Aquaporins and Neurodegenerative Diseases

Aquaporins (AQPs) are a family of widely distributed membrane-inserted water channel proteins providing a pathway for osmotically-driven water, glycerol, urea or ions transport through cell membranes and mechanisms to control particular aspects of homeostasis. Beside their physiological expression patterns in Central Nervous System (CNS), it is conceivable that AQPs are also abnormally expressed in some pathological conditions interesting CNS (e.g. neurodegenerative diseases) in which preservation of brain homeostasis is at risk

Role of Apolipoproten E in liver aging protection

Aging is characterized by a progressive decline of cellular functions. Reactive oxygen species (ROS) are involved in the aging process and result mainly from nonenzymatic processes in the liver. Endogenous free radicals are generated within mitochondria and suspected to cause severe injury to mitochondrial DNA. This damaged DNA accumulates with aging. In addition, polyunsaturated fatty acids, highly sensitive to ROS, decrease in liver mitochondria from human centenarians, a feature acquired during evolution as a protective mechanism to favor longevity. Diet is considered the main environmental factor having effect on lifespan. It has a major impact on aging liver, the central metabolic organ of the body. Apolipoprotein E (apoE) null mice are a very popular model for studying spontaneous hypercholesterolemia, but only limited data are available for the role of apolipoprotein E in liver disease. The purpose of this study is to evaluate liver disease in apolipoprotein E deficient mice. For this study, apoE null mice and control mice at different ages (6 weeks and 15 months) were used. Liver morphological damage and proteins involved in oxidative stress, apoptosis and aging (Bax, Sirt 1, p53) were analyzed. ApoE deficient mice have morphological alterations that are the hallmark of liver pathogenesis, which increase with the age of the animals. In apoE null mice livers, there is also increased oxidative stress as compared to control mice at the same age and fewer antioxidant enzymes. Our findings add to the growing list of protective effects that apoE possesses

Aging and vascular dysfunction: beneficial melatonin effects

The study of biological aging has seen spectacular progress in the last decade. Aging is characterized by a progressive deterioration of physiological functions and metabolic processes. Moreover, aging is accompanied with the development of age-related diseases, such as cardiovascular diseases, which are the major causes of morbidity and mortality in the developed nations. Sirtuin1 (SIRT1) is a well investigated member of the sirtuin family of protein deacetylases which has attracted attention as a potent mediator of life span extension. Recently, melatonin, a pleiotropic molecule which functions as a highly effective antioxidant and free radical scavenger, was shown to activate SIRT1 in primary neurons of young animals, as well as in aged neurons of a murine model of senescence. Melatonin is known to modulate oxidative stress-induced senescence and pro-survival pathways. We treated ApoE-deficient mice with two melatonin formulations (kindly provided by Nathura s.r.l, Reggio Emilia, Italy), showing different pharmacokinetic: melatonin Fast, rapid-release formulation, and Retard, extended-release formulation. Morphological changes in vessels were evaluated using histological procedures and immunohistochemical analyses of SIRT1, p53, eNOS and ET-1 markers. We demonstrate that SIRT1 and eNOS dropped dramatically in ApoE mice and that atherogenesis induced an elevated expression of p53 and ET-1. Melatonin not only improved the impairment of endothelial damage, but also reduced the loss of SIRT1 and eNOS decreasing p53 and ET-1 expression. Also, the extended-release melatonin preparation (Retard) caused a greater improvement of aorta cytoarchitecture. In summary, our findings implicated the SIRT1-p53-eNOS axis as one of the important process involved in endothelial senescence. Moreover, the role of SIRT1 as a driver of cellular stress resistance and longevity is noteworthy in the context of its expression profile. Finally, we suggest that extended-release melatonin provides a more appropriate option for cellular longevity compared with rapid-release melatonin administration

Vascular oxidative stress-induced senescence is minimized by melatonin intake in ApoE-deficient mice

