Histamine H4 receptor agonists induce epithelial-mesenchymal transition events and enhance mammosphere formation via Src and TGF-β signaling in breast cancer cells

Epithelial-mesenchymal transition (EMT) contributes to cell invasion and metastasis during the progression of epithelial cancers. Though preclinical evidence suggests a role for histamine H4 receptor (H4R) in breast cancer growth, its function in the EMT is less known. In this study we proposed to investigate the effects of H4R ligands on EMT and mammosphere formation as a surrogate assay for cancer stem cells in breast cancer cells with different invasive phenotype. We also investigated the participation of Src and TGF-β signaling in these events. Breast cancer cells were treated with the H4R agonists Clobenpropit, VUF8430 and JNJ28610244 and the H4R antagonist JNJ7777120. Immunodetection studies showed cytoplasmic E-cadherin, cytoplasmic and nuclear beta-catenin, nuclear Slug and an increase in vimentin and α-smooth muscle actin expression. There was also an enhancement in cell migration and invasion assessed by transwell units. All these effects were prevented by JNJ7777120. Moreover, H4R agonists induced an increase in phospho-Src levels detected by Western blot. Results revealed the involvement of phospho-Src in EMT events. Upon treatment with H4R agonists there was an increase in phospho-ERK1/2 and TGF-β1 levels by Western blot, in Smad2/3 positive nuclei by indirect immunofluorescence, and in tumor spheres formation by the mammosphere assay. Notably, the selective TGF-β1 kinase/activin receptor-like kinase inhibitor A83-01 blocked these effects. Moreover, cells derived from mammospheres exhibited higher Slug expression and enhanced migratory behavior. Collectively, findings support the interaction between H4R and TGF-β receptor signaling in the enhancement of EMT features and mammosphere formation and point out intracellular TGF-β1 as a potential mediator of these events.Fil: Galarza, Tamara Ester. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Táquez Delgado, Mónica Alejandra. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mohamad, Nora A.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Martin, Gabriela Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Cricco, Graciela P.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentin

Immunomodulatory role of histamine H4 receptor in breast cancer

Background: Although the role of histamine H4 receptor (H4R) in immune cells is being extensively investigated, its immunomodulatory function in cancer is completely unknown. This study aimed to investigate the role of H4R in antitumour immunity in a model of triple-negative breast cancer. Methods: We evaluated growth parameters, histological characteristics and the composition of tumour, splenic and tumour draining lymph node (TDLN) immune subsets, in a syngeneic model, developed orthotopically with 4T1 cells in H4R knockout (H4R-KO) and wild-type mice. Results: Mice lacking H4R show reduced tumour size and weight, decreased number of lung metastases and percentage of CD4 + tumour-infiltrating T cells, while exhibiting increased infiltration of NK cells and CD19 + lymphocytes. Likewise, TDLN of H4R-KO mice show decreased CD4 + T cells and T regulatory cells (CD4 + CD25 + FoxP3 + ), and increased percentages of NK cells. Finally, H4R-deficient mice show decreased Tregs in spleens and non-draining lymph nodes, and a negative correlation between tumour weight and the percentages of CD4 + , CD19 + and NK splenic cells, suggesting that H4R also regulates antitumour immunity at a systemic level. Conclusions: This is the first report that demonstrates the participation of H4R in antitumour immunity, suggesting that H4R could be a target for cancer treatment.Fil: Sterle, Helena Andrea. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Nicoud, Melisa Beatriz. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Massari, Noelia Andrea. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Comodoro; ArgentinaFil: Táquez Delgado, Mónica Alejandra. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Herrero Ducloux, María Verónica. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Comodoro; ArgentinaFil: Cremaschi, Graciela Alicia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Medina, Vanina Araceli. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentin

Cross-talk between the RcsCDB and RstAB systems to control STM1485 gene expression in Salmonella Typhimurium during acid-resistance response

Bacterial survive and respond to adverse changes in the environment by regulating gene transcription through two-component regulatory systems. In Salmonella Typhimurium the STM1485 gene expression is induced under low pH (4.5) during replication inside the epithelial host cell, but it is not involved in sensing or resisting to this condition. Since the RcsCDB system is activated under acidic conditions, we investigated whether this system is able to modulate STM1485 expression. We demonstrated that acid-induced activation of the RcsB represses STM1485 transcription by directly binding to the promoter. Under the same condition, the RstA regulator activates the expression of this gene. Physiologically, we observed that RcsB-dependent repression is required for the survival of bacteria when they are exposed to pancreatic fluids. We hypothesized that STM1485 plays an important role in Salmonella adaptation to pH changes, during transition in the gastrointestinal tract. We suggest that bacteria surviving the gastrointestinal environment invade the epithelial cells, where they can remain in vacuoles. In this new environment, acidity and magnesium starvation activate the expression of the RstA regulator in a PhoPQ-dependent manner, which in turn induces STM1485 expression. These levels of STM1485 allow increased bacterial replication within vacuoles to continue the course of infection.Fil: Torrez Lamberti, Monica Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; ArgentinaFil: Farizano, Juan Vicente. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; ArgentinaFil: Lopez, Fabian Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; Argentina. Universidad Nacional de Chilecito; ArgentinaFil: Martinez Zamora, Martin Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; ArgentinaFil: Pescaretti, María de Las Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; ArgentinaFil: Táquez Delgado, Mónica Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; Argentin

Study of the antitumour effects and the modulation of immune response by histamine in breast cancer

Background: The aim of this work was to improve the knowledge of the role of histamine in breast cancer by assessing the therapeutic efficacy of histamine and histamine H4 receptor (H4R) ligands in a triple-negative breast cancer (TNBC) model developed in immunocompetent hosts. By using publicly available genomic data, we further investigated whether histidine decarboxylase (HDC) could be a potential biomarker. Methods: Tumours of 4T1 TNBC cells were orthotopically established in BALB/c mice. Treatments employed (mg kg−1): histamine (1 and 5), JNJ28610244 (H4R agonist, 1 and 5) and JNJ7777120 (H4R antagonist, 10). Results: Increased HDC gene expression is associated with better relapse-free and overall survival in breast cancer patients. Histamine treatment (5 mg kg−1) of 4T1 tumour-bearing mice reduced tumour growth and increased apoptosis. Although no immunomodulatory effects were observed in wild-type mice, significant correlations between tumour weight and cytotoxic lymphocyte infiltration were detected in H4R knockout mice. H4R agonist or antagonist differentially modulated tumour growth and immunity in 4T1 tumour-bearing mice. Conclusions: Histamine plays a complex role and stands out as a promising drug for TNBC treatment, which deserves to be tested in clinical settings. HDC expression level is associated with clinicopathological characteristics, suggesting a prognostic value in breast cancer.Fil: Nicoud, Melisa Beatriz. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Sterle, Helena Andrea. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Massari, Noelia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de la Patagonia "San Juan Bosco"; ArgentinaFil: Táquez Delgado, Mónica Alejandra. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Formoso, Karina. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Herrero Ducloux, María Verónica. Universidad Nacional de la Patagonia "San Juan Bosco"; ArgentinaFil: Martinel Lamas, Diego José. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Cremaschi, Graciela Alicia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Medina, Vanina Araceli. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentin

Participación del receptor H4 de histamina en la transición epiterial-mesenquimática de células de carcinoma mamario humano MDA-MB-231

Metastases are the cause of 90% of human cancer deaths. The mesenchymal epithelial transition (EMT) is a process that contributes to invasion and metastasis. During EMT epithelial cells acquire a more elongated morphology, exhibit changes in adhesion, motility and ability to degrade the extracellular matrix, as well as resistance to apoptosis.\nWe previously demonstrated that histamine is able to differentially modulate migration and gelatinolytic activity in mammary tumor cells MDA-MB-231, stimulating at doses lower than 1 ?M and inhibiting at doses greater than 10 ?M. Preliminary results from our studies indicated that stimulation of histamine H4 receptor in MDA-MB-231 cells reproduces the effects observed with histamine at low doses whereas H2 receptor stimulation is associated with effects obtained with doses of histamine greater than 10 ?M.\nThe objective of this work was to go further into the study of the role of histamine H4 receptor in the TEM of the triple negative mammary carcinoma MDA-MB-231 human cell, evaluating morphological changes, molecular and functional markers and some components of potential signaling pathways involved as well as the activation of TGF-? type I receptor induced by H4 agonists.\nThe H4 agonists promoted cell scattering, increased the expression of the mesenchymal marker vimentin and increased nuclear localization or/and the expression of ?-catenin and Slug transcription factor. Significant improvements in MMP9 metalloproteinase activity, cell migration and invasion were also observed. We also demonstrated that phosphorylation of c-Src protein kinase was involved in cell migration among other characteristic events of TEM. Previous treatment of mammary tumor cells with the H4 antagonist JNJ7777120 blocked the effects produced by H4 agonists and helped to highlight the role of the H4 receptor in the induction of TEM-related events. Moreover, H4 agonists increased the expression of TGF-?1 in MDA-MB-231 cells whereas the use\nof the TGF-? type I receptor kinase inhibitor suggested a potential crosstalk between both receptors to promote TEM through a signaling involving Src phosphorylation.\nIn summary, the results of this work indicate that stimulation of histamine H4 receptors favors the expression of the invasive phenotype in MDA-MB-231 cells and the activation of TGF-? Type I receptor.\nBasal and triple-negative tumors are difficult to treat, biologically more aggressive, and of very poor prognosis. We believe that the identification of factors that initiate, modulate and execute EMT-related events could provide the basis for the development of more efficient strategies to fight against metastasis of epithelial cancers, providing targets for the improvement of therapies that address pharmacological modification of pathways and signaling elements.Fil: Táquez Delgado, Mónica Alejandra. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Buenos Aires, ArgentinaEl 90% de las muertes por cáncer se debe a la formación de metástasis. La transición epitelial\nmesenquimática (TEM) es un proceso que contribuye en muchos casos a la invasión y\nmetástasis. Durante la TEM, las células epiteliales adquieren una morfología ahusada,\nexhiben cambios en la adhesión, en la motilidad y en la capacidad para degradar la matriz\nextracelular, así como resistencia a la apoptosis.\nPreviamente demostramos que la histamina es capaz de modular en forma diferencial la\nmigración y la actividad gelatinolítica en las células tumorales mamarias MDA-MB-231,\nestimulando con dosis menores a 1 ?M e inhibiendo con dosis mayores que 10 ?M. Resultados\npreliminares de nuestros estudios indicaron que la estimulación del receptor H4 en las células\nMDA-MB-231 reproduce los efectos observados con histamina a bajas dosis mientras que la\nestimulación del receptor H2 se asocia a los efectos obtenidos con dosis de histamina mayores\nque 10 ?M.\nEl objetivo de este trabajo fue profundizar el estudio de la participación del receptor H4 de\nhistamina en la TEM inducida por ligandos H4 en la línea celular humana de carcinoma\nmamario triple negativo MDA-MB-231, evaluando los cambios morfológicos, los marcadores\nmoleculares y funcionales, algunos componentes de potenciales vías de señalización así como\nla participación del receptor de tipo I del TGF-?.\nLos agonistas H4 empleados promovieron la pérdida del contacto intercelular, el aumento del\nmarcador mesenquimático vimentina, y la mayor localización nuclear y/o expresión de ?-\ncatenina y del factor de transcripción Slug. También se observaron mejoras significativas en\nla actividad de la metaloproteasa MMP9, en la migración y en la invasión celular. Asimismo,\ndemostramos que la fosforilación de la proteína quinasa c-Src está implicada en la migración\ncelular entre otros eventos característicos de la TEM. El tratamiento previo de las células\ntumorales mamarias con el antagonista H4 JNJ7777120 bloqueó los efectos producidos por\nlos agonistas H4 y contribuyó a destacar el papel del receptor H4 en la inducción de eventos\nrelacionados con la TEM. Por otra parte, los agonistas H4 aumentaron la expresión del factor\nTGF-?1 en las células MDA-MB-231 mientras que el empleo del inhibidor de la actividad\nquinasa del receptor de tipo I de TGF-? expuso una potencial comunicación entre ambos\nreceptores para promover la TEM a través de una señalización que involucra la fosforilación\nde Src.\nEn resumen, los resultados de este trabajo indican que la activación de los receptores H4 de\nhistamina favorece la expresión del fenotipo invasivo en las células MDA-MB-231 y que la TEM\ninducida por los agonistas H4 podría estar mediada por la activación del receptor de tipo I de\nTGF-?.\nLos tumores de tipo basal y triple negativo son difíciles de tratar, biológicamente más agresivos\ny de muy mal pronóstico. Pensamos que la identificación de factores que inician, modulan y\nejecutan la cascada de eventos de la TEM podría proveer las bases para el desarrollo de\nestrategias más eficientes en la lucha contra la progresión a la metástasis de los cánceres\nepiteliales, proporcionando blancos para el desarrollo de tratamientos que se dirijan a la\nmodificación farmacológica de las vías y elementos de señalización

