Fernando Ribeiro Gomes

Obesidade e doença arterial coronariana: papel da inflamação vascular

A obesidade vem se tornando uma epidemia global. Cerca de 1,1 bilhoes de adultos e 10% das criancas do mundo sao atualmente considerados portadores de sobrepeso ou obesos. Classicamente associada a fatores de risco para doenca cardiovascular, como diabete melito e hipertensao arterial sistemica, a obesidade vem sendo cada vez mais encarada como fator de risco independente para doenca arterial coronariana (DAC). A aterosclerose coronariana compreende uma serie de respostas inflamatorias em nivel celular e molecular, cujas reacoes se encontram mais exacerbadas em pacientes obesos. Antes considerado mero deposito de gordura, o tecido adiposo e visto hoje em dia como orgao endocrino e paracrino ativo, produtor de diversas citocinas inflamatorias, como as adipocinas. Este artigo visa alertar para o grave problema de saude publica em que a obesidade se tornou nas ultimas decadas e correlacionar o processo inflamatorio exacerbado nos individuos obesos com a maior incidencia de DAC nessa populacao.Obesity is becoming a global epidemic. Around 1.1 billion adults and 10% of the worlds children are currently overweight or considered obese. Generally associated with risk factors for cardiovascular disease, such as Diabetes Mellitus and systemic arterial high blood pressure, the obesity has been more and more seen as an independent risk factor for Coronary Artery Disease (CAD). Coronary arteriosclerosis comprises a series of inflammatory responses at cellular and molecular level, whose reactions are stronger in obese patients. In the past, the adipose tissue was regarded as a mere fat deposition. Now it is seen from a totally different standpoint, as an active endocrine and paracrine organ that produces several inflammatory cytokines, such as the adipokines. This article aims to raise awareness about obesity as an increasingly significant public health issue over the past decades, as well as to relate the intense inflammatory process in obese individuals with an increased tendency for this group of individuals to develop CAD.

Obesity and coronary artery disease: role of vascular inflammation

A obesidade vem se tornando uma epidemia global. Cerca de 1,1 bilhoes de adultos e 10% das criancas do mundo sao atualmente considerados portadores de sobrepeso ou obesos. Classicamente associada a fatores de risco para doenca cardiovascular, como diabete melito e hipertensao arterial sistemica, a obesidade vem sendo cada vez mais encarada como fator de risco independente para doenca arterial coronariana (DAC). A aterosclerose coronariana compreende uma serie de respostas inflamatorias em nivel celular e molecular, cujas reacoes se encontram mais exacerbadas em pacientes obesos. Antes considerado mero deposito de gordura, o tecido adiposo e visto hoje em dia como orgao endocrino e paracrino ativo, produtor de diversas citocinas inflamatorias, como as adipocinas. Este artigo visa alertar para o grave problema de saude publica em que a obesidade se tornou nas ultimas decadas e correlacionar o processo inflamatorio exacerbado nos individuos obesos com a maior incidencia de DAC nessa populacao.Obesity is becoming a global epidemic. Around 1.1 billion adults and 10% of the worlds children are currently overweight or considered obese. Generally associated with risk factors for cardiovascular disease, such as Diabetes Mellitus and systemic arterial high blood pressure, the obesity has been more and more seen as an independent risk factor for Coronary Artery Disease (CAD). Coronary arteriosclerosis comprises a series of inflammatory responses at cellular and molecular level, whose reactions are stronger in obese patients. In the past, the adipose tissue was regarded as a mere fat deposition. Now it is seen from a totally different standpoint, as an active endocrine and paracrine organ that produces several inflammatory cytokines, such as the adipokines. This article aims to raise awareness about obesity as an increasingly significant public health issue over the past decades, as well as to relate the intense inflammatory process in obese individuals with an increased tendency for this group of individuals to develop CAD.

Intraspecific relationships between resting and activity metabolism in anuran amphibians: influence of ecology and behavior.

