68 results on '"Bordas M"'
Search Results
2. Plant regeneration and Agrobacterium-mediated transformation of cotyledon explants of Citrullus colocynthis (L.) Schrad.
- Author
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Dabauza, M., Bordas, M., Salvador, A., Roig, L.-A., and Moreno, V.
- Published
- 1997
- Full Text
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3. Use of an annular241Am−Be neutron source for INAA of some major constituents in large samples
- Author
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Bordas, M. D. and Das, H. A.
- Published
- 1996
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- View/download PDF
4. Occurrence of heterocyclic amines in several home-cooked meat dishes of the Spanish diet
- Author
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Busquets, R, Bordas, M, Toribio, F, Puignou, L, and Galceran, M.T
- Published
- 2004
- Full Text
- View/download PDF
5. Formation and stability of heterocyclic amines in a meat flavour model system: Effect of temperature, time and precursors
- Author
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Bordas, M., Moyano, E., Puignou, L., and Galceran, M.T.
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- 2004
- Full Text
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6. Molecular Rydberg states: Classical chaos and its correspondence in quantum mechanics.
- Author
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Lombardi, M., Labastie, P., Bordas, M. C., and Broyer, M.
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MOLECULAR dynamics ,RYDBERG states ,SODIUM ,QUANTUM theory - Abstract
The Rydberg spectrum of Na2 has been shown previously to alternate when increasing energy between ‘‘stroboscopic fringes’’ which correspond to a well known separable Hund’s coupling case (a), and a complex, unidentifiable intermediate coupling. We use this system as a prototypic example to test some current ideas on the correspondence between classical chaos and properties of quantum spectra. We first determine the phase space structure and transition to chaos in classical mechanics. We then determine the change in line intensities and level spacing statistics in quantum mechanics. We show that this system has the expected behavior in the semiclassical limit in the presence of classical chaos, except for a peculiarity in level spacing statistics, but that this behavior is not a signature of chaos, since the same system shows similar behavior for some values of the parameters which correspond to a nonchaotic situation in classical mechanics. We discuss also some problems related to the nonvalidity of the semiclassical limit. [ABSTRACT FROM AUTHOR]
- Published
- 1988
- Full Text
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7. Highly excited Rydberg states of Na2: Decoupling between electronic and nuclear motion.
- Author
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Martin, S., Chevaleyre, J., Bordas, M. Chr., Valignat, S., Broyer, M., Cabaud, B., and Hoareau, A.
- Published
- 1983
- Full Text
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8. Alternative to supply of health services in physical medicine and rehabilitation: From mobile team to home hospitalization
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Duruflé, Aubry, J.F., Bordas, M., Gallien, P., Le Meur, C., and Nicolas, B.
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- 2018
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9. TRANSCRIPTIONAL AND GENOMIC INTRA‐TUMOR HETEROGENEITY DRIVES SUBCLONE SPECIFIC DRUG RESPONSES IN DIFFUSE LARGE B CELL LYMPHOMA.
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Roider, T., Frauhammer, F., Seufert, J., Bordas, M., Stolarczyk, M., Rabe, S., Malm, J., Bruch, P., Hundemer, M., Rippe, K., Goeppert, B., Seiffert, M., Brors, B., Mechtersheimer, G., Müller‐Tidow, C., Fröhling, S., Schlesner, M., Huber, W., Anders, S., and Dietrich, S.
- Subjects
DIFFUSE large B-cell lymphomas ,B cells ,T helper cells ,CELL populations ,T cells ,DRUGS - Published
- 2019
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10. Ecoulement et transferts de sédiments dans les bassins versants de grande culture sur basalte du Rio Grande do Sul (Brésil)
- Author
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Nilza, Castro, Auzet, Anne-Véronique, Bordas, M., Leprun, Jean-Claude, Chevallier, Pierre, Mietton, Michel, Actualisation et valorisation des données pédologiques tropicales et méditerranéennes. Contributions à la recherche, à l'expertise et à l'aide à la gestion des ressources (VALPEDO), Environnement Ville Société (EVS), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-École nationale supérieure d'architecture de Lyon (ENSAL)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École Nationale des Travaux Publics de l'État (ENTPE)-Université Jean Monnet [Saint-Étienne] (UJM)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université Lumière - Lyon 2 (UL2)-École normale supérieure - Lyon (ENS Lyon), Centre de Recherche de Géographie et Aménagement (Lyon 3) (CRGA), Université de Lyon-Université Lumière - Lyon 2 (UL2)-École normale supérieure - Lyon (ENS Lyon)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Environnement, Ville, Société (EVS), École normale supérieure de Lyon (ENS de Lyon)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-École Nationale des Travaux Publics de l'État (ENTPE)-École nationale supérieure d'architecture de Lyon (ENSAL)-Centre National de la Recherche Scientifique (CNRS), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-École Nationale des Travaux Publics de l'État (ENTPE)-École nationale supérieure d'architecture de Lyon (ENSAL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE)
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Rio Grande do Sul ,grands bassins versants ,[SDE]Environmental Sciences ,grande culture ,basalte ,[SHS.GEO]Humanities and Social Sciences/Geography ,erosion ,ComputingMilieux_MISCELLANEOUS ,Brésil ,Ecoulements ,[SHS]Humanities and Social Sciences - Abstract
International audience
- Published
- 1997
11. Chaos in molecular Rydberg states.
- Author
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Lombardi, M., Labastie, P., Bordas, M. C., and Broyer, M.
- Published
- 1990
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12. Bubbly Flow Through Fixed Beds: Microscale Experiments in the Dilute Regime and Modeling.
- Author
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Bordas, M. L., Cartellier, A., Sechet, P., and Boyer, Ch.
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PRESSURE ,FORCE & energy ,FLUID dynamics ,DYNAMICS ,FLUID mechanics - Abstract
In order to predict the pressure drop and the mean void fraction for bubbly flows in packed beds, a new one-dimensional (l-D) model is proposed. The balance equations for both phases are derived from local Eulerian two-fluid equations which are spatially averaged at a mesoscale, that is, at a length-scale large compared with the microscale that characterizes the fixed bed. This model that differs from previous mechanistic models, has been supplemented by closure laws for the liquid-solid and the gas-liquid interactions, those structures account for the flow dynamics at the pore scale. It is first experimentally demonstrated that, in dilute conditions, the bubble-size distribution only depends on the pore size, when the later is smaller than the capillary length scale. It is also shown that the mean-bubble dynamics is similar to that of a slug, with a relative velocity at mesoscale linearly increasing with the liquid superficial velocity. Besides, that relative velocity monotonically increases with the gas flow rate ratio, a behavior that can be attributed to the formation of preferential paths for the gas phase. Concerning the liquid-solid interactions, the two-phase flow pressure drop scaled by its single-phase flow counterpart at the same superficial liquid velocity is predicted to linearly increase with the void fraction, with a prefactor evolving with the Capillary number. These closures prove consistent with available experiments, both in upward and in downward situations. Although these proposals deserve to be further tested over an extended range of flow parameters, this model paves the way to reasonably accurate predictions of bubbly flows in packed beds able to account for refined parameters related with the flow dynamics. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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13. Kinetics of adhesion of Listonella anguillarum to the mucus of gilt-head seabream, and the implication of surface components.
- Author
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Chabrillón, M., Bordas, M. A., Moriñigo, M. A., and Balebona, M. C.
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CELLS , *ADHESION , *SKIN , *SUSPENSIONS (Chemistry) , *BACTERIA , *MICROORGANISMS - Abstract
The kinetics of adhesion of Listonella anguillarum cells to skin, intestinal and gill mucus suspensions of gilt-head seabream was studied. A Langmuir adsorption isotherm was calculated, and the results obtained indicated that this microorganism showed a saturation kinetics. The pretreatment of the mucus suspensions with a surface extract obtained from L. anguillarum cells promoted a very important inhibition of the number of adhered bacteria to the different mucus suspensions. The potential role of surface structures on the adhesion of L. anguillarum to mucus of gilt-head seabream is discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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- View/download PDF
14. Kinetics of adhesion of selected fish-pathogenic Vibrio strains to skin mucus of gilt-head sea...
- Author
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Bordas, M. Angeles and Balebona, M. Carmen
- Subjects
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VIBRIO , *BACTERIAL adhesion , *FISH microbiology - Abstract
Presents a study of the kinetics of adhesion of Vibrio strains isolated from diseased skin mucus of gilt-head sea bream. Biological activities detected in the skin mucus; Adhesive processes; Adhesive kinetics; Effects of temperature and salinity on the adhesion process.
- Published
- 1996
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15. Microbial origin of the abdominal swelling affecting farmed larvae of gilt-head seabream, Sparus aurata L.
- Author
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Sedano, J., Zorrilla, I., Moriñigo, M. A., Balebona, M. C., Vidaurreta, A., Bordas, M. A., and Borrego, J. J.
