ABSTRACT
Chronic rhinosinusitis with nasal polyps is a widespread pathology characterized by persistent inflammation of nasal and paranasal mucosa. Although it represents one of the most frequent diseases of the nasal cavities, its etiology is still not completely elucidated. There is evidence suggesting that the Notch signaling, a highly conserved intercellular pathway known to regulate many cellular processes, including inflammation, is implicated in nasal polyps formation. The purpose of this study was to investigate the expression of genes of the Notch pathway in nasal polyps from patients with chronic rhinosinusitis. Nasal polyps and adjacent mucosa tissue were obtained from 10 patients. RNA was analyzed by quantitative reverse transcriptase-polymerase chain reaction for the expression level of (1) Notch pathway components such as receptors (NOTCH1-4), ligands (DLL4, JAGGED-1), and target genes (HEY1, 2, and HES1) and (2) genes providing information on the pathogenesis of polyposis (C-MYC and SCGB1A1) and on eosinophils content (CCL26, IL5, and SAA2). We report a Notch-driven gene expression pattern in nasal polyps which correlates with the expression of genes highly expressed in eosinophils, whose presence is an important parameter to define the pathophysiologic diversity characterizing nasal polyps. Taken together, our results suggest a role for Notch signaling in the pathophysiology of polyposis. Further studies are needed to elucidate the role of Notch in nasal polyps formation and to establish whether it could represent a novel therapeutic target for this pathology.
Subject(s)
Nasal Polyps , Sinusitis , Chronic Disease , Eosinophils , Humans , Inflammation , Pilot ProjectsABSTRACT
Ticagrelor is a powerful P2Y12 inhibitor with pleiotropic effects in the cardiovascular system. Consistently, we have reported that in patients with stable coronary artery disease (CAD) and concomitant chronic obstructive pulmonary disease (COPD) who underwent percutaneous coronary intervention (PCI), 1-month treatment with ticagrelor was superior in improving biological markers of endothelial function, compared with clopidogrel. The objective of this study was to investigate the mechanisms underlying these beneficial effects of ticagrelor by conducting molecular analyses of RNA isolated from peripheral blood cells of these patients. We determined mRNAs levels of markers of inflammation and oxidative stress, such as RORγt (T helper 17 cells marker), FoxP3 (regulatory T cells marker), NLRP3, ICAM1, SIRT1, Notch ligands JAG1 and DLL4, and HES1, a Notch target gene. We found that 1-month treatment with ticagrelor, but not clopidogrel, led to increased levels of SIRT1 and HES1 mRNAs. In patients treated with ticagrelor or clopidogrel, we observed a negative correlation among changes in both SIRT1 and HES1 mRNA and serum levels of Epidermal Growth Factor (EGF), a marker of endothelial dysfunction found to be reduced by ticagrelor treatment in our previous study. In conclusion, we report that in stable CAD/COPD patients ticagrelor positively regulates HES1 and SIRT1, two genes playing a protective role in the context of inflammation and oxidative stress. Our observations confirm and expand previous studies showing that the beneficial effects of ticagrelor in stable CAD/COPD patients may be, at least in part, mediated by its capacity to reduce systemic inflammation and oxidative stress.
Subject(s)
Blood Cells/drug effects , Coronary Artery Disease/metabolism , Platelet Aggregation Inhibitors/pharmacology , Pulmonary Disease, Chronic Obstructive/metabolism , Sirtuin 1/genetics , Ticagrelor/pharmacology , Transcription Factor HES-1/genetics , Blood Cells/metabolism , Cells, Cultured , Epidermal Growth Factor/genetics , Epidermal Growth Factor/metabolism , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Humans , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Notch/genetics , Receptors, Notch/metabolism , Signal Transduction , Sirtuin 1/metabolism , Transcription Factor HES-1/metabolismABSTRACT
Despite the currently available pharmacotherapies, today, thirty percent of worldwide deaths are due to cardiovascular diseases (CVDs), whose primary cause is atherosclerosis, an inflammatory disorder characterized by the buildup of lipid deposits on the inside of arteries. Multiple cellular signaling pathways have been shown to be involved in the processes underlying atherosclerosis, and evidence has been accumulating for the crucial role of Notch receptors in regulating the functions of the diverse cell types involved in atherosclerosis onset and progression. Several classes of nutraceuticals have potential benefits for the prevention and treatment of atherosclerosis and CVDs, some of which could in part be due to their ability to modulate the Notch pathway. In this review, we summarize the current state of knowledge on the role of Notch in vascular health and its modulation by nutraceuticals for the prevention of atherosclerosis and/or treatment of related CVDs.
