Interplay of oxidative, nitrosative/nitrative stress, inflammation, cell death and autophagy in diabetic cardiomyopathy.

Diabetes is a recognized risk factor for cardiovascular diseases and heart failure. Diabetic cardiovascular dysfunction also underscores the development of diabetic retinopathy, nephropathy and neuropathy. Despite the broad availability of antidiabetic therapy, glycemic control still remains a major challenge in the management of diabetic patients. Hyperglycemia triggers formation of advanced glycosylation end products (AGEs), activates protein kinase C, enhances polyol pathway, glucose autoxidation, which coupled with elevated levels of free fatty acids, and leptin have been implicated in increased generation of superoxide anion by mitochondria, NADPH oxidases and xanthine oxidoreductase in diabetic vasculature and myocardium. Superoxide anion interacts with nitric oxide forming the potent toxin peroxynitrite via diffusion limited reaction, which in concert with other oxidants triggers activation of stress kinases, endoplasmic reticulum stress, mitochondrial and poly(ADP-ribose) polymerase 1-dependent cell death, dysregulates autophagy/mitophagy, inactivates key proteins involved in myocardial calcium handling/contractility and antioxidant defense, activates matrix metalloproteinases and redox-dependent pro-inflammatory transcription factors (e.g. nuclear factor kappaB) promoting inflammation, AGEs formation, eventually culminating in myocardial dysfunction, remodeling and heart failure. Understanding the complex interplay of oxidative/nitrosative stress with pro-inflammatory, metabolic and cell death pathways is critical to devise novel targeted therapies for diabetic cardiomyopathy, which will be overviewed in this brief synopsis. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.

Targeting autophagy to prevent neonatal stroke damage.

Cell death due to cerebral ischemia has been attributed to necrosis and apoptosis, but autophagic mechanisms have recently been implicated as well. Using rats exposed to neonatal focal cerebral ischemia, we have shown that lysosomal and autophagic activities are increased in ischemic neurons, and have obtained strong neuroprotection by post-ischemic inhibition of autophagy.

Metabolic and structural rearrangement during dark-induced autophagy in soybean (Glycine max L.) nodules: An electron microscopy and P-31 and C-13 nuclear magnetic resonance study

The effects of dark-induced stress on the evolution of the soluble metabolites present in senescent soybean (Glycine max L.) nodules were analysed in vitro using C-13- and P-31-NMR spectroscopy. Sucrose and trehalose were the predominant soluble storage carbons. During dark-induced stress, a decline in sugars and some key glycolytic metabolites was observed. Whereas 84% of the sucrose disappeared, only one-half of the trehalose was utilised. This decline coincides with the depletion of Gln, Asn, Ala and with an accumulation of ureides, which reflect a huge reduction of the N-2 fixation. Concomitantly, phosphodiesters and compounds like P-choline, a good marker of membrane phospholipids hydrolysis and cell autophagy, accumulated in the nodules. An autophagic process was confirmed by the decrease in cell fatty acid content. In addition, a slight increase in unsaturated fatty acids (oleic and linoleic acids) was observed, probably as a response to peroxidation reactions. Electron microscopy analysis revealed that, despite membranes dismantling, most of the bacteroids seem to be structurally intact. Taken together, our results show that the carbohydrate starvation induced in soybean by dark stress triggers a profound metabolic and structural rearrangement in the infected cells of soybean nodule which is representative of symbiotic cessation.

Neuronal death after perinatal cerebral hypoxia-ischemia: Focus on autophagy-mediated cell death.

Neonatal hypoxic-ischemic encephalopathy is a critical cerebral event occurring around birth with high mortality and neurological morbidity associated with long-term invalidating sequelae. In view of the great clinical importance of this condition and the lack of very efficacious neuroprotective strategies, it is urgent to better understand the different cell death mechanisms involved with the ultimate aim of developing new therapeutic approaches. The morphological features of three different cell death types can be observed in models of perinatal cerebral hypoxia-ischemia: necrotic, apoptotic and autophagic cell death. They may be combined in the same dying neuron. In the present review, we discuss the different cell death mechanisms involved in neonatal cerebral hypoxia-ischemia with a special focus on how autophagy may be involved in neuronal death, based: (1) on experimental models of perinatal hypoxia-ischemia and stroke, and (2) on the brains of human neonates who suffered from neonatal hypoxia-ischemia.

A macro-ecological perspective on crassulacean acid metabolism (CAM) photosynthesis evolution in Afro-Madagascan drylands: Eulophiinae orchids as a case study.

Crassulacean acid metabolism (CAM) photosynthesis is an adaptation to water and atmospheric CO2 deficits that has been linked to diversification in dry-adapted plants. We investigated whether CAM evolution can be associated with the availability of new or alternative niches, using Eulophiinae orchids as a case study. Carbon isotope ratios, geographical and climate data, fossil records and DNA sequences were used to: assess the prevalence of CAM in Eulophiinae orchids; characterize the ecological niche of extant taxa; infer divergence times; and estimate whether CAM is associated with niche shifts. CAM evolved in four terrestrial lineages during the late Miocene/Pliocene, which have uneven diversification patterns. These lineages originated in humid habitats and colonized dry/seasonally dry environments in Africa and Madagascar. Additional key features (variegation, heterophylly) evolved in the most species-rich CAM lineages. Dry habitats were also colonized by a lineage that includes putative mycoheterotrophic taxa. These findings indicate that the switch to CAM is associated with environmental change. With its suite of adaptive traits, this group of orchids represents a unique opportunity to study the adaptations to dry environments, especially in the face of projected global aridification.

Implication of different domains of the Leishmania major metacaspase in cell death and autophagy.

Metacaspases (MCAs) are cysteine peptidases expressed in plants, fungi and protozoa, with a caspase-like histidine-cysteine catalytic dyad, but differing from caspases, for example, in their substrate specificity. The role of MCAs is subject to debate: roles in cell cycle control, in cell death or even in cell survival have been suggested. In this study, using a Leishmania major MCA-deficient strain, we showed that L. major MCA (LmjMCA) not only had a role similar to caspases in cell death but also in autophagy and this through different domains. Upon cell death induction by miltefosine or H2O2, LmjMCA is processed, releasing the catalytic domain, which activated substrates via its catalytic dyad His/Cys and a proline-rich C-terminal domain. The C-terminal domain interacted with proteins, notably proteins involved in stress regulation, such as the MAP kinase LmaMPK7 or programmed cell death like the calpain-like cysteine peptidase. We also showed a new role of LmjMCA in autophagy, acting on or upstream of ATG8, involving Lmjmca gene overexpression and interaction of the C-terminal domain of LmjMCA with itself and other proteins. These results allowed us to propose two models, showing the role of LmjMCA in the cell death and also in the autophagy pathway, implicating different protein domains.

Idiosyncratic Volatility Puzzle: Influence of Macro-Finance Factors

In this paper, we scrutinize the cross-sectional relation between idiosyncratic volatility and stock returns. As a novelty, the idiosyncratic volatility is obtained by conditioning upon macro-finance factors as well as upon traditional asset pricing factors. The macro-finance factors are constructed from a large pool of macroeconomic and financial variables. Cleaning for macro-finance e§ects reverses the puzzling negative relation between returns and idiosyncratic volatility documented previously. Portfolio analysis shows that the effects from macro-finance factors are economically strong. The relation between idiosyncratic volatility and returns does not vary with the NBER business cycles. The empirical results are highly robust. Keywords: Idiosyncratic volatility puzzle; Macro-finance predictors; Factor analysis; Business cycle. JEL Classifications: G12; G14

Comparative effects of macro-sized aluminum oxide and aluminum oxide nanoparticles on erythrocyte hemolysis: influence of cell source, temperature and size

Al2O3 is the most abundantly produced nanomaterial and has been used in diverse fields, including the medical, military and industrial sectors. As there are concerns about the health effects of nanoparticles, it is important to understand how they interact with cells, and specifically with red blood cells. The hemolysis induced by three commercial nano-sized aluminum oxide particles (nanopowder 13 nm, nanopowder <50 nm and nanowire 2-6 nm × 200-400 nm) was compared to aluminum oxide and has been studied on erythrocytes from humans, rats and rabbits, in order to elucidate the mechanism of action and the influence of size and shape on hemolytic behavior. The concentrations inducing 50% hemolysis (HC50) were calculated for each compound studied. The most hemolytic aluminum oxide particles were of nanopowder 13, followed by nanowire and nanopowder 50. The addition of albumin to PBS induced a protective effect on hemolysis in all the nano-forms of Al2O3, but not on Al2O3. The drop in HC50 correlated to a decrease in nanomaterial size, which was induced by a reduction of aggregation Aluminum oxide nanoparticles are less hemolytic than other oxide nanoparticles, and behave differently depending on the size and shape of the nanoparticles. The hemolytic behavior of aluminum oxide nanoparticles differs from that of aluminum oxide.

