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ABSTRACT: Macrophages, the major cellular components of atherosclerotic plaques, consist of two main subsets: the pro-inflammatory, M1 or classically-activated macrophages, and the anti-inflammatory, M2 or alternatively activated macrophages. The molecular and cellular mechanisms that orchestrate the macrophage polarization and activation that may play a role in plaque progression and stability are poorly understood. Recent studies suggest that oxysterols, oxidative stress-mediated cholesterol oxidation products that are abundant in atherosclerotic lesions, may affect macrophage biology. We investigated whether 7-oxo-cholesterol (7oxo-C) affected polarized human M1 and M2 macrophage phenotypes and functions. Monocyte-derived M1 and M2 macrophages were challenged with 7oxo-C and their phenotype analyzed using flow cytometric analysis, and their function via secretome profiling, the presence of endocytosis and matrix metalloproteinase-9 (MMP-9) release. 7oxo-C increased the expression of HLA-DR in M1 macrophages, and CD14 on M2 macrophages. The oxysterol also reduced CD16 expression on M1 macrophages, while reducing their endocytotic capability and increasing MMP-9 secretion in M2 macrophages. Secretome profiling from cultured cell supernatants showed that 7oxo-C stimulated the production of key pro-atherogenic mediators involved in pro-inflammatory, pro-invasive and pro-angiogenic mechanisms in both in M1 and M2 cells. Hypoxic conditions potentiated the effects of 7oxo-C on M1 and M2 cells. The ability of 7oxo-C to polarize macrophages towards a pro-inflammatory state represents a potentially novel mechanism by which oxidative stress can contribute to atherosclerotic lesion progression.
Biochemical pharmacology 04/2013; · 4.25 Impact Factor
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Lucia Gabriele,
Giovanna Schiavoni,
Fabrizio Mattei,
Massimo Sanchez,
Paola Sestili,
Cinzia Butteroni, Rita Businaro,
Ananda Mirchandani,
Wanda Niedbala,
Foo Y Liew,
Claudia Afferni
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ABSTRACT: BACKGROUND: Cypress pollen causes respiratory syndromes with different grades of severity, including asthma. IL-33, its receptor ST2, and dendritic cells (DCs) have been implicated in human respiratory allergy. OBJECTIVE: We sought to define a new mouse model of allergy to cypress pollen that recapitulates clinical parameters in allergic patients and to evaluate the implications of DCs and the IL-33/ST2 pathway in this pathology. METHODS: BALB/c mice, either wild-type or ST2 deficient (ST2(-/-)), were sensitized and challenged with the Cupressus arizonica major allergen nCup a 1. Local and systemic allergic responses were evaluated. Pulmonary cells were characterized by means of flow cytometry. DCs were stimulated with nCup a 1 and tested for their biological response to IL-33 in coculture assays. RESULTS: nCup a 1 causes a respiratory syndrome closely resembling human pollinosis in BALB/c mice. nCup a 1-treated mice exhibit the hallmarks of allergic pathology associated with pulmonary infiltration of eosinophils, T cells, and DCs and a dominant TH2-type immune response. IL-33 levels were increased in lungs and sera of nCup a 1-treated mice and in subjects with cypress allergy. The allergen-specific reaction was markedly reduced in ST2(-/-) mice, which showed fewer infiltrating eosinophils, T cells, and DCs in the lungs. Finally, stimulation of DCs with nCup a 1 resulted in ST2 upregulation that endowed DCs with increased ability to respond to IL-33-mediated differentiation of IL-5- and IL-13-producing CD4 T cells. CONCLUSIONS: Our findings define a novel preclinical model of allergy to cypress pollen and provide the first evidence of a functionally relevant linkage between pollen allergens and TH2-polarizing activity by DCs through IL-33/ST2.
The Journal of allergy and clinical immunology 04/2013; · 9.17 Impact Factor
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ABSTRACT: Obesity is now growing at an alarming rate reaching epidemic proportions worldwide thus increasing morbidity and mortality rates for chronic disease. But although we have ample information on the complications associated with obesity, precisely what causes obesity remains poorly understood. Some evidence attributes a major role to a low-grade chronic inflammatory state (neurogenic inflammation) induced in obesity by inflammatory mediators produced and secreted within the expanded activated adipocyte pool. Adipose tissue is an endocrine organ that secretes numerous adipose tissue-specific or enriched hormones, known as adipokines, cytokine-like molecules thought to play a pathogenic role in cardiovascular diseases. The imbalance between increased inflammatory stimuli and decreased anti-inflammatory mechanisms may depend on chronic stress. Hence the positive correlation found between stress, obesity and cardiovascular diseases. The chronic inflammatory state associated with insulin resistance and endothelial dysfunction is highly deleterious for vascular function. This review focuses on the proposed neuroimmunodulatory mechanisms linking chronic (psychological) stress, obesity and cardiovascular diseases.
