Inhibition of renin angiotensin system decreases renal protein oxidative damage in diabetic rats

Renin angiotensin system (RAS) worsens diabetic nephropathy (DN) by increasing oxidative stress. We compared the effect of three different RAS inhibitors: the angiotensin converting enzyme inhibitor Ramipril, the vasopeptidase inhibitor AVE7688 and the angiotensin receptor (AT1) antagonist Losartan on the formation of oxidative and carbonyl stress derived protein modifications in kidney from Zucker obese hyperglycemic rats (ZDFn Gm-fa/fa). Gas chromatography-mass spectrometry was used to measure representative markers of several protein oxidative pathways: direct oxidation [dinitrophenylhydrazine reactive carbonyls (DNP), glutamic (GSA), and aminoadipic (AASA) semialdehydes], mixed glyco- and lipoxidation [N^ε-carboxyethyl-lysine (CEL) and N^ε-(carboxymethyl)-lysine (CML)] and lipoxidation-[N^ε-(malondialdehyde)-lysine-(MDAL)], as well as renal fatty acid composition. Urinary albumin (a marker of DN), DNP, GSA, and MDAL levels, were increased in all obese rats and were dose dependently decreased by AVE7688 whereas Ramipril and Losartan were less efficient. These results show that RAS inhibition improves DN at several levels, independently of its effects on blood pressure and glycemic control, via mechanisms depending of renal oxidative stress.     

Effect of free fatty acids on the bioavailability of plasma testosterone and dihydrotestosterone

Free fatty acids (FFA) are known to interfere with the binding of thyroid hormone and estrogens to circulating proteins, but their effect on androgen binding is unknown. The effect of linoleic, oleic and palmitic acids at physiological concentrations on the binding of testosterone (T) and dihydrotestosterone (DHT) to circulating proteins was evaluated in vitro, using equilibrium dialysis and ammonium sulfate precipitation techniques. The results indicate that FFA can inhibit T binding to albumin and SHBG. They also can inhibit DHT binding to albumin, whereas DHT binding to SHBG is not altered, suggesting that FFA at physiological concentrations may be important regulators of bioavailability of T to tissues.     

Early life environment determines the development of adult phobic‐like fear responses in BALB/cAnN mice

Environmental factors may unleash genetically determined susceptibility to psychopathology. Great effort has been spent in identifying both the genetic basis and environmental sources of exaggerated fear in animal models of anxiety disorders. Here, we show that the origin of inbred mice, probably via subtle differences in breeding and rearing conditions, may have large consequences specifically on acquisition and retention of fear memories, while leaving anxiety‐related behaviours unaffected. These effects could be seen in BALB/cAnN (BALB), but not in C57BL/6N (C57BL/6) mice, thus suggesting their dependency on the genetic background. Increased susceptibility for developing exaggerated fear responses was accompanied by decreased long‐term depression and increased surface trafficking of the AMPA receptor GluR1 subunit at the level of the basolateral amygdala complex. Together, these data raise a novel caveat in the debate about the origins of variation in behavioural studies with experimental animals. Considering that there are currently no animal models which explicitly consider conceptual analogy to the specific gene–environment interactions observed in the aetiology of phobias, our study might suggest a novel approach and direction for further preclinical studies focusing on such aspects of phobic‐like fears.     

Evaluation of the WHO classification of dengue disease severity during an epidemic in 2011 in the state of Ceará, Brazil

In 2009, the World Health Organization (WHO) issued a new guideline that stratifies dengue-affected patients into severe (SD) and non-severe dengue (NSD) (with or without warning signs). To evaluate the new recommendations, we completed a retrospective cross-sectional study of the dengue haemorrhagic fever (DHF) cases reported during an outbreak in 2011 in northeastern Brazil. We investigated 84 suspected DHF patients, including 45 (53.6%) males and 39 (46.4%) females. The ages of the patients ranged from five-83 years and the median age was 29. According to the DHF/dengue shock syndrome classification, 53 (63.1%) patients were classified as having dengue fever and 31 (36.9%) as having DHF. According to the 2009 WHO classification, 32 (38.1%) patients were grouped as having NSD [4 (4.8%) without warning signs and 28 (33.3%) with warning signs] and 52 (61.9%) as having SD. A better performance of the revised classification in the detection of severe clinical manifestations allows for an improved detection of patients with SD and may reduce deaths. The revised classification will not only facilitate effective screening and patient management, but will also enable the collection of standardised surveillance data for future epidemiological and clinical studies.     