Comparative effects of macro-sized aluminum oxide and aluminum oxide nanoparticles on erythrocyte hemolysis: influence of cell source, temperature and size

Al2O3 is the most abundantly produced nanomaterial and has been used in diverse fields, including the medical, military and industrial sectors. As there are concerns about the health effects of nanoparticles, it is important to understand how they interact with cells, and specifically with red blood cells. The hemolysis induced by three commercial nano-sized aluminum oxide particles (nanopowder 13 nm, nanopowder <50 nm and nanowire 2-6 nm × 200-400 nm) was compared to aluminum oxide and has been studied on erythrocytes from humans, rats and rabbits, in order to elucidate the mechanism of action and the influence of size and shape on hemolytic behavior. The concentrations inducing 50% hemolysis (HC50) were calculated for each compound studied. The most hemolytic aluminum oxide particles were of nanopowder 13, followed by nanowire and nanopowder 50. The addition of albumin to PBS induced a protective effect on hemolysis in all the nano-forms of Al2O3, but not on Al2O3. The drop in HC50 correlated to a decrease in nanomaterial size, which was induced by a reduction of aggregation Aluminum oxide nanoparticles are less hemolytic than other oxide nanoparticles, and behave differently depending on the size and shape of the nanoparticles. The hemolytic behavior of aluminum oxide nanoparticles differs from that of aluminum oxide.

Um panorama da nanotecnologia no Brasil (e seus macro-desafios)

The objectives of this essay are to describe the development of nanoscience and nanotechnology (N&N) in Brazil. The analysis shows that Brazilian research in N&N is considered satisfactory and, although under other denominations, dates from at least 20 years. Innovation is still less satisfactory and there are different points of views on the issue. However, there is already a tendency towards the promotion of innovation in nanotechnology in the country. Scientists and the industrial sector have been showing interest in partnerships and some scientific policies stimulate this articulation between academy and companies.

Estudo morfológico macro e microscópico da gastrite cáustica em ratos

OBJETIVOS: A ingestão de álcalis provoca graves lesões no tubo digestório alto. A comercialização de substâncias cáusticas em forma líquida facilita o seu uso com intenções suicidas e torna as afecções por elas provocadas relativamente comuns. Nesse sentido, o objetivo do presente trabalho foi avaliar as conseqüências morfológicas da infusão de substância cáustica no estômago murino. MÉTODO: Foram estudados 20 ratos Wistar adultos, de ambos os sexos. Após jejum alimentar de 12 horas, instilou-se 1ml de hidróxido de sódio (NaOH) a 5% através de cateter orogástrico. Os ratos foram divididos aleatoriamente em quatro grupos (n=5), de acordo com o tempo de acompanhamento: 24 horas, sete dias, 30 dias e 90 dias, respectivamente. Decorrido o tempo de acompanhamento, os ratos foram mortos e seus estômagos foram avaliados macro e microscopicamente. RESULTADOS: Após 24 horas, os estômagos estavam dilatados e com aderências ao fígado, omentos e pâncreas. Suas mucosa e submucosa apresentavam áreas de necrose de coagulação do corpo e do antro entremeada por intensa infiltração bacteriana. Após sete dias, os estômagos permaneciam dilatados e mantendo o mesmo padrão necrótico anterior, porém sem os focos sépticos. Nos grupos de um e três meses, a cavidade abdominal teve aspecto normal. Os estômagos apresentavam consistência endurecida e com proliferação fibrovascular. CONCLUSÃO: Os animais que sobreviveram à necrose e à intensa infiltração bacteriana da primeira semana desenvolveram reparação progressiva de seus estômagos, porém acompanhada de complicações decorrentes da fibrose cicatricial.

Avaliação macro e microscópica dos testículos em modelo experimental de criptorquidia pela secção do Gubernaculum testis em ratos

OBJETIVO: Verificar o efeito da secção distal do Gubernaculum testis como modelo experimental de criptorquidia unilateral em ratos. MÉTODO: Foram usados 36 ratos machos de linhagem Wistar-EPM, distribuídos em dois grupos: A (Grupo Experimento: animais submetidos à secção distal do gubernaculum direito) e B (Grupo Controle: operação simulada do lado direito). Cada grupo foi subdividido em 3 subgrupos com 6 animais cada : A-1, A-2 e A-3: B-1, B-2 e B-3. Os animais dos subgrupos A-1 e B-1 foram re-operados após 30 dias. Os animais dos subgrupos A-2 e B-2 foram mortos após 50 dias e os dos subgrupos A-3 e B-3 após 90 dias. RESULTADOS: Houve diferenças quanto ao peso, tamanho e posição do testículo afetado em relação ao lado controle,as quais só foram evidenciadas a partir do subgrupo A-2 (50 dias).O testículo não foi palpável na bolsa testicular em 88,9% dos casos e não houve óbito dos animais. Foram observadas alterações da maturidade celular, atrofia tubular, diminuição do diâmetro dos túbulos e ausência de espermatozóides na luz tubular no grupo A e presença de normalidade histológica para a idade nos animais do grupo B. CONCLUSÃO: O modelo experimental de produção de criptorquidia experimental unilateral pela secção do Gubernaculum testis em ratos foi eficaz e prático.