrocytes, and differentiation was confirmed by cytochemical assays and RT-PCR. (2) The expression of stem cell markers was determined by RT-PCR. (3) Cloning efficiency was evaluated by limited dilution. (4) Immunoregulatory activity in vivo was estimated in DBA/2-mated CBA/J female mice, a murine model of immune-based recurrent abortion. (5) Survival of preDSC in immunocompetent mice was analyzed by RT-PCR and flow cytometry., Results: 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., Conclusions: Together, our results confirm that preDSCs are decidual MSCs and suggest that these cells are involved in the mechanisms of maternal-fetal immune tolerance.
- Published
- 2019
- Full Text
- View/download PDF
30. Adaptations in Mitochondrial Enzymatic Activity Occurs Independent of Genomic Dosage in Response to Aerobic Exercise Training and Deconditioning in Human Skeletal Muscle.
- Author
-
Fritzen AM, Thøgersen FB, Thybo K, Vissing CR, Krag TO, Ruiz-Ruiz C, Risom L, Wibrand F, Høeg LD, Kiens B, Duno M, Vissing J, and Jeppesen TD
- Subjects
- Cardiolipins metabolism, DNA, Mitochondrial genetics, Humans, Male, Muscle, Skeletal anatomy & histology, Oxygen Consumption physiology, Porins metabolism, Young Adult, Adaptation, Physiological genetics, Exercise physiology, Gene Dosage, Mitochondria enzymology, Mitochondria genetics, Muscle, Skeletal physiology
- Abstract
Mitochondrial DNA (mtDNA) replication is thought to be an integral part of exercise-training-induced mitochondrial adaptations. Thus, mtDNA level is often used as an index of mitochondrial adaptations in training studies. We investigated the hypothesis that endurance exercise training-induced mitochondrial enzymatic changes are independent of genomic dosage by studying mtDNA content in skeletal muscle in response to six weeks of knee-extensor exercise training followed by four weeks of deconditioning in one leg, comparing results to the contralateral untrained leg, in 10 healthy, untrained male volunteers. Findings were compared to citrate synthase activity, mitochondrial complex activities, and content of mitochondrial membrane markers (porin and cardiolipin). One-legged knee-extensor exercise increased endurance performance by 120%, which was accompanied by increases in power output and peak oxygen uptake of 49% and 33%, respectively ( p < 0.01). Citrate synthase and mitochondrial respiratory chain complex I⁻IV activities were increased by 51% and 46⁻61%, respectively, in the trained leg ( p < 0.001). Despite a substantial training-induced increase in mitochondrial activity of TCA and ETC enzymes, there was no change in mtDNA and mitochondrial inner and outer membrane markers (i.e. cardiolipin and porin). Conversely, deconditioning reduced endurance capacity by 41%, muscle citrate synthase activity by 32%, and mitochondrial complex I⁻IV activities by 29⁻36% ( p < 0.05), without any change in mtDNA and porin and cardiolipin content in the previously trained leg. The findings demonstrate that the adaptations in mitochondrial enzymatic activity after aerobic endurance exercise training and the opposite effects of deconditioning are independent of changes in the number of mitochondrial genomes, and likely relate to changes in the rate of transcription of mtDNA., Competing Interests: The authors declare no conflict of interest and the founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; and in the decision to publish the results.
- Published
- 2019
- Full Text
- View/download PDF
31. Otilonium and pinaverium trigger mitochondrial-mediated apoptosis in rat embryo cortical neurons in vitro.
- Author
-
García-Alvarado F, Govoni G, de Pascual R, Ruiz-Ruiz C, Muñoz-Montero A, Gandía L, de Diego AMG, and García AG
- Subjects
- Animals, Apoptosis physiology, Cattle, Cell Line, Tumor, Cell Survival drug effects, Cell Survival physiology, Cells, Cultured, Cerebral Cortex pathology, Cerebral Cortex physiology, Dose-Response Relationship, Drug, Embryo, Mammalian, Female, Humans, Mitochondria pathology, Mitochondria physiology, Muscarinic Antagonists, Neurons pathology, Neurons physiology, Pregnancy, Rats, Rats, Sprague-Dawley, Apoptosis drug effects, Cerebral Cortex drug effects, Mitochondria drug effects, Morpholines toxicity, Neurons drug effects, Quaternary Ammonium Compounds toxicity
- Abstract
In the frame of a repositioning programme with cholinergic medicines in clinical use searching for neuroprotective properties, we surprisingly found that spasmolytic antimuscarinics otilonium and pinaverium exhibited neurotoxic effects in neuronal cultures. We decided to characterize such unexpected action in primary cultures of rat embryo cortical neurons. Neurotoxicity was time- and concentration-dependent, exhibiting approximate EC
50 values of 5 μM for both drugs. Seven antimuscarinic drugs endowed with a quaternary ammonium, and another 10 drugs with different cholinergic activities, carrying in their molecule a ternary ammonium did not exhibit neurotoxicity. Both drugs caused a concentration-dependent blockade of whole-cell inward currents through voltage-activated calcium channels (VACCs). Consistent with this, they also blocked the K+ -elicited [Ca2+ ]c transients. Neither antioxidant catalase, glutathione, n-acetylcysteine, nor melatonin protected against neurotoxicity of otilonium or pinaverium. However cyclosporine A, a blocker of the mitochondrial permeability transition pore, prevented the neurotoxic effects of otilonium and pinaverium monitored as the fraction of cells undergoing apoptosis. Furthermore, the caspase-9 and caspase-3 inhibitor Ac-LEHD-CHO mitigated the apoptotic neuronal death of both drugs by around 50%. Data are compatible with the hypothesis that otilonium and pinaverium elicit neuronal death by activating the intrinsic mitochondrial-mediated signaling pathway of apoptosis. This may have its origin in the mitigation of Ca2+ entry and the uncoupling of the Ca2+ -dependent generation of mitochondrial bioenergetics, thus causing the opening of the mitochondrial mPTP to elicit apoptotic neuronal death., (Copyright © 2018 Elsevier B.V. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF
32. The Decrease in Mitochondrial DNA Mutation Load Parallels Visual Recovery in a Leber Hereditary Optic Neuropathy Patient.