- Subjects
SPARUS aurata ,SPARUS ,LARVAE ,BACTERIA ,MICROBIAL virulence ,LIVER cells ,DEATH (Biology) ,DEVELOPMENTAL biology ,AQUACULTURE - Abstract
The aetiological agents of the abdominal swelling affecting farmed larvae of gilt-head seabream, Sparus aurata L., were studied. Four Vibrio strains were isolated from larvae of S. aurata affected by this disease, and all strains reproduced the disease in healthy larvae under controlled infection experiments, producing a significant increase of the mortality rates compared to the control (non-inoculated larvae). Several enzymatic properties, which can act as virulence factors, were demonstrated both in the extracellular products (ECPs) and in live cells of the strains tested. Histopathological examinations of the infected fish larvae revealed important changes of the anterior intestine and liver characterized by a marked hyperthrophy of the intestinal epithelium and hepatocytes, and by a separation of the mucosal and submucosal layers in the digestive tube. These histological alterations were associated with the constant presence of cocobacillar bacteria in the anterior intestine and in the liver. However, the precise pathogenic mechanisms of the strains tested have not been completely elucidated yet. [ABSTRACT FROM AUTHOR]
- Published
- 1996
- Full Text
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16. Energy partitioning between the equilibrated A and X states of the CN radical formed in the C+N2O reaction.
- Author
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Torchin, L., Bordas, M. C., and Robert, J. C.
- Subjects
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ELECTRONS , *RADICALS (Chemistry) - Abstract
Similar populations have been observed between the A and X states of the CN radical, formed in the C+N2O chemical reaction. Relative vibrational populations were measured by laser-induced fluorescence (X state) and chemiluminescence (A state). The electronic branching ratio was then obtained by assuming a Boltzmann equilibrium between the v‘=4–6 and v’=1–4 levels of the X and A states. This assumption was checked by absolute calibration of the number densities of both states. About 1/3 of the radicals were found in the A state. [ABSTRACT FROM AUTHOR]
- Published
- 1985
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- View/download PDF
17. Thick target X-ray yields and intensity ratios for MeV Br and Kr ion impact and application to the analysis of pottery
- Author
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Tenorio, D., Costa, G., Bordas, M., Larcher, J., Lagarde, G., Heitz, C., and Jaidar, A.
- Published
- 1986
- Full Text
- View/download PDF
18. Ar ion induced X-ray emission for the analysis of light elements in CdTe
- Author
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Al Neami, A., Al Neami, A.Kadom, Bordas, M., Hage-Ali, M., Larcher, J., Siffert, P., and Heitz, C.
- Published
- 1992
- Full Text
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19. ChemInform Abstract: Synthesis of Enantiomerically Pure trans-Aziridine-2-carboxylates by Diastereoselective Gabriel-Cromwell Reaction.
- Author
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CARDILLO, G., GENTILUCCI, L., TOMASINI, C., and CASTEJON-BORDAS, M. P. V.
- Published
- 1996
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- View/download PDF
20. Chemotaxis of pathogenic Vibrio strains towards a mucus surfaces of gilt-head sea bream...
- Author
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Balebona, M. Carmen, Borrego, Juan J., Angeles Bordas, M., Rodriguez-Maroto, Jose M., and Moriñigo, Miguel A.
- Subjects
- *
CHEMOTAXIS , *VIBRIO , *MUCUS - Abstract
Presents a study to measure bacterial chemotaxis of pathogenic Vibrio strains towards mucus surfaces of gilt-head sea bream (Sparus aurata L.) Methodology used to conduct study; Indication of findings; Discussion on results.
- Published
- 1998
21. Lipid droplets and small extracellular vesicles: More than two independent entities.
- Author
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Genard GC, Tirinato L, Pagliari F, Da Silva J, Giammona A, Alquraish F, Reyes MP, Bordas M, Marafioti MG, Franco SD, Janssen J, Garcia-Calderón D, Hanley R, Nistico C, Fukasawa Y, Müller T, Krijgsveld J, Todaro M, Costanzo FS, Stassi G, Nessling M, Richter K, Maass KK, Liberale C, and Seco J
- Abstract
Despite increasing knowledge about small extracellular vesicle (sEV) composition and functions in cell-cell communication, the mechanism behind their biogenesis remains unclear. Here, we reveal for the first time that sEV biogenesis and release into the microenvironment are tightly connected with another important organelle, Lipid Droplets (LDs). The correlation was observed in several human cancer cell lines as well as patient-derived colorectal cancer stem cells (CR-CSCs). Our results demonstrated that external stimuli such as radiation, pH, hypoxia or lipid-interfering drugs, known to affect the number of LDs/cell, similarly influenced sEV secretion. Importantly, through multiple omics data, at both mRNA and protein levels, we revealed RAB5C as a potential important molecular player behind this organelle connection. Altogether, the potential to fine-tune sEV biogenesis by targeting LDs could significantly impact the amount, cargos and properties of these sEVs, opening new clinical perspectives., Competing Interests: All authors declare no conflict of interest., (© 2024 The Author(s). Journal of Extracellular Biology published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)
- Published
- 2024
- Full Text
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22. WLB-87848, a Selective σ 1 Receptor Agonist, with an Unusually Positioned NH Group as Positive Ionizable Moiety and Showing Neuroprotective Activity.
- Author
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Christmann U, Garriga L, Llorente AV, Díaz JL, Pascual R, Bordas M, Dordal A, Porras M, Yeste S, Reinoso RF, Vela JM, and Almansa C
- Subjects
- Animals, Rats, Humans, Male, Structure-Activity Relationship, Amyloid beta-Peptides metabolism, Neurons drug effects, Neurons metabolism, Pyrimidines pharmacology, Pyrimidines chemical synthesis, Pyrimidines chemistry, Memory Disorders drug therapy, Cell Survival drug effects, Pyrimidinones pharmacology, Pyrimidinones chemical synthesis, Pyrimidinones chemistry, Rats, Wistar, Hippocampus drug effects, Hippocampus metabolism, Receptors, sigma agonists, Receptors, sigma metabolism, Neuroprotective Agents pharmacology, Neuroprotective Agents chemical synthesis, Neuroprotective Agents chemistry, Sigma-1 Receptor
- Abstract
The synthesis and pharmacological activity of a new series of thieno[2,3- d ]pyrimidin-4(3 H )-one derivatives as sigma-1 receptor (σ
1 R) ligands are reported. A hit from a high-throughput screening program was evolved into a highly potent and selective σ1 R agonist ( 14qR ) that contains a free NH group as positive ionizable moiety, not fulfilling the usual pharmacophoric features of the σ1 R. The compound shows good physicochemical and ADMET characteristics, displays an agonist profile in the binding immunoglobulin protein/σ1 R association assay, induces neuron viability in an in vitro model of β-amyloid peptide intoxication, and presents positive results against recognition memory impairment induced by hippocampal injection of Aβ peptide in rats after oral treatment, altogether making 14qR (WLB-87848) an interesting candidate for neuroprotection.- Published
- 2024
- Full Text
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23. Discovery of WLB-89462, a New Drug-like and Highly Selective σ 2 Receptor Ligand with Neuroprotective Properties.
- Author
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Christmann U, Díaz JL, Pascual R, Bordas M, Álvarez I, Monroy X, Porras M, Yeste S, Reinoso RF, Merlos M, Vela JM, and Almansa C
- Subjects
- Animals, Rats, Ligands, Neuroprotection, Amyloid beta-Peptides, Neuroprotective Agents pharmacology, Neuroprotective Agents therapeutic use
- Abstract
The synthesis and pharmacological activity of a new series of isoxazolylpyrimidines as sigma-2 receptor (σ
2 R) ligands are reported. Modification of a new hit retrieved in an HTS campaign allowed the identification of the compound WLB-89462 ( 20c ) with good σ2 R affinity ( Ki = 13 nM) and high selectivity vs both the σ1 R ( Ki = 1777 nM) and a general panel of 180 targets. It represents one of the first σ2 R ligands with drug-like properties, linked to a good physicochemical and ADMET profile (good solubility, no CYP inhibition, good metabolic stability, high permeability, brain penetration, and high oral exposure in rodents). Compound 20c shows neuroprotective activity in vitro and improves short-term memory impairment induced by hippocampal injection of amyloid β peptide in rats. Together with the promising effects in the chronic models where 20c is currently being evaluated, these results pave the way toward its clinical development as a neuroprotective agent.- Published
- 2023
- Full Text
- View/download PDF
24. Red Light Mitigates the Deteriorating Placental Extracellular Matrix in Late Onset of Preeclampsia and Improves the Trophoblast Behavior.
