Stimulation of phosphoinositide hydrolysis via class I antigen-specific recognition in murine cardiac tissue

AbstractInduction of polyphosphoinositide hydrolysis in cardiac tissue by specific recognition of class I histocompatibility antigens was assayed. C3H (H-2k) mice auricles were labelled with myo-3H]inositol precursor and inositol phosphate production in the presence or absence of anti-class I k products was measured. Anti-class I, but not anti-class II products specifically increased phosphoinositide turnover. This increment was partially blocked by muscarinic cholinergic and α-adrenergic blockers and even more so by the phospholipase C inhibitor NCDC. Alloantibodies specifically directed against class I antigens could then exert stimulation of phospholipase C-mediated phosphoinositide hydrolysis through the interaction with muscarinic cholinergic and/or α-adrenergic receptors. The induction of intracellular second messengers by class I antigens and hormone-receptor interactions is discussed

Non-genomic Actions of Thyroid Hormones Regulate the Growth and Angiogenesis of T Cell Lymphomas

T-cell lymphomas (TCL) are a heterogeneous group of aggressive clinical lymphoproliferative disorders with considerable clinical, morphological, immunophenotypic, and genetic variation, including ~10–15% of all lymphoid neoplasms. Several evidences indicate an important role of the non-neoplastic microenvironment in promoting both tumor growth and dissemination in T cell malignancies. Thus, dysregulation of integrin expression and activity is associated with TCL survival and proliferation. We found that thyroid hormones acting via the integrin αvβ3 receptor are crucial factors in tumor microenvironment (TME) affecting the pathophysiology of TCL cells. Specifically, TH-activated αvβ3 integrin signaling promoted TCL proliferation and induced and an angiogenic program via the up-regulation of the vascular endothelial growth factor (VEGF). This was observed both on different TCL cell lines representing the different subtypes of human hematological malignancy, and in preclinical models of TCL tumors xenotransplanted in immunodeficient mice as well. Moreover, development of solid tumors by inoculation of murine TCLs in syngeneic hyperthyroid mice, showed increased tumor growth along with increased expression of cell cycle regulators. The genomic or pharmacological inhibition of integrin αvβ3 decreased VEGF production, induced TCL cell death and decreased in vivo tumor growth and angiogenesis. Here, we review the non-genomic actions of THs on TCL regulation and their contribution to TCL development and evolution. These actions not only provide novel new insights on the endocrine modulation of TCL, but also provide a potential molecular target for its treatment

Differential expression of protein kinase C isoenzymes related to high nitric oxide synthase activity in a T lymphoma cell line

AbstractProtein kinase C (PKC) is critical for T lymphocyte activation and proliferation, while nitric oxide synthase (NOS) may function both as an activator or inhibitor of T cell apoptosis. Both enzymatic activities were studied in T lymphoma cells in comparison to normal and activated T lymphocytes. Here we show a higher translocation of PKC in BW5147 lymphoma cells than in mitogen-stimulated T lymphocytes. Tumor cells overexpressed PKC ζ isoform, while high levels of the PKC β isotype were found in mitogen-stimulated T lymphocytes. Moreover, tumoral T cells showed high NOS activity, almost undetectable in normal or stimulated T lymphocytes. PKC and NOS inhibitors or the intracellular delivery of an anti-PKC ζ antibody diminished both NO production and proliferation in tumor cells.These results suggest that atypical PKC ζ isoform expression and its association with NOS activity regulation would participate in the multistep process leading to BW5147 cell malignant transformation

Donde comienza la sustentabilidad o ¿dónde comienza la sustentabilidad?”: la experiencia PDTS en Santa Fé ciudad

Hemos presentado en reuniones anteriores algunas experiencias de transferencia tecnológica que nuestro equipo realiza desde tanto Laboratorios y Cátedras donde la tarea universitaria ha sido vista como hecho integral, intentando potenciar el círculo virtuoso de retroalimentación entre docencia, investigación y extensión. Siempre hemos considerado a la extensión como la forma de transferir conocimientos al medio y a la vez la forma de detectar problemas que tiene la sociedad, hacerlos luego objetos de investigación y posteriormente también incorporarlos a la tarea docente. Así, toda nuestra tarea está enmarcada por una visión filosófica de la vida universitaria y del porqué de la Universidad Pública. Esta afirmación demás está decirlo tiene mayor vigencia en los momentos como el actual en que los gobiernos agobiados por problemas económicos, echan frecuentemente mano para cuestiones que entiende de mayor urgencia, a los recursos que deberían servir para alimentar el sistema. En el momento de presentar ante CONICET el PDTS, en conjunto constituido por la Universidad Nacional de La Plata, Universidad Nacional del Litoral y la Municipalidad de Santa Fe tuvimos claro que los objetivos del mismo debían exceder, casi obligatoriamente, la mera experiencia de transferencia. Era necesario intentar ideas que pudieran servir de base para iniciar a futuro trabajos direccionables a la resolución de los grandes temas detectados. Particularmente el hábitat carenciado y el mundo del trabajo. Desarrollándose entonces una pregunta conductora: ¿es posible con la utilización de tecnología adecuada la resolución simultánea de hábitat y trabajo de personas con poca o nula capacitación específica? Nuestro eje fue la exploración y la realización de experiencias que demostraran la viabilidad a futuro de una fábrica social de casa-partes. Nuestros encuentros en Congresos anteriores CRETA han posibilitado exponer algunos avances. Por lo dicho la revisión en torno al momento de inicio del proceso de la sustentabilidad creemos es pertinente ya que el trabajo presenta implícitamente la hipótesis: ¿es sostenible o siquiera posible vivir en un lugar donde no se tiene trabajo? El trabajo, aún en curso, intenta explorar y debatir lo antes dicho.We have presented in previous meetings some experiences of technology transfer that our team carries out from both Laboratories and Chairs where the university task has been seen as an integral fact, trying to strengthen the virtuous circle of feedback between teaching, research and extension. We have always considered extension as the way to transfer knowledge to the environment and at the same time how to detect problems that society has, then make them objects of research and then also incorporate them into the teaching task. Thus, all our work is framed by a philosophical vision of university life and why the Public University. This affirmation, in other words, is more valid at times like the current one in which governments, overwhelmed by economic problems, frequently make use of issues that they deem most urgent, of the resources that should serve to feed the system. At the time of presenting the PDTS to CONICET, jointly constituted by the National University of La Plata, the National University of the Litoral and the Municipality of Santa Fe, we were clear that its objectives should exceed, almost compulsorily, the mere experience of transfer. It was necessary to try ideas that could serve as a basis to start future works that can be directed to the resolution of the big issues detected. Particularly the deprived habitat and the world of work. Developing a conductive question then: is it possible with the use of appropriate technology the simultaneous resolution of habitat and work of people with little or no specific training? Our axis was the exploration and the realization of experiences that demonstrate the future viability of a social factory of house-parties. Our meetings at previous CRETA Congresses have made it possible to present some advances. For what has been said, the review around the moment of beginning of the process of sustainability we believe is pertinent since the work implicitly presents the hypothesis: is it sustainable or even possible to live in a place where there is no work? The work, still in progress, tries to explore and debate what was said before.Laboratorio de Tecnología y Gestión Habitaciona

Beneficial effect of fluoxetine and dertraline on chronic stress-induced tumor crowth and cell dissemination in a mouse model of lymphoma : crucial role of antitumor immunity

Abstract: Clinical data and experimental studies have suggested a relationship between psychosocial factors and cancer prognosis. Both, stress effects on the immune system and on tumor biology were analyzed independently. However, there are few studies regarding the stress influence on the interplay between the immune system and tumor biology. Moreover, antidepressants have been used in patients with cancer to alleviate mood disorders. Nevertheless, there is contradictory evidence about their action on cancer prognosis. In this context, we investigated the effect of chronic stress on tumor progression taking into account both its influence on the immune system and on tumor biology. Furthermore, we analyzed the action of selective serotonin reuptake inhibitors, fluoxetine and sertraline, in these effects. For this purpose, C57BL/6J mice submitted or not to a chronic stress model and treated or not with fluoxetine or sertraline were subcutaneously inoculated with EL4 cells to develop solid tumors. Our results indicated that chronic stress leads to an increase in both tumor growth and tumor cell dissemination. The analysis of cell cycle regulatory proteins showed that stress induced an increase in the mRNA levels of cyclins A2, D1, and D3 and a decrease in mRNA levels of cell cycle inhibitors p15, p16, p21, p27, stimulating cell cycle progression. Moreover, an augment of mRNA levels of metalloproteases (MMP-2 and MMP-9), a decrease of inhibitors of metalloproteases mRNA levels (TIMP 1, 2, and 3), and an increase in migration ability were found in tumors from stressed animals. In addition, a significant decrease of antitumor immune response in animals under stress was found. Adoptive lymphoid cell transfer experiments indicated that the reduced immune response in stressed animals influenced both the tumor growth and the metastatic capacity of tumor cells. Finally, we found an important beneficious effect of fluoxetine or sertraline treatment on cancer progression. Our results emphasize the crucial role of the immune system in tumor progression under stress situations. Although a direct effect of stress and drug treatment on tumor biology could not be ruled out, the beneficial effect of fluoxetine and sertraline appears to be mainly due to a restoration of antitumor immune response

Del laboratorio a la clínica : importancia de la regulación de la inmunidad ejercida por el estado tiroideo

Resumen: Una fina y compleja red de mecanismos autorregulados le permite al sistema inmune reaccionar ante el desafío antigénico para activar una respuesta de defensa contra agentes patógenos o extraños y volver luego a un modo de espera o vigilancia. Esta red de autorregulación mantiene la homeostasis y evita las dañinas respuestas autoinmunes. A pesar de su autonomía se ha demostrado que los sistemas inmune y neuroendócrino interactúan entre sí a través de una red bidireccional de la que participan los receptores para ligando s comunes y sus vías intracelulares de señalización. Las hormonas y neurotransmisores pueden afectar la función inmune y, a su vez, los factores inmunitarios como las citoquinas pueden ejercer cambios neuroendocrinos (Melmed, 2001; Wrona, 2006). Además, las células inmunes pueden producir hormonas y neurotransmisores, mientras que las citoquinas, principales factores solubles liberados por las células inmunes, pueden funcionar como hormonas y moduladores de ciertas respuestas del sistema nervioso central (Haddad, 2008). Las consecuencias de la disfunción entre estos componentes neuroendocrinos y la inmunidad son evidentes durante situaciones de estrés, lesiones físicas, infecciones y otras condiciones fisiopatológicas

Polyphenol-rich fraction from Larrea divaricata and its main flavonoid Quercetin-3-Methyl Ether induce apoptosis in lymphoma cells through nitrosative stress

Abstract: Larrea divaricata is a plant with antiproliferative principles. We have previously identified the flavonoid quercetin-3-methyl ether (Q-3-ME) in an ethyl acetate fraction (EA). Both the extract and Q-3-ME were found to be effective against the EL-4 T lymphoma cell line. However, the mechanism underlying the inhibition of tumor cell proliferation remains to be elucidated. In this work, we analyzed the role of nitric oxide (NO) in the induction of apoptosis mediated by Q-3-ME and EA. Both treatments were able to induce apoptosis in a concentration-dependent and time-dependent manner. The western blot analysis revealed a sequential activation of caspases-9 and 3, followed by poly-(ADP-ribose)-polymerase cleavage. EA and Q-3-ME lowered the mitochondrial membrane potential, showing the activation of the intrinsic pathway of apoptosis. Q-3-ME and EA increased NO production and inducible NO synthase expression in tumor cells. The involvement of NO in cell death was confirmed by the nitric oxide synthases inhibitor L-NAME. In addition, EA and Q-3-ME induced a cell cycle arrest in G0/G1 phase. These drugs did not affect normal cell viability. This data suggested that EA and Q-3-ME induce an increase in NO production that would lead to the cell cycle arrest and the activation of the intrinsic pathway of apoptosis. Copyright © 2016 John Wiley & Sons, Ltd

