Dengue virus infection induces inflammation and oxidative stress on the heart.

OBJECTIVE: Dengue fever is one of the most important arboviral diseases in the world, and its severe forms are characterised by a broad spectrum of systemic and cardiovascular hallmarks. However, much remains to be elucidated regarding the pathogenesis triggered by Dengue virus (DENV) in the heart. Herein, we evaluated the cardiac outcomes unleashed by DENV infection and the possible mechanisms associated with these effects. METHODS: A model of an adapted DENV-3 strain was used to infect male BALB/c mice to assess haemodynamic measurements and the functional, electrophysiological, inflammatory and oxidative parameters in the heart. RESULTS: DENV-3 infection resulted in increased systemic inflammation and vascular permeability with consequent reduction of systolic blood pressure and increase in heart rate. These changes were accompanied by a decrease in the cardiac output and stroke volume, with a reduction trend in the left ventricular end-systolic and end-diastolic diameters and volumes. Also, there was a reduction trend in the calcium current density in the ventricular cardiomyocytes of DENV-3 infected mice. Indeed, DENV-3 infection led to leucocyte infiltration and production of inflammatory mediators in the heart, causing pericarditis and myocarditis. Moreover, increased reactive oxygen species generation and lipoperoxidation were also verified in the cardiac tissue of DENV-3 infected mice. CONCLUSIONS: DENV-3 infection induced a marked cardiac dysfunction, which may be associated with inflammation, oxidative stress and electrophysiological changes in the heart. These findings provide new cardiac insights into the mechanisms involved in the pathogenesis triggered by DENV, contributing to the research of new therapeutic targets for clinical practice.

Autophagy-targeted therapy to modulate age-related diseases: Success, pitfalls, and new directions.

Autophagy is a critical metabolic process that supports homeostasis at a basal level and is dynamically regulated in response to various physiological and pathological processes. Autophagy has some etiologic implications that support certain pathological processes due to alterations in the lysosomal-degradative pathway. Some of the conditions related to autophagy play key roles in highly relevant human diseases, e.g., cardiovascular diseases (15.5%), malignant and other neoplasms (9.4%), and neurodegenerative conditions (3.7%). Despite advances in the discovery of new strategies to treat these age-related diseases, autophagy has emerged as a therapeutic option after preclinical and clinical studies. Here, we discuss the pitfalls and success in regulating autophagy initiation and its lysosome-dependent pathway to restore its homeostatic role and mediate therapeutic effects for cancer, neurodegenerative, and cardiac diseases. The main challenge for the development of autophagy regulators for clinical application is the lack of specificity of the repurposed drugs, due to the low pharmacological uniqueness of their target, including those that target the PI3K/AKT/mTOR and AMPK pathway. Then, future efforts must be conducted to deal with this scenery, including the disclosure of key components in the autophagy machinery that may intervene in its therapeutic regulation. Among all efforts, those focusing on the development of novel allosteric inhibitors against autophagy inducers, as well as those targeting autolysosomal function, and their integration into therapeutic regimens should remain a priority for the field.

Efeitos da Dieta Paleolítica nos Parâmetros Comportamentais, Bioquímicos e Teciduais em Camundongos Sadios / The Effects the Paleolithic Diet in Biochemical, Behavioral and Tissue Parameters in HealthyMice

A obesidade está associada aos riscos para a saúde, devido a sua relação com o aumento da pressão arterial, dos níveis de colesterol e triglicerídeos sanguíneos e também a resistência à insulina. A causa principal da obesidade está intrinsecamente relacionada aos hábitos alimentares e interações do material genético do indivíduo e, também, está ligada aos fatores sociais, ambientais e comportamentais. Atualmente, são utilizadas muitas dietas com diferentes parâmetros, dentre estas a Dieta Paleolítica. A Dieta Paleolítica tem o propósito de usar como classes principais de alimentos: proteínas, vegetais, frutas e gorduras não-industrializadas, excluindo não-inteiramente o consumo de hidratos de carbono, sendo este o grande diferencial da Dieta Paleolítica, quando comparada às dietas modernas para perda de peso. O objetivo do presente trabalho foi avaliar os efeitos da dieta paleolítica nos níveis comportamentais em camundongos C57BL/6 sadios. O estudo foi realizado na unidade Uniderp Agrárias, na cidade de Campo Grande ­ MS. Foram utilizados camundongos C57BL/6, organizados aleatoriamente em oito grupos e foi realizado o monitoramento dos parâmetros comportamentais, de peso e ingesta de ração, pelos períodos de 15 ou 30 dias de tratamento. Os resultados demonstraram que os grupos que receberam a Dieta Paleolítica por 15 ou 30 dias não apresentaram diferença significativa nos parâmetros comportamentais e ingesta de água e ração. Por tanto, é possível concluir que a Dieta Paleolítica não altera o comportamento, o consumo de ração e peso corporal. (AU).

The obesity is associated to health risks, due to its relation in increasing the blood pressure, cholesterol and triglycerides levels and also to its increase in insulin resistance. The main cause of obesity is intrinsically related to eating habits and interactions of genetics and, also, bounded to social, environmental e behavioral factors. Nowadays, many diets with different parameters have been used, among them is the Paleolithic Diet. The Paleolithic Diet has as purpose to use as main food groups: proteins, vegetables, fruits and non-industrialized fat, excluding not entirely the intake of carbohydrates, this being the great differential in comparison to modern weight loss diets. The objective of the present paper is to evaluate the effects of the Paleolithic Diet in behavioral levels in C57BL/6 healthy mice. The experiment was carried out in UNIDERP Agrárias, in Campo Grande ­ MS. C57BL/6 mice were divided randomly in 8 groups, and the monitoring of behavior, weight and food intake were done during 15 or 30 days of diet. The results demonstrated that the groups that took the Paleolithic Diet for 15 or 30 days did not present any important difference in behavioral, food and water intake parameters. Therefore, it is possible to conclude that the Paleolithic Diet does not alter the, behavioral, food intake and weight parameters. (AU)

Alpha1D-adrenoceptor-induced relaxation on rat carotid artery is impaired during the endothelial dysfunction evoked in the early stages of hyperhomocysteinemia.

Hyperhomocysteinemia is a known risk factor for cardiovascular diseases, but the underlying mechanisms of this pathology are complex. We aimed to evaluate the effect of hyperhomocysteinemia in vasorelaxations induced by alpha(1D)-adrenoceptor agonists. Vascular reactivity of rat carotid artery to the alpha-adrenoceptor agonist, phenylephrine, was enhanced in hyperhomocysteinemia. Mechanical removal of endothelium did not modify the carotid responsiveness to phenylephrine, compared to control. Phenylephrine induces endothelium-dependent relaxation, in the presence of 5-methyl urapidil (alpha(1A)-adrenoceptor antagonist). We hypothesised that endothelial-relaxant alpha(1)-adrenoceptors are impaired by hyperhomocysteinemia. Incubation with prazosin (selective alpha(1)-adrenoceptor antagonist) or BMY7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-7, 9-dione dihydrochloride) (selective alpha(1D)-adrenoceptor antagonist), similarly inhibited phenylephrine-induced relaxations in both control and hyperhomocysteinemic carotids. Immunohistochemistry showed enhanced immunoreactivity for eNOS and iNOS in hyperhomocysteinemic rats. In carotid arteries from hyperhomocysteinemic rats there was a decrease in superoxide dismutase activity and enhanced superoxide anion production. We conclude that alpha(1D)-adrenoceptors mediate endothelium-dependent relaxation triggered by phenylephrine in rat carotid artery and affect the final tone. Furthermore, the enhanced phenylephrine-induced contraction in carotid artery due to hyperhomocysteinemia is endothelium-dependent and involves a loss of the inhibitory effect of relaxant alpha(1D)-adrenoceptors by reducing NO biodisponibility.