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    New Insights Into Blood-Brain Barrier Maintenance: The Homeostatic Role of β-Amyloid Precursor Protein in Cerebral Vasculature

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    Cerebrovascular homeostasis is maintained by the blood-brain barrier (BBB), a highly selective structure that separates the peripheral blood circulation from the brain and protects the central nervous system (CNS). Dysregulation of BBB function is the precursor of several neurodegenerative diseases including Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA), both related to β-amyloid (Aβ) accumulation and deposition. The origin of BBB dysfunction before and/or during CAA and AD onset is not known. Several studies raise the possibility that vascular dysfunction could be an early step in these diseases and could even precede significant Aβ deposition. Though accumulation of neuron-derived Aβ peptides is considered the primary influence driving AD and CAA pathogenesis, recent studies highlighted the importance of the physiological role of the β-amyloid precursor protein (APP) in endothelial cell homeostasis, suggesting a potential role of this protein in maintaining vascular stability. In this review, we will discuss the physiological function of APP and its cleavage products in the vascular endothelium. We further suggest how loss of APP homeostatic regulation in the brain vasculature could lead toward pathological outcomes in neurodegenerative disorders

    Opposite effects of beta amyloid on endothelial cell survival: role of fibroblast growth factor-2 (FGF-2)

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    Amyloid beta-peptides (Abeta) aggregate during Alzheimer's disease contributing to the development of the pathology. At micromolar concentration Abeta is toxic and accumulates in neurons and in the vasculature. However, Abeta is found at nanomolar concentrations in the plasma of healthy individuals and is also produced by endothelial cells. Here, we investigate the dual role exerted by Abeta(1-40) on endothelial cell functions. Coronary vascular endothelial cells were utilized to study whether Abeta affects endothelial cell growth and its action was compared with the effect of fibroblast growth factor-2 (FGF-2). In a range from 5 to 100 nM, Abeta(1-40) concentration-dependently increased cell growth, whereas higher concentrations of Abeta(1-40) reduced cell number compared to control. At nanomolar concentration of the peptide Abeta(1-40) also stimulated FGF-2mRNA expression and protein production, which was negatively affected by micromolar concentration of the peptide. The dual role observed on endothelial cell growth, was mediated by FGF-2 biodisponibility. In fact, neutralizing anti-FGF-2 antibody inhibited Abeta(1-40)-induced ERK1/2 phosphorylation at 50 nM. 5 muM inhibited ERK1/2 activation over control and this was reflected by diminished cell growth which was recovered by exogenous FGF-2 administration. These results suggest that low Abeta concentrations stimulate endothelial cells to acquire an angiogenic phenotype through interaction with endogenous FGF-2 and induction of its synthesis. In contrast, accumulation of Abeta results toxic for endothelial cells and at these concentrations Abeta peptide looses its ability to prime FGF-2 cycle. This may be a fundamental pathological event which might contribute to the worsening of the pathology

    Morphophysiological markers apt to individuate different susceptibility of pear rootstocks cultivated in 'in vitro' iron-deficient conditions

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    In many deciduous fruit trees species lime-induced chlorosis represents a serious economical damage. It may be overcome by agronomic strategies, as the use of tolerant rootstocks, valid alternative to reduce expensive iron-chelate fertilisation and chemical environmental impact. Since few years in vitro culture technique is applied to test rootstocks for iron chlorosis susceptibility. Micropropagated shoots were used for screening of quince rootstocks MA and BA 29, and pear cv. Conference under stress conditions on MS medium supplemented with different concentrations of FeNaEDTA, 100%=0.1 mM Fe (FeN) and 15%=0.015 mM (Fe15), and/or potassium bicarbonate, 0 mM (FeN) and 1 mM KHCO3 (FeNC and Fe15C). After 24 days, substrate pH, shoot growth markers, total leaf iron and photosynthetic pigment contents were determined. The medium pH reduction resulted similar among genotypes but different among treatments. Iron deficiency and high bicarbonate concentration induced different growth performances among the genotypes, reflecting a different sensibility and plastic adapation to the induced iron chlorosis. Total leaf iron content decreased in all genotypes, when iron deficiency and bicarbonate concentration increasing onto the medium, although pear cultivar showed more slight reduction. Photosynthetic pigments, analysed by HPLC, decreased in all type of stress, and the lowest levels were detected in Fe15C treatment, except for cv. Conference. A similar trend was exhibited by carotenoids, in particular by Violaxanthin. Our preliminary data confirm the potential of in vitro culture as a rapid screening method. The choice of markers and the result interpretation will be deeply discussed in the paper

    Nitric oxide in tumor angiogenesis

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    Nitric oxide (NO), produced from L-arginine by NO synthases (NOS), is a short-lived molecule required for many physiological functions and contributing to different pathological conditions. In the last decade, we and others contributed to demonstrate that NO stimulates angiogenesis and mediates the effect of different angiogenic molecules. In human tumors, NOS expression and activity correlate with tumor growth and aggressiveness through angiogenesis stimulation and regulation of angiogenic factor expression. Interrelations among the NOS pathway, prostanoids and tyrosine kinase receptors have been reported in regulating tumor progression and malignancy. Drugs affecting the NOS pathway may be forseen as anti-tumor strategies able to reduce edema, inhibit angiogenesis and facilitate the delivery of chemotherapeutical agents. Recent developments include research on NOS gene polymorphisms which might become useful biomarkers for predicting cancer susceptibility as well as the role of NO in chemopreventive strategies. © 2008 Springer US

    Differential responses in pear and quince genotypes induced by Fe deficiency and bicarbonate

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    Most of the studies carried out on Fe deficiency condition in arboreous plants have been performed, with the exception of those carried out on plants grown in the field, in hydroponic culture utilizing a total iron depletion growth condition.This can cause great stress to plants. By introducing Fe deficiency induced by the presence of bicarbonate,we found significant differences between Pyrus communis L. cv. Conference and Cydonia oblonga Mill. BA29 and MA clones,characterized by different levels of tolerance to chlorosis. Pigment content and the main protein–pigment complexes were investigated by HPLC and protein gel blot analysis, respectively. While similar changes in the structural organization of photosystems(PSs)were observed in both species under Fe deficiency, a different reorganization of the photosynthetic apparatus was found in the presence of bicarbonate between tolerant and susceptible genotypes, in agreement with the photosynthetic electron transport rate measured in isolated thylakoids. In order to characterize the intrinsic factors determining the efficiency of iron uptake in a tolerant genotype, the main mechanisms induced by Fe deficiency in Strategy I species, such as Fe3+ -chelate reductase (EC1.16.1.7) and H+-ATPase (EC 3.6.3.6) activities, were also investigated. We demonstrate that physiological and biochemical root responses in quince and pear are differentially affected by iron starvation and bicarbonate supply, and we show a high correlation between tolerance and Strategy I activation
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