José Alberto Duarte

Paraquat Poisonings: Mechanisms of Lung Toxicity, Clinical Features, and Treatment

Paraquat dichloride (methyl viologen; PQ) is an effective and widely used herbicide that has a proven safety record when appropriately applied to eliminate weeds. However, over the last decades, there have been numerous fatalities, mainly caused by accidental or voluntary ingestion. PQ poisoning is an extremely frustrating condition to manage clinically, due to the elevated morbidity and mortality observed so far and due to the lack of effective treatments to be used in humans. PQ mainly accumulates in the lung (pulmonary concentrations can be 6 to 10 times higher than those in the plasma), where it is retained even when blood levels start to decrease. The pulmonary effects can be explained by the participation of the polyamine transport system abundantly expressed in the membrane of alveolar cells type I, II, and Clara cells. Further downstream at the toxicodynamic level, the main molecular mechanism of PQ toxicity is based on redox cycling and intracellular oxidative stress generation. With this review we aimed to collect and describe the most pertinent and significant findings published in established scientific publications since the discovery of PQ, focusing on the most recent developments related to PQ lung toxicity and their relevance to the treatment of human poisonings. Considerable space is also dedicated to techniques for prognosis prediction, since these could allow development of rigorous clinical protocols that may produce comparable data for the evaluation of proposed therapies.

Effect of surface coating on the biodistribution profile of gold nanoparticles in the rat

Successful application of gold nanoparticles (AuNPs) in biomedicine requires extensive safety assessment for which biokinetic studies are crucial. We evaluated the biodistribution of AuNPs (∼20 nm) with different surface coatings: citrate, 11-MUA and 3 pentapeptides, CALNN, CALND and CALNS, after i.v. administration to rats (0.6-1 mg Au/kg). Biodistribution was evaluated based on Au tissue content measured by GFAAS. Citrate-AuNPs were rapidly removed from circulation with 60% of the injected dose depositing in the liver. Thirty minutes post-injection, the lungs presented about 6% of the injected dose with levels decreasing to 0.7% at 24 h. Gold levels in the spleen were of 2.6%. After 24 h, liver presented the highest Au level, followed by spleen and blood. A similar biodistribution profile was observed for MUA-coated AuNPs compared to Cit-AuNPs at 24h post-injection, while significantly higher levels of peptide-capped AuNPs were found in the liver (74-86%) accompanied by a corresponding decrease in blood levels. TEM analysis of liver slices showed AuNPs in Kupffer cells and hepatocytes, trapped inside endosomes. Our data demonstrate that AuNPs are rapidly distributed and that the liver is the preferential accumulation organ. Peptide capping significantly increased hepatic uptake, showing the influence of AuNPs functionalization in biodistribution.

Pesticides exposure as etiological factors of Parkinson's disease and other neurodegenerative diseases—A mechanistic approach

The etiology of most neurodegenerative disorders is multifactorial and consists of an interaction between environmental factors and genetic predisposition. The role of pesticide exposure in neurodegenerative disease has long been suspected, but the specific causative agents and the mechanisms underlying are not fully understood. For the main neurodegenerative diseases such as Parkinsons disease, Alzheimers disease and amyotrophic lateral sclerosis there are evidences linking their etiology with long-term/low-dose exposure to pesticides such as paraquat, maneb, dieldrin, pyrethroids and organophosphates. Most of these pesticides share common features, namely the ability to induce oxidative stress, mitochondrial dysfunction, α-synuclein fibrillization and neuronal cell loss. This review aims to clarify the role of pesticides as environmental risk factors in genesis of idiopathic PD and other neurological syndromes. For this purpose, the most relevant epidemiological and experimental data is highlighted in order to discuss the molecular mechanisms involved in neurodegeneration.

Exercise, Muscle Damage and Fatigue

SummaryFatigue as a functional sign and muscle damage as a structural sign can be observed after prolonged exercise like marathon running or after strenuous exercise, especially with the involvement of eccentric contractions. For fatigue due to prolonged exercise, hypoxic conditions and the formation of free oxygen radicals seem to be of aetiological importance, resulting in an elevated lysosomal activity. Eccentric exercise of high intensity rather results in a mechanical stress to the fibres. Although these different mechanisms can be discerned experimentally, both result in similar impairments of muscle function. A good training status may attenuate the clinical signs of fatigue and muscle damage. The symptoms and events occurring during delayed onset of muscle soreness (DOMS) can be explained by a cascade of events following structural damage to muscle proteins.

Physical activity and school recess time: differences between the sexes and the relationship between children's playground physical activity and habitual physical activity.

The aims of this study were: (1) to observe participation in moderate-to-vigorous physical activity (MVPA) during school recess periods; (2) to determine the relative importance of physical activity during recesses to overall daily physical activity; and (3) to examine differences in physical activity between the sexes during unstructured recess periods. The participants were 22 school children (10 boys, 12 girls) aged 8 – 10 years (mean  =  8.9, s  =  0.7) in the third and fourth grades. Daily totals for the physical activity variables were calculated by summing the values for each hour of 14 h of physical activity measurements (08:00 to 22:00 h). Recess times (minutes) were as follows: morning 10:30 to 11:00 h and afternoon 15:30 to 16:00 h. We did not differences between boys and girls in daily total accelerometer counts or the overall time spent in MVPA. However, girls were significantly (P  < 0.05) more involved (38%) in MVPA during recess time than boys (31%). Participation in MVPA during recess contributes significantly more (P  < 0.05) for girls (19%) than boys (15%) to the total amount of physical activity suggested by international health-related physical activity guidelines, while the percentage of time engaged in MVPA during recess time at school accounts for a small amount of the daily MVPA (6% for boys and 8% for girls). The results of this study suggest that school recess time is an important setting to promote MVPA and contributes to daily physical activity in young children, especially in girls.

