A multidimensional sight on cardiac failure: uncovered from structural to molecular level.

Heart failure is one of the leading causes of death, with high mortality rate within 5 years after diagnosis. Treatment and prognosis options for heart failure primarily targeted on hemodynamic and neurohumoral components that drive progressive deterioration of the heart. However, given the multifactorial background that eventually leads to the "phenotype" named heart failure, better insight into the various components may lead to personalized treatment opportunities. Indeed, currently used criteria to diagnose and/or classify heart failure are possibly too focused on phenotypic improvement rather than the molecular driver of the disease and could therefore be further refined by integrating the leap of molecular and cellular knowledge. The ambiguity of the ejection fraction-based classification criteria became evident with development of advanced molecular techniques and the dawn of omics disciplines which introduced the idea that disease is caused by a myriad of cellular and molecular processes rather than a single event or pathway. The fact that different signaling pathways may underlie similar clinical manifestations calls for a more holistic study of heart failure. In this context, the systems biology approach can offer a better understanding of how different components of a system are altered during disease and how they interact with each other, potentially leading to improved diagnosis and classification of this condition. This review is aimed at addressing heart failure through a multilayer approach that covers individually some of the anatomical, morphological, functional, and tissue aspects, with focus on cellular and subcellular features as an alternative insight into new therapeutic opportunities.

Melatonin influences NO/NOS pathway and reduces oxidative and nitrosative stress in a model of hypoxic-ischemic brain damage.

In this work, using a rat model combining ischemia and hypobaric hypoxia (IH), we evaluate the relationships between the antioxidant melatonin and the cerebral nitric oxide/nitric oxide synthase (NO/NOS) system seeking to ascertain whether melatonin exerts its antioxidant protective action by balancing this key pathway, which is highly involved in the cerebral oxidative and nitrosative damage underlying these pathologies. The application of the IH model increases the expression of the three nitric oxide synthase (NOS) isoforms, as well as nitrogen oxide (NOx) levels and nitrotyrosine (n-Tyr) impacts on the cerebral cortex. However, melatonin administration before IH makes nNOS expression response earlier and stronger, but diminishes iNOS and n-Tyr expression, while both eNOS and NOx remain unchanged. These results were corroborated by nicotine adenine dinucleotide phosphate diaphorase (NADPH-d) staining, as indicative of in situ NOS activity. In addition, the rats previously treated with melatonin exhibited a reduction in the oxidative impact evaluated by thiobarbituric acid reactive substances (TBARS). Finally, IH also intensified glial fibrillary acidic protein (GFAP) expression, reduced hypoxia-inducible factor-1alpha (HIF-1α), but did not change nuclear factor kappa B (NF-κB); meanwhile, melatonin did not significantly affect any of these patterns after the application of the IH model. The antioxidant melatonin acts on the NO/NOS system after IH injury balancing the release of NO, reducing peroxynitrite formation and protecting from nitrosative/oxidative damage. In addition, this paper raises questions concerning the classical role of some controversial molecules such as NO, which are of great consequence in the final fate of hypoxic neurons. We conclude that melatonin protects the brain from hypoxic/ischemic-derived damage in the first steps of the ischemic cascade, influencing the NO/NOS pathway and reducing oxidative and nitrosative stress.