Journal of Neuroimmune Pharmacology 01/2013; · 4.57 Impact Factor
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ChemMedChem 01/2013; In Press. · 3.15 Impact Factor
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ABSTRACT: Atherosclerosis initiation and progression is controlled by inflammatory molecular and cellular mediators. Cells of innate immunity, stimulated by various endogenous molecules that have undergone a transformation following an oxidative stress or nonenzymatic glycation processes, activate cells of the adaptive immunity, found at the borders of atheromas. In this way, an immune response against endogenous modified antigens takes place and gives rise to chronic low-level inflammation leading to the slow development of complex atherosclerotic plaques. These lesions will occasionally ulcerate, thus ending with fatal clinical events. Plaque macrophages represent the majority of leukocytes in the atherosclerotic lesions, and their secretory activity, including proinflammatory cytokines and matrix-degrading proteases, may be related to the fragilization of the fibrous cap and then to the rupture of the plaque. A considerable amount of work is currently focused on the identification of locally released proinflammatory factors that influence the evolution of the plaque to an unstable phenotype. A better understanding of these molecular processes may contribute to new treatment strategies. Mediators released by the immune system and associated with the development of carotid atherosclerosis are discussed.
Annals of the New York Academy of Sciences 07/2012; 1262:134-41. · 3.15 Impact Factor
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ABSTRACT: To delineate the panel of expression of phosphoinositide-specific phospholipase C (PI-PLC) signaling enzymes in normal endometrium and in endometriosis.
Clinical/experimental study.
University.
Healthy donor woman and endometriosis-affected woman.
Normal endometrium and endometriosis surgical biopsies were analyzed using gene expression analyses methodology (reverse transcriptase-polymerase chain reaction [PCR], bioanalyses).
Gene expression (messenger RNA concentration) measures of 12 PI-PLC enzymes: PI-PLC β1, PI-PLC β2, PI-PLC β3, PI-PLC β4, PI-PLC γ1, PI-PLC γ2, PI-PLC δ1, PI-PLC δ3, PI-PLC δ4, PI-PLC ε, PI-PLC η1, and PI-PLC η2.
PI-PLC β1, PI-PLC β3, PI-PLC δ1, and PI-PLC δ3 enzymes were detected, although differently expressed in normal and endometriosis tissues.
The involvement of PI-PLC enzymes in inflammation and the consistency of susceptible endometriosis loci with PI-PLC genes mapping corroborate the hypothesis that PI signaling might be involved in the pathogenesis of endometriosis.
Fertility and sterility 05/2012; 98(2):410-4. · 3.97 Impact Factor
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ABSTRACT: The incidence of AD is increasing in parallel with the increase in life expectancy. At the same time the prevalence of metabolic syndrome and obesity is reaching epidemic proportions in western populations. Stress is one of the major inducers of visceral fat and obesity development, underlying accelerated aging processes. Adipose tissue is at present considered as an active endocrine organ, producing important mediators involved in metabolism regulation as well as in inflammatory mechanisms. Insulin and leptin resistance has been related to the dysregulation of energy balance and to the induction of a chronic inflammatory status which have been recognized as important cofactors in cognitive impairment and AD initiation and progression. The aim of this paper is to disclose the correlation between the onset and progression of AD and the stress-induced changes in lifestyle, leading to overnutrition and reduced physical activity, ending with metabolic syndrome and obesity. The involved molecular mechanisms will be briefly discussed, and advisable guide lines for the prevention of AD through lifestyle modifications will be proposed.
Current Gerontology and Geriatrics Research 01/2012; 2012:986823.
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ABSTRACT: Intrauterine growth restriction (IUGR) and/or neonatal low birth weight are often associated with increased intima/media thickness of the abdominal aortic wall (aIMT). Several studies in children suggested that aIMT might be related to inflammation, probably indicating an early stage of adulthood diseases, such as atherosclerosis. Our previous study performed on the abdominal aortic wall of a stillbirth presenting with IUGR and aIMT suggested an association among IUGR, aIMT, and inflammation, also highlighting the presence of fibroblastoid cells, which are thought to represent peculiar elements of the pre-atherosclerotic lesions. These observations led us to analyze two cytokines involved in the inflammation cascade, IL-1β and IL-23, in amniotic fluid samples of IUGR fetuses and small-for-gestational-age newborns presenting with aIMT and in normal controls. Our results indicate that IL-23, but not IL-1β, concentrations differed in the groups analyzed. Therefore, IL-23, a regulatory element that bridges the innate and adaptive arms of the immune system, might be involved in the inflammatory process observed in fetal aIMT.
Journal of Reproductive Immunology 12/2011; 93(1):64-7. · 2.97 Impact Factor
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ABSTRACT: Increasing evidence has been accumulating about the role of stress as an important challenge to the onset and progression of Alzheimer's disease (AD). The hippocampus, one of the areas of the brain damaged during AD, was the first brain region, besides the hypothalamus, to be recognized as a target of stress hormones, including cortisol, sympathetic and parasympathetic transmitters, cytokines, and metabolic hormones. The present review aims at summarizing neuroinflammatory mechanisms induced by stress, resulting in neuronal dysfunction and impaired neurogenesis. Lifestyle and environmental factors related to metabolic and inflammatory alterations observed in stressed subjects and thought to favor AD development and progression, as well as the possible ways of prevention, are discussed.
Journal of Alzheimer's disease: JAD 11/2011; 28(1):11-24. · 3.74 Impact Factor
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ABSTRACT: Several studies have reported that fetuses with intrauterine growth restriction (IUGR) and infants with low birth weight present increased intima/media thickness (aIMT) of the abdominal aorta wall compared with fetuses and infants appropriate for gestational age (AGA). Evidence suggested that aIMT might be related to inflammation, probably indicating a very early stage of future adulthood disease, such as atherosclerosis. We aimed to investigate histological findings in the abdominal aorta wall of one IUGR stillbirth in which ultrasound had detected aIMT. Microscopy observations of the abdominal aorta wall confirmed the intima thickening and detected condensation of the elastic fibers forming an evident internal elastic membrane and presence of inflammatory elements, such as macrophages, activated endothelial cells, and fibroblastoid cells. The present study highlights that IUGR associated with aIMT is related to inflammation, which might represent a very early sign of future adult lesions.
Journal of Reproductive Immunology 07/2011; 91(1-2):103-7. · 2.97 Impact Factor
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ABSTRACT: Mechanisms that drive innate immune cell recruitment into atherosclerotic lesions are still not well defined. We tested the role of haemoglobin (Hb) to promote chemotaxis, adhesion to endothelial cells and transendothelial migration of human monocytes and monocyte-derived immature dendritic cells (iDCs) and its possible role in atherogenic cell recruitment.
We demonstrated that Hb triggers chemotaxis, adhesion to endothelial cells and transendothelial migration of monocytes and monocyte-derived iDCs. Innate immune cell chemotaxis significantly increased in the presence of Hb in a dose-dependent manner involving extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) activation and actin remodeling. The pre-treatment of cells with pre-titrated concentration of the anti-CD163 blocking antibody reduced the Hb-induced cell migration, thus suggesting the involvement of CD163 receptor. Conversely, N-acetyl cysteine and soluble Hb-scavenger protein haptoglobin (Hp) inhibited the Hb-induced iDC migration. Finally, spontaneous iDC migration significantly increased in the presence of serum of patients with haemorrhagic complicated plaques and partially decreased in the presence of Hp.
Hb by interacting with CD163 on monocytes and iDCs might induce cell recruitment and activation within vascular wall, thus contributing to the complex cross talk of chemotactic signals that mediate atherosclerotic lesions instability.
Atherosclerosis 01/2011; 215(2):316-22. · 3.79 Impact Factor
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ABSTRACT: AIM: To establish a mouse model for the study of congenital defects, using exposure of pregnant females to the teratogen BMS-189453, a multiple retinoic acid competitive antagonist.We found not less than 60% of fetuses had transposition of the great arteries and l5% had other congenital heart defects such as double outlet right ventricle, tetralogy of Fallot, truncus and right aortic arch. Newborns exposed in utero to BMS-189453 were affected by thymus aplasia or hypoplasia, and severe congenital anomalies of the central nervous system due to neural tube defects. An anterior rotation of the right lung was also frequently present in our model. We also report a case of murine congenital diaphragmatic hernia associated with thymic aplasia and transposition of the great arteries. CONCLUSION: These findings support the hypothesis that the combination of diaphragmatic hernia and congenital heart defects may be related to an alteration of the retinoic acid signaling pathways.