Mitochondrial signaling contributes to disuse muscle atrophy.

It is well established that long durations of bed rest, limb immobilization, or reduced activity in respiratory muscles during mechanical ventilation results in skeletal muscle atrophy in humans and other animals. The idea that mitochondrial damage/dysfunction contributes to disuse muscle atrophy originated over 40 years ago. These early studies were largely descriptive and did not provide unequivocal evidence that mitochondria play a primary role in disuse muscle atrophy. However, recent experiments have provided direct evidence connecting mitochondrial dysfunction to muscle atrophy. Numerous studies have described changes in mitochondria shape, number, and function in skeletal muscles exposed to prolonged periods of inactivity. Furthermore, recent evidence indicates that increased mitochondrial ROS production plays a key signaling role in both immobilization-induced limb muscle atrophy and diaphragmatic atrophy occurring during prolonged mechanical ventilation. Moreover, new evidence reveals that, during denervation-induced muscle atrophy, increased mitochondrial fragmentation due to fission is a required signaling event that activates the AMPK-FoxO3 signaling axis, which induces the expression of atrophy genes, protein breakdown, and ultimately muscle atrophy. Collectively, these findings highlight the importance of future research to better understand the mitochondrial signaling mechanisms that contribute to disuse muscle atrophy and to develop novel therapeutic interventions for prevention of inactivity-induced skeletal muscle atrophy.

Is exercise training an effective therapy targeting endothelial dysfunction and vascular wall inflammation

There is an increasing evidence that endothelial dysfunction and vascular wall inflammation are present in all stages of atherosclerosis. Atherosclerosis does not have to necessarily progress to an acute clinical event. Several therapeutic strategies exist, such as exercise training, which mitigates endothelial dysfunction and inflammation. Exercise training consistently improves the nitric oxide bioavailability, and the number of endothelial progenitor cells, and also diminishes the level of inflammatory markers, namely pro-inflammatory cytokines and C-reactive protein. However, the mechanisms by which exercise improves endothelial function in coronary artery disease patients are not fully clarified. Several mechanisms have been proposed to explain the positive effect of exercise on the disease progression. They include the decrease in cytokine production by the adipose tissue, skeletal muscles, endothelial cells, and blood mononuclear cells, and also, the increase in the bioavailability of nitric oxide, antioxidant defences, and regenerative capacity of endothelium. This study aims to provide a critical review of the literature linking exercise, inflammation, and endothelial dysfunction in coronary artery patients, and to discuss the potential mechanisms behind the exercise-training improvement of endothelial function and inflammatory status.

Analysis of the human saliva proteome

Interest in the characterization of the salivary proteome has increased in the last few years. This review discusses the different techniques and methodologies applied to the separation and identification of salivary proteins. Nowadays, proteomic techniques are the state of the art for the analysis of biologic materials and saliva is no exception. 2D electrophoresis and tryptic digest analysis by mass spectrometry are the typical methodology, but new approaches using 2D liquid chromatography/mass spectrometry methods have already been introduced for saliva analysis. Due to their important physiologic role in the oral cavity, low-molecular-weight proteins and peptides are also included in this article and the methodologies discussed.

The role of mitochondria in aging of skeletal muscle

Aging can be characterized as a time dependent decline of maximal functionality that affects tissues and organs of the whole body. Such is induced by the progressive loss of redundant components and leads to an increased susceptibility to disease and risk of death. Regarding the aging of skeletal muscle, it has been pointed out that mitochondria is a key factor behind the loss of redundancy and functionality, since this organelle has a major role in cellular homeostasis particularly at the level of the bioenergetic status. Decreased activities of the mitochondrial electron transport chain complexes and an increased release of reactive oxygen species from mitochondria are well documented with age; it is suggested that the mitochondrial loss of function results from the increased oxidative damage to proteins, lipids, and DNA of this organelle. However, it is important to be aware that the mitochondrial loss of function could also be a consequence, rather than a cause, of the cellular deterioration with age, which compromises mitochondrial biogenesis, mitochondrial protein turnover and autophagocytosis of damaged mitochondria. In this review several topics will be addressed regarding the age-related loss of skeletal muscle redundancy associated with mitochondrial dysfunction, emphasizing hypotheses for underlying mechanisms. In addition, we discuss some of the cellular mechanisms that can be pointed out as being responsible for the age-related mitochondrial dysfunction.

Genes and elite athletes: a roadmap for future research

Abstract  There is compelling evidence that genetic factors influence several phenotype traits related to physical performance and training response as well as to elite athletic status. Previous case‐control studies showed that ∼20 genetic variants seem to be associated with elite endurance athletic status. The present review aims to introduce novel methodological approaches in the field of sports genetics research, which can be applied in the near future to analyse the genotype profile associated with elite athletic status. These include genotype–phenotype association studies using gene expression analysis, analysis of post‐transcriptional factors, particularly microRNAs, genome‐wide scan linkage or genome‐wide association studies, and novel algorithm approaches, such as ‘genotype scores’. Several gaps in the current body of knowledge have been indentified including, among others: small sample size of most athletic cohorts, lack of corroboration with replication cohorts of different ethnic backgrounds (particularly, made up of non‐Caucasian athletes), the need of research accounting for the potential role of epigenetics in elite athletic performance, and also the need for future models that take into account the association between athletic status and complex gene–gene and gene–environment interactions. Some recommendations are provided to minimize research limitations in the field of sport genetics.