Antitumor role of histamine h4 receptor in human t-cell lymphoma: therapeutic benefit for combination therapy with histamine and histone deacetylase inhibitors

The discovery of the human histamine H4 receptor (H4R) has contributed to our understanding of histamine role in numerous physiological and pathological conditions, including tumor development and progression. High histamine levels have been determined in lymph nodes of patients with malignant lymphomas, but as far as we know there is no evidence of the expression and function of the H4R in this tumor type. The aims of this work were to study the expression of the H4R and to evaluate the therapeutic efficacy of histamine and H4R?s ligands as a single treatment or in combination with inhibitors of the histone deacetylase (HDACi) for the treatment of T-cell lymphoma (TCL). Results demonstrate the expression of H4R isoforms at the mRNA and protein levels in 3 human aggressive TCL cell lines (OCI-Ly12 and Karpas 299, Peripheral TCL; HuT78 Sezary Syndrome). HEK293T was used as a negative control. Histamine and specific H4R agonists (VUF8430 and JNJ28610244) significantly reduced cell viability (CellTiter-Blue Assay) in a dose-dependent manner and induced cell apoptosis (Caspase-Glo 3/7 Assay) in the three cell lines (p<0.05, n=3 independent experiments performed in triplicates). The combined treatment with the H4R antagonist (JNJ7777120, 10 µM) reversed the effects of the H4R ligands (10 µM) on TCL. Importantly, we screened active compounds against TCL, evaluating a dug repurposing library of 384 FDA-approved compounds (1 μM) in combination with histamine (10 μM) in Hut78 cells. Histamine produced a synergistic antitumor effect, evaluated with a metabolic assay, with 18 of these compounds, including the HDACi panobinostat. Apoptosis, proliferation and oxidative stress studies confirmed the antitumoral effects of the combination. We conclude that H4R is expressed in TCL and it is involved in histamine-mediated responses. Histamine could be an attractive compound to be used as a single therapy or in combination with HDACi for the treatment of TCL.Fil: Clauzure, Mariangeles. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Táquez Delgado, Mónica Alejandra. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Cerchietti, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Cornell University; Estados UnidosFil: Medina, Vanina Araceli. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaReunión Anual de Sociedades de BiocienciaMar del PlataArgentinaSociedad Argentina de Investigación ClínicaAsociación Argentina de Farmacología ExperimentalSociedad Argentina de BiologíaSociedad Argentina de ProtozoologíaAsociación Argentina de Ciencia y Tecnología de Animales de LaboratorioAsociación Argentina de NanomedicinasThe Histochemical Societ