- Author
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Griffin J, Krolikowski JG, Kounga K, Struve J, Keszler A, Lindemer B, Bordas M, Broeckel G, Lohr NL, and Weihrauch D
- Subjects
- Extracellular Matrix metabolism, Female, Humans, Placenta metabolism, Placenta Growth Factor, Placentation, Pregnancy, Pre-Eclampsia metabolism, Trophoblasts metabolism
- Abstract
Preeclampsia is a serious pregnancy disorder which in extreme cases may lead to maternal and fetal injury or death. Preexisting conditions which increase oxidative stress, e.g., hypertension and diabetes, increase the mother's risk to develop preeclampsia. Previously, we established that when the extracellular matrix is exposed to oxidative stress, trophoblast function is impaired, and this may lead to improper placentation. We investigated how the oxidative ECM present in preeclampsia alters the behavior of first trimester extravillous trophoblasts. We demonstrate elevated levels of advanced glycation end products (AGE) and lipid oxidation end product 4-hydroxynonenal in preeclamptic ECM (28%, and 32% increase vs control, respectively) accompanied with 35% and 82% more 3-chlorotyrosine and 3-nitrotyrosine vs control, respectively. Furthermore, we hypothesized that 670 nm phototherapy, which has antioxidant properties, reverses the observed trophoblast dysfunction as depicted in the improved migration and reduction in apoptosis. Since NO is critical for placentation, we examined eNOS activity in preeclamptic placentas compared to healthy ones and found no differences; however, 670 nm light treatment triggered enhanced NO availability presumably by using alternative NO sources. Light exposure decreased apoptosis and restored trophoblast migration to levels in trophoblasts cultured on preeclamptic ECM. Moreover, 670 nm irradiation restored expression of Transforming Growth Factor (TGF β ) and Placental Growth Factor (PLGF) to levels observed in trophoblasts cultured on healthy placental ECM. We conclude the application of 670 nm light can successfully mitigate the damaged placental microenvironment of late onset preeclampsia as depicted by the restored trophoblast behavior., Competing Interests: None of the authors have a conflict of interest., (Copyright © 2022 Jakara Griffin et al.)
- Published
- 2022
- Full Text
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25. An autologous culture model of nodal B-cell lymphoma identifies ex vivo determinants of response to bispecific antibodies.
- Author
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Roider T, Brinkmann BJ, Kim V, Knoll M, Kolb C, Roessner PM, Bordas M, Dreger P, Müller-Tidow C, Huber W, Seiffert M, and Dietrich S
- Subjects
- Antigens, CD19, Humans, Tumor Microenvironment, Antibodies, Bispecific pharmacology, Lymphoma, B-Cell
- Abstract
Bispecific antibodies (BsAbs) can induce long-term responses in patients with refractory and relapsed B-cell lymphoma. Nevertheless, response rates across patients are heterogeneous, and the factors determining quality and duration of responses are poorly understood. To identify key determinants of response to BsAbs, we established a primary, autologous culture model allowing us to mimic treatment with CD3xCD19 and CD3xCD20 BsAbs within the lymph node microenvironment ex vivo. T cell-mediated killing of lymphoma cells and proliferation of T cells varied significantly among patients but highly correlated between BsAbs targeting CD20 or CD19. Ex vivo response to BsAbs was significantly associated with expansion of T cells and secretion of effector molecules (eg, granzyme B, perforin) but not with expression of T-cell exhaustion (eg, PD1, TIM3) or activation markers (eg, CD25, CD69) or formation of intercellular contacts. In addition, we identified a distinct phenotype of regulatory T cells that was linked to ex vivo response independently from T-cell frequency at baseline. High expression levels of Aiolos (IKZF1), ICOS, and CXCR5 were positively associated with ex vivo response, whereas strong expression of Helios (IKZF2) had an unfavorable impact on ex vivo response to BsAbs. We further showed that lenalidomide, nivolumab, and atezolizumab improved ex vivo response to BsAbs by potentiating T-cell effector functions. In summary, our ex vivo study identified a distinct regulatory T-cell phenotype as a potential contributor to treatment failure of BsAbs and suggests drug combinations of high clinical relevance that could improve the efficacy of BsAbs., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
26. EOMES is essential for antitumor activity of CD8 + T cells in chronic lymphocytic leukemia.
- Author
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Llaó-Cid L, Roessner PM, Chapaprieta V, Öztürk S, Roider T, Bordas M, Izcue A, Colomer D, Dietrich S, Stilgenbauer S, Hanna B, Martín-Subero JI, and Seiffert M
- Subjects
- Animals, Case-Control Studies, Female, Genome-Wide Association Study, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, T-Box Domain Proteins genetics, CD8-Positive T-Lymphocytes immunology, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Lymph Nodes immunology, T-Box Domain Proteins metabolism, T-Box Domain Proteins physiology
- Abstract
Genome-wide association studies identified a single-nucleotide polymorphism (SNP) affecting the transcription factor Eomesodermin (EOMES) associated with a significantly increased risk to develop chronic lymphocytic leukemia (CLL). Epigenetic analyses, RNA sequencing, and flow cytometry revealed that EOMES is not expressed in CLL cells, but in CD8
+ T cells for which EOMES is a known master regulator. We thus hypothesized that the increased CLL risk associated with the EOMES SNP might be explained by its negative impact on CD8+ T-cell-mediated immune control of CLL. Flow cytometry analyses revealed a higher EOMES expression in CD8+ T cells of CLL patients compared to healthy individuals, and an accumulation of PD-1+ EOMES+ CD8+ T cells in lymph nodes rather than blood or bone marrow in CLL. This was in line with an observed expansion of EOMES+ CD8+ T cells in the spleen of leukemic Eµ-TCL1 mice. As EOMES expression was highest in CD8+ T cells that express inhibitory receptors, an involvement of EOMES in T-cell exhaustion and dysfunction seems likely. Interestingly, Eomes-deficiency in CD8+ T cells resulted in their impaired expansion associated with decreased CLL control in mice. Overall, these observations suggest that EOMES is essential for CD8+ T-cell expansion and/or maintenance, and therefore involved in adaptive immune control of CLL., (© 2021. The Author(s).)- Published
- 2021
- Full Text
- View/download PDF
27. EOMES and IL-10 regulate antitumor activity of T regulatory type 1 CD4 + T cells in chronic lymphocytic leukemia.
- Author
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Roessner PM, Llaó Cid L, Lupar E, Roider T, Bordas M, Schifflers C, Arseni L, Gaupel AC, Kilpert F, Krötschel M, Arnold SJ, Sellner L, Colomer D, Stilgenbauer S, Dietrich S, Lichter P, Izcue A, and Seiffert M
- Subjects
- Animals, Cell Differentiation, Female, Gene Expression Regulation, Leukemic, Humans, Interferon-gamma, Interleukin-10 genetics, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Mice, Mice, Inbred C57BL, Prognosis, Signal Transduction, T-Box Domain Proteins genetics, Transcriptome, Tumor Cells, Cultured, CD4-Positive T-Lymphocytes immunology, Interleukin-10 metabolism, Leukemia, Lymphocytic, Chronic, B-Cell prevention & control, T-Box Domain Proteins metabolism, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Regulatory immunology, Th1 Cells immunology
- Abstract
The transcription factor eomesodermin (EOMES) promotes interleukin (IL)-10 expression in CD4
+ T cells, which has been linked to immunosuppressive and cytotoxic activities. We detected cytotoxic, programmed cell death protein-1 (PD-1) and EOMES co-expressing CD4+ T cells in lymph nodes (LNs) of patients with chronic lymphocytic leukemia (CLL) or diffuse large B-cell lymphoma. Transcriptome and flow cytometry analyses revealed that EOMES does not only drive IL-10 expression, but rather controls a unique transcriptional signature in CD4+ T cells, that is enriched in genes typical for T regulatory type 1 (TR 1) cells. The TR 1 cell identity of these CD4+ T cells was supported by their expression of interferon gamma and IL-10, as well as inhibitory receptors including PD-1. TR 1 cells with cytotoxic capacity accumulate also in Eµ-TCL1 mice that develop CLL-like disease. Whereas wild-type CD4+ T cells control TCL1 leukemia development after adoptive transfer in leukopenic Rag2-/ - mice, EOMES-deficient CD4+ T cells failed to do so. We further show that TR 1 cell-mediated control of TCL1 leukemia requires IL-10 receptor (IL-10R) signaling, as Il10rb-deficient CD4+ T cells showed impaired antileukemia activity. Altogether, our data demonstrate that EOMES is indispensable for the development of IL-10-expressing, cytotoxic TR 1 cells, which accumulate in LNs of CLL patients and control TCL1 leukemia in mice in an IL-10R-dependent manner., (© 2021. The Author(s).)- Published
- 2021
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28. Propionamide Derivatives as Dual μ-Opioid Receptor Agonists and σ 1 Receptor Antagonists for the Treatment of Pain.
