The role of the Neuregulin-1/Erbb signaling pathway in cardiac morphogenesis and remodeling

Neuregulin-1 (NRG1) signaling through tyrosine kinase receptors erbB2 and erbB4 was revealed essential for cardiac development as mouse mutated in the Nrg1 or either cognate receptors Erbb2 or Erbb4 genes lack the formation of trabeculae at the ventricular wall. Indeed, the injection of the NRG1 active peptide in developing embryos induced trabeculation of the ventricular free wall. The components of the NRG1 pathway have been identified and the cardiac activities are being progressively characterized. An acquired form of dilated cardiomyopathy was evidenced in a subpopulation of breast tumor patients undergoing a combined treatment with antibodies against erbB2 and chemotherapy. In this regard, the cardiomyocyte-specific gene deletion of either erbb2 or erbb4 leads to ventricular dilation in adult mice, providing an experimental model system to examine the NRG1-mediated activities. We reviewed the evidence on the growing field of research for NRG1 signaling in both cardiac morphogenesis and in the postnatal myocardial remodeling.Fil: Vasti, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; ArgentinaFil: Hertig, Cecilia Margarita. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentin

Neuregulin-1/erbB activities with focus on the susceptibility of the heart to anthracyclines

Neuregulin-1 (NRG1) signaling through the tyrosine kinase receptors erbB2 and erbB4 is required for cardiac morphogenesis, and it plays an essential role in maintaining the myocardial architecture during adulthood. The tyrosine kinase receptor erbB2 was first linked to the amplification and overexpression of erbb2 gene in a subtype of breast tumor cells, which is indicative of highly proliferative cells and likely a poor prognosis following conventional chemotherapy. The development of targeted therapies to block the survival of erbB2-positive cancer cells revealed that impaired NRG1 signaling through erbB2/erbB4 heterodimers combined with anthracycline chemotherapy may lead to dilated cardiomyopathy in a subpopulation of treated patients. The ventricular-specific deletion of either erbb2 or erbb4 manifested dilated cardiomyopathy, which is aggravated by the administration of doxorubicin. Based on the exacerbated toxicity displayed by the combined treatment, it is expected that the relevant pathways would be affected in a synergistic manner. This review examines the NRG1 activities that were monitored in different model systems, focusing on the emerging pathways and molecular targets, which may aid in understanding the acquired dilated cardiomyopathy that occurs under the conditions of NRG1-deficient signaling.Fil: Vasti, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Hertig, Cecilia Margarita. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentin

The role of the neuregulin-1/erbb signaling pathway in cardiac morphogenesis and remodeling

Neuregulin-1 (NRG1) signaling through tyrosine kinase receptors erbB2 and erbB4 was revealed essential for cardiac development as mouse mutated in the Nrg1 or either cognate receptors Erbb2 or Erbb4 genes lack the formation of trabeculae at the ventricular wall. Indeed, the injection of the NRG1 active peptide in developing embryos induced trabeculation of the ventricular free wall. The components of the NRG1 pathway have been identified and the cardiac activities are being progressively characterized. An acquired form of dilated cardiomyopathy was evidenced in a subpopulation of breast tumor patients undergoing a combined treatment with antibodies against erbB2 and chemotherapy. In this regard, the cardiomyocyte-specific gene deletion of either erbb2 or erbb4 leads to ventricular dilation in adult mice, providing an experimental model system to examine the NRG1-mediated activities. We reviewed the evidence on the growing field of research for NRG1 signaling in both cardiac morphogenesis and in the postnatal myocardial remodeling.Sociedad Argentina de Fisiologí

Camuflaje biológico para las nanoterapias del siglo XXI

Camuflaje biológico para las nanoterapias delsiglo XXICientos de grupos de investigación alrededor del mundo realizan esfuerzos con el objetivo de obtener terapias más efectivas y con menores efectos secundarios para millones de pacientes. Uno de ellos es el equipo de Biofisicoquímica de superficies, que trabaja en la Facultad de Ciencias Químicas de la Universidad Nacional de Córdoba. El grupo, bajo la dirección de la Dra. Carla Giacomelli, investiga las propiedades de distintos tipos de hidróxidos dobles laminares de tamaño nanométrico (NanoHDLs). Resultan materiales interesantes para ser utilizados como nanoportadores.Por Ricardo Rojas, Cecilia Vasti y Dariana Bedoya