The aerobic capacity model, as well as other models for the evolution of aerobic metabolism and the origin of endothermy, requires a mechanistic link between rates of resting and activity oxygen consumption (V̇o2 rest and V̇o2 act). The existence of such link is still controversial, but studies with anuran amphibians support a correlation between V̇o2 rest and V̇o2 act at both the intraspecific and interspecific levels. Because results at the intraspecific level are based only on a few species, we test for the generality of a link between these two metabolic variables in anurans by studying the intraspecific correlational patterns between mass‐independent V̇o2 rest and V̇o2 act in anurans. We focus on 21 Neotropical species from different geographical areas that include remarkable diversity in behavior and thermal ecology. Although uncorrelated, V̇o2 rest and V̇o2 act seem to be consistent among individuals. Diverse intraspecific phenotypic correlational trends were detected, indicating that the intraspecific relationships between V̇o2 rest and V̇o2 act might be very diverse in anurans. The three possible trends (positive, negative, and absent correlations) were observed and appeared to be predictable from ecological and behavioral variables that relate to evolutionary physiological shifts in anurans. Positive correlations between V̇o2 rest and V̇o2 act were more common in species with active lifestyles (e.g., intense vocal activity) and in species that call at low temperatures (e.g., winter or high‐elevation specialists).

Defective functionality of small, dense HDL3 subpopulations in ST segment elevation myocardial infarction: Relevance of enrichment in lysophosphatidylcholine, phosphatidic acid and serum amyloid A

BACKGROUND Low plasma levels of high-density lipoprotein-cholesterol (HDL-C) are typical of acute myocardial infarction (MI) and predict risk of recurrent cardiovascular events. The potential relationships between modifications in the molecular composition and the functionality of HDL subpopulations in acute MI however remain indeterminate. METHODS AND RESULTS ST segment elevation MI (STEMI) patients were recruited within 24h after diagnosis (n=16) and featured low HDL-C (-31%, p<0.05) and acute-phase inflammation (determined as marked elevations in C-reactive protein, serum amyloid A (SAA) and interleukin-6) as compared to age- and sex-matched controls (n=10). STEMI plasma HDL and its subpopulations (HDL2b, 2a, 3a, 3b, 3c) displayed attenuated cholesterol efflux capacity from THP-1 cells (up to -32%, p<0.01, on a unit phospholipid mass basis) vs. CONTROLS Plasma HDL and small, dense HDL3b and 3c subpopulations from STEMI patients exhibited reduced anti-oxidative activity (up to -68%, p<0.05, on a unit HDL mass basis). HDL subpopulations in STEMI were enriched in two proinflammatory bioactive lipids, lysophosphatidylcholine (up to 3.0-fold, p<0.05) and phosphatidic acid (up to 8.4-fold, p<0.05), depleted in apolipoprotein A-I (up to -23%, p<0.05) and enriched in SAA (up to +10.2-fold, p<0.05); such changes were most marked in the HDL3b subfraction. In vitro HDL enrichment in both lysophosphatidylcholine and phosphatidic acid exerted deleterious effects on HDL functionality. CONCLUSIONS In the early phase of STEMI, HDL particle subpopulations display marked, concomitant alterations in both lipidome and proteome which are implicated in impaired HDL functionality. Such modifications may act synergistically to confer novel deleterious biological activities to STEMI HDL. SIGNIFICANCE Our present data highlight complex changes in the molecular composition and functionality of HDL particle subpopulations in the acute phase of STEMI, and for the first time, reveal that concomitant modifications in both the lipidome and proteome contribute to functional deficiencies in cholesterol efflux and antioxidative activities of HDL particles. These findings may provide new biomarkers and new insights in therapeutic strategy to reduce cardiovascular risk in this clinical setting where such net deficiency in HDL function, multiplied by low circulating HDL concentrations, can be expected to contribute to accelerated atherogenesis.

Effects of Acute Restraint Stress, Prolonged Captivity Stress and Transdermal Corticosterone Application on Immunocompetence and Plasma Levels of Corticosterone on the Cururu Toad (Rhinella icterica)

Glucocorticoid steroids modulate immunocompetence in complex ways with both immunoenhancing and immunosuppressive effects in vertebrates exposed to different stressors. Such bimodal effects have been associated with variation in duration and intensity of the stress response. Given that natural populations have been exposed to a multitude of stressors, a better understanding of the functional association between duration and intensity of the stress response, the resulting changes in glucocorticoid plasma levels and their impact on different aspects of immunocompetence emerges as a cornerstone for vertebrate conservation strategies. We investigated the effects of a restraint challenge (with and without movement restriction), long-term captivity, and transdermal corticosterone application on plasma levels of corticosterone (hereinafter referred to as CORT) and different parameters of innate immunocompetence in the male cururu toads (Rhinella icterica). We show that for R. icterica restraint for 24h proved to be a stressful condition, increasing CORT by 3-fold without consistent immunological changes. However, the application of a more intense stressor (restraint with movement restriction), for the same period, potentiated this response resulting in a 9-fold increase in CORT, associated with increase Neutrophil/Lymphocyte ratio (N:L) and a lower bacterial killing ability (BKA). Transdermal application of corticosterone efficiently mimics repeated acute stress response events, without changing the immune parameters even after 13 days of treatment. Interestingly, long-term captivity did not mitigate the stress response, since the toads maintained 3-fold increased CORT even after 3 months under these conditions. Moreover, long-term captivity in the same condition increased total leukocyte count (TLC) and generated an even greater decrease in BKA, suggesting that consequences of the stress response can be aggravated by time in captivity.

Vocal and territorial behavior in the Smith frog (Hypsiboas faber): relationships with plasma levels of corticosterone and testosterone.

The possible trade-off between the roles of glucocorticoids as facilitators of energy substrate mobilization and neural inhibitors of sexual behavior during breeding season is under debate. We studied the relationship between calling and territorial behavior with plasma levels of corticosterone (CORT) and plasma levels of testosterone (T) across the breeding season of Hypsiboas faber, a large and territorial Neotropical treefrog. We investigated these relationships through focal observations of males calling naturally, followed by blood sampling for hormonal radioimmunoassay. We additionally used an experimental approach, which consisted of broadcasting recorded advertisement calls for 10 min to simulate an invasion in the territory of the focal subjects, followed by behavioral observation and blood sampling for hormonal radioimmunoassay. Results showed a pattern of co-variation between CORT and T across the breeding season. Furthermore, individual variation in CORT and T was related to different aspects of behavior: individuals with higher CORT showed higher calling rates, and individuals with higher steroid levels, mainly T, showed higher responsivity to social stimulation by other males in the chorus. Experimental simulation of territorial intrusion by using playback of advertisement calls of this species did not elicit consistent changes in agonistic behavior and CORT, but decreased T in focal males.

Over-expression of COQ10 in Saccharomyces cerevisiae inhibits mitochondrial respiration

COQ10 deletion in Saccharomyces cerevisiae elicits a defect in mitochondrial respiration correctable by addition of coenzyme Q(2). Rescue of respiration by Q(2) is a characteristic of mutants blocked in coenzyme Q(6) synthesis. Unlike Q(6) deficient mutants, mitochondria of the coq10 null mutant have wild-type concentrations of Q(6). The physiological significance of earlier observations that purified Coq10p contains bound Q(6) was examined in the present study by testing the in vivo effect of over-expression of Coq10p on respiration. Mitochondria with elevated levels of Coq10p display reduced respiration in the bc1 span of the electron transport chain, which can be restored with exogenous Q(2). This suggests that in vivo binding of Q(6) by excess Coq10p reduces the pool of this redox carrier available for its normal function in providing electrons to the bc1 complex. This is confirmed by observing that extra Coq8p relieves the inhibitory effect of excess Coq10p. Coq8p is a putative kinase, and a high-copy suppressor of the coq10 null mutant. As shown here, when over-produced in coq mutants, Coq8p counteracts turnover of Coq3p and Coq4p subunits of the Q-biosynthetic complex. This can account for the observed rescue by COQ8 of the respiratory defect in strains over-producing Coq10p.

nde1 deletion improves mitochondrial DNA maintenance in Saccharomyces cerevisiae coenzyme Q mutants