- Author
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García M, Llorente V, Garriga L, Christmann U, Rodríguez-Escrich S, Virgili M, Fernández B, Bordas M, Ayet E, Burgueño J, Pujol M, Dordal A, Portillo-Salido E, Gris G, Vela JM, and Almansa C
- Subjects
- Amides chemical synthesis, Amides chemistry, Analgesics, Opioid chemical synthesis, Analgesics, Opioid chemistry, Animals, Dose-Response Relationship, Drug, Humans, Mice, Molecular Structure, Narcotic Antagonists chemical synthesis, Narcotic Antagonists chemistry, Structure-Activity Relationship, Sigma-1 Receptor, Amides pharmacology, Analgesics, Opioid pharmacology, Narcotic Antagonists pharmacology, Pain drug therapy, Receptors, Opioid, mu agonists, Receptors, sigma antagonists & inhibitors
- Abstract
A new series of propionamide derivatives was developed as dual μ-opioid receptor agonists and σ
1 receptor antagonists. Modification of a high-throughput screening hit originated a series of piperazinylcycloalkylmethyl propionamides, which were explored to overcome the challenge of achieving balanced dual activity and convenient drug-like properties. The lead compound identified, 18g , showed good analgesic effects in several animal models of both acute (paw pressure) and chronic (partial sciatic nerve ligation) pain, with reduced gastrointestinal effects in comparison with oxycodone.- Published
- 2021
- Full Text
- View/download PDF
29. Discovery of EST73502, a Dual μ-Opioid Receptor Agonist and σ 1 Receptor Antagonist Clinical Candidate for the Treatment of Pain.
- Author
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García M, Virgili M, Alonso M, Alegret C, Farran J, Fernández B, Bordas M, Pascual R, Burgueño J, Vidal-Torres A, Fernández de Henestrosa AR, Ayet E, Merlos M, Vela JM, Plata-Salamán CR, and Almansa C
- Subjects
- Administration, Oral, Analgesics, Opioid metabolism, Analgesics, Opioid pharmacology, Analgesics, Opioid therapeutic use, Animals, Binding Sites, Blood-Brain Barrier drug effects, Blood-Brain Barrier metabolism, Dose-Response Relationship, Drug, Drug Design, Drug Evaluation, Preclinical, Half-Life, Ligands, Male, Mice, Molecular Dynamics Simulation, Pain drug therapy, Receptors, Opioid, mu metabolism, Receptors, sigma metabolism, Spiro Compounds chemistry, Spiro Compounds metabolism, Spiro Compounds pharmacology, Spiro Compounds therapeutic use, Structure-Activity Relationship, Sigma-1 Receptor, Analgesics, Opioid chemistry, Receptors, Opioid, mu agonists, Receptors, sigma antagonists & inhibitors
- Abstract
The synthesis and pharmacological activity of a new series of 4-alkyl-1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the σ
1 receptor (σ1 R) and the μ-opioid receptor (MOR) are reported. A lead optimization program over the initial 4-aryl analogues provided 4-alkyl derivatives with the desired functionality and good selectivity and ADME profiles. Compound 14u (EST73502) showed MOR agonism and σ1 R antagonism and a potent analgesic activity, comparable to the MOR agonist oxycodone in animal models of acute and chronic pain after single and repeated administration. Contrary to oxycodone, 14u produces analgesic activity with reduced opioid-induced relevant adverse events, like intestinal transit inhibition and naloxone-precipitated behavioral signs of opiate withdrawal. These results provide evidence that dual MOR agonism and σ1 R antagonism may be a useful strategy for obtaining potent and safer analgesics and were the basis for the selection of 14u as a clinical candidate for the treatment of pain.- Published
- 2020
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30. Optimized Protocol for Isolation of Small Extracellular Vesicles from Human and Murine Lymphoid Tissues.
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Bordas M, Genard G, Ohl S, Nessling M, Richter K, Roider T, Dietrich S, Maaß KK, and Seiffert M
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- Animals, Exosomes genetics, Humans, Lipids chemistry, Mice, Ultracentrifugation, Cell Separation methods, Exosomes chemistry, Extracellular Vesicles chemistry, Lymphoid Tissue chemistry
- Abstract
Small extracellular vesicles (sEVs) are nanoparticles responsible for cell-to-cell communication released by healthy and cancer cells. Different roles have been described for sEVs in physiological and pathological contexts, including acceleration of tissue regeneration, modulation of tumor microenvironment, or premetastatic niche formation, and they are discussed as promising biomarkers for diagnosis and prognosis in body fluids. Although efforts have been made to standardize techniques for isolation and characterization of sEVs, current protocols often result in co-isolation of soluble protein or lipid complexes and of other extracellular vesicles. The risk of contaminated preparations is particularly high when isolating sEVs from tissues. As a consequence, the interpretation of data aiming at understanding the functional role of sEVs remains challenging and inconsistent. Here, we report an optimized protocol for isolation of sEVs from human and murine lymphoid tissues. sEVs from freshly resected human lymph nodes and murine spleens were isolated comparing two different approaches-(1) ultracentrifugation on a sucrose density cushion and (2) combined ultracentrifugation with size-exclusion chromatography. The purity of sEV preparations was analyzed using state-of-the-art techniques, including immunoblots, nanoparticle tracking analysis, and electron microscopy. Our results clearly demonstrate the superiority of size-exclusion chromatography, which resulted in a higher yield and purity of sEVs, and we show that their functionality alters significantly between the two isolation protocols.
- Published
- 2020
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31. Dissecting intratumour heterogeneity of nodal B-cell lymphomas at the transcriptional, genetic and drug-response levels.
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Roider T, Seufert J, Uvarovskii A, Frauhammer F, Bordas M, Abedpour N, Stolarczyk M, Mallm JP, Herbst SA, Bruch PM, Balke-Want H, Hundemer M, Rippe K, Goeppert B, Seiffert M, Brors B, Mechtersheimer G, Zenz T, Peifer M, Chapuy B, Schlesner M, Müller-Tidow C, Fröhling S, Huber W, Anders S, and Dietrich S
- Subjects
- Female, Gene Expression Profiling, Humans, Lymphoma, B-Cell drug therapy, Lymphoma, B-Cell genetics, Lymphoma, B-Cell immunology, Male, Middle Aged, Sequence Analysis, RNA, Single-Cell Analysis, T-Lymphocytes drug effects, T-Lymphocytes metabolism, Antineoplastic Agents pharmacology, Biomarkers, Tumor genetics, Gene Expression Regulation, Neoplastic, Lymphoma, B-Cell pathology, T-Lymphocytes immunology, Transcriptome drug effects, Tumor Microenvironment immunology
- Abstract
Tumour heterogeneity encompasses both the malignant cells and their microenvironment. While heterogeneity between individual patients is known to affect the efficacy of cancer therapy, most personalized treatment approaches do not account for intratumour heterogeneity. We addressed this issue by studying the heterogeneity of nodal B-cell lymphomas by single-cell RNA-sequencing and transcriptome-informed flow cytometry. We identified transcriptionally distinct malignant subpopulations and compared their drug-response and genomic profiles. Malignant subpopulations from the same patient responded strikingly differently to anti-cancer drugs ex vivo, which recapitulated subpopulation-specific drug sensitivity during in vivo treatment. Infiltrating T cells represented the majority of non-malignant cells, whose gene-expression signatures were similar across all donors, whereas the frequencies of T-cell subsets varied significantly between the donors. Our data provide insights into the heterogeneity of nodal B-cell lymphomas and highlight the relevance of intratumour heterogeneity for personalized cancer therapy.
- Published
- 2020
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32. Cardiomyocyte-Specific Snrk Prevents Inflammation in the Heart.