Journal of Cardiovascular Medicine 11/2010; · 1.51 Impact Factor
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Rita Businaro,
Elisabetta Profumo,
Angela Tagliani,
Brigitta Buttari,
Stefano Leone,
Giulia D'Amati,
Flora Ippoliti,
Martina Leopizzi,
Daniela D'Arcangelo,
Raffaele Capoano,
Lorenzo Fumagalli,
Bruno Salvati,
Rachele Riganò
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ABSTRACT: The known role of heat-shock proteins (HSPs) in the pathogenesis of atherosclerosis prompted us to investigate whether HSP90 is a target autoantigen of immune responses in patients with carotid atherosclerosis. METHODS AND RESULTS: The presence of HSP90 on 26 cryostat and 6 paraffin embedded sections of carotid atherosclerotic plaques was determined by immunohistochemistry and immunofluorescence. Plaque-infiltrating T lymphocytes from 9 patients and circulating PBMC from 26 patients and 21 healthy subjects were tested by cell proliferation assay and by flow cytometry and ELISA for cytokine production in response to HSP90. ELISA was used to detect soluble HSP90 and anti-HSP90 antibodies in serum samples. Strong HSP90 immunoreactivity was detected in the muscle and endothelial cell layer and in the inflammatory infiltrate of carotid plaques. Plaque-derived and circulating T lymphocytes from patients proliferated in response to HSP90 whereas cells from healthy subjects did not. HSP90-specific T lymphocytes expressed IFN-gamma and IL-4 suggesting concomitant Th1 and Th2 activation. ELISA detected soluble HSP90 in 42% and anti-HSP90 antibodies in 46% of patients' sera. CONCLUSIONS: These new findings, showing that HSP90 is overexpressed in plaque and serum from patients with atherosclerosis and induces an immune response in these patients, implicate HSP90 as a possible target autoantigen in the pathogenesis of carotid atherosclerosis.
Atherosclerosis 06/2009; 207(1):74-83. · 3.79 Impact Factor
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ABSTRACT: Periconceptional supplementation with multivitamins containing folic acid reduces the risk of congenital malformations. We have previously investigated the effect on the murine development of a multiple retinoic acid competitive antagonist, Bristol-Myers-Squibb 189453, showing that treated fetuses were affected with heart defects, thymus aplasia or hypoplasia, and severe anomalies of the central nervous system. Hereby, we analyzed the effects of nutritive therapy involving folic acid and methionine on teratogen-induced congenital defects in mice.
A total of 132 outbred CD1 litters were studied. Pregnant mice were divided into four experimental groups, and an oral supplementation of H(2)O or folic acid, or methionine, or folic acid+methionine was administered from 0.5 days postcoitum until the end of pregnancy. At 7.5 days postcoitum, mice from all these groups were administered Bristol-Myers-Squibb 189453 to induce the teratogenic effect. At the end of pregnancy, fetuses were dissected and tissues were analyzed by histology and flow cytometric assays.
Folic acid reduces congenital heart diseases from 81.3% to 64.8%, neural tube defects from 20.3% to 3.7%, and thymus abnormalities from 98.4% to 27.8%, restoring a normal number of differentiated thymus cells. Methionine is less effective in contrasting congenital heart diseases and neural tube defects, and induces thymus cell proliferation but not differentiation. Folic acid+methionine weakly reduce congenital heart diseases and neural tube defects, but consistently reduce the incidence of fetuses affected with thymus pathologies from 98.4% to 67.7%.
Our results suggest that folic acid and methionine periconceptional supplementations may influence the incidence of congenital defects and may probably induce negative selection of embryos presenting developmental anomalies.