- Author
-
Emperador S, Vidal M, Hernández-Ainsa C, Ruiz-Ruiz C, Woods D, Morales-Becerra A, Arruga J, Artuch R, López-Gallardo E, Bayona-Bafaluy MP, Montoya J, and Ruiz-Pesini E
- Abstract
The onset of Leber hereditary optic neuropathy is relatively rare in childhood and, interestingly, the rate of spontaneous visual recovery is very high in this group of patients. Here, we report a child harboring a rare pathological mitochondrial DNA mutation, present in heteroplasmy, associated with the disease. A patient follow-up showed a rapid recovery of the vision accompanied by a decrease of the percentage of mutated mtDNA. A retrospective study on the age of recovery of all childhood-onset Leber hereditary optic neuropathy patients reported in the literature suggested that this process was probably related with pubertal changes.
- Published
- 2018
- Full Text
- View/download PDF
33. Glycogen Synthesis in Glycogenin 1-Deficient Patients: A Role for Glycogenin 2 in Muscle.
- Author
-
Krag TO, Ruiz-Ruiz C, and Vissing J
- Subjects
- Aged, Carbohydrate Metabolism, Case-Control Studies, Female, Glucans metabolism, Glucose metabolism, Glycogen metabolism, Glycogen ultrastructure, Glycogen Storage Disease genetics, Glycoproteins metabolism, Humans, Microscopy, Electron, Middle Aged, Muscle Fibers, Fast-Twitch ultrastructure, Muscle, Skeletal pathology, Muscle, Skeletal ultrastructure, Myofibrils ultrastructure, Glucosyltransferases genetics, Glucosyltransferases metabolism, Glycogen biosynthesis, Glycoproteins genetics, Muscle, Skeletal metabolism
- Abstract
Context: Glycogen storage disease (GSD) type XV is a rare disease caused by mutations in the GYG1 gene that codes for the core molecule of muscle glycogen, glycogenin 1. Nonetheless, glycogen is present in muscles of glycogenin 1-deficient patients, suggesting an alternative for glycogen buildup. A likely candidate is glycogenin 2, an isoform expressed in the liver and heart but not in healthy skeletal muscle., Objective: We wanted to investigate the formation of glycogen and changes in glycogen metabolism in patients with GSD type XV., Design, Setting, and Patients: Two patients with mutations in the GYG1 gene were investigated for histopathology, ultrastructure, and expression of proteins involved in glycogen synthesis and metabolism., Results: Apart from occurrence of polyglucosan (PG) bodies in few fibers, glycogen appeared normal in most cells, and the concentration was normal in patients with GSD type XV. We found that glycogenin 1 was absent, but glycogenin 2 was present in the patients, whereas the opposite was the case in healthy controls. Electron microscopy revealed that glycogen was present between and not inside myofibrils in type II fibers, compromising the ultrastructure of these fibers, and only type I fibers contained PG bodies. We also found significant changes to the expression levels of several enzymes directly involved in glycogen and glucose metabolism., Conclusions: To our knowledge, this is the first report demonstrating expression of glycogenin 2 in glycogenin 1-deficient patients, suggesting that glycogenin 2 rescues the formation of glycogen in patients with glycogenin 1 deficiency., (Copyright © 2017 Endocrine Society)
- Published
- 2017
- Full Text
- View/download PDF
34. The antihypertensive drug hydralazine activates the intrinsic pathway of apoptosis and causes DNA damage in leukemic T cells.
- Author
-
Ruiz-Magaña MJ, Martínez-Aguilar R, Lucendo E, Campillo-Davo D, Schulze-Osthoff K, and Ruiz-Ruiz C
- Subjects
- Antihypertensive Agents pharmacology, Humans, Jurkat Cells, Antineoplastic Agents pharmacology, Apoptosis drug effects, DNA Damage drug effects, Hydralazine pharmacology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
- Abstract
Epigenetic therapies have emerged as promising anticancer approaches, since epigenetic modifications play a major role in tumor initiation and progression. Hydralazine, an approved vasodilator and antihypertensive drug, has been recently shown to act as a DNA methylation inhibitor. Even though hydralazine is already tested in clinical cancer trials, its mechanism of antitumor action remains undefined. Here, we show that hydralazine induced caspase-dependent apoptotic cell death in human p53-mutant leukemic T cells. Moreover, we demonstrate that hydralazine triggered the mitochondrial pathway of apoptosis by inducing Bak activation and loss of the mitochondrial membrane potential. Hydralazine treatment further resulted in the accumulation of reactive oxygen species, whereas a superoxide dismutase mimetic inhibited hydralazine-induced cell death. Interestingly, caspase-9-deficient Jurkat cells or Bcl-2- and Bcl-xL-overexpressing cells were strongly resistant to hydralazine treatment, thereby demonstrating the dependence of hydralazine-induced apoptosis on the mitochondrial death pathway. Furthermore, we demonstrate that hydralazine treatment triggered DNA damage which might contribute to its antitumor effect., Competing Interests: There are no potential conflicts of interest