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Thirugnanam K, Cossette SM, Lu Q, Chowdhury SR, Harmann LM, Gupta A, Spearman AD, Sonin DL, Bordas M, Kumar SN, Pan AY, Simpson PM, Strande JL, Bishop E, Zou MH, and Ramchandran R
- Subjects
- Angiotensin II pharmacology, Animals, Cell Line, Fibrosis genetics, Fibrosis metabolism, Fibrosis pathology, Heart drug effects, Heart Failure metabolism, Heart Failure pathology, In Vitro Techniques, Inflammation metabolism, Inflammation pathology, Macrophages metabolism, Macrophages pathology, Mice, Mice, Knockout, Myocardium pathology, Vasoconstrictor Agents pharmacology, Ventricular Dysfunction, Left, Endothelial Cells metabolism, Heart Failure genetics, Inflammation genetics, Myocardium metabolism, Myocytes, Cardiac metabolism, NF-kappa B metabolism, Protein Serine-Threonine Kinases genetics
- Abstract
Background The SNRK (sucrose-nonfermenting-related kinase) enzyme is critical for cardiac function. However, the underlying cause for heart failure observed in Snrk cardiac conditional knockout mouse is unknown. Methods and Results Previously, 6-month adult mice knocked out for Snrk in cardiomyocytes (CMs) displayed left ventricular dysfunction. Here, 4-month adult mice, on angiotensin II (Ang II) infusion, show rapid decline in cardiac systolic function, which leads to heart failure and death in 2 weeks. These mice showed increased expression of nuclear factor κ light chain enhancer of activated B cells (NF-κB), inflammatory signaling proteins, proinflammatory proteins in the heart, and fibrosis. Interestingly, under Ang II infusion, mice knocked out for Snrk in endothelial cells did not show significant systolic or diastolic dysfunction. Although an NF-κB inflammation signaling pathway was increased in Snrk knockout endothelial cells, this did not lead to fibrosis or mortality. In hearts of adult mice knocked out for Snrk in CMs, we also observed NF-κB pathway activation in CMs, and an increased presence of Mac2
+ macrophages was observed in basal and Ang II-infused states. In vitro analysis of Snrk knockdown HL-1 CMs revealed similar upregulation of the NF-κB signaling proteins and proinflammatory proteins that was exacerbated on Ang II treatment. The Ang II-induced NF-κB pathway-mediated proinflammatory effects were mediated in part through protein kinase B or AKT, wherein AKT inhibition restored the proinflammatory signaling protein levels to baseline in Snrk knockdown HL-1 CMs. Conclusions During heart failure, SNRK acts as a cardiomyocyte-specific repressor of cardiac inflammation and fibrosis.- Published
- 2019
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33. Downregulation of TREM-like transcript-1 and collagen receptor α2 subunit, two novel RUNX1-targets, contributes to platelet dysfunction in familial platelet disorder with predisposition to acute myelogenous leukemia.
- Author
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Glembotsky AC, Sliwa D, Bluteau D, Balayn N, Marin Oyarzún CP, Raimbault A, Bordas M, Droin N, Pirozhkova I, Washington V, Goette NP, Marta RF, Favier R, Raslova H, and Heller PG
- Subjects
- Blood Platelet Disorders blood, Blood Platelets metabolism, Disease Susceptibility, Gene Expression Profiling, Humans, Leukemia, Myeloid, Acute diagnosis, Megakaryocytes metabolism, Mutation, Platelet Aggregation, Platelet Function Tests, Protein Binding, Blood Platelet Disorders genetics, Blood Platelet Disorders metabolism, Core Binding Factor Alpha 2 Subunit metabolism, Gene Expression Regulation, Integrin alpha2 genetics, Leukemia, Myeloid, Acute etiology, Receptors, Immunologic genetics
- Abstract
Germline RUNX1 mutations lead to thrombocytopenia and platelet dysfunction in familial platelet disorder with predisposition to acute myelogenous leukemia (AML). Multiple aspects of platelet function are impaired in these patients, associated with altered expression of genes regulated by RUNX1 We aimed to identify RUNX1 -targets involved in platelet function by combining transcriptome analysis of patient and sh RUNX1 -transduced megakaryocytes (MK). Down-regulated genes included TREM-like transcript (TLT)-1 (TREML1) and the integrin subunit alpha (α)-2 (ITGA2) of collagen receptor α2-beta (β)-1, which are involved in platelet aggregation and adhesion, respectively. RUNX1 binding to regions enriched for H3K27Ac marks was demonstrated for both genes using chromatin immunoprecipitation. Cloning of these regions upstream of the respective promoters in lentivirus allowing mCherry reporter expression showed that RUNX1 positively regulates TREML1 and ITGA2 , and this regulation was abrogated after deletion of RUNX1 sites. TLT-1 content was reduced in patient MK and platelets. A blocking anti-TLT-1 antibody was able to block aggregation of normal but not patient platelets, whereas recombinant soluble TLT-1 potentiated fibrinogen binding to patient platelets, pointing to a role for TLT-1 deficiency in the platelet function defect. Low levels of α2 integrin subunit were demonstrated in patient platelets and MK, coupled with reduced platelet and MK adhesion to collagen, both under static and flow conditions. In conclusion, we show that gene expression profiling of RUNX1 knock-down or mutated MK provides a suitable approach to identify novel RUNX1 targets, among which downregulation of TREML1 and ITGA2 clearly contribute to the platelet phenotype of familial platelet disorder with predisposition to AML., (Copyright© 2019 Ferrata Storti Foundation.)
- Published
- 2019
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34. Critical comparison of shake-flask, potentiometric and chromatographic methods for lipophilicity evaluation (log P o/w ) of neutral, acidic, basic, amphoteric, and zwitterionic drugs.
- Author
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Port A, Bordas M, Enrech R, Pascual R, Rosés M, Ràfols C, Subirats X, and Bosch E
- Subjects
- Chromatography, High Pressure Liquid, Hydrogen-Ion Concentration, Potentiometry, 1-Octanol chemistry, Pharmaceutical Preparations chemistry, Water chemistry
- Abstract
In the present study three different procedures have been compared for the determination of the lipophilicity of the unionized species (log P
o/w ) of neutral, acidic, basic, amphoteric, and zwitterionic drugs. Shake-flask, potentiometric and chromatographic approaches have been assayed in a set of 66 representative compounds in different phases of advanced development. An excellent equivalence has been found between log Po/w values obtained by shake-flask and potentiometry, while the chromatographic approach is less accurate but very convenient for screening purposes when a high-throughput is required. In the case of zwitterionic and amphoteric compounds, either for shake-flask and chromatographic methods, the pH has to be accurately selected in order to ensure the compound to be in its neutral form., (Copyright © 2018 Elsevier B.V. All rights reserved.)- Published
- 2018
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35. Non-arteritic anterior ischemic optic neuropathy - Case report.
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Bordas M, Tabacaru B, and Stanca TH
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- Humans, Male, Middle Aged, Visual Acuity, Visual Fields, Optic Disk, Optic Neuropathy, Ischemic diagnosis, Optic Neuropathy, Ischemic therapy
- Abstract
We present a case of Non-Arteritic Anterior Ischemic Optic Neuropathy (NA-AION) with uncertain etiology but a good recovery with a total gain of central visual acuity.
- Published
- 2018
36. Nfix Promotes Survival of Immature Hematopoietic Cells via Regulation of c-Mpl.
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Hall T, Walker M, Ganuza M, Holmfeldt P, Bordas M, Kang G, Bi W, Palmer LE, Finkelstein D, and McKinney-Freeman S
- Subjects
- Animals, Humans, Mice, Signal Transduction, Hematopoietic Stem Cells metabolism, NFI Transcription Factors metabolism, Receptors, Thrombopoietin metabolism
- Abstract
Hematopoietic stem and progenitor cells (HSPCs) are necessary for life-long blood production and replenishment of the hematopoietic system during stress. We recently reported that nuclear factor I/X (Nfix) promotes HSPC survival post-transplant. Here, we report that ectopic expression of Nfix in primary mouse HSPCs extends their ex vivo culture from about 20 to 40 days. HSPCs overexpressing Nfix display hypersensitivity to supportive cytokines and reduced apoptosis when subjected to cytokine deprivation relative to controls. Ectopic Nfix resulted in elevated levels of c-Mpl transcripts and cell surface protein on primary murine HSPCs as well as increased phosphorylation of STAT5, which is known to be activated down-stream of c-MPL. Blocking c-MPL signaling by removal of thrombopoietin or addition of a c-MPL neutralizing antibody negated the antiapoptotic effect of Nfix overexpression on cultured HSPCs. Furthermore, NFIX was capable of binding to and transcriptionally activating a proximal c-Mpl promoter fragment. In sum, these data suggest that NFIX-mediated upregulation of c-Mpl transcription can protect primitive hematopoietic cells from stress ex vivo. Stem Cells 2018;36:943-950., (© AlphaMed Press 2018.)
- Published
- 2018
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37. SNRK (Sucrose Nonfermenting 1-Related Kinase) Promotes Angiogenesis In Vivo.
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Lu Q, Xie Z, Yan C, Ding Y, Ma Z, Wu S, Qiu Y, Cossette SM, Bordas M, Ramchandran R, and Zou MH
- Subjects
- Animals, Antigens, CD genetics, Antigens, CD metabolism, Apoptosis, Blood Flow Velocity, Cadherins genetics, Cadherins metabolism, Cell Movement, Cell Proliferation, Cells, Cultured, Disease Models, Animal, Endothelial Cells pathology, Gene Expression Regulation, Enzymologic, Hindlimb, Human Umbilical Vein Endothelial Cells enzymology, Humans, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Integrin beta1 genetics, Integrin beta1 metabolism, Ischemia genetics, Ischemia physiopathology, Mice, Inbred C57BL, Mice, Knockout, Promoter Regions, Genetic, Protein Serine-Threonine Kinases deficiency, Protein Serine-Threonine Kinases genetics, Regional Blood Flow, Sp1 Transcription Factor genetics, Sp1 Transcription Factor metabolism, Endothelial Cells enzymology, Ischemia enzymology, Lung blood supply, Muscle, Skeletal blood supply, Neovascularization, Physiologic, Protein Serine-Threonine Kinases metabolism, Retinal Vessels enzymology
- Abstract
Objective: SNRK (sucrose nonfermenting 1-related kinase) is a novel member of the AMPK (adenosine monophosphate-activated protein kinase)-related superfamily that is activated in the process of angiogenesis. Currently, little is known about the function of SNRK in angiogenesis in the physiological and pathological conditions., Approach and Results: In this study, in Snrk global heterozygous knockout mice, retina angiogenesis and neovessel formation after hindlimb ischemia were suppressed. Consistently, mice with endothelial cell (EC)-specific Snrk deletion exhibited impaired retina angiogenesis, and delayed perfusion recovery and exacerbated muscle apoptosis in ischemic hindlimbs, compared with those of littermate wide-type mice. Endothelial SNRK expression was increased in the extremity vessel samples from nonischemic human. In ECs cultured in hypoxic conditions, HIF1α (hypoxia inducible factor 1α) bound to the SNRK promoter to upregulate SNRK expression. In the nuclei of hypoxic ECs, SNRK complexed with SP1 (specificity protein 1), and together, they bound to an SP1-binding motif in the ITGB1 (β1 integrin) promoter, resulting in enhanced ITGB1 expression and promoted EC migration. Furthermore, SNRK or SP1 deficiency in ECs ameliorated hypoxia-induced ITGB1 expression and, consequently, inhibited EC migration and angiogenesis., Conclusions: Taken together, our data have revealed that SNRK/SP1-ITGB1 signaling axis promotes angiogenesis in vivo., (© 2017 American Heart Association, Inc.)
- Published
- 2018
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38. Pyrazolo[3,4- d ]pyrimidines as sigma-1 receptor ligands for the treatment of pain. Part 2: Introduction of cyclic substituents in position 4.
- Author
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Díaz JL, Corbera J, Martínez D, Bordas M, Sicre C, Pascual R, Pretel MJ, Marín AP, Montero A, Dordal A, Alvarez I, and Almansa C
- Abstract
The replacement of acylamino by cyclic substituents in the position 4 of the pyrazolo[3,4- d ]pyrimidine scaffold, led to highly active sigma-1 receptor (σ
1 R) ligands. Phenyl or pyrazolyl groups were the best in terms of affinity for the σ1 R and the 4-(1-methylpyrazol-5-yl) derivative, 12f , was the most selective. Compound 12f is also one of the best σ1 R ligands ever described in terms of lipophilic ligand efficiency, which translates into a good physicochemical and ADMET profile. In addition, 12f was identified as an antagonist of the σ1 R in view of its potent antinociceptive profile in several pain models in mice.- Published
- 2017
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39. Dual Specificity Phosphatase 5 Is Essential for T Cell Survival.
- Author
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Kutty RG, Xin G, Schauder DM, Cossette SM, Bordas M, Cui W, and Ramchandran R
- Subjects
- Animals, Blotting, Western, CD8-Positive T-Lymphocytes enzymology, CD8-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes virology, Cell Survival genetics, Cells, Cultured, Dual-Specificity Phosphatases metabolism, Gene Expression Regulation, Enzymologic, Interferon-gamma metabolism, Lymphocytic choriomeningitis virus physiology, Mice, Inbred C57BL, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes enzymology, T-Lymphocytes virology, Tumor Necrosis Factor-alpha metabolism, Apoptosis genetics, Cell Proliferation genetics, Dual-Specificity Phosphatases genetics, T-Lymphocytes metabolism
- Abstract
The mitogen-activated protein kinase (MAPK) pathway regulates many key cellular processes such as differentiation, apoptosis, and survival. The final proteins in this pathway, ERK1/2, are regulated by dual specificity phosphatase 5 (DUSP5). DUSP5 is a nuclear, inducible phosphatase with high affinity and fidelity for ERK1/2. By regulating the final step in the MAPK signaling cascade, DUSP5 exerts strong regulatory control over a central cellular pathway. Like other DUSPs, DUSP5 plays an important role in immune function. In this study, we have utilized new knockout mouse reagents to explore its function further. We demonstrate that global loss of DUSP5 does not result in any gross phenotypic changes. However, loss of DUSP5 affects memory/effector CD8+ T cell populations in response to acute viral infection. Specifically, Dusp5-/- mice have decreased proportions of short-lived effector cells (SLECs) and increased proportions of memory precursor effector cells (MPECs) in response to infection. Further, we show that this phenotype is T cell intrinsic; a bone marrow chimera model restricting loss of DUSP5 to the CD8+ T cell compartment displays a similar phenotype. Dusp5-/- T cells also display increased proliferation, increased apoptosis, and altered metabolic profiles, suggesting that DUSP5 is a pro-survival protein in T cells., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2016
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40. Sucrose Nonfermenting-Related Kinase Enzyme-Mediated Rho-Associated Kinase Signaling is Responsible for Cardiac Function.
- Author
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Cossette SM, Bhute VJ, Bao X, Harmann LM, Horswill MA, Sinha I, Gastonguay A, Pooya S, Bordas M, Kumar SN, Mirza SP, Palecek SP, Strande JL, and Ramchandran R
- Subjects
- Animals, Cells, Cultured, Echocardiography, Embryonic Stem Cells drug effects, Embryonic Stem Cells pathology, Fibrosis, Genetic Predisposition to Disease, Heart Failure genetics, Heart Failure pathology, Heart Failure physiopathology, Homozygote, Human Umbilical Vein Endothelial Cells enzymology, Lipid Metabolism, Magnetic Resonance Spectroscopy, Metabolomics methods, Mice, Knockout, Myocytes, Cardiac drug effects, Myocytes, Cardiac pathology, Oxidative Phosphorylation, Phenotype, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases deficiency, Protein Serine-Threonine Kinases genetics, RNA Interference, Signal Transduction, Transfection, rho-Associated Kinases antagonists & inhibitors, Embryonic Stem Cells enzymology, Energy Metabolism drug effects, Heart Failure enzymology, Myocytes, Cardiac enzymology, Protein Serine-Threonine Kinases metabolism, rho-Associated Kinases metabolism
- Abstract
Background: Cardiac metabolism is critical for the functioning of the heart, and disturbance in this homeostasis is likely to influence cardiac disorders or cardiomyopathy. Our laboratory has previously shown that SNRK (sucrose nonfermenting related kinase) enzyme, which belongs to the AMPK (adenosine monophosphate-activated kinase) family, was essential for cardiac metabolism in mammals. Snrk global homozygous knockout (KO) mice die at postnatal day 0, and conditional deletion of Snrk in cardiomyocytes (Snrk cmcKO) leads to cardiac failure and death by 8 to 10 months., Methods and Results: We performed additional cardiac functional studies using echocardiography and identified further cardiac functional deficits in Snrk cmcKO mice. Nuclear magnetic resonance-based metabolomics analysis identified key metabolic pathway deficits in SNRK knockdown cardiomyocytes in vitro. Specifically, metabolites involved in lipid metabolism and oxidative phosphorylation are altered, and perturbations in these pathways can result in cardiac function deficits and heart failure. A phosphopeptide-based proteomic screen identified ROCK (Rho-associated kinase) as a putative substrate for SNRK, and mass spec-based fragment analysis confirmed key amino acid residues on ROCK that are phosphorylated by SNRK. Western blot analysis on heart lysates from Snrk cmcKO adult mice and SNRK knockdown cardiomyocytes showed increased ROCK activity. In addition, in vivo inhibition of ROCK partially rescued the in vivo Snrk cmcKO cardiac function deficits., Conclusions: Collectively, our data suggest that SNRK in cardiomyocytes is responsible for maintaining cardiac metabolic homeostasis, which is mediated in part by ROCK, and alteration of this homeostasis influences cardiac function in the adult heart., (© 2016 American Heart Association, Inc.)
- Published
- 2016
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41. Nogo-B receptor deficiency causes cerebral vasculature defects during embryonic development in mice.