Aging is a natural process that produces deleterious changes in all tissues of the organism. One leading theory about the cause of aging suggest that oxidative stress play a fundamental role in pathogenesis. Oxidative stress induces intracellular damage that affects all biological components, including, DNA, lipids, sugars and proteins. Therefore, the imbalance between intracellular reactive oxygen species (ROS) and antioxidant defence mechanisms results in harmful oxidative stress. One of the most widely considered strategies for preventing aging and for treating age-related disease is the use of natural anti-oxidant agents, such as melatonin and resveratrol. Melatonin is a potent endogenous anti-oxidant neurohormone, which acts through various mechanisms to ameliorate the toxic effects of ROS. However, little is known about the mechanisms of signalling pathways through which melatonin acts to reverse the effects of ROS. In the present study we treated ApoE-deficient mice, a well-known senescence model, from 6th week to 15th week of life, with a specific melatonin formulation: Armonia Retard (kindly provided by Nathura s.r.l, Reggio Emilia, Italy), with an extended-release pharmacokinetic, at different progressive doses 0.04, 0.1, 10 mg/kg/day. We used the same treatment in C57BL6 mice, as control group. Vascular alterations were evaluated in aorta by morphology and immunofluorescence analysis was focused on pleiotropic inflammatory markers, such as interleukins (IL) 6 and 10, inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α). We observed in ApoE-deficient mice endothelial cell detachment and  IL-6, IL-10, iNOS and TNF-α overexpression. Melatonin treatment improved not only the endothelial damage, but also the overall vascular cytoarchitecture and reduced inflammation and macrophages infiltration. In particular, melatonin Retard at the highest dose, recovered all the above markers to the levels of C57BL6 mice. These results outline the anti-inflammatory and anti-oxidant properties of melatonin and its beneficial anti-aging and anti-atherosclerotic effects, especially in extended-release formulation

Museografia, archeologia e paesaggio: le necropoli villanoviane di Verucchio

Progetto di un parco archeologico all'interno del territorio della Valmarecchia. Il progetto comprende un percorso museografico che mette a sistema il patrimonio storico e archeologico del territorio verucchiese.Vengono inseriti all'interno del percorso: un edificio polifunzionale identificato come unità introduttiva, un edificio posto sull'area di scavo e un edificio esplositivo che pone in mostra il patrimonio villanoviano

HMGB1-Mediated Activation of the Inflammatory-Reparative Response Following Myocardial Infarction

Different cell types belonging to the innate and adaptive immune system play mutually non-exclusive roles during the different phases of the inflammatory-reparative response that occurs following myocardial infarction. A timely and finely regulation of their action is fundamental for the process to properly proceed. The high-mobility group box 1 (HMGB1), a highly conserved nuclear protein that in the extracellular space can act as a damage-associated molecular pattern (DAMP) involved in a large variety of different processes, such as inflammation, migration, invasion, proliferation, differentiation, and tissue regeneration, has recently emerged as a possible regulator of the activity of different immune cell types in the distinct phases of the inflammatory reparative process. Moreover, by activating endogenous stem cells, inducing endothelial cells, and by modulating cardiac fibroblast activity, HMGB1 could represent a master regulator of the inflammatory and reparative responses following MI. In this review, we will provide an overview of cellular effectors involved in these processes and how HMGB1 intervenes in regulating each of them. Moreover, we will summarize HMGB1 roles in regulating other cell types that are involved in the different phases of the inflammatory-reparative response, discussing how its redox status could affect its activity

Long pentraxin-3 modulates the angiogenic activity of fibroblast growth factor-2

Angiogenesis, the process of new blood vessel formation from pre-existing ones, plays a key role in various physiological and pathological conditions. Alteration of the angiogenic balance, consequent to the deranged production of angiogenic growth factors and/or natural angiogenic inhibitors, is responsible for angiogenesis-dependent diseases, including cancer. Fibroblast growth factor-2 (FGF2) represents the prototypic member of the FGF family, able to induce a complex “angiogenic phenotype” in endothelial cells in vitro and a potent neovascular response in vivo as the consequence of a tight cross talk between pro-inflammatory and angiogenic signals. The soluble pattern recognition receptor long pentraxin-3 (PTX3) is a member of the pentraxin family produced locally in response to inflammatory stimuli. Besides binding features related to its role in innate immunity, PTX3 interacts with FGF2 and other members of the FGF family via its N-terminal extension, thus inhibiting FGF-mediated angiogenic responses in vitro and in vivo. Accordingly, PTX3 inhibits the growth and vascularization of FGF-dependent tumors and FGF2-mediated smooth muscle cell proliferation and artery restenosis. Recently, the characterization of the molecular bases of FGF2/PTX3 interaction has allowed the identification of NSC12, the first low molecular weight pan-FGF trap able to inhibit FGF-dependent tumor growth and neovascularization. The aim of this review is to provide an overview of the impact of PTX3 and PTX3-derived molecules on the angiogenic, inflammatory, and tumorigenic activity of FGF2 and their potential implications for the development of more efficacious anti-FGF therapeutic agents to be used in those clinical settings in which FGFs play a pathogenic role