Genetic and biological characterization of a densovirus isolate that affects dengue virus infection

Brevidensoviruses have an encapsidated, single-stranded DNA genome that predominantly has a negative polarity. In recent years, they have received particular attention due to their potential role in the biological control of pathogenic arboviruses and to their unnoticed presence in cell cultures as contaminants. In addition, brevidensoviruses may also be useful as viral vectors. This study describes the first genetic and biological characterization of a mosquito densovirus that was isolated in Brazil; moreover, we examined the phylogenetic relationship between this isolate and the other brevidensoviruses. We further demonstrate that this densovirus has the potential to be used to biologically control dengue virus (DENV) infection with in vitro co-infection experiments. The present study provides evidence that this densovirus isolate is a fast-spreading virus that affects cell growth and DENV infection.     

Thyroid status modulates glycoxidative and lipoxidative modification of tissue proteins.

Steady state protein modification by carbonyl compounds is related to the rate of carbonyl adduct formation and the half-life of the protein. Thyroid hormones are physiologic modulators of both tissue oxidative stress and protein degradation. The levels of the glycation product N(epsilon)-fructoselysine (FL) and those of the oxidation products, N(epsilon)-(carboxymethyl)lysine (CML) and malondialdehyde-lysine (MDA-lys), identified by GC/MS in liver proteins, decreased significantly in hyperthyroid rats, as well as (less acutely) in hypothyroid animals. Immunoblotting of liver proteins for advanced glycation end-products (AGE) is in agreement with the results obtained by GC/MS. Cytosolic proteolytic activity against carboxymethylated foreign proteins measured in vitro was significantly increased in hypo- and hyperthyroidism. Oxidative damage to DNA, estimated as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8oxodG), did not show significant differences between groups. The results suggests that the steady state levels of these markers depend on the levels of thyroid hormones, presumably through their combined effects on the rates of protein degradation and oxidative stress, whereas DNA is more protected from oxidative damage.     

Presence of Blastocystis in gut microbiota is associated with cognitive traits and decreased executive function

Growing evidence implicates the gut microbiome in cognition. Blastocystis is a common gut single-cell eukaryote parasite frequently detected in humans but its potential involvement in human pathophysiology has been poorly characterized. Here we describe how the presence of Blastocystis in the gut microbiome was associated with deficits in executive function and altered gut bacterial composition in a discovery (n = 114) and replication cohorts (n = 942). We also found that Blastocystis was linked to bacterial functions related to aromatic amino acids metabolism and folate-mediated pyrimidine and one-carbon metabolism. Blastocystis-associated shifts in bacterial functionality translated into the circulating metabolome. Finally, we evaluated the effects of microbiota transplantation. Donor’s Blastocystis subtypes led to altered recipient’s mice cognitive function and prefrontal cortex gene expression. In summary, Blastocystis warrant further consideration as a novel actor in the gut microbiome-brain axis.Subject terms: Biomarkers, Pathogenesis, Diagnosis     

Cerebral malaria and the hemolysis/methemoglobin/heme hypothesis: shedding new light on an old disease

Malaria causes more than 1 million deaths every year with cerebral malaria (CM) being a major cause of death in Sub-Saharan African children. The nature of the malaria-associated pathogenesis is complex and multi-factorial. A unified hypothesis involving sequestration of infected red blood cells, systemic host inflammatory response and hemostasis dysfunction has been proposed to explain the genesis of CM. In this review, we discuss the role of hemolysis, methemoglobin and free heme in CM, brought to light by our recent studies in mice as well as by other studies in humans.