Mechanistic insights into the intracellular release of doxorubicin from pH-sensitive liposomes.

pH-sensitive liposomes are interesting carriers for drug-delivery, undertaking rapid bilayer destabilization in response to pH changes, allied to tumor accumulation, a desirable behavior in the treatment of cancer cells. Previously, we have shown that pH-sensitive liposomes accumulate in tumor tissues of mice, in which an acidic environment accelerates drug delivery. Ultimately, these formulations can be internalized by tumor cells and take the endosome-lysosomal route. However, the mechanism of doxorubicin release and intracellular traffic of pH-sensitive liposomes remains unclear. To investigate the molecular mechanisms underlying the intracellular release of doxorubicin from pH-sensitive liposomes, we followed HeLa cells viability, internalization, intracellular trafficking, and doxorubicin's intracellular delivery mechanisms from pH-sensitive (SpHL-DOX) and non-pH-sensitive (nSpHL-DOX) formulations. We found that SpHL-DOX has faster internalization kinetics and intracellular release of doxorubicin, followed by strong nuclear accumulation compared to nSpHL-DOX. The increased nuclear accumulation led to the activation of cleaved caspase-3, which efficiently induced apoptosis. Remarkably, we found that chloroquine and E64d enhanced the cytotoxicity of SpHL-DOX. This knowledge is paramount to improve the efficiency of pH-sensitive liposomes or to be used as a rational strategy for developing new formulations to be applied in vivo.

Thiol-antioxidants interfere with assessing silver nanoparticle cytotoxicity.

Many studies have shown that silver nanoparticles (AgNP) induce oxidative stress, and it is commonly assumed that this is the main mechanism of AgNP cytotoxicity. Most of these studies rely on antioxidants to establish this cause-and-effect relationship; nevertheless, details on how these antioxidants interact with the AgNP are often overlooked. This work aimed to investigate the molecular mechanisms underlying the use of antioxidants with AgNP nanoparticles. Thus, we studied the molecular interaction between the thiol-antioxidants (N-acetyl-L-Cysteine, L-Cysteine, and glutathione) or non-thiol-antioxidants (Trolox) with chemically and biologically synthesized AgNP. Both antioxidants could mitigate ROS production in Huh-7 hepatocarcinoma cells, but only thiol-antioxidants could prevent the cytotoxic effect, directly binding to the AgNP leading to aggregation. Our findings show that data interpretation might not be straightforward when using thiol-antioxidants to study the interactions between metallic nanoparticles and cells. This artifact exemplifies potential pitfalls that could hinder the progress of nanotechnology and the understanding of the nanotoxicity mechanism.

Deficits in Response Inhibition in Patients with Attention-Deficit/Hyperactivity Disorder: The Impaired Self-Protection System Hypothesis.

Problems in inhibitory control are regarded in Psychology as a key problem associated with attention-deficit/hyperactivity disorder (ADHD). They, however, might not be primary deficits, but instead a consequence of inattention. At least two components have been identified and dissociated in studies in regards to inhibitory control: interference suppression, responsible for controlling interference by resisting irrelevant or misleading information, and response inhibition, referring to withholding a response or overriding an ongoing behavior. Poor error awareness and self-monitoring undermine an individual's ability to inhibit inadequate responses and change course of action. In non-social contexts, an individual depends on his own cognition to regulate his mistakes. In social contexts, however, there are many social cues that should help that individual to perceive his mistakes and inhibit inadequate responses. The processes involved in perceiving and interpreting those social cues are arguably part of a self-protection system (SPS). Individuals with ADHD not only present impulsive behaviors in social contexts, but also have difficulty perceiving their inadequate responses and overriding ongoing actions toward more appropriate ones. In this paper, we discuss that those difficulties are arguably a consequence of an impaired SPS, due to visual attention deficits and subsequent failure in perceiving and recognizing accurately negative emotions in facial expressions, especially anger. We discuss evidence that children with ADHD exhibit problems in a series of components involved in the activation of that system and advocate that the inability to identify the anger expressed by others, and thus, not experiencing the fear response that should follow, is, ultimately, what prevents them from inhibiting the ongoing inappropriate behavior, since a potential threat is not registered. Getting involved in high-risk situations, such as reckless driving, could also be a consequence of not registering a threat and thus, not experiencing fear.

Attenuation of colitis injury in rats using Garcinia cambogia extract.

Inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis are chronic enteropathies that probably result from a dysregulated mucosal immune response. These pathologies are characterized by oxidative and nitrosative stress, leukocyte infiltration and up-regulation of pro-inflammatory substances. Current IBD treatment presents limitations in both efficacy and safety that stimulated the search for new active compounds. Garcinia cambogia extract has attracted interest due to its pharmacological properties, including gastroprotective effects. In this study, the antiinflammatory activity of a garcinia extract was assessed in TNBS-induced colitis rats. The results obtained revealed that garcinia administration to colitic rats significantly improved the macroscopic damage and caused substantial reductions in increases in MPO activity, COX-2 and iNOS expression. In addition, garcinia extract treatment was able to reduce PGE(2) and IL-1beta colonic levels. These antiinflammatory actions could be related to a reduction in DNA damage in isolated colonocytes, observed with the comet assay. Finally, garcinia extract caused neither mortality nor toxicity signals after oral administration. As such, the antiinflammatory effects provided by the Garcinia cambogia extract result in an improvement of several parameters analysed in experimental colitis and could provide a source for the search for new antiinflammatory compounds useful in IBD treatment.

Significando a morte, através de redes sociais, em um contexto de vulnerabilidade social: um estudo com crianças pré-escolares, seus pais e professores / The meaning of death, through social networks, in a socially vulnerable context: a study with children, their parents and their teachers

O presente artigo resulta de uma pesquisa realizada durante 2004, em um bairro popular de Salvador, com o objetivo de compreender os processos de significação da morte, apresentados por um grupo de crianças pré-escolares, que se encontravam em uma situação de vulnerabilidade social. O intuito primordial não foi descrever tais significados, mas compreender como o contexto vivenciado, intermediado pelas relações com pais e outros educadores, promoviam o surgimento de determinadas falas e comportamentos por parte das crianças. No contexto investigado, as crianças se encontravam expostas a mortes decorrentes de conflitos relacionados ao tráfico de drogas. Para atingir tal objetivo, foi desenvolvido um estudo exploratório, em uma creche, na qual entrevistamos doze crianças, nove dos seus responsáveis e quatro educadores. Os instrumentos foram adequados de acordo com cada um dos grupos. Como resultado do estudo, observamos que, apesar das crianças conviverem com situações de violência e morte, os pais encontram grandes dificuldades em abordarem o tema com as mesmas que não obstante trazem, principalmente para a escola, através da fala e das brincadeiras, as experiências vividas em sua comunidade.(AU)

This paper is the result of a research carried out in 2004, in a poor area of the city of Salvador. The objective was to understand the process of the meaning of death to a group of socially vulnerable preschool children. The study focused on the children's social network of parents and other educators in order to understand how these relationships gave a social basis to the construction of death meanings. In the social context of investigation, the children were frequently exposed to deaths caused by drug related conflicts. The research was carried out as an exploratory study, in a day care center with twelve children, nine of their caretakers and four teachers. The instruments were adapted to each group. As a result of this study, we observed that the parents had a hard time approaching the subject of violence and death with the children, although they lived in a context of violence and death. Nevertheless, these children would bring to school, through play and talk, their experiences of violence and death in their community.(AU)

Significando a morte, através de redes sociais, em um contexto de vulnerabilidade social: um estudo com crianças pré-escolares, seus pais e professores / The meaning of death, through social networks, in a socially vulnerable context: a study with children, their parents and their teachers

O presente artigo resulta de uma pesquisa realizada durante 2004, em um bairro popular de Salvador, com o objetivo de compreender os processos de significação da morte, apresentados por um grupo de crianças pré-escolares, que se encontravam em uma situação de vulnerabilidade social. O intuito primordial não foi descrever tais significados, mas compreender como o contexto vivenciado, intermediado pelas relações com pais e outros educadores, promoviam o surgimento de determinadas falas e comportamentos por parte das crianças. No contexto investigado, as crianças se encontravam expostas a mortes decorrentes de conflitos relacionados ao tráfico de drogas. Para atingir tal objetivo, foi desenvolvido um estudo exploratório, em uma creche, na qual entrevistamos doze crianças, nove dos seus responsáveis e quatro educadores. Os instrumentos foram adequados de acordo com cada um dos grupos. Como resultado do estudo, observamos que, apesar das crianças conviverem com situações de violência e morte, os pais encontram grandes dificuldades em abordarem o tema com as mesmas que não obstante trazem, principalmente para a escola, através da fala e das brincadeiras, as experiências vividas em sua comunidade.

This paper is the result of a research carried out in 2004, in a poor area of the city of Salvador. The objective was to understand the process of the meaning of death to a group of socially vulnerable preschool children. The study focused on the children's social network of parents and other educators in order to understand how these relationships gave a social basis to the construction of death meanings. In the social context of investigation, the children were frequently exposed to deaths caused by drug related conflicts. The research was carried out as an exploratory study, in a day care center with twelve children, nine of their caretakers and four teachers. The instruments were adapted to each group. As a result of this study, we observed that the parents had a hard time approaching the subject of violence and death with the children, although they lived in a context of violence and death. Nevertheless, these children would bring to school, through play and talk, their experiences of violence and death in their community.