Oxidative stress produced by hyperthyroidism status induces the antioxidant enzyme transcription through the activation of the nrf-2 factor in lymphoid tissues of balb/c mice

Abstract: Hyperthyroidism is an endocrine disorder characterized by excessive secretion of thyroid hormones T3 and T4. Thyroid hormones exert pleiotropic actions on numerous tissues and induce an overall increase in metabolism, with an increase in energy demand and oxygen consumption. Therefore, the purpose of this study was to investigate the effects of hyperthyroidism on the production of reactive oxygen species (ROS) in lymph node and spleen cells of euthyroid and hyperthyroid mice, analyzing antioxidant mechanisms involved in the restitution of the cellular redox state. For this, thirty female Balb/c (H-2d) mice were randomly divided into two groups: euthyroid (by treatment with placebo) and hyperthyroid (by treatment with 12 mg/l of T4 in drinking water for 30 days). We found a significant increase in ROS and an increase in the genomic and protein expression of the antioxidant enzymes catalase (CAT) and glutathione peroxidase-1 (GPx-1) in lymph node and spleen cells of hyperthyroid mice. In vitro treatment with H2O2 (250 μM) of the lymphoid cells of euthyroid mice increased the expression levels of CAT and GPx-1. The hyperthyroidism increased the phosphorylation levels of Nrf2 (nuclear factor erythroid 2-related factor) and the kinase activity of protein kinase C (PKC) and extracellular signal-regulated kinase (ERK). Additionally, we found an increase in the expression of the classic isoenzymes of PKCα, β and γ. In conclusion, these results indicated that the increase in ROS found in the hyperthyroid state induces the antioxidant enzyme transcription through the activation of the Nrf-2 factor in lymphoid tissues. This shows the influence of hyperthyroidism on the regulation of the cellular antioxidant system

Experimental evidence pointing to the bidirectional interaction between the immune system and the thyroid axis

Among the many examples of neuroendocrine-immune system interactions the relationship between the thyroid axis and the immune function has yet to be clearly established. Here we studied the influence of thyroid hormones on the course of an alloimmune response. Murine T3 and T4 levels were found to be increased a few days after the immunization of mice with allogeneic lymphoid cells. Besides in vivo treatment with T4 was shown to increase alloantibody titers during the early stages of alloimmunization and to enforce lymphoid proliferation in vitro in a mixed lymphocyte reaction. Conversely, lowering thyroid hormone seric levels by propylthiouracil treatment, negatively modulates the humoral and cellular alloimmune responses. The evidence here points to the existence of a bidirectional communication between both systems. The possibility that the antigenic challenge would increase the thyroid gland activity thus leading to a positive modulatory action upon the immune response is also discussed.Fil: Klecha, Alicia Juana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ingeniería. Departamento de Física. Laboratorio de Radioisótopos; ArgentinaFil: Genaro, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Ingeniería. Departamento de Física. Laboratorio de Radioisótopos; ArgentinaFil: Lysionek, A. E.. Universidad de Buenos Aires. Facultad de Ingeniería. Departamento de Física. Laboratorio de Radioisótopos; ArgentinaFil: Caro, R. A.. Universidad de Buenos Aires. Facultad de Ingeniería. Departamento de Física. Laboratorio de Radioisótopos; ArgentinaFil: Coluccia, A. G.. Universidad de Buenos Aires. Facultad de Ingeniería. Departamento de Física. Laboratorio de Radioisótopos; ArgentinaFil: Cremaschi, Graciela Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Ingeniería. Departamento de Física. Laboratorio de Radioisótopos; Argentin