Cardiovascular pathology: the official journal of the Society for Cardiovascular Pathology 05/2008; 18(2):100-9. · 1.63 Impact Factor
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Rachele Riganò,
Elisabetta Profumo,
Brigitta Buttari,
Angela Tagliani,
Linda Petrone,
Giulia D'Amati,
Flora Ippoliti,
Raffaele Capoano,
Lorenzo Fumagalli,
Bruno Salvati, Rita Businaro
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ABSTRACT: Studies aimed at elucidating the pathogenetic mechanisms underlying the initiation and progression of human atherosclerosis have emphasized the central role of inflammatory and immune cells. Atherosclerotic plaques are infiltrated by activated macrophages, T and B lymphocytes, plasma cells, and mast cells, releasing inflammatory molecules, which amplify the severity of the disease. Endothelial cells subjected to various stress conditions express increased amounts of heat shock proteins (HSPs), some of the most successfully conserved proteins throughout evolution. Many experimental observations reviewed in this article draw attention to several HSPs targeted by a specific cellular and humoral immune response in patients with atherosclerotic disease. The review also reports preliminary data obtained by our group on the possible role of HSP90 as a candidate autoantigen in carotid atherosclerosis. Our study deals with the presence of specific antibodies and T cells directed against HSP90 in patients with carotid atherosclerotic plaques. In 60% of these subjects' sera but in none of the sera from healthy controls immunoblotting (IB) detected the presence of specific antibodies. Moreover, 20% of peripheral blood mononuclear cells (PBMC) samples from patients but none from healthy subjects proliferated in response to human purified HSP90. In vitro experiments showed an upregulation of HSP90 expression in endothelial cells exposed to oxidative stress by treatment with H(2)O(2) and greater release of soluble HSP90 in culture supernatants from H(2)O(2)-treated cells than from untreated cells.
Annals of the New York Academy of Sciences 07/2007; 1107:1-10. · 3.15 Impact Factor
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ABSTRACT: S100B is a calcium-binding protein that, in the nervous system, is mainly concentrated in glial cells. Although its biological role is still unclear, the protein is hypothesized, at high concentrations, to act in the pathogenesis of neurodegenerative processes, possibly through oxidative stress mechanisms. To investigate this hypothesis we studied the spinal cord of wobbler mice, an animal model of motor neuron degeneration. Using immunocytochemistry, we detected an overexpression of S100B in astrocytes of the cervical spinal cord of these animals. We also confirmed this finding by reverse transcriptase polymerase chain reaction. In the same spinal cord regions, scattered neurons appeared to be immunostained for 4-hydroxynonenal-modified proteins, an indicator of lipid peroxidation. This finding constitutes a sign of oxidative stress-induced neurodegeneration.
Neurochemical Research 03/2003; 28(2):341-5. · 2.24 Impact Factor
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ABSTRACT: In the model of trimethyltin (TMT)-induced neurodegeneration in developing rat hippocampus, calretinin (CR)-immunoreactive neurons are selectively spared and even more numerous than in controls. We investigated the possibility of an additional synthesis of CR using RT-PCR. The amount of CR mRNA increased significantly after TMT treatment. CR mRNA production after TMT treatment could hypothetically be regarded as a compensatory phenomenon in developing rats.
Molecular Brain Research 02/2002; 98(1-2):141-4. · 2.00 Impact Factor
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ABSTRACT: Heme oxygenase-1 (HO-1), also known as heat-shock protein 32 (HSP-32), is induced in many cells by a large variety of stimuli. Its induction in nervous system cells following toxic and oxidative stress was suggested to play a protective role. Its presence was recently detected by immunohistochemical studies at the level of inflammatory lesions of rat experimental autoimmune encephalomyelitis. In the present study, we demonstrate that myelin basic protein (MBP) induces HO-1 in human astroglial cells, as shown by Western blots and RT-PCR. Proteolytic fragments derived from the whole MBP show a different behavior in the HO-1 induction: MBP152-167 was able to produce a light but still significant increase in HO-1 mRNA and protein levels, whereas MBP68-84 was not. The increase in HO-1 production seems to be mediated by a Ca(2+)-dependent mechanism, since MBP addition to astrocytoma cultures induced a strong and immediate increment of [Ca(2+)](i) increase; MBP152-167 elicited a delayed and less pronounced [Ca(2+)](i) increase; no [Ca(2+)](i) changes were induced following cell treatment with MBP68-84. NO pathway involvement in the induction of HO-1 by MBP was ruled out since the expression of the inducible isoform of nitric oxide synthase was not upregulated in treated cells, neither nitrite levels were modified, as demonstrated by Greiss reaction. The possible significance of HO-1 induction following MBP stimulation is discussed.
Glia 02/2002; 37(1):83-8. · 4.82 Impact Factor