Doxorubicin and NRG-1/erbB4-Deficiency Affect Gene Expression Profile: Involving Protein Homeostasis in Mouse

The accumulating evidence demonstrates the essential role of neuregulin-1 signaling in the adult heart, and, moreover, indicates that an impaired neuregulin signaling exacerbates the doxorubicin-mediated cardiac toxicity. Despite this strong data, the specific cardiomyocyte targets of the active erbB2/erbB4 heterodimer remain unknown. In this paper, we examined pathways involved in cardiomyocyte damage as a result of the cardiac sensitization to anthracycline toxicity in the ventricular muscle-specific erbB4 knockout mouse. We performed morphological analyses to evaluate the ventricular remodeling and employed a cDNA microarray to assess the characteristic gene expression profile, verified data by real-time RT-PCR, and then grouped into functional categories and pathways. We confirm the upregulation of genes related to the classical signature of a hypertrophic response, implicating an erbB2-dependent mechanism in doxorubicin-treated erbB4-KO hearts. Our results indicate the remarkable downregulation of IGF-I/PI-3′ kinase pathway and extends our current knowledge by uncovering an altered ubiquitin-proteasome system leading to cardiomyocyte autophagic vacuolization.Centro de Investigaciones Cardiovasculare

Pros and cons of coating layered double hydroxide nanoparticles with polyacrylate

Preventing the aggregation of layered double hydroxide nanoparticles (LDH-NP) and producing additional functionality are two important objectives for their applications as drug nanocarriers, among others. Adsorption of polyelectrolytes like polyacrylate (PA) is a promising approach to produce protective, functional coatings, but the effect of factors such as chain length, as well as the pros and cons of this strategy, have not been described. In this work, these aspects were studied using LDH-NP intercalated with chloride and benzoate as interlayer probes. The interaction between LDH-NP and PA, as well as the effect in the aggregation of the former, was studied as a function of the molecular weight (MW = 1.2, 8.0 and 450 kDa) and the PA concentration. High MW were more effective for preventing LDH-NP aggregation as well as for minimizing the PA intercalation between the layers. Thus, the 8.0 kDa PA allowed obtaining benzoate intercalated LDH-NP with a particle size around 200 nm that maintained 40% of the exchange sites occupied by benzoate anions. PA coating not only hindered aggregation and changed the particle charge, but also provided new functionality, such as a protective layer towards proton diffusion and, consequently, dissolution of LDH-NP. PA coating is then an effective tool for LDH-NP stabilization and customization, if interlayer anion loss is controlled.Fil: Vasti, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Giacomelli, Carla Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Rojas Delgado, Ricardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentin

Risedronate functionalized layered double hydroxides nanoparticles with bone targeting capabilities

Layered double hydroxides nanoparticles (LDH-NPs) are increasingly studied as drug nanocarriers for cellular delivery. Nevertheless, stable functionalizations providing targeting capabilities without disrupting the size of the carriers are necessary to achieve optimized performance. Here, LDH-NPs were functionalized with risedronate (Ris) to improve the osteotropicity of the nanocarriers without altering the nanosized distribution. Ris is a nitrogen containing bisphosphonate with rich acid-base reactivity that can lead Ris functionalized LDH-NPs also as pH-responsive drug nanocarriers. The current work is focused on the strategy to synthesize functionalized LDH-NPs with a maximum adsorption and a minimum intercalation of Ris while maintaining their nanosize. The speciation and interactions of Ris at the surface of LDH-NPs were analyzed using Raman microscopy whereas the functionalization stability and size distribution were checked in simulated biological media. Finally, pH sensitivity and hydroxyapatite binding capacity of Ris functionalized LDH-NPs were evaluated. HRis3 − anions were incorporated to the LDH-NPs surface with high affinity providing with a negative zeta potential that controlled the size at around 100 nm. The size of Ris functionalized LDH-NPs was not affected by the high ionic strength or the presence of proteins in simulated biological media. Further, the functionalization was stable against protein adsorption and anionic exchange. As expected, Ris functionalized LDH-NPs are bioresponsive with a high sensitivity for pH changes and specific affinity for hydroxyapatite, which makes them appealing drug nanocarriers for new bone therapies.Fil: Aristizabal, Dariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Vasti, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Rojas Delgado, Ricardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Giacomelli, Carla Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentin

Effect of the protein corona on the colloidal stability and reactivity of LDH-based nanocarriers

The physicochemical properties of drug nanocarriers such as layered double hydroxide nanoparticles (LDH-NPs) determine their circulation times in biological media and their interaction with the targeted cells. Nevertheless, the components of the biological fluid, and particularly the formation of a protein corona, change the properties of as-prepared nanocarriers. Here, we discuss the effect of the protein corona formation on the colloidal stability and reactivity of LDH-NPs intercalated with chloride (LDH-Cl), carbonate (LDH-CO3) or dodecylsulfate (LDH-DS). These solids present model physicochemical properties (hydrophillic character, surface charge, and exchange capacity) that can be obtained depending on the interaction of drugs with LDH layers. The colloidal stability of LDH-NPs was determined in simulated biological fluids at high ionic strength and/or the presence of albumin (the main protein of human blood plasma), whereas the reactivity was evaluated by dissolution kinetics in acidic media, compatible with the environment of cell internalized nanocarriers. The protein corona increased the colloidal stability of the nanocarriers by steric hindrance at high ionic strength, reverted the positive zeta potential of as-prepared LDH-NPs and protected them from dissolution at low pHs. The properties of the anionic cargo of LDH-NPs strongly affected the protein corona and hence the fate of NPs in biological fluids. Drug nanocarriers with interfacial properties similar to those of LDH-Cl and LDH-CO3 seem to be more promising than LDH-DS in forming a protein corona. Then, LDH-Cl and LDH-CO3 would enable long circulation times due to their size, colloidal stability and low protein damage. Our results indicate that LDH-NPs preserve and even improve their properties as drug nanocarriers after interacting with the biological media, particularly their ability to reach the site of therapeutic action from the injection place.Fil: Vasti, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Aristizabal, Dariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Rojas Delgado, Ricardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Giacomelli, Carla Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentin

Layered double hydroxide nanoparticles customization by polyelectrolyte adsorption: mechanism and effect on particle aggregation

Adsorption of polyelectrolytes (PEs) is a common strategy for stabilizing nanoparticles and customizing their properties. Although scarcely explored for layered double hydroxide nanoparticles (LDH-NPs), it can be used to increase their functionality in pharmaceutical and biomedical applications, among others. In this work, LDH-NPs intercalated with chloride, ibuprofen and ketoprofen were synthesized and modified with carboxylate containing PEs with different structures and physicochemical properties. The PEs adsorption mechanism on LDH-NPs and its effect on the aggregation of the obtained hybrids were studied by zeta potential and hydrodynamic diameter determinations on chloride intercalated LDH-NPs dispersions in the presence of polyacrylate (PA) at different concentrations. PA adsorption behavior was compared to that of citrate anion to contrast the adsorption mechanism of PEs and anions. Afterwards, the study was extended to other PEs (alginate and carbomer) as well as to drug intercalated LDH-NPs. PA adsorbed at the surface of LDH-NPs with high affinity: at low concentrations, PA was irreversibly adsorbed due to the positive structural charge of LDH-NPs and the flexible and negatively charged structure of PA. This high affinity caused a particle charge inversion, which results in negatively charged LDH-NPs stabilized by both electrostatic interactions and steric hindrance. Due to their structure, alginate and carbomer showed a lower affinity and, consequently, a lower capacity to produce LDH-NPs disaggregation. Finally, PEs adsorption allowed enhancing the disaggregation and modifying the interfacial properties of both ibuprofen and ketoprofen intercalated LDH-NPs producing only a small release of the drug loading.Fil: Vasti, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Borgiallo, Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Giacomelli, Carla Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Rojas Delgado, Ricardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentin