Disfunção endotelial em pacientes hiperandrogênicas : associação do óxido nítrico com variáveis antropométricas, metabólicas e hormonais

37

Suppressed anti-inflammatory heat shock response in high-risk COVID-19 patients : lessons from basic research (inclusive bats), light on conceivable therapies

The major risk factors to fatal outcome in COVID-19 patients, i.e., elderliness and pre-existing metabolic and cardiovascular diseases (CVD), share in common the characteristic of being chronic degenerative diseases of inflammatory nature associated with defective heat shock response (HSR). The molecular components of the HSR, the principal metabolic pathway leading to the physiological resolution of inflammation, is an anti-inflammatory biochemical pathway that involves molecular chaperones of the heat shock protein (HSP) family during homeostasis-threatening stressful situations (e.g., thermal, oxidative and metabolic stresses). The entry of SARS coronaviruses in target cells, on the other hand, aggravates the already-jeopardized HSR of this specific group of patients. In addition, cellular counterattack against virus involves interferon (IFN)-mediated inflammatory responses. Therefore, individuals with impaired HSR cannot resolve virus-induced inflammatory burst physiologically, being susceptible to exacerbated forms of inflammation, which leads to a fatal “cytokine storm”. Interestingly, some species of bats that are natural reservoirs of zoonotic viruses, including SARS-CoV-2, possess an IFN-based antiviral inflammatory response perpetually activated but do not show any sign of disease or cytokine storm. This is possible because bats present a constitutive HSR that is by far (hundreds of times) more intense and rapid than that of human, being associated with a high core temperature. Similarly in humans, fever is a physiological inducer of HSR while antipyretics, which block the initial phase of inflammation, impair the resolution phase of inflammation through the HSR. These findings offer a rationale for the reevaluation of patient care and fever reduction in SARS, including COVID-19

Metabolic fate of glutamine in lymphocytes, macrophages and neutrophils

Eric Newsholmes laboratory was the first to show glutamine utilization by lymphocytes and macrophages. Recently, we have found that neutrophils also utilize glutamine. This amino acid has been shown to play a role in lymphocyte proliferation, cytokine production by lymphocytes and macrophages and phagocytosis and superoxide production by macrophages and neutrophils. Knowledge of the metabolic fate of glutamine in these cells is important for the understanding of the role and function of this amino acid in the maintenance of the proliferative, phagocytic and secretory capacities of these cells. Glutamine and glucose are poorly oxidized by these cells and might produce important precursors for DNA, RNA, protein and lipid synthesis. The high rate of glutamine utilization and its importance in such cells have raised the question as to the source of this glutamine, which, according to current evidence, appears to be muscle

Effect of trolox C on cardiac contracture induced by hydrogen peroxide

Hydrogen peroxide (H2O2) perfused into the aorta of the isolated rat heart induces a positive inotropic effect, with cardiac arrhythmia such as extrasystolic potentiation or cardiac contractures, depending on the dose. The last effect is similar to the “stone heart” observed in reperfusion injury and may be ascribed to lipoperoxidation (LPO) of the membrane lipids, to protein damage, to reduction of the ATP level, to enzymatic alterations and to cardioactive compounds liberated by LPO. These effects may result in calcium overload of the cardiac fibers and contracture (“stone heart”). Hearts from male Wistar rats (300- 350 g) were perfused at 31o C with Tyrode, 0.2 mM trolox C, 256 mM H2O2 or trolox C + H2O2. Cardiac contractures (baseline elevation of the myograms obtained) were observed when hearts were perfused with H2O2 (Tyrode: 5.9 ± 3.2; H2O2: 60.5 ± 13.9% of the initial value); perfusion with H2O2 increased the LPO of rat heart homogenates measured by chemiluminescence (Tyrode: 3,199 ± 259; H2O2: 5,304 ± 133 cps mg protein-1 60 min-1), oxygen uptake (Tyrode: 0.44 ± 0.1; H2O2: 3.2 ± 0.8 nmol min-1 mg protein-1) and malonaldehyde (TBARS) formation (Tyrode: 0.12 ± 0; H2O2: 0.37 ± 0.1 nmol/ml). Previous perfusion with 0.2 mM trolox C reduced the LPO (chemiluminescence: 4,098 ± 531), oxygen uptake (0.51 ± 0) and TBARS (0.13 ± 0) but did not prevent the H2O2-induced contractures (33.3 ± 16%). ATP (Tyrode: 2.84 ± 0; H2O2: 0.57 ± 0) and glycogen levels (Tyrode: 0.46 ± 0; H2O2: 0.26 ± 0) were reduced by H2O2. Trolox did not prevent these effects (ATP: 0.84 ± 0 and glycogen: 0.27 ± 0). Trolox C is known to be more effective than α-tocopherol or γ-tocopherol in reducing LPO though it lacks the phytol portion of vitamin E to be fixed to the cell membranes. Trolox C, unlike vitamin A, did not prevent the glycogen reduction induced by H2O2. Trolox C induced a positive chronotropic effect that resulted in higher energy consumption. The reduction of energy level seemed to be more important than LPO in the mechanism of H2O2-induced contracture

GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation

Glucagon-like peptide-1 (GLP-1) promotes insulin secretion from pancreatic β-cells in a glucose dependent manner. Several pathways mediate this action by rapid, kinase phosphorylation-dependent, but gene expression-independent mechanisms. Since GLP-1-induced insulin secretion requires glucose metabolism, we aimed to address the hypothesis that GLP-1 receptor (GLP-1R) signalling can modulate glucose uptake and utilization in β-cells. We have assessed various metabolic parameters after short and long exposure of clonal BRIN-BD11 β-cells and rodent islets to the GLP-1R agonist Exendin-4 (50nM). Here we report for the first time that prolonged stimulation of the GLP-1R for 18hours promotes metabolic reprogramming of β-cells. This is evidenced by up-regulation of glycolytic enzyme expression, increased rates of glucose uptake and consumption, as well as augmented ATP content, insulin secretion and glycolytic flux after removal of Exendin-4. In our model, depletion of HypoxiaInducible Factor 1 alpha (HIF-1α) impaired the effects of Exendin-4 on glucose metabolism, while pharmacological inhibition of Phosphoinositide 3-kinase (PI3K) or mTOR completely abolished such effects. Considering the central role of glucose catabolism for stimulus-secretion coupling in β-cells, our findings suggest that chronic GLP-1 actions on insulin secretion include elevated β-cell glucose metabolism. Moreover, our data reveal novel aspects of GLP-1 stimulated insulin secretion involving de novo gene expression

Antegrade versus retrograde lung perfusion in pulmonary preservation for transplantation in a canine model of post-mortem lung viability

A doação pulmonar após parada cardiocirculatória tem sido estudada experimentalmente na obtenção de órgãos para transplante, porém a severa lesão isquêmica/reperfusão exigem métodos de preservação que permitam viabilidade pulmonar. A perfusão do enxerto com solução cristalóide hipotérmica via anterógrada (artéria pulmonar) é o método de preservação mais utilizado, porém esta via não perfunde a circulação brônquica, permitindo a retenção sanguínea neste território capaz de desencadear fenômenos de lesão de reperfusão. Isto nos levou a testar os efeitos da perfusão anterógrada versus retrógrada (via átrio esquerdo, capaz de perfundir a circulação brônquica) em modelo canino de transplante unilateral cujos pulmões foram extraídos 3 horas após parada cardiorrespiratória. Doze cães doadores foram sacrificados com tiopental sódico e mantidos à temperatura ambiente sob ventilação mecânica durante 3 horas, após as quais os animais foram randomizados e os blocos cardiopulmonares perfundidos via retrógrada (n = 6) ou anterógrada (n = 6) com solução de Euro-Collins modificada e extraídos. Os receptores (n = 12) foram anestesiados, pneumonectomizados e submetidos a transplante pulmonar esquerdo recebendo enxertos perfundidos por via retrógrada (grupo I) ou anterógrada (grupo II). Após a reperfusão do enxerto, os animais foram mantidos sob ventilação mecânica (FiO2 = 1) por 6 horas, sendo então sacrificados. Durante este período obtiveram-se medidas hemodinâmicas e gasometrias arteriais, além de amostras de tecido pulmonar para dosagem de ATP intracelular. As medidas hemodinâmicas não diferiram entre os grupos. Nos animais do grupo I a PaO2 e PaCO2 foram superiores às do grupo II (p = 0,016 e p = 0,008, respectivamente). O ATP intracelular não diferiu entre os grupos, embora tenha se reduzido nas amostras obtidas na extração do enxerto do doador quando comparados aos valores após a reperfusão (p = 0,01) e ao término do período de avaliação (p = 0,01). Os autores concluem que, neste modelo experimental, a perfusão retrógrada hipotérmica resulta em função superior do enxerto após 3 horas de isquemia normotérmica sob ventilação mecânica.Lung retrieval following cardio-circulatory arrest has been studied experimentally, however severe ischemia/reperfusion injury requires improved methods of graft preservation. Allograft perfusion with crystalloid solution delivered via pulmonary artery (antegrade perfusion) remains the standard procedure, however it does not provide adequate washout of the blood retained within the bronchial circulation which may trigger reperfusion injury. This has led the authors to test the impact of antegrade versus retrograde (via left atrium) perfusion of lung grafts submitted to 3 hours of warm ischemia after cardio-circulatory arrest in a dog model of left lung allotransplantation. Twelve donor dogs were sacrificed with thiopental sodium and kept under mechanical ventilation at room temperature for 3 hours. They were randomized and the heart-lung blocks harvested after being perfused in a retrograde (group I, n = 6) or antegrade (group II, n = 6) fashion with modified Euro-Collins solution. Twelve recipient animals were submitted to a left lung transplant receiving the grafts from both groups and the assessment was performed during 6 hours. Hemodynamic parameters were similar for animals in both groups. The gas exchange (arterial PaO2 and PaCO2) in recipients of group I (retrograde perfusion) was significantly better when compared to recipients of grafts perfused via pulmonary artery. Intracellular ATP did not show difference between the groups, however there was a measurable drop in its values when samples obtained upon extraction were compared to those measured after reperfusion and at the end of the assessment. The authors concluded that retrograde perfusion yields better pulmonary function after 6 hours of reperfusion in this animal model of left lung allotransplantation following 3 hours of normothermic ischemia under mechanical ventilation

Metabolic and molecular subacute effects of a single moderate-intensity exercise bout, performed in the fasted state, in obese male rats

Introduction and objectives: Obesity represents a major global public health problem. Its etiology is multifactorial and includes poor dietary habits, such as hypercaloric and hyperlipidic diets (HFDs), physical inactivity, and genetic factors. Regular exercise is, per se, a tool for the treatment and prevention of obesity, and recent studies suggest that the beneficial effects of exercise can be potentiated by the fasting state, thus potentially promoting additional effects. Despite the significant number of studies showing results that corroborate such hypothesis, very few have evaluated the effects of fasted-state exercise in overweight/obese populations. Therefore, the aim of this study was to evaluate the subacute effects (12 h after conclusion) of a single moderate-intensity exercise bout, performed in either a fed or an 8 h fasted state, on serum profile, substrate-content and heat shock pathway–related muscle protein immunocontent in obese male rats. Methods: Male Wistar rats received a modified high-fat diet for 12 weeks to induce obesity and insulin resistance. The animals were allocated to four groups: fed rest (FER), fed exercise (FEE), fasted rest (FAR) and fasted exercise (FAE). The exercise protocol was a 30 min session on a treadmill, with an intensity of 60% of VO2max. The duration of the fasting period was 8 h prior to the exercise session. After a 12 h recovery, the animals were killed and metabolic parameters of blood, liver, heart, gastrocnemius and soleus muscles were evaluated, as well as SIRT1 and HSP70 immunocontent in the muscles. Results: HFD induced obesity and insulin resistance. Soleus glycogen concentration decreased in the fasted groups and hepatic glycogen decreased in the fed exercise group. The combination of exercise and fasting promoted a decreased concentration of serum total cholesterol and triglycerides. In the heart, combination fasting plus exercise was able to decrease triglycerides to control levels. In the soleus muscle, both fasting and fasting plus exercise were able to decrease triglyceride concentrations. In addition, heat shock protein 70 and sirtuin 1 immunocontent increased after exercise in the gastrocnemius and soleus muscles. Conclusions: An acute bout of moderate intensity aerobic exercise, when realized in fasting, may induce, in obese rats with metabolic dysfunctions, beneficial adaptations to their health, such as better biochemical and molecular adaptations that last for at least 12 h. Considering the fact that overweight/obese populations present an increased risk of cardiovascular events/diseases, significant reductions in such plasma markers of lipid metabolism are an important achievement for these populations

Effects of n-3 fatty acids and exercise on oxidative stress parameters in type 2 diabetic : a randomized clinical trial

Background: The relationship between diabetes and oxidative stress has been previously reported. Exercise represents a useful non-pharmacological strategy for the treatment in type 2 diabetic (T2DM) patients, but high intensity exercise can induce a transient inflammatory state and increase oxidative stress. Nutritional strategies that may contribute to the reduction of oxidative stress induced by acute exercise are necessary. The aim of this study was to examine if n-3 PUFA supplementation intervention can attenuate the inflammatory response and oxidative stress associated with high intensity exercise in this population. As a primary outcome, lipoperoxidation measurements (TBARS and F2-isoprostanes) were selected. Methods: Thirty T2DM patients, without chronic complications, were randomly allocated into two groups: placebo (gelatin capsules) or n-3 PUFA (capsules containing 180 mg of eicosapentaenoic acid and 120 mg of docosahexaenoic acid). Blood samples were collected fasting before and after 8 weeks supplementation. In the beginning and at the end of protocol, an acute exercise was performed (treadmill), and new blood samples were collected before and immediately after the exercise for measurements of oxidative stress and high-sensitivity C-reactive protein (hs-CRP). Results: After the supplementation period, a decrease in triglycerides levels was observed only in n-3 PUFA supplementation group (mean difference and 95% CI of 0.002 (0.000–0.004), p = 0.005). Supplementation also significantly reduced TRAP levels after exercise (mean difference and 95% CI to 9641 (− 20,068–39,351) for − 33,884 (− 56,976 - -10,793), p = 0.004, Cohen’s d effect size = 1.12), but no significant difference was observed in n-3 PUFA supplementation group in lipoperoxidation parameters as TBARS (mean difference and 95% CI to − 3.8 (− 10–2.4) for − 2.9 (− 1.6–7.4) or F2-isoprostanes (mean difference and 95% CI -0.05 (− 0.19–0.10) for − 0.02 (− 0.19–0.16), p > 0.05 for both. Conclusion: PUFA n-3 supplementation reduced triglycerides as well as TRAP levels after exercise, without a significant effect on inflammatory and oxidative stress markers. This study is registered at ClinicalTrials.gov with the registration number of NCT03182712

Hoja oficial de la provincia de Barcelona: Época Segunda Número 154 - 1928 Diciembre 10

Universidade Federal do Rio Grande do SulCiências Básicas da SaúdeDepositad