Saccharomyces cerevisiae has three distinct inner mitochondrial membrane NADH dehydrogenases mediating the transfer of electrons from NADH to CoQ (coenzyme Q): Nde1p, Nde2p and Ndi1p. The active site of Ndi1p faces the matrix side, whereas the enzymatic activities of Nde1p and Nde2p are restricted to the intermembrane space side, where they are responsible for cytosolic NADH oxidation. In the present study we genetically manipulated yeast strains in order to alter the redox state of CoQ and NADH dehydrogenases to evaluate the consequences on mtDNA (mitochondrial DNA) maintenance. Interestingly, nde1 deletion was protective for mtDNA in strains defective in CoQ function. Additionally, the absence of functional Nde1p promoted a decrease in the rate of H2O2 release in isolated mitochondria from different yeast strains. On the other hand, overexpression of the predominant NADH dehydrogenase NDE1 elevated the rate of mtDNA loss and was toxic to coq10 and coq4 mutants. Increased CoQ synthesis through COQ8 overexpression also demonstrated that there is a correlation between CoQ respiratory function and mtDNA loss: supraphysiological CoQ levels were protective against mtDNA loss in the presence of oxidative imbalance generated by Nde1p excess or exogenous H2O2. Altogether, our results indicate that impairment in the oxidation of cytosolic NADH by Nde1p is deleterious towards mitochondrial biogenesis due to an increase in reactive oxygen species release.

Interspecific Variation in Innate Immune Defenses and Stress Response of Toads from Botucatu (São Paulo, Brazil)

ABSTRACT. Glucocorticoid hormone levels increase in the blood stream in response to a large range of social and physical stressors, affecting variables associated to fitness, such as reproductive output and immunocompetence. Although quantification of plasma levels of glucocorticoids has been used as an indicator of environmental stress in different clades of vertebrates, the existence of interspecific differences in magnitude of stress response, their functional bases and ecological correlates remain poorly investigated. In the present study, we tested the following hypotheses: (1) phyllogenetically close species of Bufonids differ in innate immunocompetence, baseline activity of the hypothalamic-pituitary-interrenal (HPI) axis, and response of the HPI axis to stressors; and (2) species showing higher baseline activity of the HPI axis are characterized by lower innate immunocompetence. To test these hypotheses, we compared plasma bactericidal ability against Escherichia coli, baseline field levels of corticosterone (CORT) during reproductive season, and levels of CORT under stressful conditions (captive maintenance plus physical restraint) of three species of toads from the genus Rhinella from Botucatu (SP/Brazil): R. icterica, R. schneiden, and R. ornata. We found interspecific variation in bactericidal ability and CORT levels, with R. ornata showing higher baseline and post-stress CORT levels, and R. schneiden showing higher plasma bactericidal ability. Bactericidal ability and baseline CORT levels are inversely related among species, suggesting that lower innate immunocompetence might be associated to immunosupressive effects of elevated CORT levels. Possible associations between these results and interspecific differences in reproductive behavior and sensitivity to environmental changes are discussed.

Breeding under unpredictable conditions: Annual variation in gonadal maturation, energetic reserves and plasma levels of androgens and corticosterone in anurans from the Brazilian semi-arid.

Anurans living in arid and semi-arid habitats are subjected to unpredictable rain patterns. Consequently, they should be prepared to reproduce at the onset of rain events. We investigated the covariation between calling behavior, testicular maturation, abdominal fat body index (FBI), plasma levels of androgens (T-DHT) and corticosterone (CORT) of males from three species of anurans in the Brazilian semi-arid during the reproductive period and drought. One of these species aestivates during the drought, while the other two species remain foraging. Although the three species display different behavioral strategies during the dry period, they present the same general reproductive patterns. T-DHT levels on the plasma and germinative cyst diameters were higher during the reproductive and breeding period compared to the drought. Additionally, the germinative cysts had all cell stages including sperm bundles during the dry season, however, it was only during the breeding event that free spermatozoa were found in the cyst lumen. These results suggest that these species present the reproductive pattern typical of desert anurans, consisting of opportunistic breeders that reproduce when triggered by a rain stimulus. Rhinella jimi and Pleurodema diplolister had higher CORT when males were calling. Moreover, Rhinella granulosa and P. diplolister showed lower FBI during breeding event, when males were calling. The high levels of CORT and lower FBI during reproductive period are associated, indicating that CORT modulates the recruitment of energy stores to prepare and maintain reproduction, particularly the expensive calling effort.