17 β-estradiol/genistein protected fibroblasts/keratinocytes against peroxidation by modulating oxidant/antioxidant system and mitochondria membrane potential, through mechanisms related to ERs and GPER30 and kinases activation.

Des-acyl ghrelin (DAG), the most abundant form of ghrelin in humans, has been found to reduce arterial blood pressure and prevent cardiac and endothelial cell apoptosis. Despite this, data regarding its direct effect on cardiac function and coronary blood flow, as well as the related involvement of autonomic nervous system and nitric oxide (NO), are scarce. We therefore examined these issues using both in vivo and in vitro studies. In 20 anesthetized pigs, intracoronary 100 pmol/mL DAG infusion with a constant heart rate and aortic blood pressure, increased coronary blood flow and NO release, whereas reducing coronary vascular resistances (P Ͻ .05). Dose responses to DAG were evaluated in five pigs. No effects on cardiac contractility/relaxation or myocardial oxygen consumption were observed. Moreover, whereas the blockade of muscarinic cholinoceptors (n ϭ 5) or ␣-and ␤-adrenoceptors (n ϭ 5 each) did not abolish the observed responses, NO synthase inhibition (n ϭ 5) prevented the effects of DAG on coronary blood flow and NO release. In coronary artery endothelial cells, DAG dose dependently increased NO release through cAMP signaling and ERK1/2, Akt, and p38 MAPK involvement as well as the phosphorylation of endothelial NO synthase. In conclusion, in anesthetized pigs, DAG primarily increased cardiac perfusion through the involvement of NO release. Moreover, the phosphorylation of ERK1/2 and Akt appears to play roles in eliciting the observed NO production in coronary artery endothelial cells. (Endocrinology 157: 2403-2415, 2016) T he ghrelin-related peptides, acylated ghrelin and desacylated ghrelin, are gastrointestinal hormones that have been reported to exert variable effects on the cardiovascular system. Apart from being able to stimulate food intake and adiposity (1-4), ghrelin has been found to reduce arterial and pulmonary blood pressure (BP) (5-8), to increase myocardial contractility (5, 9), and to exert opposite effects on different vascular beds (10 -13). For example, ghrelin has been shown to increase human forearm blood flow and dilate human mammary and rat mesenteric arteries, whereas in rats and pigs, it caused coronary vasoconstriction.The deacylated form of ghrelin, des-acyl ghrelin, is far more abundant in circulation than ghrelin and is devoid of any endocrine activity (1, 2, 4, 14), although several authors strongly suggest that des-acyl ghrelin has intrinsic and specific actions in many physiological and pathophysiological conditions, mainly as a functional antagonist of ghrelin (15). To date, however, the function of des-acyl ghrelin is currently unknown, with the few studies exam- Abbreviations: BP, blood pressure; CEC, coronary artery endothelial cell; DAG, des-acyl ghrelin; dP/dt max , maximum rate of change of LV systolic pressure; eNOS, endothelial NO synthase; GHSR, GH secretagogue receptor; LAD, left anterior descending coronary artery; L-NAME, N-nitro-L arginine methyl ester; LV, left ventricular; NO, nitric oxide; NOS, NO synthase; PKA, protein kinase A; PLC, phospholipase C; PO 2...

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of the corticospinal motor neurons, which ultimately leads to death. The repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) represents the most common genetic cause of ALS and it is also involved in the pathogenesis of other neurodegenerative disorders. To offer insights into C9ORF72-mediated pathogenesis, we quantitatively analyzed the proteome of patient-derived primary skin fibroblasts from ALS patients carrying the C9ORF72 mutation compared with ALS patients who tested negative for it. Differentially expressed proteins were identified, used to generate a protein-protein interaction network and subjected to a functional enrichment analysis to unveil altered molecular pathways. ALS patients were also compared with patients affected by frontotemporal dementia carrying the C9ORF72 repeat expansion. As a result, we demonstrated that the molecular pathways mainly altered in fibroblasts (e.g., protein homeostasis) mirror the alterations observed in C9ORF72-mutated neurons. Moreover, we highlighted novel molecular pathways (nuclear and mitochondrial transports, vesicle trafficking, mitochondrial bioenergetics, glucose metabolism, ER-phagosome crosstalk and Slit/Robo signaling pathway) which might be further investigated as C9ORF72-specific pathogenetic mechanisms. Data are available via ProteomeXchange with the identifier PXD023866.

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Objective:To examine the effects of asenapine on nitric oxide (NO) release and Ca2+ transients in H9C2 cell line, which were either subjected to peroxidation or not.Materials and Methods:H9C2 were treated with asenapine alone or in presence of intracellular kinase blockers, serotoninergic and dopaminergic antagonists, and voltage Ca2+ channels inhibitors. Experiments were also performed in H9C2 treated with hydrogen peroxide. NO release and intracellular Ca2+ were measured through specific probes.Results:In H9C2, asenapine differently modulated NO release and Ca2+ movements depending on peroxidative condition. The Ca2+ pool mobilized by asenapine mainly originated from the extracellular space and was slightly affected by thapsigargin. Moreover, the effects of asenapine were reduced or prevented by kinases blockers, dopaminergic and serotoninergic receptors inhibitors, and voltage Ca2+ channels blockers.Conclusions:On the basis of our findings, we can conclude that asenapine by interacting with its specific receptors, exerts dual effects on NO release and Ca2+ homeostasis in H9C2; this would be of particular clinical relevance when considering their role in cardiac function modulation.

We found that monomeric adiponectin was able to increase cell viability in porcine aortic endothelial cells (PAE) cultured both in normal and high glucose condition. Moreover, in normal glucose condition monomeric adiponectin increased p38MAPK, Akt, ERK1/2 and eNOS phosphorylation in a dose- and time-dependent way. Also in high glucose condition monomeric adiponectin increased eNOS and above kinases phosphorylation with similar patterns but at lower extent. For interpretation of the data presented in this article, please see the research article “Monomeric adiponectin modulates nitric oxide release and calcium movements in porcine aortic endothelial cells in normal/high glucose conditions” (Grossini et al., in press) [1].

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