- Author
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Rana U, Liu Z, Kumar SN, Zhao B, Hu W, Bordas M, Cossette S, Szabo S, Foeckler J, Weiler H, Chrzanowska-Wodnicka M, Holtz ML, Misra RP, Salato V, North PE, Ramchandran R, and Miao QR
- Subjects
- Animals, Female, Mice, Mice, Knockout, Pregnancy, Blood Vessels embryology, Cerebrovascular Circulation, Receptors, Cell Surface genetics
- Abstract
Nogo-B receptor (NgBR) was identified as a receptor specific for Nogo-B. Our previous work has shown that Nogo-B and its receptor (NgBR) are essential for chemotaxis and morphogenesis of endothelial cells in vitro and intersomitic vessel formation via Akt pathway in zebrafish. Here, we further demonstrated the roles of NgBR in regulating vasculature development in mouse embryo and primitive blood vessel formation in embryoid body culture systems, respectively. Our results showed that NgBR homozygous knockout mice are embryonically lethal at E7.5 or earlier, and Tie2Cre-mediated endothelial cell-specific NgBR knockout (NgBR ecKO) mice die at E11.5 and have severe blood vessel assembly defects in embryo. In addition, mutant embryos exhibit dilation of cerebral blood vessel, resulting in thin-walled endothelial caverns. The similar vascular defects also were detected in Cdh5(PAC)-CreERT2 NgBR inducible ecKO mice. Murine NgBR gene-targeting embryonic stem cells (ESC) were generated by homologous recombination approaches. Homozygous knockout of NgBR in ESC results in cell apoptosis. Heterozygous knockout of NgBR does not affect ESC cell survival, but reduces the formation and branching of primitive blood vessels in embryoid body culture systems. Mechanistically, NgBR knockdown not only decreases both Nogo-B and VEGF-stimulated endothelial cell migration by abolishing Akt phosphorylation, but also decreases the expression of CCM1 and CCM2 proteins. Furthermore, we performed immunofluorescence (IF) staining of NgBR in human cerebral cavernous malformation patient tissue sections. The quantitative analysis results showed that NgBR expression levels in CD31 positive endothelial cells is significantly decreased in patient tissue sections. These results suggest that NgBR may be one of important genes coordinating the cerebral vasculature development., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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42. Endothelial Cell Surface Expressed Chemotaxis and Apoptosis Regulator (ECSCR) Regulates Lipolysis in White Adipocytes via the PTEN/AKT Signaling Pathway.
- Author
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Kilari S, Cossette S, Pooya S, Bordas M, Huang YW, Ramchandran R, and Wilkinson GA
- Subjects
- 3T3-L1 Cells, Adipocytes, White cytology, Animals, Apoptosis Regulatory Proteins genetics, Membrane Proteins, Mice, Mice, Knockout, PTEN Phosphohydrolase genetics, Proto-Oncogene Proteins c-akt genetics, Triglycerides genetics, Triglycerides metabolism, Adipocytes, White metabolism, Apoptosis Regulatory Proteins metabolism, Lipolysis physiology, PTEN Phosphohydrolase metabolism, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction physiology
- Abstract
Elevated plasma triglycerides are associated with increased susceptibility to heart disease and stroke, but the mechanisms behind this relationship are unclear. A clearer understanding of gene products which influence plasma triglycerides might help identify new therapeutic targets for these diseases. The Endothelial Cell Surface expressed Chemotaxis and apoptosis Regulator (ECSCR) was initially studied as an endothelial cell marker, but has recently been identified in white adipocytes, the primary storage cell type for triglycerides. Here we confirm ECSCR expression in white adipocytes and show that Ecscr knockout mice show elevated fasting plasma triglycerides. At a cellular level, cultured 3T3-L1 adipocytes silenced for Ecscr show a blunted Akt phosphorylation response. Additionally we show that the phosphatase and tensin homology containing (PTEN) lipid phosphatase association with ECSCR is increased by insulin stimulation. These data suggest a scenario by which ECSCR contributes to control of white adipocyte lipolysis. In this scenario, white adipocytes lacking Ecscr display elevated PTEN activity, thereby reducing AKT activation and impairing insulin-mediated suppression of lipolysis. Collectively, these results suggest that ECSCR plays a critical function in regulating lipolysis in white adipose tissue.
- Published
- 2015
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43. Sucrose non-fermenting related kinase enzyme is essential for cardiac metabolism.
- Author
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Cossette SM, Gastonguay AJ, Bao X, Lerch-Gaggl A, Zhong L, Harmann LM, Koceja C, Miao RQ, Vakeel P, Chun C, Li K, Foeckler J, Bordas M, Weiler H, Strande J, Palecek SP, and Ramchandran R
- Abstract
In this study, we have identified a novel member of the AMPK family, namely Sucrose non-fermenting related kinase (Snrk), that is responsible for maintaining cardiac metabolism in mammals. SNRK is expressed in the heart, and brain, and in cell types such as endothelial cells, smooth muscle cells and cardiomyocytes (CMs). Snrk knockout (KO) mice display enlarged hearts, and die at postnatal day 0. Microarray analysis of embryonic day 17.5 Snrk hearts, and blood profile of neonates display defect in lipid metabolic pathways. SNRK knockdown CMs showed altered phospho-acetyl-coA carboxylase and phospho-AMPK levels similar to global and endothelial conditional KO mouse. Finally, adult cardiac conditional KO mouse displays severe cardiac functional defects and lethality. Our results suggest that Snrk is essential for maintaining cardiac metabolic homeostasis, and shows an autonomous role for SNRK during mammalian development., (© 2015. Published by The Company of Biologists Ltd.)
- Published
- 2014
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44. Isolation, selection, and characterization of highly ethanol-tolerant strains of Oenococcus oeni from south Catalonia.
- Author
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Bordas M, Araque I, Alegret JO, El Khoury M, Lucas P, Rozès N, Reguant C, and Bordons A
- Subjects
- Fermentation, France, Genetic Variation, Molecular Sequence Data, Multilocus Sequence Typing, Oenococcus classification, Oenococcus genetics, Phylogeny, Ethanol metabolism, Oenococcus isolation & purification, Oenococcus metabolism, Wine microbiology
- Abstract
Twenty-one strains of Oenococcus oeni were isolated during the malolactic fermentation of wines from south Catalonia. Due to their high ethanol tolerance (14 %, or more), these strains may serve as promising starters. The strains were screened by assays in a wine-like medium and by their co-inoculation in wine, resulting in the selection of well-performing strains, subsequently shown not to produce the main biogenic amines and lacking the genes involved in their synthesis. The genetic diversity of the isolates was studied by multilocus sequence typing (MLST), in which seven housekeeping genes were sequenced. Although the concatenated allelic profile of some strains was the same, the profiles obtained by random amplification of polymorphic DNA together with the variable number of tandem repeats at several loci showed that none of the strains were identical. A phylogenetic tree was constructed based on MLST with the seven genes and clearly showed two phylogroups, in accordance with previous studies. The best-performing strains occurred in members of both subgroups, suggesting that the grouping of housekeeping genes is not directly related to adaptation and ethanol tolerance.
- Published
- 2013
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45. Synthesis and biological evaluation of a new series of hexahydro-2H-pyrano[3,2-c]quinolines as novel selective σ1 receptor ligands.
- Author
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Díaz JL, Christmann U, Fernández A, Luengo M, Bordas M, Enrech R, Carro M, Pascual R, Burgueño J, Merlos M, Benet-Buchholz J, Cerón-Bertran J, Ramírez J, Reinoso RF, Fernández de Henestrosa AR, Vela JM, and Almansa C
- Subjects
- Analgesics chemistry, Analgesics pharmacokinetics, Animals, Chemical Phenomena, Chemistry Techniques, Synthetic, Drug Evaluation, Preclinical, Female, Guinea Pigs, High-Throughput Screening Assays, Humans, Ligands, Male, Mice, Models, Molecular, Protein Conformation, Quinolines chemistry, Quinolines pharmacokinetics, Receptors, sigma chemistry, Structure-Activity Relationship, Analgesics chemical synthesis, Analgesics metabolism, Quinolines chemical synthesis, Quinolines metabolism, Receptors, sigma metabolism
- Abstract
The synthesis and pharmacological activity of a new series of hexahydro-2H-pyrano[3,2-c]quinoline derivatives as potent σ1 receptor (σ1R) ligands are reported. This family, which does not contain the highly basic amino group usually present in other σ1R ligands, showed high selectivity over the σ2 receptor (σ2R). The activity was shown to reside in only one of the four possible diastereoisomers, which exhibited a perfect match with known σ1R pharmacophores. A hit to lead program based on a high-throughput screening hit (8a) led to the identification of compound 32c, with substantially improved activity and physicochemical properties. Compound 32c also exhibited a good ADMET (absorption, distribution, metabolism, excretion, toxicity) profile and was identified as a σ1R antagonist on the basis of its analgesic activity in the mouse capsaicin and formalin models of neurogenic pain.
- Published
- 2013
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46. Heparin rescues factor V Leiden-associated placental failure independent of anticoagulation in a murine high-risk pregnancy model.
- Author
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An J, Waitara MS, Bordas M, Arumugam V, Hoffmann RG, Petrich BG, Sinha U, North PE, and Sood R
- Subjects
- Animals, Anticoagulants pharmacology, Anticoagulants therapeutic use, Blood Coagulation genetics, Embryo, Mammalian, Factor V genetics, Female, Heparin pharmacology, Humans, Mice, Mice, Inbred C57BL, Placenta Diseases genetics, Pregnancy, Pregnancy Complications, Hematologic drug therapy, Pregnancy Complications, Hematologic etiology, Pregnancy Complications, Hematologic genetics, Blood Coagulation drug effects, Disease Models, Animal, Factor V physiology, Heparin therapeutic use, Mice, Knockout, Placenta Diseases drug therapy, Placenta Diseases etiology, Pregnancy, High-Risk blood
- Abstract
Low molecular weight heparin (LMWH) is being tested as an experimental drug for improving pregnancy outcome in women with inherited thrombophilia and placenta-mediated pregnancy complications, such as recurrent pregnancy loss. The role of thrombotic processes in these disorders remains unproven, and the issue of antithrombotic prophylaxis is intensely debated. Using a murine model of factor V Leiden-associated placental failure, we show that treatment of the mother with LMWH allows placental development to proceed and affords significant protection from fetal loss. Nonetheless, the therapeutic effect of LMWH is not replicated by anticoagulation; fondaparinux and a direct Xa inhibitor, C921-78, achieve anticoagulation similar to LMWH but produce little or no improvement in pregnancy outcome. Genetic attenuation of maternal platelet aggregation is similarly ineffective. In contrast, even a partial loss of thrombin sensitivity of maternal platelets protects pregnancies. Neonates born from these pregnancies are growth retarded, suggesting that placental function is only partially restored. The placentae are smaller but do not reveal any evidence of thrombosis. Our data demonstrate an anticoagulation-independent role of LMWH in protecting pregnancies and provide evidence against the involvement of thrombotic processes in thrombophilia-associated placental failure. Importantly, thrombin-mediated maternal platelet activation remains central in the mechanism of placental failure.
- Published
- 2013
- Full Text
- View/download PDF
47. Evaluation of pathways involved in pentachlorophenol-induced apoptosis in rat neurons.
- Author
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Folch J, Yeste-Velasco M, Alvira D, de la Torre AV, Bordas M, López M, Sureda FX, Rimbau V, Camins A, and Pallàs M
- Subjects
- Animals, Cell Culture Techniques, Cell Cycle Proteins drug effects, Cell Survival drug effects, Down-Regulation drug effects, Oxidative Stress drug effects, Rats, Rats, Sprague-Dawley, Reactive Oxygen Species metabolism, Up-Regulation drug effects, Apoptosis physiology, Cerebellum drug effects, Cerebellum metabolism, Neurons drug effects, Neurons metabolism, Pentachlorophenol toxicity
- Abstract
Pentachlorophenol (PCP) (C(6)HCl(5)O) is a synthetic toxic organochloride fungicide for humans which exhibit neurotoxic properties. In the present research, we describe the potential pathways implicated in PCP-induced apoptosis in an acute model of toxicity in rat cerebellar granule neurons (CGNs). In our experiments, acute exposure of CGNs to micromolar concentrations of PCP induced the transcriptional activity of genes related to the classical apoptosis pathway (caspase 3, caspase 8, Bad), oxidative stress and glutathione metabolism (glutathione peroxidase-1, catalase, glutathione-S-transferase-3 and superoxide dismutase-1), and mitogenic response (cyclin D1, cdk2, cdk4, cdkn2b). Results from Western blot also shown significative increases in the expression of cyclins D1, E and A and cdk4. The mitogenic response was also related to a significative increase in the phosphorylation of retinoblastoma protein (Rb). PCP would cause apoptosis up-regulating the transcriptional activity of p53 gene and also increasing their activation by phosphorylation, concomitant with a decrease in the sirtuin 1 content. In conclusion, acute exposure of CGNs to PCP induces the classical p53 apoptotic pathway, promotes the up-regulation of several genes related to oxidative stress and the over-expression of molecules involved in the cell cycle control.
- Published
- 2009
- Full Text
- View/download PDF
48. Pathogenicity of Vibrio alginolyticus for cultured gilt-head sea bream (Sparus aurata L.).
- Author
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Balebona MC, Andreu MJ, Bordas MA, Zorrilla I, Moriñigo MA, and Borrego JJ
- Subjects
- Animals, Bacterial Adhesion, Bacterial Toxins toxicity, Cell-Free System, Erythrocytes drug effects, Fish Diseases pathology, Gills microbiology, Hemagglutination Tests, Horses, Intestinal Mucosa microbiology, Muscle, Skeletal microbiology, Muscle, Skeletal pathology, Skin microbiology, Skin pathology, Skin ultrastructure, Vibrio isolation & purification, Vibrio physiology, Vibrio Infections microbiology, Vibrio Infections pathology, Virulence, Fish Diseases microbiology, Perciformes microbiology, Vibrio pathogenicity, Vibrio Infections veterinary
- Abstract
The in vivo and in vitro pathogenic activities of whole cells and extracellular products of Vibrio alginolyticus for cultured gilt-head sea bream were evaluated. The 50% lethal doses ranged from 5.4 x 10(4) to 1.0 x 10(6) CFU/g of body weight. The strains examined had the ability to adhere to skin, gill, and intestinal mucus of sea bream and to cultured cells of a chinook salmon embryo cell line. In addition, the in vitro ability of V. alginolyticus to adhere to mucus and skin cells of sea bream was demonstrated by scanning electron microscopy. The biological activities of extracellular products of V. alginolyticus were hydrolytic activities; the products were able to degrade sea bream mucus. V. alginolyticus was cytotoxic for fish cell lines and lethal for sea bream. Moreover, the extracellular products could degrade sea bream tissues. However, experiments performed with the bath immersion inoculation technique demonstrated that V. alginolyticus should be considered a pathogen for sea bream only when the mucus layer is removed and the skin is damaged.
- Published
- 1998
- Full Text
- View/download PDF
49. Chemotaxis of pathogenic Vibrio strains towards mucus surfaces of gilt-head sea bream (Sparus aurata L.).
- Author
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Bordas MA, Balebona MC, Rodriguez-Maroto JM, Borrego JJ, and Morinigo MA
- Subjects
- Animals, Bacterial Adhesion, Chemotaxis, Fish Diseases microbiology, Gills microbiology, Intestines microbiology, Mucus microbiology, Skin microbiology, Temperature, Vibrio Infections microbiology, Vibrio Infections veterinary, Perciformes microbiology, Vibrio pathogenicity, Vibrio physiology
- Abstract
Vibrio anguillarum and Vibrio alginolyticus exhibited significant adhesion to and chemotactic abilities towards mucus collected from the skin, gills, and intestine of gilt-head sea bream. Quadratic polynomial models for chemotaxis designed to estimate the influence of temperature demonstrated a differential bacterial chemotaxis depending of the source of the mucus, with the chemotaxis towards intestinal mucus being the least influenced.
- Published
- 1998
- Full Text
- View/download PDF
50. Transfer of the yeast salt tolerance gene HAL1 to Cucumis melo L. cultivars and in vitro evaluation of salt tolerance.
- Author
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Bordas M, Montesinos C, Dabauza M, Salvador A, Roig LA, Serrano R, and Moreno V
- Subjects
- Acetophenones pharmacology, Blotting, Northern, Blotting, Southern, Coculture Techniques, Culture Techniques, DNA analysis, Fungal Proteins, Gene Expression Regulation, Plant, Genes, Reporter, Glucuronidase metabolism, Intracellular Signaling Peptides and Proteins, Kanamycin Kinase, Plants metabolism, Plants, Genetically Modified, Polymerase Chain Reaction, Rhizobium genetics, Salts metabolism, Transformation, Genetic, Cloning, Molecular, Glucuronidase genetics, Phosphotransferases (Alcohol Group Acceptor) genetics, Plants genetics, Saccharomyces cerevisiae Proteins, Transgenes, Yeasts genetics
- Abstract
An Agrobacterium-mediated gene transfer method for production of transgenic melon plants has been optimized. The HAL1 gene, an halotolerance gene isolated from yeast, was inserted in a chimaeric construct and joined to two marker genes: a selectable-neomycin phosphotransferase-II (nptII)-, and a reporter-beta-glucuronidase (gus)-. The entire construct was introduced into commercial cultivars of melon. Transformants were selected for their ability to grow on media containing kanamycin. Transformation was confirmed by GUS assays, PCR analysis and Southern hybridization. Transformation efficiency depended on the cultivar, selection scheme used and the induction of vir-genes by the addition of acetosyringone during the cocultivation period. The highest transformation frequency, 3% of the total number of explants cocultivated, was obtained with cotyledonary explants of cv. 'Pharo'. Although at a lower frequency (1.3%), we have also succeeded in the transformation of leaf explants. A loss of genetic material was detected in some plants, and results are in accordance with the directional model of T-DNA transfer. In vitro cultured shoots from transgenic populations carrying the HAL1 gene were evaluated for salt tolerance on shoot growth medium containing 10 gl-1 NaCl. Although root and vegetative growth were reduced, transgenic HAL1-positive plants consistently showed a higher level of tolerance than control HAL1-negative plants.
- Published
- 1997
- Full Text
- View/download PDF
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