Histamine in cancer immunology and immunotherapy. Current status and new perspectives

Cancer is the second leading cause of death globally and its incidence and mortality are rapidly increasing worldwide. The dynamic interaction of immune cells and tumor cells determines the clinical outcome of cancer. Immunotherapy comes to the forefront of cancer treatments, resulting in impressive and durable responses but only in a fraction of patients. Thus, understanding the characteristics and profiles of immune cells in the tumor microenvironment (TME) is a necessary step to move forward in the design of new immunomodulatory strategies that can boost the immune system to fight cancer. Histamine produces a complex and fine-tuned regulation of the phenotype and functions of the different immune cells, participating in multiple regulatory responses of the innate and adaptive immunity. Considering the important actions of histamine-producing immune cells in the TME, in this review we first address the most important immunomodulatory roles of histamine and histamine receptors in the context of cancer development and progression. In addition, this review highlights the current progress and foundational developments in the field of cancer immunotherapy in combination with histamine and pharmacological compounds targeting histamine receptors.Fil: Sarasola, María de la Paz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Táquez Delgado, Mónica Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Nicoud, Melisa Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Medina, Vanina Araceli. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentin

Histamine H4 receptor agonism induces antitumor effects in human T-cell lymphoma

Abstract: The discovery of the human histamine H4 receptor (H4R) has contributed to our understanding of the role of histamine in numerous physiological and pathological conditions, including tumor development and progression. The lymph nodes of patients with malignant lymphomas have shown to contain high levels of histamine, however, less is known regarding the expression and function of the H4R in T-cell lymphoma (TCL). In this work we demonstrate the expression of H4R isoforms (mRNA and protein) in three human aggressive TCL (OCI-Ly12, Karpas 299, and HuT78). Histamine and specific H4R agonists (VUF8430 and JNJ28610244) significantly reduced cell viability in a dose-dependent manner (p < 0.05). The combined treatment with the H4R antagonist (JNJ7777120, 10 µM) reversed the effects of the H4R ligands. Importantly, we screened a drug repurposing library of 433 FDA-approved compounds (1 µM) in combination with histamine (10 µM) in Hut78 cells. Histamine produced a favorable antitumor effect with 18 of these compounds, including the histone deacetylase inhibitor panobinostat. Apoptosis, proliferation, and oxidative stress studies confirmed the antitumoral effects of the combination. We conclude that the H4R is expressed in TCL, and it is involved in histamine-mediated responses

RcsB-dependent effects on nar operon regulation during the aerobic growth of Salmonella Typhimurium

The intracellular pathogen Salmonella is an important cause of human foodborne diseases worldwide. Salmonella takes advantage of the phosphorelay regulatory systems to survive in the hostile environment of the host´s gastrointestinal tract. It has been reported that the nitrate reductase Z (NR-Z), encoded by the narUZYV operon, is required during Salmonella transition to anaerobic environments and is constitutively produced at low levels, but little is known about the regulatory mechanism involved in the operon gene expression. In this work, we found that the RcsCDB system is activated by high concentrations of specific sugars as a carbon source. In this activation state, the RcsCDB system participates in the negative control of narUZYWV expression. This control strategy occurs during exponential growth when the carbon source is high, allowing for normal aerobic respiration. The RcsCDB system´s participation in aerobic respiration is necessary to ensure efficient metabolism and optimal energy consumption when the bacteria are growing exponentially.Fil: Torrez Lamberti, Monica Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; ArgentinaFil: Ballesteros, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; ArgentinaFil: Lopez, Fabian Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; ArgentinaFil: Pescaretti, María de Las Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; ArgentinaFil: Táquez Delgado, Mónica Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentin