Physical activity (PA) has been central in the life of our species for most of its history, and thus shaped our physiology during evolution. However, only recently the health consequences of a sedentary lifestyle, and of highly energetic diets, are becoming clear. It has been also acknowledged that lifestyle and diet can induce epigenetic modifications which modify chromatin structure and gene expression, thus causing even heritable metabolic outcomes. Many studies have shown that PA can reverse at least some of the unwanted effects of sedentary lifestyle, and can also contribute in delaying brain aging and degenerative pathologies such as Alzheimer’s Disease, diabetes, and multiple sclerosis. Most importantly, PA improves cognitive processes and memory, has analgesic and antidepressant effects, and even induces a sense of wellbeing, giving strength to the ancient principle of “mens sana in corpore sano” (i.e., a sound mind in a sound body). In this review we will discuss the potential mechanisms underlying the effects of PA on brain health, focusing on hormones, neurotrophins, and neurotransmitters, the release of which is modulated by PA, as well as on the intra- and extra-cellular pathways that regulate the expression of some of the genes involved.

More than two hundred years after its discovery, lactate still remains an intriguing molecule. Considered for a long time as a waste product of metabolism and the culprit behind muscular fatigue, it was then recognized as an important fuel for many cells. In particular, in the nervous system, it has been proposed that lactate, released by astrocytes in response to neuronal activation, is taken up by neurons, oxidized to pyruvate and used for synthesizing acetyl-CoA to be used for the tricarboxylic acid cycle. More recently, in addition to this metabolic role, the discovery of a specific receptor prompted a reconsideration of its role, and lactate is now seen as a sort of hormone, even involved in processes as complex as memory formation and neuroprotection. As a matter of fact, exercise offers many benefits for our organisms, and seems to delay brain aging and neurodegeneration. Now, exercise induces the production and release of lactate into the blood which can reach the liver, the heart, and also the brain. Can lactate be a beneficial molecule produced during exercise, and offer neuroprotection? In this review, we summarize what we have known on lactate, discussing the roles that have been attributed to this molecule over time.

In the last few decades, the prevalence of overweight and essential obesity has been undergoing a fast and progressive worldwide increase. Obesity has been in turn linked to type II diabetes, with the total number of diabetic patients worryingly increasing, in the last fifteen years, suggesting a pandemic phenomenon. At the same time, an increase in the prevalence of cardiovascular diseases has been also recorded. Increasing evidence suggests that the diet is involved in such escalation. In particular, the progressive globalization of food industry allowed massive supply, at a relatively low price, of a great variety of pre-packed food and bakery products, with very high energy content. Most of this food contains high amounts of saturated fatty acids (SFA) and of hydrogenated or trans fatty acids (TFA), that probably represent the prominent risk factors in the diet. Herein we will report diffusion and possible impact on health of such molecules, with reference to coronary heart disease, insulin resistance, metabolic syndrome and diabetes. We will also discuss the cellular and molecular mechanisms of action of fatty acids and fatty acid-derivatives which have been involved either in promoting or in preventing human pathologies. Free fatty acids (FFA) are not indeed only essential fuels for the organism. They also act as ligands for both membrane and nuclear receptors involved in different signaling pathways. Notably, some of these pathways can induce cell stress and apoptosis. Most important, FFA can affect glucose-induced insulin secretion and activate β-cell death. These events can be at least in part counteracted by polyunsaturated fatty acids.

We report that extracellular matrix and neurons modulate the expression of occludin, one of the main components of tight junctions, by rat brain endothelial cells (RBE4.B). Of the three extracellular matrix proteins which we tested (collagen I, collagen IV, and laminin), collagen IV stimulated at the best the expression of occludin mRNA. The corresponding protein, however, was not synthesized. Significant amounts of occludin accumulated only when RBE4.B cells were cultured on collagen IV-coated inserts, in the presence of cortical neurons, plated on laminin-coated companion wells. Finally, occludin segregated at the cell periphery, only when endothelial cells were co-cultured with neurons for > or = 1 week.

Abstract. We previously set a three-cell-type coculture system in which neurons and astrocytes synergistically induce brain capillary endothelial cells to form a monolayer with permeability properties resembling those of the physiological blood-brain barrier. Moreover, we recently found that neurons produce fibroblast growth factor-2 and vascular endothelial growth factor and secrete them at least in part by shedding extracellular vesicles. In this study, on the basis of immunofluorescence, scanner electron microscopy and Western blot analyses, we concluded that also astrocytes in culture shed extracellular vesicles that contain the same angiogenic factors, as well as ß1-integrin, a membrane protein that is considered a marker of shedding. Vesicles released by astrocytes are smaller than the ones produced by neurons and have an average size of 150-500 nm. IntroductionWe previously found that neurons and astrocytes cooperate in controlling occludin expression and permeability in brain capillary endothelial cells (BCECs), in a three-cell-type in vitro model of the blood-brain barrier (BBB) (1-3). Since in this culture system physical contacts among the different cell types are not allowed, it is likely that neurons and astrocytes affect endothelial cells by releasing soluble factors. In support of this hypothesis it should be noted that other authors have reported that, in vivo, astrocytes not only form direct contacts with BCECs through astrocyte feet but also release soluble factors, such as basic fibroblast growth factor (bFGF or FGF-2) and vascular endothelial growth factor (VEGF) (4), which find receptors on BCECs. FGF-2 is a protein that lacks a standard signal sequence and cannot be sorted to the endoplasmic reticulum (5). It has been reported to be secreted by tumor cells through an unusual way, which involves shedding of extracellular vesicles from the plasma membrane (5). FGF-2 is a potent inducer of blood vessel formation (angiogenesis), with a fundamental role in the development and differentiation of various tissues (6,7), including the nervous system (7). In addition to a main polypeptide of 18 kDa, other FGF-2 isoforms have been described, ranging in size from 22 to 34 kDa (7).VEGF, another factor with well-known actions on endothelial cells, has also been reported to be associated with extracellular vesicles released by tumor cells (5,8). VEGF exists as a homodimer of isoforms of different sizes (i.e. 121, 145, 165, 189, 206), derived from alternative splicing of the same primary transcript (9). In addition to these smaller forms, a larger isoform, with an N-terminal extension of 200 amino acids and an apparent mass of 45 kDa has been described in the human and the mouse (10,11).As it has been recently found that some glial tumor cells (oligodendroglioma cells) (12) as well as primary neurons in culture (13) are able to release extracellular vesicles, we investigated the possibility that astrocytes can do the same. We found that indeed astrocytes produce extracellular structures that contain FGF-2...