Dendrimers as vectors for genetic material delivery to the nervous system.

Transfection of genetic material into primary neuronal cultures remains a challenge because of the intrinsic difficulty in transfecting this type of cell. This review covers the recent developments in the use of dendrimers for siRNA and DNA transfection in both neuronal and glial cells. Crossing the blood brain barrier crossing represents a challenge for the effective use of dendrimer-mediated delivery of therapeutic agents to the central nervous system. We will discuss the effectiveness, both in vitro and in vivo, of various dendrimers in delivering genetic material to neural tissue and its ability to cross the blood-brain barrier. In addition, the use of dendrimers as a potential new therapy in the treatment of glioblastoma will be presented.

Role of generation, architecture, pH and ionic strength on successful siRNA delivery and transfection by hybrid PPV-PAMAM dendrimers.

Small interfering RNA (siRNA) constitutes an excellent way of knocking down genes. However, it requires the use of delivery systems to reach the target cells, especially to neuronal cells. Dendrimers are one of the most widely used synthetic nanocarriers for siRNA delivery. However, due to the complexity of the dendrimer-siRNA interactions, when a new dendritic carrier is designed it is difficult to predict its efficiency to bind and to deliver siRNA. At the same time it is not easy to understand the origin of eventual limited functionalities. We have modeled the interactions between two dendrimers (TDG-G1 and TDG-G2) and siRNA using molecular dynamics (MD) simulation. The results were compared to experimental physico-chemical parameters such as siRNA complexation, complex stability, size, and zeta potentials and biological effects such as down-regulation of a specific RNA expression in cortical neurons in culture. Data indicate that the combination of rigid core and flexible branches guarantees strong siRNA binding, which is important to have a good transfection profile. However, the successful nanocarrier for siRNA delivery (TDG-G1) is identified not only by a high affinity for siRNA, but by a favorable equilibrium between a strong binding and the ability to release siRNA to exert its biological action. The conditions under which the dendriplex is formed are also relevant for transfection efficiency and biological activity.

Phytoestrogen modulation of bone-related cytokines and its impact on cell viability in human prostate cancer cells.

AIMS: Prostate cancer (PCa) has a high propensity to metastasize to the bone. PCa cells produce several bone-related factors, namely parathyroid hormone related protein (PTHrP), its PTH type 1 receptor (PTH1R), osteoprotegerin (OPG), and receptor activator of NF-kappa B ligand (RANKL). The effects of these factors might explain, at least in part, the ability of PCa cells to grow in and interact with bone. MAIN METHODS: We first analyzed the expression of the aforementioned factors (by western blot and flow cytometry), and their modulation by the phytoestrogens genistein and daidzein (as potential anti-tumoral agents), in human PCa cells in vitro. We also assessed the impact of these osteomimetic factors on PCa cell viability (by propidium iodide staining and flow cytometry, and trypan blue staining). KEY FINDINGS: Genistein and daidzein, at nM range, increased both the PTHrP/PTH1R system and the OPG/RANKL protein ratio, while genistein and, to a lesser extent, daidzein, at >microM doses, inhibited cell viability in PCa cells. Both N- and C-terminal domains of PTHrP inhibited genistein-induced cell death by modulating transcription factor Runx-2 and the Bcl-2/Bax protein ratio in PCa cells. SIGNIFICANCE: Our findings indicate that high doses of genistein and daidzein cause PCa cell death. On the other hand, low doses of these phytoestrogens induce some osteomimetic features in PCa cells with putative impact on PCa development.

[Duloxetine and other tricyclic antidepressants: pharmacodynamic effects in the lower urinary tract]. / Duloxetina y otros antidepresivos tricíclicos: efectos farmacodinámicos en el tracto urinario inferior.

INTRODUCTION: During years the pharmacology of the lower urinary tract function has been presided by the protagonism of the autonomic nervous system and its components, sympathetic and parasympathetic. Recent investigations proved a greater complexity of micturional dynamics, attributing a more important role to the central nervous system (SNC), to the striated sphincter and to the afferent arc, offering a new opportunity to the Tricyclic Antidepressants (T.A.), reason for this general review. MATERIAL AND METHODS: Using as reference the work of the First Consultation on Incontinence (Montecarlo, 1999), the previous and later publications about T.A. have been reviewed, including experimental (isometric and "in vivo" studies) and clinical studies, investigating on pharmacological evidences, mechanism of action, tolerance and other effects of T.A. RESULTS: Only a reduced group of T.A. have been submitted to experimental evaluations and employed in clinical trials. The recent works on Duloxetine have waked up a special interest by their pharmacological potential. CONCLUSIONS: New knowledge on the peripheral and central control of the continence-miction dynamic offer new pathways for the treatment with T.A., whose effectiveness and tolerance are reviewed.