- Published
- 2016
- Full Text
- View/download PDF
35. Analysis of entries into the penalty area as a performance indicator in soccer.
- Author
-
Ruiz-Ruiz C, Fradua L, Fernández-García A, and Zubillaga A
- Subjects
- Analysis of Variance, Competitive Behavior, Group Structure, Humans, Observation, Reproducibility of Results, Athletic Performance, Game Theory, Group Processes, Soccer classification
- Abstract
This study examines entries into the penalty area as a performance indicator that distinguishes between winning, drawing and losing soccer teams. It assesses whether entries into the penalty area are influenced by match status, a player's dismissal and the respective quality of the competing teams. Two observers analysed the relation between defensive and offensive strategies and their scoring consequences for all 64 matches played in the 2006 World Cup. Kappa values ranged between 0.93 and 0.98 for intra-reliability and between 0.88 and 0.98 for inter-reliability. It was found that winning teams received significantly fewer entries into their own penalty area (mean=41.42, s=11.86) than drawing (mean=50.07, s=14.75) and losing teams (mean=47.23, s=12.14). Teams that received more entries into their own penalty area than the opposing team were significantly more likely to concede a goal (P <0.001). Teams losing by one (mean=0.41, s=0.21), two (mean=0.42, s=0.26) or more than two goals (mean=0.34, s=0.13) received significantly fewer entries into the penalty area per minute than teams winning by one (mean=0.55, s=0.27) or two goals (mean=0.59, s=0.39). Teams with fewer players on the pitch received significantly more entries into the penalty area per minute than teams with more (mean=0.22, s=0.07) or the same number (mean=0.14, s=0.05) of players. Based on these results, it is suggested that teams should enter the opposing team's penalty area but should not allow their opponents to do the same. These results also highlight the significance of the dismissal of a player.
- Published
- 2013
- Full Text
- View/download PDF
36. Designing small-sided games for training tactical aspects in soccer: extrapolating pitch sizes from full-size professional matches.
- Author
-
Fradua L, Zubillaga A, Caro O, Iván Fernández-García A, Ruiz-Ruiz C, and Tenga A
- Subjects
- Humans, Male, Athletic Performance, Competitive Behavior, Soccer, Task Performance and Analysis
- Abstract
The aims of this study were to examine the (1) individual playing area, (2) length and width of the rectangle encompassing the individual playing area and (3) distance between the goalkeepers and their nearest team-mates during professional soccer matches and compare these to previously reported pitch sizes for small-sided games (SSGs). Data were collected from four Spanish La Liga matches of the 2002-03 season, and notated post-event using the Amisco system. The pitch sizes obtained from real matches were smaller and different from those used previously for SSGs. In addition, the current pitch sizes show significant (P < 0.001) effect of ball location in all variables examined. For example, overall individual playing area (F [5, 2562] = 19.99, P < 0.001, η2= 0.04) varied significantly across six different zones of the pitch. Based on these empirical results, pitch sizes with individual playing areas ranging from 65 m2 to 110 m2 and length to width ratio of 1:1 and 1:1.3 are generally recommended for training tactical aspects according to different phases of play. It is possible to design SSGs with a more valid representation of the tactical conditions experienced in full-size matches and their use may improve the training effect of tactical aspects of match performance in soccer.
- Published
- 2013
- Full Text
- View/download PDF
37. ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy.
- Author
-
Rodríguez-Vargas JM, Ruiz-Magaña MJ, Ruiz-Ruiz C, Majuelos-Melguizo J, Peralta-Leal A, Rodríguez MI, Muñoz-Gámez JA, de Almodóvar MR, Siles E, Rivas AL, Jäättela M, and Oliver FJ
- Subjects
- Animals, Apoptosis genetics, Apoptosis physiology, Autophagy genetics, Blotting, Western, Cell Line, Cell Survival genetics, Cell Survival physiology, DNA Damage genetics, Fluorescent Antibody Technique, Mice, Microscopy, Fluorescence, Models, Biological, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerases genetics, Autophagy physiology, DNA Damage physiology, Poly(ADP-ribose) Polymerases metabolism, Reactive Oxygen Species metabolism
- Abstract
In response to nutrient stress, cells start an autophagy program that can lead to adaptation or death. The mechanisms underlying the signaling from starvation to the initiation of autophagy are not fully understood. In the current study we show that the absence or inactivation of PARP-1 strongly delays starvation-induced autophagy. We have found that DNA damage is an early event of starvation-induced autophagy as measured by γ-H2AX accumulation and comet assay, with PARP-1 knockout cells displaying a reduction in both parameters. During starvation, ROS-induced DNA damage activates PARP-1, leading to ATP depletion (an early event after nutrient deprivation). The absence of PARP-1 blunted AMPK activation and prevented the complete loss of mTOR activity, leading to a delay in autophagy. PARP-1 depletion favors apoptosis in starved cells, suggesting a pro-survival role of autophagy and PARP-1 activation after nutrient deprivation. In vivo results show that neonates of PARP-1 mutant mice subjected to acute starvation, also display deficient liver autophagy, implying a physiological role for PARP-1 in starvation-induced autophagy. Thus, the PARP signaling pathway is a key regulator of the initial steps of autophagy commitment following starvation.
- Published
- 2012
- Full Text
- View/download PDF
38. The DNA methyltransferase inhibitors zebularine and decitabine induce mitochondria-mediated apoptosis and DNA damage in p53 mutant leukemic T cells.
- Author
-
Ruiz-Magaña MJ, Rodríguez-Vargas JM, Morales JC, Saldivia MA, Schulze-Osthoff K, and Ruiz-Ruiz C
- Subjects
- Apoptosis drug effects, Apoptosis genetics, Azacitidine pharmacology, Caspase 9 metabolism, Cell Cycle drug effects, Cell Line, Tumor, Cytidine pharmacology, Decitabine, Humans, Leukemia, T-Cell pathology, Mutation, Reactive Oxygen Species metabolism, T-Lymphocytes pathology, Azacitidine analogs & derivatives, Cytidine analogs & derivatives, DNA (Cytosine-5-)-Methyltransferases antagonists & inhibitors, DNA Damage drug effects, Genes, p53, Leukemia, T-Cell genetics, Mitochondria physiology
- Abstract
DNA methyltransferase (DNMT)-inhibiting nucleoside analogs reactivate the expression of tumor suppressor genes and apoptosis-related genes silenced by methylation, thus favoring the induction of apoptosis in tumor cells. Moreover, induction of DNA damage seems to contribute to their antitumor effect. However, the apoptotic signaling pathway induced by these demethylating drugs is not well understood. Here, we have investigated the induction of apoptosis by two nucleoside DNMT inhibitors, decitabine and zebularine, in leukemic T cells. Both inhibitors induced caspase-dependent apoptosis in Jurkat, CEM-6 and MOLT-4 leukemia T cell lines, all with mutant p53, whereas resting and activated normal T lymphocytes were highly resistant to these demethylating agents. Although decitabine and zebularine showed different ability to induce apoptosis and cell cycle arrest among the three cell lines, they similarly activated the intrinsic apoptotic pathway by inducing mitochondrial alterations such as Bak activation, loss of transmembrane potential and generation of reactive oxygen species (ROS). Accordingly, Bcl-2- and Bcl-x(L) -overexpressing Jurkat cells, as well as caspase-9-deficient Jurkat cells, were resistant to apoptosis induced by decitabine and zebularine. Interestingly, ROS production seemed to be necessary for the induction of apoptosis. Apoptotic events, such as Bak and caspase activation, started as soon as 20 hr after treatment with either decitabine or zebularine. In addition, progression of apoptosis triggered by both DNMT inhibitors was paralleled by the induction of DNA damage. Our results suggest that the mitochondrial apoptotic pathway activated by decitabine and zebularine in p53 mutant leukemic T cells depends mainly on the induction of DNA damage., (Copyright © 2011 UICC.)
- Published
- 2012
- Full Text
- View/download PDF
39. The importance of bystander effects in radiation therapy in melanoma skin-cancer cells and umbilical-cord stromal stem cells.
- Author
-
Gómez-Millán J, Katz IS, Farias Vde A, Linares-Fernández JL, López-Peñalver J, Ortiz-Ferrón G, Ruiz-Ruiz C, Oliver FJ, and Ruiz de Almodóvar JM
- Subjects
- Apoptosis radiation effects, Cell Line, Cell Survival radiation effects, DNA Breaks, Dose Fractionation, Radiation, Dose-Response Relationship, Radiation, Humans, Melanoma pathology, Radiation Tolerance, Skin Neoplasms pathology, Bystander Effect, Melanoma radiotherapy, Mesenchymal Stem Cells radiation effects, Skin Neoplasms radiotherapy, Umbilical Cord cytology
- Abstract
Purpose: To examine direct and bystander radiation-induced effects in normal umbilical-cord stromal stem cell (HCSSC) lines and in human cancer cells., Materials and Methods: The UCSSC lines used in this study were obtained in our laboratory. Two cell lines (UCSSC 35 and UCSSC 37) and two human melanoma skin-cancer cells (A375 and G361) were exposed to ionizing radiation to measure acute radiation-dosage cell-survival curves and radiation-induced bystander cell-death response. Normal cells, although extremely sensitive to ionizing radiation, were resistant to the bystander effect whilst tumor cells were sensitive to irradiated cell-conditioned media, showing a dose-response relationship that became saturated at relatively low doses. We applied a biophysical model to describe bystander cell-death through the binding of a ligand to the cells. This model allowed us to calculate the maximum cell death (χ(max)) produced by the bystander effect together with its association constant (K(By)) in terms of dose equivalence (Gy). The values obtained for K(By) in A375 and G361 cells were 0.23 and 0.29 Gy, respectively., Conclusion: Our findings help to understand how anticancer therapy could have an additional decisive effect in that the response of sub-lethally hit tumor cells to damage might be required for therapy to be successful because the survival of cells communicating with irradiated cells is reduced., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
40. Relation between total body load and session rating of perceived exertion in professional soccer players.
- Author
-
Gomez-Piriz PT, Jiménez-Reyes P, and Ruiz-Ruiz C
- Subjects
- Adult, Humans, Male, Monitoring, Ambulatory instrumentation, Young Adult, Geographic Information Systems, Monitoring, Ambulatory methods, Physical Exertion physiology, Soccer physiology, Soccer psychology
- Abstract
The aims of this study were to assess (a) the validity of total body load (TBL)-obtained from the global position system (GPS) devices-to quantify soccer training load, assessing its relationship with session rating of perceived exertion (session-RPE) and (b) to analyze the differences in terms of TBL and session-RPE among defenders, midfielders, and forwards. Twenty-two professional soccer players (Spanish first division, season 2007-2008; 26.74 ± 4.2 years; height 179.74 ± 4.04 cm; weight 73.7 ± 3.35 kg) participated in the study. During 13 training sessions composed predominantly of small-sided games, TBL and RPE multiplied by the minutes of session duration were determined using GPS and the 21-point scale, respectively. In each session, data from 10 players randomly selected and classified according to player position (defenders, midfielders, and forwards) were collected. Although session-RPE was a significant predictor of TBL (β = 0.23, p < 0.05), this method only accounted for 5% of the variance in TBL. No significant differences in terms of TBL and session-RPE were found regarding player position. The results of this study suggest that TBL is not a valid measure to quantify training load because it is not strongly correlated with session-RPE. Furthermore, TBL and session-RPE in small-sided soccer games do not vary according to player positions.
- Published
- 2011
- Full Text
- View/download PDF
41. Expression of the vasoactive proteins AT1, AT2, and ANP by pregnancy-induced mouse uterine natural killer cells.
- Author
-
Hatta K, Carter AL, Chen Z, Leno-Durán E, Ruiz-Ruiz C, Olivares EG, Tse MY, Pang SC, and Croy BA
- Subjects
- Animals, Atrial Natriuretic Factor genetics, Female, Gestational Age, Immunohistochemistry, Killer Cells, Natural immunology, Mice, Mice, Inbred C57BL, Pregnancy, Reverse Transcriptase Polymerase Chain Reaction, Uterus immunology, Atrial Natriuretic Factor metabolism, Killer Cells, Natural metabolism, Receptor, Angiotensin, Type 1 metabolism, Receptor, Angiotensin, Type 2 metabolism, Uterus metabolism
- Abstract
Angiotensin II receptor type 1 (AT1) activation leads to vasoconstriction and type 2 receptor (AT2) leads to vasodilation. Atrial natriuretic peptide (ANP) antagonizes the effects of AT1. In human and murine pregnancies, uterine natural killer (uNK) cells closely associate with decidual blood vessels. Protein localization of AT1, AT2, and ANP to mouse uNK cells was examined between gestation days (gds) 6 and 12, the interval of uNK cell expansion. Percentages of uNK cells expressing AT1 or AT2 changed between gd6 and gd10. Atrial natriuretic peptide did not localize to uNK cells at gd6 or 8, but did colocalize to uNK cells at gd10 and 12, times immediately after spiral arterial modification. This is the first report of AT1, AT2, and ANP expression in uterine immune cells. Expression of these molecules suggests that uNK cells have the potential to contribute to the changes in blood pressure that occur between days 5 and 12 of pregnancy in mice.
- Published
- 2011
- Full Text
- View/download PDF
42. An exopolysaccharide produced by the novel halophilic bacterium Halomonas stenophila strain B100 selectively induces apoptosis in human T leukaemia cells.
- Author
-
Ruiz-Ruiz C, Srivastava GK, Carranza D, Mata JA, Llamas I, Santamaría M, Quesada E, and Molina IJ
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents metabolism, Cell Cycle drug effects, Cell Line, Tumor, Halomonas chemistry, Halomonas genetics, Halomonas isolation & purification, Humans, Molecular Sequence Data, Polysaccharides, Bacterial chemistry, Soil Microbiology, Antineoplastic Agents pharmacology, Apoptosis drug effects, Halomonas metabolism, Leukemia-Lymphoma, Adult T-Cell physiopathology, Polysaccharides, Bacterial metabolism, Polysaccharides, Bacterial pharmacology, Sodium Chloride metabolism
- Abstract
Microbial exopolysaccharides (EPSs) are highly heterogeneous polymers produced by fungi and bacteria and have recently been attracting considerable attention from biotechnologists because of their potential applications in many fields, including biomedicine. We have screened the antitumoural activity of a panel of sulphated EPSs produced by a newly discovered species of halophilic bacteria. We found that the novel halophilic bacterium Halomonas stenophila strain B100 produced a heteropolysaccharide that, when oversulphated, exerted antitumoural activity on T cell lines deriving from acute lymphoblastic leukaemia (ALL). Only tumour cells were susceptible to apoptosis induced by the sulphated EPS (B100S), whilst primary T cells were resistant. Moreover, freshly isolated primary cells from the blood of patients with ALL were also susceptible to B100S-induced apoptosis. The newly discovered B100S is therefore the first bacterial EPS that has been demonstrated to exert a potent and selective pro-apoptotic effect on T leukaemia cells, and thus, we propose that the search for new antineoplastic drugs should include the screening of other bacterial EPSs, particularly those isolated from halophiles.
- Published
- 2011
- Full Text
- View/download PDF
43. Regulation of the resistance to TRAIL-induced apoptosis in human primary T lymphocytes: role of NF-kappaB inhibition.
- Author
-
Morales JC, Ruiz-Magaña MJ, and Ruiz-Ruiz C
- Subjects
- Antineoplastic Agents pharmacology, CASP8 and FADD-Like Apoptosis Regulating Protein metabolism, Down-Regulation, Drug Resistance, Neoplasm genetics, Enzyme Inhibitors pharmacology, Humans, NF-kappa B antagonists & inhibitors, Receptors, TNF-Related Apoptosis-Inducing Ligand metabolism, T-Lymphocytes immunology, Apoptosis genetics, Drug Resistance, Neoplasm physiology, NF-kappa B physiology, T-Lymphocytes drug effects, TNF-Related Apoptosis-Inducing Ligand pharmacology
- Abstract
Several combined strategies have been recently proposed to overcome the resistance to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) showed by some tumor cells, thus improving the use of this death ligand in antitumor therapy. However, the molecular mechanisms of the tumor selective activity of TRAIL are not completely understood and hence the effects of the combined therapy on normal cells are unknown. Here, we have studied the resistance of primary T lymphocytes to TRAIL-mediated apoptosis. No significant differences were found in the expression of proteins involved in TRAIL-mediated apoptosis between resting and activated T cells. The low expression of death receptors TRAIL-R1/-R2 as well as the high levels of the antiapoptotic proteins TRAIL-R4 and cellular Fas-associated death domain-like IL-1beta-converting enzyme-inhibitory protein (c-FLIP) may explain the lack of caspase-8 activation observed upon TRAIL treatment in both cell types. We have also analyzed the effect of different sensitizing agents such as genotoxic drugs, phosphatidylinositol-3 kinase (PI3K) inhibitors, proteasome inhibitors, microtubule depolymerizing agents, histone deacetylase inhibitors (HDACi), and NF-kappaB inhibitors. Although some of them induced T cell death, only NF-kappaB inhibitors sensitized activated T cells to TRAIL-induced apoptosis, maybe through the regulation of the antiapoptotic proteins TRAIL-R4, c-FLIP(S) and members of the inhibitors of apoptosis proteins (IAP) family. These results question the safety of the combined treatments with TRAIL and NF-kappaB inhibitors against tumors.
- Published
- 2007
- Full Text
- View/download PDF
44. GSK-3beta inhibition by lithium confers resistance to chemotherapy-induced apoptosis through the repression of CD95 (Fas/APO-1) expression.
- Author
-
Beurel E, Kornprobst M, Blivet-Van Eggelpoël MJ, Ruiz-Ruiz C, Cadoret A, Capeau J, and Desbois-Mouthon C
- Subjects
- Apoptosis drug effects, Camptothecin pharmacology, Etoposide pharmacology, Glycogen Synthase Kinase 3 metabolism, Glycogen Synthase Kinase 3 beta, Humans, Promoter Regions, Genetic physiology, Topoisomerase I Inhibitors, Topoisomerase II Inhibitors, Tumor Suppressor Protein p53 metabolism, fas Receptor biosynthesis, Apoptosis physiology, Gene Expression Regulation physiology, Glycogen Synthase Kinase 3 antagonists & inhibitors, Lithium pharmacology, fas Receptor genetics
- Abstract
Lithium exerts neuroprotective actions that involve the inhibition of glycogen synthase kinase-3beta (GSK-3beta). Otherwise, recent studies suggest that sustained GSK-3beta inhibition is a hallmark of tumorigenesis. In this context, the present study was undertaken to examine whether lithium modulated cancer cell sensitivity to apoptosis induced by chemotherapy agents. We observed that, in different human cancer cell lines, lithium significantly reduced etoposide- and camptothecin-induced apoptosis. In HepG2 cells, lithium repressed drug induction of CD95 expression and clustering at the cell surface as well as caspase-8 activation. Lithium acted through deregulation of GSK-3beta signaling since (1) it provoked a rapid and sustained phosphorylation of GSK-3beta on the inhibitory serine 9 residue; (2) the GSK-3beta inhibitor SB-415286 mimicked lithium effects by repressing drug-induced apoptosis and CD95 membrane expression; and (3) lithium promoted the disruption of nuclear GSK-3beta/p53 complexes. Moreover, the overexpression of an inactivated GSK-3beta mutant counteracted the stimulatory effects of etoposide and camptothecin on a luciferase reporter plasmid driven by a p53-responsive sequence from the CD95 gene. In conclusion, we provide the first evidence that lithium confers resistance to apoptosis in cancer cells through GSK-3beta inhibition and subsequent repression of CD95 gene expression. Our study also highlights the concerted action of GSK-3beta and p53 on CD95 gene expression.
- Published
- 2004
- Full Text
- View/download PDF
45. The up-regulation of human caspase-8 by interferon-gamma in breast tumor cells requires the induction and action of the transcription factor interferon regulatory factor-1.
- Author
-
Ruiz-Ruiz C, Ruiz de Almodóvar C, Rodríguez A, Ortiz-Ferrón G, Redondo JM, and López-Rivas A
- Subjects
- Amino Acid Motifs, Apoptosis, Base Sequence, Binding Sites, Blotting, Northern, Caspase 8, Caspases metabolism, Cell Line, Tumor, Cell Nucleus metabolism, DNA Methylation, Gene Deletion, Humans, Immunoblotting, Interferon Regulatory Factor-1, Interferon-gamma metabolism, Luciferases metabolism, Models, Genetic, Molecular Sequence Data, Plasmids metabolism, Promoter Regions, Genetic, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Single-Strand Specific DNA and RNA Endonucleases metabolism, Sp1 Transcription Factor metabolism, Time Factors, Transcription, Genetic, Transcriptional Activation, Transfection, Breast Neoplasms metabolism, Caspases biosynthesis, DNA-Binding Proteins physiology, Interferon-gamma biosynthesis, Phosphoproteins physiology, Up-Regulation
- Abstract
Treatment of human breast tumor cells with interferon-gamma (IFN-gamma) elevates caspase-8 expression and sensitizes these cells to death receptor-mediated apoptosis through the increased processing and activation of apical procaspase-8. We have characterized the human caspase-8 gene promoter and studied the transcriptional regulation of caspase-8 gene expression in MCF-7 breast tumor cells treated with IFN-gamma. Our findings show that IFN-gamma induces the up-regulation of caspase-8 mRNA expression through a protein synthesis-dependent mechanism involving the action of the IFN-gamma-inducible transcription factor interferon regulatory factor-1 (IRF-1) and without altering mRNA stability. The human caspase-8 gene promoter lacks recognizable TATA and CAAT boxes but contains a consensus Sp1 binding site. We have identified two major IFN-gamma-inducible transcriptional start sites in these cells by S1 nuclease mapping, confirmed by primer extension analysis. Deletion analysis of the promoter defined an 82-bp minimal region responsible for IFN-gamma-inducible promoter activity. In this region, we have identified an IFN-stimulated response element that is important for both the basal and IFN-gamma-enhanced transcriptional activities. Electrophoretic mobility shift assay analysis demonstrated that IFN-gamma induces a complex between an oligonucleotide probe containing the ISRE motif and IRF-1 over a similar time scale to the induction of caspase-8 mRNA. Exogenously expressed IRF-1 in MCF-7 cells up-regulated the activity of a luciferase reporter plasmid containing an 82-bp region of the caspase-8 promoter. These data define a new pathway through which IFN-gamma might control the sensitivity of tumor cell to death receptor-mediated apoptosis.
- Published
- 2004
- Full Text
- View/download PDF
46. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) decoy receptor TRAIL-R3 is up-regulated by p53 in breast tumor cells through a mechanism involving an intronic p53-binding site.
- Author
-
Ruiz de Almodóvar C, Ruiz-Ruiz C, Rodríguez A, Ortiz-Ferrón G, Redondo JM, and López-Rivas A
- Subjects
- Antibiotics, Antineoplastic pharmacology, Apoptosis, Base Sequence, Binding Sites genetics, Breast Neoplasms pathology, Cell Line, Tumor, Cloning, Molecular, Consensus Sequence, DNA, Neoplasm genetics, DNA, Neoplasm metabolism, Doxorubicin pharmacology, Female, GPI-Linked Proteins, Gene Expression Regulation, Neoplastic drug effects, Humans, Introns, Promoter Regions, Genetic, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Neoplasm genetics, RNA, Neoplasm metabolism, Receptors, Tumor Necrosis Factor, Member 10c, Transfection, Tumor Necrosis Factor Decoy Receptors, Up-Regulation drug effects, Breast Neoplasms genetics, Breast Neoplasms metabolism, Receptors, Tumor Necrosis Factor genetics, Tumor Suppressor Protein p53 metabolism
- Abstract
Tumor necrosis factor-related apoptosis-inducing ligand receptor 3 (TRAIL-R3) is a decoy receptor for TRAIL, a member of the tumor necrosis factor family. In several cell types decoy receptors inhibit TRAIL-induced apoptosis by binding TRAIL and thus preventing its binding to proapoptotic TRAIL receptors. We studied the regulation of TRAIL-R3 gene expression in breast tumor cells treated with the genotoxic drug doxorubicin (DXR). The breast tumor cell line MCF-7 (p53 wild type) responded to DXR with a marked elevation of TRAIL-R3 expression at the mRNA, total protein, and cell surface levels. In contrast, in EVSA-T cells (p53 mutant) DXR did not induce increased expression of TRAIL-R3. In MCF-7 cells overexpressing the human papillomavirus protein E6, which causes p53 degradation, DXR-induced TRAIL-R3 expression was notably reduced. Furthermore, in MCF-7 cells overexpressing a temperature-sensitive p53 mutant (Val135), shifting the cultures to the permissive temperature was sufficient to induce the expression of TRAIL-R3. We also cloned and characterized a p53 consensus element located within the first intron of the human TRAIL-R3 gene. This element binds p53 and confers responsiveness to genotoxic damage to constructs of the TRAIL-R3 promoter in transient transfection experiments. Our results indicate that genotoxic treatments such as DXR, frequently used in cancer therapy, may also induce genes such as TRAIL-R3 that potentially have antiapoptotic actions and thus interfere with the TRAIL signaling system. This is particularly important in view of the proposed use of TRAIL in antitumor therapy.
- Published
- 2004
- Full Text
- View/download PDF
47. Interferon-gamma and TRAIL in human breast tumor cells.
- Author
-
Ruiz de Almodóvar C, López-Rivas A, and Ruiz-Ruiz C
- Subjects
- Animals, Apoptosis, Apoptosis Regulatory Proteins, Caspase 8, Caspases metabolism, Gene Expression Regulation, Humans, Signal Transduction, TNF-Related Apoptosis-Inducing Ligand, Transcription, Genetic, Breast Neoplasms pathology, Interferon-gamma pharmacology, Interferon-gamma physiology, Membrane Glycoproteins genetics, Membrane Glycoproteins physiology, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha physiology
- Abstract
Induction of apoptosis in tumor cells by death receptor activation is a novel therapeutic strategy. However, in systemic antitumor treatments, severe toxic effects have been observed with tumor necrosis factor-alpha (TNF-alpha) and CD95 ligand. TNF-alpha causes a lethal inflammatory response and CD95L produces lethal liver damage. Preclinical studies in mice and nonhuman primates showed no systemic cytotoxicity upon injection of recombinant TNF-related apoptosis-inducing ligand (TRAIL) at doses that effectively suppressed solid tumors such as colon and mammary carcinomas. Although unwanted effects of some TRAIL preparations have been reported in normal cells, these data suggest that TRAIL could be a suitable approach in cancer therapy. However, several mechanisms of resistance to TRAIL-mediated apoptosis have been described in tumor cells such as lack of TRAIL apoptotic receptors, enhanced expression of TRAIL-decoy receptors, and expression of apoptosis inhibitors. In combination regimes, interferon-gamma (IFN-gamma) could provide a promising antitumor therapeutic approach as it has been described to enhance cellular susceptibility to apoptosis in a variety of tumor cells. The mechanism by which IFN-gamma promotes cell death seems to be via the regulation of the expression of different proteins involved in apoptosis. Altogether, these data suggest a combination strategy to selectively kill tumor cells that need to be further explored.
- Published
- 2004
- Full Text
- View/download PDF
48. Characterization of p53-mediated up-regulation of CD95 gene expression upon genotoxic treatment in human breast tumor cells.
- Author
-
Ruiz-Ruiz C, Robledo G, Cano E, Redondo JM, and Lopez-Rivas A
- Subjects
- Base Sequence, Breast Neoplasms pathology, DNA Primers, Humans, Promoter Regions, Genetic, Proto-Oncogene Proteins c-bcl-2 physiology, Tumor Cells, Cultured, Breast Neoplasms genetics, Gene Expression Regulation physiology, Mutagens toxicity, Tumor Suppressor Protein p53 physiology, Up-Regulation physiology, fas Receptor genetics
- Abstract
Death receptor CD95 gene expression is frequently low in human breast tumors and is up-regulated by genotoxic treatments in a p53-dependent manner. We have evaluated the relative contribution of promoter and intronic p53 consensus sites to the regulation of the human CD95 gene in breast tumor cells following doxorubicin treatment. Deletion constructs of the promoter region and site-directed mutagenesis of p53 consensus sites in a fragment spanning 1448 bp of the 5'-promoter demonstrate that these sites are not involved in the observed up-regulation of the CD95 gene upon doxorubicin treatment. In contrast, a p53 consensus site located within the first intron of CD95 gene is absolutely required for the inducible expression of CD95 upon genotoxic treatment in breast tumor cells. Analysis of the transcriptional activity of the two most common p53 mutants found in human breast tumors that are associated with resistance to doxorubicin reveals that these mutations completely eliminate the ability of p53 protein to transactivate CD95 gene expression. On the other hand, Bcl-2 overexpression albeit preventing doxorubicin-induced apoptosis, has no effect on p53-mediated CD95 up-regulation in breast tumor cells. Altogether, these results indicate the lack of involvement of p53 consensus sites of the CD95 promoter region and the pivotal role of intronic p53-responsive element in the regulation of human CD95 gene expression in breast tumor cells. Our results also suggest that in breast cancer patients with certain mutations in the p53 gene, expression of death receptor CD95 in response to genotoxic treatments could be severely compromised.
- Published
- 2003
- Full Text
- View/download PDF
49. Inhibition of glucose metabolism sensitizes tumor cells to death receptor-triggered apoptosis through enhancement of death-inducing signaling complex formation and apical procaspase-8 processing.
- Author
-
Muñoz-Pinedo C, Ruiz-Ruiz C, Ruiz de Almodóvar C, Palacios C, and López-Rivas A
- Subjects
- Adenosine Triphosphate metabolism, Apoptosis drug effects, Apoptosis Regulatory Proteins, Breast Neoplasms, Caspase 8, Caspase 9, Cytochrome c Group metabolism, Deoxyglucose metabolism, Enzyme Activation, Female, Glucose antagonists & inhibitors, HeLa Cells, Humans, Kinetics, Lymphoma, Mitochondria physiology, Protein Processing, Post-Translational, Pyruvates metabolism, TNF-Related Apoptosis-Inducing Ligand, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha pharmacology, U937 Cells, fas Receptor physiology, Apoptosis physiology, Caspases metabolism, Enzyme Precursors metabolism, Glucose metabolism, Membrane Glycoproteins physiology, Signal Transduction physiology, Tumor Necrosis Factor-alpha physiology
- Abstract
Tumors display a high rate of glucose uptake and glycolysis. We investigated how inhibition of glucose metabolism could affect death receptor-mediated apoptosis in human tumor cells of diverse origin. We show that both substitution of glucose for pyruvate and treatment with 2-deoxyglucose enhanced apoptosis induced by tumor necrosis factor (TNF)-alpha, CD95 agonistic antibody, and TNF-related apoptosis-inducing ligand (TRAIL). Inhibition of glucose metabolism enhanced killing of myeloid leukemia U937, cervical carcinoma HeLa, and breast carcinoma MCF-7 cells upon death receptor ligation. Caspase activation, mitochondrial depolarization, and cytochrome c release were increased under these conditions. Glucose deprivation-mediated sensitization to apoptosis was prevented in MCF-7 cells overexpressing BCL-2. Interestingly, the human B-lymphoblastoid cell line SKW6.4, a prototype for mitochondria-independent death receptor-induced apoptosis, was also sensitized to anti-CD95 and TRAIL-induced apoptosis under glucose-free conditions. Changes in c-FLIP(L) and cFLIPs levels were observed in some but not all the cell lines studied following glucose deprivation. Glucose deprivation enhanced death receptor-triggered formation of death-inducing signaling complex and early processing of procaspase-8. Altogether, these results suggest that the glycolytic pathway may be an important target for therapeutic intervention to sensitize tumor cells to selectively toxic soluble death ligands or death ligand-expressing cells of the immune system by facilitating the activation of initiator caspase-8.
- Published
- 2003
- Full Text
- View/download PDF
50. Mitochondria-dependent and -independent mechanisms in tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis are both regulated by interferon-gamma in human breast tumour cells.
- Author
-
Ruiz-Ruiz C and López-Rivas A
- Subjects
- Apoptosis Regulatory Proteins, Caspase 3, Caspase 8, Caspase 9, Caspases metabolism, Female, Humans, Ligands, Proto-Oncogene Proteins c-bcl-2 metabolism, TNF-Related Apoptosis-Inducing Ligand, Tumor Cells, Cultured, Apoptosis physiology, Breast Neoplasms metabolism, Interferon-gamma metabolism, Membrane Glycoproteins metabolism, Mitochondria metabolism, Tumor Necrosis Factor-alpha metabolism
- Abstract
Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL/APO-2L) induces apoptosis in a variety of tumour cells upon binding to death receptors TRAIL-R1 and TRAIL-R2. Here we describe the sensitization by interferon (IFN)-gamma to TRAIL-induced apoptosis in the breast tumour cell lines MCF-7 and MDA-MB231. IFN-gamma promoted TRAIL-mediated activation of caspase-8, Bcl-2 interacting domain death agonist (Bid) degradation, Bcl-2-associated X protein (Bax) translocation to mitochondria, cytochrome c release to the cytosol and activation of caspase-9 in these cell lines. No changes in the expression of TRAIL receptors were observed upon IFN-gamma treatment. Overexpression of Bcl-2 in MCF-7 cells completely inhibited IFN-gamma-induced sensitization to TRAIL-mediated cell death. Interestingly, TRAIL-induced apoptosis was also clearly enhanced by IFN-gamma in caspase-3-overexpressing MCF-7 cells, in the absence of Bax translocation to mitochondria and cytochrome c release to the cytosol. In summary, our results suggest that IFN-gamma facilitates TRAIL-induced activation of mitochondria-regulated as well as mitochondria-independent apoptotic pathways in breast tumour cells.
- Published
- 2002
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.